Long-Term Outcomes and Sequelae Analysis of Intracranial Germinoma: Need to Reduce the Extended-Field Radiotherapy Volume and Dose to Minimize Late Sequelae

Joo Ho Lee; Keun-Yong Eom; Ji Hoon Phi; Chul-Kee Park; Seung Ki Kim; Byung-Kyu Cho; Tae Min Kim; Dae Seog Heo; Kyung Taek Hong; Jung Yoon Choi; Hyoung Jin Kang; Hee Young Shin; Seung Hong Choi; Soon Tae Lee; Sung Hye Park; Kyu-Chang Wang; Il Han Kim

doi:10.4143/crt.2020.1052

Articles

Page Path: HOME > Cancer Res Treat > Volume 53(4); 2021 > Article

Original Article CNS cancer Long-Term Outcomes and Sequelae Analysis of Intracranial Germinoma: Need to Reduce the Extended-Field Radiotherapy Volume and Dose to Minimize Late Sequelae: Joo Ho Lee^1,2, Keun-Yong Eom³, Ji Hoon Phi⁴, Chul-Kee Park⁴, Seung Ki Kim⁴, Byung-Kyu Cho⁵, Tae Min Kim⁶, Dae Seog Heo⁶, Kyung Taek Hong⁷, Jung Yoon Choi⁷, Hyoung Jin Kang⁷, Hee Young Shin⁷, Seung Hong Choi⁸, Soon Tae Lee⁹, Sung Hye Park¹⁰, Kyu-Chang Wang¹¹, Il Han Kim¹; Cancer Research and Treatment : Official Journal of Korean Cancer Association 2021;53(4):983-990.
DOI: https://doi.org/10.4143/crt.2020.1052
Published online: January 13, 2021

¹Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

²Institute of Radiation Medicine, Medical Research Center, Seoul National University, Seoul, Korea

³Department of Radiation Oncology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea

⁴Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

⁵Department of Neurosurgery, The Armed Forces Capital Hospital, Seongnam, Korea

⁶Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

⁷Department of Pediatrics, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

⁸Department of Radiology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

⁹Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

¹⁰Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

¹¹Department of Neurosurgery, National Cancer Center, Goyang, Korea

Correspondence: Il Han Kim, Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea,
Tel: 82-2-2072-2819, Fax: 82-2-2072-2073, E-mail: ihkim@snu.ac.kr

Co-correspondence: Kyu-Chang Wang, Department of Neurosurgery, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 10408, Korea,
Tel: 82-31-920-0889, Fax: 82-31-920-2799, E-mail: kcwang@snu.ac.kr

• Received: October 14, 2020 • Accepted: January 8, 2021

This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

11,336 Views
359 Download
13 Web of Science
12 Crossref
13 Scopus

prev next

Full Article

Download PDF

Abstract

Purpose
We aimed to refine the radiotherapy (RT) volume and dose for intracranial germinoma considering recurrences and long-term toxicities.
Materials and Methods
Total 189 patients with intracranial germinoma were treated with RT alone (n=50) and RT with upfront chemotherapy (CRT) (n=139). All cases were confirmed histologically. RT fields comprised the extended-field and involved-field only for primary site. The extended-field, including craniospinal, whole brain (WB), and whole ventricle (WV) for cranial field, is followed by involved-field boost. The median follow-up duration was 115 months.
Results
The relapses developed in 13 patients (6.9%). For the extended-field, cranial RT dose down to 18 Gy exhibited no cranial recurrence in 34 patients. In CRT, 74 patients (56.5%) showed complete response to chemotherapy and no involved-field recurrence with low-dose RT of 30 Gy. WV RT with chemotherapy for the basal ganglia or thalamus germinoma showed no recurrence. Secondary malignancy developed in 10 patients (5.3%) with a latency of 20 years (range, 4 to 26 years) and caused mortalities in six. WB or craniospinal field rather than WV or involved-field significantly increased the rate of hormone deficiencies, and secondary malignancy. RT dose for extended-field correlated significantly with the rate of hormone deficiencies, secondary malignancy, and neurocognitive dysfunction.
Conclusion
De-intensifying extended-field rather than involved-field or total scheme of RT will be critical to decrease the late toxicities. Upfront chemotherapy could be beneficial for the patients with complete response to minimize the RT dose down to 30 Gy. Prospective trials focused on de-intensification of the extended-field RT are warranted.
Key words: Germinoma, Radiotherapy, Radiation toxicity, Radiation-induced neoplasms

Introduction

Intracranial germinomas are relatively rare tumors, accounting for about 3% of primary pediatric brain tumors worldwide, but in East Asia show a higher proportion of 10% [1]. Although the traditional cure rate is over 95% with radiotherapy (RT) [2], RT could produce late complications, such as hormone insufficiency, secondary malignancy, and neurocognitive dysfunction. For concern over the toxicities, the omission of RT was previously attempted, but caused a high rate of failure and survival compromise [3]. Thus, previous studies have tried to decrease the dose and volume of RT over concerns with RT complications [4–15]. However, the optimal intensity of RT is still under debate, and various patterns of treatments, including craniospinal, whole brain (WB), whole ventricle (WV), involved-field RT alone, and with or without chemotherapy are applied in the clinics [16].

In the present study, we retrospectively analyzed 189 cases of intracranial germinomas that had been pathologically proven. For 25 years, our policy of treatment in intracranial germinomas has changed over time from craniospinal RT alone, to modified RT with reduced field and upfront chemotherapy. From the cohort of intracranial germinomas in this institute, we could analyze the pattern of failures and toxicities according to the intensity of RT. The present study aimed to find the optimal volume and dose of RT to secure oncological safety and minimize late toxicities in intracranial germinomas.

Materials and Methods

1. Patients

The medical records of 195 patients with intracranial germinoma who underwent RT from January 1981 to December 2015 were retrospectively reviewed. Inclusion criteria were as follows: (1) intracranial germinoma, newly diagnosed by histologic exam; and (2) RT alone or CRT (radiotherapy with upfront chemotherapy). Of these 195 patients, 189 met the inclusion criteria. The reasons for exclusion were non-germinomatous elements on pathologic examination (except for nonmalignant teratoma) (n=3), refusal or incompletion of radiotherapy (n=2), and incompletion or insufficient documentation (n=1).

The median age was 15 years (range, 4 to 47 years) (Table 1). Male patients were 151 (79.9%), while females were 38 (20.1%). The number of patients with Eastern Cooperative Oncology Group score (0–1), 2, and (3–4) was 156, 22, and 11, respectively. Presenting signs and symptoms were diabetes insipidus (n=64, 33.9%), visual impairment or diplopia (n=59, 31.2%), headache (n=40, 21.2%), and vomiting (n=26, 13.8%).

The primary tumors in the patients without seeding were most frequently located in the suprasellar region (n=61) or pineal region (n=63). Also, germinomas arising only in basal ganglia or thalamus were found in 29 patients.

Solitary disease was defined as solitary lesion of germinoma without evidence of dissemination (negative craniospinal fluid [CSF] cytology and negative imaging). Bifocal disease was defined as radiological detection of bifocal tumors in the pineal or the suprasellar or basal ganglia/thalamus regions with negative CSF cytology and imaging. Initial positive seeding was defined as the presence of an intracranial multiple lesions (except bifocal disease), spinal metastases, or tumor cells in CSF. According to this definition of disease, of 189 patients, 119 had solitary disease, and 25 had bifocal disease. Initial positive seeding in the ventricle or spine was detected in 45, as determined by magnetic resonance imaging (n=22), cerebrospinal fluid cytology (n=10), and both (n=13) (Table 1).

The tumor marker level was unavailable in three patients. The serum human chorionic gonadotropin level was undetectable in 133 patients, ≤ 50 mIU/mL in 46 patients, and > 50 mIU/mL in seven patients. The α-fetoprotein (AFP) level was considered normal when it was ≤ 11 ng/mL; however, the AFP level was greater or fluctuating in patients with chronic hepatitis. The AFP level was ≤ 5 ng/mL in 177 patients, 7–11 ng/mL in six patients, and 22–30 ng/mL in three hepatitis B virus carrier.

2. Treatment

Of the 189 patients, 50 underwent RT alone, and 139 underwent CRT. RT alone was applied to 40 patients bet-ween 1982 and 1999, and CRT was introduced from 1992. CRT was applied to 11 patients between 1992 and 1999. After 1999, the main treatment policy had been changed to CRT (n=136). However, 10 patients (20% of RT alone) received RT alone after 1999 due to comorbidities (n=3), patients’ refusal of chemotherapy (n=5) or other reasons (n=2).

In the RT alone group (n=50), craniospinal RT was followed by involved-field RT boost, except for five patients with poor performance (Table 2). The craniospinal axis dose was 24 Gy (range, 20 to 30 Gy) for those with initial negative seeding, but 30 Gy (range, 24 to 36 Gy) for those with initial positive seeding. The primary tumor dose was 54 Gy (range, 45 to 57 Gy).

In the CRT group (n=139), upfront chemotherapy was undertaken with two cycles (range, one to four) of bleomycin, etoposide, and cisplatin or etoposide and cisplatin for 66 patients > 18 years old, five cycles (range, 1 to 5) of cisplatin, etoposide, cyclophosphamide, and vincristine (CCG 9921A or 9931A) for 67 patients, and “8-in-1” (solumedrol, vincristine, lomustine, procarbazine, hydroxyurea, cisplatin, cytosine arabinoside, and cyclophosphamide) for four patients. In the CRT group (n=139), extended-field RT, including craniospinal RT, WB RT, and WV RT, was followed by involved-field RT boost, of which the extent depended on the initial tumor extent or preferences of physicians (Table 2). Involved-field RT alone without extended-field RT after upfront chemotherapy was performed in 28 patients. Of the 28 patients, three patients had initial positive seeding in the periventricular area, although after upfront chemotherapy, the seeding lesions were disappeared in the magnetic resonance imaging. Extended-field dose was 23 Gy (range, 16 to 39 Gy). The radiation dose to the primary tumor depended on the response to upfront chemotherapy. To the primary tumor, patients showing complete response (CR) to upfront chemotherapy received 45 Gy (range, 25 to 50 Gy), and patients not showing CR received 50 Gy (range, 45 to 55 Gy) (p < 0.001). The patients in the RT-alone group had a significant tendency to undergo craniospinal RT, rather than cranial RT or involved-field RT alone, and high dose of both the extended-field and involved-field RT (p < 0.001, p < 0.001, and p < 0.001, respectively).

Germinoma located only in the basal ganglia or thalamus without initial seeding were found in 29 patients. Of the 29 patients, six patients underwent RT alone with craniospinal RT, and 23 patients underwent CRT with involved-field RT alone (n=7), WV RT (n=10), WB RT (n=4), and craniospinal RT (n=2).

3. Toxicities

Patients with initial hormone deficiency at diagnosis (n=67) were excluded from counting the number of patients requiring hormone-replacement therapy for the analysis of toxicities. Patients with insufficient follow-up duration lower than 36 months (n=10) were excluded from counting the number of patients in the analysis of the secondary malignancy. For the analysis of school activity, we excluded 69 adult patients and counted the number of patients who could return to their own grade of school without flunking after the completion of radiotherapy among the school-aged child or adolescent.

Neurocognitive dysfunction was defined as a subjective report of having a severe disability in learning memory, attention, processing, and executive functioning limiting school performance at school-age, or occupational activities at adult age. Neurocognitive dysfunction was assessed regularly with subjective questionnaire in the outpatient clinics of the department of radiation and pediatric oncology or the pediatric clinic of long-term survivors. We excluded 10 patients in pre-school age, 18 patients inaccessible to the medical records of regular neurocognitive questionnaire, and 11 patients with poor performance, Eastern Cooperative Oncology Group (ECOG) 3–4 at diagnosis.

4. Statistical analysis

Analyses were performed using SPSS ver. 18 (SPSS Inc., Chicago, IL). We used the chi-square test for categorical variables, and a Student’s t test for continuous variables. Overall survival (OS) and recurrence-free survival (RFS) were calculated as the interval from the date of diagnosis to the date of death, and to the date that death or progression was detected, respectively. Survival curves were generated using the Kaplan-Meier method, and univariate survival comparison was performed using the log-rank test. A value of p < 0.05 was considered statistically significant.

Results

1. Response to RT and upfront chemotherapy

In the RT-only group, 30 patients (60.0%) had a CR and 20 (40.0%) a partial response (PR) at 3 months after RT. All the PR patients had a CR by 21 months, and no progression was observed. In the CRT group, the response to upfront chemotherapy was a CR in 74 patients (56.5%), a PR in 57 (43.5%), and stable/progressive disease in eight patients, according to an imaging study before radiotherapy. After radiotherapy following chemotherapy, all patients except one were transited to a CR at 3 months after RT. One case of a delayed CR was observed at 9.5 months.

2. Failures and survival patterns

The median follow-up duration was 116 months (range, 3 to 358 months), from the date of diagnosis. In the RT alone group, the median follow-up duration was 112 months (range, 3 to 358 months), while in the CRT group, 117 months (range, 8 to 308 months) (p=0.470). The relapses developed in five patients (10.0%) in the RT alone, and eight patients (5.8%) in the CRT group (Table 2). Regarding the RT field, the out-field recurrence was in two patients in the RT alone group, who did not receive spinal irradiation. The other three patients of recurrence after RT alone showed in-field recurrence at the periventricular area. Otherwise, in the CRT group, all of the eight patients showing recurrence experienced out-field recurrence. Except for one patient of spinal recurrence, seven patients of eight received the involved-field RT alone, without any extended-field RT.

Regarding the radiation dose in CRT group, low dose down to 18 Gy to cranial field exhibited no cranial recurrence (Table 3). For positive seeding, low dose down to 23 Gy showed no spinal recurrence. For the involved-field boost after the upfront chemotherapy, low dose down to 30 Gy (range, 26 to 30 Gy) in the patients with CR to the upfront chemotherapy showed no primary recurrence (n=9).

Low dose down to 45 Gy in the patients with partial or stable response showed one recurrence of 19 patients. However, the recurrence of one patient extended from multiple intracranial recurrences to the primary site after the involved-field RT alone.

The OS rate at 10 years was 85.2% in the RT alone, and 92.8 % in the CRT group (p=0.066). The RFS at 10 years was 79.5% in the RT alone group, and 89.3 % in the CRT group (p=0.083). OS and RFS were not affected by any clinical parameter.

After the development of recurrence in 13 patients, 10 patients received salvage treatment, and three with poor performance did not. Of the 10 patients, five underwent CRT, four underwent chemotherapy only, and one patient underwent radiotherapy only. All radiotherapy for salvage aim was performed with craniospinal irradiation. Salvage treatment rescued five patients (50%) with disease-free status. All rescued patients received re-irradiation as a salvage treatment.

3. Basal ganglia and thalamus

Of 29 patients who had germinoma at the basal ganglia or thalamus, relapses developed in three patients among a total seven patients who underwent CRT with involved-field RT alone. Two of the three recurrences were located in the periventricular area. Another recurrence developed widely from the primary site of the basal ganglia to the periventricular region in the ipsilateral frontal and temporal lobe. No relapse developed in the other 22 patients who underwent extended-field RT, including RT to craniospinal axis (n=2), WB (n=4), or WV (n=10) after upfront chemotherapy and craniospinal RT alone (n=6). The OS and RFS rates at 10 years were 86.8% and 84.3%, respectively.

4. Late toxicities and treatment factors

The frequency of hormone-replacement therapy was significantly correlated to WB RT rather than WV or involved-field RT alone (p=0.003), and the high RT dose over 30 Gy for extended-field RT (p=0.036) (Table 4). Secondary malignancy developed in 10 patients (5.3%) with a latency period of 20 years (range, 4 to 26 years) and caused mortalities in six of the 10 patients (Table 5). Solid cancer in the nine patients was located inside the RT field. Otherwise, another patient experienced lymphoma at the distal femur outside of the RT field. Glioblastoma was the most common type of secondary malignancy (n=5). The incidence rate ratio of secondary malignancy was increased to 7.208 (95% confidence interval, 0.999 to 315.915) in the larger RT volume of extended-field with WB RT or craniospinal RT, and 7.375 (95% confidence interval, 1.472 to 71.294) in the higher RT dose of extended-field (Table 5). The rate of neurocognitive dysfunction was significantly related to high dose of extended-field RT (p=0.027). RT alone rather than upfront chemotherapy followed by RT was significantly related to the rates of late toxicities including hormone deficiency, school activity, neurocognitive dysfunction, and secondary malignancy.

Discussion

The optimal RT fields and dose are still controversial, and discussion of this issue should consider both maintaining tumor control and minimizing late toxicities. The present study of 189 patients with pathologically proven germinoma has confirmed that radiotherapy with or without upfront chemotherapy results in excellent tumor control and survival, comparable to previous studies [4–13]. Excellent tumor control could be sustained when RT covered the initial disease extent with craniospinal RT for patients with initial positive seeding, and WV RT for patients with initial negative seeding. However, the minimum coverage of RT could not be further decreased to below the initial disease extent, whether chemotherapy is combined or not. We experienced high rates of periventricular recurrence in the brain as the out-field recurrences after the involved-field RT alone with chemotherapy, similar to the previous studies using the involved-field RT alone after chemotherapy or chemotherapy alone [3–5,7,9,14]. Chemotherapy could not sterilize the disease spread along the CSF. Otherwise, without chemotherapy, two of five patients with initial negative seeding showed spinal recurrence after cranial RT alone. Although Yen et al. [17] and Byun et al. [4] reported fairly good outcomes after the omission of spinal RT without chemotherapy, they both reported one case of spinal failure. Upfront chemotherapy might be beneficial for patients with initial negative seeding to omit spinal irradiation safely. Therefore, with upfront chemotherapy, the pattern of recurrences will conservatively support WV for initial negative seeding, and craniospinal RT for initial positive seeding.

Moreover, the volume and dose of the extended-field RT were also important for the development of late toxicities. To the best of our knowledge, the present study is the first report to show the statistical correlation between the RT factors and late toxicities in patients with intracranial germinoma. We found that WB RT, rather than WV or involved-field RT alone, significantly increased the rate of hormone deficiencies and secondary malignancy, and the high dose of extended-field RT to the brain increased the rate of hormone deficiencies, secondary malignancy, and neurocognitive dysfunction. In particular, the patients receiving low dose under 30 Gy to the brain showed quite good quality of life. Moreover, median 18 Gy to cranial field in the CRT group showed excellent in-field control in 34 patients of our studies, which were also observed in the previous studies using low-dose of cranial RT ranging 19 to 24 Gy [5,8,18]. Our study further supported low-dose cranial RT with WV RT, rather than WB RT, to deal with late toxicities, as well as tumor control.

Adequate RT field in the germinoma originating from the basal ganglia or thalamus, a distinct entity located in the brain parenchyma nearby ventricle, has also been a critical issue [5,19]. For the patients, the involved-field RT alone with upfront chemotherapy resulted in high rates of intracranial recurrences outside the RT field. In contrast, the extended-field with WB or WV, followed by involved-field boost, showed no recurrence in or outside the RT field. The previous studies also showed insufficient disease control in the involved-field RT alone, and no recurrence with WB or craniospinal RT [5,19]. Notably, we employed WV RT as the extended-field RT after upfront chemotherapy in 10 patients, and experienced no recurrence. Modern magnetic resonance imaging and RT technique enable delineation of the tumor location, and safely covered the possible tumor infiltration with RT [20]. Also, considering the toxicities related to WB RT in our study, WV RT with focal boost after upfront chemotherapy might be adequate for the germinoma in the basal ganglia or thalamus.

Concerning the total RT dose to the involved-field, the present study showed that median 30 Gy ranging 26 to 30 Gy can prevent in-field recurrence after CR to upfront chemotherapy. In contrast, one patient among 19 patients showing partial or stable response to chemotherapy showed in-field recurrence after median 45 Gy (range, 36 to 49 Gy). For CRT, Aoyama et al. [13] previously reported that 24 Gy WV RT without further involved-field RT boost resulted in no failure in six patients who showed CR to upfront chemotherapy. For RT alone, Cho et al. [8] previously suggested that RT dose to the involved site can be decreased to 39.3 Gy with RT alone. Although the optimal RT dose is still controversial, the present study suggests that dose adaptation according to the response of chemotherapy could decrease the RT dose low to 30 Gy in the subgroup showing CR to upfront chemotherapy. Moreover, in the future, further optimization of the RT dose should be followed to test the minimal limit of the RT dose.

However, this study is not free from limitations. First, in this retrospective study, no systematic and scoring assessment of neurocognitive function had been performed. To minimize the uncertainty of assessing neurocognitive function, we narrowed the criteria to severe limitation in neurocognitive function of school activity under 18 years, and occupational activity in the adult. Systematic assessment of neurocognitive function will be necessary to define the RT factor affecting specific function in the patients with germinoma. Second, although the number of patients in this study is relatively large, we confirmed the pattern of relapse in a small-sized subgroup, especially around the low margin of RT dose. Prospective evaluation of oncologic safety should be verified in future clinical trials. Third, although the CRT group showed the lower rate of late toxicities than RT lone in the analysis of late toxicities, the intensity of extended-field radiotherapy in CRT group were significantly lower than RT alone group. Therefore, from the results of this study, the combination of chemotherapy alone cannot guarantee the lower toxicities without taking care of extended-field RT. The potential benefit of upfront chemotherapy will be the oncologically safe de-intensity of extended-field RT without compromising the tumor control rate.

De-intensifying extended-field rather than involved-field or total scheme of RT will be critical to decrease the late toxicities. Upfront chemotherapy could be beneficial for patients with negative seeding to omit the spinal RT and for patients with CR to minimize the RT dose down to 30 Gy. WV RT with upfront chemotherapy can be recommended for intracranial germinoma arising from basal ganglia or thalamus. Prospective trials focused on de-intensification of the extended-field RT are warranted.

NOTES

Ethical Statement

All of data collection and analysis were performed after approval from the institutional review board (IRB No. 1904-010-1023) in accordance with the declaration of Helsinki. The written informed consent was waived in this retrospective study.

Author Contributions

Conceived and designed the analysis: Wang KC, Kim IH.

Collected the data: Lee JH, Eom KY, Phi JH, Park CK, Kim SK, Cho BK, Kim TM, Heo DS, Hong KT, Choi JY, Kang HJ, Shin HY, Choi SH, Lee ST, Park SH, Wang KC, Kim IH.

Contributed data or analysis tools: Lee JH, Kim IH.

Performed the analysis: Lee JH, Eom KY, Wang KC, Kim IH.

Wrote the paper: Lee JH, Wang KC, Kim IH.

Conflicts of Interest

Conflict of interest relevant to this article was not reported.

Acknowledgements

This research was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2018R1D1A1A02085487, NRF-2020M2D9A-2092373 to J.H.L) and by the SNUH Research Fund (04-2019-0830 to J.H.L.) funded by Seoul National University Hospital.

Table 1

Patient characteristics

Factor	Value
Age (yr)	15 (4–47)
Sex
Male	151 (79.9)
Female	38 (20.1)
ECOG PS
0–1	156 (82.6)
2	22 (11.6)
3–4	11 (5.8)
Tumor site
Solitary
Suprasellar	41 (21.7)
Pineal	46 (24.3)
BG/Thalamus	29 (15.3)
Others^a)	3 (1.6)
Bifocal
Suprasellar and pineal	15 (7.9)
Suprasellar and other	5 (2.6)
Pineal and other	2 (1.1)
Others^b)	3 (1.6)
Seeding (+)
CSF cytology (+)	10 (5.3)
Multiple lesions in MRI (+)	22 (11.6)
CSF cytology and MRI (+)	13 (6.9)

Values are presented as median (range) or number (%). BG, basal ganglia; CSF, craniospinal fluid; ECOG PS, Eastern Cooperative Oncology Group performance status; MRI, magnetic resonance imaging.

^a) Including frontal lobe and temporal lobe,

^b) Including temporal lobe, and midbrain.

Table 2

Field of radiotherapy and pattern of recurrence

Tumor site	CTx	RT field	No.	Recurrence
				Intracranial		Spinal
				In-field	Out-field	Spinal
Solitary/Bifocal	(−)	WB	5	1	-	2
		CSA	36	2	-	-
	(+)	IF only	25	1^a)	4+1^a)	-
		WV	54	-	-	1
		WB	3	-	-	-
		CSA	21	-	-	-
Multifocal/Seeding	(−)	CSA	9	-	-	-
	(+)	IF only	3	-	2	-
		WV	2	-	-	-
		WB	1	-	-	-
		CSA	30	-	-	-

CSA, craniospinal axis followed by involved-field boost; CTx, chemotherapy; IF, involved-field; RT, radiotherapy; WB, whole brain followed by involved-field boost; WV, whole ventricle followed by involved-field boost.

^a) Combined intracranial in-field and out-field recurrences in a case.

Table 3

In-field recurrence according to radiation dose after upfront chemotherapy

Dose, median (range)	No.^a)
Cranial field (WB/WV)
18 Gy (16–19)	0/34
23 Gy (20–27)	0/60
36 Gy (30–39)	0/16
Spinal field to positive seeding
9 Gy (9)	0/1
23 Gy (19–24)	0/24
36 Gy (30–36)	0/5
Involved field
Complete response
30 Gy (26–30)	0/9
39 Gy (36–43)	0/18
45 Gy (45–46)	0/31
50 Gy (46–50)	0/16
Not complete response
45 Gy (45–49)	1/19
54 Gy (50–60)	0/46

WB, whole brain followed by involved-field boost; WV, whole ventricle followed by involved-field boost.

^a) Number of recurrences/total number of patients.

Table 4

Late toxicities and treatment factors

Factor	Hormone-replacement therapy^a)		Back to school (%)^b)		NCF (%)^c)

	Positive	p-value^d)	Yes	p-value^d)	Declined	p-value^d)
Treatment

RT	10/19 (52.6)	0.011	25/31 (80.7)	0.022	8/29 (27.6)	0.002

CRT	22/93 (23.7)		84/89 (94.4)		9/121 (7.4)

RT, total dose (Gy)

≤ 50	13/57 (22.8)	0.169	47/51 (92.0)	0.670	4/69 (6.0)	0.051

> 50	19/55 (34.6)		62/69 (90.0)		13/81 (16.0)

WB RT

WBRT	22/52 (42.3)	0.003	56/65 (86.2)	0.053	12/79 (15.2)	0.116

WVRT or IFRT only	10/60 (16.7)		53/55 (96.4)		5/71 (7.0)

WB/WV dose (Gy)

≤ 30	12/85 (44.4)	0.036	75/80 (94.0)	0.120	8/111 (7.2)	0.007

> 30	20/27 (23.5)		34/40 (85.0)		9/39 (23.1)

Values are number/total (%). CRT, radiotherapy with upfront chemotherapy; IFRT, involved-field RT; NCF, severe neurocognitive dysfunction (limitation in daily activities, working or school performance); RT, radiotherapy; WB, whole brain; WV, whole ventricle.

^a) Excluding initial hormone deficiency,

^b) Patients in school-age,

^c) Excluding patients inaccessible to neurocognitive questionnaire in the medical records,

^d) Chi-square test.

Table 5

Secondary malignancy and treatment factors

Factor	Total	Event (%)	Incidence rate^a)	Incidence rate ratio (95% CI)
Treatment
CRT	135	3 (2.2)	1.6	0.163 (0.027–0.715)
RT	44	7 (15.9)	10.0
WB RT
WBRT	96	9 (9.4)	6.4	7.208 (0.999–315.915)
WVRT or IFRT only	83	1 (1.2)	0.9
Total dose (Gy)
> 50	105	9 (8.6)	6.3	7.001 (0.970–306.874)
≤ 50	74	1 (1.3)	0.1
WB/WV RT dose (Gy)
> 30	58	8 (13.8)	9.0	7.375 (1.472–71.294)
≤ 30	121	2 (1.6)	0.1

CI, confidence interval; CRT, radiotherapy with upfront chemotherapy; IFRT, involved-field RT; RT, radiotherapy; WB, whole brain; WV, whole ventricle.

^a) Per 10,000 person-year.

REFERENCES

1. Dho YS, Jung KW, Ha J, Seo Y, Park CK, Won YJ, et al. An updated nationwide epidemiology of primary brain tumors in Republic of Korea, 2013. Brain Tumor Res Treat. 2017;5:16–23. Article PubMed PMC
2. Lee SH, Jung KW, Ha J, Oh CM, Kim H, Park HJ, et al. Nationwide population-based incidence and survival rates of malignant central nervous system germ cell tumors in Korea, 2005–2012. Cancer Res Treat. 2017;49:494–501. Article PubMed
3. da Silva NS, Cappellano AM, Diez B, Cavalheiro S, Gardner S, Wisoff J, et al. Primary chemotherapy for intracranial germ cell tumors: results of the third international CNS germ cell tumor study. Pediatr Blood Cancer. 2010;54:377–83. Article PubMed
4. Byun HK, Yoon HI, Cho J, Kim DS, Shim KW, Han JW, et al. Optimization of intracranial germinoma treatment: a single institution experience with 213 patients supports radiotherapy alone with reduced volume and dose. Int J Radiat Oncol Biology Phys. 2019;105:909.Article
5. Lee DS, Lim DH, Kim IH, Kim JY, Han JW, Yoo KH, et al. Upfront chemotherapy followed by response adaptive radiotherapy for intracranial germinoma: prospective multicenter cohort study. Radiother Oncol. 2019;138:180–6. Article PubMed
6. Calaminus G, Kortmann R, Worch J, Nicholson JC, Alapetite C, Garre ML, et al. SIOP CNS GCT 96: final report of outcome of a prospective, multinational nonrandomized trial for children and adults with intracranial germinoma, comparing craniospinal irradiation alone with chemotherapy followed by focal primary site irradiation for patients with localized disease. Neuro Oncol. 2013;15:788–96. Article PubMed PMC
7. Jensen AW, Laack NN, Buckner JC, Schomberg PJ, Wetmore CJ, Brown PD. Long-term follow-up of dose-adapted and reduced-field radiotherapy with or without chemotherapy for central nervous system germinoma. Int J Radiat Oncol Biol Phys. 2010;77:1449–56. Article PubMed
8. Cho J, Choi JU, Kim DS, Suh CO. Low-dose craniospinal irradiation as a definitive treatment for intracranial germinoma. Radiother Oncol. 2009;91:75–9. Article PubMed
9. Nakamura H, Takeshima H, Makino K, Kochi M, Ushio Y, Kuratsu J. Recurrent intracranial germinoma outside the initial radiation field: a single-institution study. Acta Oncol. 2006;45:476–83. Article PubMed
10. Nguyen QN, Chang EL, Allen PK, Maor MH, Ater JL, Mahajan A, et al. Focal and craniospinal irradiation for patients with intracranial germinoma and patterns of failure. Cancer. 2006;107:2228–36. Article PubMed
11. Shirato H, Aoyama H, Ikeda J, Fujieda K, Kato N, Ishi N, et al. Impact of margin for target volume in low-dose involved field radiotherapy after induction chemotherapy for intracranial germinoma. Int J Radiat Oncol Biol Phys. 2004;60:214–7. Article PubMed
12. Haas-Kogan DA, Missett BT, Wara WM, Donaldson SS, Lamborn KR, Prados MD, et al. Radiation therapy for intracranial germ cell tumors. Int J Radiat Oncol Biol Phys. 2003;56:511–8. Article PubMed
13. Aoyama H, Shirato H, Ikeda J, Fujieda K, Miyasaka K, Sawamura Y. Induction chemotherapy followed by low-dose involved-field radiotherapy for intracranial germ cell tumors. J Clin Oncol. 2002;20:857–65. Article PubMed
14. Eom KY, Kim IH, Park CI, Kim HJ, Kim JH, Kim K, et al. Upfront chemotherapy and involved-field radiotherapy results in more relapses than extended radiotherapy for intracranial germinomas: modification in radiotherapy volume might be needed. Int J Radiat Oncol Biol Phys. 2008;71:667–71. Article PubMed
15. Shin KH, Kim IH, Choe G. Impacts of elevated level of hCG in serum on clinical course and radiotherapy results in the histology-confirmed intracranial germinomas. Acta Oncol. 2001;40:98–101. Article PubMed
16. Murray MJ, Bartels U, Nishikawa R, Fangusaro J, Matsutani M, Nicholson JC. Consensus on the management of intracranial germ-cell tumours. Lancet Oncol. 2015;16:e470–7. Article PubMed
17. Yen SH, Chen YW, Huang PI, Wong TT, Ho DM, Chang KP, et al. Optimal treatment for intracranial germinoma: can we lower radiation dose without chemotherapy? Int J Radiat Oncol Biol Phys. 2010;77:980–7. Article PubMed
18. Shim KW, Park EK, Lee YH, Suh CO, Cho J, Choi JU, et al. Treatment strategy for intracranial primary pure germinoma. Childs Nerv Syst. 2013;29:239–48. Article PubMed
19. Sonoda Y, Kumabe T, Sugiyama S, Kanamori M, Yamashita Y, Saito R, et al. Germ cell tumors in the basal ganglia: problems of early diagnosis and treatment. J Neurosurg Pediatr. 2008;2:118–24. Article PubMed
20. Phi JH, Cho BK, Kim SK, Paeng JC, Kim IO, Kim IH, et al. Germinomas in the basal ganglia: magnetic resonance imaging classification and the prognosis. J Neurooncol. 2010;99:227–36. Article PubMed

Figure & Data

REFERENCES

Citations

Citations to this article as recorded by

Optimal treatment approach for intracranial germinoma: a systematic review and meta-analysis
Zhirui Zhou, Jiabing Liu, Qi Yue, Lingxiao Chen, Xiwei Zhang, Xin Lin, Lin Zheng, Enmin Wang, Yang Wang, Ying Mao
BMC Cancer.2025;[Epub] CrossRef
Distribution and failure patterns of primary central nervous system lymphoma related to the hippocampus: implications for hippocampal avoidance irradiation
Hyejo Ryu, Xue Li, Tae Hoon Lee, Tae Min Kim, Seung Hong Choi, Chul-Kee Park, Soon Tae Lee, Sung-Hye Park, Jae-Kyung Won, Bum-Sup Jang, Il Han Kim, Joo Ho Lee
Journal of Neuro-Oncology.2025; 173(1): 95. CrossRef
NTRK-fused central nervous system tumours: clinicopathological and genetic insights and response to TRK inhibitors
Eric Eunshik Kim, Chul-Kee Park, Seung-Ki Kim, Ji Hoon Phi, Sun Ha Paek, Jung Yoon Choi, Hyoung Jin Kang, Joo Ho Lee, Jae Kyung Won, Hongseok Yun, Sung-Hye Park
Acta Neuropathologica Communications.2024;[Epub] CrossRef
Clinical significance of cerebral microbleeds in patients with germinoma who underwent long-term follow-up
Masayuki Kanamori, Shunji Mugikura, Osamu Iizuka, Naoko Mori, Yoshiteru Shimoda, Ichiyo Shibahara, Rei Umezawa, Keiichi Jingu, Ryuta Saito, Yukihiko Sonoda, Toshihiro Kumabe, Kyoko Suzuki, Hidenori Endo
Journal of Neuro-Oncology.2024; 170(1): 173. CrossRef
Excluding prepontine cistern from whole ventricle radiotherapy target volume in localized germinoma
Hyejo Ryu, Joo Ho Lee
Radiation Oncology Journal.2023; 41(1): 48. CrossRef
Intracranial Germinomas: Diagnosis, Pathogenesis, Clinical Presentation, and Management
Natalia Kremenevski, Michael Buchfelder, Nirjhar Hore
Current Oncology Reports.2023; 25(7): 765. CrossRef
Proton therapy for pediatric diencephalic tumors
Adam J. Grippin, Susan L. McGovern
Frontiers in Oncology.2023;[Epub] CrossRef
Intracranial Germinoma—Association between Delayed Diagnosis, Altered Clinical Manifestations, and Prognosis
Iwona Jabłońska, Marcin Goławski, Elżbieta Nowicka, Katarzyna Drosik-Rutowicz, Anna Trybus, Rafał Tarnawski, Marcin Miszczyk
Cancers.2023; 15(10): 2789. CrossRef
Outcomes of intracranial germinoma—A retrospective multinational Asian study on effect of clinical presentation and differential treatment strategies
Kyung-Nam Koh, Ru Xin Wong, Dong-Eun Lee, Jung Woo Han, Hwa Kyung Byun, Hong In Yoon, Dong-Seok Kim, Chuhl Joo Lyu, Hyoung Jin Kang, Kyung Taek Hong, Joo Ho Lee, Il Han Kim, Ji Hoon Phi, Seung-Ki Kim, Tai-Tong Wong, Hsin-Lun Lee, I-Chun Lai, Yu-Mei Kang,
Neuro-Oncology.2022; 24(8): 1389. CrossRef
Photon versus proton whole ventricular radiotherapy for non‐germinomatous germ cell tumors: A report from the Children's Oncology Group
David Y. Mak, Zain Siddiqui, Zhihui Amy Liu, Hitesh Dama, Shannon M. MacDonald, Shengjie Wu, Erin S. Murphy, Matthew D. Hall, Victor Malkov, Arzu Onar‐Thomas, Sameera Ahmed, Girish Dhall, Derek S. Tsang
Pediatric Blood & Cancer.2022;[Epub] CrossRef
Factors Influencing Craniospinal Relapse of Intracranial Germinoma After Complete Remission
Takao Tsurubuchi, Kei Hara, Shingo Takano, Ai Muroi, Hiroko Fukushima, Masashi Mizumoto, Noriaki Sakamoto, Masahide Matsuda, Hiroyoshi Akutsu, Hideyuki Sakurai, Eiichi Ishikawa
World Neurosurgery.2022; 166: e325. CrossRef
Molecular Pathology and Targeted Therapies for Personalized Management of Central Nervous System Germinoma
Cristina Ilcus, Horatiu Silaghi, Carmen Emanuela Georgescu, Carmen Georgiu, Anca Ileana Ciurea, Simona Delia Nicoara, Cristina Alina Silaghi
Journal of Personalized Medicine.2021; 11(7): 661. CrossRef

PubReader
ePub Link

Cite

CITE: export Copy Download Format; Close

Download Citation

Download a citation file in RIS format that can be imported by all major citation management software, including EndNote, ProCite, RefWorks, and Reference Manager.

Format:

RIS — For EndNote, ProCite, RefWorks, and most other reference management software
BibTeX — For JabRef, BibDesk, and other BibTeX-specific software

Include:

Citation for the content below
Citation and abstract for the content below

Long-Term Outcomes and Sequelae Analysis of Intracranial Germinoma: Need to Reduce the Extended-Field Radiotherapy Volume and Dose to Minimize Late Sequelae

Cancer Res Treat. 2021;53(4):983-990. Published online January 13, 2021

DOI: https://doi.org/10.4143/crt.2020.1052

XML Download

Top of article

Abstract
Introduction
Materials and Methods
Results
Discussion
NOTES
REFERENCES

Long-Term Outcomes and Sequelae Analysis of Intracranial Germinoma: Need to Reduce the Extended-Field Radiotherapy Volume and Dose to Minimize Late Sequelae

Table 1

Patient characteristics

Factor	Value
Age (yr)	15 (4–47)
Sex
Male	151 (79.9)
Female	38 (20.1)
ECOG PS
0–1	156 (82.6)
2	22 (11.6)
3–4	11 (5.8)
Tumor site
Solitary
Suprasellar	41 (21.7)
Pineal	46 (24.3)
BG/Thalamus	29 (15.3)
Others^a)	3 (1.6)
Bifocal
Suprasellar and pineal	15 (7.9)
Suprasellar and other	5 (2.6)
Pineal and other	2 (1.1)
Others^b)	3 (1.6)
Seeding (+)
CSF cytology (+)	10 (5.3)
Multiple lesions in MRI (+)	22 (11.6)
CSF cytology and MRI (+)	13 (6.9)

Values are presented as median (range) or number (%). BG, basal ganglia; CSF, craniospinal fluid; ECOG PS, Eastern Cooperative Oncology Group performance status; MRI, magnetic resonance imaging.

^a)Including frontal lobe and temporal lobe,

^b)Including temporal lobe, and midbrain.

Table 2

Field of radiotherapy and pattern of recurrence

Tumor site	CTx	RT field	No.	Recurrence
				Intracranial		Spinal
				In-field	Out-field	Spinal
Solitary/Bifocal	(−)	WB	5	1	-	2
		CSA	36	2	-	-
	(+)	IF only	25	1^a)	4+1^a)	-
		WV	54	-	-	1
		WB	3	-	-	-
		CSA	21	-	-	-
Multifocal/Seeding	(−)	CSA	9	-	-	-
	(+)	IF only	3	-	2	-
		WV	2	-	-	-
		WB	1	-	-	-
		CSA	30	-	-	-

^a)Combined intracranial in-field and out-field recurrences in a case.

Table 3

In-field recurrence according to radiation dose after upfront chemotherapy

Dose, median (range)	No.^a)
Cranial field (WB/WV)
18 Gy (16–19)	0/34
23 Gy (20–27)	0/60
36 Gy (30–39)	0/16
Spinal field to positive seeding
9 Gy (9)	0/1
23 Gy (19–24)	0/24
36 Gy (30–36)	0/5
Involved field
Complete response
30 Gy (26–30)	0/9
39 Gy (36–43)	0/18
45 Gy (45–46)	0/31
50 Gy (46–50)	0/16
Not complete response
45 Gy (45–49)	1/19
54 Gy (50–60)	0/46

WB, whole brain followed by involved-field boost; WV, whole ventricle followed by involved-field boost.

^a)Number of recurrences/total number of patients.

Table 4

Late toxicities and treatment factors

Factor	Hormone-replacement therapy^a)		Back to school (%)^b)		NCF (%)^c)

	Positive	p-value^d)	Yes	p-value^d)	Declined	p-value^d)
Treatment

RT	10/19 (52.6)	0.011	25/31 (80.7)	0.022	8/29 (27.6)	0.002

CRT	22/93 (23.7)		84/89 (94.4)		9/121 (7.4)

RT, total dose (Gy)

≤ 50	13/57 (22.8)	0.169	47/51 (92.0)	0.670	4/69 (6.0)	0.051

> 50	19/55 (34.6)		62/69 (90.0)		13/81 (16.0)

WB RT

WBRT	22/52 (42.3)	0.003	56/65 (86.2)	0.053	12/79 (15.2)	0.116

WVRT or IFRT only	10/60 (16.7)		53/55 (96.4)		5/71 (7.0)

WB/WV dose (Gy)

≤ 30	12/85 (44.4)	0.036	75/80 (94.0)	0.120	8/111 (7.2)	0.007

> 30	20/27 (23.5)		34/40 (85.0)		9/39 (23.1)

^a)Excluding initial hormone deficiency,

^b)Patients in school-age,

^c)Excluding patients inaccessible to neurocognitive questionnaire in the medical records,

^d)Chi-square test.

Table 5

Secondary malignancy and treatment factors

Factor	Total	Event (%)	Incidence rate^a)	Incidence rate ratio (95% CI)
Treatment
CRT	135	3 (2.2)	1.6	0.163 (0.027–0.715)
RT	44	7 (15.9)	10.0
WB RT
WBRT	96	9 (9.4)	6.4	7.208 (0.999–315.915)
WVRT or IFRT only	83	1 (1.2)	0.9
Total dose (Gy)
> 50	105	9 (8.6)	6.3	7.001 (0.970–306.874)
≤ 50	74	1 (1.3)	0.1
WB/WV RT dose (Gy)
> 30	58	8 (13.8)	9.0	7.375 (1.472–71.294)
≤ 30	121	2 (1.6)	0.1

CI, confidence interval; CRT, radiotherapy with upfront chemotherapy; IFRT, involved-field RT; RT, radiotherapy; WB, whole brain; WV, whole ventricle.

^a)Per 10,000 person-year.

Table 1 Patient characteristics

Values are presented as median (range) or number (%). BG, basal ganglia; CSF, craniospinal fluid; ECOG PS, Eastern Cooperative Oncology Group performance status; MRI, magnetic resonance imaging.

Including frontal lobe and temporal lobe,

Including temporal lobe, and midbrain.

Table 2 Field of radiotherapy and pattern of recurrence

Combined intracranial in-field and out-field recurrences in a case.

Table 3 In-field recurrence according to radiation dose after upfront chemotherapy

WB, whole brain followed by involved-field boost; WV, whole ventricle followed by involved-field boost.

Number of recurrences/total number of patients.

Table 4 Late toxicities and treatment factors

Excluding initial hormone deficiency,

Patients in school-age,

Excluding patients inaccessible to neurocognitive questionnaire in the medical records,

Chi-square test.

Table 5 Secondary malignancy and treatment factors

CI, confidence interval; CRT, radiotherapy with upfront chemotherapy; IFRT, involved-field RT; RT, radiotherapy; WB, whole brain; WV, whole ventricle.