Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial.

BACKGROUND: Postmastectomy radiotherapy is associated with a lower locoregional recurrence rate and improved disease-free and overall survival when combined with chemotherapy in premenopausal high-risk breast-cancer patients. However, whether the same benefits apply also in postmenopausal women treated with adjuvant tamoxifen for similar high-risk cancer is unclear. In a randomised trial among postmenopausal women who had undergone mastectomy, we compared adjuvant tamoxifen alone with tamoxifen plus postoperative radiotherapy. METHODS: Between 1982 and 1990, postmenopausal women with high-risk breast cancer (stage II or III) were randomly assigned adjuvant tamoxifen (30 mg daily for 1 year) alone (689) or with postoperative radiotherapy to the chest wall and regional lymph nodes (686). Median follow-up was 123 months. The endpoints were first site of recurrence (locoregional recurrence, distant metastases, or both), and disease-free and overall survival. FINDINGS: Locoregional recurrence occurred in 52 (8%) of the radiotherapy plus tamoxifen group and 242 (35%) of the tamoxifen only group (p<0.001). In total there were 321 (47%) and 411 (60%) recurrences, respectively. Disease-free survival was 36% in the radiotherapy plus tamoxifen group and 24% in the tamoxifen alone group (p<0.001). Overall survival was also higher in the radiotherapy group (385 vs 434 deaths; survival 45 vs 36% at 10 years, p=0.03). INTERPRETATION: Postoperative radiotherapy decreased the risk of locoregional recurrence and was associated with improved survival in high-risk postmenopausal breast-cancer patients after mastectomy and limited axillary dissection, with 1 year of adjuvant tamoxifen treatment. Improved survival in high-risk breast cancer can best be achieved by a strategy of both locoregional and systemic tumour control.

Randomized trial of single dose versus fractionated palliative radiotherapy of bone metastases.

PURPOSE: Data in the literature suggest that for painful bone metastases a single dose is as effective as fractionated radiotherapy. In the present multicentre prospective trial, the effects of 8 Gy x1 and 5 Gy x4 were compared. PATIENTS AND METHODS: A total of 241 patients were randomized to 8 Gy (122 patients) or 20 Gy (119 patients). The primary tumour was in the breast in 39% of patients, in the prostate in 34% of patients, in the lung in 13% of patients and in other locations in 14% of patients. Outcome measures were pain relief as measured by VAS and in half of the patients also by a five-point categorical pain scale, global quality of life (QoL) and analgesic consumption. Evaluation was performed before and 4, 8, 12 and 20 weeks after treatment. RESULTS: A total of 239 patients were evaluable for response. The two groups did not differ with respect to age, sex, primary tumour, metastasis localization, analgesic consumption (type and dose), performance status, prior systemic treatment, degree of pain and QoL. The treatment was completed as planned in 98% of patients. The degree of pain relief did not differ between the two treatment groups. At 4 weeks the difference in pain relief was 6% (95% CI 7, 20%) and at 8 weeks the difference was 13% (95% CI 3, 28%). Neither was there any significant difference in the duration of pain relief, the number of new painful sites and the need for reirradiation and toxicity was minor. CONCLUSION: The present randomized study showed that a single fraction of 8 Gy was as effective as 5 Gy x4 in relieving pain from bone metastasis.

Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial.

BACKGROUND: Irradiation after mastectomy can reduce locoregional recurrences in women with breast cancer, but whether it prolongs survival remains controversial. We conducted a randomized trial of radiotherapy after mastectomy in high-risk premenopausal women, all of whom also received adjuvant systemic chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF). METHODS: A total of 1708 women who had undergone mastectomy for pathological stage II or III breast cancer were randomly assigned to receive eight cycles of CMF plus irradiation of the chest wall and regional lymph nodes (852 women) or nine cycles of CMF alone (856 women). The median length of follow-up was 114 months. The end points were locoregional recurrence, distant metastases, disease-free survival, and overall survival. RESULTS: The frequency of locoregional recurrence alone or with distant metastases was 9 percent among the women who received radiotherapy plus CMF and 32 percent among those who received CMF alone (P<0.001). The probability of survival free of disease after 10 years was 48 percent among the women assigned to radiotherapy plus CMF and 34 percent among those treated only with CMF (P<0.001). Overall survival at 10 years was 54 percent among those given radiotherapy and CMF and 45 percent among those who received CMF alone (P<0.001). Multivariate analysis demonstrated that irradiation after mastectomy significantly improved disease-free survival and overall survival, irrespective of tumor size, the number of positive nodes, or the histopathological grade. CONCLUSIONS: The addition of postoperative irradiation to mastectomy and adjuvant chemotherapy reduces locoregional recurrences and prolongs survival in high-risk premenopausal women with breast cancer.

A phase 2 study with epirubicin as second-line treatment of patients with advanced epithelial ovarian cancer.

Thirty-six patients with advanced epithelial ovarian cancer received epirubicin as second-line therapy after primary treatment with carboplatin and cyclophosphamide. Thirty-four patients were evaluatable for response, 36 for toxicity. There were 9 responses (response rate 26.4%, 95% CI = 12.9-44.4), 2 complete and 7 partial. Median duration of response was 149 days (range 42-183); 4 patients with partial remission are still on study. Toxicity consisted of fatal cardiac failure and paravenous injection (1 patient), fatal leukopenia and sepsis (1 patient), and severe loss of appetite, nausea and vomiting, fatigue, and general malaise in 3 patients. Platelet nadir grade 4 (WHO) was observed in 2 patients while leukocyte nadir grade 4 was seen in 3 patients. The present study showed a high response rate from standard-dose epirubicin. Toxicity was acceptable in most patients, but 2 patients died from treatment complications which gives a treatment-related mortality rate of 6%. Response was primarily seen in patients with minor tumor load and in good general condition.

A randomized feasibility study evaluating the effect of radiotherapy alone or combined with 5-fluorouracil in the treatment of locally recurrent or inoperable colorectal carcinoma.

The effect of radiotherapy alone or given simultaneously with 5-FU in the treatment of locally recurrent or inoperable colorectal carcinoma was investigated in a randomized feasibility trial. Twenty-nine patients were randomized to radiotherapy alone (50 Gy/5 weeks + 10-20 Gy boost), and 30 patients to the same radiotherapy with weekly 5-FU (600 mg/m2) given before treatment every Monday during the first 5 weeks. The two groups were comparable with regard to age, sex, previous treatment, symptoms, tumour size and performance status. Treatment compliance to radiotherapy was the same in both groups with 87% receiving at least 50 Gy. Drug treatment was completed in 18/30 patients. Overall the treatment resulted in a significant palliative effect in 73% of evaluable patients with a median duration of 26 months, and objective response in 32% (8 CR, 11 PR), with a median duration of 18 months. The 3-year actuarial survival rate was 9% (median 12 months). Only patients who achieved CR became long-time survivors (63% 3-year actuarial survival). Similarly, performance status had a strong association with survival. Multivariate analysis showed complete response and high performance status to be the only parameters having prognostic influence on survival. Addition of 5-FU did neither influence the objective or symptomatic response, nor the development of distant metastases. However, addition of the drug resulted in an apparent increase in the frequency of severe acute radiation complications (33% vs. 13% after irradiation alone).

Weekly oral idarubicin in advanced prostatic cancer. A phase II study.

Twenty-five patients with advanced prostatic cancer progressing after one course of endocrine treatment entered a phase II study of weekly administration of 30 mg Idarubicin orally. Twenty-two patients were evaluable for response and partial response (PR) was noted in 2 patients and stable disease (NC) in 10 patients. Median survival was 31 weeks and median time to progression was 14 weeks. Twenty-three patients were eligible in a score system combining analgetic consumption and pain reduction measured on a Visual Analogue Scale (VAS) and 30% achieved a subjective response. Fifteen patients fulfilled treatment with the planned dose and 10 patients had dose reduction to a median of 23.8 mg Idarubicin. Haematological toxicity was greater than or equal to grade 3 (WHO) in 20% of the patients. Non-haematological toxicity was dominated by nausea/vomiting with 48% grade 3 (WHO). In conclusion, Idarubicin seems of limited value in the treatment of patients refractory to first line endocrine treatment.

Primary radiotherapy of T1 squamous cell carcinoma of the larynx: analysis of 478 patients treated from 1963 to 1985.

Radiotherapy was administered to 478 consecutively treated patients with laryngeal T1 squamous cell carcinoma between 1963-1985. One hundred and seventeen had a supraglottic, 358 a glottic, and 3 a subglottic tumor. Supraglottis: 71% males; 49% T1a; 14 patients with nodes. Glottis: 90% males; 82% T1a; 1 patient with node. The 10-year value for local control in the supraglottic group was 55% and in the glottic group 81%. No difference was observed between T1a and T1b. Regional nodes and distant metastases were seldom seen in the glottic, but frequently observed in the supraglottic group. The treatment results appeared to be most favorable in women. The 10-year corrected survival for supraglottic and glottic tumors demonstrated a highly significant difference, 67% compared to 94%. There was a significantly increasing incidence of events with lower tumor differentiation. Split-course and conventional radiotherapy gave equal treatment results, but late complications were significantly more common with the former. A major problem was new primary cancers, which within 20 years occurred in 34% of patients surviving a supraglottic tumor and in 23% of the glottic patients. The predominant new site was the lung (23% and 13%, respectively). Thus, in the glottic group more patients died from the new cancer than from the glottic carcinoma.

Weekly oral idarubicin in postmenopausal women with advanced breast cancer. A phase II study.

Sixty postmenopausal women with advanced breast cancer entered a phase II study, evaluating idarubicin (IDA) in a weekly schedule. Starting dose was 22.5 mg/m2, and median age was 65 years. Five patients were considered ineligible and the response rate among 55 eligible patients was 33%. Median time to treatment failure was 19 weeks and median duration of tumor regression for 18 responding patients was 40 weeks. Hematologic toxicity was moderate and non-hematologic toxicity was mild. The study shows that IDA, administered orally in a weekly schedule, has pharmacodynamic properties comparable to IDA in a 3-weekly schedule and to doxorubicin in the treatment of advanced breast cancer.

Oral idarubicin in the treatment of advanced breast cancer.

Idarubicin (IDA), a more lipophilic derivative of daunorubicin, has shown activity after oral administration. In November 1983 we initiated a phase II study administering IDA, 45 mg/m2, in a 3 weekly schedule as first line chemotherapy to postmenopausal women with advanced breast cancer. Among 50 eligible patients a response rate of 36% (95% confidence interval (CI): 23-51) was obtained. Median time to treatment failure was 22 weeks (95% CI: 15-32). In November 1986, a sequential phase II study with IDA given in a weekly schedule was initiated. Patient characteristics was comparable to the first study. Among 53 evaluable patients, the response rate was 34% (95% CI: 22-48), and median time to treatment failure was 19 weeks (95% CI: 13-33). Therapeutic efficacy in the two studies was comparable and similar to published data on doxorubicin. Hematologic toxicity was equal while non-hematologic toxicity was considerably lower in the weekly schedule. A phase III comparison of IDA to doxorubicin or epi-doxorubicin is warranted, in order to clarify the role of IDA in the treatment of advanced breast cancer.

Bone mineral content and estrogen receptors in women with breast tumors.

The investigation was carried out to elucidate a possible relationship between the amount of estrogen receptors and bone mineral content in patients with breast tumors. Bone mineral content (BMC) was measured by photon absorptiometry in the distal forearm of 54 women with untreated breast carcinoma and 19 with benign breast tumor. The concentration of unoccupied high affinity estrogen receptors was measured in breast tumor biopsy specimens. Higher values of BMC were found in the total group of estrogen receptor-positive patients with breast carcinoma compared with estrogen receptor-negative patients, but not after dividing the patients into smaller groups according to age. No significant correlation could be seen between the amount of estrogen receptors and bone mineral content. In conclusion the present study could not support a relationship between the amount of estrogen receptors in breast cancer tissue and the amount of bone mineral and bone mass in women with breast tumors.

Malignant tumours of the paranasal sinuses and nasal cavity. A series of 180 patients.

In a series of 180 malignant tumours in the paranasal sinuses and nasal cavity the largest groups comprised 90 epidermoid carcinomas, 25 adenocarcinomas, and 19 adenocystic carcinomas. The epidermoid carcinomas were classified according to various proposed methods. The planned treatment schedule for carcinoma was 57 to 60 Gy in 30 fractions over 42 days, followed 8 to 12 weeks later by radical surgery. In the group of 80 patients with epidermoid carcinomas treated with radical intention, the 5-year corrected survival was 42 per cent. The prognosis has been analysed against a number of parameters, and it is found that sex, tumour size, and histologic score are important but neither totally independent nor evenly distributed parameters.

Serum calcitonin in patients with osteolytic and osteosclerotic metastases from mammary carcinoma.

Serum concentrations of calcitonin, calcium, phosphorus and alkaline phosphatase were measured in 19 patients with osteolytic metastases and in 8 patients with osteosclerotic metastases from mammary carcinoma. A significantly higher mean S-iCT concentration was found in patients with osteolytic metastases as compared with those with osteosclerotic. No significant difference was found in S-calcium, S-phosphorus or S-alkaline phosphatase between the two groups.