Pancreatic Cancer - Adjuvant Therapy

JP Presents on adjuvant treatment for pancreatic cancer.

Case presentation is of a 55yo man presenting with obstructive jaundice:  Staging reveals a 2.5cm mass mod diff adenocarcinoma at pancreatic head via diagnosed via biopsy at EUS and ERCP.  Whipple performed with multiple positive margins at neck, with 4/10 lymph nodes positive.  (pT3N1).  PET CT was negative for distant disease.

BC: Whipple in this scenario was probably attempted initially as Pt seemed to be node negative at initial staging.  If nodes were known prior to the patient may have been better served by CTRT upfront, with reevaluation for resection afterwards.

34,000 pancreatic ca per year, with 32,000 deaths per year.  2/3 are found in the head.  80% are unresectable at diagnosis.  Risk factors: Smoking, chronic pancreatitis, obesity, high fat diet.  3y OS with resection 17%, at best 6% unresected.

Whipple classically resected distal stomach, duodenum, pancreatic head, common bile duct above the cystic duct, and the gallbladder.  For tumor in the body or tail, a distal pancreatectomy can be performed, sparing the head.  Spleen may be taken with this procedure.  Recently, pylorus sparing whipples have been gaining popularity at Duke.

T1 <=2cm, T2 >2cm, T3 out of pancreas, T4 celiac axis/sma

N0 no nodes, N1 nodes 

Randomized Trials Examining Adjuvant Treatment.

GITSG 9173 (Kalser, Arch Surg, 1985): n=43 (goal of 100, very poor and slow accrual), resected with negative margins.  XRT (40 gy split course) + 5FU vs. Observation.  2y OS 43% CMT vs 18% obs (p=0.03), Median DFS 11mo vs 9mo (SS).

EORTC 40891 (Ann Surg 1999) ChTRT vs obs.  2 yr OS 51% CMT vs 41% Obs (p=0.208).  Pancreatic head tumors seemed to do slightly better with CMT but not significant.  Again split course RT to 40Gy (split), low 5FU dose.  Poor treatment compliance (>20% in treatment arm did not receive treatment).  Updated in 2007 (link above)

ESPAC-1 (Neoptolemos, Lancet 2001) n=541.  This is a complicated study, which really is three trials, A: 2x2 trial of chemo, and chemort,  B: CMT vs obs, or C: Chemo vs obs.  Investigators could determine which trial patients went on.  RT remains antiquated at 40Gy split course.  No significant difference in CMT vs observation with pooling of the various trials.  Chemotherapy in the pooled arms did have a benefit.  A better analysis was presented of just the 2x2 trial (Neoptolemos, NEJM, 2004) - which demonstrated a benefit to chemotherapy alone, and a detriment to CMT.  The overall results are also poor compared to other trials. 

CONKO-001 (Oettle JAMA 2007). n=386 resected Pancreatic Cancer.  Randomized to Gemcitabine x 6 cycles vs observation.  Primary endpoint was DFS.  5y DFS was 16.5% vs 5.5% (SS).  OS trended toward significance - BC comments that on update, OS has become positive.

RTOG 97-04 (Regine JAMA 2008).  n=451 (388 for head tumors).  After surgery, randomization was to 5FU - ChtRT - 5FU vs Gem - ChtRT - Gem.  Dose was 50.4Gy.  Powered for OS for all comers and for the pancreatic head subset.  3yOS 31% Gem arm vs 22% 5FU in head tumors (p=0.09), HR 0.82 (95% CI 0.65-1.03).

So this leaves us with a mix of less than perfect trials, none of which answer the central question of wether modern RT is beneficial in the setting of adjuvant gemcitabine.  Stay tuned for upcoming randomized trials opening...

Christopher Counter: Oncogene addition in Pancreatic Cancer

Dr. Christopher Counter (Duke Associate Professor Pharmacology, Associate Professor Radiation Oncology) - Oncogene addiction in Pancreatic cancer

 

Below is a summary of Dr. Counters talk. I have left out a fair amount of the experimental details; all results come from in vitro animal models.

 

Ras Intro

EGF couples with GEF which then binds to Ras-GDP -> Ras->GTP (ras is membrane bound)

Ras-GTP interacts with RalGEF, Raf, PI3K

GAP then inactivates Ras-GTP -> Ras-GDP

KRas is mutated in 90% of pancreatic cancer, to the constitutively active form

in about 1/3 of human cancers this is also mutated, and predicts for resistance to EGFR inhibitors (specifically cetuximab in colon)

Ras oncogene addiction - Chin, Nature 2000: in a mouse model - turning off ras activation led to involution of the tumor.

 

Thinking of Tumor Initiation and Maintenance, and how Ras fits in:

Created a similar mouse model to Chin 2000 (mouse with a constitutive ras switch)

tumor is initiated in a mouse with ras active.

ras is then inactivated and then investigations focused on the three secondary pathways downstream from ras:

·         Ral-GEF only activation led to involution

·         Raf only activation led to involution

·         PI3K only activation led to tumor maintenance

Therefore for maintenance, it seems that PI3K is necessary for tumor maintenance.

Tumor microenvironment seems to activate a fair amount of paracrine signaling to maintain the tumor.

 

IL-6 story:

Ras induces secretion of IL-6

IL-6 is also found in pancreatic patients serum (along with IL-8)

if IL-6 is inhibited, tumor generated in xenograft model where much smaller and slower growing.  there was also a decrease in the amount of CD31 staining (an endothelial stain, and a surrogate for angiogenesis).

IL-6 knockout mice also were resistant to Ras-mediated tumorgenesis (papilloma model)

IL-6 monoclonal antibodies are available and are shown in mouse model to delay tumor growth.  in 10 human pancreatic lines tested, 2 had a response.  

IL-6 inhibition also seems to reduce cachexia. 

 

PI3K/AKT/eNOS story:

AKT is a downstream target from PI3K, and similar to the above seems to be a key component of tumor maintenance.

AKT works on a large number of targets, including eNOS (endothelial nitric oxide synthase), which also seems to be a key component of tumor maintenance.

Phosporylation of eNOS is performed on a specific serine (S1177), which seems to be necessary for tumor maintenance.

eNOS knockout model:  resistant to ras mediated tumorigenesis.

L-NAME inhibits eNOS, which was developed for another clinical application.  In xenograft model, L-NAME led to tumor growth delay.  in 9 cell lines, activity was seen in 7 (in contrast to the IL-6 mab intervention). (L-NAME developed for septic shock treatment by GSK)

 

eNOS nitrosylates Wild type Ras and activates it

N, K, and H are all subtypes of Ras, K being the most important for human tumors

eNOS (activated by KRas) then activates NRas and HRas via nitrosylation.

HRas nitrosylation seems to be required for tumor growth.

 

Farnesyl transferase inhibitors were developed to target Ras.  To be active Ras needs to get to the plasma membrane, most often by gaining franesyl groups.  FTIs inhibited the ability of Ras to get to the membrane, but it turns out that KRas is able to escape this by a number of other methods.  FTIs do however work well on HRas.  Perhaps some combination with the previously mentioned investigations would be fruitful.

Obviously a lot of this is ‘in the pipeline’ work, but it may well be key to improving the overall dismal results with current standard of care treatment.