Hepatic Resection of Metastatic Testicular Carcinoma: A Further Update

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1 Annals of Surgical Oncology, 6(7): Published by Lippincott Williams & Wilkins 1999 The Society of Surgical Oncology, Inc. Hepatic Resection of Metastatic Testicular Carcinoma: A Further Update Tara L. Hahn, MD, Lewis Jacobson, MD, Lawrence H. Einhorn, MD, Richard Foster, MD, and Robert J. Goulet, Jr., MD Background: The goal of this study was to update the multidisciplinary review of patients who underwent resection of hepatic metastases of nonseminomatous germ cell testicular carcinoma at the Indiana University Medical Center. Methods: The study involved retrospective chart review for 57 patients who underwent hepatic resection for treatment of metastatic nonseminomatous testicular carcinoma between June 1974 and May Patients were categorized according to the worst postchemotherapy pathologic diagnosis. Results: Chemotherapy has been highly effective in curing testicular carcinoma. However, even with platinum-based chemotherapy, one-third of patients either do not achieve complete cures or experience relapses. Since 1965, only 57 of the 2219 patients who underwent postchemotherapy retroperitoneal lymph node dissections for treatment of testicular carcinoma at our center underwent hepatic resection for treatment of metastatic disease. Because teratomas have the propensity to degenerate into sarcomas and can cause symptoms resulting from compression, these lesions must be resected to achieve cures. In addition, the only chance for survival for patients with active disease but normal serum marker levels is with complete resection of the tumor burden. Conclusions: We conclude that hepatic resection for treatment of metastatic testicular carcinoma is safe and efficacious for all patients except those with elevated marker levels after preoperative chemotherapy. Key Words: Hepatic resection Testicular carcinoma. In 1990, the Departments of General Surgery, Urology, and Oncology of the Indiana University School of Medicine (Indianapolis, IN) combined to review the records for patients who had undergone hepatic resection for treatment of metastatic germ cell carcinoma. 1 Twenty-nine more patients can now be added to this cohort. Between June 1974 and May 1996, 57 patients underwent hepatic resection for treatment of metastatic nonseminomatous germ cell carcinoma. Received March 4, 1999; accepted May 25, From the Departments of General Surgery (TLH, LJ, RJG), Medicine (LHE), and Urology (RF), Indiana University School of Medicine, Indianapolis, Indiana. These results were presented in a poster at The Society of Surgical Oncology Meeting, 52nd Annual Cancer Symposium, March 4 7, 1999, Orlando, Florida. Address correspondence and reprint requests to: Robert J. Goulet, Jr., MD, Division of General Surgery, Indiana Cancer Pavilion, Indiana University School of Medicine, 535 Barnhill Dr., Room 431, Indianapolis, IN Fax: During that period, platinum-based chemotherapy became instituted as first-line therapy for the treatment of nonseminomatous germ cell testicular tumors. Refinements of the therapy over time have included the addition of the highly successful drugs etoposide and ifosfamide for salvage chemotherapy. Currently, 95% of patients who receive a diagnosis of testicular cancer can be cured with standard chemotherapy regimens. 2 4 In addition, 80% of patients who present with widespread metastatic disease can be cured of their cancer. 5 As discussed in the 1990 review, 1 the role of surgical therapy has expanded with the use of this effective chemotherapy. Some patients continue to have disease after standard chemotherapy and even after salvage chemotherapy. These patients become candidates for cytoreductive therapy. In the previous report from Indiana University, 1 hepatic resection has been shown to be a safe and efficacious cytoreductive therapy for testicular carcinoma. The purpose of this report is to update the 640

2 HEPATIC RESECTION OF METASTATIC TESTICULAR CARCINOMA 641 previous work and again to help define the role of surgery for these patients. PATIENTS AND METHODS Between June 1974 and May 1996, 57 patients underwent 60 hepatic resections for treatment of metastatic testicular carcinoma. The majority (38 of 60) were performed between 1985 and All patients except five received standard induction chemotherapy. Of these five, two exhibited normal serum marker levels and showed no evidence of metastatic lesions before retroperitoneal lymph node dissection (RPLND), and three were treated in 1980 or earlier. In this series, clinical staging results ranged from minimal to advanced-stage testicular cancer, as delineated by Einhorn. 6 Except for the three patients with primary retroperitoneal disease, all patients underwent orchiectomy either before or in conjunction with RPLND. Induction chemotherapy regimens were as follows: bleomycin, etoposide, and cisplatin (n 30); cisplatin, vinblastine, and bleomycin (n 14); vinblastine, ifosfamide, and cisplatin (n 4); vinblastine, bleomycin, cisplatin, cyclophosphamide, and dactinomycin (n 2); or others (n 2). Patients received three or four cycles of induction chemotherapy. After completion of induction chemotherapy, tumor marker levels were reassessed. These markers are -human chorionic gonadotropin and -fetoprotein. Patients also underwent preoperative computed tomographic (CT) scanning. Those who exhibited normal marker levels and no evidence of metastatic disease were considered to have experienced complete responses to chemotherapy. They were monitored closely for any signs of recurrence. If the marker levels normalized but radiographic evidence of disease persisted, patients were considered to have experienced partial responses to chemotherapy and were candidates for surgical resection of remaining disease from the mediastinum, lungs, retroperitoneum, and liver. Patients who continued to exhibit elevated enzyme levels after induction therapy, however, were then treated with salvage chemotherapy according to protocol. Patients who experienced failure of salvage therapy were given the option of desperation resection for cytoreduction. RESULTS Preoperative evaluations included abdominal and pelvic CT scanning, chest roentgenography, chest CT scanning if chest x-ray results were not entirely normal, and measurement of the serum markers -fetoprotein and -human chorionic gonadotropin. Seventeen patients TABLE 1. Surgical procedures for treatment of hepatic lesions Wedge resection (single or multiple) 22 Right lobectomy 11 Left lobectomy 5 Multiple resections 15 Trisegmentectomy 3 Segmentectomy 4 were found, at the time of surgery, to have hepatic lesions that had not been diagnosed in the preoperative evaluations. None of these missed lesions was diagnosed after These lesions were resected at the time of other cytoreductive procedures. Surgical procedures for hepatic lesions (Table 1) were determined on the basis of the extent and location of disease. Single-wedge resections were performed in 37% of the cases. Disease was confined to the right lobe in 18% of the cases and to the left lobe in 8%. Multiple resections were required in 37% of the cases. Attempts were made to obtain 1.0-cm margins when possible. Concomitant procedures (Table 2) were performed in 53 of the total of 60 resections (87%). Of these 53 concomitant procedures, 48 (91%) were cytoreductive in nature. Extrahepatic metastases were present in 51 of 57 patients (89%). Cytoreductive procedures included RPLND (n 37), RPLND with pulmonary or mediastinal resection (n 10), nephrectomy (n 5), inferior vena cava resection (n 3), and orchiectomy (n 1). Complications (Table 3) occurred in 18 of 60 procedures (30%). Of interest, 15 of the 18 patients (83%) underwent concomitant procedures with the hepatic resection. There were no perioperative deaths in this series. Postoperatively, hepatic specimens were examined histologically. Patients were then classified according to the worst postchemotherapy pathologic diagnoses (Table 4) for their hepatic lesions. In accordance with the previous reports, group I consisted of only necrotic fibrotic specimens or those with benign pathologic features (i.e., TABLE 2. Concomitant procedures performed at the time of hepatic resection PCRPLND/VRPLND 37 RPLND thoracic procedure 10 Cholecystectomy 10 Nephrectomy 5 Inferior vena cava resection 3 Other 3 PCRPLND, post-chemotherapy retroperitoneal lymph node dissection; VRPLND, virgin retroperitoneal lymph node dissection; RPLND, retroperitoneal lymph node dissection. Ann Surg Oncol, Vol. 6, 7, 1999

3 642 T. L. HAHN ET AL. TABLE 3. Complications Gastrointestinal complications 6 Wound infection/dehiscence 4 Abscess 4 Bile leak 4 Pulmonary complications 4 Deep-vein thrombosis 2 Other 2 TABLE 4. Postchemotherapy pathologic diagnoses Teratoma 29 Benign 9 Embryonal 8 Yolk sac 6 Sarcoma (or variant) 2 Choriocarcinoma 1 Non-germ cell 1 Sertoli cell 1 bile duct proliferation), group II consisted of teratomas, and group III consisted of active disease. These groups included 9, 29, and 19 patients, respectively. Again, to follow the previously used method, group III was divided into two subsets of patients. Group IIIa patients exhibited normal serum marker levels before surgery (n 14), whereas patients in group IIIb (n 5) underwent desperation procedures after undergoing induction and salvage chemotherapy and exhibiting persistently elevated serum marker levels. 1 Eight of nine group I patients were alive with no evidence of disease (NED) at the last follow-up examination. One patient was lost to follow-up monitoring before the 2-year time point but showed NED at the last follow-up examination, and one patient died as a result of late recurrence. The average follow-up period for all group I patients was 47.1 months. In group II, 21 of 29 patients showed NED, 2 were lost to follow-up monitoring, and 6 died as a result of recurrence. The average follow-up period for all group II patients was 56.9 months. In group IIIa, 6 of 14 patients were alive at the last follow-up examination; 4 of these patients showed NED and 1 was living with disease. One patient was lost to follow-up monitoring at 23 months. Eight group IIIa patients died as a result of disease progression. The average follow-up period for all group IIIa patients was 38.4 months. Of the group IIIb patients, three of five died as a result of progression, with a total average follow-up period of 20.4 months. One living patient showed NED but, at the time of this report, only 22 months had elapsed after his resection. Nine patients received postoperative chemotherapy. Treatments ranged from cisplatin and etoposide combinations to high-dose chemotherapy with bone marrow transplantation. Of these patients, one was from group I and experienced recurrence in his lungs and central nervous system. Two patients were from group II; one underwent two RPLNDs, with postoperative chemotherapy between the RPLND procedures. Group IIIa contained five patients, and group IIIb contained one. The patient from group IIIb underwent bone marrow transplantation twice. Patients who survive for 2 years with NED are unlikely to experience relapse. In this series, the overall survival rate for patients who underwent hepatic resection and then 2 years of follow-up monitoring was 97.1%. One patient has undergone follow-up monitoring for 2 years but is living with disease. A total of four patients (7.02%) were lost to follow-up monitoring before the 2-year time point but exhibited NED after an average of 8.9 months. DISCUSSION Despite the advent of platinum-based chemotherapy, one-third of patients either do not achieve complete remission or experience relapse. 7 Of further concern, only 20 25% achieve long-term disease-free survival with conventional salvage chemotherapy. 8,9 Another solution must be found to help the remaining patients, who do not respond to chemotherapeutic modalities. Cytoreductive surgery has been well documented in the past Two goals of cytoreductive surgery for the treatment of testicular carcinoma have been established, i.e., eradication of any residual tumor and determination of patients who are candidates for further chemotherapy. 12,13 Patients who experience relapse or are nonresponsive to the conventional chemotherapeutic protocols currently in use have been the focus of this study. At our institution, 2219 patients underwent RPLND for treatment of testicular cancer between 1965 and the present (2020 between 1980 and the present). The 57 patients described in this study were those patients who had metastatic testicular cancer and were deemed to be candidates for hepatic resection. This points to the fact that the current chemotherapeutic regimen is highly effective in eliciting cures. In this series, the final pathologic diagnosis was of either a benign lesion or a necrotic tumor for 58% (37 of 64) of the hepatic specimens. Because this was the majority, the risks of hepatic resection must not outweigh the potential benefits. Currently, the overall mortality risk for major hepatic resection is 5%. 13 There were no perioperative deaths in this series. The complication rate was 30%. Intra-abdominal abscesses were the most fre- Ann Surg Oncol, Vol. 6, 7, 1999

4 HEPATIC RESECTION OF METASTATIC TESTICULAR CARCINOMA 643 quently observed complications, with a rate of only 8.7%. This represents a decrease from the rate in the previous review (18%). 1 Of note, there have been no intra-abdominal abscesses in the last 10 years (35 patients), with only three wound infections in the same group. However, during the same time period, biliary leaks (n 2) and pancreatitis (n 3) were more common, although infrequent. The one episode of respiratory distress syndrome was probably transfusion-related; it occurred in the patient who required aortic resection, as part of his cytoreductive procedure, 4 days before hepatic resection. Overall, we conclude that hepatic resection is a safe procedure for these patients. Unfortunately, there is currently no method for preoperative lesion evaluation, to prevent resection of benign or necrotic lesions. Preoperative CT scanning, serum marker measurement, and needle biopsy methods are insensitive and have been shown to yield false results because of sampling errors. 6,11,14 Identification by gross inspection at the time of surgery has not been shown to be beneficial, as described by Donohue et al. 15 This point is illustrated by the patients with normal serum marker levels and preoperative radiologic results who exhibited active tumors in their livers. For these reasons, group I patients are known to be of group I only after resection and permanent histologic sectioning of hepatic specimens. Patients belonging to group II benefit from thorough resection. It has been reported that residual teratomas have the propensity to degenerate into sarcomas Although teratomas may not undergo malignant change and metastasize, they can cause morbidity through local growth, with compression of vital structures. Because teratomas (mature or immature) are not chemoresponsive tumors, surgical extirpation is the only cure. Also worrisome is the finding that non-germ cell malignancies have developed in unresected teratomas. These lesions have included rhabdomyosarcomas and fibrosarcomas. 16,17 On the basis of these reports, we think that resection of all teratomas is central to achieving cures. Several studies have demonstrated the efficacy of resection of mediastinal and pulmonary metastases for patients with advanced-stage disease. 6,10,11 Therefore, resection of hepatic metastases also seems to be logical. Current chemotherapy is often overwhelmed by the massive tumor burden seen in late-stage disease. For these patients, surgical resection is the only chance for cure. If residual tumor remains, postoperative chemotherapy is warranted. 6 In the current series, 43% of the patients with active tumors at the time of resection but normal serum marker levels before surgery (group IIIa) achieved survival. Five of these 19 patients underwent 2 years of follow-up monitoring and should therefore be considered cured. Of the group IIIb patients, 40% (two of five) survived, but one of these patients has yet not undergone 2 years of follow-up monitoring. Because this group has the poorest prognosis, on the basis of survival rates, they could benefit from new salvage chemotherapeutic regimens. CONCLUSIONS Testicular cancer is one of the first solid tumors that can be cured with chemotherapy. This has changed the prognosis for the majority of these patients, even those with disseminated metastatic disease. Through the work of oncologists, urologists, general surgeons, and thoracic surgeons, great strides have been made in establishing the treatment of this disease in the past 20 years. We conclude that hepatic resection not only is safe but also is efficacious in achieving cures or improving survival rates for all patients except those in group IIIb. Those patients may achieve improved survival rates in the future, as new chemotherapeutic regimens and drugs are developed and instituted. Acknowledgment: Special thanks go to Jessica Shi for assistance in data collection. REFERENCES 1. Goulet RJ Jr, Hardacre JM, Einhorn LH, et al. Hepatic resection for disseminated germ cell carcinoma. Ann Surg 1990;212: Nichols C, Einhorn L, William S. Disseminated testicular cancer: refining the cure. Cancer Chemother 1989;4: Loehrer PJ Sr, Lauer R, Roth BJ, et al. Salvage therapy in recurrent germ cell cancer: ifosfamide and cisplatin plus either vinblastine or etoposide. Ann Intern Med 1988;109: Loehrer PJ Sr, Einhorn LH, Williams SD. VP-16 plus ifosfamide plus cisplatin as salvage therapy in refractory germ cell cancer. J Clin Oncol 1986;4: Loehrer PJ Sr. Testicular Cancer. In: Brain MC, Carbone PP, eds. Current Therapy in Hematology-Oncology, Ed. 4. Philadelphia: Decker, 1992: Einhorn LH. Cancer of the testis: a new paradigm. Hosp Pract 1986;21: Loehrer PJ Sr. Salvage therapy in recurrent germ cell cancer. Hematol Oncol Clin North Am 1991;5: Murphy BR, Breeden ES, Donohue JP, et al. Surgical salvage of chemorefractory germ cell tumors. J Clin Oncol 1993;11: McCaffrey JA, Mazumdar M, Bajorin DF, et al. Ifosfamide- and cisplatin-containing chemotherapy as first-line salvage therapy in germ cell tumors: response and survival. J Clin Oncol 1997;15: Mandelbaum I, William SD, Einhorn LH. Aggressive surgical management of testicular carcinoma metastatic to the lungs and mediastinum. Ann Thorac Surg 1980;30: Mandelbaum I, Yaw PB, Einhorn LH, et al. The importance of Ann Surg Oncol, Vol. 6, 7, 1999

5 644 T. L. HAHN ET AL. one-stage median sternotomy and retroperitoneal node dissection in disseminated testicular cancer. Ann Thorac Surg 1983;36: Gelderman WAH, Koops SH, Sleijfer DT, et al. Results of adjuvant surgery in patients with stage III and IV nonseminomatous testicular tumors after cisplatin-vinblastine-bleomycin chemotherapy. J Surg Oncol 1988;38: Meyers WC. Neoplasms of the Liver. In: Sabiston DC Jr, ed. Textbook of Surgery: The Biological Basis of Modern Surgical Practice, Ed. 14. Philadelphia: WB Saunders, 1991: Libshitz HI, Jing BS, Wallace S, et al. Sterilized metastases: a diagnostic and therapeutic dilemma. AJR 1983;140: Donohue JP, Roth LM, Zachery JM, et al. Cytoreductive surgery for metastatic testis cancer: tissue analysis of retroperitoneal masses after chemotherapy. J Urol 1982;127: Ahlgren AD, Simrell CR, Triche TJ. Sarcoma arising in a residual testicular teratoma after cytoreductive chemotherapy. Cancer 1984;54: Ulbright TM, Loehrer PJ, Roth LM, et al. The development of non-germ cell malignancies within germ cell tumors. Cancer 1984; 54: Loehrer PJ Sr, Hui S, Clark S, et al. Teratoma following cisplatin-based combination chemotherapy for nonseminomatous germ cell tumors: a clinicopathological correlation. J Urol 1986;135: Quist HL, Fossa SD, Ous S, et al. Post-chemotherapy tumor residuals in patients with advanced nonseminomatous testicular cancer: is it necessary to resect all residual masses? J Urol 1991; 145: Ann Surg Oncol, Vol. 6, 7, 1999

Resection of retroperitoneal residual mass after chemotherapy in patients with nonseminomatous testicular cancer

Turkish Journal of Cancer Vol.31/ No. 2/2001 Resection of retroperitoneal residual mass after chemotherapy in patients with nonseminomatous testicular cancer AHMET ÖZET 1, ALİ AYDIN YAVUZ 1, MURAT BEYZADEOĞLU