Gy Intensity-modulated Radiotherapy Research Articles

Phase II Trial of Cisplatin, Gemcitabine, and Intensity-Modulated Radiation Therapy for Locally Advanced Vulvar Squamous Cell Carcinoma: NRG Oncology/GOG Study 279.

To assess efficacy and toxicity of cisplatin (C) and gemcitabine (G) with intensity-modulated radiation therapy (IMRT) in patients with locally advanced vulvar cancer not amenable to surgery. Patients enrolled in a single-arm phase II study. Pretreatment inguinal-femoral nodal assessment was performed. Sixty-four Gy IMRT was prescribed to the vulva, with 50-64 Gy delivered to the groins/low pelvis. Radiation therapy (RT) plans were quality-reviewed pretreatment. C 40 mg/m2 and G 50 mg/m2 were administered once per week throughout IMRT. Complete pathologic response (CPR) was the primary end point. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and adverse events were assessed with Common Terminology Criteria for Adverse Events v 4.0. Fifty-seven patients enrolled, of which 52 were evaluable. The median age was 58 years (range, 25-58), and 94% were White. Forty (77%) had stage II or III disease, and all had squamous histology. A median of six chemotherapy cycles (range, 1-8) were received. Eighty-five percent of RT plans were quality-reviewed with 100% compliance to protocol. Seven patients came off trial because of toxicity or patient withdrawal. Of 52 patients available for pathologic assessment, 38 (73% [90% CI, 61 to 83]) achieved CPR. No pelvic exenterations were performed. With a median follow-up of 51 months, the 12-month PFS was 74% (90% CI, 62.2 to 82.7) and the 24-month OS was 70% (90% CI, 57 to 79). The most common grade 3 or 4 adverse events were hematologic toxicity and radiation dermatitis. There was one grade 5 event unlikely related to treatment. Weekly C and G concurrent with IMRT sufficiently improved CPR in women with locally advanced vulvar squamous cell carcinoma not amenable to surgical resection.

A dosimetric evaluation of intensity modulated radiotherapy and three-dimensional conformal radiotherapy for prostate cancer in Ghana.

External beam radiotherapy incorporates treatment techniques such as three-dimensional conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT), image-guided radiotherapy and volumetric modulated arc therapy to deliver high-energy radiation to cancer. The use of IMRT for cancer treatment is also associated with significant costs for patients in low-middle-income countries. The purpose of this study was to compare the dosimetric properties of 3DCRT and IMRT treatment plans for the external beam irradiation of patients with prostate cancer (Pca) to ascertain the superiority of IMRT in terms of dose homogeneity, conformity and dose limitation to organs at risk (OAR) in a resource-limited setting. One hundred and sixty treatment plans for 80 patients were created using 3DCRT and IMRT on the Eclipse treatment planning system (version 13.6). Data were collected and assessed from the dose-volume histogram of each plan. The conformity and homogeneity index (HI) for each of the plans were calculated. The doses to the OAR were also recorded and evaluated. The mean HIs for the IMRT and 3DCRT treatment techniques were 0.04 ± 0.02 (range: 0.01-0.011) and 0.09 ± 0.02 (range: 0.04-0.016), respectively. The mean conformity index (CI) for IMRT and 3DCRT techniques were 1.257 ± 0.112 (range: 0.99-1.58) and 1.302 ± 0.196 (range: 1.10-2.26). IMRT had a better significant mean HI and CI compared to 3DCRT. Generally, for this study, IMRT had better organ sparing compared to 3DCRT. The mean doses for the OARs ranged from 4.3-74.6 Gy for IMRT and 3.1-75.9 Gy for the 3DCRT technique. Overall, this study demonstrates that IMRT may offer an enhanced therapeutic profile, potentially reducing toxicity to the patient and ensuring more precise dose delivery to the target volume compared to 3DCRT in PCa external beam irradiation.

Long-Term Outcomes of De-Intensified Chemoradiotherapy for Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma

To report long-term oncologic outcomes among patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) treated with definitive de-intensified chemoradiotherapy. Major criteria for de-intensification were (1) AJCC 7th edition T0-T3, N0-N2c, M0 (AJCC 8th edition T0-T3, N0-N2, M0), (2) pathologically confirmed p16 positive, and (3) no or minimal/remote smoking history (non-mutated p53 if ≥30 pack-years). Treatment was 60 Gy intensity-modulated radiotherapy with first-choice concurrent cisplatin 30 mg/m2 once per week (alternative regimens permissible for cisplatin ineligible patients). Patients with T0-T2 N0-1 (AJCC 7th edition) were recommended 60 Gy radiation alone. Systemic therapy received included: cisplatin 30 mg/m2 (n = 122), cetuximab (n = 15), cisplatin 40 mg/m2 (n = 12), carboplatin/paclitaxel (n = 2), and radiation alone (n = 25). Kaplan Meier estimates for overall survival (OS), progression-free survival (PFS), locoregional control (LRC), and freedom from distant metastasis (FFDM) were calculated. Cox regression models were used for comparisons among subgroups. A total 176 patients received de-intensified treatment (n = 153 prospective protocol, n = 23 off-protocol). Median follow-up was 52.6 months (range 5.3 - 102.0, 90.8% with minimum 2-year follow-up); 56.8% (n = 100) were never smokers and 43.2% (n = 76) former smokers; former smokers had median 9 pack-years smoking history (range 0.25 - 50) with 46% ≥10 pack-years. Outcomes were as follows: 2-year OS 99.4% and 5-year OS 91.8%; 2-year PFS 94.1% and 5-year PFS 84.3%; 2-year LRC 98.3% and 5-year LRC 95.8%; 2-year FFDM 95.8% and 5-year FFDM 93.2%. Median time to progression events were 21.1 months (range, 7.2 - 54.1) with 37.5% (6 of 16) of recurrences occurring after 24 months. Six total locoregional events occurred (five recurrences and one site of persistent disease), within the 60 Gy planning target volume. Twenty-three patients with T0-T2 N0-1 disease received radiation alone with 2-year PFS 92.9% (5-year 83.8%) and 2-year LRC 100% (5-year 95.2%). Outcomes for former smokers with ≥10 pack-years were comparable to patients with less or no smoking history (2-year PFS 94.1% vs 94.1%; 5-year PFS 90.6% vs 82.7%; HR 0.58, p = 0.38). Early results suggest similar oncologic outcomes among those treated off-protocol (median follow-up 25.6 months) with 1 of 23 patients experiencing locoregional recurrence. Dose de-intensification of 60 Gy radiotherapy with weekly cisplatin results in favorable long-term tumor control in patients with HPV-associated OPSCC. De-intensified 60 Gy alone may be efficacious in carefully selected patients with T0-T2 N0-1 (AJCC 7th edition) disease. Inclusion of biologically favorable patients with more extensive former smoking history in de-intensification clinical trials may be warranted.

Reduced-dose radiotherapy for Epstein-Barr virus DNA selected staged III nasopharyngeal carcinoma: A single-arm, phase 2 trial

BackgroundRadiotherapy-related toxicities of nasopharyngeal carcinoma (NPC) caused by a standard dose of 70 Gy remain a critical issue. Therefore, we assessed whether a radiotherapy dose of 60 Gy was non-inferior to the standard dose in patients with low-risk stage III NPC with a favourable response to induction chemotherapy (IC). Patients and methodsWe did a single-arm, single-centre, phase II clinical trial in China. Patients with low-risk (Epstein-Barr virus [EBV] DNA level <4000 copies/ml) stage III NPC were treated with two cycles IC. Patients with complete/partial response and undetectable EBV DNA level were assigned 60 Gy intensity-modulated radiotherapy concurrently with three cycles of cisplatin. The primary end-point was 2-year progression-free survival (PFS). This trial is registered with ClinicalTrials.gov, number NCT 03668730. ResultsOne patient quit because of withdrawal of informed consent after IC. In total, 215 patients completed two cycles of IC, after which 116 (54.0%) and 99 (46.0%) patients were assigned 60 and 70 Gy radiotherapy, respectively. For 215 patients, the 2-year PFS was 90.7% (95% CI, 86.8%–94.6%) with a median follow-up of 43.9 months (interquartile range [IQR], 39.8–46.2). For patients treated with 60 Gy radiotherapy, the 2-year PFS rate was 94.8% (95%CI 90.7%–98.9%) with a median follow-up of 43.9 months (IQR 40.2–46.2). The most common late toxicity was grade 1–2 dry mouth (incidence rate: 54.3%). No grade 3+ long-term adverse event was observed, and most quality-of-life items, domains, and symptom scores returned to baseline by 6 months. ConclusionReduced-dose radiation (60 Gy) is associated with favourable survival outcomes and limited treatment-related toxicities in patients with low-risk stage III NPC sensitive to IC.

High-dose (60 Gy) intensity-modulated radiotherapy with concurrent weekly cisplatin followed by intracavitary radiation in locally advanced cervical cancer: A phase II prospective clinical trial

ObjectiveRadiotherapy dose-escalation using intensity-modulated radiotherapy (IMRT) has been necessary to improve treatment results in cervical cancer. MethodsThis was a phase II prospective clinical trial. 88 patients with FIGO II-IVa cervical cancer were enrolled in a single center. They received high-dose (60 Gy) IMRT with weekly cisplatin to the primary tumor and clinically positive nodes followed by intracavitary radiation. The primary endpoint was 30-month PFS rate (Target; 82%, an increase of 20% compared to GOG 120 trial using standard-dose radiotherapy). Secondary endpoints were tumor response, toxicity, recurrence, distant metastasis, and overall survival. ResultsProgression-free survival rate at 30 months was 82.8%. Overall survival, locoregional recurrence, distant metastasis, and para-aortic recurrence rates at 30 months were 93.6%, 8.2%, 9.2%, and 2.4%, respectively. Forty-five (51.1%) of 88 patients achieved downstaging on MRI during radiotherapy and 80 (90.9%) patients had clinically complete response at three months after high-dose IMRT and intracavitary radiotherapy. The 30-month recurrence-free survival (92.9% vs. 73.1%, P = 0.009) and overall survival (100% vs. 87.0%, P = 0.006) were significantly higher in the downstaged group than in the non-downstaged group during radiotherapy. Grade 3 or higher hematologic toxicity was found in 11 (12.5%) patients and grade 3 or higher non-hematologic toxicity was found in 3 (3.4%) patients. Fourteen had chronic urinary (8.0%), intestinal (5.7%) toxicity, pelvic insufficiency fracture (2.3%) or vesicovaginal fistula (2.3%). ConclusionHigh-dose (60 Gy) IMRT with concurrent weekly cisplatin in locally advanced cervical cancer yielded favorable progression-free survival outcome. Tumor response during radiotherapy can be a significant prognostic factor for PFS.Clinical trial information: This prospective trial is registered at ClinicalTrials.gov Identifier: NCT02993653.

Post radiation mucosal ulcer risk after a hypofractionated stereotactic boost and conventional fractionated radiotherapy for oropharyngeal carcinoma

Background/purpose Post radiation mucosal ulcers (PRMU) after treatment for oropharyngeal squamous cell carcinoma (OPSCC) can have a huge negative impact on patients’ quality of life, but little is known concerning risk factors and the impact of fraction size. Therefore, the goal of this study was to determine the pattern of PRMU development and to identify risk factors after a hypofractionated stereotactic body radiotherapy boost (SBRT) compared to conventionally fractionated radiotherapy for OPSCC. Material and methods We performed a retrospective cohort study (N = 332) of OPSCC patients with ≥ 1-year disease-free survival, treated with 46 Gy Intensity Modulated Radiotherapy (IMRT) (2 Gy fractions) followed by either an SBRT boost of 16.5 Gy (5.5 Gy fractions) (N = 180), or 24 Gy IMRT (2 Gy fractions) (N = 152). PRMU (grade ≥ 2) was scored when observed > three months after the last radiotherapy (RT) fraction (CTCAE v5.0). Potential risk factors were analyzed with Cox regression models using death as competing risk. Dose at the PRMU site was calculated by projecting delineated PRMU on the planning CT. Results All cases of PRMU (N = 64) occurred within 24 months; all were grade 2. The cumulative incidence at 2 years in the SBRT boost group was 26% (N = 46) vs. 12% (N = 18) for conventional fractionation (p = 0.003). Most PRMU developed within nine months (N = 48). PRMU occurring > nine months (N = 16) were mainly observed in the SBRT boost group (N = 15). Sex (p = 0.048), acute tube feeding (p = < 0.001), tumor subsite tonsil (p = 0.001), and N stage (p = 0.017) were associated with PRMU risk at multivariable regression in the hypofractionated SBRT boost group. All 25 delineated PRMU were located within the high dose regions. Conclusion The risk of PRMU should be included in the cost benefit analysis when considering future research using a hypofractionated SBRT boost for OPSCC patients.

Simultaneous or Sequential Boost to Clinically Involved Lymph Nodes in Cervical Cancer

<h3>Purpose/Objective(s)</h3> The optimal approach to metastatic lymph nodes (LNs) in locally advanced cervical cancer (LACC) is controversial. This study aimed to evaluate the efficacy and toxicity profile of dose escalation with simultaneous integrated (SIB) or sequential boost (SB) for clinically positive LNs in LACC. <h3>Materials/Methods</h3> The data of 43 patients who underwent chemoradiotherapy (CRT) with a SIB or SB dose to positive LNs between 2015 and 2021 for LACC were retrospectively analyzed. All patients were applied 50.4 Gy intensity-modulated radiotherapy (IMRT) or modulated volumetric arc therapy (VMAT) to the lymphatic and primary regions in 28 fractions with concurrent platinum-based chemotherapy followed by 28 Gy HDR intracavitary brachytherapy (BRT) in four fractions. Response evaluations were performed via magnetic resonance imaging (MRI) and positron emission tomography (PET)-CT on the third month. <h3>Results</h3> Median age was 53 years (range: 34-80 years). The FIGO stage was IIIC1 in 30 (70%), IIIC2 in 10 (23%), and IVA in three patients (7%), respectively. Pelvic CRT was applied to 25 patients (58%), and pelvic-paraaortic CRT was applied to 18 patients (41%). A total of 94 LNs were boosted. The median longest diameter of the LNs was 1.7 cm (range: 1–7 cm) and median volume was 2.5 cc (range: 0.6-21.5 cc). A SIB was applied in 24 (56%), SB in 13 (30%), and both in 6 patients (14%), respectively. Patients in the SIB group received a total dose of 56-64 Gy in 28 fractions. The patients with SB on the other hand received 56.4-60.4 Gy in 31-33 fractions and patients with SIB+SB received 60-66 Gy in 30-32 fractions. The dose from the BRT was also calculated to the LNs and the minimum dose to LNs from BRT was between 0-7.6 Gy (median 3.6 Gy). The maximum dose from BRT was as 0-9.7 Gy (median 4.8 Gy). Median follow-up (FU) was 21 months (range: 3-77 months). Following CRT, 41 (98%) patients had a complete response (CR) and one (2%) had a partial response (PR) in boosted LNs on MRI whereas 39 (98%) patients had a CR and one (2%) had a PR on PET/CT. Recurrence occurred in 12 patients during FU: one local recurrence (LR), two regional recurrence out of the RT field, seven distant metastases (DM), and two LR+DM. There was no recurrence in any of the 94 boosted LNs and the local control (LC) rate was 100%. The 1- and 2-year rate of overall survival was 89.5% and 82.3%, disease-free survival was 80% and 65.8%, locoregional recurrence-free survival was 84.6% and 70.5%, and DM-free survival rate was 80.4% and 69.9%, respectively. Treatment was well tolerated without any serious acute toxicity. Grade 3 late toxicity was observed in two patients (1-rectovaginal fistula, 1-ureteral stenosis). <h3>Conclusion</h3> Dose escalation with IMRT/VMAT yields an excellent LC rate for the involved LNs, even for very large ones, in LACC with a low toxicity profile. Routine LN dissection may not be necessary for patients with a LACC, but prospective randomized trials are needed to clarify this.

Safety of Nivolumab Added to Chemoradiation Therapy Platforms for Intermediate and High-Risk Locoregionally Advanced Head and Neck Squamous Cell Carcinoma: RTOG Foundation 3504

Programmed death-1 immune checkpoint blockade improves survival of patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), but the benefits of addition to (chemo)radiation for newly diagnosed patients with HNSCC remain unknown. We evaluated the safety of nivolumab concomitant with 70 Gy intensity modulated radiation therapy and weekly cisplatin (arm 1), every 3-week cisplatin (arm 2), cetuximab (arm 3), or alone for platinum-ineligible patients (arm 4) in newly diagnosed intermediate- or high-risk locoregionally advanced HNSCC. Patients received nivolumab from 2 weeks prior to radiation therapy until 3 months post-radiation therapy. The primary endpoint was dose-limiting toxicity (DLT). If ≤2 of the first 8 evaluable patients experienced a DLT, an arm was considered safe. Secondary endpoints included toxicity and feasibility of adjuvant nivolumab to 1 year, defined as all 7 additional doses received by ≥4 of the first 8 evaluable patients across arms. Of 39 patients (10 in arms 1, 3, 4 and 9 in arm 2), 72% had T3-4 tumors, 85% had N2-3 nodal disease, and 67% had >10 pack-years of smoking. There were no DLTs in arms 1 and 2, 1 in arm 3 (mucositis), and 2 in arm 4 (lipase elevation and mucositis in 1 and fatigue in another). The most common grade ≥3 nivolumab-related adverse events were lipase increase, mucositis, diarrhea, lymphopenia, hyponatremia, leukopenia, fatigue, and serum amylase increase. Adjuvant nivolumab was feasible as defined in the protocol. Concomitant nivolumab with the 4 tested regimens was safe for patients with intermediate- and high-risk HNSCC, and subsequent adjuvant nivolumab was feasible as defined (NCT02764593).

A hybrid 2D/4D-MRI methodology using simultaneous multislice imaging for radiotherapy guidance.

PurposeRespiratory motion management is important in abdominothoracic radiotherapy. Fast imaging of the tumor can facilitate multileaf collimator (MLC) tracking that allows for smaller treatment margins, while repeatedly imaging the full field‐of‐view is necessary for 4D dose accumulation. This study introduces a hybrid 2D/4D‐MRI methodology that can be used for simultaneous MLC tracking and dose accumulation on a 1.5 T Unity MR‐linac (Elekta AB, Stockholm, Sweden).MethodsWe developed a hybrid 2D/4D‐MRI methodology that uses a simultaneous multislice (SMS) accelerated MRI sequence, which acquires two coronal slices simultaneously and repeatedly cycles through slice positions over the image volume. As a result, the fast 2D imaging can be used prospectively for MLC tracking and the SMS slices can be sorted retrospectively into respiratory‐correlated 4D‐MRIs for dose accumulation. Data were acquired in five healthy volunteers with an SMS‐bTFE and SMS‐TSE MRI sequence. For each sequence, a prebeam dataset and a beam‐on dataset were acquired simulating the two phases of MR‐linac treatments. Prebeam data were used to generate a 4D‐based motion model and a reference mid‐position volume, while beam‐on data were used for real‐time motion extraction and reconstruction of beam‐on 4D‐MRIs. In addition, an in‐silico computational phantom was used for validation of the hybrid 2D/4D‐MRI methodology. MLC tracking experiments were performed with the developed methodology, for which real‐time SMS data reconstruction was enabled on the scanner. A 15‐beam 8× 7.5 Gy intensity‐modulated radiotherapy plan for lung stereotactic body radiotherapy with isotropic 3 mm GTV‐to‐PTV margins was created. Dosimetry experiments were performed using a 4D motion phantom. The latency between target motion and updating the radiation beam was determined and compensated. Local gamma analyses were performed to quantify dose differences compared to a static reference delivery, and dose area histograms (DAHs) were used to quantify the GTV and PTV coverage.ResultsIn‐vivo data acquisition and MLC tracking experiments were successfully performed with the developed hybrid 2D/4D‐MRI methodology. Real‐time liver–lung interface motion estimation had a Pearson's correlation of 0.996 (in‐vivo) and 0.998 (in‐silico). A median (5th–95th percentile) error of 0.0 (−0.9 to 0.7) mm and 0.0 (−0.2 to 0.2) mm was found for real‐time motion estimation for in‐vivo and in‐silico, respectively. Target motion prediction beyond the liver–lung interface had a median root mean square error of 1.6 mm (in‐vivo) and 0.5 mm (in‐silico). Beam‐on 4D MRI reconstruction required a median amount of data equal to an acquisition time of 2:21–3:17 min, which was 20% less data compared to the prebeam‐derived 4D‐MRI. System latency was reduced from 501 ± 12 ms to −1 ± 3 ms (SMS‐TSE) and from 398 ± 10 ms to −10 ± 4 ms (SMS‐bTFE) by a linear regression prediction filter. The local gamma analysis agreed within −3.8% to 3.3% (SMS‐bTFE) and −5.3% to 10% (SMS‐TSE) with a reference MRI sequence. The DAHs revealed a relative D98% GTV coverage between 97% and 100% (SMS‐bTFE) and 100% and 101% (SMS‐TSE) compared to the static reference.ConclusionsThe presented 2D/4D‐MRI methodology demonstrated the potential for accurately extracting real‐time motion for MLC tracking in abdominothoracic radiotherapy, while simultaneously reconstructing contiguous respiratory‐correlated 4D‐MRIs for dose accumulation.

An institutional review: dosimetry comparison between simultaneous integrated boost IMRT and VMAT for prostate cancer

AbstractPurpose:A comparative study was performed about the plan parameters and quality indices between volumetric arc therapy (VMAT) and intensity-modulated radiotherapy (IMRT) for the treatment of high-risk prostate cancer patients. The aim of this retrospective study was to compare the two methods of external beam radiotherapy IMRT and VMAT in terms of plan quality and efficacy.Material and method:Fifteen high-risk prostate patients were planned for radiotherapy using 6 MV photon. Three dose levels were contoured having Planning Tumour Volume 1 (PTV1 = 48 Gy), Planning Tumour Volume 2 (PTV2 = 57.6 Gy) and Planning Tumour Volume 3 (PTV3 = 60 Gy). Setup margins were given using the CHIP trial method. The prescribed PTV3 dose was 60 Gy in 20 fractions which is biologically equivalent to 74 Gy in 37 fractions using α/β = 3. In case of IMRT, seven fixed beam angles 30, 60, 105, 180, 255, 300 and 330 were used and the dose was optimised using the sliding window method. In case of rapid arc technique, one or two full arcs were used for dose optimisation while keeping all the dose constraints and other planning parameters same used in IMRT. The plan evaluation parameters and Organ at risks (OARs) doses were calculated using a dose volume histogram (DVH).Results:The average D2, D5, D95 and PTVmean for PTV3 were 61.22, 61.13, 58.12, 60.00 Gy and 62.41 62.24 59.53 61.12 Gy for IMRT and VMAT, respectively. The averages V60 for bladder and V30 for rectum were 22.81, 25 and 67, 65% for IMRT and VMAT, respectively. The average homogeneity index (HI), conformity index (CI) and gradient index (GI) were 1.04, 1.4833, 14.79 and 1.04, 1.704, 7.89 for IMRT and VMAT, respectively.Conclusion:VMAT takes less dose-delivery time and lesser number of monitoring units than IMRT, thus it compensates the intrafractional movements during dose delivery. The Dose GI in VMAT was much better than IMRT. This indicates sharper dose fall off near the normal tissue. No other major differences were observed in terms of plan evaluation parameters between IMRT and VMAT techniques. So, we conclude that VMAT technique is more efficient than IMRT in terms of plan quality and dose delivery.

ROMAN: Reduction in oral mucositis with avasopasem manganese (GC4419)–Phase III trial in patients receiving chemoradiotherapy for locally advanced, nonmetastatic head and neck cancer.

TPS6596 Background: Approximately 70% of patients receiving intensity-modulated radiotherapy (IMRT) plus cisplatin for locally advanced head and neck cancer (HNC) develop SOM, defined as WHO Grade 3 or 4, which limits patients' ability to eat solids (Gr 3) or liquids (Gr 4, requiring enteral nutrition). An RT-induced burst of superoxide initiates oral mucositis (OM) development. GC4419, a superoxide dismutase mimetic, interrupts this process by converting superoxide to H2O2. It showed promising reduction of SOM in a published open-label Phase 1b/2a trial (IJROBP 1 Feb 2018). In a subsequent randomized, double-blind placebo-controlled trial in 223 patients receiving IMRT/cisplatin for HNC (ASCO 2018), 90 mg of GC4419 administered M-F prior to IMRT demonstrated statistically significant reduction in SOM duration (p=0.024, median 1.5 days @ 90 mg vs. 19 days placebo) and meaningful reductions @ 90 mg in SOM incidence (43% vs. 65%) and severity (incidence of Grade 4, 16% vs. 30%). The safety results were acceptable and consistent with the known toxicities of IMRT/cisplatin. Methods: 335 patients at multiple centers in the U.S. and Canada with locally-advanced, nonmetastatic head and neck cancer (oral cavity/oropharyngeal) receiving 70 Gy IMRT (&gt;50 Gy to &gt; 2 oral sites) plus cisplatin (40 mg/m2 qwk x 6-7, or 100 mg/m2 q3wk x 3) are being randomized (double-blinded) 3:2 to 90 mg of GC4419 or placebo, M-F before each RT fraction. Enrollment is stratified by cisplatin schedule and treatment setting (definitive vs. post-op). OM by the WHO scale will be assessed twice weekly during RT &amp; weekly for 2 weeks post RT. The primary efficacy endpoint is incidence of SOM through the end of IMRT. Secondary efficacy endpoints include severity (incidence of Grade 4 OM through the end of IMRT), &amp; days of SOM (days from first to last SOM for all patients, with patients never developing SOM having 0 days of SOM by definition). Days of SOM for the subset developing SOM will be analyzed descriptively. Patients will be followed for one year post IMRT for tumor progression/recurrence and for two years for survival. Clinical trial information: NCT03689712 .

Phase II study of preoperative chemotherapy with nab-paclitaxel and gemcitabine followed by chemoradiation for borderline resectable or node-positive pancreatic ductal adenocarcinoma.

697 Background: Pre-operative therapy for resectable pancreatic ductal adenocarcinoma (PDAC) may eliminate micro-metastatic disease early and help achieve negative surgical margins. The present study is based on the hypothesis that gemcitabine/nab-paclitaxel chemotherapy followed by chemo-radiation with fluoropyrimidine is a feasible and efficacious pre-operative treatment for borderline resectable or node-positive PDAC. Methods: This is a single-arm phase II trial to evaluate pre-operative treatment with 2 cycles of gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 on days 1, 8, 15 every 28 days followed by 50.4 Gy of intensity-modulated radiation therapy over 28 fractions with concurrent 5-fluorouracil or capecitabine prior to pancreatic resection. Patients were eligible if they met borderline resectable criteria or had abnormal regional nodes visible on contrast CT. After surgery, they were eligible to receive up to 4 additional cycles of gemcitabine/nab-paclitaxel. The primary endpoint was the R0 resection rate. Secondary endpoints included response to pre-operative therapy, overall toxicities, relapse-free survival, and overall survival. Results: Nineteen of 24 screened patients have been enrolled. Median age was 68, 10 (53%) were female, and 4 (21%) were non-Caucasian. Eleven (78%) had head of pancreas cancers, 13 (68%) exhibited both arterial and venous involvement, and 12 (63%) had positive clinical nodes. All 19 patients received 2 months of gemcitabine/nab-paclitaxel, of which 17 patients continued to chemo-radiation (1 developed metastatic disease and 1 moved out of state). In the interval between chemo-radiation and surgery, 3 developed metastatic disease, 1 became unresectable, 1 withdrew from study, and 1 was deemed too frail for surgery. Nine have undergone successful pancreatic resection, and 2 are pending resection. Conclusions: Pre-operative gemcitabine/nab-paclitaxel followed by chemo-radiation with fluoropyrimidine is feasible in patients with borderline resectable PDAC and represents another strategy to FOLFIRINOX-based therapy. A planned interim analysis is ongoing. Clinical trial information: NCT02427841.

Complete neoadjuvant treatment for rectal cancer: A single institution experience.

148 Background: Full dose adjuvant chemotherapy following preoperative chemoradiation and surgery is poorly tolerated in stage II and III rectal cancer. We reviewed our institution’s experience with complete neoadjuvant treatment for rectal cancer since publication of the BrUOG R-224 trial results. Methods: After obtaining IRB approval, Data on patients with stage II and III rectal cancer who underwent complete neoadjuvant therapy were collected.. Patients who were planned to receive 8 cycles of modified FOLFOX6, chemoradiation with capecitabine 825 mg/m2 twice daily and 50.4 Gy intensity-modulated radiation therapy, then surgery were included. Results: Thirty-five patients were treated with complete neoadjuvant therapy between January 2014 and December 2017. Median age was 58 years (27 to 75 y); 1 patient (3%) was clinical stage II and 34 (97%) stage III. Twenty-seven patients (77%) received all 8 cycles of mFOLFOX6, of whom 24 completed subsequent chemoradiation. Therefore 69% of patients completed therapy according to the BrUOG R-224 protocol. Pathologic complete response (ypT0N0) was observed in 9 patients (26%). Treatment related toxicities resulted in dose reductions or treatment interruption in 57% and 29% of patients receiving chemotherapy and chemoradiation respectively. Conclusions: Complete neoadjuvant therapy for clinical stage II to III rectal cancer is well-tolerated in routine practice and offers an alternative to preoperative chemoradiation, surgery, then adjuvant full dose chemotherapy.

PIK3CA Mutation in HPV-Associated OPSCC Patients Receiving Deintensified Chemoradiation.

PIK3CA is the most frequently mutated gene in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). Prognostic implications of such mutations remain unknown. We sought to elucidate the clinical significance of PIK3CA mutations in HPV-associated OPSCC patients treated with definitive chemoradiation (CRT). Seventy-seven patients with HPV-associated OPSCC were enrolled on two phase II clinical trials of deintensified CRT (60 Gy intensity-modulated radiotherapy with concurrent weekly cisplatin). Targeted next-generation sequencing was performed. Of the 77 patients, nine had disease recurrence (two regional, four distant, three regional and distant). Thirty-four patients had mutation(s) identified; 16had PIK3CA mutations. Patients with wild-type-PIK3CA had statistically significantly higher 3-year disease-free survival than PIK3CA-mutant patients (93.4%, 95% confidence interval [CI] = 85.0% to 99.9% vs 68.8%, 95% CI = 26.7% to 89.8%; P = .004). On multivariate analysis, PIK3CA mutation was the only variable statistically significantly associated with disease recurrence (hazard ratio = 5.71, 95% CI = 1.53 to 21.3; P = .01). PIK3CA mutation is associated with worse disease-free survival in a prospective cohort of newly diagnosed HPV-associated OPSCC patients treated with deintensified CRT.

Patterns of Recurrence Following Stereotactic Body Radiation Therapy for Localized Prostate Cancer

Stereotactic body radiation therapy (SBRT) is increasingly offered for the treatment of localized prostate cancer. However, the patterns of recurrence are not well characterized. The aim of this study was to determine the recurrence rate in a large cohort of prostate cancer patients undergoing SBRT and to identity tumor and treatment factors predictive of the patterns of relapse following SBRT. Between 2007 and 2018, 1415 patients with organ-confined prostate cancer treated at a single academic institution were included in this analysis. Patients were treated with either five-fraction SBRT to a dose of 35-36.25 Gy (n=1135) or 19.5 Gy SBRT with 45-50.4 Gy intensity-modulated radiotherapy (IMRT) (n=280). PSA was monitored every 3 months during the first year, biannually for 2 years, and annually thereafter. Biochemical failure was defined using the nadir + 2 ng/mL definition. Detection of local recurrences included digital rectal examination, pelvic MRI, and/or prostate biopsy. Imaging studies such as bone scan, abdominal/pelvic CT, and more recently PET imaging were utilized to identify distant failures. Patterns of failure were classified as PSA only, local, or distant. Cox regression analysis was performed to evaluate the tumor and treatment characteristics associated with patterns of failure. Median age at diagnosis of patients was 69 years (range 42-92). The median follow-up of all patients was 36 months. Per D’Amico classification, 18% of patients had low risk disease, 57% of patients had intermediate risk disease, and 25% of patients had high risk disease. Androgen deprivation therapy (ADT) was administered to 32% of all patients. Disease free survival (DFS) for all patients at 5 years was 91.2% (low risk-99.3%, intermediate risk-91.5%, and high risk-82%). 93 patients experienced a disease recurrence with a median time to failure of 72 months (PSA only n=20; local n=30; distant n=36; and combined local and distant n=7). Median time to failure was 72 months for PSA only recurrences, 84 months for local recurrences, and 48 months for distant recurrences. Multivariate Cox regression model identified initial PSA, clinical T staging, and Gleason score (GS) as independent predictors of disease failure while controlling for ADT and supplemental IMRT. Incidence of failure following SBRT for prostate cancer remains low at 5 years. A similar number of local and distant failures were identified. Multivariate analysis identified initial PSA, clinical T staging, and GS as predictors of failure. In general, local failures occurred later than distant failures. This data supports careful monitoring of patients for early identification of salvageable local failures.

Roman: Reduction in oral mucositis with avasopasem manganese (GC4419)—Phase 3 trial in patients receiving chemoradiotherapy for locally-advanced, non-metastatic head and neck cancer.

TPS6096 Background: Approximately 70% of patients receiving intensity-modulated radiotherapy (IMRT) plus cisplatin for locally advanced head and neck cancer (HNC) develop SOM, defined as WHO Grade 3 or 4, which limits patients' ability to eat solids (Gr 3) or liquids (Gr 4, requiring enteral nutrition). An RT-induced burst of superoxide initiates oral mucositis (OM) development. GC4419, a superoxide dismutase mimetic, interrupts this process by converting superoxide to H2O2. It showed promising reduction of SOM in a published open-label Phase 1b/2a trial (IJROBP 1 Feb 2018). In a subsequent randomized, double-blind placebo-controlled trial in 223 patients receiving IMRT/cisplatin for HNC (ASCO 2018), 90 mg of GC4419 administered M-F prior to IMRT demonstrated statistically significant reduction in SOM duration (p=0.024, median 1.5 days @ 90 mg vs 19 days placebo) and meaningful reductions @ 90 mg in SOM incidence (43% vs 65%) and severity (incidence of Grade 4, 16% vs 30%). The safety profile was acceptable and consistent with the known toxicities of IMRT/cisplatin. Methods: 335 patients at multiple centers in the U.S. and Canada with locally-advanced, nonmetastatic head and neck cancer (oral cavity/oropharyngeal) receiving 70 Gy IMRT (&gt;50 Gy to &gt; 2 oral sites) plus cisplatin (40 mg/m2 qwk x 6-7, or 100 mg/m2 q3wk x 3) are being randomized (double-blinded) 3:2 to 90 mg of GC4419 or placebo, M-F before each RT fraction. Enrollment is stratified by cisplatin schedule and treatment setting (definitive vs post-op). OM by the WHO scale will be assessed twice weekly during RT &amp; weekly for 2 weeks post RT. The primary efficacy endpoint is incidence of SOM through the end of IMRT. Secondary efficacy endpoints include severity (incidence of Grade 4 OM through the end of IMRT), &amp; days of SOM (days from first to last SOM for all patients, with patients never developing SOM having 0 days of SOM by definition). Days of SOM for the subset developing SOM will be analyzed descriptively. Patients will be followed for one year post IMRT for tumor progression/recurrence and for two years for survival. Supported by Galera Therapeutics, Inc. Clinical trial information: NCT03689712.

Impact of Multi-leaf Collimator Parameters on Head and Neck Plan Quality and Delivery: A Comparison between Halcyon™ and Truebeam® Treatment Delivery Systems.

PurposeA new dual-layer multi-leaf collimator (MLC) system with several improved characteristics was introduced with the Varian Halcyon™ treatment platform. This study evaluated this new MLC’s impact on head and neck plan quality and delivery efficiency.MethodsNine patients were retrospectively studied with Institutional Review Board (IRB) approval. To compare plan quality between the Halcyon dual-layer MLC and Truebeam® MLC, all patients were replanned with the same prescription and target coverage following the institutional clinical protocol for both platforms and using both intensity modulated radiation therapy (IMRT) or volumetrically modulated arc therapy (VMAT) techniques. Organs-at-risk (OAR) dose-volume histogram (DVH) statistics were compared along with total plan monitor units (MU). To evaluate delivery efficiency, actual beam-on time for five patients’ plans were recorded and compared. To evaluate the impact of MLC performance parameters on plan quality, virtual MLC models were generated by matching Truebeam MLC’s parameters to those of the Halcyon dual-layer MLC both individually and combined. OAR doses were then compared between these virtual MLCs, the Truebeam MLC, and the actual Halcyon MLC.ResultsOverall the Halcyon dual-layer MLC provided similar plan quality compared to Truebeam MLC for VMAT plans, and improved sparing for majority of the OARs when using IMRT. Paired comparison showed median dose differences in mean doses to the parotids, cochlea, esophagus, and larynx ranged from -0.83 Gy to 0.37 Gy for VMAT, and from -4.79 Gy to -0.04 Gy for IMRT, with negative values indicating improved performance by Halcyon. Despite a slight increase in plan MU, the Halcyon reduced the total beam-on time by 42.8 ± 8.5%. Virtual MLC simulations demonstrated that matching MLC transmission accounted for nearly half of the total dose difference between Halcyon and Truebeam IMRT plans.ConclusionWhen compared to the Truebeam, the Halcyon’s dual-layer MLC achieved similar plan quality using VMAT, and improved OAR sparing using IMRT, while providing nearly twice as fast treatment delivery. Reduction in MLC transmission is the dominating factor contributing to dosimetric differences in OAR sparing.

A Randomized, Placebo (PBO) Controlled, Double-Blind P2b Trial of GC4419 (Avisopasem Manganese) to Reduce Severe Radiation-Related Oral Mucositis (SOM) in Patients (pts) with Locally Advanced Squamous Cell Cancer of the Oral Cavity (OC) or Oropharynx (OP)

Intensity-modulated radiation therapy (IMRT) plus cisplatin (CDDP) is established treatment for locally advanced OC/OP cancer, but appx. 70% of patients develop SOM, defined as WHO Grade 3 or 4, which limits patients' ability to eat solids (Gr 3) or liquids (Gr 4, requiring artificial nutrition). An RT-induced burst of superoxide initiates oral mucositis (OM) development. GC4419, a superoxide dismutase mimetic, interrupts this process by potently converting superoxide to H2O2. It showed promising reductions of SOM in a published open-label Phase 1b/2a trial (IJROBP 1 Feb 2018). Hypothesis: GC4419 reduces SOM without increasing toxicity or decreasing tumor control of IMRT/CDDP. A total of 223 pts with OC or OP cancers receiving 70 Gy IMRT (≥50 Gy to > 2 oral sites) plus CDDP (qwk or q3wk), were randomized 1:1:1 to PBO, 30 or 90 mg of GC4419, by 60-minute IV infusion, M-F before each RT fraction. OM by the WHO scale was assessed by trained evaluators during RT & for up to 8 wks post RT. Primary endpoint was duration of SOM. Secondary endpoints included incidence & time to onset of SOM, & safety. Efficacy analyses (each active dose v PBO, ITT) proceeded by a sequential, conditional approach; 2-sided α=0.05. Baseline patient & tumor characteristics were balanced: 86% M, 77% OP, 77% definitive, 82% IVa, 34% T4, 72% HPV+, 38% q3wk CDDP, number of oral sites receiving ≥ 50 Gy [3-4 sites; 53%; 5+ sites, 38%]); as was treatment delivery (median 70 Gy; 6% had RT breaks ≥ 5 consecutive fractions; 80% received ≥ 200 mg/m2 CDDP; 87% received ≥ 80% of planned GC4419/PBO doses). 90 mg GC4419 reduced SOM across endpoints, including a statistically significant reduction in the primary endpoint of duration (TABLE). Cumulative SOM incidence throughout RT (i.e., through 30, 40, 50 Gy) was also consistently lower with 90 mg GC4419 v PBO. Safety was comparable across arms with no significant GC4419-specific toxicity; chemotherapy toxicity of IMRT/cisplatin did not appear to be increased. 2-year follow up for tumor outcomes is in progress. GC4419 90 mg produced a clinically meaningful reduction of SOM; the primary analysis (duration) was statistically significant. Efficacy results with 30 mg were intermediate and did not reach significance. The safety profile was comparable to placebo. Interim tumor control data and exploratory correlative analyses will be presented.Abstract 223; TableNPBO30mg90mg90mg vs. PBO747376Relative δp-valueDuration SOM, median days1981.592%0.024Incidence SOM thru 60 Gy58%40%37%36%0.010*Incidence SOM thru last RT65%60%43%34%0.009*Incidence Grade 4 OM30%21%16%47%0.045*Onset SOM, median days39476156%0.080**nominal p value, pre-specified secondary endpoint Open table in a new tab

Results of a randomized, placebo (PBO) controlled, double-blind P2b trial of GC4419 (avisopasem manganese) to reduce duration, incidence and severity and delay onset of severe radiation-related oral mucositis (SOM) in patients (pts) with locally advanced squamous cell cancer of the oral cavity (OC) or oropharynx (OP).

6006 Background: Intensity-modulated radiotherapy (IMRT) plus cisplatin is established treatment for locally advanced OC/OP cancer, but appx. 70% of patients develop SOM, defined as WHO Grade 3 or 4, which limits patients' ability to eat solids (Gr 3) or liquids (Gr 4, requiring artificial nutrition). An RT-induced burst of superoxide initiates oral mucositis (OM) development. GC4419, a superoxide dismutase mimetic, interrupts this process by potently converting superoxide to H2O2. It showed promising reductions of SOM in a published open-label Phase 1b/2a trial (IJROBP 1 Feb 2018). Methods: 223 pts with OC or OP cancer receiving 70 Gy IMRT (≥50 Gy to > 2 oral sites) plus cisplatin (qwk or q3wk), were randomized 1:1:1 to PBO, 30 or 90 mg of GC4419, by 60-minute IV infusion, M-F before each RT fraction. OM by the WHO scale was assessed by trained evaluators biw during RT & qwk for up to 8 wks post RT. Primary endpoint was duration of SOM. Secondary endpoints included incidence & time to onset of SOM. Analyses (each active dose v PBO, ITT) proceeded by a sequential, conditional approach; 2-sided α = 0.05. Results: 90 mg GC4419 reduced SOM across endpoints, including a statistically significant reduction in the primary endpoint of duration. Efficacy results with 30 mg were intermediate and did not reach significance. Baseline patient & tumor characteristics, & treatment delivery, were well-balanced. Safety was comparable across arms with no significant GC4419-specific toxicity or increased toxicity of IMRT/cisplatin. Conclusions: GC4419 provides a clinically meaningful reduction of SOM in terms of duration, incidence and severity (Grade 4), with a safety profile comparable to placebo. Clinical trial information: NCT02508389. PBO 30mg 90mg 90mg vs. PBO N 74 73 76 Relative δ p = Duration SOM, median days 19 8 1.5 92% 0.024 Incidence SOM thru 60 Gy 58% 40% 37% 36% 0.010* Incidence SOM thru last RT 65% 60% 43% 34% 0.009* Incidence Grade 4 OM 30% 21% 16% 47% 0.045* Onset SOM, median days 39 47 61 56% 0.080* *nominal p value, pre-specified secondary endpoint

Initial Results from a Phase 2 Prospective Trial of De-intensified Chemoradiation therapy for Low-Risk HPV-associated Oropharyngeal Squamous Cell Carcinoma

To report initial results from a prospective phase 2 clinical trial of highly de-intensified chemoradiation therapy (CRT) for patients with favorable risk HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). The major inclusion criteria were: 1) T0-T3, N0-N2c, M0, 2) HPV or p16 positive, and 3) minimal/remote smoking history. Treatment was limited to 60 Gy intensity modulated radiation therapy with concurrent weekly intravenous cisplatin 30 mg/m2 (second choice was cetuximab). Patients received neither induction chemotherapy nor definitive surgery. Patients with T0-T2 N0-1 disease did not receive chemotherapy (i.e. received 60 Gy alone). All patients had a 10- to 12-week posttreatment PET/CT to determine need for planned neck dissection. The primary study endpoint is 2-year progression-free survival (PFS). Secondary endpoint measures include 2-year local control (LC), regional control (RC), distant metastasis free survival (DMFS), and overall survival (OS), and patient reported symptoms (PRO-CTCAE) and quality of life (EORTC QLQ-C30 & H&N35). Data analysis was performed for patients with a minimum of 1 year of follow-up. One hundred and thirteen patients have enrolled, with 82 having a minimum follow-up of 1 year. Smoking status was as follows: 49% never, 35% ≤ 10 pack-years, and 16% > 10 pack-years. Forty-four percent were HPV and p16 positive and 56% were HPV negative/unknown and p16 positive. Posttreatment PET/CT complete response rate was 97% at the primary site and 81% in the neck. Eight patients had planned neck dissection with 1 having pathological residual disease. Twoyear PFS, LC, RC, DMFS, CSS, and OS are the following: 93%, 98%, 99%, 95%, 96%, and 95%. Sixteen patients were treated with RT alone and all remain in cancer control. Mean pre- and 1-year posttreatment EORTC QOL scores were: Global 79/82 (lower worse), Swallowing 8/12 (higher worse), Dry Mouth 15/55 (higher worse), and Sticky Saliva 10/33 (higher worse). Of all patients, 39% patients required a feeding tube (none permanent) for a median of 10.5 weeks (range 3-42 weeks). Mean pre- and 1-year posttreatment PRO-CTCAE (0 to 4 scale, higher worse) scores were: Swallowing 0.5/0.9 and Dry mouth 0.5/1.6. There were no ≥ Grade 3 late adverse events. Initial clinical outcomes with highly de-intensified CRT are excellent in favorable risk OPSCC with evidence of better preservation of quality of life compared to standard therapies (ClinicalTrials.gov, NCT02281955).