- Email: [email protected]
Update on randomized trials on recurrent disease
symposium article
Annals of Oncology 24 (Supplement 10): x48–x52, 2013 doi:10.1093/annonc/mdt471
Update on randomized trials on recurrent disease A. González-Martín* MD Anderson Cancer Center, Madrid, Spain
symposium article
introduction
when should therapy be started?
Ovarian cancer is the leading cause of death from gynecological cancer in the Western World [1]. Despite adequate management of advanced ovarian cancer with upfront surgery and paclitaxel–carboplatin-based chemotherapy, ∼75% of patients will relapse within the first 3 years [2]. Unfortunately, recurrent ovarian cancer is an incurable disease in the great majority of cases. However, there are several options that can help, not only for palliation, but also for prolonging progression-free interval and even overall survival (OS). Several factors must be considered when designing the strategy for dealing with recurrent ovarian cancer in every individual case. The most relevant factors are progression-free interval since the last platinum administration in front-line therapy, the number and sites of relapsed disease, the clinical situation of the patient, residual toxicity from previous therapy, and patient preferences and expectations. Patient’s hopes were explored in a recent European survey where patients with recurrent ovarian cancer were asked to fill out a questionnaire [3]. The three most common answers were the following: ‘no recurrence of tumor-related symptoms’ (35%), ‘complete healing without any further complication’ (28%), and ‘live longer than I otherwise would’ (24%). Additionally, the last ovarian cancer consensus conference highlighted the importance of secondary end points such as health-related quality of life, patient-reported outcomes, and time without symptoms or toxicity, especially for patients with early relapse ( progression-free interval since last line of platinum of <6 months) [4].
Some patients present with an elevation of CA 125 that can be detected several months before symptoms or signs occur, or before the disease can be detected by imaging. For a long time, there was a dilemma on how to treat these patients. It was believed that an early treatment based only on an elevated CA 125 would affect the outcome, assuming that treating lowvolume disease with chemotherapy might lead to better survival. However, systemic therapy may cause harmful side-effects that may not be worth suffering if there would be no impact on survival. The MRC OV05/EORTC 55955 collaborative trial was designed with the aim to establish beneficial effects of early treatment based on an increase of CA125 only compared with delayed treatment based on clinical evidence of a recurrence [5]. One thousand four hundred forty-two patients were registered in the trial, of whom 529 were randomly assigned to early therapy (265 patients) or delayed therapy based on signs or symptoms of disease (264 patients); both were treated according to local practice in each center. The primary end point of this trial was OS. The final analysis showed no difference in survival between early or delayed treatment [hazard ratio (HR) 0.98, 95% confidence interval (CI) 0.80–1.20, P = 0.85]. Median survival from randomization was 25.7 months (95% CI 23.0– 27.9) for patients on early treatment and 27.1 months (95% CI 22.8–30.9) for those on delayed treatment. Moreover, early treatment was associated with an early deterioration of quality of life. The outcome of the trial was accepted in the 4th Ovarian Cancer Consensus Conference (OCCC), in that the participants confirmed and stated that treating patients with an asymptomatic CA-125 increase did not improve OS. However, at the same time, it was stated that asymptomatic patients without radiologic evidence of disease who meet the GCIG definition of CA-125 progression could be eligible for specific clinical trials [4].
*Correspondence to: Dr A. González-Martín, C/Arturo Soria 270, 28033-Madrid, Spain; E-mail: [email protected]
© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from http://annonc.oxfordjournals.org/ at Nipissing University on October 19, 2014
Approximately 75% of patients with advanced ovarian cancer will have a recurrence of their disease within the first 3 years after upfront surgery and paclitaxel–carboplatin-based chemotherapy. An optimal choice of treatment of patients with a recurrence is an important issue, and several factors should be taken into account in this decision-making, including disease, patients, and treatment. Fortunately, we have several strategies that can be of help not only with respect to palliation, but also in terms of survival benefit. Apart from surgery, which will be reviewed in another article of this series, different single cytotoxic agents and combinations and, more recently, the addition of antiangiogenic agents have shown that they can have impact on progression-free survival and, for some strategies, on the overall survival in such patients. In this review, we present an update of the clinical trials that have led to these achievements.
symposium article
Annals of Oncology
update on randomized trials in early relapse
update on randomized trials in late relapse Late relapse refers to patients with a progression-free interval longer than 6 months after the last dose of platinum-based chemotherapy. The 4th OCCC identified two different groups of patients, those with a progression-free interval of 6–12 months (also called partially platinum-sensitive) and those with a progression-free interval longer than 12 months (also called fully platinum-sensitive). Two large phase III trials, ICON-4 and AGO OVAR 2.5, and one small randomized phase II trial confirmed the superiority of platinum-based chemotherapy over monotherapy with platinum in patients with a late relapse (>6 months) in terms of response rate and PFS [21–23]. Additionally, the ICON-4 trial also showed a benefit in OS (Table 3). A meta-analysis of individual patient data of the two phase III and two randomized phase II trials confirmed the benefit in PFS (HR 0.68; 95% CI 0.57–0.81) and OS (HR 0.8; 95% CI 0.64–1.00) for the combination. Additionally, this meta-analysis confirmed the benefit for the combination in different subgroups of patients
Table 1. Randomized clinical trials with polychemotherapy in early relapsed ovarian cancer Schedule (author)
N
Response rate (%)
Median time to progression (months)
Median OS (months)
G3–4 Neutropeniaa (%)
Paclitaxel Paclitaxel + Doxorubicin (Torri et al.) Paclitaxel Paclitaxel + Epirubicin (Bolis et al.) Paclitaxel Paclitaxel + Epirubicin (Buda et al.) Topotecan Topotecan + Etoposide Topotecan + Gemcitabine (Sehouli et al.b) PLD Trabectedina + PLD (Monk et al.)c
116 118 40 41 106 106 178 177 147 117 115
54 52 17.1 34.2 37 47 27.8 36.1 31.6 – –
7.5 6.6 – – 6 6 7 7.8 6.3 3.7 4
12 14 9 13 14 12 17.2 17.8 15.2 – –
7 24 24.4 45 18.2 37.4 51 61 32 22.5 62.8
a
Data for Sehouli’s study correspond to leukopenia. The study by Sehouli et al. also included platinum-sensitive patients. c Subgroup analysis of the study OVA-301. b
Volume 24 | Supplement 10 | December 2013
doi:10.1093/annonc/mdt471 | x
Downloaded from http://annonc.oxfordjournals.org/ at Nipissing University on October 19, 2014
According to the 4th OCCC early relapse includes patients with progression while receiving last line of platinum-based therapy or within 4 weeks of last platinum dose to those with a progression-free interval since last line of platinum (treatment) of <6 months. This is the population with the worst prognosis and the expected median OS is usually <12 months. For this reason, controlling symptoms without significant side-effects and quality of life must be the main objectives for the treatment of patients with early relapse. A few trials showed that even moderately active chemotherapy prolongs OS in comparison to nonactive chemotherapy [6, 7]. Several randomized clinical trials have compared polychemotherapy with monotherapy in patients with early relapse of ovarian cancer [8–12]. However, none of these trials have shown significant differences in time-toprogression or OS (Table 1). Moreover, toxicity was substantially higher with the combinations, especially hematological toxicity. As quality of life is the main end point in this poor prognostic population, the treatment of patients with this so-called platinum-resistant disease should be based on sequential monotherapy. Several single agents have shown modest but unequivocal activity in platinum-resistant disease [13–19]. Response rates of 10%–15% and median OS figures of 9–12 months have been reported in randomized clinical trials with paclitaxel, topotecan, pegylated liposomal doxorubicin (PLD), oxaliplatin, gemcitabine, docetaxel, trabectedine, and etoposide. However, no randomized trial has shown any single agent to be superior in this clinical situation (Table 2), and selection of the therapeutic agent should be based on the expected toxicity of the available drug, the convenience of administration, and the preference of the patient. Early relapse ovarian cancer is the optimal field for testing new agents, and patients in a good clinical condition should be offered to participate in such clinical trials. One of the most promising new generations of trials has tested the value of
antiangiogenic therapy in this scenario. Bevacizumab, a monoclonal antibody against vascular endothelial growth factor showed clear activity in phase II trials for patients with recurrent disease. Its value in early relapse disease was explored in the AURELIA trial, a randomized phase III trial evaluating bevacizumab 15 mg/kg every 3 weeks plus standard chemotherapy selected by the physician versus the same chemotherapy alone [20]. This trial provides evidence that adding bevacizumab to standard chemotherapy leads to a statistically significant and clinically meaningful improvement in progression-free survival (PFS: 6.7 versus 3.4 months; HR 0.48; 95% CI 0.38–0.60) and objective response rate (ORR) versus chemotherapy alone (30.9% versus 12.6%). This is the first phase III trial in patients with early relapse to show benefit with a targeted therapy and improved outcome with a combination versus monotherapy.
symposium article
Annals of Oncology
Table 2. Randomized clinical trials with monotherapy in early relapsed ovarian cancer Agents
N
RR (%)
TTP (weeks)
OS (weeks)
Topotecan Paclitaxel
112 (60 PR) 114 (59 PR)
13.3 6.7
61a 43a
Gordon
Topotecan PLD PLD Paclitaxel Oxaliplatin Topotecan PLD Gemcitabine PLD Gemcitabine Topotecan Topotecan weekly
235 (124 PR) 239 (130 PR) 106 (60% PR) 107 (63% PR) 79 (51 PR) 79 (53 PR) 76 (43 PR) 77 (43 PR) 96 99 97 97
8 16 19a 24a 3.9 5.7 16a 29a 6.1 8.3 14.4 7.2
23a 14a P = 0.002 13.6 9.1 22a 22a – – 16a 20a 3.6 months 3.1 months 4.4 months 3.0 months
O’Byrne Vermorken Ferrandina Mutch Sehouli
41 35 46.7a 56a – – 56a 51a 12.7 months 13.5 months 9.6 months 9.3 months
a
Results for the whole population (platinum-resistant plus platinum-sensitive). RR, response rate; TTP, time to progression; PR, platinum-resistant; PLD, pegylated liposomal doxorubicin; hazard ratio; CI, confidence interval; OS, overall survival. Table 3. Carboplatinum-based combination versus carboplatin in patients with late-relapsed ovarian cancer
ARM Schedule
N Patients
RR (%) TTP (months) HR OS (months) HR
ICON-4/AGO 2.2
GEICO 9901
Platinum Paclitaxel Platinum 71% Carbo 80% PCb 17% CAP 10% PCis 12% other 10% other 392 410 100% PFI >6 months 92% 1 previous line 75% PFI >12 months 40% previous taxane 54 66 P = 0.06 9 12 HR 0.76 (95% CI 0.66–0.89); P = 0.0004 24 29 0.82 (95% CI 0.69–0.97); P = 0.02
Platinum Carbo
AGO-OVAR 2.5 Paclitaxel Platinum Paclitaxel Carbo
41
Carboplatin Carboplatin
41 100% PFI >6 months 85% 1 previous line 60% PFI >12 months 80% previous taxane 50 75.6 P = 0.017 8.4 12.2 HR 0.54 (95% CI 0.32–0.92)
178
18.1
17.3
NR Log-rank 0.0021
31 5.8
Carboplatin Gemcitabine Carboplatin Gemcitabine
178 100% PFI >6 months 100% 1 previous line 60% PFI >12 months 70% previous taxane 47 P = 0.0016 8.6 HR 0.72 (95% CI 0.58–0.90) 18 0.96 (95% CI 0.75–1.23); P = 0.73
Carbo, carboplatin; PCb, paclitaxel–carboplatin; PCis, paclitaxel–cisplatin; PFI, platinum free interval; NR, not reached; RR, response rate.
independent of previous use of paclitaxel, the platinum-free interval (6–12 versus >12 months), and the number of previous chemotherapy lines (1 versus 2 or more) [24]. As mentioned above, the paclitaxel–carboplatin combination is inducing a survival benefit over the use of carboplatin alone in this platinum-sensitive subpopulation. However, the almost universal alopecia and grade 2–3 peripheral neuropathy, affecting 20%–30% of the patients, have a negative impact on quality of life. Therefore, other carboplatin-based doublets have been designed with the aim to avoid the paclitaxel-associated toxicity. Gemcitabine, PLD and topotecan have been the selected partners for carboplatin. The CALYPSO trial was a randomized phase III noninferiority trial that showed the PLD/carboplatin combination to be as effective as the
x | González-Martín
paclitaxel–carboplatin but with a different toxicity profile, which consisted of less alopecia and neuropathy but more grade 3–4 thrombocytopenia, mucositis, and hand-foot syndrome [25]. An updated assessment of this trial has confirmed a similar median OS in both arms (33 months with paclitaxel– carboplatin and 30.7 months with carboplatin–PLD) [26]. The HECTOR trial explored the combination of carboplatin and topotecan versus other carboplatin-doublets and showed no significant difference in outcome but a lower hematological toxicity for the experimental arm [27]. In summary, no carboplatin-doublet can be considered superior to the other in terms of efficacy and the choice between treatment options should be based on toxicity profile and preference of the patient.
Volume 24 | Supplement 10 | December 2013
Downloaded from http://annonc.oxfordjournals.org/ at Nipissing University on October 19, 2014
Author Ten Bokkel Huinink
Annals of Oncology
conclusion The treatment of patients with recurrent ovarian cancer is still a great challenge for the physician, as several factors have to be
Volume 24 | Supplement 10 | December 2013
considered when selecting a regimen or a strategy, including the hopes and desires of the patient. This review has updated some of the most relevant phase III randomized clinical trials with chemotherapy and new agents in recurrent disease in order to provide the most recent evidence for available drugs. A well justified choice of single drugs or combination of drugs and treatment strategies (i.e. surgery, prolongation of platinum-free interval, or antiangiogenic therapy) may prolong survival for the individual patient with recurrent ovarian cancer.
disclosure The author has declared no conflicts of interest.
references 1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013; 63: 11–30. 2. Bookman MA, Brady MF, McGuire WP et al. Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer: a phase III trial of the Gynecologic Cancer Intergroup. J Clin Oncol 2009; 27: 1419–1425. 3. Oskay-Özcelik G, Chekerov R, Neubert S et al. What do 676 primary and recurrent ovarian cancer patients expect from their doctors and therapy management— results of a German survey of the northeastern German Society of Gynecological Oncology (NOGGO). J Clin Oncol 2012; 30 (suppl): abstr 5044. 4. Friedlander M, Trimble E, Tinker A et al. Clinical trials in recurrent ovarian cancer. Int J Gynecol Cancer 2011; 21: 771–775. 5. Rustin GJS, van der Burg MEL, Griffin CL et al. Early versus delayed treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): a randomised trial. Lancet 2010; 376: 1155–1163. 6. Meier W, du Bois A, Reuss A et al. Topotecan versus treosulfan, an alkylating agent, in patients with epithelial ovarian cancer and relapse within 12 months following 1st-line platinum/paclitaxel chemotherapy. A prospectively randomized phase III trial by the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group (AGO-OVAR). Gynecol Oncol 2009; 114: 199–205. 7. Vergote I, Finkler N, del Campo J et al. Phase 3 randomised study of canfosfamide (Telcyta, TLK286) versus pegylated liposomal doxorubicin or topotecan as thirdline therapy in patients with platinum-refractory or -resistant ovarian cancer. Eur J Cancer 2009; 45: 2324–2332. 8. Torri V, Floriani I, Tinazzi A et al. Randomized trial comparing paclitaxel +doxorubicin (AT) versus paclitaxel (T) as second line therapy for advanced ovarian cancer (AOC) patients in early progression after platinum based chemotherapy. Proc Am Soc Clin Oncol 2000; 19 (abstract 1506). 9. Bolis G, Parazzini F, Scarfone G et al. Paclitaxel vs epidoxorubicin plus paclitaxel as second-line therapy for platinum-refractory and -resistant ovarian cancer. Gynecol Oncol 1999; 72: 60–64. 10. Buda A, Floriani I, Rossi R et al. Randomised controlled trial comparing single agent paclitaxel vs epidoxorubicin plus paclitaxel in patients with advanced ovarian cancer in early progression after platinum-based chemotherapy: an Italian Collaborative Study from the Mario Negri Institute, Milan, G.O.N.O. (Gruppo Oncologico Nord Ovest) group and I.O.R. (Istituto Oncologico Romagnolo) group. Br J Cancer 2004; 90: 2112–2117. 11. Sehouli J, Stengel D, Oskay-Oezcelik . Nonplatinum topotecan combinations versus topotecan alone for recurrent ovarian cancer: results of a phase III study of the North-Eastern German Society of Gynecological Oncology Ovarian Cancer Study Group. J Clin Oncol 2008; 26: 3176–3182. 12. Monk BJ, Herzog TJ, Kaye SB et al. Trabectedin plus pegylated liposomal Doxorubicin in recurrent ovarian cancer. J Clin Oncol 2010; 28: 3107–3114. 13. Ten Bokkel Huinink W, Gore M, Carmichael J et al. Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. J Clin Oncol 1997; 15: 2183–2193. 14. Gordon AN, Tonda M, Sun S et al. Long-term survival advantage for women treated with pegylated liposomal doxorubicin compared with topotecan in a phase
doi:10.1093/annonc/mdt471 | x
Downloaded from http://annonc.oxfordjournals.org/ at Nipissing University on October 19, 2014
There are two other strategies beyond carboplatin-based chemotherapy that have demonstrated benefit for patients with a late relapse, i.e. the use of a nonplatinum-based combination, and the addition of the antiangiogenic agent bevacizumab. The OVA-301 trial tested the combination of trabectedin with PLD against PLD monotherapy in patients who were no candidate or not willing to receive additional platinum-based therapy at relapse. Trabectedin/PLD provided a 21% risk reduction for progressive disease or death compared with PLD monotherapy (HR 0.79; 95% CI 0.65–0.96; P = 0.0190) by independent radiology review [12]. Median PFS was 7.3 months for trabectedin/PLD and 5.8 months for PLD alone. By subgroup analysis, trabectedin/PLD only improved PFS in platinum-sensitive patients (9.2 versus 7.5 months), with a 27% risk reduction (HR 0.73; 95% CI 0.56–0.95; P = 0.0170), and no significant difference was observed in platinum-resistant patients (median, 4.0 and 3.7 months with combination and monotherapy, respectively). An update of the OS data confirmed a trend toward better OS for the combination arm that did not reach statistical significance [28]. One interesting subanalysis showed that the group of patients with a progression-free interval of 6–12 months obtained an increment in OS when treated with trabectedin and PLD compared with PLD monotherapy [29]. This difference was more evident when platinum was the next regimen used after progression on the trial medication, raising the hypothesis that a prolongation of the platinum-free interval by a nonplatinumbased regimen could restore platinum sensitivity and be beneficial for the patient [30]. This hypothesis is the background of the randomized clinical trial INternational OVArian Cancer Patients Trial With YONdelis (INOVATYON), which includes patients with recurrent OC and a progressionfree interval of 6–12 months after first-line treatment and compares the combination of carboplatin–PLD followed by the regimen selected by the investigator at progression or trabectedine–PLD followed by a platinum-based regimen at progression. The OCEANS trial tested the addition of bevacizumab to a standard carboplatin doublet for the treatment of patients with a late relapse. This randomized clinical trial compared carboplatin–gemcitabine plus bevacizumab with carboplatin– gemcitabine–placebo in 484 patients with a recurrent ovarian cancer over 6 months after first line of platinum-based chemotherapy. Patients included needed to have measurable disease and the primary end point was PFS determined by RECIST progression. The association of bevacizumab increased the median PFS from 8.4 to 12.4 months (HR 0.48; 95% CI 0.34–0.60), and was confirmed by an independent radiology committee [31]. Additionally, the response rate was also higher (78.5% versus 57.4%; P < 0.0001). The third preplanned analysis of OS has not shown significant differences (33.4 with bevacizumab versus 33.7 with placebo), which most probably was due to the long postprogression time and the substantial number of chemotherapy lines given during that period.
symposium article
symposium article 15.
16.
17.
18.
19.
21.
22.
23.
x | González-Martín
24. Raja FA, Counsell N, Colombo N et al. Platinum versus combination platinum chemotherapy in platinum-sensitive recurrent ovarian cancer; a meta-analysis of randomised trials using individual patient data (IPD). Ann Oncol 2013; in press. 25. Pujade-Lauraine E, Wagner U, Aavall-Lundqvist E et al. Pegylated liposomal Doxorubicin and Carboplatin compared with Paclitaxel and Carboplatin for patients with platinum-sensitive ovarian cancer in late relapse. J Clin Oncol 2010; 28: 3323–3329. 26. Wagner U, Marth C, Largillier R et al. Final overall survival results of phase III GCIG CALYPSO trial of pegylated liposomal doxorubicin and carboplatin vs paclitaxel and carboplatin in platinum-sensitive ovarian cancer patients. Br J Cancer 2012; 107: 588–591. 27. Sehouli J, Meier W, Wimberger P et al. Topotecan plus carboplatin versus standard therapy with paclitaxel plus carboplatin (PC) or gemcitabine plus carboplatin (GC) or pegylated liposomal doxorubicin plus carboplatin (PLDC): a randomized phase III trial of the NOGGO-AGO-Germany-AGO Austria and GEICO-ENGOT-GCIG intergroup study (HECTOR). J Clin Oncol 2012; 30 (suppl): abstr 5031. 28. Monk BJ, Herzog TJ, Kaye SB et al. Trabectedin plus pegylated liposomal doxorubicin (PLD) versus PLD in recurrent ovarian cancer: overall survival analysis. Eur J Cancer 2012; 48: 2361–2368. 29. Poveda A, Vergote I, Tjulandin S et al. Trabectedin plus pegylated liposomal doxorubicin in relapsed ovarian cancer: outcomes in the partially platinumsensitive ( platinum-free interval 6-12 months) subpopulation of OVA-301 phase III randomized trial. Ann Oncol 2011; 22: 39–48. 30. Colombo N et al. Efficacy of trabectedin in platinum-sensitive-relapsed ovarian cancer: new data from the randomized OVA-301 study. Int J Gynecol Cancer 2011; 21 (Suppl 1): S12–S16. 31. Aghajanian C, Blank SV, Goff BA et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol 2012; 30: 2039–2045.
Volume 24 | Supplement 10 | December 2013
Downloaded from http://annonc.oxfordjournals.org/ at Nipissing University on October 19, 2014
20.
3 randomized study of recurrent and refractory ovarian cancer. Gynecol Oncol 2004; 95: 1–8. O’Byrne KJ, Bliss P, Graham JD et al. A phase III study of Caelyx versus paclitaxel in platinum-treated taxane-naive relapsed ovarian cancer. Proc Am Soc Clin Oncol 2002; 21 203 (abstract 808). Vermorken J, Gore M, Perren T et al. Multicenter randomised phase II study of oxaliplatin or topotecan in platinum-pretreated epithelial ovarian cancer patients. Proc Am Soc Clin Oncol 2001; 20 212 (abstract 847). Ferrandina G, Ludovisi M, Lorusso D et al. Phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in progressive or recurrent ovarian cancer. J Clin Oncol 2008; 26: 890–896. Mutch DG, Orlando M, Goss T et al. Randomized phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer. J Clin Oncol 2007; 25: 2811–2818. Sehouli J, Stengel D, Harter P et al. Topotecan Weekly Versus Conventional 5-Day Schedule in Patients With Platinum-Resistant Ovarian Cancer: a randomized multicenter phase II trial of the North-Eastern German Society of Gynecological Oncology Ovarian Cancer Study Group. J Clin Oncol 2011; 29: 242–248. Eric P-L, Felix H, Béatrice W et al. AURELIA: a randomized phase III trial evaluating bevacizumab (BEV) plus chemotherapy (CT) for platinum (PT)-resistant recurrent ovarian cancer (OC). J Clin Oncol 2012; 30 (suppl): abstr LBA5002. The ICON and AGO Collaborators. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet 2003; 361: 2099–2106. González-Martín A, Calvo E, Bover I et al. Randomised phase II study of carboplatin versus paclitaxel-carboplatin in platinum–sensitive recurrent advanced ovarian cancer: a GEICO study. Ann Oncol 2005; 16: 749–755. Pfisterer J, Plante M, Vergote I et al. Gemcitabine/carboplatin vs. carboplatin in platinum sensitive recurrent ovarian cancer. Results of a Gynecologic Cancer Intergroup randomized phase III trial of the AGO OVAR, the NCIC CTG and the EORTC GCG. J Clin Oncol 2006; 24: 4699–4707.
Annals of Oncology
Annals of Oncology 24 (Supplement 10): x48–x52, 2013 doi:10.1093/annonc/mdt471
Update on randomized trials on recurrent disease A. González-Martín* MD Anderson Cancer Center, Madrid, Spain
symposium article
introduction
when should therapy be started?
Ovarian cancer is the leading cause of death from gynecological cancer in the Western World [1]. Despite adequate management of advanced ovarian cancer with upfront surgery and paclitaxel–carboplatin-based chemotherapy, ∼75% of patients will relapse within the first 3 years [2]. Unfortunately, recurrent ovarian cancer is an incurable disease in the great majority of cases. However, there are several options that can help, not only for palliation, but also for prolonging progression-free interval and even overall survival (OS). Several factors must be considered when designing the strategy for dealing with recurrent ovarian cancer in every individual case. The most relevant factors are progression-free interval since the last platinum administration in front-line therapy, the number and sites of relapsed disease, the clinical situation of the patient, residual toxicity from previous therapy, and patient preferences and expectations. Patient’s hopes were explored in a recent European survey where patients with recurrent ovarian cancer were asked to fill out a questionnaire [3]. The three most common answers were the following: ‘no recurrence of tumor-related symptoms’ (35%), ‘complete healing without any further complication’ (28%), and ‘live longer than I otherwise would’ (24%). Additionally, the last ovarian cancer consensus conference highlighted the importance of secondary end points such as health-related quality of life, patient-reported outcomes, and time without symptoms or toxicity, especially for patients with early relapse ( progression-free interval since last line of platinum of <6 months) [4].
Some patients present with an elevation of CA 125 that can be detected several months before symptoms or signs occur, or before the disease can be detected by imaging. For a long time, there was a dilemma on how to treat these patients. It was believed that an early treatment based only on an elevated CA 125 would affect the outcome, assuming that treating lowvolume disease with chemotherapy might lead to better survival. However, systemic therapy may cause harmful side-effects that may not be worth suffering if there would be no impact on survival. The MRC OV05/EORTC 55955 collaborative trial was designed with the aim to establish beneficial effects of early treatment based on an increase of CA125 only compared with delayed treatment based on clinical evidence of a recurrence [5]. One thousand four hundred forty-two patients were registered in the trial, of whom 529 were randomly assigned to early therapy (265 patients) or delayed therapy based on signs or symptoms of disease (264 patients); both were treated according to local practice in each center. The primary end point of this trial was OS. The final analysis showed no difference in survival between early or delayed treatment [hazard ratio (HR) 0.98, 95% confidence interval (CI) 0.80–1.20, P = 0.85]. Median survival from randomization was 25.7 months (95% CI 23.0– 27.9) for patients on early treatment and 27.1 months (95% CI 22.8–30.9) for those on delayed treatment. Moreover, early treatment was associated with an early deterioration of quality of life. The outcome of the trial was accepted in the 4th Ovarian Cancer Consensus Conference (OCCC), in that the participants confirmed and stated that treating patients with an asymptomatic CA-125 increase did not improve OS. However, at the same time, it was stated that asymptomatic patients without radiologic evidence of disease who meet the GCIG definition of CA-125 progression could be eligible for specific clinical trials [4].
*Correspondence to: Dr A. González-Martín, C/Arturo Soria 270, 28033-Madrid, Spain; E-mail: [email protected]
© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from http://annonc.oxfordjournals.org/ at Nipissing University on October 19, 2014
Approximately 75% of patients with advanced ovarian cancer will have a recurrence of their disease within the first 3 years after upfront surgery and paclitaxel–carboplatin-based chemotherapy. An optimal choice of treatment of patients with a recurrence is an important issue, and several factors should be taken into account in this decision-making, including disease, patients, and treatment. Fortunately, we have several strategies that can be of help not only with respect to palliation, but also in terms of survival benefit. Apart from surgery, which will be reviewed in another article of this series, different single cytotoxic agents and combinations and, more recently, the addition of antiangiogenic agents have shown that they can have impact on progression-free survival and, for some strategies, on the overall survival in such patients. In this review, we present an update of the clinical trials that have led to these achievements.
symposium article
Annals of Oncology
update on randomized trials in early relapse
update on randomized trials in late relapse Late relapse refers to patients with a progression-free interval longer than 6 months after the last dose of platinum-based chemotherapy. The 4th OCCC identified two different groups of patients, those with a progression-free interval of 6–12 months (also called partially platinum-sensitive) and those with a progression-free interval longer than 12 months (also called fully platinum-sensitive). Two large phase III trials, ICON-4 and AGO OVAR 2.5, and one small randomized phase II trial confirmed the superiority of platinum-based chemotherapy over monotherapy with platinum in patients with a late relapse (>6 months) in terms of response rate and PFS [21–23]. Additionally, the ICON-4 trial also showed a benefit in OS (Table 3). A meta-analysis of individual patient data of the two phase III and two randomized phase II trials confirmed the benefit in PFS (HR 0.68; 95% CI 0.57–0.81) and OS (HR 0.8; 95% CI 0.64–1.00) for the combination. Additionally, this meta-analysis confirmed the benefit for the combination in different subgroups of patients
Table 1. Randomized clinical trials with polychemotherapy in early relapsed ovarian cancer Schedule (author)
N
Response rate (%)
Median time to progression (months)
Median OS (months)
G3–4 Neutropeniaa (%)
Paclitaxel Paclitaxel + Doxorubicin (Torri et al.) Paclitaxel Paclitaxel + Epirubicin (Bolis et al.) Paclitaxel Paclitaxel + Epirubicin (Buda et al.) Topotecan Topotecan + Etoposide Topotecan + Gemcitabine (Sehouli et al.b) PLD Trabectedina + PLD (Monk et al.)c
116 118 40 41 106 106 178 177 147 117 115
54 52 17.1 34.2 37 47 27.8 36.1 31.6 – –
7.5 6.6 – – 6 6 7 7.8 6.3 3.7 4
12 14 9 13 14 12 17.2 17.8 15.2 – –
7 24 24.4 45 18.2 37.4 51 61 32 22.5 62.8
a
Data for Sehouli’s study correspond to leukopenia. The study by Sehouli et al. also included platinum-sensitive patients. c Subgroup analysis of the study OVA-301. b
Volume 24 | Supplement 10 | December 2013
doi:10.1093/annonc/mdt471 | x
Downloaded from http://annonc.oxfordjournals.org/ at Nipissing University on October 19, 2014
According to the 4th OCCC early relapse includes patients with progression while receiving last line of platinum-based therapy or within 4 weeks of last platinum dose to those with a progression-free interval since last line of platinum (treatment) of <6 months. This is the population with the worst prognosis and the expected median OS is usually <12 months. For this reason, controlling symptoms without significant side-effects and quality of life must be the main objectives for the treatment of patients with early relapse. A few trials showed that even moderately active chemotherapy prolongs OS in comparison to nonactive chemotherapy [6, 7]. Several randomized clinical trials have compared polychemotherapy with monotherapy in patients with early relapse of ovarian cancer [8–12]. However, none of these trials have shown significant differences in time-toprogression or OS (Table 1). Moreover, toxicity was substantially higher with the combinations, especially hematological toxicity. As quality of life is the main end point in this poor prognostic population, the treatment of patients with this so-called platinum-resistant disease should be based on sequential monotherapy. Several single agents have shown modest but unequivocal activity in platinum-resistant disease [13–19]. Response rates of 10%–15% and median OS figures of 9–12 months have been reported in randomized clinical trials with paclitaxel, topotecan, pegylated liposomal doxorubicin (PLD), oxaliplatin, gemcitabine, docetaxel, trabectedine, and etoposide. However, no randomized trial has shown any single agent to be superior in this clinical situation (Table 2), and selection of the therapeutic agent should be based on the expected toxicity of the available drug, the convenience of administration, and the preference of the patient. Early relapse ovarian cancer is the optimal field for testing new agents, and patients in a good clinical condition should be offered to participate in such clinical trials. One of the most promising new generations of trials has tested the value of
antiangiogenic therapy in this scenario. Bevacizumab, a monoclonal antibody against vascular endothelial growth factor showed clear activity in phase II trials for patients with recurrent disease. Its value in early relapse disease was explored in the AURELIA trial, a randomized phase III trial evaluating bevacizumab 15 mg/kg every 3 weeks plus standard chemotherapy selected by the physician versus the same chemotherapy alone [20]. This trial provides evidence that adding bevacizumab to standard chemotherapy leads to a statistically significant and clinically meaningful improvement in progression-free survival (PFS: 6.7 versus 3.4 months; HR 0.48; 95% CI 0.38–0.60) and objective response rate (ORR) versus chemotherapy alone (30.9% versus 12.6%). This is the first phase III trial in patients with early relapse to show benefit with a targeted therapy and improved outcome with a combination versus monotherapy.
symposium article
Annals of Oncology
Table 2. Randomized clinical trials with monotherapy in early relapsed ovarian cancer Agents
N
RR (%)
TTP (weeks)
OS (weeks)
Topotecan Paclitaxel
112 (60 PR) 114 (59 PR)
13.3 6.7
61a 43a
Gordon
Topotecan PLD PLD Paclitaxel Oxaliplatin Topotecan PLD Gemcitabine PLD Gemcitabine Topotecan Topotecan weekly
235 (124 PR) 239 (130 PR) 106 (60% PR) 107 (63% PR) 79 (51 PR) 79 (53 PR) 76 (43 PR) 77 (43 PR) 96 99 97 97
8 16 19a 24a 3.9 5.7 16a 29a 6.1 8.3 14.4 7.2
23a 14a P = 0.002 13.6 9.1 22a 22a – – 16a 20a 3.6 months 3.1 months 4.4 months 3.0 months
O’Byrne Vermorken Ferrandina Mutch Sehouli
41 35 46.7a 56a – – 56a 51a 12.7 months 13.5 months 9.6 months 9.3 months
a
Results for the whole population (platinum-resistant plus platinum-sensitive). RR, response rate; TTP, time to progression; PR, platinum-resistant; PLD, pegylated liposomal doxorubicin; hazard ratio; CI, confidence interval; OS, overall survival. Table 3. Carboplatinum-based combination versus carboplatin in patients with late-relapsed ovarian cancer
ARM Schedule
N Patients
RR (%) TTP (months) HR OS (months) HR
ICON-4/AGO 2.2
GEICO 9901
Platinum Paclitaxel Platinum 71% Carbo 80% PCb 17% CAP 10% PCis 12% other 10% other 392 410 100% PFI >6 months 92% 1 previous line 75% PFI >12 months 40% previous taxane 54 66 P = 0.06 9 12 HR 0.76 (95% CI 0.66–0.89); P = 0.0004 24 29 0.82 (95% CI 0.69–0.97); P = 0.02
Platinum Carbo
AGO-OVAR 2.5 Paclitaxel Platinum Paclitaxel Carbo
41
Carboplatin Carboplatin
41 100% PFI >6 months 85% 1 previous line 60% PFI >12 months 80% previous taxane 50 75.6 P = 0.017 8.4 12.2 HR 0.54 (95% CI 0.32–0.92)
178
18.1
17.3
NR Log-rank 0.0021
31 5.8
Carboplatin Gemcitabine Carboplatin Gemcitabine
178 100% PFI >6 months 100% 1 previous line 60% PFI >12 months 70% previous taxane 47 P = 0.0016 8.6 HR 0.72 (95% CI 0.58–0.90) 18 0.96 (95% CI 0.75–1.23); P = 0.73
Carbo, carboplatin; PCb, paclitaxel–carboplatin; PCis, paclitaxel–cisplatin; PFI, platinum free interval; NR, not reached; RR, response rate.
independent of previous use of paclitaxel, the platinum-free interval (6–12 versus >12 months), and the number of previous chemotherapy lines (1 versus 2 or more) [24]. As mentioned above, the paclitaxel–carboplatin combination is inducing a survival benefit over the use of carboplatin alone in this platinum-sensitive subpopulation. However, the almost universal alopecia and grade 2–3 peripheral neuropathy, affecting 20%–30% of the patients, have a negative impact on quality of life. Therefore, other carboplatin-based doublets have been designed with the aim to avoid the paclitaxel-associated toxicity. Gemcitabine, PLD and topotecan have been the selected partners for carboplatin. The CALYPSO trial was a randomized phase III noninferiority trial that showed the PLD/carboplatin combination to be as effective as the
x | González-Martín
paclitaxel–carboplatin but with a different toxicity profile, which consisted of less alopecia and neuropathy but more grade 3–4 thrombocytopenia, mucositis, and hand-foot syndrome [25]. An updated assessment of this trial has confirmed a similar median OS in both arms (33 months with paclitaxel– carboplatin and 30.7 months with carboplatin–PLD) [26]. The HECTOR trial explored the combination of carboplatin and topotecan versus other carboplatin-doublets and showed no significant difference in outcome but a lower hematological toxicity for the experimental arm [27]. In summary, no carboplatin-doublet can be considered superior to the other in terms of efficacy and the choice between treatment options should be based on toxicity profile and preference of the patient.
Volume 24 | Supplement 10 | December 2013
Downloaded from http://annonc.oxfordjournals.org/ at Nipissing University on October 19, 2014
Author Ten Bokkel Huinink
Annals of Oncology
conclusion The treatment of patients with recurrent ovarian cancer is still a great challenge for the physician, as several factors have to be
Volume 24 | Supplement 10 | December 2013
considered when selecting a regimen or a strategy, including the hopes and desires of the patient. This review has updated some of the most relevant phase III randomized clinical trials with chemotherapy and new agents in recurrent disease in order to provide the most recent evidence for available drugs. A well justified choice of single drugs or combination of drugs and treatment strategies (i.e. surgery, prolongation of platinum-free interval, or antiangiogenic therapy) may prolong survival for the individual patient with recurrent ovarian cancer.
disclosure The author has declared no conflicts of interest.
references 1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013; 63: 11–30. 2. Bookman MA, Brady MF, McGuire WP et al. Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer: a phase III trial of the Gynecologic Cancer Intergroup. J Clin Oncol 2009; 27: 1419–1425. 3. Oskay-Özcelik G, Chekerov R, Neubert S et al. What do 676 primary and recurrent ovarian cancer patients expect from their doctors and therapy management— results of a German survey of the northeastern German Society of Gynecological Oncology (NOGGO). J Clin Oncol 2012; 30 (suppl): abstr 5044. 4. Friedlander M, Trimble E, Tinker A et al. Clinical trials in recurrent ovarian cancer. Int J Gynecol Cancer 2011; 21: 771–775. 5. Rustin GJS, van der Burg MEL, Griffin CL et al. Early versus delayed treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): a randomised trial. Lancet 2010; 376: 1155–1163. 6. Meier W, du Bois A, Reuss A et al. Topotecan versus treosulfan, an alkylating agent, in patients with epithelial ovarian cancer and relapse within 12 months following 1st-line platinum/paclitaxel chemotherapy. A prospectively randomized phase III trial by the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group (AGO-OVAR). Gynecol Oncol 2009; 114: 199–205. 7. Vergote I, Finkler N, del Campo J et al. Phase 3 randomised study of canfosfamide (Telcyta, TLK286) versus pegylated liposomal doxorubicin or topotecan as thirdline therapy in patients with platinum-refractory or -resistant ovarian cancer. Eur J Cancer 2009; 45: 2324–2332. 8. Torri V, Floriani I, Tinazzi A et al. Randomized trial comparing paclitaxel +doxorubicin (AT) versus paclitaxel (T) as second line therapy for advanced ovarian cancer (AOC) patients in early progression after platinum based chemotherapy. Proc Am Soc Clin Oncol 2000; 19 (abstract 1506). 9. Bolis G, Parazzini F, Scarfone G et al. Paclitaxel vs epidoxorubicin plus paclitaxel as second-line therapy for platinum-refractory and -resistant ovarian cancer. Gynecol Oncol 1999; 72: 60–64. 10. Buda A, Floriani I, Rossi R et al. Randomised controlled trial comparing single agent paclitaxel vs epidoxorubicin plus paclitaxel in patients with advanced ovarian cancer in early progression after platinum-based chemotherapy: an Italian Collaborative Study from the Mario Negri Institute, Milan, G.O.N.O. (Gruppo Oncologico Nord Ovest) group and I.O.R. (Istituto Oncologico Romagnolo) group. Br J Cancer 2004; 90: 2112–2117. 11. Sehouli J, Stengel D, Oskay-Oezcelik . Nonplatinum topotecan combinations versus topotecan alone for recurrent ovarian cancer: results of a phase III study of the North-Eastern German Society of Gynecological Oncology Ovarian Cancer Study Group. J Clin Oncol 2008; 26: 3176–3182. 12. Monk BJ, Herzog TJ, Kaye SB et al. Trabectedin plus pegylated liposomal Doxorubicin in recurrent ovarian cancer. J Clin Oncol 2010; 28: 3107–3114. 13. Ten Bokkel Huinink W, Gore M, Carmichael J et al. Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. J Clin Oncol 1997; 15: 2183–2193. 14. Gordon AN, Tonda M, Sun S et al. Long-term survival advantage for women treated with pegylated liposomal doxorubicin compared with topotecan in a phase
doi:10.1093/annonc/mdt471 | x
Downloaded from http://annonc.oxfordjournals.org/ at Nipissing University on October 19, 2014
There are two other strategies beyond carboplatin-based chemotherapy that have demonstrated benefit for patients with a late relapse, i.e. the use of a nonplatinum-based combination, and the addition of the antiangiogenic agent bevacizumab. The OVA-301 trial tested the combination of trabectedin with PLD against PLD monotherapy in patients who were no candidate or not willing to receive additional platinum-based therapy at relapse. Trabectedin/PLD provided a 21% risk reduction for progressive disease or death compared with PLD monotherapy (HR 0.79; 95% CI 0.65–0.96; P = 0.0190) by independent radiology review [12]. Median PFS was 7.3 months for trabectedin/PLD and 5.8 months for PLD alone. By subgroup analysis, trabectedin/PLD only improved PFS in platinum-sensitive patients (9.2 versus 7.5 months), with a 27% risk reduction (HR 0.73; 95% CI 0.56–0.95; P = 0.0170), and no significant difference was observed in platinum-resistant patients (median, 4.0 and 3.7 months with combination and monotherapy, respectively). An update of the OS data confirmed a trend toward better OS for the combination arm that did not reach statistical significance [28]. One interesting subanalysis showed that the group of patients with a progression-free interval of 6–12 months obtained an increment in OS when treated with trabectedin and PLD compared with PLD monotherapy [29]. This difference was more evident when platinum was the next regimen used after progression on the trial medication, raising the hypothesis that a prolongation of the platinum-free interval by a nonplatinumbased regimen could restore platinum sensitivity and be beneficial for the patient [30]. This hypothesis is the background of the randomized clinical trial INternational OVArian Cancer Patients Trial With YONdelis (INOVATYON), which includes patients with recurrent OC and a progressionfree interval of 6–12 months after first-line treatment and compares the combination of carboplatin–PLD followed by the regimen selected by the investigator at progression or trabectedine–PLD followed by a platinum-based regimen at progression. The OCEANS trial tested the addition of bevacizumab to a standard carboplatin doublet for the treatment of patients with a late relapse. This randomized clinical trial compared carboplatin–gemcitabine plus bevacizumab with carboplatin– gemcitabine–placebo in 484 patients with a recurrent ovarian cancer over 6 months after first line of platinum-based chemotherapy. Patients included needed to have measurable disease and the primary end point was PFS determined by RECIST progression. The association of bevacizumab increased the median PFS from 8.4 to 12.4 months (HR 0.48; 95% CI 0.34–0.60), and was confirmed by an independent radiology committee [31]. Additionally, the response rate was also higher (78.5% versus 57.4%; P < 0.0001). The third preplanned analysis of OS has not shown significant differences (33.4 with bevacizumab versus 33.7 with placebo), which most probably was due to the long postprogression time and the substantial number of chemotherapy lines given during that period.
symposium article
symposium article 15.
16.
17.
18.
19.
21.
22.
23.
x | González-Martín
24. Raja FA, Counsell N, Colombo N et al. Platinum versus combination platinum chemotherapy in platinum-sensitive recurrent ovarian cancer; a meta-analysis of randomised trials using individual patient data (IPD). Ann Oncol 2013; in press. 25. Pujade-Lauraine E, Wagner U, Aavall-Lundqvist E et al. Pegylated liposomal Doxorubicin and Carboplatin compared with Paclitaxel and Carboplatin for patients with platinum-sensitive ovarian cancer in late relapse. J Clin Oncol 2010; 28: 3323–3329. 26. Wagner U, Marth C, Largillier R et al. Final overall survival results of phase III GCIG CALYPSO trial of pegylated liposomal doxorubicin and carboplatin vs paclitaxel and carboplatin in platinum-sensitive ovarian cancer patients. Br J Cancer 2012; 107: 588–591. 27. Sehouli J, Meier W, Wimberger P et al. Topotecan plus carboplatin versus standard therapy with paclitaxel plus carboplatin (PC) or gemcitabine plus carboplatin (GC) or pegylated liposomal doxorubicin plus carboplatin (PLDC): a randomized phase III trial of the NOGGO-AGO-Germany-AGO Austria and GEICO-ENGOT-GCIG intergroup study (HECTOR). J Clin Oncol 2012; 30 (suppl): abstr 5031. 28. Monk BJ, Herzog TJ, Kaye SB et al. Trabectedin plus pegylated liposomal doxorubicin (PLD) versus PLD in recurrent ovarian cancer: overall survival analysis. Eur J Cancer 2012; 48: 2361–2368. 29. Poveda A, Vergote I, Tjulandin S et al. Trabectedin plus pegylated liposomal doxorubicin in relapsed ovarian cancer: outcomes in the partially platinumsensitive ( platinum-free interval 6-12 months) subpopulation of OVA-301 phase III randomized trial. Ann Oncol 2011; 22: 39–48. 30. Colombo N et al. Efficacy of trabectedin in platinum-sensitive-relapsed ovarian cancer: new data from the randomized OVA-301 study. Int J Gynecol Cancer 2011; 21 (Suppl 1): S12–S16. 31. Aghajanian C, Blank SV, Goff BA et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol 2012; 30: 2039–2045.
Volume 24 | Supplement 10 | December 2013
Downloaded from http://annonc.oxfordjournals.org/ at Nipissing University on October 19, 2014
20.
3 randomized study of recurrent and refractory ovarian cancer. Gynecol Oncol 2004; 95: 1–8. O’Byrne KJ, Bliss P, Graham JD et al. A phase III study of Caelyx versus paclitaxel in platinum-treated taxane-naive relapsed ovarian cancer. Proc Am Soc Clin Oncol 2002; 21 203 (abstract 808). Vermorken J, Gore M, Perren T et al. Multicenter randomised phase II study of oxaliplatin or topotecan in platinum-pretreated epithelial ovarian cancer patients. Proc Am Soc Clin Oncol 2001; 20 212 (abstract 847). Ferrandina G, Ludovisi M, Lorusso D et al. Phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in progressive or recurrent ovarian cancer. J Clin Oncol 2008; 26: 890–896. Mutch DG, Orlando M, Goss T et al. Randomized phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer. J Clin Oncol 2007; 25: 2811–2818. Sehouli J, Stengel D, Harter P et al. Topotecan Weekly Versus Conventional 5-Day Schedule in Patients With Platinum-Resistant Ovarian Cancer: a randomized multicenter phase II trial of the North-Eastern German Society of Gynecological Oncology Ovarian Cancer Study Group. J Clin Oncol 2011; 29: 242–248. Eric P-L, Felix H, Béatrice W et al. AURELIA: a randomized phase III trial evaluating bevacizumab (BEV) plus chemotherapy (CT) for platinum (PT)-resistant recurrent ovarian cancer (OC). J Clin Oncol 2012; 30 (suppl): abstr LBA5002. The ICON and AGO Collaborators. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet 2003; 361: 2099–2106. González-Martín A, Calvo E, Bover I et al. Randomised phase II study of carboplatin versus paclitaxel-carboplatin in platinum–sensitive recurrent advanced ovarian cancer: a GEICO study. Ann Oncol 2005; 16: 749–755. Pfisterer J, Plante M, Vergote I et al. Gemcitabine/carboplatin vs. carboplatin in platinum sensitive recurrent ovarian cancer. Results of a Gynecologic Cancer Intergroup randomized phase III trial of the AGO OVAR, the NCIC CTG and the EORTC GCG. J Clin Oncol 2006; 24: 4699–4707.
Annals of Oncology