Standard Intensity-modulated Radiotherapy Research Articles

Reducing Salivary Toxicity with Adaptive Radiotherapy (ReSTART): A Randomized Controlled Trial Comparing Conventional IMRT to Adaptive IMRT in Head and Neck Squamous Cell Carcinomas

BackgroundThe utility of Adaptive Radiotherapy (ART) in Head and Neck Squamous Cell Carcinoma (HNSCC) remains to be ascertained. While multiple retrospective and single-arm prospective studies have demonstrated its efficacy in decreasing parotid doses and reducing xerostomia, adequate randomized evidence is lacking. Methods and AnalysisReSTART (Reducing Salivary Toxicity with Adaptive Radiotherapy) is an ongoing phase III randomized trial of patients with previously untreated, locally advanced HNSCC of the oropharynx, larynx, and hypopharynx. Patients are randomized in a 1:1 ratio to the standard Intensity Modulated Radiotherapy (IMRT) arm {Planning Target Volume (PTV) margin 5 mm} vs. Adaptive Radiotherapy arm (standard IMRT with a PTV margin 3 mm, two planned adaptive planning at 10th and 20th fractions). The stratification factors include the primary site and nodal stage. The RT dose prescribed is 66Gy in 30 fractions for high-risk PTV and 54Gy in 30 fractions for low-risk PTV over six weeks, along with concurrent chemotherapy.The primary endpoint is to compare salivary toxicity between arms using salivary scintigraphy 12 months' post-radiation. To detect a 25% improvement in the primary endpoint at 12 months in the ART arm with a two-sided 5% alpha value and a power of 80% (and 10% attrition ratio), a sample size of 130 patients is required (65 patients in each arm). The secondary endpoints include acute and late toxicities, locoregional control, disease-free survival, overall survival, quality of life, and xerostomia scores between the two arms. DiscussionThe ReSTART trial aims to answer an important question in Radiation Therapy for HNSCC, particularly in a resource-limited setting. The uniqueness of this trial, compared to other ongoing randomized trials, includes the PTV margins and the xerostomia assessment by scintigraphy at 12 months as the primary endpoint.

Disease Control and Late Toxicity in Adaptive Dose Painting by Numbers Versus Nonadaptive Radiation Therapy for Head and Neck Cancer: A Randomized Controlled Phase 2 Trial

Local recurrence remains the main cause of death in stage III-IV nonmetastatic head and neck cancer (HNC), with relapse-prone regions within high 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET)-signal gross tumor volume. We investigated if dose escalation within this subvolume combined with a 3-phase treatment adaptation could increase local (LC) and regional (RC) control at equal or minimized radiation-induced toxicity, by comparing adaptive 18F-FDG-PET voxel intensity-based dose painting by numbers (A-DPBN) with nonadaptive standard intensity modulated radiation therapy (S-IMRT). This 2-center randomized controlled phase 2 trial assigned (1:1) patients to receive A-DPBN or S-IMRT (+/-chemotherapy). Eligibility: nonmetastatic HNC of oral cavity, oro-/hypopharynx, or larynx, needing radio(chemo)therapy; T1-4N0-3 (exception: T1-2N0 glottic); KPS ≥ 70; ≥18 years; and informed consent. 1-year LC and RC. The dose prescription for A-DPBN was intercurrently adapted in 2 steps to an absolute dose-volume limit (≤1.75 cm3 can receive >84 Gy and normalized isoeffective dose >96 Gy) as a safety measure during the study course after 4/7 A-DPBN patients developed ≥G3 mucosal ulcers. Ninety-five patients were randomized (A-DPBN, 47; S-IMRT, 48). Median follow-up was 31 months (IQR, 14-48 months); 29 patients died (17 of cancer progression). A-DPBN resulted in superior LC compared with S-IMRT, with 1- and 2-year LC of 91% and 88% versus 78% and 75%, respectively (hazard ratio, 3.13; 95% CI, 1.13-8.71; P = .021). RC and overall survival were comparable between arms, as was overall grade (G) ≥3 late toxicity (36% vs 20%; P = .1). More ≥G3 late mucosal ulcers were observed in active smokers (29% vs 3%; P = .005) and alcohol users (33% vs 13%; P = .02), independent of treatment arm. Similarly, in the A-DPBN arm, significantly more patients who smoked at diagnosis developed ≥G3 (46% vs 12%; P = .005) and ≥G4 (29% vs 8%; P = .048) mucosal ulcers. One arterial blowout occurred after a G5 mucosal toxicity. A-DPBN resulted in superior 1- and 2-year LC for HNC compared with S-IMRT. This supports further exploration in multicenter phase 3 trials. It will, however, be challenging to recruit a substantial patient sample for such trials, as concerns have arisen regarding the association of late mucosal ulcers when escalating the dose in continuing smokers.

Feasibility of Achieving Dose Constraints for Dysphagia Aspiration-Related Structures and Its Clinical Significance in Intensity-Modulated Radiotherapy Planning of Head and Neck Cancer.

Introduction Dysphagia is commonly seen in patients with head and neck cancers after undergoing chemoradiotherapy and is often under-reported and also not given clinical importance. The quality of life of the patients can be significantly improved if the required dose constraints to the dysphagia aspiration-related structures (DARS) are achieved. The present study was conducted in order to determine the feasibility of achieving the dose constraints to DARS between the standard intensity-modulated radiotherapy(st-IMRT) arm and the dysphagia-optimized IMRT (do-IMRT) arm. Material and methods Sixty patients with head and neck cancer were recruited and randomized into two groups: In one group called the st-IMRT, constraints were not given to DARS, and in the other group called the do-IMRT, constraints were given to DARS. Treatment was given in the form of chemoradiation with a dose of 70 Gy in 35 fractions by IMRTtechnique, over seven weeks, 2 Gy per fraction along with weekly concurrent Cisplatin (35 mg/m2) in both the groups. Step and shoot IMRT setup was used for planning, and the system used forplanning was Eclipse 13.6 (Varian Medical System, Inc., Palo Alto, CA, US); progressive resolution optimizeralgorithm was used for optimization, and Anisotropic Analytical Algorithmalgorithm was used for dose calculation. Truebeam was used for treatment delivery. DARS dosimetric parameters assessed were Dmean, V30, V50, V60, V70, D50, and D80. Radiation-induced toxicities to the skin, mucosa, larynx, salivary gland, and dysphagiaand hematological toxicities were assessed in between both the groups during and after radiotherapy up to six months based on Common Terminology Criteria for Adverse Effects v5.0. p-values were calculatedusing the unpaired T-test. Results In the cohort of 60 patients with head and neck cancers, 95% were males. Dosimetric parameters of the planning target volume (PTV) were compared but were not found to be significant. In the dosimetry of the organs at risk, a p-value of some structures was found to be significant although the doses received were well within the tolerable limits in both arms. DARS dosimetry V60 and V70 of the inferior constrictor muscle was found to be statistically significant (p=0.01 and 0.008, respectively). V60 and V70 of larynx were also statistically significant (p=0.009 and 0.000, respectively). V70 and D50 of cricopharyngeus were found to be statistically significant (p=0.01 and 0.03, respectively), V30 and V60 for combined pharyngeal constrictor muscles were found to be statistically significant (p=0.02 and 0.01), and lastly, V60 for combined DARS was also significant (p=0.004). Post-treatment 33.3% of patients in the st-IMRT arm required Ryle's tube placement. No grade 4 toxicities were seen in either arm regarding hematological toxicities, acute or chronic radiation-induced toxicities. In site-wise comparison of doses, the p-value was not found to be significant in patients with oropharyngeal and oral cavity carcinomas but was found to be statistically significant in the larynx and hypopharynx subsites. Conclusion The feasibility of achieving dose constraints to the DARS was seen in cases of laryngeal and hypopharyngeal cancers where the constrictor muscles were at a distance from the PTV. Further, the feasibility of achieving dose constraints may be seen in lower-dose prescriptions either in postoperative cases or in low-risk clinical target volumenodal volumes.

Ezabenlimab (BI 754091) plus modified docetaxel, cisplatin, and 5-fluorouracil (mDCF) followed by chemoradiotherapy (CRT) in patients (pts) with stage III squamous cell anal carcinoma (SCCA): Early efficacy endpoint results from the phase II INTERACT-ION study.

2 Background: CRT is the standard of care for locally advanced SCCA. However, up to 50% of pts experience recurrence/definitive colostomy; there is an unmet need for novel treatment (Tx) options to improve pt outcomes. mDCF is a standard first-line Tx for advanced SCCA, and anti-programmed death protein-1 (PD-1) immunotherapy has been shown to be effective in a subset of chemorefractory SCCA. Preclinical and clinical data support the feasibility and the potential of combining mDCF with anti-PD-1 immunotherapy. Methods: INTERACT-ION (NCT04719988) is an open-label, single-arm study in pts with Tx-naïve Stage III (T4N0 or TxN+) SCCA to evaluate ezabenlimab (anti-PD-1 antibody) plus mDCF as induction therapy, followed by CRT and then maintenance with ezabenlimab. Pts received induction ezabenlimab (240 mg intravenously, every 3 weeks, 3 cycles) plus mDCF (D [40 mg/m2], C [40 mg/m2] on Day 1; F [1200 mg/m2/day for 2 days] every 2 weeks, 4 cycles). If there was no disease progression after 2 months, pts received an additional cycle of ezabenlimab plus 2 cycles of mDCF. Planned early efficacy endpoint analyses were performed after 2 months of Tx. Pts with radiological objective response (OR; RECIST v1.1), pathological (p) complete response (CR)/near CR (<10% viable tumor cells) by repeat biopsy, and molecular CR (undetectable human papillomavirus [HPV] circulating tumor DNA) by liquid biopsy, received involved nodetumor bed CRT with intensity-modulated radiation therapy (IMRT) followed by 7 cycles of ezabenlimab. All other pts received standard IMRT based-CRT. The primary endpoint is the clinical CR rate 10 months after Cycle 1 of ezabenlimab plus mDCF. Results: At analysis cut-off date,43 pts had been enrolled; 37 pts had preliminary early efficacy endpoint evaluation. All but 1 pt (97.3%) received the planned 4 cycles of ezabenlimab plus mDCF prior to evaluation; 1 pt presented with treatment-related capillary leak syndrome after Cycle 1 and died of a lung infection 3 months later. Radiological assessment was performed in 33 pts; 32 (97.0%) had radiological OR including 14 (42.4%) with CR. One HPV- pt had disease progression. Pathological response data were available for 21 pts; 16 (76.2%) had pCR/near pCR. For molecular response, 3 pts were HPV- (excluded). Among 23 HPV+ evaluable pts, 21 (91.3%) had a molecular CR. Two pts had a significant decrease at 2 months (decrease: 14/1 and 54/1); then molecular CR after radiotherapy. No safety signals were identified by an independent safety review committee. Conclusions: Preliminary results from this ongoing Phase II study show promising antitumor activity and manageable safety of ezabenlimab plus mDCF in pts with Tx-naïve, locally advanced SCCA. Further evaluation of this new treatment regimen is warranted. Clinical trial information: NCT04719988 .

Toxicities and clinical outcome of adjuvant dysphagia optimized versus standard intensity-modulated radiotherapy for post-operative oral cavity cancers: A prospective comparative study.

We prospectively assessed acute and late toxicity in post-operative oral cavity squamous cell carcinoma (PO-OCSCC) treated with adjuvant dysphagia optimized intensity-modulated radiotherapy (Do-IMRT) versus standard IMRT (S-IMRT). Fifty-six patients of PO-SCC without indications of concurrent chemotherapy were alternatively allocated to adjuvant Do-IMRT (n = 28) versus S-IMRT (n = 28) arms. High- and low-risk planning target volume received 60 and 54 Gy, respectively, in 30 fractions over 6 weeks. Dysphagia aspiration-related structures (DARS) were contoured in both arms. While dosimetric constraints were given in Do-IMRT arm, doses to DARS were only observed without dose constraints in S-IMRT arm. Acute and late toxicity were assessed by common terminology criteria for adverse events (CTCAE) v5.0 and RTOG criteria, respectively. The primary site of disease was buccal mucosa (64% vs. 53%) and oral tongue (21% vs. 32%), in Do-IMRT and S-IMRT, respectively. The mean doses to DARS was significantly less with Do-IMRT (all p < 0.001) as compared to S-IMRT. Median follow-up was 24.2 months. Grade ≥2 oral pain was less in the Do-IMRT arm (50% vs. 78.6%, p = 0.05). Grade ≥2 late dysphagia at 2 years were significantly less in Do-IMRT arm (0% vs. 17.9%, p = 0.016). Two-year locoregional control was 89.2% in Do-IMRT and 78.5% in S-IMRT (p = 0.261). DARS can be spared in PO-OCSCC patients treated with Do-IMRT without compromising coverage of the target volumes. Limiting doses to DARS leads to lesser acute and late toxicity without compromising locoregional control.

Dysphagia-optimised intensity-modulated radiotherapy versus standard intensity-modulated radiotherapy in patients with head and neck cancer (DARS): a phase 3, multicentre, randomised, controlled trial

Most newly diagnosed oropharyngeal and hypopharyngeal cancers are treated with chemoradiotherapy with curative intent but at the consequence of adverse effects on quality of life. We aimed to investigate if dysphagia-optimised intensity-modulated radiotherapy (DO-IMRT) reduced radiation dose to the dysphagia and aspiration related structures and improved swallowing function compared with standard IMRT. DARS was a parallel-group, phase 3, multicentre, randomised, controlled trial done in 22 radiotherapy centres in Ireland and the UK. Participants were aged 18 years and older, had T1-4, N0-3, M0 oropharyngeal or hypopharyngeal cancer, a WHO performance status of 0 or 1, and no pre-existing swallowing dysfunction. Participants were centrally randomly assigned (1:1) using a minimisation algorithm (balancing factors: centre, chemotherapy use, tumour type, American Joint Committee on Cancer tumour stage) to receive DO-IMRT or standard IMRT. Participants and speech language therapists were masked to treatment allocation. Radiotherapy was given in 30 fractions over 6 weeks. Dose was 65 Gy to primary and nodal tumour and 54 Gy to remaining pharyngeal subsite and nodal areas at risk of microscopic disease. For DO-IMRT, the volume of the superior and middle pharyngeal constrictor muscle or inferior pharyngeal constrictor muscle lying outside the high-dose target volume had a mandatory 50 Gy mean dose constraint. The primary endpoint was MD Anderson Dysphagia Inventory (MDADI) composite score 12 months after radiotherapy, analysed in the modified intention-to-treat population that included only patients who completed a 12-month assessment; safety was assessed in all randomly assigned patients who received at least one fraction of radiotherapy. The study is registered with the ISRCTN registry, ISRCTN25458988, and is complete. From June 24, 2016, to April 27, 2018, 118 patients were registered, 112 of whom were randomly assigned (56 to each treatment group). 22 (20%) participants were female and 90 (80%) were male; median age was 57 years (IQR 52-62). Median follow-up was 39·5 months (IQR 37·8-50·0). Patients in the DO-IMRT group had significantly higher MDADI composite scores at 12 months than patients in the standard IMRT group (mean score 77·7 [SD 16·1] vs 70·6 [17·3]; mean difference 7·2 [95% CI 0·4-13·9]; p=0·037). 25 serious adverse events (16 serious adverse events assessed as unrelated to study treatment [nine in the DO-IMRT group and seven in the standard IMRT group] and nine serious adverse reactions [two vs seven]) were reported in 23 patients. The most common grade 3-4 late adverse events were hearing impairment (nine [16%] of 55 in the DO-IMRT group vs seven [13%] of 55 in the standard IMRT group), dry mouth (three [5%] vs eight [15%]), and dysphagia (three [5%] vs eight [15%]). There were no treatment-related deaths. Our findings suggest that DO-IMRT improves patient-reported swallowing function compared with standard IMRT. DO-IMRT should be considered a new standard of care for patients receiving radiotherapy for pharyngeal cancers. Cancer Research UK.

Weekly Adaptive Radiotherapy vs Standard Intensity-Modulated Radiotherapy for Improving Salivary Function in Patients With Head and Neck Cancer

Xerostomia is a major toxic effect associated with intensity-modulated radiotherapy (IMRT) for oropharyngeal cancers. To assess whether adaptive radiotherapy (ART) improves salivary function compared with IMRT in patients with head and neck cancer. This phase 3 randomized clinical trial was conducted in 11 French centers. Patients aged 18 to 75 years with stage III-IVB squamous cell oropharyngeal cancer treated with chemoradiotherapy were enrolled between July 5, 2013, and October 1, 2018. Data were analyzed from November 2021 to May 2022. The patients were randomly assigned (1:1) to receive standard IMRT (without replanning) or ART (systematic weekly replanning). The primary end point was the frequency of xerostomia, measured by stimulating salivary flow with paraffin. Secondary end points included salivary gland excretory function measured using technetium-99m pertechnetate scintigraphy, patient-reported outcomes (Eisbruch xerostomia-specific questionnaire and the MD Anderson Symptom Inventory for Head and Neck Cancer questionnaire), early and late toxic effects, disease control, and overall and cancer-specific survival. A total of 132 patients were randomized, and after 1 exclusion in the ART arm, 131 were analyzed: 66 in the ART arm (mean [SD] age at inclusion, 60 [8] years; 57 [86.4%] male) and 65 in the standard IMRT arm (mean [SD] age at inclusion, 60 [8] years; 57 [87.7%] male). The median follow-up was 26.4 months (IQR, 1.2-31.3 months). The mean (SD) salivary flow (paraffin) at 12 months was 630 (450) mg/min in the ART arm and 584 (464) mg/min in the standard arm (P = .64). The mean (SD) excretory function of the parotid gland at 12 months, measured by scintigraphy, improved in the ART arm (48% [17%]) compared with the standard arm (41% [17%]) (P = .02). The 2-year-overall survival was 76.9% (95% CI, 64.7%-85.4%) in both arms. This randomized clinical trial did not demonstrate a benefit of ART in decreasing xerostomia compared with standard IMRT. No significant differences were found in secondary end points except for parotid gland excretory function, as assessed by scintigraphy, or in survival rates. ClinicalTrials.gov Identifier: NCT01874587.

XRay Vision: A phase 3 study of xevinapant plus radiotherapy (RT) for high-risk, cisplatin-ineligible patients with resected, locally advanced squamous cell carcinoma of the head and neck (LA SCCHN).

TPS6101 Background: The current standard of care for patients with resected LA SCCHN who are at high-risk of disease recurrence and are cisplatin eligible is chemoradiotherapy (CRT; cisplatin + RT). For patients at high risk of disease recurrence who cannot receive cisplatin, treatment options are limited, and there is currently no treatment specifically recommended by international guidelines. Xevinapant is a first-in-class, small-molecule IAP (inhibitor of apoptosis protein) inhibitor that has been shown to restore cancer cell sensitivity to apoptosis, thereby enhancing the effects of chemotherapy and RT. In a randomized phase 2 study in patients with unresected LA SCCHN, treatment with xevinapant + CRT was associated with a 53% lower risk of death after 5 years of follow-up and reduced the risk of death or disease progression by 67% after 3 years of follow-up vs placebo + CRT. In preclinical SCCHN models, xevinapant + RT alone also demonstrated antitumor activity. These promising clinical and preclinical data provide a strong rationale for combining xevinapant and RT in cisplatin-ineligible patients with LA SCCHN. Methods: XRay Vision (NCT05386550) is a randomized, double-blind, placebo-controlled, phase 3 study comparing xevinapant or placebo in combination with intensity-modulated RT (IMRT) in patients with resected LA SCCHN who are ineligible for cisplatin and have a high risk of relapse. Eligible patients must have histologically confirmed cancer of the oral cavity, oropharynx, hypopharynx, or larynx; undergone surgery with curative intent 4 to 8 weeks before the start of treatment; high risk of relapse; no residual disease by computed tomography scan; and ineligible for cisplatin (meeting ≥1 of the following criteria: estimated glomerular filtration rate &lt;60 mL/min/1.73 m2; hearing loss [grade ≥2 audiometric hearing loss or grade ≥2 tinnitus]; grade ≥2 peripheral neuropathy; and if aged ≥70 years old, unfit according to the G8 questionnaire [score ≤14]). Other eligibility criteria include ECOG performance status of 0 or 1 and adequate hematologic and hepatic function. Approximately 700 eligible patients will be randomized to oral xevinapant (200 mg/day on days 1-14 of a 3-week cycle) or placebo for 3 cycles + standard fractionation IMRT (66 Gy in 33 fractions, 2 Gy per fraction, 5 days per week) followed by 3 cycles of xevinapant or placebo. The primary endpoint is disease-free survival. Secondary endpoints include overall survival, time to subsequent cancer treatments, safety, and health-related quality of life. Patients will be followed up for a minimum of 60 months. Enrollment is planned in 27 countries, including the US, and countries in South America, Europe, and Asia. The study started in October 2022, and recruitment is ongoing. Clinical trial information: NCT05386550 .

Long-Term Results of a Phase 3 Randomized Prospective Trial of Erectile Tissue-Sparing Intensity-Modulated Radiation Therapy for Men With Clinically Localized Prostate Cancer

The objective of this study was to determine whether limiting the doses delivered to the penile bulb (PB) and corporal bodies with intensity modulated radiation therapy (IMRT) preserves erectile function compared with standard IMRT in men with prostate cancer. A total of 117 patients with low- to intermediate-risk, clinical T1a-T2c prostate adenocarcinoma were enrolled in a single-institution, prospective, single-blind, phase 3 randomized trial. All received definitive IMRT to 74 to 80 Gy in 37 to 40 fractions and standard IMRT (s-IMRT) or erectile tissue-sparing IMRT (ETS-IMRT), which placed additional planning constraints that limited the D90 to the penile bulb and corporal bodies to ≤15 Gy and ≤7 Gy, respectively. Erectile potency was assessed with components of the International Index of Erectile Function and phosphodiesterase type 5 inhibitor (PDE5) medication records. Sixty-two patients received ETS-IMRT, and 54 received s-IMRT; 1 patient did not receive radiation therapy. Before treatment, all patients reported erectile potency. No patients received androgen deprivation therapy. In the intention-to-treat analysis, treatment arms did not differ in potency preservation at 24 months (37.1% ETS-IMRT vs 31.5% s-IMRT, P=.53). Of 85 evaluable patients with International Index of Erectile Function and PDE5 medication follow-up, erectile potency was seen in 47.9% of patients in the ETS-IMRT arm and 46.0% of patients in the s-IMRT arm (P=.86). PDE5 inhibitors were initiated in 41.7% of ETS-IMRT patients and 35.1% of s-IMRT patients (P=.54). Among all patients enrolled, there was no difference in freedom from biochemical failure between those treated with ETS-IMRT and s-IMRT (5-year 91.8% vs 90.7%, respectively, P=.77), with a median follow-up of 7.4 years. There were no differences in acute or late gastrointestinal or genitourinary toxicity. An unplanned per-protocol analysis demonstrated no differences in potency preservation or secondary endpoints between patients who exceeded erectile tissue-sparing constraints and those who met constraints, although power was limited by attrition and unplanned dosimetric crossover. ETS-IMRT that strictly limits dose to the penile bulb and corporal bodies is safe and feasible. Use of this planning technique did not show an effect on potency preservation outcomes at 2 years, though power to detect a difference was limited.

Long-term follow up of patients with hematological malignancies treated with total body irradiation using intensity modulated radiation therapy.

With the advent of modern radiation treatment technologies such as intensity modulated radiation therapy (IMRT), there has been increasing interest in its use for total body irradiation (TBI) conditioning regimens for hematopoietic cell transplantation (HCT) to achieve lower doses to critical organs such as the lungs and kidneys. Although this has been reported on in early studies, long-term safety and efficacy data is limited. We performed a single institution matched-pair retrospective analysis of patients treated with IMRT TBI and standard TBI between 2010 and 2020 to provide data on long-term outcomes. Patients with hematologic malignancies, who could not tolerate standing for traditional TBI or who received prior radiation received IMRT TBI. Patients were matched based on age, diagnosis, disease status, and year of transplant, and were matched 2:1 to the standard TBI and IMRT TBI cohorts. Patient and treatment characteristics, toxicity, graft-versus-host disease (GVHD), dosimetry, and outcomes were evaluated for each cohort. A total of 13 patients met inclusion criteria for the IMRT cohort, leading to 26 patients in the standard TBI cohort. There was no significant difference in relevant clinical factors between the cohorts. Reasons for using IMRT over conventional TBI included being unable to stand (n=5), prior radiation (n=5), and pediatric patient requiring anesthesia (n=3). Among living patients, median follow-up for all patients was 5.1 years in the IMRT TBI cohort and 5.5 years in the standard TBI cohort. The 5-yr estimate of OS was 68% in the IMRT TBI cohort and 60% in the standard TBI cohort (p=0.706). The 5-yr estimate of RFS was 54% in the IMRT TBI cohort and 60% in the standard TBI cohort (p=0.529). There was no clinically significant pneumonitis, nephritis, hypothyroidism, or cataracts reported in the IMRT TBI cohort. 41.7% of patients in the IMRT TBI cohort and 79.2% of patients in the standard TBI cohort experienced Grade II-IV acute GVHD (p=0.023). IMRT TBI appears to lead to favorable long-term outcome and dosimetry, and therefore potentially improved long-term toxicity profile compared to conventional TBI. IMRT TBI warrants further investigation as part of larger prospective trials.

Price Variability of Standard Radiotherapy Procedure Codes in a Large Metropolitan Area from 2015-2021

<h3>Purpose/Objective(s)</h3> Compliance amongst cancer centers has been poor despite price transparency rules by the US Centers for Medicare & Medicaid Services in 2021. We investigated variability in the charged and reimbursed payments in Medicare claims for standard intensity modulated radiation therapy (IMRT) for breast and prostate cancer within a large metropolitan area. <h3>Materials/Methods</h3> Medicare claims data for radiation therapy CPT codes 77336, 77385, and 77412 from 2015 to 2021 were selected from the Definitive Healthcare claims database for providers in New York within 25 miles of the zip code 10065. Providers with unknown number of claims were excluded. Average charges, reimbursements, and total claims were obtained. Annual percentage changes (APC) were calculated. The 10 highest volume centers by total number of claims for code 77336 over the study period were analyzed. Inflation adjustment (2021 US dollars) was done. Analyses were performed in spreadsheet software. <h3>Results</h3> Of 10 cancer centers, 5 were NCI-centers including 1 that was Prospective Payment System (PPS) exempt; these 10 high-volume centers represented 82% of claims. There was variability in charges for Medicare claims for each code; for example, in 2021, the average charges ranged widely for CPT 77336 ($644-1994), 77385 ($2797-7324), and 77412 ($1775-4527). The average reimbursement per procedure was similar across centers: CPT 77336 ($110-114), 77385 ($511-526), and 77412 ($225-234) in 2021. While average charges increased yearly, the percentage reimbursed remained stable or decreased (Table). The highest average charge for each code in 2021 were from non-NCI centers; the lowest charge per code varied from PPS-exempt (77336), NCI-center (77385), and non-NCI (77412). Reimbursement per code did not appear to vary greatly by center status. <h3>Conclusion</h3> We note significant price variability for commonly used IMRT codes within one large metropolitan area with multiple high-volume cancer centers. These prices outpaced annual rate of inflation. Service charges higher than what a hospital reasonably expects to be reimbursed may both prevent competitive price shopping by the consumer and result in catastrophic financial toxicity for small payors and under/uninsured individuals. This study supports the continued efforts to prioritize price transparency and associated policy reform.

High-dose Intensity-modulated proton therapy versus Standard-dose Intensity-modulated RadIation therapy for esophageal squamous cell carcinoma (HI-SIRI): study protocol for a randomized controlled clinical trial

BackgroundChemoradiotherapy is the standard of care for esophageal cancer as a neoadjuvant treatment before surgery, or as a definitive treatment for unresectable disease. Intensity-modulated radiotherapy (IMRT) has been considered the standard radiation technique. However, patients suffer from treatment-related toxicities, and most die from disease progression or recurrence. With emerging technological advancement, proton therapy has theoretical advantages over IMRT because it offers apparent dosimetric benefits to allow dose escalation to the target while better sparing surrounding tissues such as the lungs, heart, liver, and spinal cord. The purpose of this study protocol is to investigate the survival benefit of proton therapy using modern intensity-modulated proton therapy (IMPT) compared to standard IMRT for esophageal cancer.MethodsThis is a two-arm open phase II/III multi-institution randomized controlled trial. Eligible patients will have histologically confirmed squamous cell carcinoma of the thoracic esophagus with no evidence of tracheoesophageal/esophagobronchial fistula or distant metastasis. After stratification according to resectability status (resectable vs. borderline resectable/unresectable), a total of 232 patients will be randomized to receive IMPT or IMRT using a 1:1 allocation ratio. In resectable cases, surgical resection following concurrent chemoradiation will be attempted for the patients who are medically fit at the time of surgery. In those with initially borderline resectable/unresectable disease, definitive concurrent chemoradiation will be performed. The phase II study will assess safety (toxicity and postoperative complications) and feasibility (recruitment rate and chemoradiation dose modification) in 40 patients into each arm. The study will then continue into phase III, further recruit 76 patients into each arm, and compare progression-free survival between IMPT vs IMRT groups. The secondary endpoints will be overall survival, local and distant control, toxicities, health-related quality of life, and cost-utility. This protocol describes a detailed radiotherapy and chemotherapy.DiscussionThis randomized clinical trial will demonstrate the clinical benefit of IMPT in esophageal cancer treatment in terms of survival and toxicity outcomes which will further establish high-level evidence for radiation modality in squamous cell carcinoma of the thoracic esophagus.Trial registrationTCTR20200310006. Registered 10 March 2020.

Fluence map analyzer reduces low dose volume in locally advanced post mastectomy breast cancer patients

Multi-leaf collimator dose leakage in intensity-modulated radiotherapy (IMRT) plans causes higher low dose volume which increases the long-term risks of radiotherapy. We have developed Fluence Map Analyzer (FMA) program that suggests the ideal field geometry to reduce low dose volume in locally advanced breast cancer IMRT plans. In this comparative experimental study, FMA has been applied to standard IMRT plans (STD-IMRT) of randomly selected 15 left and 15 right-sided locally advanced breast cancer patients. All patients underwent a modified radical mastectomy. The chest wall, IMN, axillary, and supraclavicular lymph nodes are included in planning target volume (PTV). The heart, lungs, contralateral breast, and medulla spinalis were delineated as organs at risk (OARs). Two sets of plans, namely STD-IMRT and FMA-IMRT, were generated for each patient. The dosimetric analysis was performed using dose-volume histogram (DVH) and standard evaluation parameters of PTV and OARs. No differences could be observed among the two techniques for PTV coverage. However, FMA-IMRT plans achieved significantly lower V5 volumes and mean doses of the heart, lungs, contralateral breast, and body contours. FMA-IMRT used a smaller number of sub-fields and fewer monitor units (MU). FMA automizes the field geometry determination process for locally advanced breast cancer IMRT planning while reducing low dose volume significantly.

Dosimetric Effects and Estimated Osteoradionecrosis Development in Oropharynx Cancer Patients Treated With Intensity Modulated Radiotherapy With the Adoption of Dose Volume Histogram Based Mandibular Constraints

<h3>Purpose/Objective(s)</h3> Dose constraint recommendations to limit mandible (MN) osteoradionecrosis (ORN) are largely unchanged since the advent of head and neck intensity modulated radiotherapy (IMRT). Updated MN dose volume histogram (DVH) constraints have been proposed but not validated in a prospective dataset. We hypothesize that after adopting more stringent MN constraints at our institution, we lowered the estimated ORN rate without compromising target coverage / organ at risk (OAR) avoidance. <h3>Materials/Methods</h3> This is a single institution retrospective study of a prospective database of non-metastatic oropharynx cancer (OPC) patients ≥ 18 years treated with standard fractionation adjuvant or definitive IMRT from 01 / 2014 – 08 / 2020. In 09 / 2017, MN dose constraint was changed from 0.1 cm³ < 70 Gy – historical constraints (HC) – to V44 < 42%, V58 < 25%, 0.5cc < 70 Gy – modified constraints (MC). No other target / OAR criteria were altered. ORN was defined as having exposed MN bone for ≥ 3 months without recurrence. Impact on ORN rate and resulting dosimetric changes in MN and other OARs (parotid and submandibular glands, oral cavity, pharyngeal constrictors) between HC and MC groups were evaluated. Continuous variables were compared via the Wilcoxon test, discrete variables via Fisher's exact test. Due to shorter follow-up (FU), regression modeling was used to estimate ORN cases in MC group. <h3>Results</h3> There were 174 patients total, 71 in MC group. The mean prescription dose was 67.7 Gy and 68.5 Gy in HC and MC groups, respectively. More of the HC group (37%) had clinical T3 - T4 tumors compared to MC group (25%). More patients in the MC group met both the V44 < 42% (62 v 87%, <i>P</i> < 0.01) and the V58 < 25% constraints (73 v 92%, <i>P</i> < 0.01). Percent of patients meeting neither, one, or both MN constraints in the HC group was 23%, 13%, and 63%, versus 8%, 4%, and 87% in the MC group, respectively (<i>P</i> < 0.01). Mandible V44 and V58 were significantly associated with ORN (<i>P</i> < 0.01 and <i>P</i> = 0.03, respectively) across entire patient cohort. In HC group, mean MN V44 was significantly associated with ORN (62% in ORN cases vs 38%, <i>P</i> = 0.01) while mean MN V58 was approaching significance (<i>P</i> < 0.06). There were too few ORN cases in the MC group for similar analysis. Mean dose to OARs was not increased in MC group. There were 7 cases (76%) of ORN in the HC group at median FU 39 months (range: 2 - 78 months) and 2 cases (33%) of ORN in the MC group at median FU 11 months (range: 2 - 39 months). To account for shorter FU in MC group, logistic regression of ORN based on V44 in HC patients resulted in a model to predict ORN cases in MC group. This model estimates a total of 3.2 ORN cases (55%) in MC group (95% CI: 0.00 - 6.4). <h3>Conclusion</h3> We confirm MN V44 and V58 are predictive of ORN development. The goals of MN V44 < 42% and V58 < 25% were achievable in 87% of cases without sacrificing target coverage or other OAR constraints. Regression modeling estimates fewer ORN cases in MC group.

PROTECT: Prospective Phase-II-Trial Evaluating Adaptive Proton Therapy for Cervical Cancer to Reduce the Impact on Morbidity and the Immune System.

Simple SummaryChemoradiation with photon radiotherapy is very effective as a locally advanced cervical cancer (LACC) treatment. However, the majority of women with LACC experience treatment-related toxicity involving the gastrointestinal and urogenital tracts and the immune system. Compared to that of photon therapy, proton therapy substantially reduces undesired dose to the organs around the tumor, leading to a decrease in radiotherapy-related side-effects. At present, few studies on proton therapy in patients with LACC will be conducted. The PROTECT trial aims to evaluate the differences in side effects between photon therapy and proton therapy, both combined with chemotherapy, for LACC. Fifteen patients will be enrolled per treatment group. Information will be collected on the differences in dose to the organs around the tumor, treatment-related side effects, and the impact on the immune system. This information will be used to assess the potential of proton therapy as an innovative treatment for LACC.External beam radiation therapy (EBRT) with concurrent chemotherapy followed by brachytherapy is a very effective treatment for locally advanced cervical cancer (LACC). However, treatment-related toxicity is common and reduces the patient’s quality of life (QoL) and ability to complete treatment or undergo adjuvant therapies. Intensity modulated proton therapy (IMPT) enables a significant dose reduction in organs at risk (OAR), when compared to that of standard intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (VMAT). However, clinical studies evaluating whether IMPT consequently reduces side effects for LACC are lacking. The PROTECT trial is a nonrandomized prospective multicenter phase-II-trial comparing clinical outcomes after IMPT or IMRT/VMAT in LACC. Thirty women aged >18 years with a histological diagnosis of LACC will be included in either the IMPT or IMRT/VMAT group. Treatment includes EBRT (45 Gy in 25 fractions of 1.8 Gy), concurrent five weekly cisplatin (40 mg/m2), and 3D image (MRI)-guided adaptive brachytherapy. The primary endpoint is pelvic bones Dmean and mean bowel V15Gy. Secondary endpoints include dosimetric parameters, oncological outcomes, health-related QoL, immune response, safety, and tolerability. This study provides the first data on the potential of IMPT to reduce OAR dose in clinical practice and improve toxicity and QoL for patients with LACC.

Technical Note: End-to-end verification of an MR-Linac using a dynamic motion phantom.

MR-Linac integrates an MRI scanner and a linear accelerator to provide adaptive radiation treatment. Superior tissue contrast and real-time imaging can give the clinicians confidence to reduce the margins of the planning target volume (PTV). The purpose of this study was to verify the dosimetric accuracy of an MR-Linac system in treating a moving target and assess the error with different motion patterns and adaptation methods. We performed an end-to-end test for Elekta Unity (Elekta) using the 4D Dynamic Thorax Phantom (CIRS MRgRT 008Z), comparing the measured and planned dose. The moving phantom had four measurement locations in the tumor, liver, kidney, and spinal cord regions with a PTW30013 ion chamber. For seven different motion patterns, we first acquired simulation CT using a slow-scanning protocol, based on which we generated reference plans. The treatment technique was the standard intensity-modulated radiation therapy (IMRT). We tested both adaptation workflows: the Adapt-to-Position (ATP) and the Adapt-to-Shape (ATS). The three-dimensional (3D) distribution was measured using a diode array phantom (Sun Nuclear Inc.) to check the dose distribution accuracy as part of the routine QA process. We also performed end-to-end tests on a conventional Linac. Finally, we used SPSS Statistics 22.0 (Inc., Chicago, IL, USA) for data analysis. All pretreatment reference plans and delivered plans had excellent QA results with a better than 95% passing rate of relative gamma analysis (2%/2mm criteria). The adaptive planning for MR-Linac produced quality plans. The measured dose in the target agreed with the calculated dose. The adaptive treatment on the MR-Linac system investigated met the expected performance with tumor motions. The outline of the target could be visualized and accurately contoured on the 3D MR for online planning. Under different motion patterns, the difference between the measured and calculated dose was acceptable clinically.

Normal Tissue Injury Induced by Photon and Proton Therapies: Gaps and Opportunities.

Despite technological advances in radiation therapy (RT) and cancer treatment, patients still experience adverse effects. Proton therapy (PT) has emerged as a valuable RT modality that can improve treatment outcomes. Normal tissue injury is an important determinant of the outcome; therefore, for this review, we analyzed 2 databases: (1) clinical trials registered with ClinicalTrials.gov and (2) the literature on PT in PubMed, which shows a steady increase in the number of publications. Most studies in PT registered with ClinicalTrials.gov with results available are nonrandomized early phase studies with a relatively small number of patients enrolled. From the larger database of nonrandomized trials, we listed adverse events in specific organs/sites among patients with cancer who are treated with photons and protons to identify critical issues. The present data demonstrate dosimetric advantages of PT with favorable toxicity profiles and form the basis for comparative randomized prospective trials. A comparative analysis of 3 recently completed randomized trials for normal tissue toxicities suggests that for early stage non-small cell lung cancer, no meaningful comparison could be made between stereotactic body RT and stereotactic body PT due to low accrual (NCT01511081). In addition, for locally advanced non-small cell lung cancer, a comparison of intensity modulated RTwith passive scattering PT (now largely replaced by spot-scanned intensity modulated PT), PT did not provide any benefit in normal tissue toxicity or locoregional failure over photon therapy. Finally, for locally advanced esophageal cancer, proton beam therapy provided a lower total toxicity burden but did not improve progression-free survival and quality of life (NCT01512589). The purpose of this review is to inform the limitations of current trials looking at protons and photons, considering that advances in technology, physics, and biology are a continuum, and to advocate for future trials geared toward accurate precision RT that need to be viewed as an iterative process in a defined path toward delivering optimal radiation treatment. A foundational understanding of the radiobiologic differences between protons and photons in tumor and normal tissue responses is fundamental to, and necessary for, determining the suitability of a given type of biologically optimized RT to a patient or cohort.

Clinico-Dosimetric Correlation Of Doses To Dysphagia Aspiration Related Structures (DARS) With Acute Toxicities In Post-Operative Patients Of Oral Cavity Carcinoma Treated With Dysphagia Optimized Versus Standard IMRT

Limiting the radiation dose to dysphagia aspiration related structures (DARS) may reduce toxicities in patients of oral cavity squamous cell carcinoma (OCSCC) treated with adjuvant radiotherapy. We analyzed acute toxicity in patients of OCSCC treated with adjuvant intensity modulated radiation therapy (IMRT) reducing the dose of radiation received by DARS: dysphagia optimized IMRT (Do-IMRT) and compared it with standard IMRT (S-IMRT: without dose constraints to DARS). Fifty OCSCC patients between 18-70 years of age were randomized in this prospective study to receive either adjuvant Do-IMRT or S-IMRT. None received concurrent chemoradiotherapy. Target volume was divided into high, intermediate and low risk areas receiving doses in the range of 60-66 Gy, 54-58 Gy, 51-56 Gy in 30-33 fractions over 6-6.5 weeks, respectively. In addition to the conventional organs at risk, dose constraints were given to DARS in Do-IMRT arm. The primary end point was acute toxicity evaluated by common terminology criteria for adverse events (CTCAE) version 5.0. Each arm had 25 patients. Median age was 46.5 years (range 28-74 years). Patient characteristics were balanced between two groups. Buccal mucosa: Tongue: other primary were seen in 72% vs. 48%:12% vs. 36%: 16% vs. 16% respectively in Do-IMRT vs. S-IMRT. Similarly, T1:T2:T3:T4 were 8% vs. 4%: 60% vs. 40%: 24% vs. 32%: 8% vs. 24%; N0:N1:N2 were 68% vs. 48%: 16% vs. 36%: 16% vs. 16% in Do-IMRT vs. S-IMRT arm. respectively. Lymphovascular invasion and peri-neural invasion were observed in 20% vs. 36% and 20% vs. 12% respectively in Do-IMRT vs. S-IMRT. There was a statistically significant difference in the mean doses to DARS in Do-IMRT vs. S-IMRT arm without compromising PTV coverage (Table 1). Grade 3 dysphagia was significantly lower in the Do-IMRT vs. S-IMRT group (0% vs. 16%; p = 0.067). Do-IMRT significantly delivers lesser doses to DARS as compared to S-IMRT and trended to lesser acute grade ≥3 dysphagia and grade ≥2 oral pain compared to S-IMRT. Longer follow up and correlation of late toxicities would better define the role of Do-IMRT compared to S-IMRT in post-operative OCSCC patients.Abstract 3845; Rest is summarized in Table 1Dosimetric AnalysisDo-IMRT (Mean ± SD)S-IMRT (Mean ± SD)P valuePTV-HR V9597.86±1.1797.57±1.530.463PTV-IR V9599.03±1.3198.59±1.280.402PTV-LR V9598.82±1.6198.92±1.120.809Superior constrictor43.24±7.1652.33±6.66<0.001Middle Constrictor40.33±5.9352.86±5.59<0.001Inferior Constrictor29.05±9.9248.76±7.10<0.001Supraglottic Larynx40.06±5.4253.86±5.60<0.001Glottic Larynx31.76±9.3747.54±7.51<0.001Cricopharyngeus33.77±11.9446.48±7.54<0.001Cervical esophagus22.12±15.2532.18±12.780.015Acute toxicityDo-IMRTS-IMRTp-valueDysphagia Grade ≥287%100%0.102Oral mucositis Grade ≥330.4%44%0.252Pharyngeal mucositis Grade ≥30%12%0.133Oral pain Grade ≥252.2%76%0.077Oropharyngeal pain Grade ≥256.5%72%0.207 Open table in a new tab

A Dosimetric Comparison Of A Novel Clitoris-Sparing Intensity Modulated Radiotherapy (IMRT) Approach vs. Standard IMRT for Treatment of Female Patients with Anal Cancer

A Dosimetric Comparison Of A Novel Clitoris-Sparing Intensity Modulated Radiotherapy (IMRT) Approach vs. Standard IMRT for Treatment of Female Patients with Anal Cancer

Radiobiological assessment of nasopharyngeal cancer IMRT using various collimator angles and non-coplanar fields

AbstractAim:The aim of this study was to evaluate clinical efficacy and radiobiological outcome of intensity-modulated radiation therapy (IMRT) modalities using various collimator angles and non-coplanar fields for nasopharyngeal cancer (NPC).Materials and methods:A 70-Gy planning target volume dose was administered for 30 NPC patients referred for IMRT. Standard IMRT plans were constructed based on the target and organs at risk (OARs) volume; and dose constraints recommended by Radiation Therapy Oncology Group (RTOG). Using various collimator angles and non-coplanar fields, 11 different additional IMRT protocols were investigated. Homogeneity indexes (HIs) and conformation numbers (CNs) were calculated. Poisson and relative seriality models were utilised for estimating tumour control probability (TCP) and normal tissue complication probabilities (NTCPs), respectively.Results:Various collimator angles and non-coplanar fields had no significant effect on HI, CN and TCP, while significant effects were noted for some OARs, with a maximum mean dose (Dmax). No significant differences were observed among the calculated NTCPs of all the IMRT protocols. However, the protocol with 10° collimator angle (for five fields out of seven) and 8° couch angle had the lowest NTCP. Furthermore, the standard and some of non-coplanar IMRT protocols led to the reduction in OARs Dmax.Conclusions:Using appropriate standard/non-coplanar IMRT protocols for NPC treatment could potentially reduce the dose to the OARs and the probability of inducing secondary cancer in patients.