Digestive and Liver Disease
Volume 38, Issue 2 , Pages 71-77, February 2006

Targeted therapy in colorectal cancer: do we know enough?

  • M.A. Pantaleo

      Affiliations

    • Institute of Hematology and Medical Oncology “L.A. Seràgnoli”, University of Bologna, Sant’Orsola-Malpighi Hospital, Via Massarenti 9, Bologna 40138, Italy
    • ,
  • E. Palassini

      Affiliations

    • Institute of Hematology and Medical Oncology “L.A. Seràgnoli”, University of Bologna, Sant’Orsola-Malpighi Hospital, Via Massarenti 9, Bologna 40138, Italy
    • ,
  • R. Labianca

      Affiliations

    • Ospedali Riuniti, Bergamo, Italy
    • ,
  • G. Biasco

      Affiliations

    • Institute of Hematology and Medical Oncology “L.A. Seràgnoli”, University of Bologna, Sant’Orsola-Malpighi Hospital, Via Massarenti 9, Bologna 40138, Italy
    • Corresponding Author InformationCorresponding author. Tel.: +39 051 6364078; fax: +39 051 6364037.

Received 11 April 2005; accepted 3 October 2005.

Article Outline

Abstract 

The present paper is a critical review about the recent development of new agents that have revolutioned the therapeutical approach of solid tumours with a particular focus on colorectal cancer. Until a few years ago, chemotherapy has been considered the only medical treatment for advanced disease. At the moment, new drugs blocking some cell functions, such as monoclonal antibodies or tyrosin kinase inhibitors are available for many oncologists, but their efficacy should be debated for several reasons. Despite having a strong biological and preclinical rationale, the clinical results of these agents are not comparable to the results obtained by imatinib in gastrointestinal stromal tumour or in chronic myeloid leukaemia even though superior to chemotherapy alone. Moreover, the efficacy does not show any correlation with the molecular expressions of the tumours. In this review, we considered different hypotheses in order to explain these results.

Keywords: Colorectal cancer, Epidermal growth factor receptor, Targeted therapy, Vascular endothelial growth factor

 

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1. Introduction 

In recent years, agents specifically blocking some functions of neoplastic cells have been developed for the treatment of tumours. Among these agents, some tyrosine kinase inhibitors have been used successfully in the therapy of malignancies, such as gastrointestinal stromal tumours (GIST) and chronic myeloid leukaemia (CML) [1], [2]. Today, other molecules such as cyclo-oxygenase-2 (COX-2) inhibitors, the antibody to the epidermal growth factor receptor (EGFr) cetuximab and the antibody to the vascular endothelial growth factor (VEGF) bevacizumab have been proposed for the treatment of colorectal cancer [3], [4], [5]. Some clinical trials have suggested that these agents could provide a benefit in progression free survival and in the overall survival of patients with advanced disease [5]. These substances will be authorised or will become available shortly for clinical practice and are now considered by many oncologists as an important option in the treatment of colorectal cancer. In the meantime, the media is generating mounting expectations for patients suffering from this condition.

A revolution in therapeutic decision for patients with colorectal cancer is incoming. But, do we know enough about both the efficacy and the safety of these new agents? Have the economic consequences of their use been adequately evaluated? Have criteria been defined to enable patients who may benefit from the treatment to be selected? Has the combination with chemotherapy been studied enough to plan combined therapeutic strategies? In other words, are we really ready for them in clinical practice?

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2. Blocking epidermal growth factor receptor (EGFr) 

EGFr is a transmembrane receptor with tyrosine kinase activity that belongs to c-erb family. EGFr disregulation plays different roles in the tumorigenesis process: control of cell proliferation, control of apoptosis and stimulus to the secretion of many growth factors involved in angiogenesis [6]. In colorectal cancer EGFr overexpression was found in 25–75% of the subjects [7], [8], [9]. EGFr expression has been reported to be associated with advanced disease, lymph-node invasion, poor tumour differentiation, shorter disease-free survival in patients with liver resection and poor overall survival [7], [10], [11], [12]. Different strategies for targeting EGFr have been developed: anti-receptor monoclonal antibodies or small molecular inhibitors of intracellular tyrosine kinase.

2.1. Preclinical studies 

Preclinical studies have shown that anti-EGFr monoclonal antibodies inhibit cell growth by competing with ligand for the receptor [13], [14]. Moreover, in vitro as well as in vivo animal studies, cetuximab (a chimeric IgG1 monoclonal antibody that binds to EGFr with high affinity and specificity) has been shown to increase the antitumour activity of chemotherapy suggesting that the combination of cetuximab and chemotherapy in patients with metastatic colorectal cancer could improve the efficacy of chemotherapy alone [15], [16].

2.2. Clinical studies 

The efficacy of cetuximab in the treatment of advanced colorectal cancer has been studied initially in irinotecan-refractory patients [17], [3], [4].

The first clinical evidence of its antitumoural activity in colorectal cancer was published by Saltz et al. [17]. One hundred and twenty patients with irinotecan-refractory EGFr-positive colorectal cancer were treated with a combination of irinotecan and cetuximab, following a previous preclinical study showing synergy between these two agents [16]. The objective responses were 17%, and the stable disease was 31%. To evaluate the safety and the antitumour activity of cetuximab as single agent, a phase II trial was conducted in 57 patients with chemotherapy refractory colorectal cancer with evidence of EGFr positivity on immunohistochemistry (IHC) assessment [3]. An objective response was seen in 26 patients: 6 (10.5%) partial responses and 20 (35%) minor responses or stable disease were observed. Response was not correlated with the degree of EGFr expression.

A multicentre randomised trial was conducted in Europe (BOND study) to assess the efficacy of cetuximab alone or in combination with CPT-11 in 329 patients with refractory colorectal cancer expressing EGFr [4]. The response rate observed was 10.8% for cetuximab alone versus 22.9% for the combination therapy (p=0.007). The median time to progression was 1.5 months versus 4.1 months (p=0.001). The response rate again did not correlate with the percentage of EGFr-positive tumour cells or EGFr intensity per cell; however, skin toxicity of cetuximab correlated with response.

Several trials assessing the safety and efficacy of cetuximab and chemotherapy containing irinotecan or oxaliplatin as front line therapy of metastatic colorectal cancer expressing EGFr have also been conducted [18], [19], [20], [21], [22], [23], [24].

The tyrosine kinase inhibitor of EGFr, as erlotinib, has been investigated. One phase I study evaluated the maximum-tolerated dose (MTD) of gefitinib combined to irinotecan [25]. Five phase II studies showed its activity as first- and last-line treatment of colorectal cancer in monotherapy or in combination with FOLFOX-4, with capecitabine, irinotecan or oxaliplatin [26], [27], [28], [29], [30]. These studies underlined its safety but little efficacy. Phase III studies are needed to evaluate the role of gefitinib or erlotinib in the treatment of advanced colorectal cancer.

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3. Blocking vascular endothelial growth factor 

VEGF is a growth factor with several isoforms derived by RNA splicing (from VEGF-A to VEGF-E). As a regulator of angiogenesis, VEGF promotes arterial and venous formation, endothelial and tumour cell migration and growth [31]. VEGF is upregulated by hypoxia and by several growth factors, such as EGF, transforming growth factor-α (TGF-α) and other cytokines like interleukin 1 [32].

VEGF overexpression was found in 30–53% of patients with colorectal cancer, being associated with shorter disease-free survival in patients with non-metastatic colorectal cancer [33], [34], [35]. There are many ways to block the VEGF signalling pathway including the use of monoclonal antibodies against VEGF (bevacizumab) or against its receptor (IMC-1C11) and the use of inhibitors of VEGF signalling (SU5416, SU11428) or binding.

3.1. Preclinical studies 

Inhibition of the VEGF pathway has been investigated in several preclinical studies and has shown the suppression of tumour growth and liver metastases in mice [36], [37]. Moreover, the anti-VEGF antibody bevacizumab has been shown to be able to alter vasculature in cancers promoting the antitumour effects of chemotherapy [38].

3.2. Clinical studies 

Bevacizumab was investigated in two phase I trials and shown to be well-tolerated and without interactions with chemotherapy [39], [40]. A phase II trial compared bevacizumab 5 and 10mg/kg plus chemotherapy (fluorouracil and leucovorin) versus chemotherapy alone [41]. Bevacizumab 5mg/kg plus chemotherapy obtained improvement in the response rate (40% versus 24% for high dose arm versus 17% for chemotherapy alone), time to progression (9 months versus 7.2 months versus 5.2 months) and median survival time (21.5 months versus 16.1 months versus 13.8 months) supporting further studies about this combination therapy in this setting.

A randomised trial to evaluate the efficacy of the addition of bevacizumab to irinotecan plus fluorouracil and folinic acid (IFL) versus IFL and placebo as front-line therapy has also been conducted in 813 patients affected by metastatic colorectal cancer. The combination therapy containing bevacizumab was shown to be superior for median survival (20.3 months versus 15.6 months) (p=0.001), for time to progression (10.6 months versus 6.2 months) (p=0.001), response rate (44.8% versus 34.8%) (p=0.004) and median duration time of response (10.4 months versus 7.1 months) [5]. Survival was also prolonged in multiple subgroups of different base-line prognostic factors. The incidence of grade 3 or 4 adverse events were higher in the IFL and bevacizumab arm (p<0.001), in particular grade 3 hypertension although was manageable with standard oral antihypertensive agents. Gastrointestinal perforation occurred in six patients receiving IFL and bevacizumab and one patient died. All other antiangiogenic-related adverse events (thrombotic events, deep thrombophlebitis, pulmonary embolus, grade 3–4 bleeding) were not statistically different in the two groups. The evaluation of tumour VEGF or tumour microvessel density was not performed.

Bevacizumab has also been combined with FOLFOX-4 and compared with FOLFOX-4 alone or bevacizumab alone in irinotecan refractory patients with advanced colorectal cancer. This phase III trial showed, firstly (toxicity analysis), that the combination therapy did not alter the profile seen with FOLFOX-4 alone, and then showed an increment in survival (12.5 months versus 10.7 months, p=0.0024) [42], [43].

Bevacizumab in combination with FOLFOX-4 or capecitabine is currently under investigation in front-line therapy of metastatic colorectal cancer and in adjuvant setting in patients with resected colon cancer [44], [45].

Recently, the combination with bevacizumab and cetuximab with or without irinotecan, has been investigated in irinotecan-refractory patients with colorectal cancer [46]. The interim analysis does not show substantial differences about toxicity from the single-monoclonal antibody treatment.

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4. Blocking cyclo-oxygenase-2 

COX-1 promotes physiological responses and COX-2 promotes angiogenesis, apoptosis and proliferation through PPARδ. PPARδ is regulated by the APC/β-catenina/Tcf-4 pathway, promoting some unidentified genes activation important for cell growth [47]. COX-2 expression has been shown to be involved in apoptosis, cellular adhesion, angiogenesis and intestinal tumorigenesis [48]. Fifty percent of colonic adenomas and about 70–90% of colorectal tumours overexpress COX-2 enzymes or prostaglandins [49], [50]. COX-2 expression correlates with invasiveness, metastasis and reduced survival [49], [51], [52]. The selective COX-2 inhibitors developed in clinical trials are celecoxib and rofecoxib.

4.1. Preclinical studies 

Preclinical studies showed colon tumour inhibition by NSAIDs. In addition, clinical studies conducted in patients affected by familial adenomatous polyposis showed a reduction of colonic polyps by sulindac [53], [54]. The inhibition of COX-2 had a chemopreventive effect on colonic carcinogenesis [55].

Cyclo-oxygenase inhibition with celecoxib has been shown to enhance cytotoxicity if combined with chemotherapeutic drugs like irinotecan, 5-fluorouracil, vincristine, cisplatin, doxorubicin and bleomicin [56].

4.2. Clinical studies 

Two phase II studies were conducted in the untreated patients affected by advanced colorectal cancer to evaluate antitumour efficacy of the combination therapy with celecoxib, fluorouracil and folinic acid [57], [58]. Partial remission (RP) resulted in 28 and 32%, and stable disease (SD) in 56 and 38%, respectively. Toxicity was minimal and not worse than that seen with chemotherapy alone. A promising activity has also been shown for the addition of celecoxib to an irinotecan and capecitabine regimen [59]. In a phase I study, the combination of rofecoxib with irinotecan/fluorouracil/folinic acid in 15 pretreated patients showed a good toxicity profile. A phase II study is still ongoing [60].

No phase III studies are available to define the role of the COX-2 inhibitors in the treatment of metastatic colorectal cancer.

EORTC has begun a randomised phase II study (EORTC 40015) with the intention of enrolling 692 previously untreated patients with advanced colonic cancer to receive four different schedules containing capecitabine (1000mg/mq on days 1–14 every 3 weeks) and irinotecan (250mg/mq once every 3 weeks) or the FOLFIRI regimen associated with placebo or celecoxib (400mg twice daily).

In the adjuvant setting, two studies have also been planned: the VICTOR trial (VIOXX in colorectal cancer therapy: definition of optimal regimen) and the ACTION trial or PETACC-5 (adjuvant celecoxib therapy in oncology). Both of these studies were planned to investigate the role of COX-2 inhibitors in combination with fluorouracil/folinic acid in patients with Dukes’ B2 o C colorectal cancer. Both of these studies have recently been stopped probably because of the potential cardiovascular toxicity, which has resulted in rofecoxib being voluntarily withdrawn from the market by pharmaceutical manufacturer. In fact, the VICTOR trial showed that the relative risk of thrombotic cardiovascular event was 2.28 (p=0.002) for rofecoxib treatment compared with naproxen. No difference in the cardiovascular event rates between celecoxib and other FANS has been reported [61], [62].

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5. Discussion 

Until a few years ago, chemotherapy was considered the standard treatment for patients with advanced colorectal cancer. If the median survival for patients with advanced disease treated with fluorouracil and folinic acid has been reported in clinical trials as 11–13 months, the combination regimens with fluorouracil and folinic acid plus irinotecan or oxaliplatin have achieved OS of 14.8–21.5 months [63]. The role of new drugs in the treatment of colorectal cancer, as single agent or in combination with standard chemotherapy, has been investigated in several studies but should be debated for almost two reasons.

Firstly, the results of treatment with these new drugs, even though superior to chemotherapy alone in some randomised clinical trials, are not comparable to the results obtained in other malignancies, such as GIST or CML [1], [2].

Secondly, their activity is not apparently related to the expression of the target: receptor, factor or enzyme. In particular, the response to cetuximab does not show any correlation with the percentage of EGFr-positive tumour cells or EGFr intensity per cell. Patients with EGFr-negative tumour cells could respond to cetuximab [3], [4], [64]. In other clinical trials, no data about these parameters are reported [17], [18], [19], [20], [21], [22], [24]. In clinical trials investigating the role of bevacizumab, none of the surrogate markers for angiogenesis have been done, such as VEGF, vascular cell adhesion molecule-1 (VCAM-1), microvessel density, platelet-derived endothelial cell growth factor (PDGF) or basic fibroblast growth factor (b-FGF) [5], [39], [40], [41], [42], [43], [44]. The same statements apply for studies with COX-2 inhibitors because no COX-2 or prostaglandins level were measured [57], [58], [59], [60]. Urinary VEGF and b-FGF levels were determined in a phase I study of SU5416 and did not correlate with response even though they were one to twofold higher in patients with advanced malignancies treated with this drug [65]. The ‘targeted therapy’ strategy, despite having a strong biological and preclinical rationale, should be discussed because these drugs are able to induce responses independently from the expression of their targets.

Several hypotheses therefore need consideration and evaluation (Table 1).

1.In colorectal cancer, the current evaluation of the ‘target’ or ‘target-related molecules’ is not adequate to support appropriate decisions regarding care, while in breast cancer the correlation between c-erbB2 expression and clinical response to trastuzumab is well known [66]. At the moment, IHC has been considered the method of choice in clinical trials to detect EGFr but we think IHC has not been an ideal determinant of response for several reasons. EGFr in colorectal cancer is reported to be overexpressed in 25–77% of the subjects [7], [8], [9]. This wide range could be explained by interobserver variation or by no standardised score in IHC evaluation. Moreover, EGFr IHC determination is dependent on the storage time of archived tissue sections and on the fixative used [67]. It could be dependent on different affinity of the EGFr for antibodies in use today. In addition, phenotypical or morphological expression of a molecule may not be related to its real functioning presence in cancer. A molecular determination of the receptor and related intracellular molecules with western blotting, Elisa, real time-PCR or FISH could be more appropriate to have a true biological and global background of the neoplasia, an essential condition for using the targeted therapy. In fact, the response to EGFr monoclonal antibodies may be related to EGFr copies number detected by FISH or to levels of some members of EGFr signalling pathway detected by RT-PCR, like VEGF [68], [69].

2.The distribution of specified molecules within the tumour area is not uniform. The expression of EGFr may be higher in the invasion front than in neoplasia [7]. So the biological definition of tumour could be dependent on the studied area. In published clinical studies concerning blocking EGFr we cannot find the details regarding this particular aspect [3], [4]. For this reason, the experience of breast cancer, probably, cannot be extrapolated to colon cancer. In addition, the EGFr status may be different on primary tumour and related metastases [70]. The detection of EGFr on primary tumour could be inadequate for planning therapy in metastatic cancer.A novel approach for studying the clinical application of target therapies could be the use of functional or imaging techniques, such as positron emission tomography (PET) that provides information, firstly, on the in vivo distribuition of the target and then on response or resistance to such targeted agents [71], [72]. Novel tracers for imaging VEGF, cyclo-oxygenase or EGFr have been studied in vitro and in animal studies. Because of the heterogeneity of tumour biology with respect of drugs uptake and clearance, we believe that one of the most important issues in this field is the characterisation in vivo of the tumour expression. The anti-cancer efficacy of the biological agents should be tested with the distribution of the biological process in the primary tumour and metastases, probably being used to identify the best setting like advanced or minimal disease for predicting response to these drugs.

3.Different mutations of the target molecules may be associated to a different activity of the drugs and consequently to a different clinical response [73], [74], [75], [76]. In fact, patients affected by GIST with c-kit mutations on exon 11 showed a response rate to imatinib of 83.5% in comparison to 47.8% in case of mutation on exon 9 (p=0,0006) and to 0% of those without a detectable mutation (p<0,0001) [73]. The signalling pathway of EGFR could also be important, as in patients with lung cancer phosphorylation of AKT (p-AKT) in the tumour is associated with a better response to gefitinib and slower time to progression than in patients with p-AKT negative tumours [76].

4.The mechanism of action of these agents may be different from the presumed ones. In particular, their activity could not only be due to the blockade of their targets but also due to the interference with other important pathways. Solid tumours, in contrast to haematological malignancies, such as CML, are polyclonal and heterogeneous [77], [78]. Several pathways are responsible of tumorigenesis and metastatic process. The inhibition of one pathway could reflect on another or could promote a preferred signalling mechanism that provides maintenance of the neoplasia.

Table 1. Hypothetical reasons of inefficacy of target therapies
Heterogenous and polyclonal characteristics of solid tumours
Multiple pathways of tumorigenesis
No appropriate evaluation of the target:
• Absent in many trials
• Interobserver variation in IHC evaluation
• No standardised techniques
• Variation of biological distribution
Different mutations of target molecules: sensibility and resistance prediction to therapy
Mechanism of action different from the presumed ones

Targeted therapies for colorectal cancer: do we know enough? Several uncertainties still exist. Despite this the Federal and Drug Administration approved the use of cetuximab and bevacizumab in colorectal cancer treatment. The same approval was made in the European Community. It has been evaluated that in the US the costs for the use of cetuximab according to the clinical indications will be 30,790 dollars for an 8-week course for a gain of 1.7 months in survival which will only be seen in the 20% of patients who respond [79]. In a time of economic constraint such cost-benefit ratios may not appear ideal. The issue of economic impact is actually strongly debated in Europe and United States. On the other hand, we are observing that following the marketing of gefitinib, transtuzumab and gleevec, the pharmaceutical companies devoted substantial funds for the development of even more selective substances. As a consequence of this policy, many new agents are now ready to enter phase I and II clinical trials. The EORTC-NCI-ACCR symposium on molecular targets and cancer therapeutics in Geneva in 2004 gave us the state-of-the art information on the development of new anticancer drugs: vaccines and response modifiers that have hypoxia, stroma, angiogenesis and apoptosis as their target. Information about nearly 100 agents was presented, but the number is so large that some doubt must arise about the availability of a sufficiently large number of patients to assess their usefulness.

Selection of patients who are likely to benefit from a targeted therapy is mandatory not only for clinical but also for economic reasons. Offering or withholding potentially effective therapy to subjects is a strong ethical issue and the final decision should be dependent on a solid base of knowledge and research. The recent studies on gefitinib in lung cancer clearly demonstrate this fact [74], [75], [76]. More effort clearly needs to be made for the evaluation of new agents in colorectal cancer therapy.

Conflict of interest statement

None declared.

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Acknowledgement 

Funded by Fondazione Cassa di Risparmio di Bologna (CARISBO).

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PII: S1590-8658(05)00424-X

doi:10.1016/j.dld.2005.10.004

Digestive and Liver Disease
Volume 38, Issue 2 , Pages 71-77, February 2006

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