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Complete Resection of Primary Tumors in Metastatic Breast Cancer Patients May Increase Survival

Watson, Paul

doi: 10.1097/01.COT.0000293398.17984.d1
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Metastatic breast cancer patients who underwent a complete surgical excision of their primary tumors had a 50% reduction in mortality in a retrospective study conducted at the Geneva Cancer Registry in Switzerland.

In the study, led by Elisabetta Rapiti, MD, MPH, a senior researcher there, and published in the June 20th Journal of Clinical Oncology (2006;24:2743–2749), surgery was performed on breast cancer patients found to have metastatic disease at initial diagnosis. Survival benefits derived from these excisions were limited to women with tumor-free margins of resection and were more pronounced in patients with bone metastases only.

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Rethinking the Paradigm

Conventional wisdom has traditionally been that surgical removal of primary tumors offers little survival benefit to metastatic breast cancer patients and may, in fact, further stimulate the growth of metastases, noted Monica Morrow, MD, Chairman of Surgical Oncology at Fox Chase Cancer Center, who wrote an accompanying editorial.

“This prevailing dogma is based on the correct idea that women do not die from tumor in the breast but from tumor in other sites. Because we have not been able to cure tumor in other sites, this led to the idea that surgery had no role.”

In the study, though, the opposite was found to be true. “Our study clearly shows that surgery of the primary tumor in women with metastatic breast cancer at initial diagnosis is not associated with a more rapid progression of the metastases or worse outcome,” Dr. Rapiti said. “Furthermore, it strongly suggests that surgery with negative margins could provide an important survival gain in such patients.”

Based on the data from Dr. Rapiti's study, Dr. Morrow concluded that, “it may be time to reconsider the role of surgery in patients with an intact primary tumor and metastatic breast cancer.”

She cautioned, however, that a complete surgical excision of primary tumors would probably benefit only patients with a limited metastatic tumor burden that has responded to initial systemic therapy.

“Patients who are developing new metastatic sites, or progressing, are clearly not going to benefit from surgery,” Dr. Morrow said.

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Retrospective Trial Design

Researchers culled the archives of the Geneva Cancer Registry for the period of 1977 to 1996 and examined the survival data of 300 women, mean age of 67.4, found to have Stage IV metastatic breast cancer at initial diagnosis. A comparison was then made between women who had their primary tumors surgically resected via mastectomy (87 women) or tumorectomy (40 patients) with those who did not—127 (42%) vs 173 (58%) patients, respectively. Women who underwent surgery of the primary tumor were generally younger (61.8 years) than women who did not undergo surgery (71.6 years).

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Promising Results

Of the 127 surgical-excision patients, 48% had negative surgical margins, 26% had positive margins, and 26% had unknown margins. The five-year survival rate was 27% for women with negative margins, 16% for women with positive margins, 12% for women with unknown margins, and 12% for women who did not have surgery.

Only women who had surgery with negative margins experienced a statistically significant survival benefit. Furthermore, axillary dissections were found to offer no statistically significant benefit.

After stratifying by site of metastasis, the researchers also discovered that the positive effect of surgery with negative margins was particularly evident in women who only had bone metastases but not in women diagnosed with metastases at other sites.

To rule out selection bias and confirm the benefits of surgery, Dr. Rapiti and her coauthors repeated the original analysis excluding breast cancer patients with a poorer prognosis. Even so, “the protective effect of surgery remained unchanged and important,” Dr. Rapiti said.

She said she was not particularly surprised by these results, since previous studies have demonstrated the benefit of removing the primary tumor in metastatic cancers.

“Today, it is well established that in renal cell cancer, colorectal cancer, gastric cancer, and melanoma, a resection of the tumor increases patient survival, even when metastases were present at the diagnosis.”

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‘Subset Patients More Precisely’

“There may be an entire subset of women with metastatic disease who will benefit from this type of surgery,” commented William Gradishar, MD, Professor of Medicine at Robert H. Lurie Comprehensive Cancer Center at Northwestern University School of Medicine.

“As of now, we do not definitively know which of these women would benefit from having their primary tumor taken out. It's all going to come down to being able to subset patients more precisely. By identifying the specific patient, or tumor, characteristics at the molecular level, you may figure out what it is that characterizes a woman who will benefit from this type of surgery.”

Dr. Morrow noted that the results of Dr. Rapiti's trial were remarkably similar to a study her own group had published several years ago (Khan et al, Surgery 2002;132:620–627), so they did not come as a surprise.

In that study, a retrospective analysis of 16,000 women with Stage IV breast cancer at diagnosis, complete resection of the primary tumor was associated with a 39% reduction in the risk of death. The three-year survival rate was 35% for women with negative margins, 26% for those with positive margins, and 17.3% for those who did not have surgery.

Furthermore, axillary dissection did not significantly contribute to survival.

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Improved Technology

Regarding Dr. Rapiti's study, Dr. Morrow noted that patients diagnosed as Stage IV between 1992 and 1996 had improved survival compared with patients diagnosed between 1977 and 1981. She wondered if this was due to better diagnostic imaging techniques.

“Newer imaging modalities detect very small metastatic deposits resulting in patients who would have previously been called Stage II [a category of patient who frequently undergo surgery] being upstaged to Stage IV and managed for palliation,” Dr. Morrow said.

Dr. Rapiti said that the reduced risk of breast cancer mortality in more recent years could partly be explained by metastatic diseases diagnosed at earlier stages, as well as by the use of improved adjuvant treatments. “However, our results—of improved survival after surgery—are independent from the period of diagnosis, the number and the site of metastases, and the use of other therapies. Furthermore, in the multivariate analysis, the difference in survival by period is not significant anymore.”

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Practical Implications

Dr. Morrow said that the evidence in Dr. Rapiti's study, coupled with the introduction of improved systemic therapies such as trastuzumab and bevacizumab, made her think that now is an appropriate time to assess the relative benefit of aggressive multimodality therapy for women with Stage IV breast cancer and a low disease burden.

“We know very little about the natural history of this group, but these are patients where I would consider surgery,” Dr. Morrow said. “The more effective systemic therapy becomes at eliminating small foci of disease and extending survival, the greater the rationale for surgery to debulk large areas of residual disease which are likely to harbor drug-resistant cells.”

She suggested that the most likely candidates for this type of surgery would be patients with a limited metastatic tumor burden (i.e., disease in one site, and limited in amount) that has responded to initial systemic therapy.

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Follow-up Necessary

Confirmatory follow-up studies are necessary before the surgical excision of primary tumors in metastatic breast cancer patients is considered a viable option.

“Selection bias remains a critical issue,” said Clifford Hudis, MD, Director of the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center. “A prospective study is needed to test the hypothesis that surgery on the primary tumor might change outcomes in metastatic disease.”

Until such a trial is conducted, Dr. Hudis suggested that surgery be limited to patients experiencing local complications or who are in need of palliative care.

“Dr. Rapiti's study is hypothesis-forming; it's evidence-based on a lot of observational data,” Dr. Gradishar said. “The way to really figure out how much surgery contributes to treating metastatic breast cancer would require a clinical trial”—a difficult prospect considering the finite number of breast cancer patients presenting with metastatic disease at initial diagnosis.

“A few years back, Dr. Seema Khan proposed such a trial through the cooperative groups but there wasn't a great deal of interest in utilizing resources for that end,” Dr. Gradishar said.

Dr. Rapiti and colleagues recently submitted a protocol for a prospective, multicenter randomized trial to compare survival in Stage IV breast cancer patients with and without surgical removal of the primary tumor.

“We need prospective, multicentric randomized clinical trials to definitively conclude that there is a benefit to surgery of the primary tumor in women with metastatic breast cancer,” said Dr. Rapiti.

Dr. Gradishar said he also considers that accompanying molecular studies are warranted. “It comes down to the following issue: What is the biology driving this? Only by getting a better understanding of what takes place at the molecular level will we be able to figure out which patients are most appropriate for surgical resection, as well as specific chemotherapy drugs and targeted therapies.”

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Electronic Versions of OT Articles

Many OT articles are available in pdf versions at www.oncology-times.com under the Selected Articles link. Articles are posted after the next print issue has been mailed.

© 2006 Lippincott Williams & Wilkins, Inc.
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