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To study the frequency and effect associated with postoperative radiotherapy (RT) for patients with resected gastrointestinal (GI) cancers.In observational cohort from the Surveillance, Epidemiology, and End Results (SEER) program, a total of 23,049 patients were identified with resected pancreatic, gastric, esophageal, or rectal carcinomas diagnosed from 1988 to 2003. Using a propensity score analysis, survival differences associated with postoperative RT were analyzed.Adjuvant RT was given to 51.2%, 26.3%, 33.0%, and 58.0% of pancreatic, gastric, esophageal, and rectal cancer patients, respectively. Age and stage of disease were associated with RT use for each site (P0.001), with younger patients and those with advanced disease receiving RT more frequently. Postoperative RT was associated with a survival benefit for patients with pancreatic cancer (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.79-0.96), gastric cancer (HR, 0.93; 95% CI, 0.87-0.99), and rectal cancer (HR, 0.84; 95% CI, 0.79-0.90). Subgroups of patients were also identified who experienced the greatest improvement in survival with RT (stage IIB pancreatic cancer, HR = 0.71 [95% CI 0.62-0.80]; stage IIIA and IV gastric cancer, HR = 0.86 [95% CI 0.77-0.97] and HR = 0.77 [95% CI 0.67-0.89], respectively; stages IIA, IIIB, and IIIC rectal cancer, HR = 0.87 [95% CI 0.78-0.97], HR = 0.71 [95% CI 0.63-0.80], and HR = 0.79 [95% CI 0.70-0.90], respectively).Postoperative RT is associated with improved survival for patients who undergo curative resection of pancreatic, gastric, and rectal malignancies. Significant differences are observed for this effect according to stage of disease, with more advanced cases in general experiencing a greater benefit with RT.

Purpose Reirradiation to the esophagus carries a significant risk of complications. Proton therapy may offer an advantage in the reirradiation setting due to the lack of exit dose and potential sparing of previously radiated normal tissues. Methods and Materials Between June 2010 and February 2014, 14 patients with a history of thoracic radiation and newly diagnosed or locally recurrent esophageal cancer began proton beam reirradiation on a prospective trial. Primary endpoints were feasibility and acute toxicity. Toxicity was graded according Common Toxicity Criteria version 4.0. Results The median follow-up was 10 months (2-25 months) from the start of reirradiation. Eleven patients received concurrent chemotherapy. The median interval between radiation courses was 32 months (10-307 months). The median reirradiation prescription dose was 54.0 Gy (relative biological effectiveness [RBE]) (50.4-61.2 Gy[RBE]), and the median cumulative prescription dose was 109.8 Gy (76-129.4 Gy). Of the 10 patients who presented with symptomatic disease, 4 patients had complete resolution of symptoms, and 4 had diminished or stable symptoms. Two patients had progressive symptoms. The median time to symptom recurrence was 10 months. Maximum acute nonhematologic toxicity attributable to radiation was grade 2 (64%, N=9), 3 (29%, N=4), 4 (0%), and 5 (7%, N=1). The acute grade 5 toxicity was an esophagopleural fistula more likely related to tumor progression than radiation. Grade 3 nonhematologic acute toxicities included dysphagia, dehydration, and pneumonia. There was 1 late grade 5 esophageal ulcer more likely related to tumor progression than radiation. There were 4 late grade 3 toxicities: heart failure, esophageal stenosis requiring dilation, esophageal ulceration from tumor, and percutaneous endoscopic gastrostomy tube dependence. The median time to local failure was 10 months, and the median overall survival was 14 months. Conclusions Our data demonstrate that proton reirradiation is feasible, with an encouraging symptom control rate, modest radiation-related toxicity, and favorable survival in this high-risk population.

The purpose of this study was to assess the feasibility of proton pencil beam scanning (PBS) for the treatment of mediastinal lymphoma. A group of 7 patients of varying tumor size (100?800?cc) were planned using a PBS anterior field. We investigated 17 fractions of 1.8?Gy(RBE) to deliver 30.6?Gy(RBE) to the internal target volume (ITV). Spots with ? ranging from 4?mm to 8?mm were used for all patients, while larger spots (??=?6?16?mm) were employed for patients with motion perpendicular to the beam (?5?mm), based on initial 4-dimensional computed tomography (4D CT) motion evaluation. We considered volumetric repainting such that the same field would be delivered twice in each fraction. The ratio of extreme inhalation amplitude and regular tidal inhalation amplitude (free-breathing variability) was quantified as an indicator of potential irregular breathing during the scanning. Four-dimensional dose was calculated on the 4D CT scans based on the respiratory trace and beam delivery sequence, implemented by partitioning the spots into separate plans on each 4D CT phase. Four starting phases (end of inhalation, end of exhalation, middle of inhalation and middle of exhalation) were sampled for each painting and 4 energy switching times (0.5?s, 1?s, 3?s and 5?s) were tested, which resulted in 896 dose distributions for the analyzed cohort. Plan robustness was measured for the target and critical structures in terms of the percent difference between ?delivered? dose (4D-evaluated) and planned dose (calculated on average CT). It was found that none of the patients exhibited highly variable or chaotic breathing patterns. For all patients, the ITV D98% was degraded by?

Background. Concurrent chemoradiotherapy cures most patients with anal squamous cell carcinoma at the cost of significant treatment-related toxicities. Intensity-modulated radiotherapy (IMRT) reduces side effects compared to older techniques, but whether proton beam therapy (PBT) offers additional advantages is unclear.Material and methods. Eight patients treated with PBT for anal cancer were chosen for this study. We conducted detailed plan comparisons between pencil-beam scanning PBT via two posterior oblique fields and seven-field IMRT. Cumulative dose-volume histograms were analyzed by Wilcoxon signed-rank test, and plan delivery robustness was assessed via verification computed tomography (CT) scans obtained during treatment.Results. Compared to IMRT, PBT reduced low dose radiation (≤ 30 Gy) to the small bowel, total pelvic bone marrow, external genitalia, femoral heads, and bladder (all p < 0.05) without compromising target coverage. For PBT versus IMRT, mean small bowel volume receiving ≥ 15 Gy (V15) was 81 versus 151 cm3, mean external genitalia V20 was 14 versus 40%, and mean total pelvic bone marrow V15 was 66 versus 83% (all p = 0.008). The lumbosacral bone marrow dose was higher with PBT due to beam geometry. PBT was delivered with ≤ 1.3% interfraction deviation in the dose received by 98% of the clinical target volumes.Conclusion. Pencil-beam scanning PBT is clinically feasible and can be robustly delivered for anal cancer patients. Compared with IMRT, PBT reduces low dose radiation to important organs at risk in this population. While the clinical benefit of these differences remains to be shown, existing data suggest that limiting low dose to the small bowel and pelvic bone marrow may reduce treatment toxicity.

The dose distributions that can be achieved with protons are usually superior to those of conventional photon external-beam radiation. There are special cases where proton therapy may offer a substantial potential benefit compared to photon treatments where toxicity concerns dominate. Re-irradiation may theoretically be made safer with proton therapy due to lower cumulative lifetime doses to sensitive tissues, such as the spinal cord. Proton therapy has been used in a limited number of patients with rectal, pancreatic, esophageal, and lung cancers. Chordomas and soft tissue sarcomas require particularly high radiation doses, posing additional challenges for re-irradiation. Lymphoma is another special case where proton therapy may be advantageous. Late toxicities from even relatively low radiation doses, including cardiac complications and second cancers, are of concern in lymphoma patients with high cure rates and long life expectancies. Proton therapy has begun to be used for consolidation after chemotherapy in patients with Hodgkin and non-Hodgkin lymphoma. Breast cancer is another emerging area of proton therapy development and use. Proton therapy may offer advantages compared to other techniques in the setting of breast boosts, accelerated partial breast irradiation, and post-mastectomy radiotherapy. In these settings, proton therapy may decrease toxicity associated with breast radiotherapy. As techniques are refined in proton therapy, we may be able to improve the therapeutic ratio by maintaining the benefits of radiotherapy while better minimizing the risks.

Purpose Stereotactic body radiation therapy (SBRT) for treatment of liver tumors is often limited by liver dose constraints. Protons offer potential for more liver sparing, but clinical situations in which protons may be superior to photons are not well described. We developed and validated a treatment decision model to determine whether liver tumors of certain sizes and locations are more suited for photon versus proton SBRT. Methods and materials Six spherical mock tumors from 1 to 6 cm in diameter were contoured on computed tomography images of 1 patient at 4 locations: dome, caudal, left medial, and central. Photon and proton plans were generated to deliver 50 Gy in 5 fractions to each tumor and optimized to deliver equivalent target coverage and maximal liver sparing. Using these plans, we developed a hypothesis-generating model to predict the optimal modality for maximal liver sparing based on tumor size and location. We then validated this model in 10 patients with liver tumors. Results Protons spared significantly more liver than photons for dome or central tumors ≥3 cm (dome: 134 ± 21 cm 3 , P = .03; central: 108 ± 4 cm 3 , P = .01). Our model correctly predicted the optimal SBRT modality for all 10 patients. For patients with dome or central tumors ≥3 cm, protons significantly increased the volume of liver spared (176 ± 21 cm 3 , P = .01) and decreased the mean liver dose (8.4 vs 12.2 Gy, P = .01) while offering no significant advantage for tumors Conclusions When feasible, protons should be considered as the radiation modality of choice for dome and central tumors >3 cm to allow maximal liver sparing and potentially reduce radiation toxicity. Protons should also be considered for any tumor >5 cm if photon plans fail to achieve adequate coverage or exceed the mean liver threshold.

Hypoxia induces Hif-1alpha and selects for loss of wild-type p53 function, both of which can promote tumor cell survival. We evaluated the ability of TRAIL to induce apoptosis of human tumor cell lines exposed to hypoxia. H460 lung cancer cells express low levels of Hif-1alpha, stabilize wild-type p53 during hypoxia, and undergo TRAIL-induced apoptosis. In U2OS osteosarcoma or PA1 ovarian teratocarcinoma cells, high levels of Hif-1alpha and low levels of stable p53 are detected during hypoxia, and cells undergo low levels of TRAIL-induced apoptosis as compared to H460 cells. H460 cells are sensitized to TRAIL-induced apoptosis, whereas U2OS are protected, and little apoptosis is observed in relatively TRAIL-resistant PA1 during hypoxia. Forced expression of Hif-1alpha is also surprisingly a potent inducer of apoptosis in wild-type p53 expressing H460 cells and further promotes TRAIL-induced apoptosis. TRAIL-sensitive wild-type p53-expressing HCT116 colon carcinoma cells modestly elevate Hif-1alpha levels and are equally or slightly more sensitive to TRAIL during hypoxia. In contrast, p53-null HCT116 have higher levels of Hif-1alpha during normoxia and are extremely sensitive to TRAIL, but are protected from TRAIL-induced apoptosis during hypoxia. We hypothesize that a hypoxic tumor microenvironment may alter sensitivity to TRAIL, which may be impacted by Hif-1alpha levels and p53 status. These findings suggest that particular attention to hypoxic regions of tumors and sensitizers to hypoxia-induced cell death may be required to optimize therapeutic combinations using TRAIL.

Oxidation products of lipids, proteins, and DNA in the blood, plasma, and urine of rats were measured as part of a comprehensive, multilaboratory validation study searching for noninvasive biomarkers of oxidative stress. This article is the second report of the nationwide Biomarkers of Oxidative Stress Study using acute CCl4 poisoning as a rodent model for oxidative stress. The time-dependent (2, 7, and 16 h) and dose-dependent (120 and 1200 mg/kg i.p.) effects of CCl4 on concentrations of lipid hydroperoxides, TBARS, malondialdehyde (MDA), isoprostanes, protein carbonyls, methionine sulfoxidation, tyrosine products, 8-hydroxy-2'-deoxyguanosine (8-OHdG), leukocyte DNA-MDA adducts, and DNA-strand breaks were investigated to determine whether the oxidative effects of CCl4 would result in increased generation of these oxidation products. Plasma concentrations of MDA and isoprostanes (both measured by GC-MS) and urinary concentrations of isoprostanes (measured with an immunoassay or LC/MS/MS) were increased in both low-dose and high-dose CCl4-treated rats at more than one time point. The other urinary markers (MDA and 8-OHdG) showed significant elevations with treatment under three of the four conditions tested. It is concluded that measurements of MDA and isoprostanes in plasma and urine as well as 8-OHdG in urine are potential candidates for general biomarkers of oxidative stress. All other products were not changed by CCl4 or showed fewer significant effects.

369 Background: Diabetes mellitus (DM) has been linked to poor prognosis in pancreatic cancer in numerous retrospective datasets, potentially due to higher levels of insulin and insulin-like growth factor increasing cellular proliferation. Additionally, the hyperglycemic state as well as obesity may lead to a pro-inflammatory state that may enhance tumor progression and metastases. In this analysis, the prognostic significances of diabetes, insulin use, and BMI are evaluated in a prospective, randomized trial of resectable pancreatic ductal adenocarcinoma. Methods: As previously reported, RTOG 9704 pts with resected pancreatic cancer were randomized to 5-fluorouracil (5-FU) or gemcitabine (Gem), given pre and post radiation (RT). Pts in both arms received RT to 50.4 Gy with 5-FU. DM and insulin use were collected on the RTOG 9704 CRFs. BMI was dichotomized as normal/underweight vs. overweight/obese. Overall survival (OS) and disease-free survival (DFS) were estimated by Kaplan-Meier method and variable levels were compared using log-rank test. Cox models were used for multivariable analyses. Results: 538 pts were enrolled from 1998-2002. 238 pts were eligible with analyzable diabetes and insulin use data, in addition to surgical pathology, and CA19-9 data. 32% and 35% of pts in the 5-FU and Gem arms, respectively, had DM. Of which, 24% and 19% used insulin in the 5-FU and Gem arms, respectively. 55% were overweight/obese. The 4 yr OS was 25% (95% CI: 18, 32) in pts with no diabetes, vs. 18% (10, 27) with DM (HR = 1.3 [0.9, 1.7]; p = 0.11). The 4-yr DFS was 14% (9, 20) in pts with no diabetes, vs. 9% (4, 16) with diabetes (HR = 1.2 [0.9, 1.5]; p = 0.31). Neither insulin use nor BMI was univariately associated with OS or DFS. On multivariate analysis, including nodal status, CA19-9, and other variables, DM, insulin use, and BMI were not associated with OS or DFS. Conclusions: DM, insulin use, and BMI were not associated with OS in pts with resected pancreatic cancer treated with adjuvant chemotherapy and chemoradiation. Node involvement and CA19-9 remain the most significant predictors of OS. Supported by NCI grants U10CA180868, U10CA180822, UG1CA189867 and Eli Lilly Clinical trial information: NCT00003216.

Uncontrolled local growth is the cause of death in ∼ 30% of patients with unresectable pancreatic cancers. The addition of standard-dose radiotherapy to gemcitabine has been shown to confer a modest survival benefit in this population. Radiation dose escalation with three-dimensional planning is not feasible, but high-dose intensity-modulated radiation therapy (IMRT) has been shown to improve local control. Still, dose-escalation remains limited by gastrointestinal toxicity. In this study, the authors investigate the potential use of double scattering (DS) and pencil beam scanning (PBS) proton therapy in limiting dose to critical organs at risk.The authors compared DS, PBS, and IMRT plans in 13 patients with unresectable cancer of the pancreatic head, paying particular attention to duodenum, small intestine, stomach, liver, kidney, and cord constraints in addition to target volume coverage. All plans were calculated to 5500 cGy in 25 fractions with equivalent constraints and normalized to prescription dose. All statistics were by two-tailed paired t-test.Both DS and PBS decreased stomach, duodenum, and small bowel dose in low-dose regions compared to IMRT (p0.01). However, protons yielded increased doses in the mid to high dose regions (e.g., 23.6-53.8 and 34.9-52.4 Gy for duodenum using DS and PBS, respectively; p0.05). Protons also increased generalized equivalent uniform dose to duodenum and stomach, however these differences were small (5% and 10%, respectively; p0.01). Doses to other organs-at-risk were within institutional constraints and placed no obvious limitations on treatment planning.Proton therapy does not appear to reduce OAR volumes receiving high dose. Protons are able to reduce the treated volume receiving low-intermediate doses, however the clinical significance of this remains to be determined in future investigations.

The main objectives of follow-up studies after completion of treatment for Hodgkin lymphoma are detection of recurrence for salvage therapy and monitoring for sequelae of treatment. The focus of the follow-up shifts, with time after treatment, from detection of recurrence to long-term sequelae. A majority of recurrence is detected by history and physical examination. The yield for routine imaging studies and blood tests is low. Although routine surveillance CT scan can detect recurrence not detected by history and physical examination, its benefit in ultimate survival and cost-effectiveness is not well defined. Although PET scan is a useful tool in assessing response to treatment, its routine use for follow-up is not recommended. Long-term sequelae of treatment include secondary malignancy, cardiovascular disease, pneumonitis, reproductive dysfunction, and hypothyroidism. Follow-up strategies for these sequelae need to be individualized, as their risks in general depend on the dose and volume of radiation to these organs, chemotherapy, age at treatment, and predisposing factors for each sequela. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is either lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

Background. Adjuvant chemoradiotherapy improves both overall- and relapse-free survival in patients with resected gastric cancer. However, this comes at the cost of increased treatment-related toxicity. Proton therapy (PT) has distinct dosimetric characteristics that may reduce dose to normal tissues, improving the therapeutic ratio. The purpose of this treatment planning study is to compare PT and intensity-modulated x-ray therapy (IMXT) in gastric cancer with regards to normal tissue sparing.Material and methods. The patient population consisted of resected gastric cancer patients treated at a single institution between 2008 and 2013. Patients who had undergone 4D CT simulation were replanned to the originally delivered doses (45–54 Gy in 25–30 daily fractions) using six-field photon IMXT and 2–3-field PT (double scattering-uniform scanning techniques).Results. Thirteen patients were eligible for the planning comparison. IMXT provided slightly higher homogeneity indices (median values 0.04 ± 0.01 vs. 0.07 ± 0.01, p = 0.03). PT resulted in significantly (p < 0.05) lower intermediate-low doses for all the normal tissues examined (small bowel V15 82 ml vs. 133 ml, liver mean doses Gy 11.9 vs. 14.4 Gy, left/right kidney mean doses 5/0.9 Gy vs. 7.8/3.1 Gy, heart mean doses 7.4 Gy vs. 9.5 Gy). The total energy deposited outside the target volume was significantly lower with PT (median integral dose 90.1 J vs. 129 J). Four patients were treated with PT: treatment was feasible and verifications scans showed that target coverage was robust.Conclusion. PT can contribute to normal tissue sparing in the adjuvant treatment of gastric cancer, with a potential benefit in terms of compliance to treatment, acute and late toxicities.

Background: Optimal therapy for patients with early stage Hodgkin lymphoma (HL) is controversial. Combined modality therapy (CMT) utilizes chemotherapy plus consolidative radiotherapy (RT). CMT produces higher initial cure rates, but also increases the long-term risk of radiation toxicity. The most important risks include higher rates of breast and lung cancer, and ischemic heart disease due to mediastinal radiation exposure. Chemotherapy-only (CT) treatment with ABVD produces lower initial cure rates versus CMT, but also yields less long-term toxicity. Furthermore, those CT patients that fail initial therapy can often be salvaged with autologous stem cell transplant (ASCT). To help guide patient-specific strategies, we developed a Markov decision-analytic model to estimate long-term mortality in patients with early stage unfavorable HL involving the mediastinum treated with CMT vs. CT. Methods: We builta decision tree with Markov modeling to compare long-term mortality due to relapse, ischemic heart disease, and breast or lung cancer in hypothetical patients treated with CT or CMT using TreeAge Pro 2016. The model follows a hypothetical cohort of patients from primary therapy through 20-year follow-up. Patients transition between health states (Figure 1) based on probabilities extracted from 13 published studies. Patients that fail therapy then move to survival curves based on early vs. late relapse. The probability of toxicity was based on relative risks found in studies that used ABVD alone or ABVD with involved field or larger RT volumes. Patients who develop a toxicity move to a survival curve specific to that adverse effect. The model estimated 20-year survival in cohorts based on sex, upper vs. lower mediastinal disease, and age (20 y/o vs. 40 y/o) in non-smokers. Results: In 20 y/o patients, CMT showed better long-term survival than CT alone with slightly larger difference in mortality (1.6%) in males with upper mediastinal disease than in females (1.4%) (Table 1). In the cohort of 20 year old males, the causes of death in CMT vs. CT 20 years from starting therapy, respectively, were as follows: HL (4.7% vs. 6.6%); breast cancer (0% vs. 0%); lung cancer (0.1% vs. 0.1%); ischemic heart disease (0.6% vs. 0.3%). In 40 y/o patients, CT showed better long-term survival. The largest difference in mortality was 7.6% in 40 y/o females with lower mediastinal disease (19.9% in CMT vs. 12.3% in CT-only). In this cohort, the causes of death in CMT vs. CT, respectively were: HL (4.6% vs. 6.6%); breast cancer (4.7% vs. 1.0%); lung cancer (2.9% vs. 2.1%); ischemic heart disease (7.8% vs. 2.6%). CT-only also showed a survival benefit of 4.9% in 40 y/o males with lower mediastinal disease. Causes of death in CMT vs. CT, respectively: HL (4.6% vs. 6.6%); lung cancer (3.3% vs. 2.2%); ischemic heart disease (8.5% vs. 2.7%). At 20 years post treatment, CT-only tends to favor older patients, while CMT tends to favor younger patients due to lower baseline risks of dying from second cancers and ischemic heart disease in 40 y/o compared to 60 y/o survivors. Conclusions: This model may help multidisciplinary decision making when determining the optimum strategy for different types of patients based on disease location and risk factors for relapse and toxicity. In this study the benefits of radiation were erased by the higher rates of toxicities in older patients. Of note, the published relative risks used in this model were from studies using outdated large radiation fields rather than modern approaches. The impact of using much smaller "involved site" volumes, intensity modulated RT, and/or proton therapy is unknown but would likely lower long-term mortality from CMT. Further work using probabilistic sensitivity analyses can test these initial conclusions. Figure 1 Schematic Diagram of Markov Model Figure 1. Schematic Diagram of Markov Model Table 1 Comparison of Long-term Survival in Cohorts Table 1. Comparison of Long-term Survival in Cohorts Disclosures Hwang: Novartis: Research Funding. Nasta:Millennium Pharmaceuticals: Research Funding. Mato:Abbvie, Gilead Sciences, Pharmacyclics, TG Therapeutics: Consultancy; Abbvie, Acerta Pharma, Gilead Sciences, ProNAi, TG Therapeutics, Theradex: Research Funding. Schuster:Hoffman-LaRoche: Research Funding; Genentech: Consultancy, Honoraria; Gilead: Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Research & Development: Research Funding. Svoboda:Celgene: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding.

The present guidelines review epidemiology, pathology, presentation, workup, staging, prognostic factors, and treatment options for patients with localized nodal indolent lymphoma, with an emphasis on radiation guidelines, including radiation dose, field design, and radiation techniques. Following a discussion of the current literature and available data for treatment and outcomes of patients with indolent lymphoma, several different example cases are reviewed to help physicians make appropriate treatment decisions. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) by which the panel rates the appropriateness of imaging and treatment procedures. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

Malondialdehyde (MDA), a mutagenic product of lipid peroxidation, reacts with DNA to form the premutagenic lesion, pyrimido[1, 2-a]purin-10(3H)-one (M(1)G). M(1)G is present in normal human tissues, but the contribution of other endogenously produced MDA analogues is poorly understood. Oxidation of the DNA backbone can cause strand breaks and release base propenals, and MDA condensation with proteins yields N(epsilon)-oxopropenyllysine. Here we compare the M(1)G-forming ability and Salmonella typhimurium mutagenicity of MDA with adenine, thymine, and cytosine propenals and N(alpha)-acetyl-N(epsilon)-oxopropenyllysine methyl ester. Base propenals are 30-150 times more potent than MDA in M(1)G formation and are 30-60 times more mutagenic than MDA. In addition, the Fe-bleomycin complex, which generates base propenals, induced M(1)G, but gamma-radiation, which generates mostly MDA, did not. M(1)G formation by MDA and base propenals was concentration-dependent, time-dependent, and enhanced by acidic conditions. N(alpha)-Acetyl-N(epsilon)-oxopropenyllysine methyl ester was less reactive and less mutagenic than MDA. These differences in potency are consistent with differences in leaving group ability. This work supports a role for other MDA analogues, especially base propenals, in the formation of endogenous M(1)G adducts.

Malondialdehyde (MDA) is a product of lipid peroxidation and prostaglandin biosynthesis. It is mutagenic and carcinogenic and the major adduct formed by reaction with DNA, a highly fluorescent pyrimidopurinone (M 1 -dG), has been detected in healthy human liver and leukocyte DNA. Analytical methods used so far for the detection of M 1 -dG have not been applied to a large number of individuals or variety of samples. Often, only a few μg of DNA from human tissues are available for analysis and a very sensitive assay is needed in order to detect background levels of M 1 -dG in very small amounts of DNA. In this paper, the development of an immunoslot blot (ISB) assay for the measurement of M 1 -dG in 1 μg of DNA is described. The limit of detection of the assay is 2.5 adducts per 10 8 bases. A series of human samples were analysed and levels of 5.6-9.5 (n = 8) and 3.1-64.3 (n = 42) of M 1 -dG per 10 8 normal bases were detected in white blood cell and gastric biopsy DNA, respectively. Results on four human samples were compared with those obtained using an HPLC/ 32 P-post-labelling (HPLC/PPL) method previously developed and indicated a high correlation between M 1 -dG levels measured by the two assays. The advantages of ISB over other assays including HPLC/PPL, such as the possibility of analysing 1 μg DNA/sample and the fact that it is less time-consuming and laborious, means that it can be more easily used for routine analysis of a large number of samples in biomonitoring studies.

Commentary to:Antagonistic Interactions Between Gemcitabine and 5-Fluorouracil in the Human Pancreatic Carcinoma Cell Line Capan-2Graziella Bellone, Anna Carbone, Valeria Busso, Tiziana Scirelli, Alessandra Buffolino, Carlo Smirne, Anna Novarino, Oscar Bertetto, Luciano Tosetti and Giorgio Emanuelli

Purpose The aim of this study was to quantify the impact of rectal stool/gas volumes on intrafraction prostate motion for patients undergoing prostate radiotherapy with daily endorectal balloon (ERB). Methods Total and anterior stool/gas rectal volumes were quantified in 30 patients treated with daily ERB. Real-time intrafraction prostate motion from 494 treatment sessions, at most 6min in length, was evaluated using Calypso® tracking system. Results The deviation of prostate intrafraction motion distribution was a function of stool/gas volume, especially when stool/gas is located in the anterior part of the rectum. Compared to patients with small anterior stool/gas volumes ( 3 ), those with large volume (10–60cm 3 ) had a twofold increase in 3D prostate motion and interquartile data range within the 6th minute of treatment time. The 10% of the overall CBCT session where large anterior rectal volumes were observed demonstrated larger percentage of time at displacement greater than our proposed internal margin 3mm. Conclusion Volume and location of stool/gas can directly impact the ERB's intrafraction immobilization ability. Although our patient preparation protocol and the 100cm 3 daily ERB effectively stabilized prostate motion for 90% of the fractions, a larger-sized ERB may improve prostate fixation for patients with greater and/or variable daily rectal volume.

The role of 18F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT) in the staging and radiation treatment planning of locally advanced rectal cancer is ill defined. We studied the role of integrated PET/CT in the staging, radiation treatment planning, and use as an imaging biomarker in rectal cancer patients undergoing multimodality treatment.Thirty-four consecutive patients with T3-4N0-2M0-1 rectal adenocarcinoma underwent FDG-PET/CT scanning for staging and radiation treatment planning. Planned clinical management was compared before and after the addition of PET/CT information. Three radiation oncologists independently delineated CT-based gross tumor volumes (GTVCT) using clinical information and CT imaging data, as well as gradient autosegmented PET/CT-based GTVs (GTVPETCT). The mean GTV, interobserver concordance index (CCI), and proximal and distal margins were compared. The maximal standardized uptake value (SUVmax), metabolic tumor volume (MTV), and dual-time point PET parameters were correlated with clinicopathologic endpoints.Clinical management was altered by PET/CT in 18% (n = 6) of patients with clinical upstaging in 6 patients and radiation treatment planning altered in 5 patients. Of the 30 evaluable preoperative patients, the mean GTVPETCT was significantly smaller than the mean GTVCT volumes: 88.1 versus 102.8 cc (P = .03). PET/CT significantly increased interobserver CCI in contouring GTV compared with CT only-based contouring: 0.56 versus 0.38 (P.001). The proximal and distal margins were altered by a mean of 0.4 ± 0.24 cm and -0.25 ± 0.18 cm, respectively. MTV was inversely associated with 2-year progression-free survival (PFS) and overall survival (OS): smaller MTVs (33 cc) had superior 2-year PFS (86% vs 60%, P = .04) and OS (100% vs 45%, P.01) compared with larger MTVs (33 cc). SUVmax and dual-time point PET parameters did not correlate with any endpoints.FDG-PET/CT imaging impacts overall clinical management and is useful in the radiation treatment planning of rectal cancer patients by decreasing interobserver variability in contouring target boost volumes. Pretreatment MTV may provide useful prognostic information and requires further study.

Potential collision between the patient∕couch and the gantry could delay the start of the treatment and reduce clinical efficiency. The ability to accurately detect possible collisions during the treatment planning phase is desired. Such collision detection should account for the specific proton gantry design, the treatment beam configuration, couch orientation, and the patient specific geometry. In this paper the authors developed an approach to detect possible patient-machine collisions using patient treatment plan data.The geometry of the machine and the patient was reconstructed relative to the isocenter of the proton treatment room. The surface contour of the gantry was first captured from the proton computer aided design and reconstructed to account for specific gantry rotation, snout position, collimator rotation, and range compensator dimensions based on the patient treatment plan data. The patient body and couch contours were captured from the patient's CT DICOM structure file. They were reconstructed relative to the isocenter taking into account treatment couch rotation. For potential collision that occurs at body portions where no CT images exist, scout images are used to construct the body contour. A software program was developed using a ray casting algorithm that was applied to detect collisions by determining if any of the patient and couch contour points fall into the spatial polygons formed by the proton gantry surfaces.Twenty-four patient plans with or without potential collisions were retrospectively identified and analyzed using the collision detection software. In addition, five collision cases were artificially generated using an anthropomorphic phantom. The program successfully detected the collisions in all cases. The calculation time for each case was within 20 s. The software program was implemented in the authors' clinic to detect patient-gantry or gantry-couch collisions in the treatment planning phase.The authors developed a fast and clinically feasible patient-specific collision detection program for proton therapy based on a ray casting algorithm. If incorporated during the treatment planning phase it may lead to improved clinical efficiency. This methodology could also be applied to patient collision detection in photon therapy.

312 Background: Reasons for hospitalizations in patients undergoing curative-intent radiotherapy (RT) have not been well characterized previously. Implementation of urgent cancer care clinics could decrease rates of hospitalization, but the reasons for acute visits must be better understood. This retrospective cohort study investigates emergency department (ED) visits or admissions in patients treated with definitive RT. Methods: Under an IRB-approved protocol, the cohort was defined as all consecutive patients >=18 yo who began RT (RTSTART) between 7/1/11 and 12/31/13 for nonmetastatic disease with curative intent. An acute encounter was defined as an ED visit or inpatient admission during RT or 30 days after the conclusion of RT (30DA). Results: A total of 1852 unique RT courses from 1823 patients were identified, within which there were 666 RT unique courses (657 patients) who had at least one acute encounter. There were 1006 acute encounters, comprising 287 ER and 719 inpatient visits. The number of admissions per RT course ranged from 1 to 9, with 3. The mean difference between post- and pre-RT ECOG performance status was greater for patients with acute encounters than those without (0.47 vs. 0.06). For those admitted, the median days from RTSTART to admission were 36 (0-81) and 68.2% received concurrent chemotherapy. Conclusions: In this large analysis from a single quaternary cancer center,over one-third of patients receiving curative-intent RT had an acute encounter, a high percentage of whom received chemotherapy. Further investigations are needed to classify which admissions were unanticipated, which in turn would guide design of urgent cancer care centers for RT patients and improve quality of care. [Table: see text]

Basic Concepts: Historically, radiation therapy was an early curative treatment for Hodgkin lymphoma (HL), and it was also an effective treatment for non-Hodgkin lymphoma (NHL). Although effective multi-agent chemotherapy regimens for both HL and NHL have since been developed, radiation therapy remains an integral part of both curative and palliative management of lymphomas. Combined-modality therapy (CMT) has become standard in more clinical scenarios for HL than NHL, likely due to the more predictable progression and spread of HL. Nevertheless, the basic concepts affecting the optimal use of radiation in both diseases are similar, namely: staging, the dose–response relationship, combined-modality therapy, and risk/response-adapted therapy.

The purpose of this study is to evaluate the sensitivities of 3D diode arrays to setup error for patient‐specific quality assurance (QA) of volumetric‐modulated arc therapy (VMAT). Translational setup errors of ±1,±2, and ±3 mm in the RL, SI, and AP directions and rotational setup errors of ±1° and ±2° in the pitch, roll, and yaw directions were set up in two phantom systems, ArcCHECK and Delta4, with VMAT plans for 11 patients. Cone‐beam computed tomography (CBCT) followed by automatic correction using a HexaPOD 6D treatment couch ensured the position accuracy. Dose distributions of the two phantoms were compared in order to evaluate the agreement between calculated and measured values by using γ analysis with 3%/3 mm, 3%/2 mm, and 2%/2 mm criteria. To determine the impact on setup error for VMAT QA, we evaluated the sensitivity of results acquired by both 3D diode array systems to setup errors in translation and rotation. For the VMAT QA of all patients, the pass rate with the 3%/3 mm criteria exceeded 95% using either phantom. For setup errors of 3 mm and 2°, respectively, the pass rates with the 3%/3 mm criteria decreased by a maximum of 14.0% and 23.5% using ArcCHECK, and 14.4% and 5.0% using Delta4. Both systems are sensitive to setup error, and do not have mechanisms to account for setup errors in the software. The sensitivity of both VMAT QA systems was strongly dependent on the patient‐specific plan. The sensitivity of ArcCHECK to the rotational error was higher than that of Delta4. In order to achieve less than 3% mean pass rate reduction of VMAT plan QA with the 3%/3 mm criteria, a setup accuracy of 2 mm/1° and 2 mm/2° is required for ArcCheck and Delta4 devices, respectively. The cumulative effect of the combined 2 mm translational and 1° rotational errors caused 3.8% and 2.4% mean pass rates reduction with 3%/3 mm criteria, respectively, for ArcCHECK and Delta4 systems. For QA of VMAT plans for nasopharyngeal cancer (NPC) using the ArcCHECK system, the setup should be more accurate. PACS numbers: 87.55.ne, 87.55.Qr, 87.55.km

A force field, developed and designated here as DNA/Pt, was optimized for modeling Pt ammine/amine complexes of guanine derivatives (G) bound via N7. DNA/Pt was based on the all-atom type force field of Weiner et al. (Weiner, S . J.; Kollman, P. A.; Nguyen, D. T.; Case, D. A. J . Comput. Chem. 1986, 7, 230) as modified by Veal and Wilson (Veal, J. M.; Wilson, D. W. J . Biomol. Struct. Dyn. 1991, 8, 1119). New atom types were created for Pt, N7 of G, and the amine/a"ine N and H atoms. Force field parameters for these new atom types were developed by comparing force field parameters found in the literature with the structural features of published crystal structures. Pt out-of-plane bending was treated by a single improper torsion barrier, C8-N7-C5-Pt. The force constant parameter for the improper torsional deformation barrier was determined in this study by fitting the resulting out-of-plane bending potential curve onto the corresponding profile from ab initio calculations on [Pt(NH3)3(Ade)12+ (Kozelka, J.; Savinelli, R.; Berthier, G.; Flament, J.-P.; Lavery, R. J . Comput. Chem. 1993, 14, 45). The DNA/Pt force field also includes parameters for the van der Waals radius of the Pt atom and for 06-HN(amine/a"ine) H-bonding. An empirical charge distribution method was used to modify the atomic point charges on the cis-[PtA2Gz] moiety, where A = amine or l/2 of a diamine. In general, widely used procedures were adopted. For example, a distance-dependent dielectric constant of E = 4ru and partially neutralized phosphates were used to represent solvent and counterion. The validity of this new DNA/Pt force field was evaluated by a number of test cases. Conformational features determined by either X-ray crystallographic or NMR techniques were reproduced well by the calculations. The rotational barriers for a number of complexes were calculated and were found to agree with NMR data quite well. The calculated relative stabilities of head-to-head and head-totail conformers of some complexes are also in good agreement with experimental results. Finally, an initial attempt to model lattice effects was found to improve the fit between calculated and crystal structures of the cis-[PtA2G2] species.

Radiation therapy (RT) is an important treatment modality in relapsed or refractory Hodgkin lymphoma (HL), providing local control and potentially durable responses when used as salvage therapy. For decades, RT has also been administered before and after autologous stem cell transplantation (ASCT) for consolidation, but no consensus exists regarding the efficacy or optimal timing of peri-transplant RT. Data is especially lacking on post-transplant consolidative RT, which may be associated with reduced toxicity and improved disease control compared with pre-transplant RT. We provide here a single-institution retrospective analysis comparing survival outcomes and toxicities according to receipt of post-transplant consolidative RT. Sixty-four patients with relapsed or refractory HL received ASCTs at our institution between 2006 and 2013. Seventeen patients received post-transplant consolidative RT, defined as completing RT within 5 months of ASCT, whereas 47 received no RT. All patients received staging PET/CT scans prior to ASCT and had at least 1 year of follow-up after ASCT. Primary outcomes included progression-free survival (PFS), overall survival (OS), and local control (LC), defined as the absence of relapse at previous sites of PET-avid disease. The log rank test was used to compare survival measures. Radiation-associated toxicities, including pulmonary and hematologic complications, were reviewed. For the entire cohort, median age at ASCT was 41 years and median follow-up after ASCT was 40 months. In the post-transplant RT group, there were more cases of disease limited to one side of the diaphragm, as shown in Table 1. There were also more cases of refractory HL, defined as persistent disease following frontline therapy, and a trend towards younger age and absence of prior RT. Median dose of post-transplant RT was 3540 cGy (Range: 1500 - 4050 cGy) and median time from ASCT to RT was 4 months (Range: 2 - 5 months). 16/17 (94%) patients received RT to supra-diaphragmatic sites only. For the entire cohort, OS was 84% and PFS was 50% at 36 months following ASCT. There was no significant difference in OS₃₆ among patients who received post-transplant RT (87% v. 83% for no RT, p = 0.68). There was also no significant difference in PFS₃₆ among post-transplant RT patients (55% v. 47% for no RT, p = 0.33). There was significant improvement in LC₃₆ among patients who received post-transplant RT (78% v. 48%, p = 0.02). There were also non-significant trends toward improved PFS₃₆ among patients who received post-transplant RT and had relapsed (rather than refractory) disease (75% v. 48%, p = 0.13) or had no prior RT (53% v. 35%, p = 0.14). 3/17 (18%) post-transplant RT patients died during the follow-up period, all secondary to disease progression. 9/47 (20%) patients with no post-transplant RT died during the follow-up period, of which 7 deaths were secondary to disease progression and 1 was a complication of ASCT. One patient developed grade III anemia and thrombocytopenia as an early complication of post-transplant RT, but no other acute or late RT-associated toxicities were observed. Patients receiving post-transplant consolidative RT have improved LC and limited RT-associated toxicity. While there was no significant improvement in PFS or OS in this group, patients who have not received radiation previously or who have relapsed disease may preferentially benefit from post-transplant RT. Our study was limited by small numbers. Selection bias may influence which patients are referred for post-transplant RT. For these reasons, analyses of larger patient populations and prospective study are warranted. Table 1. Baseline Patient Characteristics Characteristics With Post-Transplant RT (n = 17) Without Post-Transplant RT (n = 47) p-Value Median Age at ASCT (y) 37 43 0.06 Male Gender - n (%) 10 (59) 23 (49) 0.58 Stage Category - n (%) I / II 11 (65) 22 (47) 0.26 III / IV 6 (35) 25 (53) Bulky Mediastinal Adenopathy - n (%) 5 (29) 7 (15) 0.28 Presence of B Symptoms - n (%) 10 (59) 24 (51) 0.77 Prior Radiation - n (%) 3 (18) 18 (38) 0.14 Relapsed v. Refractory Disease - n (%) Relapsed 6 (35) 31 (66) 0.04 Refractory 11 (65) 16 (34) Disease Burden at Relapse - n (%) One Side of Diaphragm 16 (94) 28 (60) 0.01 Both Sides of Diaphragm 1 (6) 19 (40) Disease Status at Transplant - n (%) Complete Response 8 (47) 28 (60) 0.40 Partial Response 9 (53) 19 (40) Disclosures Schuster: Genentech: Consultancy; Pharmacyclics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Hoffman-LaRoche: Research Funding; Janssen: Research Funding; Gilead: Research Funding; Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding.

Pancreas cancer can potentially be cured by resection, but the role of adjuvant chemotherapy and/or chemoradiation has been controversial.To better define clinicopathological factors that may serve as predictive and/or prognostic variables.Between 1984 and 2006, we retrospectively analyzed 91 patients with pancreas cancer treated with pancreaticoduodenectomy or total pancreatectomy followed by adjuvant 5-fluorouracil-based chemoradiation at the University of Pennsylvania. Final pathological coding including margin status was confirmed by a pathologist.Patients were treated with 48.6 to 63.0 Gy, and 96.7% completed their prescribed radiation dose.The prognostic significance of demographic factors, stage, year of surgery, tumor location, grade, resection status, and number of positive lymph nodes on overall survival were examined.With a median follow-up of 6.5 years, the overall median survival was 2.3 years (95% CI 1.5-3.2 years), and the 5-year overall survival was 28.9%. In multivariate analysis, completeness of resection (P0.001), fewer number of positive lymph nodes (0 vs. 1-2 vs. 3 or more) (P=0.004), and age less than, or equal to, 60 years (P=0.006) were all independently associated with improved overall survival. The overall survival reported in this study compares favorably with the results of other single-institution studies and with the RTOG 97-04 trial.Adjuvant 5-FU-based chemoradiation following radical pancreatectomy can be delivered safely and results in comparatively good overall survival. The results of this analysis underscore the importance of resection status, number of involved lymph nodes and patient age as prognostic characteristics. These factors may be considered stratification variables for future post-pancreatectomy adjuvant therapy trials.

Purpose The primary objective of this study was to determine the feasibility of electromagnetic transponder implantation in patients with locally advanced unresectable pancreatic cancer. Secondarily, the use of transponders to monitor inter- and intrafractional motion, and the efficacy of breath holding for limiting target motion, were examined. Methods and Materials During routine screening laparoscopy, 5 patients without metastatic disease were implanted with transponders peri-tumorally. The Calypso System's localization and tracking modes were used to monitor inter- and intrafractional motion, respectively. Intrafractional motion, with and without breath holding, was also examined using Calypso tracking mode. Results Transponder implantation was well tolerated in all patients, with minimal migration, aside from 1 patient who expulsed a single transponder. Interfractional motion based on mean shifts from setup using tattoos/orthogonal imaging to transponder based localization from 164 treatments was significant in all dimensions. Mean shift (in millimeters), followed by the standard deviation and p value, were as follows: X-axis: 4.5 mm (1.0, p = 0.01); Y axis: 6.4 mm (1.9, p = 0.03); and Z-axis 3.9 mm (0.6, p = 0.002). Mean intrafractional motion was also found to be significant in all directions: superior, 7.2 mm (0.9, p = 0.01); inferior, 11.9 mm (0.9, p p = 0.01); posterior, 2.9 mm (0.5, p = 0.02); left, 2.2 mm (0.4, p = 0.02); and right, 3.1 mm (0.6, p = 0.04). Breath holding during treatment significantly decreased tumor motion in all directions. Conclusions Electromagnetic transponder implantation appears to be safe and effective for monitoring inter- and intrafractional motion. Based on these results a larger clinical trial is underway.

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) in conjunction with microtubule-targeting agents may be a promising novel anticancer treatment strategy. In vitro studies have suggested that relatively low concentrations of TRAIL enhance the lethality of paclitaxel (Taxol) against human cancer cells. The increased efficacy may be due to the triggering of caspase activation, resulting in mitotic checkpoint abrogation and catastrophe. We show here that wild-type p53 protects cells from caspase-dependent death induced by this therapeutic combination in vitro. We have now also developed an imaging-based model system to test the in vivo efficacy of combined TRAIL and Taxol, in which tumor growth and treatment response can be monitored noninvasively and in real-time. We further utilize bioluminescence, F18-fluorodeoxyglucose-positron emission tomography, and microscale computed tomography imaging to confirm the effects of combined treatment on tumors. These studies together provide the first in vivo confirmation that combined TRAIL plus paclitaxel results in better tumor control compared with either TRAIL or paclitaxel alone, and with no discernable increased normal tissue toxicity in the mouse. Interestingly, the in vivo antitumor response elicited by combined treatment was not affected by the p53 status of the tumor cells. These preclinical observations together suggest the therapeutic potential of combining TRAIL plus paclitaxel in cancer treatment, and support further preclinical and future clinical testing. [Mol Cancer Ther 2009;8(12):3285–95]

Before the advent of neoadjuvant chemoradiation therapy (NCRT) for locally advanced rectal cancer, local failure represented half of treatment failures. The German Rectal Cancer Study Group trial demonstrated that NCRT along with total mesorectal excision can improve local control and the rate of sphincter-preserving surgery. Thus, the National Comprehensive Cancer Network now recommends NCRT as the standard of care for stage III and IV rectal cancer. Recent trials and analysis have questioned accepted wisdom regarding patient selection for NCRT and methods of administration. EORTC 22921 demonstrated that the addition of chemotherapy to radiation therapy, regardless of timing, improved local control but not overall survival, and subgroup analysis from this study generated the hypothesis that the subgroup of patients with good pathologic response to NCRT would benefit the most from additional chemotherapy following surgery. The prognosis of rectal cancer is stage dependent, and 2 major analyses question whether T1/2 N1 and T3 N0 patients benefit from NCRT. Application of the results from these studies is hindered by imperfections in staging. Future improvement in patient selection might result from biologic analysis of tumor sensitivity. NCRT might be improved with the use of oral fluoropyrimidines and perhaps the addition of a second agent such as oxaliplatin, irinotecan, or cetuximab. Improvements in radiation, such as the use of more conformal techniques, might decrease the toxicity of therapy. Given the success of NCRT in improving local control, distant metastasis now predominates as the cause of treatment failure, and larger gains will likely be made from improvements in adjuvant chemotherapy.

Activation of the PI3K/Akt pathway is associated with tumorigenesis and resistance to apoptosis and ionizing radiation (IR). We sought to characterize the effects of physiologic and genetic manipulation of Akt signaling on IR-induced gastrointestinal (GI) apoptosis in mice. PI3K/Akt signaling is stimulated by insulin. We evaluated the time course of Akt stimulation by insulin and found it overlapped with protection from apoptosis induced by TRAIL (TNFalpha Related Apoptosis Inducing Ligand) in cell lines. Mice were treated with insulin and glucose and the kinetics of in vivo Akt stimulation were determined by phospho-Akt (S473) (P-Akt) immunofluorescence in the gut. Irradiation of mice by five Gy at 30 minutes after insulin/glucose administration induced apoptosis in the crypts of the ileum and colon after six hours, but induced little apoptosis in the liver or esophagus. Pre-treatment with insulin and glucose did not significantly alter levels of IR-induced apoptosis in the gut. IR alone led to sustained increases in P-Akt in the gut at six hours, a protective response that may have precluded additional protection from insulin/glucose. In Akt1-/- mice, there was significantly more apoptosis in ileum crypts of irradiated mice compared to Akt1+/+ mice, suggesting a role for the pathway in the GI tract in response to IR. Taken together, modulation of the PI3K/Akt pathway may sensitize or protect against cancer therapies in both tumor and normal tissues.

There are numerous therapeutic approaches to the management of low-grade follicular lymphoma (grades 1 and 2), ranging in intensity. For asymptomatic patients with advanced-stage disease, observation is an option, given the usually indolent nature of low-grade lymphomas. When disease is limited in stage, local radiation therapy can potentially cure patients [1]. For advanced-stage patients who need treatment, there is a variety of single-agent or multiagent chemotherapy options with high response rates. However, even very intensive regimens, such as high-dose chemotherapy with autologous stem cell transplant (ASCT), do not lead to longer overall survival times compared with less intensive regimens despite some improvement in progression-free survival (PFS) times. Relapse following therapies using conventional chemotherapy agents is common, and serial treatment is usually hampered by decreased response rates and ever shortening durations of remission with each successive treatment [2, 3]. When evaluating these various treatment options, median survival times or hazard functions are often compared; however, there is more to the story, namely, the tale that is told by the tail of the curves. The median survival time is a standard measurement for clinical trials that facilitates comparisons by taking all the data from a survival curve and compacting them into a single number that can be used for statistical evaluations. In this process, the tail of the curve (if there is a tail) can be overlooked. The presence of a tail or plateau on a PFS curve connotes that long-term continuous remission is possible for some patients. The review by Buchegger et al. [4] in this issue describes the exciting addition of antibody-based therapies to the therapeutic armamentarium for follicular lymphoma by including radioimmunotherapy (RIT), in which radioactive isotopes are targeted to lymphoma cells by highly specific monoclonal antibodies. The authors hypothesize that combinations of optimized biological treatments together with radiolabeled antibodies and chemotherapy early in the disease course of advanced-stage follicular lymphoma may be an ideal strategy for prolonging disease-free survival. Rituximab, a nonradiolabeled anti-CD20 antibody, has enjoyed success as a single agent and as an adjunct to traditional chemotherapy regimens and, used together with combination chemotherapy, can result in longer survival times than with chemotherapy alone when used as a first therapy [5–7]. Radiolabeled anti-CD20 antibodies (Itositumomab, Bexxar ; GlaxoSmithKline, Philadelphia

The role of adjuvant radiotherapy (RT) for pancreatic cancer remains controversial despite the completion of three multi-institutional randomized trials. This study examines the survival impact of postoperative RT in a large population-based database.Patients with pancreatic cancer diagnosed from 1988 to 2003 were identified in the Surveillance, Epidemiology, and End Results (SEER) database. The cohort was limited to patients who underwent resection of nonmetastatic disease to yield a population of 3252 patients. The primary end point was overall survival. Survival analyses were conducted using corrections for perioperative mortality as well as a propensity score analysis to account for baseline differences in patient characteristics.Multiple independent factors were associated with RT use, including patient age and disease stage (P0.0001). In general, younger patients and those with more advanced disease were more likely to receive RT. Disease stage significantly affected survival (P0.0001). For patients who survived at least 6 months, adjuvant RT was associated with increased survival [hazard ratio (HR), 0.87; 95% confidence interval (CI), 0.80-0.96]. On subgroup analysis, only stage IIB (T1-3N1) patients enjoyed a statistically significant benefit associated with RT (HR, 0.70; 95% CI, 0.62-0.79).Adjuvant RT is frequently given to patients in the United States after resection of their pancreatic cancer. Although RT is associated with a survival benefit for nonmetastatic patients as a whole, this trend appears to predominantly derive from a survival benefit in patients with stage IIB disease.

The antineoplastic drug sorafenib (BAY 43-9006) is a multikinase inhibitor that targets the serine-threonine kinase B-Raf as well as several tyrosine kinases. Given the numerous molecular targets of sorafenib, there are several potential anticancer mechanisms of action, including induction of apoptosis, cytostasis, and antiangiogenesis. We observed that sorafenib has broad activity in viability assays in several human tumor cell lines but selectively induces apoptosis in only some lines. Sorafenib was found to decrease Mcl-1 levels in most cell lines tested, but this decrease did not correlate with apoptotic sensitivity. Sorafenib slows cell cycle progression and prevents irradiated cells from reaching and accumulating at G2-M. In synchronized cells, sorafenib causes a reversible G1 delay, which is associated with decreased levels of cyclin D1, Rb, and phosphorylation of Rb. Although sorafenib does not affect intrinsic radiosensitivity using in vitro colony formation assays, it significantly reduces colony size. In HCT116 xenograft tumor growth delay experiments in mice, sorafenib alters radiation response in a schedule-dependent manner. Radiation treatment followed sequentially by sorafenib was found to be associated with the greatest tumor growth delay. This study establishes a foundation for clinical testing of sequential fractionated radiation followed by sorafenib in gastrointestinal and other malignancies. [Cancer Res 2007;67(19):9443–54]

696 Background: Preoperative chemoradiotherapy (CRT) is standard treatment for locally advanced rectal cancer (LARC). GI toxicity leading to ED visits, hospitalization, and need for IV hydration remains a management challenge. Previous studies have established volume of bowel receiving low dose radiation (V15) as the strongest predictor of GI toxicity. We have previously shown pencil beam scanned proton therapy (PBSPT) is dosimetrically superior to IMRT in LARC with respect to low dose to the bowel. This studycompares the toxicity of patients treated with PBSPT and IMRT in neoadjuvant treatment of LARC. Methods: A retrospective review was conducted of patients treated at the University of Pennsylvania with neoadjuvant 5-FU or capecitabine CRT. Patient and tumor characteristics, treatment, and toxicity data were collected. PBSPT (50.4 Gy RBE to standard volumes) was delivered using either two opposed lateral fields or posterior oblique fields with a patient supine or prone. These patients were registered on a prospective registry study. IMRT plans were delivered with 7-9 field IMRT or volumetric arc therapy in the supine or prone position. Statistical analysis was performed using STATA v12.0. Results: Between 3/2009 and 6/2014, 39 patients treated with IMRT and 26 patients treated with PBSPT were studied. Continuous-infusion 5-FU was administered in 31 (79%) IMRT patients and 16 (62%) PBSPT patients (p = 0.162); the remainder received capecitabine. PBSPT patients had significantly lower rates of acute Grade ≥ 2 diarrhea, 12% versus 39% with IMRT (p = 0.022). On multivariable analysis incorporating the type of chemotherapy, use of PBSPT remained a significant predictor of lower rate of Grade ≥ 2 diarrhea (OR = 0.20, 95% CI 0.05 - 0.82, p = 0.025). There was also a borderline significant reduction in Grade ≥ 2 fatigue with the use of PBSPT, occurring in 8% versus 29% of IMRT patients, p = 0.057. Conclusions: These preliminary results indicate PBSPT is associated with significant reduction in acute Grade ≥ 2 diarrhea compared to IMRT. PBSPT may play an important role in the treatment of LARC, a disease with high cure rate where radiation toxicity should be minimized.