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Purpose: To update the analysis of the Dutch dose-escalation trial of radiotherapy for prostate cancer. Patients and Methods: A total of 669 patients with localized prostate cancer were randomly assigned to receive 68 or 78 Gy. The patients were stratified by age, institution, use of neoadjuvant or adjuvant hormonal therapy, and treatment group. The primary endpoint was freedom from failure (FFF), with failure defined as clinical or biochemical failure. Two definitions of biochemical failure were used: the American Society for Therapeutic Radiology and Oncology definition (three consecutive increases in prostate-specific antigen level) and the Phoenix definition (nadir plus 2 μg/L). The secondary endpoints were freedom from clinical failure, overall survival, and genitourinary and gastrointestinal toxicity. Results: After a median follow-up of 70 months, the FFF using the American Society for Therapeutic Radiology and Oncology definition was significantly better in the 78-Gy arm than in the 68-Gy arm (7-year FFF rate, 54% vs. 47%, respectively; p = 0.04). The FFF using the Phoenix definition was also significantly better in the 78-Gy arm than in the 68-Gy arm (7-year FFF rate, 56% vs. 45%, respectively; p = 0.03). However, no differences in freedom from clinical failure or overall survival were observed. The incidence of late Grade 2 or greater genitourinary toxicity was similar in both arms (40% and 41% at 7 years; p = 0.6). However, the cumulative incidence of late Grade 2 or greater gastrointestinal toxicity was increased in the 78-Gy arm compared with the 68-Gy arm (35% vs. 25% at 7 years; p = 0.04). Conclusion: The results of our study have shown a statistically significant improvement in FFF in prostate cancer patients treated with 78 Gy but with a greater rate of late gastrointestinal toxicity. [Copyright &y& Elsevier]

Purpose: The purpose of this study is to provide information about sexual function (SF) after three-dimensional conformal radiotherapy (3D-CRT) for prostate cancer while taking important factors into account that influence SF. Methods and Materials: Between June 1997 and February 2003, a total of 268 patients from a randomized dose-escalation trial comparing 68 Gy and 78 Gy agreed to participate in an additional part of the trial that evaluated SF. Results: At baseline 28% of patients had erectile dysfunction (ED). After 1 year, 27% of the pretreatment potent patients had developed ED. After 2 years this percentage had increased to 36%. After 3 years it almost stabilized at 38%. Satisfaction with sexual life was significantly correlated with ED. After 2 years one third of the pre-treatment potent patients still had considerable to very much sexual desire and found sex (very) important. No significant differences were found between the two dose-arms. Potency aids were used on a regular base by 14% of the patients. Conclusion: By taking adjuvant hormonal therapy (HT), HT during follow-up and potency aids into account, we found a lower percentage of ED after 3D-CRT than reported in previous prospective studies. A large group of patients still had sexual desire, considered sex important and 14% used potency aids after 3D-CRT. [Copyright &y& Elsevier]

Background: Urokinase-type plasminogen activator (uPA) and its inhibitor (PAI-1) play essential roles in tumor invasion and metastasis. High levels of both uPA and PAI-1 are associated with poor prognosis in breast cancer patients. To confirm the prognostic value of uPA and PAI-1 in primary breast cancer, we reanalyzed individual patient data provided by members of the European Organization for Research and Treatment of Cancer-Receptor and Biomarker Group (EORTC-RBG).Methods: The study included 18 datasets involving 8377 breast cancer patients. During follow-up (median 79 months), 35% of the patients relapsed and 27% died. Levels of uPA and PAI-1 in tumor tissue extracts were determined by different immunoassays; values were ranked within each dataset and divided by the number of patients in that dataset to produce fractional ranks that could be compared directly across datasets. Associations of ranks of uPA and PAI-1 levels with relapse-free survival (RFS) and overall survival (OS) were analyzed by Cox multivariable regression analysis stratified by dataset, including the following traditional prognostic variables: age, menopausal status, lymph node status, tumor size, histologic grade, and steroid hormone-receptor status. All P values were two-sided.Results: Apart from lymph node status, high levels of uPA and PAI-1 were the strongest predictors of both poor RFS and poor OS in the analyses of all patients. Moreover, in both lymph node-positive and lymph node-negative patients, higher uPA and PAI-1 values were independently associated with poor RFS and poor OS. For (untreated) lymph node-negative patients in particular, uPA and PAI-1 included together showed strong prognostic ability (all P<.001).Conclusions: This pooled analysis of the EORTC-RBG datasets confirmed the strong and independent prognostic value of uPA and PAI-1 in primary breast cancer. For patients with lymph node-negative breast cancer, uPA and PAI-1 measurements in primary tumors may be especially useful for designing individualized treatment strategies. [ABSTRACT FROM AUTHOR]

A reply is presented by Drs. Leo F. Verdonck, Wim L.J. van Putten and Anton Hagenbeek to letters to the editor about their article "Comparison of CHOP chemotherapy with autologous bone marrow transplantation for slowly responding patients with aggressive non-Hodgkin's lymphoma."

Background: High-dose chemoradiotherapy combined with autologous bone marrow transplantation can cure patients with disseminated, aggressive non-Hodgkin's lymphoma in whom first-line chemotherapy has failed. In contrast, cure is rare with second-line chemotherapy. It has been suggested that patients with slow responses to the initial phase of first-line chemotherapy are at high risk for relapse. Therefore, such patients are potential candidates for early bone marrow transplantation. Methods: To investigate whether patients with slow responses, defined as only a partial response after three courses of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), would benefit from early transplantation, we conducted a prospective, randomized trial. The early application of high-dose chemoradiotherapy and autologous bone marrow transplantation was compared with the continuation of CHOP therapy for another five courses. Patients with complete responses after three courses of CHOP (fast responses) and patients who responded partially but still had tumor-positive marrow continued with another five courses of CHOP. The study end points were the response rate, overall survival, disease-free survival, and event-free survival. Results: Of 286 patients who could be evaluated for the rapidity of their response after three courses of CHOP, 38 percent had fast responses, 47 percent had slow responses, and 15 percent had no response. Among 106 patients with slow responses who had lymphoma-negative marrow, 69 patients (65 percent) were randomized. Seventy-four percent of the CHOP group and 68 percent of the transplantation group had complete remissions (P = 0.54). At four years the rates of overall, disease-free, and event-free survival were 85, 72, and 53 percent, respectively, in the CHOP group and 56, 60, and 41 percent in the transplantation group (P>0.10). The disease-free survival in both groups did not differ significantly from that of nonrandomized patients with fast responses (54 percent at four years). Conclusions: The early application of high-dose, marrow-ablative chemoradiotherapy with autologous bone marrow transplantation does not improve the outcome in patients with aggressive non-Hodgkin's lymphoma that responds slowly to first-line CHOP chemotherapy. (N Engl J Med 1995;332:1045-51.) [ABSTRACT FROM AUTHOR]

Purpose: To analyze the correlation between dose-volume parameters of the corpora cavernosa and erectile dysfunction (ED) after external beam radiotherapy (EBRT) for prostate cancer. Methods and Materials: Between June 1997 and February 2003, a randomized dose–escalation trial comparing 68 Gy and 78 Gy was conducted. Patients at our institute were asked to participate in an additional part of the trial evaluating sexual function. After exclusion of patients with less than 2 years of follow-up, ED at baseline, or treatment with hormonal therapy, 96 patients were eligible. The proximal corpora cavernosa (crura), the superiormost 1-cm segment of the crura, and the penile bulb were contoured on the planning computed tomography scan and dose–volume parameters were calculated. Results: Two years after EBRT, 35 of the 96 patients had developed ED. No statistically significant correlations between ED 2 years after EBRT and dose–volume parameters of the crura, the superiormost 1-cm segment of the crura, or the penile bulb were found. The few patients using potency aids typically indicated to have ED. Conclusion: No correlation was found between ED after EBRT for prostate cancer and radiation dose to the crura or penile bulb. The present study is the largest study evaluating the correlation between ED and radiation dose to the corpora cavernosa after EBRT for prostate cancer. Until there is clear evidence that sparing the penile bulb or crura will reduce ED after EBRT, we advise to be careful in sparing these structures, especially when this involves reducing treatment margins. [Copyright &y& Elsevier]

Purpose: To identify dosimetric parameters derived from anorectal, rectal, and anal wall dose distributions that correlate with different late gastrointestinal (GI) complications after three-dimensional conformal radiotherapy for prostate cancer. Methods and Materials: In this analysis, 641 patients from a randomized trial (68 Gy vs. 78 Gy) were included. Toxicity was scored with adapted Radiation Therapy Oncology Group/European Organization for the Research and Treatment of Cancer (RTOG/EORTC) criteria and five specific complications. The variables derived from dose–volume histogram of anorectal, rectal, and anal wall were as follows: % receiving ≥5–70 Gy (V5–V70), maximum dose (Dmax), and mean dose (Dmean). The anus was defined as the most caudal 3 cm of the anorectum. Statistics were done with multivariate Cox regression models. Median follow-up was 44 months. Results: Anal dosimetric variables were associated with RTOG/EORTC Grade ≥2 (V5–V40, Dmean) and incontinence (V5–V70, Dmean). Bleeding correlated most strongly with anorectal V55–V65, and stool frequency with anorectal V40 and Dmean. Use of steroids was weakly related to anal variables. No volume effect was seen for RTOG/EORTC Grade ≥3 and pain/cramps/tenesmus. Conclusion: Different volume effects were found for various late GI complications. Therefore, to evaluate the risk of late GI toxicity, not only intermediate and high doses to the anorectal wall volume should be taken into account, but also the dose to the anal wall. [Copyright &y& Elsevier]

Examines the normal female mammalian development both in paternal and maternal X chromosome activation. Assessment on X inactivation in placental tissue; Evaluation on the methylation status of the polymorphic androgen-receptor gene in full-term female placentas; Importance of methylation in the androgen receptor of human full term placenta.