Ipsilateral breast tumor relapse: local recurrence versus new primary tumor and the effect of whole-breast radiotherapy on the rate of new primaries.

PURPOSE: The justification for partial breast radiotherapy after breast conservation surgery assumes that ipsilateral breast tumor relapses (IBTR) outside the index quadrant are mostly new primary (NP) tumors that develop despite radiotherapy. We tested the hypothesis that whole-breast radiotherapy (WBRT) is ineffective in preventing NP by comparing development rates in irradiated and contralateral breasts after tumor excision and WBRT. METHODS AND MATERIALS: We retrospectively reviewed 1,410 women with breast cancer who were entered into a prospective randomized trial of radiotherapy fractionation and monitored annually for ipsilateral breast tumor relapses (IBTR) and contralateral breast cancer (CLBC). Cases of IBTR were classified into local recurrence (LR) or NP tumors based on location and histology and were subdivided as definite or likely depending on clinical data. Rates of ipsilateral NP and CLBC were compared over a 15-year period of follow-up. RESULTS: At a median follow-up of 10.1 years, there were 150 documented cases of IBTR: 118 (79%) cases were definite or likely LR; 27 (18%) cases were definite or likely NP; and 5 (3%) cases could not be classified. There were 71 cases of CLBC. The crude proportion of definite-plus-likely NP was 1.9% (27/1,410) patients compared with 5% (71/1,410) CLBC patients. Cumulative incidence rates at 5, 10, and 15 years were 0.8%, 2.0%, and 3.5%, respectively, for definite-plus-likely NP and 2.4%, 5.8%, and 7.9%, respectively for CLBC, suggesting a difference in the rates of NP and CLBC. CONCLUSIONS: This analysis suggests that WBRT reduces the rate of ipsilateral NP tumors. The late presentation of NP has implications for the reporting of trials that are testing partial breast radiotherapy.

A phase II trial of induction chemotherapy followed by continuous hyperfractionated accelerated radiotherapy in locally advanced non-small-cell lung cancer.

BACKGROUND AND PURPOSE: We conducted a phase II study combining induction chemotherapy with continuous hyperfractionated accelerated radiotherapy (CHART) in locally advanced non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: A total of 40 patients with stage III NSCLC were enrolled. All patients received 3 cycles of chemotherapy followed by CHART (56 Gy in 36 fractions over 12 days). The primary outcome measure was radiation toxicity. Secondary endpoints were response rate, overall survival, disease-free survival and loco-regional progression-free survival. RESULTS: Acute radiation toxicity was minimal and there were no significant late toxicities. The response rate after completion of chemoradiation was 65%. The median and 2-year overall survival, progression-free survival and loco-regional progression-free survivals were 15.7 months, 28%; 12.1 months, 23%; and 26.4 months, 51%, respectively. CONCLUSIONS: Induction chemotherapy can be safely combined with CHART. The survival results are consistent with previous studies of chemotherapy followed by accelerated radiotherapy. This approach should be compared with synchronous chemoradiation to determine if it represents a less toxic alternative.

Effect of radiotherapy fraction size on tumour control in patients with early-stage breast cancer after local tumour excision: long-term results of a randomised trial.

BACKGROUND: Standard curative schedules of radiotherapy to the breast deliver 25 fractions of 2.0 Gy over 5 weeks. In a randomised trial, we tested whether fewer, larger fractions were at least as safe and as effective as standard regimens. In this analysis, we assessed the long-term results of tumour control in the same population. METHODS: In 1986-98, we randomly assigned 1410 women with invasive breast cancer (tumour stage 1-3 with a maximum of one positive node and no metastasis) who had had local tumour excision of early stage breast cancer to receive 50 Gy radiotherapy given in 25 fractions, 39 Gy given in 13 fractions, or 42.9 Gy given in 13 fractions, all given over 5 weeks. The primary endpoint was late change in breast appearance, which has been reported elsewhere. Here, we report ipsilateral tumour relapse, one of the secondary endpoints. Relapse was defined as any appearance of cancer in the irradiated breast. Analysis was by intention to treat. FINDINGS: After a median follow-up of 9.7 years (IQR 7.8-11.8) for the 838 (95%) patients who survived, the risk of ipsilateral tumour relapse after 10 years was 12.1% (95% CI 8.8-15.5) in the 50 Gy group, 14.8% (11.2-18.3) in the 39 Gy group, and 9.6% (6.7-12.6) in the 42.9 Gy group (difference between 39 Gy and 42.9 Gy groups, chi2 test, p=0.027). The sensitivity of breast cancer to dose per fraction was estimated to be 4.0 Gy (95% CI 1.0-7.8), similar to that estimated for the late adverse effects in healthy tissue from breast radiotherapy. INTERPRETATION: Breast cancer tissue is probably just as sensitive to fraction size as dose-limiting healthy tissues. If this finding is confirmed, radiotherapy schedules can be greatly simplified by the delivery of fewer, larger fractions without compromising effectiveness or safety, and possibly improving both.

Fractionation sensitivity and dose response of late adverse effects in the breast after radiotherapy for early breast cancer: long-term results of a randomised trial.

BACKGROUND AND PURPOSE: Unlike squamous carcinomas, breast adenocarcinoma may be as sensitive to fraction size as late dose-limiting normal tissues. If so, fewer larger fractions would be as safe and effective as regimens based on 2.0 Gy fractions. The first step is to test the effects of radiotherapy fractions >2.0 Gy on late normal tissue responses in the breast after tumour excision and radiotherapy for early breast cancer. PATIENTS AND METHODS: One thousand four-hundred and ten women with T1-3 N0-1 M0 invasive breast cancer were randomised between 1986-98 into one of three radiotherapy regimens after local tumour excision of early stage breast cancer; 50 Gy in 25 fractions (F) vs two dose levels of a test schedule giving 39 or 42.9 Gy in 13 F over 5 weeks. Fraction sizes were 2.0, 3.0 and 3.3 Gy, respectively. The primary endpoint was late change in breast appearance compared to post-surgical appearance scored from annual photographs blinded to treatment allocation. Secondary endpoints included palpable breast induration (fibrosis) and ipsilateral tumour recurrence. RESULTS: After a minimum 5-year follow up, the risk of scoring any change in breast appearance after 50 Gy/25 F, 39 Gy/13 F and 42.9 Gy/13 F was 39.6, 30.3 and 45.7%, from which an alpha/beta value of 3.6 Gy (95% CI 1.8-5.4) is estimated. The alpha/beta value for palpable breast induration was 3.1 Gy (95% CI 1.8-4.4). CONCLUSIONS: An alpha/beta value of around 3 Gy for late normal tissue changes in the breast is derived from the estimated equivalence of 41.6 Gy in 13 fractions and 50 Gy in 25 fractions over 5 weeks, in line with trial predictions.