G. Cohn-Cedermark

Maintaining success, reducing treatment burden, focusing on survivorship: highlights from the third European consensus conference on diagnosis and treatment of germ-cell cancer

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, ∼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.

Guidelines on Testicular Cancer: 2015 Update

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.

A genome-wide association study of men with symptoms of testicular dysgenesis syndrome and its network biology interpretation

Background Testicular dysgenesis syndrome (TDS) is a common disease that links testicular germ cell cancer, cryptorchidism and some cases of hypospadias and male infertility with impaired development of the testis. The incidence of these disorders has increased over the last few decades, and testicular cancer now affects 1% of the Danish and Norwegian male population. Methods To identify genetic variants that span the four TDS phenotypes, the authors performed a genome-wide association study (GWAS) using Affymetrix Human SNP Array 6.0 to screen 488 patients with symptoms of TDS and 439 selected controls with excellent reproductive health. Furthermore, they developed a novel integrative method that combines GWAS data with other TDS-relevant data types and identified additional TDS markers. The most significant findings were replicated in an independent cohort of 671 Nordic men. Results Markers located in the region of TGFBR3 and BMP7 showed association with all TDS phenotypes in both the discovery and replication cohorts. An immunohistochemistry investigation confirmed the presence of transforming growth factor β receptor type III (TGFBR3) in peritubular and Leydig cells, in both fetal and adult testis. Single-nucleotide polymorphisms in the KITLG gene showed significant associations, but only with testicular cancer. Conclusions The association of single-nucleotide polymorphisms in the TGFBR3 and BMP7 genes, which belong to the transforming growth factor β signalling pathway, suggests a role for this pathway in the pathogenesis of TDS. Integrating data from multiple layers can highlight findings in GWAS that are biologically relevant despite having border significance at currently accepted statistical levels.

2-18fluoro-deoxy-D-glucose positron emission tomography (FDG-PET) for postchemotherapy seminoma residual lesions: a retrospective validation of the SEMPET trial

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). CONCLUSION 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.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.

Metastatic Patterns, Clinical Outcome, and Malignant Phenotype in Malignant Cutaneous Melanoma

The objective of this population-based study was to assess metastatic pathways and outcomes vs. selected clinical and histopathologic features of the primary tumor in patients with recurrent cutaneous malignant melanoma. At a median follow-up time of 11 years, 569/2493 patients with recurrence were identified. We demonstrated a 5-year survival rate of 82% and 30% among those with a primary local or regional recurrence, respectively. Patients with primary distant skin, distant lymph node, or pulmonary metastases had a significantly better survival compared with those with CNS, bone, visceral, liver, or multiple sites of first distant metastases. The metastatic pathways were similar with regard to histogenetic type, primary tumor thickness, Clarks level of invasion, and primary tumor ulceration. Different histogenetic types, as assessed by light microscopy, imply different risks of recurrence. However, once the recurrence is manifest, the metastatic pathways are uniform, as well as prognosis, and survival.

One course of adjuvant BEP in clinical stage I nonseminoma mature and expanded results from the SWENOTECA group

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. RESULTS 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%. CONCLUSIONS 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.

Surveillance vs. adjuvant therapy of clinical stage I testicular tumors – a review and the SWENOTECA experience

Although clinical stage I (CS I) testicular cancer is highly curable, the optimal management is controversial. The aims of the Swedish and Norwegian Testicular Cancer Group (SWENOTECA) studies for CS I non‐seminoma (NS) and seminoma (S) have been to reduce treatment intensity while maintaining high survival rates, reduce the number of patients needing salvage treatment and implement patient autonomy with regard to adjuvant treatment. During 1998–2010 NS CSI patients with lymphovascular invasion (LVI) of the primary tumor (high risk) were recommended bleomycin, etoposide, cisplatin (BEP) × 1. During 2000–2006 S CS I patients had the option to choose surveillance or adjuvant radiotherapy (AR). In 2004, carboplatin × 1 (AUC7) was added as a third treatment option. In 2007 a new risk‐adapted treatment protocol for S CS I was initiated. Patients with two risk factors (tumor size > 4 cm, tumor growth in the rete testis) were recommended carboplatin × 1 and patients with 0–1 risk factor were recommended surveillance. All patients were provided with oral and written information of possible management options and could choose the other alternative. The relapse rate for NS CS I with BEP × 1 was 3.2% for high risk, and 1.6% for low‐risk patients. Five‐year cause‐specific survival was 100%. For S CS I‐patients treated before 2007, 14.3% on surveillance relapsed, 3.9% after carboplatin, and 0.8% after AR. Five‐year cause‐specific survival was 99.9%. For S CS I‐patients treated from 2007, a relapse rate <3% was confirmed for patients without risk factors. SWENOTECA considers BEP × 1 standard adjuvant treatment in NS CS I high‐risk patients. Low‐risk patients should have the opportunity to receive BEP × 1 following thorough information regarding pros and cons. For S CS I patients without risk factors, adjuvant treatment is not necessary. For patients with risk factors, patient autonomy should be respected.

Personalizing, not patronizing: the case for patient autonomy by unbiased presentation of management options in stage I testicular cancer

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 ∼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.

Long-term follow-up after risk-adapted treatment in clinical stage 1 (CS1) nonseminomatous germ-cell testicular cancer (NSGCT) implementing adjuvant CVB chemotherapy. A SWENOTECA study

BACKGROUND To offer minimized risk-adapted adjuvant treatment on a community and nationwide basis for patients with clinical stage 1 (CS1) nonseminomatous germ-cell testicular cancer (NSGCT). The aim was to reduce the risk of relapse and thereby reducing the need of later salvage chemotherapy while maintaining a high cure rate. PATIENTS AND METHODS From July 1995 to January 1998, a total of 232 Swedish and Norwegian patients were treated for CS1 NSGCT. All were eligible for inclusion into one of two community-based multicenter Swedish and Norwegian Testicular Cancer Project (SWENOTECA) III studies. One study was a prospective randomized study for patients without vascular invasion in the testicular tumor (VASC-), evaluating the effect of one adjuvant course of cisplatin, vinblastine and bleomycin (CVB) compared with surveillance. The second study was a prospective study evaluating the effect of two adjuvant courses of CVB for VASC+ patients. RESULTS Due to slow accrual and emerging data on toxicity of CVB, the studies were prematurely closed for inclusion in 1998. Of the 232 CS1 patients treated during the study period, only 97 were included in the studies. As all remaining patients were managed according to the SWENOTECA III protocol, although not randomized, the data were pooled. At a median follow-up of 10.1 years, there have been 24 relapses. While one course of CVB to VASC- patients had limited effect on the relapse rate, two courses of adjuvant CVB reduced the relapse rate among VASC+ patients by >90%. Toxicity was high in patients administered adjuvant CVB as 24% of patients experienced grade 3 or 4 obstipation/ileus and 23% grade 3 or 4 infection. CONCLUSIONS There was no statistical difference in relapse rate between one course of adjuvant CVB and surveillance for VASC- NSGCT patients. Two courses of adjuvant CVB for VASC+ NSGCT patients reduced the relapse rate with >90% in comparison to the surveillance group. Toxicity was unacceptably high for all patients receiving CVB. Adjuvant CVB chemotherapy has no place in the treatment of CS1 NSGCT.

Treatment of stage I seminoma, with one course of adjuvant carboplatin or surveillance, risk-adapted recommendations implementing patient autonomy: a report from the Swedish and Norwegian Testicular Cancer Group (SWENOTECA)

BACKGROUND The purpose of the protocol was to reduce the treatment burden in clinical stage I (CSI) seminoma by offering risk-adapted treatment. The protocol aimed to prospectively validate the proposed risk factors for relapse, stromal invasion of the rete testis and tumor diameter >4 cm, and to evaluate the efficacy of one course of adjuvant carboplatin. PATIENTS AND METHODS From 2007 to 2010, 897 patients were included in a prospective, population-based, risk-adapted treatment protocol implementing one course of adjuvant carboplatin AUC7 (n = 469) or surveillance (n = 422). In addition, results from 221 patients receiving carboplatin between 2004 and 2007 are reported. RESULTS At a median follow-up of 5.6 years, 69 relapses have occurred. Stromal invasion of the rete testis [hazard ratio (HR) 1.9, P = 0.011] and tumor diameter >4 cm (HR 2.7, P < 0.001) were identified as risk factors predicting relapse. In patients without risk factors, the relapse rate (RR) was 4.0% for patients managed by surveillance and 2.2% in patients receiving adjuvant carboplatin. In patients with one or two risk factors, the RR was 15.5% in patients managed by surveillance and 9.3% in patients receiving adjuvant carboplatin. We found no increased RR in patients receiving carboplatin <7 × AUC compared with that in patients receiving ≥7 × AUC. CONCLUSION Stromal invasion in the rete testis and tumor diameter >4 cm are risk factors for relapse in CSI seminoma. Patients without risk factors have a low RR and adjuvant therapy is not justified in these patients. The efficacy of adjuvant carboplatin is relatively low and there is need to explore more effective adjuvant treatment options in patients with high-risk seminoma. The data do not support the concept of a steep dose response for adjuvant carboplatin.