There will be no further randomized phase III trials of cytotoxic IP chemotherapy; IP therapy in ovarian cancer will soon be an historical footnote along with other failed approaches in cancer care.
The decades-long controversy regarding intraperitoneal (IP) therapy in ovarian cancer is over-but it did not end in the way many had predicted. With the publication of data showing that the benefit of IP therapy extended beyond 10 years, oncologists favoring IP therapy felt vindicated. To them, it was “tragic” that many eligible patients were not receiving IP therapy. Now, oncologists would have “no more excuses” for not administering IP therapy, and patients were encouraged to seek out physicians who would use this modality.
However, in the same way that many asked “what happened?” after our last presidential election, these oncologists were left to ponder the fate of IP therapy after the results of the definitive Gynecologic Oncology Group (GOG) 252 study were presented. This large, well-designed trial failed to show any advantage for IP therapy compared with a completely intravenous (IV) regimen of carboplatin plus paclitaxel (carbo/pac). The results of a single trial rarely define the standard of care in oncology. However, GOG 252 was designed specifically to address the design problems of previous trials of IP therapy, the results of which had led some to draw erroneous conclusions about the benefits of this therapy. Consequently, the results of GOG 252 were a game-changer, and there is no longer any role for IP therapy. While there may be some future trials in which IP administration of targeted therapy is studied, there will be no further randomized phase III trials of cytotoxic IP chemotherapy. The number of patients treated via the IP route will rapidly decrease. IP therapy in ovarian cancer will soon be an historical footnote along with other failed approaches, such as second-look laparotomies, which also had advocates despite there being no prospective evidence of clinical benefit.
Some advocates of IP therapy have held out hope that three other IP trials may show benefit, and they have also suggested that the results of GOG 252 should be compared with earlier trials, which, in their mind, had shown a marked clinical benefit for the IP route of administration. An ongoing Japanese trial of IP therapy (ClinicalTrials.gov identifier: NCT01506856), no matter the results, will not have an impact on clinical practice in Western countries, since trials showing a benefit for Japanese patients have not always been confirmed outside of Japan. For example, while weekly paclitaxel was shown to have a survival advantage in a Japanese study, the recently reported large randomized ICON8 trial in predominantly European women failed to show any advantage over the traditional 3-week schedule of paclitaxel administration.
Two trials which included IP therapy as part of interval cytoreduction also have not changed the standard of care. The Gynecologic Cancer Intergroup (GCIG) OV21/PETROC study was a trial of IP therapy in the neoadjuvant setting and reported a statistically significant decrease in the rate of progressive disease at 9 months for IP therapy, but no statistical difference for the clinically meaningful endpoints of progression-free survival (PFS) and overall survival (OS) was shown. Consequently, this underpowered phase II trial does not provide meaningful evidence of clinical benefit for IP therapy. In a Dutch trial, patients with advanced ovarian cancer received 3 cycles of IV carbo/pac and were randomly assigned to cytoreductive surgery or cytoreductive surgery plus high-dose IP cisplatin (100 mg/m2) and hyperthermia (HIPEC). All patients received an additional 3 cycles of IV carbo/pac after surgery. Patients receiving HIPEC had a 3.5-month improvement in median PFS and a 11.8-month improvement in median OS. HIPEC has been used for many years, primarily in Europe, with controversial claims about efficacy. It is up to the GOG, and the National Cancer Institute (NCI), to determine whether these results are of sufficient merit to warrant a confirmatory trial in US patients. Such a trial by necessity would have to include newer forms of therapy (such as poly [ADP-ribose] polymerase [PARP] inhibitors, see further on) and incorporate a design to determine the contribution of the individual components of HIPEC. The results of such a trial may not be available for another decade, by which time molecular targeted therapy will likely diminish the role of nonspecific cytotoxic chemotherapy.
GOG 252 was designed with an IV-only arm containing carbo/pac precisely because the two previous GOG trials of IP therapy were compromised by the selection of an outdated IV arm of cisplatin plus paclitaxel (cis/pac). The results of prior studies should not be given equal weight to the results of GOG 252, which invalidated the conclusion that these prior studies provided evidence that IP therapy was of clinical benefit.
The debate about the merits of IP therapy began with the publication of the first randomized trial of IP vs IV therapy. The primary reservation about the results of this study was that the IV control arm did not include paclitaxel. Subsequently, GOG 114 and GOG 172 were conducted, using IV cis/pac as the control, with two different experimental arms that included IP therapy; these trials have been the most frequently cited by the advocates of IP therapy to support their position.
In GOG 114, the experimental arm consisted of 2 cycles of moderate-dose (area under the curve [AUC]=9) IV carboplatin followed by 6 cycles of IV paclitaxel plus IP cisplatin. Both PFS and OS were superior in the experimental arm (28 vs 22 months, and 63 vs 52 months, respectively). The severe toxicity in the experimental arm led to a large number of patients not completing the prescribed number of IP treatments. The authors concluded that this regimen could “not be recommended for routine use” and also “could not be recommended for continued development.” Despite the fact that the 2 cycles of AUC=9 carboplatin could have had an impact on PFS and OS, and the authors’ conclusion that this regimen should not be further developed, this trial was included in a meta-analysis of IP trials and has been repeatedly cited as providing evidence that IP therapy is of clinical benefit.
The IP/IV debate reached its peak when the results of GOG 172 were reported. The control arm in this trial was once again IV cis/pac, and the experimental arm utilized IP cisplatin and IV and IP paclitaxel. The experimental arm resulted in improvements in PFS (23.8 vs 18.3 months) and OS (65.6 vs 49.7 months). However, the control arm in GOG 172 was selected before the results of GOG 158 were known. In this trial, IV carbo/pac was compared with IV cis/pac. The carbo/pac arm had less toxicity, with trends towards a decrease in risk of progression (relative risk, 0.88; 95% CI, 0.75–1.03) and death (relative risk, 0.84; 95% CI, 0.70–1.02). These results established that IV carbo/pac, not IV cis/pac, was the standard of care for patients with advanced ovarian cancer. A cross-trial comparison of GOG 158 and GOG 172 suggested that if IV carbo/pac had been the control arm of GOG 172, there would have been only an 8.2-month difference in OS, rather than the 15.9-month improvement that was reported. Cross-trial comparisons are not definitive and are only useful when comparing randomized trials in which the same treatment has produced equivalent results. In such situations, as in GOG 158 and GOG 172, in which the same control arm (IV cis/pac) in patients who had met the same eligibility criteria produced essentially identical results, comparing the experimental arms in the two trials-eg, IV carbo/pac vs IP chemotherapy-is informative. The IP advocates immediately and emphatically rejected any such comparison. There were other major concerns voiced about GOG 172, including the fact that many patients could not finish the 6 cycles of IP chemotherapy and that patients who stopped IP therapy were crossed over to IV carbo/pac, but these were also dismissed by the IP advocates. They concluded that the benefit of IP therapy had been firmly established and that future randomized trials “should not use a totally IV-administered chemotherapy regimen as the control arm.” The GOG Ovarian Committee and the NCI rightfully did not accept this recommendation when they designed GOG 252.
With the publication of the long-term survival advantage for IP cisplatin in GOG 172, some IP advocates were emboldened to step up their rhetoric pressing the merits of IP therapy. In response to a report demonstrating that many eligible patients at National Comprehensive Cancer Network centers were not receiving IP therapy, it was alleged that some physicians did not use IP therapy because they would “make little money.” It seems inappropriate to impugn the motives of practicing oncologists who selected IV chemotherapy at the same time that the GOG was performing a randomized trial of IP therapy using a completely IV comparator arm. Physicians could legitimately elect to use IV therapy until the GOG, and its sponsor, the NCI, concluded that IP therapy was the preferred choice. In any event, the results of GOG 252 reaffirmed the recommendation that IV chemotherapy be the standard of care for advanced ovarian cancer.
The results of GOG 252 were definitive, and there should be no equivocation regarding the conclusions. The study enrolled 1,560 patients who were randomly assigned to one of three treatment arms. The IV arm included carboplatin with weekly dosing of paclitaxel; the two IP arms contained carboplatin and cisplatin, respectively. All three arms included IV bevacizumab. There was no difference in median PFS for patients with visible tumor of 1 cm or less or for those patients with no visible residual disease. It now appears that bevacizumab provides little, if any, benefit for patients with small-volume disease, and weekly paclitaxel has recently been shown to offer no advantage over a traditional 3-week schedule. Thus, it can be reasonably concluded that such modifications to standard IV carbo/pac, such as the addition of bevacizumab or the use of weekly paclitaxel dosing, would not have altered the conclusions of GOG 252. Additional trials of modifications of cytotoxic IP/IV therapy are simply not warranted.
It is time to close the chapter on IP therapy in ovarian cancer. It is over. No more debates, no new trials-and oncologists will treat small-volume ovarian cancer with treatments based on definitive trials. What all oncologists and investigators treating ovarian cancer agree upon is the fact that we need to do much more to improve outcomes in this disease. Certainly ovarian cancer patients agree, as they have tirelessly advocated for more innovative research focused on improving survival. Unfortunately, in contrast to major advances in survival in melanoma, kidney cancer, and lung cancer resulting from immunotherapy and targeted treatments, until recently, little progress has been made in mortality and survival in ovarian cancer. Inhibiting a specific DNA repair pathway with PARP inhibitors has produced significant improvements in PFS in patients with recurrent disease, and olaparib, rucaparib, and niraparib have been approved by the US Food and Drug Administration. These encouraging results validate the hypothesis that inhibiting defined molecular pathways can produce a significant improvement in outcomes with acceptable toxicity. Targeting the right molecular/genetic target with a specific therapy will lead to a greater survival benefit than has been observed over the past 2 decades with cytotoxic chemotherapy, regardless of the route of administration.
Financial Disclosure: The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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