|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 22, No 7 (April 1), 2004: pp. 1195-1200 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.07.102 Outcome of Patients With Residual Germ Cell or Non-Germ Cell Malignancy After Resection of Primary Mediastinal Nonseminomatous Germ Cell CancerFrom the Divisions of Hematology-Oncology, Thoracic Surgery, and Biostatistics, Indiana University Medical Center and Walther Cancer Institute, Indianapolis, IN Address reprint requests to Lawrence H. Einhorn, MD, Indiana Cancer Pavilion, 535 Barnhill Dr RT #473, Indianapolis, IN 46202-5289; e-mail: leinhorn{at}iupui.edu
PURPOSE: To identify prognostic variables and outcomes in patients with primary mediastinal nonseminomatous germ cell tumor (PMNSGCT) with postchemotherapy resection of persistent cancer. PATIENTS AND METHODS: Forty-seven consecutive patients with residual cancer after resection of PMNSGCT were retrospectively reviewed. Univariate comparisons were performed. RESULTS: At diagnosis, 43 patients had elevated serum tumor markers (STMs), and 20 had extramediastinal disease. At resection, 21 patients had elevated STMs. After resection, 26 patients had germ cell tumors (GCT), 12 had malignant transformation of teratoma with elements of non-GCT, and nine had both GCT and non-GCT. Sixteen of 47 patients continuously have no evidence of disease (NED). This includes eight of 26 patients with GCT histology and two of 12 patients with non-GCT histology. Of 27 patients with mediastinal-only disease at presentation, 14 have continuously NED. Of 20 patients with extramediastinal disease at presentation, two have continuously NED. Seven of 21 patients with elevated STMs at time of resection have continuously NED. Sixteen patients received adjuvant chemotherapy, and seven have continuously NED. Overall, 16 of 47 patients have continuously NED, an additional four patients have NED with further therapy (currently NED), two patients are alive with disease, 23 patients died of disease, and two patients died postoperatively. CONCLUSION: The presence of elevated STMs at resection does not appear to alter outcome if residual disease is completely resected. In this poor-risk patient population, surgical resection of persistent cancer, even in the presence of elevated STMs, can still achieve long-term survival.
Extragonadal germ cell tumors (GCT) most commonly originate in the retroperitoneum or the anterior mediastinum. Primary mediastinal GCTs are rare. These account for approximately 15% of adult anterior mediastinal tumors.1 Also, anterior mediastinal GCTs account for approximately 5% of all GCTs.2 The serologic and histologic characteristics of primary mediastinal nonseminomatous GCTs (PMNSGCTs) are similar to their testicular counterparts, but their biology3,4 and clinical outcomes are markedly different.5 PMNSGCTs are categorized as poor-risk disease by the International Germ Cell Cancer Collaborative Group consensus classification regardless of any other variable.6 Long-term survival of patients with PMNSGCT ranges between 30% and 60%.5,7-13 Currently the standard therapeutic approach includes platinum-based chemotherapy followed by surgical resection of any radiographic evidence of residual disease.5,12,14-17 Patients who relapse after this approach have a poor response to salvage chemotherapy alone, with only 7% of patients attaining long-term disease-free survival in one series.18 A prechemotherapy prognostic variable that has been shown to impact 5-year overall survival (OS) is the presence of extramediastinal metastases, whereas the presence of prechemotherapy and preoperative serum tumor marker (STM) elevation did not impact 5-year OS.14,19 In a retrospective review of 39 patients with PMNSGCT reported by Ganjoo et al,20 the most important postchemotherapy prognostic variable was the presence of viable cancer in the resected specimen.20 Other studies have confirmed the uniform adverse prognostic variable of residual cancer in resected specimens.14,19 In this article, we report on patients who presented with PMNSGCT and had residual viable cancer in postchemotherapy resected specimens. The purpose of this study was to identify prognostic variables and outcomes in this group of patients who had received standard platinum-based chemotherapy and who subsequently underwent complete resection of residual disease. The investigational review board of our institution approved this study.
A retrospective chart review was performed including 127 consecutive patients with primary mediastinal disease that was resected at Indiana University between 1987 and 2002. Forty-seven patients from this cohort had PMNSGCT and had received platinum-based chemotherapy; these patients subsequently underwent surgical resection of residual disease and were then found to have viable cancer in the resected specimen. All patients received the standard chemotherapy regimen at the time (cisplatin-based chemotherapy) or were randomly assigned to an ongoing protocol. Aggressive surgery to remove residual disease with tumor-free margins was performed in all patients. Surgery was technically demanding because the residual mass was typically infiltrated into surrounding mediastinal structures after chemotherapy. Because the postchemotherapy histology was not usually predictable from preoperative STMs, the surgical approach to remove all residual masses was similar and has been previously described.21 All patients in this review had residual disease radiographically at the completion of chemotherapy, which warranted further surgical intervention. In addition, the histology of the residual disease was either viable germ cell cancer (comprised of embryonal cell carcinoma, yolk sac tumor, choriocarcinoma, or a combination of these) or non–germ cell cancer (teratoma that had transformed to a sarcomatoid or carcinomatous histology). The OS and progression-free survival outcomes were calculated from the time of surgical resection until death or progression of disease, respectively. Data for subjects who were alive or disease-free at the conclusion of the study were censored at the most recent date that their survival and disease status were known. The distribution of the time until death or progression of disease was performed by the Kaplan-Meier method. Univariate comparisons of several variables were performed and tested by the log-rank test. These included evaluation of outcome by extent of disease at diagnosis (mediastinal only v extramediastinal), histology (germ cell, non–germ cell, or both), STMs at the time of resection (normal v elevated), the use of adjuvant therapy, and site of relapse.
Patient Characteristics at Diagnosis
Patient Characteristics at Time of Resection Twenty-one (45%) of the 47 patients had either an elevated AFP or ßhCG at the time of resection. The median AFP was 13.05 ng/mL (range, normal to 2,534 ng/mL), and the median ßhCG was less than 2 mU/mL (range, normal to 5,093 mU/mL). Eleven patients had a documented increasing STM at the time of resection. In addition, at least two patients had a rapidly growing mass preoperatively with normal STMs.
Histology
Survival and Outcomes The median OS for the entire group was 64 weeks (range, 3 to 576 weeks), with a median overall relapse-free survival of 25 weeks (range, 1 to 576 weeks; Table 3 and Fig 1). Sixteen patients (34%) continuously have no evidence of disease (NED), with a median follow-up of 98 weeks (range, 7 to 576 weeks). An additional 4 patients (43%) have currently NED, with a median follow-up of 156 weeks (range, 65 to 304 weeks), and two patients (4%) are alive with active disease. Twenty-three patients (49%) have died from disease, and two patients (4%) experienced postoperative mortality. Of the four patients who have currently NED with additional therapy, three had recurrent, resected teratoma. Patient 1 had recurrent teratoma in the region of the right inferior pulmonary ligament approximately 25 weeks after the initial resection. This patient has had NED for 147 weeks from the most recent surgery. Patient 2 had recurrent mediastinal mature teratoma resected 240 weeks after the initial resection. This patient has had currently NED for 64 weeks since the last resection. Patient 3 had resection of recurrent thoracic spinal disease, which recurred 27 weeks after initial resection and histologically was found to be mature teratoma. This patient has had NED for 113 weeks since the last resection. Patient 4 had biopsy-proven recurrent metastatic GCT in the left acetabulum and proximal tibia and an elevated AFP equal to 321 ng/mL at 15 weeks after resection. The patient was treated with radiation therapy to the sites of bony involvement and was then treated with gemcitabine and paclitaxel. The patient subsequently has had NED both radiographically and serologically for 50 weeks since the completion of all therapy.
Outcome by Disease Distribution at Presentation and Sites of Recurrence Twenty-seven patients (57%) had mediastinal-only disease, whereas 20 patients (43%) had extramediastinal disease at presentation. Of the 27 patients with mediastinal-only disease at presentation, 14 (52%) have continuously NED with a median follow-up of 98 weeks (range, 7 to 576 weeks). Of the 20 patients with extramediastinal disease at presentation, only two (10%) have continuously NED. The median OS was not reached in the mediastinal-only group and was 40 weeks for the extramediastinal group (P = .040; Fig 2). At relapse, two patients had relapse only in the mediastinum, and 25 patients had extramediastinal sites of relapse.
Outcome by Histology of Resected Disease At resection, 26 patients (55%) were found to have histologic evidence of NSGCT, 12 patients (26%) had non-GCT, and nine patients (19%) had predominant involvement of GCT and non-GCT histology (Table 4). Of patients with NSGCT histology, eight (31%) have continuously NED with median follow-up of 388 weeks (range, 7 to 576 weeks), three additional patients (42%) have currently NED with median follow-up of 140 weeks (range, 65 to 304 weeks), 13 patients (50%) are dead from disease, and two patients (8%) died postoperatively. Of patients with non-GCT histology, two (17%) have continuously NED with follow-up of 93 and 289 weeks, one additional patient (25%) has currently NED with follow-up of 172 weeks, one patient (8%) is alive with disease, and eight patients (67%) are dead from disease. Six patients (67%) with both histologies have continuously NED with a median follow-up of 65 weeks (range, 27 to 109 weeks). The median OS for NSGCT and non-GCT histology are similar at 64 weeks and 53 weeks, respectively.
Outcome According to Adjuvant Chemotherapy The use of chemotherapy in the adjuvant setting was also analyzed in our review (Table 5). The status of adjuvant chemotherapy was not known in three patients. Of the remaining 44 patients, 16 (36%) received adjuvant chemotherapy, whereas 28 (64%) did not. Twelve patients received platinum-based therapy, and four patients received oral etoposide. The median OS for the 16 patients who received adjuvant therapy was not reached, whereas in the remaining 28 patients, the median OS was 61 weeks (P = .140). The median RFS was 134 weeks and 21 weeks for patients who did and did not receive adjuvant therapy, respectively (P = .270).
In patients who had a germ-cell component (histology of GCT or both GCT and non-GCT; n = 35), the outcome according to adjuvant chemotherapy was also analyzed (Table 6). Data concerning adjuvant chemotherapy was unknown in two of the 35 eligible patients. Sixteen patients (48%) received adjuvant chemotherapy (the same 16 patients as mentioned earlier), and 17 patients (52%) did not. Of the patients who did receive adjuvant chemotherapy, seven have continuously NED with a median follow-up of 389 weeks (range, 37 to 576 weeks), and three additional patients are currently NED. Of the patients with a GCT component who did not receive adjuvant chemotherapy, six are continuously NED with a median follow-up of 43 weeks (range, 7 to 75 weeks).
Outcome by STM Value at Time of Resection The median AFP was 13.05 ng/mL (range, normal to 2,534 ng/mL), and the median ßhCG was less than 2 mIU/mL (range, normal to 5,093 mIU/mL). Twenty-one patients (45%) had either an elevated serum AFP or ßhCG at the time of resection. Seven (33%) of these patients have continuously NED with a median follow-up of 75 weeks (range, 7 to 576 weeks). Twenty-six patients (55%) had normal STMs at the time of resection, and nine (35%) of these patients have continuously NED with a median follow-up of 104 weeks (range, 37 to 545 weeks). Eleven patients had documented increasing STMs at the time of resection. Of these patients, four have continuously NED with follow-ups of 27, 35, 75, and 389 weeks.
PMNSGCT represents a rare disease,1,2 and therefore, data concerning outcome analyses have been limited by the paucity of cases. In addition, the data regarding outcome after resection of postchemotherapy cancer are scant. Unfortunately, the cure rate with this presentation is inferior to primary testicular NSGCT.5 PMNSGCT is classified as a poor-risk disease regardless of other prognostic variables.6 Several variables further stratify outcomes in these patients.22 One important variable seems to be the presence of residual viable cancer in the resected specimen.14,19,20 Both germ cell cancer or non–germ cell histologies represent common pathologic findings at resection, and both are associated with a dismal prognosis. Non–germ cell histology is the result of malignant transformation of prior teratoma.23 Similar to its gonadal counterpart, standard therapy for PMNSGCT is platinum-based chemotherapy.24 Surgical excision of radiographically residual disease after chemotherapy represents an important component to the multimodality approach to this disease when feasible.5,12,14-17 Also, because of dismal results with second-line chemotherapy11,18,20,25-28 and reasonable outcomes with surgery, it has been our institutional approach to perform resection in patients with PMNSGCT who have elevated STMs after first-line chemotherapy when anatomically possible.19 This is a retrospective review of patients who had PMNSGCT and who had pathologic evidence of cancer after primary platinum-based chemotherapy and resection of residual disease. The patients with extramediastinal disease at the time of presentation had an inferior outcome when compared with patients with disease radiographically confined to the mediastinum. This was expected because extramediastinal disease at presentation is a well-described adverse prognostic variable.14,19 When evaluating sites of recurrence, only two recurrences in our series occurred in the mediastinum alone. This underscores the importance of surgery to achieve local control. The lungs were the predominate site of relapse, and the bones were the next most common site for all histologic subtypes. There was no apparent predisposition for site of recurrence based on histology of residual disease. Outcome was evaluated by histology. There was no clinically meaningful difference in median OS between the patients who had NSGCT versus those who had residual non-GCT. Although the median OS for patients who had both NSGCT and non-GCT was not reached, it was felt that the number of patients in this group prohibited reliable analysis. In testicular primary NSGCT, surgical resection of disease is typically reserved for patients who have had normalization of STMs or late relapse (> 2 years after completion of therapy) or for patients who need desperation salvage resection.15 Surgical resection of PMNSGCT after completion of chemotherapy is typically undertaken after front-line chemotherapy at Indiana University regardless of the STM status.19 This is because of poor results with salvage chemotherapy11,18,20,25-28 and the efficacy with salvage surgery.14,19 Also, unlike NSGCT of testicular origin, the STM status after completion of platinum-based chemotherapy does not seem to accurately predict the presence of residual cancer. Although the power of this conclusion is limited by a small patient sample size and retrospective data acquisition, the relative equivalent survival efficacy seen here is further supported by the series reported by Vuky et al14 who described no significant difference in survival when comparing patients with presurgical elevated markers versus patients with normal markers. In that report, however, there was a trend toward inferior survival when comparing patients with increasing STMs compared with patients who had normal or decreasing STMs. In our review, four (36%) of 11 patients with documented increasing STMs have continuously NED. Although this certainly represents a small subset of patients, it does reinforce the importance of not denying aggressive therapy to this population. The survival curve indicates that, in patients who relapse or progress, death occurs shortly after definitive therapy. This patient population, in general, has a dramatically truncated survival. There is a plateau of the survival curve, however, which indicates that a significant number of these patients are likely cured of their disease. Thus, even in this poor-risk patient population, surgical resection of persistent cancer, even in the presence of elevated STMs, can still confer long-term survival. In our opinion, the skill and experience of the oncology center and especially the expertise of the thoracic surgical oncologist are of pivotal importance in achieving successful outcome.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Owns stock (not including shares held through a public mutual fund): Lawrence H. Einhorn, Amgen, GlaxoSmithKline. Acted as a consultant within the last 2 years: Lawrence H. Einhorn, Bristol-Myers Squibb.
Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Mullen B, Richardson JD: Primary anterior mediastinal tumors in children and adults. Ann Thorac Surg 42:338-345, 1986[Abstract] 2. Hainsworth JD, Greco FA: Extragonadal germ cell tumors and unrecognized germ cell tumors. Semin Oncol 19:119-127, 1992[Medline]
3. Nichols CR, Heerema NA, Palmer C, et al: Klinefelter's syndrome associated with mediastinal germ cell neoplasms. J Clin Oncol 5:1290-1294, 1987
4. Bosl GJ, Motzer RJ: Testicular germ-cell cancer. N Engl J Med 337:242-253, 1997
5. Bokemeyer C, Nichols CR, Droz JP, et al: Extragonadal germ cell tumors of the mediastinum and retroperitoneum: Results from an international analysis. J Clin Oncol 20:1864-1873, 2002
6. International Germ Cell Consensus Classification: A prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. J Clin Oncol 15:594-603, 1997 7. Nichols CR, Saxman S, Williams SD, et al: Primary mediastinal nonseminomatous germ cell tumors: A modern single institution experience. Cancer 65:1641-1646, 1990[CrossRef][Medline] 8. Bukowski RM, Wolf M, Kulander BG, et al: Alternating combination chemotherapy in patients with extragonadal germ cell tumors: A Southwest Oncology Group study. Cancer 71:2631-2638, 1993[CrossRef][Medline] 9. Logothetis CJ, Samuels ML, Selig DE, et al: Chemotherapy of extragonadal germ cell tumors. J Clin Oncol 3:316-325, 1985[Abstract]
10. Garnick MB, Canellos GP, Richie JP: Treatment and surgical staging of testicular and primary extragonadal germ cell cancer. JAMA 250:1733-1741, 1983 11. Toner GC, Geller NL, Lin SY, et al: Extragonadal and poor risk nonseminomatous germ cell tumors: Survival and prognostic features. Cancer 67:2049-2057, 1991[CrossRef][Medline] 12. Dulmet EM, Macchiarini P, Suc B, et al: Germ cell tumors of the mediastinum: A 30-year experience. Cancer 72:1894-1901, 1993[CrossRef][Medline] 13. Wright CD, Kesler KA, Nichols CR, et al: Primary mediastinal nonseminomatous germ cell tumors: Results of a multimodality approach. J Thorac Cardiovasc Surg 99:210-217, 1990[Abstract]
14. Vuky J, Bains M, Bacik J, et al: Role of postchemotherapy adjunctive surgery in the management of patients with nonseminoma arising from the mediastinum. J Clin Oncol 19:682-688, 2001 15. Toner GC, Panicek DM, Heelan RT, et al: Adjunctive surgery after chemotherapy for nonseminomatous germ cell tumors: Recommendations for patient selection. J Clin Oncol 8:1683-1694, 1990[Abstract] 16. Goss PE, Schwertfeger L, Blackstein ME, et al: Extragonadal germ cell tumors: A 14-year Toronto experience. Cancer 73:1971-1979, 1994[CrossRef][Medline] 17. Gonzalez-Vela JL, Savage PD, Manivel JC, et al: Poor prognosis of mediastinal germ cell cancers containing sarcomatous components. Cancer 66:1114-1116, 1990[CrossRef][Medline] 18. Saxman SB, Nichols CR, Einhorn LH: Salvage chemotherapy in patients with extragonadal nonseminomatous germ cell tumors: The Indiana University experience. J Clin Oncol 12:1390-1393, 1994[Abstract]
19. Kesler KA, Rieger KM, Ganjoo KN, et al: Primary mediastinal nonseminomatous germ cell tumors: The influence of postchemotherapy pathology on long-term survival after surgery. J Thorac Cardiovasc Surg 118:692-700, 1999 20. Ganjoo KN, Rieger KM, Kesler KA, et al: Results of modern therapy for patients with mediastinal nonseminomatous germ cell tumors. Cancer 88:1051-1056, 2000[CrossRef][Medline] 21. Wright CD, Kesler KA: Surgical techniques and outcomes for primary nonseminomatous germ cell tumors. Chest Surg Clin N Am 12:707-715, 2002[Medline]
22. Hartmann JT, Nichols CR, Droz JP, et al: Prognostic variables for response and outcome in patients with extragonadal germ-cell tumors. Ann Oncol 13:1017-1028, 2002 23. Motzer RJ, Amsterdam A, Prieto V, et al: Teratoma with malignant transformation: Diverse malignant histologies arising in men with germ cell tumors. J Urol 159:133-138, 1998[CrossRef][Medline]
24. Motzer RJ, Rodriguez E, Reuter VE, et al: Molecular and cytogenetic studies in the diagnosis of patients with poorly differentiated carcinomas of unknown primary site. J Clin Oncol 13:274-282, 1995 25. Fizazi K, Culine S, Droz JP, et al: Primary mediastinal nonseminomatous germ cell tumors: Results of modern therapy including cisplatin-based chemotherapy. J Clin Oncol 16:725-732, 1998[Abstract]
26. Hidalgo M, Paz-Ares L, Rivera F, et al: Mediastinal non-seminomatous germ cell tumours (MNSGCT) treated with cisplatin-based combination chemotherapy. Ann Oncol 8:555-559, 1997 27. Broun ER, Nichols CR, Einhorn LH, et al: Salvage therapy with high-dose chemotherapy and autologous bone marrow support in the treatment of primary nonseminomatous mediastinal germ cell tumors. Cancer 68:1513-1515, 1991[CrossRef][Medline]
28. Hartmann JT, Einhorn L, Nichols CR, et al: Second-line chemotherapy in patients with relapsed extragonadal nonseminomatous germ cell tumors: Results of an international multicenter analysis. J Clin Oncol 19:1641-1648, 2001 Submitted July 14, 2003; accepted January 12, 2004.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
