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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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Presentation on theme: "Surveillance of patients after initial treatment of ovarian cancer Angiolo Gadducci Department of Gynecology and Obstetrics, Unit of Gynecologic Oncology,"— Presentation transcript:

1 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 Mediterranean School of Oncology Highlights in the management of ovarian cancer

2 Carcinoma of the ovary:5-year survival by FIGO stage FIGO StagePts5-year survival (%) Ia Ib Ic IIa IIb IIc IIIa IIIb IIIc IV (FIGO Annual Report 25, patients treated in )

3 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

4 Adjuvant treatment for early OC Sites of recurrencesTrial 1Trial 2 CDDP vs observationCDDP vs 32 P 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

5 224 pts with early EOC: sites of recurrence SITES Patients N. % Pelvis Abdomen Nodes Distant Pelvis + Abdomen Pelvis + Nodes SITES Patients N. % Pelvis Abdomen Nodes Distant Pelvis + Abdomen Pelvis + Nodes CTF 1997

6 Variable Adjuvant 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) Pelvic14 (6)20 (9)34 (8) Extrapelvic20 (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

7 Disease-free survival in patients with stage I OC ptsDFS 5-yOS 7-yp value FIGO stage Ia %91.6% Ib2183.0%83.0% Ic %66.2% Histological type Endometroid + muc9181.9%80.3% Serous9883.3%79.4%ns Clear cell1462.3%62.3% Histological grade G %92.8% G %76.9% G %47.3% CTF, 1997

8 Variables predictive of disease-free survival in patients with stage I OC: Cox model VariablesWald  2 p valuerisk ratio 95% CI G G CTF, 1997

9 Time to recurrence from surgery Pts n% < < t < < t < < t < < t < < t < > CTF, pts with early EOC: times of recurrence

10 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

11 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 Rahaman  The value of secondary cytoreductive surgery at the time of SL is still debated

12 198 pts with advanced EOC who achieved a pathologic complete responses: site of recurrence SitesPts n% Pelvis Abdomen Nodes77.4 Distant Pelvis + abdomen Abdomen +nodes22.1 Pelvis + nodes22.1 Pelvis + distant11.1 Distant + nodes22.1 Abdomen + distant CTF, 1998

13 198 pts with advanced EOC who achieved a pathologic complete responses: times of recurrence Time to recurrence from SL (momths) Pts n% < < t < < t < < t < < t < < t < > CTF, 1998

14 PFS in 198 pts with stage III-IV OC after negative SL (I) pts pts withPFS 5-yOS 7-yp value recurrences Age < %50.8 > %40.6% FIGO stage IIIa %77.7% IIIb %39.7% IIIc + IV %40.2% Histological type Endometroid %80.3% Serous+ oth %79.4%ns Cc + muc + und %49.6% Histological grade G %81.3% G %42.8% G %33.7% CTF, 1998

15 PFS in 198 pts with stage III-IV OC after negative SL (II) pts pts withPFS 5-yOS 7-yp value recurrences RD after 1 st surgery <1 cm % cm %37.3% >2 cm %32.0% st CT Single CDDP %49.7% Or CBDCA CDDP or CBDCA %44.0%ns based CT Other %41.7% SL Laparoscopy % 28.9% Laparotomy %48.0% CTF, 1998

16 Variables predictive of PFS in patients with stage III-IV OC after negative SL: Cox model VariablesWald  2 p valuerisk ratio 95% CI RD 1-2 cm RD > 2 cm G G SL CTF, 1998

17 Few formal guidelines exist regarding the surveillance of EOC pts The objective of follow-up in pts who have already been treated with primary cytoreductive surgery and first-line chemotherapy is not clear, as recurrent disease continues to be a therapeutic dilemma. The vast majority of women with relapses will eventually succumb to their disease. The primary goal of salvage therapy therefore is to maximize disease-free survival and quality of life. It is not clear whether early detection of recurrent disease is beneficial. The follow-up of EOC: general consideration Vaidya, Curtin 2003

18 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

19 Patients and methods: Retrospective analysis of 52 pts with recurrent EOC. Clinical examination and CA 125 assay were compared to US findings. Pathological findings Physical examination 73% CA 125 assay 85% US 54% CA 125, physical and US findings in follow-up of EOC patients Wu 2003

20 CA 125, physical and radiological findings in follow-up of EOC patients Patients and methods: Retrospective analysis of 58 pts with recurrent EOC. Clinical examination and CA 125 assay were compared to radiologic findings. ptsPathological findings Physical interview and physical examination 58 78% CA 125 assay 54 83% US 47 70% CT 4280% Physical examination and CA % In pts with a pelvic recurrence, physical examination had the highest SE compared to US and CT scan Fehm 2005

21 Cut-off >35 u/ml > 65 u/ml Sensitivity 68-94% 50-88% Specificity 67-94% 83-99% (collected series) CA125 in the diagnostic evaluation of ovarian masses

22 Histotype CA125 >35 U/ml CA125 >65 U/ml Mucinous 15/ % 12/ % p< Non mucinous 109/ % 102/ % Total 124/ /147 Sensitivity 84.4% 77.6% Incidence of presurgical elevated serum levels of CA125 in pts with EOC: Relationship with histotype Gadducci et al., 1995

23 Elevated CA125 levels at the 82-96% clinical detection of progression Elevated CA125 levels before 56-94% clinical detection of progression Serum CA125 assay in the early detection of progression Collected series

24 A rise of CA 125:  of 50% Krebs et al  of 100% Bast et al  just above the cut-off van der Burg et al  a doubling of CA 125 from the upper limit of normalRustin et al Defining progression of EOC during follow-up according to CA 125

25 Rise from 60 Two consecutive values > 60 TP FP 4 1 TN FN SE 85.9% 83.9% SP 91.3% 97.7% PPV 94.8% 98.6% NPV 77.8% 75.0% Median lead time 63 days 63 days Ability of serum CA125 to predict early progression in 131 patients by using a doubling of the normal cut-off (30 U/ml) Rustin et al., 1996

26 Recurrent epithelial ovarian cancer ELEVATED CA-125 No evidence of clinical or radiological disease in asymptomatic patients Late recurrence (>24 mos) Platinum sensitive Platinum resistant Platinum refractory Measurable or evaluable disease symptomatic patients

27  Response to CT can be better in patients with small lesions and good PS  Early administration of CT at the time of CA125 elevation is associated with a greater anxiety due to an earlier knowledge of disease status  Drug related toxicities can be heavier the lower is time interval from the first CT Serum CA125 elevation in asymptomatic patients

28 Intergroup phase III study comparing early versus delayed chemotherapy in EOC patients with raised CA125 levels and no evidence of disease EORTC Gynaecologic Cancer Cooperative Group (GCCG) (Dept. Gynecol. Obstet. and Dept. Oncol., Univ. PISA) EORTC 55955

29 Marker Elevated marker Positive correlation between at diagnosis marker levels and disease course CA /225 instances 87.4% CA /80 instances 76.3% CA /122 instances 71.3% TAG /167 instances 76.0% (Dept. Gynecol. Obstet. and Dept. Oncol., Univ. PISA) The relationship between tumor markers and the clinical course of disease Gadducci al. 1993

30 Marker Pts elevatedCorrelation of Pts with Pts with marker at diagnosis marker levels s progression rising markers with clinical after CT before clinical. disease course progression CA125 35/ % 3 or 8 3 CA / % 2 CA / % 9 or 23 9 CA / % 6 CA / % 10 or TAG / % 8 (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

31 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

32 ptsSE SP PPV NPV Clarke-Pearson % 77% 79% 30% Silverman % 99% 96%87% Reuter % 88% 89%83% De Rosa % 87% 84% 53% Topuz % 100% 100% 76% Cho %99% 97%91% Fazio % 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

33 CT accuracy in the detection of recurrent EOC ptsSE SP DA Kainz, Prayer % 94%83% Kubik-Huck % 50% 43% Cho % 91.7% Garcia-Velloso % 43%- Havrileski 2005^ 68% 58% 59% Grabiec %60%52% Sebastian % 60% 83% ^Pooled analyses of 10 studies

34 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

35 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

36  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 Value of chest CT scans in routine EOC follow-up Sella 2001

37 ptsSE SP PPVNPV Kubich-Huck % 100% 100%67% Low6991%87%96%72% Balestrieri % 100% 100% 50% Recurrent EOC: MRI

38 ptsSE SP PPVNPV Ricke upper abdomen67% 89% 87%70% bowel72% 70% 87%47% lower pelvis73%83%73%83% abdominal wall83% 60%77% 69% lymph node67% 86%93%46% carcinomatosis 69% 74% 65% 77% Recurrent EOC: MRI

39 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

40 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

41 ptsSE SP PPVNPV Kubich-Huck % 50% 90%89% Nakamoto % 50% 89%33% Yen % 92% -- Chang % 87% -- Torizuka % 100%100%55% Takekuma % 100% 100% 43% Recurrent EOC: PET

42 PET MRI/CT CA125 n. SESP SE SP SE SP Torizuma 25 80% 83% 55% 83% 75% 100% 2002 Yen 24 91% 92% 91% 46% 91% 77% 2001 GarciaVeloso % 90% 47% 43% 84% 86% 2003 FDG-PET, convetional imaging, and CA 125 for detection of recurrent EOC in the presence of clinical suspicion

43 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

44 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 ( U/ml) Abnormal findings (67 studies) U/ml (13.3-4,060 U/ml) p< With one exception, there were no normal PET above CA 125 levels of 30 U/ml Between 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

45 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 % 83% Negative CA125 PET 54% 73% Negative conventional imaging Rising CA125 PET 96% 80% Negative conventional imaging Recurrent EOC: PET Havrilesky 2005

46 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

47 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 18 FDG uptake with improved anatomic specificity Charron 2000 Martinez-Roman2005 Martinelli 2000 Bristow 2005 Makhija 2002 Hauth2005 Vergote 2003 Sebastian 2007 Fazio 2004Chung2007 Pannu 2005Thrall 2007 PET/CT

48 ptsSESPPPV NPV Nanni % 71% 93% 55% Pannu 2005* 16 73% 40% 73% 40% Bristow % 75% 94% 50% Sebastian % 80% - - Chung %97%95% 98% Thrall %100% 100% 87% *PET/CT detected 100% of 7 positive N, 13% of 23 peritoneal lesions 1 cm Recurrent EOC: PET/CT

49 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

50 PET/TC is able to detect unusual supradiaphragmatic lymphatic diffusion of EOC (ie supraclavicular nodes) Fanti 2006 Recurrent EOC: PET/CT

51 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 detecting recurrent disease > 1 cm at surgery 83.3% 93.8% 81.8% PET/CT in clinically occult recurrent EOC Bristow 2003

52 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

53 Lo stato dell’arte Attualmente si definisce corretto il follow-up che si compone di: Attualmente si definisce corretto il follow-up che si compone di : anamnesi patologica prossima esame obiettivo generale e pelvico : esame obiettivo generale e pelvico : permette di diagnosticare una recidiva in sede pelvica, presente nel 60% dei casi di ripresa di malattia 1 Dosaggio Ca esame clinico generale + visita ginecologica = identificazione del 90% delle pazienti con recidiva 2 2. Rustin GJS et al. Tumor markers. Ann Oncol 1993; 4 (Suppl 4): PNLG – Diagnosi e terapia del carcinoma ovarico Cap. 8 : p69-73 dosaggio del Ca125 : dosaggio 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 mesi 1 esami strumentali radiologici : esami strumentali radiologici : es. ecografia TV, ecografia addome completo, TAC o RMN o PET

54  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

55 What 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 Apr 5-7;12(3):1-30. routine complete history, physical, rectovaginal pelvic exam, and CA 125.optimal intervals for monitoring have not been determined, The follow-up of asymptomatic patients after primary therapy should include routine complete history, physical, rectovaginal pelvic exam, and CA 125. Although optimal intervals for monitoring 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 the detection of recurrenceexams done on a routine basis have not been shown to improve the detection of recurrence. Their use should be individualized.

56 Follow-Up program: MD Anderson– University of Texas – Ovarian cancer guidelines Clinical and gynecological examination every 3 months X 4 times then every 4 months for 3 times, then every 6 months for 6 times Clinical and gynecological examination every 3 months X 4 times then every 4 months for 3 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 appear Abdominal/pelvic CT scan when symptoms /signs appear

57 Opzioni Grado di raccomandazione Visita, CA 125, ecografiaogni 3 mesi x 1-2 annoA ogni 4 mesi x 3 anno ogni 6 mesi x 4-5 anno ogni 12 mesi oltre 5 anno Rx toraceogni 6 mesi x 1-2 annoB Ogni 12 mesi successivamente TC:annualeC PETin caso di elevazione asintomatica del CA125C Algoritmo di Follow-Up: Linee guida Istituto Tumori Toscano (ITT)

58 Clinical historyPhysical examination US CA 125 Suspicious symptoms Abnormal findings Rising levels CT scan or MRI Additional investigation is needed negative Close F/U positive Therapy CT scan or MRI positive negative Chest imaging positive negative PET or TC/PET positive negative Close F/U or immediate therapy Follow-up procedures: CTF proposal


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