Outcomes of intracranial non-germinomatous germ cell tumors: a retrospective Asian multinational study on treatment strategies and prognostic factors.

PURPOSE: Non-germinomatous germ cell tumors (NGGCTs) are rare pediatric conditions. This multicenter study using Asian multinational patient data investigated treatment outcomes and prognostic factors for NGGCTs. METHODS: Medical records of 251 patients with NGGCTs treated from 1995 to 2015 were retrospectively analyzed from participating centers in Asian countries (Korea, Taiwan, Singapore, and Japan). RESULTS: The median follow up was 8.5 years (95% CI 7.8-9.9). In the total cohort, 5-year event-free survival (EFS) and overall survival (OS) rates were 78.2% and 85.4%, respectively. In 17.9% of the patients, diagnosis was determined by tumor markers alone (alpha-fetoprotein ≥ 10 ng/mL (Korea) or > 25 ng/mL (Taiwan and Singapore), and/or ß-human chorionic gonadotropin (ß-hCG) ≥ 50 mIU/mL). Patients with immature teratomas and mature teratomas comprised 12.0% and 8.4%, respectively. The 5-year EFS rate was higher in patients with histologically confirmed germinoma with elevated ß-hCG (n = 28) than those in patients with malignant NGGCTs (n = 127). Among malignant NGGCTs, patients with choriocarcinoma showed the highest 5-year OS of 87.6%, while yolk sac tumors showed the lowest OS (68.8%). For malignant NGGCT subgroups, an increase in serum ß-hCG levels by 100 mIU/mL was identified as a significant prognostic factor associated with the EFS and OS. CONCLUSION: Our result shows excellent survival outcomes of overall CNS NGGCT. However, treatment outcome varied widely across the histopathologic subgroup of NGGCT. Hence, this study suggests the necessity for accurate diagnosis by surgical biopsy and further optimization of diagnosis and treatment according to the histopathology of NGGCTs. Future clinical trials should be designed for individualized treatments for different NGGCTs subsets.

Evaluation of inter- and intra-observer variations in prostate gland delineation using CT-alone versus CT/TPUS.

Background: This study aims to explore the role of four-dimensional (4D) transperineal ultrasound (TPUS) in the contouring of prostate gland with planning computed tomography (CT) images, in the absence of magnetic resonance imaging (MRI). Materials and methods: Five radiation oncologists (ROs) performed two rounds of prostate gland contouring (single-blinded) on CT-alone and CT/TPUS datasets obtained from 10 patients who underwent TPUS-guided external beam radiotherapy. Parameters include prostate volume, DICE similarity coefficient (DSC) and centroid position. Wilcoxon signed-rank test assessed the significance of inter-modality differences, and the intraclass correlation coefficient (ICC ) reflected inter- and intra-observer reliability of parameters. Results: Inter-modality analysis revealed high agreement (based on DSC and centroid position) of prostate gland contours between CT-alone and CT/TPUS. Statistical significant difference was observed in the superior-inferior direction of the prostate centroid position (p = 0.011). All modalities yielded excellent inter-observer reliability of delineated prostate volume with ICC > 0.9, mean DSC > 0.8 and centroid position: CT-alone (ICC = 1.000) and CT/TPUS (ICC = 0.999) left-right (L/R); CT-alone (ICC = 0.999) and CT/TPUS (ICC = 0.998) anterior-posterior (A/P); CT-alone (ICC = 0.999) and CT/TPUS (ICC = 1.000) superior-inferior (S/I). Similarly, all modalities yielded excellent intra-observer reliability of delineated prostate volume, ICC > 0.9 and mean DSC > 0.8. Lastly, intra-observer reliability was excellent on both imaging modalities for the prostate centroid position, ICC > 0.9. Conclusion: TPUS does not add significantly to the amount of anatomical information provided by CT images. However, TPUS can supplement planning CT to achieve a higher positional accuracy in the S/I direction if access to CT/MRI fusion is limited.

Outcomes following limited-volume proton therapy for multifocal spinal myxopapillary ependymoma.

PURPOSE: Spinal myxopapillary ependymoma (MPE) often presents with a multifocal distribution, complicating attempts at resection. There remains no standard approach to irradiating these patients. We report disease control and toxicity in pediatric patients with multifocal spinal MPE treated with limited-volume proton therapy. MATERIALS/METHODS: Twelve patients (≤21 years old) with multifocal spinal MPE were treated between 2009 and 2018 with limited-volume brain-sparing proton therapy. Median age was 13.5 years (range, 7-21). Radiotherapy was given as adjuvant therapy after primary surgery in five patients (42%) and for recurrence in seven (58%). No patient received prior radiation. Eleven patients (92%) had evidence of gross disease at radiotherapy. Eleven patients received 54 GyRBE; one received 50.4 GyRBE. Treatment toxicity was graded per the CTCAEv4.0. We estimated disease control and survival using the Kaplan-Meier product-limit method. RESULTS: The median follow-up was 3.6 years (range, 1.8-10.6). The five-year actuarial rates of local control, progression-free survival, and overall survival were 100%, 92%, and 100%, respectively. One patient experienced an out-of-field recurrence in the spine superior to the irradiated region. No patients developed in-field recurrences. Following surgery and irradiation, one patient developed grade three spinal kyphosis and one patient developed grade 2 unilateral L5 neuropathy. CONCLUSION: 54 GyRBE to a limited volume appears effective for disseminated spinal MPE in both the primary and salvage settings, sparing children the toxicity of full craniospinal irradiation. Compared with historical reports, this approach using proton therapy improves the therapeutic ratio, resulting in minimal side effects and high rates of disease control.

A comparative analysis between low-dose-rate brachytherapy and external beam radiation therapy for low- and intermediate-risk prostate cancer in Asian men.

OBJECTIVE: To report the long-term clinical outcomes of low-risk (LR) and intermediate-risk (IR) prostate cancer patients treated with low-dose-rate brachytherapy (LDR-BT) and external beam radiation therapy (EBRT). PATIENTS AND METHODS: Men with biopsy-proven low- and intermediate-risk prostate cancer received EBRT and LDR-BT in an Asian academic center from 2000 to 2019 were reviewed. Kaplan-Meier survival analysis was performed to compare biochemical failure-free survival (bFFS) and overall survival (OS) between LDR and EBRT in the low- and intermediate-risk cohorts. RESULTS: 642 patients (521 EBRT and 121 LDR-BT) with low- and intermediate-risk prostate cancer were included for analysis. In the intermediate-risk group, 5- and 10-year bFFS was 96%, 89% and 86%, 61% for LDR-BT and EBRT, respectively. LDR-BT was associated with a statistically significant improvement of bFFS in the intermediate-risk cohort (HR 2.7, p = 0.02). In the low-risk cohort, no difference of bFFS was found between LDR-BT and EBRT (HR 1.9, p = 0.08). Hormone therapy was more common in EBRT than LDR-BT for intermediate-risk group (71% versus 44%, p < 0.05). Prostate cancer-specific mortality was low in both EBRT (1%) and LDR-BT (2%) cohorts. No significant difference in OS was found between LDR-BT and EBRT in low- and intermediate-risk group (HR 2.1, p = 0.2 and HR = 1.7, p = 0.3). CONCLUSION: In our retrospective study, LDR-BT is associated with superior bFFS compared with EBRT in Asian men with intermediate-risk prostate cancer.

The Role of Radiation Therapy for Symptomatic Desmoid Tumors.

OPINION STATEMENT: Desmoid tumors have a variable clinical course that ranges from indolence or spontaneous regression to an aggressive pattern marked by local invasion. Up to half may remain stable or regress; watchful waiting is the preferred approach in the initial management of desmoid tumors. Symptomatic or progressive tumors or those that may affect adjacent critical structures require surgery, radiotherapy, or systemic therapy. Although radiotherapy effectively controls desmoid tumors in most cases, concerns regarding late toxicity exist. Definitive radiotherapy for macroscopic disease is indicated when a non-morbid complete surgical resection cannot be accomplished and provides similar control rates to surgery plus radiotherapy but avoids toxicity from combined-modality treatment (surgery and radiotherapy). Adjuvant radiotherapy can be considered for microscopically involved margins, particularly for recurrent cases or when a future recurrence may be challenging to treat. Large size, extremity site, and younger age are poor prognostic factors after radiotherapy. In the extremity, radiotherapy may have superior outcomes to surgery. Younger patients, especially children, are challenging to manage as they are at particular risk for late toxicity due to the number of potential years at risk. For patients under 20 years old, for whom a non-morbid complete resection is not possible, we recommend systemic therapy as the first line of treatment. Although the long-term efficacy of systemic therapy is unproven, this strategy allows additional time for growth and development prior to radiotherapy. In younger patients and those with axial desmoid tumors adjacent to critical organs, consideration should be given to using proton therapy as the dosimetric advantages may mitigate some of the toxicity associated with conventional radiotherapy.

Adolescent with facial swelling.

BackgroundA previously well 15-year-old girl presented with a 2-month history of facial swelling that progressively worsened to involve the neck. There was associated dyspnoea, orthopnoea, headache and throat discomfort. Two weeks before presentation, the patient had an episode of fever for 5 days. On examination, vital signs were within normal limits. Swelling, plethora and venous distension of the face and neck were apparent (figure 1).

Duration-dependent margins for prostate radiotherapy-a practical motion mitigation strategy.

BACKGROUND AND OBJECTIVE: The magnitude of intra-fractional prostate displacement (change from initial position over time) is associated with the duration of the patient lying on the radiotherapy treatment couch. This study reports a minute-by-minute association and calculates the impact of this displacement on duration-dependent margins using real-time intra-fractional position data monitored by four-dimensional transperineal ultrasound (4D TPUS). MATERIALS AND METHODS: A total of 55 patients were recruited prospectively. Intra-fractional position of the prostate was monitored in real-time using a 4D TPUS Clarity® system. A total of 1745 monitoring sessions were analysed. Van Herk's margin recipe (2.5∑ + 1.64((σ2 + σp2)1/2 - σp)) was used to estimate the duration-dependant margins for every minute, up to the 15th minute. Linear regression analysis was then performed on the overall margins against time and direction. RESULTS: The mean intra-fractional position was 0.76 mm Inferior (Inf), 0 mm Lateral (Lat) and 0.94 mm Posterior (Post) at the 15th minute. A minimum margin expansion of 2.42 mm (Superior/Inf), 1.02 mm (Left/Right) and 2.65 mm (Anterior/Post) was required for an 8­minute treatment compared to 4.29 mm (Sup/Inf), 1.84 mm (Lt/Rt) and 4.63 mm (Ant/Post) for a 15-minute treatment. The required margin expansion increased linearly (R2 = 0.99) in all directions (p < 0.01). However, while there was no statistically significant difference (p = 0.10) in the required margin expansion in the Sup/Inf and Ant/Post directions respective of the time duration, the margins were much bigger compared to those in the Lt/Rt direction (p < 0.01). CONCLUSION: We report our experience in deriving the minimum duration-dependant margin to generate the required planning target volume for prostate radiotherapy. The required margin increases linearly in all directions within the 15-min duration; thus, the margin will depend on the duration of the technique chosen (IMRT/VMAT/3DCRT/proton).

Cerebrospinal fluid cytokines in metastatic group 3 and 4 medulloblastoma.

BACKGROUND: Metastatic medulloblastoma (MB) portends a poor prognosis. Amongst the 4 molecular subtypes, Group 3 and Group 4 patients have a higher incidence of metastatic disease, especially involving the neuroaxis. At present, mechanisms underlying MB metastasis remain elusive. Separately, inflammation has been implicated as a key player in tumour development and metastasis. Cytokines and their inflammation-related partners have been demonstrated to act on autocrine and, or paracrine pathways within the tumour microenvironment for various cancers. In this study, the authors explore the involvement of cerebrospinal fluid (CSF) cytokines in Group 3 and 4 MB patients with disseminated disease. METHODS: This is an ethics approved, retrospective study of prospectively collected data based at a single institution. Patient clinicpathological data and corresponding bio-materials are collected after informed consent. All CSF samples are interrogated using a proteomic array. Resultant expression data of selected cytokines are correlated with each individual's clinical information. Statistical analysis is employed to determine the significance of the expression of CSF cytokines in Group 3 and 4 patients with metastatic MB versus non-metastatic MB. RESULTS: A total of 10 patients are recruited for this study. Median age of the cohort is 6.6 years old. Based on Nanostring gene expression analysis, 5 patients have Group 3 as their molecular subtype and the remaining 5 are Group 4. There are 2 non-metastatic versus 3 metastatic patients within each molecular subtype. Proteomic CSF analysis of all patients for both subtypes show higher expression of CCL2 in the metastatic group versus the non-metastatic group. Within the Group 3 subtype, the MYC-amplified Group 3 MB patients with existing and delayed metastases express higher levels of CXCL1, IL6 and IL8 in their CSF specimens at initial presentation. Furthermore, a longitudinal study of metastatic Group 3 MB observes that selected cytokines are differentially expressed in MYC-amplified metastatic Group 3 MB, in comparison to the non-MYC amplified metastatic Group 3 MB patient. CONCLUSION: This study demonstrates higher expression of selected CSF cytokines, in particular CCL2, in metastatic Group 3 and 4 MB patients. Although our results are preliminary, they establish a proof-of-concept basis for continued work in a larger cohort of patients affected by this devastating disease.

Pulsed low-dose rate radiotherapy for recurrent bone sarcomas: case reports and brief review.

PURPOSE: Re-irradiation for bulky recurrent sarcoma carries significant risks. Pulsed low-dose rate radiotherapy (PLDR) is an attractive option for re-irradiation due to inherent radiobiological advantages. MATERIALS AND METHODS: We present two patients who underwent reirradiation using PLDR technique, followed by a literature review. RESULTS: The first case is that of a 76-year-old male who developed an in-field recurrence of a bulky pelvic bone high-grade chondrosarcoma after he was treated with definitive radiotherapy using helical TomoTherapy with a total dose of 66 Gy. The patient was re-irradiated using PLDR with a shrinking field technique; 50 Gy in 2 Gy fractions followed by a boost of 20 Gy in 2 Gy fractions. The patient remains disease-free without significant toxicity 60 months post-irradiation. The second case is that of an 82-year-old female who was treated with a definitive irradiation of 66 Gy in 33 fractions for a right shoulder grade II chondrosarcoma. She developed an in-field recurrence 28 months later and presented with bulky disease causing brachial plexopathy and lymphedema. The patient was re-irradiated with a palliative intent to a total dose of 50 Gy in 2 Gy fractions over 5 weeks using PLDR. Brachial plexopathy resolved shortly after re-irradiation, but local progression near the surface was evident 8 months later. She passed away from unrelated causes 11 months later. CONCLUSION: We present two cases highlighting our early experience with PLDR, which was effective in the reirradiation of recurrent bony sarcoma. Our study highlights PLDR as an option for reirradiation in recurrent unresectable tumors.

Hyperfractionated-Accelerated Reirradiation with Proton Therapy for Radiation-Associated Breast Angiosarcoma.

Purpose: Radiation-associated angiosarcoma (RAAS) is a rare complication among patients treated with radiation therapy for breast cancer. Hyperfractionated-accelerated reirradiation (HART) improves local control after surgery. Proton therapy may further improve the therapeutic ratio by mitigating potential toxicity. Materials and Methods: Six patients enrolled in a prospective registry with localized RAAS received HART with proton therapy between 2015 and 2021. HART was delivered twice or thrice daily in fraction sizes of 1.5 or 1.0 Gy, respectively. All patients received 45 Gy to a large elective volume followed by boosts to a median dose of 65 (range, 60-75) Gy. Toxicity was recorded prospectively by using the Common Terminology Criteria for Adverse Events, version 4.0. Results: The median follow-up duration was 1.5 (range, 0.25-2.9) years. The median age at RAAS diagnosis was 73 (range, 60-83) years with a median latency of 8.9 (range, 5-14) years between radiation therapy completion and RAAS diagnosis. The median mean heart dose was 2.2 (range, 0.1-4.96) Gy. HART was delivered postoperatively (n = 1), preoperatively (n = 3), preoperatively for local recurrence after initial management with mastectomy (n = 1), and as definitive treatment (n = 1). All patients had local control of disease throughout follow-up. Three of 4 patients treated preoperatively had a pathologic complete response. The patient treated definitively had a complete metabolic response on her posttreatment PET/CT (positron emission tomography-computed tomography) scan. Two patients developed distant metastatic disease despite local control and died of their disease. Acute grade 3 toxicity occurred in 3 patients: 2 patients undergoing preoperative HART experienced wound dehiscence and 1 postoperatively developed grade 3 wound infection, which resolved. Conclusion: HART with proton therapy appears effective for local control of RAAS with a high rate of pathologic complete response and no local recurrences to date. However, vigilant surveillance for distant metastasis should occur. Toxicity is comparable to that in photon/electron series. Proton therapy for RAAS may maximize normal tissue sparing in this large-volume reirradiation setting.

Monomodality versus Combined Therapy in Optic Pathway Gliomas-20-Year Experience from a Singapore Children's Hospital.

Introduction: The treatment of pediatric optic pathway gliomas (OPG) is challenging. At present, most centers provide individualized treatment to maximize progression free survival (PFS) and minimize morbidity. We aim to report our experience in the management of pediatric OPG, and investigate factors associated with an increased duration of remission after treatment. Methods: This is a single-institution study approved by the hospital ethics board. A retrospective review of consecutive OPGs managed from 2000 to 2020 was performed. Patients were divided into those managed with monomodality treatment (MT) and those who received combined therapy (CT). MT included various forms of surgery, chemotherapy and radiotherapy given alone, while CT involves a combination of surgery and adjuvant chemotherapy and/or radiotherapy. Results: Twenty-two patients were selected for this study. They had 40 treatment cycles; and a total follow up duration of 194.8 patient-years. Most of them were male (63.6%) and presented with visual deficits (72.7%). The mean age at initial presentation was 65 months and majority (86.4%) had their tumors arising directly from the optic chiasm, with 77.3% with hypothalamic extension. One patient had Neurofibromatosis type I (4.5%). The most common histological diagnosis was pilocytic astrocytoma (90.9%), followed by pilomyxoid astrocytoma (9.1%). The 5- and 10- year PFS were 46.2% and 36.4% respectively, while the 5- and 10-year OS were both 100%. When accounting for treatment type, there were 24 treatment cycles with MT (60.0%) and 16 CT (40.0%). After adjustment, treatments with MT were shown to have a shorter mean duration of remission (MT: 45 ± 49, CT: 84 ± 79 months; p = 0.007). Cox regression curve plotted after adjusting for patient's age at treatment demonstrated a significantly longer PFS in the CT group (p = 0.037). Conclusions: Our results suggest a significant survival benefit of CT over MT for affected patients due to the prolonged the duration of disease remission, for both primary and subsequent treatments. Nonetheless, we acknowledge that our study reflects the outcomes of treatment strategies that have evolved over time. We emphasize the need for collective efforts from a dedicated multidisciplinary team and international collaborations for better disease understanding.

Biopsy of paediatric brainstem intrinsic tumours: Experience from a Singapore Children's Hospital.

BACKGROUND: Biopsy of intrinsic brainstem tumours presumed to be diffuse midline gliomas (previously known as DIPG) is controversial. Surgery has risks of injury to the eloquent brainstem and may not have direct benefit to the patient. Technological improvements in operative adjuncts have allowed the role of biopsy for paediatric brainstem lesions to be revisited with new insights. This study aims to evaluate our institutional experience in brainstem biopsy. METHODS: This is an ethics-approved retrospective study based in KK Women's and Children's Hospital. Patients diagnosed with intrinsic brainstem tumours and managed by the Neurosurgical Service were included. Variables of interest included patient demographics, neuroimaging features, type of surgery, histological and molecular diagnosis, treatment, and outcomes. RESULTS: From 2006 to 2021, a total of 27 brainstem intrinsic tumours were referred to the Neurosurgical Service. Eleven (40.7 %) patients underwent stereotactic biopsy and 10 (37 %) had open biopsies. Histologically, 10 (37 %) were confirmed to be high grade gliomas, eight (29.6 %) were low grade gliomas and 3 (11.1 %) were malignant embryonal tumours. No negative diagnostic results or permanent postoperative complications were encountered. Five patients went on to have their tumours interrogated via next-generation sequencing to look for targetable mutations. The remaining 6 (22.2 %) patients did not undergo biopsy, whereby 1 of them is still alive after 6 years. CONCLUSION: Biopsy of paediatric brainstem intrinsic tumours is a safe procedure that concurrs with accurate tissue diagnosis. This option can be offered to affected patients, especially to identify relevant markers for targeted therapy.

Cardiovascular toxicities of androgen deprivation therapy in Asian men with localized prostate cancer after curative radiotherapy: a registry-based observational study.

BACKGROUND: Androgen deprivation therapy (ADT) and radiotherapy (RT) are the mainstay treatment for localized prostate cancer and recurrence after surgery. Cardiovascular (CV) toxicity of ADT is increasingly recognized, and the risk relates to pre-existing risk factors and ADT modalities. Despite ethnic differences in the prevalence of CV risk factors and variations of CV mortality, data on ADT-related cardiotoxicities in the Asian population remain inconclusive. Our registry-based study investigated ADT-related major adverse cardiovascular events (MACE) after primary or salvage RT. METHODS: Our study combined two prospectively established registry databases from National Cancer Center Singapore and National Heart Center Singapore. The primary endpoint is time to first MACE after treatment. MACE is defined as myocardial infarction, stroke, unstable angina, or cardiovascular death. Two types of propensity score adjustments, including ADT propensity score as a covariate in the multivariable regression model and propensity score weighting, were applied to balance baseline features and CV risk factors between RT alone and RT + ADT groups. RESULTS: From 2000 to 2019, 1940 patients received either RT alone (n = 494) or RT + ADT (n = 1446) were included. After a median follow-up of 10 years (RT) and 7.2 years (RT+ ADT), the cumulative incidence of MACE at 1, 3 and 9 years was 1.2, 5 and 16.2% in RT group, and 1.1, 5.2 and 17.6% in RT + ADT group, respectively. There were no differences in the incidence of MACE between 2 groups (HR 1.01, 95% CI 0.78-1.30, p = 0.969). Pre-treatment CV risk factors were common (80%), and CV disease (15.9%) was the second leading cause of death after prostate cancer (21.1%). On univariate analysis, older age, Indians and Malays, pre-existing CV risk factors, and history of MACE were associated with higher MACE risk. After propensity score adjustments, there remained no significant differences in MACE risk between RT + ADT and RT group on multivariable analysis. CONCLUSIONS: In our registry-based study, ADT is not associated with increased risk of major cardiovascular events among Southeast Asian men with prostate cancer after curative radiotherapy.

Outcomes of intracranial germinoma-A retrospective multinational Asian study on effect of clinical presentation and differential treatment strategies.

BACKGROUND: This multinational study was conducted to report clinical presentations and treatment strategies in patients with intracranial germinomas across selected Asian centers, including failure patterns, risk factors, and outcomes. METHODS: A retrospective data collection and analysis of these patients, treated between 1995 and 2015 from eight healthcare institutions across four countries was undertaken. RESULTS: From the results, 418 patients were analyzed, with a median follow-up of 8.9 years; 79.9% of the patients were M0, and 87.6% had ß-human chorionic gonadotropin values <50 mIU/mL. The 5/10-year overall survival (OS) and recurrence-free survival (RFS) rates were 97.2%/96.2% and 89.9%/86.9%, respectively. RFS was predicted by the radiotherapy (RT) field, with focal RT having the worst outcome, whereas chemotherapy usage had no impact on survival. Among patients who received chemotherapy, response to chemotherapy did not predict survival outcomes. In M0 patients, primary basal ganglia tumors predicted a worse RFS. In patients with bifocal tumors, an extended field RT was associated with better outcomes. In multivariable analysis, only RT fields were associated with RFS. In relapsed patients, salvage rates were high at 85.7%. Additionally, patients who received salvage RT had a better outcome (91.6% vs. 66.7%). CONCLUSIONS: Survival outcomes of patients with germinoma were excellent. Thus, the focus of treatment for intracranial germinoma should be on survivorship. Further studies are warranted to find the optimal intensity and volume of radiation, including the role of chemotherapy in the survival of patients with intracranial germinomas, considering age, primary tumor location, and extent of disease.