IP Chemo Ups Survival in Ovarian Cancer, So Why Limited Use?

Nick Mulcahy

August 06, 2015

A "real-world" study conducted at six top cancer clinics has confirmed that the intraperitoneal (IP) administration of chemotherapy in patients with ovarian cancer significantly improves survival.

But despite previous findings from the randomized Gynecologic Oncology Group (GOG)-172 trial supporting this unconventional route of administration, it's use is limited (N Engl J Med. 2006;354:34-43). However, top cancer centers did adopt IP administration after results from the GOG-172 trial were published.

In fact, in this real-world study, historic data showed that IP administration for patients with optimally debulked, stage III ovarian cancer increased from 0% in 2003 to 33% in 2006. It then rose to 50% in 2007/08, but has since leveled off.

These numbers represent a missed opportunity because IP administration is so effective, suggest the authors of the real-world study, led by Alexi Wright, MD, from the Dana-Farber/Brigham and Women's Cancer Center in Boston.

Dr Wright and her colleagues compared the combination of IP and intravenous (IV) chemotherapy with the conventional approach of IV alone in a propensity score-matched sample of 402 patients.

They demonstrated that the 3-year rate of overall survival was significantly better with the IP/IV combination than with IV alone (81% vs 71%; hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.47 - 0.99).

Their report was published online August 3 in the Journal of Clinical Oncology.

Of the 114 patients who died during the median follow-up period of 32 months, 51 were treated with the IP/IV combination and 63 were treated with IV alone.

In the GOG-172 trial, median overall survival was 16 months longer with combination IP/IV chemo than with IV alone. But Dr Wright and her colleagues explain that their study is unique because it is a demonstration of the effectiveness in "real world" clinical practice.

This is the first prospective, multi-institutional, comparative-effectiveness study (that is not a clinical trial) to demonstrate that IP/IV chemotherapy is associated with significantly better survival in women with optimally debulked, stage III ovarian cancer, they point out.

But two studies — of patients treated in an integrated healthcare network and of Medicare beneficiaries — demonstrated the "infrequent use" of IP/IV chemotherapy.

IP/IV chemotherapy is an "important and possibly underused evidence-based treatment strategy for improving outcomes in ovarian cancer," the investigators report. And they note that the National Cancer Institute issued a "rare" Clinical Announcement encouraging combination IP/IV use in 2006.

However, the debate over route of chemotherapy administration has been called "one of the longest running controversies in gynecologic oncology" and is not a simple matter, as reported by Medscape Medical News.

Some Ideas About Why Usage Has Been Limited

To learn more about IP/IV usage in everyday practice, Dr Wright and her colleagues looked at patients at six institutions: the City of Hope Comprehensive Cancer Center in Los Angeles, the Dana-Farber/Brigham and Women's Cancer Center in Boston, the Fox Chase Cancer Center in Philadelphia, the Ohio State University Comprehensive Cancer Center in Columbus, the University of Texas M.D. Anderson Cancer Center in Houston, and the University of Michigan Comprehensive Cancer Center in Ann Arbor.

All 823 patients were diagnosed with ovarian, fallopian, or primary peritoneal cancer from 2005 to 2012. The investigators used this pool of patients to tally usage of the different chemotherapy options.

During the study period, use of the IP/IV approach ranged from 4% to 67% of eligible patients.

Overall, 202 of 498 (41%) eligible patients received IP/IV chemotherapy. In adjusted analyses, patients who were younger and patients with fewer comorbidities were more likely to receive the IP/IV combination than IV alone (P ≤ .002 for both).

This variability in use and the age-related trend are important and could explain a lot about the usage of IP/IV, according to an expert not involved with the study

"Younger, healthier women were more likely to receive IP/IV chemotherapy, which may reflect concern for tolerance of treatment-related toxicity. Furthermore, there was variable acceptance among the six sites, suggesting that providers may believe that alternative chemotherapy regimens, especially dose-dense paclitaxel, may be better tolerated and offer similar survival benefits," Gina M. Mantia-Smaldone, MD, a surgical oncologist at the Fox Chase Cancer Center, told Medscape Medical News.

The investigators acknowledge that a Japanese study of similar patients has demonstrated improved survival with dose-dense paclitaxel (Lancet Oncol. 2013;14:1020-1026). However, they did not evaluate the use of paclitaxel because their real-world study was undertaken before the data from Japan were available.

They also acknowledge that "selection bias" might have skewed the survival result in favor of IP/IV.

"If healthier patients were more likely to receive IP/IV chemotherapy than less healthy patients, that could explain the survival benefit we observed," they write. This is a criticism that has also been aimed at the GOG trial, as reported by Medscape Medical News.

But the investigators note that their "rich" clinical data and statistical analyses allowed adjustment for key clinical variables with important prognostic implications (such as performance status, comorbid disease, and extent of residual disease).

In terms of toxicities, adjusted rates of anemia were higher with IP/IV than with IV alone (10.9% vs 5.0%; adjusted odds ratio [OR], 2.20; 95% CI, 1.04 - 4.65), as were adjusted rates of hospitalization (14.4% vs 10.0%; adjusted OR, 1.47; 95% CI, 0.82 - 2.64). However, the difference in hospitalizations was not statistically significant.

Otherwise, clinical complications did not differ by route of administration.

However, women who received IP/IV chemotherapy were more likely to change treatments because of treatment-related toxicities (adjusted rates, 20.4% vs 10.0%; adjusted OR, 2.83; 95% CI, 1.47 - 5.47).

Notably, the adjusted odds of presenting with distant disease at first recurrence was higher in women treated with IP/IV chemotherapy than with IV chemotherapy (58.8% vs 29.4%; adjusted OR, 3.14; 95% CI, 1.34 - 7.36).

This recurrence phenomenon has been found in other studies and has been a criticism of the combination therapy. But the current study authors observe that distant recurrences tend to happen later in time and that IP/IV-treated patients have longer survival.

This recurrence phenomenon has been found in other studies and has been a criticism of the combination therapy. But Dr Wright and her colleagues point out that distant recurrences tend to happen later in time, and that IP/IV-treated patients have longer survival.

J Clin Oncol. Published online August 3, 2015. Abstract

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