Brunner Kw

Treatment of bronchogenic carcinoma with simultaneous or sequential combination chemotherapy, including methotrexate, cyclophosphamide, procarbazine and vincristine

One hundred and eighteen patients with inoperable carcinoma of the lung were randomly selected for treatment with methotrexate, cyclophosphamide, procarbazine, and vincristine. These drugs were administered simultaneously to one group of patients and sequentially to the second group. As the statistically significant superior remission rates in the simultaneously treated patients became evident (51% vs. 21%), an additional 85 cases were treated in this manner without randomization. The objective clinical responses were associated with prolonged survival. A higher response rate with the simultaneous treatment was also evident in patients with anaplastic small cell carcinoma (65% vs. 36%) as well as those with epidermoid carcinoma (33% vs. 13%). These differences were not statistically significant. Toxicity remained within acceptable limits, with a 2% drug related mortality, and was similar in both treatment regimens. Initial performance status was definitely related to survival, but not to tumor response. Patients with epidermoid carcinomas showing stabilization of tumor growth under treatment had the longest survival. Maintenance therapy with continued four‐drug polychemotherapy was not superior to single agent maintenance with cyclophosphamide.

A controlled study in the use of combined drug therapy for metastatic breast cancer

Three prospectively planned and controlled cooperative clinical studies in the use of combination drug therapy for metastatic breast cancer are reported. Each study contained two drug regimen arms. A total of 326 evaluable patients was treated with one of the five various drug combinations employed. As the number of drugs used in each regimen was increased from two to five, a concommitant increase in remission rates from 50% to 75% was observed. Remission duration of approximately 8 months and survival from the onset of treatment, however, remained relatively constant at 13 to 16 months in all drug regimens. Patients achieving tumor remission survived an average of three times longer than those with progressive disease under therapy. The results are correlated to patient age and predominant metastatic type. Subjective improvement was definitely related to objective tumor regression or stabilization. Treatment was relatively well tolerated and well applicable to outpatient care. Dosage adjustments were often necessary during the initial phases of therapy. Combined cystostatic drug therapy is highly effective in the prognostically worst forms of metastatic breast cancer, and is the treatment of choice for younger patients with visceral type metastases.

Comparison of the combination of 1, 3-bis(2-chloroethyl)-l-nitrosourea (BCNU) and vincristine with two dose schedules of 5-(3,3-dimethyl-l-triazino) imidazole 4-carboxamide (DTIC) in the treatment of disseminated malignant melanoma

One hundred twenty patients with inoperable metastatic malignant melanoma were randomly allocated to treatment with either a combination of BCNU 150 mg/m2 and vincristine 2 mg/m2 given every 30 days, or one of two regimens of DTIC: 300 mg/m2/day × 6 or 100 mg/m2/8 hours × 18 given every 30 days. Eight of the 51 (16%) patients who were originally treated with the BCNU and vincristine combination had 50% or more objective tumor regression, compared to 6 out of 25 (24%) patients treated with daily injections of DTIC, and 6 out of 21 (29%) patients treated with DTIC injections every 8 hours. The median duration of response to the BCNU and vincristine combination was 60 days, and the median duration of survival from initiation of treatment was 6.5 months in the responders and 3.3 months in the nonresponders. The median duration of response was 90 and 100 days for the daily and 8‐hour regimens of DTIC respectively, and the median duration of survival from commencement of treatment was 8.5 months for the responders and 3.5 months for the nonresponders. None of the 43 patients who failed to respond to the initial treatment program or whose disease progressed after initial improvement responded to the alternate treatment regimen.

New agents in non-small cell lung cancer

Combination chemotherapy has changed the outlook for patients with a variety of human malignancies, inducing clinically useful tumor responses, prolongation of median survival and, in patients with certain diseases, resulting in long-term disease-free survival. Development of an effective combination chemotherapy regimen depends primarily on the activities of its individual component drugs (12). In 1979 Cohen and Perevodchikova published an extensive review of single-agent chemotherapy of lung cancer (28). The purpose of the present paper is to update this review for non-small cell lung cancer.

“Fatigue and malaise” as a quality-of-life indicator in small-cell lung cancer patients

Abstract“Fatigue and malaise” (FM) is a frequent, non-specific symptom of cancer patients caused by the disease, its treatment and psychological distress. Since comprehensive quality of life assessment is often not feasible in multicentre clinical trials, short, but clinically relevant, quality of life indicators have to be defined. In a representative subsample of 127 patients in a phase-III randomized small-cell lung cancer trial comparing two different regimens of combination chemotherapy, quality of life was assessed at the beginning of each of the six treatment cycles with a self-rating questionnaire including an early version of the EORTC questionnaire, a mood adjective check list (Bf-S) and a single linear-analogue self-assessment scale (LASA) measuring general well-being. FM, measured with a five-item Likert subscale of the EORTC questionnaire, showed moderate to high intercorrelations with other EORTC subscales assessing disease symptoms, toxicity of treatment, role functioning, personal functioning, restriction of social activity, psychological distress, emotional (Bf-S) and general well-being (LASA). At baseline, FM was one of the most pronounced symptoms. Over the six cycles 43%–31% of the patients complained of moderate to severe fatigue. Over the first two cycles FM tended to decrease, slightly increasing during cycles 3 and 4 and decreasing again before cycle 6. In a multiple regression analysis over the six cycles, 53% of the variance of FM was explained by patient-rated symptoms of disease and toxicity (disease alone: 43%; toxicity alone: 35%). Initial performance status, previous weight loss, treatment arm, cycle number and age predicted the scores of FM over the six cycles. We conclude that, among other disease- and treatment-related scales, FM can be used as a global indicator of quality of life in small-cell lung cancer patients.

A comparative study of a bcnu containing 4-drug program versus mopp versus 3-drug combinations in advanced Hodgkin's disease. A cooperative study by the cancer and leukemia group B

A prospective randomized trial by CALGB examined the relative value of four chemotherapy regimens in 537 patients with stage III B and IV Hodgkins disease. A new combination BOPP, derived by substitution of BCNU for nitrogen mustard in the MOPP regimen, was compared to MOPP and to two 3‐drug regimens, derived by removing the procarbazine in BOPP (BOP) or removing the alkylating agent (OPP). The 4‐drug programs gave significantly higher frequency of complete remissions (BOPP 67%, MOPP 63%) than the 3‐drug regimens (BOP 40%, OPP 42%), and significantly longer duration of remission and survival. BOPP had a therapeutic activity equal to MOPP, and was accompanied by less toxicity. After 6 cycles of induction chemotherapy, responding patients, both CR and PR, were continued on maintenance chemotherapy for 3 years. No significant difference in relapse rate was demonstrated following maintenance treatment with either vinblastine, chlorambucil, or chlorambucil plus monthly vincristine + prednisone doses. Nor could a reinforcement phase late in the maintenance program be shown to influence the relapse rate. The median survival for all patients entered on the 4‐drug programs was 5 years, while the median has not yet been reached at 6 years for those patients, who obtained CR.

A Phase I trial of Cis-diammine-1,1-cyclobutane dicarboxylate platinum II (Carboplatin, CBDCA, JM-8) with a single dose every five week-schedule

SummaryCarboplatin, a new platinum analogue, was administered intravenously on a schedule of a single dose every five weeks to 23 patients with advanced malignant solid tumors. Patients were treated at six dosage levels ranging from 200–550 mg/m2 every five weeks. Thrombocytopenia was dose-limiting. At 550 mg/m2 Carboplatin, the median platelet nadir was 65 000/mm3. Leukopenia was common, but usually of mild to moderate degree. Gastrointestinal upset was commonly seen at all dose levels, but 35% of the patients experienced no vomiting. No significant increase of the serum creatinine following Carboplatin was seen. In 16 patients serial determinations of the creatinine clearance were performed. The median base line creatinine clearance was 87 (50–155) ml/min and dropped to a median lowest creatinine clearance of 69 (23–171) ml/min on day four (p < 0.05). The median creatinine clearance before the next Carboplatin treatment was 89 (42–155) ml/min. No significant proteinuria or electrolyte disturbances were noted. Carboplatin exhibited antitumor activity in ovarian, endometrial, thyroid and gastric carcinomas. The maximally tolerated dose appears to be 550 mg/m2 every five weeks. A starting dose of 450 mg/m2 seems to be appropriate for Phase II studies. In patients with impaired renal function and/or prior cis-Platin chemotherapy, Carboplatin at doses of 200–500

Unexpected High Toxicity in a Phase II Study of Teniposide (VM-26) in Elderly Patients with Untreated Small Cell Lung Cancer (SCLC)

Teniposide (VM 26) as a single agent has shown promising results in the treatment of patients with small cell lung cancer. We treated 32 (30 evaluable) non-pretreated elderly and poor prognosis patients with small cell lung cancer with teniposide 100 mg/day (30 min infusion) days 1-5, every 3-4 weeks. Overall initial performance status was poor (WHO 2 or 3 in 62%). Extensive disease (ED) was documented in 50% including five patients with CNS metastases all of whom received simultaneous cranial irradiation. There was an unexpected high early death rate of 30% (9/30) including five patients with early toxic death due to severe bone marrow suppression leading to fatal septicaemia. The overall response rate was only 33% with no complete response. Where appropriate non-responding or relapsing patients received second line treatment with multidrug regimens +/- radiotherapy. The overall median survival was 5.6 months [ED: 1.7, limited disease (LD): 7.5 months]. Median response duration was 5.4 months (ED: 5.1, LD: 6.7 months). For responding patients median survival was 8.8 months (ED) and 11.5 months (LD). We conclude that in elderly and poor performance status patients single agent teniposide as used in this study has an unacceptable high early death rate and that the response rate is inferior to modern standard multidrug regimens.

Randomized trial of 3 different regimens of combination chemotherapy in patients receiving simultaneously a hormonal treatment for advanced breast cancer

We report the results of a randomized trial carried out by the Swiss Group for Clinical Cancer Research (SAKK) and in which 230 patients with advanced breast cancer receiving concurrently a hormonal treatment (oophorectomy for pre- and tamoxifen for postmenopausal women) were randomly allocated to three different regimens of combination chemotherapy. The therapeutic results registered with the two more intensive combinations (LMP/FVP and LMFP/ADM) were similar with regard to response rates, time to progression and survival. The patients receiving the low-dose chemotherapy lmfp showed a statistically significant lower response rate (32%, P less than 0.001) and a shorter survival (P = 0.03) than the results observed in patients treated with the two other regimens. This difference was particularly pronounced, at least regarding survival, in the following subgroups: postmenopausal women, patients with a poor performance status, dominant visceral lesions, two sites of disease and a disease-free interval longer than 12 months. Patients with bony metastases as dominant lesion fared similarly with all three regimens of chemotherapy. This latter subset of advanced breast cancer patients should probably be spared too intensive cytotoxic treatment. This is, to our knowledge, the first report of a randomized trial showing an evident correlation between response rate and survival in various subgroups of patients with advanced breast cancer treated with different chemotherapeutic regimens.

Continuous 5-day infusion of ifosfamide with mesna in inoperable pancreatic cancer patients: a phase II study

SummaryPhase II studies on ifosfamide and mesna in pancreatic cancer have mostly been inconclusive. In all of these studies ifosfamide was administered as an i.v. bolus or by short infusions. Since dose fractionation of ifosfamide over several days increases its therapeutic index, we chose to maximize the dose fractioning by selecting a continuous-infusion schedule (1.75 g/m2 on days 1–5 every 21–28 days, with mesna 60%–100% of the ifosfamide dose up to 12 h after ifosfamide). Since 1987 29 patients (performance status ≦ 2) with advanced inoperable adenocarcinoma of the pancreas were studied (8 women and 21 men; median age 58 years: 36–73 years). A total of 25 patients are evaluable for response (1 ineligible; 3 inevaluable: 2 early deaths due to disseminated intravascular coagulation, 1 refusal). One female patient with a complete response on computed tomography scan (after five cycles) but residual liver metastases on surgical exploration survived for 473 days. Three male patients with partial response survived for 205, 335 and 355 days. Six more patients with minor response (3) or no change (3) but significant decrease of tumour marker CA 19-9 had a median survival of 213 days (106–243). Responders seemed to benefit in terms of pain relief and general wellbeing. The median overall survival of all patients was 148 days (21–473). Haematotoxicity was rarely dose-limiting [median nadirs: white blood cells=2.1×109/l (0.45–6.4), Hb=10.7g/dl (7.5–13), platelets=137×109/l (21–411)]. Nausea and vomiting were mild with prophylactic oral metoclopramide. No central nervous system toxicity or urotoxicity was observed. Alopecia was seen in all patients who had received at least two cycles. Continuous infusion of ifosfamide was generally well tolerated and useful for palliation in 10 of 25 patients. A higher dose intensity is recommended.