Chemotherapy In Advanced Non-Small Cell Lung Cancer: A ReviewCorrespondence Address :
Dr. Sanjeev Chandra Joshi Lecturer and Consultant (Oncology & Radiotherapy)
Advanced Medical and Dental Institute, University Sains Malaysia, Pinang, Malaysia. Tel: +6 04 â€“ 5791990. Fax: +6 04 â€“ 5742099. Email: firstname.lastname@example.org
Treatment of advanced non small cell lung cancer (NSCLC) has been a challenge for oncologists in the past two decades. Meta-analysis conducted decade determined that cisplatin based chemotherapy prolonged survival in advanced NSCLC. Since then various combinations of cytotoxic agents like gemcitabine, docetaxel, paclitaxel and vinorelbine with either cisplatin or carboplatin have made undeniable gains in survival rates among the patients with advanced NSCLC and this has been confirmed by various randomized studies between 1991 and 2001. This article gives a critical appraisal of published data related to chemotherapeutic approaches for advanced NSCLC including a recent meta-analysis which aims to quantify the treatment effect of gemcitabine plus platinum agents in advanced NSCLC using randomized clinical trials. The evidence suggests an improvement in progression free survival for gemcitabine-platinum compared to other agents. Some encouraging data about various targeted therapies (Eroltinib and Gefitinib) in advanced NSCLC has also been discussed.
NSCLC, Chemotherapy, targeted therapy
Lung cancer is one of the most common cancers in the world, in terms of incidence and mortality with over one million new cases annually(1).Non Small Cell Lung Cancer (NSCLC) accounts for atleast 80% of all lung cancer cases, presenting as locally advanced disease in approximately 25-30% of cases and as metastatic disease in approximately in 40-50% of cases(2)The use of chemotherapy in patients with NSCLC has been under investigation for several decades. It has evolved from administration in the palliative care setting to the integration into combined modality curative therapy settings in patients with locally advanced disease. Prior to 1993, attempts to identify new chemotherapeutic agents and combinations with activity against NSCLC met with little success. Recently, however, several new compounds have offered hope for some improvement in response and survival while being relatively well tolerated in patients with this disease. A wide- reaching meta-analysis conducted during last decade suggested that cisplatin-based chemotherapy prolonged survival in advanced NSCLC, and an addition of third generation cytotoxic agent like gemcitabine, taxanes and vinorelbine with either cisplatin or carboplatin have made definite gains in the survival rates for the patients with advanced NSCLC.
Review of Meta-Analysis
There are incremental advances in the treatment of NSCLC during the last two decades. Platinum based combination chemotherapies emerged as the standard treatment for advanced NSCLC(3),(4).. Randomized studies from 1980â€™s reported survival gains with cisplatin based chemotherapy over best supportive care, which was confirmed by a large meta-analysis of cisplatin based chemotherapy that estimated significant increases in median survival of 1.5 months and 1 year survival of 10% (5).. A 1995 meta-analysis of chemotherapy in patients with advanced non-small cell lung carcinoma indicated clinical benefit from cisplatin based chemotherapy. Subsequent studies have aimed either to increase the efficacy or decrease the toxicity of chemotherapy. (Table/Fig 1)(6)
Reviews from various studies and meta analyses of different aspects of chemotherapy which have taken place over the last decade, suggest that the use of third generation chemotherapy agents has resulted in a further increase in patient survival. Gemcitabine was shown to be associated with an increase in progression free survival (PFS) when compared to other third generation agents as well as a strong tendency to increased overall survival. An increase in survival was also shown with doublet chemotherapy regimes as compared to the use of single agents only. The use of triplet agent chemotherapy results in no further increased survival, but increased toxicity. Cisplatin is associated with increased survival over carboplatin based chemotherapy regimens when third generation agents are used, but increased nausea and vomiting. Non-platinum third generation combinations give equivalent survival to platinum-based regimens. Thereby a conclusion was drawn that, the first line chemotherapy given to patients with advanced NSCLC should be two-drug combination regimen. Non-platinum containing regimens may be used as an alternative to platinum based regimens in the first line(7).
A recently published data on meta-analysis of survival outcomes in advanced NSCLC (4556 patients from 13 randomized trials ) aims to quantify the treatment effects of gemcitabine plus a platinum agent, cisplatin or carboplatin, in the treatment of advanced NSCLC using randomized clinical trials(8). The primary comparator was any regimen containing a platinum agent alone or in combination. The main out come of interest w
Gemcitabine is one of the most active drugs approved for advanced NSCLC in recent years. It is a novel nucleoside analogue exercising a wide spectrum of anti tumoural activity, and in combination with cisplatin has activity in NSCLC. Several phase II studies of gemcitabine plus cisplatin reported median survival times of(15),(16),(17),(18),(19) months and response rates of 40-50% while phase III studies showed superiority of gemcitabine plus cisplatinum in advanced NSCLC in terms of both survival and QOL benefits when compared with platinum alone or in combination with older chemotherapy agent(17),(18) Gemcitabine plus cisplatin is widely used in clinical practice globally, and in several European countries has become a common doublet for treatment of advanced NSCLC. Replacement of cisplatin with carboplatin is attractive because it avoids cisplatin side effects and administration requirements. The combination of gemcitabine and carboplatin has been shown to be feasible and active in various recent clinical trials(19),(20),(21).
The recently published report on meta-analysis of survival outcomes of advanced NSCLC evaluated a large data of 4556 patients from 13 randomized clinical trials. Since 1995 ten primary meta-analyses have been published on NSCLC(9),(22),(23) and out of these ten, two used individual patient data while the remaining used summary data from published sources. The meta-analysis ranges from several trials and 700 patients to 25 trials and 5156 patients.
Treatment with gemcitabine-platinum regimens produced a statistically significant reduced risk of mortality with an absolute benefit on OS of 3.9% at one year and 2.6% at two years. This benefit translates to 1039 gemcitabine-platinum treated patients alive at one year compared to 1000 non gemcitabine-platinum treated patients. The estimated difference in median survival of 3 weeks for gemcitabine-platinum regimen represents a slight, but meaningful improvement in median survival in NSCLC (9.0 months versus 8.2 months). The treatment benefit obtained from using meta-analysis is enough evidence for use by consolidating data of individual trials.
Based on the above results, it is possible to conclude that NSCLC patients today are receiving treatment that is superior in terms of efficacy to treatment 10 years ago. The meta-analysis also suggests an improvement in progression free survival for gemcitabine-platinum compared to other third generation agent platinum combination, as well as a clear trend towards improved survival, although the latter just missed statistical significance, making the gemcitabine-cisplatinum doublet a reference regimen not surpassed by any of the other current doublets.
Genomic and proteomic studies have started to shed new light on the biology of NSCLC(24),(25). Gene mutations have been discovered that predict clinical benefits from treatment with the EGFR tyrosine kinase inhibitor gefitinib(26). The day is not far when the patient will receive treatment that gives them the best chance of benefit while sparing them from toxicity associated with treatment that they likely would not benefit from. Until then, the oncologist should select the chemotherapy regimen based on probability of survival benefit balanced by the toxicity profile.
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