Administered activity and outcomes of glass versus resin ⁹⁰Y microsphere radioembolization in patients with colorectal liver metastases

Introduction

Colorectal cancer is the third most common cancer worldwide, with nearly 1.4 million new cases diagnosed each year (1). Approximately 50–60% of patients with colorectal cancer present with or develop hepatic metastases through the course of their disease (2,3). Surgical liver resection offers the best prognosis for these patients but is only an option for 10–20% of patients diagnosed with colorectal liver metastases (2,4).

Over the past 2 decades, selective internal radiation therapy (SIRT) using yttrium-90 (⁹⁰Y) microspheres (also called radioembolization) has emerged as an effective and safe treatment option for patients with unresectable metastatic colorectal cancer with liver-dominant metastases (5). ⁹⁰Y microspheres emit beta radiation within a relatively small radius (mean 2.5 mm), delivering tumoricidal radiation doses to localized regions in the liver while limiting the dose to healthy liver tissue (6,7). Currently, 2 different ⁹⁰Y microsphere products are commercially available: glass ⁹⁰Y microspheres (TheraSphere^®; Biocompatibles UK Ltd., Surrey, England) and resin ⁹⁰Y microspheres (⁹⁰Y-resin; SIR-Spheres^®; SIRTeX Medical Limited, North Sydney, NSW, Australia) (6). Glass ⁹⁰Y microspheres (⁹⁰Y-glass) measure 20–30 µm in size and contain approximately 2,500 Bq per sphere, while resin ⁹⁰Y microspheres (⁹⁰Y-resin) measure 20–60 µm in size and contain 50 Bq per sphere. A compartmental model is the manufacturer-recommended method to calculate the appropriate activity of ⁹⁰Y-glass, and the body surface area (BSA) method is recommended for the activity calculation of ⁹⁰Y-resin (5,8).

Both ⁹⁰Y-glass and ⁹⁰Y-resin have shown efficacy in patients with unresectable liver metastases (9,10), however given their differences in specific activity, size, and dosimetry methods, these products may expose the liver to different amounts of radiation, thereby affecting their efficacy and tolerability. To date, no individual study has directly compared the dosimetry of ⁹⁰Y-glass versus ⁹⁰Y-resin used in SIRT in patients with unresectable hepatic metastases from colorectal cancer.

In this retrospective analysis of patients undergoing radioembolization for colorectal liver metastases at a single institution, we assessed the calculated prescribed radiation activity in patients treated with ⁹⁰Y-glass versus ⁹⁰Y-resin and compared efficacy and adverse event outcomes.

Methods

Patients

This study was a single-institution retrospective analysis of patients with unresectable colorectal liver metastases treated with ⁹⁰Y microsphere radioembolization at Cleveland Clinic between June 11, 2008, and May 16, 2011.

Patient records, including contrast enhanced computed tomography (CT) or magnetic resonance (MR) images, were retrospectively reviewed. This study was approved by Cleveland Clinic’s Institutional Review Board and is compliant with the Health Insurance Portability and Accountability Act.

Radioembolization

Radioembolization was delivered via a hepatic artery catheter infusion with either ⁹⁰Y-glass (TheraSphere^®; Biocompatibles UK Ltd., Surrey, England) or ⁹⁰Y-resin (SIR-Spheres^®; SIRTeX Medical Limited, North Sydney, NSW, Australia) as previously described (5,11). The treatment strategy of either bilobar treatment, sequential lobar, or whole-liver ⁹⁰Y radioembolization was at the discretion of the interventional radiologist. Selection of ⁹⁰Y-glass or ⁹⁰Y-resin was also determined by the managing interventional radiologist with discussion from the nuclear medicine authorized user, as needed.

⁹⁰Y activity calculations

⁹⁰Y activity was determined according to the manufacturer and recommended practice guidelines at the time of treatment (5,12-15).

For glass ⁹⁰Y microspheres (TheraSphere^®):

Target liver lobar volume was multiplied by 1.03 g/cm³ conversion factor to calculate target liver lobe mass. Target ⁹⁰Y activity was determined by the following formula, using 120 Gy as the desired dose (5,15):

For resin ⁹⁰Y microspheres (SIR-Spheres):

The target activity was calculated using the body surface area (BSA) method, adjusted for the fraction of the liver to be treated (5,12-14):

Prescribed ⁹⁰Y activity was obtained from patient records. For each ⁹⁰Y-glass treatment, the corresponding projected activity of ⁹⁰Y-resin was calculated using the formula above, using tumor and liver volumes determined by MIM^® software (Cleveland, OH, USA) analysis of baseline CT or MR images. For each ⁹⁰Y-resin treatment, the corresponding projected activity of ⁹⁰Y-glass was calculated using the formula above.

Evaluation of response and survival

CT or MR imaging was performed at baseline and at follow-up, typically 1 to 3 months posttreatment. Response assessment was performed according to Response Evaluation Criteria in Solid Tumors combined with necrosis criteria (mRECIST). Time to progression and overall survival time in months was calculated as the difference from the date of first ⁹⁰Y radioembolization to date of the event or last observation date in case of censoring. The date of death was obtained from patient records. For patients lost to follow-up, date of death was obtained by searching available public records.

Toxicity assessments and adverse events

Laboratory data from tests performed at baseline and at follow-up observations were obtained from the patients’ charts, including liver function tests, hemoglobin, and blood cell counts. The presence and severity of adverse events occurring within 90 days of radioembolization and deemed to be related to the treatment were obtained from patient records, including fatigue, nausea/vomiting, abdominal pain, jaundice, cholecystitis, and gastritis. Liver enzyme toxicities were classified using the National Cancer Institute common terminology criteria for adverse events v4.03 (16).

Statistical analyses

Differences in baseline characteristics between the treatment groups were evaluated by a Wilcoxon rank sum test for ordinal variables and a Fisher’s exact test for categorical variables. Overall survival probabilities were evaluated using the Kaplan-Meier method with 95% confidence intervals (95% CI) for the difference in median survival time between ⁹⁰Y-resin and ⁹⁰Y-glass patients constructed with the percentile bootstrap method. Ten thousand bootstrap samples were generated, each sampled with replacement at the patient level. Fisher’s exact test was used to assess differences in the rate of disease progression (or death) between ⁹⁰Y-resin and ⁹⁰Y-glass patients at 3 and 6 months after first ⁹⁰Y treatment. A Cox proportional hazards model was used to assess the effect of treatment on survival while adjusting for age and tumor extent at first treatment. In this model, treatment (⁹⁰Y-glass vs. ⁹⁰Y-resin) was included as the main predictor of interest, while age and tumor extent at first treatment were included as covariates. A significance level of 0.05 was used for all analyses.

Results

Patient characteristics and treatment strategy

Between June 11, 2008, and May 16, 2011, a total of 28 consecutive patients with colorectal liver metastases underwent transarterial radioembolization with ⁹⁰Y microspheres at Cleveland Clinic. Fifteen patients received 29 treatments with ⁹⁰Y-glass, and 13 patients received 22 treatments with ⁹⁰Y-resin. All patients had received prior chemotherapy, typically multiple lines of chemotherapy. Baseline demographics and liver enzymes were similar between the 2 groups (Table 1). The median time from diagnosis of liver metastases to ⁹⁰Y treatment was more than twice as long for ⁹⁰Y-resin-treated patients vs. ⁹⁰Y-glass–treated patients (448 vs. 184 days, respectively; P=0.025). The ⁹⁰Y-glass prescribed activity per treatment was significantly higher than that of ⁹⁰Y-resin [mean 1.77 gigabecquerel (GBq) vs. 1.05 GBq; P=0.007]. The mean administered activity per patient over the entire course of treatment was almost 3 times higher among ⁹⁰Y-glass–treated patients compared to ⁹⁰Y-resin–treated patients (mean: 3.5 vs. 1.3 GBq; P<0.001). Differences in lobar involvement and treatment plan also existed between the ⁹⁰Y-resin and ⁹⁰Y-glass groups. ⁹⁰Y-resin–treated patients with bilobar involvement received treatment for each lobe on the same day, while ⁹⁰Y-glass–treated patients typically received sequential lobar treatments ≤1 month apart.

Table 1 Patient characteristics and treatment strategy
Full table

⁹⁰Y activity prescribed with glass vs. resin ⁹⁰Y microspheres

By contouring tumors on baseline CT or MR images from patients in the ⁹⁰Y-glass group, we calculated the ⁹⁰Y-resin projected activity (Figure 1A,B) for each ⁹⁰Y-glass radioembolization treatment. Conversely, by contouring the liver lobes on baseline CT or MR images from patients in the ⁹⁰Y-resin group, we calculated the ⁹⁰Y-glass projected activity (Figure 1C) for each ⁹⁰Y-resin radioembolization treatment.

Figure 1 Pre-radioembolization CT images: examples of lobar and tumor contours used in calculating ⁹⁰Y activity. (A) Right lobe, left lobe medial segment and left lobe lateral segment contours used to determine glass microsphere prescribed dose in a 35-year-old male patient; (B) tumor contours used to determine projected resin microsphere activity in the same 35-year-old male patient; (C) right lobe and left lobe contours used to determine projected glass microsphere activity in a 57-year-old male patient who received a separate resin microsphere treatment for each lobe.

If patients in the ⁹⁰Y-glass group had been treated with ⁹⁰Y-resin, their mean radiation activity per treatment would have been 53% lower (mean prescribed ⁹⁰Y-glass activity =1.77 GBq; mean projected ⁹⁰Y-resin activity =0.84 GBq; Figure 2A). Likewise, if patients in the ⁹⁰Y-resin group had been treated with ⁹⁰Y-glass, their mean radiation activity per treatment would have been 136% higher (mean projected ⁹⁰Y-glass activity =2.48 GBq; mean prescribed ⁹⁰Y-resin activity =1.05 GBq; Figure 2B).

Figure 2 Comparisons of ⁹⁰Y Microsphere Activity. (A) In 29 glass ⁹⁰Y microsphere treatments, prescribed glass ⁹⁰Y activity versus projected resin ⁹⁰Y activity; (B) in 22 resin ⁹⁰Y microsphere treatments, prescribed resin microsphere ⁹⁰Y activity versus projected glass microsphere ⁹⁰Y activity.

Time to progression and overall survival

Eleven of 14 patients (79%) treated with ⁹⁰Y-glass and 8 of 13 patients (62%) treated with ⁹⁰Y-resin progressed ≤3 months posttreatment (P=0.420). By 6 months, 79% of ⁹⁰Y-glass–treated patients and 85% of ⁹⁰Y-resin–treated patients showed progression (P=0.999).

The date of death was obtained for all 28 patients. Public records confirmed the date of death for 17 ⁹⁰Y microsphere patients lost to follow-up (8 ⁹⁰Y-glass, 9 ⁹⁰Y-resin). Median survival was 547 days (18.2 months)for ⁹⁰Y-resin–treated patients as compared to 279 days(9.3 months) for ⁹⁰Y-glass–treated patients, although the 268 day difference was not statistically significant (95% CI: −186–458; P=0.292; Figure 3). Of note, 2 ⁹⁰Y-glass patients and 1 ⁹⁰Y-resin patient had prolonged survival times (1,170 days, 1,225 days, and 1,259 days, respectively), and 2 ⁹⁰Y-resin patients died ≤40 days. Excluding the 3 outliers with prolonged survival from the analysis revealed a significantly longer overall survival for ⁹⁰Y-resin–treated patients as compared with ⁹⁰Y-glass–treated patients (496 vs. 273 days, respectively; P=0.021. No significant difference in survival between ⁹⁰Y-glass–treated patients and ⁹⁰Y-resin–treated patients was observed when 2 ⁹⁰Y-resin patients with survival ≤40 days were excluded from the analysis (279 vs. 603 days; P=0.121).

Figure 3 Kaplan-Meier survival curves of 28 patients treated with glass or resin ⁹⁰Y microspheres. Overall survival in all 28 patients.

After adjusting for age and hepatic tumor burden, the hazard ratio (HR) of death for ⁹⁰Y-glass–treated patients was an estimated 4 times greater than that of ⁹⁰Y-resin–treated patients during the second year after initial SIRT (HR: 4.0; 95% CI: 1.3,12.3; P=0.017).

Total administered activity and survival

In all but 1 ⁹⁰Y-glass—treated patient, the total ⁹⁰Y administered activity was higher in ⁹⁰Y-glass—treated patients than in ⁹⁰Y-resin–treated patients. After adjusting for age and hepatic tumor burden the observed survival tended to be higher for ⁹⁰Y-resin–treated patients (Figure 4), although this difference was not statistically significant (HR ⁹⁰Y-glass vs. ⁹⁰Y-resin: 1.8; 95% CI: 0.8,4.3; P=0.156).

Figure 4 Effect of total administered activity on patient survival in glass and resin ⁹⁰Y-treated patients. Arrows indicate three outliers with relatively prolonged survival times (1,170, 1,225 and 1,259 days).

Clinical and laboratory toxicities

Fatigue was the most common reported symptom (⁹⁰Y-glass group: 53%; ⁹⁰Y-resin group: 77%; Tables 2,3). Most adverse events were mild and occurred within a month of the first ⁹⁰Y treatment. Abdominal pain resolved without surgical intervention. No deaths were deemed to have resulted as a direct consequence of the treatments themselves. No patient experienced radioembolization-induced liver disease (REILD). Similar liver toxicities were observed in patients receiving ⁹⁰Y-glass and ⁹⁰Y-resin treatments.

Table 2 Adverse events and liver toxicities (I)
Full table

Table 3 Adverse events and liver toxicities (II)
Full table

Conclusions

Using dosimetry calculations based on CT and MR images of real-world patients, we found that the treatment of a particular volume of liver tissue required significantly less ⁹⁰Y activity with ⁹⁰Y-resin when compared to ⁹⁰Y-glass. Our results suggest a trend toward improved survival in patients receiving ⁹⁰Y-resin, particularly during the second year following SIRT.

One of the core principles of radiation therapy is to keep radiation exposure as low as reasonably achievable (17). In our study, patients in the ⁹⁰Y-glass group received almost 3 times the total liver radiation activity over the entire course of treatment than the ⁹⁰Y-resin group received. When we compared the prescribed and corresponding projected activity for each ⁹⁰Y treatment, we found that ⁹⁰Y-glass treatment would more than double the ⁹⁰Y activity that would be used if the same patient were treated with ⁹⁰Y-resin. This significant finding raises the question of whether radiation dosage to normal liver tissue can be minimized by using ⁹⁰Y-resin or by altering the dosimetry for ⁹⁰Y-glass.

The median survival of 18.2 months (⁹⁰Y-resin) and 9.3 months (⁹⁰Y-glass) is in line with recently published studies of SIRT in patients with hepatic colorectal metastases (11,18-27). The results from these studies have shown a wide range for median survival of patients undergoing SIRT: 8.3–17.0 months with ⁹⁰Y-resin (19,22-27) and 9.3–15.2 months with ⁹⁰Y-glass (11,18,20,21). The extent of liver tumor burden, extrahepatic disease and number of prior chemotherapy lines have been shown to have a significant impact on overall survival following SIRT and may explain the variation in overall survival seen in our and prior studies (11,18,19,27,28). For the most part, our patients had ≤25% liver tumor burden with no recorded extrahepatic disease and were being treated in a salvage setting. The 3 ⁹⁰Y-resin patients with >25% tumor burden died at 15, 40, and 547 days; the 1 ⁹⁰Y-glass patient with >25% tumor burden died at 83 days. The longer interval between the diagnosis of liver metastases and SIRT in the ⁹⁰Y-resin cohort might predict that this cohort would have a shorter overall survival compared to the ⁹⁰Y-glass cohort, however we observed a nonsignificant trend toward longer survival in the ⁹⁰Y-resin cohort. Due to the small size of this study and the significant difference in the interval between the diagnosis of metastases and SIRT, we cannot draw any strong conclusions when comparing overall survival with ⁹⁰Y-resin and ⁹⁰Y-glass.

During the second year following SIRT ⁹⁰Y-glass—treated patients had roughly 4 times the hazard of death as compared to ⁹⁰Y-resin—treated patients. One possible explanation for this finding could be that the lower ⁹⁰Y activity of the ⁹⁰Y-resin caused less insult to normal liver tissue than ⁹⁰Y-glass. Recent ⁹⁰Y PET/CT studies in ⁹⁰Y-glass-treated patients have demonstrated an absorbed radiation dose of 67–94 Gy in normal parenchyma and found that complications increase with higher absorbed radiation doses to normal liver tissue (29,30). No patient in this small study experienced REILD, a rare but serious complication of SIRT that is associated with higher prescribed ⁹⁰Y activity in patients treated for unresectable hepatic tumors (31,32). Although we observed no significant differences in adverse events or liver toxicities between the ⁹⁰Y-glass or ⁹⁰Y-resin groups, our findings were based on medical records that may not accurately capture all complications. Nevertheless, the authors would conjecture that the radiation exposure to normal liver parenchyma has enough biologic effect to influence overall survival, even though the exposures in both ⁹⁰Y-glass and ⁹⁰Y-resin groups do not typically reach the threshold required for inducing REILD.

A strength of this study is that these real-world patient cohorts were treated at the same institution and were similar in disease stage, prior chemotherapy, demographics, performance status, and liver function. Any cohort differences would not impact our finding that prescribed ⁹⁰Y activity was significantly lower with ⁹⁰Y-resin versus ⁹⁰Y-glass per treatment, as we compared the prescribed activity and the projected activity to be used for the same treatment. We acknowledge that the interpretation of overall survival data is substantially limited by the small cohort size and retrospective design. Survival results may also have been impacted by differences in the ⁹⁰Y-resin and ⁹⁰Y-glass cohorts and concurrent chemotherapy in some patients. Our institution’s interventional radiologists’ particular practices may account for differences in the treatment strategies for the ⁹⁰Y-glass and ⁹⁰Y-resin groups, including the significantly longer interval between diagnosis of metastases and SIRT in the ⁹⁰Y-resin group and the apparent preference for ⁹⁰Y-resin for unilobar treatments and ⁹⁰Y-glass for bilobar treatments. We also note that there was no uniform follow-up testing or systematic post-therapy imaging to confirm the distribution of ⁹⁰Y, which has recently become more common in SIRT. At the Cleveland Clinic, post-therapy ⁹⁰Y PET/CT has been the standard practice since 2012, but at the time of this cohort study Bremsstrahlung SPECT/CT scans were performed on only a few patients on an ad hoc basis.

In conclusion, our study shows that SIRT using ⁹⁰Y-resin delivers significantly less ⁹⁰Y activity to patients with liver-dominant colorectal metastases as compared to SIRT using ⁹⁰Y-glass. Our results also suggest a possible survival benefit for patients treated with ⁹⁰Y-resin as compared to those treated with ⁹⁰Y-glass and a similar adverse event profile for both products. Larger, prospective studies are warranted to examine the effect of dosimetry on SIRT efficacy and safety outcomes.

Acknowledgements

The authors would like to thank Jennifer Nepo of Eubio Medical Communications for editorial support (funding provided by SIRTeX Medical Inc.). Special thanks to Drs. Sankaran Shrikanthan and Ram Gurajala at Cleveland Clinic for their helpful discussions over the course of the study.

Footnote

Conflicts of Interest: S.S. has served on advisory boards for Siemens and Bayer Healthcare and as a consultant for Siemens, has received speaker honoraria from SIRTeX Medical Inc. and BTG International, Inc., and has received payment for the development of educational presentations for Bayer Healthcare. V.K. received a speaker honorarium from SIRTeX Medical Inc. Authors E.N., J.B., and A.P. declare that they have no competing interests. S.S. was affiliated with the Cleveland Clinic during the time of this study.

Ethical Statement: The study was approved by institutional ethics board of Cleveland Clinic (No. IORG0000301).

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