Neutropenia and Survival in NSCLC
Neutropenia and Survival in NSCLC
Abstract & Commentary
By William B. Ershler, MD
Synopsis: Examining data from a randomized trial of two different chemotherapy regimens for non-small cell lung cancer, Kishida et al found that chemotherapy-induced neutropenia is a predictor of better survival. The authors call for future trials in which dose increases are employed in the absence of neutropenia or other chemotherapy-induced toxicity.
Source: Kishida Y, et al. Chemotherapy-induced neutropenia as a prognostic factor in advanced non-small cell lung cancer: results from Japan Mutational Trial Organization lC00-03. Br Journal of Cancer. 2009;101:1537-1542.
Neutropenia is a common adverse reaction of chemotherapy. However, it has also been apparent that chemotherapy-induced neutropenia is associated with better overall outcomes under certain circumstances. For example, several studies have reported that neutropenia that occurs during chemotherapy is a predictor of significantly longer survival for patients with breast cancer.1,2 More recently, Di Maio et al3 confirmed the positive correlation between chemotherapy-induced neutropenia and increased survival in a pooled analysis of three randomized trials, which included 1265 patients with advanced non-small-cell lung cancer (NSCLC). Pallis et al4 have also demonstrated an association between chemotherapy-induced neutropenia and better clinical outcome for patients with NSCLC. In light of these reports, Kishidaet al analyzed the associations between the extent of chemotherapy-induced neutropenia, overall survival, and tumor response by reviewing data from a clinical trial conducted throughout Japan of patients with advanced NSCLC.
A total of 387 chemotherapy-naive patients who received chemotherapy (vinorelbine and gemcitabine followed by docetaxel, or paclitaxel and carboplatin) in a randomized, controlled trial were evaluated. Enrolled NSCLC patients included those with stage IIIB or IV who were Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1 during the years 2001 to 2005. Details of the trial, including dose modifications and responses, were published in 2008.5 Briefly, the experimental group (VGD arm, n = 192) received three cycles of intravenous vinorelbine (25 mg/m2) and gemcitabine (1000 mg/m2) administered on days 1 and 8 of each 21-day cycle, followed by three cycles of single-agent intravenous docetaxel (60 mg/m2) administered on day 1 of each 21-day cycle. The standard regimen (PC arm, n = 195) consisted of six cycles of intravenous paclitaxel (225 mg/m2) plus carboplatin (area under curve = 6) infused on day 1 of each 21-day cycle. The protocol permitted use of granulocyte-colony-stimulating factor (G-CSF) for patients with grade-3 neutropenia with fever or grade-4 leukopenia or neutropenia, but did not permit prophylactic use.
There was no difference in median progression-free or overall survival between treatment groups, and there were no complete responses. The incidence of grade 3 and 4 neutropenia, neuropathy, arthralgia, and myalgia was lower in the experimental group than in the standard group, although the incidence of pulmonary toxicity was higher.
For the current post-hoc analysis on the effect of chemotherapy-induced neutropenia on tumor response on overall survival, the proportional-hazards regression model was used. Landmark analysis was undertaken to lessen the bias of more severe neutropenia resulting from more treatment cycles allowed by longer survival. Accordingly, patients (n=33) who died within 126 days (6 cycles) of starting chemotherapy were excluded.
The adjusted hazard ratios (HR) for patients with grade-1 to 2 neutropenia or grade-3 to 4 neutropenia compared with no neutropenia were 0.59 (95% confidence interval (CI), 0.36-0.97) and 0.71 (95% CI, 0.49-1.03), respectively. The HRs did not differ significantly between the patients who developed neutropenia with stable disease (SD) and those who lacked neutropenia with partial response (PR).
Commentary
In this review of data from a randomized clinical trial, patients with advanced stage NSCLC who developed neutropenia showed longer survival than those who had no neutropenia. Furthermore, severe neutropenia (grade 3-4) was not better than mild neutropenia (grade 1-2) for prediction of overall survival. It is likely that the neutropenia itself is of little consequence, other than as a marker of adequate chemotherapy response.
Clinical oncologists calculate the appropriate dose and schedule of chemotherapy based upon body mass index, renal, and liver function. However, such an approach may not be sufficient to predict metabolism and excretion of drugs sufficiently to assure adequate exposure for some and to prevent toxicity in others. The current findings might be interpreted to suggest that the absence of neutropenia is the result of lower than necessary chemotherapeutic dose to produce an antitumor response. From this perspective, neutropenia or other toxicities induced by chemotherapy could be used to tailor dose/scheduling for individual patients. Of course, it would be nice if it were this simple, but this premise is based upon assumptions that are not at all established. Certainly, the experience with hematopoietic stem cell transplantation for patients with solid tumors would counter this premise. Nonetheless, the concept that to the extent that chemotherapy comparably affects bone marrow and tumor-proliferating cells, it is reasonable to explore the hypothesis, in a clinical research setting, that increasing dose intensity in the second and subsequent cycles for patients with NSCLC who had not experienced neutropenia or other toxicity in earlier cycles. Indeed, prospective, randomized trials that include early-dose increases guided by the absence of chemotherapy-induced toxicities is a concept worthy of consideration.
References
1. Saarto T, et al. Haematological toxicity: a marker of adjuvant chemotherapy efficacy in stage II and III breast cancer. Br J Cancer. 1997;75:301-305.
2. Cameron DA, et al. Moderate neutropenia with adjuvant CMF confers improved survival in early breast cancer. Br J Cancer. 2003;89:1837-1842.
3. Di Maio M, et al. Chemotherapy-induced neutropenia and treatment efficacy in advanced non-small-cell lung cancer: A pooled analysis of three randomised trials. Lancet Oncol. 2005;6:669-677.
4. Pallis AG, et al. Chemotherapy-induced neutropenia as a prognostic factor in patients with advanced non-small cell lung cancer treated with front-line docetaxel-gemcitabine chemotherapy. Lung Cancer. 2008;62:356-363.
5. Kubota K, et al. Vinorelbine plus gemcitabine followed by docetaxel versus carboplatin plus paclitaxel in patients with advanced non-small-cell lung cancer: A randomised, open-label, phase III study. Lancet Oncol. 2008;9:1135-1142.
Examining data from a randomized trial of two different chemotherapy regimens for non-small cell lung cancer, Kishida et al found that chemotherapy-induced neutropenia is a predictor of better survival. The authors call for future trials in which dose increases are employed in the absence of neutropenia or other chemotherapy-induced toxicity.Subscribe Now for Access
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