Originally published as JCO Early Release 10.1200/JCO.2009.23.2785 on August 3 2009

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Radioembolization of Liver Metastases in Patients With Colorectal Cancer: A Nonsurgical Treatment With Combined Modality Potential

Riverside Methodist Hospital, Columbus, OH

The liver is the dominant site for metastatic spread of colorectal cancer. Surgical resection of isolated hepatic metastases offers the only potential cure for hepatic metastases, with 5-year survival rates ranging from 27% to 58%.^1–3 Unfortunately, bilateral tumor location, number and location of lesions, and inadequate hepatic reserve or comorbid conditions tend to limit an aggressive surgical approach in approximately 10% of patients presenting with liver metastases.

Modern chemotherapeutic regimens, including oxaliplatin or irinotecan with at least one biologic agent, have improved response rates and can move some patients with operable but initially unresectable metastases into the surgical suite. However, even after resection, hepatic recurrence—often in conjunction with extra-hepatic disease—is the eventual outcome in most patients.

A number of treatment options exist for patients with unresectable liver-dominant disease. Local or regional therapy using ablative techniques such as radiofrequency ablation, hepatic intra-arterial chemotherapy, or external beam radiotherapy can provide local control, which may delay the need for systemic chemotherapy. Hepatic artery infusions are technically complex and may not be available at most institutions. Conventional radiotherapy is even more rarely used because of limitations in hepatic parenchymal tolerance.⁴ Radiofrequency ablation is a more viable option, but it is often dependent on lesion characteristics such as size (> 3 cm), location, and number of metastases.

An emerging therapy for patients with unresectable hepatic metastases involves microbrachytherapy with yttrium-90 (⁹⁰Y) –impregnated resin-based microspheres such as SIR-Spheres (Sirtex, Sydney, Australia). This approach reflects observations that metastatic tumors larger than 3 mm derive the majority of their blood supply from the hepatic artery rather than from the portal vein.⁵ After injection into the appropriate hepatic artery, the 20- to 40-µm spheres (perhaps 50 million per injection) become preferentially lodged in the arteriolar vasculature surrounding metastatic tumor deposits, delivering selectively targeted high doses of radiation to the area. Maximum tissue penetration for the pure-beta emitter ⁹⁰Y is 1.1 cm, so most normal liver parenchyma is spared. In a recent meta-analysis by Vente et al,⁶ response (which included stable disease) occurred in 79% of patients in the salvage setting and in 91% of previously untreated patients.

In this issue of Journal of Clinical Oncology, van Hazel et al⁷ report a phase I study in which the experienced group of authors sought to combine ⁹⁰Y-resin microspheres with concomitant single-agent irinotecan chemotherapy. In all 25 patients in the study, first-line therapy—with either fluorouracil (FU) plus leucovorin (eight patients) or other FU-based combinations—had failed. Eight patients had progressed with second- and third-line treatment, but none had received biologic agents. Although it was initially planned to administer irinotecan as four weekly infusions followed by a 2-week break, early toxicity in the first three patients forced a change in schedule. The irinotecan was subsequently increased from 50 to 75 mg/m² and then to 100 mg/m² in three dose-escalated groups; it was administered on days 1 and 8 of a 3-week cycle for the first two cycles, followed by full doses (100 mg/m²) from cycles three to nine. ⁹⁰Y radioembolization (⁹⁰Y RE) was delivered only in the first cycle. The goal of the study was to determine the maximum-tolerated dose of irinotecan in combined therapy.

Given the relative absence of grade 3 to 4 adverse events, van Hazel et al⁷ conclude quite correctly that the maximum-tolerated dose of irinotecan was not determined and that 100 mg/m² on days 1 and 8 of a 3-week cycle in combination with ⁹⁰Y RE is a safe regimen. Use of ⁹⁰Y RE in the first cycle of this study did not seem to enhance chemotherapy-induced toxicity compared with the full-dose irinotecan therapy administered from cycles three to nine in nine patients. Few adverse events were attributable to ⁹⁰Y RE, and only one patient developed a gastric ulcer, a known complication of RE related to shunting of radioactive particles to the gastric mucosa. Absence of significant toxicity is perhaps not unexpected, given the limited tissue penetration of the pure-beta emission from ⁹⁰Y. In addition, the dose of irinotecan was also somewhat less than the 125 mg/m² often used in weekly therapy.

Of 23 evaluable patients, partial responses at 12 weeks post- treatment were confirmed in 11 patients (48%), and stable disease was confirmed in nine patients (39%). These results seem higher than expected for previously treated patients. The contribution of ⁹⁰Y RE to response rate cannot be determined, but it should be noted that 48% of patients had extrahepatic sites of disease. Site of first progression was extrahepatic in 57% of patients. Median progression-free survival was 6.0 months, but disease control in the liver lasted somewhat longer, with median progression-free survival of 9.2 months for progression at that site, which implies some persistent effect from ⁹⁰Y RE.

Selective internal radiation therapy with ⁹⁰Y using resin microspheres as a unique delivery vehicle has become a viable option in treatment of liver metastases in patients with colorectal cancer. Administration of SIR-Spheres—available in the United States and approved for use with hepatic arterial injection of floxuridine (FUDR)—is complex, requiring pretherapy angiograms to assess liver vascular anatomy and a nuclear study to confirm absence of significant shunting to the lung. Dose calculations are difficult and often include adjustments that are unpredictable and not consistent between patients. Because of the embolization of vessels as microspheres are injected, the delivered dose of radioactivity may be less than the calculated dose. Published clinical experience remains limited; a total of 208 patients were involved in the largest series from seven institutions.⁸ Partial-response rate measured by computed tomography scan was 35.5%, and overall survival of responders was 10.5 months. It remains to be seen whether these results are inferior to the combined-modality therapy with irinotecan used by van Hazel et al.⁷ Most published experience involves far fewer numbers, and in the meta-analysis by Vente et al,⁶ only six of 14 studies used Response Evaluation Criteria in Solid Tumors (RECIST), making assessment of efficacy difficult. Comparison of results is additionally complicated, because maximum efficacy with ⁹⁰Y RE is often not reached for up to 12 weeks.⁸ Even then, lesions may not shrink in size, although changes may be detected by positron emission tomography imaging.

Although ⁹⁰Y microspheres have been utilized in combination with chemotherapy (intrahepatic FUDR⁹; FU¹⁰; infusional FU, leucovorin, and oxaliplatin¹¹; and irinotecan⁷), the data are limited, and to my knowledge, only two randomized trials have been reported. In one study, which led to US Food and Drug Administration approval of SIR-Spheres, 74 patients with liver-only metastases were randomly assigned to receive hepatic artery infusion of FUDR or the same therapy with ⁹⁰Y RE.⁹ Although response, disease progression in the liver, and survival were improved with the combination therapy, this particular therapy is not available for patients at most institutions. The other randomized trial compared FU plus leucovorin with and without SIR-Spheres, but there were only 11 patients in each arm.¹⁰ The results predictably favored the combination therapy.

It is hoped the study by van Hazel et al⁷ will be followed by larger randomized studies using modern chemotherapy regimens in combination with biologic agents. Given the difficulty in assessing results, variation of delivered doses among patients, and limited institutional experience and availability, the optimal situation for use of ⁹⁰Y RE becomes problematic. A consensus panel from the Radioembolization Brachytherapy Oncology Consortium has emphasized that candidates for treatment should be patients who have unresectable liver-dominant metastatic disease.¹² Disease in some of these patients could become resectable after neoadjuvant chemotherapy. Thus, it is reasonable that ⁹⁰Y RE, and perhaps other ablative approaches, be reserved for those patients in whom initial chemotherapy fails. Instances of safe resection occurring after ⁹⁰Y-RE treatment have been reported, but more data are needed.

RE with ⁹⁰Y-resin microspheres will clearly add to the armamentarium available for patients with metastatic colorectal cancer. Given the potential advantages of combination with chemotherapy, especially in patients with extra-hepatic disease, ⁹⁰Y RE may become the therapy of choice compared with other forms of ablation. Optimal treatment planning should include multidisciplinary input from medical oncologists, surgeons, radiotherapists, and interventional radiologists. This may necessitate referral of patients to larger academic or community institutions with established experience. Treatment options for colorectal cancer have evolved dramatically over the past few years. It is now time for decision making in patient care to evolve as well.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

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10. Van Hazel G, Blackwell A, Anderson J, et al: Randomised phase 2 trial of SIR-Spheres plus fluorouracil/leucovorin chemotherapy versus fluorouracil/leucovorin chemotherapy alone in advanced colorectal cancer. J Surg Oncol 88:78–85, 2004.[CrossRef][Medline]

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