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A hypofractionated radiation regimen avoids the lymphopenia associated with neoadjuvant chemoradiation therapy of borderline resectable and locally advanced pancreatic adenocarcinoma.

ABSTRACT: Preclinical studies have shown synergy between radiation therapy and immunotherapy. However, in almost all preclinical models, radiation is delivered in single doses or short courses of high doses (hypofractionated radiation). By contrast in most clinical settings, radiation is delivered as standard small daily fractions of 1.8-2 Gy to achieve total doses of 50-54 Gy (fractionated radiation). We do not yet know the optimal dose and scheduling of radiation for combination with chemotherapy and immunotherapy.To address this, we analyzed the effect of neoadjuvant standard fractionated and hypofractionated chemoradiation on immune cells in patients with locally advanced and borderline resectable pancreatic adenocarcinoma.We found that standard fractionated chemoradiation resulted in a significant and extended loss of lymphocytes that was not explained by a lack of homeostatic cytokines or response to cytokines. By contrast, treatment with hypofractionated radiation therapy avoided the loss of lymphocytes associated with conventional fractionation.Hypofractionated neoadjuvant chemoradiation is associated with reduced systemic loss of T cells.ClinicalTrials.gov NCT01342224, April 21, 2011; NCT01903083, July 2, 2013.

SUBMITTER: Crocenzi T

PROVIDER: S-EPMC4986363 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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A hypofractionated radiation regimen avoids the lymphopenia associated with neoadjuvant chemoradiation therapy of borderline resectable and locally advanced pancreatic adenocarcinoma.

Crocenzi Todd T Cottam Benjamin B Newell Pippa P Wolf Ronald F RF Hansen Paul D PD Hammill Chet C Solhjem Matthew C MC To Yue-Yun YY Greathouse Amy A Tormoen Garth G Jutric Zeljka Z Young Kristina K Bahjat Keith S KS Gough Michael J MJ Crittenden Marka R MR

Journal for immunotherapy of cancer 20160816

<h4>Background</h4>Preclinical studies have shown synergy between radiation therapy and immunotherapy. However, in almost all preclinical models, radiation is delivered in single doses or short courses of high doses (hypofractionated radiation). By contrast in most clinical settings, radiation is delivered as standard small daily fractions of 1.8-2 Gy to achieve total doses of 50-54 Gy (fractionated radiation). We do not yet know the optimal dose and scheduling of radiation for combination with ...[more]

PMID: 27532020

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is currently ranked fourth place of cancer related mortality. Only a minority of 10-20% of patients with PDAC have a primarily resectable disease, while 50-60% of the patients are diagnosed with irresectable disease. A certain group of patients is defined as "borderline resectable", which is mainly relied to contact of the tumor to major abdominal vessels. For preoperative evaluation of resectability CT and MRI is commonly used. Although CT-scanning, which is the standard preoperative imaging modality, has striking limitations concerning evaluation of lymph node status as well as vessel involvement and approximately 20% of the patients are staged incorrectly. A central part of modern therapy of locally advanced or not primarily resectable PDAC is neoadjuvant therapy. Especially neoadjuvant chemotherapy according to the FOLFIRINOX protocol resulted in high resection rates of initially not resectable patients. Furthermore, treatment with FOLFIRINOX was shown to be an independent predictor of improved prognosis and resection after neoadjuvant treatment with FOLFIRINOX was associated with improved survival. Neoadjuvant treatment was able to increases the rates of R0 resection, which depicts an independent prognostic factor and FOLFIRINOX outmatched other treatment regimes (e.g., gemcitabine-based radio-chemotherapy) concerning achievement of a R0 resection. While most evidence of neoadjuvant treatment of PDAC is conferred by retrospective analysis, there is growing data from randomized controlled trials, confirming the beneficial effects of neoadjuvant therapy on the prognosis of PDAC. Thus, patients with borderline resectable and locally advanced PDAC should be evaluated for neoadjuvant treatment. If there is no progression of the disease during neoadjuvant treatment exploration with the goal of R0 resection should be performed. If possible, patients should be included in well-designed randomized controlled trials at specialized pancreatic centers.

Project description:BackgroundThere is no agreed upon standard of care for borderline-resectable pancreatic cancer (BRPC) or locally-advanced pancreatic cancer (LAPC) patients regarding the benefit of chemotherapy or radiation alone or in combination.Patients and methodsWe completed a retrospective cohort analysis of BRPC and LAPC patients at a cancer center with expertise in multi-disciplinary pancreatic ductal adenocarcinoma (PDAC) treatment over a 5-year period from 03/01/2014 to 03/01/2019 (cut-off date). The total evaluable newly diagnosed, treatment naïve, BRPC, and LAPC patients with adequate organ function and ability to obtain treatment after multidisciplinary review was 52 patients. After analysis, patients were evaluated for rates of resection, extent of resection (R0 or R1), median progression-free survival (mPFS), and median overall survival (mOS).ResultsPatients were treated with chemotherapy alone (gemcitabine and nab-paclitaxel = 77% (20/26); FOLFIRINOX = 19% (5/26); single agent gemcitabine 3.8% (1/26)), or chemotherapy followed by chemoradiation (gemcitabine +5 Gy × 5 weeks), or chemoradiation alone prior to re-staging and potential resection. Of the 29% (15/52) of patients who went on to surgical resection, 73% (11/15) achieved R0 resection. An R0 resection was achieved in 35% (9/26) of patients treated with chemotherapy alone, 7.6% (1/13) in a patient treated with chemotherapy followed by radiation, and 7.6% (1/13) with concurrent chemoradiotherapy alone. Chemotherapy alone achieved a mPFS of 16.4 months (p < 0.0025) and mOS of 26.2 months (p < 0.0001), chemotherapy followed by chemoradiation was 13.0 months and 14.9 months respectively, while concurrent chemoradiotherapy was 6.9 months and 7.3 months.Conclusions and relevanceBRPC and LAPC patients capable of surgery after only receiving neoadjuvant treatment with chemotherapy had higher rates of R0 resection with prolonged median PFS and OS compared with any patient needing combination chemotherapy with radiotherapy.

Project description:Approximately 20% of pancreatic ductal adenocarcinoma (PDAC) patients have (borderline) resectable pancreatic cancer [(B)RPC] at diagnosis. Upfront resection with adjuvant chemotherapy has long been the standard of care for these patients. However, although surgical quality has improved, still about 50% of patients never receive adjuvant treatment. Therefore, recent developments have focused on a neoadjuvant approach. Directly comparing results from neoadjuvant and adjuvant regimens is challenging due to differences in patient populations that influence outcomes. Neoadjuvant trials include all patients who have (B)RPC on imaging, while adjuvant-only trials include patients who underwent a complete resection and recovered to a good performance status without any evidence of residual disease. Guidelines recommend neoadjuvant treatment for BRPC patients mainly to improve negative resection margin (R0) rates. For resectable PDAC, upfront resection is still considered the standard of care. However, theoretical advantages of neoadjuvant treatment, including the increased R0 resection rate, early delivery of systemic therapy to all patients, directly addressing occult metastatic disease, and improved patient selection for resection, may also apply to these patients. A systematic review by intention-to-treat showed a superior median overall survival (OS) for any neoadjuvant approach (19 months) compared to upfront surgery (15 months) in (B)RPC patients. A neoadjuvant approach was recently supported by three randomized controlled trials (RCTs). For resectable PDAC, neoadjuvant treatment was superior in a Japanese RCT of neoadjuvant gemcitabine with S-1 vs. upfront surgery, with adjuvant S-1 in both arms (median OS: 37 vs. 27 months, p = 0.015). A Korean trial of neoadjuvant gemcitabine-based chemoradiotherapy vs. upfront resection in BRPC patients was terminated early due to superiority of the neoadjuvant group (median OS: 21 vs. 12 months, p = 0.028; R0 resection: 52 vs. 26%, p = 0.004). The PREOPANC-1 trial for (B)RPC patients also showed favorable outcome for neoadjuvant gemcitabine-based chemoradiotherapy vs. upfront surgery (median OS: 17 vs. 14 months, p = 0.07; R0 resection: 63 vs. 31%, p < 0.001). FOLFIRINOX is likely a better neoadjuvant regimen, because of superiority compared to gemcitabine in both the metastatic and adjuvant setting. Currently, five RCTs evaluating neoadjuvant modified or fulldose FOLFIRINOX are accruing patients.

Project description:PurposeAlliance A021501 is the first randomized trial to evaluate stereotactic body radiation therapy (SBRT) for borderline resectable pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant chemotherapy. In this post hoc study, we reviewed the quality of radiation therapy (RT) delivered.Methods and materialsSBRT (6.6 Gy × 5) was intended but hypofractionated RT (5 Gy × 5) was permitted if SBRT specifications could not be met. Institutional credentialing through the National Cancer Institute-funded Imaging and Radiation Oncology Core (IROC) was required. Rigorous RT quality assurance (RT QA) was mandated, including pretreatment review by a radiation oncologist. Revisions were required for unacceptable deviations. Additionally, we performed a post hoc RT QA analysis in which contours and plans were reviewed by 3 radiation oncologists and assigned a score (1, 2, or 3) based on adequacy. A score of 1 indicated no deviation, 2 indicated minor deviation, and 3 indicated a major deviation that could be clinically significant. Clinical outcomes were compared by treatment modality and by case score.ResultsForty patients were registered to receive RT (1 planned but not treated) at 27 centers (18 academic and 9 community). Twenty-three centers were appropriately credentialed for moving lung/liver targets and 4 for static head and neck only. Thirty-two of 39 patients (82.1%) were treated with SBRT and 7 (17.9%) with hypofractionated RT. Five cases (13%) required revision before treatment. On post hoc review, 23 patients (59.0%) were noted to have suboptimal contours or plan coverage, 12 (30.8%) were scored a 2, and 11 (28.2%) were scored a 3. There were no apparent differences in failure patterns or surgical outcomes based on treatment technique or post hoc case score. Details related to on-treatment imaging were not recorded.ConclusionsDespite rigorous QA, we encountered variability in simulation, contouring, plan coverage, and dose on trial. Although clinical outcomes did not appear to have been affected, findings from this analysis serve to inform subsequent PDAC SBRT trial designs and QA requirements.

Project description:Background The complete resection rate of pancreatic cancer has increased because of the advent of efficacious first-line treatments for unresectable pancreatic cancer. Still, strategies regarding adjuvant therapy after neoadjuvant FOLFIRINOX treatment remain to be established. Methods Data on 144 patients with borderline resectable and locally advanced pancreatic cancer who underwent resection after neoadjuvant FOLFIRINOX between January 2013 and April 2021 were retrospectively reviewed. Results Among the study patients, 113 patients (78.5%) were diagnosed with borderline resectable pancreatic cancer and 31 patients (21.5%) were diagnosed with locally advanced pancreatic cancer. Seventy-five patients (52.1%) received radiotherapy before surgery. After radical resection, 84 patients (58.3%) received 5-fluorouracil-based adjuvant therapy and 60 patients (41.7%) received non-5-fluorouracil-based adjuvant therapy. Adjuvant therapy with 5-fluorouracil-based regimen [hazard ratio (HR), 0.43 (95% CI, 0.21–0.87); p = 0.019], preoperative assessment as locally advanced pancreatic cancer [HR, 2.87 (95% CI, 1.08–7.64); p = 0.035], positive resection margin [HR, 3.91 (95% CI, 1.71–8.94); p = 0.001], and presence of pathologic lymph node involvement [HR, 2.31 (95% CI, 1.00–5.33), p = 0.050] were associated with decreased recurrence-free survival. Adjuvant therapy with 5-fluorouracil-based regimen [HR, 0.35 (95% CI, 0.15–0.84); p = 0.018], positive resection margin [HR, 4.14 (95% CI, 1.75–9.78); p = 0.001], presence of pathologic lymph node involvement [HR, 3.36 (95% CI, 1.23–9.15); p = 0.018], poor differentiation [HR, 5.69 (95% CI, 1.76–18.36); p = 0.004], and dose reduction during adjuvant therapy [HR, 1.78 (95% CI, 1.24–24.37); p = 0.025] were associated with decreased overall survival. Conclusions The 5-fluorouracil-based adjuvant therapy seems to be the proper adjuvant therapy for patients who received neoadjuvant FOLFIRINOX for borderline resectable and locally advanced pancreatic cancer.

Dataset Information

A hypofractionated radiation regimen avoids the lymphopenia associated with neoadjuvant chemoradiation therapy of borderline resectable and locally advanced pancreatic adenocarcinoma.

Publications

A hypofractionated radiation regimen avoids the lymphopenia associated with neoadjuvant chemoradiation therapy of borderline resectable and locally advanced pancreatic adenocarcinoma.

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