Prostate-specific antigen response after short-term hormone therapy plus external-beam radiotherapy and outcome in patients treated on Radiation Therapy Oncology Group study 9413.

BACKGROUND: The objective of this study was to assess the impact of a prostate-specific antigen (PSA) complete response (PSA-CR), measured at the end of external-beam radiotherapy and short-term hormone therapy, on treatment outcomes. METHODS: The phase 3 Radiation Therapy Oncology Group 9413 trial, as part of its original protocol, used the assessment of PSA-CR (ie, PSA ≤0.3 ng/mL) at the end of short-term HT as a secondary endpoint. Short-term HT consisted of futamide plus a lutenizing hormone-releasing hormone agonist for 4 months. The Kaplan-Meier method was used to estimate overall survival (OS) and disease-free survival. Cumulative incidence was used to estimate biochemical failure, distant metastasis, and disease-specific survival. Univariate and multivariate analyses were performed to correlate PSA-CR after short-term hormone therapy with all endpoints, and the following variables were considered for analysis: PSA at baseline, Gleason score, treatment arm, age, and baseline testosterone status. Phoenix consensus definition was used to define PSA failure. RESULTS: For 1070 evaluable patients, the median PSA at the end of short-term hormone therapy was 0.2 ng/mL. In total, 744 patients (70%) had a PSA-CR. At a median follow-up of 7.2 years, failure to obtain a PSA-CR was associated significantly with worse disease-specific survival (P = .0003; hazard ratio [HR], 2.03; 95% confidence interval [CI], 1.38-2.97), with worse disease-free survival (P = .003; HR, 1.28; 95% CI, 1.09-1.50), and with a higher incidence of distant metastasis (P = .0002; HR, 1.92; 95% CI, 1.37-2.69) and biochemical failure (P < .0001; HR, 1.57; 95% CI, 1.29-1.91). Other factors that were associated with worse disease-specific survival were Gleason scores from 8 to 10 (P = .0002; HR, 3.06; 95% CI, 1.71-5.47) and PSA levels >20 ng/mL (P = .04; HR, 1.55; 95% CI, 1.02-2.30). CONCLUSIONS: The current results indicated that failure to obtain a PSA-CR (PSA ≤0.3 ng/mL) after short-term hormone therapy and external-beam radiotherapy appears to be an independent predictor of unfavorable outcomes and could help identify patients who may benefit from the addition of long-term androgen ablation.

DNA strand breakage by bivalent metal ions and ionizing radiation.

PURPOSE: To investigate mechanisms of DNA breakage via the interaction of bivalent metal ion, thiol reducing agent and ionizing radiation, in *OH scavenging abilities comparable to those in cells. MATERIALS AND METHODS: We measured the effects of 10 min exposure to 200 microM Fe2+ vs. Fe3+ on the induction of single (SSB) and double (DSB) strand breaks in unirradiated and oxically irradiated SV40 DNA, in aqueous solution containing 75 or 750 mM glycerol and/or 5 mM glutathione (GSH). RESULTS: Fe2+ or GSH alone produced little DNA damage. However, their combination produced a dramatic increase in the production of both SSB and DSB. Experiments with ferric ion suggest that it produces DNA damage only after partial reduction to ferrous by GSH. Induction efficiencies for SSB in the presence of Fe2+/GSH showed additivity of the effects of radiation alone with those from Fe2+/GSH. However, the corresponding induction efficiencies for DSB demonstrated a 2.5-fold enhancement. CONCLUSIONS: Our results are consistent with a model in which reduced bivalent metal ions plus thiols, in the presence of O2, produce DSB in DNA primarily via local clusters of hydroxyl radicals arising from site specific Fenton reactions. The synergism observed between DSB production by Fe/GSH and by ionizing radiation, also believed to occur via local clusters of hydroxyl radicals, is consistent with this model. Our results suggest that both normally present intracellular iron and ionizing radiation may be important sources of oxidative stress in cells.

Low-dose radiotherapy for primary cutaneous anaplastic large-cell lymphoma while on low-dose methotrexate.

Primary cutaneous anaplastic large-cell lymphoma (pcALCL) is part of a spectrum of CD30+ primary cutaneous lymphoproliferative disorders (pcLPDs) that also includes lymphomatoid papulosis (LyP). Localized radiotherapy at doses of 34 to 44 Gy is first-line treatment of pcALCL, but the use of low-dose radiotherapy for pcALCL has not been reported. We present the case of a patient with a history of pcALCL/LyP who was treated with low-dose radiotherapy while on oral low-dose methotrexate (MTX) once weekly. This report suggests that low-dose radiotherapy can be an effective palliative treatment of pcALCL. Low-dose radiotherapy may offer certain advantages over traditional radiotherapy, such as a more economical and efficient treatment for patients, potentially fewer short-term and long-term side effects, and the potential for concomitant use with low-dose MTX.

Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma--long-term results of phase III RTOG 85-31.

PURPOSE: Radiation Therapy Oncology Group protocol 85-31 was designed to evaluate the effectiveness of adjuvant androgen suppression, using goserelin, in unfavorable prognosis carcinoma of the prostate treated with definitive radiotherapy (RT). METHODS AND MATERIALS: Eligible patients were those with palpable primary tumor extending beyond the prostate (clinical Stage T3) or those with regional lymphatic involvement. Patients who had undergone prostatectomy were eligible if penetration through the prostatic capsule to the margin of resection and/or seminal vesicle involvement was documented histologically. Stratification was based on histologic differentiation, nodal status, acid phosphatase status, and prior prostatectomy. The patients were randomized to either RT and adjuvant goserelin (Arm I) or RT alone followed by observation and application of goserelin at relapse (Arm II). In Arm I, the drug was to be started during the last week of RT and was to be continued indefinitely or until signs of progression. RESULTS: Between 1987 and 1992, when the study was closed, 977 patients were entered: 488 to Arm I and 489 to Arm II. As of July 2003, the median follow-up for all patients was 7.6 years and for living patients was 11 years. At 10 years, the absolute survival rate was significantly greater for the adjuvant arm than for the control arm: 49% vs. 39%, respectively (p = 0.002). The 10-year local failure rate for the adjuvant arm was 23% vs. 38% for the control arm (p <0.0001). The corresponding 10-year rates for the incidence of distant metastases and disease-specific mortality was 24% vs. 39% (p <0.001) and 16% vs. 22% (p = 0.0052), respectively, both in favor of the adjuvant arm. CONCLUSION: In a population of patients with unfavorable prognosis carcinoma of the prostate, androgen suppression applied as an adjuvant after definitive RT was associated not only with a reduction in disease progression but in a statistically significant improvement in absolute survival. The improvement in survival appeared preferentially in patients with a Gleason score of 7-10.

Correlation between Doppler vascular density and PSA response to radiation therapy in patients with localized prostate carcinoma.

RATIONALE AND OBJECTIVES: The authors performed this study to ascertain whether there is a correlation between pretreatment Doppler vascular density (DVD) of the prostate and prostate-specific antigen (PSA) response following radiation therapy in prostate cancer patients. MATERIALS AND METHODS: Prior to radiation therapy, 14 patients with biopsy-proven carcinoma (of Gleason grades 2-7) were imaged with transrectal ultrasound in gray-scale, color Doppler, and power Doppler modes. The Doppler images were analyzed for mean DVD with the aid of a computer program. PSA levels were measured before therapy and every 3 months after therapy. The PSA measurements were fitted to an exponential to determine PSA halving time (T1/2). Correlations were made between T1/2 and the following pretherapy measurements: mean DVD, PSA level, prostate volume, and Gleason grade. RESULTS: Median follow-up time was 392 days. A linear correlation with regression coefficient (R) of 0.75-0.80 was observed between mean DVD and T1/2 for color Doppler and power Doppler imaging. In both imaging modes, each percentage increase in mean DVD led to an increase in T1/2 by 25 days. Pretherapy prostate volume, PSA level, and Gleason score did not correlate with T1/2. CONCLUSION: The pretreatment mean DVD correlates inversely with the rate of posttherapy decline in PSA in patients with prostate cancer. That is, pretreatment vascularity prognosticates postirradiation PSA response. The mechanism underlying this correlative relationship is not known.

Predicting PSA response of prostate cancer to radiation therapy with Doppler sonography.

OBJECTIVE: We report a prospective investigation of the correlation between pretreatment Doppler vascular density (DVD) of the entire prostate gland and subsequent prostate-specific antigen (PSA) response following external beam radiation therapy, for patients with low- or intermediate-risk prostate cancer. This report updates a previous report (Sehgal et al., Acad Radiol 2003;10:366) with longer patient follow-up and additional quantitative and clinically relevant end points. METHODS: Before radiation therapy, we imaged 12 patients with transrectal Doppler sonography and measured the mean DVD of the prostate for each. For analysis, patients were separated into 3 groups by low, intermediate, and high DVD. The mean DVD for each group was linearly correlated with mean values for time above a PSA threshold of 1.0 ng/ml, post-therapy plateau PSA, and nadir PSA. RESULTS: We previously observed that pretreatment mean DVD had a strong inverse correlation with initial rate of post-therapy decline in PSA. With substantially longer follow-up on the same cohort of patients (median, 52 months), we now observe that pretreatment mean DVD also correlates with post-therapy nadir PSA (R = 0.94) and with time above a PSA threshold of 1.0 ng/mL (R = 0.99). CONCLUSION: The results of the current study are consistent with our earlier suggestion that pretreatment measurement of DVD of the entire prostate gland may be a clinically useful prognostic indicator in early prostate cancer treated with radiation. However, additional data from larger numbers of patients are needed to draw firm conclusions.