CHILDREN’S ONCOLOGY GROUP ARAR0331 Treatment of …ngeo.pdf · THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY ARAR0331 Page 7 The Children's Oncology Group

ARAR0331

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Activated: 02/20/06 Closed: Version Date: May 25, 2005

CHILDREN’S ONCOLOGY GROUP

ARAR0331

Treatment of Childhood Nasopharyngeal Carcinoma with Neoadjuvant Chemotherapy and Concomitant Chemoradiotherapy

A Groupwide Phase III Study THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED OR USED FOR ANY OTHER PURPOSE. THE PROCEDURES IN THIS PROTOCOL ARE INTENDED ONLY FOR USE BY CLINICAL ONCOLOGISTS IN CAREFULLY STRUCTURED SETTINGS, AND MAY NOT PROVE TO BE MORE EFFECTIVE THAN STANDARD TREATMENT. A RESPONSIBLE INVESTIGATOR ASSOCIATED WITH THIS CLINICAL TRIAL SHOULD BE CONSULTED BEFORE USING OR ATTEMPTING ANY PROCEDURE IN THIS PROTOCOL.

STUDY CHAIR

Carlos Rodriguez-Galindo, MD Department of Hematology-Oncology St. Jude Children’s Research Hospital 332 N Lauderdale St., MS 260 Memphis, TN 38105 Phone: (901) 495-2203 Fax: (901) 521-9005 Email: [email protected]

For Statistics and Data Center Contact Person see: http://members.childrensoncologygroup.org

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TABLE OF CONTENTS SECTION PAGE

STUDY COMMITTEE 5 ABSTRACT 7 EXPERIMENTAL DESIGN SCHEMA 8 1.0 GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 9 2.0 BACKGROUND 9

2.1 Epidemiology and Pathogenesis of Nasopharyngeal Carcinoma 9 2.2 Clinical Presentation 10 2.3 Treatment of Nasopharyngeal Carcinoma 10 2.4 Nasopharyngeal Carcinoma in Children 13 2.5 Ototoxicity and Xerostomia Associated with CDDP and Radiation Therapy 13 2.6 Use of amifostine as a cytoprotectant 15 2.7 EBV and Nasopharyngeal Carcinoma 16 2.8 NUT-rearranged carcinomas 18 2.9 Rationale for Current Protocol 18

3.0 STUDY ENROLLMENT AND PATIENT ELIGIBILITY 19 3.1 Study Enrollment 19 3.2 Patient Criteria 20

4.0 TREATMENT PLAN 21 4.1 Administration Schedule for Patients on Stratum A 23 4.2 Administration Schedule for Patients on Stratum B during Induction (Weeks 1 - 9) 26 4.3 Administration Schedule for Stratum B Consolidation during Radiation Therapy (Weeks 10 -18) 29

5.0 DOSE MODIFICATIONS FOR TOXICITIES 36 5.1 Myelosuppression 36 5.2 Ototoxicity 36 5.3 Nephrotoxicity 37 5.4 Mucositis 37 5.5 Hepatotoxicity 37

6.0 DRUG INFORMATION 38 6.1 AMIFOSTINE (Ethyol®) NSC#296961 38 6.2 CISPLATIN (Cis-diamminedichloroplatinum II, Platinol-AQ) NSC #119875 39 6.3 5-FLUOROURACIL (5-FU) NSC #19893 41 6.4 PILOCARPINE (Salagen®) 41

7.0 EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 43 7.1 Required and Optional Clinical, Laboratory and Disease Evaluations 43 7.2 Guidelines for Oral and Dental Evaluation 45 7.3 Performing Sialometry 45 7.4 Other Recommended Evaluations 45 7.5 Specimen Submission 46 7.6 Required Material for QARC Central Review 47 7.7 Evaluations During Follow-Up After Completion of Therapy 47

8.0 SUPPORTIVE CARE GUIDELINES 48 8.1 Pneumocystis prophylaxis 48

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8.2 Venous Access 48 8.3 Nutritional Management 48 8.4 Anti-emetic Care 48 8.5 Mouth Care 48

9.0 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 49 9.1 Criteria for Removal from Protocol Therapy 49 9.2 Off Study Criteria 49

10.0 STATISTICAL CONSIDERATIONS 49 10.1 Statistical Design 49 10.2 Patient Accrual and Expected Duration of Trial 50 10.3 Statistical Analysis Methods 50 10.4 Gender and Minority Accrual Estimates 53

11.0 EVALUATION CRITERIA 53 11.1 Common Terminology Criteria for Adverse Events v3.0 (CTCAE) 53 11.2 Response Criteria for Patients with Solid Tumors 54

12.0 ADVERSE EVENT REPORTING REQUIREMENTS 56 12.1 Purpose 56 12.2 Determination of Reporting Requirements 56 12.3 Reporting of Adverse Events for Commercial Agents - AdEERS abbreviated pathway 57 12.4 Reporting Secondary AML/MDS 57

13.0 RECORDS AND REPORTING 58 13.1 Categories of Research Records 58 13.2 CDUS 58

14.0 SURGICAL GUIDELINES 58 15.0 PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 59

15.1 Pathology guidelines for diagnosis 59 15.2 Pathology Review Requirements 59

16.0 BIOLOGY STUDIES 60 16.1 Specimens Requested for Biologic Studies 60 16.2 Specimen Shipping 61 16.3 Special Studies Performed on Biology Specimens 61

17.0 IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 64 17.1 Timing of imaging studies: 64 17.2 Imaging of the primary tumor: 64 17.3 Imaging of metastatic disease: 64 17.4 Submitting Imaging for Central Review 64

18.0 RADIATION THERAPY GUIDELINES 65 18.1 Imaging Based Techniques 65 18.2 QARC Review 65 18.3 Equipment: 65 18.4 Target Volume Definitions: 66 18.5 Target Dose: 67 18.6 Treatment Technique 69 18.7 Organs at Risk: 69 18.8 Dose Calculation and Reporting 70

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18.9 Quality Assurance Documentation 71 18.10 Definitions of Deviations in Protocol Performance: 72

APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 73 APPENDIX II: AJCC STAGING SYSTEM FOR NASOPHARYNGEAL CARCINOMA (5TH

EDITION)117 74 APPENDIX III: TANNER SYSTEM FOR PUBERTAL STAGING118 75 REFERENCES 76 SAMPLE INFORMED CONSENT FORM / PARENTAL PERMISSION FOR

PARTICIPATION IN RESEARCH 82

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STUDY COMMITTEE

STUDY CHAIR STUDY COMMITTEE MEMBERS Carlos Rodriguez-Galindo, M.D. Kay W. Chang, M.D. Hematology-Oncology Otolaryngology St. Jude Children’s Research Hospital Stanford University Medical Center 332 N Lauderdale St., MS 260 725 Welch Road Memphis, TN 38105 ENT Clinic Phone: (901) 495-2203 Palo Alto, CA 94304 Fax: (901) 521-9005 Phone: (650) 736-1314 E-mail: [email protected] Fax: (650) 498-2734 E-mail: [email protected] STUDY VICE CHAIR James Fontanesi, M.D. Alberto Pappo, M.D. Radiation-Oncology Pediatrics University of Mississippi Medical Center Children's Hospital Hospital for Sick Children Department of Radiation Oncology Division of Hematology/Oncology 2500 North State Street 555 University Avenue, 9411 A Jackson, MS 39216 Toronto ON M5G 1X8 Phone: (601) 984-2550 Canada Fax: (601) 815-3204 Phone: (416) 813-6194 E-mail: [email protected] Fax: (416) 813-5327 E-mail: [email protected] STUDY STATISTICIAN Mark Krailo, Ph.D. RoseAnne Speights, C.R.A. Statistics Data Management Children's Oncology Group - Operations Center St. Jude Children's Research Hospital 440 E. Huntington Drive Hematology/Oncology P.O. Box 60012 332 N. Lauderdale St., MS 260 Arcadia, CA 91066-6012 Memphis, TN 38105 Phone: (626) 241-1529 Phone: (901) 495-3561 Fax: (626) 445-4334 Fax: (901) 495-5482 E-mail: [email protected] E-mail: [email protected] STUDY COMMITTEE MEMBERS Julia Glade Bender, M.D. Mary Beth McCarville, M.D. Pediatric Oncology Diagnostic Imaging Columbia Presbyterian College of Phys & Surgeons St. Jude Children's Research Hospital 161 Fort Washington Avenue 332 N. Lauderdale St., MS 310 Irving 7-748 Memphis, TN 38105-2794 New York, NY 10032 Phone: (901) 495-2399 Phone: (212) 305-3379 Fax: (901) 495-4398 Fax: (212) 305-5848 E-mail: [email protected] E-mail: [email protected] John Hicks, M.D. Moody D. Wharam, M.D. Pathology Radiation Oncology Texas Children's Cancer Center at Baylor College of Medicine Johns Hopkins Hospital 6621 Fannin Street 401 N. Broadway Houston, TX 77030 Room 1460 Phone: (832) 824-1869 Baltimore, MD 21287-8922 Fax: (832) 825-1032 Phone: (410) 955-7312 E-mail: [email protected] Fax: (410) 955-3691 E-mail: [email protected]

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Laurie E. Cohen, M.D. Randall Hayden, M.D. Endocrinology Pathology Dana-Farber Cancer Institute and Children's Hosp St. Jude Children's Research Hospital 300 Longwood Avenue 332 N. Lauderdale St., MS 250 Boston, MA 02115 Memphis, TN 38105 Phone: (617) 355-7476 Phone: (901) 495-3525 Fax: (617) 730-0194 Fax: (901) 495-3100 E-mail: [email protected] E-mail: [email protected] David Crichton Gammon, B.S.Ph. COG RESEARCH COORDINATOR Pharmacy Susan Conway, BA CCRP University of Massachusetts Medical School Children's Oncology Group - Data Center (Gaines) 55 Lake Avenue North COG Data Research Center Worcester, MA 01655 104 North Main Street, Suite 600 Phone: (508) 856-2915 College of Medicine/Dept. of Statistics Fax: (508) 856-4141 Gainesville, FL 32601-3330 E-mail: [email protected] Phone: (352) 273-0559 Fax: (352) 392-8162 Dana Rene Hawkins, A.P.N. E-mail: [email protected] Nursing St. Jude Children's Research Hospital COG PROTOCOL COORDINATOR Hematology/Oncology Catherine Shannon, MS 332 N. Lauderdale St., MS 260 Children's Oncology Group - Operations Center Memphis, TN 38105 SDO Phone: (901) 495-4616 P.O. BOX 60012 Fax: (901) 495-5482 440 E. Huntington Drive, Suite 402 E-mail: [email protected] Arcadia, CA 91066-6012 Phone: (626) 241-1583 Fax: (626) 445-4334 E-mail: [email protected] Milton J. Finegold, M.D. Pathology For Group Operations (GOC) and Texas Children's Cancer Center at Baylor College of Medicine Statistics and Data Center (SDC) contacts see: 6621 Fannin Street http://members.childrensoncologygroup.org Houston, TX 77030-2399 Telephone: (626) 447-0064 Phone: (832) 824-1856 Fax: (832) 825-1032 AGENT NSC# E-mail: [email protected] Amifostine (radioprotectant) NSC# 296961 Cisplatin/CDDP/Platinol NSC# 119875 5-Fluorouracil/5-FU NSC# 19893

SEE SECTIONS 7.5 and 7.6 FOR SPECIMEN SHIPPING ADDRESSES

THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY ARAR0331

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The Children's Oncology Group has received a Certificate of Confidentiality from the federal government, which will help us protect the privacy of our research subjects. The Certificate protects against the involuntary release of information about your subjects collected during the course of our covered studies. The researchers involved in the studies cannot be forced to disclose the identity or any information collected in the study in any legal proceedings at the federal, state, or local level, regardless of whether they are criminal, administrative, or legislative proceedings. However, the subject or the researcher may choose to voluntarily disclose the protected information under certain circumstances. For example, if the subject or his/her guardian requests the release of information in writing, the Certificate does not protect against that voluntary disclosure. Furthermore, federal agencies may review our records under limited circumstances, such as a DHHS request for information for an audit or program evaluation or an FDA request under the Food, Drug and Cosmetics Act.

ABSTRACT Nasopharyngeal carcinoma (NPC) is very rare in children. Only 1% of all NPC occurs in patients < 19 years. In the U.S., the incidence of NPC in children is approximately 1-1.5 cases per million per year. This represents approximately 1% of all pediatric malignancies, but it accounts for 35-50% of all nasopharyngeal malignancies. Information regarding the clinical characteristics and biology of childhood NPC is scarce, in particular that related to the role of the Epstein-Barr virus (EBV) in its pathogenesis. Several studies have analyzed the clinical characteristics and outcome of NPC in children. Virtually all cases of NPC in children are Type III histology and present at advanced stages. The majority of studies have used cisplatin and/or doxorubicin-based chemotherapy. With this combined approach, survival for patients with advanced disease is 60-70%. In the U.S. the only group initiative was a Phase II study performed by POG between September 1996 and August 1998 (POG-9486). This study was designed to explore the antitumor effect of the combination of methotrexate, cisplatin, and 5-fluorouracil (with leucovorin). Recent trials performed in adults show that concomitant chemoradiotherapy offers a survival advantage to sequential radiation and chemotherapy, and this approach should be investigated in children. However, an especial effort must be made to decrease the acute and long-term toxicity associated with NPC therapy, particularly in children. In this regard, the use of amifostine and IMRT are considered important elements of therapy. The role of EBV in the pathogenesis of NPC has been very well established, particularly in endemic areas. Less is known about children in non-endemic areas, although the age at presentation and the histology suggest that EBV also plays a role in children. Studies performed in endemic areas have shown that patients with NPC have detectable levels of EBV DNA in peripheral blood, and that these levels correlate with outcome. We anticipate that children with NPC will also have detectable circulating levels of EBV DNA, and that these levels will correlate with clinical events. Our study will explore the prognostic impact of the EBV DNA levels and its kinetics in the outcome of children with NPC. Current therapy for NPC includes intensive chemotherapy and radiation therapy. This treatment is associated with significant acute and chronic toxicities, such as xerostomy, dental problems, trismus, endocrine deficits, ototoxicity and nephrotoxicity. Should the EBV DNA levels prove to be a prognostic indicator, risk-adapted therapies could be designed that would minimize treatment to a proportion of patients.


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EXPERIMENTAL DESIGN SCHEMA

* Further therapy at Investigator discretion. **Patients with extranodal metastatic disease only.

Stratum A: AJCC Stages I and IIa Stratum B: AJCC Stages IIb-IV

EVALUATION EVALUATION

EVALUATION

Off Protocol Therapy* - Follow

Off Protocol Therapy - Follow

PD CR, PR or SD

Consolidation Therapy 3 Cycles of Cisplatin

+ XRT with

Daily Amifostine

Off Protocol Therapy* - Follow


Surgery** Unresectable Disease

PD CR, PR or SD

Resectable Disease**

Resectable Disease**

Surgery**

STUDY ENTRY

Stratum A

XRT with

Daily Amifostine

Stratum B

Induction Therapy: 3 Cycles of Cisplatin +

5-Fluorouracil


PD

Off Protocol Therapy* -

Follow


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1.0 GOALS AND OBJECTIVES (SCIENTIFIC AIMS) Primary Objectives 1.1 To estimate the response rate, survival, and event-free survival of children with advanced nasopharyngeal carcinoma who are treated with Induction chemotherapy followed by concomitant chemoradiotherapy. 1.2 To evaluate the radioprotective effect of amifostine when given daily prior to radiation therapy. Secondary Objectives 1.3 To characterize the role of EBV in the pathogenesis of nasopharyngeal carcinoma in children. 1.4 To investigate the predictive value of the detection of the EBV-DNA in the peripheral blood of children with nasopharyngeal carcinoma. 1.5 To determine the incidence of NUT rearrangements in childhood nasopharyngeal carcinoma. 2.0 BACKGROUND 2.1 Epidemiology and Pathogenesis of Nasopharyngeal Carcinoma Nasopharyngeal carcinoma (NPC) is a tumor of epidermoid origin that differs from other head and neck carcinomas by its very distinct histologic, epidemiologic and biologic characteristics. NPC is a rare disease, with an incidence of 0.5-2/100,000 persons per year. However, it has an endemic distribution among well-defined ethnic groups, such as inhabitants of some areas of Southeast Asia and in Alaskan Eskimos, where the incidence is 25-50 and 15-20/100,000 persons per year, respectively.1 Three histologic subtypes of NPC are recognized: Type I, or keratinizing squamous cell carcinoma, which is similar to carcinomas that arise from other sites of head and neck; Type II, or non-keratinizing squamous cell carcinoma; and Type III, or undifferentiated carcinoma (also called lymphoepithelioma), which is the most common form of the disease. In the western world NPC occurs sporadically, it is usually Type I, and is primarily related to exposure to the classic head and neck cancer risk factors, such as alcohol and tobacco.2 The endemic form, which occurs in areas of Southeast Asia, Mediterranean basin and in Alaskan Eskimos, is usually the Type II or III histologic subtypes. Unlike the sporadic, Type I form, the etiology of the endemic form includes virological and environmental risk factors, and genetic susceptibility.1-3 The distinct geographic and ethnic distribution of NPC suggests a contribution of genetic factors to its pathogenesis. Although environmental factors may actually account for this distribution, there is evidence of a higher risk of NPC among people with the HLA A2 Bsin2 haplotype.4 In patients with the sporadic form of NPC in western countries where the Type I is more prevalent, those of Asian origin usually develop the undifferentiated type, typical of the endemic form in South East Asia.5 A common characteristic among some of the ethnic groups with an increased incidence of NPC is the ingestion of salted fish. Several carcinogenic volatile nitrosamines have been detected in Cantonese style salted fish.6


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Cytogenetic studies have identified several abnormalities in NPC. The most consistent changes have been deletions in 3p and 16q, which suggest that the loss of a tumor suppressor gene is involved in the pathogenesis of NPC.7 As a member of the herpes virus family, the EBV infects and establishes persistent infection in the host. Most human EBV infections initiate in the oropharynx. Among the EBV genes, the Nuclear Proteins (EBNA) are involved in replication, and the Latent Membrane Proteins (LMP) may stimulate cell growth. Evidence strongly suggests that EBV has a role in the pathogenesis of NPC. Increased levels of IgG and IgA against EBV are frequently observed in patients with NPC, particularly those with the undifferentiated type.8 The anti-EBV serologic profile has been used in the screening and early diagnosis of NPC in high-incidence areas.9,10 In addition to the serological evidence there is also molecular evidence, EBV DNA is present in the NPC tumor cells.11-14 Further, EBV DNA appears to be clonal, which indicates that EBV is present within the cell at the time of carcinogenic transformation, and suggests a role for the virus in the transformation event. Taken together these data suggest the etiology of NPC appears to follow a multistep process. A persistent EBV infection results in stimulation of growth of nasopharyngeal cells by the EBV LMP and NA genes. A secondary exposure to some environmental carcinogens such as volatile nitrosamine or others, may induce the loss of a tumor suppressor gene that will eventually result in an uncontrolled proliferation and carcinogenic transformation.15 2.2 Clinical Presentation NPC may develop in all age groups, although its peak incidence is in the 5th and 6th decades of life. The nasopharynx has a rich vascular supply and lymphatic drainage system. These characteristics define the route of tumor spread, symptomatology, and treatment. Clinically, NPC has few early signs, such as nose bleeding, congestion or otitis media. It spreads locally to adjacent areas of the oropharynx and may invade the skull base, resulting as well in cranial nerve paralysis. The drainage is usually through the internal jugular vein and posterior cervical and retropharyngeal chains, which results in early lymph node invasion, usually bilateral and bulky. Up to 80% of patients have lymph node involvement at diagnosis.2 2.3 Treatment of Nasopharyngeal Carcinoma NPC is considered to be unresectable due to the complex anatomical location. NPC is a very radiosensitive tumor, and radiation therapy is considered to be the primary treatment modality. High doses (usually > 65 Gy) are usually required to achieve good locoregional control.16-18 The regional lymph nodes in the entire head and neck area are irradiated, and the structures surrounding the nasopharynx and entire neck should be also included in the treatment. The disease control rates with radiation therapy are stage dependent, with survival rates of 65-85% for patients with Stage II and of less than 50% for patients with Stage IV disease.17 The development of both locoregional and distant recurrence correlates with the size of the primary tumor and the nodal staging.16,17 Tumors of undifferentiated histology (WHO Type III) are more radiosensitive, and this correlates with better outcome.18 2.3.1 Treatment of locoregionally advanced disease Despite the progress in the delivery of radiation therapy and supportive care, a significant proportion of patients with locoregionally advanced disease fail treatment, and long-term survival rates are unsatisfactory. Unlike other head and neck cancers NPC is a very chemosensitive neoplasm, and the use of chemotherapy might thus provide benefit for patients with advanced disease. Among the drugs tested those with best single-agent activity include methotrexate, bleomycin, 5-fluorouracil (5-FU), cisplatin (CDDP) and carboplatin.19-21 The response rates in combination studies range from 38-91%,21 with CDDP-containing regimens showing clear advantage over non-CDDP containing regimens.22-25 Despite


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the evident chemosensitivity of NPC, the role of chemotherapy in the treatment of NPC is not clear. Multiple randomized,26-29 and non-randomized studies30 have investigated this issue (Table 1). All these studies investigated the use of neoadjuvant chemotherapy with CDDP-containing regimens. CDDP (60-100 mg/m2) was combined with fluorouracil (800-1000 mg/m2 x 3-5 days),26,28,30 epirubicin (70-110 mg/m2),27,29 or bleomycin (10-12 mg/m2 x 5 days),27,28 and 2-3 courses of chemotherapy were administered before definitive radiation therapy. Only one study explored the use of adjuvant chemotherapy after radiation therapy.26 The response rates for those patients treated with chemotherapy were of 79-94%.26,29,30 However, none of the randomized studies demonstrated a significant benefit for patients receiving chemotherapy (Table 1). In order to reconcile the demonstrated chemosensitivity of NPC with the lack of benefit in the treatment of patients with advanced disease, two major explanations should be considered. First, the intensity of treatment: all but one of these randomized studies incorporated 2 or 3 cycles of chemotherapy in the neoadjuvant setting, when a more intensive treatment might be required. Whether the use of additional cycles after radiation therapy might contribute to an improved overall outcome remains to be tested. However, the use of adjuvant chemotherapy most likely would decrease only the proportion of distant recurrences, but approximately 20-30% of patients fail treatment with locoregional recurrence.26-30 Second, the sequence of administration of chemotherapy and radiation therapy may not be optimal. Given the radiosensitizing properties of CDDP, the best timing for the administration of chemotherapy could be concomitantly with the radiation therapy. Table 1. Studies Comparing Radiotherapy Alone versus Radiotherapy and Chemotherapy in Advanced Nasopharyngeal Carcinoma

Author Study N. Chemotherapy N. Cycles Outcome Comments

CT + RT

RT p

Chan et al26

Randomized

77

CDDP 100 mg/m2 d. 1 5-FU 1000 mg/m2/d CI d. 2-4

2 pre RT 4 post RT

2-yr DFS 2-yr OS

68% 80%

72% 80.5%

> 0.1 > 0.1

VUMCA I trial27

Randomized

339

CDDP 100 mg/m2 d. 1 EPI 70 mg/m2 d. 1 BLEO 12 mg/m2 CI d. 1-5

3 pre RT

3-yr DFS

58%

35%

< 0.01

No improvement in OS

Ma et al28

Randomized

449

CDDP 100 mg/m2 d. 1 5-FU 800 mg/m2/d CI d. 1-5 BLEO 12 mg/m2 d. 1,5

2-3 pre RT

5-yr RFS 5-yr OS

59% 63%

49% 56%

= 0.05 = 0.11

Chua et al29

Randomized

324

CDDP 60 mg/m2 d. 1 EPI 110 mg/m2 d. 1

2-3 pre RT

3-yr RFS 3-yr OS

48% 78%

42% 71%

= 0.45 = 0.57

Patients with bulky disease (LN > 6 cm)

3-yr RFS 3-yr OS

63% 73%

28% 37%

= 0.026 = 0.057

Benefit for patients with bulky disease

Hong et al30

Non-randomized

172

CDDP 100 mg/m2 d. 1 5-FU 1000 mg/m2/d CI d. 1-5

3 pre RT

5-yr DFS 5-yr OS

63% 71%

52% 59%

= 0.04 = 0.04

CT = chemotherapy RT = radiotherapy DFS = disease-free survival OS = overall survival RFS = relapse-free survival


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2.3.2 Treatment of locoregionally advanced disease with concurrent chemoradiotherapy Cisplatin may enhance radiation toxicity by inhibiting the repair of sublethal damage, reoxygenation and recruitment of cells into a proliferative state, and radiosensitization of hypoxic cells.31 The use of concurrent chemoradiotherapy with cisplatin-containing regimens for the treatment of advanced disease has been explored, and the results of non-randomized32-34 and randomized studies35,36 have been recently reported (Table 2). All of these studies used concomitant chemoradiotherapy with cisplatin, followed by adjuvant chemotherapy with cisplatin and fluorouracil,32,33,35 or preceded by induction chemotherapy. 34 The North American Intergroup randomized study 0099 demonstrated a significant advantage of the use of concomitant chemoradiotherapy.35 The proportion of patients achieving CR after radiation therapy was significantly superior in the chemotherapy arm (49% vs. 36%). Also the proportion of patients with local and distant failures was significantly lower (14.1% vs. 40.6% and 12.8% vs. 34.8%, respectively). Overall, both the 3-yr progression-free survival (PFS) and overall survival (OS) were superior in the chemoradiotherapy arm (69% vs. 24% and 78% vs. 47%, respectively). The results of the Intergroup 0099 study have been confirmed by other non-randomized studies.32,33 Although the toxicity of this regimen is significantly worse,32 75% of the patients receive all the scheduled chemotherapy.37 In the other randomized study performed with patients with the endemic form of the disease, patients were randomized to radiation therapy alone, or chemoradiotherapy with weekly cisplatin (40 mg/m2/week), without induction or adjuvant chemotherapy. The results of the chemoradiotherapy arm were superior to radiotherapy alone (2-yr PFS 76% vs. 69%, respectively), and this advantage was even more notable in patients with advanced locoregional disease. With the improvement in the outcome using concomitant chemoradiotherapy, patients with advanced NPC may now be stratified into different risk groups that could potentially result in risk-adapted therapy.38 Table 2. Studies Using Concomitant Chemoradiotherapy in the Treatment of Advanced Nasopharyngeal Carcinoma

Author Study N. Concurrent

Chemotherapy Adjuvant

Chemotherapy Outcome

CRT RT p Al-Sarraf et al35

Randomized

147

CDDP 100 mg/m2 x 3 courses

CDDP 100 mg/m2 d 1 5-FU 1000 mg/m2/d CI d 1-4 x 3 courses

3-yr PFS 3-yr OS

69% 78%

24% 47%

< 0.001 = 0.005

Chan et al36 Randomized 350 CDDP 40 mg/m2/wk None 2-yr PFS 76% 69% = 0.10 Wolden et al32

Non-randomized

101

CDDP 100 mg/m2 x 2 courses


3-yr PFS 3-yr OS

66% 84%

54% 71%

= 0.01 = 0.04

Cheng et al33

Non-randomized No RT control group

107



3-yr DFS 3-yr OS

74.4% 84.1%

NA

3-yr OS by stage: II 100% III 92.8% IV 69.4%

Rischin et al34

Non-randomized No RT control group

35 CDDP 20 mg/m2/d x 5, 2 courses

EPI 50 mg/m2 d 1 CDDP 75 mg/m2 d 1 5-FU 200 mg/m2 CI for 9 weeks

4-yr PFS 4-yr OS

81% 90%

NA NA

CRT = chemoradiotherapy RT = radiation therapy PFS = progression-free survival DFS = disease-free survival 2.3.3 Use of Induction therapy followed by concomitant CRT The practicality of concurrent chemoradiotherapy as delivered in the Intergroup 0099 study has been questioned since the use of concomitant chemoradiotherapy may result in more severe toxicity. Only


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63% of patients on INT0099 received all 3 cycles of concurrent chemoradiotherapy, and the 3 additional cycles of adjuvant chemotherapy were given in only 55% of the patients.35 An alternative approach to the use of adjuvant chemotherapy is the administration of chemotherapy prior to radiation therapy. Rischin et al have reported excellent results with a non-randomized trial that used induction therapy with 3 cycles of epirubicin (50 mg/m2) and CDDP (75 mg/m2) with 8-week continuous infusion of fluorouracil (200 mg/m2/d), followed by concurrent chemoradiotherapy using 2 courses of CDDP (20 mg/m2/d x 5 days).34 This regimen resulted in acceptable toxicity, with all patients receiving the 3 induction cycles and the 2 cycles of concurrent chemoradiotherapy. The 4-year PFS and OS were 81% and 90%, respectively. 2.4 Nasopharyngeal Carcinoma in Children Nasopharyngeal carcinoma is very rare in children (reviewed by Ayan et al39). Only 1% of all NPC occur in patients < 19 years.5 In the U.S., the incidence of NPC in children is approximately 1-1.5 cases per million per year. This represents approximately 1% of all pediatric malignancies, but it accounts for 35-50% of all nasopharyngeal malignancies.40 In the US, NPC appears to be more prevalent in the southern states and among African-American children. 41 Several studies have analyzed the clinical characteristics and outcome of NPC in children.40-51 Virtually all cases of NPC are Type III histology and present at advanced stages. The majority of these studies incorporated the use of cisplatin and/or doxorubicin-based neoadjuvant and adjuvant chemotherapy.40,42-49 With this combined approach, survival for patients with advanced disease is 60-70%. 2.4.1 St Jude NPC-1 protocol Between 1990 and 1994, investigators at St. Jude Children’s Research Hospital developed the NPC-1 protocol for children with NPC. This protocol included an induction phase in which four courses of chemotherapy were given at 3-week intervals, followed by radiation therapy (66-70 Gy). On Day 1 of each cycle, patients received methotrexate 120 mg/m2 by IV bolus. On Day 2, patients received cisplatin (100 mg/m2) as a 6-hour infusion. Twenty-four hours after the administration of methotrexate, patients received leucovorin, 25 mg/m2 IV bolus every six hours for a total of six doses. Beginning immediately after the first dose of leucovorin, a continuous infusion of 5-fluorouracil was started, at a dose of 1000 mg/m2/day for three days. The NPC-1 protocol was subsequently used in a collaborative non-funded study, and preliminary results were reported on a group of 21 patients. All 21 patients achieved complete remission, and 20 of them were survivors.52 2.4.2 POG-9486 protocol The encouraging results of the NPC-1 protocol led to the proposal of a Phase II study in the Pediatric Oncology Group using the same regimen to further define its efficacy (POG-9486 protocol, opened in August 1996, and closed in August 1998). This protocol included two treatment strata. Stratum 01 included patients with T1-T2, N0, M0 disease, and Stratum 02 included patients with T3-T4 and/or N1-N3, and/or M1. Patients in Stratum 01 were treated with radiation therapy alone; patients in Stratum 02 were treated with four courses of chemotherapy, followed by radiation therapy. The study accrued 17 patients, and it was closed after 12 of the first 14 evaluable patients showed PR or CR. The results of this study have not been published. Of the 16 evaluable patients for response to chemotherapy in Stratum 02, 5 patients had complete response and 10 patients had partial response, for a total response rate of 94%. One patient had progressive disease on chemotherapy. The 2-yr event-free survival for all patients enrolled was 76% (95% CI 49%, 90%). No failures were observed after 15 months from study enrollment. 2.5 Ototoxicity and Xerostomia Associated with CDDP and Radiation Therapy 2.5.1 Ototoxicity Cisplatin-related ototoxicity in children has been well described.53 Dose-related deficits are noted initially in the high-frequency range, followed by significant deficits in the speech range. Cranial


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irradiation is a well-known cause of hearing loss, and hearing impairment appears to be associated with cochlear doses greater than 32 Gy.54 Cranial irradiation and cisplatin have superadditive ototoxic effects, and deficits occur at lower cumulative cisplatin doses in children with prior cranial irradiation.53,54 In patients with NPC, hearing loss occurs as a result of two different phenomena: 1) Irradiation causes edema around the eustachian tube, resulting in middle ear inflammation and conductive hearing loss, which is usually transient and reversible; and 2) Sensori-neural hearing loss as a result of direct irradiation on the inner ear. Sensori-neural loss significantly correlates with the radiation dose to the cochlea, and 25-30% of patients with NPC develop severe hearing loss when treated with radiation therapy alone.55 With intensity modulated radiation therapy, it may be possible to decrease the dose delivered to the cochlea significantly. Typical mean cochlear doses of 40% of the prescription are achievable when treating the posterior fossa in medulloblastoma patients with IMRT. Dosimetric sparing of the cochlea will be attempted when treating patients in this study with IMRT.56 In this study, patients will receive cumulative doses of cisplatin of 540 mg/m2. Based on available published data53 and the results of two Intergroup studies in which similar cumulative doses of cisplatin were administered (P9645 and INT-0097), the expected incidence of cisplatin-related severe hearing loss would be approximately 20%. However, this incidence is expected to be higher with the addition of radiation therapy: 1) Even with the use of conformal radiation therapy, sparing the inner ear from irradiation is unlikely; 2) Because of the significant nodal involvement, the cochlea will receive full radiation doses in many instances; 3) Although the ototoxic potential of chemoradiation has not been evaluated, we expect that concomitant administration of cisplatin and radiation therapy will increase the likelihood of sensori-neural loss. There are some data that can be used to estimate the incidence of severe hearing loss in this protocol. Patients with medulloblastoma treated on the St. Jude SJMB-96 protocol received 4 courses of cisplatin (cumulative dose 300 mg/m2), and cranial or craniospinal irradiation (23 – 39 Gy), and 37% of them developed severe ototoxicity requiring hearing aid. For these reasons, we estimate that the incidence of severe hearing loss with the treatment approach proposed in this protocol may be even greater than 40%. However, it is possible that the use of amifostine during radiation therapy will have a protective effect. 2.5.2 Xerostomia Xerostomia is one of the most consistent side effects of radiation therapy to the head and neck, and it may be exacerbated by chemotherapy.57,58 Xerostomia is caused by the effects of radiation on acinar cells, especially of the serous glands, such as the parotid glands.58 Consequently, inflammation, degeneration, and fibrosis of the glandular parenchyma occur. The extent, duration, and degree of recovery are a function of the dose rate and total dose. Onset of xerostomia may be noted as early as 1 week following the onset of radiation in which the salivary glands, especially the parotid, are exposed. The saliva turns thick as serous function is diminished. Patients who receive radiation to the head and neck in cumulative doses in excess of 60 Gy have irreversible xerostomia, with an 80% loss in salivary gland function.57 The toxicity effect follows a strong dose-volume response, and seems to be related to mean dose to whole gland volume) In addition to functional changes caused by xerostomia, such as difficulty in swallowing and alteration of taste, loss of saliva also is associated with a reduction in oral clearance, diminished oral IgA levels and salivary antibacterial enzymes. Patients with xerostomia are consequently susceptible to increases in local oral infections, including caries, periodontal disease, and candidiasis.57 Radiation-induced caries can be a common problem in patients with xerostomia. Changes in salivary composition, decreases in buffering capacity, and loss of the cleansing action of saliva result in the accumulation of bacteria, increases in the local oral carcinogenic flora, and tooth decalcification with consequent caries development.57,58 Four major goals should be considered for the prevention and treatment of xerostomia. First, preservation of salivary function is critical, and the amount of salivary tissue that is exposed to direct radiation should be minimized. Parotid-sparing using three-dimensional treatment and intensity-modulated radiotherapy offer the greatest chance. Stimulation of salivary flow should start simultaneously


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with radiation therapy. Pilocarpine has been shown to stimulate salivary flow in this group of patients. 59,60 Second, as discussed below, the radioprotective agent amifostine has been shown to have a protective effect on the salivary glands, and its use is recommended for the prevention of radiation-induced xerostomia.61-63 Third, patients should receive saliva replacement, which can be accomplished with the use of a salivary substitute; most of these products contain carboxymethylcellulose and provide transient symptomatic relief of dryness.60 And finally, the most effective protection of the dentition from radiation caries is the aggressive use of topical fluorides.59,60 2.6 Use of amifostine as a cytoprotectant The cytoprotectant ethyol compound amifostine has been shown to decrease some of the acute and chronic toxicities associated with radiation therapy and chemotherapy. Amifostine itself is unable to mediate protection. Amifostine is a pro-drug that requires conversion by dephosphorylation to the metabolite WR-1065, by the cell membrane-bound alkaline phosphatase. The selective protection of normal tissues is due to differences in the microenvironment that results in slow and less entry of the free thiol into the tumor cells.64 The uptake of WR 1065 into normal tissues occurs by a carrier-mediated facilitated diffusion process.65,66 In contrast, uptake in tumor tissue is slow to negligible. The concentration of membrane bound alkaline phosphatase is about 275 fold greater in normal than in neoplastic tissue. The neutral pH of normal tissue favors conversion to the active drug WR 1065, whereas the relative acidic environment of the tumor does not.67,68 Comparative in vitro and in vivo studies using murine and human tumor xenografts show no attenuation of the antitumor effects of chemotherapy, despite protection of normal organs.69 In Phase I and Phase II studies in adults, amifostine, at doses of 740-910 mg/m2, has been shown to reduce drug-induced neutropenia, thrombocytopenia, nephrotoxicity, neurotoxicity (including ototoxicity), musculoskeletal toxicity, cardiotoxicity, and mutagenicity, with no attenuation of antitumor effects.70,71 2.6.1 Ototoxicity Prevention by Amifostine In a large Phase III trial, 242 patients with advanced ovarian cancer were randomized to receive six courses of cyclophosphamide (1 g/m2) and cisplatin (100 mg/m2) with or without amifostine (910 mg/m2) every three weeks.70 Over the 6 courses of therapy, 26% of patients in the control arm had treatment limited renal or ototoxicity from cisplatin compared with 10% in the amifostine arm. Pathological tumor response rates were 37% with amifostine and 28% in controls, with comparable median survival times. Pretreatment with amifostine resulted in a 43% reduction in the incidence of ototoxicity defined as clinical hearing loss or tinnitus that required dose reduction of the cisplatin dose. However, other randomized studies have failed to show a protective effect of amifostine on cisplatin-induced ototoxicity.72 2.6.2 Prevention of Xerostomia by Amifostine The administration of amifostine is beneficial in patients receiving radiation therapy to the head and neck area. In a report by Brizel et al, adult patients with head and neck cancer receiving radiation therapy were randomized to receive amifostine, given daily before radiation therapy (200 mg/m2).73 Moderate to severe chronic xerostomia was significantly less prevalent with the use of amifostine (34% vs. 57%), and the volume of saliva produced was significantly greater in patients receiving amifostine. Importantly, the long-term outcome was similar for both groups of patients, demonstrating that the use of amifostine does not influence the antitumor efficacy of the treatment. No studies of amifostine prior to radiation therapy have been performed in children. However, based on the adult data, the recommended daily dose prior to radiation is 200 mg/m2.63,73 Together with the use of imaging-based radiation planning, amifostine is considered to be an important component in xerostomia prevention in radiation of the head and neck.74,75


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2.6.3 Radioprotective Efficacy of Subcutaneously Administered Amifostine Cassat et al have investigated the radioprotective effects and pharmacokinetics of subcutaneously administered amifostine in animals.76 Studies in rats using a single dose of amifostine showed that subcutaneous administration gave protection from radiation-induced mucositis equivalent to that achieved after intravenous administration. In the same studies, multiple-dose administration showed radioprotective effects equal to or greater than those obtained with intravenous administration during fractionated radiation. The pharmacokinetics of amifostine after subcutaneous administration in primates indicate a profile similar to the intravenous administration in humans. In this primate model, tissue WR-1065 levels were higher at 30 minutes after subcutaneous administration than they were after intravenous dosing, and were comparable for the two routes at 60 minutes.76 Subcutaneous daily administration of amifostine prior to radiation therapy has been explored in adults. In a randomized Phase III trial performed in adults receiving radiation therapy for head and neck cancer, patients were randomized to intravenous (200 mg/m2/d) or subcutaneous (500 mg/d in two injections at two different sites) administration of amifostine.77 The preliminary results suggest that tolerance after subcutaneous administration is better than after intravenous administration, particularly because of the absence of hypotension, which facilitates patient monitoring and management in radiotherapy departments. 2.6.4 Studies of Amifostine in Children Several Phase I studies have been performed in the pediatric population. In the first Phase I study,78 children with refractory solid tumors were treated with increasing doses of melphalan, and amifostine was also escalated from 740 to 2,700 mg/m2. The maximum tolerated dose of amifostine was 1650 mg/m2. In that study, amifostine was ineffective in preventing melphalan induced myelosuppression. More recently, Fouladi et al performed a Phase I study of a twice-daily regimen of amifostine in children with refractory solid tumors receiving ICE (ifosfamide, carboplatin and etoposide) therapy.79 The dose limiting toxicities for amifostine were somnolence and anxiety at 740 mg/m2. Other Grade 3 and 4 toxicities at this level were asymptomatic, reversible hypocalcemia, vomiting, and reversible hypotension. At a dose of 600 mg/m2, amifostine was well tolerated. In this twice-daily schedule, the recommended pediatric dose was 600 mg/m2. Two recently completed COG trials have evaluated the protective effect of amifostine against cisplatin-induced nephro and ototoxicity. In the POG-9749 protocol, adolescents with high-risk germ cell tumors received 200 mg/m2 of cisplatin (40 mg/m2/d x 5 days), with amifostine 825 mg/m2/d before cisplatin.80 In this study, no protective effect against ototoxicity was found, and 78% of patients developed severe hearing loss. In a second study (P9645), children with hepatoblastoma received 100 mg/m2 of cisplatin, preceded by amifostine 740 mg/m2, with no documented benefit against ototoxicity or nephrotoxicity. Therefore, in this trial, amifostine will only be used during radiation therapy with the objective of decreasing xerostomia. Amifostine will not be used as an otoprotectant with cisplatin. 2.7 EBV and Nasopharyngeal Carcinoma Molecular epidemiological studies have shown that for most of the tumors related to EBV infection, the association with the virus is variable, depending on factors such as geographical origin (for Burkitt’s lymphoma) or histological subtype (for Hodgkin disease). In the case of NPC, however, the association with EBV is much stronger. First, there is serological evidence of EBV infection, and the anti-EBV serologic profile has been used in the screening and early diagnosis of NPC in high-incidence areas.81 In addition to the serological evidence, there is also molecular evidence. In non-keratinizing NPC, EBV DNA is present in almost all cancer cells.11-14 Further, EBV DNA is present as a monoclonal episome, which indicates that EBV is present within the cell at the time of carcinogenic transformation, and suggests a role for the virus in the transformation event.82,83 The fact that EBV is not found in epithelial cells adjacent to NPC lesions,84-87 but is found in in situ carcinoma lesions,82,88 suggests that EBV


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infection takes place before the expansion of the malignant cell clone occurs, but probably does not represent the first step in the pathogenesis of NPC. The expression of the viral genome in EBV-positive NPC is consistent with the adoption of a restricted latency infection. In-situ hybridization studies have demonstrated the presence of EBER.12 EBNA-1 and LMP-1 are also detected at the protein level.89,90 EBV has been detected in virtually all non-keratinizing NPC, irrespective of geographic origin, and thus appears to be a rate-limiting step in the pathogenesis of these tumors. By contrast, association of squamous-NPC with EBV is much more controversial. EBV DNA is detected in a very small proportion of cases.91 There appears to be a geographical variation for the relationship of EBV with NPC. In endemic areas, squamous NPC is associated with EBV, whereas in non-endemic areas, its relationship is less frequent. Therefore, squamous NPC probably represents a pathogenetically heterogeneous group of tumors. For example, smoking may account for up to 2/3 of the cases.92 2.7.1 Circulating EBV DNA in Plasma of NPC Patients Studies have shown the feasibility of detecting tumor-derived DNA in the plasma of patients with a variety of neoplasms,93,94 and have suggested its potential role as a prognostic indicator. In patients with advanced NPC, despite the high rate of local control, the disease will subsequently recur in 30-40% of them. Current staging systems and imaging techniques are inadequate to detect patients at higher risk of recurrence and to design risk-adapted therapeutic regimens. Evidences accumulated in recent years indicate that circulating EBV DNA may represent a very reliable prognostic indicator:

1. EBV DNA levels are detected in the majority of patients with non-keratinizing NPC in endemic areas. Using real-time quantitative PCR with primers for the EBNA-1 and the BamHI-W regions, Lo et al showed that EBV DNA was detectable in the plasma of 96% of patients with non-keratinizing NPC, compared with only 7% of controls.95

2. EBV DNA levels correlate with tumor response. Following treatment with radiation therapy, there is a steady decline in the circulating EBV DNA levels, and this decline correlates with the clinical response.95-97 There is a strong correlation between the EBV DNA levels and clinical events; undetectable or very low levels correlate with continuous clinical remission, whereas progressive or persistent elevation of EBV DNA levels precedes the development of recurrence.97 The kinetics of plasma EBV DNA during radiation therapy show an initial rise, followed by an steady decline, suggesting that EBV DNA is released after cell death.96

3. Quantitative analysis of circulating EBV DNA at diagnosis is a strong prognostic indicator. In a prospective study performed on patients in Southeast China with non-keratinizing NPC uniformly treated, those patients who had disease recurrence during the first year had significantly higher copies of EBV DNA in their plasma at diagnosis than patients that remained in remission.96, 98 Furthermore, the number of EBV DNA copies at diagnosis correlated with NPC-related death. In multivariate logistic regression analysis, plasma EBV DNA was an independent prognostic indicator. For prognostication within the first year after treatment, the level of circulating EBV DNA was a more powerful prognostic indicator than disease stage.

4. EBV DNA levels after treatment predict outcome among patients in complete remission. In a prospective study of 170 patients with NPC treated on a uniform radiation protocol, Chan et al performed a quantitative analysis of circulating EBV DNA at diagnosis and 6-8 weeks after completing radiation therapy. Complete clinical remission was obtained in 99% of the patients. Post-treatment levels were significantly associated with overall survival. When combined with the pretreatment levels, the levels of post-treatment EBV DNA dominated the effects of pretreatment levels for progression free survival, and had better positive and negative predictive values for detecting disease progression than pre-treatment values. Therefore, the levels of post-treatment plasma EBV DNA in patients with NPC appear to strongly predict outcome and to accurately reflect the post treatment residual tumor load.99


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2.8 NUT-rearranged carcinomas It is important to distinguish EBV-associated nasopharyngeal carcinomas from a distinct group of non-EBV-associated poorly differentiated carcinomas that frequently occur in the nasopharyngeal region.100-107 These cancers were initially characterized by the t(15;19) translocation that resulted in the BRD4-NUT oncogene, and are collectively called NUT-rearranged carcinomas.108 NUT-rearranged carcinomas arise from midline structures in young people (median age 17.6 years), and those harboring the BRD4-NUT fusion oncogene are highly lethal (average survival 28 weeks, N = 8), despite intensive therapies.107 NUT-variant carcinomas have NUT rearrangement but lack BRD4 rearrangement, and might have a less fulminant clinical course (average survival 96 weeks, N=3) than those with BRD4-NUT fusions.107,108 Nevertheless, anecdotal evidence suggests that treatment that is successful for EBV-associated nasopharyngeal carcinomas is not for NUT-rearranged carcinomas. To explore the potential differences between EBV-associated nasopharyngeal and NUT-rearranged carcinomas in response to treatment, we will screen all cases for NUT rearrangement using dual color in situ hybridization. 2.9 Rationale for Current Protocol 2.9.1 Induction Chemotherapy and Chemoradiotherapy for patients with advanced disease The proposed treatment plan in this study includes induction chemotherapy with three cycles of cisplatin and fluorouracil, followed by concomitant chemoradiotherapy (with three additional cycles of cisplatin during radiation therapy). Using induction therapy will have two major purposes. First, studies have shown that tolerance to chemotherapy after radiation or chemoradiation is poor, resulting in poor treatment compliance. However, patients tolerate all the prescribed chemotherapy when the sequence of administration is inverted, using induction instead of adjuvant chemotherapy. Second, the response to induction chemotherapy will be used to tailor the doses of radiation therapy. The regimen selected for this study will be the combination of cisplatin and fluorouracil. As discussed above, a previous initiative by the POG explored a combination with the same agents with the addition of methotrexate and leucovorin. The EFS of the group of 17 patients treated was 76%, which does not appear to be superior to current regimens using cisplatin and fluorouracil alone. Furthermore, the addition of leucovorin and methotrexate results in significantly worse oral toxicity. 2.9.2 Radiation therapy: decreased doses and imaging-based techniques In the treatment of NPC, the regional lymph nodes in the entire head and neck area are irradiated, and the structures surrounding the nasopharynx and entire neck should be also included in the treatment. The administration of such high doses of radiation therapy to children is associated with severe acute and long-term toxicities, and an effort must be made to minimize those while maintaining good disease control. As the use of concurrent chemoradiotherapy appears to be beneficial, lower doses of radiation therapy may be possible. This is especially important in the pediatric population. In the study by Rischin et al, excellent local control was achieved with a dose of 60 Gy.34 In this study, patients with complete or partial responses will receive a decreased dose of 60 Gy to the primary tumor and 54-60 Gy to the neck. Also, in the POG-9486 protocol, patients with CR and PR to chemotherapy received 61.2 Gy to nasopharynx and neck, and no local failures were reported. With the use of intensity-modulated radiation therapy (IMRT), the intensity can be modulated so that the dose to the surrounding tissues is decreased significantly, while maintaining a high dose to the tumor. In NPC, single-institution studies have recently shown that the efficacy of this technique is comparable to other radiation modalities, with a marked decrease in the incidence and severity of acute and long-term toxicities, particularly xerostomia.109,110 However, there are no randomized data in head and neck malignancies that would support that IMRT is better than 3D conformal in terms of salivary salvage. This approach is currently being evaluated prospectively in adults in a multi-institutional study of the


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Radiation Therapy Oncology Group (RTOG 0225). While the technique of IMRT is very promising, only one third of American institutions routinely use it.111 Although at present, experience with IMRT in many pediatric institutions is limited, it is not clear how many COG facilities will have access to IMRT 2 years from now. Therefore, in this trial, imaging-based radiation therapy (IMRT or conformal) will be required, although IMRT will be strongly recommended. We anticipate that approximately 50% of the patients in the protocol will receive IMRT.

2.9.3 Use of Amifostine All patients will receive daily amifostine during radiation therapy. An interim analysis is planned to better evaluate the protective effect of amifostine. As discussed above, currently available information does not support the use of amifostine as a protectant during cisplatin chemotherapy. 2.9.4 EBV role in the pathogenesis of childhood NPC and determination of EBV-DNA levels The pathogenesis of NPC, and in particular the role of EBV, has been studied predominantly in adults residing in endemic areas, where unique ethnic and environmental factors are of utmost importance. In non-endemic areas, such as the U.S., adult NPC is usually of the keratinizing type. In these cases the association with EBV is less evident, and other factors common to other head and neck cancers play a more dominant role. Very little is known regarding childhood NPC in non-endemic areas. However, the age of the patients and the predominance of the undifferentiated type suggest that EBV plays a role. We anticipate that children with NPC will have detectable circulating levels of EBV DNA, and that these levels will correlate with clinical events. We will explore the prognostic impact of the EBV DNA levels and its kinetics in the outcome of children with NPC. Should the EBV DNA levels prove to be a prognostic indicator, risk-adapted therapies could be designed that would minimize treatment for a proportion of patients. 3.0 STUDY ENROLLMENT AND PATIENT ELIGIBILITY 3.1 Study Enrollment 3.1.1 IRB Approval Upon receipt of local IRB approval for a GOC study, fax the officially signed IRB approval to the Group Operations Center (GOC) at: (626) 445-6715. The COG IRB Approval Fax Cover Sheet is required to be faxed with the official approval. A copy of this cover memo can be obtained from the protocol links area of the COG website. After this approval is recorded by GOC staff, the institution will have access to the eRDE enrollment screens. 3.1.2 Patient Registration Prior to study enrollment, all patients must have been registered via the eRDE system into the COG Cancer Registry (Diagnosis/Registry). The patient registration application is available 24 hours a day, 7 days a week. The assigned COG patient identification number will be used to identify the patient in all future interactions with the COG. If you have problems with registration, please refer to the online help in the eRDE area of the COG website. A Biopathology Center (BPC) number will be assigned as part of the registration process. Each patient will be assigned only one BPC number per COG Patient ID. Please use this number as part of the labeling information on all banking and biology specimens sent to the Biopathology Center or a COG Reference Laboratory. If you have a question about a patient’s BPC Number, please call the Biopathology Center at (800) 347-2486.


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3.1.3 Study Enrollment Patients may be enrolled on the study once all eligibility requirements for the study have been met. Study enrollment is accomplished by going to the Enrollment application in the RDE system. If you have problems with registration, refer to online help in the Applications area of the COG website. 3.1.4 Timing Study enrollment must take place within five calendar days of beginning protocol therapy. If enrollment takes place before starting therapy, the date protocol therapy is projected to start must be no later than 5 calendar days after enrollment. 3.1.5 Bilingual Services To allow non-English speaking patients to participate in the study, bilingual health care services will be provided in the appropriate language. 3.2 Patient Criteria Important note: The eligibility criteria listed below are interpreted literally and cannot be waived (per COG policy posted 5/11/01). All clinical and laboratory data required for determining eligibility of a patient enrolled on this trial must be available in the patient's medical/research record which will serve as the source document for verification at the time of audit. Tests to determine eligibility must be performed within two weeks prior to enrollment (unless otherwise specified). 3.2.1 Age Patients must be less than 19 years of age at the time of diagnosis. 3.2.2 Diagnosis Newly diagnosed patients with histological diagnosis of nasopharyngeal carcinoma WHO Type II or III. Specimens for rapid central review of the diagnostic material must be sent within 72 hours of study enrollment. 3.2.3 Performance Level (See Appendix I) Patients ≤ 16 years of age: Lansky ≥ 60% Patients > 16 years of age: Karnofsky ≥ 60% 3.2.4 Prior Therapy The patient must have received no previous chemotherapy or radiotherapy to the nasopharynx or neck for the treatment of nasopharyngeal carcinoma. 3.2.5 Organ Function Requirements: 3.2.5.1 Adequate renal function defined as:

- Creatinine clearance or radioisotope GFR ≥ 70mL/min/1.73m2 OR - A serum creatinine based on age as follows:

Age (Years)

Maximum Serum Creatinine (mg/dL)

≤ 5 0.8 5 < age ≤ 10 1.0 10 < age ≤ 15 1.2

> 15 1.5


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It is strongly encouraged that all patients (and in particular patients < 5 years) undergo a creatinine clearance or isotope GFR before enrollment. In cases where radioisotope GFR is not possible, the Schwartz formula is recommended for calculation of creatinine clearance:

Creatinine Clearance (ml/min/m2) = [k x height (cm)]/serum creatinine (mg/dL) K: the constant is 0.33-0.45 in infants, 0.55 in children or adolescent girls, or 0.70 in adolescent boys.

3.2.5.2 Adequate liver function defined as: - Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age, and - SGOT (AST) or SGPT (ALT) < 2.5 x upper limit of normal (ULN) for age. 3.2.6 Other Criteria Since there is no available information, as yet, regarding human fetal or teratogenic toxicities, the following restriction apply:

• Female patients of childbearing potential must have a negative pregnancy test. • Lactating females must agree that they will not breastfeed a child while on this study. • Males and females of reproductive potential may not participate unless they have agreed to use an

effective contraceptive method. 3.2.7 Regulatory 3.2.7.1 All patients and/or their parents or legal guardians must sign a written informed consent. 3.2.7.2 All institutional, FDA, and NCI requirements for human studies must be met. 4.0 TREATMENT PLAN Overview This protocol includes two strata. Patients with early stage disease will receive radiation therapy only, and patients with locoregionally advanced or metastatic disease will receive Induction chemotherapy followed by chemoradiotherapy. Staging will be performed using the AJCC staging system (see Appendix II). All patients will receive amifostine as radioprotectant daily Monday through Friday during radiation therapy. Stratum A Patients with AJCC Stages I and IIa will be treated with radiation therapy only. Patients with Stage I disease will receive a total dose of 61.2 Gy, and patients with Stage IIa will receive a total dose of 66.6 Gy (see Section 18.0). Amifostine will be administered subcutaneously daily Monday through Friday prior to radiation therapy. Stratum B Patients with AJCC Stages IIb-IV will receive three cycles of Induction chemotherapy with cisplatin and 5-fluorouracil, and three additional cycles of cisplatin alone during radiation therapy. All cycles of chemotherapy may begin as soon as the absolute neutrophil count (ANC) is ≥ 750/µL and the platelet count ≥ 75,000/µL. Radiation Therapy Radiation therapy will be administered Monday through Friday of each week. The dose of radiation therapy will be based on the tumor response to chemotherapy (Stratum B only), see Section 18.0.


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REVIEW OF THE RADIATION THERAPY TREATMENT PLAN IS REQUIRED FOR ALL PATIENTS. THE RADIATION THERAPY TREATMENT PLAN MUST BE SUBMITTED TO QARC FOR A REVIEW WITHIN 3 DAYS OF THE START OF RADIOTHERAPY (see Section 18.9).


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4.1 Administration Schedule for Patients on Stratum A Patients with AJCC Stages I and IIa will be treated with radiation therapy only (see Section 18.0) for approximately 8 weeks. Amifostine will be administered daily Monday through Friday prior to radiation therapy.

Drug Rte Dose Time/Days Important Notes Amifostine

(AMI) Sub-Q 200 mg/m2

(6.7 mg/kg if < 1 yr of age)

Within 15-30 min prior to XRT

For doses > 300 mg: Give 2 separate injections in 2 different sites, with the total amount of amifostine split equally.

Monitoring of blood pressure will be performed before and 10 minutes after administration of amifostine, and after XRT.

See next page for amifostine administration guidelines. 4.1.1 Therapy Delivery Map Use a copy of this page to track each patient’s cycle by entering the week of therapy plus the actual dates and doses administered on the Therapy Delivery Map below. Radiation therapy with amifostine will be given Mondays through Fridays only for approximately 8 weeks. Week ____ Note Patient’s: Wgt _______kg Hgt________cm BSA __________m2 DATE DAY 1 2 3 4 5 6 7

XRT* AMI *Please add a check mark in the box on the days XRT is given. The reporting period for therapy is the duration of XRT (approximately 8 weeks). Following radiation therapy patients will be followed as indicated in Section 7.7.

Reg # Accession # Reporting Period Page 1 of 3


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4.1.2 Guidelines for Amifostine Administration During Radiation Therapy The following guidelines were developed for IV infusions of amifostine and are recommendations only since this study uses Subcutaneous administration of amifostine. Subcutaneous administration is better tolerated than IV infusions, with less hypotension, nausea and vomiting. • It is suggested to transfuse PRBC to keep Hb > 9 g/dL • Patients receiving amifostine should be in the supine position and the blood pressure should be

monitored prior to administration of amifostine, 10 minutes after administration, and after radiation therapy.

• Have at the bedside NS 20 mL/Kg. Should hypotension develop (see table below), the patient should be placed in the Trendelenburg position, and a bolus of normal saline should be given over 20 minutes.

Baseline Systolic Blood Pressure Decrease in Blood Pressure

< 100 > 20 100 – 119 > 25 120 – 139 > 30 140 – 179 > 40

• Patients should receive ondansetron prior to amifostine administration. • Transient asymptomatic hypocalcemia is often seen in patients receiving amifostine, and serum

calcium and ionized calcium should be monitored daily. • Management of severe hypocalcemia:

o For Ionized calcium < 1.1 mg/dL, it is suggested to give CaCl 20 mg/kg IV. o Investigators may also consider replacement with 40-50 mg/kg/day of elemental calcium as

Calcium Carbonate, divided QID for prevention of hypocalcemia. Calcium Carbonate contains 400 mg of Ca per gram of calcium carbonate.



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4.1.3 Table of Required Observations for Patients in Stratum A during Radiation Therapy

1 Document intensity and location of pain, cranial nerve deficits, respiratory difficulties. A nutritional evaluation is recommended. 2 Calcium should be monitored daily as per Section 4.1.2. 3 Pure tone audiogram or BAER if the patient is too young to cooperate for an audiogram. Copies of audiograms or BAERs will be submitted for central review and toxicity monitoring. 4 All patients should have a sialometry performed at study entry and at completion of radiation therapy (see Section 7.3). 5 Optional biology studies for quantitative determination of EBV DNA in peripheral blood (see Section 16.0).

OBTAIN ADDITIONAL STUDIES AS REQUIRED FOR GOOD PATIENT CARE See Section 7.0 for complete list of observations. 4.1.4 COMMENTS For Institutional Use: COMMENTS (Must be dated; document any change from required therapy):


STUDIES TO BE OBTAINED After three weeks of therapy

End of Therapy

History X_ X_ Physical Exam (Ht, Wt, BSA, VS)1 X_ X_ Performance Status X_ X_ CBC, differential, platelets X_ X_ Urinalysis X_ X_ Electrolytes2 including Ca++, PO4, Mg++ X_ X_ Creatinine, ALT, AST, Alkaline Phosphatase, Bilirubin X_ X_ Total protein/albumin, Serum glucose, Uric acid X_ X_ MRI head and neck X_ CT chest X_ Bone Scan X_ Audiogram/BAER3 X_ X_ Salivary flow measurements4 X_ X_ Dental XR (Panorex) X_ EBV DNA levels5 X_ X_


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4.2 Administration Schedule for Patients on Stratum B during Induction (Weeks 1 - 9) The Induction Phase consists of 3 cycles of chemotherapy given every 21 days (Weeks 1, 4 and 7) or as soon thereafter as the ANC ≥ 750/µL and the platelet count ≥ 75,000/µL. Each cycle of chemotherapy will last 21 days. This course consists of a 3 week cycle repeated x 3. 1. Pre-hydration: Hours -2 to 0 (4 days): Prehydrate with D5W 0.45NS 500 mL/m2 + Mannitol 10 g/m2 (infuse over 2 hr at 250 mL/m2/hr) 2. Cisplatin administration Hours 0 to 6:

Drug Rte Dose Time/Days Important Notes Cisplatin (CDDP)

IV over 6 hours 80 mg/m2/dose (2.7 mg/kg/dose if < 1 year of age)

Hours 0-6 on Days 1, 22, 43

+ Mannitol 10 g/m2 (infuse over 6hr) in 125 mL/m2/hr of D5W 0.45NS

3. Post Hydration: Hours 6-30 Post hydrate with D5W 0.45NS + KCl 20mEq/L at 125 mL/m²/hr for 24 hours 4. 5-Fluorouracil Administration Hours 6-102 Starting at Hour 6, immediately following Cisplatin

Drug Rte Dose Time/Days Important Notes 5-Fluorouracil (FU)

IV continuous infusion

1000 mg/m2/day x 4 (33 mg/kg/day if < 1 year of age)

Hours 6-102 on Days 1-4, 22-25, 43-46

Prepare in 480 mL D5W to infuse at 20 mL/hr/day x 4 days

4.2.1 Therapy Delivery Map for Induction Cycle 1 (Weeks 1-3) Use a copy of this page to track each patient’s cycle by entering the actual dates and doses administered on the Therapy Delivery Map below.

Weeks 2 and 3 No therapy Rest Days 5 through to 21. Proceed to cycle 2 on Day 22, or as soon thereafter as the ANC ≥ 750/µL and the platelet count ≥ 75,000/µL.

The reporting period for therapy is the duration of Induction therapy (approximately 9 weeks). See Section 5.0 for Specific Dose Modifications for Toxicities.


Week 1 Note Patient’s: Wgt ___________kg Hgt_______cm BSA ____________m2 DATE DAY 1 2 3 4 5 6 7

CDDP FU


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4.2.2 Therapy Delivery Map for Induction Cycle 2 (Weeks 4-6) Use a copy of this page to track each patient’s cycle by entering the actual dates and doses administered on the Therapy Delivery Map below.

Weeks 5 and 6 No therapy Rest Days 26 through to 42. Proceed to cycle 3 on Day 43, or as soon thereafter as the ANC ≥ 750/µL and the platelet count ≥ 75,000/µL. The reporting period for therapy is the duration of Induction therapy (approximately 9 weeks). 4.2.3 Therapy Delivery Map for Induction Cycle 3 (Weeks 7-9) Use a copy of this page to track each patient’s cycle by entering the actual dates and doses administered on the Therapy Delivery Map below.

Weeks 8 and 9 No therapy Rest Days 47 through to 63. Proceed to the Consolidation phase (concurrent chemoradiotherapy) at the end of Cycle 3 of Induction (approximately 3 weeks from the last cycle of Induction therapy), or as soon thereafter as the ANC ≥ 750/µL and the platelet count ≥ 75,000/µL. The reporting period for therapy is the duration of Induction therapy (approximately 9 weeks).



CDDP FU


CDDP FU


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4.2.4 Table of Required Observations for Stratum B during Induction Therapy

STUDIES TO BE OBTAINED After each cycle After Cycle 3 History X_X_X_ X_ Physical Exam (Ht, Wt, BSA, VS)1 X_X_X_ X_ Performance Status X_X_X_ X_ CBC, differential, platelets X_X_X_ X_ Urinalysis X_X_X_ X_ Electrolytes including Ca++, PO4, Mg++ X_X_X_ X_ Creatinine2, ALT, AST, Alkaline Phosphatase, Bilirubin X_X_X_ X_ Total protein/albumin, Serum glucose, Uric acid X_X_X_ X_ MRI head and neck X_ CT chest3 X_ Bone Scan3 X_ Audiogram/BAER4 X_X_X_ X_ Radioisotope GFR or Creatinine clearance5 X_ Salivary flow measurements6 X_ EBV DNA levels7 X_8 X_ 1 Document intensity and location of pain, cranial nerve deficits, respiratory difficulties. A nutritional evaluation is recommended. 2 Radioisotope GFR or Creatinine clearance should also be obtained if serum creatinine is > 1.5 x ULN. 3 If positive at diagnosis. 4 Pure tone audiogram, or BAER if the patient is too young to cooperate for an audiogram. Copies of audiograms or BAERs will be submitted for central review and toxicity monitoring. 5 For better monitoring of the renal toxicity, a baseline isotope GFR or creatinine clearance is strongly recommended. At institutions where GFR is unavailable, creatinine clearance is acceptable. 6 All patients should have a sialometry performed at study entry (see Section 7.3). 7 Optional biology studies for quantitative determination of EBV DNA in peripheral blood (see Section 16.0). 8 After Cycle 1 only (see Section 16.0).

OBTAIN ADDITIONAL STUDIES AS REQUIRED FOR GOOD PATIENT CARE See Section 7.0 for complete list of observations. 4.2.5 COMMENTS For Institutional Use: COMMENTS (Must be dated; document any change from required therapy):



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4.3 Administration Schedule for Stratum B Consolidation during Radiation Therapy (Weeks 10 -18)

The Consolidation Phase consists of radiation therapy with amifostine (lasting 7 to 8 weeks) plus three 21 day cycles of cisplatin, administered concurrently, that begin on Weeks 10, 13 and 16. All cycles of chemotherapy may begin as soon as the ANC ≥ 750/µL and the platelet count ≥ 75,000/µL. The course of chemotherapy is a 3 week cycle repeated x 3.

1. Pre-hydration: Hours -2 to 0: Prehydrate with D5W 0.45NS 500 mL/m2 + Mannitol 10 g/m2 (infuse over 2 hr at 250 mL/m2/hr)

2. Cisplatin administration Hours 0 to 6:





3. Post Hydration: Hours 6-30 Post Hydrate with D5W 0.45NS + KCl 20mEq/L at 125 mL/m²/hr for 24 hours

4. Amifostine

Amifostine (AMI)

Sub-Q 200 mg/m2

(6.7 mg/kg if < 1 year of age Within 15-30 min prior to XRT

For doses > 300 mg: Give 2 separate injections in 2 different sites, with the total amount of amifostine split equally. Monitoring of blood pressure will be performed before and 10 minutes after administration of amifostine, and again after completing radiotherapy. See next page for amifostine administration guidelines. 4.3.1 Therapy Delivery Map for Consolidation during Radiation Therapy Cycle 1 of Consolidation (Weeks 10-12) Use a copy of this page to track each patient’s cycle by entering the actual dates and doses administered on the Therapy Delivery Map below.

*Please add a check mark in the box on the days XRT is given.

Weeks 11 and 12 XRT and AMI only (see next page)

Do NOT administer Cisplatin on Days 2 through to 21. Proceed to cycle 2 on Day 22, or as soon thereafter as the ANC ≥ 750/µL and the platelet count ≥ 75,000/µL.

The reporting period for therapy is the duration of XRT (approx. 7-8 weeks) and continues over the page.

See Section 5.0 for Specific Dose Modifications for Toxicities.



CDDP XRT* AMI


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4.3.1.1 Therapy Delivery Maps for XRT with Amifostine (AMI) Weeks 11 and 12 Use a copy of this page to track each patient’s cycle by entering the actual dates and dose administered on the Therapy Delivery Map below.

Radiation therapy with amifostine will be given Mondays through Fridays only. See Section 4.3.1.2 below for amifostine administration guidelines.

Week 11 Note Patient’s: Wgt _______kg Hgt________cm BSA __________m2 DATE DAY 8 9 10 11 12 13 14

XRT* AMI *Please add a check mark in the box on the days XRT is given.



The reporting period for therapy is the duration of XRT (approx. 7-8 weeks). Proceed to Cycle 2 on Day 22, or as soon thereafter as the ANC ≥ 750/µL and the platelet count ≥ 75,000/µL.

4.3.1.2 Guidelines for Amifostine Administration During Radiation Therapy The following guidelines were developed for IV infusions of amifostine and are recommendations only since this study uses Subcutaneous administration of amifostine. Subcutaneous administration is better tolerated than IV infusions, with less hypotension, nausea and vomiting.

• It is suggested to transfuse PRBC to keep Hb > 9 g/dL • Patients receiving amifostine should be in the supine position and the blood pressure should be monitored prior

to administration of amifostine, 10 minutes after administration, and after radiation therapy. • Have at the bedside NS 20 mL/Kg. Should hypotension develop (see table below), the patient should be placed

in the Trendelenburg position, and a bolus of normal saline should be given over 20 minutes.

Baseline Systolic Blood Pressure Decrease in Blood Pressure < 100 > 20 100 – 119 > 25 120 – 139 > 30 140 – 179 > 40

• Patients should receive ondansetron prior to amifostine administration. • Transient asymptomatic hypocalcemia is often seen in patients receiving amifostine, and serum calcium and

ionized calcium should be monitored daily. • Management of severe hypocalcemia:

o For Ionized calcium < 1.1 mg/dL, it is suggested to give CaCl 20 mg/kg IV. o Investigators may also consider replacement with 40-50 mg/kg/day of elemental calcium as Calcium

Carbonate, divided QID for prevention of hypocalcemia. Calcium Carbonate contains 400 mg of Ca per gram of calcium carbonate.



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4.3.2 Administration Schedule for Stratum B Consolidation during Radiation Therapy, Cycle 2 (Weeks 13 - 15)

The Consolidation Phase consists of radiation therapy with amifostine (lasting 7 to 8 weeks) plus 3 21 day cycles of cisplatin, administered concurrently, that begin on weeks 10, 13 and 16. All cycles of chemotherapy may begin as soon as the ANC ≥ 750/µL and the platelet count ≥ 75,000/µL.







3. Post Hydration: Hours 6-30 Post Hydrate with D5W 0.45NS + KCl 20mEq/L at 125 mL/m²/hr for 24 hours

4. Amifostine

Amifostine (AMI)

Sub-Q 200 mg/m2


For doses > 300 mg: Give 2 separate injections in 2 different sites, with the total amount of amifostine split equally. Monitoring of blood pressure will be performed before and 10 minutes after administration of amifostine, and again after completing radiotherapy See next page for amifostine administration guidelines. 4.3.2.1 Therapy Delivery Map for Consolidation during Radiation Therapy Cycle 2 of Consolidation (Weeks 13-15) Use a copy of this page to track each patient’s cycle by entering the actual dates and doses administered on the Therapy Delivery Map below. Week 13 Note Patient’s: Wgt ___________kg Hgt_______cm BSA ____________m2 DATE DAY 22 23 24 25 26 27 28

CDDP XRT* AMI *Please add a check mark in the box on the days XRT is given.

Weeks 14 and 15 XRT and AMI only (see next page)

Do NOT administer Cisplatin on Days 23 through to 42. Proceed to Cycle 3 on Day 43 or as soon thereafter as the ANC ≥ 750/µL and the platelet count ≥ 75,000/µL.

The reporting period for therapy is the duration of XRT (approx. 7-8 weeks) and continues over the page.

See Section 5.0 for Specific Dose Modifications for Toxicities.



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4.3.2.2 Therapy Delivery Maps for XRT with Amifostine (AMI) Weeks 14 and 15 Use a copy of this page to track each patient’s cycle by entering the actual dates and dose administered on the Therapy Delivery Map below.

Radiation therapy with amifostine will be given Mondays through Fridays only. See Section 4.3.2.3 below for amifostine administration guidelines.





The reporting period for therapy is the duration of XRT (approx. 7-8 weeks). Proceed to Cycle 3 on Day 43 or as soon thereafter as the ANC ≥ 750/µL and the platelet count ≥ 75,000/µL.

4.3.2.3 Guidelines for Amifostine Administration During Radiation Therapy The following guidelines were developed for IV infusions of amifostine and are recommendations only since this study uses Subcutaneous administration of amifostine. Subcutaneous administration is better tolerated than IV infusions, with less hypotension, nausea and vomiting.



in the Trendelenburg position, and a bolus of normal saline should be given over 20 minutes.

Baseline Systolic Blood Pressure Decrease in Blood Pressure < 100 > 20 100 – 119 > 25 120 – 139 > 30 140 – 179 > 40

• Patients should receive ondansetron prior to amifostine administration. • Transient asymptomatic hypocalcemia is often seen in patients receiving amifostine, and serum calcium and






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4.3.3 Administration Schedule for Stratum B Consolidation during Radiation Therapy Cycle 3 (Weeks 16 -18) The Consolidation Phase consists of radiation therapy with amifostine (lasting 7 to 8 weeks) plus three 21 day cycles of cisplatin, administered concurrently, that begin on Weeks 10, 13 and 16. All cycles of chemotherapy may begin as soon as the ANC ≥ 750/µL and the platelet count ≥ 75,000/µL. The course of chemotherapy is a 3 week cycle repeated x 3.







3. Post Hydration: Hours 6-30 Post Hydrate with D5W 0.45NS + KCl 20mEq/L at 125 ml/m²/hr for 24 hours

4. Amifostine

Amifostine (AMI)

Sub-Q 200 mg/m2


For doses > 300 mg: Give 2 separate injections in 2 different sites, with the total amount of amifostine split equally. Monitoring of blood pressure will be performed before and 10 minutes after administration of amifostine, and again after completing radiotherapy See next page for amifostine administration guidelines. 4.3.3.1 Therapy Delivery Map for Consolidation during Radiation Therapy Cycle 3 of Consolidation (Weeks 16-18) Use a copy of this page to track each patient’s cycle by entering the actual dates and doses administered on the Therapy Delivery Map below. Week 16 Note Patient’s: Wgt ___________kg Hgt_______cm BSA ____________m2 DATE DAY 43 44 45 46 47 48 49

CDDP XRT* AMI *Please add a check mark in the box on the days XRT is given.

Please note: Those patients with PR or CR to induction will stop XRT and AMI on Day 46. Those patients with SD following Induction will receive a further 5 days of XRT and AMI (see over page). Do NOT administer Cisplatin beyond Day 43. Following chemotherapy and XRT, patients will be followed as indicated in Section 7.7. The reporting period for therapy is the duration of XRT (approx. 7-8 weeks) and continues over the page. See Section 5.0 for Specific Dose Modifications for Toxicities.



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4.3.3.2 Additional Therapy Delivery Map for XRT with Amifostine (AMI) Week 17, if necessary Use a copy of this page to track each patient’s cycle by entering the actual dates and dose administered on the Therapy Delivery Map below. Radiation therapy with amifostine will be given Mondays through Fridays only. See Section 4.3.3.3 below for amifostine administration guidelines.



Week 18 No therapy The reporting period for therapy is the duration of XRT (approx. 7-8 weeks). 4.3.3.3 Guidelines for Amifostine Administration During Radiation Therapy The following guidelines were developed for IV infusions of amifostine and are recommendations only since this study uses Subcutaneous administration of amifostine. Subcutaneous administration is better tolerated than IV infusions, with less hypotension, nausea and vomiting.



in the Trendelenburg position, and a bolus of normal saline should be given over 20 minutes. Baseline Systolic Blood Pressure Decrease in Blood Pressure < 100 > 20 100 – 119 > 25 120 – 139 > 30 140 – 179 > 40 • Patients should receive ondansetron prior to amifostine administration. • Transient asymptomatic hypocalcemia is often seen in patients receiving amifostine, and serum calcium and






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4.3.4 Table of Required Observations for Stratum B Consolidation during Radiation Therapy

STUDIES TO BE OBTAINED After each cycle End of Therapy

History1 X_X_X_ X_ Physical Exam (Ht, Wt, BSA, VS) X_X_X_ X_ Performance Status X_X_X_ X_ Pubertal Staging (Tanner) X_ CBC, differential, platelets X_X_X_ X_ Urinalysis X_X_X_ X_ Electrolytes2 including Ca++, PO4, Mg++ X_X_X_ X_ Creatinine3, ALT, AST, Alkaline Phosphatase, Bilirubin X_X_X_ X_ Total protein/albumin, Serum glucose, Uric acid X_X_X_ X_ MRI head and neck X_ CT chest X_ Bone Scan X_ Audiogram/BAER4 X_X_X_ X_ Radioisotope GFR or Creatinine clearance5 X_ Salivary flow measurements6 X_ Dental XR (Panorex) X_ EBV DNA levels7 X_ 1 Document intensity and location of pain, cranial nerve deficits, respiratory difficulties. A nutritional evaluation is recommended. 2 Calcium should be monitored daily as per Section 4.3.1.2. 3 Radioisotope GFR or Creatinine clearance should also be obtained if serum creatinine is > 1.5 x ULN. 4 Pure tone audiogram, or BAER if the patient is too young to cooperate for an audiogram. Copies of audiograms or BAERs will be submitted for central review and toxicity monitoring. 5 For better monitoring of the renal toxicity, a baseline isotope GFR or creatinine clearance is strongly recommended. At institutions where GFR is unavailable, creatinine clearance is acceptable. 6 All patients should have a sialometry performed at study entry and at completion of radiation therapy (see Section 7.3) 7 Optional biology studies for quantitative determination of EBV DNA in peripheral blood (see Section 16.0).

OBTAIN ADDITIONAL STUDIES AS REQUIRED FOR GOOD PATIENT CARE

See Section 7.0 for complete list of observations. 4.3.5 COMMENTS


For Institutional Use: COMMENTS (Must be dated; document any change from required therapy):


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5.0 DOSE MODIFICATIONS FOR TOXICITIES 5.1 Myelosuppression 5.1.1 Treatment may begin if ANC ≥ 750/µL, and platelets ≥ 75,000/µL. Delay chemotherapy until these criteria are met. If delay is > 1 week: 5.1.1.1 If delay is due to prolonged neutropenia, add filgrastim in subsequent courses. Filgrastim should be given at a dose of 5 micrograms/kg subcutaneously, daily, starting 24 hours post chemotherapy, until ANC > 5,000/µL after the expected nadir. Discontinue filgrastim at least 24 hours prior to the next cycle of chemotherapy. Chemotherapy can proceed even if the ANC has decreased after discontinuing filgrastim. If the patient is greater than 40 kg, peg-filgrastim 6 mg subcutaneously may be given 24 hours after the last dose of chemotherapy. Do not administer peg-filgrastim within 14 days prior to the next chemotherapy cycle. For patients on whom filgrastim was started during neoadjuvant chemotherapy, its continued use during chemoradiation is at the discretion of the treating physician. 5.1.1.2 If delay is due to thrombocytopenia, decrease the dose of the involved agents by 20% for the remainder of the treatment (for example, if the full dose is 80 mg, then administer 64 mg for a 20% dose reduction). 5.2 Ototoxicity 5.2.3 A decrease in auditory acuity at frequencies above the normal hearing range (4000 – 8000 Hz) is expected. • For CTCAE version 3, Grade 1 or 2 ototoxicity, cisplatin dose will not be modified. • For CTCAE version 3, Grade 3 ototoxicity, reduce the dose of cisplatin by 50% for all subsequent

cycles (for example, if the full dose is 80 mg, then administer 40 mg for a 50% dose reduction). • For CTCAE version 3, Grade 4 ototoxicity, hold cisplatin dose and do not restart unless follow-up

audiograms show improvement in the hearing function. From CTCAE version 3:

Grade 1 Grade 2 Grade 3 Grade 4 Threshold shift or loss of 15-25 dB relative to baseline, averaged at 2 or more contiguous test frequencies in at least one ear; or subjective change in the absence of a Grade 1 threshold shift

Threshold shift or loss of >25 – 90 dB, averaged at 2 contiguous test frequencies in at least one ear

Adults: Threshold shift of > 25 – 90 dB, averaged at 3 contiguous test frequencies in at least one ear. Children: Hearing loss sufficient to indicate therapeutic intervention, including hearing aids (e.g., ≥ 20 dB bilateral HL in the speech frequencies; ≥ 30 dB unilateral HL; and requiring additional speech-language related services)

Adults: Profound bilateral hearing loss (> 90 dB) Children: Audiologic indication for cochlear implant and requiring additional speech-language related services

5.2.4 Monitoring for Ototoxicity This study will include close monitoring for ototoxicity. All audiograms must be submitted in real time for central review, and cisplatin dose reductions should be reported.


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5.3 Nephrotoxicity 5.3.1 Creatinine clearance or GFR < 50% of baseline value: withhold cisplatin until the creatinine clearance rises above 50% of the baseline value. If repeat GFR > 50% but < 75% of baseline, reduce dose of cisplatin by 50%, and repeat creatinine clearance after 2 cycles (for example, if the full dose is 80 mg, then administer 40 mg for a 50% dose reduction). If GFR rises to ≥ 75%, resume cisplatin at full dose. 5.3.2 Creatinine clearance or GFR < 75% of baseline value: reduce the dose of cisplatin by 50% until GFR returns to ≥ 75% of baseline value, and then resume full dose (for example, if the full dose is 80 mg, then administer 40 mg for a 50% dose reduction). 5.4 Mucositis 5.4.1 For Grade 4 mucositis after administration of fluorouracil: Decrease dose of fluorouracil by 25% by reducing the total duration of the infusion (for example, if the full dose is administered over 4 days, then stop the administration after 3 days for a 25% dose reduction). 5.5 Hepatotoxicity 5.5.1 If direct bilirubin is > 3 mg/dL prior to a cycle containing fluorouracil, hold chemotherapy until

bilirubin normalizes. If liver function fails to normalize within 1 week, omit fluorouracil. 5.5.2 Hold pilocarpine if direct bilirubin is > 3 mg/dL.


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6.0 DRUG INFORMATION 6.1 AMIFOSTINE (Ethyol®) NSC#296961 (092004) Source and Pharmacology: Amifostine is a prodrug that is dephosphorylated by alkaline phosphatase in tissues to a pharmacologically active free thiol metabolite. This metabolite is believed to be responsible for the reduction of the cumulative renal toxicity of cisplatin and for the reduction of the toxic effects of radiation on normal oral tissues. The ability of Amifostine to differentially protect normal tissues is attributed to the higher capillary alkaline phosphatase activity, higher pH and better vascularity of normal tissues relative to tumor tissue, which results in a more rapid generation of the active thiol metabolite as well as a higher rate constant for uptake into cells. The higher concentration of the thiol metabolite in normal tissues is available to bind to, and thereby detoxify, reactive metabolites of cisplatin. This thiol metabolite can also scavenge reactive oxygen species generated by exposure to either cisplatin or radiation. Clinical pharmacokinetic studies show that amifostine is rapidly cleared from the plasma with a distribution half-life of < 1 minute and an elimination half-life of approximately 8 minutes. Less than 10% of amifostine remains in the plasma 6 minutes after drug administration. For Amifostine’s approved uses in Ovarian cancer, Non-Small Cell Lung Cancer or to reduce the incidence of moderate to severe xerostomia in patients undergoing post-operative radiation treatment for head and neck cancer, the clinical data do not suggest that the effectiveness of cisplatin based chemotherapy regimens or radiation therapy is altered by Amifostine. Toxicity:

Common Happens to 21-100 children

out of every 100

Occasional Happens to 5-20 children out of

every 100

Rare Happens to <5 children out of every 100

Immediate: Within 1-2 days of receiving drug

Vomiting, nausea, transient hypotension, hypocalcemia, warm or flushed feeling, sneezing. With Sub-Q: mild pain, bruising and Erythema at injection site.

Sleepiness, dizziness, anxiety, rashes

Hiccups, chills, anaphylactic reactions, syncope, seizures, apnea, dyspnea, hypoxia, tachycardia, bradycardia, extrasystoles, chest pain, myocardial ischemia, drug fever, and hypomagnesemia

Prompt: Within 2-3 weeks, prior to next course

Symptomatic hypocalcemia* (with schedules using multiple day dosing); Severe skin rashes, including Erythema Multiforme, Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis, Toxoderma, and Exfoliative Dermatitis.

Delayed: Any time later during therapy

Renal failure

Late: Any time after completion of treatment

*Systemic reactions are less frequent with subcutaneous administration of amifostine.

Formulation and Stability: Amifostine is the trihydrate form of amifostine and is supplied as a sterile lyophilized powder requiring reconstitution for intravenous infusion. Each single-use 10 mL vial contains 500 mg of amifostine on the anhydrous basis. For subcutaneous administration: Amifostine 500 mg is diluted with 2.9 ml of 0.9% Sodium Chloride to provide a concentration approximating 160 mg/mL, which is chemically stable for up to 5 hours when stored at room temperature (approximately 25°C) or up to 24 hours when stored under refrigeration (2°C


Page 39

to 8°C). More concentrated solutions may take longer to dissolve and may crystallize under refrigeration. Do not use if cloudiness or a precipitate is present. Guidelines for Administration: See the treatment plan in Sections 4.1 and 4.3 for administration guidelines, guidelines on blood pressure monitoring, and information regarding premedication with antiemetics. For doses > 300 mg: Give 2 separate injections in 2 different sites subcutaneously, with the total amount of amifostine split equally. Supplier: Commercially available. See package insert for more detailed information.

6.2 CISPLATIN (Cis-diamminedichloroplatinum II, Platinol-AQ) NSC #119875 (122004) Source and Pharmacology: Cisplatin is an inorganic, water-soluble complex containing a central platinum atom, 2 chlorine atoms and 2 ammonia molecules. In aqueous solution, the chloride ions are slowly displaced by water generating a positively charged aquated complex. This activated complex is then available to react with nucleophilic sites on DNA, RNA, or protein resulting in the formation of bi-functional covalent links, very similar to alkylating reactions. The intra-strand cross-links, in particular with guanine and cytosine, change DNA conformation and inhibit DNA synthesis leading to the cytotoxic and anti-tumor effects of cisplatin. Cisplatin has synergistic cytotoxicity with radiation and other chemotherapeutic agents. Cisplatin has a rapid distribution phase of 25-80 minutes with a slower secondary elimination half-life of 60-70 hours. The platinum from cisplatin, but not cisplatin itself, becomes bound to several plasma proteins including albumin, transferrin, and gamma globulin. Three hours after a bolus injection and two hours after the end of a three hour infusion, 90% of the plasma platinum is protein bound. The complexes between albumin and the platinum from cisplatin do not dissociate to a significant extent and are slowly eliminated with a minimum half-life of five days or more. Platinum is present in tissues for as long as 180 days after the last administration. Both cisplatin and platinum are excreted through the kidneys ranging from 10-50%. Fecal elimination is minimal. Cisplatin’s penetration into the CNS is poor.


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Toxicities

Common Happens to 21-100 children out of

every 100

Occasional Happens to 5-20 children

out of every 100

Rare Happens to < 5 children out of every

100 Immediate: Within 1-2 days of receiving drug

Nausea (L), vomiting (L)

Metallic taste (L) Anaphylactic reaction ( facial edema, wheezing, tachycardia, and hypotension), phlebitis

Prompt: Within 2-3 weeks, prior to the next course

Anorexia (L), myelosuppression, Hypomagnesemia (L), high frequency hearing loss (L), Nephrotoxicity (↑ Cr, BUN, Uric Acid) (L)

Electrolyte disturbances (L), (hypocalcemia, natremia, kalemia, & phosphatemia ),peripheral neuropathy (paresthesias in a stocking-glove distribution) (L)

Vestibular dysfunction, tinnitus (L), rash, seizure (L), elevated liver function tests (L),


Hearing loss in the normal hearing range

Areflexia, loss of proprioception and vibratory sensation, (very rarely loss of motor function) (L), optic neuritis, papilledema, cerebral blindness, blurred vision and altered color perception (improvement or total recovery usually occurs after discontinuing), chronic renal failure, deafness


Secondary malignancy

Unknown Frequency and Timing: Fetal toxicities and teratogenic effects of cisplatin have been noted in animals and cisplatin can cause fetal harm in humans. Cisplatin is excreted into breast milk. (L) Toxicity may also occur later. Formulation and Stability: Available as an aqueous solution containing 1 mg/ml of cisplatin and 9mg (1.54mEq)/ml of sodium chloride in 50 ml, 100 ml and 200 ml multi-dose non-preserved vials. Store at 15°C-25°C (68-77ºF). Do not refrigerate. Protect unopened container from light. The cisplatin remaining in the amber vial following initial entry is stable for 28 days protected from light or for 7 days under fluorescent room light. Cisplatin removed from its amber container should be protected from light if not used within 6 hours. Guidelines for Administration: See the Treatment and Dose Modifications Sections of this protocol. Cisplatin may be further diluted in dextrose and saline solutions provided the solution contains ≥ 0.2% sodium chloride. Dextrose/saline/mannitol containing solutions, protected from light, are stable refrigerated or at room temperature for 24-72 hours but since such admixtures contain no preservative, use within 24 hours. Needles or intravenous sets containing aluminum parts that may come in contact with cisplatin should not be used for preparation or administration. Aluminum reacts with cisplatin causing precipitate formation and a loss of potency. Supplier: Commercially available. See package insert for more detailed information.


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6.3 5-FLUOROURACIL (5-FU) NSC #19893 Source and Pharmacology: A fluorinated pyrimidine antimetabolite, which is metabolized to 5-FUR or 5-FUdR and then phosphorylated. 5-FU interferes with DNA and to a lesser extent RNA metabolism. 5-FUdUMP inhibits thymidylate synthetase blocking thymidine metabolism. 5-FUR interferes with RNA metabolism. 5-FUdUMP is S phase specific. 5-FU is catabolized in the liver by dihydropyrimidine dehydrogenase which is absent in rare individuals. The inactive catabolites are excreted in the urine, with some excretion in the bile. It diffuses readily across the blood-brain barrier. Its plasma half-life is approximately 16 minutes (range 8 to 20). No intact drug can be detected in the plasma after 3 hours. Toxicity:

Common Happens to 21-100 children

out of every 100

Occasional Happens to 5-20 children out of

every 100

Rare Happens to <5 children out of

every 100 Immediate: Within 1-2 days of receiving drug

Nausea, vomiting, metallic taste, anorexia

Hypotension, angina, EKG changes, anaphylaxis


Myelosuppression, alopecia Diarrhea, stomatitis, esophagopharyngitis, photosensitivity, palmar-plantar erythrodysesthesia syndrome

Tearing, conjunctivitis and blurred vision, rashes, GI ulceration and inflammation


Hyperpigmentation of the skin including the vein through which the drug is given, dry skin

Nail changes (including: diffuse blue superficial pigment, onycholysis, dystrophy, pain and thickening of the nail bed, transverse striations), headache, visual disturbances, cerebellar ataxia, leukoencephalopathy (symptoms of which may include:ataxia, speech disturbances, memory loss, confusion, aphasia, seizures, coma), proctitis


Unknown Frequency and Timing: **Fetal toxicities and teratogenic effects of 5-FU have been noted in animals. It is unknown whether the drug is excreted in breast milk. Supplier: Commercially available. See package insert for more detailed information.

6.4 PILOCARPINE (Salagen®) Source and Pharmacology: Pilocarpine is a direct acting muscarinic agonist with activity at all muscarinic receptors (M1-M5). It is a tertiary alkaloid that was originally derived from the South American shrubs of the Pilocarpus genus. Pilocarpine in appropriate dosage can increase secretion by the exocrine glands. The sweat, salivary, lacrimal, gastric, pancreatic, intestinal glands, and the mucous cells of the respiratory tract may be stimulated. Dose-related smooth muscle stimulation of the intestinal tract may cause increased tone, increased motility, spasm, and tenesmus. Bronchial smooth muscle tone may increase. The tone and motility of urinary tract, gallbladder, and biliary duct smooth muscle may be enhanced. Pilocarpine may have paradoxical effects on the cardiovascular system. The expected effect of a muscarinic agonist is vasodepression, but administration of pilocarpine may produce hypertension after a brief episode of hypotension. Bradycardia and tachycardia have both been reported with use of pilocarpine.


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Pilocarpine increases salivation secondary to direct stimulation of post-ganglionic muscarinic M1 and M3 receptors on the salivary glands. Pilocarpine has been shown to increase resting and stimulated salivary flow, decrease subjective oral dryness, and improve chewing and speaking in patients with xerostomia. Pilocarpine is primarily hydrolyzed in tissues and plasma to pilocarpic acid. Additional hydrolytic and oxidative metabolism may occur in the liver and approximately 20% is excreted unchanged in the urine. The elimination t½ ranges from 0.76 to 1.3 hours. Mild to moderate hepatic impairment will delay the excretion (t½ ~2.1 hrs) and increase peak plasma levels by about 30%. The onset of action is approximately 20 minutes and the duration of action is > 10 hours with multiple dosing.

Toxicity: Common

Happens to 21-100 children out of every 100Occasional

Happens to 5-20 children out of every 100

Rare Happens to <5 children out of every

100 Immediate: Within 1-2 days of receiving drug

Sweating, Flushing, nervousness, lacrimation, rhinitis

Urinary frequency, nausea, vomiting, headache, dizziness, chills, asthenia, diarrhea, abdominal cramping, dyspepsia, cardiac arrhythmias, increased bronchial secretions, hypertension, bronchospasm, tremors, visual disturbance, amblyopia




Unknown Frequency and Timing: **Fetal and teratogenic toxicities of pilocarpine in humans are not known. However, there have been adverse effects on the birth weight of animals given higher doses than those given to humans. It is not known whether pilocarpine is excreted into breast milk.

Formulation and Stability: Available as 5 mg and 7.5 mg tablets for oral administration, containing 5 mg or 7.5 mg pilocarpine hydrochloride respectively. Inactive ingredients in the tablets, the tablet's film coating, and polishing are: carnauba wax, hydroxypropyl methylcellulose, microcrystalline cellulose, stearic acid, titanium dioxide and other ingredients. Guidelines for Administration: For dosing information see Section 8.5.1 Supplier: Commercially available. See package insert for further information


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7.0 EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED

All entry/eligibility studies must be performed within 2 weeks prior to entry onto the trial (unless otherwise specified).

7.1 Required and Optional Clinical, Laboratory and Disease Evaluations

7.1.1 Stratum A Patients (Radiation Therapy Only) STUDIES TO BE OBTAINED Baseline After three weeks

of therapy End of

Therapy History X X X Physical Exam (Ht, Wt, BSA, VS)1 X X X Performance Status X X X Pubertal Staging (Tanner) X X CBC, differential, platelets X X X Urinalysis X X X Electrolytes2 including Ca++, PO4, Mg++ X X X Creatinine, ALT, AST, Alkaline phosphatase, Bilirubin

X X X

Total protein/albumin, Serum glucose, Uric acid X X X MRI head and neck X X CT chest X X Bone Scan X X Audiogram/BAER3 X X X Salivary flow measurements4 X X X Dental XR (Panorex) X X Bone Age X Pregnancy test5 X EBV serology (EBV NA, VCA and EA antibodies)* X EBV DNA levels6* X X X Endocrine laboratory evaluation - Pubertal staging (see Appendix III) and

progression, regularities of menstrual cycle. - Bone age - Laboratory evaluation:

o Growth hormone axis: IGF-1, IGFBP-3 o Thyroid hormone axis: TSH, free T4 or T4

with T uptake o Adrenal axis: 8:00 a.m. Cortisol, DHEA-

sulphate o Gonadal axis: LH, FSH; testosterone (males),

estradiol (females) (at 8 am)

X X

1 Document intensity and location of pain, cranial nerve deficits, respiratory difficulties. A nutritional evaluation is recommended. 2 Calcium should be monitored daily as per Section 4.1.2. 3 Pure tone audiogram, or BAER if the patient is too young to cooperate for an audiogram. Copies of audiograms or BAERs will be submitted for central review and toxicity monitoring. 4 All patients should have a sialometry performed at study entry and at completion of radiation therapy (see Section 7.3). 5 Female patients of childbearing potential. 6 Quantitative determination of EBV DNA in peripheral blood (see Section 16.0) * Optional biology studies.

**The radiation therapy treatment plan must be submitted to QARC for a QA review within 3 days of the start of radiotherapy. Follow up data must be submitted within 1 week of the completion of radiotherapy (see Section 18.9).


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7.1.2 Stratum B Patients

STUDIES TO BE OBTAINED Baseline After each cycle

After Cycle 3

End of Therapy

History X X X Physical Exam (Ht, Wt, BSA, VS)1 X X X Performance Status X X X Pubertal Staging (Tanner) X X CBC, differential, platelets X X X Urinalysis X X X Electrolytes2 including Ca++, PO4, Mg++ X X X Creatinine3, ALT, AST, Alkaline phosphatase, bilirubin

X X X

Total protein/albumin, Serum glucose, Uric acid X X X MRI head and neck X X X CT chest X X4 X Bone Scan X X4 X Audiogram/BAER5 X X X Radioisotope GFR or Creatinine clearance6 X X X Salivary flow measurements7 X X X Dental XR (Panorex) X X Bone Age X Pregnancy test8 X EBV serology (EBV NA, VCA and EA antibodies)* X EBV DNA levels9* X X10 X Endocrine laboratory evaluation - Pubertal staging (see appendix III) and

progression, regularities of menstrual cycle. - Bone age - Laboratory evaluation:

o Growth hormone axis: IGF-1, IGFBP-3 o Thyroid hormone axis: TSH, free T4 or T4

with T uptake o Adrenal axis: 8:00 a.m. Cortisol, DHEA-

sulfate o Gonadal axis: LH, FSH; testosterone

(males), estradiol (females)

X X

1 Document intensity and location of pain, cranial nerve deficits, respiratory difficulties. A nutritional evaluation is recommended. 2 Calcium should be monitored daily as per Section 4.3.1.2. 3 Radioisotope GFR or Creatinine clearance should be also obtained if serum creatinine is > 1.5 x ULN. 4 If positive at diagnosis. 5 Pure tone audiogram, or BAER if the patient is too young to cooperate for an audiogram. Copies of audiograms or BAERs will be submitted for central review and toxicity monitoring. 6 For better monitoring of the renal toxicity, a baseline isotope GFR or creatinine clearance is strongly recommended. At institutions where GFR is unavailable, creatinine clearance is acceptable. 7 All patients should have a sialometry performed at study entry and at completion of radiation therapy (see Section 7.3). 8 Female patients of childbearing potential. 9 Quantitative determination of EBV DNA in peripheral blood (see Section 16.0). 10 After Cycles 1 and 3 only. * Optional biology studies

**The radiation therapy treatment plan must be submitted to QARC for a QA review within 3 days of the start of radiotherapy. Follow up data must be submitted within 1 week of the completion of radiotherapy (see Section 18.9).


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7.2 Guidelines for Oral and Dental Evaluation 7.2.1 Oral and Dental evaluations will be performed by a dentist, at diagnosis and every 6 months

thereafter. The following information will be documented:

a. General examination, documenting microdonts, missing teeth, root stunting, etc. b. Salivary function:

a. Clinical examination: Normal, Moderate, or Severe changes (CTCAE Grades 1 to 3) b. Patient’s perception: Normal, Moderate, Severe changes (CTCAE Grades 1 to 3) c. Sialometry (see Section 7.3)

c. Mucositis: a. Clinical examination: CTCAE Grades 1-4

d. Caries: a. Permanent: Document 1 - 17, and 17 – 32 b. Primary: Document A – J, and K – T

e. Panorex (every year): a. Permanent: 1 – 17, and 17 – 32 b. Primary: A – J, and K – T

7.3 Performing Sialometry 7.3.1 Sialometry (if possible) will be performed at diagnosis, before starting radiation therapy, at completion of radiation and at approximately 3, 6, and 12 months after completion of radiation. 7.3.2 Unstimulated Whole Saliva: Patients should refrain from eating, drinking or dental hygiene for at least 60 minutes before collection. During collections, patients should be seated and instructed to minimize orofacial movements and not to attempt to influence salivary flow (such as sucking or swallowing). Just before the collection, the patient should be instructed to swallow. The patient should then be instructed to allow saliva to accumulate in the floor of the mouth for 60 seconds without swallowing. The patient should then spit the accumulated saliva into a pre-weighted 50 mL vial. The patient should repeat this procedure four more times, for a total collection of five minutes. Subjects should be instructed not to swallow during the entire collection procedure. 7.3.3 Stimulated Whole Saliva: After the collection of unstimulated saliva, patients will have a 2% citrate solution applied with cotton tipped applicators to the lateral tongue bilaterally five times over a two minute period (0, 30, 60, 90 and 120 seconds). The mouth should then be emptied of retained citrate solution. Saliva should then be collected for five minutes, using the same procedure as for unstimulated saliva. 7.4 Other Recommended Evaluations 7.4.1 It is suggested that all patients undergo a nutritional evaluation at diagnosis and continue to have nutritional evaluations during the treatment.


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7.5 Specimen Submission

A Specimen Transmittal Form must be completed and submitted with all specimens sent to the Biopathology Center.

CENTRAL PATHOLOGY REVIEW - REQUIRED SPECIMEN/MATERIAL TIME POINTS SEND TO Slides: 1) 10 unstained slides from a representative block of tumor tissue. 2) 2 H&E stained slides from each representative block of tumor tissue.

Reports: 1. Institutional Surgical Pathology Report.

Recommended Reports: 1. Cytogenetics Report, when available. 2. Report from DNA Ploidy flow cytometry, when available.

At diagnosis. Rapid review: These specimens must be sent within 72 hours of study enrollment.

Biopathology Center Attention: ARAR0331 Children’s Hospital of Columbus 700 Children’s Drive, WA1340 Columbus, OH 43205 Phone: (614) 722-2810 Fax: (614) 722-2897 See Section 15.2.4 for labeling requirements and shipping details.

BIOLOGY STUDIES AND BANKING - OPTIONAL SPECIMEN/MATERIAL TIME POINTS SEND TO Frozen Tissue: 10-15 grams of non-sterile tumor and surrounding normal tissue, frozen separately a.s.a.p. after surgery.

*This takes priority over the formalin-fixed tissue sample if there is insufficient material for both.

See Section 16.1 for details.

At diagnosis. Biopathology Center See Section 16.1 for packaging and labeling requirements. See Section 16.2 for shipping details.

Formalin-Fixed Tissue: 1 representative formalin-fixed paraffin-embedded tissue block from primary and metastatic tumor.


At diagnosis. As above.

Slides: 20 tissue sections from formalin-fixed paraffin-embedded block.


At diagnosis. As above.

Blood: 5 mL of blood in an EDTA (purple top) tube.


Stratum A patients: 1) At diagnosis. 2) After three weeks of therapy. 3) At the end of therapy. 4) At 6 months and 12 months from completion of therapy. 5) At recurrence. Stratum B patients: 1) At diagnosis. 2) After the first cycle of chemotherapy. 3) At the end of Induction therapy. 4) After completion of Consolidation. 5) 6 months after completing therapy. 6) At recurrence.

As above.


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7.6 Required Material for QARC Central Review 7.6.1 Imaging Studies MATERIAL TIME POINTS SEND TO 1) MRI of head and neck 2) Chest CT* 3) Bone scan* 4) Other appropriate studies if a recurrence occurs 5) Corresponding radiology reports 6) Operative report See Section 17.4 for details.

1) At diagnosis 2) After Cycle 3 for Stratum B patients only. 3) At end of therapy. 4) Disease progression or recurrence.

QARC 272 West Exchange Street, Suite 101 Providence, Rhode Island 02903-1025 Phone: (401) 454-4301 Fax: (401) 454-4683

* Send at time point 2) if positive at diagnosis. 7.6.2 Radiation Therapy Materials for the rapid review must be sent within three days of the start of radiotherapy. Materials for the follow up review must be sent within one week of the completion of radiotherapy. Please see Section 18.9 for a complete list of the requirements. 7.7 Evaluations During Follow-Up After Completion of Therapy

Months Post Treatment

H & P

Labs MRI 1o

CT Chest

Bone scan

Audiogram GFR1 EBV-DNA

Sialometry Dental Tanner Endo. Evaluation2

3 X X X X X X 6 X X X X X X X X X X X X 9 X X X X X 12 X X X X X X X X X X X 18 X X X X X X 24 X X X X X X X X X 30 X X X X X X 36 X X X X X X X X X Annually X X X X X

1 Only for patients receiving chemotherapy (Stratum B). 2 Endocrine evaluation includes laboratory, Tanner staging and bone age (see Sections 7.1.1 and 7.1.2). 7.7.1 Endocrine Evaluations It is expected that patients receiving treatment for NPC will develop multiple (neuro)endocrine deficits. For this reason, it is recommended that patients are referred for evaluation and monitoring by endocrinology. For questions regarding endocrine monitoring and treatment, please contact the endocrinologist of this study, Dr Laurie Cohen.


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8.0 SUPPORTIVE CARE GUIDELINES These are provided for institutional consideration. Investigator discretion should be used, and individual considerations made for specific patient situations and institutional practices. The Study Chair may be called with questions or problems. 8.1 Pneumocystis prophylaxis It is recommended that patients receive trimethroprim/sulfamethoxazole twice a day for three consecutive days a week. BSA (m2) Tablet* Liquid (mL)** < 0.3 - 2.5 0.3 – 0.79 ½ 5 0.8 – 1.39 1 10 1.4 – 1.89 1½ 15 > 1.89 2 20 * 1 single strength tablet = Sulfamethoxazole 400 mg / Trimethroprim 80 mg. ** Oral Suspension = Sulfamethoxazole 40 mg / Trimethroprim 8 mg per mL. Patients with allergy to trimethroprim/sulfamethoxazole may be treated with dapsone or monthly pentamidine per investigator preference. 8.2 Venous Access It is recommended that patients have a central line placed prior to starting chemotherapy. 8.3 Nutritional Management A very close monitoring of the nutritional status is necessary. Any patient with greater than 10% weight loss over pretreatment baseline should begin nutritional support. It is recommended that patients have a gastrostomy tube placed at diagnosis or during Induction chemotherapy in anticipation of the need for enteral support. 8.4 Anti-emetic Care Use standard institutional guidelines for the prevention of cisplatin and amifostine induced nausea and vomiting. 8.5 Mouth Care It is expected that patients will develop xerostomia after starting radiation therapy, and strict adherence to the following guidelines is recommended once radiation therapy is started: 8.5.1 All patients > 40 kg will begin treatment with pilocarpine HCl 5 mg PO three times a day. Patients < 40 kg will begin treatment with pilocarpine HCl 2.5 mg PO three times a day. 8.5.2 All patients should start treatments with artificial saliva once the first signs of dry mouth develop. Most of these products contain salivary enzymes - lactoperoxidase, glucose oxidase and lysozyme – and are available in different presentations: 8.5.2.1 Mouthwash: Biotene® Gentle Mouthwash


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8.5.2.2 Aerosol Spray: Salivart® Oral Moisturizer 8.5.2.3 Gel: Oralbalance® Long-Lasting Moisturizing Gel 8.5.2.4 Toothpaste: Biotene® Dry Mouth Toothpaste 8.5.2.5 Gum: Biotene® Dry Mouth Gum 8.5.3 It is recommended that all patients use fluoride for dental caries prevention. Fluoride can be applied as dental rinse or gel (5-10 mL rinse or apply to teeth and spit daily after brushing) 8.5.4 Normal saline 15 mL rinse four times daily. 9.0 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY

CRITERIA 9.1 Criteria for Removal from Protocol Therapy

a) Progressive disease. b) Diagnosis of a second malignant neoplasm. c) Refusal of further protocol therapy by patient/parent/guardian. d) Completion of planned therapy. e) Physician determines it is in patient’s best interest.

Patients who are off protocol therapy are to be followed until they meet the criteria for Off Study (see below). Follow-up data will be required unless consent was withdrawn. 9.2 Off Study Criteria

a) Death. b) Lost to follow-up. c) Entry onto another COG therapeutic study. d) Withdrawal of consent for any further data submission.

10.0 STATISTICAL CONSIDERATIONS 10.1 Statistical Design This is a non-randomized study with patients assigned to radiation therapy or radiation therapy plus chemotherapy according to disease stage at the time of study enrollment. The two-year event-free survival will be compared with a standard established from adult oncology data and the results of POG-9486, a pilot study of radiation therapy plus chemotherapy for NPC. The enrollment requirements and analytic strategy are presented subsequently.


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Although the primary analytic outcome for this study is event-free survival, biological specimens will be obtained from patients who consent to the required procedures. The relationship between risk for analytic event and Epstein-Barr viral load will be assessed using methods for censored survival analysis.112 10.2 Patient Accrual and Expected Duration of Trial One hundred seven (107) patients with a tumor of the nasopharynx were reported to the COG registration database for the 18 month period ending 31 December 2002. Eighty (80) had histology reported and 34 (42.5%) of those reported carcinoma as histological diagnosis. After imputing the results for the cases without reported histology, we estimate 41 patients with NPC were registered over the 18 month period noted above. Data from the SEER data and 2000 census figures estimate the annual US incidence of NPC to be 63 cases per year in children 19 years of age or less and 41 cases per year in children 14 years of age or less. This is in rough agreement with the COG registration database estimates. For the purposes of planning, we use 40 patients per year as the estimate of potential study enrollment. Data from POG-9486 demonstrated one of 17 patients had disease at was T1, T2 or N0 and M0 at diagnosis, according to TNM stage. POG-9486 was open to patients with NPC regardless of stage. From this we estimate approximately 10% of patients will have stage I-IIa and 90% will be enrolled with IIb-IV disease. Patients will be enrolled for four years and the last patient followed for two years before the final study analysis will be done. We expect, therefore, one hundred sixty (160) patients to be enrolled on this study. 10.3 Statistical Analysis Methods Primary Objective: Results from POG-9486 yield a Kaplan-Meier estimate of the 2-year event-free survival for the aggregate study population as 76% with a 95% confidence interval of 49%-90%. These data, taken with the review of information provided above, are consistent with an aggregate 2-year event-free survival of approximately 70%. Patients will be enrolled for four years and the last patient will be followed for two years after study entry. At that time, the two-year Kaplan-Meier estimate of event-free survival will be compared with 70% using the test statistic:

ln( ln( 2 )) ln( ln(0.70))[ln( ln( 2 ))]

Kaplan Meier Year EFS EstimateEstimated SD Kaplan Meier Year EFS Estimate

− − − − −− − −

If the outcome is identified as consistent with 70% 2-year EFS, the therapy will not be considered for recommendation as standard therapy, since the proposed treatment plan is of greater intensity for high risk patients than that outlined in POG 9486. A one-sided test of 0.05 will be used. If the therapy is considered significantly more effective, the study treatment will be identified as the standard of care for nasopharyngeal carcinoma. Table 10.3.1 below gives the approximate characteristics of this design as a function true two-year EFS of the study regimen.

Table 10.3.1

True Two-Year EFS of the Study Regimen Probability of Identifying the Regimen as Having Two-Year EFS Superior to 70%

65% 0.01 75% 0.40 80% 0.90 85% >0.99


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The type of radiation therapy delivered is determined by the technique available to each institutional investigator. For the definitive analysis, the patient population will be stratified by type of radiation therapy used (IMRT v. conformal) and the stratified result will be reported. In addition to the hypothesis test to determine whether the therapeutic result aggregated for all patients is consistent with 2-year EFS of 70%, we will provide confidence intervals for the estimated two year EFS. The expected widths of the confidence intervals, based on the true 2-year EFS probability are given subsequently:

Table 10.3.2

True 2-Year EFS Expected Width of the 95% Confidence Interval for 2-Year Event-Free Survival

50% 15% 60% 15% 70% 14% 80% 12%

Interim Monitoring: The one-sample one-sided log-rank test comparing the observed data with the hypothesized model of size 0.05 will be used to assess whether the data are consistent with the target model.113 Monitoring will take place starting with two years after the first enrollment and annually thereafter. Since this test has independent increments, the method of Lan and DeMets will be used to derive the p-values for testing procedure.114

Table 10.3.3

Analysis Time (Years) Expected Information Time Value of the Test Statistic 2 0.26 -2.71 3 0.51 -2.29 4 0.76 -2.00 5 0.88 -1.93 6 1.0 -1.83

If the test statistic is smaller than the boundary value above, the study will be considered for closure. Because such a situation will indicate protocol therapy is superior to the historical baseline, the study may remain open to complete the evaluation of the secondary aims. At each time of interim monitoring, we will calculate the conditional probability that the test statistic will be less than the final monitoring boundary at the projected end of accrual and follow-up given the true distribution of the data come from the target improvement, viz., 2-year EFS of 0.70 for patients. If the noted conditional probability is less than 0.10, the study will be considered for termination because there will be little chance of concluding protocol therapy to be superior to historical outcome. Monitoring Plan for the Feasibility of Delivering Chemoradiotherapy The study will be monitored to ensure the therapy can be delivered as planned during chemoradiotherapy (‘chemoradiotherapy feasibility’). All eligible stratum B patients who start chemoradiotherapy (planned week 10 of protocol treatment) and who have not had cisplatin eliminated from their treatment plan because of ototoxicity observed during the combination chemotherapy (the first nine weeks of the


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protocol treatment) will be considered in the analysis for chemoradiotherapy feasibility. Patients who have cisplatin reduced at least once during radiation therapy or who electively terminate chemoradiotherapy, regardless of reason, or die because of complications of chemoradiotherapy will be considered to have experienced a feasibility-event. Patients who complete chemoradiotherapy or who are removed from protocol therapy for reasons related to disease progression, second malignancy or death unrelated to protocol therapy will be considered to have successfully tolerated treatment. We plan to enroll 144 stratum B patients on this protocol. We expect no more than 10% of those patients to be inevaluable for chemoradiotherapy feasibility. If, at any time, 32 or more patients experience a feasibility-event, enrollment to the combination chemotherapy will be suspended and we will consider terminating further enrollment. If there are 130 patients evaluable for the feasibility endpoint and the true feasibility-event rate is 20%, the therapy will be considered feasible with probability 0.90. If there are 130 patients evaluable for the feasibility endpoint and true feasibility-event rate is 30%, the therapy will be considered tolerable with probability 0.11. If all 144 patients evaluable for the feasibility endpoint and the true feasibility-event rate is 20%, the therapy will be considered feasible with probability 0.78. If there are 144 patients evaluable for the feasibility endpoint and true feasibility-event rate is 30%, the therapy will be considered tolerable with probability 0.03. Secondary Objective: Prognostic significance of EBV viral load. The clinical trial provides a mechanism for collecting a blood specimen at the time of study enrollment. The prevalence of EBV DNA in the pretreatment blood specimen will be compared across stage groups using the exact conditional test of proportions. The differences detectable with 80% power are described in Table 10.3.4 as a function of the proportion of children on whom a specimen is obtained. From the background described above, circulating EBV DNA was absent in over 90% of normal controls but detected in the majority of patients with NPC. We postulate that a smaller proportion of early stage patients will have circulating EBV.

Table 10.3.4 Differences Detectable with 80% Probability Using a Two-Sided Exact Test of Proportions of Size 0.05

Number With

Specimens Submitted

Expected Number of Early Stage

Patients

Prevalence in Early Stage

Patients

Expected Number of Advanced

Stage Patients

Prevalence in Advanced Stage

Patients Detectable with 80% Probability

80 40 25% 40 58% 70 35 25% 35 60% 60 30 25% 30 63%

Most of the differences detectable with high probability represent odds ratios of 2 or greater.

The assessment of the prognostic significance of EBV changes and risk for clinical events will be conducted using survival analysis techniques. The prognostic value of the presence of EBV DNA will be assessed using the log-rank test, adjusted by initial stage of disease, if appropriate. The proposed analysis will take place at the analytic endpoint of the clinical trial. This is proposed to be six years after the study is opened. We project the therapeutic strategy proposed for the clinical trial will result in long-term EFS of approximately 70%. The table below gives the differences in long-term EFS detectable with 80% probability.


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Table 10.3.5 Differences on Long-Term EFS Detectable with 80% Probability Using a Log-Rank Test of Size 0.05

The differences detectable with good power are large representing relative risks in excess of 5. This aim, however, is secondary. Analysis of the relationship between changes in circulating EBV DNA levels will be assessed using time dependent proportional hazards regression techniques. Such analyses are considered exploratory and any trends detected would require subsequent confirmation.

10.4 Gender and Minority Accrual Estimates The gender and minority distribution of the study population is expected to be:

Accrual Targets

Sex/Gender Ethnic Category Females Males Total

Hispanic or Latino 9 0 9

Not Hispanic or Latino 29 122 151

Ethnic Category: Total of all subjects 38 122 160

Racial Category

American Indian or Alaskan Native 0 0 0

Asian 4 17 21

Black or African American 9 28 37

Native Hawaiian or other Pacific Islander 0 0 0

White 25 77 102

Racial Category: Total of all subjects 38 122 160

This distribution was derived from SEER and POG-9486. 11.0 EVALUATION CRITERIA 11.1 Common Terminology Criteria for Adverse Events v3.0 (CTCAE) This study will utilize the CTCAE of the National Cancer Institute (NCI) for toxicity and performance reporting. A copy of the current version of the CTCAE can be downloaded from the CTEP home page (http://ctep.info.nih.gov). Additionally, toxicities are to be reported on the appropriate data collection forms.

Number With Specimens Submitted

Expected Number Without Circulating

EBV DNA

Long-Term EFS Expected Number With Circulating EBV

DNA

Long-Term EFS

80 40 0.95 40 0.65 70 35 0.95 35 0.61 60 30 0.95 30 0.56


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11.2 Response Criteria for Patients with Solid Tumors This study will use a modified version of the Response Evaluation Criteria in Solid Tumor (RECIST) from the NCI to evaluate disease response. The modifications will include volumetric measurement of the primary NPC and assessment of associated adenopathy. Measurable and non-measurable metastatic foci in the lungs, bones and liver will be evaluated as per RECIST. 11.2.1 Primary Tumor Measurement The primary tumor will be measured in the largest anterior-posterior, transverse and longitudinal dimensions and tumor volume will be estimated using the formula for an ellipsoid model: (AP X transverse X longitudinal) X 0.52. The radiologist must also document the presence and extent of skull base invasion.

COG GUIDELINE: TUMOR SIZE MEASUREMENT BASED ON CROSS-SECTIONAL IMAGING

• A, B, C. D, & E are contiguous parallel slices

in the X-Y plane (usually axial) showing the tumor

• W and T are the maximal perpendicular diameters on the slice (C in this example) showing the largest surface area

• Tumor length in the Z-axis (L) (perpendicular to X-Y plane) can be obtained either by the [a] (difference in table position of the first and last slices showing the tumor + one slice thickness) or [b] the product of (slice thickness + gap) and the number of slices showing the tumor

11.2.1.1 Response of the Primary tumor: Complete Response (CR): Complete disappearance of the tumor confirmed at > 4 weeks. Partial Response (PR): At least 64% decrease in volume compared to the baseline. Progressive Disease (PD): At least 40% increase in tumor volume compared to the smallest measurement obtained since the beginning of therapy. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest disease measurement since the treatment started. 11.2.2 Adenopathy The three largest nodes or nodal masses (neck, supraclavicular and/or mediastinal) should be recorded if they measure over 1.0 cm in greatest diameter. Recorded measurements should be the sum of the products of the longest perpendicular diameters of the three individual measurable lesions. Response of adenopathy:


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11.2.2.1 Response of Adenopathy Complete Response (CR): No clinical or imaging evidence of adenopathy. Partial Response (PR): Decrease by at least 50% in the sum of the products of the largest perpendicular diameters of three index lesions compared to the baseline. Progressive Disease (PD): 25% or more increase in the product of the largest diameters of at least one index lesion compared to the smallest it ever became since the beginning of therapy. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest disease measurement since the treatment started.

11.2.3 Measurable Metastatic Disease Target lesions: The presence of at least one lesion that can be accurately measured in at least one dimension with the longest diameter at least twice the thickness of the CT or MR slice. The investigator will identify up to 10 measurable lesions total and up to 5 per organ to be followed for response. This includes pulmonary nodules and liver lesions. Serial measurements of lesions are to be done with CT or MRI. The same method of assessment is to be used to characterize each identified and reported lesion at baseline and during follow-up. 11.2.3.1 Response of target metastatic lesions: Complete Response (CR): Disappearance of all target lesions. If immunocytology is available, no disease must be detected by that methodology. Partial Response (PR): At least a 30% decrease in the sum of the longest diameters of all target lesions, taking as reference the disease measurement done to confirm measurable disease at study entry. Progressive Disease (PD): At least a 20% increase in the sum of the longest diameters of all target lesions, taking as reference the smallest disease measurement recorded since the start of treatment, or the appearance of one or more new lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest disease measurement since the treatment started. 11.2.4 Non-measurable Metastatic Disease Non-target lesions: Includes all lesions that do not qualify as target lesions (all lesions < twice the slice thickness and truly non-measurable disease such as bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, inflammatory breast disease, lymphangitis cutis/pilmonis, abdominal masses not confirmed by biopsy and cystic lesions). These lesions should be noted and recorded and response indicated as improved, no change or worse.


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11.2.5 Overall response assessment The overall response assessment takes into account response in the primary tumor, adenopathy, target and non-target lesion, and the appearance of new lesions, where applicable, according to the criteria described in the table below. The overall response assessment is shown in the last column, and depends on the assessments of the primary tumor, adenopathy, target, non-target, and new lesions in the preceding columns.

Two objective status determinations of CR before progression are required for best response of CR. Two determinations of PR or better before progression, but not qualifying for a CR, are required for a best response of PR. Two determinations of stable/no response or better before progression, but not qualifying as CR or PR, are required for a best response of stable/no response; if the first objective status is unknown, only one such determination is required. Patients with an objective status of progression on or before the second evaluations (the first evaluation is the first radiographic evaluation after treatment has been administered) will have a best response of increasing disease. Best response is unknown if the patient does not qualify for a best response of increasing disease and if all objective statuses after the first determination and before progression are unknown. 12.0 ADVERSE EVENT REPORTING REQUIREMENTS 12.1 Purpose Adverse event data collection and reporting, which are required as part of every clinical trial, are done to ensure the safety of patients enrolled in the studies as well as those who will enroll in future studies using similar agents. 12.2 Determination of Reporting Requirements Reporting requirements may include the following considerations: 1) the characteristics of the adverse event including the grade (severity); 2) the relationship to the study therapy (attribution); and 3) the prior experience (expectedness) of the adverse event. Commercial agents are those agents not provided under an IND but obtained instead from a commercial source. In some cases an agent obtained commercially may be used for indications not included in the package label. In addition, NCI may on some occasions distribute commercial supplies for a trial. Even in these cases, the agent is still considered to be a commercial agent and the procedures described below should be followed.

Primary Tumor Adenopathy Metastatic

Target Lesions Metastatic Non-Target Lesions New Lesions Overall

Response CR CR CR CR No CR CR PR PR/SD Non-PD No PR PR PR PR/SD Non-PD No PR PR CR PR/SD Non-PD No PR SD Non-PD Non-PD Non-PD No SD

Non-PD SD Non-PD Non-PD No SD PD Any Any Any Any PD Any PD Any Any Any PD Any Any PD Any Any PD Any Any Any PD Any PD Any Any Any Any Yes PD


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Determine the prior experience Expected events are those that have been previously identified as resulting from administration of the agent. An adverse event is considered unexpected, for reporting purposes only, when either the type of event or the severity of the event is not listed in:

• the current NCI Agent-Specific Adverse Event List (provided in the Drug Information

Section of this protocol); or • the drug package insert (for treatments with commercially available agents).

12.3 Reporting of Adverse Events for Commercial Agents - AdEERS abbreviated pathway Commercial reporting requirements are provided in Table B. The commercial agent(s) used in this study are listed in the Drug Information Section of this protocol.

• COG requires the AdEERS report to be submitted within 5 calendar days of learning of the event.

• Use the NCI protocol number and the protocol-specific patient ID provided during trial registration on all reports.

Table B Reporting requirements for adverse events experienced by patients on study who have NOT received any doses of an investigational agent on this study. AdEERS Reporting Requirements for Adverse Events That Occur During Therapy With a Commercial Agent or Within 30 Days1

12.4 Reporting Secondary AML/MDS All cases of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) that occur in patients on NCI-sponsored trials following their chemotherapy for cancer must be reported to the Investigational Drug Branch (IDB) of the NCI Cancer Therapy Evaluation Program (CTEP) and included as part of the second malignant neoplasm reporting requirements for this protocol (see data submission packet). Submit the following information within two weeks of an AML/MDS diagnosis occurring after treatment for cancer on NCI-sponsored trials:

Attribution Grade 4 Grade 5 Unexpected Expected Unrelated or Unlikely

AdEERS

Possible, Probable, Definite

AdEERS AdEERS

1This includes all deaths within 30 days of the last dose of treatment with a commercial agent, regardless of attribution. Any death that occurs more than 30 days after the last dose of treatment with a commercial agent which can be attributed (possibly, probably, or definitely) to the agent and is not due to cancer recurrence must be reported via AdEERS.


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• a completed NCI/CTEP Secondary AML/MDS Report Form (do not use AdEERS); • a copy of the pathology report confirming the AML/MDS; and • a copy of the cytogenetics report (if available).

Submit the information via fax to: NCI (fax # 301-230-0159) and COG (fax # 626-445-6715; attention AE Coordinator) Note: If a patient has been enrolled in more than one NCI-sponsored study, the NCI/CTEP Secondary AML/MDS Report Form must be submitted for the most recent trial. The COG must also be provided with a copy of the report even if the study was not the patient’s most recent trial.

13.0 RECORDS AND REPORTING 13.1 Categories of Research Records Research records for this study can be divided into three categories: 1. Non-computerized Information: Pathology Narrative Reports, Surgical Reports. These forms are

faxed to the Statistics and Data Center at (626) 445-4334. 2. Reference Labs’ required reports, and QARC data: These data accompany submissions to these

centers, which forward their review data electronically to the COG Statistics and Data Center. 3. Computerized Information Electronically Submitted: All other computerized data will be entered

in the COG Remote Data Entry System with the aid of schedules and worksheets (essentially paper copies of the RDE screens) provided in the data form packet.

See separate Data Form Packet posted on the COG web site, which includes submission schedule. 13.2 CDUS This study will be monitored by the Clinical Data Update System (CDUS). Cumulative CDUS data will be submitted quarterly to CTEP by electronic means. Reports are due January 31, April 30, July 31 and October 31. This is not a responsibility of institutions participating in this trial. 14.0 SURGICAL GUIDELINES 14.1 NPC is considered to be unresectable. A biopsy of the primary tumor is always preferred, although a biopsy of a cervical lymph node in the presence of a nasopharyngeal mass is also acceptable. A tumor sample is to be processed for banking for future studies as described in Section 16.1, if the patient has consented to banking.


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14.2 Patients with distant (extranodal) metastatic disease will be reassessed after induction therapy. Those patients with residual disease considered to be resectable will undergo surgical resection. Unresectable disease will be treated with radiation therapy (see Section 18.0). Following consolidation therapy those patients with residual disease considered to be resectable will also undergo surgical resection. 15.0 PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 15.1 Pathology guidelines for diagnosis Nasopharyngeal carcinomas (NPC) have been divided into three grades by the WHO: Grade 1 keratinizing NPC; Grade 2 nonkeratinizing NPC; and Grade 3 undifferentiated NPC (lymphoepithelial-like in prior literature). The WHO grading system will be utilized for this study. Grade 2 and Grade 3 NPCs have a strong association with Epstein-Barr virus integration. The histopathologic criteria for NPC are:

1) Grade 1 NPC – conventional squamous cell carcinoma pattern with keratinization and intercellular bridges, invasion of surrounding tissues characterized by desmoplastic reaction, classified as well, moderately or poorly differentiated;

2) Grade 2 NPC – Minimal to absent keratinization, growth pattern similar to transitional carcinoma of urinary bladder, lacks desmoplastic stromal reaction;

3) Grade 3 NPC – absence of keratinization, syncytial growth pattern, oval tumor cells with prominent large nucleoli, scant cytoplasm and prominent mitotic activity, lacks desmoplastic reaction, association with non-neoplastic lymphocytic infiltrate. All NPC grades are cytokeratin positive and leukocyte common antigen negative.

Cytokeratin immunocytochemistry, EBER-1 in situ hybridization and Latent Membrane Protein-1 immunocytochemistry, mib-1 (Ki-67, cell cycle proliferation marker) will be performed routinely on formalin-fixed paraffin-embedded tissue sections for diagnostic purposes. Mib-1 (Ki-67) index will be performed and reported as a percentage of tumor cells that express mib-1 (low index >5% of cells, intermediate index 5-15% of cells, and high index >15% of cells). Correlation with proliferative index from DNA ploidy analysis will also be performed. Once the diagnostic criteria listed above and exclusion of any other diagnosis has been made, the patient will be eligible for the study.

15.2 Pathology Review Requirements 15.2.1 Rapid Central Review The aim of the rapid central pathology review is to provide confirmation of the diagnosis at the originating institution, to avoid inappropriate treatment for nasopharyngeal carcinoma if an incorrect diagnosis is rendered, and ensure accuracy of the data. The review will also provide staging information, provide WHO grading, provide information regarding EBV status of the tumor, and provide a proliferative index to the treating oncologist for possible prognostic significance. All patients enrolling on this protocol require Rapid Central Review of their diagnostic tissue within the first two weeks of study entry, because eligibility is based on histology. Treatment assignment will occur


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at study entry based on institutional pathology. The diagnosis will be confirmed/corrected within 14 days of study enrollment. 15.2.2 Required Material. Send the following required material within 72 hours of enrollment on study:

1) 10 unstained slides from a representative block of tumor tissue 2) 2 H&E stained slides from each representative block of tumor tissue 3) Institutional Surgical Pathology Report 4) Transmittal Form

15.2.3 Recommended Material

1) Cytogenetic analysis is encouraged and should be performed by the originating institution and results, when available, forwarded to COG Biopathology Center. 2) DNA ploidy flow cytometry is encouraged and should be performed by the originating institution and the results, when available, forwarded to COG Biopathology Center.

15.2.4 Specimen Shipping Pathology review materials must labeled with the patient’s COG Patient ID Number and the Surgical Pathology ID (SPID) Number from the corresponding pathology report. Please label the parcel “Rapid Review”. Material must be sent by OVERNIGHT carrier for next day delivery. If material is sent by Federal Express use account 2504-6481-9. Send all pathology central rapid review materials to:

Biopathology Center Attention: ARAR0331 Children’s Hospital of Columbus 700 Children’s Drive, WA 1340 Columbus, OH 43205 Phone: (614) 722-2810 Fax: (614) 722-2897

16.0 BIOLOGY STUDIES 16.1 Specimens Requested for Biologic Studies Tissue: Please submit any available tissue not required for diagnostic purposes at originating institution. If a tissue piece of at least 0.5 cm in diameter is available, then tissue should be equally divided between formalin-fixation and cryopreservation at -70oC. If less is available, please send frozen tissue as the priority.

1) Frozen Tissue: Submit representative primary and metastatic tumor tissue at diagnosis. 10-15 grams of non-sterile tumor should be frozen as soon as possible after biopsy. Wrap in aluminum foil, freeze in liquid nitrogen or isopentane and then place in the plastic zip-lock bag provided in the Specimen Procurement Kit. Store at -70oC until shipped to BPC.


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2) Formalin Fixed Tissue: Submit a minimum of one representative formalin-fixed paraffin-embedded tissue block from primary and metastatic tumor. If a block is not available, submit primary and metastatic tissue in 10% buffered formalin. Store and ship at room temperature.

3) Slides: 20 tissue sections from formalin-fixed paraffin-embedded block. Sections should be 3-5µm in thickness and placed on coated slides for immunocytochemical studies. Store and ship at room temperature.

Blood: Collect 5 mL of blood in an EDTA (purple top) tube. Centrifuge sample and draw off plasma. Distribute plasma evenly among the 6 vials from the Specimen Procurement Kit so that approximately 0.5 ml is in each vial. Store plasma at –70oC to –80oC until shipped. Plasma will be collected from all patients at diagnosis. Additional collection time points will vary depending on the patient’s treatment arm. Refer to Section 16.3.2 for details regarding collection, processing and timing. Label specimens for biologic studies with the BPC Number, collection date and specimen type.

16.2 Specimen Shipping To facilitate collection of biologic samples, the Biopathology Center (BPC) will provide a Specimen Procurement Kit. The specimen procurement kit is constructed to allow shipment of frozen (on dry ice) and ambient temperature tissues in the same container. The kit provides specimen collection containers, instructions, a pre-printed Federal Express air bill and required biohazard and dry-ice labels. For further information, or to obtain kit, please contact the BPC at (800) 347-2486. Dry ice may be placed in either compartment of the kit, but should not be put in both. Place the frozen tissue and plasma in one compartment of the kit along with 4 lbs. of dry ice. Place the fixed tissue and slides in the other compartment of the kit. All specimens should be shipped in three layers of packaging. Remember to package ambient and frozen specimens separately. First place the specimens in a zip-lock bag and seal securely. Next place the zip-lock bag into a Biohazard Secondary Shipping Envelope with absorbent material and seal securely. Then, place the Biohazard envelope into the Tyvek Diagnostic Envelope and seal securely. Always include a specimen transmittal form with each shipment. Specimens should only be sent to the BPC Monday-Thursday for Tuesday-Friday delivery. If a specimen is obtained Friday through Sunday, please hold it under appropriate conditions (as described above) until the following Monday. Send the Specimen Procurement Kit by Federal Express Priority Overnight. Arrange for Federal Express pick-up through your usual institutional procedure or by calling 1-800-238-5355. When requesting pick-up, be sure to give the account number on the pre-printed air-bill (1290-2562-0), but stress that pick-up is at your institutional address. Ship to the following address:

Biopathology Center Attention: ARAR0331 Children’s Hospital of Columbus 700 Children’s Drive, WA 1340 Columbus, OH 43205 Phone: (614) 722-2810 Fax: (614) 722-2897

16.3 Special Studies Performed on Biology Specimens


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16.3.1 Characterization of the presence of EBV DNA and protein in tumor cells of childhood NPC Tissue Microarrays Tissue microarrays of the tumor samples will be prepared using formalin-fixed paraffin-embedded tissue blocks of the biopsy material and a tissue arrayer (Beecher Instruments, Silver Spring, MD). One hematoxylin and eosin (H&E)-stained section will be obtained from each tumor sample block (“donor” block). After microscopic examination by a pathologist (M.O.) the area/areas of the section to be sampled for the tissue microarray will be outlined with a permanent slide marker. Subsequently, 2 to 3 1 mm tissue cores will be removed from each tumor sample block from areas corresponding to those areas outlined on the H&E-stained sections. These cores will be embedded into a single “recipient” paraffin block. Samples from each tumor will be embedded at distance from each other, to compensate for variability in staining that may occur across the histologic sections obtained from the recipient block. Each recipient block prepared in the laboratory includes approximately 25-30 tissue cores (i.e. approximately 10-15 tumor samples). For smaller samples, the method may be adapted by using fewer or smaller (0.6 mm) cores. Histologic sections, 3-5 µm in thickness, will then be obtained from the final recipient blocks and used for the in situ hybridization assay. In situ Hybridization for EBER In situ hybridization for EBER will be performed using sections of the tissue microarrays (see above). Following is the method employed in the laboratory. The assay is performed on a Ventana NEXES Discovery staining system (Ventana, Tucson, AZ). After deparaffinization and pretreatment with proteinase K (DAKO) hybridization is carried out using the FITC-conjugated EBER PNA probe (DAKO, Carpinteria, CA) at 55°C for 2 hours, followed by a stringency wash, using stringent wash solution (DAKO) 1:60 dilution, at 55°C for 25 minutes. The detection of the hybridization product is performed using anti-FITC alkaline-phosphatase conjugated antibody (Ventana), prediluted and the Blue Map Alkaline Phosphatase detection kit (Ventana). The tissue is then counterstained with nuclear fast red. Positive controls are performed with each test, including a positive RNA control (FITC-conjugated anti-G-3-PDH probe, DAKO) and a positive EBER PNA control using sections of EBV-positive nasopharyngeal carcinoma, as well as a positive RNA control using the sections of tissue to be assessed for EBER. A negative control (FITC-conjugated random PNA probe, DAKO) is also prepared for each test section. Immunohistochemical staining Immunohistochemical staining will be performed on the formalin-fixed paraffin-embedded tissue array sections using the avidin-biotin peroxidase technique and hematoxylin counterstaining. Briefly, after paraffin sections will be deparaffinized and rehydrated, antigen retrieval will be performed by maintaining in citrate buffer (0.1M citric acid, pH 6.0) at 90-96o Celsius for 30 minutes, followed by 30 minute cool-down in a Black and Decker steamer model # HS2776 (Black and Decker, Towson, MD). Staining will be performed on an autostainer (DAKO, Carpinteria, CA) using the enhanced peroxidase-diaminobenzidine (DAB) chromogen kit and the EBV-LMP antibody from DAKO (Carpinteria, CA) at a 1:10 dilution.A hematoxylin counterstain will be used. A negative control (no primary antibody) and a positive control (section of EBV-LMP positive nasopharyngeal carcinoma) will be prepared with each tissue array. 16.3.2. Quantitative analysis of plasma EBV DNA at diagnosis and during and after treatment in children

with NPC Specimen Collection and Preparation Blood samples will be drawn from each patient entered in the study according to the following schedules. For patients receiving external beam radiotherapy (EBRT) only: at diagnosis, after three weeks of therapy, at the end of therapy, and at 6 months and 12 months from completion of therapy.


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For patients with advanced disease, receiving chemotherapy and EBRT: at diagnosis, after the first cycle of chemotherapy, at the end of induction therapy (after three cycles of chemotherapy, before initiation of consolidation), after completion of consolidation (approx 6 months from diagnosis) and 6 months after completing therapy (approximately 12 months from diagnosis). For those patients sustaining a recurrence, a sample will be collected at the time of recurrence. Each sample will consist of 5 mL of whole blood, drawn in an EDTA tube. Specimens will be refrigerated within 2 hours of phlebotomy. Within 24 hours of phlebotomy, the specimens will be centrifuged at 1500 X g for 20 minutes; plasma will be removed and frozen at –70oC to –80oC until transport/processing. Plasma from specimens collected at institutions other than St. Jude Children’s Research Hospital (SJCRH) will be transported on dry ice. DNA will be extracted from 200 µL each of plasma, using QIAamp Blood Mini-kit, with a final elution volume of 50-200 µL. Extract will be stored at -20 oC until further processing. Remaining plasma will be stored at –80oC. A 0.5 ml aliquot of whole blood from patients treated at SJCRH will be removed prior to plasma separation and extracted using identical methodology. The resulting whole blood extract will be stored at –80oC for future studies to compare the efficacy of plasma vs. whole blood for the detection and quantification of EBV in this patient population. Real-Time Quantitative PCR Real-time quantitative PCR will be performed in duplicate on each plasma sample, and the result will be reported in viral copies/mL of plasma. The assay utilizes PCR primers and TaqMan® probes labeled with FAM (reporter) and TAMRA (quencher) fluorogenic dyes and targeted against the EBV DNA polymerase gene, BALF5. Standard curves for quantitation are generated using purified EBV viral particles, quantified by electron microscopy and assayed in triplicate on each test run. Amplification and detection is performed on an Applied Biosystems 7900HT instrument. Exogenous internal positive control ((EIPC) reagents® (Applied Biosystems)) is added to each sample prior to amplification. Significant inhibition is defined by a lack of EPIC target amplification in a given sample. Results of whole blood and plasma testing will be compared to each other and to clinical information to help determine which specimen type provides the most useful information. 16.3.3 NUT-rearrangement detection by fluorescence in situ hybridization Dual-color FISH assays evaluating chromosome 19p13.1 BRD4 and 15q13 NUT breakpoints will be performed on formalin-fixed, paraffin-embedded, unstained, 4µm sections as described. 105 Probes used for the 19p13.1 breakpoint included telomeric BAC clone 87m17 (green), and centromeric YAC clone, 766e7 (red). Probes used for the 15q13 breakpoint, flanking a 181kb region, included telomeric BAC clones 1H8 and 64o3 (green), and centromeric clones 412e10 and 3d4 (red). FISH on paraffin sections will be performed using a modification of the technique described by Bull JH and Harnden. 115 Briefly, formalin-fixed, 4µm thick paraffin-embedded sections are baked overnight (60˚C) and deparaffinized in xylene. Slides are immersed in 100mM Tris-base, 50mM EDTA, and incubated at 100˚C in a temperature control microwave for 30-60 minutes. Tissue digestion is performed with pepsin solution (Digest-All III, Zymed, San Francisco, CA), applied directly to the slides at 37˚C for 10 minutes, and post-fixed in 10% formaldehyde for 1 minute. The biotin and digoxigenin-labeled YAC and BAC DNA and Cot1 mixture is diluted in a 50% formamide solution containing 10% dextran sulphate, applied and cover-slipped onto the slide. The slide is denatured on a flatbed PCR machine at 94˚C for 3 minutes. Hybridization and washing steps are performed as described. 116 Detection is with FITC-anti-digoxigenin (Roche, Indianapolis, IN) and 594 rhodamine streptavidin (Molecular Probes, Eugene, OR), and nuclei are counter-stained with 1mg/ml 4,6-diamidino-2-phenylindole-dihydrochloride (DAPI). Images are captured using a charge-coupled device camera (Photometrics, Tucson, AZ).


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17.0 IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 17.1 Timing of imaging studies:

Study to be obtained Pre-study After Cycle 3 (Stratum B

patients only)

End of therapy

Follow-up At Disease Progression

or Recurrence

MRI head and neck X X X X CT chest X X1 X X Bone Scan X X1 X

See Section 7.7

X 1If positive at diagnosis 17.2 Imaging of the primary tumor: MR imaging of the head and neck must include non-enhanced axial, sagittal and coronal T1W, axial fat-saturated T2 weighted and STIR coronal images of the primary tumor. All coronal images should be obtained with a field of view that includes from the superior orbital rim to the clavicles in order to assess for cervical and supraclavicular adenopathy. Post contrast imaging should include axial T1W images and either sagittal or coronal T1W images depending on which plane best demonstrated the tumor on the pre-contrast imaging. The slice thickness should be 4.0 or 5.0 mm with no skip between slices. 17.3 Imaging of metastatic disease: 17.3.1 Chest: CT of the chest must be performed with IV contrast in order to evaluate for possible supraclavicular or mediastinal adenopathy. It is strongly recommend that imaging be obtained in the bone algorithm which incorporates edge-enhancement and improves the visibility of pulmonary nodules. Imaging performed on helical scanners should utilize 5 to 8 mm slice thickness. Imaging on non-helical scanners can utilize a slice thickness up to 10 mm. Patients ≤ 5 years of age should be scanned using 5 mm slice thickness regardless of the type of scanner used. Images must be reviewed in both the mediastinal and lung windows. 17.3.2 Bone disease: Single phase nuclear bone scanning must be performed using Technetium 99 labeled methyl-diphosphonate. Whole body planar imaging should be performed within 2 to 3 hours after the injection and should include anterior and posterior images of the entire skeleton including the digits of the hands and feet. 17.4 Submitting Imaging for Central Review Good quality copies of the following studies must be submitted for central review along with the corresponding radiology reports:

1 - MRI of head and neck, Chest CT and Bone scan at diagnosis (all patients) 2 - MRI of head and neck, Chest CT and Bone scan after Cycle 3 for Stratum B patients 3 - MRI of head and neck, Chest CT and Bone scan at end of therapy (all patients) 4 - MRI of head and neck, Chest CT, Bone scan, and other appropriate studies at the time of

disease progression or recurrence.


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Please note: The operative report is required for those patients who undergo resection. Submission of Diagnostic Imaging data in digital format is preferred over hard copies of films. Digital files must be in DiCom format. These files can be burned to a CD and mailed to QARC. Multiple studies for the same patient may be submitted on one CD; however, please submit only one patient per CD. Institutions with PACS systems can contact QARC regarding installation of the COG DiCommunicator software that manages e-mailing studies securely to QARC. Contact [email protected] for further information Imaging studies for central review should be sent to:

Quality Assurance Review Center 272 West Exchange Street, Suite 101 Providence, Rhode Island 02903-1025 Telephone: (401) 454-4301 Fax: (401) 454-4683

18.0 RADIATION THERAPY GUIDELINES Radiation therapy for patients on COG protocols can only be delivered at approved COG RT facilities (see Administrative Policy 3.9, April 2004). 18.1 Imaging Based Techniques Either three-dimensional planning or IMRT are required for this study. The use of IMRT is strongly encouraged. Treatment with parallel-opposed lateral fields with successive cone-downs and matching electron fields for the posterior neck is acceptable conformal treatment providing the fields are designed using CT-guidance and Beam’s-Eye-View (BEV) for target and normal tissue localization and all other requirements of this protocol including planning techniques, target dose criteria and prescription dose are fulfilled. If 3D conformal planning is used, institutions must have an approved 3D benchmark on file at QARC. If IMRT is to be used, then the benchmark specific to IMRT must be submitted before the patient can be evaluated. See Section 18.8.1 for Benchmark information. 18.2 QARC Review The Quality Assurance Review Center (QARC) will be doing two separate reviews; a rapid review at the initiation of radiation therapy and a final review at the completion of radiation therapy (see Section 18.9). The submission of rapid review materials by rapid courier is recommended. Any changes in patient status (i.e. discontinuation of protocol treatment, delay, break in treatment) should be communicated in writing to QARC by fax (401-454-4683). 18.3 Equipment: 18.3.1 Modality: X-rays with nominal energy of 4-6 MV and electrons with appropriate energy for supplementary boosting of nodes. If higher energies (8-10 MV) are being considered, the treating physician should contact the Radiation Oncologist of the study (Dr J. Fontanesi). Co-60 is not allowed on this study. 18.3.2


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Calibration: The calibration of therapy machines used in this protocol shall be verified by the Radiological Physics Center (RPC). 18.4 Target Volume Definitions: For this protocol, MRI with gadolinium (T1 and T2 images) of the head and neck will be required at the time of initial diagnosis for support of target volume definition. The imaging study should extend from 5 cm above the base of the skull to 5 cm below the head of the clavicles and below all disease that is either clinically evident or evident on the imaging study. This applies to both the primary lesion and neck adenopathy. ICRU-50 and 62 prescription methods and nomenclature shall be utilized for this study. This applies to both 3D conformal and IMRT planning techniques.

18.4.1 Gross Tumor Volume (GTV): The GTV for this protocol will be the disease of both the primary lesion and neck adenopathy as visualized on MRI. The GTV will also include clinical evidence of disease not well defined on image studies. All lymph nodes measuring greater than 1.5 cm and/or any size lymph node with a necrotic center will be considered part of the GTV. 18.4.2 Clinical Target Volume (CTV): 18.4.2.1 CTV1: CTV1 shall include the GTV and all sites of potential sub clinical disease with a margin of 1.0 cm – 1.5 cm. The CTV can be modified for anatomical barriers at the discretion of the investigator. The pretreatment MRI/CT will be used to define all known sites of lymph node disease. The CTV1 will include the entire nasopharynx, retropharyngeal lymph nodal regions, clivus, skull base, pterygoid fossae, parapharyngeal space, inferior sphenoid sinus and posterior third of the nasal cavity and maxillary sinuses. It is recommended that fusion of the diagnostic MRI images and the treatment planning CT images be performed to delineate the GTV and the surrounding normal structures. It is anticipated that in most patients, lymphatic levels I-V will require treatment:

- Upper deep jugular (junctional, parapharyngeal) nodes, bilaterally - Submandibular lymph nodes, bilaterally - Subdigastric (jugulodigastric) nodes, bilaterally - Midjugular, bilaterally - Low jugular and supraclavicular, bilaterally - Posterior cervical nodes, bilaterally - Retropharyngeal nodes, bilaterally

CTV1 in Stratum A patients may exclude the lower ½ of levels IV and V. 18.4.2.2 Each patient shall receive no more than 45 Gy to the spinal cord during the course of therapy. As a result, it may be necessary to deliver some portion of the CTV1 treatment using off-cord portals. It is strongly recommended that every effort be made to ensure that treatment breaks do not occur secondary to not planning appropriate off cord portals. If IMRT or 3D plans are developed to take this into account it may be possible that fields changes are unnecessary. Planning Target Volume 1 (PTV1): A minimum of 0.5 cm beyond the CTV in all directions with the upper limits dependent upon known institutional setup variability. The normal critical structures must be contoured including the spinal cord (diameter on every slice should be 10 mm larger than the actual cord,


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i.e. apply. A 5 mm axial expansion) brain stem, chiasm, optic nerve, parotid glands, oral cavity, pituitary, temporomandibular joints, middle and inner ears, glottic larynx, temporal lobes, skin, lens, and eyes. 18.4.2.3 Clinical Target Volume 2 (CTV2) (final boost) The final boost for the nasopharynx and/or lymph nodes will be based on the enhanced radiation treatment planning MRI/CT scans done at the initiation of radiation treatments. The CTV2 will be as follows: 1 – Nasopharynx:

a) If a CR is obtained after chemotherapy (Stratum B patients), then the CTV2 will be the entire nasopharynx with a 1 cm margin

b) If less than CR is obtained after chemotherapy (Stratum B patients) and for all Stratum A patients, the CTV2 will be the entire nasopharynx, plus residual enhancing mass with a 1 cm margin.

2 – Lymph Nodes: In patients with residual lymph nodes requiring a boost, CTV2 will consist of the entire lymph node level with a 1 cm margin. 18.4.2.4 Planning Target Volume 2 (PTV2) The PTV2 will be the CTV2 plus 0.5 cm margin. Chart of Definitions

CTV IMAGE-BASED CTV DEFINITION

PLANNING TARGET VOLUME

CTV1 Determined from pretreatment T1 enhanced MRI or contrast enhanced CT plus 1-1.5 cm margin

PTV1 is the CTV1 plus 0.5 cm

CTV2 Determined from radiation treatment planning T1 MRI or contrast enhanced CT scan

PTV2 is the CTV2 plus 0.5 cm

18.5 Target Dose: 18.5.1 Prescription Point: Dose will be prescribed to an isodose surface that encompasses the PTV and allows the dose uniformity requirements in Section 18.5.5 to be satisfied. Anterior fields used to treat the lower neck are to be prescribed to a depth of 3 cm or deeper if appropriate. When using IMRT the lower neck can be treated using IMRT or a conventional field (dosimetric details regarding the match should be provided). Electron fields shall be prescribed to ensure that the homogeneity criteria listed in Section 18.5.5 are adhered to. Sequential IMRT plans require that the critical structure doses of the sum of the two plans must not exceed tolerance. Because the plans are independently optimized, obtaining two plans with an acceptable sum is a trial and error process. A rule of thumb is to assign the tolerance dose for each plan in proportion to the prescription dose. For example, if the spinal cord limit is 45 Gy and the prescription dose is 50 Gy followed by a 20 Gy boost, the planning goals are to limit the spinal cord to 5/7 of 45 Gy, 32 Gy, in the first plan, and to 2/7 of 45 Gy, 13 Gy, in the second plan. 18.5.2 Dose Definition: Dose is specified in Gy to muscle. 18.5.3 Tissue Heterogeneity: Density corrections are required as all patients will be treated using CT-based planning.


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18.5.4 Prescription Dose and Fractionation: 18.5.4.1 Stratum A patients: Radiation Alone 18.5.4.1.1 CTV1 As outlined in Section 18.4.2.1, CTV1 encompasses the entire nasopharynx and the following lymph node regions with a 1 to 1.5 cm margin: Levels I, II, III, and the upper ½ of levels IV and V. PTV1 is defined as the CTV 1 with a 0.5 cm margin. The daily dose to PTV1 will be 1.80 Gy to a total dose of 45 Gy. 18.5.4.1.2 CTV2

CTV2 will be as described in Section 18.4.2.3 PTV2 will be the CTV2 with a 0.5 cm margin There will be no additional dose to the draining lymph node regions unless they are part of the PTV2.

The daily dose to PTV2 will be 1.80 Gy to a total dose of 61.2 Gy for Stage I patients and 66.6 Gy for Stage IIa patients. 18.5.4.2 Stratum B patients: Combined chemotherapy/irradiation Dose to the PTV1/PTV2 will be based on tumor response to chemotherapy

a) CR to chemotherapy i. PTV1: 1.8 Gy per fraction to 45 Gy ii. PTV2: 1.8 Gy per fraction for an additional 16.2 Gy (total 61.2 Gy in 34 fractions)

b) PR to chemotherapy i. PTV1: same as in “a” ii. PTV2: 1.8 Gy per fraction for an additional 16.2 Gy (total 61.2 Gy in 34 fractions)

c) SD to chemotherapy i. PTV1: same as in “a” ii. PTV2: 1.8 Gy per fraction for an additional 25.2 Gy (total 70.2 Gy in 39 fractions)

Unresectable Metastatic Disease For patients with unresectable metastatic disease (i.e. bone) it will be up to the discretion of the treating radiation oncologist to determine the final dose. However, the minimum dose will be 36 Gy with a maximum of 46 Gy. This will be delivered using 2-3 Gy/fraction. 18.5.5 Dose Uniformity: No more than 20% of PTV2 should receive more than 110% of the total prescribed dose. No more than 1% of any PTV should receive less than 93% of the prescribed dose. Wedges, compensators, beam segmentation, and other methods of generating a uniform dose distribution are encouraged. 18.5.6 Rests/interruptions:


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There are no planned rests on this study. Please contact the Radiation Oncology Co-Chair for interruptions greater than three treatment days. The reason for any interruption in treatment must be documented in the treatment chart. 18.6 Treatment Technique 18.6.1 Either 3D conformal or IMRT treatment planning may be used on this study. The use of IMRT is strongly encouraged. Techniques which shield/protect normal tissue are essential providing that they do not compromise treatment of the PTV. Fields should be chosen to minimize dose to organs at risk as defined in Section 18.7. Multiple beam techniques, both coplanar and non-coplanar may be used to achieve the objective. Parallel opposed fields with successive cone-downs and electron fields to treat the posterior neck are acceptable as long as they are designed using CT-guidance and Beam’s-Eye-View (BEV) for target and normal tissue localization and the other requirements of the protocol can be met. 18.6.2 Guidelines for Treatment Planning: CT with immobilization is required for planning. The slice thickness must be no greater than 5 mm, and the GTV, CTV, and PTV must be defined on all axial CT slices. Treatment techniques must satisfy the dose uniformity criteria in Section 18.5.5. Spinal cord dose is to be limited to 45 Gy. The use of photon and electron techniques is permitted to achieve this objective. 18.6.3 Patient Position: Reproducible setups are critical and the use of immobilization devices is required for all patients. 18.6.4 Field Shaping: Field shaping can be done with blocks or multi-leaf collimation. 18.6.5 The low neck or supraclavicular region may be treated with conventional AP or AP/PA fields at the discretion of the physician and will receive 45 Gy in 25 fractions unless there are gross nodes in which case all gross nodes should receive the dose specified for PTV2 according to Section 18.4.2.4. 18.7 Organs at Risk: 18.7.1 Spinal Cord: No segment of the spinal cord should receive more than 45 Gy. 18.7.2 Parotids: Parotid sparing techniques are encouraged whenever possible. 18.7.3 Suggested OAR Constraints for IMRT Planning: High Priority:

• Spinal cord – ordinarily a maximum dose of 45 Gy. If necessary, 1 cc cannot exceed 50 Gy. • Mandible/TM joint –No more than 1 cc exceeding 77 Gy. • Temporal lobes – no more than 1 cc exceeding 60 Gy, maximum dose of 65 Gy. • Brain Stem, optic nerve and chiasm – no more than 1 cc exceeding 54 Gy, cannot exceed 60

Gy max.


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Low Priority • Parotid- mean dose to at least one gland ≤ 26 Gy or at least 50% of either parotid receiving ≤

30 Gy or at least 20 cc of the combined volume of both parotids receiving ≤ 20 Gy. • Oral cavity –mean dose ≤ 40 Gy, no more than 1cc exceeding 70 Gy. • Glottic larynx – mean dose ≤ 45 Gy. • Eyes – mean dose ≤ 40 Gy. • Lens – as low as possible. • Cochlea- Mean dose < 40 Gy • Pituitary- Mean dose < 25 Gy • Unspecified Tissue (tissue contained within the skin, but not otherwise identified by

containment within any other structure): No more than 1% or 1cc of the tissue outside of either PTV receiving more than 110% of the prescribed dose.

18.8 Dose Calculation and Reporting 18.8.1 Patients will be considered unevaluable if approved benchmarks are not on file at QARC. Centers participating in this protocol using 3D conformal techniques are required to complete the 3D Benchmark; those treating with IMRT must complete the IMRT Questionnaire and either the QARC Benchmark or irradiate the RPC's IMRT head and neck phantom. The Benchmark material can be obtained from the Quality Assurance Review Center (www.QARC.org ) Contact the RPC (http://rpc.mdanderson.org/rpc) for information regarding their IMRT phantoms. 18.8.2 Prescribed Dose: 18.8.2.1 The monitor units required to deliver the prescribed dose shall be calculated and submitted. 18.8.2.2 For IMRT techniques: The IMRT Dosimetry Summary Form shall be completed and submitted. The monitor units generated by the IMRT planning system must be independently checked prior to the patient’s first treatment. Measurements in a QA phantom can suffice for a check as long as the plan’s fluence distributions can be recomputed for a phantom geometry. 18.8.2.3 Dose Uniformity: The maximum and minimum doses in the PTV shall be calculated and reported. These may be extracted from isodose distributions, calculated separately or derived from DVH’s. The appropriate dose volume histograms shall be submitted with the QA documentation. 18.8.2.4 Critical Organs: Dose volume histograms for the critical organs indicated in Section 18.7.3 shall be calculated whenever the critical organs are included in the radiation therapy treatment fields. The appropriate dose volume histograms shall be submitted with the QA documentation. 18.8.2.5 Hard copy isodose distributions for the total dose plan in the axial, sagittal, and coronal planes, which includes the isocenter of the planning target volume (PTV) must be submitted. If sagittal and coronal planes are not available, then five axial distributions may be submitted (central axis, two superior and two inferior planes). These dose distributions must include the following:


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A sufficient number of isodose contours should be shown to determine that the dose distribution conforms to the protocol guidelines. These isodoses should be superimposed over treatment planning CT images. However, if such hard copy presents difficulty, similar plots without the gray scale image are acceptable if enough critical contours are identifiable to verify the dose distribution to target volumes and critical normal structures. Specifically, include those volumes for which there are dose volume histograms. 18.9 Quality Assurance Documentation 18.9.1 Within three days of the start of radiotherapy, the following data for 3D or IMRT plans must be submitted for on treatment review:

a. Copies of all diagnostic materials used in defining the target volume. The initial (pre-study) imaging is required. Post-induction chemotherapy scans are required for Stratum B patients. The operative report is required for those patients who undergo resection.

b. A copy of the treatment planning CT. c. Photographs of the patient in the treatment position with the fields marked. d. Prescription sheet for the entire treatment course. e. Copies of the worksheets and/or printouts used for calculation of monitor units. f. Color copies of composite isodose distributions to demonstrate that the dose variation is

within protocol guidelines. The target volume must be clearly shown. g. Documentation of an independent check of the calculated dose if IMRT is used. h. Simulator films (if used as part of the treatment planning process) and digitally

reconstructed radiographs of each treatment portal (if possible). i. First day portal films (or hard copy of real time portal images) if achievable. j. A completed RT-1 Dosimetry Summary Form, or IMRT Dosimetry Summary Form if

IMRT is used. k. One set of orthogonal anterior/posterior and lateral films for isocenter localization for each

group of concurrently treated beams. If portals being submitted contain an orthogonal set, this is sufficient.

l. Beam’s eye views if 3D conformal planning is used. m. A “room view” display of all fields and their angles, if available, should be submitted. n. Dose volume histograms for the total treatment for the GTV, CTV, and PTV and the

normal tissues specified in Section 18.7.3 including the unspecified tissue. o. If IMRT is used and the lower neck/supraclavicular region is treated with a conventional

field, details of the method used to junction the conventional field with the IMRT fields should be provided.

18.9.2 Within one week of the completion of radiotherapy, the following data shall be submitted.

a. The "RT-2 Radiotherapy Total Dose Record" form. b. A copy of the patient's radiotherapy record including the prescription, daily and cumulative

doses to all required areas and dose specification points. c. A completed RT-1 or IMRT Dosimetry Summary Form if any changes have been made

subsequent to submission of the data for initial review. d. Copies of additional DRR's and portal films or hard copy of portal images for any field

modifications made subsequent to the initial review. e. Copies of isodose distributions and calculations performed subsequent to the submission of

the initial review. f. Dose volume histograms (DVH's) for the target volume and normal tissue structures, if

modifications have been made subsequent to the initial review.


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These data should be forwarded to: Quality Assurance Review Center 272 West Exchange Street, Suite 101 Providence, Rhode Island 02903-1025 Telephone: 401-454-4301 FAX: 401-454-4683

Questions regarding the dose calculations or documentation should be directed to:

COG Protocol Dosimetrist Quality Assurance Review Center 272 West Exchange Street, Suite 101 Providence, Rhode Island 02903-1025 Telephone 401-454-4301

Questions regarding the radiotherapy section of this protocol should be directed to:

James Fontanesi, M.D. University of Mississippi Medical Center Department of Radiation Oncology E-mail: [email protected] Phone: (601) 984-2550 Fax: (601) 815-3204

18.10 Definitions of Deviations in Protocol Performance: 18.10.1 Prescription Dose: Minor Deviation: The dose to the prescription isodose level differs from that in the protocol by between 6% and 10% Major Deviation: The dose to the prescription isodose level differs from that in the protocol by more than 10%

18.10.2 Dose Uniformity: Minor Deviation: Conformal Planning: A volume of at least 95% but less than 99% of either PTV receives at least 93% of the prescription dose. Twenty percent of PTV2 receives more than 110% but less than 120% of the prescription dose. Major Deviation: Conformal Planning: Less than 95% of either PTV receives at least 93% of the prescription dose. Twenty percent of PTV2 receives more than 120% of the prescription dose.

18.10.3 Volume: Minor Deviation: Margins less than specified or fields excessively large as deemed by the study. Major Deviation: Transection of tumor (GTV) or potentially tumor bearing area (CTV) (i.e. geographic miss of any part of the GTV).


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APPENDIX I: PERFORMANCE STATUS SCALES/SCORES Performance Status Criteria Karnofsky and Lansky performance scores are intended to be multiples of 10

ECOG (Zubrod) Karnofsky Lansky*

Score Description Score Description Score Description

100 Normal, no complaints, no evidence of disease

100 Fully active, normal.

0 Fully active, able to carry on all pre-disease performance without restriction. 90 Able to carry on normal

activity, minor signs or symptoms of disease.

90 Minor restrictions in physically strenuous activity.

80 Normal activity with effort; some signs or symptoms of disease.

80 Active, but tires more quickly

1

Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work.

70 Cares for self, unable to carry on normal activity or do active work.

70 Both greater restriction of and less time spent in play activity.

60 Required occasional assistance but is able to care for most of his/her needs.

60 Up and around, but minimal active play; keeps busy with quieter activities.

2

Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours

50 Requires considerable assistance and frequent medical care.

50 Gets dressed, but lies around much of the day; no active play, able to participate in all quiet play and activities.

40 Disabled, requires special care and assistance.

40 Mostly in bed; participates in quiet activities.

3

Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.

30 Severely disabled, hospitalization indicated. Death not imminent.

30 In bed; needs assistance even for quiet play.

20 Very sick, hospitalization indicated. Death not imminent.

20 Often sleeping; play entirely limited to very passive activities.

4 Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 10 Moribund, fatal processes

progressing rapidly. 10 No play; does not get out of bed.

*The conversion of the Lansky to ECOG scales is intended for NCI reporting purposes only.


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APPENDIX II: AJCC STAGING SYSTEM FOR NASOPHARYNGEAL CARCINOMA (5TH EDITION)117

Value Definition

T1 Tumor confined to the nasopharynx

T2

Tumor extends to soft tissue of oropharynx and/or nasal fossa T2a: Without parapharyngeal extension T2b: With parapharyngeal extension

T3

Tumor invades bony structures and/or paranasal sinuses

T4

Tumor with intracranial extension and/or involvement of cranial nerves, infratemporal fossa, hypopharynx, or orbit

N0

No regional lymph node metastasis

N1

Unilateral metastasis in lymph node(s) measuring < 6 cm in greatest dimension above the supraclavicular fossa

N2

Bilateral metastasis in lymph node(s) measuring < 6 cm in greatest dimension above the supraclavicular fossa

N3

Metastasis in a lymph node(s) N3a: > 6 cm in greatest dimension N3b: Extension to the supraclavicular fossa

M0

No distant metastasis

M1

Distant metastasis

Stage I

T1

N0

M0

Stage IIA T2a N0 M0 Stage IIB T1

T2a T2b

N1 N1

N0-1

M0 M0 M0

Stage III T1 T2 T3

N2 N2

N0-2

M0 M0 M0

Stage IVA T4 N0-2 M0 Stage IVB Any T N3 M0 Stage IVC Any T Any N M1


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APPENDIX III: TANNER SYSTEM FOR PUBERTAL STAGING118 Tanner Stages of Female Puberty

Stage Breast Pubic Hair 1 Preadolescent; only papillae are

elevated. Preadolescent; vellus hair only (i.e., no pubic hair).

2 Breast bud and papilla are elevated and a small mount is present; areola diameter is enlarged.

Sparse growth of long, slightly pigmented, downy hair or only slightly curled hair, appearing along labia.

3 Further enlargement of breast mound; increased palpable glandular tissue.

Hair is darker, coarser, more curled, and spreads to the pubic junction.

4 Areola and papilla are elevated to form a second mound above the level of the rest of the breast.

Adult-type hair; area covered is less than that in most adults; there is no spread to the medial surface of thighs

5 Adult mature breast; recession of areola to the mound of breast tissue, rounding of the breast mound, and projection of only the papilla is evident.

Adult-type hair with increased spread to medial surface of thighs; distribution is as an inverse triangle.

Tanner Stages of Male Puberty

Testicular Size Stage Genital Stage Length (cm) (Mean ± SD)

Volume(mL)

Pubic Hair Stage

1 Preadolescent. Testes, scrotum, and penis are about the same size and proportion as those in early childhood.

2.0 ± 0.5 2 Preadolescent. Vellus over the pubes is no further developed than that over the abdominal wall, i.e., no pubic hair.

2 Scrotum and testes have enlarged, and there is a change in the texture of scrotal skin and some reddening of scrotal skin.

2.7 ± 0.7 5 There is sparse growth of long, slightly pigmented, downy hair, straight or only slightly curled, appearing chiefly at base of penis.

3 Growth of the penis has occurred, at first mainly in length but with some increase in breadth. There has been further growth of the testes and the scrotum.

3.4 ± 0.8 10 Hair is considerably darker, coarser, and more curled and spreads sparsely over junction of pubes.

4 The penis is further enlarged in length and breadth, with development of glans. The testes and the scrotum are further enlarged. There is also further darkening of scrotal skin.

4.1 ± 1.0 20 Hair is now adult in type, but the area covered by it is smaller than that in most adults. There is no spread to the medial surface of the thighs.

5 Genitalia are adult in size and shape. No further enlargement takes place after stage 5 is reached.

5.0 ± 0.5 29 Hair is adult in quantity and type, distributed as an inverse triangle. There is spread to the medial surface of the thighs but not up the linea alba or elsewhere above the base of the inverse triangle.


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76. Cassatt DR, Fazenbaker CA, Kifle G, et al: Preclinical studies on the radioprotective efficacy and pharmacokinetics of subcutaneously administered amifostine. Semin Oncol 29 (suppl 19):2-8, 2002

77. Bardet E, Martin L, Calais G, et al: Preliminary data of the GORTEC 2000-02 phase III trial comparing intravenous and subcutaneous administration of amifostine for head and neck tumors treated by external radiotherapy. Semin Oncol 29 (suppl 19):57-60, 2002

78. Adamson PC, Balis FM, Belasco JE, et al: A phase I trial of amifostine (WR-2721) and melphalan in children with refractory cancer. Cancer Res 55:4069-72, 1995

79. Fouladi M, Stempak D, Gammon J, et al: Phase I trial of a twice-daily regimen of amifostine with ifosfamide, carboplatin, and etoposide chemotherapy in children with refractory carcinoma. Cancer 92:914-23, 2001

80. Marina N, Malogolowkin M, London WB, et al: Amifostine does not protect against the ototoxicity with high-dose cisplatin, etoposide and bleomycin (HD-PEB) in pediatric germ cell tumors (PGCT): A PGCT Intergroup Study. Proc Annu Meet Am Soc Clin Oncol 22:798, 2003

81. Chien Y-C, Chen J-Y, Liu M-Y, et al: Serologic markers of Epstein-Barr virus infection and nasopharyngeal carcinoma in Taiwanese men. N Engl J Med 345:1877-1882, 2001


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82. Niedobitek G, Agathangelou A, Nicholls JM: Epstein-Barr virus infection and the pathogenesis of nasopharyngeal carcinoma:viral gene expression, tumour cell phenotype, and the role of lymphoid stroma. Semin Cancer Biol 7:165-174, 1996

83. Raab-Traub N, Flynn K: The structure of the termini of the Epstein-Barr virus as a marker of clonal cellular proliferation. Cell 47:883-889, 1986

84. Tao Q, Srivastava G, Chan A CL, et al: Evidence for lytic infection by Epstein-Barr virus in mucosal lymphocytes instead of nasopharyngeal epithelial cells in normal individuals. J Med Virol 45:71-77, 1995

85. Sam CK, Brooks LA, Niedobitek G, et al: Analysis of Epstein-Barr virus infection in naospharyngeal biopsies from a group at high risk of nasopharyngeal carcinoma. Int J Cancer 53:957-962, 1993

86. Niedobitek G, Hansmann ML, Herbst H, et al: Epstein-Barr virus anc carcinomas: undifferentiated carcinomas but not squamous cell carcinomas of the nasopharynx are regularly associated with the virus. J Pathol 165:17-24, 1991

87. Weiss LM, Mohaved LA, Butler AE, et al: Analysis of lymphoepithelioma and lymphoepithelioma-like carcinomas for Epstein-Barr virus by in-situ hybridization. Am J Surg Pathol 13:625-631, 1989

88. Pathmanathan R, Prasad U, Sadler R, et al: Clonal proliferation of cells infected with Epstein-Barr virus in preinvasive lesions related to nasopharyngeal carcinoma. N Engl J Med 333:693-698, 1995

89. Young L, Dawson C, Clark D, et al: Epstein-Barr virus gene expression in nasopharyngeal carcinoma. J Gen Virol 69:1051-1065, 1988

90. Murray PG, Niedobitek G, Kremmer E, et al: In situ detection of the Epstein-Barr virus-encoded nuclear antigen 1 in oral hairy leukoplakia and virus-associated carcinomas. J Pathol 178:44-47, 1996

91. Hording U, Nielsen HW, Albeck H, et al: Nasopharyngeal carcinoma - histopathological types and association with Epstein-Barr virus. Eur J Cancer Oral Oncol 29B:137-139, 1993

92. Vaughan TL, Shapiro JA, Burt RD, et al: Nasopharyngeal cencer in a low-risk population - defining risk factors by histological type. Cancer Epidemiol Biomarkers Prev 5:587-593, 1996

93. Chen XQ, Stroun M, Magnenat J-L, et al: Microsatellite alterations in plasma DNA of small cell lung cancer. Nat Med 2:1033-1035, 1996

94. Nawroz H, Koch W, Anker P, et al: Microsatelite alterations in serum DNA of head and neck cancer patients. Nat Med 2:1035-1037, 1996

95. Lo Y, Chay L YS, Lo K-W, et al: Quantitative analysis of cell-free Epstein-Barr virus DNA in plasma of patients with nasopharyngeal carcinoma. Cancer Res 59:1188-1191, 1999

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97. Lo Y, Chan L YS, Chan A TC, et al: Quantitative and temporal correlation between circulating cell-free Epstein-Barr virus DNA and tumor recurrence in nasopharyngeal carcinoma. Cancer Res 59:5452-5455, 1999

98. Lo Y, Chan A TC, Chan L YS, et al: Molecular prognostication of nasopharyngeal carcinoma by quantitative analysis of circulating Epstein-Barr virus DNA. Cancer Res 60:6878-6881., 2000

99. Chan A TC, Lo Y, Zee B, et al: Plasma Epstein-Barr virus DNA and residual disease after radiotherapy for undifferentiated nasopharyngeal carcinoma. J Natl Cancer Inst 94:1614-1619, 2002

100. Kubonishi I, Takehara N, Iwata J, et al: Novel t(15;19)(q15;p13) chromosome abnormality in a thymic carcinoma. Cancer Res 2003 51:3327-3328, 1991

101. Kees UR, Mulcahy MT, Willoughby ML: Intrathoracic carcinoma in an 11-year-old girl showing a translocation t(15;19). Am J Pediatr Hematol Oncol 13:459-464, 1991

102. Lee AC, Kwong YI, Fu KH, et al: Disseminated mediastinal carcinoma with chromosomal translocation (15;19). A distinctive clinicopathologic syndrome. Cancer 72:2273-2276, 1993


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103. Dang TP, Gazdar AF, Virmani AK, et al: Chromosome 19 translocation, over-expression of Notch3, and human lung cancer. J Natl Cancer Inst 92:1355-1357, 2000

104. Vargas SO, French CA, Faul PN, et al: Upper respiratory tract carcinoma with chromosomal translocation 15;19. evidence for a distinct disease entity of young patients with a rapidly fatal course. Cancer 92:1195-1203, 2001

105. French CA, Miyoshi I, Aster JC, et al: BRD4 bromodomain gene rearrangement in aggressive carcinoma with translocation t(15;19). Am J Pathol 159:1987-1992, 2001

106. Toretsky JA, Jenson J, Sun CC, et al: Translocation (11;15;19): a highly specific chromosome rearrangement associated with poorly differentiated thymic carcinoma in young patients. Am J Clin Oncol 26:300-306, 2003

107. French CA, Kutok JL, Faquin WC, et al: Midline carcinoma of children and young adults with NUT rearrangement. J Clin Oncol:(I press), 2004

108. French CA, Miyoshi I, Kubonishi I, et al: BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma. Cancer Res 63:304-307, 2003

109. Lee N, Xia P, Quivey JM, et al: Intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: An update of the UCSF experience. In J Radiat Oncol Biol Phys 53:12-22, 2002

110. Kam M KM, Chau R MC, Suen J, et al: Intensity-modulated radiotherapy in nasopharyngeal carcinoma: Dosimetric advantage over conventional plans and feasibility of dose escalation. Int J Radiat Oncol Biol Phys 56:145-157, 2003

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SAMPLE INFORMED CONSENT FORM / PARENTAL PERMISSION FOR PARTICIPATION IN RESEARCH

ARAR0331, Treatment of Childhood Nasopharyngeal Carcinoma with Neoadjuvant Chemotherapy and Concomitant Chemoradiotherapy If you are a parent or legal guardian of a child who may take part in this study, permission from you is required and the assent (agreement) of your child may be required. When the word “you” appears in this consent from, it refers to your son or daughter. This is a clinical trial, a type of research study. Your study doctor will explain the clinical trial to you. Clinical trials include only people who choose to take part. Please take your time to make your decision about taking part. You may discuss your decision with your friends, family or other trusted advisor. You can also discuss it with your health care team. If you have any questions, you can ask your study doctor for more explanation. This study is being carried out by the Children’s Oncology Group (COG). The COG is an international research group that consists of more than 200 hospitals that treat children with cancer in the United States, Canada, Australia, New Zealand, the Netherlands and Switzerland. WHAT IS THIS STUDY ABOUT? You are being asked to take part in this study because you have a rare malignant (cancerous) tumor called nasopharyngeal carcinoma (NPC). The tumor is in the nasopharynx, the upper part of the throat behind the nose. Air passes through it to the lungs and food passes through it as it is swallowed. An opening on each side of the nasopharynx leads into an ear. Because of where it sits, an NPC-type tumor cannot usually be totally removed by surgery. Standard (usual) treatment for people diagnosed very early is radiation therapy only. Others, with more advanced disease get chemotherapy and radiation therapy. These people commonly have larger tumors, or cancer that has spread to the lymph nodes of the neck. This study will use radiation therapy, chemotherapy and chemoradiotherapy.

• Radiation therapy is the use of high-energy x-rays or other types of radiation to kill cancer cells. • Chemotherapy is the use of anti-cancer drugs to stop the growth of cancer cells. • Chemoradiotherapy is chemotherapy given at the same time as radiation therapy

This model informed consent form has been reviewed by the DCT/NCI and is the official consent document for this study. Institutions should use the sections of this document which are in bold type in their entirety. Editorial changes to these sections may be made as long as they do not change information or intent. If the institutional IRB insists on making deletions or more substantive modifications to any of the sections in bold type, they must be justified in writing by the investigator at the time of the institutional audit.

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WHY IS THIS STUDY BEING DONE? Recent studies done in adults have shown that chemoradiotherapy works better than radiation therapy followed by chemotherapy. Studies in adults have also shown that the drug amifostine can help prevent the loss of, and thickening of, saliva. This side effect of radiation therapy to the head and neck causes dryness of the mouth which leads to dental problems, problems swallowing and infections. The goals of this study are: 1) To see if a combination of chemotherapy followed by chemoradiotherapy works better at

treating children with advanced NPC than the standard therapy. 2) To see how well amifostine protects children against dry mouth when given daily before

radiation therapy. HOW MANY PEOPLE WILL TAKE PART IN THE STUDY? About 160 people will take part in this study. WHAT WILL HAPPEN IF I TAKE PART IN THIS RESEARCH STUDY? Before you start the study You will need to have the following exams, tests or procedures to find out if you can be in the study. These exams, tests or procedures are part of regular cancer care and may be done even if you do not join the study. If you have had some of them recently, they may not need to be repeated. This will be up to your study doctor.

• Physical exam • Blood tests • Urine tests • Kidney function tests • Liver function tests • Bone scan • MRI of the head and neck (MRI is Magnetic Resonance Imaging, the use of magnetic waves to

look at soft tissues of the body) • CT scan of the chest (CT is Computed Tomography, a CT scan takes a picture of the inside of

your body) • Pregnancy test (if you are a female of childbearing potential)

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During the study If the exams, tests and procedures show that you can be in the study, and you choose to take part, then you will need the following tests and procedures. They are part of regular cancer care.

• Hearing tests • Measurements of saliva production • Dental x-rays • Hormone and Growth/Development tests • Imaging Studies (MRI and CT scans) • Bone scans • Kidney function tests

You will need these tests and procedures that are part of regular cancer care. They are being done more often because you are in this study.

• Hearing tests • Measurements of saliva production • Imaging Studies (MRI and CT scans) • Bone scan • Kidney function tests

You will need these tests and procedures to see how being on the study is affecting your body.

• Hearing tests • Measurements of saliva production • Dental x-rays • Kidney function tests

Some of the tissue already taken and copies of the films used to make the diagnosis of your disease will be sent to central review centers as part of COG quality control. The central review of tissue and films to confirm a diagnosis helps to make sure that an acceptable standard of expertise is maintained at each institution that is a member of the COG. You will not get any information from these reviews. STUDY TREATMENT You will be treated in 1 of 2 ways depending on the stage of the disease:

• Treatment Group 1: Subjects with early stages of disease will get radiation therapy only.

• Treatment Group 2: Subjects with advanced disease, or disease that has spread, will first get chemotherapy alone and then get a combination of chemotherapy and radiation therapy.

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Treatment Group 1 You will get radiation therapy to the head and neck 5 days a week for about 7 or 8 weeks. You will also get the drug amifostine every day before getting radiation therapy. Amifostine will be given by an injection under the skin 15-30 minutes before radiation therapy starts. Some larger subjects will get 2 doses a day. Although amifostine is not being used as a chemotherapy drug it may also cause nausea and vomiting, so you will be given some drugs to prevent these side effects. Also, amifostine may cause a drop in blood pressure and some drop in blood calcium, so your blood pressure and the blood calcium will be measured often. You may need some extra fluids to increase your blood pressure, and extra calcium. If you are taking blood pressure medicine you may be told not to take it on the morning of your treatment. Other drugs will be given to help prevent or manage any side effects that may be caused by the treatment. Also, because radiation causes thickened saliva and dry mouth, you will be given a drug (pilocarpine) that helps the production of saliva. Pilocarpine, along with mouth washes, will help to keep your mouth moist and protect you from infections. You will also get fluoride to protect your teeth. Treatment Group 2 You will first get Induction therapy, over a period of 9 weeks, in order to shrink the tumor. Then you will get Consolidation therapy, also over a period of about 9 weeks.

• Induction therapy is the use of chemotherapy to reduce/get rid of the cancer. If the cancer goes away then the disease will be in “remission”.

• Consolidation therapy is treatment intended to make the cancer stay in remission. In this study both chemotherapy and radiation therapy will be given

Your study doctor will evaluate you after Induction therapy and after Consolidation therapy. If he/she thinks that surgery could be used to remove the tumor then he/she will talk about it with you. Induction therapy: Induction therapy will be 3 cycles of chemotherapy. Each cycle will last 21 days. You will receive the drugs cisplatin (on Day 1 of each cycle) and 5-fluorouracil (on Days 1 to 4 of each cycle) as described below. These drugs have been used in the past for NPC and are likely to be the standard treatment, given even if you do not take part in this study.

Drug Route Dose Days Cisplatin (CDDP)

IV over 6 hours 80 mg/m2/dose Days 1, 22, 43

5-Fluorouracil (FU)

IV continuous infusion

1000 mg/m2/day Days 1-4, 22-25, 43-46

IV means the drug will be given by a needle or tubing inserted into a vein Other drugs will be given to help prevent or manage the side effects of the chemotherapy drugs, like nausea and vomiting.

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Consolidation therapy: The chemotherapy part will be 3 cycles of cisplatin that last 21 days each. While you are getting chemotherapy you will also get radiation therapy to the head and neck area. This radiation therapy will be given 5 days a week for about 7 to 8 weeks. The amount of radiation therapy you get will depend upon how well the tumor responds to Induction therapy. On the days you get radiation therapy you will also get the drug amifostine. Amifostine will be given by an injection under the skin 15-30 minutes before radiation therapy starts. Some larger subjects will get 2 doses a day. Although amifostine is not being used as a chemotherapy drug it may also cause nausea and vomiting, so you will be given some drugs to prevent these side effects. Also, amifostine may cause a drop in blood pressure and some drop in blood calcium, so your blood pressure and the blood calcium will be measured often. You may need some extra fluids to increase your blood pressure, and extra calcium. If you are taking blood pressure medicine you may be told not to take it on the morning of your treatment. You will get cisplatin on Day one of each cycle, as follows:

Drug Route Dose Days Cisplatin (CDDP)

IV over 6 hours 100 mg/m2/dose Days 1, 22, 43

IV means the drug will be given by a needle or tubing inserted into a vein Other drugs will be given to help prevent or manage any side effects that may be caused by the treatment. Drugs will be given to prevent nausea and vomiting that may occur after you get cisplatin. Also, because radiation causes thickened saliva and dry mouth, you will be given a drug (pilocarpine) that helps the production of saliva. Pilocarpine, along with mouth washes, will help to keep your mouth moist and protect you from infections. You will also get fluoride to protect your teeth. A treatment plan for this study is provided on the following page.

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TREATMENT PLAN

STUDY ENTRY

GROUP 1 Subjects with an

early stage of NPC

GROUP 2 Subjects with a

later stage of NPC

XRT with

Amifostine

INDUCTION Chemotherapy*

FOLLOW UP

Disease worsens

OFF STUDY THERAPY

FOLLOW UP

CONSOLIDATION THERAPY: Chemotherapy**

+ XRT with Amifostine

Response to therapy or

Disease is no worse

OFF STUDY THERAPY

FOLLOW UP

EVALUATION#

EVALUATION#

NPC = nasopharyngeal carcinoma. XRT = radiation therapy. * Induction chemotherapy will use the drugs cisplatin and fluorouracil. ** Consolidation chemotherapy will use the drug cisplatin. # If your study doctor thinks that surgery can be used to remove the cancer then he/she will talk about it with you.

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WHEN I AM FINISHED THE STUDY TREATMENT… You will have a number of tests and procedures as part of your follow up to treatment. We will use these tests to watch for improvements, monitor side effects and look for any signs that the cancer has come back. You will have a physical exam and standard lab tests, including blood tests, plus scans (MRI and CT scans) of the affected area every 3 months during the first year after treatment. These tests will only be done every 6 months for the second and third years after treatment. After 3 years you should have a physical exam and standard lab tests every year. In addition to the tests to evaluate the cancer, you will have other tests to monitor the effects of the treatment on your body. These tests will be done more often because you are taking part in this study:

• We will measure your saliva production at 3, 6 and 12 months after treatment. • You will have a hearing test at 6 and 12 months after treatment, and again after 2 and 3 years. • We will monitor your growth and development by measuring certain hormone levels twice in the

first year after treatment, and then once a year after that. • A dental exam will be done every 6 months for the first year, and then once a year after that. • Subjects who are in Treatment Group 2 will also have a kidney function test at 6 and 12 months

after therapy. HOW LONG WILL I BE IN THE STUDY? Treatment Group 1: You will get radiation therapy for about 7 to 8 weeks. Then the study doctor will ask you to come back for follow-up exams for at least 3 years. Treatment Group 2: You will get therapy for about 16 to 18 weeks. Then the study doctor will ask you to come back for follow-up exams for at least 3 years. Both Treatment Groups: We would like to continue to find out about your health for about 10 years after the study closes to new patients. We would like to do this by calling you on the telephone once a year to see how you are doing. Keeping in touch with you and checking on how your health is every year for a while after the study closes helps us understand the long-term effects of the study. CAN I STOP BEING IN THE STUDY? Yes. You can decide to stop at any time. Tell the study doctor if you are thinking about stopping or decide to stop. He or she will tell you how to stop safely. It is important to tell the study doctor if you are thinking about stopping so any risks from the chemotherapy or radiation therapy can be reviewed by your doctor. Another reason to tell your doctor that you are thinking about stopping is to discuss what follow-up care and testing could be most helpful for you. The study doctor may stop you from taking part in this study at any time if he/she believes it is in your best interest; or if the study is stopped.

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WHAT SIDE EFFECTS OR RISKS CAN I EXPECT FROM BEING IN THE STUDY? You may have side effects while on the study. Everyone taking part in the study will be watched carefully for any side effects. However, doctors don’t know all the side effects that may happen. Side effects may be mild or very serious. Your health care team may give you medicines to help lower the side effects. Many side effects go away soon after you stop taking the chemotherapy drugs and/or stop getting radiation therapy. In some cases, side effects can be serious, long lasting, or may never go away. There also is a risk of death. Both radiation therapy and chemotherapy have been linked to the development of other cancers. This means that some of the people that get rid of this cancer may get a second kind of cancer. The risk is very small. Subjects in Treatment Group 1 would normally get radiation therapy. So, the only added risks of being on this study are the side effects of receiving amifostine. These include nausea, vomiting, low blood pressure and dizziness. A complete list is provided in the table on the next page. Subjects in Treatment Group 2 would normally get chemotherapy and radiation therapy, but not at the same time. Since you will get chemotherapy during radiation therapy, this may increase any damage to the lining of the mouth, and increase the risk of hearing loss. Also, amifostine may cause side effects like nausea, vomiting, low blood pressure and dizziness. A complete list of the known side effects caused by amifostine is provided in the table on the next page. In this study you may get a lower dose of radiation therapy than normal. The dose that you get will depend upon your response to therapy. If you have a good response you will get less radiation. We think that the lower dose will be effective and cause less side effects. But the lower dose may not be as effective and could increase the chance that the tumor will return.

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**Possible side effects or risks for ALL SUBJECTS (Treatment Groups 1 and 2)** Risks and side effects related to amifostine (when given as an injection under the skin) include:

Likely Less Likely Rare but serious • Mild rashes • Lowering of the calcium

in the blood • Sneezing • Mild pain, bruising and

redness at the injection site

• Sleepiness • Warm or flushed feeling • Dizziness • Anxiety • Low amount of

magnesium in the blood • Nausea and vomiting • A temporary drop in

blood pressure • Chills • Hiccups

• Severe allergic reactions • Convulsions • Kidney failure • Severe skin rashes

Risks and side effects related to pilocarpine include:

Likely Less Likely Rare but serious • Sweating

• Facial flushing with red cheeks

• Nervousness • Excessive tearing from the

eyes • Runny nose • Upset and irritated stomach

with heartburn • Dizziness • Frequent urination • Nausea or vomiting • Headache • Chills • Diarrhea and abdominal

cramping • Tremors • Visual disturbances that may

decrease vision at night • Increased sputum

• Asthma like breathing difficulty

• Abnormal heart beat which may make the heart beat faster or slower

• High blood pressure • Severe allergic reaction

which can be life threatening with shortness of breath, low blood pressure, rapid heart rate, chills and fever.

Possible side effects of radiation therapy to the head and neck include: Short term-side effects:

• Redness, irritation, and sores in the mouth • Dry mouth or thickened saliva • Difficulty in swallowing • Changes in taste • Nausea • Loss of taste, which may decrease appetite and affect nutrition

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Long-term side effects:

• Dry mouth and thickened saliva • Tooth decay • Gum infections • Difficulty swallowing • Earaches, caused by hardening of the ear wax • Swelling or drooping of the skin under the chin and changes in the texture of the skin • The jaw may feel stiff and subjects may not be able to open their mouth as wide as before

treatment. You should talk to your study doctor about any side effects that you have while taking part in the study. For more information about risks and side effects, ask your study doctor.

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**More Possible side effects or risks for subjects in TREATMENT GROUP 2 ONLY** Subjects in Treatment Group 2 have added risks because they will get chemotherapy. One of the most common side effects of chemotherapy is lowered blood cell counts.

• A lowered red blood cell count will make you feel weak and tired (anemia). • A lowered white blood cell count will lower your resistance to infection. • A lowered platelet count will cause an increased risk of bleeding.

The following kinds of side effects may result from the chemotherapy drugs used in this study: Risks and side effects related to cisplatin include:

Likely Less Likely Rare but serious • Nausea and vomiting • fewer red blood cells and

white blood cells and platelets in the blood o a low number of red

blood cells can make you feel tired and weak

o a low number of white blood cells can make it easier to get infections

o a low number of platelets causes you to bruise and bleed more easily

• Abnormal levels of magnesium in the body which may require that you take extra magnesium by mouth or in the vein

• Loss of appetite • Damage to the ear causing

difficulty in hearing high pitched sounds

• Temporary and mild increases in levels of certain chemicals in the blood because the kidney is not working as well as normal

• Abnormal levels of certain salts in the body like sodium, calcium, potassium and phosphate

• Metallic taste • Rash • Numbness and tingling in the

fingers and toes • Temporary changes in vision • Damage to the ear causing

hearing loss, balance problems and ringing in the ears

• Elevation in the blood of certain enzymes found in the liver

• Inflammation and discomfort in the vein through which the medicine was given

• Allergic reactions which may be severe and life-threatening, causing difficulty in breathing, rapid heart rate, facial swelling and or a drop in blood pressure

• Damage to the kidney which may be permanent

• Deafness • Seizures • Damage to the vision

which could lead to blurred vision, blue-green color blindness and to loss of vision which usually goes away after stopping the drug

• Decrease in muscle and nerve reflexes that may affect normal functions such as walking

• Leukemia later in life

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Risks and side effects related to 5-fluorouracil include:

Likely Less Likely Rare but Serious • Nausea • Vomiting • Metallic taste • Loss of appetite • Fewer red blood cells and

white blood cells and platelets in the blood o a low number of red

blood cells can make you feel tired and weak

o a low number of white blood cells can make it easier to get infections

o a low number of platelets causes you to bruise and bleed more easily

• Temporary hair loss

• Diarrhea • Darkening of the skin and

the vein through which the drug is given

• Increased risk of sunburn • Dry skin • Inflammation and/or

sores in the mouth, throat and/or esophagus

• Rash • Headache • Severe rash with redness

and pain on the palms of the hands and soles of the feet

• Nail changes including loosening of the nails from the nail bed, changes in color, pain and thickening of the nails

• Tearing, eye irritation/soreness, and blurred vision

• Severe allergic reaction which can be life threatening with shortness of breath, low blood pressure, rapid heart rate chills and fever

• Low blood pressure • Chest pain • Abnormal electrical

function of the heart when measured by the EKG machine

• Irritation of the rectum which can cause pain or bleeding while having a bowel movement

• Damage to the brain that may result in an unsteady walk, memory loss, speech disturbances, confusion, seizures or coma

• Severe damage to the stomach lining that could lead to ulcerations of the bowels with abdominal pain and bloody diarrhea

Reproductive risks: Because the drugs in this study can affect an unborn baby you should not become pregnant or father a baby while on this study. Women should not breastfeed a baby while on this study. It is important you understand that you need to use birth control while on this study. Check with your study doctor about what kind of birth control methods to use and how long to use them. Some methods might not be approved for use in this study. If you are a woman, we will give you a pregnancy test before starting treatment. The drugs used in this study may make you unable to have children in the future, although this risk is low. For more information about risks and side effects, ask your study doctor.

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ARE THERE BENEFITS TO TAKING PART IN THE STUDY? Taking part in this study may or may not improve your health. While doctors hope that the treatments used will be more useful against cancer compared to the usual treatment, there is no proof of this yet. The information from this study will help doctors learn more about: the effects of giving chemotherapy and radiation therapy together, and any protection that amifostine can give against the side effects of radiation therapy. This information could help future cancer patients. Some subjects in Treatment Group 2 will get a lower dose of radiation than is given to patients not getting chemotherapy along with radiation therapy. This might offer the benefit of less long-term side effects. WHAT OTHER CHOICES DO I HAVE IF I DO NOT TAKE PART IN THIS STUDY? Your other choices may include:

• Getting treatment or care for your cancer without being in a study • Taking part in another study

Talk to your doctor about your choices before you decide if you will take part in this study.

WILL MY MEDICAL INFORMATION BE KEPT PRIVATE? We will do our best to make sure that the personal information in your medical record will be kept private. However, we cannot guarantee total privacy. Your personal information may be given out if required by law. If information from this study is published or presented at scientific meetings, your name and other personal information will not be used. It is very unlikely that the research testing might uncover important information about you or your child’s current or future health. If this unlikely event occurs, the researchers may contact your child’s doctor through COG’s Data Center about what the research test results might mean. Only the doctor will be notified and the information will remain confidential. Your child’s doctor may discuss this unexpected finding with you, and may recommend consultation with a genetic counselor and/or repeat testing in a clinical (not research) laboratory if necessary. It is possible that your child’s doctor may recommend that no additional action is necessary The Children’s Oncology Group has a Certificate of Confidentiality from the federal government, which will help us protect the privacy of our research subjects. Information about the certificate is attached at end of this consent. Organizations that may look at and/or copy your medical records for research, quality assurance, and data analysis include:

• The Children’s Oncology Group • Representatives of the National Cancer Institute (NCI), Food and Drug Administration

(FDA), and • other U.S. and international governmental regulatory agencies involved in keeping research

safe for people • The Institutional Review Board of this hospital (IRB) • The Pediatric Central Institutional Review Board (CIRB) of the National Cancer Institute

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WHAT ARE THE COSTS OF TAKING PART IN THIS STUDY? You and/or your health plan/ insurance company will need to pay for some or all of the costs of treating your cancer in this study. Some health plans will not pay these costs for people taking part in studies. Check with your health plan or insurance company to find out what they will pay for. Taking part in this study may or may not cost your insurance company more than the cost of getting regular cancer treatment. You will not be paid for taking part in this study. For more information on clinical trials and insurance coverage, you can visit the National Cancer Institute’s Web site at http://cancer.gov/clinicaltrials/learning/insurance-coverage . You can print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site. Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to send you a free copy. WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THIS STUDY? It is important that you tell your study doctor, __________________ [investigator’s name(s)], if you feel that you have been injured because of taking part in this study. You can tell the doctor in person or call him/her at __________________ [telephone number]. You will get medical treatment if you are injured as a result of taking part in this study. You and/or your health plan will be charged for this treatment. The study will not pay for medical treatment. WHAT ARE MY RIGHTS IF I TAKE PART IN THIS STUDY? Taking part in this study is your choice. You may choose either to take part or not to take part in the study. If you decide to take part in this study, you may leave the study at any time. No matter what decision you make, there will be no penalty to you and you will not lose any of your regular benefits. Leaving the study will not affect your medical care. You can still get your medical care from our institution. We will tell you about new information or changes in the study that may affect your health or your willingness to continue in the study. In the case of injury resulting from this study, you do not lose any of your legal rights to seek payment by signing this form. WHO CAN ANSWER MY QUESTIONS ABOUT THE STUDY? You can talk to your study doctor about any questions or concerns you have about this study. Contact your study doctor __________________ [name(s)] at __________________ [telephone number]. For questions about your rights while taking part in this study, call the ________________________ [name of center] Institutional Review Board (a group of people who review the research to protect your rights) at __________________ (telephone number). [Note to Local Investigator: Contact information for patient

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representatives or other individuals in a local institution who are not on the IRB or research team but take calls regarding clinical trial questions can be listed here.] OPTIONAL BIOLOGY STUDIES This section of the informed consent form is about the additional research studies that are being done. You may take part in these additional studies if you want to. You can still be a part of the main study even if you say “no” to taking part in any of these additional studies. Please read the information below and think about your choices. After making your decisions, circle “Yes” or “No”, then add your initials and the date after your answer. No matter what you decide to do, it will not affect your care. If you have any questions, please talk to your doctor or nurse, or call our research review board at the IRB’s phone number included in this consent. We would like to use information collected on this study to answer some research questions that might benefit future cancer patients. You can choose to take part in the main study without taking part in this optional research. The reason for the optional research studies is that investigators have found a link between the Epstein-Barr virus (EBV) and NPC. (EBV is a common virus that remains inactive in most people but has been linked with certain cancers, including NPC.) Studies have shown that people with NPC often have levels of EBV in their blood that can be measured. These levels may be able to tell us about the person’s likely response to treatment and chance of cure. If we find that the EBV levels can be used to predict a persons’s ability to be cured, then we may be able to change the treatment for certain cancer patients in the future. Not every case of NPC is linked with EBV. Some of these cancers can be linked to a certain genetic feature, called a “NUT rearrangement”. It is possible that the disease may respond differently to treatment depending on whether it is linked to the presence of EBV or to the NUT rearrangement. The additional research goals are:

• To look at the presence of EBV in NPC tumors • To see if the levels of EBV in the blood can be used to help predict the likely outcome of patients

with NPC. • To look at the presence of the NUT rearrangement in NPC tumors. • To better understand the genetic make-up of tumor cells and the blood cells of subjects with NPC.

If you agree to take part in the optional research, we will take a blood sample at the following times:

• before you start treatment (at diagnosis) • once or twice during treatment • at the end of your therapy • once or twice during the first year after completing therapy • if the disease comes back after therapy

The exact timing of the samples will depend upon the therapy you have. The amount of blood removed each time will be about 1 teaspoon. The test for NUT will use leftover tissue, if available, from your diagnostic procedure (biopsy or surgery). It will not require you to have any additional procedures performed while on this study.

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These tests will be performed at a COG laboratory. The results of these studies will not directly affect your care, therefore the results of the tests will not become part of your health records. These tests are optional and will only be done if you agree. You may choose not to allow these optional genetic tests. Your decision will not affect your participation in this study and will not affect your health or treatment. 1. I agree to allow leftover tissue (if available) and extra blood samples to be used for research to determine the importance of EBV, the NUT rearrangement and certain genetic factors that are present in NPC tumors and the blood of subjects with these tumors.

#1: Yes No ________ / _______ Initials Date

We are also asking your permission to save leftover tumor tissue and blood samples from your diagnosis and treatment in a special tumor bank. A tumor bank is a lab where tumor and blood specimens are kept for future research studies.

Consent Form for Use of Tissue for Research

About Using Tissue for Research You are going to have a biopsy (or surgery) to see if you have cancer. Your doctor will remove some body tissue to do some tests. The results of these tests will be given to you by your doctor and will be used to plan your care. We would like to keep some of the tissue that is leftover for future research. If you agree, this tissue will be kept and may be used in research to learn more about cancer and other diseases. Please read the information sheet called "How is Tissue Used for Research?" to learn more about tissue research. [Note to Local Investigator: This information sheet is available on the COG web site at: https://members.childrensoncologygroup.org/prot/reference_materials.asp under CONSENTS AND IRB FORMS] Your tissue may be helpful for research whether you do or do not have cancer. The research that may be done with your tissue is not specifically to help you. It might help people who have cancer and other diseases in the future. Reports about research done with your tissue will not be given to you or your doctor. These reports will not be put in your health record. The research will not have an effect on your care. Things to Think About The choice to let us keep the leftover tissue for future research is up to you. No matter what you decide to do, it will not affect your care. If you decide now that your tissue can be kept for research, you can change your mind at any time. Just contact us and let us know that you do not want us to use your tissue. Then any tissue that remains will no longer be used for research. In the future, people who do research may need to know more about your health. While this institution may give them reports about your health, it will not give them your name, address, phone number, or any other information that will let the researchers know who you are.

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Sometimes tissue is used for genetic research (about diseases that are passed on in families). Even if your tissue is used for this kind of research, the results will not be put in your health records. Your tissue will be used only for research and will not be sold. The research done with your tissue may help to develop new products in the future. Benefits The benefits of research using tissue include learning more about what causes cancer and other diseases, how to prevent them, and how to treat them. Subjects will not profit from any new product developed from research done on their specimens. Risks The greatest risk to you is the release of information from your health records. We will do our best to make sure that your personal information will be kept private. The chance that this information will be given to someone else is very small. Making Your Choice Please read each sentence below and think about your choice. After reading each sentence, circle "Yes" or "No" and write your initials in the space provided. If you have any questions, please talk to your doctor or nurse, or call our research review board at IRB's phone number.

No matter what you decide to do, it will not affect your care.

1. My tissue may be kept for use in cancer research.

YES NO ________ / _______ Initials Date

2. My tissue may be kept for use in research to learn about other health problems (for example: diabetes, Alzheimer disease, or heart disease).


3. Someone may contact me in the future to ask me to take part in more research.


WHERE CAN I GET MORE INFORMATION? You may call the National Cancer Institute's Cancer Information Service at:

• 1-800-4-CANCER (1-800-422-6237) or TTY: 1-800-332-8615 You may also visit the NCI Web site at: http://cancer.gov/

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• For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/ • For NCI’s general information about cancer, go to: http://cancer.gov/cancerinfo/

You will get a copy of this form. You will be given a copy of the protocol (full study plan) upon request. If you want more information about this study, ask your study doctor. SIGNATURE I have been given a copy of all _____ [insert total of number of pages] pages of this form. I have read it or it has been read to me. I understand the information and have had my questions answered. I agree to take part in this study. SUBJECT ________________________________ DATE _________________________ PARENT/LEGAL GUARDIAN ________________________________ DATE _____________________________________

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Attachment: Information about the Certificate of Confidentiality

The Children's Oncology Group has received a Certificate of Confidentiality from the federal government, which will help us protect the privacy of our research subjects. The Certificate protects against the involuntary release of information about subjects collected during the course of our covered studies. The researchers involved in the studies cannot be forced to disclose the identity or any information collected in the study in any legal proceedings at the federal, state, or local level, regardless of whether they are criminal, administrative, or legislative proceedings. However, the subject or the researcher may choose to voluntarily disclose the protected information under certain circumstances. For example, if the subject or his/her guardian requests the release of information in writing, the Certificate does not protect against that voluntary disclosure. Furthermore, federal agencies may review our records under limited circumstances, such as a DHHS request for information for an audit or program evaluation or an FDA request under the Food, Drug and Cosmetics Act. The Certificate of Confidentiality will not protect against the required reporting by hospital staff of information on suspected child abuse, reportable communicable diseases, and/or possible threat of harm to self or others.

CHILDREN’S ONCOLOGY GROUP ARAR0331 Treatment of …ngeo.pdf · THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY ARAR0331 Page 7 The Children's Oncology Group

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