Combined treatment with buserelin and tamoxifen in premenopausal metastatic breast cancer: a randomized study.

BACKGROUND: Surgical or medical castration and antiestrogenic treatment with tamoxifen are common endocrine treatments for premenopausal women with breast cancer. However, tamoxifen therapy induces high levels of plasma estradiol, with unknown long-term effects. In this study, we investigated the effect of combining estrogen suppression with the luteinizing hormone-releasing hormone agonist buserelin and estradiol receptor blockade with tamoxifen to determine whether the high estradiol levels induced by tamoxifen could be reduced and whether the antitumor effects would be better. METHODS: In a three-arm, randomized, prospective trial, from 1988 through 1995, a total of 161 premenopausal patients with advanced breast cancer were randomly assigned to treatment with buserelin, tamoxifen, or both. Patients with steroid receptor-negative tumors or with tumors of unknown receptor status who had a disease-free interval of less than 2 years were excluded. The median follow-up was 7.3 years, during which 76% of the patients died, all of breast cancer. Patient and tumor characteristics were well balanced among treatment groups. All P values are from two-sided tests. RESULTS: Combined treatment with buserelin and tamoxifen was superior to treatment with buserelin or tamoxifen alone by objective response rate (48%, 34%, and 28% of patients who could be evaluated, respectively; P =.11 [chi(2) test]), median progression-free survival (9.7 months, 6.3 months, and 5.6 months; P =.03), and overall survival (3.7 years, 2.5 years, and 2.9 years; P =.01). Actuarial 5-year survival percentages were 34.2% (95% confidence interval [CI] = 20.4%-48.0%), 14.9% (95% CI = 3.9%-25.9%), and 18.4% (95% CI = 7.0%-29.8%), respectively. No differences in antitumor effects were observed between single-agent treatment groups. During combined treatment or treatment with buserelin alone, plasma estradiol levels were suppressed equally; in contrast, during treatment with tamoxifen alone, plasma estradiol levels increased threefold to fourfold over pretreatment levels. CONCLUSION: Combined treatment with buserelin and tamoxifen was more effective and resulted in longer overall survival than treatment with either drug alone.

Randomized phase III trial of edatrexate versus methotrexate in patients with metastatic and/or recurrent squamous cell carcinoma of the head and neck: a European Organization for Research and Treatment of Cancer Head and Neck Cancer Cooperative Group study.

PURPOSE: To compared the response rates and the toxicity of the new antifolate edatrexate (EDX) with that of methotrexate (MTX) in a randomized trial in patients with metastatic or recurrent squamous cell cancer of the head and neck (SCC) and to compare the durations of response and survival. PATIENTS AND METHODS: Two hundred seventy-three patients with SCC were randomized to receive either EDX or MTX as a weekly intravenous (IV) bolus injection. Doses of EDX were initially 80 mg/m2/wk, but because of the toxicity, this was later reduced to 70 mg/m2/wk. MTX was administered at a dose of 40 mg/m2/wk throughout. In both arms, two dose increments of 10% were scheduled in case of no toxicity. RESULTS: Of 264 eligible patients, 131 were treated with EDX and 133 with MTX. There were five treatment-related deaths: four on EDX and one on MTX. Overall, toxicity was similar in both arms; however, stomatitis, skin toxicity, and hair loss were more pronounced on the EDX arm. The overall response rate was 21% (six complete responses [CRs] and 21 partial responses [PRs]) for EDX and 16% (nine CRs and 12 PRs) for MTX (P = .392). Responses were mainly seen in patients with locoregional disease. Tumors that originated from the hypopharynx responded poorly in comparison to tumors from other sites. The median duration of response was 6.1 months for EDX and 6.4 months for MTX (log-rank P = .262). There was no difference in overall or progression-free survival. The median survival duration was 6 months on both treatment groups. CONCLUSIONS: Both EDX and MTX are moderately active against SCC. In this large phase III study, response rates, time to treatment failure, and overall survival appeared to be similar for both antifolates. However, EDX had more side effects than MTX and therefore cannot be recommended for routine palliative treatment of patients with SCC.

Paclitaxel versus doxorubicin as first-line single-agent chemotherapy for metastatic breast cancer: a European Organization for Research and Treatment of Cancer Randomized Study with cross-over.

PURPOSE: To compare the efficacy of paclitaxel versus doxorubicin given as single agents in first-line therapy of advanced breast cancer (primary end point, progression-free survival ¿PFS) and to explore the degree of cross-resistance between the two agents. PATIENTS AND METHODS: Three hundred thirty-one patients were randomized to receive either paclitaxel 200 mg/m(2), 3-hour infusion every 3 weeks, or doxorubicin 75 mg/m(2), intravenous bolus every 3 weeks. Seven courses were planned unless progression or unacceptable toxicity occurred before the seven courses were finished. Patients who progressed within the seven courses underwent early cross-over to the alternative drug, while a delayed cross-over was optional for the remainder of patients at the time of disease progression. RESULTS: Objective response in first-line therapy was significantly better (P =.003) for doxorubicin (response rate ¿RR, 41%) than for paclitaxel (RR, 25%), with doxorubicin achieving a longer median PFS (7.5 months for doxorubicin v 3.9 months for paclitaxel, P <.001). In second-line therapy, cross-over to doxorubicin (91 patients) and to paclitaxel (77 patients) gave response rates of 30% and 16%, respectively. The median survival durations of 18.3 months for doxorubicin and 15.6 months for paclitaxel were not significantly different (P =.38). The doxorubicin arm had greater toxicity, but this was counterbalanced by better symptom control. CONCLUSION: At the dosages and schedules used in the present study, doxorubicin achieves better disease and symptom control than paclitaxel in first-line treatment. Doxorubicin and paclitaxel are not totally cross-resistant, which supports further investigation of these drugs in combination or in sequence, both in advanced disease and in the adjuvant setting.

"Classical" CMF versus a 3-weekly intravenous CMF schedule in postmenopausal patients with advanced breast cancer. An EORTC Breast Cancer Co-operative Group Phase III Trial (10808).

The "classical" CMF (cyclophosphamide/methotrexate/5-fluorouracil) schedule was compared with a modified 3-weekly intravenous CMF schedule in postmenopausal patients with advanced breast cancer, as concern had arisen as to whether the classical schedule was the optimal way to give these drugs. The response rate with classical CMF was 48% compared with 29% for intravenous CMF (P = 0.003). Response duration was similar at 11 months, but survival longer for the classical schedule (17 versus 12 months, P = 0.016). We conclude that classical CMF is the superior regimen and attribute this to the higher dose intensity achieved.

Continuing chemotherapy or not after the induction treatment in advanced breast cancer patients. clinical outcomes and oncologists' preferences.

The optimal duration of cytostatic treatment for metastatic breast cancer is still a matter of debate. Possible gain in the duration of remission has to be weighed against the side-effects of treatment. Our aim was to define the optimal duration of cyclophosphamide, methotrexate, 5-fluorouracil (CMF) treatment by studying the time to treatment failure, overall survival and using a Q-TWiST analysis. The treating physician's opinion was asked. The European Organization for Research and Treatment of Cancer (EORTC) Breast Cancer Group conducted a randomised trial in 204 non-progressing metastatic breast cancer patients after induction chemotherapy (CMF) to stop or continue treatment. Progression-free (PFS) and overall survival (OS) were studied. To gain more insight into the burden of treatment-related side-effects, Q-TWiST was analysed. In addition, we asked for oncologists' preferences as patients are likely to be influenced by their physicians' opinion. Continuation of CMF had a significantly longer time to treatment failure (TTF) 5.2 versus 3.5 months (P=0.011). There was no overall survival (OS) difference 14.0 versus 14.4 months (P=0.77). Mean quality-adjusted survival time was equal to 8.4 months for no further treatment and decreased to 7.9 months for continuation of CMF (95% Confidence Interval (CI) of difference equals 0.5+/-2.5 months). Almost half of the oncologists said they would favour continuous treatment for a 3-month gain in time to progression-a difference which was not found in this study. Based on these data, an interruption of chemotherapy (CMF), if this is the wish of the patient, is justified.

Treatment of operable breast cancer in the elderly: a randomised clinical trial EORTC 10851 comparing tamoxifen alone with modified radical mastectomy.

For treatment of early breast cancer in older women, little evidence is available from randomised trials. We conducted a randomised trial comparing modified radical mastectomy (MRM) with tamoxifen (TAM) as the sole initial therapy in 164 patients aged >/=70 years with operable breast cancer. 82 were treated by MRM and 82 with TAM. Survival curves were estimated using the Kaplan-Meier method: multivariate analyses were performed using the Cox's proportional hazards model. Endpoints included survival, time to first relapse or progression, loco-regional progression, time to distant progression and progression-free survival. After a median follow-up of approximately 10 years, there was a significantly decreased time to progression in the TAM only group (logrank P<0.0001) and significantly shorter time to local progression within the TAM group (logrank P<0.0001). Overall survival of the two groups was similar. The results indicate that tamoxifen alone leads to an unacceptably high rate of local progression or relapse.

Role of bone and kidney in tumor-induced hypercalcemia and its treatment with bisphosphonate and sodium chloride.

The efficacy of intravenous aminohydroxypropylidene bisphosphonate as treatment for the hypercalcemia of malignancy was examined in a phase II multicenter study in 132 patients with a large variety of primary tumors. This provided an opportunity for an analysis of the separate influences of bone resorption and renal calcium handling on the genesis and maintenance of hypercalcemia. The results demonstrated that increased bone resorption is the major contributory factor and that inhibition with bisphosphonate normalizes the serum calcium concentration within five days in more than 90 percent of patients. Hypercalcemia is sustained by an inability of the kidney to deal efficiently with a chronically increased calcium load. This is influenced by the requirements of volume regulation in the presence of a sodium diuretic effect of hypercalcemia and is very sensitive to induced variations of sodium load. In addition, in a minority of patients, direct renal actions of tumor-derived humoral factors adversely reduce the ability to excrete calcium. For optimal treatment of tumor-induced hypercalcemia, bisphosphonate treatment should be combined with intravenous administration of saline solution.

Second line endocrine treatment of postmenopausal advanced breast cancer. Preliminary endocrine results of a 5-arm randomized phase II trial of medium vs low dose aminoglutethimide, with or without hydrocortisone vs hydrocortisone alone (EORTC 10861).

The supposed mechanism of action of aminoglutethimide (AG), medical adrenalectomy, has been challenged. AG is now considered to act as an inhibitor of the aromatization of mainly adrenal androgens to estrogens in peripheral tissues and/or breast cancer itself. To further establish the AG dose required to sufficiently reduce estrogen levels in plasma and the possible role of hydrocortisone (HC) in combination with AG or by itself, postmenopausal advanced breast cancer patients received AG low (125 mg bid) or medium (250 mg bid) dose alone or combined with HC (20 mg bid) or HC alone (20 mg bid). Preliminary hormonal data show a similar reduction of serum estrone and estrone sulphate by at least some 50% at 8 wk in all treatment groups. At 6 months these effects persist except for patients treated with HC alone. In the latter a normalization of estrone levels is observed with effective suppression of adrenal androgen precursors, suggesting increased aromatase activity with prolonged glucocorticoid treatment.

Oral versus intramuscular high-dose medroxyprogesterone acetate (HD-MPA) in advanced breast cancer. A randomized study of the Belgian Society of Medical Oncology.

Ninety postmenopausal women with advanced breast cancer were randomly assigned to be treated with HD-MPA administered either by oral route (daily dose 900 mg) or by intramuscular injections (1 g IM daily X 5 q w during 4 consecutive weeks followed by maintenance with 1 g twice weekly). Among 78 evaluable cases, most heavily pretreated, remissions, lasting for a median duration of 11 months, were more frequent on oral (8/37 = 22%) than on IM therapy (5/41 = 12%). In both arms, high estrogen receptor levels and various clinical factors were associated with higher response rates i.e., age greater than 60, Karnofsky greater than 70, light prior systemic treatment. Side-effects, consisting mainly of weight gain, hypertension and tremor occurred with equal frequency on oral or IM treatment. Five patients complained of pain at the sites of IM injections. Thus, we recommended that, whenever possible, the oral route should be preferred. During the same study, in 20 patients (11 on oral and 9 on IM therapy), blood was drawn at 0, 30, and 60 days of treatment for the assessment of MPA and hormone levels. In both arms, at 60 days, comparable levels of circulating MPA were obtained, with a very significant drop of cortisol, androstenedione, and estrone. These endocrine results, together with our clinical data, indicate that HD-MPA therapy is active on estrogen-dependent tumors with the same specificity as that of other modalities aiming to suppress the adrenal function. Its antineoplastic action in humans could be ascribed at least in part to its suppressive action on the adrenals, resulting in a severe estrogenic deprivation in postmenopausal women.

Oral (E)-5-(2-bromovinyl)-2'-deoxyuridine treatment of severe herpes zoster in cancer patients.

BVDU [(E)-5-(2-bromovinyl)-2'-deoxyuridine] is a highly potent and selective anti-herpes drug. It is particularly active against Varicella zoster virus, as demonstrated in cell culture and animals (monkeys). BVDU has been administered orally, at a dose of 7.5 mg/kg/day for 5 days, to 20 patients with severe localised or disseminated Herpes zoster. All patients had a malignant disorder for which they had been given intensive chemo- or radiotherapy. Upon BVDU treatment a rapid cessation of the acute Herpes zoster episode was noted in all but one patient. In the majority of patients progression of the infection was arrested within 1 day of starting treatment. No toxic side-effects could be attributed to the drug at the dosage used.

Relevance of hydroxyproline excretion to bone metastasis in breast cancer.

In 181 consecutive patients with breast cancer, urinary hydroxyproline excretion has been critically evaluated in conjunction with clinical, biochemical, radiological and scintigraphic parameters. The urinary hydroxyproline/creatinine ratio is a sensitive index of the presence of bone metastases. Urinary hydroxyproline excretion is a reliable method of selecting those patients whose elevated serum alkaline phosphatase is secondary to bone disease rather than liver idsease. The estimation of hydroxyproline excretion furthermore gives information on the activity of bone metastasis, and its response to treatment, which cannot be given by radiological or scintigraphic methods. It is doubtful whether urinary hydroxyproline estimation will help to detect bone metastases before they are apparent on scintigrams. When the bone scan is doubtful, as often occurs in older subjects, hydroxyproline excretion has been found to be helpful in classifying the patient. When scintigraphy is not available, an elevation of hydroxyproline excretion, together with an elevation of Ca/cr ratio or alkaline phosphatase activity, may pre-date by several months the radiological demonstration of osseous metastases.

Docetaxel is a potent cytotoxic drug in the treatment of advanced breast cancer.

Docetaxel (Taxotere) belongs to a new class of anti-neoplastic agents, the taxanes. As the structurally related compound, paclitaxel, it enhances microtubule assembly and inhibits depolymerization of tubulin, thereby disrupting mitosis and cell replication. From august 1994 till december 1995, we treated thirty patients with advanced or metastatic breast cancer in a protocol aiming at evaluating the efficacy of docetaxel, administered in second, third or fourth line chemotherapy. The drug was given at a dosage of 100 mg/m2, delivered as a 1-hour infusion once every 3 weeks. Among the 30 patients, 9 (30%) showed an objective response (PR) and 15 (50%) had disease stabilization. For those 2 groups, the median time to progression was 20 weeks (range 13-61) and 13.5 weeks (range 10-37) respectively; the median survival for the whole group was 22.5 weeks (range 1-72). Myelosuppression (neutropenia) was the dose-limiting toxicity. We conclude that docetaxel is a potent single agent in heavily pretreated locally advanced or metastatic breast cancer, even in those who are resistant to an anthracycline or an anthracenedione.

Carminomycin versus doxorubicin in advanced breast cancer, a randomized phase II study of the E.O.R.T.C. Breast Cancer Cooperative Group.

Sixty-four patients with advanced progressive breast cancer resistant to conventional treatments were entered into the present study. They were randomized to receive either Carminomycin (CMM) 20 mg/m2 or Doxorubicin (DOX) 75 mg/m2, both drugs being administered by i.v. bolus every 3 weeks until progression of the disease. Five patients were not eligible and response could not be evaluated in another eight patients. Three patients had only one course due to disease-related early death. Among twenty-seven evaluable patients who received at least two courses of DOX one complete response and seven partial responses were observed for an overall response rate of 30%. CMM showed significantly lower (P = 0.04) antitumor activity with only one partial response (4%) among the 24 patients who received at least two courses of therapy. Median duration of response dating from the start of chemotherapy was 46 weeks on DOX (range 18-102+) and 30 weeks for the single partial response on CMM. Although the median time to progression for all patients receiving CMM (9 weeks) was significantly shorter (P = 0.04) than for those receiving DOX (30 weeks), patients on DOX had only a marginally longer duration of survival (P = .28) than those initially treated with CMM. Myelotoxicity was more severe in the CMM treated group than in the DOX group. Other toxicities such as alopecia, nausea and vomiting were slightly more severe in the DOX treated group. On the basis of this and other similar randomized studies, CMM cannot be recommended for further application in the treatment of advanced breast cancer.

Randomized comparison of cisplatin, methotrexate, bleomycin and vincristine (CABO) versus cisplatin and 5-fluorouracil (CF) versus cisplatin (C) in recurrent or metastatic squamous cell carcinoma of the head and neck. A phase III study of the EORTC Head and Neck Cancer Cooperative Group.

BACKGROUND: The EORTC Head and Neck Cancer Cooperative Group conducted a randomized comparison of cisplatin, methotrexate, bleomycin and vincristine (CABO) versus cisplatin and 5-fluorouracil (CF) versus cisplatin (C) in chemotherapy naive patients with recurrent or metastatic squamous cell carcinoma of the head and neck. The primary objectives of this study were to investigate whether the CF regimen was in anyway superior to the CABO regimen and to detect any superiority of these two combinations over cisplatin alone. PATIENTS AND METHODS: Three hundred eighty-two patients were randomized to one of three treatments: (1) methotrexate (40 mg/m2) days 1 and 15, bleomycin (10 mg) and vincristine (2 mg) days 1, 8 and 15, cisplatin (50 mg/m2) day 4, repeated every 21 days, (2) cisplatin (100 mg/m2) and 5-FU (1 g/m2 x 4), repeated every 21 days, and (3) cisplatin (50 mg/m2) days 1 and 8, repeated every 28 days. After 3 cycles, all responding and stable disease patients in the three arms of the study continued with cisplatin alone. RESULTS: The overall response rates to CABO (34%) and CF (31%) were superior to C (15%) (p < 0.001, p = 0.003, respectively). In addition, complete response rate to CABO (9.5%) was superior to that of C (2.5%) (p = 0.02), and also superior to that of CF (1.7%) (p = 0.01). Response was associated with performance status and prior treatment, but by multivariate analysis treatment type was the important determinant of response (p = 0.0006). Although CABO and CF were superior to C with respect to time to progression within the first 6 to 8 months after randomization, there was no overall difference in progression-free survival or survival between the three arms of the study. Both hematologic and non-hematologic toxicity were worse in the combination chemotherapy arms. CONCLUSION: We conclude that the CF regimen has no advantage over the CABO regimen, which in fact showed a higher complete response rate. Both combinations showed improved response rates but also more toxicity and no improvement in overall survival in comparison with cisplatin alone.

An EORTC pilot study of filgrastim (recombinant human granulocyte colony stimulating factor) as support to a high dose-intensive epiadriamycin-cyclophosphamide regimen in chemotherapy-naive patients with locally advanced or metastatic breast cancer.

BACKGROUND: In an attempt to increase chemotherapy dose intensity by step-wise reduction of the time interval between treatment cycles, filgrastim was administered to breast cancer patients receiving a three-month combination chemotherapy with epirubicin (E) and cyclophosphamide (C). PATIENTS AND METHODS: Chemotherapy-naïve patients with locally advanced or metastatic breast cancer received fixed doses of E (120 mg/m2) and C 9830 mg/m2) by 15-min i.v. infusion on day 1 of each cycle and filgrastim at a dose of 4 micrograms/kg once daily by SC injection starting 24 hours after chemotherapy. Cohorts of patients were treated in successive schedules, each schedule corresponding to a specified time interval between chemotherapy cycles. The toxicity observed in each schedule was evaluated before patients were accrued to the next schedule, which corresponded to a shorter time interval between chemotherapy cycles. RESULTS: The maximum tolerated schedule was E (120 mg/m2) plus C 9830 mg/m2) given every 14 days with filgrastim support from day 2 until day 13. On this schedule, 5 of 12 patients experienced dose-intensity-limiting toxicities (DLT) during the 3-month study period. Non-hematological DLT occurred in 2/12 patients (mucositis, skin toxicity) while /312 experienced febrile neutropenia requiring i.v. antibiotics. All patients achieved recovery of ANC to >1.5 x 10(9)/l by the time of scheduled retreatment. The combination of filgrastim with this regimen did not seem to add major toxicities. The efficacy was high, with 87% of patients achieving an objective response and a median response duration of 18 months (range: 4-52 months). CONCLUSIONS: Filgrastim permits at 33% increase in 'EC' dose intensification over that of the conventional every-3-week administration. Randomized studies should now be initiated to evaluate the merit, if any, of 'accelerated' chemotherapy in advanced breast cancer.