In conventional chemotherapy, when one drug fails to be effective it is quite usual to combine it with another or even two other drugs in order to provide benefit. Now, targeted therapy has joined the ranks of conventional chemotherapy. [Targeted therapy agents are monoclonal antibodies against angiogenesis (growth of new blood vessels). Angiogenesis helps cancer to grow and vascular endothelial growth factor (VEGF) and epidermal growth-factor receptor (EGFR) play important roles in angiogenesis. The antibodies available on the market act against VEGF or EGFR. Bevacizumab (Avastin) acts on VEGF while cetuximab (Erbitux) and panitumumab (Vectibix) act on EGFR.] When more agents of targeted therapy became available, the logic was that by combining these antibodies with conventional chemotherapy, one would expect added benefit when compared to use of one antibody only. The addition of bevacizumab to the FOLFOX / FOLFIRI regime in metastatic colorectal cancer (mCRC) has been shown to be better than FOLFOX / FOLFIRI alone. Thus, adding bevacizumab and cetuximab / panitumumab to FOLFOX / FOLFIRI should, by logic, give added benefit to mCRC patients.

The results of 2 studies doing just that have been published recently. The first study from USA, the PACCE study, involved 823 mCRC patients. In addition to the FOLFOX regimen, the patients also received either bevacizumab alone (the control group) or bevacizumab and panitumumab (the panitumumab group). The study showed that the median free survival was shorter in the panitumumab group (10 months) than the control group (11.4 months). The median survival was also shorter for the panitumumab group (19.4 vs 24.5 months). Furthermore, side effects such as skin toxicity (36% vs 1%), diarrhoea (24% vs 13%), infections (19% vs 10%) and pulmonary embolism (6% vs 4%) were more frequent in the panitumumab group when compared to controls (bevacizumab only group). Another cohort of 230 patients in the same study, treated with the FOLFIRI regime, were also given bevacizumab alone or bevacizumab and panitumumab. Adding panitumumab to bevacizumab did not improve efficacy but led to increased toxic side-effects (J Clin Oncol 2009: 27: 672 – 680). In the second study from The Netherlands, 755 mCRC patients were randomly assigned to capecitabine, oxaliplatin and bevacizumab (CB regimen, 378 patients) or the same regimen plus weekly cetuximab (CBC regimen, 377 patients). After a median follow-up of 23 months, adding cetuximab did not lead to better outcome. The median progression-free survival of the patients on the CBC regimen was shorter (9.4 vs 10.7 months). The median overall survival of the patients on the CBC regimen was also shorter (19.4 vs 20.3 months). Patients on the CBC regimen also experienced more skin toxic side-effects (N Engl J Med 2009; 360: 563 – 572).

Bevacizumab, cetuximab, panitumumab when used alone with other chemotherapy agents have been shown to work. However, when these monoclonal antibody medicines were used in combination, patients did not experience added benefits in terms of progression-free and overall survival. In fact, they experienced more side-effects. This is one case where more is not better.

The completion of the first survey of the entire human genome was announced with much excitement to the world by President Clinton on 25^th June 2000. Subsequent to that many researchers and clinician scientists spoke enthusiastically about the day when we will be able to tailor medical treatment specifically to each individual. This will lead to reduced side-effects, better efficacy and success in treating or even curing their condition. If this indeed becomes a reality, personalized medicine would arguably be most welcome in the field of medical oncology. This is because chemotherapy is associated with side-effects, some of which can be life-threatening. Personalized medicine will also take away the ‘trial & error’ evil of trying various drug combinations in order to arrive at one which suits your tumour best.

Molecular targeted therapy with agents such as bevacizumab (Avastin), cetuximab (Erbitux) and panitumumab (Vectibix) have made an impact in the field of medical oncology. However, they are expensive agents and clearly not all patients would benefit from their use. The approach so far has been ‘try it and see if there is a response’. Two recent scientific studies may help to put some science into this empirical approach to the treatment of colorectal cancer.

The first study from Australia studied the K-ras gene within the colorectal tumour of 394 patients with advanced cancer. These patients were randomly assigned to best supportive care alone or cetuximab [an anti-epidermal growth factor receptor (EGFR) antibody] plus best supportive care (NEJM 2008; 359: 1757 – 1765). The researchers assessed whether the presence or absence of the K-ras gene mutation was associated with survival in the cetuximab + supportive care group. The study found that K-ras gene mutation adversely affected survival. In patients with wild-type (meaning non-mutated) K-ras tumours, cetuximab treatment was associated with significantly improved overall survival (median survival 9.5 vs 4.8 months in supportive care alone) and progression-free survival (median 3.7 vs 1.9 months). In patients with K-ras gene mutation tumours, the overall survival and progression-free survival between those treated with or without cetuximab was no different.

At the recent second Annual Molecular Markers in Cancer Meeting held in Hollywood, Florida, researchers presented their pooled analysis of 4 large trials of patients with metastatic colorectal cancer treated with panitumumab. Panitumumab, an anti-EGFR antibody, has been approved as monotherapy for patients with metastatic colorectal cancer who have failed previous chemotherapeutic regimens in USA and for patients with wild-type K-ras tumours in the European Union. A total of 715 cases were studied, 395 cases of wild-type K-ras tumour and 320 cases of K-ras mutated tumour. None of the patients with K-ras mutated tumour responded to panitumumab. Of those with wild-type K-ras tumour, only 13.7% showed an overall response to panitumumab. The overall survival was 37% longer in those with wild-type K-ras tumours (8.3 months) than in those with K-ras mutated tumours (5.7 months). The progression-free survival for patients with wild-type K-ras tumours was nearly twice as long (3.3 vs 1.7 months).

These studies have shown us that we have taken the first step of what looks like a long journey towards truly personalized medicine. However, we must not lose hope and must pray that we will come up with better agents that target the tumour more effectively in the future.

(In the mean time, you can get your K-ras tumour status checked for free if you are receiving treatment in Singapore, courtesy of Merck, the manufacturer for Erbitux.)