The Role of Early Tumor Shrinkage in Metastatic Colorectal Cancer

July 29, 2016
Greg Kennelty

Early tumor shrinkage is linked to overall survival and could be a stronger surrogate marker than progression-free survival in metastatic colorectal cancer.

Volker Heinemann, MD, PhD

Early tumor shrinkage (ETS) is linked to overall survival and could be a stronger surrogate marker than progression-free survival (PFS) in metastatic colorectal cancer (mCRC), says Volker Heinemann, MD, PhD.

In an interview withTargeted Oncology, Heinemann, director of the Comprehensive Cancer Center at Ludwig Maximilian University of Munich, discusses the connection between OS, depth of response (DpR), and early tumor shrinkage (ETS), its role in several clinical trials, and what it could mean for the future of mCRC treatment.

TARGETED ONCOLOGY:What can we learn from ETS in mCRC?

Heinemann:

What we tried to find is a surrogate parameter that we can measure early on, which relates response to overall survival. The first step was to investigate only tumor response, and we found that early tumor shrinkage was in fact related to overall survival. Patients reaching tumor shrinkage of equal to or greater than 20% had a prolonged survival. This was, to some extent, not understood. Then we looked at depth of response and we could demonstrate that early tumor shrinkage was a very good predictor of chemo-sensitivity and, thereby, of depth of response. Depth of response in and of itself was very well correlated to overall survival in colorectal cancer.

Most importantly, the depth of response goes one step beyond RESIST. RESIST will differentiate stable disease from partial response and from complete response, which categorically differentiates different response if you're looking for categories. Now depth of response is a continuous parameter, which goes from, let's say, 0% to 100%, with 100% being complete response and 0% being no response at all. So by looking at depth of response as a continuous parameter, we can for a single patient, more precisely demonstrate how effective treatment was. Partial response just categorically defines a patient that has a tumor reduction of more than 30%.

TARGETED ONCOLOGY:What is the need for a surrogate marker to show overall survival in metastatic colorectal cancer other than progression free survival?

Heinemann:

Progression free survival has been, until now, the most popular surrogate parameter predictive of overall survival, and has been used also in registration trials. With the advent of targeted agents, progression free survival in itself is losing its predictive power to some extent, specifically because patients are surviving for a very prolonged period of time.

Progression free survival is now typically only useful for 10 months. In fact, there is a seeding effect that we cannot extend progression free survival to much more than 12 months in some studies, and for that reason we believe that progression free survival is not a very good surrogate parameter anymore for overall survival.

We believe that if you look specifically at first line treatment response rate, or parameters of response such as early tumor shrinkage or depth of response, that is much more appropriate.

TARGETED ONCOLOGY:How is the depth of response being used to analyze patient data?

Heinemann:

What we could show specifically is that with regard to treatment intensification, this could mean either intensification with a triple chemotherapy like FOLFOXIRI or by adding an anti-EGFR agent to a chemotherapy doublet in RAS wild type patients. In these kind of settings, we want to demonstrate that not only response by itself, but early tumor shrinkage and depth of response were significantly correlated to overall survival.

So in these kinds of studies, these concepts have been evaluated and found relevant.

TARGETED ONCOLOGY:Why is it valuable to use depth of response?

Heinemann:

In the most recent presentation that we had at ASCO 2016 and our meeting in Barcelona, we evaluated the SIRFLOX study in regards to depth of response. The first step was that we analyzed tumor burden, and that specifically with regard to tumor burden in the liver. That's because SIRT is active in the liver, so we looked at the liver tumor burden. Using a finite mixed modeling, which was also supported by an ROC analysis, we could define a 12% cutoff for tumor burden, which was interesting. We differentiated patients with more than a 12% tumor burden in the liver than those with equal or less than 12%.

We have 2 different groups. One group was more extensive with their tumor burden in the liver, and one was a smaller extent. We could understand the effect of SIRT in addition to chemotherapy was markedly greater in the patients with the larger tumor burden. This was evaluated with regard to depth of response. We could demonstrate that when we added SIRT to chemotherapy in patients with a greater tumor burden than 12%, we could show that depth of response was 77%, as compared to 57% in the comparator arm.

In other words, we demonstrated that by the addition of SIRT to chemotherapy, we could increase depth of response by roughly 20%. This was not standing alone, but was accompanied by a marked increase in progression free survival in the liver in this particular group.

I think it is clinically relevant and it gives us the hope that this improvement in progression free survival to some extent also relates to improvement in overall survival, which is finally the most important topic.

TARGETED ONCOLOGY:What are the broader implications of these results?

Heinemann: