A New Paradigm Shift: Platinum-Based Doublets Better than Monotherapy even in Patients with Advanced Non-Small Cell Lung Cancer and Performance Status 2

Omar Abdel-Rahman

Lung cancer is the leading cause of cancer mortality in many developed as well as developing countries. According to European cancer forecasts, male lung cancer estimated rates in 2012 varied between 56,8/100,000 in Poland and 30,1/100,000 in the UK. While in women rising trends were observed in all countries (approximately 20/100,000 women) (1).  In the USA, it has been estimated that approximately 221,130 people will be diagnosed with the disease in 2011, including 115,060 men and 106,070 women. Moreover, the mortality of lung cancer closely follows the incidence, with an estimated 156,940 deaths in 2011 (2).

Approximately a half of patients present with advanced, stage IV disease at the time of diagnosis. In addition, a significant number of patients who present with early-stage non-small cell lung cancer (NSCLC) eventually relapse within distant disease scenario.

Patients who present with or develop distant disease have a median survival ranging from  4-6 months when managed with best supportive care alone. Since the landmark British meta analysis from 1995 (3) that showed statistically significant benefit for chemotherapy versus best supportive care, platinum-based doublet chemotherapy has been considered the standard of care for patients with advanced NSCLC.

However, the management of elderly patients and those with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2  and advanced NSCLC has been debated, because these 2 subsets have not been properly represented in the majority of chemotherapy studies for advanced disease. In 2004, European panel of experts recommend that in patients with ECOG PS2 “single-agent chemotherapy (gemcitabine, vinorelbine, taxanes) could be the preferred option, although carboplatin-based or low-dose cisplatin-based doublets may represent alternative options” (4).

In the current study, Zukin and colleagues (5) conducted a multicenter phase III randomized study to compare single-agent pemetrexed versus the combination of carboplatin and pemetrexed in first-line therapy for patients with advanced NSCLC and ECOG PS2, the study was intended for any histology at first and later amended to non-squamous only.

In this study, a total of 205 eligible patients were enrolled from eight centers in Brazil and one in the United States from April 2008 to July 2011. Notably, the median progression-free survival was 2,8 months for pemetrexed monotherapy arm and 5,8 months for combination chemotherapy arm (p<0.001), while the median overall survival was 5,3 months for pemetrexed and 9,3 months for pemetrexed/carboplatin (p<0.001).  Interestingly enough, similar results were seen when patients with squamous disease were excluded from the analysis.

As expected, more hematological toxicity (anaemia and neutropenia) were seen with the combination arm compared to the monotherapy arm; however, the majority of toxicities were grade 1/2. There were four documented treatment-related deaths in the combination arm (3,9%) as a result of renal failure, sepsis, pnaeumonia, and thrombocytopaenia.

Overall, this study provides the strongest evidence until now for superiority of platinum-based doublets over monotherapy in patients with advanced NSCLC and ECOG PS2 with tolerable toxicity. It may support clinical consideration of combination chemotherapy as the standard of care in this subset of patients.

However, the above results, especially regarding patients with non-squamous histology, seems highly challenging for interpretation and immediate clinical adoption, at least without consideration of molecular characterization, due to the wealth of data on the growing role of EGFR/ALK inhibitors in selected subsets of patients with advanced non-squamous NSCLC.

Discussion questions

  • In your practice, do you consider that platinum-based doublet chemotherapy should be adopted as the standard of care for all NSCLC patients with ECOG PS 2?
  • What is the role of other factors (age, comorbidity or EGFR/ALK mutational status) you will consider in your decision?

 References:

  1. Malvezzi M, Bertuccio P, Levi F, et al. European cancer mortality predictions for the year 2012. Ann Oncol 2012;23(4):1044-52.
  2. Siegel R, Ward E, Brawley O et al.. Cancer statistics, 2011. CA Cancer J Clin. 2011;61:212-236.
  3. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 1995; 311(7010):899-909.
  4. Gridelli C, Ardizzoni A, Le Chevalier T,et al.Treatment of advanced non-small-cell lung cancer patients with ECOG performance status 2: results of an European Experts Panel. Ann Oncol 2004;15(3):419-26.
  5. Zukin M, Barrios CH, Rodrigues Pereira J,et al.Randomized Phase III Trial of Single-Agent Pemetrexed Versus Carboplatin and Pemetrexed in Patients With Advanced Non-Small-Cell Lung Cancer and Eastern Cooperative Oncology Group Performance Status of 2. JCO 2013; Jun 17. [Epub ahead of print]

The content of this article reflects the personal opinions of the authors and is not necessarily the official position of the European Society for Medical Oncology.

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