PURPOSE: Several recent trials have shown a significant overall survival (OS) benefit from postoperative cisplatin-based chemotherapy in patients with non-small-cell lung cancer (NSCLC). The aim of the Lung Adjuvant Cisplatin Evaluation was to identify treatment options associated with a higher benefit or groups of patients who particularly benefit from postoperative chemotherapy.
PATIENTS AND METHODS: Individual patient data were collected and pooled from the five largest trials (4,584 patients) of cisplatin-based chemotherapy in completely resected patients that were conducted after the 1995 NSCLC meta-analysis. The interactions between patient subgroups or treatment types and chemotherapy effect on OS were analyzed using hazard ratios (HRs) and log-rank tests stratified by trial.
RESULTS: With a median follow-up time of 5.2 years, the overall HR of death was 0.89 (95% CI, 0.82 to 0.96; P = .005), corresponding to a 5-year absolute benefit of 5.4% from chemotherapy. There was no heterogeneity of chemotherapy effect among trials. The benefit varied with stage (test for trend, P = .04; HR for stage IA = 1.40; 95% CI, 0.95 to 2.06; HR for stage IB = 0.93; 95% CI, 0.78 to 1.10; HR for stage II = 0.83; 95% CI, 0.73 to 0.95; and HR for stage III = 0.83; 95% CI, 0.72 to 0.94). The effect of chemotherapy did not vary significantly (test for interaction, P = .11) with the associated drugs, including vinorelbine (HR = 0.80; 95% CI, 0.70 to 0.91), etoposide or vinca alkaloid (HR = 0.92; 95% CI, 0.80 to 1.07), or other (HR = 0.97; 95% CI, 0.84 to 1.13). Chemotherapy effect was higher in patients with better performance status. There was no interaction between chemotherapy effect and sex, age, histology, type of surgery, planned radiotherapy, or planned total dose of cisplatin.
CONCLUSION: Postoperative cisplatin-based chemotherapy significantly improves survival in patients with NSCLC.
To evaluate the effect of adjuvant chemotherapy on survival rates after curative resection of gastric cancer, MEDLINE (1969-2006), EMBASE (1974-2006), bibliographies, and review articles were searched for relevant articles. The meta-analysis was finally based on 15 trials that included 3212 patients. RR for death in the treated group was 0.90 (95% CI, 0.84-0.96) (P = 0.0010). Little or no significant benefits were suggested in subgroup analyses between different population and regimens either. Postoperative adjuvant chemotherapy for gastric cancer confers slightly significant benefits compared to the surgery only group. The prognoses after surgery may differ among various population groups or because of different regimens.
The authors examined the role of systemic adjuvant therapy in patients with high-risk, resected, primary melanoma. Outcomes of interest included overall survival, disease-free survival, adverse effects, and quality of life. A systematic review of the literature was conducted to locate randomized controlled trials, practice guidelines, meta-analyses, and reviews published between 1980 and 2004. Thirty-seven randomized controlled trials, 2 meta-analyses, and 1 systematic review were identified that investigated interferon, levamisole, vaccine, or chemotherapy as adjuvant therapy. For high-dose interferon-alpha, the results from 3 randomized trials conducted by the Eastern Cooperative Oncology Group were pooled, and a meta-analysis of 2-year death rates yielded a risk ratio of 0.85 (95% confidence interval, 0.73-0.99; P = .03). Five randomized trials comparing low-dose interferon-alpha with observation only after surgery did not detect a statistically significant improvement in overall survival. A meta-analysis of 4 levamisole trials did not demonstrate a significant survival benefit for levamisole over control; similarly, no survival benefit was demonstrated by data from randomized controlled trials with vaccines (9 trials) or with chemotherapy (10 trials). In this review of the available literature, no systemic adjuvant therapy was identified that conferred a significant overall survival benefit in patients with high-risk, resected, primary melanoma. However, high-dose interferon should be considered in the treatment of these patients, because such therapy is associated with a significant improvement in disease-free survival and a reduction in 2-year mortality. Until the results of ongoing trials are available, the authors could not state with confidence whether such therapy benefits patients with microscopically detected, sentinel lymph node-positive disease.
BACKGROUND: Colorectal cancer metastatic to the liver, when technically feasible, is resected with a moderate chance of cure. The most common site of failure after resection is within the remaining liver. With this pattern of clinical failure in mind and in order to enhance survival, chemotherapy has been delivered directly to the liver post resection via the hepatic artery.
OBJECTIVES: To assess the effect of post hepatic resection hepatic artery chemotherapy on overall survival. Secondary objectives include adverse events related to the chemotherapy, the risk of intra-hepatic tumour recurrence and tumour free survival.
SEARCH STRATEGY: Randomised trials were sought in MEDLINE; the Cochrane Central Register of Controlled Trials; the Cochrane Hepato-Biliary Group Controlled Trials Register; and through contact of trial authors and reference lists using key words: Colorectal, cancer, hepatic metastases, hepatic artery, chemotherapy.
Searches were performed in December, 2008.
SELECTION CRITERIA: Trials in which patients having resection of colorectal cancer metastatic to the liver were randomised either to hepatic artery chemotherapy or any alternative treatment.
DATA COLLECTION AND ANALYSIS: Survival data were obtained principally from abstraction from survival curves in published studies using the method of Parmar. A study specific log hazard ratio and then combined effect log hazard ratio were calculated, as well as a combined Kaplan-Meier survival probability curve.
MAIN RESULTS: Seven randomised trials addressed this issue, encompassing 592 patients. No significant advantage was found in the meta-analysis for hepatic artery chemotherapy measuring overall survival and calculating survival based upon "intention to treat" (lnHR = 0.0848; favouring the control group, 95% confidence interval = -0.1189 to 0.2885, or a Hazard Ratio of 1.089, an 8.9% survival advantage for the control group, 95% CI of the HR = 0.887 - 1.334). Adverse events related to the hepatic artery therapy were common, including five therapy related deaths. Intra-hepatic recurrence was more frequent in the control group (97 patients versus 43 in the HAI group), though denominators are not reported, and additional outcomes could not be subjected to a combined analysis.
AUTHORS' CONCLUSIONS: Though recurrence in the remaining liver happened less in the hepatic artery chemotherapy group, overall survival was not improved, and even favoured the control group, though not significantly. This added intervention cannot be recommended at this time.
PURPOSE: This article reports the results of a pooled analysis of six randomized trials conducted to study the efficacy of uracil and tegafur (UFT) in the adjuvant treatment of node-negative breast cancer patients.
PATIENTS AND METHODS: Six randomized controlled trials on node-negative breast cancer patients were conducted from 1992 through 1995 in Japan that included the three, three-arm trials (control [no adjuvant], UFT, and tamoxifen [TAM] groups) and the three, four-arm trials (control, UFT, TAM, and UFT plus TAM groups). Pooled analysis was performed on the data obtained from these six trials (involving 2,934 patients).
RESULTS: Overall survival was compared between the UFT group (including both the UFT group and the TAM plus UFT group) and the non-UFT group (control group and TAM group). A significant difference (P = .04) was observed in 5-year survival rates between the UFT (95.9%) and the non-UFT (94.0%) groups. Overall survival was also compared between the TAM group (TAM group and TAM plus UFT group) and the non-TAM group (control group plus UFT group). The 5-year survival rate (95.2%) in the TAM group was not significantly different from that (93.9%) in the non-TAM group, but the subset analysis showed a significant (P = .01) improvement in the estrogen receptor-positive subset.
CONCLUSION: Adjuvant UFT improves the overall survival of node-negative breast cancer patients. Given that UFT has milder adverse effects, it is suggested that UFT can be a useful alternative to doxorubicin and cyclophosphamide, or cyclophosphamide, methotrexate, and fluorouracil in the adjuvant treatment for node-negative breast cancer.
PURPOSE: Recent clinical trials have shown the efficacy of platinum-based adjuvant chemotherapy for completely resected non-small-cell lung cancer (NSCLC). In Japan, many clinical trials of adjuvant chemotherapy with tegafur-uracil (UFT) have been conducted, and some trials showed positive results while others showed negative results. Thus, we performed a meta-analysis to assess the efficacy of postoperative adjuvant chemotherapy with UFT in NSCLC.
METHODS: Among nine trials of postoperative adjuvant UFT-containing chemotherapy, six trials comparing surgery alone with surgery plus UFT were identified. Of six trials, two were three-arm trials including cisplatin-based chemotherapy followed by UFT, and data from that arm were not included in the meta-analysis.
RESULTS: Of 2,003 eligible patients, most (98.8%) had squamous cell carcinoma or adenocarcinoma, and most had stage I disease; the tumor classification was T1 in 1,308 (65.3%), T2 in 674 (33.6%), and the nodal status was N0 in 1,923 (96.0%). The two treatment groups did not differ significantly in major prognostic factors. The median duration of follow-up was 6.44 years. The survival rates at 5 and 7 years were significantly higher in the surgery plus UFT group (81.5% and 76.5%, respectively) than in the surgery alone group (77.2% and 69.5%, respectively; P = .011 and .001, respectively). The overall pooled hazard ratio was 0.74, and its 95% CI was 0.61 to 0.88 (P = .001).
CONCLUSION: This meta-analysis showed that postoperative adjuvant chemotherapy with UFT was associated with improved 5- and 7-year survival in a Japanese patient population composed primarily of stage I adenocarcinoma patients.
BACKGROUND: Quinquennial overviews (1985-2000) of the randomised trials in early breast cancer have assessed the 5 year and 10-year effects of various systemic adjuvant therapies on breast cancer recurrence and survival. Here, we report the 10-year and 15-year effects.
METHODS: Collaborative meta-analyses were undertaken of 194 unconfounded randomised trials of adjuvant chemotherapy or hormonal therapy that began by 1995. Many trials involved CMF (cyclophosphamide, methotrexate, fluorouracil), anthracycline-based combinations such as FAC (fluorouracil, doxorubicin, cyclophosphamide) or FEC (fluorouracil, epirubicin, cyclophosphamide), tamoxifen, or ovarian suppression: none involved taxanes, trastuzumab, raloxifene, or modern aromatase inhibitors.
FINDINGS: Allocation to about 6 months of anthracycline-based polychemotherapy (eg, with FAC or FEC) reduces the annual breast cancer death rate by about 38% (SE 5) for women younger than 50 years of age when diagnosed and by about 20% (SE 4) for those of age 50-69 years when diagnosed, largely irrespective of the use of tamoxifen and of oestrogen receptor (ER) status, nodal status, or other tumour characteristics. Such regimens are significantly (2p=0.0001 for recurrence, 2p<0.00001 for breast cancer mortality) more effective than CMF chemotherapy. Few women of age 70 years or older entered these chemotherapy trials. For ER-positive disease only, allocation to about 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31% (SE 3), largely irrespective of the use of chemotherapy and of age (<50, 50-69, > or =70 years), progesterone receptor status, or other tumour characteristics. 5 years is significantly (2p<0.00001 for recurrence, 2p=0.01 for breast cancer mortality) more effective than just 1-2 years of tamoxifen. For ER-positive tumours, the annual breast cancer mortality rates are similar during years 0-4 and 5-14, as are the proportional reductions in them by 5 years of tamoxifen, so the cumulative reduction in mortality is more than twice as big at 15 years as at 5 years after diagnosis. These results combine six meta-analyses: anthracycline-based versus no chemotherapy (8000 women); CMF-based versus no chemotherapy (14,000); anthracycline-based versus CMF-based chemotherapy (14,000); about 5 years of tamoxifen versus none (15,000); about 1-2 years of tamoxifen versus none (33,000); and about 5 years versus 1-2 years of tamoxifen (18,000). Finally, allocation to ovarian ablation or suppression (8000 women) also significantly reduces breast cancer mortality, but appears to do so only in the absence of other systemic treatments. For middle-aged women with ER-positive disease (the commonest type of breast cancer), the breast cancer mortality rate throughout the next 15 years would be approximately halved by 6 months of anthracycline-based chemotherapy (with a combination such as FAC or FEC) followed by 5 years of adjuvant tamoxifen. For, if mortality reductions of 38% (age <50 years) and 20% (age 50-69 years) from such chemotherapy were followed by a further reduction of 31% from tamoxifen in the risks that remain, the final mortality reductions would be 57% and 45%, respectively (and, the trial results could well have been somewhat stronger if there had been full compliance with the allocated treatments). Overall survival would be comparably improved, since these treatments have relatively small effects on mortality from the aggregate of all other causes.
INTERPRETATION: Some of the widely practicable adjuvant drug treatments that were being tested in the 1980s, which substantially reduced 5-year recurrence rates (but had somewhat less effect on 5-year mortality rates), also substantially reduce 15-year mortality rates. Further improvements in long-term survival could well be available from newer drugs, or better use of older drugs.
The aim of this study was to investigate the worldwide evidence of the roles of adjuvant chemoradiation and adjuvant chemotherapy on survival in potentially curative resected pancreatic cancer. Five randomised controlled trials of adjuvant treatment in patients with histologically proven pancreatic ductal adenocarcinoma were identified, of which the four most recent trials provided individual patient data (875 patients). This meta-analysis includes previously unpublished follow-up data on 261 patients. The pooled estimate of the hazard ratio (HR) indicated a 25% significant reduction in the risk of death with chemotherapy (H = 0.75, 95% confidence interval (CI): 0.64, 0.90, P-values(stratified) (Pstrat) = 0.001) with median survival estimated at 19.0 (95% CI: 16.4, 21.1) months with chemotherapy and 13.5 (95% CI: 12.2, 15.8) without. The 2- and 5-year survival rates were estimated at 38 and 19%, respectively, with chemotherapy and 28 and 12% without. The pooled estimate of the HR indicated no significant difference in the risk of death with chemoradiation (HR = 1.09, 95% CI: 0.89, 1.32, Pstrat = 0.43) with median survivals estimated at 15.8 (95% CI: 13.9, 18.1) months with chemoradiation and 15.2 (95% CI: 13.1, 18.2) without. The 2- and 5-year survival rates were estimated at 30 and 12%, respectively, with chemoradiation and 34 and 17% without. Subgroup analyses estimated that chemoradiation was more effective and chemotherapy less effective in patients with positive resection margins. These results show that chemotherapy is effective adjuvant treatment in pancreatic cancer but not chemoradiation. Further studies with chemoradiation are warranted in patients with positive resection margins, as chemotherapy appeared relatively ineffective in this patient subgroup.
Several recent trials have shown a significant overall survival (OS) benefit from postoperative cisplatin-based chemotherapy in patients with non-small-cell lung cancer (NSCLC). The aim of the Lung Adjuvant Cisplatin Evaluation was to identify treatment options associated with a higher benefit or groups of patients who particularly benefit from postoperative chemotherapy.
PATIENTS AND METHODS:
Individual patient data were collected and pooled from the five largest trials (4,584 patients) of cisplatin-based chemotherapy in completely resected patients that were conducted after the 1995 NSCLC meta-analysis. The interactions between patient subgroups or treatment types and chemotherapy effect on OS were analyzed using hazard ratios (HRs) and log-rank tests stratified by trial.
RESULTS:
With a median follow-up time of 5.2 years, the overall HR of death was 0.89 (95% CI, 0.82 to 0.96; P = .005), corresponding to a 5-year absolute benefit of 5.4% from chemotherapy. There was no heterogeneity of chemotherapy effect among trials. The benefit varied with stage (test for trend, P = .04; HR for stage IA = 1.40; 95% CI, 0.95 to 2.06; HR for stage IB = 0.93; 95% CI, 0.78 to 1.10; HR for stage II = 0.83; 95% CI, 0.73 to 0.95; and HR for stage III = 0.83; 95% CI, 0.72 to 0.94). The effect of chemotherapy did not vary significantly (test for interaction, P = .11) with the associated drugs, including vinorelbine (HR = 0.80; 95% CI, 0.70 to 0.91), etoposide or vinca alkaloid (HR = 0.92; 95% CI, 0.80 to 1.07), or other (HR = 0.97; 95% CI, 0.84 to 1.13). Chemotherapy effect was higher in patients with better performance status. There was no interaction between chemotherapy effect and sex, age, histology, type of surgery, planned radiotherapy, or planned total dose of cisplatin.
CONCLUSION:
Postoperative cisplatin-based chemotherapy significantly improves survival in patients with NSCLC.
