Metastatic colorectal cancer: treatment with panitumumab.

The Guidelines Project, an initiative of the Brazilian Medical Association, aims to combine information from the medical field in order to standardize producers to assist the reasoning and decision-making of doctors. The information provided through this project must be assessed and criticized by the physician responsible for the conduct that will be adopted, depending on the conditions and the clinical status of each patient.


INTRODUCTION
Panitumumab is a fully human recombinant monoclonal IgG2 antibody that binds with high affinity and epithelial growth factor receptor (EGFR) specificity. EGFR is a transmembrane glycoprotein which is a member of a type I receptor tyrosine kinase subfamily including EGFR (HER1/c-ErbB-1), HER2, HER3 and HER4 3 . EGFR promotes cell growth in normal epithelial tissues including skin and hair follicle, and expresses itself in a variety of tumour cells 4 .
Panitumumab binds to the binding domain of the EGFR ligand and inhibits the receptor autophosphorylation induced by all known EGFR ligands. This binding results in receptor internalization, inhibition of cell growth, induction of apoptosis and decreased production of interleukin 8 and vascular endothelial growth factor 5, 6 .

Monotherapy -Second or third-line
The results of a multicentre, international (Western Europe, Central Europe, Eastern Europe, Canada, Australia, New Zealand), open-label phase III Randomized Controlled Trial (RCT) in which 463 patients with metastatic colorectal cancer with EGFR expression were randomized to receive panitumumab (6 mg/kg per IV infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity) and "best supportive care" (BSC) [n = 231] or "better supportive care alone" [n = 232]. The study was reported in a major publication 7 (B) and five complementary publications 8,9,10,11,12 which are summarized in Table 1. The eligibility criteria included pathological diagnosis of metastatic colorectal adenocarcinoma and radiological documentation of disease progression during treatment or within 6 months after the last administration of fluoropyrimidines, irinotecan and oxaliplatin (second or third-line).
The most common adverse event associated with panitumumab was skin toxicity (90% in the PAN group and 9% in the BSC), although it has been shown that the severity of skin toxicity may be associated with efficacy 11 (B). Grade 3 or 4 hypomagnesemia occurred in 3% of patients in the PAN group.
The single arm extension study showed that 92% of the patients had adverse events related to panitumumab (16% had grade 3 and 2% had grade 4 acute renal failure, pulmonary embolism). 9 (B)
Subsequently, a retrospective analysis of a predefined subset of data from this study 15  The most common grade 3 and 4 adverse events known to be associated with anti-EGFR therapy were neutropenia, skin toxicity, diarrhoea, and neurological toxicity.

SECOND-LINE
Patients with mCRC without prior therapy with Anti-EGFR and ECOG performance status from 0 to 2. Patients (N = 1,186) who had not responded to a prior chemotherapeutic treatment (fluoropyrimidine scheme) were randomized to panitumumab 6 mg/kg every two weeks plus FOLFIRI or FOLFIRI alone, until disease progression or intolerability. The most common grade 3 and 4 adverse events were skin toxicity, neutropenia and diarrhea. 17 (B)

PANITUMUMAB + BEVACIZUMAB
Multicentre open-label RCT that evaluated panitumumab added to bevacizumab associated with chemotherapy based on oxaliplatin and irinotecan as the first-line in non-selected mCRC patients with KRAS mutation. Panitumumab was discontinued after planned interim analysis showed that when it was added to the FOLFOX/bevacizumab regimen, there was a worsening in PFS and increased toxicity compared to the FOLFOX/bevacizumab regimen alone. In both chemotherapy regimens (oxaliplatin and irinotecan), panitumumab was associated with a higher rate of disease progression or death (NNH = 16) and overall mortality (NNH = 11 in oxaliplatin and NNH = 14 in irinotecan). 18 (B) RECOMMENDATIONS

PAN + BSC versus BSC (second or thirdline monotherapy)
Patients with mCRC with EGFR expression, after confirmation of failure of regimens containing fluoropyrimidine, oxaliplatin and irinotecan.
• There was no statistically significant difference between groups in the analysis of overall survival (HR =

SUMMARY OF EVIDENCE:
In patients with metastatic colorectal cancer and wild-type KRAS, the addition of panitumumab to the first-line chemotherapy regimen (FOLFOX-4) added 1.6 months to the progression-free survival, but did not show improvement in overall survival. When associated with a second-line chemotherapy regimen (monotherapy or FOLFIRI) in patients with good performance status and adequate organic function, it added 1 to 2 months in progression-free survival without showing a favourable result with an increase in overall survival.
The results of the studies were affected by crossover and sequential treatments. There are also important biases found in the critical analysis of studies such as subgroup analysis and lack of independent evaluator for data analysis.

Clinical Question
Do patients with metastatic colorectal cancer benefit from the use of panitumumab?

Papers Recovered
Obtaining the evidence to be used followed the steps of preparation of the clinical question, structuring the question, search for evidence, critical evaluation and selection of evidence, exposure of results and recommendations.
The bases of scientific information consulted were Medline via PubMed and Cochrane/Lilacs/BVS. Manual search from references of reviews (narratives or systematic), as well as the selected papers, was performed. 595 recovered papers were recovered until the last search date with the final search strategy.

Criteria for inclusion of selected papers
The selection of the studies, evaluation of titles and abstracts obtained with the search strategy in the consulted information bases was carried out by two researchers with skills in the preparation of systematized reviews, independently and blindly, strictly following the inclusion and exclusion criteria estab-lished and described in the PICO components, finally separating the papers with potential relevance.
All the papers recovered in the primary and secondary information bases were evaluated. In the primary bases, after the first critical evaluation, we selected PubMed-Medline (12) and Cochrane/Lilacs/ BVS (zero). In the manual search, no papers were selected.

According to the study designs
Only studies with a Randomized Clinical Trial (phase III) study design were included. When the clinical question was considered relevant, the protocol of this review allowed to broaden the search criteria including some evidence with subgroup analysis.

Language
Studies available in Portuguese, English or Spanish were included.

According to the publication
Only papers whose complete texts were available were considered for critical evaluation.

Method of critical evaluation
The papers considered for full text reading were critically evaluated according to the inclusion and exclusion criteria, by Study design, PICO, language and availability of the full text.
Of 12 papers considered for critical evaluation, none were excluded due to the lack of full text.
The papers included in the evaluation are from between 2007 and 2014.
When, after applying the inclusion and exclusion criteria, the selected evidence was defined as a ran-

Result
Benefit or harm in absolute data, average benefit or harm domized controlled trial (RCT), it underwent an appropriate critical evaluation checklist ( Table 1). The critical evaluation of the RCT allows classification according to the JADAD score 19 , considering the JADAD tests < three (3) as inconsistent (grade B), and those with score ≥ three (3), consistent (grade A), and according to the GRADE score 20 (strong or moderate evidence).
When the selected evidence was defined as a comparative study (observational cohorts or non-randomized clinical trial), it was submitted to an appropriate critical evaluation checklist (Table 2), allowing the classification of the study according to the NEWCAS-TLE OTTAWA SCALE score 21 , considering cohort studies with score ≥ 6 consistent, and <6 inconsistent.

Exposure of results
For results with available evidence, the population, intervention, outcomes, presence or absence of benefit and/or harm and controversies will be specifically defined, whenever possible.
The results will be preferentially exposed in absolute data, absolute risk, number needed to treat (NNT), or number needed to harm (NNH), and possibly in average and standard deviation (table 3).

Recommendations
The recommendations will be prepared by the authors of the review, with the initial characteristic of the evidence synthesis being submitted to the validation by all authors participating in the preparation of the Guideline.
The degree of recommendation to be used comes directly from the available strength of the studies included according to Oxford 22 , and the use of the GRADE 20 system.