Efficacy and safety of a cisplatin and paclitaxel (TP) induction regimen followed by chemoradiotherapy for patients with locally advanced head and neck squamous cell carcinoma (LAHNSCC)

Efficacy and safety of a cisplatin and paclitaxel (TP) induction regimen followed

by chemoradiotherapy for patients with locally advanced head and neck squamous

cell carcinoma (LAHNSCC).

ClinicalTrials.gov Identifier: NCT00959387

Running head: cisplatin and paclitaxel induction chemotherapy for LAHNSCC

Luciano de Souza Viana, Felipe Coelho de Aguiar Silva, Alexandre Andrade dos Anjos

Jacome, Danielle Calheiros Campelo Maia, Marcos Duarte de Mattos, Alexandre Arthur

Jacinto, Augusto Elias Mamere, Domingos Boldrini Junior, Renato de Castro Capuzzo,

Carlos Roberto Santos, Andre Lopes Carvalho

Barretos Cancer Hospital, Brazil

Corresponding author:

Luciano de Souza Viana

Rua Antenor Duarte Vilela, 1331, Bairro Dr. Paulo Prata, Barretos, São Paulo,

Brazil. ZIP CODE: 14 784-400

[email protected]

+55 17 3321 6600 ext6953

+55 17 3321 6600

Funding: Barretos Cancer Hospital

Disclaimers: No potential conflicts of interest

This article has been accepted for publication and undergone full peer review but has not beenthrough the copyediting, typesetting, pagination and proofreading process which may lead todifferences between this version and the Version of Record. Please cite this article as an‘Accepted Article’, doi: 10.1002/hed.24137

This article is protected by copyright. All rights reserved.

2

ABSTRACT

Background: The purpose of this phase II trial was to evaluate the tolerability, safety

and efficacy of a non-5-FU-based induction chemotherapy followed by

chemoradiotherapy (CRT) for patients with locally advanced head and neck squamous

cell carcinoma (LAHNSCC).

Methods: Sixty patients with stage III-IV HNSCC were treated with induction TP

(paclitaxel 175mg/m2; cisplatin 80mg/m

2 – 3 cycles) followed by CRT (cisplatin

100mg/m2; D1, 22 and 43 of radiotherapy).

Results: Fifty-six patients (93.3%) completed three-cycles of induction TP (no

treatment-related deaths), 52 (86.7%) completed definitive CRT per protocol (AE grade

≥2 in 53.3%). The overall response rate (ORR) after induction TP was 82.5% for

patients with resectable disease (RD) and 55.5% for unresectable disease (UD)

(p=0.023), and complete response rate after CRT was 70.0% for patients with RD and

30.0% for UD (p=0.005).

Conclusion: Induction TP followed by cisplatin based-CRT was well tolerated, safe

and had high ORR in selected patients with LAHNSCC.

KEY WORDS: head and neck cancer; induction chemotherapy; chemoradiation

therapy; organ preservation; squamous cell carcinoma

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John Wiley & Sons, Inc.

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INTRODUCTION

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer

worldwide.(1) Its treatment is complex and evolving. In general, early-stage disease

may be managed with single-modality treatment while an advanced stage (about 60% of

clinical presentation) needs a multidisciplinary approach.(2)

Over the last 30 years, much has been learned regarding the role of

chemotherapy, radiation therapy, and combined-modality treatment with

chemoradiation (CRT) in the therapy of locally advanced head and neck cancer.(3) As

the taxanes have been proven to have significant single-agent activity in advanced

disease there is increasing interest in the incorporation of taxanes into induction

regimens in the treatment of patients with locally advanced HNSCC (LAHNSCC).(4-

11)

The results reported in the TAX 323 (6) and TAX 324 (12) trials indicate that

the TPF regimen (docetaxel, cisplatin and 5-fluorouracil) improves overall survival

comparing with the PF regimen (cisplatin and 5-fluorouracil), and the TPF regimen is

globally the most accepted induction regimen for the treatment of LAHNSCC (10).

However, this new regimen has been associated with high toxicity rates, and patients

frequently do not tolerate cisplatin during concurrent radiotherapy.(6, 12-14)

Although sequential treatment with an aggressive induction chemotherapy (IC)

regimen leads to high response rates and enhanced complete response rates prior to

chemoradiotherapy, recently, the DeCIDE(15), PARADIGM(16) and the Spanish Head

and Neck Cancer Cooperative Group(14) trial failed to demonstrate overall survival

benefit from the addition of IC to definitive chemoradiotherapy. The use of

chemoradiotherapy regimens that are not generally considered the standard of care, the

early termination of the trial (17) and the number of patients that did not receive CRT

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after induction due to toxicity(14) are possibility reasons for the lack of difference in

survival in these trials. Therefore, the standard of care for most clinicians is a

multidisciplinary approach with cisplatin-based concurrent chemoradiotherapy.(14)

Recent publication of the randomized phase II TREMPLIN trial suggests that

sequential therapy using TPF regimen during induction phase followed by concurrent

therapy based on cisplatin is feasible and safe. But, a key observation of authors of this

trial was that CRT or bioradiotherapy (BRT) based on cetuximab was difficult to deliver

after TPF based IC because of limiting acute toxicity.(18)

The head and neck patients are often a relatively unfit group with significant

comorbidity and from a poor socio-economic class. There is significant concern that the

benefits of TPF may be lost in a non-trial cohort of patients who are likely to be less

fit.(19) This concern is warranted, as a retrospective study reported 15.3% mortality

during IC with a TPF regimen in LAHNSCC patients of low socioeconomic status and

high tumor burden. Furthermore, the administration of IC precluded 38.2% of these

patients from initiating or completing the planned definitive therapy (20). Similarly,

Sanders and co-authors also reported high toxicity rates during retrospective analysis of

sequential TPF chemotherapy followed by concurrent chemoradiotherapy in

LAHNSCC. In this study, 32% of patients were admitted as an emergency after TPF

chemotherapy, two patients had a fatal event while on TPF (1 cerebrovascular accident

and 1 neutropenic sepsis) and only 64% of patients received at least two cycles during

concurrent chemotherapy. As a result, the authors have suggested that strict criteria

should be enforced to eligibility for induction chemotherapy with TPF.(19, 21)

Preliminary data from a prospective study of the Dutch Head and Neck Society

named CONDOR study was presented at the American Society for Clinical Oncology

(ASCO) 2013 Annual Meeting. The authors concluded that after IC with TPF cisplatin-

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containing concomitant CRT is not feasible in LAHNSCC, because the total planned

dose of cisplatin could only be administered in 32% of the patients due to severe

toxicity (unpublished data).

Consequently, extensive efforts are ongoing to identify alternative schemes that

are less toxic than but as effective as the TPF regimen for LAHNSCC and safely allow

the use of definitive concurrent treatment based on cisplatin and radiotherapy.(22-29)

This phase II trial was designed to evaluate the feasibility of delivering cisplatin

concurrent with radiotherapy after 3 cycles of an IC regimen based on the combination

of cisplatin plus paclitaxel in LAHNSCC patients with a high tumor burden.

PATIENTS AND METHODS

Study Design

This was a prospective, single center, open-label, non-randomized phase II trial.

The study was approved by the Local Research Ethic Committee and was conducted in

accordance with the Declaration of Helsinki, Good Clinical Practice, and local ethical

and legal requirements. All patients signed an informed consent document prior to

enrollment in the study.

Eligibility Criteria

Patients were eligible if they had histologically confirmed locally advanced

stage III or IVa-b (M0) squamous cell carcinoma of the larynx, oral cavity, oropharynx

or hypopharynx. All patients were required to have measurable disease by Response

Evaluation Criteria in Solid Tumors (RECIST, version 1.1), an ECOG-PS ≤ 2 (Eastern

Cooperative Oncology Group Performance Status), age of at least ≥ 18 years and

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adequate liver, renal and bone marrow function. Oral cavity patients were included only

if they had unresectable disease.

Patients were excluded from the study if they had previously received

chemotherapy, radiotherapy or surgery (except diagnostic biopsy) for the primary tumor

or lymph nodes, or if they were using concurrent investigational, biological or immune

therapies. Other exclusion criteria included a history of another malignancy, presence of

a serious concomitant illness, a psychiatric illness that would preclude providing

informed consent.

Interventions

The allocation of all patients according to their resectability status, as defined by

the primary site and staging of the tumor (according to 6th edition of the AJCC criteria),

was performed by a multidisciplinary team consisting of medical oncologist, head and

neck surgeon, radiologist and radiation oncologist before starting IC.

The tumor was classified as unresectable if exists at least one of the following

condition: T4b staging; massive invasion of the carotid artery due to primary tumor or

lymph nodes metastasis; tumor fixation to the clavicle or involvement of the

nasopharynx.(30) In order to minimize the subjectivity of the resectability classification

(resectable or unresectable disease), tumors that would require extensive surgery were

still classified as resectable tumors, although the morbidity may create a compromised

quality of life of questionable additional value.(31)

Treatment Characteristics and Dose Modifications

Induction chemotherapy

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Chemotherapy consisted of intravenous paclitaxel (175 mg/m2) and cisplatin (80

mg/m2) on day 1 every 3 weeks for 3 cycles, unless disease progression, unacceptable

toxicity or consent withdrawal. Chemotherapy dose modification guidelines were

consistent with standard clinical practice. Cisplatin had to be replaced by carboplatin if

the patients developed peripheral neuropathy or ototoxicity of grade 2 or greater. A

cycle could be delayed for up to 2 weeks to allow the severity of grade 3 or greater toxic

events to decrease to a severity of grade 1 or lower (with the exception of alopecia).

Delays beyond 2 weeks required discontinuation of chemotherapy.

Concurrent treatment

Radiotherapy and cisplatin (100 mg/m2) were initiated at a minimum interval of

3 weeks and no later than 7 weeks after cycle 3 of IC. Cisplatin was administered

intravenously on days 1, 22 and 43. Cisplatin was reduced to 70 mg/m2 for grade 2

neurotoxicity or grade 2 myelosupression and was discontinued for grade 3

neurotoxicity. Weekly cisplatin (30 mg/m2) was accepted as a suitable option, at the

discretion of the attending physicians (before CRT or during this treatment; i.e.,

declining performance status related to toxicity). For patients unable to tolerate cisplatin

(neurotoxicity or CrCl < 50 mL/min) after IC, weekly carboplatin (AUC 1,5) was

administered. Subsequent cycles were delayed up to 2 weeks if there was evidence of

ongoing dehydration or serum creatinine levels 25% above the pretreatment value at day

22. A delay of subsequent cycles beyond day 35 necessitated withdrawal from

chemotherapy treatment. No dose re-escalations were permitted.

For patients with grades 3–4 mucositis, radiation therapy was delayed until these

reduced to less than grade 2 toxicities. Moreover, all patients received supportive care

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during radiotherapy, including dietary measures, local antiseptics and laser therapy as

preventive and curative support for oral mucositis.

Radiotherapy

Radiation treatment was delivered with 6 MV photon beams from a linear

accelerator with a standard fractionated radiotherapy of 70 Gy in 35 fractions for the

primary tumor (2 Gy/day, 5 days/week for 7 weeks). The dose administered to

uninvolved lymph nodes was at least 50 Gy and involved lymph nodes were to receive

60 to 70 Gy (2 Gy/day, 5 days/week), depending on whether an elective neck dissection

was indicated after IC. A combination of lateral-opposed portals, anterior and lateral

wedged fields or other field arrangements was used to treat the primary tumor and the

lymph nodes in the upper neck. A single anterior field was used to treat the neck below

the fields for the primary tumor. All fields were treated on each treatment day, and the

absorbed target dose of the photon fields was at least 95% and not more than 107% of

the specified centrally absorbed dose. Spinal cord sparing was performed at 46 Gy.

Gross tumor volume (GTV) was defined as the primary gross tumor or involved

node(s), and this measure was based on clinical, radiological and endoscopic

examinations at baseline (before IC). An additional margin of 1.0 cm was added to the

GTV to create the CTV. Intensity-modulated radiation therapy (IMRT) was not used.

Surgery

Patients with resectable disease and no response after IC were eligible for

salvage surgery within 4 to 6 weeks of the last scheduled dose of chemotherapy, prior to

starting CRT.

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Patients with documented persistent/residual disease after 6-8 weeks of

completing CRT were also eligible to undergo salvage surgery (for the primary tumor or

the neck).

Assessments

Clinical tumor response was determined by clinical evaluation and imaging

studies (performed at baseline, 2 weeks after the third cycle of IC and 6-8 weeks after

the end of radiotherapy). An independent review of radiologic data was performed.

Efficacy

The overall response rate (ORR) was defined as the proportion of patients whose

best overall response was either a complete response (CR) or a partial response (PR),

according to RECIST 1.1 criteria. Complete response (CR) was defined as the

disappearance of all clinically and radiological evident tumors.

Safety

Clinical and laboratory parameters were assessed to evaluate safety and toxicity.

Adverse events were assessed by National Cancer Institute - Common Terminology

Criteria for Adverse Events (NCI-CTCAE, version 3.0).

Acute radiation effects were defined as effects occurring within 90 days from the

beginning of radiotherapy. The relative dose intensity was calculated as the ratio of the

dose intensity actually delivered to the planned dose.

Follow-up and Outcomes

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Patients were monitored every 3 months during the first 2 years and every 6

months thereafter. Physical examination, radiographic disease assessment (CT/MRI

scan of head and neck and chest) and fiberoptic endoscopy of the upper digestive tract

were performed during regular monitoring or when disease progression/recurrence was

suspected or until a subject began a new anti-cancer therapy, whichever was sooner. OS

was calculated as the time of study entry to the date of death. Progression-free survival

(PFS) was calculated as the date of assignment to recurrence/progression or death

resulting from any cause. If the patient had no evidence of the aforementioned events,

survival was censored at the time of the last documented evaluation of efficacy/contact

or death resulting from another cause.

All deaths occurring during treatment or within 30 days after the completion of

treatment were considered possibly treatment-related unless tumor progression was

previously documented.

Human Papillomavirus Testing

p16 immunohistochemistry (IHC) was performed on formalin-fixed paraffin

embedded (FFPE) tissue sections cut at 4 mm thick using the CINtec® p16INK4A

assay, according to the manufacturer’s instructions (CINtec® Histology Kit, Ventana

Medical Systems, Inc., Tucson, Arizona, USA). Positive cases were considered for

staining in ≥ 75% of tumor cells.

Statistic Considerations

The primary endpoints were tolerability and safety of chemoradiotherapy based

on cisplatin following IC with TP regimen. Secondary endpoints were ORR, PFS and

overall survival rates.

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The following assumptions were made for this phase II sample size. In the

RTOG 91-11 study, the authors reported that 93% of patients randomized to concurrent

therapy based on cisplatin and radiotherapy received at least 2 cycles of chemotherapy

(70% received all 3 planned cycles of cisplatin, and 23% received 2 cycles) (32). Then,

54 patients were required to accept the hypothesis that at least 83% of the patients

submitted to 3 cycles of TP induction chemotherapy would be able to complete the

concurrent planned treatment (at least 2 cycles of bolus cisplatin or 5 courses of weekly

cisplatin or carboplatin and all radiotherapy planned), with a power of 80% (β = 0.20)

and a one-sided significance level of α = 0.05. The estimated rate of early dropout or

loss at follow-up was 10%. Therefore, this study was designed to enroll 20 qualified

patients in each group, defined as having resectable oropharynx tumors; resectable

hypopharynx or larynx tumors; and unresectable disease (total of 60 patients).

Descriptive statistics, including the mean, standard deviation, median, range and

percentage, were used to describe patient demographic and clinical characteristics. Chi-

square or Fisher’s exact tests were used to test differences in categoric variables, and

the Wilcoxon rank sum test or Kruskal-Wallis tests were used to detect differences in

continuous variables. The exact binominal test was used to test the significance of the

observed CR rate. Survival analysis was conducted using the Kaplan-Meier method and

log-rank test. Hazard ratio (HR) was calculated using the Cox proportional hazards

model. All multivariate model were tested including all covariates with p-value <0.20 in

the univariate analysis.

A two-sided level of significance of 0.05 was applied to all tests. Analyses were

performed by using the IBM SPSS statistical software package version 19.0 (SPSS,

Chicago, IL).

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RESULTS

Patients

From July 31, 2009, to Nov 12, 2010, a total of 64 patients were enrolled in the

study. Four patients failed the screening (2 due to elevated serum creatinine and 2 due to

systemic metastases diagnosed during the screening period). A CONSORT diagram of

the patient composition is shown in Figure 1 and the baseline demographic and clinical

characteristics of the patients are summarized in Table 1.

Treatment Characteristics

Tolerability

The study met its primary objective [56 patients (93.3%) received all three-

cycles of IC and 52 patients (86.7%) completed at least 2 cycles of concurrent bolus

cisplatin or 5 courses of weekly cisplatin or carboplatin and the planned dose of

radiotherapy], demonstrating that a majority of patients received the full course of

induction and concurrent treatment planned per the protocol (i.e., the number of

chemotherapy cycles and dose intensity) (Table 2).

Seven patients (11.6%) discontinued the planned treatment. The reasons for

discontinuation were as follows: disease progression in 3 patients (1 during induction

chemotherapy; 2 during CRT), 2 AEs related to treatment (1 death), withdrawal of

consent by 1 patient, and noncompliance with the study protocol by 1 patient.

Safety

Table 3 displays the most frequent AEs by NCI-CTCAE version 3.0 grade 2-5

during IC and CRT.

Adverse events related to induction chemotherapy

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During this phase, all patients presented alopecia, 75.0% of which were grade 2.

The other most common non-hematological toxicities were fatigue and

nausea/vomiting. Grade 2 fatigue occurred in 13 patients (21.7%); 1 patient presented

grade 3 fatigue. Thirteen patients (21.7%) reported grade 2 nausea/vomiting, and 2

patients had grade 3 nausea/vomiting. Grade 2 peripheral neuropathy occurred in only 1

patient.

The most common grade 2 or higher hematological toxicity was neutropenia

(grade 2 in 6.7%, grade 3 in 1.7% and grade 4 in 1.7% of patients).

Treatment delays of more than 7 days occurred in 4 patients (6.7%), and only 1

patient (1.7%) required discontinuation of treatment due a serious AE (left femoral

acute arterial occlusion that was properly treated by vascular surgical intervention and

evolved with no sequelae).

Only 7 patients (11.7%) had AEs of grade 3 or higher during IC. No deaths were

reported during IC.

Adverse events related to CRT

The most common non-hematological toxicities were xerostomia, anorexia,

nausea/vomiting, radiodermatitis, stomatitis/mucositis, dysgeusia, fatigue and peripheral

neuropathy.

The most common grade 2 or higher hematological toxicity was neutropenia

(grade 2, 3, or 4 in 14.0%, 14.0% and 3.5% of patients, respectively), and only 1 patient

had febrile neutropenia during CRT.

Thirty-two patients (56.1%) displayed some grade 3 or 4 AEs, and 1 death was

deemed to be treatment-related.

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Efficacy

Table 4 displays the response assessment rates by RECIST 1.1 criteria after IC

and CRT considering resectability status.

Among the 40 patients classified as having potentially resectable disease, the

ORR was 82.5% after IC and 28 patients (70.0%) achieved CR after CRT. Of the 23

patients who presented a PR by RECIST 1.1 criteria after IC, 17 (73.9%) achieved CR

after CRT in the potentially resectable disease group.

Among the 20 patients classified as having unresectable disease, the ORR was

55.0% after IC and 6 (30.0%) achieved CR. Of the 10 patients with a PR after

induction, 4 patients (40.0%) achieved CR after CRT in the unresectable disease group.

Predictive Factors for Favorable Response to IC

Univariate analysis were performed and the covariates significantly associated

with presence of complete or partial response were: age (p = 0.038), T stage (p = 0.037),

resectability status (p = 0.023) and level of serum calcium (p = 0.038). All other

variables related to the patient (gender, performance status and smoking status), tumor

(primary site, tumor grading, N stage and HPV status) and treatment (cycles of

chemotherapy, cisplatin vs carboplatin) were not significant predictors of response to IC

(p > 0.05 in each case; data not shown).

In the multivariate analysis the only independent variable able to predict the

response after IC was the resectability status (OR 3.86; 95% CI, 1.17-12.81; p = 0.028).

Thus the risk to achieve a complete or partial response is 3.86-fold higher for a patient

with resectable disease than for a patient with unresectable disease.

Predictive Factors for Favorable Response to CRT

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Univariate analysis were performed and the covariates associated significantly

with presence of complete response were: response after IC (p < 0.001), resectability

status (p = 0.005), T stage (p = 0.005) and N stage (p = 0.021). Treatment intensity

(complete vs incomplete; p = 0.146) and gender (p = 0.139) were also tested in the

multivariate analysis. All other covariates were not significant predictors of response to

IC (p > 0.05 in each case; data not shown).

In the multivariate analysis the independent variable able to predict the complete

response after CRT were the presence of response (CR or PR) after IC (OR 111.70;

95% CI, 6.72-1,857.28; p = 0.001), T stage [T1-T3 versus T4; (OR 5.44; 95% CI, 1.06-

27.84; p = 0.042)] and N stage [N0-1versus N2-3; (OR 9.37; 95% CI, 1.01-86.58; p =

0.049)].

Salvage Surgery

Salvage neck dissections were performed before CRT in 3 patients due a poor

response rate in the neck. After CRT, 8 patients (6 in the resectable group and 2 in the

unresectable group) underwent salvage surgery due to residual disease (3 neck

dissections, 2 primary site resections, and 3 both neck and primary site salvage surgery).

Progression-Free Survival and Overall Survival

After a median follow-up of 30 months, 33 patients died (27 deaths related to

disease progression, 1 death due to toxicity, 3 deaths due to comorbidities, 1 death after

salvage surgery due to residual head and neck carcinoma and 1 death after surgery for a

second primary tumor). Five patients remain alive with disease and 22 patients are alive

with no evidence of disease (19 cases in the resectable group and 3 cases in the

unresectable group; p < 0.001).

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The median PFS was 23.0 months for patients with resectable disease and 8.0

months for patients with unresectable disease [resectable versus unresectable disease;

(HR 2.81; 95% CI, 1.48-5.33; p = 0.002)]. The median OS was 13.0 months for

unresectable disease and it was not reached for patients with resectable disease (HR

3.80; 95% CI, 1.89-7.64; p < 0.001)]. (Figure 2 and Table 5).

Others Secondary Endpoints

Table 5 displays the pattern of first relapse, some functional outcomes (feeding

tube dependence, pneumonia and tracheostomy events), risk and causes of early deaths

according to their resectability status.

The pattern of first failure was as follows: early disease progression (< 6 months

after study enrollment), n = 12 (4 and 8 patients had resectable and unresectable disease,

respectively; p < 0.001); persistent locoregional disease after CRT, n =11; locoregional

recurrence, n = 15; locoregional and distant metastases, n = 2; and second primary

tumor, n = 8. Among the 17 patients who relapsed, 4 (23.5%) underwent salvage

surgery.

DISCUSSION

This phase II non-randomized trial was designed to establish a tolerable and safe

outpatient regimen using cisplatin and paclitaxel for IC followed by concurrent CRT

based on cisplatin for LAHNSCC patients of low socioeconomic status and high tumor

burden.

The combination of platinum and taxane is the backbone of several IC regimens

for LAHNSCC (8, 10, 33). As a safer and more tolerable induction regimen, some

authors maintain that cisplatin and docetaxel, with a range of options for the third drug.

5FU has been replaced by capecitabine (29), ifosfamide (24, 26), cetuximab (23) and

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gemcitabine (34). Other authors have replaced docetaxel with paclitaxel (24, 25, 27, 28)

or split the docetaxel dose (biweekly docetaxel) (35) to reduce hematological toxicity,

while others omit the third agent (36).

By contrast, the TPF regimen affects the administration of definitive

locoregional treatment in the majority of patients with LAHNSCC.(22, 37) The

TREMPLIN trial showed that only 45% of patients receiving 3 cycles of induction TPF

chemotherapy completed concomitant chemoradiotherapy.(15) We strongly believe that

the better tolerance profile reported in our study is due to omission of the 5-Fluorouracil

agent during IC need to be better evaluated in further study.

Prestwich et al.(38) reported treating selected patients with LAHNSCC with 3

cycles of induction TPF followed by concurrent three-weekly bolus cisplatin (100

mg/m2) chemoradiotherapy. Between March 2006 and February 2010, only 66 patients

with non-metastatic stage IV head-and-neck squamous cell carcinoma were included.

During TPF, grade 3 toxicity occurred in 18 patients (27%) and unplanned admissions

in 6 (9%). Sixty-two patients (94%) received radical radiotherapy, but only 3 patients

(5%) received the planned concurrent cisplatin therapy (29% and 61% of patients

received 1 and 2 cycles of cisplatin, respectively).(38)

The superior survival observed in the North American TPF compared to the

European TPF arms may be due to the inclusion of resectable patients with better

prognosis, a consequence of the more intensive TPF regimen or a result of the addition

of CRT as part of the treatment plan. It is possible that all three of these factors

contributed to the end result to some extent.(10)

Although IC has a proven role in organ preservation and might reduces the

incidence of distant metastases, its efficacy in prolonging overall survival has not been

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demonstrated,(16, 39) and the role of IC prior to concurrent chemoradiotherapy remains

controversial.(17, 33, 40-42)

The DeCIDE and PARADIGM trials sought to address whether the addition of

IC to definitive chemoradiotherapy improved survival. Unfortunately, in both trials,

patients in the induction arms were treated with chemoradiotherapy regimens that are

not generally considered the standard of care, and a large number of biologically distinct

HPV-positive patients were included. Both studies terminated early due to poor accrual,

failing to meet their primary endpoint.(17, 18, 33, 39-42)

The TP regimen used in this study proved to be safe and tolerable with low

toxicity during the induction phase, permitting CRT based on cisplatin in the majority

of patients included. The efficacy of the TP regimen was also promising in these

predominantly HPV-negative patients (ORR after IC with TP regimen was 82.5% for

patients with resectable disease and 55.5% for unresectable disease) that are comparable

to previous reports regarding intensive IC as a TPF regimen (TPF regimen showed ORR

of 68% in TAX 323 trial and ORR of 72% in TAX 324 trial) (6, 12)

In this study, encouraging functional outcomes were observed compared to the

existing literature considering the conventional standard fractionated radiotherapy used

(2 Gy per day; 5 days per week), which claim feeding tube dependence rates of 15% to

30%.(43-45) Likewise, the pneumonia rates within two years after study inclusion were

12.5% and 5.0% in resectable and unresectable disease, respectively. However,

attention has recently focused on new technology in radiation oncology (such as IMRT).

Target delineation has become more complex to selectively decrease radiation dose to

specified anatomic structures responsible for a functional swallow. Recent reports have

proposed a variety of dose thresholds or constraints to these swallowing-related

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structures, which may guide IMRT planning with the aim of reducing dysphagia and

consequently decrease the feeding tube dependence.(46)

The most common pattern of relapse in the present study was locoregional

failure, which is comparable to the finding that patients treated with induction regimens

display a lower rate of systemic recurrence (8, 47). Early disease progression (< 6

months after study enrollment) was diagnosed in 12 patients (4 and 8 patients had

resectable and unresectable disease, respectively; p < 0.001), locoregional recurrence

was noticed in 15 patients and only two patients had both locoregional and distant

metastases. All these locorregional recurrence happened in-field of previous

radiotherapy. There is limited published literature regarding patterns of disease

recurrence after conventional radiotherapy for HNSCC. This has been best documented

in several IMRT series.(48) As the success of radiotherapy depends on the accurate

delineation of the clinical target volume, it is important to document the patterns of

disease recurrence in order to continued efforts to improve therapy to enhance

locorregional control.(49)

Another important observation in this study was the difference in response rate

between groups of patients according to resectability status. Several studies have made

no distinction between resectable and unresectable disease, and the definitions of

resectable and unresectable disease vary among practitioners due to the lack of well-

established criteria to uniformly classify the status of resectability in LAHNSCC (30).

Our study used undoubted technical unresectability condition to classify the disease as

unresectable.(30, 31) In clinical practice, the definition of resectability allows clinicians

to plan different strategies for patients with LAHNSCC. Thereby, the resectability status

was used in this phase 2 trial to allow different strategies during the treatment, including

salvage surgery for resectable tumor that failure to IC. However, a large fraction of

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resectable tumors can be treated non-surgically (CRT with or without IC) in an effort to

preserve organ anatomy and function and some patients with unresectable disease might

become candidates for salvage surgery.(50)

The stage TNM and HPV status is actually the most accepted important

prognostic factor in patients with squamous cell cancer in the head and neck region.(51)

Even though some authors had showed that response to IC predicts response to

CRT(21), as regards predictive factors of response to induction chemotherapy in

patients with HPV negative LAHNSCC, no factor is currently validated. Surprisingly,

this study showed that the resectability status was an independent variable able to

predict the response after IC, and the presence of response to IC, T stage and N stage

were statistically significant predictive factor of response to CRT. The resectability

status as predict for response to IC may be partly explained by reason to exist some

degree of overlap between resectability status and TNM stage as these two covariates to

evaluate the extent of disease. Although it has been published that hypercalcemia in

head and neck malignancy determine poor median of overall survival(52), this is the

first time that the presence of high value of level of serum calcium at baseline was

correlated with significant lower chance to response to IC (p = 0.038) in univariate

analysis (data not confirmed in multivariate analysis). Future advances are expected in

order to identify prognostic and predictive biomarkers for efficacy and toxicity.(53, 54)

This small, single institutional non-randomized trial has its limitations. First, the

higher proportion of patients with oropharyngeal cancer may have affected the response,

although only two patients were never smokers and only two patients were p16 positive.

The low number of patients with p16 overexpression in this study impaired our analysis

exploring the effect of HPV on prognosis and/or as a predictive factor. In addition,

chronic toxicity was not evaluated because the aim of this study was to determine the

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21

tolerability and efficacy of a TP regimen followed by concurrent therapy. Some patients

received carboplatin during CRT, which is not as effective as cisplatin as a direct

antitumor agent (55, 56).

Moreover, the safety and tolerability observed during IC and CRT in this study

may be explained by patient selection, improved control of emesis, and greater

awareness of hydration and hydration protocols as supportive care during radiotherapy,

including dietary measures, local antiseptics and laser therapy for oral mucositis.

Currently, the standard of care for most patients is a multidisciplinary approach

with concomitant chemotherapy plus radiotherapy,(32, 39, 57-59) but the addition of IC

remains an appropriate approach for advanced disease with a high risk of local or distant

failure.(7)

In summary, a TP regimen (cisplatin plus paclitaxel) followed by CRT based on

cisplatin is safe, well tolerated and had high ORR in patients with LAHNSCC (stage III

and IV M0).

Conflict of Interest Statement: We declare that we have no conflict of interest

Acknowledgements: This study was funded by Barretos Cancer Hospital

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1

Figure 1

Assessed for elegibility

(n = 64)

Excluded (n = 4)

Did not meet

inclusion criteria

Included (n = 60)

Locally advanced head and neck carcinoma

• resectable oropharynx (n = 20)

• resectable hypopharynx/larynx (n = 20)

• unresectable disease (n = 20)

Resectable disease Unresectable disease

Induction chemotherapy (IC)

Surgical salvage if applicable

Induction chemotherapy

To anticipate CRT if applicable

Chemoradiotherapy (CRT)

Salvage surgery in case of resectable residual disease

Induction phase: n = 60 Concomitant phase: n = 57 Excluded from CRT: n = 3 (1 consent withdrawal; 1 noncompliance; 1 progression of disease and declining performance status for CRT)

En

rollm

en

t A

llo

cati

on

T

reatm

en

t A

naly

sis

Follow-up

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Figure 2

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Table 1. Characteristics of the 60 patients included in the study.

Variable No. of

patients %

Median Age (years) 56 (37-76)

Gender M 56 93.3

F 4 6.7

ECOG-PS 0 2 3.4

1 53 88.3

2 5 8.3

Primary site Oral Cavity 3 5.0

Oropharynx 32 53.3

Hypopharynx 8 13.3

Larynx 17 28.4

Tracheostomy Yes (baseline) 2 3.3

Tumor grade G1 9 15.0

G2 41 68.3

G3 9 15.0

T classification T2 4 6.7

T3 35 58.3

T4 21 35.0

N classification N0 13 21.7

N1 8 13.3

N2 30 50.0

N3 9 15.0

Stage III 18 30.0

IV 42 70.0

Resectability status* Resectable 40 66.6

Unresectable disease 20 33.3

Smoking status Current 43 71.7

Former 15 25.0

Never 2 3.3

HPV status** Positive (p16+) 2*** 3.33

Negative 50 83.33

Unevaluable 8 13.34

* Twenty patients with oropharynx tumors, 20 patients with non-oropharynx tumors and 20 patients with

unresectable tumors (2 patient had synchronous head and neck carcinoma).

** HPV status was determined retrospectively using archival tumor specimens.

*** Both patients presented oropharynx tumors, were current heavy smokers, male and stage IV.

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Table 2. Treatment administered during induction phase and concurrent treatment.

Parameter Induction Phase (n = 60) Combined Phase (n = 57)

Cisplatin

Median cumulative dose (mg/m2) 233.72 229.97

Median relative dose intensity % 97.38 76.65

Paclitaxel

Median cumulative dose (mg/m2) 520.23 NA

Median relative dose intensity % 99.09 NA

Carboplatin instead of cisplatin 4 (6.7%) 8 (14.0%)

Patients with ≥ 1 dose held for ≥ 7 days 4 (6.7%) 17 (29.8%)

Patients with dose reductions 4 (6.7%) 27 (47.4%)

Cycles of chemotherapy (every 3 weeks)

0 cycles 0 1 (1.8%)

1 cycles 1 (1.7%)† 2 (3.5%)

2 cycles 3 (5.0%)† 17 (29.8%)

††

3 cycles 56 (93.3%) 29 (50.9%)

Weekly session of chemotherapy

≥ 5 weeks sessions of carboplatin NA 7 (12.2%)

< 5 weeks sessions of carboplatin NA 1 (1.8%)

Weekly cisplatin NA 0 (0%)

Completed platin-dose during CRT 53 (92.9%)

Radiotherapy

Total dose ≥ 66 Gy NA 54 (94.7%)

RT major deviation NA 10* (17.5%)

Completed planned IC followed by CRT 52 (86.7%)

Legend. RT, radiotherapy; NA, Not applicable; IC, induction chemotherapy; CRT, concurrent

chemoradiotherapy

*Treatment interruption > 10 days in 8 patients (14.0%). †

Four patients received less than 3 cycles of IC [1 due to toxicity, 1 due to disease progression (unresectable

disease) and 2 due to incorrect anticipation of concurrent chemoradiotherapy] that was not specified in the

protocol. ††

Two patients received 100mg/m2 of cisplatin at the first cycle and further three sessions of weekly cisplatin

(30mg/m2).

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Table 3. Most common AE/SAEs associated with the treatment (NCI-CTCAE v.3.0).

AE TP Induction Chemotherapy (n = 60) Chemoradiotherapy (n = 57)

Grade 2 Grade 3 Grade 4 Grade 5 Grade 2 Grade 3 Grade 4 Grade 5

No. of patients (%) by grade of toxicity No. of patients (%) by grade of toxicity

Hematological

Anemia 7 (11.7) 1 (1.7) 0 0 20 (35.0) 1 (1.7) 0 0

Lymphopenia 0 0 1 (1.7) 0 8 (14.0) 6 (10.5) 0 0

Thrombocytopenia 0 0 0 0 1 (1.7) 1 (1.7) 0 0

Neutropenia 4 (6.7) 1 (1.7) 1 (1.7) 0 8 (14.0) 8 (14.0) 2 (3.5) 0

Febrile neutropenia 0 0 1 (1.7) 0 0 0 1 (1.7) 0

Non-Hematological

Alopecia 45 (75.0) 0 0 0 40 (70.1) - - 0

Nausea/vomiting 13 (21.7) 2 (3.3) 0 0 23 (40.3) 4 (7.0) 0 0

Diarrhea 3 (5.0) 0 0 0 3 (5.2) 0 0 0

Anorexia 5 (8.4) 0 0 0 25 (43.8) 2 (3.5) 0 0

Dysgeusia 0 0 0 0 17 (29.8) 0 0 0

Fatigue 13 (21.7) 1 (1.7) 0 0 13 (22.8) 8 (14.0) 0 0

Myalgia 7 (11.7) 0 0 0 0 0 0 0

Peripheral neuropathy 1 (1.7) 0 0 0 4 (7.0) 0 0 0

Stomatitis/Mucositis 0 0 0 0 15 (26.3) 10

(17.5) 1 (1.7) 0

Xerostomia 0 0 0 0 29 (50.8) 0 0 0

Radiodermatitis - - - - 18 (31.5) 0 0 0

Infection 1 (1.7) 0 1 (1.7) 0 0 0 0 0

Acute arterial occlusion 0 0 1 (1.7) 0 0 0 0 0

Increased serum

creatinine 1 (1.7) 0 0 0 1 (1.7) 1 (1.7) 0 0

Sudden death - - - 0 - - - 1 (1.7)

Legend: AE, adverse event; TP, paclitaxel and cisplatin chemotherapy

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Table 4. Response assessment rates by RECIST 1.1 criteria after induction

chemotherapy (IC) and concurrent chemoradiotherapy (CRT) considering resectability

status (n = 60).

Response assessment (RECIST 1.1)

After IC

No. of patients (%)

After CRT

No. of patients (%)

CR PR SD PD

Not

evaluable*

Resectable

disease

(n = 40)

CR 10 (25.0) 10 (25.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

PR 23 (57.5) 17 (42.5) 3 (7.5) 0 (0.0) 2 (5.0) 1 (2.5)

SD 4 (10.0) 1 (2.5) 2 (5.0) 1 (2.5) 0 (0.0) 0 (0.0)

PD 3 (7.5) 0 (0.0) 1 (2.5) 0 (0.0) 2 (5.0) 0 (0.0)

Unresectable

disease

(n = 20)

CR 1 (5.0) 1 (5.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

PR 10 (50.0) 5 (25.0) 1 (5.0) 0 (0.0) 3 (15.0) 1 (5.0)

SD 6 (30.0) 0 (0.0) 3 (15.0) 0 (0.0) 3 (15.0) 0 (0.0)

PD 3 (15.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (10.0) 1 (5.0)

Legend. CR: complete response; PR: partial response; SD: stable disease; PD: progression of disease; IC:

induction chemotherapy; CRT: concurrent chemotherapy and radiotherapy.

*A total of 3 patients were not evaluated after the concurrent therapy phase (1 consent withdrawal; 1

noncompliance; 1 progression of disease and declining performance status for CRT).

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Table 5. Secondary endpoints.

Resectable

disease (n = 40)

Unresectable

disease (n = 20)

p value***

3 year OS

62.5%

15.0%

0.001

OS median (months) NR 13.0

3 year PFS

47.5%

15.0%

< 0.001

PFS median (months) 23.0 8.0

Early Deaths* 4 (10%) 7 (35%) 0.031

Disease progression 3 (7.5%) 6 (30%)

Surgery related 1 (2.5%) 0

Treatment related (during CRT) 0 1 (5.0%)

No evidence of disease at the end of the planned

treatment†

33 (82.5%) 8 (40.0%) <0.001

Pattern of first failure

23 (57.5%) 17 (85.0%) 0.015

Early disease progression**

3 (7.5%) 6 (30.0%)

Persistent locorregional disease after CRT

2 (5.0%) 5 (25.0%)

Locorregional recurrence††

11 (27.5%) 5 (25.0%)

Locorregional and distant metastases 2 (5.0%) 0

Systemic recurrence 1 (2.5%) 0

Second primary tumor††† 6 (15.0%) 2 (10.0%)

Death without progression 5 (12.5%) 1 (5.0%)

Tracheostomy at last follow-up 11 (27.5%) 4 (20%) 0.326

2 years feeding tube dependence 6 (15%) 3 (15%) 1.000

2 years pneumonia event 5 (12.5%) 1 (5.0%) 0.792

* Deaths within the first year ** Progression within the first 6 months after study enrollment *** Chi-square or Fisher’s exact test.

NR = not reached † Including patients with complete response after the end of treatment and patients submitted to salvage surgery due to

residual disease †† Four patients with locorregional recurrence (25.0%) underwent salvage surgery. ††† The second primary tumors sites were: head and neck carcinoma (n=3), esophageal carcinoma (n=2), gastrointestinal

cancer (n=2) and lung cancer (n=1)

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Efficacy and safety of a cisplatin and paclitaxel (TP) induction regimen followed by chemoradiotherapy for patients with locally advanced head and neck squamous cell carcinoma (LAHNSCC)

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