Lay Summary: Chemotherapy for non-small cell lung cancer is discussed.
Palliative chemotherapy for metastatic lung cancer is now standard. Platinum-based combinations were the first regimens to convincingly have an impact on survival and have been the standard of care in NSCLC. A European study showed that gemcitabine/cisplatin was essentiall equivalent to paclitaxel and a platin and the former became standard in Europe whereas the latter is most often used in the USA. Docetaxel has been shown to be equivalent to paclitaxel in phase III studies.A randomized comparative study showed that paclitaxel and gemcitabine (PG) and paclitaxel and carboplatin (PC) combinations for the treatment of advanced non–small-cell lung cancer (NSCLC)are equivalent and equally tolerated.
More recently Avastin has been shown to add to the survival benefit. Bevacizumab (Avastin®) is a humanized recombinant antibody to vascular endothelial growth factor-A (VEGF-A). VEGF-A bound to bevacizumab cannot bind to or activate VEGF receptors (VEGF-R) on vascular endothelial and other cells. Biological consequences include inhibition of angiogenesis (growth of new blood vessels) in tumors. Bevacizumab combined with intravenous fluorouracil-based chemotherapy is indicated as first- or second-line therapy for advanced or metastatic colon or rectal cancers.
An Eastern Cooperative Oncology Group (ECOG) multicenter RCT (E2100) on paclitaxel with (n=341) versus without (n=339) bevacizumab as first-line therapy for inoperable metastatic disease found that it was of value. The first interim analysis reported statistically significant improvement in overall response rate (ORR), PFS, and OS. The second interim analysis also found statistically significant improvement in ORR (30% versus 14%, p<0.0001) and PFS (11.4 versus 6.1 months; p<0.0001), but effects on OS were no longer statistically significant (28.4 versus 25.2 months; p=0.12). Avastin has subsequently gained approval for breast cancer in the US and EU, and for first-line NSCLC in the US.
A second large multicenter study, AVAIL, has shown that adding bevacizumab (Avastin, Genentech) to chemotherapy improves survival in patients with advanced non–small-cell lung cancer (NSCLC). This latest study was conducted in Europe and used a different chemotherapy regimen, gemcitabine and cisplatin, the European standard, from that used in the first trial, which was carried out in the United States. But the results from both trials were similar — adding bevacizumab significantly improved progression-free survival (PFS).
In breast cancer where Avastin was FDA approved, the role of Avastin is beng re-evaluated following reports of a new study showing no benefit in first line. One can question the true benefit of bevacizumab for lung canner as well, pointing out that the improvement in median PFS over control was only 2 weeks. On the other hand, the drug increases the risk for adverse events and costs thousands of dollars. However, the same is true of the now accepted in the USA paclitaxel and carboplatin + Avastin. In the USA paclitaxel and carboplatin is now standard and Avastin was approved by the FDA in a “a first-line treatment of patients with locally advanced, metastatic or recurrent non-small cell lung cancer in combination with platinum-based chemotherapy”. NCCN now recommends bevacizumab with “chemotherapy” without defining is solely as being platin based.
NCCN has first and second line therapy recommendations, both single agents and in combination. For third line therapy NCCN recommends Docetaxel, Pemetrexed, Erlotinib or Docetaxel, Pemetrexed, Erlotinib, Gemcitabine. Therefore, there are standard options and a clinical study is not standard of care.
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