- Email: [email protected]
Mucinous advanced epithelial ovarian carcinoma: clinical presentation and sensitivity to platinum–paclitaxel-based chemotherapy, the GINECO experience
original article
Annals of Oncology 21: 2377–2381, 2010 doi:10.1093/annonc/mdq257 Published online 21 May 2010
Mucinous advanced epithelial ovarian carcinoma: clinical presentation and sensitivity to platinum– paclitaxel-based chemotherapy, the GINECO experience J. Alexandre1*, I. Ray-Coquard2, F. Selle3, A. Floquet4, P. Cottu5, B. Weber6, C. Falandry7, D. Lebrun8 & E. Pujade-Lauraine1 for the GINECO 1
Background: Advanced mucinous epithelial ovarian carcinoma (mEOC) has been associated with a worse prognosis than the more common serous epithelial ovarian carcinomas (sEOC), but it remains unclear whether this observation reflects a more aggressive clinical presentation and/or chemoresistance. Patients and methods: Data from four randomized phase III and one phase II advanced epithelial ovarian carcinoma (EOC) first-line clinical trials were retrospectively collected, yielding 1118 patients with advanced EOC (International Federation of Gynecology and Obstetrics stages IIB–IV), 85% of whom were treated with paclitaxel (Taxol)-carboplatin-based chemotherapy. Results: Based on 786 patients with sEOC and 54 (5%) with mEOC, peritoneal carcinomatosis were more limited in mEOC, which was more frequently stages IIB–IIIB (32% versus 19%, P = 0.001) and had more frequently macroscopic complete resection after initial surgery (50% of stages II–III versus 30%, P = 0.02). In contrast, visceral metastases (stage IV) were more frequent in mEOC (30% versus 15%, P = 0.004). mEOC had a lower response rate to carboplatin–paclitaxel, and shorter progression-free and overall survival rates, for both stage IV and optimally debulked stages II–III patients. Conclusions: Advanced mEOC appears to be highly chemoresistant and complete resection of peritoneal metastases is unable to reverse its poor prognosis. New therapeutic options are needed. Key words: mucinous, epithelial ovarian tumor, carboplatin, paclitaxel, chemoresistant
introduction The mucinous cell type accounts for 10% of all primary epithelial ovarian carcinomas (EOC) in Western countries [1]. Most mucinous epithelial ovarian carcinomas (mEOC) are diagnosed early [International Federation of Gynecology and Obstetrics (FIGO) stages I–IIA] and confined to one ovary. In stage I mEOC, the 5-year disease-free survival rate is 90%, which is slightly better than the 76% observed for patients with serous epithelial ovarian carcinomas (sEOC), the more common histopathological group [2]. Less frequently, primary mEOC is associated with peritoneal carcinomatosis and/or extraperitoneal metastases (FIGO stages IIB–IV). Unlike FIGO stage I tumors, advanced mEOC reportedly have poorer prognoses than sEOC [3, 4].
*Correspondence to: Dr J. Alexandre, Medical Oncology Unit, Hoˆtel-Dieu, 1, place du Parvis Noˆtre-Dame, 75004 Paris, France. Tel: +33-1-42-34-82-22; Fax: +33-1-42-34-81-10; E-mail: [email protected]
To date, patients with advanced mEOC receive the same first-line treatment as patients with sEOC. Based on randomized phase III studies, the current standard treatment is surgery followed by combined carboplatin–paclitaxel chemotherapy [5, 6]. Results of a recent randomized study suggested that a neoadjuvant strategy, combining primary chemotherapy followed by surgery, could improve the surgery-associated mortality and morbidity without impairing progression-free survival (PFS) and overall survival (OS) [7]. However, the small number of patients with mEOC in those phase III studies does not allow confirmation that such strategies are as optimal as they are for patients with sEOC. Moreover, it is unclear if the poor prognosis of advanced mEOC following standard treatment primarily reflects more aggressive disease, chemoresistance or both. To clarify this major concern, we retrospectively analyzed the GINECO experience, using data from our first-line clinical trials [8–12].
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
original article
Received 15 December 2009; revised 30 March 2010; accepted 31 March 2010
Downloaded from http://annonc.oxfordjournals.org/ at East Tennessee State University on June 29, 2015
Medical Oncology Unit, Universite´ Paris-Descartes, Hoˆtel-Dieu, Paris; 2Medical Oncology Department, Centre Le´on Be´rard, Lyon; 3Medical Oncology Department, Hoˆpital Tenon, Paris; 4Medical Oncology Department, Institut Bergonie´, Bordeaux; 5Medical Oncology Department, Institut Curie, Paris; 6Medical Oncology Department, Centre Alexis Vautrin, Nancy; 7Medical Oncology Department, CHU Lyon Sud, Pierre-Be´nite; 8Medical Oncology Department, Centre Jean Godinot, Reims, France
original article
Annals of Oncology
patients and methods
date of registration in the trial to the date of death and progression or death.
patient selection
data collection The following characteristics were extracted from the database for each patient with advanced sEOC or mEOC: age, performance status and baseline hemoglobin level, tumor grade, FIGO stage, macroscopic residual tumor after initial surgery, evidence of liver metastases and number of extraperitoneal tumor sites, best tumor response to chemotherapy and dates of progression and death. The EOC cell type was confirmed by histopathological review at the time of initial patient inclusion in the respective trial when the diagnosis had been difficult. A pathological examination of the appendix as well as gastroscopy and colonoscopy were a general practice in patients with bilateral and/or advanced ovarian mucinous carcinoma in order to rule out a gastrointestinal primary. The best tumor response was prospectively assessed in patients with measurable disease according to the World Health Organization definitions except for the carboplatin–paclitaxel with/without gemcitabine trial, which used the RECIST[13, 14]. OS and PFS were assessed, respectively, from the
Table 1. Number of patients included in the five trials selected for the present analysis Treatment [reference]
CbTx with/without epirubicin [8] CbTx with/without gemcitabine [9] CbTx with/without topotecan [10] CbTx in elderly patients [12] Total given CbTxbased ChT CpCy HD versus STD [11] Total, n (%)
Total no. of patients with advanced EOC
Patients included in the analysis sEOC mEOC
330
237
18
304
207
13
245
178
13
75
52
4
954
674
48
112 786 (70)
6 54 (5)
164 1118 (100)
CbTx, carboplatin–paclitaxel; ChT, chemotherapy; CpCy, cisplatin– cyclophosphamide; HD, high dose; STD, standard dose; EOC, epithelial ovarian carcinoma; sEOC, serous epithelial ovarian carcinoma; mEOC, mucinous epithelial ovarian carcinoma.
2378 | Alexandre et al.
statistical methods The main study objectives were to assess the baseline disease characteristics of patients and to compare carboplatin-paclitaxel-based chemotherapy efficacy (overall response rate, PFS and OS) in patients with advanced mEOC or sEOC. Predefined baseline characteristics were compared between groups using chi-square test (qualitative variables) or Student’s t-test (continuous variables). The Kaplan–Meier method was used to estimate the cumulative distribution of PFS and OS times according to histological subtype for the overall population and specifically for patients with stage IV and optimally debulked stages IIB–IIIC disease.
results patient characteristics A total of 1118 patients with advanced EOC were enrolled by the GINECO centers in the four selected clinical trials (Table 1): 786 (70%) sEOC and 54 (4.8%) mEOC. The patients with Table 2. Baseline characteristics of patients with sEOC or mEOC Characteristic
sEOC (n = 786)
Age (years), median (range) 61 (22–89) Performance status, n (%) 0–1 688 (89) 2–3 88 (11) Missing 10 Hemoglobin (g/dl), median 11.6 (6.9–15.9) (range) Tumor grade, n (%) 1–2 320 (61) 3 207 (39) Missing 259 Tumor stage, n (%) IIB–IIIB 150 (19) IIIC 513 (66) IV 119 (15) Missing 4 Stage IIB–IIIC, n 663 Macroscopic residual tumor after surgery, n (%) Yes 290 (70) No 119 (30) Missing 254 Stage IV, n 119 Liver metastases, n (%) Yes 27 (28) No 70 (72) Missing 22 Number of extraperitoneal sites, n (%) 1 77 (79) >1 20 (21) Missing 22
mEOC (n = 54)
P
54.5 (39–79)
0.18a
44 (83) 9 (17) 1 11.7 (7.8–14.8)
0.21
0.77a
29 (78) 8 (22) 17
0.03
17 (31) 20 (38) 16 (30) 1 37
0.001
14 (50) 14 (50) 9 16
0.02
7 (54) 6 (46) 3
0.06
10 (77) 3 (23) 3
0.8
0.004
Comparisons made by v2 test. a Comparisons made by Student’s t-test. sEOC, serous epithelial ovarian carcinoma; mEOC, mucinous epithelial ovarian carcinoma.
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The GINECO database provided individual data for patients with advanced EOC who participated in our clinical trials. The clinical trials were selected based on the following criteria: inclusion of patients with chemo-naı¨ve advanced EOC (FIGO stages IIB–IV), treatment with platinum-based chemotherapy and completed study. Four randomized phase III and one nonrandomized phase II trials were identified (Table 1) [8–12]. Three trials compared the standard carboplatin–paclitaxel (Taxol; Bristol-Myers Squibb, Rueil-Malmaison, France) combination with an experimental triplet combining carboplatin–paclitaxel with topotecan (Hycamtin; GlaxoSmithKline, Philadelphia, PA), epirubicin or gemcitabine [8–10]. One study compared standard and high doses of the cisplatin– cyclophosphamide combination [11]. The results of none of these studies showed any advantage in terms of response rate, PFS or OS of the experimental treatment over standard therapy. The phase II study evaluated the safety of carboplatin–paclitaxel in elderly women [12].
original article
Annals of Oncology
mEOC were slightly, but not significantly, younger than patients with sEOC (Table 2). Baseline performance status and hemoglobin levels were comparable for the two groups. Most patients were in good general condition. Compared with sEOC, mEOC were more frequently low grade (Table 2). Compared with sEOC, mEOC were associated with a significantly higher percentage of FIGO stages IIB–IIIB (P = 0.001) and complete resection achieved after initial surgery (P = 0.02). However, Table 3. Best tumor responses to carboplatin-paclitaxel–based chemotherapy in patients with measurable sEOC or mEOC sEOC (n = 340)
mEOC (n = 25)
P (v2)
Partial + complete, n (%) [95% CI] Stable disease, n (%) Progression, n (%)
275 (81) [77–85]
15 (60) [41–79]
<0.001
36 (11) 29 (9)
1 (4) 9 (36)
0.0001
sEOC, serous epithelial ovarian carcinoma; mEOC, mucinous epithelial ovarian carcinoma; CI, confidence interval.
carboplatin-paclitaxel-based chemotherapy efficacy Overall, 954 (85%) of the 1118 patients included in the study received a carboplatin-paclitaxel-based chemotherapy (Table 1). The percentage was similar in patients with serous and mucinous cell types (86% and 89%, respectively). Among patients with measurable disease, the objective (complete and partial) response rate to carboplatin-paclitaxelbased chemotherapy was significantly lower for mEOC patients than those with sEOC (P < 0.001; Table 3). Progressive disease as the best response to chemotherapy was significantly more frequently observed for mEOC patients (P < 0.0001). For the entire population, the median follow-up was 36.7 months. The patients with advanced mEOC receiving
Figure 1. Kaplan–Meier progression-free survival (PFS) and overall survival (OS) curves for patients with advanced serous ( ) or mucinous ( ) epithelial ovarian carcinoma (EOC). (A) Advanced FIGO stages IIB–IV EOC. (B) FIGO stage IV EOC. (C) FIGO stages IIB–IIIC EOC and complete surgical resection.
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Response
extraperitoneal metastases (FIGO stage IV) were also more frequent in mEOC than in sEOC patients (Table 2). Liver metastases tended to be more frequent in patients with mEOC (P = 0.06), while the metastasis frequencies in other sites (pleural, lung and lymph nodes) were comparable (data not shown).
original article
discussion Herein, we reported on one of the largest series of patients with advanced mEOC treated with modern chemotherapy. Based on data from four prospective studies, we observed that, compared with sEOC, mEOC was associated with lower response rate to carboplatin-paclitaxel-based chemotherapy and shorter PFS and OS. These results are in agreement with smaller previous reports. The Royal Marsden Hospital group reported the outcomes of 27 patients with advanced mEOC and 54 matched controls with non-mucinous histology, all treated with various platinum-based chemotherapies [15]: mEOC was independently associated with shorter PFS and OS. The retrospective analysis from the Hellenic Cooperative Oncology Group found that the 47 patients with advanced mEOC had a lower response rate to platinum-based chemotherapy than the 94 sEOC patients, but survival was similar for both populations [16]. Several explanations could be done to explain the worse prognosis of this subgroup of epithelial ovarian cancer. The poor prognosis of advanced mEOC could, at least in part, reflect the initial more aggressive clinical characteristics. Indeed, extraperitoneal spread appeared twice as frequently in mEOC than in sEOC and was associated with a very short median OS of about 1 year. However, well-recognized good prognostic factors were also more frequently associated with mucinous histology: patients were slightly younger, tumors were more frequently low grade and peritoneal carcinomatosis was more limited. Most importantly, macroscopic complete resection was more frequently achieved than for sEOC, which agrees with a previous report [17]. One important original finding is that the worse prognosis associated with mEOC remained significant for FIGO stages II–III patients with macroscopic complete resection, suggesting that microscopic residual mucinous disease is resistant to adjuvant carboplatin–
2380 | Alexandre et al.
paclitaxel chemotherapy. Hence, even in patients with favorable clinical features, the mucinous histology was associated with a poorer outcome of advanced EOC. Together with the fact that cell type was not a prognostic factor for early-stage carcinoma confined to the ovary and treated by surgery alone in two prospective randomized trials [18], our results strongly suggest that the more dismal prognosis of advanced mEOC is mainly the result of resistance to carboplatin-paclitaxel-based chemotherapy, rather than tumor aggressiveness. Therefore, given the high expected rate of disease progression under chemotherapy, the neoadjuvant strategy using current protocols should be avoided. The poor efficacy of carboplatin– paclitaxel chemotherapy against mEOC strongly suggests that new therapeutic options are needed. Our findings support the hypothesis based on molecular studies that mEOC represents a separate disease entity. Recent observations indicated that mEOC arises from an ovarian cortical inclusion cyst, which has acquired a gastrointestinal or endocervical epithelium phenotype through metaplasia [19]. Mutations in the tumor-suppressor gene p53, often seen in sEOC, are not present in mEOC. In contrast, activating mutation of the K-RAS oncogene was observed in 50% of mEOC but very rarely in high-grade sEOC [20]. Finally, the gene-expression profile of mEOC appeared clearly distinct from that of sEOC and was correlated to those of normal colonic mucosa [21]. Taken together, those results plead for the evaluation of new therapeutics options for mEOC that have already been validated in digestive cancer, such as fluropyrimidines, oxaliplatin, irinotecan or bevacizumab. International efforts will be necessary to conduct large-scale randomized trials specifically tailored for advanced mEOC to rapidly establish new therapeutic options for this rare disease of poor prognosis.
disclosure None of the authors declare conflicts of interest.
references 1. Chan JK, Teoh D, Hu JM et al. Do clear cell ovarian carcinomas have poorer prognosis compared to other epithelial cell types? A study of 1411 clear cell ovarian cancers. Gynecol Oncol 2008; 109: 370–376. 2. Vergote I, De drabanter J, Fyles A et al. Prognostic importance of degree of differentiation and cyst rupture in stage I invasive epithelial ovarian carcinoma. Lancet 2001; 357: 176–182. 3. Omura GA, Brady MF, Homesley HD et al. Long-term follow-up and prognostic factor analysis in advanced ovarian carcinoma: the Gynecologic Oncology Group experience. J Clin Oncol 1991; 9: 1138–1150. 4. Teramukai S, Ochiai K, Tada H, Fukushima M. PIEPOC: a new prognostic index for advanced epithelial ovarian cancer-Japan Multinational Trial Organization OC01-01. J Clin Oncol 2007; 25: 3302–3306. 5. McGuire WP, Hoskins WJ, Brady MF et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996; 334: 1–6. 6. Piccart MJ, Bertelsen K, James K et al. Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results. J Natl Cancer Inst 2000; 92: 699–708. 7. Vergote I, Trope CG, Amant F et al. EORTC-GCG/NCIC-CTG randomized trial comparing primary debulking surgery with neoadjuvant chemotherapy in stage
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carboplatin-paclitaxel-based chemotherapy had a significantly shorter PFS and OS compared with sEOC patients with serous cell type (Figure 1A): respective median PFS and OS were 11.4 [95% confidence interval (CI) 8.3–14.5] months and 21.6 (95% CI 11.7–31.6) months for mEOC patients versus 17.5 (95% CI 16.2–18.8, P = 0.002) months and 47.2 (95% CI 42.6–51.9, P < 0.0001) months for sEOC. For patients with FIGO stage IV disease, mEOC was associated with very poor outcome (Figure 1B): respective median and 1-year PFS were 6.2 (95% CI 3.3– 91) months and 15% for mEOC patients versus 12.8 (95% CI 11.2–14.3, P < 0.0001) months and 51% (P = 0.02) for sEOC patients. Their respective median OS rates were 13.5 (95% CI 5.5–19.1) months and 27.4 (95% CI 23.2–33.2) months for stage IV mEOC and sEOC, respectively (P < 0.0001). The poorer prognosis of mEOC was also observed in patients with optimally debulked stages IIB–IIIC disease (Figure 1C). For this subpopulation, the median OS was 40.8 (95% CI 27.3–54.3) months for mEOC patients but was not reached for sEOC patients after a median follow-up of 46.2 months (P = 0.02). Median PFS was also shorter for mEOC patients but the difference was not significant [20.8 (95% CI 15.3–26.3) months versus 39.0 (95% CI 21.2–56.8) months, P = 0.4]. Their respective 2-year PFS rates were 42% and 66% (P = 0.05).
Annals of Oncology
Annals of Oncology
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9.
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14. Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92: 205–216. 15. Hess V, A’Hern R, Nasiri N et al. Mucinous epithelial ovarian cancer: a separate entity requiring specific treatment. J Clin Oncol 2004; 22: 1040–1044. 16. Pectasides D, Fountzilasb G, Aravantinos G et al. Advanced stage mucinous epithelial ovarian cancer: the Hellenic Cooperative Oncology Group experience. Gynecol Oncol 2005; 97: 436–441. 17. Tian C, Markman M, Zaino R et al. CA-125 change after chemotherapy in prediction of treatment outcome among advanced mucinous and clear cell epithelial ovarian cancers. Cancer 2009; 115: 1395–1403. 18. Trimbos JB, Parmar M, Vergote I et al. International Collaborative Ovarian Neoplasm trial 1 and Adjuvant Chemotherapy in Ovarian Neoplasm Trial: two parallel randomized phase III trials of adjuvant chemotherapy in patients with early-stage ovarian carcinoma. J Natl Cancer Inst 2003; 95: 105–112. 19. Levanon K, Crum C, Drapkin R. New insights into the pathogenesis of serous ovarian cancer and its clinical impact. J Clin Oncol 2008; 26: 5284–5293. 20. Gemignani ML, Schlaerth AC, Bogomolniy F et al. Role of KRAS and BRAF gene mutations in mucinous ovarian carcinoma. Gynecol Oncol 2003; 90: 378–381. 21. Marquez RT, Baggerly KA, Patterson AP et al. Patterns of gene expression in different histotypes of epithelial ovarian cancer correlate with those in normal fallopian tube, endometrium, and colon. Clin Cancer Res 2005; 11: 6116–6126.
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IIIC-IV ovarian, fallopian tube and peritoneal cancer. In 12th Meeting International Gynecologic Cancer Society (Abstr). Bangkok, Thailand 25–28 October 2008. Du Bois A, Weber B, Rochon J et al. Addition of epirubicin as a third drug to carboplatin-paclitaxel in first-line treatment of advanced ovarian cancer: a prospectively randomized Gynecologic Cancer Intergroup Trial by the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group and the Groupe d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens. J Clin Oncol 2006; 24: 1127–1135. Herrstedt J, Huober J, Priou F et al. A randomized, phase III study (AGO-OVAR-9, GINECO-TCG, NSGO-OC-0102): gemcitabine-paclitaxel-carboplatin (TCG) versus paclitaxel-carboplatin (TC) as first-line treatment of ovarian cancer (OC): survival of FIGO stage I-IIA patients. J Clin Oncol 2009; 27 (Suppl 2): 18s. Pfisterer J, Weber B, Reuss A et al. Randomized phase III trial of topotecan following carboplatin and paclitaxel in first-line treatment of advanced ovarian cancer: a Gynecologic Cancer Intergroup Trial of the AGO-OVAR and GINECO. J Natl Cancer Inst 2006; 98: 1036–1045. Ray-Coquard I, Paraiso D, Guastalla JP et al. Intensified dose of cyclophosphamide with G-CSF support versus standard dose combined with platinum in first-line treatment of advanced ovarian cancer a randomised study from the GINECO group. Br J Cancer 2007; 97: 1200–1205. Tre´dan O, Geay JF, Touzet S et al. Carboplatin/cyclophosphamide or carboplatin/ paclitaxel in elderly patients with advanced ovarian cancer? Analysis of two consecutive trials from the Groupe d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens. Ann Oncol 2007; 18: 256–262. World Health Organization. WHO Handbook for Reporting Results of Cancer Treatment. Offset publication 40. Geneva, Switzerland: World Health Organization 1979.
original article
Annals of Oncology 21: 2377–2381, 2010 doi:10.1093/annonc/mdq257 Published online 21 May 2010
Mucinous advanced epithelial ovarian carcinoma: clinical presentation and sensitivity to platinum– paclitaxel-based chemotherapy, the GINECO experience J. Alexandre1*, I. Ray-Coquard2, F. Selle3, A. Floquet4, P. Cottu5, B. Weber6, C. Falandry7, D. Lebrun8 & E. Pujade-Lauraine1 for the GINECO 1
Background: Advanced mucinous epithelial ovarian carcinoma (mEOC) has been associated with a worse prognosis than the more common serous epithelial ovarian carcinomas (sEOC), but it remains unclear whether this observation reflects a more aggressive clinical presentation and/or chemoresistance. Patients and methods: Data from four randomized phase III and one phase II advanced epithelial ovarian carcinoma (EOC) first-line clinical trials were retrospectively collected, yielding 1118 patients with advanced EOC (International Federation of Gynecology and Obstetrics stages IIB–IV), 85% of whom were treated with paclitaxel (Taxol)-carboplatin-based chemotherapy. Results: Based on 786 patients with sEOC and 54 (5%) with mEOC, peritoneal carcinomatosis were more limited in mEOC, which was more frequently stages IIB–IIIB (32% versus 19%, P = 0.001) and had more frequently macroscopic complete resection after initial surgery (50% of stages II–III versus 30%, P = 0.02). In contrast, visceral metastases (stage IV) were more frequent in mEOC (30% versus 15%, P = 0.004). mEOC had a lower response rate to carboplatin–paclitaxel, and shorter progression-free and overall survival rates, for both stage IV and optimally debulked stages II–III patients. Conclusions: Advanced mEOC appears to be highly chemoresistant and complete resection of peritoneal metastases is unable to reverse its poor prognosis. New therapeutic options are needed. Key words: mucinous, epithelial ovarian tumor, carboplatin, paclitaxel, chemoresistant
introduction The mucinous cell type accounts for 10% of all primary epithelial ovarian carcinomas (EOC) in Western countries [1]. Most mucinous epithelial ovarian carcinomas (mEOC) are diagnosed early [International Federation of Gynecology and Obstetrics (FIGO) stages I–IIA] and confined to one ovary. In stage I mEOC, the 5-year disease-free survival rate is 90%, which is slightly better than the 76% observed for patients with serous epithelial ovarian carcinomas (sEOC), the more common histopathological group [2]. Less frequently, primary mEOC is associated with peritoneal carcinomatosis and/or extraperitoneal metastases (FIGO stages IIB–IV). Unlike FIGO stage I tumors, advanced mEOC reportedly have poorer prognoses than sEOC [3, 4].
*Correspondence to: Dr J. Alexandre, Medical Oncology Unit, Hoˆtel-Dieu, 1, place du Parvis Noˆtre-Dame, 75004 Paris, France. Tel: +33-1-42-34-82-22; Fax: +33-1-42-34-81-10; E-mail: [email protected]
To date, patients with advanced mEOC receive the same first-line treatment as patients with sEOC. Based on randomized phase III studies, the current standard treatment is surgery followed by combined carboplatin–paclitaxel chemotherapy [5, 6]. Results of a recent randomized study suggested that a neoadjuvant strategy, combining primary chemotherapy followed by surgery, could improve the surgery-associated mortality and morbidity without impairing progression-free survival (PFS) and overall survival (OS) [7]. However, the small number of patients with mEOC in those phase III studies does not allow confirmation that such strategies are as optimal as they are for patients with sEOC. Moreover, it is unclear if the poor prognosis of advanced mEOC following standard treatment primarily reflects more aggressive disease, chemoresistance or both. To clarify this major concern, we retrospectively analyzed the GINECO experience, using data from our first-line clinical trials [8–12].
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
original article
Received 15 December 2009; revised 30 March 2010; accepted 31 March 2010
Downloaded from http://annonc.oxfordjournals.org/ at East Tennessee State University on June 29, 2015
Medical Oncology Unit, Universite´ Paris-Descartes, Hoˆtel-Dieu, Paris; 2Medical Oncology Department, Centre Le´on Be´rard, Lyon; 3Medical Oncology Department, Hoˆpital Tenon, Paris; 4Medical Oncology Department, Institut Bergonie´, Bordeaux; 5Medical Oncology Department, Institut Curie, Paris; 6Medical Oncology Department, Centre Alexis Vautrin, Nancy; 7Medical Oncology Department, CHU Lyon Sud, Pierre-Be´nite; 8Medical Oncology Department, Centre Jean Godinot, Reims, France
original article
Annals of Oncology
patients and methods
date of registration in the trial to the date of death and progression or death.
patient selection
data collection The following characteristics were extracted from the database for each patient with advanced sEOC or mEOC: age, performance status and baseline hemoglobin level, tumor grade, FIGO stage, macroscopic residual tumor after initial surgery, evidence of liver metastases and number of extraperitoneal tumor sites, best tumor response to chemotherapy and dates of progression and death. The EOC cell type was confirmed by histopathological review at the time of initial patient inclusion in the respective trial when the diagnosis had been difficult. A pathological examination of the appendix as well as gastroscopy and colonoscopy were a general practice in patients with bilateral and/or advanced ovarian mucinous carcinoma in order to rule out a gastrointestinal primary. The best tumor response was prospectively assessed in patients with measurable disease according to the World Health Organization definitions except for the carboplatin–paclitaxel with/without gemcitabine trial, which used the RECIST[13, 14]. OS and PFS were assessed, respectively, from the
Table 1. Number of patients included in the five trials selected for the present analysis Treatment [reference]
CbTx with/without epirubicin [8] CbTx with/without gemcitabine [9] CbTx with/without topotecan [10] CbTx in elderly patients [12] Total given CbTxbased ChT CpCy HD versus STD [11] Total, n (%)
Total no. of patients with advanced EOC
Patients included in the analysis sEOC mEOC
330
237
18
304
207
13
245
178
13
75
52
4
954
674
48
112 786 (70)
6 54 (5)
164 1118 (100)
CbTx, carboplatin–paclitaxel; ChT, chemotherapy; CpCy, cisplatin– cyclophosphamide; HD, high dose; STD, standard dose; EOC, epithelial ovarian carcinoma; sEOC, serous epithelial ovarian carcinoma; mEOC, mucinous epithelial ovarian carcinoma.
2378 | Alexandre et al.
statistical methods The main study objectives were to assess the baseline disease characteristics of patients and to compare carboplatin-paclitaxel-based chemotherapy efficacy (overall response rate, PFS and OS) in patients with advanced mEOC or sEOC. Predefined baseline characteristics were compared between groups using chi-square test (qualitative variables) or Student’s t-test (continuous variables). The Kaplan–Meier method was used to estimate the cumulative distribution of PFS and OS times according to histological subtype for the overall population and specifically for patients with stage IV and optimally debulked stages IIB–IIIC disease.
results patient characteristics A total of 1118 patients with advanced EOC were enrolled by the GINECO centers in the four selected clinical trials (Table 1): 786 (70%) sEOC and 54 (4.8%) mEOC. The patients with Table 2. Baseline characteristics of patients with sEOC or mEOC Characteristic
sEOC (n = 786)
Age (years), median (range) 61 (22–89) Performance status, n (%) 0–1 688 (89) 2–3 88 (11) Missing 10 Hemoglobin (g/dl), median 11.6 (6.9–15.9) (range) Tumor grade, n (%) 1–2 320 (61) 3 207 (39) Missing 259 Tumor stage, n (%) IIB–IIIB 150 (19) IIIC 513 (66) IV 119 (15) Missing 4 Stage IIB–IIIC, n 663 Macroscopic residual tumor after surgery, n (%) Yes 290 (70) No 119 (30) Missing 254 Stage IV, n 119 Liver metastases, n (%) Yes 27 (28) No 70 (72) Missing 22 Number of extraperitoneal sites, n (%) 1 77 (79) >1 20 (21) Missing 22
mEOC (n = 54)
P
54.5 (39–79)
0.18a
44 (83) 9 (17) 1 11.7 (7.8–14.8)
0.21
0.77a
29 (78) 8 (22) 17
0.03
17 (31) 20 (38) 16 (30) 1 37
0.001
14 (50) 14 (50) 9 16
0.02
7 (54) 6 (46) 3
0.06
10 (77) 3 (23) 3
0.8
0.004
Comparisons made by v2 test. a Comparisons made by Student’s t-test. sEOC, serous epithelial ovarian carcinoma; mEOC, mucinous epithelial ovarian carcinoma.
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The GINECO database provided individual data for patients with advanced EOC who participated in our clinical trials. The clinical trials were selected based on the following criteria: inclusion of patients with chemo-naı¨ve advanced EOC (FIGO stages IIB–IV), treatment with platinum-based chemotherapy and completed study. Four randomized phase III and one nonrandomized phase II trials were identified (Table 1) [8–12]. Three trials compared the standard carboplatin–paclitaxel (Taxol; Bristol-Myers Squibb, Rueil-Malmaison, France) combination with an experimental triplet combining carboplatin–paclitaxel with topotecan (Hycamtin; GlaxoSmithKline, Philadelphia, PA), epirubicin or gemcitabine [8–10]. One study compared standard and high doses of the cisplatin– cyclophosphamide combination [11]. The results of none of these studies showed any advantage in terms of response rate, PFS or OS of the experimental treatment over standard therapy. The phase II study evaluated the safety of carboplatin–paclitaxel in elderly women [12].
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Annals of Oncology
mEOC were slightly, but not significantly, younger than patients with sEOC (Table 2). Baseline performance status and hemoglobin levels were comparable for the two groups. Most patients were in good general condition. Compared with sEOC, mEOC were more frequently low grade (Table 2). Compared with sEOC, mEOC were associated with a significantly higher percentage of FIGO stages IIB–IIIB (P = 0.001) and complete resection achieved after initial surgery (P = 0.02). However, Table 3. Best tumor responses to carboplatin-paclitaxel–based chemotherapy in patients with measurable sEOC or mEOC sEOC (n = 340)
mEOC (n = 25)
P (v2)
Partial + complete, n (%) [95% CI] Stable disease, n (%) Progression, n (%)
275 (81) [77–85]
15 (60) [41–79]
<0.001
36 (11) 29 (9)
1 (4) 9 (36)
0.0001
sEOC, serous epithelial ovarian carcinoma; mEOC, mucinous epithelial ovarian carcinoma; CI, confidence interval.
carboplatin-paclitaxel-based chemotherapy efficacy Overall, 954 (85%) of the 1118 patients included in the study received a carboplatin-paclitaxel-based chemotherapy (Table 1). The percentage was similar in patients with serous and mucinous cell types (86% and 89%, respectively). Among patients with measurable disease, the objective (complete and partial) response rate to carboplatin-paclitaxelbased chemotherapy was significantly lower for mEOC patients than those with sEOC (P < 0.001; Table 3). Progressive disease as the best response to chemotherapy was significantly more frequently observed for mEOC patients (P < 0.0001). For the entire population, the median follow-up was 36.7 months. The patients with advanced mEOC receiving
Figure 1. Kaplan–Meier progression-free survival (PFS) and overall survival (OS) curves for patients with advanced serous ( ) or mucinous ( ) epithelial ovarian carcinoma (EOC). (A) Advanced FIGO stages IIB–IV EOC. (B) FIGO stage IV EOC. (C) FIGO stages IIB–IIIC EOC and complete surgical resection.
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Response
extraperitoneal metastases (FIGO stage IV) were also more frequent in mEOC than in sEOC patients (Table 2). Liver metastases tended to be more frequent in patients with mEOC (P = 0.06), while the metastasis frequencies in other sites (pleural, lung and lymph nodes) were comparable (data not shown).
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discussion Herein, we reported on one of the largest series of patients with advanced mEOC treated with modern chemotherapy. Based on data from four prospective studies, we observed that, compared with sEOC, mEOC was associated with lower response rate to carboplatin-paclitaxel-based chemotherapy and shorter PFS and OS. These results are in agreement with smaller previous reports. The Royal Marsden Hospital group reported the outcomes of 27 patients with advanced mEOC and 54 matched controls with non-mucinous histology, all treated with various platinum-based chemotherapies [15]: mEOC was independently associated with shorter PFS and OS. The retrospective analysis from the Hellenic Cooperative Oncology Group found that the 47 patients with advanced mEOC had a lower response rate to platinum-based chemotherapy than the 94 sEOC patients, but survival was similar for both populations [16]. Several explanations could be done to explain the worse prognosis of this subgroup of epithelial ovarian cancer. The poor prognosis of advanced mEOC could, at least in part, reflect the initial more aggressive clinical characteristics. Indeed, extraperitoneal spread appeared twice as frequently in mEOC than in sEOC and was associated with a very short median OS of about 1 year. However, well-recognized good prognostic factors were also more frequently associated with mucinous histology: patients were slightly younger, tumors were more frequently low grade and peritoneal carcinomatosis was more limited. Most importantly, macroscopic complete resection was more frequently achieved than for sEOC, which agrees with a previous report [17]. One important original finding is that the worse prognosis associated with mEOC remained significant for FIGO stages II–III patients with macroscopic complete resection, suggesting that microscopic residual mucinous disease is resistant to adjuvant carboplatin–
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paclitaxel chemotherapy. Hence, even in patients with favorable clinical features, the mucinous histology was associated with a poorer outcome of advanced EOC. Together with the fact that cell type was not a prognostic factor for early-stage carcinoma confined to the ovary and treated by surgery alone in two prospective randomized trials [18], our results strongly suggest that the more dismal prognosis of advanced mEOC is mainly the result of resistance to carboplatin-paclitaxel-based chemotherapy, rather than tumor aggressiveness. Therefore, given the high expected rate of disease progression under chemotherapy, the neoadjuvant strategy using current protocols should be avoided. The poor efficacy of carboplatin– paclitaxel chemotherapy against mEOC strongly suggests that new therapeutic options are needed. Our findings support the hypothesis based on molecular studies that mEOC represents a separate disease entity. Recent observations indicated that mEOC arises from an ovarian cortical inclusion cyst, which has acquired a gastrointestinal or endocervical epithelium phenotype through metaplasia [19]. Mutations in the tumor-suppressor gene p53, often seen in sEOC, are not present in mEOC. In contrast, activating mutation of the K-RAS oncogene was observed in 50% of mEOC but very rarely in high-grade sEOC [20]. Finally, the gene-expression profile of mEOC appeared clearly distinct from that of sEOC and was correlated to those of normal colonic mucosa [21]. Taken together, those results plead for the evaluation of new therapeutics options for mEOC that have already been validated in digestive cancer, such as fluropyrimidines, oxaliplatin, irinotecan or bevacizumab. International efforts will be necessary to conduct large-scale randomized trials specifically tailored for advanced mEOC to rapidly establish new therapeutic options for this rare disease of poor prognosis.
disclosure None of the authors declare conflicts of interest.
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carboplatin-paclitaxel-based chemotherapy had a significantly shorter PFS and OS compared with sEOC patients with serous cell type (Figure 1A): respective median PFS and OS were 11.4 [95% confidence interval (CI) 8.3–14.5] months and 21.6 (95% CI 11.7–31.6) months for mEOC patients versus 17.5 (95% CI 16.2–18.8, P = 0.002) months and 47.2 (95% CI 42.6–51.9, P < 0.0001) months for sEOC. For patients with FIGO stage IV disease, mEOC was associated with very poor outcome (Figure 1B): respective median and 1-year PFS were 6.2 (95% CI 3.3– 91) months and 15% for mEOC patients versus 12.8 (95% CI 11.2–14.3, P < 0.0001) months and 51% (P = 0.02) for sEOC patients. Their respective median OS rates were 13.5 (95% CI 5.5–19.1) months and 27.4 (95% CI 23.2–33.2) months for stage IV mEOC and sEOC, respectively (P < 0.0001). The poorer prognosis of mEOC was also observed in patients with optimally debulked stages IIB–IIIC disease (Figure 1C). For this subpopulation, the median OS was 40.8 (95% CI 27.3–54.3) months for mEOC patients but was not reached for sEOC patients after a median follow-up of 46.2 months (P = 0.02). Median PFS was also shorter for mEOC patients but the difference was not significant [20.8 (95% CI 15.3–26.3) months versus 39.0 (95% CI 21.2–56.8) months, P = 0.4]. Their respective 2-year PFS rates were 42% and 66% (P = 0.05).
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