Marshall, John L. MD
JOHN L. MARSHALL, MD
ASCO 2013 was not a year of innovative novel agents or identifying significant driver mutations with dramatic improvements in survival, at least not for the gastrointestinal malignancies and certainly not for colorectal cancer. ASCO 2013 will be remembered as a year of refinement where we continue to learn how best to manage our current medicines, how to optimize the sequence of our treatments, and how to extend our patients' survival as best we can while minimizing toxicity.
Interestingly, the lead abstract in the oral session was not about chemotherapy or treatment but about patient follow-up. A study out of Britain looked at various intensities of follow-up of patients with stages I through III colorectal cancer, looking at both CEA and CT scan frequency (Abstract 3500).
The authors compared four different approaches to follow-up and in fact discovered that doing a CT scan and CEA within the first one to two years after surgery proved as useful as a more intensive intervention. This to me is potentially practice-changing. Our current standard, including those that are prescribed in clinical trials, is a much more intensive follow-up through five years. Some have even argued that longer follow-up is of value. However, this study suggests that a single evaluation at 12 to 18 months after surgical intervention identifies the majority of patients who would be potentially curable through subsequent metastasectomy.
There were many criticisms raised about this abstract, including the low rate of liver resections (6%), but we should take this study to heart and minimize our follow-up in patients with colorectal cancer, saving those resources for other more innovative approaches down the line.
A second practice-changing abstract involves the use of calcium and magnesium. A nicely done study (Abstract 3501) actually demonstrated that calcium and magnesium did not have an impact on the acute neurotoxicity of oxaliplatin, but I was disheartened from the presentation that chronic neurotoxicity was not discussed or described in the clinical trial presentation. Certainly many have incorporated calcium and magnesium into their daily use with oxaliplatin, but this paper suggests that is of little to no benefit and therefore should be discontinued.
There was a fair bit of discussion about maintenance therapy in colorectal cancer and two clinical trials looking at bevacizumab or bevacizumab plus capecitabine were presented, both of which suggesting that maintenance therapy is of benefit. To me the more important of the two trials is known as CAIRO3, done by the Dutch Group, which showed that continuously dosed capecitabine and bevacizumab was of use in terms of progression-free survival, nearly doubling that over no treatment, and had a suggestion of an overall survival benefit (Abstract 3502). It is always good to hear when a practice that one is doing is actually of proven benefit, and the CAIRO3 study, I think, delivers this for me.
The most controversial issues that were raised during the meeting for colorectal cancer involved the use of biologics, and specifically which biologic approach should be used as initial therapy.
The buzz of the meeting surrounded a study called FIRE-3 (Abstract LBA3506 ). This is a German study that randomized patients between FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab. All patients were KRAS wild type. The striking finding was that while there was no difference in progression-free survival between the two arms, there was a significant difference in overall survival in patients receiving frontline cetuximab.
This is, of course, a result that is difficult to explain, and you must trust me in telling you that there were many attempts to try and provide rationale for how this result could be explained. In one camp, there was a discussion of whether this was just a quirk of the clinical trial and the impact of second-line therapy being imbalanced, while another group focused on the underlying tumor biology and the possibility that with optimized KRAS testing and sequential therapies that, in fact, EGFR should be used in the frontline setting for an overall survival benefit. The jury is, of course, still out on this issue and this clinical trial does not answer the question. We are anticipating that the Intergroup clinical trial 80405 will, in fact, answer this important question of biological sequencing.
Other important clinical trials looking at biologics included a study known as EPOC, where a combination of cetuximab and chemotherapy was used in frontline patients with operable mets from colon cancer, which strikingly showed an inferior outcome (Abstract 3504 ); and then a study of FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab demonstrated a strong progression-free survival and suggestion of overall survival benefit from the FOLFOXIRI/bevacizumab arm (Abstract 3505 ).
While new medicines were tested in metastatic colorectal cancer, we certainly have not uncovered key drivers for this disease at this point, and so we must re-look at how we are doing clinical research and drug discovery in GI malignancies.
Non-Colorectal Cancer GI Malignancies
Like colorectal cancer, there were no major breakthroughs in the world of pancreas cancer or gastric cancer. However, there were two very interesting approaches in the adjuvant setting which are worth noting for all of us. There was a Japanese study known as JASPAC-01, randomizing patients post-pancreatectomy to adjuvant gemcitabine versus adjuvant S1 (an oral fluoropyrimidine approved in Asia) (Abstract 4008). The results showed that the S1 arm did much better in terms of progression-free and overall survival.
I have long had a bias that we have been ignoring oral fluoropyrimidines in the adjuvant setting in diseases such as pancreas cancer, and certainly this head-to-head paper supports my bias that we should be incorporating oral fluoropyrimidines more into this setting.
Whether this is translatable to the agents we have such as capecitabine and IV 5-FU is unclear, but certainly additional clinical trials looking at possibly sequential therapy of gemcitabine and oral fluoropyrimidines are warranted in this difficult disease.
Similarly another clinical trial in gastric cancer looking at adjuvant taxane plus oral fluoropyrimidine was suggestive of benefit from a sequential approach. If you will, this is looking at our “AC followed by T” kind of approach in GI cancers. I am supportive of these approaches and think they will be clinically relevant, and these two clinical trials support that.
Apart from that, very little of importance was presented at the meeting, and therefore if you stayed home, you did not miss much from the GI world.
So in summary, we still have miles to go in the treatment of gastrointestinal cancers. We need to urgently look at new medicines through new lenses in the hopes that we will find significant subtypes of these diseases where interventions have much more significant positive impact.