Advantages to Chemo BEFORE Surgery in Ova Ca

In Advanced Ovarian Cancer, Chemotherapy Before Surgical Debulking Is Preferable

Nick Mulcahy,

Medscape Medical News 2008.

In the treatment of advanced ovarian cancer, neoadjuvant chemotherapy before surgical debulking may be the new standard of care — especially in countries where the scheduling of a major surgery frequently requires a waiting period, according to the results of a first-of-its-kind, randomized trial reported at the 12th Biennial Meeting of the International Gynecologic Cancer Society (IGCS), in Bangkok, Thailand.

In the trial of 718 women from the European Union and Canada, the use of chemotherapy before surgery significantly reduced postoperative deaths and adverse events yet provided similar survival outcomes compared with the current standard of care, in which chemotherapy follows surgery.

"Most women diagnosed with ovarian cancer have advanced-stage disease. Surgery before chemotherapy is not a practical course of treatment for patients in many countries because of the difficulty scheduling surgery for patients with extensive cancer and associated complications," said the study’s lead investigator, Ignace B. Vergote, MD, PhD, from University Hospital Leuven, in Belgium, in a statement.

However, there are other reasons that some patients are not good candidates for the standard "primary" cytoreductive surgery followed by chemotherapy, explained Michael A. Bookman, MD, a gynecologic oncologist at Fox Chase Cancer Center, in Philadelphia, Pennsylvania, in an interview with Medscape Oncology.

"In many cases, [advanced ovarian cancer patients'] preoperative nutritional status and general health is compromised at the time of diagnosis, making aggressive [primary] cytoreductive surgery riskier to perform and also more difficult to achieve optimal results," he said. In such cases, 3 cycles of chemotherapy may be used prior to and after surgery, which is delayed.

Oncologists have not been certain that this “interval" cytoreductive surgery was as effective as primary cytoreductive surgery with regard to progression-free survival and overall survival, said Dr. Bookman, who was not involved with the study but acts as the director of the Office of Educational Resources for the IGCS.

A previous American study that examined this issue, the Gynecologic Oncology Group's Protocol 80, closed after 2 years, having only enrolled 2 patients.

"Historically, primary surgery has a very important role in the treatment of ovarian cancer, and there are some biases on the part of physicians [in the United States]," said Dr. Bookman about the failure of the earlier study. "The new results are very compelling and could change clinical practice. The results should make doctors more comfortable with this approach," he added.

In an interview with Medscape Oncology, Dr. Vergote agreed. "In Europe, about 25% of the patients [are] already treated with neoadjuvant chemotherapy.

This study will and should change the standard globally for patients with very advanced stage IIIC and IV disease," he said.

The results were not surprising to Dr. Vergote but might be to others. "Many other experts, especially in the US, had their doubts about this," he said.

Dr. Vergote made the study presentation in Bangkok on behalf of the his fellow investigators from the European Organization for Research and Treatment of Cancer-Gynaecological Cancer Group (EORTC-GCG) and the National Cancer Institute Canada-Clinical Trial Group (NCIC-CTG).

Reduction in Complications

Study participants with stage IIIC/IV ovarian, peritoneal, and fallopian tube carcinoma were randomized to receive either primary debulking surgery (followed by 6 cycles of platinum-based chemotherapy, which was mostly paclitaxel/carboplatin) or interval debulking surgery (which was preceded and followed by 3 cycles of the chemotherapy)

The median follow-up for all participants was 4.8 years. For the primary– and interval–debulking-surgery groups of the study, median overall survival (29 vs 30 months) and progression-free survival (both 12 months) were similar in an intention-to-treat analysis.

However, reductions in complications were observed in the interval–debulking-surgery group, including a statistically significant reduction in postoperative deaths (2.7% in the primary cohort vs 6% in the interval cohort). The other reductions included postoperative fever, grade 3/4 (8% vs 2%); hemorrhage, grade 3/4 (7% vs 1%); and blood clots (2.4% vs 0.3%).

"Interval cytoreductive surgery is at least as good as the old way and potentially safer with regard to risks of surgery," said Dr. Bookman.

However, there is 1 caveat to the study. "Chemotherapy before surgery should not be used in patients with less than [International Federation of Gynecology and Obstetrics] FIGO stage IIIC ovarian cancer or small IIIC ovarian cancers, as these patients were not well represented in the study,” said Dr. Vergote.

Optimal Debulking Still Matters Most, Surgical Timing Does Not

In a multivariate analysis by the investigators, optimal debulking surgery was the strongest independent prognostic factor for overall survival among the study participants in both groups (P = .0001). Other significant prognostic factors included: histological type (P = .0003), largest tumor size at randomization (P = .0008) and disease stage (IIIC vs IV) (P = .0008).

Optimal debulking to no residual tumor should remain the goal of every surgical effort, noted Dr. Vergote. The timing of this procedure (primary or interval) "does not seem to play a role," he said.

With regard to surgical results, the patients who underwent interval debulking had better findings, with 53% having no residual tumors and 82% having tumors of less than 1 cm after surgery, compared with 21% and 46% of the primary debulking patients, respectively. "The masses were significantly smaller after chemotherapy. This makes the surgery easier," said Dr. Vergote.

Dr. Bookman also noted that this phase 3 study, which had more than 700 patients, was powered "to make sure that interval surgery was not worse than primary surgery," which is a "noninferiority" design. Only 400 patients were needed for a more traditional, "superiority" design, he said.

International Relevance

"This study is important for patients throughout the world, as it validates the safety and efficacy of a new approach that can be applied in many settings where scheduling, resources, and/or clinical feasibility could limit availability of immediate front-line surgery," said Dr. Bookman in a statement.

Interval cytoreductive surgery is also currently the subject of the Chemotherapy or Upfront Surgery in Ovarian Cancer Patients (CHORUS) study in Canada and the United Kingdom, which are both countries with national health systems that can have scheduling backlogs for major surgeries such as cytoreduction, Dr. Bookman told Medscape Oncology.

This year's international meeting was fortunate in terms of timing, added Dr. Bookman, who attended. The political turmoil that led to airport closures in Bangkok had begun but not yet escalated while the conference was going on. However, the growing trouble was palpable, he noted. "You could tell things were going to get a lot worse if the government did not cooperate with the protestors."

The study investigators made no disclosures regarding conflict of interest.

12th Biennial Meeting of the International Gynecologic Cancer Society. Presented October 25, 2008.

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