Background and rationale: EGFR represents the main and more studied signal activation pathway
in the development of colorectal carcinoma. KRAS, NRAS, BRAF and PI3KA mutations and ERBB2
and MET amplification are responsible for most of the cases of primary resistance to
anti-EGFR antibody treatments. Despite the identification of these resistance mechanisms, a
primary resistance to the therapy was detected in a certain percentage of cases, in which
tumour bio-molecular characteristics would suggest a possible response to anti-EGFR antibody
treatment. In these cases, pathway activation mechanisms should exist, which act in an
alternative, complementary or parallel way than the EGFR one, allowing tumour progression
despite of EGFR pharmacological deactivation. Skin toxicity is a characteristic of drugs
having EGFR as a target and it shows itself mainly as a sterile acneiform folliculitis
together with neutrophils perifollicular infiltrates but also as skin xerosis and paronychia
starting from the earliest cycles of treatment. This skin toxicity seems to be closely
related to EGFR activation of pro-inflammatory cytokines able to activate specific
inflammatory activators, which induce neutrophils granulocytes chemotaxis. Lycopene is a
compound belonging to carotenoid group, largely contained in tomatoes and their derivatives,
which has an extreme antioxidant activity. In Dermatology, prolonged use of β-carotenoids in
general and of lycopene in particular in the diet showed to be effective in skin protection
from ageing, sunlight and radiotherapy damages because these compounds may accumulate in skin
and thus contribute to reduce free radicals and inflammation effects. Moreover, lycopene
ability to induce apoptosis and to inhibit cell cycle progression in some types of tumour
cells, both in vitro and in vivo, has already been described. Lycopene seems to be able to
suppress significantly PCNA (Proliferating cell nuclear antigen, cofactor of DNA
polymerase-β) and β-catenin nuclear expression in neoplastic cells, essential substrate of
WNT/β-catenin pathway, which is itself closely connected to activating pathways often
involved in carcinogenesis of some kinds of tumours, in particular of colorectal carcinoma,
like Akt/GSK3β/β-catenin and Hippo pathways. For its proved skin anti-inflammatory activity
as powerful free radicals scavenger, lycopene, which accumulates itself specifically in skin,
could be effective in reducing anti-EGFR drugs toxicity. Contemporary use of lycopene could
have a positive effect on anti-EGFR drugs treatment effectiveness in patients with metastatic
colorectal carcinoma due to its ability to interfere with pathways involved in neoplastic
cells proliferation.
Estimated population:100 patients (50 for each of the two groups of treatment)
Study Framework: In this study, patients suffering from metastatic colorectal cancer and
submitted to therapy with panitumumab would be enrolled. According to indications,
panitumumab would be used:
in first line combined with Folfox or Folfiri;
in second line combined with Folfiri or treatments containing Irinotecan
in monotherapy in any therapeutic line in patients resistant to Fluoropyrimidines,
Oxaliplatin and Irinotecan or intolerant to these drugs.
Standard schedules of these treatments would be used.
This is a phase-II, randomized, double-blind study between experimental prophylactic
treatment with Lycopene vs placebo:
- Treatment A - lycopene tablets 20 mg
- Treatment B - placebo tablets
Patients should take orally Lycopene/placebo after dinner (to promote its absorption),
starting the day before the beginning of treatment with panitumumab for the entire duration
of the therapy, until progression of the disease or definitive drug suspension for toxicity.
Objectives of the study
Primary objective: to assess the effectiveness of lycopene versus placebo in reducing skin
toxicity induced by panitumumab in patients treated for metastatic colorectal carcinoma.
Secondary objective: to assess lycopene pharmacokinetics
Exploratory objectives: to assess lycopene effectiveness versus placebo in increasing
panitumumab effectiveness in terms of Disease Control (DC), Objective Response (OR) and
Stabilisation of the Disease (SD). To assess lycopene effectiveness versus placebo in
increasing panitumumab effectiveness in terms of Progression Free Survival (PFS).
As far as randomization is concerned, the two groups will be balanced according to sex,
therapeutic line and institution in which patients will be treated.