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© 2001 American Society for Clinical Oncology Low-Volume Nodal Metastases Detected at Retroperitoneal Lymphadenectomy for Testicular Cancer: Pattern and Prognostic Factors for RelapseFrom the Departments of Urology and Pathology and the Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY. Address reprint requests to Joel Sheinfeld, MD, Department of Urology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, Room C-1076, New York, NY 10021; email: sheinfej{at}mskcc.org
PURPOSE: To determine the incidence, pattern, and predictive factors for relapse in patients with low-volume nodal metastases (stage pN1) at retroperitoneal lymphadenectomy (RPLND) and identify who may benefit from chemotherapy in the adjuvant or primary setting. PATIENTS AND METHODS: Fifty-four patients with testicular nonseminomatous germ cell tumor had low-volume retroperitoneal metastases (pathologic stage pN1, 1997 tumor-node-metastasis classification) resected at RPLND, 50 of whom were managed expectantly without adjuvant chemotherapy. The dissection was bilateral in 12 and was a modified template in 38 patients. Retroperitoneal metastases were limited to microscopic nodal involvement in 14 patients. Follow-up ranged from 1 to 106 months (median, 31.4 months). RESULTS: Eleven patients (22%) suffered a relapse at a median follow-up of 1.8 months (range, 0.6 to 28 months). The most frequent form of recurrence was marker elevation in nine (18%) patients. Persistent marker elevation after orchiectomy and before retroperitoneal lymphadenectomy was a significant independent predictor of relapse (relative risk, 8.0; 95% confidence interval, 2.3 to 27.8; P = .001). Four of five (80%) patients with elevated markers (alpha-fetoprotein alone in three, alpha-fetoprotein and beta human chorionic gonadotropin in one) suffered a relapse, compared with seven of 45 (15.6%) patients with normal markers. CONCLUSION: Clinical stage I and IIA patients with normal markers who have low-volume nodal metastases have a low incidence of relapse and can be managed by observation only if compliance can be assured. In contrast, patients with elevated markers before retroperitoneal lymphadenectomy have a high rate of relapse and should be considered for primary chemotherapy.
CURE RATES FOR clinical stage I and low-volume stage II testis tumor patients approach 100%; selecting the best initial modality of treatment and integration of surgery and chemotherapy is critical to optimizing cure and minimizing morbidity. Currently, three approaches are considered for treatment of stage I and low-volume stage II patients, including primary retroperitoneal lymphadenectomy (RPLND), surveillance (for stage IA) or primary chemotherapy (for stages IB and IS and for low-volume stage II). Patients on surveillance have a 24% to 31% risk of relapse,1-4 and most relapsing patients are treated with salvage therapy consisting of chemotherapy with surgery for residual masses.2 In the United States, primary RPLND has been favored5-8 because this approach has both a diagnostic and therapeutic role. The pattern of relapse is altered in patients with negative nodes because they are unlikely to relapse in the retroperitoneum. Retroperitoneal nodal metastases detected at RPLND can be classified as low volume (pathologic stage pN1) or high volume (pathologic stage pN2-pN3), with pathologic stage as classified by the 1997 American Joint Committee on Cancer (AJCC) classification ( Table 1). 9 Patients with high-volume disease have a 33% to 56%10,11 relapse rate, which is virtually eliminated with two cycles of cisplatin-based adjuvant chemotherapy.11-13
However, there is continued controversy regarding the optimal treatment of patients with low-volume nodal metastases. While some investigators have reported relapse rates as low as 6.3% in patients with low-volume (pN1) nodal disease managed expectantly,14 others have reported rates as high as 45%.11,15 Williams et al11 demonstrated a significant reduction in relapse rates with two cycles of adjuvant cisplatin-based chemotherapy in a multicenter, randomized trial, but 93 of 195 (48%) patients in this study had pN2-pN3 disease.11 Given the wide disparity in relapse rates reported after expectant management of pathologic stage pN1 disease, with three series reporting relapse rates more than 35%,10,11,15 we reviewed our experience in patients with low-volume nodal metastases to determine the incidence, pattern, and predictors of relapse to determine which patients would benefit from adjuvant chemotherapy after RPLND and which patients are best managed by initial chemotherapy.
Study Population Between January 1988 and February 1998, 336 primary RPLNDs were performed on 335 patients with testicular germ cell tumor with clinical-stage distributions as follows: I in 217, IS in 7, IIA in 90, and IIB in 21 patients. Fifty-four patients (16%) with nonseminomatous germ cell tumors had low-volume (pN1) nodal metastases at RPLND. Four patients received adjuvant chemotherapy and are excluded from the analysis. Fifty patients did not receive adjuvant chemotherapy and form the subject of this report. Pathologic stage was assigned according to the 1997 AJCC classification (Table 1).9 Patients ranged in age from 14 to 62 years (median, 28.3 years), and median follow-up was 52.4 months (range, 1 to 117 months). Five patients (10%) have been lost to follow-up. The initial clinical stages, according to the 1997 AJCC staging classification,9 were I in 30 (60%), IS in two (4.0%), IIA in 17 (34%), and IIB in one (2.0%) patient. Forty-eight were diagnosed at radical orchiectomy, one at simple orchiectomy, and the other at partial orchiectomy. Twenty-one tumors were right-sided and 29 left-sided. The primary tumor contained elements of embryonal carcinoma in 42 (84%), yolk sac tumor in 22 (44%), seminoma in 15 (30%), mature teratoma in 15 (30%), immature teratoma in 13 (26%), and choriocarcinoma in five (10%) patients. Thirty-three (66%) patients had mixed germ cell tumor containing embryonal carcinoma, nine (18%) had pure embryonal carcinoma, and eight (16%) had no embryonal carcinoma. Vascular invasion was present in 29 (58%) patients.
Technique of RPLND
Follow-Up
Statistical Analysis
Adjuvant Chemotherapy Four patients received adjuvant chemotherapy with two cycles of etoposide and cisplatin13 because of poor compliance or a psychologically fragile patient profile. The retroperitoneal metastases were microscopic in one and gross in three patients. The primary tumor histology included embryonal carcinoma elements in all four, yolk sac tumor in one, immature teratoma in two, mature teratoma in one, seminoma in two, and choriocarcinoma in no patients. One patient had elevated markers before RPLND. All four patients had embryonal carcinoma in the retroperitoneal lymph nodes. All four patients have been free from relapse at 15.6 to 64.7 months (median, 30.5 months) after RPLND. These patients are excluded from further analysis.
Patterns of Relapse
Marker Status Before RPLND There were five patients with persistent marker elevation before RPLND. Two patients with clinical stage IIA had an elevated FP, with a normal half-life of decline after orchiectomy and normal serum concentration of ßHCG. One of these (with a preoperative FP level of 18.3 ng/mL) had microscopic disease at RPLND and has had no relapse; the other (with a preoperative FP level of 49 ng/mL) had gross nodal metastases and had persistent marker elevation after RPLND as the only manifestation of treatment failure. A third patient had an elevated FP level of 77.5 ng/mL with a prolonged half-life after orchiectomy and a normal ßHCG. He presented with a right-sided stage IS tumor, had gross nodal metastases at RPLND, and has had a retrocaval recurrence with marker elevation at 16.7 months. He was treated with four cycles of etoposide and cisplatin,20 resection of residual disease and with salvage chemotherapy (vinblastine, ifosfamide, and cisplatin)21 for a second relapse. He died of disease at 31.6 months. The remaining two patients had either no decrease in or demonstrated rising values of FP (both) or ßHCG (one) before RPLND. One of these patients, with a preoperative FP level of 26.1 ng/mL and ßHCG level of 5.3 mIU/mL, had a left-sided stage IIA tumor with gross nodal metastases at RPLND and had a marker relapse after initially normalizing after RPLND with suspicious suprahilar adenopathy at 2 months. The other patient, with a preoperative FP level of 18.6 ng/mL and a nonmeasurable ßHCG, had a left-sided stage IS tumor, with microscopic nodal metastases at RPLND, persistently elevated markers after RPLND, and a suspicious left external iliac node at 1 month. The recurrence pattern in the four patients with relapse who had persistently elevated markers before RPLND was serologic in all four, possible retroperitoneal adenopathy in three, suprahilar adenopathy in one, and pelvic adenopathy in one patient. When patients with marker elevation before RPLND are excluded, the relapse rate was seven of 45 (16%). Among the seven patients with normal markers before RPLND who relapsed, the recurrence pattern distribution was as follows: serologic in five patients, suspicious retroperitoneal adenopathy in one, retrocrural adenopathy in two, pulmonary nodules in four, pelvic adenopathy in one, and scalp metastasis in one. Median time to recurrence in these seven patients was 2.1 months (range, 0.6 to 28 months). The median time to relapse was not significantly different for patients with relapse who had elevated markers versus those in whom pre-RPLND markers were normal (P = .55, median test).
Mortality
Burden of Therapy
The value of adjuvant chemotherapy for low-volume (pN1) nodal disease is controversial. Investigators have reported relapse rates ranging from 6.3% to 45% for patients with pN1 nodal metastases managed expectantly.11,14,15,23,24 In the present series, 11 of 50 (22%) of such patients managed expectantly after RPLND suffered relapse. Persistent marker elevation before RPLND was a significant independent predictor of relapse with a relative risk of 8.0. When the five patients with persistently elevated markers are excluded, the rate of relapse with expectant management is seven of 45 (16%). In our series of 50 patients managed expectantly, a total of 50 cycles of chemotherapy and four surgical procedures (one RPLND, one pelvic lymph node dissection, and two thoracotomies) were required, compared with 100 cycles of chemotherapy if each patient were to receive two cycles of adjuvant chemotherapy. The relapse rate was within the range reported by other series.11,14,15,23,24 The wide range of relapse rates reported in the literature may be accounted for by the selection biases present in the different studies, including differing templates of dissection, patient selection, and different study criteria. A modified template dissection was performed in 76% of patients included in the present series, compared with 26% in Richie and Kantoffs series.23 Although the likelihood of relapse was lower in patients undergoing a bilateral compared with a modified-template dissection (one of 12 = 8.3% v 10 of 38 = 26%), this difference did not attain statistical significance (P = .21, log-rank test). However, more extensive dissections were performed in patients with higher volumes of retroperitoneal disease. In one series,11 the likelihood of relapse in patients with pathologic stage II disease did not differ significantly between bilateral and modified template dissections when the latter was restricted to patients with no serologic, radiologic, or intraoperative evidence of disease. Nevertheless, in the presence of retroperitoneal disease, a bilateral RPLND with nerve sparing is the operation of choice. Surgical margins should not be compromised in an attempt to preserve ejaculation. The various studies reported in the literature have used different selection criteria for patients included in the analysis. In the series by Socinski et al, patients with two separate involved lymph node areas received adjuvant chemotherapy.24 The relapse rate in the present series was seven of 41 (17%) with one positive site, compared with three of eight (38%) with two positive sites; however, the small numbers preclude meaningful statistical comparison. Finally, in Richie and Kantoffs series,23 only patients with normal tumor markers before RPLND were included in the study, compared with our series in which five of 50 (10%) had persistently elevated markers before RPLND. In the present series, the relapse rate was four of five (80%) with elevated markers before RPLND, compared with seven of 45 (16%) with normal marker levels (P < .0001, log-rank test). Our series includes two patients with clinical stage IS, both of whom relapsed and for whom RPLND is no longer recommended.
In a 1994 report from Memorial Sloan-Kettering Cancer Center, all 11 patients with clinical stage IS disease treated with primary RPLND suffered relapse requiring chemotherapy, including four patients (two included herein) with low-volume disease.25 Saxman et al reported on 30 clinical stage IS patients with prolonged marker half-life treated with RPLND alone.26 Five of six (83%) patients with persistently elevated In summary, our study does not support the routine use of adjuvant chemotherapy in patients with low-volume (pN1) nodal metastases and markers that are normal before RPLND. However, these data underscore the importance of careful patient selection and a meticulous bilateral RPLND in the presence of retroperitoneal disease. Additionally, patients with persistently elevated markers before RPLND have a high risk of relapse when treated with RPLND alone and should be considered for primary chemotherapy, followed by RPLND for residual disease.
Supported by a grant from the American Foundation of Urologic Disease, Baltimore, MD, and Ortho-McNeil Pharmaceuticals, Raritan, NJ, to F.R.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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