Retroperitoneal Lymph Node Dissection for Nonseminomatous Germ Cell Testicular Cancer: Impact of Patient Selection Factors on Outcome
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《临床肿瘤学》
the Departments of Urology, Epidemiology, and Biostatistics, and Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, New York, NY
ABSTRACT
PURPOSE: To investigate the impact of patient selection criteria on the outcome of patients with nonseminomatous germ cell testicular cancer (NSGCT) treated by primary retroperitoneal lymph node dissection (RPLND). Since 1999, our criteria have excluded patients with persistent postorchiectomy elevation of serum tumor markers (STM) or clinical stage (CS) IIB disease from RPLND.
PATIENTS AND METHODS: Between 1989 and 2002, 453 patients underwent primary RPLND at our institution for CS I to IIB NSGCT. Patient information was obtained from a prospective database. Retroperitoneal pathology and relapse rates were compared for patients treated before and after application of the current selection criteria in 1999.
RESULTS: By excluding patients with elevated STM or CS IIB disease after 1999, the proportion of pathologic stage II patients with low-volume (pN1) retroperitoneal disease increased significantly (40% before 1999 v 64% after 1999; P = .01), without significantly affecting the rate of retroperitoneal teratoma (21% v 22%, respectively; P = .89) or pathologic stage I disease (56% v 67%, respectively; P = .06). For patients who did not receive adjuvant chemotherapy, the 4-year progression-free probability improved significantly from 83% before 1999 (95% CI, 79% to 88%) to 96% after 1999 (95% CI, 91% to 100%; P = .005). Elevated postorchiectomy STM (P < .0001), clinical stage (P = .0002), and pre-1999 RPLND (P = .05) were independent pretreatment predictors of progression.
CONCLUSION: Excluding patients with CS IIB disease or elevated postorchiectomy STM from primary RPLND has had a favorable impact on the extent of retroperitoneal disease and has significantly reduced the risk of relapse after RPLND. For patients with normal STM and CS I to IIA disease, the low rate of systemic progression and 22% incidence of retroperitoneal teratoma supports RPLND as the preferred primary intervention.
INTRODUCTION
In 2004, an estimated 6,000 men will be diagnosed with nonseminomatous germ cell testicular cancer (NSGCT) in the United States, and approximately 70% will have clinical stage (CS) I, IIA, or IIB disease at initial presentation.1,2 More than 95% of these low-stage patients are cured with either retroperitoneal lymph node dissection (RPLND) or cisplatin-based chemotherapy.3-6 Given the excellent results with surgery and chemotherapy, recent efforts have focused on developing management strategies to minimize treatment-related morbidity without compromising cure.
The rationale for primary RPLND for patients with CS I to IIB NSGCT is based on evidence that the retroperitoneum is the initial site of metastatic spread in more than 80% of patients, and it is also the most frequent site of chemoresistant malignant germ cell cancer and teratoma.2,7-9 RPLND is preferred over induction chemotherapy for the majority of patients with low-stage NSGCT because the long-term morbidity of RPLND is considerably less, infield retroperitoneal relapse after a proper RPLND is rare, and most patients with low-volume retroperitoneal disease are cured after RPLND alone. However, a minority of CS I to IIB patients has occult systemic metastases, and these patients may be better managed with induction chemotherapy and surgical resection of residual masses.
An understanding of the pretreatment variables associated with disease progression and the increased sensitivity of computed tomography (CT) imaging for clinical staging of the thorax have more clearly defined the patients at highest risk for systemic relapse. We previously reported that elevated postorchiectomy levels of the serum tumor markers (STM) alpha fetoprotein (AFP) and/or beta human chorionic gonadotropin (HCG) predict for persistence of disease after RPLND for patients with CS I and pathologic stage (PS) pN2-3 disease10,11 and for relapse in patients with pN1 disease.12 Other investigators have reported that most patients with CS IIB disease have extensive retroperitoneal disease (pN2-3),13,14 and most studies have reported relapses in more than 50% of these patients.4,15-18
The criteria to select patients with NSGCT for primary RPLND at our institution have evolved over the last decade as the variables associated with disease relapse were identified. We recommend induction chemotherapy to patients with persistently elevated postorchiectomy STM or CS IIB. Patients with rapid progression on interval abdominal imaging, tumor-related back pain, or adenopathy in the suprahilar or pelvic regions or intimately associated with the renal hilum also receive induction chemotherapy because of the risk of relapse or injury to adjacent viscera.19 These selection criteria have been applied in a uniform manner at our institution since 1999. We evaluated the impact of these selection criteria on retroperitoneal pathology and relapse rates by comparing patients treated before and after 1999.
PATIENTS AND METHODS
Between 1989 and 2002, 453 patients with CS I to IIB NSGCT underwent primary RPLND. All patients were classified as good risk by International Germ Cell Consensus Classification Group criteria.20 Clinical information was obtained from an institutional review board–approved prospective database. Although several patients underwent initial radical orchiectomy at a referring institution, all orchiectomy specimens were reviewed by pathologists at our institution before RPLND. Patients were classified as having embryonal carcinoma (EC) predominance if EC constituted more than 50% of the tumor in the orchiectomy specimen. The presence of lymphovascular invasion (LVI) was assigned if aggregations of tumor cells were seen within the lumen of an artery, vein, or lymphatic vessel.
Patients were staged preoperatively by serum AFP, HCG, and lactate dehydrogenase, CT of the abdomen and pelvis, and either chest CT imaging (n = 251) or chest x-ray (n = 202). Patients were considered to have elevated STM if the level of AFP and/or HCG was elevated (> 15.0 ng/mL for AFP and > 2.2 U/mL for HCG) and not declining according to half-life after orchiectomy. CS was assigned according to the 2002 American Joint Committee on Cancer classification.21
After RPLND, two cycles of etoposide-cisplatin (EP) as adjuvant therapy were administered to most patients with pN2-3 disease because of the high risk of relapse22 and to selected patients with pN1 disease because of anticipated noncompliance or strong patient insistence for psychological or occupational reasons. 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 then annually thereafter. At each visit, a history, physical examination, chest x-ray, and STM were performed. A baseline abdominal CT scan was routinely obtained 2 to 4 months after RPLND.
The current selection criteria for primary RPLND have been applied in a uniform manner at our institution since 1999. Their impact on retroperitoneal pathology and relapse was analyzed by comparing patients managed before and after 1999. Categoric variables were compared between patient groups using the 2 or Fisher's exact test. Cancer-specific survival and progression-free probability (PFP) were estimated using the Kaplan-Meier method.23 Factors associated with disease progression after RPLND were analyzed in multivariable analyses using Cox proportional hazards regression. In the multivariable analysis, the use of adjuvant chemotherapy was treated as a time-dependent covariate.24 Competing risk analysis was used to estimate the risk of systemic and local progression over time. The median follow-up was 59 months overall (range, 2 to 179 months), and 81 and 30 months for patients treated before and after 1999, respectively. Statistical analysis was performed using SPSS version 10.0 (SPSS Inc, Chicago, IL) and R version 1.9.0 (The R Foundation for Statistical Computing, http://www.r-project.org) statistical software.
RESULTS
Preoperative Patient Characteristics
The patient clinical features are listed in Table 1. Overall, 308 (68%), 122 (27%), and 23 (5%) patients had CS I, IIA, and IIB disease, respectively. Twenty-six patients (6%) had elevated STM (10 CS I patients, nine CS IIA patients, and seven CS IIB patients). Since 1999, no patient with CS IIB disease or elevated STM has undergone primary RPLND. Regarding the histology of the orchiectomy specimen, the proportion of patients with EC predominance, teratoma, and yolk sac tumor did not change significantly over time, although LVI was more common in patients after 1999 than before 1999 (70% v 56%, respectively; P = .008). After 1999, CT imaging was used more frequently to stage the thorax preoperatively (74% after 1999 v 50% before 1999; P < .0001). The proportion of patients who underwent a full, bilateral template dissection (48% after 1999 v 24% before 1999; P < .0001) and the number of lymph nodes resected (median, 35 nodes after 1999 v 27 nodes before 1999; P = .0002) were significantly higher after 1999.
Pathologic Findings at RPLND
Overall, 187 patients (41%) had positive retroperitoneal nodes (PS II) at RPLND (Table 2). The pathologic findings at RPLND were more favorable for patients treated after 1999 because significantly more post-1999 PS II patients had low-volume disease (pN1) compared with the pre-1999 PS II patients (64% v 40%, respectively; P = .01). Despite more patients with pN1 disease after 1999, the rate of retroperitoneal teratoma remained constant (21% before 1999 v 22% after 1999; P = .9). Overall, 266 patients (59%) had pathologically negative retroperitoneal lymph nodes (PS I), including 217 patients (70%) with CS I and 49 patients (40%) with CS IIA disease; all CS IIB patients were PS II. Although the extent of retroperitoneal disease decreased over time, the proportion of patients with PS I disease did not increase significantly (PS I rate 56% before 1999 v 67% after 1999; P = .06; Table 2).
Adjuvant Chemotherapy
Overall, 93 patients with PS II disease (50%) received two cycles of adjuvant EP, with significantly more pN1 (52% after 1999 v 10% before 1999; P < .0001) and pN2 patients (100% after 1999 v 69% before 1999; P = .02) receiving adjuvant chemotherapy after 1999. The pN1 patients who did and did not receive adjuvant chemotherapy did not differ significantly in terms of the proportion with testicular teratoma (39% v 53%, respectively; P = .3), EC predominance (44% v 32%, respectively; P = .3), elevated STM (5% v 3%, respectively; P = 0.6), LVI (67% v 65%, respectively; P = .9), or malignant germ cell cancer in the retroperitoneal nodes (89% v 91%, respectively; P = .8).
Outcome After RPLND
Three patients died from progressive testicular cancer (one patient each with CS I, IIA, and IIB disease). The 4-year cancer-specific survival rate was 99% (95% CI, 98% to 100%) for pre-1999 patients and 100% for post-1999 patients (P = .5).
Overall, 47 patients relapsed after RPLND, including one patient who relapsed after receiving adjuvant chemotherapy. Among patients who did not receive adjuvant chemotherapy, those treated after 1999 had a significantly better prognosis (4-year PFP, 83% before 1999 v 96% after 1999; P = .005; Table 3 and Fig 1). The improved relapse rate after 1999 was still evident when completely resected pN2 patients were excluded (4-year PFP, 85% before 1999 v 96% after 1999; P = .01). Nonstatistically significant trends towards improved relapse rates after 1999 were observed for patients with PS I (4-year PFP, 92% before 1999 v 97% after 1999; P = .2) and pN1 disease (4-year PFP, 79% before 1999 v 90% after 1999; P = .4; Table 3).
The risk of systemic relapse also improved significantly over time. The 4-year risk of systemic progression was 14% before 1999 (95% CI, 12% to 15%) versus 1.3% after 1999 (95% CI, 0.5% to 2%; P = .002; Fig 2). The one patient with systemic relapse after 1999 (CS I, PS I) experienced recurrence in an inguinal lymph node, which was likely secondary to aberrant testicular lymphatic drainage. The two other post-1999 patients who relapsed did so in the retroperitoneum; one pN1 patient had a suprahilar recurrence after a full, bilateral RPLND, and one PS I patient had a para-aortic recurrence after a modified RPLND. The rarity of systemic relapse after 1999 suggests an improved ability to risk stratify patients for systemic disease using the current selection criteria.
Pre-RPLND Predictors of Progression
Considering all patients, elevated postorchiectomy STM (hazard ratio [HR], 5.6; P < .0001), CS IIB disease (HR, 12.3; P < .0001), and pre-1999 RPLND (HR, 3.3; P = .05) were significant predictors of progression after adjusting for the use of adjuvant chemotherapy (HR, 0.03; P < .0001; Table 4). Of the 42 patients with either elevated STM or CS IIB disease, 36 patients (86%) had pN2 disease, and the 4-year PFP in the absence of adjuvant chemotherapy was 28% (95% CI, 8% to 47%). Patients with elevated STM and/or CS IIB disease had a diminished cancer-specific survival compared with patients with CS I to IIA disease and normal STM (5-year disease-specific survival, 94% v 99.7%, respectively; P = .0001).
Since 1999, 40 patients with low-stage NSGCT and either CS IIB disease or elevated STM have been referred to our institution for definitive management. All patients received induction chemotherapy with four cycles of EP followed by postchemotherapy RPLND. The progression rate for these patients was significantly better than for the 42 patients with elevated STM and CS IIB disease who were managed by RPLND before 1999 (of whom, 20 patients received two cycles of adjuvant EP; 4-year PFP, 97% v 60%, respectively; P < .0001). Although not statistically significant, a trend towards improved 4-year overall survival (100% after 1999 v 90% before 1999; P = .2) and disease-specific survival (100% after 1999 v 94% before 1999, P = 0.3) was observed among patients with elevated STM or CS IIB disease who were treated by induction chemotherapy after 1999 versus primary RPLND before 1999.
DISCUSSION
Since 1999, we have restricted primary RPLND to patients with normal postorchiectomy STM, CS I to IIA disease, and stable retroperitoneal disease between the renal vessels and common iliac bifurcation. Patients with CS IIB disease or elevated STM currently receive induction chemotherapy. As a result of these selection criteria, substantially more patients with PS II disease were likely to be cured by RPLND alone (by virtue of having pN1 disease) without significantly increasing the proportion of patients with pathologically negative nodes. More importantly, the overall relapse rate decreased significantly over time, and currently the risk of systemic disease progression among patients selected for RPLND is low. The fact that the treatment year was an independent predictor of progression suggests that selection factors besides STM status and CS have contributed to low rates of progression. Alternatively, the prognostic significance of treatment year may be secondary to a stage migration phenomenon. Despite the influence of these selection criteria on the extent of retroperitoneal disease and progression, the incidence of retroperitoneal teratoma did not change over time. The 22% incidence of retroperitoneal teratoma and the low rate of systemic progression support RPLND as the preferred primary intervention for patients with CS I to IIA disease and normal postorchiectomy AFP and HCG.
Experience with RPLND has identified factors that predict for disease progression, which thereby identify candidates for induction chemotherapy. These results confirm our previous observations regarding the prognostic significance of elevated postorchiectomy serum levels of AFP or HCG for disease progression; CS was also a significant predictor of relapse.10-12 The vast majority of patients with elevated STM or CS IIB disease had extensive (pN2) retroperitoneal disease, and only an estimated 28% were free of disease in the absence of systemic therapy. These patients also had a diminished cancer-specific survival compared with patients with CS I to IIA disease and normal STM. The poor results achieved with primary RPLND alone argue for induction chemotherapy as the primary intervention, followed by postchemotherapy resection of residual masses. In support of this change in practice, patients with elevated STM or CS IIB disease who were treated with induction chemotherapy after 1999 had a significantly lower risk of progression compared with similar patients treated by primary RPLND before 1999, and there was a nonsignificant trend towards improved 4-year overall and disease-specific survival.
An alternative strategy for patients with CS IIB disease or elevated STM is RPLND followed by adjuvant chemotherapy because recurrences in this setting are reported in less than 3% of patients.15,22,25,26 In our study, relapse occurred in only one of 20 patients (4-year PFP, 95%) with CS IIB disease or elevated STM who received two cycles of adjuvant EP. However, 10 patients (24%) with CS IIB disease or elevated STM had persistence of disease (usually elevated STM) after RPLND and required an induction chemotherapy regimen. A small but potentially significant risk of disease progression also exists if chemotherapy is delayed because of perioperative complications or prolonged convalescence after RPLND (particularly for those with persistent disease). The morbidity of RPLND may also be increased in the setting of extensive retroperitoneal disease as opposed to after chemotherapy for minimal residual masses. For these reasons, we believe induction chemotherapy and postchemotherapy RPLND is preferred for patients with CS IIB disease or elevated STM.
We believe the overall improved outcomes for patients who were treated by RPLND after 1999 indicate an improved ability to risk stratify patients for occult systemic metastases rather than simply a result of restricting RPLND to low-risk patients. This view is supported by the fact that the proportion of patients with retroperitoneal metastases did not decrease significantly over time by excluding patients with elevated STM or CS IIB disease. However, of the patients with PS II disease, an increasing proportion of them were curable by RPLND alone by virtue of having low-volume (pN1) retroperitoneal metastases. Although 52% of post-1999 pN1 patients received adjuvant chemotherapy, it seems that chemotherapy could have been avoided in 90% of these patients if it had been withheld until evidence of relapse. After 1999, there was a significant reduction in the proportion of patients requiring chemotherapy as adjuvant therapy for pN2 disease (26% before 1999 v 12% after 1999) and for treatment of relapse (17% before 1999 v 12% after 1999). Of particular importance, there was a significant improvement in the rate of systemic progression after 1999 compared with before 1999 (14% v 1.3%, respectively). Patients who were selected for RPLND after 1999 were as likely to have regional metastatic disease as patients selected before 1999, but the overall risk of systemic progression and chemotherapy requirements was substantially less.
Compared with published results, the low rates of disease progression that we observed for patients with PS I and pN1 disease after 1999 is further evidence of the efficacy of these criteria for identifying patients at low risk for occult distant metastases. For patients with PS I disease, most studies have reported relapse rates of 10% to 15% after RPLND,3,4,13,14,27-29 which are similar to the 8% relapse rate that we observed before 1999. The 4% relapse rate that we observed for PS I patients after 1999 (in particular, the 1% 4-year systemic relapse rate) would seem to represent an improvement over these previous results. Likewise, for patients with pN1 disease, the 19% relapse rate for pre-1999 patients is similar to most studies, which have reported 18% to 46% progression rates after RPLND for pN1 patients.3,4,12,15-18,27,30 By comparison, the 10% relapse rate for pN1 after 1999 (including no systemic relapses) would also seem to be an improvement over previous results. Although not statistically significant, the trend towards improved relapse rates for post-1999 patients with both PS I and pN1 disease suggest that the improvement in disease progression over time as a result of these selection criteria may not solely be related to their impact on retroperitoneal pathology.
Changes in clinical practice, as opposed to these selection criteria, may have contributed to the improved clinical outcomes for patients treated after 1999. After 1999, proportionately more patients were staged preoperatively with CT chest imaging, and the number of nodes resected at RPLND was significantly higher because of the increased use of full, bilateral template dissections. However, the lack of staging CT chest imaging (P = .8) was not a predictor of relapse after RPLND in the multivariable analysis. Likewise, we did not observe a lower rate of retroperitoneal relapse after 1999 (4-year rate, 3% before 1999 v 1% after 1999; P = .4) as a result of resecting more nodes. Thus, we believe the rigorous application of selection criteria after 1999 is the main reason for the improved outcomes observed in these patients.
Despite the impact of patient selection trends on the extent of retroperitoneal disease and disease relapse, the rate of retroperitoneal teratoma has remained constant over time at 22% among patients with PS II disease. Teratoma is resistant to chemotherapy. Although it is histologically benign, its biologic potential is unpredictable. If left unresected, teratoma may grow and become unresectable,31 undergo malignant transformation,32 or result in late recurrence,9 all of which may have lethal consequences. The 20% to 30% incidence of teratoma among patients with low-stage NSGCT supports RPLND (either as primary therapy or after chemotherapy) as an essential component to the cure of these patients.
The excellent survival rates achieved in low-stage NSGCT patients with both primary RPLND and induction chemotherapy mandates that efforts be made to reduce the toxicity of treatment. After cisplatin-based chemotherapy, long-term toxicity has been reported in 20% to 30% of patients including persistent Raynaud's phenomenon (25% to 30%), sensory peripheral neuropathy (15%), ototoxicity (20%), and nephropathy (31%).33-36 Although the reported incidence of these complications is less after two cycles of chemotherapy,37,38 ototoxicity is reported in 15% of patients, and 10% to 16% of patients experience peripheral neuropathy.22,37 The risk of pulmonary toxicity is low after two cycles of bleomycin, although Raynaud's phenomenon is observed in a substantial proportion of patients.38 A 0.2% to 0.5% risk of secondary leukemias is associated with cumulative etoposide doses of 2 g/m2 or less, and there is no safe lower limit.33,39 Testicular cancer patients receiving cisplatin-based chemotherapy have a significantly increased incidence of cardiac risk factors and a 2.6- to 7.0-fold increased long-term risk of major cardiovascular events.36,40 Although Nichols et al41 did not observe an increased risk of cardiac events after two cycles of adjuvant chemotherapy over a median follow-up of 5 years, the risk of late cardiac events after two cycles is not presently known because the majority of events occurs after 10 years.36,40
In contrast, primary RPLND is associated with negligible mortality, and the major long-term morbidity is a risk of ejaculatory dysfunction of less than 5% when nerve-sparing techniques are used and a 1% to 2% incidence of small bowel obstruction.42-45 Given the increased risk of significant long-term toxicity, primary chemotherapy should be reserved to patients with a high risk of systemic disease (those with elevated STM or CS IIB disease). Primary RPLND is preferred for patients with CS I to IIA disease and normal STM given the significant risk of retroperitoneal metastases and 22% incidence of chemoresistant teratoma, the low risk of occult distant metastases, and the potential for reduced long-term treatment-related toxicity.
Surveillance is a reasonable option for CS I patients with normal postorchiectomy STM because 60% to 70% of these patients have disease confined to the orchiectomy specimen. However, patient compliance is essential to successful surveillance. Noncompliance rates of 30% to 80% have been reported in surveillance series, and these patients frequently relapse with advanced disease.46,47 The inability to successfully treat all patients with salvage therapy is highlighted by the 2% to 5% cancer-specific death rates reported in several surveillance series.47-50 In our own series, the cancer-specific mortality rate on surveillance was 2.8%.50 In contrast, the cancer-specific survival rate after primary RPLND for CS I patients in the cisplatin era in the Memorial Sloan-Kettering Cancer Center and Indiana experience was 100% (297 patients) and 99.4% (666 of 670 patients), respectively.3,27 At our institution, surveillance is restricted to CS I patients without evidence of LVI or EC predominance in whom compliance is anticipated.
In summary, we believe the results of this analysis of our experience with primary RPLND for NSGCT validate the selection criteria that we have used. These selection criteria have not increased the proportion of patients with pathologically negative nodes. However, most patients with PS II disease have pN1 disease, and the overall risk of systemic progression is 1.3%. These selection criteria effectively identify a cohort of patients with isolated retroperitoneal metastases who are likely to be cured after RPLND alone and can be spared the long-term toxicity of chemotherapy. Patients with elevated STM or CS IIB disease are at high risk for systemic progression. Our current practice of induction chemotherapy followed by postchemotherapy RPLND for these patients is justified given the significant improvement in disease progression and the trend towards improved disease-specific and overall survival compared with primary RPLND. The 22% incidence of teratoma in the retroperitoneum, which has not changed over time, emphasizes the importance of RPLND (either as primary therapy or after induction chemotherapy) as an essential component to the successful treatment of patients with NSGCT.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Supported in part by a grant from the American Foundation for Urologic Disease, training grant No. T32-82088 from the National Institutes of Health (Bethesda, MD), and a gift from the Tina and Richard V. Carolan Foundation (all to A.J.S.).
Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Pizzocaro G, Zanoni F, Milani A, et al: Orchiectomy alone in clinical stage I nonseminomatous testis cancer: A critical appraisal. J Clin Oncol 4:35-40, 1986
Sogani PC, Perrotti M, Herr HW, et al: Clinical stage I testis cancer: Long-term outcome of patients on surveillance. J Urol 159:855-858, 1998(Andrew J. Stephenson, Geo)
ABSTRACT
PURPOSE: To investigate the impact of patient selection criteria on the outcome of patients with nonseminomatous germ cell testicular cancer (NSGCT) treated by primary retroperitoneal lymph node dissection (RPLND). Since 1999, our criteria have excluded patients with persistent postorchiectomy elevation of serum tumor markers (STM) or clinical stage (CS) IIB disease from RPLND.
PATIENTS AND METHODS: Between 1989 and 2002, 453 patients underwent primary RPLND at our institution for CS I to IIB NSGCT. Patient information was obtained from a prospective database. Retroperitoneal pathology and relapse rates were compared for patients treated before and after application of the current selection criteria in 1999.
RESULTS: By excluding patients with elevated STM or CS IIB disease after 1999, the proportion of pathologic stage II patients with low-volume (pN1) retroperitoneal disease increased significantly (40% before 1999 v 64% after 1999; P = .01), without significantly affecting the rate of retroperitoneal teratoma (21% v 22%, respectively; P = .89) or pathologic stage I disease (56% v 67%, respectively; P = .06). For patients who did not receive adjuvant chemotherapy, the 4-year progression-free probability improved significantly from 83% before 1999 (95% CI, 79% to 88%) to 96% after 1999 (95% CI, 91% to 100%; P = .005). Elevated postorchiectomy STM (P < .0001), clinical stage (P = .0002), and pre-1999 RPLND (P = .05) were independent pretreatment predictors of progression.
CONCLUSION: Excluding patients with CS IIB disease or elevated postorchiectomy STM from primary RPLND has had a favorable impact on the extent of retroperitoneal disease and has significantly reduced the risk of relapse after RPLND. For patients with normal STM and CS I to IIA disease, the low rate of systemic progression and 22% incidence of retroperitoneal teratoma supports RPLND as the preferred primary intervention.
INTRODUCTION
In 2004, an estimated 6,000 men will be diagnosed with nonseminomatous germ cell testicular cancer (NSGCT) in the United States, and approximately 70% will have clinical stage (CS) I, IIA, or IIB disease at initial presentation.1,2 More than 95% of these low-stage patients are cured with either retroperitoneal lymph node dissection (RPLND) or cisplatin-based chemotherapy.3-6 Given the excellent results with surgery and chemotherapy, recent efforts have focused on developing management strategies to minimize treatment-related morbidity without compromising cure.
The rationale for primary RPLND for patients with CS I to IIB NSGCT is based on evidence that the retroperitoneum is the initial site of metastatic spread in more than 80% of patients, and it is also the most frequent site of chemoresistant malignant germ cell cancer and teratoma.2,7-9 RPLND is preferred over induction chemotherapy for the majority of patients with low-stage NSGCT because the long-term morbidity of RPLND is considerably less, infield retroperitoneal relapse after a proper RPLND is rare, and most patients with low-volume retroperitoneal disease are cured after RPLND alone. However, a minority of CS I to IIB patients has occult systemic metastases, and these patients may be better managed with induction chemotherapy and surgical resection of residual masses.
An understanding of the pretreatment variables associated with disease progression and the increased sensitivity of computed tomography (CT) imaging for clinical staging of the thorax have more clearly defined the patients at highest risk for systemic relapse. We previously reported that elevated postorchiectomy levels of the serum tumor markers (STM) alpha fetoprotein (AFP) and/or beta human chorionic gonadotropin (HCG) predict for persistence of disease after RPLND for patients with CS I and pathologic stage (PS) pN2-3 disease10,11 and for relapse in patients with pN1 disease.12 Other investigators have reported that most patients with CS IIB disease have extensive retroperitoneal disease (pN2-3),13,14 and most studies have reported relapses in more than 50% of these patients.4,15-18
The criteria to select patients with NSGCT for primary RPLND at our institution have evolved over the last decade as the variables associated with disease relapse were identified. We recommend induction chemotherapy to patients with persistently elevated postorchiectomy STM or CS IIB. Patients with rapid progression on interval abdominal imaging, tumor-related back pain, or adenopathy in the suprahilar or pelvic regions or intimately associated with the renal hilum also receive induction chemotherapy because of the risk of relapse or injury to adjacent viscera.19 These selection criteria have been applied in a uniform manner at our institution since 1999. We evaluated the impact of these selection criteria on retroperitoneal pathology and relapse rates by comparing patients treated before and after 1999.
PATIENTS AND METHODS
Between 1989 and 2002, 453 patients with CS I to IIB NSGCT underwent primary RPLND. All patients were classified as good risk by International Germ Cell Consensus Classification Group criteria.20 Clinical information was obtained from an institutional review board–approved prospective database. Although several patients underwent initial radical orchiectomy at a referring institution, all orchiectomy specimens were reviewed by pathologists at our institution before RPLND. Patients were classified as having embryonal carcinoma (EC) predominance if EC constituted more than 50% of the tumor in the orchiectomy specimen. The presence of lymphovascular invasion (LVI) was assigned if aggregations of tumor cells were seen within the lumen of an artery, vein, or lymphatic vessel.
Patients were staged preoperatively by serum AFP, HCG, and lactate dehydrogenase, CT of the abdomen and pelvis, and either chest CT imaging (n = 251) or chest x-ray (n = 202). Patients were considered to have elevated STM if the level of AFP and/or HCG was elevated (> 15.0 ng/mL for AFP and > 2.2 U/mL for HCG) and not declining according to half-life after orchiectomy. CS was assigned according to the 2002 American Joint Committee on Cancer classification.21
After RPLND, two cycles of etoposide-cisplatin (EP) as adjuvant therapy were administered to most patients with pN2-3 disease because of the high risk of relapse22 and to selected patients with pN1 disease because of anticipated noncompliance or strong patient insistence for psychological or occupational reasons. 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 then annually thereafter. At each visit, a history, physical examination, chest x-ray, and STM were performed. A baseline abdominal CT scan was routinely obtained 2 to 4 months after RPLND.
The current selection criteria for primary RPLND have been applied in a uniform manner at our institution since 1999. Their impact on retroperitoneal pathology and relapse was analyzed by comparing patients managed before and after 1999. Categoric variables were compared between patient groups using the 2 or Fisher's exact test. Cancer-specific survival and progression-free probability (PFP) were estimated using the Kaplan-Meier method.23 Factors associated with disease progression after RPLND were analyzed in multivariable analyses using Cox proportional hazards regression. In the multivariable analysis, the use of adjuvant chemotherapy was treated as a time-dependent covariate.24 Competing risk analysis was used to estimate the risk of systemic and local progression over time. The median follow-up was 59 months overall (range, 2 to 179 months), and 81 and 30 months for patients treated before and after 1999, respectively. Statistical analysis was performed using SPSS version 10.0 (SPSS Inc, Chicago, IL) and R version 1.9.0 (The R Foundation for Statistical Computing, http://www.r-project.org) statistical software.
RESULTS
Preoperative Patient Characteristics
The patient clinical features are listed in Table 1. Overall, 308 (68%), 122 (27%), and 23 (5%) patients had CS I, IIA, and IIB disease, respectively. Twenty-six patients (6%) had elevated STM (10 CS I patients, nine CS IIA patients, and seven CS IIB patients). Since 1999, no patient with CS IIB disease or elevated STM has undergone primary RPLND. Regarding the histology of the orchiectomy specimen, the proportion of patients with EC predominance, teratoma, and yolk sac tumor did not change significantly over time, although LVI was more common in patients after 1999 than before 1999 (70% v 56%, respectively; P = .008). After 1999, CT imaging was used more frequently to stage the thorax preoperatively (74% after 1999 v 50% before 1999; P < .0001). The proportion of patients who underwent a full, bilateral template dissection (48% after 1999 v 24% before 1999; P < .0001) and the number of lymph nodes resected (median, 35 nodes after 1999 v 27 nodes before 1999; P = .0002) were significantly higher after 1999.
Pathologic Findings at RPLND
Overall, 187 patients (41%) had positive retroperitoneal nodes (PS II) at RPLND (Table 2). The pathologic findings at RPLND were more favorable for patients treated after 1999 because significantly more post-1999 PS II patients had low-volume disease (pN1) compared with the pre-1999 PS II patients (64% v 40%, respectively; P = .01). Despite more patients with pN1 disease after 1999, the rate of retroperitoneal teratoma remained constant (21% before 1999 v 22% after 1999; P = .9). Overall, 266 patients (59%) had pathologically negative retroperitoneal lymph nodes (PS I), including 217 patients (70%) with CS I and 49 patients (40%) with CS IIA disease; all CS IIB patients were PS II. Although the extent of retroperitoneal disease decreased over time, the proportion of patients with PS I disease did not increase significantly (PS I rate 56% before 1999 v 67% after 1999; P = .06; Table 2).
Adjuvant Chemotherapy
Overall, 93 patients with PS II disease (50%) received two cycles of adjuvant EP, with significantly more pN1 (52% after 1999 v 10% before 1999; P < .0001) and pN2 patients (100% after 1999 v 69% before 1999; P = .02) receiving adjuvant chemotherapy after 1999. The pN1 patients who did and did not receive adjuvant chemotherapy did not differ significantly in terms of the proportion with testicular teratoma (39% v 53%, respectively; P = .3), EC predominance (44% v 32%, respectively; P = .3), elevated STM (5% v 3%, respectively; P = 0.6), LVI (67% v 65%, respectively; P = .9), or malignant germ cell cancer in the retroperitoneal nodes (89% v 91%, respectively; P = .8).
Outcome After RPLND
Three patients died from progressive testicular cancer (one patient each with CS I, IIA, and IIB disease). The 4-year cancer-specific survival rate was 99% (95% CI, 98% to 100%) for pre-1999 patients and 100% for post-1999 patients (P = .5).
Overall, 47 patients relapsed after RPLND, including one patient who relapsed after receiving adjuvant chemotherapy. Among patients who did not receive adjuvant chemotherapy, those treated after 1999 had a significantly better prognosis (4-year PFP, 83% before 1999 v 96% after 1999; P = .005; Table 3 and Fig 1). The improved relapse rate after 1999 was still evident when completely resected pN2 patients were excluded (4-year PFP, 85% before 1999 v 96% after 1999; P = .01). Nonstatistically significant trends towards improved relapse rates after 1999 were observed for patients with PS I (4-year PFP, 92% before 1999 v 97% after 1999; P = .2) and pN1 disease (4-year PFP, 79% before 1999 v 90% after 1999; P = .4; Table 3).
The risk of systemic relapse also improved significantly over time. The 4-year risk of systemic progression was 14% before 1999 (95% CI, 12% to 15%) versus 1.3% after 1999 (95% CI, 0.5% to 2%; P = .002; Fig 2). The one patient with systemic relapse after 1999 (CS I, PS I) experienced recurrence in an inguinal lymph node, which was likely secondary to aberrant testicular lymphatic drainage. The two other post-1999 patients who relapsed did so in the retroperitoneum; one pN1 patient had a suprahilar recurrence after a full, bilateral RPLND, and one PS I patient had a para-aortic recurrence after a modified RPLND. The rarity of systemic relapse after 1999 suggests an improved ability to risk stratify patients for systemic disease using the current selection criteria.
Pre-RPLND Predictors of Progression
Considering all patients, elevated postorchiectomy STM (hazard ratio [HR], 5.6; P < .0001), CS IIB disease (HR, 12.3; P < .0001), and pre-1999 RPLND (HR, 3.3; P = .05) were significant predictors of progression after adjusting for the use of adjuvant chemotherapy (HR, 0.03; P < .0001; Table 4). Of the 42 patients with either elevated STM or CS IIB disease, 36 patients (86%) had pN2 disease, and the 4-year PFP in the absence of adjuvant chemotherapy was 28% (95% CI, 8% to 47%). Patients with elevated STM and/or CS IIB disease had a diminished cancer-specific survival compared with patients with CS I to IIA disease and normal STM (5-year disease-specific survival, 94% v 99.7%, respectively; P = .0001).
Since 1999, 40 patients with low-stage NSGCT and either CS IIB disease or elevated STM have been referred to our institution for definitive management. All patients received induction chemotherapy with four cycles of EP followed by postchemotherapy RPLND. The progression rate for these patients was significantly better than for the 42 patients with elevated STM and CS IIB disease who were managed by RPLND before 1999 (of whom, 20 patients received two cycles of adjuvant EP; 4-year PFP, 97% v 60%, respectively; P < .0001). Although not statistically significant, a trend towards improved 4-year overall survival (100% after 1999 v 90% before 1999; P = .2) and disease-specific survival (100% after 1999 v 94% before 1999, P = 0.3) was observed among patients with elevated STM or CS IIB disease who were treated by induction chemotherapy after 1999 versus primary RPLND before 1999.
DISCUSSION
Since 1999, we have restricted primary RPLND to patients with normal postorchiectomy STM, CS I to IIA disease, and stable retroperitoneal disease between the renal vessels and common iliac bifurcation. Patients with CS IIB disease or elevated STM currently receive induction chemotherapy. As a result of these selection criteria, substantially more patients with PS II disease were likely to be cured by RPLND alone (by virtue of having pN1 disease) without significantly increasing the proportion of patients with pathologically negative nodes. More importantly, the overall relapse rate decreased significantly over time, and currently the risk of systemic disease progression among patients selected for RPLND is low. The fact that the treatment year was an independent predictor of progression suggests that selection factors besides STM status and CS have contributed to low rates of progression. Alternatively, the prognostic significance of treatment year may be secondary to a stage migration phenomenon. Despite the influence of these selection criteria on the extent of retroperitoneal disease and progression, the incidence of retroperitoneal teratoma did not change over time. The 22% incidence of retroperitoneal teratoma and the low rate of systemic progression support RPLND as the preferred primary intervention for patients with CS I to IIA disease and normal postorchiectomy AFP and HCG.
Experience with RPLND has identified factors that predict for disease progression, which thereby identify candidates for induction chemotherapy. These results confirm our previous observations regarding the prognostic significance of elevated postorchiectomy serum levels of AFP or HCG for disease progression; CS was also a significant predictor of relapse.10-12 The vast majority of patients with elevated STM or CS IIB disease had extensive (pN2) retroperitoneal disease, and only an estimated 28% were free of disease in the absence of systemic therapy. These patients also had a diminished cancer-specific survival compared with patients with CS I to IIA disease and normal STM. The poor results achieved with primary RPLND alone argue for induction chemotherapy as the primary intervention, followed by postchemotherapy resection of residual masses. In support of this change in practice, patients with elevated STM or CS IIB disease who were treated with induction chemotherapy after 1999 had a significantly lower risk of progression compared with similar patients treated by primary RPLND before 1999, and there was a nonsignificant trend towards improved 4-year overall and disease-specific survival.
An alternative strategy for patients with CS IIB disease or elevated STM is RPLND followed by adjuvant chemotherapy because recurrences in this setting are reported in less than 3% of patients.15,22,25,26 In our study, relapse occurred in only one of 20 patients (4-year PFP, 95%) with CS IIB disease or elevated STM who received two cycles of adjuvant EP. However, 10 patients (24%) with CS IIB disease or elevated STM had persistence of disease (usually elevated STM) after RPLND and required an induction chemotherapy regimen. A small but potentially significant risk of disease progression also exists if chemotherapy is delayed because of perioperative complications or prolonged convalescence after RPLND (particularly for those with persistent disease). The morbidity of RPLND may also be increased in the setting of extensive retroperitoneal disease as opposed to after chemotherapy for minimal residual masses. For these reasons, we believe induction chemotherapy and postchemotherapy RPLND is preferred for patients with CS IIB disease or elevated STM.
We believe the overall improved outcomes for patients who were treated by RPLND after 1999 indicate an improved ability to risk stratify patients for occult systemic metastases rather than simply a result of restricting RPLND to low-risk patients. This view is supported by the fact that the proportion of patients with retroperitoneal metastases did not decrease significantly over time by excluding patients with elevated STM or CS IIB disease. However, of the patients with PS II disease, an increasing proportion of them were curable by RPLND alone by virtue of having low-volume (pN1) retroperitoneal metastases. Although 52% of post-1999 pN1 patients received adjuvant chemotherapy, it seems that chemotherapy could have been avoided in 90% of these patients if it had been withheld until evidence of relapse. After 1999, there was a significant reduction in the proportion of patients requiring chemotherapy as adjuvant therapy for pN2 disease (26% before 1999 v 12% after 1999) and for treatment of relapse (17% before 1999 v 12% after 1999). Of particular importance, there was a significant improvement in the rate of systemic progression after 1999 compared with before 1999 (14% v 1.3%, respectively). Patients who were selected for RPLND after 1999 were as likely to have regional metastatic disease as patients selected before 1999, but the overall risk of systemic progression and chemotherapy requirements was substantially less.
Compared with published results, the low rates of disease progression that we observed for patients with PS I and pN1 disease after 1999 is further evidence of the efficacy of these criteria for identifying patients at low risk for occult distant metastases. For patients with PS I disease, most studies have reported relapse rates of 10% to 15% after RPLND,3,4,13,14,27-29 which are similar to the 8% relapse rate that we observed before 1999. The 4% relapse rate that we observed for PS I patients after 1999 (in particular, the 1% 4-year systemic relapse rate) would seem to represent an improvement over these previous results. Likewise, for patients with pN1 disease, the 19% relapse rate for pre-1999 patients is similar to most studies, which have reported 18% to 46% progression rates after RPLND for pN1 patients.3,4,12,15-18,27,30 By comparison, the 10% relapse rate for pN1 after 1999 (including no systemic relapses) would also seem to be an improvement over previous results. Although not statistically significant, the trend towards improved relapse rates for post-1999 patients with both PS I and pN1 disease suggest that the improvement in disease progression over time as a result of these selection criteria may not solely be related to their impact on retroperitoneal pathology.
Changes in clinical practice, as opposed to these selection criteria, may have contributed to the improved clinical outcomes for patients treated after 1999. After 1999, proportionately more patients were staged preoperatively with CT chest imaging, and the number of nodes resected at RPLND was significantly higher because of the increased use of full, bilateral template dissections. However, the lack of staging CT chest imaging (P = .8) was not a predictor of relapse after RPLND in the multivariable analysis. Likewise, we did not observe a lower rate of retroperitoneal relapse after 1999 (4-year rate, 3% before 1999 v 1% after 1999; P = .4) as a result of resecting more nodes. Thus, we believe the rigorous application of selection criteria after 1999 is the main reason for the improved outcomes observed in these patients.
Despite the impact of patient selection trends on the extent of retroperitoneal disease and disease relapse, the rate of retroperitoneal teratoma has remained constant over time at 22% among patients with PS II disease. Teratoma is resistant to chemotherapy. Although it is histologically benign, its biologic potential is unpredictable. If left unresected, teratoma may grow and become unresectable,31 undergo malignant transformation,32 or result in late recurrence,9 all of which may have lethal consequences. The 20% to 30% incidence of teratoma among patients with low-stage NSGCT supports RPLND (either as primary therapy or after chemotherapy) as an essential component to the cure of these patients.
The excellent survival rates achieved in low-stage NSGCT patients with both primary RPLND and induction chemotherapy mandates that efforts be made to reduce the toxicity of treatment. After cisplatin-based chemotherapy, long-term toxicity has been reported in 20% to 30% of patients including persistent Raynaud's phenomenon (25% to 30%), sensory peripheral neuropathy (15%), ototoxicity (20%), and nephropathy (31%).33-36 Although the reported incidence of these complications is less after two cycles of chemotherapy,37,38 ototoxicity is reported in 15% of patients, and 10% to 16% of patients experience peripheral neuropathy.22,37 The risk of pulmonary toxicity is low after two cycles of bleomycin, although Raynaud's phenomenon is observed in a substantial proportion of patients.38 A 0.2% to 0.5% risk of secondary leukemias is associated with cumulative etoposide doses of 2 g/m2 or less, and there is no safe lower limit.33,39 Testicular cancer patients receiving cisplatin-based chemotherapy have a significantly increased incidence of cardiac risk factors and a 2.6- to 7.0-fold increased long-term risk of major cardiovascular events.36,40 Although Nichols et al41 did not observe an increased risk of cardiac events after two cycles of adjuvant chemotherapy over a median follow-up of 5 years, the risk of late cardiac events after two cycles is not presently known because the majority of events occurs after 10 years.36,40
In contrast, primary RPLND is associated with negligible mortality, and the major long-term morbidity is a risk of ejaculatory dysfunction of less than 5% when nerve-sparing techniques are used and a 1% to 2% incidence of small bowel obstruction.42-45 Given the increased risk of significant long-term toxicity, primary chemotherapy should be reserved to patients with a high risk of systemic disease (those with elevated STM or CS IIB disease). Primary RPLND is preferred for patients with CS I to IIA disease and normal STM given the significant risk of retroperitoneal metastases and 22% incidence of chemoresistant teratoma, the low risk of occult distant metastases, and the potential for reduced long-term treatment-related toxicity.
Surveillance is a reasonable option for CS I patients with normal postorchiectomy STM because 60% to 70% of these patients have disease confined to the orchiectomy specimen. However, patient compliance is essential to successful surveillance. Noncompliance rates of 30% to 80% have been reported in surveillance series, and these patients frequently relapse with advanced disease.46,47 The inability to successfully treat all patients with salvage therapy is highlighted by the 2% to 5% cancer-specific death rates reported in several surveillance series.47-50 In our own series, the cancer-specific mortality rate on surveillance was 2.8%.50 In contrast, the cancer-specific survival rate after primary RPLND for CS I patients in the cisplatin era in the Memorial Sloan-Kettering Cancer Center and Indiana experience was 100% (297 patients) and 99.4% (666 of 670 patients), respectively.3,27 At our institution, surveillance is restricted to CS I patients without evidence of LVI or EC predominance in whom compliance is anticipated.
In summary, we believe the results of this analysis of our experience with primary RPLND for NSGCT validate the selection criteria that we have used. These selection criteria have not increased the proportion of patients with pathologically negative nodes. However, most patients with PS II disease have pN1 disease, and the overall risk of systemic progression is 1.3%. These selection criteria effectively identify a cohort of patients with isolated retroperitoneal metastases who are likely to be cured after RPLND alone and can be spared the long-term toxicity of chemotherapy. Patients with elevated STM or CS IIB disease are at high risk for systemic progression. Our current practice of induction chemotherapy followed by postchemotherapy RPLND for these patients is justified given the significant improvement in disease progression and the trend towards improved disease-specific and overall survival compared with primary RPLND. The 22% incidence of teratoma in the retroperitoneum, which has not changed over time, emphasizes the importance of RPLND (either as primary therapy or after induction chemotherapy) as an essential component to the successful treatment of patients with NSGCT.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Supported in part by a grant from the American Foundation for Urologic Disease, training grant No. T32-82088 from the National Institutes of Health (Bethesda, MD), and a gift from the Tina and Richard V. Carolan Foundation (all to A.J.S.).
Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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