Abstract
Background: Despite accounting for more than half of the patients diagnosed with non-small cell lung cancer (NSCLC), only 20% of elderly patients receive chemotherapy. One reason for withholding systemic therapy is the concern for an increased incidence of side-effects, especially cytopenia from bone marrow toxicity. Limited data exist regarding specific factors that affect blood count nadirs following chemotherapy. Patients and Methods: A retrospective chart review was conducted of chemotherapy-naïve patients who had received standard doses of carboplatin and paclitaxel for NSCLC. Hemoglobin levels, total white blood cell counts (WBC) and platelet counts before each chemotherapy cycle and nadir counts following each cycle were obtained. Wilcoxon test and Chi-square test were used for univariate comparisons of patient characteristics and unpaired t-test for hematological parameters. Multivariate analyses of change over time in the hematological parameters by age groups were performed using mixed models while adjusting for other clinical factors. Results: Of the 91 consecutive patients identified from the medical records between 1992 and 2007, 37 (41%) were <60 years old at diagnosis. Pre-chemotherapy and nadir values for hemoglobin, WBC and platelet counts did not vary by age over time. The nadir values correlated with the corresponding pre-chemotherapy values. Both the pre-chemotherapy and nadir values showed a decreasing trend with increasing numbers of chemotherapy cycles administered. Conclusion: Age does not affect the nadir counts of hemoglobin, WBC and platelets following administration of carboplatin and paclitaxel for NSCLC. Pre-chemotherapy blood counts are more important determinants of hematologic toxicity following administration of carboplatin and paclitaxel for advanced NSCLC.
- Chemotherapy
- carboplatin
- paclitaxel
- hematologic toxicity
- age
- non-small cell lung cancer
Approximately 1.35 million new cases of lung cancer are diagnosed every year. This disease is the largest cause of cancer-related deaths in the world (1). The median age of patients diagnosed with lung cancer is 69 years (2). Patients older than 65 years account for more than half of all patients with advanced non-small cell lung cancer (NSCLC), while nearly 40% of patients are older than 70 years (3). Age is not a poor prognostic factor for overall survival in advanced NSCLC (4). Nonetheless, studies estimate that only about 20% of patients over the age of 65 receive chemotherapy (5).
One reason older patients with newly diagnosed NSCLC are not treated with standard chemotherapy is the concern that associated bone marrow suppression can result in life-threatening complications (6) and older individuals are perceived to be at increased risk of myelotoxicity because of either a reduced hemopoietic reserve (7-9) or a limited ability to mobilize progenitor cells in the marrow (10, 11). Although hematopoiesis is believed to be altered even in healthy older persons (6), studies have demonstrated that the numbers of circulating hematopoietic cells in healthy elderly persons do not differ from those of young adults (12, 13).
Studies in patients with non-Hodgkin's lymphoma or breast cancer have demonstrated that older patients have greater hematological toxicity following administration of cytotoxic chemotherapy when compared to younger individuals (14, 15), but specific data in NSCLC are lacking. In addition, the lymphoma and breast cancer studies measured the proportion of patients who developed grade 3 and 4 cytopenia following chemotherapy. Sparse data are available regarding the effect of age and other factors affecting the drop in blood counts following administration of cytotoxic chemotherapy in patients with cancer. This study was designed to evaluate of the association of age and other factors with changes in blood cell counts in individuals with NSCLC following administration of cytotoxic chemotherapy.
Patients and Methods
A retrospective chart review was conducted on consecutive chemotherapy-naïve patients who received identical doses of carboplatin and paclitaxel between 1996 and 2007 for NSCLC in the Medical Oncology Clinic at the University of Nebraska Medical Center by one of two physicians (AG, AK). Patients were chemotherapy naïve and received carboplatin (area under the curve 5 mg/ml/min) and paclitaxel (175 mg/m2) every three weeks for a maximum of six cycles. Patients with stage III disease also received thoracic radiation therapy concurrently with the same doses of chemotherapy as described above.
After Institutional Review Board approval, the following data were collected: age, gender, smoking and alcohol history and stage at diagnosis. Values for hemoglobin, total white blood cell (WBC) and platelet counts before each chemotherapy cycle and nadir counts following each cycle were obtained. From these values, the percentage drop in counts for each cycle were calculated. Chemotherapy administration delays due to low blood counts were also recorded. Only patients with nadir hematological values for at least one cycle were included in this analysis.
Patients were divided into two groups according to age: <60 and ≥60 years old. Patient characteristics were compared according to age group using Wilcoxon test and Chi-square test for continuous and categorical data respectively. Pointwise univariate comparison of various hematological parameters according to age group was carried out using unpaired t-test. Multivariate comparisons of changes in hematological parameters between age over time were performed using mixed models (PROC MIXED) while assuming autoregressive covariance correlation. Other covariates included in the model included gender, disease stage, smoking and alcohol intake. An alpha of ≤0.05 was considered statistically significant. All analyses were performed using SAS for Windows v9.1 (SAS Institute Inc., Cary, NC, USA).
Results
A review of the database revealed that there were 397 patients with NSCLC. Of these, 143 patients received a regimen containing carboplatin and paclitaxel as their initial chemotherapy. Ninety-one patients had pre-chemotherapy and nadir values for hemoglobin, WBC and platelet counts following at least one cycle and hence were included in this analysis. There was no difference in age between the 91 patients who were included in this analysis and the 52 who were not (p=0.78). The median age of these patients was 61 years (range: 21-83 years). Thirty-seven patients (49%) were less than 60 years old and 54 patients (51%) were 60 years or older, and data from these patients were analyzed on this basis. These two groups were similar in terms of gender, smoking status, stage at diagnosis and previous or concurrent radiation therapy (Table I). Patients with primarily resected disease (clinical stages I and II) received carboplatin and paclitaxel either as adjuvant therapy (n=17) or as initial chemotherapy at relapse (n=4).
Pre-treatment cycle values of hemoglobin, WBC and platelet counts were available for all patients before cycle 1 and for 81 (32 younger and 49 older), 67 (26 younger and 41 older), 57 (21 younger and 36 older) and 29 (10 younger and 19 older) patients before cycles 2, 3, 4 and 5 respectively. There was no difference in the pre-chemotherapy values for hemoglobin, WBC and platelets counts between the two groups for any of the cycles of chemotherapy (Table II). However, there was a downward trend in the levels of hemoglobin, WBC and platelet counts with number of cycles of chemotherapy administered in both the younger and the older groups (p<0.001 for all comparisons) (Table II).
In the multivariate analysis, nadir values of the hematological parameters showed a statistically significant decrease over time (chemotherapy cycles). However, age was not significantly associated with the observed decrease of nadir values according to chemotherapy cycles of hemoglobin (F value 0.87, p=0.48), WBC count (F value 0.51, p=0.73) and platelet counts (F value 0.79. p=0.53) (Table III). There were no differences between the two groups when transfusion requirements were considered. Six older patients and eight younger patients required blood transfusions, four younger patients and no older patients required platelet transfusions while no younger patients and four older patients required myeloid growth factor support.
Discussion
A gradual decrease in peripheral blood counts with continued exposure to cytotoxic chemotherapy was identified in both the older and younger patients. These results are similar to those reported in experimental studies that have identified an exhaustion of regenerative ability after repeated exposure to myelosuppressive stimuli (16, 17).
The observations that peripheral blood cell counts in older patients do not differ from those in younger patients suggest that hematopoiesis in aged persons and young adults is similar. These findings are in concordance with laboratory studies which found that the marrow mass and numbers of cultured progenitor cells from carefully screened healthy older persons is equal to or greater than that found in young adult persons (12, 18, 19). Experimental studies involving mice have shown similar results (20-24).
These results would suggest that in the absence of a physiological increase in hematopoiesis, healthy older animals and humans can and do sustain baseline hematopoiesis comparable to that of young adults. Results of some studies in experimental animals (25) and in anemic elderly persons (6, 25) do however demonstrate an age-associated defect during periods of increased hematopoietic demand. In these studies, there was a defect in the expression of hematopoietic growth factors in aged humans and mice (25). Since exposure to cytotoxic chemotherapy is a period of stress challenging the hematopoietic regenerative response of the bone marrow, older patients would be expected to have a lower nadir count and slower recovery. Indeed, studies in non-Hodgkin's lymphoma, breast cancer and NSCLC have demonstrated that older patients have a greater hematologic toxicity following administration of cytotoxic chemotherapy as compared to younger individuals (14, 15, 26).
However, the results of the present study do not confirm these findings in patients receiving carboplatin and paclitaxel for NSCLC. The reasons for these disparate findings are unclear, but may be due to the small size of this study. Evidence in the published literature however suggests that the findings of the current investigation may in fact be valid. A study in dogs subjected to hematopoietic stress by way of repeated non-lethal doses of whole body irradiation showed that age did not influence the speed of hematopoietic recovery (17). Similarly, age was found not to be a biologically adverse parameter for patients with multiple myeloma receiving high-dose melphalan-based therapy with peripheral blood stem cell support (27).
Another explanation may be the difference in the data. In this study, the percentage drop from baseline after exposure to cytotoxic agents was evaluated. In contrast, most studies have reported the proportion of patients experiencing grade 3 or 4 cytopenia. However, since there does not seem to be a difference in peripheral counts based on age (28), it is difficult to imagine the difference in the way of measuring myelosuppression being the cause of this disparity.
The limitations of the present study include its small size and retrospective nature. Since only those patients who had available data were included in this analysis, this may not be a true representation of the entire patient population. We did not evaluate the co-morbid conditions of these patients, but rather assumed that since standard doses of chemotherapy were administered, they were relatively healthy otherwise.
In summary, a gradual decrease in peripheral blood counts with repeated exposure to cytotoxic chemotherapy was identified. There were no differences in the percentage declines of hemoglobin, WBC and platelet counts from baseline between the older and younger patients after chemotherapy with carboplatin and paclitaxel. These findings suggest that elderly patients do not exhibit a higher degree of bone marrow suppression as compared to younger patients following treatment with carboplatin and paclitaxel for NSCLC.
Footnotes
- Received October 22, 2009.
- Revision received March 26, 2010.
- Accepted March 26, 2010.
- Copyright© 2010 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved