Radiation therapy for intracranial germ cell tumors

PURPOSE: To review the combined experiences of University of California, San Francisco, and Stanford University Medical Center in the treatment of intracranial germ cell tumors (GCT) and to assess the impact of craniospinal radiation (CSI) on patterns of relapse, progression-free survival (PFS), and overall survival (OS). PATIENTS AND METHODS: Ninety-three patients received radiation for newly diagnosed intracranial GCTs, including 49 germinomas, 16 nongerminomatous GCTs (NGGCT), and 28 with no biopsy. Median follow-up for surviving patients was 4.5 years (range 0.25-34). Tests for variables correlating with OS and PFS were conducted using Cox proportional hazards model. RESULTS: Five-year PFS and OS rates were 60% +/- 15% and 68% +/- 14% for patients with NGGCT and 88% +/- 5% and 93% +/- 4% for those with germinoma. Of 6 patients with localized NGGCT who did not receive CSI, 1 experienced an isolated spinal recurrence but was salvaged. Of 41 patients with localized germinoma, 6 who received CSI and 35 who did not, no isolated spinal cord relapses occurred. Twenty-one patients with localized germinoma received neither CSI nor whole brain radiation. Of these, none of 18 with ventricular radiation relapsed. One of 3 patients with primary tumor radiation relapsed intracranially but had only received 11 Gy at initial treatment. On multivariate analysis, germinoma histology but not CSI correlated with improved PFS and OS. CONCLUSION: CSI is not indicated in the treatment of localized germinomas. For patients with localized germinomas treated with radiation alone, we recommend ventricular irradiation followed by primary tumor boost to a total of 45-50 Gy.     

颅内生殖细胞肿瘤的治疗进展

颅内生殖细胞肿瘤(intracranial germ cell tumors,ICGCTs)是一种少见的颅内胚胎性肿瘤,具有多种组织学类型。大多数类型的生殖细胞肿瘤对放化疗敏感,早期治疗可治愈,5年总生存率(overall survival rate,OSR)可达90%,其他恶性非生殖细胞瘤性生殖细胞肿瘤(non-germinomatous germ cell tumors,NGGCTs)的5年OSR低于70%。近年,随着外科学、影像学、核医学、药学等相关学科的发展,IGGCTs的总体治疗效果有了长足的进展,然而囿于病理基因等方面研究进展缓慢,治疗方案并不统一,缺乏规范化和明确的临床路径和诊治指南。本文就ICGCTs的治疗经验和进展进行综述,以期为临床治疗提供新的思路。     

Results of the treatment of intracranial germ cell tumors

Presented is a retrospective study of 20 patients with intracranial germ cell tumors who the authors have treated during past 10 years. The cases among these patients included thirteen germinomas, three teratomas, two embryonal carcinomas, and two malignant teratomas. A ventriculoperitoneal shunt was installed in 15 cass and the tumor was surgically removed in four cases. All cases were irradiated with 33 to 61 Gy; in 18 cases, more than half of the total dose was delivered to the whole brain, and in 9 cases, spinal irradiation was given because of a verified CSF dissemination. Chemotherapy was the regimen for four cases. The tumor responded to therapy in 16 (84%) of 19 evaluable cases. Overall, the median and five year survival were 102 months and 83%, respectively. The survival rate was found to vary between the benign group (germinoma, teratoma) and the malignant group (embryonal carcinoma, malignant teratoma, germinoma with STGC) (p less than 0.01).     

Stereotactic radiotherapy for pediatric intracranial germ cell tumors

PURPOSE: Intracranial germ cell tumors are rare, radiosensitive tumors seen most commonly in the second and third decades of life. Radiotherapy alone has been the primary treatment modality for germinomas, and is used with chemotherapy for nongerminomatous tumors. Stereotactic radiotherapy techniques minimize the volume of surrounding normal tissue irradiated and, hence, the late radiation morbidity. This study reports our experience with stereotactic radiotherapy in this group of tumors. METHODS AND MATERIALS: Between December 1992 and December 1998, 18 patients with intracranial germ cell tumors were treated with stereotactic radiotherapy. A total of 23 histologically proven tumors were treated. Thirteen patients had a histologic diagnosis of germinoma, and 5 patients had germinoma with nongerminomatous elements. Of those patients with a histologic diagnosis of germinoma, 5 had multiple midline tumors. The median age of the patients was 12.9 years (range, 5.6-17.5 years). RESULTS: A boost using stereotactic radiotherapy was delivered to 19 tumors following whole-brain radiation in 8 cases and craniospinal radiation in 11 cases. Three tumors were treated with stereotactic radiotherapy to the tumor volume alone following chemotherapy, and 1 tumor received a boost using stereotactic radiosurgery following craniospinal radiation. A median dose of 2520 cGy (range, 1500-3600) cGy was given to the whole brain, and a median dose of 2160 (range, 2100-2600) cGy was given to the spinal field. The median boost dose to the tumor was 2600 (range, 2160-3600) cGy, given by stereotactic radiotherapy delivered to the 95% isodose line. At a median follow-up time of 40 (range, 12-73) months, no local or marginal recurrences were reported in patients with germinoma. Two patients with nongerminomatous tumors have relapsed. One had elevation of tumor markers only at 37 months following treatment, and the other had persistent disease following chemotherapy and radiation therapy. Eight patients documented pituitary-hypothalamic dysfunction; in 7 (87.5%) of these patients, the dysfunction was present before commencing radiotherapy. Four patients (22%) developed newly diagnosed diabetes insipidus following surgery. Three patients (17%) received antidepressant medication at follow-up. CONCLUSION: Our series shows that stereotactic radiotherapy is achievable and well tolerated in this group of patients. Longer follow-up is required to fully assess the impact on long-term toxicity. Psychologic assessment of mood and affect should be performed as part of routine follow-up in this group of adolescent children.     

Management of primary intracranial germ cell tumors

Primary intracranial germ cell tumors are rare and usually localized in the pineal and the suprasellar regions. They are divided into the following histologic types: germinoma, teratoma (mature, immature, malignant), choriocarcinoma, embryonal carcinoma, endodermal sinus tumor (yolk sac tumor), and mixed tumors. Clinically, they are manifested with ocular signs or signs of obstructive hydrocephalus. Localized germinomas are treated with radiation therapy and exhibit a relatively good prognosis. Chemotherapy is reserved for disseminated germinomas. Mature teratomas are treated with surgery. The rest of germ cell tumors are managed with various combinations of surgery, chemotherapy, and radiotherapy depending on the tumor type. If the tumors secrete beta-human chorionic gonadotrophin (hCG) or alpha-fetoprotein (FP), these tumor markers can be used to accurately monitor response to treatment. Prognosis is best for germinomas and mature teratomas and worst for choriocarcinomas and embryonal carcinomas.     

Radiation therapy of intracranial germ cell tumors

The results of radiation therapy in 31 patients with intracranial germ cell tumors have been analyzed. The five-year survival rates were 70.1% for germinomas and 38.1% for teratomas. Three patients with germinoma have since died of spinal seeding. The prophylactic irradiation of the spinal canal has been found effective in protecting spinal seeding, since no relapse of germinoma has been observed in cases that received entire neuraxis irradiation, whereas teratomas and marker (AFP, HCG) positive tumors did not respond favorably to radiation therapy, and the cause of death in these patients has been local failure. Long-term survivors over 3 years after radiation therapy have been determined as having a good quality of life.     

Chemotherapy trials in recurrent primary intracranial germ cell tumors

Summary Gonadal germ cell tumors respond favorably to chemotherapy either at diagnosis or when they recur. Histologically similar tumors may arise in the CNS usually in the pineal or suprasellar regions. Although radiation therapy may produce a 5 year disease-free survival in excess of 60% in localized pure germinoma, gern cell tumors of other histology tend to recur. We have conducted 14 chemotherapy trials in 8 patients with recurrent CNS germ cell tumors using 3 different single agent and 2 multi-agent chemotherapy regimens. The histologic diagnoses of the patients were germinoma (4), endodermal sinus tumor (2), embryonal carcinoma (1), and mixed tumor — germinoma plus choriocarcinoma (1). There were 7 males and 1 female with a median age of 13 years. The primary tumor arose in the pineal region in 6 and was multicentric in 2. Seven patients had local recurrences and one developed an initial recurrence in the spinal canal. Three patients had CNS metastases at relapse and 2 had systemic metastases. Objective responses were documented in 7 of 14 trials (50%). Responses were observed with cyclophosphamide (80 mg/kg) in 3 of 4 patients for 2⁺, 3, and 5 mos, cisplatin (120 mg/m²) in 1 of 2 patients for 2⁺ mos, and the VAB 6 protocol (vinblastine, bleomycin, cyclophosphamide, actinomycin-d, cisplatin) in 3 of 5 patients for 5, 8, and 18 mos. The median duration of response was 5 mos. (2¹-18). High doses of single chemotherapy agents such as cyclophosphamide and cisplatin as well the VAB6 regimen have definite activity in recurrent CNS germ cell tumors, especially germinoma. Good palliation may be achieved with chemotherapy alone with acceptable morbidity. Adjuvant chemotherapy should be considered in patients with newly diagnosed primary intracranial germ cell tumors whose tumors are considered unlikely to be permanently controlled with radiation alone.     

Novel treatment options for refractory germ cell tumors

Although testicular germ cell tumors (GCTs) are a model for a curable neoplasm, a significant proportion will relapse and require salvage therapy. While currently available conventional and high-dose chemotherapy salvage regimens attain durable complete remissions in a significant proportion of patients, the long-term outcomes are still suboptimal in this young population. Several novel agents are being evaluated for recurrent germ cell tumors, including chemotherapeutic and biologic agents, notably anti-angiogenic agents. A better understanding of biology may lead to enhanced outcomes for cisplatin-refractory patients with germ cell tumors.     

Modified grading system for clinical outcome of intracranial non-germinomatous malignant germ cell tumors

This study investigated the clinical outcome of intracranial non-germinomatous malignant germ cell tumors (NGMGCTs). All histologically proven cases of NGMGCTs treated in Shanghai Huashan Hospital, Fudan University were reviewed. A total of 39 cases were analyzed. There were 15 mixed germ cell tumors, 15 immature teratomas, 7 embryonal carcinomas and 2 yolk sac tumors. Patients were treated surgically first, followed by radiotherapy and/or chemotherapy. Some patients also received gamma knife surgery. The common 5-year survival rate was 36.8%. According to Matsutani's grading system, the 5-year actuarial survival rate for patients in the intermediate and poor prognosis groups were 45.8 and 14.3%, respectively. Individual analysis of each type of tumor showed that the median survival time of embryonal carcinoma was 27 months, which is very close to that of the intermediate group (28 months). We therefore classified embryonal carcinoma into the intermediate group where the 5-year actuarial survival rate for patients in the new intermediate prognosis group was 42.6%. Further analysis of immature teratoma cases found that the 5-year survival rate of patients with immature teratoma who received gamma knife surgery is 100%. This rate exhibited a significant difference (P=0.0049) compared to that of patients who did not undergo gamma knife surgery. In conclusion, we consider surgery as the first choice of treatment although for different histologis, the type of the tumor should be treated separately.     

Induction chemotherapy followed by low-dose involved-field radiotherapy for intracranial germ cell tumors.

PURPOSE: To investigate the efficacy of chemotherapy followed by low-dose involved-field radiotherapy for the treatment of intracranial germ cell tumors (GCTs). PATIENTS AND METHODS: Thirty-three patients with GCTs, including 16 pure germinomas, 11 human chorionic gonadotropin-beta (HCG-beta)-secreting germinomas, three mixed GCTs composed of immature teratomas plus germinomas (IMT/G), and three highly malignant mixed GCTs, were treated. Etoposide and cisplatin (EP) were used for the treatment of solitary pure germinomas, and ifosfamide, cisplatin, and etoposide (ICE) were used for the treatment of other GCTs. The dose schedule was 24 Gy for germinomas and 40 to 54 Gy for other GCTs. An involved-field set-up was used except for highly malignant GCTs, in which craniospinal irradiation was used. The median follow-up was 58 months (range, 18 to 102 months). RESULTS: Disease-related, overall, and relapse-free survival rates at 5 years were 100%, 93%, and 69% for all patients, 100%, 100%, and 86% for patients with pure germinomas, and 100%, 75%, and 44% for patients with HCG-beta-secreting germinomas, respectively. All six patients with nongerminomatous GCTs were alive at the last follow-up. All eight relapses (one pure germinoma, five HCG-beta-secreting germinomas, and two IMT/G), except one in a course of salvage treatment, were salvaged and free of disease at the last follow-up. No decline was observed in the full-scale, verbal, or performance intelligence quotient at 12 to 51 months after the treatment in 11 patients. CONCLUSION: Our results support an excellent prognosis after EP and ICE regimens followed by radiotherapy. Dose and volume can be reduced to 24 Gy in 12 fractions and involve a field set-up after EP chemotherapy for the treatment of pure germinomas.     

Surgery for germ cell tumors

We performed a review of the current modalities of surgical treatment of malignant ovarian germ cell tumors by clinical stages and histological types. Stage IA dysgerminoma is performed with a unilateral salpingo-oophorectomy (USO) without chemotherapy. However, for Stage IB or IC patients with dysgerminoma, USO plus chemotherapy as a primary treatment may or may not be followed with a second-look operation (SLO). For non-dysgerminomas, USO is indicated only for Stage IA immature teratoma grade 1. The treatment for Stage IA immature teratoma grade 2 or 3 and other histological types is USO plus chemotherapy. Patients with Stage IB, IC or higher with non-dysgerminoma are treated with USO plus chemotherapy or USO with contralateral partial ovariectomy plus chemotherapy. For patients who require non-conservative surgery, a total abdominal hysterectomy (TAH) and a bilateral salpingo-oophorectomy (BSO) plus chemotherapy are performed. For patients with Stage II of all histological types, conservative surgery consists of USO and a cytoreductive operation plus chemotherapy, followed by SLO or a second cytoreductive operation. For non-conservative surgery, TAH+BSO with or without a cytoreductive operation plus chemotherapy is followed by SLO. Conservative surgery for patients with Stage III and IV is USO and a cytoreductive operation plus chemotherapy followed by a second cytoreductive operation. Non-conservative surgery is TAH+BSO with a cytoreductive operation plus chemotherapy, followed by SLO or a second cytoreductive operation. However, primary or secondary cytoreductive surgery with or without lymphadenectomy and SLO are still controversial in terms of improving patient survival.     

Improved prognosis of intracranial non-germinoma germ cell tumors with multimodality therapy

The 5 year survival for patients with malignant intracranial non-germinoma germ cell tumors (NGGCT) which include endodermalsinus tumors, embryonal carcinomas, choriocarcinomas and immatureteratomas is less than 25% following a small resection and radiotherapy. In an effort to improve the survival of these patients, an approach using an attempt at radical resection wherefeasible, followed by multi-modality sandwich therapy (chemotherapy-radiation-chemotherapy) was used to treat 18 newly diagnosed patients between 1986 and 1994 in a multi-institution study. Fourteen patients had histologically proven NGGCT andfour were presumed NGGCT because of markedly elevated concentrations of serum and/or CSF alpha fetoprotein (AFP) and/or beta human chorionic gonadatrophin (b-HCG). The primary tumor was confined to thepineal region in 12 patients, the suprasellar region in five, and acerebral hemisphere in one. None of the patients had central nervoussystem metastases at diagnosis by MRI imaging of the spine and CSF cytology. Radical surgical resection was performedinitially in 11 patients (gross total — 6, subtotal — 5);four had a biopsy and three had no surgery. All patients then received3 or 4 cycles of neoadjuvant chemotherapy with cisplatin (100 mg/m²/cycle) and VP-16 (500 mg/m²/cycle)/cycle). Of the 12 patients with evaluabledisease there were 9 responses to the neoadjuvant chemotherapy (5 CR,4 PR); 2 patients had stable disease and 1 progressed duringchemotherapy. Six patients with no evaluable disease after a grosstotal resection had a continuous complete response. Seventeen patientsreceived radiation therapy (involved field — 11, involved field + craniospinal — 4, involved field+ whole brain — 2). Twelve patients received 4 cycles post-radiation chemotherapy with vinblastine (6.5 mg/m²/cycle), bleomycin (15 U/m²/cycle),VP-16 (300 mg/m²/cycle, carboplatin (450 mg/m²/cycle). A total of four patients have died (3 — progressive/recurrent disease, 1 — metabolic). Four year actuarialevent-free and total survival rates are 67% and 74%. This multi-modality adjuvant therapy approach appears to dramatically improve the outcome of malignant intracranialNGGCT.     

Metastatic nonseminomatous germ cell tumors of the testis: results of elective and salvage surgery for patients with residual retroperitoneal masses

BACKGROUND: A mass may persist in the para-aortic region after patients undergo chemotherapy for metastatic, nonseminomatous germ cell tumor of the testis (NSGCT). Retroperitoneal lymphadenectomy removes the mass, which may contain residual active malignancy, and allows histologic assessment of the effectiveness of the chemotherapy. Whereas some have favored early, elective removal of such masses, others have chosen to observe them, reserving salvage surgery for patients who experience disease recurrence. A retrospective analysis was undertaken to define the outcome in these two groups of patients. METHODS: After receiving chemotherapy for metastatic NSGCT, 442 men underwent lymphadenectomy for residual masses (measuring > or = 1 cm in greatest dimension) between 1976 and 1999, inclusive. Three hundred thirty men underwent elective surgery within 3 months of the completion of chemotherapy, and 112 men underwent salvage surgery after receiving reinduction chemotherapy for tumor recurrence. RESULTS: The residual mass was removed completely in 87% and 72% of patients in the elective and salvage lymphadenectomy groups, respectively; was removed with difficulty and possibly incompletely in 9% and 21% of patients, respectively; and was definitely removed incompletely in 4% and 7% of patients, respectively. The operative mortality rate was 0.9% in the elective surgery group and 1.8% in the salvage surgery group. There was malignant teratoma, undifferentiated in 8.5% of patients in the elective surgery group and in 49% of patients in the salvage surgery group (P < 0.001). Differentiated teratoma and necrosis/fibrosis were present in 66.0% and 25.4% of patients in the elective surgery group, respectively, and in 38.4% and 12.5% of patients in the salvage surgery group, respectively. The authors were unable to produce a clinically useful model to predict the presence of necrosis/fibrosis only in either group. The 5-year recurrence free and overall survival rates were 83% and 89%, respectively, in the elective surgery group and 62% and 56%, respectively, in the salvage surgery group. For the salvage surgery group, the completeness of surgical excision and the presence of undifferentiated teratoma were of overriding importance for overall survival. A variety of other patient-related, tumor-related, and surgery-related factors also were significant in the final model for the elective surgery group. CONCLUSIONS: The current results demonstrate the low level of morbidity that can be obtained, even in the salvage surgery group, and the importance of complete surgical resection in this setting. Because it is not possible to predict with sufficient accuracy which patients will have favorable pathology (necrosis/fibrosis), the authors continue to recommend elective surgery for all suitable men with residual masses after they receive first-line chemotherapy.     

Neuropsychological functions and quality of life in survived patients with intracranial germ cell tumors after treatment

Background

The notable survival chances of intracranial germ cell tumors (icGCTs) lead to a rising concern over long-term neurocognitive outcome. Yet, prior evidence related to this issue fails to provide a comprehensive examination of the effects of tumor location and radiotherapy. We attempt to explore their impacts on the neuropsychological functions and life quality in children with icGCT after multimodality treatments.

Methods

A retrospective review of 56 patients diagnosed with icGCTs at age <20 and treated at the Taipei Veterans General Hospital was provided. Intelligence, memory, visual organization, attention, and executive function were assessed by neurocognitive tests; adaptation to life, emotional and behavioral changes, interpersonal relationships, and impact on the family were evaluated by parent-report instruments. Effects of tumor locations (germinomas and nongerminomatous malignant germ cell tumors in the pineal, suprasellar, and basal ganglia) and irradiation on these measurements were examined.

Results

Patients with tumors in the basal ganglia region had lower full-scale IQs than those with tumors in the pineal or suprasellar regions. Subscores of intelligence scale and short-term retention of verbal and visual stimuli showed evident group differences, as did the quality of life and adaptive skills, particularly in psychosocial domains. Patients treated with whole-ventricular irradiation had better outcomes. Extensive irradiation field and high irradiation dosage influenced intellectual functions, concept crystallization, executive function, and memory.

Conclusions

Tumor location and irradiation field/dosage appear to be the crucial factors related to certain neuropsychological, emotional, and behavioral dysfunctions that in turn alter the quality of life in children with icGCTs who survive after treatment.