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...