What’s the Best Treatment for Metastatic Colorectal Cancer?

The answer is: nobody knows.

We have previously described a patient with a small bowel cancer for whom a treatment regimen contrary to the most widely used triplet was recommended. While it is arguable that small bowel adenocarcinoma is rare enough that no one really has a favorite regimen, colorectal management has become somewhat rigidly focused on FOLFOX. Yet, this popular combination may not be right for every patient with colon cancer.

We know, for example, that FOLFOX combined with Avastin provided no advantage in the adjuvant setting. We also know that the random addition of Erbitux to FOLFOX similarly failed to provide an advantage. As the modes of action differ between drugs, it is not surprising that subsets of colon cancer patients may do better with Irinotecan based therapies. Indeed, clinical trials combining the new monoclonal antibodies with Irinotecan have proven quite favorable, including the 2007 BOND-2 trial reported by investigators at Memorial Sloan Kettering in New York.

With this in mind, patients who present with both untreated colon cancer and a favorable profile for Irinotecan based combinations always interest us. One such patient presented to our attention in the last few weeks. This patient, in his mid 30s, was found to have inoperable, widely metastatic disease with extensive liver involvement. Confirmatory biopsies provided tissue for analysis and revealed no evidence of mismatch repair.

The results of the EVA-PCD platform were interesting on many levels. First, the EGFr active drugs provided a uniquely favorable profile, as did the down-stream inhibition of the MEK-ERK inhibitor we studied. These findings strongly suggested that the patient was RAS wild type (i.e. non-mutated). It is known that RAS mutation confers resistance to the EGFr active drugs. By inference, his sensitivity to the EGFr active drugs was prima facie evidence of RAS wild type, a finding that was confirmed later by molecular analysis. There was also a favorable profile for VEGF active drugs. Most favorable of all was the combination of Irinotecan with inhibitors of both VEGF and EGFr. This was the regimen that we selected.

We wait with interest the results of the therapy, as re-staging for response will be conducted in the coming months.

Is Metastatic Colon Cancer Curable?

Following the introduction of 5FU in 1958, response rates for metastatic colon cancer remained in the range of 12-14 percent. After several decades, the addition of Leucovorin to 5FU improved these response rates to 20 percent. Optimal infusion schedules further enhanced responses providing objective benefits in 20-30 percent of patients. Subsequent to the introduction of Irinotecan and later Oxaliplatin, colon cancer response rates are now observed in 40-50 percent of patients — even higher in some series.

This has spawned a new interest in post-chemotherapy surgical cytoreduction. Under these circumstances, patients who present with Stage 4 disease (most often metastatic to liver) undergo aggressive combination therapy — usually Folfox-based. Those achieving substantial response (complete or partial) are then considered for partial hepatectomy to reduce residual tumor burden. In a series of trials conducted by large institutions like MD Anderson, a subset of patients is now achieving durable complete remissions using this multi-modality approach.

One example of this approach represents a novel opportunity to explore the biology of this disease.

Case Report
A 44-year-old previously healthy male presents with T3, N2, M1 colon cancer with multiple positive lymph nodes and a liver metastases. Despite the primacy of Folfox-based therapies in this setting, functional profiling of his tumor revealed superior activity for the dual modulation of Irinotecan activity with Erbitux and Avastin After several cycles of therapy, all disease had disappeared with the exception of a small residual focus in the liver.

The patient underwent a partial hepatectomy and tissue removed at the time of surgery was re-examined in the laboratory. The Ex-Vivo Analysis of Programmed Cell Death (EVA-PCD®) functional profile results had completely changed, now favoring Folfox over Irinotecan-based therapy. Following surgical recovery, the patient was provided post-operative adjuvant Folfox.

Today, more than two years since diagnosis, all biochemical and radiographic restaging reveals no evidence of disease. While the patient will require continued surveillance, he represents a genuine advance in the management of this disease and may escape recurrence. This allows him to continue a normal life, despite a diagnosis that a decade earlier would have been considered a death sentence. Cases like this will ultimately enable us to answer the question: Is metastatic colon cancer curable?