A. Horwich

Multiple newly identified loci associated with prostate cancer susceptibility

Prostate cancer is the most common cancer affecting males in developed countries. It shows consistent evidence of familial aggregation, but the causes of this aggregation are mostly unknown. To identify common alleles associated with prostate cancer risk, we conducted a genome-wide association study (GWAS) using blood DNA samples from 1,854 individuals with clinically detected prostate cancer diagnosed at ≤60 years or with a family history of disease, and 1,894 population-screened controls with a low prostate-specific antigen (PSA) concentration (<0.5 ng/ml). We analyzed these samples for 541,129 SNPs using the Illumina Infinium platform. Initial putative associations were confirmed using a further 3,268 cases and 3,366 controls. We identified seven loci associated with prostate cancer on chromosomes 3, 6, 7, 10, 11, 19 and X (P = 2.7 × 10−8 to P = 8.7 × 10−29). We confirmed previous reports of common loci associated with prostate cancer at 8q24 and 17q. Moreover, we found that three of the newly identified loci contain candidate susceptibility genes: MSMB, LMTK2 and KLK3.

Comparison of radiation side-effects of conformal and conventional radiotherapy in prostate cancer: a randomised trial

BACKGROUND Radical radiotherapy is commonly used to treat localised prostate cancer. Late chronic side-effects limit the dose that can be given, and may be linked to the volume of normal tissues irradiated. Conformal radiotherapy allows a smaller amount of rectum and bladder to be treated, by shaping the high-dose volume to the prostate. We assessed the ability of this new technology to lessen the risk of radiation-related effects in a randomised controlled trial of conformal versus conventional radiotherapy. METHODS We recruited men with prostate cancer for treatment with a standard dose of 64 Gy in daily 2 Gy fractions. The men were randomly assigned conformal or conventional radiotherapy treatment. The primary endpoint was the development of late radiation complications (> 3 months after treatment) measured with the Radiation Therapy and Oncology Group (RTOG) score. Indicators of disease (cancer) control were also recorded. FINDINGS In the 225 men treated, significantly fewer men developed radiation-induced proctitis and bleeding in the conformal group than in the conventional group (37 vs 56% > or = RTOG grade 1, p=0.004; 5 vs 15% > or = RTOG grade 2, p=0.01). There were no differences between groups in bladder function after treatment (53 vs 59% > or = grade 1, p=0.34; 20 vs 23% > or = grade 2, p=0.61). After median follow-up of 3.6 years there was no significant difference between groups in local tumour control (conformal 78% [95% CI 66-86], conventional 83% [69-90]). INTERPRETATION Conformal techniques significantly lowered the risk of late radiation-induced proctitis after radiotherapy for prostate cancer. Widespread introduction of these radiotherapy treatment methods is appropriate. Our results are the basis for dose-escalation studies to improve local tumour control.

European Consensus Conference on Diagnosis and Treatment of Germ Cell Cancer: A Report of the Second Meeting of the European Germ Cell Cancer Consensus group (EGCCCG): Part I

OBJECTIVES The first consensus report presented by the European Germ Cell Cancer Consensus Group (EGCCCG) in the year 2004 has found widespread approval by many colleagues throughout the world. In November 2006, the group met a second time under the auspices of the Department of Urology of the Amsterdam Medical Center, Amsterdam, The Netherlands. METHODS Medical oncologists, urological surgeons, radiation oncologists as well as pathologists from several European countries reviewed and discussed the data that had emerged since the 2002 conference, and incorporated the new data into updated and revised guidelines. As for the first meeting, the methodology of evidence-based medicine (EBM) was applied. The results of the discussion were compiled by the writing committee. All participants have agreed to this final update. RESULTS The first part of the consensus paper describes the clinical presentation of the primary tumor, its treatment, the importance and treatment of testicular intraepithelial neoplasia (TIN), histological classification, staging and prognostic factors, and treatment of stage I seminoma and non-seminoma. CONCLUSIONS Whereas the vast majority of the recommendations made in 2004 remain valid 3 yr later, refinements in the treatment of early- and advanced-stage testicular cancer have emerged from clinical trials. Despite technical improvements, expert clinical skills will continue to be one of the major determinants for the prognosis of patients with germ cell cancer. In addition, the particular needs of testicular cancer survivors have been acknowledged.

Prognostic factors for relapse in stage I seminoma managed by surveillance: A pooled analysis.

PURPOSE: Several management options are available to patients with stage I seminoma, including adjuvant radiotherapy, surveillance, and adjuvant chemotherapy. We performed a pooled analysis of patients from the four largest surveillance studies to better delineate prognostic factors associated with disease progression. PATIENTS AND METHODS: Individual patient data were obtained from each center (Princess Margaret Hospital, Danish Testicular Cancer Study Group, Royal Marsden Hospital, and Royal London Hospital) for 638 patients. Tumor characteristics (size, histologic subtype, invasion of rete testis, and tumor invasion into small vessels [SVI]) as well as age at diagnosis were analyzed for prognostic importance for relapse. RESULTS: With a median follow-up of 7.0 years (range, 0.02 to 17.5 years), 121 relapses were observed for an actuarial 5-year relapse-free rate (RFR) of 82.3%. On univariate analysis, tumor size (RFR: ≤ 4 cm, 87%; > 4 cm, 76%; P = .003), rete testis invasion (RFR: 86% [absent] v 77% [p...

Cardiovascular Disease as a Long-Term Complication of Treatment for Testicular Cancer

PURPOSE To assess the risk of cardiovascular morbidity and cardiac risk factors in long-term survivors of testicular cancer according to treatment received. PATIENTS AND METHODS All resident male patients registered in the United Kingdom between 1982 and 1992 attending for follow-up were eligible for recruitment. Patients completed a current health questionnaire and underwent clinical review, along with hematologic, biochemical, and hormonal profiles. For patients not under routine review, follow-up information was sought from their general practitioner and mortality data were sought from the Office of National Statistics. Descriptive analysis was performed on all variables and comparisons were made among patients treated by orchidectomy and follow-up only, chemotherapy alone (C), radiotherapy alone (RT), and radiotherapy and chemotherapy (C/RT). RESULTS Data on cardiovascular events were available on 992 patients. After a median follow-up of 10.2 years, 68 events had been reported, including 18 deaths. After adjusting for age, increased risk for cardiac events was seen after C (relative risk [RR] = 2.59; 95% confidence interval [CI], 1.15 to 5.84; P =.022), RT (RR = 2.40; 95% CI, 1.04 to 5.45; P =.036), and C/RT (RR = 2.78; 95% CI, 1.09 to 7.07; P =.032). There were no significant differences in cardiac risk factors. On multivariate analysis, age, treatment group, free thyroxine, protein, and magnesium levels were associated with cardiovascular disease. CONCLUSION In long-term survivors of testicular cancer, we observed a two-fold or greater risk of developing cardiovascular disease. This was not due to increases in cardiac risk factors, which suggests a direct or indirect treatment effect. These data support the continued research into the minimization of treatment in good-prognosis testicular cancer.

Risk of Second Malignancy After Hodgkin’s Disease in a Collaborative British Cohort: The Relation to Age at Treatment

PURPOSE To assess long-term site-specific risks of second malignancy after Hodgkins disease in relation to age at treatment and other factors. PATIENTS AND METHODS A cohort of 5,519 British patients with Hodgkins disease treated during 1963 through 1993 was assembled and followed-up for second malignancy and mortality. Follow-up was 97% complete. RESULTS Three hundred twenty-two second malignancies occurred. Relative risks of gastrointestinal, lung, breast, and bone and soft tissue cancers, and of leukemia, increased significantly with younger age at first treatment. Absolute excess risks and cumulative risks of solid cancers and leukemia, however, were greater at older ages than at younger ages. Gastrointestinal cancer risk was greatest after mixed-modality treatment (relative risk [RR] = 3.3; 95% confidence interval [CI], 2.1 to 4.8); lung cancer risks were significantly increased after chemotherapy (RR = 3. 3; 95% CI, 2.4 to 4.7), mixed-modality treatment (RR = 4.3; 95% CI, 2.9 to 6.2), and radiotherapy (RR = 2.9; 95% CI, 1.9 to 4.1); breast cancer risk was increased only after radiotherapy without chemotherapy (RR = 2.5; 95% CI, 1.4 to 4.0); and leukemia risk was significantly increased after chemotherapy (RR = 31.6; 95% CI, 19.7 to 47.6) and mixed-modality treatment (RR = 38.1; 95% CI, 24.6 to 55. 9). These risks were generally greater after treatment at younger ages: for patients treated at ages younger than 25 years, there were RRs of 18.7 (95% CI, 5.8 to 43.5) for gastrointestinal cancer after mixed-modality treatment, 14.4 (95% CI, 5.7 to 29.3) for breast cancer after radiotherapy, and 85.2 (95% CI, 45.3 to 145.7) for leukemia after chemotherapy (with or without radiotherapy). CONCLUSION Age at treatment has a major effect on risk of second malignancy after Hodgkins disease. Although absolute excess risks are greater for older patients, RRs of several important malignancies are much greater for patients who are treated when young. The increased risk of gastrointestinal cancers may relate particularly to mixed-modality treatment, and that of lung cancer to chemotherapy as well as radiotherapy; there are also well-known increased risks of breast cancer from radiotherapy and leukemia from chemotherapy. The roles of specific chemotherapeutic agents in the etiology of solid cancers after Hodgkins disease require detailed investigation.

Medical Research Council prospective study of surveillance for stage I testicular teratoma. Medical Research Council Testicular Tumors Working Party.

PURPOSE A prospective study of surveillance after orchidectomy alone in patients with stage I nonseminomatous germ cell testicular tumor (NSGCT) was performed to determine the relapse-free rate and to identify the histologic criteria that predict for relapse. PATIENTS AND METHODS Three hundred ninety-six patients from 16 United Kingdom and one Norwegian centers were entered onto the study between January 1, 1984 and October 1, 1987 of whom 373 were eligible for analysis. In a previous retrospective study, we defined a prognostic index based on histologic criteria that identified a group of patients with a high risk of relapse. This index was based on the presence of venous and lymphatic invasion, undifferentiated cells, and the absence of yolk sac elements in the primary tumor. RESULTS The 2-year actuarial relapse-free rate after orchidectomy was 75% (95% confidence interval, 71% to 79%), and the rate at 5 years was 73%. Five patients died of tumor or treatment-related complications, which resulted in a 5-year survival of 98%. The relapse-free rate in patients with three or four risk factors was 54%. CONCLUSIONS This study confirms the safety of surveillance as a method of management and identifies a group of patients with a high risk of relapse. A prospective phase II study has been initiated to determine whether two courses of platinum-based adjuvant chemotherapy will prevent relapse in these high-risk patients.

Testicular germ-cell cancer

Testicular germ-cell tumours (TGCTs) represent the model of a curable malignancy; sensitive tumour markers, accurate prognostic classification, logical series of management trials, and high cure rates in both seminomas and non-seminomas have enabled a framework of effective cancer therapy. Understanding the molecular biology of TGCT could help improve treatment of other cancers. The typical presentation in young adults means that issues of long-term toxicity become especially important in judging appropriate management. A focus of recent developments has been to tailor aggressiveness of treatment to the severity of the prognosis. Recent changes affect the most common subtypes and include the reduction of chemotherapy for patients who have metastastic non-seminomas and a good prognosis, and alternatives to adjuvant radiotherapy in stage I seminomas. We summarise advances in the understanding and management of TGCT during the past decade.

Optimal Planning Target Volume for Stage I Testicular Seminoma: A Medical Research Council Randomized Trial

PURPOSE To compare relapse rates and toxicity associated with para-aortic (PA) strip or PA and ipsilateral iliac lymph node irradiation (dogleg [DL] field) (30 Gy/15 fractions/3 weeks) for stage I testicular seminoma. PATIENTS AND METHODS Between July 1989 and May 1993, 478 men with testicular seminoma stage I (T1 to T3; no ipsilateral inguinoscrotal operation before orchiectomy) were randomized (PA, 236 patients; DL, 242 patients). RESULTS Median follow-up time is 4.5 years. Eighteen relapses, nine in each treatment group, have occurred 4 to 35 months after radiotherapy; among these, four were pelvic relapses, all occurring after PA radiotherapy. However, the 95% confidence interval (CI) for the difference in pelvic relapse rates excludes differences of more than 4%. The 3-year relapse-free survival was 96% (95% CI, 94% to 99%) after PA radiotherapy and 96.6% (95% CI, 94% to 99%) after DL (difference, 0.6%; 95% confidence limits, -3.4%, +4.6%). One patient (PA field) has died from seminoma. Survival at 3 years was 99.3% for PA and 100% for DL radiotherapy. Acute toxicity (nausea, vomiting, leukopenia) was less frequent and less pronounced in patients in the PA arm. Within the first 18 months of follow-up, the sperm counts were significantly higher after PA than after DL irradiation. CONCLUSION In patients with testicular seminoma stage I (T1 to T3) and with undisturbed lymphatic drainage, adjuvant radiotherapy confined to the PA lymph nodes is associated with reduced hematologic, gastrointestinal, and gonadal toxicity, but with a higher risk of pelvic recurrence, compared with DL radiotherapy. The recurrence rate is low with either treatment. PA radiotherapy is recommended as standard treatment in these patients.

Short-course adjuvant chemotherapy in high-risk stage I nonseminomatous germ cell tumors of the testis: a Medical Research Council report.

PURPOSE This United Kingdom Medical Research Council (UK-MRC) study prospectively evaluated efficacy and long-term toxicity of adjuvant chemotherapy in high-risk stage I nonseminomatous germ cell tumors of the testis (NSGCTT). PATIENTS AND METHODS Eligible patients were those identified by the local histopathologist as having features confirmed in MRC surveillance studies to indicate an approximate 50% risk of relapse. Central histopathology review was undertaken. Chemotherapy consisted of two courses of cisplatin 100 mg/m2, bleomycin 30 mg weekly x 3, and etoposide 120 mg/m2 x 3, every 21 days (BEP). RESULTS One hundred fourteen eligible cases were enrolled. Median time of follow-up was 4 years, with 93 patients followed-up for at least 2 years. There have been two relapses, including one patient who did not have a germ cell tumor (GCT), according to the reference histopathologist. This patient is alive with active disease, the other has died. There was one death after a cerebrovascular accident during treatment. Assessment of fertility, lung function, and audiometry pretreatment and more than 9 months posttreatment indicated no clinically significant changes. A mean decrease in transfer factor coefficient (KCO) of 15% of the predicted value was noted, but no patient had symptomatic respiratory dysfunction. CONCLUSION There have been only two relapses among 114 cases of high-risk stage I NSGCTT treated with two courses of adjuvant BEP chemotherapy. The 95% confidence interval (CI) excludes a true relapse rate of more than 5%. Of 104 patients confirmed on histopathology review to have GCT, there has been only one relapse. Adjuvant chemotherapy is free from significant long-term toxicity, offering an effective alternative to surveillance or retroperitoneal lymph node dissection (RPLND) followed by surveillance, and may be preferred by some patients.