Treatment Outcome of Radiation Therapy for Intracranial Germinoma: Adaptive Radiation Field in Relation to Response to Chemotherapy

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1 Treatment Outcome of Radiation Therapy for Intracranial Germinoma: Adaptive Radiation Field in Relation to Response to Chemotherapy JI HYEON JOO 1, JIN-HONG PARK 1, YOUNG-SHIN RA 2, HO JOON IM 3, KYUNG NAM KOH 3, SHIN KWANG KHANG 4 and SEUNG DO AHN 1 Departments of 1 Radiation Oncology, 2 Neurosurgery, 3 Pediatrics and 4 Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea Abstract. Aim: To determine the optimal radiotherapy (RT) target volume in correlation with tumor response to chemotherapy in patients with intracranial germinoma. Patients and Methods: Seventy-two patients received chemotherapy followed by RT. The RT field was tailored to chemotherapy response. Results: Five-year recurrence-free survival (RFS) was 87% and overall survival was 97%. RT field was significantly associated with RFS, with 5-year RFS rates of 95%, 91%, and 62% in those who received craniospinal irradiation, whole-brain/whole-ventricle RT, and focal RT, respectively (p=0.01). In the complete-response group after chemotherapy, 5-year RFS rates were 100% after whole-brain RT/whole-ventricle RT and 70% after focal RT (p=0.04). In the partial-response group, 5-year RFS rates after craniospinal irradiation, whole-brain RT, and focal RT were 100%, 85%, and 33%, respectively (p<0.01). Conclusion: Regardless of response, those treated with focal RT had an excessively high relapse rate. Whole-brain/wholeventricle RT could be applied to patients who show a complete response to chemotherapy, but the optimal strategy for patients with partial response needs further investigation. Intracranial germinoma is a radiosensitive tumor with a cure rate of more than 90% in patients treated with radiotherapy (RT)-alone using craniospinal irradiation (CSI) (1-3). However, the complications associated with CSI have raised concerns, particularly in younger patients. These include growth disturbances, endocrine dysfunction, and cognitive impairment (4, 5). This has led to the combination of systemic Correspondence to: Jin-hong Park, MD, Ph.D., Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro-43-gil, Songpa-gu, Seoul , Republic of Korea. Tel: , Fax: , jpark@amc.seoul.kr Key Words: Intracranial germinoma, radiotherapy, chemotherapy. chemotherapy and RT with a reduced target volume and low dose. Using platinum-based chemotherapy, the omission of spinal irradiation seems not to jeopardize disease control (6-8). However, the optimal RT field and dose in this approach remain to be determined. The effects of combination treatment with focal RT and chemotherapy were analyzed in two large prospective trials. In a study conducted by the French Society of Pediatric Oncology (SFOP TGM-TC-90), relapses occurred predominantly in the periventricular subependymal area in eight of the 10 patients with relapse and the authors proposed ventricular field radiation as a logical alternative (9). In 1996, the International Society of Pediatric Oncology (SIOP CNS GCT 96) initiated a trial comparing low-dose CSI and chemotherapy followed by local RT. The results showed no differences in overall survival (OS) or event-free survival between the two treatment arms, but 5- year progression-free survival rates were lower among patients treated with local RT (97% vs. 88%, p=0.04). Six out of seven patients with relapse showed ventricular recurrences. Although the two treatment regimens showed comparable results in the treatment of localized germinoma, the authors suggested the inclusion of ventricles in the radiation field (10). However, a reduced field RT using whole-ventricle RT (WVRT) or whole-brain RT (WBRT) has been analyzed only in small retrospective series (11, 12). We report our Institutional experience treating 72 intracranial germinomas by combined chemoradiation therapy (CRT) to determine the optimal RT target volume. The aim of the present study was to suggest future directions in the treatment of germinoma with special emphasis on the definition of the RT field in relation to the response to chemotherapy by investigating long-term recurrence patterns. Patients and Methods Patients. The medical records of all patients diagnosed with germinoma and treated with combined CRT at our institution between 1996 and 2010 were retrospectively reviewed. This study /2014 $

2 Table I. Characteristics of patients. Characteristic No. (%) Median age, years (range) 16 (7-35) Gender Male 62 (86) Female 10 (14) Tumor location Pineal gland 34 (47) Suprasellar 25 (35) Basal ganglia 5 (7) Multifocal 6 (8) Other 2 (3) CSF seeding Positive 14 (19) Negative 58 (81) Serum β-hcg (IU/dl) <50 71 (99) 50 1 (1) Chemotherapy agent Etoposide/cisplatin 55 (76) Etoposide/carboplatin/ cyclophosphamide 5 (7) Other 12 (17) CSF, Cerebrospinal fluid; β-hcg, beta-human chorionic gonadotropin. Table II. Summary of radiotherapy (RT) doses according to response to chemotherapy. RT dose (Gy) No. of patients Spinal dose Brain Tumor CR after CT CSI WBRT/WVRT Focal RT PR after CT CSI WBRT/WVRT Focal RT SD after CT CSI CT, Chemotherapy; CR, complete response; CSI, craniospinal irradiation; PR, partial response; SD, stable disease; WBRT, whole-brain RT; WVRT, whole-ventricle RT. was approved by the Asan Medical Center Institutional Review Board (IRB number: ). Patients with intracranial germinoma that was pathologically proven or diagnosed by established clinical criteria were included in the analysis. The clinical diagnosis was based on computed tomography (CT) or magnetic resonance imaging (MRI) findings and the levels of serum tumor markers. The initial evaluation included a clinical examination, cranial and spinal MRI, complete blood cell count and chemistries, assessment of serum and cerebrospinal fluid (CSF) tumor markers, and cytological examination of the CSF. β-human chorionic gonadotropin (β-hcg) and α-fetoprotein (AFP) levels in the serum and CSF were measured. Patients with β-hcg concentration of 50 IU/dl or more in the serum and CSF at diagnosis or AFP concentration in the serum of >10 ng/ml or >2 ng/ml in the CSF were excluded from the analysis. Only one patient with mild elevation of β-hcg (89.8 IU/dl) was exceptionally included because histological and other clinical data including AFP and MRI findings supported the diagnosis. A total of 72 patients were included in the analysis. The characteristics of the patients are summarized in Table I. The median age of the patients was 16 years (range=7-35 years). Seventy-five percent of the patients were under the age of 20 years. Sixty-six patients had a solitary lesion and six patients had multifocal tumors. Among the patients with solitary lesions, the majority of primary tumors (59/72) were located in the pineal gland and suprasellar area. Five out of six patients with multifocal lesions had tumors in the pineal gland and suprasellar area. Eleven patients were diagnosed using clinical criteria and 61 using pathology results. Spinal MRI was performed in 64 cases and CSF cytology in 47 patients. Fourteen patients had CSF seeding on presentation. Treatment. A vacuum immobilization device was used for all patients. The target volumes were determined based on prechemotherapy tumor volumes. For CSI, the whole brain and spinal canal were irradiated. For focal RT, the target volume was defined as the anatomic tumor-bearing area based on the MRI scans obtained before biopsy. For RT planning, a 1-2 cm margin was added. The fraction sizes were Gy. A three-dimensional planning system was used for treatment planning. RT was delivered with 6 or 10 MV photon beams. The RT field varied according to the tumor response. In patients with complete response (CR), the WBRT/WVRT dose was Gy and the total dose to the tumor was Gy. In patients treated exclusively with focal RT, the total dose was 30.6 Gy. None of the patients with CR received CSI, with the exception of patients with initial multifocal disease or CSF seeding. Patients with partial response (PR) received CSI doses ranging from 19.5 to 30.6 Gy, or WBRT/WVRT at Gy, and the total tumor dose was Gy. In this group, three patients received focal RT at Gy. One patient with stable disease (SD) after chemotherapy received 24 Gy CSI followed by 16.2 Gy boost RT. RT doses according to the response to chemotherapy are summarized in Table II. Chemotherapy consisted of two cycles of cisplatin and etoposide in 56 patients (76%). Four patients (9%) received carboplatin, etoposide, and cyclophosphamide. In 12 patients, regimens were based on etoposide with various combinations of cisplatin, carboplatin, cyclophosphamide, bleomycin, and vincristine. Response to chemotherapy was assessed two to four weeks after treatment completion. Statistical methods. Because WVRT was used in only two patients, these patients were included in the WBRT group for statistical analysis. Survival rates were analyzed using the Kaplan Meier method. OS was calculated from the start of treatment to the date of last follow-up or death. The survival distribution was compared between the two groups using the log-rank test. The univariate prognostic factor analysis included the following variables: age ( 20 years vs. >20 years), gender, primary tumor site, multifocality, CSF seeding at diagnosis, response to chemotherapy, and RT field. All statistical analyses were performed using SPSS ver. 21 software (IBM, Armonk, NY, USA). 5716

3 Joo et al: Radiotherapy Field in Intracranial Germinoma Figure 1. Relapse-free survival (RFS) of total patients. The type of radiotherapy (RT) field was significantly associated with RFS, with 5-year rates of 95%, 91%, and 62% for those treated with craniospinal irradiation (CSI), whole-brain radiotherapy (WBRT), and focal RT (p=0.01). Figure 2. Relapse-free survival (RFS) of patients who showed complete response to chemotherapy. Five-year RFS was 83%, 100% and 70% for those treated with craniospinal irradiation (CSI), whole-brain radiotherapy (WBRT), and focal RT (p=0.17). Results Survival. The median follow-up time was 87 months (range=7-197 months). The 5-year OS and relapse-free survival (RFS) rates were 97% and 87%, respectively. The 10-year OS and RFS rates were 87% and 78%, respectively. Thirteen out of 72 patients experienced relapse. The characteristics of patients with relapse and those without did not differ with regard to gender distribution, age, tumor location, and CSF seeding. The median time-to-relapse was 45 months (range=6-137 months). The type of RT field was significantly associated with RFS, with 5-year RFS rates of 95%, 91%, and 62% in patients treated with CSI, WBRT/WVRT, and focal RT, respectively (p=0.01, Figure 1). The difference in RFS between the WBRT/WVRT and focal RT groups was statistically significant (p=0.02), whereas that between the CSI and WBRT/WVRT groups was not (p=0.33). OS was not significantly different according to RT field, with 5-year OS rates of 100%, 100%, and 83% in patients treated with CSI, WBRT/WVRT, and focal RT, respectively (p=0.49). The RFS of the CR group after chemotherapy is shown in Figure 2 (p=0.17). For patients who showed CR after induction chemotherapy, the CSI group and WBRT/WVRT group had similar RFS rates: 5-year RFS was 83% after CSI and 100% after WBRT/WVRT (p=0.35). However, there was a significant difference in RFS between patients treated with WBRT/WVRT and patients with focal RT: 5-year RFS was 70% after focal RT (p=0.04). The RFS of the PR group after chemotherapy is shown in Figure 3. RFS was significantly associated with type of RT field (p<0.01). For patients who showed PR after chemotherapy, the RFS difference between the CSI and WBRT/WVRT groups was not significant: 5-year RFS was 100% after CSI and 85% after WBRT/WVRT (p=0.08). The focal RT group had a 5-year RFS of 33%, which was significantly lower than that of the CSI group (p<0.01) and of the WBRT/WVRT group (p<0.01). In multivariate analysis, the RT field (hazard ratio=2.09, 95% confidence interval= , p=0.01) was the only prognostic factor for RFS. No patient- or treatment-related factors were significantly associated with OS. Overall, 13 patients experienced disease relapse. Salvage treatment consisted of chemotherapy followed by RT in five patients. Out of these, four patients showed no recurrence during a period of months and one patient showed CR after treatment and is currently under observation. Three were treated with salvage chemotherapy alone. Out of these, two patients had second relapses and were treated with CSI and WBRT, respectively. One patient was successfully salvaged with chemotherapy alone. Salvage RT alone was performed in one patient, and he has been under observation 5717

4 Table III. Number of patients with relapse according to the response to chemotherapy and the field of radiotherapy (RT). No. of patients with relapses/ Total no. of patients (%) Response to chemotherapy RT field CSI WBRT/WVRT Focal RT CR (n=31) 1/6 (17) 1/15 (6) 3/10 (30) PR (n=40) 0/15 (0) 6/22 (27) 2/3 (67) SD (n=1) 0/1 (0) CR, Complete response; CSI, craniospinal irradiation; PR, partial response; SD, stable disease; WBRT, whole-brain RT; WVRT, wholeventricle RT. Figure 3. Relapse-free survival (RFS) of patients who showed partial response to chemotherapy. The type of RT field was significantly associated with RFS, with 5-year rates of 100%, 85%, and 33% for those treated with craniospinal irradiation (CSI), whole-brain radiotherapy (WBRT), and focal RT (p<0.01). for 30 months without recurrence. One patient was treated with chemotherapy and gamma-knife radiosurgery, and died after a second relapse. One refused salvage treatment, and two were lost to follow-up before salvage treatment. Radiation field and patterns of relapse. Table III shows the number of relapses by RT field according to response to chemotherapy. The characteristics, initial treatment and relapse sites of 13 patients are summarized in Table IV. Among the 31 patients who showed CR to chemotherapy, five experienced relapse. Among patients treated with CSI, WBRT, and focal RT, 17% (1/6), 6% (1/15), and 30% (3/10) experienced relapse. The patient whose disease relapsed after CSI had CSF seeding at diagnosis and relapse in multiple intracranial and spinal areas six months after treatment. One patient who received WBRT experienced relapse in the cerebral cortex. Among the patients who received focal RT, two had relapses in the periventricular area and one in the primary site. Of the 40 patients who showed PR to chemotherapy, eight experienced relapse. Among patients treated with CSI, WBRT, and focal RT, 0% (0/15), 27% (6/22), and 67% (2/3), respectively, experienced relapse. Among these patients, in the WBRT group, six had leptomeningeal relapses, of which three showed isolated spinal seeding, two had both intracranial and spinal seeding and one had ventricular relapse. Of the two patients with relapse in the focal RT group with PR to upfront chemotherapy, one had ventricular seeding and the other patient had failure at the primary site. Discussion Traditionally, CSI is considered the gold-standard in the treatment of patients with intracranial germinoma (13, 14). As the recommended radiation doses are greater than 50 Gy (15), concerns over complications in the pediatric population have been raised. These complications include potential neurocognitive deficits such as pituitary dysfunction, and secondary malignancies. However, most of these concerns were based on the treatment results of non-germinomatous germ cell tumors (NGGCT) and medulloblastomas, which require high doses of radiation (16). After the introduction of platinum-based induction chemotherapy, attempts were made to reduce RT dose and volumes (11, 17). Induction chemotherapy can reduce the size of primary tumors. Therefore, restricting the RT field can reduce the incidence of side-effects. Furthermore, chemotherapy has the ability to control microscopic disease developing in the leptomeningeal space, resulting in a reduction in the elective RT area (11). Currently, two to four cycles of etoposide and cisplatin are widely used as induction chemotherapy, and CR rates of % have been reported (17, 18). For localized pure germinoma cases with CR to induction chemotherapy, limited-field RT of up to Gy and omission of spinal RT are generally used. For metastatic cases, RT doses of 24 Gy to the spinal area and 40 Gy to the tumor are recommended (7, 10, 11, 17). Recent studies showed that the current dose protocol does not contribute to growth retardation nor does it aggravate pituitary dysfunction (19). Further efforts to reduce the RT field to include only the primary tumor area have been made. In a phase II trial conducted in the United States, 17 germ cell tumor patients 5718

5 Joo et al: Radiotherapy Field in Intracranial Germinoma Table IV. Characteristics, initial treatment, and sites of relapse in patients with relapse. Patient no. Tumor Treatment Response to RT Relapse-free survival Site of location chemotherapy time (months) recurrence 27 S+PG CRT PR WB 28 Leptomeningeal (spinal) 28 S CRT CR Focal 47 Periventricular (pontine) 33 PG CRT PR WB 82 Primary site+leptomeningeal (spinal) 45 PG CRT CR WB 137 Cerebral cortex 51 PG, CSF CRT PR WB 97 Leptomeningeal (spinal) 52 S CRT CR Focal 45 Primary site 60 S, CSF CRT CR CSI 6 Periventricular + leptomeningeal 62 S CRT PR WB 44 Leptomeningeal (ventricle) 72 PG CRT PR Focal 17 Leptomeningeal (ventricle) 73 PG CRT PR WB 57 Leptomeningeal (spinal) 76 S CRT PR Focal 12 Primary site 83 S+PG CRT PR WB 86 Multiple brain + leptomeningeal (spinal) 84 PG CRT CR Focal 42 Periventricular RT, Radiotherapy; S, suprasellar area; PG, pineal gland; CR, complete response; CRT, chemoradiotherapy; CSF, cerebrospinal fluid; CSI, craniospinal irradiation; PR, partial response; WB, whole-brain. were treated with induction chemotherapy with four cycles of etoposide-plus-cisplatin, followed by RT. Patients with localized germinoma were treated with local field RT with dose stratification according to response (30.6 Gy or 54.0 Gy). All but one patient remained free of disease for 51 months (20). These data are supported by a Japanese study that analyzed 33 patients with germ cell tumor with 16 with pure germinomas who were treated with a combined regimen. For the treatment of germinoma, chemotherapy with etoposide plus cisplatin was followed by 24 Gy local field RT. During the 5-year follow-up, only one patient relapsed among the 16 germinomas (17). Although these data suggested the possibility of limiting the RT target volume and lowering the RT dose after chemotherapy without compromising disease control, two large prospective trials initiated in Europe in the 1990s showed high relapse rates with use of focal RT. In these trials, periventricular relapse was the major pattern of failure (9, 10). In the present study, 10 patients with CR after chemotherapy were treated with focal RT of up to 30 Gy, and three of them experienced relapse. The recurrent sites were the primary tumor area (n=1) or periventricular area (n=2). They all had localized tumors, and the RT target volume coverage was adequate according to the treatment plan. In the PR group, two out of three patients treated with focal RT developed recurrences. The excessive risk and the relapse pattern after focal RT shown in our study are in agreement with those reported in prospective trials. Furthermore, our results support the association between focal RT and high relapse rates even when localized germinoma showed CR to induction chemotherapy. The current study showed that the recurrence pattern differed according to the chemotherapy response. The overall relapse rates were 6% in the CR-WBRT/WVRT group and 27% in the PR-WBRT/WVRT group. Leptomeningeal seeding at the spinal level was the main pattern of recurrence in these patients. Among the seven patients with recurrence, five had spinal seeding at the time of relapse, including spinal failure only in three patients, and all these patients with spinal seeding showed PR to induction chemotherapy. However, the 23 patients who showed CR to induction chemotherapy did not receive spinal RT and none developed spinal failure. The reason for the high relapse rate in the PR group is not clear, but these patients may have a nongerminomatous component that explained the high rate of leptomeningeal relapses when CSI was omitted (21). Some studies reported a correlation with poor response to chemotherapy and the presence of non-germinoma in patients with intracranial germinoma. In a study by Saito et al., 34 germinoma-like tumor patients received induction chemotherapy and four had minimal response. The final diagnoses of those tumors after surgery were pineoblastoma, glioblastoma, and a mixed germ cell tumor (22). In another report by Kanamori et al., most pineal germ cell tumors were identified by clinical findings only. But in cases with unusual responses, the authors suggested that second-look surgery can be considered (23). In our report, of the 11 clinically diagnosed tumors, seven showed PR after induction chemotherapy. Although no definitive conclusions can be made as second-look surgery was not performed, the presence of a non-germinomatous component cannot be ruled out. Based on these results, we suggest that in patients with localized germinoma who show CR to induction chemotherapy after precise evaluation, spinal RT can be omitted. When the patients with PR after chemotherapy were 5719

6 treated with WBRT/WVRT, the spinal failure rate seemed higher than that of the CSI group. The correlation is not clearly understood from this analysis, because of the small number of patients and the fact that these may have a nongerminomatous component. Spinal axis RT might be considered but we should be very careful to make the conclusion that spinal RT is optimal in patients with PR. When clinically diagnosed germinoma shows PR after induction chemotherapy, distinguishing it from other tumor types is necessary. Non-invasive methods such as minimum apparent diffusion coefficient value and proton magnetic resonance spectroscopy could be helpful to avoid invasive surgical biopsy (22). The high risk of relapse associated with the patients showing PR after chemotherapy is intriguing and needs to be investigated in future prospective studies. Because WVRT was performed in only two patients, a comparison between WBRT and WVRT was difficult. However, the recurrence patterns of focal RT reported by our study and others indicate that the predominant sites of relapse are the ventricle or periventricular areas (7, 10). The natural spread of intracranial germinoma is believed to be laminar, occurring along the subependymal lining of the walls of the third and fourth ventricles, leading to multifocal disease and regional intraventricular relapse before spinal dissemination. The predominant pattern of relapse in localized intracranial germinomas treated by the combined-modality approach is periventricular failure (19). We retrospectively reviewed radiation volumes and all relapsed lesions were to be included in the radiation volume when we attempted to treat the whole ventricle. These findings suggest that WVRT is adequate to treat intracranial localized germinoma. The definition of the ventricular volume should consider the risk of subependymal recurrence in the lower part of the fourth ventricle. Therefore, inclusion of the caudal edge of the fourth ventricle in the RT volume is recommended (9). Moreover, newer RT techniques have been introduced for the treatment of pediatric CNS tumors, especially for WVRT. Intensity-modulated RT provides adequate target coverage while minimizing normal tissue irradiation (24). The mean volume and dose to the cerebral hemispheres and temporal lobes can be reduced significantly with intensity-modulated RT compared to conventional RT planning (25, 26). To achieve further normal tissue sparing, current efforts aim to develop the use of proton therapy in WVRT (27). The present study has several limitations. One of the major limitations was that the RT guidelines varied according to the treatment period and physician s preference. In addition, the chemotherapy regimens used were not uniform. However, compared to previous studies, the present study included a large number of patients and patient characteristics were homogeneous. In conclusion, we treated 72 intracranial germinomas using chemotherapy followed by various RT fields. Analysis of recurrence patterns according to the chemotherapy response indicated that WBRT/WVRT can be the treatment of choice in patients showing CR. The optimal treatment strategy for patients with PR after chemotherapy could not be drawn from this study, and needs further investigation. Regardless of the response, the RT field should include whole ventricles at least. Conflicts of Interest No potential conflicts of interest exist. None of the Authors have any external funding or grants to disclose. References 1 Shirato H, Nishio M, Sawamura Y, Myohjin M, Kitahara T, Nishioka T, Mizutani Y, Abe H and Miyasaka K: Analysis of long-term treatment of intracranial germinoma. 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