Background
Worldwide, lung cancer is responsible for most cases of cancer-related death among individuals of both sexes. For adult patients with advanced disease, therapy regimens based on the combination of cisplatin or carboplatin with a different agent are considered the standard of care. However, few elderly patients have been included in relevant trials for chemotherapy, raising concerns about the safety and efficacy of such regimens, which are considered the standard of care for adult patients. As a consequence, older patients are often treated with less intense chemotherapy regimens.
Review objectives
Our objectives were to investigate the effects of different chemotherapy regimens (non-platinum single-agent, non-platinum combination, and platinum combination) on survival, quality of life, tumor shrinkage, and toxicity in older people with advanced lung cancer.
Study characteristics
We performed a systematic search (up to 31 October 2014) for trials that compared non-platinum single-agent therapy versus non-platinum combination therapy or non-platinum combination therapy versus platinum combination therapy in patients over 70 years of age who have advanced non-small cell lung cancer. We included in the review a total of 51 studies (seven studies in the non-platinum single-agent therapy vs non-platinum combination therapy group and 44 studies in the non-platinum combination therapy vs platinum combination therapy group); however, we were able to include only 19 studies in the meta-analysis.
Key results
Non-platinum single-agent versus non-platinum combination therapy
We analyzed five trials involving 1294 participants. We found that these regimens are equally effective for survival. However, combinations of non-platinum agents are associated with a greater chance of decreasing tumor size. We also found that these regimens are similar regarding chance of major toxicity such as low hemoglobin levels, platelets, and white cell counts (neutrophils). Only two trials assessed the impact of treatment on quality of life, and we were not able to combine these results because of lack of information.
Non-platinum therapy versus platinum combination therapy
We analyzed 14 trials involving 1705 elderly participants. We found that platinum therapy is associated with longer survival and greater chance of decreasing tumor size among elderly patients. However, we found that these regimens are more toxic than those based on non-platinum agents and provide greater risk of low hemoglobin and platelet levels, fatigue, nausea or vomiting, and numbness or tingling in the hands and feet. Only five trials assessed the impact of treatment on quality of life, and we were not able to combine these results because of lack of information.
Quality of evidence
Non-platinum single-agent versus non-platinum combination therapy
We downgraded to low the quality of evidence on survival because different results were reported across studies, and because three included trials were stopped early, which also influenced the quality of evidence for chance of decreasing tumor size and low hemoglobin, platelet, and white cell counts. For theses outcomes, issues with study design were also a matter of concern, leading to low quality of evidence.
Non-platinum combination versus platinum combination therapy
We downgraded to moderate the quality of evidence on the benefit of platinum combination therapy for survival based on inclusion of nine trials that were not specifically designed for older patients. Other issues with study design influenced the quality of evidence on interval to tumor growth after start of treatment, rate of tumor shrinkage, and toxicity. Regarding low hemoglobin and platelet levels, we further reduced the quality of evidence to low because of imprecision of reported results. We recognize that other limitations such as age alone might not be adequate criteria for selection of the best treatment. Older people can be very different from one another in terms of other health conditions associated with aging. Older patients included in randomized trials were selected through strict eligibility criteria that excluded most patients with other health problems. Therefore, we believe that these results must be interpreted with clinical judgement applied regarding selection of an appropriate treatment regimen.
In people over the age of 70 with advanced NSCLC who do not have significant co-morbidities, increased survival with platinum combination therapy needs to be balanced against higher risk of major adverse events when compared with non-platinum therapy. For people who are not suitable candidates for platinum treatment, we have found low-quality evidence suggesting that non-platinum combination and single-agent therapy regimens have similar effects on survival. We are uncertain as to the comparability of their adverse event profiles. Additional evidence on quality of life gathered from additional studies is needed to help inform decision making.
Approximately 50% of patients with newly diagnosed non-small cell lung cancer (NSCLC) are over 70 years of age at diagnosis. Despite this fact, these patients are underrepresented in randomized controlled trials (RCTs). As a consequence, the most appropriate regimens for these patients are controversial, and the role of single-agent or combination therapy is unclear. In this setting, a critical systematic review of RCTs in this group of patients is warranted.
To assess the effectiveness and safety of different cytotoxic chemotherapy regimens for previously untreated elderly patients with advanced (stage IIIB and IV) NSCLC. To also assess the impact of cytotoxic chemotherapy on quality of life.
We searched the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 10), MEDLINE (1966 to 31 October 2014), EMBASE (1974 to 31 October 2014), and Latin American Caribbean Health Sciences Literature (LILACS) (1982 to 31 October 2014). In addition, we handsearched the proceedings of major conferences, reference lists from relevant resources, and the ClinicalTrial.gov database.
We included only RCTs that compared non-platinum single-agent therapy versus non-platinum combination therapy, or non-platinum therapy versus platinum combination therapy in patients over 70 years of age with advanced NSCLC. We allowed inclusion of RCTs specifically designed for the elderly population and those designed for elderly subgroup analyses.
Two review authors independently assessed search results, and a third review author resolved disagreements. We analyzed the following endpoints: overall survival (OS), one-year survival rate (1yOS), progression-free survival (PFS), objective response rate (ORR), major adverse events, and quality of life (QoL).
We included 51 trials in the review: non-platinum single-agent therapy versus non-platinum combination therapy (seven trials) and non-platinum combination therapy versus platinum combination therapy (44 trials).
Non-platinum single-agent versus non-platinum combination therapy
Low-quality evidence suggests that these treatments have similar effects on overall survival (hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.72 to 1.17; participants = 1062; five RCTs), 1yOS (risk ratio (RR) 0.88, 95% CI 0.73 to 1.07; participants = 992; four RCTs), and PFS (HR 0.94, 95% CI 0.83 to 1.07; participants = 942; four RCTs). Non-platinum combination therapy may better improve ORR compared with non-platinum single-agent therapy (RR 1.79, 95% CI 1.41 to 2.26; participants = 1014; five RCTs; low-quality evidence).
Differences in effects on major adverse events between treatment groups were as follows: anemia: RR 1.10, 95% 0.53 to 2.31; participants = 983; four RCTs; very low-quality evidence; neutropenia: RR 1.26, 95% CI 0.96 to 1.65; participants = 983; four RCTs; low-quality evidence; and thrombocytopenia: RR 1.45, 95% CI 0.73 to 2.89; participants = 914; three RCTs; very low-quality evidence. Only two RCTs assessed quality of life; however, we were unable to perform a meta-analysis because of the paucity of available data.
Non-platinum therapy versus platinum combination therapy
Platinum combination therapy probably improves OS (HR 0.76, 95% CI 0.69 to 0.85; participants = 1705; 13 RCTs; moderate-quality evidence), 1yOS (RR 0.89, 95% CI 0.82 to 0.96; participants = 813; 13 RCTs; moderate-quality evidence), and ORR (RR 1.57, 95% CI 1.32 to 1.85; participants = 1432; 11 RCTs; moderate-quality evidence) compared with non-platinum therapies. Platinum combination therapy may also improve PFS, although our confidence in this finding is limited because the quality of evidence was low (HR 0.76, 95% CI 0.61 to 0.93; participants = 1273; nine RCTs).
Effects on major adverse events between treatment groups were as follows: anemia: RR 2.53, 95% CI 1.70 to 3.76; participants = 1437; 11 RCTs; low-quality evidence; thrombocytopenia: RR 3.59, 95% CI 2.22 to 5.82; participants = 1260; nine RCTs; low-quality evidence; fatigue: RR 1.56, 95% CI 1.02 to 2.38; participants = 1150; seven RCTs; emesis: RR 3.64, 95% CI 1.82 to 7.29; participants = 1193; eight RCTs; and peripheral neuropathy: RR 7.02, 95% CI 2.42 to 20.41; participants = 776; five RCTs; low-quality evidence. Only five RCTs assessed QoL; however, we were unable to perform a meta-analysis because of the paucity of available data.