Hypofractionated Radiotherapy In Patients Research Articles

Short-course Palliative Hypofractionated Radiotherapy in Patients with Poor-prognosis High-grade Glioma: Survival and Quality of Life Outcomes from a Prospective Phase II Study

AimsTo report longitudinal quality of life (QoL) outcomes and survival in patients with poor-prognosis high-grade glioma (HGG) treated with palliative hypofractionated radiotherapy. Materials and methodsPatients with poor-prognosis HGG were accrued on a prospective study of short-course palliative hypofractionated radiotherapy (35 Gy/10 fractions/2 weeks). The European Organization for Research and Treatment of Cancer QoL core questionnaire (QLQ-C30) and brain cancer module (BN20) were used in English or validated Indian vernacular languages (Hindi and Marathi) for QoL assessment at baseline (before radiotherapy), the conclusion of radiotherapy, 1 month post-radiotherapy and subsequently at 3-monthly intervals until disease progression/death. Baseline QoL scores were compared with corresponding scores from a historical HGG cohort. Summary QoL scores were compared longitudinally over time by related samples Friedman's two-way test. Progression-free survival and overall survival were calculated using the Kaplan–Meier method and reported as 1-year estimates with 95% confidence intervals. ResultsForty-nine (89%) of 55 patients completed the planned course of hypofractionated radiotherapy. Longitudinal QoL data were available in 42 (86%) of 49 patients completing radiotherapy, comprising the present cohort. The median age of included patients, comprised mainly of glioblastoma patients (81%), was 57 years, with an interquartile range (IQR) of 50–66 years and a median baseline Karnofsky score of 60 (IQR = 50–60). Baseline QoL scores were significantly worse for several domains compared with a historical institutional cohort of HGG patients treated previously with conventionally fractionated radiotherapy, indicating negative selection bias. QoL scores remained stable for most domains after palliative hypofractionated radiotherapy, with statistically significant improvements in fatigue (P = 0.032), dyspnoea (P = 0.042) and motor dysfunction (P = 0.036) over time. At a median follow-up of 8 months, Kaplan–Meier estimates of 1-year progression-free survival and overall survival were 33.3% (95% confidence interval 21.7–51.1%) and 38.1% (95% confidence interval 25.9–56%), respectively. ConclusionShort-course palliative hypofractionated radiotherapy in patients with poor-prognosis HGG is associated with stable and/or improved QoL scores in several domains, making it a viable resource-sparing regimen.

Hypo-fractionated Radiotherapy (HF-RT) Versus Conventionally Fractionated Radiotherapy (CF-RT) for Glioblastoma.

Hypo-fractionated radiotherapy (HF-RT) is increasingly used for elderly and frail glioblastoma patients. In countries with limited radiotherapy capacities, HF-RT is more widely applied. This allowed us to compare conventional fractionation (CF-RT) vs. HF-RT in patients of any age and performance status. We retrospectively analysed 277 patients [110 HF-RT (52.5 Gy in 15 fractions) vs. 167 CF-RT (54.0-60.0 Gy in 27-33 fractions)] for local control (LC) and overall survival (OS) including subgroups considering specific patient characteristics. On univariable comparisons, CF-RT was associated with significantly better LC and OS in patients with KPS ≤70 and unifocal glioblastoma, and with OS in the entire cohort. Trends were found for LC and OS in patients aged <60 years, and for OS in additional four subgroups. On multivariable analyses, improved LC and OS were significantly associated with CF-RT, KPS 80-100, unifocal glioblastoma, resection, and receipt of chemotherapy. Maximum diameter <45 mm was associated with improved OS. Given the limitations of this study, CF-RT appeared associated with better outcomes. Selected patients may benefit from HF-RT.

Significance of Hypofractionated Radiotherapy in Postoperative Irradiation for Breast Cancer: An Asian Multi-institutional Prospective Study

AimsThere is a need for the adequate distribution of healthcare resources in Southeast Asia. Many countries in the region have more patients with advanced breast cancer who are eligible for postmastectomy radiotherapy (PMRT). Therefore, it is critical that hypofractionated PMRT is effective in most of these patients. This study investigated the significance of postoperative hypofractionated radiotherapy in patients with breast cancer, including advanced breast cancer, in these countries. Materials and methodsEighteen facilities in 10 Asian countries participated in this prospective, interventional, single-arm study. The study included two independent regimens: hypofractionated whole-breast irradiation (WBI) for patients who had undergone breast-conserving surgery and hypofractionated PMRT for patients who had undergone total mastectomy at a dose of 43.2 Gy in 16 fractions. In the hypofractionated WBI group, patients with high-grade factors received additional 8.1 Gy boost irradiation sessions for the tumour bed in three fractions. ResultsBetween February 2013 and October 2019, 227 and 222 patients were enrolled in the hypofractionated WBI and hypofractionated PMRT groups, respectively. The median follow-up periods in the hypofractionated WBI and hypofractionated PMRT groups were 61 and 60 months, respectively. The 5-year locoregional control rates were 98.9% (95% confidence interval 97.4–100.0) and 96.3% (95% confidence interval 93.2–99.4) in the hypofractionated WBI and hypofractionated PMRT groups, respectively. Regarding adverse events, grade 3 acute dermatitis was observed in 2.2% and 4.9% of patients in the hypofractionated WBI and hypofractionated PMRT groups, respectively. However, no other adverse events were observed. ConclusionAlthough further follow-up is required, hypofractionated radiotherapy regimens for postoperative patients with breast cancer in East and Southeast Asian countries are effective and safe. In particular, the proven efficacy of hypofractionated PMRT indicates that more patients with advanced breast cancer can receive appropriate care in these countries. Hypofractionated WBI and hypofractionated PMRT are reasonable approaches that can contain cancer care costs in these countries. Long-term observation is required to validate our findings.

Preliminary results of a phase II study of retifanlimab (PD-1 inhibitor) plus or minus epacadostat (IDO1 inhibitor) in combination with bevacizumab and hypofractionated radiotherapy for recurrent glioblastoma: NCT03532295.

2058 Background: Immunotherapies targeting the programmed cell death-1 (PD-1) pathway in recurrent glioblastoma (rGBM) have failed. We hypothesize that combining therapies targeting multiple immunosuppressive pathways with cytotoxic and antiangiogenic therapies will improve survival. Here, we evaluate the safety and efficacy of an anti-PD-1 monoclonal antibody (retifanlimab), hypofractionated radiotherapy (HFRT), and bevacizumab, with or without an oral IDO1 inhibitor (epacadostat), in patients with rGBM in a nonrandomized, noncomparative sequential two-arm Phase II study. Methods: This is an open-label Phase II study of 2 sequential cohorts (Table). Cohort A first examines retifanlimab + bevacizumab + HFRT in patients with IDH1/2-WT rGBM. After a toxicity monitoring period, Cohort B, which adds epacadostat, starts enrolling. Key inclusion criteria includes dexamethasone ≤ 4 mg/day at registration and candidacy for reirradiation. Previous bevacizumab use for radiation necrosis is permitted. The primary endpoint is OS probability at 9 months (OS-9). Secondary endpoints include PFS, OS, and toxicity. Exploratory endpoints include immunological phenotyping of blood and tissue. An increase of OS-9 from 38% (bevacizumab alone) to 60% is considered clinically relevant. Results: From 6/2020 to 12/2021, we have completed accrual for cohort A and the interim analysis results are presented here: 25 patients with rGBM enrolled, with 23 evaluable. Median age is 64.3 years (42.1-81.8), 30.4% female, 30.4% MGMT promotor methylated, median KPS 90 (range 70-100), baseline dexamethasone 0 mg (range 0-4) with 52.2% of patients on dexamethasone during the first 3 cycles, median baseline ALC 1,000 cells/µl (range 300-3,700). Patients received a median of 6 cycles to date (range 2-20). Median follow-up is 11.97 months per the reverse Kaplan-Meier method. Interim analysis shows a median PFS of 9.9 months (95%CI: 5.5 to not reached (NR)) and median OS of 12.2 months (95%CI 7.3-NR). Notably, Cohort A met the primary endpoint with an OS-9 of 71.4% (95%CI: 46.7% -86.1%). No dose limiting toxicities have been yet observed. Two treatment-related grade 3 toxicities have occurred (myositis, hypertension). Cohort B enrollment is ongoing, and correlative studies pending. Conclusions: Interim analysis suggests retifanlimab combined with HFRT and bevacizumab in patients with rGBM is well-tolerated and had encouraging OS and PFS at the time of data cutoff. Cohort B, which adds epacadostat, is currently enrolling. Clinical trial information: NCT03532295. [Table: see text]

A Phase II Open-Label Multi-center Trial of Isotoxic Hypofractionated Radiotherapy for NSCLC

Background: The standard treatment for advanced unresectable non-small cell lung cancer (NSCLC) is concurrent chemoradiotherapy. However, many poor Karnofsky score or elderly patients cannot tolerate it due to heir serious side effects. For patients who cannot tolerate concurrent chemoradiotherapy, conventional treatment is sequential chemoradiotherapy or radiotherapy alone. But the median survival time of sequential chemoradiotherapy and radiotherapy alone is 11-16 months. In order to improve curative effect, radiotherapy, as an important treatment method, has been tried, innovated and improved continuously. The goal of this trial is to evaluate feasibility and safety of isotoxic hypofractionated radiotherapy in patients with NSCLC.&#x0D; Methods: This is a phase Ⅱ open-label multi-center two-step non-randomised Trial. In the first stage, 12 patients will be included in the trial with radiotherapy of 3Gy per fraction. If more than 3 patients have serious side effects of radiotherapy, the trial will be terminated. Otherwise, the second phase will continue, and the total number of participants will be 30. All patients eventually will be followed up for 5 years.&#x0D; The primary endpoint is the safety of isotoxic hypofractionated radiotherapy. The secondary outcomes are time to progression (TTP), progression free survival (PFS), overall survival (OS), local control (LC).&#x0D; Discussion: In clinical practice, the local control rate of conventional fractionated radiotherapy for NSCLC is very low. We hope that this trial can verify the safety of isotoxic hypofractionated radiotherapy.&#x0D; Trial Registration: NCT03606291, REGISTERED JULY, 30, 2018.

Final Results of a Phase I “RadVax” Trial of Hypofractionated Radiation Combined With Pembrolizumab in Patients With Metastatic Solid Tumors

Many patients treated with anti-PD-1 therapy do not show a clinical response. Preclinical studies suggest that adding hypofractionated radiotherapy (HFRT) to anti-PD1 can increase the efficacy of immunotherapy through several mechanisms including increased antigen presentation. We conducted a prospective trial testing the combination of pembrolizumab and HFRT in patients with metastatic solid tumors.This prospective single-institution phase I trial tested pembrolizumab in combination with HFRT in patients with metastatic cancers (NSCLC, melanoma, pancreas, breast, others) and an ECOG performance status of 0-1. Melanoma and NSCLC patients were required to have progression of disease on anti-PD1, having received ≥ 2 doses of anti-PD1 and progression documented by RECIST v1.1. Patients were required to have an index lesion ≥1 cm that was amenable to HFRT and at least one other lesion that was not irradiated and could be followed for response using RECIST criteria. Pembrolizumab 200 mg IV every 3 weeks was administered beginning 1 week prior to the first fraction of radiation. The HFRT dose was 8 Gy x 3 fractions or 17 Gy x 1 fraction, determined by randomization during the Expansion phase. The primary objective was the safety of HFRT combined with pembrolizumab, with dose-limiting toxicity (DLT) defined as Grade ≥ 3 non-hematological toxicity related to the combination of Pembrolizumab and HFRT. The secondary objective was the radiographic response of metastatic lesions outside the radiation field as measured by RECIST.A total of 59 patients aged 27-90 years (median 60) were enrolled from March 2015 to December 2018 (24 in the Safety Phase and 35 in Expansion Phase). 40 patients (67.7%) had treatment-related AEs, of which 4 were grade 3 and none were grade 4. One patient experienced hepatitis, classified as DLT. While most patients did not have a radiologic response, in patients with metastatic melanoma, 7 of 16 (43.8%, exact 95% CI 19.8-70.1%) had an objective response of non-irradiated lesions to HFRT + pembrolizumab, including 3 complete and 4 partial responses. Responses are durable with 3/3 complete responders alive with no progression, and 3/4 partial responders alive with 2 having no evidence of progression. Among melanoma patients, only 2 of 7 (29%) responders received ipilimumab prior to enrollment, compared to 8 of 9 (89%) non-responders (P = 0.035). An increase in Ki67+ PD-1+ non-naïve CD8 T-cells was observed in the blood 2 weeks after HFRT, but the magnitude did not correlate with likelihood of response. Responses were observed after either 17 Gy x 1 fraction or 8 Gy x 3 fractions, with no difference in response rate by fractionation.This study suggests that HFRT administered with concurrent pembrolizumab is associated with acceptable toxicity and that in patients with metastatic melanoma progressing on anti-PD-1 therapy, this approach yields an ORR of 44%.

Final results of a phase I “RadVax” trial of hypofractionated radiation combined with pembrolizumab in patients with metastatic solid tumors.

2576 Background: Many patients treated with anti-PD-1 therapy do not show a clinical response. Preclinical studies suggest that adding hypofractionated radiotherapy (HFRT) to anti-PD1 can increase the efficacy of immunotherapy through several mechanisms including increased antigen presentation. We conducted a prospective trial testing the combination of pembrolizumab and HFRT in patients with metastatic solid tumors. Methods: This prospective single-institution phase I trial tested pembrolizumab in combination with HFRT in patients with metastatic cancers (NSCLC, melanoma, pancreas, breast, others) and an ECOG performance status of 0-1. Melanoma and NSCLC patients were required to have progression of disease on anti-PD1, having received ≥ 2 doses of anti-PD1 and progression documented by RECIST v1.1. Patients were required to have an index lesion ≥1 cm that was amenable to HFRT and at least one other lesion that was not irradiated and could be followed for response using RECIST criteria. Pembrolizumab 200 mg IV every 3 weeks was administered beginning 1 week prior to the first fraction of radiation. The HFRT dose was 8 Gy x 3 fractions or 17 Gy x 1 fraction, determined by randomization during the Expansion phase. The primary objective was the safety of HFRT combined with pembrolizumab, with dose-limiting toxicity (DLT) defined as Grade ≥ 3 non-hematological toxicity related to the combination of Pembrolizumab and HFRT. The secondary objective was the radiographic response of metastatic lesions outside the radiation field as measured by RECIST. Results: 59 patients aged 27-90 years (median 60) were enrolled from March 2015 to December 2018 (24 in the Safety Phase and 35 in Expansion Phase). 40 patients (67.7%) had treatment-related AEs, of which 4 were grade 3 and none were grade 4. One patient experienced hepatitis, classified as DLT. While most patients did not have a radiologic response, in patients with metastatic melanoma, 7 of 16 (43.8%, exact 95% CI 19.8-70.1%) had an objective response to HFRT + pembrolizumab, including 3 complete and 4 partial responses. Responses are durable with 3/3 complete responders alive with no progression, and 3/4 partial responders alive with 2 having no evidence of progression. Among melanoma patients, only 2 of 7 (29%) responders received ipilimumab prior to enrollment, compared to 8 of 9 (89%) non-responders (p = 0.035). An increase in Ki67+ PD-1+ non-naïve CD8 T-cells was observed in the blood 2 weeks after HFRT, but the magnitude did not correlate with likelihood of response. Responses were observed after either 17 Gy x 1 fraction or 8 Gy x 3 fractions, with no difference in response rate by fractionation. Conclusions: This study suggests that HFRT administered with concurrent pembrolizumab is associated with acceptable toxicity and that in patients with metastatic melanoma progressing on anti-PD-1 therapy, this approach yields an ORR of 44%. Clinical trial information: NCT02303990.

Nivolumab and Hypofractionated Radiotherapy in Patients With Advanced Lung Cancer: ABSCOPAL-1 Clinical Trial

BackgroundMore clinical practice need to be performed to verify the toxicity of the hypofractionated radiotherapy (HFRT) combined with PD-1 blockade in lung cancer. This phase I study aimed to investigate the safety and efficacy of nivolumab combined with HFRT in patients with progressive advanced lung cancer following multiline treatment.MethodsWe enrolled 31 patients with advanced lung cancer pathologically confirmed to have progressive disease and treated with first-line or a higher therapy. Selected lesions were treated using HFRT, and nivolumab was administered within 7 days subsequently. Nivolumab was administered once a month following partial remission. Peripheral blood was collected before and after 1 month of treatment to evaluate relevant cytokines between nivolumab responders and non-responders.ResultsOverall, 23 patients who completed the treatment were evaluated. Of them, 9 and 14 patients underwent hypofractionated brachytherapy with 30 Gy in a single fraction via percutaneous interstitial implantation of (192)Ir and 40–50 Gy in 5 fractions via stereotactic body radiation therapy, respectively. The median follow-up period was 11 months. At the 1-year follow-up, no patient developed grade ≥ 3 pneumonitis. The overall objective response and complete remission rates were 39.13% and 13.04%, respectively. The 1-year overall survival and median progression-free survival were 60.9% and 6 months, respectively. The plasma levels of interleukin IL-6, IL-10, and IL-17A were significantly reduced after treatment in nivolumab responders.ConclusionsHFRT could increase the responsivity to nivolumab and reduce its administration frequency. This combination treatment is well tolerated with acceptable toxicity and thus merits further trials to validate benefits.Clinical Trial Registration http://www.chictr.org.cn/index.aspx, identifier ChiCTR-1900027768.

A Phase II Pilot Study of Avelumab in Combination with Hypofractionated Radiotherapy in Patients with Relapsed Refractory Multiple Myeloma

Background: Multiple myeloma (MM) is the 2nd most common hematologic malignancy and remains incurable despite significant treatment advances over the last decade. Patients with relapsed/refractory multiple myeloma (RRMM), who have exhausted available therapies, have limited treatment options and a median survival as brief as 6 months (Richardson PG et al., Oncology 2010). Immune checkpoint inhibitors (CPI) have dramatically changed treatment paradigms in multiple cancers, with growing evidence that radiation therapy (XRT) may synergize with these agents via the abscopal effect. MM cells express high levels of PD-L1. Preclinical models have demonstrated rejection of murine myeloma when PD-L1 blockade was combined with XRT (Kearl TJ et al., Journal of Immunology 2013), as well as longer survival in myeloma-bearing mice compared to controls (Jing W et al., Journal for ImmunoTherapy of Cancer 2015). Early phase single arm clinical trials with combinations of immunomodulatory drugs (IMiDs) and CPI showed response rates between 33 and 76% (Pianko MJ et al., Stem Cell Investigation 2017)(San Miguel J et al., Blood 2015)(Badros A et al., Blood 2017). However, subsequent phase 3 studies revealed a potential safety signal of this combination (FDA 2017). Nonetheless, a subset of patients appear to attain durable responses (Badros A et al., Blood Advances 2019). CPI combined with other therapies such as XRT, that help to prime the immune system, hold great promise in the treatment of patients with RRMM. Herein, we describe our phase II study of avelumab, an anti-PD-L1 IgG1 antibody with potential antibody-dependent cellular cytotoxic properties, in combination with XRT in patients with RRMM. Methods: Trial Design: The primary endpoint of this trial is to assess the systemic response rate with the combination of avelumab and XRT in the treatment of extramedullary plasmacytomas or active lytic lesions in patients with RRMM using the 2016 IMWG response criteria. Secondary endpoints include determination of complete response rate, progression-free survival, and overall survival. Patients will undergo bone marrow biopsies and imaging (PET/CT and DW-MRI) at baseline, during disease response evaluations, and at the end of treatment. Treatment: Treatment consists of a 4-week lead-in with avelumab at a flat dose of 800mg IV every 2 weeks followed by concurrent XRT of 5Gy for 5 consecutive days directed toward the plasmacytoma/lytic lesion (Figure 1). Monotherapy avelumab, 800mg IV every 2 weeks, will continue indefinitely until disease progression or unacceptable toxicity. Analysis: This is a single arm trial with a Simon minimax two-stage phase II trial design that will enroll up to 27 patients. The first stage will enroll 13 evaluable patients, and if 0 of the 13 have a clinical response, then no further patients will be accrued due to futility. If 1 or more of the first 13 patients have a response, then accrual will continue until a total of 27 evaluable patients have been treated in the second stage. This will provide a two-sided alpha of 5% and a Power of 80% to rule out an ORR of 5% in favor of a response rate of 20%. Response fractions and time to event endpoints will be reported along with 90 and 95% two-sided confidence intervals with nominal p values. Eligibility: Patients must have previously treated relapsed MM or RRMM refractory to, ineligible for, or intolerant of, available myeloma therapies and have ≥ 1 extramedullary plasmacytoma and/or lytic lesion. Lesions must be amenable to, and clinically indicated for, treatment with localized XRT. Eligible patients must have documented evidence of progressive disease on, or after, their most recent regimen as defined by the IMWG criteria. They must have achieved at least a minimal response to one or more prior regimens. Exclusionary criteria include patients with: clinically unstable lesions where a delay in XRT may be detrimental; active autoimmune diseases or history of serious autoimmune-related disorders; uncontrolled intercurrent illnesses; concurrent use of immunosuppressant medications; and recent or current anti-cancer treatment prior to the first dose of avelumab. Current Enrollment: This study is actively enrolling patients to the first stage. At the time of this submission, 4 patients have been enrolled and have received at least one dose of trial therapy. Clinical trial registry number: NCT03910439. Figure Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: avelumab not approved in myeloma

Does Preoperative Hypofractionated Radiation Therapy for Soft Tissue Sarcoma Impact Post-operative Wound Complications?

Standard treatment for soft tissue sarcoma (STS) includes conventionally fractionated radiotherapy at 1.8-2 Gy/fx followed by surgical resection resulting in wound complication rates of 35% (O’Sullivan et al., Lancet 2002). STS has a low α/β ratio suggesting higher doses per fraction should lead to improved tumor control with a similar side effect profile. This single arm phase 2 clinical trial assessed the safety of preoperative hypofractionated radiotherapy in patients with STS. Patients with newly diagnosed and histologically confirmed Stage I-III STS of the extremity or chest wall were enrolled on this protocol at one institution. Patients were deemed resectable with negative margins and treated with radiotherapy to 3500 cGy in 5 fractions administered every other day prior to undergoing resection 4 to 6 weeks after completion of treatment. The primary outcome was wound complications assessed using the NCIC definition. Secondary outcomes included local control, disease free survival, and overall survival. Twenty-six patients enrolled with 24 completing surgical resection. Of these patients, 14 were male and 10 female and the median age was 66. Median tumor size was 9.5 cm. The vast majority of patients had undifferentiated histology (n=11, 46%) followed by liposarcoma/leiomyosarcoma (n=6, 25%), myxofibrosarcoma (n=5, 21%), and other (n=2, 8%). Tumor anatomic location was proximal lower extremity/buttock, upper extremity, distal lower extremity, and chest wall in 71%, 13%, 8%, and 8%, respectively. Most patients presented with stage III disease (79%) followed by I (13%) and II (8%). Histologic grade was high, low, and intermediate in 79%, 13%, and 8%, respectively. Two patients (8.3%) had positive margins on surgical specimens and plastic surgery was involved in 9 of the operations (38%). Median RT elapsed days was 9.5 and the median time from initiation of RT to time of surgery was 50.5 days. At a median follow-up time of 19.8 months, 6 patients (25%) experienced a post-operative wound complication. Local control was 100%. Five patients developed distant metastatic disease (20.8%) with a median time to distant metastases of 15.4 months. Two patients (8%) died of metastatic disease. Results of preoperative hypofractionated radiotherapy for treatment of patients with STS of the extremity and trunk demonstrates post-operative wound complication rates comparable to historical rates using conventionally fractionated RT. Although local control was optimal at 100%, further follow-up is needed to corroborate these findings.

Avelumab in Combination With Hypofractionated Radiotherapy in Patients With Relapsed Refractory Multiple Myeloma

Avelumab in Combination With Hypofractionated Radiotherapy in Patients With Relapsed Refractory Multiple Myeloma

A phase 1 dose-escalation study of the oral histone deacetylase inhibitor abexinostat in combination with standard hypofractionated radiotherapy in advanced solid tumors.

Current treatments for advanced solid tumors tend to be only palliative. Although radiotherapy is administered with a curative intent, radioresistance and dose-limiting toxicities pose limitations to treatment. Abexinostat, an oral pan-histone deacetylase inhibitor, demonstrated enhanced sensitivity to radiation in various solid tumor cell lines. We conducted an exploratory, phase 1, dose-escalation study of abexinostat in combination with standard hypofractionated radiotherapy in patients with advanced solid tumors treated in a palliative setting. Among 58 treated patients, the median age was 61.5 years (range, 20-82); 47% of the patients had M1 stage disease, and 95% had received previous chemotherapy alone or chemotherapy in combination with surgery and/or radiotherapy. The recommended phase 2 dose was determined to be 90 mg/m2 (140 mg). Of the 51 patients evaluable for response, best overall response was 8% (1 complete response [CR], 3 partial responses [PRs]), and best loco-regional response was 12% (1 CR and 5 PRs) at a median follow-up of 16 weeks. Of note, patients with target or non-target brain lesions showed encouraging responses, with 1 patient achieving a best loco-regional response of CR. Treatment-emergent grade ≥3 adverse events (AEs) were few, with most common being thrombocytopenia (17%), lymphopenia (12%), and hypokalemia (7%). Six patients (10%) discontinued treatment due to AEs. No grade ≥3 prolongation of the QTc interval was observed, with no treatment discontinuations due to this AE. Oral abexinostat combined with radiotherapy was well tolerated in patients with advanced solid tumors. The combination may have potential for treatment of patients with brain lesions.

Efficacy of neoadjuvant hypofractionated radiotherapy in patients with locally advanced myxoid liposarcoma

BackgroundMyxoid liposarcoma (MLPS) has been reported to be more radiosensitive compared with other soft tissue sarcomas (STS). The use of preoperative hypofractionated radiotherapy 5 × 5 Gy for five consecutive days, and then immediate surgery in patients with locally advanced STS showed a good local control rate. The main objective of our work was to assess the efficacy of hypofractionated radiotherapy in preoperative setting in patients with locally advanced primary MLPS. MethodsFrom February 1999 to March 2014, 32 patients with primary MLPS were treated with preoperative hypofractionated radiotherapy for 5 consecutive days followed by immediate surgery (median dose 5 × 5 Gy). Median size of the tumor 10.5 cm. In one patient the tumor was located on the upper extremity, the other (31 patients) had their tumors located on the lower extremity. ResultsIn 90% patients histologically negative surgical margins (R0) were obtained. 34% patients had distant recurrence of the disease, local recurrence was found in 9.3% of the patients. 5-year local relapse-free survival rate was 90% and overall survival was 68%. In all analyzed surgical specimens the radiotherapy response features (hyalinization, fibrosis, paucicelularity, hemorrhages, dilatation of vessels) were detected. We have not found statistically significant differences in terms of OS and LRFS for RCC component, tumor grade, BCL2, TP53, postsurgery necrosis and tumor size. In postradiotherapy specimens significantly higher positivity of TP53 expression was detected as compared to primary biopsies. ConclusionCombined therapy with hypofractionated radiotherapy followed by immediate surgery seems to be effective therapy in MLPS demonstrating good local control and pathological response to therapy.

Accelerated Hypofractioned Postoperative Radiotherapy for Prostate Cancer: A Prospective Phase I/II Study

AimsTo present the initial findings of a single institution, phase I/II study investigating hypofractionated radiotherapy in patients undergoing post-prostatectomy treatment. Materials and methodsPatients requiring postoperative radiotherapy were prospectively enrolled. Dose was prescribed to the prostate bed with 51 Gy in 17 daily fractions. Androgen deprivation was optional. Acute and late gastrointestinal/genitourinary toxicity were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 and quality of life was assessed using the Expanded Prostate Cancer Index Composite evaluation tool. Prostate-specific antigen (PSA) was evaluated at every follow-up. ResultsThirty patients were enrolled between 2009 and 2011. The median age was 65 years and most had Gleason 7 disease (86%) with pT2c or pT3a (82%). Positive margins were documented in 67% of the patients. The median pre-treatment PSA was 0.12 ng/ml. The median follow-up was 24 months. Overall toxicity was low, with >80% of patients having ≤ grade 1 acute toxicity in both genitourinary and gastrointestinal realms. Similarly, only two patients (6%) experienced grade 2/3 late gastrointestinal/genitourinary toxicity. Quality of life scores were also indicative of a well-tolerated treatment. PSA failure was seen in five patients (17%). ConclusionsWe present a hypofractionated schedule of postoperative prostate radiotherapy that is both well tolerated in terms of both toxicity and quality of life measures. Initial PSA control is encouraging. Further evaluation with a longer follow-up and a larger cohort is warranted.

High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Can Synchronous Chemotherapy be Added to Accelerated Hypofractionated Radiotherapy in Patients with Base of Tongue Cancer?

Aim To evaluate the tolerability of synchronous chemotherapy and accelerated hypofractionated radiotherapy in patients with locally advanced squamous cell carcinoma of the base of the tongue. Materials and methods Between 1999 and 2004, 43 patients with stage II–IV squamous cell carcinoma of the base of the tongue were treated with a combined modality of radiotherapy (prescribed 55 Gy in 20 fractions), synchronous chemotherapy and in some cases surgical neck dissection. End points were acute and late toxicity, 3 year locoregional control, overall survival, cancer-specific survival and compliance. Results The median follow-up for surviving patients was 3.9 years. All patients completed radiotherapy and 30% received neoadjuvant chemotherapy. The median time for the completion of treatment was 27 days (range 25–36). Overall, only 42% completed the prescribed synchronous chemotherapy. However, compliance increased to 60% in patients who did not receive neoadjuvant chemotherapy. Grade 3 mucositis developed in 90% of patients. Prolonged grade 3 mucositis (>4 weeks) was seen in 24/43 (56%) and none developed grade 4 mucositis. There were no toxic deaths. Feeding tube dependency at 1 year was 14%. The 3 year locoregional control, overall survival and cancer-specific survival were 70, 60 and 60%, respectively. Clinical T staging was most significantly associated with poor overall survival, cancer-specific survival and local control. Distant metastases occurred in 6/43 patients (14%), 5/6 without locoregional recurrence. Conclusion The addition of synchronous chemotherapy to accelerated hypofractionated radiotherapy consistently led to grade 3 mucositis. Tumour control rates compare well with published outcomes. Higher mucosal toxicity and lower synchronous chemotherapy compliance compared with other series may suggest that this approach is at the limit of patient tolerability. However, the tumour site investigated and the choice of synchronous chemotherapy agent may also be important. Compliance may be improved using intensity-modulated radiotherapy and agents that do not enhance mucosal toxicity. Longer fractionation will probably increase compliance with chemotherapy, particularly when induction is used before synchronous treatment.