Roberto Salvioni

European Consensus Conference on Diagnosis and Treatment of Germ Cell Cancer: A Report of the Second Meeting of the European Germ Cell Cancer Consensus group (EGCCCG): Part I

OBJECTIVES The first consensus report presented by the European Germ Cell Cancer Consensus Group (EGCCCG) in the year 2004 has found widespread approval by many colleagues throughout the world. In November 2006, the group met a second time under the auspices of the Department of Urology of the Amsterdam Medical Center, Amsterdam, The Netherlands. METHODS Medical oncologists, urological surgeons, radiation oncologists as well as pathologists from several European countries reviewed and discussed the data that had emerged since the 2002 conference, and incorporated the new data into updated and revised guidelines. As for the first meeting, the methodology of evidence-based medicine (EBM) was applied. The results of the discussion were compiled by the writing committee. All participants have agreed to this final update. RESULTS The first part of the consensus paper describes the clinical presentation of the primary tumor, its treatment, the importance and treatment of testicular intraepithelial neoplasia (TIN), histological classification, staging and prognostic factors, and treatment of stage I seminoma and non-seminoma. CONCLUSIONS Whereas the vast majority of the recommendations made in 2004 remain valid 3 yr later, refinements in the treatment of early- and advanced-stage testicular cancer have emerged from clinical trials. Despite technical improvements, expert clinical skills will continue to be one of the major determinants for the prognosis of patients with germ cell cancer. In addition, the particular needs of testicular cancer survivors have been acknowledged.

miR-205 Exerts Tumor-Suppressive Functions in Human Prostate through Down-regulation of Protein Kinase Cε

Limited information is available concerning the expression and role of microRNAs in prostate cancer. In this study, we investigated the involvement of miR-205 in prostate carcinogenesis. Significantly lower miR-205 expression levels were found in cancer than in normal prostate cell lines as well as in tumor compared with matched normal prostate tissues, with a particularly pronounced reduction in carcinomas from patients with local-regionally disseminated disease. Restoring the expression of miR-205 in prostate cancer cells resulted in cell rearrangements consistent with a mesenchymal-to-epithelial transition, such as up-regulation of E-cadherin and reduction of cell locomotion and invasion, and in the down-regulation of several oncogenes known to be involved in disease progression (i.e., interleukin 6, caveolin-1, EZH2). Our evidence suggests that these events are driven by the concurrent repression of specific predicted miR-205 targets, namely N-chimaerin, ErbB3, E2F1, E2F5, ZEB2, and protein kinase Cepsilon. Strikingly, the latter seemed to play a direct role in regulating epithelial-to-mesenchymal transition. In fact, its down-regulation led to a cell phenotype largely reminiscent of that of cells ectopically expressing miR-205. Overall, we showed for the first time that miR-205 exerts a tumor-suppressive effect in human prostate by counteracting epithelial-to-mesenchymal transition and reducing cell migration/invasion, at least in part through the down-regulation of protein kinase Cepsilon.

Viable Malignant Cells After Primary Chemotherapy for Disseminated Nonseminomatous Germ Cell Tumors: Prognostic Factors and Role of Postsurgery Chemotherapy—Results From an International Study Group

PURPOSE To assess the value of postsurgery chemotherapy in patients with disseminated nonseminomatous germ-cell tumors (NSGCTs) and viable residual disease after first-line cisplatin-based chemotherapy. PATIENTS AND METHODS The outcome of 238 patients was reviewed. Tumor markers had normalized in all patients before resection. A multivariate analysis of survival was performed on 146 patients. RESULTS The 5-year progression-free survival (PFS) rate was 64% and the 5-year overall survival (OS) rate was 73%. Three factors were independently associated with both PFS and OS: complete resection (P <.001), < 10% of viable malignant cells (P =.001), and a good International Germ Cell Consensus Classification (IGCCC) group (P =.01). Patients were assigned to one of three risk groups: those with no risk factors (favorable group), those with one risk factor (intermediate group), and those with two or three risk factors (poor-risk group). The 5-year OS rate was 100%, 83%, and 51%, respectively (P <.001). The 5-year PFS rate was 69% (95% confidence interval [CI], 62% to 76%) and 52% (95% CI, 40% to 64%) in postoperative chemotherapy recipients and nonrecipients, respectively (P <.001). No significant difference was detected in 5-year OS rates. After adjustment on the three prognostic factors, postoperative chemotherapy was associated with a significantly better PFS (P <.001) but not with better OS. Patients in the favorable risk group had a 100% 5-year OS, with or without postoperative chemotherapy. Postoperative chemotherapy appeared beneficial in both PFS (P <.001) and OS (P =.02) in the intermediate-risk group but was not statistically beneficial in the poor-risk group. CONCLUSION A complete resection may be more critical than recourse to postoperative chemotherapy in the setting of postchemotherapy viable malignant NSGCT. Immediate postoperative chemotherapy or surveillance alone with chemotherapy at relapse may be reasonable options depending on the completeness of resection, IGCCC group, and percent of viable cells. Validation is necessary.

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.

miR-21: an oncomir on strike in prostate cancer.

BackgroundAberrant expression of microRNAs, small non-coding RNA molecules that post-transcriptionally repress gene expression, seems to be causatively linked to the pathogenesis of cancer. In this context, miR-21 was found to be overexpressed in different human cancers (e.g. glioblastoma, breast cancer). In addition, it is thought to be endowed with oncogenic properties due to its ability to negatively modulate the expression of tumor-suppressor genes (e.g. PTEN) and to cause the reversion of malignant phenotype when knocked- down in several tumor models. On the basis of these findings, miR-21 has been proposed as a widely exploitable cancer-related target. However, scanty information is available concerning the relevance of miR-21 for prostate cancer. In the present study, we investigated the role of miR-21 and its potential as a therapeutic target in two prostate cancer cell lines, characterized by different miR-21 expression levels and PTEN gene status.ResultsWe provide evidence that miR-21 knockdown in prostate cancer cells is not sufficient per se i) to affect the proliferative and invasive potential or the chemo- and radiosensitivity profiles or ii) to modulate the expression of the tumor-suppressors PTEN and Pdcd4, which in other tumor types were found to be regulated by miR-21. We also show that miR-21 is not differently expressed in carcinomas and matched normal tissues obtained from 36 untreated prostate cancer patients subjected to radical prostatectomy.ConclusionsOverall, our data suggest that miR-21 is not a central player in the onset of prostate cancer and that its single hitting is not a valuable therapeutic strategy in the disease. This supports the notion that the oncogenic properties of miR-21 could be cell and tissue dependent and that the potential role of a given miRNA as a therapeutic target should be contextualized with respect to the disease.

Pazopanib in advanced and platinum-resistant urothelial cancer: an open-label, single group, phase 2 trial

BACKGROUND The development of new drugs for patients with refractory urothelial cancer is still an unmet medical need. Preclinical evidence lends support to a rationale for targeting of the VEGF or platelet-derived growth-factor axis. We therefore investigated the activity and safety of pazopanib, a multitarget drug with antiangiogenic activity, in patients with urothelial cancer. METHODS In an open-label, single-group, phase 2 study, patients (aged ≥18 years) with relapsed or refractory urothelial cancer were given pazopanib 800 mg per day, orally. They were treated until disease progression or prohibitive toxicity occurred. The primary endpoint was the proportion of patients who achieved a confirmed objective response, defined as complete or partial response, after independent review, and was analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT01031875. FINDINGS The trial has been completed. 21 (51%) of 41 patients enrolled were given pazopanib as third-line or further-line treatment. 26 (63%) patients had an Eastern Cooperative Oncology Group performance status of 1 or 2. Seven patients had a confirmed objective response (17·1%, 95% CI 7·2-32·1), all of which were partial responses. The most frequent treatment-related grade 3 adverse events were hypertension (three [7%]), fatigue (two [5%]), and gastrointestinal and vaginal fistulisations (two each [5%]). One patient died as a result of duodenal fistulisation that was related to tissue response of bulky tumour masses. INTERPRETATION Pazopanib has single-agent activity in patients with heavily pretreated metastatic urothelial cancer, and warrants further study in this setting. Particular attention should be paid to patients with bulky tumour masses adjacent to viscera because fistulisation is probably related to the response to pazopanib and is the most frequent serious adverse event. FUNDING Fondazione IRCCS Istituto Nazionale dei Tumori provided the grant. GlaxoSmithKline provided the study drug and provided funding for the independent radiological review.

Peniscopically Controlled CO2 Laser Excision for Conservative Treatment of In Situ and T1 Penile Carcinoma: Report on 224 Patients

OBJECTIVE To evaluate the outcome of peniscopically controlled laser excision of early-stage penile carcinoma. METHODS Patients treated from 1982 to 2006 were investigated. The primary treatment was excisional surgery alone for in situ or initially invasive flat tumors, and reductive chemotherapy followed by surgery for the exophytic lesions. All excisional procedures were conducted by CO(2) laser under peniscopic control. RESULTS Of a total of 224 patients, 111 underwent partial excision of the glans and/or coronal sulcus surface, and 113 total surface excision. Forty patients underwent reductive chemotherapy. Complete excision was obtained in 221 cases (98.7%) at lateral margins and in 217 cases (96.9%) at deep margin. Postoperative complications were negligible. Overall, the 10-yr recurrence rate was 17.5% (95% confidence interval, 16.4-18.6%), and apparently was not affected by the in situ or invasive nature of the lesion. Amputation was required in nine patients, for a 10-yr amputation rate of 5.5% (range, 5.2-5.7%). In the remaining cases, organ form and curvature were preserved, with satisfactory cosmetic and functional results. CONCLUSIONS Early-stage penile carcinomas can be effectively treated with the organ-sparing strategy described here. Because local recurrences occur in a minority of patients and can be safely treated, organ preservation is compatible with local disease control. Reductive systemic chemotherapy in selected exophytic cases broadens the indication for our conservative approach.

Unilateral lymphadenectomy in intraoperative stage I nonseminomatous germinal testis cancer.

Bilateral retroperitoneal lymphadenectomy is mainly a staging procedure in patients with stage I nonseminomatous testis cancer, and it causes permanent loss of antegrade ejaculation in approximately two-thirds of the cases. Between May 1978 and August 1981, 61 consecutive patients with no intraoperative evidence of lymph node involvement underwent unilateral retroperitoneal lymph-adenectomy for nonseminomatous germinal testis tumors. Microscopic metastases were found in 1 to 4 retroperitoneal nodes in 6 cases (9.8 per cent). Antegrade ejaculation was absent postoperatively in 11 patients (18 per cent), with no significant difference between patients who underwent lymph node dissection on the left or right side. Ejaculation returned spontaneously in 3 patients, 1 of whom fathered a child. The disease recurred in 10 patients 3 to 35 months after lymphadenectomy (median 6 months). Disease recurred in 8 of 55 patients (14.5 per cent) with negative nodes and 2 of 6 (33.3 per cent) with positive histological findings. No patient suffered retroperitoneal recurrence. The more than 3-year survival rates free of disease were 96.4 and 83.3 per cent in patients with pathological stages I and II disease, respectively. Unilateral retroperitoneal lymphadenectomy in patients with intraoperative stage I nonseminomatous germinal testis cancer preserves antegrade ejaculation in more than 80 per cent of the cases without apparently compromising the long-term survival.

Difficulties of a surveillance study omitting retroperitoneal lymphadenectomy in clinical stage I nonseminomatous germ cell tumors of the testis.

Between August 1981 and December 1984, 85 consecutive patients with clinical stage I nonseminomatous germ cell tumors of the testis who were suitable for close observation entered a surveillance study after orchiectomy alone. All patients had unequivocally negative chest x-ray, bipedal lymph-angiography, and computerized tomography of the abdomen and pelvis, and normal levels of alpha-fetoprotein and human chorionic gonadotropin before entering the study. Patients were followed closely for 24 to 64 months (median 42 months) with regular chest x-rays, plain films of the abdomen for lymphangiography control, and serum determinations of alpha-fetoprotein and human chorionic gonadotropin but it was difficult to obtain computerized tomography scans of the abdomen at scheduled intervals for such a long period. Followup was closed December 31, 1986. At that date 62 patients (73 per cent) were continuously free of disease after orchiectomy alone and 23 (27 per cent) suffered relapse. The over-all occurrence rate of retroperitoneal relapses was 16.5 per cent and they usually were detected late, 4 to 36 months (median 10 months) after orchiectomy. Lung metastases were detected much earlier, 2 to 10 months (median 3 months) after orchiectomy. Alpha-fetoprotein and human chorionic gonadotropin elevations preceded the radiographic demonstration of metastases in 8 patients only (35 per cent) and in 1 they were the only sign of relapse. All but 1 patient with relapse were cured with chemotherapy and/or surgery, with an over-all survival rate free of disease of 98.8 per cent. Invasion of the epididymis, rete testis and spermatic cord, primary scrotal surgery, peritumor vascular invasion and embryonal carcinoma were associated with a higher risk for relapse but it was impossible to find clear-cut indications to select patients for adjuvant chemotherapy, retroperitoneal lymphadenectomy or no treatment. Furthermore, the followup of retroperitoneal nodes proved to be much more difficult than expected. Unilateral or modified retroperitoneal lymphadenectomy facilitates management of clinical stage I nonseminomatous germ cell tumors of the testis: only the chest and markers must be followed, the status of the retroperitoneal nodes is known immediately and antegrade ejaculation is preserved in the majority of cases.

Predictors of Health-related Quality of Life and Adjustment to Prostate Cancer During Active Surveillance

BACKGROUND Active surveillance (AS) is emerging as an alternative approach to limit the risk of overtreatment and impairment of quality of life (QoL) in patients with low-risk localised prostate cancer. Although most patients report high levels of QoL, some men may be distressed by the idea of living with untreated cancer. OBJECTIVE To identify factors associated with poor QoL during AS. DESIGN, SETTING, AND PARTICIPANTS Between September 2007 and March 2012, 103 patients participated in the Prostate Cancer Research International Active Surveillance (PRIAS) QoL study. Mental health (Symptom Checklist-90), demographic, clinical, and decisional data were assessed at entrance in AS. Health-related QoL (HRQoL) Functional Assessment of Cancer Therapy-Prostate version and Mini-Mental Adjustment to Cancer outcomes were assessed after 10 mo of AS. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Multivariate logistic regression models were used to identify predictors of low (<25th percentile) HRQoL, adjustment to cancer, and a global QoL index at 10 mo after enrollment. RESULTS AND LIMITATIONS The mean age of the study patients was 67 yr (standard deviation: ±7 yr). Lack of partner (odds ratio [OR]: 0.08; p=0.009) and impaired mental health (OR: 1.2, p=0.1) were associated with low HRQoL (p=0.006; area under the curve [AUC]: 0.72). The maladaptive adjustment to cancer (p=0.047; AUC: 0.60) could be predicted by recent diagnosis (OR: 3.3; p=0.072). Poor global QoL (overall p=0.02; AUC: 0.85) was predicted by impaired mental health (OR: 1.16; p=0.070) and time from diagnosis to enrollment in AS <5 mo (OR: 5.52; p=0.009). Influence of different physicians on the choice of AS (OR: 0.17; p=0.044), presence of a partner (OR: 0.22; p=0.065), and diagnostic biopsy with >18 core specimens (OR: 0.89; p=0.029) were predictors of better QoL. Limitations of this study were the small sample size and the lack of a control group. CONCLUSIONS Factors predicting poor QoL were lack of a partner, impaired mental health, recent diagnosis, influence of clinicians and lower number of core samples taken at diagnostic biopsy. Educational support from physicians and emotional/social support should be promoted in some cases to prevent poor QoL.