•Ablative radiation therapy (A-RT) is effective for locally advanced pancreas cancer.•30 patients received A-RT using diagnostic quality MR-adaptive treatment delivery.•Cumulative incidences of ...1-year local and distant progression were 19.3% and 47.4%•Overall and progression-free survival 1-year from A-RT was 80.0% and 39.7%•50 Gray in 5 fractions led to promising 1-year local control and survival.•Most local failures were marginal at the tumor-organ-at-risk (OAR) interface.•No grade 3 or higher toxicities were observed despite adjacent sensitive OARs.
Ablative radiation therapy (A-RT) appears to improve outcomes in locally advanced pancreatic cancer (LAPC) yet requires solutions for respiratory and digestive motion. We report outcomes of A-RT for pancreatic cancer using 1.5 T MR-adaptive treatment delivery.
Between March 2020 and July 2021, we treated 30 patients with pancreatic cancer with 50 Gy in 5 fractions (biologically effective dose BED10 = 100 Gy10) using a novel compression belt workflow and remote planning on the Unity 1.5 T MR linac system. Cumulative incidence of progression was computed from A-RT initiation with death as a competing risk. Overall (OS) and progression-free survival (PFS) were calculated using Kaplan Meier methods.
Of 30 patients, most (73 %) were locally advanced, 4 (13 %) were metastatic, 2 (7 %) were medically inoperable, and 2 (7 %) were locally recurrent. Most (73 %) received FOLFIRINOX prior to A-RT. Median follow-up times from diagnosis and A-RT were 17.6 (IQR 15.8–23.1) and 11.5 months (IQR 9.7–16.1), respectively. Cumulative incidences at 1-year of local and distant progression were 19.3 % (95 %CI 6.7–36.8 %) and 47.4 % (95 %CI 26.7–65.6 %), respectively. Median OS from diagnosis and A-RT were not reached. One-year OS from diagnosis and A-RT were 96.4 % (95 %CI 77.2–99.5 %) and 80.0 % (95 %CI 57.3–91.4 %), respectively. Median and 1-year PFS were 10.1 months (95 %CI 4.4–14.4) and 39.7 % (95 %CI 20.3–58.5 %), respectively. No grade 3 + toxicities were observed.
A-RT using the 1.5 T Unity MR Linac resulted in promising LC and OS with no severe toxicity in patients with LAPC despite radiosensitive organs adjacent to the target volumes. Longer follow-up is needed to assess long-term outcomes.
Acute cholangitis (AC) is a common complication of pancreatic ductal adenocarcinoma (PDAC). Herein, we evaluated outcomes after the first AC episode and predictors of mortality and AC recurrence in ...patients with stage IV PDAC.
We conducted a single-center, retrospective observational study using institutional databases. Clinical data and outcomes for patients with stage IV PDAC and at least one documented episode of AC, were assessed. Overall survival (OS) was estimated using the Kaplan-Meier method, and Cox regression model was employed to identify predictors of AC recurrence and mortality.
One hundred and twenty-four patients with stage IV PDAC and AC identified between January 01, 2014 and October 31, 2020 were included. Median OS after first episode of AC was 4.1 months (95 % CI, 4.0–5.5), and 30-day, 6, and 12-month survival was 86.2 % (95 % CI, 80.3–92.5), 37 % (95 % CI, 29.3–46.6 %) and 18.9 % (95 % CI, 13.1–27.3 %), respectively. Primary tumor in pancreatic body/tail (HR 2.29, 95 % CI: 1.26 to 4.18, p = 0.011), concomitant metastases to liver and other sites (HR 1.96, 95 % CI: 1.16 to 3.31, p = 0.003) and grade 3 AC (HR 2.26, 95 % CI: 1.45 to 3.52, p < 0.001), predicted worse outcomes. Intensive care unit admission, sepsis, systemic therapy, treatment regimen, and time to intervention did not predict survival or risk of recurrence of AC.
AC confers significant morbidity and mortality in advanced PDAC. Worse outcomes are associated with higher grade AC, primary tumor location in pancreatic body/tail, and metastases to liver and other sites.
This two-part phase Ib trial determined the maximum tolerated dose (MTD) of the combination of trifluridine/tipiracil (FTD/TPI) and irinotecan in patients with advanced gastrointestinal tumors, and ...evaluated the safety, pharmacokinetics, and antitumor activity of the FTD/TPI, irinotecan, and bevacizumab triplet combination in previously treated metastatic colorectal cancer (mCRC).
Dose escalation (3+3 design) in advanced gastrointestinal tumors was followed by expansion in mCRC. During dose escalation, patients received FTD/TPI (20-35 mg/m
twice daily; days 1-5 of a 14-day cycle) and irinotecan (120-180 mg/m
; day 1). During expansion, the MTD of FTD/TPI and irinotecan plus bevacizumab (5 mg/kg; day 1) was administered.
Fifty patients (26 across six dose-escalation cohorts and 24 in the expansion phase) were enrolled. Two dose-limiting toxicities (fatigue and neutropenia) were observed in the dose-escalation phase, and MTD was defined as FTD/TPI 25 mg/m
twice daily plus irinotecan 180 mg/m
. In the expansion phase, 83% (20/24) experienced any-cause grade ≥3 adverse events (AEs) with the triplet combination, most frequently neutropenia (42%), leukopenia (25%), and diarrhea (12%). AEs of any-cause led to dosing interruptions, modifications, and discontinuations in 29%, 17%, and 4% of patients, respectively. No treatment-related deaths occurred. Three patients (12%) experienced partial responses and 16 (67%) patients had stable disease lasting >4 months. The median progression-free survival was 7.9 months (95% confidence interval, 5.1-13.4 months).
Tolerability and activity observed in this phase I trial support further investigation of the FTD/TPI-irinotecan-bevacizumab combination in previously treated mCRC.
Background
Pancreatic adenocarcinoma (PDAC) remains a refractory disease; however, modern cytotoxic chemotherapeutics can induce tumor regression and extend life. A blood‐based, pharmacogenomic, ...chemosensitivity assay using gene expression profiling of circulating tumor and invasive cells (CTICs) to predict treatment response was previously developed. The combination regimen of 5‐fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) and gemcitabine/nab‐paclitaxel (G/nab‐P) are established frontline approaches for treating advanced PDAC; however, there are no validated biomarkers for treatment selection. A similar unmet need exists for choosing second‐line therapy.
Methods
The chemosensitivity assay was evaluated in metastatic PDAC patients presenting for frontline treatment. A prospective study enrolled patients (n = 70) before receiving either FOLFIRINOX or G/nab‐P at a 1:1 ratio. Six milliliters of peripheral blood was collected at baseline and at time of disease progression. CTICs were isolated, gene‐expression profiling was performed, and the assay was used to predict effective and ineffective chemotherapeutic agents. Treating physicians were blinded to the assay prediction results.
Results
Patients receiving an effective regimen as predicted by the chemosensitivity assay experienced significantly longer median progression‐free survival (mPFS; 7.8 months vs. 4.2 months; hazard ratio HR, 0.35; p = .0002) and median overall survival (mOS; 21.0 months vs. 9.7 months; HR, 0.40; p = .005), compared with an ineffective regimen. Assay prediction for effective second‐line therapy was explored. The entire study cohort experienced favorable outcomes compared with historical controls, 7.1‐month mPFS and 12.3‐month mOS.
Conclusions
Chemosensitivity assay profiling is a promising tool for guiding therapy in advanced PDAC. Further prospective validation is under way (clinicaltrials.gov NCT03033927).
Objectives
Patients with locally advanced pancreatic adenocarcinoma (PDAC) receive induction chemotherapy with or without radiation, with the goal of R0 resection and improving survival. Herein, we ...evaluate the outcomes of patients who presented with Stage III PDAC and received induction FOLFIRINOX.
Methods
An institutional database was queried for consecutive patients who received induction FOLFIRINOX for locally unresectable PDAC between 2010 and 2016. Clinical and radiographic parameters were assessed pre‐ and posttreatment, and clinical outcomes were evaluated.
Results
There were 200 patients who met the inclusion criteria. The median number of cycles of FOLFIRINOX was 8, 70% (n = 140) received radiation, and 18% (n = 36) underwent resection. Median overall survival (OS) in resected patients was 36 months (95% confidence interval CI: 24–56), and this group had improved OS compared to patients that did not undergo resection (hazard ratio (95% CI): 0.41 (0.26–0.64), p < 0.001). Patients (n = 112) who did not progress on induction therapy but remained unresectable had a median OS of 23.9 months (95% CI: 21.1–25.4).
Conclusion
Nearly 20% of patients with locally advanced PDAC responded sufficiently to induction FOLFIRINOX to undergo resection, which was associated with improved OS compared to patients that did not undergo resection. Patients with stable disease who remain unresectable represent a group of patients with locally advanced PDAC who may benefit from optimization of additional nonoperative treatment.
The rate of isolated locoregional recurrence after surgery for pancreatic adenocarcinoma (PDAC) approaches 25%. Ablative radiation therapy (A-RT) has improved outcomes for locally advanced disease in ...the primary setting. We sought to evaluate the outcomes of salvage A-RT for isolated locoregional recurrence and examine the relationship between subsequent patterns of failure, radiation dose, and treatment volume.
: We conducted a retrospective analysis of all consecutive participants who underwent A-RT for an isolated locoregional recurrence of PDAC after prior surgery at our institution between 2016 and 2021. Treatment consisted of ablative dose (BED10 98-100 Gy) to the gross disease with an additional prophylactic low dose (BED10 < 50 Gy), with the elective volume covering a 1.5 cm isotropic expansion around the gross disease and the circumference of the involved vessels. Local and locoregional failure (LF and LRF, respectively) estimated by the cumulative incidence function with competing risks, distant metastasis-free and overall survival (DMFS and OS, respectively) estimated by the Kaplan-Meier method, and toxicities scored by CTCAE v5.0 are reported. Location of recurrence was mapped to the dose region on the initial radiation plan.
: Among 65 participants (of whom two had two A-RT courses), the median age was 67 (range 37-87) years, 36 (55%) were male, and 53 (82%) had undergone pancreaticoduodenectomy with a median disease-free interval to locoregional recurrence of 16 (range, 6-71) months. Twenty-seven participants (42%) received chemotherapy prior to A-RT. With a median follow-up of 35 months (95%CI, 26-56 months) from diagnosis of recurrence, 24-month OS and DMFS were 57% (95%CI, 46-72%) and 22% (95%CI, 14-37%), respectively, while 24-month cumulative incidence of in-field LF and total LRF were 28% (95%CI, 17-40%) and 36% (95%CI 24-48%), respectively. First failure after A-RT was distant in 35 patients (53.8%), locoregional in 12 patients (18.5%), and synchronous distant and locoregional in 10 patients (15.4%). Most locoregional failures occurred in elective low-dose volumes. Acute and chronic grade 3-4 toxicities were noted in 1 (1.5%) and 5 patients (7.5%), respectively.
: Salvage A-RT achieves favorable OS and local control outcomes in participants with an isolated locoregional recurrence of PDAC after surgical resection. Consideration should be given to extending high-dose fields to include adjacent segments of at-risk vessels beyond direct contact with the gross disease.
Fibroblast growth factor receptor (FGFR) 2 alterations, present in 5%-15% of intrahepatic cholangiocarcinomas (IHC), are targets of FGFR-directed therapies. Acquired resistance is common among ...patients who respond. Biopsies at the time of acquired resistance to targeted agents may not always be feasible and may not capture the genetic heterogeneity that could exist within a patient. We studied circulating tumor DNA (ctDNA) as a less invasive means of potentially identifying genomic mechanisms of resistance to FGFR-targeted therapies.
Serial blood samples were collected from eight patients with FGFR-altered cholangiocarcinoma for ctDNA isolation and next-generation sequencing (NGS) throughout treatment and at resistance to anti-FGFR-targeted therapy. ctDNA was sequenced using a custom ultra-deep coverage NGS panel, incorporating dual index primers and unique molecular barcodes to enable high-sensitivity mutation detection.
Thirty-one acquired mutations in
, 30/31 located in the kinase domain, were identified at resistance in six of eight patients with detectable ctDNA. Up to 13 independent
mutations were detected per patient, indicative of striking genomic concordance among resistant subclones.
ctDNA could be an effective means to longitudinally monitor for acquired resistance in FGFR2-altered IHC. The numerous acquired genetic alterations in
suggest frequent polyclonal mechanisms of resistance that cannot be detected from single-site tissue biopsies.
/Objectives: Pancreatic adenocarcinoma (PDAC) metastatic to the leptomeninges is a rare and lethal event. Leptomeningeal disease (LMD) research is limited in PDAC, and insights into clinical ...descriptors, possible disease predictors, and treatment strategies is necessitated.
Memorial Sloan Kettering databases were queried with Institutional Review Board approval to identify patients with LMD and PDAC treated between January 2000 and June 2020. Medical record review was used to abstract clinical, genomic, pathologic, and radiographic data. Overall survival was calculated from date of PDAC diagnosis to date of death. Previously published literature on LMD from PDAC was reviewed.
Four patients with LMD from PDAC were identified, two males and two females. Age at diagnosis ranged from 57 to 68 years. All four patients had predominant lung metastasis and a relatively low burden of intra-abdominal disease. Somatic testing indicated alterations typical of PDAC and no PDAC defining pathogenic germline mutations were identified. An extended clinical course prior to LMD diagnosis was observed in all patients, ranging from 16 to 148 months. Upon diagnosis of LMD, three patients elected for supportive care and one patient received a limited course of craniospinal radiation. The median survival following diagnosis of LMD was 1.6 months (range 0.5–2.8 months).
LMD from PDAC is a rare occurrence that may be more frequent in patients with lung metastasis and/or a more indolent clinical course. Following diagnosis of LMD, prognosis is poor, and survival is short. New treatment strategies for this manifestation of PDAC are needed.
Background and Objective
Pancreatic ductal adenocarcinoma (PDAC) is characterized by the occurrence of pathogenic variants in
BRCA1/2
in 5–6% of patients. Biallelic loss of
BRCA1/2
enriches for ...response to platinum agents and poly (ADP-ribose) polymerase 1 inhibitors. There is a dearth of evidence on the mechanism of inactivation of the wild-type
BRCA1
allele in PDAC tumors with a germline
BRCA1
(
gBRCA1
) pathogenic or likely pathogenic variant (P/LPV). Herein, we examine promotor hypermethylation as a “second hit” mechanism in patients with
gBRCA1
-PDAC.
Methods
We evaluated patients with PDAC who underwent Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) somatic and germline testing from an institutional database. DNA isolated from tumor tissue and matched normal peripheral blood were sequenced by MSK-IMPACT. In patients with
gBRCA1
-PDAC, we examined the somatic
BRCA1
mutation status and promotor methylation status of the tumor
BRCA1
allele via a methylation array analysis. In patients with sufficient remaining DNA, a second methylation analysis by pyrosequencing was performed.
Results
Of 1012 patients with PDAC, 19 (1.9%) were identified to harbor a
gBRCA1
P/LPV. Fifteen patients underwent a methylation array and the mean percentage of
BRCA1
promotor methylation was 3.62%. In seven patients in whom sufficient DNA was available, subsequent pyrosequencing confirmed an unmethylated
BRCA1
promotor. Loss of heterozygosity was detected in 12 of 19 (63%, 95% confidence interval 38–84) patients, demonstrating loss of heterozygosity is the major molecular mechanism of
BRCA1
inactivation in PDAC. Two (10.5%) cases had a somatic
BRCA1
mutation.
Conclusions
In patients with
gBRCA1-
P/LPV-PDAC, loss of heterozygosity is the main inactivating mechanism of the wild-type
BRCA1
allele in the tumor, and methylation of the
BRCA1
promoter is a distinctly uncommon occurrence.
In a series of 53 patients with advanced anal squamous cell cancer, we demonstrate that a modified 5-fluorouracil and cisplatin schedule (FOLFCIS) with lower dose, more frequent administration of ...cisplatin is effective and well-tolerated. This regimen should be considered a standard treatment option. Human papillomavirus-negative anal squamous cell cancers were less sensitive to platinum-based therapy and exhibited a distinct molecular profile.
Treatment of advanced anal squamous cell cancer (SCC) is usually with the combination of cisplatin and 5-fluorouracil, which is associated with heterogeneous responses across patients and significant toxicity. We examined the safety and efficacy of a modified schedule, FOLFCIS (leucovorin, fluorouracil, and cisplatin), and performed an integrated clinical and genomic analysis of anal SCC.
We reviewed all patients with advanced anal SCC receiving first-line FOLFCIS chemotherapy – essentially a FOLFOX (leucovorin, fluorouracil, and oxaliplatin) schedule with cisplatin substituted for oxaliplatin – in our institution between 2007 and 2017, and performed deep sequencing to identify genomic markers of response and key genomic drivers.
Fifty-three patients with advanced anal SCC (48 metastatic; 5 unresectable, locally advanced) received first-line FOLFCIS during this period; all were platinum-naive. The response rate was 48% (95% confidence interval CI, 32.6%-63%). With a median follow-up of 41.6 months, progression-free survival and overall survival were 7.1 months (95% CI, 4.4-8.6 months) and 22.1 months (95% CI, 16.9-28.1 months), respectively. Among all patients with advanced anal SCC that underwent sequencing during the study period, the most frequent genomic alterations consisted of chromosome 3q amplification (51%) and mutations in PIK3CA (29%) and KMT2D (22%). No genomic alteration correlated with response to platinum-containing treatment. Although there were few cases, patients with human papillomavirus-negative anal SCC did not appear to benefit from FOLFCIS, and all harbored distinct genomic profiles with TP53, TERT promoter, and CDKN2A mutations.
FOLFCIS appears effective and safe as first-line chemotherapy in patients with advanced anal SCC and represents an alternative treatment option for these patients.
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