Perspective on therapeutic application of selective internal radiotherapy in colorectal cancer liver metastasis

Incidence and definition of colorectal cancer with liver metastasis

Locally advanced rectal cancer is challenging with lots of debate still the current time. MCRC, however, is a serious issue to consider, which accounted for relatively higher percentage in CRC. Moreover, MCRC could be a worse scenario when presented with multiple live involvement combined with locally advanced tumor, make surgery is impossible and began to look for alternative intervention. Short course radiotherapy (SCRT) and internal radiotherapy (IRT) are on top of various type of regimen that will be addressed in our point of you.

Interestingly, issue to consider before going further in our discussion is intent of curability in colorectal cancer liver metastasis (CRCLM) is significantly less often in synchronous metastases than for metachronous metastases (6.3% vs. 16.9%, respectively) (1). Also, 5-year survival rates were shorter in synchronous than metachronous CRCLM (3.3% vs. 6.1%, respectively). Unfortunately, percentage of synchronous CRCLM is steadily increasing compared to metachronous metastases, which may reflect high quality radiological image, and promoting national screening program and could be unexplained fast tumor growth (2). Moreover, treatment strategies are different among them. However both entities have poorly defined in the literature that ads further confusion and difficulty to determine treatment approach.

Therefore, discriminate between synchronous and metachronous liver metastasis is warranted, still definitions are uncertain among studies. Detection at or before diagnosis of the primary tumor (3), if metastases detected up to 3 (4), 4 (5) or 6 months (6,7) following diagnosis. In order to emphasize patient safety, we should be well oriented about patient diagnosis and tumor stage to avoid over or under treatment.

Current radiotherapy approach in CRCLM

In order to achieve appropriate tumor down staging, potentiate the dose and pathway of RT therapy to target tumor cells. Delivery of RT therapy has been proposed among studies, however RT dose and pathway were varies among the studies and standardization is lacking. Recently, interesting trial addressed novel approach in treating CRCLM. SIRFLOX: Randomized Phase III Trial Comparing First-Line mFOLFOX6 (Plus or Minus Bevacizumab) vs. mFOLFOX6 (Plus or Minus Bevacizumab) Plus Selective Internal Radiation Therapy in Patients with Metastatic Colorectal Cancer. This trial published in the Journal of Clinical Oncology, described unique way to deliver SIRT to CRCLM in order to achieve appropriate control. SIRT is a new radio-embolization technique that has recently been approved by the FDA for treatment of patients with non-resectable CRCLM. SIRT is yttrium-90 resins microspheres given into hepatic artery to achieve high doses of radiation targeted liver tumors, regardless of their number or position. On top of that, smaller diameter of microspheres has attributed in effective radio-embolization within microvasculature of the tumor without damaging adjacent normal liver tissue and that because, liver tumors derived blood supply from hepatic artery while liver parenchyma is predominated by portal vain (8). However SIRT has drawn serious attention for investigation, still consideration of technical demanding part and delicate precaution as well as the need of invasive preoperative studies to rule out arterio-venous shunt or existing anatomical variations, add an obstacle in decision plan, at which weight the risk and benefit of certain procedure before planning liver metastasis management. The technique of SIRT, dosing has been described previously (9). In addition, Systemic chemotherapy has tremendous investigation in the field of CRCLM, however still results are unsatisfactory till current time (10). Therefore, seeking for an alternative option should be considered to potentiate chemotherapy effect. Currently, SIRT is a new modality of treatment that attains great success in the patients with hepatocellular carcinoma (HCC) (11). Therein, application of SIRT has extrapolated from HCC that keep evolving in CRCLM. Till then, SIRT have studied and examined in different primaries colonizing liver that indeed showing early success in their initial series (12,13). In a recent meta-analysis, SIRT has accounted for the first line therapy in unresectable CRCLM in 90% of the time (14).

Interestingly, treatment with SIRT has promising results in patients with advanced unresectable CRCLM as initial therapy or after failure of frequent chemotherapy regimens trial (12). Van Hazel et al. (15) conducted a randomized clinical trial to assess SIRT technique plus fluorouracil/leucovorin vs. Chemotherapy only in11 patients diagnosed with untreated advanced CRCLM. The time to progression disease was in favor of SIRT arm (18.6 vs. 3.6 months, P<0.0005). Median survival was significantly longer for patients received SIRT (29.4 vs. 12.8 months, P = 0.02) respectively. SIRT has initiated and progressed well in the section of CRCLM with acceptable toxicity. Recently, SIRFLOX trial conducted by van Hazel et al. (16), invented a novel clinical trial, they aimed to compare efficacy of combination therapy of SIRT plus mFOLFOX6 plus or minus bevacizumab vs. mfolfox6 in unresectable CRCLM. They investigated 530 patients deemed to be unresectable CRCLM, gathered from 87 centers in Australia, Europe, Israel, New Zealand, and the United States. A total of 263 were assigned to control and 267 were assigned to SIRT arm. They demonstrated SIRT plus FOLFOX-based first-line chemotherapy did not improve progression free survival (PFS) at any site (10.2 vs. 10.7 months) however it is significantly delayed disease progression in liver only (12.6 vs. 20.5 months).

Apparently, there were several reports delineate positive feedback of SIRT utilization in CRCLM since initial series (17), however it is at early milestone and comprehensive outcome still uncertain. Therefore, SIRFLOX trial accounted for the fundamental start of SIRT technology in CRCLM that delivered valuable information through this trial. Interestingly, complete response rate had been achieved up to 6% in SIRT arm compared to 1.9% in control group, P=0.020. In this trial, SIRT directed to take care of liver metastasis, which represented a new entity of RT utilization. Often time, the use of radiotherapy directed toward rectum in metastasis CRC in form of CRT or SCRT, aiming to achieve down staging and then facilitate R0 resection. Nevertheless, in current trial, he deviated from the standard way and invented new approach at which oxaliplatin take care of both local and distant metastasis along with additional management directed to serve liver metastasis (SIRT). Indeed, FOLFOX regimen could accomplish mild local control insufficient to achieve appropriate downsizing in locally advanced rectal cancer. Therefore, this approach will raise another inquiry; in how to achieve R0 resection in those with margin threatening or borderline respectability without radiotherapy directed toward rectum and pelvic? Answer could be yes for liver only metastasis but would be questionable if rectum was unresectable. Then, would it be suitable to consider SCRT on top of SIRT treatment? This is a new era of debates which has to be clarified in the future. Nevertheless, additional information is required to estimate recurrent rate and overall survival in those patients group. SIRT is a promising cut off technology in the field of radio-oncology, however it is technical demanding and awareness of technical preparation is a must to avoid unintended complication. Moreover, assessing tumor response is another debates issue to consider, however PET/CT has shown superiority among conventional imaging methods after SIRT treatment (18,19). Lastly, SIRT is a new modality of treatment that serves most patients with unresectable CRCLM in a resectable primary lesion with limitation to liver only metastasis. GERCOR database patients with unresectable disease, the response rate is higher in patients with liver-limited metastases than in those with non-liver-limited metastases (20). Several subset studies published in regards of clinical impact of using SIRT technology in CRCLM illustrated in Table 1.

Table 1 Outcome of selective internal radiotherapy in CRCLM
Full table

In counterpart, Radiofrequency ablation (RFA) is a localized thermal treatment induce tumor necrosis and then cell destruction by rising tissue temperatures up to 50–100 C for 10–30 minutes (23,24). RFA has shown its superiority among others, which been validated in a recent phase II randomized trial. This trial is an extension of EORTC intergroup randomized study 40004 (CLOCC) (4). This trial evaluated the benefit of combining FOLFOX chemotherapy plus RFA vs. FOLFOX in 119 patients with unresectable CRCLM. They designed RFA indication very well for a max of nine liver lesions without extra-hepatic involvement. They illustrated 30-months overall survival rate 61.7% vs. 57.6% in RFA and control group respectively. In addition, they stated median overall survival was 45.6 vs. 40.5 months, P<0.01, respectively. In a systemic review (25) assessing RFA in CRCLM. Clearly declared paucity of data in RFA as well and proved EORTC intergroup randomized study randomized trial is accounting for a single well designed trial along with other small studies (26-30). They showed promising results of RFA in CRCLM as illustrated in Table 2.

Table 2 Results of Radiofrequency Ablation Trials in CRCLM
Full table

Nevertheless, the effectiveness of RFA is limited to tumor size (<3 cm) and localization (1 cm or more deep to the liver parenchyma), and close to major vessels, ≥2 cm from large liver veins (24). Berber et al. (29), suggested predicted criteria to estimate poor response to RFA approach. More than three liver metastases, CEA level greater than 200 ng/mL, the presence of extra-hepatic disease, and liver metastasis larger than 5 cm could estimate poor response to RFA alongside with higher rate of procedure related complication. Hence then, RFA is good enough with certain restrictions that mandate modification or alternative method to deal with extensive form of CRCLM.

In the current era of debates, when and how SIRT or RFA is indicated in CRCLM? Yet, has to investigate several parameters to weight the risk and benefit of each pathway. Indeed, RFA picture is clearer than SIRT in term of predicting response and their impact in the overall survival. Whereas in SIRT, is a valid technique with a history of success literally, yet prognostic factors and indication as well as impact on overall survival has to be addressed in the future. In SIRFLOX trial (16), had few limitation that in our opinion might be important. From our point of you, liver metastasis might be stratified according to the number and size of the tumor involved in liver or other any site. Other era of debates is whether any way possible to modify SIRT dose or pathway for lesser extent of SIRT related liver toxicity. SIRT is in its infancy stage and required further analysis in order to validate its application and feasibility in the field of CRCL

Acknowledgments

Funding: None

Footnote

Provenance and Peer Review: This article was commissioned and reviewed by the Section Editor Lei Huang (Department of Gastrointestinal Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, China; German Cancer Research Center(DKFZ), Heidelberg, Germany).

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr.2016.10.07). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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