Abstract Purpose Grade 4 lymphopenia (G4L) during radiation therapy (RT) is associated with higher rates of distant metastasis and decreased overall survival in a number of malignancies, including ...esophageal cancer (EC). Through a reduction in integral radiation dose, proton RT (PRT) may reduce G4L relative to photon RT (XRT). The purpose of this study was to compare G4L in patients with EC undergoing PRT versus XRT. Methods and materials Patients receiving curative-intent RT and concurrent chemotherapy for EC were identified. Lymphocyte nadir was defined as the lowest lymphocyte count during RT. G4L was defined as absolute lymphocyte count <200/mm3 . Univariate and multivariable logistic regression analyses (MVA) were performed to assess patient and treatment factors associated with lymphopenia. A propensity-matched (PM) cohort was created using logistic regression, including baseline covariates. Results A total of 144 patients met the inclusion criteria. The median age was 66 years (range, 32-85 years). Of these patients, 79 received XRT (27% 3-dimensional chemo-RT and 73% intensity modulated RT) and 65 received PRT (100% pencil-beam scanning). Chemotherapy consisted of weekly carboplatin and paclitaxel (99%). There were no significant differences in baseline characteristics between the groups, except for age (median 4 years older in the PRT cohort). G4L was significantly higher in patients who received XRT versus those who received PRT (56% vs 22%; P < .01). On MVA, XRT (odds ratio OR: 5.13; 95% confidence interval CI, 2.35-11.18; P < .001) and stage III/IV (OR: 4.54; 95% CI, 1.87-11.00; P < .001) were associated with G4L. PM resulted in 50 PRT and 50 XRT patients. In the PM cohort, G4L occurred in 60% of patients who received XRT versus 24% of patients who received PRT. On MVA, XRT (OR: 5.28; 95% CI, 2.14-12.99; P < .001) and stage III/IV (OR: 3.77; 95% CI, 1.26-11.30; P = .02) were associated with G4L. Conclusions XRT was associated with a significantly higher risk of G4L in comparison with PRT. Further work is needed to evaluate a potential association between RT modality and antitumor immunity as well as long-term outcomes.
This series reports long-term clinical outcomes of patients with salivary duct carcinoma (SDC), which is associated with a poor prognosis.
Eighty-nine patients with SDC were treated with curative ...intent from February 5, 1971, through September 15, 2018. Kaplan-Meier and competing risk analyses were used to estimate locoregional control, distant metastasis-free survival (DMFS), progression-free survival, and overall survival (OS). Cox regression analyses of disease and treatment characteristics were performed to discover predictors of locoregional control, DMFS, and OS.
Median follow-up was 44.1 months (range, 0.23-356.67). The median age at diagnosis was 66 years (interquartile range, 57-75). Curative surgery followed by adjuvant radiation therapy was performed in 73 patients (82%). Chemotherapy was delivered in 26 patients (29.2%). The 5-year local recurrence and distant metastasis rates were 27% and 44%, respectively, with death as a competing risk. Distant metastasis was associated with lymph node–positive disease (hazard ratio HR, 3.16; 95% confidence interval CI, 1.38-7.23; P = .006), stage IV disease (HR, 4.78; 95% CI, 1.14-20.11; P = .033), perineural invasion (HR, 4.56; 95% CI, 1.74-11.97; P = .002), and positive margins (HR, 9.06; 95% CI, 3.88-21.14; P < .001). Median OS was 4.84 years (95% CI, 3.54-7.02). The 5-year OS was 42%. Reduced OS was associated with lymphovascular space invasion (HR, 3.49; 95% CI, 1.2-10.1; P = .022), perineural invasion (HR, 2.05; 95% CI, 1.06-3.97; P = .033), positive margins (HR, 2.7; 95% CI, 1.3-5.6; P = .011), N2 disease (HR, 1.88; 95% CI, 1.03-3.43; P = .04), and N3 disease (HR, 11.76; 95% CI, 3.19-43.3; P < .001).
In this single-institution, multicenter retrospective study, the 5-year survival was 42% in patients with SDC. Lymphovascular space invasion, lymph node involvement, and higher staging at diagnosis were associated with lower DMFS and OS.
Abstract Purpose Pencil-beam scanning intensity modulated proton therapy (IMPT) may allow for an improvement in the therapeutic ratio compared with conventional techniques of radiation therapy ...delivery for pancreatic cancer. The purpose of this study was to describe the clinical implementation of IMPT for intact and clinically localized pancreatic cancer, perform a matched dosimetric comparison with volumetric modulated arc therapy (VMAT), and report acute adverse event (AE) rates and patient-reported outcomes (PROs) of health-related quality of life. Methods and materials Between July 2016 and March 2017, 13 patients with localized pancreatic cancer underwent concurrent capecitabine or 5-fluorouracil-based chemoradiation therapy (CRT) utilizing IMPT to a dose of 50 Gy (radiobiological effectiveness: 1.1). A VMAT plan was generated for each patient to use for dosimetric comparison. Patients were assessed prospectively for AEs and completed PRO questionnaires utilizing the Functional Assessment of Cancer Therapy-Hepatobiliary at baseline and upon completion of CRT. Results There was no difference in mean target coverage between IMPT and VMAT ( P > .05). IMPT offered significant reductions in dose to organs at risk, including the small bowel, duodenum, stomach, large bowel, liver, and kidneys ( P < .05). All patients completed treatment without radiation therapy breaks. The median weight loss during treatment was 1.6 kg (range, 0.1-5.7 kg). No patients experienced grade ≥3 treatment-related AEs. The median Functional Assessment of Cancer Therapy-Hepatobiliary scores prior to versus at the end of CRT were 142 (range, 113-163) versus 136 (range, 107-173; P = .18). Conclusions Pencil-beam scanning IMPT was feasible and offered significant reductions in radiation exposure to multiple gastrointestinal organs at risk. IMPT was associated with no grade ≥3 gastrointestinal AEs and no change in baseline PROs, but the conclusions are limited due to the patient sample size. Further clinical studies are warranted to evaluate whether these dosimetric advantages translate into clinically meaningful benefits.
PURPOSEExternal beam radiotherapy is used in a subset of high-risk patients with differentiated thyroid cancer (DTC). Recurrent, radioactive iodine (RAI)-refractory DTC carries a poor prognosis. We ...report our initial experience of intensity-modulated proton therapy (IMPT) for recurrent, RAI-refractory DTC. PATIENTS AND METHODSFourteen patients with recurrent, RAI-refractory DTC were consecutively treated with IMPT from November 2016 to March 2020 at our multisite institution. Patient, tumor, and treatment characteristics were recorded. Overall survival and local-regional recurrence-free survival were recorded and estimated using the Kaplan-Meier method. Acute and late treatment-related toxicities were recorded based on the Common Terminology Criteria for Adverse Events version 5.0. Patients completed the European Organization for Research and Treatment of Cancer Quality of Life Head and Neck Module at baseline and after IMPT. Eleven patients were included in the final analysis. RESULTSMedian follow-up was 8 months (range, 3-40) for all patients. Median age at treatment with IMPT was 64 years (range, 40-77), and the majority were men (64%). Recurrent histologies included papillary (55%), Hurthle cell (36%), and poorly differentiated (9%) carcinoma; 1 patient had tall cell variant. Concurrent chemotherapy was not administered for any patient in this cohort. At 8 months, all patients were alive without local-regional failure. Acute grade 3 toxicities were limited to 1 patient with dysphagia, requiring feeding tube placement. Two patients experienced late grade 3 esophageal stenosis requiring dilation. There were no grade 4 or 5 toxicities. There were no differences in pretreatment versus posttreatment patient-reported outcomes in terms of dysphagia or hoarseness. CONCLUSIONIn our early experience, IMPT provided promising local-regional control for recurrent, RAI-refractory DTC. Further study is warranted to evaluate the long-term efficacy and safety of IMPT in this patient population.
To understand how verification computed tomography-quality assurance (CT-QA) scans influenced clinical decision-making to replan patients with head and neck cancer and identify predictors for ...replanning to guide intensity-modulated proton therapy (IMPT) clinical practice.
We performed a quality-improvement study by prospectively collecting data on 160 consecutive patients with head and neck cancer treated using spot-scanning IMPT who underwent weekly verification CT-QA scans. Kaplan-Meier estimates were used to determine the cumulative probability of a replan by week. Predictors for replanning were determined with univariate (UVA) and multivariate (MVA) Cox model hazard ratios (HRs). Logistic regression was used to determine odds ratios (ORs).
< .05 was considered statistically significant.
Of the 160 patients, 79 (49.4%) had verification CT-QA scans, which prompted a replan. The cumulative probability of a replan by week 1 was 13.7% (95% confidence interval CI, 8.82-18.9), week 2, 25.0% (95% CI, 18.0-31.4), week 3, 33.1% (95% CI, 25.4-40.0), week 4, 45.6% (95% CI, 37.3-52.8), and week 5 and 6, 49.4% (95% CI, 41.0-56.6). Predictors for replanning were sinonasal disease site (UVA: HR, 1.82,
= .04; MVA: HR, 3.64,
= .03), advanced stage disease (UVA: HR, 4.68,
< .01; MVA: HR, 3.10,
< .05), dose > 60 Gy equivalent (GyE; relative biologic effectiveness, 1.1) (UVA: HR, 1.99,
< .01; MVA: HR, 2.20,
< .01), primary disease (UVA: HR, 2.00 versus recurrent,
= .01; MVA: HR, 2.46,
= .01), concurrent chemotherapy (UVA: HR, 2.05,
< .01; MVA: not statistically significant NS), definitive intent treatment (UVA: HR, 1.70 versus adjuvant,
< .02; MVA: NS), bilateral neck treatment (UVA: HR, 2.07,
= .03; MVA: NS), and greater number of beams (5 beam UVA: HR, 5.55 versus 1 or 2 beams,
< .02; MVA: NS). Maximal weight change from baseline was associated with higher odds of a replan (≥3 kg: OR, 1.97,
= .04; ≥ 5 kg: OR, 2.13,
= .02).
Weekly verification CT-QA scans frequently influenced clinical decision-making to replan. Additional studies that evaluate the practice of monitoring IMPT-treated patients with weekly CT-QA scans and whether that improves clinical outcomes are warranted.
PURPOSERadiation therapy (RT) is the standard treatment for patients with inoperable skin malignancies of the head and neck region (H&N), and as adjuvant treatment post surgery in patients at high ...risk for local or regional recurrence. This study reports clinical outcomes of intensity-modulated proton therapy (IMPT) for these malignancies. MATERIALS AND METHODSWe retrospectively reviewed cases involving 47 patients with H&N malignancies of the skin (squamous cell, basal cell, melanoma, Merkel cell, angiosarcoma, other) who underwent IMPT for curative intent between July 2016 and July 2019. Overall survival was estimated via Kaplan-Meier analysis, and oncologic outcomes were reported as cumulative incidence with death as a competing risk. RESULTSThe 2-year estimated local recurrence rate, regional recurrence rate, local regional recurrence rate, distant metastasis rate, and overall survival were 11.1% (95% confidence interval CI, 4.1%-30.3%), 4.4% (95% CI, 1.1%-17.4%), 15.5% (95% CI, 7%-34.3%), 23.4% (95% CI, 5.8%-95.5%), and 87.2% (95% CI, 75.7%-100%), respectively. No patient was reported to have a grade 3 or higher adverse event during the last week of treatment or at the 3-month follow-up visit. CONCLUSIONIMPT is safe and effective in the treatment of skin malignancies of the H&N.
To assess any correlation between swallowing dysfunction and radiation dose to 5 subregions of the larynx.
A cohort of 136 patients with head and neck cancer, treated with either photon or proton ...radiation therapy, was assessed using an endpoint of patient-reported swallowing scores, evaluated with the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-H&N35 survey, within 1 month after treatment. Five subregions of the larynx were contoured, and dosimetric metrics were extracted for each subregion as well as the total larynx. Univariate and multivariate logistic regression statistical analyses were used to determine statistical correlation with the dose metrics and clinical variables. Univariate regression models were statistically compared using a non-nested model test.
Under univariate analysis, unilateral versus bilateral nodal irradiation (P = .004), concurrent chemotherapy (P = .007), and surgery (P = .015) were statistically significant predictors of poor swallowing score. Unilateral versus bilateral irradiation was statistically significant under multivariate analysis (P = .039). The epiglottis was the most predictive subregion of swallowing score, with a majority (21 of 25) of dosimetric variables being identified as statistically significant. The maximum dose to the epiglottis was the most significant dosimetric variable tested for poor swallowing score in both univariate (P = .003) and multivariate (P = .051) analyses. Comparison of univariate models indicated a general preference for epiglottic variables with the mean dose to the epiglottis being preferred at a statistically significant level in many cases.
These results show the relatively increased sensitivity of the epiglottis compared with the rest of the larynx when considering patient-reported decrements in quality-of-life swallowing score and support both the inclusion of the epiglottis in standard larynx contours and the assessment of the epiglottis dose during plan evaluation. Our data suggest that keeping the mean and max doses to the epiglottis <20 to 37 Gy and <53 to 60 Gy, respectively, will reduce swallowing difficulties.
Human papillomavirus–associated oropharyngeal squamous cell carcinoma (HPV+OPSCC) requires further study to optimize the existing clinical staging system and guide treatment selection. We hypothesize ...that incorporation of the number of radiographically positive lymph nodes will further stratify patients with clinical N1 (cN1) HPV(+)OPSCC.
A post hoc analysis from 2 prospective clinical trials at a high-volume referral center was conducted. Patients underwent primary tumor resection and lymphadenectomy, followed by either standard-of-care radiation therapy (60 Gy in 30 fractions) with or without cisplatin (40 mg/m2 weekly) or de-escalated radiation therapy (30 Gy in 20 twice-daily fractions) with concomitant 15 mg/m2 docetaxel once weekly. Imaging studies were independently reviewed by a blinded neuroradiologist classifying radiographic extranodal extension (rENE) and the number and maximal size of involved lymph nodes. Patients without pathologic data available for assessment were excluded.
A total of 260 patients were included. Of these, 216 (83%) were cN1. Patients had a median of 2 radiographically positive lymph nodes (range, 0-12), and 107 (41%) had rENE. For cN1 patients, stratifying by radiographically positive lymph nodes (1-2 vs 3-4 vs >4) was predictive of progression-free survival (PFS) (P = .017), with 2-year PFS rates of 96%, 88%, and 81%, respectively. More than 2 radiographically positive lymph nodes was identified as a significant threshold for PFS (P = .0055) and overall survival (P = .029). Radiographic ENE and lymph node size were not predictive of PFS among cN1 patients.
The number of radiographically positive lymph nodes is predictive of PFS and overall survival and could be used to meaningfully subcategorize cN1 patients with HPV(+)OPSCC. We recommend further validation of our proposal that cN1 patients with 1 to 2 radiologically positive lymph nodes be categorized as cN1a, patients with 3 to 4 radiologically positive lymph nodes categorized as cN1b, and patients with >4 radiographically positive lymph nodes categorized as cN1c.
For treatment of rectal cancer, pencil beam scanning proton therapy (PBS-PT) may reduce radiation exposure to normal tissues compared with 3-dimensional conformal photon radiation therapy (3DCRT) or ...volumetric modulated arc photon radiation therapy (VMAT). The purpose of this study was to report the clinical implementation and dosimetric analysis of preoperative short-course PBS-PT for rectal cancer.
Eleven patients with stage IIA-IVB rectal cancer received preoperative short-course (25 Gy in 5 fx) PBS-PT between 2018 and 2019 preceding curative-intent total mesorectal excision. PBS-PT plans were generated using single-field optimization with 2 posterior-oblique fields. Verification computed tomography scans were performed on the first 3 days of treatment. Each patient had a backup 3DCRT and VMAT plan.
Clinical target volume coverage was similar between PBS-PT, 3DCRT, and VMAT. PBS-PT had statistically significant reductions in dose to the small bowel, large bowel, bladder, and femoral heads across multiple dosimetric parameters. All patients completed PBS-PT as planned without need for replanning. All computed tomography verification scans demonstrated good target coverage with clinical target volume V100 > 95%.
Preoperative short-course PBS-PT has been successfully implemented and offers a significant reduction of dose to normal tissues. Prospective studies are warranted to evaluate if dosimetric advantages translate into clinical benefit.
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