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IP therapy for ovarian cancer: A continued area of debate
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Once upon a time, there was an argument as to whether paclitaxel plus platinum was the standard of care in ovarian cancer as opposed to single-agent carboplatin or cisplatin plus cyclophosphamide with or without an anthracycline.
The argument was settled for most people once all the data were published, and although not every trial gave exactly the same answer, the benefit was clear. In particular, the components, dosing and schedule of the new regimen were set. Parts of the world held out for single-agent carboplatin to remain the standard, but interestingly, the groups that took this view used the new standard as the control arm in their trials.
The use of intraperitoneal (IP) therapy is based on GOG 172, a very well-conducted, large randomized trial that showed benefit against the standard of care; two supportive trials; and several reviews, retrospective studies, data updates and meta-analyses.
Why, then, does IP therapy continue to be an area of argument? Only 43% of suitable patients in major centers in the United States are offered this treatment, and collaborative groups do not automatically use this route in the control arm of trials that involve patients with optimally debulked disease.
The answer is a mixture of the lack of true robustness of the data, the lack of an agreed-upon standard IP regimen, and the complexity of treatment delivery and toxicity. The operative word here is “mixture” — no one element alone is a show stopper.
Robustness of data
I will deal with the last two points first because I completely agree with the most fervent proponents of IP therapy: Complexity of delivery and side effects should not be a barrier to offering a new effective therapy.
A new standard of care that is associated with such issues is completely acceptable to patients and physicians alike, provided the benefit in terms of outcome — particularly OS — is unequivocal.
It is clear that centers that use IP administration routinely are able to do so efficiently and can manage the side effects encountered. The onus, therefore, is on the wider oncological community to get to the same place and make every effort to reduce complexity and to find ways of managing the toxicities effectively.
Lack of true robustness of the data lies in the design of the main IP trials, not their conduct or analysis.
Randomized trials that are designed to alter a standard of care must have that standard of care as the control arm. Randomized trials that ask a more pharmacological question — such as route of administration — require the arms of the trial to be the same in terms of drugs, dose and schedule, and different only in regard to the question being asked (eg, the route).
A Cochrane Review found only eight IP trials of high enough quality from which meaningful survival data could be extracted. None of these trials had carboplatin–paclitaxel as the control arm, a treatment that most would regard as standard of care for patients with advanced ovarian cancer. It has certainly been used as the control arm for most randomized trials in advanced ovarian cancer in the last 15 years.
This may seem a bit picky, as cisplatin–paclitaxel was an old standard of care and has been shown in three randomized trials to be equivalent — or, perhaps to use a more correct statistical term, noninferior — to carboplatin–paclitaxel.
Three of the eight trials have this “equivalent” old standard as the control arm. One trial shows a statistically significant survival benefit for IP therapy (GOG 172); one is equivocal, with a P value of 0.05 (GOG 114); and one, published by Yen and colleagues in 2009, is negative.
The study by Yen and colleagues is difficult to interpret because their publication is not presented in a standard way. Patients received cisplatin or carboplatin, but there is no clarity on how it was decided which patients received which platinum compound. Strangely, in order to find the OS result of this study according to route of administration, one has to go to the Cochrane Review, rather than the original publication.
The survival of patients in the control arms of these three trials is just about comparable by proxy to the results obtained with carboplatin–paclitaxel, but the interpretation of the relative increase in toxicity of IP therapy is not. If IP therapy is more toxic than cisplatin–paclitaxel in randomized trials, then how much more toxic is IP therapy compared with carboplatin–paclitaxel? It is not an unreasonable assumption that if directly compared to carboplatin–paclitaxel, IP therapy would be shown to be very much more toxic.
Route of administration
Only three of the eight high-quality Cochrane-reviewed trials are designed to answer the pharmacological question of route. Two trials — one by Gadducci and colleagues, the other by Yen and colleagues — show no survival advantage to IP administration. Yet, famously, one of them — GOG 104 — does show a statistically significant impact on survival.
So, we do have a trial that clearly demonstrates that it is more efficacious to give IP cisplatin as opposed to IV cisplatin. Unfortunately, this information is irrelevant to current practice. When was the last time any of us used cisplatin as first-line therapy in a patient with advanced ovarian cancer?
Further, the IP cisplatin data are not really transferrable to carboplatin because the two drugs have different pharmacokinetics and dynamics for the IV and IP routes.
GOG 172 evaluated an experimental regimen that includes IP administration of chemotherapy, resulting in a statistically significant survival advantage compared with a previous standard of care, cisplatin plus paclitaxel.
Offering suitable patients the experimental regimen as described by Armstrong and colleagues in GOG 172 is completely reasonable. Such a suggestion would need to be accompanied by detailed counseling about toxicity as it relates to the side effects of carboplatin–paclitaxel rather than cisplatin–paclitaxel, because outside of a clinical trial, the former — not the latter — is the alternative. The offer of any other IP regimen outside a clinical trial would not be based on level one evidence.
My only real argument with some of the protagonists for IP therapy relates to the adjectives used to describe the data and the statements made about the benefits of IP therapy when they are made without qualification or equivocation.
What is unarguable is that the data — particularly the reviews and meta-analyses — are strong enough to warrant further research into this route of administration, because there is a positive signal here.
I applaud the collaborative groups that are engaged in the three main current randomized trials — GOTIC-001/JGOG-3019, GOG 252 and OV.21 — particularly because the controls arms consist of IV carboplatin–paclitaxel.
References:
Alberts DS, et al. N Engl J Med. 1996;doi:10.1056/NEJM19961226335260.
Armstrong DK, et al. N Engl J Med. 2006;doi:10.1056/NEJMoa052985.
Gadducci A, et al. Gynecol Oncol. 2000;doi:10.1006/gyno.1999.5677.
Jaaback K, et al. Cochrane Database Syst Rev. 2011;doi:10.1002/14651858.CD005340.pub3.
Kirmani S, et al. Gynecol Oncol. 1994;doi:10.1006/gyno.1994.1220.
Markman M, et al. J Clin Oncol. 2001;19:1001-1007.
Wright AA, et al. J Clin Oncol. 2015;doi:10.1200/JCO.2015.61.4776.
Yen M-S, et al. Gynecol Oncol. 2009; doi: 10.1016/j.ygyno.2009.05.034.
Yen M-S, et al. Int J Gynecol Obstet. 2001;doi:10.1016/S0020-7292(00)00340-4.
Zylberberg B, et al. J Gynecol Obstet Biol Reprod (Paris). 1986;15:671-676.
For more information:
Martin Gore, PhD, FRCP, is a consultant medical oncologist and professor of cancer medicine at Royal Marsden Hospital in London. He can be reached at martin.gore@rmh.nhs.uk.
Disclosure: Gore reports no relevant financial disclosures.