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. Joint Lung Cancer Study Group. Chemotherapy versus supportive care in advanced non-small cell lung cancer: improved survival without detriment to quality of life. Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer--report of a Canadian multicenter randomized trial. Supportive care versus supportive care and combination chemotherapy in metastatic non-small cell lung cancer. Does chemotherapy make a difference? Randomized trial of high-dose chemotherapy and blood cell autografts for high-risk primary breast carcinoma. Induction chemotherapy plus high-dose radiotherapy versus radiotherapy alone in locally advanced unresectable non-small-cell lung cancer. Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer--results from two randomised studies. Improving the quality of life during chemotherapy for advanced breast cancer. A comparison of intermittent and continuous treatment strategies. A randomized trial of alternating chemotherapy versus best supportive care in advanced non-small-cell lung cancer. Early compared with late radiotherapy in combined modality treatment for limited disease small-cell lung cancer: a London Lung Cancer Group multicenter randomized clinical trial and meta-analysis. Duration of chemotherapy in small cell lung cancer: a Cancer Research Campaign trial. A randomised phase III study of palliative radiation with concomitant carboplatin for brain metastases from non-small cell carcinoma of the lung.
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. In 1995 a meta-analysis of randomised trials investigating the value of adding chemotherapy to primary treatment for non-small cell lung cancer (NSCLC) suggested a small survival benefit for cisplatin-based chemotherapy in each of the primary treatment settings. However, the meta-analysis included many small trials and trials with differing eligibility criteria and chemotherapy regimens.
                The aim of the Big Lung Trial was to confirm the survival benefits seen in the meta-analysis and to assess quality of life and cost in the supportive care setting. A total of 725 patients were randomised to receive supportive care alone (n = 361) or supportive care plus cisplatin-based chemotherapy (n = 364).
                65% of patients allocated chemotherapy (C) received all three cycles of treatment and a further 27% received one or two cycles. 74% of patients allocated no chemotherapy (NoC) received thoracic radiotherapy compared with 47% of the C group. Patients allocated C had a significantly better survival than those allocated NoC: HR 0.77 (95% CI 0.66 to 0.89, p = 0.0006), median survival 8.0 months for the C group v 5.7 months for the NoC group, a difference of 9 weeks. There were 19 (5%) treatment related deaths in the C group. There was no evidence that any subgroup benefited more or less from chemotherapy. No significant differences were observed between the two groups in terms of the pre-defined primary and secondary quality of life end points, although large negative effects of chemotherapy were ruled out. The regimens used proved to be cost effective, the extra cost of chemotherapy being offset by longer survival.
                The survival benefit seen in this trial was entirely consistent with the NSCLC meta-analysis and subsequent similarly designed large trials. The information on quality of life and cost should enable patients and their clinicians to make more informed treatment choices. The survival benefit of combination chemotherapy to patients with advanced non-small-cell carcinoma of the lung (NSCLC) is controversial. To study this question, the National Cancer Institute of Canada (NCIC) Clinical Trials Group conducted a prospective randomized trial comparing best supportive care (BSC) to two chemotherapy regimens, vindesine and cisplatin (VP), and cyclophosphamide, doxorubicin, and cisplatin (CAP). Between February 1983 and January 1986, 23 centers across Canada entered 251 patients on study. Eighteen centers participated in the three-arm schema (150 patients); centers choosing not to participate in a study with a no-chemotherapy arm followed a two-arm schema comparing VP with CAP (101 additional patients). Altogether, 233 patients were eligible. Patients had measurable or evaluable disease, with either distant metastases (82.5%) or bulky limited disease considered inoperable or unsuitable for radical radiotherapy. The treatment groups were comparable in terms of age, sex, performance status, histology, disease extent, and weight loss. The overall response rates (complete response [CR] plus partial response [PR]) on the chemotherapy arms were CAP, 15.3%, and VP, 25.3% (P = .06). Patients on the three-arm portion of the trial had a median survival of 32.6 weeks when treated with VP, 24.7 weeks with CAP, and 17 weeks with BSC. The significance of the differences in survival, adjusted for prognostic factors, is as follows: chemotherapy v BSC, P = .02; VP v BSC, P = .01; and CAP v BSC, P = .05. Toxicity on the chemotherapy arms was significant, with leukopenia of severe or greater degree occurring in 37.8% (CAP) and 40.0% (VP), severe vomiting in 12.2% (CAP) and 23.3% (VP), and severe neurotoxicity in 15.6% (VP). Current chemotherapy treatment of metastatic non-small cell lung cancer has demonstrated some objective responses, but is still largely palliative. This report reviews the results of a randomized trial in patients with advanced metastatic non-small cell lung cancer which compared treatment with supportive care (treatment with palliative radiation, psychosocial support, analgesics, nutritional support) to supportive care plus combination chemotherapy with cisplatin and vinblastine. Although the patients receiving combination chemotherapy had a slightly longer median survival (20.43 weeks versus 13.57 weeks), it was not statistically significant (P = 0.09). In addition, the patients receiving chemotherapy experienced serious toxicity, and showed no significant benefit in terms of quality of life as measured by Karnofsky performance status score. The authors conclude that contemporary combination chemotherapy provides only modest survival benefit to patients with advanced metastatic non-small cell lung cancer and should not be considered standard therapy. Future investigations of chemotherapy in patients with unresectable non-small cell lung cancer should continue to utilize control arms which provide high-quality supportive care. Uncontrolled studies have reported encouraging outcomes for patients with high-risk primary breast cancer treated with high-dose chemotherapy and autologous hematopoietic stem cell support. We conducted a prospective randomized trial to compare standard-dose chemotherapy with the same therapy followed by high-dose chemotherapy. PATIENTS and
                Patients with 10 or more positive axillary lymph nodes after primary breast surgery or patients with four or more positive lymph nodes after four cycles of primary (neoadjuvant) chemotherapy were eligible. All patients were to receive eight cycles of 5-fluorouracil, doxorubicin (Adriamycin), and cyclophosphamide (FAC). Patients were stratified by stage and randomly assigned to receive two cycles of high-dose cyclophosphamide, etoposide, and cisplatin with autologous hematopoietic stem cell support or no additional chemotherapy. Tamoxifen was planned for postmenopausal patients with estrogen receptor-positive tumors and chest wall radiotherapy was planned for all. All P values are from two-sided tests.
                Seventy-eight patients (48 after primary surgery and 30 after primary chemotherapy) were registered. Thirty-nine patients were randomly assigned to FAC and 39 to FAC followed by high-dose chemotherapy. After a median follow-up of 6.5 years, there have been 41 relapses. In intention-to-treat analyses, estimated 3-year relapse-free survival rates were 62% and 48% for FAC and FAC/high-dose chemotherapy, respectively (P =.35), and 3-year survival rates were 77% and 58%, respectively (P =.23). Overall, there was greater and more frequent morbidity associated with high-dose chemotherapy than with FAC; there was one septic death associated with high-dose chemotherapy.
                No relapse-free or overall survival advantage was associated with the use of high-dose chemotherapy, and morbidity was increased with its use. Thus, high-dose chemotherapy is not indicated outside a clinical trial. High-dose radiation therapy is generally recommended as standard treatment in regionally advanced unresectable non-small-cell lung cancer (NSCLC), but median- and long-term survival remain poor. Some reports have recently shown an improvement of results in advanced NSCLC when cisplatin was included in the chemotherapy regimens. Therefore, we designed a randomized trial to determine whether induction chemotherapy before high-dose radiotherapy improves response rate and survival in stage III NSCLC over that achieved with radiotherapy alone.
                From March, 1984 to December, 1988, 66 consecutive patients with stage III unresectable NSCLC were randomized to one of two treatment arms; 61 were evaluable for survival and 58 for response and toxicity. Patients randomly assigned to arm A received cisplatin (CDDP 100 mg/m2 on day 1) and etoposide (VP 16 120 mg/m2 on days 1, 2, 3) every 3 wks for 3 courses followed by radiotherapy 56 Gy on pre-treatment tumor volume and 40 Gy on mediastinum and bilateral supraclavicular nodes. Patients assigned to arm B received only the same radiotherapy. The 61 eligible patients were comparable in terms of age, performance status, histology and treatment.
                Response rate was 53% in arm A and 32% in arm B. The median survival was 52 wks for the combined treatment arm and 36 wks for the radiation therapy arm. At six years of follow-up all the patients were dead. Toxicity was mild and no treatment-related deaths were recorded.
                Induction chemotherapy produced a better response rate and a trend of improved survival (4 months) but a significant survival advantage was not achieved (p < 0.11), probably because of the small number of patients enrolled in the trial. Endometrial cancer patients with high grade tumours, deep myometrial invasion or advanced stage disease have a poor prognosis. Randomised studies have demonstrated the prevention of loco-regional relapses with radiotherapy (RT) with no effect on overall survival (OS). The possible additive effect of chemotherapy (CT) remains unclear. Two randomised clinical trials (NSGO-EC-9501/EORTC-55991 and MaNGO ILIADE-III) were undertaken to clarify if sequential combination of chemotherapy and radiotherapy improves progression-free survival (PFS) in high-risk endometrial cancer. The two studies were pooled.
                Patients (n=540; 534 evaluable) with operated endometrial cancer International Federation of Obstetrics and Gynaecology (FIGO) stage I-III with no residual tumour and prognostic factors implying high-risk were randomly allocated to adjuvant radiotherapy with or without sequential chemotherapy.
                In the NSGO/EORTC study, the combined modality treatment was associated with 36% reduction in the risk for relapse or death (hazard ratio (HR) 0.64, 95%confidence interval (CI) 0.41-0.99; P=0.04); two-sided tests were used. The result from the Gynaecologic Oncology group at the Mario Negri Institute (MaNGO)-study pointed in the same direction (HR 0.61), but was not significant. In the combined analysis, the estimate of risk for relapse or death was similar but with narrower confidence limits (HR 0.63, CI 0.44-0.89; P=0.009). Neither study showed significant differences in the overall survival. In the combined analysis, overall survival approached statistical significance (HR 0.69, CI 0.46-1.03; P=0.07) and cancer-specific survival (CSS) was significant (HR 0.55, CI 0.35-0.88; P=0.01).
                Addition of adjuvant chemotherapy to radiation improves progression-free survival in operated endometrial cancer patients with no residual tumour and a high-risk profile. A remaining question for future studies is if addition of radiotherapy to chemotherapy improves the results.
                Copyright 2010 Elsevier Ltd. All rights reserved. Since chemotherapy for metastatic breast cancer is not curative, consideration of the quality of life is important in selecting a treatment regimen. We conducted a randomized trial comparing continuous chemotherapy, administered until disease progression was evident, with intermittent therapy, whereby treatment was stopped after three cycles and then repeated for three more cycles only when there was evidence of disease progression. Each approach was tested with doxorubicin combined with cyclophosphamide or with cyclophosphamide combined with methotrexate, fluorouracil, and prednisone. Intermittent therapy resulted in a significantly worse response (P = 0.02 by Mann-Whitney test), a significantly shorter time to disease progression (relative risk based on proportional-hazards model, 1.8; 95 percent confidence interval, 1.4 to 2.4), and a trend toward shorter survival (relative risk, 1.3; confidence interval, 0.99 to 1.6). The quality of life was expressed as linear-analogue self-assessment scores for physical well-being, mood, pain, and appetite and as a quality-of-life index. It improved significantly during the first three cycles, when all patients received treatment. Thereafter, intermittent therapy was associated with worse scores for physical well-being (by 23 percent of scale; 95 percent confidence interval, 11 to 35 percent), mood (25 percent; 13 to 37 percent), and appetite (12 percent; 0 to 24 percent) and for the quality-of-life index as indicated by the patient (14 percent; 5 to 23 percent) and the physician (16 percent; 7 to 26 percent). Changes in the quality of life were independent prognostic factors in proportional-hazards models of subsequent survival. We conclude that, as tested, continuous chemotherapy is better than intermittent chemotherapy for advanced breast cancer. From April 1985 to September 1988, 128 patients with advanced non-small-cell lung cancer (NSCLC) were enrolled in a prospective randomized trial evaluating chemotherapy (arm A) versus best supportive care (arm B). Chemotherapy consisted of cyclophosphamide 500 mg/m2 intravenously (IV) day 1, epirubicin 50 mg/m2 IV day 1, and cisplatin 80 mg/m2 IV day 1 (CE'P regimen) alternating every 4 weeks with methotrexate 30 mg/m2 IV day 1, etoposide 200 mg/m2 IV day 1, and lomustine (CCNU) 70 mg/m2 orally day 1 (MEC' regimen) until progression. Of the 123 patients (62 treated and 61 controls) eligible for survival, 115 were fully evaluable for response (58 treated and 57 controls). Response rates were 21% partial response, 53% stable disease, and 26% progressive disease in arm A, and 47% stable disease and 53% progressive disease in arm B. Median survival was 34.3 weeks (range, 4.3 to 218.6+ weeks) in arm A versus 21.1 weeks (range, 4.3 to 188.6 weeks) in arm B; the difference was not significant at P = .153 (Mantel-Cox). Subgroups of patients retrospectively analyzed by age, performance status, stage M0/M1, and weight loss or not showed no significant difference in survival. Poor-risk patients (at least two of the following: poor performance status, stage M1, weight loss) of arm A survived significantly longer than poor-risk patients of arm B (23.6 weeks v 12.4 weeks, Mantel-Cox P = .008); a significant difference in survival was also observed between nonsquamous cell patients of arm A and those of arm B (median survival, 38.6 weeks v 16.7 weeks; Mantel-Cox P = .041). Toxicity on the chemotherapy arm was hematologic (World Health Organization [WHO] grade greater than 3) in 12% of CE'P and in 13% of MEC' courses and gastroenteric (WHO grade greater than 3) in 24% of CE'P courses and in 8% of MEC' courses. Our alternating treatment was not significantly superior to supportive care. It is likely that certain subgroups of the NSCLC category may have an advantage with chemotherapy. To replicate an earlier National Cancer Institute of Canada (NCIC) trial that examined the effect on survival of the timing of thoracic radiotherapy (TRT) in patients with limited disease small-cell lung cancer (SCLC).
                Patients received three cycles of cyclophosphamide, doxorubicin, and vincristine alternating with three cycles of etoposide and cisplatin. Three hundred twenty five chemotherapy- and radiotherapy-naïve patients were randomly assigned to either early TRT administered concurrently in the second cycle or late TRT administered concurrently with the sixth cycle; the dose was 40 Gy in 15 fractions over 3 weeks.
                TRT was received by 92% and 82% of patients in the early and late arms, respectively (P = .01). Sixty-nine percent of patients in the early arm received all six courses of chemotherapy compared with 80% in the late arm (P = .003). There was no evidence of a survival difference; median overall survival time was 13.7 and 15.1 months in the early and late arms, respectively (P = .23). In a meta-analysis of all eight trials that compared early and late TRT, there were three in which the proportion of patients who completed their planned chemotherapy was similar between the TRT arms (hazard ratio [HR] = 0.73; 95% CI, 0.62 to 0.86) and five in which proportionally fewer patients in the early TRT arm completed their chemotherapy (HR = 1.06; 95% CI, 0.97 to 1.17).
                This study failed to show a survival advantage for early TRT with chemotherapy in limited-stage SCLC, unlike the NCIC trial. However, the results of a meta-analysis suggest that it is essential to ensure that the delivery of chemotherapy is optimal when administered with early TRT. A total of 610 patients with small cell lung cancer were entered into a randomised trial designed to assess the effect of duration of initial chemotherapy on survival. Patients were randomised to receive either four or eight courses of cytotoxic chemotherapy with cyclophosphamide, vincristine and etoposide and also randomised to receive, on disease progression, either second line chemotherapy (methotrexate and doxorubicin) or symptomatic treatment only. In the whole study 196 (32.1%) had limited disease and 414 (67.9%) extensive disease. During initial chemotherapy the response rate (complete and partial responses) after four courses of treatment was 61% with no significant increase in patients receiving eight courses (63%). In those randomised to receive relapse chemotherapy the response rate was improved slightly for those who had originally received four courses of chemotherapy (25.6%) over those receiving eight (18.7%). The overall results show that of the four possible treatment randomizations, four courses of chemotherapy alone is inferior in terms of overall survival (30 weeks median survival) to the other three treatment options (39 weeks median survival, P less than 0.01). In patients responding to initial chemotherapy the disadvantage of four courses of chemotherapy alone was apparent (median survival of 40 weeks versus 49 weeks, P = 0.003) but not if drug treatment was given on relapse. The study shows that limiting treatment to four courses of chemotherapy alone is associated with inferior survival, but this is not the case if chemotherapy is given at relapse. To determine if the addition of carboplatin chemotherapy to whole brain irradiation improves response and survival in patients with brain metastases from non-small cell lung cancer (NSCLC).
                Forty-two patients with brain metastases from NSCLC and performance status ECOG 0-2 were randomised to receive either whole brain radiotherapy (WBRT) alone (20Gy in five fractions) or the same radiotherapy plus concomitant carboplatin (70 mg/m(2) intravenously for 5 days).
                The median survival was 4.4 months in the radiotherapy alone (RT) arm and 3.7 months in the combined treatment (RTC) arm (P = 0.64). The objective response rates of 10% on the RT arm and 29% on the RTC arm were not significantly different (P = 0.24). The trial was closed early because of poor accrual.
                Although no firm conclusions can be made regarding the efficacy of the combined treatment, this prospective study highlights the poor objective response rates and relatively poor symptom control despite standard treatment of brain metastases from NSCLC.
All trials were of good methodological quality with no risk of bias. This meta-analysis of chemotherapy in the supportive care setting demonstrates that chemotherapy improves overall survival in all patients with advanced NSCLC. Patients who are fit enough and wish to receive it should be offered chemotherapy.