Bengt Bergman

The EORTC QLQ-LC13: a modular supplement to the EORTC core quality of life questionnaire (QLQ-C30) for use in lung cancer clinical trials

The EORTC Study Group on Quality of Life has developed a modular system for assessing the quality of life of cancer patients in clinical trials composed of two basic elements: (1) a core quality of life questionnaire, the EORTC QLQ-C30, covering general aspects of health-related quality of life, and (2) additional disease- or treatment-specific questionnaire modules. Two international field studies were carried out to evaluate the practicality, reliability and validity of the core questionnaire, supplemented by a 13-item lung cancer-specific questionnaire module, the EORTC QLQ-LC13. In this paper, the results of an evaluation of the QLQ-LC13 are reported. The lung cancer questionnaire module comprises both multi-item and single-item measures of lung cancer-associated symptoms (i.e. coughing, haemoptysis, dyspnoea and pain) and side-effects from conventional chemo- and radiotherapy (i.e. hair loss, neuropathy, sore mouth and dysphagia). It was administered to patients with non-resectable lung cancer recruited from 17 countries. In total, 883 and 735 patients, respectively, completed the questionnaire prior to and once during treatment. The symptom measures discriminated clearly between patients differing in performance status. All item scores changed significantly in the expected direction (i.e. lung cancer symptoms decreased and treatment toxicities increased) during treatment. With one exception (problems with a sore mouth), the change of toxicity measures over time was related specifically to either chemo- or radiotherapy. However, the single item on neuropathy did not measure adequately the full range of symptoms. The hypothesised scale structure of the questionnaire was partially supported by the data. The multi-item dyspnoea scale met the minimal standards for reliability (Cronbach alpha coefficient > 0.70), while the pain items did not form a scale with reliability estimates acceptable for group comparisons. In conclusion, the results form international field testing lend support to the EORTC QLQ-LC13 as a clinically valid and useful tool for assessing disease- and treatment-specific symptoms in lung cancer patients participating in clinical trials, when combined with the EORTC core quality of life questionnaire. In a few areas, however, the questionnaire module could benefit from further refinements. In addition, its performance over a longer period of time still needs to be investigated.

Multilingual translation of the Functional Assessment of Cancer Therapy (FACT) quality of life measurement system.

There is need for multilingual cross-culturally valid quality of life (QOL) instrumentation to assess the QOL endpoint in international oncology clinical trials. We therefore initiated a multilingual translation of the Functional Assessment of Cancer Therapy (FACT) Quality of Life Measurement System (Version 3) into the following languages: Dutch, French, German, Italian, Norwegian and Swedish. Prior to this project, the FACT Measurement System was available in English, Spanish and Canadian French. The FACT is a self-report instrument which measures multidimensional QOL. The FACT (Version 3) evaluation system uses a 29–49 item compilation of a generic core (29 Likert-type items) and numerous subscales (9–20 items each) which reflect symptoms associated with different diseases, symptom complexes and treatments. The FACT-G (general version) and eight of 18 available cancer-related subscales were translated using an iterative forward-backward translation sequence. After subsequent review by 21 bilingual health professionals, all near final language versions underwent pretesting with a total of 95 patients in the native countries. Available results indicate good overall comprehensibility among native language-speakers. Equivalent foreign language versions of the FACT will permit QOL evaluation of people from diverse cultural backgrounds.

Long-Term Results of the International Adjuvant Lung Cancer Trial Evaluating Adjuvant Cisplatin-Based Chemotherapy in Resected Lung Cancer

PURPOSE Based on 5-year or shorter-term follow-up data in recent randomized trials, adjuvant cisplatin-based chemotherapy is now generally recommended after complete surgical resection for patients with non-small-cell lung cancer (NSCLC). We evaluated the results of the International Adjuvant Lung Cancer Trial study with three additional years of follow-up. PATIENTS AND METHODS Patients with completely resected NSCLC were randomly assigned to three or four cycles of cisplatin-based chemotherapy or to observation. Cox models were used to evaluate treatment effect according to follow-up duration. Results The trial included 1,867 patients with a median follow-up of 7.5 years. Results showed a beneficial effect of adjuvant chemotherapy on overall survival (hazard ratio [HR], 0.91; 95% CI, 0.81 to 1.02; P = .10) and on disease-free survival (HR, 0.88; 95% CI, 0.78 to 0.98; P = .02). However, there was a significant difference between the results of overall survival before and after 5 years of follow-up (HR, 0.86; 95% CI, 0.76 to 0.97; P = .01 v HR, 1.45; 95% CI, 1.02 to 2.07; P = .04) with P = .006 for interaction. Similar results were observed for disease-free survival. The analysis of non-lung cancer deaths for the whole period showed an HR of 1.34 (95% CI, 0.99 to 1.81; P = .06). CONCLUSION These results confirm the significant efficacy of adjuvant chemotherapy at 5 years. The difference in results beyond 5 years of follow-up underscores the need for the long-term follow-up of other adjuvant lung cancer trials and for a better identification of patients deriving long-term benefit from adjuvant chemotherapy.

Palliative chemotherapy beyond three courses conveys no survival or consistent quality-of-life benefits in advanced non-small-cell lung cancer.

This randomised multicentre trial was conducted to establish the optimal duration of palliative chemotherapy in advanced non-small-cell lung cancer (NSCLC). We compared a policy of three vs six courses of new-generation platinum-based combination chemotherapy with regard to effects on quality of life (QoL) and survival. Patients with stage IIIB or IV NSCLC and WHO performance status (PS) 0–2 were randomised to receive three (C3) or six (C6) courses of carboplatin (area under the curve (AUC) 4, Chateluts formula, equivalent to Calverts AUC 5) on day 1 and vinorelbine 25 mg m−2 on days 1 and 8 of a 3-week cycle. Key end points were QoL at 18 weeks, measured with EORTC Quality of Life Questionnaire (QLQ)-C30 and QLQ-LC13, and overall survival. Secondary end points were progression-free survival and need of palliative radiotherapy. Two hundred and ninety-seven patients were randomised (C3 150, C6 147). Their median age was 65 years, 30% had PS 2 and 76% stage IV disease. Seventy-eight and 54% of C3 and C6 patients, respectively, completed all scheduled chemotherapy courses. Compliance with QoL questionnaires was 88%. There were no significant group differences in global QoL, pain or fatigue up to 26 weeks. The dyspnoea palliation rate was lower in the C3 arm at 18 and 26 weeks (P<0.05), but this finding was inconsistent across different methods of analysis. Median survival in the C3 group was 28 vs 32 weeks in the C6 group (P=0.75, HR 1.04, 95% CI 0.82–1.31). One- and 2-year survival rates were 25 and 9% vs 25 and 5% in the C3 and C6 arm, respectively. Median progression-free survival was 16 and 21 weeks in the C3 and C6 groups, respectively (P=0.21, HR 0.86, 95% CI 0.68–1.08). In conclusion, palliative chemotherapy with carboplatin and vinorelbine beyond three courses conveys no survival or consistent QoL benefits in advanced NSCLC.

Quality of life and survival in patients with advanced non-small cell lung cancer receiving supportive care plus chemotherapy with carboplatin and etoposide or supportive care only. A multicentre randomised phase III trial

The aim of the present trial was to evaluate the effects of chemotherapy on the quality of life and survival of patients with advanced non-small cell lung cancer (NSCLC) (stage IIIB or IV). In a controlled multicentre trial, patients were randomised to receive supportive care only or supportive care plus chemotherapy. Chemotherapy consisted of intravenous (i.v.) carboplatin 300 mg/m2 on day 1 and etoposide 120 mg/m2 orally on days 1-5 every 4 weeks for a maximum of eight courses. Quality of life was measured at randomisation and prior to each treatment course and at corresponding 4-week intervals in the control arm, using the EORTC QLQ-C30 + LC13 questionnaire. 48 patients were randomised (supportive care 26, chemotherapy 22), being eligible for comparative analyses. Another 102 patients, 97 of which received chemotherapy, were subsequently included in the study on an individual treatment preference basis. Data from these patients were used for confirmative purposes. Patients in the chemotherapy group reported better overall physical functioning and symptom control compared with the supportive care group. Group differences were smaller within the psychosocial domain, although trends were seen in favour of the chemotherapy group. No significant differences were seen in favour of the supportive care group, except for hair loss. Median survival times were 29 weeks in the chemotherapy group versus 11 weeks in the supportive care group, and 1-year survival rates were 28% versus 8%. Quality of life and survival outcomes were similar in the randomised and non-randomised patients receiving chemotherapy. No treatment-related deaths occurred. In conclusion, treatment with carboplatin and etoposide can improve both the quality of life and the survival of patients with advanced NSCLC.

Irinotecan Plus Carboplatin Versus Oral Etoposide Plus Carboplatin in Extensive Small-Cell Lung Cancer: A Randomized Phase III Trial

PURPOSE A Japanese randomized trial showed superior survival for patients with extensive-disease (ED) small-cell lung cancer (SCLC) receiving irinotecan plus cisplatin compared with etoposide plus cisplatin. The present trial evaluated the efficacy of irinotecan plus carboplatin (IC) compared with oral etoposide plus carboplatin (EC). PATIENTS AND METHODS Patients with ED SCLC were randomly assigned to receive either IC, which consisted of carboplatin (area under the curve = 4; Chatelut formula) and irinotecan (175 mg/m2) intravenously both on day 1, or EC, which consisted of carboplatin as in IC and etoposide (120 mg/m(2)/d) orally on days 1 through 5. Courses were repeated every 3 weeks with four cycles planned. Doses were reduced by one third in patients with a WHO performance status (PS) of 3 to 4 and/or age older than 70 years. Primary end point was overall survival (OS). Secondary end points were quality of life (QOL) and complete response (CR) rate. RESULTS Of 220 randomly assigned patients, 209 were eligible for analysis (IC, n = 105; EC, n = 104). Thirty-five percent were older than 70 years, and 47% had a PS of 2 to 4. The groups were well balanced with respect to prognostic factors. OS was inferior in the EC group (hazard ratio = 1.41; 95% CI, 1.06 to 1.87; P = .02). Median survival time was 8.5 months for IC compared with 7.1 months for EC. One-year survival rate was 34% for IC and 24% for EC. CR was seen in 18 IC patients compared with seven EC patients (P = .02). There were no statistically significant differences in hematologic grade 3 or 4 toxicity. Grade 3 or 4 diarrhea was more common in the IC group. QOL differences were small, with a trend toward prolonged palliation with the IC regimen. CONCLUSION IC prolongs survival in ED SCLC with slightly better scores for QOL.

SPACE – A randomized study of SBRT vs conventional fractionated radiotherapy in medically inoperable stage I NSCLC

BACKGROUND Stereotactic body radiotherapy (SBRT) has been introduced for small lung tumors due to excellent local control and few side effects, even though there are no comparative studies. SPACE (Stereotactic Precision And Conventional radiotherapy Evaluation) is the first randomized phase II trial comparing SBRT and conventional fractionated radiotherapy (3DCRT). METHODS Patients with stage I medically inoperable NSCLC were randomized to receive SBRT to 66Gy in 3 fractions (one week) or 3DCRT to 70Gy (7weeks). Patients were followed to assess efficacy, toxicity and HRQL. FINDINGS Between 2007 and 2011, 102 patients were randomized. Mean age 74 (57-86), 60% women, the vast majority (92%) had COPD or cardiovascular comorbidity. The SBRT arm included more patients with T2-tumors (p=0.02) and male gender (p=0.35). The median follow-up was 37months with a 1-, 2- and 3-year PFS of: SBRT: 76%, 53%, 42% and 3DCRT: 87%, 54% 42%, HR=0.85 (95% CI 0.52-1.36) with no difference between the groups and no difference in OS (HR=0.75, 95% CI 0.43-1.30). At the end of the study 70% of SBRT patients had not progressed compared to 59% (3DCRT, p=0.26). Toxicity was low with no grade 5 events. Pneumonitis of any grade was observed in 19% (SBRT) and 34% (3DCRT, p=0.26), and esophagitis in 8% and 30% respectively (p=0.006). HRQL was evaluated with the EORTC QLQ 30 and LC14 module and patients treated with 3DCRT experienced worse dyspnea (p=0.01), chest pain (p=0.02) and cough (>10 points difference). INTERPRETATION There was no difference in PFS and OS between SBRT and conventionally treated patients despite an imbalance of prognostic factors. We observed a tendency of an improved disease control rate in the SBRT group and they experienced better HRQL and less toxicity. SBRT is convenient for patients and should be considered standard treatment for patients with inoperable stage I NSCLC.

Quality of Life During Chemotherapy for Small Cell Lung Cancer: II. A longitudinal study of the EORTC Core Quality of Life Questionnaire and comparison with the Sickness Impact Profile

Sixty-two patients with small cell lung cancer, 36-80 years of age, who were receiving chemotherapy during a maximum of one year, were consecutively included in a study of quality of life during treatment. An interim version (C-36) of the EORTC Core Quality of Life Questionnaire (QLQ) was applied for quality of life assessment prior to treatment and every third month during the treatment period. The assessments were related to clinical variables (performance status and tumour response), and compared with results from assessment with the Sickness Impact Profile (SIP). The QLQ was sensitive to differences in clinical status and responded to clinical change over time. In general, the pattern of correlations with SIP lends support to the construct validity of the QLQ. However, some questions arose from the comparison with SIP: QLQ emotional functioning did not change in concordance with SIP, and assessment of social functioning was not optimal prior to treatment. The questionnaire was well accepted by the patients. The EORTC QLQ C-36 constitutes a promising step in the development of a feasible standard instrument for quality of life assessment in cancer clinical trials.

Single-agent gemcitabine: an active and better tolerated alternative to standard cisplatin-based chemotherapy in locally advanced or metastatic non-small cell lung cancer

This randomized study was designed to determine the response rates, survival and toxicities of single-agent gemcitabine (GEMZAR) and a combination of cisplatin/etoposide in chemonaive patients with non-resectable, locally advanced or metastatic non-small cell lung cancer (NSCLC). Gemcitabine 1000 mg/m2 was given as a 30-min intravenous infusion on days 1, 8, 15 of a 28-day cycle, cisplatin 100 mg/m2 on day 1, and etoposide 100 mg/m2 on days 1 (following cisplatin), 2 and 3. Major eligibility criteria included histologically confirmed non-small cell lung cancer, measurable disease, Zubrod performance status 0-2, no prior chemotherapy, no prior radiation of the measured lesion, and no CNS metastases. One hundred and forty-seven patients were enrolled, 72 in the gemcitabine and 75 in the cisplatin/etoposide arm. Patient characteristics were well-matched across both arms. Sixty-seven gemcitabine and 72 cisplatin/etoposide patients were qualified for efficacy analysis. There were no complete responses, but 12 partial responses in the gemcitabine arm and 11 in the cisplatin/etoposide arm, for protocol-qualified response but 12 partial responses in the gemcitabine arm and 11 in the cisplatin/etoposide arm, for protocol-qualified response rates of 17.9% (95%, CI: 9.6-29.2%,) and 15.3% (95% CI: 7.9-25.7%,), respectively. Median survival times were 6.6 months (95% CI: 4.9-7.3 months) for gemcitabine and 7.6 months (95% CI: 5.4-9.3 months) for cisplatin/etoposide. The 1-year survival probability estimate was 26% for gemcitabine and 24% for cisplatin/etoposide. There were no statistically significant between-group differences in time-to-event measures, but patients in the gemcitabine arm had a greater probability of achieving a tumour response after 2 months (probability estimate: 8 vs. 0%,) and of the response lasting at least 6 months (73 vs. 45%,). Clinical and haematologic toxicity was more pronounced in the cisplatin/etoposide arm. Quality-of-life measures indicated a significant worsening of symptomatology in the cisplatin/etoposide arm for hair loss, nausea and vomiting, and appetite loss. This randomized study provides further evidence that single-agent gemcitabine is an active and effective therapy for patients with non-resectable. locally advanced or metastatic NSCLC and good performance status, and that it is better tolerated than the combination cisplatin/ etoposide.

Quality of Life During Chemotherapy for Small Cell Lung Cancer :I. An evaluation with generic health measures

The Sickness Impact Profile (SIP) and the Hospital Anxiety and Depression scale (HAD) were used for assessment of physical and psychosocial functioning and emotional distress in patients with small cell lung cancer (SCLC) receiving chemotherapy. Treatment schedules extended over 12 months. Before treatment sixty-two patients, 36-80 years of age, completed the questionnaires and a selection of lung cancer symptom items. Approximately 50% of the patients reported clinically significant physical dysfunction, while emotional distress was reported by 25% and social restraints by 40%. Self-reported overall dysfunction, as assessed by SIP total index, was clinically significant in 60% of the patients. SIP physical and total indices were strongly related to WHO performance status (grade 0-4). The assessment was subsequently repeated every third month during the treatment period. Overall tumour response rate was 82%. The changes of physical and psychosocial functioning, as assessed by SIP, were significantly related to tumour response, although a persistent substantial overall dysfunction was shown among 50% of the responders after 3 months and among c. 40% after 6 months. In addition to tumour response, pain and appetite changes correlated with the change of overall SIP in multivariate analysis, implying the importance of pain control and appetite stimulating measures for patients with advanced cancer. Anxiety and depression, as measured by HAD, were reduced in 21 patients who completed 12 months chemotherapy, but only anxiety co-varied with tumour response. The results lend support to the use of the generic SIP and HAD as outcome measures in clinical research with SCLC patients receiving chemotherapy.