Moving beyond cytotoxic drug dosing in ovarian cancer
Authors: Ramez N Eskander, Bradley J Monk
Journal: The Lancet (2019)

Epithelial ovarian cancer remains the most lethal gynaecological malignancy in developed countries despite efforts to improve oncological outcomes by building on the established front-line chemotherapy backbone of carboplatin and paclitaxel administered every 3 weeks.1Siegel RL Miller KD Jemal A Cancer statistics, 2019.CA Cancer J Clin. 2019; 69: 7-34Crossref PubMed Scopus (14120) Google Scholar Investigators have examined platinum-based triplet regimens, and sequential doublets without improvements in progression-free survival.2Bookman 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: 1419-1425Crossref PubMed Scopus (584) Google Scholar It was not until the incorporation of the anti-angiogenic antibody bevacizumab that considerable improvements in progression-free survival were made.3Perren TJ Swart AM Pfisterer J et al.A phase 3 trial of bevacizumab in ovarian cancer.N Engl J Med. 2011; 365: 2484-2496Crossref PubMed Scopus (1597) Google Scholar, 4Burger RA Brady MF Bookman MA et al.Incorporation of bevacizumab in the primary treatment of ovarian cancer.N Engl J Med. 2011; 365: 2473-2483Crossref PubMed Scopus (1728) Google Scholar Recently, substantial gains were realised with the incorporation of maintenance poly(ADP-ribose) polymerase inhibitors (PARPi) in biomarker selected populations (patients with BRCA mutation and homologous recombination deficient). SOLO-1 randomly assigned patients with a BRCA mutation and newly diagnosed advanced stage ovarian cancer to olaparib or placebo after a complete or partial response to platinum-based chemotherapy.5Moore K Colombo N Scambia G et al.Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer.N Engl J Med. 2018; 379: 2495-2505Crossref PubMed Scopus (1338) Google Scholar Olaparib maintenance resulted in a 3-year improvement in median progression-free survival over placebo (hazard ratio [HR] 0·30; p<0·001) and the median progression-free survival had not yet been reached in the olaparib group (vs 13·8 months in the placebo group). The magnitude of benefit, in terms of HR, identified in the SOLO-1 trial has since been approached in three studies examining maintenance PARPi in the front-line setting. PRIMA/GOG-3012, PAOLA-1, and VELIA/GOG-3005, all presented at the 2019 European Society for Medical Oncology meeting, showed a significant reduction in the risk of progression in biomarker selected cohorts, calling into question the relevance of cytotoxic drug dosing as part of primary therapy. Before the biomarker driven drug discovery that resulted in PARPi approval, investigators studied the potential benefits of weekly paclitaxel drug delivery.6Lau DH Xue L Young LJ Burke PA Cheung AT Paclitaxel (Taxol): an inhibitor of angiogenesis in a highly vascularized transgenic breast cancer.Cancer Biother Radiopharm. 1999; 14: 31-36Crossref PubMed Scopus (163) Google Scholar, 7Griffon-Etienne G Boucher Y Brekken C Suit HD Jain RK Taxane-induced apoptosis decompresses blood vessels and lowers interstitial fluid pressure in solid tumors: clinical implications.Cancer Res. 1999; 59: 3776-3782PubMed Google Scholar In JGOG 3016, carboplatin and paclitaxel every 3 weeks versus carboplatin every 3 weeks plus weekly paclitaxel was assessed. This trial showed both a significant improvement in progression-free survival and overall survival.8Katsumata N Yasuda M Isonishi S et al.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: 1020-1026Summary Full Text Full Text PDF PubMed Scopus (337) Google Scholar Subsequently, Chan and colleagues (GOG-0262) looked to establish whether dose-dense weekly paclitaxel and carboplatin would prolong progression-free survival in patients receiving and those not receiving bevacizumab.9Chan JK Brady MF Penson RT et al.Weekly vs. every-3-week paclitaxel and carboplatin for ovarian cancer.N Engl J Med. 2016; 374: 738-748Crossref PubMed Scopus (239) Google Scholar In the intention-to-treat population, no improvement in progression-free survival was identified. Conversely in the non-bevacizumab cohort (16% of patients), a 3·9-month improvement in progression-free survival was seen in the dose-dense paclitaxel group. In The Lancet, Andrew Clamp and colleagues report the results of the ICON8 study,10Clamp AR James EC McNeish IA et al.Weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal carcinoma treatment (ICON8): primary progression free survival analysis results from a GCIG phase 3 randomised controlled trial.Lancet. 2019; (published online Nov 29)https://doi.org/10.1016/S0140-6736(19)32259-7Summary Full Text Full Text PDF PubMed Scopus (106) Google Scholar which investigated the potential therapeutic benefit of dose-dense paclitaxel in conjunction with carboplatin in 1566 women with stage 1C–IV epithelial ovarian cancer. The study compared 3-weekly carboplatin plus 3-weekly paclitaxel (group 1, n=522) with two separate study groups: 3-weekly carboplatin plus weekly paclitaxel (group 2, n=523) and weekly carboplatin plus weekly paclitaxel (group 3, n=521). The authors reported no significant improvement in progression-free survival in either weekly regimen compared with the control group despite successfully achieving paclitaxel dose intensification. The restricted mean survival time was 24·5 months in group 1 (97·5% CI 23·0–26·0), 24·9 months in group 2 (24·0–25·9), and 25·4 months in group 3 (23·9–26·9; group 1 vs group 2 log-rank p=0·35; group 1 vs group 3 log-rank p=0·51). Estimated 2-year overall survival was 80% (95% CI 76–83) in group 1, 82% (78–85) in group 2, and 78% (74–81) in group 3. Furthermore, the weekly regimens were associated with an increased frequency of anaemia and neutropenia. On the basis of the study findings, the authors concluded that 3-weekly carboplatin and paclitaxel should remain the preferred chemotherapy regimen for the front-line treatment of ovarian carcinoma. The results of ICON8 are informative, re-establishing 3-weekly delivery as standard care, although questions remain. The discrepant adverse event frequencies reported in JGOG 3016, GOG-0262, and ICON8 might reflect the relevance of pharmacogenomics in drug delivery and efficacy, or alternatively reflect differences in drug dosing between trials. The JGOG 3016 study reported a 53% discontinuation rate in the weekly paclitaxel study group, greater than that reported on ICON8 or GOG-0262, although both carboplatin and paclitaxel dosing were higher than that in the comparator trials. The relevance of haematological toxicity on outcomes remains unclear, although investigators have suggested that the presence of chemotherapy-induced neutropenia might be associated with improved outcomes.11Tewari KS Java JJ Gatcliffe TA Bookman MA Monk BJ Chemotherapy-induced neutropenia as a biomarker of survival in advanced ovarian carcinoma: an exploratory study of the gynecologic oncology group.Gynecol Oncol. 2014; 133: 439-445Summary Full Text Full Text PDF PubMed Scopus (25) Google Scholar Additionally, polymorphisms in paclitaxel-metabolising enzymes, transporters, and targets might influence toxicity and response, with ethnicity-specific differences.12Rodríguez-Antona C Pharmacogenomics of paclitaxel.Pharmacogenomics. 2010; 11: 621-623Crossref PubMed Scopus (48) Google Scholar In the context of the ethnic diversity between the above-mentioned trials, weekly paclitaxel might have a beneficial effect on survival in a particular patient subset. Further limitations of the ICON8 trial include the incorporation of early stage patients at high risk (20% stage 1C–II), which might have diluted the treatment effect, as well as a greater frequency of patients on neoadjuvant chemotherapy than initially anticipated, affecting the power to detect a meaningful difference among study groups. Furthermore, incorporation of bevacizumab could abrogate any benefits seen with weekly paclitaxel administration. Although JGOG 3016 did not incorporate bevacizumab, the potential results of the ICON8B trial (NCT01654146) might support the findings of GOG-0262. Ultimately, the 3-weekly regimen appears to be equally efficacious, less toxic, and easier to administer. However, some argue that we are beyond the era of cytotoxic drugs, as novel combinatorial approaches using PARPi, immune checkpoint inhibitors, and anti-angiogenics are currently being examined. RNE has received consulting fees, honoraria, and compensation for advisory board participation from AstraZeneca, Clovis Oncology, GSK/Tesaro, Iovance, Merck, and Pfizer, and speaker fees from AstraZeneca and Clovis Oncology, all outside the area of work commented on here. BJM has received honoraria and consulting fees from AstraZeneca, Clovis Oncology, Merck, Pfizer, GSK/Tesaro, and Genentech/Roche, and received speaker fees from AstraZeneca, Clovis Oncology, and GSK/Tesaro, all outside the area of work commented on here. Weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal carcinoma treatment (ICON8): primary progression free survival analysis results from a GCIG phase 3 randomised controlled trialWeekly dose-dense chemotherapy can be delivered successfully as first-line treatment for epithelial ovarian cancer but does not significantly improve progression-free survival compared with standard 3-weekly chemotherapy in predominantly European populations. Full-Text PDF Open Access