January 10, 2016
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Despite survival benefits, role of IP chemotherapy remains unclear

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Treatment options for ovarian cancer have remained largely unchanged over the last 40 years.

Surgical debulking of the ovarian tumor, followed by cytotoxic IV chemotherapy, continues to serve as the standard of care for the majority of women diagnosed with advanced ovarian cancer, the fifth leading cause of cancer-related death among women in the U.S.

Although the age-adjusted ovarian cancer death rate decreased 14% from 1990 to 2010, the improvement is not as drastic as that seen in other cancer types. The death rate decreased 31% for breast cancer, 46% for colorectal cancer and 44% for prostate cancer during that time.

According to SEER data, approximately 22,000 American women received an ovarian cancer diagnosis in 2015, with 14,000 deaths projected annually.

However, intraperitoneal (IP) chemotherapy — which delivers chemotherapy directly into the abdominal cavity via an inserted catheter — has the potential to shift the survival trends in ovarian cancer. The method allows for a highly concentrated dose of the chemotherapeutic agents to reach cancer cells outside the abdominal cavity.

The Gynecologic Oncology Group (GOG) has conducted three phase 3 trials evaluating IP chemotherapy, all of which resulted in significantly improved OS for women who received IP chemotherapy in addition to IV chemotherapy. A growing rank of clinicians believe that IP chemotherapy should become a standard of care.

“IP chemotherapy should absolutely be added to the list of basic quality treatment measures for ovarian cancer because it’s one of the few treatments that extends survival in both randomized clinical trials and the real world,” Alexi Anne Wright, MD, MPH, assistant professor of medicine at Harvard Medical School and physician at Dana-Farber Cancer Institute, told HemOnc Today. “There should be transparency about rates of use by center so that patients can make informed decisions about where they choose to be treated.”

Data from Alexi Anne Wright, MD, and colleagues showed the adoption of intraperitoneal/IV chemotherapy varied from 4% to 67% between institutions.
Data from Alexi Anne Wright, MD, and colleagues showed the adoption of intraperitoneal/IV chemotherapy varied from 4% to 67% between institutions. “This kind of variation among such similar patients is more likely to reflect the preferences of physicians or treatment centers rather than patients,” Wright told HemOnc Today.

Photo by Len Rubenstein.

Despite the survival benefit, data have shown IP chemotherapy is drastically underused. The rate of IP chemotherapy usage was only 43% between 2009 and 2012, down from 50% between 2007 and 2008.

Cost, availability of treatment and the potential for severe adverse events may be barriers hindering the use of IP chemotherapy.

“IP chemotherapy is more challenging to provide safely than IV chemotherapy,” Wright said. “It requires specialized training, is more intensive, and often requires more of what we call ‘high-touch care,’ such as IV fluids to prevent dehydration, antiemetics to present nausea and vomiting, or growth factors to prevent infections. There is also evidence that some physicians just may not believe in IP chemotherapy.”

HemOnc Today spoke with gynecologic oncologists about the positive outcomes but controversial design of the GOG trials, a potential lack of patient and provider information regarding IP delivery, and how risk for toxicity and lack of reimbursement may compromise patients’ potential survival gain.

Preponderance of evidence

IP delivery of chemotherapy is not a novel concept.

Even before the phase 3 GOG trials, many ovarian cancer researchers surmised that the method could significantly improve outcomes, according to William Robinson III, MD, Maxwell E. Lapham professor and section chief of gynecologic oncology at Tulane University School of Medicine’s Tulane Cancer Research Center.

“I have been interested in the concept of IP chemotherapy since I was a fellow, 25 years ago,” Robinson said in an interview. “I remember, even then, thinking that this is a good thing. This is going to work. In my opinion, we have proven it over and over again.”

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The GOG trials — the first of which was conducted by Alberts and colleagues and published in 1996 in The New England Journal of Medicine — substantiated that belief, Robinson said. The GOG 104 trial showed IP cisplatin plus IV cyclophosphamide conferred an 8-month OS advantage compared with the IV-only delivery of these agents (median OS, 49 months vs. 41 months; P = .02).

The GOG 114 trial, led by Maurie Markman, MD, president of medicine and science at Cancer Treatment Centers of America in Philadelphia, as well as a HemOnc Today Editorial Board member, evaluated standard-dose IV cisplatin plus paclitaxel vs. moderately high-dose IV carboplatin followed by IV paclitaxel and IP cisplatin. Results — published in 2001 in Journal of Clinical Oncology — showed the IP chemotherapy regimen prolonged PFS (median, 28 months vs. 22 months; P = .01) and OS (median, 63 months vs. 52 months; P = .05).

Armstrong and colleagues conducted the GOG 172 trial — published in 2006 in The New England Journal of Medicine — which compared IV paclitaxel and cisplatin with IV paclitaxel plus IP cisplatin and paclitaxel. The IP combination conferred a 15.9-month median OS advantage (65.6 months vs. 49.7 months; P = .03) and 5.5-month median PFS advantage (23.8 months vs. 18.3 months; P = .05).

“I am a proponent of the evidence, the overwhelming data and the focus on the benefits to the patients that IP chemotherapy confers,” Markman told HemOnc Today. “This is not a line of reasoning or a philosophy. I am focused here on the hardcore objective data. How often do we see three well-designed phase 3 trials showing an improvement in survival?”

Don S. Dizon, MD, clinical co-director of gynecologic oncology at Massachusetts General Hospital Cancer Center, agreed that IP chemotherapy is extremely beneficial.

“I have been performing IP chemotherapy since I was a fellow at Memorial Sloan Kettering Cancer Center,” Dizon told HemOnc Today. “My institution continues to offer IP chemotherapy. The data that are being published show that, for eligible patients, IP treatment is an excellent treatment option; these patients should no longer be limited to treatment using IV chemotherapy every 3 weeks.”

Further, Tewari and colleagues conducted a retrospective analysis of the GOG 114 and GOG 172 trial protocols that showed the survival benefits associated with IP chemotherapy often extended beyond 10 years.

Results, published in 2015 in Journal of Clinical Oncology, showed median OS was 61.8 months with IP therapy vs. 51.4 months with IV therapy. Overall, IP chemotherapy reduced the risk for death 23% (adjusted HR = 0.77; 95% CI, 0.65-0.9). The survival benefit extended to patients with gross residual disease (adjusted HR = 0.75; 95% CI, 0.62-0.92) and increased with the number of IP cycles completed (per additional cycle, adjusted HR = 0.88; 95% CI, 0.83-0.94).

“The long-term survival benefits described in this report may encourage more clinicians to adopt IP chemotherapy in the community,” Tewari and colleagues wrote. “In addition, IP chemotherapy may be implemented as a quality measure at institutions with the expertise and the support teams necessary to administer IP treatment. Clinicians should support patients through the IP regimen, particularly if there are no significant or excessive toxicities.”

Underutilization

Despite the benefits associated with IP chemotherapy demonstrated on the GOG trials, the procedure has been considerably underused for the treatment of ovarian cancer.

Wright and colleagues conducted a prospective cohort study — presented at the 2014 ASCO Annual Meeting and later published in Journal of Clinical Oncology — that included data from 823 women diagnosed with stage III ovarian cancer between 2003 and 2012. Results showed that the use of IP/IV chemotherapy increased from 0% in 2003 to 33% in 2006, reaching an all-time high of 50% between 2007 and 2008. However, rates plateaued thereafter.

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Of the women who received IP/IV chemotherapy, 29% received the GOG 172 regimen, 28% received IP chemotherapy on a clinical trial and 43% received modified regimens. The adoption of IP/IV chemotherapy varied from 4% to 67% between institutions, and the proportion of patients who received a modified regimen also varied (7% vs. 87%; P < .001 for both).

“This kind of variation among such similar patients is more likely to reflect the preferences of physicians or treatment centers rather than patients,” Wright said.

Further, analyses that considered patient characteristics showed only 41% of patients eligible for IP chemotherapy received that mode of delivery. IP chemotherapy was used more frequently among younger women with fewer comorbidities (P < .002 for both), but race, ethnicity, substage or extent of residual disease did not significantly impact usage.

Despite these findings, interest in IP chemotherapy does appear to have extended from academic treatment centers — where it is more commonly administered — to U.S. community oncology practices, Robinson said.

“I have been invited to multiple practices across the country to demonstrate how to use the procedure,” Robinson said. “There is a skill to it that not all doctors and infusion nurses have, but it seems like something they want to learn.”

Further, the data from Wright and colleagues do not indicate that clinicians lack education regarding IP chemotherapy, according to Stephen C. Rubin, MD, chief of gynecologic oncology and professor of surgical oncology at Fox Chase Cancer Center.

Stephen C. Rubin

“It is fair to say that 30 years [after the original phase 2 trials were conducted], we still do not exactly know the place of IP chemotherapy in ovarian cancer for a variety of reasons,” Rubin told HemOnc Today. “The country’s top gynecologic oncologists, practicing at NCI-designated comprehensive cancer centers, use IP chemotherapy in fewer than half of eligible patients. These are the top people in the country, who know exactly what they are doing. The question to ask is, ‘Why aren’t they using it?’”

Questions of trial design, toxicity

The design of the GOG trials, as well as the toxicity observed among patients assigned IP chemotherapy, has prompted controversy regarding this route of chemotherapy delivery. These concerns may contribute to the underuse of IP chemotherapy.

For instance, the GOG 104 trial did not include paclitaxel, because the results of GOG 111 — which established paclitaxel plus cisplatin as the standard over cyclophosphamide plus cisplatin — had not yet been published.

“Critics opined that the IP arm did not represent contemporary chemotherapy,” David M. Gershenson, MD, professor of gynecologic oncology and reproductive medicine at The University of Texas MD Anderson Cancer Center, as well as HemOnc Today’s gynecologic oncology section editor, told HemOnc Today. “Additionally, a post-hoc subset analysis did not show any benefit in the group with the smallest volume of residual disease.”

Further, the control arms of the GOG 114 and 172 trials evaluated paclitaxel and cisplatin instead of paclitaxel and carboplatin, Gershenson said.

Toxicity is another concern.

In the GOG 172 trial, only 42% of patients assigned IP chemotherapy completed all six cycles compared with 83% of patients assigned IV chemotherapy. Catheter-related infections were the primary reason for discontinuation of IP chemotherapy.

Significantly more patients assigned IP chemotherapy experienced grade 3 or grade 4 fatigue; pain; or hematologic, gastrointestinal, metabolic or neurologic toxicities (P .001 for all).

“Undoubtedly, the cumulative concerns regarding the design of these trials, combined with the increase in adverse events, have biased certain physicians against IP chemotherapy,” Gershenson said.

These risks may specifically be of concern for community oncologists who may not see many patients with ovarian cancer.

“Generally, we use cisplatin, which is more toxic than carboplatin,” Markman said. “There is also a risk that the catheter will cause an infection in the abdomen, which then requires additional treatment. If you are a doctor who does not treat patients with ovarian cancer regularly, it might be difficult to understand this procedure.”

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Because cisplatin is associated with renal toxicities, proper follow-up is key to effective treatment, Dizon said.

“The ability to anticipate and manage the toxicities of this therapy is crucial to patient safety,” Dizon said. “We used to see women treated with IP chemotherapy who were not followed closely, and they would return in renal failure. Because it is such a specialized procedure, it is not normally taught in the context of medical oncology fellowship, and people sometimes do not know what to anticipate.”

Patients must consider this risk–benefit ratio.

“If a patient raises concerns about toxicities, I try to address each potential problem, because there are often solutions,” Wright said. “These might include blood transfusions, IV fluids or better supportive care. I always let patients know that they can stop IP chemotherapy at any point if they decide it is no longer right for them, or opt to avoid it altogether, once they are knowledgeable about the potential trade-offs.”

Influence of time, profit

Toxicity and trial design are not the only concerns regarding the use of IP chemotherapy.

The time, labor and costs associated with IP delivery also appear to have hindered its use.

The average nurse–patient ratio for administering standard IV chemotherapy is 1-to-4 Robinson said. However, because administration of IP chemotherapy is more complicated, the ratio for this procedure is usually 1-1.

“The administration of IP cisplatin takes between 4 and 5 hours altogether,” Robinson said. “That means you have one nurse caring for one patient exclusively for up to 5 hours. On top of that, the patient needs to be supine, not sitting in a chair in the chemotherapy room, as is standard for IV chemotherapy. This requires a degree of privacy — a curtained area, at least, if not a private room.”

Robinson — who owned a chemotherapy infusion center in his former practice — noted oncologists who own infusion centers may be wary of the potential for lost profits associated with IP chemotherapy.

“I am sad to say that money is a part of it,” Robinson said. “Oncologists who own infusion centers make money by giving chemotherapy to patients. When I owned an infusion center, we offered IP chemotherapy, and it was something that I had to justify to my colleagues based on the OS benefits, because the financial benefit is not there.”

Certain IP treatments may require hospitalization, thus increasing cost and labor needs.

“Some of the combined IP/IV regimens used over the past decade have been 2-day inpatient regimens rather than the 4-hour outpatient regimens,” Gershenson said. “In addition, if a port for delivery of IP chemotherapy was not placed at the time of the primary cytoreductive surgery, a second procedure — albeit, rather minor — is required for placement. This will increase cost.”

Wright agreed cost is a concern.

“The cost of IP chemotherapy rarely translates to substantially higher out-of-pocket costs for our patients, but it is more resource-intensive for payers and the system,” Wright said. “For IP chemotherapy, there is a double disadvantage — it is not profitable and it is quite time intensive.”

Further, agents used within IP chemotherapy regimens are generic and, thus, unprofitable, Markman said. Because drug companies do not stand to reap large profits from these agents, they may encourage doctors to focus on other, more lucrative treatments.

“Money is the less pragmatic, but real, issue,” Markman said. “In addition to the administration fees and the labor time that you do not get paid for, there is the fact that these drugs have no mark-up. Cisplatin has been generic for over 30 years. Doctors are paid for procedures and drug administration, not for time and effort.”

Although seminars are often held to educate clinicians when new drugs are introduced, generic drugs rarely are the subject of these seminars, even when they are used in innovative procedures, Markman added.

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“There is no pharmaceutical or device sponsor to talk to people, to hold meetings and educate people about this procedure,” Markman said. “IP chemotherapy is simply a way to give a drug. No one has any vested interest in it, except for the patient.”

Without support from the pharmaceutical industry, additional trials to support IP chemotherapy have been difficult to conduct, Wright said.

This dearth of trials may contribute to a lack of use, Rubin said.

“If there was a clinical trial for IP chemotherapy, I would put patients on it,” Rubin said. “Outside of a clinical trial setting, we really do not know the ideal regimen.”

The issue of choice

A fourth GOG trial evaluating IP chemotherapy is currently underway. Patients on GOG 252 receive bevacizumab (Avastin, Genentech) plus dose-dense IV chemotherapy with paclitaxel and/or carboplatin, with or without IP cisplatin.

The outcomes of GOG 252 will drive the acceptance — or lack thereof — of IP chemotherapy in clinical practice, Rubin said.

“Many people think that dose-dense IV chemotherapy is likely to be less toxic than IP chemotherapy,” Rubin said. “The results of GOG 252 might do a lot to help people understand the role of IP chemotherapy. If it shows that IP chemotherapy is better, a lot of people are going to go to it. If it shows that dose-dense chemotherapy is better, a lot of people will probably give up IP chemotherapy.”

Gershenson agreed.

“Several physicians have assumed that this regimen may produce equivalent outcomes compared with IV/IP chemotherapy, despite the lack of evidence,” Gershenson said. “The findings of GOG 252 will hopefully resolve the question of relative benefit of these treatment strategies.”

Regardless of the results, IP chemotherapy should continue to be an option for women, according to Robinson.

“Virtually all facilities could acquire the skills needed to promote and perform IP chemotherapy, if they had the commitment,” Robinson said. “It is frustrating for those of us who have been in the thick of it for a long time to see it remain so underutilized.”

Still, dose-dense IV chemotherapy presents a potential choice for doctors and patients who remain uncomfortable with IP chemotherapy, Dizon said.

“There has been data from the U.S. and Japan that weekly paclitaxel, or dose-dense treatment, with standard carboplatin given every 3 weeks may be more effective than treatment with both drugs dosed every 3 weeks,” Dizon said. “These data illustrate something we have seen in the treatment of other cancers, like breast cancer — dose density is important.”

Ultimately, the decision should fall to the woman undergoing treatment, he added.

“For any of us who are evaluating women with advanced ovarian cancer who have had a successful surgery — particularly fit women with a good performance status — IP chemotherapy needs to be offered,” Dizon said. “If that woman was being treated at an institution that did not offer it, I hope that we would think about her best interest and refer her to an institution that has the ability to provide such treatment. We have to tell patients that this option does exist and give them the opportunity to make an informed decision. For physicians to withhold the option because they don’t believe in the benefits of IP treatment — or do not offer it themselves — robs patients of choice.” – by Cameron Kelsall

References:

Alberts DS, et al. N Engl J Med. 1996;doi:10.1056/NEJM199612263352603.

Armstrong DK and Brady MF. J Clin Oncol. 2006;doi:10.1200/JCO.2006.06.7140.

Armstrong DK, et al. N Engl J Med. 2006;doi:10.1056/NEJMoa052985.

Markman M, et al. J Clin Oncol. 2001;9:1001-1007.

Robinson WR, et al. J Oncol Pract. 2008;doi:10.1200/JOP.0858503.

Tewari D, et al. J Clin Oncol. 2015;doi:10.1200/JCO.2014.55.9898.

Wright AA, et al. J Clin Oncol. 2015;doi:10.1200/JCO.2015.61.4776.

For more information:

Don S. Dizon, MD, can be reached at ddizon@mgh.harvard.edu.

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David M. Gershenson, MD, can be reached at dgershen@mdanderson.org.

Maurie Markman, MD, can be reached at maurie.markman@ctca-hope.com.

William Robinson III, MD, can be reached at wrobinso@tulane.edu.

Stephen C. Rubin, MD, can be reached at stephen.rubin@fccc.edu.

Alexi Anne Wright, MD, can be reached at alexi_wright@dfci.harvard.edu.

Disclosure: Dizon, Gershenson, Markman, Robinson, Rubin and Wright report no relevant financial disclosures.

 

POINTCOUNTER 

Is further study required before intraperitoneal chemotherapy becomes standard of care for ovarian cancer?

POINT

Yes.

Intraperitoneal (IP) chemotherapy is an effective treatment strategy for advanced epithelial ovarian cancer, but other options for management should be considered. It has been 10 years since Armstrong and colleagues published the results of a randomized trial that showed a 16-month survival advantage in patients with ovarian cancer who were treated with IP chemotherapy. Despite these results, as well as results from other randomized trials showing an advantage to this approach and a clinical announcement from the NCI, IP chemotherapy has not become the standard of care. In a recent study from Dana-Farber Cancer Institute, fewer than 50% of patients with ovarian cancer were found to receive IP chemotherapy.

Noelle G. Cloven, MD, FACOG
Noelle G. Cloven

When faced with a diagnosis of advanced epithelial ovarian cancer, a patient has many options. For some patients with serious medical comorbidity or bulky unresectable disease, neoadjuvant chemotherapy is a valid option and is associated with less postoperative morbidity. Prospective randomized trials in patients with stage III and stage IV disease showed no difference in PFS or OS in patients receiving preoperative platinum-based combination chemotherapy followed by interval debulking surgery compared with patients undergoing primary debulking surgery. Rates of optimal debulking are increased and postoperative morbidity is decreased in the neoadjuvant/interval debulking group.

Another option to consider is dose-dense chemotherapy. In the Japanese Gynecologic Oncology Group, impressive improvements in PFS and OS were seen in patient receiving weekly paclitaxel and carboplatin every 3 weeks compared with standard carboplatin and paclitaxel every 3 weeks. The OS of over 100 months in the experimental group exceeds the 65.6-month OS reported by Armstrong and colleagues in their IP study. In another prospective randomized study of dose-dense chemotherapy by Chan and colleagues, patients were secondarily randomized to receive bevacizumab (Avastin, Genentech/Roche). Interestingly, there was no benefit of dose-dense treatment in patients who also received bevacizumab, but there was an improvement in PFS among the patients receiving dose-dense chemotherapy alone.

Adding a biologic agent to front-line chemotherapy in combination or as maintenance is another option that warrants consideration. Frontline trial GOG 218 and ICON 7 both showed improvement in PFS in patients receiving bevacizumab in combination with standard IV chemotherapy and continued as maintenance. Other biologic agents are being studied in this setting, most recently PARP inhibitors for high-grade serous cancers with and without BRCA mutations.

IP chemotherapy is an excellent option for well-suited and motivated patients. It is associated with increased complexity, toxicity and costs. Epithelial ovarian cancer represents a diverse spectrum of disease in a varied patient population. Each case must be individualized based on these characteristics as well as a patient’s personal preference and life style. The optimal patient population for intraperitoneal chemotherapy has yet to be defined and similar improvements in survival may be gained using biologic or dose-dense therapy. The results GOG 252 in which IP, dose-dense and biologic chemotherapy are compared are eagerly awaited and may give further insight into optimal upfront management of these patients.

 
References:

Armstrong DK, et al. N Engl J Med. 2006;doi:10.1056/NEJMoa052985.

Burger RA, et al. N Engl J Med. 2011;doi:10.1056/NEJMoa1104390.

Katsumata N, et al. Lancet Oncol. 2013;doi:10.1016/S1470-2045(13)70363-2.

Perren TJ, et al. N Engl J Med. 2011;doi:10.1056/NEJMoa1103799.

Trimble EL, Alvarez RD. Gynecol Oncol. 2006;doi:10.1016/j.ygyno.2006.08.020.

Vergote I, et al. J Clin Oncol. 2011;doi:10.1200/JCO.2011.36.9785.

Noelle G. Cloven, MD, FACOG, is associate chair of the gynecologic research program at Texas Oncology in Fort Worth, Texas. She can be reached at noelle.cloven@usoncology.com. Disclosure: Cloven reports no relevant financial disclosures.

COUNTER

No.

Is there a need for validation trials for intraperitoneal (IP) chemotherapy to be considered the standard of care for women with advanced ovarian cancer? Yes, in the 1980s and 1990s. Those decades represented a crossroads in the pioneering work by innovative physicians, initially Weisberger and colleagues, who in the 1950s injected nitrogen mustard into the peritoneal cavity in an attempt to treat malignant ascites. The IP approach was slow to gain traction over the ensuing decades until Dedrick and colleagues, in their seminal 1978 paper, reported that “pharmacokinetic calculations indicate that such drugs administered IP in large volumes are expected to maintain a significantly greater concentration in the peritoneal space than in the plasma. This concentration difference offers a potentially exploitable biochemical advantage in the treatment of patients with presumed microscopic residual ovarian cancer confined to the peritoneal cavity.” With this, a paradigm shift was born.

Joshua P. Kesterson, MD
Joshua P. Kesterson

Subsequent phase 2 trials using IP cisplatin in women with persistent or recurrent ovarian cancer supported the efficacy and feasibility of IP chemotherapy in a population with a historically grim prognosis. A phase 3 trial was warranted. Starting in 1986, 654 women with stage III epithelial ovarian cancer were randomized to IP cisplatin plus IV cyclophosphamide (GOG 104). Women who received IP chemotherapy lived longer (49 months vs. 41 months). Paclitaxel subsequently replaced cyclophosphamide as the agent more effective in combination with platinum for the treatment of advanced ovarian cancer. Another IP phase 3 trial (GOG 114) was performed, comparing high-dose IV carboplatin followed by IV paclitaxel and IP cisplatin vs. IV cisplatin plus paclitaxel. Women in the IP chemotherapy arm had a longer PFS (28 months vs. 22 months) and a longer OS (63 months vs. 52 months). GOG 114’s initial dose-intense carboplatin prior to initiation of IP chemotherapy complicated interpretation of outcome data, specifically what beneficial effect could be attributed solely to the IP administration of chemotherapy, as well as contributed to the regimen’s toxicity. GOG 172 was developed and began enrolling patients in 1998. It compared the IP administration of cisplatin and paclitaxel vs. IV paclitaxel plus cisplatin in women with stage III ovarian cancer. Results were quite impressive in favor of the IP arm, including a nearly 6-month improvement in PFS and a 16-month improvement in OS. Based on these results in aggregate, the NCI urged physicians to use a combination of IV and IP chemotherapy in the treatment of women with advanced ovarian cancer.

Recently Tewari and colleagues, in their analysis of GOG 114 and GOG 172, noted an advantage of IP chemotherapy over IV chemotherapy that persisted beyond 10 years.

The results of the aforementioned randomized controlled trials support the superiority of IP chemotherapy. One of the main issues with IP chemotherapy is its poor penetrance into clinical practice and its underutilization in eligible patients. I do not believe that an additional clinical trial will further validate IP chemotherapy as the standard of care for women with epithelial ovarian cancer, as it already is. Long live IP chemotherapy for ovarian cancer, so that women with ovarian cancer may live longer.

 
References:

Alberts DS, et al. N Engl J Med. 1996;doi:10.1056/NEJM199612263352603.

Armstrong DK, et al. N Engl J Med. 2006;doi:10.1056/NEJMoa052985.

Dedrick RL, et al. Cancer Treat Rep. 1978;62:1-11.

Howell SB, et al. J Clin Oncol. 1987;5:1607-1612.

Kirmani S, et al. J Clin Oncol. 1991;9:649-657.

Markman M, et al. J Clin Oncol. 2001;9:1001-1007.

McGuire WP, et al. N Engl J Med. 1996;doi:10.1056/NEJM199601043340101.

Tewari D, et al. J Clin Oncol. 2015;doi:10.1200/JCO.2014.55.9898.

Weisberger AS, et al. J Am Med Assoc. 1955;159:1704-7.

Wright AA, et al. J Clin Oncol. 2015;doi:10.1200/JCO.2015.61.4776.

Joshua P. Kesterson, MD, is chief of the division of gynecologic oncology, as well as associate professor of obstetrics and gynecology, at Penn State College of Medicine in Hershey, Pa. He can be reached at jkesterson@hmc.psu.edu. Disclosure: Kesterson reports no relevant financial disclosures.