Spatially fractionated radiation therapy: a critical review on current status of clinical and preclinical studies and knowledge gaps.

Spatially fractionated radiation therapy (SFRT) is a therapeutic approach with the potential to disrupt the classical paradigms of conventional radiation therapy. The high spatial dose modulation in SFRT activates distinct radiobiological mechanisms which lead to a remarkable increase in normal tissue tolerances. Several decades of clinical use and numerous preclinical experiments suggest that SFRT has the potential to increase the therapeutic index, especially in bulky and radioresistant tumors. To unleash the full potential of SFRT a deeper understanding of the underlying biology and its relationship with the complex dosimetry of SFRT is needed. This review provides a critical analysis of the field, discussing not only the main clinical and preclinical findings but also analyzing the main knowledge gaps in a holistic way.

Mitochondria-Modulating Liposomes Reverse Radio-Resistance for Colorectal Cancer.

Complete remission of colorectal cancer (CRC) is still unachievable in the majority of patients by common fractionated radiotherapy, leaving risks of tumor metastasis and recurrence. Herein, clinical CRC samples demonstrated a difference in the phosphorylation of translation initiation factor eIF2α (p-eIF2α) and the activating transcription factor 4 (ATF4), whose increased expression by initial X-ray irradiation led to the resistance to subsequent radiotherapy. The underlying mechanism is studied in radio-resistant CT26 cells, revealing that the incomplete mitochondrial outer membrane permeabilization (iMOMP) triggered by X-ray irradiation is key for the elevated expression of p-eIF2α and ATF4, and therefore radio-resistance. This finding guided to discover that metformin and 2-DG are synergistic in reversing radio resistance by inhibiting p-eIF2α and ATF4. Liposomes loaded with metformin and 2-DG (M/D-Lipo) are thus prepared for enhancing fractionated radiotherapy of CRC, which achieved satisfactory therapeutic efficacy in both local and metastatic CRC tumors by reversing radio-resistance and preventing T lymphocyte exhaustion.

Stereotactic Radiosurgery and Stereotactic Fractionated Radiotherapy in the Management of Brain Metastases.

The management of brain metastases (BM) remains an important and complex issue in the treatment of cancer-related neurological complications. BM are particularly common in patients diagnosed with lung, melanoma, or breast cancer. Over the past decade, therapeutic approaches for the majority of BM patients have changed. Considering and addressing the fact that patients with BM are living longer, the need to provide effective local control while preserving quality of life and neurocognition is fundamental. Over the past decade, SRS and SRT have become a more commonly chosen treatment option for BM. Despite significant advances in the treatment of BM, numerous questions remain regarding patient selection and optimal treatment sequencing. Clinical trials are critical to advancing our understanding of BM, especially as more therapeutic alternatives become available. Therefore, it is imperative for interdisciplinary teams to improve their understanding of the latest advances in SRS-SRT. This review aims to comprehensively explore SRS and SRT as treatments for BM, covering clinical considerations in their application (e.g., patient selection and eligibility), managing limited and multiple intact BM, addressing brainstem metastases, exploring combination therapies with systemic treatments, and considering the health economic perspective.

Efficacy and safety analysis of hypofractionated and conventional fractionated radiotherapy in postoperative breast cancer patients.

OBJECTIVES: In this meta-analysis, we conducted a comparative analysis of the safety and efficacy of hypofractionated and conventional fractionated radiotherapy in individuals who had undergone surgery for breast cancer. METHODS: This study involved a systematic and independent review of relevant research articles published in reputable databases such as PubMed, Embase, Cochrane Library, and Web of Science. Two investigators conducted the review, which included studies published up to January 3, 2023. The quality of the eligible studies was evaluated and data were extracted using Review Manager software 5.4 (RevMan 5.4) to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The analysis comprised 35 studies and encompassed a collective sample of 18,246 individuals diagnosed with breast cancer. We did not find a statistically significant disparity in efficacy between conventional fractionated (CF) radiotherapy and hypofractionated (HF) radiotherapy regarding local recurrence (LR; OR = 0.91, 95% CI: 0.76-1.09, P = 0.30), disease-free survival (DFS; OR = 1.20, 95% CI: 1.01-1.42, P = 0.03), and overall survival (OS; OR = 1.08, 95% CI: 0.93-1.26, P = 0.28). Concerning safety, there was no significant difference between the HF and CF regimens in terms of breast pain, breast atrophy, lymphedema, pneumonia, pulmonary fibrosis, telangiectasia, and cardiotoxicity. However, the HF regimen resulted in lower skin toxicity (OR = 0.43, 95% CI: 0.33-0.55, P < 0.01) and improved patient fatigue outcomes (OR = 0.73, 95% CI: 0.60 - 0.88, P < 0.01). CONCLUSIONS: Although there is no substantial difference in LR, DFS, OS, or many other side effects between the HF and CF regimens, the HF regimen reduces skin toxicity and relieves patient fatigue. If these two issues need to be addressed in clinical situations, the HF regimen may be a superior alternative to conventional radiotherapy in postoperative breast cancer patients.

Partial-Volume Irradiation of Murine Tumors.

Radiotherapy is a widely used approach for cancer treatment. However, delivering a single high dose of radiation to bulky tumors can be challenging due to the toxicities induced in the surrounding healthy tissue. To overcome this issue, a nonuniform high dose can be delivered using partial-volume tumor irradiation or spatially fractionated radiotherapy (SFRT). Moreover, SFRT has the potential to induce a stronger antitumor immune response compared to traditional radiotherapy due to the preservation of immune cells in the unirradiated tumor regions. There are several SFRT approaches, including GRID therapy, three-dimensional GRID therapy (LATTICE), microbeam radiation therapy (MRT), and Stereotactic Body Radiation Therapy for PArtial Tumor irradiation targeting exclusively the HYpoxic segment (SBRT-PATHY). The following protocol describes partial-volume tumor irradiation, a technique that enables dose delivery to only a part of the tumor in mice using an X-ray generator and collimators of different dimensions that limit the size of the irradiation field.

Mini-GRID radiotherapy on the CLEAR very-high-energy electron beamline: collimator optimization, film dosimetry, and Monte Carlo simulations.

Objective.Spatially-fractionated radiotherapy (SFRT) delivered with a very-high-energy electron (VHEE) beam and a mini-GRID collimator was investigated to achieve synergistic normal tissue-sparing through spatial fractionation and the FLASH effect.Approach.A tungsten mini-GRID collimator for delivering VHEE SFRT was optimized using Monte Carlo (MC) simulations. Peak-to-valley dose ratios (PVDRs), depths of convergence (DoCs, PVDR ≤ 1.1), and peak and valley doses in a water phantom from a simulated 150 MeV VHEE source were evaluated. Collimator thickness, hole width, and septal width were varied to determine an optimal value for each parameter that maximized PVDR and DoC. The optimized collimator (20 mm thick rectangular prism with a 15 mm × 15 mm face with a 7 × 7 array of 0.5 mm holes separated by 1.1 mm septa) was 3D-printed and used for VHEE irradiations with the CERN linear electron accelerator for research beam. Open beam and mini-GRID irradiations were performed at 140, 175, and 200 MeV and dose was recorded with radiochromic films in a water tank. PVDR, central-axis (CAX) and valley dose rates and DoCs were evaluated.Main results.Films demonstrated peak and valley dose rates on the order of 100 s of MGy/s, which could promote FLASH-sparing effects. Across the three energies, PVDRs of 2-4 at 13 mm depth and DoCs between 39 and 47 mm were achieved. Open beam and mini-GRID MC simulations were run to replicate the film results at 200 MeV. For the mini-GRID irradiations, the film CAX dose was on average 15% higher, the film valley dose was 28% higher, and the film PVDR was 15% lower than calculated by MC.Significance.Ultimately, the PVDRs and DoCs were determined to be too low for a significant potential for SFRT tissue-sparing effects to be present, particularly at depth. Further beam delivery optimization and investigations of new means of spatial fractionation are warranted.

Comparison of peripheral leukocyte parameters in patients receiving conventionally and hypofractionated radiotherapy schemes for the treatment of newly diagnosed glioblastoma.

Introduction: Treatment for glioblastomas, aggressive and nearly uniformly fatal brain tumors, provide limited long-term success. Immunosuppression by myeloid cells in both the tumor microenvironment and systemic circulation are believed to contribute to this treatment resistance. Standard multi-modality therapy includes conventionally fractionated radiotherapy over 6 weeks; however, hypofractionated radiotherapy over 3 weeks or less may be appropriate for older patients or populations with poor performance status. Lymphocyte concentration changes have been reported in patients with glioblastoma; however, monocytes are likely a key cell type contributing to immunosuppression in glioblastoma. Peripheral monocyte concentration changes in patients receiving commonly employed radiation fractionation schemes are unknown. Methods: To determine the effect of conventionally fractionated and hypofractionated radiotherapy on complete blood cell leukocyte parameters, retrospective longitudinal concentrations were compared prior to, during, and following standard chemoradiation treatment. Results: This study is the first to report increased monocyte concentrations and decreased lymphocyte concentrations in patients treated with conventionally fractionated radiotherapy compared to hypofractionated radiotherapy. Discussion: Understanding the impact of fractionation on peripheral blood leukocytes is important to inform selection of dose fractionation schemes for patients receiving radiotherapy.

Locally advanced head and neck squamous cell carcinoma treatment efficacy and safety: a systematic review and network meta-analysis.

Head and neck squamous cell carcinoma (HNSCC) accounts for approximately 3% of new cancer cases and 3% of all deaths worldwide. Most HNSCC patients are locally advanced (LA) at diagnosis. The combination of radiotherapy (RT), chemotherapy, targeted therapy, and immunotherapy are the primary LA-HNSCC treatment options. Nevertheless, the choice of optimal LA-HNSCC treatment remains controversial. We systematically searched public databases for LA-HNSCC-related studies and assess treatment effectiveness and safety by assessing the objective response rate (ORR), ≥3 adverse events (AEs), overall survival (OS), progression-free survival (PFS), disease-free survival (DFS), local-region control (LRC), and disease-specific survival (DSS). 126 randomized controlled clinical trials (RCTs) were included in this study. We show that concurrent RT with nimotuzumab or conventional concurrent chemo-radiotherapy (CCRT) had significantly better efficacy and long-term survival without increasing AEs than RT alone. Accelerated fractionated radiotherapy (AFRT) showed better efficiency than conventional fractionated RT, although it had higher AEs. In addition, concurrent cetuximab combined with RT failed to show a significant advantage over RT alone. Trial registration: PROSPERO CRD42022352127.

Obtaining organ-specific radiobiological parameters from clinical data for radiation therapy planning of head and neck cancers.

Objective.Different radiation therapy (RT) strategies, e.g. conventional fractionation RT (CFRT), hypofractionation RT (HFRT), stereotactic body RT (SBRT), adaptive RT, and re-irradiation are often used to treat head and neck (HN) cancers. Combining and/or comparing these strategies requires calculating biological effective dose (BED). The purpose of this study is to develop a practical process to estimate organ-specific radiobiologic model parameters that may be used for BED calculations in individualized RT planning for HN cancers.Approach.Clinical dose constraint data for CFRT, HFRT and SBRT for 5 organs at risk (OARs) namely spinal cord, brainstem, brachial plexus, optic pathway, and esophagus obtained from literature were analyzed. These clinical data correspond to a particular endpoint. The linear-quadratic (LQ) and linear-quadratic-linear (LQ-L) models were used to fit these clinical data and extract relevant model parameters (alpha/beta ratio, gamma/alpha,dTand BED) from the iso-effective curve. The dose constraints in terms of equivalent physical dose in 2 Gy-fraction (EQD2) were calculated using the obtained parameters.Main results.The LQ-L and LQ models fitted clinical data well from the CFRT to SBRT with the LQ-L representing a better fit for most of the OARs. The alpha/beta values for LQ-L (LQ) were found to be 2.72 (2.11) Gy, 0.55 (0.30) Gy, 2.82 (2.90) Gy, 6.57 (3.86) Gy, 5.38 (4.71) Gy, and the dose constraint EQD2 were 55.91 (54.90) Gy, 57.35 (56.79) Gy, 57.54 (56.35) Gy, 60.13 (59.72) Gy and 65.66 (64.50) Gy for spinal cord, optic pathway, brainstem, brachial plexus, and esophagus, respectively. Additional two LQ-L parametersdTwere 5.24 Gy, 5.09 Gy, 7.00 Gy, 5.23 Gy, and 6.16 Gy, and gamma/alpha were 7.91, 34.02, 8.67, 5.62 and 4.95.Significance.A practical process was developed to extract organ-specific radiobiological model parameters from clinical data. The obtained parameters can be used for biologically based radiation planning such as calculating dose constraints of different fractionation regimens.

Cytokine Levels in Saliva Are Associated with Salivary Gland Fibrosis and Hyposalivation in Mice after Fractionated Radiotherapy of the Head and Neck.

Cytokines are mediators of inflammation that could lead to fibrosis. The aim was to monitor cytokine levels in saliva and serum after locally fractionated radiotherapy of the head and neck in mice and investigate associations with salivary gland fibrosis and hyposalivation. C57BL/6 mice were randomized to sham or X-ray irradiation of 66 Gy in 10 fractions over 5 days. Blood and saliva were collected on days -7, 5, 35, 80, and 105 following cytokine analysis. The harvested submandibular salivary gland was assessed for the presence of fibrosis. Decision tree regression analysis was used to investigate whether cytokine levels could predict late endpoints in terms of hyposalivation or fibrosis. Significant formation of fibrosis in gland tissue and reduced saliva production was found after irradiation. The pro-inflammatory cytokines IL-1α, TNF, TIMP1, G-CSF, KC, and MIP-1α showed increased levels in saliva in irradiated mice and a strong correlation with late endpoints. The decision tree analysis largely separated controls from irradiated animals, with IL-1α being the strongest predictor. Pro-inflammatory cytokines in saliva, but not in serum, were associated with late endpoints. This indicates that cytokine expression in saliva is a good biomarker for local salivary gland damage with IL-1α as the strongest single predictor.

Radiotherapy-Induced Neurocognitive Dysfunction in Brain Tumor Survivors: Burden and Rehabilitation.

Radiotherapy-induced neurocognitive dysfunction after cranial irradiation has an incidence of 40-100%. It may affect both children and adults, and represents a significant burden not only on ill individuals and their caregivers but also on the health care system and society in general. Multiple patient-, tumor-, and treatment-related factors may contribute to development of this complication, but its pathophysiological mechanisms are still not understood clearly. It is hoped that introduction of more advanced techniques for conformal irradiation, optimized dosimetry, and specific prophylactic measures will decrease the risk of neurocognitive decline in brain tumor survivors in the future.

The impact of short-course hypofractionated radiotherapy on multimodality treatment utilisation, compliance, and outcome in glioblastoma patients: a Danish patterns of care study.

BACKGROUND: The aim of this retrospective registry-based Danish patterns of care study was (1) to evaluate the real-world utilisation of short-course hypofractionated radiotherapy (HFRT) in glioblastoma (GBM) patients over time, and (2) to evaluate the impact of short-course HFRT by assessing trends in multimodality treatment utilisation, compliance, and outcome. MATERIAL AND METHODS: Data of all adults with newly diagnosed pathology-confirmed GBM between 2011 and 2019 were extracted from the nationwide Danish Neuro-Oncology Registry. Short-course HFRT was defined as a fraction size of > 2 Gy to a planned dose of > 30 Gy. Patterns of care were assessed. To analyse trends in the assignment to short-course HFRT, and in radiotherapy (RT) compliance, multivariable logistic regression was applied. To analyse trends in survival, multivariable Cox regression was used. RESULTS: In this cohort of 2416 GBM patients, the utilisation of short-course HFRT significantly increased from ca. 10% in 2011 to 33% in recent years. This coincided with the discontinued use of palliative regimens and a decreased use of conventional fractionation. The proportion of patients proceeding to RT remained stable at ca. 85%. The proportion of patients assigned to chemoradiotherapy (CRT) remained stable at ca. 60%; the use of short-course hypofractionated CRT increased with ca. 10%, while the use of conventionally fractionated CRT decreased with ca. 10%. Compliance with conventionally fractionated and short-course HFRT was respective 92% and 93%, and significantly increasing in recent years. In the complete cohort, the median overall survival remained stable at ca. 11 months. Assignment to short-course HFRT was independently associated with shorter survival. CONCLUSION: In Denmark, the use of short-course HFRT significantly increased in recent years. Nonetheless, the overall utilisation of RT and chemotherapy did not increase on a population level. Nor did survival change. In contrast, compliance with both conventionally fractionated RT and short-course HFRT increased.

Hypofractionated radiotherapy compared with conventionally fractionated radiotherapy to treat initial distant metastases in nasopharyngeal carcinoma: A multicenter, prospective, randomized, phase II trial.

BACKGROUND AND PURPOSE: To investigate the safety and efficacy of hypofractionated plus chemotherapy in patients with initially distant metastatic nasopharyngeal carcinoma (mNPC). MATERIALS AND METHODS: Between May 2014 and June 2020, 35 patients initially diagnosed with mNPC were enrolled on prospective trial. The enrolled patients were assigned randomly to receive either hypofractionated plus chemotherapy (HFRT) or conventionally fractionated radiotherapy plus chemotherapy (CFRT). 60 Gy over 25 fractions was administered to the HFRT group (n = 17) and 69.96 Gy over 33 fractions was administered to the CFRT group (n = 18), both groups five times each week.Progression free survival (PFS) comprised the primary endpoint. Overall survival (OS), locoregional relapse-free survival (LRRFS), distant metastasis-free survival (DMFS), and acute and late toxicity comprised the secondary endpoints. RESULTS: Twenty-eight patients (seven were excluded) were enrolled. The 2-year PFS was 33.3% (HFRT group) versus 30.0% (CFRT group) (stratified hazard ratio (HR):1.09; 95% confidence interval (CI): 0.45-2.65, P = 0.843). The 2-year OS was 66.7% (HFRT group) versus with 62.5% (CFRT group) (stratified HR, 0.88; 95% CI; 0.31-2.51, P = 0.806). All patients experienced acute grade 1 or 2, skin toxicity, oral mucositis, difficulty swallowing, xerostomia, but no acute grade 3 or 4 toxicities. All patients had grade 1 late xerostomia. Two patients experienced hearing loss in the HFRT group (one grade 1 and one grade 3), and three patients experienced grade 1 hearing loss in the CFRT group. One patient developed mucosal necrosis in the HFRT group. CONCLUSION: Improving the balance between severe late toxicities and local control by appropriately reducing the total dose but increasing the fractionated dose has marked clinical significance for those patients.

Cost-effectiveness of stereotactic body radiotherapy versus conventional fractionated radiotherapy for medically inoperable, early-stage non-small cell lung cancer.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is a novel radio-therapeutic technique that has recently emerged as standard-of-care treatment for medically inoperable, early-stage non-small cell lung cancer (NSCLC). In this study, we compared the cost-effectiveness of SBRT with that of conventional fractionated radiotherapy (CFRT) in patients with medically inoperable, early-stage NSCLC from the perspective of the Chinese health system. METHODS: A Markov model was developed to describe health states of patients after treatment with SBRT and CFRT. The recurrence risks, treatment toxicities, and utilities inputs were obtained from the literature. The costs were based on listed prices and real-world evidence. A simulation was conducted to determine the post-treatment lifetime years. For each treatment, the total costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) per QALY were calculated. Deterministic and probabilistic sensitivity analyses were performed to assess the uncertainty of the model parameters. RESULTS: In the base case analysis, SBRT was associated with a mean cost of USD16,933 and 2.05 QALYs, whereas CFRT was associated with a mean cost of USD17,726 and 1.61 QALYs. SBRT is a more cost-effective strategy compared with CFRT for medically inoperable, early-stage NSCLC, with USD 1802 is saved for every incremental QALY. This result was validated by DSA and PSA, in which SBRT remained the most cost-effective option. CONCLUSIONS: The findings suggested that, compared to CFRT, SBRT may be considered a more cost-effective strategy for medically inoperable, early-stage NSCLC.

Hypo-fractionated accelerated radiotherapy with concurrent and maintenance temozolomide in newly diagnosed glioblastoma: updated results from phase II HART-GBM trial.

BACKGROUND: Glioblastoma (GBM) patients have poor survival outcomes despite treatment advances and most recurrences occur within the radiation field. Survival outcomes after dose escalation through hypofractionated accelerated RT(HART) were evaluated in this study. We previously reported the study's initial results showing similar survival outcomes with acceptable toxicities. Updated results after 5 years are being analysed to determine long-term survival trends. PATIENTS AND METHODS: 89 patients of newly diagnosed GBM after surgery were randomized to conventional radiotherapy (CRT) or HART. CRT arm received adjuvant RT 60 Gy in 30 fractions over 6 weeks and the HART arm received 60 Gy in 20 fractions over 4 weeks, both with concurrent and adjuvant temozolomide. RESULTS: 83 patients were eligible for analysis. After a median follow-up of 18.9 months, the median OS was 26.5 months and 22.4 months in the HART and CRT arms respectively. 5 year OS was 18.4% in the HART arm versus 3.8% in the CRT arm. This numerical difference in overall survival between the two arms was not statistically significant. The median PFS was not significantly different. CONCLUSION: The long-term results of the trial support HART as a promising treatment option with comparable survival outcomes to the current standard of care. Phase III trials are required for further validation of this regimen which has the potential to become the new standard of care in GBM.

Effect of definitive hypo-fractionated radiotherapy concurrent with weekly cisplatin in locally advanced squamous cell carcinoma of the head and neck.

To mitigate the risk of COVID-19 infection in cancer patients, it is recommended to utilize hypo-fractionated treatment schedules that aim to minimize the overall duration of treatment. In this study, we aimed to determine whether hypo-fractionated intensity-modulated radiotherapy (hypo-IMRT) with concurrent chemotherapy was practical, effective, and could achieve acceptable tumor control rates for squamous cell carcinoma of the head and neck (SCCHN). We enrolled 62 patients with high-risk stage II, stage III, and IVA SCCHN who received hypo-IMRT (62.5 Gy in 25 fractions over 5 weeks 2.5Gy/fraction with weekly cisplatin 40 mg/m2). Our primary endpoint was to assess acute toxicity, while our secondary endpoints were late toxicity, loco-regional control, disease-free survival, and overall survival. The percentages of grade 3 acute pain, dermatitis, mucositis, and dysphagia were 71%, 19.4%, 72.6%, and 41.9%, respectively. The rates of late xerostomia, dysphagia, dental complications, grade 3 pain, and grade 3 weight loss were 72.6%, 62.9%, 27.4%, 4.8%, and 4.3%, respectively. At a median follow-up time of 24 months, 2-year loco-regional control and overall survival were 87.1% and 83.9%, respectively. Disease-free survival was 100%, 89.5%, and 69% in stages II, III, and IV%, respectively, with a significant p-value of 0.024. This regimen was effective and relatively safe, with acceptable and tolerable acute and late toxicity. Given the reduced need for hospital visits, hypo-fractionated schedules may represent an alternative treatment during the COVID-19 outbreak.

A feasibility study of ultra-high dose rate mini-GRID therapy using very-high-energy electron beams for a simulated pediatric brain case.

Ultra-high dose rate (UHDR, >40 Gy/s), spatially-fractionated minibeam GRID (mini-GRID) therapy using very-high-energy electrons (VHEE) was investigated using Monte Carlo simulations. Multi-directional VHEE treatments with and without mini-GRID-fractionation were compared to a clinical 6 MV volumetric modulated arc therapy (VMAT) plan for a pediatric glioblastoma patient using dose-volume histograms, volume-averaged dose rates in critical patient structures, and planning target volume D98s. Peak-to-valley dose ratios (PVDRs) and dose rates in organs at risk (OARs) were evaluated due to their relevance for normal-tissue sparing in FLASH and spatially-fractionated techniques. Depths of convergence, defined where the PVDR is first ≤1.1, and depths at which dose rates fall below the UHDR threshold were also evaluated. In a water phantom, the VHEE mini-GRID treatments presented a surface (5 mm depth) PVDR of (51±2) and a depth of convergence of 42 mm at 150 MeV and a surface PVDR of (33±1) with a depth of convergence of 57 mm at 250 MeV. For a pediatric GBM case, VHEE treatments without mini-GRID-fractionation produced 25% and 22% lower volume-averaged doses to OARs compared to the 6 MV VMAT plan and 8/9 and 9/9 of the patient structures were exposed to volume-averaged dose rates >40 Gy/s for the 150 MeV and 250 MeV plans, respectively. The 150 MeV and 250 MeV mini-GRID treatments produced 17% and 38% higher volume-averaged doses to OARs and 3/9 patient structures had volume-averaged dose rates above 40 Gy/s. VHEE mini-GRID plans produced many comparable dose metrics to the clinical VMAT plan, encouraging further optimization.

Investigating the Influence of Growth Arrest Mechanisms on Tumour Responses to Radiotherapy.

Cancer is a heterogeneous disease and tumours of the same type can differ greatly at the genetic and phenotypic levels. Understanding how these differences impact sensitivity to treatment is an essential step towards patient-specific treatment design. In this paper, we investigate how two different mechanisms for growth control may affect tumour cell responses to fractionated radiotherapy (RT) by extending an existing ordinary differential equation model of tumour growth. In the absence of treatment, this model distinguishes between growth arrest due to nutrient insufficiency and competition for space and exhibits three growth regimes: nutrient limited, space limited (SL) and bistable (BS), where both mechanisms for growth arrest coexist. We study the effect of RT for tumours in each regime, finding that tumours in the SL regime typically respond best to RT, while tumours in the BS regime typically respond worst to RT. For tumours in each regime, we also identify the biological processes that may explain positive and negative treatment outcomes and the dosing regimen which maximises the reduction in tumour burden.

Comparative Effectiveness of Chemotherapy Alone Versus Radiotherapy-Based Regimens in Locally Advanced Pancreatic Cancer: A Real-World Multicenter Analysis (PAULA-1).

Different options for locally advanced pancreatic cancer (LAPC) are available based on international guidelines: chemotherapy (CHT), chemoradiation (CRT), and stereotactic body radiotherapy (SBRT). However, the role of radiotherapy is debated in LAPC. We retrospectively compared CHT, CRT, and SBRT ± CHT in a real-world setting in terms of overall survival (OS), local control (LC), and distant metastasis-free survival (DMFS). LAPC patients from a multicentric retrospective database were included (2005-2018). Survival curves were calculated using the Kaplan-Meier method. Multivariable Cox analysis was performed to identify predictors of LC, OS, and DMFS. Of the 419 patients included, 71.1% were treated with CRT, 15.5% with CHT, and 13.4% with SBRT. Multivariable analysis showed higher LC rates for CRT (HR: 0.56, 95%CI 0.34-0.92, p = 0.022) or SBRT (HR: 0.27, 95%CI 0.13-0.54, p < 0.001), compared to CHT. CRT (HR: 0.44, 95%CI 0.28-0.70, p < 0.001) and SBRT (HR: 0.40, 95%CI 0.22-0.74, p = 0.003) were predictors of prolonged OS with respect to CHT. No significant differences were recorded in terms of DMFS. In selected patients, the addition of radiotherapy to CHT is still an option to be considered. In patients referred for radiotherapy, CRT can be replaced by SBRT considering its duration, higher LC rate, and OS rate, which are at least comparable to that of CRT.

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

BACKGROUND/AIM: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: Given the limitations of this study, CF-RT appeared associated with better outcomes. Selected patients may benefit from HF-RT.