Emergency Irradiation with 3.4 Gy/2f in Sellar/Suprasellar Germinoma Patients with Rapid Visual Acuity Decline
Introduction
Primary intracranial germ cell tumors (GCTs) are rare malignancies predominantly found in children and adolescents. According to the 2016 World Health Organization (WHO) classification for tumors of the central nervous system, GCTs are histologically classified into germinoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, teratoma, teratoma with malignant transformation, and mixed GCT. Germinoma is the most common subtype, accounting for two-thirds of all cases. Due to the high sensitivity of germinoma cells to chemoradiotherapy, patients with germinoma have excellent prognoses, with a 5-year overall survival rate exceeding 90%.
The sellar/suprasellar region is one of the most commonly involved areas in germinoma. Visual function impairments, such as visual acuity (VA) decline and visual field defects, are frequent complaints among patients with sellar/suprasellar germinoma. Some patients experience rapid VA deterioration due to the rapid progression of tumor cells, necessitating immediate intervention to prevent irreversible loss of visual function. While surgery can debulk the tumor and provide a histological diagnosis, it may lead to rapid vision deterioration postoperatively. Additionally, tumor regrowth during the postoperative recovery period can compromise surgical outcomes. Chemotherapy is an alternative due to germinoma’s high sensitivity to antitumor agents. However, patients with sellar/suprasellar germinoma often present with poorer general conditions at diagnosis, secondary to adipsic diabetes insipidus and endocrinopathy, increasing the risk associated with systemic therapy.
In this context, emergency irradiation with 3.4 Gy/2f was applied initially to preserve visual function and enable subsequent antitumor therapy. This study presents the results from 33 patients diagnosed and treated at Beijing Tiantan Hospital, retrospectively analyzing the efficacy of this approach.
Methods
Ethical Approval
The study was reviewed and approved by the Institutional Review Board of Beijing Tiantan Hospital (Grant number: KY 2018-064-02). Patient informed written consent was waived by the Institutional Review Board.
Study Population
Medical records from patients diagnosed with germinoma at Beijing Tiantan Hospital between January 2014 and December 2017 were screened. Inclusion criteria were: (1) age <30 years, (2) primary lesion located in the sellar/suprasellar region, (3) elevation of serum beta-human chorionic gonadotropin (b-HCG; normal value <5.0 U/L) or placental alkaline phosphatase (PLAP; normal value 30.0–114.0 U/L), (4) mandatory pathology for patients with negative serum tumor markers, (5) severe and acute VA decline within 3 months, and (6) emergency irradiation administered due to VA decline. Exclusion criteria were: (1) primary lesion located outside the sellar/suprasellar region, (2) mild and chronic VA decline, (3) elevated alpha-fetoprotein (AFP), or (4) chemotherapy as the initial treatment modality.
Due to the rapid visual function deterioration, the diagnosis of germinoma was primarily based on clinical presentations, tumor site, tumor markers, and radiological findings. Clinical data from eligible patients were obtained from the institutional archive and analyzed retrospectively.
Treatment Strategy
Before treatment, all patients underwent baseline evaluations, including medical history, general physical examination, VA examination, complete blood count, serum chemistry, serum tumor markers (b-HCG, AFP, and PLAP), endocrine function evaluation, and radiographic examinations (plain computed tomography scan, enhanced-contrast magnetic resonance imaging [MRI]). Humphrey perimetry was optional. Emergency irradiation of 3.4 Gy/2f was subsequently administered to the primary lesions. Approximately one week later, baseline evaluations were repeated, and spinal MRI was performed. For patients with tumor regression, two cycles of platinum-based chemotherapy were administered, followed by radiotherapy. Otherwise, surgery was considered. Radiotherapy consisted of whole-brain irradiation with a dose of 24 to 30 Gy and a boost to the primary lesions. The total prescription dose reached 40 Gy for patients with complete remission (CR) to chemotherapy and 50 Gy for those with less than CR. Patients with disseminated disease also received cranial spinal irradiation (CSI) to the entire cranial contents and spinal axis. After completion of radiotherapy, up to four cycles of platinum-based chemotherapy was recommended. Routine follow-up was repeated every 3 months for the first 2 years and every 6 months for the next 3 years.
Visual Examination
The standard VA chart was used to collect best-corrected VA (BCVA). For statistical analysis, the logarithm of the minimum angle of resolution (LogMAR) was used and converted from BCVA according to the formula LogMAR = Log (1/BCVA). Humphrey perimetry was used in visual field examination, with the mean deviation (MD) applied for assessment of the visual field defect.
Statistical Analysis
IBM SPSS Statistics version 19.0 software was used for data analysis. Non-normal distribution data were shown as median (range), and normal distribution data were shown as mean ± standard deviation. The Wilcoxon rank sum test was used to compare continuous variables, and the Chi-square test was used to compare categorical variables. The Spearman rank correlation test was applied to analyze the correlation between visual function change and clinical factors such as age at diagnosis, duration of VA decline, extent of tumor regression, and serum levels of tumor markers (b-HCG and PLAP). The response assessment in neuro-oncology criteria was used in the response evaluation. A P < 0.05 was considered statistically significant, and all statistical tests were two-sided.
Results
Patient Characteristics
The study included 33 patients with a median follow-up period of 19 months (range: 3–42 months). The median age was 11 years (range: 5–27 years), with a majority of female patients (24/33, 72.7%). The median diameter and volume of sellar/suprasellar lesions were 32 mm (range: 5–55 mm) and 12.9 cm³ (range: 0.6–58.5 cm³), respectively. Tumor markers were elevated in 93.9% (31/33) of patients. The median levels of b-HCG and PLAP were 14.2 U/L (range: 5.5–222.0 U/L) and 137.0 U/L (range: 120.0–326.0 U/L), respectively. Both patients with negative tumor markers were diagnosed with germinoma after initial surgery and had progressive disease 4 and 5 months later, respectively.
In addition to VA decline, adipsic diabetes insipidus was reported by all patients, with a median duration of 10 months (range: 1–48 months) before diagnosis. Up to 60.6% (20/33) of patients also had hypernatremia. Endocrine examination found that 66.7% (22/33) of patients had T3/T4 deficiency and 81.8% (27/33) had cortisol deficiency. Ten patients had psychological symptoms such as drowsiness, agitation, fatigue, and dizziness. One patient had cachexia, believed to be secondary to pituitary abnormalities.
Treatment Results
At a median of 7 days (range: 3–25 days) after emergency irradiation, the median percentage of tumor remission was 55.0% (range: 15.0%–90.0%), with partial remission (PR) achieved in 72.7% (24/33) of patients and stable disease in the remainder. Subsequently, 26 patients received two cycles of chemotherapy, and three received one cycle. Before chemoradiotherapy, CR was achieved in 23 patients, and six patients still had residual disease (<0.5 cm). Four patients received no chemotherapy prior to radiotherapy due to creatinine elevation, leukopenia, or tachycardia. In terms of radiotherapy, 22 patients received a total dose of 40 Gy, eight received 50 Gy, and three received CSI. No patients relapsed or died.
Visual Acuity
Data on pre- and post-emergency-irradiation BCVA were obtained in 32 patients, except for one 5-year-old girl who failed to cooperate with the examination. For the right eye, BCVA improved in 23 patients (71.9%), was unchanged in 7 (21.9%), and worsened in 2 (6.2%). For the left eye, BCVA improved in 27 patients (84.4%), was unchanged in 4 (12.5%), and worsened in 1 (3.1%). If improvement was defined as achieved in at least one eye, 30 patients (93.8%) achieved improvement. One patient (3.1%) was unchanged in both eyes, and one patient (3.1%) had one eye unchanged and one eye worsened.
For the LogMAR score, the median pre- and post-emergency-irradiation LogMAR scores of the right eyes were 0.8 (range: –0.1 to 3.0) and 0.3 (range: –0.1 to 3.0), respectively, and for the left eyes, these numbers were 0.7 (range: 0 to 3.0) and 0.3 (range: 0 to 3.0), respectively. The LogMAR score improvement reached a significant level in both eyes (P < 0.001).
To further explore factors correlating with LogMAR score improvement, the Spearman rank correlation test was conducted. Unfortunately, none of the factors, including age at diagnosis, duration of VA decline, extent of tumor regression, and serum levels of tumor markers (b-HCG and PLAP), showed a correlation with LogMAR score improvement.
Visual Field Defects
Post-emergency-irradiation Humphrey perimetry data were available in 19 patients, with pre-emergency-irradiation data available in only six patients. In six patients with paired data, MD improvement was marginal in the right eyes (P = 0.068) and reached a significant level in the left eyes (P = 0.043). However, no clinical factor showed a correlation with MD change.
Discussion
This study investigated the efficacy of emergency irradiation with 3.4 Gy/2f in patients with sellar/suprasellar germinoma experiencing rapid visual function deterioration. The results demonstrated that this modality was effective in preserving patient visual function, with significant improvements in VA and visual field defects.
In patients with sellar/suprasellar lesions, diagnosing germinoma remains challenging, especially for those with negative tumor markers. Although biopsy is an option, it carries high risks due to the critical brain and cranial nerve structures adjacent to the pituitary area. Diagnostic radiotherapy, first reported by Japanese authors in the 1990s, involves delivering a dose of 20 Gy/10f. However, this dosage is high, and potential side effects are a concern. Therefore, lower doses, such as 10 Gy/5f and 3.4 Gy/2f, have been explored. In our study, 72.7% of patients achieved PR with 3.4 Gy/2f, suggesting that this approach is reasonable for diagnostic purposes with minimal impact on subsequent medical procedures.
In terms of treatment, cranial spinal irradiation (CSI) was traditionally the standard care for germinoma, with a cure rate exceeding 90%. However, its toxicities are a concern. Many studies have found that adding chemotherapy can reduce the dose and/or field of radiotherapy without compromising long-term survival in patients with localized lesions. In our cohort, the treatment modality included induction chemotherapy, radiotherapy, and maintenance chemotherapy. Induction chemotherapy may extinguish possible micrometastasis and test tumor sensitivity to antitumor therapy. For patients with residual disease after induction chemotherapy, the histological content other than germinoma can be considered, and the dose of radiotherapy can be escalated.
In conclusion, emergency irradiation with 3.4 Gy/2f was effective in preserving patient visual function and enabling subsequent antitumor therapy in patients with sellar/suprasellar germinoma experiencing rapid visual acuity decline.
doi.org/10.1097/CM9.0000000000000315
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