Circulating cytokine levels in prostate cancer patients undergoing radiation therapy: influence of neoadjuvant total androgen suppression.

BACKGROUND: The purpose of this study was to investigate the immunological impact of combining neoadjuvant total androgen suppression (TAS) with radiotherapy (xRT) in the treatment of prostate cancer by monitoring blood cytokine levels. PATIENTS AND METHODS: Participants were stage I-II prostate cancer patients receiving xRT alone (n=18) or TAS+xRT (n=19) under the procedures outlined in RTOG protocols #94-08 and #94-13. Peripheral blood samples were collected immediately prior to TAS (xRT+TAS group), immediately prior to xRT, 24 hours after initiation of xRT, and weekly during xRT. Samples were monitored for the immunoregulatory cytokines interleukin (IL)-1beta, IL-6 and transforming growth factor (TGF)beta using ELISA procedures. RESULTS: Following initiation of xRT, both patient groups demonstrated an immediate elevation of the proinflammatory cytokines IL-1beta and IL-6 in their plasma. These cytokine levels appeared to peak after 1-2 weeks of xRT before returning toward pre xRT levels. In contrast, the profibrotic cytokine TGFbeta appeared to decrease immediately following initiation of xRT, but, subsequently, underwent two distinct waves of elevation, occurring at 1-2 weeks and 5-6 weeks into the xRT. Surprisingly, while the temporal pattern of plasma cytokine response was similar in both treatment groups, the magnitude of cytokine expression was noticeably different, appearing to be significantly affected by the addition of TAS. Indeed, administration of neoadjuvant TAS appeared to bring about a marked elevation of IL-1beta and IL-6 and a significant reduction in TGFbeta when compared to patients receiving xRT alone. CONCLUSION: The precise mechanisms underlying this TAS-related increase of the proinflammatory cytokines IL-1beta and IL-6 and decrease of the profibrotic cytokine TGFbeta remain unclear. However, previous reports have documented that androgens tend to be immunosuppressive in nature. It is conceivable, therefore, that administration of TAS shifts the ratio of proinflammatory and profibrotic cytokines toward a more immunostimulatory state.

Response of T lymphocyte populations in prostate cancer patients undergoing radiotherapy: influence of neoajuvant total androgen suppression.

BACKGROUND: This study sought to better define the immunological impact of combining neoadjuvant total androgen suppression (TAS) with radiotherapy (xRT) in treating prostate cancer. MATERIALS AND METHODS: Subjects selected (n = 37) were stage I-II prostate cancer patients meeting the eligibility requirements for RTOG protocols 94-08 or 94-13. Flow cytometric monitoring of circulating T helper (Th), T suppressor/cytotoxic (Ts), natural killer (NK) and B lymphocytes was performed weekly. RESULTS: Significant reduction of all lymphocyte subsets occurred as a result of xRT. Comparison between treatment groups demonstrated that the B lymphocyte and NK lymphocyte radioresponse was not influenced by TAS, but the Th and Ts lymphocyte response was, with addition of TAS leading to less radiation-induced decline. CONCLUSION: The basis for this T cell response is unclear, but may involve a TAS-induced reduction of testosterone's immunomodulation of T cell proliferation and apoptosis and/or a direct, TAS-induced thymic stimulation. Our data suggest that addition of TAS to xRT appears to have no detrimental effects on lymphocyte subsets, and, indeed, may have favorable effects on T cells.

Lymphocyte radiosensitivity correlated with pelvic radiotherapy morbidity.

PURPOSE: To test the hypothesis that, before treatment, prostate cancer patients who demonstrate a high yield of ex vivo radiation-induced micronucleus (MN) in G(0) lymphocytes represent a patient population with a greater-than-average risk of developing radiotherapy (RT)-related morbidity. METHODS AND MATERIALS: We prospectively conducted the cytokinesis-block MN assay of peripheral blood lymphocytes (PBLs) in 38 prostate cancer patients. Before the initiation of RT, PBLs from each patient were irradiated (1-4 Gy). The mean patient age +/- SEM was 68.7 +/- 1.0 years. The clinical stage was T1 in 17, T2 in 15, and T3 in 6. The preoperative prostate-specific antigen level was < or =4 ng/mL in 5, 4-10 ng/mL in 18, and >10 ng/mL in 15. All patients underwent standardized pelvic external beam radiotherapy (range 41.4-50.4 Gy) and boost (range 16-26 Gy). The mean follow-up +/- SEM was 32.8 +/- 4.6 months. At the end of follow-up, a radiation oncologist scored the GI or GU morbidity according to the Radiation Therapy Oncology Group criteria without knowledge of the MN data. RESULTS: We found that between the average reactors (n = 25; i.e., patients who had Grade 1 or less RT-related morbidity) and over reactors (n = 13; i.e., patients who developed Grade 2 or greater RT-related morbidity), the differences in the ex vivo radiation dose-response relationship of MN yield in PBLs were highly significant, especially at doses of > or =2 Gy. Also, the development of RT-related morbidity correlated with the radiation dose-response relationship of MN yield in PBLs before treatment, but did not correlate with any of the patients' clinical variables. CONCLUSION: Our findings suggest that the pre-RT ex vivo radiation dose-response relationship of MN yield in PBLs may be a significant predictive factor for the development of GI or GU morbidity in prostate cancer patients after pelvic RT.

Persistence of micronuclei in lymphocytes of cancer patients after radiotherapy.

To verify the applicability of the micronucleus (MN) yield in peripheral blood lymphocytes (PBLs) as a quantitative biodosimeter for monitoring in vivo ionizing radiation damage, we applied the cytokinesis-blocked micronucleus assay in PBLs of cancer patients treated with partial-body radiotherapy. Dosimetric information on these 13 patients represented a wide range in the number of fractions, cumulative tumor dose, total integral dose, and equivalent total-body absorbed dose. We found in PBLs of these patients that (1) the MN yield increased linearly with the equivalent total-body absorbed dose (r = 0.8, P = 0.002), (2) the distributions of the MN yields deviated significantly from Poisson, and (3) there was a general decline in MN yields with increasing length of follow-up, but with considerable variation between individuals. The average rate of decline was found to be linear and was correlated with the equivalent total-body absorbed dose (r = 0.7, P = 0.007). Further, at 19-75 months of follow-up time, seven patients showed higher MN yields than their respective levels before radiotherapy, indicating the persistence of radiation-induced residual cytogenetic damage. Our findings suggest that the MN yield in human PBLs offers a reliable acute and perhaps chronic biodosimeter for in vivo radiation dose estimation. After the completion of radiotherapy, the persistence of elevated MN yield in PBLs is a reflection of the surviving population of radiation-induced genetically aberrant cells.