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The Current Role of Radiation in Pancreatic Cancer and Future Directions

Hill, Colin S; Herman, Joseph M
Survival outcomes for localized pancreatic adenocarcinoma remains poor. Multimodality therapeutic regimens are critical to maximizing survival outcomes for these patients, which includes the use of systemic therapy, surgery, and radiation. In this review, the evolution of radiation techniques are discussed with a focus on modern techniques such as intensity modulated radiation and stereotactic body radiation therapy. However, the current role of radiation within the most common clinical scenarios for pancreatic cancer in the neoadjuvant, definitive, and adjuvant settings continues to be highly debated. The role of radiation in these settings is reviewed in the context of historical and modern clinical studies. In addition, emerging concepts including dose-escalated radiation, magnetic resonance-guided radiation therapy, and particle therapy are discussed to promote an understanding of how such concepts may change the role of radiation in the future.
PMID: 36804206
ISSN: 1938-0674
CID: 5467292

The Timing of Surgery Following Stereotactic Body Radiation Therapy Impacts Local Control for Borderline Resectable or Locally Advanced Pancreatic Cancer

Lin, Timothy; Reddy, Abhinav; Hill, Colin; Sehgal, Shuchi; He, Jin; Zheng, Lei; Herman, Joseph; Meyer, Jeffrey; Narang, Amol
We aimed to evaluate the impact of time from stereotactic body radiation therapy (SBRT) to surgery on treatment outcomes and post-operative complications in patients with borderline resectable or locally advanced pancreatic cancer (BRPC/LAPC). We conducted a single-institutional retrospective analysis of patients with BRPC/LAPC treated from 2016 to 2021 with neoadjuvant chemotherapy followed by SBRT and surgical resection. Covariates were stratified by time from SBRT to surgery. A Cox regression model was used to identify variables associated with survival outcomes. In 171 patients with BRPC/LAPC, the median time from SBRT to surgery was 6.4 (range: 2.7"“25.3) weeks. Hence, patients were stratified by the timing of surgery: ≥6 and <6 weeks after SBRT. In univariable Cox regression, surgery ≥6 weeks was associated with improved local control (LC, HR 0.55, 95% CI 0.30"“0.98; p = 0.042), pathologic node positivity, elevated baseline CA19-9, and inferior LC if of the male sex. In multivariable analysis, surgery ≥6 weeks (p = 0.013; HR 0.46, 95%CI 0.25"“0.85), node positivity (p = 0.019; HR 2.09, 95% CI 1.13"“3.88), and baseline elevated CA19-9 (p = 0.002; HR 2.73, 95% CI 1.44"“5.18) remained independently associated with LC. Clavien"“Dindo Grade ≥3B complications occurred in 4/63 (6.3%) vs. 5/99 (5.5%) patients undergoing surgery <6 weeks and ≥6 weeks after SBRT (p = 0.7). In summary, the timing of surgery ≥6 weeks after SBRT was associated with improved local control and low post-operative complication rates, irrespective of the surgical timing. Further investigation of the influence of surgical timing following radiotherapy is warranted.
ISSN: 2072-6694
CID: 5446192

Multi-Agent Chemotherapy and Stereotactic Body Radiation Therapy in Patients with Unresectable Pancreatic Adenocarcinoma: A Prospective Nonrandomized Controlled Trial

Hill, Colin S; Rosati, Lauren; Wang, Hao; Tsai, Hua-Ling; He, Jin; Hacker-Prietz, Amy; Laheru, Daniel A; Zheng, Lei; Sehgal, Shuchi; Bernard, Vincent; Le, Dung T; Pawlik, Timothy M; Weiss, Matthew J; Narang, Amol K; Herman, Joseph M
PURPOSE/OBJECTIVE:In a prospective multicenter study, gemcitabine monotherapy followed by stereotactic body radiation therapy (SBRT) was well tolerated with outcomes comparable to chemoradiation for locally advanced pancreatic cancer (LAPC). Recent trials have reported improved survival with multi-agent chemotherapy (MA-CTX) alone. This prospective trial explored whether SBRT could be safely delivered following MA-CTX. Herein, we report the long-term outcomes of adding SBRT after MA-CTX in LAPC patients and evaluate whether genetic profiles of specimens obtained prior to SBRT influence outcomes. METHODS:This prospective non-randomized controlled phase II trial enrolled 44 LAPC and 4 locally recurrent patients after multidisciplinary evaluation between 2012-2015 at a high-volume pancreatic cancer center. For induction CTX, most received modified FOLFIRINOX (mFFX), or gemcitabine and nab-paclitaxel (GnP) followed by 5-fraction SBRT for all. During fiducial placement, biopsies were obtained with DNA extracted for targeted sequencing using the MSK-IMPACT platform. RESULTS:Median induction CTX duration was ≥ 4 mos, and 31 patients received mFFX (65%). Among 44 LAPC patients, 17 (39%) were surgically explored, and 12/16 (75%) achieved a R0 resection. Median overall survival (mOS) was 20.2/14.6 mos from diagnosis/SBRT. 1 and 2-year OS from SBRT was 58%/28%. The mOS after resection was 28.6/22.4 mos from diagnosis/SBRT. Median local progression-free survival (LPFS) was 23.9/15.8 mos from diagnosis/SBRT. The mOS for pre-SBRT CA 19-9 ≤180 U/mL vs. >180 was 23.1/11.3 months respectively (HR = 0.53, p=0.04). Only one patient (2.1%) had late grade ≥2 gastrointestinal toxicity attributable to SBRT. Despite significant pre-treatment with chemotherapy, 88% of tumor specimens were effectively sequenced; survival outcomes were not significantly associated with specific mutational patterns. Quality of life was prospectively collected pre- and post-SBRT with the EORTC QLQ-C30/PAN26 questionnaire showing no significant change. CONCLUSION/CONCLUSIONS:SBRT was safely administered with MA-CTX with minimal toxicity. A high proportion of LAPC patients underwent R0 resection with favorable survival outcomes.
PMID: 35306231
ISSN: 1879-8519
CID: 5191252

Efficacy and Safety of Reirradiation with Stereotactic Body Radiation Therapy for Locally Recurrent Pancreatic Adenocarcinoma

Reddy, A V; Hill, C S; Sehgal, S; He, J; Zheng, L; Herman, J M; Meyer, J; Narang, A K
AIMS:The purpose of this study was to report on outcomes of a cohort of patients who were treated with reirradiation with stereotactic body radiation therapy (SBRT) for locally recurrent pancreatic adenocarcinoma. MATERIALS AND METHODS:Patients treated with SBRT reirradiation for locally recurrent pancreatic adenocarcinoma from December 2009 to April 2020 were included in the study. Descriptive statistics were used to record patient demographics, tumour and treatment characteristics. Kaplan-Meier analysis was used to evaluate overall survival, local progression-free survival (LPFS), distant metastasis-free survival and progression-free survival (PFS). RESULTS:In total, 27 patients were included in the study. The median follow-up time from local recurrence was 19.7 months (range 4.2-43.1 months). Most patients received five-fraction SBRT (26/27, 96%). The median overall survival after local recurrence treatment was 18.3 months (range 3.0-42.6 months), with 6-month, 1-year and 2-year overall survival rates of 88.5%, 73.1% and 33.6%. The median LPFS after local recurrence treatment was 16.2 months (range 2.3-33.6 months), with 6-month, 1-year and 2-year LPFS rates of 95.8%, 62.9% and 27.2%. Peri-SBRT chemotherapy improved LPFS (median 17.5 versus 8.5 months; P = 0.010) and overall survival (median 19.3 versus 5.5 months; P = 0.049). Tumours ≤ 3 cm in the greatest dimension showed better local control (median LPFS 19.2 versus 10.2 months; P = 0.130). There was one case (4%) of acute grade 3 pain and one case (4%) of late grade 3 gastrointestinal toxicity. CONCLUSIONS:Reirradiation with five-fraction SBRT is safe, but local control remains suboptimal. Patients with smaller tumours experienced improved outcomes, as did patients whose treatment plan included the administration of peri-SBRT chemotherapy.
PMID: 34974972
ISSN: 1433-2981
CID: 5294312

Post-radiation neutrophil-to-lymphocyte ratio is a prognostic marker in patients with localized pancreatic adenocarcinoma treated with anti-PD-1 antibody and stereotactic body radiation therapy

Reddy, Abhinav V; Hill, Colin S; Sehgal, Shuchi; Zheng, Lei; He, Jin; Laheru, Daniel A; Jesus-Acosta, Ana De; Herman, Joseph M; Meyer, Jeffrey; Narang, Amol K
PURPOSE/OBJECTIVE:To investigate the role of pre- and post-stereotactic body radiation therapy (SBRT) neutrophil-to-lymphocyte ratio (NLR) in patients with localized pancreatic cancer treated with anti-PD-1 (programmed cell death protein-1) antibody and SBRT. MATERIALS AND METHODS/METHODS:This was a retrospective review of 68 patients with borderline resectable or locally advanced pancreatic cancer treated with anti-PD-1 antibody and SBRT after multi-agent chemotherapy. Immunotherapy was administered with 5-fraction SBRT in the neoadjuvant, concurrent, or adjuvant/maintenance setting. Clinical outcomes included overall survival (OS), local progression-free survival, distant metastasis-free survival, and progression-free survival. Median pre- and post-SBRT peripheral blood markers were compared with the Mann-Whitney U test. Univariate and multivariable analyses (UVA and MVA) were performed to identify variables associated with clinical outcomes. Linear regression was performed to determine correlations between variables and peripheral blood markers. RESULTS:A total of 68 patients were included in the study. The percent change between median pre- and post-SBRT absolute lymphocyte count (ALC), absolute neutrophil count, and NLR were -36.0% (p < 0.001), -5.6% (p = 0.190), and +35.7% (p = 0.003), respectively. Median OS after SBRT was 22.4 months. On UVA, pre-SBRT CA19-9 (hazard ratio [HR] = 1.001; 95% confidence interval [CI], 1.000-1.001; p = 0.031), post-SBRT ALC (HR = 0.33; 95% CI, 0.11-0.91; p = 0.031), and post-SBRT NLR (HR = 1.13; 95% CI, 1.04-1.22; p = 0.009) were associated with OS. On MVA, induction chemotherapy duration (HR = 0.75; 95% CI, 0.57-0.99; p = 0.048) and post-SBRT NLR (HR = 1.14; 95% CI, 1.04-1.23; p = 0.002) predicted for OS. Patients with post-SBRT NLR ≥3.2 had a median OS of 15.6 months versus 27.6 months in patients with post-SBRT NLR <3.2 (p = 0.009). On MVA linear regression, log10CTV had a negative correlation with post-SBRT ALC (regression coefficient = -0.314; 95% CI, -0.626 to -0.003; p = 0.048). CONCLUSION/CONCLUSIONS:Elevated NLR after SBRT is primarily due to depletion of lymphocytes and associated with worse survival outcomes in localized pancreatic cancer treated with anti-PD-1 antibody. Larger CTVs were associated with decreased post-SBRT ALC.
PMID: 35796114
ISSN: 2234-1900
CID: 5294332

Stereotactic body radiation therapy for the treatment of locally recurrent pancreatic cancer after surgical resection

Reddy, Abhinav V; Hill, Colin S; Sehgal, Shuchi; He, Jin; Zheng, Lei; Herman, Joseph M; Meyer, Jeffrey; Narang, Amol K
Background/UNASSIGNED:To report on a cohort of radiation-naïve patients with pancreatic cancer who developed isolated local recurrence following surgical resection and were subsequently treated with stereotactic body radiation therapy (SBRT). Methods/UNASSIGNED:Patients with pancreatic cancer who were treated with SBRT for isolated local recurrence after surgical resection were retrospectively reviewed. Clinical outcomes were calculated from completion of SBRT and included overall survival (OS), local progression-free survival (LPFS), distant metastasis-free survival (DMFS), and progression-free survival (PFS). Univariate (UVA) analysis was performed to identify variables associated with clinical outcomes. Kaplan-Meier method was used for survival outcomes. Toxicity was assessed using the Common Terminology Criteria for Adverse Events version 4.0. Results/UNASSIGNED:80.2%, P<0.009). Median DMFS and PFS were 15.6 months. There was 1 case (5.3 %) of grade 3 gastric perforation. There were no cases of grade 4-5 toxicity events. Conclusions/UNASSIGNED:<54.8 Gy was significantly associated with inferior local control. Further studies investigating dose escalation and optimal treatment volumes in the locally recurrent setting are warranted.
PMID: 35837183
ISSN: 2078-6891
CID: 5294342

Location, Location, Location: What Should be Targeted Beyond Gross Disease for Localized Pancreatic Ductal Adenocarcinoma? Proposal of a Standardized Clinical Tumor Volume for Pancreatic Ductal Adenocarcinoma of the Head: The "Triangle Volume"

Hill, Colin S; Fu, Wei; Hu, Chen; Sehgal, Shuchi; Reddy, Abhinav V; He, Jin; Herman, Joseph M; Meyer, Jeffrey J; Zaheer, Atif; Narang, Amol K
PURPOSE/OBJECTIVE:In patients with borderline resectable or locally advanced pancreatic adenocarcinoma (BRPC/LAPC), local failure rates after resection remain significant, even in the setting of neoadjuvant chemotherapy and radiation. Suboptimal local control may relate to variable radiation target delineation, as no consensus exists around clinical tumor volume (CTV) design in this context. In the surgical literature, recent attention has been given to the "triangle" volume (TV) as a source of subclinical, residual disease. To understand whether the TV can inform optimal CTV design, we mapped locoregional failures after resection in a large cohort of patients with BRPC/LAPC and compared locations of failure to the TV. METHODS AND MATERIALS/METHODS:Patients with BRPC/LAPC of the head or neck diagnosed between 2016 AND 2019 who developed locoregional failure after surgery, neoadjuvant chemotherapy, and radiation were identified. Descriptive statistics were generated to report the frequency of locoregional failures located within the TV and the frequency of new vascular involvement at time of failure, compared with vascular involvement at diagnosis. Additionally, dosimetric coverage of the TV with the preoperative radiation plan that had been used was assessed. RESULTS:In 31 patients who experienced locoregional failure, the centroid of failure was located within the TV in 28 cases (90%). Extent of vascular involvement at time of locoregional failure included vasculature that had not been involved at diagnosis in 13 cases (42%). The preoperative radiation plan that had been used provided a median V33 Gy and V25 Gy of the TV of only 53% (interquartile range, 34%-72%) and 70% (IQR, 48%-85%), respectively. CONCLUSIONS:The TV encompassed the vast majority of locoregional failures, but dosimetric coverage of the TV was poor when only targeting gross disease and the full circumference of involved vasculature. As such, the TV may better serve as a basis for CTV design in patients with BRPC/LAPC undergoing neoadjuvant radiation.
PMID: 35144016
ISSN: 1879-8519
CID: 5294322

Neoadjuvant Stereotactic Body Radiotherapy After Upfront Chemotherapy Improves Pathologic Outcomes Compared With Chemotherapy Alone for Patients With Borderline Resectable or Locally Advanced Pancreatic Adenocarcinoma Without Increasing Perioperative Toxicity

Hill, Colin S; Rosati, Lauren M; Hu, Chen; Fu, Wei; Sehgal, Shuchi; Hacker-Prietz, Amy; Wolfgang, Christopher L; Weiss, Matthew J; Burkhart, Richard A; Hruban, Ralph H; De Jesus-Acosta, Ana; Le, Dung T; Zheng, Lei; Laheru, Daniel A; He, Jin; Narang, Amol K; Herman, Joseph M
BACKGROUND:Patients with borderline resectable pancreatic cancer (BRPC) or locally advanced pancreatic cancer (LAPC) are at high risk of margin-positive resection. Neoadjuvant stereotactic body radiation therapy (SBRT) may help sterilize margins, but its additive benefit beyond neoadjuvant chemotherapy (nCT) is unclear. The authors report long-term outcomes for BRPC/LAPC patients explored after treatment with either nCT alone or nCT followed by five-fraction SBRT (nCT-SBRT). METHODS:Patients with BRPC or LAPC from 2011 to 2016 who underwent resection after nCT alone or nCT-SBRT were retrospectively reviewed. Baseline characteristics were compared, and the propensity score with inverse probability weighting (IPW) was used to compare pathologic/survival outcomes. RESULTS:Of 198 patients, 76 received nCT, and 122 received nCT-SBRT. The nCT-SBRT cohort had a higher proportion of LAPC (53% vs 22%; p < 0.001). The duration of nCT was longer for nCT-SBRT (4.6 vs 2.9 months; p = 0.03), but adjuvant chemotherapy was less frequently administered (53% vs 67.1%; p < 0.001). Adjuvant radiation was administered to 30% of the nCT patients. The nCT-SBRT regimen more frequently achieved negative margins (92% vs 70%; p < 0.001), negative nodes (59% vs 42%; p < 0.001), and pathologic complete response (7% vs 0%; p = 0.02). In the multivariate analysis, nCT-SBRT remained associated with R0 resection (p < 0.001). The nCT-SBRT cohort experienced no significant difference in median overall survival (OS) (22.1 vs 24.5 months), local progression-free survival (LPFS) (13.5 vs. 15.4 months), or distant metastasis-free survival (DMFS) (11.7 vs 16.3 months) after surgery. After SBRT, 1-year OS was 77.0% and 2-year OS was 50.4%. Perioperative Claven-Dindo grade 3 or greater morbidity did not differ significantly between the nCT and nCT-SBRT cohorts (p = 0.81). CONCLUSIONS:Despite having more advanced disease, the nCT-SBRT cohort was still more likely to undergo an R0 resection and experienced similar survival outcomes compared with the nCT alone cohort.
PMID: 35129721
ISSN: 1534-4681
CID: 5167102

High local failure rates despite high margin-negative resection rates in a cohort of borderline resectable and locally advanced pancreatic cancer patients treated with stereotactic body radiation therapy following multi-agent chemotherapy

Hill, Colin; Sehgal, Shuchi; Fu, Wei; Hu, Chen; Reddy, Abhinav; Thompson, Elizabeth; Hacker-Prietz, Amy; Le, Dung; De Jesus-Acosta, Ana; Lee, Valerie; Zheng, Lei; Laheru, Daniel A; Burns, William; Weiss, Matthew; Wolfgang, Christopher; He, Jin; Herman, Joseph M; Meyer, Jeffrey; Narang, Amol
BACKGROUND:Stereotactic body radiation therapy (SBRT) for patients with borderline resectable and locally advanced pancreatic adenocarcinoma (BRPC/LAPC) remains controversial. Herein, we report on surgical, pathologic, and survival outcomes in BRPC/LAPC patients treated at a high-volume institution with induction chemotherapy (CTX) followed by 5-fraction SBRT. METHODS:BRPC/LAPC patients treated between 2016 and 2019 were retrospectively reviewed. Surgical and pathological outcomes were descriptively characterized. Overall survival (OS) and progression-free survival (PFS) were analyzed using Cox proportional hazard regression. Locoregional failure and distant failure were analyzed with Fine-Gray competing risk model. RESULTS:Of 155 patients, 91 (59%) had LAPC and 64 (41%) had BRPC. Almost all were treated with induction multi-agent CTX with either FOLFIRINOX (75%) or gemcitabine and nab-paclitaxel (24%) for a median duration of 4.0 months (1-18 months). All received SBRT to a median dose of 33 Gy. Among 64 BRPC patients, 50 (78%) underwent resection, of whom 48 (96%) achieved margin-negative (R0) resection. Among 91 LAPC patients, 57 (63%) underwent resection, of whom 50 (88%) achieved R0 resection. Despite the high R0 rate, 33% of patients experienced locoregional failure, which was a component of 44% of all failures. After SBRT, median OS and PFS were 18.7 and 7.7 months, respectively. After SBRT, 1- and 2-year OS probabilities were 70% and 45%, whereas, from diagnosis, they were 93% and 51%. CONCLUSIONS:Although a high proportion of BRPC/LAPC patients treated with induction multi-agent CTX followed by SBRT successfully achieved R0 resection, locoregional failure remained common, highlighting the need to continue to optimize radiation delivery in this context.
PMID: 35142085
ISSN: 2045-7634
CID: 5167252

Establishing a Deaf and American Sign Language Inclusive Residency Program

Hill, Colin; Deville, Curtiland; Kiess, Ana; Narang, Amol; Ratnanather, Tilak; Bienstock, Jessica; Brinckerhoff, Loring; Hodukavich, Aaron; Anderson, Roberta; Alcorn, Sara; DeWeese, Theodore; Viswanathan, Akila; Page, Brandi R
Improving diversity in residency programs has been increasingly emphasized as a means to address gender, racial, and ethnic disparities in medicine. However, limited attention has been given to the potential benefits of training physicians with differences other than gender or race and ethnicity. Americans with a disability represent about 27% of the U.S. population, whereas 1%-3% of physician trainees report having a disability. In 2013, a national survey identified only 86 physicians or trainees reporting deafness or hearing loss as a disability. To date, there are no published strategies on how to create an inclusive program for Deaf trainees. Herein, the authors report on the development of a Deaf and American Sign Language (ASL) inclusive residency program that can serve as an academic model for other programs, in any medical specialty, seeking to create an accessible training program for Deaf physicians and that can be adapted for trainees with other disabilities. In March 2017, the radiation oncology residency program at Johns Hopkins University matched an ASL-signing Deaf resident who would begin the program in July 2018. In preparation, department leadership engaged key stakeholders and leaders within the university's health system and among the department faculty, residents, and staff as well as the incoming resident to create an ASL inclusive program. A 5-step transition process for the training program was ultimately developed and implemented. The authors focused on engaging the Deaf trainee and interpreters, engaging health system and departmental leadership, contracting a training consultant and developing oral and written training materials for faculty and staff, and optimizing the workspace via accommodations. Through collaborative preparation, a Deaf and ASL-signing resident was successfully integrated into the residency program. The proposed 5-step transition process provides an effective, engaging model to encourage other institutions that are seeking to employ similar inclusivity initiatives.
PMID: 34670241
ISSN: 1938-808x
CID: 5294302