Approach Considerations
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.
Medical Care
Mediastinal germ cell tumors (MGCTs)
Cisplatin-based chemotherapy has made a significant improvement in treatment of seminoma of the mediastinum. [28] 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. [29]
In nonseminomatous mediastinal germ cell tumors (NS-MGCT), four cycles of BEP 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 had been referred for salvage therapy following progression of their tumors after treatment at other facilities. [30]
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 (Vepesid), 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 kidney 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.
The 5-year overall survival of patients with seminomatous and non-seminomatous EGCT was 100% and 44%, respectively in a study of patients treated with cisplatin-based combination chemotherapeutic regimens followed by a multimodal strategy that included high-dose chemotherapy, aggressive surgery, and early salvage chemotherapy. [14]
Analysis of data from 75 patients treated at Indiana University for nonseminomatous germ cell tumors showed that of those treated, 48 patients received BEP, 9 patients received VIP, 9 patients received VIP/vinblastine (Velban) 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 were long-term survivors. Overall survival rate for the group was 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. [31]
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. [32] 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%. [33]
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. [34] Cisplatin-based (or carboplatin-based) chemotherapy resulted in CR 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). [35] 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.
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.
Complications
Chemotherapy-related complications
Chemotherapy-related complications may be immediate or delayed. Nausea and vomiting became less common with the advent of 5-hydroxytryptamine 3 (5-HT3) antagonists. Postcisplatin delayed emesis is better treated by oral administration of metoclopramide, benzodiazepine, and dexamethasone for 2-4 days. A certain degree of cisplatin-related nephrotoxicity is almost always present and is cumulative. Hypomagnesemia is common, requiring supplementation for prolonged periods in some patients.
Arthralgias, myalgias, peripheral neuropathy, and paralytic ileus are common toxic effects of vinblastine. However, since replacement of vinblastine with etoposide in first-line therapy began, these complications are no longer seen. Auditory toxicity with reduced high-tone hearing may be seen after cisplatin. It rarely requires hearing aids.
Neutropenic fever and severe thrombocytopenia are relatively uncommon with etoposide and cisplatin (EP) as first-line chemotherapy. The addition of bleomycin and salvage chemotherapy results in significant increase of these complications (50%), requiring the prophylactic use of hematopoietic growth factors after the first episode of neutropenic fever.
Pulmonary toxicity from bleomycin is unpredictable and rare (10% of treated patients) and is dose- and age-dependent (rate is higher in patients >70 y and after a cumulative dose >1200 IU or 400 mg). The progression to pulmonary fibrosis is uncommon and occasionally fatal (1%). Although carbon monoxide diffusing capacity may not predict clinically significant lung damage, its use was recommended along with chest x-ray as a screening test in patients treated with bleomycin. If radiographic changes or a decrease of diffusing capacity of lung for carbon monoxide (DLCO) greater than 30% is detected, discontinue the drug. Raynaud phenomenon and, to a lesser degree, stroke and myocardial infarction were reported after use of bleomycin.
Infertility is seen in as many as 50% of patients after chemotherapy. Standard bilateral retroperitoneal lymph node dissection almost always is associated with retrograde ejaculation. Nerve-dissecting, nerve-avoiding, and posterior approaches decrease, but do not abolish, this adverse effect.
The frequency of etoposide-related secondary leukemia is dose dependent. It is seen in less than 0.5% of patients who received a total dose less than 2000 mg/m2 and in about 6% of those who received more than 3000 mg/m2. Abnormalities of chromosome band 11q23 are very common in this setting. Latency period varies from 2-4 years. The incidence of gastrointestinal malignancies, especially gastric cancers, and soft-tissue sarcomas is increased slightly after combined radiation and chemotherapy. Latency period is about 10 years or more.
Weijl et al reported a high rate of thromboembolic events (8.4%) during chemotherapy in 179 patients with germ cell tumors. Liver metastases and high-dose corticosteroids were identified as risk factors for these complications. [36]
Radiotherapy-related complications
Accelerated coronary artery disease is a well-recognized complication of mediastinal radiotherapy.
With the achievement of prolonged survival for patients with intracranial germ cell tumors (ICGCTs), researchers became increasingly aware of long-term effects of cranial radiation on intellectual and endocrine functions. These complications are correlated with the total dose and fraction sizes of irradiation and are correlated conversely to the patient's age at the time of treatment. Concomitant chemotherapy increases the risk of toxicity.
Verbal IQs and reading skills are affected to a lesser degree than performance IQs or mathematic ability. Personality changes include anxiety, depression, lability, belligerence, hypersexuality, reduced attention span, memory problems, and reduced reasoning ability. GH deficiency with growth retardation and hypothyroidism are much more common than gonadotropin and corticotropin deficiencies. Leukoencephalopathy, hearing loss, and second malignancies (20-y cumulative probability of about 12% for the latter) are increased after cranial irradiation.
Long-Term Monitoring
Detection of late recurrences (>2 y after treatment discontinuation), development of testicular tumors several years after the initial diagnosis of extragonadal germ cell tumors (EGGCTs), and treatment-related complications justify prolonged periods of follow-up care with clinical evaluation, tumor markers, and imaging studies.
In children (and probably in adults) with intracranial germ cell tumors (ICGCTs), obtain baseline intelligence quotient (IQ) and achievement tests before starting radiotherapy. Perform follow-up intellectual assessments at 1 year after completion of radiation, then at 2, 3, and 5 years, and if any intellectual deterioration is noted. Evaluate hearing if intellectual deterioration occurs. Evaluation of thyroid, corticotropin, gonadotropin, prolactin, and GH functions is obtained before and regularly after radiation therapy.
