Locoregional failure 10 years after mastectomy and adjuvant chemotherapy with or without tamoxifen without irradiation: experience of the Eastern Cooperative Oncology Group.

PURPOSE: To assess patterns of failure and how selected prognostic and treatment factors affect the risks of locoregional failure (LRF) after mastectomy in breast cancer patients with histologically involved axillary nodes treated with chemotherapy with or without tamoxifen without irradiation. PATIENTS AND METHODS: The study population consisted of 2,016 patients entered onto four randomized trials conducted by the Eastern Cooperative Oncology Group. The median follow-up time for patients without recurrence was 12.1 years (range, 0.07 to 19.1 years). RESULTS: A total of 1,099 patients (55%) experienced disease recurrence. The first sites of failure were as follows: isolated LRF, 254 (13%); LRF with simultaneous distant failure (DF), 166 (8%); and distant only, 679 (34%). The risk of LRF with or without simultaneous DF at 10 years was 12.9% in patients with one to three positive nodes and 28.7% for patients with four or more positive nodes. Multivariate analysis showed that increasing tumor size, increasing numbers of involved nodes, negative estrogen receptor protein status, and decreasing number of nodes examined were significant for increasing the rate of LRF with or without simultaneous DF. CONCLUSION: LRF after mastectomy is a substantial clinical problem, despite the use of chemotherapy with or without tamoxifen. Prospective randomized trials will be necessary to estimate accurately the potential disease-free and overall survival benefits of postmastectomy radiotherapy for patients in particular prognostic subgroups treated with presently used and future systemic therapy regimens.

Prognostic factors in metastatic malignant melanoma. An analysis of 236 patients treated on clinical research studies at the Department of Medical Oncology, University of Pretoria, South Africa from 1972-1992.

Prognostic factors in 236 patients with metastatic malignant melanoma were analyzed. The patients were all entered on clinical research studies at a single institution. Univariate and multivariate analyses were performed on data which was prospectively collected. Seven independent variables were analyzed for effect on response, time to treatment failure (TTF) and survival. Univariate analysis identified four factors which significantly effected response, TTF and survival: PS, dominant site of disease, number of sites of disease and treatment. In multivariate analyses dominant site of disease and treatment remained significant factors influencing response rates, but performance status (PS) and number of sites of metastases lost statistical significance. Treatment and number of sites were significant for TTF and treatment, PS and disease-free interval were significant for survival. The identification of prognostic factors may lead to identification of subgroups of patients who may benefit from existing treatment programs, and may allow for new treatment programs to be designed with greater insight, logic and rationale.

Postchemotherapy adjuvant tamoxifen therapy beyond five years in patients with lymph node-positive breast cancer. Eastern Cooperative Oncology Group.

BACKGROUND: Data from a pilot study published in 1984 suggested that tamoxifen administration (as adjuvant hormonal therapy) for more than 5 years after initial breast cancer surgery might have therapeutic benefit. PURPOSE: A randomized trial was performed to assess the efficacy of maintaining tamoxifen therapy beyond 5 years in women with axillary lymph node-positive breast cancer who had been treated with surgery followed by 1 year of chemotherapy and 5 years of tamoxifen. METHODS: One hundred ninety-four women (87 postmenopausal and 107 premenopasual) enrolled in two concurrent Eastern Cooperative Oncology Group adjuvant trials (E4181 for postmenopausal patients and E5181 for premenopausal patients) were randomly assigned to continued tamoxifen therapy or observation. Data for 193 women (87 postmenopausal and 106 premenopausal) were available for analysis. Median follow-up is 5.6 years since the randomization at 5 years, with the longest follow-up being 8.0 years. The major analyses measured events from the time of randomization until relapse or death; these included time-to-relapse analyses, with new opposite-breast cancers counted as treatment failures, and survival analyses. Time-to-relapse comparisons and survival comparisons for women in the two treatment groups were made by use of the Kaplan-Meier method and the logrank test. Reported P values are two-sided. RESULTS: Five years after the randomization, no statistically significant differences were noted in either time to relapse or survival between women continuing to receive tamoxifen and those on observation. Eight-five percent of the women receiving tamoxifen were disease free at this time compared with 73% of those on observation (P = .10); survival was 86% for those continuing to receive tamoxifen and 89% for those on observation (P = .52). Differences in the time to relapse and survival between premenopausal and postmenopausal women assigned to the two treatment groups were also not statistically significant (time to relapse: P = .38 and P = .16 for premenopausal and postmenopausal patients, respectively; survival; P = .18 and P = .72 for premenopausal and postmenopausal patients, respectively). There was an indication that women with estrogen receptor-positive tumors may experience a longer time to relapse with continued tamoxifen therapy (P = .014); however, the survival difference for this subgroup was not statistically significant (P = .81). The toxicity patterns in the two treatment groups were similar. CONCLUSIONS AND IMPLICATIONS: Our results suggest that further evaluation of adjuvant tamoxifen therapy beyond 5 years in women with axillary lymph node-positive, estrogen receptor-positive breast cancer who have also been treated with adjuvant chemotherapy would be appropriate.

A randomised study of CGS 16949A (fadrozole) versus tamoxifen in previously untreated postmenopausal patients with metastatic breast cancer.

BACKGROUND: Fadrozole, a potent, highly specific inhibitor of aromatase activity, has only been used as second-line therapy in treatment of post-menopausal women with advanced breast cancer. A prospectively randomised study was therefore undertaken to compare relative clinical efficacy of fadrozole as first-line treatment to that of tamoxifen. PATIENTS AND METHODS: Eighty postmenopausal women who had not received prior treatment for advanced/metastatic breast cancer were randomised to receive either fadrozole, 1 mg twice daily, or tamoxifen, 20 mg daily. RESULTS: Toxicity was not statistically different on the two treatment arms. Only mild to moderate toxicity was documented: hot flashes in 37%, headaches in 6.5%, mild fatigue in 2.6%. There were also no statistically significant differences in objective response rates, survival or time to treatment failure (TTF). Objective response rate on fadrozole was 50% (complete response (CR) 8.3% and partial response (PR) 42%). On tamoxifen objective response was 44.7% (CR 21% and PR 24%). Median TTF was 4.9 months on fadrozole and 5 months on tamoxifen. Median survival was 22.7 months on fadrozole and 27.5 months on tamoxifen. CONCLUSION: While response rates, survival and TTF were not statistically significantly different, there were more complete responses on tamoxifen and duration of objective response (CR + PR) was significantly longer in the patients treated with tamoxifen.

Cisplatin versus cisplatin plus D-Trp-6-LHRH in the treatment of ovarian cancer: a pilot trial to investigate the effect of the addition of a GnRH analogue to cisplatin.

Thirty-four patients with histologically confirmed ovarian cancer were entered into a pilot study. Patients were randomized to receive cisplatin alone or cisplatin plus D-Trp-6-LHRH(decapeptyl). Objective response (complete and partial response) was documented in 9 of 14 patients on cisplatin and in 12 of 18 patients on cisplatin plus decapeptyl. Median time to treatment failure and median survival times were the same in the two treatment regimens. Toxicities were similar in the two treatment arms, except for hot flashes which only occurred in patients on cisplatin plus decapeptyl.

Antiemetic efficacy of tropisetron in patients failing previous antiemetic therapy.

Tropisetron was studied for efficacy and safety in 164 patients who were refractory to other antiemetic agents. 5 mg tropisetron was given intravenously, followed by 5 mg by mouth per day for 4 days. Complete prevention of nausea and vomiting was documented in 42% of patients on day 1 of cycle 1. Delayed nausea and vomiting were prevented in 41% in the first cycle. The antiemetic control did not decrease with subsequent cycles. Side effects ascribed to tropisetron were mild.

FIVB plus GM-CSF in metastatic colorectal cancer.

The response rate of patients with metastatic colorectal cancer to the 4-drug combination [5-Fluorouracil (5-FU), dacarbazine, vincristine and bis-chloronitrosourea given 5 weekly (FIVB)] was better than the response rate to 5-FU. The dose limiting toxicity of the FIVB was myelosuppression. The present study investigates the effect of FIVB given with GM-CSF so that drug cycles could be given every 4 weeks. Thirty-five ambulatory patients with measurable metastatic colorectal cancer were treated with FIVB plus GM-CSF 4 weekly. All patients were evaluable for toxicity. Among the 163 cycles given only 4 were delayed because of leucopenia and 8 cycles were delayed because of gastrointestinal (GI) toxicity. A 50% dose reduction was given to 10 patients who had Grade 2 and 3 GI toxicity. Four of the 35 patients developed thromboembolic complications, 2 of which were lethal. Two patients were not evaluable for response as they were removed from study early because of toxicity. There were 2 complete responses and 6 partial responses. The median time to treatment failure was 3.8 months and median survival time 9.9 months. The addition of GM-CSF to FIVB decreased the expected leucopenia allowing drug treatment to be given 4 weekly to most patients. GI toxicity was dose limiting. Despite the increased dose intensity that could be delivered (to two thirds of patients), response rates were not definitely increased, no survival benefit was seen and important thromboembolic complications occurred.

Phase II trial of fotemustine in patients with metastatic malignant melanoma.

Fotemustine is a novel chloroethylnitrosourea, that readily penetrates the blood brain barrier. Preliminary French studies reported encouraging results with fotemustine in patients with cerebral metastases of malignant melanoma. Thirty-one patients with histologically confirmed metastatic malignant melanoma were entered on a phase II trial. The treatment regimen consisted of fotemustine, administered intravenously as a rapid infusion, at a dose of 100 mg/m2 on day 1, 8 and 15 every 4 to 5 weeks. Objective response (CR + PR) was documented in 3 patients. Median time to treatment failure (TTF) was 44 days and median survival was 164 days. Life threatening toxicity did not occur; hematological toxicity and nausea and vomiting were the most common toxicities. Despite a somewhat disappointing response rate, objective responses were documented in patients with cerebral metastases. Since no other chemotherapeutic agent has shown therapeutic efficacy in cerebral metastases from malignant melanoma fotemustine therefore warrants further study.

Postmenopausal breast cancer. Drug therapy in the 1990s.

In summarising current drug treatment strategies for postmenopausal women with breast cancer, it is essential to emphasise that we are dealing with a group of diseases that are treatable, and that appropriate treatment decisions will give longer disease-free intervals for patients with early breast cancer, and better control with better survival for patients with advanced (i.e. locally advanced and/or metastatic) disease. Women greater than 65 years of age have a predictably better response to hormone treatment versus women less than 65 years of age. Hormone treatment may, therefore, be considered as primary treatment or as adjuvant treatment after limited surgery. Hormone treatment is also the treatment of first choice for elderly patients with advanced disease. For middle-aged women (45 to 65 years of age), various patient factors are important in predicting the value of treatment. Estrogen receptor (ER) status is prognostic of survival irrespective of treatment. Patients with ER-positive disease have a better prognosis than those with ER-negative disease, both in the adjuvant setting and in the face of metastatic disease. This is because ER-positive tumours tend to grow slower. The availability of the serotonin type 3 (5-hydroxytryptamine;5-HT3) antagonists, which effectively control nausea and vomiting in most patients, make chemotherapy combinations more acceptable, and combination chemotherapy can more readily be considered as first treatment option both as adjuvant treatment and for treatment of advanced disease. For patients with organ metastases there is no doubt that combined chemotherapy treatment is indicated.

A randomized trial of mitomycin-C (M) versus mitomycin-C plus high-dose medroxyprogesterone acetate (MMPA) in the treatment of patients with advanced breast cancer.

Seventy-six women with previously treated breast cancer were randomized to receive mitomycin (M) or M plus high-dose oral medroxyprogesterone acetate (MMPA). Patients were balanced with respect to age, performance status, hormone receptor status, previous treatment, and number of metastatic sites. There were more patients with visceral metastases in the M arm of the study. Side effects were tolerable and not significantly different for the two regimens. No life-threatening toxicity occurred. Objective response was documented in 4 of 37 patients on M and 11 of 39 on MMPA. On M the median time to treatment failure (TTF) was 3 months, and median survival was 7.8 months. On MMPA the median TTF was 4.4 months, and median survival was 9.7 months. There was a tendency for higher response and longer TTF and survival on MMPA, but statistical significance was not reached (p = 0.09).

Cyclophosphamide, doxorubicin and fluorouracil (CAF) plus depo-buserelin in the treatment of premenopausal women with metastatic breast cancer.

A phase II study was undertaken to assess the effect of CAF plus depo-buserelin, as first-line treatment, in premenopausal women with breast cancer. Of 66 patients entered 60 are eligible and evaluable; their median age was 45, estrogen receptor (ER) was positive in 9, negative in 11 and unknown in 40. The median disease free interval (DFI) was 11 months. Metastatic sites were visceral in 14, bone in 34 and soft tissue in 37. Twenty-nine patients had metastatic disease of one site, while 31 had 2-4 sites. An objective response of 82% was documented (29 complete responders and 20 partial responders). Median time to treatment failure was 11.5 months and median survival 37 months. Most commonly encountered side effects attributable to CAF were alopecia, nausea and vomiting, leucopenia and thrombocytopenia. Side effects attributable to buserelin were hot flashes. After one cycle baseline mean serum estradiol fell from premenopausal levels to postmenopausal levels. This study showed that CAF plus buserelin is well tolerated, with a very high response rate in selected premenopausal patients with advanced breast cancer.

Fadrozole hydrochloride, a new nontoxic aromatase inhibitor for the treatment of patients with metastatic breast cancer.

Eighty previously treated postmenopausal women with metastatic breast cancer were randomized to receive fadrozole (CGS 16 949A), a new aromatase inhibitor, 1 or 4 mg orally per day. Seventy eight patients were evaluable for toxicity and response. Only mild to moderate toxicity, namely hot flushes (28%), nausea and vomiting (13%), fatigue (8%) and loss of appetite (5%) occurred. Complete response was documented in 10% and partial response in 13% of patients with 45% having a no change status for at least 2 months. The median time to treatment failure is 4.1 months. The median survival is 23.7 months. The median survival is 23.7 months. The response and survival in patients with estrogen receptor positive and estrogen receptor unknown disease were not significantly different. Neither response nor survival was significantly different between the patients receiving 1 or 4 mg of fadrozole per day. Fadrozole is a well tolerated, effective second line treatment for women with metastatic breast cancer.

Mitomycin C + high-dose medroxyprogesterone versus cyclophosphamide+doxorubicin plus fluorouracil as first-line treatment for metastatic breast cancer.

A pilot study was undertaken to compare mitomycin C plus oral high-dose medroxyprogesterone acetate (MMPA) to cyclophosphamide+doxorubicin+ fluorouracil (CAF). Thirty-four women were randomized at first relapse to receive MMPA or CAF. Patients were balanced with respect to age, performance status, hormone receptor status, prior adjuvant treatment, site of metastases, and number of metastatic sites. On MMPA 9/18 objective responses occurred and on CAF 12/18. Median time to treatment failure was 5.7 months on MMPA and 7.6 months on CAF; median survival on MMPA was 22.5 months and on CAF 16.7 months. Although there were more objective responses on CAF, this was not statistically significantly different, and CAF was associated with significantly more hemopoietic toxicity. It is concluded that mitomycin C should be further studied in front-line regimens for patients with metastatic breast cancer.

A study of fadrozole, a new aromatase inhibitor, in postmenopausal women with advanced metastatic breast cancer.

PURPOSE: The study investigated the therapeutic effects of fadrozole (CGS 16949A), a new aromatase inhibitor, in women who had received prior treatment for metastatic breast cancer. MATERIALS AND METHODS: Eighty postmenopausal women who had received prior treatment for metastatic breast cancer were randomized to receive fadrozole 1 mg/d or 4 mg/d per day orally. Seventy-eight patients were assessable for toxicity and response. RESULTS: Toxicity was limited to mild (grade 1) to moderate (grade 2) hot flashes in 28%, nausea and vomiting in 13%, fatigue in 8%, and mild loss of appetite in 5% of patients. No electrolyte or unanticipated hormonal changes occurred. The overall response was 23% (complete response, 10%; partial response, 13%). In addition, 45% of the patients had a no change status. There was no difference in response rate between the patients randomized to the two different doses of fadrozole. Only dominant site of metastases significantly affected response. The median time to treatment failure (TTF) was 4.4 months (4.7 months on 1 mg/d and 3.7 months on 4 mg/d). The median survival was 22.6 months (17.5 months on 1 mg/d; median survival has not been reached in patients on 4 mg/d). The response and survival in patients with estrogen receptor (ER)-positive and ER-unknown disease were not significantly different. CONCLUSIONS: Fadrozole has good therapeutic effect as a second-line treatment in postmenopausal women with metastatic breast cancer. In this study there was no significant difference in toxicity or response between 1 mg/d and 4 mg/d. Further trials comparing fadrozole to other hormone treatment are indicated.

Improved results with the addition of interferon alfa-2b to dacarbazine in the treatment of patients with metastatic malignant melanoma.

Sixty-four patients with histologically confirmed metastatic malignant melanoma were entered on a prospectively controlled randomized trial. Patients received dacarbazine (DTIC) alone or DTIC plus interferon (IFN) alfa-2b. Patients were reasonably balanced with respect to age, sex, performance status (PS), site of metastases, and number of metastatic sites. Objective response (complete plus partial remission [CR + PR]) was documented in six patients on DTIC and in 16 patients on DTIC plus IFN alfa-2b. Median time to treatment failure (TTF) and median survival are significantly better on the combination arm, with some long-term CRs observed. More toxicity was encountered in the combination arm, which was acceptable except in three patients where treatment was discontinued because of IFN toxicity.

Long term follow-up of patients with advanced prostatic cancer treated with nasal buserelin.

Sixty one men, with advanced prostatic cancer, were entered on a trial using a nasally administered gonadotropin-releasing hormone analogue agonist, buserelin, as first line treatment. This is the first trial to use intranasal buserelin without primary injections and without antiandrogens. No 'flare' phenomenon was observed. The only side effects were hot flashes (69%) and decreased libido (25%). The response rate of 82%, with a median response duration of 16 months, compares favourably to responses reported with orchidectomy or estrogens. Serum testosterone, FSH and LH were monitored at regular intervals. Mean serum testosterone baseline values of 15 nmol/L decreased to castrate levels, and remained low while patients were on study. It is concluded that intranasal buserelin is an effective, simple and safe method to achieve androgen deprivation and is an alternative to orchidectomy in the treatment of advanced prostatic cancer.

Prognostic factors affecting the survival of patients with multiple myeloma. A retrospective analysis of 86 patients.

A retrospective analysis of data concerning 86 patients with multiple myeloma was carried out in order to evaluate factors affecting survival. The overall median survival was 621 days. In a univariate analysis the following factors were significantly associated with poor survival: serum creatinine greater than or equal to 150 mmol/l, haemoglobin less than 11 g/dl and serum calcium values greater than 2.75 mmol/l; and Eastern Cooperative Oncology Group performance status 3-4. However, age, sex, Durie and Salmon staging, lytic lesions, serum immunoglobulin concentration, urine Bence Jones protein, percentage of plasma cells in the bone marrow, proteinuria, and type of chemotherapy given were not significantly associated with survival. A strong prediction of survival was found by grouping the serum creatinine and haemoglobin levels of patients at presentation.

Effect of chemotherapy with or without buserelin on serum hormone levels in premenopausal women with breast cancer.

Serial determinations of serum oestradiol (E2), follicle-stimulating hormone (FSH) and luteinising hormone (LH) were done to assess the effect of chemotherapy, with or without a gonadotropin-releasing hormone analogue, buserelin, on ovarian function in 147 premenopausal women treated for breast cancer. Cyclophosphamide, doxorubicin and 5-fluorouracil (CAF) plus buserelin was given to 81 women with metastatic disease, and 66 women were randomised to adjuvant cyclophosphamide, methotrexate and 5-fluorouracil (CMF) with buserelin or CMF alone. Baseline mean E2 of patients treated with cytostatics plus buserelin fell from premenopausal levels and remained low while patients were on study. E2 levels remained at premenopausal values in patients treated with CMF alone. Downregulation of FSH and LH occurred with cytostatics plus depot buserelin, but fluctuated with the nasal administration; on CMF alone, FSH and LH levels increased. Buserelin plus cytostatics more effectively caused ovarian ablation than cytostatic treatment alone. Depot buserelin was more effective than nasal buserelin.

Long-term survival of patients treated with combination chemotherapy for metastatic breast cancer.

Long-term survival of patients with metastatic breast cancer treated on two prospective stratified randomised trials has been analysed. Patients on study B122 received either cyclophosphamide, methotrexate and 5-fluorouracil (CMF) or cyclophosphamide, doxorubicin and 5-fluorouracil (CAF). On study B141 patients received CAF or mitolactol (dibromodulcitol), doxorubicin and vincristine alternating after every three cycles with three cycles of CMF (DAV/CMF). Long-term follow-up of 172 patients showed no significant survival difference (in multivariate regression models) for treatment with either CMF vs. CAF or CAF vs. DAV/CMF. The difference in median survival times between CMF and CAF showed a trend in favour of CAF. Advances in the management of metastatic breast cancer in postmenopausal women obtained by doxorubicin regimens have had a small but measurable impact on survival, but known patient discriminants were not overridden by the treatment regimens investigated in these studies.