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© Oxford University Press 2006.
NEWS |
Intraperitoneal Therapy for Advanced Ovarian Cancer: Will It Become Standard Care?
The National Cancer Institute's recent endorsement of intraperitoneal (IP) chemotherapy as the preferred method of treating advanced ovarian cancer has met with cautious optimism about the technique's chances of helping more women survive longer.
Results of a Gynecologic Oncology Group (GOG) study, which prompted the NCI announcement in January, demonstrated that IP chemotherapy improves survival in patients with surgically treated ovarian cancer when added to intravenous (IV) therapy, compared with IV therapy alone. However, the study did nothing to assuage concerns about IP therapy's toxicity and tolerability, as fewer than half of patients completed the planned treatment. The tradeoff between survival and tolerability sets the stage for future clinical investigation to identify effective IP regimens that are more patient friendly.
"[IP chemotherapy] is not a magic bullet," said Deborah Armstrong, M.D., associate professor of medical oncology at Johns Hopkins University in Baltimore, and first author on the study, published in the January 5 issues of the New England Journal of Medicine. "If you look at improvements over the past two or three decades in the outcome for ovarian cancer, each is a small step forward. I certainly consider this a step forward. By no means do I think it is a cure-all, but with every step forward you improve the outcome for patients as a group."
The GOG trial involved 429 patients who underwent surgical resection of stage III ovarian cancer or primary peritoneal cancer and were then randomly given either IV cisplatin and paclitaxel or IV paclitaxel followed by IP cisplatin and paclitaxel. The results showed a 16-month improvement in median survival in the IP group (65.6 months versus 49.7 months).
Coinciding with publication of the results, NCI issued an announcement encouraging doctors to use the IV–IP protocol as the preferred chemotherapy regimen for advanced ovarian cancer (http://ctep.cancer.gov/highlights/clin_annc_010506.pdf).
On the other hand, the Society of Gynecologic Oncologists has neither endorsed nor discouraged use of IP chemotherapy. The organization alluded to good evidence that IP chemotherapy improves survival but noted that improved survival does not mean a higher cure rate. Their statement also noted challenges associated with use of IP chemotherapy and emphasized that no consensus exists as to what constitutes the "standard" IP regimen (http://www.sgo.org/policy/IPChemotherapy.pdf).
Clinical application of IP chemotherapy dates to the 1950s, when it was used to treat malignant ascites, cancerous fluid in the peritoneal cavity. The first evidence of a survival advantage in ovarian cancer emerged a decade ago, as IP cisplatin–cyclophosphamide led to an 8-month improvement in overall survival compared with IV administration of the same drugs. Five years later, a large intergroup study showed a statistically significant 11-month survival advantage with a combination IV–IP regimen containing cisplatin and paclitaxel versus IV administration of the same drugs. The GOG study added to the evidence that IP delivery of contemporary chemotherapy could improve survival.
"We now have three randomized clinical trials that show a survival advantage," said Maurie Markman, M.D., vice president for clinical research at the University of Texas M. D. Anderson Cancer Center in Houston. "They all show the same survival advantage in terms of a 20%–30% reduction in death. From the point of view of science, from the perspective of our ability to demonstrate that something is of value to our patients, it just doesn't get better than this."
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Despite the data from those three trials, IP chemotherapy has been slow to catch on. Experts say that there are several reasons for the lag. First, not all studies have demonstrated a clear advantage for IP chemotherapy. Toxicity, higher cost, and clinicians' lack of familiarity with the catheter-placement and administration techniques have contributed to the lukewarm reception.
An assessment of catheter outcomes in the GOG trial highlighted some of the issues that have turned off many oncologists and patients to IP chemotherapy. The study, published in January in Gynecologic Oncology, showed that only 42% of patients randomly assigned to IP chemotherapy received the planned six cycles of therapy. One-third of patients who dropped out did so because of catheter complications.
But high rates of complications are not inevitable with IP chemotherapy, according to Joan Walker, M.D., first author of the catheter study. She maintains that as clinicians gain experience with the technique, problems tend to decrease.
"We personally feel that our complication rate is acceptable in our institution and in our hands," said Walker, chief of gynecologic oncology at the Oklahoma University Health Sciences Center in Oklahoma City. "If you can get to 10% or less problems and those problems are not life threatening, that's fine. If you do this nationwide, there will be higher complication rates because of the experience factor. That will take some transition."
Oncologists agree that IP chemotherapy is more cumbersome, potentially more time-consuming for clinicians, more uncomfortable for patients, and involves a learning curve. There are other problems as well. Both agents used in the GOG protocol are generic. And clinicians haven't figured out how to charge for their time. "There really aren't any good and easy ways to bill for the time it takes to give the infusion," said Armstrong. "We will probably have to figure out how to bill for the services provided. If we can do that, it will probably help a lot, but right now, it's potentially a hurdle."
All those factors could impinge on future acceptance and use of IP chemotherapy, but none is insurmountable. Society President Beth Karlan, M.D., said her experience with IP chemotherapy does not reflect a substantial increase in treatment time. The dosing schedule makes IP administration more cumbersome, but with proper training, physicians and support personnel can master the technique.
"There is abdominal pain, and patients often need anti-inflammatory drugs and occasionally narcotics to tolerate IP treatment," said Karlan, director of gynecologic oncology at Cedars-Sinai Medical Center in Los Angeles. "Patients need to be educated in terms of what to expect. There is delayed nausea because of increased dwell time. Fluid shifts go on for a number of days, and patients will have to get up at night to urinate. Some quality-of-life and symptom management issues will need to be refined."
The NCI announcement has created a quandary for some patients with ovarian cancer, said Daniel Donato, M.D., a gynecologic oncologist with the Rocky Mountain Cancer Centers in Denver. Media coverage of the announcement left some patients thinking that IP chemotherapy is the only way to go, but their enthusiasm is often tempered by information about potential complications and side effects.
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"I have not seen a big push to get it so far," said Donato. "A lot of people are looking at it critically and saying that maybe this isn't the best way to go until we have more data."
Noting that most patients in the GOG study did not receive the planned six cycles of therapy, Donato said he would like to "jump on the bandwagon" of investigators interested in evaluating a shorter course of IP chemotherapy, followed by IV therapy.
"Certainly the data are interesting in that they show a survival advantage, but the question is how many treatments do people really need and how can IP chemotherapy be used to take full advantage, which is getting a full volume of distribution to every place in the abdomen that needs it," said Donato.
Gynecologic oncologist Michael Teneriello, M.D., predicted that the GOG study, the NCI announcement, and continued evolution of IP techniques and technology will help bring IP chemotherapy into the mainstream.
"The learning curve is kind of steep but it is short," said Teneriello, who practices with Texas Oncology Inc. in Austin. "If a doctor is patient and committed to doing this kind of therapy and willing to deal with the kinds of hassles that happen with the catheter, then I think as more people get experience with IP chemotherapy, it will become an easier technique. The materials are a lot better. The technique is more refined, so you no longer have to make it up as you go."
The weight of the evidence from clinical trials should eventually sway oncologists in favor of IP chemotherapy, despite its downsides, which "made it easier to go strictly with IV treatment," said Phillip Di Saia, M.D., chairman of GOG and director of gynecologic oncology at the University of California, Irvine. "Now that we have three or four studies showing the superiority of intraperitoneal mode, I think everybody is rethinking this."
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