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Belinson S, Chopra R, Yang Y, et al. Local Hepatic Therapies for Metastases to the Liver From Unresectable Colorectal Cancer [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2012 Dec. (Comparative Effectiveness Reviews, No. 93.)
This publication is provided for historical reference only and the information may be out of date.
Local Hepatic Therapies for Metastases to the Liver From Unresectable Colorectal Cancer [Internet].
Show detailsKey Findings and Strength of Evidence
No comparative studies met the inclusion criteria for any of the four KQs about local hepatic therapy for the treatment of unresectable CRC metastases to the liver. Thirty-one studies met our inclusion criteria and addressed local hepatic therapy for unresectable CRC metastases to the liver.
We assessed the strength of evidence for all KQs for the primary health outcomes of overall survival and quality of life and for the intermediate outcomes of length of stay, local recurrence, and adverse events. In addition strength of evidence was assessed for the intermediate outcomes of time to progression (KQs 1 and 2) and time to recurrence (KQs 3 and 4). We judged the strength of evidence to be insufficient to draw conclusions for effectiveness outcomes (overall survival, quality of life, length of stay, time to progression, time to recurrence, and local recurrence) and for adverse events for all KQs (Table 16 and Table 17). The body of evidence provided no comparative information about differences in effectiveness by type of intervention. Indirect comparisons were not considered because of the heterogeneity in the patient population, intervention characteristics, and outcome definitions, as well as the biases inherent in observational studies.
Table 16
Strength of evidence for KQ1 and KQ2.
Table 17
Strength of evidence for KQ3 and KQ4.
Findings in Relationship to What Is Already Known
We are not aware of any published systematic reviews of the comparative effectiveness of local hepatic therapies for CRC metastases to the liver, and the literature base does not contain studies that compare one local hepatic therapy with another. Some systematic reviews of single local hepatic therapies have been published. Although the reviews vary in quality, they generally agree that evidence is insufficient to demonstrate the effectiveness of these modalities, particularly in terms of survival benefit.95–99 Earlier reviews conforming to a high quality standard interpreted their findings similarly to the present review; that is, evidence was insufficient to permit conclusions.31,100
This review sought evidence on the comparative benefits and harms of local hepatic therapies in two patient groups for CRC metastasis to the liver. Although we did not find this evidence the strength of this present review is in the identification of this important evidence gap. While distinct patient groups exist within the population receiving local hepatic therapies, data to analyze these differences are limited. In our review, we addressed two distinct patient populations: those receiving local hepatic therapies as an adjunct to systemic chemotherapy and those whose disease is refractory to systemic treatment. Because we focused on patient groups rather than a specific intervention, we were able to present the outcomes for a wide range of local hepatic therapies for each target population.
Applicability
It is challenging to comment on the applicability of findings from our CER because we that found that the available evidence was insufficient for us to draw conclusions. The degree to which the data presented in this report are applicable to clinical practice hinges on the degree to which the populations in the included studies represent the patient populations receiving clinical care in diverse settings, as well as the availability of the interventions. We comment below on the relevance of included studies for PICOTS elements. The PICOTS format provides a practical and useful structure to review applicability in a systematic manner and is employed in the subsections that follow.101
Population and Settings
The question of which subgroups of patients with CRC metastases to the liver may benefit from any particular local hepatic therapy compared with another remains unanswered. This uncertainty is reflected in the heterogeneity of the patient populations included in the published literature. Patient characteristics were often poorly characterized and not uniformly reported. Patients with varying degrees of resectability, extrahepatic disease, portal vein tumor thrombosis, and size and number of lesions are often grouped together and reported on as one group, even though it is uncertain whether these factors are likely to affect outcomes. Patient heterogeneity, combined with poor reporting of stratified or patient-level data, limited our ability to compare patient groups in any meaningful way. As a result, we are currently unable to determine which patients should be receiving which local hepatic therapies.
The setting in which treatment occurs is a major factor in the outcomes of local hepatic therapy. Expertise of both clinicians and centers varies. Based on the available clinical expertise and technology, the choice of a local hepatic therapy may be limited to one option in many centers. Local hepatic therapies, such as radioembolization102 and hepatic arterial infusion,103 often require high levels of training and familiarity with the procedure. Lack of experience may not only affect patient outcomes but also result in adverse effects; patients treated by less-experienced clinicians and centers will likely experience poorer outcomes.
Detailed analysis of differences in outcomes by center has important implications for the relevance of the findings in the literature. Unfortunately, these data were unavailable as part of our systematic review of the published literature.
Interventions
Even for a single local hepatic therapy, variations in how the procedure is performed may be substantial. For instance, variations may occur in the approach (open vs. percutaneous), the choice of chemotherapy drugs delivered, and the schedule of delivery of chemotherapy and radiation therapy. Given the lack of comparative data, the present review did not allow for a more rigorous and systematic comparison of the relative performance of local hepatic therapies stratified by these factors. How these factors may alter health outcomes remains unclear.
Additional heterogeneity exists for the context in which the intervention was delivered. Patients often receive more than one local hepatic therapy over time or more than one session of the same therapy. This often results in variations of prior therapy at study enrollment. The complex treatment history of each patient can further limit the conclusions that can be drawn about the benefits attributable to any one component of the treatment plan.
Comparators
All studies in this review are observational (including the arm of one RCT that was extracted as a case-series); as such, they report on the experience of a particular center with one or more local hepatic therapies. Although case series can be useful for hypothesis generation, this approach cannot provide the comparative data the field needs for evaluating effectiveness. The applicability of any case series to another study group is very limited.
Outcomes
Little controversy exists regarding the most appropriate direct health outcomes to measure in a study of local hepatic therapies for CRC metastases to the liver. Overall survival is the ultimate outcome; it was reported in all of the studies included in this review. Quality of life is also a very important patient-centered outcome, but was not routinely reported in the literature in this review.
The importance of outcomes such as disease-free survival or local progression-free survival can be debated. Outcomes such as progression-free survival may not accurately predict changes in overall survival. However, these clinical events may mark changes in therapies and treatment that may be important to patients. Few experts would suggest that these outcomes replace the need for data on overall survival.
Studies of a comparative design are needed to measure accurately the differences in overall survival, quality of life, and harms that may be attributed to a local hepatic therapy.
Timing
The timing of followup assessment was appropriate given the natural history of unresectable CRC liver metastases and the primary outcome of overall survival. Median survival was reached in 21 of 24 studies. We judged this to be an appropriate length of assessment. In addition, two of the studies that did not reach median survival followed patients for up to 3 years to assess overall survival rates.
Implications for Clinical and Policy Decisionmaking
The goal of any local hepatic therapy for unresectable CRC metastases to the liver is to prolong life by eliminating the metastases if possible or to palliate symptoms such as pain. This report has reviewed the literature on local hepatic therapies to achieve these goals.
Due to the noncomparative nature of the literature base, both clinicians and policymakers are limited in their ability to apply the published literature base to decisions on effectiveness and comparative effectiveness of these interventions. Survival estimates from individual studies of local hepatic therapies suggest that local hepatic therapies may provide some benefit in terms of survival and symptom relief for some patients, but without comparative data, it is not possible to choose the therapy that will produce the best outcomes for specific patients. Several ongoing clinical trials pertaining to the interventions and population of interest to this review were identified through clinicaltrials.gov and are presented in Appendix D. None of these trials compares a local hepatic therapy with another local hepatic therapy.
Limitations of the Comparative Effectiveness Review Process
Determination of the scope of this review was a lengthy process that began in topic development but did not end until the CER was well underway. The topic was initially broader, encompassing other primary tumors metastasizing to the liver and hepatocellular carcinoma, a primary liver cancer. Although these liver tumors are all treated with a subset of the local hepatic therapies reviewed here, the evidence of their effectiveness is distinct, as are the clinical circumstances. During the scoping process, the review was narrowed to focus solely on unresectable CRC metastases to the liver. After the scope was set and inclusion and exclusion criteria were refined and reviewed by clinical experts, the literature search revealed an evidence base comprised of case-series studies. The decision was made to complete the report with its limitations. CRC metastases to the liver are a common condition and patients and providers may need to choose from many treatment options. The evaluation of the quality of the body of literature to assess our KQs and the identification of research needs are important contributions to the field.
Limitations of the Evidence Base
Limitations of the present review are related largely to the lack of comparative evidence. Because of the limited number of patients and clinical heterogeneity, we did not systematically review doses, regimens, or treatment-specific characteristics. A very large sample size with uniform data collection of these variables would be required to assess whether specific treatment characteristics were associated with survival differences. We did abstract from the literature information on patient characteristics such as performance status (degree of physical impairment typically assessed by an instrument such as ECOG or Karnofsky scale), number of lesions, and size of lesions. However, because of limitations of these data, the association between these variables and overall survival, quality of life, or adverse effects could not be assessed.
Evaluation of comparative effectiveness requires an intervention and a comparator. Case-series do not use comparators. Therefore, comparative effectiveness cannot be assessed using this type of literature. Further, factors that may affect the effectiveness of the interventions within these populations were not controlled for in the included studies. Control may be achieved either though randomized design or statistically though careful adjustment in the analysis. Studies that aim to determine the effectiveness or comparative effectiveness of local treatment for unresectable CRC metastases to the liver should use randomized designs. If randomization is not possible, care should be taken to control for covariates such as size and number of hepatic lesions, extrahepatic lesion number, CEA, treatment characteristics prior to local hepatic therapy (i.e. number of lines of previous chemotherapy), and performance status through regression analysis as these have been shown to impact survival outcomes.
Research Gaps
In this section, we first present a set of gaps focused on issues in the body of literature. Then we discuss the use of RCTs and observational studies to address these gaps, followed by an example of how a registry might overcome the drawbacks of single-center case series.
Gaps
This systematic review attempted to compare outcomes of local hepatic therapies for patients treated for unresectable CRC metastases to the liver. The review focused on two patient populations: those patients whose disease is refractory to systemic chemotherapy and patients who are receiving local hepatic therapy as an adjunct to systemic chemotherapy. Evidence on patient outcomes is limited, and the strength of evidence is insufficient for us to draw conclusions on effectiveness or harms for either patient population. As detailed above under applicability, there are specific evidence gaps that, if addressed, could enhance this literature base.
We identified four broad evidence gaps during this review organized by PICOTS framework. No gaps were identified for timing and setting.
- Populations: An objective of comparative effectiveness research is to understand the comparative effects for different population subgroups. To achieve this, we must fully delineate the population subgroups of interest. As detailed in the population and setting section above, these data are limited. Future studies must present data by subgroups of interest so that evidence can be interpreted by these variables. Based on published multivariate analyses examples of patient or tumor characteristics found to be associated with improved overall survival include: ECOG status (0 vs. ≥1 and in another study 0 or 1 vs. ≥2), performance status (0 or 1 vs. ≥ 2), number of extrahepatic metastases sites (0 or 1 vs. ≥2), number of lines of previous chemotherapy (0–1 vs. ≥ 2), performance status (0 or 1 vs. ≥ 2), carcinoembryonic antigen response (Yes, No), and Response Evaluation Criteria in Solid Tumors (RECIST). These variables should be considered when designing future studies. Because there are so many variables being collated, clinical risk scores may be particularly beneficial as a summary measure.104
- Intervention: There can be substantial variation in the role of local hepatic therapy in the overall treatment strategy for patient populations with unresectable CRC liver metastases reviewed in this report. A thorough delineation of prior and concurrent treatment is necessary to assess the incremental benefit of local hepatic therapy and the comparative outcomes of these therapies for the reviewed patient populations. All other therapies, systemic and local, should be taken into account when evaluating the effectiveness of the intervention under study, as these therapies may have an effect on patient survival. Previous resections and other local hepatic therapies were often not reported in the studies included in this review.
- Comparator: A major limitation of the current evidence review was that there was no comparative evidence at the time of publication of this report comparing the various liver-directed therapies with one another.
- Outcomes: Outcomes of interest to patients and their physicians include survival, quality of life, and adverse effects such as radiation-induced liver disease, liver failure, and local recurrence (i.e., treatment failure). Evidence comparing these outcomes of local hepatic therapies in the populations of interest for the review are needed. For survival and other time-to-event outcomes, it is essential for authors to report the time point from which the event was measured (e.g., time from liver-directed therapy, time from CRC diagnosis, time from diagnosis of metastases).Collection and reporting of quality-of-life data (e.g., pain) using standard measurement tools was inconsistently reported in the literature included in this review. These data are particularly important for the population of patients in which palliation of symptoms, rather than cure, is the intent of therapy.
Study Designs To Address These Gaps
RCTs are the gold standard of clinical evaluation and there is an absence of randomized controlled clinical trial evidence on the use of local hepatic therapies for the included indications. Because we were unable to find evidence to answer any of our key questions, we conducted additional discussions with members of our TEP to elicit ideas that could address the gaps in the literature. TEP members identified common barriers to conducting RCTs that would answer our key questions, including limited sources of research funding to support RCTs, reluctance of physicians to randomize patients, and the reluctance of patients to be randomized.
In addition to the resistance to randomize, consensus around the most compelling hypothesis for a comparative RCT is lacking. Clinical investigators have competing hypotheses of which treatment is best suited for which patients, and these hypotheses are often based on their own institution’s experience. TEP members agreed that certain broad categories of patients with CRC metastasis to the liver, such as the populations included in this review, may well benefit from local hepatic therapies, but they also recognized that the published literature did not permit analysis of patient subgroups to identify characteristics more favorable to one local hepatic therapy over another. RCTs with well-documented patient and treatment characteristics could address the lack of comparative evidence. Lack of funding sources will continue to be an issue under the current regulatory structure. Under this system, the FDA does not require the same level of evidence for device approval as it does for drug approval. Because device companies can obtain approval without data from RCTs, they have very little incentive to provide funding.105
Regardless of the study design, we suggest that studies aiming to address the effectiveness or comparative effectiveness of local hepatic therapies take care to address potential confounders and effect measure modification that could obscure the results. This is particularly important for patient characteristics such as size and number of metastases and performance status, which could serve as both modifiers of the effectiveness and factors that are considered when choosing the best local hepatic therapy.
Although RCTs may not be possible for all comparisons in all centers, well done multivariate analyses from existing case series can aid in identifying additional factors that should be documented and potentially controlled for in the comparative analysis of these data. These analyses can enhance the design of future RCTs or observational studies.
Patient Registries
In the absence of consensus regarding the most salient comparative research question, observational data could be useful in driving the generation and prioritization of hypotheses for future research. One approach is the use of a registry to systematically collect observational data. According to the Agency for Healthcare Research and Quality publication on registries for evaluating patient outcomes, patient registries are often constructed to study patient outcomes, the natural history of disease, and disease management under various treatment scenarios.106 Registries need to be created with a question in mind, which will then guide the identification of the target patient population, the interventions of interest (e.g., a local hepatic therapy), the outcomes of interest, the number of patients (to be adequately powered for future analysis), and the length of followup.
The KQs from this CER could serve as guide for designing one or more registries focused on this clinical area. The aim would be to establish a prospective registry that tracks the outcomes, quality of life, and adverse events in those who receive local nonsurgical treatment for unresectable metastatic CRC to the liver in order to identify the most effective local hepatic therapy strategies. The effectiveness of any one local hepatic therapy is expected to vary by patient subgroup. TEP members also indicated that the provider experience with the local hepatic therapy is also an important factor in patient outcomes.
We have identified a core set of variables or core dataset, defined as the information set needed to address the critical questions the registry is developed to answer. This is presented in Table 18, organized by PICOTS.
Table 18
Core dataset elements for local hepatic therapy registry by PICOTS.
Conclusions
Due to the absence of published comparative data, the evidence is insufficient for us to draw conclusions about the comparative effectiveness of local hepatic therapies for unresectable CRC metastases to the liver for the patient populations addressed in this review. Important outcomes of therapy include overall survival, quality of life, and adverse effects (harms). A patient registry is one tool for future research that may generate hypotheses for clinical trials or observational evidence on the comparative effectiveness of local hepatic therapies.
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