eMedicine Specialties > Oncology > Carcinomas of the Genitourinary Tract

Extragonadal Germ Cell Tumors: Treatment & Medication

Author: Kush Sachdeva, MD, Private Practice, Southern Oncology and Hematology Associates, South Jersey Hospital System, Fox Chase Cancer Center
Coauthor(s): Issam Makhoul, MD, Associate Professor, Department of Medicine, Division of Hematology/Oncology, University of Arkansas for Medical Sciences; Brendan Curti, MD, Director, Genitourinary Oncology Research, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center
Contributor Information and Disclosures

Updated: Aug 15, 2008

Treatment

Medical Care

Treatment modality is determined by the site and the histologic type of the primary tumor. Seminomas are very sensitive to chemotherapy and radiotherapy. Nonseminomatous germ cell tumors (NS-GCTs) are less sensitive to these modalities and may require surgery for resection of a postchemotherapy residual mass. Prior to the availability of cisplatin-based chemotherapy, cure rates for nonseminomatous germ cell tumors were less than 10%. Mature teratomas are relatively insensitive to both chemotherapy and radiation therapy therefore surgery is the only treatment for teratomas

  • Mediastinal germ cell tumors (MGCTs): Cisplatin-based chemotherapy has made a significant improvement in treatment of seminoma of the mediastinum.13   
    • Treatment with 4 cycles of bleomycin, etoposide, and cisplatin (BEP) is the current standard of care. Radiotherapy can be used after chemotherapy in bulky mediastinal seminomas.14
    • In nonseminomatous mediastinal germ cell tumors (NS-MGCT), 4 cycles of bleomycin, etoposide, and cisplatin also are recommended. If the serum tumor markers remain elevated, give salvage chemotherapy. If the CT scan shows residual disease with or without tumor marker elevation, perform surgical resection followed by 2 cycles of chemotherapy. The nature of the salvage and postsurgical chemotherapy remains debated. Intensive cisplatin-based chemotherapy followed by resection of residual tumor was shown to yield survival rates of 48-73% in nonseminomatous mediastinal germ cell tumors.
    • Walsh et al reported on the experience at M.D. AndersonCancerCenter over 5 years with 20 patients treated for nonseminomatous mediastinal germ cell tumors. Of those treated, 11 patients had received no prior chemotherapy, and 9 patients were referred following treatment at other facilities for salvage therapy after progression of their tumors.15
      • Patients received combination chemotherapy with alternating sequential courses comprising, first, bleomycin, vincristine, and cisplatin (BOP); followed in 7 days by cisplatin, cyclophosphamide, doxorubicin (Adriamycin) (CISCA); followed in 14 days by cisplatin, vincristine, methotrexate, and bleomycin (POMB); followed in 10 days by actinomycin, cyclophosphamide, and etoposide (ACE).
      • In addition to this regimen, etoposide, ifosfamide, and cisplatin (VIP) were also used in the salvage group.
      • Major toxic effects occurred in all these patients, including neuropathy, ototoxicity, mucositis, cytopenias, and renal toxicity.
      • The 2-year survival rate of the entire group was 58%. However, the 2-year survival rate for the previously untreated group was 72%, whereas it was 39% for the salvage group.
      • Intensification of the chemotherapy was achieved by decreasing the interval between cycles and by alternating drugs from course to course. This was made possible by the systemic use of hematopoietic growth factors. Stem cell rescue has been used in certain centers to achieve dose intensification.
    • Data from 75 patients treated at IndianaUniversity for nonseminomatous germ cell tumors have been analyzed.16   
      • Of those treated, 48 patients received BEP, 9 patients received VIP, 9 patients received VIP/Velban (vinblastine) and bleomycin (VeB), and the rest were treated with different cisplatin-containing regimens.
      • No significant difference in survival was reported between those who received BEP and those who received VIP.
      • Of the 62 patients (58%) who underwent surgical resection of a residual mass, 36 are long-term survivors. Overall survival rate for the group is 48%.
      • None of the 17 patients whose disease relapsed after or progressed on first-line chemotherapy and surgery could achieve complete remission despite salvage therapy with cisplatin-based regimens, high-dose chemotherapy, paclitaxel, or oral etoposide.
  • Intracranial germ cell tumors (ICGCTs): The standard treatment for intracranial germ cell tumors has been radiotherapy, either alone (seminomas) or in combination with chemotherapy (nonseminomatous germ cell tumors).  
    • A wide range of survival rates (37-100%) is reported after radiation. However, because of its long-term toxicity, attempts are made to use lower doses of craniospinal irradiation (CSI) in combination with chemotherapy. Regardless of the type of the initial treatment, combined modality therapy comprising radiation and chemotherapy is the recommended salvage therapy for relapse.
    • Radiation therapy varies in intensity from craniospinal irradiation (CSI) with boost (the most intense), to whole brain irradiation with boost, ventricular irradiation with boost, and focal irradiation alone (the least intense).
    • Event-free survival rate (EFS) of 90% for patients with seminomas who received only CSI was reported by Calaminus et al.17 Chemotherapy alone resulted in an EFS of 53%, although the follow-up period was short and the number of patients was limited in this group. Patients receiving combined modality achieved an EFS of about 92%. In nonseminomas, EFS was affected by the cumulative dose of cisplatin. Patients who received a cumulative dose of 400 mg/m2 had an EFS of 86%. Those who received 200 mg/m2 had a significantly lower EFS, 56%. The 2 groups were observed for 46 and 65 months, respectively.
    • Balmaceda and colleagues reported on 71 patients treated by chemotherapy alone for intracranial germ cell tumors (45 seminomas and 26 nonseminomatous germ cell tumors). Diagnosis was established by resection (approximately 50% of patients) or biopsy. Patients were evaluated after 4 cycles of carboplatin, etoposide, and bleomycin. If complete response (CR) was achieved, 2 more cycles were given. Surgery alone resulted in 3 CR. Of 68 patients, 39 achieved CR after chemotherapy alone. Of the 29 patients with partial response (PR), 10 achieved CR with intensified chemotherapy and 3 more after second surgery, bringing the number of CRs to 55 (78%). Although response to chemotherapy was not affected by the histologic type (81% for nonseminomas vs 82% for seminomas), long-term survival differed significantly by histologic type (84% for seminomas vs 62% for nonseminomas). Treatment mortality rate was 10%.18
    • The optimal role for surgery remains to be defined. Because of the risk of intraspinal metastases related to surgery or even to stereotactic biopsy, a sandwich protocol using preoperative chemotherapy, followed by surgery, then postoperative chemotherapy was suggested. Surgery is indicated only if a residual mass is present after chemotherapy. Such a protocol uses BEP preoperatively and VIP postoperatively. The tumor marker elevation in nonseminomatous germ cell tumors obviates the need for surgical biopsies.
    • Third ventriculostomy via neuroendoscopy can be performed to drain obstructive hydrocephalus. This procedure prevents peritoneal seeding related to VP shunt.
  • Retroperitoneal germ cell tumors (RGCTs): Primary chemotherapy with 4 cycles of bleomycin, etoposide, and cisplatin (BEP) is recommended for both seminomas and nonseminomas, with excision of residual mass in nonseminomas.  
    • Pectasides reported on 16 patients with retroperitoneal germ cell tumors, 11 with nonseminomatous germ cell tumors, and 5 with seminomatous germ cell tumors.19 Cisplatin-based (or carboplatin-based) chemotherapy resulted in complete or PR in 14 patients. Ten patients underwent surgery, bringing the number of patients with CR to 14 (87.5%); 9 of them are long-term survivors (56.25%).
    • Nichols recommends primary abdominal radiotherapy for patients with small-volume retroperitoneal seminomas (abdominal mass <5 cm) and chemotherapy for patients with larger volume disease (abdominal mass >10 cm).20 Patients with intermediate disease may be treated with either modality.
  • Sacrococcygeal germ cell tumors have a poor prognosis. Long-standing remission is attained in only 31% of patients treated with multiagent chemotherapy.

Surgical Care

Surgery is the primary and only effective modality in teratomas. It is also used as primary or secondary treatment of nonseminomatous germ cell tumors (NS-EGGCTs). The current standard of care is surgery if a residual mass is present after neoadjuvant chemotherapy. Used in this setting, chemotherapy allows translation of partial responses into complete responses and evaluation of the chemosensitivity of the tumor.

However, the size of residual mass for which surgery is indicated remains controversial. In the experience at the MemorialSloan-KetteringCancerCenter, 5 of 20 patients underwent surgery for residual mass after receiving chemotherapy or radiotherapy for retroperitoneal seminoma. No viable seminoma was found in masses less than 3 cm. Therefore, they recommend surgical resection for residual tumors greater than 3 cm to ascertain the need for subsequent chemotherapy.

No further chemotherapy is recommended if the final pathology is consistent with mature teratoma or necrotic tissue. Additional postoperative chemotherapy is given if the patient is found to have viable tumors. Although the same chemotherapy used preoperatively may be used after surgery, it is reasonable to switch to another drug combination.

The surgical resection should include all gross disease with en bloc resection of all involved structures that can be sacrificed. Orchiectomy or testicular biopsy is not required unless testicular examination and/or ultrasound findings are suggestive or frankly abnormal.

  • Mediastinal germ cell tumors (MGCT): Midline sternotomy is the most common approach, followed by posterolateral thoracotomy. Partial pericardial resection is required in most cases. Thymectomy is performed routinely because the thymus is often replaced totally by tumor. Dissection of the aorta and sometimes resection of certain veins occasionally are required to achieve complete resection.
  • Retroperitoneal germ cell tumors (RGCT): Midline, transverse, or oblique transperitoneal approaches have been used to remove retroperitoneal germ cell tumors. Excision via a thoracoabdominal extraperitoneal approach has been suggested recently. The alleged benefits of this approach are more ready removal of the primary tumor and its possible intrathoracic extensions, avoidance of paralytic ileus, and decreased risk of ejaculatory dysfunction.
  • Pineal germ cell tumors: En bloc resection of the pineal mass is performed via the supracerebellar infratentorial approach.

Medication

The goals of pharmacotherapy are to induce remission, reduce morbidity, and prevent complications.

Chemotherapeutic agents

Regardless of the tumor location and whenever chemotherapy is considered, a BEP combination (bleomycin, etoposide, and cisplatin) is the treatment of choice (BEP for 4 cycles at 3-wk intervals). VIP (etoposide, ifosfamide, and cisplatin) has been used as salvage therapy for progressive disease or as postoperative therapy following resection of residual mass containing viable tumor. Vinblastine has occasionally replaced etoposide if the latter was used in the initial regimen.


Cisplatin (Platinol)

Platinum-containing compound that exerts antineoplastic effect by covalently binding to DNA with preferential binding to N-7 position of guanine and adenosine. Can react with 2 different sites on DNA to produce cross-links. Platinum complex also can bind to nucleus and cytoplasmic protein. A bifunctional alkylating agent, once activated to aquated form in cell it binds to DNA, resulting in interstrand and intrastrand cross-linking.
Modify dose on basis of CrCl. Avoid use if CrCl <60 mL/min.

Adult

20 mg/m2/d IV infusion over 20-60 min for 5 d q21d

Pediatric

Not established

Increases toxicity of bleomycin and ethacrynic acid; aminoglycosides and amphotericin B increase nephrotoxicity; bleomycin, cytarabine, methotrexate, and ifosfamide may accumulate because of decreased renal excretion; may enhance cytotoxicity of etoposide; mesna and sodium thiosulfate directly inactivate cisplatin; dipyridamole increases cytotoxicity by enhancing cellular uptake

Documented hypersensitivity; preexisting renal insufficiency; myelosuppression; hearing impairment

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Administer adequate hydration before and for 24 h after dosing to reduce risk of nephrotoxicity; adverse effects include bone marrow suppression, nausea, vomiting, mucositis, and high-frequency hearing loss; major dose-limiting toxic effect is peripheral neuropathy; can cause acute or chronic renal failure in as many as one third of patients treated, but usually can be prevented by vigorous hydration and saline diuresis; renal tubular wasting of potassium and magnesium are common (monitor closely); cellulitis and fibrosis rarely have occurred after extravasation; avoid aluminum needles


Etoposide (Toposar, VePesid)

Inhibits topoisomerase II and causes DNA strand breakage, causing cell proliferation to arrest in late S or early G2 portion of cell cycle. Prodrug activated by dephosphorylation.
Reduce dose in hepatic (increased total bilirubin [TB]) and renal (decreased CrCl) impairment.

Adult

100 mg/m2 IV daily for 5 d; repeat cycle every 3 wk
TB 1.5-3 mg/dL: 50% dose reduction
TB 3.1-4.9 mg/dL: 75% dose reduction
TB >5 mg/dL: Avoid use
CrCl 15-50 mL/min: 25% dose reduction

Pediatric

Not established

May prolong effects of warfarin and increase clearance of methotrexate; has additive effects with cyclosporine in cytotoxicity of tumor cells; clearance decreased by high dose of cyclosporine (serum concentration >2000 ng/mL), leading to increased risk of neutropenia; zidovudine increases serum concentration, resulting in increased toxicity

Documented hypersensitivity; IT administration may cause death

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Bleeding, severe myelosuppression, nausea, vomiting, hypotension, allergic reaction, and alopecia may occur


Bleomycin (Blenoxane)

Glycopeptide antibiotic that acts by intercalating and binding to guanosine and cytosine portions of DNA. May induce single- or double-stranded DNA breaks by ability to form oxygen free radicals.
Test dose is optional: 1-2 U IV/IM prior to full dose.

Adult

30 U IV bolus weekly on days 2, 9, and 16; repeat q21d; modify dose based on CrCl
CrCl 20-30 mL/min: 50% of normal dose
CrCl <20 mL/min: 40% of normal dose

Pediatric

Not established

May decrease plasma levels of digoxin and phenytoin; cisplatin may increase toxicity

Documented hypersensitivity; significant renal function impairment; compromised pulmonary function

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in renal impairment; possibly secreted in breast milk; may cause mutagenesis and pulmonary toxicity (10%); idiosyncratic reactions similar to anaphylaxis (1%) may occur; monitor for adverse effects during and after treatment; erythema, rash, vesiculations, hyperpigmentation, stomatitis, alopecia, and nail changes may occur


Ifosfamide (Ifex)

Alkylating agent—2 major metabolites are produced after its activation in liver. Ifosfamide mustard, by its ability to cross-link DNA strands, responsible for therapeutic effect. Acrolein related to bladder toxicity.

Adult

1200 mg/m2/d IV continuous infusion d 1-5

Pediatric

Not established

Phenobarbital, phenytoin, chloral hydrate, and other drugs that interfere with cytochrome P-450 activity may alter effects

Documented hypersensitivity; depressed bone marrow function; uncontrolled infection

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

May cause hemorrhagic cystitis and severe myelosuppression; caution in renal function impairment or compromised bone marrow reserve; nausea, vomiting, diarrhea, and occasionally constipation may occur; CNS toxic effects include somnolence, confusion, depressive psychosis, and hallucinations; seizures and coma may occasionally occur; use mesna concomitantly at dose of 1200 mg/m2/d IV continuous infusion days 1-6


Vinblastine (Velban)

Vinca alkaloid, inhibits microtubule formation, which in turn disrupts formation of mitotic spindle, causing cell proliferation to arrest at metaphase.
Reduce dose by 50% in patients with TB > 3 mg/dL. Dose reduction not required in impaired renal function.

Adult

0.11 mg/kg IV days 1 and 2

Pediatric

3 mg/m2 IVP q2-4wk

May reduce plasma phenytoin levels; mitomycin-C may increase toxicity significantly; avoid heparin and furosemide

Documented hypersensitivity; bone marrow suppression

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in impaired liver function and neurotoxicity; when patient is receiving mitomycin-C, monitor closely for shortness of breath and bronchospasm; very irritating (a vesicant) and should be given exclusively via side port of freely flowing IV; if extravasation occurs, antidote is hyaluronidase (Wydase); warm compresses should be applied at site of extravasation; adverse effects include myelosuppression, alopecia, nausea, vomiting, anorexia, constipation, and paresthesia

More on Extragonadal Germ Cell Tumors

Overview: Extragonadal Germ Cell Tumors
Differential Diagnoses & Workup: Extragonadal Germ Cell Tumors
Treatment & Medication: Extragonadal Germ Cell Tumors
Follow-up: Extragonadal Germ Cell Tumors
References
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Further Reading

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Keywords

extragonadal germ cell tumor, EGGCT, seminomas, germinomas, nonseminomatous germ cell tumors, NS-GCT, nongerminomas, nongerminomatous germ cell tumors, mediastinal germ cell tumors, MGCT, retroperitoneal germ cell tumors, RGCT, sacrococcygeal germ cell tumors, SCGCT, intracranial germ cell tumors, ICGCT, Klinefelter syndrome, Klinefelter's syndrome, 47XXY

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Contributor Information and Disclosures

Author

Kush Sachdeva, MD, Private Practice, Southern Oncology and Hematology Associates, South Jersey Hospital System, Fox Chase Cancer Center
Disclosure: Nothing to disclose.

Coauthor(s)

Issam Makhoul, MD, Associate Professor, Department of Medicine, Division of Hematology/Oncology, University of Arkansas for Medical Sciences
Issam Makhoul, MD is a member of the following medical societies: American Society of Clinical Oncology and American Society of Hematology
Disclosure: Nothing to disclose.

Brendan Curti, MD, Director, Genitourinary Oncology Research, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center
Brendan Curti, MD is a member of the following medical societies: American College of Physicians, Oregon Medical Association, and Society for Biological Therapy
Disclosure: Nothing to disclose.

Medical Editor

Robert C Shepard, MD, FACP, Associate Professor of Medicine in Hematology and Oncology at University of North Carolina at Chapel Hill; Vice President of Scientific Affairs, Therapeutic Expertise, Oncology, at PRA International
Robert C Shepard, MD, FACP is a member of the following medical societies: American Association for Cancer Research, American College of Physician Executives, American College of Physicians, American Federation for Clinical Research, American Federation for Medical Research, American Medical Association, American Medical Informatics Association, American Society of Hematology, Association of Clinical Research Professionals, Eastern Cooperative Oncology Group, European Society for Medical Oncology, Massachusetts Medical Society, and Society for Biological Therapy
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

CME Editor

Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Jules E Harris, MD, Clinical Professor of Medicine, Division of Hematology/Medical Oncology, Department of Internal Medicine, University of Arizona College of Medicine at Tucson; Consulting Staff, Arizona Cancer Center
Jules E Harris, MD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Immunologists, American Society of Hematology, and Central Society for Clinical Research
Disclosure: GlobeImmune Salary Consulting; Amplimed Consulting fee Consulting; FibroGen Consulting fee Consulting

 
 
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