Back to the basics
True/False
1- African Americans have 14 times higher risk of pancreatic cancer compared to whites/Latinos.
2- Smoking and T-II DM almost double the risk.
3- HER2 neu and KRAS are early events, p16 intermediate, and p53, DPC 4, and BRCA 2 are late events in pancreatic cancer pathogenesis.
True.
True.
True.
Define reseactable disease?
No venous contact with SMV or PV, or ≤ 180 degree contact without vein contour irregularity.
No arterial contact with CA, SMA, CHA
Define Borderline Resectable Disease?
Borderline Resectable Disease
• Stage II/III (Abutment on artery ≤ 180º)
• Vein> 180 or if ≤ 180 with contour irregularity
Define locally advanced disease?
> 180* with SMA, CA.
Complete occlusion of SMV, PV.
median survival for untreated patients?
3-4 months.
Risk factors for developing pancreatic cancer?
Atleast 3 general, 3 genetic and 2 somatic mutations.
Smoking
Pesticides
Asbestos
periodontal disease
Heavy alcohol consumption {+6 drinks/day}
Elevated BMI {>35}
Low vitamin D
Chronic pancreatitis.
Diabetes Mellitus type II, even prediabetes
New-onset Diabetes
Genetics
Premalignant tumors of the pancreas [mucinous cystic neoplasms, IPMs]
Germline
BRCA 1,2, PALB2 carrier
ATM
HNPCC
MMR def
CDKN2A/p16
STK11/LKB1 carrier Peutz Jeger syndrome
Li Fraumani
PRSS1 [Heriditary pancreatitis]
FDR
Somatic
KRAS G12D,G12V,G12C..
TP53--mutated >50% of the times
CDKN2A(p16)
SMAD(DPC4)
MLL3
BRCA 2 can occur somatically as well.
MMR/MLH1/MSH2/MSI high 1-2%
SOC approach for resectable disease?
Upfront surgical resection or neoadjuvant therapy?
Neoadjuvant regimens?
Adjuvant regimens?
Resectable Pancreatic Cancer (10-15%)
• T1-3,N0-1,M0 • Stage I, IIa, IIb
- Standard of care is upfront surgical resection or neoadjuvant therapy
- No standard neoadjuvant approach (most centers use gemcitabine nab-paclitaxel or (m)FOLFIRINOX w/wo subsequent CRT, If BRCA 1/2 or PALB2 mutated--gem+cis, (m)FOLFIRINOX w/wo subsequent CRT with cape/FU/or gem with RT
- (m)FOLFIRINOXfor ECOG 0-1
- Don't do upfront Sx if high-risk features (equivocal or indeterminate imaging findings, markedly elevated CA 19-9, Large primary tumors, large regional LN's, excessive weight loss, extreme pain)
- Multiple options for adjuvant therapy
- Gemcitabine x 6 months 2007-2016 [m OS 25?35?37? mo)
- Gemcitabine + Capecitabine 2017* [m OS 28 mo)
- mFOLFIRINOX 2018* --m OS 54 months PRODIGE 24 --ECOG 0-1
- Gemcitabine + nab-paclitaxel 2023 ---m OS 40.5 -41.8
Consider chemoradiation after 4-6 months of chemotherapy for patients with R1 resections
What Neoadjuvant regimens?
Gemcitabine nab-paclitaxel or (m)FOLFIRINOX w/wo subsequent CRT with cape/FU/or gem RT
If BRCA 1/2 or PALB2 mutated--gem+cis, (m)FOLFIRINOX w/wo subsequent CRT with cape/FU/or gem with RT.
SOC Treatment
--> Standard of care is chemotherapy with options dependent on performance status:
Gemcitabine/nab-p, (m) FOLFIRINOX, NALIRIFOX
BRCA1/2, PALB2 mutations- (m) FOLFIRINOX, gem+cis
--> Int PS 2--include gem, Cape, gem+abraxane
--> Poor PS 3-- gem, FU, cape
--> Delivering radiation after induction chemotherapy does not improve median survival over chemotherapy alone but does improve PFS • At 5 years, the survival rate is higher for those undergoing radiation (10% vs 4%)
Targeted therapies, CPI for TMP>=10 can be considered in certain circumstances.
Treatment options?
• Gemcitabine/nab-paclitaxel for KPS > 70%
• nal-IRIFOX superior to Gem/nab-p*
• FOLFIRINOX reserved for patients with PS 0-1
OS same 11.1 mo with nal-IRIFOX and FOLFIRINOX
--> Int PS 2--include gem, Cape, gem+abraxane, FOLFOX, CAPOX
--> Poor PS 3--BSC
• Performance status is clearly linked to survival
• Combination therapy in poor PS patients appears to be detrimental
Targeted therapies, CPI for TMP>=10 can be considered in certain circumstances.
Workup?
--> CT/MRI dedicated Pancreatic protocol
--> Endoscopic Ultrasound* • Tissue acquisition for localized disease*
--> Image-guided biopsy of accessible metastatic site
--> ERCP +/- stent in setting of jaundice
NCCN Guidelines for Pancreatic Adenocarcinoma recommend that clinicians consider germline testing for all patients with pancreatic cancer and molecular analysis for those with metastatic disease
Staging Studies
--> Thin Cut (3mm) abdominopelvic CT Scan - Clear Demonstration of Relationship of Tumor to Portal Vein, SMV, SMA - Potential to Demonstrate Metastatic Disease to Liver or Peritoneum - Image Lung Bases [if regular CT was done before]
• Serum tumor markers – CA 19-9 (10% of patients are non-producers) – CEA – CA 125
• CT scan of the chest
• Laparoscopy – Limited to Special Cases --do it for clearly resectable tumors.
* PET imaging is not routinely recommended or approved for pancreatic cancer staging
High tumor marker with no CT evidence of metastatic disease
Patients who had sx and high tumor marker and you cant tell if it is recurrence (Locally recurrent disease) or just fibrosis in surgical bed.
What is the CT pancreas protocol? How is it different from regular contrast CT?
Multiphase CT scan
1. Non-Contrast Phase [images right after injecting contrast]
2. Arterial / Late Arterial Phase (a.k.a. Pancreatic Parenchymal Phase) Timing: ~35–50 seconds after IV contrast--You see pancreatic tumors (PDAC appears hypoenhancing). It helps with optimal visualization of arterial anatomy: SMA/ Celiac artery/ Common/proper hepatic artery----Helps assess arterial invasion, which determines resectability
3. Portal Venous Phase Timing: ~60–70 seconds-- Evaluate venous involvement- SMV/ Portal vein/ Splenic vein. It detect liver metastases and lymphadenopathy
4. Optional Delayed Phase (90–120 seconds)
Used for: Characterizing cystic lesions, Evaluating enhancement washout, Checking pancreatic duct strictures or delayed duct filling
You can do multiphase imaging with MRI of the pancreas, and it is commonly done. It is not identical to CT pancreas protocol, but MRI has its own multiphase contrast-enhanced sequences.
CT preferred.
* Simple Contrast CT is single phase (almost always portal venous phase around 60–70 seconds).
Nal IRI
MOA?
Side effects?
ONIVYDE is a topoisomerase inhibitor. [Topoisomerases relieve DNA supercoiling ]
WARNING: SEVERE NEUTROPENIA and SEVERE DIARRHEA
The most common adverse reactions (≥ 20%) of ONIVYDE: diarrhea, nausea, vomiting, fatigue/asthenia, decreased appetite, stomatitis, and pyrexia. The most common laboratory abnormalities (≥ 10% Grade 3 or 4) were lymphopenia and neutropenia.
--> Interstitial lung disease (ILD)
--> Severe hypersensitivity reaction.
- Recommended dose of ONIVYDE is 70 mg/m2 intravenous infusion over 90 minutes every two weeks.
- Recommended starting dose of ONIVYDE in patients homozygous for UGT1A1*28 is 50 mg/m2 every two weeks.
- There is no recommended dose of ONIVYDE for patients with serum bilirubin above the upper limit of normal.
Gemcitabine
MOA?
Side effects?
ANC and Platelet threshold to cut the dose by 25% and hold it? [Optional Question]
DNA synthesis inhibition
The most common adverse reactions for the single agent (≥20%) are nausea/vomiting, myelosuppression, hepatic transaminitis, proteinuria, fever, hematuria, rash, dyspnea, and peripheral edema.
--> Schedule-dependent toxicity: Increased toxicity with infusion time greater than 60 minutes or dosing more frequently than once weekly.
--> Myelosuppression
--> Pulmonary toxicity and respiratory failure: Discontinue Gemcitabine Injection immediately for unexplained new or worsening dyspnea or evidence of severe pulmonary toxicity
--> Hemolytic-uremic syndrome (HUS): Monitor renal function prior to initiation and during therapy. Discontinue Gemcitabine Injection for HUS or severe renal impairment. (5.4)
--> Hepatoxicity
--> Exacerbation of radiationtherapy toxicity: May cause severe and lifethreatening toxicity when administered during or within 7 days of radiation therapy.
--> Capillary leak syndrome: Discontinue Gemcitabine Injection.
Recommended Dose Reductions for Gemcitabine Injection for Myelosuppression in Pancreatic Cancer and Non-Small Cell Lung Cancer
ANC ≥ to 1000 and Platelet count and ≥ to 100,000 No dose modifications.
ANC ≥ 500-999 and Platelet count 50 K-99.99k-- 75% of full dose
ANC < 500 and Platelet count < 50,000 Hold
When can you add olaparib maintenance? What trial supports it?
Metastatic pancreatic with BRCA 1/2 germline mutation who recieved Gem/Cis or FFX x 16 weeks with stable or response--can add olaparib maintainence.
PFS 7.4 months Olaparib 3.8 months Placebo
18.9 months Olaparib 18.1 months Placebo
POLO Trial
TNM Staging?
Is TNM staging relevant in pancreatic or do you just look at the resectable, borderline resectable, LA, metastatic status?
N0- No regional node metastasis
N1- 1-3 regional LNs
N2- 4 or more regional LNs
M0- No distant mets
M1- Distant mets
T3,N0 Stage IIA
T1-T3 with N1--Stage IIB
T1-T3 with N2--Stage III
T4 any N stage III
M1- Stage IV
Is the 5-year survival regardless of stage < 20%?
What about pancreatic adenocarcinoma is so challenging to treat?
True!
Pancreatic Cancer Creates a “Hostile” Microenvironment that Blocks Chemo. It produces a highly fibrotic, collagen-rich stroma, (like scar tissue) which physically blocks chemotherapy penetration and Increases interstitial pressure → squeezes vessels and creates very poor blood flow, so drugs barely reach the tumor cells.
In general, pancreatic tumors are not very vascular, so pumps can't be used.
Match the following mutations with their associated syndromes?
Mutations
BRCA 1/2.
ATM
PALB2
PRSS
STK 11
CDKN2A
MLH 1/2, MSH6, PMS2
Syndromes
Ataxia telangiectasia
Hereditary breast and ovarian syndrome.
Hereditary Breast Cancer
Lynch syndrome.
Hereditary pancreatitis
Peutz Jeghers syndrome
FAMM syndrome (Familial atypical multiple mole and melanoma syndrome)
BRCA 1/2 - Hereditary breast and ovarian syndrome.
ATM- Ataxia telangiectasia
PALB2 Hereditary Breast Cancer
PRSS Hereditary pancreatitis
STK 11 Peutz Jeghers syndrome
CDKN2A FAMM syndrome (Familial atypical multiple mole and melanoma syndrome)
MLH 1/2, MSH6, PMS2- Lynch syndrome.
Q--Targets and Drugs.
NTREK--Entrectinib, Larotectinib, Repotrectinib.
MSI-H/MMRd or TMB>=10--Pembro if no prior immuno. Can also use dostar or even ipi+nivo.
BRAF600E-Dabra+Tremi
RET- selpercatinib
KRAS G12C-Adagrasib, Sotorasib
HER2 +(IHC3+ or IHC 2+ with FISH HER2 amplified) fam-trastuzumab deruxtecan
NRG1 Zenocutuzumab-zbco [It works by blocking the NRG1 protein from binding to HER3, which prevents HER2/HER3 dimerization and the resulting cancer cell proliferation.], Afatinib?
FGFE-Erdafitinib
Q1--If someone got mFOLFIRINOX in first line and progressed on it, can you give gem+abraxane if ECOG remains 0-1 and visa versa
Q2--Components of FOLFIRINOX and NALIRIFOX. What are the Key Differences in Toxicity?
1-Yes
2- FOLFIRINOX
5-FU
Leucovorin
Irinotecan (conventional)
Oxaliplatin
NALIRIFOX
NAL-IRI (liposomal irinotecan)
5-FU
Leucovorin
Oxaliplatin
Key Differences in Toxicity
FOLFIRINOX = more myelosuppression
NALIRIFOX = more diarrhea and nausea