Hypofractionated Intensity Modulated Radiation Therapy Research Articles

Postoperative Hypofractionated Intensity-Modulated Radiotherapy With Concurrent Chemotherapy in Cervical Cancer

Prospective data assessing the safety of hypofractionated (40 Gy in 16 fractions) radiotherapy (RT) among patients who receive postoperative concurrent chemoradiotherapy for cervical cancer are lacking. To evaluate the acute toxic effects of hypofractionated pelvic intensity-modulated radiotherapy (IMRT) with concurrent chemotherapy among women with cervical cancer who underwent radical hysterectomy. The POHIM-CCRT (Postoperative Hypofractionated Intensity-Modulated Radiation Therapy With Concurrent Chemotherapy in Cervical Cancer) study was designed as a multicenter, phase 2 nonrandomized controlled trial that accrued and followed up patients from June 1, 2017, to February 28, 2023. In total, 84 patients were enrolled from 5 institutions affiliated with the Korean Radiation Oncology Group. Eligible patients experienced lymph node metastasis, parametrial invasion, or positive resection margins after radical hysterectomy for treatment of confirmed cervical cancer. Postoperative pelvic radiation using hypofractionated IMRT with 40 Gy in 16 fractions to the whole pelvis combined with concurrent chemotherapy. The primary end point was incidence of acute grade 3 or higher gastrointestinal tract, genitourinary, and hematologic toxic effects (based on the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0) in the evaluable population during RT or within 3 months after RT completion. Of 84 patients enrolled, 5 dropped out prior to RT, and data from 79 patients were analyzed. The patients' median (IQR) age was 48 (42-58) years, and the median (IQR) tumor size was 3.7 (2.7-4.5) cm. Of these patients, 31 (39.7%) had lymph node metastasis, 4 (5.1%) had positive resection margins, and 43 (54.4%) had parametrial invasion. Grade 3 or higher acute toxic effects occurred in 2 patients (2.5% [90% CI, 0%-4.8%]). After a median (IQR) follow-up of 43.0 (21.1-59.0) months, the 3-year disease-free survival rate was 79.3%, and the overall survival rate was 98.0%. Findings from this nonrandomized control trial indicated that postoperative pelvic irradiation combined with concurrent chemotherapy using hypofractionated IMRT with 40 Gy in 16 fractions was safe and well-tolerated in women with cervical cancer. Studies assessing long-term toxic effects and oncological outcomes with longer follow-up periods are needed. ClinicalTrials.gov Identifier: NCT03239613.

A Japanese multi-institutional phase II study of moderate hypofractionated intensity-modulated radiotherapy with image-guided technique for prostate cancer

A Japanese multi-institutional phase II study of moderate hypofractionated intensity-modulated radiotherapy with image-guided technique for prostate cancer

A pooled patient-reported outcomes analysis of moderately hypofractionated proton beam therapy and photon-based intensity modulated radiation therapy for low- or intermediate-risk prostate cancer.

We sought to characterize and compare late patient-reported outcomes (PROs) after moderately hypofractionated intensity modulated radiation therapy (IMRT) and proton beam therapy (PBT) for localized prostate cancer (PC). This multi-institutional analysis included low- or intermediate-risk group PC patients treated with moderately hypofractionated radiation to an intact prostate stratified by treatment modality: IMRT or PBT. The primary outcomes were prospectively collected patient-reported late gastrointestinal (GI) and genitourinary (GU) toxicity assessed by International Prostate Symptom Score (IPSS) and Expanded PC Index Composite (EPIC). Multivariable regression analysis (MVA) controlling for age, race, and risk group tested the effect of time, treatment, and their interaction. 287 IMRT and 485 PBT patients were included. Intermediate risk group (81.2 vs. 68.2%; p < 0.001) and median age at diagnosis (70 vs. 67 years; p < 0.001) were higher in the IMRT group. On MVA, there was no significant difference between modalities. PBT IPSS did not differ from IMRT IPSS at 12 months (odds ratio [OR], 1.19; p = 0.08) or 24 months (OR, 0.99; p = 0.94). PBT EPIC overall GI function at 12 months (OR, 3.68; p = 0.085) and 24 months (OR 2.78; p = 0.26) did not differ from IMRT EPIC overall GI function. At 24 months, urinary frequency was no different between PBT and IMRT groups (OR 0.35; p = 0.096). This multi-institutional analysis of low- or intermediate-risk PC treated with moderately hypofractionated PBT and IMRT demonstrated low rates of late patient-reported GI and GU toxicities. After covariate adjustment, late GI and GU PROs were not significantly different between PBT or IMRT cohorts.

Randomized Trial of Concomitant Hypofractionated Intensity Modulated Radiation Therapy Boost Versus Conventionally Fractionated Intensity Modulated Radiation Therapy Boost for Localized High-Risk Prostate Cancer (pHART2-RCT)

The aim of this work is to report on the results of a phase 2 randomized trial of moderately hypofractionated (MH) versus conventionally fractionated (CF) radiation therapy to the prostate with elective nodal irradiation. This was a single-center, prospective, phase 2 randomized study. Patients with high-risk disease (cT3, prostate-specific antigen level >20 ng/mL, or Gleason score 8-10) were eligible. Patients were randomized to either MH using a simultaneous integrated boost (68 Gy in 25 fractions to prostate; 48 Gy to pelvis) or CF (46 Gy in 23 fractions with a sequential boost to the prostate of 32 Gy in 16 fractions), with long-term androgen deprivation therapy. The primary endpoint was grade ≥2 acute gastrointestinal (GI) and genitourinary (GU) toxicity (Common Terminology Criteria for Adverse Events version 3.0). Secondary endpoints included late GI and GU toxicity, quality of life, and oncologic outcomes. One-hundred eighty patients were enrolled; 90 were randomized to and received MH and 90 to CF. The median follow-up was 67.4 months. Seventy-five patients (41.7%) experienced a grade ≥2 acute GI and/or GU toxicity, including 34 (37.8%) in the MH and 41 (45.6%) in the CF arms, respectively (P = .29). Late grade ≥2 GI (P = .07) and GU (P = .25) toxicity was not significantly different between arms; however, late grade ≥3 GI toxicity was worse in the MH group (P = .01). There were no statistically significant quality-of-life differences between the 2 treatments. There were no statistically significant differences observed in cumulative incidence of biochemical failure (P = .71) or distant metastasis (P = .31) and overall survival (P = .46). MH to the prostate and pelvis with androgen deprivation therapy for men with high-risk localized prostate cancer was not significantly different than CF with regard to acute toxicity, quality of life, and oncologic efficacy. However, late grade ≥3 GI toxicity was more common in the MH arm.

Ten-Year Outcomes of Hypofractionated (45 Gy in 9 Fractions) Intensity Modulated Radiotherapy for Localized Prostate Cancer.

We reported 10-year outcomes of localized prostate cancers treated with hypofractionated intensity-modulated radiotherapy of 45 Gy in 9 consecutive fractions. From October 2011 to April 2017, thirty patients with localized prostate cancer were enrolled in this prospective trial. The median age of the patients was 72.5 years. According to NCCN recurrence risk criteria, eight patients were at low-risk group, 17 at intermediate risk group, 5 at high-risk group. All patients were treated with hypofractionated intensity-modulated radiotherapy (IMRT) of 45 Gy in 9 consecutive fractions to their prostate with or without seminal vesicles. Before radiotherapy, three gold fiducials were implanted into the prostate. In order to reduce the rectal high dose irradiation volume, an inflated rectal balloon was placed in the rectum at simulation and every treatment and patients were treated with comfortable full bladder. Static Intensity-modulated radiotherapy (SIMRT) was applied in 1 patient, Volumetric Modulated Arc Therapy (VMAT) in 27 patients, and tomotherapy in 2 patients. Image guided radiotherapy (IGRT) with gold fiducial registration was adopted. Twenty-six patients also received androgen deprivation therapy (ADT). The median time of ADT was 6 months. Progression⁃free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier analysis. All grade ≥1 genitourinary (GU) and gastrointestinal (GI) toxicities were recorded using Common Terminology Criteria for Adverse Event version 5.0 (CTCAE 5.0) and Radiation Therapy Oncology Group (RTOG) late morbidity criteria, and GU and GI toxicities were cumulatively calculated. After a median follow-up of 102 months (65∼131 months), the 10-year OS was 90.0% (95% confidence interval, 83.3%-96.7%), and the 10-year PFS was 86.5% (95% confidence interval, 79.1%-93.9%). According to CTCAE 5.0, grade 1 acute gastrointestinal (GI) toxicity developed in 12 patients, grade 2 in 2 patients, grade 3 in 2 patients, and grade 1 acute genitourinary (GU) toxicity developed in 12 patients, grade 2 in 2 patients, and no grade 3 or higher toxicity occurred. According to RTOG late morbidity criteria, late (≥3 months after radiotherapy) grade 1 GI toxicity developed in 4 patients (13.3%), grade 2 in 1 (3.3%), grade 3 in 1 (3.3%), and late grade 1 GU toxicity occurred in 1 patient (3.3%), grade 2 in 1 (3.3%), grade 3 in 1 (3.3%). No grade 4 or higher GI and GU toxicities developed. Only one grade 3 GI and one grade 2 GU toxicities were observed for the maximum toxicity at the last follow-up. The potency was not evaluated. The 10-year oncologic outcomes of this shortened hypofractionated IMRT regimen for mainly low/intermediate risk prostate cancer patients is favorable with acceptable acute and late toxicities.

Analysis of risk factors of radiation-induced toxicity in limited-stage small cell lung cancer treated with hypofractionated intensity-modulated radiotherapy

Objective: To compare the incidence of radiation-related toxicities between conventional and hypofractionated intensity-modulated radiation therapy (IMRT) for limited-stage small cell lung cancer (SCLC), and to explore the risk factors of hypofractionated radiotherapy-induced toxicities. Methods: Data were retrospectively collected from consecutive limited-stage SCLC patients treated with definitive concurrent chemoradiotherapy in Cancer Hospital of Chinese Academy of Medical Sciences from March 2016 to April 2022. The enrolled patients were divided into two groups according to radiation fractionated regimens. Common Terminology Criteria for Adverse Events (CTCAE, version 5.0) was used to evaluate the grade of radiation esophagus injuries and lung injuries. Logistic regression analyses were used to identify factors associated with radiation-related toxicities in the hypofractionated radiotherapy group. Results: Among 211 enrolled patients, 108 cases underwent conventional IMRT and 103 patients received hypofractionated IMRT. The cumulative incidences of acute esophagitis grade ≥2 [38.9% (42/108) vs 35.0% (36/103), P=0.895] and grade ≥ 3 [1.9% (2/108) vs 5.8% (6/103), P=0.132] were similar between conventional and hypofractionated IMRT group. Late esophagus injuries grade ≥2 occurred in one patient in either group. No differences in the cumulative incidence of acute pneumonitis grade ≥2[12.0% (13/108) vs 5.8% (6/103), P=0.172] and late lung injuries grade ≥2[5.6% (6/108) vs 10.7% (11/103), P=0.277] were observed. There was no grade ≥3 lung injuries occurred in either group. Using multiple regression analysis, mean esophageal dose ≥13 Gy (OR=3.33, 95% CI: 1.23-9.01, P=0.018) and the overlapping volume between planning target volume (PTV) and esophageal ≥8 cm(3)(OR=3.99, 95% CI: 1.24-12.79, P=0.020) were identified as the independent risk factors associated with acute esophagitis grade ≥2 in the hypofractionated radiotherapy group. Acute pneumonitis grade ≥2 was correlated with presence of chronic obstructive pulmonary disease (COPD, P=0.025). Late lung injuries grade ≥2 was correlated with tumor location(P=0.036). Conclusions: Hypofractionated IMRT are tolerated with manageable toxicities for limited-stage SCLC patients treated with IMRT. Mean esophageal dose and the overlapping volume between PTV and esophageal are independently predictive factors of acute esophagitis grade ≥2, and COPD and tumor location are valuable factors of lung injuries for limited-stage SCLC patients receiving hyofractionated radiotherapy. Prospective studies are needed to confirm these results.

Long-Term Outcomes of a Prospective Study on Highly Hypofractionated Intensity Modulated Radiation Therapy for Localized Prostate Cancer for 3 Weeks

Reports of radiation therapy for prostate cancer using dose fractions between moderate hypofractionation and ultrahypofractionation are limited. This pilot study involved the application of highly hypofractionated intensity modulated radiation therapy (IMRT) in 15 fractions for 3 weeks and the number of fractions was intermediate between the 2 previously mentioned dose fractions. The long-term outcomes are reported. From April 2014 to September 2015, patients with low- to intermediate-risk prostate cancer received 54 Gy in 15 fractions (3.6 Gy per fraction) for 3 weeks using IMRT without intraprostatic fiducial markers or a rectal hydrogel spacer. Neoadjuvant hormone therapy (HT) was administered for 4 to 8 months. Adjuvant HT was not administered to any patients. Rates of biochemical relapse-free survival, clinical relapse-free survival, overall survival, and the cumulative incidence of late grade ≥2 toxicities were analyzed. Twenty-five patients were enrolled in this prospective study; 24 of them were treated with highly hypofractionated IMRT (17% had low-risk and 83% had intermediate-risk disease). The median neoadjuvant HT duration was 5.3 months. The median follow-up period was 77 months (range, 57-87 months). Biochemical relapse-free survival, clinical relapse-free survival, and overall survival rates were 91.7%, 95.8%, and 95.8% at 5 years, and 87.5%, 86.3%, and 95.8% at 7 years, respectively. Neither grade ≥2 late gastrointestinal toxicity nor grade ≥3 late genitourinary toxicity was observed. The cumulative incidence rates of grade 2 genitourinary toxicity were 8.5% and 18.3% at 5 and 7 years, respectively. Highly hypofractionated IMRT delivering 54 Gy in 15 fractions for 3 weeks for prostate cancer without intraprostatic fiducial markers facilitated favorable oncological outcomes without severe complications. This treatment approach may be a possible alternative to moderate hypofractionation, but further validation is needed.

Dose outside of the prostate is associated with improved outcomes for high-risk prostate cancer patients treated with brachytherapy boost.

One in three high-risk prostate cancer patients treated with radiotherapy recur. Detection of lymph node metastasis and microscopic disease spread using conventional imaging is poor, and many patients are under-treated due to suboptimal seminal vesicle or lymph node irradiation. We use Image Based Data Mining (IBDM) to investigate association between dose distributions, and prognostic variables and biochemical recurrence (BCR) in prostate cancer patients treated with radiotherapy. We further test whether including dose information in risk-stratification models improves performance. Planning CTs, dose distributions and clinical information were collected for 612 high-risk prostate cancer patients treated with conformal hypo-fractionated radiotherapy, intensity modulated radiotherapy (IMRT), or IMRT plus a single fraction high dose rate (HDR) brachytherapy boost. Dose distributions (including HDR boost) of all studied patients were mapped to a reference anatomy using the prostate delineations. Regions where dose distributions significantly differed between patients that did and did-not experience BCR were assessed voxel-wise using 1) a binary endpoint of BCR at four-years (dose only) and 2) Cox-IBDM (dose and prognostic variables). Regions where dose was associated with outcome were identified. Cox proportional-hazard models with and without region dose information were produced and the Akaike Information Criterion (AIC) was used to assess model performance. No significant regions were observed for patients treated with hypo-fractionated radiotherapy or IMRT. Regions outside the target where higher dose was associated with lower BCR were observed for patients treated with brachytherapy boost. Cox-IBDM revealed that dose response was influenced by age and T-stage. A region at the seminal vesicle tips was identified in binary- and Cox-IBDM. Including the mean dose in this region in a risk-stratification model (hazard ratio=0.84, p=0.005) significantly reduced AIC values (p=0.019), indicating superior performance, compared with prognostic variables only. The region dose was lower in the brachytherapy boost patients compared with the external beam cohorts supporting the occurrence of marginal misses. Association was identified between BCR and dose outside of the target region in high-risk prostate cancer patients treated with IMRT plus brachytherapy boost. We show, for the first-time, that the importance of irradiating this region is linked to prognostic variables.

Ten-year outcomes of hypofractionated (45 Gy in 9 fractions) intensity-modulated radiotherapy for localized prostate cancer.

e17100 Background: We reported 10-year outcomes of localized prostate cancers treated with hypofractionated intensity-modulated radiotherapy of 45 Gy in 9 consecutive fractions. Methods: From October 2011 to April 2017, thirty patients with localized prostate cancer were enrolled in this prospective trial. The median age of the patients was 72.5 years. According to NCCN recurrence risk criteria, eight patients were at low risk group, 17 at intermediate risk group, 5 at high risk group. All patients were treated with hypofractionated intensity-modulated radiotherapy (IMRT) of 45 Gy in 9 consecutive fractions to their prostate with or without seminal vesicles. Before radiotherapy, three gold fiducials were implanted into the prostate. In order to reduce the rectal high dose irradiation volume , an inflated rectal balloon was placed in the rectum at simulation and every treatment and patients were treated with comfortable full bladder. Static Intensity-modulated radiotherapy (SIMRT) was applied in 1 patient, Volumetric Modulated Arc Therapy (VMAT) in 27 patients, and tomotherapy in 2 patients. Image guided radiotherapy (IGRT) with gold fiducial registration was adopted. Twenty-six patients also received androgen deprivation therapy (ADT). The median time of ADT was 6 months. Progression⁃free survival(PFS) and overall survival(OS) were analyzed using Kaplan-Meier analysis. All grade ≥1 genitourinary (GU) and gastrointestinal (GI) toxicities were recorded using Common Terminology Criteria for Adverse Event version 5.0 (CTCAE 5.0) and Radiation Therapy Oncology Group (RTOG) late morbidity criteria , and GU and GI toxicities were cumulatively calculated. Results: After a median follow-up of 102 months (65~131 months), the 10-year OS was 90.0%(95% confidence interval, 83.3%-96.7%), and the 10-year PFS was 86.5% (95% confidence interval, 79.1%-93.9%). According to CTCAE 5.0, grade 1 acute gastrointestinal (GI) toxicity developed in 12 patients, grade 2 in 2 patients, grade 3 in 2 patients, and grade 1 acute genitourinary (GU) toxicity developed in 12 patients, grade 2 in 2 patients, and no grade 3 or higher toxicity occurred. According to RTOG late morbidity criteria, late (≥3 months after radiotherapy) grade 1 GI toxicity developed in 4 patients (13.3%), grade 2 in 1 (3.3%), grade 3 in 1 (3.3%), and late grade 1 GU toxicity occurred in 1 patient (3.3%), grade 2 in 1 (3.3%), grade 3 in 1 (3.3%). No grade 4 or higher GI and GU toxicities developed. Only one grade 3 GI and one grade 2 GU toxicities were observed for the maximum toxicity at the last follow-up. The potency was not evaluated. Conclusions: The 10-year oncologic outcomes of this shortened hypofractionated IMRT regimen for mainly low/intermediate risk prostate cancer patients is favorable with acceptable acute and late toxicities.

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.

Hypofractionated Whole-Breast-IMRT with HDR Brachytherapy Boost in Early-Stage Breast Cancer: Long Term Results of a Single Center Study

<h3>Purpose/Objective(s)</h3> In breast cancer patients, the addition of a boost over the lumpectomy bed after whole breast radiotherapy is frequently included in the therapeutic protocol and interstitial brachytherapy (BT) is one of the options for its administration. When BT is performed after conventional fractionation (50Gy) is considered safe, effective and strongly supported by literature. However, few studies have described its efficacy and side effects after a hypofractionated scheme, and even fewer have reported treatment/patient-dependent factors that may influence toxicity. The aim of this study is to show our results from a group of patients treated under a hypofractionated forward-planned whole-breast IMRT (Hypo-WB-IMRT) scheme followed by a high-dose-rate brachytherapy boost (HDR-BT) after conservative surgery. <h3>Materials/Methods</h3> We evaluated all patients treated at our facility with Hypo-WB-IMRT without elective irradiation of lymphatic areas (40Gy/15sessions) with a sequential single application of HDR-BT of 7 to 12Gy. A breast MRI was performed in all patients at the time of diagnosis. The BT implant was designed using both diagnostic MRI and planning CT as a reference for tumor bed localization and was planned according to the modified Paris system, with rigid needles, local anesthesia and outpatient regimen. <h3>Results</h3> Between 2009 and 2017, 638 patients with early-stage invasive breast cancer or ductal carcinoma in situ received adjuvant treatment according to the aforementioned protocol after breast-conserving surgery. Median follow-up was 6 years (4-11ys). We did not identify any relationship between the volume in cubic centimeters of the isodoses of 90%, 100%, 120% and 150% of the prescribed dose with acute (bleeding, mastitis) or long-term toxicity (12-month fibrosis, pain, edema, hypochromia, telangiectasia) or with an increased likelihood of local relapse or a second primary tumor in the same breast. However, and despite the low incidence of side effects and their slightness, we did identify an impact of breast volume with an increased risk of radiodermatitis at the end of WBRT (p=0.019), post-treatment mastitis (p=0,023), tumor bed fibrosis after 12 months (p=0.002), chronic pain (p=0.018) and breast edema (p<0.001) in women with >1000cc breasts with respect to smaller volume breasts. 13 patients had an actual local relapse (2.21%), 14 had a 2^nd primary in the same breast (2.39%) and 14 were diagnosed with contralateral breast cancer (2.39%). 16 patients (2.73%) developed metastatic disease and the overall survival at 11 years was 85.5%. <h3>Conclusion</h3> Hypo-WB-IMRT followed by a single dose HDR-BT boost is well tolerated, with a low rate of side effects and excellent oncologic outcomes. However, it may be of interest to individualize the treatment protocol choice in large breasts women who may be at higher risk of toxicity.

Prospective Comparison of Hypofractionated Versus Normofractionated Intensity-Modulated Radiotherapy in Breast Cancer: Late Toxicity Results of the Non-Inferiority KOSIMA Trial (ARO2010-3).

PurposeTo compare the late toxicity profile of hypofractionation and normofractionation for whole-breast radiotherapy in breast cancer (BC) patients after conserving surgery.MethodsSixty-year-old or older patients with pTis-pT3, pN0-pN1a, M0 BC were recruited and stratified to hypofractionated (arm R-HF) or normofractionated (arm L-NF) intensity-modulated radiotherapy (IMRT), for right- and left-sided BC, respectively, in this single-center, non-randomized, non-inferiority trial. A boost was allowed if indicated. The primary outcome was the cumulative percentage of patients developing grade III fibrosis, grade I telangiectasia, and/or grade II hyperpigmentation after 2 years, with a pre-specified non-inferiority margin of 15% increase from an expected 2-year toxicity rate of 20%.ResultsThe Median follow-up was 4.93 (0.57–8.65) years for R-HF and 5.02 (0.65–8.72) years for L-NF (p=0.236). The median age was 68 (60–83 and 60–80) years, respectively. In total, 226 patients were recruited (107 for R-HF and 119 for L-NF), with 100 and 117 patients suitable for assessment, respectively. A boost was delivered in 51% and 53% of each arm, respectively. Median PTV volumes were 1013.6 (273–2805) cm3 (R-HF) and 1058.28 (315–2709) cm3 (L-NF, p=0.591). The 2-year primary endpoint rate was 6.1% (95% CI 1.3-11.7, n=5 of 82) and 13.3% (95% CI 7-20.2, n=14 of 105), respectively (absolute difference -7.2%, one-sided 95% CI ∞ to -0.26, favoring R-HF). No local recurrence-free- or overall-survival differences were found.ConclusionIn this prospective non-randomized study, hypofractionation did not have higher toxicity than normofractionated whole-breast IMRT.

Limited Toxicity of Hypofractionated Intensity Modulated Radiation Therapy for Head and Neck Cancer.

Hypofractionated radiation therapy is not commonly used in head and neck cancers (HNC) due to increased toxicity observed in historical cohorts. This study reviews our institutional experience using hypofractionated intensity modulated radiation therapy (H-IMRT) for HNC. A retrospective cohort study of 56 patients with HNC treated with H-IMRT with ≥50 Gy in 20 fractions was conducted. The primary outcomes were acute and late toxicity. Two-year locoregional control was 87% and median overall survival was 46 months. There were no acute or late grade 4 or 5 toxicities. Acute grade 2 and 3 toxicity was seen in 79% (N=44) and 25% (N=14), respectively. Late grade 2 toxicity was seen in 9% (N=5). No patients required the placement of a feeding tube or tracheostomy. H-IMRT for the definitive or post-operative treatment of HNC using ≥50 Gy in 20 fractions appears safe and well tolerated with modest toxicity.

Long-term outcomes of a pilot study on highly hypofractionated intensity-modulated radiation therapy over three weeks for localized prostate cancer.

259 Background: A number of reports have been published on both moderately hypofractionated intensity-modulated radiation therapy (IMRT) for localized prostate cancers using 2.4 – 3.4 Gy per fraction over 4 – 6 weeks, and ultrahypofractionation over 1 – 2 weeks using 6 Gy or more per fraction. However, long-term outcomes have sparsely been reported using doses between these two fractionations (3.4 – 6.0 Gy per fraction) over 2 – 3 weeks (high hypofractionation). Therefore, we performed a pilot study of highly hypofractionated IMRT in 15 fractions using 3.6 Gy per fraction over 3 weeks for localized prostate cancer. We now report the long-term outcomes of the study. Methods: Twenty-five patients with low- to intermediate-risk prostate cancer were enrolled in this prospective study from April 2014 to September 2015. Fifty-four Gy in 15 fractions (3.6 Gy per fraction) was delivered over three weeks using IMRT with CBCT-based image guidance without intraprostatic fiducial markers. Based on an estimated alpha/beta ratio for prostate cancer of 1.5 Gy, the EQD2 was 78.7 Gy for the present dose fractionation. Neoadjuvant hormonal therapy (HT) was administered to intermediate-risk patients for 4 – 8 months, but was not mandatory in patients with low-risk disease. Adjuvant HT was not provided for any patient. Biochemical relapse-free survival (BRFS), clinical relapse-free survival (CRFS), overall survival (OS), and the cumulative incidence rate of late toxicities were analyzed using the Kaplan Meier method. Results: Twenty-four patients were treated with highly hypofractionated IMRT, except one case switched to conventionally fractionated IMRT because we could not meet the dose constraint of the small bowel in treatment planning. Among the 24 patients, 17 % had low-risk, and 83% had intermediate-risk disease. Neoadjuvant HT was administered to 23 patients, and the median duration of HT was 5.3 months. The median follow-up period was 77 months (range, 57–87 months). BRFS, CRFS, and OS were 91.7%, 95.8% and 95.8% at 5 years, and 87.5%, 86.3% and 95.8% at 7 years, respectively. No patient died of prostate cancer, but one patient died due to the other cancer. Neither grade ≥2 late gastrointestinal toxicity nor ≥3 late genitourinary toxicity was observed. Grade 2 late genitourinary toxicity did not occur during the first 4 years, but was developed in 5 patients after more than 4-year follow-up. The cumulative incidence rate was 12.9% and 22.8% at 5 and 7 years, respectively. Conclusions: Highly hypofractionated IMRT delivering 54 Gy in 15 fractions over 3 weeks for prostate cancer without intraprostatic fiducial markers demonstrates favorable oncological outcomes with no severe complications. This treatment approach could be a possible alternative of moderate hypofractionation, although further studies will be mandatory.

Impact of rectal spacer on toxicity reduction in men treated with proton versus photon therapy.

247 Background: Dose escalation in prostate cancer (PCa) radiotherapy (RT) is limited by toxicity to surrounding tissue, including the rectum. Rectal spacers improve bowel toxicity in men treated with photons (i.e. IMRT). However, the relative benefit of rectal spacers in men treated with protons remains unknown. Further, proton therapy may result in high-dose exposure to the anterior rectal wall due to lateral penumbra with conventional opposed lateral beam arrangement. We hypothesize that rectal spacers will confer greater toxicity benefit in the setting of proton therapy compared with photon therapy. Methods: We conducted an IRB approved, single institution, retrospective review of patients receiving definitive conventional or moderate hypofractionated photon IMRT or pencil-beam scanning proton RT for localized PCa from 2018-2021. Four cohorts were compared: Photon with (Ph+RS) or without (Ph-RS) rectal spacer, and proton with (Pr+RS) or without (Pr-RS) rectal spacer. Rates of pelvic nodal treatment were equivalent between protons and photons within the +/- rectal spacer cohorts. Acute (&lt;3 months) and late (≥ 3 month) toxicity was compared amongst the four cohorts. Cumulative incidence of physician-reported grade 1-2 gastrointestinal (GI) toxicity (CTCAE V5.0) was compared using Chi-square or Fisher’s exact test. Patient-reported bowel toxicity was evaluated using International Prostate Expanded Prostate Composite Index- Clinical Practice (EPIC-CP) and compared using linear mixed modeling. Results: 164 patients were eligible for analysis: 38 Ph-RS, 50 Ph+RS, 26 Pr-RS, &amp; 50 Pr+RS. Median follow-up was 17.6 months. In men treated with protons, physician-reported acute G1-2 GI toxicity was significantly lower in men with versus without rectal spacer (6.12 vs 30.77%, Pr+RS vs Pr-RS, respectively; p=0.009) and there was a trend towards lower late G1-2 GI toxicity (8.51 vs 26.09%, Pr+RS vs Pr-RS, respectively; p=0.08). In men treated with photons, there were no significant differences in physician-reported acute or later GI toxicity with versus without rectal spacer. No significant differences in patient-reported outcomes were observed with versus without spacer in the proton or photon cohorts. Conclusions: Rectal spacer use was associated with a lower CTCAE grade 1-2 acute GI toxicity in men treated with protons, and this difference was not observed in men treated with photons. While this study is limited by low sample size, a relatively greater benefit of rectal spacer with proton vs. photon therapy was observed. Further prospective analyses in larger cohorts are ongoing to validate these hypothesis-generating findings.

Multiparametric MRI-guided Hypofractionated Intensity-modulated Radiation Therapy With Simultaneous Integrated Boost for Glioblastoma

This study investigated the feasibility and efficacy of multiparametric magnetic resonance imaging (MRI)-guided dose-escalated hypofractionated intensity-modulated radiation therapy with simultaneous integrated boost (IMRT-SIB) for glioblastoma. Eighteen patients underwent postoperative IMRT-SIB for glioblastoma using three MRI sequences: double inversion recovery (DIR), diffusion tensor imaging (DTI), and post-gadolinium T1-weighted imaging. Prescribed doses were 60 Gy and 40 Gy in 15 fractions for residual enhancing lesions and surrounding tumor-infiltrating areas, respectively. For surrounding tumor-infiltrating areas, asymmetric margins were set with reference to DTI imaging. The 1-year overall survival rate was 58.0%, and the 1-year local control rate for the residual enhancing lesions was 76.2%, while that for surrounding tumor-infiltrating areas was 39.4%. One patient (6%) developed grade 2 cerebral radiation necrosis 10 months after IMRT-SIB, but there was no grade 3 or higher adverse event. Multiparametric MRI-guided dose-escalated IMRT-SIB with DIR and DTI imaging has the potential to improve local control rates without increasing adverse events.

Limited Toxicity of Hypofractionated Intensity Modulated Radiation Therapy (H-IMRT) for Head and Neck Cancer

Hypofractionated intensity modulated radiation therapy (H-IMRT) is uncommonly used in head and neck cancers due to concern for toxicity. This study reviews our experience using H-IMRT for head and neck cancers and explores its tolerability and efficacy.This single institution IRB approved retrospective study includes patients with head and neck cancers treated with definitive or post-operative H-IMRT from 2011-2020. Patients treated with ≥50Gy in 20 fractions to the primary tumor site and/or neck with at least 3 months of follow up were included. Patients treated to a superficial target only without proximity to mucosal surfaces or coverage of the elective neck (e.g., scalp; skin only targets) were excluded. Patients undergoing re-irradiation were excluded. Toxicity was scored using CTCAE v4.0. Acute toxicity included events occurring within 90 days of H-IMRT completion. Late toxicities occurred any time thereafter. Multiple toxicities in the same patient were scored separately.Fifty-nine patients with a median follow up of 10.9 months (range 3.0-111.5) were included. The majority of patients were white (93%) and male (78%) with a median age of 79.1. The most common primary tumor sites were skin (42%), major salivary glands (22%), and oral cavity (9%). The most frequent histologies included squamous cell carcinoma (66%) followed by thyroid cancer (7%), melanoma (5%), and Merkel cell carcinoma (5%). Treatment was delivered post-operatively in 80% and definitively in 20% of patients. All patients were treated with ≥50 Gy in 20 fractions, with the most common dose being 50 Gy (53%) followed by 55 Gy (44%). In 64% of patients a secondary elective dose of 45-50 Gy was used. Site treated included primary tumor site/bed with unilateral neck (54%), primary tumor site/bed with bilateral neck (19%), primary tumor site/bed alone (14%), unilateral neck (8%), and bilateral neck (5%). Five patients (8%) experienced a locoregional failure at a median time of 5.4 months (range 2.8-13.9). There were no grade 4 or 5 toxicities. Ten patients (17%) experienced acute grade 3 toxicity including mucositis (12%) and dermatitis (5%). Forty-six patients (78%) had an acute grade 2 toxicity, most commonly dermatitis (41%), pain (32%), fatigue (32%), dysgeusia (31%) and xerostomia (22%). Five patients (8%) experienced grade 2 late complications including neck fibrosis in three patients and trismus, aspiration pneumonia, and osteoradionecrosis in one patient each. No patient experienced grade 3 or higher late toxicity. No patients required the placement of a feeding tube or tracheostomy.Hypofractionated IMRT in the definitive or post-operative treatment of head and neck cancers using ≥50Gy in 20 fractions appears safe and well tolerated with modest toxicity. Prospective studies comparing the safety and efficacy of H-IMRT to conventionally fractionated IMRT are warranted.

A Japanese Multi-Institutional Phase II Study of Moderate Hypofractionated Intensity-Modulated Radiotherapy With Image-Guided Technique for Prostate Cancer

<h3>Purpose/Objective(s)</h3> While the non-inferiority of hypofractionation (HF) to conventional fractionation for prostate cancer had been investigated in some randomized clinical trials, we started a multi-institutional phase II study to confirm the safety with the efficacy of HF intensity-modulated radiotherapy (IMRT) with image-guided technique for Japanese patients. <h3>Materials/Methods</h3> Eligibility criteria of the study included: pathologically proven adenocarcinoma; low or intermediate risk (cT1-T2c, PSA ≤ 20 and Gleason score (GS) ≤ 7) or high risk having one of the following factors, cT3a, PSA > 20/ ≤ 30, or GS = 8/9; cN0M0; age 50-80; performance status (PS) 0-1; written informed consent. HF IMRT with 70 Gy/28 fr (2.5 Gy/fr) was performed. The position of the prostate gland or inserted fiducial markers was verified with a full bladder before each treatment. Neoadjuvant hormonal therapy (HT) for 4-8 months was allowed for patients with intermediate or high risk. The GTV was defined as the prostate (+ extracapsular invasion for cT3a). The CTV was defined as the GTV for low risk, and the GTV plus proximal seminal vesicles for intermediate and high risk. The PTV was defined as the CTV plus 4-8 mm margins for organ motions and set-up errors. The bladder, rectum, small and large intestines, and femoral heads were defined as the organs at risk (OAR) as the solid organ. The dose prescription was D_50% for the PTV, with D_max ≤ 105% and D_min ≥ 95%. The dose constraints for OARs were defined as follows: bladder V₇₀/V₆₅/V₆₀/V₅₅, 15%/25%/35%/50%; rectum V₆₅/V₅₅/V₅₀/V₄₅, 15%/25%/35%/50%; small intestine V₅₅ < 0.5 cc; large intestine V₆₀ < 0.5 cc; femoral heads V_max ≤ 50 Gy. The primary endpoint was the incidence of late toxicities at 5 years. The secondary endpoints were the incidence of acute toxicities, biochemical failure-free, clinical failure-free, and overall survivals at 5 years. The sample size was calculated to 130 patients using alpha/beta errors of 0.05/0.2, with the threshold/expectation values of ≥ grade 2 late toxicities as 15%/7%. <h3>Results</h3> From Jul/2012 to Oct/2014, 134 patients from 20 institutions were registered. Patients and tumor characteristics were as follows: median age 71 (54 - 79); cT1c/T2a/T2b/T2c/T3a, 53/50/7/19/5; GS 6/7/8/9, 32/80/16/6; median pretreatment PSA 9.0 ng/ml (3.15 – 28.6); low/intermediate/high risk, 20 (15%)/80 (60%)/34 (25%); PS 0/1, 67/67. HT was used for 121 patients (90%). The median follow-up time was 5.16 years. The incidences of grade 2/ ≥ 3 gastrointestinal and genitourinary late toxicities at 5 years (primary endpoint) were 5.3%/0% and 5.3%/0%, respectively. The corresponding figures of acute toxicities were 3.8%/0% and 14.5%/0%, respectively. The biochemical failure-free, clinical failure-free, and overall survivals at 5 years were 90.4%, 93.8%, and 94.5%, respectively. <h3>Conclusion</h3> The primary endpoint was met, and the safety and efficacy of HF IMRT was confirmed in this trial, and accepted as one of the standard of care for Japanese patients with prostate cancer.

Retrospective comparison of rectal toxicity between carbon-ion radiotherapy and intensity-modulated radiation therapy based on treatment plan, normal tissue complication probability model, and clinical outcomes in prostate cancer.

This retrospective study assessed the treatment planning data and clinical outcomes for 152 prostate cancer patients: 76 consecutive patients treated by carbon-ion radiation therapy and 76 consequtive patients treated by moderate hypo-fractionated intensity-modulated photon radiation therapy. These two modalities were compared using linear quadratic model equivalent doses in 2Gy per fraction for rectal or rectal wall dose-volume histogram, 3.6Gy per fraction-converted rectal dose-volume histogram, normal tissue complication probability model, and actual clinical outcomes. Carbon-ion radiation therapy was predicted to have a lower probability of rectal adverse events than intensity-modulated photon radiation therapy based on dose-volume histograms and normal tissue complication probability model. There was no difference in the clinical outcome of rectal adverse events between the two modalities compared in this study.

Highly hypofractionated intensity-modulated radiation therapy for nonmetastatic prostate cancer with a simultaneous integrated boost to intraprostatic lesions: a planning study.

The purpose of this planning study was to develop an acceptable technique for highly hypofractionated intensity-modulated radiation therapy using simultaneous integrated boost technique (SIB-hHF-RT) for nonmetastatic National Comprehensive Cancer Network high-risk prostate cancer. We created SIB-hHF-RT plans for 14 nonmetastatic prostate cancer patients with MRI-detectable intraprostatic lesions (IPLs) and without intestines locating close to the seminal vesicle and prostate. We prescribed 57Gy for IPLs and 54Gy for the remainder of planning target volume (PTV) in 15 fractions. The IPLs were contoured based on magnetic resonance imaging, and PTV was generated by adding 6-8-mm margins to the clinical target volume. For the dose-volume constraints of organs at risk (OARs), the same constraints as 54Gy plans were used so as not to increase the toxicity. All created plans fulfilled the dose-volume constraints of all targets and OARs. The median estimated beam-on time was 108.5s. For patient-specific quality assurance, the global gamma passing rates (3%/2mm) with 10% dose threshold criteria were greater than 93% in all cases and greater than 95% in 11 cases. SIB-hHF-RT plans were developed that fulfill the acceptable dose-volume constraints and pass patient-specific quality assurance. We believe these plans can be applied to selected patients with nonmetastatic prostate cancer.