Extragonadal Germ Cell Tumors Treatment & Management

Updated: Apr 16, 2015
  • Author: Kush Sachdeva, MD; Chief Editor: Jules E Harris, MD, FACP, FRCPC  more...
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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. [17] Treatment with four cycles of bleomycin, etoposide, and cisplatin (BEP) is the current standard of care. Radiotherapy can be used after chemotherapy in bulky mediastinal seminomas. [18]

In nonseminomatous mediastinal germ cell tumors (NS-MGCT), four 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 two 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. Anderson Cancer Center 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. [19]

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.

Analysis of data from 75 patients treated at Indiana University for nonseminomatous germ cell tumors showed the following [20] :

  • 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. [21] 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 two 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 four cycles of carboplatin, etoposide, and bleomycin. If complete response (CR) was achieved, two more cycles were given.

Surgery alone resulted in three 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%. [22]

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 four 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. [23] 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%); nine 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). [24] Patients with intermediate disease may be treated with either modality.

Sacrococcygeal germ cell tumors

Patients with sacrococcygeal germ cell tumors have a poor prognosis. Long-standing remission is attained in only 31% of patients treated with multiagent chemotherapy.

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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 Memorial Sloan-Kettering Cancer Center, 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.
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