Nerve-sparing retroperitoneal lymph node dissection for advanced testicular cancer after chemotherapy

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1 Blackwell Science, LtdOxford, UK IJU International Journal of Urology Blackwell Science Asia Pty Ltd 910October Postchemotherapy nerve-sparing RPLND N Nonomura et al /j x Original Article539544BEES SGML International Journal of Urology (2002) 9, Original Article Nerve-sparing retroperitoneal lymph node dissection for advanced testicular cancer after chemotherapy NORIO NONOMURA, 1 KAZUO NISHIMURA, 1 NATSUKI TAKAHA, 1 HITOSHI INOUE, 1 TAKESHI NOMOTO, 2 YOUICHI MIZUTANI, 2 MASAHIRO NAKAO, 2 AKIHIKO OKUYAMA 1 AND TSUNEHARU MIKI 2 1 Department of Specific Organ Regulation (Urology), Osaka University Graduate School of Medicine, Suita and 2 Department of Urology, Kyoto Prefectural University of Medicine, Kyoto, Japan Abstract Key words Background: Nerve-sparing techniques are commonly used in retroperitoneal lymph node dissection (RPLND) in patients with early stage testicular germ cell tumors to preserve postoperative ejaculation. The indications for nerve-sparing procedures have been extended to patients who have residual retroperitoneal tumor postchemotherapy with an increase in the incidence of local recurrence. Here, we report on 26 Japanese men with advanced testicular cancer who underwent nerve-sparing RPLND after partially successful chemotherapy. Methods: Between January 1995 and December 2000, 26 patients with metastatic or recurrent testicular cancer underwent nerve-sparing RPLND after chemotherapy. Eight patients had seminoma and 18 had non-seminoma. Three patients received high-dose chemotherapy with carboplatin (250 mg/m 2 per day 5 days), etoposide (300 mg/m 2 per day 5 days) and ifosfamide (1.5 g/m 2 per day 5 days) in combination with peripheral blood stem cell transplantation. Results: In all cases, lumbar splanchnic nerves were preserved macroscopically during the operation, at least unilaterally. Twenty-two patients (84.6%) achieved antegrade ejaculation during a mean follow-up at 3.9 months (range: 1 7 months). Three patients have fathered children. Only one patient suffered a retroperitoneal recurrence during a median follow-up at 25.8 months (range: 6 76 months). Conclusion: Nerve-sparing procedures for RPLND are appropriate for patients with metastatic testicular cancer, even after chemotherapy. The procedure preserves ejaculatory function in the majority of the patients without increasing the risk of local recurrence. Nerve-sparing RPLND improves the quality of life in patients who require postchemotherapy RPLND to treat residual tumor. chemotherapy, germ cell tumor, nerve-sparing retroperitoneal lymph node dissection, testicular cancer. Introduction Conventional bilateral retroperitoneal lymph node dissection (RPLND) for testicular tumors results in permanent loss of seminal emission and ejaculation in a Correspondence: Norio Nonomura MD PHD, Department of Specific Organ Regulation (Urology), Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita , Japan. nono@uro.med.osaka-u.ac.jp Received 5 December 2001; accepted 8 April majority of patients. 1 3 Anatomical studies have shown that the lumbar splanchnic nerves that form the superior hypogastric plexus at the aortic bifurcation are essential for normal ejaculation. 4,5 These anatomical studies led to attempts to preserve normal ejaculation in patients with early stage testicular germ cell tumors without increasing the incidence of retroperitoneal recurrence by modifying the dissection template. 4,6 Most patients with a residual retroperitoneal mass after chemotherapy have impaired ejaculatory function because standard RPLND had been performed, rather than nerve-sparing RPLND. 3,7 However, based on the

2 540 N Nonomura et al. success of nerve-sparing procedures in patients with early stage testicular tumors, the group at Indiana University performed nerve-sparing RPLND in selected patients with relatively small residual retroperitoneal tumors after chemotherapy. 8 Based on their successful results, the indications for nerve-sparing dissection in postchemotherapy patients have been expanded without any increase in the rate of local recurrence. 9,10 Nervesparing procedures can improve the quality of life in patients who must undergo RPLND. Here, we report the clinical results of nerve-sparing RPLND in 26 Japanese men with residual retroperitoneal tumor after chemotherapy for metastatic or recurrent testicular germ cell tumors, and assessed their ejaculatory function and the outcome of cancer control in the relatively short-term. Methods Patients Between January 1995 and December 2000, 26 patients underwent nerve-sparing RPLND for residual retroperitoneal tumor after chemotherapy. Demographics, clinical characteristics, pathologic findings, and chemotherapy regimens are summarized in Table 1. Staging was done according to the General Rules for Clinical and Pathological Studies on Testicular Tumors (Second edition). 11 Eight patients had a seminoma, and the other 18 had non-seminoma. Before the operation, all the patients were informed that we do not have our own long-term results of this procedure in terms of cancer control. Written informed consent was obtained before the operation from all 26 patients who requested nervesparing RPLND. Chemotherapy Three patients received high-dose chemotherapy with carboplatin (250 mg/m 2 per day 5 days), etoposide (300 mg/m 2 per day 5 days), and ifosfamide (1.5 g/m 2 per day 5 days) in combination using peripheral blood stem cell transplantation. One of these patients developed a recurrence of his seminoma after primary chemotherapy and nerve-sparing RPLND. In this case, infra-renal-hilar paracaval lymph node metastasis was identified 6 months after radical orchiectomy. The patients underwent limited right-sided (nerve-sparing) RPLND with the modified template 6 after three courses of chemotherapy (BEP: bleomycin, etoposide, and cisplatinum). Six months after RPLND, right hydronephrosis developed due to obstruction by enlarged paracaval and interaortocaval lymph nodes. The patient underwent two courses of BEP, two courses of VIP (etoposide, ifosfamide, and cisplatinum), two courses of high-dose chemotherapy and then received 40 Gy of radiation. After that, we performed full bilateral nerve-sparing RPLND. In some of the patients, serum tumor markers such as alpha-fetoprotein (AFP), b-subunit of human chorionic gonadotropin (bhcg) and/or lactate dehydrogenase (LDH) were elevated. All of these serum tumor markers have been normalized during the chemotherapy. After chemotherapy, they stayed normal levels for at least 4 weeks until RPLND. Nerve-sparing retroperitoneal lymph node dissection All patients underwent complete bilateral RPLND through a midline transperitoneal incision. The posterior peritoneal incision was made through the mesenteric root from the cecum to the ligament of Treitz. Selfretaining retractors provided good exposure of the paracaval, interaortocaval, and paraaortal zones. The lymphatic tissue was incised over the anterior surface of the aorta and the vena cava. The precaval incision was extended from the origin of the renal veins to the confluence of the internal iliac veins, and the preaortic from the left renal vein to the inferior mesenteric artery. Lymphatic tissue was then rolled medially and laterally off the vena cava and the aorta. The superior hypogastric plexus was identified and preserved at the bifurcation of the aorta. On the right side, the branches of the right lumbar splanchnic nerves leading to the superior hypogastric plexus were identified underneath the inferior vena cava during the split and roll procedures. On the left side, the sympathetic trunks and the lumbar splanchnic nerves were identified dorsolaterally to the aorta. Then, the fibers from L2, L3, and L4 were dissected distally. Results Perioperative data The mean time of operation (including the time for resection of lung or liver metastases) was 636 min (range: ), and the mean intraoperative blood loss was 1037 g (range: g). No patient suffered a major complication (Table 2). Pathology of the surgical specimen Of the 10 patients with pulmonary metastases, six achieved complete remission with systemic chemo-

3 Postchemotherapy nerve-sparing RPLND 541 Table 1 Characteristics of 26 patients who underwent nerve-sparing retroperitoneal lymph node dissection (RPLND) Case no. Age Site Pathology Tumor marker Stage Metastatic sites Chemotherapy before RPLND 1 24 Rt E + T AFP + bhcg + LDH I RPLN BEP(1)ÆVIP(4) 2 37 Rt S LDH I RPLN BEP(3)ÆRPLNDÆBEP(2)ÆVIP(2)ÆHDCÆRT 3 24 Lt S bhcg IIA RPLN PVB(3) 4 34 Lt S + E AFP + bhcg IIA RPLN BEP(4) 5 35 Lt S+ E AFP IIA RPLN BEP(3) 6 18 Lt S + E AFP + bhcg IIB RPLN BEP(4)ÆCPT-ND(7)ÆTIP(4) 7 21 Rt S bhcg IIB RPLN BEP(3) 8 29 Lt S+ E + T AFP + bhcg + LDH IIB RPLN BEP(2)ÆEP(2) 9 31 Rt S bhcg + LDH IIB RPLN BEP(3)ÆVIP(1)ÆBEP(1)ÆVIP(1) Rt S + E + IT AFP + bhcg + LDH IIB RPLN BEP(3)ÆEP(1) Rt S + Y LDH IIB RPLN BEP(4) Rt S LDH IIB RPLN BEP(5) Lt S IIB RPLN BEP(3)ÆEP(2) Lt S LDH IIB RPLN BEP(5) Lt S IIB RPLN BEP(3)ÆEP(1) Lt S + C LDH IIIA RPLN + Mediastinal LN BEP(5) Rt Y + C AFP IIIB1 RPLN + Lung VIP(4) Lt E + Y AFP + bhcg IIIB2 RPLN + Lung BEP(3)ÆHDC Lt E + T AFP + LDH IIIB2 RPLN + Lung BEP(3)ÆVIP(2) Lt E AFP + bhcg + LDH IIIB2 RPLN + Lung BEP(3)ÆEP(1) Lt E AFP + bhcg + LDH IIIB2 RPLN + Lung VIP(5) Lt S + E AFP + bhcg + LDH IIIB2 RPLN + Lung BEP(5) Rt S + E bhcg IIIB2 RPLN + Lung BEP(3) Rt E + T AFP IIIB2 RPLN + Lung BEP(3) Lt E + T AFP + LDH IIIC RPLN + Lung + Liver BEP(5) Rt E + T AFP + LDH IIIC RPLN + Lung + Liver BEP(4)ÆVIP(4)ÆHDC C, choriocarcinoma; E, embryonal carcinoma; IT, immature teratoma; S, seminoma; T, teratoma; Y, yolk sac tumor. AFP, alpha-fetoprotein; bhcg, b-subunit of human chorionic gonadotropin; LDH, lactate dehydrogenase. retroperitoneal lymph node structure. BEP, bleomycin + etoposide + cisplatinum; CPT-ND, cisplatinum S; EP, etoposide + cisplatinum; HDC, high-dose chemotherapy; PVB, cisplatinum + vinblastin + bleomycin; RT, radiotherapy; TIP, paclitaxel + ifosfamide S; VIP, etoposide + ifosfamide + cisplatinum.

4 542 N Nonomura et al. Table 2 Demographics, clinical characteristics and outcome of nerve-sparing retroperitoneal lymph node dissection (RPLND) Case no. Operation time (min) Blood loss during operation (ml) Spared lumbar roots (months after RPLND) Ejaculation recovery Pathology of surgical specimen Outcome Follow-up (months) Bil. L2-3 Yes (1) T (growing NED 23 teratoma) Lt. L2-4 Yes (7) N/F NED Rt. L2-4, Lt. L3 Yes (2) N/F NED Bil. L2-3 Yes (5) T NED Rt. L2-3 Yes (3) T NED Rt. L2-3, Lt. L3 Yes (2) T NED Bil. L2-4 Yes (7) N/F NED Rt. L2-3 Yes (4) Residual cancer NED Rt. L3-3, Lt. L2-4 Yes (2.5) N/F NED Rt. L2-3 Yes (1) T NED Bil. L2-3 No (4) N/F NED Rt. L2-3 Yes (6) N/F NED Bil. L2-4 Yes (7) N/F NED Bil. L2-3 No (5) N/F NED Rt. L2-4 No (24) N/F NED Bil. L2-3 Yes (1) N/F NED Bil. L2-3 Yes (3) T NED Rt. L2-3 No (27) IT NED Rt. L2-3 Yes (6) N/F NED Lt. L2-3 Yes (1) N/F NED Rt. L2-3 Yes (6) N/F NED Rt. L2-3 Yes (1) Residual cancer AWT 8 (recurred at 6 months) Rt. L2-3 Yes (1) N/F NED Rt. L3 Yes (7) T NED Rt. L2-3 Yes (6) T (growing NED 13 teratoma) Bil. L2-4 Yes (1) T NED 37 Time of operation included resection of lung or liver metastases. AWT, alive with tumor; IT, immature teratoma; NED, no evidence of disease; N/F, necrotic fibrotic tissue; RPLND, retroperitoneal lymph node dissection; T, teratoma. therapy. However, none of the primary tumors contained teratoma elements. The remaining four patients (cases 19 and 24 26) underwent resection of residual pulmonary metastasis concurrent with RPLND. In two patients with stage 3C disease, resection of the liver metastases was also performed concomitantly with RPLND. None of the surgical specimens of lung or liver contained viable cancer cells. Fourteen retroperitoneal specimens showed necrotic fibrotic tissue, nine contained mature teratoma, and one contained immature teratoma (case 18). Viable cancer cells were seen in two cases (cases 8 and 22). Outcome and ejaculatory status All of the patients except for one (case 22) are alive with no evidence of disease during a mean follow-up of 25.8 months (range: 6 76 months). Twenty-two patients (84.6%) reported normal antegrade ejaculation within a mean period of 4.9 months after the nerve-sparing RPLND. Moreover, two patients (cases 7 and 23) fathered children 16 and 14 months after RPLND, respectively. Semen analysis was not routinely performed before or after RPLND. Discussion Retroperitoneal lymph node dissection plays an important role in the treatment of advanced testicular germ cell cancers. The objectives of postchemotherapy resection of a residual retroperitoneal mass and RPLND are to (i) document the presence or absence of viable cancer cells, and (ii) remove any teratoma. 12 Radical RPLND leads to disordered seminal emission and retrograde

5 Postchemotherapy nerve-sparing RPLND 543 ejaculation. Neuroanatomical studies created a basis for attempting to preserve normal ejaculation in patients with early stage testicular germ cell tumors without increasing the retroperitoneal recurrence rate by modifying the dissection template. 4 6 Nerve-sparing RPLND in selected patients with relatively small residual retroperitoneal masses after several courses of primary chemotherapy was first reported by Wahle et al. 8 Recently, nerve-sparing techniques have been extended to patients with advanced-stage disease who have relatively large residual retroperitoneal masses. Only a few cases of nerve-sparing postchemotherapy RPLND for relatively large residual retroperitoneal masses have been reported in the Japanese literature. 13 Solsona et al. 9 reported that 15 of 18 (83%) patients recovered ejaculatory function after RPLND, with recurrence in two patients (11.1%) during a mean follow-up of 28.1 months. In the other study, Coogan et al. 10 reported that emission and ejaculation were preserved in 62 of 81 patients (76.5%) after postchemotherapy RPLND, and tumor recurred in 7.4% of patients during a mean follow-up of 35.5 months. In both studies, the recurrence was at a site other than the retroperitoneum. In our study, ejaculatory function was preserved in 84.6% (22 of 26 patients) with only one retroperitoneal recurrence (case 22). This preservation rate (84.6%) of ejaculatory function is compatible with previous studies. 9,10 Coogan et al. 10 reported that bilateral nerve-sparing, or multilevel or right nerve-sparing improves the probability of preserving postoperative ejaculation. Wahle et al. 8 reported that a full left side dissection in the area below the inferior mesenteric artery increases the risk of distal sympathetic fiber injury. Nevertheless, there was no difference in the mean interval until the first antegrade ejaculation after RPLND between patients in whom the nerves were preserved bilaterally or unilaterally. Moreover, in one patient (case 24), only one nerve root was preserved on the right side, yet the patient was able to ejaculate normally within 7 months. These facts suggest that preservation of at least one of the lumbar splanchnic nerves is necessary and sufficient for normal ejaculation to occur. However, these nerves may be inadvertently damaged by mechanical manipulation or heat without the knowledge of the operators. Therefore, we try to preserve as many nerve roots as possible, even in patients with bilateral residual tumors. From the surgical point of view, it is easier to identify and preserve the right than the left lumbar splanchnic nerves. The right lumbar splanchnic nerves are easily identified as they run underneath the inferior vena cava. That is why the right-sided nerves usually are preserved in patients in whom unilateral preservation is done. Not only the lumbar splanchnic nerves, but also the superior hypogastric plexus are important for ejaculatory function. Therefore, great care must be taken to preserve this plexus when dissecting residual tumor located below the origin of the inferior mesenteric artery or around the aortic bifurcation. In terms of patient selection, a good candidate is one with a low tumor volume and unilateral disease after chemotherapy and, of course, who desires to remain fertile. Decreased fertility associated with testicular cancer and the risk of persistent azoospermia associated with chemotherapy must be considered when we select patients for nerve-sparing RPLND. 14 But, we do not have enough information about the patient s fertility status because we do not perform semen analyses routinely. In our study, all the patients request nerve-sparing procedure even after being informed that we do not have our own long-term results of this procedure in terms of cancer control. Testicular cancer often occurs in young patients. Chemotherapy-associated infertility and ejaculatory dysfunction after RPLND are serious problems for these men. According to Boyer and Raghaven s report 15 only 25% of patients remain persistently azoospermic. Nevertheless, ejaculatory dysfunction after RPLND compromises the quality of sexual life. Even if he is azoospermic, preservation of ejaculatory function may be desired and can improve the quality of a man s life. Therefore, nerve-sparing procedure can safely be extended to selected patients with metastatic testicular cancer. References 1 Donohue JP, Rowland RG. Complications of retroperitoneal node dissection. J. Urol. 1981; 125: Narayan P, Lange PH, Fraley EE. Ejaculation and fertility after extended retroperitoneal lymph node dissection for testicular cancer. J. Urol. 1982; 127: Arai Y, Kawakita M, Okada Y, Yoshida O. Sexuality and fertility in long-term survivors of testicular cancer. J. Clin. Oncol. 1997; 15: Jewett MA, Kang SP, Goldberg SD et al. Retroperitoneal lymphadenectomy for testis tumor with nervesparing for ejaculation. J. Urol. 1988; 139: Colleselli K, Poisel S, Schachter W, Bartsch G. Nervepreserving bilateral retroperitoneal lymphadenectomy: anatomical study and operative approach. J. Urol. 1990; 144: Donohue JP, Foster RS, Rowland RG, Bihrle R, Jones D, Geier G. Nerve-sparing retroperitoneal lymphadenectomy with preservation of ejaculation. J. Urol. 1990; 144:

6 544 N Nonomura et al. 7 Lange PH, Chang WY, Fraley EE. Fertility issues in the treatment of nonseminomatous testicular tumors. Urol. Clin. North Am. 1987; 14: Wahle GR, Foster RS, Bihrle R, Rowland RG, Bennet RM, Donohue JP. Nerve-sparing retroperitoneal lymphadenectomy after primary chemotherapy for metastatic testicular carcinoma. J. Urol. 1994; 152: Solsona E, Iborra I, Ricos JV et al. Preservation of antegrade ejaculation in retroperitoneal lymphadenectomy due to residual masses after primary chemotherapy for testicular carcinoma. Eur. Urol. 1994; 25: Coogan CL, Hejase JH, Wahle GR et al. Nerve-sparing post-chemotherapy retroperitoneal lymph node dissection for advanced testicular cancer. J. Urol. 1996; 156: The Japanese Urological Association and the Japanese Pathological Society. General Rules for Clinical and Pathological Studies on Testicular Tumors, 2nd edn. Kanehara Shuppan, Tokyo, 1997 (in Japanese). 12 Skinner EC, Skinner DG. Surgery of testicular neoplasms. In: Walsh PC, Retik AB, Vaughan ED, Wein AJ (eds). Campbell s Urology, 7th edn. WB Saunders, Philadelphia, 1998: Arai Y, Ishitoya S, Kazutoshi O et al. Nerve-sparing retroperitoneal lymph node dissection for metastatic testicular cancer. Int. J. Urol. 1997; 4: Drasga RE, Einhorn LH, Williams SD, Patel DN, Stevens EE. Fertility after chemotherapy for testicular cancer. J. Clin. Oncol. 1983; 1: Boyer M, Raghaven D. Toxicity of treatment of germ cell tumors. Semin. Oncol. 1992; 19:

RETROPERITONEAL LYMPHADENECTOMY IN STAGING AND TREATMENT

~~~~ IFSTIS CANCtK 0094-0143/98 $8.00 +.00 RETROPERITONEAL LYMPHADENECTOMY IN STAGING AND TREATMENT The Development of Nerve-Sparing Techniques John P. Donohue, MD, and Richard S. Foster, MD Two decades