Treatment-related Toxicity In Patients Research Articles

Impact of chrono-radiotherapy on the prognosis and treatment-related toxicity in patients with locally advanced nasopharyngeal carcinoma: A multicenter propensity-matched study

ABSTRACT The timing of radiotherapy (RT) delivery has been reported to affect both cancer survival and treatment toxicity. However, the association among the timing of RT delivery, survival, and toxicity in locally advanced nasopharyngeal carcinoma (LA-NPC) has not been investigated. We retrospectively reviewed patients diagnosed with LA-NPC who received definitive RT at multiple institutions. The median RT delivery daytime was categorized as morning (DAY) and night (NIGHT). Seasonal variations were classified into the darker half of the year (WINTER) and brighter half (SUMMER) according to the sunshine duration. Cohorts were balanced according to baseline characteristics using propensity score matching (PSM). Survival and toxicity outcomes were evaluated using Cox regression models. A total of 355 patients were included, with 194/161 in DAY/NIGHT and 187/168 in WINTER/SUMMER groups. RT delivered during the daytime prolonged the 5-year overall survival (OS) (90.6% vs. 80.0%, p = 0.009). However, the significance of the trend was lost after PSM (p = 0.068). After PSM analysis, the DAY cohort derived a greater benefit in 5-year progression-free survival (PFS) (85.6% vs. 73.4%, p = 0.021) and distant metastasis-free survival (DMFS) (89.2% vs. 80.8%, p = 0.051) in comparison with the NIGHT subgroup. Moreover, multivariate analysis showed that daytime RT was an independent prognostic factor for OS, PFS, and DMFS. Furthermore, daytime RT delivery was associated with an increase in the incidence of leukopenia and radiation dermatitis. RT delivery in SUMMER influenced only the OS significantly (before PSM: p = 0.051; after PSM: p = 0.034). There was no association between toxicity and the timing of RT delivery by season. In LA-NPC, the daytime of radical RT served as an independent prognostic factor. Furthermore, RT administered in the morning resulted in more severe toxic side effects than that at night, which needs to be confirmed in a future study.

The conundrum of total neoadjuvant therapy in rectal cancer.

Total neoadjuvant therapy (TNT) has fast become the paradigm in the management of rectal cancer. The widespread adoption of this approach across the world, not only for locally advanced cancers but even for cancers that otherwise would not merit chemotherapy, leads both to an increase in treatment-related toxicity for patients and burdens the healthcare services of the country. It is important to tailor treatment to each patient based not only on the tumour but, even more importantly, on the patient's expectations and goals. The intent of treatment while prescribing TNT needs to be clear, understanding that not all patients are suitable for an organ preservation (watch and wait) approach and that the survival benefits of TNT are not as obvious as most proponents believe.

A Single-center Experience of Radiotherapy in Pediatric Ewing Sarcoma/Primitive Neuroectodermal Tumor of the Chest Wall.

To evaluate the treatment results, prognostic parameters, and treatment-related toxicity in patients with Ewing sarcoma (ES)/primitive neuroectodermal tumor (PNET) of the chest wall who underwent surgery, chemotherapy, and radiotherapy (RT) in a tertiary referral center. The data of 24 patients under 18 years of age with a histologic diagnosis of ES/PNET in the chest wall that received RT in our department between February 2003 and July 2020 were retrospectively evaluated. RT was applied to the primary site±whole involved chest wall and to the whole lung in patients with lung metastasis. The median age was 8.5 years (range: 1.5 to 17y), 15 (63%) patients were female and 9 were male (37%). The tumor localization was extrathoracic in 18 (75%) and intrathoracic in 6 (25%) patients. Mediastinal lymph node and distant metastasis (DM) was present in 5 (21%) and 4 (16%) cases at diagnosis, respectively. The median follow-up after RT was 47 months (range: 11 to 162mo). The 2-year and 5-year overall survival, event-free survival, local recurrence-free survival, and pleural recurrence-free survival were 83% and 48%, 48% and 42%, 74% and 48%, and 61% and 52%, respectively. The overall local control rate was 83% and the pleural control rate was 67%. RT was well tolerated, with 1 case of grade 3 acute dermatitis and 1 case of grade 3 subacute radiation pneumonitis. Late toxicity was observed in 3 (13%) cases. Long-term survival can be achieved with extended-field RT even in patients with ES/PNET of the chest wall with DM. The low toxicity rates allow us to draw the conclusion that RT with modern techniques is an effective and safe treatment modality for these patients.

Clinical experience of consolidative radiotherapy for localized metastatic non-small cell lung cancer who showed favorable tumor response after systemic treatment

BackgroundOur study has aimed to assess the effects of consolidative high-dose radiotherapy on clinical outcomes in patients with localized metastatic non-small cell lung cancer (NSCLC) who showed favorable tumor response after systemic treatment.MethodsWe retrospectively reviewed the medical records of 83 patients with localized metastatic NSCLC, who received systemic therapy followed by consolidative local radiotherapy at the Korea University Guro Hospital between March 2017 and June 2022. In the current study, we defined localized metastatic disease as the presence of one to three metastatic sites at the time of diagnosis. And patients who showed favorable tumor response after systemic treatment, including oligo-progressive disease at the thoracic site which was amenable to curative high-dose local radiotherapy, were included. The planned total dose and fraction size mainly depended on the location of lesions.ResultsThe median follow-up time after consolidative radiotherapy was 16 months (range: 5–52 months). The overall 2-year progression-free survival rates were 81.4%. Of 83 patients, only four (4.3%), treated with intensity-modulated radiation therapy, showed an in-field local recurrence. Interestingly, only one patient experienced a local failure among the 20 patients who showed an oligo-progressive disease at the thoracic site on the tumor response evaluation after systemic treatment. Regarding treatment-related pulmonary toxicity, three patients with grade-3 and one patient with grade-4 radiation pneumonitis were presented.ConclusionsIf the disease is sufficiently controlled and localized by systemic therapy, local consolidative radiotherapy is thought to improves local control rates with acceptable treatment-related toxicities in patients with localized metastatic NSCLC, especially those with oligo-progressive disease.

Sarcopenia predicts short-term treatment-related toxicity in patients undergoing curative-intent therapy for head and neck cancer: A systematic review and meta-analysis.

Sarcopenia is an increasingly recognized biomarker associated with poorer outcomes. The objective of this study was to ascertain the effect of sarcopenia on treatment tolerance and short-term toxicity in head and neck cancer (HNC). A systematic review was performed using multiple databases. An inverse-variation, random-effects model was used to perform the meta-analysis to evaluate the effect of sarcopenia on severe treatment toxicity and poor treatment tolerance. Sixteen observational studies, including 3187 patients with HNC, were analyzed. The combined odds ratio (OR) for severe treatment toxicity and tolerance was 2.22 (95%CI 1.50-3.29) and 1.40 (95%CI 0.84-2.32), respectively. The effect of sarcopenia on short-term severe treatment toxicity was similar with upfront surgery (OR 2.03, 95%CI 1.22-3.37) and definitive radiotherapy (OR 2.24, 95%CI 1.18-4.27) Patients with sarcopenia are more than twice as likely to suffer a short-term treatment-related toxicity when undergoing curative-intent HNC treatment.

Adverse Events Relating to Radiation Therapy in Patients with Collagen Vascular Disorders

To evaluate treatment related toxicity in patients with collagen vascular disorder (CVD) undergoing contemporary radiotherapy. This is a retrospective cohort study of patients with CVD undergoing radiation therapy from 2005 to 2022 at a single institution. CVD evaluated included lupus, scleroderma, rheumatoid arthritis, and Sjogren's syndrome or other nonspecific CVD. Patient characteristics, diagnostic and treatment information were extracted from various institutional EMR systems. This study was designated the status of EXEMPT by the institutional IRB. A total of 40 patients undergoing 44 treatment courses with a minimum follow up of 3 months are included in this study. Among the 40 patients identified, 8 were male and 32 were female, with a median age of 62 (range, 17 to 88). Out of the 40 patients in our study, 30 were diagnosed with lupus, 6 with scleroderma, and 4 with other CVDs. In regard to treatments, 38 were performed for malignant conditions and 6 for benign conditions. Treatment locations included 10 to the head and neck region, 16 to the thorax, 6 to the pelvis, and 11 to the skin, soft tissue, or other locations. Treatment modalities were protons for 6 treatments, photons for 33 treatments, and electrons for 5 treatments. Ten patients also received chemotherapy concurrently. Median follow up time was 33.2 months. Table 1 illustrates the extent of skin and subcutaneous reaction by treatment region and radiation doses. One patient, who had Grade 3 radiation dermatitis, underwent a short break in RT due to severity of symptoms. Three patients experienced severe, painful lupus flares during the course of RT, but were managed by medication; however, one was hospitalized due to severe pain and blistering of the skin. Two patients experienced radiation related dermal thickening and fibrosis of the treatment area skin. Contemporary radiation techniques may allow for the treatment of patients with significant collagen vascular disorders. In general, the treatments are well tolerated with the most common side effects relating to skin and subcutaneous tissue or flare up in generalized symptoms. However, the time to resolution of these symptoms may be longer and requires diligent care. Caution should be used in treating patients with CVD.

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.

Compliance and Toxicity of Total Neoadjuvant Therapy for Rectal Cancer: A Secondary Analysis of the OPRA Trial

Patients with locally advanced rectal cancer treated with total neoadjuvant therapy (TNT) may achieve organ preservation without a compromise to oncologic outcomes. However, reports on patient compliance with TNT and with treatment-related toxicities are limited. The OPRA trial assessed organ preservation rates and oncologic outcomes in patients with clinical stage II/III rectal adenocarcinoma randomized to induction chemotherapy followed by chemoradiation (INCT-CRT) or chemoradiation followed by consolidation chemotherapy (CRT-CNCT). Systemic chemotherapy consisted of 8 cycles (16 weeks) of fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or 5 cycles (15 weeks) of capecitabine and oxaliplatin (CAPEOX). Patients received >4500 cGy of radiation with sensitizing capecitabine or fluorouracil. In this report, we compare compliance and treatment-related toxicity in patients receiving INCT-CRT versus CRT-CNCT. Additionally, we evaluate the association of compliance to chemotherapy, compliance to chemoradiation, and toxicity with organ preservation and disease-free survival (DFS). Of the 324 patients randomized, fewer patients started chemoradiation in the INCT-CRT group compared with the CRT-CNCT group (93% vs 98%, P=.03), and fewer patients started systemic chemotherapy in the CRT-CNCT group compared with the INCT-CRT group (94% vs 99%, P=.04). Order of TNT did not affect the ability to complete all intended cycles of FOLFOX (86% INCT-CRT vs 83% CRT-CNCT, P=.60) or CAPEOX (74% INCT-CRT vs 77% CRT-CNCT, P=.80). A total of 97% of INCT and 98% of CRT-CNCT patients received >4500 cGy radiation (P=.93). Sixty-four patients (41%) treated with INCT-CRT and 57 CRT-CNCT patients (34%) experienced a grade 3+ adverse event (P=.30). Compliance and toxicity were not associated with organ preservation or DFS. We identified only minor differences in treatment compliance between patients treated with INCT-CRT and CRT-CNCT. No difference in adverse events was observed between groups. Treatment compliance and toxicity did not correlate with organ preservation rates or DFS.

Application of big data analyses to compare the impact of oral and gastrointestinal mucositis on risks and outcomes of febrile neutropenia and septicemia among patients hospitalized for the treatment of leukemia or multiple myeloma.

Oral ulcerative mucositis (UM) and gastrointestinal mucositis (GIM) have been associated with increased likelihood of systemic infection (bacteremia and sepsis) in patients being treated for hematological malignancies. To better define and contrast differences between UM and GIM, we utilized the United States 2017 National Inpatient Sample and analyzed patients hospitalized for the treatment of multiple myeloma (MM) or leukemia. We utilized generalized linear models to assess the association between adverse events-UM and GIM-among hospitalized MM or leukemia patients and the outcome of febrile neutropenia (FN), septicemia, burden of illness, and mortality. Of 71,780 hospitalized leukemia patients, 1255 had UM and 100 GIM. Of 113,915 MM patients, 1065 manifested UM and 230 had GIM. In an adjusted analysis, UM was significantly associated with increased risk of FN in both the leukemia (aOR = 2.87, 95% CI = 2.09-3.92) and MM cohorts (aOR = 4.96, 95% CI = 3.22-7.66). Contrastingly, UM had no effect on the risk of septicemia in either group. Likewise, GIM significantly increased the odds of FN in both leukemia (aOR = 2.81, 95% CI = 1.35-5.88) and MM (aOR = 3.75, 95% CI = 1.51-9.31) patients. Similar findings were noted when we restricted our analysis to recipients of high-dose condition regimens in preparation for hematopoietic stem-cell transplant. UM and GIM were consistently associated with higher burden of illness in all the cohorts. This first use of big data provided an effective platform to assess the risks, outcomes, and cost of care of cancer treatment-related toxicities in patients hospitalized for the management of hematologic malignancies.

Sarcopenia detected with bioelectrical impedance versus CT scan and chemotherapy tolerance in patients with early breast cancer.

Early breast cancer (EBC) is a potentially curable disease. Some patients with EBC require chemotherapy, exposing patients to undesirable side effects. Loss of muscle mass, or sarcopenia, has been associated with worse outcomes in patients with EBC and worse treatment-related toxicity in patients with advanced breast cancer. CT scans can identify sarcopenia; however, most patients with EBC do not require routine CT scans. Bioelectrical impedance spectrometry (BIS) is another method to detect sarcopenia and can be performed quickly in the office without radiation exposure. We sought to investigate whether sarcopenia measurements by CT scan versus BIS correlated with each other and whether sarcopenia identified by each method is associated with chemotherapy toxicity and adherence in patients with EBC. This is a retrospective study; eligible patients received chemotherapy treatment for EBC and had undergone BIS. A subset of patients had also had a CT abdomen with a Lumbar L3 level. Measures of sarcopenia were obtained from the BIS and CT data. In addition, patient characteristics, treatment, and toxicity-related outcomes were obtained from medical records. Multivariate logistic regression models were used to associate sarcopenia status with toxicity endpoints, adjusted for other patient characteristics. There was a moderate correlation between sarcopenia detected by CT scan and BIS (r = 0.64 p < 0.0001). Patients with sarcopenia detected by BIS had more chemotherapy toxicity (OR = 2.56; CI 1.72-3.84), dose reductions or dose delays (OR = 1.58; CI 1.06-2.38), and hospitalizations (OR = 2.38; CI 1.33-4.16) due to side effects than patients without sarcopenia. The presence of sarcopenia in patients with EBC is associated with worse chemotherapy tolerance. BIS represents a high-value alternative to CT scans for sarcopenia assessment.

Treatment-related toxicities associated with hospitalization in children, adolescents, and young adults with acute lymphoblastic leukemia: population level analysis

Treatment-related toxicities (TRTs) are a potential cause of survival disparities in patients with acute lymphoblastic leukemia (ALL). We aimed to identify the most frequent TRTs associated with hospitalizations at a population level in children, adolescents and young adults (AYAs). We used the California Cancer Registry linked to a statewide hospital discharge database to identify children and AYAs with TRTs within 3 years of diagnosis. We assessed the frequency of TRTs, length of stay (LOS), admission rates associated with TRTs and TRTs impact on survival. Febrile neutropenia, hypertension, and thrombocytopenia were the most common TRTs for both children and AYAs. AYAs had longer median LOS compared to children for most toxicities. AYAs at non-specialized cancer centers (SCCs) had higher frequency of admissions associated with TRTs compared to non-SCC. Cardiovascular, respiratory, gastrointestinal, renal, and infectious TRTs were associated with worse survival. This study demonstrates the burden of TRTs in patients with ALL.

Which Type of Exercise During Radiation Therapy Is Optimal to Improve Fatigue and Quality of Life in Men with Prostate Cancer? A Bayesian Network Analysis

ContextPhysical exercise in men with prostate cancer (CaP) has shown benefits in improving cancer-related fatigue (CRF) and quality of life (QoL) during radiation therapy. However, types of exercises that are more effective are not well understood. Evidence acquisitionWe searched PubMed, Web of Science, and ClinicalTrials.gov up to November 2021 to identify potentially relevant studies. Randomized controlled trials (RCTs) testing the effects of exercise training on CRF, QoL, and treatment-related toxicities in patients with CaP undergoing radiation therapy were included. The quality of individual studies was evaluated using the Tool for the assEssment of Study qualiTy and reporting in Exercise (TESTEX) scale. The certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation method. A meta-regression analysis was conducted to test the study-level covariates. A random-effect network meta-analysis was conducted based on a Bayesian model. Evidence synthesisEight RCTs with 466 participants were included. Exercise achieved significant improvements in CRF (standardized mean difference [SMD] = 1.24, 95% confidence interval or CI [0.43, 2.06], I2 = 93%) and QoL (SMD = 1.40, 95% CI [0.05, 2.75], I2 = 95%). Based on the meta-regression and Bayesian model, combined moderate-intensity continuous training aerobic exercise and resistance exercise (MICT/RES) showed the highest probability of ranking first in terms of CRF and QoL improvement, but the results of QoL were unstable. Exercise training also had a positive effect on urinary toxicities (SMD = –0.53, 95% CI [–0.79, –0.27], I2 = 0%). A subgroup analysis indicated that MICT/RES might be the most promising exercise modality for reducing intestinal toxicities (SMD = –1.76, 95% CI [–2.32, –1.20]). ConclusionsMICT/RES might be superior to any other types of exercise at reducing CRF. MICT/RES was more effective on significantly mitigating urinary and intestinal toxicities. Patient summaryIn prostate cancer (CaP) survivors during radiation therapy, exercise training is an effective and safe intervention to reduce cancer-related fatigue (CRF) and improve quality of life (QoL), and should be prescribed as a rehabilitation option for clinical management. As for the types of exercises, moderate-intensity continuous training aerobic exercise and resistance exercise seem to be the most effective interventions to reduce CRF, improve QoL, and mitigate treatment-related symptoms.

The Insider: Impact of the Gut Microbiota on Cancer Immunity and Response to Therapies in Multiple Myeloma.

The human microbiota is a unique set of microorganisms colonizing the human body and evolving within it from the very beginning. Acting as an insider, the microbiota provides nutrients, and mutualistically interacts with the host’s immune system, thus contributing to the generation of barriers against pathogens. While a strong link has been documented between intestinal dysbiosis (i.e., disruption to the microbiota homeostasis) and diseases, the mechanisms by which commensal bacteria impact a wide spectrum of mucosal and extramucosal human disorders have only partially been deciphered. This is particularly puzzling for multiple myeloma (MM), a treatable but incurable neoplasia of plasma cells that accumulate in the bone marrow and lead to end-organ damage. Here we revise the most recent literature on data from both the bench and the bedside that show how the gut microbiota modulates cancer immunity, potentially impacting the progression of asymptomatic monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM) to full blown MM. We also explore the effect of the gut microbiome on hematopoietic stem cell transplantation, chemotherapy, immunomodulating therapy and cancer immunotherapy in MM patients. Additionally, we identify the most cogent area of investigation that have the highest chance to delineate microbiota-related and pathobiology-based parameters for patient risk stratification. Lastly, we highlight microbiota-modulating strategies (i.e., diet, prebiotics, probiotics, fecal microbiota transplantation and postbiotics) that may reduce treatment-related toxicity in patients affected by MM as well as the rates of undertreatment of SMM patients.

Upfront DPYD Genotyping and Toxicity Associated with Fluoropyrimidine-Based Concurrent Chemoradiotherapy for Oropharyngeal Carcinomas: A Work in Progress.

Simple SummaryThe combination of carboplatin and 5-fluorouracil (5-FU) is effective when used concurrently with radiotherapy for locoregionally advanced oropharyngeal carcinomas. DPYD polymorphisms can be associated with an increased risk of severe toxicity to fluoropyrimidines. Upfront screening for the DPYD*2A allele has been available in the province of Québec, Canada, since March 2017. This study aimed to determine the effect of upfront genotyping on the incidence of grade ≥3 toxicities. We included 181 patients in the analysis. Extended screening for three supplemental at-risk DPYD variants was also retrospectively performed in August 2019. The DPYD*2A, c.2846A>T and c.1236G>A polymorphisms were associated with an increased risk of grade ≥3 toxicity to 5-FU. Upfront DPYD genotyping can thus identify patients in whom 5-FU-related toxicity should be avoided.Background: 5-FU-based chemoradiotherapy (CRT) could be associated with severe treatment-related toxicities in patients harboring at-risk DPYD polymorphisms. Methods: The studied population included consecutive patients with locoregionally advanced oropharyngeal carcinoma treated with carboplatin and 5-FU-based CRT one year before and after the implementation of upfront DPYD*2A genotyping. We aimed to determine the effect of DPYD genotyping on grade ≥3 toxicities. Results: 181 patients were analyzed (87 patients before and 94 patients following DPYD*2A screening). Of the patients, 91% (n = 86) were prospectively genotyped for the DPYD*2A allele. Of those screened, 2% (n = 2/87) demonstrated a heterozygous DPYD*2A mutation. Extended genotyping of DPYD*2A-negative patients later allowed for the retrospective identification of six additional patients with alternative DPYD variants (two c.2846A>T and four c.1236G>A mutations). Grade ≥3 toxicities occurred in 71% of the patients before DPYD*2A screening versus 62% following upfront genotyping (p = 0.18). When retrospectively analyzing additional non-DPYD*2A variants, the relative risks for mucositis (RR 2.36 [1.39–2.13], p = 0.0063), dysphagia (RR 2.89 [1.20–5.11], p = 0.019), and aspiration pneumonia (RR 13 [2.42–61.5)], p = 0.00065) were all significantly increased. Conclusion: The DPYD*2A, c.2846A>T, and c.1236G>A polymorphisms are associated with an increased risk of grade ≥3 toxicity to 5-FU. Upfront DPYD genotyping can identify patients in whom 5-FU-related toxicity should be avoided.

Fractionated Radiotherapy for Pleomorphic Adenoma

Purpose/Objective(s)Pleomorphic adenoma is the most common benign salivary gland tumor. It is primarily treated with definitive surgery. Rarely, radiation therapy can be utilized for recurrent lesions and in other scenarios such as positive margins. There are relatively few studies reporting efficacy and outcomes of pleomorphic adenoma treated with radiation therapy. The purpose of this project is to report tumor control, complications, and survival outcomes of patients treated with fractionated radiotherapy at our institution with pleomorphic adenoma.Materials/MethodsThis was a retrospective analysis of survival outcomes and treatment-related toxicity in patients with pleomorphic adenoma treated with fractionated radiotherapy at our institution between 1970 and 2016. We excluded patients who did not have a histologic diagnosis and those with prior unrelated head or neck radiation. We identified 35 patients who met these criteria. The Kaplan-Meier product limit method was utilized to assess time-dependent endpoints.ResultsMedian clinical follow-up was 9.1 years and median imaging follow-up was 6.9 years. The 15-year cause-specific survival rate was 86% and the 15-year overall survival rate was 68%. The rate of 15-year local control was 64%; however, 42% of patients with local failures were ultimately successfully controlled with salvage therapies. The rate of patients who experienced grade 3 or higher CTCAE toxicity was 17%.ConclusionTo the best of our knowledge, this study comprises the largest cohort of pleomorphic adenoma patients treated with fractionated radiotherapy in the last 25 years. Our data suggests that radiation therapy is efficacious and minimally toxic in this rare clinical scenario. Furthermore, in patients who do recur following radiation therapy, there is a relatively high rate of successful salvage. Pleomorphic adenoma is the most common benign salivary gland tumor. It is primarily treated with definitive surgery. Rarely, radiation therapy can be utilized for recurrent lesions and in other scenarios such as positive margins. There are relatively few studies reporting efficacy and outcomes of pleomorphic adenoma treated with radiation therapy. The purpose of this project is to report tumor control, complications, and survival outcomes of patients treated with fractionated radiotherapy at our institution with pleomorphic adenoma. This was a retrospective analysis of survival outcomes and treatment-related toxicity in patients with pleomorphic adenoma treated with fractionated radiotherapy at our institution between 1970 and 2016. We excluded patients who did not have a histologic diagnosis and those with prior unrelated head or neck radiation. We identified 35 patients who met these criteria. The Kaplan-Meier product limit method was utilized to assess time-dependent endpoints. Median clinical follow-up was 9.1 years and median imaging follow-up was 6.9 years. The 15-year cause-specific survival rate was 86% and the 15-year overall survival rate was 68%. The rate of 15-year local control was 64%; however, 42% of patients with local failures were ultimately successfully controlled with salvage therapies. The rate of patients who experienced grade 3 or higher CTCAE toxicity was 17%. To the best of our knowledge, this study comprises the largest cohort of pleomorphic adenoma patients treated with fractionated radiotherapy in the last 25 years. Our data suggests that radiation therapy is efficacious and minimally toxic in this rare clinical scenario. Furthermore, in patients who do recur following radiation therapy, there is a relatively high rate of successful salvage.

Machine Learning Classifier Using Pretreatment Factors to Predict Radiation Pneumonitis Following Stereotactic Body Radiation Therapy for Lung Cancer

<h3>Purpose/Objective(s)</h3> Symptomatic radiation pneumonitis (RP) is a common cause of treatment related toxicity in patients receiving radiation therapy for lung cancer. Machine learning techniques have been utilized to determine predictors of RP, but most of these models have used dosimetric features to generate results. The identification of pretreatment factors related to the development of symptomatic RP and implementation of these factors into a machine learning model would be clinically useful to guide treatment decisions, risk estimation, and risk reduction of development of symptomatic RP. <h3>Materials/Methods</h3> We retrospectively reviewed data from 278 lung cancer patients that underwent stereotactic body radiation therapy (SBRT). Pretreatment factors including patient demographics, pulmonary function data, and tumor characteristics were previously analyzed for the development of symptomatic RP, defined as CTCAE v4.0 ≥ Grade 2. A programming environment was used to generate classification machine learning models based on this dataset. Models were tested for accuracy in classification, area-under-the-curve (AUC), and special attention was paid to the false negative rate. The performance of several different algorithms using various combinations of predictors was evaluated including Decision Trees, Discriminant Analysis, Logistic Regression, Naive Bayes Classifiers, Support Vector Machines, Nearest Neighbor Classifiers and Ensemble Classifiers. Each model utilized 5-fold cross-validation to prevent overfitting. <h3>Results</h3> Of the 278 patients receiving SBRT, 42 patients (15.1%) developed symptomatic RP. A RUSBoosted Trees Ensemble Classifier was found to be the most accurate model tested. Features identified as significant risk factors for symptomatic RP in prior univariate and multivariate analyses were found to be the most important predictors in the machine learning models tested. These features included prior radiation treatment to the thorax or lung resection, location of tumor in the right lower lobe, a higher T Stage and age. When this model was used to classify cases of symptomatic RP, it had an AUC of 0.86 and an accuracy of 87%, correctly predicting 36 out of 42 pneumonitis cases. The model had a false negative rate of 14% and false positive rate of 13%. <h3>Conclusion</h3> A machine learning model was developed to identify pretreatment factors predictive of symptomatic RP. The advantage of this model when compared to others with a similar goal is that it depends solely on pretreatment factors, and therefore could be applied in a clinical setting prior to radiation therapy. Next steps include testing with an independent dataset to confirm the model's accuracy and prospective studies to verify the model's clinical utility.

The benefit of MR-only radiotherapy treatment planning for anal and rectal cancers: A planning study.

IntroductionLimited evidence exists showing the benefit of magnetic resonance (MR)‐only radiotherapy treatment planning for anal and rectal cancers. This study aims to assess the impact of MR‐only planning on target volumes (TVs) and treatment plan doses to organs at risks (OARs) for anal and rectal cancers versus a computed tomography (CT)‐only pathway.Materials and methodsForty‐six patients (29 rectum and 17 anus) undergoing preoperative or radical external beam radiotherapy received CT and T2 MR simulation. TV and OARs were delineated on CT and MR, and volumetric arc therapy treatment plans were optimized independently (53.2 Gy/28 fractions for anus, 45 Gy/25 fractions for rectum). Further treatment plans assessed gross tumor volume (GTV) dose escalation. Differences in TV volumes and OAR doses, in terms of Vx Gy (organ volume (%) receiving x dose (Gy)), were assessed.ResultsMR GTV and primary planning TV (PTV) volumes systematically reduced by 13 cc and 98 cc (anus) and 44 cc and 109 cc (rectum) respectively compared to CT volumes. Statistically significant OAR dose reductions versus CT were found for bladder and uterus (rectum) and bladder, penile bulb, and genitalia (anus). With GTV boosting, statistically significant dose reductions were found for sigmoid, small bowel, vagina, and penile bulb (rectum) and vagina (anus).ConclusionOur findings provide evidence that the introduction of MR (whether through MR‐only or CT‐MR pathways) to radiotherapy treatment planning for anal and rectal cancers has the potential to improve treatments. MR‐related OAR dose reductions may translate into less treatment‐related toxicity for patients or greater ability to dose escalate.

The Potential for Midtreatment Albumin-Bilirubin (ALBI) Score to Individualize Liver Stereotactic Body Radiation Therapy.

Our individualized functional response adaptive approach to liver stereotactic body radiation therapy (SBRT) with assessment of indocyanine green (ICG) retention at baseline and midtreatment to detect subclinical changes in liver function, permitting dose adjustment, has decreased toxicity while preserving efficacy. We hypothesized that assessment of the albumin-bilirubin (ALBI) score at baseline and midtreatment would allow for more practical identification of patients at risk for treatment-related toxicity (TRT). Patients with hepatocellular carcinoma were treated on 3 prospective institutional review board-approved trials using baseline and midtreatment ICG to deliver individualized functional response adaptive liver SBRT. Patients received 3 or 5 fractions, with fraction 3 followed by a 1-month treatment break. TRT was a ≥2-point rise in Child-Pugh score within 6 months of SBRT. Logistic regression was used to estimate odds ratios (ORs) and confidence intervals (CIs) for assessment of TRT. Area under the receiver operating curve was used to compare predictive ability across models. In total, 151 patients underwent 166 treatments. Baseline Child-Pugh class and ALBI grade were A (66.9%), B (31.3%), or C (1.8%) and 1 (25.9%), 2 (65.7%), or 3 (8.4%), respectively. Thirty-five patients (20.3%) experienced TRT. On univariate analysis, baseline ALBI (OR, 1.8; 95% CI, 1.24-2.62; P=.02), baseline ICG (OR, 1.66; 95% CI, 1.17-2.35; P=.04), and change in ALBI (OR, 3.07; 95% CI, 1.29-7.32; P=.003) were associated with increased odds of TRT. ALBI-centric models performed similarly to ICG-centric models on multivariate analyses predicting toxicity (area under the receiver operating curve of 0.79 for both). In a model incorporating baseline and midtreatment change in ALBI and ICG, both ALBI values were statistically significantly associated with toxicity, whereas ICG values were not. Incorporation of midtreatment change in ALBI in addition to baseline ALBI improves the ability to predict TRT in patients with hepatocellular carcinoma receiving SBRT. Our findings suggest that functional response adaptive treatment could be implemented in a practical manner because the ALBI score is easily obtained from standard laboratory values.

Oral manifestations of immune-related adverse events in cancer patients treated with immune checkpoint inhibitors.

Immunotherapy with immune checkpoint inhibitors (ICIs) has transformed cancer treatment over the past decade, improving survival rates in numerous advanced cancers. Immune-related adverse events (irAEs) are common and can affect any organ system, with many of these toxicities being well-characterized with clear grading criteria and management approaches. There has been less emphasis on oral manifestations of irAEs. This review provides an overview of oral manifestations of irAEs, including mucosal and salivary gland toxicities, and proposes a grading system and management guidelines. irAEs are common treatment-related toxicities in patients treated with ICIs. Oral irAEs can range from asymptomatic white reticulations to life-threatening mucocutaneous reactions requiring aggressive management with corticosteroids and/or permanent discontinuation of ICIs. Oral healthcare providers should be prepared to identify and manage oral irAEs in collaboration with oncologists and other specialists.

Avatrombopag, a Novel Oral Thrombopoietin Receptor Agonist, Demonstrates Superiority to Placebo for the Treatment of Chronic Immune Thrombocytopenic Purpura in a Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial

Background: Avatrombopag (AVA) is an oral, 2nd generation thrombopoietin receptor agonist (TPO-RA) currently in development for the treatment of thrombocytopenia. Two other TPO-RAs have been approved for the treatment of chronic immune thrombocytopenic purpura (ITP) refractory to corticosteroids, immunoglobulins, or splenectomy, to maintain platelet counts and reduce the incidence of bleeding. Given the need for chronic administration, it is important to minimize treatment-related toxicities in patients with ITP. This trial investigated the efficacy and safety of AVA versus placebo (PBO) for the treatment of patients with chronic ITP in a multicenter, multinational, randomized, parallel group, PBO-controlled Phase 3 trial (NCT01438840). The once daily oral dosing of AVA, which can be taken with food, has no signal for hepatotoxicity, and a reliable pharmacokinetic-pharmacodynamic response profile due to limited metabolism of the parent molecule may provide advantages for its use in patients with ITP.Methods: Adult patients (age ≥18 years) with chronic ITP (Baseline platelet count <30 X 109/L) were recruited from 27 study sites and randomized 2:1 to 20 mg/day AVA or PBO over the 6-month study period. Dose titration of AVA and PBO were permitted based on individual responses (final dose range: 5-40 mg/day). Patients and investigators were blinded to treatment which was given in addition to standard of care. The primary efficacy endpoint was the number of cumulative weeks with a platelet response defined as a platelet count ≥50 x 109/L, in the absence of rescue therapy. Secondary endpoints included platelet response at Day 8, and the proportion of patients with a reduction in concomitant ITP medications from Baseline. Safety analyses included the monitoring of adverse events (AE) and clinical laboratory results.Results: In total, 49 patients met eligibility criteria and were included in the full analysis set and safety analysis sets. The majority of patients were White (93.9%) and female (63.3%) with a mean age of 44.6 years. At Baseline, 67.3% had not been splenectomized, 55.1% did not use concomitant ITP medication, and ~30% had received >5 previous ITP medications. The AVA treatment group included 32 patients; 22 (68.8%) completed the study. In the PBO group, which included 17 patients, only one (5.9%) completed the study. The most common reason for study discontinuation was inadequate therapeutic effect, which was lower in the AVA treatment group (21.9%) compared with the PBO group (88.2%).AVA was superior to PBO in the mean cumulative number of weeks with a platelet count ≥50 x 109/L during the 6-month treatment period, the primary study endpoint (12.4 weeks vs 0 weeks; P<0.0001). Day 8 platelet responses were also significantly higher for patients who received AVA treatment, 65.6% compared with 0% for PBO (P<0.0001). The proportion of AVA-treated patients with reduced concomitant ITP medication use from Baseline was 33.3% compared with 0% in PBO-treated subjects, although this treatment difference was not significant (P=0.1348). A durable platelet response, defined as the proportion of subjects who had at least 6 out of 8 weekly platelet responses during the last 8 weeks of treatment in the absence of rescue therapy, was observed in significantly more AVA-treated patients (34.3%) compared with PBO-treated patients (0%; P=0.009).Treatment emergent AEs (TEAEs) were reported by 31 patients (96.9%) in the AVA-treated group compared with 10 patients (58.5%) in the PBO-treated group; the incidence of TEAEs, Grade 3/4 TEAEs, and serious AEs were similar in the two treatment groups when adjusted for treatment exposure. The most commonly reported TEAEs included headache, contusion, upper respiratory tract infection, arthralgia, and epistaxis. Five patients had TEAEs leading to study drug dose adjustment in the AVA group, which led to study drug withdrawal for 3 patients. No patients in the PBO treatment group required study drug dose adjustment.Conclusions: AVA is novel 2nd generation TPO-RA that has been shown to be well tolerated and superior to PBO in patients with chronic ITP, as measured by the cumulative number of weeks with a platelet response, platelet response at Day 8, and durability of platelet response. The overall safety profile of AVA was similar to PBO when adjusted for treatment exposure. AVA may potentially provide an additional treatment option for patients with refractory chronic ITP. DisclosuresJurczak:Jagiellonian University: Employment; Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Research Funding; Merck: Research Funding; Celtrion: Research Funding; Spectrum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; Pfizer: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sandoz Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding. Chojnowski:Novo Nordisk: Honoraria; Baxalte: Honoraria. Mayer:Novartis: Research Funding; Eisai: Research Funding. Bibbiani:Eisai, Inc.: Employment.