Palliative treatment of unresectable pancreatico-biliary cancer by either Gemcitabine or Octreotide/Imatinib – impact on biomarkers of angiogenesis

Aims: Gemcitabine represents standard Tx for unresectable cancers of the pancreas/distal biliary tract. Recent interest has focused on antiangiogenic properties in a mouse model of pancreatic cancer (JCI 2003); either VEGF or PDGF inhibition alone were less effective than the combination of both in terms of angiogenesis. In HCC pts. we recently evaluated the impact of biomarkers on disease progression and survival (Cancer Res Clin Oncol 2006; 132:699–708).

Methods: To investigate in a phase I/II trial the feasability of a combination (group I, n=11) of octreotide (30mg im every 4 weeks, targeting VEGF-A) plus imatinib (400mg po daily, targeting PDGF-B) vs. gemcitable (group II, n=11, 1000mg/m² weekly for 7/8 wks, then for 3/4 wks). Pts had either unresectable pancreatic cancer (n=18) or ampullary cancer (n=4). Primary outcome measure were changes in biomarkers (VEGF-A, PDGF-BB, soluble E-selectin, Ca19–9, CEA). Secondary outcome measures were TTP and OS.

Results: 19/22 pts. had biomarker data available within the first 12 wks, changes over time are shwon in table. Median TTP was 109 vs. 166 days (p<0.05) and median OS was 163 vs. 325 days (p=NS) for group I vs. II. Baseline Ca19–9 levels correlated with prognosis independent of Tx (p=0.05). In group I, high levels of PDGF-BB and VEGF-A levels at wk 12 but in group II, low levels of VEGF-A and s-E-selectin correlated with a better OS (p<0.05 each). TTP showed no correlations with biomarkers.

PDGF-BB Group I [pg/ml]	Wk 0: 515	Wk 2: 234	Wk 4: 427	Wk 12: 250	-54.6% (max. decrease)
VEGF-A Group I [pg/ml]	Wk 0: 69	Wk 2: 32	Wk 4: 40.7	Wk 12: 41.9	-53.3% (max. decrease)
s-E-Selectin Group I [ng/ml]	Wk 0: 90	Wk 2: 73.5	Wk 4: 85.3	Wk 12: 107	-18.3% (max. decrease)
CEA Group I [ng/ml]	Wk 0: 4.7	Wk 2: 6.7 *	Wk 4: 7.3 *	Wk 12: 8.3 *	+76.6% (max. increase)
Ca 19–9 Group I [U/l]	Wk 0: 562	Wk 2: 982	Wk 4: 1201	Wk 12: 447	-20.6% (max. decrease)
PDGF-BB Group II [pg/ml]	Wk 0: 425	Wk 2: 195	Wk 4: 338	Wk 12: 402	-54.6% (max. decrease)
VEGF-A Group II [pg/ml]	Wk 0: 76.2	Wk 2: 39	Wk 4: 86.8	Wk 12: 111	-48.2% (max. decrease)
s-E-Selectin Group II [ng/ml]	Wk 0: 78	Wk 2: 62	Wk 4: 70	Wk 12: 76	-20.5% (max. decrease)
CEA Group II [ng/ml]	Wk 0: 6 *	Wk 2: 4.8 *	Wk 4: 4.1 *	Wk 12: 3.8 *	-37.5% (max. decrease)
Ca 19–9 Group II [U/l]	Wk 0: 38.7	Wk 2: 36.5	Wk 4: 28.6	Wk 12: 30.2	-20.6% (max. decrease)

Conclusions: The combination of octreotide plus imatinib is clinically less effective compared to gemcitabine. Although the absolute changes of angiogenesis markers are comparable between groups, chemotherapy compared to targeted therapy has a different impact on these in terms of survival.