Surveillance of patients after initial treatment of ovarian cancer Angiolo Gadducci Department of Gynecology and Obstetrics, Unit of Gynecologic Oncology, University of Pisa Rome October 5-6 2007 Mediterranean School of Oncology Highlights in the management of ovarian cancer
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Surveillance of patients after initial treatment of ovarian cancer Angiolo Gadducci Department of Gynecology and Obstetrics, Unit of Gynecologic Oncology,
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Surveillance of patients after initial treatment
of ovarian cancer
Angiolo Gadducci
Department of Gynecology and Obstetrics, Unit of
Gynecologic Oncology, University of Pisa
Rome October 5-6 2007
Mediterranean School of Oncology
Highlights in the management of ovarian cancer
Carcinoma of the ovary:5-year survival by FIGO stage
Follow-up of patients with epithelial ovarian cancer (EOC)
Analysis of recurrence: rates and sites
Early stage patients
Advanced stage patients who achieved a complete response
Examinations of patient surveillance
Physical examination
Tumor marker assay
Ultrasound (US)
Computed tomography (CT)
Magnetic resonance imaging (MRI)
PET/CT
Follow-up protocols
PET
Adjuvant treatment for early OC
Sites of recurrences Trial 1 Trial 2
CDDP vs observation CDDP vs 32P
Pelvis only 8 (38.1%) 18 (47.4%)
Nodes only 2 (9.5%) 3 (7.4%)
Multiple abdominal 11 (52.4%) 17 (44.7%)
or distant metastases
GICOG, 1995
224 pts with early EOC: sites of recurrence
SITES Patients
N. % Pelvis
10 25.6
Abdomen 12 30.8
Nodes 1 2.6
Distant 5 12.8
Pelvis + Abdomen 7 17.9
Pelvis + Nodes 4 10.3
39
SITES Patients
N. % Pelvis
10 25.6
Abdomen 12 30.8
Nodes 1 2.6
Distant 5 12.8
Pelvis + Abdomen 7 17.9
Pelvis + Nodes 4 10.3
39
CTF 1997
VariableAdjuvant chemotherapy
(N = 224)Observation
(N = 224)Total
(N = 448)
No recurrence, n (%) 184 (82) 164 (73) 348 (78)
Recurrence, n (%) 40 (18) 60 (27) 100 (22)
Pelvic 14 (6) 20 (9) 34 (8)
Extrapelvic 20 (9) 28 (13) 48 (11)
Both (pelvic + extrapelvic) 6 (3) 12 (5) 18 (4)
Impact of adjuvant chemotherapy and surgical staging in early-stage EOC : EORTC/ACTION trial.
Trimbos, 2003
Disease-free survival in patients with stage I OC
pts DFS 5-y OS 7-y p value
FIGO stage
Ia 111 93.0% 91.6%
Ib 21 83.0% 83.0%0.0006
Ic 92 69.7% 66.2%
Histological type
Endometroid + muc 91 81.9% 80.3%
Serous 98 83.3% 79.4%ns
Clear cell 14 62.3% 62.3%
Histological grade
G1 95 94.3% 92.8%
G2 77 76.9% 76.9%0.0001
G3 36 57.2% 47.3%
CTF , 1997
Variables predictive of disease-free survival in patients with stage I OC: Cox model
Variables Wald 2 p value risk ratio 95% CI
G2 5.75755 0.0164 2.831 1.210-6.624
G3 22.03627 0.0001 7.725 3.29.-18.140
CTF , 1997
Time to recurrence from surgeryPts
n %<6 1 2.6
6 < t < 12 7 17.9
12 < t < 24 8 20.5
24 < t < 36 8 20.5
36 < t < 48 7 17.9
48 < t < 60 3 7.7
>60 5 12.8
94
CTF, 1997
224 pts with early EOC: times of recurrence
Follow-up of patients with epithelial ovarian cancer (EOC)
Analysis of recurrence: rates, times, sites
Early stage patients
Advanced stage patients who achieved a complete responseExaminations of patient surveillance
Physical examination
Tumor marker assay
Ultrasound (US)
Computed tomography (CT)
Magnetic resonance imaging (MRI)
PET/CT
Follow-up protocols
PET
Second-look (SL)No convincing data are available showing that SL improves the chances for cure or prolongs survival.
A lack of randomized prospective studies directly evaluating the therapeutic benefits of a SL procedure restricts its role to research protocols or to selected cases
Patients with primary suboptimal primary surgery appear to achieve a survival benefit from SL (early identification and treatment of residual disease) Rahaman 2005
The value of secondary cytoreductive surgery at the time of SL is still debated
(Dept. Gynecol. Obstet. and Dept. Oncol., Univ. PISA)
Correlation of CA125 and each of the other antigens with disease status in patients
with elevated multiple markers at diagnosis
Gadducci et al. 1993
Follow-up of patients with epithelial ovarian cancer (EOC)
Analysis of recurrence: rates, times, sites
Early stage patients
Advanced stage patients who achieved a complete responseExaminations of patient surveillance
Physical examination
Tumor marker assay
Ultrasound (US)
Computed tomography (CT)
Magnetic resonance imaging (MRI)
PET/CT
Follow-up protocols
PET
pts SE SP PPV NPV Clarke-Pearson 1986 46 32% 77% 79% 30%Silverman 1988 64 40% 99% 96% 87% Reuter 1989 35 84% 88% 89% 83%De Rosa 1995 58 47% 87% 84% 53%Topuz 2000 52 50% 100% 100% 76%Cho 2002 21 54% 99% 97% 91%Fazio 2003 25 70% 83% 89% 59% SE is dependent on site and size of tumor lesion (good for N , average for pelvic and omental lesion, and low for other peritoneal locations; lesions < 1.5 are often undetectable)
CT accuracy in the detection of persistent disease at SL
Patients and methods: 127 advanced EOC pts undergone surgery and chemotherapy and follow-ed with radiologic
imaging
82 (65%) pts had had at least one chest CT scan, with > 50% having
had > 3 scans.
32 (39%) patients had no radiologic evidence of disease.
28 (34%) had disease in the abdomen/pelvis, but not in the chest.
18 (22%) had both chest and abdominal/pelvic CT scans that
indicated disease. In all of these patients, abdominal/pelvic disease
had appeared on scans before spreading to the chest.
4 (5%) of the patients had isolated chest disease.
Value of chest CT scans in routine EOC follow-up
Sella 2001
Patients and methods: 96 EOC pts who had at least one CT scan of the chest, abdomen, and pelvis during follow-up. A total of 266 CT scans were obtained 41 (41.7%) of the 96 pts had metastatic chest disease on one or more scans.
In the absence of disease in abdomen/pelvis, chest progression was seen in 6 (2.7%) of the 226 follow-up CT scans. 5 of the six pts had rising CA-125 levels.
Value of chest CT scans in routine EOC follow-up
Dachman 2001
Pulmonary metastases are rare (6%) and usually preceded by recurrent
disease in the abdomen or pelvis.
Chest CT is not indicated in the routine follow-up
Chest CT should be performed for those patients with elevated serum
CA125 but without evidence of abdominal / pelvic disease
Patients and Methods: 24 pts treated for EOC who were prospectively examined by US CT and MRI
SE SP PPV NPV DA US 50% 100% 100% 80% 83% CT 63% 94% 83% 83% 83%MRI 75% 94% 86% 88% 88%CT + MRI 75% 88% 75% 88% 83%
CT is the primary imaging modality to prove macroscopic recurrence, and MRI should be performed in women with questionable macroscopic recurrent tumor and negative CT
US, CT, and MRI accuracy in the detection of recurrent EOC
Kainz, Prayer 1994
Follow-up of patients with epithelial ovarian cancer (EOC)
Analysis of recurrence: rates, times, sites
Early stage patients
Advanced stage patients who achieved a complete response
Examinations of patient surveillance
Physical examination
Tumor marker assay
Ultrasound (US)
Computed tomography (CT)
Magnetic resonance imaging (MRI)
PET/CT
Follow-up protocols
PET
pts SE SP PPV NPV
Kubich-Huck 2000 10 100% 50% 90%
89%
Nakamoto 2001 12 80% 50% 89% 33%
Yen 2001 24 91% 92% - -
Chang 2002 28 95.0% 87% - -
Torizuka 2002 25 80% 100% 100% 55%
Takekuma 2005 29 85% 100% 100% 43%
Recurrent EOC: PET
PET MRI/CT CA125 n. SE SP SE SP SE SP Torizuma 25 80% 83% 55% 83% 75% 100% 2002
Yen 24 91% 92% 91% 46% 91% 77%
2001
GarciaVeloso 19 100% 90% 47% 43% 84% 86%2003
FDG-PET, convetional imaging, and CA 125 for detectionof recurrent EOC in the presence of clinical suspicion
Patients and methods: 106 PET performed in 54 EOC pts followed- up after primary treatment
58 PET performed in pts with suspected recurrence and 48 in clinically-free
pts PET SE SP
Whole series 83% 83% Pts with suspected recurrence 94% Pts with rising CA125 alone 96% Clinically-free pts 65% The median relapse-free interval after a negative PET scan was 20 months
PET in the follow-up of EOC
Zimmy 2001
Patients and methods: A total of 90 PET studies and the associated CA 125 values (cut-off < 35 U/ml) were available in 71 pts during the follow-up after primary therapy for EOC .
PET CA 125 levels median , range Normal findings (23 studies) 13.3 U/ml ( 4.2-168 U/ml)Abnormal findings (67 studies) 166.7 U/ml (13.3-4,060 U/ml) p< 0.001
With one exception, there were no normal PET above CA 125 levels of 30 U/mlBetween 20 and 30 U/ml PET was positive in 4/7 studies.
a PET indication is worthwhile at CA 125 levels of approximately 30 U/ml.
Recurrent EOC: PET
Menczel 2004
Studies published between 1966 and 2003 were identified using MEDLINE database. Two reviewers independently abstracted data regarding SE and SP of PET. 10 studies met inclusion criteria for full text review.
Pooled SE SP PET 90% 86% CT/MRI 68% 58%CA 125 81% 83%Negative CA125 PET 54% 73% Negative conventional imaging Rising CA125 PET 96% 80% Negative conventional imaging
Recurrent EOC: PET
Havrilesky 2005
Follow-up of patients with epithelial ovarian cancer (EOC)
Analysis of recurrence: rates, times, sites
Early stage patients
Advanced stage patients who achieved a complete response
Examinations of patient surveillance
Physical examination
Tumor marker assay
Ultrasound (US)
Computed tomography (CT)
Magnetic resonance imaging (MRI)
PET/CT
Follow-up protocols
PET
PET suffers from a lack of anatomic resolution . Combined PET/CT devices can acquire PET and CT images that are contemporaneous in order to localize areas of increased 18FDG uptake with improved anatomic specificity
*PET/CT detected 100% of 7 positive N , 13% of 23 peritoneal lesions < 1 cm , and 50% of peritoneal lesions > 1 cm
Recurrent EOC: PET/CT
Patients and methods: 14 pts with rising CA125 , and negative or equivocal conventional CT imaging > 6 months after primary therapy were retrospectively identified as having recurrent disease limited to retroperitoneal N by combined PET/CT and underwent surgical reassessment Results: 11 (78.6%) pts had disease in N targeted by PET/CT. Of 143 N retrieved, 59 contained recurrent disease SE SP NPV PPV DA PET: 40.7% 94.0% 82.8% 69.3% 72.0% PET/CT failed to identify microscopic disease in 59.3% of pathologically positive N
Combined PET/CT for detecting recurrent EOC limited to retroperitoneal lymph nodes
Bristow 2005
PET/TC is able to detect unusual
supradiaphragmatic lymphatic diffusion of EOC (ie
supraclavicular nodes)
Fanti 2006
Recurrent EOC: PET/CT
Patients and methods: 22 EOC pts with rising CA125 and negative or equivocal CT findings > 6 months after primary therapy who underwent PET/CT followed by surgical reassessment
SE PPV DA Ability of PET/CT in detectingrecurrent disease > 1 cm at surgery 83.3% 93.8% 81.8%
PET/CT in clinically occult recurrent EOC
Bristow 2003
Follow-up of patients with epithelial ovarian cancer (EOC)
Analysis of recurrence: rates, times, sites
Early stage patients
Advanced stage patients who achieved a complete response
Examinations of patient surveillance
Physical examination
Tumor marker assay
Ultrasound (US)
Computed tomography (CT)
Magnetic resonance imaging (MRI)
PET/CT
Follow-up protocols
PET
Lo stato dell’arte• Attualmente si definisce corretto il follow-up che si Attualmente si definisce corretto il follow-up che si compone dicompone di :: anamnesi patologica prossimaanamnesi patologica prossima
esame obiettivo generale e pelvicoesame obiettivo generale e pelvico : : permette di diagnosticare una recidiva in sede pelvica, presente nel 60% dei casi di ripresa di malattia1
Dosaggio Ca 125 + esame clinico generale + visita Dosaggio Ca 125 + esame clinico generale + visita ginecologica = identificazione del 90% delle pazienti con ginecologica = identificazione del 90% delle pazienti con recidivarecidiva22
2 . Rustin GJS et al . Tumor markers. Ann Oncol 1993; 4 (Suppl 4): 71-771. PNLG – Diagnosi e terapia del carcinoma ovarico Cap. 8 : p69-73
dosaggio del Ca125dosaggio del Ca125 : : il suo incremento costituisce il primo indicatore di recidiva in circa il 70% delle pazienti e può anticipare l’evidenza clinica di circa 4 mesi1
esami strumentali radiologiciesami strumentali radiologici : : es. ecografia TV, ecografia addome completo, TAC o RMN o PET
Specific guidelines for surveillance of EOC of this disease are controversial, partly because evidence to support such guidelines
is scant and partly because the management of identified recurrences continues to be of minimal success.
Whether early detection actually can make a difference is not
necessarily made clear in the literature.
Most of the recent literature involving detection of recurrent EOC addresses the use of PET.
While radiological technology improvements are noteworthy, their potential impact on surveillance appears to be limited at this
time . Unsatisfactory Low SE and SP, along with expense, continue to be limiting
New modalities in detection of recurrent EOC
Tammela, Lele, Curr Opin Obstet Gynecol 2004
What Is Appropriate Follow-up After Primary TherapyWhat Is Appropriate Follow-up After Primary Therapy??
• The ideal follow-up of asymptomatic women who have completed primary debulking surgery and chemotherapy and have no clinical evidence of disease is unclear.
NIH Consensus Statement. 1994 Apr 5-7;12(3):1-30.
• The follow-up of asymptomatic patients after primary therapy should include routine complete history, physical, rectovaginal routine complete history, physical, rectovaginal
pelvic exam, and CA 125pelvic exam, and CA 125.. Although optimal intervals for monitoring optimal intervals for monitoring
have not been determined,have not been determined, current practice is to follow the patient every 3 to 4 months. After 2 years, less frequent follow-up intervals can be considered. CA 125 has been shown to be a reliable method of monitoring for early detection of recurrence in women whose CA 125 was elevated preoperatively. • A rising CA 125 is a predictor of relapse; however, a negative CA 125 does not exclude the presence of disease.
•exams done on a routine basis have not been shown to improve exams done on a routine basis have not been shown to improve the detection of recurrencethe detection of recurrence. Their use should be individualized.
Follow-Up program: MD Anderson– University of Texas – Ovarian cancer guidelines
Clinical and gynecological examination every 3 Clinical and gynecological examination every 3
months X 4 times then every 4 months for 3 times, months X 4 times then every 4 months for 3 times,
then every 6 months for 6 times then every 6 months for 6 times
Ca125 at any examination (if elevated at diagnosis)Ca125 at any examination (if elevated at diagnosis)
Abdominal/pelvic CT scan when symptoms /signs Abdominal/pelvic CT scan when symptoms /signs
appear appear
Opzioni Grado di raccomandazione
Visita, CA 125, ecografia ogni 3 mesi x 1-2 anno A ogni 4 mesi x 3 anno
ogni 6 mesi x 4-5 annoogni 12 mesi oltre 5 anno
Rx torace ogni 6 mesi x 1-2 anno BOgni 12 mesi successivamente
TC: annuale C
PET in caso di elevazione asintomatica del CA125 C
Algoritmo di Follow-Up: Linee guida Istituto Tumori Toscano (ITT)