NEW YORK CITY—Issues of toxicity and complexity continue to cause intraperitoneal therapy to be overlooked by clinicians in the treatment of ovarian cancer despite the potential to dramatically increase overall survival. So said presenters here at the Chemotherapy Foundation Symposium in discussions that reviewed the latest therapeutic research.
Regarding the history of the technique, Maurie Markman, MD, Vice President for Clinical Research and Professor and Chair of Gynecologic Medical Oncology at the University of Texas M. D. Anderson Cancer Center, noted that since ovarian cancer mostly remains confined to the peritoneal cavity, researchers in the early 1950s introduced the idea of administering chemotherapy intraperitoneally. However, because of the toxicity of the available chemotherapeutic agents at the time and the ability to deliver drugs intravenously, the concept was largely abandoned.
It wasn't until 1978 that the concept reemerged with a study by Robert Dedrick, PhD, et al published in Cancer Therapy Reports indicating that certain drugs placed in the peritoneal cavity could exhibit dramatic pharmacokinetic advantage for the tumor present in that compartment of the body.
“With knowledge of the pharmacology of drugs, including metabolism, the potential exists that when drugs are taken up from the peritoneal cavity, passed through the liver, and metabolized in the liver, one can expose 10, 100, even 1,000 times higher concentrations of the drugs,” Dr. Markman said.
This potential is especially true for drugs where there is preclinical evidence that the activity of the agent would be increased at higher concentrations or with longer durations of exposure than could not be done safely intravenously.
Still, there were concerns over IP therapy: the local toxicity of antineoplastic agents; the complexity of the treatment, which includes the time involved in administration, inadequate insurance reimbursement, catheter failure, infection risks, and bowel obstruction. There is also a question of limited distribution. Although it is possible to measure high concentrations of drug in the peritoneal fluid, that does not mean that the drug will be able to penetrate into solid tumor masses, Dr. Markman explained.
“Even if you are able to achieve these very high local interactions between tumor and drug, one thing one cannot forget is that if the drug does not get to the tumor by capillary flow through the systemic compartment, the overall effectiveness of the therapy may actually be reduced.”
To combat the issue of distribution, Dr. Markman suggests using IP therapy along with systemic exposure so that both local concentrations can have an impact on the tumor.
Three Prospective Randomized Phase III Trials
There have now been three prospective randomized Phase III trials conducted in the United States by National Cancer Institute cooperative groups demonstrating that the intraperitoneal administration of a cisplatin-based chemotherapy strategy increases survival in advanced ovarian cancer compared with intravenous administration of a platinum-based regimen.
In the first study, published in the New England Journal of Medicine (1996;335:1950–1955), 546 patients were randomized to receive cyclophosphamide with either intravenous or intraperitoneal cisplatin. The median survival for the IP cisplatin group was significantly longer, 49 months, compared with 41 months for the IV cisplatin group.
IP therapy was also associated with less systemic toxicity compared with IV administration, but patients experienced more abdominal pain. The pain, however, was mild to moderate in severity and did not lead to an increase in any serious treatment morbidity or mortality.
The second study, five years later and led by Dr. Markman, compared standard-dose IV cisplatin plus paclitaxel with moderately high-dose carboplatin followed by IV paclitaxel and IP cisplatin (JCO 2001;19:1001–1007).
Progression-free survival increased from 22 to 28 months in the IP arm, and overall survival increased from 52 to 63 months in this study, making it the first randomized controlled trial in ovarian cancer to demonstrate a median overall survival longer than five years, Dr. Markman said.
The final study comparing IV cisplatin and paclitaxel with IP cisplatin and either IV or IP paclitaxel was published in 2006 in the New England Journal of Medicine (2006;354:34–43). That study showed a 16-month median improvement in progression-free survival associated with the use of an IP cisplatin-based chemotherapy regimen. And although the IP regimen was associated with greater toxicity, no increase in treatment-related death was shown.
Together, these three trials have demonstrated a 20% to 30% relative increase in survival associated with putting platinum in the peritoneal cavity as opposed to giving it intravenously, Dr. Markman said.
Still, despite evidence demonstrating survival improvements, IP therapy remains far from routine practice, he noted.
Deborah K. Armstrong, MD, principal investigator of the most recent randomized Phase III study comparing IV and IP therapy, who is Associate Professor of Oncology and Associate Professor of Gynecology and Obstetrics at Johns Hopkins Kimmel Cancer Center, explained, “There still remain some issues about people's level of comfort with giving IP therapy because of toxicity and catheter management, and staff familiarity with that.”
Dr. Markman suggests giving a cycle or two of IV therapy followed with IP therapy to reduce some of the toxicity, as well as using a lower dose of cisplatin, or exploring the use of carboplatin, as another speaker, Keiichi Fujiwara, MD, of the Department of Obstetrics and Gynecology at Kawasaki Medical School in Japan, discussed at the symposium, reviewing data from two studies comparing the agents.
The first study, a nonrandomized comparative Phase II trial reported at the most recent ASCO Annual Meeting, accrued 24 IP patients and 25 IV patients, all of whom received paclitaxel. Response, which was the primary endpoint, was 80% for the IP arm and 60% for the IV arm, and median progression-free survival was also higher in the IP arm, 25 months, compared with 21 months for the IV arm.
Hematological and nonhematological toxicities were essentially the same, but the study had to be closed early due to a conflict of protocols for IP treatment.
In the second study, also reported at the same ASCO Meeting, the tolerability of an all-IP carboplatin and paclitaxel regimen was assessed for 40 evaluable patients. Eighty-two percent of patients completed four cycles of treatment, and there was no Grade 3 or 4 peripheral neuropathy or alopecia.
However, 34 patients left the study, reporting: port-related complications (7 patients), allergy (2), heme toxicity (2), vaginal leak (2), and infection (4). Toxicity was mild, with Grade 3 or 4 side effects consisting of neutropenia (10 patients), platelet problems (2), vomiting (2), fatigue (2), and anemia (1).
Patients were able to complete more cycles of therapy with this trial than in the previous Gynecologic Oncology Group trial comparing IV and IP therapy, the researchers noted, and the preliminary second look operation rate compared favorably as well.
“It's still investigational,” Dr. Armstrong said. “We don't have all the data from those large randomized trials that were using carboplatin as the intraperitoneal platinum agent rather than cisplatin, but it certainly holds some promise, and is expected to be less toxic than intraperitoneal cisplatin.”
Dr. Markman closed his discussion highlighting other settings where IP therapy could be beneficial in treating ovarian cancer, noting its potential as a consolidation therapy or second-line therapy in patients with advanced disease, and as a primary therapy in patients with high-risk early-stage disease.