H. J. Stewart

Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy.

PURPOSE To examine long-term cause-specific mortality in patients irradiated for breast cancer as part of a randomized clinical trial. PATIENTS AND METHODS We studied all available information from randomized trials initiated before 1975 in which radiotherapy was the randomized option and surgery was the same for both treatment arms. Eight such trials were identified. RESULTS The increased all-cause mortality rate in 10-year survivors previously reported is no longer significant, although a numerical difference in favor of non-irradiated patients remains. This result was strongly influenced by the earliest trials, and more recent trials have found a nonsignificant net benefit in overall mortality associated with radiation therapy. An excess of cardiac deaths was apparent in both early and more recent trials (P < .001), but this was offset by a reduced number of deaths due to breast cancer, especially in more recent trials. CONCLUSION The reduction of breast cancer deaths suggests that radiation therapy may have a value beyond the clearly established improvements obtainable for local control. Use of techniques that minimize cardiac dose is important in reducing the risks of adjuvant radiotherapy, especially in good-prognosis patients.

Randomised controlled trial of conservation therapy for breast cancer: 6-year analysis of the Scottish trial

Summary Background To determine whether, when primary breast cancer is treated by local excision supported by systemic therapy appropriate to the oestrogen receptor status (ER) of the tumour, local radiotherapy can be avoided. Methods We carried out a randomised controlled trial in 585 patients aged less than 70 years with primary breast cancers of 4 cm or less in size in four specialist units and seven other hospitals in Scotland. After local excision of the tumour (1 cm margin) and an axillary lymph-node clearance or sample, all patients received systemic therapy with oral tamoxifen 20 mg daily or six 3-weekly intravenous bolus injections of cyclophosphamide 600 mg, methotrexate 50 mg, and fluorouracil 600 mg per m 2 , depending upon the ER concentration in the primary tumour. Patients were then randomly allocated to postoperative radical radiotherapy (50 Gy to breast with boost to the tumour bed) or to no further local treatment. The median follow-up of living patients was 5·7 years. The primary analysis was by intention to treat but since some patients did not receive systemic therapy appropriate to their ER status, a subsidiary analysis was restricted to 464 patients in whom all details of the protocol had been observed. Findings In the primary analysis survival was equal in the radiotherapy and non-radiotherapy groups (hazard ratio [HR] 0·98, 95% CI 0 67–1·44). Event-free survival showed an advantage in the irradiated patients (HR 0·54, 95% CI 0·39–0·74), largely due to fewer loco-regional relapses (HR 0·20, 95% CI 0·12–0·33). The relapse rate in the ipsilateral breast was 24·5% in the non-irradiated group and 5·8% following breast irradiation. The subsidiary analysis confirmed these findings and indicated the advantage of radiotherapy irrespective of ER concentration. There was a non-significant trend towards fewer distant metastases in the irradiated group. Interpretation After local excision of a primary breast cancer, we conclude that radiotherapy to the residual breast tissue is advisable even when selective adjuvant systemic therapy is given.

Overview of Randomized Trials of Postoperative Adjuvant Radiotherapy in Breast Cancer

One of the first major randomized trials in cancer therapy was concerned with the value of postoperative adjuvant radiotherapy for breast cancer. Since then, a large number of trials have addressed this issue, but the impact of this treatment on long-term survival still remains clouded. This is due partly to the long natural history of breast cancer and partly to the changing approach to primary treatment, where a trend toward less surgery and more radiotherapy has taken place. The current interest in procedures aimed at breast conservation (Calle et al. 1978; Hell- man et al. 1980; Veronesi et al. 1981; Fisher et al. 1985 a) highlights this shift and emphasizes the need for a greater understanding of the role of radiotherapy in primary management.

Cardiac and vascular morbidity in women receiving adjuvant tamoxifen for breast cancer in a randomised trial. The Scottish Cancer Trials Breast Group.

Abstract Objective: To determine any cardiac or vascular morbidity associated with long term treatment with tamoxifen given after mastectomy for primary breast cancer. Design: Cohort study using linkage between database of a randomised trial and statistics of Scottish hospital inpatients to identify episodes of cardiac and vascular morbidity. Setting: NHS hospitals in Scotland. Subjects: 1312 women who had undergone mastectomy for breast cancer and who were randomised either to a treatment group to receive adjuvant tamoxifen or to a control group to be given tamoxifen only on first relapse of disease. Maximum duration of tamoxifen treatment was 14 years. Total woman years of follow up were 9943. Main outcome measures: Randomised and observational comparisons of risk (expressed as hazard ratios) of myocardial infarction, other cardiac event, cerebrovascular disease, or thromboembolic event according to treatment allocated and between non-users, former users, and current users of tamoxifen. Results: Use of tamoxifen was associated with lower rates of myocardial infarction. Hazard ratio for women in control group was 1.92 (95% confidence interval 0.99 to 3.73) compared with women allocated to adjuvant treatment. The association was stronger for current use: hazard ratio for non-users was 3.49 (1.52 to 8.03) compared with current users. Current users of tamoxifen, however, had higher rates of thromboembolic events: hazard ratio for non-users was 0.40 (0.18 to 0.90) compared with current users. Conclusions: Our results provide further evidence that tamoxifen reduces the risk of myocardial infarction. Thromboembolic events should be carefully monitored in trials of tamoxifen, particularly those of prophylactic treatment, in which tamoxifen is given to healthy women.

Tumour cyclic AMP binding proteins and endocrine responsiveness in patients with inoperable breast cancer

Tumour cyclic AMP binding proteins and endocrine responsiveness in patients with inoperable breast cancer

South-east Scottish trial of local therapy in node negative breast cancer

Abstract Between April 1974 and December 1979, 348 women, with Stage I or II breast cancer without node involvement on lymph node sampling, were randomized, after simple mastectomy, for routine postoperative radiotherapy or no further treatment in a trial conducted in the South-east of Scotland. After a median follow-up of 15 years from randomization for the alive patients, the two treatment groups had very similar results for both distant disease-free rates and total survival. A non-significant advantage in event-free survival was found for those irradiated (HR = 1.21, CI = 0.91–1.61) which was accounted for by a significant increase in loco-regional relapse in those not given radiotherapy (HR = 2.19, CI = 1.38–3.48). In one-third of those randomized, no information on node histology was available. Subgroup analysis within the resulting two categories of nodal status confirmed an advantage in distant disease-free rates for those classified histologically as node negative compared to those without node histology (HR = 0.54, CI = 0.38–0.77). It is concluded that, for women with stage I or II breast cancer, when histological examination of lower axillary nodes suggests absence of axillary spread, a watching policy is safe but that when no nodes have been examined, postoperative radiotherapy should be considered in order to achieve maximal local control of disease.

IS APOCRINE DIFFERENTIATION IN BREAST-CARCINOMA OF PROGNOSTIC-SIGNIFICANCE

Apocrine differentiation in human breast cancers has been assessed using immunohistochemistry to detect zinc alpha 2 glycoprotein and the findings related to standard prognostic factors, disease free interval (DFI) and survival in 145 women with early breast cancer. Breast tumour samples from women with a minimum follow-up of 5 years were assessed. Routinely fixed and processed tissue was used throughout. Sixty-six (45%) tumours did not stain with the antibody. Fifty-two (36%) exhibited positive apocrine staining while for 27 (19%) only a few cells were reactive. The presence of apocrine differentiation was unrelated to lymph node status, menstrual status, tumour grade or size, oestrogen receptor (E2R) or progesterone receptor status. However, patients whose tumours exhibited apocrine staining had a shorter disease-free interval (DFI) (P = 0.03) and survival (P = 0.03). A Coxs multiple regression analysis of the data found that the presence of staining added significantly (P = 0.047) to the predictive value of node status (P = 0.0001), menstrual status (P = 0.0001), tumour size (P = 0.0026) and E2R status (P = 0.0014) for patient survival. The other seven prognostic factors tested did not reach significance and were rejected from the model. Apocrine differentiation in breast cancer appears to be an independent predictor of poor prognosis tumours.

Relation between apocrine differentiation and receptor status, prognosis and hormonal response in breast cancer

The release of a gross cystic disease fluid protein (GCDFP 15) by tumour explants grown in tissue culture was used to measure apocrine differentiation in 117 women with breast carcinoma. GCDFP 15 was detected by radioimmunoassay in the media from 90% of tumours (range 2-2100 ng/ml, mean 41). Tumour secretion of GCDFP 15 was higher in oestrogen receptor rich (over 20 fmol/mg) tumours (P less than 0.05) but did not correlate with any other prognostic factors or with survival. Response to hormonal therapy was assessable by UICC criteria in 33 women (6 partial responses, 8 stable disease, 19 progression). Responders had significantly higher tumour oestrogen receptor levels (P less than 0.005) but a lower GCDFP 15 secretion than non-responders (P less than 0.02). Apocrine differentiation in breast cancer may be a marker for oestrogen receptor positive tumours that do not respond to hormonal therapy.

Accuracy of screening methods for the diagnosis of breast disease.

Clinical examination, thermography, and 70-mm. mammography were performed in 891 patients—414 presented to hospital with symptoms of breast disease and 477 were asymptomatic. Comparison of the diagnostic accuracy of these methods showed that neither thermography nor 70-mm. mammography has a useful place as an isolated screening procedure for breast cancer. In fact, we consider such a policy dangerous.

The Cardiff local therapy trial — results at 20 years

Abstract From 1963–1973, 200 women with operable breast cancer were randomized in a trial comparing two local therapy policies: 97 to the ‘radical’ policy (radical mastectomy) and 103 to the ‘conservative’ (total mastectomy and axillary node sample). The extent of local therapy also varied with axillary node histology: if node negative or no node identified — no radiotherapy (XRT) and, if node positive, radiotherapy to the chest wall and regional lymph nodes in the radical group and to the axilla alone in the conservative group. There were no differences overall either in total survival (log rank test P = 0.23) or in distant disease-free rates ( P = 0.092). The risk of loco-regional relapse favoured those radically treated ( P = 0.047). 71 patients were found to have involved nodes (4 XRT violations). Following an axillary clearance 60 were node negative and 3 had no nodes identified whilst following an axillary sample 37 were node negative and 29 had no nodes identified ( 3 29 XRT violations). Excluding the XRT violations, the distant disease free rates for these three groups were 64%, 36% and 57% and the axillary relapse rates were 1.5%, 1.6% and 16% respectively. It is concluded that the node sampling was insufficient to identify the node positive cases to the detriment of the assessment of the conservative policy.