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Executive Summary

Tamoxifen, marketed by Stuart as Nolvadex, is the "treatment of choice" for adjuvant breast cancer therapy in "postmenopausal women with positive nodes ]cancer cells present in lymph nodes[ and positive hormone receptor levels," the Natl. Institutes of Health Consensus Development Conference on Adjuvant Chemotherapy for Breast Cancer concluded in its Sept. 11 consensus statement. The consensus panel made its recommendations based on data presented at the conference Sept. 9-11. Summary data, presented by Richard Peto, Oxford University, England, pooled the results of trials involving approximately 40,000 breast cancer patients, most of whom received adjuvant therapy following mastectomy as their primary therapy. * HHS Secty. Heckler told the consensus conference that tamoxifen may be available as a generic shortly. Heckler said: "Applications for production of both tamoxifen citrate and megistrol acetate are currently in the pipeline and being reviewed, and we expect to have approval in six months or less." Stuart maintains that the patent for tamoxifen was not issued until August 1985 and the firm has 17 years of marketing exclusivity to look forward to. Commenting on the results of "three to four dozen" tamoxifen trials, Peto reported that for women over 50, the five-year survival rate for those receiving the endocrine agent tamoxifen was 72% compared with 67% for the control group. Peto suggested that the five-year mortality rate of 30% for women over 50 who have received primary breast cancer therapy might be reduced to 24% if tamoxifen was used as adjuvant therapy following the primary therapy. The difference between tamoxifen therapy and control was "highly significant" in terms of mortality in these trials, and there was also a "definite delay" of cancer recurrence, Peto maintained. Addressing tamoxifen dosing issues, the consensus statement explains that "the optimal duration of tamoxifen therapy remains to be defined." However, "it appears that a longer duration of adjuvant tamoxifen (e.g., at least two years) may be more effective than one year." The consensus statement adds: "There is no evidence to suggest that a dose of tamoxifen higher than 20 mg per day is indicated." The panel report notes that "tamoxifen is extremely well tolerated by patients. Side effects, including hot flashes and vaginal dryness, are common and are related to estrogen deprivation." The consensus statement adds that "potential long-term toxicity of tamoxifen is unknown at this time but appears negligible in studies with followup data up to eight years." Nolvadex is currently approved for use "in the palliative treatment of advanced breast cancer in postmenopausal women," according to the labeling. Stuart said that it filed a supplemental NDA in November 1981 for use in "delaying recurrance of metastatic (breast cancer) in postmenopausal women." The firm plans to submit a supplemental NDA for tamoxifen for adjunctive use as a single agent. Because U.S. trials in the past have focused on tamoxifen in combination with chemotherapeutic agents, Stuart's pending supplemental is for adjunctive use in combination with a chemotherapeutic regimen. The conference report notes that "the role of tamoxifen combined with cytotoxic chemotherapy compared with tamoxifen alone for patients with positive axillary lymph nodes and positive hormone receptors remains unresolved." One of the major areas of contention during discussion at the conference was whether adjunctive therapy, either chemotherapy or endocrine therapy, is beneficial in breast cancer patients with negative nodes. Although Peto reported that mortality figures in the postmenopausal tamoxifen trials were proportionally the same when broken down by node status, the panel concluded that "routine administration of adjunctive systemic therapy in women with histologically negative axillary lymph nodes is not recommended at the present time." The panel emphasized that while there is not significant data to recommend adjuvant therapy for patients with negative nodes, "these women are encouraged to participate in randomized clinical trials comparing observation with adjunctive therapy." The panel added that for patients who "are at increased risk for relapse. . .who cannot be entered into an ongoing trial, chemotherapy may be considered." * Five years ago a consensus conference was convened on the same subject. At that time, the panel did not feel there was sufficient data to recommend any type of adjuvant therapy for postmenopausal breast cancer patients. Adjuvant therapy was recommended at that time for premenopausal women. With regard to premenopausal women, the panel concluded that if nodes are positive, "regardless of hormone receptor status, treatment with established combination chemotherapy should become standard care" as adjunctive therapy. Adjuvant endocrine therapy for this population "has not been shown to result in a survival benefit" and thus is not recommended outside clinical investigation, the statement concludes. Although the panel did not recommend a particular chemotherapeutic regimen, the majority of chemotherapeutic studies presented were with a CMF (cyclophosphamide, methotrexate, 5-fluorouracil) regimen, and the panel recommends "the adjuvant chemotherapy combination selected should be one that has demonstrated efficacy in major clinical trials."

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