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Background To report on our institutional experience using Proton stereotactic body radiation therapy (SBRT) for patients with liver metastases. Methods All patients with liver metastases treated with Proton SBRT between September 2012 and December 2017 were retrospectively analyzed. Local control (LC) and overall survival (OS) were estimated using the Kaplan-Meier method calculated from the time of completion of Proton SBRT. LC was defined according to Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1). Toxicity was graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Results Forty-six patients with 81 lesions were treated with Proton SBRT. The median age was 65.5 years old (range, 33-86 years) and the median follow up was 15 months (range, 1-54 months). The median size of the gross tumor volume (GTV) was 2.5 cm (range, 0.7-8.9 cm). Two or more lesions were treated in 56.5% of patients, with one patient receiving treatment to a total of five lesions. There were 37 lesions treated with a biologically effective dose (BED) ≤60, 9 lesions with a BED of 61-80, 22 lesions with a BED of 81-100, and 13 lesions with a BED >100. The 1-year and 2-year LC for all lesions was 92.5% (95% CI, 82.7% to 96.8%). The grade 1 and grade 2 toxicity rates were 37% and 6.5%, respectively. There were no grade 3 or higher toxicities and no cases of radiation-induced liver disease (RILD). Conclusions Proton SBRT for the treatment of liver metastases has promising LC rates with the ability to safely treat multiple liver metastases. Accrual continues for our phase II trial treating liver metastases with Proton SBRT to 60 GyE (Gray equivalent) in 3 fractions.

Introduction Retroperitoneal sarcoma (RPS) is a rare malignancy, and curative resection is considered the main therapy. Use of chemotherapy and/or radiation in addition to surgery (multimodality therapy) is controversial. Objective To determine treatment factors that influence overall survival in RPS. Methods This retrospective Institutional Review Board-approved study identified patients with RPS treated at a single institution between 2000 and 2017. Patient, tumor, and treatment modalities were collected. Prism (v.8.2.1) was used to calculate Kaplan-Meier survival curves. Results There were 695 patients with sarcoma between 2000 and 2017, and 61 adults had RPS. The mean age was 59 (range 31-86) years, with 57.4% females (n = 35). Patients were 68.9% Caucasian (n = 42), 21.3% Hispanic (n = 13), 8.2% black (n = 5), and 1.6% Asian (n = 1). There were 4 patients who had neoadjuvant therapy (chemotherapy, n = 3; radiation, n = 2) and 17 who had adjuvant therapy (chemotherapy, n = 6; radiation, n = 14). There was no significant difference in survival between the groups who received multimodality therapy compared to surgery alone. There was a significant improvement in the median overall survival for patients who underwent one or multiple surgeries ( P < .05). Conclusions These institutional data suggest that treatment factors associated with overall survival included multiple resections. Use of multimodality therapy was low and did not influence overall survival in patients with RPS compared to surgery alone.

Epidermal growth factor receptor (EGFR) is overexpressed in pancreatic cancer. EGFR expression plays a potentially important role in modulation of tumor sensitivity to either chemotherapy or radiotherapy. Erlotinib is a receptor tyrosine kinase inhibitor with specificity for EGFR/HER1. A phase II trial was conducted to explore the efficacy of a regimen utilizing erlotinib and proton therapy.Patients with unresectable or borderline resectable non-metastatic adenocarcinoma of the pancreas were included. Patients received 8-week systemic treatment with gemcitabine 1,000 mg/mThe study enrolled 9 patients ages 47-81 years old (median 62) between January 2013 and March 2016, when the trial was closed due to low patient accrual. The 1-year OS rate was 55.6% (95% CI: 31% to 99%). The median OS was 14.1 months (95% CI: 11.4-NE) and the median PFS was 10.8 months (95% CI: 7.44-NE). A majority of patients completed CPT and GE, but only 33.3% completed the four cycles of CapOx. A third of patients experienced grade 3 toxicities, which were all hepatic along with one patient who also had grade 3 diarrhea. There were no grade 4 or 5 toxicities. Four patients were enrolled with borderline resectable disease, three of which were eligible for pancreaticoduodenectomy after GE and CPT treatment. One of two patients who underwent resection had a negative margin.This regimen for locally advanced pancreatic cancer (LAPC) exceeded the pre-specified benchmark and was safe and well tolerated. Additional investigations utilizing more current systemic treatment regimens with proton therapy are warranted.ClinicalTrials.gov identifier (NCTNCT01683422).

Image guidance for radiation therapy can improve the accuracy of the delivery of radiation, leading to an improved therapeutic ratio. Proton radiation is able to deliver a highly conformal dose to a target due to its advantageous dosimetric properties, including the Bragg peak. Proton therapy established the standard for daily image guidance as a means of minimizing uncertainties associated with proton treatment. With the increasing adoption of the use of proton therapy over time, image guidance systems for this modality have been changing. The unique properties of proton radiation present a number of differences in image guidance from photon therapy. This paper describes CT and MRI-based simulation and methods of daily image guidance. Developments in dose-guided radiation, upright treatment, and FLASH RT are discussed as well.

BACKGROUND: A phase I trial to determine the maximum tolerated dose (MTD) of Proton stereotactic body radiation therapy (SBRT) for liver metastases in anticipation of a subsequent phase II study. METHODS: An institutional IRB approved phase I clinical trial was conducted. Eligible patients had 1–3 liver metastases measuring less than 5 cm, and no metastases location within 2 cm of the GI tract. Dose escalation was conducted with three dose cohorts. The low, intermediate, and high dose cohorts were planned to receive 36, 48, and 60 respectively to the internal target volume (ITV) in 3 fractions. At least 700 mL of normal liver had to receive

BackgroundRecent randomized controlled trials have failed to show a survival difference between adjuvant chemotherapy (CT) and adjuvant chemoradiotherapy (CRT) in patients with resected gastric cancer (GC). However, a subset of patients with lymph node (LN) positive disease may still benefit from CRT. Additional evidence is needed to help guide physicians in identifying patients in whom CRT should be considered. Our objective was then to compare survival outcomes based on lymph node ratio (LNR) (ratio of metastatic to harvested LNs) for patients with gastric and gastroesophageal junction (GEJ) adenocarcinoma treated with surgery and either CT or CRT.MethodsThis retrospective population-based study used California Cancer Registry (CCR) data from 2004 to 2013. It included 1,493 patients diagnosed with stage IB-III gastric/GEJ adenocarcinoma and treated with CT or CRT following total or partial gastrectomy. Overall survival (OS) was the primary outcome and GC-specific survival was secondary. Mortality hazards ratios (HR) for these outcomes were computed using propensity score weighted Cox regression models, stratified by LNR strata categories as 0%, 1-9%, 10-25% and >25%.ResultsOut of 1,493 patients that met inclusion criteria, 462 were treated with CT while 1,031 received CRT. Median follow-up for all subjects was 76 months and median survival was 54 months for CRT and 35 for the CT cohort, P25% [HR =0.67 (95% CI, 0.56-0.80)]. Similar findings were observed for GC-specific survival and for analyses limited to patients that had at least 15 LNs evaluated.ConclusionsLNR appears to be a simple and readily available measure that could be used in treatment planning for resected GC. CRT offers significant survival advantage over CT among patients with high LN disease burden (LNR of ≥10%).

Background: The goal of this study is to determine whether a phase or reconstruction of a 10-phase 4 dimensional computed tomography (4D CT) scan can be used as the primary planning scan for proton treatment of the pancreas, thus eliminating the need for second a slow CT or free breathing CT. Methods: Ten patients with pancreatic adenocarcinoma were simulated with 4D CT and a proton treatment plan generated based upon one of three primary planning scans, the T0 phase, T50 phase or average reconstruction. These plans were then exported to each of the remaining phases of the 4D CT and the dose to 95% of the target (D95) calculated. Plans were deemed adequate if the D95 remained at 99% of the prescribed dose or greater. Results: For the ten patients in this study anterior abdominal motion was found to range from 2–27 mm (mean 7.50±6.79 mm). For 9 of 10 patients the anterior abdominal motion was ≤8 mm and all three primary planning scans provided adequate target coverage, resulting in minimum D95 coverage per plan of T0_plan 99.7%, T50_plan 99.3% and AVE_plan 99%. However no plan provided adequate target coverage on the single patient with the largest anterior abdominal motion, 27 mm, and cranio-caudal motion, 20 mm, with minimum D95 values of T0_plan 96.3%, T50_plan 68%, and AVE_plan 68%. Conclusions: The primary plans tested based up on the T0, T50 and average reconstructions provided adequate D95 coverage throughout the respiratory cycle as long as the anterior abdominal motion was ≤8 mm and can be considered for use as the primary proton planning scan.

Background. While neoadjuvant concurrent chemoradiotherapy has improved outcomes for esophageal cancer patients, surgical complication rates remain high. The most frequent perioperative complications after trimodality therapy were cardiopulmonary in nature. The radiation modality utilized can be a strong mitigating factor of perioperative complications given the location of the esophagus and its proximity to the heart and lungs. The purpose of this study is to make a dosimetric comparison of Intensity-Modulated Radiation Therapy (IMRT), proton and 3D conformal radiotherapy (3D-CRT) with regard to reducing perioperative cardiopulmonary complications in esophageal cancer patients. Materials. Ten patients with esophageal cancer treated between 2010 and 2013 were evaluated in this study. All patients were simulated with contrast-enhanced CT imaging. Separate treatment plans using proton radiotherapy, IMRT, and 3D-CRT modalities were created for each patient. Dose-volume histograms were calculated and analyzed to compare plans between the three modalities. The organs at risk (OAR) being evaluated in this study are the heart, lungs, and spinal cord. To determine statistical significance, ANOVA and two-tailed paired t-tests were performed for all data parameters. Results. The proton plans showed decreased dose to various volumes of the heart and lungs in comparison to both the IMRT and 3D-CRT plans. There was no difference between the IMRT and 3D-CRT plans in dose delivered to the lung or heart. This finding was seen consistently across the parameters analyzed in this study. Conclusions. In patients receiving radiation therapy for esophageal cancer, proton plans are technically feasible while achieving adequate coverage with lower doses delivered to the lungs and cardiac structures. This may result in decreased cardiopulmonary toxicity and less morbidity to esophageal cancer patients.

Purpose: Pancreatic cancer is a highly aggressive malignancy. Chemoradiation therapy (CRT) is used in many cases to improve local-regional control; however, toxicities associated with radiation can be significant given the location of the pancreas. The purpose of this study is to quantify the dosimetric changes seen when using photons or protons in patients receiving CRT for cancer of the pancreas. Patients and Methods: Ten patients with pancreatic head adenocarcinoma treated between 2010 and 2013 were evaluated in this study. All patients underwent simulation with contrast-enhanced computed tomography imaging. Separate treatment plans using proton radiation therapy, intensity-modulated radiation therapy, and 3-dimensional photon radiation therapy modalities were created for each patient. Dose-volume histograms were calculated and analyzed to compare plans between the 3 modalities. The organs at risk evaluated in this study are the kidneys, liver, small bowel, and spinal cord. To determine statis...

Throughout this chapter, the methods utilized to provide clinical proton treatment delivery will be reviewed. This will begin with the historical rationale for use of particle therapy followed by particle-specific issues in patient selection, patient setup and immobilization, proton treatment planning and delivery, dose constraints, and carbon therapy. The discussion will primarily focus on proton therapy with some discussion of the utility of carbon therapy. Clinical outcomes of particle therapy will be discussed in separate chapters of this text. The final section of this chapter will be devoted to the future direction of particle therapy.

Purpose: Elderly patients with esophageal cancer who are not candidates for chemoradiation may benefit from targeted agents; hence erlotinib combined with radiotherapy was evaluated in this trial. Materials and Methods: Patients >65 years with carcinoma of the thoracic esophagus or gastroesophageal junction who were not eligible for platinum-based treatment received erlotinib daily for 1 year starting on day 1 of radiotherapy [50.4 Gy days 1-28 (Mon-Fri) at 1.8 Gy per fraction]. Response was assessed by endoscopy and computed tomography. The primary endpoint was overall survival (OS), and secondary endpoints were complete response, progression-free survival (PFS) and toxicity. Results: The ECOG performance status in the 17 study patients was 0,1 and 2 in 2, 12 and 3 patients, respectively; 1, 5, 7 and 4 patients were in stage I, II, III and IV, respectively; adenocarcinoma was noted in 16 patients and squamous cell carcinoma in 1; there were 3 current, 12 past and 2 never smokers. Median OS was 7.3 months (95% confidence interval, CI: 3.8-22.3) with 14 deaths. There were 2 mucosal complete responses, 1 residual carcinoma in situ and 3 partial endoscopic responses in 9 patients who had endoscopy after radiotherapy. Estimated PFS was 4.5 months (95% CI: 2.4-7.3). Progression was distant (n = 3), locoregional (n = 6), unknown (n = 5) and too early (n = 3). Estimated 1-year survival was 29% (95% CI: 11-51%), 5 patients lived >12 months. Treatment-related toxicities of grade 3-4 occurred in 5 patients. Patients with epidermal growth factor receptor amplification and never smokers had the longest OS (22.3 and 16.6 months, respectively). Conclusions: Erlotinib with radiotherapy is tolerable and warrants further biomarker-driven evaluation in this population.

Proton radiotherapy has seen an increasing role in the treatment of hepatocellular carcinoma (HCC). Historically, external beam radiotherapy has played a very limited role in HCC due to a high incidence of toxicity to surrounding normal structures. The ability to deliver a high dose of radiation to the tumor is a key factor in improving outcomes in HCC. Advances in photon radiotherapy have improved dose conformity and allowed dose escalation to the tumor. However, despite these advances there is still a large volume of normal liver that receives a considerable radiation dose during treatment. Proton beams do not have an exit dose along the beam path once they enter the body. The inherent physical attributes of proton radiotherapy offer a way to maximize tumor control via dose escalation while avoiding excessive radiation to the remaining liver, thus increasing biological effectiveness. In this review we discuss the physical attributes and rationale for proton radiotherapy in HCC. We also review recent literature regarding clinical outcomes of using proton radiotherapy for the treatment of HCC.

Cancers of the esophagus, stomach, and the esophagogastric junction (EGJ) remain a global health problem. There has been a dramatic increase in the incidence of adenocarcinoma of the distal esophagus and EGJ in the past two decades with little change in the poor prognosis associated with these cancers. Previously surgery alone was the mainstay of therapeutic intervention, but high rates of local and systemic failure have prompted investigation into neoadjuvant and adjuvant therapy. Treatment paradigms differ across continents, but the unifying theme that has emerged in the past decade implies that surgery alone can no longer be considered the standard of care. The multi-disciplinary management of patients with locally advanced esophagogastric carcinomas using trimodality therapy with radiotherapy, chemotherapy, and surgery confers the greatest opportunity for margin negative resection, improved loco-regional control and cure, and should be the accepted treatment paradigm. The traditional backbone of platinum plus fluorouracil concurrent with radiotherapy may be supplanted by more modern, easier-to-administer regimens incorporating taxanes and irinotecan. The current generation of clinical trials in this heterogeneous group of diseases is examining targeted therapy, newer methods of radiotherapy, and predictors of response to therapy aiming to tailor management to an individual patient.

Chemoradiation plays a core role in the definitive and preoperative management of esophageal cancer. Remarkable advances in technology now allow for the implementation of intensity modulated radiation therapy (IMRT) to minimize normal organ damage and to maximize coverage of tumorous targets. While IMRT is commonly accepted in the treatment of prostate and head and neck cancers, there have been clinical and dosimetric studies supporting the use of IMRT in esophagus cancer. In addition, the IMRT technique was recently enhanced by the availability of volumetric intensity modulated arc therapy (VMAT). VMAT may allow for faster delivery of IMRT with the advantage of normal organ protection compared to the stop-and-shoot IMRT, with faster delivery time and reduced monitor units. This review summarizes the use of chemoradiation in esophageal cancer, discusses current dosimetric data and clinical outcomes with the use of IMRT, and reviews IMRT as part of multi-modality treatment in esophageal cancer.

Objective This Phase II study was conducted to evaluate the activity and feasibility of a regimen of nedaplatin and 5-fluorouracil as induction chemotherapy, followed by intensity-modulated radiotherapy concurrent with chemotherapy in patients with locoregionally advanced nasopharyngeal carcinoma. Methods Patients received neoadjuvant chemotherapy comprised two cycles of 5-fluorouracil at 700 mg/m(2)/day administered on days 1-4 as continuous intravenous infusion and nedaplatin (100 mg/m(2) administered i.v. over 2 h) given after the administration of 5-fluorouracil on day 1, repeated every 3 weeks, followed by intensity-modulated radiotherapy concurrent with nedaplatin. During intensity-modulated radiotherapy, nedaplatin was administered at a dose of 100 mg/m(2) intravenous infusion on days 1, 22 and 43, given approximately 60 min before radiation. Results Fifty-nine (95.8%) of the 60 patients were assessable for response. Thirty-eight cases of complete response and 14 cases of partial response were confirmed after completion of chemoradiation, with the objective response rate of 86.7% (95% CI, 78.1-95.3%). The median follow-up period was 48 months (range, 30-62 months). The 3-year progression-free survival and overall survival were 75.0% (95% CI, 63.0-87.0%) and 85.5% (95% CI, 75.9-95.1%). No patient showed Grade 3 or higher renal dysfunction. The most commonly observed late effect was xerostomia, but the severity diminished over time, and the detectable xerostomia at 24 months was 10.2%. There were no treatment-related deaths during this study. Conclusions Neoadjuvant chemotherapy with nedaplatin and 5-fluorouracil followed by concomitant nedaplatin and intensity-modulated radiotherapy is an effective and safe treatment for Southern China patients affected by locoregionally advanced nasopharyngeal carcinoma.

Approximately one out of every three patients with non-small cell lung cancer (NSCLC) has locally advanced disease that is surgically unresectable. If their performance status allows, it is current practice to treat these patients with a combination of chemotherapy and external beam irradiation. There have been several studies supporting the addition of chemotherapy to radiation, particularly when delivered concurrently. There is debate over which treatment agents and schedules are most optimal, even with the most proven treatments delivering only modest results, with high rates of local and distant disease failure. Advances in imaging and radiation planning and delivery technology have allowed for the potential for improvement of the therapeutic ratio by reducing normal tissue exposure and ensuring for more precise delivery, while new systemic agents show promising activity in NSCLC. Pemetrexed is a pyrrolopyrimidine-based folate anti-metabolite that works by inhibiting a variety of enzymes of thymidylate and purine synthesis, thus leading to cell stasis and death. Similar to other cytotoxic antifolates, pemetrexed has been shown in pre-clinical study to act as an effective radiosensitizer. At present, it is being studied in phase I and II studies when combined with other systemic agents and radiation therapy in the treatment of locally advanced NSCLC, and the results have been promising. It has the advantage of allowing for relatively safe delivery of full systemic doses when combined other agents and radiation therapy, a distinction over combined modality treatments. Its efficacy, particularly in non-squamous NSCLC, in phase I and II studies has lead to investigations in the phase III setting where a more defined role for pemetrexed in locally advanced non-squamous NSCLC will potentially be defined. This review summarizes the use of combined modality treatment in locally advanced NSCLC, outlines recent advances in radiation planning and treatment, and reviews the current data on the use concurrent chemoradiation regimens featuring pemetrexed.

Purpose: To determine the maximal tolerated dose of capecitabine with oxaliplatin + radiotherapy in a phase I study of localized esophageal cancer. Patients and Methods: Oxaliplatin (85 mg/m2) administered on days 1, 15, and 29. Capecitabine administered twice daily 5 days weekly; dose levels (DL) were 1, 1000; 2, 1250; and 3, 1500 mg/m2 with 50.4 Gy radiation. Results: Dose-limiting toxicity was reached at DL 3. Carboxylesterase expression in day 2 tumor specimens and induction correlated with response (p ≤ 0.05). Conclusion: The maximal tolerated dose was 85 mg/m2 of oxaliplatin, 1,250 mg/m2/day of capecitabine, and 50.4 Gy of radiation.

Purpose: The combination of oxaliplatin, 5-fluorouracil, and leucovorin with concurrent radiotherapy was demonstrated to be a safe regimen for locally advanced esophageal carcinoma in a prior phase I study. We now report the efficacy data for 42 patients treated with this regimen. Methods: Each chemotherapy cycle lasted 29 days and consisted of 5-fluorouracil, 180 mg/m 2 protracted-infusion from days 1 to 29, and oxaliplatin, 85 mg/m 2 on days 1,15, and 29. The first cycle was administered concurrently with radiation. The radiation field included regional lymph nodes as well as the primary tumor or tumor bed to a dose of 50.4 Gy in 28 fractions. After concurrent chemoradiotherapy, 1 to 2 additional cycles of chemotherapy were administered. If esophagectomy was indicated, it occurred 4 weeks after completion of concurrent chemoradiotherapy. In the adjuvant group, concurrent chemoradiotherapy was initiated 4 weeks after surgery. Results: Median age was 61 years (range 38-78 years); 30 (71%) of the patients were male. Thirty-three patients had adenocarcinoma, and 9 had squamous cell carcinoma. Concurrent chemoradiotherapy was administered preoperatively (group 1) in 24 patients, definitively (group 2) in 13 patients, and as adjuvant treatment (group 3) in 5 patients. In group 1, 16 patients were down-staged including 1 patient with minimal residual disease and 5 with a complete pathologic response; 4 patients were not down-staged, and 4 did not undergo esophagectomy (2 progressed, 1 died of unrelated causes, and 1 refused). In group 2, 1 patient had a complete clinical response, 4 others were down-staged, 2 had stable disease, and 6 progressed. Four patients in group 3 progressed. Median survival was 28 months for group 1, 12 months for group 2, and not reached at 14 months for group 3. There was one grade 4 toxicity (anaphylaxis) in group 2. Grade 3 toxicities were reported for 5 patients in group 1 and 1 patient in group 2. They consisted of hypotension (n = 1), fatigue (n = 2), diarrhea (n = 2), neuropathy (n = 1), mucositis (n = 1), pneumonitis (n = 1), dehydration (n = 1), emesis (n = 1), and weight loss (n = 1). Conclusions: Our study supports the incorporation of oxaliplatin into a multimodal concurrent chemoradiotherapy protocol for locally advanced esophageal cancer.

Background Exploiting biologic imaging, studies have been performed to boost dose to gross intraprostatic tumor volumes (GTV) while reducing dose elsewhere in the prostate. Interest in proton beams has increased due to superior normal-tissue sparing they afford. Our goal was to dosimetrically compare 3D conformal proton boost plans with intensity-modulated radiation therapy (IMRT) plans with respect to target coverage and avoiding organs at risk. Methods Treatment planning computer tomography scans of ten patients were selected. For each patient, two hypothetical but realistic GTVs each with a fixed volume were contoured in different anatomical locations of the prostate. IMRT and proton beam plans were created with a prescribed dose of 50.4 Gy to the initial planning target volume (PTV) including the PTV of the seminal vesicles (PSV), 70.2 Gy to the PTV of the prostate (PPS), and 90 Gy to the PTV of the gross tumor volumes (PGTVs). For proton plans, uncertainties of range and patient setup were accounted for; apertures were adjusted until the dose-volume coverage of PTVs matched that of the IMRT plan. For both plans, prescribed PTV doses were made identical to allow for comparing normal-tissue doses. Results Protons delivered more homogeneous but less conformal doses to PGTVs than IMRT did and comparable doses to PSV and PPS. Volumes of bladder and rectum receiving doses higher than 65 Gy were similar for both plans. However, volumes receiving less than 65 Gy were significantly reduced, i.e., protons reduced integral dose by 45.6 % and 26.5 % for rectum and bladder, respectively. This volume-sparing was also seen in femoral heads and penile bulb. Conclusions Protons delivered comparable doses to targets in dose homogeneity and conformity and spared normal tissues from intermediate-to-low doses better than IMRT did. Further improvement of dose sparing and changes in homogeneity and conformity may be achieved by reducing proton range uncertainties and from implementing intensity modulation.

Purpose: We conducted a Phase I study to determine the maximum tolerated dose (MTD) of neoadjuvant capecitabine, oxaliplatin, and radiation therapy (RT) in Stage II to III rectal adenocarcinoma. Methods and Materials: Capecitabine was given orally twice daily Monday through Friday concurrently with RT. Oxaliplatin was given i.v. once weekly × 5 (for 5 weeks) starting the first day of RT. RT was given daily except on weekends and holidays at 1.8 Gy per fraction × 28. Escalation for capecitabine or oxaliplatin was to occur in cohorts of three patients until the maximum tolerated dose (MTD) was defined. Endorectal tumor biopsy samples were obtained before and on Day 3 of treatment to explore the effects of treatment on thymidine phosphorylase, thymidylate synthase, dihydropyrimidine dehydrogenase, DNA repair, and apoptosis. Results: Twelve patients were enrolled on this study. Two of 6 patients at dose level (DL) 1 (capecitabine 825 mg/m 2 orally (p.o.) given twice daily (b.i.d.); oxaliplatin 50 mg/m 2 /week) had a dose-limiting diarrhea. One of 6 patients at DL (−)1 (capecitabine 725 mg/m 2 p.o., b.i.d.; oxaliplatin 50 mg/m 2 /week) experienced-dose-limiting diarrhea. Three of 11 patients who underwent resection had a complete pathologic response. No remarkable variations in rectal tumor biologic endpoints were noted on Day 3 of treatment in comparison to baseline. However, a higher apotosis index was observed at baseline and on Day 3 in complete pathologic responders (no statistical analysis performed). Conclusions: Capecitabine 725 mg/m 2 p.o., twice daily in combination with oxaliplatin 50 mg/m 2 /week and RT 50.4 Gy in 28 fractions is the recommended dose for future studies.

Introduction Authorship misrepresentations have been described for residency and fellowship applications for various medical specialties. This study assessed the prevalence of misrepresented publications in radiation oncology residency applications. Materials and Methods The authors reviewed 117 applications to their residency program for a single 2004 position offered through the National Resident Matching Program. Publications listed on the applications were verified for accuracy, with the results and applicants' demographic information recorded. Results A total of 49 applicants (42%) claimed authorship of published research citations. The number of published citations averaged 3.6 per applicant (range, 1-23). Of the applicants reporting citations, 22% (11 of 49) listed inaccurate citation information. Overall, 9% of the citations (15 of 174) were considered misrepresentations, with 9% of the total number of applicants (11 of 117) responsible for inaccurate bibliographies. There was a significant relationship of United States Medical Licensing Examination score with publication misrepresentation, in which those with scores of 235 or greater who listed publications were more than 7 times more likely to have inaccurately listed citations (odds ratio, 7.67; 95% confidence interval, 1.12-52.31; P = .04). Conclusion The misrepresentation of bibliographic citations does exist among radiation oncology residency applicants. Using a comprehensive search, the authors found that 22% of those who had listed at least 1 article had misrepresented publications on their applications.

Objectives: To investigate the incidence of carcinoembryonic antigen (CEA) surge in patients with metastatic colorectal cancer (MCRC) and its implications on clinical outcome. Methods: A retrospective chart review of patients with MCRC treated with chemotherapy at Roswell Park Cancer Institute from January 2000 to May 2004 was conducted. A CEA surge was defined as an increase of >20% from baseline followed by a >20% drop in one or more subsequent CEA levels compared to baseline. The incidence of CEA surge and its association with clinical outcome was investigated. Results: Eighty-nine patients were evaluable for CEA surge. A CEA surge was documented in 10 patients. The CEA surge lasted Conclusions: CEA surges can be observed in patients receiving chemotherapy for MCRC and are often associated with a clinical benefit. None of the CEA surges satisfied the American Society of Clinical Oncology definition of CEA progression. A rise in CEA after initiation of chemotherapy, unless lasting >4 months, cannot be used as an indicator of progressive disease.

Recent mechanistic studies on the role of heat-shock proteins (HSPs) to induce innate and adaptive immune responses have resulted in conflicting reports. Whereas some groups reported that HSPs have direct immunological function, others emphasised the endotoxin contamination of HSP preparations and questioned the antigen-specificity of HSP vaccines. The present review will discuss these issues and suggest that HSPs have diverse and distinct immunological functions that could be superimposed on effects resulting from endotoxin contamination or misunderstood by using experimental procedures with inadequate controls. To understand the actual function of HSPs in their interaction with the immune system, methods and procedures need to be optimised and appropriate controls need to be used. These points should also clarify the conflicting findings about HSPs and promote our knowledge about other immuologically important components that may be present in HSP preparations.

RTOG 9704 demonstrated a prognostic role for postoperative CA 19-9 in patients with resectable pancreatic carcinoma following surgery. Our study aimed to investigate whether CA 19-9 provided similar prognostic information in patients with locally advanced unresectable pancreatic cancer (LAPC) treated with chemoradiotherapy (CRT) and to determine whether such endpoints should therefore be reported in future randomized trials.Between December 1998 and October 2009, 253 patients with LAPC were treated with 5-fluourouracil-based concurrent CRT at our institution. Median radiation dose was 50.4 Gy. Only patients with a bilirubin of less than 2 mg/dL at the time the CA 19-9 was evaluated were included in the analysis to avoid the confounding effect of hyperbilirubinemia. Of the eligible patients, 54 had pre and post CRT CA 19-9 values available. The median age was 68 years and 52% were female. Categorized versions of the first post-CRT CA 19-9 were tested in 50 point increments beginning at50 to1,000 and percent change in pre to post-CRT CA 19-9 using cut points of 10% increments from0% (increased) to90%. Survival was measured from the date of first post CRT CA 19-9 level until death or last follow-up. Univariate and multivariate statistical methodologies were used to determine significant prognostic factors for overall survival.Median CA 19-9 prior to CRT was 363 U/mL and post CRT median was 85.5 U/mL. Following CRT, patients with a decrease of90% from their baseline CA 19-9 level had a significantly improved median survival than those that did not (16.2 vs. 7.5 months, P=0.01). The median survival of patients with a CA 19-9 level lower than the median post CRT value was 10.3 months, compared with 7.1 months for those with a CA 19-9 level greater than the median (P=0.03). Post CRT CA 19-9 less than 50 U/mL and histologic grade I-II also showed prognostic significance (both P=0.03). In multivariate analysis, post CRT CA 19-9 less than the median level of 85.5 U/mL was an independent prognostic factor for overall survival (HR 0.34; 95% CI, 0.13-0.85, P=0.02).Our results indicate that post treatment CA 19-9 is predictive for overall survival in patient with LAPC following CRT. We recommend that pre and post treatment CA 19-9 levels be obtained in patients receiving CRT and that these values be considered for prognostic nomograms and future clinical trials.

Proton radiotherapy has seen an increasing role in the treatment of hepatocellular carcinoma (HCC). Historically, external beam radiotherapy has played a very limited role in HCC due to a high incidence of toxicity to surrounding normal structures. The ability to deliver a high dose of radiation to the tumor is a key factor in improving outcomes in HCC. Advances in photon radiotherapy have improved dose conformity and allowed dose escalation to the tumor. However, despite these advances there is still a large volume of normal liver that receives a considerable radiation dose during treatment. Proton beams do not have an exit dose along the beam path once they enter the body. The inherent physical attributes of proton radiotherapy offer a way to maximize tumor control via dose escalation while avoiding excessive radiation to the remaining liver, thus increasing biological effectiveness. In this review we discuss the physical attributes and rationale for proton radiotherapy in HCC. We also review recent literature regarding clinical outcomes of using proton radiotherapy for the treatment of HCC.

Given the complexity of prostate cancer progression and metastasis, multimodalities that target different aspects of tumor biology, for example, radiotherapy in conjunction with immunotherapy, may provide the best opportunities for promoting clinical benefits in patients with high-risk localized prostate cancer. Here, we show that intratumoral administration of unmodified dendritic cells (DC) failed to synergize with fractionated radiotherapy. However, ionizing radiation combined with in situ vaccination with DCs, in which the immunosuppressive scavenger receptor A (SRA/CD204) has been downregulated by lentivirus-mediated gene silencing, profoundly suppressed the growth of two mouse prostate cancers (e.g., RM1 and TRAMP-C2) and prolonged the lifespan of tumor-bearing animals. Treatment of subcutaneous tumors with this novel combinatorial radioimmunotherapeutic regimen resulted in a significant reduction in distant experimental metastases. SRA/CD204-silenced DCs were highly efficient in generating antigen or tumor-specific T cells with increased effector functions (e.g., cytokine production and tumoricidal activity). SRA/CD204 silencing-enhanced tumor cell death was associated with elevated IFN-γ levels in tumor tissue and increased tumor-infiltrating CD8+ cells. IFN-γ neutralization or depletion of CD8+ cells abrogated the SRA/CD204 downregulation-promoted antitumor efficacy, indicating a critical role of IFN-γ–producing CD8+ T cells. Therefore, blocking SRA/CD204 activity significantly enhances the therapeutic potency of local radiotherapy combined with in situ DC vaccination by promoting a robust systemic antitumor immunity. Further studies are warranted to test this novel combinatorial approach for translating into improved clinical outcomes in patients with prostate cancer. Mol Cancer Ther; 11(11); 2331–41. ©2012 AACR.

Chemoradiation plays a core role in the definitive and preoperative management of esophageal cancer. Remarkable advances in technology now allow for the implementation of intensity modulated radiation therapy (IMRT) to minimize normal organ damage and to maximize coverage of tumorous targets. While IMRT is commonly accepted in the treatment of prostate and head and neck cancers, there have been clinical and dosimetric studies supporting the use of IMRT in esophagus cancer. In addition, the IMRT technique was recently enhanced by the availability of volumetric intensity modulated arc therapy (VMAT). VMAT may allow for faster delivery of IMRT with the advantage of normal organ protection compared to the stop-and-shoot IMRT, with faster delivery time and reduced monitor units. This review summarizes the use of chemoradiation in esophageal cancer, discusses current dosimetric data and clinical outcomes with the use of IMRT, and reviews IMRT as part of multi-modality treatment in esophageal cancer.

Background Postoperative anastomotic strictures produce significant morbidity after esophagectomy. Previous reports have described a variable association between the diameter of the circular end-to-end anastomosis (EEA) stapler commonly used in esophagogastric anastomoses and the incidence of stricture formation. Stapler technology has improved. We investigated an association between stapler diameter and the incidence of postoperative anastomotic strictures in a contemporary series. This has renewed importance given the limited diameter of trans-oral staplers that are being increasingly used. Methods Retrospective chart review revealed that of 194 patients undergoing an esophagectomy over a 10-y period (10/1998–8/2008) at our institution, an EEA stapler was used in 91. EEA size information and follow-up were available in 89 patients. Patients were divided into two groups based on EEA size: ‘small’ = 23–25 mm ( n = 24) and ‘large’ = 28–33 mm ( n = 65). Patients with strictures were identified based on symptoms of dysphagia requiring an esophageal dilation procedure. Patients with postoperative leaks were excluded when analyzing for the association of stricture with EEA size, as postoperative leaks are known to be associated with stricture. Wilcoxon and Fisher’s exact tests were used for statistical analysis; a 5% α error was accepted. Results Fifteen (16.8%) of 89 patients developed a stricture postoperatively. The anastomotic leak rate was 3.3%. There was no statistically significant association between EEA size group and stricture formation ( P = 0.7506). Conclusions No association was found between the size of the EEA stapler used and stricture formation. EEA size should be determined at surgery by the native esophageal diameter.

Gastric cancer is a leading cause of cancer death worldwide. Complete resection offers the only chance for permanent control, and accurate staging and evaluation of treatment response are crucial for appropriate management. Positron Emission Tomography (PET) is increasingly used to complement anatomic imaging in cancer management. PET use in gastric cancer has been limited by 1) some gastric histologies are not PET avid, 2) spatial resolution limits the ability to distinguish between primary tumor and compartment I or II lymph nodes, and 3) the lack of a unified criteria in how to interpret PET for management decisions. New criteria have been proposed establishing response metrics in the utilization of PET. More study is needed to support these criteria in routine practice and establish the place of PET in the staging and management of gastric cancer.

Gastric cancer is rampant in several countries around the world. Its incidence in the West has been on the decline for more than 40 years; however, the location of gastric cancer has shifted proximally in the past 15 years. The reason for this shift is not clear. Diffuse histology is also more common now than intestinal type of histology. Advances have been made in staging procedures such as laparoscopy and endoscopic ultrasonography and in possible functional imaging techniques. The current TNM classification requires an examination of at least 15 lymph nodes; therefore, at least a D1 dissection is recommended. Patients with locoregional gastric carcinoma should also be referred to high-volume treatment centers. Combination chemotherapy and radiotherapy in the adjuvant setting for select group of patients is considered the new standard in the United States. The NCCN Gastric Cancer Guidelines portray uniformity in the systemic approach to cancer in the United States. We look forward to the results of investigations of a number of new chemotherapeutic agents, including antireceptor agents, vaccines, gene therapy, and antiangiogenic agents. The panel anticipates many advances in the treatment of esophageal carcinoma in the future.

Pelvic and distant recurrences in rectal cancer can be associated with substantial morbidity, and patients with stage II and III disease are at increased risk for both local and distant failure when compared to patients with earlier stage disease. Refinement of surgical techniques have helped to reduce the risk of recurrence, and adjuvant therapies such as radiation to the tumor and regional lymph nodes and 5-fluorouracil-based systemic therapies have helped to further provide local control and may have an impact on overall survival. Numerous studies have been completed internationally in an effort to determine the optimal treatment regimen for this patient population. The importance of pre-therapy staging is of key importance as sequencing of therapy appears to significantly impact outcome. In the United States, patients with stage II/III rectal cancer are recommended to undergo preoperative concurrent pelvic radiation and chemotherapy followed by surgery several weeks later in order to maximize treatment response, which is then followed by approximately 4 months of adjuvant 5-fluorouracil-based systemic therapy. In Europe, there is substantial evidence supporting the use of neoadjuvant radiation therapy, however the role of concurrent chemotherapy remains a question of debate. Regardless of definitive management strategy, close follow-up in the post-treatment setting is important for early tumor detection and for managing treatment-related side-effects.

Positron emission tomography (PET) shows great promise as a tool to evaluate the effectiveness of rectal cancer neoadjuvant therapy as it has demonstrated high predictive value in several studies. Creating a standardized method of using PET has the potential to reduce ineffective treatments. However, relevant studies have been heterogenous in approach, making any unified standard difficult to establish. PET related parameters used to assess treatment response include magnitude and change of standard uptake value, total lesion glycolysis, and visual response. Finding the best evaluation interval and parameters to use for interpreting PET results in the neo-adjuvant treatment of rectal cancer needs additional study.

Esophageal cancer is rising in incidence and has a poor prognosis. Positron Emission Tomography (PET) is increasingly being investigated as a tool to more discriminately manage these patients. Several studies have indicated benefits in the use of PET for staging and assessment of treatment response while others have provided contradicting results. There are many possible factors that might contribute to these results, including variability in the manner of PET administration and interpretation, timing, and study design. PET acquired after chemoradiation or chemotherapy may give important prognostic information that can guide additional management decisions. Studies have had substantial variability in the timing and manner of assessing PET for this purpose, and additional study is needed.

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.

To analyze clinical and dosimetric factors associated with change in renal function in patients with gastrointestinal malignancies after chemoradiation to the abdomen.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.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 (p0.0001). 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 Gradeor =2 renal complications at 1 year after chemoradiation (p = 0.0025, 0.0170, and 0.0095, respectively).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.

Overexpression of epidermal growth factor receptor (EGFR) in esophageal cancer is associated with poor prognosis. Preclinical studies indicate synergism between the EGFR inhibitor gefitinib and oxaliplatin or radiotherapy (RT). We report here early results of a planned phase I/II study of gefitinib, oxaliplatin, and RT for locally advanced, unresectable esophageal cancer.The protocol consisted of oral gefitinib 250 mg daily for 1 year plus intravenous oxaliplatin 85 or 100 mg/m(2) on days 1, 15, and 29, and RT (50.4 Gy in 28 1.8-Gy fractions). Four-quadrant biopsies were obtained at 1-cm intervals along the length of the tumor before and after treatment and the specimens were immunostained for EGFR, Erk, Akt, and their phosphorylated (activated) forms.Enrollment was halted at 6 evaluable cases [all male; median age, 72.5 years (range, 51-75); and all with Eastern Cooperative Oncology Group performance status of 1]. All 6 tumors were adenocarcinomas; 5 were stage III and 1 stage IVA. Oxaliplatin was given at 85 mg/m(2) in 3 cases and at 100 mg/m(2) in 3 cases. Gefitinib therapy lasted a median 24 weeks; the median number of oxaliplatin doses was 6.5. Best responses were mucosal complete response (n = 1), partial response (n = 1), stable disease (n = 1), and progressive disease (n = 3). EGFR was expressed by tumor in 5 cases and Erk and Akt in 6 cases before treatment; no changes were noted after treatment. EGFR expression did not correlate with survival or response. No grade 4 toxicities were noted; grade 3 toxicities were diarrhea (n = 1), vomiting (n = 1), fatigue (n = 1), and constipation (n = 2). Median overall and disease-free survival times were 10.8 months and 8.4 months.Gefitinib in combination with oxaliplatin and RT was tolerable, but had limited clinical activity and did not down-regulate total or activated EGFR, Akt, or Erk in esophageal tumor samples.

Gastric cancer is a highly virulent neoplasm with high morbidity and mortality. Although the benefit of radiation therapy (RT) combined with chemotherapy in gastric cancer has been established, challenges remain in providing accurate and safe radiation delivery. Improved understanding of patterns of gastric cancer relapse and tumor spread, and of organ motion in the abdomen, has allowed for implementation of more conformal radiation techniques. At a minimum, successful implementation of conformal RT requires a detailed understanding of gastric anatomy and radiobiologic principles, an individualized assessment of organ motion, precise patient immobilization techniques, and adequate physics and dosimetry expertise. To aid the practicing clinician, the Gastric Surgical Adjuvant Radiotherapy Consensus Report and National Comprehensive Cancer Network have recently formulated detailed recommendations on simulation, treatment planning, target volumes, and dose limits for select critical normal structures. The practicing clinician is urged to draw upon the multitude of resources now available to ensure that optimal RT for gastric cancer is delivered safely and accurately.

Dimerization of epidermal growth factor receptor (EGFR) on the cell membrane of tumor cells has been implicated in triggering a complex signal cascade that leads to increased tumor proliferation and survival. Cetuximab is a human-murine chimeric monoclonal antibody designed to target EGFR and competitively inhibit dimerization by circulating ligands. By this mechanism, it works to prevent this signal cascade thus hindering tumor proliferation. Cetuximab has been shown in a randomized phase III clinical trial to significantly increase overall survival when it is added to radiation therapy in the treatment of locally advanced squamous cell carcinoma of the head and neck. In this manuscript, the mechanism of cetuximab with its associated patents is reviewed, with its role with chemotherapy and radiation in the management of head and neck cancer along with future directions of this targeted cancer therapy.

Radiation therapy serves an integral role in the primary and adjuvant treatment of esophagus cancer. Radiation techniques continue to improve, providing more accurate localization of the tumor while limiting dose to normal structures. This article reviews current practices and recommendations for radiation therapy technique for esophageal and gastroesophageal malignancies.