Anemia and Limited-stage Small Cell Lung Cancer

Abstract & Commentary

By William B. Ershler, MD, Editor, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC.

Synopsis: By analysis of two National Cancer Institute of Canada clinical trials for limited-stage small cell lung cancer, it was found that anemia was present in approximately one-third prior to treatment and was associated with other negative prognostic factors but by itself was not significant with regard to overall survival. When anemia occurs as a consequence of therapy, the data indicates an interesting trend towards improved local control; a finding that runs counter to expectations. This, however, was not associated with improved overall survival.

Source: Laurie SA, et al. The impact of anemia on outcome of chemoradiation for limited small cell cancer: a combine analysis of studies of the National Cancer Institute of Canada Clinical Trials Group. Ann Oncol. 2007;18:1051-1055.

There has been much written about the importance and management of anemia in cancer patients this past year. For certain tumors, it is clear that the appearance of anemia prior to therapy confers adverse prognostic implications.1-3 One aspect of the controversy surrounding anemia is whether directed intervention (ie, by recombinant erythropoietin or transfusion) results in favorable or unfavorable outcomes; an issue not directly addressed in this report. Dr. Laurie and colleagues provide an analysis of the importance of anemia in limited small cell lung cancer, derived from two National Cancer Institute of Canada (NCIC) clinical trials. In these trials, the relationship between the presence of anemia prior to therapy or the development of anemia during therapy was related to outcomes such as local control and overall survival.

The two clinical trials involved patients with previously untreated limited stage small cell lung cancer. In the first trial (BR.3), patients were randomized to receive six cycles of chemotherapy with cisplatin and etoposide (EP) and cyclophosphamide, doxorubicin, vincristine (CAV) given either sequentially (three cycles of CAV followed by three cycles of EP) or alternating. In this trial, thoracic radiotherapy (either 37.5 Gy in 15 fractions or 25 Gy in 10 fractions) was administered to all patients following the completion of the chemotherapy while prophylactic cranial radiation (20 Gy in 5 fractions) was administered to all patients during week seven. The second trial (BR.6) was designed to evaluate the importance of early vs late concurrent thoracic radiotherapy. All patients in this trial received six cycles of alternating CAV/EP with thoracic radiotherapy (40 Gy in 15 fractions) administered concurrently with either cycle two or six of chemotherapy. Prophylactic cranial irradiation (25 Gy in 10 fractions) was administered following the completion of chemoradiation. Three hundred twenty-two patients were enrolled in BR.3 and 330 in BR.6. Thus, there were a total of 652 patients available for this review.

Of the 652 patients enrolled, anemia, defined as a hemoglobin concentration of less than 13.6 g/dL for men and less than 12 g/dL for women, was present in 32%. Males, patients over the age of 65, those with ECOG Performance Status of > 2, and those with increased LDH were most likely to present with a low baseline hemoglobin concentration. During therapy grade 2 anemia (hemoglobin less than 10 g/dL) occurred in 55% of patients. Female gender, the presence of a low baseline hemoglobin concentration, age > 65 years, and a BSA < 2 all were associated with the development of anemia during therapy.

Baseline anemia was not statistically associated with either overall survival or progression-free survival in univariate analysis. In the multivariate COX regression model, male gender, a performance status greater or equal to 2, and an elevated LDH were associated with poorer overall survival and progression-free survival while baseline hemoglobin remained nonsignificant. Additionally, the baseline hemoglobin concentration had no impact on the rate of local progression and relapse. The evaluation of the implications of anemia occurring during therapy also revealed that the nadir hemoglobin was not independently associated with overall or progression-free survival. Those with nadir hemoglobin of less than 10 g/dL, however, had a longer duration of freedom from local recurrence (hazard ratio = 0.70, 95% confidence interval 0.54-0.90, P = 0.005). By multivariate analysis, males had a higher risk of local progression and the nadir hemoglobin of less than 10 remained marginally significant (P = 0.06).

Commentary

This comprehensive analysis of limited stage small cell lung cancer demonstrates that anemia is common in this clinical setting and that it is associated with adverse outcomes. However, in this series, anemia was not independent of other adverse factors such as poor performance status and elevated LDH. Thus, the association between baseline anemia and poor outcome is more likely an indicator of increased disease burden and possibly the presence of comorbidities. The current study demonstrated that the majority of treated patients (55%) developed grade II (hemoglobin < 10 g/dL) anemia. It was of some interest to note a trend towards improved local control in those who had the greatest drop in hemoglobin during therapy. This, however, does not translate into improved overall survival. Thus, it might seem that the development of anemia enhanced local measures such as radiotherapy; a concept that runs counter to the premise that hypoxia would favor radioresistance and thereby less adequate local control.

With the widespread use of recombinant erythropoietin in anemic cancer patients, concerns have been raised lately about the efficacy and safety of correcting anemia. This report will do little to settle the issue. What we do take from the analysis is that anemia is common both at presentation for which it is a marker for poor prognosis and during therapy for which the implications are less clear. One of the many unanswered questions is whether correction of anemia either prior to or during treatment is of value or detriment to the patient. A study in which erythropoietin, transfusion, and observation alone are compared would seem warranted at this time.

References

1. Glaser CM, et al. Impact of hemoglobin level and use of recombinant erythropoietin on efficacy of preoperative chemoradiation therapy for squamous cell carcinoma of the oral cavity and oropharynx. Int J Radiat Oncol Biol Phys. 2001;50(3):705-715.

2. MacRae R, et al. Declining hemoglobin during chemoradiotherapy for locally advanced non-small cell lung cancer is significant. Radiother Oncol. 2002;64(1):37-40.

3. Obermair A, et al. Impact of hemoglobin levels before and during concurrent chemoradiotherapy on the response of treatment in patients with cervical carcinoma: preliminary results. Cancer. 2001;92(4):903-908.