Penile and Testicular Cancer: What s New in 2006?

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1 european urology supplements 6 (2007) available at journal homepage: Penile and Testicular Cancer: What s New in 2006? Eric Lechevallier a, *, Nicolas Mottet b, Richard Berges c a Hôpital Salvator, Marseille, France b Clinique Mutualité, Saint-Etienne, France c PAN-Klinik am Neumarkt, Cologne, Germany Article info Keywords: Chemotherapy Germ cell tumour Lymph node dissection Morbidity Mortality Penile cancer Risk factor Surgery Testicular cancer Please visit europeanurology to read and answer questions on-line. The EU-ACME credits will then be attributed automatically. Abstract Objectives: This paper communicates the most relevant new findings on penile and testicular cancer that were presented at the European Association of Urology (EAU), American Urological Association (AUA), and American Society of Clinical Oncology (ASCO) 2006 annual meetings. Methods: Data were selected by urologic experts in the field of penile and testicular cancer, and discussed during a closed meeting in September Selection of data was based on expert experience. Results: Progress is being made with respect to penile-preserving surgery in not only T1 but also T2 4 patients and in the selection of patients suitable for inguinal lymph node dissection (LND). The role of neoadjuvant chemotherapy to LND in N2 3 penile cancer is getting more established. An important contribution on testicular cancer suggested that the actual role of retroperitoneal LND (RPLND) in stage I non seminoma germ cell tumour (NSGCT) is becoming marginal compared with chemotherapy. The major conclusion on postchemotherapy residual testicular masses was that a modified nerve-sparing postchemotherapy RPLND is appropriate for many patients with stage II NSGCT but that a full bilateral postchemotherapy RPNLD is mandatory in patients with metastatic NSGCT. Other data showed that patients with a postchemotherapy nodal size >5 cm, clinical stage III, and absence of a full postchemotherapy RPLND are at higher risk of relapse following postchemotherapy RPLND and should be closely followed. Conclusions: Despite the rarity of penile and testicular cancer, progress is being made in treatment strategies and risk factors. # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Hôpital Salvator, Service d Urologie et Transplantation Rénale, 249 Bd Ste Marguerite, Marseille Cedex 9 France. Tel ; Fax: address: elechevallier@mail.ap-hm.fr (E. Lechevallier). 1. Introduction Penile cancer and testicular cancer are rare malignancies. In the United States penile cancer accounts for only about 0.2% of cancers in men and 0.1% of cancer deaths in men [1]. The American Cancer Society estimates that in the United States in 2006 about 1530 new cases of penile cancer will be diagnosed and an estimated 280 men will die of penile cancer [1]. Higher incidence rates are seen in /$ see front matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eursup

2 414 european urology supplements 6 (2007) some parts of Africa and South America, where it accounts for up to 10% of cancers in men [2]. Penile cancer is typically a disease of middle-aged to older men, most commonly affecting those between 60 and 70 yr of age [3]. Testicular cancer is somewhat more common than penile cancer representing 1 1.5% of male cancers and 5% of all urologic tumours [4]. The American Cancer Society estimates that in the United States about 8250 new cases of testicular cancer will be diagnosed and an estimated 370 men will die of testicular cancer in 2006 [1]. Testicular cancer usually develops in young and middle-aged men. The Surveillance Epidemiology and End Result (SEER) data report a median age of 34 yr at diagnosis of testis cancer and a median age of 40 yr at death due to testis cancer [5]. Testicular cancer is one of the most curable forms of cancer. SEER data report that the 5-yr relative survival rate for all men with this cancer is 95.7%. If the cancer is confined to the testicle, the 5-yr relative survival rate is 99.5%. The 5-yr relative survival rate is still 96.3% when the cancer has spread to the regional lymph nodes. If the cancer has spread beyond the lymph nodes, the 5-yr relative survival rate is 70.1% [5]. Survival rates are more grim for penile cancer: an overall 5-yr survival rate of 52% has been reported, ranging from 66% in patients with negative lymph nodes to 27% in patients with positive nodes. The 5-yr survival rate ranges from 0% to 38.4% in patients with pelvic node involvement [6]. Because of the rarity of both cancers relatively slow progress is being made in the development of diagnostic methods, understanding of risk factors, and development of treatment modalities. However, at the 2006 annual meetings of the European Association of Urology (EAU), American Urological Association (AUA) and the American Society of Clinical Oncology (ASCO), interesting data were presented with regard to penile and testicular cancer. This paper focuses on the most relevant data presented at these congresses. The objective of the paper is to update the audience on the current trends in penile and testicular cancer; however, it should be noted that, from the abstracts presented at the urologic and oncologic meetings, only limited information could be drawn. 2. Methods This paper focuses on the most relevant data presented at the EAU, AUA, and ASCO annual meetings. These data were selected by urologic experts (ie, the authors of this paper) and discussed during a closed meeting in Cannes, September The selection of the abstracts was made on expert experience, and no specific selection criteria were used, which may have led to selection bias. The data presented in this paper are derived from the published abstracts; if data were retrieved by the experts attending the sessions at the meetings, this fact has been indicated by data presented at meeting. 3. Penile cancer 3.1. Organ-preserving surgery For patients with penile primary tumours exhibiting favourable histologic features (stages Tis, Ta, T1, grade 1 2 tumours), the EAU guidelines recommend organ-sparing surgery [6]. In the United Kingdom, a supraregional referral centre has specialised in the management of penile cancer. At the EAU meeting, urologists from this centre reported on the management of 230 consecutive patients managed over a 5-yr period [7]. Of these 230 patients, 202 underwent surgery for penile cancer, and 181 of the latter had organ-sparing surgery. The stage distribution of these patients before surgery was 55 patients Tis, 2 patients Ta, 76 patients T1, 70 patients T2, 13 patients T3, and 7 patients T4 (data presented at EAU 2006 annual meeting). So remarkably, organsparing surgery at this specialised centre was also performed in T2 4 patients. However, it was discussed that these were highly selected patients and that no long-term results for them were available. It was concluded that penile-preserving surgery might be considered in stages higher than T1 in a specialised centre. However the long-term safety of this management strategy remains to be studied Lymph node dissection It is assumed that patients with T1G1 penile cancer have a low risk of lymph node metastasis. For these patients the EAU guidelines recommend active surveillance [6]. However, data on lymph node metastases in penile T1 carcinoma are scarce and contradictory [8]. Naumann et al [8] evaluated the metastatic risk of T1 carcinoma and compared it with that of T2 tumours. A total of 37 patients with T1 or T2 tumours were retrospectively reviewed. Tumours were well differentiated (G1) in 19% of patients, moderately differentiated (G2) in 70% of patients, and poorly differentiated (G3) in 8% of patients. Tumour stage was T1 in 57% of patients and T2 in 43% of patients. Metastatic disease was observed in 38% of T1 and 38% of T2 tumours. Remarkably, no G1 but all G3 tumours developed metastatic disease, independently of tumour stage. Positive lymph nodes were found in 38% of G2

3 european urology supplements 6 (2007) tumours and 70% of these patients had a T1 tumour. It was concluded by the authors of the abstract that the metastatic potential of T1 tumours is often underestimated. Tumour grading has a substantially stronger impact on the metastatic risk in early invasive penile cancer than tumour stage. It was therefore concluded during the closed meeting that early inguinal lymph node dissection (LND) might have a place in T1G2 and T1G3 penile cancer. During the EAU annual meeting the risk of additional node involvement next to sentinel node involvement was also discussed. It is generally assumed that the majority of penile cancer patients with a tumour-positive sentinel node require a complete standardized groin LND [9]. Kroon et al [9] evaluated the relationship between the size of sentinel node metastasis and additional lymph node involvement. A total of 155 penile cancer patients with clinically node-negative groins underwent sentinel node biopsy. Inguinal LND was carried out when the sentinel node was found to be tumourpositive. Tumour-positive sentinel nodes were found in 46 groins of 37 patients, and 46 complementary LNDs were carried out. Size of the sentinel node metastasis was the only significant prognostic variable for additional lymph node involvement ( p = 0.02). A micrometastasis 2 mm in the sentinel node was not associated with additionally involved lymph nodes. It was therefore concluded by the author that, in selected patients with a sentinel micrometastasis 2 mm, complementary LND could be avoided. Although LND is a proven treatment, it has a high morbidity, which precludes its prophylactic use. From these two abstracts it can be concluded that complementary LND could be omitted in patients with micrometastasis 2 mm in the sentinel lymph node. However, inguinal LND is mandatory in patients with T1 and moderately to poorly differentiated (G2 G3) tumours Neoadjuvant chemotherapy prior to lymph node dissection There are little data on chemotherapy for penile cancer and even less about neoadjuvant chemotherapy prior to LND in T4 or fixed N3 cases. Pizzocaro et al [10] compared neoadjuvant chemotherapy (N = 16) with neoadjuvant radiotherapy (N = 10) in patients with fixed inguinal nodes. In the group treated with radiotherapy only one patient could be operated upon and all patients died within 3 yr. In the neoadjuvant chemotherapy group nine patients (56%) underwent successful surgical resection, and 5 (31%) achieved 5-yr disease-free survival. At the AUA 2006 annual meeting the efficacy of neoadjuvant chemotherapy prior to pelvic LND for stage Tx, N2 3, and M0 penile squamous carcinoma (SCC) was evaluated [11]. The chemotherapy consisted of the combination of paclitaxel, ifosfamide, and cisplatin (PIC). Four PIC courses were administered at 21-d intervals prior to inguinal/pelvic LND. Twenty patients were enrolled between 2000 and Two of these patients died without receiving surgery. Seventeen patients underwent surgery. Of these, 2 (11.8%) had no evidence of tumour on pathologic staging (pt0), and 15 (88.2%) had residual disease. Eleven of 20 patients (55%) showed either clinical or radiographic improvement prior to surgery. The PIC regimen was well tolerated. Grade 3 or 4 toxicities included infection (4 patients), central catheterrelated thrombosis (2 patients), deep vein thrombosis (1 patient), tumour pain (1 patient), allergic reaction (1 patient), cardiac ischemia (1 patient), and hyperglycaemia (1 patient). It was concluded that four courses of PIC as neoadjuvant therapy prior to LND is well tolerated and effective in patients with bulky regional metastases from penile carcinoma. These data strongly suggest a role of neoadjuvant therapy to LND, although this approach should still be considered experimental. 4. Testicular cancer 4.1. Stage I testicular cancer Testicular microlithiasis is a frequently encountered finding on scrotal ultrasound. It is unclear whether testicular microlithiasis should be regarded as a predictor for the development of germ cell tumours (GCT) [12]. Van Leeuwen et al [13] described the incidence of GCT developing in testes with microlithiasis. Microlithiasis was defined as at least five microcalcifications per testis. A total of 4227 patients underwent scrotal ultrasound because of orchialgia, subfertility, or scrotal swelling from 1993 to 2005 for example. Testicular microlithiasis was present in 207 patients (4.9%) and 82 patients had a subsequent ultrasound. Mean follow-up time was 34 mo. During follow-up 3 of the 82 patients (3.7%) who had another ultrasound developed a palpable malignance in a testis with preexisting microlithiasis. However, 2 of these patients had a history of nonseminoma with contralateral testicular microlithiasis, in which a nonseminoma developed after 5 and 10 yr, respectively. The third patient had a history of cryptochidism and bilateral orchidopexy. He developed a left-sided seminoma testis 5 yr after bilateral testicular microlithiasis was found. In

4 416 european urology supplements 6 (2007) conclusion, there were no GCTs found in patients with testicular microlithiasis except in 3 patients who were already at an increased risk of testicular cancer. Testicular microlithiasis is, in absence of other risk factors, probably not predictive for the development of GCTs. Routine follow-up by scrotal ultrasound of coincidentally encountered testicular microlithiasis is therefore not indicated. However, it was discussed that longer follow-up is needed to definitively evaluate whether microlithiasis is indeed not a risk factor for the development of GCTs. The overall progression rate of stage I seminoma is about 20% [14]. To decrease the risk of relapse, patients at risk are treated with adjuvant para-aortic radiotherapy or recently with chemotherapy such as carboplatin after orchidectomy. The determination of risk factors for relapse could aid in stratifying patients according to risk levels to provide the most appropriate therapy. Rete testis invasion and large tumour size have been suggested as risk factors for relapse [14]. A Spanish group of investigators evaluated the risk factors for relapse in 588 men with stage I seminoma [15]. Mean follow-up was 48 mo, median patient age was 33 yr, and median tumour size was 45 mm. Serum b-human chorionic gonadotrophin (b-hcg) levels were elevated preoperatively in 14.6% of patients and rete testis invasion was present in 26.9% of patients. A total of 304 patients (51.7%) with these risk factors received two courses of adjuvant carboplatin, whereas 284 patients (48.3%) without risk factors were managed by surveillance. After a median follow-up of 48 mo, 43 relapses (7.3%) occurred. Relapses were less frequent in patients treated with carboplatin than in patients managed with surveillance ( p < ; Fig. 1). Risk factors for relapse (univariate analysis) included rete testis invasion, age <30 yr, pathologic stage T2 4, and vascular invasion. These risk factors Fig. 1 Relapse is statistically significantly less frequent in patients with stage I seminomal germ cell tumours treated with adjuvant carboplatin than in those managed with surveillance [15]. Fig. 2 Relapse is statistically significantly less frequent in patients with stage I non seminomatous germ-cell tumours (NSGCT) treated with one course of adjuvant cisplatin, etoposide, and bleomycin (BEP) than in those treated with adjuvant retroperitoneal lymph node dissection (RPLND) [16]. could aid in the selection of patients who would benefit from adjuvant therapy with carboplatin or who could be managed by surveillance. However, it was discussed that this study was limited by the follow-up of 48 mo, which is relatively short for relapse in stage 1 seminoma. In addition, there are no randomised controlled trials performed in this area; thus, the adjuvant treatment of patients at risk with carboplatin should still be considered experimental and is not yet the standard of care. At the ASCO 2006 annual meeting, a group of German investigators presented their results of a randomised study evaluating the incidence of relapse in patients with stage I non seminomatous GCT (NSGCT) after either retroperitoneal LND (RPLND) or one course of adjuvant cisplatin, etoposide, and bleomycin (BEP) chemotherapy [16]. A total of 382 patients were included between 1996 and After orchidectomy 172 patients were treated with RPLND and 174 patients were treated with one course of BEP. Median time of follow-up was 47 mo, with 323 patients (93%) followed-up for at least 1 yr. Thirteen patients (8%) experienced a relapse after RPLND, whereas 2 patients (1%) relapsed after one course of adjuvant BEP ( p = ; Fig. 2). The complication rate was lower with adjuvant BEP than with RPLND. Minor complications were observed in 1.0% of patients on BEP and in 14.9% of patients receiving RPLND. Major complications were observed in 0.6% of patients receiving BEP and 1.0% of patients receiving RPLND (data presented during ASCO 2006 annual meeting). It was concluded that the results of this randomised trial no longer support the use of RPLND for the adjuvant treatment of patients with clinical stage 1 NSGCT.

5 european urology supplements 6 (2007) However, it should be noted that, in this study, no stratification of patients according to risk of relapse took place (based on histologic factors and vascular invasion). In addition, a follow-up of 47 mo may be too short because patients may relapse even after 5 yr. It was also discussed that although one course of BEP was shown to be better than RPLND, two courses are considered standard of care Metastatic germ cell tumour It has been shown that metastatic patients with poor-prognosis NSGCT (according to the classification of the International Germ Cell Cancer Collaborative Group (IGCCCG) [17,18]) show insufficient cure rates with standard cisplatin-based combination therapy: four cycles of standard-dose BEP chemotherapy resulted in a 5-yr survival rate of 48% [14]. Therefore, research has begun to focus on dose-intensified chemotherapy for poor-prognosis patients. Early studies that evaluated increased doses of cisplatin with classic dosed chemotherapy showed that the higher dose was both ineffective and highly toxic [14,19]. A more recent retrospective matched-pair analysis comparing patients who had been treated with either high-dose cisplatin, etoposide, and ifosfamide (VIP) therapy, or standard-dose BEP or VIP therapy showed increased 2-yr progression-free survival (75% vs. 59%) and overall survival (82% vs. 71%) with the high-dose regimen [20]. At the ASCO 2006 annual meeting the results of a phase 3 trial of conventional-dose chemotherapy alone or with high-dose chemotherapy for metastatic GCT were presented [21]. Patients with untreated intermediate- or poor-prognosis GCT, according to the classification of the IGCCCG, were randomised to either two cycles of standard BEP followed by two cycles of high-dose chemotherapy (cyclophosphamide, etoposide, and carboplatin) plus stem-cell rescue or to four cycles of BEP. A total of 219 patients were randomised to BEP plus high-dose chemotherapy (N = 108) and to BEP alone (N = 111). A total of 52% of patients in the BEP plus high-dose chemotherapy group had a complete response at 1 yr, which was the case for 48% of patients treated with BEP alone ( p = 0.53). In the same study, the prognostic impact of the marker velocity during the first chemotherapy cycles was explored in a prospective manner. A total of 70 patients had a slow decline of the markers alpha-fetoprotein (AFP) or b-hcg during the first and second cycles of BEP. These patients had a shorter progression-free and overall survival compared with patients who had a satisfactory decline of these markers ( p 0.02). In addition, in these patients the complete response Fig. 3 The complete response rate is statistically significantly higher in poor-risk testicular cancer patients with a slow decline of serum markers receiving high-dose chemotherapy compared with those receiving standarddose chemotherapy [21]. rate at 1 yr was 61% for patients receiving high-dose chemotherapy during the third and fourth cycles, whereas this rate was 31% for those receiving three or more cycles of BEP ( p = 0.008; Fig. 3). The subgroup of patients with abnormally slow serum marker decline in the first and second cycles of BEP thus seemed to benefit from high-dose chemotherapy. It was concluded that the routine inclusion of highdose chemotherapy for intermediate- and poor-risk GCT patients does not improve treatment outcome. Four cycles of BEP can therefore still be considered the standard of care in intermediate- and poorprognosis metastatic GCT patients. However, the decline of serum markers AFP and HCG during the first two cycles of chemotherapy may be useful for selecting those patients who are likely to respond to high-dose chemotherapy Residual masses after chemotherapy About one third of patients with stage II IV NSGCT have residual masses after chemotherapy. Some consist of necrotic or fibrotic tissue; others can be undifferentiated malignancy or differentiated teratoma [22] fluoro-deoxy-d-glucose positron emission tomography ( 18 FDG-PET) is increasingly used for differentiating between necrosis and viable seminoma in postchemotherapy residual masses. Although some studies have suggested increased diagnostic accuracy of 18 FDG-PET compared with computed tomography (CT), others have challenged this observation [22]. De Wit and colleagues [23] evaluated the viability of residual masses following chemotherapy in patients with GCT 79% being

6 418 european urology supplements 6 (2007) Table 1 Comparison of 2-18 fluoro-deoxy-d-glucose positron emission tomography ( 18 FDG-PET) with computed tomography (CT) in patients with postchemotherapy residual masses (data presented at the ASCO 2006 annual meeting) [23] Sensitivity Specificity Negative predictive value Positive predictive value Accuracy CT scan 100% 0% 0% 51% 51% 18 FDG-PET 72% 44% 59% 57% 57% NSGCT using 18 FDG-PET and CT. A total of 140 patients with GCT at primary diagnosis or at relapse were included if residual masses >1 cm were present following chemotherapy. Patients were evaluated with 18 FDG-PET and CT scans; all patients underwent surgery for residual masses. 18 FDG-PET and CT scans were validated by histology. Correct classification of the residual mass by 18 FDG-PET was achieved in 56% of patients, whereas CT scans were correct in 42% of patients. Table 1 shows that the accuracy of 18 FDG-PET was better than that of CT (data presented at the ASCO 2006 annual meeting). However, the sensitivity of 18 FDG-PET was lower than that of CT. It was concluded that the sensitivity of the 18 FDG-PET is still too low to decide to avoid resections in patients with NSGCT. The use of 18 FDG-PET in the evaluation of postchemotherapy residual masses therefore cannot be recommended. Because residual masses after primary chemotherapy might represent viable residual disease, they are to be removed in order to prevent tumour progression [14]. Shayegan et al [24] investigated the impact of residual extraperitoneal (ERP) masses on cancer progression and survival in patients with advanced NSGCT. A total of 532 patients underwent postchemotherapy RPLND, 130 of whom (24%) underwent resection of the ERP masses. Histology of ERP masses revealed fibrosis in 66%, teratoma in 24%, and viable GCT in 10%. A weak concordance between the histology of the retroperitoneal (RP) masses and the ERP masses was found: RP histology was 83% for fibrosis, 42% for teratoma, and 47% for viable GCT. At a median follow-up of 41 mo, overall progression-free probability was 83%. Overall disease-specific survival at 5 yr was 91%. In a multivariate analysis, IGCCCG risk classification, size of residual RP masses, completeness of postchemotherapy RPLND, and viable GCT in RP and ERP residual masses independently predicted cancer progression. In contrast to RP teratoma, residual ERP teratoma independently predicted cancer progression. The presence of viable GCT in ERP masses resulted in death from disease in all but one patient at a median time of 11 mo. In contrast, the presence of viable GCT in RP was associated with a 5-yr disease-specific survival of 77%. Overall, the presence of residual masses in the ERP was associated with a lower progression-free probability and a lower disease-specific survival than the presence of residual masses in the RP (Table 2). It was concluded that patients with residual ERP teratoma and viable GCT are at higher risk of cancer progression and death compared with those with disease confined to the retroperitoneum. Furthermore, on the basis of low concordance between the histology of RP and ERP residual masses, every effort should be made during surgery to remove all the residual tissue, whatever its localisations. Retrograde ejaculation occurs in approximately 90% of patients after a postchemotherapy RPLND for residual masses. Therefore, in patients with lowvolume residual disease, a modified nerve-sparing RPLND may be performed, which may preserve ejaculation in over 80% of men [25]. A prospective study [26] evaluated the long-term outcome of patients who underwent a modified postchemotherapy RPLND. From 1988 to 2005, 102 patients with NSGCT, RP stage IIC,B, and tumour marker positive IIA underwent a modified postchemotherapy RPLND. Within a median follow-up of 70 mo, three relapses were observed after 7, 39, and 192 mo. Only one of these relapses occurred in the RP within the boundaries of a full bilateral RPLND. Ejaculation was preserved in 94% of patients. It was concluded that, in this selected group of stage II NSGCT postchemotherapy patients, a modified nervesparing postchemotherapy RPLND for residual masses is oncologically efficient, while ejaculation function is being preserved. In these patients, a full Table 2 Patients with residual extraretroperitoneal (ERP) masses after chemotherapy are at higher risk of cancer progression and death compared with those with residual masses that are confined to the retroperitoneum [24] 5-year progressionfree probability 5-year diseasespecific survival Residual mass in ERP 74% 83% Residual mass confined to 85% 93% retroperitoneum

7 european urology supplements 6 (2007) bilateral postchemotherapy RPLND can thus be avoided. In contradiction to these data, Carver et al [27] argued that a full bilateral RPLND is necessary for the management of men with metastatic NSGCT following chemotherapy. A total of 532 men underwent postchemotherapy RPLND for metastatic NSGCT. Of the 532 men, 269 (51%) had viable GCT or teratoma in the RPLND specimen, and 86 (32%) of the latter had teratoma or viable GCT outside the boundaries of the modified template. During the AUA annual meeting it was discussed that the risk of teratoma/gct outside the boundaries of the modified template was dependent on the size of the tumour within the boundaries of the template (Table 3). The larger the tumour inside the template, the higher is the risk of teratoma/gct outside the template. On multivariable analysis RP nodal size prechemotherapy ( p = 0.002) and postchemotherapy ( p < 0.001), positive radiographic imaging outside the template ( p < 0.001), and clinical stage III disease ( p = 0.027) were predictors for the presence of disease outside the modified template. The 5-yr probability of disease-free survival was 70% for men with disease outside the modified template and 82% for men with disease confined to the modified template ( p = 0.048; Fig. 4). The 5-yr probability of disease-specific survival was 84% for men with disease outside the modified template and 90% for men with disease confined to the modified template ( p = 0.31; Fig. 4). The apparent discordance between the two discussed abstracts seems to relate to the selection of patients. A modified postchemotherapy RPLND may be indicated in only a very select group of patients (ie, those with NSGCT, RP stage IIC,B, and tumour marker positive IIA), and a bilateral postchemotherapy RPLND seems to be the prudent approach for the management of men with postchemotherapy metastatic NSGCT. It should be noted that, while up to 32% of teratoma/gct was discovered outside the modified RPLND template, the Table 3 The percentage of teratoma/germ cell tumours outside the boundaries of the modified template in function of tumour size inside the boundaries of the template [27] Size of tumour inside boundaries of modified template Percentage of teratoma/germ cell tumour outside the boundaries of modified template <1 cm cm cm 29 >5 cm 25 Fig. 4 The presence of disease outside the modified template after a postchemotherapy retroperitoneal lymph node dissection (RPLND) is associated with a decreased disease-free survival [27]. secondary RP relapse rate following this modified RPLND is below the 10% rate. There is limited evidence as to the optimal treatment of patients with residual postchemotherapy liver metastases. Available data suggest that hepatic metastases should be removed in eligible patients [14]. Hartman et al [28] discussed the role of postchemotherapy adjunctive surgery in patients with liver metastases at the AUA 2006 meeting. Forty-three men with NSGCT and liver metastases who underwent hepatic surgery were evaluated with a mean follow-up of 37 mo. Histologic findings differed among liver and other resection sites in 39% of patients, which indicates that residual mass in one organ does not predict the type of residual masses in other organs, as previously observed for lung metastases. The 5-yr survival rate was 71% (data presented during AUA meeting). It was concluded that, in case of liver metastases, hepatic surgery is worthwhile because the 5-yr survival rate is relatively high. However, because patients with hepatic metastases are often in a poor condition, patients eligible for surgery should be carefully selected Relapse following postchemotherapy RPLND A study from the Memorial Sloan-Kettering Cancer Centre in New York evaluated 532 patients with NSGCT who underwent postchemotherapy RPLND to determine predictors of disease relapse [29]. A total of 473 patients (89%) had fibrosis or teratoma present in the RPLND specimen and underwent a complete resection of residual RP masses. Within a median follow-up of 41 mo, 47 patients (10%) relapsed with a viable NSGCT. Multivariate analysis

8 420 european urology supplements 6 (2007) Fig. 5 Non seminoma germ cell tumour (NSGCT) patients who underwent a postchemotherapy retroperitoneal lymph node dissection (RPLND) for residual disease and who have two or more risk factors for relapse have a lower progression-free probability than NSGCT patients who have one or no risk factor for relapse ( p < 0.001) [29]. showed that postchemotherapy nodal size >5cm ( p = 0.008), clinical stage III ( p = 0.002), and absence of a full bilateral postchemotherapy RPLND ( p = 0.002) were independent predictors for relapse. On the basis of these three risk factors, a prognostic index was developed. For favourable patients, defined as having no risk factors, the 2-yr progression-free probability was 97% (Fig. 5). For intermediate prognosis patients having one risk factor, the 2-yr progression-free probability was 90%. Poor-prognosis patients who had two or more risk factors had a 2-yr progressionfree probability of 66%. It was concluded that it is important to consider risk factors for relapse. Patients who have a high risk of relapse should undergo more frequent follow-up during the first 2 yr with imaging and serum tumour markers. In addition it was discussed that these data suggest that a modified postchemotherapy RPLND is not sufficient for men with metastatic postchemotherapy NSGCT and that these men should undergo a full bilateral postchemotherapy RPLND. This approach should probably be the case for all stage III patients with postchemotherapy residual masses >5 cm. However, it remains unclear if this approach should be the standard for small residual masses Long-term effects As testicular cancer is one of the most curable forms of cancer, treated patients may potentially survive many decades and be considered cured. Many studies have evaluated the long-term morbidity and mortality in testicular cancer survivors. This was also the subject of several studies presented at the ASCO 2006 annual meeting. Palmer et al [30] evaluated the risk of coronary heart disease (CHD) in 50 testicular cancer survivors who did or did not receive cisplatin-based chemotherapy. Previous studies have suggested that testicular cancer survivors who received cisplatin-based chemotherapy are at an increased risk of CHD [31]. However, Palmer et al demonstrated that the risk of CHD is independent of chemotherapy. Measures of CHD were abnormal in both testicular cancer survivors who were treated with and without cisplatin. However, it should be noted that this study was performed in a limited number of patients, and further study is therefore needed to confirm the results. Another group of US investigators reported on the occurrence of late toxicity of cisplatin-based chemotherapy based on community data from the Los Angeles SEER tumour registry [32]. A total of 298 testicular cancer survivors and 67 controls returned questionnaires on demographic, treatment-related, and psychosocial issues. The follow-up was yr. Compared with controls, long-term testicular cancer survivors showed an excess of late toxicity, including neurologic, haematologic, musculoskeletal, and neoplasic problems. Another follow-up study of 1319 testicular cancer survivors evaluated the persistence of side-effects due to cisplatin-based chemotherapy [33]. These survivors had a median follow-up of 11 yr. The study showed that toxicities induced by cisplatin chemotherapy, such as paresthesias, Raynaud s phenomena, tinnitus, and hearing impairment, persist in many testicular cancer survivors. The long-term noncancer mortality in testicular cancer survivors was also addressed. A total of 39,657 testicular cancer survivors were identified in 14 population-based cancer registries in North America and Europe with follow-up of yr; 17,856 patients had 10-yr follow-up, 13,084 patients had 20-yr follow-up, and 6298 patients had 30-yr follow-up [34]. Compared with the general population, the overall risk of mortality due to all noncancer causes combined was not increased in testicular cancer survivors. However, mortality due to infection and digestive disease (including gastric and duodenal ulcers) was increased in testicular cancer survivors (mainly for those having received radiotherapy with or without chemotherapy) compared with the general population. In contrast the mortality due to cardiovascular disease was reduced. A Polish study [35] showed that, among 326 testicular cancer survivors, hormonal abnormalities are frequent, with only 24% having hormonal levels within normal ranges. Testosterone, estradiol, thyreotropin, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin levels were

9 european urology supplements 6 (2007) determined. Luteinizing hormone FSH levels were often above normal and testosterone levels below normal. This abnormality had a negative impact on well-being and sexual functioning. Depression and anxiety levels were higher, and many survivors encountered sexual problems that went along with deteriorated well-being. 5. Conclusions Although penile and testicular cancers are relatively rare malignancies and therefore research on these topics is limited, interesting data were presented at the 2006 urologic and oncologic congresses. It should be noted that, although the quality of the abstracts dealing with testicular cancer can generally be considered as good, the quality of the abstracts relating to penile cancer is somewhat poorer, which can be explained by the fact that little research is being performed and not many resources are available for penile cancer. In spite of these problems, progress is being made with respect to penilepreserving surgery in not only T1 but also in T2 4 patients and in the selection of patients suitable for inguinal LND. The role of neoadjuvant chemotherapy prior to LND in N2 3 penile cancer is getting more established. Progress has also occurred with respect to risk factors and treatment of testicular cancer. One of the most important contributions with respect to stage I NSGCT confirms that the place of RPLND is nowadays becoming limited compared with chemotherapy. In addition, high-dose chemotherapy for poor-prognosis NSGCT does not seem to be beneficial compared with the standard dose. Many relevant new data were presented with respect to postchemotherapy residual masses. The major conclusion was that a modified nerve-sparing postchemotherapy RPLND is appropriate for patients with stage II NSGCT, but that a full bilateral postchemotherapy RPNLD is mandatory in patients with metastatic NSGCT. In addition, the use of the 18 FDG-PET in the evaluation of NSGCT postchemotherapy residual masses was questioned. The data on relapse following postchemotherapy RPLND showed that patients with a postchemotherapy nodal size >5 cm, clinical stage III, and absence of a full postchemotherapy RPLND are at higher risk of relapse and should be closely followed. Finally, long-term follow-up of survivors of testicular cancer show that these patients have a high morbidity (eg, neurologic, musculoskeletal, sexual problems) and mortality from noncancer causes. It can be concluded that significant progress is being made in diagnostic methods, assessment of risk factors, and treatment strategies. These developments should aid urologists and oncologists in their daily management of patients. References [1] Available at URL: index asp. Accessed [2] Misra S, Chaturvedi A, Misra NC. Penile carcinoma: a challenge for the developing world. Lancet Oncol 2004;5: [3] McDougal WS. 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