Multidisciplinary GI Tumor Board · 2017. 3. 11. · EPOC • Phase III RTC of mCRC with liver only...
Transcript of Multidisciplinary GI Tumor Board · 2017. 3. 11. · EPOC • Phase III RTC of mCRC with liver only...
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17th Multidisciplinary Management of Cancers: A Case‐based Approach
GI Tumor BoardAlan Venook
Carling Ursem
Emily Bergsland
Carlos Corvera
Mary Feng
Margaret Tempero
George Fisher
Zach Koontz
Pam Kunz
Brendan VisserYan LiEd Kim
Case #1
• 62yo F without significant PMH presents w/RLQ abdominal pain. • CT: asymmetric wall thickening of the cecum with enlarged pericolonicmesenteric 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 MSI2. Test KRAS exon 2/3, NRAS, BRAF and MSI3. Start FOLFIRI + cetuximab4. 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 ClinOncol March 2015 Comments & Controversies
In this patient with right sided colon cancer, does KRAS status change your choice of therapy?1. Yes2. No
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Side N (events) Median (95%CI) HR (95% CI) PLeft 732 (550) 33.3 (31.4-35.7) 1.55
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Office [3]1 discuss how often these two occur at the same time int he same patientMicrosoft Office User, 1/31/2017
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What is the next step in management?
1. Start FOLFIRI2. Start irinotecan + cetuximab + vemurafenib3. Start nivolumab4. Start FOLFOXIRI + bevacizumab
BRAF V600E CRC has Distinct Biology
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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.
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Case #2
• CT C/A/P shows no other sites of metastatic disease• MSI stable• RAS and BRAF wild type
Next step
1. Start chemotherapy2. Radiation oncology consultation3. Surgical oncology consultation4. Comprehensive geriatric assessment
EPOC• Phase III RTC of mCRC with liver only metastases, deemed resectable
• 364 patients assigned to either surgery alone or surgery + 12 peri‐operative 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
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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 of 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
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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 older 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
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What is the next step in management?
1. Start octreotide or lanreotide2. Liver directed therapy (SIRT, TAE, TACE)3. Liver debulking surgery4. 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 available2. Add everolimus3. 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 octreotide 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 available2. Add everolimus3. 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
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1 updaemily bergsland, 2/12/2017
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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.
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
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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 phos532, 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:
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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
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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
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Bonus Question! What mutations are potentially actionable in clinical trials in cholangiocarcinoma?1. IDH 1/22. FGFR23. IDH & FGFR24. BRCA 1/25. pMMR6. All of the above