Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma.

BACKGROUND: Malignant melanoma, one of the most aggressive of all skin cancers, is increasing in incidence throughout the world. Surgery remains the cornerstone of curative treatment in earlier stages. Metastatic disease is incurable in most affected people, because melanoma does not respond to most systemic treatments. A number of novel approaches are under evaluation and have shown promising results, but they are usually associated with increased toxicity and cost. The combination of chemotherapy and immunotherapy has been reported to improve treatment results, but it is still unclear whether evidence exists to support this choice, compared with chemotherapy alone. No language restrictions were imposed. OBJECTIVES: To compare the effects of therapy with chemotherapy and immunotherapy (chemoimmunotherapy) versus chemotherapy alone in people with metastatic malignant melanoma. SEARCH STRATEGY: We searched the Cochrane Skin Group Specialised Register (14 February 2006), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2005), MEDLINE (2003 to 30 January 2006 ), EMBASE (2003 to 20 July 2005) and LILACS (1982 to 20 February 2006). References, conference proceedings, and databases of ongoing trials were also used to locate trials. SELECTION CRITERIA: All randomised controlled trials that compared the use of chemotherapy versus chemoimmunotherapy on people of any age, diagnosed with metastatic melanoma. DATA COLLECTION AND ANALYSIS: Two authors independently assessed each study to determine whether it met the pre-defined selection criteria, with differences being resolved through discussion with the review team. Two authors independently extracted the data from the articles using data extraction forms. Quality assessment included an evaluation of various components associated with biased estimates of treatment effect. Whenever possible, a meta-analysis was performed on the extracted data, in order to calculate a weighed treatment effect across trials. MAIN RESULTS: Eighteen studies met our criteria and were included in the meta-analysis, with a total of 2625 participants. We found evidence of an increase of objective response rates in people treated with chemoimmunotherapy, in comparison with people treated with chemotherapy. Nevertheless, the impact of these increased response rates was not translated into a survival benefit. We found no difference in survival to support the addition of immunotherapy to chemotherapy in the systemic treatment of metastatic melanoma, with a hazard ratio of 0.89 (95% CI 0.72 to 1.11, p=0.31). Additionally, we found increased hematological and non-hematological toxicities in people treated with chemoimmunotherapy. AUTHORS' CONCLUSIONS: We failed to find any clear evidence that the addition of immunotherapy to chemotherapy increases survival of people with metastatic melanoma. Further use of combined immunotherapy and chemotherapy should only be done in the context of clinical trials.

Colony stimulating factors for prevention of myelosupressive therapy induced febrile neutropenia in children with acute lymphoblastic leukaemia.

BACKGROUND: Acute lymphoblastic leukaemia (ALL) is the most common cancer in childhood and febrile neutropenia is a potentially life-threatening side effect of its treatment. Current treatment consists of supportive care plus antibiotics. Clinical trials have attempted to evaluate the use of colony-stimulating factors (CSF) as additional therapy to prevent febrile neutropenia in children with ALL. The individual trials do not show whether there is significant benefit or not. Systematic review provides the most reliable assessment and the best recommendations for practice. OBJECTIVES: To evaluate the safety and effectiveness of the addition of G-CSF or GM-CSF to myelosuppressive chemotherapy in children with ALL, in an effort to prevent the development of febrile neutropenia. Evaluation of number of febrile neutropenia episodes, length to neutrophil count recovery, incidence and length of hospitalisation, number of infectious disease episodes, incidence and length of treatment delays, side effects (flu-like syndrome, bone pain and allergic reaction), relapse and overall mortality (death). SEARCH STRATEGY: The search covered the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CANCERLIT, LILACS, and SciElo. We manually searched records of conference proceedings of ASCO and ASH from 1985 to 2003 as well as databases of ongoing trials. We consulted experts and scanned references from the relevant articles. SELECTION CRITERIA: We looked for randomised controlled trials (RCTs) comparing CSF with placebo or no treatment as primary or secondary prophylaxis to prevent febrile neutropenia in children with ALL. DATA COLLECTION AND ANALYSIS: Two authors independently selected, critically appraised studies and extracted relevant data. The end points of interest were:* Primary end points: number of febrile neutropenia episodes and overall mortality (death) * Secondary end points: time to neutrophil count recovery, incidence and length of hospitalisation, number of infectious diseases episodes, incidence and length of treatment delays, side effects (flu-like syndrome, bone pain and allergic reaction) and relapse. We conducted a meta-analysis of these end points and expressed the results as Peto odds ratios. For continuous outcomes we calculated a weighted mean difference and a standardised mean difference. For count data, meta-analysis of the logarithms of the rate ratios using generic inverse variance was employed. MAIN RESULTS: We scanned more than 5500 citations and included six studies with a total of 332 participants in the analysis. There were insufficient data to assess the effect on survival. The use of CSF significantly reduced the number of episodes of febrile neutropenia episodes (Rate Ratio = 0.63; 95% confidence interval (CI) 0.46 to 0.85; p =0.003, with substantial heterogeneity), the length of hospitalisation (weighted mean difference (WMD) = -1.58; 95% CI -3.00 to -0.15; p = 0.03), and number of infectious diseases episodes (Rate Ratio=0.44; 95%CI 0.24 to 0.80; p=0.002). In spite of these results, CSF did not influence the length of episodes of neutropenia (WMD = -1.11; 95% CI -3.55 to 1.32; p = 0.4) or delays in chemotherapy courses (Rate Ratio=0.77; 95%CI 0.49 to 1,23; p=0.28) . AUTHORS' CONCLUSIONS: Children with ALL treated with CSF benefit from shorter hospitalisation and fewer infections. However, there was no evidence for a shortened duration of neutropenia nor fewer treatment delays, and no useful information about survival. The role of CSF regarding febrile neutropenia episodes is still uncertain. Although current data shows statistical benefit for CSF use, substantial heterogeneity between included trials does not allow this conclusion.

Colony stimulating factors for chemotherapy induced febrile neutropenia.

BACKGROUND: Febrile neutropenia is a frequent event for cancer patients undergoing chemotherapy and it is potentially a life threatening situation. The current treatment is supportive care plus antibiotics. Colony stimulating factors (CSF) are cytokines that stimulate and accelerate the production of one or more cellular lines in bone marrow. Some clinical trials addressed the question of whether the addition of CSF to antibiotics (ATB) could improve the outcomes of patients with febrile neutropenia. The results of these trials are conflicting and no definitive conclusion could be reached. OBJECTIVES: To evaluate the safety and effectiveness of adding colony stimulating factors to ATB when treating febrile neutropenia caused by cancer chemotherapy. SEARCH STRATEGY: The search covered the major electronic databases: CANCERLIT, EMBASE, LILACS, MEDLINE, SCI and The Cochrane Controlled Trials Register. Experts were consulted and references from the relevant articles scanned. SELECTION CRITERIA: We looked for all randomized controlled trials (RCTs) that compare CSF plus antibiotics versus antibiotics alone for the treatment of established febrile neutropenia in adults and children. DATA COLLECTION AND ANALYSIS: Two of the reviewers independently selected, critically appraised and extracted data from the studies. A meta-analysis of the select studies was performed, using Review Manager. MAIN RESULTS: More than 8000 references were screened. Thirteen studies were included. The overall mortality was not influenced by the use of CSF [Odds Ratio (OR) = 0.68; 95% Confidence Interval (CI) = 0.43 to 1.08; p=0.1]. A marginally significant result was obtained for the use of CSF in reducing infection related mortality [OR= 0.51; 95% CI = 0.26 to 1.00; p=0.05], but this result was highly influenced by one study. When this study is excluded from our analysis, this possible benefit disappears [OR= 0.85; 95% CI = 0.33 to 2.20; p= 0.7]. The group of patients treated with CSF had a shorter length of hospitalization [Hazard Ratio (HR) = 0.63; 95% CI = 0.49 to 0.82; p=0.0006] and a shorter time to neutrophil recovery [HR= 0.32; 95% CI = 0.23 to 0.46; p < 0.00001]. REVIEWER'S CONCLUSIONS: The use of CSF in patients with febrile neutropenia due to cancer chemotherapy does not affect overall mortality, but reduces the amount of time spent in hospital and the neutrophil recovery period. It was not clear whether CSF has an effect on infection-related mortality.