Mary F. Mulcahy, MD

The EPOCH study demonstrated that there’s an improvement in progression-free survival with the addition of Yttrium-90 [Y-90] TheraSphere to systemic chemotherapy. This demonstrates a number of important features that we can take advantage of going forward. One is that colorectal cancer metastases respond to intra-arterial therapy. There was previously some concern that these would not respond very well, but this study, in addition to others, demonstrates that there’s a role for intra-arterial therapy in colorectal cancer metastases. No. 2, by looking at some of these subgroup analyses, we can better define the population of patients who may get true benefit by the addition of a liver-directed therapy to their systemic chemotherapy.

The challenge is always in managing the extrahepatic metastases. We found that patients who had any extrahepatic lesion detected at the time of enrollment—a lesion that we felt was not metastatic disease—had the identical benefit from Y-90 as patients who didn’t have any extrahepatic lesion identified at baseline. This allows us to apply this therapy to the real world, where we always find some type of an extrahepatic lesion on the imaging aside from the disease in the liver. By knowing that, with careful patient selection, we can identify patients who don’t have significant extrahepatic burden of disease, and we can identify patients who could potentially benefit from the addition of Yttrium-90 to their systemic chemotherapy.

Further studies are needed to identify the right way to deliver Yttrium-90 for these patients. There may be a role for splitting the dose and doing lobar therapy instead of whole liver, as we did. There may be a role for re-treating areas at the time of progression. Understanding how to best use this treatment to achieve the greatest benefit is a reasonable research pursuit. This therapy can be very beneficial for a select number of patients who have good liver function, have liver-only metastatic disease, don’t have a surgical or ablative local option, and have a good performance status and preserved liver function to tolerate the therapy. While it might not be a large percentage of patients with colon cancer, it represents a significant number of patients with metastatic disease to the liver who can benefit from this therapy.

In addition to the advancement in colorectal cancer treatment, there’s a lot to be learned from this study. This was a major undertaking, an international study of a procedure that we were able to take to completion and demonstrate a benefit. This sets the stage for doing other international studies with device-related procedures so that we can accrue to them and complete them in a timely fashion and learn more how to advance this field. There’s a lot to be learned about how to assess and measure the response to the therapy. That’s always a challenge after radioembolization or any other liver-directed therapy. What’s a pertinent response that will give us a hint into a survival benefit? Understanding how to best evaluate these patients in an ongoing fashion so that we can get answers relatively quickly, we can get these studies accrued to so that we can get this therapy out to people who could benefit and not pursue therapy that’s not beneficial.

Videos

Mary F. Mulcahy discusses the potential implications of the EPOCH trial in clinical practice.

Implications of the EPOCH Trial in Clinical Practice

The EPOCH trial enrolled 215 patients into the Y-90 [Yttrium-90] plus chemotherapy arm, and 213 patients into the chemotherapy alone arm. Patient characteristics were well balanced in both arms. About 60% of these cases were from European countries, 10% from Asia and 30% from the United States. All these patients were required to have an albumin of greater than 3 g/dL and a good ECOG [Eastern Cooperative Oncology Group] performance status. Of all these cases, 46% had 

 wild type, which is comparable to what we see in the general population. Bilobar disease was present in 81% of patients enrolled in both arms. The primary tumor was left in site in about 35% of all cases. There were extrahepatic nonmetastatic lesions seen in other organs in about 50% of patients in both arms. Sixty percent of patients received irinotecan as their second line of therapy. Only about 5% of patients received an EGFR [epidermal growth factor receptor] inhibitor in addition to their second line of therapy.

There were 2 coprimary end points: progression-free survival and hepatic progression-free survival. Progression-free survival was found to favor the Yttrium-90 with chemotherapy arm, with a hazard ratio of 0.69, a confidence interval of 0.54 to 0.88, and a p-value [probability value] of less than 0.0013. This was a statistically significant benefit in progression-free survival with the addition of Yttrium-90 to systemic chemotherapy. Hepatic progression-free survival was also a primary end point. Hepatic progression-free survival also favored the Yttrium-90 with chemotherapy arm, with a hazard ratio of 0.59, confidence interval of 0.46 to 0.77, and a p-value of less than 0.0001. The hepatic progression-free survival was 7.2 months for patients in the chemotherapy alone arm and 9.1 months for patients who received Yttrium-90 in addition to systemic chemotherapy.

We identified subsets to explore prospectively during the course of this study: patients who had 

 mutations, hepatic tumor burden of greater than 10%, fewer than 3 liver lesions, and metastatic disease arising from the left side of the colon. With the addition of a biologic agent, each of these independently had a statistically significant benefit with the addition of Yttrium-90 to chemotherapy.

Secondary end points included overall survival. There was no benefit in overall survival for the patient population enrolled in this study. Secondary end points also included response rate. An overall response rate, being either at a complete response or a partial response, was seen in 34% of cases in the Yttrium-90 arm and 21% of cases in the chemotherapy alone arm. We found that the addition of Y-90 didn’t impact the ability of patients to receive full dose systemic chemotherapy. There was no difference in either the number of cycles received or the dose intensity of chemotherapy received during the second line of therapy. In addition, there was no difference in the number of patients who were able to go on to receive third-line and subsequent chemotherapy whether or not they received Yttrium-90.

Chemotherapy-related adverse events were seen in both arms of the study. However, there was no increase in chemotherapy-related adverse events for patients who got the Yttrium-90 radioembolization in addition to chemotherapy. There was an increase in any adverse event related to the radioembolization, device, and angiogram. However, most of those weren’t serious. Approximately 10% of cases had a serious adverse event related to the device. There were an equal number of treatment-related adverse events that required discontinuation of chemotherapy: about 12% in both arms. This shows us that while the addition of the Yttrium-90 is associated with some procedure and device-related adverse events, it doesn’t impact the ability to receive adequate chemotherapy.

Dr Mary Mulcahy, a key opinion leader, describes the efficacy and safety outcomes of the EPOCH clinical trial.

The EPOCH Trial: Efficacy and Safety

The majority of metastatic colorectal cancer is metastatic disease to the liver. The addition of liver-directed therapies can theoretically enhance somebody’s progression-free survival and hopefully overall survival. Many liver-directed therapies have been evaluated, and it’s been shown that surgery or ablation can enhance somebody’s cure rate. However, 80% of cases aren’t amenable to surgical resection or local ablation. For those cases, we pursued Yttrium-90 TheraSphere as an option for controlling liver disease while also delivering systemic chemotherapy.

This study was designed as a second-line study, and second line was chosen because we wanted to give patients time to have their first line of therapy demonstrate that they truly have liver-only disease, and then enroll in second-line treatment with systemic chemotherapy and the addition of Yttrium-90 TheraSphere. Patients who had unresectable unilobar or bilobar colorectal liver metastases were enrolled. They were able to receive either irinotecan or oxaliplatin as their second line of therapy. They had measurable disease by RECIST [Response Evaluation Criteria in Solid Tumors], a good performance status, a bilirubin of less than 1.2 times the upper limit of normal, and an albumin of greater than or equal to 3 g/dL.

These patients were stratified by whether they had unilobar or bilobar disease, their 

 mutation status being wild type or mutant, and whether they received oxaliplatin or irinotecan as their first line of therapy. They were then randomized 1:1 to either systemic chemotherapy alone, which was combination chemotherapy with an appropriate biologic agent as available—whatever the standard of care was at the institution—or the same systemic chemotherapy with the addition of Yttrium-90 TheraSphere in place of their second cycle. Patients received whole liver treatment in place of their second cycle of systemic chemotherapy.

We chose to design it this way so that all patients could start their second line of chemotherapy at comparable times, and it allows for time to do the planning studies that are needed to deliver Yttrium-90 TheraSphere. Patients continued on systemic chemotherapy and were evaluated for response assessment every 8 weeks. The end point that we were seeking was either progression anywhere in the body or progression within the liver. Both of those—progression-free survival and hepatic progression-free survival—are independent primary end points for this study.

Dr Mary Mulcahy explains the rationale and study design of the phase III EPOCH clinical trial.

The EPOCH Trial: Rationale and Design

Historically, radioembolization for colorectal liver metastases has been used for patients who have progressed on all standard therapies to help control the disease burden in the liver despite them having progressed through all systemic options. The use of radioembolization earlier on in disease, while they still have active systemic chemotherapy, is the area that we’ve been exploring recently. We’ve been able to do that as a result of the advances in our delivery of radioembolization. Radioembolization beads are delivered through the hepatic artery and become embedded in the small vessels of the tumor. We’ve had a lot of advances and gotten much more experience understanding how much radiation can be delivered to a certain lobe, the potential damage to blood vessels, and any hepatic artery injury or hepatic parenchymal injury that can occur as a result of radiation, so we feel confident in safely delivering this therapy.

Therapy can be delivered either into a particular lobe or into the whole liver, depending on the distribution of disease and the underlying liver function. Many of our systemic chemotherapy agents may cause some liver dysfunction. It can cause some steatohepatitis or other damage to the liver parenchyma. This needs to be considered when we’re thinking about adding radiation, such as radioembolization, to the liver. By studying patients who have progressed on therapy, we’ve learned a lot about how to best deliver this treatment. This has informed the study that was recently completed.

Dr Mary Mulcahy, an expert oncologist, details how radioembolization is involved in the treatment of colorectal cancer with liver metastasis.

Radioembolization in Colorectal Cancer with Liver Metastasis

Hello, I’m Mary Mulcahy from the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

Liver metastasis is the most common site of metastases for colorectal cancer. Standard treatment involves systemic chemotherapy with multidrug agents and often biologic agents in addition, either a VEGF [vascular endothelial growth factor] or an EGFR [epidermal growth factor receptor] inhibitor. In a small number of cases, immunotherapy may be beneficial. For liver-only disease, we try to incorporate liver resection when possible. However, of all patients with metastatic disease to the liver, about 80% aren’t amenable to any surgical intervention or local ablative therapy intervention. For those, we’re seeking out other treatments to enhance the effects of the chemotherapy on liver-only metastasis. Right now, the standard of care therapy is multiagent systemic chemotherapy with a biologic agent. When there’s disease confined to a small area, to a lobe, or perhaps multilobar disease, some of it may be amenable to surgical resection or ablative therapy. However, the majority of these cases aren’t.

Patients who have liver-only disease may have disease isolated to 1 section of the liver, or they may have diffuse metastatic disease. Patients with diffuse metastatic disease throughout multiple lobes of the liver often don’t have a local ablative option. For those who have disease isolated to or perhaps predominant in 1 lobe of the liver and minimal disease in the other lobe, with lots of intervention and a good response to therapy, we may be able to clear the liver of all disease. That might require using things like hepatic artery infusion or ablative techniques. There are a number of different techniques that have been used in the liver to try to clear it of all disease. However, for those cases that are multifocal in multiple lobes—bilobar, multifocal disease—oftentimes, liver-directed therapies with ablation or surgery won’t clear all disease. It will leave disease behind.

Mary F. Mulcahy, MD, describes the treatment options available for colorectal cancer with liver metastasis in the first and second line.

Mary F. Mulcahy, MD | Authors

Articles

Implications of the EPOCH Trial in Clinical Practice

The EPOCH Trial: Efficacy and Safety

The EPOCH Trial: Rationale and Design

Radioembolization in Colorectal Cancer with Liver Metastasis

Treatment Options for Colorectal Cancer with Liver Metastasis