In a previous study, we showed that anemia was common among patients with newly diagnosed, metastatic prostate cancer (25% of patients presented with hemoglobin levels <12 g/dL) and that anemia prior to the initiation of treatment was associated with shorter survival, shorter progression-free survival, and lower likelihood of prostate-specific antigen (PSA) normalization after adjusting for disease status and other covariates.1 Anemia is a described adverse effect of androgen-deprivation therapy (ADT). In a group of patients with largely nonmetastatic prostate cancer and normal mean hemoglobin levels at baseline, ADT was associated with a significant decline in hemoglobin after the initiation of therapy.2 Similar results were reported recently by Japanese investigators.3
Relatively little is known about the change in hemoglobin in anemic patients who are starting ADT for advanced prostate cancer. Anemia may be expected to worsen to the extent that therapy-induced hypogonadism reduces red cell production, but it also may improve as a result of successful cancer treatment.
The clinical significance of hemoglobin change after initiation of hormone therapy remains poorly defined. Recently, D'Amico et al. reported that a decline in hemoglobin of ≥1 g/dL during the first month of neoadjuvant ADT was a predictor of early recurrence in patients who received neoadjuvant ADT followed by radiation for high-risk, localized prostate cancer.4 The prognostic or predictive value of hemoglobin change after initiation of hormone therapy for metastatic prostate cancer is not known.
We hypothesized that a change in hemoglobin level after the initiation of therapy may be heterogeneous in patients with advanced prostate cancer and may be an independent prognostic factor in advanced prostate cancer. The objective of the current study was to characterize this change by reviewing hemoglobin levels, relevant covariates, and outcome data from the Southwest Oncology Group (SWOG) 8894 trial, a randomized study that compared orchiectomy alone with orchiectomy plus the antiandrogen flutamide in the initial treatment of metastatic prostate cancer.
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The baseline hemoglobin level was an independent determinant of 3-month change in hemoglobin after initiation of ADT, as we hypothesized. Although overall hemoglobin levels declined with ADT initiation, this masked the finding that hemoglobin levels increased in patients who were anemic prior to therapy and decreased in patients with no anemia at baseline. We cannot exclude the possibility that a portion of this observation represents regression to the mean, but this observation also is consistent with the hypothesis that, in patients with more severe, cancer-associated anemia, the salutatory effects of successful cancer treatment exceed the reduction in hemoglobin level caused by androgen loss. In addition to baseline hemoglobin, a multivariate analysis identified flutamide treatment, black race, worse performance status, increasing age, and prior radiation therapy as statistically significant factors (P < .05) that were associated with a 3-month decline in hemoglobin level. It is not surprising that elderly patients or those with a poor performance status may be at greater risk of treatment-associated anemia. Similarly, prior radiation therapy may reduce the bone marrow reserves needed to maintain hemoglobin in a hypogonadal state. Flutamide may be associated with a greater drop in hemoglobin caused by greater suppression of androgen signaling. Hemolotic anemia also rarely has been reported in association with flutamide therapy (Eulexin Prescribing Information).
The current results provide additional evidence of a link between anemia and poorer outcomes in patients with advanced prostate cancer. In addition to pretreatment anemia, which was identified previously as an adverse prognostic factor, this is the first report to our knowledge demonstrating that a decline in hemoglobin after 3 months of hormone therapy independently predicts a shorter survival and progression-free survival. It is noteworthy that our results are consistent with the findings of D'Amico et al., who showed that a decline in hemoglobin during the first month of neoadjuvant ADT was associated with a higher risk of early disease recurrence after combined treatment with ADT and radiation therapy.4 Thus, a change in hemoglobin level after the initiation of ADT may be a clinical sign of more aggressive disease, or it may contribute to resistance to therapy not only in early stages but also in metastatic prostate cancer.
The pathophysiology behind this observation merits further study. Anemia may lead to therapy resistance either directly or by association. Anemia-related tumor hypoxia may contribute to treatment resistance. An association between anemia and tumor hypoxia has been demonstrated in breast cancer,6 cervical cancer,7 and others. In addition, hypoxia has been observed in the prostate of rats that received ADT.8 Tumor hypoxia has been implicated in prostate cancer resistance to apoptosis9 as well as resistance to radiation therapy10 and chemotherapy.11 Cellular response to hypoxia may mediate resistance to androgen deprivation. Thus, a possible interpretation of these results is that androgen resistance in these patients is influenced by anemia-related tumor hypoxia.
Another possible explanation is that anemia and androgen resistance share a common pathophysiology. Several cytokines have been associated with anemia of chronic disease, including interleukin 1 (IL-1), IL-6, IL-12, tumor necrosis factor (TNF), transforming growth factor β (TGFβ), interferon-α, interferon-β, and interferon-γ.12, 13 Many of the same cytokines also may promote androgen resistance and the growth of prostate cancer metastases in the bone microenvironment.14 One example is IL-6, which may contribute to the development of androgen resistance.15 IL-6 is secreted by androgen-independent prostate cancer (AIPC) cells, is found at elevated levels in the blood of patients with AIPC,16 and produces an autocrine mitogenic signal in these cells.17 Similarly, it has been shown that TGFβ1, IL-1, and IL-8 induce changes that may be related to androgen independence.14, 18, 19
Furthermore, we identified a thought-provoking correlation between race and anemia. In a multivariate analysis, African-American race alone was not a strong predictor of death or disease progression. However, our results suggest that the effect of baseline hemoglobin level on overall and progression-free survival varied significantly by race. Overall, anemic African Americans fared worse than anemic Caucasians, and African Americans with high baseline hemoglobin fared better than Caucasians with similar hemoglobin levels.
The racial disparity in prostate cancer outcomes is well described. African Americans are at greater risk of being diagnosed with the disease,20 have higher risk disease at diagnosis,21, 22 and, overall, have a higher risk of dying from prostate cancer.20 Generally, it is believed that the differences in prostate cancer outcomes are explained by disease-related factors. After correcting for stage, grade, and other known prognostic factors, race generally is not predictive of worse outcomes in men with prostate cancer. This has been demonstrated in studies of clinically localized prostate cancer23–25 and metastatic disease. Analyses of 5284 men with newly diagnosed, primarily distant-stage disease26 and of 1183 patients with metastatic, hormone-refractory disease27 showed no independent effect of race on survival. Although a previous analysis of SWOG 8894 identified a significant race effect,28 hemoglobin data were unavailable at that time. In the current analysis of SWOG 8894, we observed that, after adjusting for both baseline hemoglobin and 3-month change in hemoglobin, race no longer was an adverse prognostic factor.
Thus, the complex relation between baseline anemia, race, and survival identified here is unexpected and novel. Although our study was not designed to determine the underlying cause for the observed anemia-race interaction, several hypotheses may be considered. Prior analyses showed that African-American men who presented with either hormone-naive or hormone-resistant, metastatic prostate cancer had lower hemoglobin concentrations than their Caucasian counterparts.1, 27 Healthy African Americans also had significantly lower mean concentrations of hemoglobin than Caucasians.29 These discrepancies may be explained by a higher prevalence of hemoglobinopathies30, 31 and by a higher incidence of folate deficiency32 among African Americans.
The prevalence of sickle cell trait among African Americans is between 8% and 10%.33 Although this is a clinically benign carrier trait, little is known about the impact of sickle cell trait on tumor hypoxia. A single case study of a sickle trait carrier with squamous cell carcinoma of the cervix demonstrated extensive intratumoral sickling and tumor hypoxia.34 To the best of our knowledge, no other studies have examined the possibility that otherwise benign hemoglobin abnormalities may exacerbate tumor hypoxia and, consequently, promote tumor resistance to therapy. Another hypothesis worthy of consideration is that there may be race-specific differences in prostate cancer hypoxic response. For example, in a study of 223 patients, the patterns of expression of N-myc downstream-regulated gene-1 (NDRG1), a hypoxia-related and androgen-regulated gene, differed significantly between African Americans and Caucasians.35
It also is possible that the pathophysiology of cancer-related anemia may differ across races. For example, if African Americans were less susceptible to developing cancer-associated anemia, then it would be expected that the same degree of anemia would be associated with more severe disease in African Americans. We are not aware of data that address this question, although functional polymorphisms of many of the cytokines that are important in the anemia of chronic disease have been described. A number of investigators have found differences in racial distributions of these polymorphisms. For example, Ness et al. reported that polymorphisms known to increase expression of proinflammatory cytokines IL-1A, IL-1B, IL-18, and IL-6 were significantly more likely to be expressed in African-American women than in white women.36 In another study, it was observed that individuals of African descent predominantly carried low-producing IL-10 alleles and high-producing IL-6 alleles.37 If differences in the racial distribution of gene polymorphisms that regulate the development of cancer-associated anemia exist, then such differences may explain the complex relation between anemia, race, and outcome observed in this study.
In summary, our data extend previous findings that link anemia with poor outcomes in men with advanced prostate cancer. We observed that, in addition to baseline anemia, a decline in hemoglobin after 3 months of ADT was associated independently with shorter progression-free and overall survival. Furthermore, we identified an unexpected, complex interaction between race, anemia, and progression-free and overall survival in men with advanced prostate cancer. Although these findings provide important new information about prognosis in patients with advanced prostate cancer, they should not be interpreted as supportive of the therapeutic correction of anemia to improve outcome. It is not known whether anemia-directed interventions in these patients can modify the association between baseline anemia, 3-month hemoglobin decline, and patient outcomes. Further investigation of anemia and outcomes in patients with prostate cancer should be pursued, and prospective clinical trials of anemia correction during hormone therapy should be considered.