The Total Incidence of Loco-Regional Recurrence in a Randomized Trial of Breast Cancer Tnm Stage Ii the South Sweden Breast Cancer Trial

We studied loco-regional recurrence during follow-up (median observation time 8 years) in 1153 patients, who underwent modified mastectomy and were randomly assigned to one of the following postoperative treatments; Premenopausal patients: radiotherapy, cyclophosphamide, or both; Postmenopausal patients: radiotherapy, tamoxifen, or both. Recurrence occurred in a total of 419 patients, 123 of whom had loco-regional recurrence with or without distant metastasis. the loco-regional recurrence rate was 7% in the irradiated subgroups and 17% in the non-irradiated subgroups, the corresponding cure rates being 43% and 58%. Complete remission of all local recurrence was obtained after the first treatment in 67% of the cases, and was persistent in 67% of them (44% overall). Complete remission was obtained in all patients with local recurrence who received local treatment only, and was persistent in 65%. of local recurrences treated with a combination of surgery, radiotherapy and hormone therapy, complete response was obtained in 94% of the patients, and was persistent in 94% of them (88% overall). Complete remission of all regional recurrence was obtained after the first treatment in 58% of the patients and was persistent in 67% of them (39% overall). Postoperative radiotherapy reduced not only the total number of loco-regional recurrences but also the number of uncontrolled loco-regional recurrences. Aggressive local treatment would appear to yield both satisfactory initial control and, when combined with the hormone therapy, a high rate of persistent loco-regional control.     

Carcinogenic effects of adjuvant tamoxifen treatment and radiotherapy for early breast cancer.

The occurrence of new primary tumours among postmenopausal patients with primary breast cancer subsequent to adjuvant treatment in Denmark was assessed by linkage to the cancer registry. Following primary surgery, patients in low risk of recurrence (n = 1,828) received no further treatment while patients in high risk randomly received either adjuvant radiotherapy alone (n = 846) or radiotherapy + tamoxifen 30 mg daily for 48 weeks (n = 864). With a median follow-up of 8 years, the incidence of tumours in the contralateral breast was similar among tamoxifen-treated, and non-treated high-risk patients even after adjusting for tumours arising within the first year. The standardized incidence ratio for endometrial cancer was 1.9 (95% confidence interval 0.8-3.9) among tamoxifen treated, the cumulative incidence 1% compared to 0.3% among non-treated patients (p = 0.11). The cumulative risk of non-lymphocytic leukaemia was 0.9% and 0.1% among irradiated and non-irradiated patients respectively (p = 0.4). Prolonged follow-up of tamoxifen-treated patients with regard to new tumours is recommended.     

The Scottish trial of adjuvant tamoxifen in node-negative breast cancer. Scottish Cancer Trials Breast Group.

This paper presents results, 5 years after closure, of a randomized trial comparing adjuvant with postrelapse tamoxifen in 747 women with histological node-negative breast cancer. Two hundred thirty-six disease-free patients on adjuvant therapy were secondarily randomly assigned at 5 years to stop or to continue tamoxifen until relapse. Adjuvant tamoxifen, taken for a median duration of 60 months, has significantly prolonged disease-free survival overall (P = .0001), in the 214 premenopausal group (P = .018), in the 533 postmenopausal group (P = .0026), and for the 246 patients with estrogen receptor levels greater than 19 fmol/mg of protein (P = .0032); distant relapse has also been delayed overall (P = .029). Total survival comparison by Kaplan-Meier life-table analysis shows a nonsignificant trend in the same direction (P = .07). Adjuvant tamoxifen has also reduced the incidence of contralateral breast cancer and of death from myocardial infarction. No increase in the incidence of endometrial cancer has been found.     

Cyclophosphamide and tamoxifen as adjuvant therapies in the management of breast cancer. CRC Adjuvant Breast Trial Working Party.

In 1980 the Cancer Research Campaign launched a multi-centre breast cancer trial; aimed at repeating the Scandinavian Chemotherapy Study Group''s cyclophosphamide trial, and the NATO tamoxifen study; thereby further evaluating the role of these two adjuvant regimens in patients with early breast cancer. Two thousand two hundred and thirty women were randomized into this trial between 1980 and 1985 and preliminary analyses demonstrate a significant improvement in event-free survival for both regimens. Results from this study closely parallel the two trials it set out to repeat.     

Randomized trial of adjuvant tamoxifen in node negative postmenopausal breast cancer. Stockholm Breast Cancer Study Group.

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.     

Randomized trial of adjuvant tamoxifen and/or goserelin in premenopausal breast cancer--self-rated physiological effects and symptoms

After primary surgery, 149 premenopausal breast cancer patients, with node-negative disease, were randomized to one of four treatment groups: goserelin, tamoxifen, goserelin plus tamoxifen or to a systematically untreated control group. The aim was to assess the effects of adjuvant endocrine therapy in terms of physical symptoms and perception of anxiety and depressive symptoms. Assessments were made before randomization, at 3-4 months and at 12 months. Treatment with goserelin resulted in early and more intense menopausal symptoms, while the effects of tamoxifen were slower and milder. The side effects with goserelin appeared to be alleviated by concurrent tamoxifen except for vasomotor symptoms (hot flashes, sweating, feeling warm). No significant group differences were found for anxiety and depressive symptoms. In conclusion, chemical castration with goserelin was associated with the highest level of physical symptoms. The group treated with tamoxifen alone showed the lowest levels of symptoms among the treatment groups, except for vaginal discharge and irregular bleedings.     

Long-term survival following levamisole or placebo adjuvant treatment of colorectal cancer: a Western Cancer Study Group Trial

In 1976, the Western Cancer Study Group initiated a prospectively randomized, double-blind trial of an 18-month adjuvant program comparing levamisole with placebo treatment following surgical resection in patients with colorectal adenocarcinoma. After stratification for site of disease (colon vs. rectum) and stage (B vs. C), 78 patients were entered. The levamisole schedule was 2.5 mg/kg/day given on days 1 and 2 of each week. The median follow-up of entered patients is now 7.5 years. Toxic effects of treatment were minimal. However, no long-term survival advantage was associated with levamisole compared to placebo administration in this population with resected large-bowel adenocarcinoma.     

Randomised comparison of 5 years of adjuvant tamoxifen with continuous therapy for operable breast cancer. The Scottish Cancer Trials Breast Group.

In 1985 a second randomisation was initiated for women in the treatment arm of the Scottish Tamoxifen Trial either to stop tamoxifen at 5 years or to continue indefinitely. A preliminary analysis of outcome in 342 patients at a median follow-up of 6 years suggests that a worthwhile gain in disease control from continuing adjuvant tamoxifen beyond 5 years is unlikely. [Hazard ratio for events (relapse or death without relapse) is 1.27, 95% CI = 0.87 - 1.85.] There is a suggestion that therapy for longer than 5 years may increase the risk of endometrial carcinoma (P = 0.064).     

Long-term adjuvant therapy with tamoxifen: effects on sex hormone binding globulin and antithrombin III

Plasma levels of luteinizing hormone, sex hormone binding globulin, and antithrombin III were measured in pre- and postmenopausal breast cancer patients receiving adjuvant combination chemotherapy or combination chemotherapy and long-term tamoxifen therapy. The aim was to determine the estrogen-like effects of tamoxifen. The premenopausal patients had received tamoxifen for between 434 and 2592 days and postmenopausal patients between 91 and 1560 days. Tamoxifen caused a consistent rise in sex hormone binding globulin in premenopausal (P less than 0.03) and postmenopausal (P less than 0.01) patients compared to chemotherapy controls. Luteinizing hormone levels were only significantly lowered (P less than 0.008) in premenopausal patients compared to chemotherapy controls. Antithrombin III levels were significantly depressed (P less than 0.001) in postmenopausal patients compared with chemotherapy controls. However, none of the patients had a value that was depressed by more than 30% of the laboratory control (the level of clinical significance). The mean for the group was 90% +/- 4 (mean +/- SD, N = 11). The estrogen-like rise in sex hormone binding globulin produced by adjuvant tamoxifen therapy could be advantageous for maintaining the antiestrogenic action of the drug. A decrease in antithrombin III occurred but was not within a range of clinical concern. We recommend, however, that patients with a history of thromboembolic disorders should be monitored carefully if placed on tamoxifen therapy.     

Histologic grading in breast cancer--reproducibility between seven pathologic departments. South Sweden Breast Cancer Group

Histologic grade, including tubular formations, nuclear grade, and mitotic activity, is a well-documented prognostic factor in breast cancer. In comparison with other prognostic parameters, the evaluation of histologic grade is cheap and can be performed, in principle, in all cases of breast cancer. One possible disadvantage is that the evaluation may vary between different pathological departments. The aim of the present work was therefore to study the reproducibility of the histologic grading system by distributing haematoxylin-erythrosin-stained slides from 93 invasive breast cancers to the seven pathology departments within the southern healthcare region of Sweden. The evaluation was performed blindly and without any knowledge of other clinical parameters. In 31% of the cases the same histologic grade was obtained for all departments. The overall mean kappa was 0.54, indicating a moderate reproducibility. Of the three factors included in histologic grade, the agreement was best for tubular formations and poorest for nuclear grade and mitotic activity. The overall moderate reproducibility should be considered when the clinical usefulness of histologic grading is compared with other prognostic instruments.     

Preoperative radiotherapy in operable breast cancer: results in the Stockholm Breast Cancer Trial.

A randomized trial of preoperative radiotherapy in operable breast cancer was conducted from 1971 to 1976. The diagnosis was established by fine-needle aspiration biopsy. A dose of 4500 rad over five weeks was given to the chest wall, the breast and the lymph nodes of the axilla, the supraclavicular fossa and the internal mammary chain. Modified radical mastectomy was performed six weeks or more after completed radiotherapy. In control patients the same operation was performed without prior radiotherapy. By random allocation, one control group received no further treatment and postoperative irradiation was given to the other controls. Preoperative radiotherapy reduced the incidence of local and regional recurrence and of distant metastases, and also the mortality, as compared with the surgery only group. Postoperative radiotherapy as given in this trial gave almost equal reduction of local and regional recurrence but did not diminish the frequency of distant metastases or the mortality.     

The combination of radiotherapy, adjuvant chemotherapy (cyclophosphamide-doxorubicin-ftorafur) and tamoxifen in stage II breast cancer. Long-term follow-up results of a randomised trial.

Two hundred patients with node positive stage II breast cancer were randomised to four groups after radical mastectomy and axillary evacuation: (1) Postoperative radiotherapy, (2) Adjuvant chemotherapy with eight courses of CAFt (cyclophosphamide 500 mg m-2 + doxorubicin 40 mg/m-2 + ftorafur 20 mg kg-1 orally day 1-14) every fourth week, (3) Postoperative radiotherapy and adjuvant chemotherapy and (4) postoperative radiation, adjuvant chemotherapy and tamoxifen 40 mg daily for 2 years. Thirty-two per cent of the patients discontinued treatment due to GI-toxicity, while 26% required dose reductions due to leukopenia. Radiation pneumonitis was more frequent after the combination of postoperative radiotherapy with chemotherapy. There was a better relapse-free survival in the groups receiving chemotherapy compared to radiotherapy alone (P = 0.05), which was highly significant in a multivariate Cox analysis (P = 0.004). No significant survival differences were seen. Tamoxifen had no clear overall effect but there were better relapse-free (P = 0.04) and overall (P = 0.004) survival with tamoxifen in estrogen receptor positive patients, while estrogen receptor negative patients had a somewhat poorer survival (P = 0.07) after tamoxifen. Local control was better (NS) after the combination (93%) radiotherapy and chemotherapy compared to either treatment alone (76% with radiotherapy and 74% with chemotherapy at 5 years).     

Cardiovascular effects of tamoxifen in women with and without heart disease: breast cancer prevention trial. National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial Investigators

BACKGROUND: The overall effect of prophylactic tamoxifen in women depends on the balance between the effects of the drug, which include preventing breast cancer and altering cardiovascular risk. In a recent clinical trial, postmenopausal estrogen-progestin therapy was shown to increase the risk of early cardiovascular events among women with a history of coronary heart disease (CHD). The cardiovascular effects of tamoxifen in women with and without CHD are not known. The National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial (BCPT) is the only clinical trial that provides data to assess the cardiovascular effects of tamoxifen in women with and without CHD. METHODS: A total of 13 388 women at increased risk for breast cancer were randomly assigned in the BCPT to receive either tamoxifen (20 mg/day) or placebo. Cardiovascular follow-up was available for 13 194 women, 1048 of whom had prior clinical CHD. Fatal and nonfatal myocardial infarction, unstable angina, and severe angina were tabulated (mean follow-up: 49 months). All statistical tests were two-sided. RESULTS: Cardiovascular event rates were not statistically significantly different between women assigned to receive tamoxifen and those assigned to receive placebo, independent of pre-existing CHD. Among women without CHD (6074 on tamoxifen versus 6072 on placebo), risk ratios (95% confidence intervals [CIs]) for tamoxifen users were 1.75 (0.44 to 8.13) for fatal myocardial infarction, 1.11 (0.55 to 2.28) for nonfatal myocardial infarction, 0.69 (0.29 to 1.57) for unstable angina, and 0.83 (0.32 to 2.10) for severe angina. In women with CHD (516 on tamoxifen versus 532 on placebo), risk ratios (95% CIs) for tamoxifen users were 0.00 (0 to 1.58) for fatal myocardial infarction, 1.25 (0.32 to 5.18) for nonfatal myocardial infarction, 2.26 (0.87 to 6.55) for unstable angina, and 1.39 (0.23 to 9.47) for severe angina. There was no evidence that the lack of association between tamoxifen and cardiovascular events was related to an early increase in risk that may have been offset by a late decrease in risk. CONCLUSION: When used for breast cancer prevention in women with or without heart disease, tamoxifen is not associated with beneficial or adverse cardiovascular effects.     

Burdens and benefits of adjuvant cyclophosphamide, methotrexate, and fluorouracil and tamoxifen for elderly patients with breast cancer: the International Breast Cancer Study Group Trial VII.

PURPOSE: Information on the tolerability and efficacy of adjuvant chemoendocrine therapy for older women is limited. We studied these issues using the data collected as part of the International Breast Cancer Study Group Trial VII. PATIENTS AND METHODS: Postmenopausal women with operable, node-positive breast cancer were randomized to receive either tamoxifen alone for 5 years (306 patients) or tamoxifen plus three consecutive cycles of classical cyclophosphamide (100 mg/m(2) orally days 1 to 14), methotrexate (40 mg/m(2) intravenous days 1 and 8), and fluorouracil (600 mg/m(2) intravenous days 1 and 8) every 28 days (CMF; 302 patients). The median follow-up was 8.0 years. RESULTS: Among the 299 patients who received at least one dose of CMF, women 65 years of age or older (n = 76) had higher grades of toxicity compared with women less than 65 years old (n = 223) (P =.004). More women in the older age group compared with the younger women experienced grade 3 toxicity of any type (17% v 7%, respectively), grade 3 hematologic toxicity (9% v 5%, respectively), and grade 3 mucosal toxicity (4% v 1%, respectively). Older patients also received less than their expected CMF dose compared with younger postmenopausal women (P =.0008). The subjective burdens of treatment, however, were similar for younger and older patients based on quality-of-life measures (performance status, coping, physical well-being, mood, and appetite). For older patients, the 5-year disease-free survival (DFS) rates were 63% for CMF plus tamoxifen and 61% for tamoxifen alone (hazards ratio [HR], 1.00; 95% confidence interval [CI], 0.65 to 1.52; P =.99). For younger patients, the corresponding 5-year DFS rates were 61% and 53% (HR, 0.70; 95% CI, 0.53 to 0.91; P =.008), but the test for heterogeneity of CMF effect according to age group was not statistically significant. The reduced effectiveness of CMF among older women could not be attributed to dose reductions according to dose received. CONCLUSION: CMF tolerability and effectiveness were both reduced for older patients compared with younger postmenopausal node-positive breast cancer patients who received tamoxifen for 5 years. The development and evaluation of less toxic and more effective chemotherapy regimens are required for high-risk elderly patients.     

The Christie Hospital adjuvant tamoxifen trial.

A clinical trial was carried out at The Christie Hospital, Manchester, England, between November 1976 and June 1982. Following surgery, patients with clinical stage T1-T3a, N1-N2b, M0 tumors were randomly allocated in the following way: premenopausal women to either tamoxifen 20 mg/day for 1 year or to an irradiation-induced menopause; postmenopausal women to either tamoxifen for 1 year or no further treatment (controls). In the node-negative subgroup, an analysis at a median follow-up of 10 years shows no statistically significant difference in overall or disease-free survival between tamoxifen-treated patients and irradiation-induced menopause and control patients. Side effects were few, and compliance was excellent. There was no significant increase of second primary tumors in target endocrine organs in the tamoxifen-treated patients. For the whole series of 961 patients, a log-rank analysis of events, allowing for node status, still shows a statistically significant benefit for tamoxifen-treated patients (P = .04).     

Radiotherapy and tamoxifen after mastectomy in postmenopausal women -- 20 year follow-up of the South Sweden Breast Cancer Group randomised trial SSBCG II:I

AimsTo evaluate long-term effects of radiotherapy and tamoxifen after mastectomy on recurrence and survival in stage II breast cancer.MethodsA randomised phase III study with three treatment alternatives. (1) Radiotherapy 50 Gy/25 fractions to chest wall and regional lymph nodes (RT). (2) Radiotherapy and tamoxifen 30 mg/day for one year (RT + tam) and 3. Tamoxifen (tam).Results724 postmenopausal women were included between 1978 and 1985 and the trial was close to population based. Follow-up for survival was 23 years. Locoregional recurrences were reduced from 18.5% in the tam arm to 5.3% in the RT + tam arm. Overall mortality at 20 years was 71% in the RT arm, 68% in the RT + tam arm and 62% in the tam arm. The difference between RT + tam and tam was not significant except in the receptor positive subgroup in favour of non-irradiated patients (p = 0.047). The cumulative incidence of systemic disease at 20 years was lower in the RT + Tam arm than in the RT arm, 40% versus 50% (p = 0.047).ConclusionPostmastectomy radiotherapy significantly reduced loco-regional recurrences, but overall survival was not improved. At 20 years, a lower mortality was recorded for non-irradiated patients treated with tam.     

Duration of adjuvant tamoxifen therapy.

The benefit of using adjuvant tamoxifen to treat breast cancer has been firmly established for patients with estrogen receptor (ER)-positive tumors, regardless of age, lymph node status, or menopausal status. Uncertainty remains, however, regarding the optimal duration of tamoxifen therapy. We reviewed the findings of randomized clinical trials that directly compared alternative treatment durations. Trials comparing short-term adjuvant treatment with tamoxifen (i.e., 1-3 years) with treatments having durations of about 5 years consistently have demonstrated additional benefits stemming from the longer therapy. Trials testing 5 years of treatment with longer durations have, in the aggregate, suggested no additional benefit for the patient. Nevertheless, the number of recurrences reported to date in these trials is not large, and the results of the individual trials are heterogeneous. Furthermore, as a result of tamoxifen's "carryover" effect, duration trials require considerable follow-up before definitive results can be established. Until more definitive data become available, adjuvant treatment with tamoxifen should be limited to 5 years outside the clinical trials setting. Continued accrual of ER-positive patients to ongoing tamoxifen duration trials, including the Adjuvant Tamoxifen Treatment Offer More (aTTom) and Adjuvant Tamoxifen Longer Against Shorter (ATLAS) trials, is appropriate. Alternatively, patients who remain disease free after 5 years of tamoxifen therapy should be encouraged to participate in trials testing crossover to other hormonal interventions, including selective ER modulators or aromatase inhibitors.     

Long-term effects of adjuvant chemotherapy in breast cancer.

Late effects of adjuvant chemotherapy (ACT) may include second malignant neoplasms (SMN), cardiotoxicity and ovarian suppression. Effects on the biology of residual tumour may be important in protocol design. Studies of SMN need large and reliable data sets. The leukaemia risk with current ACT is likely to be less than a five-fold increase. Leukaemia is predominantly a result of alkylating agents and peaks before 10 years. Solid SMN result also from radiotherapy and this risk continues after 10 years. Cardiotoxicity can be caused by anthracyclines but should not be a problem with current ACT regimens. It can be reduced by careful monitoring and by the cardioprotector ICRF-187. Amenorrhoea is a crude marker of ovarian suppression which may explain conflicting data on its relationship to outcome after ACT. Ovarian suppression following ACT is more likely and more permanent in older premenopausal women, but only explains a part of the ACT effects on outcome. Effects of early ACT on residual tumour are important for planning retreatments and combined modality protocols.     

Positive effect of tamoxifen as part of adjuvant chemo-endocrine therapy for breast cancer. Hokkaido Adjuvant Chemo-Endocrine Therapy for Breast Cancer Study Group.

A prospective randomised multicentre clinical study was undertaken for 2 years and 3 months from November 1982, with the aim of examining the significance of using a combination of ftorafur (FT) and tamoxifen (TAM) for post-operative adjuvant therapy of breast cancer. Patients had either stage II or stage IIIa disease, were age 75 or below and had undergone radical mastectomy. Patients were divided into two groups and received one of the following treatment protocols: treatment A, intravenous administration of doxorubicin (DOX), 20 mg on the day of surgery and 10 mg the next day, followed by oral FT 50 mg day-1 for 2 years from the 14th day; treatment B, the same pattern of DOX administration for the first 2 days, followed by a combined therapy of FT and TAM 20 mg day-1 for 2 years. The number of patients was 546 (treatment A 274 and treatment B 272), of whom 34 (6%) were ineligible. The remaining 512 patients (treatment A 254 and treatment B 258) were followed up for 5 years for analysis. Significantly higher 5 year disease-free rate and 5 year survival rates were observed with treatment B compared with treatment A. When seen in terms of background factors, node-positive patients appeared to derive more benefit from tamoxifen than node-negative patients, but the oestrogen receptor-negative and premenopausal subgroups appeared to derive about the same benefit as those who were oestrogen receptor positive and post-menopausal. Indeed, survival in the premenopausal group was significantly better with tamoxifen (P = 0.04). No increase in side-effects was seen by combining TAM with FT. The study results demonstrate that concomitant administration of FT and TAM is better than FT alone for post-operative adjuvant therapy for breast cancer.