Rudolf Joss

“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 randomized comparison of doxifluridine and fluorouracil in colorectal carcinoma

In a randomized study 52 patients with advanced colorectal cancer and measurable lesions were treated with doxifluridine 4000 mg/m2 or fluorouracil 450 mg/m2 i.v. on 5 consecutive days over 3 weeks. None had prior fluoropyrimidines except two who received adjuvant fluorouracil. Partial responses with a duration ranging from 259 to 406 days were observed in five patients treated with doxifluridine and two patients treated with fluorouracil. Toxic reactions were evaluated in 88 doxifluridine courses and 105 fluorouracil courses. The most frequent adverse effects were neurotoxicity (48% of patients) and mucositis (43%) for doxifluridine, leukopenia (48%) and nausea/emesis (37%) for fluorouracil. Mucositis, diarrhea, nausea, emesis and skin reactions were observed in both treatment groups. Fluorouracil produced neurotoxic effects in 26% of patients. Reversible cardiac dysfunctions were observed in four patients treated with doxifluridine, expressed by ectopic ventricular beats (2) precordial pains (1) and ventricular fibrillation (1). This latter toxicity justified the premature interruption of the study. Doxifluridine is an active agent in colorectal cancer. Compared to fluorouracil it produces, when used i.v., a lower myelosuppression and a greater incidence of neurological and cardiac toxicity.

Combination chemotherapy with mitomycin, vindesine, and cisplatin for non-small cell lung cancer. Association of antitumor activity with initial tumor burden and treatment center.

From 1984 through 1986, 205 patients with non‐small cell lung cancer were entered into a group‐wide trial of the Swiss Group for Clinical Cancer Research (SAKK). This trial evaluated the combination of mitomycin (8 mg/m2 intravenously [IV] on day 1), vindesine (3 mg/m2 IV on days 1 and 8), and cisplatin (60 mg/m2 IV on day 1) with forced diuresis, repeated every 4 weeks (MiViP regimen). One hundred eighty‐three patients were evaluable. Six complete and 69 partial responses were documented for an overall response rate of 41% (95% confidence interval, 34% to 50%). In the multivariate analysis the strongest predictors for response were the participating institution and the number of initially involved organ sites. The estimated median time to progression for patients with a complete response, partial response, or stable disease was 155 days (estimated inter‐quartile range, 99 to 258 days). In the multivariate analysis the time to progression was significantly associated with the number of involved organ sites (P = 0.041). The estimated median survival time for the 183 evaluable patients was 239 days (estimated interquartile range, 137 to 436 days). In univariate and multivariate analyses performance status, number of involved organ sites, pretreatment status with radiation therapy, and participating institution were all significantly associated with survival. The principal toxicities were myelosuppression and nausea and vomiting with 16% of the patients refusing further treatment after a median of four cycles of chemotherapy. In conclusion, the MiViP regimen was an active combination chemotherapy in patients with non‐small cell lung cancer in a large trial performed by the SAKK. The prognostic value of the participating institution and the number of organ sites involved by metastatic deposits in non‐small cell lung cancer needs further investigation.

Acute Cerebrovascular Accident after Treatment with Cis-Platinum and Methylprednisolone

A 53-year-old woman with recurrent ovarian cancer sustained an intracerebral hemorrhage after the 4th course of a chemotherapy regimen which included cis-platinum (DDP). She received high-dose methylprednisolone as an antiemetic along with the DDP. No metastases or abnormal vascularity were found on histological examination of the right frontal lobe which had been removed surgically. Causes of cerebrovascular accidents during and following chemotherapy are discussed.

Etoposide, cisplatin and doxorubicin in patients with small cell lung cancer: Tumor response and long term survival

One hundred and fourteen patients with small cell lung cancer received a combination of etoposide 80 mg/m2 IV days 1,2,3,15,16,17, cisplatin 20 mg/m2 IV days 1,2,3 and doxorubicin 40 mg/m2 IV day 1, repeated every 4 weeks. The observation time from the initiation of treatment is longer than 4 years for all patients. An 85% response rate (38% complete response) was obtained after 1-4 cycles in 105 evaluable patients (96 without prior antitumour treatments). The response rate was not influenced by initial performance status and minimally by disease extension, whereas the same prognostic factors correlated significantly with complete responses. For limited disease and WHO performance 0 all responses were complete. For extensive disease and performance 3 no complete response was obtained. Various chemotherapy regimens with or without radiotherapy were used during the maintenance phase. Forty five per cent of first relapses were in the lung or mediastinum and 18% in the nervous system (20% without and 7% with prophylactic cranial irradiation). The median survival was 13.4 months for limited and 8.5 months for extensive disease, and correlated with performance and response. Only 2 patients survived free of disease after 4.8 and 5.5 years. We conclude that the induction treatment as used here produces a high rate of partial and complete responses but a low rate of long survivors.

A phase II study of spirogermanium in patients with advanced malignant lymphoma

SummarySpirogermanium was given as a 90 minute infusion to 47 eligible patients with refractory Hodgkins (9 patients) or non-Hodgkins lymphoma (38 patients). The schedule was 80 mg/m2 three times a week for the first two weeks and 100 mg/m2, 3 times a week, for the two subsequent weeks. In case of response or stable disease, the treatment was continued with biweekly infusions of 100 mg/m2 until tumor progression. In 64% of cases, three or more combinations had been previously administered; 66% of patients presented an extra-lymphatic spread of disease. Two patients with Hodgkins disease showed a partial response of 11 and 23 weeks and two patients with non-Hodgkins lymphoma achieved a complete response of 12 and 24 weeks. Overall, 14 patients showed a tumor progression within the first month of treatment. The main toxicity was neurological, with dizziness and lethargy during the infusion in 50% of cases. Hematologic toxicity was almost absent. Spirogermanium is ineffective in heavily pretreated patients with non-Hodgkins lymphoma. The confirmed lack of activity in patients with refractory malignant lymphoma and the need of repeated and prolonged infusions definitely discourage the clinical use of the drug.

Phase II trial of diaziquone (AZQ) in advanced malignant melanoma

Forty-two evaluable patients with malignant melanoma received AZQ 27 mg/m2 i.v. every 4 weeks. In 5 patients with poor marrow reserve this dose was reduced to 20 mg/m2. Doses were rapidly escalated when no significant myelosuppression was encountered in previous courses. Twenty-five patients had received no prior chemotherapy. A single partial response was obtained for 3 months. Inconsistent myelosuppression was the main toxic effect in this trial. The median WBC and platelet nadirs were 3200/mm3 (900-19,500) and 105,000/mm3 (33,000-530,000) respectively. In 2 patients leukopenia was complicated by a transient episode of infection. One-third of the patients did not experience significant myelosuppression. Non-hematologic adverse reactions were generally mild to moderate and consisted of nausea and vomiting in 26 patients and alopecia in 1. It is concluded that at this dose schedule AZQ is ineffective against malignant melanoma.

Levonantradol, a new antiemetic with a high rate of side-effects for the prevention of nausea and vomiting in patients receiving cancer chemotherapy.

SummaryLevonantradol, a new antiemetic compound pharmacologically related to the cannabinoids, was given to 17 patients who had experienced severe and protracted nausea and vomiting during previous courses of cancer chemotherapy, and to six patients receiving a first course of strongly emetic cytostatic treatment. Eight patients were partially protected from acute gastrointestinal disturbances. Of the 23 patients, 21 exhibited some toxicity, with six patients exhibiting major affective side-effects and 13 patients complaining of pain at the injection site. Levonantradol is an active antiemetic compound. Due to the rate of side-effects observed in our study however, we would not recommend use of this agent as an antiemetic drug.