Japanese Journal of Clinical Oncology Advance Access originally published online on June 23, 2008
Japanese Journal of Clinical Oncology 2008 38(7):486-492; doi:10.1093/jjco/hyn049
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© The Author (2008). Published by Oxford University Press. All rights reserved
Low-dose Craniospinal Irradiation and Ifosfamide, Cisplatin and Etoposide for Non-metastatic Embryonal Tumors in the Central Nervous System
1 Department of Radiology, Hokkaido University School of Medicine
2 Department of Neurosurgery, Hokkaido University School of Medicine
3 Department of Pediatrics, Hokkaido University School of Medicine
4 Department of Otolaryngology, Hokkaido University School of Medicine, Sapporo, Japan
For reprints and all correspondence: Koichi Yasuda, Hokkaido University School of Medicine, North-15 West-7, Kita-ku, Sapporo, Japan. E-mail: kyasuda{at}radi.med.hokudai.ac.jp
Received February 5, 2008; accepted May 26, 2008
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Abstract |
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Objective: The current study was conducted to evaluate the effects of low-dose craniospinal irradiation (CSI) combined with chemotherapy on non-metastatic embryonal tumors in the central nervous system (CNS), including medulloblastoma and supra-tentorial primitive neuroectodermal tumors (ST-PNET).
Methods: All patients were treated according to the following protocol. After surgery, the patients 
5 years old received 18 Gy and the patients >5 years old received 24 Gy CSI. The dose to the primary tumor bed was 39.6–54 Gy. Chemotherapy consisted of ifosfamide, cisplatin and etoposide (ICE chemotherapy).
Results: Sixteen patients aged 0.5–20.4 (median 6.1) years were enrolled and followed for 11–165 (median 112) months. Both 5-year actuarial overall survival (OAS) and progression-free survival (PFS) were 81% (95% confidence interval (CI): 62–100%) for the 16 patients. Both 5-year OAS and PFS were 82% (CI: 59–100%) for the patients with medulloblastoma and 80% (CI: 45–100%) for the patients with ST-PNET. Both 5-year OAS and PFS were 75% for the eight patients 5 years old and 88% for the eight patients >5 years old. Both 5-year OAS and PFS were 100% for six average-risk patients (3 years or older, total resection and posterior fossa) and 70% for 10 poor-risk patients (others). The median total intellectual quotient at the last follow-up was 85 (ranging from 48 to 103) in 12 patients who were followed for 3–145 (median 49) months. Eight patients received hormone replacement therapy.
Conclusion: Low-dose CSI and ICE chemotherapy may have a role as a treatment option for a subset of patients with non-metastatic embryonal tumors in the CNS.
Key Words: medulloblastoma • primitive neuroectodermal tumor • chemotherapy • radiotherapy • late effect
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INTRODUCTION |
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TOPAbstractINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONFundingReferences |
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The standard therapy for medulloblastoma has been 35–36 Gy craniospinal irradiation (CSI) and 54–55.8 Gy to the tumor bed after surgical resection (1). A recent randomized trial has shown that a combination of pre-radiotherapy intensive chemotherapy and 35 Gy CSI was significantly better in outcome than 35 Gy CSI alone for non-metastatic medulloblastoma in terms of event-free survival and possibly overall survival (OAS) (2). However, since CSI has produced neuro-cognitive dysfunction and endocrine deficiency in young children and infants (3), dose reduction in CSI with or without chemotherapy has been tested. A total of 25 Gy of CSI was associated with the poorer outcomes in multi-institutional phase III trials with or without chemotherapy (4,5). Subset analysis, however, showed that for patients treated with radiotherapy alone, event-free survival at 5 years was identical between 25 and 35 Gy CSI (4). Pilot studies and a multi-institutional phase II study suggested that 23.4–30 Gy CSI with pre- or post-radiation chemotherapy could achieve similar results with standard-dose CSI for average-risk medulloblastoma (6–8). Important questions remain with respect to the radiotherapy dose in CSI for medulloblastoma. To reduce the incidence of the late adverse effects of CSI, we performed a prospective protocol study using reduced-dose CSI sandwiched between chemotherapy that consisted of an ifosfamide, cisplatin and etoposide (ICE) regimen.
Patients with supra-tentorial primitive neuroectodermal tumors (ST-PNET) have clinical features different from those with medulloblastoma (9–12). However, these two diseases were categorized as the embryonal tumors in the WHO classification of brain tumor (9). Because of the similarity in pathological features, these two diseases have been often treated similarly (13,14). We have also determined the treatment strategy for ST-PNET to be similar to that of medulloblastoma with regard to maximal surgical resection, intensive chemotherapy and radiotherapy. Patients with ST-PNET were also entered and evaluated in this study.
In this study, we have evaluated long-term outcome, both in survival and adverse effect of patients with non-metastatic medulloblastoma and ST-PNET, or embryonal tumors in the central nervous system (CNS).
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MATERIALS AND METHODS |
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Selection Criteria
Entry criteria for patients were as follows: the age between 6 months and 30 years, and with histologically proven medulloblastoma or ST-PNET. The patients or guardians had to give informed consent prior to surgery and again prior to adjuvant therapy.
Treatment
The flow chart of the treatment strategy is shown in Fig. 1.
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Total surgical resections were attempted in patients with medulloblastoma who had Chang's Stage T1, T2 or T3a without evidence of metastasis (Stage M0) (15). Brainstem origin tumors were biopsied or partially removed. Patients with ST-PNET without evidence of metastasis were also treated at first with maximum surgical resection. Ventriculostomy, but not venticuloperitoneal shunting, was performed at tumor removal in patients with hydrocephalus.
Patients with either medulloblastoma or ST-PNET received ICE chemotherapy and CSI with a generous local boost to the tumor site (16). The ICE regimen consisted of three agents; ifosfamide at 900 mg/m2 (Days 1–5), cisplatin at 20 mg/m2 (Days 1–5) and etoposide at 60 mg/m2 (Days 1–5) every 4 weeks. To prevent hemorrhagic cystitis and to suppress emesis, sodium 2-mercaptoethane sulfonate (810 mg/m2/day) and granisetron hydrochloride (40 or 80 mg/kg/day), a 5-hydroxy-tryptamine receptor antagonist, were intravenously administered from Day 1 to 5. Hydration, including the infusion of mannitol, was done routinely.
In principle, the ICE chemotherapy regimen should have begun within 2 weeks of the surgery. The intent was for the ICE chemotherapy regimen to begin within 2 weeks of the surgery, but this did not always occur, as the timing of the chemotherapy and radiotherapy varied. Patients <2.5 years old received eight cycles of chemotherapy every 4 weeks and then received 18 Gy CSI and a local boost of 30–36 Gy when they became 2.5 years old. For patients between 2.5 and 5 years old, one course of ICE followed by 18 Gy CSI and a local boost of 30–36 Gy were scheduled. For patients <5 years old, one course of ICE followed by 24 Gy CSI and a local boost of 30 Gy were scheduled. Thus, the irradiation dose to the hypophysis and hypothalamus was 18 Gy for patients 5 years old or younger and 24 Gy (20–30) for patients >5 years in medulloblastoma. For patients with ST-PNET, the dose to the hypophysis and hypothalamus was distributed from 18 to 38 Gy.
After the radiotherapy, up to six cycles of ICE was administered to the patients 2.5 years old or older. The intent was for patients to receive CSI immediately followed by the local tumor boost, but if myelosuppression had been prolonged by the ICE before radiotherapy, they received local irradiation first, followed by CSI.
Whole-brain irradiation was performed using nearly parallel-opposed lateral fields with multi-leaf collimators to block the lenses of both eyes and including all cerebrospinal fluid space. Whole-spinal irradiation was performed using posterior single or two serially arranged posterior fields including all cerebro-spinal fluid space leaving the patient in the same position on the table. Dose distribution was calculated using a three-dimensional radiotherapy planning system. The radiotherapy dose was prescribed at the center of the midline for the whole brain and at the mean depth of the spinal canal. The boost to the posterior fossa in medulloblastoma and to the tumor bed in ST-PNET was performed using two angled and wedged fields to reduce the dose to the ear structures, temporal and posterior lobes for medulloblastoma. In patients treated in the latter half of the study period, three or more non-coplanar fields were used to reduce unnecessary dose to the surrounding structures. Daily fractions of 1.8–2.0 Gy were used at the isocenter.
Toxicity-related Dose Adjustment for the ICE Regimen
All patients underwent urological and audiological examination and renal monitoring before each cycle of chemotherapy. The chemotherapy doses were modified if there was any evidence of hematological, renal or audiological toxicity according to the dose-reduction criteria (16). If the creatinine clearance was <70%, cisplatin was omitted for that cycle and only given thereafter if renal or hearing function improved. Routine urological examination was performed from Day 1 to 5 in each cycle. Ifosfamide was omitted if macrohematuria was observed and was begun again when microscopic hematuria disappeared. Etoposide and ifosfamide were reduced according to the myelosuppression score consisting of the blood count nadir and symptoms related to the previous course of ICE (16). The score was cumulative overall courses. When using this method, the next cycle would be omitted if the score was higher than anticipated for a long time without recovery.
Follow-up
Patients were followed-up by regular clinical examination. The follow-up intervals after the end of the treatment were every month in the first year, every 3 months in the second year, every 4 months in the third year and subsequently every 6 months. Repeat cranial MRIs with or without spinal MRI were performed every 3 months in the first year and every 6 months in the second to fifth years. After that, the follow-up was performed annually at our institution or at local hospitals.
Statistical Methods
The final analysis was performed in March 2007. OAS and PFS were analyzed. OAS was calculated as the time from the date of surgical diagnosis to the date of death. Patients still alive were censored at date last seen. Subjects with average risk included children >3 years of age with posterior fossas and those with tumors that were totally or ‘nearly totally’ (1.5 cc of residual disease) resected. Subjects with poor risk included children <3 years of age and/or those with subtotal resection ((1.5 cc's residual disease) and/or a non-posterior fossa location, including supra-tentorial location (10,11,12,17,18).
PFS was calculated as the time from the date of surgery to the date of recurrence or death. In those cases where death followed recurrence, the date of recurrence was used. Kaplan–Meier survival curves were produced, and log-rank tests were performed to compare OAS. Greenwood's formula was used to calculate the standard errors, which were then used to calculate the CI. The t-test was used to compare the interval between surgery and radiotherapy between groups.
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RESULTS |
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Sixteen patients aged 0.5–20.4 (median 6.1) years were enrolled and followed for 11–165 months with a median of 112 months. The characteristics of the patients are listed in Table 1. In total, both the 5-year actuarial OAS and PFS were 81% (95% confidence interval, CI: 62–100%) for the 16 patients (Fig. 2). Both 5-year OAS and PFS were 82% (CI: 59–100%) for patients with medulloblastoma and 80% (CI: 45–100%) for patients with ST-PNET. The 5-year OAS and PFS were both 100% (CI: 100–100%) for the six average-risk patients and 70% (CI: 42–98%) for the 10 high-risk patients (Fig. 3). There was no statistical difference between the two groups (OAS: P = 0.35; PFS: P = 0.26). OAS and PFS were 81% (CI: 62–100%) and 68% (CI: 44–99), respectively, at 7 years, and were 74% (CI: 53–96%) and 68% (CI: 44–99%), respectively, at 9 years.
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All eight patients
5 years of age received 18 Gy CSI. One of these eight patients (No. 10) experienced dissemination of the disease at 11 months after surgery and died at 16 months after surgery. Another patient (No. 11) who underwent a biopsy followed by three courses of chemotherapy and radiotherapy died at 11 months after biopsy without disappearance of the disease. The other six patients are alive at 117–months after surgery without evidence of disease. The 5-year OAS and PFS for the eight patients were both 75% (CI: 45–100%).
In the eight patients >5 years old, 24 Gy CSI was given to six patients. The CSI was stopped at 20 Gy due to severe myelosuppression in one patient (No. 4), and an additional 6 Gy (i.e. 30 Gy CSI) was given to another patient (No. 7) because of a strong fear that surgery would disseminate the disease. The 5-year OAS and PFS for the eight patients were both 88% (CI: 65–100%). Local relapse was observed in two patients, and dissemination disease was observed in one patient. All patients received 24 Gy CSI. One of them was rescued by high-dose chemotherapy with stem cell transplantation and lived for 44 months after the diagnosis of relapse. There was no statistical difference between patients 5 years and patients >5 years of age (OAS: P = 0.51; PFS: P = 0.69).
The total amounts of chemotherapeutic agents are listed in Table 2. Because we used reduction criteria for each agent in each cycle of the treatment, the total amount of chemotherapeutic agent varied. Two patients experienced relapse of the local tumor during chemotherapy, and the treatment was stopped after three courses. The regimen of chemotherapy was changed in one patient after relapse, and a salvage operation was performed in another patient for the relapsed tumor.
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Total intellectual quotient (IQ) was measured in 12 patients with the follow-up period ranging from 3 to 145 months with a median of 49 months (Fig. 4, Table 1). The median total IQ at the last follow-up was 85 (ranging from 48 to 103). In nine patients who were able to undergo the examination for verbal IQ (VIQ) and performance IQ (PIQ), there was no apparent discrepancy between VIQ (median 82, 95%CI: 48–119%) and PIQ (92, 58–113%) (P = 0.75). In eight patients whose total IQ was measured more than twice during the follow-up (median follow-up 78, 19–145%), two patients, whose latest IQ scores were 74 and 86, respectively, showed apparent deterioration in total IQ of >10 points (–24 and –17 points).
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Eight patients received hormone replacement therapy because of deficiencies in thyroid hormone, corticosteroid hormone, growth hormone, antidiuretic hormone or gonadotropin (seven, two, two, one and one patients, respectively). Irradiated dose to the hypophysis and hypothalamus of the eight patients were 18–32 Gy (median 22 Gy). Two of the eight patients had ST-PNET.
No patients suffered from symptomatic hearing deficiency or required hearing aids. One patient experienced hemangioma in the skull in the irradiated region 4.4 years at the region which received 18 Gy and underwent surgical removal of the tumor.
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DISCUSSION |
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TOPAbstractINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONFundingReferences |
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For medulloblastoma, the results of a multi-institutional study confirmed that low-dose CSI cannot be justified with or without chemotherapy (4,5). However, the possibility of serious late complications related to radiotherapy after standard-dose CSI suggests that we should investigate better treatment options with less morbidity. Packer et al. (6) have shown that reduced-dose craniospinal radiation therapy (23.4 Gy) followed by adjuvant chemotherapy of lomustine 75 mg/m2, vincristine 1.5 mg/m2 and cisplatin 75 mg/m2 for average-risk patients can achieve PFS of 79 ± 7% at 5 years for average-risk medulloblastoma. Recently, Packer et al. have conducted a phase III trial for average-risk patients in which they compared the adjuvant chemotherapy described above with a therapy in which cyclophosphamide was substituted for lomustine with the same low-dose craniospinal radiation therapy (23.4 Gy). They found that either choice of chemotherapy resulted in similar event-free survival rates: 82 ± 2.8% for chemotherapy with lomustine and 80% ± 3.1% for that with cyclophosphamide (19). Gajjar et al. (20) performed a prospective study of risk-adapted radiotherapy followed by chemotherapy in children with average-risk and high-risk medulloblastoma. In their analysis, 5-year event-free survival was 83% (73–93%) for the average-risk group, which received 23.4 Gy craniospinal radiotherapy, and 70% (55–85%) for the high-risk group, which received a conventional dose of 36–39.6Gy. They compared decreases in IQ and found that the difference between the low-dose craniospinal radiotherapy group and the conventional dose group was not statistically significant (P = 0.097) (21). The present study was consistent with their studies, showing similar survival rates and a moderate decrease in IQ. The reduced-dose CSI and chemotherapy may be as effective as standard CSI in terms of tumor control and neuro-cognitive function in long-term follow-up.
The combination of 18 Gy CSI and chemotherapy has been tested in 10 patients in a previous clinical trial, and seven of the 10 patients survived >5 years (22). Six out of eight patients 5 years old received 18 Gy CSI and survived >9 years in the present study. If we combine our results involving eight patients with these 10 patients in the literature, 13/18 survived longer than 5 years. The 5-year survival rate is not inferior to the previous results obtained with a higher CSI dose. However, Jakacki et al. (23) have reported that the administration of 1800 cGy CSI with chemotherapy to seven patients aged from 20 to 64 months was not advisable because of the high recurrence rate. Again, the number of patients was too small to exclude the possibility of a bias.
The superiority of low-dose CSI to conventional CSI for the purpose of reducing the late adverse effects remains a subject of debate (24,25). A full-scale IQ <80 was reported to be observed even in children with brain tumors who received irradiation only at the posterior fossa (26). Oyharcabal-Bourden et al. (27) have shown that the median total IQ in the follow-up was reported to be 83, and hormone replacement therapy was required in 41.9% of the patients who received adjuvant chemotherapy followed by 25 Gy craniospinal radiation therapy. Our results, which included a median total IQ of 85 and a requirement of hormone replacement therapy in 50% of the patients, were highly consistent with their study.
Treatment outcome of patients with ST-PNET has been reported to be poorer than that of those with medulloblastoma (10–11), and thus patients with ST-PNET are now treated with intensive chemotherapy in clinical trials (12). Because of the cerebral location of ST-PNET, the neuro-cognitive function is usually much poorer in these patients than in those with medulloblastoma. Our series is too small to be compared with the previous larger series, but the treatment outcome was comparable to other poor-risk patients with medulloblastoma. Careful evaluation of the long-term outcome of recent high-dose chemotherapy studies with low-dose radiotherapy for ST-PNET are warranted.
It has recently been suggested that three-dimensional conformal radiotherapy is useful for reducing the dose to the ear structures (28). Intensity-modulated radiotherapy (IMRT) was reported to reduce the dose more, but we must be careful about inducing secondary cancer due to increased whole-body irradiation by IMRT (29). The fact that one patient developed radiation-induced hemangioma in our study showed the importance of reducing unnecessary irradiation in children.
Remarkable advances in molecular biology have led us to routinely use molecular markers to select patients who would be cured with low-dose CSI and those who would respond to chemotherapy. Promeroy et al. have reported that micro-array analysis may be effective for dividing patients with medulloblastoma into favorable and unfavorable groups (30). Gajjar et al. (31) have found a possible relationship between the expression of erbB2 and PFS. Rutkowski et al. (32) have shown that the definitions of favorable and unfavorable risk groups can be improved by the determination of c-myc and trkC mRNA expression. A combined clinical and molecular staging system may well be the breakthrough to accurately predicting disease risk for patients with embryonal tumors in CNS.
The greatest shortcoming of this paper is the small number of patients. Also, combining patients with medulloblastoma and ST-PNET makes it difficult to compare our study with the previous literatures. However, the long-term follow-up of the patients in a single institution has added some potentially important findings. Our experience can be added as supplemental data suggesting a possible role for reduced-dose CSI and chemotherapy in patients with non-metastatic medulloblastoma and ST-PNET.
In conclusion, the combination of surgical resection, ICE chemotherapy and low-dose CSI may have a role in the treatment of a subset of patients with embryonal tumors in the CNS. The possibility of reducing the risk of late neuro-cognitive damage through reduction of the CSI dose is to be further evaluated.
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Funding |
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Supported by a grain-in-aid from the Japanese Ministry of Education, Culture, Sports, Science, and Technology.
Conflict of interest statement
None declared.
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Footnotes |
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Presented in part at the 49th annual meeting of the American Society of Therapeutic Radiology and Oncology in October 2007.
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References |
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