COMMENTARY

GI Cancer: Provocative and Practice-Changing Studies

Louis M. Weiner, MD

Disclosures

June 17, 2011

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Introduction

Hello. I'm Dr. Louis Weiner, Professor and Chair of the Department of Oncology at Georgetown University in Washington DC. I'm Director of the Georgetown Lombardi Comprehensive Cancer Center. I'd like to welcome you to this edition of Medscape Oncology Insights on Gastrointestinal (GI) Cancer. Today, I'd like to discuss some of the GI studies that were presented at ASCO® 2011. This year's meeting has been a period of consolidation in the field of GI cancer. In the absence of new drugs that might revolutionize the therapy of these diseases, many investigators have been focusing on identifying better ways to use the drugs that we have.

Rectal Cancer Advances

One of the major efforts in this respect has been in the therapy of patients with rectal cancer. The colorectal cancer session held on Saturday morning, June 4th, focused on several important abstracts that give us information on how to better treat patients with adenocarcinoma of the rectum in the neoadjuvant setting. The first abstract I would like to highlight is by Roh and colleagues[1] from the National Surgical Adjuvant Breast and Bowel Project. This was a noninferiority trial comparing treatment with capecitabine vs continuous infusion 5-fluorouracil for the preoperative chemoradiation therapy of patients with stage 2 or stage 3 rectal cancer. Importantly, the results showed that there were equivalent outcomes whether somebody was treated with either capecitabine or continuous infusion 5-fluorouracil. Given the greater ease of therapy with capecitabine compared with 5 days of continuous intravenous infusions of the chemotherapy, this is likely to emerge as a standard of care and indeed as one of the true practice-changing observations of this year's meeting in the gastrointestinal (GI) cancer arena.

An abstract by Hofheinz and colleagues[2]summarized the results of the LARC [Locally Advanced Rectal Cancer] trial, which had a similar design to the Roh trial and, in fact, had similar results. To give us more comfort about the decision to switch to capecitabine, if anything, the capecitabine results trended toward superiority compared with the 5-fluorouracil-based therapy, although again, the sober conclusion from this would be that it passes the test of noninferiority.

In the treatment of people with rectal cancer, a study using neoadjuvants from chemotherapy prospectively evaluated the role of oxaliplatin used in conjunction with 5-fluorouracil. First is a study of 5-fluorouracil combined with leucovorin in the treatment of patients with early stage rectal cancer by Roedel and colleagues.[3] They found that the addition of oxaliplatin did not substantially enhance toxicities as we might have expected, and in fact there were more pathologic complete responses, suggesting that this is a valuable addition to preoperative chemoradiation strategies. An interesting abstract was presented by Bonnetain and colleagues,[4] and this represented a pooled analysis of the EORTC 22921 and FFCD 9203 studies, which involved a total of 1767 patients. In this analysis they actually drilled down on various measures of surrogacy for overall outcome of patients. They found that what we have frequently used; namely, the degree of local control of the tumor, may in fact not be a valid surrogate, suggesting that we need to do a better job of identifying important surrogates to help us know whether our early interventions, if you will, are actually going to be helpful.

Provocative, But Not Practice Changing (Yet)

For me in the gastrointestinal sessions, particularly the colorectal session, the most exciting and provocative abstract was presented by Dr. Tejpar.[5] The reason that I found this most provocative is that it really helps us make some important decisions about how we might want to use an important class of anticancer agents, namely the epidermal growth factor-receptor (EGFR)-directed antibodies, with greater input from biomarkers. Dr. Tejpar and colleagues took a look at the 2 large EGFR therapy-based chemotherapy combination studies, CRYSTAL [Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer] and OPUS [Oxaliplatin and Cetuximab in First-line Treatment of Metastatic Colorectal Cancer] and asked whether the type of KRAS mutation status was important with respect to response to cetuximab-based therapy. They made some very interesting observations. First, as you might expect, KRAS wild-type patients had a very high objective response rate (57%) in combination with cetuximab, significantly exceeding the response seen with chemotherapy alone. As expected, patients who had mutations on codon 12 of KRAS had a potentially detrimental effect of cetuximab, and certainly no improvement in objective responses. What is really interesting is that patients who have mutations in codon 13 (the G13D mutation) appeared to have a moderate improvement in response rates through roughly 40%, nearly double that seen for chemotherapy alone.

It's important to understand that this does not give us a blank check to start employing cetuximab in patients who have the G13 mutation. First, patients with a G13 mutation do have a potentially worse prognosis compared with the wild-type patients, and we have to factor that in. Second, this is a retrospective analysis of a single biomarker, and as we have all learned over the years it's very important to place these results in a larger context and even more importantly, these results have not yet been validated in a prospective clinical trial. However, it is certainly provocative, and certainly worth studying in a prospective trial to determine if the G13D mutation actually confers a potential responsiveness to cetuximab-based therapy. If so, it will mean that not all mutations in RAS are created equal and in fact the specific nature of the mutation really will matter and of course this will have powerful implications not only for the analysis of RAS mutations but ultimately as we uncover additional mutations in other genes and examine their roles as either prognostic or predictive markers, it will certainly be important. These results are not yet practice-changing but they certainly are provocative.

Observations From a Poster Crawl

I have made some other observations by prowling around the GI cancer posters and attending some of the other sessions here at ASCO. One of the interesting observations from the posters was that there were probably 5 or 6 different presentations that examined early response to treatments, both in GI cancers characterized by origin in the colon or rectum but also in other sources of GI cancers that suggest that the people who are most likely to exhibit long-term benefits are those who exhibit early responses to the treatments. As clinical oncologists, we have always known that this is the case, that some of our patients who have dramatic early responses are in fact likely to do very well. The question is how do we use that information as we move forward and begin to develop new drugs, new treatments, and new treatment strategies. It may be that in fact this early response marker is similar to how we think about how early PET responses may teach us important lessons about how to decide whether a new treatment is worthy of merit both in standard clinical practice and in clinical trial settings.

Help Is on the Way

The final important observation that I would like to make is that I was lucky enough to attend a developmental therapeutic session here at ASCO and I would say that help is on the way. A number of new drugs are in development targeting a variety of critical signaling molecules that are clearly relevant to the biology and the therapy of GI cancers. These include PI3 kinase, BRAF, MEK, AKT, and a host of other intracellular targets. It is clear that it is now possible to identify drugs that have activity as single agents, combinations of signaling inhibitors that look like they are going to be potentially active in selective biomarker-enriched populations, and of course single or combination targeted therapies that can be used in conjunction with standard chemotherapy regimens. As always, GI cancers will be important sources of patients who can help us test these ideas and in fact the biology of our GI cancer patients is almost certainly going to identify therapeutic niches that will be useful and exploited to the benefit of our patients.

That's what I had to say about my time here at ASCO looking at GI cancer- related presentations and it has been a very interesting experience. Thank you for joining me. This is Louis Weiner for Medscape Oncology Insights.

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