NCCN Guidelines for the Treatment of Breast Cancer: Changes for 2005
The 10th annual conference of the National Comprehensive Cancer Network (NCCN) announced changes to the guidelines for the treatment of breast cancer. The NCCN guidelines now state that radiation therapy may be skipped in the treatment of women with stage 1 breast cancer who are over 70 years of age. Stratification for systemic therapy now emphasizes hormone receptor status, while risk of recurrence is no longer included. Also added are footnotes to the adjuvant hormonal therapy for postmenopausal women and a definition of menopause. And notable in the treatment of breast cancer is a new NCCN guideline mandating the use of myeloproliferative growth factors in the treatment of adult patients with solid tumors, which would include patients with breast cancer.
Guideline Change: Radiation Therapy for Stage I Breast
The Dr. Beryl McCormick from the Memorial Sloan-Kettering Cancer Center announced that the NCCN guidelines now suggest that irradiation may be skipped in the treatment of patients with stage I breast cancer who are over 70 years of age. The rationale for this change comes from the results of 2 studies reported in The New England Journal of Medicine in September 2004.
CALGB 9343/RTOG 9702: A joint CALGB/RTOG trial involving 647 patients over 70 years of age with stage I breast cancer showed that the addition of irradiation to lumpectomy and tamoxifen did not improve outcomes. After a median follow-up of 60 months, there was no significant benefit to administering irradiation in this population with regard to rates of mastectomy for local recurrence, distant metastases, or 5-year rates of overall survival compared to treatment with tamoxifen alone. Five-year overall survival was 87% in the group treated with irradiation compared to 86% among patients who were treated with tamoxifen alone (p=0.94). Local failure was the only endpoint that showed statistically significant difference: 1% in the group treated with radiation therapy and 5% in the tamoxifen only group. Both physicians and patients reported high morbidity, including inferior cosmetic results and adverse events among patients who received irradiation.
Canadian trial: A trial conducted in Canada reported similar results to the CALGB. However, the 769 patients included in this trial were younger (50 years of age or older) and breast cancers with slightly larger (a diameter of 5 cm or less compared to 2 cm or less in the CALGB 9343). After a median follow-up of 5.6 years, the rate of local relapse at five years was 7.7 percent in the tamoxifen group and 0.6 percent in the group given tamoxifen plus irradiation, which is twice that reported in the CALGB trial. Five-year disease-free survival rates were 84% and 91%, respectively (p=0.004).
Guideline Change: Stratification for Systemic Therapy by Hormone Responsiveness
Dr. Robert W. Carlson from the Stanford Hospital and Clinics reported that the 2005 NCCN guidelines now place hormone resonsiveness as the initial consideration in stratification for systemic therapy. The previous version of the guidelines stratified first by risk of recurrence, low, intermediate, and high, then by ER/PR responsiveness. The decision to elevate hormone responsiveness and eliminate risk status is based on emerging evidence that chemotherapy responsiveness may be related to hormone status.
New Guidelines for the Use of Myeloproliferative Growth Factors
The NCCN Myeloid Growth Factor Panel introduced its first set of guidelines for the use of myeloid growth factors. Dr. Jeffrey Crawford, the panel’s chairman, introduced the new guideline on behalf of the panel. The guideline development committee confined their initial efforts to adult patients with solid tumors, which would include patients with breast cancer, and non-myeloid malignancies. The panel determined that there was enough evidence of clinical benefit to recommend the use of growth factors in the first cycle or prophylactically in patients who are treated with:
- curative intent
- regimens with a high chance of neutropenia (greater than 20% chance)
- adjuvant chemotherapy with intent to augment surgical cure
- myelotoxic chemotherapy with the intent of prolongation of survival or quality of life improvement or symptom management
Degree of consensus for specific growth factors: There was uniform concensus for the use of filgrastim and pegfilgrastim and lesser support for sagramostim use. The NCCN uses a system for reporting the level of concensus for a guideline recommendation that is a scale from category 1, representing uniform NCCN concensus, to category 3, which represents major disagreement among NCCN members. The panel reported category 1 evidence for filgrastim and pegfilgrastim, which is defined as uniform NCCN consensus based on high level evidence. Support for sagramostim use was category 2b, considered non-uniform NCCN consensus but no disagreement, based on low level evidence including clinical experience. The filgrastim and pegfilgrastim agents should start day two, the day after chemotherapy. Pegfilgrastim is administered once per chemotherapy cycle, and filgrastim through day 10 or until the absolute neutrophil count is greater than 2,000 per µL.
The high level evidence for the use of pegfilgrastim sited and discussed at the NCCN meeting is a study of “same day” pegfilgrastim dosing that was reported at the 2004 San Antonio Breast Cancer Symposium. In this small, randomized study, administration of pegfilgrastim on the same day of chemotherapy was reported to be associated with a lower incidence of hospitalization and neutropenia compared with the standard treatment of pegfilgrastim on the next day of chemotherapy in the adjuvant treatment of patients with node positive breast cancer. There was a 7% incidence of hospitalization for febrile neutropenia among patients treated with TAC (docetaxel, doxorubicin and cyclophosphamide) and next day pegfilgrastim compared with a 33% incidence of hospitalization for patients treated with same day pegfilgrastim. Same day pegfilgrastim resulted in similar febrile neutropenia hospitalization rates with TAC chemotherapy when no prophylactic growth factors were used.
Footnotes to Adjuvant Hormonal Therapy for Postmenopausal Women
Based on results from the ATAC, MA-17, and the IES trials, which demonstrated that aromatase inhibitors provide superior outcomes to tamoxifen, the 2004 and 2005 versions of the NCCN guidelines mandate that adjuvant endocrine therapy for postmenopausal women should include an aromatase inhibitor, either alone or sequentially with tamoxifen. NCCN has established footnotes to the adjuvant hormonal therapy of breast cancer that read as follows:
“The panel believes that the three aromatase inhibitors (anastrazole, letrozole, exemestane)have similar antitumor efficacy and similar toxicity profiles. The aromatase inhibitor(s) specified is that used in the clinical trial(s) that most loosely approximates the clinical situation.”
For patients who become postmenopausal after 2-3 years of tamoxifen with or without ovarian suppression or ablation, the guidelines recommend continued tamoxifen to complete 5 years or crossover to exemestane or anastrazole, with the following footnote as rationale:
“This specific patient subset was not included in the trials of aromatase inhibitors given sequentially with adjuvant tamoxifen. Some women who appear to become postmenopausal on tamoxifen therapy have resumption of ovarian function after discontinuation of tamoxifen and initiation of an aromatase inhibitor. Therefore, serial monitoring of plasma estradiol and FSH levels is encouraged in this clinical setting. Should ovarian function resume, the aromatase inhibitor should be discontinued and tamoxifen resumed.”
Also newly included in the 2005 guidelines is a definition of menopause. While broadly understood as the permanent cessation of menses, the guidelines acknowledge that “clinical trials in breast cancer have utilized a variety of definitions of menopause”. As such, the 2005 guidelines identify “reasonable criteria for determining menopause to include any of the following:”
- Prior bilateral oophorectomy
- Age ≥60 years
- Age <60>
- If taking tamoxifen or toremifene, and age <60>
“It is not possible to assign menopausal status to women who are ceceiving a LH-RH agonist or antagonist. In women premenopausal at the time of adjuvant chemotherapy, amenorrhea is not a reliable indicator of menopausal status.” 
 Hughes KS, Schnaper LA, Berry D, et al. Lumpectomy plus Tamoxifen with or without Irradiation in Women 70 Years of Age or Older with Early Breast Cancer. The New England Journal of Medicine. 2004;351:971-977.
 Fyles AW, McCready DR, Manchul LA, et al. Tamoxifen with or without Breast Irradiation in Women 50 Years of Age or Older with Early Breast Cancer. The New England Journal of Medicine. 2004:351;963-970.
 Kaufman PA, Paroly W, Rinaldi DA, and Sonnier S. Randomized double-blind phase 2 study evaluating same-day vs next-day administration of pegfilgrastim with docetaxel, doxorubicin, and cyclophosphamide (TAC) in women with early stage and advanced breast cancer [abstract]. Breast Cancer Res Treat . 2004;88:Abstract # 1054.
 Nabholtz JM, Pienkowski T, Mackey J, Pawlicki M Phase III trial comparing TAC (docetaxel, doxorubicin, cyclophosphamide) with FAC (5-fluorouracil, doxorubicin, cyclophosphamide) in the adjuvant treatment of node positive breast cancer (BC) patients: interim analysis of the BCIRG 001 study. 2002.
 The ATAC (Arimidex, tamoxifen alone or in combination) trialists’ group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer. Cancer . 2003;98 (9):1802-1810.
 Goss P, Ingle J, Martino S, et al. Updated analysis of the NCIC CTC MA.17 randomized placebo (P) controlled trial of letrozole (L) after five years of tamoxifen in postmenopausal women with early stage breast cancer. Proceedings from the 40th annual meeting of the American Society of Clinical Oncology. New Orleans, LA 2004. Abstract #847. “Best of oncology symposium” presented June 8, 2004.
 Coombes R, Hall E, Gibson L, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. The New England Journal of Medicine. 2004;350:1081-1092.
 NCCN Practice Guidelines in Oncology-v.1.2005. www.nccn.org/professional/physician-gls/PDF/breast.pdf. Accessed 3/21/05.