GI Tumor Board Alan Venook George Fisher 62yo F without significant - - PDF document

3/7/2017 1

17th Multidisciplinary Management of Cancers: A Case‐based Approach

GI Tumor Board

Alan Venook Carling Ursem Emily Bergsland Carlos Corvera Mary Feng Margaret Tempero George Fisher Zach Koontz Pam Kunz Brendan Visser Yan Li Ed Kim

Case #1

• 62yo F without significant PMH presents w/RLQ abdominal pain.
• CT: asymmetric wall thickening of the cecum with enlarged pericolonic

mesenteric LAD.

• Colonoscopy: partially obstructing tumor in cecum.
• Undergoes laparoscopic right hemicolectomy.
• Surgical path: high grade adenocarcinoma, 13/19 pericolonic LN

positive, positive mesenteric LN, and positive mesenteric margin.

Case #1

• While awaiting medical oncology consultation patient develops

worsening abdominal pain

• CT a/p: interval development of markedly bulky retroperitoneal,

mesenteric and peritoneal nodal lesions or implants.

• CT chest: enlarged para‐aortic and retrocrural LAD, suspicious for

metastatic disease.

What is the next step in management?

• 1. Test KRAS exon 2/3, and MSI
• 2. Test KRAS exon 2/3, NRAS, BRAF and MSI
• 3. Start FOLFIRI + cetuximab
• 4. Start FOLFOXIRI + bevacizumab

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Retrospective analysis of the PRIME study showed that mutations in any of the following conferred a similar lack of benefit from anti‐EGFR therapy as KRAS exon 2 mutations: ‐KRAS exon 3,4 ‐NRAS exon 2,3,4

Atreya, Corcoran & Kopetz, J Clin Oncol March 2015 Comments & Controversies

In this patient with right sided colon cancer, does KRAS status change your choice of therapy?

• 1. Yes
• 2. No

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Side N (events) Median (95%CI) HR (95% CI) P Left 732 (550) 33.3 (31.4-35.7) 1.55 <.0001 Right 293 (242) 19.4 (16.7-23.6) (1.32-1.82) Side N (events) Median (95%CI) HR (95% CI) P Left 376 (270) 36.0 (32.6-40.3) 1.87 <.0001 Right 143 (121) 16.7 (13.1-19.4) (1.48-2.32)

Case #1 Continued

• Patient continues to experience abdominal pain and weight loss, but
• therwise maintains excellent performance status
• Molecular profiling shows BRAF V600E mutation and MSI‐high by IHC

*Approximately 25% of MSI‐high tumors are also BRAF mutated. *BRAF mutation is seen only in sporadic MSI‐high cases.

Office [3]1

Slide 12 Office [3]1 discuss how often these two occur at the same time int he same patient

Microsoft Office User, 1/31/2017

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What is the next step in management?

• 1. Start FOLFIRI
• 2. Start irinotecan + cetuximab + vemurafenib
• 3. Start nivolumab
• 4. Start FOLFOXIRI + bevacizumab

BRAF V600E CRC has Distinct Biology

0% 50% 100% 150% 200% 250% Increased incidence compared to BRAF wild type

P<0.05 P<0.05 P<0.05 P<0.05

Tran et al, Cancer 2011

BRAFwt BRAFm

• BRAF mutation frequency in CRC: ~8%
• Associated with microsatellite instability
• Hyper‐methylated
• Mucinous histology
• RAS wild‐type
• Patients: female, peritoneal & lymph

node metastases

TRIBE

• Phase III RCT of FOLFIRI +

bevacizumab vs FOLFOXIRI + bevacizumab

• At a median of 48 months of

follow up, median OS was 25.8mo w/FOLFIRI + bev vs 29.8 w/FOLFOXIRI + bev, HR 0.8 CI 0.65‐0.98

Loupakis F, et al, J Clin Oncol 33, 2015

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Can we do better for BRAF mutant disease?

• Kopetz et al. Randomized trial of irinotecan and cetuximab with or without

vemurafenib in BRAF‐mutant metastatic colorectal cancer (SWOG 1406). GI ASCO 2017.

Vemurafenib + cetuximab + irinotecan

• Most common grade 3‐4 AES:
• Diarrhea
• Neutropenia, anemia
• Nausea
• Fatigue
• Still waiting on OS data
• Planned for a sub‐group analysis

by MSI status

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Immunotherapy for MSI‐high mCRC

• Nivolumab in Patients With DNA Mismatch Repair Deficient/Microsatellite

Instability High Metastatic Colorectal Cancer: Update From CheckMate 142. Overman et al. GI ASCO 2017.

‐ORR 31.1% (95% CI 20.8‐42.9) ‐table disease in 39.2% ‐Disease control for ≥12 weeks 68.9%

Nivolumab in MSI‐high mCRC

Reduction in size of target lesion regardless of: ‐PDL‐1 expression ‐Clinical history of Lynch Syndrome ‐BRAF mutation status

Case #1 Take Home Points

• Current actionable mutations: KRAS codon 12, 13, 61, 117, 146;

NRAS codons 12, 13, 61, 117, 146; BRAF codon 600

• Consider FOLFOXIRI +/‐ bev induction therapy for fit patients w

unresectable CRC irrespective of RAS/RAF mutation status

• BRAF targeted therapy can be effective, but survival is still poor
• If BRAF mutation or MSI present, plan ahead for clinical trial

enrollment

Case #2

A 72yo M w/no prior medical problems has a CT done for kidney stones and is found to have a single lesion in the right lobe of the liver. CT guided biopsy shows metastatic colon cancer. Colonoscopy identifies a rectal primary.

3/7/2017 7

Case #2

• CT C/A/P shows no other sites of metastatic disease
• MSI stable
• RAS and BRAF wild type

Next step

• 1. Start chemotherapy
• 2. Radiation oncology consultation
• 3. Surgical oncology consultation
• 4. Comprehensive geriatric assessment

EPOC

• Phase III RTC of mCRC with liver
• nly metastases, deemed

resectable

• 364 patients assigned to either

surgery alone or surgery + 12 peri‐

• perative cycles of FOLFOX
• Non‐significant improvement in

3yr PFS of 7.3 months (HR 0.79, 95% CI 0.62–1.02; p=0.058)

• Non‐significant improvement in

5yr OS from 47.8% to 51.2% (HR 0.88, 95% CI 0.68‐1.14; p=0.34)

Nordlinger, Bernard, et al. "Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial." The lancet oncology 14.12 (2013): 1208-1215.

New EPOC

• Phase III RCT of KRASwt mCRC w/liver only mets, resectable or

suboptimally resectable

• Randomized to 12 cycles of peri‐operative chemotherapy (68%

FOLFOX) +/‐ cetuximab

• At 20 months of follow up median PFS was 20.5 months without vs

14.1 months with cetuximab. (HR 1∙48, 95% CI 1∙04–2∙12, p=0∙030)

• Radiographic complete or partial response in 62% without vs 70%

with cetuximab, p=0.59

3/7/2017 8

New EPOC Comments

• Organizing trials with surgery and chemotherapy is difficult:

heterogeneous patients, surgeons and centers

• Study was terminated at intermediate analysis: 236/257 randomized WT KRAS exon 2

patients

• Quality assurance:
• Surgery: margin < 1 cm (40% of patients)
• R1 resection (cetuximab: 12%; no cetuximab 8%)
• Entry criteria (13% not assessable)
• CapeOx: 20%, FOLFIRI 10%
• Unresected: cetuximab 27/112 (24%); no cetuximab: 17/110 (15%)1

Consider Geriatric Assessment

• Older adult patients are at higher risk for chemotherapy toxicity than

their younger counterparts

• Because of this they are less likely to be offered chemotherapy, across

disease types

• At the same time, a multitude of studies have shown that older adults

who can tolerate treatment experience chemotherapy efficacy similar to younger patients

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MyCarg.org

Case #2 Clinical Course

• Patient receives 4 cycles of FOLFOX
• Repeat CT shows stability of the initial segment 7 lesion, but question
• f a possible new segment 6 lesion
• Patient is taken for partial hepatectomy, with pathology showing 2

separate lesions, both with negative margins

• Post‐operatively he resumed FOLFOX for 4 additional cycles, which he

tolerated well

Case #2 Clinical Course

• MRI after 8 cycles of FOLFOX shows significant decrease in size and

bulk of rectal mass

• Patient then receives chemoradiation with capecitabine to a total of

5000 cGy in 25 daily fractions

• Currently scheduled for low anterior resection 6 weeks out from his

completion of chemoradiation

3/7/2017 10

Case #2 Take Home Points

• It is not clear what the role of cetuximab is in oligometastatic,

potentially resectable disease

• Get surgical and radiation oncology input early for patients who may

be resectable

• Consider incorporating geriatric assessment into the evaluation of
• lder adult patients

Case #3

• 64yo previously healthy woman admitted for

SBO and noted on imaging to have liver metastases

• In retrospect, intermittent flushing without

significant diarrhea

• Working full time, ECOG PS 0
• Labs: Normal LFTs, albumin, CBC, creatinine.

24 hour urine 5 HIAA: 105 mg/24 hours (nl <8)

• Lives biopsy: well‐differentiated neuroendocrine

tumor (NET), Ki67 3%

Case #3: Imaging

CT: (+) 2 cm spiculated mass in small bowel mesentery (near TI); (+) several peripherally enhancing hepatic lesions consistent with metastatic disease (at least two in the left and two in the right lobes of the liver); (+) two tiny noncalcified pulmonary nodules; rib and T1 lesions of uncertain significance

TI, terminal ilieum

• 111In‐octreotide scan: No extrahepatic disease (2 liver lesions, right lobe and segment

4); no primary tumor identified

Case #3: Imaging

3/7/2017 11

What is the next step in management?

• 1. Start octreotide or lanreotide
• 2. Liver directed therapy (SIRT, TAE, TACE)
• 3. Liver debulking surgery
• 4. Exploratory laparoscopy

SIRT, selective internal radiation therapy, TAE, transarterial embolization; TACE, transarterial chemoembolization

• Patient underwent laparoscopic resection of nearly obstructing 3.2 cm

terminal ileum primary tumor

• Pathology (+) well differentiated NET, Ki 67 4%, 0/5 LN (+);

(+) CgA, synaptophysin

• Intraoperative ultrasound identified a 7.3 cm necrotic mass in the right

lobe with multiple satellite lesions plus at least 6 additional left sided lesions (largest 4 cm in lateral segment)

• Liver disease was left in place

Case #3 Clinical Course

• Post‐operatively:
• Required octreotide LAR up to 40 mg/month for

diarrhea 6‐8 x day

• Urine 5 HIAA 40 mg/24 hours
• Scans show SD at 12 months
• Continues to have diarrhea 6‐8x/day

Case #3 Clinical Course

What is the next step in management of her persistent diarrhea in the setting of stable disease?

• 1. Add telotristat ethyl, if available
• 2. Add everolimus
• 3. Evaluate for other causes of diarrhea besides carcinoid syndrome

(pancreatic insufficency, bacterial overgrowth, short gut)

• 4. PRRT, if available (ex: Lu177 DOTATATE)
• 5. Liver directed therapy (SIRT, TAE, TACE)
• 6. Liver debulking surgery

PRRT, peptide receptor radiotherapy

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• s/p R hepatectomy, cholecystectomy and microwave ablation of all

left sided liver lesions

• Normalization of urine 5‐HIAA and diarrhea post‐op
• Scans remain no evidence of disease x4 years
• Continues octreotide LAR 20mg/month due to lung and bone

lesions of uncertain significance

• At 5 years, some diarrhea returns, does not improve with increased
• ctreotide dose

Case #3 Clinical Course

Case #3 Imaging: Ga68 DOTATOC PET MRI

• Ga68 DOTATOC PET MRI: interval progressive disease (PD) in liver with new and

increasing liver lesions over 2 years (largest 1.4 cm), no extrahepatic disease

What is the next step in management?

• 1. Add telotristat ethyl, if available
• 2. Add everolimus
• 3. Evaluate for other causes of diarrhea besides carcinoid syndrome

(pancreatic insufficiency, bacterial overgrowth, short gut)

• 4. PRRT, if available (ex: Lu177 DOTATATE)
• 5. Liver directed therapy (SIRT, TAE, TACE)

PRRT, peptide receptor radiotherapy

TELESTAR Study

• Randomized, double blind, placebo controlled trial of telotristat ethyl
• Telotristat is an oral, small molecule inhibitor of tryptophan hydroxlyase,

the rate limiting step in serotonin synthesis

Telotristat

1

Slide 48 1 upda

emily bergsland, 2/12/2017

3/7/2017 13

TELESTAR Study

• Enrolled 135 patients w/well

differentiated NET and carcinoid syndrome

• On stable somatostatin analog dose
• 4+ BMs/day
• At 12 weeks mean reduction in

BMs/day was ‐0.9 for placebo, ‐1.7 for telotristat 250mg and ‐2.1 for telotristat 500mg

Kulke, Matthew H., et al. "Telotristat Ethyl, a Tryptophan Hydroxylase Inhibitor for the Treatment of Carcinoid Syndrome." Journal of Clinical Oncology 35.1 (2016): 14‐23.

NET NETTER‐1

• Randomized, open label, phase III trial
• Inclusion Criteria
• Well differentiated midgut NET (Ki67  20%)
• Metastatic or locally advanced, unresectable
• Radiographic disease progression on octreotide LAR (20‐30mg Q 3‐4 weeks)
• On octreotide LAR for up to 3 years
• Somatostatin receptors present on target lesions
• Randomized to 177 Lu‐Dotatate plus octreotide LAR 30 mg Q4 weeks

vs octreotide LAR 60mg Q4 weeks

HR 0.21; 95%CI:0.13‐0.33; P<0.001 HR 0.4, P=0.004 Strosberg, Jonathan, et al. "Phase 3 Trial of 177Lu‐Dotatate for Midgut Neuroendocrine Tumors." New England Journal

• f Medicine 376.2 (2017): 125‐135.

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Case #3 Take Home Points

• Surgery may be able to identify an otherwise occult

primary in midgut NET

• Surgical debulking and liver directed therapy continue to

play an important role

• Many exciting new treatments on the horizon
• Consider referral for clinical trials

Case #4

• 65yo M presents w/nausea,

vomiting, epigastric pain and early satiety after a trip to Japan

• Labs show a t bili of 2.9, alk phos

532, ALT/AST 892/467. CA 19‐9 WNL.

• Abdominal US shows a 3.3 cm

hypoechoic solid mass in the pancreatic head with associated pancreatic and biliary ductal dilatation

• EUS identified a 3.8 X 2.8cm mass

in the head of the pancreas; FNA = atypical cells, suspicious for invasive adenocarcinoma. The main pancreatic duct was dilated; no abnormal lymph nodes were seen.

• ERCP attempted but bile duct could

not be successfully cannulated

• Percutaneous biliary drain was

placed

Case #4

• CT A/P with contrast:
• No encasement of the celiac axis,

SMA, or common hepatic artery.

• The tumor abuts the

gastroduodenal artery

• Main portal vein contact: <180

degrees, with contour irregularity. + Portal vein thrombosis

• No distant metastatic disease or

enlarged lymph nodes

What is the next step in management?

• 1. Whipple
• 2. Neoadjuvant FOLFIRINOX
• 3. Neoadjuvant RT with concurrent capecitabine
• 4. Gemcitabine + Abraxane

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Neoadjuvant therapy for borderline resectable PDA

• No large phase III studies to guide treatment currently
• Generally R0 rates reported at 30+ % and median OS 2+ years, but no

surgery alone comparison arm

• FOLFIRINOX
• FOLFIRINOX  RT
• Gemcitabine + oxaliplatin RT + gem
• Gemcitabine + capecitabine
• Capecitabine + RT

Neoadjuvant FOLFIRINOX +/‐ RT

• Kim et al Journal of Surgical Oncology 2016 Oct;114(5):587‐596:

Retrospective study of 26 patients treated at UCSF 2011‐2015 with neoadjuvant FOLFIRINOX for borderline resectable or locally advanced pancreatic cancer.

• 22 FOLFIRINOX alone, 4 FOLFIRINOX + radiation
• R0 resections in 90.9%
• Path treatment response moderate or marked in 72.7%
• Estimated median DFS 22.6mo, and OS not yet reached
• Too few patients received RT to evaluate what it adds to the

chemotherapy

Neoadjuvant FOLFIRINOX +/‐ RT

• Katz et al. JAMA Surg. 2016 Aug 17;151(8):e161137: Pilot study, single

arm multi‐center eval of neoadjuvant FOLFIRINOX‐‐> RT + capecitabine for borderline resectable pancreatic caner

• Included central radiographic review to establish borderline resectability
• Of 29 patients, 23 met central review criteria
• 68% underwent pancreatectomy, 93% of those had R0 resections
• 33% had <5% residual cancer cells, 13% had path CR
• Based on this the Alliance trial A021501 is now open: "Preoperative

Extended Chemotherapy vs. Chemotherapy Plus Hypofractionated Radiation Therapy for Borderline Resectable Adenocarcinoma of the Head of the Pancreas."

3/7/2017 16

Case #4 Clinical Course

• Patient received 8 cycles of FOLFIRINOX
• Interval imaging showed no change in size of the pancreatic head

mass, but some improvement in the portal vein thrombosis

• He goes to Whipple, with an R0 resection and path showing <10%

residual viable tumor cells

What is the next step in management?

• 1. RT
• 2. Chemo/RT
• 3. More FOLFIRINOX
• 4. Surveillance only

Case #4 Take Home Points

• Good rates of RO resections and long‐term survival can be seen with

neoadjuvant therapy in borderline resectable pancreatic cancer

• Although we lack head to head data with surgery alone, R0 resection

rates are higher with neoadjuvant treatment than historically seen in borderline resectable disease

• Many combinations of chemotherapy +/‐ RT are in use, without

strong data to support one over another

• It is unclear what the length of treatment should, and what the role
• f adjuvant treatment is

3/7/2017 17

Bonus Question! What mutations are potentially actionable in clinical trials in cholangiocarcinoma?

• 1. IDH 1/2
• 2. FGFR2
• 3. IDH & FGFR2
• 4. BRCA 1/2
• 5. pMMR
• 6. All of the above