- Email: [email protected]
Retroperitoneal Lymph Node Dissection as First-Line Treatment of Node-Positive Seminoma
Original Study
Retroperitoneal Lymph Node Dissection as First-Line Treatment of Node-Positive Seminoma Brian Hu, Swar Shah, Sepehr Shojaei, Siamak Daneshmand Abstract Radiation and chemotherapy for seminoma are associated with significant long-term morbidity. We identified 4 patients with lymph node-positive seminoma who had been treated with front-line retroperitoneal lymph node dissection (RPLND). No patient had experienced disease recurrence at a mean follow-up period of > 2 years. A phase II trial is planned to evaluate the efficacy of RPLND for seminoma. Introduction: The long-term morbidity associated with treating advanced seminoma can be significant. Retroperitoneal lymph node dissection (RPLND) has established oncologic efficacy in treating germ cell tumors with minimal long-term toxicity. We describe our experience with RPLND as a front-line treatment of lymph node-positive seminoma. Materials and Methods: We reviewed our institutional review boardeapproved testicular cancer database to find the patients with pure seminoma and isolated retroperitoneal lymph node disease who had undergone primary RPLND. The clinical and pathologic variables were obtained. The follow-up data were used to determine recurrence and death. Results: Four patients with a mean age of 37 years were identified. All patients had normal tumor markers and retroperitoneal lymphadenopathy measuring 1.1, 1.5, 1.8, and 5.5 cm before RPLND. Of the 4 patients, 3 had had seminoma diagnosed at orchiectomy and 1 (with a 5.5-cm retroperitoneal lymphadenopathy and a burned out primary testicular mass) had had seminoma diagnosed at RPLND after 2 nondiagnostic retroperitoneal biopsies. All patients had undergone nerve-sparing, template, extraperitoneal RPLND and were discharged home after 3 days. An average of 3 positive lymph nodes were found. Of the 4 patients, 3 had pathologic stage IIA and 1 stage IIB disease, with no patient undergoing adjuvant therapy. At a mean follow-up period of 25 months, no patient had experienced disease recurrence, and none had died. All patients maintained antegrade ejaculation, and no long-term complications had developed. Conclusion: Our small series has demonstrated encouraging oncologic efficacy for RPLND as a primary treatment of retroperitoneal lymph node-positive seminoma. A multi-institutional phase II trial of RPLND for stage IIA seminoma is being developed. Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2015 Elsevier Inc. All rights reserved. Keywords: Morbidity, Recurrence, Retroperitoneal lymph node dissection, Seminoma, Testicular cancer
Introduction The standard treatment of seminoma-type germ cell tumors of the testis with clinically positive lymph nodes includes external beam radiotherapy (EBRT) and systemic chemotherapy (CT). These therapies are well-established, and no significant changes have been made to the treatment recommendations for decades.
Department of Urology, USC Institute of Urology, USC Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA Submitted: Dec 5, 2014; Revised: Jan 4, 2015; Accepted: Jan 16, 2015 Address for correspondence: Siamak Daneshmand, MD, Department of Urology, USC Institute of Urology, USC Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, 1441 Eastlake Avenue, Suite 7416, Los Angeles, CA 90089 E-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2015.01.002
Although EBRT and CT are effective, with a 5-year relapse-free survival rate of approximately 90%, they have also been associated with significant long-term morbidity.1,2 These morbidities can be significant, with their effects often accentuated given the long life expectancy of testicular cancer survivors. The risk of a second solid malignancy in testicular cancer survivors is twofold greater in patients treated with EBRT or CT and increases to threefold in those who undergo both treatment modalities.3 CT places patients at risk of hematologic malignancies, which typically develop within 10 years of treatment.4 The risk of long-term cardiovascular disease with these treatments is also high, with a greater relative risk of up to 2.6-fold.5 The increased incidence of cardiovascular disease and secondary malignancy has been linked to decrements in overall survival.6,7 Bleomycin-induced pulmonary injury has also been well-documented, with an incidence of 7% to 21% and approximately 1% of these patients dying as a
Clinical Genitourinary Cancer Month 2015
-1
RPLND as First-Line Treatment of Node-Positive Seminoma result.8 Finally, testicular cancer survivors are more likely to develop metabolic syndrome and neurologic, renal, and otologic toxicities.9,10 The multitude of cumulative long-term morbidities associated with treating advanced seminoma presents a challenge for treating testicular cancer—reducing morbidity without sacrificing efficacy. Alterations to current treatments have been attempted to reduce morbidity, including reducing the radiation fields or opting for single-agent CT.11,12 Reducing the radiation dosage has been shown to be safe and effective in treating seminoma.12 It is unclear, however, whether decreases in the radiation field will significantly reduce long-term morbidity. An attempt at reducing morbidity using single-agent CT has not been shown to maintain treatment efficacy, with unacceptably high recurrence rates.11 To achieve the goal of reducing morbidity, it could be necessary to expand the treatment paradigm. Retroperitoneal lymph node dissection (RLND) has known efficacy for treating germ cell tumors with clinically positive retroperitoneal lymph nodes. As a front-line treatment, RPLND has shown efficacy against stage IIA nonseminomatous germ cell tumors (NSGCTs), with excellent local control.13,14 In seminoma, RPLND can be used for residual tumor after CT.15 We examined the outcomes of 4 patients who had undergone RPLND as first-line treatment of testicular seminoma with isolated, low-volume retroperitoneal disease.
Materials and Methods
2
-
We reviewed our institutional review boardeapproved testicular cancer database, which includes all patients treated at our institution for testicular cancer. The database was queried for patients with pure seminoma who had undergone primary RPLND from 2010 to 2014 for low pathologic volume retroperitoneal disease. The patients who had received treatment other than radical orchiectomy before RPLND were excluded. The clinical and pathologic variables were obtained, including the length of hospitalization and complications. Follow-up data were used to determine recurrence or death. Patients without evidence of recurrence were censored at the last follow-up visit. All surgeries were performed using a previously described midline extraperitoneal approach.16 All patients underwent a modified template RPLND. For a right-sided testicular tumor, the limits of dissection were as follows: lateraleright ureter; medial superior to the inferior mesenteric arteryeleft ureter; medial inferior to the inferior mesenteric arteryeanterior abdominal aorta; superiorerenal vessels; and inferioreright common iliac artery just caudal to its bifurcation. For a left-sided testicular tumor, the limits of dissection were as follows: lateraleleft ureter; medial superior on inferior mesenteric arteryeanterior inferior vena cava; medial inferior to inferior mesenteric arteryeanterior abdominal aorta; superiorerenal vessels; and inferioreleft common iliac artery just caudal to its bifurcation. Nerve-sparing dissection and excision of the remnant spermatic cord was performed in all patients. The patients were seen at regular follow-up visits for a targeted history (including assessment of ejaculatory function), physical examination, and laboratory tests, including serum tumor marker measurement. Abdominal and pelvic computed tomography was typically performed every 6 months.
Clinical Genitourinary Cancer Month 2015
Results Four patients met the inclusion criteria, with a mean age of 37 6 years. All patients had normal tumor marker levels. The clinical and pathologic characteristics of the patients are listed in Table 1. The preoperative computed tomography scan of 2 patients is shown in Figure 1. Three patients had pure seminoma diagnosed at orchiectomy. One patient had 5.5-cm retroperitoneal lymphadenopathy and a burned out primary testicular mass with pure seminoma diagnosed at RPLND after 2 nondiagnostic biopsies of the retroperitoneal mass. Three patients had pathologic stage N1 disease and were classified as having stage IIA, and one had extranodal extension and was classified as stage IIB. The mean number of positive lymph nodes was 3, and the largest positive lymph node averaged 1.6 cm. Intraoperatively, the dissection planes in the retroperitoneum were consistent with those during primary RPLND for NSGCT. All patients were discharged home on postoperative day 3. One Clavien grade 1 complication of an ileus developed necessitating overnight observation and no further intervention. No patient underwent adjuvant therapy. With a mean follow-up period of 25 months, no patient experienced disease recurrence (retroperitoneal or distant) or died. All 4 patients maintained antegrade ejaculation. No long-term complications developed.
Discussion Historically, RPLND was known to be efficacious against germ cell tumors, although it resulted in significant morbidity. Despite the greater risk, surgery remained integral as a primary treatment of NSGCT in part owing to its unique therapeutic effect against teratoma, which is resistant to CT and. In seminoma, however, EBRT provided an effective alternative with considerably less morbidity. As a more attractive option for this relatively rare clinical presentation, EBRT gained acceptance for stage IIA disease and has continued to be the recommended treatment.1 However, evidence has increased regarding the long-term complications of EBRT, and, concurrently, significant improvements have occurred in the surgical technique and anesthetic care with respect to RPLND. The efficacy of RPLND has been established against germ cell tumors with retroperitoneal metastasis as a first-line treatment. In patients with stage IIA NSGCT and normal serum tumor marker levels, RPLND offers a recurrence-free survival rate of 86% to 95%.13,14 It results in excellent local control, with in-field recurrence developing in only 2% of patients.14 Theoretically, the distant recurrence rate could be lower after RPLND for seminoma, given that it has a more predictable lymphatic disease spread compared with NSGCT. Surgery provides the added benefit of sparing patients from CT, whether complete resection or downstaging to stage I disease. Downstaging from clinical stage IIA NSGCT to pathologic stage I disease will be seen in 40% of cases.13 Finally, patients who experience recurrence after RPLND will typically do well after salvage CT. Two international groups have reported the efficacy of RPLND as a primary treatment of seminoma.17,18 The first study was an institutional review from the University Hospital of Magdeburg (Magdeburg, Germany), where RPLND was used for stage I and II seminoma.17 Surgery was the preferred management at their institution until 1985. Seven patients had undergone primary RPLND
Brian Hu et al Table 1 Patient Characteristics Before RPLND
Orchiectomy Pt. Pathologic No. Findings
Primary Tumor Stage
After RPLND
Total Largest Positive Lymph Positive Serum Retroperitoneal Lymph Nodes Lymph Retroperitoneal Tumor Clinical Pathologic Nodes Removed Node Extranodal Pathologic Overall Mass (cm) MarkerLevels N Stage Findings (n) (n) (cm) Extension N Stage Stage
1
Pure seminoma
T1
1.1
Negative
N1
Pure seminoma
5
55
1.5
No
N1
IIA
2
Pure seminoma
T1
1.5
Negative
N1
Pure seminoma
2
20
0.7
No
N1
IIA
3
Pure seminoma
T2
1.8
Negative
N1
Pure seminoma
2
35
2.0
Yes
N2
IIB
4
Scar with dystrophic calcification
T0
5.5
Negative
N3
Pure seminoma
4
48
1.9
No
N1
IIA
Abbreviations: Pt. No. ¼ patient number; RPLND ¼ retroperitoneal lymph node dissection.
for stage IIA disease, and none had developed a relapse at a median follow-up period of 6.6 years. For stage I seminoma, 45 patients were treated with RPLND, and the recurrence rate was 7%. All these recurrences had developed out of the RPLND field. Of those with stage IIB/IIC disease, 11 patients underwent RPLND, and the in-field relapse rate was 55%. The recurrence rate after EBRT for the same stage of disease was 50%. These findings reinforce the current understanding that CT is preferred for patients with bulky lymphadenopathy.1 The second study was from a group in Tbilisi, Georgia.18 They evaluated primary RPLND between 1997 and 2002 for patients with high-risk stage I (n ¼ 10) and stage IIA (n ¼ 4) seminoma.18 No patient had experienced local or distant recurrence at a mean follow-up period of 4.7 years. Our series included 3 patients with stage IIA seminoma and 1 with stage IIB seminoma. In patients with low volume (< 2 cm) seminoma after orchiectomy (patients 1-3), RPLND was offered after informed consent that surgery in this setting is, although small studies have shown promise. Patient 4 had had an Azzopardi tumor (burned out testicular primary) and a large retroperitoneal mass with 2 nondiagnostic biopsies.19 Therefore, RPLND was used for both diagnostic and therapeutic purposes. The tumor was downstaged from clinical IIC to pathologic IIA, likely because the 5.5-cm mass represented several positive lymph nodes and tumor necrosis. Adjuvant CT was considered for all patients, in particular, for those with more advanced nodal disease (patients 3 and 4), given the
previously cited relapse rates in those with stage IIB/IIC disease of > 50%.17 Ultimately, these patients elected to undergo expectant treatment and were free of relapse during the follow-up period. Including our series, 14 patients in published studies have undergone primary RPLND for stage IIA seminoma with no documented recurrence. Although representing a small sample size, the data compare favorably with the recurrence rates seen after EBRT and CT (Table 2).11,12,17,18,20-27 Most studies have examined the recurrence rate after EBRT, which has been 0% to 17%. The outcomes after cisplatin-based CT, although also of smaller sample sizes, have been favorable. The studies that analyzed the outcomes after treatment of stage IIA disease did not report any recurrence. One study that grouped patients with stage IIA and IIB together reported a 9% recurrence rate after CT.25 A recent metaanalysis compared EBRT and CT and found them to represent equal options for stage IIA seminoma.28 The appeal of RPLND for this disease is that it offers a treatment with a significantly different side effect profile than that of EBRT and CT. RPLND has been used to treat germ cell tumors since the 1900s, and ample data are available on its long-term efficacy and safety.16,29-31 Surgery has not been associated with the development of cardiopulmonary disease, secondary malignancy, or metabolic syndrome. The use of RPLND to treat stage I NSGCT has been associated with a lower risk of secondary malignancy development.32 The main long-term complications of RPLND are
Figure 1 (A) A 1.1-cm Para-Aortic Lymph Node. (B) A 1.8-cm Interaortocaval Lymph Node
Clinical Genitourinary Cancer Month 2015
-3
RPLND as First-Line Treatment of Node-Positive Seminoma Table 2 Treatment Options for Stage IIA Seminoma Variable
Patients (n)
Treatment Characteristics
Follow-up (years)
Recurrence Rate (%) 0
RPLND 4 (stage IIA and IIB)
Modified template
2.1
Mezvrishvili et al,18 2006
Present study
4
Modified template
4.7
0
Warszawski et al,17 1997
7
Bilateral
6.6
0
Hallemeier et al,20 2013
24
30.7 Gy
10
17.0
Tandstad et al,21 2011
29
27 Gy
5
10.9
Detti et al,22 2009
83
30 Gy
21
9.6
Chung et al,23 2004
95
25-45 Gy
5
8.3
Classen et al,12 2003
66
30 Gy
6
4.7
18
BEP 3 or EP 4
5
0
Radiation therapy
Chemotherapy Garcia-del-Muro et al,24 2008
51
Carboplatin 3
2.3
34 (IIA and IIB)
EP 3-6
2.8
9.0
6
Unclear
5.2
0
Krege et al,11 2006 Arranz Arija et al,25 2001 Tandstad et al,21 2011
15.7
Combination therapy Pichler et al,27 2012 Patterson et al,26 2001
4
BEP 2 RPLND
5
0
30
Carboplatin þ EBRT (30-45 Gy)
5
3.0
Abbreviations: BEP ¼ bleomycin/etoposide/cisplatin; EBRT ¼ external beam radiation therapy; EP ¼ etoposide/cisplatin; RPLND ¼ retroperitoneal lymph node dissection.
ejaculatory dysfunction (2%-20%), incisional hernia (4%), bowel obstruction (2%), and ureteral obstruction (1%).30,33-35 The risk of infertility increases with RPLND.36 Compared with EBRT and CT, however, the fertility rates have been best in patients with testicular cancer who had undergone RPLND.37 Minimally invasive RPLND techniques have been shown to be feasible and might reduce the short-term morbidity of RPLND. This approach remains limited to specialized centers, although modifications to the open technique, such as the midline extraperitoneal approach, have been shown to similarly improve the short-term outcomes.16 Because it is difficult to draw conclusions from the outcomes of a small number of patients with a relatively short follow-up period (25 months), our group plans to expand on the present series by starting a multi-institutional phase II trial. We are planning a study of RPLND as a front-line treatment of testicular pure seminoma with isolated low volume retroperitoneal disease (< 2 cm). The primary endpoint will be the recurrence-free survival. If the recurrence rate is found to be equivalent to those with current treatments, it could provide patients with an attractive alternative with less long-term morbidity.
Conclusion The standard of care therapy for lymph node-positive seminoma is EBRT or CT. Our small series has demonstrated encouraging oncologic efficacy when RPLND was used as a primary treatment. A multi-institutional phase II trial of RPLND for patients with stage IIA seminoma is being developed. The outcome of that trial could alter the landscape of treating seminoma with low-volume nodal metastases.
4
-
Clinical Genitourinary Cancer Month 2015
Clinical Practice Points The treatment of advanced seminoma has not significantly
changed in decades. The long-term morbidity of EBRT and chemotherapy can be
significant. RPLND has known oncologic efficacy against germ cell tumors. Our small series has demonstrated encouraging efficacy of
RPLND to treat retroperitoneal lymph node-positive seminoma. A multicenter trial is planned to study the efficacy of RPLND for
stage IIA seminoma.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Wood L, Kollmannsberger C, Jewett M, et al. Canadian consensus guidelines for the management of testicular germ cell cancer. Can Urol Assoc J 2010; 4:e19-38. 2. Haugnes HS, Bosl GJ, Boer H, et al. Long-term and late effects of germ cell testicular cancer treatment and implications for follow-up. J Clin Oncol 2012; 30: 3752-63. 3. Travis LB, Fossa SD, Schonfeld SJ, et al. Second cancers among 40,576 testicular cancer patients: focus on long-term survivors. J Natl Cancer Inst 2005; 97:1354-65. 4. Kollmannsberger C, Beyer J, Droz JP, et al. Secondary leukemia following high cumulative doses of etoposide in patients treated for advanced germ cell tumors. J Clin Oncol 1998; 16:3386-91. 5. Huddart RA, Norman A, Shahidi M, et al. Cardiovascular disease as a long-term complication of treatment for testicular cancer. J Clin Oncol 2003; 21:1513-23. 6. Hanks GE, Peters T, Owen J. Seminoma of the testis: long-term beneficial and deleterious results of radiation. Int J Radiat Oncol Biol Phys 1992; 24:913-9. 7. Zagars GK, Ballo MT, Lee AK, Strom SS. Mortality after cure of testicular seminoma. J Clin Oncol 2004; 22:640-7. 8. O’Sullivan JM, Huddart RA, Norman AR, Nicholls J, Dearnaley DP, Horwich A. Predicting the risk of bleomycin lung toxicity in patients with germ-cell tumours. Ann Oncol 2003; 14:91-6.
Brian Hu et al 9. Fossa SD, Gilbert E, Dores GM, et al. Noncancer causes of death in survivors of testicular cancer. J Natl Cancer Inst 2007; 99:533-44. 10. Beyer J, Albers P, Altena R, et al. Maintaining success, reducing treatment burden, focusing on survivorship: highlights from the third European consensus conference on diagnosis and treatment of germ-cell cancer. Ann Oncol 2013; 24: 878-88. 11. Krege S, Boergermann C, Baschek R, et al. Single agent carboplatin for CS IIA/B testicular seminoma: a phase II study of the German Testicular Cancer Study Group (GTCSG). Ann Oncol 2006; 17:276-80. 12. Classen J, Schmidberger H, Meisner C, et al. Radiotherapy for stages IIA/B testicular seminoma: final report of a prospective multicenter clinical trial. J Clin Oncol 2003; 21:1101-6. 13. Stephenson AJ, Bosl GJ, Motzer RJ, Bajorin DF, Stasi JP, Sheinfeld J. Nonrandomized comparison of primary chemotherapy and retroperitoneal lymph node dissection for clinical stage IIA and IIB nonseminomatous germ cell testicular cancer. J Clin Oncol 2007; 25:5597-602. 14. Rabbani F, Sheinfeld J, Farivar-Mohseni H, et al. Low-volume nodal metastases detected at retroperitoneal lymphadenectomy for testicular cancer: pattern and prognostic factors for relapse. J Clin Oncol 2001; 19:2020-5. 15. Daneshmand S, Djaladat H, Nichols C. Management of residual mass in nonseminomatous germ cell tumors following chemotherapy. Ther Adv Urol 2011; 3: 163-71. 16. Kim P, Syan-Bhanvadia S, Djaladat H, et al. Midline extraperitoneal approach for retroperitoneal lymph node dissection for testicular germ cell tumor. Urology 2012; 80:941-5. 17. Warszawski N, Schmucking M. Relapses in early-stage testicular seminoma: radiation therapy versus retroperitoneal lymphadenectomy. Scand J Urol Nephrol 1997; 31:355-9. 18. Mezvrishvili Z, Managadze L. Retroperitoneal lymph node dissection for high-risk stage I and stage IIA seminoma. Int Urol Nephrol 2006; 38:615-9. 19. Azzopardi JG, Hoffbrand AV. Retrogression in testicular seminoma with viable metastases. J Clin Pathol 1965; 18:135-41. 20. Hallemeier CL, Pisansky TM, Davis BJ, Choo R. Long-term outcomes of radiotherapy for stage II testicular seminoma—the Mayo Clinic experience. Urol Oncol 2013; 31:1832-8. 21. Tandstad T, Smaaland R, Solberg A, et al. Management of seminomatous testicular cancer: a binational prospective population-based study from the Swedish Norwegian Testicular Cancer Study Group. J Clin Oncol 2011; 29:719-25. 22. Detti B, Livi L, Scoccianti S, et al. Management of stage II testicular seminoma over a period of 40 years. Urol Oncol 2009; 27:534-8. 23. Chung PW, Gospodarowicz MK, Panzarella T, et al. Stage II testicular seminoma: patterns of recurrence and outcome of treatment. Eur Urol 2004; 45:754-60.
24. Garcia-del-Muro X, Maroto P, Guma J, et al. Chemotherapy as an alternative to radiotherapy in the treatment of stage IIA and IIB testicular seminoma: a Spanish Germ Cell Cancer Group Study. J Clin Oncol 2008; 26:5416-21. 25. Arranz Arija JA, Garcia del Muro X, Guma J, et al. E400P in advanced seminoma of good prognosis according to the International Germ Cell Cancer Collaborative Group (IGCCCG) classification: the Spanish Germ Cell Cancer Group experience. Ann Oncol 2001; 12:487-91. 26. Patterson H, Norman AR, Mitra SS, et al. Combination carboplatin and radiotherapy in the management of stage II testicular seminoma: comparison with radiotherapy treatment alone. Radiother Oncol 2001; 59:5-11. 27. Pichler R, Leonhartsberger N, Stohr B, Horninger W, Steiner H. Two cycles of cisplatin-based chemotherapy for low-volume stage II seminoma: results of a retrospective, single-center case series. Chemotherapy 2012; 58:405-10. 28. Giannatempo P, Greco T, Mariani L, et al. Radiotherapy or chemotherapy for clinical stage IIA and IIB seminoma: a systematic review and meta-analysis of patient outcomes [e-pub ahead of print]. Ann Oncol http://dx.doi.org/10.1093/ annonc/mdu447, Accessed November 1, 2014. 29. Donohue JP. Evolution of retroperitoneal lymphadenectomy (RPLND) in the management of non-seminomatous testicular cancer (NSGCT). Urol Oncol 2003; 21:129-32. 30. Subramanian VS, Nguyen CT, Stephenson AJ, Klein EA. Complications of open primary and post-chemotherapy retroperitoneal lymph node dissection for testicular cancer. Urol Oncol 2010; 28:504-9. 31. Beck SD, Peterson MD, Bihrle R, Donohue JP, Foster RS. Short-term morbidity of primary retroperitoneal lymph node dissection in a contemporary group of patients. J Urol 2007; 178:504-6. 32. Chamie K, Kurzrock EA, Evans CP, et al. Secondary malignancies among nonseminomatous germ cell tumor cancer survivors. Cancer 2011; 117:4219-30. 33. Baniel J, Sella A. Complications of retroperitoneal lymph node dissection in testicular cancer: primary and post-chemotherapy. Semin Surg Oncol 1999; 17: 263-7. 34. Beck SD, Bey AL, Bihrle R, Foster RS. Ejaculatory status and fertility rates after primary retroperitoneal lymph node dissection. J Urol 2010; 184:2078-80. 35. Donohue JP, Thornhill JA, Foster RS, Rowland RG, Bihrle R. Primary retroperitoneal lymph node dissection in clinical stage A non-seminomatous germ cell testis cancer: review of the Indiana University experience 1965-1989. Br J Urol 1993; 71:326-35. 36. Daneshmand S, Djaladat H, Porter C, Nichols C. Evaluation and preservation of fertility in patients with testicular cancer. J Adolesc Young Adult Oncol 2011; 1: 25-9. 37. Brydoy M, Fossa SD, Klepp O, et al. Paternity following treatment for testicular cancer. J Natl Cancer Inst 2005; 97:1580-8.
Clinical Genitourinary Cancer Month 2015
-5
Retroperitoneal Lymph Node Dissection as First-Line Treatment of Node-Positive Seminoma Brian Hu, Swar Shah, Sepehr Shojaei, Siamak Daneshmand Abstract Radiation and chemotherapy for seminoma are associated with significant long-term morbidity. We identified 4 patients with lymph node-positive seminoma who had been treated with front-line retroperitoneal lymph node dissection (RPLND). No patient had experienced disease recurrence at a mean follow-up period of > 2 years. A phase II trial is planned to evaluate the efficacy of RPLND for seminoma. Introduction: The long-term morbidity associated with treating advanced seminoma can be significant. Retroperitoneal lymph node dissection (RPLND) has established oncologic efficacy in treating germ cell tumors with minimal long-term toxicity. We describe our experience with RPLND as a front-line treatment of lymph node-positive seminoma. Materials and Methods: We reviewed our institutional review boardeapproved testicular cancer database to find the patients with pure seminoma and isolated retroperitoneal lymph node disease who had undergone primary RPLND. The clinical and pathologic variables were obtained. The follow-up data were used to determine recurrence and death. Results: Four patients with a mean age of 37 years were identified. All patients had normal tumor markers and retroperitoneal lymphadenopathy measuring 1.1, 1.5, 1.8, and 5.5 cm before RPLND. Of the 4 patients, 3 had had seminoma diagnosed at orchiectomy and 1 (with a 5.5-cm retroperitoneal lymphadenopathy and a burned out primary testicular mass) had had seminoma diagnosed at RPLND after 2 nondiagnostic retroperitoneal biopsies. All patients had undergone nerve-sparing, template, extraperitoneal RPLND and were discharged home after 3 days. An average of 3 positive lymph nodes were found. Of the 4 patients, 3 had pathologic stage IIA and 1 stage IIB disease, with no patient undergoing adjuvant therapy. At a mean follow-up period of 25 months, no patient had experienced disease recurrence, and none had died. All patients maintained antegrade ejaculation, and no long-term complications had developed. Conclusion: Our small series has demonstrated encouraging oncologic efficacy for RPLND as a primary treatment of retroperitoneal lymph node-positive seminoma. A multi-institutional phase II trial of RPLND for stage IIA seminoma is being developed. Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2015 Elsevier Inc. All rights reserved. Keywords: Morbidity, Recurrence, Retroperitoneal lymph node dissection, Seminoma, Testicular cancer
Introduction The standard treatment of seminoma-type germ cell tumors of the testis with clinically positive lymph nodes includes external beam radiotherapy (EBRT) and systemic chemotherapy (CT). These therapies are well-established, and no significant changes have been made to the treatment recommendations for decades.
Department of Urology, USC Institute of Urology, USC Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA Submitted: Dec 5, 2014; Revised: Jan 4, 2015; Accepted: Jan 16, 2015 Address for correspondence: Siamak Daneshmand, MD, Department of Urology, USC Institute of Urology, USC Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, 1441 Eastlake Avenue, Suite 7416, Los Angeles, CA 90089 E-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2015.01.002
Although EBRT and CT are effective, with a 5-year relapse-free survival rate of approximately 90%, they have also been associated with significant long-term morbidity.1,2 These morbidities can be significant, with their effects often accentuated given the long life expectancy of testicular cancer survivors. The risk of a second solid malignancy in testicular cancer survivors is twofold greater in patients treated with EBRT or CT and increases to threefold in those who undergo both treatment modalities.3 CT places patients at risk of hematologic malignancies, which typically develop within 10 years of treatment.4 The risk of long-term cardiovascular disease with these treatments is also high, with a greater relative risk of up to 2.6-fold.5 The increased incidence of cardiovascular disease and secondary malignancy has been linked to decrements in overall survival.6,7 Bleomycin-induced pulmonary injury has also been well-documented, with an incidence of 7% to 21% and approximately 1% of these patients dying as a
Clinical Genitourinary Cancer Month 2015
-1
RPLND as First-Line Treatment of Node-Positive Seminoma result.8 Finally, testicular cancer survivors are more likely to develop metabolic syndrome and neurologic, renal, and otologic toxicities.9,10 The multitude of cumulative long-term morbidities associated with treating advanced seminoma presents a challenge for treating testicular cancer—reducing morbidity without sacrificing efficacy. Alterations to current treatments have been attempted to reduce morbidity, including reducing the radiation fields or opting for single-agent CT.11,12 Reducing the radiation dosage has been shown to be safe and effective in treating seminoma.12 It is unclear, however, whether decreases in the radiation field will significantly reduce long-term morbidity. An attempt at reducing morbidity using single-agent CT has not been shown to maintain treatment efficacy, with unacceptably high recurrence rates.11 To achieve the goal of reducing morbidity, it could be necessary to expand the treatment paradigm. Retroperitoneal lymph node dissection (RLND) has known efficacy for treating germ cell tumors with clinically positive retroperitoneal lymph nodes. As a front-line treatment, RPLND has shown efficacy against stage IIA nonseminomatous germ cell tumors (NSGCTs), with excellent local control.13,14 In seminoma, RPLND can be used for residual tumor after CT.15 We examined the outcomes of 4 patients who had undergone RPLND as first-line treatment of testicular seminoma with isolated, low-volume retroperitoneal disease.
Materials and Methods
2
-
We reviewed our institutional review boardeapproved testicular cancer database, which includes all patients treated at our institution for testicular cancer. The database was queried for patients with pure seminoma who had undergone primary RPLND from 2010 to 2014 for low pathologic volume retroperitoneal disease. The patients who had received treatment other than radical orchiectomy before RPLND were excluded. The clinical and pathologic variables were obtained, including the length of hospitalization and complications. Follow-up data were used to determine recurrence or death. Patients without evidence of recurrence were censored at the last follow-up visit. All surgeries were performed using a previously described midline extraperitoneal approach.16 All patients underwent a modified template RPLND. For a right-sided testicular tumor, the limits of dissection were as follows: lateraleright ureter; medial superior to the inferior mesenteric arteryeleft ureter; medial inferior to the inferior mesenteric arteryeanterior abdominal aorta; superiorerenal vessels; and inferioreright common iliac artery just caudal to its bifurcation. For a left-sided testicular tumor, the limits of dissection were as follows: lateraleleft ureter; medial superior on inferior mesenteric arteryeanterior inferior vena cava; medial inferior to inferior mesenteric arteryeanterior abdominal aorta; superiorerenal vessels; and inferioreleft common iliac artery just caudal to its bifurcation. Nerve-sparing dissection and excision of the remnant spermatic cord was performed in all patients. The patients were seen at regular follow-up visits for a targeted history (including assessment of ejaculatory function), physical examination, and laboratory tests, including serum tumor marker measurement. Abdominal and pelvic computed tomography was typically performed every 6 months.
Clinical Genitourinary Cancer Month 2015
Results Four patients met the inclusion criteria, with a mean age of 37 6 years. All patients had normal tumor marker levels. The clinical and pathologic characteristics of the patients are listed in Table 1. The preoperative computed tomography scan of 2 patients is shown in Figure 1. Three patients had pure seminoma diagnosed at orchiectomy. One patient had 5.5-cm retroperitoneal lymphadenopathy and a burned out primary testicular mass with pure seminoma diagnosed at RPLND after 2 nondiagnostic biopsies of the retroperitoneal mass. Three patients had pathologic stage N1 disease and were classified as having stage IIA, and one had extranodal extension and was classified as stage IIB. The mean number of positive lymph nodes was 3, and the largest positive lymph node averaged 1.6 cm. Intraoperatively, the dissection planes in the retroperitoneum were consistent with those during primary RPLND for NSGCT. All patients were discharged home on postoperative day 3. One Clavien grade 1 complication of an ileus developed necessitating overnight observation and no further intervention. No patient underwent adjuvant therapy. With a mean follow-up period of 25 months, no patient experienced disease recurrence (retroperitoneal or distant) or died. All 4 patients maintained antegrade ejaculation. No long-term complications developed.
Discussion Historically, RPLND was known to be efficacious against germ cell tumors, although it resulted in significant morbidity. Despite the greater risk, surgery remained integral as a primary treatment of NSGCT in part owing to its unique therapeutic effect against teratoma, which is resistant to CT and. In seminoma, however, EBRT provided an effective alternative with considerably less morbidity. As a more attractive option for this relatively rare clinical presentation, EBRT gained acceptance for stage IIA disease and has continued to be the recommended treatment.1 However, evidence has increased regarding the long-term complications of EBRT, and, concurrently, significant improvements have occurred in the surgical technique and anesthetic care with respect to RPLND. The efficacy of RPLND has been established against germ cell tumors with retroperitoneal metastasis as a first-line treatment. In patients with stage IIA NSGCT and normal serum tumor marker levels, RPLND offers a recurrence-free survival rate of 86% to 95%.13,14 It results in excellent local control, with in-field recurrence developing in only 2% of patients.14 Theoretically, the distant recurrence rate could be lower after RPLND for seminoma, given that it has a more predictable lymphatic disease spread compared with NSGCT. Surgery provides the added benefit of sparing patients from CT, whether complete resection or downstaging to stage I disease. Downstaging from clinical stage IIA NSGCT to pathologic stage I disease will be seen in 40% of cases.13 Finally, patients who experience recurrence after RPLND will typically do well after salvage CT. Two international groups have reported the efficacy of RPLND as a primary treatment of seminoma.17,18 The first study was an institutional review from the University Hospital of Magdeburg (Magdeburg, Germany), where RPLND was used for stage I and II seminoma.17 Surgery was the preferred management at their institution until 1985. Seven patients had undergone primary RPLND
Brian Hu et al Table 1 Patient Characteristics Before RPLND
Orchiectomy Pt. Pathologic No. Findings
Primary Tumor Stage
After RPLND
Total Largest Positive Lymph Positive Serum Retroperitoneal Lymph Nodes Lymph Retroperitoneal Tumor Clinical Pathologic Nodes Removed Node Extranodal Pathologic Overall Mass (cm) MarkerLevels N Stage Findings (n) (n) (cm) Extension N Stage Stage
1
Pure seminoma
T1
1.1
Negative
N1
Pure seminoma
5
55
1.5
No
N1
IIA
2
Pure seminoma
T1
1.5
Negative
N1
Pure seminoma
2
20
0.7
No
N1
IIA
3
Pure seminoma
T2
1.8
Negative
N1
Pure seminoma
2
35
2.0
Yes
N2
IIB
4
Scar with dystrophic calcification
T0
5.5
Negative
N3
Pure seminoma
4
48
1.9
No
N1
IIA
Abbreviations: Pt. No. ¼ patient number; RPLND ¼ retroperitoneal lymph node dissection.
for stage IIA disease, and none had developed a relapse at a median follow-up period of 6.6 years. For stage I seminoma, 45 patients were treated with RPLND, and the recurrence rate was 7%. All these recurrences had developed out of the RPLND field. Of those with stage IIB/IIC disease, 11 patients underwent RPLND, and the in-field relapse rate was 55%. The recurrence rate after EBRT for the same stage of disease was 50%. These findings reinforce the current understanding that CT is preferred for patients with bulky lymphadenopathy.1 The second study was from a group in Tbilisi, Georgia.18 They evaluated primary RPLND between 1997 and 2002 for patients with high-risk stage I (n ¼ 10) and stage IIA (n ¼ 4) seminoma.18 No patient had experienced local or distant recurrence at a mean follow-up period of 4.7 years. Our series included 3 patients with stage IIA seminoma and 1 with stage IIB seminoma. In patients with low volume (< 2 cm) seminoma after orchiectomy (patients 1-3), RPLND was offered after informed consent that surgery in this setting is, although small studies have shown promise. Patient 4 had had an Azzopardi tumor (burned out testicular primary) and a large retroperitoneal mass with 2 nondiagnostic biopsies.19 Therefore, RPLND was used for both diagnostic and therapeutic purposes. The tumor was downstaged from clinical IIC to pathologic IIA, likely because the 5.5-cm mass represented several positive lymph nodes and tumor necrosis. Adjuvant CT was considered for all patients, in particular, for those with more advanced nodal disease (patients 3 and 4), given the
previously cited relapse rates in those with stage IIB/IIC disease of > 50%.17 Ultimately, these patients elected to undergo expectant treatment and were free of relapse during the follow-up period. Including our series, 14 patients in published studies have undergone primary RPLND for stage IIA seminoma with no documented recurrence. Although representing a small sample size, the data compare favorably with the recurrence rates seen after EBRT and CT (Table 2).11,12,17,18,20-27 Most studies have examined the recurrence rate after EBRT, which has been 0% to 17%. The outcomes after cisplatin-based CT, although also of smaller sample sizes, have been favorable. The studies that analyzed the outcomes after treatment of stage IIA disease did not report any recurrence. One study that grouped patients with stage IIA and IIB together reported a 9% recurrence rate after CT.25 A recent metaanalysis compared EBRT and CT and found them to represent equal options for stage IIA seminoma.28 The appeal of RPLND for this disease is that it offers a treatment with a significantly different side effect profile than that of EBRT and CT. RPLND has been used to treat germ cell tumors since the 1900s, and ample data are available on its long-term efficacy and safety.16,29-31 Surgery has not been associated with the development of cardiopulmonary disease, secondary malignancy, or metabolic syndrome. The use of RPLND to treat stage I NSGCT has been associated with a lower risk of secondary malignancy development.32 The main long-term complications of RPLND are
Figure 1 (A) A 1.1-cm Para-Aortic Lymph Node. (B) A 1.8-cm Interaortocaval Lymph Node
Clinical Genitourinary Cancer Month 2015
-3
RPLND as First-Line Treatment of Node-Positive Seminoma Table 2 Treatment Options for Stage IIA Seminoma Variable
Patients (n)
Treatment Characteristics
Follow-up (years)
Recurrence Rate (%) 0
RPLND 4 (stage IIA and IIB)
Modified template
2.1
Mezvrishvili et al,18 2006
Present study
4
Modified template
4.7
0
Warszawski et al,17 1997
7
Bilateral
6.6
0
Hallemeier et al,20 2013
24
30.7 Gy
10
17.0
Tandstad et al,21 2011
29
27 Gy
5
10.9
Detti et al,22 2009
83
30 Gy
21
9.6
Chung et al,23 2004
95
25-45 Gy
5
8.3
Classen et al,12 2003
66
30 Gy
6
4.7
18
BEP 3 or EP 4
5
0
Radiation therapy
Chemotherapy Garcia-del-Muro et al,24 2008
51
Carboplatin 3
2.3
34 (IIA and IIB)
EP 3-6
2.8
9.0
6
Unclear
5.2
0
Krege et al,11 2006 Arranz Arija et al,25 2001 Tandstad et al,21 2011
15.7
Combination therapy Pichler et al,27 2012 Patterson et al,26 2001
4
BEP 2 RPLND
5
0
30
Carboplatin þ EBRT (30-45 Gy)
5
3.0
Abbreviations: BEP ¼ bleomycin/etoposide/cisplatin; EBRT ¼ external beam radiation therapy; EP ¼ etoposide/cisplatin; RPLND ¼ retroperitoneal lymph node dissection.
ejaculatory dysfunction (2%-20%), incisional hernia (4%), bowel obstruction (2%), and ureteral obstruction (1%).30,33-35 The risk of infertility increases with RPLND.36 Compared with EBRT and CT, however, the fertility rates have been best in patients with testicular cancer who had undergone RPLND.37 Minimally invasive RPLND techniques have been shown to be feasible and might reduce the short-term morbidity of RPLND. This approach remains limited to specialized centers, although modifications to the open technique, such as the midline extraperitoneal approach, have been shown to similarly improve the short-term outcomes.16 Because it is difficult to draw conclusions from the outcomes of a small number of patients with a relatively short follow-up period (25 months), our group plans to expand on the present series by starting a multi-institutional phase II trial. We are planning a study of RPLND as a front-line treatment of testicular pure seminoma with isolated low volume retroperitoneal disease (< 2 cm). The primary endpoint will be the recurrence-free survival. If the recurrence rate is found to be equivalent to those with current treatments, it could provide patients with an attractive alternative with less long-term morbidity.
Conclusion The standard of care therapy for lymph node-positive seminoma is EBRT or CT. Our small series has demonstrated encouraging oncologic efficacy when RPLND was used as a primary treatment. A multi-institutional phase II trial of RPLND for patients with stage IIA seminoma is being developed. The outcome of that trial could alter the landscape of treating seminoma with low-volume nodal metastases.
4
-
Clinical Genitourinary Cancer Month 2015
Clinical Practice Points The treatment of advanced seminoma has not significantly
changed in decades. The long-term morbidity of EBRT and chemotherapy can be
significant. RPLND has known oncologic efficacy against germ cell tumors. Our small series has demonstrated encouraging efficacy of
RPLND to treat retroperitoneal lymph node-positive seminoma. A multicenter trial is planned to study the efficacy of RPLND for
stage IIA seminoma.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Wood L, Kollmannsberger C, Jewett M, et al. Canadian consensus guidelines for the management of testicular germ cell cancer. Can Urol Assoc J 2010; 4:e19-38. 2. Haugnes HS, Bosl GJ, Boer H, et al. Long-term and late effects of germ cell testicular cancer treatment and implications for follow-up. J Clin Oncol 2012; 30: 3752-63. 3. Travis LB, Fossa SD, Schonfeld SJ, et al. Second cancers among 40,576 testicular cancer patients: focus on long-term survivors. J Natl Cancer Inst 2005; 97:1354-65. 4. Kollmannsberger C, Beyer J, Droz JP, et al. Secondary leukemia following high cumulative doses of etoposide in patients treated for advanced germ cell tumors. J Clin Oncol 1998; 16:3386-91. 5. Huddart RA, Norman A, Shahidi M, et al. Cardiovascular disease as a long-term complication of treatment for testicular cancer. J Clin Oncol 2003; 21:1513-23. 6. Hanks GE, Peters T, Owen J. Seminoma of the testis: long-term beneficial and deleterious results of radiation. Int J Radiat Oncol Biol Phys 1992; 24:913-9. 7. Zagars GK, Ballo MT, Lee AK, Strom SS. Mortality after cure of testicular seminoma. J Clin Oncol 2004; 22:640-7. 8. O’Sullivan JM, Huddart RA, Norman AR, Nicholls J, Dearnaley DP, Horwich A. Predicting the risk of bleomycin lung toxicity in patients with germ-cell tumours. Ann Oncol 2003; 14:91-6.
Brian Hu et al 9. Fossa SD, Gilbert E, Dores GM, et al. Noncancer causes of death in survivors of testicular cancer. J Natl Cancer Inst 2007; 99:533-44. 10. Beyer J, Albers P, Altena R, et al. Maintaining success, reducing treatment burden, focusing on survivorship: highlights from the third European consensus conference on diagnosis and treatment of germ-cell cancer. Ann Oncol 2013; 24: 878-88. 11. Krege S, Boergermann C, Baschek R, et al. Single agent carboplatin for CS IIA/B testicular seminoma: a phase II study of the German Testicular Cancer Study Group (GTCSG). Ann Oncol 2006; 17:276-80. 12. Classen J, Schmidberger H, Meisner C, et al. Radiotherapy for stages IIA/B testicular seminoma: final report of a prospective multicenter clinical trial. J Clin Oncol 2003; 21:1101-6. 13. Stephenson AJ, Bosl GJ, Motzer RJ, Bajorin DF, Stasi JP, Sheinfeld J. Nonrandomized comparison of primary chemotherapy and retroperitoneal lymph node dissection for clinical stage IIA and IIB nonseminomatous germ cell testicular cancer. J Clin Oncol 2007; 25:5597-602. 14. Rabbani F, Sheinfeld J, Farivar-Mohseni H, et al. Low-volume nodal metastases detected at retroperitoneal lymphadenectomy for testicular cancer: pattern and prognostic factors for relapse. J Clin Oncol 2001; 19:2020-5. 15. Daneshmand S, Djaladat H, Nichols C. Management of residual mass in nonseminomatous germ cell tumors following chemotherapy. Ther Adv Urol 2011; 3: 163-71. 16. Kim P, Syan-Bhanvadia S, Djaladat H, et al. Midline extraperitoneal approach for retroperitoneal lymph node dissection for testicular germ cell tumor. Urology 2012; 80:941-5. 17. Warszawski N, Schmucking M. Relapses in early-stage testicular seminoma: radiation therapy versus retroperitoneal lymphadenectomy. Scand J Urol Nephrol 1997; 31:355-9. 18. Mezvrishvili Z, Managadze L. Retroperitoneal lymph node dissection for high-risk stage I and stage IIA seminoma. Int Urol Nephrol 2006; 38:615-9. 19. Azzopardi JG, Hoffbrand AV. Retrogression in testicular seminoma with viable metastases. J Clin Pathol 1965; 18:135-41. 20. Hallemeier CL, Pisansky TM, Davis BJ, Choo R. Long-term outcomes of radiotherapy for stage II testicular seminoma—the Mayo Clinic experience. Urol Oncol 2013; 31:1832-8. 21. Tandstad T, Smaaland R, Solberg A, et al. Management of seminomatous testicular cancer: a binational prospective population-based study from the Swedish Norwegian Testicular Cancer Study Group. J Clin Oncol 2011; 29:719-25. 22. Detti B, Livi L, Scoccianti S, et al. Management of stage II testicular seminoma over a period of 40 years. Urol Oncol 2009; 27:534-8. 23. Chung PW, Gospodarowicz MK, Panzarella T, et al. Stage II testicular seminoma: patterns of recurrence and outcome of treatment. Eur Urol 2004; 45:754-60.
24. Garcia-del-Muro X, Maroto P, Guma J, et al. Chemotherapy as an alternative to radiotherapy in the treatment of stage IIA and IIB testicular seminoma: a Spanish Germ Cell Cancer Group Study. J Clin Oncol 2008; 26:5416-21. 25. Arranz Arija JA, Garcia del Muro X, Guma J, et al. E400P in advanced seminoma of good prognosis according to the International Germ Cell Cancer Collaborative Group (IGCCCG) classification: the Spanish Germ Cell Cancer Group experience. Ann Oncol 2001; 12:487-91. 26. Patterson H, Norman AR, Mitra SS, et al. Combination carboplatin and radiotherapy in the management of stage II testicular seminoma: comparison with radiotherapy treatment alone. Radiother Oncol 2001; 59:5-11. 27. Pichler R, Leonhartsberger N, Stohr B, Horninger W, Steiner H. Two cycles of cisplatin-based chemotherapy for low-volume stage II seminoma: results of a retrospective, single-center case series. Chemotherapy 2012; 58:405-10. 28. Giannatempo P, Greco T, Mariani L, et al. Radiotherapy or chemotherapy for clinical stage IIA and IIB seminoma: a systematic review and meta-analysis of patient outcomes [e-pub ahead of print]. Ann Oncol http://dx.doi.org/10.1093/ annonc/mdu447, Accessed November 1, 2014. 29. Donohue JP. Evolution of retroperitoneal lymphadenectomy (RPLND) in the management of non-seminomatous testicular cancer (NSGCT). Urol Oncol 2003; 21:129-32. 30. Subramanian VS, Nguyen CT, Stephenson AJ, Klein EA. Complications of open primary and post-chemotherapy retroperitoneal lymph node dissection for testicular cancer. Urol Oncol 2010; 28:504-9. 31. Beck SD, Peterson MD, Bihrle R, Donohue JP, Foster RS. Short-term morbidity of primary retroperitoneal lymph node dissection in a contemporary group of patients. J Urol 2007; 178:504-6. 32. Chamie K, Kurzrock EA, Evans CP, et al. Secondary malignancies among nonseminomatous germ cell tumor cancer survivors. Cancer 2011; 117:4219-30. 33. Baniel J, Sella A. Complications of retroperitoneal lymph node dissection in testicular cancer: primary and post-chemotherapy. Semin Surg Oncol 1999; 17: 263-7. 34. Beck SD, Bey AL, Bihrle R, Foster RS. Ejaculatory status and fertility rates after primary retroperitoneal lymph node dissection. J Urol 2010; 184:2078-80. 35. Donohue JP, Thornhill JA, Foster RS, Rowland RG, Bihrle R. Primary retroperitoneal lymph node dissection in clinical stage A non-seminomatous germ cell testis cancer: review of the Indiana University experience 1965-1989. Br J Urol 1993; 71:326-35. 36. Daneshmand S, Djaladat H, Porter C, Nichols C. Evaluation and preservation of fertility in patients with testicular cancer. J Adolesc Young Adult Oncol 2011; 1: 25-9. 37. Brydoy M, Fossa SD, Klepp O, et al. Paternity following treatment for testicular cancer. J Natl Cancer Inst 2005; 97:1580-8.
Clinical Genitourinary Cancer Month 2015
-5