Chemo/Radiotherapy Sequence May Not Affect Breast Cancer Outcomes

SAN FRANCISCO—Time to failure, time to distant metastasis, and time to death in patients with early-stage breast cancer are not influenced by the order in which chemotherapy and radiotherapy are initiated, according to updated results of a study presented at the 43rd Annual Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO plenary 4). These latest long-term results are in contrast to earlier findings from the study.

"The initial results of the study were published in 1996 with 58 months of follow-up," said Jennifer Bellon, MD, an instructor at Brigham and Women’s Hospital, Boston. At that time, she said, patients randomized to the radiotherapy-first arm had a lower 5-year crude rate of local recurrence, whereas the patients randomized to the chemotherapy-first arm had a lower rate of distant and/or regional metastasis.

"Adjuvant chemotherapy preceding radiation has become common practice in women with early-stage breast cancer who undergo breast-conserving surgery," she said.

The new 10-year findings show no significant difference in freedom from any recurrence, freedom from distant metastasis, or overall survival between the two arms, Dr. Bellon said, based on a median follow-up of 135 months. She added that the power to detect differences, which is based on number of failures, is still low, and that additional results from this and other trials are necessary to determine the optimal therapy sequence.

The Boston-based study followed 244 women with stage I/II carcinoma of the breast treated with breast-conserving surgery. They were randomized to receive, after surgery, 12 weeks of chemotherapy either before radiotherapy (CT-first arm) or following radiotherapy (RT-first arm).

The two arms were matched for tumor and patient characteristics, including age, T stage, margins, and nodal status (for details, see N Engl J Med 334:1356-1361, 1996).

Chemotherapy consisted of a six-drug regimen repeated every 3 weeks for four cycles. Tamoxifen (Nolvadex) was given following completion of all chemotherapy and radiotherapy to 11 patients in the CT-first arm and 7 patients in the RT-first arm.

Radiotherapy included the whole breast for the first 45 Gy followed by a 16 to 18 Gy lumpectomy site boost. Regional nodes were included at the discretion of the radiation oncologist.

Influence of Margin Status

The researchers also looked at the interaction between treatment arm and margin status. Negative margins were defined as the presence of more than 1 mm of uninvolved breast tissue between the tumor and the inked surface; "close" margins as 1 mm or less; and positive margins as the presence of tumor at the inked resection margin.

Patients with negative margins had a 13% risk of local recurrence in the RT-first arm, compared with 6% in the CT-first arm, and those with close margins had a 4% risk of local recurrence in the RT-first arm vs 32% in the CT-first arm. The risk was more than 20% for both arms for those with positive margins.

"We have previously reported that patients with close or negative margins have similar local recurrence rates when radiotherapy is given promptly after surgery. On the basis of this study, we believe that patients who have close margins and receive chemotherapy first may be at an unacceptably high risk of local recurrence," Dr. Bellon said.

She said that the study results suggest the following recommendations:

• Patients with negative margins can reasonably be treated with four cycles of chemotherapy first. Whether this remains true with longer chemotherapy regimens, however, is still unknown.

• Patients with close margins may have high local recurrence rates when radiotherapy is delayed. These patients should be considered for re-excision.

• Patients with positive margins have a high rate of recurrence even with radiotherapy first and should undergo additional breast surgery.

The discussant, Barbara Fowble, MD, suggested to the audience that the sequence of therapy should be adjusted to the specific circumstances of each patient.

"How best to integrate radiation with chemotherapy for the maximal advantage in terms of local regional control, distant metastasis, survival, cosmesis, and complications may be disease specific," Dr. Fowble said. "It may be stage specific, and certainly in locally advanced breast cancer, chemotherapy is given first. It may be drug specific, and I would like to suggest that in certain circumstances, it may also be patient specific."