Role of Surgery in Locally Advanced Disease Following Neoadjuvant Therapy Matthew HG Katz, MD Chief, Pancreatic Surgery Service Vice Chair for Research Department of Surgical Oncology UT MD Anderson Cancer Center ISGIO, Arlington VA, October 10, 2019
Objectives • Understand limitations of surgery in setting of locally advanced PDAC • Recognize existing and potential markers of biology and response • Begin to understand indications for surgery
Case presentation: Dr. S • 35 year old surgical resident, engaged to be married • Abdominal pain, jaundice • CT scan • CA 19-9 19U/dl, mild elev. bilirubin • EUS-FNA: adenocarcinoma
Spectrum of resectability SMV SMV SMV SMA T SMA T T SMA R1 likely R0 likely R2 likely “ Resectable” “ Borderline ” “Unresectable” Potential for R0 resection can be predicted on basis of relationship between the tumor and mesenteric vasculature Katz, Cancer 2012
Multimodality therapy for PDAC Four primary components CTX XRT S OR R S S NR • CTX: Destroy systemic cancer cells and improve systemic control • XRT: Sterilize regional tissues and improve local control • Surgery: Remove primary tumor and improve local control • Time: Select tumors and patients to maximize chance for cure Varadhachary, Ann Surg Onc 2006 Katz, JACS 2008
Case presentation: Dr. S • ERCP, endobiliary stent • FOLFIRINOX x 4, FOLFIRI x 4 • Stable disease, stable CA 19-9 • SBRT 36g / 5 fx • Stable disease, stable CA 19-9 Upon completion of CTX, SBRT
Should I operate? He’s been through a lot He’s a VIP! LET’S GIVE THIS PATIENT THE He’s so young! What other option is there? and his disease is stable! He’s my neighbor’s cousin! That will come out! BENEFIT OF THE DOUBT!!! He’s a surgical resident! This is his chance for cure! The tumor must be dead! He’s a super nice guy!
Improvement in survival following pancreatectomy at The Johns Hopkins Hospital Unequivocal Failure: ~25% After decades of refinement by some of the world’s best surgeons, median OS ~ 2 years “Cure (?)”: ~20% Winter, JOGS 2006
Case presentation: Dr. S • Staging laparoscopy negative • PD, temporary mesocaval shunt, segmental resection of SMV-PV with ligation of splenic vein and IJ reconstruction (V3) • 3.5cm tumor, T3N2, 20% viable (!), R0 (?!) • Discharged quickly • High five!
Case presentation: Dr. S • Slow but steady recovery • Initiated FOLFOX • Ascites @ 5 months • LR and liver mets • PV obstruction stented • Dead: 11 months, 3 weeks PV stent, mets
Is this outcome surprising? Should it be?
RNA expression analysis 4 major subtypes RNA expression analysis demonstrates heterogeneity: some are inherently more aggressive Bailey, Nature 2016
EMT, invasion of basement membrane, hematogenous spread, seeding of liver may precede formation of invasive cancer! Rhim, Cell 2012
Cancer cells infiltrate through the retroperitoneum - Neurotropic Katz, JOGS 2010 Bapat, Nature Reviews Cancer 2011
For cure following treatment: • Inherently indolent cancer biology, AND EITHER: • Complete local and systemic response – all dead, OR • Incomplete response, but ability to remove any residual local disease with surgery and destroy any residual systemic disease with chemotherapy
These are potentially morbid operations 73 y/o 66 y/o 66 y/o Vein + hepatic artery Vein + splenorenal shunt Vein + celiac trunk And if we’re not going for cure there are better ways to improve local control and simply prolong life– and these patients already selected
Non-invasive interrogation of tumor biology High Delta Low Delta Radiographic interface between tumor and parenchyma Koay, Clin Cancer Res 2018
Mutational landscape Metastatic Potential Survival following resection High delta tumors: radiomic signature of aggressive biology and poor prognosis Koay, Clin Cancer Res 2018
Response can be measured pathologically… but not in real time 583 patients who received preoperative therapy 1990 - 2015 Major PR = 13.2% pCR = 3.9% P<0.0001 Median Survival: 73.4 vs 32.2 months Cloyd, JAMA Surgery, 2017
RECIST of 122 patients restaged following preoperative therapy Resected RECIST Example N n +6% +6 v Stable v 84 (69%) 70 (83%) Disease Major PR rate: RECIST SD: 5.5% -38% 38% v RECIST PR: 27% Partial 15 (12%) 15 (100%) v Response +22% 22% v Progressive Disease 2 (2%) 0 (0%) (Local) Perri, Unpublished 21 (17%) progressive disease due to metastases, 0 resected Katz, Cancer 2012
Novel radiomic signatures of response • Retrospective study showing prognostic significance in 4 cohorts • Prospective validation in MDACC borderline trial • Ongoing validation in Alliance A021501 Amer, Cancer 2018
Preop CA 19-9 is a signal of response Stratified by resection status and preop CA 19-9 Although major PR rate 15% (~base rate) Perri, unpublished Tzeng, HPB 2014 Katz, Ann Surg Onc 2010
Novel serologic measures of response Fraction of mutant kras in exosome DNA increases in progressors and decreases in nonprogressors Complementary with CA 19-9 Bernard, Gastroenterology 2019
Should we operate? • Locally advanced after tx • Locally advanced after tx • “Low delta” tumor • “High delta” tumor • RECIST PR • RECIST SD • Type I radiomic response • Type II radiomic response • CA 19-9 level normalized • CA 19-9 level abnormal • MAF exoDNA decreased • MAF exoDNA increased Maybe for both – but one scenario is probably better than the other
Summary • The role of surgery in locally advanced disease is currently limited • Resection should be restricted to patients likely to be cured • Blood and imaging signatures promising indicators of behavior and response • We are getting better and better at determining who will benefit from surgery following preop therapy – but we have a long way to go
Pancreatic Tumor Study Group UT MD Anderson Cancer Center Thank you! Surgical Oncology Radiation Oncology Radiology Matthew HG Katz Joseph Herman Eric Tamm Jeffrey E Lee Prajnan Das Priya Bhosale Michael Kim Sunil Krishnan Ott Le Ching-Wei Tzeng Eugene Koay Naru Ikoma Cullen Tanaguchi Pathology Emma Holliday Anirban Maitra Medical Oncology Huamin Wang Robert Wolff GI Endoscopy Melissa Taggart Gauri Varadhachary Jeffrey H Lee Susan Abraham Milind Javle Manoop Bhutani Jeannelyn Estrella David Fogelman Brian Weston Tim Foo Michael Overman Bill Ross Dipen Maru Shubham Pant Emmanuel Coronel Dongfeng Tang Florencia McAllister Philip Ge Christine Parseghian mhgkatz@mdanderson.org
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