Conventional Fractionation Radiotherapy Research Articles

Quality assurance in a phase III, multicenter, randomized trial of POstmastectomy radioThErapy in Node posiTive breast cancer with or without Internal mAmmary nodaL irradiation (POTENTIAL): a planning benchmark case

PurposeTo report the planning benchmark case results of the POTENTIAL trial—a multicenter, randomized, phase 3 trial—to evaluate the value of internal mammary nodal (IMN) irradiation for patients with high-risk breast cancer.MethodsAll participating institutions were provided the outlines of one benchmark case, and they generated radiation therapy plans per protocol. The plans were evaluated by a quality assurance team, after which the institutions resubmitted their revised plans. The information on beams arrangement, skin flash, inhomogeneity corrections, and protocol compliance was assessed in the first and final submission.ResultsThe plans from 26 institutions were analyzed. Some major deviations were found in the first submission. The protocol compliance rates of dose coverage for the planning target volume of chest wall, supraclavicular fossa plus axilla, and IMN region (PTVim) were all significantly improved in the final submission, which were 96.2% vs. 69.2%, 100% vs. 76.9%, and 88.4% vs. 53.8%, respectively. For OARs, the compliance rates of heart Dmean, left anterior descending coronary artery V40Gy, ipsilateral lung V5Gy, and stomach V5Gy were significantly improved. In the first and final submission, the mean values of PTVim V100% were 79.9% vs. 92.7%; the mean values of heart Dmean were 11.5 Gy vs. 9.7 Gy for hypofractionated radiation therapy and 11.5 Gy vs. 11.0 Gy for conventional fractionated radiation therapy, respectively.ConclusionThe major deviations were corrected and protocol compliance was significantly improved after revision, which highlighted the importance of planning benchmark case to guarantee the planning quality for multicenter trials.

Phase II multicenter trial: first-line immunochemotherapy with or without radiotherapy in metastatic esophageal squamous cell cancer (SCR-ESCC-01).

This randomized phase II trial (NCT05978193) combines low-dose radiotherapy (LDRT) and conventionally fractionated radiotherapy (CFRT) with immunochemotherapy for metastatic esophageal squamous cell carcinoma, aiming to assess the potential enhanced effect of radiotherapy on immunotherapy. Patients are administered a PD-1 inhibitor along with paclitaxel and platinum-based chemotherapy (arm B), or combined with LDRT and CFRT (arm A). Immunotherapy is given every 3 weeks with chemotherapy for 4 cycles, followed by immunotherapy maintenance therapy for up to 24months. In arm A, LDRT (2Gy, 2 fractions; delivered to the primary and all metastatic tumors) precedes each immunochemotherapy cycle for 4 cycles, followed by CFRT (40-50Gy, 20-25 fractions; delivered to the primary tumor) starting from the fifth immunotherapy cycle. The primary end point is median progression-free survival. Clinical Trial Registration: NCT05978193 (clinicaltrials.gov).

Efficacy and Safety of Radiotherapy Combined with Pyrotinib in the Treatment of HER2-Positive Breast Cancer with Brain Metastases.

To explore the efficacy and safety of pyrotinib combined with different radiotherapy modes in human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) patients with brain metastasis (BM). This study is a retrospective analysis of patients diagnosed with BM who underwent treatment with pyrotinib between November 2018 and April 2023. A total of 66 patients were administered radiotherapy in conjunction with pyrotinib (Group A), while 26 patients received pyrotinib as a standalone treatment (Group B). Within Group A, 18 patients underwent conventional fractionated radiotherapy (2Gy/F), while 48 patients received hyperfractionated radiotherapy (HFRT) (≥3Gy/F). The primary endpoints were intracranial progression-free survival (IC-PFS) and overall survival (OS). The secondary endpoints were objective response rate (ORR) and clinical benefit rate (CBR). The ORR of Group A was 54.5% (36/66), while the ORR of Group B was 34.6% (9/26) (P= 0.047). The CBR of Group A was 89.4% (59/66) and that of Group B was 69.2% (18/26) (P= 0.041). The IC-PFS between Group A and Group B were 12 months and 8 months, respectively (P< 0.001), and the OS were 20 months and 16 months, respectively (P= 0.065). In Group A, the IC-PFS and OS between the conventional fractionation radiotherapy group and the HFRT group were 10 months and 12 months, respectively (P= 0.001) and 16 months and 24 months, respectively (P< 0.001). No serious adverse reactions were observed in Group A and Group B. For HER2-positive BC patients with BM, it is recommended to adopt the treatment mode of HFRT combined with pyrotinib, which can improve the local control and survival of patients.

A comparison of conventional and accelerated hypofractionated radiotherapy in definitive chemoradiation for locally advanced head and neck carcinoma: a retrospective cohort study.

The study evaluates accelerated hypofractionated radiotherapy (AHRT) compared to conventional fractionation radiotherapy (CFRT) in patients with locally advanced head and neck cancer (LAHNC) receiving definitive chemoradiation therapy. The study includes a retrospective cohort analysis of 120 patients. CFRT arm (n = 65) received 2 Gy per fraction to a dose of 70 Gy over 7 weeks in a three-volume approach, whereas the AHRT arm (n = 55) received 2.2 Gy per fraction to a dose of 66 Gy in 6 weeks with a two-volume approach. The primary outcome was overall survival (OS). With a median follow-up of 18.9 months, 23 patients died in the AHRT arm, and 45 deaths in the CFRT arm. The median OS was 23.4 and 37.63 months in the CFRT and AHRT arms, respectively (hazard ratio [HR] = 0.709; 95% confidence interval [CI], 0.425-1.18; p = 0.189). The median time to loco-regional control was 33.3 months in the CFRT arm and was not reached in the patient group receiving AHRT (HR = 0.558; 95% CI, 0.30-1.03; p = 0.065). The median progression-free survival was 15.9 months in the CFRT arm and 26.9 months in the AFRT arm (HR = 0.801; 95% CI, 0.49-1.28; p = 0.357). Out of 11 acute toxic deaths, eight were in the CFRT arm. The study showed a trend towards benefit in terms of locoregional control in the AHRT arm and similar OS. A longer follow-up of patients receiving AHRT is required to assess the benefit.

Long-Term Outcomes Following Fairly Brief Androgen Suppression and Stereotactic Radiation Therapy in High-Risk Prostate Cancer: Update from the FASTR/FASTR-2 Trials.

There has been emerging interest in the role of ultra-hypofractionated radiotherapy for high-risk prostate cancer, especially given its low α/β ratio. However, there is limited data on the long-term outcomes of this treatment strategy. The FASTR and FASTR-2 clinical trials were designed to assess the tolerability of stereotactic ablative body radiotherapy (SABR) in high-risk prostate cancer. FASTR was discontinued early due to unacceptable acute toxicity, whereas the acute toxicities in FASTR-2 were minimal. Herein, the long-term results from these trials are reported. Eligible patients had at least 1 high-risk feature as per the National Comprehensive Cancer Network criteria for high-risk prostate cancer, no evidence of metastatic disease, and either a score of 3+ on the Vulnerable Elderly Scale or declined standard therapy. A total of 19 patients from a single institution were enrolled on FASTR between 2011 and 2015. They received 40 Gy to the prostate and 25 Gy to the pelvic lymph nodes in 5 fractions delivered once weekly for 5 weeks, along with 1 year of androgen deprivation therapy (ADT). The excessive acute toxicity in FASTR prompted several modifications in FASTR-2, including the omission of nodal irradiation. A total of 30 patients from the same institution were enrolled on FASTR-2 between 2015 and 2017. They received 35 Gy to the prostate alone in 5 fractions delivered once weekly for 5 weeks, along with 18 months of ADT. A total of 44 patients were eligible for analysis, 16 from FASTR and 28 from FASTR-2. Most patients were >70 years old (77%). High-risk features included Gleason score ≥8 (46%), T3-T4 disease (27%) and baseline PSA >20 (50%). With a median follow-up of 6.4 years, the cumulative incidence of grade ≥3 genitourinary/gastrointestinal toxicity was 50% among FASTR patients and 7% among FASTR-2 patients. At 5 years, the combined rates of biochemical failure-free survival, freedom from distant metastases, prostate cancer-specific survival and overall survival were 72%, 90%, 92% and 83%, respectively. A total of 12 patients (27%) required further treatment. No significant differences in clinical outcomes were noted between the FASTR and FASTR-2 cohorts. SABR for high-risk prostate cancer is an attractive option for reducing treatment burden. Clinical outcomes and toxicity with the FASTR-2 protocol were comparable to conventionally-fractionated radiotherapy plus ADT. Larger prospective, randomized trials exploring the role of SABR with ADT in high-risk disease are necessary to better understand the efficacy and tolerability of this approach.

The Updated Landscape of Tumor Microenvironment and Pre-Metastasis Niches for Radiotherapy Resistant Tumors

In the current clinical work, hypo-fractionated radiotherapy (HFRT) and conventional fractionated radiotherapy (CFRT) are considered to be completely different treatments. However, the difference between the HFRT and CFRT in reprogramming the tumor immune microenvironment (TIME) is still inconclusive. Our previous work found that compared with HFRT, CFRT is more inclined to trigger immunosuppressive phenotype, but the underlying mechanism is still unclear. Based on this, we use single-cell mRNA sequencing to describe the landscape of TIME with HFRT and CFRT, and find the key targets or pathways to combine with radiotherapy. By simulating the in vivo radiotherapy strategy, we built recurrent murine cell lines mimicking CFRT and HFRT recurrent tumors (CFRT_R and HFRT_R tumors) with small animal radiation research platform (SARRP). Based on this unique model, we found that CFRT_R tumors can promote local relapse and lung metastasis significantly compared to HFRT_R tumors. Results of single-cell mRNA sequencing and FCAS also indicate that CFRT_R tumors possess more macrophages in the tumor site and neutrophils in the metastatic site. By using quantitative proteomics of secreted proteins, we prove that CFRT_R tumors secret more Ccl2, S100a11 and Slpi. Mechanically, CFRT_R tumors influence the polarization of M2 TAMs leading to tumor growth through secretion of Ccl2 and S100a11. Meanwhile, CFRT_R tumors also augment the infiltration of neutrophils in the lung through Slpi altering the lung immune landscape to support metastasis. ChIP and EMSA results also reveal that RelB is the core transcription factor of Ccl2, S100a11 and Slpi. Furthermore, local relapse and lung metastasis can be reversed by targeting non-canonical NF-kB pathway. The effect of CFRT_R and HFRT_R tumors in reprogramming TIME is different, CFRT_R tumors can trigger immunosuppressive phenotype compared to HFRT_R tumors by possessing more M2 TAMs in the tumor site and neutrophils in the metastatic site. The killing function of tumor infiltrated T cells can be inhibited by accumulated M2 TAMs, and abundant neutrophils in lungs contribute to the formation of the pre-metastatic niche. Targeting non-canonical NF-kB pathway can reverse local relapse and lung metastasis in CFRT_R tumors by suppressing Ccl2, S100a11 and Slpi secretion. In short, our study not only deepens the understanding of the immune landscape of CFRT and HFRT recurrence tumors, but also provides a novel therapy of CFRT recurrence patients.

A Phase II Randomized Clinical Trial to Assess Toxicity and Quality of Life of Breast Cancer Patients with Hypofractionated vs. Conventional Fractionation Radiotherapy with Regional Nodal Irradiation

To compare acute toxicity between conventional fractionated radiation therapy (CFRT) and hypofractionated radiation therapy (HFRT) for patients undergoing breast-conserving surgery or mastectomy with breast or chest wall and regional nodal irradiation (RNI). The secondary endpoints were acute and subacute toxicity, cosmesis, quality of life, and lymphedema features. Unblinded randomized trial with a total of 86 patients treated with CFRT (n = 33; 50 Gy/25 fractions ± sequential boost [10 Gy/5 fractions]) versus HFRT (n = 53; 40 Gy/15 fractions ± concomitant boost [8 Gy/15 fractions]). Women included for enrollment were 18 years or older and diagnosed with breast carcinoma, staging T1-4, with at least one positive lymph node (American Joint Committee on Cancer - AJCC 8th). The surgery performed was mastectomy or breast-conservative surgery with the investigation of sentinel lymph node or axillary dissection. Toxic effects and cosmesis evaluation used the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE) and the Harvard/NSABP/RTOG scale. Patients-reported QoL was determined using the European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30) and the breast cancer-specific supplementary questionnaire (QLQ-BR23). The comparative analysis of categorical variables between the control and experimental groups used the Chi-square test and Fisher's exact test, while numerical variables basing on the Mann-Whitney U test. The intergroup comparison of the EORTC QLQ-C30 used the Generalized Equations Estimating method. All analyses used 2-sided α = 0.05 with R software version 4.1.2. Lymphedema determination compared volume differences between the affected and contralateral arms using the Casley-Smith volume formula. Grade 2 and grade 3 skin rash dermatitis were lower with HFRT than with CF-RT (28% vs. 52%, 0% vs. 6%; p = 0.022, respectively). HFRT vs. CFRT had lower rate of grade 2 hyperpigmentation (23% vs. 55%; p = 0.005). Overall rates of any physician-assessed grade ≥ 2 and grade ≥ 3 acute toxicities were no different between HFRT vs. CFRT arms. There was no statistical difference between the CFRT and the HFRT regarding cosmesis, lymphedema rate (13% vs. 12% HFRT vs. CFRT; p = 1.000, respectively), and functional and symptom scales during irradiation and after six months of treatment. HF-RT showed lower rates of acute toxicity, with no changes in quality-of-life outcomes.

Hypofractionated Accelerated Radiation Dose-Painting (HARD) vs. Standard Radiotherapy for Unresected Soft-Tissue Sarcoma

Conventionally fractionated radiotherapy (CFRT) offers modest local control (LC) for unresected soft tissue sarcoma (STS). Although STS has a low α/β (∼2 - 6) that may benefit from a hypofractionated radiotherapy regimen, it is often limited due to the toxicity risk to surrounding organs. A simultaneous integrated boost to gross disease (2.5 - 3 Gy/fraction), with lower doses to the intermediate and low risk target volume, may offer a safe isotoxic dose escalation approach. We hypothesize that this hypofractionated accelerated radiotherapy dose-painting (HARD) will improve local control compared to CFRT. We performed a single institution retrospective analysis of patients who received external beam radiotherapy with definitive intent (≥50 Gy) for unresected STS. CFRT was defined as 1.8 - 2 Gy/fraction (Gy/fx). HARD regimens consisted of 60 - 66 Gy at 3 Gy/fx or 70 Gy at 2.5 Gy/fx to gross disease, with 1.8 - 2.4 Gy/fx to intermediate and low risk regions. All anatomical sites and histologies were included. Local control (LC) was defined from date of current diagnosis, estimated by Kaplan-Meier methods via log-rank tests or Cox regression for univariate analysis (UVA), when appropriate. Cox regression multivariate analysis (MVA) included regimen, biological effective dose (α/β 6; BED6), lesion size, age, and grade. We identified 77 patients with primary and metastatic STS treated with HARD (n = 40) or CFRT (n = 37) between 1990 and 2022, with a median follow up of 24 months in surviving patients. The mean dose for CFRT and HARD are 56.8 Gy (50 - 77.4 Gy) and 64.9 Gy (60 - 70 Gy), respectively. HARD was comprised of 65% for 3 Gy/fx and 35% for 2.5 Gy/fx regimens. At the time of RT, grade 3 (69%) and extremity (39%) tumors were the most common. Tumor histology was very heterogenous across both cohorts, with undifferentiated pleomorphic sarcoma being the most common for HARD (33%) and CFRT (19%). HARD was more often utilized in stage IV patients (55% vs. 19%, p = 0.001) and had a higher mean BED6 (96 vs. 74.2 Gy, p < 0.001) than CFRT, but without differences in age (67 vs. 59 years), tumor size (8 vs. 10 cm), concurrent chemotherapy (35% vs. 30%), Karnofsky performance status (86 vs. 85), follow-up (19 vs. 28 months), and grade (all p > 0.1). On UVA, there was a LC benefit associated with higher BED6 (HR 0.94, 95% CI 0.9 - 0.98, p = 0.002) and the HARD regimen (2-year LC 95% vs. 62%, p < 0.001). On MVA, only HARD (HR 0.07, 95% CI 0.006 - 0.729, p = 0.027) was independently associated with LC. Although the HARD regimen and higher BED6 were both associated with significant improvement in LC, only the HARD regimen independently associated with a local control benefit for unresected STS. These results suggest biologic dose-intensification exploiting the low α/β of STS with an isotoxic hypofractionated regimen may be a favorable strategy for unresectable STS. Future prospective studies are necessary to validate these findings.

Choosing Wisely between Radiotherapy Dose-Fractionation Schedules: The Molecular Graded Prognostic Assessment (molGPA) for Elderly Glioblastoma (eGBM-molGPA)

This study aimed to develop a graded prognostic assessment (GPA) model integrating genomic characteristics in patients with elderly glioblastoma (eGBM), and compare the efficacy between conventionally fractionated radiotherapy (CFRT) vs. hypofractionated radiotherapy (HFRT) in each risk group. Patients aged ≥65 years who underwent surgical resection followed by radiotherapy (RT) with or without temozolomide (TMZ) for newly diagnosed IDH-wildtype eGBM between 2006 and 2021 were included in this multicenter cohort study. Patients who were planned for a ≥6-week or ≤4-week radiotherapy were regarded as being treated with CFRT or HFRT, respectively. Based on the prognostic factors significantly identified through multivariate analysis for overall survival (OS), we developed the molecular GPA for eGBM (eGBM-molGPA) and assigned 0.0, 0.5, and 1.0 points in proportion to the corresponding hazard ratio (HR) of each factor. Then, the survival outcomes by treatment groups were evaluated according to the eGBM-molGPA scores. A total of 334 and 239 patients who underwent CFRT and HFRT were included, respectively, and 86% of patients were treated with TMZ-based chemoradiation. With a median follow-up of 17.4 months for survivors, the median OS was 18.7 months for CFRT plus TMZ group, 15.1 months for HFRT plus TMZ group, and 10.4 months for RT alone group, respectively (all p<0.001). In the multivariate analysis, Karnofsky performance scale, surgical extent, TMZ, and the methylation status of the MGMT promoter were identified as strong prognostic factors for OS, with an estimated HR of greater than 1.5 (all p<0.001). Additionally, subventricular zone involvement, temporalis muscle thickness, RT regimen, and the mutation status of TERT promoter and TP53 gene were found to be significant prognostic factors for OS, with an estimated HR of less than 1.5. The eGBM-molGPA was established based on these prognostic factors (Table 1) and patients were allocated to three risk groups, which included high risk (total score of 3.0-4.5), intermediate risk (1.5-2.5), and low risk (0.0-1.0). Patients treated with CFRT plus TMZ had significantly improved OS compared to those treated with HFRT plus TMZ or RT alone in the low and intermediate risk groups (p<0.001). However, in the high-risk group, there was no significant difference in OS between treatment options (p = 0.770). CFRT plus TMZ can be a more effective strategy for selected eGBM patients compared to HFRT. For high-risk patients, a protracted treatment schedule might not be beneficial. The novel eGBM-molGPA can be used as a clinical tool for choosing wisely among treatment options. Further prospective studies are warranted to establish optimal RT guidelines for eGBM patients.

Conventional vs. Hypo-Fractionated, Radiotherapy for High-Risk Prostate Cancer (PCS5), Randomized, Non-Inferiority, Phase 3 Trial: Posthoc Analysis of IMRT vs. 3D-CRT Radiation Therapy Associated Toxicities

The Prostate Cancer Study number 5 (PCS5), is a multi-centric non-inferiority, phase 3, randomized controlled trial of high-risk prostate cancer patients of treated with either conventionally fractionated radiotherapy (CFRT) or hypofractionated radiotherapy (HFRT). The 7 years' pre-planned analysis showed that HFRT (68 Gy in 25 fractions) was as effective and well tolerated as CFRT (76 Gy in 38 fractions). In this posthoc analysis we aim to report the genitourinary (GU) and gastrointestinal (GI) toxicities associated with radiation therapy techniques: intensity-modulated radiotherapy (IMRT) and 3D-conformal radiotherapy (3D-CRT). PCS5 randomized patients in a 1:1 ratio to receive either CFRT or HFRT. All patients received long term neoadjuvant, concurrent and adjuvant androgen suppression, with a median duration of 24 months. The toxicities were reported as per the Common Terminology Criteria for Adverse Events version 4. Acute toxicities were defined as presenting ≤ 180 days post-RT start and delayed > 180 days. The cumulative acute and delayed GI and GU toxicities were classified in grade groups: grade 1 or higher (G1+), G2+, and G3+. For each grade group, acute and delayed, we performed multivariable logistic regression analyses, adjusting for age, CTV volume, diabetes, fractionation (CRFT or HFRT), hypertension, and stage < T3b or ≥ T3b. For efficacy analyses cox-regression was utilized. A p-value < 0.05 was considered significant. Three hundred twenty of the 329 patients enrolled in the trial were included in this posthoc analyses. The mean age was 71.4 ± 6.1 years, and the mean CTV volume (n = 219) was 47.25 ± 19.9 cc. IMRT was used in 195 (60.6%) patients and 3D-CRT in 125 (39.1%) patients. Multivariable logistic regression showed a significant difference in favor of IMRT for GI G2+ acute toxicity (OR = 0.285 [0.14-0.59]; CI: 95%; p<0.001) and GI G2+ delayed toxicity (OR = 0.202 [0.60-0.69]; CI: 95%; p = 0.01). There were no differences in G3+ GI or GU toxicities and there were no grade 4 toxicities. There were no differences in efficacy at 7 years between the two treatment technics. Outcomes for IMRT vs. 3D-CRT respectively, overall survival (81.5% vs 79.2%; HR: 0.92 [0.55-1.53]; CI: 95%; p-value: 0.74), distant metastasis free survival (90,7% vs 92.8%; HR: 1.4 [0.63-3.1]; CI: 95%; p-value: 0.42), prostate cancer mortality (95.8% vs. 92.2%; HR: 0.93 [0.32-2.67]; CI: 95%; p-value: 0.89), and biochemical failure (85.1% vs 88%; HR: 1.35 [0.72-2.52]; CI: 95%; p-value: 0.35). This is the first phase 3 randomized controlled trial assessing the use of HFRT vs. CFRT, exclusively in high-risk prostate cancer patients. Given that our efficacy data at 7 years follow-up establishes moderate HFRT as a new standard of care and no difference between IMRT and 3D-CRT, we strongly recommend that patients who are treated with EBRT should receive IMRT, given the reduced acute and delayed grade 2 or higher GI toxicities.

Conventionally Fractionated vs. Hypofractionated Radiotherapy for Treatment of Unresectable Pancreatic Cancer: Local Control and Survival Outcomes in a Retrospective Single-Institutional Analysis

Unresectable pancreatic cancer (UPC) is associated with dismal survival outcomes, with a reported median survival of 8-12 months. The role of radiotherapy (RT) and the choice of optimal fractionation remains unclear. Our objective was analyzing the outcomes associated with local radiotherapy as well as determine the best radiotherapeutic approach to treat these patients. From a database of 209 radiation plans of patients treated for pancreatic cancer in a single institution between August 2007 to August 2021, patients with UPC were selected for this REB approved retrospective study. From the 209 plans, 136 unique patients were identified who had RT for UPC. The mean age of the cohort was 67.6 years, 10% were >80 years and 37% were female. Median follow-up was 9.3 months. 54 patients had distant metastases at the time of RT and were analyzed separately. Outcomes where analyzed based on whether patients received Conventionally fractionated RT (CFRT) (defined as >15 fractions) (n = 23 (17%)), Hypofractionated RT (HypoRT) (defined as ≤15 fractions and EQD2<40Gy for α/β = 3) (n = 40 (29%)) and those treated with Stereotactic Body RT (SBRT) (defined as ≤5 fractions and EQD2≥40Gy for α/β = 3) (n = 19 (14%)). The mean overall survival (OS) and freedom from progression (FFP) in the SBRT cohort was 17.2 and 7.4 months respectively, in the CFRT cohort was 22.6 and 9.9 months respectively and in the HypoRT cohort was 11.4 and 4.9 months respectively. All CFRT patients received chemotherapy. Mean OS was drastically lower in SBRT and HypoRT patients who did not receive any chemotherapy (11.9 and 3.4 months respectively). Patients with metastatic disease at presentation and receiving HypoRT had mean OS of 13.4 months. The average EQD2 for the cohorts were 45.4 Gy, 49.2 Gy and 30.3 Gy for CFRT, SBRT and HypoRT respectively. Our study demonstrates that CFRT with concurrent chemotherapy offers better therapeutic outcomes in patients with UPC compared to HypoRT. The role of dose escalated SBRT needs to be explored as an equal alternative.

Partial Stereotactic Ablative Radiotherapy in Bulky Urinary Tract Malignancy: An Update Clinical Outcomes and Dosimetric Analysis

Patients with bulky urinary tract malignancy have poor prognosis. Stereotactic ablative radiotherapy (SABR) needs careful consideration in abdominopelvic bulky tumors because of dose constraints on the OARs. We reported updated clinical outcomes to evaluate the safety and efficacy of partial stereotactic ablative radiotherapy(P-SABR) in bulky urinary tract malignancy. The study also aims to investigate the feasibility of P-SABR in dose and biologic effective dose (BED) escalation inside the tumors with equivalent toxicity. A total of 26 patients with urinary tract malignancy underwent P-SABR radiotherapy from January 2013 to September 2018 were retrospectively analyzed in this study. All the patients were in inoperable locally advanced or metastatic stage with tumor diameter > 4.0 cm. The P-SABR plan consisted of the SABR for gross tumor volume boost (GTVb) and following conventionally fractionated radiotherapy for planning target volume (PTV). The first SABR plan to GTVb was delivered in 15-32Gy/3-5f. The second conventionally fractionated radiotherapy plan to PTV was delivered in 40.0-58.08Gy/15-26f. The total P-SABR plan met the OARs constraints. Local control and overall survival were estimated. Acute and late toxicity were evaluated according to RTOG criteria. Paired conventionally fractionated radiotherapy (CFRT) plans were re-designed for all patients, with the same OARs dose constraints and total dose of PTV margin. Dosimetric and BED parameters were compared in P-SABR and paired CFRT plans. Median age of the patients was 66.5 years (range, 46-90 years). The tumor treated by P-SABR had a median diameter of 8.4 cm (4.1-19.5 cm) and a median volume of 99.2 cc (23.9-631.8 cc). Median follow-up time was 19.1 months. The local control at 1 and 2 years were 83.2%, 77.3%, respectively. The overall survival at 1 and 2 years were 72.2% ,45.5%, respectively. 6 cases have no local recurrence after 36 months. 4 cases remained alive after 60 months. Local symptoms improved in 15/16 cases after P-SABR. Multivariate analysis showed tumor diameter (≥8cm vs. <8cm) was the independent factor affecting local control and overall survival (P=0.033, P=0.016). No patient was observed radiotherapy directly induced ≥grade 3 toxicity. Compared with the paired CFRT plans, the P-SABR plans had no significant difference in most OAR dose parameters, except for the small intestine/colon V15, V45 with an increase of 14.6 cc, 3.4 cc. However, P-SABR plans increased the dose of PTV Dmean, Dmax by 8.7Gy, 14.4Gy (P < 0.001), respectively. In addition, the dose and BED of GTVb had a significant escalation of 15.8Gy and 30.2Gy (P<0.001) respectively in P-SABR plans. We had reported P-SABR is well-tolerated in bulky urinary tract malignancy in previous study. Updated outcomes showed P-SABR may have long-term local control in these people. Compared with traditional CFRT plans, P-SABR plans escalated the dose and BED inside bulky tumors with equivalent toxicity.

An Analysis of Delays in Treatment Time for Prostate Cancer Patients in Sub-Saharan Africa

Time interval from diagnosis of prostate cancer to treatment is an important predictor of survival outcomes for patients. These time intervals can be prolonged in resource-limited settings, such as those in Sub-Saharan Africa (SSA). The purpose of this project was to analyze the time interval between diagnosis and either hormonal or radiotherapy treatment for prostate cancer patients in Nigeria and Tanzania. The outcomes can inform the implementation of the recent Lancet Oncology Commission recommendations on increasing access to radiotherapy services in SSA to curb the growing cancer burden in the region. Data were extracted from electronic patient records at the NSIA-LUTH Cancer Center (NLCC) in Lagos, Nigeria and at the Ocean Road Cancer Institute (ORCI) in Dar Es Salaam, Tanzania. Included patients were prostate cancer patients who received hypofractionated radiotherapy (HFRT) at ORCI between January 6 - June 16, 2022, and either HFRT or conventionally fractionated radiotherapy (CFRT) at NLCC between February 1 - July 27, 2022. Simple descriptive statistics were used to calculate the mean time interval between the patient's date of diagnosis of prostate cancer and the start of hormonal or radiotherapy treatment. Time to hormonal therapy was collected for 23 ORCI patients and 28 NLCC patients. The mean time interval from date of diagnosis to start of hormonal therapy was 19.3 weeks for patients in Tanzania and 8.0 weeks for patients in Nigeria. Time to radiotherapy was collected for 23 ORCI patients and 50 NLCC patients. The mean time interval from date of diagnosis to start of radiotherapy was 59.13 weeks for patients in Tanzania and 48.5 weeks for patients in Nigeria. Prostate cancer patients in Nigeria and Tanzania experience significant delay in receiving hormonal and radiotherapy treatment, especially when compared to wait times in well-resourced countries. For example, a recent assessment of U.S. patients in the National Cancer Database who were diagnosed with prostate cancer between 2004-2015 revealed that the mean interval from diagnosis to definitive therapy (either surgery or some form of radiotherapy) was 11.3 weeks - significantly less than the mean times documented in our study of SSA patients (Cone et al., 2020). Additionally, patients in Tanzania experienced longer treatment delays compared to patients in Nigeria, highlighting potential disparities in access to care between SSA countries. These prolonged delay times are likely to negatively impact survival and represent an intervention opportunity to alleviate the cancer crisis in SSA.

Expanding Radiotherapy Access in Sub-Saharan Africa: An Analysis of Travel Burdens and Patient-Related Benefits of Hypofractionation

The purpose of this project was to examine the travel burdens for radiotherapy patients in Nigeria, Tanzania, and South Africa, and to assess the patient-related benefits of hypofractionated radiotherapy (HFRT) for breast and prostate cancer patients in these countries. The outcomes can inform the implementation of the recent Lancet Oncology Commission recommendations on increasing the adoption of HFRT in Sub-Saharan Africa (SSA) to enhance radiotherapy access in the region. Data were extracted from electronic patient records at the NSIA-LUTH Cancer Center (NLCC) in Lagos, Nigeria and the Inkosi Albert Luthuli Central Hospital (IALCH) in Durban, South Africa, from written records at the University of Nigeria Teaching Hospital (UNTH) Oncology Center in Enugu, Nigeria, and from phone interviews at Ocean Road Cancer Institute (ORCI) in Dar Es Salaam, Tanzania. Google Maps was used to calculate the shortest driving distance between a patient's home address and their respective radiotherapy center. QGIS was used to map the straight-line distances to each center. Descriptive statistics were used to compare transportation costs, time expenditures, and lost wages when using HFRT versus conventionally fractionated radiotherapy (CFRT) for breast and prostate cancer. All transportation- and wage-related cost data were contextualized within each country's monthly adjusted net national income (MANNI) per capita, as reported by 2020 data from the World Bank. Patients in Nigeria (n = 390) traveled a median distance of 24.0 km (interquartile range (IQR) = 238.5 km) to NLCC and 86.7 km (IQR = 87.3 km) to UNTH, patients in Tanzania (n = 23) traveled a median distance of 537.0 km (IQR = 587.5 km) to ORCI, and patients in South Africa (n = 412) traveled a median distance of 18.0 km (IQR = 15.0 km) to IALCH. Estimated transportation cost savings for breast cancer patients in Lagos and Enugu were 12,895 Naira and 7,369 Naira (20% and 11% of MANNI per capita), respectively, and for prostate cancer patients were 25,329 and 14,276 Naira (38% and 22% of MANNI per capita), respectively. Prostate cancer patients in Tanzania saved a median of 137,765 Shillings (78% of MANNI per capita) in transportation costs. Significant time expenditures - a relevant consideration for patient convenience - were also saved for ORCI patients, including a median of 80.0 hours (includes travel, treatment, and wait times). Mean transportation cost savings for patients in South Africa were 4,777 Rand (72% of MANNI per capita) for breast cancer and 9,486 Rand (143% of MANNI per capita) for prostate cancer. Cancer patients in SSA travel considerable distances to access radiotherapy services. HFRT decreases patient-related costs and time expenditures, which may increase radiotherapy access and alleviate the growing burden of cancer in the region.

Dose Constraints and Planning Considerations for Thoracic Radiation Therapy: Delphi Consensus from a National Survey of Experts

Many physicians refer to trial protocols or published guidelines (NCCN, QUANTEC, HyTEC) for dose-volume histogram (DVH) metrics. However, there may be variation in implementing these metrics during plan optimization. Some studies have suggested better outcomes for patients treated at high-volume, high-expertise centers. These differences may in part be due to greater standardization or center-specific treatment planning processes. We surveyed radiation oncologists with stated thoracic-specific expertise using the Delphi method to formulate consensus DVH metrics that would be considered ideal for high-quality radiation treatment plans. Thoracic radiation oncology experts were identified using departmental websites of ACGME-accredited radiation oncology programs. After confirming their expertise, panelists were invited to submit their institutional templates and complete three rounds of questions related to normal organ dose constraints, target coverage metrics, prescribing practices, and other planning considerations. Queried radiation schemes included conventional fractionation, twice-daily fractionation, and stereotactic body radiation therapy (3 and 5 fractions). Preliminary consensus statements were generated using median values for DVH metrics and were iteratively refined in subsequent surveys. Consensus was pre-defined as ≥75% agreement among panelists. A total of 194 experts were invited, and 100 agreed to participate. The panel was 28% female and included experts from 29 states with a median of 11 years of clinical experience (IQR 6-19). 89% specialized in 1-2 disease sites. Response rates for the Demographics, round 1, 2, and 3 surveys were 83%, 78%, 57%, and 55%, respectively. 93% of panelists believed that DVH metrics should provide thresholds for both optimal and acceptable criteria for treatment planning. 49 of the 96 proposed normal tissue dose constraint statements were iterated to consensus (Table 1), and 5 of 7 proposed target coverage metric statements achieved consensus. This study highlights the heterogeneity in metrics used by thoracic radiation oncologists and provides levels of consensus on ideal and acceptable dose constraints as guidance for treatment planning. Future directions include using these statements to develop prescription templates and acceptance criteria for treatment planning systems for widespread use as well as extending this Delphi approach to additional disease sites.

Biological Effective Dose (BED) in Evaluation of Rectal Dose in Prostate Cancer Patients with Hydrogel Spacer Who Underwent an EBRT with Different Fractionation Schemes

To evaluate rectal dose sparing in prostate cancer patients with hydrogel spacer who underwent an external beam radiotherapy (EBRT) with different fractionation schemes. In a previous study, we have reported that rectal sparing was achieved in prostate cancer patients with hydrogel spacer who underwent a combination therapy of EBRT and LDR brachytherapy (Zhang H, et al. J Appl Clin Med Phys, 2022). In this study, we focused on evaluation of spacer-related rectal sparing in patients who underwent an EBRT with conventional fractionation (81 Gy in 45 fractions), hypofractionation (70 Gy in 28 fractions), or stereotactic body radiotherapy (SBRT) for 40 Gy or 42.5 Gy in 5 fractions. In 172 patients, 119 patients were applied with injection of polyethylene-glycol hydrogel and others without the injection as control. In VMAT plans, doses to rectal wall were examined and converted to BED according to AAPM TG-137 (α/β ratio = 4 Gy). On average, an interspace of 1cm between prostate and rectum was achieved by spacer insertion. Rectal wall was defined as 0.4cm thickness inside the outer contour of rectum, and the volume ranged from 4.5 cm3 to 21.3cm3 for patients with spacer and from 8.2cm3 to 35.1cm3 for those with no spacer. In conventional scheme, an average rectal BED was 120.0 Gy, 116.9 Gy, 114.0 Gy, 108.6 Gy, 87.6 Gy and 55.6 Gy to the volume of 0.1, 0.5, 1, 2, 5 and 10cm3, respectively, and BEDmean was 55.3 Gy in patients with no spacer. The BED decreased to 105.1 Gy, 96.3 Gy, 86.1 Gy, 75.4 Gy, 51.7 Gy and 26.9 Gy to the volume of 0.1, 0.5, 1, 2, 5 and 10cm3, respectively (p < 0.01), and BEDmean was 46.0 Gy in patients with spacer. In hypofractionation, rectal BED was in average of 115.8 Gy, 112.3 Gy, 109.8 Gy, 103 Gy, 81.6 and 52.8 Gy to the volume of 0.1, 0.5, 1, 2, 5 and 10cm3, respectively, and BEDmean was 48.6 Gy in patients with no spacer. Patients with spacer had significantly decreases of rectal BED, an average of 103 Gy, 91.7 Gy, 84.1 Gy, 72.8 Gy, 48.8 Gy and 26.0 Gy to the volume of 0.1, 0.5, 1, 2, 5 and 10cm3, respectively (p < 0.01), BEDmean was 42.4 Gy. In SBRT, average rectal BED in patients with spacer decreased to 93.6 Gy, 78.4 Gy, 69 Gy, 57.5 Gy, 38.5 Gy and 21.5 Gy, in comparison of 124.1 Gy, 117,4 Gy, 110.9 Gy, 97.3 Gy, 59.7 Gy and 32.3 Gy to the volume of 0.1, 0.5, 1, 2, 5 and 10cm3 in those without spacer, respectively (p <0.01). BEDmean decreased to 32.0 Gy in patient with spacer, compared with 43.2 Gy in those with no spacer. Insertion of hydrogel spacer significantly improved rectal dose sparing, about 11.1% to 50.8% in conventional scheme, 12.4% to 51.6% in hypofractionation scheme, and 24.6% to 40.9% in SBRT patients. Furthermore, relatively more dose sparing on rectum was seen on the volume from 0.1cm3 to 2cm3 in SBRT patients.

A Combined Phase 0/2 "Trigger" Trial of Niraparib in Combination with Radiation in Patients with Newly-Diagnosed Glioblastoma

Poly ADP-ribose (PAR) polymerase (PARP) mediates DNA damage response. Niraparib is an investigational PARP1/2-selective inhibitor. We conducted a combined phase 0/2 study to evaluate niraparib pharmacokinetics (PK) and pharmacodynamics (PD) in patients with newly-diagnosed glioblastoma (GBM), graduating patients to a phase 2 study evaluating a therapeutic regimen of niraparib with concurrent conventionally-fractionated radiotherapy (RT) in O6-methylguanine methyltransferase (MGMT) unmethylated tumors exceeding a prespecified PK threshold in non-enhancing tumor. Patients with presumed newly-diagnosed GBM were enrolled in a phase 0 study receiving 4 days of niraparib (300 or 200 mg QD) prior to planned resection 3-5 or 8-12 hours following the last dose. Tumor tissue (enhancing and non-enhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound niraparib concentrations were measured using validated LC-MS/MS methods. PARP inhibition was assessed by quantification of PAR induction after 10 Gy ex vivo irradiation in surgical tissue compared to non-irradiated control tissue. A PK 'trigger' determined eligibility for the therapeutic phase 2 expansion portion of the study. This was defined as unbound [niraparib] > 5-fold biochemical IC50 (i.e., 19 nM) in non-enhancing tumor. Patients with MGMT unmethylated tumors exceeding this PK threshold were eligible for expansion phase dosing of niraparib with concurrent RT followed by a maintenance phase of niraparib. Patients with MGMT methylated tumors were not eligible for the expansion phase and proceeded with temozolomide (TMZ) plus RT followed by maintenance TMZ. RT dose was 60 Gy in 30 fractions using volumetric-modulated arc therapy (VMAT). All 29 patients enrolled in the phase 0 portion of the study met the PK threshold. In non-enhancing regions, the mean unbound concentration of niraparib was 258.2 nM. The suppression of PAR levels after ex vivo RT was observed in 79% of the patients (17/22). Sixteen patients had unmethylated tumors, and of those, 11 patients enrolled in phase 2. Five of the 6 initial patients enrolled in phase 2 experienced thrombocytopenia related to niraparib, and 3/5 cases were deemed serious and life-threatening. Consequently, starting dose in both phases was lowered to 200 mg, and no serious AEs were observed thereafter. At a median follow-up of 8.1 months [range: 6.0-12.9 months], 6-month PFS was 64% with 4 patients remaining on treatment and 5 patients ongoing survival follow-up. Niraparib achieves pharmacologically-relevant concentrations in non-enhancing, newly-diagnosed GBM tissue in excess of any other studied PARP inhibitor. When delivered with concurrent RT, niraparib was well-tolerated, with low rates of grade 3+ toxicity. Initial clinical efficacy data are encouraging.

Effect of radiation fractionation on IDO1 via the NF-κB/COX2 axis in non-small cell lung cancer

Radiotherapy (RT) is the mainstay treatment modality for lung cancer. We recently reported that conventionally fractionated radiotherapy (CRT) with daily fractionation of 2Gy significantly increased the activity of indoleamine 2,3-dioxygenase (IDO1), a known immune checkpoint, which predicted poorer long-term survival in patients with non-small cell lung cancer (NSCLC), while stereotactic body radiotherapy (SBRT) using fractionation size of 10Gy did not increase IDO1 activity and had better survival. Here we hypothesized that the hypofractionated SBRT kind of dose fraction stimulates host antitumor immunity via downregulating IDO1 in which CRT could not. We tested this hypothesis in vitro and in vivo using 10Gyx1 and 2Gyx8 fractionations in the laboratory. The results demonstrated that, although there was an initial downregulation after RT, the expression of IDO1 was ultimately upregulated by both fractionation regimens. The 10Gyx1 regimen had minimum upregulation, while the 2Gyx8 regimen significantly increased in IDO1 expression which was positively correlated with the elevated expressions of p-NF-κB and COX2. Pharmacological inhibition of COX2 abolished RT-induced IDO1 expression. Furthermore, the IDO1 inhibitor, D-1-methyl-tryptophan (D-1MT), exerted RT-related tumor-killing effects in the NSCLC cell lines and mouse models. These findings suggest that, in addition to being an immune suppressor, IDO1 may serve as an adaptive resistance factor in RT. Furthermore, an unappreciated mechanism may exist, where a larger fraction size might be superior to conventional sizes in cancer treatment. This study may provide a rationale for future research in using IDO1 as a biomarker to personalize RT dose fractionation and COX2 inhibitor to decrease radiation immune suppression from CRT.

Dosimetric investigation of radiation-induced trigeminal nerve toxicity in parotid tumor patients.

We aimed to describe the association between trigeminal nerve (TN) dose and toxicity and determine a threshold value that leads to TN toxicity in patients with parotid tumors treated with adjuvant conventional fractionated radiation therapy. Eighteen patients who underwent adjuvant radiotherapy (RT) between 2013 and 2018 were included in this retrospective study. TN and its branches were outlined subsequently on the planning CT scans. The doses received by TN were obtained based on the dose-volume histogram. The dose and toxicity relationship was investigated over the total prescribed dose. RT-related toxicity was graded according to Common Terminology Criteria for Adverse Events V4.0 (CTCAEv4.0). The median follow-up was 29.5 months. After RT, 61% of patients had Grade I-II late TN toxicity divided into Grade I in 4 (22%) and Grade II in 7 (39%) patients. TN injury symptoms were as follows: loss of sensation in the chin area in 3, difficulty in jaw movements in 3, and paresthesia in 5 patients. The total RT dose (p = 0.001), Dmax (p = 0.001), PTV-TN Dmax (p = 0.001), D1cc (p = 0.004), D0.5cc (p = 0.001), and D0.1cc (p = 0.01) had a significant effect on TN toxicity. Cut-off values leading to toxicity were determined as 66, 65.5, 65.25, 63.6, and 62.7 Gy for Dmax, PTV-TN Dmax, D0.1cc, D 0.5cc, and D1cc, respectively. Radiation-induced TN injury in head and neck cancer patients may further be investigated in clinically prospective trials by virtue of high toxicity rates with current RT doses in our retrospectively designed dosimetric study in parotid tumors.

Carcinoma buccal mucosa treated with definitive hypofractionated accelerated radiotherapy: a retrospective analysis of treatment outcomes.

Oral cancer is a major public health concern in India. Both conventional and altered fractionation radiotherapy schedules have been used in curative treatment of oral cancer. This study aimed to retrospectively evaluate the clinical profile and treatment outcomes of patients with carcinoma buccal mucosa who underwent treatment with definitive hypofractionated accelerated radiotherapy. A total of 517 patients treated from January 2011 to December 2016 were eligible for the analysis. All patients were treated with definitive hypofractionated accelerated radiotherapy schedule of 5,250 cGy in 15 fractions over 3 weeks. Survival estimates were generated using the Kaplan-Meier method. At a median follow-up of 77.4 months, 473 (91.5%) patients attained complete remission with radiation therapy. The 5-year disease-free survival (DFS) and overall survival (OS) rates were 69% and 80.5%, respectively. The 5-year OS for stage I, II, III and IVa tumours was 80.3%, 84.4%, 81.4% and 73.7%, respectively, and the DFS was 75.7%, 73.2%, 69.6% and 60.2%, respectively. Age >50 years was found to be a significant factor affecting DFS (P = 0.026) and OS (P = 0.048) in multivariate analysis. Fifty-three (10.3%) patients developed osteoradionecrosis of the mandible. Excellent outcome could be achieved in less-aggressive, low-volume carcinoma of the buccal mucosa with radical accelerated hypofractionated radiotherapy. A radiotherapy schedule over a 3-week period is useful in high-volume centres.