Small Cell Lung Cancer Trials Research Articles

Quality-of-life assessment in cancer clinical trials: an intervention by itself?

Feasibility issues of quality-of-life (QL) assessment in cancer clinical trials have been discussed mainly in regard to compliance with QL questionnaires. In the case of an acceptable compliance, it is usually taken for granted that questionnaires received at the office for central data management have been filled in according to the rules and guidelines stated in the study protocol. The question whether local conditions of data collection might have a substantial influence on patients' QL estimation is not considered. In clinical experience, QL assessment in cancer patients may be a supportive intervention by itself, increasing awareness to QL issues in both patients and staff. To elaborate further on this question and the potentially interfering effects on patients' self-estimation we asked the nurses involved in the QL assessment of a randomized trial in small-cell lung cancer to describe their experiences. Meetings between the nurses collecting the data and the study coordinator took place on a regular basis. The detailed protocols of these meetings are used to describe qualitatively the possible influence of such unsystematically assessed factors on compliance and data quality. Implications regarding QL methodology are discussed.

Dose intensity of the CAVE regimen in small cell lung cancer correlates to response rate

Sixty-three patients with limited or extensive small cell lung cancer (SCLC), were treated in the Department of Respiratory Diseases, Huddinge Hospital, between 1985 and 1990, with chemotherapy consisting of cyclophosphamide, doxorubicin, vincristine and etoposide (CAVE). The patients were analyzed retrospectively concerning dose intensity (DI) of the chemotherapy actually delivered during induction treatment, the response rate, toxicity and survival. The mean combined relative DI (CRDI) of the induction treatment, consisting of three chemotherapy courses, was 0.7 (projected CRDI = 1.0). The overall response rate was 57% and the median survival time was 291 days. We found a correlation between the combined relative DI (all four drugs together) and the response rate. Increasing the CRDI from the range of 0.28–0.6 to 0.76–0.90 resulted in an increase in the response rate from 35 to 90%. Toxicity was scarce, suggesting that the actual delivered chemotherapy had low intensity. No correlation was found between DI and toxicity or between the response rate and toxicity. A correlation between DI of this induction treatment and survival could not be established. Our findings suggest the utility of reporting the actual DI of chemotherapy trials in SCLC.

Serum neuron-specific enolase (S-NSE) in progressive small-cell lung cancer (SCLC)

Clinical decision making is based on results from qualitative and quantitative information. To provide quantitative data, various laboratory variables are widely used in the clinical evaluation of patients with small-cell lung cancer (SCLC). The tumour marker serum neuron-specific enolase (S-NSE) and the routine laboratory parameter serum lactate dehydrogenase (S-LDH) have been investigated, mostly separately. Few studies have compared their importance in SCLC, especially in progressive disease (PD). The present investigation was undertaken to evaluate S-NSE for diagnostic efficacy in PD and compare it with S-LDH. In 27 patients in a treatment trial of SCLC, regular follow-up laboratory values were prospectively obtained. Chemotherapy was given according to trial protocols, and all clinical evaluation followed the WHO recommendations. At re-evaluation all but three values had normalised (two S-NSE, one S-LDH). S-NSE at progression was increased in 93% of the patients and S-LDH in 59%. The efficacy of S-NSE to discriminate between response and PD was superior to S-LDH (0.92 vs 0.70). There was no additive effect of the two parameters in prediction of PD, and the discriminating power was higher for S-NSE than for S-LDH (P < 0.0008). The disease status-related marker increments in relation to upper reference limits, i.e. the signal-noise relation, were higher for S-NSE than for S-LD. Both of the markers carry information on PD. S-NSE is, however, clearly superior to S-LDH in reflecting disease status during therapy. This prompts us to conclude that S-NSE should replace S-LDH as prognostic factor and disease activity monitor in SCLC.

Treatment-related deaths in small cell lung cancer trials: can patients at risk be identified?

Objectives: This paper investigates the problem of treatment-related deaths in small cell lung cancer (SCLC). Design: To observe and define increased hazard levels, and to identify factors relating to these excess deaths. Setting: The United Kingdom. Subjects: A total of 2196 patients entered into the series of six randomised clinical trials in SCLC conducted by the Medical Research Council (MRC) Lung Cancer Working Party (LCWP). Results: In this large series of patients an increased risk of death in the second week after commencing the first cycle of chemotherapy was observed, suggesting that of the 10% of patients who died within 3 weeks of starting chemotherapy, half may have been treatment-related. Much less additional risk was associated with subsequent cycles of chemotherapy, and no additional risk with either initial surgery or radiotherapy. Radford et al. [Eur J Cancer 1993; 29A: 81–86] suggested that the risk factors for death from sepsis were a Karnofsky Performance (KP) score of ≤ 50 (translated as a WHO performance grade (PS) ≥ 3), age > 50 years and three or more drugs in the chemotherapy regimen utilised. Starting with this model we found that our data suggest it can be refined by omitting age and including a white blood cell count ≥ 10 000/mm 3 (this variable was not tested by Radford), and changing the other categories to WHO PS ≥ 2 (KP ≤ 70), and four or more drugs. Within our data this revised model identified a high risk group of patients with an excess death rate of more than 15% in the second week after starting chemotherapy. Radford et als' suggestion that high risk patients be given half doses of drugs at the first cycle should be tested in a randomised clinical trial.

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

"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.(ABSTRACT TRUNCATED AT 250 WORDS)

The evolving role of systemic therapy in carcinoma of the lung : Haraf DJ, Devine S, Ihde DC, Vokes EE. Dept. of Radiation/Cellular Oncology, University of Chicago, 5841 S Maryland, Chicago, IL 60637. Semin Oncol 1992;19 Suppl 11:72–87

Locally advanced lung cancer carries a poor prognosis, and its treatment continues to challenge medical, radiation, and surgical oncologists. While systemic chemotherapy has improved the survival of patients with small cell lung cancer (SCLC), the role and timing of thoracic radiotherapy has not been clearly defined. The roles of chemotherapy and radiotherapy appear to be reversed in the treatment of locally advanced non-small cell lung cancer (NSCLC). The routine use of thoracic radiotherapy has been shown to improve local control after surgery without affecting survival, due to a high incidence of distant metastases. This contrasts with the marginal survival benefit seen with chemotherapy in NSCLC. Nevertheless, the results of recent clinical trials in both SCLC and NSCLC are encouraging and support continued investigation. These studies and the results of recent pilot studies suggest that a closer integration of chemotherapy and radiotherapy (concomitant chemoradiotherapy) may be necessary for further improvement in outcome. This review will present the results of recent studies in systemic therapy of lung cancer and the evidence supporting concomitant chemoradiotherapeutic treatment of this disease.

Single-agent chemotherapy trials in small-cell lung cancer, 1970 to 1990: The case for studies in previously treated patients : Grant SC, Gralla RJ, Kris MG, Orazem J, Kitsis EA. Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021. J Clin Oncol 1992;10:484-98

Single-agent chemotherapy trials in small-cell lung cancer, 1970 to 1990: The case for studies in previously treated patients : Grant SC, Gralla RJ, Kris MG, Orazem J, Kitsis EA. Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021. J Clin Oncol 1992;10:484-98

Single-agent chemotherapy trials in small-cell lung cancer, 1970 to 1990: the case for studies in previously treated patients.

This review was undertaken (1) to determine the antitumor activity of agents studied in phase II trials in small-cell lung cancer (SCLC) patients, (2) to evaluate the adequacy of published trials, (3) to determine if previously treated patients are suitable for phase II trials in SCLC, and (4) to develop an improved design for phase II trials. English-language, single-agent efficacy trials in SCLC, published from 1970 to 1990, were reviewed. Study design and reporting of results were assessed for clinical and statistical methodology. Response rates observed in previously treated patients were compared with those observed in previously untreated patients. One hundred forty-one articles evaluating 57 agents in 3,042 patients were reviewed. Eleven drugs were active (defined as a response rate greater than or equal to 20% in a trial with greater than or equal to 14 assessable patients), and 12 were inactive. Due to methodologic problems with the clinical trials, the usefulness of the remaining 34 drugs (60%) remains uncertain. Deficiencies identified in trials include inappropriate sample sizes, poorly defined response criteria, and failure to report important prognostic factors. When studied in adequate trials, all agents known to be active in SCLC had an observed response rate greater than or equal to 10% in previously treated patients. Over the past 2 decades, phase II trials in SCLC have failed in their primary task of effectively identifying agents that warrant further clinical study and rejecting inactive agents. If only previously treated patients had been entered into these trials, no useful agent would have been missed provided that a lower observed response rate had been used as evidence of antitumor activity. We propose a two-stage sequential study design, entering previously treated patients, for future phase II trials in SCLC.

Cost-effectiveness of cancer chemotherapy: An economic evaluation of a randomized trial in small-cell lung cancer : Goodwin PJ, Feld R, Evans WK, Pater J. Department of Medicine, Women's College Hospital, Toronto, Ont. M5S IB6. J Clin Oncol 1988;6:1537-47

Cost-effectiveness of cancer chemotherapy: An economic evaluation of a randomized trial in small-cell lung cancer : Goodwin PJ, Feld R, Evans WK, Pater J. Department of Medicine, Women's College Hospital, Toronto, Ont. M5S IB6. J Clin Oncol 1988;6:1537-47

Small cell lung cancer trials in the EORTC

An overview of activities of the EORTC Lung Cancer Coöperative Group in small cell lung cancer is given. Optimal length of therapy, identification of patients with good/bad prognostic factors, role of surgery and the study of new drugs presently are the main areas of interest for the group. With its large patient potential the group is able to verify "early favourable reports" and to quickly perform phase II studies.