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Surveillance of patients after initial treatment of ovarian cancer Angiolo Gadducci

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

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Surveillance of patients after initial treatment of ovarian cancer Angiolo Gadducci

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

  2. Carcinoma of the ovary:5-year survival by FIGO stage FIGO Stage Pts 5-year survival (%) Ia 467 89.3 Ib 58 64.8 Ic 560 78.2 IIa 73 79.2 IIb 105 64.3 IIc 206 68.2 IIIa 120 49.2 IIIb 251 40.8 IIIc 1653 28.9 IV 511 13.4 (FIGO Annual Report 25, patients treated in 1996-98)

  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 PET/CT Follow-up protocols

  4. 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

  5. 224 pts with early EOC: sites of recurrence SITES PatientsN. %Pelvis1025.6 Abdomen 1230.8 Nodes 12.6 Distant 512.8 Pelvis + Abdomen 717.9 Pelvis + Nodes 4 10.339 CTF 1997

  6. Variable Impact of adjuvant chemotherapy and surgical staging in early-stage EOC : EORTC/ACTION trial. 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)     Pelvic 14 (6) 20 (9) 34 (8)     Extrapelvic 20 (9) 28 (13) 48 (11)     Both (pelvic + extrapelvic) 6 (3) 12 (5) 18 (4) Trimbos, 2003

  7. 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

  8. 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

  9. 224 pts with early EOC: times of recurrence Time to recurrence from surgery Pts 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

  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 PET/CT Follow-up protocols

  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 • 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 Sites Pts n % Pelvis 26 27.7 Abdomen 21 22.3 Nodes 7 7.4 Distant 14 14.9 Pelvis + abdomen 16 17.0 Abdomen +nodes 2 2.1 Pelvis + nodes 2 2.1 Pelvis + distant 1 1.1 Distant + nodes 2 2.1 Abdomen + distant 3 3.2 94 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 % <6 7 7.4 6 < t < 12 21 22.3 12 < t < 24 29 30.9 24 < t < 36 13 13.8 36 < t < 48 12 12.8 48 < t <60 6 6.4 >60 6 6.4 94 CTF, 1998

  14. PFS in 198 pts with stage III-IV OC after negative SL (I) pts pts with PFS 5-y OS 7-y p value recurrences Age <50 41 17 59.4% 50.8 >50 88 44 40.6% 40.6% 0.0519 FIGO stage IIIa 20 4 77.7% 77.7% IIIb 40 19 49.5% 39.7% 0.0080 IIIc + IV 132 71 42.0% 40.2% Histological type Endometroid 22 12 47.7% 80.3% Serous + oth 98 70 44.9% 79.4% ns Cc + muc + und 34 12 56.7% 49.6% Histological grade G1 24 5 87.1% 81.3% G2 70 35 45.9% 42.8% 0.0021 G3 87 50 36.3% 33.7% CTF, 1998

  15. PFS in 198 pts with stage III-IV OC after negative SL (II) pts pts with PFS 5-y OS 7-y p value recurrences RD after 1st surgery <1 cm 87 31 62.2% 57.3 1-2 cm 49 28 41.1% 37.3% >2 cm 56 35 32.0% 32.0% 0.0038 1st CT Single CDDP 18 8 49.9% 49.7% Or CBDCA CDDP or CBDCA- 162 79 47.7% 44.0% ns based CT Other 12 7 41.7% 41.7% SL Laparoscopy 34 22 28.9% 28.9% Laparotomy 158 72 51.3% 48.0% 0.0061 CTF, 1998

  16. Variables predictive of PFS in patients with stage III-IV OC after negative SL: Cox model Variables Wald 2 p value risk ratio 95% CI RD 1-2 cm 5.65351 0.0174 1.877 1.117-3.156 RD > 2 cm 9.54639 0.0020 2.156 1.324-3.511 G2 5.33134 0.0209 2.386 1.140-4.990 G3 9.53244 0.0020 3.118 1.515-6.416 SL 5.85793 0.0155 1.826 1.121-2.973 CTF, 1998

  17. The follow-up of EOC: general consideration • 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. 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 PET/CT Follow-up protocols

  19. CA 125, physical and US findings in follow-up of EOC patients 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% 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. pts Pathological findings Physical interview and physical examination 58 78% CA 125 assay 54 83% US 47 70% CT 42 80% Physical examination and CA 125 54 98% In pts with a pelvic recurrence, physical examination had the highest SE compared to US and CT scan Fehm 2005

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

  22. Incidence of presurgical elevated serum levels of CA125 in pts with EOC: Relationship with histotype Histotype CA125 >35 U/ml CA125 >65 U/ml Mucinous 15/22 68.2% 12/22 54.5% p<0.0115 Non mucinous 109/125 87.2% 102/125 81.6% Total 124/147 114/147 Sensitivity 84.4% 77.6% Gadducci et al., 1995

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

  24. Defining progression of EOC during follow-up according to CA 125 • A rise of CA 125: • of 50% Krebs et al. 1986 • of 100% Bast et al. 1983 • just above the cut-off van der Burg et al. 1986 • a doubling of CA 125 from the upper limit of normal Rustin et al. 1996

  25. Ability of serum CA125 to predict early progression in 131 patients by using a doubling of the normal cut-off (30 U/ml) Rise from < 30 to > 60 Two consecutive values > 60 TP 73 73 FP 4 1 TN 42 42 FN 12 14 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 Rustin et al., 1996

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

  27. Serum CA125 elevation in asymptomatic patients • 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

  28. EORTC 55955 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)

  29. The relationship between tumor markers • and the clinical course of disease Marker Elevated marker Positive correlation between at diagnosis marker levels and disease course CA125 35 188/225 instances 87.4% CA19.9 16 61/80 instances 76.3% CA15.3 24 87/122 instances 71.3% TAG-72 30 27/167 instances 76.0% (Dept. Gynecol. Obstet. and Dept. Oncol., Univ. PISA) Gadducci al. 1993

  30. Correlation of CA125 and each of the other • antigens with disease status in patients • with elevated multiple markers at diagnosis Marker Pts elevated Correlation of Pts with Pts with marker at diagnosis marker levels s progression rising markers with clinical after CT before clinical . disease course progression CA125 35/40 87.5% 3 or 8 3 CA19.9 30/40 75.0% 2 CA125 100/118 84.7% 9 or 23 9 CA15.3 83/118 70.3% 6 CA125 123/144 85.4% 10 or 25 10 TAG-72 107/144 74.3% 8 (Dept. Gynecol. Obstet. and Dept. Oncol., Univ. PISA) 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 PET/CT Follow-up protocols

  32. CT accuracy in the detection of persistent disease at SL 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)

  33. CT accuracy in the detection of recurrent EOC pts SE SP DA Kainz, Prayer 1994 24 63% 94% 83% Kubik-Huck 2000 11 40% 50% 43% Cho 1992 21 54.5 99.6% 91.7% Garcia-Velloso 2003 19 47% 43% - Havrileski 2005^ 68% 58% 59% Grabiec 2006 27 56% 60% 52% Sebastian 2007 51 92% 60% 83% ^Pooled analyses of 10 studies

  34. Value of chest CT scans in routine EOC follow-up 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. Sella 2001

  35. Value of chest CT scans in routine EOC follow-up 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. Dachman 2001

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

  37. Recurrent EOC: MRI pts SE SP PPV NPV Kubich-Huck 200 9 86% 100% 100% 67% Low 69 91% 87% 96% 72% Balestrieri 2002 22 84% 100% 100% 50%

  38. Recurrent EOC: MRI pts SE SP PPV NPV Ricke 200 39 upper abdomen 67% 89% 87% 70% bowel 72% 70% 87% 47% lower pelvis 73% 83% 73% 83% abdominal wall 83% 60% 77% 69% lymph node 67% 86% 93% 46% carcinomatosis 69% 74% 65% 77%

  39. US, CT, and MRI accuracy in the detection of recurrent EOC 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 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 PET/CT Follow-up protocols

  41. Recurrent EOC: 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%

  42. FDG-PET, convetional imaging, and CA 125 for detection of recurrent EOC in the presence of clinical suspicion PET MRI/CT CA125   n. SE SP SE SPSE 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

  43. PET in the follow-up of EOC 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 Zimmy 2001

  44. Recurrent EOC: PET 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/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. Menczel 2004

  45. Recurrent EOC: PET 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 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 PET/CT Follow-up protocols

  47. PET/CT 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 Charron 2000 Martinez-Roman 2005 Martinelli 2000 Bristow 2005 Makhija 2002 Hauth 2005 Vergote 2003   Sebastian 2007 Fazio 2004 Chung 2007 Pannu 2005 Thrall 2007

  48. Recurrent EOC: PET/CT pts SE SP PPV NPV Nanni 2005 41 88% 71% 93% 55% Pannu 2005* 16 73% 40% 73% 40% Bristow 2005 22 83% 75% 94% 50% Sebastian 2007 51 97% 80% - - Chung 2007 77 93% 97% 95% 98% Thrall 2007 22 94% 100%  100% 87% *PET/CT detected 100% of 7 positive N , 13% of 23 peritoneal lesions < 1 cm , and 50% of peritoneal lesions > 1 cm  

  49. Combined PET/CT for detecting recurrent EOC limited to retroperitoneal lymph nodes 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 Bristow 2005

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

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