Colorectal cancer (CRC) is now a common cancer in both the western and eastern countries. Apart from the regional lymph nodes, the next most common site for colorectal metastases is the liver. In the past, these patients, when treated solely with fluorouracil / leucovorin, would have an overall survival of 8 – 12 months only. With the advent of safer liver surgery and better chemotherapeutic agents, most doctors have the distinct impression that the outlook for patients with metastatic colorectal disease has improved over the last 10 years. Is this observation correct?

Researchers from the University of Texas M D Anderson Cancer Center and the Mayo Clinic performed a retrospective review of 2470 patients with metastatic CRC treated at the Mayo Clinic (n=856) and MD Anderson (n=1614) during the period 1990 to 2006 (J Clin Oncol, epub 2009 May 26). From 1990 to 1997, the median overall survival for patients with metastatic CRC was 14.2 months. However this improved to 29.2 months for the time period 2004 – 2006. The overall 5 year survival rates showed similar improvements, from 9.1% in the 1990 – 1997 period to 19.2% for the 2001 – 2003 period.

Overall Median Survival – 1998 to 2006

Overall 5-Year Survival Rates – 1998 to 2006

From 1990 to 2006, 231 patients had liver resection for metastatic CRC. Liver resections were performed with increasing frequency from 1998 and between 2000 and 2006 approximately 20% of patients had liver surgery. From 1998 to 2006, the 5 – year survival rate among patients who had undergone liver resection was different from those with unresectable disease. The 5 – year survival rate was 55.2% for resected patients compared to 19.5% for unresectable patients. The median overall survival for these 2 groups of patients was 65.3 months and 26.7 months respectively.

Survival analyses of patients with metastatic CRC who could not undergo liver surgery but treated with chemotherapy only, showed that the survival rates from 1998 to 2000 were not different from that before 1998. From 2001 to 2003, the survival rates improved only minimally but improved significantly for those diagnosed between 2004 and 2006.

In the last 5 years, newer chemotherapy drugs have made a difference to patients with metastatic CRC. It has improved overall survival and in some cases, can convert metastatic CRC into a ‘chronic’ condition. However, chemotherapy alone cannot provide a cure. If liver surgery can be performed, it can potentially provide a chance to cure. Even if it could not cure, liver surgery can significantly increase your survival time. While liver surgery is a very major operation, it is very safe when performed properly. Even though it is a big operation, it does not mean you will have a long hospital stay. Can you hazard a guess on the average length of hospital stay for someone undergoing liver surgery for metastatic CRC?

7 days!

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.