A recent study by Holzapfel et al. reported no significant difference in diagnostic accuracy and sensitivity between diffusion weighted imaging, Gd-EOB-DTPA-enhanced imaging and combined imaging for the detection of focal liver lesions. However, for lesions smaller than 10 mm, a combination of DWI and Gd-EOB-DTPA significantly increased the overall detection rate. Similar to our findings regarding HCC-related diagnostic accuracy, Gadolinium-enhanced MRI and the combination of DWI and Gd-EOB-DTPA enhanced MRI demonstrated equal results (Holzapfel et al. 2012). In our 50 patients, just one additional HCC suspicious lesion was detected with DWI compared to conventional dynamic MRI, an 8 mm lesion that was also detected with hepatobiliary phase imaging. Therefore, DWI did not improve the detection of HCC compared to imaging with Gd-EOB-DTPA (Chung et al. 2011).

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Literature Review on DWI?

DWI is commonly used in liver imaging to assess various focal lesions. In particular, DWI has a higher detection rate and diagnostic performance for small, malignant liver lesions compared to conventional dynamic MRI with different contrast agents; however, these results are not always significant (Kim et al. 2012). A recent study by Holzapfel et al. reported no significant difference in diagnostic accuracy and sensitivity between diffusion weighted imaging, Gd-EOB-DTPA-enhanced imaging and combined imaging for the detection of focal liver lesions. However, for lesions smaller than 10 mm, a combination of DWI and Gd-EOB-DTPA significantly increased the overall detection rate. Similar to our findings regarding HCC-related diagnostic accuracy, Gadolinium-enhanced MRI and the combination of DWI and Gd-EOB-DTPA enhanced MRI demonstrated equal results (Holzapfel et al. 2012). In our 50 patients, just one additional HCC suspicious lesion was detected with DWI compared to conventional dynamic MRI, an 8 mm lesion that was also detected with hepatobiliary phase imaging. Therefore, DWI did not improve the detection of HCC compared to imaging with Gd-EOB-DTPA (Chung et al. 2011).

Park et al. also demonstrated that DWI was outperformed by contrast enhanced T1-weighted imaging for the detection of HCC, but it represents a reasonable alternative (Park et al. 2012). However, if Gd-EOB-DTPA is used in the hepatic imaging, a time gap occurs between the equilibrium phase and the hepatobiliary phase, and because there is no significant impact of contrast media on achieving diffusion-weighted imaging and ADC-maps (Kinner et al. 2012). This gap can easily be filled with respiratory-triggered, diffusion-weighted imaging, which can provide additional information for the characterization of focal liver lesions. An important advantage of DWI is that no contrast agent is necessary, a property that is especially valuable for patients with poor renal function (Holzapfel et al. 2012b)

Patients suffering from a malignant tumor or metastases undergo extensive therapies including various side effects. Up to date treatment response is evaluated by morphological, clinical and laboratory outcome. Radiological tumor response is based on the extent of tumor size reduction as measured by anatomical imaging modalities such as CT or MRI. However, therapy is typically delivered in fractionated doses thus requiring sufficient time for enough treatment to be delivered to kill cells within the tumor as well as additional time needed for immunological removal of the macromolecular debri. Thus therapeutic-induced changes in tumor volumes often occurs relatively late in the time course of treatment.

Current therapeutic strategies in oncology include surgery, radiation therapy, and chemotherapy which include molecularly targeted agents against oncogenic signaling pathways as well as vascular targets. However, timely evaluation of treatment response in patients undergoing radiation therapy or chemotherapy depending on the underlying pathology or treatment strategy is often very difficult. Evaluation of the response to chemotherapy based on changes in the size of solid tumors is typically evaluable after six to eight weeks. Development of antiangiogenic agents, vascular and molecularly-targeted agents may not lead to significant reduction in tumor size. Antiangiogenic agents inhibit neovascularisation of tumors, vascular targeting agents selectively destroy pathological vessels without interfering with normal vessels. Molecularly targeted agents for example, are directed at oncogenic signaling molecules which can for example lead to a variety of biological effects including inhibition of growth or apoptotic-induced cell death. In 2000 RECIST (response evaluation criteria in solid tumors) defined the response to treatment in terms of alteration of tumor size only. However as newer agents might provide therapeutic benefit by other mechanisms than size reduction new evaluation criteria are of utmost importance. Recently these RECIST criteria were reconsidered and are considering imaging biomarkers such as PET (2). In these articles it has already been considered that the up to date anatomic unidimensional assessment of tumor burden has to be changed to volumetric anatomical assessment as well as functional assessment including PET and MRI.

Clinical assessment of new treatments in oncology is evaluated by numerous response criteria including tissue and plasma biomarker readouts, improvement in quality of life, and survival among others. As the process to quantify response of agents undergoing clinical trials may be lengthy there is a significant need for timelier outcome measures to be identified and validated. The ability to quantify the effectiveness of experimental therapies would significantly impact the overall drug development process and offers the potential of using DW-MRI to provide for early evaluation and go, no go decisions in phase 1 clinical trials thus saving money and time. Thus early surrogate indicators which correlate with long term outcome metrics are urgently needed ((3)). Clinical trial measures that could provide early readouts of drug-target interactions and subsequent efficacy would facilitate quantification of outcomes in clinical trials and ultimately provide assistance in the regulatory approval process. The current functional methods for response assessment as suggested by RECIST 1.1 includes PET, PET-CT, magnetic resonance spectroscopy as well as dynamic contrast enhanced MRI. PET and PET-CT are quite expensive methods and the differentiation between residual tumor and inflammation is often quite difficult using traces such as [F18]fluorodeoxyglucose. Furthermore, radiation exposure is a drawback mainly in younger patients undergoing several follow-up studies for response assessment. Magnetic resonance spectroscopy is a very promising method however, its limitations include low spatial resolution, restricted availability and lack of expertise of many radiologists. Dynamic contrast enhanced MRI provides information on changes in vascularization of the tumor during treatment however, image analysis is relatively complicated and therefore not suited for daily clinical routine. Furthermore, the risk of nephrogenic systemic fibrosis – although being very small – has to be taken into account in patients with renal insufficiency. Diffusion-weighted MRI (DW-MRI) has not been considered in RECIST 1.1 however this noninvasive MR technique has been discussed as cancer biomarker in a consensus meeting at the ISMRM 2008 and a publication on consensus and recommendations for DW-MRI as a cancer biomarker has been published recently highlighting the potential of this promising technique in cancer patients (4).

DW-MRI for the evaluation of early treatment response is very promising. As diffusion within tumors is impeded by the presence of cellular membranes and macromolecular structures, treatment with for example radiation and/or chemotherapy can result in the loss of cell membrane integrity which can be detected as an increase in mean diffusion value for the tumor. Thus DW-MRI can provide microstructural information on the cellular level. Animal and clinical studies to date have revealed that successful treatments of a wide variety of tumor types can be detected as an increase in tumor ADC values due to the loss of cellular density.

The advantages of DWI in measuring treatment response are well-documented, including identification of tumour-volume reduction for single metastatic lesions within a 2-day period following administration of SIRT.

Colorectal cancer (CRC) is the fourth most common cancer in the West and the second most common cause of cancer related mortality after lung cancer in Europe and North America[1,2]. More than 50% of patients with CRC will develop liver metastases during their lifespan (Misiakos et al. 2011). A quarter of patients with primary CRC are found to have synchronous hepatic secondaries. Almost half of patients undergoing resection for primary CRC eventually develop metachronous liver secondaries.Despite improvements in chemotherapies and biological agents, survival is rarely longer than three years lifespan (Misiakos et al. 2011).

Evidence based on numerous retrospective and comparative studies indicates that hepatic resection is the only available treatment that allows long-term survival (Misiakos et al. 2011). Experiences with liver resection is associated with a 25% to 51% 5-year survival (Misiakos et al. 2011). By contrast, five-year survivors with chemotherapy alone are anecdotal. Historically, only 5%-10% of patients with colorectal liver metastases were resectable; currently, with the advances in diagnostic methods and new therapies, resectability rates have increased to 20%-25% (Misiakos et al. 2011).

Quality Assessment

According to Whiting et al. (2011), the main goal of the quality assessment was to evaluate the internal validity of the studies and to assess the extent to which a study addressed the bias issues in its design, performance, and analysis of the results. Ramlaul (2010) Since the degree to which a structured literature review (SLR) can be viewed as having achieved its aims is dependent on the quality, reliability, and validity of the primary sources it utilises, suitable quality assessment criteria must be applied to evaluate their strength. In view of this, the present SLR draws on the Critical Appraisal Skills Programme (CASP) criteria to gain insight into the methodological quality of the studies, as well as the likelihood of bias. One of the main reasons for selecting this mode of quality assessment stems from the fact that numerous scholars, including Aveyard (2010) and Boland et al. (2014), highlight its utility when evaluating evidence-based research.

Although it is routinely recommended in the literature that an SLR should employ the CASP criteria, it is important to recognise that its inherent limitations sometimes motivate the use of other criteria. Perhaps the most frequent criticism directed towards the CASP criteria is the high likelihood the tool has of producing ambiguous findings, which Craig and Smyth (2007) and Higgins and Green (2008) argue is not a feature of other assessment criteria (for example, the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2)). Nevertheless, a consideration of a tool’s limitations should not preclude a rational evaluation of its strengths. In the case of the CASP criteria, these strengths include its structured approach to quality assessment, its viability for studies addressing the effectiveness of a therapeutic intervention or system, its usability for training researchers, and its 12-item approach to the assessment of internal validity, findings, practical relevance.

Data Extraction

As explained by Joanna Briggs Institute (JBI) (2015) and Aveyard (2014), data extraction included sourcing and recording related information from the studies employed. Elamin et al. (2009) indicated that a form was created to display all significant constituents of the review question, which assured that flexibility and consistency were observed in the assessment and review of the purpose and quality of the selected articles. Microsoft Word (electronic) copies of the extraction form were used to obtain a lower data recording error during the transcription, as suggested by Bettany-Saltikov (2012). Electronic copies allowed the extraction and entry of the data to be performed in one step (Elamin et al., 2009). Additionally, the extraction form was piloted before actual usage, as recommended by Aveyard (2014), for the reviewer to be confident that the form was appropriate and suitable.

The extraction was performed by entering information from the included studies into the form, and a separate sheet was used for each study. The information was gathered in accordance with the following major categories: general information, methods, participants, interventions, and outcomes, as indicated by Reitsma et al. (2012). The collection of general information helped to determine the date of data extraction, author name, and the source of the primary research (CRD, 2009). Bettany-Saltikov (2012) suggested that the study method section should attempt to locate the study design, inclusion, and exclusion criteria. Additionally, this section gives information regarding the index test and reference standard and their interpretation process. Thus, the variables under the method section were aimed to set up to what degree the mistakes were decreased and accuracy enhanced (Leeflang et al., 2008). The participants section was important because it focused on the patient demographic features (Holly et al., 2012). Higgins and Green (2011) reported that the intervention variable gives an overview of the intervention (DWI-ADC), such as description of intervention, frequency and duration of intervention, and compliance with intervention. The outcomes section provided details of the outcome measures, study results, and how they were measured statistically (Elamin et al., 2009).