Locally Advanced Pancreas Cancer Research Articles

Stereotactic MR-guided on-table adaptive radiation therapy (SMART) for borderline resectable and locally advanced pancreatic cancer: A multi-center, open-label phase 2 study

Background and purposeRadiation dose escalation may improve local control (LC) and overall survival (OS) in select pancreatic ductal adenocarcinoma (PDAC) patients. We prospectively evaluated the safety and efficacy of ablative stereotactic magnetic resonance (MR)-guided adaptive radiation therapy (SMART) for borderline resectable (BRPC) and locally advanced pancreas cancer (LAPC). The primary endpoint of acute grade ≥ 3 gastrointestinal (GI) toxicity definitely related to SMART was previously published with median follow-up (FU) 8.8 months from SMART. We now present more mature outcomes including OS and late toxicity. Materials and methodsThis prospective, multi-center, single-arm open-label phase 2 trial (NCT03621644) enrolled 136 patients (LAPC 56.6 %; BRPC 43.4 %) after ≥ 3 months of any chemotherapy without distant progression and CA19-9 ≤ 500 U/mL. SMART was delivered on a 0.35 T MR-guided system prescribed to 50 Gy in 5 fractions (biologically effective dose10 [BED10] = 100 Gy). Elective coverage was optional. Surgery and chemotherapy were permitted after SMART. ResultsMean age was 65.7 years (range, 36–85), induction FOLFIRINOX was common (81.7 %), most received elective coverage (57.4 %), and 34.6 % had surgery after SMART. Median FU was 22.9 months from diagnosis and 14.2 months from SMART, respectively. 2-year OS from diagnosis and SMART were 53.6 % and 40.5 %, respectively. Late grade ≥ 3 toxicity definitely, probably, or possibly attributed to SMART were observed in 0 %, 4.6 %, and 11.5 % patients, respectively. ConclusionsLong-term outcomes from the phase 2 SMART trial demonstrate encouraging OS and limited severe toxicity. Additional prospective evaluation of this novel strategy is warranted.

Evolution of Radiation Therapy in Pancreas Cancer Management toward MRI-Guided Adaptive Radiation Therapy

Pancreas cancer has a poor prognosis despite aggressive treatment and is the fourth leading cause of cancer death in the United States. At diagnosis, most patients have either metastatic or locally advanced disease. In this article, we review the evolution of treatments in locally advanced pancreas cancer (LAPC) and discuss the various radiation therapy fractionation schemes. Furthermore, we examine the data supporting dose escalation and the delivery of ablative biologically effective doses in the setting of LAPC. Finally, we review the role of MRI-guided radiation therapy in escalating dose while sparing organs at risk in the era of stereotactic magnetic resonance-guided adaptive radiation therapy.

Distal pancreatectomy with celiac artery resection (DP-CAR) & portal vein resection as a conversion surgery after neoadjuvant chemotherapy for pancreatic adenocarcinoma

The authors performed distal pancreatectomy with celiac artery resection (DP-CAR) & portal vein (PV) resection and reconstruction with allogeneic iliac vein as a conversion surgery after neoadjuvant chemotherapy for locally advanced pancreas cancer (LAPC) and report here with video. A 58-year-old man presented with LAPC. There was a 4 cm sized tumor at pancreas body abutting celiac axis, superior mesenteric artery, common hepatic artery, splenic artery and portosplenic confluence. There was no evidence of distant metastasis. Modified FOLFIRINOX was given for 17 cycles per 8 months. The tumor shrunk to 3.2 cm with markedly decreased area of abutment to major vasculatures. The DP-CAR procedures were proceeded as planned except portosplenic confluence management where resection and reconstruction with an allogeneic iliac vein graft of 4 cm length was performed. The operation took 355 minutes. Intraoperatively blood loss amounted 900 g with no transfusion. R0 resection was achieved pathologically. There was one lymph node metastasis. Postoperatively infected fluid collection due to pancreas leakage was identified and percutaneous drainage was inserted 3 weeks after the operation. PV graft was stenotic due to the fluid collection. PV stent was inserted. PCD tube was removed 6 weeks after its insertion. He is well except diarrhea 3 times a day 3 months after the operation. DP-CAR with PV resection and reconstruction is a demanding operation. PV reconstruction should be anticipated and prepared before surgery when pancreas body cancer abuts portosplenic confluence. Interposition graft rather than primary anastomosis should be considered when PV resection is needed during DP-CAR.

Proclivity to Explore Locally Advanced Pancreas Cancer Is Not Associated with Surgeon Volume

Background and PurposeThere is limited high-level evidence to guide locally advanced pancreas cancer (LAPC) management. Recent work shows that surgeons’ preferences in LAPC management vary broadly. We sought to examine whether surgeon volume was associated with attitudes regarding LAPC management. MethodsAn electronic survey was distributed by email to an international cohort of pancreas surgeons to evaluate practice patterns regarding LAPC management. Clinical vignette-based questions evaluated surgeons’ attitudes regarding patient eligibility and the proclivity to offer exploration. Surgeons were classified into “low-“ or “high-volume” categories according to thresholds of self-reported annual pancreatectomy volume. Surgeon’s attitudes regarding LAPC management and inclination to consider exploration were compared across annual volume categories. ResultsA total of 153 eligible responses were received from 4 continents, for an estimated response rate of 10.6%. Median duration of practice was 12 years (IQR 6–20). Most respondents reported >25 cases/year (89, 58.2%), of which 34 (22.2%) reported >50. Compared to surgeons with <25 cases/year, surgeons with >25 cases/year practiced longer (median 15 vs. 7.5 years, P<0.001) and were more likely to “always” recommend neoadjuvant chemotherapy (83.2% vs. 56.3%, P=0.001). Surgeons performing >50 cases/year were more likely to offer arterial resection (70.6% vs. 43.7%, P=0.006). The willingness to offer (or defer) exploration did not differ across any categories of surgeons’ annual case volume. ConclusionsIn an international survey of pancreas surgeons, the proclivity to consider exploration for LAPC was not associated with multiple categories of surgeon volume. Better evidence is needed to define the optimal management approach to LAPC.

A phase 2 study of cyclophosphamide (CY), GVAX, pembrolizumab (Pembro), and stereotactic body radiation (SBRT) in patients (pts) with locally advanced pancreas cancer (LAPC).

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 &gt; 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 &gt; 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.

Australasian Gastro-Intestinal Trials Group (AGITG) MASTERPLAN: Randomized phase II study of modified neoadjuvant FOLFIRINOX alone or in combination with stereotactic radiotherapy (SBRT) for patients with high-risk and locally advanced pancreatic cancer.

TPS4172 Background: Eighty per cent of patients with non-metastatic pancreatic cancer have high-risk, borderline resectable (BRPC) or locally advanced pancreas cancer (LAPC), conferring a 5-year overall survival of only 12%. MASTERPLAN evaluates the safety and activity of stereotactic body radiotherapy (SBRT) added to neoadjuvant chemotherapy in these patient cohorts. Methods: MASTERPLAN is an investigator-initiated prospective multi-centre randomized phase II trial. Inclusion criteria include histologically confirmed high-risk, BRPC or LAPC. High risk is defined as tumour &gt; 4cm, extrapancreatic extension or node positive. Randomisation is 2:1 to chemotherapy + SBRT (investigational arm) or chemotherapy (control arm) by minimisation with stratification by operability (potentially operable - high risk; BRPC versus inoperable – LAPC; medically inoperable), planned chemotherapy and institution. Both treatment arms receive 6 x 2 weekly cycles of modified FOLFIRINOX (mFOLFIRINOX). Gemcitabine and nab-paclitaxel is permitted if mFOLFIRINOX is unsuitable. The investigational arm receives SBRT (40Gy in 5 fractions) with real time quality assurance. Resectability will be evaluated following initial chemotherapy +/- SBRT. Adjuvant chemotherapy is 6 cycles (12 weeks) of mFOLFIRINOX, or the same duration of gemcitabine and capecitabine (GEMCAP) if neoadjuvant gemcitabine/ nab-paclitaxel given. SBRT adverse events (AEs) will be recorded until study cessation. The primary endpoint is 12-month locoregional control. Secondary endpoints: safety, surgical morbidity and mortality, radiological response rate, progression free survival, pathological response rate, surgical resection rate, R0 resection rate, quality of life, deterioration free survival and overall survival. Biospecimens are collected for translational research for potential prognostic/predictive biomarkers of clinical endpoints and include serial tumour tissue collection from patients undergoing fiducial marker insertion and/or surgery, biopsy at disease progression, serial blood collection and serial buccal and faecal sample collection. An interim analysis will review locoregional failure, distant metastasis and rate of death on the first 40 patients after completion of 12 months follow up. The sample size is 120 patients (80 intervention:40 control), balanced for BRPC/LAPC (60 in each cohort). The minimum follow up is 12 months. The first site opened in October 2019 and 10 patients have been recruited from five sites at 17 Feb 2021. Overall 15 sites in Australia and New Zealand are planned to open to recruitment. Australian Clinical Trials Registry Number: ACTRN12619000409178. Clinical trial information: ACTRN12619000409178.

Arterial divestment (AD) versus arterial resection/reconstruction (AR) at the time of pancreatectomy for locally advanced pancreas cancer (LAPC)

Arterial divestment (AD) versus arterial resection/reconstruction (AR) at the time of pancreatectomy for locally advanced pancreas cancer (LAPC)

Geographic Variation in Attitudes Regarding Locally Advanced Pancreatic Cancer Management

Introduction: Studies suggest attitudes regarding management of locally advanced pancreas cancer (LAPC) vary widely. We sought to examine the influence of geographic practice location on attitudes regarding LAPC management.

Impact of neoadjuvant chemotherapy and stereotactic body radiation therapy (SBRT) on R0 resection rate for borderline resectable and locally advanced pancreatic cancer

BackgroundThe role of neoadjuvant stereotactic body radiation therapy (SBRT) in patients with borderline resectable pancreas cancer (BRPC) and locally advanced pancreas cancer (LAPC) remains controversial. MethodsWe retrospectively evaluated BRPC and LAPC patients treated at our institution who underwent 2–3 months of chemotherapy followed by SBRT to a dose of 30–33 Gy. Overall survival (OS) and recurrence-free survival (RFS) were estimated and compared by Kaplan–Meier and log-rank methods. ResultsWe identified 103 (85 BRPC and 18 LAPC) patients treated per our neoadjuvant paradigm between 2011 and 2018, with resectability based on NCCN definitions. Median follow up was 25 months. Of patients completing neoadjuvant therapy, 73 (71%) underwent definitive resection. Seventy-one (97%) patients with definitively resected tumors had R0 resection and 5 (7%) had a complete pathologic response CR to neoadjuvant therapy. The median overall survival (OS) of the cohort was 24 months. Those with a complete or marked pathologic response had significantly better OS than those with a moderate response (41 vs 24 months, p < 0.02) and patients unable to undergo definitive surgery (17 months, p < 0.0003). Six resected patients experienced grade ≥3 surgical complications. ConclusionsNeoadjuvant chemotherapy and SBRT are associated with promising pathologic response rates and R0 resection rates, with acceptable perioperative morbidity.

Geographic variation in attitudes regarding locally advanced pancreatic cancer management

Presenter: Bradley Reames MD, MS | University of Nebraska Medical Center Background: Evidence to guide management of locally advanced pancreas cancer (LAPC) is limited to retrospective reports. Numerous studies suggest attitudes regarding LAPC management are inconsistent between surgeons and across institutions. We sought to examine the influence of geographic practice location on surgeon attitudes regarding management of LAPC. Methods: An extensive electronic survey was distributed by email to an international cohort of pancreas surgeons. Data collected included practice characteristics, preferences for staging and management, and 6 clinical vignettes (with detailed videos of post-neoadjuvant arterial and venous CT imaging) to assess attitudes regarding eligibility for surgical exploration. Descriptive and comparative statistics were used to examine differences in attitudes across geographic locations of practice. Results: A total of 153 eligible responses (estimated response rate: 10.6%) were received from 4 continents: North and South America (NSA, combined N=94, 61.4%), Europe (EUR, N=25, 16.3%), and Asia (N=34, 22.2%). Median duration of practice was 12 years (IQR 6-20) and most particpants are considered high volume surgeons (>10 pancreatectomies/year, 86.3%) working at high volume hospitals (>25/year, 88.9%). Examination of attitudes regarding LAPC management revealed numerous significant differences across practice locations. Participants from Asia more frequently prefer MRI (67.6%) and PET/CT (44.1%) for initial staging, versus NSA (23.4% and 8.5%) and EUR (32% and 16%, P < 0.001 for both). Neoadjuvant chemotherapy is "always" recommended by a majority of participants in NSA (81.9%) and EUR (68.0%), but a minority of those in Asia (47.1%, P=0.001). The preferred duration of neoadjuvant systemic therapy varied: participants from Asia commonly prefer 2 months (61.8%), while NSA participants prefer 4 months (52.1%), and responses from EUR were mixed (P=0.006). Participants from EUR were less likely to recommend neoadjuvant radiation (32% never recommend), compared to those from NSA (3.2% never recommend) and Asia (17.6% never recommend, P < 0.001). Participants offering minimally-invasive surgery from NSA and EUR were more likely to use a robotic approach (48% and 75%, respectively) than those from Asia (33.3%, P=0.01). Participants from Asia were less likely to consider isolated liver (67.6%) or lung (61.8%) metastases contraindications to exploration, versus those from NSA (90.4% and 88.3%) and EUR (72% and 72%, P < 0.005 for both), and this corresponded to a greater propensity to consider exploration in a vignette of olgiometastatic disease (56.7%, vs. 25.6% for NSA and 43.5% for EUR, P=0.007). For all three groups, concern regarding arterial involvement was the most common reason to avoid exploration in 6 vignettes. Participants from Asia commonly recommended continuing current chemotherapy as an alternative to exploration, while those from NSA frequently recommended clinical trial options, and responses from EUR were mixed. Conclusion: In an international survey of high volume pancreas surgeons, attitudes regarding LAPC management varied across geographic locations of practice. Better evidence is needed define the optimal management approach to LAPC.

SBRT (Stereotactic Body Radiation Therapy) for locally advanced pancreas cancer (LAPC). Institutional experience

SBRT (Stereotactic Body Radiation Therapy) for locally advanced pancreas cancer (LAPC). Institutional experience

Impact of neoadjuvant chemotherapy and stereotactic body radiation therapy (SBRT) on R0 resection rate for borderline resectable and locally advanced pancreas cancer.

370 Background: Management for borderline resectable pancreas cancer (BRPC) and locally advanced pancreas cancer (LAPC) is controversial. Multiagent chemotherapy (CT) followed by SBRT may allow for tumor downstaging and the ability to perform an R0 resection. Methods: We retrospectively evaluated BRPC and LAPC patients (pts) treated on our multidisciplinary treatment pathway. Pts underwent 2-3 months of CT. Pts without systemic progression received five fractions of SBRT, delivered every other day, to a dose of 30-33 Gy. After restaging, pts underwent surgery if resectable. Overall survival (OS), distant metastasis free survival (DMFS) and local progression free survival (LPFS) were estimated and compared by Kaplan-Meier and log-rank methods. Results: We identified 80 pts with BRPC (65) or LAPC (15) treated with neoadjuvant CT + SBRT between 2011-2017. Median follow up was 20 months. CT primarily included FOLFIRINOX (65%) and gemcitabine/nab-paclitaxel (30%). Of pts completing CT + SBRT, 67 (84%) went to surgery and 53 (79%) of those pts underwent definitive surgery including seven LAPC patients. The remaining 14 pts underwent palliative or exploratory surgery due to intraoperative metastases (43%) or vascular involvement (57%). Of pts undergoing definitive surgery, 51 had R0 resection (96%) and 5 (9%) had a complete pathologic response (PR) to CT + SBRT. The R0 resection rate of the cohort was 64%. OS was 24.5 months. Pts with a complete or marked (14%) PR had significantly better OS than those with a moderate (40%) PR (41.3 vs 30 months, p = 0.04) and pts unable to undergo definitive surgery (18.2 months, p &lt; 0.001). Zero of 11 pts who had a marked or complete PR had local progression, significant compared to those with moderate PR (p = 0.012). DMFS between these two groups was not statistically significantly different. Conclusions: Neoadjuvant CT + SBRT are associated with favorable PR rates and R0 resection rates. Marked or complete PR was associated with improved LPFS and OS compared to moderate PR and pts who did not undergo definitive surgery. DMFS was not significantly different between complete and marked PR compared to those with moderate PR.

Modified Appleby procedure for locally advanced pancreatic cancer

Locally advanced pancreas cancer (LAPC) involving the celiac axis is typically considered unresectable and carries a poor prognosis. We present a case of a patient with LAPC who underwent a modified Appleby procedure for tumor clearance following neoadjuvant therapy. Technical aspects include diagnostic laparoscopy to exclude occult metastatic disease followed by complete mobilization of the pancreas and spleen, preservation of the left gastric artery, and resection and reconstruction of the common hepatic artery. With proper patient selection and preparation, LAPC with celiac axis involvement can be safely resected with favorable outcomes.

Phase II study of GM-CSF secreting allogeneic pancreatic cancer vaccine (GVAX) with PD-1 blockade antibody and stereotactic body radiation therapy (SBRT) for locally advanced pancreas cancer (LAPC).

TPS4154 Background: Optimal treatment strategy beyond systemic chemotherapy for LAPC remains undefined. SBRT improves local control, but distant metastasis free survival (DMFS) is only 7.7 months. Checkpoint inhibitors are poor monotherapies in pancreas cancer, but may be primed by SBRT via absocopal effect and GVAX, which induces novel lymphoid infiltrates and increased effector T-cells in tumor microenvironment. Methods: This is a single-arm, single-institution, open-label study for pts with LAPC. Eligibility: surgically unresectable LAPC, predominant adenocarcinoma at diagnosis, with ECOG 0-1, who remain metastases free after 4-8 cycles of FOLFIRINOX or gemcitabine/abraxane based-chemotherapy. Exclusion: those off chemotherapy &gt; 49 days prior to study treatment, prior immunotherapy, active immunosuppressive use, autoimmune disease, HIV, HBV, or HCV infection, and non-oncology vaccines within 28 days of study treatment. Pts receive cyclophosphamide (200mg/m2 IV) and pembrolizumab (200mg IV) on day 1, followed by GVAX (six intradermal injections) on day 2 every three weeks for two cycles, with cycle 2 initiating concurrently with five days of SBRT. If non-metastatic, pts undergo surgical resection, nano-knife, or EUS guided biopsy (if non-surgical). Pts receive two further cycles of chemotherapy, and if remain free of metastases, receive q3 week cyclophosphamide, pembrolizumab, and GVAX for six cycles, then are monitored for two years. The primary endpoint is DMFS. Secondary endpoints include overall survival, surgical resectability, pathologic response, quality of life, and toxicity. Exploratory objectives of peripheral antigen specific t-cell responses, and changes in immune parameters of tumor microenvironment. 11 of 54 pts have been enrolled since July 2016. Clinical trial information: NCT02648282.

Impact of presence and degree of pretreatment weight loss in locally-advanced pancreatic cancer patients treated with definitive concurrent chemoradiotherapy

BackgroundTo assess the impact of the presence and degree of pretreatment weight loss (WL) on the survival of locally-advanced pancreas cancer (LAPC) patients treated with concurrent chemoradiotherapy (C-CRT). MethodsSeventy-three patients who received 50.4 Gy C-CRT were analyzed. All patients underwent laparoscopy (n = 18) or laparotomy (n = 55), and biopsies were obtained for histologic examination of the primary tumor and enlarged/metabolically active regional lymph nodes. Pretreatment WL and percentage WL (PWL) were calculated by utilizing data obtained 6 months prior to and during hospital admission. The primary objective was to assess the influence WL status on overall survival (OS), and the secondary objective was the identification of a PWL cut-off value, if available. ResultsForty-five (61.6%) patients had WL. Median OS was 14.4 months for the entire study population which was significantly longer in the non-WL than the WL cohort (21.4 vs. 11.3 months; p < 0.003). On further analysis a cut-off value of 3.1% was identified for WL. Accordingly, patients with WL < 3.1% had significantly longer OS than those with WL ≥ 3.1% (25.8 vs. 10.1 months; p < 0.001). In multivariate analysis, both the WL status (p < 0.001) and PWL (p = 0.002) retained their independent significance. ConclusionBoth the presence and degree of WL prior to C-CRT had strong adverse effects on the survival of LAPC patients, even if they presented with a BMI > 20 kg/m2. Additionally, a WL of ≥3.1% in the last 6 months appeared to be a strong cut-off for the stratification of such patients into distinctive survival groups.

Intensity modulated radiation therapy reduces gastrointestinal toxicity in locally advanced pancreas cancer

PurposeWe compared gastrointestinal (GI) and hematologic toxicity in patients with locally advanced pancreas cancer (LAPC) undergoing definitive chemoradiation using intensity modulated radiation therapy (IMRT) or 3-dimensional conformal radiation therapy (3D-CRT) planning. Methods and materialsWe retrospectively studied 205 patients with LAPC undergoing IMRT (n = 134) and 3D-CRT (n = 71) between May 2003 and March 2012. Patient, tumor, and treatment characteristics and acute GI/hematology toxicity according to the Common Terminology Criteria for Adverse Events, version 3.0, were recorded. Multivariable logistic regression models were used to test association between acute grade 2+ GI and hematologic toxicity outcomes and predictors. Propensity score analysis for grade 2+ GI toxicity was performed to reduce bias for confounding variables: age, gender, radiation dose, field size, and chemotherapy type. ResultsMedian follow-up time for survivors was 22 months and was similar between groups. Median RT dose was significantly higher for IMRT versus 3D-CRT (5600 cGy vs 5040 cGy, P < .001); concurrent chemotherapy was mainly gemcitabine (56%) or 5-fluorouracil (38%). Grade 2+ GI toxicity occurred in 34% (n = 24) of 3D-CRT compared with 16% (n = 21) of IMRT patients. Using propensity score analysis, 3D-CRT had significantly higher grade 2+ GI toxicity (odds ratio, 1.26; 95% confidence interval, 1.08-1.45; P = .001). Grade 2+ hematologic toxicity was similar between IMRT and 3D-CRT groups, but was significantly greater in recipients of concurrent gemcitabine than in 5-fluorouracil (62% vs 29%, P < .0001). ConclusionsIMRT is associated with significant lower grade 2+ GI toxicity versus 3D-CRT for patients undergoing definitive chemoradiation therapy for LAPC. Because IMRT is better tolerated at higher doses and may allow further dose escalation, potentially improving local control for this aggressive disease. Further prospective studies of dose-escalated chemoradiation using IMRT are warranted.

Intensity Modulated Radiation Therapy Reduces Gastrointestinal Toxicity in Locally-Advanced Pancreas Cancer

Intensity modulated radiation therapy (IMRT) has been shown to reduce gastrointestinal (GI) toxicity for patients receiving adjuvant chemoradiation (CRT) for resected pancreas cancer as compared to 3D conformal radiation therapy (3DCRT). We assessed the impact of IMRT as compared with 3DCRT on GI and hematologic toxicity in the setting of definitive CRT for patients with locally advanced pancreas cancer (LAPC).

Dose-Painted Intensity Modulated Radiation Therapy Improves Local Control for Locally Advanced Pancreas Cancer

Background. To evaluate the outcomes, adverse events, and therapeutic role of Dose-Painted Intensity-Modulated Radiation Therapy (DP-IMRT) for locally advanced pancreas cancer (LAPC). Methods. Patients with LAPC were treated with induction chemotherapy (n = 25) and those without metastasis (n = 20) received DP-IMRT consisting of 45 Gy to Planning Treatment Volume 1 (PTV1) including regional lymph nodes with a concomitant boost to the PTV2 (gross tumor volume + 0.5 cm) to either 50.4 Gy (n = 9) or 54 Gy (n = 11) in 25 fractions. DP-IMRT cases were compared to three-dimensional conformal radiation therapy (3D-CRT) plans to assess the potential relationship of radiation dose to adverse events. Kaplan-Meier and Cox regression analyses were used to calculate survival probabilities. The Fisher exact test and t-test were utilized to investigate potential prognostic factors of toxicity and survival. Results. Median overall and progression-free survivals were 11.6 and 5.9 months, respectively. Local control was 90%. Post-RT CA-19-9 levels following RT were predictive of survival (P = 0.02). Grade 2 and ≥grade 3 GI toxicity were 60% and 20%, respectively. In comparison to 3D-CRT, DP-IMRT plans demonstrated significantly lower V45 values of small bowel (P = 0.0002), stomach (P = 0.007), and mean liver doses (P = 0.001). Conclusions. Dose-escalated DP-IMRT offers improved local control in patients treated with induction chemotherapy for LAPC. Radiation-related morbidity appears reduced with DP-IMRT compared to 3D-CRT techniques, likely due to reduction in RT doses to organs at risk.

A Dose Escalation and Pharmacodynamic Study of Triapine and Radiation in Patients With Locally Advanced Pancreas Cancer

Triapine, a novel inhibitor of the M2 subunit of ribonucleotide reductase (RR), is a potent radiosensitizer. This phase 1 study, sponsored by the National Cancer Institute Cancer Therapy Evaluation Program, assessed the safety and tolerability of triapine in combination with radiation (RT) in patients with locally advanced pancreas cancer (LAPCA). We evaluated 3 dosage levels of triapine (24 mg/m2, 48 mg/m2, 72 mg/m2) administered with 50.4 Gy of RT in 28 fractions. Patients with LAPCA received triapine thrice weekly, every other week during the course of RT. Dose-limiting toxicity (DLT) was assessed during RT and for 4 weeks after its completion. Dynamic contrast-enhanced magnetic resonance imaging and serum RR levels were evaluated as potential predictors for early response. Twelve patients were treated. Four patients (1 nonevaluable) were enrolled at dosage level 1 (DL1), 3 patients at DL2, and 5 patients (2 nonevaluable) at DL3. No DLTs were observed, and the maximum tolerated dose was not reached. Two patients (17%) achieved partial response, and 6 patients (50%) had stable disease. One patient underwent R0 resection after therapy. Ninety-two percent of patients (100% at DL3) experienced freedom from local tumor progression. In 75% of patients who eventually experienced progression, metastases developed without local progression. RR levels did not seem to predict outcome. In 4 patients with available data, dynamic contrast-enhanced magnetic resonance imaging may predict early response or resistance to therapy. The combination of triapine at 72 mg/m2 3 times weekly every other week and standard RT is tolerable with interesting activity in patients with LAPCA.

P-0120 Prognostic Value of Gross Tumor Volume Delineated by Fdg-Pet-Ct-Based Radiotherapy Treatment Planning Locally Advanced Pancreatic cancer Treated with Chemoradiotherapy

IntroductionWe aimed to assess whether gross tumor volume (GTV) determined by fusion of contrast-enhanced computerized tomography (CT) and 18F-fluoro-deoxy-D-glucose positron emission tomography-CT (FDG-PET-CT) based radiotherapy planning could predict outcomes, namely overall survival (OS), local-regional progression-free survival (LRPFS), and progression-free survival (PFS) in cases with locally advanced pancreas cancer (LAPC) treated with definitive concurrent chemoradiotherapy. MethodsA total of 30 patients with histological proof of LAPC underwent 50.4 Gy (1.8 Gy/28 fractions) of radiotherapy concurrent with continuously infused 5-FU followed by 4 to 6 courses of maintenance gemcitabine. Target volume delineations were performed on FDG-PET-CT-based RTP. Patients were stratified into 2 groups: GTV lesser (GTVL) versus greater (GTVG) than cut off value determined by receiver operating characteristic (ROC) analysis, and compared in terms of OS, LRPFS and PFS. ResultsMedian GTV delineated according to the FDG-PET-CT data was 100.0 cm3. Cut off GTV value determined from ROC curves was 91.1cm3. At a median follow up of 11.2 months, median OS, LRPFS and PFS for the entire population were 10.3, 7.8 and 5.7 months, respectively. Median OS, LRPFS and PFS for GTVL and GTVG cohorts were 16.3 vs. 9.5 (p=0.005), 11.0 vs. 6.0 (p=0.013), and 9.0 vs. 4.8 months (p=0.008), respectively. ConclusionThe superior OS, LRPFS and PFS observed in GTV L patients over GTVG ones suggests a potential for FDG-PET-CT-defined GTV size in predicting outcomes of LAPC patients treated with definitive C-CRT, which needs to be validated by further studies with larger cohorts.