Continuous interrogation into the biology of ovarian cancer and its microenvironment may hold new avenues of clinical investigation for intraperitoneal treatment.
—Robert L. Coleman, MD
An analysis of Gynecologic Oncology Group (GOG) studies recently reported in the Journal of Clinical Oncology by Tewari and colleagues and reviewed in this issue of The ASCO Post showed a survival benefit of intraperitoneal chemotherapy vs intravenous chemotherapy over long-term follow-up in women with advanced ovarian cancer.1 The findings add to the ongoing conversation on the fate of intraperitoneal treatment in this setting.
A ‘Trifecta’ of Sorts
The publication of GOG-172 in 2006 completed an intraperitoneal chemotherapy “trifecta” of sorts in demonstrating its utility as primary adjuvant therapy in women with advanced-stage ovarian cancer.2-4 Although at the time of its publication, there had been eight prospective clinical trials of intraperitoneal therapy, the three from GOG/Southwest Oncology Group (SWOG) represented the largest, with the strongest treatment effects.5 Concomitant with this latter trial’s publication came a National Cancer Institute (NCI) clinical announcement on January 4, 2006, stating that intraperitoneal therapy was “encouraged…after surgery, for women with advanced ovarian cancer.”
However, long before this landmark publication and rare NCI media release, presentations and debates at national and international conferences discussing the implications of each of these three studies (GOG-104/SWOG-8501, GOG-114, and GOG-172) had already tainted the touted benefit as bittersweet, citing excessive toxicity of the regimen, poorer patient-reported outcomes, catheter complications, and physician and patient inconvenience among the oncology community.6,7
It was noteworthy, and in some respects affirming, that the NCI announcement did not endorse a specific intraperitoneal regimen, despite heralding the results of GOG-172. This is likely due to the unique designs, endpoints, and findings of the three trials, not the least of which was that each evaluated a different intraperitoneal experimental arm. Since GOG-114 and GOG-172 compared intraperitoneal therapy with a common intravenous regimen (24-hour paclitaxel on day 1 followed by cisplatin on day 2) in a relatively contemporary ovarian cancer population, Tewari and colleagues combined the data sets and performed a long-term follow-up analysis.
As expected in this setting, the combined analysis (now with 10-year follow-up) of two individually “positive” trials was a “positive” evaluation—notably, there was an impressive 23% adjusted reduced risk of death for patients treated with intraperitoneal vs intravenous therapy. This amounted to an approximate 10.4-month survival advantage at the median between the two modalities of delivery. Few trials before or since have documented this kind of impact among this patient cohort. Progression-free survival was similarly and consistently “positive” in this analysis.
However, one of the acknowledged difficulties with intraperitoneal therapy is inconsistent delivery success throughout the intent-to-treat interval after surgery. In GOG-104, GOG-114, and GOG-172, only 58%, 71%, and 42% of intraperitoneal patients, respectively, received all six cycles of intended therapy via that route.
Although these data were/are alarming for any modality in front-line therapy, they grossly underestimated the difficulty of extrapolation to a broader medical community, particularly those outside the experienced investigators, nurses, and support staff of the cooperative group sites. Thus, it is not surprising that many clinicians considering intraperitoneal therapy as a practice standard never embraced the data and that some brave enough to try experienced significant challenges—particularly in adoption of GOG-172’s multiday/weekly strategy.
Criticisms Temper Clinical Adoption
One of the many criticisms of the “trifecta” was choice of the control arm in each of the studies. GOG-104, published the same year as GOG-111, which introduced paclitaxel in the front-line setting to poorer-prognosis patients, lacked this new agent. GOG-114 and GOG-172 used 24-hour infusion of paclitaxel and cisplatin (day 2). However, data from GOG-158, featuring paclitaxel (3-hour infusion) with carboplatin (area under the curve = 7.5) compared with the same intravenous control arm used in GOG-172, were already known and a community standard.
In addition, cross-trial evaluation (albeit statistically invalid) of the control arm in GOG-172 vs the experimental arm in GOG-158 implied “underperformance” of GOG-172’s control arm. Furthermore, at the time of GOG-172’s publication, intense interest was focused on bevacizumab (Avastin), which was serving in experimental arms of new GOG and international front-line phase III trials.8,9 This, along with an extremely provocative dose-dense, dose-intense intravenous paclitaxel phase III study by the Japanese GOG demonstrating similar efficacy results on overall survival, tempered clinical adoption of intraperitoneal therapy.10
New Light on Its Potential
Nevertheless, a series of reports like the current article by Tewari et al have cast new light on the potential for intraperitoneal therapy. First is the significant improvement in surgical standards for primary cytoreduction. At the time of initial reports on intraperitoneal therapy, the rate of complete surgical cytoreduction (R0) was 10% to 25%; R0 rates have now doubled, largely due to more aggressive surgery and advanced surgical training, globally, of gynecologic oncologists.11 Several reports, including the Tewari et al analysis, have suggested that the R0 cohort represents the subgroup most likely to benefit from intraperitoneal therapy.
Second, improvements in supportive care and alterations in the dosing/infusion schedules of the agents have dramatically improved the proportion of patients completing all six cycles of intended intraperitoneal chemotherapy.12 Although it remains a risk that alterations in dosing/schedule could impact survival efficacy, this may be countered by the ability to complete all therapy via intraperitoneal administration.
Third, understanding genomic alterations in the tumor may further clarify who should be given intraperitoneal therapy. Recently, an analysis of somatic loss of BRCA1 in patients participating in GOG-172 demonstrated a profound effect on overall survival.13 In this analysis of 393 patients (94% of GOG-172 participants), somatic loss of BRCA1 was observed in 48%. Among this cohort, the median overall survival for intraperitoneal vs intravenous therapy was 84 vs 47 months (P = .0002), amounting to a 33% reduction in the hazard for death. There was no difference between intraperitoneal and intravenous therapy among patients with normal expression of BRCA1.
Finally, histology may be important, as patients with serous cancer, the most prevalent subtype, appeared to benefit from intraperitoneal therapy, but only if six cycles could be administered.
The future of intraperitoneal therapy will likely undergo another transition, as the results of the GOG-252 (clinicaltrials.gov, NCT00951496), iPocc (NCT01506856), and NCIC-OV21 (NCT00993655) trials become available. In GOG-252, two different intraperitoneal infusion strategies are being evaluated in combination with bevacizumab against a contemporary control arm (paclitaxel, carboplatin, bevacizumab followed by bevacizumab maintenance).
The Japanese iPocc trial is comparing the same dose-dense, dose-intense paclitaxel intravenous arm as in its previous trial vs intraperitoneal carboplatin (same intravenous and intraperitoneal doses) but is allowing both optimal and suboptimal surgical cytoreduction patients to participate.
NCIC-OV21 is focusing exclusively on the neoadjuvant chemotherapy population, administering intravenous or one of two intraperitoneal regimens following interval debulking surgery planned after three to four induction cycles of intravenous platinum-based therapy.
Although each of these trials has the potential to solidify and/or broaden the potential audience for intraperitoneal therapy, they may also define it as a relic of early ovarian cancer clinical therapy. Nevertheless, continuous interrogation into the biology of ovarian cancer and its microenvironment may hold new avenues of clinical investigation for intraperitoneal treatment. ■
Disclosure: Dr. Coleman is a consultant for AbbVie, AstraZeneca, Bayer, Caris Life Sciences, Celgene, Cerulean, Clovis Oncology, CritiTech, Inc, EDU-Pharma, Eisai-Morphotek, Genmab, GlaxoSmithKline, ImmunoGen, Merck Sharp & Dohme, Merrimack, Millennium Pharmaceuticals, Nektar, Oxigene, and Vermillion, Inc; a speaker for AstraZeneca, Caris MPI, GlaxoSmithKline, and Merck (ESGO); on the scienctific/advisory board for Amgen, Bayer Healthcare, Cerulean (GOG funded), Clovis Oncology, Eisai-Morphotek, Endocyte (GOG funded), GlaxoSmithKline, Gradalis (GOG funded) Janssen, Merck Sharp & Dohme, National Comprehensive Cancer Network, and VentiRx (GOG); and receives research funding from Array Bio Pharmaceuticals, Clovis Oncology, EMD Serono, Janssen, Merck, Millennium Pharmaceuticals, and OncoMed Pharmaceuticals.
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