David J. Kerr, CBE, MD, DSc, FRCP, FMedSci

Disclosures

May 23, 2014

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Hi. I'm David Kerr, Professor of Cancer Medicine at the University of Oxford. It's that time of year again -- American Society of Clinical Oncology (ASCO®). Hoorah! I thought it might be interesting to give you some of the expected highlights of the meeting.

Perhaps most interesting from the colorectal cancer point of view will be Alan Venook's presentation[1] of the Cancer and Leukemia Group B/Southwest Oncology Group study. This is a much-awaited trial. The investigators have done a masterful job of keeping the results entirely secret, with no leakage of information at all. It will be one of the plenary presentations. They looked at frontline chemotherapy with irinotecan/5-fluorouracil (5-FU)/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (FOLFOX ) with bevacizumab or cetuximab. Given all of the hugely interesting data presented at our European Society for Medical Oncology meeting, the FIRE-3 study,[2] particularly with the marked benefits from frontline therapy with cetuximab, is an important trial, and many people will be waiting to hear the results.

My good friend Fortunato Ciardiello is making an important presentation of the reworked CRYSTAL study.[3] In this study, they went back to the 630 patients in the first CRYSTAL trial and looked at the addition of cetuximab to FOLFIRI frontline treatment of metastatic colorectal cancer. They have extended the RAS mutation analysis, so now it is RAS wild-type. There was a very marked improvement in disease-free and overall survival, benefitting patients treated with first-line cetuximab.

The Dutch group who have made some great inroads with their portfolio of CAIRO studies will present a final analysis of CAIRO 3.[4] In this study, they looked at following induction chemotherapy with maintenance with capecitabine and bevacizumab. They show in their final results that the benefits of maintenance treatment are maintained. Of interest, in a subgroup analysis, they demonstrated that the benefits are more marked in patients who presented with synchronous primary tumors and whose primary tumors are resected, so this is a nice piece of work.

There is a very well-performed and large community-based study from the Canadian group.[5] We know that there is some controversy about patients with stage IV disease who are asymptomatic but who present with the primary tumor in situ. The controversy is whether we should resect the primary tumor. They have shown in this rather well-designed study that resection of the primary tumor remains, in multivariate modeling, an important prognostic indicator compared with age, the addition of chemotherapy, and so on. I find my compass turning somewhat and ask surgical members of the multidisciplinary team to consider primary resection in patients who have oligometastatic disease at presentation.

I have always been interested in the concept of chemotherapy holidays. In a very nice meta-analysis from the Brazilian group,[6] they looked at 106 trials in which there was randomization between giving chemotherapy until progression or stopping it. The meta-analysis had a few thousand patients, and it showed a modest but statistically significant improvement in overall survival in patients with metastatic disease who receive chemotherapy until progression. But they make the point of the heterogeneity of colorectal cancer and that we need to use biological markers that would allow us to define a significant subpopulation of patients who would not have any detriment in overall survival with chemotherapy holidays.

As always at ASCO, we celebrate not only the game-changing clinical studies, but also the rather strong spectrum of translational science studies. The ACCENT Collaborative group, of which I am a member, has a large, compelling study led by Dan Sargent,[7] looking at microcellular instability in a group of almost 8000 colorectal cancer patients treated with adjuvant therapy. They reaffirm the prognostic importance of mismatch-repair deficient tumors carrying a good prognosis. This is probably clinically most important in patients with stage II disease who have microsatellite unstable tumors, in that they have such a good prognosis that we likely wouldn't offer them adjuvant chemotherapy. Of interest, however, in stage III disease, although there is some prognostic import, this doesn't significantly influence the clinical treatment offered them.

Another study[8] looked at the fate of a group of several hundred patients with microsatellite unstable disease (both stage II and stage III) and the effect of surgery, 5-FU alone, or combination therapy with 5-FU and oxaliplatin. Using a fairly sophisticated multivariate model, these investigators showed -- with some plausible biochemical and preclinical evidence backing it up -- that the addition of oxaliplatin restores chemosensitivity to microsatellite unstable tumors. In a stage III colon cancer patient with microsatellite unstable disease and 1 or 2 other bad prognostic features, rather than giving single-agent 5-FU, they suggest that it is better to give combination therapy with oxaliplatin.

The final abstract in this poster session that caught my eye was a nice Spanish study[9] in which they looked at the molecular evolution of resistance to cetuximab. They took 38 patients with paired biopsies before and after treatment with cetuximab and looked at the evolution of the molecular genotype. They showed that in cetuximab-resistant patients, 40% had RAS mutations, 19% had mutations in PIK3CA, and another 11% had BRAF mutations. So there is heterogeneity in terms of the molecular clonal evolution of cetuximab resistance. It is a situation in which one might consider rebiopsy of patients who have progressed or who have become resistant to cetuximab. If we want to try to select the best subsequent therapy for these patients, given the significant degree of heterogeneity in terms of molecular resistance, in some situations it might be worth rebiopsying.

I am looking forward to seeing you at ASCO and hope that you have a fantastic time. The gastrointestinal sessions are really excellent, especially the colorectal cancer topics. I recommend that you spend some time in the poster sessions. It’s a very rich meeting this year with a great synergy of science and medicine.

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