Re-irradiation for recurrent glioblastoma (GBM): a systematic review and meta-analysis.

PURPOSE: To determine the efficacy and toxicity of re-irradiation for patients with recurrent GBM. MATERIALS AND METHODS: We searched various biomedical databases from 1998 to 2018, for eligible studies where patients were treated with re-irradiation for recurrent GBM. Outcomes of interest were 6 and 12-month overall survival (OS-6, OS-12), 6 and 12-month progression free survival (PFS-6, PFS-12) and serious (Grade 3 +) adverse events (AE). We used the random effects model to pool outcomes across studies and compared pre-defined subgroups using interaction test. Methodological quality of each study was assessed using the Newcastle-Ottawa scoring system. RESULTS: We found 50 eligible non-comparative studies including 2095 patients. Of these, 42% were of good or fair quality. The pooled results were as follows: OS-6 rate 73% (95% confidence interval (CI) 69-77%), OS-12 rate 36% (95% CI 32-40%), PFS-6 rate 43% (95% CI 35-50%), PFS-12 rate 17% (95% CI 13-20%), and Grade 3 + AE rate 7% (95% CI 4-10%). Subgroup analysis showed that prospective studies reported higher toxicity rates, and studies which utilized brachytherapy to have a longer OS-12. Within the external beam radiotherapy group, there was no dose-response [above or below 36 Gy in 2 Gy equivalent doses (EQD2)]. However, a short fractionation regimen (≤ 5 fractions) seemed to provide superior PFS-6. CONCLUSION: The available evidence, albeit mostly level III, suggests that re-irradiation provides encouraging disease control and survival rates. Toxicity was not uniformly reported, but seemed to be low from the included studies. Randomized controlled trials (RCT) are needed to establish the optimal management strategy for recurrent GBM.

Stroke Risk in Survivors of Head and Neck Cancer.

Importance: Survivors of head and neck cancers (HNC) have increased risk of stroke. A comprehensive report using standardized methods is warranted to characterize the risk and to inform on survivorship strategy. Objective: To determine the stroke risk in subpopulations of survivors of HNC in Singapore. Design, Setting, and Participants: This national, registry-based, cross-sectional study aimed to estimate stroke risk in subgroups of the HNC population between January 2005 and December 2020. Participants were identified from the Singapore Cancer Registry, the Singapore Stroke Registry, and the Registry of Birth and Deaths using relevant International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Australian Modification (ICD-10-AM) codes. HNC subgroups were defined based on patient demographic, disease, and treatment factors. Data were analyzed from September 2022 to September 2023. Exposure: Diagnosis of HNC. Main Outcomes and Measures: Both ischemic and hemorrhagic stroke were studied. The age-standardized incidence rate ratio (SIRR) and age-standardized incidence rate difference (SIRD) were reported. The Singapore general population (approximately 4 million) served as the reference group for these estimations. Results: A total of 9803 survivors of HNC (median [IQR] age at diagnosis, 58 [49-68] years; 7166 [73.1%] male) were identified. The most common HNC subsites were nasopharynx (4680 individuals [47.7%]), larynx (1228 individuals [12.5%]), and tongue (1059 individuals [10.8%]). A total of 337 individuals (3.4%) developed stroke over a median (IQR) follow-up of 42.5 (15.0-94.5) months. The overall SIRR was 2.46 (95% CI, 2.21-2.74), and the overall SIRD was 4.11 (95% CI, 3.37-4.85) strokes per 1000 person-years (PY). The cumulative incidence of stroke was 3% at 5 years and 7% at 10 years after HNC diagnosis. The SIRR was highest among individuals diagnosed at younger than 40 years (SIRR, 30.55 [95% CI, 16.24-52.35]). All population subsets defined by age, sex, race and ethnicity, HNC subsites (except tongue), stage, histology, and treatment modalities had increased risk of stroke compared with the general population. The SIRR and SIRD were significantly higher among individuals who had a primary radiation treatment approach (SIRR, 3.01 [95% CI, 2.64-3.43]; SIRD, 5.12 [95% CI, 4.18-6.29] strokes per 1000 PY) compared with a primary surgery approach (SIRR, 1.64 [95% CI, 1.31-2.05]; SIRD, 1.84 [95% CI, 0.923.67] strokes per 1000 PY). Conclusions and Relevance: In this cross-sectional study of survivors of HNC, elevated stroke risks were observed across different age, subsites, and treatment modalities, underscoring the importance of early screening and intervention.

Comparing log file to measurement-based patient-specific quality assurance.

Recent technological advances have allowed the possibility of performing patient-specific quality assurance (QA) without time-intensive measurements. The objectives of this study are to: (1) compare how well the log file-based Mobius QA system agrees with measurement-based QA methods (ArcCHECK and portal dosimetry, PD) in passing and failing plans, and; (2) evaluate their error sensitivities. To these ends, ten phantom plans and 100 patient plans were measured with ArcCHECK and PD on VitalBeam, while log files were sent to Mobius for dose recalculation. Gamma evaluation was performed using criteria 3%/2 mm, per TG218 recommendations, and non-inferiority of the Mobius recalculation was determined with statistical testing. Ten random plans were edited to include systematic errors, then subjected to QA. Receiver operating characteristic curves were constructed to compare error sensitivities across the QA systems, and clinical significance of the errors was determined by recalculating dose to patients. We found no significant difference between Mobius, ArcCHECK, and PD in passing plans at the TG218 action limit. Mobius showed good sensitivity to collimator and gantry errors but not MLC bank shift errors, but could flag discrepancies in treatment delivery. Systematic errors were clinically significant only at large magnitudes; such unacceptable plans did not pass QA checks at the TG218 tolerance limit. Our results show that Mobius is not inferior to existing measurement-based QA systems, and can supplement existing QA practice by detecting real-time delivery discrepancies. However, it is still important to maintain rigorous routine machine QA to ensure reliability of machine log files.

Radiation oncology training in Singapore - A non-Australasian RANZCR training site.

The Radiation Oncology Department at The National Cancer Institute, Singapore (NCIS) and the Royal Australian and New Zealand College of Radiology (RANZCR) has had a well-established relationship that began as a partnership to grow a pool of local radiation oncologists to meet a nation's demand for radiotherapy services. This journey has surpassed its initial aims and now has produced a generation of radiation oncologists leading a national cancer institute. We recount the history and progress of this partnership here, as well as the unique success of its product; the only RANZCR-accredited radiation oncology training site outside of Australia and New Zealand since 2002. We outline the mutual benefits through many years of collaboration and deliberate efforts to grow the partnership. We also outline the distinctive specialist training path that our trainees take to meet both the local accreditation body as well as the RANZCR requirements.

GAGE mediates radio resistance in cervical cancers via the regulation of chromatin accessibility.

Radiotherapy (RT) resistance is a major cause of treatment failure in cancers that use definitive RT as their primary treatment modality. This study identifies the cancer/testis (CT) antigen G antigen (GAGE) as a mediator of radio resistance in cervical cancers. Elevated GAGE expression positively associates with de novo RT resistance in clinical samples. GAGE, specifically the GAGE12 protein variant, confers RT resistance through synemin-dependent chromatin localization, promoting the association of histone deacetylase 1/2 (HDAC1/2) to its inhibitor actin. This cumulates to elevated histone 3 lysine 56 acetylation (H3K56Ac) levels, increased chromatin accessibility, and improved DNA repair efficiency. Molecular or pharmacological disruption of the GAGE-associated complex restores radiosensitivity. Molecularly, this study demonstrates the role of GAGE in the regulation of chromatin dynamics. Clinically, this study puts forward the utility of GAGE as a pre-screening biomarker to identify poor responders at initial diagnosis and the therapeutic potential of agents that target GAGE and its associated complex in combination with radiotherapy to improve outcomes.

Phase 1 Study of Low-Dose Fractionated Whole Abdominal Radiation Therapy in Combination With Weekly Paclitaxel for Platinum-Resistant Ovarian Cancer (GCGS-01).

PURPOSE: Low-dose fractionated whole abdominal radiation therapy (LDFWART) has synergistic activity with paclitaxel in preclinical models. The aim of this phase 1 trial was to determine the recommended phase 2 dose and preliminary activity of weekly paclitaxel (wP) concurrent with LDFWART in patients with platinum-resistant ovarian cancer (PROC). METHODS AND MATERIALS: Patients were enrolled at de-escalating dose levels of wP (part A), starting at 80 mg/m2, concurrent with fixed-dose LDFWART delivered in 60 cGy fractions twice-daily, 2 days per week, for 6 continuous weeks. After completing the 6-week course of wP + LDFWART, patients received wP until disease progression. Dose-limiting toxicity was evaluated during the first 3 weeks of wP + LDFWART. At wP (80 mg/m2) + LDFWART, no dose-limiting toxicities were observed; this was the established maximum tolerated dose. The trial was expanded (part B) with 7 additional patients with platinum-resistant, high-grade serous ovarian cancer to confirm toxicity and activity. RESULTS: A total of 10 heavily pretreated patients were recruited (3 patients to part A, 7 patients to part B). They had received a median of 5 prior lines of therapy, and 70% of patients had received prior wP; 60% of patients completed 6 weeks of wP + LDFWART. Common related grade ≥3 adverse events were neutropenia (60%) and anemia (30%). Median progression-free survival was 3.2 months, and overall survival was 13.5 months. Of patients evaluable for response, 33% (3 of 9) achieved confirmed biochemical response (CA125 decrease >50% from baseline), 11% (1) achieved a partial response, and 5 patients had stable disease, giving a disease control rate of 66.7% (6 of 9). Four patients had durable disease control of ≥12 weeks, completing 12 to 21 weeks of wP. CONCLUSIONS: The recommended phase 2 dose of wP + LDFWART for 6 weeks is 80 mg/m2. Encouraging efficacy in heavily pretreated PROC patients was observed, suggesting that further development of this therapeutic strategy in PROC should be considered.

Applying the ASCO and European Society for Medical Oncology Value Frameworks to Nasopharyngeal Cancer Treatments: Is Adding Induction Chemotherapy or Adjuvant Chemotherapy to Concurrent Chemoradiotherapy Worthwhile?

PURPOSE: To determine and compare the incremental clinical benefit (ICB) and costs of induction chemotherapy (IC) when added to concurrent chemoradiotherapy (CCRT), concurrent chemotherapy (CC) when added to radiotherapy (RT), and CC plus adjuvant chemotherapy (AC) when added to RT for locally advanced nasopharyngeal cancer (LA-NPC). MATERIALS AND METHODS: We searched phase III randomized controlled trials (RCTs) that reported overall survival benefit with the use of IC, CC, and CC + AC in LA-NPC. We quantified the ICB using the ASCO and European Society for Medical Oncology (ESMO) value frameworks. We calculated the incremental drug costs in US dollars using the lowest average wholesale price reported in the Lexicomp drug database. RESULTS: We identified three RCTs on IC, three RCTs on CC, and four RCTs on CC + AC. The ICB was judged to be grade A based on the ESMO framework. The ASCO Net Health Benefit score ranged from 17.43 to 57.39. The incremental drug costs ranged from $133.46 to $626.14. There were no statistically significant differences in the mean Net Health Benefit scores (39.37 for IC v 37.61 for CC v 33.98 for CC + AC; P = .89) and costs ($383 for IC v $253 for CC v $460 for CC + AC; P = .27) between the three approaches. There was no statistically significant correlation between ICB and costs. CONCLUSION: The magnitudes of ICB and incremental drug costs of adding of IC to CCRT, CC to RT, and CC + AC to RT for LA-NPC are not significantly different.

Emerging radiotherapy technologies and trends in nasopharyngeal cancer.

Technology has always driven advances in radiotherapy treatment. In this review, we describe the main technological advances in radiotherapy over the past decades for the treatment of nasopharyngeal cancer (NPC) and highlight some of the pressing issues and challenges that remain. We aim to identify emerging trends in radiation medicine. These include advances in personalized medicine and advanced imaging modalities, standardization of planning and delineation, assessment of treatment response and adaptive re-planning, impact of particle therapy, and role of artificial intelligence or automation in clinical care. In conclusion, we expect significant improvement in the therapeutic ratio of radiotherapy treatment for NPC over the next decade.

Long-term outcomes after reirradiation in nasopharyngeal carcinoma with intensity-modulated radiotherapy: A meta-analysis.

BACKGROUND: The purpose of this clinical review was to summate the published data for the long-term outcomes of reirradiation with intensity-modulated radiotherapy (IMRT) for locally recurrent nasopharyngeal carcinoma (NPC). METHODS: We searched biomedical literature databases for eligible studies published from January 2005 to September 2016. Outcomes of interests were 5-year local failure-free survival, distant failure-free survival, overall survival (OS), and toxicities. Meta-analysis was performed using a random effects model. RESULTS: We found 4 comparative and 8 noncomparative studies (n = 1768). Reirradiation was associated with pooled event rates of 72% (95% confidence interval [CI] 66%-78%; I2 = 84%), 85% (95% CI 82%-88%; I2 = 69%), and 41% (95% CI 36%-47%; I2 = 80%) for 5-year local failure-free survival, distant failure-free survival, and OS, respectively, with significant heterogeneity among the study results. The pooled event rate for grade 5 toxicities was 33% (95% CI 30%-35%; I2 = 0%) with minimal heterogeneity. CONCLUSION: Reirradiation with IMRT for locally recurrent NPC could confer long-term disease control and survival but is associated with significant mortality.

Outcomes of neoadjuvant chemoradiotherapy followed by total mesorectal excision surgery for locally advanced rectal cancer: a single-institution experience.

INTRODUCTION: Neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision (TME) surgery for locally advanced rectal cancer has been shown to improve local control and reduce toxicity, as compared to adjuvant CRT. We reported the outcomes of our patients with locally advanced rectal cancer treated at National University Hospital, Singapore. METHODS: From April 2002 to December 2014, 117 patients with T3/4, N0/+, M0 rectal cancer received neoadjuvant CRT followed by TME surgery. The treatment regimen comprised a total radiotherapy dose of 50.4 Gy in 28 daily fractions delivered concurrently with 5-fluorouracil or capecitabine chemotherapy over 5.5 weeks. All patients were planned for TME surgery. Local control, disease-free survival, overall survival and treatment toxicities were analysed. RESULTS: Median follow-up was 34 (range 2-122) months. 11.5% (13/113) of patients achieved a pathological complete response (pCR) and 72.6% (85/117) had either tumour or nodal downstaging following neoadjuvant CRT. 5.2% (5/96) of patients had Grade 3 acute toxicities (dermatitis and diarrhoea) and 3.1% (3/96) had Grade 3 late toxicities (fistula and stricture). There was no Grade 4 toxicity noted. The five-year local recurrence, disease-free survival and overall survival rates were 4.5%, 65.7% and 80.6%, respectively. Multivariate analysis showed that nodal positivity was a predictor of poor disease-free survival and poor overall survival. Tumour downstaging and pCR did not improve outcomes. CONCLUSION: Our outcomes were comparable to internationally published data, and this treatment regimen remains the standard of care for locally advanced rectal cancer in our local population.

Novel anesthetic technique for combined intracavitary and interstitial brachytherapy for cervix cancer in an outpatient setting.

PURPOSE: To determine the feasibility and safety of outpatient combined intracavitary and interstitial brachytherapy for cervix cancer with sedation and local anesthesia. MATERIAL AND METHODS: We included patients diagnosed with non-metastatic cervix cancer and have completed brachytherapy between December 2015 and December 2016. Moderate to deep sedation was achieved using intravenous midazolam, propofol, fentanyl, and oxycodone. Local anesthesia was achieved with 2% lignocaine gel and a paracervical block containing a mixture of 1% ropivacaine, 2% lignocaine, and 1 : 1,000 adrenaline. Ceftriaxone and ondansetron were given prophylactically. Physiologic monitoring was performed throughout and pain scores were recorded using the Numeric Rating Scale. Follow-up was conducted at 8 weeks from the last fraction of brachytherapy. The feasibility and safety endpoints were a post-anesthesia discharge score (PADS) of 9 or above, and no grade 3 or above adverse events, respectively. RESULTS: A total of thirty-five brachytherapy insertions were carried out on nine patients. The median age of the patients was 56 years (range, 40-65). Eight patients had American Society of Anesthesiologists' physical status of I or II, and one had a status of III. The mean duration of the insertion was 39 minutes (standard deviation [SD] = 14), during which no adverse events occurred. There was no significant nausea or vomiting post-sedation. The median pain scores post-insertion and during recovery were 0 (range, 0-6) and 0 (range, 0-7), respectively. At discharge, all patients had pain scores of 0 and maximum PADS of 10. The mean time to discharge was 4.1 hours (SD = 0.95). There were no brachytherapy-related admissions or complications. CONCLUSIONS: Outpatient combined intracavitary and interstitial brachytherapy for cervix cancer with sedation and local anesthesia is feasible and safe. This could potentially lead to significant cost savings.

Oncologic outcomes of neoadjuvant chemoradiation for locally advanced rectal cancer: a single-institution experience.

INTRODUCTION: This study reports the outcomes of patients with locally advanced rectal cancer treated with neoadjuvant chemoradiation followed by surgery in a local population of Singapore. MATERIALS AND METHODS: The records of 85 patients who underwent neoadjuvant chemoradiation for locally advanced rectal cancer followed by surgery at the Tan Tock Seng Hospital (TTSH) between November 2002 and January 2012 were reviewed. The treatment protocol comprised radiotherapy to a total dose of 50.4 Gy concurrent with 5-fluorouracil-based chemotherapy. Patients underwent total mesorectal excision surgery following the completion of neoadjuvant chemoradiation. Local control, disease-free survival and overall survival were analysed using Kaplan-Meier methods. RESULTS: Median age of the patients was 61 years. All of them completed radiotherapy. One patient did not complete neoadjuvant chemotherapy. The median time to surgery was 52 days. Fifty-five percent (47 of 85) of patients achieved pathological downstaging and 13% (11 of 85) of patients had a pathologic complete response to preoperative treatment. The neoadjuvant chemoradiation was well tolerated. Four percent of patients had grade 3 diarrhoea and 4% of them had grade 3 dermatitis. There were no grade 4 toxicities. With a median follow-up of 41 months, the 5-year actuarial local recurrence, disease-free survival and overall survival rates were 7%, 71.9%, and 83.2% respectively. Univariate analysis showed that patients with positive surgical margins had significantly worse disease-free survival and overall survival (P=0.012 and P<0.001 respectively) and a trend towards a higher rate of local recurrence (P=0.08). CONCLUSION: Our study provides evidence that neoadjuvant chemoradiation is an effective treatment for locally advanced rectal cancer. Our outcomes are comparable with internationally published data and demonstrate the reproducibility of the neoadjuvant approach in an Asian population.