Colorectal cancer is the third most common can¬cer and the second most common cause of cancer death in developed countries (1). The mainstay for the management of metastatic colorectal cancer (mCRC) is chemotherapy ± biologic therapies (2). Drug and regimen advances in systemic therapy (3) have substantially improved median survivals over the last decades and provided a meaningful window for the localized control of liver metastases (a common presentation in mCRC patients), especially whenever the extrahepatic disease appears to have an indolent clinical course. Liver-directed approaches to therapy are used to treat: (I) discrete, visually-targeted tumors using resection, ablation, NanoKnife® (U/S), irreversible electroporation (IRE), or stereotactic body radiation therapy (SBRT); and (II) more, widespread, multinodular disease in the liver using selective internal radiation therapy (SIRT), also known as radioembolization (RE) (4). Encouraging evidence suggests that there might be a potential synergy between systemic therapy and the use of loco-regional approaches to improve outcomes in mCRC patients (5,6). When we combined the skills of radiation oncologists, medical oncologists, oncologic surgeons, interventional radiologists, and nuclear medicine experts, we found that a sustained clinical response (not usually observed with chemotherapy alone) can be achieved in the liver, perhaps even slowing the spread of disease beyond the liver when used earlier in the treatment paradigm (7). However, most candidates for RE have been heavily pre-treated with more or less all-available systemic agents. In a prospective randomized study of 44 such patients with liver-only disease, researchers found that patients who received RE plus 5-fluorouracil (FU) in the chemo-refractory setting significantly benefited from a longer time to progression of target liver lesions compared with FU alone (5.5 vs. 2.1 months) (5). The management of patients with mCRC is evolving from an empiric chemotherapy approach to a more individually tailored-approach, which is focused on identifying molecular biomarkers and/or disease characteristics that can predict response and/or toxicity to systemic and/or liver-directed treatments.
The mCRC liver metastases outcomes after radioembolization (MORE) study represents a unique repository comprising data of consecutive patients with unresectable, liver-dominant mCRC, who received RE between July 2002 and December 2011. In the MORE retrospective cohort analyses, our objectives were to: (I) investigate the safety and survival impacts of pretreatment, laboratory parameters on outcomes following RE in the chemotherapy refractory setting; (II) identify potentially correctable pre-radiation abnormalities, which may assist in improving treatment outcomes beyond the current recommended RE guidelines (Table 1); and (III) examine the impact of prior chemotherapy (in patients stratified by line of therapy) on standard liver function tests (LFT) and haemoglobin (HGB) prior to rescue treatment with RE.
MORE was a retrospective observational study (clinicaltrials.gov identifier: NCT01815879) of consecutive patients who received RE with yttrium-90 (90Y)-resin microspheres (SIR-Spheres®; Sirtex Medical, Sydney, Australia) at 11 United States (US) institutions, chosen for their experience with RE techniques. The methods used to obtain and collect the data were previously described (8). An institution review board granted exemptions prior to the collection of data at each site.
The US institutions were guided in the selection of patients, pre-treatment work-up, and dosimetry (using body surface area methodology) by the published consensus from the Radioembolization Brachytherapy Oncology Consortium (REBOC) and other earlier reviews (4,9,10). During the pre-treatment work-up, patients were excluded from RE if there was evidence of any uncorrectable blood flow to non-target sites—gastrointestinal tract or other extra-hepatic organs—observed on angiography or Technetium-99m macroaggregated albumin (99mTc-MAA) scan. Based on the clinical judgment of the multidisciplinary team, some patients, under exceptional circumstances and with informed consent, were treated outside the recommended criteria (Table 1). Study patients received a median of two RE procedures [delivering 1.46 (range, 0.11–5.51) GBq of total 90Y activity] mainly using either a whole liver (65.7%) approach or right lobar (27.7%) l approach; the design (i.e., number, sequence and time between each RE procedure was previously reported (8,11). In 98% of cases, hospitalization after each procedure was less than 24 hours.
Data collection and analysis
The following values were obtained within 10 days prior to RE: HGB, albumin, alkaline phosphatase (Alk phosph), aspartate aminotransferase (AST), alanine transaminase (ALT), total bilirubin, and creatinine. The nature and severity of all AEs were graded using the CTC version 3.0 (CTC v3) (12). The highest grade occurring at any time between day 0 and 90 post-procedure was reported.
Statistical analyses were conducted using statistical analysis software (SAS) (SAS Institute Inc., Cary, NC, USA). Where applicable, the most recently published Consensus Guidelines and/or clinical trial selection criteria were used to establish the abnormal limits for RE (Table 1). Summary statistics of continuous variables included the number of non-missing observations, the mean, standard deviation, interquartile range, median, minimum, and maximum values. Statistical significance was tested at two-sided p=0.05, without adjustment for multiple comparison, or imputation of missing values. Median follow-up time was calculated using the reverse Kaplan-Meier method on the time to death. The association between LFT categorical variables and CTC grade and LFT variables and prior chemotherapy was tested by the Chi-square test.
Overall survival time was measured from the date of the first SIRT procedure until recorded date of death or loss to follow-up. Median survival was estimated by the Kaplan-Meier method. Proportional hazards models were applied to evaluate the consistency and robustness of the treatment effect over strata, and include the model estimate, standard error, hazard ratio (HR), and 95% confidence interval (CI) of the HR. AEs terminology reporting is standardized using the medical dictionary for Regulatory Authorities (MedDRA). The number and percentage of subjects reporting treatment-emergent AEs were tabulated using System Organ Class (SOC) and preferred term. For summaries by preferred term and by SOC, subjects with more than one AE were counted once.
Of 606 consecutive patients in the study with a diagnosis of mCRC who received at least one RE procedure (Table 2), median follow-up was 9.6 months, 95% CI: 9.0–11.1 months. Five hundred and three deaths were reported, and 103 patients were censored.
RE was administered as a second-line, third-line or fourth-plus line of therapy in 35.3%, 32.6% and 27.1% of patients in the study, respectively—mostly during a chemotherapy holiday or in patients who were either intolerant or refractory to systemic chemotherapy. Six percent of cases received RE first-line, mainly due to significant comorbidities or intolerance to prior adjuvant chemotherapy for the treatment of the primary tumor. Eighty three point two percent (501 of 606) of patients in the Study had at least one pretreatment laboratory value beyond the normal limits, CTC grade >0. Results of stratification of patients by prior chemotherapy showed the proportion of patients and the severity of abnormal pretreatment values rose significantly (P<0.01) with increasing lines of RE and chemotherapy for ALT, AST and Alk phosph but not for total bilirubin, albumin, creatinine, and HGB levels (Figure S1). Fewer than 13.6% of study patients were treated because one or more laboratory parameters were outside current recommended RE guidelines. Pretreatment CTC grade 2-plus changes in albumin (<3 g/dL) was the most common reason for non-adherence in 12% of patients (Table S1). The non-adherence guideline did not increase significantly in patients who received RE after more lines of prior chemotherapy; however, the proportion of patients with Alk phosph >300 U/L rose significantly from 13.6% to 27.4% (P=0.001) when RE was given second-line versus fourth-plus line, respectively. Additionally, there was a non-significant rise (from 1.0% to 3.8%; P=0.073) in patients with total bilirubin beyond the recommended limit for RE of 2 mg/dL in the second-line and fourth-plus line setting, respectively.
Overall, RE was well tolerated; the most commonly reported AEs (grades 1–2 and grade 3+) within 90 days post-treatment were gastrointestinal (41.4% and 10.2%); constitutional (39.8% and 6.4%) and hepatobiliary (11.4% and 8.6%). Study patients (34%) who showed abnormal changes in albumin at baseline had an increased risk of grade 3+ AEs over the 90 days after RE (P=0.013): specifically grade 3+ constitutional symptoms (fatigue) and hepatobiliary signs and symptoms (hyperbilirubinemia) (Tables 3,S2).
The 59% of patients who had an abnormal (grade >0) Alk phosph at baseline had a significantly greater risk of any AEs (P=0.001) or grade 3+ (P=0.002) AEs, and specifically a rise in any or grade 3+ constitutional symptoms (fatigue grade 3+ and any fever), and any but not grade 3+, hepatobiliary events; this trend was mirrored for patients with raised pretreatment AST levels (grade >0). Patients with low HGB levels at baseline did not have any increased incidence of AEs overall or hepatobiliary events, but were significantly more likely to present with gastrointestinal AEs (any grade, but not grade 3 + events) and particularly abdominal pain and nausea.
The total reported incidence of grade 3+ hepatitis and radioembolization-induced liver disease (REILD) within 90 days post-treatment was 0.8% and 0.5%, respectively. Raised total bilirubin (all grades; all causality including liver progression) was recorded in 6.2% of study patients at baseline, increasing to 22.6% of study patients by day 90 following the first treatment, with a minority experiencing grade 3 (4.9%) or 4 (2.7%) events at day 90. Although REILD was a rare event, the 6.2% of patients who had raised total bilirubin (grade >0) at baseline had a significantly greater risk of REILD and hepatic failure compared to patients with normal baseline total bilirubin levels (Tables S2-S4). Raised bilirubin was the only observed pretreatment laboratory value that predicted REILD in this study (Table 3).
Kaplan-Meier analysis of the overall cohort found that median survivals significantly decreased with increasing severity of pretreatment laboratory parameters (beyond CTC grade 0), and this trend was consistent across all cohorts, regardless of the number of prior lines of chemotherapy (Table S5).
Univariate analysis found that for each increasing grade of dysfunction, Alk phosph (HR 1.9), total bilirubin (HR 1.8), and AST (HR 1.7) were the most predictive of diminishing overall survival (Figure 1). Compared with patients who had normal laboratory values at baseline, median overall survivals were significantly reduced in patients who were treated outside the current RE guidelines for all parameters evaluated (Table 4). Any pretreatment grade beyond the norm (CTC grade 0) for total bilirubin, albumin, Alk phosph and AST, but not ALT or creatinine, was associated with significantly shorter survivals.
HGB levels are not defined by the RE guidelines; however, we found that a pretreatment anemia (defined as HGB <10 g/dL) significantly reduced overall survival (HR 1.8; 95% CI: 1.3–2.5]; P<0.001) compared with patients with normal baseline levels (Table 4).
The MORE study provides important insights into the impact of standard laboratory tests on prior identification of correctable pre-radiation abnormalities before delivery of liver-directed radiation and thereby assist in improving outcome.
Pre-treatment liver dysfunction affects outcomes after RE
It was previously established that pre-treatment liver dysfunction affects outcomes and tolerability to first-line chemotherapy (13). A variety of baseline laboratory data were evaluated in prospective chemotherapy studies and found to predict treatment outcome including: elevated lactate dehydrogenase (LDH) (14,15), white blood cell (WBC) count (15,16), serum albumin (17), elevated liver transaminases (18), Alk phosph (19), and HGB (20). In a pooled analysis of source data from >3,800 patients treated with FU-based treatments (21) and a subsequent analysis of >1,600 patients from Intergroup trial N9741 of FU-, oxaliplatin-, and irinotecan-containing chemotherapy regimens (13), three prognostic groups (low, intermediate, and high risk) were identified in the first-line setting according to the following baseline factors: Eastern Cooperative Oncology Group Performance Status (ECOG PS), WBC, Alk phosph, and number of sites of metastatic disease (the Kohne criteria) (21). The intergroup (N9741) study also showed that the odds of experiencing any grade 3 or greater toxicity were significantly increased in patients with raised baseline total bilirubin and Alk phosph levels (13). It is not surprising that pre-treatment laboratory values also affect overall survival and safety outcomes with RE in the refractory setting.
RE is a highly safe therapy
RE is a form of intra-arterial brachytherapy where high-localized doses of beta radiation are delivered to the tumoral tissue relative to non-tumoral tissue (22). The primary consideration for the application of RE is safety, which can be achieved through the correct selection of patients and use of an appropriate treatment approach (23) e.g., by decreasing the treated volume (using lobar or segmental treatment approach) or prescribed activity of yttrium-90. The low incidence of overall, as well as, grade 3+ AEs in this intention-to-treat analysis is testament to the ongoing process of patient selection and audit at most specialized centers, where risks associated with RE are continuously monitored and an adaptive approach is implemented to improve safety. A conservative approach was adopted in the majority of patients in this study, as the treatment intent was palliation (extending in overall survival where possible without impacting of quality of life). Recognizing the limitations of 90Y-RE in patients with severe liver dysfunction is key to optimizing patient outcomes. However, especially in the palliative setting, it is difficult to balance, improving the patient’s health status and their ability to tolerate treatment better, without leaving treatment until it is too late to have a significant impact on survival.
We found that although any abnormal changes in Alk phosph, ALT, AST, or albumin at baseline were associated with an increased risk of hyperbilirubinemia post-treatment, only raised pretreatment bilirubin, found in 6% of study patients, was significantly associated with an increased risk of REILD, which is a serious, but fortunately rare event, observed in 0.5% of patients in this cohort. REILD is a form of sinusoidal obstruction syndrome appearing 4 to 8 weeks after RE, described in non-cirrhotic patients as jaundice, mild ascites, and a moderate increase in gamma-glutamyl transpeptidase (GGTP) and Alk phosph (24). Factors that impact the occurrence of REILD include: prior liver function and functional reserve and prior or concurrent use of other antineoplastic therapies (25,26).
Liver function trend and cumulative chemotherapy prior to RE
MORE study data show that with each successive line of prior chemotherapy, the frequency of reported abnormal pre-RE, AST, ALT and Alk phosph levels increased, including total bilirubin beyond the recommended guidelines for RE. Therefore, a review of liver function trends in the months prior to 90Y should be performed to optimize patient selection. These study data suggest that the use of RE earlier in the treatment course would not only improve tolerability to RE, but also increase the number of patients potentially eligible for RE. Studies of the relative safety and efficacy of chemotherapy, with or without RE, in the first-line setting for unresectable liver-dominant mCRC are now the subject of extensive analysis in three ongoing prospective phase 3 trials (27-29).
Anemia and RE
Data also suggest that if anemia (i.e., HGB <10 g/dL) was corrected with either a blood transfusion or subcutaneous erythropoietin (EPO) prior to RE, median survivals (as well as tolerability to GI events) could be potentially improved. A strategy of reducing anemia prior to radiotherapy with external beam radiation therapy (EBRT) or brachytherapy including RE (30-34), is supported by wealth of published evidence indicating that a low HGB level before or during radiation therapy is an important risk factor for poor survival and/or locoregional disease control. The more hypoxic environment of solid tumors is associated with decreased radiosensitivity thereby enabling malignant cells to remain viable, especially in patients with anemia (35). Clinically significant anemia is believed to be one cause of intratumoral hypoxia, which is a well-known negative factor in radioresistance of solid tumors (36). Oxygen is the most important agent enabling maximal tumor sensitivity to ionizing radiation, as demonstrated by numerous preclinical studies. The magnitude of enhancement of radiation effect is a factor of between 2 and 3 times over hypoxic conditions receiving the same radiation treatment. Prospective clinical trials in a variety of tumor types have associated pre-radiotherapy hypoxia (2.5–10 mm Hg partial pressure of oxygen) with statistically significant reductions in local control, disease free survival and overall survival via multivariate analyses (35,36). A recent report analyzing anemia in cervical cancer patients suggested anemia during radiotherapy (external beam and brachytherapy) with our without concurrent chemotherapy was not an independent predictor of central recurrence (37).
The fact that MORE was a retrospective analysis is the chief limitation of the study; however, all patients treated during the pre-specified period were included in all evaluations. Patients were also selected from specialist tertiary care centers and (previously shown in evaluation of the elderly versus the young), there was an inevitable selection bias at these centers towards younger and/or fitter patients; although, elderly and young patients were found to tolerate the treatment equally well (38).
MORE data support previous analyses, which show that low HGB (18,21) and low albumin (39), as well as, Alk phosph (≥300 U/L) (13,21) and AST (18) are recognized factors that are predictive for shorter survival in mCRC. However, if disease-related anemia and treatment-related anemia can be limited, RE can be performed more efficiently. A review of pre-treatment laboratory parameters may improve median survivals if correctable values (e.g., HGB <10 g/dL) are addressed prior to RE. Liver function trends prior to use of RE should always be considered, especially in the chemotherapy refractory setting, and the calculated activity of 90Y adapted accordingly for each patient to optimize outcome.
We would like to thank Mark Van Buskirk for his outstanding statistical work and advice; and Rae Hobbs for her editorial assistance.
Funding: This was an investigator-initiated study funded by Sirtex Medical Limited, Sydney, Australia through an educational grant awarded to Dr. Kennedy, Sarah Cannon Research Institute. AS Kennedy, D Ball, NK Sharma received grants for clinical trials from Sirtex Medical; E Ehrenwald, S Kanani, S Schirm have nothing to disclose.
Conflicts of Interest: DM Coldwell is a consultant to Sirtex Medical; M Cohn, A Drooz, FM Moeslein, CW Nutting, SG Putnam III, SC Rose, EA Wang are proctors for Sirtex Medical; MA Savin is a speaker for BSD Medical. Prior presentations: AS Kennedy et al. ACRO Annual Meeting 2014.
Ethical Statement: MORE was a retrospective observational study (clinicaltrials.gov identifier: NCT01815879) of consecutive patients who received RE with yttrium-90 (90Y)-resin microspheres (SIR-Spheres®; Sirtex Medical, Sydney, Australia) at 11 United States (US) institutions, chosen for their experience with RE techniques. An institution review board granted exemptions prior to the collection of data at each site.
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