The role of retroperitoneal surgery in testis cancer

Critical Reviews in Oncology/Hematology 44 (2002) 71 – 80 www.elsevier.com/locate/critrevonc

The role of retroperitoneal surgery in testis cancer Hans-Ju¨rg Leisinger a,*, John P. Donohue b a

Department of Urology, Uni6ersity Hospital, CH-1011 Lausanne, Switzerland b Scottsdale, AZ, USA Accepted 22 October 2001

Contents 1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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2. Staging of testis cancer . . . . . . . . . . . . 2.1. Serum tumor markers . . . . . . . . . . 2.1.1. Human chorionic gonadotrophin 2.1.2. Alpha-fetoprotein (AFP) . . . . . 2.1.3. Lactate dehydrogenase (LDH). . 2.2. Molecular biological markers . . . . . . 2.3. Histologic parameters . . . . . . . . . . 2.4. Imaging . . . . . . . . . . . . . . . . . .

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72 72 72 72 73 73 73 73

3. Management of clinical stage I non-seminomatous germ cell tumors (NSGCT) . . . . . . . . .

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4. Treatment of stage II A/B non-seminomatous germ cell tumors. . . . . . . . . . . . . . . . . .

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5. RPLND for residual masses after chemotherapy in non-seminomatous germ cell tumors . . .

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6. RPLND for seminoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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7. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract Testis cancer is today a curable malignancy. But controversy remains about the appropriate management of patients presenting different stages. There is an increasing interest in surveillance rather than in primary retroperitoneal lymph node dissection (RPLND) for stage I non-seminomatous germ cell tumors (NSGCT). Adjuvant chemotherapy has become an efficient treatment option for high risk non-seminomatous germ cell testis cancer, however, biological and histologic risk factors of the primary tumor are not yet precisely defined. To determine the appropriate management of patients with testicular cancer, postoperative morbidity after RPLND and risk of chemotherapy-induced morbidity must be balanced. Whoever reviews the literature must take into consideration that the excellent postoperative results after RPLND depend on high volume and large experience with testis cancer. As treatment morbidity and its intensity have a major impact on testis cancer patient quality of life, the choice of management must be based on the patient’s social situation, his personal needs, and the doctor’s experience and resources. © 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Testis cancer; Surgery; Chemotherapy; Lymph node dissection

* Corresponding author. Tel.: + 41-21-314-2981; fax: + 41-21-314-2982. E-mail address: [email protected] (H.-J. Leisinger). 1040-8428/02/$ - see front matter © 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 1 0 4 0 - 8 4 2 8 ( 0 1 ) 0 0 2 0 1 - 3

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H.-J. Leisinger, J.P. Donohue / Critical Re6iews in Oncology/Hematology 44 (2002) 71–80

1. Introduction

2. Staging of testis cancer

Testis cancer is remarkable in two respects: first, by demonstrating the impact of regional lymphadenectomy on survival and secondly, because its treatment with chemotherapy has improved dramatically with cure rates near to 95%. Thus, most patients are today expected to be cured and our central interest must focus on reducing the morbidity, as well as the acute, shortor long-term toxicity of the different treatment options. In the prechemotherapy era, many series have shown that node-positive disease could be cured by retroperitoneal surgery alone. Due to the difficulty in establishing a precise preoperative staging in stage I NSGCT disease, elective primary retroperitoneal lymph node dissection (RPLND) has become the standard procedure over years in the USA and in most European countries. In the UK, lymph node irradiation was at that time the preferred treatment after orchiectomy for clinical stage I non-seminomatous germ cell testicular cancer (NSGCTC). This policy was abandoned in 1979 in favor of close surveillance with deferred chemotherapy until the diagnosis of relapse became evident. Indeed, the introduction of cisplatin-based chemotherapy [1] changed the therapeutic approach of testis cancer dramatically. Today, it is generally world-wide accepted that chemotherapy is the appropriate initial treatment for high stage disease. But, controversy remains regarding the management of early stage I and stage II testis cancer. Partly, this actual controversy is based on the performance of today’s available staging methods and finally, on the high cure rates independent of the different treatment procedures.

Serum tumor markers, molecular biological markers, histologic parameters from the primary tumor, and imaging techniques have become valuable parameters to direct the different treatment options for low stage disease (Tables 1–4).

2.1. Serum tumor markers 2.1.1. Human chorionic gonadotrophin (HCG) Human chorionic gonadotrophin (HCG) is produced by syncytiotrophoblasts of the placenta in pregnancy. Normal adults have less than 5 mlU/ml of its bioactive beta-subunit. In 40–60% of the patients with testis cancer, associated with the presence of syncytiotrophoblasts, (embryonic cell carcinoma in 80%, pure seminoma in 20%), beta-HCG levels are elevated [2]. The serum half-life for HCG is 24–36 h. With complete tumor excision, even markedly elevated serum levels return to the normal within 5–7 days [3]. Elevated beta-HCG is not specific to testicular cancer, it may also be elevated in patients with bladder, breast, lung, pancreatic, and hepatocellular cancers. 2.1.2. Alpha-fetoprotein (AFP) Alpha-fetoprotein (AFP) is a serum binding glycoprotein found primarily in the fetus. AFP is elevated in 50–70% of the testis tumors, especially in embryonic carcinomas and yolk sac carcinomas [2,3]. Its serum half-life is 5–7 days. With complete tumor excision, elevated serum levels return to the normal within 25–30 days. Pure seminomas never express elevated AFP values. As beta-HCG, AFP is not specific to testis cancer.

Table 1 TNM clinical classification T — primary tumor The extent of the primary tumor is classified after radical orchiectomy; see pT. If no radical orchiectomy has been performed, TX is used N —regional lymph nodes NX N0 N1

N2

N3 M — distant metastasis MX M0 M1 M1a M1b

Regional lymph nodes cannot be assessed No regional lymph node metastasis Metastasis with a lymph node mass 2 cm or less in greatest dimension or multiple lymph nodes, none more than 2 cm in greatest dimension Metastasis with a lymph node mass more than 2 cm but not more than 5 cm in greatest dimension, or multiple lymph nodes, any one mass more than 2 cm but not more than 5 cm in greatest dimension Metastasis with a lymph node mass more than 5 cm in greatest dimension Distant metastasis cannot be assessed No distant metastasis Distant metastasis Non-regional lymph node or pulmonary metastasis Distant metastasis other than to non-regional lymph nodes and lungs

H.-J. Leisinger, J.P. Donohue / Critical Re6iews in Oncology/Hematology 44 (2002) 71–80 Table 2 pTNM pathological classification pT —primary tumor pT0

No evidence of primary tumor (e.g. histologic scar in testis) Intratubular germ cell neoplasia (carcinoma in situ) Tumor limited to testis and epididymis without vascular/lymphatic invasion, tumor may invade tunica albuginea but not tunica vaginalis Tumor limited to testis and epididymis with vascular/lymphatic invasion, or tumor extending through tunica albuginea with involvement of tunica vaginalis Tumor invades spermatic cord with or without vascular/lymphatic invasion Tumor invades scrotum with or without vascular/lymphatic invasion

pTis pT1

pT2

pT3

pT4

pN— regional lymph nodes The pN classification is analogous to the N classification after RPLND and histologic examination

2.1.3. Lactate dehydrogenase (LDH) Lactate dehydrogenase (LDH) is a protein enzyme. Its elevation, especially its isotype 1 elevation, is noted in patients with large volume disease of all histologic types of germ cell tumors, even in pure seminoma. Since LDH levels correlate well with the tumor volume, they can be used for risk factor prognosis.

Stage Stage Stage Stage Stage Stage Stage

II IIA IIB IIC III IIIA IIIB

Stage IIIC

2.2. Molecular biological markers The three tumor markers mentioned above are routinely used and should be assessed before any treatment. There is little data on the prognostic value of expression of tumor-suppressing genes and oncogenes, with regard to their deletions, mutations, and RNA expression. DNA parameters evaluated by DNA cytometry as prognostic indicators have been reported [5]; as yet, it is not possible to predict metastatic potential by these means. p-53 Tumor-suppressing gene is actually one of the most examined genetic markers for malignant disease in humans [5]. Multiple studies show that p-53 expression, immunohistochemically determined, has no prognostic value in testicular cancer.

Among the different histologic parameters, the presence of vascular invasion has been established as one of the most important prognostic factors [6]. Several recent prospective studies have confirmed this finding [7,8]. They identified venous invasion, lymphatic invasion, presence of undifferentiated tumor, and absence of yolk sac elements, as independent factors of poor prognosis with high risk of relapse. In pure seminomas, age, size of the primary tumor, and small vessel invasion must be considered as important prognostic factors for relapse in patients with stage I seminoma treated with surveillance.

2.4. Imaging

Table 3 Stage grouping 0 I IA IB

These markers have value in both diagnosis and staging. The persistence of elevated markers after primary tumor ablation probably indicates residual metastatic disease despite negative imaging. But one must keep in mind that 20–30% of the patients with normalized markers may relapse after orchiectomy [4].

2.3. Histologic parameters

pM —distant metastasis The pM category corresponds to the M category

Stage Stage Stage Stage

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pTis pT1–4 pT1 pT2 pT3 pT4 Any pT/TX Any pT/TX Any pT/TX Any pT/TX Any pT/TX Any pT/TX Any pT/TX Any pT/TX Any pT/TX Any pT/TX Any pT/TX

N0 N0 N0 N0 N0 N0 N1–3 N1 N2 N3 Any N Any N N1–3 Any N N1–3 Any N Any N

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1, M1a M1, M1a M0 M1, M1a M0 M1, M1a M1b

Most testicular cancers spread primarily in the locoregional lymph nodes located retroperitoneally in the renal hilar area, para- and preaortic for left-sided tumors, and interaortocaval, precaval, and preaortic for right-sided tumors. Today, CT-scan is the standard examination in this regard for primary staging, as well as for follow-up examinations. The main problem is its accuracy with false-negative rates of 23–40% [9,10], depending on the size of the cut-off for nodes in the interested locoregional lymph node zone. Although chest radiograph has an equal value as chest CT-scan to find chest metastases in patients with negative abdominal CT-scans, combined CT-scan of the chest and the abdomen have become the routine imaging examination in the staging and follow-up of patients with testicular cancer.

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Table 4 Pathological staging according to the American ABC System Stage

Definition

A B1

I IA

N0 N1, N2A

B2

IIB

N2B

B3

IIC

N3

C

III

M+

Tumor confined to testis Evidence of minimal retroperitoneal lymph node metastases, detected by retroperitoneal lymph node dissection (fewer than six positive nodes); no node greater than 2 cm in diameter Evidence of moderate retroperitoneal lymph node spread (more than six positive nodes) or any node larger than 2 cm in diameter Massive retroperitoneal lymph node involvement, but without evidence of spread above the diaphragm or to solid visceral organs Metastatic tumor noted above the diaphragm or involvement of solid visceral organs, brain, or bone

3. Management of clinical stage I non-seminomatous germ cell tumors (NSGCT) The optimal treatment of clinical stage I testis cancer, and particularly the role of retroperitoneal lymph node dissection for this cancer, remains controversial. There are in principle three treatment options— surveillance and immediate administration of cisplatin-based combination chemotherapy at the time of relapse [11– 13], retroperitoneal lymphadenectomy [14] either through open or laparoscopic surgery [15,16], and primary chemotherapy for patients with high risk of relapse [17,18]. In patients with clinical stage I disease having no evidence of lymph node metastasis on preoperative staging studies and showing normalization of the tumor markers after semicastration, the relapse rate is between 27 and 35% [7,11,12,19]. Advocates of lymphadenectomy focus on the understaging of clinical/radiological studies, which is about 30% [14], but 10–17% of the patients with negative nodes develop metastasis, mostly in the thorax [20,21]. As probable risk factors of relapse, several histologic parameters have been identified —vascular or/and lymphatic invasion observed in the primary tumor, presence of embryonic carcinoma, infiltration of the tunica albuginea, absence of yolk sac elements [7,11,22,23]. If there is more or less a consensus that patients with one or more of the mentioned risk factors, and especially with embryonic carcinoma predominant disease, are bad candidates for surveillance, the debate remains open whether RPLND or primary chemotherapy should be performed. RPLND enables the urologist to determine the exact retroperitoneal staging; in the event of positive nodes, it also can have a therapeutic effect, as surgical cure with RPLND alone can be obtained in 65– 90% of the cases [24]. In order to reduce postoperative morbidity, modified templates [21,25,26], and subsequently nerve sparing techniques, have been introduced [27]. Thus, the major objection to RPLND, which was postoperative ejaculatory dysfunction, can now be avoided. Additionally, fertility of these patients can be retained [28]. While

postoperative ejaculation nearly approaches 100% after RPLND in clinical stage I disease in the Indiana series, the same results cannot be expected in centers with less experience [29,30]. The same statement can be made about the percentage of local retroperitoneal relapse after RPLND in pathological stage II disease. In the Indiana series, it is extremely rare (under 1%), while in less experienced centers a 10% relapse rate after RPLND in pathological stage II disease, 25% in the retroperitoneum, is reported [31]. Thus, careful follow-up examinations including CT-scan remain mandatory also for these patients. The review of the Indiana experience has shown that the only significant long-term morbidity is in an approximate 1% chance of developing small bowel obstruction due to adhesions [24,32]. Additionally, patients will have a permanent postoperative scar from the operative incision. Considering these minor long-term morbidities, one should wonder whether the laparoscopic approach for RPLND would bring any benefit to the patient. Some reports show that the laparoscopic procedure is a safe and accurate, minimally invasive, method for low stage testis cancer [15,16]. But because of its technical difficulty and its significant learning curve, it should be restricted to experienced centers [33]. Laparoscopic RPLND is without any doubt an appropriate staging procedure, but long-term results still have to prove its therapeutic capability. Until those with positive nodes are left untreated (i.e. no adjuvant chemotherapy), the therapeutic potential of laparoscopic RPLND per se will not be demonstrated. A ‘no treatment’ arm, similar to the cooperative study reported by Williams [34], will be required to prove any therapeutic potential of laparoscopic RPLND alone. While RPLND for clinical stage I non-seminomatous germ cell tumors provides both excellent staging and therapeutic effect, combined with a low complication and local recurrence rate, and a low long-term morbidity, one has to point out that these good results depend on the urologist’s operative experience. Thus, the argument of low morbidity, especially ejaculation disorders, must be relativized. Also, it must be emphasized that there is a 11% relapse rate after RPLND despite negative nodes

H.-J. Leisinger, J.P. Donohue / Critical Re6iews in Oncology/Hematology 44 (2002) 71–80

and that approximately 10% of the patients in the most recent series from the Indiana Center were lost to follow-up. Therefore, even with negative nodes after RPLND, lost to follow-up means uncontrolled risk to the patient. Hence, follow-up must be emphasized in every treatment program. After RPLND, 80% of the patients have negative nodes and 10% of them relapse with metastatic disease out of the retroperitoneum. Thus, 70% of all these patients [31,35] may be considered overtreated, as orchiectomy only would have been curative. At the time when efficient chemotherapy is available to cure the probably 30% of relapsed patients after orchiectomy, a surveillance policy becomes a real alternative, especially when we know that survival is not different between RPLND and a surveillance protocol. However, chemotherapy for relapse after orchiectomy under surveillance consists in a three- to four-cycle cisplatinbased protocol, where toxicity should be taken into consideration. Thus, in order to diminish chemotherapy dose-related toxicity, new therapeutic approaches have been evaluated. In patients presenting risk factors, two cycles of adjuvant chemotherapy after orchiectomy has been proposed [18,36]. Although the selection criteria of the different studies with regard to risk factors and treatment regimens are different, the cure rate obtained corresponds to the one after RPLND. Advocates of the RPLND strategy would point to the fact that depending on the definition of risk factors, a high percentage of the treated cases would never have metastatic disease and would receive chemotherapy unnecessarily. In this regard, Bo¨ hlen reports from Berne [37] that two cycles of chemotherapy have no major impact on fertility, and that sexual activity is not impaired. But late relapses have been reported with this approach [38,17,36,39]. In pooled studies, about half of the late relapses prove to be fatal. Late relapse of testis cancer is defined as a recurrence of the disease more than 2 years after the date of completion of initial successful therapy. This occurs in 2 – 5% of all patients treated for testis cancer [38]. Baniel presented a series of 35 patients who had late relapse but initially presented with clinical stage I disease [40]. His Indiana study illustrates clearly that a meticulous RPLND reduces the rate of late relapse in the retroperitoneum, and that results of chemotherapy for late relapse are poor (only 17% of patients had a complete response) despite the fact that most of the patients presented minimal or moderate extent of disease, whereas we know that patients with newly diagnosed disease have a high complete response rate up to 99%. It seems that late relapse per se represents a bad risk aggressive tumor with initial resistance to chemotherapy similar to the one found in certain chemorefractory germ cell tumor lines. The overall relapse rate for stage I testis cancer in a

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nonstratified population is about 30%. When selecting only high risk patients, the relapse risk must obviously be higher. Thus, long-term follow-up is mandatory and the results of any treatment option for high risk patients must be carefully followed and analyzed (Table 5). In summary, nerve sparing RPLND and surveillance have excellent results on survival for patients with non-seminomatous stage I testicular cancer. These patients should be informed regarding the various treatment options. Patient compliance, social and psychological status, as well as cost are factors which must be taken into consideration for the treatment decision. In European centers where patient compliance is probably easier to achieve, a surveillance policy is widely used. Based on the excellent results of the first studies on adjuvant chemotherapy in high risk patients, this treatment option should become a real alternative to RPLND if long-term follow-up indicates low morbidity and no more than 1% late relapse. Further studies focusing on the standardization of high risk factors and optimal chemotherapy regimens are needed.

4. Treatment of stage II A/B non-seminomatous germ cell tumors Clinical stage II is defined as metastatic disease limited to the retroperitoneum, confirmed by CT-scan. It also includes tumors without evidence of distant metastasis, but with persisting tumor markers after orchiectomy. The role of primary RPLND alone or with adjuvant chemotherapy (as opposed to primary chemotherapy) remains controversial. RPLND is traditionally used in the USA, where this technique has been introduced in 1919 [41]. Appropriate pathological staging of the retroperitoneum, capability of cure, easier follow-up with easier detection of relapse are arguments for this treatment option. In his Indiana University experience on 174 clinical stage B cases, Donohue reports a staging error of 23% overstaging, which means that 23% of the clinical stage II cases had negative lymph nodes [42]. The relapse rate in pathological stage B patients, who had no adjuvant chemotherapy, was 35%. Thus, RPLND only was considered in 65% as curative, and not only as a staging procedure. Since relapse occurs very rarely in the retroperitoneum (0–2%), but mostly in the lungs where it is early and easily detected, surveillance in these cases consists in lesser retroperitoneal CT-scan investigations. It is generally accepted that stage II bulky disease receives primary chemotherapy. It is reasonable to assume that the risk of progression and the results, with regard to ejaculatory disorders after node dissection, are related to the total tumor burden in the retroperitoneum. In stage IIB disease, nerve sparing dissection is more difficult because of increased technical demands.

Patient number

20

11

268

Abratt [70]

Ondrus [71]

Total

a

N/A (R: 12-60)

Median-40 (R: 7-68)

PVB×3

BEP×3

PVB, cisplatin, vinblastine, bleomycin; BEP: bleomycin, etoposide, cisplatin.

Three courses

Mean 8.5 (R: 3-14)

PVB×3 or 4 in 7 patients BEP×3 in four patients

Median-31 (R: 12-53) Mean-20.9 (R: 4-43)

Median-79 (R: 27-119)

Median-48 (R: 7-88)

BEP×2

BEP×2

Median-43 (R: 20-69)

BEP×2

Two or more of MRC risk BEP×2 factors Vascular invasion and majority of BEP×2 tumor was EC 2 courses

Presence of vascular invasion

(b) Three courses for ‘High Risk’ clinical stage I NSGCT Drianno [72] 11 One or more of: (1) vascular invasion; (2) \50% EC; (3) stage greater than pT1; (4) presence of yolk sac Madej [73] 30 One or more of: (1) vascular or lymphatic invasion; (2) involvement of epididymis or rete testis Klepp [74] 32 Vascular invasion and a normal AFP at orchiectomy Total 73

42

Pont [39]

Median-93 (R: 32-146)

Follow-up months

PVB×2 or BEP×2

Risk factors found in orchiectomy Therapya specimen

(a) Two courses for ‘High Risk’ clinical stage I NSGCT Bohlen [18] 59 One or more of: (1) pathologic stage \T1; (2) vascular invasion; (3) presence of embryonal carcinoma (EC) Oliver [17] 22 Two or more of Medical Research Council (MRC) risk factors Cullen [36] 114 Three or more of MRC risk factors

Study (reference)

Table 5 Pooled results from adjuvant therapy

N/A

Ileus in five patients neutropenia in 5 patients no loss of hearing or renal impairment No grade III or IV WHO toxicities

Difference in pre- and post-chemotherapy: sperm density and motility-none-DLCO-15% decrease Adjuvant chemotherapy compared with patients on surveillance (control): 18 AC patients and 15 control, no difference in desire or ability to father a child or sperm concentration or motility; no difference in hearing impairment or DLCO (diffusing capacity of lungs for carbon monoxide) No renal or pulmonary complications None reported

Hearing loss×1

Paralytic ileus×1, cardiac toxicity×1

Toxicities

One teratoma, cured with surgery Three relapses 0.0410 (4%) 0 deaths as yet

0

One teratoma, cured with surgery, 1 GCT, cured with surgery

Six relapses 0.0223 (2%), three deaths 0.0111 (1%)

0

0

Two relapses in 29 patients with follow-up \2 years: one with teratoma, one with EC and died of disease

One adenocarcinoma one GCT with carcinoma and died of disease

One GCT with carcinoma and died of disease

One teratoma

Relapses

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Immediate post-lymphadenectomy adjuvant chemotherapy versus observation with treatment at the time of relapse has been examined by Williams in a cooperative randomized study of 195 patients [34]. He could find no association between recurrence and any histopathological risk factor, and concluded that no subgroup could be identified, whose relapse rate was so high as to make adjuvant therapy mandatory. However, other series have supported that greater tumor burdens have higher relapse rates [43,44]. Thus, most authors recommend adjuvant chemotherapy in patients with stage IIB disease. The disadvantage of adjuvant chemotherapy is that 65% of the patients, who would have been cured by surgery only, have been unnecessarily exposed to the toxicity of chemotherapy. In 1994, Horwich presented a study from the Royal Marsden Hospital [45] on 122 patients treated with four cycles of cisplatin-based chemotherapy; lymph node dissection was only indicated in patients with a persistent mass measuring at least 1 cm. In this protocol, 68% of the patients had no node dissection. Ten patients relapsed-5 with the development of a mature teratoma cured by RPLND alone, and five with an histologically proven recurrence necessitating intensive cycled chemotherapy. As only 32% of these patients required node dissection, and as node dissection in these cases was confined to the involved nodes only, resulting in a 4% ejaculatory disorder rate, one can agree with the authors’ conclusion that primary chemotherapy achieves survival equivalent to primary lymph node dissection, but with a low incidence of long-term ejaculatory failure. Since nerve sparing lymph node dissection — demonstrating excellent results in the preservation of ejaculation in stage I and IIA disease— may not be appropriate for high tumor volume disease, primary chemotherapy may be indicated in these cases. However, its advantages in terms of preservation of ejaculation should be balanced against its toxicity and long-term morbidity. As there are two equivalent and effective treatment options for stage II non-seminomatous germ cell testis cancer, treatment decisions can be based on cost/benefit and risk/benefit considerations. Thus, the Indiana Group studied in 1995 the overall direct cost for 100 patients undergoing, respectively, RPLND or primary chemotherapy [46]. In this analysis, the overall 5-year cost for RPLND was significantly lower than the cost for primary chemotherapy. No differences had been found in terms of survival or quality of life. At the Indiana Center, patients receiving surgery were found to have an advantage also in terms of fertility, toxicity and late relapse. This study underlines that the choice of management may be judged better after discussion with the patient, taking into account alternative toxicities, resources, experience available, personal needs including fertility, and quality of life issues.

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5. RPLND for residual masses after chemotherapy in non-seminomatous germ cell tumors Persistent radiographic masses in the retroperitoneum 4–6 weeks after chemotherapy, elevated tumor markers after chemotherapy in tumors which had clinically localized retroperitoneal disease, and persistent tumors after incomplete previous RPLND are indications for surgery, including retroperitoneum, thorax, and mediastinum, as well as the retrocrural area. Residual masses may histologically correspond to necrosis or fibrosis, differentiated mature teratoma, viable germ cell cancer, or non-germ cell cancer. Aprikian and co-workers of the Memorial Sloan Kettering Group found in a series of 40 patients with residual masses, in 45% of them necrosis/fibrosis, in 42.5% teratoma, and in 12.5% viable germ cell tumors [47]. Other authors [48] confirmed this distribution of histological results. In the Indiana report on 870 patients operated for residual disease, pure teratoma was found in 52% of the cases, viable germ cell tumors in 22.6%, and necrosis/fibrosis in 25.4%. These findings differ from those of most other centers, and reflect a selection factor in referring patients with persistent and bulky disease to this Center [49]. Thus, 202 (23.2%) out of the 870 patients from the Indiana Center underwent secondary RPLND for relapse or progression after a previous RPLND, and only nine of these were treated with primary RPLND at the Indiana Center. In analyzing outcomes for relapse and survival after postchemotherapy RPLND, the finding of viable cancer had significant adverse impact by both univariate and multivariate analysis. However, resection of necrotic masses is of no therapeutic benefit for the patient. Resection of differentiated teratomas is necessary, because these masses may increase in size causing local problems, or may transform into non-germ cell cancer. There are no clearly defined risk factors predicting the histology of residual masses, although the absence of teratoma [50] in the orchiectomy specimen, the amount of shrinking during chemotherapy, and the normalization of tumor markers are indicative of necrosis rather than teratoma. Analyzing 78 patients from the Norwegian Radium Hospital Oslo in 1992, Fossa and coworkers [51] concluded that post-chemotherapy RPLND could be omitted if no teratoma had been found at orchiectomy, if tumor markers had normalized after 3 or 4 cycles of chemotherapy, and if the residual mass on CT-scan was less than 2 cm. However, controversy remains concerning the omission of postchemotherapy RPLND. Thus, Donohue [49] found in a subgroup of 414 patients with persistent positive CTscans directly referred for RPLND after primary chemotherapy, but without additional risk factors such as unresectable masses, prior incomplete postchemotherapy RPLND, and desperation or salvage

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RPLND (i.e. RPLND for patients with persistent tumor markers after chemotherapy), an overall relapse rate of 11.8%, of which 5% died of cancer. If there was cancer in the RPLND specimens, 77% of the patients had no evidence of disease. If there was no cancer in the specimens, 96.3% remain with no evidence of disease. These results can be considered as the most powerful direct evidence yet available, confirming the therapeutic value of RPLND after primary chemotherapy. Complete tumor resection for masses after primary chemotherapy is mandatory. Cure is more dependent on completeness of surgery than on any further salvage chemotherapy, as has been demonstrated in earlier reports [49,52– 54]. At the Indiana University, 37.2% of the 870 patients had full bilateral RPLND, 33.5% bilateral suprahilar RPLND, 14.3% unilateral suprahilar RPLND, and 15% modified unilateral RPLND. In 11%, nerve sparing procedures had been performed. Complete tumor resection also included associated procedures; thus, 12.2% had pulmonary resection, 8% mediastinal mass resection, 10.1% retrocural dissection, 5.8% hepatic and 5.2% gastrointestinal resections or repair [49]. Post-chemotherapy RPLND may quite often be confronted with large residual masses at the renal hilum. Nash et al. [55] from the Indiana Group report on 848 patients, where in 19% en-bloc nephrectomy had to be carried out because of contiguous involvement of the perirenal structures. Nephrectomy in these patients did not decrease the outcome of these patients. Intensive chemotherapy alters the perivascular structures, and vascular interventions may be necessary during RPLND [56]. Rarely, segments of the aorta or inferior vena cava must be removed [57–59]. If post-chemotherapy RPLND can be considered as the usual practice, most authors underline that this kind of surgery should be centralized in experienced centers, because of its medical and surgical complexity.

surgery only in case of progression [67,68], others for surveillance or irradiation of the residual mass [63,66]. Most reports, however, confirm that residual masses less than 3 cm in diameter can be observed and have a very low chance of progressing. One report suggests in masses over 3 cm in diameter, mostly well defined and distinct from the adjacent structures of the retroperitoneum, viable cancer may be present in over 55% of the cases. Such masses should be and can be removed despite local reactive changes often present [69].

7. Summary RPLND is not indicated in clinical low stage seminomas and remains an option in clinical low stage non-seminomatous germ cell tumors, where surveillance is also a common option, at least in most European centers. Decision making for any possible option is based on cost-risk benefits and depends on the patient social and psychological status, as well as on his compliance to follow-up. Histological risk factors of the orchiectomy specimen may help in decision making. RPLND is still a common option in lower volume clinical stage II non-seminomatous germ cell tumors. Postoperative morbidity after RPLND, and risk of immediate and long-term toxicity after chemotherapy must be taken into consideration, because both treatment options may achieve the same high cure rates. Post-chemotherapy RPLND is the indicated treatment for residual masses after chemotherapy for non-seminomatous germ cell tumors. Post-chemotherapy RPLND signifies complex surgery, with a high rate of complementary vascular and thoracic interventions. Best results are obtained in centers with a large experience.

Reviewers 6. RPLND for seminoma Radiotherapy after orchiectomy for testicular seminomas remains the standard treatment, even though different treatment options like e.g. single-agent carboplatin therapy or surveillance are being evaluated. RPLND is clearly not indicated in clinical low stage seminomas. However, it remains some controversy about the management of residual mass on CTscan after platin-based chemotherapy [64– 66] which is considered as the initial treatment of patients with advanced seminoma [60– 63]. Some authors are in favor of surveillance and

Prof. Dr Med. D. Hauri, Head,Urology Clinic and Poiclinic, University Hospital of Zu¨ rich, FrauenKlinikstrasse 10, 8091 Zu¨ rich. Dr Cora Sternberg, foundation Vincenzo Pansadoro, clinic Pio XI, Division of Medical Oncology, Via Aurelia 559, I-00165 rome, Italy. Prof. Urs E. Studer, Department of Urology, University of Berne, Inselspital— Anna Seiler-Haus, CH3010 Berne. Joel Sheinfeld, MD, Department of Urology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021-6007, USA.

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Biography Hans-Ju¨rg Leisinger. Professor and Chairman of the Department of Urology at the University Hospital of Lausanne, Switzerland. He obtained the Swiss Board of Surgery in 1974 and Urology in 1976 after postgraduate training in Zurich, Paris and in the United States. Special interest in uro-oncology and reconstructive surgery.