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Journal of Clinical Oncology, Vol 22, No 18 (September 15), 2004: pp. 3713-3719 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.07.124 Residual Tumor Resection After High-Dose Chemotherapy in Patients With Relapsed or Refractory Germ Cell CancerFrom the Department of Hematology and Oncology, Charité, Campus Mitte; Department of Urology, Krankenhaus Am Urban, Berlin; Department of Hematology and Oncology, Eberhards-Karl Universität, Tübingen; Department of Thoracic Surgery, Dr-Horst-Schmidt Kliniken, Wiesbaden; Department of Urology, Bundeswehrkrankenhaus, Hamburg; and Department of Hematology and Oncology, Philipps Universität, Marburg, Germany Address reprint requests to J. Beyer, MD, Department of Hematology and Oncology, Philipps Universität Marburg, Baldinger Strasse, 35033 Marburg, Germany; e-mail: joerg.beyer{at}mailer.uni-marburg.de
PURPOSE: To assess the role of residual tumor resection performed after high-dose chemotherapy (HDCT) in patients with relapsed or refractory germ cell tumors (GCT). PATIENTS AND METHODS: Between July 1987 and October 1999, postchemotherapy resections of residual tumors were performed in 57 patients who had been treated with HDCT for relapsed or refractory GCT and who had achieved a partial remission to this treatment. RESULTS: Complete resections of residual masses were achieved in 52 (91%) of 57 patients who were rendered disease free; in five (9%) of 57 patients, the resections were incomplete. Resection of a single site was performed in 39 (68%) of 57 patients, and the remaining 18 (32%) of 57 patients required interventions at two or more residual tumor sites. Necrosis was found in 22 (38%) of 57 patients, mature teratoma with or without necrosis was found in nine (16%) of 57 patients, and viable cancer with or without additional necrosis or mature teratoma was found in 26 (46%) of 57 patients. Viable cancer consisted either of residual germ cell or undifferentiated cancer in 22 (85%) of 26 patients, with additional non-GCT histologies in the remaining four patients. Patients with viable cancer had a significantly inferior outcome after surgery compared with patients with necrosis and/or mature teratoma even if all cancer was completely resected. Pulmonary lesions with a diameter of more than 2 cm were the only predictive variable for viable cancer in univariate analysis. CONCLUSION: Resections of all residual tumors should be attempted in patients with relapsed or refractory GCT and partial remissions after HDCT.
Surgical resection of residual tumors (RTR) after first-line chemotherapy is recommended in patients with metastatic germ cell tumors (GCT).1-3 Necrosis will be the only histologic finding in the majority of these patients. However, in others, mature teratoma, viable cancer consisting of residual GCT, non-GCTs, undifferentiated cancer, or a combination of these histologies, may be found. Whereas the resection of necrosis offers no therapeutic benefit, resection of mature teratoma or viable cancer adds to long-term event-free and overall survival in these patients. Limited data exist on the results of surgery and the respective histologies in patients after first or subsequent salvage chemotherapy.3-6 To assess the contribution of RTR in this setting, we retrospectively analyzed a cohort of 216 consecutive patients who had been treated with HDCT for relapsed or refractory GCT, of whom 57 patients proceeded to RTR (Fig 1).
Patients Between July 1989 and October 1999, 216 patients were treated in three consecutive HDCT trials at Charité University Hospital, Berlin, Germany.7,8 All patients had GCT and were eligible for inclusion if there was unequivocal evidence of relapse or progression after cisplatin-based combination chemotherapy as defined by either increasing alpha-fetoprotein (AFP) or human chorionic gonadotropin (HCG) serum levels or histology. All HDCT protocols were approved by the Ethics Committee of the Charité University Hospital, and all patients gave their written informed consent before participating in the trials. Partial remissions with negative tumor markers (PRm–) or partial remissions with positive tumor markers (PRm+) after HDCT were achieved in 128 (59%) of 216 patients, who were further evaluated for RTR. Among these patients, 57 (45%) of 128 eventually proceeded to RTR and were operated on at a median of one site (range, one to three sites). The remaining 71 (55%) of the 128 patients could not be operated on because of progressive disease before RTR (n = 45), inoperable tumor masses or poor performance status (n = 14), and patient refusal (n = 12). Therefore, data from 57 patients were available for analysis (Fig 1).
Treatment A partial remission on routine computed tomography scans 12 weeks after HDCT with a residual mass of 1 cm or more in diameter after HDCT was the criterion for performing RTRs, which were performed as radical surgical procedures with the attempt to remove all radiologic residual tumors, except in patients with cerebral metastases in whom surgical removal was not routinely attempted. The extent of surgery and additional procedures required for a radical resection, such as the use of vascular grafts, were left to the discretion of the operating surgeon. Patients with histologic evidence of viable cancer among resected specimens were offered adjuvant chemotherapy after RTR. Two different treatment regimens were used for this purpose, either oral etoposide 50 mg/m2/d for 21 consecutive days repeated every 4 weeks or combination chemotherapy with cisplatin, vincristine, methotrexate, bleomycin, dactinomycin, cyclophosphamide, and etoposide.
Clinical Monitoring and Follow-Up
Definitions and Evaluation of Response Sensitivity to cisplatin was defined as previously described.8 Any disease was considered sensitive to cisplatin when more than SD was achieved for more than 4 weeks. Any disease was considered refractory to cisplatin when SD or better was achieved but when there was evidence of tumor progression within 4 weeks of the last cisplatin-based treatment. Any disease was considered absolutely refractory to cisplatin when not even SD was achieved despite cisplatin-based chemotherapy. For the purpose of this study, the original pathology reports at the time of RTR were retrospectively classified as follows: (1) necrosis if no viable tissue was demonstrated; (2) mature teratoma if only viable mature teratoma was detected; (3) viable germ cell cancer if pure GCT elements (eg, embryonal carcinoma or chorioncarcinoma) or cancer that was probably arising from GCT (eg, immature teratoma or undifferentiated cancer) was detected; and (4) teratoma with malignant transformation if unequivocal non-GCT histologies (eg, adenocarcinoma or sarcoma) were found. The following residual tumor manifestations were considered as sites: abdominal lymph nodes, liver, chest (eg, lung and mediastinum), and neck. In patients with sites above and below the diaphragm, surgical interventions were performed at two or more separate occasions.
Statistical Analysis
Patient Characteristics Patient characteristics at the time of prior salvage chemotherapy are listed in Table 1. Only one patient had pure seminoma; all other patients had nonseminomatous or mixed histologies at initial presentation. Among nonseminoma patients, only one had a mediastinal extragonadal primary tumor. In 37 (65%) of 57 patients, conventional-dose cisplatin, ifosfamide, and etoposide followed by HDCT with carboplatin, etoposide, and ifosfamide was administered as salvage treatment before RTR.7 Salvage chemotherapy with cisplatin, ifosfamide, and paclitaxel and HDCT with carboplatin, etoposide, and thiotepa was administered in 20 (35%) of 57 patients.8 Patient characteristics before RTR are shown in Table 2. The majority of the patients had residual tumor masses in the abdominal lymph nodes, in the mediastinum, or in the lungs; 18 (32%) of 57 patients had residual tumors at more than one site.
Tumor markers before RTR were normal in the majority of the patients. Overall, 77 surgical interventions, 72 complete resections, and five incomplete resections were performed. Resections were performed at the following sites: abdominal lymph nodes in 36 (63%) of 57 patients, chest in 31 (54%) of 57 patients, liver in five (9%) of 57 patients, and neck in four (7%) of 57 patients. In one patient, a single central nervous lesion was resected. Resections at a single residual site were performed in 39 (68%) of 57 patients, 16 (28%) of 57 patients had resections at two sites, and two (4%) of 57 patients had resections at three sites. The results in 18 (32%) of 57 patients with multiple interventions are listed in Table 3. Further resections were omitted in 16 (47%) of 34 patients with residual tumors at multiple sites (abdomen, n = 3; lungs, n = 7; liver, n = 2; and brain, n = 4). The causes for these decisions were residual tumors less than 1 cm (n = 9), poor physical condition (n = 3), patient refusal (n = 2), and progression (n = 2) before the scheduled second resection.
Histologic Findings Viable cancer, mature teratoma, or both was found in 25 (69%) of 36 patients with residual tumors in the abdominal lymph nodes. In contrast, these histologies were found in only 12 (39%) of 31 patients with residual tumors in the lung (P < .05). Viable cancer or mature teratoma in resected liver lesions was rare (Table 4).
Viable cancer consisted of foci of residual GCT histologies in the majority of patients (embryonal carcinoma, n = 5; chorioncarcinoma, n = 1; seminoma, n = 1; or immature teratoma, n = 10). In five patients, viable cancer cells were classified as undifferentiated but probably arising from germ cell cancer. Only four patients had non-GCT elements in their resected specimen; two patients had adenocarcinoma, and one patient had sarcoma that was found in addition to mature teratoma (teratoma with malignant transformation). In one patient, a fibrolaminar hepatocellular carcinoma was unexpectedly found.
Prognostic Factors
Survival after RTR With a median follow-up of 87 months (range, 12 to 132 months), 37 (65%) of 57 patients were alive, and 34 (59%) of 57 patients remained continuously disease free. The majority of patients who relapsed had evidence of systemic disease with increasing tumor markers, new radiologic lesions, or both. Three patients who relapsed 4, 12, and 42 months after RTR were successfully treated with salvage therapy; one patient with an isolated marker relapse was treated successfully with five cycles of paclitaxel, one patient was treated successfully by surgical resection alone, and another patient with a localized inguinal relapse achieved an ongoing complete response after surgical resection followed by radiotherapy. All three patients became long-term survivors. Patients with viable cancer in their residual tumors had inferior treatment outcomes after RTR compared with patients with mature teratoma and/or necrosis. Only 10 (39%) of 26 of those patients remain continuously disease free compared with 24 (77%) of 31 patients with mature teratoma and/or necrosis. The projected overall and event-free survival rates after 5 years in patients with and without viable cancer is 42% versus 84% (P < .01) and 38% versus 77% (P < .01), respectively (Fig 2).
Adjuvant Chemotherapy after RTR Among 26 patients with viable cancer in their resected specimen, eight patients (31%) received adjuvant chemotherapy. Six of these patients eventually survived event free. Among those patients were all three patients in whom teratoma with malignant transformation was demonstrated as well as three patients with viable GCT histologies (one undifferentiated cancer and two immature teratomas). Two patients with embryonal carcinoma and one patient with immature teratoma progressed despite adjuvant treatment. Adjuvant chemotherapy was offered based on individual patient preferences; six patients received one to four cycles of oral etoposide, and two patients received two courses of combination chemotherapy using the cisplatin, vincristine, methotrexate, bleomycin, dactinomycin, cyclophosphamide, and etoposide regimen. Four patients with viable cancer at RTR survived event free without adjuvant chemotherapy (one patient with fibrolaminar hepatocellular carcinoma, one patient with embryonal carcinoma, one patient with immature teratoma, and one patient with undifferentiated cancer). All other patients with viable cancer did not receive adjuvant treatment mainly because of disease progression after RTR.
We retrospectively studied 216 patients treated with HDCT for relapsed or refractory GCTs to assess the contribution of RTR in their immediate management and long-term outcome. Only 26% of patients finally proceeded to postchemotherapy surgery (Fig 1). The major reason not to operate was tumor progression before surgery. Thus, only a small subgroup of patients after HDCT may eventually be evaluated for and profit from RTR. Only 6% of patients were considered to have unresectable disease. In contrast to the results of RTR after first-line chemotherapy, 61% of patients after HDCT either had viable cancer, mature teratoma, or both in their resected specimens. Whereas the benefit from RTR remains uncertain in 22 patients who had necrosis as their only histologic finding, RTR was justified in six of nine patients with mature teratoma who remain free of progression. After RTR, the event-free and overall survival rates were almost identical in patients with mature teratoma and necrosis, respectively. RTR was also justified in 10 of 26 patients with viable cancer who remain continuously free of disease; among these patients, four had non-GCT histologies (two adenocarcinomas, one sarcoma, and one fibrolaminar hepatocellular carcinoma). Nevertheless, identification of viable cancer at RTR was a strong adverse prognostic factor. Patients with viable cancer had significantly inferior survival rates after RTR compared with patients with necrosis and/or mature teratoma, irrespective of the anatomic site at which viable cancer was found and irrespective of the histologic subtype at the time or RTR. On the basis of the present analysis and the results from other groups who found comparable incidence rates, the frequency of mature teratoma or viable cancer is much higher in patients after salvage HDCT compared with patients after first-line treatment.4-6 Whereas viable cancer was most often present in resected retroperitoneal residual tumors, discordant histologic results were found in 12 (67%) of 18 patients with residual tumors at multiple anatomic sites. In one patient, viable cancer was identified in resected mediastinal lymph nodes after necrosis had been the only histologic finding at retroperitoneal RTR. Because there are usually no curative treatment options left in patients with relapse or progression after HDCT, we recommend that all patients with residual tumors after HDCT should undergo RTR at all anatomic localizations outside the CNS.3,6,11,12 In the present series, RTR was performed using separate surgical interventions in patients with residual tumors at multiple anatomic sites, with the initial intervention being at the location with the highest tumor burden. However, because viable cancer was significantly more frequent in retroperitoneal residual tumors, retroperitoneal RTR followed by resections at other anatomic locations is an alternative treatment strategy. Moreover, several groups have published encouraging data on a single-step simultaneous thoracoabdominal approach.13,14 This latter strategy might have prevented disease progression in two patients in the present series who progressed before the scheduled second surgery. However, although simultaneous thoracoabdominal resections might be superior in terms of immediate removal of all potentially malignant residual tumor, they may also be technically more demanding and require the availability of a multidisciplinary surgical team. Several relevant issues cannot be answered from the present series. First, all patients reported in this series had been treated with a single HDCT cycle. Sequential HDCT, as it is more commonly used recently, might influence the rate of viable cancer at the time of RTR.15,16 Data from an ongoing prospective randomized trial in Germany comparing single versus sequential HDCT in patients with relapsed or refractory GCT might help to address this issue in the future. Second, because of the small number of patients analyzed, we were unable to reliably identify prognostic factors for the presence or absence of viable cancer or mature teratoma. Patients with large pulmonary residual lesions had a higher likelihood of viable cancer at RTR, but other variables, such as the size of retroperitoneal lesions, positivity of serum tumor markers before RTR, or clinical evidence of chemotherapy-refractory disease before HDCT, might also have become relevant if data of more patients had been available. Similarly, the issue of whether or not positron emission tomography might have helped in selecting patients for RTR could not be addressed in the current analysis. Third, treatment with daily oral etoposide, gemcitabine, or oxaliplatin has shown to produce responses in small proportions of patients with relapse or progression after HDCT.17,18 Adjuvant chemotherapy after RTR has also been shown to benefit patients in whom teratoma with malignant transformation is found.19 Indeed, all three patients in whom teratoma with malignant transformation could be demonstrated also received adjuvant chemotherapy and became long-term survivors. However, because the patient numbers are small and adjuvant treatment was based on individual patient preferences, it remains unclear from the present series whether adjuvant chemotherapy did or would have improved the prognosis of patients with evidence of viable cancer at the time of RTR. This issue is being addressed in an ongoing randomized trial. In conclusion, postchemotherapy resections contribute to the overall treatment outcome and should be offered to all patients with partial remissions after HDCT. Complete resections of all residual tumors outside the CNS should be attempted.
The authors indicated no potential conflicts of interest.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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2. Fizazi K, Tjulandi S, Salvioni R, et al: Viable malignant cells after primary chemotherapy for disseminated nonseminomatous germ-cell tumors: Prognostic factors and role of postsurgery chemotherapy-results from an international study group. J Clin Oncol 19:2647-2657, 2001 3. Hendry WF, Norman AR, Dearnaley DP, et al: Metastatic nonseminomatous germ-cell tumors of the testis: Results of elective and salvage surgery for patients with residual retroperitoneal masses. Cancer 94:1668-1676, 2002[CrossRef][Medline]
4. Hartmann JT, Schmoll HJ, Kuczyk MA, et al: Postchemotherapy resections of residual masses from metastatic non-seminomatous testicular cell tumors. Ann Oncol 8:531-538, 1997 5. Donohue JP, Fox EP, Williams SD, et al: Persistent cancer in postchemotherapy retroperitoneal lymph-node dissection: Outcome analysis. World J Urol 12:190-195, 1994[Medline] 6. McGuire MS, Rabbani F, Mohseni H, et al: The role of thoracotomy in managing postchemotherapy residual thoracic masses in patients with nonseminomatous germ-cell tumours. BJU Int 91:469-473, 2003[CrossRef][Medline]
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8. Rick O, Bokemeyer C, Beyer J, et al: Salvage treatment with paclitaxel, ifosfamide and cisplatin (TIP) plus high-dose carboplatin, etoposide and thiotepa (CET) followed by autologous stem cell rescue in patients with relapsed or refractory germ-cell cancer. J Clin Oncol 19:81-88, 2001 9. Rick O, Beyer J, Kingreen D, et al: High-dose chemotherapy in germ-cell tumours: A large single centre experience. Eur J Cancer 34:1883-1888, 1998 10. Hartmann JT, Candelaria M, Kuczyk MA, et al: Comparison of histological results from the resection of residual masses at different sites after chemotherapy for metastatic non-seminomatous germ-cell tumors. Eur J Cancer 33:843-847, 1997
11. Gels ME, Hoekstra HJ, Sleijfer DT, et al: Thoracotomy for postchemotherapy resection of pulmonary residual tumor mass in patients with nonseminomatous testicular germ-cell tumors: Aggressive surgical resection is justified. Chest 112:967-973, 1997 12. Sonneveld DJ, Sleijfer DT, Koops HS, et al: Mature teratoma identified after postchemotherapy surgery in patients with disseminated nonseminomatous testicular germ-cell tumors: A plea for an aggressive surgical approach. Cancer 82:1343-1351, 1998[CrossRef][Medline]
13. Brenner PC, Herr HW, Morse MJ, et al: Simultaneous retroperitoneal, thoracic, and cervical resection of postchemotherapy residual masses in patients with metastatic nonseminomatous germ-cell tumors of the testis. J Clin Oncol 14:1765-1769, 1996
14. Fadel E, Court B, Chapelier AR, et al: One-stage approach for retroperitoneal and mediastinal metastatic testicular tumor resection. Ann Thorac Surg 69:1717-1721, 2000
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 cm (P < .01; 
