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© 1999 American Society for Clinical Oncology Radiation Therapy for Intracranial Germinoma: Results of the German Cooperative Prospective Trials MAKEI 83/86/89From the Department of Radiotherapy and Institute for Medical Information Processing, University of Tübingen, Tübingen; Children's Hospital, University of Düsseldorf, Düsseldorf; and Institute of Pediatric Pathology, University of Kiel, Kiel, Germany. Address reprint requests to Michael Bamberg. MD, Department of Radiotherapy, University of Tübingen, Hoppe-Seyler-Str. 3, D-72076 Tübingen, Germany; email michael.bamberg{at}med.uni-tuebingen.de
PURPOSE: A multicenter prospective trial was conducted (Maligue Keimzelltümoren [MAKEI] 83/86/89) to assess outcome in intracranial germinoma after treatment with radiotherapy alone at reduced doses. PATIENTS AND METHODS: Between 1983 and 1993, 60 patients with histologically (n = 58) or cytologically (n = 2) confirmed germinoma were enrolled onto the study. Patients received radiotherapy alone (craniospinal axis/local boost). In the MAKEI 83/86 study (involving 11 patients), the dose to the craniospinal axis was 36 Gy and the dose to the tumor region was 14 Gy. In the MAKEI 89 study (involving 49 patients), doses were 30 and 15 Gy, respectively. RESULTS: Median patient age was 13 years (range, 6 to 31 years). Complete remission was achieved in all patients. The estimated (Kaplan-Meier) 5-year relapse-free survival rate was 91.0% ± 3.9% at a mean follow-up of 59.5 months (range, 3 to 180 months); the estimated overall survival rate was 93.7% ± 3.6%. Relapse occurred in five patients 10 to 33 months (mean, 18.4 months) after diagnosis (one patient developed a spinal canal metastasis and underwent salvage radiotherapy and chemotherapy; four patients had metastases outside the CNS and underwent salvage chemotherapy alone). Four patients died: one died from disease, two died from therapy-related complications, and one committed suicide. Acute complications with long-lasting sequelae were tumor or surgery related (three cases of blindness, six of reduced vision, two of hemiparesis). Psychosocial development was normal in the majority of patients. CONCLUSION: Radiotherapy directed toward the craniospinal axis or tumor site alone at decreased dose levels is effective. To reduce the risk of late side effects, further attempts to decrease total doses are justified. In cases of recurrent disease, chemotherapy administered outside the CNS is the treatment of choice.
PRIMARY INTRACRANIAL germ cell tumors are rare, making up less than 1% of all intracranial neoplasms. The majority are radiosensitive intracranial germinomas with cure rates of 70% to 100%. These represent approximately 60% of all intracranial germ cell tumors located in the pineal gland, suprasellar region, basal ganglia, and hypothalamus.1-5 Although radiation therapy has been the standard treatment for intracranial germinoma for many years, the optimal radiation treatment is a matter of debate. Diagnostic accuracy has improved with the use of tumor markers, computed tomography (CT), and magnetic resonance imaging (MRI), and recent advances in neurosurgery and radiation techniques as well as the introduction of platinum-based chemotherapy have led to new approaches but also to controversies regarding the optimal management of intracranial germinoma. For the most part, prospective studies are lacking. Most published studies are retrospective analyses that include small numbers of patients and a lack of histologically confirmed cases.1,5-12 Because of the high radiosensitivity of these germ cell tumors and their marked tendency to spread via the CSF, systemic craniospinal irradiation was recommended. Considerable differences in radiation procedures and treatment results were reported in the literature. The German Society for Pediatric Oncology and Hematology initiated cooperative prospective trials to evaluate the efficacy of precise irradiation alone in histologically confirmed intracranial germinoma. Furthermore, reducing the total dose seemed to be a promising approach, given the clinical experience in curing testicular seminoma, one of germinoma's extracranial counterpart. With reduced total doses, the potential adverse effects on the CNS and spinal growth were also diminished. Our aim was to investigate therapeutic outcome in histologically proven intracranial germinoma after treatment with radiotherapy alone in a multicenter prospective trial. The Maligue Keimzelltümoren (MAKEI) 83/86/89 trial was designed to assess the time until relapse, patterns of relapse, and survival time. The feasibility of this approach was tested in a prospective pilot study that was started in 1983 (MAKEI 83). In the MAKEI 86 trial, detailed therapeutic guidelines were given. In the MAKEI 89 trial, results from the preceding study were used in the evaluation of therapeutic outcome after dose reduction.
Patient Eligibility and Pretherapeutic Assessment Patients with a diagnosis of secreting or nonsecreting intracranial germ cell tumor were entered onto the MAKEI 83/86/89 study. Alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (ß-HCG) levels in serum and CSF were evaluated to identify a secreting tumor. A ß-HCG level of less than 100 ng/µL (MAKEI 83/86) and an AFP level of less than 50 ng/µL (MAKEI 89) were considered normal according to the normal range in very young children and their elevation in secreting germ cell tumors.13-15 Evaluated were all patients with histologically proven intracranial germinoma who did not have elevated ß-HCG and/or AFP levels and in whom radiation had been delivered to the craniospinal axis alone. Eighteen registered patients who had received different treatments involving varying treatment schedules not in accordance with the protocol guidelines were excluded from evaluation. When ß-HCG and/or AFP levels were elevated, a secreting tumor was diagnosed. If CT or MRI showed a characteristic tumor site, the subsequent treatment was started with chemotherapy according to a separate protocol.16,17 Intracranial tumor manifestation and possible metastatic spread were diagnosed by imaging of the brain and spinal canal, using CT, MRI, or myelography; in the last years of the accrual period, MRI was the imaging technique chosen most often. Cytologic examination of CSF was performed in all patients, to obtain information regarding leptomeningeal seeding. Surgery was used for diagnosis and was followed by radiotherapy. If ß-HCG and/or AFP levels indicated a secreting tumor, a histologic diagnosis was required. It was recommended that a biopsy be performed and total resection be avoided, to prevent surgery-related morbidity. If patients had symptomatic hydrocephalus, a ventriculoperitoneal or ventriculoatrial shunt was placed. Histologic sections of the tumors were sent to the local pathologist. Additionally, 37 cases (61.6%) were also reviewed at the reference center by one of us (D.H.). Patients were entered onto the study on the basis of the individual institution's pathology report or, in case of review, on the basis of the report from the reference center. All patients who had macroscopic disease before radiotherapy (n = 55) had complete remission as assessed by CT or MRI.
Treatment Modalities
Response Criteria and Follow-Up Investigations
Statistical Considerations Kaplan-Meier (life-table) estimates of overall survival and relapse- and event-free survival were used throughout the analysis and were calculated from the date of diagnosis to the date of last follow-up or death. Estimates are presented as means ± SE. Overall survival calculations involved tumor-related deaths only. Event-free survival rate was the percentage who remained alive without complications or disease recurrence. Follow-up for all surviving patients was terminated in September 1997.
Consequences of Treatment Data were collected from patient records, regular follow-up visits, and a questionnaire dealing with psychosocial development (education and current occupation). The questionnaire was completed either during the last follow-up visit or by telephone interviews with the patient or physician.
Completeness of Data Collection
The MAKEI 83 trial was started on January 1, 1983, and the MAKEI 86 study was started on January 1, 1986. No relapses were noted, and the pilot studies were therefore ended on November 1, 1988. The MAKEI 89 study began in December 1989 and ended in January 1993. A total of 60 patients with histologically proven intracranial germinoma in whom radiation was delivered to the craniospinal axis alone were enrolled, 11 onto the 83/86 study and 49 onto the 89 study.
Patient Sex and Age
Patterns of Spread at Time of Diagnosis Cytologic examination of CSF demonstrated leptomeningeal seeding in 15.2% of all patients. In 54 patients, serum AFP and ß-HCG levels were within normal range, and in 38 patients, AFP and ß-HCG levels in the CSF were within normal range. In six patients, AFP and ß-HCG levels were not measured, and in seven patients (one in the MAKEI 83/86 study, six in the MAKEI 89 study), serum and CSF levels were not evaluated before radiotherapy was begun.
Surgery
Histology
Radiotherapy
Survival and Remission Rates
In the MAKEI 89 study, one patient died from disease 21 months after diagnosis, during a third relapse (there was meningeal spread). Two additional patients died from therapy-related complications. One patient committed suicide. At last follow-up (30 months after the end of treatment), he had been relapse-free.
Pattern of Relapse and Salvage Therapy
Two patients had secreting tumors at the time of relapse. One of these patients had a testicular tumor and was in complete remission 75 months after surgery and two courses of BEP therapy (Table 1, patient no. 4). In the other patient with extensive intra-abdominal metastastic spread (to the lymph nodes; no shunt had been placed in this patient), complete remission was achieved with three courses of vinblastine, bleomycin, and cyclophosphamide therapy and one course of PEI therapy (Table 1, patient no. 5). However, a second relapse, with leptomeningeal seeding, occurred 8 months later. The patient did not respond to further chemotherapy and died 2 months later.
Quality of Survival A detailed endocrinologic diagnostic work-up was performed in 46 patients. At the time of diagnosis, 23 patients (41.0%) had evidence of at least one endocrine abnormality requiring continual hormone replacement. At follow-up, no additional impairment of endocrine function was noted. In one patient, severe neurocognitive disturbances initially led to diagnosis. Although his condition improved significantly after radiotherapy, he continued to have persistent deficits. Fifty-two patients (92.8%) were attending or had attended schools and 35 (62.5%) obtained degrees. Four patients needed special education (three were blind, two were hemiparetic, and one had neurocognitive dysfunction). Four patients were attending universities, 10 were in other higher education programs, 16 had permanent occupations (skilled work), two were looking for jobs (having finished their education), and only three were unemployed.
Intracranial germinoma poses a challenge to the clinician because it is rare and the therapeutic approach is controversial. The German Society for Pediatric Oncology and Hematology therefore conducted a cooperative prospective trial (MAKEI 83/86/89) to elucidate the benefit of radiotherapy alone and to create guidelines for case management and future treatment strategies. In the present study, we found a male preponderance (75%) as well as a median age of 13 years, which is consistent with the peak incidence of 10 to 15 years reported elsewhere.2,5,9,10 In contrast to previous studies involving small patient numbers and no histologic confirmation, our cooperative prospective trial involved a large homogeneous group of patients who received a uniform and standardized radiotherapy as the sole first-line treatment. The 5-year relapse-free survival rate was 91.0% and the overall survival rate was 93.7% at a median follow-up of 61 months. We observed a recurrence rate of 1.6% in the CNS, which is in accordance with published long-term relapse rates of 0% to 12.7% within the CNS in cases of histologically verified intracranial germinoma.2,9,10,18,19 In our study, relapse occurred 10 to 33 months after diagnosis, in comparison with 2 to 47 months or even, in one case, 6.3 years, as reported elsewhere.9,11,19,20 Most relapses occurred at intracranial sites (62% to 66%).2,5,9 The spinal relapse rate is reported to range from 5% to 40% and is critically dependent on the target volume irradiated.5,21,22 The size of the radiation field required for optimal tumor control continues to be debated. A review of published data shows that when the treatment volume is restricted to the whole brain, partial brain, or tumor site, there is an increased risk of spinal or intracranial recurrence.3,6,21,23 However, most published studies have involved heterogeneous patient groups, low patient numbers, or short follow-up.3,6,9,21,23-25 The MAKEI 83/86/89 study was not designed as a randomized trial, because of the low incidence of intracranial germinoma, but the patients were treated similarly according to definite guidelines. The risk of potential spinal seeding after therapy and the low relapse rate in our study remain the only guidelines for deciding on the extent of radiotherapy. We therefore favor irradiation of the craniospinal axis in all patients, and it seems reasonable that presently an individualized approach based on a positive CSF cytology at the time of diagnosis cannot be recommended.21,22 Most relapses occurred outside the CNS (four of five patients). In two cases the relapse was abdominal, in one case there were osseous and lung metastases, and in one case a testicular tumor with retroperitoneal lymph node metastases was found. In our series, distant metastases were considerably more frequent than in previous studies, which found a much lower frequency in up to 3.8% of cases, with these metastases generally occurring in association with CNS recurrence.2,9,11 However, in our study, an embryonal carcinoma was found in the patient who developed a testicular tumor with retroperitoneal lymph node involvement, and in the patient with abdominal lymph node metastases, a component of a highly malignant germ cell tumor was detected. Possibly metachronous germ cell tumors originating from the testes or ovaries have led to these results. Therefore, it seems unlikely that the previously treated histologically proven intracranial germinoma metastasized in these cases. Although observed in three patients, the frequency of recurrence is too low for a reliable statistical method to assess the significance of prognostic factors for time to relapse and survival. It is important to investigate the possibility of dose reduction, because after administration of high doses, adverse effects may develop, such as hypothalamic or hypophyseal dysfunction and decreases in intellectual ability, especially in the very young.26 In the MAKEI 83/86 study, irradiation of the craniospinal axis with 36 Gy followed by a local boost to 50 Gy resulted in no recurrence in 11 patients. Consequently, the total dose was reduced to 30 and 15 Gy (local boost) and the fractionated dose was reduced from 1.8 Gy to 1.5 Gy in the subsequent MAKEI 89 study, to reduce the risk of adverse effects to the CNS. Only one relapse occurred in 49 patients. These results justify efforts to further reduce the total dose delivered to the neuroaxis and primary tumor site. In our study, chemotherapy was given to three patients who developed recurrent disease and two patients with metachronous extracranial germ cell tumors of the testes or ovaries. As in other studies,27-29 patients achieved second complete remissions, and one patient achieved a third complete remission. Therefore, it can be assumed that chemotherapy plays a definite role in cases of recurrent intracranial germinoma. As primary treatment, however, chemotherapy given alone is associated with unexpectedly high recurrence rates (all patients relapsed) and considerable toxicity.18,29 Additionally, the long-term toxicity is unclear.19,29 Balmaceda et al20 reported better response rates with BEP therapy, achieving continuous complete remission in 23 of 45 patients. However, there were four chemotherapy-related deaths. Recurrent disease could effectively be treated with chemotherapy combined with radiotherapy of the whole CNS.20,30 Similarly, adjuvant chemotherapy followed by irradiation of the tumor site only was used in small series. Eleven patients were treated with carboplatin before irradiation. One relapse was noted at 25-month follow-up.28 In a French study, 31 patients with nonmetastatic primary cerebral germinoma were treated with two cycles of platinum-based chemotherapy followed by local irradiation; 29 children were treated according to protocol guidelines and achieved first complete continuous remissions, but the length of follow-up was not reported.31 However, in an Italian study, a similar treatment was associated with a high intracranial recurrence rate: five of seven patients had disease recurrence at the field margins.32 Given that radiotherapy administered alone cured patients with even multiple midline germinomas in our study and others, the role of adjuvant chemotherapy remains uncertain. The complication rate during primary treatment and salvage treatment was low. The consequences of treatment are of increasing concern in long-term survivors of childhood cancer. Radiation treatment, although highly efficacious, is often suspected to cause damage, especially to the developing CNS.26 In contrast to other investigators,33 who reported that only 33% of patients who had received treatment for intracranial germinoma had no gross late effects, we found that nearly all patients who were in complete remission were living active and useful lives. In our study, the factors having the greatest influence on severe and permanent late effects were tumor- and/or surgery-related deficits, accounting for three cases of blindness, six cases of reduced visual capacity, two cases of hemiparesis, and one case of mental disability. Endocrine dysfunction is often linked to cranial irradiation. In our study, however, no patient developed abnormalities after irradiation, whereas disorders at the time of diagnosis were caused by tumor and necessitated continual replacement therapy. Our findings therefore do not support the idea that endocrine dysfunctions are mainly radiotherapy induced. Using school education and occupation as indicators for psychosocial development, we did not find overt deficits in the vast majority of patients. Although no detailed psychologic tests were performed, it seems that the psychosocial development of the children and young adolescents was not compromised. In no patient was psychosocial development decreased after completion of therapy, although minor deficits cannot be excluded. The risk of neurocognitive dysfunction is mainly age dependent. Although an increased rate of neurocognitive dysfunction could not be seen in our analysis, the potential neurotoxicity of radiotherapy should be considered. Therefore, a further dose reduction should be performed, because there is less risk of late effects with total doses of less than 30 Gy.34 Radiotherapy administered alone cures patients with intracranial germinoma and is the standard treatment. In this study, reduced doses of radiation did not worsen outcome and were associated with acceptable acute and long-term toxicity. Given the high sensitivity of testicular seminoma (histologically identical to germinoma) to radiation at low dose levels, we assume that patients with intracranial germinoma may possibly be cured by much lower doses than those currently used. Use of lower doses would eliminate the major adverse effects of radiation, especially in younger children. Radical extirpation should not be attempted, because these tumors are highly radiosensitive and because there is a high risk of severe morbidity, as evidenced by the two patients in our study who lost vision. The preliminary results of chemotherapy alone and chemotherapy with irradiation of the tumor site only may be equivalent, but no firm conclusions can be drawn at present. The high cure rates seem to justify reducing the total dose to 24 Gy (adjuvant treatment at the craniospinal axis), as suggested by the current International Society of Pediatric Oncology (SIOP) Central Nervous System Germ Cell Tumors (CNS GCT) 96 Study, and administering a boost of 16 Gy to the primary tumor site (Great Britain/Germany). In Italy and France, preirradiation chemotherapy followed by local radiotherapy at doses of 40 to 45 Gy will be investigated. Only in cases of metastatic disease or when there is cytologic evidence in CSF will irradiation of the craniospinal axis be performed. This strategy is similar to that used in the Pediatric Oncology Group trial POG-9530, in which chemotherapeutic regimens were tested that were different from those in the SIOP trial. In cases of nonmetastatic disease, chemotherapy was followed by irradiation of gross disease. The SIOP CNS GCT study group decided to use both strategies (radiotherapy directed toward the craniospinal axis, and chemotherapy followed by limited-volume irradiation) and to document late effects in the same way, to compare both treatment strategies.
We thank Susanne Dippert for her valuable help in collecting data and the Deutsche Krebshilfe, Bonn, which enabled us to publish this article.
1. Bjornsson J, Scheithauer BW, Okazaki H, et al: Intracranial germ cell tumors: Pathobiological and immunohistochemical aspects of 70 cases. J Neuropathol Exp Neurol44:32-46, 1985[Medline] 2. Dearnaley DP, A'Hern RP Whittaker S, et al: Pineal and CNS germ cell tumors: Royal Marsden Hospital experience, 1962-1987. Int J Radiat Oncol Biol Phys18:773-781, 1990[Medline] 3. Linstadt D, Wara WM, Edwards MS, et al: Radiotherapy of primary intracranial germinomas: The case against routine craniospinal irradiation. Int J Radiat Oncol Biol Phys15:291-297, 1988[Medline] 4. Russel DS, Rubinstein LJ: Maldevelopmental tumors and tumor-like lesions, in Russel DS, Rubinstein LJ (eds): Pathology of Tumors of the Nervous System (ed 5). Baltimore, MD, Williams & Wilkins, 1989, pp 664-751 5. Shibamoto Y, Abe M, Yamashita J, et al: Treatment results of intracranial germinoma as a function of the irradiated volume. Int J Radiat Oncol Biol Phys15:285-290, 1988[Medline] 6. Amendola BE, McClatchey K, Amendola MA: Pineal region tumors: Analysis of treatment results. Int J Radiat Oncol Biol Phys10:991-997, 1984[Medline]
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Silber JH, Radcliffe J, Peckham C, et al: Whole-brain irradiation and decline in intelligence: The influence of dose and age on IQ score. J Clin Oncol10:1390-1396, 1992 Submitted March 27, 1998; accepted April 12, 1999.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
