Role of Transplant in Breast Cancer Still Controversial

FORT LAUDERDALE, Fla--There still is insufficient evidence about theuse of high-dose chemotherapy plus bone marrow or peripheral stem cellsto support its inclusion as a path on the updated National ComprehensiveCancer Network (NCCN) practice guidelines on breast cancer, said panelchair Robert W. Carlson, MD, at the NCCN's second annual conference.

"The role of high-dose chemotherapy continues to be controversialbecause there is so very little data on it," Dr. Carlson said in aninterview. "This is one of the areas of the guidelines that will haveto be looked at every single year."

Although the role of high-dose chemotherapy remains contentious, thedebate over how to handle this therapy in the NCCN guidelines has beenresolved, at least for the moment.

At a special meeting convened after the first NCCN conference, the breastcancer guidelines panel and representatives from the bone marrow transplantationcommittee agreed that, until more definitive data become available, high-dosechemotherapy should still be relegated to a footnote.

NCCN Breast Cancer Guidelines Panel

Robert W. Carlson, MD
Panel Chairman, Stanford University
Medical Center

Lori J. Goldstein, MD
Fox Chase Cancer Center

William J. Gradishar, MD
Northwestern University Medical School

Allen S. Lichter, MD
University of Michigan Medical Center, Ann Arbor

Beryl McCormack, MD
Memorial Sloan-Kettering Cancer Center

Roger E. Moe, MD
Fred Hutchinson Cancer Research Center

Richard L. Theriault, DO
University of Texas M.D. Anderson
Cancer Center

The wording of that footnote, however, has been changed to highlightthree "special situations" in which participation in a clinicaltrial of high-dose therapy is "especially appropriate": womenwith 10 or more positive nodes, those with locally advanced (stage IIIB)disease, and those with metastatic or recurrent disease.

More Specific Adjuvant Therapy

The revised guidelines contain other substantive changes from the earlierversion, said Dr. Carlson, of Stanford University Medical Center. The mostsignificant changes relate to adjuvant therapy for women who have node-negativedisease and relatively small tumors, a group with an excellent prognosisoverall.

"The changes in the current guidelines were designed to identifysubsets of women within that overall prognostic category who may have aprognosis that is less favorable than other women in that group, and whomay benefit, in a meaningful way, from adjuvant chemotherapy," Dr.Carlson said.

"Previously, we simply lumped all tumors less than 1 cm in sizetogether and said that no adjunctive therapy was appropriate," Dr.Carlson noted. Now, however, the guidelines stratify both the unusual andusual tumor histologies by size, with treatment recommendations varyingdepending on histology, size, and other prognostic features.

For unusual histologies that have a particularly favorable prognosis,such as tubular, colloid, medullary, and adenocystic tumors, adjuvant therapyis not recommended if the tumor is less than 1 cm, whereas such therapyshould be considered if the tumor is between 1 and 2.9 cm, and is deemedappropriate if the lesion is 3 cm or larger.

For the usual histologies of ductal or lobular invasive carcinoma, theupdated guidelines do not recommend adjuvant therapy if the tumor is between0.5 and 0.9 cm in size and has no unfavorable features (eg, angiolymphaticinvasion, high S-phase, high histologic or nuclear grade). If those poorprognostic features are present, adjuvant therapy should be considered,although Dr. Carlson pointed out that the panel labeled this recommendationcontroversial (category 2).

Categories of Acceptability for Guideline Recommendations

Category 1: Recommendations that are uncontested and generallyaccepted by all authorities in that particular cancer

Category 2: Recommendations that are somewhat controversial

Category 3: Items that will require further analysis for firmrecommendations

Category 4: Recommendations that caused real disagreements amongmembers of the NCCN panel

For women under age 50 years with receptor-positive ductal or lobularcarcinomas, the guidelines have been altered such that tamoxifen (Nolvadex)or chemotherapy is endorsed if the tumor is 1 to 3 cm, and chemotherapywith or without tamoxifen is recommended if the tumor is greater than 3cm.

The updated guidelines also provide more specific adjuvant therapy recommendationsfor women with node-positive disease. "We felt that, for women withone to three involved lymph nodes with negative hormone receptors, adjuvantchemotherapy was appropriate," Dr. Carlson said.

Among women with one to three positive lymph nodes and receptor-positivedisease, adjuvant chemotherapy with or without tamoxifen is deemed appropriatefor those under age 50, whereas tamoxifen with or without chemotherapyshould be considered for those age 50 or older. The panel felt that theuse of chemotherapy in older women was a controversial (category 2) recommendation,he added.

For younger women with four or more positive nodes, regardless of receptorstatus, adjuvant chemotherapy is recommended, with the addition of tamoxifendeemed "optional" for those with receptor-positive tumors. Inolder women with four or more involved nodes, adjuvant chemotherapy isadvocated for those with receptor-negative tumors, and tamoxifen with orwithout chemotherapy for those with receptor-positive disease.

"The forms of adjuvant chemotherapy that we felt were appropriatewe actually specified," Dr. Carlson said. While emphasizing that theregimens undoubtedly will be changed as data from new trials become available,he noted that currently, CMF, FAC, CAF, and AC are listed as appropriatechoices for women with zero to three positive nodes, and the same combinationsplus the Milan regimen (Adriamycin followed by CMF) are recommended forthose with four or more positive nodes.