J. Wildiers

Locally advanced breast cancer: The contribution of cytotoxic and endocrine treatment to radiotherapy. An EORTC breast cancer co-operative group trial (10792)

Patients with locally advanced carcinoma of the breast were randomized to receive either radiotherapy alone, radiotherapy + endocrine therapy, radiotherapy + chemotherapy or radiotherapy + endocrine therapy + chemotherapy. In 363 evaluable patients, time to first progression was delayed significantly by both endocrine treatment and chemotherapy, the greatest effect being achieved by the combination of endocrine treatment and chemotherapy. This effect was almost entirely due to a major effect of systemic treatment on time to loco-regional progression, for which the result is highly significant, rather than time to distant metastasis in which only a non-significant trend was observed. For survival, a trend was seen in favour of the combination of hormone treatment and chemotherapy, but this effect did not achieve statistical significance. This trial suggests that current endocrine and cytotoxic treatments are only of marginal value in improving the prognosis in locally advanced breast cancer.

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.

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.

PURPOSEnTo 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.nnnPATIENTS AND METHODSnTwo 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.nnnRESULTSnOf 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.nnnCONCLUSIONSnBoth 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.

Doxorubicin vs epirubicin, report of a second-line randomized phase II/III study in advanced breast cancer

The EORTC Breast Cancer Cooperative Group carried out a randomized trial to compare doxorubicin with epirubicin as second-line chemotherapy in patients with metastatic breast cancer. Two hundred and fifty-nine patients with at least one site of metastatic disease entered this trial, of whom 232 patients were eligible. Treatment consisted of doxorubicin 75 mg m(-2) or epirubicin 90 mg m(-2) i.v. every 3 weeks. The overall response rates for doxorubicin and epirubicin were 36% and 28% respectively (P = 0.173). The median time to progression was 23 weeks for doxorubicin and 19 weeks for epirubicin (P = 0.063) and the median duration of response was 40 weeks for doxorubicin and 32 weeks for epirubicin (P = 0.059). The median survival was 47 weeks for doxorubicin and 44 weeks for epirubicin (P = 0.196). Leucocyte count on retreatment day (P = 0.011) and platelet nadir (P = 0.031) were significantly lower in the doxorubicin-treated group. Also mucositis (P < 0.001), diarrhoea (P = 0.005) and haemorrhage (P = 0.048) were significantly worse in the doxorubicin arm. Nine patients on doxorubicin and two patients on epirubicin experienced congestive heart failure (CHF). At the dose levels used in this study, no statistical differences in response rate and survival were found between the two treatment arms. Treatment with doxorubicin tended to result in a slightly longer duration of response and time to progression but doxorubicin was more toxic than epirubicin.

Safety, activity and estrogen inhibition by exemestane in postmenopausal women with advanced breast cancer: a phase I study

Exemestane is an irreversible, steroidal, oral aromatase inhibitor under evaluation in postmenopausal women with advanced breast cancer. A phase I study was conducted in 27 postmenopausal patients who were candidates for hormone therapy because they had advanced breast cancer and estrogen receptor-positive or unknown status. Most patients were moderately or heavily pretreated. Cohorts of at least three patients received sequentially escalating daily oral doses of 5-600 mg. The median duration of exemestane treatment was 13 weeks (range: 3-166 weeks). The maximal tolerated dose was not reached because of lack of treatment-related grade 3 or 4 toxicity. The most common adverse events, including those not related to treatment, were mild to moderate headache (44% of patients), dizziness (33%), nausea (33%), hot flushes (30%) and tumor-related pain (30%). There were three complete and four partial responses for an objective response rate of 26% (95% CI: 11.1-46.3%) in the intent-to-treat population; the median duration of response was 74 weeks (95% CI: 48-99 weeks). Exemestane, at the dose of 25 mg, maximally suppressed estradiol, estrone and estrone sulfate serum levels to 13, 5 and 10% of baseline, respectively. Exemestane appears to suppress estrogen, be well tolerated and have antitumor activity in postmenopausal women with advanced breast cancer. A large, safe therapeutic window of up to 600 mg was defined. In view of its safety and estrogen-suppression profiles, the most favorable effects were observed at the 25 mg daily dose.

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.

Acute blindness during treatment of recurrent or metastatic nasopharyngeal carcinoma with doxorubicin and CCNU

NASOPHARNYNGEAL cancer (NIX) is almost exclusively treated by radiation therapy, which provides local complete regression of tumour and lymph nodes in 85% of the cases. Five-year survival rates, however, range from 44 to 59% after such therapy, and the high rate of distant metastasis precludes cure of most patients [l]. There is no standard chemotherapy for recurrent or metastatic NPC, although doxorubicin (response rate 39%), cyclophosphamide (31%), bleomycin (28%) and methotrexate (17%) are active on their own [2]. Because of good results with a combination of doxorubicin and CCNU in five patients [3] (three out of five patients achieved complete remission, two of which have been sustained for over 104 and 115 months, respectively, and one partial remission) we started a phase II study to assess the antitumour activity and toxicity of doxorubicin-CCNU in recurrent or metastastic NPC. Inclusion criteria were histologically confirmed poorly differentiated or anaplastic NPC, documented progressive measurable or evaluable disease, age 75 or less, WHO performance status O-2, adequate renal function, normal liver function tests and hamatological indices. No patient had received previous chemotherapy. Doxorubicin was given by intravenous bolus injection at a dose of 50 mg/m* every 3 weeks; CCNU 120 mg/m* was given orally every 6 weeks. Standard WHO criteria were used for the assessment of response and toxicity [4]. Fifteen patients entered this study (Table 1). Median performance status was 1. The patients received a median of four courses. Five responses (one complete response and four partial responses) were achieved (33%), three patients had no change (three to six cycles) and six patients had progressive disease: one patient was not evaluable for response (one cycle only). Toxicity was considerable. Eight patients (53%) had grade 3 or 4 leucopenia; four of these had treatment-related infections. One patient had acute blindness in his right eye after two cycles. This was followed by blindness in the left eye. Since no other

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.