Introduction
5-Fluorouracil (5-FU) has remained the single most effective systemic agent against metastatic colorectal cancer for the past 40 years. However its efficacy was very limited. Treatment with 5-FU produced a response rate of around 20% and improved survival by several months compared to best supportive care (12 months vs. 9 months). The turn of the new millennium saw the broadening of therapeutic options for colorectal cancer patients brought about by the emergence of two new cytotoxic agents – irinotecan and oxaliplatin. Adding irinotecan to 5-FU (FOLFIRI) or oxaliplatin to 5-FU (FOLFOX) resulted in highly active combination regimens. Both regimens were shown to be equally effective with response rates of around 50% in first-line treatment and median survivals of around 15 months. Sequential treatment with FOLFIRI and FOLFOX in whichever order produced a median overall survival of around 20 months. Although these two new agents have taken the management of systemic colorectal cancer two big steps forward, one major inherent problem remains – cytotoxic drugs remain indiscriminate in their action. These “dirty bombs” also kill healthy dividing cells, which is often the main dose limiting effect. Both physicians and patients have long desired for a “magic bullet” that could specifically target and effectively kill cancer cells without harming the healthy cells.
Definition
What is targeted therapy? The advent of imatinib (Glivec) in the treatment of chronic myeloid leukemia and gastrointestinal stromal tumour heralded a new era in the battle against cancer. It was the first rationally developed “magic bullet” to be approved for the treatment of cancer. Targeted therapy is t reatment aimed at specific targets in or on the cancer cells that blocks cancer growth or cancer spread. Three main strategies employed to achieve this are (i) monoclonal antibodies (MABs) that attach to cancer cells, (ii) small molecules that can block intracellular signaling pathways, and (iii) gene therapy to block expression of oncogenes or replace defective/missing tumour suppressor genes. The discussion in this article will be largely limited to the MABs, which have recently been approved for clinical use in colorectal cancer.
Mechanism
Monoclonal antibodies can be classified according to their origin: (i) murine, (ii) chimeric, (iii) humanized, and (iv) human. The origin of these MABs is reflected in its nomenclature – “momab” for murine, “ximab” for chimeric, “zumab” for humanized, and lastly “mumab” for human monoclonal antibody. MABs mediate their anticancer effect through several mechanisms. They may bind to growth factor receptors to block ligand signalling. They may mark cancer cells for attack by the body’s immune system. They may deliver radioactive or cytotoxic conjugates to cancer cells. These various mechanisms take place extracellularly and are dependent on the ability of these antibodies to recognize specific antigens on the surface of the cancer cells.
Cell surface receptors such as epidermal growth factor receptor (EGFR) transduce growth stimulatory signals such as EGF and TGF a into the cell interior, evoking effector downstream mitogenic pathways. Ligand binding to the extracellular domain of the EGFR leads to EGFR activation. Activated EGFR then homodimerizes, resulting in the phosphorylation of the intracellular tyrosine kinase initiating a series of intracellular signals including the central Ras-/mitogen activated protein kinase pathway. Colorectal cancer cells have been shown to highly express EGFR. Over-expression of EGFR has been associated with cell proliferation, migration and resistance to apoptosis. Cetuximab is a chimeric monoclonal antibody that binds to the epidermal growth factor receptor (EGFR). This blocks receptor activation thus preventing signal transduction into the cell.
Neovascularization is a prerequisite for tumour growth, invasion and metastasis. Neovasculariztion is mediated by vascular endothelial growth factor (VEGF), which is a ligand for the VEGF family of transmembrane tyrosine kinase receptors. Bevacizumab (Avastin) is a recombinant humanized version of a murine anti-human VEGF monoclonal antibody. Binding to VEGF blocks ligand activation of the VEGFR and its downstream biological effects.
The implications of these new techniques and ideas are huge. We stand at the threshold of new and exciting times for radiotherapy, and cancer management as a whole. With the advent of new technologies and the redefinition of old theories, coupled with modern surgical techniques and new molecular based targeted drugs, we look forward to the day when we can safely eradicate cancer cells without doing any harm to our normal tissue, all in quick and simple measures.
Indications
Irinotecan-based chemotherapy was the standard of care for metastatic colorectal cancer in the US. The response rate of second-line chemotherapy after failure from irinotecan was around 10%. In the BOND 1 study, more than 300 patients with EGFR-positive metastatic colorectal cancer who have progressed on irinotecan were randomized (2:1) to receive either irinotecan again with cetuximab or cetuximab alone. An exceptional 23% response rate was reported in patients retreated with irinotecan plus cetuximab. Additionally, cetuximab was also active as a single agent with a response rate of around 10%. The results of this study led to the approval of cetuximab for treating irinotecan-refractory metastatic colorectal cancer either as a single agent or in combination with chemotherapy.
A randomized controlled phase III trial with more than 800 subjects studied the effect of adding bevacizumab to first-line irinotecan-based chemotherapy for metastatic colorectal cancer. It was shown that the addition of bevacizumab to first-line chemotherapy improved response rates and prolonged survival by another 5 months (20 months vs. 15 months without bevacizumab). Bevacizumab is currently indicated for first-line treatment of metastatic colorectal cancer in combination with irinotecan-based chemotherapy. Other studies have failed to demonstrate meaningful activity of bevacizumab as a monotherapy and thus its use as a single agent is not advocated.
Toxicities
The actions of targeted therapy are developed to be more cancer cell-specific, thus minimizing undesired effects on the healthy cells. One major benefit of this specificity is the general absence of the traditional adverse effects expected with conventional cytotoxics such as alopecia, emesis, mucositis, diarrhoea and most importantly myelosuppression. This advantage has permitted the easy integration of targeted agents with conventional chemotherapy without incurring excess systemic toxicity. However, these unique molecular agents do have their own set of peculiar side effects.
Cetuximab is very well tolerated and has an excellent safety profile with only 12% of patients experiencing grade ≥ 3 (severe) side effects. The most frequent side effect is that of an acneiform rash. Interestingly, response to therapy is correlated to the rash but not to EGFR expression by immunohistochemistry. Other side effects include asthenia, transaminitis, and infusion-related events such as fever, chills and allergic reaction.
In contrast, the use of bevacizumab is associated with certain small but potentially serious concerns. There appears to be an excess of vascular thrombosis, haemorrhage, and perforation in patients treated with bevacizumab compared to those without. Hypertension and proteinuria are additional side effects encountered with this agent.
Further Developments
Three new developments in the therapeutic use of targeted therapy were reported this year.
Firstly, cetuximab was added to either first-line FOLFOX or FOLFIRI in a randomized CALGB (Cancer and Leukemia Group B) study. Although one would intuitively anticipate that the addition of cetuximab to two equal chemotherapy regimens would have an equal effect, preliminary results from this study suggested that patients receiving FOLFIRI and cetuximab appear to enjoy a longer time to progression. However the authors cautioned that that the data was immature and that accrual was poor for this study.
The final analysis of the TREE-1 and TREE-2 studies was also presented at the American Society of Clinical Oncology (ASCO) in 2006. In the TREE-1 study, the investigators compared three oxaliplatin/fluoropyrimidine (bolus 5-FU, infusional 5-FU, oral 5-FU) regimens whereas in the TREE-2 study bevacizumab was added to the same regimens used in TREE-1. The TREE-2 study found that adding bevacizumab to the same regimens improved overall survival (median survival of 24.2 vs. 18.2 months).
Finally, combined targeted therapy, concurrent cetuximab and bevacizumab, was shown to be promising in irinotecan-refractory patients in the BOND-2 study. Patients with advanced colorectal cancer who has failed irinotecan were randomized to receive either a combination of cetuximab and bevacizumab with or without irinotecan. The response rate was 37% for the combined targeted therapy with irinotecan compared to 20% without and the progression free survival was 8 months for combined targeted therapy with irinotecan compared to 6 months without. In any case, the use of combined targeted therapy in second-line treatment when compared to historical controls was superior to cetuximab alone or with irinotecan (BOND-1 study).
Novel targeted agents
Two novel targeted agents are being investigated as therapy for advanced colorectal cancer. PTK/ZK is a novel oral small molecule anti-angiogenic compound. Unlike bevacizumab, PTK/ZK targets the intracellular tyrosine kinase domain of the VEGF receptor (VEGF TKR). In the CONFIRM-2 study, the addition of PTK/ZK to FOLFOX offered a progression free survival advantage, especially for patients with high serum LDH, although this failed to result in an overall survival difference. Another EGFR antibody is panitumumab. It differs from cetuximab in that it is a fully humanized monoclonal antibody. Panitumumab has been studied as a monotherapy in patients who have failed all lines of chemotherapy (AACR 2006;47:abstract CP-1). In this trial patients randomized to receive panitumumab had a 24-week survival benefit compared to those on best supportive care (18% vs. 5%).
Conclusions
Despite improvements in chemotherapy, unresected advanced colorectal cancer remains incurable. Also the number of concurrent agents selected, the dose and the duration of treatment are very often limited by systemic toxicities or “collateral damage”. Targeting EGFR, VEGF or VEGF TKR is a paradigm shift from the standard chemotherapy treatment. We now have a means to target cancer cells specifically without harming the normal healthy cells such as those in the bone marrow and those lining the gut. As more of the cancer cell’s internal circuitry becomes unravelled, more molecular targets will avail themselves to our use. In the future, perhaps cancer may be managed like a chronic illness using multitargeting molecular therapies with or without conventional cytotoxic agents.
Dr Simon Ong
Senior Consultant
Medical Oncology
National Cancer Centre
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