Surgery or Chemo First in Advanced Ovarian Cancer? New Data Fuel Debate

Janis C. Kelly

September 07, 2010

September 6, 2010 — Primary debulking surgery before adjuvant chemotherapy is the standard of care for patients with advanced ovarian cancer, but new data from a multinational study suggest that patients with stage IIIC or IV disease might do as well with neoadjuvant chemotherapy followed by surgery.

Lead author Ignace Vergote, MD, PhD, from Leuven University Hospitals in Belgium, told Medscape Medical News that outcomes were essentially the same in terms of overall and progression-free survival, and suggested that the neoadjuvant approach might lower the risk for postoperative death, grade 3 or 4 hemorrhage, infection, and venous complications.

Dr. Vergote emphasized that this applies only to stage IIIC and IV patients. "Primary surgery should remain the treatment of choice in patients with earlier stages of ovarian cancer," he said.

The trial was a collaborative study by researchers from the European Organization for Research and Treatment of Cancer Gynaecological Cancer Group and the National Cancer Institute of Canada Clinical Trials Group, and included researchers in Belgium, Norway, Canada, Scotland, England, the Netherlands, Italy, and Spain.

In the September 2 issue of the New England Journal of Medicine, Dr. Vergote and colleagues report data from 632 patients with stage IIIC or IV epithelial ovarian carcinoma, fallopian-tube carcinoma, or primary peritoneal carcinoma. Patients were randomized to primary debulking surgery followed by platinum-based chemotherapy or to neoadjuvant platinum-based chemotherapy followed by debulking surgery (interval debulking surgery).

The hazard ratio for death was 0.98 for neoadjuvant chemotherapy vs primary debulking. The hazard ratio for progressive disease was 1.01.

The strongest predictor of overall survival was the complete resection of all macroscopic disease in both the primary debulking and neoadjuvant chemotherapy groups.

Residual tumor was 10 mm or less (described as optimal debulking) in 41.6% of patients in the primary debulking group and in 80.6% of patients in the neoadjuvant chemotherapy group. However, data provided in the supplementary online appendix to the paper show that complete resection was achieved in fewer than half of the patients who had tumors 10 mm or less after primary debulking, but in two thirds of those who had tumors 10 mm or less after neoadjuvant chemotherapy.

Differences by Country

There were also striking differences in surgical completeness by country. Belgium accounted for the majority of patients in the study; there was no residual disease in 62.9% of Belgian patients treated with primary debulking and in 87.3% of those treated with neoadjuvant chemotherapy.

No other country approached these results with primary debulking. Rates for no residual disease ranged from 3.9% in the Netherlands to 11.1% in Canada.

Similarly, rates for no residual disease with neoadjuvant chemotherapy ranged from 27.7% in the Netherlands to 42.9% in the United Kingdom.

Median survival was 44.98 months in patients who had no residual disease after primary debulking surgery and 27.01 months in those after neoadjuvant chemotherapy. Five-year survival was 31.31% in patients with no residual disease after primary debulking surgery and 17.52% after neoadjuvant chemotherapy.

Interestingly, median and 5-year survival were both better in patients who had some residual tumor (1 to 10 mm) after primary debulking surgery (32.26 months and 23.47%, respectively) than in those who had no residual disease after neoadjuvant chemotherapy (27.01 months and 17.52%, respectively).

Complete resection of all macroscopic disease was the strongest predictor of survival.

Adverse Events Caveat

Dr. Vergote emphasized to Medscape Medical News that this trial consisted only of patients with extensive stage IIIC or IV disease, and the outcomes should not be compared with those in patients with stage IIIB or earlier-stage ovarian carcinoma. He also noted the importance of ruling out other primary tumors (especially of gastrointestinal origin) when selecting patients for neoadjuvant chemotherapy.

The researchers concluded that "neoadjuvant chemotherapy is not inferior to primary cytoreductive surgery for patients with stage IIIC or IV ovarian carcinoma. No significant advantages of neoadjuvant therapy or primary debulking surgery were observed with respect to survival, adverse effects, quality of life, or postoperative morbidity or mortality."

Dr. Vergote later explained that although the study design did not permit a statistically valid comparison of adverse effects, the lower incidence of postoperative death, grade 3 or 4 hemorrhage, infection, and venous complications is clinically important, as is the greatly reduced operative time required after neoadjuvant chemotherapy.

Dr. Vergote said that the data also suggest that patients with very small metastases seem to do better with primary debulking surgery, whereas those with larger tumors seem to do better with neoadjuvant chemotherapy and interval debulking.

"My advice is to estimate how difficult surgery will be. For example, if the patient is 75 years old and [computed tomography] scan plus laparoscopy show extensive tumors that will require a lot of bowel resection, I would consider neoadjuvant chemotherapy rather than primary surgery," Dr. Vergote said. "It is important to be aggressive, regardless of the approach. The goal is no residual tumor, not 'less than 10 mm' residual tumor."

Operative time is another consideration. Dr. Vergote said that primary surgery in very extensive stage III or IV ovarian cancer might require 7 hours, whereas surgery for a similar patient after neoadjuvant therapy might require only 4.5 hours.

American Expert Has Concerns

Dr. Vergote suggested that the lower complete resection rates in this study, compared with data from major American cancer centers, might reflect differences in patient population, in that American series might have included patients with less extensive disease.

Robert E. Bristow, MD, director of gynecologic oncology at the University of California Irvine Medical Center in Orange, who reviewed the study for Medscape Medical News, was not completely convinced.

"The researchers are to be congratulated for completing this big, multi-institution study," Dr. Bristow said. "However, the conclusions challenge the conventional wisdom on treatment of advanced ovarian cancer. Nearly all other studies show that patients who undergo primary debulking surgery do better."

Dr. Bristow expressed concerns about the completeness of surgery in this study. He said that in the United States, generally, optimal debulking rates (less than 10 mm residual disease) are above 70% (compared with 41% in this study), and two thirds of those are complete, with no residual disease (compared with 19.2% in this study) .

"It may be that in some of the institutions in this study, the primary debulking surgery performed was not significantly different from no surgery at all," Dr. Bristow said. "This is an important study, but results are not necessarily transferable to surgical oncology clinical practice. I would like to see it replicated with participating hospitals where the optimal debulking rate is 75% or better and two thirds of those patients have no residual disease."

Dr. Vergote and Dr. Bristow have disclosed no relevant financial relationships.

N Engl J Med. 2010;363:943-953.

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