Role of Surgery in Locally Advanced Disease Following Neoadjuvant - - PowerPoint PPT Presentation

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Role of Surgery in Locally Advanced Disease Following Neoadjuvant - - PowerPoint PPT Presentation

Sep 03, 2022 38 likes •315 views

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,

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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

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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
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  • 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

Case presentation: Dr. S

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SMA SMV T

R2 likely “Unresectable”

SMA SMV T SMA SMV T

R0 likely “Resectable” R1 likely “Borderline”

Potential for R0 resection can be predicted on basis of relationship between the tumor and mesenteric vasculature

Spectrum of resectability

Katz, Cancer 2012

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CTX S OR

Multimodality therapy for PDAC

Four primary components

Varadhachary, Ann Surg Onc 2006 Katz, JACS 2008

XRT S S R 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
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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

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Should I operate?

He’s so young! He’s a surgical resident! He’s a VIP! He’s my neighbor’s cousin! He’s a super nice guy!

LET’S GIVE THIS PATIENT THE BENEFIT OF THE DOUBT!!!

He’s been through a lot and his disease is stable! The tumor must be dead! What other option is there? This is his chance for cure! That will come out!

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Winter, JOGS 2006

After decades of refinement by some of the world’s best surgeons, median OS ~ 2 years

Unequivocal Failure: ~25% “Cure (?)”: ~20% Improvement in survival following pancreatectomy at The Johns Hopkins Hospital

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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!
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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

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Is this outcome surprising? Should it be?

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Bailey, Nature 2016

RNA expression analysis demonstrates heterogeneity: some are inherently more aggressive

RNA expression analysis 4 major subtypes

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Rhim, Cell 2012

EMT, invasion of basement membrane, hematogenous spread, seeding of liver may precede formation of invasive cancer!

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Katz, JOGS 2010 Bapat, Nature Reviews Cancer 2011

Cancer cells infiltrate through the retroperitoneum - Neurotropic

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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

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66 y/o Vein + splenorenal shunt 73 y/o Vein + hepatic artery 66 y/o Vein + celiac trunk

These are potentially morbid operations

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

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High Delta Low Delta

Koay, Clin Cancer Res 2018

Radiographic interface between tumor and parenchyma

Non-invasive interrogation of tumor biology

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Survival following resection Mutational landscape Metastatic Potential

Koay, Clin Cancer Res 2018

High delta tumors: radiomic signature of aggressive biology and poor prognosis

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Response can be measured pathologically… but not in real time

Median Survival: 73.4 vs 32.2 months

P<0.0001

Cloyd, JAMA Surgery, 2017

583 patients who received preoperative therapy 1990 - 2015

Major PR = 13.2% pCR = 3.9%

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RECIST of 122 patients restaged following preoperative therapy RECIST Example N Resected n Stable Disease 84 (69%) 70 (83%) Partial Response 15 (12%) 15 (100%) Progressive Disease (Local) 2 (2%) 0 (0%)

21 (17%) progressive disease due to metastases, 0 resected

v v

+6 +6%

v v

  • 38%

38%

v

+22% 22%

Perri, Unpublished Katz, Cancer 2012

Major PR rate: RECIST SD: 5.5% RECIST PR: 27%

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Amer, Cancer 2018

  • Retrospective study showing prognostic significance in 4 cohorts
  • Prospective validation in MDACC borderline trial
  • Ongoing validation in Alliance A021501

Novel radiomic signatures of response

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Perri, unpublished Tzeng, HPB 2014 Katz, Ann Surg Onc 2010

Preop CA 19-9 is a signal of response

Although major PR rate 15% (~base rate)

Stratified by resection status and preop CA 19-9

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Bernard, Gastroenterology 2019

Novel serologic measures of response

Complementary with CA 19-9

Fraction of mutant kras in exosome DNA increases in progressors and decreases in nonprogressors

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Should we operate?

  • Locally advanced after tx
  • “Low delta” tumor
  • RECIST PR
  • Type I radiomic response
  • CA 19-9 level normalized
  • MAF exoDNA decreased

Maybe for both – but one scenario is probably better than the other

  • Locally advanced after tx
  • “High delta” tumor
  • RECIST SD
  • Type II radiomic response
  • CA 19-9 level abnormal
  • MAF exoDNA increased
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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

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Pancreatic Tumor Study Group UT MD Anderson Cancer Center Thank you!

Surgical Oncology Matthew HG Katz Jeffrey E Lee Michael Kim Ching-Wei Tzeng Naru Ikoma Medical Oncology Robert Wolff Gauri Varadhachary Milind Javle David Fogelman Michael Overman Shubham Pant Florencia McAllister Christine Parseghian Radiation Oncology Joseph Herman Prajnan Das Sunil Krishnan Eugene Koay Cullen Tanaguchi Emma Holliday GI Endoscopy Jeffrey H Lee Manoop Bhutani Brian Weston Bill Ross Emmanuel Coronel Philip Ge Radiology Eric Tamm Priya Bhosale Ott Le Pathology Anirban Maitra Huamin Wang Melissa Taggart Susan Abraham Jeannelyn Estrella Tim Foo Dipen Maru Dongfeng Tang

mhgkatz@mdanderson.org