Antiangiogenis vs. chemotherapy: Impact upon biomarkers in advanced hepatocellular cancer (HCC)

Introduction: We have shown, that octreotide can effectively inhibit systemic VEGF-A secretion (J Cancer Res Clin Oncol 2006) in HCC patients. In a HCC mouse model, PDGF-B was associated with cell proliferation. This study was therefore designed to evaluate the impact of different Tx on established (s-Eselectin, VEGF-A) and new biomarkers (PDGF-BB) for angiogenesis. It was hypothesised that

1) conventional chemotherapy would activate angiogenesis,

2) PDGF inhibition by imatinib would enhance the effect of octreotide, and

3) that metronomic chemotherapy added by antiangiogenesis (Hanahan D, JCO 2005) would inhibit an increase in biomarkers.

Methods: Prospective, randomised, phase-I/II trial in patients with advanced or metastatic HCC. Outcome measure was the relative change in plasma biomarkers (s-E-selectin, VEGF-A, PDGF-BB) and serum AFP from baseline to EOT.

Results: 38 patients were randomised to 4 Tx groups (3 cycles per group intended, 1 cycle=4 wks:

A) octreotide 30mg im on day 1;

B) octreotide 30mg on day 1 plus imatinib 400mg po day 1–28;

C) oxaliplatin on day 1 (cycle 1: 60mg/m2, cycle 2: 75mg/m², cycle 3: 90mg/m2);

D) oxaliplatin on day 1,8,15 (cycle 1: 20mg/m², cycle 2: 25mg/m², cycle 3: 30mg/m²) in combination with octreotide 30mg on day 1 plus imatinib 400mg po day 1–28. The cumulative dosages of oxaliplatin within one cycle were thus identical. 2/10 (group A), 4/11 (group B), 2/7 (group C), and 2/10 (group D) did not receive all cycles, mainly because of tumor progression. For biomarker results see table below (# denotes p<0.05 compared to baseline values).

Groups/Parameters (median values)	s-E-selectin [ng/ml]	VEGF-A [ng/ml]	PDGF-BB [ng/ml]	AFP [ng/ml]
Group A	+ 15% at wk 12 #	+3% at wk 2	+24% at wk 12	+10% at wk 12
Group B	+16% at wk 12	+/- 0% from wk 2–12	+9% at wk 12	+31% at wk 8
Group C	+ 57% at wk 12 #	+29% at wk 2	+114% at wk 12 #	+39% at wk 4
Group D	+4% at wk 12	+7% at wk 2	+21% at wk 4	+17% at wk 8

Conclusions: The increase seen for s-E-selectin and PDGF-BB with standard chemotherapy alone may reflect activation of angiogenesis. In contrast, low-dose metronomic chemotherapy in combination with antiangiogenic drugs seem to correlate with the least increase in biomarkers. However, AFP changes were comparable in all groups.