- Email: [email protected]
Update of randomized trials in recurrent disease
Annals of Oncology 22 (Supplement 8): viii61–viii64, 2011 doi:10.1093/annonc/mdr518
symposium article Update of randomized trials in recurrent disease E. Pujade-Lauraine* & J. Alexandre De´partement d’Oncologie Me´dicale, Universite´ Paris Descartes, Hoˆpital Hoˆtel-Dieu, Paris, France
Pegylated liposomal doxorubicin (PLD), topotecan, paclitaxel or gemcitabine have shown similar activity in ovarian cancer in relapse. In two trials, overall survival (OS) was found significantly prolonged in patients (mainly in the platinumsensitive subset) treated with PLD compared with topotecan or gemcitabine, but progression-free survival (PFS) was not increased. In platinum-resistant disease, the choice between these active drugs depends on their toxicity profile and convenience of administration, with PLD being the currently preferred control arm in resistant patient trials. Importantly, alkylating agents such as treosulfan or canfosfamide have been found significantly less active than standard topotecan or PLD. The large trial with canfosfamide is the first to show that in third-line treatment standard active drugs such as PLD or topotecan still bring a significant benefit in OS compared with less active agents [1–8] (Table 1). Currently, the activity of nonpegylated liposomal doxorubicin (Myocet) is being explored and compared with gemcitabine in platinum-resistant/refractory patients (NCT01100372). Another face-to-face comparison in relapsed disease include paclitaxel versus a new nano particle formulation of paclitaxel (Paclical) (NCT00989131).
platinum-resistant disease: comparison of combination versus single agent Six randomized trials in resistant disease (or with a majority of patients with resistant disease) have failed to show superiority in outcome for a combination versus single agent. *Correspondence to: Prof. E. Pujade-Lauraine, De´partement d’Oncologie Me´dicale, Hoˆpital Hoˆtel-Dieu, Place du Parvis Notre-Dame, 75004 Paris, France. Tel: +33-142348222; Fax: +33-142348110; E-mail: [email protected]
However, toxicity was increased in the combination arm [9–14] (Table 2).
platinum-sensitive disease: comparison of combination versus single agent In platinum-sensitive disease, a single trial has compared a nonplatinum drug, paclitaxel, with a platinum combination (cyclophosphamide/doxorubicin/cisplatin) and has found a significant benefit in PFS and OS for the platinum combination [15]. Another trial has compared a nonplatinum drug, PLD, with a nonplatinum combination, PLD + trabectedin, and found in the platinum-sensitive subset a PFS and OS advantage for the nonplatinum combination [13]. The benefit for patients with platinum-sensitive disease to be treated with a combination has been confirmed by the results of five trials comparing single agent carboplatin with a carboplatin combination. Four of these trials demonstrated an advantage in outcome for the combination either in PFS (three trials) or in OS (three trials) [16–20] (Table 3). The question of which is the best carboplatin-based chemotherapy has been addressed by two randomized trials. The large CALYPSO trial has shown that carboplatin–PLD has a more favourable benefit/risk ratio than carboplatin– paclitaxel [21] (Figure 1). The results of the randomized trial (HECTOR) between carboplatin–topotecan and other carboplatin-based combinations are awaited (NCT00437307). In order to better define the respective role of nonplatinum drugs versus platinum combinations in patients with partially platinum-sensitive disease (6–12 months), the MITO 8 trial compares the sequence of PLD followed by carboplatin– paclitaxel versus the reverse sequence (NCT00657878). A comparison between the best carboplatin combination
ª The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
symposium article
face-to-face comparison of drugs
Downloaded from http://annonc.oxfordjournals.org/ at University of Prince Edward Island on November 13, 2012
In the absence of significant advance in first-line therapy until recently, the increased knowledge of how to manage relapse accounts for most of the advances observed in ovarian cancer during the last 10 years. In addition, a large number of new drugs, mostly in the category of ‘targeted therapy’, are currently being tested in the setting of recurrent ovarian and are expected to change the course of the disease in the near future. The acknowledgement of the platinum-free interval (PFI) as the major criterion predicting therapy success in ovarian cancer relapse has allowed the development of distinct therapeutic strategies according to the PFI length. This update will indicate the pivotal trials that have led to the largest steps in the management of recurrent ovarian cancer during the last 10 years. Future advances in ovarian cancer treatment need randomized phase II or phase III trials in the recurrent disease setting before being tested in first line. The main ongoing randomized trials in relapsed disease will be reviewed, f ocusing on phase II or phase III trials. Key words: cancer, ovarian, randomized, relapse, review
symposium article
Annals of Oncology
(carboplatin–PLD) and a nonplatinum combination (trabectedin–PLD) is also planned in these patients.
Table 1. Face-to-face comparison of chemotherapy drugs in ovarian cancer in relapse
Author
Benefit PFS OS
surgery
Paclitaxel versus oxaliplatin Paclitaxel versus topotecan PLD versus topotecan PLD versus paclitaxel PLD versus gemcitabine PLD versus gemcitabine Topotecan versus treosulfan PLD or topotecan versus canfosfamide
Piccart et al., 2000 Ten Bokkel et al., 2004 Gordon et al., 2001 O’Byrne et al., 2002 Mutch et al., 2007 Ferrandina et al., 2008 Meier et al., 2005 Vergote et al., 2009
No No No No No No Yes Yes
DESKSTOP III is an AGO-led trial assessing the impact on OS of surgery at relapse in patients with platinum-sensitive disease and a positive AGO score. Accrual has started in a trial with >400 patients planned. Several randomized trials in the United States, Korea and France are ongoing or planned to question the role of chemotherapy plus hyperthermia in relapsing patients treated with surgery plus hyperthermic intraperitoneal chemotherapy (NCT00045461 and NCT01091636).
No No Yes No No Yes Yes Yes
PFS, progression-free survival; OS, overall survival; PLD, pegylated liposomal doxorubicin.
antiangiogenic agents
Table 2. Resistant disease: comparison of combination versus single agent Regimen
Author
Benefit PFS/OS
Paclitaxel versus epirubicin + paclitaxel Paclitaxel versus doxorubicin + paclitaxel Paclitaxel versus epirubicin + paclitaxel Topotecan versus topotecan + etoposide or gemcitabine PLD versus PLD + trabectedin Weekly paclitaxel (wP) versus wP + carboplatin or weekly topotecan
Bolis et al., 1999
No
Torri et al., 2000
Noa
Buda et al., 2004
Nob
Sehouli et al., 2008
No
Monk et al., 2010
Noc
Gladieff et al., 2009
No
Three trials with bevacizumab (15 mg/kg/3 weeks until progression) have been launched in nearly 2500 patients with ovarian cancer in relapse: one in resistant relapse (AURELIA) and two in sensitive relapse (GOG 213 and OCEANS). OCEANS reached its primary end point (PFS) in 2011 [22]. Bevacizumab plus carboplatin–gemcitabine followed by single agent bevacizumab until progression significantly increased PFS compared with chemotherapy alone [hazard ratio (HR): 0.484; P<0.0001], with a median PFS of 8.4 and 12.4 months, respectively. The results of AURELIA will be delivered in 2012 (Table 4). BIBF1120 (Vargatef ), a tyrosine kinase inhibitor of vascular endothelial growth factor, FGF and platelet-derived growth factor (PDGF), delivered in the maintenance of patients with resistant or partially platinum-sensitive disease who have previously responded to chemotherapy, has shown a prolongation of PFS at 36 weeks compared with placebo
PFS, progression-free survival; OS, overall survival; PLD, pegylated liposomal doxorubicin. a At least 50% of patients with resistant disease. b Seventy-four per cent of patients with resistant disease. c Subset analysis
2
PLD 30 mg/m IV d 1 Carboplatin AUC 5 d 1 Q 28 days X 6 courses
Table 3. Platinum-sensitive disease: comparison of combination versus single agent 2
Paclitaxel 175 mg/m IV d 1
Regimen
Author
Benefit PFS OS
Carboplatin versus epirubicin + carboplatin Carboplatin versus paclitaxel + carboplatin Carboplatin versus paclitaxel + carboplatin Carboplatin versus gemcitabine + carboplatin Carboplatin versus PLD + carboplatin
Bolis et al., 2001
No
No
Parmar et al., 2003
Yes
Yes
Gonzales-Martin et al., 2005
Yes
Yes
Pfisterer et al., 2005
Yes
No
Markman et al., 2010
No
Yes
PFS, progression-free survival; OS, overall survival; PLD, pegylated liposomal doxorubicin.
viii62 | Pujade-Lauraine & Alexandre
Carboplatin AUC 5 d 1 Q 21 days X 6 courses
Figure 1. CALYPSO study schema. Table 4. Randomized trials with bevacizumab in ovarian cancer in relapse Name
Chemotherapy
Patient subset
Patients (N)
AURELIA
PLD or paclitaxel or topotecan Paclitaxel/carboplatin Gemcitabine/carboplatin
Resistant
330
Sensitive Sensitive
1600 450
GOG 213 OCEANS
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Regimen
Annals of Oncology
antifolate-receptor agents Olaparib is the most advanced anti-PARP compound in development and the dose-relationship has been explored in 2 randomized phase II trials in BRCA-mutated ovarian cancer patients in relapse. Olaparib has been found more active in relapse at a dose of 400 mg per os twice a day (p.o. b.i.d.) than at 100 mg p.o. b.i.d., with a median PFS of 5.8 and 1.9 months, respectively [26]. In platinum-resistant patients, the dose of olaparib 400 mg p.o. b.i.d. induces a higher response rate (GCIG including CA125 criteria) of 59% than that of olaparib 200 mg p.o. b.i.d. (38%) which was similar to PLD (39%). PFS curves, however, were similar between the three arms [27]. EC145 is a conjugate of folate and the vinca alkaloid desacetylvinblastine hydrazide (DAVLBH), which binds to the folate receptor and delivers DAVLBH into the cell via endocytosis. The results of a randomized phase II comparing the combination of EC145 and PLD with PLD alone are encouraging [25]. A large phase III is planned.
anti-PARP agents Olaparib is the most advanced anti-PARP compound in development and the dose-relationship has been explored in 2 randomized phase II trials in BRCA-mutated ovarian cancer patients in relapse. Olaparib has been found more active in relapse at a dose of 400 mg per os twice a day (p.o. b.i.d.) than at 100 mg p.o. b.i.d., with a median PFS of 5.8 and 1.9 months, respectively [26]. In platinum-resistant patients, the dose of olaparib 400 mg p.o. b.i.d. induces a higher response rate (GCIG including CA125 criteria) of 59% than that of olaparib 200 mg p.o. b.i.d. (38%) which was similar to PLD (39%). PFS curves, however, were similar between the three arms [27]. Ledermann et al. [28] have recently presented the results of a randomized comparison in 265 patients of olaparib versus placebo in maintenance of a platinum-based chemotherapyinduced partial or complete response platinum-sensitive relapse. PFS by RECIST was significantly longer in the olaparib group than in the placebo group (HR: 0.35; 95% CI: 0.25–0.49; P<0.00001; median 8.4 versus 4.8 months). We are also
Volume 22 | Supplement 8 | December 2011
awaiting the results of a randomized phase II trial in platinumsensitive high-grade serous cancer of olaparib in combination with chemotherapy versus combination alone (NCT01081951). Moreover, large phase III trials are planned. ABT-888 (veliparib) is a another anti-PARP compound. The accrual of a randomized phase II trial comparing ABT888 + temozolomide versus PLD in patients with high-grade serous ovarian cancer in relapse has recently been completed (NCT01113957).
results from others drugs chemotherapy Patupilone, an epothilone B, was investigated within the largest trial ever performed in 829 resistant/refractory patients. No benefit in OS was found for patupilone over PLD [29]. NKTR-102 (PEG-irinotecan) has shown interesting activity in a randomized trial of resistant/refractory patients, but at the expense of significant toxicity [30]. Decitabine (Dacogen) was ineffective in combination with carboplatin versus carboplatin alone [31]. targeted therapies or immunotherapy AZD0530 (Saracatinib), an anti-Src agent, has not met its primary end point in combination with chemotherapy (taxolcarboplatin) versus chemotherapy alone in a randomized trial in platinum-sensitive disease (NCT00610714). GDC-0449, a hedgehog pathway inhibitor, failed to improve PFS in maintenance of a second or third complete remission over placebo [32]. Thalidomide was not superior to tamoxifen in patients with an asymptomatic rise of CA125 [33].
other new drugs currently investigated BIBF 6727 (Volasertib), a polo-like kinase 1 inhibitor; MLN8237, an Aurora A kinase inhibitor; ZD4054 (Zibotentan), an endothelin inhibitor; ZD9331 (Plevitrexed), an oral antifolate quinazoline derivative thymidine synthetase inhibitor; E7080, an orally active inhibitor of multiple receptor tyrosine kinases; IMC-3G3, an anti-PDGF receptor-monoclonal antibody; SGN-15, a monoclonal antibody directed against Lewis-y antigen–doxorubicin conjugate; MUC1 dendritic cell vaccine (CVac) (NCT01068509); tucotuzumab celmoleukin (EMD 273066), a novel immunocytokine (NCT00408967); a polyvalent antigen-KLH conjugate vaccine with or without adjuvant OPT-821 (NCT00857545). In conclusion, randomized trials in recurrent ovarian cancer have brought new chemotherapy standards according to the platinum-free interval: a single nonplatinum agent in refractory/ resistant disease; drug combination for partially platinumsensitive disease (relapse between 6 and 12 months); and platinum combinations for fully platinum-sensitive disease (>12 months). The combination of monoclonal antibodies or tyrosine kinase inhibitors with chemotherapy and/or in maintenance has shown promising results. Antiangiogenic agents (bevacizumab) and anti-PARP agents (olaparib) are leading the way for the future advances in the management of ovarian cancer.
doi:10.1093/annonc/mdr518 | viii63
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[HR: 0.68; 95% confidence interval (CI): 0.44–1.07; P = 0.07] (NCT00710762) [23]. The drug is tested in first line. AMG 386 is an antiangiopoietin receptor (Tie2 receptor) peptide-Fc fusion protein. Patients treated with weekly paclitaxel and a high dose of weekly intravenous AMG 386 (10 mg/kg) tend to have a more prolonged median PFS (7.2 months) than those treated in combination with 3 mg/kg low-dose AMG 386 (5.7 months) or placebo (4.6 months) [24]. Large phase III trials are planned. Cediranib (Recentin) is being explored in combination with carboplatin-based chemotherapy and in maintenance in a three-step trial expecting >2600 patients with platinum-sensitive disease. This ICON6 trial has currently accrued >250 patients. Sorafenib (Nexavar) in combination with topotecan is currently being compared with topotecan alone in resistant patients (NCT01047891). It is also being compared in combination with chemotherapy (taxol-carboplatin) versus chemotherapy alone in platinum-sensitive disease (NCT00096200).
symposium article
symposium article
Annals of Oncology
disclosures The author declares no conflict of interest.
18.
references
viii64 | Pujade-Lauraine & Alexandre
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
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1. Piccart MJ, Green JA, Lacave AJ et al. Oxaliplatin or paclitaxel in patients with platinum-pretreated advanced ovarian cancer: a randomized phase II study of the European Organization for Research and Treatment of Cancer Gynecology Group. J Clin Oncol 2000; 18: 1193–1202. 2. ten Bokkel Huinink W, Lane SR, Ross GA. International Topotecan Study Group. Long-term survival in a phase III, randomised study of topotecan versus paclitaxel in advanced epithelial ovarian carcinoma. Ann Oncol 2004; 15: 100–103. 3. Gordon AN, Tonda M, Sun S et al. Doxil Study 30-49 Investigators. Long-term survival advantage for women treated with pegylated liposomal doxorubicin compared with topotecan in a phase 3 randomized study of recurrent and refractory epithelial ovarian cancer. Gynecol Oncol 2004; 95: 1–8. 4. O’Byrne KJ, Bliss P, Graham JD et al. A phase III study of Doxil/Caelyx versus paclitaxel in platinum-treated, taxane-naive relapsed ovarian cancer. Proc Am Soc Clin Oncol 2002; 21: 203a (Abstr 808). 5. Mutch DG, Orlando M, Goss T et al. Randomized phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in patients with platinumresistant ovarian cancer. J Clin Oncol 2008; 26: 890–896. 6. 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 25; 19: 2811–2818. 7. Meier W, du Bois A, Reuss A et al. Topotecan versus treosulphan in early recurrent ovarian cancer after primary platinum/paclitaxel chemotherapy. A prospective randomized phase III trial of the AGO Ovarian Cancer Study Group. Int J Gynecol Cancer 2004; 14 (Suppl 1): 2 (Abstr 5). 8. Vergote I, Finkler N, del Campo J et al. ASSIST-1 Study Group. Phase 3 randomised study of canfosfamide (Telcyta, TLK286) versus pegylated liposomal doxorubicin or topotecan as third-line therapy in patients with platinum-refractory or -resistant ovarian cancer. Eur J Cancer 2009; 45: 2324–2332. 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. Torri V, Floriani I, Tinazzi A et al. Randomized trial comparing paclitaxel + doxorubicin versus paclitaxel as second line therapy for advanced ovarian cancer patients in early progression after platinum based chemotherapy. Proc Am Soc Clin Oncol 2000; 19: 381a (Abstr 1506). 11. 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, GONO (Gruppo Oncologico Nord Ovest) group and IOR (Istituto Oncologico Romagnolo) group. Br J Cancer 2004; 90: 2112–2117. 12. Sehouli J, Stengel D, Oskay-Oezcelik G et al. 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. 13. Monk BJ, Herzog TJ, Kaye SB et al. Trabectedin plus pegylated liposomal doxorubicin in recurrent ovarian cancer. J Clin Oncol 2010; 28: 3107–3114. 14. Lortholary A, Largillier R, Weber B et al. Weekly paclitaxel as single agent or in combination with carboplatin or weekly topotecan in patients with resistant ovarian cancer: the CARTAXHY randomized phase II trial from GINECO. Ann Oncol 2011 May 11 [epub ahead of print] doi:10.1093/annonc/mdr149. 15. Cantuˆ MG, Buda A, Parma G et al. Randomized controlled trial of single-agent paclitaxel versus cyclophosphamide, doxorubicin, and cisplatin in patients with recurrent ovarian cancer who responded to first-line platinum-based regimens. J Clin Oncol 2002; 20: 1232–1237. 16. Bolis G, Scarfone G, Giardina G et al. Carboplatin alone vs carboplatin plus epidoxorubicin as second-line therapy for cisplatin- or carboplatin-sensitive ovarian cancer. Gynecol Oncol 2001; 81: 3–9. 17. Parmar MK, Ledermann JA, Colombo N et al. 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. Gonzalez-Martin AJ, Calvo E, Bover I et al. Randomized phase II trial of carboplatin versus paclitaxel and carboplatin in platinum-sensitive recurrent advanced ovarian carcinoma: a GEICO (Grupo Espanol de Investigacion en Cancer de Ovario) study. Ann Oncol 2005; 16: 749–755. Pfisterer J, Plante M, Vergote I et al. Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC-CTG, and the EORTC-GCG. J Clin Oncol 2006; 24: 4699–4707. Markman M, Moon J, Wilczynski S et al. Single agent carboplatin versus carboplatin plus pegylated liposomal doxorubicin in recurrent ovarian cancer: final survival results of a SWOG (S0200) phase 3 randomized trial. Gynecol Oncol 2010; 116: 323–325. 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. Aghajanian C, Finkler NJ, Rutherford T. OCEANS: a randomized, double-blinded, placebo-controlled phase III trial of chemotherapy with or without bevacizumab (BEV) in patients with platinum-sensitive recurrent epithelial ovarian (EOC), primary peritoneal (PPC), or fallopian tube cancer (FTC). J Clin Oncol 2011; 29 (Suppl 15): Abstr LBA 5007. Ledermann J, Hackshaw A, Kaye S et al. Randomized phase II placebo-controlled trial of maintenance therapy using the oral triple angiokinase inhibitor BIBF 1120 after chemotherapy for relapsed ovarian cancer. J Clin Oncol 2011 August 22 [epub ahead of print]. Karlan BY, Oza AM, Hansen VL et al. Randomized, double-blind, placebocontrolled phase II study of AMG 386 combined with weekly paclitaxel in patients (pts) with recurrent ovarian carcinoma. J Clin Oncol 2010; 28: 15s (Abstr 5000). Naumann RW, Coleman RL, Burger RA et al. PRECEDENT: a randomized phase II trial comparing EC145 and pegylated liposomal doxorubicin (PLD) in combination, versus PLD alone, in subjects with platinum-resistant ovarian cancer. J Clin Oncol 2011; 29 (Suppl 15); Abstr 5045. Audeh MW, Penson RT, Friedlander M et al. Phase II trial of the oral PARP inhibitor olaparib (AZD2281) in BRCA-deficient advanced ovarian cancer. J Clin Oncol 2009; 27 (Suppl 15); Abstr 5500. Kaye S, Kaufman B, Lubinski J et al. Phase II study of the oral PARP inhibitor olaparib (AZD2281) vs liposomal doxorubicin in ovarian cancer patients with BRCA1 and/or BRCA2 mutations. Ann Oncol 2010; 21 (Suppl 8); viii304–viii313 (Abstr 9710). Ledermann JA, Harter P, Gourley C et al. Phase II randomized placebo-controlled study of olaparib (AZD2281) in patients with platinum-sensitive relapsed serous ovarian cancer (PSR SOC). J Clin Oncol 2011; 29 (Suppl 15); Abstr 5003. Colombo N, Schwartz PE, Bamias A . Results of a randomized, open-label, phase III trial of patupilone (P) versus pegylated liposomal doxorubicin (PLD) in taxane/ platinum refractory/resistant patients with recurrent ovarian, fallopian, or peritoneal cancer. Thirty-fifth European Society for Medical Oncology Congress (Abstr 4843). Milan 2010. Vergote IB, Micha JP, Pippitt CH Jr et al. Phase II study of NKTR-102 in women with platinum-resistant/refractory ovarian cancer. J Clin Oncol 2010; 28: 15s (Abstr 5013). Glasspool RM, Gore M, Rustin G et al. Randomized phase II study of decitabine in combination with carboplatin compared with carboplatin alone in patients with recurrent advanced ovarian cancer. J Clin Oncol 2009; 27: 15s (Abstr 5562). Fehrenbacher L, Kaye S, Holloway R . A phase 2, randomized, placebo-controlled study of Hedgehog (Hh) pathway inhibitor GDC-0449 as maintenance therapy in patients with ovarian cancer in 2nd or 3rd complete remission (CR). Thirty-fifth European Society for Medical Oncology Congress (LBA 25). Milan 2010. Hurteau JA, Brady MF, Darcy KM et al. Randomized phase III trial of tamoxifen versus thalidomide in women with biochemical-recurrent-only epithelial ovarian, fallopian tube or primary peritoneal carcinoma after a complete response to firstline platinum/taxane chemotherapy with an evaluation of serum vascular endothelial growth factor (VEGF): a Gynecologic Oncology Group study. Gynecol Oncol 2010; 119: 444–450.
symposium article Update of randomized trials in recurrent disease E. Pujade-Lauraine* & J. Alexandre De´partement d’Oncologie Me´dicale, Universite´ Paris Descartes, Hoˆpital Hoˆtel-Dieu, Paris, France
Pegylated liposomal doxorubicin (PLD), topotecan, paclitaxel or gemcitabine have shown similar activity in ovarian cancer in relapse. In two trials, overall survival (OS) was found significantly prolonged in patients (mainly in the platinumsensitive subset) treated with PLD compared with topotecan or gemcitabine, but progression-free survival (PFS) was not increased. In platinum-resistant disease, the choice between these active drugs depends on their toxicity profile and convenience of administration, with PLD being the currently preferred control arm in resistant patient trials. Importantly, alkylating agents such as treosulfan or canfosfamide have been found significantly less active than standard topotecan or PLD. The large trial with canfosfamide is the first to show that in third-line treatment standard active drugs such as PLD or topotecan still bring a significant benefit in OS compared with less active agents [1–8] (Table 1). Currently, the activity of nonpegylated liposomal doxorubicin (Myocet) is being explored and compared with gemcitabine in platinum-resistant/refractory patients (NCT01100372). Another face-to-face comparison in relapsed disease include paclitaxel versus a new nano particle formulation of paclitaxel (Paclical) (NCT00989131).
platinum-resistant disease: comparison of combination versus single agent Six randomized trials in resistant disease (or with a majority of patients with resistant disease) have failed to show superiority in outcome for a combination versus single agent. *Correspondence to: Prof. E. Pujade-Lauraine, De´partement d’Oncologie Me´dicale, Hoˆpital Hoˆtel-Dieu, Place du Parvis Notre-Dame, 75004 Paris, France. Tel: +33-142348222; Fax: +33-142348110; E-mail: [email protected]
However, toxicity was increased in the combination arm [9–14] (Table 2).
platinum-sensitive disease: comparison of combination versus single agent In platinum-sensitive disease, a single trial has compared a nonplatinum drug, paclitaxel, with a platinum combination (cyclophosphamide/doxorubicin/cisplatin) and has found a significant benefit in PFS and OS for the platinum combination [15]. Another trial has compared a nonplatinum drug, PLD, with a nonplatinum combination, PLD + trabectedin, and found in the platinum-sensitive subset a PFS and OS advantage for the nonplatinum combination [13]. The benefit for patients with platinum-sensitive disease to be treated with a combination has been confirmed by the results of five trials comparing single agent carboplatin with a carboplatin combination. Four of these trials demonstrated an advantage in outcome for the combination either in PFS (three trials) or in OS (three trials) [16–20] (Table 3). The question of which is the best carboplatin-based chemotherapy has been addressed by two randomized trials. The large CALYPSO trial has shown that carboplatin–PLD has a more favourable benefit/risk ratio than carboplatin– paclitaxel [21] (Figure 1). The results of the randomized trial (HECTOR) between carboplatin–topotecan and other carboplatin-based combinations are awaited (NCT00437307). In order to better define the respective role of nonplatinum drugs versus platinum combinations in patients with partially platinum-sensitive disease (6–12 months), the MITO 8 trial compares the sequence of PLD followed by carboplatin– paclitaxel versus the reverse sequence (NCT00657878). A comparison between the best carboplatin combination
ª The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
symposium article
face-to-face comparison of drugs
Downloaded from http://annonc.oxfordjournals.org/ at University of Prince Edward Island on November 13, 2012
In the absence of significant advance in first-line therapy until recently, the increased knowledge of how to manage relapse accounts for most of the advances observed in ovarian cancer during the last 10 years. In addition, a large number of new drugs, mostly in the category of ‘targeted therapy’, are currently being tested in the setting of recurrent ovarian and are expected to change the course of the disease in the near future. The acknowledgement of the platinum-free interval (PFI) as the major criterion predicting therapy success in ovarian cancer relapse has allowed the development of distinct therapeutic strategies according to the PFI length. This update will indicate the pivotal trials that have led to the largest steps in the management of recurrent ovarian cancer during the last 10 years. Future advances in ovarian cancer treatment need randomized phase II or phase III trials in the recurrent disease setting before being tested in first line. The main ongoing randomized trials in relapsed disease will be reviewed, f ocusing on phase II or phase III trials. Key words: cancer, ovarian, randomized, relapse, review
symposium article
Annals of Oncology
(carboplatin–PLD) and a nonplatinum combination (trabectedin–PLD) is also planned in these patients.
Table 1. Face-to-face comparison of chemotherapy drugs in ovarian cancer in relapse
Author
Benefit PFS OS
surgery
Paclitaxel versus oxaliplatin Paclitaxel versus topotecan PLD versus topotecan PLD versus paclitaxel PLD versus gemcitabine PLD versus gemcitabine Topotecan versus treosulfan PLD or topotecan versus canfosfamide
Piccart et al., 2000 Ten Bokkel et al., 2004 Gordon et al., 2001 O’Byrne et al., 2002 Mutch et al., 2007 Ferrandina et al., 2008 Meier et al., 2005 Vergote et al., 2009
No No No No No No Yes Yes
DESKSTOP III is an AGO-led trial assessing the impact on OS of surgery at relapse in patients with platinum-sensitive disease and a positive AGO score. Accrual has started in a trial with >400 patients planned. Several randomized trials in the United States, Korea and France are ongoing or planned to question the role of chemotherapy plus hyperthermia in relapsing patients treated with surgery plus hyperthermic intraperitoneal chemotherapy (NCT00045461 and NCT01091636).
No No Yes No No Yes Yes Yes
PFS, progression-free survival; OS, overall survival; PLD, pegylated liposomal doxorubicin.
antiangiogenic agents
Table 2. Resistant disease: comparison of combination versus single agent Regimen
Author
Benefit PFS/OS
Paclitaxel versus epirubicin + paclitaxel Paclitaxel versus doxorubicin + paclitaxel Paclitaxel versus epirubicin + paclitaxel Topotecan versus topotecan + etoposide or gemcitabine PLD versus PLD + trabectedin Weekly paclitaxel (wP) versus wP + carboplatin or weekly topotecan
Bolis et al., 1999
No
Torri et al., 2000
Noa
Buda et al., 2004
Nob
Sehouli et al., 2008
No
Monk et al., 2010
Noc
Gladieff et al., 2009
No
Three trials with bevacizumab (15 mg/kg/3 weeks until progression) have been launched in nearly 2500 patients with ovarian cancer in relapse: one in resistant relapse (AURELIA) and two in sensitive relapse (GOG 213 and OCEANS). OCEANS reached its primary end point (PFS) in 2011 [22]. Bevacizumab plus carboplatin–gemcitabine followed by single agent bevacizumab until progression significantly increased PFS compared with chemotherapy alone [hazard ratio (HR): 0.484; P<0.0001], with a median PFS of 8.4 and 12.4 months, respectively. The results of AURELIA will be delivered in 2012 (Table 4). BIBF1120 (Vargatef ), a tyrosine kinase inhibitor of vascular endothelial growth factor, FGF and platelet-derived growth factor (PDGF), delivered in the maintenance of patients with resistant or partially platinum-sensitive disease who have previously responded to chemotherapy, has shown a prolongation of PFS at 36 weeks compared with placebo
PFS, progression-free survival; OS, overall survival; PLD, pegylated liposomal doxorubicin. a At least 50% of patients with resistant disease. b Seventy-four per cent of patients with resistant disease. c Subset analysis
2
PLD 30 mg/m IV d 1 Carboplatin AUC 5 d 1 Q 28 days X 6 courses
Table 3. Platinum-sensitive disease: comparison of combination versus single agent 2
Paclitaxel 175 mg/m IV d 1
Regimen
Author
Benefit PFS OS
Carboplatin versus epirubicin + carboplatin Carboplatin versus paclitaxel + carboplatin Carboplatin versus paclitaxel + carboplatin Carboplatin versus gemcitabine + carboplatin Carboplatin versus PLD + carboplatin
Bolis et al., 2001
No
No
Parmar et al., 2003
Yes
Yes
Gonzales-Martin et al., 2005
Yes
Yes
Pfisterer et al., 2005
Yes
No
Markman et al., 2010
No
Yes
PFS, progression-free survival; OS, overall survival; PLD, pegylated liposomal doxorubicin.
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Carboplatin AUC 5 d 1 Q 21 days X 6 courses
Figure 1. CALYPSO study schema. Table 4. Randomized trials with bevacizumab in ovarian cancer in relapse Name
Chemotherapy
Patient subset
Patients (N)
AURELIA
PLD or paclitaxel or topotecan Paclitaxel/carboplatin Gemcitabine/carboplatin
Resistant
330
Sensitive Sensitive
1600 450
GOG 213 OCEANS
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Regimen
Annals of Oncology
antifolate-receptor agents Olaparib is the most advanced anti-PARP compound in development and the dose-relationship has been explored in 2 randomized phase II trials in BRCA-mutated ovarian cancer patients in relapse. Olaparib has been found more active in relapse at a dose of 400 mg per os twice a day (p.o. b.i.d.) than at 100 mg p.o. b.i.d., with a median PFS of 5.8 and 1.9 months, respectively [26]. In platinum-resistant patients, the dose of olaparib 400 mg p.o. b.i.d. induces a higher response rate (GCIG including CA125 criteria) of 59% than that of olaparib 200 mg p.o. b.i.d. (38%) which was similar to PLD (39%). PFS curves, however, were similar between the three arms [27]. EC145 is a conjugate of folate and the vinca alkaloid desacetylvinblastine hydrazide (DAVLBH), which binds to the folate receptor and delivers DAVLBH into the cell via endocytosis. The results of a randomized phase II comparing the combination of EC145 and PLD with PLD alone are encouraging [25]. A large phase III is planned.
anti-PARP agents Olaparib is the most advanced anti-PARP compound in development and the dose-relationship has been explored in 2 randomized phase II trials in BRCA-mutated ovarian cancer patients in relapse. Olaparib has been found more active in relapse at a dose of 400 mg per os twice a day (p.o. b.i.d.) than at 100 mg p.o. b.i.d., with a median PFS of 5.8 and 1.9 months, respectively [26]. In platinum-resistant patients, the dose of olaparib 400 mg p.o. b.i.d. induces a higher response rate (GCIG including CA125 criteria) of 59% than that of olaparib 200 mg p.o. b.i.d. (38%) which was similar to PLD (39%). PFS curves, however, were similar between the three arms [27]. Ledermann et al. [28] have recently presented the results of a randomized comparison in 265 patients of olaparib versus placebo in maintenance of a platinum-based chemotherapyinduced partial or complete response platinum-sensitive relapse. PFS by RECIST was significantly longer in the olaparib group than in the placebo group (HR: 0.35; 95% CI: 0.25–0.49; P<0.00001; median 8.4 versus 4.8 months). We are also
Volume 22 | Supplement 8 | December 2011
awaiting the results of a randomized phase II trial in platinumsensitive high-grade serous cancer of olaparib in combination with chemotherapy versus combination alone (NCT01081951). Moreover, large phase III trials are planned. ABT-888 (veliparib) is a another anti-PARP compound. The accrual of a randomized phase II trial comparing ABT888 + temozolomide versus PLD in patients with high-grade serous ovarian cancer in relapse has recently been completed (NCT01113957).
results from others drugs chemotherapy Patupilone, an epothilone B, was investigated within the largest trial ever performed in 829 resistant/refractory patients. No benefit in OS was found for patupilone over PLD [29]. NKTR-102 (PEG-irinotecan) has shown interesting activity in a randomized trial of resistant/refractory patients, but at the expense of significant toxicity [30]. Decitabine (Dacogen) was ineffective in combination with carboplatin versus carboplatin alone [31]. targeted therapies or immunotherapy AZD0530 (Saracatinib), an anti-Src agent, has not met its primary end point in combination with chemotherapy (taxolcarboplatin) versus chemotherapy alone in a randomized trial in platinum-sensitive disease (NCT00610714). GDC-0449, a hedgehog pathway inhibitor, failed to improve PFS in maintenance of a second or third complete remission over placebo [32]. Thalidomide was not superior to tamoxifen in patients with an asymptomatic rise of CA125 [33].
other new drugs currently investigated BIBF 6727 (Volasertib), a polo-like kinase 1 inhibitor; MLN8237, an Aurora A kinase inhibitor; ZD4054 (Zibotentan), an endothelin inhibitor; ZD9331 (Plevitrexed), an oral antifolate quinazoline derivative thymidine synthetase inhibitor; E7080, an orally active inhibitor of multiple receptor tyrosine kinases; IMC-3G3, an anti-PDGF receptor-monoclonal antibody; SGN-15, a monoclonal antibody directed against Lewis-y antigen–doxorubicin conjugate; MUC1 dendritic cell vaccine (CVac) (NCT01068509); tucotuzumab celmoleukin (EMD 273066), a novel immunocytokine (NCT00408967); a polyvalent antigen-KLH conjugate vaccine with or without adjuvant OPT-821 (NCT00857545). In conclusion, randomized trials in recurrent ovarian cancer have brought new chemotherapy standards according to the platinum-free interval: a single nonplatinum agent in refractory/ resistant disease; drug combination for partially platinumsensitive disease (relapse between 6 and 12 months); and platinum combinations for fully platinum-sensitive disease (>12 months). The combination of monoclonal antibodies or tyrosine kinase inhibitors with chemotherapy and/or in maintenance has shown promising results. Antiangiogenic agents (bevacizumab) and anti-PARP agents (olaparib) are leading the way for the future advances in the management of ovarian cancer.
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[HR: 0.68; 95% confidence interval (CI): 0.44–1.07; P = 0.07] (NCT00710762) [23]. The drug is tested in first line. AMG 386 is an antiangiopoietin receptor (Tie2 receptor) peptide-Fc fusion protein. Patients treated with weekly paclitaxel and a high dose of weekly intravenous AMG 386 (10 mg/kg) tend to have a more prolonged median PFS (7.2 months) than those treated in combination with 3 mg/kg low-dose AMG 386 (5.7 months) or placebo (4.6 months) [24]. Large phase III trials are planned. Cediranib (Recentin) is being explored in combination with carboplatin-based chemotherapy and in maintenance in a three-step trial expecting >2600 patients with platinum-sensitive disease. This ICON6 trial has currently accrued >250 patients. Sorafenib (Nexavar) in combination with topotecan is currently being compared with topotecan alone in resistant patients (NCT01047891). It is also being compared in combination with chemotherapy (taxol-carboplatin) versus chemotherapy alone in platinum-sensitive disease (NCT00096200).
symposium article
symposium article
Annals of Oncology
disclosures The author declares no conflict of interest.
18.
references
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19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
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