Thromboembolic Events During Treatment with Cisplatin-based Chemotherapy in Metastatic Testicular Germ-cell Cancer 2000-2014: A Population-based Cohort Study.

BACKGROUND: Cisplatin-based chemotherapy (CBCT) in testicular cancer (TC) is associated with elevated venous thromboembolism (VTE) risk, but trials evaluating the safety and efficacy of thromboprophylaxis are lacking. OBJECTIVE: To evaluate the arterial thromboembolism (ATE) and VTE incidence and risk factors during first-line CBCT for metastatic TC, and the effect of thromboprophylaxis on VTE and bleeding. DESIGN SETTING AND PARTICIPANTS: In a population-based study, 506 men administered first-line CBCT during 2000-2014 at three university hospitals in Norway were included. Clinical variables were retrieved from medical records. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patients with ATE and VTE diagnosed at initiation of or during CBCT until 3 mo after completion were registered. Age-adjusted logistic regression was performed to identify possible VTE risk factors. RESULTS AND LIMITATIONS: Overall, 69 men (13.6%) were diagnosed with 70 thromboembolic events. Twelve men (2.4%) experienced ATE. Overall, 58 men (11.5%) experienced VTE, of whom 13 (2.6%) were prevalent at CBCT initiation, while 45 (8.9%) were diagnosed with incident VTE. Age-adjusted logistic regression identified retroperitoneal lymph node metastasis >5 cm (odds ratio [OR] 1.99, 95% confidence interval [CI] 1.01-3.91), central venous access (OR 2.84, 95% CI 1.46-5.50), and elevated C-reactive protein (>5 mg/l; OR 2.38, 95% CI 1.12-5.07) as incident VTE risk factors. Thromboprophylaxis (n = 84) did not influence the risk of VTE (VTE incidence with or without prophylaxis 13% vs 8%, p = 0.16). The incidence of bleeding events was significantly higher among those who received thromboprophylaxis than among those without thromboprophylaxis (14.5% vs 1.1%, p < 0.001). CONCLUSIONS: We found a high rate of thromboembolism incidence of 13.6%. Thromboprophylaxis did not decrease the risk of VTE but was associated with an increased risk of bleeding. PATIENT SUMMARY: We found a high rate of thromboembolism (13.6%) during cisplatin-based chemotherapy for metastatic testicular cancer. Prophylactic treatment against thromboses did not reduce the thrombosis frequency, but it resulted in a high incidence of bleeding events.

Interventions and symptom relief in hospital palliative cancer care: results from a prospective longitudinal study.

PURPOSE: To study the use of interventions and symptom relief for adult patients with incurable cancer admitted to an acute palliative care unit providing integrated oncology and palliative care services. METHODS: All admissions during 1 year were assessed. The use of interventions was evaluated for all hospitalizations. Patients with assessments for worst and average pain intensity, tiredness, drowsiness, nausea, appetite, dyspnea, depression, anxiety, well-being, constipation, and sleep were evaluated for symptom development during hospitalization. Descriptive statistics was applied for the use of interventions and the paired sample t-test to compare symptom intensities (SIs). RESULTS: For 451 admissions, mean hospital length of stay was 7.0 days and mean patient age 69 years. More than one-third received systemic cancer therapy. Diagnostic imaging was performed in 66% of the hospitalizations, intravenous rehydration in 45%, 37% received antibiotics, and 39% were attended by the multidisciplinary team. At admission and at discharge, respectively, 55% and 44% received oral opioids and 27% and 45% subcutaneous opioids. For the majority, opioid dose was adjusted during hospitalization. Symptom registrations were available for 180 patients. Tiredness yielded the highest mean SI score (5.6, NRS 0-10) at admission and nausea the lowest (2.2). Significant reductions during hospitalization were reported for all assessed SIs (p ≤ 0.01). Patients receiving systemic cancer therapy reported symptom relief similar to those not on systemic cancer therapy. CONCLUSION: Clinical practice and symptom relief during hospitalization were described. Symptom improvements were similar for oncological and palliative care patients.

Detection of Recurrent Prostate Cancer With 18F-Fluciclovine PET/MRI.

OBJECTIVE: Simultaneous PET/MRI combines soft-tissue contrast of MRI with high molecular sensitivity of PET in one session. The aim of this prospective study was to evaluate detection rates of recurrent prostate cancer by 18F-fluciclovine PET/MRI. METHODS: Patients with biochemical recurrence (BCR) or persistently detectable prostate specific antigen (PSA), were examined with simultaneous 18F-fluciclovine PET/MRI. Multiparametric MRI (mpMRI) and PET/MRI were scored on a 3-point scale (1-negative, 2-equivocal, 3-recurrence/metastasis) and detection rates (number of patients with suspicious findings divided by total number of patients) were reported. Detection rates were further stratified based on PSA level, PSA doubling time (PSAdt), primary treatment and inclusion criteria (PSA persistence, European Association of Urology (EAU) Low-Risk BCR and EAU High-Risk BCR). A detailed investigation of lesions with discrepancy between mpMRI and PET/MRI scores was performed to evaluate the incremental value of PET/MRI to mpMRI. The impact of the added PET acquisition on further follow-up and treatment was evaluated retrospectively. RESULTS: Among patients eligible for analysis (n=84), 54 lesions were detected in 38 patients by either mpMRI or PET/MRI. Detection rates were 41.7% for mpMRI and 39.3% for PET/MRI (score 2 and 3 considered positive). There were no significant differences in detection rates for mpMRI versus PET/MRI. Disease detection rates were higher in patients with PSA≥1ng/mL than in patients with lower PSA levels but did not differ between patients with PSAdt above versus below 6 months. Detection rates in patients with primary radiation therapy were higher than in patients with primary surgery. Patients categorized as EAU Low-Risk BCR had a detection rate of 0% both for mpMRI and PET/MRI. For 15 lesions (27.8% of all lesions) there was a discrepancy between mpMRI score and PET/MRI score. Of these, 10 lesions scored as 2-equivocal by mpMRI were changed to a more definite score (n=4 score 1 and n=6 score 3) based on the added PET acquisition. Furthermore, for 4 of 10 patients with discrepancy between mpMRI and PET/MRI scores, the added PET acquisition had affected the treatment choice. CONCLUSION: Combined 18F-fluciclovine PET/MRI can detect lesions suspicious for recurrent prostate cancer in patients with a range of PSA levels. Combined PET/MRI may be useful to select patients for appropriate treatment, but is of limited use at low PSA values or in patients classified as EAU Low-Risk BCR, and the clinical value of 18F-fluciclovine PET/MRI in this study was too low to justify routine clinical use.

Second Cancers in Patients With Locally Advanced Prostate Cancer Randomized to Lifelong Endocrine Treatment With or Without Radical Radiation Therapy: Long-Term Follow-up of the Scandinavian Prostate Cancer Group-7 Trial.

BACKGROUND: Curative radiation therapy (RT) constitutes a cornerstone in prostate cancer (PC) treatment. We present long-term follow-up estimates for second cancer (SC) risk and overall survival (OS) in patients randomized to hormone therapy (ET) alone or combined with 70 Gy prostatic RT in the Scandinavian Prostate Cancer Group-7 (SPCG-7) study. We explored the effect of salvage RT (≥60 Gy to the ET group) and reported causes of death. METHODS AND MATERIALS: The SPCG-7 study (1996-2002) was a randomized controlled trial that included 875 men with locally advanced nonmetastatic PC. In this analysis, including data from the Norwegian and Swedish Cancer and Cause of Death registries for 651 Norwegian and 209 Swedish study patients, we estimated hazard ratios (HRs) for SC and death, and cumulative incidences of SC. RESULTS: Median follow-up of the 860 (431 ET and 429) ET + RT patients was 12.2 years for SC risk analysis and 12.6 years for the OS analysis. Eighty-three of the Norwegian ET patients received salvage RT, and median time to salvage RT was 5.9 years. We found 125 and 168 SCs in the ET and ET + RT patients, respectively. With ET alone as reference, ET + RT patients had an HR of 1.19 (95% confidence interval [CI], 0.92-1.54) for all SCs and 2.54 (95% CI, 1.14-5.69) for urinary bladder cancer (UBC). The total number of UBC was 31 (23 in ET + RT; 8 in ET), and the vast majority (85%) were superficial. The HR for SC in salvage RT patients was 0.48 (95% CI, 0.24-0.94). Median OS was 12.8 (95% CI, 11.8-13.8) and 15.3 (95%, CI 14.3-16.4) years in the ET and ET + RT groups, respectively. Compared with ET alone, the risk of death was reduced in ET + RT patients (HR, 0.73; 95% CI, 0.62-0.86) and in ET patients receiving salvage RT (HR, 0.44; 95% CI, 0.30-0.65). CONCLUSIONS: Although the risk of UBC was increased in PC patients who received RT in addition to ET, this disadvantage is outweighed by the OS benefit of RT confirmed in our study. The risk of SC, and especially UBC, should be discussed with patients and be reflected in follow-up programs.

Causes of inferior relative survival after testicular germ cell tumor diagnosed 1953-2015: A population-based prospective cohort study.

BACKGROUND: Testicular germ cell tumor (TGCT) patients and survivors have excess mortality compared to the general male population, but relative survival (RS) has been scarcely studied. We investigated causes of excess mortality and their impact on RS among men diagnosed with TGCT in Norway, 1953-2015. METHODS AND FINDINGS: Using registry data (n = 9541), standardized mortality ratios (SMRs) and RS were calculated. By December 31st, 2015, 816 testicular cancer (TC) and 1508 non-TC deaths had occurred (non-TC SMR: 1.36). Within five years of TGCT diagnosis, 80% were TC deaths. Non-TC second cancer (SC) caused 65% of excess non-TC deaths, of which 34% from gastric, pancreatic or bladder cancer. SC SMRs remained elevated ≥26 years of follow-up. In localized TGCT diagnosed >1979, SC SMRs were only elevated after seminoma. Cardiovascular disease caused 9% and other causes 26% of excess non-TC deaths, of which 58% from gastrointestinal and genitourinary disorders. RS continuously declined with follow-up. TGCT patients diagnosed >1989 had superior five-year TC-specific RS (98.3%), lower non-TC SMR (1.21), but elevated SMRs for several SCs, infections, Alzheimer's disease, genitourinary disease and suicide. A limitation was lack of individual treatment data. CONCLUSIONS: RS declines mainly from TC deaths <5 years after TGCT diagnosis. Later, excess SC mortality becomes particularly important, reducing RS even ≥26 years. Radiotherapy; standard adjuvant seminoma treatment 1980-2007, is likely an important contributor, as are chemotherapy and possibly innate susceptibilities. Vigilant long-term follow-up, including psychosocial aspects, is important. Further research should focus on identifying survivor risk groups and optimizing treatment.

Rectal volume variations and estimated rectal dose during 8 weeks of image-guided radical 3D conformal external beam radiotherapy for prostate cancer.

•Modern IGRT has given new insight regarding organ motion in radiotherapy.•Rectal volume variation may increase the risk of biochemical and local failure.•Rectal volume decreased significantly during eight weeks of radiotherapy.•The percentage of irradiated rectal volume did not change statistically significant.•Our study shows that IGRT ensures a close to stable dose to the rectum.

Second cancers in radically treated Norwegian prostate cancer patients.

Introduction: The aim of this registry-based cohort study was to estimate second cancer (SC) risk following radical prostate cancer (PC) treatment and evaluate if the risk was influenced by radiotherapy. Materials and methods: We collected data from the Cancer Registry of Norway on all patients with PC as first cancer diagnosis, from 1997 to 2014. Standardized incidence ratios (SIRs) for SC were calculated by comparing our cohort to the standard male population. Subdistribution hazard ratios were estimated in treatment groups, using patients treated with radical prostatectomy (RP) as reference. Results: We analyzed 24,592 radically treated PC patients. The median follow-up was 7.75 and 6.25 years in the external beam radiotherapy (EBRT) and RP-groups, respectively. SIR for SC was indifferent from the reference population in 24,592 radically treated patients, higher following EBRT, SIR 1.12 (1.07-1.17), and lower following RP, SIR 0.93 (0.87-0.99). EBRT treated patients had higher rectal and urinary bladder cancer incidences, SIR 1.38 (1.16-1.64) and 1.49 (1.31-1.69), respectively. The EBRT patients and the patients treated with radiation after RP (RT after RP) had 38 and 27% higher risk of any SC. We found higher risk of bladder cancer for all treatment groups as compared to RP patients. Only EBRT treated patients showed higher risk of rectal and lung cancer. Discussion/conclusions: In our study, we found that PC patients treated with EBRT had an increased incidence of SC compared to the general population. Patients treated with EBRT and RT after RP were found to have increased risk of SCs, using RP patients as reference. The risks of rectal and urinary bladder cancer in patients receiving EBRT were higher compared to both the general population and to patients treated with radical prostatectomy. The risk of SC should be taken into account when discussing treatment for patients and designing follow-up.

Dose to penile bulb is not associated with erectile dysfunction 18 months post radiotherapy: A secondary analysis of a randomized trial.

BACKGROUND: Erectile dysfunction is a common side effect of prostate cancer (PC) therapy. In this randomized study (The RIC-study) we used patient reported outcomes to evaluate sexual function 18 months after combined endocrine therapy and radical radiotherapy (RT) given with either wide or tight planning target volume (PTV) margins. We also analyzed the impact of radiation dose to penile bulb on sexual function. METHODS: The RIC-study included 257 men with intermediate and high-risk PC. All patients received 6 months of total androgen blockage started 3 months prior to randomization. In high-risk patients, an oral anti-androgen (Bicalutamide) was administered for an additional 2.5 years. Patients were randomized to receive 78 Gy in 39 fractions guided either by weekly offline orthogonal portal imaging or by daily online cone beam computed tomography image-guided RT. Sexual function was evaluated at 18 months after start of RT using the Questionnaire Umeå Fransson Widmark 1994. Ability to have an erection was assessed on an 11-point scale numerical rating scale (0 = no and 10 = very much) as the primary outcome. In addition, the association between penile bulb (PB) radiation dose and erectile function was analyzed. FINDINGS: Of 250 evaluable patients, 228 (mean age 71.8 years) returned the questionnaires. The patients reported a high degree of sexual related problems with mean scores to the primary outcome question (221 respondents) of 7.44 and 7.39 in the 2D weekly IGRT-arm and 3D daily IGRT-arm (p = 0.93) respectively. For four additional questions (scale 0-10) regarding sexual function resulted in mean scores >6.5 with no difference between study arms. The mean dose to PB was substantially larger in the 2D weekly IGRT-arm vs the 3D daily IGRT-arm (mean 59.8 Gy vs mean 35.1 Gy).We found no effect of mean PB-dose on the primary outcome adjusted for study-site, risk-group and age. When adjusting for serum-testosterone level at 18 months in addition, the effect of mean PB-dose remained insignificant. INTERPRETATION: IGRT protocol or PB dose had no effect on ED 18 months after RT in this study population. The low potency rates can partly be explained by the prolonged use of anti-androgen in high risk patients. Longer follow-up is needed to confirm the results from the RIC-study.

Does Prophylactic Radiation Therapy to Avoid Gynecomastia in Patients With Prostate Cancer Increase the Risk of Breast Cancer?

PURPOSE: Prostate cancer (PC) patients who undergo antiandrogen monotherapy are offered prophylactic radiation therapy (PRT) to the breast buds to avoid gynecomastia. The aim of the present study was to evaluate whether the risk of breast cancer (BC) in men with PC as their first cancer diagnosis was influenced by PRT. METHODS AND MATERIALS: From the Norwegian Cancer Registry, we collected data from all patients with PC as their first cancer diagnosis from 1997 to 2014. We registered all RT given to the patients in the same period and the occurrence of BC diagnosed ≥3 months after the PC diagnosis. The histopathologic diagnoses of all BC cases were collected. Subdistribution hazard ratios for the risk of BC in the PRT and non-PRT groups were estimated. A standardized incidence ratio for BC was calculated by comparing our cohort to the standard male population. RESULTS: We analyzed 59,169 patients with PC, of whom 7864 (13.3%) had received PRT. The median follow-up time was 4 years. Of the 12 men with a diagnosis of BC, 3 had received PRT, and 2 of the 3 were phyllodes tumors. The risk of BC was not significantly different statistically for the patients given PRT compared with the non-PRT group (subdistribution hazard ratio 1.62, 95% confidence interval 0.41-5.62, adjusted for age and time of diagnosis). The standardized incidence ratio was 0.996 (95% confidence interval 0.57-1.75). CONCLUSIONS: In this registry-based study, we did not find an increased risk of BC in PC patients who received PRT. The number of BC cases in our study was low, and the risk of secondary BC after PRT seems to be negligible. The incidence of BC could, however, increase with additional follow-up. Also, 2 patients who had received PRT developed a malignant phyllodes tumor, an extremely rare type of BC associated with gynecomastia.

Radiotherapy for prostate cancer - Does daily image guidance with tighter margins improve patient reported outcomes compared to weekly orthogonal verified irradiation? Results from a randomized controlled trial.

BACKGROUND: Novel cancer drugs are subject to strict scientific evaluation of safety and efficacy and usually undergo a cost effectiveness analysis before approval for use in clinical practice. For new techniques in radiotherapy (RT) such as image-guided radiotherapy (IGRT), this is often not the case. We performed a randomized controlled trial to compare daily cone beam computer tomography (CBCT) IGRT with reduced planning target volume (PTV) margins vs weekly orthogonal portal imaging with conventional PTV margins. The primary aim of the study was to investigate the effect of two different image guidance techniques on patient reported outcome (PRO) using early side effects as proxy outcome of late rectal side effects in patients receiving curative RT for prostate cancer. METHODS: This open label, phase 3 trial conducted at two RT centers in Norway enrolled men aged 18 years or older with previously untreated histologically proven intermediate or high-risk adenocarcinoma of the prostate. Patients eligible for radical RT received it after 3 months of total androgen blockage and were randomly assigned to 78 Gy in 39 fractions guided either by weekly offline orthogonal portal imaging (15 mm margins to PTV) or by daily online CBCT IGRT (7 mm margins to PTV). Based on previous results indicating that acute rectal side effects are a valid proxy outcome for late rectal side effects, the primary outcome was acute rectal toxicity at end of RT as evaluated by rectal bother scale (five of the items from PRO's QUFW94). The RIC-trial is registered with ClinicalTrials.gov, number NCT01550237. FINDINGS: Between October 2012 and June 2015, 257 patients were randomly assigned to weekly offline portal imaging (n = 129) or daily online CBCT IGRT (n = 128). Out of 250 evaluable patients, 96% completed PROs at baseline and 97% at end of RT. Baseline analyses demonstrated balance between groups for baseline characteristics as well as for PROs. In general, patients reported a small degree of side effects at end of RT, and there was no difference between groups for primary outcome (rectal bother scale of QUFW94 1.871 vs 1.884, p = 0.804). In addition, there were no significant differences between groups for any other gastrointestinal or urinary symptom as reported by QUFW94. Health related quality of life analyses (EORTC QLQ 30) demonstrated no differences between groups. INTERPRETATION: In radical RT for prostate cancer, daily CBCT IGRT with reduced PTV margins demonstrated no advantage with respect to patient reported side effects at end of RT as compared to weekly orthogonal offline portal imaging with standard PTV margins.

Three-year Safety of Radium-223 Dichloride in Patients with Castration-resistant Prostate Cancer and Symptomatic Bone Metastases from Phase 3 Randomized Alpharadin in Symptomatic Prostate Cancer Trial.

BACKGROUND: In Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial, radium-223 versus placebo prolonged overall survival with favorable safety in castration-resistant prostate cancer patients with symptomatic bone metastases. Long-term radium-223 monitoring underlies a comprehensive safety and risk/benefit assessment. OBJECTIVE: To report updated ALSYMPCA safety, including long-term safety up to 3 yr after the first injection. DESIGN, SETTING, AND PARTICIPANTS: Safety analyses from phase 3 randomized ALSYMPCA trial included patients receiving ≥1 study-drug injection (600 radium-223 and 301 placebo). Patients (405 radium-223 and 167 placebo) entered long-term safety follow-up starting 12 wk after the last study-drug injection, to 3 yr from the first injection. Forty-eight of 405 (12%) radium-223 and 12/167 (7%) placebo patients completed follow-up, with evaluations every 2 mo for 6 mo, then every 4 mo until 3 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: All adverse events (AEs) were collected until 12 wk after the last injection; subsequently, only treatment-related AEs were collected. Additional long-term safety was assessed by development of acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), aplastic anemia, and secondary malignancies. Data analysis used descriptive statistics. RESULTS AND LIMITATIONS: During treatment to 12 wk following the last injection, 564/600 (94%) radium-223 and 292/301 (97%) placebo patients had treatment-emergent AEs (TEAEs). Myelosuppression incidence was low. Grade 3/4 hematologic TEAEs in radium-223 and placebo groups were anemia (13% vs 13%), neutropenia (2% vs 1%), and thrombocytopenia (7% vs 2%). Ninety-eight of 600 (16%) radium-223 and 68/301 (23%) placebo patients experienced grade 5 TEAEs. Long-term follow-up showed no AML, MDS, or new primary bone cancer; secondary non-treatment-related malignancies occurred in four radium-223 and three placebo patients. One radium-223 patient had aplastic anemia 16 mo after the last injection. No other cases were observed. Limitations include short (3-yr) follow-up. CONCLUSIONS: Final long-term safety ALSYMPCA analysis shows that radium-223 remained well tolerated, with low myelosuppression incidence and no new safety concerns. PATIENT SUMMARY: Updated Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial findings show that radium-223 remained well tolerated during treatment and up to 3 yr after each patient's first injection.

Ten- and 15-yr Prostate Cancer-specific Mortality in Patients with Nonmetastatic Locally Advanced or Aggressive Intermediate Prostate Cancer, Randomized to Lifelong Endocrine Treatment Alone or Combined with Radiotherapy: Final Results of The Scandinavian Prostate Cancer Group-7.

BACKGROUND: In high-risk prostate cancer (PCa), no study with observation times beyond 10 yr has demonstrated survival improvement after addition of prostatic radiotherapy (RAD) to endocrine treatment (ET) alone. OBJECTIVE: To compare mortality rates in patients receiving ET alone versus ET + RAD. DESIGN, SETTINGS, AND PARTICIPANTS: From 1996 to 2002, 875 Scandinavian patients with high-risk (90%) or intermediate PCa were randomized to ET or ET + RAD (The Scandinavian Prostate Cancer Group-7). After 3 mo with total androgen blockade in all patients, all individuals continued lifelong antiandrogen monotherapy. Those randomized to ET + RAD started prostate radiotherapy (70Gy) at 3 mo. OUTCOME, MEASUREMENTS AND STATISTICAL ANALYSIS: PCa-specific 15-yr mortality represented the primary endpoint. Assessment of the combination treatment effect and prognostic factors was performed in competing risk analyses and Cox proportional-hazard models. INTERVENTION: RAD added to ET. RESULTS AND LIMITATIONS: With a median observation time of 12 yr, the 15-yr PCa-specific mortality rates were 34% (95% confidence interval, 29-39%) and 17% (95% confidence interval, 13-22%) in the ET and ET + RAD arms respectively (p<0.001). Compared with the ET arm, the median overall survival in the ET + RAD arm was prolonged by 2.4 yr. Treatment with ET alone, age ≥65 yr and increasing histology grade independently increased the risk of PCa-specific and overall mortality. Limitations include nonformal evaluation of comorbidity, the inability to calculate progression-free survival, and lack of information about salvage therapy and toxicity. CONCLUSIONS: In patients with nonmetastatic locally advanced or aggressive PCa, ET + RAD reduces the absolute risk of PCa-specific death by 17% at 15 yr compared with ET alone; the comparable 15-yr PCa-specific mortality rates being 17% and 34%. The results warrant a phase 3 study comparing ET + RAD with radical prostatectomy in high-risk PCa. PATIENT SUMMARY: Adding prostatic therapy to lifelong antiandrogen therapy halves the absolute risk of death from prostate cancer from 34% to 17% 15 yr after diagnosis.

Long-term Relative Survival after Diagnosis of Testicular Germ Cell Tumor.

BACKGROUND: Long-term relative survival (RS) data for testicular germ cell tumor (TGCT) patients are scarce. We aimed to analyze long-term RS among TGCT patients diagnosed in Norway, between 1953 and 2012. METHODS: Data sources were the Cancer Registry of Norway and the Norwegian Cause of Death Registry. TGCT patients diagnosed during 1953 to 2012 were classified by time of diagnosis, histology, age, and disease extent at diagnosis. Estimates for RS were obtained, and a test comparing overall RS was performed. Corresponding data were obtained for men diagnosed with localized malignant melanoma before age 50. RESULTS: A total of 8,736 TGCT patients were included. RS generally continued to decline with increasing follow-up time, particularly beyond 15 to 30 years, unlike in localized malignant melanoma. Although RS was generally higher for seminomas, the continuing decline was more pronounced than for nonseminomas, even when diagnosed with localized disease. TGCT patients diagnosed before 1980 or after age 40 had lower RS. CONCLUSIONS: Although TGCT RS has improved in recent decades, it continues to decline even beyond 30 years of follow-up, regardless of disease extent at diagnosis. The main cause is probably treatment-induced late effects, particularly affecting seminoma patients. The continued use of adjuvant radiotherapy in seminomas until year 2000 is suspected as a culprit. IMPACT: Long-term TGCT survivors should be closely monitored for the development of late comorbidity. The challenge is to reduce negative consequences of previous and current TGCT treatment on RS while maintaining the excellent cure rates. Further research on causes of long-term morbidity and mortality among TGCT survivors is warranted. Cancer Epidemiol Biomarkers Prev; 25(5); 773-9. ©2016 AACR.

Bilateral testicular germ cell tumors in patients treated for clinical stage I non-seminoma within two risk-adapted SWENOTECA protocols.

BACKGROUND: A contralateral tumor occurs in 3.5-5% of men diagnosed with testicular germ cell cancer (TGCC). Biopsy of the contralateral testis may detect intratubular germ cell neoplasia ITGCNU, a precursor of TGCC. Biopsy of the contralateral testis to detect ITGCNU is controversial. If adjuvant chemotherapy (ACT) protects against bilateral cancer is debated. MATERIAL AND METHODS: A total of 1003 patients with clinical stage I (CS I) non-seminomatous testicular germ cell cancer (NSGCT) were included in two prospective, population-based protocols. Fifteen patients were excluded. Treatment was either adjuvant chemotherapy (n = 494), or surveillance (n = 494). Contralateral testicular biopsy was recommended for all patients, but was performed only in 282 patients. In case of ITGCNU radiotherapy (RT) to 16 Gy was recommended. RESULTS: During a follow-up of 8.3 years, 31 (3.6%) patients developed contralateral TGCC. ITGCNU was detected in 3.2% (9/282) of biopsied patients. The incidence of bilateral TGCC was similar following ACT, 2.5% (11/494), and surveillance, 3.4% (13/494), p = 0.41. Young age was a risk factor for metachronous TGCC (HR 0.93; 95% CI 0.88-0.99, p = 0.02). In total 2.2% (6/273) of patients without ITGCNU in the biopsy developed contralateral TGCC. One irradiated patient developed contralateral cancer, and one developed contralateral tumor before RT was given. CONCLUSION: ACT did not reduce the incidence of contralateral TGCC. Young patients had the highest risk of developing contralateral TGCC. The proportion of false negatives biopsies was higher than reported in earlier trials, but this may in part be related to patient selection, single biopsies and lack of mandatory immunohistochemistry.

Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial.

BACKGROUND: Bone metastases frequently cause skeletal events in patients with metastatic castration-resistant prostate cancer. Radium-223 dichloride (radium-223) selectively targets bone metastases with high-energy, short-range α-particles. We assessed the effect of radium-223 compared with placebo in patients with castration-resistant prostate cancer and bone metastases. METHODS: In this phase 3, double-blind, randomised ALSYMPCA trial, we enrolled patients who had symptomatic castration-resistant prostate cancer with two or more bone metastases and no known visceral metastases, who were receiving best standard of care, and had previously either received or were unsuitable for docetaxel. Patients were stratified by previous docetaxel use, baseline total alkaline phosphatase level, and current bisphosphonate use, then randomly assigned (2:1) to receive either six intravenous injections of radium-223 (50 kBq/kg) or matching placebo; one injection was given every 4 weeks. Randomisation was done with an interactive voice response system, taking into account trial stratification factors. Participants and investigators were masked to treatment assignment. The primary endpoint was overall survival, which has been reported previously. Here we report on time to first symptomatic skeletal event, defined as the use of external beam radiation to relieve bone pain, or occurrence of a new symptomatic pathological fracture (vertebral or non-verterbal), or occurence of spinal cord compression, or tumour-related orthopeadic surgical intervention. All events were required to be clinically apparent and were not assessed by periodic radiological review. Statistical analyses of symptomatic skeletal events were based on the intention-to-treat population. The study has been completed and is registered with ClinicalTrials.gov, number NCT00699751. FINDINGS: Between June 12, 2008, and Feb 1, 2011, 921 patients were enrolled, of whom 614 (67%) were randomly assigned to receive radium-223 and 307 (33%) placebo. Symptomatic skeletal events occurred in 202 (33%) of 614 patients in the radium-223 group and 116 (38%) of 307 patients in the placebo group. Time to first symptomatic skeletal event was longer with radium-223 than with placebo (median 15·6 months [95% CI 13·5-18·0] vs 9·8 months [7·3-23·7]; hazard ratio [HR]=0·66, 95% CI 0·52-0·83; p=0·00037). The risks of external beam radiation therapy for bone pain (HR 0·67, 95% CI 0·53-0·85) and spinal cord compression (HR=0·52, 95% CI 0·29-0·93) were reduced with radium-233 compared with placebo. Radium-223 treatment did not seem to significantly reduce the risk of symptomatic pathological bone fracture (HR 0·62, 95% CI 0·35-1·09), or the need for tumour-related orthopaedic surgical intervention (HR 0·72, 95% CI 0·28-1·82). INTERPRETATION: Radium-223 should be considered as a treatment option for patients with castration-resistant prostate cancer and symptomatic bone metastases. FUNDING: Algeta and Bayer HealthCare Pharmaceuticals.

Investigation of six testicular germ cell tumor susceptibility genes suggests a parent-of-origin effect in SPRY4.

Recent genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) associated with testicular germ cell tumor (TGCT) risk in the genes ATF7IP, BAK1, DMRT1, KITLG, SPRY4 and TERT. In the present study, we validate these associations in a Scandinavian population, and explore effect modification by parental sex and differences in associations between the major histological subtypes seminoma and non-seminoma. A total of 118 SNPs in the six genes were genotyped in a population-based Swedish-Norwegian sample comprising 831 TGCT case-parent triads, 474 dyads, 712 singletons and 3919 population controls. Seven hundred and thirty-four additional SNPs were imputed using reference haplotypes from the 1000 genomes project. SNP-TGCT association was investigated using a likelihood-based association test for nuclear families and unrelated subjects implemented in the software package UNPHASED. Forward stepwise regression within each gene was applied to determine independent association signals. Effect modifications by parent-of-origin and effect differences between histological subtypes were explored. We observed strong association between SNPs in all six genes and TGCT (lowest P-value per gene: ATF7IP 6.2 × 10(-6); BAK1 2.1 × 10(-10); DMRT1 6.7 × 10(-25); KITLG 2.1 × 10(-48); SPRY4 1.4 × 10(-29); TERT 1.8 × 10(-18)). Stepwise regression indicated three independent signals for BAK1 and TERT, two for SPRY4 and one each for DMRT1, ATF7IP and KITLG. A significant parent-of-origin effect was observed for rs10463352 in SPRY4 (maternal odds ratio = 1.72, paternal odds ratio = 0.99, interaction P = 0.0013). No significant effect differences between seminomas and non-seminomas were found. In summary, we validated previously reported genetic associations with TGCT in a Scandinavian population, and observed suggestive evidence of a parent-of-origin effect in SPRY4.