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During the time period 1977-2007 postoperative radiotherapy in DBCG has varied considerably with regard to techniques and indications together with changes in the extent of surgery and adjuvant systemic therapy. The radiation treatment has been developed on the basis of clinical, radiophysical and radiobiological principles, encompassing also practical problems such as available equipment in the different centres and at times lack of sufficient machine capacity. The paper focus especially on the comprehensive work done prior to the DBCG 82 b&c studies, in order to optimize radiotherapy in all aspects prior to the evaluation of the efficacy of this treatment modality. The results from these trials did succeed in clear evidence that radiotherapy has an important role in the multidisciplinary treatment of early breast cancer. In parallel to these studies a new and challenging use of radiotherapy after breast conserving surgery was evaluated in the DBCG TM 82 protocol. The experience obtained with different techniques in this study formed the basis for the current principles of radiotherapy after lumpectomy. Reduction of radiation related morbidity has been a major issue for the DBCG radiotherapy group, and in this aspect several studies, including quality control visits, have been carried out to make the relevant modifications and to evaluate deviations from the guidelines between the centres. The background for the changes in radiotherapy is described for each of the programme periods as well as future perspectives which will include further refinements of the target and adjustments of dose and fractionation in selected patients.

Introduction: In the DBCG 82 b&c trials 3083 patients with stages II and III breast cancer were randomised to receive postmastectomy radiotherapy (RT) versus no RT in addition to systemic therapy. The study showed a decrease in loco-regional recurrences and an improved survival in patients receiving RT. The aim of the present study was to describe the delivered RT for the 1538 patients who were randomised to RT, and to evaluate the compliance with the RT guidelines., Patients and Methods: Basic information about the given RT was recorded in the DBCG data centre. For the current study, missing and additional information was collected from individual RT treatment charts. We defined some criteria for complying with the DBCG RT guidelines regarding target coverage and dose and fractionation and based on that we also defined some criteria for having clinically acceptable RT treatments., Results: Of the 1538 patients, 87% received megavoltage RT, 8% had orthovoltage RT and 5% never began or completed RT. Of the 1341 megavoltage irradiated patients, the guideline compliance regarding target coverage of the axillary/periclaviculary region, internal mammary nodes and chest wall was 88, 79 and 85%, respectively. Only 0, 0.2 and 0.4% did not have clinically acceptable target coverage. The dose and fractionation was according to the guidelines in 96% and none had clinically unacceptable dose and fractionation schedules., Conclusion: The guideline compliance for megavoltage RT was high with 88, 79 and 85% complying with the guidelines regarding target coverage of the axillary/periclaviculary region, internal mammary nodes and chest wall, respectively, and with 96% complying with the guidelines regarding dose and fractionation schedules. Less than 1% had clinically unacceptable target coverage and none had unacceptable dose and fractionation schedules.

Aim: It is often complicated to include the internal mammary lymph nodes in the radiation field after breast-conserving therapy. Using the wide tangent technique the internal mammary lymph nodes are generally presumed to be included if the medial tangential field border is placed 3 cm across the midline. The current study was designed to test the validity of this assumption, and if possible, to correct the wide tangents without using computed tomography (CT) scanning., Patients and Methods: Twenty-one consecutive, high-risk, post-lumpectomy patients were included. An arrangement of three copper wires was mounted in wax placed perpendicular to the skin surface at the ipsilateral border of sternum at intercostal spaces 2 to 4. During a standard simulation for wide tangents, it was examined if the length of the copper wires projected beneath the skin surface (representing the depth of the internal mammary lymph nodes, measured by ultrasound) were included in the wide tangent fields., Results: In only one patient were the internal mammary lymph nodes covered by the wide tangent technique. In 14 of the remaining 20 patients the lateral tangential field border was subsequently moved in the posterior direction, and the internal mammary lymph nodes could be included without unacceptable normal tissue involvement. In the last six patients the irradiated heart and lung volumes exceeded acceptable tolerance levels with this correction, and these patients were referred for three-dimensional CT dose planning., Conclusion: The presented simple technique may be helpful if CT scanning is not available. In all other cases CT-based dose plan should ideally be used as a standard in the planning of radiotherapy after breast-conserving surgery to assure optimal inclusion of the relevant target, and to avoid irradiation of large volumes of critical normal tissue.

Background: Radiotherapy in addition to systemic treatment after mastectomy prolongs survival in high-risk breast-cancer patients. However, adjuvant radiotherapy has a potential association with ischaemic heart disease. We assessed morbidity and mortality from ischaemic heart disease in patients treated with postmastectomy radiotherapy., Methods: Between 1982 and 1990, we randomly assigned 3083 women at high risk of breast cancer, after mastectomy, adjuvant systemic treatment with (n=1538) or without (n=1545) radiotherapy. An anterior photon field was used against the periclavicular region and the axilla. The chest wall was treated through two anterior shaped electron fields, one including the internal mammary nodes. The intended dose was 48-50 Gy in 22-25 fractions, at four to five fractions per week. We obtained information on morbidity and mortality of ischaemic heart disease over a median of 10 years. Analysis was by intention to treat., Findings: More women in the no-radiotherapy group than in the radiotherapy group died of breast cancer (799 [52.5%] vs 674 [44.2%]), whereas similar proportions of each group died from ischaemic heart disease (13 [0.9%] vs 12 [0.8%]). The relative hazard of morbidity from ischaemic heart disease among patients in the radiotherapy compared with the no-radiotherapy group was 0.86 (95% CI 0.6-1.3), and that for death from ischaemic heart disease was 0.84 (0.4-1.8). The hazard rate of morbidity from ischaemic heart disease in the radiotherapy group compared with the no-radiotherapy group did not increase with time from treatment., Interpretation: Postmastectomy radiotherapy with this regimen does not increase the actuarial risk of ischaemic heart disease after 12 years.

The role of postmastectomy irradiation together with systemic treatment was evaluated in high-risk patients included in the Danish Breast Cancer Cooperative Group (DBCG) protocol 82. As of June 1989, a total of 1473 pre- and menopausal patients were randomized to postmastectomy irradiation + CMF versus CMF alone (protocol 82-b). A total of 1202 postmenopausal patients were randomized to postmastectomy irradiation + Tamoxifen versus Tamoxifen alone (protocol 82-c). At 5 years the actuarial loco-regional recurrence rate was significantly lower in the irradiated patients (82-b: 9% vs 28%, 82-c: 6% vs 36%). Further, disease-free survival was significantly improved in both pre- and postmenopausal irradiated patients compared with those who had only systemic treatment (82-b: 54% vs 47%, 82-c: 52% vs 38%). At present, overall survival is significantly different in 82-b patients (68% vs 63%) but not in post-menopausal 82-c patients (62% vs 61%). Thus, adjuvant systemic treatment alone (chemotherapy or tamoxifen) did not prevent loco-regional recurrences in high-risk patients after mastectomy and axillary lymph node sampling. However, a longer observation time is necessary to evaluate the consequence of primary optimal loco-regional tumor control in high-risk breast cancer patients with respect to overall survival.

All pre- and postmenopausal high-risk breast cancer patients in the protocols DBCG 77 of the Danish Breast Cancer Cooperative Group received postmastectomy irradiation before randomization to either adjuvant systemic therapy or no such treatment. The actuarial loco-regional recurrence rate at 9 years was 6-17%, with the lowest rate in patients who also received additional adjuvant chemotherapy or tamoxifen. In a subsequent study (DBCG 82) the role of postmastectomy irradiation together with systemic treatment was evaluated in high-risk patients. Pre- and menopausal patients were randomized to postmastectomy irradiation + CMF (cyclophosphamide, methotrexate, 5-fluorouracil), CMF alone or CMF + TAM (tamoxifen). Postmenopausal patients were randomized to postmastectomy irradiation + TAM, TAM or CMF + TAM. At 4 years the loco-regional recurrence rate was significantly lower in the irradiated patients (5-7% vs. 23-33%). Further, disease-free survival was significantly improved in both pre- and postmenopausal irradiated patients compared with those who had only systemic treatment. At present, there are no significant differences between survival in the treatment groups. Thus, adjuvant systemic treatment alone (chemotherapy and/or tamoxifen) did not prevent loco-regional recurrences in high-risk patients after mastectomy and axillary lymph node sampling. However, a longer observation time is necessary to evaluate the consequence of primary optimal loco-regional tumour control in high-risk breast cancer patients with respect to survival.

In 1978-1980, inclusive, all breast cancer patients referred for postmastectomy irradiation were treated by 2 fractions per week (73 patients) but due to a high incidence of late complications this fractionation schedule was changed from early 1981 to 5 fractions per week (66 patients) with dose adjustment according to the nominal standard dose (NSD) concept. The dose aim in both regimens was 1345 ret minimum target dose. This allowed a comparison of acute and late complications in the two patient groups treated to the same NSD value, but with different fractionation. The patients have been analysed with respect to acute and late reaction in the skin, subcutaneous tissue, lung and bone, as well as related complications, such as arm oedema and impairment of shoulder movement. Except for the acute skin reactions, all other endpoints could not be adequately predicted by the NSD formula. Thus, telangiectasia greater than or equal to grade 1 and skin fibrosis greater than or equal to grade 2 were found to be 75% and 67% in patients treated with the 2-fraction scheme versus 39% and 5% in patients treated with the 5-fraction scheme. In the 2-fraction regimen, a higher frequency of impairment of shoulder movement and arm oedema was found compared to the 5-fraction regimen, 38% versus 11% and 44% versus 33%, respectively. The acute lung reaction as well as late lung reaction were significantly more pronounced in the 2-fraction regimen than in the 5-fraction regimen (pneumonitis greater than or equal to grade 2, 43% versus 23%, and lung fibrosis greater than or equal to grade 2, 32% versus 17%, in the photon fields, respectively). Further, radiation-induced osteonecrosis in the ribs was significantly more frequent in patients treated with large dose per fraction (19% versus 2%). The data clearly demonstrates the danger by using the NSD formula in equation of two different fractionation schedules. This formula as well as other mathematical models can only be used with caution within the limitations defined by the underlying clinical and experimental data on which they have been derived.

A number of biological, dosimetric, and statistical problems encountered in the determination of alpha/beta ratios and the relative biological efficiency (RBE) of high energy electrons are discussed. The analysis is based on isoeffect dose determination from logit analysis of dose-response data. Monte Carlo simulations of the logit analysis show that the estimated isoeffect dose may be treated as a normally distributed random variable. Under this assumption, formulae for the standard error of the derived radiobiological parameters are presented. The importance of specifying not only parameter estimates but also their confidence limits is emphasized. As a practical example, the dose-response relationships for severe erythema and subcutaneous fibrosis are discussed in two series of patients treated with postmastectomy irradiation with electrons and photons in two fractionation schedules. Because of a different dose per fraction in the electron and photon fields, a determination of RBE requires a fraction size correction. This is performed using the alpha/beta formalism. The present analysis suggests a high energy electron RBE for severe erythema of 0.93 (95% confidence limits 0.89 and 0.96) and for subcutaneous fibrosis of 0.84 (95% confidence limits 0.77 and 0.92).