Whole-ventricle Irradiation Research Articles

GCT-17. EXPLORING NEW THRESHOLDS FOR BETA-HCG IN CENTRAL NERVOUS SYSTEM GERMINOMA

Abstract BACKGROUND Human chorionic gonadotropin (beta-HCG) levels in serum and cerebrospinal fluid (CSF) are critical in the management of patients with germinoma. The threshold for beta-HCG diagnosis is a topic of debate and differs in Europe, ≤50 IU/L, North America ≤100 IU/L, and ≤200 IU/L in Brazil/Japan. METHODS We conducted a meta-analysis of English-language publications (1990-2023) to assess how beta-HCG cut-off levels impact treatment outcomes. Standard descriptive statistics summarized all data. RESULTS Forty-nine patients with biopsied germinoma were identified. Eighteen had beta-HCG level of 50-100 IU/L (cohort 1), 21 had 100-200 IU/L (cohort 2), and 10 had >200 IU/L (cohort 3). In cohort 1, treatment with chemotherapy plus radiotherapy was administered to 9 patients. Eight of them received radiotherapy like germinoma treatment (≤30Gy), primarily employing whole ventricle irradiation (WVI). Nine patients received radiotherapy alone with total dose 30-59.6Gy. Fifteen patients in cohort 2 received chemotherapy plus radiotherapy. Eight of them received radiotherapy ≤30Gy for different fields [WVI – 4, whole brain (WB) – 3, cerebrospinal irradiation (CSI) – 1). In 7 patients the dose of radiotherapy exceeded 30Gy (local radiotherapy – 4, CSI – 3). Radiotherapy alone was used in 5 patients, chemotherapy alone – 1 patient. In cohort 3, radiotherapy only was primarily used. Six patients received CSI (50-54Gy), one – CSI+WB+local radiotherapy (12.8Gy+27.2Gy+50.6Gy). One patient received combined treatment and 2 patients received chemotherapy alone. Relapses occurred in each cohort. In cohort 1 – 2 metastatic relapses (1 after WVI 24Gy, 1 after radiotherapy >30Gy). Three children from cohort 2, who received chemotherapy plus radiotherapy were diagnosed with relapse (1 after WB 23.4Gy, 2 after radiotherapy >30Gy). In cohort 3 two metastatic relapses were diagnosed – only after chemotherapy. CONCLUSIONS Relapse rates across all beta-HCG level are similar. However, study groups are small and treatment regimens vary, warranting further investigation.

Bifocal lesions have a poorer treatment outcome than a single lesion in adult patients with intracranial germinoma.

Intracranial germinoma (IG) rarely occurs in adults. Its optimal treatment strategy is unclear. We evaluated the outcomes of radiotherapy in adults with intracranial germinoma. Data of 29 adult patients (age, 18–52 years; median age, 24.3 years) with IG treated with radiotherapy at Taipei Veterans General Hospital were retrospectively reviewed. They were followed up for a median time of 5.9 years (range, 1.0–12.8 years). We used the Kaplan–Meier method to estimate the progression-free survival (PFS) and overall survival (OS), and univariate and multivariate Cox proportional hazards regression models to identify the factors affecting PFS. PFS and OS were compared between adult and pediatric patients with IG. The 1-, 3-, and 5-year PFS rates were 96.6%, 85.8%, and 77.8%, respectively, in the adult patients, and the OS rate were all 100%. Seven patients (24.1%) experienced recurrence, and in six of them, salvage therapy successfully controlled the disease. Two patients (6.9%) died after 5 years of follow-up due to disease progression and central pontine myelinolysis. In the univariate and multivariate Cox analysis, bifocal lesions had a significantly lower PFS than those with single lesions (p = 0.008). Kaplan–Meier survival analysis showed that adult patients had a poorer PFS (p = 0.06) and OS (p = 0.025) than pediatric patients. Our study showed bifocal lesions were associated with lower PFS than a single lesion among adult IG patients, and adult IG patients tended to have poorer PFS and OS compared to pediatric IG patients. For adult patients with bifocal IG, we recommend treatment with craniospinal irradiation, whole ventricle irradiation (WVI) with chemotherapy, or frequent spine images follow-up for patients who received only WVI.

GCT-17. WHAT IS THE CLINICAL OUTCOME OF PROTON BEAM THERAPY FOR PATIENTS WITH INTRACRANIAL GERM CELL TUMOR IN KOREA?

PURPOSETo evaluate the clinical outcome of patients with intracranial germ cell tumor treated with proton beam therapy (PBT).MATERIALS AND METHODSFifty-seven patients with intracranial germ cell tumor treated with PBT between 2009 and 2016 were retrospectively analyzed.RESULTSMedian follow-up duration was 63.7 months (range, 5.6–204.5). Thirty-seven patients (64.9%) were pure germinoma and 20 patients (35.1%) were non-germinomatous germ cell tumor (NGGCT). All patients except 2 patients received chemotherapy before PBT. Twenty-one patients (36.8%) of localized germinoma were treated with whole ventricle irradiation (WVI), while 36 (63.2%) patients who were diagnosed as disseminated germinoma or NGGCT received cranio-spinal irradiation (CSI). Two patients with pure germinoma in basal ganglia showed disease relapse at 3.0 and 6.9 years after PBT at the primary site and pituitary gland, respectively. There was one patient with NGGCT who died of chemotherapy-related mortality at 4.7 years after PBT while her disease was complete remission. The 7-year progression-free survival and overall survival were 70.8% and 100% for focal germinoma, 100% and 100% for disseminated germinoma, 100% and 100% for focal NGGCTs, and 100% and 80.0% for disseminated NGGCTs, respectively.CONCLUSIONSPBT of pure germinoma resulted in comparable clinical outcomes to that with photon radiotherapy. Our result for NGGCT is also excellent compared to other reports. Failure patterns of germ cell tumors originating in basal ganglia needs to be assessed in large pooled data.

GCT-50. LONG-TERM OUTCOMES OF INTRACRANIAL GERMINOMA IN A SINGLE INSTITUTION

The treatment for intracranial germinoma has been well-established. Complete removal is not necessary, but radiation therapy is important. As the prognosis of patients with germinoma has become better, side effect of radiotherapy and chemotherapy must be well considered. The aim of this study was to evaluate the outcome of intracranial germinomas at Kyoto University Hospital from 1979 to 2019. 64 patients were diagnosed as intracranial germinoma. Patients with hCG > 100 IU/l and/or AFP > 10 ng/ml were excluded. Patients, who were histologically diagnosed as germinoma without information of hCG and AFP, were included. Follow-up time was from 2 to 486 months (median 136 months). Recently, germinoma patients were diagnosed with biopsy and received low dose whole-ventricle irradiation with intensity modulated radiation therapy (IMRT) (total 24-30Gy) and chemotherapy dominated by platinating agent. 10-year PFS was 80.21% (high dose radiation alone), 86.36% (high dose radiation with chemotherapy) and 100% (low dose radiation with chemotherapy). Many recurrent sites were out of irradiation areas. Late cognitive dysfunction was identified in 6 patients, and 5 of them were treated with high dose radiation. Patients with intracranial germinoma can obtain long-term survival. It is important to prevent recurrence without increasing late iatrogenic complications. Low dose radiotherapy and chemotherapy is highly effective, and it potentially reduces late adverse effects.

Early outcomes and patterns of failure following proton therapy for nonmetastatic intracranial nongerminomatous germ cell tumors.

Although dosimetric comparisons demonstrate the advantage of proton therapy (PT) over conventional radiotherapy for nongerminomatous germ cell tumors (NGGCT), clinical outcome data for this rare tumor are lacking. We sought to evaluate outcomes for children with NGGCT treated with PT. Between 2007 and 2016, 14 children (median age 11, range, 5-19 years) with nonmetastatic NGGCT were treated with PT after induction chemotherapy. Most (8/14) were mixed germ cell. Five of 14 patients had complete resection of their primary tumor before radiation. Off study, eight patients received 36Gy (RBE [relative biological effectiveness]) craniospinal irradiation (CSI). On study, two patients received 30.6Gy (RBE) whole-ventricle irradiation and four received focal radiation alone. All patients received a total dose of 54Gy (RBE) to the tumor/tumor bed. At a median follow-up of 2.8 years, all patients were alive with no local recurrences. Three-year progression-free survival was 86%. Both metastatic recurrences occurred in patients treated with focal radiation alone; one with an immature teratoma developed an isolated spinal recurrence 5 months after treatment. Another with a mixed germ cell tumor developed a multifocal ventricular and shunt tract recurrence 7 months after treatment. Serious toxicity was minimal, including cataracts and hormone deficiency, and limited to children who received CSI. Early outcomes in children treated for NGGCT suggest the high conformality of PT does not compromise disease control and yields low toxicity. This pattern of failure data adds to growing evidence suggesting chemotherapy followed by focal radiotherapy alone is inadequate in controlling localized NGGCT.

Reduced-volume radiotherapy for patients with localized intracranial nongerminoma germ cell tumors.

Craniospinal irradiation is standard radiotherapy (RT) for localized intracranial nongerminoma germ cell tumors (NGGCT). Given its toxicity, there is interest in using smaller fields. We examined outcomes of NGGCT patients receiving reduced-volume RT at a single institution. Records of 16 patients who received reduced-volume RT as part of definitive treatment between 1996 and 2016 were reviewed. Median age at presentation was 10.8 years (range 4.6-41.0 years). Ten patients had pineal tumors and 6 had suprasellar tumors. All received chemotherapy and 9 patients received second-look surgery thereafter. RT volume was tumor-only to a median of 54Gy (range 50.4-54Gy) in 3 patients and whole-ventricle irradiation to a median of 30.6Gy (range 30.6-36Gy) with a boost to 54Gy in 13 patients. Median follow-up was 4.1 years (range 1.9-19.3 years). Three patients recurred locally at a median 9.9 months (range 9.6-10.6 months) after diagnosis, and one of these developed leptomeningeal relapse after 30 months. One patient expired from disease 2.6 years post-diagnosis and another due to stroke 19.3 years post-diagnosis. Fourteen patients are alive with no evidence of disease. Kaplan-Meier estimates of the 4-year overall survival and failure-free survival are 92% (95% confidence interval [CI], 57-99%) and 81% (95% CI 53-94%), respectively. Excellent disease control was observed in these patients with no initial relapses outside of these RT fields. The results of ACNS1123 may better delineate patterns of failure and identify subgroups likely to benefit from this approach.

Outcomes for pediatric patients with central nervous system germ cell tumors treated with proton therapy

PurposeWe assessed outcomes after proton therapy (PT) for central nervous system germinomas or non-germinomatous germ cell tumors (NGGCTs) in children. Patients and methodsWe identified children with germ cell tumors of the central nervous system who received proton therapy in 2006–2009 and extracted information on tumor response, treatment failures, and toxicity. ResultsOf the 20 identified patients (median age 12years [range 3–16]), 9 had germinoma and 11 NGGCTs; 19 patients received three-dimensional conformal PT and 1 scanning-beam PT. Fourteen patients had craniospinal irradiation (CSI), 4 had ventricular irradiation that excluded the 4th ventricle, and 2 had whole-ventricle irradiation. All received involved-field boosts. At a median follow-up interval of 5.6years (range, 0.3–8.2years), 1 patient with germinoma had an out-of-field failure in the 4th ventricle and 2 with NGGCT died from disease progression after CSI. Rates of local control, progression-free survival, and overall survival at 5years were 89%, 89%, and 100% for patients with germinoma; corresponding rates for NGGCTs were 82%, 82%, and 82%. The most common late toxicity (9 patients [45%]) was endocrinopathy. ConclusionsPT for CNS germ cell tumors is associated with acceptable disease control rates and toxicity profiles.

Pure germinomas of the central nervous system: treatment strategies and outcomes.

To evaluate the role of chemotherapy and radiation therapy in the treatment of pure germinomas of the central nervous system (CNS). We reviewed a historical cohort of 79 patients between the ages of 3-35years who received definitive treatment for newly diagnosed, pure CNS germinoma between 1985 and 2010 at the University of California, San Francisco (UCSF). Median age at diagnosis was 15years (interquartile range, IQR 12-20years) and 61 (77.2%) patients were male. Median follow-up for the cohort was 111.1months (IQR 45.7-185.1months). Five-year PFS rate was 86.4% (95% CI 76.1-92.4) and 5year OS rate was 93.0% (95% CI 84.1-97.1). Median PFS was 104.6months (IQR 41.4-170.1months). Fourteen patients progressed and 8 died of their disease. Patients who received focal irradiation (XRT) and chemotherapy had a significantly higher rate of progression compared to those who received whole brain irradiation (WBI) or whole ventricle irradiation (WVI). Three of 8 patients had a PR to chemotherapy and received focal XRT progressed whereas only 1 of 9 patients who had a CR to chemotherapy who went on to receive focal XRT progressed. Elevation of hCGβ>50mIU/ml was not significantly associated with disease progression (HR 5.64, 95% CI 0.97-32.7, p=0.054). Patients treated with WBI or WVI with or without chemotherapy achieve better disease control compared to patients treated with focal XRT+chemotherapy.

SU-E-CAMPUS-T-04: Plan Quality of Proton Vs. Photon IMRT for Whole Ventricle Irradiation

Purpose: To assess whether photon IMRT is an alternative to protons for whole ventricle irradiation (WVI), we compare dosimetric plans of helical tomotherapy with passively-scattered protons for WVI based upon target dose uniformity and conformity and organ-at-risk (OAR) sparing. Methods: Six representative pediatric patients treated for CNS disease were evaluated retrospectively. A 3 mm isotropic expansion of the ventricles' contour was designated as the PTV and prescribed to 24 Gy. Among the OARs considered were the temporal lobes, optic chiasm, optic nerves, inner ears, and lenses. Tomotherapy plans were generated using the TomoTherapy planning system v. 4.2 (Accuray, Inc.) with the longitudinal jaw size of 2.5 cm and the pitch of 0.287. Three-field proton plans were created using CMS XiO v. 4.70 (Elekta, Inc.), using a passively-scattered proton beam model with maximum range of 32 g/cm2 (225 MeV), range modulation in 0.5 g/cm2 increments, and Lucite range compensators. Plan quality was compared using a series of parameters including conformity index (CI), uniformity index (UI), and a EUD-based plan quality index (fEUD), a composite value calculated using the generalized EUD of all targets and OARs. Results: Among the 6 patients, proton plans exhibited slightly better CI for 4 cases and slightly better UI for 5 cases. If all OARs are considered, the proton plans had slightly better fEUD (0.20 vs. 0.17). This was attributed to the total avoidance of the eyes and lenses among the proton plans. If the eyes and lenses are excluded, the average fEUD is equal to 0.20 for both planning techniques. Conclusion: For WVI, if the sparing of distal ROIs such as the eyes and lenses is a concern, classical proton planning is a more favorable choice. Otherwise, the overall dose to the target and proximal OARs are comparable for both planning techniques.

Salvage Treatment for Recurrent Intracranial Germinoma After Reduced-Volume Radiotherapy: A Single-Institution Experience and Review of the Literature

Intracranial germinomas (IGs) are highly curable with radiotherapy (RT). However, recurrence still occurs, especially when limited-field RT is applied, and the optimal salvage therapy remains controversial. Between January 1989 and December 2010, 14 patients with clinically or pathologically diagnosed recurrent IGs after RT were reviewed at our institution. Of these, 11 received focal-field RT, and the other 3 received whole-brain irradiation, whole-ventricle irradiation, and Gamma Knife radiosurgery as the respective first course of RT. In addition, we identified from the literature 88 patients with recurrent IGs after reduced-volume RT, in whom the details of salvage therapy were recorded. The median time to recurrence was 30.3 months (range, 3.8-134.9 months). One patient did not receive further treatment and was lost during follow-up. Of the patients, 7 underwent salvage with craniospinal irradiation (CSI) plus chemotherapy (CT), 4 with CSI alone, 1 with whole-brain irradiation plus CT, and 1 with Gamma Knife radiosurgery. The median follow-up time was 105.1 months (range, 24.2-180.9 months). Three patients died without evidence of disease progression: two from second malignancies and one from unknown cause. The others remained disease free. The 3-year survival rate after recurrence was 83.3%. A total of 102 patients from our study and the literature review were analyzed to determine the factors affecting prognosis and outcomes. After recurrence, the 5-year survival rates were 71% and 92.9% for all patients and for those receiving salvage CSI, respectively. Univariate analysis showed that initial RT volume, initial RT dose, initial CT, and salvage RT type were significant prognostic predictors of survival. On multivariable analysis, salvage CSI was the most significant factor (p = 0.03). Protracted follow-up is recommended because late recurrence is not uncommon. CSI with or without CT is an effective salvage treatment for recurrence after reduced-volume RT.

Optimal Treatment for Intracranial Germinoma: Can We Lower Radiation Dose Without Chemotherapy?

To review the effectiveness of reduced-dose and restricted-volume radiation-only therapy in the treatment of intracranial germinoma and to assess the feasibility of reducing or eliminating the use of chemotherapy. Between January 1996 and March 2007, a retrospective analysis was performed that included 38 patients who received either reduced radiation alone (30 Gy for 26 patients) or reduced radiation with chemotherapy (n = 12 patients). All 38 patients received extended focal (including whole-ventricle) irradiation and were followed up until February 2008. Overall survival (OS) and relapse-free survival (RFS) rates were calculated. Variables associated with survival were evaluated by univariate Cox proportional hazards regression. Median follow-up was 62.4 months (range, 10.1-142.5 months). The total 5-year OS rate was 93.7%. The 5-year OS and RFS rates for patients receiving radiation only were 100% and 96.2%, respectively. The rates for those receiving radiation plus chemotherapy were 83.3 % and 91.7%, respectively (not statistically significant). No predictive factor was significantly associated with the OS or RFS rate. Chemotherapy had no significant effect on survival but was associated with a higher incidence of treatment-related toxicity. A further decrease in the radiation dose to 30 Gy with whole-ventricle irradiation is sufficient to treat selected patients with intracranial germinoma. Wide-field irradiation or chemotherapy should be avoided as these methods are unnecessary. Thus, reduction of the radiation dose to 30 Gy may be feasible, even without chemotherapy.

Long term outcomes in patients with intracranial germinomas: a single institution experience of irradiation with or without chemotherapy

Complete remission can be achieved soon after irradiation in patients with intracranial germinoma. This study aimed to analyze the follow-up outcome of intracranial germinoma patients. About 39 intracranial germinoma patients (29 males and 10 females; average age, 15 years; range, 7-27 years) treated at Kyoto University Hospital from 1978 to 2004 were included in the study group. Six patients had multifocal disease at initial diagnosis, and 10 had human chorionic gonadotropin (HCG)-producing tumors. Thirteen patients were treated with craniospinal axis irradiation, 6 with whole-brain irradiation, 17 with whole-ventricle irradiation, and 3 with local field irradiation. Since 1997, 15 patients were treated with reduced-dose whole-ventricle irradiation (median, 23.4 Gy; range, 20.4-27 Gy) followed by a local boost (median, 40.8 Gy; range, 36-54 Gy) combined with chemotherapy. The median follow-up was 94 months (18 months to 25 years). The 5- and 10-year overall survival (OS) rates of the entire group were 97 and 90%, respectively. The 5- and 10-year progression-free survival (PFS) rates of the entire group were 91 and 87%, respectively. The 8-year OS and PFS in 15 patients treated by whole-ventricle irradiation combined with chemotherapy were 100% and 92%, respectively. Four patients had recurrences within a median period of 59.5 months (51-85 months). All relapses occurred outside the radiation fields. Tumor site, tumor size, HCG production, multifocal disease and radiation dose to the primary site or whole ventricle did not significantly affect PFS. All initial recurrences of intracranial germinoma occurred at the distant site out of the radiation field. Our data suggested that reduced doses to the whole ventricle, combined with chemotherapy, should be sufficiently effective in patients with intracranial germinoma.

Commentary

We assessed outcomes after proton therapy (PT) for central nervous system germinomas or non-germinomatous germ cell tumors (NGGCTs) in children.We identified children with germ cell tumors of the central nervous system who received proton therapy in 2006–2009 and extracted information on tumor response, treatment failures, and toxicity.Of the 20 identified patients (median age 12 years [range 3–16]), 9 had germinoma and 11 NGGCTs; 19 patients received three-dimensional conformal PT and 1 scanning-beam PT. Fourteen patients had craniospinal irradiation (CSI), 4 had ventricular irradiation that excluded the 4th ventricle, and 2 had whole-ventricle irradiation. All received involved-field boosts. At a median follow-up interval of 5.6 years (range, 0.3–8.2 years), 1 patient with germinoma had an out-of-field failure in the 4th ventricle and 2 with NGGCT died from disease progression after CSI. Rates of local control, progression-free survival, and overall survival at 5 years were 89%, 89%, and 100% for patients with germinoma; corresponding rates for NGGCTs were 82%, 82%, and 82%. The most common late toxicity (9 patients [45%]) was endocrinopathy.PT for CNS germ cell tumors is associated with acceptable disease control rates and toxicity profiles.

P-5-564 - Chemotherapy-based treatment protocol using a new classification for the management of primary intracranial germ cell tumors

We assessed outcomes after proton therapy (PT) for central nervous system germinomas or non-germinomatous germ cell tumors (NGGCTs) in children.We identified children with germ cell tumors of the central nervous system who received proton therapy in 2006–2009 and extracted information on tumor response, treatment failures, and toxicity.Of the 20 identified patients (median age 12 years [range 3–16]), 9 had germinoma and 11 NGGCTs; 19 patients received three-dimensional conformal PT and 1 scanning-beam PT. Fourteen patients had craniospinal irradiation (CSI), 4 had ventricular irradiation that excluded the 4th ventricle, and 2 had whole-ventricle irradiation. All received involved-field boosts. At a median follow-up interval of 5.6 years (range, 0.3–8.2 years), 1 patient with germinoma had an out-of-field failure in the 4th ventricle and 2 with NGGCT died from disease progression after CSI. Rates of local control, progression-free survival, and overall survival at 5 years were 89%, 89%, and 100% for patients with germinoma; corresponding rates for NGGCTs were 82%, 82%, and 82%. The most common late toxicity (9 patients [45%]) was endocrinopathy.PT for CNS germ cell tumors is associated with acceptable disease control rates and toxicity profiles.

Analysis of long-term treatment of intracranial germinoma

Purpose : To determine an appropriate treatment policy for intracranial germinoma. Methods and Materials : From 1976 to 1992, 51 patients with germinoma (18 with pathologically verified germinoma and 33 diagnosed as having germinoma by neuroimagings) were treated by radiation therapy. Various radiation doses and treatment fields were used. Results :The 10-year cause-specific survival rate for pathologically verified and unverified germinoma was 100% and 96%, respectively. Relapse were noted in four patients, three of whom died from the disease. Two of the four patients with a tumor larger than 4 cm in gross diameter experienced relapse. Two relapse occurred in a nonirradiated spinal canal and two occurred in the irradiation area treated by 25 Gy in 10 fractions and 30 Gy in 20 fractions. No relapse was noted in patients in whom the whole ventricle field was determined precisely using three-dimensional treatment planning. Five patients who were followed at an outpatient clinic experienced significant late neurocognitive dysfunction, which set in after radiotherapy. Conclusion : After pathological confirmation, 40 Gy whole-ventricle irradiation using precise three-dimensional treatment planning is appropriate as a standard treatment for most intracranial germinoma.