Liver Metastatic Disease: Year in Review

David Liu, MD, FSIR, FRCPC, presented on liver metastatic disease this year at the Symposium on Clinical Interventional Oncology (CIO) in Miami, Florida. His talk focused on important concepts and trends relating to the treatment of metastatic colorectal carcinoma (mCRC), including identification of knowledge gaps and opportunities for locoregional therapy. Dr. Liu is an interventional radiologist with the current appointment of Clinical Professor of Radiology in the Faculty of Medicine at the University of British Columbia in Vancouver, British Columbia, with cross appointments in Surgical Oncology and Medical Oncology. 

What are some recent trends in the treatment of metastatic liver disease? 
My talk focuses on mCRC, which represents the largest proportion of patients with liver metastatic disease. The latest discussions in the world of systemic therapy as relating to mCRC is the narrative surrounding the class of therapy is referred to as immuno-oncologics, or immunomodulatory drugs. These therapies enable the body’s own immune system to recognize cancer cells as foreign bodies, and signal the body to attack cancer cells. More specifically, drugs such as PD-1/PD-L1 inhibitors ramp up the immune system and unveil the tumor from behind its mask. Another type of immuno-oncologic treatment, chimeric antigen receptor-T cell (CAR-T) therapy, involves removing cells from the body, re-engineering them so that they recognize a cancer cell as cancer (chimeric cell), expanding the population of those cells, and then re-injecting these cells into the body to wage war on cancer cells that are targeted by the chimeric population. However, although this entire class of systemic therapeutics shows promise, the results relating to the treatment of metastatic colorectal carcinoma have not yet demonstrated a clear effect or improvement in quality of life or survival. Earlier studies do demonstrate a signal, but current studies are early phase 2 trials and have not yet reached mainstream therapy.  
Since immunomodulatory therapy has not yet arrived for the treatment of colorectal carcinoma, we have the opportunity to introduce locoregional therapies into the therapeutic paradigm both in terms of sequencing of therapy, and as supportive/adjunctive techniques to support the mechanisms of actions as relating to immune system activation. 

In what circumstances would locoregional therapy have a role in treating metastatic colorectal carcinoma? 
Locoregional therapies can potentially serve a curative intent, as an adjunct to either curative therapy, or as a palliative therapy. Ablation really does demonstrate a curative role. The CLOCC trial has shown clear survival benefit in the use of ablation strategies in patients who can receive ablation or surgery with supplemental data both on a biological and morphological perspective providing a clear profile of lesions that can be targeted. 

Regarding adjunctive therapies that support a backbone of systemic chemotherapy, both radiofrequency ablation as well as Y-90 have demonstrated an adjunctive role to support chemotherapy. Although clinical trials relating to Y-90 with respect to overall survival  have been disappointing in colorectal carcinoma, there are subsets of patients who can benefit from the use of adjunctive therapy with Y-90, such as patients with right-sided primary cancer. In the category of palliative therapy, therapies including drug-eluting beads, Y-90, and cTACE 
(conventional transarterial chemoembolization) have established a potential role in the palliative setting. However, it is hard to amplify the signal seen in the palliative setting because those patients often are not amenable to randomization in formal clinical trials.  

What are some of the gaps in current research?  

We know that we have very powerful tools both within systemic and locoregional therapy for the treatment of mCRC, but we have not fully addressed the question of appropriate sequencing or personalization of treatment for patients. Systemic therapy trials generally examine the alteration of the biology of the disease, with survival as an endpoint. Once the complexities of tumor anatomy and morphology are introduced, it becomes difficult to randomize these systemic therapy trials. I would like to see more research focusing specifically on sequencing. 

There are also gaps in research surrounding certain biologies in colorectal carcinoma that have not been fully understood. Certain locoregional therapies have shown compelling therapeutic signals in these areas, such as colorectal carcinoma with right-sided primary cancer.​^1,2​ Patients with right-sided primary cancer typically have a poor prognosis, but subset analysis in the SIRFLOX trial and FOXFIRE Global trials has shown that patients with right-sided cancer who receive resin Y-90 microspheres have a substantial improvement in overall survival. The mechanism is not known, but this is a clinical domain in which radioembolization could potentially improve survival.  

In the ablation field, more research is needed into which ablation technology to use. Radiofrequency ablation versus microwave ablation remains highly controversial, though a number of registries are underway to provide more data in this area. The COLLISION trial and the CIEMAR registry will be reporting data regarding ablation in coming years, and we look forward to those results. In the Y-90 field, the RESIN registry represents a real-world utilization of resin microspheres that has achieved recruitment of over 700 patients and is ongoing. The RESIN registry should be reporting within the next two years. 

Have you made any changes in your practice this year?  

I have made several major changes in my practice this year, based on the current literature and advances in treatment opportunities. For example, we have broadly adopted microwave ablation. The physics of microablation allow for a much larger ablation zone, and techniques such as image-guided splanchnic blocks have allowed us to minimize patient discomfort and perform the vast majority of these therapies under moderate sedation. Another change is that we have been using radiation lobectomy with Y-90 microspheres. In patients with portal vein thrombosis, a four-fold increase in survival in specific populations has been demonstrated when radiation lobectomy is used with Y-90 microspheres. Additionally, we have seen a resurgence in cisplatin-based cTACE with lipiodol due to the growing number of patients with progressive multicentric cholangiocarcinoma. 

What are the main takeaways from your presentation? 

Locoregional therapy and the role of the interventional oncologist continues to grow. Despite some disappointing trial results within the past three years, we have fairly strong level-one evidence for the use of therapies such as ablation, and potentially Y-90, in the correct settings. With this growing body of data in mind, I think we should focus future research on the sequencing of therapy and the appropriateness of therapy. Upcoming registries and subset analyses should help us to better refine patient selection and thereby increase our likelihood of successful treatment.  

References

1. Gibbs P, Heinemann V, Sharma NK, et al. Effect of primary tumor side on survival outcomes in untreated patients with metastatic colorectal cancer when selective internal radiation therapy is added to chemotherapy: combined analysis of two randomized controlled studies. ​Clin Colorectal Cancer.​ 2018;17(4):e617-e629.

2. Garlipp B, Gibbs P, Van Hazel GA, et al. Secondary technical resectability of colorectal cancer liver metastases after chemotherapy with or without selective internal radiotherapy in the randomized SIRFLOX trial. ​Br J Surg. ​2019. doi:10.1002/bjs.11283. [Epub ahead of print].