Treatment Options Under Clinical Evaluation:

Only a small number of children and adolescents with extracranial germ cell tumors relapse as a result of the effectiveness of treatment, though 20% to 30% of patients with advanced-stage extragonadal disease and adolescents with advanced gonadal disease may develop recurrent disease.[1,2] The approach to recurrent disease and its success depend on the initial treatment regimen and on the response of the tumor to treatment.

Boys with stage I testicular disease originally treated with surgical resection and observation can usually be salvaged, if relapse occurs, by further surgical excision and standard cisplatin, etoposide and bleomycin (PEB) or carboplatin, etoposide, and bleomycin (JEB) chemotherapy.[3,4] Several European studies also have reported encouraging salvage rates for stage I ovarian germ cell tumor patients originally treated with surgery and observation.[5,6] This strategy is being tested in the Children's Oncology Group (COG) trial, AGCT0132.

Most children with recurrent sacrococcygeal tumors will recur locally at the primary tumor site. For these children, complete surgical resection of the recurrent tumor and the coccyx is the basis of salvage treatment; preoperative chemotherapy may assist the surgical resection. In patients in whom a complete salvage resection is not achieved, postoperative local irradiation should be considered.[7]

Despite overall cure rates greater than 80%, children with extracranial germ cell tumors who have disease recurrence after surgery and three-agent platinum-based combination chemotherapy (PEB or JEB) have an unfavorable prognosis. Reports regarding the treatment and outcome of these children include small patient samples.[7] Reports of salvage treatment strategies used in adult recurrent germ cell tumors include larger numbers of patients, but the differences between children and adults regarding the location of the primary germ cell tumor site, pattern of relapse, and the biology of childhood germ cell tumors may limit the applicability of adult salvage approaches to childhood patients.[8]

In adults, combinations of conventional-dose ifosfamide and cisplatin combined with etoposide or vinblastine (VeIP) have been utilized as initial salvage therapy for patients who did not progress on standard PEB therapy.[9] These regimens can achieve relatively good disease-free status among patients with primary gonadal germ cell tumors who had a complete response (CR) to previous cisplatin-based chemotherapy; the outcome is poorer for patients who never achieved a CR or patients with mediastinal nonseminomatous germ cell tumors who relapse after a CR.[9] A combination of paclitaxel and gemcitabine has demonstrated activity in adults with testicular germ cell tumors who have relapsed after high-dose chemotherapy and hematopoietic stem cell transplant.[10]The combination of paclitaxel, ifosfamide, and cisplatin (TIP) has demonstrated a durable CR rate greater than 70% among these good-prognosis adults with relapsed nonseminomatous testicular cancer.[11]

High-dose chemotherapy with autologous stem cell rescue has been explored in adults. In a study of men with primary testicular germ cell tumor relapse, the use of high-dose carboplatin and etoposide with stem cell rescue (two cycles) as an initial salvage approach demonstrated better survival results than the use of this approach in patients with multiply relapsed germ cell tumor.[12] Studies of sequential dose-intensive paclitaxel/ifosfamide and carboplatin/etoposide with stem cell rescue or conventional-dose TIP followed by carboplatin/etoposide/thiotepa with stem cell rescue have demonstrated survival rates of 40% and 30%, respectively, in pilot studies.[13,14] Patients in second relapse with very high human chorionic gonadotropin levels, mediastinal nonseminomatous germ cell tumor, or progression soon after cisplatin-based chemotherapy have demonstrated less benefit from high-dose salvage chemotherapy.[15,16] A randomized trial of 211 adult testicular cancer patients treated in Germany and Canada showed that sequential high-dose chemotherapy (HDC) gave similar progression-free survival results (49% to 53% at 1 year) with less toxic deaths than single HDC.[17] Salvage attempts using HDC regimens may be of little benefit if local tumor control is not achieved initially.[18,19]

The role of HDC and hematopoietic stem cell rescue for recurrent pediatric germ cell tumors is not established, despite anecdotal reports. In one European series, 10 of 23 children with relapsed extragonadal germ cell tumors achieved long-term (median follow-up 66 months) disease-free survival by using HDC with stem cell support.[20] Further study is needed in children and adolescents.

The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

• AGCT0521: Though a standard pediatric salvage approach does not exist, the COG trial, AGCT0521, is for children with relapsed germ cell tumors. The trial will include the use of paclitaxel, ifosfamide, and carboplatin.

References

1. Mann JR, Raafat F, Robinson K, et al.: The United Kingdom Children's Cancer Study Group's second germ cell tumor study: carboplatin, etoposide, and bleomycin are effective treatment for children with malignant extracranial germ cell tumors, with acceptable toxicity. J Clin Oncol 18 (22): 3809-18, 2000.  [PUBMED Abstract]
   
   
2. Cushing B, Giller R, Cullen JW, et al.: Randomized comparison of combination chemotherapy with etoposide, bleomycin, and either high-dose or standard-dose cisplatin in children and adolescents with high-risk malignant germ cell tumors: a pediatric intergroup study--Pediatric Oncology Group 9049 and Children's Cancer Group 8882. J Clin Oncol 22 (13): 2691-700, 2004.  [PUBMED Abstract]
   
   
3. Schlatter M, Rescorla F, Giller R, et al.: Excellent outcome in patients with stage I germ cell tumors of the testes: a study of the Children's Cancer Group/Pediatric Oncology Group. J Pediatr Surg 38 (3): 319-24; discussion 319-24, 2003.  [PUBMED Abstract]
   
   
4. Rogers PC, Olson TA, Cullen JW, et al.: Treatment of children and adolescents with stage II testicular and stages I and II ovarian malignant germ cell tumors: A Pediatric Intergroup Study--Pediatric Oncology Group 9048 and Children's Cancer Group 8891. J Clin Oncol 22 (17): 3563-9, 2004.  [PUBMED Abstract]
   
   
5. Baranzelli MC, Bouffet E, Quintana E, et al.: Non-seminomatous ovarian germ cell tumours in children. Eur J Cancer 36 (3): 376-83, 2000.  [PUBMED Abstract]
   
   
6. Dark GG, Bower M, Newlands ES, et al.: Surveillance policy for stage I ovarian germ cell tumors. J Clin Oncol 15 (2): 620-4, 1997.  [PUBMED Abstract]
   
   
7. Schneider DT, Wessalowski R, Calaminus G, et al.: Treatment of recurrent malignant sacrococcygeal germ cell tumors: analysis of 22 patients registered in the German protocols MAKEI 83/86, 89, and 96. J Clin Oncol 19 (7): 1951-60, 2001.  [PUBMED Abstract]
   
   
8. Nichols CR: Treatment of recurrent germ cell tumors. Semin Surg Oncol 17 (4): 268-74, 1999.  [PUBMED Abstract]
   
   
9. Loehrer PJ Sr, Gonin R, Nichols CR, et al.: Vinblastine plus ifosfamide plus cisplatin as initial salvage therapy in recurrent germ cell tumor. J Clin Oncol 16 (7): 2500-4, 1998.  [PUBMED Abstract]
   
   
10. Einhorn LH, Brames MJ, Juliar B, et al.: Phase II study of paclitaxel plus gemcitabine salvage chemotherapy for germ cell tumors after progression following high-dose chemotherapy with tandem transplant. J Clin Oncol 25 (5): 513-6, 2007.  [PUBMED Abstract]
    
    
11. Motzer RJ, Sheinfeld J, Mazumdar M, et al.: Paclitaxel, ifosfamide, and cisplatin second-line therapy for patients with relapsed testicular germ cell cancer. J Clin Oncol 18 (12): 2413-8, 2000.  [PUBMED Abstract]
    
    
12. Bhatia S, Abonour R, Porcu P, et al.: High-dose chemotherapy as initial salvage chemotherapy in patients with relapsed testicular cancer. J Clin Oncol 18 (19): 3346-51, 2000.  [PUBMED Abstract]
    
    
13. Motzer RJ, Mazumdar M, Sheinfeld J, et al.: Sequential dose-intensive paclitaxel, ifosfamide, carboplatin, and etoposide salvage therapy for germ cell tumor patients. J Clin Oncol 18 (6): 1173-80, 2000.  [PUBMED Abstract]
    
    
14. Rick O, Bokemeyer C, Beyer J, et al.: Salvage treatment with paclitaxel, ifosfamide, and cisplatin plus high-dose carboplatin, etoposide, and thiotepa followed by autologous stem-cell rescue in patients with relapsed or refractory germ cell cancer. J Clin Oncol 19 (1): 81-8, 2001.  [PUBMED Abstract]
    
    
15. Beyer J, Rick O, Siegert W, et al.: Salvage chemotherapy in relapsed germ cell tumors. World J Urol 19 (2): 90-3, 2001.  [PUBMED Abstract]
    
    
16. Beyer J, Kramar A, Mandanas R, et al.: High-dose chemotherapy as salvage treatment in germ cell tumors: a multivariate analysis of prognostic variables. J Clin Oncol 14 (10): 2638-45, 1996.  [PUBMED Abstract]
    
    
17. Lorch A, Kollmannsberger C, Hartmann JT, et al.: Single versus sequential high-dose chemotherapy in patients with relapsed or refractory germ cell tumors: a prospective randomized multicenter trial of the German Testicular Cancer Study Group. J Clin Oncol 25 (19): 2778-84, 2007.  [PUBMED Abstract]
    
    
18. Rick O, Bokemeyer C, Weinknecht S, et al.: Residual tumor resection after high-dose chemotherapy in patients with relapsed or refractory germ cell cancer. J Clin Oncol 22 (18): 3713-9, 2004.  [PUBMED Abstract]
    
    
19. Einhorn LH, Williams SD, Chamness A, et al.: High-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumors. N Engl J Med 357 (4): 340-8, 2007.  [PUBMED Abstract]
    
    
20. De Giorgi U, Rosti G, Slavin S, et al.: Salvage high-dose chemotherapy for children with extragonadal germ-cell tumours. Br J Cancer 93 (4): 412-7, 2005.  [PUBMED Abstract]
    
    

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