What is the optimal duration of first-line chemotherapy for treatment of stage IV inoperable NSCLC?
The majority of patients treated with NSCLC have stage IV disease, with common sites of metastases including lymph nodes, the pleura, liver, adrenal glands, bone and brain. Consequently, systemic therapy has been the mainstay of treatment attempting to control overall disease. A historical summary of the evolution of systemic drug treatment for stage IV NSCLC can be found here. The focus of the following question is based on the evidence in support of the old and new practice paradigms for stage IV NSCLC. Empirical therapy refers to therapy given to all fit patients deemed suitable without any particular restrictions.
Duration of first-line chemotherapy
By convention, many clinical trials evaluating chemotherapy in stage IV NSCLC capped treatment to a maximum of six cycles, often being limited due to toxicity. Efficacy assessments usually occurred after the second or third chemotherapy cycle at six to eight weekly intervals. Although several small randomised controlled trials (RCTs) have been conducted addressing the question of duration of treatment, there is a great deal of heterogeneity in the design of these studies in terms of the treatment regimens used, the scheduling and duration of chemotherapy being explored. Two systematic reviews have attempted to address the optimal duration of chemotherapy .
The study by Soon et al was designed to determine the effects of extending chemotherapy beyond a standard number of cycles. It evaluated 3,027 patients from 13 RCTs comparing a defined number of cycles with continuation of the same chemotherapy until disease progression, a larger defined number of cycles of identical chemotherapy, RCTs comparing a defined number of cycles of identical initial chemotherapy followed by additional cycles of an alternative chemotherapy.
The key findings were that extending chemotherapy appeared to significantly improve progression free survival (PFS; HR0.75; 95% CI: 0.69 -0.81; p < .00001) whereas the effect on overall survival (OS) was modest and less certain (HR, 0.92; 95% CI: 0.86 - 0.99; P < .03). Subgroup analysis revealed that the effects on PFS were greater for trials extending chemotherapy with 3G regimens rather than older regimens (P < .003). Extending chemotherapy was associated with more frequent adverse events in all trials where it was reported and impaired health related quality of life (QOL) in two of seven trials.
The study by Lima et al was designed to determine the effects of continuing first-line chemotherapy. It evaluated 1559 patients from seven RCTs (included in the Soon meta-analysis) comparing different durations of first-line treatment of advanced NSCLC. Treatment for more than four cycles was not associated with a decrease in mortality relative to shorter treatment (HR = 0.97; 95% CI = 0.84 - 1.11; P = 0.65). Patients receiving more chemotherapy had significant longer progression-free survival (HR = .75; 95% CI = 0.60 – 0.85; P < 0.0001) than the group with shorter duration of treatment, but there was no difference in response rate (RR) and longer treatment was associated with more severe leucopaenia, although non-haematological toxicities were not significantly increased.
The study by Lima et al more closely addressed the question of duration of first line chemotherapy, whereas the study by Soon et al, focused on whether more chemotherapy is better than a fixed amount. It, however, contains a more heterogeneous mix of studies with a greater variety of regimens, including regimens not in use (involving alkylating agents). However, the overall study findings are not changed with the inclusion of these individual studies. Both studies agree in the finding that PFS is prolonged with longer chemotherapy however, a consistent improvement in overall survival was not observed. Given the toxicity associated with standard first-line chemotherapy, it appears reasonable to stop after four cycles of treatment. Continuing the same first line treatment beyond this should be individually based and consider the evidence for continuation or switch maintenance therapy discussed in detail in the section below.
Evidence summary and recommendations
| Extending the duration of first-line combination chemotherapy beyond four cycles of chemotherapy, in non-progressive patients, improves progression free survival but not overall survival, and at the expense of increased toxicity and potentially reduced quality of life.
Last reviewed September 2017
First-line combination chemotherapy should in most cases be stopped at disease progression or after four cycles in patients with advanced NSCLC.
Last reviewed September 2017
The duration of first-line chemotherapy in a given patient in practice may be based on the benefit being obtained in terms of tumour response, the desire to delay tumour progression and improve or maintain quality of life balanced against treatment toxicity. In practice maximum benefit from first-line chemotherapy has usually been obtained by four cycles of treatment.
- Soon YY, Stockler MR, Askie LM, Boyer MJ. Duration of chemotherapy for advanced non-small-cell lung cancer: a systematic review and meta-analysis of randomized trials. J Clin Oncol 2009 Jul 10;27(20):3277-83 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19470938.
- Lima JP, dos Santos LV, Sasse EC, Sasse AD. Optimal duration of first-line chemotherapy for advanced non-small cell lung cancer: a systematic review with meta-analysis. Eur J Cancer 2009 Mar;45(4):601-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19111457.