Ulla Glas

ADJUVANT TAMOXIFEN IN EARLY BREAST CANCER: OCCURRENCE OF NEW PRIMARY CANCERS

The frequency of new primary cancers was studied in 1846 postmenopausal patients included in a randomised trial of tamoxifen as an adjunct to primary surgery for early breast cancer. The median follow-up was 4.5 years (range 0.5-10.5 years). The number of new cancers in the tamoxifen group (n = 57) did not differ significantly from that in the control group (n = 70). However, in tamoxifen patients second breast cancers occurred less often and endometrial cancer occurred more often than in the controls. The increase in endometrial cancers was probably related to the agonistic oestrogenic effects of tamoxifen and was most pronounced in those treated for over 2 years.

Myocardial damage in breast cancer patients treated with adjuvant radiotherapy : A prospective study

PURPOSE To look for early and late signs of cardiac side effects of postoperative radiotherapy in patients with left-sided breast cancer. METHODS AND MATERIALS Seventeen left-sided primary (Stage I-III) breast cancer patients considered eligible were recruited. Their computer tomography-based dose planning showed a part of the hearts left ventricle irradiated with at least 85-95% of the total dose. Twelve patients were examined both before treatment and an average of 13 months later, at a first follow-up. In partially mastectomized patients tangential opposed photon fields were used to the breast tissue, while in patients with modified radical mastectomy electrons were given to the thorax. Echocardiography and a bicycle ergometry stress test with myocardial perfusion scintigraphy were carried out before and after radiotherapy to assess if any myocardial damage could be detected. RESULTS Six of the 12 patients exhibited new fixed scintigraphic defects after radiotherapy indicating regional hypoperfusion. Four of them received treatment only to the breast after breast-conserving surgery. The localization of the defects corresponded well with the irradiated volume of the left ventricle. No deterioration in left ventricular systolic or diastolic function could be detected by echocardiography. CONCLUSIONS In this study half of the patients exhibited new scintigraphic defects that indicate radiation-induced myocardial damage, probably affecting the microcirculation. There were no changes on electrocardiography or any deterioration of the left ventricular function at this stage. Long-term follow-up is necessary to assess whether this finding is a prognostic sign for developing radiation-induced coronary artery disease.

Radiotherapy, chemotherapy, and tamoxifen as adjuncts to surgery in early breast cancer: A summary of three randomized trials☆

The paper summarizes up-dated results of three randomized adjuvant trials from the Stockholm Breast Cancer Group. The objective of all studies included an evaluation of the role of megavoltage radiation in the primary management of patients with early breast cancer. The first trial was started in 1971 and included 960 pre- and postmenopausal patients with operable disease. The study compared adjuvant radiotherapy with surgery alone. All patients were treated with a modified radical mastectomy. There was a sustained improvement of the recurrence-free survival with radiotherapy (p less than 0.001). Among node positive cases radiation reduced the frequency of both loco-regional recurrence (p less than 0.001) and distant metastasis (p less than 0.01). This observation indicates that distant dissemination in subgroups of patients can originate from uncontrolled local deposits of tumor cells, for instance in the regional lymph nodes. No adverse effect from radiation on long-term survival was observed. The second study was started in 1976 and compared postmastectomy radiation with adjuvant chemotherapy in pre- and postmenopausal high-risk patients. At a mean follow-up of 6 1/2 years there was no significant difference in recurrence-free survival between the two treatments. However, postmenopausal patients fared better with radiotherapy (p less than 0.01). In this subgroup, radiation was more effective than adjuvant chemotherapy in reducing both distant metastases (p less than 0.01) and loco-regional recurrences (p less than 0.001). In the third trial--which only included postmenopausal patients--2 years of adjuvant tamoxifen was compared with no adjuvant endocrine treatment. The number of treatment failures was significantly reduced with tamoxifen (p less than 0.01) but there was no significant overall survival benefit. Subset analysis indicated that tamoxifen improved the recurrence-free survival among patients treated with adjuvant chemotherapy (p less than 0.01) but only to a level close to that achieved with radiotherapy alone. Addition of tamoxifen to radiotherapy failed to further increase the recurrence-free survival.

The Stockholm trial on adjuvant tamoxifen in early breast cancer

SummaryThe paper presents interim results of an on-going randomized trial of adjuvant tamoxifen (40 mg daily for 2 years) versus no endocrine adjuvant therapy in postmenopausal women with early breast cancer. A total of 1407 patients were included in the study between November 1976 through June 1984. Estrogen receptor (ER) data were available on 1184 patients (84%). The median follow-up was 53 months. Adjuvant tamoxifen increased the recurrence-free interval (P<0.01) but had no significant effect on overall survival. Treatment failures were reduced by 25% (P<0.01) and deaths by 7% (P>0.05). Tamoxifen mainly decreased the frequency of loco-regional recurrence whereas distant metastases were less affected. The treatment effect was independent of tumor stage but was significantly related to the estrogen receptor (ER) content of the primary tumor. Tamoxifen appeared ineffective among ER negative patients, and the greatest effect was seen among those with high levels of ER. The results indicate that the main mechanism of action of adjuvant tamoxifen is similar to that suggested in advanced disease, i.e. an interaction with the estrogen receptor.

Randomized mammographic screening for breast cancer in Stockholm. Design, first round results and comparisons.

In March 1981 a randomized single-view mammographic screening for breast cancer was started in the south of Stockholm. The screened population in the first round numbered 40,318 women, and 20,000 women served as a well-defined control group. The age groups represented were 40–64 years, and 80.7% of the invited women participated in the study. The first round disclosed 128 breast cancers (113 invasive and 15 noninvasive), or 4.0 per 1,000 women. Mean tumour size was 14.1 mm and axillary lymph node metastases were found in 21.8%. Fifty-five per cent of the tumours were small (⩽10 mm) or non-invasive, and 71% were stage I.Participation rates are high in all Swedish trials. The present results differ only slightly from other screening programs; the percentages of patients with axillary metastases and stage II tumours are similar in the Stockholm, Malmö and Kopparberg/Östergötland studies. Comparisons of cancer prevalence in the various Swedish screening trials show that, in comparable age groups, there are some differences, even when the differences in the natural cancer incidence are taken into account.A decreased mortality was found recently in a Swedish trial in ages above 50 years but not below. In the Stockholm study more than one-third of the participants were aged 40–49 years.

Pulmonary function following adjuvant chemotherapy and radiotherapy for breast cancer and the issue of three-dimensional treatment planning

BACKGROUND AND PURPOSE The frequency and grade of pulmonary complications following adjuvant radiotherapy for breast cancer are still debated. This study focuses on loss of pulmonary function. MATERIALS AND METHODS We have measured the reduction of pulmonary function 5 months following radiotherapy in 144 node-positive stage II breast cancer patients by using pulmonary function tests. RESULTS No deterioration of pulmonary function was detected among the patients who were treated with local radiotherapy. On the contrary, there was a mean increase in diffusion capacity by 7% (P = 0.004) following radiotherapy, which most likely was explained by the adjuvant chemotherapy administered prior to the baseline pulmonary function tests. Patients undergoing loco-regional radiotherapy showed a mean reduction in diffusion capacity by 5% (P < 0.001) and in vital capacity by 3% (P = 0.001). The subset of patients (9%) who were diagnosed with severe pulmonary complications needing cortisone treatment had significantly larger mean paired differences in vital capacity (-0.446 L, -15% (equivalent to 15 years of normal ageing or the loss of 3/4 of a lung lobe)) compared to the patients who were asymptomatic (-0.084 L) (P < 0.05). When the effects of potential confounding factors and different radiotherapy techniques were tested on the reduction of pulmonary function by stepwise multiple regression analysis, a significant correlation was found only to locoregional radiotherapy including the lower internal mammary lymph nodes. CONCLUSIONS We conclude that a clinically important reduction of pulmonary function is seen in the subset of patients who are diagnosed with severe pulmonary complication following loco-regional radiotherapy for breast cancer. The results of this study warrant further studies based on individual lung dose volume histograms.

Detection of radiation-induced myocardial damage by technetium-99m sestamibi scintigraphy.

A prospective study was initiated to assess the side-effects of postoperative adjuvant radiotherapy in patients with left-sided early breast cancer. Twelve patients with early breast cancer were examined before and a year after radiotherapy. Echocardiography, ECG and bicycle ergometry stress test with technetium-99m sestamibi myocardial perfusion scintigraphic were carried out to assess changes in regional myocardial blood flow. Six of the 12 patients had new fixed scintigraphic defects after radiotherapy (as compared with the preradiation examination). The localization of the defects corresponded well with the irradiated volume of the left ventricle. These defects were probably due to microvascular damage to the myocardium. Neither ECG changes nor left ventricular segmental wall motion abnormalities could be detected by echocardiography. To our knowledge this study is the first to show that radiation-induced microvascular damage to the myocardium may be detected by perfusion scintigraphy. This may limit the use of scintigraphy in diagnosing coronary artery disease in patients treated with thoracic radiotherapy. Long-term follow-up is necessary to assess whether the presence of microvascular damage is a prognostic sign for the development of radiation-induced coronary artery disease.

Randomized trial of adjuvant tamoxifen combined with postoperative radiation therapy or adjuvant chemotherapy in postmenopausal breast cancer.

From 1976 to 1984, 427 postmenopausal women with high‐risk breast cancer (pN+ or pT > 30 mm) were randomized between postoperative radiation therapy (RT), radiation therapy plus tamoxifen (RT‐TAM), adjuvant chemotherapy (CT), or chemotherapy plus tamoxifen (CT‐TAM). Surgery was a modified radical mastectomy in all cases. The radiation therapy was given with high‐voltage techniques and included the chest wall and regional nodes. The dose was 4600 cGy/4 1/2 weeks. Tamoxifen was given at a dose of 40 mg daily for 2 years. The adjuvant chemotherapy consisted of 12 cycles of cyclophosphamide, methotrexate, and 5‐fluorouracil (CMF) (or chlorambucil, methotrexate, and 5‐fluorouracil [LMF] for patients entered before 1978). At a median follow‐up time of 6 1/2 years the recurrence‐free survival was significantly better for patients allocated to radiation therapy compared to chemotherapy and for patients allocated to tamoxifen compared to no adjuvant endocrine treatment (P < 0.01). At 10 years the recurrence‐free survival for patients in the RT‐TAM, RT, CT‐TAM, and CT groups was 63%, 57%, 47%, and 31%, respectively. A significant reduction of treatment failures with tamoxifen was only observed among patients with estrogen receptor‐positive tumors. The overall survival difference in favor of patients allocated to radiation therapy or tamoxifen was not significant: the respective survival percentage at 10 years in the RT‐TAM, RT, CT‐TAM, and CT group was 65%, 62%, 52%, and 50%. The results indicate that postoperative radiation therapy continues to play an important role in the primary management of postmenopausal women with high‐risk breast cancer and that the addition of tamoxifen may further improve the results among ER‐positive patients.

The Stockholm breast cancer screening trial — 5-year results and stage at discovery

In screening programmes it is important to assess a preliminary effectiveness of the screening method as soon as possible in order to forecast survival figures. In March 1981 a controlled single-view mammographic screening trial for breast cancer was started in the south of Stockholm. The population invited for screening mammography consisted of 40,000 women aged 40–64 years, and 20,000 women served as a well-defined control group. The main aim of the trial was to determine whether repeated mammographic screening could reduce the mortality in the study population (SP) compared to the control population (CP).The cumulative number of advanced mammary carcinomas in the screening and the control populations from the first five years of screening have shown a tendency towards more favourable stages in the screened population aged 40–64 years. A breakdown by age suggests an effect in age group 50–59 years, but not yet in age groups 40–49 and 60–64 years.When comparing the rates of stage II+ cancer, an increased number is found in the study group. As the total rate of breast cancer is higher in SP than in CP, there ought to be a concealed group of stage II+ cancers in the CP which makes the comparison biased. A new approach has been designed, where an estimation of the ‘hidden’ number of stage II+ cancers in CP is added to the clinically detected cases, and in this respect a comparison has shown a decrease in the cumulative number of advanced cancers in the SP in relation to the CP (p<0.05). According to this it could be important to add the estimated number of undetected, hidden cases in the control group in order to utilize the difference in detection rate in the screening- and control group respectively.

Randomized trial of adjuvant tamoxifen in node negative postmenopausal breast cancer

The paper presents long-term results of a randomized trial of adjuvant tamoxifen (40 mg daily for 2 or 5 years) versus surgery alone including 1,347 postmenopausal patients with histologically negative axillary nodes and a tumour diameter less than or equal to 30 mm. Data on the estrogen receptor status of the primary tumour were available in 1,136 patients (84%). At a median follow-up of 7 years (range 1.7-13.0 years) there was a significant prolongation of the recurrence-free survival among those allocated to tamoxifen (p less than 0.01), significantly fewer deaths due to breast cancer (p = 0.02) and a trend towards improved overall survival (p = 0.11). The treatment benefit was restricted to patients with ER-positive tumours. There was no significant reduction of breast cancer recurrences in the tamoxifen group among patients whose tumours were classified as ER-negative. The results support and extend previous studies in showing a long-term benefit of tamoxifen in postmenopausal breast cancer patients with node-negative, estrogen receptor positive disease.