Felip E, Rosell R.

Vall d’Hebron University Hospital Barcelona, Spain.

Abstract

NSCLC accounts for 80% of all cases of lung cancer, which is the leading cause of cancer mortality. The majority of NSCLC patients present with advanced, unresectable disease, which remains incurable. In advanced disease, chemotherapy with platinum (cisplatin or carboplatin) in combination with a third-generation cytotoxic drug (vinorelbine, gemcitabine, paclitaxel, or docetaxel) can provide a modest improvement in survival without impairing quality of life. In chemotherapy-naïve, advanced, non-squamous NSCLC patients, the combination of bevacizumab with chemotherapy was shown to produce better outcomes than chemotherapy alone. Response rates of 20%-40% can now be expected, with a median survival of 8-11 months and a 1-year survival rate of 30%-40%. In second-line treatment, docetaxel has shown superiority to best supportive care in terms of survival and quality of life. A pooled analysis comparing docetaxel administered weekly versus 3-weekly found similar survival rates between the schedules and a non-significant reduction in febrile neutropenia for the weekly regimen. Pemetrexed, a multitargeted antifolate agent, has shown clear activity in several tumors, including mesothelioma and NSCLC. In a phase III trial, second-line treatment with pemetrexed demonstrated overall survival comparable to docetaxel, with a more manageable toxicity profile.

Keywords: pemetrexed, second-line therapy, NSCLC

Abstract

(1) Chemotherapy does not appear to prolong the survival of patients with inoperable pleural mesothelioma, and the tumour response rate barely exceeds 20%. A combination of cisplatin + doxorubicin seems to provide the best response rates. (2) In a trial of second-line docetaxel therapy in patients with non small cell lung cancer, survival was extended by about 3 months compared with palliative care (7.5 versus 4.6 months). (3) Pemetrexed, an antifolate closely related to methotrexate and raltitrexed, has been authorized for use for both conditions. (4) In a randomised single-blind trial involving 456 patients with previously untreated pleural mesothelioma, survival was prolonged by about 3 months by a cisplatin + pemetrexed combination in comparison with cisplatin + placebo (12.1 versus 9.3 months). The respective tumour response rates were 41.3% and 16.7%. This is the only available comparative trial of pemetrexed in patients with mesothelioma. A more appropriate comparator would have been a cisplatin-based regimen such as cisplatin + doxorubicin. (5) A "non inferiority" trial of second-line treatment in 571 patients with locally advanced or metastatic non small cell lung cancer showed no significant difference in median survival time with pemetrexed versus docetaxel (about 8 months with both treatments). However, this trial does not rule out the possibility that pemetrexed is less effective than docetaxel. (6) Supplementation with folic acid and vitamin B12 reduces haematological and gastrointestinal complications associated with the antifolate activity of pemetrexed. (7) Despite this supplementation, more than 15% of patients in the mesothelioma trial developed severe neutropenia, leukopenia or fatigue during cisplatin + pemetrexed therapy. Pemetrexed aggravates the nausea and vomiting provoked by cisplatin, a drug that is highly emetic. (8) The adverse effects of pemetrexed were similar to those of docetaxel in the trial comparing the two drugs. However, neutropenia (5% versus 40%) and febrile neutropenia (2% versus 13%) occurred less frequently with pemetrexed. (9) Patients receiving pemetrexed must be monitored closely for some rare but potentially severe adverse effects; they include angina, myocardial infarction and stroke, liver damage, and bullous skin rash. (10) According to the summary of product characteristics (SPC), pemetrexed therapy must be administered in combination with folic acid and vitamin B12 supplementation in order to reduce haematological toxicity, and also with corticosteroid therapy to reduce the risk of serious skin reactions. (11) In practice, given the absence of a better alternative, and pending the results of a second trial, the cisplatin + pemetrexed combination can be used as a first-line regimen for patients with pleural mesothelioma. However, pemetrexed cannot replace docetaxel in second-line treatment of non small cell lung cancer.