Hospital Garcia de Orta
Colorectal cancer (CRC) is one of the most common malignancies. In Portugal it is the second most frequent cancer. The standard treatment for CRC has changed in recent years, from single-agent chemotherapy (fluorouracil with leucovorin modulation) to combination regimens that include irinotecan or oxaliplatin associated with fluorouracil and folinic acid (FOLFIRI and FOLFOX, respectively), in both first- and second-line therapy. Both these regimens have shown improved survival rates in patients with metastatic CRC (mCRC), with no apparent differences associated with the sequence in which they are given.
The development of new target therapies offers the potential to improve this survival rate. Cetuximab is a chimeric anti-epidermal growth factor receptor (EGFR) monoclonal antibody that shows efficacy in patients with EGFR-positive mCRC. EGFR is over‑expressed in a large number of solid tumours, including colon adenocarcinoma. EGFR over‑expression has been correlated with disease progression, poor prognosis and reduced sensitivity to chemotherapy.
The main study that led to cetuximab approval in mCRC, the BOND (Bowel Oncology with cetuximab aNtiboDy) study, was an open-label, multicentre, randomised phase II trial that included 329 EGFR-positive mCRC patients. This study compared the efficacy of cetuximab in combination with irinotecan with that of cetuximab alone in mCRC that was refractory to treatment with irinotecan. Although the overall response rate (22.9% [95% CI: 17.5–29.1%] vs 10.8% [95% CI: 5.7–18.1%], p = 0.007) and the median time to progression (4.1 months vs 1.5 months; p < 0.001) were greater in the combination therapy group, there was no statistically significant difference between the two groups for median overall survival time (8.6 months vs 6.9 months; p = 0.48). It is important to note that this study did not compare cetuximab with current standard therapy, either in second- or subsequent-line therapy. Both study arms included cetuximab.
To date, EGFR positivity has been mandatory for clinical use of cetuximab, as well as for eligibility in clinical trials. However, considerable evidence exists, suggesting that EGFR expression, measured by immunohistochemistry (IHC), does not correlate with tumour response to cetuximab.[3,4] Prospective trials to assess the activity level of cetuximab are still needed in EGFR-negative patients.
The current licensed indication of cetuximab by the EMEA is in association with irinotecan as second-line treatment following failure of an irinotecan-containing regimen, in EGFR-positive mCRC patients. Therefore, decisions about the use of this drug would have to be based on this current marketing authorisation. Utilisations in EGFR-negative mCRC patients are considered off-label.
A recent study evaluated the efficacy of cetuximab, in combination with irinotecan, in mCRC patients refractory to previous treatments based on oxaliplatin or irinotecan. It included 55 pretreated patients. Median time to progression was 4.7 months (95% CI: 2.5–7.1 months) and the median survival time was 9.8 months (95% CI: 3.9–10.1 months). These results are comparable with those obtained in the BOND study, confirming that pre-treatment with oxaliplatin does not represent a negative factor for response to cetuximab plus irinotecan. Cetuximab remains clinically active even in heavily pretreated mCRC patients, after failure of both irinotecan and oxaliplatin-based chemotherapy regimens.
The cost of these new therapies for mCRC is particularly high, being a heavy economic burden to health systems in many countries. The UK’s National Health Service (NHS), through its National Institute for Health and Clinical Excellence (NICE), does not consider cetuximab cost-effective as regards NHS resources. A NICE technology appraisal published in January 2007 does not recommend cetuximab for routine use in mCRC patients within the NHS. In Portugal, resources are limited by new economic rules from the Ministry of Health, and the high cost of these new drugs is difficult to manage. Pharmaco‑genomic and molecular biology are needed to help select patients with a higher chance of responding to specific treatments, allowing resources to be optimised.
A survey of cetuximab activity in mCRC patients was carried out in our hospital from November 2004 to April 2007. It included all mCRC patients who had received cetuximab. Data were obtained from chemo‑therapy prescription forms and pharmacy registers. Our main objective was to establish the time to progression (TTP) of tumours, based on the number of cycles of cetuximab. It is recommended that cetuximab treatment be continued until progression of the underlying disease, meaning that the median treatment duration is similar to the median time to progression.
The characteristics of the 29 mCRC patients included were: male : female, 21 : 8; median age, 60.3 years (range 43–76). The median number of chemotherapy regimens preceding first cetuximab administration was two (range 1–5). All patients received cetuximab combined with irinotecan (cetuximab given at an initial dose of 400 mg/m2, followed by weekly infusions of 250 mg/m2, combined with bi-weekly infusions of 250 mg/m2 of irinotecan, repeated every 14 days). EGFR status was positive in all except one patient. The median number of cycles of the combination cetuximab + irinotecan (C + Iri) was 7.7 (range 1–20) and was not significantly different if the regimen was used in second-, third- or subsequent-line therapy. Mean TTP was 3.5 months (IC 95%: 1.1–6.1).
The median TTP in patients with mCRC, treated with cetuximab at Hospital Garcia de Orta was slightly shorter, but in accordance with the data reported in the BOND study. In our patients, when cetuximab was used as second-line therapy directly after irinotecan failure, the median time to progression was similar to when it was used as a third-line or later treatment.
The real-world use of new therapies, authorised by pharmaceutical and therapeutics committees, must always be analysed in order to validate results obtained in clinical trials. New drugs are usually involved in major information campaigns promoted by the pharmaceutical industry, with focus on product advantages instead of possible problems. Experiences with utilisation of new drugs must be monitored, incorporating data from other drugs approved for the same indications, and considering the evolution of costs of the different options, in constant change with the introduction of generic drugs.
1. Instituto Português de Oncologia de Lisboa Francisco Gentil. Registo Oncológico Regional Sul (Southern Region Oncological Register). Lisbon: IPOLFG; 2007. Available at: www.ror-sul.org.pt/TiposDeTumor/Top5/ColonRecto/Pages/Epidemologia.aspx
2. Tournigand C, André T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004;22(2):229-37.
3. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351:337-45.
4. Chung K, Shia J, Kemeny N, et al. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol 2005;23(9):1803-10.
5. European Medicines Agency. EPARs for authorised medicinal products for human use: Erbitux. London: EMEA; 2007. Available at: www.emea.europa.eu/humandocs/Humans/EPAR/erbitux/erbitux.htm
6. Vincenzi B, Santini D, Rabitti C, et al. Cetuximab and irinotecan as third-line therapy in advanced colorectal cancer patients: a single-centre phase II trial. Br J Cancer 2006;94:792-7.
7. UK National Institute for Health and Clinical Excellence. Bevacizumab and cetuximab for the treatment of metastatic colorectal cancer: NICE technology appraisal guidance 118. London: NICE; 2007. Available at: www.nice.org.uk/guidance/TA118