Anders Somell

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.

Randomized study of mammography screening--preliminary report on mortality in the Stockholm trial.

SummaryIn March 1981, 40,318 women in Stockholm, aged 40–64, entered a randomized trial of breast cancer screening by single-view mammography alone versus no intervention in a control group of 20,000 women. The attendance rate during the first screening round was 81 per cent and the cancer detection rate was 4.0 per 1000 women. The detection the rate fell to 3.1 per 1000 in the second round, which was completed in October 1985. During 1986 the controlled design of the study was broken and the contro women were invited once to screening which was completed the same year. A total of 428 cases of breast cancer were thus diagnosed in the study group and 439 in the adjusted control group. After a mean follow-up of 7.4 years the number of breast cancer deaths in the study and control groups was 39 and 30 respectively. The relative risk of breast cancer death (screening versus control) was 0.71 (95 per cent confidence interval: 0.4–1.2). Among women older than 50 years at entry the relative risk was 0.57 (95 per cent confidence interval: 0.3–1.1). Cancer deaths among women under 50 were few and perhaps because of this no mortality reduction was seen in this age group. The estimate of mortality reduction lies between the results from two earlier Swedish randomized controlled trials.

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.

Analysis of interval breast carcinomas in a randomized screening trial in Stockholm

In the interval between screening examinations, some cases of breast cancer are invariably detected clinically in patients whose mammogram was considered to be normal at the earlier screening. During the first interval in the Stockholm study, 60 interval cancers were detected, giving a rate of 1.8 cases/1000 examinations/24 months. About half of these interval cases (31/60) were true interval tumours in that no sign of them could be found on the first mammogram; the other half, non-true, were possible to trace on the first mammogram. It is mainly women under 50 who feature in the interval group, above all in the sub-group of true interval cancers (p<0.05).The incidence of interval cancer rises, as expected, with the length of the interval (Fig. 1). In the final six months of the 2-year interval the incidence of interval cancers had risen to 88 per cent of the cancers detected in the control group in the same period of time.The cumulative incidence of interval cancers supports the hypothesis that the distribution of sojourn time in the interval 0–2 years is approximately rectangular. This means that shortening the interval by one-half would halve the number of interval cases.If mammography becomes a wide spread screening method for early detection of breast cancer, the number of non-true interval cancers could be a feed back on the effectiveness of the screening.An analysis of the malignancy of the true interval cancers, based on tumour size, axillary status, tumour stage, and estrogen receptor content, shows that these are the more malignant tumours with an unfavourable prognosis, while the control group is intermediate in this respect and the tumours detected at screening have the most favourable prognosis.

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.

Breast-conserving treatment for breast cancer in stockholm, sweden, 1977 to 1981

Since 1977 patients living in Stockholm with Stage I breast cancer fulfilling specific criteria are offered breast‐conserving treatment. The treatment includes a partial mastectomy and a low‐axillary dissection followed by radiotherapy, 5000 rad, to the remaining breast. Between 1977 and 1981, 262 patients underwent the breast conserving therapy. One hundred eighty‐six patients had pathologic Stage I tumors. Radiotherapy was given to 158 of those patients. During the follow‐up time (6 months to 5 years), 4 of 186 patients had recurrence to the breast. Two of those had not received radiotherapy. Recurrent tumor in regional lymph nodes occurred in 4/186, and distant metastases in 10/186 patients. Six patients have died of their disease. The cosmetic results were favorable overall, but often impaired when surgical complications occurred. A comparison between these results and those obtained in similar patients treated with modified radical mastectomy showed no significant differences in rate of local, regional, or distant recurrence. In selected patients a partial mastectomy with a low‐axillar dissection followed by radiotherapy to the remaining breast seems to be an alternative treatment to modified radical mastectomy. Longer follow‐up time is needed before final conclusions can be drawn. Cancer 53:1253‐1255, 1984.