bluuebunny/crossref_metadata_2025 huggingface dataset:
Neoadjuvant gemcitabine and nab-paclitaxel followed by concurrent capecitabine/radiation in borderline resectable (BR) pancreatic cancer: A single-institution experience.
Authors: Gupta Niraj K. , Singh Kirpal , Aburajab Murad , Mathavan Vinay , Al-Satie Mazen , Glass Timothy , Leagre Christopher A. , Rowe Michael , Tigges Thomas , Liebross Robert H. , Davis Chad , Tandra Sweta , Tumati Vas , Tian Jianmin , Martinez Brandon , Dowell Joshua , Schmidt Kristen Kay , Flanders Vincent ,   St Vincent Cancer Care
Published: February 2020

718

Background: Neo-adjuvant therapy is becoming a preferred approach in the management of BR pancreatic cancer patients. There is no consensus on an ideal treatment regimen. We report our experience with a combination of nab-Paclitaxel/Gemcitabine followed by concurrent Capecitabine and radiation treatments in BR pancreatic cancer patients. Methods: A prospectively maintained database of patients with BR pancreatic cancer undergoing neo-adjuvant treatments at our cancer center between 01/2013- 11/2017 was reviewed. Patients were treated with Gemcitabine(1gm/m2) and nab-paclitaxel (125mg/m2) given on D1-8-15 every 28 days. Pts. were re-assessed after two cycles and the responding pts received two additional cycles. Pts. who continued to respond after four cycles were treated with capecitabine (825mg/m2) and radiation treatments(50.4Gy). Results: A total of 32 patients with PS 0/1 were treated. Median age was 59 yrs (42-76), 19 Males and 13 females. After 2 cycles of Gem/nab-paclitaxel, none of the pts. had progressive disease. Thirty patients (93%) were able to complete all four cycles of Gem/nab-paclitaxel. Twenty nine (90%) received capecitabine and radiation treatments. Imaging to assess response was done 4 weeks after completing radiation and the results were were; 2 CR, 11 PR, 14 SD, 2 PD. Surgery was performed 6-8 weeks after completing radiation. Twenty six (81%) underwent planned resection, 2 had PD, 3 declined surgery and 1 had significant decline in PS. Twenty two out of Twenty six patients undergoing surgery had a R0 resection (80%). Grade-III/IV toxicities with the neo-adjuvant treatments were seen in 41% and 7 % of the pts., respectively. No thirty day post-op mortality, pancreatic leaks or re-operations were observed. The median PFS among all patients was 11.7 months, 2 yr OS 49% and median OS was 27.6 months, compared to 23.4 months, 65% and median OS not reached, in patients who underwent surgical resection. Conclusions: Nab-Paclitaxel and Gemcitabine followed by Capecitabine and radiation is an effective neo-adjuvant treatment strategy with acceptable toxicity-profile for patients with BR pancreatic cancer.
A study of preoperative FOLFIRINOX in potentially curable pancreatic cancer.
Authors: Javan Hamed , Niazi Tamim , Vanounou Tsafrir , Pelletier Jean-Sebastien , Dalfen Richard , Lecavalier-Barsoum Magali , Batist Gerald , Kavan Petr
Published: February 2020

719

Background: Although Folfirinox (FFX) prolonged survival in metastatic and adjuvant setting, the role of preoperative FFX is still controversial. Our aim is to evaluate how surgery after neoadjuvant FFX with or without radiotherapy (RT) affects the clinical outcome in these patients. Methods: This is a single arm, open-label, phase 2 prospective study. Based on resectability criteria (NCCN-V.1.2017), patients prospectively were divided into 3 groups of resectable, borderline resectable (BR), locally advanced (LA). Patients received 6 cycles of preoperative FFX. Patients with adequate response, underwent resection. Continuation of chemotherapy or radiation was given to the patients who were deemed unresectable after 6 cycles. Primary objective is time to progression (TTP), and secondary objectives are safety, R0/R1 resection rate, response rate (RR) and overall survival (OS). Results: 20 consecutive patients with pancreatic adenocarcinoma enrolled. The frequency of each group was 4, 8, 8 patients, respectively. Median age was 64 years old (range, 49-78). 45% of patients had primary tumor in head or uncinate process. 25% of cases presented with normal CA 19-9 value. 85% (17/20) of patients completed the preoperative treatment. Folfirinox was given within median of 11.5 weeks (range, 8-17) and median of 6 cycles (range, 1-7). Median relative dose intensity (RDI) was 85.89%. Grade III-IV (G3+4) adverse event (CTCAE-4.03) observed in 47.4% (9/19). RR (RECIST) was 89% (16/18). Best response was partial response (PR) and stable disease (SD) with 22.2% (4/18) and 66.7% (12/18). Resection rate was 64.3% (9/14, 1 case scheduled for resection). R0 and negative lymph node (LN) achieved in 87.50% (7/8) and 62.50% (5/8) of patients. Complete pathological response (cPR) was seen in one patient 12.5% (1/8) who preoperatively reported as SD. Patients TTP and OS will be reported during the meeting. Conclusions: Preoperative FFX was associated with high clinical and pathological response rate translating in high resection rate in majority of BRPC and LAPC, and appears to be a safe treatment strategy. Patients received higher FFX dose intensity than it was reported in adjuvant setting. However, these results need to be assessed in a randomized trial. Clinical trial information: NCT03167112.
The impact of pancreatic cancer resection in the era of effective systemic treatment.
Authors: Lawrence Yaacov Richard , Margalit Ofer , Jacobson Galia , Hamer Liat , Amit Uri , Halpern Naama , Shmueli Einat Shacham , Boursi Ben , Goldes Yuri , Azoulay Daniel , Golan Talia , Symon Zvi
Published: February 2020

722

Background: Surgical resection is the only curative modality in pancreatic cancer, yet the vast majority of patients undergoing surgery succumb of their disease. No randomized studies have been performed to assess the survival impact of the procedure. We hypothesized that in the era of effective systemic treatments, the survival advantage of surgical resection would be lessened. Methods: A meta-analysis of published phase III clinical trials in pancreatic cancer in both the post resection adjuvant setting and the locally advanced metastatic setting, based upon indirect aggregate data. Data was stratified based upon the systemic agents used. Patients from trials arms for which there were not complementary data sets with/without surgical resection were excluded. Primary endpoint was 3 year overall survival (OS). Results: Trials were published between 1997 and 2018. A total of 2722 patients were included in the data analysis, of whom 1645 underwent tumor resection and 814 were metastatic. Median follow-up was 40 months. Analyses were performed of five systemic options with / without tumor resection. Across the trials averaged 3 yr OS was 0%, 0.8%, 0%, and 3.8% for 5FU, gemcitabine, gemcitabine + capecitabine, & FOLFIRINOX respectively; and 18.1%, 30.0%, 37.9%, 42.5%, and 62.5% for the same systemic treatments delivered following surgical resection. Hence the additive impact of surgical resection on absolute 3 yr OS was only 18.1% in the absence of systemic treatment, but 30.0%, 37.1%, 42.5% and 58.8% in the presence of 5FU, gemcitabine, gemcitabine + capecitabine, FOLFIRINOX respectively. Conclusions: Within the limitations of this analysis, it appears that our hypothesis was incorrect, and that the opposite is true. The introduction of effective systemic therapies has greatly increased the impact of pancreatic surgery on long-term survival in pancreatic cancer. Consequently, every effort should be made to bring patients to curative resection.
Homologous recombination deficiency (HRD) scoring in pancreatic ductal adenocarcinoma (PDAC) and response to chemotherapy.
Authors: O'Kane Grainne M. , Denroche Rob , Picardo Sarah Louise , Zhang Amy , Holter Spring , Grant Robert C. , Allen Michael , Wang Yifan , Dodd Anna , Ramotar Stephanie , Hutchinson Shawn , Tehfe Mustapha , Biagi James Joseph , Wilson Julie , Notta Faiyaz , Fischer Sandra , Zogopoulos George , Gallinger Steven , Knox Jennifer J.
Published: February 2020

741

Background: Whole genome sequencing (WGS) can reveal patterns of substitution base signatures and structural variation consistent with tumours deficient in homologous recombination repair. We evaluated the published HRDetect score and a novel HRD hallmark score (HS) in patients receiving combination chemotherapy (cCT) on the COMPASS trial for advanced PDAC. Methods: The HRD-HS incorporates 10 genomic characteristics of HRD-PDAC with a score ≥ 4 defining HRD. HRD-HS and an HRDetect score ≥0.7 were applied to WGS data and overall survival (OS) and response (ORR) evaluated. Sensitivity and specificity were ascertained. Results: As of 05/19, 205 eligible patients (pts) were enrolled and 186 received cCT including modified FOLFIRINOX n = 108 (58%) or cisplatin/gemcitabine n = 2 (1%) and gemcitabine/nab-paclitaxel n = 76 (41%). HRD-HS had a sensitivity of 87.5% and specificity of 100% in detecting HRD-PDAC. In contrast, HRDetect (≥0.7) had sensitivity of 51.9% and specificity of 100%; sensitivity increased to 73.7% when using a cutoff score of ≥0.99. 23/186 (12%) pts were classified as HRdetecthi and median OS was 15.3months (mo) vs 8.7mo in HRDetectlo pts (HR 0.44 95% CI 0.27-.70, p = 0.009). In platinum treated pts, median OS was 18.1mo (HRDetecthi) vs 9.3mo (HRDetectlo) (HR 0.38 95%CI 0.21-0.69, p = 0.02). HRD-HS predicted the longest median OS for platinum of 21.0mths. ORR in HRDetecthi was not different to HRDetectlo pts treated with cCT, however in those receiving platinum the ORR was 50% vs 19% respectively (p < 0.001). Of the false positives by HRDetect, 46% had a non-BRCA1 tandem duplicator phenotype (TDP). The TDP group comprised 8% of all patients enrolled. HRD-PDAC was caused by inactivation of BRCA1/2, PALB2, RAD51C and XRCC2; all germline variants were pathogenic. Pathogenic ATM and CHEK2 germline variants were present in 3 pts with evidence of a second somatic hit or LOH, none of these identified as HRD by either classifier nor considered a TDP. Conclusions: HRD-HS most correctly identified HRD-PDAC however the HRDetect score classifies additional patients sensitive to cCT, especially platinum. The TDP cohort may be responsive to DNA damaging agents warranting further evaluation. Clinical trial information: NCT02750657.
Whole genome and transcriptome analysis and the link between insulin receptor aberration and diabetes in PDAC.
Authors: Lee Michael , Topham James T. , Kalloger Steve , Mendis Shehara Ramyalini , Tsang Erica S. , Karasinska Joanna , Loree Jonathan M. , Schaeffer David F. , Renouf Daniel John
Published: February 2020

743

Background: Pancreatic ductal adenocarcinoma’s (PDAC) association with diabetes development remains poorly understood. The insulin receptor ( INSR) can divert insulin signaling from metabolic to oncogenic pathway activation through alternative splicing of INSR in several cancer types. Methods: 54 treatment naïve patients with metastatic PDAC underwent fresh tumour biopsy in the BC Cancer Personalized Oncogenomics (POG) and PanGen studies (NCT02155621, NCT02869802) for whole genome (WGA) and transcriptome analysis (RNASeq). Copy status and expression of INSR were correlated with T2DM status, Moffitt subtypes, and overall survival (OS). The findings were then correlated with 92 resected PDAC from the International Cancer Genome Consortium (ICGC). Results: 13/54 (24%) had confirmed T2DM at enrollment, and had poorer OS compared to non-diabetic PDAC patients, independent of Moffitt subtype, HR 3.2 (1.5-6.5), p =0.001. Diabetics were more likely to have hypertension (64 v 11%, p <0.001), dyslipidemia (57 v 16%, p=0.013), and to be older (61.5 v 58 years, p=0.014) and smokers (71.4 v 21.6%, p=0.015). WGA revealed significant enrichment of heterozygous INSR copy loss in T2DM (69%) compared to all other patients (24%; p=0.03) and an enrichment of INSR copy loss for metastatic PDAC relative to resected PDAC in ICGC (35 v 18%, p=0.03). Heterozygous INSR copy loss (n = 17/54) was an independent predictor of worse OS (10.8 v 15.1 months, HR 2.29 (1.20-4.36), p=0.012), and it interacted with diabetes status (p=0.023). Moffitt basal (vs. classical) subtype (n = 17/54, of which 8/17 have INSR copy loss) was also an independent predictor of OS with HR 4.3 (2.1-8.7), p<0.001. Whilst there was no interaction between INSR status and Moffitt subtype on OS (p=0.727), INSR expression is lower in basal subtype, p<0.001. Conclusions: Presence of T2DM in our cohort is an independent predictor of worse OS, consistent with published literature. Alteration in the insulin signalling pathway with heterozygous copy loss of INSR was associated with poorer prognosis, diabetes development and overlapped with Moffitt basal subtype.
Noninvasive comprehensive genomic profiling from plasma ctDNA in pancreatic cancer patients.
Authors: Bitterman Danielle Sara , Price Kristin Sedgwick , Van Seventer Emily E. , Clark Jeffrey William , Allen Jill N. , Blaszkowsky Lawrence Scott , Ryan David P. , Eyler Christine Elissa , Wo Jennifer Yon-Li , Hong Theodore S. , Nipp Ryan David , Roeland Eric , Murphy Janet E. , Corcoran Ryan Bruce , Weekes Colin D. , Parikh Aparna Raj
Published: February 2020

753

Background: The use of comprehensive genomic profiling (CGP) is increasing in pancreatic ductal adenocarcinoma (PDAC) as knowledge improves regarding molecular drivers of tumorigenesis and effective targeted therapies emerge. However, adequate tissue sampling is often limited. Plasma-based CGP offers a non-invasive approach to assess biomarkers that may impact treatment decisions. Methods: We retrospectively evaluated genomic and clinical data from 97 PDAC patients with circulating tumor DNA (ctDNA) testing from 9/2016-8/2019 (Guardant Health, Inc.). ctDNA analysis included single nucleotide variants (SNV), fusions, indels and copy number variations (CNV) of up to 74 genes. ctDNA results were assessed across clinical variables. We evaluated for actionable alterations. Results: A total of 114 samples were obtained from 97 patients for ctDNA testing. ctDNA alterations were detected in 82% (93/114) of all samples, including 90% (18/20) at diagnosis, 88% (59/67) at progression, and 56% (10/18) while on stable therapy. ctDNA alterations were found at each stage of PDAC: in 25% (1/4) of samples with resectable disease, 75% (3/4) with borderline resectable disease, 82% (9/11) with locally advanced disease, and 85% (81/95) with metastatic disease. One or more KRAS alterations were detected in 55% (51/93) of patients with alterations present. The median maximum mutant allele frequency was similar between the cohort of patients with KRAS detected (0.55%) versus not detected (0.70%). 8% (8/97) of patients had potentially actionable alterations (2 activating BRAF SNVs, 1 ERBB2 CNV, 1 ERBB2 activating SNV, 1 KRAS G12C, and 3 indels in Homologous Recombination Deficiency genes). Median turnaround time was 8 days. 51% (49/97) of patients had both plasma-based CGP and tissue-based CGP. Of these patients, tissue-based CGP showed ≥ 1 alterations detected in 82% (40/49), test failure in 14% (7/49), and no alterations detected in 4% (2/49). Conclusions: Plasma-based CGP detected ctDNA alterations in 90% of samples tested at diagnosis and 82% of all samples. Potentially actionable mutations were found in 8% of patients, with prompt processing time allowing for rapid decision making.
Patterns of failure after adjuvant stereotactic body radiation therapy in patients with pancreatic cancer with close or positive margins.
Authors: Patel Ankur , Rodríguez-López Joshua L. , Bahary Nathan , Zureikat Amer H. , Burton Steven A. , Heron Dwight Earl , Olson Adam C.
Published: February 2020

755

Background: There is no consensus on treatment volumes for stereotactic body radiation (SBRT) in patients with pancreatic cancer (PCa). Herein, we report patterns of failure following adjuvant SBRT for close/positive margins in patients with pancreatic cancer, which may inform appropriate target volume design for SBRT. Methods: An IRB-approved retrospective review of patients with PCa treated with adjuvant SBRT for close/positive margins from 2009-2018 was conducted. Patterns of failure were assessed by review of imaging and were defined as local (LF), regional (RF), local and regional (LRF), or distant (DF). The Kaplan-Meier method was used to calculate long-term failure rates. In-field failures were defined as LFs completely within the PTV (planning target volume). The location of LFs was compared to the RTOG consensus volumes for adjuvant treatment of PCa to determine if conventional radiation volumes would have included the LF. Results: Seventy-six patients were treated with adjuvant SBRT for close (51.3%) or positive (48.7%) margins, with a median follow-up of 17.0 months (interquartile range [IQR] 7.4-28.3 mos.). Adjuvant SBRT was delivered at a median of 2.2 months after surgery (IQR 1.7-3.0 mos.). Most patients (81.6%) received 36 Gy in 3 fractions. The median PTV volume was 17.8 cc (IQR 12.3-25.2 cc). Upon examination of first failure sites, crude rates of isolated LF, isolated RF, isolated LRF, and DF +/- LF or RF were 9.2%, 6.6%, 2.6%, and 56.6% respectively; 2-year rates were 12.4%, 11.5%, 7.0%, and 66.5%, respectively. Thirty-two patients (42.1%) developed a LF at some point during follow-up. Of 28 LFs with available plans and imaging, 21.4% were in-field failures, while the remainder were completely outside (60.1%) or partially outside (17.9%) the PTV. Most LFs outside the PTV (90.9%) would have been encompassed by the RTOG consensus target volumes for postoperative conventional radiation. Conclusions: In patients with PCa who receive adjuvant SBRT for close/positive margins, the majority of LFs are outside the PTV. Future trials involving SBRT or hypofractionated radiation should consider expansion of treatment volumes if feasible.
PD-L1 expression, tumor mutational burden, and microsatellite instability status in 746 pancreas ductal adenocarcinomas.
Authors: Hemmerich Amanda , Edgerly Claire I. , Duncan Daniel , Huang Richard , Danziger Natalie , Frampton Garrett M. , Elvin Julia Andrea , Vergilio Jo-Anne , Killian Jonathan Keith , Lin Douglas I. , Williams Erik , Ali Siraj Mahamed , Reddy Prasanth , Miller Vincent A. , Owens Clarence , Brown Charlotte , Alexander Brian M , Ross Jeffrey S. , Severson Eric Allan , Ramkissoon Shakti H.
Published: February 2020

757

Background: Pancreas ductal adenocarcinomas (PDA) has a 5-year survival rate of 6% with a need for new therapeutic options. The approval of pembrolizumab for some gastrointestinal cancers shows the potential of immunotherapy (IMT) in PDA. We evaluated the IMT-associated biomarkers of PD-L1 expression, tumor mutational burden (TMB), microsatellite instability (MSI) and PD-L1 amplification in PDAs. Methods: 746 formalin-fixed paraffin embedded samples were evaluated for PD-L1 IHC using the Dako 22C3 pharmDx assay and scored using tumor proportion score (TPS). The cases had comprehensive genomic profiling (CGP) via DNA sequencing, using a hybrid-capture next-generation sequencing assay (FoundationOne and FoundationOneCDx) for genomic alterations (GAs), TMB, and MSI. Results: PD-L1 was positive (TPS ≥ 1%) in 29% (214/746) and negative in 71% (532/746). 43/214 (20%) of positive cases were high positive (TPS ≥ 50%). TMB (590 cases) had a mean of 3.20, 3.46, and 3.61 mutations/Mb for PD-L1 negative, positive, and high positive groups. 3 hypermutated (TMB ≥ 20) were negative for PD-L1 expression. 3/581 cases were MSI-high with a high TMB score (average 23.53 mutations/Mb). 2 MSI-high cases were negative for PD-L1 and 1 was high positive. PD-L1 amplification was not detected (0/746). Only BCOR was significantly different between PD-L1 high positive and PD-L1 negative tumors (Table). Conclusions: Of 729 PDA cases, 29% were positive (TPS ≥ 1%) for PD-L1 expression while only 6% of all cases showed a high level of PD-L1 expression on tumor cells. TMB high (3/729) and MSI-High (3/729) cases were rare. Only 2 of the TMB high cases were also MSI-high. PD-L1 amplification was not detected. Comparing GAs in PD-L1 high positive vs negative cases was only significantly different for BCOR. Further investigation is needed to see if a combined positive score of PD-L1 expression may identify a subset of patients with PDA who are more likely to respond to IMT. [Table: see text]
Utilization of somatic comprehensive genomic profiling (CGP) to identify patients (pts) with pancreatic cancer (PC) that harbor germline DNA damage repair (DDR) gene alterations.
Authors: Lasowski Matthew , Stachowiak Samantha , Arapi Igli , Dua Kulwinder , Khan Abdul H. , Hall William Adrian , Erickson Beth , Tsai Susan , Christians Kathleen K. , Evans Douglas B. , Urrutia Raul , Ritch Paul S. , Kamgar Mandana , Thomas James P. , George Ben
Published: February 2020

760

Background: Somatic and germline DDR gene alterations in PC have been postulated to positively predict response to DNA damaging cytotoxic agents. Due to the relatively high prevalence of germline DDR gene alterations, germline testing is recommended in all pts with PC. We examined whether somatic CGP can be used to reliably identify PC pts that merit germline testing. Methods: We retrospectively reviewed the electronic medical records of PC pts who underwent both somatic CGP (utilizing the Foundation One assay) and germline testing. DDR gene mutations were categorized as somatic-pathogenic, somatic-variant of uncertain significance (VUS), germline-pathogenic and germline-VUS. For somatic testing, DNA was extracted from formalin fixed paraffin embedded (FFPE) clinical specimens and CGP was done on hybrid-capture, adaptor ligation based libraries to a mean coverage depth of > 600 for up to 315 genes plus 47 introns from 19 genes frequently rearranged in cancer. Germline genetic testing was performed on submitted blood or saliva samples, utilizing commercial assays; next generation or Sanger sequencing of all coding regions and adjacent intronic nucleotides were performed. Results: Ninety-three pts had somatic CGP data, 51 (55%) pts had both somatic CGP and germline data available. Among the 51 pts with both germline and somatic data available, DDR gene alterations that were somatic-pathogenic, germline-pathogenic, somatic-VUS and germline-VUS were present in 7 (13.7%), 7 (13.7%), 23 (45.1%) and 16 (31.4%) pts, respectively. Of the 7 pts with somatic-pathogenic alterations, 5 (71%) had a concordant germline alteration and of the 7 pts with germline-pathogenic alterations, 5 (71%) had a concordant somatic alteration. Of the 23 pts with somatic-VUSs, 12 (52%) had a concordant germline VUS and of the 16 pts with germline-VUSs, 12 (75%) had a concordant somatic VUS. Conclusions: Both somatic and germline DDR gene alterations are common in PC pts. Despite the relatively high concordance rate between somatic and germline pathogenic DDR gene alterations, somatic CGP will miss approximately one fourth of the germline DDR gene alterations.
Prognostic significance of familial pancreatic cancer after surgery.
Authors: Tezuka Koji , Okamura Yukiyasu , Sugiura Teiichi , Ito Takaaki , Yamamoto Yusuke , Ashida Ryo , Ohgi Katsuhisa , Uesaka Katsuhiko
Published: February 2020

772

Background: Familial pancreatic cancer (FPC) is defined as two first-degree relatives with pancreatic cancer. It is known that the risk of developing pancreatic cancer increases in those who have a family history of pancreatic cancer in first-degree relatives. However, prognostic significance of FPC after surgery is not fully understood. Methods: Patients who underwent pancreatectomy for pancreatic ductal carcinoma between January 2008 and December 2016 were retrospectively reviewed. The prognostic significance of FPC was analyzed. Results: A total of 423 patients underwent pancreatectomy for pancreatic ductal carcinoma. FPC was identified in 32 (7.6%) patients. Recurrence occurred in 72% of all resected cases and in 88% of resected FPC cases. Multivariate analysis revealed FPC (hazard ratio [HR] 1.60; P=0.026), CA19-9 ≥300 U/ml (HR 1.54; P=0.001), lymph node metastasis (HR 2.10; P<0.001), microscopic venous invasion (HR 1.64; P<0.001), nerve plexus invasion (HR 1.39; P=0.010), R1 resection (HR 1.65; P=0.010), and lack of adjuvant chemotherapy (HR 2.27; P<0.001) as independent predictors for recurrence-free survival (RFS). The univariate analysis revealed that FPC is significantly associated with worse overall survival (OS) (P=0.018). The multivariate analysis showed that FPC was not an independent predictor of OS. This cohort was divided into 314 patients (FPC: 18 patients, non-FPC: 296 patients) who received adjuvant chemotherapy (AC group) and 109 patients (FPC: 14 patients, non-FPC: 95 patients) received no adjuvant chemotherapy (no AC group). In AC group, FPC is an independent predictor for RFS (HR 3.03; P<0.001) and OS (HR 2.23; P=0.018). In no AC group, FPC is not a predictor for RFS and OS. Conclusions: This study may show that FPC has a significant impact on RFS and OS after resection in patients who received adjuvant chemotherapy.
Radiotherapy use in the treatment of gastrointestinal cancers in Medicare patients: An analysis of a CMS database.
Authors: Konski Andre A. , Havrilesky Laura Jean , Jewell Elizabeth Lin , Efstathiou Jason A.
Published: February 2020

800

Background: CMS announced plans to pilot an alternative payment model (APM) utilizing a fixed payment per ICD-10 code for 17 malignancies. CMS released payment data used to calculate the base payments. The purpose of this study was to analyze radiotherapy use in patients with gastrointestinal malignancies to obtain baseline utilization and payment prior to the APM start. Methods: The CMS database, CY2015-2017, contained payment, anatomic site and limited patient data on 517,988 patients, 48,032 of which were identified as gastrointestinal (GI) cancers, (Anal (A) Colorectal (CR), Pancreatic (P), Upper GI (UGI), or Liver(L) cancers) all histologies included. Stata 15, College Station, Texas, was used to perform all statistical analysis. Payments were calculated using only CPT codes for radiotherapy and only include the first 90 days after a treatment planning charge was registered. Results: Anatomic site breakdown was 4940 A, 16,099 CR, 6,970 P, 14,750 UGI and 5,273 L cancers. Patient treatments by year were15,697 in 2015, 16,309 in 2016 and 16,026 in 2017. Use of proton therapy and IMRT increased from 2015-2017 (193 (1.2%) to 302 (1.9%) and 8,107(52%) to 8838 (55%), respectively) whereas use of conventional external beam decreased from 6544 (42%) in 2015 to 5377(34%) in 2017. Of interest, 10,336 (668 A, 3363 CR, 2847 L, 1083 P, and 2375 UGI) of the 48,032 patients receiving radiotherapy were coded as not receiving chemotherapy. Mean professional and technical payments were $28,380.97 (SD $6779.18) for proton beam therapy, $18,186.77 (SD $4534.3) for IMRT, $10,724.88 ($4797.19) for conventional external beam therapy, $13,967.66 (SD $5186.92) for stereotactic, and $19,707 (SD$7393.81) for brachytherapy. Results by anatomic site will be presented. Conclusions: This study provides a baseline for comparison for treatment technique and payment once the APM has been completed. These claims are limited by the lack of available information on specific age, stage or other co-morbidities. Use of proton beam therapy has increased in this population, but remains a small percentage of radiotherapy technique used. 25% of patients receiving radiotherapy were not coded as receiving chemotherapy.
Relevance of real-time teletransmission of physical activity, sleep, and circadian rhythms from gastrointestinal cancer (GIC) patients (pts) during daily routine (IDEAs, IRAS 233972).
Authors: Levi Francis , Komarzynski Sandra , Huang Qi , Young Teresa , Ang Yeng , Fuller Claire , Brettschneider Julia , Finkenstadt-Rand Barbel , Fursse Joanna , White David-Pollard , Innominato Pasquale
Published: February 2020

801

Background: The relative amount of activity and rest over the 24-hours, as measured by the dichotomy index I < O from actimetry records, is an independent predictor of overall survival and quality of life, and an early warning signal for emergency hospitalisation. The IDEAs study aimed to determine the sleep, physical and circadian pathologies in pts during their daily routine at home, which could lower I < O and be modifiable through personalised interventions. Methods: The rest-activity and surface temperature patterns were monitored in real time using a tele-transmitting chest sensor and a GPRS-platform for one week in 25 pts, with a WHO performance status of 0-1 and metastatic GIC (colorectal, 56%). Each pt completed questionnaires including Chronotype, HADS, and Pittsburgh Sleep Index, filled a precise diary of daily activities, meals and sleep times, and the MD Anderson Symptoms Inventory daily. I < O counts the In-bed activity bouts per min that are below the median activity Out-of-bed. Other pt-specific circadian parameters were estimated with spectral analyses and Hidden Markov models (HMM). I < O predictors were identified through correlation and regression analyses. Results: A poor I < O was found for 13 pts (52%). Self-reported scores for sleep quality or physical fitness showed no significant differences according to I < O. Yet HMM-modelled rest-activity revealed that pts with poor I < O had lower activity out-of-bed (median activity counts per minute, 110 vs 52, p = 0.001) and fractionated sleep (probability of remaining at rest when asleep, 94% vs 90%, p = 0.01). Poor I < O was significantly associated with an abnormal circadian rhythm in chest surface temperature, that was either wrongly timed or suppressed, for 83% of the pts as compared to 25% of those with a good I < O (p = 0.012). Conclusions: Nearly half of the pts displayed altered circadian rest-activity rhythm, with poor sleep and low daytime activity. In most of them, the circadian rhythm in body temperature, which critically regulates sleep, was abnormal. Exploration and specific treatment of sleep and circadian disorders are warranted for improving outcomes in cancer pts. Clinical trial information: 233972.
Family history (FH) of gastrointestinal (GI) cancer and behavioral risks: Analysis of an Internet-based risk assessment tool.
Authors: O'Keefe Ryan M. , Lariviere Michael Joseph , Amaniera Isabella , Vachani Carolyn , Hampshire Margaret K. , Bach Christina , Arnold-Korzeniowski Karen , Metz James M. , Hill-Kayser Christine E.
Published: February 2020

807

Background: Certain behaviors are known modifiable risk factors for development of GI cancers. The relationship between family history (FH) of GI cancers and individuals’ behaviors is not well understood, but is important for risk assessment/ counseling. Methods: The OncoLink “Reduce My Risk” tool is a publicly available online survey created in 2009 to provide customized information regarding cancer risk. Details of this survey have been reported; research is IRB-approved. Differences between those with v. without FH of GI cancers were analyzed using chi-square test. Results: 28,001 surveys were submitted. Median age was 26y (18-101), 60% female, 87% lived in North America, 76% White/Non-Hispanic, 64% reported FH of cancer. Individuals with FH of CRC reported eating less red meat (31% v. 34%, p = 0.007), processed grains (55% v. 59%, p < 0.001), or charred meats (14% v. 19%, p < 0.001), but were equally likely to be vegetarian (9% v. 10%, p = 0.059). Those with FH of esophageal cancer were more likely to have GERD (16% v. 9%), smoke > = 1 pack per day (7% vs. 4%) and drink alcohol (63% v. 55%) (p < 0.001 for all). Those with FH of gastric cancer were more likely to have H. Pylori or gastric ulcers (5% v. 3%, p < 0.001), but no difference in the consumption of smoked/salted foods (27% v. 25%, p = 0.20). Those with FH of HCC reported no differences in alcohol consumption (56% v. 55%, p = 0.41) or hepatitis B virus (HBV) vaccination (62% v. 62%, p = 0.66). Those with FH of anal cancer were more likely to have receptive anal intercourse (26% v. 16%, p < 0.001) but showed no differences in human papillomavirus (HPV) vaccination (21% v. 22%, p = 0.91). Those with FH of HCC (15% v. 13%, p = 0.035), gastric (16% v. 13%, p = 0.001), esophageal (17% v. 13%, p < 0.001), and anal (21% vs. 13%, p < 0.001) cancers were more likely to be smokers; those with a FH of CRC were less likely (11% v. 13%, p = 0.006), and those with FH of pancreatic (12% vs. 13%, p = 0.71) or cholangiocarcinoma (15% vs. 13%, p = 0.59) showed no difference. Conclusions: Many individuals with a FH of GI cancers engage in behavioral and other modifiable risk factors that increase risk for GI and other cancers. Future work should explore utility of targeted intervention and screening.
Gaps in caregiving for young-onset colorectal cancer patients.
Authors: Newcomer Kim Lynn , Yarden Ronit , Peterson Danielle ,   Never Too Young Advisory Board
Published: February 2020

82

Background: The rise of young-onset colorectal cancer (YO-CRC) is an alarming public health issue. Interestingly, the proportion of new cases diagnosed in young people (20-49) had increased from 6% in 1990 to 11% in 2013 and coincides with the declining CRC cases in older people. YO-CRC patients face unique clinical challenges as many are diagnosed at advanced stages of the disease and subjected to aggressive treatments. In addition, diagnosis often disrupts early family and career developmental tasks and goals, suggesting the need for additional psychosocial support. Caregivers are an important part of the patient journey. Caregivers serve as liaisons with the medical community and the patient’s social network. The goal of this study is to cast light and explore the experience of caregivers who were caring for YO-CRC patients. Methods: The online survey was completed by 208 caregivers, diverse in age, gender, and race/ethnicity. Participants indicated their relationship as either: spouse/partner, parents, siblings, children, and non-family members. Results: Caregivers self-report they do not understand the important aspects of patients' medical needs despite 79% of caregivers are college graduates and 43% had an advanced degree. Most of the respondents (76%) lack understanding about treatment options and 56% did not feel confident they understood healthcare decisions. Overall, caregivers needed more information and guidance for managing the side-effects of treatment, A majority of caregivers (93%) reported fatigue due to lack of sleep and 63% reporting they missed eight hours or more of work each month. Participants (73%) reported they needed help for panic and anxiety and employed different coping mechanisms to deal with the toll of caregiving. Conclusions: Our survey indicates we must recognize caregivers as the patient's healthcare partners and engage them in the entire plan of care. A growing population of YO-CRC patients means a growing population of caregivers who are navigating work, parenthood, impacts on sexual health, and role changes right along with that patient. Such understanding could help in developing appropriate interventions for caregivers aimed at reducing their burden and stress in caring for patients with YO-CRC.
Phase Ib trial of pembrolizumab and XL888 in patients with advanced gastrointestinal malignancies: Results of the dose-escalation phase.
Authors: Akce Mehmet , Alese Olatunji B. , Shaib Walid Labib , Wu Christina , Lesinski Gregory B. , El-Rayes Bassel F.
Published: February 2020

830

Background: XL888 is a selective inhibitor of heat shock protein 90 (HSP90). It modulates several oncogenic signaling pathways, and the tumor microenvironment. In preclinical models, XL888 potentiates efficacy of PD-1 inhibition. We report the results of the dose escalation (DE) portion of a phase Ib trial of combined XL888 and pembrolizumab (P) in advanced gastrointestinal adenocarcinomas. Methods: XL888 was administered orally (PO) in three dose levels of 45 (DL1), 90 (DL2), 60 (only if DLT on DL2) mg twice weekly with P 200 mg IV on day 1, in 21-day cycles. Eligible patients included stage IV or locally advanced unresectable gastrointestinal adenocarcinomas with at least one prior therapy (patients with colorectal (CRC) adenocarcinoma must have received oxaliplatin, irinotecan, and fluoropyrimidine), age ≥18 years, ECOG PS 0-1, adequate organ function, no prior anti-PD-1 or anti-PD-L1 agent. The primary endpoint was recommended phase II dose (RP2D), while secondary endpoints included safety and tolerability. Pre-treatment and on-treatment correlative peripheral blood specimens were collected. Results: A total of 14 patients were enrolled in the DE phase. 9 male, median age 66.5. Diagnoses included CRC (6), pancreatic adenocarcinoma (5), biliary tract cancer (1), ampullary (1), and duodenal (1). Two patients were ineligible for assessing the primary endpoint (DL2) due to biliary stent obstruction and sepsis. One DLT (grade 3 autoimmune hepatitis) was observed on DL2. We enrolled three patients on DL3. Five additional patients were subsequently enrolled on DL2 with no additional DLT. Three patients (1 duodenal, 2 CRC) had prolonged stable disease (6, 9 and 15 cycles). The most common treatment-related toxicities included autoimmune hepatitis (G3; n = 1), retinopathy (G2; n = 2), nausea (G2; n = 1), constipation (G2; n = 1), and diarrhea (G2; n = 3). Conclusions: The XL888 and pembrolizumab combination had an acceptable safety profile and the RP2D of XL888 was 90 mg twice weekly combined with P 200 mg, every 3 weeks. The dose expansion portion and a robust series of immunologic correlative laboratory studies for this study is ongoing. Clinical trial information: NCT03095781.
Splenomegaly during oxaliplatin-based chemotherapy in colon cancer.
Authors: Ji Ruoyu , Huang Guanghua , Liu Lingshan , Chen Mengyin , Yu Xiaoduo , Zhou Aiping , Du Chun-Xia
Published: February 2020

88

Background: Splenic enlargement has been reported in patients treated with oxaliplatin. However, the characteristics of oxaliplatin-induced splenomegaly were not well studied. Here we evaluated the change of splenic volume and its clinical significance in patients treated by oxaliplatin-based regimen. Methods: Patients with stage II-IV primary colon cancer treated with oxaliplatin and capecitabine in China National Cancer Center from January 2016 to December 2017 were screened for this retrospective study. Those with complete laboratory tests and computed tomographic data before, during and up to 1.5 years after the chemotherapy were selected. The splenic size was measured by AWVolumeshare5. Splenomegaly was defined as an over 30% increase of splenic size from baseline. Recovery of splenomegaly was defined as the splenic size fell back to a 0.9 to1.1-fold range of baseline. Results: Out of a total of 144 patients, 102 (70.8%) had over 30% increase, 72 (50.0%) had over 50% increase, and 22 (15.3%) had over 100% increase in splenic size after oxaliplatin-based regimen. Among the 102 splenomegaly patients, 5 (4.9%) develop splenomegaly within 3 chemotherapy cycles, 53 (53.0%) within 6 cycles, 73 (71.6%) within 9 cycles, and 102 (100.0%) within 3 months after the last administration of oxaliplatin. Compared to the group without splenomegaly, patients with splenomegaly received more cycles of oxaliplatin administrations (median 8 vs 6, p < 0.001) and greater dose intensity (total dose per square meter) (median 822.8mg/m2 vs 629.3mg/m2, p < 0.001). Patients with splenomegaly had higher incidence of thrombocytopenia (61.7% vs 38.1%, p = 0.009) and are more likely to undergo oxaliplatin dose reduction due to thrombocytopenia (21.6% vs 7.1%, p = 0.038). The recovery rates of splenic size within 0.5, 1 and 1.5 years after the end of oxaliplatin treatment were 23.2%, 50.6% and 74.3%, respectively. Conclusions: Splenomegaly are common in patients treated with oxaliplatin-based chemotherapy, and most would recover in 1.5 years after completion of therapy. Patients with splenomegaly are prone to experience thrombocytopenia and oxaliplatin dose reduction. Further studies are needed to reveal the mechanism how oxaliplatin induce splenomegaly.
Prospective DPYD testing and dose adjustment in colorectal cancer patients prior to fluoropyrimidine-based chemotherapy: Experience in a regional cancer center.
Authors: Graham Janet Shirley , Saunders Jocelyn , Naylor Gregory , Crearie Christine , Campbell Wendy , Abdullah Tareq , Dunn Mary G. , MacLeod Nicholas James , McDonald Alec , McGaffin Gillian , McKillop Anne Jane , Miller Laura , Mohammed Nazia , Othman Aqilah , Radford Liz , Smith Karen , Storey Dawn Jane , Williams Nicola , Westwood Paul , Wilson Richard H.
Published: February 2020

93

Background: The fluoropyrimidines (FP), 5-Fluorouracil (5-FU) and capecitabine are a mainstay of colorectal cancer (CRC) treatment. Dihydropyrimidine dehydrogenase (DPYD), an enzyme encoded by the DPYD gene, is the initial and rate-limiting step in pyrimidine catabolism, deactivating over 80% of 5-FU. Approximately 5% of the population are deficient in DPYD and can develop severe or fatal FP toxicities. Currently, few national guidelines recommend routine prospective DPYD testing. In July 2019, we commenced a 6 month prospective pilot, testing DPYD status of all CRC patients undergoing first FP treatment in a large regional cancer centre. Methods: All CRC patients eligible for first exposure to FP are tested using a rapid molecular assay screening for five SNPs (detects 70% of DPYD mutations) and we will present data on prevalence of each. We will use electronic chemotherapy prescribing records (July 19-Jan 20) to collect information on dose modifications and toxicities. Once the pilot is completed we will perform a cost-effectiveness analysis. Results: Data from the first 3 months of this pilot have been reviewed and 201 patients have been tested with 15 heterozygotes identified, of which 2 had more than one mutation. No homozygotes were found. All heterozygote patients are started with a dose reduction (or have alternative therapy). One patient treated at 50% dose was hospitalised with several grade 3 toxicities despite dose reduction. Two patients have had subsequent dose escalation (by 25%). Nine patients have received one dose reduced cycle without complication. Three patients are due to start dose-reduced treatment. Conclusions: Routine prospective testing of DPYD status in a large regional cancer centre is feasible and with a sufficiently swift result turnaround to permit up-front dose modification. Detailed toxicity analysis and cost-effectiveness data will be presented.
Randomized phase II trial of CAPOX with continuous versus intermittent use of oxaliplatin as an adjuvant chemotherapy after curative resection of stage II/III colon cancer (CCOG-1302 study).
Authors: Nakamura Masanori , Nakayama Goro , Ishigure Kiyoshi , Mashita Naoki , Yokoyama Hiroyuki , Hattori Norifumi , Uehara Keisuke , Yamada Suguru , Koike Masahiko , Kodera Yasuhiro
Published: February 2020

95

Background: The aim of this study was to evaluate the efficacy and safety of CAPOX with intermittent use of oxaliplatin compared to continuous use of oxaliplatin as an adjuvant setting for colon cancer. Methods: Patients with curative resection of stage II or III colon cancer were randomly assigned to receive either CAPOX with continuous use of oxaliplatin (continuous arm: 8 cycles of CAPOX) or CAPOX with intermittent use of oxaliplatin (intermittent arm: 2 cycles of CAPOX→4 cycles of capecitabine→2 cycles of CAPOX). The primary endpoints were frequency of disease-free survival (DFS) rate at 3-year after surgery and peripheral sensory neuropathy (PSN) at 1-year after surgery. The secondary end points included DFS, overall survival (OS), compliance and safety. Results: A total of 200 patients were enrolled. The intent-to-treat and safety population comprised 100 and 99 patients in the continuous arm, and 100 and 98 patients in the intermittent arm, respectively. After a median follow-up period of 39 months, disease recurrence and death occurred in 37 patients (19%) and 8 patients (4%) in the ITT population, respectively. The 3-year DFS was 78% (95% CI, 70-87%) in the continuous arm and 82% (95% CI, 74-90%) in the intermittent arm (HR, 0.80; 95% CI, 0.42-1.52; p = 0.49). In the patients with stage III disease, the 3-year DFS was 76% (95% CI, 66-86%)in the continuous arm and 80% (95% CI, 71-88) in the intermittent arm(HR, 0.75; 95% CI, 0.38-1.51; p = 0.43). The frequencies of PSF at 1-year after surgery were 58% (95% CI, 48-68%) in the continuous arm and 19% (95% CI, 11-26%) in the intermittent arm (p < 0.01), and those at 3-year after surgery were 37% (95% CI, 27-47%) and 9% (3-15%), respectively (p < 0.01). Conclusions: CAPOX with planned intermittent use of oxaliplatin could be equally effective as an adjuvant setting for colon cancer, and substantially reduce long-term PSN and potential improve patient quality of life. Clinical trial information: UMIN 000012535.
A phase III study of nivolumab (NIVO), NIVO + ipilimumab (IPI), or chemotherapy (CT) for microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC): Checkmate 8HW.
Authors: Abdullaev Sandzhar , André Thierry , Lei Ming , Lenz Heinz-Josef , Novotny James , Paulson Andrew Scott , Tejpar Sabine , Yamazaki Kentaro , Ledeine Jean-Marie
Published: February 2020

TPS266

Background: Patients (pts) with MSI-H/dMMR mCRC treated with CT have poorer outcomes than pts with microsatellite stable/MMR proficient mCRC. NIVO (anti–programmed death [PD]-1) and IPI (anti–cytotoxic T lymphocyte antigen-4 [CTLA-4]) are immune checkpoint inhibitors that act synergistically and promote antitumor immune response by complementary mechanisms. NIVO±IPI received accelerated US FDA approval for MSI-H/dMMR mCRC that progressed after fluoropyrimidine, oxaliplatin, and irinotecan treatment based on the phase 2, non-randomized, multicohort CheckMate 142 study. Indirect comparisons suggest that NIVO (3 mg/kg) + low-dose IPI (1 mg/kg) provides improved clinical benefit vs NIVO (investigator-assessed [INV] objective response rate [ORR] 55% vs 31%; 12-month [mo] INV progression-free survival [PFS] rate 71% vs 50%; 12-mo overall survival [OS] rate 85% vs 73%) with a favorable benefit-risk profile for previously treated MSI-H/dMMR mCRC (Overman et al. JCO 2018). NIVO+low-dose IPI also demonstrated robust and durable clinical benefit in first-line MSI-H/dMMR mCRC (INV ORR 64%; 12-mo INV PFS rate 77%; 12-mo OS rate 84%; Lenz et al. ASCO 2019, #3521). To date, no prospective phase 3 studies have reported results for anti–PD-1, anti–PD-1 + anti–CTLA-4, or CT in MSI-H/dMMR mCRC; these treatments will be evaluated in the international, multicenter, open-label, randomized, phase 3 CheckMate 8HW (NCT04008030) study. Methods: Approximately 494 pts aged ≥18 years with histologically confirmed recurrent or mCRC, irrespective of prior treatment with CT and/or targeted agents, not amenable to surgery, and with known tumor MSI-H or dMMR status, and Eastern Cooperative Oncology Group performance status ≤1 will be randomized to receive NIVO, NIVO+IPI, or investigator’s choice CT (pts in the CT arm can receive NIVO+IPI upon progression). The primary endpoint is PFS, assessed by blinded independent central review (BICR). Secondary endpoints include PFS by INV, ORR and disease control rate by BICR and INV, OS, time to and duration of response. Exploratory endpoints include safety. Clinical trial information: NCT04008030.