Risk-Adapted Management of Clinical Stage I Nonseminomatous Testicular Germ Cell Tumours

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1 european urology supplements 5 (2006) available at journal homepage: Risk-Adapted Management of Clinical Stage I Nonseminomatous Testicular Germ Cell Tumours Axel Heidenreich *, Carsten H. Ohlmann Division of Oncological Urology, Department of Urology, University of Cologne, Germany Article info Keywords: Management Nonseminomatous testis cancer Review Therapy Abstract Introduction and objectives: Optimal management for clinical stage I nonseminomatous testicular germ cell tumours (NSGCTs) is still controversial. The main options for standard care surveillance, primary chemotherapy, and nerve-sparing retroperitoneal lymph node dissection (nsrplnd) result in the same high cure rate of close to 100%. It is the purpose to critically review recent developments concerning primary therapy of clinical stage I NSGCT and to identify potential new prognostic risk factors predicting occult metastatic retroperitoneal lymph node disease and enabling an individualized risk-adapted therapeutic approach. Methods: Analysis of published full-length papers that were identified with Medline and Cancerlit from January 1987 to January Paper was structured according the recommendations of the European Germ Cell Cancer Consensus Group (EGCCCG). Results: In accordance with the primary goal to improve quality of life, protect fertility, and reduce long-term toxicity in survivors of testis cancer, the major advantage of surveillance protocols is that adjuvant therapy will be administered only to those patients who require therapy. This advantage has to be balanced against a constant psychological threat and a relapse rate of 20 25%, necessitating extensive polychemotherapy and residual tumor resection in 30%. Surveillance is recommended as the treatment of choice for low-risk tumours defined by absence of vascular invasion, <50% embryonal carcinoma, and MIB-1 score <70%. Primary nsrplnd has diagnostic and therapeutic capabilities in low-volume disease associated with preservation of fertility in 95% of the patients; the 5-yr progression-free survival even in pathologic stage IIA disease is 90% without chemotherapy. Because local relapses are extremely rare an effective and cost-saving follow-up concentrating on pulmonary recurrences can be initiated. nsrplnd represents the initial approach to pure mature teratomas and predominantly teratomatous primaries; furthermore, it represents a therapeutic option for those who are not amenable to chemotherapy or surveillance. Advantages of nsrplnd have to be balanced against surgery-related complications developing in about 17% of the patients. Primary chemotherapy is recommended for high-risk germ cell tumours defined by presence of vascular invasion, >50% embryonal carcinoma, and MIB-1 score >70%; however, the predictive accuracy of these markers is only 60% resulting in a high rate of overtreatment. An advantage of primary chemotherapy is the absence of surgical morbidity; disadvantages are short- and long-term toxicity, lower cure rate of relapses, and potential affect on fertility. Conclusions: Surveillance, primary chemotherapy, and primary nsrplnd result in the same high cure rate approaching 100%. Evidence-based recommendations with regard to the potentially best treatment are available but still advantages and disadvantages of all treatment modalities have to be discussed extensively with the patient. # 2006 Elsevier B.V. All rights reserved. * Corresponding author. Department of Urology, University of Cologne, Joseph Stelzmann Str. 9, Köln, Germany. Tel ; Fax: address: axel.heidenreich@uk-koeln.de (A. Heidenreich) /$ see front matter # 2006 Elsevier B.V. All rights reserved. doi: /j.eursup

2 526 european urology supplements 5 (2006) Introduction The incidence of testicular cancer has increased significantly over the last three decades, accompanied by a dramatically decreased overall mortality rate with a 5-yr survival rate approaching 95% [1]. Clinical stage (CS) I nonseminomatous testicular germ cell tumours (NSGCTs) represent a troublesome entity concerning recommendations for optimal management [2,3]. Approximately 30% of patients with CS I NSGCTs will have microscopic lymph node disease when undergoing retroperitoneal lymphadenectomy (RPLND) [4]; for this group of patients an active therapeutic regime either by means of primary nerve-sparing RPLND (nsrplnd) or by primary chemotherapy is justified. However, for the remaining 70% of patients watchful waiting appears to be the most appropriate therapeutic option. Because all clinical stage patients will be cured by one of the offered therapeutic modalities, adding an additional life span of about 50 yr, attention is now focused on potential long-term toxicities and quality of life. Because the majority of patients are young, classical therapeutic end points such as response and survival rates are thrust into the background and quality of life, protection of fertility, and long-term toxicity of the chosen therapy come to the fore [5]. Therefore, reduction of treatment-related toxicities without decreasing therapeutic efficacy appears to be the major goal in these patients. The purpose of the current article is to summarise the diagnostic approach and the advantages and disadvantages of the available therapeutic options to manage CS I NSGCTs based on the recommendations of the European Germ Cell Cancer Consensus Group (EGCCCG) [6]. 2. Definition of CS I NSGCTs CS I NSGCTs of the testes are characterized by normal serum levels of human chorionic gonadotropin (hcg), a-fetoprotein (AFP), and lactate dehydrogenase (LDH) and no evidence of retroperitoneal and pulmonary disease by abdominal and chest computed tomography (CT). In case of preoperatively elevated serum tumour markers, marker levels should decline postoperative according to their half-life. The role of positron emission tomography (PET) in the initial diagnostic approach to CS I NSGCTs is still controversial based on the lack of available prospective studies. Only recently, Lassen et al. [7] evaluated 46 patients with CS I NSGCT by PET and traditional staging methods; all patients were managed by active surveillance thereafter. Ten of 46 men (22%) developed a relapse 1 8 mo after the initial diagnosis with 7 patients having demonstrated a positive PET scan at initial staging. Based on these data, positive and negative predictive values of PET are 100% and 92% and seem to be superior to standard staging procedures. However, the results of currently ongoing prospective studies have to be awaited before PET can be recommended as primary staging modality in CS I NSGCTs. 3. Treatment options in CS I NSGCTs Improvement in imaging, the ability to identify subsets of patients with a low risk of retroperitoneal or systemic relapse, and the efficacy of chemotherapy have allowed consideration of various treatment modalities. Currently, there are three main therapeutic approaches once the primary testicular tumour has been removed: (1) active surveillance, (2) nsrplnd, and (3) primary chemotherapy. Based on reproducible and prospectively validated prognostic risk factors, an individualized riskadapted approach can be offered to basically all patients with CS I NSGCTs, thereby reducing treatment-associated morbidity without compromising therapeutic efficacy [8]. 4. Prognostic risk factors Vascular invasion (VI) has been identified as the most powerful clinical predictor of lymph node metastases with 48% of NSGCTs with VI developing metastases as compared to 14 22% of tumours without VI [9]. A combination of VI and percentage of embryonal carcinoma (EC) might be even more powerful if used as a continuous variable but both have not been tested in prospective clinical trials [10]. Quite recently, the German Testicular Cancer Study Group (GTCSG) has identified risk factors for relapse in a prospective randomised clinical phase 3 trial [11]. Two hundred patients were randomly assigned to RPLND with risk factor assessment within a multicentre pool; 165 patients had an adequate follow-up of >12 mo and formed the basis of the study. VI was the most predictive variable of stage in multifactorial analysis (65.1%); however, the positive predictive value to predict patients with either microscopic retroperitoneal disease or systemic relapse was only 52.7%. Even the addition of a MIB-1 score 70% and a percentage of EC > 50% had a positive predictive value of only 63.6%, resulting in a potential overtreatment in 36 47% of patients. On

3 european urology supplements 5 (2006) the other hand, it was possible to define a subset of patients with a very low risk of relapse and retroperitoneal metastases, respectively; combining absence of VI, MIB-1 score <70%, and percentage of EC < 50% positively predicted a low-risk group at the 86.5% level. Based on these findings, a low-risk group amenable for surveillance can be identified; however, a high-risk group of patients cannot be identified accurately and all available treatment options have to be discussed with the patient. In another study on 88 patients, three prognostic groups of CS I NSGCT were identified based on histopathologic variables. Pure mature teratoma without VI had the lowest relapse rate, whereas patients without mature teratoma but VI exhibited the highest relapse rate of 61% [12]. Currently, all molecular markers, such as p53, Ki- 67, bcl-2, cathepsin D, and E-cadherin, have not been proven to be clinically useful prognosticators [10,13]. Recently, the clinical application of reverse transcriptase-polymerase chain reaction (RT-PCR) for AFP, hcg, and GCAP mrna to detect circulating tumour cells has been described as an interesting approach [14,15]. About 60% of patients with CS I testis cancer exhibited positive RT-PCR signals at time of orchiectomy, which turn into negative signals following adjuvant chemotherapy [15]. mrna expression of the RhoA subfamily of the Rho small GTP-binding protein family has been shown to be significantly overexpressed in testicular germ cell tumours with lymph node metastases as compared to clinically organ-confined tumours [16]. Because RhoA regulates the microfilament network and the cadherin-dependent cellto-cell contact, it might be useful to evaluate the clinical utility of this marker in CS I NSGCTs to predict occult lymph node disease. In another study,schmidtetal.[17] analysed the expression of several G 1 -S regulator molecules and found lowered cyclin E and CDK2 expression in clinically localized germ cell tumours. Immunohistochemical expression of p53, Bcl-2, and Bax might be useful to tailor the decision for or against primary chemotherapy because there appears to be a significant correlation between the response to chemotherapy and p53 immunoreactivity [18]. 5. Active surveillance in CS I NSGCTs If the clinical staging is correctly performed, 17 30% of all CS I NSGCTs will harbour occult retroperitoneal metastases, whereas 8% will develop pulmonary metastases adding up to an overall relapse rate of 25 38% [19,20]. The median time to relapse is 4 13 mo with <5% of all relapses developing later than 2 yr. About two thirds of the relapses occur retroperitoneally, 25% develop in the lung, and about 10% demonstrate marker elevations only. If close surveillance protocols are being performed in all CS I patients without consideration of prognostic risk factors, therapy will be extensive in relapsing tumours; about one fourth of the patients must undergo three to four courses of polychemotherapy and in 5% secondary RPLND must be performed for residual tumour masses [21,22]. If a patient under surveillance develops a relapse, the administration of four cycles of chemotherapy will result in a cure rate of close to 100% [6]. However, cumulative cisplatin doses <400 mg/m 2 and >400 mg/m 2 are associated with a significant impairment of Leydig cell function [23]. Subnormal testosterone levels will be found in 11% and 20%, respectively; luteinisng hormone (LH) serum levels above the upper limit indicating Leydig cell dysfunction are found in 19% and 38%, respectively. Germinal cell damage identified by elevated follicle-stimulating hormone (FSH) serum levels occur in 53% and 84% of the patients, respectively. Furthermore, secondary RPLND for residual masses is associated with an acute morbidity of 30%, and retrograde ejaculation develops in about 40% of the patients [24]. Considering these data, the main issue in CS I NSGCTs is to tailor surveillance to those 70 80% of patients who will present with pathologic stage I disease. It is essential to identify prognostic risk factors indicating patients at low risk for retroperitoneal metastases. According to recent data of the GTCSG [11] absence of VI, percentage of EC < 50%, and an MIB-1 score <70% refer to a relapse risk of only 14% so that patients harbouring these characteristics might be safely included in close surveillance protocols. Therefore, the current recommendation by the EGCCCG is to manage patients with a low-risk of relapse by close surveillance (Fig. 1); with this approach 78 86% of all patients do not need any further treatment after inguinal orchiectomy. Only in situations not suitable for surveillance, primary chemotherapy with two cycles of bleomycin, etoposide, and Platinol (BEP) or nsrplnd might represent an option. Patients undergoing close surveillance protocols will have the same therapeutic outcome as men treated by active measures such as primary chemotherapy or nsrplnd. Roeleveld et al. [22] examined the issue of surveillance even in patients with high-risk CS I NSGCTs. The relapse rate among

4 528 european urology supplements 5 (2006) Fig. 1 Intraoperative site of a typical nerve-sparing retroperitoneal lymph node dissection. 95 CS I NSGCTs independent of risk factors was 26% after a mean follow-up of 8.1 yr; all patients with relapse but one were cured by standard cisplatinum-based chemotherapy resulting in a diseasespecific survival of 98.9%. Although relapse rates were higher among patients with negative risk factors such as presence of VI, percent EC, and tumor size there was no difference concerning survival rate among the two groups. Furthermore, the authors demonstrated that less than one appointment for follow-up was missed within the first 2 yr when the patients are informed adequately. In a different study [13] it was found that none of the CS I NSGCTs without EC in the primary tumour were pathologic stage II at time of RPLND, representing a low-risk group. If surveillance is chosen for standard care high compliance by both the patient and the physician and a close and rigorous follow-up protocol are mandatory to early identify and accurately manage relapses [22,25]. This recommendation is substantiated by a small study [26] using questionnaires to document follow-up visits among patients treated by surveillance and by primary chemotherapy, respectively. The authors found that patients managed by orchiectomy alone were less compliant with their follow-up visits than those treated by orchiectomy and chemotherapy. It might be speculated that insufficient patient education and the perception that a disease being managed by surveillance is less dangerous than one receiving adjuvant therapy might explain this phenomenon [26,27]. The most compelling problem with surveillance protocols, however, is due to the fact that there is a lack of randomised, controlled studies on the optimal surveillance protocol. Recommendations, however, have been published by several groups [6,28]. The potential advantages and disadvantages of surveillance are listed in Table 1. Table 1 Advantages and disadvantages of the various treatment options of clinical stage I nonseminomatous germ cell tumours Advantages Active surveillance No morbidity of RPLND/chemotherapy No impact on fertility Primary chemotherapy No morbidity of RPLND Disadvantages Dangerous if not compliant Chemotherapy and RPLND in case of relapse High burden of follow-up (costs, efforts) Short- and long-term toxicity Postchemotherapy relapses need more aggressive treatment and are more difficult to cure Potential affect on fertility Nerve-sparing RPLND Adequate histopathologic staging Short-term surgical morbidity 90% cure in pathologic stage I/IIA Convalescence Optimum cancer control in the retroperitoneum Potential affect on fertility Easy follow-up, no abdominal staging Chemotherapy-naive relapses highly responsive RPLND = retroperitoneal lymph node dissection.

5 european urology supplements 5 (2006) Primary chemotherapy in CS I NSGCTs The major drawbacks of surveillance are the need for close, cost-intensive, and long-term follow-up examinations resulting in a relapse rate of about 30%. If prognostic risk is applied the relapse rate can be reduced to about 15 20%. Patients with high risk of relapse as defined by the GTCSG might be considered for adjuvant chemotherapy consisting of two cycles BEP. By this approach 97% of the patients will remain disease free long term and the cure rate will be about 99%. There are, however, only a few studies published in the literature with small patient numbers and, currently, there is no randomised trial of primary chemotherapy versus nsrplnd in the literature. Pont et al. [29] probably were the first to recommend and to perform primary chemotherapy with two cycles BEP in patients demonstrating the risk factor of VI. After a follow-up of >2 yr, the relapse-free rate was 93% and no significant sideeffects have been identified in the chemotherapy group. The relapse rate was only 4% in the surveillance groups, demonstrating no VI with a progression-free survival rate of 96%. No long-term toxicity was observed in the chemotherapy as compared to the surveillance group after a followup of 79 mo. In a similar study, Studer et al. [30] treated 43 high-risk patients with CS I NSGCTs harbouring at least one risk factor such as VI, presence of EC, or advanced pt stage with two cycles of adjuvant BEP chemotherapy. After a median follow-up of 93 mo, the relapse-free rate was 98% and no major side-effects developed during therapy. In another prospective multicentre trial [27], two cycles of BEP chemotherapy were given to 116 patients harbouring at least three of four high-risk histopathologic characteristics (VI, lymphatic invasion, absence of yolk sac tumour, presence of undifferentiated tumour). After a 2-yr follow-up, the relapse-free rate was 98%. Based on these small, but well-performed trials, primary chemotherapy offers an overall survival rate comparable to surveillance or nsrplnd. However, even the combination of the three most powerful prognostic markers presence of VI, >50% EC, and an MIB-1 score >70% will have a predictive accuracy of only about 60% to identify those with microscopic metastatic disease. Therefore, up to 40% of the patients will be unnecessarily exposed to the potential short- and long-term side-effects of chemotherapy. Although Bohlen et al. [31] and Pont et al. [29] pointed out that two cycles of chemotherapy do not adversely effect spermatogenesis and fertility, sperm banking is recommended for all individuals undergoing primary chemotherapy. Besides negative effects on fertility, cisplatin and bleomycin might induce ototoxicity in up to 15% [31], peripheral sensory neurotoxicity in about 10 16% [32], and Raynaud phenomenon in up to 30% of patients [33]. Furthermore, it has been demonstrated that the risk for long-term cardiotoxicity is increased 7-fold following four cycles BEP; however, there are no long-term data on patients having undergone only two cycles of chemotherapy [33]. Besides potential short-term and long-term side effects one major drawback of primary chemotherapy is the finding that all patients are still at risk to develop retroperitoneal recurrences especially if the primary testis tumour contained mature teratoma [34]. In a recent retrospective analysis, the authors demonstrated that 16% of positive retroperitoneal lymph nodes of CS I/pathologic stage IIA patients harboured mature teratoma not eradicated by chemotherapy. In addition, it has been demonstrated that relapsing patients after primary chemotherapy might have an increased mortality risk as compared to chemotherapy-naïve patients having a relapse after surgery or surveillance. The mortality rate has been reported to vary between 1.5% and 5%. 7. nsrplnd in CS I NSGCTs RPLND has long been the diagnostic and therapeutic approach of choice in CS I NSGCTs because it provides important advantages: (1) accurate histopathologic staging, (2) cure of 60 70% of patients with pathologic stage IIA/B disease without the need for chemotherapy, and (3) simplified postoperative follow-up due to the low risk of retroperitoneal recurrences. The current recommendations by the EGCCCG, however, only consider RPLND as a treatment alternative in low- or high-risk patients if contraindications against surveillance or primary chemotherapy exist [6]. Only patients with CS I pure mature teratoma should undergo primary nsrlnd because up to 20% of all teratomas will harbour occult retroperitoneal lymph node metastases at time of diagnosis [35,36]. The need for nsrplnd can be tailored by an accurate histopathologic examination of the primary testis tumor with serial sections; presence of scar tissue or microscopic germ cell tumor elements in the periphery of the tumour-bearing testis is associated with occult retroperitoneal disease, whereas the

6 530 european urology supplements 5 (2006) absence of those parameters is associated with pathologic stage I disease. These patients harbour a risk of about 20% of occult retroperitoneal lymph node metastases. Follow-up and treatment of a relapse is challenging because teratoma will be marker negative and can be cured surgically only due to their intrinsic chemotherapy refractoriness. If RPLND will be performed, a modified nsrplnd is mandatory for low-volume nodal disease because of its frequency of only 1 2% of retrograde ejaculation or anejaculation [37,38]. However, the associated short-term morbidity of nsrplnd is as high as 17%, representing the major disadvantage of primary nsrplnd [38]. Nevertheless, a recent study focusing on the impairment of quality of life induced by the different treatment options demonstrated the least impairment for either laparoscopic or open nsrplnd, whereas the negative impact was highest for surveillance and chemotherapy [39]. About 8% of all pathologic CS I NSGCTs will relapse in the lung or mediastinum during follow-up after RPLND, necessitating polychemotherapy. In a recent paper, however, it was shown that the pulmonary relapse will be only 3% in patients who have non EC-predominant disease compared to a 21% relapse rate in patients with EC-predominant testis cancer [40]. In a similar retrospective analysis, Hermans et al. [41] found that only about 23% of all clinical stage I/pathologic stage II patients relapsed after RPLND alone; tumours demonstrating predominantly EC and VI had a systemic recurrence rate of about 36%. Stephenson et al. [34] retrospectively analysed the therapeutic efficacy of primary nsrplnd in a cohort of 196 CS I, high-risk NSGCTs; 129 (66%) and 67 (33%) patients had pathologically confirmed pathologic stage I and II disease, respectively. Interestingly, a total of 16% of all positive lymph nodes harboured mature teratoma as the only histologic component. Postoperatively, only 22% of patients with pn1 disease were treated by adjuvant chemotherapy, whereas the others underwent close surveillance. In the absence of adjuvant chemotherapy, the 5-yr progression-free survival rate was 87%; the 5-yr progression-free survival rate was 90% and 86% for pathologic stage I and pn1 disease, respectively. The low systemic 5-yr relapse rates of 10% and 14% in pathologic stage I and IIA disease demonstrate that the risk of systemic metastases might have been overestimated in earlier series. In patients with pathologic stage I and pn1 disease the authors did not find a significant correlation between relapse rate and the presence of VI or EC in the primary testis tumour. Increased AFP or hcg serum levels after orchiectomy remain the only reliable predictors for systemic disease in patients with low-stage NSGCTs with the need for primary chemotherapy. Considering all patients with either pathologic stage I or IIA disease, about 89% can be cured by nsrplnd alone without administering primary chemotherapy. Because none of the patients treated by nsrplnd showed a relapse in the retroperitoneum, the authors advocate primary chemotherapy in ECpredominant disease and favour nsrplnd or surveillance in non EC-predominant disease. To reduce the frequency of surgery-related complications, laparoscopic RPLND was introduced in some centres [42]. Whereas the frequency of complications appears to be lower than for open nsrplnd (7.9%) and the preservation of antegrade ejaculation is equivalent for laparoscopic RPLND (8%), the mean surgical time of 294 min is still somewhat longer than for open surgery. Time to convalescence and quality of life, however, are somewhat shorter and better, respectively, for laparoscopic RPLND. However, despite its promise laparoscopic RPLND cannot be recommended for widespread and uncritical use because (1) the worldwide experience is still quite low with fewer than 200 procedures being reported, (2) the surgical procedure described is not nerve-sparing but only modified so that rates of antegrade ejaculation can be expected to be lower as compared to series of open nsrplnd, and (3) laparoscopic RPLND is a diagnostic procedure only with basically all patients demonstrating microscopic lymph node disease having received adjuvant chemotherapy. nsrplnd for clinical stage NSGCTs can be curative in patients with fewer than three metastatic lymph nodes measuring <2 cm in diameter and demonstrating no extranodal extension [43]. Presence of these negative predictors is associated with a relapse rate of 15%, whereas 85% remain disease free and do not need adjuvant chemotherapy. Whether laparoscopic RPLND is equivalent to open RPLND when used as therapeutic modality is not yet known and has to be proven in further studies. nsrplnd enables a risk-adapted, highly effective, and cost-saving follow up. Because local relapses are extremely rare, follow-up investigations can concentrate on the detection of pulmonary and mediastinal recurrences, and the retroperitoneum does not have to be screened by abdominal CT scans [37,38]. 8. Conclusion Despite evidence-based recommendations of the EGCCCG, management of CS I NSGCTs is still

7 european urology supplements 5 (2006) surrounded by controversy. VI and percentage of EC represent the most reliable predictors for lowvolume lymph node disease. The search for additional markers has identified PET and the presence of circulating tumour cells as potential risk factors. Surveillance, primary chemotherapy, and RPLND result in excellent treatment outcome with a 98% disease-specific survival; only treatment-related morbidities and complications are different. A subset of low-risk patients can be identified with an accuracy of 86% based on the absence of VI, <50% EC, and an MIB-1 score <70%. The advantage of surveillance has to be balanced against the disadvantage of a constant psychological threat and the need for extensive polychemotherapy in case of relapse. Primary chemotherapy consisting of two cycles BEP represents the treatment of choice in high-risk patients. However, the predictive accuracy is only as high as 60%, exposing more than one third of the young men unnecessarily to systemic chemotherapy with an unknown frequency of long-term toxicities. The diagnostic and therapeutic advantage of nsrplnd has to be balanced against the surgery-associated complications in 17% of the patients. The presence of a pure mature teratoma is in favour of nsrplnd in case the whole cancer specimen is not analysed by serial sections. Even in high-risk CS I NSGCTs nsrplnd results in a 5-yr progression-free survival rate of 89% without the need for primary chemotherapy. References [1] Power DA, Brown RSD, Brock CS, et al. Trends in testicular carcinoma in England and Wales. Br J Urol Int 2001;87: [2] Krege S, Souchon R, Schmoll HJ, for the German Testicular Cancer Study Group. Interdisciplinary Consensus on Diagnosis and Treatment of testicular germ cell tumors: result of an update conference on evidence-based medicine. 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