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Retroperitoneal Lymph Node Dissection as Primary Treatment for Men With Testicular Seminoma: Utilization and Survival Analysis Using the National Cancer Data Base, 2004-2014
Original Study
Retroperitoneal Lymph Node Dissection as Primary Treatment for Men With Testicular Seminoma: Utilization and Survival Analysis Using the National Cancer Data Base, 2004-2014 Alexandra L. Tabakin,1 Brian M. Shinder,1 Sinae Kim,2 Zorimar Rivera-Nunez,3 Charles F. Polotti,1 Parth K. Modi,6 Joshua A. Sterling,1 Nicholas J. Farber,1 Kushan D. Radadia,1 Rahul R. Parikh,3 Isaac Y. Kim,1,4 Biren Saraiya,5 Tina M. Mayer,5 Eric A. Singer,1,4 Thomas L. Jang1,4 Abstract The role of retroperitoneal lymph node dissection (RPLND) as first-line treatment for stage I or IIA/B testicular seminoma is not well defined. Using the National Cancer Data Base, we identified 365 men from 2004 to 2014 who received RPLND as primary treatment for testicular seminoma and found 5-year overall survival rates of 97.3% and 92.0% for those with stage I and IIA/B disease, respectively. Background: The role of retroperitoneal lymph node dissection (RPLND) as first-line treatment for testicular seminoma is less well defined than for testicular nonseminomatous germ-cell tumors. We describe utilization of primary RPLND in the United States and report on overall survival (OS) after surgery for these men. Patients and Methods: Using 2004-2014 data from the National Cancer Data Base, we identified 62,727 men with primary testicular cancer, 31,068 of whom were diagnosed as having seminoma. After excluding men with benign, nonegerm cell, and nonseminomatous germ-cell tumor histologies, those who did not undergo RPLND, those where clinical stage and survival data were unavailable, and those with testicular seminoma who underwent RPLND in the postchemotherapy setting (n ¼ 47), 365 men comprised our final cohort. Descriptive statistics were used to summarize clinical and demographic factors. The Kaplan-Meier method was used to determine OS. Results: A total of 365 men with testicular seminoma underwent primary RPLND. At a median follow-up of 4.1 years, there were 16 deaths in the entire cohort. Five-year OS was 94.2%. Subset analysis of men with stage I and IIA/B disease who underwent primary RPLND revealed 5year OS rates of 97.3% and 92.0%, respectively (P ¼ .035). OS did not significantly differ in patients with stage IIA versus IIB disease (91.8% vs. 92.3%, respectively, P ¼ .907). Conclusion: Although RPLND is rarely used as primary therapy in testicular seminoma, OS rates appear to be comparable to rates reported in the literature for primary chemotherapy or radiotherapy. Ongoing prospective trials will clarify the role of RPLND in the management of testicular seminoma. Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2019 Elsevier Inc. All rights reserved. Keywords: Outcomes, Overall survival, RPLND, Surgery, Testicular cancer
Introduction Men with testicular seminoma and radiographic evidence of lowvolume retroperitoneal lymph node (LN) disease are traditionally 1 Division of Urology, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 2 Department of Biostatistics and Epidemiology 3 Department of Radiation Oncology 4 Section of Urologic Oncology 5 Division of Medical Oncology, Department of Medicine, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 6 Department of Urology, University of Michigan, Ann Arbor, MI
1558-7673/$ - see frontmatter ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.clgc.2019.10.018
treated with external-beam radiotherapy or primary systemic chemotherapy.1,2 Although these therapies are highly effective and result in 5-year recurrence-free survival and 5-year overall survival Submitted: Aug 3, 2019; Revised: Oct 7, 2019; Accepted: Oct 28, 2019 Address for correspondence: Thomas L. Jang, MD, MPH, FACS, Urologic Oncology Program, Division of Urology, Rutgers Cancer Institute of New Jersey, 195 Little Albany St, Suite 4560, New Brunswick, NJ 08901 Fax: (732) 235-6596; E-mail contact: [email protected]
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Retroperitoneal LN Dissection (OS) rates exceeding 90%, they can be associated with significant long-term morbidity.3-7 More specifically, patients receiving these treatments are at an increased risk of developing a secondary solid or hematologic malignancy, cardiovascular disease, bleomycin-induced pulmonary toxicity, metabolic syndrome, and toxicity to the kidneys or to the neurologic or otologic systems.8-16 Retroperitoneal LN dissection (RPLND) as first-line treatment for men with testicular nonseminomatous germ-cell tumors (NSGCT) is well established. RPLND in this setting has demonstrated excellent oncologic outcomes with minimal long-term morbidities.17-20 Historically, RPLND for patients with seminoma has been reserved for select patients in the postchemotherapy (PC) setting with normal serum tumor markers and a residual mass that is greater than 3 cm and exhibits uptake of 18fluorodeoxyglucose on imaging by positron emission tomography/ computed tomography.1 Several groups have evaluated and reported on RPLND as a primary treatment for testicular seminoma. A review summarizing RPLND as primary treatment for metastatic seminoma reported on outcomes of a total of 92 patients with stage I-IIC seminoma in 4 published series, and reported the recurrence rate to be 14%, with recurrence rates after RPLND highest for those with higher-stage disease.21 Currently, two prospective trials, the SEMS trial22 and the PRIMETEST trial,23 are underway to formally evaluate the efficacy of surgery in this setting. Given the limited data on the use of and outcomes after RPLND for men with testicular seminoma, we analyzed its utilization in the primary setting for men in the United States diagnosed with testicular seminoma and calculated the survival rates after surgery for these men.
Patients and Methods Data Source The National Cancer Data Base (NCDB) is a national hospitalbased registry sponsored by the American College of Surgeons Commission on Cancer and the American Cancer Society. Programs accredited by the American College of Surgeons Commission on Cancer report cancers diagnosed or treated in their facilities. The NCDB includes more than 1500 hospital-based programs and approximately 70% of all newly diagnosed cases of cancer in the United States.24 The database contains sociodemographic information as well as individual diagnosis and treatment information, such as American Joint Committee on Cancer (AJCC) T, N, and M stages, scope of regional LN surgery, chemotherapy receipt, and timing of systemic treatment relative to surgery.
Study Population
2
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This study was institutional review board exempt because the data set did not include any protected health information. We identified 62,727 men from 2004 to 2014 in the NCDB with primary testicular cancer, 31,068 of whom were diagnosed as having seminoma. After excluding men with benign and nonegerm-cell histology, men with NSGCT histology, those who did not undergo RPLND, and those where clinical stage (CS) and survival data were unavailable, 412 men were identified. Men were further stratified according to whether they had primary RPLND versus PC-RPLND, with primary RPLND defined as RPLND
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performed for CS IA-IIB without prior chemotherapy and PC-RPLND classified as RPLND performed for CS IIA- IIIC after chemotherapy. Those who received PC-RPLND (n ¼ 47) were excluded from the analysis. Our final analytic cohort comprised 365 men who underwent RPLND as primary treatment for CS IAIIB testicular seminoma. Descriptive statistics were used to summarize all clinical and sociodemographic factors, and the 2-sample t test (or Wilcoxon rank sum test, if necessary) was used to compare means (or medians) of the stage I versus stage IIA/B patients who received primary RPLND. Using 30-day readmission rates as a surrogate of perioperative and postoperative morbidity after RPLND, we compared readmission rates between patients undergoing RPLND for testicular seminoma versus testicular NSGCT. The Fisher exact test was used to evaluate associations between 30-day readmission rates and stage-stratified histology (seminoma vs. NSGCT). Kaplan-Meier curves were used to estimate OS. Statistical analyses were performed by SAS 9.4 (SAS Institute, Cary, NC) and were considered significant at P < .05.
Results Baseline Characteristics and Relation to Treatment From 2004 to 2014, a total of 365 men with testicular seminoma underwent RPLND; baseline sociodemographic and clinical characteristics of these men are shown in Table 1. Among those who received a primary RPLND, 41.1% (n ¼ 150), 16.4% (n ¼ 60), 18.6% (n ¼ 68), and 23.8% (n ¼ 87) had AJCC CS IA, IB, IIA, and IIB disease, respectively. When comparing men with CS I (n ¼ 250) versus CS IIA/IIB (n ¼ 155) who received a primary RPLND, there were no significant differences between the two groups with respect to age, diagnosis year, race, comorbid conditions, income, facility type, or facility location (Table 2).
Survival Analysis At a median follow-up of 4.1 years, 16 deaths occurred in the entire cohort. Five-year OS was 94.2% (Figure 1). In a subset analysis comparing men with CS I versus IIA/IIB who received primary RPLND, 5-year OS values were 97.3% and 92.0%, respectively (P ¼ .035) (Figure 2). Five-year OS did not differ significantly in patients with stage IIA versus IIB disease (91.8% vs. 92.3%, respectively, P ¼ .907).
Readmission Rates After RPLND Irrespective of CS, 30-day readmission rates after discharge from primary RPLND did not differ significantly between testicular seminoma versus testicular NSGCT patients during this same time period (5.9% vs. 7.0%, P ¼ .56) (Table 3), suggesting that recovery after primary RPLND for seminoma is not significantly different than that for NSGCT.
Discussion The role of RPLND as first-line treatment for testicular seminoma is less well defined than for testicular NSGCT. In NSGCT patients with CS I or IIA disease or with a PC residual mass, RPLND is well-established treatment, providing accurate pathologic staging information and affording therapeutic benefit.17-20
Alexandra L. Tabakin et al Table 1 Baseline Characteristics of 365 Patients Undergoing Primary Retroperitoneal Lymph Node Dissection for Testicular Seminoma Characteristic Age (y)
Age group
Diagnosis year
Pathologic tumor classification
Clinical stage
Race
Insurance
Charlson-Deyo score
Income
Education (percentage of no high school degree, 2008-2012)
Facility type
Variable
Value
Mean standard deviation Median <18 y 18-25 year 26-35 y >35 y 2004-2006 2007-2009 2010-2012 2013-2014 pT1
41.5 12.2
1 24 104 236 32 134 128 71 210
40 (0.3) (6.6) (28.5) (64.6) (8.8) (36.7) (35.1) (19.4) (57.5)
pT2 pT3 pT4 pTis pTx IA IB IIA IIB White Black Other Unknown Not insured Private Medicaid Medicare Other government Unknown 0 1 2þ <$38,000 $38,000 to $47,999 $48,000 to $62,999 $63,000þ 21%
86 25 2 1 41 150 60 68 87 326 23 10 6 41 258 33 28 4 1 333 26 6 45 82 88 146 50
(23.6) (6.8) (0.5) (0.3) (11.2) (41.1) (16.4) (18.6) (23.8) (89.3) (6.3) (2.7) (1.6) (11.2) (70.7) (9) (7.7) (1.1) (0.3) (91.2) (7.1) (1.6) (12.5) (22.7) (24.4) (40.4) (13.8)
13%-20% 7%-12.9% <7% Community cancer program Comprehensive community cancer program Academic/research program
84 120 107 36
(23.3) (33.2) (29.6) (9.9)
147 (40.3)
142 (38.9)
Table 1 Continued Characteristic
Facility location
Variable
Value
Integrated network cancer program New England Middle Atlantic South Atlantic East North Central East South Central West North Central West South Central Mountain Pacific
40 (9.7) 22 67 70 71 12 32 26 22 43
(6) (18.4) (19.2) (19.5) (3.3) (8.8) (7.1) (6) (11.8)
Data are presented as n (%) unless otherwise indicated.
According to the National Comprehensive Cancer Network (NCCN) and European Association of Urology (EAU) testicular cancer guidelines, surveillance, adjuvant chemotherapy, and adjuvant radiotherapy are appropriate treatment strategies for patients with stage I seminoma.1,2 Because the majority of patients with stage I seminoma are cured by radical orchiectomy alone, with relapse rates of 15% to 20%, surveillance is generally recommended.1,2,25 For men with radiographic evidence of low-volume early metastatic disease in the retroperitoneum (stage IIA/IIB), current clinical practice guidelines endorse radiotherapy or platinumbased chemotherapy regimens. Both therapeutic strategies are effective and result in 5-year recurrence-free survival and 5-year OS rates exceeding 90%, but significant short- and long-term toxicities may occur.1,2 The development of second primary cancers and cardiovascular disease represents potentially life-threatening late effects of treatment. Other long-term adverse toxicities include pulmonary complications, neurotoxicity, ototoxicity, nephrotoxicity, and avascular necrosis.12 The risk of a second primary solid cancer is almost 2-fold greater in testicular cancer survivors treated with radiotherapy or chemotherapy; it increases to almost 3-fold in those who received both treatments.14 Chemotherapy has also been associated with significantly increased risks of secondary leukemia among testicular cancer survivors.8,13 Long-term survivors of testicular cancer have been observed to have a significantly increased risk of developing cardiovascular disease. In a study examining 992 patients at a median follow-up of 10.2 years, Huddart et al15 reported cardiovascular events in 6.8% of patients, 18 of whom developed sudden or cardiac deaths. After adjusting for age, there was a statistically significant 2.6-fold, 2.4fold, and 2.8-fold increased risk for cardiac events after chemotherapy, radiotherapy, or combined chemotherapy/radiotherapy, respectively. There were no significant differences in cardiac risk factors among the 3 groups. In a separate study examining 990 men treated for unilateral testicular cancer from 1980 to 1994 at a 19year median follow-up, Haugnes et al16 found using age-adjusted Cox regression analyses a 2.3-fold, 2.6-fold, and 4.8-fold increased risks of atherosclerotic disease after radiotherapy only,
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Retroperitoneal LN Dissection Table 2 Characteristics of Patients With Stage I Versus Stage IIA/B Testicular Seminoma Who Received Primary Retroperitoneal Lymph Node Dissection Variable
Stage I (N [ 210)
Stage IIA/B (N [ 155)
P
Mean standard deviation Median (min, max) 25 y 26-35 y >35 y 2004-2007 2008-2011 2012-2014 pT1 pT2 pT3 pT4 pTis pTx White Black Other/unknown 0 1þ <$38,000 $38,000 to $47,999 $48,000 to $62,999 $63,000þ 21%
41.18 12.43 40 (18-78) 18 (8.6) 59 (28.1) 133 (63.3) 32 (15.2) 110 (52.4) 68 (32.4) 150 (71.4) 50 (23.8) 8 (3.8) 2 (1) 0 0 184 (87.6) 13 (6.2) 13 (6.2) 193 (91.9) 17 (8.1) 25 (12) 53 (25.4) 52 (24.9) 79 (37.8) 30 (14.4)
41.83 11.84 42 (0-78) 7 (4.5) 45 (29) 103 (66.5) 25 (16.1) 84 (54.2) 46 (29.7) 60 (38.7) 36 (23.2) 17 (11) 0 1 (0.6) 41 (26.5) 142 (91.6) 10 (6.5) 3 (1.9) 140 (90.3) 15 (9.7) 20 (13.2) 29 (19.1) 36 (23.7) 67 (44.1) 20 (13.2)
.615 .381 .317
Characteristic Age (years) Age (group)
Diagnosis year
Pathologic tumor classification
Race
Charlson-Deyo score Income (n missing ¼ 4)
Education (percentage of no high school degree 2008-2012) (n missing ¼ 4)
Facility type
Facility location
13%-20% 7%-12.9% <7% Academic/research program Community cancer program/ comprehensive community cancer program/integrated network cancer program New England/Middle Atlantic/ South Atlantic/East North Central/East South Central West North Central/West South Central/Mountain/Pacific
57 71 51 88 122
(27.3) (34) (24.4) (41.9) (58.1)
27 49 56 54 101
(17.8) (32.2) (36.8) (34.8) (65.2)
138 (65.7)
104 (67.1)
72 (34.3)
51 (32.9)
.867
<.0001
.15
.709 .472
.043
.193
.823
Data are presented as n (%) unless otherwise indicated.
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chemotherapy only, and combined radiotherapy and chemotherapy, respectively, compared to surgery only (P ¼ .02). Treatment with bleomycin, etoposide, and cisplatin (BEP) chemotherapy alone increased the risk of coronary artery disease by 5.7-fold compared to surgery only, and increased myocardial infarction risk by 3.1-fold compared to age-matched male controls. Although many of the long-term adverse effects of BEP have been well studied, less is known about the long-term toxicities associated with single-agent carboplatin for stage I seminoma; these toxicities may be less compared to BEP. In a retrospective study examining 199 men treated with one or two doses of carboplatin for stage I seminoma, investigators found no difference in risk of secondary malignancy or cardiovascular toxicity compared to the general population after a follow-up period of over 5 years. However, the
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median follow-up in this study was only 9 years; larger studies with longer follow-up will be needed to more accurately characterize the potential long-term toxicities associated with carboplatin.26 RPLND has been well established in the management of germcell tumors since the mid-1900s, and there are long-term data to support its efficacy and safety in men with testicular NSGCT.17,18,20,27,28 In addition to its therapeutic role, RPLND provides important pathologic staging information that more accurately selects patients who may potentially benefit from further adjuvant therapies. Complication rates vary according to whether RPLND is performed in the primary versus PC setting, with complication rates ranging from 10%-24% and 20%-30% in the primary and PC settings, respectively. Intraoperative, short-term, and long-term complications can occur in up to 5%, 24%, and
Alexandra L. Tabakin et al Figure 1 Overall Survival in Men With Testicular Seminoma Who Received Primary Retroperitoneal Lymph Node Dissection
7% of patients, respectively, undergoing primary RPLND.29-31 Intraoperative complications occur infrequently, with injury to vascular or retroperitoneal structures being most common. Short-
term complications include venous thromboembolic disease (0.9%), wound infection (5%), chylous ascites (0.2%-2%), atelectasis and/or pneumonia (0.2%-3.6%), and ileus (2.1%-17.9%).29-31
Figure 2 Overall Survival in Men With Testicular Seminoma Who Received Primary Retroperitoneal Lymph Node Dissection According to Clinical Stage (Stage I Versus Stage IIA/B)
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Retroperitoneal LN Dissection Table 3 Thirty-Day Readmission Rates After Primary Retroperitoneal Lymph Node Dissection According to Clinical Stage and Histology Characteristic Clinical stage
Total
Variable IA/IB IIA IIB I/II
Seminoma 14/204 2/67 5/86 21/357
(6.9%) (3%) (5.8%) (5.9%)
NSGCT 78/1071 19/297 15/236 112/1604
(7.3%) (6.4%) (6.4%) (7.0%)
Pa 1 .39 1 .56
Abbreviation: NSGCT ¼ nonseminomatous germ-cell tumor. a P values obtained by Fisher exact test for association of readmission and histology in each clinical stage defined.
Long-term complications include ejaculatory dysfunction (3%20%), bowel obstruction (0.4%-2.7%), incisional hernias (3%), and ureteral obstruction (1%).29,31,32 To date, few data exist on outcomes for men who receive RPLND as primary treatment for seminoma. This literature is well summarized by Hu and Daneshmand.21 In their review, they identified 92 patients in 4 published retrospective series with stage I-IIC seminoma; they reported an overall recurrence rate of 14%, with higher-stage disease associated with a greater risk of recurrence.21,33,34 Theoretically, RPLND in this setting is a rational and viable treatment alternative to radiotherapy or chemotherapy, as it may be associated with potentially less long-term toxicity; further, its therapeutic role has been well established in men with NSGCT. In a study using data from the Surveillance, Epidemiology, and End Results (SEER) program, Patel et al35 reported on rates of RPLND utilization in the United States from 1988 to 2013 for men diagnosed with testicular seminoma. They found utilization rates to be low for stage I disease (1.3%) and higher for stage II disease (10.6%). It is unclear in this study what proportion of stage II patients received a primary versus PC-RPLND, as chemotherapy receipt is not reported in SEER data, and therefore stage-specific survival after primary and PC-RPLND is not interpretable. Conceivably, one would expect stage IIB patients with bulky adenopathy and those with stage IIC disease to have received chemotherapy as initial primary treatment. Our study is notable for several key findings. First, utilization of RPLND in the primary setting for testicular seminoma in the United States is low. These findings are not surprising and are in line with clinical practice guideline recommendations, which endorse surveillance, single-agent carboplatin, or radiotherapy for stage IA or IB seminoma and radiotherapy and primary cisplatinbased chemotherapy regimens or radiotherapy for stage IIA or IIB seminoma. Second, OS rates were favorable and durable for patients with testicular seminoma who underwent RPLND as primary treatment. More specifically, 5-year OS was 94.2%. When comparing men with CS I versus CS IIA/IIB who received primary RPLND, 5-year OS was 97.3% and 92.0%, respectively (P ¼ .035). These survival rates are comparable to outcomes reported after stage-specific treatment after chemotherapy or radiotherapy for testicular seminoma patients. Finally, 30-day readmission rates were not significantly different between men who underwent primary RPLND for testicular seminoma versus NSGCT (5.9% vs. 7.0%, P ¼ .56), suggesting that perioperative morbidity after RPLND for seminomas may not differ significantly from that of NSGCTs.
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Several limitations of our study warrant mention. First, our study should be interpreted within the context of an observational and retrospective study design. The NCDB does not capture important oncologic outcomes such as the need for salvage therapies, recurrence rates, or cause of death, rendering recurrence-free survival and cancer-specific survival incalculable, and leaving OS as the only measurable clinical outcome. However, for testicular cancer patients who receive the appropriate risk-adapted and stage-dependent treatment for their cancer, 5-year OS generally represents an appropriate and reliable surrogate and end point for treatment success in these men, as the majority of recurrences occur within the first 2 years and the incidence of a late relapse among patients who experience a complete response to treatment has been reported to be 3%.36,37 Second, the NCDB does not capture important data on anatomic templates (modified vs. full bilateral template) or whether nerve-sparing techniques were used; nor does it report on short- and long-term potential complications or adverse effects associated with RPLND. Third, our study cohort was small, and associative factors predictive of OS in these men could not be well evaluated statistically. Finally, although it may have been meaningful to execute a comparative analysis of RPLND, chemotherapy, and radiotherapy in this group of men, such an analysis using NCDB data is subject to inherent biases that cannot be reliably adjusted for, and given the small number of men receiving RPLND in our study, such an analysis would not be statistically sound and interpretable. Therefore, this comparison was not performed. Despite these limitations, and despite our study being descriptive in nature, analysis of NCDB data allows us to report the long-term, stage-specific survival in this select group of men that would otherwise not be possible. Although favorable survival rates are observed for men with testicular seminoma who undergo primary RPLND in our study, our findings are directional and require verification with ongoing prospective trial data. Currently, two prospective trials, the SEMS trial (Surgery in Early Metastatic Seminoma) and the PRIMETEST trial (Trial to Evaluate the Progression Free Survival with Primary Retroperitoneal Lymph Node Dissection only in Patients with Seminomatous Testicular Germ Cell Tumors with Clinical Stage IIA/B), are underway to formally evaluate the efficacy of surgery in this setting.22,23 In a 2019 interim analysis of the PRIMETEST trial, Albers et al38 reported outcomes on 21 patients with stage IIA/B and 1 patient with stage IIC testicular seminoma who underwent primary RPLND. At a mean follow-up of 24 months, 77% of patients were free of recurrence. Of the 23% who developed recurrence, only one
Alexandra L. Tabakin et al patient had an in-field recurrence, and all patients who experienced recurrence were free of recurrence after receiving salvage treatment. Continued accrual and longer-term follow-up is necessary to clarify the role of primary RPLND in testicular seminoma. Finally, although stage I seminoma is often cured by radical orchiectomy alone, and surveillance for the majority of these men is preferred, 15% to 20% of patients may experience relapse, with most recurrences occurring in the retroperitoneal LNs. Future trial design may consider evaluating RPLND for men with stage 1 seminoma who are at highest risk of relapse (ie, those in whom compliance may be an issue, or those with large primary tumor size).
Conclusion Although RPLND is rarely used as first-line therapy for testicular seminoma in the United States, 5-year OS rates appear to be favorable—and comparable to survival rates reported after chemotherapy or radiotherapy. Ongoing prospective trials, namely the SEMS trial and the PRIMETEST trial, will clarify its role in the management of testicular seminoma.
5. 6. 7.
8. 9. 10. 11.
12. 13. 14.
Clinical Practice Points For testicular seminoma patients with low-volume metastatic
disease in the retroperitoneum (stage IIA/IIB), radiotherapy or platinum-based chemotherapy regimens are highly effective, with excellent recurrence-free survival and OS rates, but such regimens may be associated with significant short- and long-term toxicities. Although RPLND in this setting is not well defined, it may be associated with potentially less long-term toxicity than radiotherapy or chemotherapy. Using the NCDB, we identified 365 men from 2004 to 2014 who received primary RPLND for stage I or stage IIA/B disease. Not surprisingly, we found utilization to be low but survival rates to be favorable after RPLND, with 5year OS rates of 97.3% and 92.0% for those with stage I and IIA/B disease, respectively. Although our findings are limited by the usual biases associated with an observational study, our data are directional. The SEMS and PRIMETEST trials will clarify the role of RPLND in this setting.
15. 16. 17.
18. 19.
20.
21. 22. 23.
Acknowledgment
24.
Supported in part by the National Cancer Institute (P30 CA-072720, Rutgers Cancer Institute of New Jersey Biometrics Shared Resource).
25. 26.
Disclosure
27.
The authors have stated that they have no conflict of interest. 28.
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Second cancers among 40,576 testicular cancer patients: focus on long-term survivors. J Natl Cancer Inst 2005; 97:1354-65. 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. Haugnes HS, Wethal T, Aass N, et al. Cardiovascular risk factors and morbidity in long-term survivors of testicular cancer: a 20-year follow-up study. J Clin Oncol 2010; 28:4649-57. Stephenson AJ, Bosl GJ, Bajorin DF, Stasi J, Motzer RJ, Sheinfeld J. Retroperitoneal lymph node dissection in patients with low stage testicular cancer with embryonal carcinoma predominance and/or lymphovascular invasion. J Urol 2005; 174:557-60. Stephenson AJ, Bosl GJ, Motzer RJ, et al. Retroperitoneal lymph node dissection for nonseminomatous germ cell testicular cancer: impact of patient selection factors on outcome. J Clin Oncol 2005; 23:2781-8. Weissbach L, Bussar-Maatz R, Flechtner H, Pichlmeier U, Hartmann M, Keller L. RPLND or primary chemotherapy in clinical stage IIA/B nonseminomatous germ cell tumors? Results of a prospective multicenter trial including quality of life assessment. Eur Urol 2000; 37:582-94. Donohue JP, Thornhill JA, Foster RS, Rowland RG, Bihrle R. Clinical stage B non-seminomatous germ cell testis cancer: the Indiana University experience (1965-1989) using routine primary retroperitoneal lymph node dissection. Eur J Cancer 1995; 31A:1599-604. Hu B, Daneshmand S. Retroperitoneal lymph node dissection as primary treatment for metastatic seminoma. Adv Urol 2018; 2018:7978958. Retroperitoneal lymph node dissection in treating patients with testicular seminoma. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02537548. Accessed: January 6, 2019. Trial to evaluate progression free survival with primary retroperitoneal lymph-node dissection (pRPLND) only in patients with seminomatous testicular germ cell tumors with clinical stage IIA/B (PRIMETEST). Available at: https://clinicaltrials. gov/ct2/show/NCT02797626. Accessed: January 6, 2019. Boffa DJ, Rosen JE, Mallin K, et al. Using the National Cancer Database for outcomes research: a review. JAMA Oncol 2017; 3:1722-8. Warde P, Specht L, Horwich A, et al. Prognostic factors for relapse in stage I seminoma managed by surveillance: a pooled analysis. J Clin Oncol 2002; 20:444852. Powles T, Robinson D, Shamash J, Moller H, Tranter N, Oliver T. The long-term risks of adjuvant carboplatin treatment for stage I seminoma of the testis. Ann Oncol 2008; 19:443-7. 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. 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. Baniel J, Foster RS, Rowland RG, Bihrle R, Donohue JP. Complications of primary retroperitoneal lymph node dissection. J Urol 1994; 152:424-7. Heidenreich A, Albers P, Hartmann M, et al. Complications of primary nerve sparing retroperitoneal lymph node dissection for clinical stage I nonseminomatous germ cell tumors of the testis: experience of the German Testicular Cancer Study Group. J Urol 2003; 169:1710-4. 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.
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Retroperitoneal LN Dissection 32. Beck SDW, Bey AL, Bihrle R, Foster RS. Ejaculatory status and fertility rates after primary retroperitoneal lymph node dissection. J Urol 2010; 184:2078-80. 33. Hu B, Shah S, Shojaei S, Daneshmand S. Retroperitoneal lymph node dissection as firstline treatment of node-positive seminoma. Clin Genitourin Cancer 2015; 13:e265-9. 34. Mezvrishvili Z, Managadze L. Retroperitoneal lymph node dissection for high-risk stage I and stage IIA seminoma. Int Urol Nephrol 2006; 38:615-9. 35. Patel HD, Joice GA, Schwen ZR, et al. Retroperitoneal lymph node dissection for testicular seminomas: population-based practice and survival outcomes. World J Urol 2018; 36:73-8.
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36. Baniel J, Foster RS, Gonin R, Messemer JE, Donohue JP, Einhorn LH. Late relapse of testicular cancer. J Clin Oncol 1995; 13:1170-6. 37. Shahidi M, Norman AR, Dearnaley DP, Nicholls J, Horwich A, Huddart RA. Late recurrence in 1263 men with testicular germ cell tumors. Multivariate analysis of risk factors and implications for management. Cancer 2002; 95:520-30. 38. Albers P, Hiester A, Grosse Siemer R, Lusch A. The PRIMETEST trial: interim analysis of a phase II trial for primary retroperitoneal lymph node dissection (RPLND) in stage II A/B seminoma patients without adjuvant treatment. J Clin Oncol 2019; 37:507.
Retroperitoneal Lymph Node Dissection as Primary Treatment for Men With Testicular Seminoma: Utilization and Survival Analysis Using the National Cancer Data Base, 2004-2014 Alexandra L. Tabakin,1 Brian M. Shinder,1 Sinae Kim,2 Zorimar Rivera-Nunez,3 Charles F. Polotti,1 Parth K. Modi,6 Joshua A. Sterling,1 Nicholas J. Farber,1 Kushan D. Radadia,1 Rahul R. Parikh,3 Isaac Y. Kim,1,4 Biren Saraiya,5 Tina M. Mayer,5 Eric A. Singer,1,4 Thomas L. Jang1,4 Abstract The role of retroperitoneal lymph node dissection (RPLND) as first-line treatment for stage I or IIA/B testicular seminoma is not well defined. Using the National Cancer Data Base, we identified 365 men from 2004 to 2014 who received RPLND as primary treatment for testicular seminoma and found 5-year overall survival rates of 97.3% and 92.0% for those with stage I and IIA/B disease, respectively. Background: The role of retroperitoneal lymph node dissection (RPLND) as first-line treatment for testicular seminoma is less well defined than for testicular nonseminomatous germ-cell tumors. We describe utilization of primary RPLND in the United States and report on overall survival (OS) after surgery for these men. Patients and Methods: Using 2004-2014 data from the National Cancer Data Base, we identified 62,727 men with primary testicular cancer, 31,068 of whom were diagnosed as having seminoma. After excluding men with benign, nonegerm cell, and nonseminomatous germ-cell tumor histologies, those who did not undergo RPLND, those where clinical stage and survival data were unavailable, and those with testicular seminoma who underwent RPLND in the postchemotherapy setting (n ¼ 47), 365 men comprised our final cohort. Descriptive statistics were used to summarize clinical and demographic factors. The Kaplan-Meier method was used to determine OS. Results: A total of 365 men with testicular seminoma underwent primary RPLND. At a median follow-up of 4.1 years, there were 16 deaths in the entire cohort. Five-year OS was 94.2%. Subset analysis of men with stage I and IIA/B disease who underwent primary RPLND revealed 5year OS rates of 97.3% and 92.0%, respectively (P ¼ .035). OS did not significantly differ in patients with stage IIA versus IIB disease (91.8% vs. 92.3%, respectively, P ¼ .907). Conclusion: Although RPLND is rarely used as primary therapy in testicular seminoma, OS rates appear to be comparable to rates reported in the literature for primary chemotherapy or radiotherapy. Ongoing prospective trials will clarify the role of RPLND in the management of testicular seminoma. Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2019 Elsevier Inc. All rights reserved. Keywords: Outcomes, Overall survival, RPLND, Surgery, Testicular cancer
Introduction Men with testicular seminoma and radiographic evidence of lowvolume retroperitoneal lymph node (LN) disease are traditionally 1 Division of Urology, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 2 Department of Biostatistics and Epidemiology 3 Department of Radiation Oncology 4 Section of Urologic Oncology 5 Division of Medical Oncology, Department of Medicine, Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 6 Department of Urology, University of Michigan, Ann Arbor, MI
1558-7673/$ - see frontmatter ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.clgc.2019.10.018
treated with external-beam radiotherapy or primary systemic chemotherapy.1,2 Although these therapies are highly effective and result in 5-year recurrence-free survival and 5-year overall survival Submitted: Aug 3, 2019; Revised: Oct 7, 2019; Accepted: Oct 28, 2019 Address for correspondence: Thomas L. Jang, MD, MPH, FACS, Urologic Oncology Program, Division of Urology, Rutgers Cancer Institute of New Jersey, 195 Little Albany St, Suite 4560, New Brunswick, NJ 08901 Fax: (732) 235-6596; E-mail contact: [email protected]
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Retroperitoneal LN Dissection (OS) rates exceeding 90%, they can be associated with significant long-term morbidity.3-7 More specifically, patients receiving these treatments are at an increased risk of developing a secondary solid or hematologic malignancy, cardiovascular disease, bleomycin-induced pulmonary toxicity, metabolic syndrome, and toxicity to the kidneys or to the neurologic or otologic systems.8-16 Retroperitoneal LN dissection (RPLND) as first-line treatment for men with testicular nonseminomatous germ-cell tumors (NSGCT) is well established. RPLND in this setting has demonstrated excellent oncologic outcomes with minimal long-term morbidities.17-20 Historically, RPLND for patients with seminoma has been reserved for select patients in the postchemotherapy (PC) setting with normal serum tumor markers and a residual mass that is greater than 3 cm and exhibits uptake of 18fluorodeoxyglucose on imaging by positron emission tomography/ computed tomography.1 Several groups have evaluated and reported on RPLND as a primary treatment for testicular seminoma. A review summarizing RPLND as primary treatment for metastatic seminoma reported on outcomes of a total of 92 patients with stage I-IIC seminoma in 4 published series, and reported the recurrence rate to be 14%, with recurrence rates after RPLND highest for those with higher-stage disease.21 Currently, two prospective trials, the SEMS trial22 and the PRIMETEST trial,23 are underway to formally evaluate the efficacy of surgery in this setting. Given the limited data on the use of and outcomes after RPLND for men with testicular seminoma, we analyzed its utilization in the primary setting for men in the United States diagnosed with testicular seminoma and calculated the survival rates after surgery for these men.
Patients and Methods Data Source The National Cancer Data Base (NCDB) is a national hospitalbased registry sponsored by the American College of Surgeons Commission on Cancer and the American Cancer Society. Programs accredited by the American College of Surgeons Commission on Cancer report cancers diagnosed or treated in their facilities. The NCDB includes more than 1500 hospital-based programs and approximately 70% of all newly diagnosed cases of cancer in the United States.24 The database contains sociodemographic information as well as individual diagnosis and treatment information, such as American Joint Committee on Cancer (AJCC) T, N, and M stages, scope of regional LN surgery, chemotherapy receipt, and timing of systemic treatment relative to surgery.
Study Population
2
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This study was institutional review board exempt because the data set did not include any protected health information. We identified 62,727 men from 2004 to 2014 in the NCDB with primary testicular cancer, 31,068 of whom were diagnosed as having seminoma. After excluding men with benign and nonegerm-cell histology, men with NSGCT histology, those who did not undergo RPLND, and those where clinical stage (CS) and survival data were unavailable, 412 men were identified. Men were further stratified according to whether they had primary RPLND versus PC-RPLND, with primary RPLND defined as RPLND
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performed for CS IA-IIB without prior chemotherapy and PC-RPLND classified as RPLND performed for CS IIA- IIIC after chemotherapy. Those who received PC-RPLND (n ¼ 47) were excluded from the analysis. Our final analytic cohort comprised 365 men who underwent RPLND as primary treatment for CS IAIIB testicular seminoma. Descriptive statistics were used to summarize all clinical and sociodemographic factors, and the 2-sample t test (or Wilcoxon rank sum test, if necessary) was used to compare means (or medians) of the stage I versus stage IIA/B patients who received primary RPLND. Using 30-day readmission rates as a surrogate of perioperative and postoperative morbidity after RPLND, we compared readmission rates between patients undergoing RPLND for testicular seminoma versus testicular NSGCT. The Fisher exact test was used to evaluate associations between 30-day readmission rates and stage-stratified histology (seminoma vs. NSGCT). Kaplan-Meier curves were used to estimate OS. Statistical analyses were performed by SAS 9.4 (SAS Institute, Cary, NC) and were considered significant at P < .05.
Results Baseline Characteristics and Relation to Treatment From 2004 to 2014, a total of 365 men with testicular seminoma underwent RPLND; baseline sociodemographic and clinical characteristics of these men are shown in Table 1. Among those who received a primary RPLND, 41.1% (n ¼ 150), 16.4% (n ¼ 60), 18.6% (n ¼ 68), and 23.8% (n ¼ 87) had AJCC CS IA, IB, IIA, and IIB disease, respectively. When comparing men with CS I (n ¼ 250) versus CS IIA/IIB (n ¼ 155) who received a primary RPLND, there were no significant differences between the two groups with respect to age, diagnosis year, race, comorbid conditions, income, facility type, or facility location (Table 2).
Survival Analysis At a median follow-up of 4.1 years, 16 deaths occurred in the entire cohort. Five-year OS was 94.2% (Figure 1). In a subset analysis comparing men with CS I versus IIA/IIB who received primary RPLND, 5-year OS values were 97.3% and 92.0%, respectively (P ¼ .035) (Figure 2). Five-year OS did not differ significantly in patients with stage IIA versus IIB disease (91.8% vs. 92.3%, respectively, P ¼ .907).
Readmission Rates After RPLND Irrespective of CS, 30-day readmission rates after discharge from primary RPLND did not differ significantly between testicular seminoma versus testicular NSGCT patients during this same time period (5.9% vs. 7.0%, P ¼ .56) (Table 3), suggesting that recovery after primary RPLND for seminoma is not significantly different than that for NSGCT.
Discussion The role of RPLND as first-line treatment for testicular seminoma is less well defined than for testicular NSGCT. In NSGCT patients with CS I or IIA disease or with a PC residual mass, RPLND is well-established treatment, providing accurate pathologic staging information and affording therapeutic benefit.17-20
Alexandra L. Tabakin et al Table 1 Baseline Characteristics of 365 Patients Undergoing Primary Retroperitoneal Lymph Node Dissection for Testicular Seminoma Characteristic Age (y)
Age group
Diagnosis year
Pathologic tumor classification
Clinical stage
Race
Insurance
Charlson-Deyo score
Income
Education (percentage of no high school degree, 2008-2012)
Facility type
Variable
Value
Mean standard deviation Median <18 y 18-25 year 26-35 y >35 y 2004-2006 2007-2009 2010-2012 2013-2014 pT1
41.5 12.2
1 24 104 236 32 134 128 71 210
40 (0.3) (6.6) (28.5) (64.6) (8.8) (36.7) (35.1) (19.4) (57.5)
pT2 pT3 pT4 pTis pTx IA IB IIA IIB White Black Other Unknown Not insured Private Medicaid Medicare Other government Unknown 0 1 2þ <$38,000 $38,000 to $47,999 $48,000 to $62,999 $63,000þ 21%
86 25 2 1 41 150 60 68 87 326 23 10 6 41 258 33 28 4 1 333 26 6 45 82 88 146 50
(23.6) (6.8) (0.5) (0.3) (11.2) (41.1) (16.4) (18.6) (23.8) (89.3) (6.3) (2.7) (1.6) (11.2) (70.7) (9) (7.7) (1.1) (0.3) (91.2) (7.1) (1.6) (12.5) (22.7) (24.4) (40.4) (13.8)
13%-20% 7%-12.9% <7% Community cancer program Comprehensive community cancer program Academic/research program
84 120 107 36
(23.3) (33.2) (29.6) (9.9)
147 (40.3)
142 (38.9)
Table 1 Continued Characteristic
Facility location
Variable
Value
Integrated network cancer program New England Middle Atlantic South Atlantic East North Central East South Central West North Central West South Central Mountain Pacific
40 (9.7) 22 67 70 71 12 32 26 22 43
(6) (18.4) (19.2) (19.5) (3.3) (8.8) (7.1) (6) (11.8)
Data are presented as n (%) unless otherwise indicated.
According to the National Comprehensive Cancer Network (NCCN) and European Association of Urology (EAU) testicular cancer guidelines, surveillance, adjuvant chemotherapy, and adjuvant radiotherapy are appropriate treatment strategies for patients with stage I seminoma.1,2 Because the majority of patients with stage I seminoma are cured by radical orchiectomy alone, with relapse rates of 15% to 20%, surveillance is generally recommended.1,2,25 For men with radiographic evidence of low-volume early metastatic disease in the retroperitoneum (stage IIA/IIB), current clinical practice guidelines endorse radiotherapy or platinumbased chemotherapy regimens. Both therapeutic strategies are effective and result in 5-year recurrence-free survival and 5-year OS rates exceeding 90%, but significant short- and long-term toxicities may occur.1,2 The development of second primary cancers and cardiovascular disease represents potentially life-threatening late effects of treatment. Other long-term adverse toxicities include pulmonary complications, neurotoxicity, ototoxicity, nephrotoxicity, and avascular necrosis.12 The risk of a second primary solid cancer is almost 2-fold greater in testicular cancer survivors treated with radiotherapy or chemotherapy; it increases to almost 3-fold in those who received both treatments.14 Chemotherapy has also been associated with significantly increased risks of secondary leukemia among testicular cancer survivors.8,13 Long-term survivors of testicular cancer have been observed to have a significantly increased risk of developing cardiovascular disease. In a study examining 992 patients at a median follow-up of 10.2 years, Huddart et al15 reported cardiovascular events in 6.8% of patients, 18 of whom developed sudden or cardiac deaths. After adjusting for age, there was a statistically significant 2.6-fold, 2.4fold, and 2.8-fold increased risk for cardiac events after chemotherapy, radiotherapy, or combined chemotherapy/radiotherapy, respectively. There were no significant differences in cardiac risk factors among the 3 groups. In a separate study examining 990 men treated for unilateral testicular cancer from 1980 to 1994 at a 19year median follow-up, Haugnes et al16 found using age-adjusted Cox regression analyses a 2.3-fold, 2.6-fold, and 4.8-fold increased risks of atherosclerotic disease after radiotherapy only,
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Retroperitoneal LN Dissection Table 2 Characteristics of Patients With Stage I Versus Stage IIA/B Testicular Seminoma Who Received Primary Retroperitoneal Lymph Node Dissection Variable
Stage I (N [ 210)
Stage IIA/B (N [ 155)
P
Mean standard deviation Median (min, max) 25 y 26-35 y >35 y 2004-2007 2008-2011 2012-2014 pT1 pT2 pT3 pT4 pTis pTx White Black Other/unknown 0 1þ <$38,000 $38,000 to $47,999 $48,000 to $62,999 $63,000þ 21%
41.18 12.43 40 (18-78) 18 (8.6) 59 (28.1) 133 (63.3) 32 (15.2) 110 (52.4) 68 (32.4) 150 (71.4) 50 (23.8) 8 (3.8) 2 (1) 0 0 184 (87.6) 13 (6.2) 13 (6.2) 193 (91.9) 17 (8.1) 25 (12) 53 (25.4) 52 (24.9) 79 (37.8) 30 (14.4)
41.83 11.84 42 (0-78) 7 (4.5) 45 (29) 103 (66.5) 25 (16.1) 84 (54.2) 46 (29.7) 60 (38.7) 36 (23.2) 17 (11) 0 1 (0.6) 41 (26.5) 142 (91.6) 10 (6.5) 3 (1.9) 140 (90.3) 15 (9.7) 20 (13.2) 29 (19.1) 36 (23.7) 67 (44.1) 20 (13.2)
.615 .381 .317
Characteristic Age (years) Age (group)
Diagnosis year
Pathologic tumor classification
Race
Charlson-Deyo score Income (n missing ¼ 4)
Education (percentage of no high school degree 2008-2012) (n missing ¼ 4)
Facility type
Facility location
13%-20% 7%-12.9% <7% Academic/research program Community cancer program/ comprehensive community cancer program/integrated network cancer program New England/Middle Atlantic/ South Atlantic/East North Central/East South Central West North Central/West South Central/Mountain/Pacific
57 71 51 88 122
(27.3) (34) (24.4) (41.9) (58.1)
27 49 56 54 101
(17.8) (32.2) (36.8) (34.8) (65.2)
138 (65.7)
104 (67.1)
72 (34.3)
51 (32.9)
.867
<.0001
.15
.709 .472
.043
.193
.823
Data are presented as n (%) unless otherwise indicated.
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chemotherapy only, and combined radiotherapy and chemotherapy, respectively, compared to surgery only (P ¼ .02). Treatment with bleomycin, etoposide, and cisplatin (BEP) chemotherapy alone increased the risk of coronary artery disease by 5.7-fold compared to surgery only, and increased myocardial infarction risk by 3.1-fold compared to age-matched male controls. Although many of the long-term adverse effects of BEP have been well studied, less is known about the long-term toxicities associated with single-agent carboplatin for stage I seminoma; these toxicities may be less compared to BEP. In a retrospective study examining 199 men treated with one or two doses of carboplatin for stage I seminoma, investigators found no difference in risk of secondary malignancy or cardiovascular toxicity compared to the general population after a follow-up period of over 5 years. However, the
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median follow-up in this study was only 9 years; larger studies with longer follow-up will be needed to more accurately characterize the potential long-term toxicities associated with carboplatin.26 RPLND has been well established in the management of germcell tumors since the mid-1900s, and there are long-term data to support its efficacy and safety in men with testicular NSGCT.17,18,20,27,28 In addition to its therapeutic role, RPLND provides important pathologic staging information that more accurately selects patients who may potentially benefit from further adjuvant therapies. Complication rates vary according to whether RPLND is performed in the primary versus PC setting, with complication rates ranging from 10%-24% and 20%-30% in the primary and PC settings, respectively. Intraoperative, short-term, and long-term complications can occur in up to 5%, 24%, and
Alexandra L. Tabakin et al Figure 1 Overall Survival in Men With Testicular Seminoma Who Received Primary Retroperitoneal Lymph Node Dissection
7% of patients, respectively, undergoing primary RPLND.29-31 Intraoperative complications occur infrequently, with injury to vascular or retroperitoneal structures being most common. Short-
term complications include venous thromboembolic disease (0.9%), wound infection (5%), chylous ascites (0.2%-2%), atelectasis and/or pneumonia (0.2%-3.6%), and ileus (2.1%-17.9%).29-31
Figure 2 Overall Survival in Men With Testicular Seminoma Who Received Primary Retroperitoneal Lymph Node Dissection According to Clinical Stage (Stage I Versus Stage IIA/B)
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Retroperitoneal LN Dissection Table 3 Thirty-Day Readmission Rates After Primary Retroperitoneal Lymph Node Dissection According to Clinical Stage and Histology Characteristic Clinical stage
Total
Variable IA/IB IIA IIB I/II
Seminoma 14/204 2/67 5/86 21/357
(6.9%) (3%) (5.8%) (5.9%)
NSGCT 78/1071 19/297 15/236 112/1604
(7.3%) (6.4%) (6.4%) (7.0%)
Pa 1 .39 1 .56
Abbreviation: NSGCT ¼ nonseminomatous germ-cell tumor. a P values obtained by Fisher exact test for association of readmission and histology in each clinical stage defined.
Long-term complications include ejaculatory dysfunction (3%20%), bowel obstruction (0.4%-2.7%), incisional hernias (3%), and ureteral obstruction (1%).29,31,32 To date, few data exist on outcomes for men who receive RPLND as primary treatment for seminoma. This literature is well summarized by Hu and Daneshmand.21 In their review, they identified 92 patients in 4 published retrospective series with stage I-IIC seminoma; they reported an overall recurrence rate of 14%, with higher-stage disease associated with a greater risk of recurrence.21,33,34 Theoretically, RPLND in this setting is a rational and viable treatment alternative to radiotherapy or chemotherapy, as it may be associated with potentially less long-term toxicity; further, its therapeutic role has been well established in men with NSGCT. In a study using data from the Surveillance, Epidemiology, and End Results (SEER) program, Patel et al35 reported on rates of RPLND utilization in the United States from 1988 to 2013 for men diagnosed with testicular seminoma. They found utilization rates to be low for stage I disease (1.3%) and higher for stage II disease (10.6%). It is unclear in this study what proportion of stage II patients received a primary versus PC-RPLND, as chemotherapy receipt is not reported in SEER data, and therefore stage-specific survival after primary and PC-RPLND is not interpretable. Conceivably, one would expect stage IIB patients with bulky adenopathy and those with stage IIC disease to have received chemotherapy as initial primary treatment. Our study is notable for several key findings. First, utilization of RPLND in the primary setting for testicular seminoma in the United States is low. These findings are not surprising and are in line with clinical practice guideline recommendations, which endorse surveillance, single-agent carboplatin, or radiotherapy for stage IA or IB seminoma and radiotherapy and primary cisplatinbased chemotherapy regimens or radiotherapy for stage IIA or IIB seminoma. Second, OS rates were favorable and durable for patients with testicular seminoma who underwent RPLND as primary treatment. More specifically, 5-year OS was 94.2%. When comparing men with CS I versus CS IIA/IIB who received primary RPLND, 5-year OS was 97.3% and 92.0%, respectively (P ¼ .035). These survival rates are comparable to outcomes reported after stage-specific treatment after chemotherapy or radiotherapy for testicular seminoma patients. Finally, 30-day readmission rates were not significantly different between men who underwent primary RPLND for testicular seminoma versus NSGCT (5.9% vs. 7.0%, P ¼ .56), suggesting that perioperative morbidity after RPLND for seminomas may not differ significantly from that of NSGCTs.
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Several limitations of our study warrant mention. First, our study should be interpreted within the context of an observational and retrospective study design. The NCDB does not capture important oncologic outcomes such as the need for salvage therapies, recurrence rates, or cause of death, rendering recurrence-free survival and cancer-specific survival incalculable, and leaving OS as the only measurable clinical outcome. However, for testicular cancer patients who receive the appropriate risk-adapted and stage-dependent treatment for their cancer, 5-year OS generally represents an appropriate and reliable surrogate and end point for treatment success in these men, as the majority of recurrences occur within the first 2 years and the incidence of a late relapse among patients who experience a complete response to treatment has been reported to be 3%.36,37 Second, the NCDB does not capture important data on anatomic templates (modified vs. full bilateral template) or whether nerve-sparing techniques were used; nor does it report on short- and long-term potential complications or adverse effects associated with RPLND. Third, our study cohort was small, and associative factors predictive of OS in these men could not be well evaluated statistically. Finally, although it may have been meaningful to execute a comparative analysis of RPLND, chemotherapy, and radiotherapy in this group of men, such an analysis using NCDB data is subject to inherent biases that cannot be reliably adjusted for, and given the small number of men receiving RPLND in our study, such an analysis would not be statistically sound and interpretable. Therefore, this comparison was not performed. Despite these limitations, and despite our study being descriptive in nature, analysis of NCDB data allows us to report the long-term, stage-specific survival in this select group of men that would otherwise not be possible. Although favorable survival rates are observed for men with testicular seminoma who undergo primary RPLND in our study, our findings are directional and require verification with ongoing prospective trial data. Currently, two prospective trials, the SEMS trial (Surgery in Early Metastatic Seminoma) and the PRIMETEST trial (Trial to Evaluate the Progression Free Survival with Primary Retroperitoneal Lymph Node Dissection only in Patients with Seminomatous Testicular Germ Cell Tumors with Clinical Stage IIA/B), are underway to formally evaluate the efficacy of surgery in this setting.22,23 In a 2019 interim analysis of the PRIMETEST trial, Albers et al38 reported outcomes on 21 patients with stage IIA/B and 1 patient with stage IIC testicular seminoma who underwent primary RPLND. At a mean follow-up of 24 months, 77% of patients were free of recurrence. Of the 23% who developed recurrence, only one
Alexandra L. Tabakin et al patient had an in-field recurrence, and all patients who experienced recurrence were free of recurrence after receiving salvage treatment. Continued accrual and longer-term follow-up is necessary to clarify the role of primary RPLND in testicular seminoma. Finally, although stage I seminoma is often cured by radical orchiectomy alone, and surveillance for the majority of these men is preferred, 15% to 20% of patients may experience relapse, with most recurrences occurring in the retroperitoneal LNs. Future trial design may consider evaluating RPLND for men with stage 1 seminoma who are at highest risk of relapse (ie, those in whom compliance may be an issue, or those with large primary tumor size).
Conclusion Although RPLND is rarely used as first-line therapy for testicular seminoma in the United States, 5-year OS rates appear to be favorable—and comparable to survival rates reported after chemotherapy or radiotherapy. Ongoing prospective trials, namely the SEMS trial and the PRIMETEST trial, will clarify its role in the management of testicular seminoma.
5. 6. 7.
8. 9. 10. 11.
12. 13. 14.
Clinical Practice Points For testicular seminoma patients with low-volume metastatic
disease in the retroperitoneum (stage IIA/IIB), radiotherapy or platinum-based chemotherapy regimens are highly effective, with excellent recurrence-free survival and OS rates, but such regimens may be associated with significant short- and long-term toxicities. Although RPLND in this setting is not well defined, it may be associated with potentially less long-term toxicity than radiotherapy or chemotherapy. Using the NCDB, we identified 365 men from 2004 to 2014 who received primary RPLND for stage I or stage IIA/B disease. Not surprisingly, we found utilization to be low but survival rates to be favorable after RPLND, with 5year OS rates of 97.3% and 92.0% for those with stage I and IIA/B disease, respectively. Although our findings are limited by the usual biases associated with an observational study, our data are directional. The SEMS and PRIMETEST trials will clarify the role of RPLND in this setting.
15. 16. 17.
18. 19.
20.
21. 22. 23.
Acknowledgment
24.
Supported in part by the National Cancer Institute (P30 CA-072720, Rutgers Cancer Institute of New Jersey Biometrics Shared Resource).
25. 26.
Disclosure
27.
The authors have stated that they have no conflict of interest. 28.
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