Clinical Questions in Advanced CRC: Integrating Novel Therapy into Disease Management

Course Director

Richard M. Goldberg, MD

Richard M. Goldberg, MD
The Ohio State University Wenxer Medical Center
Columbus, Ohio

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Dr. Goldberg provides expert feedback to the questions submitted by your peers during a recent survey on this topic.


The treatment paradigm for metastatic colorectal cancer is changing rapidly. While the benefit derived from multiple lines of active therapy have been recognized for some time, the essential role of targeted therapies—antiangiogenesis and anti‐EGFR—is becoming clearer. With data from several major clinical trials demonstrating improved progression‐free survival with antiangiogenesis beyond first progression and the availability of two novel therapies, targeted therapy may now be considered the backbone of treatment for metastatic colorectal cancer. In this activity, Dr. Richard M. Goldberg provides expert insights that may help clinicians address these challenges head on and integrate latest advances into their practice.

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How can I optimize sequencing and timing of multiple agents?

Dr. Goldberg: When I think about managing patients, main principles that I consider are using all the agents that are available, as appropriate. That [involves]  testing patients early on in the management of their metastatic disease for KRAS mutations, because those with tumors that have KRAS mutations have one [fewer] option in terms of not being able to use the epidermal growth factor receptor antagonists cetuximab or panitumumab. Using all the chemotherapy agents—5-FU [5-fluorouracil], oxaliplatin, and irinotecan—clearly provides benefit over time. With respect to when to use chemotherapy agents, there are those individuals that prefer to combine 5-FU with oxaliplatin first line, others who prefer 5-FU with irinotecan first line.

People ask “Should I use bevacizumab first line, or should I use it beyond first line?” And there was data presented this year in the so-called TML [M18147] study that showed that continuing bevacizumab beyond first-line progression did provide a modest benefit for patients: median overall survival advantage of about 1.4 months in a selected group of patients.1,2 So, many people have liberalized their thinking about using bevacizumab in second-line treatment.

In the last year, we've had two new drugs that have come on the market, aflibercept and ramucirumab, adding to the targeted agents that we can use with chemotherapy.

Aflibercept is a similar drug [to bevacizumab]. It targets both VEGF1 and VEGF2; [though] bevacizumab just targets VEGF1 and is provided with chemotherapy in the VELOUR trial by Eric Van Cutsem and colleagues that was recently published.3 It again showed a 1.4-month survival advantage over [FOLFIRI] chemotherapy alone in the second-line setting [P = .0032]. There has been no head-to-head comparison in second-line therapy of aflibercept versus bevacizumab, and so I think it's up to the oncologist to choose.

Studies with ramucirumab that target both VEGF1 and VEGF2 showed an advantage in survival over placebo in patients with gastric cancer.4 We're now seeing studies that are being done in combination with chemotherapy in patients with colorectal cancer, but the data from those studies [have] not yet been released.

And now, of course, we have data with regorafenib in patients who are randomized to that drug versus placebo, and showed an extension in overall survival.5

Narrator: Specifically, overall survival was 5.0 months with placebo versus 6.4 months with regorafenib. This difference was statistically significant, with a hazard ratio of 0.77 and a P value of .0052.

Dr. Goldberg: One of the great things about managing patients with metastatic colorectal cancer now is that we have multiple agents, and so we have the opportunity to consider combinations and permutations on putting them together that can be different in individual patients, depending on their treatment goals and their physical status. In the setting of advanced disease, if a patient is not going to have resectable disease because they have multiple lesions in multiple organs, then what you're trying to do is to help people live longer, help them feel better, and not at the price of extensive side effects that compromise their lifestyle. Also sometimes it's nice to de-escalate care, even to take breaks in the treatment so that patients can enjoy chemotherapy-free intervals.

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I have a patient with metastatic CRC to liver with a performance status of 1. Notably, LFTs are elevated, despite biliary stenting: total bilirubin, 3.0; AST, 80; ALT, 70. Patient has received FOLFOX + cetuximab as first-line therapy with good response. Last received oxaliplatin 12 months prior, 5-FU 9 months prior, cetuximab 6 months prior.  What are reasonable treatment options at this point?

Dr. Goldberg: Well, a patient who has metastatic colorectal cancer and an elevated bilirubin as well as a diminished performance status represents a challenge, but a common challenge, in clinical practice. As I examine the parameters for this patient, the fact that the patient has not received oxaliplatin in 12 months and has an elevated bilirubin would lead me to choose to go back to a FOLFOX-type regimen. The reason for that is that oxaliplatin has been tested both in patients with liver failure and kidney failure, and can be safely given in both circumstances.

There [are] data from Aimery de Gramont's group that patients whose tumors have not been exposed to oxaliplatin in over a year and who were never actually refractory to oxaliplatin—it was stopped for toxicity, not for progression of disease—can still respond to [that regimen].6

Irinotecan, because it's metabolized in the liver through glucuronidation, is not well metabolized in patients with elevated bilirubin, and one has to be cautious about giving the drug [in that situation], because the drug needs to be glucuronidated in order to be excreted into the bile.

The next question would be, would you go back to cetuximab in this setting, or might you consider bevacizumab? I think either one could be considered. We really don't know how good the patient's response to treatment was with the first therapy, but likely it was reasonably good, because the patient has gone for a fairly long time with de-escalating treatment and then with no treatment before coming to attention with this progressive disease.

The quality of response certainly matters here. If you can get the patient's bilirubin down to normal with initial FOLFOX plus bevacizumab or FOLFOX plus cetuximab, then that gives you the option in later lines of therapy to use an irinotecan-based regimen.

And then another option for this patient later on would be to consider oral regorafenib. As you'll remember, that's a multitargeted tyrosine kinase inhibitor, and it's thought that, with the diversity of mutations that chemotherapy provokes in cancer cells, that using a broad-spectrum drug in later-line therapy can be more effective than using a very targeted agent. And regorafenib led to an extension of about 1.5 months in overall survival in a very treatment-refractory group of patients who were randomized to that drug or placebo.5

Narrator: It is important to note that, in the CORRECT trial,5 treatment-related adverse events occurred in 93% of patients assigned regorafenib and in 61% of those assigned placebo. The most common acute adverse events attributable to regorafenib were hand-foot skin reaction and fatigue. If regorafenib is to be a feasible third-line option for the patient in question, these toxicities should be considered, particularly if the patient’s performance status has degraded following multiple lines of therapy.

Dr. Goldberg: So in this circumstance, there are certainly things that you can do to help the patient. It's a matter of choosing carefully among the treatment options that you have and by reining in the liver dysfunction initially, in my opinion, with a FOLFOX regimen, giving you the option of later irinotecan-based therapy.

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  1. Arnold D et al. J Clin Oncol. 2012;30:suppl; abstr CRA3503.
  2. Vietiez de Prado JM et al. European Society for Medical Oncology 2012 Congress (ESMO 2012). Poster 565P.
  3. Van Cutsem E et al. J Clin Oncol. 2012;30:3499‐3506.
  4. Fuchs CS et al. Program and abstracts of the 2012 Gastrointestinal Cancer Symposium (ASCO-GI 2012). Abstract LBA5.
  5. Grothey A et al. Lancet. 2013;381:303-312.
  6. André T et al. J Clin Oncol. 2009;27:3109-3116.

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