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BACKGROUND: Neoadjuvant chemoradiotherapy can provide downstaging and improve margin negativity for borderline resectable and resectable pancreatic adenocarcinoma [(B)RPC]. Little is known about the relative efficacy of capecitabine (CAPE)-based vs. gemcitabine (GEM)-based 3-week chemoradiation (3WCRT) with 36 Gy in 15 fractions. This study aimed to compare the odds of achieving surgical resection, time to progression (TTP), and overall survival (OS) of patients treated with 3WCRT with concurrent CAPE versus GEM. METHODS: A retrospective cohort study was conducted, examining medical records from a single center for patients with (B)RPC treated with 3WCRT between 1/2009–12/2020. Odd ratios (OR) of achieving surgical resection were estimated using logistic regression for univariable and multivariable analyses. Median TTP (mTTP) and median OS (mOS) were estimated using the Kaplan-Meier method. Cox proportional hazards analysis was conducted to estimate hazard ratios (HR) of progression and survival in univariable and multivariable analyses. RESULTS: Thirty-one patients were included in the analysis. Twenty-two (71%) patients were treated with CAPE, while 9 (29%) were treated with GEM. All patients in the GEM group were borderline resectable, vs. 18 (82%) patients in the CAPE group, P=0.30. Nineteen (86%) patients in the CAPE group were treated with neoadjuvant FOLFIRINOX, vs. 4 (44%) patients in the GEM group, P=0.03. The CAPE group had higher odds of achieving surgical resection [OR =9.33; 95% confidence interval (CI): 1.50–58.20]. Adjusting for covariates, the odds of achieving surgical resection were still statistically higher in the CAPE group vs. the GEM group (OR =25.34; 95% CI: 1.14–563.72). The CAPE group had superior mTTP compared to the GEM group (15.4 months, 95% CI: 4.9–71.1 vs. 4.0 months, 95% CI: 0.4–14.5; P=0.01), corresponding to a hazard ratio of 0.33 (95% CI: 0.14–0.81). Adjusting for covariates this effect persisted; the adjusted hazard ratio (AHR) for progression was 0.24 (95% CI: 0.08–0.77). Cox proportional hazards analysis also demonstrated that the CAPE group had superior OS compared to the GEM group in unadjusted (HR =0.13; 95% CI: 0.04–0.40) and adjusted models (HR =0.13, 95% CI: 0.03–0.52). CONCLUSIONS: For neoadjuvant 3WCRT, this hypothesis-generating study suggests concurrent CAPE may be a more effective radiosensitizer than GEM for patients with (B)RPC.

Background Increased risk of a second primary malignancy (SPM) before or after diagnosis of anal squamous cell carcinoma (ASCC) has been reported in a previous single‐institution study. We hypothesize that patients diagnosed with ASCC are at increased risk for developing SPMs before or after the diagnosis of ASCC. The primary objective of this study was to identify the diagnoses of cancer most likely to occur as SPMs before or after ASCC. Methods This work employs the Surveillance, Epidemiology, and End Results (SEER) Program registry data to conduct a US‐population‐based study of patients diagnosed with ASCC between 1975 and 2016. In patients diagnosed with ASCC, we evaluated the risk of SPMs and the risk of developing ASCC as an SPM after another cancer using standardized incidence ratios (SIR) for all SPMs by calculating the ratio of observed events in the ASCC cohort compared to expected (O/E) events in a matched reference cohort of the general population. Results A total of 7,594 patients with primary ASCC were included. Patients with ASCC were at increased risk of the diagnosis of an SPM (SIR = 1.45), particularly cancers of the lung, vulva, oropharynx, or colon. Patients with ASCC had an increased rate of previous malignancy (SIR = 1.23), especially Kaposi sarcoma or vulvar cancer. Overall elevated incidence of SPMs was unrelated to prior radiation treatment. Radiation treatment was associated with increased risk for SPMs in the female genital system but appeared protective against prostate cancer as SPMs. Conclusions Our findings support increased surveillance and screening for second malignancies in patients with these diagnoses, as patients with ASCC are often either survivors of a prior cancer diagnosis or are at increased risk of developing later malignancies., Survivors of anal squamous cell carcinoma are at increased risk for particular second malignancies and should be screened for these. Risk of second malignancies is sometimes related to radiation therapy, but radiation can also be protective against second cancers in some cases.

Uveal melanoma (UM), the most frequently occurring non-cutaneous melanoma and most common primary intraocular malignancy in adults, arises from the melanocytes of the choroid in approximately 95% of cases. Prompt diagnosis and treatment is vital as primary tumor size is one of the key factors associated with survival. Despite recent advances in management, more than half of the patients develop metastatic disease which portends poor survival. Currently, treatment options for UM include local resection, enucleation, plaque brachytherapy, and/or particle beam radiotherapy (RT). Enucleation was initially the standard of care in the management of UM, but a shift towards eye-preserving therapeutic choices such as RT and local resection has been noted in recent decades. Plaque brachytherapy, a form of localized RT, is the most popular option and is now the preferred treatment modality for a majority of UM cases. In this review we discuss the etiopathogenesis, clinical presentation and diagnosis of UM and place a special emphasis on its therapeutic options. Furthermore, we review the current literature on UM management and propose a functional treatment algorithm for non-metastatic disease.

Purpose Approximately 10% of patients who received brain stereotactic radiosurgery (SRS) develop symptomatic radiation necrosis (RN). We sought to determine the effectiveness of treatment options for symptomatic RN, based on patient-reported outcomes. Materials and methods We conducted a retrospective review of 217 patients with 414 brain metastases treated with SRS from 2009 to 2018 at our institution. Symptomatic RN was determined by appearance on serial magnetic resonance images (MRIs), MR spectroscopy, requirement of therapy, and development of new neurological complaints without evidence of disease progression. Therapeutic interventions for symptomatic RN included corticosteroids, bevacizumab and/or surgical resection. Patient-reported therapeutic outcomes were graded as complete response (CR), partial response (PR), and no response. Results Twenty-six patients experienced symptomatic RN after treatment of 50 separate lesions. The mean prescription dose was 22 Gy (range, 15 to 30 Gy) in 1 to 5 fractions (median, 1 fraction). Of the 12 patients managed with corticosteroids, 6 patients (50%) reported CR and 4 patients (33%) PR. Of the 6 patients managed with bevacizumab, 3 patients (50%) reported CR and 1 patient (18%) PR. Of the 8 patients treated with surgical resection, all reported CR (100%). Other than surgical resection, age ≥54 years (median, 54 years; range, 35 to 81 years) was associated with CR (odds ratio = 8.40; 95% confidence interval, 1.27-15.39; p = 0.027). Conclusion Corticosteroids and bevacizumab are commonly utilized treatment modalities with excellent response rate. Our results suggest that patient's age is associated with response rate and could help guide treatment decisions for unresectable symptomatic RN.

ObjectiveCompared with 3D-planned pelvic radiation, intensity-modulated radiation therapy (IMRT) has been shown to reduce acute toxicity in cervical cancer patients after radical hysterectomy. This study evaluated late toxicity and patterns of failure after post-operative pelvic IMRT interdigitated weekly with high dose rate brachytherapy.MethodsThis retrospective study included 53 cervical cancer patients treated between January 2006 and August 2019 with radical hysterectomy, lymphadenectomy, and post-operative IMRT and high dose rate brachytherapy. The decision to include chemotherapy was made by the treating gynecologic oncologist based on patient-specific criteria including positive pelvic lymph nodes, positive surgical margins, or positive parametrial invasion. The actuarial rates of genitourinary and gastrointestinal toxicity, vaginal cuff/regional nodal/distant failure, and overall survival were calculated using the Kaplan–Meier method.ResultsMedian follow-up was 70 months (range 5.4–148) months and age at diagnosis was 47 (range 24–73) years. The 2018 International Federation of Gynecology and Obstetrics (FIGO) clinical stages were IB1 (n=19), IB2 (n=7), IIB (n=7), IIIC1 (n=19), and IIIC2 (n=1). Median radiation dose delivered in 160 cGy daily fractions was 5120 (range 4640–5120) cGy. Median brachytherapy dose prescribed to the vaginal surface delivered in six weekly fractions was 2400 (range 1200–4800) cGy. Concurrent chemotherapy was delivered in 35 (66%) patients. There were no acute grade >3 genitourinary or gastrointestinal toxicities. Late grade >3 occurred in two (3.8%) patients, including a small bowel obstruction and a ureteral stricture. The 5-year actuarial rate for gastrointestinal or genitourinary toxicity was 1.9%. There were no vaginal cuff recurrences. The 5-year actuarial rates for regional nodal failure, distant failure outside the radiation field, any failure, and overall survival were 11%, 11%, 14%, and 85%, respectively.ConclusionsPost-operative IMRT with high dose rate brachytherapy for patients with cervical cancer is associated with excellent outcomes and limited rates of radiation-related non-hematologic toxicity.

Inflammatory bowel disease (IBD), subdivided into Crohn's disease (CD) and ulcerative colitis (UC), is an auto-inflammatory gastrointestinal condition with an established increased risk of certain malignancies. Compared to sporadic cancers in the general population, IBD-associated malignancies present unique challenges to providing quality care. Radiation therapy (RT) targeting IBD-associated malignancies may directly impact inflamed bowel, with special considerations for the risk of toxicities. Historically, patients with IBD have been less likely to receive radiotherapy in proximity to bowel due to a poor understanding of the potential for acute and chronic toxicities and unclear treatment outcomes. We present a scoping review, to more fully assess IBD-associated malignancies and their treatment. As opposed to a systematic review, this approach allows us to analyze the broadest range of literature, including experimental and non-experimental research, and reflect on current guidelines and practices.Literature search: a systematic, scoping search of published literature was conducted using applicable PRISMA scoping review (ScR) guidelines. The literature search was conducted on PubMed and was searched systematically by screening all publications from January 1990 to June 2021. Citations from the included articles were also manually searched. Relevant National Comprehensive Cancer Network guidelines were reviewed. Final query was December 2021 in editing. Articles were selected for full text reading if the abstract reported on malignancy in IBD or bowel toxicities.The pelvic malignancies found in the IBD patient population, including colorectal carcinoma, anal carcinoma, lymphoma, small bowel adenocarcinoma (SBA), and prostate cancer (PCa) are outlined in this scoping review. Additional cancers that have a contested relationship with IBD, including cervical, bladder, and upper GI cancers, are also explored. This review provides literature guided recommendations on the eligibility of patients with IBD to receive RT, management of IBD during and after treatment, and counseling for radiation-induced toxicities.After review of the literature, IBD should not be considered an absolute contraindication to radiation therapy, given the lack of evidence for increased toxicities, and the evolution of RT techniques which limit radiation dose to the bowel.

PurposeIn radiotherapy, high radiation exposure to optic nerve (ON) can cause optic neuropathy or vision loss. In this study, we evaluated the pattern and extent of the ON movement using MRI, and investigated the potential dosimetric effect of this movement on radiotherapy.MethodsMRI was performed in multiple planes in 5 human subjects without optic pathway abnormalities to determine optic nerve motion in different scenarios. The subjects were requested to gaze toward five directions during MRI acquisitions, including neutral (straight forward), left/right (horizontal movement), and up/down (vertical movement). Subsequently, the measured displacement was applied to patients with peri-optic tumors to evaluate the potential dosimetric effect of this motion.ResultsThe motion of ON followed a nearly conical shape. By average, the anterior end of ONs moved with 10.8 ± 2.2 mm horizontally and 9.3 ± 0.8 mm vertically, while posterior end has negligible displacement. For patients who underwent stereotactic radiotherapy to a peri-optic tumors, the movement of ON in this measured range introduced non-negligible dosimetric effect.ConclusionThe range of motion of the anterior portions of the optic nerves is on the order of centimeters, which may need to be considered with extra attention during radiation therapy in treating peri-optic lesions.

Purpose: In radiotherapy, high radiation exposure to optic nerve (ON) can cause optic neuropathy or vision loss. In this study, we evaluated the pattern and extent of the ON movement using MRI, and investigated the potential dosimetric effect of this movement on radiotherapy. Methods: Five volunteers were requested to gaze toward five directions during MRI acquisitions, including neutral (straight forward), left/right (horizontal movement), and up/down (vertical movement). The motion of the ON was analyzed quantitatively. To evaluate the potential dosimetric effect of this motion, the ON motion was hypothetically applied to three patients with perioptic tumors.Results: The motion of ON followed a nearly conical shape among all five subjects. The anterior end of ONs moved with 10.4 ± 2.2 mm and 11.1 ± 1.4 mm horizontally for the left and right eyes, and 9.3 ± 0.8 mm vertically for the right eye. Posterior end of ON has negligible displacement. In the three clinical scenario, the hypothetical movement of ON in this measured range introduced non-negligible dosimetric effect. Conclusion: The range of motion of the anterior portions of the optic nerves is on the order of centimeters, which may need to be considered with extra attention during radiation therapy workflow.

PURPOSE/OBJECTIVE(S) Neoadjuvant chemoradiotherapy (CRT) serves to downstage and increase the rate of surgical resection for borderline resectable and resectable pancreatic adenocarcinoma ((B)RPC). Although conventional staging provides prognostic information, it remains a challenge to predict which patients will proceed with resection. We hypothesize that the severity of vessel involvement and the trajectory of CA19-9 levels after neoadjuvant treatment would associate with proceeding to resection. MATERIALS/METHODS Medical records were retrospectively reviewed at a single center for patients diagnosed with (B)RPC and treated with neoadjuvant CRT between 1/2005 and 12/2020. Progress notes were evaluated to determine if a patient proceeded to surgery and the trajectory of CA 19-9 levels in response to treatment. Radiologist notes were evaluated to determine the extent of mesenteric vessel (superior mesenteric artery, celiac axis, portal vein, hepatic artery, and superior mesenteric vein) involvement. A vessel involvement score was calculated as the sum of all vessels in contact with tumor: 1 point for each vessel, with partial (< 180 degrees) encasement of artery counting as 2 points. Odds ratios (OR) of proceeding to resection were computed with 95% confidence intervals (CI) for CA19-9 response to treatment. Ordinal logistic regression models were fit to estimate the impact of greater vessel involvement on the odds of NOT proceeding with surgery. RESULTS Forty-two (n = 42) patients were included in the analysis. The median age was 65 years (IQR: 61 to 71). 73% of patients were treated with 3600 cGy in 15 fractions (fx), 24% of patients were treated with 4500-5040 cGy in 25-28 fx, and 3% of patients were treated with 3300 cGy in 5 fx. 55% of patients were treated with neoadjuvant FOLFIRINOX and 45% of patients were treated with other regimens. 88% of patients were considered borderline resectable and 12% were resectable at the time of diagnosis. Patients with any decrease in CA19-9 levels after CRT had higher odds of proceeding with resection (OR = 21.0, 95% CI: 3.2 to 139.2). However, decrease in CA19-9 levels after upfront chemotherapy was not significantly associated with proceeding with resection (P = 0.91). The odds of NOT proceeding with resection after neoadjuvant CRT were 1.81 times higher (95% CI: 0.97 to 3.39) for each increase in vessel involvement score, however these findings were not statistically significant (P = 0.062). CONCLUSION Patients diagnosed with (B)RPC proceeding with CRT have different odds of proceeding to surgery based on their response to CRT and extent of vessel involvement. Post-CRT CA19-9 can help predict which patients may proceed to resection. Future investigations will develop nomograms for estimating odds of proceeding to surgery in larger datasets to help aid in patient counseling and multidisciplinary discussion.

Purpose/Objective(s) Radiation therapy (RT) is a critical modality for the treatment of unresectable hepatocellular carcinoma (HCC). Little is known about how the etiology of HCC impacts overall and progression free survival (OS and PFS) in patients treated with definitive RT. We hypothesize that patients treated with definitive RT for HCC secondary to hepatitis B and hepatitis C viruses (viral group) would have favorable OS and PFS when compared to patients with HCC secondary to other etiologies (non-viral group). Materials/Methods Medical records were retrospectively reviewed at a single institution for patients diagnosed with unresectable HCC and treated with definitive RT between 1/2011 and 12/2020. Patients treated with prior surgery or radiofrequency ablation were excluded. Progress notes were reviewed to determine date of last follow-up, progression, and death. Notes were also assessed to determine the etiology of HCC, age at diagnosis, Child-Pugh classification (CPC), AJCC 8th edition T stage, RT strategy, and planning target volume (PTV). Descriptive statistics were quantified for baseline characteristics. Survival curves were estimated via Kaplan-Meier method; statistical difference was determined using the log-rank test. Multivariate (MVA) Cox proportional hazards analysis was conducted to estimate hazard ratios (HR) when controlling for confounding factors. Results Forty-six patients were included in the analysis. 30 (65%) patients were in the viral group, while 16 (35%) patients were in the non-viral group. Median ages at diagnosis for the viral and non-viral groups were 64 (interquartile range (IQR): 60 to 69) and 71 years (IQR: 66.5 to 76.5), respectively (P = 0.014). Treatment with hypofractionated RT (P = 0.559), proton therapy (P = 0.686), performance status (P = 0.222), CPC (P = 0.270), T stage (P = 0.639), and PTV (P = 0.472) were not different between groups. There was a trend toward improved Median OS for the viral group compared to the non-viral group: 17.9 months (95% confidence interval (CI): 9.7 to not-reached (NR)) vs. 8.8 months (95% CI: 6.1 to NR) (P = 0.072). Similarly, PFS was not different between viral and non-viral groups: 9.3 (95% CI: 7.4 to 19.0) vs. 8.0 (95% CI: 4.0 to 10.3), P = 0.314. However, after controlling for confounding factors with MVA Cox proportional hazards models, the viral group had superior OS (HR = 4.20, 95% CI: 1.47 to 12.02, P = 0.008); the viral group also had superior PFS (HR = 2.48, 95% CI: 1.06 to 5.81, P = 0.037). Conclusion Our retrospective review of patients with unresectable HCC treated with definitive RT provides evidence that viral etiologies of HCC may fare better in OS and PFS when compared to non-viral etiologies. The etiology of HCC development for virally vs non-virally mediated tumors may have implications for treatment and response in the setting of radiation therapy.

Purpose Stereotactic body radiation therapy is increasingly used to treat a variety of oligometastatic histologies, but few data exist for ovarian cancer. Ablative stereotactic body radiation therapy dosing is challenging in sites like the abdomen, pelvis, and central thorax due to proximity and motion of organs at risk. A novel radiation delivery method, stereotactic magnetic-resonance–guided online-adaptive radiation therapy (SMART), may improve the therapeutic index of stereotactic body radiation therapy through enhanced soft-tissue visualization, real-time nonionizing imaging, and ability to adapt to the anatomy-of-the-day, with the goal of producing systemic-therapy–free intervals. This phase I trial assessed feasibility, safety, and dosimetric advantage of SMART to treat ovarian oligometastases. Methods and Materials Ten patients with recurrent oligometastatic ovarian cancer underwent SMART for oligometastasis ablation. Initial plans prescribed 35 Gy/5 fractions with goal 95% planning target volume coverage by 95% of prescription, with dose escalation permitted, subject to strict organ-at-risk dose constraints. Daily adaptive planning was used to protect organs-at-risk and/or increase target dose. Feasibility (successful delivery of >80% of fractions in the first on-table attempt) and safety of this approach was evaluated, in addition to efficacy, survival metrics, quality-of-life, prospective timing and dosimetric outcomes. Results Ten women with seventeen ovarian oligometastases were treated with SMART, and 100% of treatment fractions were successfully delivered. Online adaptive plans were selected at time of treatment for 58% of fractions, due to initial plan violation of organs-at-risk constraints (84% of adapted fractions) or observed opportunity for planning target volume dose escalation (16% of adapted fractions), with a median on-table time of 64 minutes. A single Grade ≥3 acute (within 6 months of SMART) treatment-related toxicity (duodenal ulcer) was observed. Local control at 3 months was 94%; median progression-free survival was 10.9 months. Median Kaplan-Meier estimated systemic-therapy–free survival after radiation completion was 11.5 months, with concomitant quality-of-life improvements. Conclusions SMART is feasible and safe for high-dose radiation therapy ablation of ovarian oligometastases of the abdomen, pelvis, and central thorax with minimal toxicity, high rates of local control, and prolonged systemic-therapy–free survival translating into improved quality-of-life.

Locally advanced rectal cancer has broadly been defined as T3, T4, or lymph node-positive disease. In the 1990s, adjuvant chemoradiation was considered the optimal management for locally advanced rectal cancer. However, the paradigm shifted when the German CAO/ARO/AIO-94 Rectal Cancer trial established neoadjuvant chemoradiation as the standard of care, based on reduced rates of toxicity and local recurrence, as well as higher rates of sphincter preservation compared with postoperative chemoradiation. Both short-course radiation and long-course chemoradiation are currently accepted methods for neoadjuvant treatment, with recent trials showing equivalence in outcomes. While surgery remains the cornerstone of treatment, there are data supporting the use of magnetic resonance imaging for risk stratification in rectal cancer and encouraging prospective data regarding nonoperative management. This review summarizes data on the evolution of treatment for locally advanced rectal cancer and discusses emerging evidence for nonoperative management.

Purpose To analyze the incidence of and risk factors for clinically significant radiation necrosis (cRN) in adult cranial oligodendrogliomas and astrocytomas treated with proton or photon therapy. Methods and Materials Between 2007 and 2015, 160 patients with grade 2 or 3 oligodendrogliomas (with 1p/19q codeletion, n = 53) or astrocytomas (without 1p/19q codeletion, n = 107) were treated with proton (n = 37) or photon (n = 123) therapy. Clinically significant radiation necrosis (RN) was defined as symptomatic RN or asymptomatic RN that resulted in surgery or bevacizumab administration. The cumulative incidence was calculated using competing risks. Risk factors were identified using Cox proportional hazards. Results After a median follow-up period of 28.5 months, cRN developed in 18 patients (proton, 6; photon, 12). The 2-year cumulative incidence of cRN for proton and photon therapy was 18.7% (95% confidence interval [CI], 7.5%-33.8%) and 9.7% (95% CI, 5.1%-16%), respectively (P = .16). On multivariate analysis, risk factors for cRN included oligodendroglioma (hazard ratio [HR], 3.57; 95% CI, 1.38-9.25; P = .009) and higher prescription dose (in gray relative biological equivalents [GyRBE]) (HR, 1.30; 95% CI, 1.05-1.61; P = .015). The 2-year cumulative incidence of cRN in oligodendrogliomas and astrocytomas was 24.2% and 6.2%, respectively (P = .01). The relative volume (percentage) of brain receiving 60 GyRBE was a significant dosimetric predictor of cRN in oligodendrogliomas (HR, 1.11; 95% CI, 1.03-1.20; P = .005). Conclusions The study showed that 1p/19q codeleted oligodendroglioma was a significant risk factor associated with cRN and the relative volume (percentage) of brain receiving 60 GyRBE was an important dosimetric predictor of cRN for oligodendroglioma patients. There is insufficient evidence at this time to conclude a significant difference in the incidence of cRN between proton and photon therapy.

PURPOSE/OBJECTIVE(S) Neoadjuvant chemoradiotherapy is a critical treatment for borderline resectable and resectable pancreatic adenocarcinoma ((B)RPC). The PREOPANC trials employ a short course chemoradiation (SCCRT) regimen of 3600 cGy in 15 fractions with concurrent gemcitabine (GEM)-based chemotherapy, but little is known about the relative efficacy of capecitabine (CAPE)-based concurrent chemotherapy in this population. We hypothesize that patients treated with SCCRT with CAPE-based concurrent chemotherapy will have superior overall survival (OS) compared to GEM-based strategies. MATERIALS/METHODS Medical records were retrospectively reviewed at a single center for patients diagnosed with (B)RPC between 1/2005 and 12/2020. Patients treated with neoadjuvant SCCRT were included in the analysis. Descriptive statistics were quantified for baseline characteristics. OS was estimated using Kaplan-Meier estimates, statistical difference was determined using the log-rank test. Multivariate Cox proportional hazards analysis was conducted to estimate hazard ratios (HR) when controlling for confounding factors. RESULTS Thirty-one (n = 31) patients were included in the analysis. 71% of patients (n = 22) were treated with CAPE-based concurrent chemotherapy, while 29% of patients (n = 9) were treated with GEM-based concurrent chemotherapy. Median age at diagnosis was 65 (interquartile range (IQR): 60 to 71) for the CAPE group, compared to 66 (IQR: 63 to 71) for the GEM group, P = 0.414. 100% of patients in the CAPE group were borderline resectable, compared to 82% of patients in the GEM group, P = 0.171. 44% of patients in the CAPE group were treated with neoadjuvant FOLFIRINOX, compared to 14% in the GEM group, P = 0.016. Patients treated with concurrent 5-CAPE-based chemotherapy had a longer median OS than other concurrent chemotherapy approaches: Not reached (95% confidence interval (CI): 24 to not reached) vs. 17 months (95% CI: 6 to 22 months), P < 0.0001. Multivariate Cox proportional hazards models, controlling for borderline vs. resectable status, age at diagnosis, and use of neoadjuvant FOLFIRINOX, demonstrated that CAPE-based concurrent chemotherapy had a HR of death of 0.081 (95% CI: 0.018 to 0.369, P = 0.0012) compared to GEM-based concurrent chemotherapy. CONCLUSION Patients diagnosed with (B)RPC have many therapeutic options; this study suggests a benefit to CAPE-based concurrent chemotherapy when treating patients with SCCRT, even after controlling for significant confounding by greater use of neoadjuvant FOLFIRINOX with CAPE-based concurrent chemotherapy. SCCRT may be more effective with concurrent capecitabine instead of concurrent gemcitabine for (B)RPC.

Purpose/Objective(s) Radiation therapy (RT) remains a critical treatment modality for unresectable hepatocellular carcinoma (HCC), with proton beam therapy (PBT) being widely utilized due to its decreased exit dose compared to photon-based RT. We hypothesize that patients with HCC receiving definitive PBT would experience decreased acute toxicity when compared to those receiving photon-based RT. Materials/Methods Electronic medical records were retrospectively reviewed at a single institution for patients diagnosed with unresectable HCC and treated with definitive RT between 1/2011 and 12/2020. Patients treated with prior surgery or radiofrequency ablation were excluded. Progress notes and treatment summaries were reviewed to determine baseline characteristics including age at diagnosis, Child-Pugh classification (CPC), AJCC 8th edition T stage, performance status, and RT dose. Acute treatment toxicities were evaluated using Common Terminology Criteria for Adverse Events v5.0. Descriptive statistics were quantified for baseline characteristics. Odds ratios (OR) with 95% confidence intervals (CI) were generated to determine the association between PBT vs. photon therapy and acute radiation toxicities in bivariate and multivariate logistic regression models. Results Forty-six patients were included in the analysis. 24 (52%) patients received PBT while 22 (48%) received photon-based RT. Median age for the PBT and photon-based RT groups were 67 (interquartile range (IQR): 58.6 to 72.5) and 65.5 years (IQR: 61.0 to 73.0), respectively (P = 0.991). 50% of patients who received PBT had a T stage greater than T2, compared to 71% of patient in the photon group (P = 0.148). 42% of the PBT group had CPC B or worse, compared to 38% in the photon group (P = 0.813). Performance status and total dose did not significantly differ between groups (P = 0.351 and P = 0.773, respectively). PBT was associated with higher odds of any grade radiation dermatitis (RD) (OR = 6.00, 95% CI: 1.13 to 31.9) and lower odds of any grade anorexia (OR = 0.21, 95% CI 0.05 to 0.91). Odds of any grade diarrhea and fatigue, did not significantly differ between groups (P = 0.086 and P = 0.958, respectively). After controlling for performance status, total dose, T stage, CPC, and age at diagnosis, PBT was still associated with higher odds of RD (OR = 11.07, 95% CI: 1.14 to 107.71) and lower odds of anorexia (OR = 0.14, 95% CI: 0.02 to 0.93). Conclusion This study provides evidence that although PBT appears to have a superior safety profile in regard to acute anorexia, patients treated with PBT have higher odds of acute RD; these effects persist even after controlling for relevant confounding factors. PBT may result in fewer GI toxicities at the cost of greater skin toxicity.

// Perry Grigsby 1, 2, 3 , Adnan Elhammali 4 , Fiona Ruiz 1 , Stephanie Markovina 1, 2 , Michael D. McLellan 5 , Christopher A. Miller 5 , Anupama Chundury 1 , Ngoc-Anh L. Ta 6 , Ramachandran Rashmi 1 , John D. Pfeifer 7, 8 , Robert S. Fulton 5 , Todd DeWees 1 and Julie K. Schwarz 1, 2, 9 1 Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA 2 Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA 3 Division of Nuclear Medicine, Mallinckrodt Institute, Washington University School of Medicine, St. Louis, MO, USA 4 Department of Radiation Oncology, MD Anderson Cancer Center, University of Texas Health Science Center, Houston, TX, USA 5 McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA 6 Saint Louis University School of Medicine, St. Louis, MO, USA 7 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA 8 Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO, USA 9 Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA Correspondence to: Julie K. Schwarz, email: jschwarz@wustl.edu Keywords: obesity; cervical cancer; PI3K; PTEN; mutation Received: September 07, 2017 Accepted: December 13, 2017 Published: December 23, 2017 ABSTRACT The purpose of this study was to evaluate the effect of obesity and obesity-associated factors on the outcomes of patients with cervical cancer. Outcomes were evaluated in 591 patients with FIGO Ib to IV cervical cancer treated uniformly with definitive radiation. Patients were stratified into 3 groups based upon pretreatment Body Mass Index (BMI): A ≤ 18.5; B 18.6 – 34.9; and C ≥ 35. The 5-year freedom from failure rates were 58, 59, and 73% for BMI groups A, B, and C (p = 0.01). Overall survival rates were 50, 59, and 68%, respectively (p = 0.02). High expression of phosphorylated AKT (pAKT) was associated with poor outcomes only in non-obese patients. Obese patients with PI3K pathway mutant tumors had a trend toward favorable outcomes, while a similar effect was not observed in non-obese patients. Compared to similar tumors from non-obese hosts, PIK3CA and PTEN mutant tumors from obese patients failed to express high levels of phosphorylated AKT and its downstream targets. These results show that patients with obesity at the time of diagnosis of cervical cancer exhibit improved outcomes after radiation. PI3K/AKT pathway mutations are common in obese patients, but are not associated with activation of AKT signaling.

SpaceOAR, a Food and Drug Administration-approved hydrogel intended to create a rectal-prostate space, was evaluated in a single-blind phase III trial of image guided intensity modulated radiation therapy. A total of 222 men were randomized 2:1 to the spacer or control group and received 79.2 Gy in 1.8-Gy fractions to the prostate with or without the seminal vesicles. The present study reports the final results with a median follow-up period of 3 years.Cumulative (Common Terminology Criteria for Adverse Events, version 4.0) toxicity was evaluated using the log-rank test. Quality of life (QOL) was examined using the Expanded Prostate Cancer Index Composite (EPIC), and the mean changes from baseline in the EPIC domains were tested using repeated measures models. The proportions of men with minimally important differences (MIDs) in each domain were tested using repeated measures logistic models with prespecified thresholds.The 3-year incidence of grade ≥1 (9.2% vs 2.0%; P=.028) and grade ≥2 (5.7% vs 0%; P=.012) rectal toxicity favored the spacer arm. Grade ≥1 urinary incontinence was also lower in the spacer arm (15% vs 4%; P=.046), with no difference in grade ≥2 urinary toxicity (7% vs 7%; P=0.7). From 6 months onward, bowel QOL consistently favored the spacer group (P=.002), with the difference at 3 years (5.8 points; P.05) meeting the threshold for a MID. The control group had a 3.9-point greater decline in urinary QOL compared with the spacer group at 3 years (P.05), but the difference did not meet the MID threshold. At 3 years, more men in the control group than in the spacer group had experienced a MID decline in bowel QOL (41% vs 14%; P=.002) and urinary QOL (30% vs 17%; P=.04). Furthermore, the control group were also more likely to have experienced large declines (twice the MID) in bowel QOL (21% vs 5%; P=.02) and urinary QOL (23% vs 8%; P=.02).The benefit of a hydrogel spacer in reducing the rectal dose, toxicity, and QOL declines after image guided intensity modulated radiation therapy for prostate cancer was maintained or increased with a longer follow-up period, providing stronger evidence for the benefit of hydrogel spacer use in prostate radiation therapy.

Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide, with a majority of HCC patients not suitable for curative therapies. Approximately 70% of initially diagnosed patients cannot undergo surgical resection or transplantation due to locally advanced disease, poor liver function/underlying cirrhosis, or additional comorbidities. Local therapeutic options for patients with unresectable HCC, who are not suitable for thermal ablation, include transarterial embolization (bland, chemoembolization, radioembolization) and/or external beam radiation therapy (EBRT). Regarding EBRT specifically, technological advancements provide a means for safe and effective radiotherapy delivery in a wide spectrum of HCC patients. In multiple prospective studies, EBRT delivery in a variety of different fractionation schemes or in combination with transcatheter arterial chemoembolization (TACE) demonstrate improved outcomes, particularly with combination therapy. The Barcelona Clinic Liver Cancer classification provides a framework for treatment selection; however, given the growing complexity of treatment strategies, this classification system tends to simplify decision-making. In this review, we discuss the current literature regarding unresectable HCC and propose a modified treatment algorithm that emphasizes the role of radiation therapy for Child-Pugh score A or B patients with ≤3 nodules measuring >3 cm, multinodular disease or portal venous thrombosis.

Locally advanced rectal cancer has broadly been defined as T3, T4, or lymph node-positive disease. In the 1990s, adjuvant chemoradiation was considered the optimal management for locally advanced rectal cancer. However, the paradigm shifted when the German CAO/ARO/AIO-94 Rectal Cancer trial established neoadjuvant chemoradiation as the standard of care, based on reduced rates of toxicity and local recurrence, as well as higher rates of sphincter preservation compared with postoperative chemoradiation. Both short-course radiation and long-course chemoradiation are currently accepted methods for neoadjuvant treatment, with recent trials showing equivalence in outcomes. While surgery remains the cornerstone of treatment, there are data supporting the use of magnetic resonance imaging for risk stratification in rectal cancer and encouraging prospective data regarding nonoperative management. This review summarizes data on the evolution of treatment for locally advanced rectal cancer and discusses emerging evidence for nonoperative management.

Low-field magnetic resonance imaging (MRI) has recently been integrated with radiation therapy systems to provide image guidance for daily cancer radiation treatments. The main benefit of the low-field strength is minimal electron return effects. The main disadvantage of low-field strength is increased image noise compared to diagnostic MRIs conducted at 1.5 T or higher. The increased image noise affects both the discernibility of soft tissues and the accuracy of further image processing tasks for both clinical and research applications, such as tumor tracking, feature analysis, image segmentation, and image registration. An innovative method, adaptive anatomical preservation optimal denoising (AAPOD), was developed for optimal image denoising, i.e., to maximally reduce noise while preserving the tissue boundaries. AAPOD employs a series of adaptive nonlocal mean (ANLM) denoising trials with increasing denoising filter strength (i.e., the block similarity filtering parameter in the ANLM algorithm), and then detects the tissue boundary losses on the differences of sequentially denoised images using a zero-crossing edge detection method. The optimal denoising filter strength per voxel is determined by identifying the denoising filter strength value at which boundary losses start to appear around the voxel. The final denoising result is generated by applying the ANLM denoising method with the optimal per-voxel denoising filter strengths. The experimental results demonstrated that AAPOD was capable of reducing noise adaptively and optimally while avoiding tissue boundary losses. AAPOD is useful for improving the quality of MRIs with low-contrast-to-noise ratios and could be applied to other medical imaging modalities, e.g., computed tomography.

Purpose/objectives Multiparametric advanced MR and [18F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) imaging may be important biomarkers for prognosis as well for distinguishing recurrent glioblastoma multiforme (GBM) from treatment-related changes. Methods/materials We retrospectively evaluated 30 patients treated with chemoradiation for GBM and underwent advanced MR and FDG-PET for confirmation of tumor progression. Multiparametric MRI and FDG-PET imaging metrics were evaluated for their association with 6-month overall (OS) and progression-free survival (PFS) based on pathological, radiographic, and clinical criteria. Results 17 males and 13 females were treated between 2001 and 2014, and later underwent FDG-PET at suspected recurrence. Baseline FDG-PET and MRI imaging was obtained at a median of 7.5 months [interquartile range (IQR) 3.7–12.4] following completion of chemoradiation. Median follow-up after FDG-PET imaging was 10 months (IQR 7.2–13.0). Receiver-operator characteristic curve analysis identified that lesions characterized by a ratio of the SUVmax to the normal contralateral brain (SUVmax/NB index) >1.5 and mean apparent diffusion coefficient (ADC) value of ≤1,400 × 10−6 mm2/s correlated with worse 6-month OS and PFS. We defined three patient groups that predicted the probability of tumor progression: SUVmax/NB index >1.5 and ADC ≤1,400 × 10−6 mm2/s defined high-risk patients (n = 7), SUVmax/NB index ≤1.5 and ADC >1,400 × 10−6 mm2/s defined low-risk patients (n = 11), and intermediate-risk (n = 12) defined the remainder of the patients. Median OS following the time of the FDG-PET scan for the low, intermediate, and high-risk groups were 23.5, 10.5, and 3.8 months (p

We previously reported the results of a phase 3 trial evaluating a prostate/rectal hydrogel spacer during prostate intensity modulated radiation therapy, which resulted in decreased rectal dose and toxicity and less decline in bowel quality of life (QOL). A secondary analysis was performed to correlate penile bulb dose and sexual QOL.Sexual QOL was measured with the Expanded Prostate Cancer Index Composite (EPIC) by mean scores, the proportion of patients with a minimal clinically important difference (MID), and analyses of the different items composing the sexual domain.A total of 222 men enrolled with median follow-up of 37 months. Hydrogel reduced penile bulb mean dose, maximum dose, and percentage of penile bulb receiving 10 to 30 Gy (all P.05) with mean dose indirectly correlated with erections sufficient for intercourse at 15 months (P = .03). Baseline EPIC was low (53 [standard deviation ± 24]) with no difference between arms (P.1). A total of 41% (88/222) of men had adequate baseline sexual QOL (EPIC60 (mean, 77 [± 8.3]). This subgroup at 3 years had better sexual function (P = .03) with a spacer with a smaller difference in sexual bother (P = .1), which resulted in a higher EPIC summary on the spacer arm (58 [±24.1] vs control 45 [± 24.4]) meeting threshold for MID without statistical significance (P = .07). There were statistically nonsignificant differences favoring spacer for the proportion of men with MID and 2× MID declines in sexual QOL with 53% vs 75% having an 11-point decline (P = .064) and 41% vs 60% with a 22-point decline (P = .11). At 3 years, more men potent at baseline and treated with spacer had "erections sufficient for intercourse" (control 37.5% vs spacer 66.7%, P = .046) as well as statistically higher scores on 7 of 13 items in the sexual domain (all P.05).The use of a hydrogel spacer decreased dose to the penile bulb, which was associated with improved erectile function compared with the control group based on patient-reported sexual QOL.

Objective The objective of this study was to present the treatment technique and evaluate clinical outcomes after intensity modulated radiation therapy (IMRT) for vulvar cancer. Methods and materials This retrospective study included 39 patients with squamous cell carcinoma of the vulva treated with IMRT from 2005 to 2015. There were 21 patients treated with postoperative IMRT, 13 with definitive IMRT, and 5 with preoperative IMRT. Tumor staging was Federation of Gynecology and Obstetrics stage I in 6, stage II in 7, stage III in 19, and stage IV in 7 patients. Concurrent chemotherapy was administered to 14 patients. Brachytherapy was delivered in 8 patients. Results The median follow-up was 34 months (range, 3.3-71). Median IMRT dose to patients receiving pre- or postoperative IMRT was 5040 cGy (range, 5040-6080). Median combined IMRT and brachytherapy dose to gross tumor was 7000 cGy (range, 5040-7520) in those treated with definitive RT. The 3-year locoregional control (LRC) and overall survival for those receiving postoperative RT were 89% and 67%, respectively. The 3-year LRC and overall survival for those receiving definitive IMRT were 42% and 49%, respectively. In patients receiving definitive or neoadjuvant IMRT, 69% had complete clinical response and 44% had complete pathologic response. The actuarial 3-year inguinal recurrence rate was 7%. There were no acute grade 3-4 hematological, gastrointestinal, or genitourinary toxicities. There were no late grade 3-4 gastrointestinal or genitourinary toxicities. Conclusions IMRT for vulvar cancer is associated with high rates of LRC in the postoperative setting and limited radiation-related toxicity. Durable LRC of disease after definitive IMRT remains challenging, and several refinements to our treatment technique are suggested.

Purpose It is unknown whether brachytherapy after external beam radiation (EBRT + BT) results in improved outcomes compared with EBRT alone for patients with inoperable vulvar cancer. The purpose of this study was to compare survival outcomes for patients who received these treatment modalities. Methods and Materials Data between 1973 and 2011 from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database were analyzed. Patients with Federation of International Gynecologists and Obstetricians stage I-IVA vulvar cancer treated with definitive EBRT + BT or EBRT alone were included. Patients with prior surgical resection were excluded. Disease-specific survival (DSS) and overall survival were compared using the Kaplan–Meier method and Cox proportional hazard models. Results A total of 649 patients were analyzed, of which 617 received EBRT alone and 32 received EBRT + BT. Median follow-up was 33 months in surviving patients. The use of brachytherapy declined from 16% of cases treated in 1973–1980 to 4% in 2001–2011 (p = 0.04). EBRT + BT vs. EBRT alone was not significantly associated with improved DSS (45% vs. 33% at 5 years) or overall survival (34% vs. 24% at 5 years) on univariate or multivariate analyses. On post hoc subgroup analyses, brachytherapy consolidation was associated with higher 5-year DSS in a composite subgroup that included patients with stage IVA disease, tumor >4 cm, or node-positive disease (52% vs. 27%, p = 0.02). Conclusions Utilization of BT consolidation with EBRT for vulvar cancer is declining in the United States. EBRT + BT is not associated with improved survival compared with EBRT alone in the overall group of patients. Certain subgroups of patients might benefit from brachytherapy, but this hypothesis requires validation in future studies.

The aim of this study was to investigate the use of post-treatment F-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for vulvar cancer and compare metabolic response to clinical outcomes.This retrospective study included 21 patients with vulvar squamous cell carcinoma treated with curative-intent radiation between 2007 and 2015. All patients received intensity-modulated radiation treatment (IMRT), a pre-treatment FDG/PET-CT, and a post-treatment FDG-PET/CT performed at a median time of 3months post-IMRT.Median follow-up time was 28months. Post-treatment FDG-PET/CT demonstrated no evidence of disease (NED) in 12 patients and residual or progressive disease (PD) in 9. FDG-PET/CT response significantly correlated with biopsy-proven locoregional failure (p=0.02) and was the only significant factor associated with overall survival (OS) (p=0.049). Patients with NED on FDG-PET had a 2-year locoregional control (LRC) of 89% versus 25% for those with PD (p0.01). Patients with NED on FDG-PET/CT had a 2-year OS of 100% versus 42% for those with PD (p=0.02). FDG-PET/CT evaluation had a sensitivity of 100% and a specificity of 71% for detecting pathologically proven residual disease in patients receiving neoadjuvant or definitive radiation.In this single-institution study of women with vulvar cancer, post-treatment response on FDG-PET/CT was associated with LRC and OS.

Objective To evaluate local control, survival outcomes, and toxicity after intensity modulated radiotherapy (IMRT) for recurrent chemorefractory ovarian cancer. Methods Between 2006 and 2014, 33 patients were treated with IMRT for recurrent ovarian cancer. Patients received a median of 3 chemotherapy regimens prior to IMRT (range, 1–12) with 11 (33%) undergoing concurrent therapy. Local control (LC), recurrence free survival (RFS), and overall survival (OS) were calculated via Kaplan-Meier method. Toxicity was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) v4.03. Impact of patient characteristics on outcomes was evaluated via Cox's proportional hazard model. Results Median follow up was 23.7months. Forty-nine sites were treated to a median dose of 5040cGy (range, 4500–7000). Nine (18%) of the 49 sites had in-field failures. Two year actuarial LC, RFS, and OS were 82%, 11%, and 63%, respectively. Seventeen patients had both a pre and post-treatment FDG-PET/CT; 6 (35%) had a complete metabolic response while 11 (65%) had a partial metabolic response. Acute≥grade 3 gastrointestinal (GI) toxicities occurred in 2 (6%) patients, late≥grade 3 GI toxicities occurred in 12 (36%), acute≥grade 3 hematological toxicities occurred in 5 (15%) and late≥grade 3 hematological toxicities occurred in 14 (42%). Conclusions IMRT for recurrent chemorefractory ovarian cancer is associated with excellent local control and limited radiation related toxicity. Future studies will be required to determine which subpopulation will benefit most from IMRT and whether alternative techniques such as stereotactic body radiotherapy may be feasible.