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© 1999 American Society for Clinical Oncology Phase II Trial of Primary Chemotherapy Followed by Reduced-Dose Radiation for CNS Germ Cell TumorsFrom the Division of Medical Oncology, Section of Pediatric Hematology and Oncology, Department of Neurology, Division of Radiation Oncology, Department of Neurosurgery, and Cancer Center Statistics, Mayo Clinic, Rochester, MN; Department of Pediatrics, Hematology-Oncology Division, University of Minnesota, Minneapolis, MN; and Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, NC. Address reprint requests to Jan C. Buckner, MD, Division of Medical Oncology, Mayo Clinic, 200 First St, SW, Rochester, MN 55905; email buckner.jan{at}mayo.edu
PURPOSE: A prospective phase II study was initiated to assess the response rate, survival, and late effects of treatment in patients with newly diagnosed CNS germ cell tumors (GCT), using etoposide plus cisplatin followed by radiation therapy prescribed by extent of disease, histology, and response to chemotherapy. PATIENTS AND METHODS: Seventeen patients aged 8 to 24 years with histologically proven CNS GCT received etoposide (100 mg/m2/d) plus cisplatin (20 mg/m2/d) daily for 5 days every 3 weeks for four cycles, followed by radiation therapy. Nine patients had germinomas; eight had mixed GCT. Four patients (three with germinomas and one with mixed GCT) presented with leptomeningeal dissemination. RESULTS: Radiographically, 14 of 17 patients were assessable for response; 11 patients experienced complete regression, and three had major partial regression before radiation. Six of seven assessable patients with elevated CSF levels of alpha-fetoprotein or beta–human chorionic gonadotropin had normalization with chemotherapy alone; all normalized with combined chemotherapy and radiation therapy. All 17 patients are alive without evidence of disease (median follow-up, 51 months). One patient developed a relapse in the spinal leptomeninges and was rendered free of disease with spinal radiation more than 5 years ago. One patient developed carotid stenosis requiring surgery. Thus far, only minimal long-term deterioration in neurocognitive function has been detected as a consequence of protocol treatment. CONCLUSION: Conventional-dose intravenous chemotherapy with etoposide and cisplatin can effect tumor regression in a high proportion of patients with CNS GCT, including those with leptomeningeal metastases. Acute and long-term toxicities are acceptable. Progression-free survival and overall survival are excellent.
CNS GERM CELL tumors (GCT) are extremely rare malignancies, occurring predominantly in the suprasellar and pineal regions of children, adolescents, and young adults.1 Patients with localized germinomas, similar to those with testicular seminoma, are often cured with radiation therapy alone,2-6 but those with leptomeningeal dissemination or nongerminoma GCT are infrequently cured with radiation.1,5 Furthermore, high doses of radiation therapy may cause growth retardation, endocrine dysfunction, and cognitive impairment, particularly in pediatric patients. Chemotherapy is known to be effective in gonadal and extragonadal GCT,7 but relatively few patients with CNS GCT have been included in most series. Recent reports indicate that high-dose chemotherapy alone can produce durable complete regressions in some patients with CNS GCT, but relapse occurs in up to half of patients who do not also receive radiation as a part of their initial therapy.8 This phase II trial was conducted to assess the response rate and survival in patients with newly diagnosed CNS GCT treated with conventional doses of etoposide and cisplatin, followed by radiation therapy, with dose and volume adjusted according to initial tumor extent, histologic type, and response to chemotherapy. In addition, prospective assessments of endocrine and cognitive function before and after treatment are reported.
Eligibility Criteria Patients aged 3 years or older with histologic confirmation of CNS germinoma, immature teratoma, embryonal cell carcinoma, yolk sac tumor, endodermal sinus tumor, or choriocarcinoma were eligible for protocol participation if a computed tomographic (CT) or magnetic resonance imaging (MRI) scan demonstrated assessable disease. Patients with pineal or suprasellar masses and elevated CSF levels of alpha-fetoprotein (AFP) or beta–human chorionic gonadotropin (HCG) were also eligible without histologic confirmation of tumor. Adults with pure germinomas were excluded on the premise that radiation was curative and safe for these patients. Patients with prior cranial or spinal radiation or prior chemotherapy were excluded. Inadequate bone marrow (adults: leukocytes < 4,000/µL or platelets < 100,000/µL; pediatric patients: absolute neutrophil counts < 1,000/µL or platelets < 100,000/µL) or renal (creatinine > 0.3 mg/dL above the upper normal limit for age) function precluded participation. No pregnant or lactating women or patients with uncontrolled infection could enter onto the trial. All patients or their guardians provided written informed consent before protocol participation. The study was conducted by the Mayo Clinic and the Children's Oncology Group of the Upper Midwest.
Protocol Tests and Examinations During treatment, the CBC count was monitored weekly during chemotherapy and before radiation therapy. Serum chemistries, magnesium, creatinine clearance, and AFP and HCG levels (if initially elevated) were monitored before each cycle of chemotherapy. An audiogram was obtained before each cycle of chemotherapy in children. A CT or MRI scan of the brain was obtained before each cycle of chemotherapy, and spinal imaging was performed as clinically indicated. During the first year after completion of treatment, patients were monitored every 2 months with a history and physical examination, CBC count, and serum chemistries and with additional studies every 4 months, including determination of AFP and HCG if initially elevated, electrolytes and creatinine, total thyroxine, thyroid-binding globulin, morning cortisol, and testosterone or estradiol, as well as an endocrinology consultation. During the second and third years posttreatment, patients returned every 4 and 6 months, respectively, with continued monitoring for long-term toxicities, including hematologic and renal impairment, ototoxicity, visual field abnormalities, and endocrine dysfunction. The same psychometric studies obtained before treatment were repeated 3 and 5 years posttreatment. Neuroimaging evaluations and pertinent tumor markers were repeated at each visit.
Protocol Treatment At the time of scheduled treatment, chemotherapy was delayed until leukocytes were at least 3,000/µL, the absolute neutrophil count was 1,000/µL, and platelets were 100,000/µL. In adults, cisplatin was reduced 25% for serum creatinine 1.5 to 2.0 times the upper normal limit, and administration was stopped for creatinine more than 2.0 times the upper normal limit. In children, for creatinine more than 1.5 times the upper normal limit or for creatinine clearance less than 60 mL/min/m2, the test was repeated in 1 week; if renal dysfunction continued, cisplatin was withheld from that course and etoposide was administered alone. If renal dysfunction resolved, cisplatin was administered in subsequent cycles. Cisplatin was discontinued for grade 3 or higher neurosensory or neuro-hearing toxicity (National Cancer Institute common toxicity criteria), or for a hearing loss of more than 40 dB at 2,000 mHz. Both children and adults were hospitalized for treatment, and their intake, output, weight, serum sodium, potassium, chloride, and creatinine levels were checked daily. Cycles were repeated every 3 weeks, for a total of four cycles. After completion of chemotherapy, patients were restaged, and radiation was given on the basis of stage, histologic type, and response to chemotherapy. Surgery. Patients with less than a complete response after chemotherapy were seen in neurosurgical consultation for consideration of resection of any residual cranial masses. Because a mature teratoma could be present and could grow despite chemotherapy and radiation, surgery was performed after chemotherapy and before radiation, whenever feasible. Radiation therapy. Patients proceeded directly to radiation therapy as soon as they recovered from myelosuppression from chemotherapy, unless surgical resection of residual masses needed to be performed. A summary of radiation therapy is presented in Fig 1. Per protocol, localized treatment was prescribed to the prechemotherapy primary tumor volume plus a 2-cm margin. The use of opposed lateral fields was discouraged in favor of alternatives, including three-field techniques (anteroposterior or vertex plus wedged laterals), a four-field technique (anteroposterior-posteroanterior plus laterals), or arc or rotational techniques. The daily dose was 1.8 Gy, prescribed to the midplane of opposed fields and to the intersection of field centers (isocenter) for multiple fields. Craniospinal axis (CSA) fields included the entire cranial contents and entire spinal axis. In the CSA field, the cranial contents, including cribriform plate, were treated with opposed lateral fields with a 1-cm margin between the skull base and the shaped inferior margin of the field. The spinal axis field was treated with one or more posterior fields. If more than one field was used, appropriate gapping at the skin to match at depth was prescribed, and the match point(s) were moved 1 cm or more once or twice during the spinal axis radiation, with the match point ideally situated at or below L2-3. The lateral borders of the spine field(s) were 1.5 cm lateral to the edges of the vertebral bodies, and the inferior border was at the inferior border of S3. For patients with gross spinal meningeal disease, all areas of gross disease detected by prechemotherapy scans were boosted with a 2-cm margin to a dose of 45 to 50.4 Gy, unless the craniospinal meninges were diffusely involved, in which case the entire craniospinal contents were boosted to a dose of 40.5 Gy. The daily dose to all CSA fields was 1.5 Gy, calculated to the midplane for the opposed lateral brain fields and to the mid spinal canal for the posteroanterior spinal field(s). Boost localized cranial or spinal fields were treated after the completion of CSA irradiation at a daily dose of 1.8 Gy according to the prescription for localized fields described above.
If, during radiation, patients developed WBC counts of less than 1,500/µL or platelets below 100,000/µL, treatment was delayed for up to 1 week. If the delay was more than 1 week, treatment to localized radiation boost fields began. If localized radiation boost fields were completed and myelosuppression by the parameters noted previously had not resolved within 4 weeks, CSA was not completed. For radiation esophagitis more than grade 2, treatment was delayed by 1 week or until esophagitis resolved to grade 1 or less. If the delay was more than 1 week, localized radiation boost fields began. If grade 2 or greater esophagitis persisted after completion of the boost fields and more than 4 weeks, CSA treatment was not completed. Quality assurance methods included portal verification films of each field taken at weekly intervals. Dosimetry requirements included a transverse isodose plot through the center of the primary tumor and a midline sagittal isodose plot showing the spinal cord in patients receiving CSA irradiation. The target volumes were required to receive between 95% and 105% of the prescribed total doses. Doses of 90% to less than 95%, or more than 105% to 110%, of the prescribed dose constituted a minor deviation, and doses of less than 90% or more than 110% constituted a major violation.
Assessment of Response
Patient Characteristics Sixteen patients have entered the trial and all are assessable for toxicity and response to treatment. In addition, one patient from another institution was treated, evaluated, and followed per protocol; therefore, 17 patients are included in the analysis. In retrospect, three patients did not have assessable disease on pretreatment neuroimaging studies. Patient characteristics are listed in Table 1. The median age was 14 years. Eight patients had nongerminoma tumors histologically or on the basis of elevated serum or CSF AFP. Thirteen patients had localized disease, and four had leptomeningeal spread at the time of diagnosis (three with germinomas and one with a nongerminoma tumor).
Treatment Delivered Fourteen of 17 patients received radiation per protocol, and three did not (Table 1). Patient no. 13 received a local field dose of 52.5 Gy versus 30.3 per protocol and a CSA dose of 30.0 Gy versus 19.5 per protocol. Patient no. 16 received 36.0 Gy local field radiation versus 23.4 per protocol and a CSA dose of 25.2 Gy versus 30.0 per protocol. Patient no. 17 received 56.0 Gy local field radiation versus 30.3 and a CSA dose of 36.0 Gy versus 19.5 per protocol. All three are considered major protocol violations. After completion of chemotherapy, nine of 17 patients received reduced-dose radiation per protocol. Three additional patients (no. 13, 16, and 17) were eligible to receive reduced-dose chemotherapy but were protocol violations. Thus, reduced-dose radiation was given in 53% of patients; a reduced dose should have been given in 71% of patients.
Acute Toxicity
Response and Survival
Endocrine dysfunction.
Ototoxicity.
Psychometric evaluations.
Neurologic examinations.
The rarity and complexity of CNS GCT makes assessment of treatment outcomes difficult; however, retrospective series suggest that chemotherapy can result in tumor regression in the majority of patients.10-12 These findings have been confirmed in our prospective study demonstrating a 100% response rate, including 79% complete responses (11 of 14 patients). Patients with pure germinomas as well as those with nongerminoma elements respond. In addition, four patients in our series had leptomeningeal dissemination of disease at the time of diagnosis, and all responded to conventional doses of intravenous chemotherapy. These complete responses indicate that sufficient concentrations of chemotherapy can reach leptomeningeal tumor deposits, suggesting that other methods of drug delivery, such as high-dose intravenous chemotherapy, blood-brain barrier modification, or intrathecal chemotherapy, are not necessary in this setting to reduce tumor burden to the subclinical level. Other prospective trials have also documented a high rate of complete response. Balmaceda et al8 used chemotherapy without irradiation as initial therapy. In that trial of 71 patients, treatment consisted of high-dose carboplatin, etoposide, and bleomycin for four cycles. Thirty-nine of 68 assessable patients (57%) achieved a complete response after four cycles of treatment. Of the remaining 29 patients, 16 achieved complete regression with subsequent high-dose cyclophosphamide or second surgery. Therefore, 55 of 71 patients (78%) had complete regressions without radiation. Sawamura et al13 used ifosfamide, cisplatin, and etoposide either before or concurrently with radiation. Treatment decisions were based upon anticipated prognosis. All patients had either complete or partial responses to chemoradiotherapy. An important issue involves the durability of responses to chemotherapy alone. In the Balmaceda study,8 28 of the 55 patients who had complete regression with chemotherapy alone had relapsed by the time of publication. In addition, nine patients died of causes other than tumor, including seven with chemotherapy-related deaths, and eight patients died of tumor progression or recurrence. The 2-year survival estimate was 76%. By contrast, in our study, in which chemotherapy was followed by reduced-dose radiation, only one patient with a localized germinoma treated with localized low-dose cranial radiation had a recurrence in the spinal leptomeninges. That patient was treated subsequently with salvage spinal radiotherapy more than 5 years ago and remains free of disease at the present time. All 17 patients remain alive without tumor progression at this time, with a median follow-up of 4.2 years. Similarly, Sawamura et al13 reported only one relapse in 20 patients treated with chemotherapy and radiation. Like our patient, this patient had a localized germinoma, relapsed, and responded successfully to salvage therapy. All 20 of their patients remain free of disease, with a median follow-up of 23 months. Using chemoradiotherapy, both we and Sawamura et al report 100% survival, compared with 75% in the Balmaceda study, which used chemotherapy alone. Although the studies are not strictly comparable, we conclude that the use of high-dose chemotherapy, with its significant morbidity and mortality, is not necessary if chemotherapy is followed by radiation. However, radiation therapy to the developing CNS can result in debilitating consequences, including significant intellectual decline, growth retardation, and endocrine dysfunction. As part of our trial, we prospectively evaluated cognitive function. Five of 10 patients followed for 36 months after the completion of radiation had both a baseline test and at least one follow-up test of cognitive function. To date, we have detected no evidence of substantive cognitive decline that can be attributed to treatment. However, no patient less than 8 years old entered onto the study, so the effects of this treatment on younger children cannot be assessed. Of five patients not requiring hormone replacement therapy before treatment, none developed pituitary insufficiency after treatment. Significant growth abnormalities were documented in no patients. In a median follow-up of 4.2 years and a 2-year follow-up in 71% of patients, we have not detected substantive intellectual, endocrine, or growth abnormalities attributable to protocol therapy. It is important to point out that local field radiation was given if the disease itself was localized. In addition, patients who attained complete regression with chemotherapy were given lower doses of radiation to sterilize any remaining microscopic disease deposits. We believe that limiting the volume and dose of radiation was sufficient to control microscopic disease but low enough to minimize the risk of late morbidity from radiation. We continue to follow all patients regularly with formal assessments of cognitive and endocrine function. In summary, primary chemotherapy with etoposide and cisplatin followed by radiation, adjusted for extent of tumor, histologic type, and response to chemotherapy, resulted in tumor regression in all patients. Late relapse has occurred to date in only one patient, who was successfully salvaged with radiation therapy. Long-term consequences of therapy appear to be minimal. Except for adults with localized germinoma who have a high probability of cure with radiation alone, we recommend this therapy as standard treatment for all pediatric patients and adults with either disseminated disease or nongerminoma variants of CNS GCT.
Supported by Mayo Cancer Center grant no. CA 15083, the Linse-Bock Foundation, and the Children's Oncology Group of the Upper Midwest. We gratefully acknowledge the contributions of Drs. Ebenezer Odunusi and Samir Mullick, University of Minnesota, Minneapolis, MN; Dr. Ann Bendel, Minneapolis, MN; and Dr. Andrew Maksymiuk, Saskatoon, SK, for protocol implementation and data collection; Jill Burton for excellent assistance with data management; Dr. Bernd Scheithauer for pathology review; Dr. Robert Ivnik, Section of Psychology, Mayo Clinic, Rochester, MN, for interpretation of neuropsychometric studies; and Dr. Donald Zimmerman, Department of Pediatrics, Mayo Clinic, Rochester, MN, for advice regarding endocrinology assessment and management.
1. Jennings MT, Gelman R, Hochberg F: Intracranial germ-cell tumors: Natural history and pathogenesis. J Neurosurg 63:155-167, 1985[Medline] 2. Wara WM, Jenkin RDT, Evans A, et al: Tumors of the pineal and suprasellar region: Children's Cancer Study Group treatment results 1960-1975. Cancer 43:698-701, 1979[Medline] 3. Sung DI, Harisiadis L, Chang CH: Midline pineal tumors and suprasellar geminomas: Highly curable by irradiation. Radiology 128:745-751, 1978[Abstract]
4.
Fields JN, Fulling KH, Thomas PRM, et al: Suprasellar germinoma: Radiation therapy. Radiology 164:247-249, 1987 5. Rich TA, Cassady JR, Strand RD, et al: Radiation therapy for pineal and suprasellar germ cell tumors. Cancer 55:932-940, 1985[Medline] 6. Jenkin RDT, Simpson JK, Keen CW: Pineal and suprasellar germinomas: Results of radiation treatment. J Neurosurg 48:99-107, 1978[Medline] 7. Williams SD, Birch R, Einhorn LH, et al: Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med 316:1435-1440, 1987[Abstract] 8. Balmaceda C, Heller G, Rosenblum M, et al: Chemotherapy without irradiation—A novel approach for newly-diagnosed CNS germ cell tumors: Results of an international cooperative trial—The First International Central Nervous System Germ Cell Tumor Study. J Clin Oncol 14:2908-2915, 1996[Abstract] 9. Folstein MF, Folstein SE, McHugh PR: "Mini-mental state": A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189-190, 1975[Medline] 10. Allen JC, Kim JH, Packer RJ: Neoadjuvant chemotherapy for newly diagnosed germ-cell tumors of the central nervous system. J Neurosurg 67:65-70, 1987[Medline] 11. Patel SR, Buckner JC, Smithson WA, et al: Cisplatin-based chemotherapy in primary central nervous system germ cell tumors. J Neurooncol 12:47-52, 1992[Medline] 12. Kida Y, Kobayashi T, Yoshida J, et al: Chemotherapy with cisplatin for AFP-secreting germ cell tumors of the central nervous system. J Neurosurg 65:470-475, 1986[Medline] 13. Sawamura Y, Shirato H, Ikeda J, et al: Induction chemotherapy followed by reduced-volume radiation therapy for newly diagnosed central nervous system germinoma. J Neursurg 88:66-72, 1998[Medline] Submitted April 24, 1998; accepted November 9, 1998. This article has been cited by other articles:
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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
90% of chemotherapy for four cycles, including one patient who received prophylactic granulocyte colony-stimulating factor on cycles 1 and 2 per physician judgment. Cisplatin was omitted in cycle 3 in one patient because of an elevated creatinine clearance and was reduced in cycle 4 in one patient by 40% owing to asymptomatic hearing loss detected by an audiogram. One patient (no. 6) received only three cycles of chemotherapy followed immediately by radiation because his AFP level remained elevated. 
