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Purpose: The purpose of this critical review is to provide an overview of the role and outcomes associated with the use of local therapy for patients with oligometastatic gastrointestinal cancers., Methods and Materials: A review of clinical data was performed to describe outcomes associated with the use of systemic therapy and/or locoregional therapies for patients with oligometastatic gastrointestinal cancers including esophagus, gastric, liver, biliary, pancreas, colorectal, and anal canal., Results: This review describes outcomes associated with current first line systemic therapy and oligometastasis directed locoregional therapy for patients with gastrointestinal cancers. Available data suggest that for well-selected patients among each gastrointestinal disease subsite, the use of local therapy is associated with favorable disease control and possible survival benefit., Conclusions: These data emphasize the importance of multidisciplinary collaboration and consideration of radiation therapy for patients with oligometastatic gastrointestinal cancers to improve locoregional control and progression-free survival. Multiple trials are ongoing to determine whether metastasis-directed radiation therapy improves overall survival., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Patients with gastrointestinal (GI) cancer frequently experience unplanned hospitalizations, but predictive tools to identify high-risk patients are lacking. We developed a machine learning model to identify high-risk patients., Methods and Materials: In the study, 1341 consecutive patients undergoing GI (abdominal or pelvic) radiation treatment (RT) from March 2016 to July 2018 (derivation) and July 2018 to January 2019 (validation) were assessed for unplanned hospitalizations within 30 days of finishing RT. In the derivation cohort of 663 abdominal and 427 pelvic RT patients, a machine learning approach derived random forest, gradient boosted decision tree, and logistic regression models to predict 30-day unplanned hospitalizations. Model performance was assessed using area under the receiver operating characteristic curve (AUC) and prospectively validated in 161 abdominal and 90 pelvic RT patients using Mann-Whitney rank-sum test. Highest quintile of risk for hospitalization was defined as "high-risk" and the remainder "low-risk." Hospitalizations for high- versus low-risk patients were compared using Pearson's χ 2 test and survival using Kaplan-Meier log-rank test., Results: Overall, 13% and 11% of patients receiving abdominal and pelvic RT experienced 30-day unplanned hospitalization. In the derivation phase, gradient boosted decision tree cross-validation yielded AUC = 0.823 (abdominal patients) and random forest yielded AUC = 0.776 (pelvic patients). In the validation phase, these models yielded AUC = 0.749 and 0.764, respectively (P < .001 and P = .002). Validation models discriminated high- versus low-risk patients: in abdominal RT patients, frequency of hospitalization was 39% versus 9% in high- versus low-risk groups (P < .001) and 6-month survival was 67% versus 92% (P = .001). In pelvic RT patients, frequency of hospitalization was 33% versus 8% (P = .002) and survival was 86% versus 92% (P = .15) in high- versus low-risk patients., Conclusions: In patients with GI cancer undergoing RT as part of multimodality treatment, machine learning models for 30-day unplanned hospitalization discriminated high- versus low-risk patients. Future applications will test utility of models to prompt interventions to decrease hospitalizations and adverse outcomes., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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 RT with 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., (Published by Elsevier Inc.)

Purpose: Older patients undergoing radiation therapy (RT) for pelvic malignancies are at increased risk for pelvic fracture, which is associated with significant morbidity and mortality. RT techniques such as brachytherapy or intensity modulated RT (IMRT) allow for more conformal dose distributions, but it is not known whether the risk for pelvic fracture varies by RT modality., Methods and Materials: This observational cohort study involved 28,354 patients ≥65 years old, treated with RT for pelvic malignancies. We evaluated the relative risk of pelvic fracture by type of RT when accounting for baseline factors. To test for nonspecific effects, we also evaluated risk of nonpelvic fractures in the same population., Results: The 5-year incidence of pelvic fractures was 12.7% (95% confidence interval [CI], 11.6%-13.8%), 11.8% (10.8%-12.8%), and 3.7% (3.4%-4.0%) for patients with gastrointestinal, gynecologic, and prostate cancer, respectively. On multivariable analysis, being treated with IMRT (hazard ratio, 0.85; 95% CI, 0.73-0.99) or brachytherapy therapy alone (hazard ratio, 0.43; 95% CI, 0.34-0.54) was associated with a reduced hazard for pelvic fractures compared with 3D conformal radiation therapy in female patients. In contrast, there was no association with RT modality and the hazard for nonpelvic fractures among females. There was no significant association between pelvic fractures and IMRT or brachytherapy for male patients. White race, advanced age, and higher comorbidity were associated with an increased hazard for pelvic fracture., Conclusions: IMRT and brachytherapy were associated with a reduced risk of pelvic fractures in older women undergoing RT for pelvic malignancies. Pelvic insufficiency fracture risk should be considered when treating with pelvic RT., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To review and assess ongoing proton beam therapy (PBT) clinical trials and to identify major gaps., Methods and Materials: Active PBT clinical trials were identified from clinicaltrials.gov and the World Health Organization International Clinical Trials Platform Registry. Data on clinical trial disease site, age group, projected patient enrollment, expected start and end dates, study type, and funding source were extracted., Results: A total of 122 active PBT clinical trials were identified, with target enrollment of >42,000 patients worldwide. Ninety-six trials (79%), with a median planned sample size of 68, were classified as interventional studies. Observational studies accounted for 21% of trials but 71% (n=29,852) of planned patient enrollment. The most common PBT clinical trials focus on gastrointestinal tract tumors (21%, n=26), tumors of the central nervous system (15%, n=18), and prostate cancer (12%, n=15). Five active studies (lung, esophagus, head and neck, prostate, breast) will randomize patients between protons and photons, and 3 will randomize patients between protons and carbon ion therapy., Conclusions: The PBT clinical trial portfolio is expanding rapidly. Although the majority of ongoing studies are interventional, the majority of patients will be accrued to observational studies. Future efforts should focus on strategies to encourage optimal patient enrollment and retention, with an emphasis on randomized, controlled trials, which will require support from third-party payers. Results of ongoing PBT studies should be evaluated in terms of comparative effectiveness, as well as incremental effectiveness and value offered by PBT in comparison with conventional radiation modalities., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To assess intrafraction respiratory motion using a commercial kilovoltage imaging system for abdominal tumor patients with implanted fiducials and breathing constrained by pneumatic compression during stereotactic body radiation therapy (SBRT)., Methods and Materials: A pneumatic compression belt limited respiratory motion in 19 patients with radiopaque fiducials in or near their tumor during SBRT for abdominal tumors. Kilovoltage images were acquired at 5- to 6-second intervals during treatment using a commercial system. Intrafractional fiducial displacements were measured using in-house software. The dosimetric effect of the observed displacements was calculated for 3 sessions for each patient., Results: Intrafraction displacement patterns varied between patients and between individual treatment sessions. Averaged over 19 patients, 73 sessions, 7.6% of craniocaudal displacements exceeded 0.5 cm, and 1.2% exceeded 0.75 cm. The calculated single-session dose to 95% of gross tumor volume differed from planned by an average of -1.2% (range, -11.1% to 4.8%) but only for 4 patients was the total 3-session calculated dose to 95% of gross tumor volume more than 3% different from planned., Conclusions: Our pneumatic compression limited intrafractional abdominal target motion, maintained target position established at setup, and was moderately effective in preserving coverage. Commercially available intrafractional imaging is useful for surveillance but can be made more effective and reliable., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: Quality assurance (QA) programs aim to identify inconsistencies that may compromise patient care. Radiation treatment planning is a well-documented source of variation in radiation oncology, leading many organizations to recommend the implementation of QA rounds in which radiation therapy plans are peer reviewed. This study evaluates the outcome of QA rounds that have been conducted by a radiation therapy department since 2004., Methods and Materials: Prospectively documented records of QA rounds, from 2004 to 2010, were obtained. During rounds, randomly selected radiation therapy plans were peer reviewed and assigned a grade of A (adequate), B (minor suggestions of change to a plan for a future patient), or C (significant change required before the next fraction). The proportion of plans that received each recommendation was calculated, and the relationship between recommendations for each plan, tumor site, and mean years of experience of the radiation oncologist (RO) were explored. Chart reviews were performed for each plan that received a C., Results: During the study period, 1247 plans were evaluated; 6% received a B and 1% received a C. The mean RO years of experience were lower for plans graded C versus those graded A (P=.02). The tumor sites with the highest proportion of plans graded B or C were gastrointestinal (14%), lung (13%), and lymphoma (8%). The most common reasons for plans to receive a grade of C were inadequate target volume coverage (36%), suboptimal dose or fractionation (27%), errors in patient setup (27%), and overtreatment of normal tissue (9%)., Conclusions: This study demonstrated that QA rounds are feasible and an important element of a radiation therapy department's QA program. Through peer review, plans that deviate from a department's expected standard can be identified and corrected. Additional benefits include identifying patterns of practice that may contribute to inconsistencies in treatment planning and the continuing education of staff members who attend., (Copyright © 2013 Elsevier Inc. All rights reserved.)

High-Dose-Rate (HDR) brachytherapy is a safe and efficacious treatment option for patients with a variety of different malignancies. Careful adherence to established standards has been shown to improve the likelihood of procedural success and reduce the incidence of treatment-related morbidity. A collaborative effort of the American College of Radiology (ACR) and American Society for Therapeutic Radiation Oncology (ASTRO) has produced a practice guideline for HDR brachytherapy. The guideline defines the qualifications and responsibilities of all the involved personnel, including the radiation oncologist, physicist and dosimetrists. Review of the leading indications for HDR brachytherapy in the management of gynecologic, thoracic, gastrointestinal, breast, urologic, head and neck, and soft tissue tumors is presented. Logistics with respect to the brachytherapy implant procedures and attention to radiation safety procedures and documentation are presented. Adherence to these practice guidelines can be part of ensuring quality and safety in a successful HDR brachytherapy program., (Copyright © 2011. Published by Elsevier Inc.)

Purpose: To identify factors predictive of renal atrophy after chemoradiotherapy of gastrointestinal malignancies., Methods and Materials: Patients who received chemotherapy and abdominal radiotherapy (RT) between 2002 and 2008 were identified for this study evaluating change in kidney size and function after RT. Imaging and biochemical data were obtained before and after RT in 6-month intervals. Kidney size was defined by craniocaudal measurement on CT images. The primarily irradiated kidney (PK) was defined as the kidney that received the greater mean kidney dose. Receiver operating characteristic (ROC) curves were generated to predict risk for renal atrophy., Results: Of 130 patients, median age was 64 years, and 51.5% were male. Most primary disease sites were pancreas and periampullary tumors (77.7%). Median follow-up was 9.4 months. Creatinine clearance declined 20.89%, and size of the PK decreased 4.67% 1 year after completion of chemoradiation. Compensatory hypertrophy of the non-PK was not seen. Percentage volumes of the PK receiving ≥10 Gy (V(10)), 15 Gy (V(15)), and 20 Gy (V(20)) were significantly associated with renal atrophy 1 year after RT (p = 0.0030, 0.0029, and 0.0028, respectively). Areas under the ROC curves for V(10), V(15), and V(20) to predict >5% decrease in PK size were 0.760, 0.760, and 0.762, respectively., Conclusions: Significant detriments in PK size and renal function were seen after abdominal RT. The V(10), V(15), and V(20) were predictive of risk for PK atrophy 1 year after RT. Analyses suggest the association of lower-dose renal irradiation with subsequent development of renal atrophy., (Published by Elsevier Inc.)

Purpose: To analyze clinical and dosimetric factors associated with change in renal function in patients with gastrointestinal malignancies after chemoradiation to the abdomen., Methods and Materials: A retrospective review of 164 patients with gastrointestinal malignancies treated between 2002 and 2007 was conducted to evaluate change in renal function after concurrent chemotherapy and three-dimensional conformal abdominal radiotherapy (RT). Laboratory and biochemical endpoints were determined before RT and after RT at 6-month intervals. Factors assessed included smoking, diabetes, hypertension, blood urea nitrogen, creatinine, creatinine clearance (CrCl), chemotherapy, and dose-volume parameters. Renal toxicity was assessed by decrease in CrCl and scored using the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer late radiation morbidity scoring schema., Results: Of 164 patients, 63 had clinical and dosimetric data available. Median follow-up was 17.5 months. Creatinine clearance declined from 98.46 mL/min before RT to 74.20 mL/min one year after chemoradiation (p < 0.0001). Mean decrease in CrCl was 21.37%. Pre-RT CrCl, percentage of bilateral renal volume receiving at least 10 Gy (V(10)), and mean kidney dose were significantly associated with development of Grade > or =2 renal complications at 1 year after chemoradiation (p = 0.0025, 0.0170, and 0.0095, respectively)., Conclusions: We observed correlation between pre-RT CrCl, V(10), and mean kidney dose and decline in CrCl 1 year after chemoradiation. These observations can assist in treatment planning and renal dose constraints in patients receiving chemotherapy and abdominal RT and may help identify patients at increased risk for renal complications., (Published by Elsevier Inc.)

Purpose: Simple scales with greater sensitivity than Radiation Therapy Oncology Group (RTOG) grading to detect acute gastrointestinal toxicity during pelvic radiotherapy, could be clinically useful., Methods and Materials: Do questionnaires used in benign gastrointestinal diseases detect toxicity in patients undergoing radiotherapy? The patient-completed Inflammatory Bowel Disease (IBDQ) and Vaizey Incontinence questionnaires were compared prospectively at baseline and at Week 5 to physician-completed RTOG grading., Results: A total of 107 patients, median age 63 years, were recruited. After 5 weeks of treatment, patients with gynecologic and gastrointestinal cancer were more symptomatic than urologic patients (p = 0.012; p = 0.014). Overall, 94% had altered bowel habits, 80% loose stool, 74% frequency, 65% difficult gas, 60% pain, >48% distress, 44% tenesmus, >40% restrictions in daily activity, 39% urgency, 37% fecal incontinence, and 40% required antidiarrheal medication. The median RTOG score was 1 (range, 0-2), median IBDQ score 204.5 (range, 74-224), and median Vaizey score 5 (range, 0-20). Chemotherapy preceding radiotherapy increased fecal incontinence (p = 0.002). RTOG scores stabilized after 3 weeks, IBDQ scores peaked at Week 4, and Vaizey scores worsened throughout treatment. IBDQ and Vaizey scores distinguished between groups with different RTOG scores., Conclusion: The IBDQ and Vaizey questionnaires are reliable and sensitive, offering greater insight into the severity and range of symptoms compared with RTOG grading.

To summarize the clinical research activities of the Radiation Therapy Oncology Group program in the treatment of patients with locally advanced, as well as resected, pancreatic cancer. Phase II and III clinical trials are underway, examining novel cytotoxic and targeted agents with irradiation (RT) for patients with locally advanced and resected pancreatic cancer.A Phase II study incorporating concurrent paclitaxel with external beam radiotherapy in the locally advanced setting has been completed and recently analyzed. This experience has served as the foundation of a Phase II study using concurrent paclitaxel and gemcitabine with RT followed by R115777, a farnesyltransferase inhibitor, as maintenance therapy. In the adjuvant treatment of pancreatic cancer, an Intergroup Phase III trial has compared "conventional" postoperative chemoirradiation (5-fluorouracil before, after, and during RT) and gemcitabine before and after RT (with 5-fluorouracil during RT). This study has recently closed, meeting its accrual goal. The successor study will evaluate the use of gemcitabine given concurrently with RT, as well as in a maintenance schedule. This report summarizes current and future Radiation Therapy Oncology Group clinical trials in the treatment of patients with localized pancreatic cancer.

Purpose: We report our clinical experience with 32 patients receiving concurrent irradiation and capecitabine., Methods and Materials: Medical records of patients with gastrointestinal malignancies treated with radiation and capecitabine therapy were reviewed., Results: The population consisted of 20 males and 12 females, with a median age of 67.5 years (45-84 years) and adequate hepatic and bone marrow function. Histology was adenocarcinoma in all patients, except two with esophageal squamous carcinoma. Twenty-one patients received the regimen as adjuvant therapy, three received preoperative therapy, and 8 patients received therapy for palliation. The median dose of capecitabine was 1600 mg/m(2)/day (1200-2500 mg/m(2)/day) orally for 5 days per week for the duration of radiation therapy. Thirty patients received a total dose ranging from 45 Gy to 64 Gy over 4-6 weeks. Two previously radiated patients received total doses of 29.9 Gy and 46 Gy. Grade 3/4 toxicities observed were neutropenia in 3 patients and diarrhea, thrombocytopenia, fatigue, and myocardial infarction in 1 patient each. No treatment-related mortality was observed. Twenty of 21 patients (95.2%) who received adjuvant therapy continue to be in complete remission. Four of 11 (36%) evaluable patients demonstrated a response., Conclusion: Concurrent capecitabine and radiation were very well tolerated and warrant further investigation in prospective trials.

Purpose: Although treatment of a field within a field to deliver a boost dose is quite common with external photon beam radiation therapy, the same is not always true with electron beam radiation or in intraoperative radiation therapy (IORT). The purpose of this work is to report the results and details of a new technique developed to treat a field within a field in intraoperative radiation therapy., Methods and Materials: This technique makes use of the nondocking IORT system currently used at our institution. Treatment is given in two segments: the large field is first treated by using standard circular lucite cones; the second dose segment is delivered using a new circular brass cone designed to fit concentrically within the large lucite cone., Results: Central axis depth dose, surface dose, output factors, and two-dimensional beam profiles have been measured for a 7 cm inner diameter (i.d.) flat lucite cone and 3.8 and 5 cm i.d. flat brass cones for electron beam energies ranging from 4-22 MeV. For different clinical target volumes, summed dose distributions differentially weighted in both energy and dose are presented., Conclusions: A simple technique for delivering differential dose in intraoperative radiation therapy is presented. The technique provides a method for escalating dose to higher values for a defined target volume.

Between March 1982 and October 1987, 375 fields in 187 patients with AIDS-related Kaposi's Sarcoma were treated in the Department of Radiation Oncology at the University of California in San Francisco (UCSF). Field sizes ranging from 2 x 2 cm to total skin received doses of 8 Gy in a single fraction to 15-40 Gy in 5-10 fractions. Seventy-four percent of the patients have died. Response to treatment was achieved in over 90% of treated fields, with a median time to progression of 21 months and an actuarial freedom from relapse at 6 months of 69% (97 patients alive). There was no difference in outcome regardless of the fractionation regimen used. Severe reactions were noted in 17% of treated fields, but this incidence was significantly lower when a single fraction of 8 Gy was used (p less than 0.001). Radiation therapy plays an important palliative role in this devastating disease. This review supports the use of a single 8 Gy fraction for all Kaposi's Sarcoma lesions of the skin. Further data regarding single fraction therapy for lesions of other sites are needed.

We have treated 15 patients with advanced gastrointestinal carcinoma with a cyclical regimen of combined Ftorafur (N1-((2-furanidyl-))-5-Fluorouracil, a 5-FU pro-drug) and external beam radiation. The Ftorafur (FT) was administered orally in daily doses of between 1.0 and 2.5 g/m2/day in 3 divided doses in a Phase I format. The drug was given daily for 5 days along with conventional X ray treatment portals and daily radiation doses of 250 rad on each of the first 4 days of each treatment cycle. The patients were then rested for a minimum of 10 days or until all significant side effects had passed. The total number of 1,000 rad cycles and radiation dose were dictated by tolerance and by normal organ dose limitations. The most common toxicity in general, and the most common limiting toxicity was nausea and vomiting, in contrast to oral FT alone where diarrhea is more prominent. Stomatitis was seen only once and no other form of serious toxicity was encountered. Two-thirds of the patients responded in subjective terms (pain relief). There was 1 partial response to FT alone (pulmonary metastases outside the treatment field). The sole patient whose treatment field was outside the abdomen (chest portals for esophageal carcinoma) developed pneumonitis which contributed to his death. No other delayed effects were noted. Serum FT levels were related to the ingested dose and in the microgram range while serum 5-FU levels were in the nanogram range indicating slow decomposition of FT into 5-FU. The therapy was reasonably well tolerated at doses of 2.0 g/m2/day or lower with abdominal radiation. FT offers the potential for replacing intra-venous infused 5-FU as a clinical radiosensitizer.

Eighteen patients with gastrointestinal and retroperitoneal non-Hodgkin's lymphoma received abdominal radiotherapy as their primary treatment. Each patient received a total tumor dose of 2200 to 4500 cGy in 5 to 9 weeks to the whole or half of one kidney. Nine patients developed unilateral radiation nephropathy demonstrable on post-treatment evaluation with 99m Tc glucoheptonate blood flow, delayed static scan, and an I-131 radio-hippurate renal perfusion study. The tests were periodically repeated over periods ranging from 5 to 8 years. Six patients with nephropathy and 4 patients without nephropathy were followed 5 years or longer. The minimum nephro-pathogenic irradiation dose was 2200 cGy delivered in 59 days. The incidence of nephropathy is higher with increase in the total dose. Short term recovery in function was observed in 3 patients and long-term complete recovery was observed in one patient. Atrophic renal change was irreversible and progressive in 3 patients over a 6 to 7 year follow-up period. In this group of patients, an abnormal creatinine clearance and serum beta-2 microglobulin level was indicative of vascular damage. Elevated arterial blood pressure was seen in 5 patients. All were controlled medically, without nephrectomy. There was no other clinically significant problem resulting from the unilateral nephropathy in this group of patients.

Intra-operative placement of 11-gauge nylon catheters into deep-seated unresectable tumors for interstitial brachytherapy permits localized heating of tumors (hyperthermia) using microwave (915 MHz) antennas which are inserted into these catheters. Four preliminary cases are described where epithelial tumors at various sites were implanted with an antenna array and heated for 1 hour, both before and after the iridium-192 brachytherapy. Temperatures were monitored in catheters required for the appropriate radiation dosimetry but not required for the interstitial microwave antenna array hyperthermia (IMAAH) system. Additional thermometry was obtained using nonperturbed fiberoptic thermometry probes inserted into the catheters' housing antennas. No significant complications, such as bleeding or infection, were observed. This approach to cancer therapy is shown to be feasible and it produces controlled, localized hyperthermia, with temperatures of 50 degrees C or more in tumors. This technique may offer a therapeutic option for pelvic, intra-abdominal and head and neck tumors.