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We report long-term outcomes from our phase 1 dose-escalation study to determine the maximum tolerated dose of single-fraction liver SABR pooled with our subsequent single institutional experience with patients treated postprotocol at the highest dose level (40 Gy) established from the phase 1 study.Patients with liver metastases from solid tumors located outside of the central liver zone were treated with single-fraction SABR on a phase 1 dose escalation trial. At least 700 cc of normal liver had to receive9.1 Gy. Seven patients with 10 liver metastases received the initial prescription dose of 35 Gy, and dose was then escalated to 40 Gy for 7 more patients with 7 liver metastases. An additional 19 postprotocol patients with 22 liver metastases were treated to 40 Gy in a single fraction. Patients were followed for toxicity and underwent serial imaging to assess local control.Median imaging follow-up for the combined cohort (n = 33, 39 lesions) was 25.9 months; 38.9 months for protocol patients and 20.2 months for postprotocol patients. Median lesion size was 2.0 cm (range, 0.5-5.0 cm). There were no dose-limiting toxicities observed for protocol patients, and only 3 grade 2 toxicities were observed in the entire cohort, with no grade ≥3 toxicities attributable to treatment. Four-year actuarial local control of irradiated lesions in the entire cohort was 96.6%, 100% in the protocol group and 92.9% in the subsequent patients. Two-year overall survival for all treated patients was 82.0%.For selected patients with liver metastases, single-fraction SABR at doses of 35 and 40 Gy was safe and well-tolerated, and shows excellent local control with long-term follow-up; results in subsequent patients treated with single-fraction SABR doses of 40 Gy confirmed our earlier results.

PURPOSE: We assessed the feasibility and safety of placing a radiopaque hydrogel in the pancreaticoduodenal groove via endoscopic ultrasound guidance in patients with borderline resectable/locally advanced pancreatic cancer (BR/LAPC). METHODS AND MATERIALS: Hydrogel injections were done at time of fiducial placement to form blebs in the pancreaticoduodenal groove. Patients subsequently underwent simulation computed tomography (sim-CT) followed by hypofractionated stereotactic body radiotherapy (SBRT; 33 Gy in 5 fractions). Four to 8 weeks after SBRT, patients underwent CT re-evaluation for surgical candidacy and assessment of hydrogel location and size. Hydrogel placement was considered successful if identified in the pancreaticoduodenal groove on sim-CT scan. Stability was evaluated using equivalence testing analyses, with a null hypothesis of the presence of a ≥20% mean percentage change in volume and ≥change in the median and mean interbleb surface distance with a P value

Purpose Variation in target positioning represents a challenge to set-up reproducibility and reliability of dose delivery with stereotactic body radiation therapy (SBRT) for pancreatic adenocarcinoma (PDAC). While on-board imaging for fiducial matching allows for daily shifts to optimize target positioning, the magnitude of the shift as a result of inter- and intra-fraction variation may directly impact target coverage and dose to organs-at-risk. Herein, we characterize the variation patterns for PDAC patients treated at a high-volume institution with SBRT. Methods We reviewed 30 consecutive patients who received SBRT using active breathing coordination (ABC). Patients were aligned to bone and then subsequently shifted to fiducials. Inter-fraction and intra-fraction scans were reviewed to quantify the mean and maximum shift along each axis, and the shift magnitude. A linear regression model was conducted to investigate the relationship between the inter- and intra-fraction shifts. Results The mean inter-fraction shift in the LR, AP, and SI axes was 3.1 ± 1.8 mm, 2.9 ± 1.7 mm, and 3.5 ± 2.2 mm, respectively, and the mean vector shift was 6.4 ± 2.3 mm. The mean intra-fraction shift in the LR, AP, and SI directions were 2.0 ± 0.9 mm, 2.0 ± 1.3 mm, and 2.3 ± 1.4 mm, respectively, and the mean vector shift was 4.3 ± 1.8 mm. A linear regression model showed a significant relationship between the inter- and intra-fraction shift in the AP and SI axis and the shift magnitude. Conclusions Clinically significant inter- and intra-fraction variation occurs during treatment of PDAC with SBRT even with a comprehensive motion management strategy that utilizes ABC. Future studies to investigate how these variations could lead to variation in the dose to the target and OAR should be investigated. Strategies to mitigate the dosimetric impact, including real time imaging and adaptive therapy, in select cases should be considered.

Purpose/objective(s) Multi-agent chemotherapy and radiation therapy (RT) has increased the proportion of locally advanced pancreatic cancer (LAPC) patients (pts) able to undergo resection and improve overall survival compared to those who are not resected. However, prior data from our institution (2016-2019) indicate that despite an R0 rate of 88%, LF developed in > 30% of LAPC pts resected after neoadjuvant therapy (NAT). This high LF rate is a rationale to explore dose escalation (DE) in the NAT setting, as data highlighting the value of DE have been limited to unresectable disease. Importantly, the optimal method for DE remains unclear. While conformal external beam RT can ablate part of the target, under-coverage in close proximity to the stomach and bowel remains problematic. For pancreatic head tumors, Whipple resection presents an opportunity for subsequent DE with IORT, as the duodenum is resected and direct access to microscopic peri-vascular residual disease is allowed. It also allows for precise DE based on the surgeons' recommendations. Herein, we model DE approaches, comparing pre-operative DE-IMRT with an approach in which a high-dose rate (HDR)-IORT boost is given after SBRT, with a goal biological effective dose (BED10) of 100 Gy. Materials/methods Ten consecutive LAPC pts were modeled with both DE-IMRT to 75 Gy in 25 fractions and SBRT to 40 Gy in 5 fractions followed by HDR-IORT to 15 Gy, using an 192Ir source. Notably, to minimize LF after surgery, our clinical tumor volume (CTV) has been the "Heidelberg Triangle" of tissue between the celiac, superior mesenteric, and common hepatic arteries and portal vein, which contains perineural and lymphatic tissue at risk of harboring subclinical disease. A 5mm planning tumor volume (PTV) expansion was used. A 3mm expansion on stomach and bowel was constrained to 60 Gy and 40 Gy for DE-IMRT and SBRT, respectively. For IORT modeling, the Freiburg Flap was superimposed on the planning CT, and dose was prescribed to the target volume surface. Given rapid dose fall-off with HDR-IORT, SBRT was optimized to compensate for IORT under-coverage, with higher dose allowed posteriorly but with an overall hotspot less than 50 Gy. Descriptive statistics were generated for coverage to target structures. Results With DE-IMRT, mean V75Gy for the CTV and PTV was only 79% +/- 14.4% and 52% +/- 13%, respectively. In comparison, posteriorly optimizing the SBRT plan in anticipation of anterior IORT supplementation improved coverage with ablative BED. For the anterior half of the target volume, HDR-IORT created a dose gradient of 10-15 Gy, whereas for the posterior half of the target volume, HDR-IORT created a dose gradient of 5-10 Gy. Optimizing the SBRT plan to complement this with 40 Gy to the anterior half of the volume and 45 Gy to the posterior half of the volume was feasible with > 90% coverage with BED10 of 100Gy in composite. Conclusion Dose escalation with SBRT/IORT may allow for better target coverage with ablative RT dose as compared to DE-IMRT and should be explored clinically.

OBJECTIVES Clinical concerns about hematologic toxicities in human immunodeficiency virus (HIV)+ patients with squamous cell anal cancer (SCAC) may lead to de-escalation of treatment intensity. The objective of this study is to evaluate clinical outcomes including toxicity following standard concurrent curative-intent chemoradiation for HIV+ and HIV- patients with SCAC. MATERIALS AND METHODS Among 97 evaluable patients treated between 2009 and 2016 (median age 52.2 y), 43 (44.3%) were HIV+ and 54 (55.7%) HIV-. The majority of the radiation was delivered using intensity-modulated radiation therapy and chemotherapy consisting primarily (93%) of 5-fluorouracil and mitomycin C. Clinical outcomes assessed included toxicity, locoregional control (LRC), distant metastasis (DM), progression-free survival (PFS), colostomy-free survival (CFS), overall survival (OS), and cause-specific survival (CSS). RESULTS With a median follow-up of 45 months, HIV+ patients exhibited a trend toward reduced OS compared with HIV- patients (4 y OS 61.2% vs. 78.3%; HR 2.09; 95% CI, 0.97-4.52; P=0.055) on univariable analysis, but HIV status was not significant after adjusting for additional parameters on multivariable analysis. Toxicity rates, LRC, CFS, PFS, freedom from DM, and CSS were similar between the 2 cohorts. On multivariable analysis, tumor size >5 cm impacted all clinical outcomes (trend for LRC) except CFS. Radiation treatment extension beyond 7 days was found to negatively impact LRC and CSS. Male sex was associated with worse CFS. CONCLUSIONS Radiation therapy with concurrent 5-fluorouracil and mitomycin C chemotherapy is reasonably well-tolerated as curative treatment for HIV+ patients with SCAC, and no significant difference in outcomes was noted relative to HIV- patients.

Purpose of Review Liver-directed SABR (stereotactic ablative body radiotherapy) is emerging as an effective local therapy option for HCC (hepatocellular carcinoma). This review summarizes recent clinical progresses and proposes future directions. Recent Findings SABR is an effective and safe, non-invasive local therapy option for HCC in the primary and salvage treatment settings, as well as a bridge to liver transplantation in selected patients. Randomized trials comparing SABR with other locoregional modalities are currently ongoing. Summary Research efforts are being made toward better predicting normal tissue toxicity and tumor radiosensitivity for a tailored maximal safe treatment in HCC SABR. More recently, potential synergy with immunotherapies is of increasing interest in HCC.

A variety of surgical and other local-regional approaches to the management of hepatocellular carcinoma (HCC) are in clinical use. External beam radiation therapy is a relative newcomer to the portfolio of treatment options. Advances in planning and delivery of radiation therapy, developing in parallel with and inspiring changing paradigms of tumor management in the field of radiation oncology, have led to growing interest in radiation therapy as a viable treatment option for HCC as well as other liver tumors. In this review, we discuss these advances, current trends in liver radiotherapy, as well as avenues of future clinical and basic research. Liver Transplantation 24 420-427 2018 AASLD.

Purpose/Objective(s) The role of radiation for pancreatic cancer remains controversial with heterogeneous clinical response. Characterization of molecular biomarkers that predict radiosensitivity may help select patients for radiation therapy. The purpose of this study was to determine if somatic mutations and mutational frequency are associated with pathologic and survival outcomes in a cohort of patients with borderline resectable pancreatic cancer (BRPC) or locally advanced pancreatic cancer (LAPC) who were treated with neoadjuvant chemotherapy and stereotactic body radiotherapy (SBRT) followed by surgical exploration. Materials/Methods Patients treated with neoadjuvant chemotherapy and SBRT followed by surgical exploration from 2017-2019 and who consented to next generation sequencing (NGS) of their primary tumor were included in the study. Tissue samples were obtained with FNA at initial biopsy (n = 5) or from surgical specimen (n = 38). Univariate (UVA) and multivariable analyses (MVA) were performed to determine associations between somatic mutations and variant allele frequency (VAF) with pathologic and survival outcomes. Local response was defined as achieving complete response, marked response, or moderate response on pathology. Results A total of 43 patients underwent NGS of their primary tumor with either solid tumor panel (n = 35) or Foundation One (n = 8). Neoadjuvant therapy consisted of FOLFIRNOX (n = 36) and/or gemcitabine/abraxane (n = 11) followed by SBRT in 33 Gy in 5 fractions (range, 30-36 Gy/5 fractions). Surgical resection was performed in 35/43 patients and aborted in 8/43. Median follow-up time was 20.4 months. Median OS, PFS, DMFS, and LPFS after SBRT were 21.3 months, 9.7 months, 10.0 months, and 22.0 months, respectively. KRAS mutations were observed in 96% (43/45) of patients. On UVA and MVA, tumors with KRAS G12V mutation demonstrated a higher local response rate to neoadjuvant therapy when compared to tumors with other KRAS mutations (100% vs 68.4%, P = 0.003). On UVA and MVA, alterations in NOTCH1/2 and KRAS VAF > 4.3 were associated with worse OS. The median OS for NOTCH1/2 mutated patients was 14.4 months vs 27.5 months in NOTCH1/2 wild type patients (P = 0.045). The median OS for patients with KRAS VAF > 4.3 was 13.8 months vs 31.3 months for patients with KRAS VAF ≤ 4.3 (P = 0.025). KRAS VAF > 4.3 was also associated with worse DMFS (median, not met vs 8.1 months; P = 0.043) and a trend towards significance with worse PFS (median, 8.1 months vs 13.9 months; P = 0.058). Conclusion Tumors with KRAS G12V mutation demonstrated a greater local response in BRPC and LAPC patients treated with neoadjuvant chemotherapy, SBRT, and surgery. Alterations in NOTCH1/2 and KRAS VAF > 4.3 were associated with worse OS. KRAS VAF > 4.3 was also associated with worse DMFS and PFS. As genetic characterization of pancreatic tumors becomes more universal, further investigation into the association between these mutations and radiation-specific response endpoints should be pursued.

PURPOSE/OBJECTIVE(S) Although overshadowed by metastatic failure, patients (pts) with locally advanced pancreatic adenocarcinoma (LAPC) who undergo resection after neoadjuvant therapy (NAT) also experience high rates of locoregional failure (LF). Prior data from our institution indicate LF developed in > 30% of LAPC pts resected after NAT with multi-agent chemotherapy (MA-CT) and RT from 2016-2019 despite an R0 rate of 88%. In this cohort, gross disease and involved vessels were the target, raising the question whether field design modification could reduce LF. Indeed, elective treatment of tissue at risk of harboring microscopic residual disease after resection may be critical, but consensus regarding what constitutes the CTV for NAT does not exist. In the surgical literature, support is growing for extended dissection of the "Heidelberg Triangle" (HT), tissue between the celiac artery (CA), superior mesenteric artery (SMA), common hepatic artery (CHA), and portal vein (PV) that contains key perineural and lymphatic tracts at risk of harboring subclinical disease. Whether this concept can be applied to CTV field design is unclear. In investigation, we mapped LF locations in LAPC pts to assess if the LF distribution matches the anatomy of the Triangle volume (TV). MATERIALS/METHODS A total of 21 consecutive LAPC pts with involvement of the head or neck at diagnosis treated at our institution with MA-CT and stereotactic body radiation who developed LF after resection were reviewed. The TV starts superiorly at the CA take-off point, extends along the CA to the trifurcation, then extends laterally along the CHA and stops at the proximal proper HA. At this lateral boundary, the PV is also included and the TV extends posteriorly to the aorta along the inferior vena cava, including the SMA take-off until the crossing of the left renal vein. From the lateral boundary of the PV, the volume descends to the superior mesenteric vein (SMV) and covers the groove between the SMA-SMV. The inferior boundary is the branching of the first jejunal artery (JA) from the SMA. Descriptive statistics were generated to report the frequency of LF in relation to the TV and the frequency of critical vasculature involvement. RESULTS In 21 consecutive pts, the median TV was 80.2 ± 30.1 cubic centimeters (cc) (27.7-110.3 cc). The LF centroid was located within the TV in 20 pts (95.2%). The SMA from take-off to the JA branch-point was the most common vessel involved at diagnosis (85.7%) and at failure (80.1%) with the next four being the CA (66.7%, 57.1%), SMV (61.9%, 66.7%), CHA (61.9%, 38.1%), and PV (38.1%, 47.6%). CONCLUSION The TV nearly universally encapsulates LF location and could serve as the basis for CTV design in the neoadjuvant setting. Future studies should investigate the feasibility of therapeutic dosimetry to this volume and ultimately whether treatment of the TV reduces LF.

Background: Squamous cell carcinoma of the anus (SCCA) is one of the few cancers with an increasing incidence in the United States. We aimed to characterize race- and sex-based disparities in receipt of therapy and overall survival (OS) of SCCA using the SEER database. Methods: Cases of locoregional SCCA (T2-T4 any N M0) diagnosed between 2000 and 2012 in the SEER database were included. Demographics, tumor characteristics, type of therapy, and outcomes were extracted. Univariable and multivariable Cox proportional hazard models were constructed to test factors associated with OS. Data were reported as hazard ratios (HRs) and 95% CIs. Results: A total of 7,882 cases of locoregional SCCA were identified, with a median age of 58 years, 61.2% of whom were women, and 86.3% were white. Most patients (82.3%) received radiation therapy (RT), with the lowest rate in black men (76.7%) and the highest in white women (86.1%). The median OS was 135 months; OS was lower in elderly patients (age ≥65 years; 68 months), men (108 months), blacks (109 months), and those who did not receive RT (121 months). In multivariable analysis, age (HR, 1.19; 95% CI, 1.17-1.21 per 5 years increase), sex (HR, 1.59; 95% CI, 1.47-1.73, men vs women), race (HR, 1.51; 95% CI, 1.34-1.71, black vs white), and RT (HR, 0.90; 95% CI, 0.82-0.99) were independently associated with OS (P

Purpose Renal cell carcinoma is refractory to conventional radiation therapy but responds to higher doses per fraction. However, the dosimetric data and clinical factors affecting local control (LC) are largely unknown. We aimed to evaluate the safety and efficacy of stereotactic ablative radiation therapy (SAbR) for extracranial renal cell carcinoma metastases. Methods and Materials We reviewed 175 metastatic lesions from 84 patients treated with SAbR between 2005 and 2015. LC and toxicity after SAbR were assessed with Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Predictors of local failure were analyzed with χ 2 , Kaplan-Meier, and log-rank tests. Results In most cases (74%), SAbR was delivered with total doses of 40 to 60 Gy, 30 to 54 Gy, and 20 to 40 Gy in 5 fractions, 3 fractions, and a single fraction, respectively. The median biologically effective dose (BED) using the universal survival model was 134.5 Gy. The 1-year LC rate after SAbR was 91.2% (95% confidence interval, 84.9%-95.0%; median follow-up, 16.7 months). Local failures were associated with prior radiation therapy (hazard ratio [HR], 10.49; P P =.0189), spinal location (HR, 5.36; P =.0041), previous systemic therapy status (0-1 vs >1; HR, 3.52; P =.0217), and BED P =.0254). Dose received by 99% of the target volume was the strongest dosimetric predictor for LC. Upon multivariate analysis, dose received by 99% of the target volume greater than BED of 98.7 Gy and systemic therapy status remained significant (HR, 0.12 and 3.64, with P =.0014 and P =.0472, respectively). Acute and late grade 3 toxicities attributed to SAbR were observed in 3 patients (1.7%) and 5 patients (2.9%), respectively. Conclusions SAbR demonstrated excellent LC of metastatic renal cell carcinoma with a favorable safety profile when an adequate dose and coverage were applied. Multimodality treatment with surgery should be considered for reirradiation or vertebral metastasis. A higher radiation dose may be required in patients who received previous systemic therapies.

Background There is continued debate regarding the optimal combinations of radiation therapy and chemotherapy in the preoperative treatment of locally advanced rectal adenocarcinomas. We report our single-institution experience of feasibility and early oncologic outcomes of short-course preoperative radiation therapy (5 Gy X 5 fractions) followed by consolidation neoadjuvant chemotherapy. Methods We reviewed the records of 26 patients with locally advanced rectal adenocarcinoma. All patients underwent short course radiotherapy (5 Gy X 5 fractions) followed by chemotherapy [either modified infusional and bolus 5-fluorouracail and oxalipatin (mFOLFOX6) or capecitabine and oxaliplatin] prior to consideration for surgery. A full course of chemotherapy was defined as at least 8 weeks of chemotherapy. Results There were five clinical (c) T2, 16 cT3, and five cT4 rectal tumors, with 88% cN+. Twenty-five patients received a median of 4 cycles (range 3 to 8) of mFOLFOX6 (with one cycle defined as a two-week period); one patient received 3 cycles of capecitabine and oxaliplatin. All patients completed SCRT; 81% completed the full course of neoadjuvant chemotherapy with 19% requiring dose reductions in chemotherapy, most commonly due to neuropathy. Nineteen patients underwent post-treatment endoscopic evaluation, and nine patients were noted to achieve a complete clinical response (CCR). Six of the nine patients who achieved CCR opted for a non-operative approach of watch-and-wait. Twenty patients underwent surgical resection; pathologic complete response was observed in seven (35%) of these twenty. The main radiation-associated toxicity was proctitis with CTCAE Grade 2 proctitis observed in seven patients (27%). Post-operative Clavien-Dindo Grade 3 complications within 30 days of surgery were identified in six patients (30%), with no Grade 4 or 5 adverse events. Median length of hospital stay was 4.5 days (range 2–16 days); three patients were readmitted within a 30 day period. Conclusions Short course preoperative radiotherapy followed by neoadjuvant chemotherapy was well-tolerated and achieved oncologic outcomes that compare favorably with short-course radiation therapy alone or long-course chemoradiotherapy. This regimen is associated with high rates of clinical and pathologic complete response.

Background Heterogeneous target doses are a common by-product from attempts to improve normal tissue sparing in radiosurgery treatment planning. These regions of escalated dose within the target may increase tumor control probability (TCP). Purposely embedding hot spots within tumors during optimization may also increase the TCP. This study discusses and compares five optimization approaches that not only eliminate homogeneity constraints, but also maximize heterogeneity and internal dose escalation. Methods Co-planar volumetric modulated arc therapy (VMAT) plans were produced for virtual spherical targets with 2–8 cm diameters, minimum target dose objectives of 25 Gy, and objectives to minimize normal tissue dose. Five other sets of plans were produced with additional target dose objectives: 1) minimum dose-volume histogram (DVH) objective on 10% of the target 2) minimum dose objective on a sub-structure within the target, and 3–5) minimum generalized equivalent uniform dose (gEUD) objectives assuming three different volume-effect parameters. Plans were normalized to provide equivalent maximum OAR dose and were compared in terms of target D0.1 cc, ratio of V12.5 Gy to PTV volume (R50%), monitor units per 5 Gy fraction (MU), and mean multi-leaf collimator (MLC) segment size. All planning approaches were also applied to a clinical patient dataset and compared. Results Mean ± standard deviation metrics achievable using the baseline and experimental approaches 1–5) included D0.1 cc: 27.7 ± 0.8, 64.6 ± 10.5, 56.5 ± 10.3, 48.9 ± 5.7, 44.8 ± 5.0, and 37.4 ± 4.5 Gy. R50%: 4.64 ± 3.27, 5.15 ± 2.32, 4.83 ± 2.64, 4.42 ± 1.83, 4.45 ± 1.88, and 4.21 ± 1.75. MU: 795 ± 27, 1988 ± 222, 1766 ± 259, 1612 ± 112, 1524 ± 90, and 1362 ± 146. MLC segment size: 4.7 ± 1.6, 2.3 ± 0.7, 2.6 ± 0.8, 2.7 ± 0.7, 2.7 ± 0.8, and 2.8 ± 0.8 cm. Conclusions The DVH-based approach provided the highest embedded doses for all target diameters and patient example with modest increases in R50%, achieved by decreasing MLC segment size while increasing MU. These results suggest that embedding doses > 220% of tumor margin dose is feasible, potentially improving TCP for solid tumors.

4134 Background: Management of locally advanced pancreas cancer (LAPC) standardly involves chemotherapy with consolidative radiation and surgery in selected pts. Checkpoint inhibitors have shown limited benefit alone in pancreas cancer but may be primed by radiation and GM-CSF secreting allogeneic pancreatic cancer vaccine (GVAX). We present data from a phase 2 study for LAPC pts who have not developed metastases after standard of care chemotherapy treated with combination cyclophosphamide (CY), GVAX, pembrolizumab (pembro), and stereotactic body radiation therapy (SBRT). Methods: This is a single-arm, single institution, open-label study for pts with LAPC at diagnosis (as per NCCN guidelines, arterial involvement > 180°, or unreconstructible SMV/PV) who remained without metastatic disease after 4-8 28-day cycles FOLFIRINOX or gemcitabine/abraxane based therapy. Pts received CY (200mg/m2 IV) and pembro (200mg IV) on day 1, followed by GVAX (6 intradermal inj) on day 2 q3 wk x 2 cycles, with cycle 2 initiating concurrently with 5 days SBRT. Pts were restaged 4-6 weeks after SBRT, and if non-metastatic, pts underwent surgical resection, irreversible electroporation (IRE), or biopsy (if not undergoing surgical resection). Pts received two cycles of chemotherapy, and if metastasis free, received q3 wk CY/pembro/GVAX x 6 cycles with restaging scans q3 mos. In 5/2017, the protocol was addended to include an extended phase with q3 wk pembro x 9 cycles and q6 mo CY/GVAX x 4. Primary endpoint was distant metastasis free survival (DMFS) defined as C1D1 to distant metastases or death. Results: From Jul 2016-Jan 2021, 58 pts with LAPC were enrolled at the Johns Hopkins Hospital, 54 completed 2 cycles CY/pembro/GVAX and SBRT and were evaluable for response (2 dropouts due to thrombocytopenia, 2 due to irAE (DKA and hepatitis)), median followup was 15.8 mos. Demographics: median age 66 (range 42-84), 53% male, 84% White, 12% African American. At first restaging (N = 54), 8 (15%) had metastatic disease, 9 (17%) were unresectable, 37 (69%) were eligible for surgical resection. 35 pts proceeded to the OR (1 died of cholangitis prior to surgery and 1 declined surgery), 24 had tumors resected (44% of evaluable pts, 10 (42%) had grade 1 (marked) pathologic response), 1 IRE, 2 were unresectable, 8 were metastatic. Common related AEs were vaccine site reactions; grade 3 irAE included 1 case each of dermatitis, colitis, DKA, nephritis, and pneumonitis. DMFS was 9.7 mos [95% CI 6.3-19.3 mos]. Conclusions: We present data from a ph II study of 54 pts w LAPC treated w CY/GVAX/pembro and SBRT. Primary endpoint of DMFS > 13.6 mos not reached, however 44% of pts underwent surgical resection of whom 42% had grade 1 path response rate. Additional correlative studies are underway. Clinical trial information: NCT02648282.

Post-radiation therapy evaluation of distal esophageal cancers with positron emission tomography/computed tomography can be problematic. Differentiation of recurrent neoplasm from postradiation changes is difficult in areas of fluorodeoxyglucose avidity in adjacent, incidentally irradiated organs. Few studies have described the magnetic resonance imaging appearance of radiation-induced hepatic injury. We report a case of focal radiation-induced liver injury with a new focus of fluorodeoxyglucose uptake on posttreatment positron emission tomography as well as masslike enhancement and signal abnormality on magnetic resonance imaging, thus mimicking new liver metastasis. Correlation with radiation planning images suggested the correct diagnosis, which was confirmed on follow-up imaging.

Targeted immunotherapy has emerged as a potentially effective systemic treatment for metastatic cancer in the past decade. However, a significant fraction of patients will either not respond or develop resistance to immunotherapy due to the immune-evasive properties of cancer. Radiation therapy can augment immunotherapy to modulate the immune suppressive tumor microenvironment and promote specific tumor targeting by the adaptive immune system. In this review, we will discuss the rationale for combining radiation therapy with immunotherapy and describe clinical studies using this combination strategy to improve the treatment response by inducing synergistic and abscopal effects. We will discuss ongoing prospective clinical trials that employ the combination of radiation therapy and immunotherapy in the treatment of genitourinary malignancies. Further advances in these combination therapy strategies are expected to improve the clinical response and disease course while further providing insight to the complex interactions and regulations between the immune system and cancer cells. Multiple additional clinical trials will be required to find routine application of this concept to the clinic.

Purpose The purpose of this work was to compare the dosimetry and delivery times of 3D-conformal (3DCRT)-, volumetric modulated arc therapy (VMAT)-, and tomotherapy-based approaches for spatially fractionated radiation therapy for deep tumor targets. Methods Two virtual GRID phantoms were created consisting of 7 "target" cylinders (1-cm diameter) aligned longitudinally along the tumor in a honey-comb pattern, mimicking a conventional GRID block, with 2-cm center-to-center spacing (GRID2 cm ) and 3-cm center-to-center spacing (GRID3 cm ), all contained within a larger cylinder (8 and 10 cm in diameter for the GRID2 cm and GRID3 cm , respectively). In a single patient, a GRID3 cm structure was created within the gross tumor volume (GTV). Tomotherapy, VMAT (6 MV + 6 MV-flattening-filter-free) and multi-leaf collimator segment 3DCRT (6 MV) plans were created using commercially available software. Two tomotherapy plans were created with field widths (TOMO2.5 cm ) 2.5 cm and (TOMO5 cm ) 5 cm. Prescriptions for all plans were set to deliver a mean dose of 15 Gy to the GRID targets in one fraction. The mean dose to the GRID target and the heterogeneity of the dose distribution (peak-to-valley and peak-to-edge dose ratios) inside the GRID target were obtained. The volume of normal tissue receiving 7.5 Gy was determined. Results The peak-to-valley ratios for GRID2 cm /GRID3 cm /Patient were 2.1/2.3/2.8, 1.7/1.5/2.8, 1.7/1.9/2.4, and 1.8/2.0/2.8 for the 3DCRT, VMAT, TOMO5 cm , and TOMO2.5 cm plans, respectively. The peak-to-edge ratios for GRID2 cm /GRID3 cm /Patient were 2.8/3.2/5.4, 2.1/1.8/5.4, 2.0/2.2/3.9, 2.1/2.7/5.2 and for the 3DCRT, VMAT, TOMO5 cm , and TOMO2.5 cm plans, respectively. The volume of normal tissue receiving 7.5 Gy was lowest in the TOMO2.5 cm plan (GRID2 cm /GRID3 cm /Patient = 54 cm3 /19 cm3 /10 cm3 ). The VMAT plans had the lowest delivery times (GRID2 cm /GRID3 cm /Patient = 17 min/8 min/9 min). Conclusion Our results present, for the first time, preliminary evidence comparing IMRT-GRID approaches which result in high-dose "islands" within a target, mimicking what is achieved with a conventional GRID block but without high-dose "tail" regions outside of the target. These approaches differ modestly in their ability to achieve high peak-to-edge ratios and also differ in delivery times.

For patients with locally advanced rectal cancer, neoadjuvant hypofractionated short-course radiation remains an underutilized regimen in the USA. We review the current clinical literature highlighting the relative merits of short-course radiation, along with modern neoadjuvant strategies that incorporate its use. As compared to long-course chemoradiation with delayed surgery, short-course radiation with early surgery offers similar oncologic efficacy for locally advanced rectal cancer patients. Delaying surgery after short-course radiation decreases post-operative complications as compared to early surgery and improves tumor downstaging. Delaying surgery also offers the opportunity to administer neoadjuvant systemic therapy, which may help increase local-regional tumor response and potentially decrease distant relapse rates, the latter a persisting problem in rectal cancer treatment. Short-course radiation, either with immediate or with delayed surgery, represents an appealing treatment alternative to long-course chemoradiation for patients with locally advanced rectal cancer.

Evidence supporting the synergistic antitumor activity of radiation therapy combined with immune checkpoint inhibitors is rapidly growing. Investigators should consider the characteristics and challenges of gastrointestinal (GI) cancers to evaluate the safety and clinical effectiveness of this combination. In this paper, we present the rationale for exploring this strategy and the opportunities it possesses to challenge our standard of care. We also discuss unique considerations to systematically develop this combination in GI cancers.

Background Nitric oxide donors decreased cell survival in vitro and tumor load in vivo in models of rectal cancer subjected to ionizing radiation. Nitroglycerin (NTG) transdermal patches, added to chemotherapy, have been shown to improve outcomes in lung cancer patients. Methods This open-label, nonrandomized, multicohort, dose escalation, phase I trial had a primary endpoint to evaluate the safety, tolerability, feasibility, dose-limiting toxicity and maximum tolerated dose of topical NTG in addition to 5-fluorouracil and radiation therapy for neoadjuvant treatment of locoregionally advanced operable rectal cancer. The secondary endpoint was rate of pathologic complete response (pCR). Patients were assigned to 3 sequential cohorts of escalating dose levels of commercially available NTG patches (0.2, 0.4, and 0.6 mg/h), each cohort was intended to consist of 3 patients. Results Thirteen patients were enrolled in the trial as specified in the dose escalation protocol. They were all male with a median age of 59.4 ± 2.5 (SEM) years. The observed toxicities were mild to moderate and manageable. Four patients developed asymptomatic grade 3 lymphopenia during the chemoradiation that resolved promptly upon completion. One patient had a non-ST segment elevation MI and 1 patient developed diarrhea. None of these toxicities were attributed to NTG except for 1 patient who developed a grade 3 headache. This required an additional group of patients at the same dose and no other patient experienced headaches. pCR was 17%. Conclusion NTG patches are well-tolerated and it is feasible to proceed with a phase II trial at the maximum dose examined (0.6 mg/h).

Background There is significant interest in the use of stereotactic ablative radiotherapy (SABR) as a treatment modality for liver metastases. A variety of SABR fractionation schemes are in clinical use. We conducted a phase I dose-escalation study to determine the maximum tolerated dose of single-fraction liver SABR. Methods Patients with liver metastases from solid tumors, for whom a critical volume dose constraint could be met, were treated with single-fraction SABR. Seven patients were enrolled to the first group, with a prescription dose of 35 Gy. Dose was then escalated to 40 Gy in a single fraction, and seven more patients were treated at this dose level. Patients were followed for toxicity and underwent serial imaging to assess lesion response and local control. Results Fourteen patients with 17 liver metastases were treated. There were no dose-limiting toxicities observed at either dose level. Nine of the 13 lesions assessable for treatment response showed a complete radiographic response to treatment; the remainder showed partial response. Local control of irradiated lesions was 100 % at a median imaging follow-up of 2.5 years. Two-year overall survival for all patients was 78 %. Conclusions For selected patients with liver metastases, single-fraction SABR at doses of 35 and 40 Gy is tolerable and shows promising signs of efficacy at intermediate follow-up.

In this edition of the Gastrointestinal Oncology Scan, our group has selected several interesting updates of large wellknown randomized trials, and a recent phase 2 trial, that shed further light on earlier results and highlight ongoing areas of debate. These offer a nice complement to some of our earlier Oncology Scans, bringing you the best literature around the journal landscape in gastrointestinal cancers (1-4). The first is the CROSS trial, a landmark study from the Netherlands, which established preoperative radiation given concurrently with carboplatin and paclitaxel, as opposed to surgery alone, as the standard of care for esophageal cancer (5). The follow-up publication provides patterns of failure data, which confirms the expected local control benefit of radiation therapy (6). The second trial is an update on the well-known German Rectal Trial, which cemented preoperative chemoradiation as standard therapy for locally advanced rectal cancer (7). The updated analysis provides important data on the correlation of pathologic response and disease outcome(8).Thequestionofadjuvantchemotherapy for patients with rectal cancer is highlighted in the third update of the EORTC 22921 trial (9). Many clinicians extrapolate from colon cancer data to support the use of adjuvant chemotherapy for high-risk patients. The long-term results of this trial question the soundness of that approach. Finally, the last report we discuss is a phase 2 trial from investigators at Memorial-Sloan Kettering using preoperative chemotherapy alone for locally advanced rectal cancer (10). The results suggest that for carefully selected patients, radiation may be omitted without a compromise in outcome. This approachisnowbeingtestedinarandomizedprospectivetrial.

Radiation therapy as a viable and major treatment option for liver metastases is a relatively recent development in clinical oncology. The limited role of radiation has largely been due to the availability of surgery and percutaneous thermal ablation therapies, as well as the relative radiosensitivity of the liver. Technological advances in treatment planning and radiation delivery have enabled the safe and effective application of hypofractionated radiation treatments to liver tumors, including patients with colorectal cancer liver metastases. In this chapter, I discuss current clinical practice regarding the management of colorectal cancer liver metastases as well as practical details of treatment planning.

There is interest in improving the tumoricidal effects of preoperative radiotherapy for rectal carcinoma by studying new radiosensitizers. The safety and toxicity profile of these combination regimens needs rigorous clinical evaluation. The primary objective of this study was to evaluate the toxicity of combining bavituximab, an antibody that targets exposed phosphatidylserine, with capecitabine and radiation therapy.Patients with stage II or III rectal adenocarcinoma were enrolled on a phase I study combining radiation therapy, capecitabine, and bavituximab. A standard 3+3 trial designed was used.In general, bavituximab was safe and well tolerated in combination with radiation therapy and capecitabine in the treatment of rectal adenocarcinoma. One patient at the highest dose level experienced a grade III infusion reaction related to the bavituximab. One tumor demonstrated a complete pathologic response to the combination treatment.Bavituximab is safe in combination with capecitabine and radiation therapy at the doses selected for the study. Further clinical investigation would be necessary to better define the efficacy of this combination.

Controversies in the selection of radiation treatment dose and fractionation pattern are an important, and ongoing, chapter in the history of radiation oncology. The recent expansion of the clinical practice of extracranial hypofractionated radiation therapy, made possible by advances in radiation treatment planning and image guidance, has raised an important host of biological questions with immediate clinical implications. In this chapter, we provide an overview of some of these questions, concluding with a discussion of the systemic effects of local therapies.

Objective The goal of this study was to explore conceptual benefits of characterizing delineated target volumes based on surface area and to utilize the concept for assessing risk of therapeutic toxicity in radiosurgery. Methods and materials Four computer-generated targets, a sphere, a cylinder, an ellipsoid and a box, were designed for two distinct scenarios. In the first scenario, all targets had identical volumes, and in the second one, all targets had identical surface areas. High quality stereotactic radiosurgery plans with at least 95% target coverage and selectivity were created for each target in both scenarios. Normal brain volumes V12Gy, V14Gy and V16Gy corresponding to received dose of 12 Gy, 14 Gy and 16 Gy, respectively, were computed and analyzed. Additionally, V12Gy and V14Gy volumes and values for seven prospective toxicity variables were recorded for 100 meningioma patients after Gamma Knife radiosurgery. Multivariable stepwise linear regression and best subset linear regression analyses were performed in two statistical software packages, SAS/STAT and R, respectively. Results In a phantom study, for the constant volume targets, the volumes of 12 Gy, 14 Gy and 16 Gy isodose clouds were the lowest for the spherical target as an expected corollary of the isoperimetric inequality. For the constant surface area targets, a conventional wisdom is confirmed, as the target volume increases the corresponding volumes V12Gy, V14Gy and V16Gy also increase. In the 100-meningioma patient cohort, the best univariate model featured tumor surface area as the most significantly associated variable with both V12Gy and V14Gy volumes, corresponding to the adjusted R2 values of 0.82 and 0.77, respectively. Two statistical methods converged to matching multivariable models. Conclusions In a univariate model, target surface area is a better predictor of spilled dose to normal tissue than target largest dimension or target volume itself. In complex multivariate models, target surface area is an independent variable for modeling radiosurgical normal tissue toxicity risk.

The article Stereotactic Ablative Radiotherapy (SABR/SBRT) for Hepatocellular Carcinoma, written by Byung-Han Rhieu, Amol K. Narang and Jeffrey Meyer, was originally published electronically on the publisher’s internet portal (currently SpringerLink) on 16 October 2018 without open access.

The purpose of this study was to analyze the pretreatment setup errors and intrafraction motion using cone beam computed tomography (CBCT) for stereotactic body radiation therapy patients immobilized and localized with a stereotactic body frame for a variety of treatment sites.Localization errors were recorded for patients receiving SBRT for 141 lung, 29 liver, 48 prostate, and 45 spine tumors representing 1005 total localization sessions. All patients were treated in a stereotactic body frame with a large custom-molded vacuum pillow. Patients were first localized to the frame using tattoos placed during simulation. Subsequently, the frame was aligned to the room lasers according to the stereotactic coordinates determined from the treatment plan. Every patient received a pretreatment and an intrafraction CBCT. Abdominal compression was used for all liver patients and for approximately 40% of the lung patients to reduce tumor motion due to respiration.The mean ± standard deviation pretreatment setup errors from all localizations were -2.44 ± 3.85, 1.31 ± 5.84, and 0.11 ± 3.76 mm in the anteroposterior, superoinferior, and lateral directions, respectively. The mean pretreatment localization results among all treatment sites were not significantly different (F test, P.05). For all treatment sites, the mean ± standard deviation intrafraction shifts were 0.33 ± 1.34, 0.15 ± 1.45, and -0.02 ± 1.17 mm in the anteroposterior, superoinferior, and lateral directions, respectively. The mean unidimensional intrafraction shifts were statistically different for several of the comparisons (P.05) as assessed by the Tukey-Kramer test.Despite the varied tumor locations, the pretreatment mean localization errors for all sites were found to be consistent among the treatment sites and not significantly different, indicating that the body frame is a suitable immobilization and localization device for a variety of tumor sites. Our pretreatment localization errors and intrafraction shifts compare favorably with those reported in other studies using different types of immobilization devices.

Historically, both local as well as distant failure rates were unsatisfactory for locally advanced rectal tumors after surgery alone (1). Significant progress has been made on the local front with the introduction of mesorectal excision as well as neoadjuvant short-course radiation therapy or long-course chemoradiotherapy. In the German CAO/ARO/ AIO-94 trial, patients with clinical stage II or III rectal carcinoma treated with neoadjuvant radiation therapy and infusional 5-fluorouracil (5-FU), surgery, and 4 cycles of adjuvant bolus 5-FU had a 7.1% rate of localeregional failure at 10 years (2). The long-term control result from this trial provides an important benchmark for patients with clinical stage II and III rectal cancer going forward. The CAO/ARO/AIO-94 study also provides another important and concerning benchmark statistic: nearly 30% of the patients treated with neoadjuvant therapy developed distant metastatic disease by 10 years (2). Thus, locally advanced rectal adenocarcinoma would seem to be a prime candidate for true multimodality therapy, with a calling for effective systemic therapy above and beyond what is delivered as a radiosensitizer concurrently with radiation therapy during neoadjuvant therapy. The integration of localeradiation and surgeryetherapies and systemic therapy is founded on the principle of spatial cooperation and is the basis for many common cancer treatment algorithms (3). Adjuvant chemotherapy for resected rectal cancer would seem all the more natural given the data from

There is a wide variety of minimally invasive tumor ablation technologies available for the management of liver tumors, including liver metastases. These treatments offer an alternative to surgical intervention in non-surgical candidates. The most commonly used ablation modalities make use of extreme heat to induce tumor necrosis. Although radiation has traditionally held a minor role in treatment of liver tumors, high-dose hypofractionated irradiation typically delivered with image-guidance is a new treatment modality with promising early results. This article will review the fundamental principles of ablative radiation therapy, compare it with other existing ablation technologies, and review early clinical results.

Purpose Cranial irradiation in pediatric patients is associated with serious long-term adverse effects. We sought to determine whether both three-dimensional conformal proton radiotherapy (3D-PRT) and intensity-modulated proton therapy (IMPT) compared with intensity-modulated radiotherapy (IMRT) decrease integral dose to brain areas known to harbor neuronal stem cells, major blood vessels, and other normal brain structures for pediatric patients with craniopharyngiomas. Methods and Materials IMRT, forward planned, passive scattering proton, and IMPT plans were generated and optimized for 10 pediatric patients. The dose was 50.4 Gy (or cobalt Gy equivalent) delivered in 28 fractions with the requirement for planning target volume (PTV) coverage of 95% or better. Integral dose data were calculated from differential dose–volume histograms. Results The PTV target coverage was adequate for all modalities. IMRT and IMPT yielded the most conformal plans in comparison to 3D-PRT. Compared with IMRT, 3D-PRT and IMPT plans had a relative reduction of integral dose to the hippocampus (3D-PRT, 20.4; IMPT, 51.3% ∗ ), dentate gyrus (27.3, 75.0% ∗ ), and subventricular zone (4.5, 57.8% ∗ ). Vascular organs at risk also had reduced integral dose with the use of proton therapy (anterior cerebral arteries, 33.3 ∗ , 100.0% ∗ ; middle cerebral arteries, 25.9% ∗ , 100% ∗ ; anterior communicating arteries, 30.8 ∗ , 41.7% ∗ ; and carotid arteries, 51.5 ∗ , 77.6 ∗ ). Relative reduction of integral dose to the infratentorial brain (190.7 ∗ , 109.7% ∗ ), supratentorial brain without PTV (9.6, 26.8% ∗ ), brainstem (45.6, 22.4% ∗ ), and whole brain without PTV (19.4 ∗ , 34.4% ∗ ) were recorded with the use of proton therapy. ( ∗ Differences were significant based on Friedman's test with Bonferroni-Dunn correction, α = 0.05) Conclusions The current study found that proton therapy was able to avoid excess integral radiation dose to a variety of normal structures at all dose levels while maintaining equal target coverage. Future studies will examine the clinical benefits of these dosimetric advantages.

Purpose Conventional proton therapy with passively scattered beams is used to treat a number of tumor sites, including prostate cancer. Spot scanning proton therapy is a treatment delivery means that improves conformal coverage of the clinical target volume (CTV). Placement of individual spots within a target is dependent on traversed tissue density. Errors in patient alignment perturb dose distributions. Moreover, there is a need for a rational planning approach that can mitigate the dosimetric effect of random alignment errors. We propose a treatment planning approach and then analyze the consequences of various simulated alignment errors on prostate treatments. Methods and Materials Ten control patients with localized prostate cancer underwent treatment planning for spot scanning proton therapy. After delineation of the clinical target volume, a scanning target volume (STV) was created to guide dose coverage. Errors in patient alignment in two axes (rotational and yaw) as well as translational errors in the anteroposterior direction were then simulated, and dose to the CTV and normal tissues were reanalyzed. Results Coverage of the CTV remained high even in the setting of extreme rotational and yaw misalignments. Changes in the rectum and bladder V45 and V70 were similarly minimal, except in the case of translational errors, where, as a result of opposed lateral beam arrangements, much larger dosimetric perturbations were observed. Conclusions The concept of the STV as applied to spot scanning radiation therapy and as presented in this report leads to robust coverage of the CTV even in the setting of extreme patient misalignments.

The linear-quadratic (LQ) model is widely used to model the effect of total dose and dose per fraction in conventionally fractionated radiotherapy. Much of the data used to generate the model are obtained in vitro at doses well below those used in radiosurgery. Clinically, the LQ model often underestimates tumor control observed at radiosurgical doses. The underlying mechanisms implied by the LQ model do not reflect the vascular and stromal damage produced at the high doses per fraction encountered in radiosurgery and ignore the impact of radioresistant subpopulations of cells. The appropriate modeling of both tumor control and normal tissue toxicity in radiosurgery requires the application of emerging understanding of molecular-, cellular-, and tissue-level effects of high-dose/fraction-ionizing radiation and the role of cancer stem cells.

Pancreatic cancer remains a highly challenging problem in oncology. Oncologists continue to search for therapies that are more effective than those currently available to improve on the existing poor treatment results. Persistence of both systemic and local disease causes high rates of morbidity and mortality for patients. Radiation continues to play a role in the treatment of pancreatic cancer, in both the adjuvant and locally advanced settings. Efforts to improve on the results of radiotherapy have led to the use of new and improved technologies. This review discusses a variety of these technological improvements and their current and potential future roles in the clinic.

This report describes the technique and initial experience using cone beam CT (CBCT) for localization of treatment targets in patients undergoing stereotactic body radiation therapy (SBRT). Patients selected for SBRT underwent 3-D or 4-D CT scans in a customized immobilization cradle. GTV, CTV, ITV, and PTV were defined. Intensity-modulated radiation beams, multiple 3-D conformal beams, or dynamic conformal arcs were delivered using a Varian 21EX with 120-leaf MLC. CBCT images were obtained prior to each fraction, and registered to the planning CT by using soft tissue and bony structures to assure accurate isocenter localization. Patients were repositioned for treatment based on the CBCT images. Radiographic images (kV, MV, or CBCT) were taken before and after beam delivery to further assess set-up accuracy. Ten patients with lung, liver, and spine lesions received 29 fractions of treatment using this technique. The prescription doses ranged 1250 approximately 6000 cGy in 1 approximately 5 fractions. Compared to traditional 2-D matching using bony structures, CBCT corrects target deviation from 1 mm to 15 mm, with an average of 5 mm. Comparison of pre-treatment to post-treatment radiographic images demonstrated an average 2 mm deviation (ranging from 0-4 mm). Improved immobilization may enhance positioning accuracy. Typical total "in-room" times for the patients are approximately 1 hour. CBCT-guided SBRT is feasible and enhances setup accuracy using 3-D anatomical information.

Sorafenib, an inhibitor of multiple tyrosine kinases including vascular endothelial growth factor receptor and Raf/mitogen-activated protein kinase, increases progression-free survival in metastatic renal cell carcinoma (RCC) compared with placebo. The efficacy and toxicity of combined sorafenib and radiation therapy (RT) in the treatment of RCC are unknown. This is a retrospective report of 3 consecutive patients with metastatic or locally recurrent RCC treated with palliative RT while undergoing sorafenib therapy. All 3 patients experienced disease progression on sorafenib and remained on the drug without dose reduction during the RT plus sorafenib regimen. They were followed for toxicity and response by clinical history, physical examination, and contrast-enhanced computed tomography scans. Soon after completion of palliative RT, all 3 patients experienced complete pain relief without the need for narcotic pain medication. Posttreatment imaging revealed partial response with > 50% regression of tumor in all patients. None reported significant acute or late side effects at follow-up of 3, 6, and 8 months after RT and sorafenib. In the 3 patients with recurrent or metastatic RCC in this report, the combination of RT and sorafenib was well tolerated and resulted in excellent clinical and radiologic responses. This combination is promising and requires further study.

Intensity-modulated photon radiation therapy (RT; IMRT) and proton therapy are advanced radiation technologies that permit improved conformation of radiation dose to target structures while limiting irradiation of surrounding normal tissues. Application of these technologies in the treatment of rectal and anal cancer is attractive, based on the potential reduction in radiation treatment toxicities that are frequently incurred in the pelvis and perineum. Furthermore, conformal RT might also allow for dose escalation to target areas, leading to improved tumor control. This review discusses the underlying principles of IMRT. In addition, the rationale and clinical data regarding the efficacy of radiation dose escalation for rectal and anal cancer will be highlighted, as well as tolerance of pelvic organs to RT and chemotherapy. Finally, preliminary results of IMRT in the treatment of lower gastrointestinal tract cancers will be reviewed. The potential and rationale for proton therapy in treatment of these malignancies are also discussed.

The Metastatic Spine Disease Multidisciplinary Working Group consists of medical and radiation oncologists, surgeons, and interventional radiologists from multiple comprehensive cancer centers who have developed evidence- and expert opinion-based algorithms for managing metastatic spine disease. The purpose of these algorithms is to facilitate interdisciplinary referrals by providing physicians with straightforward recommendations regarding the use of available treatment options, including emerging modalities such as stereotactic body radiation therapy and percutaneous tumor ablation. This consensus document details the evidence supporting the Working Group algorithms and includes illustrative cases to demonstrate how the algorithms may be applied. Implications for Practice: The Metastatic Spine Disease Multidisciplinary Working Group algorithms can facilitate interdisciplinary referrals by providing physicians with straightforward recommendations regarding available treatment options, including emerging modalities such as stereotactic body radiation therapy and percutaneous tumor ablation.

Background Treatment of cancer in the lung in octogenarians is limited by their health and functional status. Stereotactic ablative radiotherapy is an established noninvasive treatment option for medically inoperable patients, with a toxicity profile that may be more tolerable in elderly patients. Methods Patients more than 80 years old treated with stereotactic ablative radiotherapy for malignant tumors in the lung between January 2007 and August 2012 at a single institution were identified and retrospectively analyzed for toxicity and survival. Results Thirty patients were identified with a total of 32 lesions treated. Patients ranged in age from 80.8 to 90.7 years old (median 84.9) at the time of treatment. Twenty patients had ECOG performance status 0–1, and 10 had performance status 2–3. Stage distribution at treatment was: stage I (20 patients), stage III (1), stage IV (1), and 8 recurrent tumors. Patients were treated to a median total dose of 54 Gy in 3 fractions (range 20–60 Gy in 1 to 5 fractions). Median follow up was 13 months (range 2–60 months). Fifteen patients were still living at last review. There was one failure in field and one failure in the same lobe that was treated. One patient died with progressive regional disease, and four died of progressive metastatic disease. Three patients had late grade 3 pulmonary dyspnea with no grade 4 or 5 toxicities. One patient had late grade 2 pneumonitis, and 3 patients had late grade 1 pneumonitis. Three patients had grade 1 chest wall pain. Conclusions Octogenarians tolerated ablative treatment with minimal toxicity. Stereotactic ablative body radiotherapy is an option to consider in treatment of elderly patients.

691 Background: Squamous cell carcinoma of the anus (SCCA) is one of the few cancers with a rising incidence in the United States. We aimed to characterize race and gender-based disparities in receipt of therapy, and overall survival (OS) of SCCA using the Surveillance, Epidemiology and End Results (SEER) database. Methods: Cases of locoregional SCCA diagnosed between 2000-2012 in the SEER database were included. Demographics, tumor characteristics, therapy and outcomes were extracted. Primary end point was OS. Univariable and multivariable Cox proportional hazard models were constructed to test factors associated with OS. Data were reported as hazard ratios (HR) and 95% confidence intervals (CI). SAS version 9.4 was used for analysis. Results: We identified 7882 cases of locoregional SCCA, median age 58 years, 61.2% women, 86.3% white. A majority of patients (82.3%) received radiation therapy; with the lowest rate in black males (76.7%) and highest in white females (86.1%). The median OS was 135 months, and it was lower in the elderly, > 65 years (68 months), men (108 months), blacks (109 months) and those who did not receive radiation therapy (121 months). In multivariate analysis, increasing age (HR 1.19, 95 % CI 1.16-1.20 per 5 years increase), gender (HR 1.59, 95% CI 1.47- 1.73, men vs women), race (HR 1.51, 95% CI 1.34- 1.71, blacks vs whites), and receipt of radiation therapy (HR 0.90, 95% CI 0.82-0.99), were associated with OS (all p < 0.05). Race was a significant predictor of receiving radiation therapy on univariate analysis. Table 1 outlines the rates of receipt of radiation and the median OS of the four racial/gender groups. Conclusions: Significant race and gender-based disparities exist in the survival of patients with locoregional SCCA. Even after adjusting for baseline and treatment characteristics, blacks had poorer OS, suggesting difference in tumor biology. Further investigation into the causes, and methods to eliminate these disparities are warranted. [Table: see text]

There is substantial and growing interest in the use of local therapies to treat patients with metastatic cancer, especially those deemed to have "oligometastatic" disease. Much of the literature to date consists of reports on metastasectomy for liver and lung metastases. Non-surgical minimally or non-invasive treatments including thermal ablation, irreversible electroporation, and high-dose radiation therapy (stereotactic ablative radiation therapy) can also be used in the treatment of primary and secondary tumors, including in the treatment of liver metastases. In this review, we discuss the rationale for using these ablative treatments in the treatment of liver metastases including similarities and differences between them.

Introduction The hematologic indices of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are correlated with clinical outcomes after stereotactic radiation. Methods We retrospectively evaluated the pretreatment NLR and PLR in patients treated with stereotactic radiation for early stage non–small-cell lung cancer at our institution. A total of 149 patients treated for non–small-cell lung cancer were identified, and 59 had stage I disease with neutrophil, platelet, and lymphocyte levels within a 3-month period before treatment. Receiver operating characteristic (ROC) analysis was performed to examine cutoff values for survival and nonlocal failure followed by Kaplan–Meier analysis for survival. Results With a median follow-up of 17 months, 28 deaths were observed, and the median overall survival for all patients was 43 months. Based on the ROC analysis, NLR and PLR cutoff values for further survival analysis were determined based on the ROC analysis to be 2.98 and 146. The median overall survival was not reached for patients with low NLR or PLR but the survival was 23 months for patients with high NLR or PLR. There was no correlation between NLR and nonlocal failure, but on multivariate analysis PLR was found to be associated with freedom from nonlocal failure. Nonlocal failure rates were 11% for patients with PLR less than 250 and 58% for PLR greater than 250 ( p Conclusion The pretreatment NLR and PLR represented significant prognostic indicators of survival in patients treated for early-stage non–small-cell lung carcinoma with stereotactic radiation. The PLR may be used as a prognostic indicator for nonlocal failure after stereotactic radiation for early-stage lung cancer.

The value of adjuvant radiotherapy is well established in many tumor sites and is commonly used when pathologic features of a patient’s primary tumor place them at sufficiently high risk for local-regional recurrence to warrant additional intervention. The rationale for the use of adjuvant radiotherapy in such situations is the traditional shared goal of the surgical and radiation oncologist: to optimize local-regional control. Attaining local-regional control prevents the morbidity of a local recurrence, and, in some situations, improves overall survival, perhaps best exemplified in the case of postmastectomy radiotherapy for women with high-risk breast cancer.1 For pancreatic cancer management, adjuvant radiation has been delivered through fractionated external beam radiation treatments (EBRT) and/or single-fraction high-dose intraoperative radiation therapy (IORT). IORT has the benefit of directly moving critical normal tissues of the upper abdomen away from the radiation beam.2 Prevention of local recurrence leading to an improvement in survival may result through a number of mechanisms. The most straightforward of these is the underappreciated fact that local recurrence, particularly at certain sites such as the head and neck, can itself lead to disease-specific mortality. Also, radiation can sterilize remaining cells able to proliferate at the local site and then metastasize, causing eventual death; this may be all the more important in light of evidence suggesting that cells can be modulated by the postoperative microenvironment to yield more a more aggressive phenotype, as has recently been suggested in breast cancer. 3–5 Another, highly intriguing, possible effect is for irradiation of local tumor cells to induce abscopal, immune-related killing effects on distant sites of micrometastases. 5,6 Attaining local-regional control is all the more paramount when patterns of cancer failure are predominantly local-regional and/or reasonably effective chemotherapy is available to treat systemic micrometastatic disease but not sterilize local-regional disease. Therein lies the controversy over adjuvant radiotherapy (be it EBRT or IORT) for resectable pancreatic adenocarcinoma. Although clinical and autopsy series have revealed local-regional (tumor bed and regional lymph nodes) failure to be a common event (50% or greater) following pancreaticoduodenectomy, it is much less common for these failures to be in isolation with respect to distant disease and also for the local-regional failure itself to be the clear proximate cause of death.7–9 Acknowledging the high rates of distant failure (liver, peritoneal cavity), the value of primary radical surgery in patients with resectable disease may itself be questioned.10 Two randomized trials provide evidence that surgery does improve long-term survival rates compared with bypass intervention or primary chemotherapy and concurrent radiation.11,12 However, true long-term disease-free survivorship (apparent cure) is uncommon with surgery alone, and the need for effective systemic therapies is obvious. The recently reported CONKO-001 trial showed that gemcitabine following surgery delays disease failure and also likely provides higher long-term survival rates (estimated 5-year disease-free survival of 16% vs 6.5% with surgery alone).13 Whether additional locally directed therapies beyond surgery add meaningful benefit—in the context of contemporary systemic therapy options—remains an open question. Although the role of adjuvant chemoradiotherapy was established in an early Gastrointestinal Tumor Study Group trial and through retrospective institutional reports,14,15 the actual value of the radiation component has been called into question, most recently by the controversial ESPAC results.16 What are the data regarding the benefits and toxicities of IORT ± EBRT for resectable pancreatic cancer? In this issue of the Annals of Surgical Oncology, investigators from the Thomas Jefferson University departments of Radiation Oncology and Surgery report their experience with 83 patients with resected pancreatic cancer treated between 1995 and 2005. Of these, 37 patients were treated with IORT; about 75% of this group also received EBRT, and 84% received adjuvant chemotherapy. In the group treated with resection but without IORT, about two-thirds underwent adjuvant EBRT and chemotherapy. IORT did not significantly increase perioperative complication rates. As patients were not randomized to the use of IORT, the authors used a propensity score adjustment in their analysis of disease control to account for differing prognostic factors between the two groups. Although IORT was associated with an odds ratio of 0.41 for local-regional recurrence, this reduction did not reach statistical significance (P = .23). The confidence intervals for this ratio were quite large (0.10–10.30), reflecting patient numbers. IORT was not associated with improved survival. Institutional reports and a randomized trial have shown surgery followed by IORT to yield lower local-regional recurrence rates compared with surgery alone, although a positive impact on survival has not been readily demonstrated.17–19 As the authors appropriately address, improvements in systemic therapy are generally necessary before prevention of local recurrence translates into a survival benefit.20 As long as the best systemic therapy options provide only modest control of distant disease, local tumor control improvements will not translate into a survival benefit. Finally, the emergence of novel chemotherapeutic or targeted agents that impact distant metastases may also eventually impact local-regional microscopic disease control to the degree that adjuvant radiation may not be needed following R0 resection.21 Whether or not IORT contributes to overall survival was also evaluated in a group of patients treated at the University of Texas M.D. Anderson Cancer Center with neoadjuvant chemoradiation for radiographically resectable pancreatic cancer (no tumor involvement of the celiac axis or superior mesenteric artery with patent portal venous confluence). The authors reported local recurrence to be a component of the first site of failure in 9% in patients undergoing neoadjuvant fractionated EBRT (30–50 Gy) followed by surgery without IORT compared with 4% with the addition of IORT.22 The contribution of neoadjuvant EBRT to surgery cannot be determined in this study. However, the risk of local recurrence without IORT was too low in this study to see a clinically meaningful benefit in survival. In part due to these results, IORT for resected pancreatic cancer was abandoned at the M.D. Anderson Cancer Center. It is interesting to contrast these two large experiences using IORT for localized pancreatic cancer. In the current study, positive margins (R1 or R2) occurred in 30 of 83 patients (36%) overall, and the local tumor recurrence rate was numerically lower in the higher-risk IORT group (23% versus 39%). Statistical power was limited because of small numbers, but there was a suggestion that IORT improved local tumor control. In contrast, 16 of 132 patients (12%) with radiographically resectable tumors that were treated with neoadjuvant chemoradiation had positive margins (all R1) in the M.D. Anderson experience, and the crude local tumor recurrence rate was 4% with IORT and 9% without IORT. The absolute differences in the rates of positive margins and local tumor recurrence are most likely the result of differences in patient selection. However, the comparison illustrates the point that statistically nonsignificant improvements in local tumor control have been seen with the addition of IORT to resection and standard adjuvant therapies in cohorts whose combined local recurrence risk was low (

Purpose To compare the cost-effectiveness of intensity modulated radiation therapy (IMRT) and 3-dimensional conformal radiation therapy (3D-CRT) for anal cancer and determine disease, patient, and treatment parameters that influence the result. Methods and Materials A Markov decision model was designed with the various disease states for the base case of a 65-year-old patient with anal cancer treated with either IMRT or 3D-CRT and concurrent chemotherapy. Health states accounting for rates of local failure, colostomy failure, treatment breaks, patient prognosis, acute and late toxicities, and the utility of toxicities were informed by existing literature and analyzed with deterministic and probabilistic sensitivity analysis. Results In the base case, mean costs and quality-adjusted life expectancy in years (QALY) for IMRT and 3D-CRT were $32,291 (4.81) and $28,444 (4.78), respectively, resulting in an incremental cost-effectiveness ratio of $128,233/QALY for IMRT compared with 3D-CRT. Probabilistic sensitivity analysis found that IMRT was cost-effective in 22%, 47%, and 65% of iterations at willingness-to-pay thresholds of $50,000, $100,000, and $150,000 per QALY, respectively. Conclusions In our base model, IMRT was a cost-ineffective strategy despite the reduced acute treatment toxicities and their associated costs of management. The model outcome was sensitive to variations in local and colostomy failure rates, as well as patient-reported utilities relating to acute toxicities.

Historically, squamous cell carcinoma of the anal canal was treated with abdominoperineal resection. Nigro discovered that radiation therapy combined with 5-fluorouracil and mitomycin resulted in high rates of local control and colostomy-free and overall survival without surgical intervention. Recent advances include the integration of PET into staging, radiation treatment planning, disease monitoring, and the use of intensity-modulated radiation therapy. For rectal cancer, clinical trials have established the role for neoadjuvant therapy for T3-4 and/or node-positive tumor presentations. Chemotherapy and targeted agents are under study in both anal and rectal cancers to improve on the standard combinations of chemotherapy and radiation.