Ablative radiation therapy for locally advanced pancreatic cancer: techniques and results

Standard doses of conventionally fractionated radiation have had minimal to no impact on the survival duration of patients with locally advanced unresectable pancreatic cancer (LAPC). The use of low-dose stereotactic body radiation (SBRT) in 3- to 5-fractionshas thus far produced a modest improvement in median survival with minimal toxicity and shorter duration of treatment, but failed to produce a meaningful difference at 2 years and beyond. A much higher biologically effective dose (BED) is likely needed to achieve tumor ablation The challenge is the delivery of ablative doses near the very sensitive gastrointestinal tract. Advanced organ motion management, image guidance, and adaptive planning techniques enable delivery of ablative doses of radiation (\u3e = 100Gy BED) when more protracted hypofractionated regimens or advanced image guidance and adaptive planning are used. This approach has resulted in encouraging improvements in survival in several studies. This review will summarize the evolution of the radiation technique over time from conventional to ablative and describe the practical aspects of delivering ablative doses near the GI tract using cone beam CT image (CBCT) guidance and online adaptive MRI guidance

PET/MRI of Hepatic 90Y Microsphere Deposition Determines Individual Tumor Response.

PurposeThe purpose of our study is to determine if there is a relationship between dose deposition measured by PET/MRI and individual lesion response to yttrium-90 ((90)Y) microsphere radioembolization.Materials and methods26 patients undergoing lobar treatment with (90)Y microspheres underwent PET/MRI within 66 h of treatment and had follow-up imaging available. Adequate visualization of tumor was available in 24 patients, and contours were drawn on simultaneously acquired PET/MRI data. Dose volume histograms (DVHs) were extracted from dose maps, which were generated using a voxelized dose kernel. Similar contours to capture dimensional and volumetric change of tumors were drawn on follow-up imaging. Response was analyzed using both RECIST and volumetric RECIST (vRECIST) criteria.ResultsA total of 8 hepatocellular carcinoma (HCC), 4 neuroendocrine tumor (NET), 9 colorectal metastases (CRC) patients, and 3 patients with other metastatic disease met inclusion criteria. Average dose was useful in predicting response between responders and non-responders for all lesion types and for CRC lesions alone using both response criteria (p < 0.05). D70 (minimum dose to 70 % of volume) was also useful in predicting response when using vRECIST. No significant trend was seen in the other tumor types. For CRC lesions, an average dose of 29.8 Gy offered 76.9 % sensitivity and 75.9 % specificity for response.ConclusionsPET/MRI of (90)Y microsphere distribution showed significantly higher DVH values for responders than non-responders in patients with CRC. DVH analysis of (90)Y microsphere distribution following treatment may be an important predictor of response and could be used to guide future adaptive therapy trials

Outcomes of MR-guided Stereotactic Body Radiotherapy (SBRT) or yttrium-90 Transarterial Radioembolization for Hepatocellular Carcinoma Treated at an Urban Liver Transplant Center

Background: There are overlapping indications for both stereotactic body radiotherapy (SBRT) and yttrium-90 (Y90) trans-arterial radioembolization as locoregional treatments for hepatocellular cancer, though most centers preferentially use one modality over the other. MR-guided radiation allows both effective on-table localization and integrated motion management as compared with many traditional linear accelerators, allowing SBRT to be done more easily. Y90 radioembolization has been a well-established modality to deliver highly conformal dose due to the localization of the microspheres to the vascular supply of a tumor. We looked at patient characteristics and treatment outcomes for patients receiving MR-guided SBRT or Y90 at an urban transplant center. Objectives: To compare patient characteristics and treatment outcomes of MR-guided SBRT with Y90 transarterial radioembolization in a liver transplant center. Methods: This retrospective single-institution study analyzed patients with HCC treated with SBRT or Y90 from August 2017 to September 2020. To select a patient population eligible for either treatment modality, any Y90 procedures for lesions \u3e 10 cm or for treatment volumes \u3e 1000 cc were omitted from the cohort. A total of 239 patients were included in the analysis, receiving a total of 98 courses of SBRT and 187 courses of Y90 treatment. Local control (LC), freedom from liver progression (FFLP), and overall survival (OS) rates were measured from treatment completion date to death date or last follow-up. All outcomes were censored at time of loss to follow-up; LC and FFLP were censored at time of liver transplant if applicable. Cox regression models were used for survival, with significant factors on the univariate analysis further analyzed with a multivariate model. Results: Median time to follow-up was 11 months (0-44 mo). The mean size of lesions treated with SBRT were smaller than those treated with Y90 (2.7 cm vs 4.3 cm, P\u3c0.01). The groups of patients differed in liver disease characteristics, with SBRT patients having fewer Child-Pugh A disease (62% vs 80%, P\u3c0.01), more having received locoregional treatments to the liver in the past (81% v 35%, P\u3c0.01), and more disease in previously treated liver (57% vs 25%, P\u3c0.01). Dose of radiation for SBRT was 45-50 Gy administered in 5 fractions; dose of Y90 radiation to tumor was prescribed to a median of 235.2 Gy (range 55.8-512.3 Gy). There was a higher rate of one year LC in the SBRT cohort (77% vs 57%, P\u3c0.01), while median FFLP (9 mo vs 8 mo, P=NS) and median OS were not significantly different (24 mo vs 21 mo, P=NS). Multivariate analysis revealed size of largest lesion (P\u3c0.01) was correlated with decreased local control; a 1 cm increase in tumor size was associated with a 25% increased risk of local failure. Subsequent transplant (P\u3c0.01) was the remaining significant factor. Treatment modality did not remain an independent predictor of LC. Predictors of OS in multivariate analysis included age (P=0.01), prior liver treatments (HR 2.86, P\u3c0.01), size of largest lesion (P\u3c0.01), Child-Pugh stage (P\u3c0.01), portal vein thrombosis (HR 1.6, P=0.04), and subsequent liver transplant (HR 0.08, P\u3c0.01). Conclusions: These findings support the effectiveness of both MR-guided SBRT and Y90 transarterial radioembolization in locoregional management of HCC at a single institution despite clear differences in the patient cohorts. Though survival outcomes were comparable, local control differences favored the cohort treated by SBRT, in large part due to differences in tumor size. This data supports further investigation in a randomized study between SBRT and Y90

Outcomes and toxicity following Yttrium-90 radioembolization for hepatic metastases from neuroendocrine tumors-a single-institution experience

Background: The prognosis of patients with hepatic metastases from neuroendocrine tumors (NET) is generally good, and radioembolization with Yttrium-90 microspheres is a locoregional therapy that is used in efforts to improve hepatic disease control and survival. This study aims to describe the survival outcomes and toxicities associated with radioembolization for hepatic-predominant metastatic NET in a large single-institution cohort. Methods: A total of 59 patients underwent radioembolization for metastatic NET with hepatic predominant disease at a single academic center. Patient outcomes were analyzed by Kaplan-Meier survival analysis and toxicities were detailed and described. Ten patients within the cohort underwent post-treatment dosimetric analysis using PET-MRI and normal liver dosimetry was correlated with hepatic fibrosis and toxicity. Results: Median overall survival from time of radioembolization in the patient cohort was 31 months, and the 1- and 2-year overall survival was 80.4% and 65.6% respectively. Median hepatic progression-free survival and overall progression-free survival were 18 and 13 months, respectively. Three patients died of hepatic failure that was possibly therapy-related. Ten patients underwent evaluation of post-treatment dosimetry following radioembolization. In patients who did not develop hepatotoxicity or hepatic fibrosis, mean dose to normal liver was 25.4 Gy, while the mean liver dose in patients who experienced toxicity (hepatic fibrosis in n=2 and death from hepatic failure in n=1) was 59.1 Gy. Conclusions: Overall survival following radioembolization for hepatic metastases from NET is excellent; however, deaths that are potentially treatment-related have been observed. Preliminary data regarding dose to normal liver is suggestive of a relation between dosimetry and toxicity, however further work is required to further elucidate the mechanism, correlation with dosimetry, as well as additional patient and tumor factors that may predispose these patients to toxicity

Optimization of treatment planning workflow and tumor coverage during daily adaptive magnetic resonance image guided radiation therapy (MR-IGRT) of pancreatic cancer

Abstract Background To simplify the adaptive treatment planning workflow while achieving the optimal tumor-dose coverage in pancreatic cancer patients undergoing daily adaptive magnetic resonance image guided radiation therapy (MR-IGRT). Methods In daily adaptive MR-IGRT, the plan objective function constructed during simulation is used for plan re-optimization throughout the course of treatment. In this study, we have constructed the initial objective functions using two methods for 16 pancreatic cancer patients treated with the ViewRay™ MR-IGRT system: 1) the conventional method that handles the stomach, duodenum, small bowel, and large bowel as separate organs at risk (OARs) and 2) the OAR grouping method. Using OAR grouping, a combined OAR structure that encompasses the portions of these four primary OARs within 3 cm of the planning target volume (PTV) is created. OAR grouping simulation plans were optimized such that the target coverage was comparable to the clinical simulation plan constructed in the conventional manner. In both cases, the initial objective function was then applied to each successive treatment fraction and the plan was re-optimized based on the patient’s daily anatomy. OAR grouping plans were compared to conventional plans at each fraction in terms of coverage of the PTV and the optimized PTV (PTV OPT), which is the result of the subtraction of overlapping OAR volumes with an additional margin from the PTV. Results Plan performance was enhanced across a majority of fractions using OAR grouping. The percentage of the volume of the PTV covered by 95% of the prescribed dose (D95) was improved by an average of 3.87 ± 4.29% while D95 coverage of the PTV OPT increased by 3.98 ± 4.97%. Finally, D100 coverage of the PTV demonstrated an average increase of 6.47 ± 7.16% and a maximum improvement of 20.19%. Conclusions In this study, our proposed OAR grouping plans generally outperformed conventional plans, especially when the conventional simulation plan favored or disregarded an OAR through the assignment of distinct weighting parameters relative to the other critical structures. OAR grouping simplifies the MR-IGRT adaptive treatment planning workflow at simulation while demonstrating improved coverage compared to delivered pancreatic cancer treatment plans in daily adaptive radiation therapy

Evaluation of Practice Patterns and Outcomes after Implementing SMART for Pancreatic Cancer

Purpose/Objective(s): Stereotactic MRI-guided adaptive radiation therapy (SMART) enables safe dose escalation for locally advanced, borderline resectable, and medically inoperable pancreatic cancer and has shown favorable toxicity and survival outcomes. In late 2018, our institution commissioned SMART for these patients, making it available to all patient referrals. We wanted to review changes in our patient population and differences in clinical outcomes for patients before and after the implementation of SMART. Materials/Methods: In this IRB approved analysis, we retrospectively reviewed 167 consecutive patients from 2015-2021 with locally advanced, borderline resectable, or medically unresectable pancreatic cancer who were treated with radiation therapy. Chemoradiation (chemoRT) was defined as any 28-30 fraction radiation regimen that included concurrent chemotherapy. SMART was defined as 50 Gy over 5 consecutive daily fractions without concurrent chemotherapy. Baseline patient characteristics were compared between groups. Overall survival (OS) was evaluated by Kaplan-Meier (KM) and log-rank test. Univariate (UVA) and multivariate analysis (MVA) were also performed on multiple treatment variables. Results: Of the patients included, 58 received chemoRT (2015-2018) and 109 received SMART (2018-2021). Median follow up from time of diagnosis for the chemoRT and SMART cohorts were 53.7 months and 29.2 months respectively. Cohorts did not have significant differences in age, gender, race, T or N staging, rates of surgery or surgical margin status. Patients receiving SMART had overall worse performance (p = 0.011) including a lower percentage of PS 0 patients (22.9% vs 44.8%) and a higher percentage of PS 2+ patients (34% vs 15.5%). Similarly, the SMART patients did numerically more often have locally advanced (50% vs 43%) and medically inoperable (26% vs 21%) disease (p = 0.294). The SMART cohort did have longer neoadjuvant chemotherapy with mean of 3.5 months vs 2.3 months in the chemoRT cohort (p = 0.002). There was no OS difference between each group when measured from diagnosis (p=0.79) or from first day of radiation (p=0.2). Median survival in the chemoRT and SMART groups was 18.7 vs 17.4 months from diagnosis. When including only PS 0-1 patients, the median survival in the chemoRT and SMART groups was 18.8 vs 22.3 months (p=0.37). There was also no difference in locoregional control, distant control, or progression free survival using KM. On MVA positive prognostic factors for OS from diagnosis included ECOG \u3c2 (HR 0.54, p=0.015), increasing months of neoadjuvant chemo (HR 0.88, p=0.004) and pancreatectomy (HR 0.14, p \u3c0.001). Conclusion: Despite the fact that the patient cohort receiving radiation therapy per the SMART approach had poorer performance status compared with chemoRT, OS was not significantly different. The multidisciplinary team was highly supportive of SMART with increased patients being treated

Development and assessment of a clinical calculator for estimating the likelihood of recurrence and survival among patients with locally advanced rectal cancer treated with chemotherapy, radiotherapy, and surgery

Importance: Predicting outcomes in patients receiving neoadjuvant therapy for rectal cancer is challenging because of tumor downstaging. Validated clinical calculators that can estimate recurrence-free survival (RFS) and overall survival (OS) among patients with rectal cancer who have received multimodal therapy are needed. Objective: To develop and validate clinical calculators providing estimates of rectal cancer recurrence and survival that are better for individualized decision-making than the American Joint Committee on Cancer (AJCC) staging system or the neoadjuvant rectal (NAR) score. Design, Setting, and Participants: This prognostic study developed risk models, graphically represented as nomograms, for patients with incomplete pathological response using Cox proportional hazards and multivariable regression analyses with restricted cubic splines. Because patients with complete pathological response to neoadjuvant therapy had uniformly favorable outcomes, their predictions were obtained separately. The study included 1400 patients with stage II or III rectal cancer who received treatment with chemotherapy, radiotherapy, and surgery at 2 comprehensive cancer centers (Memorial Sloan Kettering [MSK] Cancer Center and Siteman Cancer Center [SCC]) between January 1, 1998, and December 31, 2017. Patients from the MSK cohort received chemoradiation, surgery, and adjuvant chemotherapy from January 1, 1998, to December 31, 2014; these patients were randomly assigned to either a model training group or an internal validation group. Models were externally validated using data from the SCC cohort, who received either chemoradiation, surgery, and adjuvant chemotherapy (chemoradiotherapy group) or short-course radiotherapy, consolidation chemotherapy, and surgery (total neoadjuvant therapy with short-course radiotherapy group) from January 1, 2009, to December 31, 2017. Data were analyzed from March 1, 2020, to January 10, 2021. Exposures: Chemotherapy, radiotherapy, chemoradiotherapy, and surgery. Main Outcomes and Measures: Recurrence-free survival and OS were the outcome measures, and the discriminatory performance of the clinical calculators was measured with concordance index and calibration plots. The ability of the clinical calculators to predict RFS and OS was compared with that of the AJCC staging system and the NAR score. The models for RFS and OS among patients with incomplete pathological response included postoperative pathological tumor category, number of positive lymph nodes, tumor distance from anal verge, and large- and small-vessel venous and perineural invasion; age was included in the risk model for OS. The final clinical calculators provided RFS and OS estimates derived from Kaplan-Meier curves for patients with complete pathological response and from risk models for patients with incomplete pathological response. Results: Among 1400 total patients with locally advanced rectal cancer, the median age was 57.8 years (range, 18.0-91.9 years), and 863 patients (61.6%) were male, with tumors at a median distance of 6.7 cm (range, 0-15.0 cm) from the anal verge. The MSK cohort comprised 1069 patients; of those, 710 were assigned to the model training group and 359 were assigned to the internal validation group. The SCC cohort comprised 331 patients; of those, 200 were assigned to the chemoradiotherapy group and 131 were assigned to the total neoadjuvant therapy with short-course radiotherapy group. The concordance indices in the MSK validation data set were 0.70 (95% CI, 0.65-0.76) for RFS and 0.73 (95% CI, 0.65-0.80) for OS. In the external SCC data set, the concordance indices in the chemoradiotherapy group were 0.71 (95% CI, 0.62-0.81) for RFS and 0.72 (95% CI, 0.59-0.85) for OS; the concordance indices in the total neoadjuvant therapy with short-course radiotherapy group were 0.62 (95% CI, 0.49-0.75) for RFS and 0.67 (95% CI, 0.46-0.84) for OS. Calibration plots confirmed good agreement between predicted and observed events. These results compared favorably with predictions based on the AJCC staging system (concordance indices for MSK validation: RFS = 0.69 [95% CI, 0.64-0.74]; OS = 0.67 [95% CI, 0.58-0.75]) and the NAR score (concordance indices for MSK validation: RFS = 0.56 [95% CI, 0.50-0.63]; OS = 0.56 [95% CI, 0.46-0.66]). Furthermore, the clinical calculators provided more individualized outcome estimates compared with the categorical schemas (eg, estimated RFS for patients with AJCC stage IIIB disease ranged from 7% to 68%). Conclusions and Relevance: In this prognostic study, clinical calculators were developed and validated; these calculators provided more individualized estimates of the likelihood of RFS and OS than the AJCC staging system or the NAR score among patients with rectal cancer who received multimodal treatment. The calculators were easy to use and applicable to both short- and long-course radiotherapy regimens, and they may be used to inform surveillance strategies and facilitate future clinical trials and statistical power calculations

Treatment utilization and outcomes in elderly patients with locally advanced esophageal carcinoma: A review of the National Cancer Database

For elderly patients with locally advanced esophageal cancer, therapeutic approaches and outcomes in a modern cohort are not well characterized. Patients ≥70 years old with clinical stage II and III esophageal cancer diagnosed between 1998 and 2012 were identified from the National Cancer Database and stratified based on treatment type. Variables associated with treatment utilization were evaluated using logistic regression and survival evaluated using Cox proportional hazards analysis. Propensity matching (1:1) was performed to help account for selection bias. A total of 21,593 patients were identified. Median and maximum ages were 77 and 90, respectively. Treatment included palliative therapy (24.3%), chemoradiation (37.1%), trimodality therapy (10.0%), esophagectomy alone (5.6%), or no therapy (12.9%). Age ≥80 (OR 0.73), female gender (OR 0.81), Charlson-Deyo comorbidity score ≥2 (OR 0.82), and high-volume centers (OR 0.83) were associated with a decreased likelihood of palliative therapy versus no treatment. Age ≥80 (OR 0.79) and Clinical Stage III (OR 0.33) were associated with a decreased likelihood, while adenocarcinoma histology (OR 1.33) and nonacademic cancer centers (OR 3.9), an increased likelihood of esophagectomy alone compared to definitive chemoradiation. Age ≥80 (OR 0.15), female gender (OR 0.80), and non-Caucasian race (OR 0.63) were associated with a decreased likelihood, while adenocarcinoma histology (OR 2.10) and high-volume centers (OR 2.34), an increased likelihood of trimodality therapy compared to definitive chemoradiation. Each treatment type demonstrated improved survival compared to no therapy: palliative treatment (HR 0.49) to trimodality therapy (HR 0.25) with significance between all groups. Any therapy, including palliative care, was associated with improved survival; however, subsets of elderly patients with locally advanced esophageal cancer are less likely to receive aggressive therapy. Care should be taken to not unnecessarily deprive these individuals of treatment that may improve survival