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© 2002 American Society for Clinical Oncology Induction Chemotherapy Followed by Low-Dose Involved-Field Radiotherapy for Intracranial Germ Cell TumorsByFrom the Departments of Radiation Medicine, Neurosurgery, and Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan. Address reprint requests to Yutaka Sawamura, MD, Department of Neurosurgery, Hokkaido University School of Medicine, North-15 West-7, Sapporo, Japan, 060-8638; email: ysawamu{at}med.hokudai.ac.jp
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-ß)–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-ß-secreting germinomas, respectively. All six patients with nongerminomatous GCTs were alive at the last follow-up. All eight relapses (one pure germinoma, five HCG-ß-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.
INTRACRANIAL GERM cell tumors (GCTs) encompass a wide pathologic spectrum, and patient prognosis is dependent on which subtype is present. Since germinomas have high radiosensitivity, a high cure rate with radiation alone can be expected. Sole usage of radiation requires a dose of 40 to 55 Gy1-11 with whole-ventricle or larger fields, which can cause endocrine disorders and neurocognitive impairment. The risk of these side effects may be reduced by lowering the dose and field size of radiation for young patients.12-14 Since cisplatin-based chemotherapy has proved to be effective for the treatment of intracranial GCTs as well as gonadal GCTs,15 several groups of physicians have tried to use chemotherapy in conjunction with radiation to reduce the radiation dose and field.14-21 The prognosis of patients with human chorionic gonadotropin-beta (HCG-ß)–secreting germinoma has been revealed to be worse than that of patients with pure germinoma in the majority of institutions, but the optimal management of the HCG-ß–secreting germinoma is still controversial.22 In contrast to the treatment for germinoma, GCTs containing highly malignant components are infrequently cured by radiation therapy alone, even if craniospinal irradiation is administered.23-25 Therefore, the aim of using a combination of chemotherapy and radiation therapy was to enhance prognosis, which is a different goal than that sought by the use of such a combined therapy for germinoma patients. Early in the 1990s, we began treating intracranial GCTs patients using induction chemotherapy followed by radiation therapy with a reduction in the dose and field size.20 Our goals were to minimize the posttreatment adverse effects, in the case of patients with germinoma, and to improve the treatment outcome, in the case of patients with other GCTs. This report describes our phase II study to assess the outcome of treatment at a single institution. The results of assessments of neurocognitive and endocrine function before and after treatment are also reported.
Eligibility Criteria Patients aged 3 years or older with a histologic diagnosis of primary CNS GCTs who had not been previously treated by chemotherapy or radiotherapy were eligible. Exclusion criteria were inadequate bone marrow function (adults: leukocyte count < 4,000/µL or platelet count < 100,000/µL; pediatric patients: absolute neutrophil count < 1,000/µL or platelet count < 100,000/µL), medical complications such as cardiac, liver, or renal dysfunction, and extra-CNS dissemination of the disease at the initial diagnosis. Pregnant or lactating women and patients with uncontrolled infectious diseases were not candidates for this trial. All patients or their guardians provided written informed consent before protocol participation. The treatment protocol was approved by the Committee for Ethics of Hokkaido University School of Medicine.
Protocol Test and Examination We measured the subjects’ intelligence quotient (IQ) using either the Wechsler Intelligence Scale of Children Revised or the Wechsler Adult Intelligence Score Revised at the time of treatment. Since the goal of this study was to reduce radiation-induced neurocognitive function, patient IQ was measured after the completion of surgery and chemotherapy and before the initiation of radiotherapy. During treatment, the complete blood cell count was monitored at least weekly during chemotherapy and radiotherapy. Serum chemistries, creatinine clearance, and AFP and HCG-ß levels were monitored after every cycle of chemotherapy and 1 month after the completion of radiation therapy. An audiogram was obtained before each cycle of chemotherapy and at any time a patient complained of a hearing deficiency. After each cycle of chemotherapy, we took brain MRI scans and spinal MRI scans for patients with disseminated diseases. During the first year after the completion of treatment, patients were monitored every month with a history and physical examination, complete blood cell count, serum chemistries, and HCG-ß for germinomas and HCG-ß and AFP for nongerminomatous GCTs. These evaluations were performed every 3 months at 2 years and every 4 months at 3 years after treatment and every 6 months thereafter. A brain MRI scan was obtained at the third, fourth, and sixth months during the first and second years, third year, and thereafter, respectively. Endocrinologists regularly followed up the patients every 3 to 6 months according to their status. Patient IQ was measured again at 1 year or later after treatment.
Protocol Treatment Chemotherapy. The chemotherapy schedule was determined according to the extent and pathologic subtype of the tumor. For solitary pure germinoma patients, we administered both etoposide (100 mg/m2) and cisplatin (20 mg/m2) (EP) for 5 consecutive days every 4 weeks for four cycles after partial resection or biopsy and for three cycles after gross total or subtotal surgical resection. For patients with multifocal/disseminated pure germinomas, HCG-ß–secreting germinomas, and other pathologic subtypes, we administered a combination of ifosfamide (900 mg/m2), cisplatin (20 mg/m2), and etoposide (60 mg/m2) (ICE) for 5 consecutive days every 4 weeks. Three cycles were given when a gross total or subtotal surgical resection with a normalized level of serum HCG-ß was achieved. If there was a nearly complete disappearance of measurable mass on MRI scans (> 95% decrease in volume) and a normalized HCG-ß level was detected after one or more cycles of chemotherapy, then three more cycles of ICE therapy were added, up to a maximum total of six cycles. To prevent hemorrhagic cystitis and to suppress emesis, mesna (810 mg/m2 per day) and granisetron (40 or 80 mg/kg per day) were administered intravenously. According to dose-reduction criteria,20 chemotherapy dosages were modified, if necessary, in subsequent cycles in case of hematuria, altered renal function, myelosuppression, or audiologic toxicity. Granulocyte colony-stimulating factor was used for granulocytopenia. An adequate dose of intranasal desmopressin was administered during chemotherapy and radiotherapy to patients with diabetes insipidus. Radiotherapy. Radiation therapy was delivered within 2 weeks after the completion of the last course of chemotherapy using a 6- or 10-MV x-ray. All patients were immobilized with a plastic shell. Treatment planning was performed by using a three-dimensional radiotherapy planning system (Focus; CMS, St Louis, MO). Because most tumors had disappeared after chemotherapy and before treatment planning for radiotherapy, the target volumes had to be determined based on gadolinium-enhanced MRI scans obtained before surgical resection. The anatomic tumor-bearing area on the MRI scan before surgical resection was used as the gross tumor volume. The clinical target volume (CTV) was the gross tumor volume of the primary tumor site for solitary germinomas and immature teratomas. The CTV for multifocal and disseminated germinomas was the whole ventricle (WV) and the whole CNS (WCNS), respectively. For the WV field setting, the third ventricle and lateral ventricle were included in all patients, and the fourth ventricle was included in cases where a pineal tumor had existed before chemotherapy. The CTV for the primary tumor site (CTV1) and for subclinical diseases (CTV2) for highly malignant GCTs was the local field and the WCNS. The planning target volume (PTV) margin was at least 1.0 cm. The daily radiation dose was 2 Gy once a day for all irradiation. The cumulative doses were 24 Gy for both WV and WCNS irradiation. The cumulative dosage to the primary tumor site was determined according to the pathologic subtype. For pure germinomas, the cumulative dose to the CTV was 24 Gy, irrespective of the surgical operation. For HCG-ß–secreting germinomas, a cumulative dose of 24 Gy was used, irrespective of the surgical operation. However, the protocol for HCG-ß–secreting germinomas was modified in 1998 as follows: 6 Gy was given to the neurohypophysis and 10 Gy was given to the pineal region after 24-Gy WV irradiation. For the primary site of an immature teratoma, 24 Gy after gross total resection and 40 Gy after less than gross total resection was administered using local-field irradiation. For the primary site of highly malignant GCTs, a cumulative dose of 50 to 54 Gy was used. If the patient had a mixed GCT, the dose and volume were determined according to the subtype of higher malignancy. For patients with highly malignant GCTs, treatment to localized radiation boost fields was used before WCNS irradiation to reduce the possibility of severe myelosuppression. During radiotherapy, if patients developed a leukocyte count less than 1,500/µL, platelet count less than 100,000/µL, or grade 2 or greater esophagitis, treatment could be delayed until the problems were resolved. Quality assurance methods included comparing portal verification films of each field at the initial treatment day to the digitally reconstructed radiogram. Dose distribution was recorded in the hard copy of a three-dimensional room’s-eye view, including three isodose curves on transverse computed tomography images at the level of the cranial edge, center, and caudal edge of the CTV. The CTVs were required to receive between 95% and 105% of the prescribed doses. The treatment plan allowed for conventional radiation therapy in patients in whom we failed to achieve a complete response after all cycles of scheduled chemotherapy. In that case, second-look surgery was also recommended. Treatment at recurrence was dictated by the protocol. The salvage therapy was identical to the initial treatment, including surgery for nongerminomatous GCTS and chemoradiotherapy for all GCTs. Stereotactic radiotherapy for the relapsed tumor was recommended if required to avoid an overdose of radiation to eloquent neural structures.
Statistical Methods Tumor response to chemotherapy was assessed before radiotherapy in patients with a postsurgical radiographically measurable mass. Complete response (CR) was defined as the complete disappearance of radiologic evidence of disease, as estimated by whole neuroaxis MRI and the additional normalization of serum tumor markers. Partial response (PR) was considered a greater than 50% decrease in tumor volume. Progressive disease (PD) was defined as an increase in radiologic manifestation of more than 25% or an increase in tumor markers of more than 10%%. Recurrent disease was defined as the radiologic appearance of new tumor(s) or the elevation of tumor markers in patients who had previously experienced a CR. The percentage of tumor decrease was determined by measuring its volume by using MRI. However, the evaluation of multifocal or disseminated diseases was practically impossible. Therefore, patients with these diseases were estimated to be responders only when a CR was achieved. Other degrees of tumor volume reduction were estimated as stable disease in these patients. The primary end point of this study was relapse-free survival; overall survival and disease-related survival were secondary end points. For the analysis of treatment outcome, we used the Kaplan-Meyer method to calculate actual overall survival or relapse-free survival rates and compared the results by univariate analysis using the log-rank test. We calculated the relapse-free, overall, and disease-related survival from the date of surgery until the date of the last follow-up or relapse, death from any causes, and disease-related death, respectively. A disease-related death was defined as death due to a tumor or to complications from the treatment. We analyzed treatment outcome and IQ for the following variables: solitary versus multifocal tumors, locations, and pathologic subtypes. We used Student’s t test to compare patients’ IQs for each variable.
Patient Characteristics Between February 1992 and June 1999, we enrolled 33 consecutive patients (Table 1). All patients with primary CNS GCTs were eligible during this period. Age at the initial visit to the hospital ranged from 8 to 28 years (mean age, 15.9 years). Thirty-two patients were male, and one patient was a nonpregnant female. There were 16 patients with pure germinomas, 11 patients with HCG-ß–secreting germinomas, three patients with immature teratomas with germinomas (IMT/Gs), and three patients with highly malignant GCTs (two patients with embryonal carcinomas mixed with germinomas and one patient with a teratoma with malignant transformation). The median serum HCG-ß level of patients with HCG-ß–secreting germinomas was 7.4 mIU/mL (0.7, 0.7, 0.7, 5, 5.3, 7.4, 8.4, 9, 10.7, 101, and 233 mIU/mL for the 11 patients). The serum HCG-ß levels of patients with mixed GCTs ranged from 1.4 to 102 mIU/mL (mean, 22.9 mIU/mL), and for AFP levels, from 0 to 168 ng/mL (mean, 42.1 ng/mL). Pathologic diagnoses were determined by specimens of either stereotactic biopsy in 19 patients or gross or partial resection in 14 patients. Dissemination of tumor cells in the CSF was examined by both CSF cytology and MRI in all patients. Solitary, multifocal, and disseminated tumors were seen in 22, eight, and three patients, respectively.
Of the patients with pure germinomas, three received a gross total resection, three received a partial resection, and 10 were biopsied. Of the patients with HCG-ß–secreting germinomas, one received a gross total resection, three received a partial resection, and seven were biopsied. Of the patients with IMT/G, one received a gross-total resection, one received a partial resection, and one was biopsied. Among patients with embryonal carcinomas mixed with germinomas, one received a gross total resection and one was biopsied. A patient with a teratoma with malignant transformation received a partial resection. Twenty-one, six, and six patients received local, WV, and WCNS irradiation, respectively (Table 2). The median of PTV margin was 1.0 cm (range, 1.0 to 2.8 cm) in patients who received local irradiation. Two patients with HCG-ß–secreting germinomas were treated after 1998 under the modified schedule described above. For patients with IMT/G, one patient received 24 Gy after gross total resection and two patients received 40 Gy after less than gross total resection. Fifty to 54 Gy was used for three patients with other malignant GCTs.
IQ test results as measured by the Wechsler Intelligence Scale of Children Revised or the Wechsler Adult Intelligence Score Revised were available for 29 patients at the time of treatment. Eleven of the 29 patients who had not experienced recurrence were examined again more than 1 year after the completion of the treatment (mean, 24.5 months; range, 12 to 52.5 months). In these 11 patients, two received WCNS irradiation, two received WV irradiation, and seven received local irradiation. The mean follow-up from the initiation of treatment to the patients’ latest visits was 58 months (range, 18 to 102 months). Informed consent forms were signed by all patients or their legal guardians before surgery.
Response to Therapy In three patients with IMT/G, one patient who had received a gross total resection remained completely tumor-free, one patient who had been biopsied showed a PR, and one patient who had received a partial resection experienced PD after chemotherapy. In three patients with highly malignant GCTs, patients who had received a gross total or partial resection showed a CR, and one receiving a biopsy showed a PR after chemotherapy. After the whole treatment, serum HCG-ß and AFP were normalized in all patients, except in one patient with IMT/G whose AFP maintained a higher than normal range. Chemotherapy toxicity was well tolerated by all patients, and no patient required an interruption of radiotherapy.
Survival and Pattern of Relapse
Recurrence of disease was observed in one of 16 patients with pure germinomas and five of 9 patients with HCG-ß–secreting germinomas. Details regarding the timing of relapses, sites of failure, and relationship to treatment volume are listed in Table 3. Six of 18 patients with pure or HCG-ß–secreting germinomas who had received local-field irradiation experienced recurrence of disease, but none of nine patients who had received WV or larger field irradiation experienced recurrence (Tables 2 and 3). The relapse-free survival after WV or larger field irradiation was significantly higher than that after local-field irradiation (log-rank: P < .025). However, the local-field irradiation was used equally in patients with HCG-ß–secreting germinoma (73%; eight of 11) and pure germinoma (63%; 10 of 16) (  2 P = .58). Five relapses of HCG-ß–secreting germinomas developed at the margin or outside of the PTV, and two of them developed both inside and outside of the PTV. There was no relapse in the two recent patients with HCG-ß–secreting germinomas treated with 24-Gy WV irradiation followed by boost of 6 Gy for the neurohypophyseal region and 16 Gy for the pineal region, with follow-up periods of 18 and 24 months, respectively.
One patient with pure germinoma and four of five patients with HCG-ß–secreting germinomas who experienced a relapse were rendered free of disease with salvage therapy. Only one patient with an HCG-ß–secreting germinoma was receiving a course of salvage treatment for his recurrent tumor at the final observation. Our policy of salvage therapy was similar to initial treatment and has been described elsewhere.27 No disease-related death due to recurrence was observed. In the six patients with nongerminomatous GCTs, two of three with IMT/G and none of the three with malignant GCTs experienced a relapse of the disease. The relapsed patients with IMT/G underwent total resection as a salvage treatment and were free of disease at the last follow-up. The pathologies of those two patients after second-look surgery revealed that only the component of a mature teratoma was contained in one patient and a component of an IMT was found in the other patient.
Patient Functional Outcome
Hormonal replacement was given on admission in 14 patients with germinomas and two patients with nongerminomatous GCTs for their hypothalamic-pituitary dysfunction due to tumor invasion. All those patients had a tumor at the neurohypophysis. After radiation therapy, no new patient experienced additional hormonal replacement attributable to chemoradiation therapy. One patient who first had a pineal germinoma required hormonal replacement because of a tumor recurrence at the neurohypophysis. To date, three adult patients have married and one patient who had pituitary hypogonadism fathered a child after hormonal therapy. Since most patients were male, we speculated that the majority of adolescent and young adult patients had azoospermia immediately after treatment due to pituitary hypogonadism and/or chemotherapy. A sperm count was performed in four young adult patients at least 1 year after the completion of all therapy. Three of them were revealed to have almost normal levels of sperm; however, one patient who received salvage chemoradiation therapy for a relapse did not recover from azoospermia. An 8-year-old boy developed asymptomatic occlusion of the middle cerebral arteries, which was found by regular follow-up magnetic resonance angiography 23 months after the completion of therapy. However, he needed no treatment to prevent a stroke. Thus far, only minimal long-term deterioration in neuroendocrine and neurocognitive function has been detected as a consequence of protocol treatment.
In the treatment of intracranial germinoma, the standard treatment has been whole-brain irradiation or craniospinal irradiation with a boost to the primary tumor site up to 40 to 55 Gy.1-11 Since patients with intracranial germinoma can expect long survival, adverse effects of radiotherapy and late sequelae in survivors have been of major concern. To reduce the risk of late side effects, attempts to decrease total doses and the size of treatment fields using chemotherapy have been increasing. Chemotherapy alone is not sufficiently effective for the treatment of germinoma patients.16 We have previously shown that induction chemotherapy before radiotherapy can achieve an excellent initial response and tumor control rate with a median follow-up period of 24 months.20 The higher local control rate with WV compared with the control rate with local irradiation for pure or HCG-ß–secreting germinoma in this study was consistent with previous experience in radiotherapy alone without induction chemotherapy.1,9 However, interpretation of the results requires attention to the serum HCG-ß level before treatment. For pure germinoma, the present study shows that 24-Gy local irradiation after EP chemotherapy can provide an excellent outcome for patients with solitary tumors. In cases of multifocal disease and disseminated pure germinoma, 24-Gy WV and WCNS irradiation appears seems be sufficient. A recent study from the Mayo Clinic has shown that chemotherapy followed by localized 30-Gy irradiation for a complete regression and 50-Gy irradiation for a partial regression achieved 100% relapse-free survival with a median follow-up period of 43 months in nine patients with pure or HCG-ß–secreting germinomas.17 The present study suggests that the radiation dose could be reduced to 24 Gy to control pure germinomas even after stereotactic biopsy. The dose and field of radiotherapy tested in this prospective study are the lowest and the smallest compared with those of previous studies demonstrating an acceptable survival rate.28 We have found that HCG-ß–secreting germinomas had a worse prognosis than pure germinomas after radiotherapy alone: the 10-year survival rate was 90% for 60 pure germinomas and 60% for 14 HCG-ß–secreting germinomas, respectively, in the previous study.22 One study showed that HCG-ß–secreting germinomas were resistant to the EP regimen and showed a higher recurrence rate than did pure germinomas.9 Therefore, we used the ICE regimen for HCG-ß–secreting germinomas and observed an excellent initial response to the chemotherapy. The relapse rate of HCG-ß–secreting germinomas was, however, significantly higher than that of pure germinomas. HCG-ß–secreting germinomas were not sufficiently controlled by 24-Gy local-field irradiation after ICE chemotherapy, even though this chemotherapy could consistently eliminate tumor mass before the radiotherapy. This result is consistent with series from Balmaceda et al16 containing 45 patients with germinomas, in which elevated serum or CSF levels of HCG-ß showed a trend toward increased progression rates but no statistically significant impact on survival after chemotherapy alone as the initial treatment. Buckner et al17 reported that a dosage of 30.6 to 56.0 Gy after chemotherapy was sufficient for seven patients with HCG-ß–secreting germinomas. Shibamoto et al7 demonstrated that doses of 45 Gy or more were curative for HCG-ß–secreting germinomas. The therapeutic dose for curing HCG-ß–secreting germinomas may be more than 24 Gy, and it is probably between 30 Gy and 40 Gy in combination with an effective chemotherapy. Because of the high frequency of relapse in an interim report, our group has modified the treatment protocol for HCG-ß–secreting germinomas to include two patients in the present study since 1998. We are currently using WV irradiation with 24 Gy, followed by an additional local boost of 6 Gy for neurohypophyseal lesions and 16 Gy for pineal lesions. Thus, the neurohypophysis receives a total dose of 30 Gy. It is notable that most of our patients with germinomas who developed recurrence have been successfully treated with salvage therapy and have remained tumor-free without significant sequelae. Because the initial radiation dose was low, we were able to treat the relapses using chemotherapy and reirradiation with a sufficient dose to obtain a second CR, avoiding considerable late complications of the reirradiation. In addition, 21 relapse-free patients were spared conventional high-dose irradiation. This is another merit of the induction chemotherapy,29 except in the case of the HCG-ß–secreting subtype. Compared with the precise studies of patients with acute lymphocyte leukemia and medulloblastoma, little has been reported about the cognitive function before and after treatment of patients with intracranial GCTs. Since patients with intracranial GCTs are usually older than those with acute lymphocyte leukemia and medulloblastoma, a less adverse effect of radiation is expected from the same dose. However, patients with intracranial GCTs have usually received higher doses of radiation for volumes as large as the whole brain or WV, so they are vulnerable to late delayed diffuse white matter injury and secondary neoplasms.2,22,30 Also, patients may receive 40 to 60 Gy to the involved field with or without chemotherapy so that other types of injury, such as focal necrosis, blindness, and occlusive vasculopathy, have occurred.1,22,30 A high incidence of severe damage after reirradiation for intracranial relapse has also been reported.1,22 Jenkin et al31 examined 21 patients with pineal region germinoma and found that brain damage as a consequence of the tumor and/or its treatment occurred in all patients to some extent. Hardenbergh et al2 reported that among 22 patients with GCTs who had endocrinopathy at diagnosis, 13 patients had an increase in the number of endocrine deficiencies requiring hormonal replacement. Merchant et al3 investigated long-term functional outcome regarding endocrine function and neurocognitive function assessed by IQ in 12 patients with CNS germinoma who had received WCNS radiation of 25.6 Gy followed by local boosting to a total dose of 50.6 Gy. Three of four patients with pineal germinoma who had no endocrinopathy before treatment developed pituitary deficiency after radiation therapy. No significant decline in IQ was observed in any except one patient within 60 months, but no data were available after 5 years. However, in our retrospective studies of 51 patients with germinomas, four of five cases of radiation-induced neurocognitive dysfunction manifested after 5 years.6 In the 84 patients with intracranial GCT who survived longer than 2 years after radiation therapy, four developed a secondary neoplasm, and the estimated 19-year cumulative probability of radiation-induced neoplasm was 16.8% (95% CI, 8.1% to 25.5%).22 In the present series, we observed no remarkable deterioration of neurocognitive function or daily activity of patients during the follow-up period, with the exception of one patient who died from hypothalamic dysfunction. The finding of no decline in IQ after treatment is encouraging, but the follow-up period is too short and the number of patients who were examined after treatment is too small both in our series and the other prospective study about conventional radiotherapy3 to compare the two studies with regard to endocrinopathy, neurocognitive function, secondary neoplasm, and other late complications. Quality of life (QOL) in long-term survivors with germinomas has been reported by several authors retrospectively and is suggested to be "acceptable" or "reasonable."2,8,11,27,32 However, this does not necessarily mean that the patients have no long-term morbidity from their radiation therapy. Moreover, it is difficult to interpret the questionnaire or psychologic test correctly while remaining free from retrospective bias. Sutton et al32 concluded that QOL after 36-Gy WCNS irradiation and 50.4 Gy to the primary site produced good QOL for 22 patients with pure germinoma, despite the fact that seven patients were unable to work because of paraplegia, premorbid mental retardation, or depression. The methodology for evaluating QOL in these young patients is difficult to interpret and requires more investigation. In contrast to patients with germinoma, those with nongerminomatous GCTs (except for mature teratomas) have had a poorer prognosis.22-24,27,33 Notably, three patients with mixed GCTs of embryonal carcinoma or teratoma with malignant transformation have not experienced recurrences. That there are so few patients in this category prevents us from forming a conclusive statement, but the present study suggests a definite role for combination chemotherapy. Radiation therapy with a higher dose and a larger volume than those for the treatment of germinomas might also have been effective. In conclusion, we treated 33 patients with intracranial GCTs using chemotherapy followed by radiotherapy. Patients with pure germinomas were successfully treated with a 24-Gy involved-field technique after EP therapy. Patients with HCG-ß–secreting germinomas should be treated with a higher radiation dose than patients with pure germinomas using WV or larger fields, although salvage treatment has been successful without significant sequelae. A combination of chemotherapy and high-dose radiotherapy was successful for the treatment of highly malignant GCTs.
Supported by grant no. 12470182 from the Japanese Ministry of Education, Culture, Sports, Science, and Technology.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
