Giorgio Pizzocaro

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.

EAU Penile Cancer Guidelines 2009

CONTEXT Squamous cell carcinoma (SCC) of the penis is a relatively rare but ominous disease. OBJECTIVE To present a condensed version of the updated 2009 European Association of Urology (EAU) guidelines on penile SCC. EVIDENCE ACQUISITION We performed a literature search of new data available up to December 2009. No randomized study was found; consequently, level of evidence (LE) and grade of recommendations (GR) are low. EVIDENCE SYNTHESIS More insight was gained into the etiology of SCC of the penis, together with improved staging and treatment: Human papillomavirus 16 plays an etiologic role in approximately 40-50% of cases. Similarities in etiology with SCC of the head and neck, the female genitalia, and the anal canal have been found. Improved diagnostics allowed earlier diagnosis, leading to more conservative treatments. Adjuvant and neoadjuvant chemotherapy showed promising results in patients with advanced or recurrent disease. Centralization of the disease contributed to standardization and rapid diffusion of new treatments with improved results and increased organ preservation. CONCLUSIONS Improvements in the management of SCC of the penis are reflected in changes in the guidelines, but the rarity of the disease precluded randomized studies, leading to low level of evidence and grade of recommendation.

Interferon Adjuvant to Radical Nephrectomy in Robson Stages II and III Renal Cell Carcinoma: A Multicentric Randomized Study

PURPOSE Because interferon gave promising results in the management of metastatic renal cell carcinoma in the 1980s, a multicentric randomized controlled trial was planned to compare adjuvant recombinant interferon alfa-2b (rIFNalpha2b) with observation after radical nephrectomy in patients with Robson stages II and III renal cell carcinoma. Overall and event-free survival were to be evaluated together with prognostic factors. PATIENTS AND METHODS Overall and event-free survival curves for 247 patients (124 controls and 123 treated) were estimated by the Kaplan-Meier method and compared using the log-rank test. Coxs multiple regression models were adopted to perform a joint analysis of treatment and prognostic factors. RESULTS The 5-year overall and event-free survival probabilities were 0.665 and 0.671, respectively, for controls and 0.660 and 0.567, respectively, for the treated group; the differences were not statistically significant (2P = .861 for overall and 2P = .107 for event-free survival with the log-rank test). Regarding prognostic factors, only grade, pT, and pN demonstrated a significant prognostic role. First-order interactions of treatment with pT and pN category were investigated; a significant interaction was found between pN and treatment. A harmful effect of rIFNalpha2b in the 97 treated pN0 patients and a protective effect in the 13 treated pN2/pN3 patients were statistically significant. CONCLUSION Adjuvant rIFNalpha2b is not indicated after radical nephrectomy for renal cell carcinoma. The protective effect in the small group of pN2/pN3 patients requires further investigation.

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.

Lymphadenectomy in the Surgical Management of Penile Cancer

CONTEXT Uncertainty remains about the extent and indications for inguinal lymphadenectomy in penile cancer, a procedure known for relatively high morbidity. Several attempts have been made to develop strategies which can improve the diagnostic quality and reduce the morbidity of the management of inguinal lymph nodes in penile cancer. OBJECTIVE To analyse the existing published data on the surgical management of inguinal nodes in penile cancer regarding morbidity and survival. EVIDENCE ACQUISITION A Medline search was performed of the English-language literature (1966-September 2008) using the MeSH terms penile carcinoma, lymph node dissection, lymphadenectomy, and complications. EVIDENCE SYNTHESIS Lymph node metastases are frequent in penile cancer, even in early pT1G2 stages. Since the results of systemic treatment of advanced penile cancer are disappointing, complete dissection of all involved lymph nodes is highly recommended. The extent of lymph node dissection should be adapted to clinical stage, as this corresponds to metastatic spread. For low-risk patients (pTis, pTa, and pT1G1) without palpable lymph nodes and with good compliance, a surveillance strategy may be chosen. For all other patients without palpable lymph nodes (including intermediate risk pT1G2 disease), a modified bilateral lymphadenectomy is recommended. An alternative to this is a dynamic sentinel lymph node biopsy in specialised centres. All patients with histologically proven lymph node metastases should undergo radical inguinal lymphadenectomy. Pelvic lymph node dissection should be done in all patients with more than two metastatic inguinal lymph nodes. In case of fixed inguinal lymph nodes, neoadjuvant chemotherapy is recommended, followed by node resection. CONCLUSIONS Lymphadenectomy is an integral part of the management of penile cancer, since early dissection of involved lymph nodes improves survival.

Unusual malignant tumours in 49 patients with HIV infection

Between December 1986 and December 1988, the Italian Cooperative Group on AIDS-Related Tumours documented 49 HIV-related tumours other than malignant lymphomas (ML) and Kaposis sarcomas (KS), predominantly among HIV-infected intravenous drug abusers (IVDA). Of 12 germinal testicular tumours collected, six were seminomas, two of which were pure embryonal and the other four embryonal mixed. Cervical carcinoma was observed in nine IVDAs (intraepithelial in eight and advanced, with rapid progression, in one). Lung cancer associated with HIV infection was reported in eight patients, of whom four had an adenocarcinoma, two a small cell carcinoma, one an epidermoid carcinoma and one a mesothelioma. All patients with non-small-cell-lung cancer (SCLC) were at stage III, while those with SCLC and mesothelioma had limited disease. Five out of eight presented with limited disease at onset. The median age was low; lung cancer occurred predominantly in young adults, of whom all but one were smokers. Three patients could not be treated; four died while on treatment because of progression of the neoplasia and one died of an overdose. Acute lymphoblastic leukaemia (ALL) was diagnosed in five patients. The immunophenotype was always Burkitt-like (L3), and acute myeloblastic leukaemia (M2) was diagnosed in one. Of the central nervous system (CNS) tumours, two cases of glioblastoma and one of medulloblastoma were described. Two cases of young adults with multiple myeloma and two cases of colorectal carcinoma were also reported. One case of chronic lymphocytic leukaemia, one anorectal carcinoma, one oral carcinoma, one pancreatic carcinoma, one thymoma, one kidney carcinoma, one malignant melanoma and thyroid carcinoma were also found. Testis carcinoma occurred mainly in patients in an early phase of HIV infection, without adversely affecting full-dose chemotherapy or radiotherapy. In situ cervical carcinoma treated with conization would suggest papanicolaou shear test screening in young IVDA. Lung carcinoma occurred in a young age group with rapid progression and resulted in death within 2 months. Intensive chemotherapy for ALL was not adversely affected by HIV infection and two complete remissions were achieved (11 and 15 months duration). This retrospective study shows that while oral and anorectal tumours were very rarely observed, a wide spectrum of other HIV-related solid tumours and leukaemias were found in this IVDA-based series. The incidence of such tumours is probably underestimated because they are not diagnostic of AIDS. The required therapeutic approaches may not necessarily be influenced by HIV infection, in contrast with the observed pattern for treatment of KS and ML in HIV-infected subjects.

EAU guidelines on testicular cancer

Objectives: To establish guidelines for the diagnosis, staging, treatment and follow–up of germ cell testicular cancer. Methods: A search of published work was conducted using Medline. Highly evidence–based articles were selected and their findings analysed by the members of the Oncological Urology Working Group of the EAU. Testis cancer is rare and affects young men in their 3rd and 4th decades of life. The majority of these tumours are derived from germ cells (seminomatous and non–seminoma germ cell testicular cancer), and more than 50% of patients are diagnosed with stage I disease. Epidemiological, pathological and clinical risk factors are well established. The tumour, node, metastasis (TNM) staging system is endorsed, and for metastatic disease a recently devised prognostic–factor–based staging system has proven to be useful. Staging assessment includes pre– and post–orchiectomy marker levels, pathology of the testis, and nodal and visceral status. Following orchiectomy, treatment depends on the tumour type, pathological risk factors for stage I disease and clinical prognostic factors for advanced disease. The cure rate is excellent for disease stages I and II, irrespective of the treatment adopted. However, the pattern of relapse (rate, timing and site) is highly influenced by therapeutic policy. For metastatic disease, survival depends on clinical prognostic factors and treatment. Follow–up schedules are tailored according to stage, tumour type and post–orchiectomy treatment schedules. Conclusions: Excellent cure rates are achieved for early–stage germ cell testis tumours following accurate staging at diagnosis. Satisfactory survival rate can be achieved in advanced metastatic disease using a multidisciplinary therapeutic approach. Follow–up schedules vary, depending on the pathology and stage of the primary tumour and on the treatment policy adopted following orchiectomy.

Organ-Sparing Surgery for Adult Testicular Tumours: A Systematic Review of the Literature

CONTEXT According to current guidelines, radical orchidectomy is the standard treatment for testis tumours of malignant and unknown origin. Testis-sparing surgery (TSS) has recently been proposed as an alternative option in selected cases. OBJECTIVE Our aim was to analyse the cumulative evidence for TSS in the treatment of adult malignant tumours of different histology, including notes on operative technique, indications, complications, and oncologic and functional outcome. EVIDENCE ACQUISITION A systematic literature search of the Medline/PubMed database for full-length papers reporting on TSS for adult malignant tumours was performed up to September 2009. Bibliographies of retrieved articles and review articles were also examined. Only those articles with complete data on operative technique, complications, and oncologic or functional outcome were selected. Furthermore, published abstracts at major urologic meetings in the last decade (1999-2009) and guidelines on testis cancer from major oncologic and urologic medical associations were searched and evaluated. EVIDENCE SYNTHESIS No randomised controlled trials have compared TSS and radical orchidectomy; only retrospective outcome studies and case reports on TSS are available. In patients with small malignant germ cell tumours arising in both or in solitary testes, TSS coupled with local adjuvant radiotherapy ensures good oncologic control and is associated with a preserved endocrine function in most cases. In patients with small Leydig cell tumours, TSS can also be performed with elective indications (healthy contralateral testes), provided that pathology fails to reveal aggressive features. Finally, TSS is an option for patients with small ultrasound-detected, nonpalpable tumours even with elective indications because the incidence of benign definitive histology is high at approximately 80%. The overall complication rate is low (<6%). Data on exocrine and endocrine gonadal function, male body image, and health-related quality of life after TSS are still immature. CONCLUSIONS TSS can be safely adopted for the treatment of carefully selected cases of tumours of different histology. Prospective multicentre studies are warranted to further qualify TSS as a treatment option to be recommended as an alternative to radical orchidectomy and to explore the perceived functional advantages of testis preservation.

A Surveillance Study of Clinical Stage I Nonseminomatous Germ Cell Tumors of the Testis: 10-Year Followup

PURPOSE We evaluate the 10-year results of a surveillance study of clinical stage I nonseminomatous germ cell tumors of the testis. MATERIALS AND METHODS Between 1981 and 1984 we recruited 85 consecutive evaluable patients with nonseminomatous germ cell tumors of the testis and normal post-orchiectomy physical examination, chest x-rays, bipedal lymphangiography, abdominal scans and serum tumor markers. The patients were followed for at least 10 years after orchiectomy alone, which was performed elsewhere in 90% of the cases. RESULTS The interval between visits was twice as long as it was scheduled. Relapses occurred in 25 patients (29.4%) after a median disease-free interval of 7 months (range 2 to 68). Five patients had further relapses and 3 (3.5%) died of cancer. Retroperitoneal relapses (19%) occurred later than lung relapses, and they were diagnosed when larger than 5 cm. in 7 patients. The percentage of embryonal carcinoma within the tumor associated with relapse (p = 0.008), T category (p = 0.023), scrotal violation (p = 0.042) and vascular invasion (p = 0.063) had a weak correlation but data on T category and vascular invasion were available for only some patients. CONCLUSIONS Surveillance is a difficult type of study and missing data may compromise the therapeutic program based on prognostic factors.

Taxanes in Combination with Cisplatin and Fluorouracil for Advanced Penile Cancer: Preliminary Results

BACKGROUND Chemotherapy is emerging in the management of advanced penile cancer. OBJECTIVE To evaluate the therapeutic activity of taxanes (T) in combination with cisplatin-fluorouracil (PF) for salvage of primarily unresectable or relapsed nodal metastases from squamous cell carcinoma (SCC) of the penis. DESIGN, SETTING, AND PARTICIPANTS Six consecutive patients were treated at Istituto Nazionale Tumori (INT), Milano, with neoadjuvant paclitaxel, cisplatin, and 5-fluorouracil (TPF) for unresectable (two cases) or recurrent nodal metastases (four cases) from SCC of the penis from 2004 to 2006. Informed consent was given by all patients. INTERVENTION Four courses of neoadjuvant TPF were to be given before salvage surgery. MEASUREMENTS Patients underwent computed tomography (CT) scans before starting chemotherapy, after two courses, and at the end of chemotherapy. Lymph node dissection was to be performed in responsive patients. RESULTS AND LIMITATIONS Two patients received more than four courses: Both had pathologically documented complete remission, and they are alive and disease free >2 yr after chemotherapy. The other four patients received only two courses. The first patient had subjective intolerance to TPF: He underwent early postchemotherapy radical lymph node dissection, which documented >90% tumour necrosis: He is alive and disease free 46 mo after starting chemotherapy. Of the other three patients, one was not responsive, changed therapy, and died within 4 mo. The other two had a clinical complete remission after the first two courses. Both refused to complete chemotherapy, and they relapsed after 10 and 4 mo. Limitations are the small number of patients and protocol violation in three cases. CONCLUSIONS TPF chemotherapy for unresectable or recurrent nodal metastases from SCC of the penis is promising, and the standard four courses of therapy are to be completed in responding patients. A larger series is necessary to confirm preliminary results.