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Nonrandomized Comparison of Primary Chemotherapy and Retroperitoneal Lymph Node Dissection for Clinical Stage IIA and IIB Nonseminomatous Germ Cell Testicular Cancer

Andrew J. Stephenson, George J. Bosl, Robert J. Motzer, Dean F. Bajorin, Jason P. Stasi, Joel Sheinfeld

From the Section of Urologic Oncology, Glickman Urological Institute, Cleveland Clinic Foundation, Cleveland, OH; and the Department of Urology and Genitourinary Oncology Service, Division of Solid Tumors, Department of Medicine, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, New York, NY

Address reprint requests to Joel Sheinfeld, MD, Department of Urology, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: sheinfej{at}mskcc.org

	ABSTRACT

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Purpose Patients with clinical stage (CS) IIA and IIB nonseminomatous germ cell tumor (NSGCT) with adenopathy more than 2 cm, multiple masses, elevated serum tumor markers, or disease outside the primary landing zone have increasingly been recommended to receive primary chemotherapy over time at our institution. The impact of these selection factors on the outcome of patients managed primarily by retroperitoneal lymph node dissection (RPLND) or chemotherapy was examined.

Patients and Methods Between 1989 and 2002, 252 patients with CS IIA and IIB NSGCT were referred to our institution for initial management, of whom 136 underwent RPLND and 116 received chemotherapy and postchemotherapy RPLND. Patient information was obtained from a prospective RPLND database.

Results Proportionately more patients received chemotherapy over time (22% in 1989 to 1993 v 68% in 1999 to 2002), and the relapse-free survival (RFS) subsequently improved from 84% (1989 to 1998) to 98% (1999 to 2002; P = .004) without increasing the proportion who received any chemotherapy (70% v 79%; P = .16). By increasingly selecting patients with adverse features for primary chemotherapy, the RFS after RPLND improved from 78% to 100% (P = .019), but rates of pathologic stage II and retroperitoneal teratoma were unaffected. Retroperitoneal histology and RFS did not change over time for chemotherapy patients. Primary chemotherapy was associated with improved RFS compared with RPLND (98% v 79%; P < .001), but disease-specific survival did not differ significantly (100% v 98%; P = .3).

Conclusion Patient selection factors have significantly improved the outcome of patients with CS IIA and IIB NSGCT without substantially increasing the proportion of patients exposed to chemotherapy.

	INTRODUCTION

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For patients with clinical stage (CS) II nonseminomatous germ cell tumor (NSGCT), there is consensus that patients with adenopathy greater than 5 cm (CS IIC) should receive chemotherapy. However, the appropriate primary intervention for CS IIA (adenopathy < 2 cm) or IIB (adenopathy 2 to 5 cm) remains controversial. Retrospective series of patients with CS II NSGCT treated primarily by chemotherapy or retroperitoneal lymph node dissection (RPLND) have reported survival rates greater than 95%,^1-6 and no significant difference in relapse-free or overall survival was reported in a prospective, nonrandomized trial.⁷ Recently, the European Germ Cell Cancer Consensus Group recommended chemotherapy for CS IIA and IIB NSGCT, though observation and RPLND were alternatives for patients with negative serum tumor markers and adenopathy less than 2 cm.⁸

Treatment considerations for CS IIA and IIB NSGCT include the risks of occult systemic disease, treatment-related morbidity, and the presence of chemotherapy-resistant malignant germ cell tumor (GCT) and teratoma. Regarding the latter point, we have advocated postchemotherapy (PC-) RPLND for all patients with residual masses after induction chemotherapy, regardless of size, because of the risks associated with unresected teratoma and viable malignancy,⁹ which are present in 20% or more of patients.^10-13 Predictive models have failed to reliably identify a subgroup of patients for whom PC-RPLND can be safely omitted.^14,15

Experience with RPLND in low-stage NSGCT throughout the last two decades has identified parameters associated with systemic progression, which include elevated postorchiectomy levels of -fetoprotein (AFP) and human choriogonadotropin (HCG), adenopathy greater than 2 cm or outside the primary landing zone, or multiple enlarged lymph nodes.^16,17 Patients with these features have increasingly been recommended over time to receive primary chemotherapy. To validate these treatment selection criteria and to establish guidelines for the treatment of CS IIA and IIB NSGCT, we analyzed their impact on relapse-free and disease-specific survival, and burden of chemotherapy.

	PATIENTS AND METHODS

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Between 1989 and 2002, 252 patients with CS IIA and IIB NSGCT were referred to our institution for definitive treatment and received RPLND (n = 136) or chemotherapy (n = 116) as their primary intervention. Patient information was obtained from a prospective RPLND database. All patients were classified as good-risk by International Germ Cell Cancer Collaborative Group criteria.¹⁸ All chemotherapy patients in this analysis received four cycles of etoposide-cisplatin (EPx4) as previously described,¹⁹ followed by PC-RPLND. Throughout this study period, all patients at our institution were recommended to undergo PC-RPLND after induction chemotherapy, with rare exceptions. Thus, the number of chemotherapy patients who did not undergo PC-RPLND and who were excluded from this analysis is anticipated to be small.

Although several patients underwent radical orchiectomy at a referring hospital, all specimens were reviewed at our institution before definitive therapy. Patients were staged with serum tumor marker determinations, computed tomography (CT) scans of the abdomen and pelvis, and either chest CT or chest x-ray. Patients were considered to have elevated AFP and/or HCG if levels were greater than 15.0 ng/mL and greater than 2.2 U/mL, respectively, and not declining according to half-life after orchiectomy. Staging was assigned according to the 2002 American Joint Committee on Cancer classification.²⁰

Of the patients who underwent RPLND, a full, bilateral and modified template dissection was performed in 58 (43%) and 78 (57%) patients, respectively. After RPLND, two cycles of adjuvant EP (EPx2) were administered to most patients with PN2-3 (> 5 nodes involved, any node > 2 cm, any extranodal extension) disease and to select patients with PN1 ( 5 nodes involved, none > 2 cm, no extranodal extension) because of anticipated noncompliance or strong patient insistence.²¹ For patients receiving chemotherapy, the residual mass size by CT imaging before PC-RPLND was 5 mm or less in 36 patients (31%), 6 to 10 mm in 32 patients (28%), 11 to 20 mm in 27 patients (23%), and 21 to 50 mm in 16 patients (14%). A full, bilateral template dissection was generally performed for patients undergoing PC-RPLND, and adjuvant EPx2 was administered to patients with evidence of viable malignancy. Postoperatively, patients were seen monthly in year 1, every second month in year 2, every third month in year 3, every fourth month in year 4, every 6 months in year 5, and annually thereafter.

We previously described the impact of selection factors on the outcome of patients undergoing primary RPLND for CS I to IIB NSGCT,¹⁶ and these criteria have been applied in a uniform manner since 1999. Thus, the impact of these selection criteria on the outcome of CS IIA to IIB patients was analyzed by comparing the years 1989 to 1993, 1994 to 1998, and 1999 to 2002. The main outcome measures were relapse-free survival, disease-specific survival, and burden of chemotherapy (assessed by the number of patients receiving chemotherapy and the number of cycles received). Categorical variables were compared using the ² or Fisher's exact test. Continuous variables were compared using the Mann-Whitney test. Survival analysis was performed using the Kaplan-Meier method, and comparisons were made using the log-rank test.²² Factors associated with disease progression and survival were analyzed in multivariable analyses using Cox proportional hazards regression.²³ For the purpose of this analysis, the primary landing zone for right-sided tumors included the para-caval, precaval, and interaortocaval regions, and the para-aortic and preaortic regions for left-sided tumors. The median follow-up after RPLND and chemotherapy was 63 months and 50 months, respectively. Statistical analysis was performed using SPSS version 14.0 (SPSS Inc, Chicago, IL). All P values result from the use of two-sided tests, and the level of significance was .05. The study was conducted under Health Insurance Portability and Accountability Act guidelines and received institutional review-board approval.

	RESULTS

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The proportion of CS IIA and IIB patients treated primarily with chemotherapy increased significantly over time from 22% in 1989 to 1993, to 48% from 1994 to 1998, to 68% from 1999 to 2002 (P < .001; Table 1). The increasing use of chemotherapy over time was seen for patients with both CS IIA and IIB. From 1989 to 1993, only 2% of CS IIA patients (1 of 45) received chemotherapy, but this increased to 45% (19 of 42) since 1999 (P < .001). Likewise, 46% of CS IIB patients underwent RPLND between 1989 and 1993, but all CS IIB patients have received chemotherapy since 1999 (P < .001).

Characteristics and Outcome of Induction Chemotherapy Patients Over Time
As a result of selecting more patients with CS IIA to receive primary chemotherapy, the median transaxial RPLN diameter decreased from 3.0 cm from 1989 to 1993 to 2.1 cm from 1994 to 2002 (P = .030; Table 3). The histology of resected specimens at PC-RPLND did not change significantly over time in terms of the proportion of patients with necrosis (50% to 64%), viable malignancy (6% to 13%), and teratoma (31% to 50%). Among the 36 patients with postchemotherapy residual masses 5 mm or smaller, 6% (95% CI, 0 to 13) had viable malignancy, and 25% (95% CI, 10 to 40) had teratoma. The 5-year relapse-free survival was excellent throughout all periods, ranging from 98% to 100% (P = .9). No cancer-related deaths have been observed for patients treated with primary chemotherapy and PC-RPLND.

	DISCUSSION

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The preferred management of CS IIA and IIB NSGCT remains controversial, as survival rates of 95% or greater are reported with cisplatin-based chemotherapy and RPLND as the primary intervention.^1-5,7 An improved understanding of disease parameters associated with systemic disease progression, an increasing appreciation of the long-term toxicity of chemotherapy, and the factors associated with the development of late relapse has more clearly defined patients appropriately suited to undergo chemotherapy or RPLND as their primary intervention. Since 1993, patients with elevated serum tumor markers and adenopathy larger than 2 cm, involving multiple lymph nodes, or located outside the primary landing zone, have been increasingly treated with chemotherapy, as those parameters are associated with the presence of occult systemic disease.¹⁶ We have also recommended PC-RPLND after induction chemotherapy to virtually all patients, due to the risks associated with unresected viable malignancy and teratoma.⁹

As a result of this patient selection, approximately two thirds of CS IIA and IIB patients now receive chemotherapy, and one third of these patients receive RPLND as their primary intervention. These selection criteria have favorably affected the outcome of these patients, as the risk of disease progression was reduced substantially without increasing the proportion who received chemotherapy (either as induction therapy, adjuvant therapy, or for treatment of relapse). Thus, we believe these refinements in patient care establish new guidelines for the management of CS IIA and IIB NSGCT.

Previous investigators have advocated primary chemotherapy and selective use of PC-RPLND for all patients with CS II NSGCT, as clinical complete responses to chemotherapy alone were achieved in 60% to 78% of patients, thus avoiding "double therapy" in the majority of patients.^2-7 However, we and others have emphasized that PC-RPLND cannot be safely omitted for patients with stable disease after induction chemotherapy, regardless of residual mass size or the absence of teratoma in the primary tumor, because of the consistent 20% or greater incidence of chemotherapy-resistant retroperitoneal disease (viable malignancy or teratoma).^10-13 Our study demonstrates that the histology of postchemotherapy specimens for patients with initial nonbulky (< 5 cm) retroperitoneal disease is similar to that of patients with more advanced disease, even for those with residual masses 5 mm or smaller.¹³ Even by treating more CS IIA and IIB patients with smaller volume disease over time, 36% to 48% of patients had residual disease at PC-RPLND, including 6% to 8% with viable malignancy. These results support the routine use of PC-RPLND after induction chemotherapy, even for those with nonbulky retroperitoneal disease at diagnosis, to avoid the risk of late recurrence associated with unresected chemotherapy-resistant disease. Thus, the avoidance of "double therapy" for CS II NSGCT patients is not an appropriate treatment consideration, as PC-RPLND should be performed routinely in patients after induction chemotherapy, with few exceptions.

However, limiting the number of patients receiving chemotherapy to avoid its long-term toxicity is an important consideration in the management of CS II A and IIB NSGCT, particularly given that 36% in our series were PS I. Serious long-term sequelae of chemotherapy among GCT survivors include cardiovascular disease and secondary malignancies.^24-26 In contrast, RPLND, in the hands of experienced surgeons, is associated with negligible perioperative mortality, a 1% risk of small bowel obstruction, and ejaculatory dysfunction in 5% of patients when nerve-sparing techniques are used.^27-30 Although 32% of CS IIA and IIB patients received adjuvant chemotherapy after RPLND in our series, the toxicity of two cycles of chemotherapy seems to be substantially less than a full induction regimen.^19,21,31,32 Increasingly selecting more patients to receive primary chemotherapy over time has not significantly increased the proportion receiving chemotherapy (70% v 79% pre-1999 and post-1999, respectively), and chemotherapy is still avoided in 21% of patients overall who were treated since 1999. Although patients after 1999 received an average of 0.6 cycles more chemotherapy, the clinical significance of this slight but statistically significant increase is not known in terms of long-term toxicity.

Although our selection criteria favorably affected the risk of relapse after primary definitive therapy, the 5-year disease-specific survival rates of patients treated before and after 1999 were 99% and 100%, respectively. Likewise, excellent disease-specific survival rates were observed for patients treated by both modalities. These results highlight the excellent prognosis of NSGCT patients when chemotherapy and surgery are optimally integrated, regardless of the sequence of therapy.

For patients with PS II disease who receive adjuvant chemotherapy after RPLND, the reported risk of relapse is 1% to 7%, and disease-specific survival approaches 100%.^7,21,31,33 Based on these excellent overall results, RPLND and adjuvant chemotherapy is considered by some to be the preferred intervention for CS IIA and IIB patients. However, we believe that primary chemotherapy is preferred for patients at high risk for systemic disease (as defined by our selection criteria), as a small but potentially significant risk of rapid disease progression may exist, particularly if chemotherapy after RPLND is delayed because of perioperative complications or prolonged convalescence. Persistence of disease after RPLND requiring a full induction chemotherapy regimen was observed in 13% of patients in our series and in 15% of patients in the trial of Weissbach et al.⁷ The only two cancer-related deaths in our study occurred in patients with persistence of disease after RPLND (both of whom had either elevated serum tumor markers, lymph nodes > 2 cm, or multiple retroperitoneal masses), highlighting the need for primary chemotherapy in patients at high risk for systemic disease. Conversely, patients with normal postorchiectomy AFP and HCG, adenopathy 2 cm or smaller, and a solitary retroperitoneal mass in the primary landing zone, are better suited to undergo RPLND. This is supported by our evidence that these patients have a 48% rate of PS I disease, a 17% rate of retroperitoneal teratoma, and that two thirds of those with PS II have PN1 disease for which RPLND alone may be curative in as many as 90%.¹⁶

An important limitation of this study is the fact that patients who did not undergo PC-RPLND after primary chemotherapy were not included in the analysis. However, during the last two decades, all NSGCT patients with normal AFP and HCG after chemotherapy have been recommended to undergo PC-RPLND, with rare exceptions.¹⁰ Thus, the number of CS IIA and IIB patients who achieved a complete radiographic response to chemotherapy and who also declined to undergo recommended PC-RPLND during the period of this study is anticipated to be small. In support of this claim, 59% (95% CI, 50 to 69) of patients in our study who underwent PC-RPLND had a complete radiographic response to chemotherapy (defined as no retroperitoneal lymph node greater than 1 cm),³⁴ which is similar to the 60% to 78% complete responses reported in the CS II NSGCT primary chemotherapy series.^2-7 The exclusion of these patients is not likely to affect our primary outcome measures significantly, as the number is small and the excluded patient population has a risk of relapse after induction chemotherapy of only 6.4%.³⁴ The ability to salvage patients who relapse after first-line chemotherapy is only 35% to 65%^35-37; thus, our results may slightly overestimate the outcome of all CS IIA and IIB patients who received chemotherapy as primary intervention.

An interesting finding of our study is the 7.7% overall incidence of viable malignancy in the retroperitoneum among patients with initial nonbulky retroperitoneal disease treated with a full induction course of chemotherapy, even for those with residual masses 5 mm or smaller. This result has remained constant despite treating smaller-volume disease over time. This finding has important implications for CS I NSGCT patients receiving adjuvant chemotherapy, as it suggests a consistent 5% to 10% incidence of viable malignancy in the retroperitoneum after good-risk chemotherapy regimens, regardless of the initial disease burden.

In summary, neither chemotherapy nor RPLND alone is sufficient as monotherapy for the majority of patients with CS IIA-B NSGCT and our patient selection criteria are effective in identifying the appropriate primary intervention. Chemotherapy is the preferred intervention for patients with elevated postorchiectomy serum tumor markers, retroperitoneal adenopathy greater than 2 cm or outside the primary landing zone, or involving multiple nodes given the high risk of systemic progression. PC-RPLND should be performed in all patients with residual masses due to the risks associated with unresected viable malignancy or teratoma. RPLND is the preferred modality for patients with normal postorchiectomy serum tumor markers with a solitary retroperitoneal mass less than 2 cm in size that is limited to the primary landing zone. Excellent long-term outcomes are anticipated when these guidelines are rigorously applied.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Conception and design: Andrew J. Stephenson, George J. Bosl, Robert J. Motzer, Dean F. Bajorin, Jason P. Stasi, Joel Sheinfeld

Administrative support: Jason P. Stasi

Provision of study materials or patients: George J. Bosl, Robert J. Motzer, Dean F. Bajorin, Joel Sheinfeld

Collection and assembly of data: Andrew J. Stephenson, Joel Sheinfeld

Data analysis and interpretation: Andrew J. Stephenson, George J. Bosl, Robert J. Motzer, Dean F. Bajorin, Joel Sheinfeld

Manuscript writing: Andrew J. Stephenson, Joel Sheinfeld

Final approval of manuscript: Andrew J. Stephenson, George J. Bosl, Robert J. Motzer, Dean F. Bajorin, Jason P. Stasi, Joel Sheinfeld

	NOTES

 
Presented in part at the 2005 American Urological Association Annual Meeting, San Antonio, TX, May 21-26, 2005.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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Submitted April 5, 2007; accepted August 16, 2007.

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