Randomized Trial of Breast Irradiation Schedules After Lumpectomy for Women With Lymph Node-Negative Breast Cancer

Timothy Whelan.  Journal of the National Cancer Institute, Vol. 94, No. 15, 1143-1150, August 7, 2002

 
Breast irradiation after lumpectomy is an integral component of breast-conserving therapy that reduces the local recurrence of breast cancer. Because an optimal fractionation schedule (radiation dose given in a specified number of fractions or treatment sessions over a defined time) for breast irradiation has not been uniformly accepted, we examined whether a 22-day fractionation schedule was as effective as the more traditional 35-day schedule in reducing recurrence.

 Women with invasive breast cancer who were treated by lumpectomy and had pathologically clear resection margins and negative axillary lymph nodes were randomly assigned to receive whole breast irradiation of 42.5 Gy in 16 fractions over 22 days (short arm) or whole breast irradiation of 50 Gy in 25 fractions over 35 days (long arm). The primary outcome was local recurrence of invasive breast cancer in the treated breast. Secondary outcomes included cosmetic outcome, assessed with the European Organisation for Research and Treatment of Cancer (EORTC) Cosmetic Rating System. All statistical tests were two-sided.
 

Results: From April 1993 through September 1996, 1234 women were randomly assigned to treatment, 622 to the short arm and 612 to the long arm. Median follow-up was 69 months. Five-year local recurrence-free survival was 97.2% in the short arm and 96.8% in the long arm (absolute difference = 0.4%, 95% confidence interval [CI] = –1.5% to 2.4%). No difference in disease-free or overall survival rates was detected between study arms. The percentage of patients with an excellent or good global cosmetic outcome at 3 years was 76.8% in the short arm and 77.0% in the long arm; the corresponding data at 5 years were 76.8% and 77.4%, respectively (absolute difference = –0.6%, 95% CI = –6.5% to 5.5%). Conclusion: The more convenient 22-day fractionation schedule appears to be an acceptable alternative to the 35-day schedule.

Study Patients

Women with invasive carcinoma of the breast treated by lumpectomy with pathologically negative axillary lymph nodes were eligible for the trial. Patients were excluded from the study for the following reasons: 1) level I and II axillary dissection not performed; 2) presence of invasive or intraductal carcinoma involving the inked margin of excision on pathologic examination; 3) presence of a tumor of more than 5 cm in diameter or clinical T4 disease; 4) presence of multicentric disease; 5) previous diagnosis of breast cancer; 6) presence of bilateral malignancy of the breast; 7) breast deemed too large to permit satisfactory radiation therapy (i.e., the maximum width of breast tissue >25 cm); 8) patient currently pregnant or lactating; 9) presence of serious nonmalignant disease (e.g., cardiovascular or pulmonary) that would preclude radiation treatment; 10) diagnosis of previous or concomitant malignancies of any type except squamous or basal cell carcinoma of the skin and carcinoma in situ of the cervix; 11) patient geographically inaccessible for follow-up; 12) presence of psychiatric or addictive disorders that would preclude informed consent or adherence to the protocol; 13) patient not treated with chemotherapy who was unable to commence radiation therapy within 16 weeks of the last surgical procedure on the breast; 14) patient treated with chemotherapy who was unable to commence radiation therapy within 8 weeks of the last dose of chemotherapy; and 15) patient enrolled in another clinical trial.

Consecutive eligible patients presenting at participating centers who met the inclusion criteria were registered. Participating centers included the Cancer Care Ontario Regional Cancer Centres in the cities of Hamilton, Toronto, Ottawa, Sudbury, London, Windsor, Kingston, and Thunder Bay; the Princess Margaret Hospital in Toronto; and the Montreal General Hospital. Reasons for noneligibility were documented. Written informed consent was obtained from eligible patients before assignment to treatment. The study protocol was approved by the institutional review board of each participating center.

Treatment Regimens

Patients were assigned to one of two regimens, according to a prescribed computer-generated central randomization schedule within strata defined by age (<50 years or >=50 years), tumor size (<=2 cm or >2 cm), adjuvant systemic therapy (tamoxifen, any chemotherapy, or no therapy), and center. Before the randomization procedure, patients were assessed for adjuvant systemic therapy, according to the guidelines of each center. Suggested guidelines for premenopausal patients stated that chemotherapy should be considered if two of the following three tumor characteristics were present: tumor size of more than 2 cm, poorly differentiated tumor, or estrogen receptor-negative status. The guidelines for postmenopausal women stated that adjuvant tamoxifen therapy should be considered if the tumor was greater than 1 cm and had an estrogen receptor-positive status. Patients who received adjuvant chemotherapy completed chemotherapy before radiation therapy.

Patients were randomly assigned to receive whole breast irradiation of 42.5 Gy in 16 fractions over 22 days or to receive whole breast irradiation of 50 Gy in 25 fractions over 35 days. Radiation therapy was delivered daily, from Monday through Friday. The intention was to treat the breast at risk and the underlying chest wall. Patients were treated in the supine position with the ipsilateral arm raised above the shoulder and immobilized. The treatment volume was irradiated by two opposed tangential fields. The medial border was located at the midsternal line. The lateral border was at the midaxillary line to include the breast with a 1- to 2-cm margin and to limit the amount of lung at the central plane to less than 3 cm. The superior border was located at a horizontal line drawn through the supersternal notch, and the inferior border was located at a horizontal line 1–2 cm below the inframammary fold. Wedge compensation was used to ensure a uniform dose distribution throughout the target volume. A contour was taken at the central plane, and a dose distribution was obtained. The treatment volume was treated uniformly to a given dose plus or minus 7%. The dose was prescribed at a point midway along the central plane, two thirds of the distance from the skin to the base of tangent fields. Portal films were obtained in the treatment position with a therapeutic beam to confirm adequate coverage. Patients were treated with a 4- to 6-megavolt linear accelerator or with cobalt-60 radiation. In this trial, no attempt was made to treat the axilla or the supraclavicular or internal mammary lymph nodes, and boost radiation was not used.