Accelerated hyper-versus normofractionated radiochemotherapy with temozolomide in patients with glioblastoma: a multicenter retrospective analysis

Background and purpose The standard treatment of glioblastoma patients consists of surgery followed by normofractionated radiotherapy (NFRT) with concomitant and adjuvant temozolomide chemotherapy. Whether accelerated hyperfractionated radiotherapy (HFRT) yields comparable results to NFRT in combination with temozolomide has only sparsely been investigated. The objective of this study was to compare NFRT with HFRT in a multicenter analysis. Materials and methods A total of 484 glioblastoma patients from four centers were retrospectively pooled and analyzed. Three-hundred-ten and 174 patients had been treated with NFRT (30 × 1.8 Gy or 30 × 2 Gy) and HFRT (37 × 1.6 Gy or 30 × 1.8 Gy twice/day), respectively. The primary outcome of interest was overall survival (OS) which was correlated with patient-, tumor- and treatment-related variables via univariable and multivariable Cox frailty models. For multivariable modeling, missing covariates were imputed using multiple imputation by chained equations, and a sensitivity analysis was performed on the complete-cases-only dataset. Results After a median follow-up of 15.7 months (range 0.8–88.6 months), median OS was 16.9 months (15.0–18.7 months) in the NFRT group and 14.9 months (13.2–17.3 months) in the HFRT group (p = 0.26). In multivariable frailty regression, better performance status, gross-total versus not gross-total resection, MGMT hypermethylation, IDH mutation, smaller planning target volume and salvage therapy were significantly associated with longer OS (all p < 0.01). Treatment differences (HFRT versus NFRT) had no significant effect on OS in either univariable or multivariable analysis. Conclusions Since HFRT with temozolomide was not associated with worse OS, we assume HFRT to be a potential option for patients wishing to shorten their treatment time.

Accelerated Hyper-Versus Normofractionated Radiochemotherapy with Temozolomide in Patients with Glioblastoma: A Multicenter Retrospective Analysis.

Background and purpose The standard treatment of glioblastoma (GB) patients consists of surgery followed by normofractionated radiotherapy (NFRT) with concomitant and adjuvant temozolomide chemotherapy. Whether accelerated hyperfractionated radiotherapy (HFRT) yields comparable results to NFRT in combination with temozolomide has only sparsely been investigated. The objective of this study was to compare NFRT with HFRT in a multicenter analysis. Materials and methods A total of 484 GB patients from four centers were retrospectively pooled and analyzed. 310 and 174 patients had been treated with NFRT (30×1.8Gy or 30×2Gy) and HFRT (37×1.6Gy or 30×1.8Gy twice/day), respectively. The primary outcome of interest was overall survival (OS) which was correlated with patient-, tumor- and treatment-related variables via univariable and multivariable Cox frailty models. For multivariable modeling, missing covariates were imputed using multiple imputation by chained equations, and a sensitivity analysis was performed on the complete-cases-only dataset. Results After a median follow-up of 15.7 months (range 0.8-88.6 months), median OS was 16.9 months (15.0-18.7 months) in the NFRT group and 14.9 months (13.2-17.3 months) in the HFRT group (p=0.26). In multivariable frailty regression, better performance status, complete versus not complete resection, MGMT hypermethylation, IDH mutation, smaller planning target volume, no steroid administration, and salvage therapy were significantly associated with longer OS (all p<0.01). Treatment differences (HFRT versus NFRT) had no significant effect on OS in either univariable or multivariable analysis. Conclusions This analysis suggests that HFRT and temozolomide is a safe option for patients wishing to shorten their treatment time and does not affect OS.

Clinical outcomes of extensive-stage small cell lung cancer patients treated with thoracic radiotherapy at different times and fractionations

Objective The purpose of this study was to assess whether thoracic radiotherapy (TRT) combined with chemotherapy (CHT) showed promising anti-tumour activity in extensive-stage small cell lung cancer (ES-SCLC), to explore practice patterns for the radiation time and dose/fractionation and to identify prognostic factors for patients who would benefit from CHT/TRT. Methods A total of 492 ES-SCLC patients were included from January 2010 to March 2019, 244 of whom received CHT/TRT. Propensity score matching was performed to minimize bias between the CHT/TRT and CHT-alone groups. Patients in the CHT/TRT group were categorized into four subgroups based on the number of induction CHT cycles. For effective dose fractionation calculations, we introduced the time-adjusted biological effective dose (tBED). Categorical variables were analysed with chi-square tests and Fisher’s exact tests. Kaplan–Meier curves were generated to estimate survival rates using the R-project. Multivariate prognostic analysis was performed with Cox proportional hazards models. Results Patients who received CHT/TRT experienced improved overall survival (OS) (18.1 vs 10.8 months), progression-free survival (PFS) (9.3 vs 6.0 months) and local recurrence-free survival (LRFS) (12.0 vs 6.6 months) before matching, with similar results after matching. In the CHT/TRT group, the median LRFS times for the groups based on the radiation time were 12.7, 12.0, 12.0, and 9.0 months, respectively. Early TRT had a tendency to prolong PFS (median 10.6 vs 9.8 vs 9.0 vs 7.7 months, respectively, p = 0.091) but not OS (median 17.6 vs 19.5 vs 17.2 vs 19.0 months, respectively, p = 0.622). Notably, patients who received TRT within 6 cycles of CHT experienced prolonged LRFS (p = 0.001). Regarding the radiation dose, patients in the high-dose group (tBED > 50 Gy) who achieved complete response and partial response (CR and PR) to systemic therapy had relatively short OS (median 27.1 vs 22.7, p = 0.026) and PFS (median 11.4 vs 11.2, p = 0.032), but the abovementioned results were not obtained after the exclusion of patients who received hyperfractionated radiotherapy (all p > 0.05). Conclusion CHT/TRT could improve survival for ES-SCLC patients. TRT performed within 6 cycles of CHT and hyperfractionated radiotherapy (45 Gy in 30 fractions) may be a feasible treatment scheme for ES-SCLC patients.

MBCL-50. DISMAL OUTCOME OF HIGH RISK MEDULLOBLASTOMA TREATED WITH CHEMOTHERAPY FIRST APPROACH IN MALAYSIA

INTRODUCTION Patients with high risk medulloblastoma are treated either with high dose chemotherapy or hyperfractionated radiotherapy. Both approaches are not feasible in resource-limited countries. POG9031 trial has reported favourable outcome for high risk medulloblastoma using standard chemotherapy and radiotherapy only. Hence, we have adopted the protocol using chemotherapy first approach due to logistical reasons. OBJECTIVE To review the outcome of children diagnosed with high risk medulloblastoma in Hospital Kuala Lumpur. METHODS Patients diagnosed with high risk medulloblastoma between January 2015 and June 2018 treated using the chemotherapy first approach as per POG9031 protocol were identified. Data was then extracted and analysed. RESULTS Nine patients were identified, 3 boys and 9 girls. Median age was 9.3 years (range 2.6 – 15.9 years). Median follow up for survivors are 3.6 years. Five patients (55.6%) had macroscopic metastatic disease at diagnosis. All patients had significant residual disease post-op. Only 3 patients are disease free till last follow up, giving a 3 years event free survival of 16%. Of the 6 patients who had relapsed, 4 have died, giving a 3 years overall survival of 46%. Patients with no metastasis at diagnosis (M0) fared better with 3 years event free survival of 38%, but 3 years event free survival for patients with macroscopic metastatic disease (M+) was 0%. CONCLUSION Outcome of children with high risk medulloblastoma treated with chemotherapy first approach was dismal.

RBIO-05. MITOTIC ENRICHMENT AS AN EFFICIENT STRATEGY TO RADIOSENSITIZE GLIOBLASTOMA

Their location and highly aggressive nature renders glioblastoma (GBM) among the most deadly and devastating of human malignancies. Despite extensive treatment involving surgery and adjuvant chemo-radiotherapy, the prognosis is still dismal and novel treatment strategies are urgently needed. Of all existing adjuvant therapies, radiotherapy contributes the most to extending the median overall survival. Increasing the efficacy of existing radiotherapeutic regimens is therefore a logical avenue to improve the survival of GBM patients. We have developed a novel radiosensitization strategy called ‘induction of mitotic enrichment’. It has long been known that the radiosensitivity of a cell depends on the phase of the cell cycle and that especially mitotic cells are especially vulnerable. Enriching the tumor for mitotic cells by arresting them during division prior to each radiotherapy fraction should therefore render the tumor population more sensitive to irradiation. Ideally, induction of mitotic enrichment should be reversible and non-cytotoxic to prevent healthy tissue toxicity and be compatible with clinically applied hyperfractionated radiotherapy regimens. We have now identified an orally available targeted tubulin polymerization inhibitor that can achieve repeated and reversible mitotic enrichment for up to 10 hours prior to radiotherapy, without causing cytotoxicity in vitro or healthy tissue toxicity in vivo. Most importantly, this tubulin inhibitor efficiently radiosensitizes a range of preclinical GBM models in vitro and in vivo, including GSC models, and significantly improves survival, but only in a mitotic enrichment setup when given 6-8 hours prior to radiotherapy to allow accumulation in mitosis. We are currently expanding our preclinical development of mitotic enrichment as a radiosensitization strategy to other mitotic targets and different intra- and extracranial cancer models representing several diseases for which radiotherapy is a mainstay treatment. In parallel, we are preparing a phase 0 trial to demonstrate induction of mitotic enrichment in human GBM.

PD-1 inhibitor combined with radiotherapy and GM-CSF as salvage therapy in patients with chemotherapy-refractory metastatic solid tumors.

e15173 Background: Patients with refractory metastatic solid tumors have poor prognoses and few therapeutic options. The application of PD-1 inhibitor has led to a paradigm shift in the treatment of advanced cancer, but its efficacy as a monotherapy is limited. Previous evidence has shown that the anti-tumor effects might be reinforced when PD-1 inhibitor combines with radiotherapy or granulocyte macrophage-colony stimulating factor (GM-CSF). An exploratory study was conducted to assess the clinical efficacy and safety of PD-1 inhibitor combined with radiotherapy and GM-CSF (PRaG regimen) for the treatment of refractory patients. Methods: Participants had multimetastatic solid tumors progressing beyond at least first-line chemotherapy.They were treated with hyperfractionated radiotherapy (3 doses of 8Gy or 5 doses of 5Gy) for each metastatic site. On the second day after radiotherapy, PD-1 inhibitor 200 mg once was intravenously administered and GM-CSF 200 µg daily was subcutaneously injected for 2 weeks. This course was repeated every 3 weeks, targeting a second metastatic site. Triple-combination therapy. (PRaG regimen) was given for at least 2 cycles. After combination therapy, maintenance with PD-1 inhibitor was administered until disease progression or unacceptable toxicity. The main outcome measures included safety, toxicity, progression-free survival (PFS) and objective response rate (ORR) after three cycles of treatment. Results: A total of 16 patients were enrolled.The median number of metastatic lesions was 7.5(95%CI, 5.3 to 19.5) and the median sum of the longest diameter of all measurable lesions was 161.7mm (95%CI, 104.1 to 279.3mm).All patients completed two cycles or more of triple-combination therapy. The ORR was 20% and the median PFS was 3.3 months (95%CI, 2.3to 7.2months) at the time of evaluation. Treatment-related adverse events of any grade occurred in 13 (81%) patients, and grade 3 and higher adverse event like pneumonitis occurred in 2 (11.0%) patients. Conclusions: The PRaG regimen is well tolerated with acceptable toxicity. For patients with resistant metastatic solid tumors, low efficacy and high cytotoxicity are commonly observed in conventional therapy. With the new chemo-free PRaG regimen, myelosuppression was not observed and gastrointestinal side effects remained low. So, PRaG regimen is considered as a promising salvage treatment for patients with chemotherapy-refractory metastatic solid tumor. The suggested mechanism might involve radiosensitization of immunotherapy. Clinical trial information: ChiCTR1900020175 .