Search

Recent randomized controlled trials have assessed the risksand benefits of thromboprophylaxis in ambulatory cancerpatients receiving chemotherapy and reported a relativerisk reduction of 30–60% in venous thromboembolic events(VTEs) but a doubling of bleeding risk [1–4]. Based on theseresults, the most recent American Society of ClinicalOncology clinical practice guideline update recommendsthromboprophylaxis with apixaban, rivaroxaban, or low-molecular–weight heparin (LMWH) for cancer patientswith a high risk of VTE and low risk of bleeding [5]. Patientswith metastatic germ-cell tumor (mGCT) were under-represented in all trials and thus it is not clear whether thisrecommendation applies to this group, although retrospec-tive data suggests similar efficacy of VTE prophylaxis.

Objectives Cisplatin-related hearing loss (HL) is claimed to progress after treatment. This controlled longitudinal study with extended follow-up investigates HL in testicular cancer survivors (TCSs) after cisplatin-based chemotherapy (CBCT). Study design Controlled longitudinal study. Methods Eighty-two TCSs treated with CBCT between 1980 and 1994 in Norway participated in two surveys (S1/S3), including pure-tone audiograms (0.125-8 kHz) and self-reported HL, 12 and 31 years after treatment, respectively. Hearing thresholds were age-adjusted based on age-matched hearing thresholds from the general population (controls). Hearing loss was defined as thresholds >20 dB at any frequency. Results Between the two surveys, the prevalence of high-frequency HL (4, 6, and 8 kHz) increased from 73% to 94% but approached those of the aging general population after age adjustment. In TCSs aged >40 years at first survey, HL at the subsequent survey equaled that of controls. Self-reported HL increased from seven (9%) at S1 to 20 (26%) at S3. At S1, age-adjusted HL was identified in all (seven) TCSs reporting decreased hearing whereas at S3, hearing thresholds did not differ from controls in seven out of 20 patients reporting HL. Conclusion CBCT-related ototoxicity causes high-frequency HL, but in contrast to reports from follow-up studies from the first post-treatment decade, no major progression was found beyond the first post-treatment decade for frequencies 0.125-8 kHz. Importantly, with extended follow-up, hearing thresholds of patients approach those of the general population, possibly due to a less-than-additive effect with age-related hearing loss (ARHL) in CBCT-treated patients. Age-and sex-matching is strongly advised in long-term follow-up of CBCT-related ototoxicity. Specificity for detecting ototoxicity with self-reported questionnaires decreases with extended follow-up. Level of evidence 3 Laryngoscope, 130:E515-E523, 2020.

The long-term toxicities after cisplatin-based chemotherapy (CBCT) reveal a remarkable inter-individual variation among testicular cancer survivors (TCSs). Therefore, we assessed long-term platinum (Pt) changes and their associations with CBCT-related late effects in TCSs.In 77 TCSs treated with CBCT from 1984 to 1990, blood samples for analyses of Pt and a questionnaire including self-reported neuro- and ototoxicity (NTX) symptoms were collected during two follow-up surveys at median 12 (Survey I; SI) and 20 (Survey II; SII) years after treatment. Information about second cancers after SII was retrieved from the Norwegian Cancer Registry.A larger Pt decline from SI to SII was associated with a decreased risk of a second cancer diagnosis (HR 0.78, 95% CI 0.62-0.99 per 10 ng/L/year), and worsening of paresthesias in hands (OR 1.98, 95% CI 1.09-3.59 per 10 ng/L/year) and tinnitus (OR 1.51, 95% CI 1.01-2.27 per 10 ng/L/year).In summary, we found a significant association between a larger Pt decline and a reduced risk of second cancers and deterioration of paresthesias in hands and tinnitus.

Testicular cancer (TC) is the most common neoplasm in males aged 15-40 years. The majority of patients have no evidence of metastases at diagnosis and thus have clinical stage I (CSI) disease [Oldenburg J, Fossa SD, Nuver J et al. Testicular seminoma and non-seminoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24(Suppl 6): vi125-vi132; de Wit R, Fizazi K. Controversies in the management of clinical stage I testis cancer. J Clin Oncol 2006; 24: 5482-5492.]. Management of CSI TC is controversial and options include surveillance and active treatment. Different forms of adjuvant therapy exist, including either one or two cycles of carboplatin chemotherapy or radiotherapy for seminoma and either one or two cycles of cisplatin-based chemotherapy or retroperitoneal lymph node dissection for non-seminoma. Long-term disease-specific survival is similar to 99% with any of these approaches, including surveillance. While surveillance allows most patients to avoid additional treatment, adjuvant therapy markedly lowers the relapse rate. Weighing the net benefits of surveillance against those of adjuvant treatment depends on prioritizing competing aims such as avoiding unnecessary treatment, avoiding more burdensome treatment with salvage chemotherapy and minimizing the anxiety, stress and life disruption associated with relapse. Unbiased information about the advantages and disadvantages of surveillance and adjuvant treatment is a prerequisite for informed consent by the patient. In a clinical scenario like CSI TC, where different disease-management options produce indistinguishable long-term survival rates, patient values, priorities and preferences should be taken into account. In this review, we provide an overview about risk factors for relapse, potential benefits and harms of adjuvant chemotherapy and active surveillance and a rationale for involving patients in individualized decision making about their treatment rather than adopting a uniform recommendation for all.

Context: This is an update of the previous European Association of Urology testis cancer guidelines published in 2011, which included major changes in the diagnosis and treatment of germ cell tumours. Objective: To summarise latest developments in the treatment of this rare disease. Recommendations have been agreed within a multidisciplinary working group consisting of urologists, medical oncologists, and radiation oncologists. Evidence acquisition: A semi-structured literature search up to February 2015 was performed to update the recommendations. In addition, this document was subjected to double-blind peer review before publication. Evidence synthesis: This publication focuses on the most important changes in treatment recommendations for clinical stage I disease and the updated recommendations for follow-up. Conclusions: Most changes in the recommendations will lead to an overall reduction in treatment burden for patients with germ cell tumours. In advanced stages, treatment intensification is clearly defined to further improve overall survival rates. Patient summary: This is an update of a previously published version of the European Association of Urology guidelines for testis cancer, and includes new recommendations for clinical stage I disease and revision of the follow-up recommendations. Patients should be fully informed of all the treatment options available to them. (C) 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Context Patients with clinical stage I (CS I) seminoma testis with large primary tumours and/or rete testis invasion (RTI) might have an increased risk of relapse. In recent years, these risk factors have frequently been employed to decide on adjuvant treatment. Objective To systematically review the literature on tumour size and RTI as risk factors for relapse in CS I seminoma testis patients under surveillance. Evidence acquisition Relevant databases including Medline, Embase, and the Cochrane Library were searched up to November 2016. Randomised controlled trials (RCTs) or quasi-RCTs, prospective observational studies with controls, retrospective matched-pair studies, and comparative studies from well-defined registries/databases were included. The primary outcome was the rate of relapse and relapse-free survival (RFS). The risk of bias was assessed by the Quality in Prognosis Studies tool. Evidence synthesis After assessing 3068 abstracts and 80 full-text articles, 20 studies met the inclusion criteria. Although evidence to justify a cut-off of 4cm for size was lacking, it was the most frequently studied. The reported hazard ratio (HR) for the RFS for tumours >4cm was 1.59–2.8. Accordingly, the reported 5-yr RFS ranged from 86.6% to 95.5% and from 73.0% to 82.6% for patients having tumours ≤4 and >4cm, respectively. For tumours with RTI present, the reported HR was 1.4–1.7. The 5-yr RFS ranged from 86.0% to 92.0% and 74.9% to 79.5% for patients without versus those with RTI present, respectively. A meta-analysis was considered inappropriate due to data heterogeneity. Conclusions Primary tumour size and RTI are associated with the risk of relapse in CS I seminoma testis patients during surveillance. However, in the presence of either risk factor, the vast majority of patients are cured by orchiectomy alone and will not relapse. Furthermore, the evidence on the prognostic value of size and RTI has significant limitations, so prudency is warranted on their routine use in clinical practice. Patient summary Primary testicular tumour size and rete testis invasion are considered to be important prognostic factors for the risk of relapse in patients with clinical stage I seminoma testis. We systematically reviewed all the literature on the prognostic value of these two postulated risk factors. The outcome is that the prognostic power of these factors in the published literature is too low to advocate their routine use in clinical practice and to drive the choice on adjuvant treatment in clinical stage I seminoma testis patients.

Do genetic variations in the testosterone pathway genes modify the effect of treatment on the levels of testosterone and LH in long-term testicular cancer (TC) survivors (TCSs)?Variations in LH receptor (LHR) and in 5α-reductase II (SRD5A2) genes may modify the effect of TC treatment on testosterone levels, whereas genetic variations in the androgen receptor (AR) may modify the effect on LH levels.TCSs experience variable degrees of long-term reduction in gonadal function after treatment. This variability can in part be explained by treatment intensity, but may also be due to individual variations in genes involved in the function and metabolism of reproductive hormones.Cross-sectional study on testosterone and LH levels in 637 Norwegian TCSs in relation to genetic variants and TC treatment.The single nucleotide polymorphisms LHR Asn291Ser (rs12470652) and Ser312Asn (rs2293275), as well as SRD5A2 Ala49Thr (rs9282858) and Val89Leu (rs523349) were analyzed by allele-specific PCR. The insertion polymorphism LHR InsLQ (rs4539842) was analyzed by sequencing. The numbers of AR CAG and GGN repeats were determined by capillary electrophoresis. Blood samples were collected 5-21 years after diagnosis (median 11 years) and serum total testosterone and LH were analyzed by commercial immunoassays. The TCSs were divided into four groups according to their treatment; surgery only, radiotherapy and chemotherapy with ≤850 or850 mg of cisplatin. Polymorphisms presenting P0.1 for the interaction term with treatment in an initial two-way analysis of covariance (ANCOVA) were investigated further in two consecutive one-way ANCOVA analyses to elucidate the interaction between treatment and genotype.For the whole group of TCSs, there were no significant differences between the hormone levels in homozygotes for the wild type and carriers of at least one polymorphic allele for the investigated polymorphisms. Three of the polymorphisms showed signs of interaction with treatment, i.e. LHR InsLQ, SRD5A2 A49T and the AR CAG repeat. Follow-up analyses revealed three situations where only one of the genotypes of the polymorphism where associated with significantly different hormone levels after surgery compared with after additional cytotoxic treatment: For LHR InsLQ, only the wild-type allele was associated with lower testosterone levels after cisplatin850 mg compared with after surgery (24% lower, P0.001). For SRD5A2 A49T, testosterone levels were lower after radiotherapy compared with after surgery, but only for the heterozygotes for the polymorphism (39% lower, P = 0.001). In comparison, the testosterone levels were just slightly lower after radiotherapy (6% lower, P = 0.039) or cisplatin ≤ 850 mg (7% lower, P = 0.041), compared with surgery, independent of genotypes. For AR CAG, only the reference length of CAG = 21-22 had significantly higher LH levels after cisplatin ≤ 850 mg compared with after surgery (70% higher, P0.001). Independent of genotypes, however, LH levels after cisplatin ≤ 850 mg were only 26% higher than after surgery (P = 0.005).Unadjusted P-values are presented. For analysis involving genotypes, the level of statistical significance was adjusted for the total number of polymorphisms tested, n = 7, i.e. to P0.007 (0.5/7). The rather weak associations indicate that additional polymorphisms are involved in the modulation.To our knowledge, this is the first study supporting the notion that polymorphisms may explain at least some of the inter-individual differences in endocrine response to TC treatment. Our findings suggest that individuals with certain genotypes may be more vulnerable to certain treatments. Knowledge on genetic predisposition concerning treatment-related endocrine gonadotoxicity to different treatment regimens may help tailoring TC therapy when possible.This study was supported by the Research Council of Norway (Grant No. 160619). There were no competing interests.

Purpose To assess longitudinal long-term alterations of testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) in testicular cancer survivors (TCSs). Patients and Methods In all, 307 TCSs treated from 1980 to 1994 provided blood samples after orchiectomy but before further treatment, at Survey I (SI; 1998-2002), and Survey II (SII; 2007-2008). Levels of sex hormones were categorized according to quartiles and reference range (2.5 and 97.5 percentiles) of 599 controls for each decadal age group. TCSs were categorized according to treatment: surgery, radiotherapy (RT), or chemotherapy (CT). The risk of higher (LH) or lower (testosterone) levels was assessed with χ2 test (FSH) or ordinal logistic regression analysis and expressed as odds ratios (ORs) with 95% CIs. Results Risk of lower testosterone and higher LH and FSH levels was significantly increased for TCSs at all time points after RT or CT. At SII, ORs were 3.3 (95% CI, 2.3 to 4.7) for lower testosterone categories and 5.2 (95% CI, 3.5 to 7.9) for RT and CT. ORs for increased LH and FSH were 4.4 (95% CI, 3.1 to 6.5) and 18.9 (95% CI, 11.0 to 32.6) for RT, respectively, and 3.6 (95% CI, 2.4 to 5.3) and 14.2 (95% CI, 8.3 to 24.4) for CT, respectively. The cumulative platinum dose was significantly associated with risk of higher LH levels at both surveys and higher FSH at SI. In total, half the TCSs had at least one of three sex hormone levels outside the reference range at SII. Conclusion Long-term TCSs are at risk of premature hormonal aging. Our findings may pertain to cancer survivors in general, underlining the importance of extended follow-up.

In November 2011, the Third European Consensus Conference on Diagnosis and Treatment of Germ-Cell Cancer (GCC) was held in Berlin, Germany. This third conference followed similar meetings in 2003 (Essen, Germany) and 2006 (Amsterdam, The Netherlands) [Schmoll H-J, Souchon R, Krege S et al. European consensus on diagnosis and treatment of germ-cell cancer: a report of the European Germ-Cell Cancer Consensus Group (EGCCCG). Ann Oncol 2004; 15: 1377-1399; Krege S, Beyer J, Souchon R et al. 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. Eur Urol 2008; 53: 478-496; Krege S, Beyer J, Souchon R et al. 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 II. Eur Urol 2008; 53: 497-513]. A panel of 56 of 60 invited GCC experts from all across Europe discussed all aspects on diagnosis and treatment of GCC, with a particular focus on acute and late toxic effects as well as on survivorship issues. The panel consisted of oncologists, urologic surgeons, radiooncologists, pathologists and basic scientists, who are all actively involved in care of GCC patients. Panelists were chosen based on the publication activity in recent years. Before the meeting, panelists were asked to review the literature published since 2006 in 20 major areas concerning all aspects of diagnosis, treatment and follow-up of GCC patients, and to prepare an updated version of the previous recommendations to be discussed at the conference. In addition, similar to 50 E-vote questions were drafted and presented at the conference to address the most controversial areas for a poll of expert opinions. Here, we present the main recommendations and controversies of this meeting. The votes of the panelists are added as online supplements.

In the article that accompanies this editorial, Frisina et al report on ototoxicity after cisplatin-based chemotherapy in the Platinum Study. This study comprehensively assesses hearing impairment, both as audiometric and as patient-reported outcome, as well as tinnitus in 488 cisplatin-treated testicular cancer (TC) survivors. One out of five survivors was found to have such severe hearing loss that a hearing aid was recommended. However, only 1.2% of the participants reported actually using such a device. Cisplatin-based chemotherapy was introduced in the late 1970s by Larry Einhorn and cures most patients with metastatic TC. However, long-term complications and late effects after cancer treatment are increasingly recognized as a major contributor to morbidity of survivors, influencing quality of life (QoL) and representing a burden for the growing community of cancer survivors. Similar to the unique position of TC as a model for a curable neoplasm, TC survivors represent a prime cohort for long-term survivorship studies because of their good life expectancy as a result of high cure rates and young age at diagnosis. Although the report by Frisina et al is a valuable contribution to the literature, it would have benefitted from inclusion of additional information, such as pretreatment assessments, the impact of ototoxicity on health-related QoL, details about and adjustment for other ototoxic agents (eg, aminoglycosides), and occupational hearing loss after completion of cisplatin-based chemotherapy. The cohort represents TC survivors receiving standard cisplatin-based chemotherapy for metastatic disease for which we do have some long-term ototoxicity outcomes, whereas high-quality data on ototoxicity after adjuvant chemotherapy with either one or two cycles of bleomycin, etoposide, and cisplatin (BEP) or carboplatin as well as after high-dose chemotherapy are still lacking. In general, long observation periods—a prerequisite for survivorship research—make translation of the impact of former to contemporary treatment challenging. Testicular cancer is an exception. For the last four decades, no alternative regimen was superior to BEP. In accordance with current guidelines, roughly nine out of 10 participants received three or four cycles of BEP or four cycles of etoposide and cisplatin (EP). Normative data from healthy individuals comprising median quartile threshold values for different age groups were applied to categorize decibel thresholds of individual TC survivors in an ordinal fashion up to 8 kHz as adjustment for physiologic age-related hearing decline—an approach similar to the percentiles of pediatric growth curves. Retesting this survivor cohort in some years would yield longitudinal data allowing testing of whether this group is vulnerable to subsequent age-related declines. A hypothesized reduced functional reserve leading to accelerated hormonal ageing could recently be demonstrated in TC survivors with a similar percentile categorization. Except for patients with TC who depend strongly on unimpaired hearing capability (eg, musicians, composers, or ornithologists), the risk of high-frequency hearing impairment should generally play no role in treatment planning of advanced testicular cancer in view of the high curative potential of platinum-based chemotherapy in this setting. In this study, hearing loss according the American SpeechLanguage-Hearing Association criteria was found in 80% of TC survivors, including 18% with a severe (71 to 90 dB) or profound (. 90 dB) hearing loss. On the other hand, one cycle of cisplatin increased the hearing threshold only by 2.5 dB. Thus, cisplatinbased chemotherapy for metastases should not cause more than 10 dB of hearing loss. Age-related hearing decline probably represented much of the observed hearing loss as defined by the American Speech-Language-Hearing Association, which might not be optimal for cross-sectional studies without preceding measurements. Calculation of hearing decline over various frequencies is complex: “For each patient i, the geometric mean Yi was calculated using standard methods by taking the arithmetic mean of the natural log-transformed hearing threshold, di, from n frequencies and then using exponentiation to return the computation to the original decibel scale (ie, log-average).” Understanding this end point, which scores high on specificity and poor on patient relevance (Fig 1), is difficult formost readers who are not familiar with this field. High specificity is needed for disentangling the impact of a single component on a given end point. Chemotherapy-related development of cardiovascular disease (CVD), for example, is complex to assess both due to interaction of different chemotherapy components and further dilution of the cause-effect relationship by multiple genetic and environmental risk factors. Chemotherapyinduced ototoxicity, on the other hand, is almost exclusively linked to cisplatin. Hypertension and hearing loss might be associated independent of cisplatin treatment. However, both symptoms might represent different cisplatin-related long-term toxicities despite adjustment for the cumulative cisplatin dose. Residual serum platinum increases the risk of paresthesia and Raynaud phenomenon more strongly than the applied cumulative cisplatin dose. Residual platinum, however, was not associated with tinnitus or hearing impairment assessed by the Scale for

In 1979, the Copenhagen group around Dr. Skakkebaek introduced contralateral biopsy in patients with testicular germ cell tumour (GCT) as a means of early diagnosing a contralateral testicular tumour (Berthelsen et al. in Br Med J 2(6186):363–364, 1). Although the rationale of contralateral biopsies is based on much of scientific evidence, no issue regarding the management of GCTs has been more controversial than the issue of contralateral biopsies (Heidenreich in BJU Int 104(9 Pt B):1346–1350, 2; Grigor and Rorth in Eur Urol 23(1):129–135, 3). A poll conducted during the GCT Consensus Meeting in Berlin 2011 revealed that 43 % of 60 leading experts would not recommend a contralateral biopsy and only 13.7 % would do the biopsy in all cases with GCT (Beyer et al. in Ann Oncol 24(4):878–888, 4). Likewise, the European Association of Urology and the European Society of Medical Oncology offer only weak recommendations with respect to contralateral biopsies in their guidelines of testicular cancer (Albers et al. in Eur Urol 68(6):1054–1068, 5; Oldenburg et al. in Ann Oncol 24(Suppl 6):vi125–vi132, 6). This review summarizes contemporary knowledge regarding contralateral biopsies to provide professionals caring for GCT patients with sufficient information to decide for or against the procedure in clinical practice.

To evaluate the associations between long-term serum levels of platinum (se-Pt) and neurotoxicity and ototoxicity (NTX), endocrine gonadal function (endocrine-GF), and cardiovascular disease (CVD) in testicular cancer survivors.A total of 292 cisplatin-treated testicular cancer survivors (1980-1994) participated in a national follow-up study (2007-2008). Se-Pt was quantified by inductively coupled plasma mass spectrometry, and categorized in quartiles. Symptoms of NTX were assessed with scale for chemotherapy-induced neurotoxicity (SCIN), with each symptom in 4 categories and total SCIN score categorized in quartiles. Endocrine-GF was categorized according to cutoff values for the 25, 50, and 75 percentiles of luteinizing hormone (LH) and testosterone within each decadal age group established from a control group. CVD was defined as ischemic heart disease, stroke, or artery occlusion. Associations between se-Pt levels and NTX, endocrine-GF, or risk for CVD, were analyzed with ordinal logistic regression and Cox regression, respectively.Median follow-up was 19 years (range: 13-28). In ordinal regression analyses, increasing quartiles of se-Pt were significantly associated with increasing quartiles of SCIN (P for trend = 0.05), increased tinnitus (P0.001), and increased hearing impairment (P = 0.04). The association remained significant for tinnitus when adjusting for cisplatin dose. Increasing LH quartiles was associated with increasing se-Pt quartiles (P = 0.04). No association between se-Pt in quartiles and CVD was established.Median 19 years after treatment, increasing quartiles of se-Pt are associated with increasing SCIN score, tinnitus, hearing impairment, and increasing LH levels. However, these associations remained significant only for tinnitus and LH when adjusting for administered cisplatin dose.

Germ cell testicular cancer (TC) represents a malignancy with high cure rates. Since the introduction of cisplatin-based chemotherapy in the late 1970s, the 5-year survival rate has increased considerably, and it is currently above 95%. Because TC is usually diagnosed before the age of 40 years, these men can expect to live for another 40 to 50 years after being successfully treated. This success, however, is hampered by an increased risk of long-term and late effects of treatment. Secondary malignant neoplasms and cardiovascular disease represent the most common potentially life-threatening late effects, typically occurring more than 10 years after treatment. Other long-term effects include pulmonary toxicity, nephrotoxicity, neurotoxicity, decreased fertility, hypogonadism, and psychosocial problems. The incidence and time to onset of these various adverse effects vary according to treatment type and intensity. There is still little knowledge about underlying mechanisms and genetic susceptibility of the various adverse effects. Apart from treatment burden, it is not yet possible to identify patients who are at high risk for certain late effects after TC treatment. In this clinical review, we present the current status regarding different somatic and psychosocial long-term late effects after treatment for TC, based on Medline searches and our own research. Moreover, we postulate recommendations for general medical evaluations that should begin after treatment is completed and continue during follow-up.

Purpose Cisplatin-induced neurotoxicity and ototoxicity (NTX) are important adverse effects after chemotherapy for testicular cancer (TC). Although serum platinum is measurable years after therapy, its impact on NTX has not been evaluated. Patients and Methods In all, 169 cisplatin-treated survivors of TC provided blood samples at Survey I and reported NTX during Survey I (1998-2002) and Survey II (2007-2008). Serum platinum was quantified by inductively coupled plasma mass spectrometry. Patient-reported outcomes were evaluated with the Scale for Chemotherapy-Induced Neurotoxicity (SCIN), regarding the extent of symptom bother as 0, “not at all”; 1, “a little”; 2, “quite a bit”; or 3, “very much.” Summing the six symptom scores yielded a total SCIN score of 0 to 18. Categorizing total SCIN scores into quartiles yielded similar-sized groups with increasing symptoms. Multivariate ordinal logistic regression analyses evaluated associations between NTX and long-term serum platinum levels, adjusting for cisplatin dose, dosing schedule, and age. Results At Survey I, a significant four- to five-fold association with total SCIN score emerged for the highest serum platinum quartile (odds ratio [OR], 4.69; 95% CI, 1.82 to 12.08). Paresthesias and Raynaud's syndrome (hands and feet) showed significant two- to four-fold increased risks with the highest platinum quartile. At Survey II, total SCIN score remained significantly associated with the highest platinum quartile (OR, 4.28; 95% CI, 1.36 to 13.48). Paresthesias (hands and feet) and tinnitus showed significant three- to four-fold increased risks for the highest platinum quartile. Cumulative cisplatin dose was not associated with total SCIN score or individual SCIN symptoms in multivariate analyses. Conclusion Here we document a significant relationship between increasing levels of residual serum platinum and NTX severity after adjusting for initial cisplatin dose.

Background 2-18fluoro-deoxy-D-glucose positron emission tomography (FDG-PET) has been recommended in international guidelines in the evaluation of postchemotherapy seminoma residuals. Our trial was designed to validate these recommendations in a larger group of patients. Patients and methods FDG-PET studies in patients with metastatic seminoma and residual masses after platinum-containing chemotherapy were correlated with either the histology of the resected lesion(s) or the clinical outcome. Results One hundred and seventy seven FDG-PET results were contributed. Of 127 eligible PET studies, 69% were true negative, 11% true positive, 6% false negative, and 15% false positive. We compared PET scans carried out before and after a cut-off level of 6 weeks after the end of the last chemotherapy cycle. PET sensitivity, specificity, negative predictive value (NPV), and positive predictive value were 50%, 77%, 91%, and 25%, respectively, before the cut-off and 82%, 90%, 95%, and 69% after the cut-off. PET accuracy significantly improved from 73% before to 88% after the cut-off (P = 0.032). Conclusions Our study confirms the high specificity, sensitivity, and NPV of FDG-PET for evaluating postchemotherapy seminoma residuals. When carried out at an adequate time point, FDG-PET remains a valuable tool for clinical decision-making in this clinical setting and spares patients unnecessary therapy.

Purpose The prognostic significance of age at testicular cancer (TC) diagnosis, socioeconomic status (SES), race, and marital status on TC-specific mortality is not well-characterized. In a cancer that is so curable, it is important to identify any influence that confers an increased risk of TC-specific mortality. Patients and Methods Using multivariate cause-specific Cox regression models that accounted for competing risks, hazard ratios (HRs) were calculated for 10-year TC-specific mortality among 27,948 patients with TC reported to the Surveillance, Epidemiology and End Results program (1978 to 2006). Independent predictors were age at diagnosis, SES, race, marital status, extent of disease (EOD), calendar year of diagnosis, radiotherapy, and retroperitoneal lymph node dissection (RPLND). Results Compared with younger patients, diagnostic age 40+ was associated with increased mortality (seminoma, HR, 2.00, P < .001; nonseminoma, HR, 2.09; P < .001; most evident in metastatic disease, HR, 8.62; P < .001; HR, 6.35; P < .001, respectively). Unmarried men had two-to three-fold excess mortality compared to married men (HR, 2.97; P < .001; HR, 1.54; P < .001, respectively). Among nonseminoma patients, decreasing SES (P trend < .001) and nonwhite race (HR, 2.11; P < .001) increased mortality. Diagnosis after 1987 resulted in reduced mortality compared to earlier calendar years (HR, 0.58; P = .001; HR, 0.74; P = .001, respectively). Lack of RPLND was associated with seven-fold increase in death (P < .001). Conclusion TC-specific mortality is doubled among US patients diagnosed with seminoma or nonseminoma after age 40, even when initial treatment and EOD are taken into account. Among men with nonseminoma, nonwhite race and lower SES also significantly increase TC-specific mortality. Additional research is needed, enabling the development of interventional strategies and preventive approaches, as applicable.

e22067Background: In this longitudinal study, we report long-term change in Pt serum concentration and associations between Pt change and cisplatin-related late effects (second cancers and neurotox...

Background Sensory neuropathy (paresthesias), tinnitus, hearing impairment, and Raynaud phenomena are side effects of cisplatin-based chemotherapy used to treat testicular cancer patients. We assessed the long-term occurrence of these side effects among testicular cancer survivors according to the treatment they received. Methods A total of 1814 men who were treated for unilateral testicular cancer in Norway during 1980 – 1994 were invited to participate in a national multicenter follow-up survey conducted during 1998 – 2002. The men were allocated to six groups according to the treatment they had received. Self-reported symptoms were assessed by a mailed questionnaire that included the Scale for Chemotherapy-Induced Neurotoxicity. A total of 1409 participants who responded to the questionnaire and/or underwent audiometry were assessable in this study. Respondents to the questionnaire (n = 1402) scored the relevant symptoms according to how troubled they were by each (not at all, a little, quite a bit, or very much). Hearing impairment was objectively assessed by audiometry at 4000 Hz in 755 men (seven of whom did not respond to the questionnaire). Group comparisons of symptom assessments were performed with 2 or Kruskal – Wallis tests. Associations between relevant factors and self-reported symptoms or hearing impairment measured by audiometry were assessed using proportional odds ordinal logistic regression models and linear regression models, respectively. All statistical tests were two-sided. Results The median follow-up for the 1409 assessable men was 10.7 years (range = 4 – 21 years). All chemotherapy groups had statistically significantly higher odds for increasing severity of all assessed symptoms and inferior audiometric results compared with men who did not receive chemotherapy. Among chemotherapytreated men, 39% (95% confidence interval [CI] = 35% to 43%) reported Raynaud-like phenomena (defined as white or cold hands or fingers [or feet or toes] on cold exposure), 29% (95% CI = 25% to 33%) reported paresthesias in the hands or feet, 21% (95% CI = 18% to 25%) reported hearing impairment, and 22% (95% CI = 19% to 26%) reported tinnitus as major symptoms troubling them quite a bit or very much. Hearing impairment (odds ratio [OR] = 5.3, 95% CI = 3.0 to 9.2) and tinnitus (OR = 7.1, 95% CI = 4.1 to 12.4) were particularly common in the dose-intensive chemotherapy group compared with the no chemotherapy group. Men who were treated with radiotherapy had higher odds of self-reported paresthesias in feet compared with those not treated with radiotherapy (OR = 1.5, 95% CI = 1.01 to 2.1, P = .04). Conclusion Long-term survivors of testicular cancer who were treated with cisplatin-based chemotherapy were more often troubled by dose-dependent neurological side effects and Raynaud-like phenomena compared with those who were not treated with chemotherapy. J Natl Cancer Inst 2009;101:1682–1695

Patients with testicular cancer are at risk of having severe short-term and life-threatening long-term effects; we reviewed previous reports of these sequelae. After orchidectomy and before further treatment patients have major mental distress which gradually decreases during the treatment phase. Gastrointestinal side-effects dominate during both chemo- and radiotherapy, with the risk of severe haematological, infectious and thromboembolic complications during chemotherapy. Long-term sequelae comprise second cancers, cardiovascular morbidity/mortality and gonadal dysfunction. Nevertheless, 70% of patients who attempt paternity after treatment are successful. About 20% of patients develop long-term neuro- and/or ototoxicity. The long-term quality of life of survivors of testicular cancer is comparable to that of controls. Risk-adapted treatment of patients with testicular cancer and adequate follow-up of those at risk of life-threatening toxicity are ways to reduce the short- and long-term morbidity in survivors. Patients should be informed about these potential complications and the importance of adjusting their lifestyle (e.g. smoking habits, physical activity and weight control).

Purpose: The purpose of this research is to study the prevalence of posttraumatic stress disorder (PTSD) and variables associated with PTSD in Norwegian long-term testicular cancer survivors (TCSs) both cross-sectionally and longitudinally. Methods: At a mean of 11 years after diagnosis, 1418 TCSs responded to a mailed questionnaire, and at a mean of 19 years after diagnosis, 1046 of them responded again to a modified questionnaire. Posttraumatic symptoms related to testicular cancer were self-rated with the Impact of Event Scale (IES) at the 11-year study only. An IES total score ≥35 defined Full PTSD, and a score 26–34 identified Partial PTSD, and the combination of Full and Partial PTSD defined Probable PTSD. Results: At the 11-year study, 4.5 % had Full PTSD, 6.4 % had Partial PTSD, and 10.9 % Probable had PTSD. At both studies, socio-demographic variables, somatic health, anxiety/depression, chronic fatigue, and neurotoxic adverse effects were significantly associated with Probable PTSD in bivariate analyses. Probable anxiety disorder, poor self-rated health, and neurotoxicity remained significant with Probable PTSD in multivariate analyses at the 11-year study. In bivariate analyses, probable PTSD at that time significantly predicted socio-demographic variables, somatic health, anxiety/depression, chronic fatigue, and neurotoxicity among participants of the 19-year study, but only probable anxiety disorder remained significant in multivariable analysis. Conclusions: In spite of excellent prognosis, 10.9 % of long-term testicular cancer survivors had Probable PTSD at a mean of 11 years after diagnosis. Probable PTSD was significantly associated with a broad range of problems both at that time and was predictive of considerable problems at a mean of 19 year postdiagnosis. Implications for cancer survivors: Among long-term testicular cancer survivors, 10.9 % have Probable PTSD with many associated problems, and therefore health personnel should explore stress symptoms at follow-up since efficient treatments are available. © 2016, Springer Science+Business Media New York.

The purpose of this study was to explore the incidence of late relapse in patients with malignant germ cell tumour (MGCT) in a population-based series, with emphasis on the mode of detection, survival, and the relevance of histological findings. The clinical records from a population-based cohort of patients with seminoma (n=1123) or non-seminoma (n=826) were evaluated for late relapses. Twenty-five patients developed a late relapse. The cumulative 10-year incidence rate was 1.3%. All 10 seminoma patients, but only eight of 15 non-seminoma patients relapsed with vital malignant tumour (P=0.02). Teratoma or necrosis was found in seven of nine primarily chemotherapy-treated non-seminoma patients with normal tumour markers at late relapse. Six of nine patients operated with limited retroperitoneal lymph node dissection as part of the primary treatment had relapsed retroperitoneally outside the original operation field. The 10-year cause-specific survival was 68% in all patients, 50% in patients relapsing with vital malignant tumour and 100% in those with teratoma/ necrosis before or after salvage chemotherapy. The 10-year incidence rate of late relapses of 1.3% might reflect the true incidence rate in a population-based cohort of MGCT patients, with cure in at least half of them.

Testicular cancer (TC) is the most common solid organ malignancy among young men at their peak of family life, education, and career. The exceptionally high cure rates are hampered by an increased risk of several treatment-related toxicities that may emerge several years after treatment. In this article, we review the current knowledge regarding pulmonary and cardiovascular toxicity in long-term survivors of TC. Bleomycin pulmonary toxicity is associated with the cumulative bleomycin dose, renal function, age and smoking status and can be avoided by a careful patient evaluation before chemotherapy. Lung function assessments are not routinely recommended for detecting bleomycin pulmonary toxicity. Long-term decreased pulmonary function may also be related to other chemotherapy agents such as cisplatin. Cardiovascular disease represents one of the most serious late effects of cytotoxic treatment in TC survivors and typically appears several years to decades after treatment. The increased risk for cardiovascular disease is probably mediated by a direct vascular damage from cytotoxic treatment that may stimulate the endothelium, possibly ultimately inducing the atherosclerotic process, as well as an indirect cytotoxic effect by increasing the levels of cardiovascular risk factors. Follow-up of these cancer survivors should include recommendations for maintaining a healthy lifestyle to reduce the risk of future cardiovascular events and to avoid declining pulmonary function.

Radiotherapy has been applied to for the treatment of testicular cancer for several decades. Due to its exquisite radiation-sensitivity, localized seminoma could efficiently be eradicated by abdominal field radiotherapy. Furthermore, adjuvant abdominal radiotherapy for stage I seminoma has been the standard approach for the last 50 years. However, the risk of long-term toxicities, mainly radiation-.induced second neoplasms, as well as overtreatment of approximately 85 % of these patients, render surveillance or adjuvant carboplatin the new standards of care in Europe and many cancer centers in the U.S. For metastatic seminoma, radiotherapy is currently mostly applied in early stage II, or for brain- and bone metastases as well as part of palliative treatment.

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.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.

Objective To advise urologists and other clinicians on the appropriate management of low-stage (clinical Stage [CS] I, IS, IIA, and IIB) nonseminomatous germ cell tumors of the testis. Methods A panel was convened of experts from 5 countries. A literature search in MEDLINE was used to identify evidence from relevant studies on the outcome and toxicity of observational, surgical, and chemotherapeutic approaches for low-stage nonseminomatous germ cell tumors to form the basis of the panel's recommendations. Results The panel has recommended the treatment of nonseminomatous germ cell tumors in centers with medical, surgical, and diagnostic expertise in testicular cancer. The cancer-specific survival rate for CS I and CS IIA-IIB should approach 100% and 95%-100%, respectively. Patients with CS I should be made aware of all treatments (ie, surveillance, primary chemotherapy, and retroperitoneal lymph node dissection) and the potential side effects. For patients with CS I at low risk of occult metastasis, surveillance is preferred. For patients at high risk of occult metastasis, all 3 options can be considered. For immediate treatment, the choice between primary chemotherapy and retroperitoneal lymph node dissection should be determined by patient preference and the specific expertise of the treating institution. Patients with increasing postorchiectomy serum α-fetoprotein or human choriogonadotropin levels (CS IS and CS IIA-IIB) should receive induction chemotherapy. Induction chemotherapy or retroperitoneal lymph node dissection can be considered for patients with CS IIA-IIB with normal postorchiectomy α-fetoprotein and human choriogonadotropin levels. Surveillance can be considered for patients with equivocal computed tomography retroperitoneal findings who are otherwise at low risk of metastatic disease. Conclusion These clinical practice guidelines are designed to improve clinical practice from the available evidence and the expert opinion of the panel. As such, deviation from these recommendations should be based on sound clinical judgment, considering the unique situation of the patient and the expertise of the treating physician and institution.

Testicular cancer represents the most curable solid tumor, with a 10-year survival rate of more than 95%. Given the young average age at diagnosis, it is estimated that effective treatment approaches, in particular, platinum-based chemotherapy, have resulted in an average gain of several decades of life. This success, however, is offset by the emergence of considerable long-term morbidity, including second malignant neoplasms, cardiovascular disease, neurotoxicity, nephrotoxicity, pulmonary toxicity, hypogonadism, decreased fertility, and psychosocial problems. Data on underlying genetic or molecular factors that might identify those patients at highest risk for late sequelae are sparse. Genome-wide association studies and other translational molecular approaches now provide opportunities to identify testicular cancer survivors at greatest risk for therapy-related complications to develop evidence-based long-term follow-up guidelines and interventional strategies. We review research priorities identified during an international workshop devoted to testicular cancer survivors. Recommendations include 1) institution of lifelong follow-up of testicular cancer survivors within a large cohort setting to ascertain risks of emerging toxicities and the evolution of known late sequelae, 2) development of comprehensive risk prediction models that include treatment factors and genetic modifiers of late sequelae, 3) elucidation of the effect(s) of decades-long exposure to low serum levels of platinum, 4) assessment of the overall burden of medical and psychosocial morbidity, and 5) the eventual formulation of evidence-based long-term follow-up guidelines and interventions. Just as testicular cancer once served as the paradigm of a curable malignancy, comprehensive follow-up studies of testicular cancer survivors can pioneer new methodologies in survivorship research for all adult-onset cancer. J Natl Cancer Inst 2010; 102: 1114-1130

Objective: To explore fear of recurrence (FoR) in long-term testicular cancer survivors (TCSs) since FoR hardly has been examined in TCSs. Methods: In a cross-sectional questionnaire study, 1336 TCSs at a mean of 11.4 years (SD 4.2) after diagnosis gave information about their medical and social situation, and completed measures on mental distress, fatigue, quality of life, coping, self-esteem and neuroticism. FoR during the last week was explored with one question, with the response categories rated on a 4-point Likert scale. Nine percent of the TCSs had a structured psychiatric interview. Results: Twenty-four percent of the TCSs reported ‘quite a bit’ FoR and 7% reported ‘very much’ FoR during the last week. The FoR question showed moderate correlations (0.22–0.51) with established psychological measures. The level of FoR was significantly positively correlated with mental distress, fatigue and neuroticism and significantly negatively correlated with quality of life, self-esteem and coping. In univariate analyses, neurotoxic side effects and somatic symptoms, but not treatment modality, were significantly associated with level of FoR. In a multivariate analysis, a medium educational level, increasing levels of traumatic cancer-related stress symptoms and of neuroticism were significantly associated with rising FoR. Among those who had a psychiatric interview, the presence of at least one current mental disorder was significantly associated with FoR. Conclusions: High levels of FoR in long-term TCSs are not uncommon. Levels of mental and somatic problems are associated with the levels of FoR. Clinical consequences of these findings for TCSs are discussed. Copyright © 2008 John Wiley & Sons, Ltd.

TO THE EDITOR: “Primum non nocere” stands for nonmaleficence in the Hippocratic Corpus, meaning “first, do no harm.” Colleagues who favor active surveillance for all patients with stage I testicular cancer consider adjuvant chemotherapy a potentially harmful and unnecessary intervention. However, the “surveillance for all” recommendation may infringe on patient autonomy and prove harmful. Adjuvant chemotherapy is, with few exceptions, well tolerated and without relevant long-term toxicities. Salvage treatment for relapsing patients, on the other hand, causes acute and long-term toxicities in a dose-dependent manner. Therefore, the fear of potential long-term effects of adjuvant chemotherapy seems disproportionate to the real and established toxicities after three to four cycles of bleomycin, etoposide, and cisplatin, including additional postchemotherapy RPLND in 26% of nonseminoma patients. Recently, Vidal et al published their article “Long-Term Outcome of Patients With Clinical Stage I High-Risk Nonseminomatous Germ Cell Tumors 15 Years After One Adjuvant Cycle of Bleomycin, Etoposide and Cisplatin Chemotherapy” in Annals of Oncology, in which essentially no relevant toxicity was reported. The editorial “Primum Non Nocere. Do We Harm Stage I Testicular Cancer Patients Less by Applying Adjuvant Chemotherapy Than by Failing to Present This Option?” hailed this report. Primum non nocere is thereby embraced both by the proponents of a risk-based management as well as by those advocating active surveillance for all patients with stage I testicular cancer. Both sides consider unnecessary treatment as the potential harm, identifying either adjuvant or salvage chemotherapy as the culprit. According the Spanish Germ Cell Group, a patient with a 6-cm testicular seminoma invading the rete testis and vasculature, like the one discussed by Vaughn, has a 40% risk of micrometastases. Typically, such men vote for adjuvant treatment, when counseled by proponents of a risk-based strategy like us. The majority of patients whose outcomes were published by Kollmannsberger et al were managed by the Swedish and Norwegian Testicular Cancer Group with a risk-based approach in which low-risk patients were selected for surveillance. Unfortunately, the Oncology Grand Rounds article appears biased in favor of active surveillance: Stating that “only 13% of 1,344 patients with CS I seminoma relapsed” while failing to mention the selection bias by including predominantly low-risk patients renders these numbers not representative for high-risk patients. Merely pointing to a lack of publications on long-term toxicities 20 to 30 years after carboplatin (while confirming their absence within 9 years) might cause patients to refrain from this “potentially harmful” treatment. This evasive approach appears, in light of the considerable toxicities after salvage treatment, questionable and potentially more harmful.

Background: Neurotoxicity is common after modern chemotherapy, and can be assessed both objectively and subjectively based on symptoms reported by patients. The aim of this study was to explore the psychometric properties of a brief self-report scale for chemotherapy induced long-term neurotoxicity (the SCIN). Methods: As part of a questionnaire survey 684 testicular cancer survivors (TCSs) filled in the SCIN, which assesses peripheral sensory neuropathy (paresthesias), Raynaud’s phenomenon, and ototoxicity. Factor structure and internal consistency reliability of the SCIN were tested by the split-half method. In 538 TCSs, audiogram data were compared to the patients SCIN ratings of hearing. Results: The internal consistency of the SCIN showed a Cronbach’s α of 0.72. The three-factor structure of the SCIN was confirmed with 77% explained variance. All the SCIN items discriminated significantly between the TCSs who had been treated with cisplatin-based chemotherapy vs. those who did not receive such treatment. The individual cumulative cisplatin dose correlated significantly with all the SCIN items. The Pearson product–moment correlation coefficient was 0.54 between hearing reduction at 4000 Hertz measured by audiogram and the SCIN self-report of reduced hearing. Conclusion: The SCIN shows good psychometric properties, and is recommended as a brief screening instrument for chemotheraphy-indeed neurotoxicity.

The pursuit of reduced-intensity treatments for testicular cancer continued with vigour in 2013. For those with metastatic disease and poor prognoses, an alternative to bleomycin, etoposide and cisplatin chemotherapy emerged. These advances suggest we are making progress by reducing treatment intensity with personalized approaches for this highly curable malignancy.

Purpose: To determine preoperative parameters that predict the histology of specimens obtained by retroperitoneal lymph node dissection (RPLND) in patients with nonseminomatous germ cell cancer (NSGCT) whose residual mass was ≤ 20 mm in diameter after modern cisplatin-based induction chemotherapy. Patients and Methods: Eighty-seven patients with metastatic NSGCT underwent RPLND after having received cisplatin- or carboplatin-based induction chemotherapy. In all patients, the largest diameter of the residual mass on the transaxial plane was ≤ 20 mm, as assessed by abdominal computed tomography (CT) immediately before RPLND. Results: Complete fibrosis or necrosis was found in 58 patients (67%), teratoma was found in 23 patients (26%), and vital malignant germ cell tumor was found in six patients (7%), including one patient with rhabdomyosarcoma in the RPLND specimen. In five of the six latter patients, the residual lesion was ≤ 10 mm at pre-RPLND CT. No pre- or postchemotherapy clinical or radiologic parameter was identified that significantly predicted the histology of the residual mass. Conclusion: One third of retroperitoneal postchemotherapy lesions ≤ 20 mm contained residual vital tumor tissue, despite modern chemotherapy regimens. Therefore, postchemotherapy RPLND remains necessary in patients with minimal-size residual lesions to facilitate easy and safe follow-up and initiate additional therapy as early as possible, thus avoiding recurrences.

4564 Background: Chronic fatigue (CF) is more prevalent in Testicular Cancer Survivors (TCSs) 12 years after treatment than in the general population (16% versus 10%). CF-related symptoms of emotional, physical and/or cognitive tiredness may be associated with poor gonadal function (low testosterone (T) and/or high Luteinizing Hormone (LH)). In this longitudinal study we assessed the prevalence of CF median 12 (12y) and 19 years (19y) after treatment in relation to applied treatment, age and levels of T and LH. Methods: T and LH levels were retrieved from 796 TCSs who completed fatigue questionnaires median 12y and 19y after treatment and categorized according to quartile thresholds of healthy controls for decadal age groups. Treatment was categorized as surgery (S, n=162), radiotherapy (RT, n=339) or chemotherapy (CT, n= 295). CF was defined according to previously published cut-off levels. Associations between CF and hormone levels, age and treatment were assessed with logistic regression. Results: CF i...

4518 Background: Previous studies have identified several long-term complications following cisplatin-based treatment in testicular cancer survivors (TCS). We evaluated the impact of long-term serum levels of platinum (Pt) on neuro- and ototoxicity (NTX), cardiovascular disease (CVD) and hypogonadism in TCS. Methods: 292 cisplatin-treated TCS (1980-1994) participated in a national follow-up study (2007-2008), including laboratory tests and a questionnaire. Serum Pt was quantified by Inductively Coupled Plasma-Mass Spectrometry. Symptoms of NTX were assessed with Scale for Chemotherapy-Induced Neurotoxicity (SCIN), with each symptom categorized in 4 categories ranging from 0, “not at all” to 3, “very much”. Total SCIN score was the sum of six scores, ranging from 0 to 18, and categorized into quartiles. Information about CVD (validated) and medication were retrieved from the questionnaire. Hypogonadism was defined as using testosterone substitution and/or having testosterone

4508 Background: Clinical stage I seminoma testicular cancer is the most frequent presentation of testicular cancer. Current treatment option include surveillance (SURV) or adjuvant chemotherapy. F...

4562 Background: Hypogonadism, i.e., low T-, high LH- and/or FSH-levels, is frequently observed in TCSs and is associated with cardiovascular disease, osteoporosis and reduced quality of life. Little is known about the impact of aging on hypogonadism in TCSs. Methods: T, LH, and FSH levels were retrieved twice from 874 TCSs median 11 (S11) and 19 (S19) years after orchiectomy and categorized based on cut-offs calculated from 570 healthy controls (C), separately for each decadal age group. Treatment was categorized into surgery (S), radiotherapy (RT) or cisplatin-based chemotherapy (CT). Impact of treatment and aging on T, LH and FSH levels was assessed by comparing proportions of TCSs grouped into the C quartiles by ordinal logistic regression and expressed with odds ratios (OR) and 95% confidence interval (CI). Results: TCSs had lower T and higher LH and FSH levels than C at S11 and S19 (p

4637 Background: Low T may increase the risk of cardiovascular disease, osteoporosis, and reduced quality of life. T might be reduced by TC, its treatment, ageing, and particularly their combination. Methods: T was retrieved from 311 TCSs after orchiectomy and prior to subsequent management with either surveillance/surgery only (S), radiotherapy (RT) or cisplatin based chemotherapy (CT). Human Chorionic Gonadotropin (hCG) was available for 211 TCSs. T was reassessed at surveys performed 9 (S9) and 18 years (S18) after treatment. T values were categorized into quartiles according to cut-off values derived from 570 healthy controls (C) for each decadal age group. Statistical associations were assessed with Chi2 tests. Results: In TCSs about to receive RT or CT, T and hCG were higher when compared to those subsequently managed by S. TCSs were more likely to belong to the lowest T quartile, more so with increasing treatment intensity (table). The proportions of TCSs belonging to the corresponding T quartiles displayed no significant changes from S9 to S18. Conclusions: TCSs had lower T than C of similar age already after orchiectomy, possibly related to removal of the affected testicle and/or testicular dysgenesis syndrome. TCSs who were to receive RT or CT had slightly increased T when compared to S, probably due to hCG stimulation. T reduction by RT or CT has been described previously but rarely in longitudinal studies. Of note, longitudinal assessment of T without comparison to C might result in overestimation of the treatment burden. Relatively stable age adjusted T levels from S9 to S18 for the TCSs independent of treatment are encouraging. [Table: see text]

4508 Background: Contralateral tumor (CLT) occurs in 3.5-5% in men diagnosed with testicular cancer. The precursor lesion, ITGCNU, transforms into invasive germ cell cancer in 50-100%. Although radiotherapy eradicates ITGCNU effectively, mandatory biopsy of the contralateral testis to detect ITGCNU is controversial. Whether, adjuvant chemotherapy (ACT) reduces the incidence of bilateral cancer is also uncertain. Methods: 988 patients with clinical stage 1 nonseminoma were included in two prospective, population-based SWENOTECA protocols. Thirteen patients were excluded due to previous contralateral biopsy, synchronous bilateral cancer or protocol violations. Treatment was either adjuvant chemotherapy (n=490), or surveillance (n=485). Contralateral testicular biopsy was recommended, but performed only in 283 patients. In case of ITGCNU radiotherapy to 16 Gy was recommended.The estimated cumulative incidence of CLT was calculated using the Kaplan-Meier method. Results: With a median follow-up of 6.3 years, twenty-nine (3.9%) patients developed CLT including five patients with synchronous cancer. Biopsies showed ITGCNU in 3.2%. The incidence of CLT was similar following ACT, 3.7 % (11/490), and surveillance, 3.1% (12/485), p=0.99. Biopsied patients had a risk of developing CLT of 4.3% (9/283), and seven patients treated for CIS never developed CLT. Unbiopsied patients had a risk of 3.0 % (14/668). The proportion of bilateral cancers was similar in biopsy negative patients 3.6% (7/274) and unbiopsied patients 3.0 % (14/668). Young age at orchiectomy was a significant risk factor for metachronous cancer, HR 0.94 (CI: 0.89-0.99), p=0.04. All patients with ITGCNU were offered RT. One irradiated patient developed CLT cancer, and one developed CLT before RT was given. Conclusions: In this selected population ACT did not reduce the incidence of CLT. There was a high proportion of false negative biopsies, which might explain why biopsy negative patients had the same risk of CLT as patients not undergoing biopsy. Young patients had the highest risk of developing contralateral cancer, the risk of CLT decreased by 6% yearly.

4563 Background: Incidence of testicular cancer (TC) in Norway is approximately three times as high as 50 years ago and the highest world-wide. A “testicular dysgenesis syndrome” (TDS) comprising r...

5036 Background: The reasons for the large inter-individual variation of chemotherapy-induced neuro- and ototoxicity (cNTX) are poorly understood. We aim to comprehensively assess the impact of age, cumulative dose of cisplatin (cdCis), polymorphic Glutathione S- transferase P1 (pGST-P1), and neuroticism on long-term cNTX in testicular cancer survivors (TCSs). Methods: A total of 635 TCSs had participated in a long-term follow-up survey (238 had received cisplatin-based chemotherapy [CisTCSs] and 397 were treated by surgery and/or radiotherapy [SurRadTCSs]). Self-reported neurotoxic symptoms (4 item-scores: 0: not at all; 1: a little; 2: quite a bit; 3: very much) and audiometrically assessed hearing impairment (6-categories according to population-based age-adjusted percentiles) were the primary outcome variables. Hearing results >75th percentile and self-reported item scores >2 were considered major symptoms. Lymphocyte-derived DNA was analyzed for pGSTP1 (functional A ⟶G polymorphism at bp 304). Neurot...

4547 Background: Persisting side-effects of treatment may impair the well-being of TC survivors. The aim of this study was to assess long-term Raynaud’s phenomena, oto-, and neurotoxicity related to prior therapy. Methods: A follow-up survey was conducted in men treated for TC 1980–1994 in Norway. The 1319 eligible responders had a median follow-up time of 11 years (range 4–21) and were allocated to four separate treatment groups: Surgery (Surg), Radiotherapy (Rt), and chemotherapy (Cisplatin [Cis] ≤ 850 mg and Cis > 850 mg). The questionnaire included six items assessing the relevant toxicities. The responders’ scores were dichotomized [minor (“not at all” or “a little”) vs. major (“quite a bit” or “very much”)] and analyzed by logistic regression with Surg as reference. Results: The proportion of cases (%) reporting major symptoms and the corresponding Odds ratios (OR) varied significantly between treatment groups ( table ). Rt was not statistically significantly different from Surg for any symptom, but showed a trend for higher scores of paresthesias in the feet. Cis > 850 mg differed significantly for all symptoms with major symptoms reported by 25–49% with the highest OR (8.1) for Raynaud’s phenomena in hands. Apart from Raynaud’s phenomena, paresthesias in feet were the only symptom significantly different in Cis < 850 mg compared to Surg. Conclusions: Toxicities induced by cisplatin-based chemotherapy persist in many TC survivors. A cold climate may contribute to the high perception of Raynaud’s phenomena in Norwegian TC survivors. [Table: see text] No significant financial relationships to disclose.

4575 Background: Cisplatin-induced ototoxicity shows considerable inter-individual variations. Genetic variations in enzymes involved in detoxification of cisplatin could contribute to the observed...

Background To assess the impact of polymorphisms in Glutathione S-transferase (GST) -P1, -M1, and -T1 on self-reported chemotherapy-induced long-term toxicities in testicular cancer survivors (TCSs). Methods A total of 238 TCSs, who had received cisplatin-based chemotherapy at median twelve years earlier, had participated in a long-term follow-up survey which assessed the prevalence of self-reported paresthesias in fingers/toes, Raynaud-like phenomena in fingers/toes, tinnitus, and hearing impairment. From all TCSs lymphocyte-derived DNA was analyzed for the functional A→G polymorphism at bp 304 in GSTP1, and deletions in GST-M1 and GST-T1. Evaluation of associations between GST polymorphisms and self-reported toxicities included adjustment for prior treatment. Results All six evaluated toxicities were significantly associated with the cumulative dose of cisplatin and/or bleomycin. Compared to TCSs with either GSTP1-AG or GSTP1-AA, the 37 TCSs with the genotype GSTP1-GG, were significantly less bothered by paresthesias in fingers and toes (p = 0.039, OR 0.46 [0.22–0.96] and p = 0.023, OR 0.42 [0.20–0.88], respectively), and tinnitus (p = 0.008, OR 0.33 [0.14–0.74]). Furthermore, absence of functional GSTM1 protected against hearing impairment (p = 0.025, OR 1.81 [1.08–3.03]). Conclusion In TCSs long-term self-reported chemotherapy-induced toxicities are associated with functional polymorphisms in GSTP1 and GSTM1. Hypothetically, absence of GST-M1 leaves more glutathione as substrate for the co-expressed GST-P1. Also intracellular inactivation of pro-apoptotic mediators represents a possible explanation of our findings. Genotyping of these GSTs might be a welcomed step towards a more individualized treatment of patients with metastatic testicular cancer.