World J Urol (2009) 27:489492 DOI 10.

1007/s00345-009-0412-2

TOPIC PAPER

Management of post-chemotherapy extra-retroperitoneal residual masses

Brett S. Carver Joel Sheinfeld

Received: 10 February 2009 / Accepted: 26 March 2009 / Published online: 17 April 2009 Springer-Verlag 2009

Abstract Introduction Testicular cancer is the most common cancer in men age 2035 years and accounts for approximately 1% of all male malignancies. While the retroperitoneum is often the Wrst and only site of metastatic disease, approximately 40% of patients presenting with metastatic disease will have disease involving extra-retroperitoneal sites. Materials and methods A medline review was conducted to evaluate peer-reviewed articles reporting on the outcome of patients with germ cell tumors and extra-retroperitoneal metastases. Results Following chemotherapy, approximately 70% of patients will have residual masses in the retroperitoneum and several series demonstrate that approximately 50% of patients will harbor teratoma or viable GCT in the retroperitoneum. Additionally, up to 35% of patients will have radiographic evidence of extra-retroperitoneal (ERP) masses after chemotherapy. Conclusion In this manuscript, we will review the current role of surgery for patients with post-chemotherapy residual ERP metastases. Keywords resection Testicular cancer Metastasis Surgical

Introduction Testicular cancer is the most common cancer in men age 2035 years and accounts for approximately 1% of all male malignancies [1]. Following radical orchiectomy, patients are clinically staged by extent and anatomic location of disease based on CT imaging of the chest, abdomen, and pelvis according to the 1997 American Joint Committee on Cancer revised the TNM staging system for testicular cancer [2]. Clinical stage III testicular cancer refers to patients with metastases involving non-retroperitoneal sites. At the time of initial presentation, approximately 50% of men will have evidence of metastatic disease. While the retroperitoneum is often the Wrst and only site of metastatic disease, approximately 40% of patients presenting with metastatic disease will have disease involving extra-retroperitoneal (ERP) sites. Patients with cIII testicular cancer are initially treated with chemotherapy according to the IGCCCG risk criteria. The International Germ Cell Cancer Collaborative Group (IGCCCG) evaluated independent prognostic factors for predicting progression-free survival in men with GCT and stratiWed these patients into 3 risk classiWcations: good, intermediate, and poor risk disease [3]. Patients with nonpulmonary visceral metastases are classiWed as poor risk, while the presence of extra-retroperitoneal nodal and pulmonary disease are not considered to be adverse predictors. Patients with good risk disease are treated with three cycles of bleomycin, etoposide and cisplatin (BEP) or four cycles of etoposide and cisplatin (EP). Randomized clinical trials comparing three cycles of BEP to four cycles of EP have demonstrated equivalent response rates and survival in men with good risk disease. While patients with intermediate risk or poor risk disease traditionally receive four cycles of BEP, approximately 3040% of patients with poor risk

B. S. Carver J. Sheinfeld Department of Surgery, Urology Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA B. S. Carver (&) Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, 353 East 68th Street, New York, NY 10021, USA e-mail: carverb@mskcc.org

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disease fail to achieve a durable response to conventional chemotherapy [46]. Following chemotherapy, approximately 70% of patients will have residual masses in the retroperitoneum and several series demonstrate that approximately 50% of patients will harbor teratoma or viable GCT in the retroperitoneum. Additionally, up to 35% of patients will have radiographic evidence of ERP masses after chemotherapy [7]. In this manuscript, we will review the current role of surgery for patients with post-chemotherapy residual ERP metastases.

approximately 50% of patients harbor teratoma or viable germ cell tumor at these sites. Additionally, there is a signiWcant histologic discordance between RP and ERP residual sites after induction chemotherapy that ranges from 25 to 47% [8, 16, 17]. In our series, histologic discordance at the ERP residual sites when Wbrosis was seen in the RP occurred in 17% of patients (12% teratoma, 5% viable GCT) [11]. Discordance rates for teratoma and viable GCT were 58 and 53%, respectively [11]. Given this discordance, the ability to accurately predict Wbrosis at ERP sites of disease is not suYcient to preclude resection of residual disease outside the RP.

Resection of extra-retroperitoneal masses: sites of disease and histology The pattern of disease spread of metastatic NSGCT has been well documented and typically occurs in a step-wise fashion from the RP lymphatics to the mediastinum, supraclavicular nodes and chest. Additional sites of disease dissemination include, but are not limited to, the liver, bone, and brain. The presence of residual ERP disease after chemotherapy in patients with advanced NSGCT has been shown to occur in approximately one-third of men [7, 8]. In a large, multicenter international study, Fizazi and colleagues reported on the distribution of ERP residual disease after chemotherapy in patients with advanced GCT [9]. Sites of residual masses included lung (27%), mediastinum (15%), cervical nodes (4%), liver (2%), bone (1%) and brain (0.5%). The majority of patients had only one site of ERP disease resected (76%) [9]. Hartmann et al. reported on 27 patients undergoing resection of ERP residual masses [10]. The most common sites of ERP residual masses were lung (74%), liver (15%), supraclavicular (7%), and brain (4%) [10]. At Memorial Sloan-Kettering Cancer Center, we have routinely resected all sites of residual masses following chemotherapy for metastatic non-seminomatous germ cell tumor. From 1989 to 2003, a total of 130 patients underwent resection of ERP post-chemotherapy residual masses [11]. In our series, 24% of all patients studied had evidence of residual ERP disease with the most common site of ERP residual disease after chemotherapy occurring in the lung in 68%, followed by the mediastinum (29%), liver (13%), neck/supraclavicular region (12%) [11]. Similar to previous published series, 81% of patients had only one site of ERP disease resected. Following induction chemotherapy approximately 50% of patients will have Wbrosis/necrosis in the retroperitoneum, 40% of patients will have teratoma, and 10% of patients will have viable germ cell tumor [1215]. The histologic distribution of ERP residual masses following chemotherapy is similar to what is observed in the retroperitoneum with previous studies demonstrating that

Simultaneous and staged resection of retroperitoneal and extra-retroperitoneal residual masses Patients with retroperitoneal and extra-retroperitoneal residual masses undergoing surgical resection require pre-surgical planning between surgical specialties and the decision to proceed with simultaneous or staged surgical resections is made on an individual basis. Brenner and colleagues demonstrated that simultaneous resection of retroperitoneal, thoracic, and supraclavicular residual masses was a feasible and a safe alternative to multiple staged procedures in carefully selected cases [16]. Indiana University reported on 143 patients undergoing simultaneous resection of retroperitoneal and thoracic residual masses following chemotherapy [18]. Overall, 35% of patients had perioperative complications, which was signiWcantly higher compared to patients undergoing a post-chemotherapy RPLND alone. However, no single major or minor complication was signiWcantly higher in patients undergoing concomitant surgical resections. These studies demonstrate that it is feasible to perform simultaneous surgical resection of multiple sites of disease in carefully selected patients. However, the combined procedures must be technically feasible with acceptable morbidity, blood loss, and performed under reasonable time constraints, otherwise a staged approach should be used.

Post-surgical management of patients with viable non-seminomatous germ cell tumor Following complete surgical resection of extra-retroperitoneal masses, the histologic Wndings guide further treatment recommendations. Patients with the histologic Wnding of Wbrosis or teratoma do not require additional systemic therapy and are followed with careful surveillance. However, select patients with residual viable germ cell tumor may be treated with additional chemotherapy. For patients with viable germ cell tumor who underwent a complete surgical

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resection following induction (Wrst-line) chemotherapy, an additional 2-cycles of cisplatin-based chemotherapy (adjuvant chemotherapy) has been the standard of care. This recommendation is based on previous studies evaluating the outcome of patients following post-chemotherapy RPLND who were found to harbor viable germ cell tumor in the retroperitoneum. Fox et al. [19] demonstrated that 70% of patients remained disease-free following an additional 2-cycles of adjuvant chemotherapy following post-chemotherapy complete surgical resection of viable disease, whereas no patients in whom surveillance was employed remained free of disease. This study concluded that two additional courses of chemotherapy signiWcantly reduced the risk of relapse for patients following complete surgical resection of viable germ cell tumor after induction chemotherapy. Additional adjuvant chemotherapy did not demonstrate beneWt for patients in whom second-line or salvage chemotherapy was administered prior to surgical resection of viable disease. Thus, for patients with residual viable germ cell tumor completely resected following induction chemotherapy, adjuvant chemotherapy is recommended, while patients previously treated with second-line chemotherapy are recommended to undergo careful surveillance. Patients with incompletely resected residual viable disease or persistently elevated serum tumor markers should be managed with appropriate systemic chemotherapy protocols.

25% of patients who have teratoma and viable GCT, respectively [8]. After resection of residual mediastinal disease, Kessler and colleagues found that in addition to an elevated preoperative -hCG, the pathologic Wnding of teratoma or viable GCT was an independent predictor of poorer disease-speciWc survival on multivariable analysis (P = 0.006) [20]. Similar Wndings were seen in patients that have non-pulmonary visceral residual masses resected after chemotherapy. Hahn and colleagues reported 89 and 29% of patients undergoing hepatic resection were alive at a median follow-up of 47 months when Wbrosis and viable GCT were identiWed on pathologic review [21].

Conclusion Following chemotherapy, approximately 35% of patients will have radiographic evidence of ERP masses after chemotherapy. Complete surgical resection of all residual ERP masses is indicated as approximately 50% of patients will harbor teratoma or viable GCT at these sites and the histologic discordance between the retroperitoneal and ERP sites is approximately 30%.
ConXict of interest statement There is no conXict of interest.

References Clinical outcome following resection of extra-retroperitoneal masses The successful multidisciplinary approach for the management of germ cell tumor has resulted in survival rates of greater than 90% overall. This paradigm is critical for the management of metastatic germ cell tumor where IGCCCG risk appropriate chemotherapy and surgical resection of all sites of residual disease optimizes clinical outcome. In our series, the 5-year probability of freedom from disease progression for patients with the histologic Wnding of Wbrosis, teratoma, or viable GCT at the ERP site was 92% (95% CI 98, 86%), 53% (95% CI 72, 34%), and 8% (95% CI, 21, 0%), respectively [11]. These outcomes are markedly inferior to what we have observed in patients with residual disease conWned to the retroperitoneum, where the 5-year probability of freedom from disease progression for teratoma or viable GCT is 85 and 68%, respectively. Previous studies have shown a more adverse histology (viable GCT vs. teratoma vs. Wbrosis) after chemotherapy in ERP sites of residual disease was a signiWcant predictor of disease progression and death [8, 20]. In patients undergoing resection of thoracic residual masses after chemotherapy, 24-month disease-free survival was 96% in 50 men found to have Wbrosis at thoracotomy compared to 82 and
1. American Cancer Society (2008) Cancer facts and Wgures 2. Fleming I (ed) (1998) AJCC Cancer staging handbook. LippincottRaven, Philidelphia 3. IGCCCG (1997) International germ cell consensus classiWcation: a prognostic factor-based staging system for metastatic germ cell cancers. J Clin Oncol 15:594603 4. Nichols CR, Williams SD, Loehrer PJ et al (1991) Randomized study of cisplatin dose intensity in poor-risk germ cell tumors: a Southeastern Cancer Study Group and Southwest Oncology Group protocol. J Clin Oncol 9:11631172 5. Ozols RF, Ihde DC, Linehan WM et al (1988) A randomized trial of standard chemotherapy v a high-dose chemotherapy regimen in the treatment of poor prognosis nonseminomatous germ-cell tumors. J Clin Oncol 6:10311040 6. Kaye SB, Mead GM, Fossa S et al (1998) Intensive inductionsequential chemotherapy with BOP/VIP-B compared with treatment with BEP/EP for poor-prognosis metastatic nonseminomatous germ cell tumor: a Randomized Medical Research Council/European Organization for Research and Treatment of Cancer study. J Clin Oncol 16:692701 7. Gerl A, Clemm C, Schmeller N et al (1994) Sequential resection of residual abdominal and thoracic masses after chemotherapy for metastatic non-seminomatous germ cell tumours. Br J Cancer 70:960965 8. McGuire MS, Rabbani F, Mohseni H et al (2003) The role of thoracotomy in managing postchemotherapy residual thoracic masses in patients with nonseminomatous germ cell tumours. BJU Int 91:469473. doi:10.1046/j.1464-410X.2003.04128.x 9. Fizazi K, Tjulandin S, Salvioni R et al (2001) Viable malignant cells after primary chemotherapy for disseminated nonseminomatous

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492 germ cell tumors: prognostic factors and role of postsurgery chemotherapy-results from an international study group. J Clin Oncol 19:26472657 Hartmann JT, Candelaria M, Kuczyk MA et al (1997) Comparison of histological results from the resection of residual masses at diVerent sites after chemotherapy for metastatic non-seminomatous germ cell tumours. Eur J Cancer 33:843847. doi:10.1016/ S0959-8049(96)00517-5 Shayegan B, Carver BS, Motzer RJ et al (2006) Impact of residual extra-retroperitoneal masses in patients with advanced non-seminomatous germ cell tumor. J Urol 175:449A Toner GC, Panicek DM, Heelan RT et al (1990) Adjunctive surgery after chemotherapy for nonseminomatous germ cell tumors: recommendations for patient selection. J Clin Oncol 8:16831694 Steyerberg EW, Keizer HJ, Fossa SD et al (1995) Prediction of residual retroperitoneal mass histology after chemotherapy for metastatic nonseminomatous germ cell tumor: multivariate analysis of individual patient data from six study groups. J Clin Oncol 13:11771187 Aass N, Klepp O, Cavallin-Stahl E et al (1991) Prognostic factors in unselected patients with nonseminomatous metastatic testicular cancer: a multicenter experience. J Clin Oncol 9:818826 Fossa SD, Qvist H, Stenwig AE et al (1992) Is postchemotherapy retroperitoneal surgery necessary in patients with nonseminomatous testicular cancer and minimal residual tumor masses? J Clin Oncol 10:569573

World J Urol (2009) 27:489492 16. Brenner PC, Herr HW, Morse MJ et al (1996) Simultaneous retroperitoneal, thoracic, and cervical resection of postchemotherapy residual masses in patients with metastatic nonseminomatous germ cell tumors of the testis. J Clin Oncol 14:17651769 17. Toner GC, Panicek DM, Heelan RT et al (1990) Adjunctive surgery after chemotherapy for nonseminomatous germ cell tumors: recommendations for patient selection. J Clin Oncol 8:16831694 18. Tognini PG, Foster RS, McGraw P et al (1998) Combined postchemotherapy retroperitoneal lymph node dissection and resection of chest tumor under the same anesthetic is appropriate based on morbidity and tumor pathology. J Urol 159:18331835. doi:10.1016/S0022-5347(01)63169-0 19. Fox EP, Weathers TD, Williams SD et al (1993) Outcome analysis for patients with persistent nonteratomatous germ cell tumor in post-chemotherapy retroperitoneal lymph node dissections. J Clin Oncol 11:12941299 20. Kessler BM, Tortorella D, Altun M et al (2001) Extended peptidebased inhibitors eYciently target the proteasome and reveal overlapping speciWcities of the catalytic beta-subunits. Chem Biol 8:913929. doi:10.1016/S1074-5521(01)00069-2 21. Hahn TL, Jacobson L, Einhorn LH et al (1999) Hepatic resection of metastatic testicular carcinoma: a further update. Ann Surg Oncol 6:640644. doi:10.1007/s10434-999-0640-0

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