Treatment of Recurrent Malignant GCTs in Children
Only a small number of children and adolescents with extracranial germ cell tumors (GCTs) have a recurrence.[1,2] However, the approach to the treatment of recurrent disease and its success depend on the initial treatment regimen and on the response of the tumor to treatment.
Treatment Options for Recurrent Malignant GCTs in Children
There are no standard treatment options for recurrent pediatric GCTs. Information about ongoing clinical trials is available from the NCI Web site.
Treatment options for recurrent childhood malignant GCTs include the following:
The role for surgery in selected patients who have recurrent GCTs has not been established but should be considered.
Despite overall cure rates greater than 80%, children with extracranial GCTs who have disease recurrence after surgery and three-agent, platinum-based combination chemotherapy (cisplatin, etoposide, and bleomycin [PEB] or carboplatin, etoposide, and bleomycin [JEB]) have an unfavorable prognosis. Reports regarding the treatment and outcome of these children are based on small patient samples.
Reports of salvage treatment strategies used in adult recurrent GCTs include larger numbers of patients, but the differences between children and adults regarding the location of the primary GCT site, pattern of relapse, and the biology of childhood GCTs may limit the applicability of adult salvage approaches to children. Treatments that have been explored in adults include the following:
- In adults with recurrent GCTs, several chemotherapy combinations have achieved relatively good disease-free status.[4-9] A combination of paclitaxel and gemcitabine has demonstrated activity in adults with testicular GCTs who relapsed after HD chemotherapy and hematopoietic stem cell transplant (HSCT).
Surgery followed by chemotherapy
If a tumor recurs, boys with stage I testicular disease originally treated with surgical resection and observation can usually undergo salvage therapy with further surgical excision and standard PEB or JEB chemotherapy.[11,12]
For stage I ovarian GCT patients originally treated with surgery and observation, several European studies have reported encouraging salvage rates with further surgical excision and chemotherapy.[13,14]
In a Children’s Oncology Group Trial (AGCT0521 [NCT00467051]), patients who relapsed after PEB therapy received two cycles of paclitaxel, ifosfamide, and carboplatin. Study results are pending.
Chemotherapy followed by surgery and possibly radiation therapy
Most children with benign sacrococcygeal tumors experience recurrence with a malignant component at the primary tumor site. For these children, complete surgical resection of the recurrent tumor and coccyx (if not done originally) is the basis of salvage treatment; preoperative chemotherapy with PEB may assist the surgical resection. In patients who had a malignant sacrococcygeal tumor that recurred after PEB treatment, surgery and additional chemotherapy may be warranted; when a complete salvage resection is not achieved, postoperative local radiation therapy may be an option.
HD chemotherapy and hematopoietic stem cell rescue
The role of HD chemotherapy and hematopoietic stem cell rescue for recurrent pediatric GCTs is not established, despite anecdotal reports. (Refer to the Autologous Hematopoietic Cell Transplantation section of the PDQ summary on Childhood Hematopoietic Cell Transplantation for more information about transplantation.) In one European series, 10 of 23 children with relapsed extragonadal GCTs achieved long-term disease-free survival (median follow-up, 66 months) after receiving HD chemotherapy with stem cell support. Further study in children and adolescents is needed.
HD chemotherapy with autologous stem cell rescue has been explored as a treatment for adults with recurrent testicular GCTs. HD chemotherapy plus hematopoietic stem cell rescue has been reported to cure adult patients with relapsed testicular GCTs, even as third-line therapy and in cisplatin-refractory patients. While several other studies support this approach,[10,17-20] others do not.[21,22] Salvage attempts using HD-chemotherapy regimens may be of little benefit if the patient is not clinically disease free at the time of HSCT.[16,23]
Radiation therapy followed by surgery (for brain metastases)
Patients with nongerminomatous brain metastases may respond to radiation therapy. In the German Maligne Keimzelltümoren (MAKEI) studies, radiation therapy and surgery for patients with brain metastases provided palliation and occasional long-term survival.[24,25][Level of evidence: 3iiiA]
Treatment Options Under Clinical Evaluation for Recurrent Malignant GCTs in Children
Other treatment options that are being investigated include the following:
- Hyperthermia. A single-institution study of 44 young people (aged 7 months to 21 years) with refractory or recurrent extracranial GCTs, using cisplatin/etoposide/ifosfamide and regional deep hyperthermia with or without surgery plus radiation therapy for residual tumor, showed a response rate of 86% in 35 patients for whom sufficient data were available. The 5-year event-free survival was 62%, and the 5-year overall survival was 72%.[Level of evidence: 3iiDi] However, regional hyperthermia facilities are limited and not readily available for children in the United States. Further study in children and adolescents is needed.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent childhood malignant germ cell tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
- 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]
- 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]
- 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]
- 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]
- 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]
- 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 (6): 1641-8, 2001. [PUBMED Abstract]
- Mandanas RA, Saez RA, Epstein RB, et al.: Long-term results of autologous marrow transplantation for relapsed or refractory male or female germ cell tumors. Bone Marrow Transplant 21 (6): 569-76, 1998. [PUBMED Abstract]
- Kondagunta GV, Bacik J, Sheinfeld J, et al.: Paclitaxel plus Ifosfamide followed by high-dose carboplatin plus etoposide in previously treated germ cell tumors. J Clin Oncol 25 (1): 85-90, 2007. [PUBMED Abstract]
- Schmoll HJ, Kollmannsberger C, Metzner B, et al.: Long-term results of first-line sequential high-dose etoposide, ifosfamide, and cisplatin chemotherapy plus autologous stem cell support for patients with advanced metastatic germ cell cancer: an extended phase I/II study of the German Testicular Cancer Study Group. J Clin Oncol 21 (22): 4083-91, 2003. [PUBMED Abstract]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- Feldman DR, Sheinfeld J, Bajorin DF, et al.: TI-CE high-dose chemotherapy for patients with previously treated germ cell tumors: results and prognostic factor analysis. J Clin Oncol 28 (10): 1706-13, 2010. [PUBMED Abstract]
- 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]
- 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]
- 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]
- Göbel U, von Kries R, Teske C, et al.: Brain metastases during follow-up of children and adolescents with extracranial malignant germ cell tumors: risk adapted management decision tree analysis based on data of the MAHO/MAKEI-registry. Pediatr Blood Cancer 60 (2): 217-23, 2013. [PUBMED Abstract]
- Göbel U, Schneider DT, Teske C, et al.: Brain metastases in children and adolescents with extracranial germ cell tumor - data of the MAHO/MAKEI-registry. Klin Padiatr 222 (3): 140-4, 2010. [PUBMED Abstract]
- Wessalowski R, Schneider DT, Mils O, et al.: Regional deep hyperthermia for salvage treatment of children and adolescents with refractory or recurrent non-testicular malignant germ-cell tumours: an open-label, non-randomised, single-institution, phase 2 study. Lancet Oncol 14 (9): 843-52, 2013. [PUBMED Abstract]