The role of radioembolization in colorectal cancer treatment

KEYWORDS:

• SIRT
• yttrium
• brachytherapy
• liver
• radiation
• TARE
• hepatic
• unresectable
• intra-arterial
• radioactive microspheres

In the management of hepatic metastases from colorectal cancers, the only proven curative-intent approach is surgical resection in appropriate patients. As the gold standard, surgery is always a first consideration with liver-only or liver-dominant metastatic disease. However, the majority of patients are not candidates for surgery due to tumor volume, location, and number of lesions in and outside the liver. For nonsurgical candidates, there are multiple treatment options to consider, all with clear limitations.

Radioembolization (RE) [1] is known by a variety of titles including selective internal radiation therapy, transarterial radioembolization, and sometimes, ‘radioactive microsphere therapy’. RE, the permanent implantation of microspheres (22–35 μm diameter) containing Yttrium-90 (⁹⁰Y) is a near-pure beta-emitting isotope with high energy that is delivered via the feeding hepatic arteries of the tumors, but does have limited penetration in tissue (3 mm). Although RE was first performed in the early 1960s, it did not become a commercially viable treatment option until 2002 [1,2].

Education about key information related to RE should be disseminated to our patients, referring physicians, researchers, administrators, and health insurers. Many sources estimate that the most common cause of mortality from metastatic colorectal carcinomas (mCRC) is related to uncontrolled hepatic metastases [3]. Two manufacturers provided approximately 8000 individual doses of commercially available RE microspheres to the United States during calendar year 2015. The 8000 doses of RE represent approximately 4% of the mCRC patients who meet eligibility requirements for treatment with RE based on level I medical evidence [3]. Careful consideration of this fact alone demands that the thoughtful oncologist ask, ‘Are our patients missing out on an established therapy that can potentially protect their quality of life and increase their survival?’

We might consider our multitude of local ablative options for limited hepatic disease – non-anatomic surgical resection, radiofrequency ablation, microwaves, super-selective arterial agents, stereotactic body radiotherapy (SBRT) and, RE – as an embarrassment of riches. However, availability of these many options is not so for the majority of mCRC patients who will present in 2016 with multifocal, usually bilobar hepatic metastases; decreased performance status; and comorbid diseases that greatly limit a patient’s eligibility for non-arterial-based approaches. While there is overlap in appropriateness in a small proportion of patients that could be treated with SBRT, RE, or surgical resection, it is the experience of most centers that at least 80% of patients will not be eligible for surgery and SBRT; therefore, RE is the best choice for local therapy [4–6]. Approximately 50% of all RE treatments in the United States are for mCRC, and more than two-thirds of patients receiving RE were previously exposed to second-line regimens of chemotherapy, and the majority of these patients are in third-line regimens [5,7,8].

A summary of supporting evidence for use of RE in all treatment lines of mCRC is beyond the space limits of this editorial; however, a few key points deserve mention and may be a catalyst for much-needed debate and discussion in multidisciplinary gastrointestinal cancer tumor boards. Based on prospective clinical trials, there are data of RE producing [4–6,9–12] (1) prolonged hepatic mCRC disease control compared to salvage chemotherapy alone, which is clinically meaningful; (2) quality of life measures that consistently affirm that RE maintains and often elevates mCRC patient’s daily living experience; (3) clinically important benefits of RE noted in both liver-only and liver-dominant mCRC patients; (4) a much-needed and welcomed break from continuous chemotherapy and monoclonal antibody agents that can be safely undertaken in liver-dominant mCRC during RE therapy – some patients became less tolerant to systemic therapy after nonstop weekly or biweekly treatments given over 18–24 months since original diagnosis [13]; and (5) expertise, personnel, equipment, and regulatory approvals for RE that already exist in over 500 centers in the United States, and eliminating the daunting task of new capital expenditures, construction of new facilities, training of staff, hiring new full-time employees, and so on. Clinicians can fit mCRC patients into the current system without significantly increasing health-care costs beyond the therapeutic agent itself with cost-effectiveness proven based on quality-adjusted life-year estimates [14].

In addition to greater awareness in prospective patient case discussions, one must recognize that RE therapy, like most oncologic interventions, requires continuous refinement and ongoing research to expand indications, improve current care, and innovate in ways that provide greater value to the patient, provider, and insurer. One aspect of RE that may benefit all stakeholders mentioned is provision of accurate estimates of absorbed ⁹⁰Y radiation in both normal and tumorous tissues (i.e. dosimetry). Compared to other forms of brachytherapy (implanting radiation into tumorous tissues), RE does not yet have a commercially available means of estimating the Gy dose that results from planned delivery, or the actual dose received by the tissues after the RE procedure is complete. At present, there are crude estimations based on delivered activity of ⁹⁰Y, and resulting imaging; however, these estimations are not clinically trusted because they were not validated, nor are they robust similar to typical brachytherapy implants. A fundamental data point – amount of radiation the tumor and normal liver absorb – can only be estimated at present, by indirect means. The absence of this data point is less than ideal and was rectified by research efforts not yet translated into clinical practice.

Beyond the above-mentioned benefits of RE, improvement of survival in first-line therapy of mCRC patients via RE currently remains unknown, and for that we must wait until 2017. A combination of three large prospective randomized clinical trials in mCRC were completed and are structured to allow aggregation of data to determine overall survival between chemotherapy, and the same chemotherapy but also RE in first-line treatment of mCRC patients [15]. RE can provide meaningful benefits for mCRC patients, and perhaps improved survival will be added to that list.

Financial and competing interests disclosure

A Kennedy works at at Sarah Cannon Research Institute who has received funding for a clinical trial from Sirtex Medical but no personal conflict to report. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.