Regional Chemotherapy Improves Outcomes in Patients with Platin-Resistant Ovarian Cancer

Roxanne Nelson

April 07, 2008

April 7, 2008 — Regional chemotherapy can be a viable alternative treatment in patients who do not respond to standard therapy. Isolated hypoxic abdominal perfusion of chemotherapeutic agents resulted in increased survival for patients with platin-refractory recurrent ovarian cancer, according to a study that appears in the April issue of Cancer Therapy.

"Because of the high drug concentration in the tumor-supplying artery, the tissue uptake is increased and the drug concentration in the venous outflow is decreased," said senior author Karl R. Aigner, MD, the medical and managing director of Medias Klinikum GmbH & Co. KG, in Burghausen, Germany. "In other words, intra-arterial infusion generates a high drug concentration in the target area combined with a low drug concentration in the systemic circulation. Thus, systemic toxicity is lower."

Treating patients with platinum refractory recurrent ovarian cancer remains a challenge for clinicians, and options are especially limited for those who relapse within 6 months after completing primary therapy. Their tumors are likely to be unresponsive to any type of treatment regimen.

Isolation perfusion techniques are not new, but their practice has been limited. "This method never had its breakthrough because in order to perform it properly with good results, technical skills and sufficient experience are needed." Dr. Aigner told Medscape Oncology. "Therefore, it is considered experimental and should be confirmed in randomized controlled studies."

But he points out that the techniques themselves are not experimental, and he and his colleagues have been performing them for nearly 30 years, with a high success rate and with low or almost no adverse effects in patients who are resistant to multiple systemic chemotherapies.

In this phase 2 clinical trial, isolated hypoxic abdominal perfusion was performed on 79 patients with clinical stage FIGO IIIC/IV ovarian cancer. Of this cohort, 61 were platin resistant and experiencing disease progression after first- and second-line treatment with cisplatin combination therapies, including anthracyclines, cyclophosphamide, and taxanes.

Through an intra-arterial line, patients received cisplatinum 1 mg/kg, adriamycin 0.7 mg/kg, and mitomycin 0.43 mg/kg bodyweight. A total of 4 cycles of isolated hypoxic abdominal perfusion was administered at 4-week intervals. A CT scan was performed after the second and fourth cycles, and 23 women underwent explorative laparotomy for possible restaging and determination of the histologic response.

The researchers observed 20 complete responses and 31 partial responses, for an overall response rate of 64%. Approximately three quarters of the cohort reported a substantial decrease in pain and abdominal discomfort, and 43% of patients experienced a complete resolution of ascites after 2 isolated perfusions.

Overall, the median survival time for all 79 patients was 14 months; the median progression-free survival was 8 months. However, 8 patients survived between 6.7 years and 18.2 years (75, 89, 91, 110, 172, 180, 187, and 218 months), and 4 patients are currently living disease- and symptom-free after 110, 180, 187, and 218 months.

The most common adverse events were lymphfistulas, experienced by more than 30% of the cohort, but bone marrow toxicity was generally mild and did not exceed grade 1 or 2, except in patients who had undergone previous intensive third- or fourth-line chemotherapy.

"The isolated abdominal perfusion is a technique that can be learned without major difficulties, provided that instructions are given by doctors who have wide experience with these procedures," said Dr. Aigner. "This way, failures will be avoided."

Dr. Aigner believes that as soon as isolated abdominal perfusion for ovarian cancer becomes a routine procedure, it will be viewed as the most favorable method of treating women with platin-refractory disease, because it appears to yield the best results with the lowest adverse effects.

"Clinicians should consider using this procedure now, becuase these patients have limited choices available," said Dr. Aigner.

In a related study, published in the February issue of Cancer Therapy, Dr. Aigner and colleagues administered intra-arterial infusion therapy for primary breast cancer to a series of 53 patients who refused to undergo a mastectomy. The treatment consisted of 6 cycles of combination mitomycin, adriamycin, and cisplatin, and 34 of the women in the cohort had undergone a local tumor excision before receiving chemotherapy.

The procedure used in the 2 studies was the same, except that for abdominal perfusion, a closed extracorporeal circuit was used, and in the breast cancer study, the drug was given more or less systemically with a first pass through the arterial supply of the tumor area, explained Dr. Aigner.

The authors observed an overall response in 74% of patients and a complete response in 26%. After 3 treatment cycles, they observed a significant shift from the T3/T4 toward T1/T2 stages. Patients reported that their quality of life was generally good, and most were able to continue working between treatment cycles.

Long-term results are convincing with this method, and adverse effects are also much lower than with conventional therapies, Dr. Aigner pointed out. "All the same, I believe that the method can only make its breakthrough when results have been confirmed in a phase 3 trial."

Fred Stephens, MD, emeritus professor of surgery at the University of Sydney, Australia, agrees that phase 3 trials are needed. "Randomized controlled studies would be ideal to study isolation perfusion techniques to determine whether the expense and difficulties of treating such patients would be justified by increased benefit to patients," he commented. "However, there are very few clinics where such randomized studies could be practiced without clinicians learning how to carry out the procedures safely."

"Ideally, abdominal perfusion as described by Professor Aigner should be available in clinical comprehensive cancer treatment settings," Dr. Stephens explained. "My take-home message is that clinicians should become more familiar with what intra-arterial infusion or isolated infusion studies have to offer, and that governments and health authorities should be reminded that in order to establish a comprehensive cancer center, it is necessary to include in the team of experts someone familiar with arterial infusion techniques and practices."

Cancer Ther. 2008; 6: 67-72, 213-220.

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