Western Regional Blog – BC, YK, AB, NWT and Nunavut
“Although questions still remain over dosing and timing of first-line treatment for patients with advanced ovarian cancer, the JGOG study provides important data that will help guide patient care in the future.”
Giovanni Scambia, Vanda Salutari, Giulia Amadio
Advanced epithelial ovarian cancer has a median progression-free survival of 16-21 months and median overall survival of 32-57 months. Standard treatment is cytoreductive surgery—either upfront or after neoadjuvant chemotherapy—followed by six cycles of 3-weekly paclitaxel and carboplatin. Attempts to improve survival by addition of a third cytotoxic drug have been unsuccessful, although encouraging results have been reported for treatment with intravenous paclitaxel plus intraperitoneal cisplatin and paclitaxel, and bevacizumab plus paclitaxel and carboplatin followed by maintenance with bevacizumab.(1, 2)
Another treatment option is dose-dense treatment, in which a higher cumulative dose is administered over a shorter period. The rationale for such treatment comes from the Norton-Simon hypothesis,(3) which posits that increasing the dose density of chemotherapy improves efficacy by reducing the regrowth of tumour cells between cycles. The positive effect(4) of weekly paclitaxel and platinum induction treatment, compared to 3-weekly regimens, for platinum-resistant ovarian cancer are the basis for a randomised first-line trial of advanced disease.
14 randomised dose-intensity studies have assessed first-line treatment with weekly paclitaxel combined with 3-weekly carboplatin. Only one—the Japanese Gynecological Oncology Group (JGOG) 3016 trial(5)—showed that the regimen improved progression-free survival and overall survival of patients with epithelial ovarian cancer. In this study, the dose-dense regimen was paclitaxel (80 mg/m2) given on days 1, 8, and 15 and carboplatin (area under the curve [AUC] 6 mg/mL per min) given on day 1 every 21 days. The standard regimen was paclitaxel (175 mg/m2) and carboplatin (AUC 6 mg/mL per min) given on day 1 every 21 days. Compared with the standard regimen, the dose-dense regimen resulted in longer median progression-free survival (28·0 months vs 17·2 months; p=0·0015) and better overall survival at 3 years (72·1% vs 65·1%; p=0·03), but also increased toxic effects.
In The Lancet Oncology, the JGOG investigators report long-term survival data from the trial.(6) After a median follow-up of 76.8 months, survival of patients given the dose-dense regimen was still higher than survival in patients who took the conventional regimen. Median progression-free survival was 28.2 months in the dose-dense group versus 17.5 months in the conventional regimen group (hazard ratio [HR] 0·76, 95% CI 0·62—0·91; p=0·0037) and median overall survival was 100.5 months versus 62.2 months (HR 0·79, 95% CI 0·63—0·99; p=0·039).
Median overall survival in the conventional regimen group, especially in optimally resected patients (residual disease <1 cm), was better than that in previous trials done in Europe and the USA. JGOG 3016 also shows promising results for progression-free survival, even in the conventional treatment group. By comparison, in the GOG 218 and ICON 7 studies,(1, 2) progression-free survival in patients treated with standard 3-weekly chemotherapy with the addition of bevacizumab was 14·1 months and 19 months, respectively.
The difficulties of choosing an optimum first-line treatment is further highlighted by the preliminary results of the MITO-7 study, presented at the annual meeting of the American Society of Clinical Oncology 2013.(7) In this trial, 822 women were randomly assigned to receive either standard treatment of 3-weekly carboplatin (AUC 6 mg/mL per min) plus paclitaxel (175 mg/m2) for six cycles or a weekly regimen of carboplatin (AUC 2 mg/mL per min) plus paclitaxel (60 mg/m2) for 18 weeks. In MITO-7, progression-free survival and overall survival were not significantly different in each group despite the fewer toxic effects—including alopecia, neuropathy, and febrile neutropenia—of the weekly regimen, as well as a better quality of life, which contrasts with the improved survival seen in the JGOG 3016 study when patients were treated with the dose-dense regimen.
These two trials have some important differences. JGOG 3016 assessed more patients with advanced disease and used a higher density weekly regimen than that used in MITO-7: in MITO-7, carboplatin was given weekly, resulting in less of a peak effect and lower cumulative dose of paclitaxel. Moreover, genetic differences between Japanese and European patients might have affected hepatic metabolism the drugs. In the JGOG study, less than half of women had optimum residual disease and patients with stage II disease were included. Additionally, in the control group, 27% of women were unable to receive standard chemotherapy because of toxic effects, which is likely to have affected their prognosis. Additional translational studies based on the JGOG regimen are urgently needed. These studies should include white as well as Asian patients and should be stratified for tumour histotype, as suggested in the The Cancer Genome Atlas study.8 Prospective pharmacogenetic analyses of the tumour—ie, single nucleotide polymorphisms in DNA repair pathways within tumour histotypes—might help to clarify the pharmacokinetic and pharmacodynamic effect of this schedule, providing insight into underlying molecular processes within different ethnic subgroups of patients.
Ongoing studies should provide important new data. GOG 262 will compare carboplatin (AUC 6 mg/mL per min) plus paclitaxel (175 mg/m2) given every 3 weeks with carboplatin (AUC 6 mg/mL per min) plus weekly paclitaxel (80 mg/m2) given every 3 weeks for suboptimally resected stage III or IV ovarian cancer with additional bevacizumab. ICON 8 is planned to be a three-armed randomised trial comparing carboplatin (AUC 5 mg/mL per min) plus paclitaxel (175 mg/m2) versus carboplatin (AUC 5 mg/mL per min) plus weekly paclitaxel (80 mg/m2) versus weekly carboplatin (AUC 1·67 mg/mL per min) plus weekly paclitaxel (80 mg/m2) for stage IC-IV ovarian cancer.
Although questions still remain over dosing and timing of first-line treatment for patients with advanced ovarian cancer, the JGOG study provides important data that will help guide patient care in the future.
1 Burger RA, Brady MF, Bookman MA, et alGynecologic Oncology Group. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 2011; 365: 2473-2483.
2 Perren TJ, Swart AM, Pfisterer J, et alICON7 Investigators. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 2011; 365: 2484-2496.
3 Norton L. Theoretical concepts and the emerging role of taxanes in adjuvant therapy. Oncologist 2001; 6 (suppl 3): 30-35.
4 Van der Burg ME, Janssen JT, Ottevanger PB, et al. Multicenter randomized phase III trial of 3-weekly paclitaxel/platinum (PC3w) versus weekly paclitaxel/platinum (PCw) induction therapy followed by PC3w maintenance therapy in advanced epithelial ovarian cancer (EOC). Proc Am Soc Clin Oncol 2009; 27 (suppl 286s): 15s.
5 Katsumata N, Yasuda M, Takahashi F, et alfor the Japanese Gynecologic Oncology Group. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial. Lancet 2009; 374: 1331-1338. Summary | Full Text | PDF(197KB)
6 Katsumata N, Yasuda M, Isonishi S, et alfor the Japanese Gynecologic Oncology Group. Long-term results of dose-dense paclitaxel and carboplatin versus conventional paclitaxel and carboplatin for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016): a randomised, controlled, open-label trial. Lancet Oncol 2013; 14: 1020-1026. Summary | Full Text | PDF(326KB)
7 Pignata S, Scambia G, Lauria R, et al. A randomized multicenter phase III study comparing weekly versus every 3 weeks carboplatin (C) plus paclitaxel (P) in patients with advanced ovarian cancer (AOC): Multicenter Italian Trials in Ovarian Cancer (MITO-7)—European Network of Gynaecological Oncological Trial Groups (ENGOT-ov-10) and Gynecologic Cancer Intergroup (GCIG) trial. Proc Am Soc Clin Oncol 2013; 31 (suppl). abstr LBA5501.
8 Bell D, Berchuch A, Birrer M, et alCancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 2011; 474: 609-615.