Adjuvant Chemotherapy With Pemetrexed and Cisplatin vs. Vinorelbine and Cisplatin in NSCLC IB, IIA, IIB, T3N1: a Randomized Phase II Study
Derived from recent large randomized clinical trials, there is clear evidence for adjuvant
chemotherapy in stage IB-IIB (incidental IIIA) non-small cell lung cancer (Arriagada et al.,
2004; Winton et al., 2005, Strauss et al., 2004, Douillard et al., 2005). The majority of
patients in the adjuvant treatment setting received a combination of Cisplatin and
Vinorelbine (Aragiada et al., 2004; Winton et al., 2005; Douillard et al., 2005). This
combination improved 5 year-survival rates up to 15% (54% to 69%) (Winton et al., 2005).
However, the combination of Cisplatin and Vinorelbine resulted in rates of grade 3/4
neutropenia of around 75%, rates of febrile neutropenia of up to 12.5% and rates of
treatment related death of 1-2%. Up to 77% of the patients had at least one dose reduction
or omission and 55% required one dose delay or more, most related to neutropenia. Only about
50 % of patients randomized on the combination of cisplatin and vinorelbine received the
intended dose of Vinorelbine (dose reduction mainly due to toxicity) and only 50% of
patients completed all four cycles of chemotherapy (Winton et al., 2005, Douillard et al.,
2005, Alam et al., 2005).
Therefore it seems reasonable to test a less toxic regimen also in early stages after R0
resection of the tumor, where reduced toxicities might improve the feasibility of drug
delivery, compliance and the convenience of treatment for the patient and hence perhaps
Pemetrexed, a folate antimetabolite, shows clear activity in non-small cell lung cancer with
several Phase II studies of Pemetrexed in combination with Cisplatin, Oxaliplatin, or
Carboplatin showing efficacy similar to other standard platinum doublets, with response
rates of 27% to 45% and median survival of 8.9 to 10.9 months (Scagliotti et al., 2005;
Clarke et al., 2002; Rusthoven et al., 1999; Manegold et al., 2000; Shepherd et al., 2001).
The combination of platin and Pemetrexed can be easily delivered and is well tolerated.
Furthermore, it only results in a 25% rate of grade 3/4 neutropenia and in vitamin
supplemented patients the incidence of febrile neutropenia was < 1%. Dose reductions occur
only in 2-4% of the patients and dose delivery of the intended Pemetrexed and platin dose is
excellent with dose deliveries of Pemetrexed up to 95% (Hanna et al., 2004; Vogelzang et
al., 2003, Scagliotti et al., 2005).
In this randomized phase II trial, the clinical feasibility of the combination of Cisplatin
and Pemetrexed as well as of the combination of Cisplatin and Vinorelbine will be assessed.
Treatment is considered to have clinical feasibility if dose limiting toxicity will not be
observed, and no non-acceptance by the patient leading to premature withdrawal, and no death
due to cancer or cancer therapy will occur.
Patients will be randomized according to center, lobectomy vs. pneumonectomy and N0 vs. N1
to 4 cycles (arm A) of 500 mg/m2 pemetrexed d1, and Cisplatin 75 mg/m2 d1, q d22 versus (arm
B) 25 mg/m2 Vinorelbine d1, 8, 15, 22, and Cisplatin 50 mg/m2 d1+8; q d29. Radiotherapy or
maintenance therapy are not intended. Study drug administration will begin on d28 to d42
after R0 resection of the tumor and within 14 days after randomization.
In an initial study phase 36 patients (i.e. 18 in each treatment arm) will be accrued to
confirm feasibility. In the second step, further patients will be recruited up to a total
number of 134 (i.e. 67 cases per treatment arm). Patients will be followed-up in 3 monthly
intervals for the first 2 years starting 30 days after end of the last cycle and in the 3rd
year patients will be followed-up in 6 monthly intervals.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
To determine the clinical feasibility rate of 4 cycles of adjuvant chemotherapy with Pemetrexed and Cisplatin vs. Vinorelbine and Cisplatin
Michael Thomas, Prof. Dr.
Clinic for thoracic diseases at the University of Heidelberg, Germany
Germany: Federal Institute for Drugs and Medical Devices