Salvage radiation therapy for intracranial germinoma recurring after primary chemotherapy

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1 Journal of Neuro-Oncology 44: , Kluwer Academic Publishers. Printed in the Netherlands. Clinical Study Salvage radiation therapy for intracranial germinoma recurring after primary chemotherapy Yuta Shibamoto 1, Keisuke Sasai 2, Masaki Kokubo 2 and Masahiro Hiraoka 2 1 Department of Oncology, Institute for Frontier Medical Sciences; 2 Department of Radiology, Faculty of Medicine, Kyoto University, Kyoto, Japan Key words: brain neoplasm, germinoma, CNS, recurrence, radiotherapy, chemotherapy Comments This is a well written descriptive article which details the results of salvage irradiation for patients treated with primary chemotherapy for primary CNS germinoma. It appropriately references relevant articles and provides some guidelines which may prove useful to oncologists caring for patients with this unusual, though highly curable malignancy. Combined modality therapy may provide improved quality of life with no compromise of survival. What the ultimate relapse rate is for patients treated with curative intent for primary CNS germinoma is still unknown. Highly effective salvage for patients has now been shown to be possible with reasonable doses of radiotherapy by both Shibamoto et al. and Merchant et al. It would seem reasonable to assume that low-dose radiotherapy may be able to prevent CNS relapse as a post-chemotherapy adjunctive treatment, but the appropriate doses and volumes to treat in such a setting are speculative, and it would thus seem appropriate to reserve irradiation for salvaging CNS failures in patients treated with primary chemotherapy. J. Knisely (Newhaven, CT, USA) Summary Systemic chemotherapy has been increasingly used in the primary treatment of intracranial germinoma. However, the recurrence rate seems to be very high after treatment with chemotherapy alone. We used radiation to treat 5 patients harboring intracranial germinoma that recurred following primary chemotherapy. They had received systemic chemotherapy (4 with cisplatin plus etoposide and 1 with adriamycin, vincristine, cyclophosphamide, prednisolone, and cisplatin) 7 24 months before referral. All patients were treated with conventional radiotherapy directed to the primary tumor site or the craniospinal axis with a dose to the primary site ranging from 39.6 to 47.0 Gy (mean, 42.6 Gy). Response to radiation of all the recurrent tumors was good and all tumors disappeared on diagnostic imaging below the dose of 24 Gy. All patients are alive without further recurrence at months after salvage radiotherapy. Germinomas recurring after primary chemotherapy do not seem to have acquired cross resistance to radiotherapy. They can usually be cured by standard radiation therapy with Gy. Introduction Intracranial germinoma is the most radiosensitive among all primary brain tumors, and until recently it has usually been treated with conventional radiotherapy alone, with resulting overall and relapse-free survival rates at 10 years usually exceeding 90% [1 6]. Radiation doses around 50 Gy have been most frequently used to treat this tumor; 50 Gy is safe in terms of the low incidence of radiation-induced brain necrosis, but endocrine dysfunction, brain atrophy, and intellectual dysfunction may develop at this dose level. To avoid these adverse effects of radiation on normal brain tissue, chemotherapy has been introduced as a treatment for intracranial germinoma. It has been shown that this tumor responds well to systemic chemotherapy, and complete response to chemotherapy is often obtained [7,8].

2 182 Based on these observations, some groups have started clinical studies of the treatment of germinomas with chemotherapy plus reduced dose (24 40 Gy) radiotherapy [9 12], while others have used systemic chemotherapy alone [7,8]. Although the short-term results of the former studies are encouraging, longterm follow-up data are not yet available. On the other hand, it has recently become evident that the latter approach (chemotherapy alone) is associated with an unacceptably high recurrence rate [8]. Despite the high recurrence rate, a minority of investigators seem to be still pursuing the approach of chemotherapy alone. Although many patients treated with chemotherapy alone seem to be still recurrence-free at present, they may develop recurrence in the near future, and management of such patients with recurrence may become an important issue. We have encountered 5 patients with intracranial germinoma recurring after primary chemotherapy. We treated them with radiation therapy using our standard (or only slightly higher) doses [1]. This report describes the results of the treatment. Patients and methods Details of the 5 patients are shown in Table 1. At first presentation, only 1 patient underwent resection of the tumor: this patient underwent subtotal removal of a pineal tumor, while his suprasellar tumor was not resected. Magnetic resonance imaging and computed tomography findings of all the tumors were compatible with those of intracranial germinoma. Since the average diameter of all the tumors at recurrence decreased by more than 80% below the dose of Gy, our criteria for clinical diagnosis of intracranial germinoma [13] were fulfilled. Four of the 5 patients had been treated with 2 or 3 cycles of cisplatin (20 mg/m 2 5 days) and etoposide (60 mg/m 2 5 days). The other patient had received a combination chemotherapy with vincristine, cyclophosphamide, adriamycin, and prednisolone (doses unknown) together with additional cisplatin (20 mg 4). All of the tumors had disappeared following chemotherapy, but they recurred 7 24 months later. Radiation therapy was given to the 5 patients at the time of recurrence using our standard techniques [14]. No patient received surgery at recurrence. Four patients were treated with radiation therapy alone, while 1 patient (the second in Table 1) was given 2 courses of the cisplatin/etoposide chemotherapy after radiation by the attending neurosurgeon at the referring hospital. For the 2 patients with negative cerebrospinal fluid (CSF) cytology and no CSF dissemination, focal radiation was given. Major parts of the ventricular system were included in the focal radiation field. For the 3 patients with disseminated tumors, craniospinal irradiation followed by focal boost was given. The daily dose was 1.7 or 1.8 Gy for the focal irradiation (except for the first patient who received 3 fractions of 1.5 Gy in the beginning of his treatment) and 1.6 or 1.7 Gy for craniospinal irradiation. The total radiation dose was determined according to our protocol of reduceddose irradiation for intracranial germinoma (40 Gy for tumors < 2.5 cm in diameter and 45 Gy for cm tumors) [1], but the first and fourth patients were given 1 or 2 more fractions because we were not certain of the radiosensitivity of recurrent germinoma as compared to primary germinoma. The fifth patient was given 1 additional fraction, because he had a relatively low hemoglobin level (10 11 g/dl). Results The outcomes of the patients are also shown in Table 1. All tumors quickly responded to radiation. The tumors in the second, third, and fourth patients were invisible on magnetic resonance imaging or computed tomography taken at the dose of Gy. The average diameters of the tumors in the first and fifth patients were less than 20% of those before radiotherapy at the doses of 13.0 and 12.6 Gy, respectively, and the tumors disappeared on the next diagnostic imaging, taken at 23.2 and 21.5 Gy, respectively. These responses did not seem to differ from those of primary germinoma. All patients are alive with no evidence of disease at 5 10 years after irradiation for their recurrent tumors. There have been no sequelae of treatment, and they are living normal active lives. Discussion The high chemosensitivity of intracranial germinoma has become well known in recent years. In the International Central Nervous System Germ Cell Tumor Study reported by Balmaceda et al. [8], 82% of 45 germinoma patients treated with 4 cycles of carboplatin, etoposide, and bleomycin achieved complete response. However, 49% of the patients had recurrence within a

3 Table 1. Patients with intracranial germinoma recurring after primary chemotherapy Age/Sex Primary tumor Recurrent tumor Site Size CSF Surgery Chemotherapy Months Site Size CSF Radiation Follow-up (mm) cytology to relapse (mm) cytology field dose (Gy) (months) 18/M S 25 Negative None Cisplatin 80 mg 24 S 23 Negative Focal VEPA 4 15/M P 23 Positive Shunt PE 2 8 P, LV 22 Negative CSA Focal /F P 23 Unknown Shunt PE 3 7 P 11 Negative Focal /M P 38 Positive Shunt PE th V 18 Negative CSA Focal /M P, S 20 Unknown Subtotal PE 3 9 S, LV 26 Negative CSA removal for P 4th V Focal 19.8 S = suprasellar; P = pineal; CSF = cerebrospinal fluid; VEPA = vincristine, cyclophosphamide, prednisolone, adriamycin; PE = cisplatin + etoposide; LV = lateral ventricle; 4th V = fourth ventricle; CSA = cerebrospinal axis. Longest diameter of tumor. 183

4 184 median follow up period of 31 months as of the report in All of the 5 patients in our series had achieved complete response following initial chemotherapy. We do not know the exact number of patients who were treated with chemotherapy alone in the hospitals from which the patients came, but we speculate that our 5 patients reported here would represent more than half of all patients treated with chemotherapy alone in those hospitals during the same periods. Chemotherapy with agents that do not cross the blood brain barrier (BBB), such as cisplatin and etoposide, may be effective against tumor mass where the BBB is disrupted, but it should be ineffective against tumor cells in the CSF. This is supported by the fact that 3 of the 5 patients in our series had CSF dissemination at the time of recurrence. Moreover, the disrupted BBB in the tumor may be restored halfway through the chemotherapy, which should make the subsequent chemotherapy ineffective [15]. Thus, there seems to be a limit to the efficacy of chemotherapy in the treatment of intracranial germinoma. Despite the high incidence of recurrence following chemotherapy alone, currently a considerable number of patients appear to be under observation following complete response to chemotherapy. Therefore, germinomas recurring after primary chemotherapy may continue to be found in the near future. Our experience indicates that the recurrent tumors have no acquired cross resistance to radiation, and that they can be cured with conventional radiotherapy, probably with our standard doses of Gy [1]. Merchant et al. [16] also reported successful treatment of 8 germinomas recurring after primary chemotherapy, although their followup periods (median, 32 months) were much shorter than those in our patients (median, 90 months). Since recurrent germinomas seem to be easily and successfully salvaged by radiation therapy, it may be argued that chemotherapy should be used first, but if the recurrence rate exceeds 50%, such an approach does not seem to be justified. To decrease the high incidence of recurrence following chemotherapy alone, the combination of chemotherapy and reduced dose radiation is now being increasingly investigated. Small studies suggest generally favorable outcomes, but the follow-up periods are relatively short [9,11,12]. Recently, Matsutani [17] reported an interim result of a Japanese multicenter trial in which 3 courses of carboplatin and etoposide were given before focal radiation with 24 Gy. Of the 71 patients with germinoma treated with this protocol, 5 patients developed recurrence within relatively short follow-up periods (median, 25 months). Four of the 5 recurrences occurred outside the radiation field; this fact again suggested the relative ineffectiveness of the chemotherapy for CSF prophylaxis. Considering the relatively short follow-up periods, the recurrence rate may still increase, and this treatment may prove to be inferior to standard radiotherapy in future. Recently, the use of radiosurgery is also being investigated to avoid unnecessary irradiation to normal brain tissue [18]. Thus, the optimal treatment for intracranial germinoma in terms of the best control rate with the least toxicity seems to remain unknown at present. Considering the relatively low incidence of this tumor, it is expected that ongoing and future multicenter cooperative studies will provide us with information about the best treatment for this highly curable disease. Acknowledgements This study was supported in part by the Grant-in-Aid for Scientific Research from the Japanese Ministry of Education, Science and Culture ( ). References 1. Shibamoto Y, Takahashi M, Abe M: Reduction of the radiation dose for intracranial germinoma: a prospective study. Br J Cancer 70: , Huh SJ, Shin KH, Kim IH, Ahn YC, Ha SW, Park CI: Radiotherapy of intracranial germinomas. Radiother Oncol 38: 19 23, Haddock MG, Schild SE, Scheithauer BW, Schomberg PJ: Radiation therapy for histologically confirmed primary central nervous system germinoma. Int J Radiat Oncol Biol Phys 38: , Hardenbergh PH, Golden J, Billet A, Scott RM, Shrieve DC, Silver B, Loeffler JS, Tarbell NJ: Intracranial germinoma: the case for lower dose radiation therapy. Int J Radiat Oncol Biol Phys 39: , Shirato H, Nishio M, Sawamura Y, Myohjin M, Kitahara T, Nishioka T, Mizutani Y, Abe H, Miyasaka K: Analysis of long-term treatment of intracranial germinoma. Int J Radiat Oncol Biol Phys 37: , Aoyama H, Shirato H, Kakuto Y, Inakoshi H, Nishio M, Yoshida H, Hareyama M, Yanagisawa T, Watarai J, Miyasaka K: Pathologically-proven intracranial germinoma treated with radiation therapy. Radiother Oncol 47: , Neuwelt EA, Williams PC, Mickey BE, Frenkel EP, Henner WD: Therapeutic dilemma of disseminated CNS germinoma and the potential of increased platinum-based chemotherapy delivery with osmotic blood brain barrier disruption. Pediatr Neurosurg 21: 16 22, 1994

5 Balmaceda C, Heller G, Rosenblum M, Diez B, Villablanca JG, Kellie S, Maher P, Vlamis V, Walker RW, Leibel S, Finlay JL: Chemotherapy without irradiation a novel approach for newly diagnosed CNS germ cell tumors: results of an international cooperative trial. J Clin Oncol 14: , Allen JC, DaRosso RC, Donahue B, Nirenberg A: A phase II trial of preirradiation carboplatin in newly diagnosed germinoma of the central nervous system. Cancer 74: , Baranzelli MC, Patte C, Bouffet E, Couanet D, Habrand JL, Portas M, Lejars O, Lutz P, Le Gall E, Kalifa C: Nonmetastatic intracranial germinoma. The experience of the French Society of Pediatric Oncology. Cancer 80: , Matsutani M, Ushio Y, Abe H, Yamashita J, Shibui S, Fujimaki T, Takakura K, Nomura K, Tanaka R, Fukui M, Yoshimoto T, Hayakawa T, Nagashima T, Kurisu K, Kayama T, The Japanese Pediatric Brain Tumor Study Group: Combined chemotherapy and radiation therapy for central nervous system germ cell tumors: preliminary results of a phase II study of the Japanese Pediatric Brain Tumor Study Group. Neurosurg Focus 5(1): Article 7, Sawamura Y, Shirato H, Ikeda J, Tada M, Ishii N, Kato T, Abe H, Fujieda K: Induction chemotherapy followed by reduced-volume radiation therapy for newly diagnosed central nervous system germinoma. J Neurosurg 88: 66 72, Shibamoto Y, Takahashi M, Sasai K: Prognosis of intracranial germinoma with syncytiotrophoblastic giant cells treated by radiation therapy. Int J Radiat Oncol Biol Phys 37: , Shibamoto Y, Abe M, Yamashita J, Takahashi M, Hiraoka M, Ono K, Tsutsui K: Treatment results of intracranial germinoma as a function of the irradiated volume. Int J Radiat Oncol Biol Phys 15: , Ott RJ, Brada M, Flower MA, Babich JW, Cherry SR, Deehan BJ: Measurements of blood brain barrier permeability in patients undergoing radiotherapy and chemotherapy for primary cerebral lymphoma. Eur J Cancer 27: , Merchant TE, Davis BJ, Sheldon JM, Leibel SA: Radiation therapy for relapsed CNS germinoma after primary chemotherapy. J Clin Oncol 16: , Matsutani M: Indication of radiation therapy for intracranial germ cell tumors. Multiinstitutional phase II study. (Abstract in Japanese) J Jpn Soc Ther Radiol Oncol 10 (Suppl 1): 98, Regine WF, Hodes JE, Patchell RA: Intracranial germinoma: treatment with radiosurgery alone a case report. J Neuro- Oncol 37: 75 77, 1998 Address for offprints: Yuta Shibamoto, Department of Oncology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto , Japan; Tel.: (+81) ; Fax: (+81) ; yuta@frontier.kyoto-u.ac.jp

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