Presenter: Natale R.B. Presenter's Affiliation: Cedar Sinai Cancer Center, Los Angeles, California Type of Session: Scientific
The most widely accepted standard of care for small call lung cancer (SCLC) for the past 20 years has been etoposide and cisplatin (EP).
Irinotecan has been shown to have efficacy in SCLS as both a single agent as well as in conjunction with cisplatin.
However, the role of irinotecan in extensive SCLC (E-SCLC) remains controversial:
The first of two large trials examining the use of irinotecan and cisplatin (IP) versus EP was performed in Japanese patients with E-SCLC ( JP511, Noda, et al. NEJM 2002). This study found a significant improvement in overall survival in patients treated with IP versus EP.
This was followed by a later study intended to confirm these results conducted by the North American/Australian Study group (Hanna, et al. JCO 2006). This study failed to confirm the results from JP511.
Irinotecan is a prodrug with complex activation and metabolism.
There are known ethnic differences in irinotecan metabolism, and this could have potentially accounted for the difference between the two studies described above.
The primary objectives of the present study were to:
try to reproduce the results seen in JP511
confirm that the results from JP511 applied to North American patients
confirm the safety of IP
Materials and Methods
Inclusion and exclusion Criteria:
patients had to have histologically confirmed E-SCLC
patients had to have adequate end organ function
patients could not have brain metastasis
Patients were stratified by:
number of metastasis (one versus multiple sites of metastasis)
normal versus elevated LDH
weight loss of 5% or less versus >5%
Patients were then randomized to either EP or IP, which was administered as follows:
Irinotecan: 60 mg/m2 on days 1, 8, and 15
Cisplatin: 60 mg/m2 on days 1, every four weeks
Etoposide: 100 mg/m2 on days 1-3
Cisplatin: 80 mg/m2 on day 1 every three weeks
Data collection for pharmacogenomic analysis was also performed. Blood samples were drawn prior to randomization, and single nucleotide polymorphisms (SNP) were assayed for using polymerase chain reaction (PCR).
Endpoints included overall survival (OS), progression free survival (PFS), and response rate (RR).
A total of 671 patients were accrued for the present study from November of 2002 to March of 2007
Of the 671 patients, 645 were eligible for the study
There were a total of 323 patients randomized to the IP arm and 322 patients to the EP arm.
Patient demographics were well-balanced between the two treatment arms.
For the entire cohort, the median age was 63 yo.
57% of patients were males
76% had multiple sites of metastasis
62% had weight loss of 5% or less
Toxicities (grade 3 + 4):
There was more hematological toxicity in the EP arm but more GI toxicity in the IP arm. When results from JP511 were compared to the present study, hematologic toxicity was similar in both the IP and EP arms in both studies. However, there was no increase in GI toxicity seen in JP511 in patients treated with IP compared with those treated with EP.
There were 12 treatment-related deaths in the IP arm as compared to 8 in the EP arm.
There were no differences in the OS (p=0.71), PFS (p=0.07) or RR between the two treatment arms.
Genomic analysis demonstrated:
oPatients with either the ABCB1 (OR=5.0) or the UGT1A1 (OR~7) SNP’s were more likely to have grade 3 or greater neutropenia and grade 3 or greater diarrhea.
This large phase III trial failed to demonstrate a benefit for IP therapy compared with EP, despite previous studies suggesting a benefit to IP. There are several possible explanations for this:
oPharmacogenomics: The Japanese population may have different polymorphisms, resulting in differences in irinotecan metabolism which could affect toxicity and efficacy.
oTumor genomics: Similarly, differences in tumor characteristics may have accounted for this discrepancy.
oJP511 was stopped early and because of this, the difference between the two groups may have been due to chance alone.
Based on these results, the authors state that EP is still the standard of care in the treatment of patients with E-SCLC
This is now the second clinical trial which has failed to demonstrate a survival benefit with IP therapy versus EP therapy in patients with E-SCLC. The authors point out that genetic variability may be responsible for the discrepancy between the two studies. Another potential confounder is smoking. There have been some data to suggest that smoking affects the metabolism of irinotecan. Unfortunately, smoking status was not recorded in the present study. However, it is also certainly possible, as the authors point out, that the results from the JP511 study were spurious. Nonetheless, from the combined results of the two American trials, it is clear that EP remains the standard of care for E-SCLC.
However, the results of this study may still be quite useful. As noted by the authors, there are differences in irinotecan metabolism based on ethnicity. They have identified SNP’s which are associated with greater toxicity with irinotecan therapy, and these SNP’s may aid in patient selection or stratification in future studies. The authors did examine a number of variables to determine if they were associated with a superior outcome, but found no such association. They did not look at the outcomes when patients with polymorphisms associated with greater toxicity were excluded, which might have led to some interesting findings.
Mar 12, 2014 - In a phase III clinical trial, gefitinib was superior to carboplatin-paclitaxel in extending survival for patients with non-small-cell lung cancer, particularly those patients with epidermal growth factor receptor gene mutations, according to a study published online Aug. 19 in the New England Journal of Medicine.