[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
[Show abstract][Hide abstract] ABSTRACT: Background:
SWENOTECA has since 1998 offered patients with clinical stage I (CS I) nonseminoma, adjuvant chemotherapy with one course of bleomycin, etoposide and cisplatin (BEP). The aim has been to reduce the risk of relapse, sparing patients the need of toxic salvage treatment. Initial results on 312 patients treated with one course of adjuvant BEP, with a median follow-up of 4.5 years, have been previously published. We now report mature and expanded results.
Patients and methods:
In a prospective, binational, population-based risk-adapted treatment protocol, 517 Norwegian and Swedish patients with CS I nonseminoma received one course of adjuvant BEP. Patients with lymphovascular invasion (LVI) in the primary testicular tumor were recommended one course of adjuvant BEP. Patients without LVI could choose between surveillance and one course of adjuvant BEP. Data for patients receiving one course of BEP are presented in this study.
At a median follow-up of 7.9 years, 12 relapses have occurred, all with IGCCC good prognosis. The latest relapse occurred 3.3 years after adjuvant treatment. The relapse rate at 5 years was 3.2% for patients with LVI and 1.6% for patients without LVI. Five-year cause-specific survival was 100%.
The updated and expanded results confirm a low relapse rate following one course of adjuvant BEP in CS I nonseminoma. One course of adjuvant BEP should be considered a standard treatment in CS I nonseminoma with LVI. For patients with CS I nonseminoma without LVI, one course of adjuvant BEP is also a treatment option.
Full-text · Article · Aug 2014 · Annals of Oncology
[Show abstract][Hide abstract] ABSTRACT: 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.1 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.
Full-text · Article · May 2014 · The Lancet Oncology
[Show abstract][Hide abstract] ABSTRACT: Background:
Radium-223 dichloride (radium-223), an alpha emitter, selectively targets bone metastases with alpha particles. We assessed the efficacy and safety of radium-223 as compared with placebo, in addition to the best standard of care, in men with castration-resistant prostate cancer and bone metastases.
In our phase 3, randomized, double-blind, placebo-controlled study, we randomly assigned 921 patients who had received, were not eligible to receive, or declined docetaxel, in a 2:1 ratio, to receive six injections of radium-223 (at a dose of 50 kBq per kilogram of body weight intravenously) or matching placebo; one injection was administered every 4 weeks. In addition, all patients received the best standard of care. The primary end point was overall survival. The main secondary efficacy end points included time to the first symptomatic skeletal event and various biochemical end points. A prespecified interim analysis, conducted when 314 deaths had occurred, assessed the effect of radium-223 versus placebo on survival. An updated analysis, when 528 deaths had occurred, was performed before crossover from placebo to radium-223.
At the interim analysis, which involved 809 patients, radium-223, as compared with placebo, significantly improved overall survival (median, 14.0 months vs. 11.2 months; hazard ratio, 0.70; 95% confidence interval [CI], 0.55 to 0.88; two-sided P=0.002). The updated analysis involving 921 patients confirmed the radium-223 survival benefit (median, 14.9 months vs. 11.3 months; hazard ratio, 0.70; 95% CI, 0.58 to 0.83; P<0.001). Assessments of all main secondary efficacy end points also showed a benefit of radium-233 as compared with placebo. Radium-223 was associated with low myelosuppression rates and fewer adverse events.
In this study, which was terminated for efficacy at the prespecified interim analysis, radium-223 improved overall survival. (Funded by Algeta and Bayer HealthCare Pharmaceuticals; ALSYMPCA ClinicalTrials.gov number, NCT00699751.).
Full-text · Article · Jul 2013 · New England Journal of Medicine
[Show abstract][Hide abstract] ABSTRACT: Recent genome-wide association studies have identified single nucleotide polymorphisms (SNPs) associated with testicular germ cell tumour (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. 734 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 modification 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.
Full-text · Article · May 2013 · Human Molecular Genetics
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND
Testicular germ cell tumour (TGCT) is the most common cancer in young men, and an imbalance between the estrogen and androgen levels in utero is hypothesized to influence TGCT risk. Thus, polymorphisms in genes involved in the action of sex hormones may contribute to variability in an individual's susceptibility to TGCT.
We conducted a Norwegian–Swedish case–parent study. A total of 105 single-nucleotide polymorphisms (SNPs) in 20 sex hormone pathway genes were genotyped using Sequenom MassArray iPLEX Gold, in 831 complete triads and 474 dyads. To increase the statistical power, the analysis was expanded to include 712 case singletons and 3922 Swedish controls, thus including triads, dyads and the case–control samples in a single test for association. Analysis for allelic associations was performed with the UNPHASED program, using a likelihood-based association test for nuclear families with missing data, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. False discovery rate (FDR) was used to adjust for multiple testing.
Five genetic variants across the ESR2 gene [encoding estrogen receptor beta (ERβ)] were statistically significantly associated with the risk of TGCT. In the case–parent analysis, the markers rs12434245 and rs10137185 were associated with a reduced risk of TGCT (OR = 0.66 and 0.72, respectively; both FDRs
[Show abstract][Hide abstract] ABSTRACT: From 1995 to 2003, 603 adult patients from Sweden and Norway with metastatic testicular nonseminomatous germ cell tumor (NSGCT) were included prospectively in a population-based protocol with strict guidelines for staging, treatment, and follow-up. Patients with extragonadal primary tumor or previous treatment for contralateral testicular tumor were excluded. The basic strategy was to individualize treatment according to initial tumor marker response.
Initial treatment for all patients was two courses of standard bleomycin, etoposide, and cisplatin (BEP), with tumor markers analyzed weekly. Good response was defined as a half-life (t(1/2)) for α-fetoprotein (AFP) of ≤ 7 days and/or for β-human chorionic gonadotropin (β-HCG) of ≤ 3 days. Patients with prolonged marker t(1/2) (ie, poor response) received intensification with addition of ifosfamide (BEP-if/PEI) in step 1. If poor response continued, the treatment was intensified with high-dose chemotherapy with stem-cell rescue as step 2.
Overall, 99% of all patients with metastatic testicular NSGCT in the population were included in the protocol. Median follow-up was 8.2 years. Seventy-seven percent of the patients were treated with BEP alone; 18% received intensification step 1%, and 5% received intensification step 2. Grouped according to International Germ Cell Consensus Classification, 10-year overall survival was 94.7% in good-prognosis patients, 90.0% in intermediate-prognosis patients, and 67.4% in poor-prognosis patients.
With detailed treatment protocols and a dedicated collaborative group of specialists, treatment results comparable to those reported from large single institutions can be achieved at national level. With the treatment principles used in Swedish-Norwegian Testicular Cancer Group study SWENOTECA IV, the survival of intermediate-prognosis patients is remarkable and close to that of good-prognosis patients.
Preview · Article · May 2011 · Journal of Clinical Oncology
[Show abstract][Hide abstract] ABSTRACT: The Scandinavian Prostate Cancer Group-7 randomized trial demonstrated a survival benefit of combined endocrine therapy and external-beam radiotherapy over endocrine therapy alone in patients with high-risk prostate cancer. In a subset of the study population, the incidence and clinical implications of residual prostate cancer in posttreatment prostate biopsy specimens was evaluated.
Biopsy specimens were obtained from 120 of 875 men in the Scandinavian Prostate Cancer Group-7 study.
Biopsies were performed at median of 45 months follow-up. In 63 patients receiving endocrine treatment only and 57 patients receiving combined treatment, residual cancer was found in 66% (n = 41) and 22% (n = 12), respectively (p < 0.0001). The vast majority of residual tumors were poorly differentiated (Gleason score ≥ 8). Endocrine therapy alone was predictive of residual prostate cancer: odds ratio 7.49 (3.18-17.7), p < 0.0001. In patients with positive vs. negative biopsy the incidences of clinical events were as follows: biochemical recurrence 74% vs. 27% (p < 0.0001), local progression 26% vs. 4.7% (p = 0.002), distant recurrence 17% vs. 9.4% (p = 0.27), clinical recurrence 36% vs. 13% (p = 0.006), cancer-specific death 19% vs. 9.7% (p = 0.025). In multivariable analysis, biochemical recurrence was significantly associated with residual cancer: hazard ratio 2.69 (1.45-4.99), p = 0.002, and endocrine therapy alone hazard ratio 3.45 (1.80-6.62), p < 0.0001.
Radiotherapy combined with hormones improved local tumor control in comparison with endocrine therapy alone. Residual prostate cancer was significantly associated with serum prostate-specific antigen recurrence, local tumor progression, clinical recurrence, and cancer-specific death in univariable analysis. Residual cancer was predictive of prostate-specific antigen recurrence in multivariable analysis.
No preview · Article · May 2011 · International journal of radiation oncology, biology, physics
[Show abstract][Hide abstract] ABSTRACT: Post-treatment prostate biopsy side-effects were evaluated in patients with locally advanced prostate cancer on endocrine therapy alone or combined with radiotherapy in the Scandinavian Prostate Cancer Group-7 randomized trial.
One-hundred and twenty patients underwent transrectalultrasound-guided biopsy, and were requested to complete a questionnaire on side-effects occurring within 7 days' follow-up.
The questionnaire was returned by 109 patients (91%) (endocrine therapy only 52%, combined endocrine therapy and radiotherapy 48%). Previous therapy had no significant influence on pain, urinary flow, haematuria or haematospermia. Pain at biopsy was reported in 63% (mild, 57%; moderate, 5.6%; severe, one patient) and pain at follow-up in 31% (mild, 27%; moderate, four patients). Haematuria (mean duration 2.2 days) was reported in 41%, and reduced urinary flow in 20% (mild, 18%; severe: four patients; no patient had urinary retention). Haematospermia was scarce. No patient reported urinary tract infection. Rectal bleeding occurred in 18% in the endocrine and 35% in the combined therapy group (p = 0.047), with a mean duration of 1.6 and 2.2 days, respectively (p = 0.031). In logistic regression analysis, a trend towards increased rectal bleeding was found in patients on combined endocrine therapy and radiotherapy (odds ratio 2.4, p = 0.050).
Patient-reported post-treatment prostate biopsy side-effects were mild and self-limiting.
No preview · Article · Mar 2011 · Scandinavian Journal of Urology and Nephrology
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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).
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.
No preview · Article · Feb 2011 · Journal of Clinical Oncology
[Show abstract][Hide abstract] ABSTRACT: To compare the trends in prostate cancer incidence, treatment with curative intent and mortality across regions and counties in Norway, and to consider changes in incidence (an indicator for early diagnosis) and treatment with curative intent as explanatory factors for the decreasing prostate cancer mortality rates.
Prostate cancer incidence and mortality data (1980-2007) alongside treatment data (1987-2005) were obtained from the national, population-based Cancer Registry of Norway. Joinpoint regression models were fitted to age-adjusted incidence, treatment and mortality rates to identify linear changes in the trends.
Both age-adjusted incidence rates and rates of curative treatment of prostate cancer increased significantly in all five regions of Norway since the early 1990s. There was a strong positive correlation between increasing incidence and increasing use of curative treatment. The frequency of curative treatment in Western Norway was almost threefold that in the Northern and Central regions around year 2000. Subsequently, the regional trends converged and only minor differences in prostate cancer incidence and use of curative treatment were observed by 2005. The declines in mortality were observed earliest in the regions with the highest incidence and the most frequent use of curative treatment, while the largest decreases in mortality were found in counties where the largest increases in curative treatment were observed.
The elucidation of the prostate cancer mortality trends is hindered by an inability to tease out the potential effects of early treatment from the more general impact of improved and more active treatment. However, it is likely that both sets of intervention have contributed to the decline in prostate cancer mortality in Norway since 1996.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
No preview · Article · Apr 2009 · Journal of Clinical Oncology