Estrogen-receptor-directed neoadjuvant therapy for breast cancer: results of a randomised trial using formestane and methotrexate, mitozantrone and mitomycin C (MMM) chemotherapy. Randomized adjuvant trial of tamoxifen and goserelin versus cyclophosphamide, methotrexate, and fluorouracil: evidence for the superiority of treatment with endocrine blockade in premenopausal patients with hormone-responsive breast cancer--Austrian Breast and Colorectal Cancer Study Group Trial 5. [A randomized trial of endocrine therapy, chemotherapy, and chemo-endocrine therapy in advanced breast cancer]. Efficacy of sequential cyclical hormonal therapy in endometrial cancer and its correlation with steroid hormone receptor status. Megestrol acetate and aminoglutethimide/hydrocortisone in sequence or in combination as second-line endocrine therapy of estrogen receptor-positive metastatic breast cancer: a Southwest Oncology Group phase III trial. [Management of advanced breast cancer in post-menopausal women. A comparative trial of hormonal therapy, chemotherapy, and a combination of both]. Trial of aminoglutethimide vs hydrocortisone as second-line hormone treatment of advanced breast cancer. A reduction in the requirements for mastectomy in a randomized trial of neoadjuvant chemoendocrine therapy in primary breast cancer. Prospective randomized study of aminoglutethimide (AG) versus medroxyprogesterone acetate (MPA) versus AG+MPA in generalized breast cancer.
We wanted to determine whether neoadjuvant systemic chemoendocrine therapy guided by the estrogen receptor (ER) status of the primary breast cancer, followed by conventional surgery and/or radiotherapy, reduces local and distant recurrence and improves survival compared with adjuvant treatment given conventionally postoperatively.
                Two hundred ten patients with primary breast cancer (T1-T4, N0, N1-2) were randomised to receive treatment with neoadjuvant chemoendocrine therapy or conventional post-operative chemoendocrine therapy. Systemic therapy was based on the estrogen receptor (ER) status of the primary tumour obtained by trucut core biopsy. ER-negative patients received MMM chemotherapy (methotrexate (30 mg/m2), mitozantrone (7 mg/m2) and mitomycin (7 mg/m2) three-weekly for three months and ER-positive patients who were premenopausal received goserelin (3.75 mg monthly), and post menopausal women formestane (250 mg every two weeks) over three months.
                With a minimum of five years follow-up, there is no evidence of any survival benefit from the pretreatment neoadjuvant therapy regimen, with five year overall survival being 79% +/- 4.7% (neoadjuvant) and 87% +/- 3.4% (adjuvant). Similarly, there was no apparent benefit in terms of disease-free survival. There was, however, a significant reduction in the incidence of distant metastases in responders (4 of 51; 8%) compared with non-responders (17 of 49; 35%) (P < 0.01). There was a reduction in the need for surgery in responding patients with T1 and T2 tumours, since 10 of 74 (14%) had no detectable residual tumour, without any apparent increase in the risk of local or distant recurrence.
                In this study neoadjuvant treatment with endocrine or chemotherapy provided no obvious survival benefit to women with breast cancer. However, it does allow avoidance of surgery in some cases. Also, the patients whose tumours respond to neoadjuvant systemic therapy have a lower incidence of distant metastases after five year follow-up compared to those whose tumours fail to respond. Effective adjuvant treatment modalities in premenopausal breast cancer patients today include chemotherapy, ovariectomy, and tamoxifen administration. The purpose of Austrian Breast and Colorectal Cancer Study Group Trial 5 was to compare the efficacy of a combination endocrine treatment with standard chemotherapy.
                Assessable trial subjects (N = 1,034) presenting with hormone-responsive disease were randomized to receive either 3 years of goserelin plus 5 years of tamoxifen or six cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF). Stratification criteria included tumor stage and grade, number of involved nodes, type of surgery, and steroid hormone receptor content. Relapse-free survival (RFS) was defined as time from randomization to first relapse, local recurrence, or contralateral incidence, and overall survival (OS) as time to date of death.
                With a 60-month median follow-up, 17.2% of patients in the endocrine group and 20.8% undergoing chemotherapy developed relapses. Local recurrences emerged in 4.7% and 8.0%, respectively. RFS and local recurrence-free survival differed significantly in favor of endocrine therapy (P =.037 and P =.015), with a similar trend observed in OS (P =.195).
                Overall, our data suggest that the goserelin-tamoxifen combination is significantly more effective than CMF in the adjuvant treatment of premenopausal patients with stage I and II breast cancer. A randomized trial of endocrine therapy (adreno-oophorectomy, H), chemotherapy (FAC, C), chemoendocrine therapy (FAC + tamoxifen, H'C, or FAC + adreno-oophorectomy, HC) was performed in 114 advanced breast cancer patients from September, 1979 to December, 1983, and 106 were evaluable. The response to H, C, H'C, and HC was shown to be 33% (10/30), 54% (14/26), 59% (17/29), and 76% (16/21), respectively. There was a significantly higher response rate in HC group than H group. Higher but not significantly different response was obtained by H'C as compared with H. There were no significant differences in the overall survival among the treatment arms. However, patients treated with H survived longer (greater than 5 years). These results suggest that higher response obtained by chemotherapy, alone or in combination with endocrine therapy does not seem to contribute to the prolongation of survival of the patients. Forty-six eligible women with metastatic endometrial cancer were randomly allocated to receive monthly cycles of either CAF (cyclophosphamide, adriamycin, 5-fluorouracil) or CAF plus Provera 200 mg daily for 3 weeks followed cyclically by Tamoxifen 20 mg daily for 3 weeks. Overall response rates of 15 and 43% were seen with CAF and CAF plus hormonal therapy. Using a multivariate analysis of the results, this difference is significant (P value 0.05). In 8 patients with operable endometrial cancer, negative estrogen receptor concentration (ER less than 15 fmole/mg protein) and Grade 3 disease, the clinical course was aggressive in 4 patients with systemic and local relapse. In 10 other similar patients (negative ER and Grade 3) who received adjuvant cyclical hormonal therapy only 1 relapsed and the other 9 are disease-free for an average of more than 31 months. Sequential cyclical hormonal therapy with ER and progesterone receptor analysis has a place in the management of endometrial carcinoma. A phase III randomized trial was performed to determine whether combination hormonal therapy with aminoglutethimide (AG) and hydrocortisone (HC) plus megestrol acetate (MA) improved response rates, response duration, or increased survival over the sequential use of each hormone in women with estrogen receptor-positive metastatic breast cancer (MBC) who had maintained stable disease for at least 6 months or responded to tamoxifen.
                Two hundred eighty-eight postmenopausal women with progressive estrogen receptor-positive MBC were randomly selected to receive MA 40 mg four times daily (arm I), AG 250 mg four times daily with HC 40 mg daily in divided doses (arm II), versus the combination of MA plus AG given at the same dosages (arm III). Patients on arms I and II who progressed after an adequate trial were crossed over to the other treatment arm.
                Two hundred thirty-five eligible patients were evaluated for response, time to treatment failure, and survival. Response was only reported for patients with measurable disease and was not statistically different among the three arms. There were two partial responses (PRs) on MA (6%), four complete responses (CRs) and six PRs on AG (24%), and eight PRs and three CRs on MA plus AG (23%) in 32, 42, and 48 measurable patients, respectively. Median times to treatment failure were also similar at 5, 4, and 7 months. Survival was also not statistically different among the three arms at 26, 27, and 26 months for arms I, II, and III, respectively. Toxicity was greater in the two AG arms with respect to fatigue, nausea and vomiting, and rash.
                With the exception of toxicity, there is no response, time to treatment failure, or survival benefit for any one group when comparing MA, AG, or the combination at their stated doses in women with estrogen receptor-positive MBC who had previously responded to or stabilized with tamoxifen. A randomized trial was done in 98 post-menopausal women with breast cancer. Hormonal receptors had not been assayed in any patient. Patients were given hormonal therapy with tamoxifen and drostanolone propionate (n = 34), or chemotherapy with the CMF protocol (n = 30), or a combination of both (n = 34). The results are in favour of hormonal therapy alone, which gave the best immediate objective responses, the least adverse side-effects, and possibly improved survival rates. In a randomized trial of second line hormone therapy 56 postmenopausal women with advanced breast cancer received low dose aminoglutethimide (AGT) 125 mg twice daily without hydrocortisone (27 patients), or hydrocortisone (HC) 20 mg twice daily (29 patients). The two groups were well-matched for previous response to tamoxifen (TAM) therapy (AGT (35%) vs HC (32%)) and for relapse on adjuvant TAM. The mean age of the two groups was 69.2 years (AGT) and 63.2 years (HC). Liver metastases were present in 29% (AGT) and 33% (HC). The response rates were 11% (AGT) and 21% (HC). At 12 months the failure of treatment rate was 80% (AGT) and 70% (HC). Survival at 12 months was 50% for both groups. At 12 months 5/12 survivors were still on AGT and 8/12 on HC. These preliminary findings have so far failed to show any statistical difference in tumour response, time to treatment failure or survival between low-dose AGT and HC as second-line hormone treatment post-tamoxifen in advanced breast cancer. A prospective randomised trial was undertaken to evaluate the role of neoadjuvant chemoendocrine therapy prior to surgery in primary operable breast cancer.
                Three hundred nine women (median age 56 years, range 27-70) with primary operable breast cancer confirmed on fine needle aspiration (FNA) cytology were recruited to this study. They were treated with a combination of mitozantrone and methotrexate (+/- mitomycin-C) combined with tamoxifen (2MT). Patients received eight cycles of 2MT (four prior to surgery in the neoadjuvant group) and tamoxifen for five years with appropriate surgery and radiotherapy. The two groups were comparable for age, menopausal status, stage and surgical requirements.
                The clinical response rates to neoadjuvant therapy were as follows: 22% complete response (CR), 29% minimal residual disease (MRD), 33% partial response (PR), 15% no change (NC) and only two patients had clinical evidence of progressive disease. Surgical requirements were reduced from 31 patients (22%) of the adjuvant group having mastectomy to 14 (10%) in the neoadjuvant group (P < 0.003). At a median follow-up of 48 months (range 10-70 months) there is no statistically significant difference between the two groups in terms of local relapse, metastatic relapse or overall survival. Symptomatic and haematologic acute toxicity was low and similar for adjuvant and neoadjuvant therapy.
                This randomised trial has shown a significant reduction in the surgical requirements for mastectomy, after treatment with neoadjuvant chemoendocrine therapy, with no deterioration in local or distal relapse. Eighty-five postmenopausal women with metastatic breast cancer were randomized to receive aminoglutethimide (AG), medroxyprogesterone acetate (MPA), or AG+MPA. Patients with aggressive visceral disease were excluded. Response was observed in 36% of the patients in the AG treatment group, 31% in the MPA treatment group, and 47% in the combination treatment group. Statistical analysis showed that the percentage of responders was not different among the three treatment groups. Similarly, the duration of response did not differ. Toxicity of all three regimens was moderate, not necessitating discontinuation of treatment. In conclusion, AG, MPA and the combination of AG+MPA were found to be equally effective therapies for metastatic breast cancer in postmenopausal women with nonaggressive visceral disease. The lack of statistically significant superiority of the combination of AG+MPA suggests that sequential endocrine monotherapies may be more beneficial than combined hormonotherapies for this patient population.
In women with metastatic breast cancer and where hormone receptors are present, a policy of treating first with endocrine therapy rather than chemotherapy is recommended except in the presence of rapidly progressive disease.