Olbjørn Klepp

Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial.

BACKGROUND Several studies have shown the efficacy of endocrine therapy in combination with radiotherapy in high-risk prostate cancer. To assess the effect of radiotherapy, we did an open phase III study comparing endocrine therapy with and without local radiotherapy, followed by castration on progression. METHODS This randomised trial included men from 47 centres in Norway, Sweden, and Denmark. Between February, 1996, and December, 2002, 875 patients with locally advanced prostate cancer (T3; 78%; PSA<70; N0; M0) were centrally randomly assigned by computer to endocrine treatment alone (3 months of total androgen blockade followed by continuous endocrine treatment using flutamide; 439 patients), or to the same endocrine treatment combined with radiotherapy (436 patients). The primary endpoint was prostate-cancer-specific survival, and analysis was by intention to treat. This study is registered as an international standard randomised controlled trial, number ISRCTN01534787. FINDINGS After a median follow-up of 7.6 years, 79 men in the endocrine alone group and 37 men in the endocrine plus radiotherapy group had died of prostate cancer. The cumulative incidence at 10 years for prostate-cancer-specific mortality was 23.9% in the endocrine alone group and 11.9% in the endocrine plus radiotherapy group (difference 12.0%, 95% CI 4.9-19.1%), for a relative risk of 0.44 (0.30-0.66). At 10 years, the cumulative incidence for overall mortality was 39.4% in the endocrine alone group and 29.6% in the endocrine plus radiotherapy group (difference 9.8%, 0.8-18.8%), for a relative risk of 0.68 (0.52-0.89). Cumulative incidence at 10 years for PSA recurrence was substantially higher in men in the endocrine-alone group (74.7%vs 25.9%, p<0.0001; HR 0.16; 0.12-0.20). After 5 years, urinary, rectal, and sexual problems were slightly more frequent in the endocrine plus radiotherapy group. INTERPRETATION In patients with locally advanced or high-risk local prostate cancer, addition of local radiotherapy to endocrine treatment halved the 10-year prostate-cancer-specific mortality, and substantially decreased overall mortality with fully acceptable risk of side-effects compared with endocrine treatment alone. In the light of these data, endocrine treatment plus radiotherapy should be the new standard.

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.

Cardiovascular Risk Factors and Morbidity in Long-Term Survivors of Testicular Cancer: A 20-Year Follow-Up Study

PURPOSE To evaluate the prevalence of cardiovascular risk factors and long-term incidence of cardiovascular disease (CVD) in survivors of testicular cancer (TC). METHODS Overall, 990 men treated for unilateral TC (1980 to 1994) were included in this national follow-up study (2007 to 2008). They were categorized into four treatment groups: surgery (n = 206), radiotherapy only (RT; n = 386), chemotherapy only (n = 364), and combined RT/chemotherapy (n = 34). Age-matched male controls from the general population (ie, NORMs) were included (n = 990). Survivors of TC who were diagnosed with CVD before or within 2 years after the TC diagnosis were excluded from analyses of CVD end points. RESULTS Median observation time was 19 years (range, 13 to 28 years). All cytotoxic treatment groups had significantly increased prevalences of antihypertensive medication, and survivors in the RT and RT/chemotherapy groups had higher prevalences of diabetes (RT: odds ratio [OR], 2.3; 95% CI, 1.5 to 3.7; RT/chemotherapy: OR, 3.9; 95% CI, 1.4 to 10.9) compared with NORMs. Overall 74 survivors of TC (8.0%) experienced atherosclerotic disease during follow-up. Increased risks for atherosclerotic disease were observed in age-adjusted Cox regression analyses after any cytotoxic treatment when compared with surgery only (RT: hazard ratio [HR], 2.3; 95% CI, 1.04 to 5.3; chemotherapy: HR, 2.6; 95% CI, 1.1 to 5.9; RT/chemotherapy: HR, 4.8; 95% CI, 1.6 to 14.4). Treatment with cisplatin, bleomycin, and etoposide (BEP) alone had a 5.7-fold higher risk (95% CI, 1.9 to 17.1 fold) for coronary artery disease compared with surgery only and a 3.1-fold higher risk (95% CI, 1.2 to 7.7 fold) for myocardial infarction compared with NORMs. CONCLUSION Treatment with infradiaphragmatic RT and/or cisplatin-based chemotherapy, particularly the BEP regimen, increases the long-term risk for CVD in survivors of TC.

Risk-Adapted Treatment in Clinical Stage I Nonseminomatous Germ Cell Testicular Cancer: The SWENOTECA Management Program

PURPOSE To offer minimized risk-adapted adjuvant treatment on a nationwide basis for patients with clinical stage 1 (CS1) nonseminomatous germ-cell testicular cancer (NSGCT). The aim was to reduce the risk of relapse and thereby reducing the need of later salvage chemotherapy while maintaining a high cure rate. PATIENTS AND METHODS From 1998 to 2005, 745 Norwegian and Swedish patients were included into a prospective, community-based multicenter Swedish and Norwegian Testicular Cancer Project (SWENOTECA) management program. Treatment strategy depended on the presence or absence of vascular tumor invasion (VASC). VASC-positive patients were recommended brief adjuvant chemotherapy (ACT) with bleomycin, etoposide, and cisplatin (BEP), whereas VASC-negative patients could choose between ACT and surveillance. RESULTS At a median follow-up of 4.7 years, there have been 51 relapses. On surveillance, 41.7% of VASC+ patients relapsed, compared with 13.2% of VASC- patients. After one course of BEP, 3.2% of VASC+ and 1.3% of VASC- patients relapsed. The toxicity of adjuvant BEP was low. Eight patients have died, none died from progressive disease. CONCLUSION One course of adjuvant BEP reduces the risk of relapse by approximately 90% in both VASC+ and VASC- CS1 NSGCT, and may be a new option as initial treatment for all CS1 NSGCT. One course of adjuvant BEP for VASC+ CS1 reduces the total burden of chemotherapy compared with surveillance or two courses of BEP. SWENOTECA currently recommends one course of BEP as standard treatment of VASC+ CS1 NSGCT, whereas both surveillance and one course of BEP are options for VASC- CS1 NSGCT.

Gonadal hormones in long-term survivors 10 years after treatment for unilateral testicular cancer

OBJECTIVE To investigate whether unilaterally orchiectomised testicular cancer survivors (TCSs) are more likely to display reduced Leydig cell function than healthy males. METHODS A national multi-centre survey of 1235 TCSs was performed in 1998-2000 (mean age: 44 years) treated between 1980 and 1994 (mean follow-up: 11 years). Serum hormone analyses were performed on 1183 TCSs, as 52 TCSs used androgen replacement (AR). TCSs were allocated to four treatment groups: Surgery only (251); Radiotherapy only (515); Chemotherapy 1, cisplatin </=850 mg (373); Chemotherapy 2, cisplatin >850 mg (96). The Controls were represented by 200 healthy blue-collar workers (mean age: 44 years). LH >12 IU/l and testosterone <8 nmol/l and the use of AR indicated hypogonadism. RESULTS Serum testosterone was similar in TCSs and Controls (16.9 vs.17.1 nmol/l), but TCSs had higher age-adjusted LH levels than the Controls (5.2 vs. 3.5 IU/l). LH increased with treatment intensity, but was elevated even in TCSs treated with surgery only. The age-adjusted odds ratio of hypogonadism was 3.8 (95%CI: 2.0-7.3) in TCSs, and increased with treatment intensity. CONCLUSION TCSs are at risk to develop pre-mature reduced Leydig cell function and hypogonadism. They may therefore be predisposed for the syndrome of androgen deficiency of aging males (ADAM).

Study of Anxiety Disorder and Depression in Long-Term Survivors of Testicular Cancer

PURPOSE To increase our knowledge of the prevalence of anxiety disorder and depression in long-term testicular cancer survivors (TCSs), and to identify variables associated with such caseness. PATIENTS AND METHODS Participants were 1,408 TCSs treated between 1980 and 1994 in Norway. Participants provided information about their medical, social, and familial situation on a questionnaire. They also completed the Hospital Anxiety and Depression Scale (HADS). Anxiety disorder and depression were defined by a score >/= 8 on the HADS subscales. The prevalence rates were compared with age-adjusted norm data. RESULTS HADS-defined anxiety disorder was more prevalent in TCSs (19.2%; 95% CI, 17.2% to 21.3%) than in the norm sample (13.5%; 95% CI, 13.1% to 13.9%; P < .001), whereas the prevalence of HADS-defined depression did not differ from the norm (TCSs, 9.7%; 95% CI, 8.1% to 11.2% v norm, 10.1%, 95% CI, 9.5 to 10.5; P = .56). The relative risk for anxiety disorder was 1.49 (95% CI, 1.31 to 1.69) and for depression the relative risk was 0.96 (95% CI, 0.81 to 1.14) in TCSs compared with norm. In multivariate analyses, HADS-defined anxiety disorder in TCSs was associated with young age, peripheral neuropathy, economic problems, alcohol problems, sexual problems, relapse anxiety, and having been treated for mental problems. CONCLUSION Long-term TCSs have an increased risk of HADS-defined anxiety disorder that warrants clinical attention. Checking easily available demographic and TC-related data and use of a simple screening test such as HADS assists the identification of TCSs with anxiety disorder.

Prognostic factors in clinical stage I nonseminomatous germ cell tumors of the testis: multivariate analysis of a prospective multicenter study. Swedish-Norwegian Testicular Cancer Group.

Between 1981 and 1986, 279 consecutive patients with clinical stage I (CS1) nonseminomatous germ cell tumors (NSGCT) of the testis underwent pathological staging (PS) with retroperitoneal lymphadenectomy (RPLND). Patients with retroperitoneal metastases (PS2) received adjuvant chemotherapy. The median follow-up time after RPLND was 50 months (range, 30 to 90). Clinical and histopathologic features were registered prospectively and analyzed for association with risk of having PS2, relapse despite pathological stage 1 (PS1) or the combined risk of either event, metastatic disease (MET). Seventy-five (26.9%) of the patients had PS2 disease, and 30 (14.7%) of the 204 PS1 patients relapsed, indicating that at least 105 (37.6%) of this CS1 population had subclinical MET at the time of orchiectomy. Four (1.4%) of the 279 CS1 patients died of testicular cancer. Multivariate analyses showed several variables to be significantly associated with outcome for the CS1 patients; vascular invasion in primary tumor and normal preorchiectomy serum alpha-fetoprotein (Pre-AFP) level indicated PS2 disease. If Pre-AFP was excluded from the model, the absence of teratoma or yolk sac elements in the primary tumor became significant predictors of PS2. Vascular invasion, absence of teratoma, and a short interval between orchiectomy and RPLND indicated increased risk of relapse in PS1 patients. Vascular invasion, normal Pre-AFP, absence of teratoma elements, and a short orchiectomy to RPLND interval were predictive of MET. Our results indicate that prognostic factors useful for stratification of CS1 patients with NSGCT to different treatment options may be established.

Association of Kaposi's sarcoma and prior immunosuppressive therapy. A 5‐year material of Kaposi's sarcoma in Norway

A retrospective study of 53 cases with a histological diagnosis of Kaposis sarcoma (KS) reported to The Cancer Registry of Norway during a five year period is presented. Four cases were excluded from the material because further information contradicted the diagnosis of KS. Of the remaining 49 cases, information of treatment received before the development of KS was obtained in 41 (83.7%). Six (14.6%) of the 41 patients developed KS during systemic treatment with corticosteroids, two of the 6 cases also used azathioprine. None of the patients had undergone renal transplantation. One additional patient had received radiotherapy for a malignant lymphoma prior to the development of KS. In a control group of 242 consecutive patients hospitalized because of basal cell carcinoma of the skin, none had used systemic corticosteroid or cytotoxic drugs. Case reports of the 7 patients with KS developing after immunopressive therapy are presented. Cancer 42:2626–2630, 1978.

Management of Seminomatous Testicular Cancer: A Binational Prospective Population-Based Study From the Swedish Norwegian Testicular Cancer Study Group

PURPOSE A binational, population-based treatment protocol was established to prospectively treat and follow patients with seminomatous testicular cancer. The aim was to standardize care for all patients with seminoma to further improve the good results expected for this disease. PATIENTS AND METHODS From 2000 to 2006, a total of 1,384 Norwegian and Swedish patients were included in the study. Treatment in clinical stage 1 (CS1) was surveillance, adjuvant radiotherapy, or adjuvant carboplatin. In metastatic disease, recommended treatment was radiotherapy in CS2A and cisplatin-based chemotherapy in CS2B or higher. RESULTS At a median follow-up of 5.2 years, 5-year cause-specific survival was 99.6%. In CS1, 14.3% (65 of 512) of patients relapsed following surveillance, 3.9% (seven of 188) after carboplatin, and 0.8% (four of 481) after radiotherapy. We could not identify any factors predicting relapse in CS1 patients who were subjected to surveillance only. In CS2A, 10.9% (three of 29) patients relapsed after radiotherapy compared with no relapses in CS2A/B patients (zero of 73) treated with chemotherapy (P = .011). CONCLUSION An international, population-based treatment protocol for testicular seminoma is feasible with excellent results. Surveillance remains a good option for CS1 patients. No factors predicted relapse in CS1 patients on surveillance. Despite resulting in a lower rate of relapse than with adjuvant carboplatin, adjuvant radiotherapy has been abandoned in the Swedish and Norwegian Testicular Cancer Project (SWENOTECA) as a recommended treatment option because of concerns of induction of secondary cancers. The higher number of relapses in radiotherapy-treated CS2A patients when compared with chemotherapy-treated CS2A/B patients is of concern. Late toxicity of cisplatin-based chemotherapy versus radiotherapy must be considered in CS2A patients.

Frequency of lymphoceles after open and laparoscopic pelvic lymph node dissection in patients with prostate cancer.

OBJECTIVE To compare the frequencies of pelvic lymphocele formation after laparoscopic and open pelvic lymph node dissection in patients with prostate cancer. MATERIAL AND METHODS A total of 132 patients operated on with pelvic lymph node dissection (PLND) underwent CT scanning of the abdomen and pelvis at a median of 29 days postoperatively. Open pelvic lymph node dissection (OPLND) was performed in 94 patients (71%) and 38 patients (29%) were operated on using a laparoscopic technique (LPLND). The frequency and size of pelvic lymphoceles were registered. Lymphoceles with a horizontal diameter of </=4.9 cm were classified as small and those with a horizontal diameter of >/=5.0 cm were classified as large. RESULTS The overall frequency of lymphoceles was 54%. The frequencies in the OPLND and LPLND groups were 61% and 37%, respectively. A total of 27% of the OPLND patients had large lymphoceles, compared to 8% of the LPLND patients. Three patients (2.3%), all in the OPLND group, had clinically significant lymphoceles. CONCLUSIONS Although the overall frequency of lymphocele formation was high, clinically significant lymphoceles were scarce. LPLND was associated with a statistically significant lower frequency of lymphocele formation compared to OPLND.