Tumor Control, Survival, and Bridge-to-Transplantation
The present results demonstrate the ability to achieve local control by radiation segmentectomy, supported by a high rate of imaging and pathological CR, acceptable time-to-local recurrence, and time-to-disease-progression. These findings are supported by the gold standard pathology assessment at explant analysis. Keeping in mind the limitations of studying overall survival in HCC treated by locoregional therapies (influenced by underlying liver disease, previous therapies, liver transplantation, crossover to other treatments), survival was not found to be dramatically different from RFA data (with respect to the Child-Pugh class); comparable local tumor control was obtained (confirmed by imaging and AFP) (Supporting Table).[20-22] It is of particular interest that progression was influenced more by the appearance of new intrahepatic lesions or tumor thrombus than by local progression or recurrence. The ability to maintain such a patient population (solitary lesion ≤5 cm, no vascular invasion, tumor disease limited to the liver), within transplantation criteria (UCSF, Milan) is of particular interest in a bridge-to-transplantation perspective. Given the high rate of mRECIST CR (with pathology correlation), it appears that high-dose Y90 using radiation segmentectomy may behave as an “ablative” therapy in select cases.
Nevertheless, due to differences in the nature of each therapy, response assessment after Y90 is more complex than for conventional ablative therapies. RFA and microwave ablation tumoricidal effect is mediated by hyperthermal damages with immediate or early response (coagulative necrosis). Y90, as a microembolic therapy, induces delayed response by radiation, inflammatory changes with hemorrhagic necrosis, edema, and persistent enhancement affecting the entire exposed area. Hence, underestimation of the response by imaging may have occurred in this analysis in patients with short-term imaging follow-up. A 3-month follow-up is generally considered necessary to detect a CR with Y90.
With comparable treatment efficacy profile, low toxicity, and rare adverse event rates, these results suggest the feasibility of head-to-head comparisons between conventional ablative techniques and high-dose (>190-200 Gy) radiation segmentectomy. This is of particular interest in lesions located in high-risk ablation areas. It is of note, at Mount Sinai, where treatment protocols favor RFA over arterial therapies for small lesions, that 8/9 patients exhibited dome lesions, a location where probe insertion is difficult (interposition of lower ribs, proximity of the diaphragm). Another technical advantage of radiation segmentectomy over conventional ablative therapies is the absence of percutaneous transhepatic puncture, decreasing the risk of iatrogenic tumor dissemination. In some centers, RFA is not recommended in potential transplant patients due to the theoretical risk of tract seeding.
Survival results were comparable to the ablation literature (53.4 months overall; 34.5 month censored). This suggests that “ablative” type treatments such as RFA or segmentectomy, if able to target the lesions adequately and provide an adequate margin, may impart the survival benefit expected in BCLC A patients. This novel concept suggests the possibility of “transarterial ablation” or “radiation segmentectomy,” with Y90 radioembolization being the subject of future research.
Gold standard pathology explant analysis also supported the ability of this technique to ablate tumor. For all lesion sizes and locations, only one treatment using this approach was necessary to achieve a CPN rate of 52% in lesions not amenable to RFA. When including partial necrosis, all lesions exhibited >90% necrosis. This supports the role of this technique in select patients where the recommended standard treatment of RFA cannot be applied. Finally, there was no correlation between mRECIST and pathology findings; this is consistent with our recent randomized study demonstrating the inability of imaging methodology to reliably predict CPN. This is explained by the lack of a true embolic effect of Y90 and the fact that enhancement may persist despite completely necrotic tissue.[24, 25]
Adverse Events and Toxicity Profile
Adverse events (all grades) were common (53% of patients); all were mild and transient (fatigue, abdominal pain, nausea, fever). Lymphopenia and platelet toxicities were found to be the most common laboratory toxicities; many of these toxicities were present at baseline and not altered during follow-up. However, both of these laboratory values are known to be associated with the postradioembolization syndrome. Y90 procedures could be performed on an outpatient basis and none required readmission. Liver function tests were not found to be dramatically altered within 2 years post-Y90. In fact, those few patients that developed severe liver insufficiency all exhibited elevated Child-Pugh score at baseline, suggestive of progression of cirrhosis to endstage liver disease per natural history. The causal relationship of segmental Y90 with resulting worsening of liver function in such a context remains to be proven.
Rationale and Comparison With Ablative Therapy
In addition to providing evidence of survival benefit, pathological review suggests better local tumor control when a dose >190-200 Gy can be achieved in the treatment area. This is of particular interest in solitary HCC limited to small liver volumes, offering the possibility of selective arterial treatment. However, some key points in treatment planning such as the familiarity with variants of normal hepatic arterial vasculature and use of cone-beam CT during the planning angiogram and treatment session appear essential in order to ensure a complete understanding of tumor perfusion (Fig. 1A,B). Although the term “segmentectomy” would imply a surgical excision of the treated segment(s), its use in this case appears fitting, as evidenced by not only excellent local tumor control with complete disappearance of the lesion by imaging, but also major atrophy of the treated segment(s) as follow-up imaging is obtained (Fig. 1C).
Technical advantages of Y90 over ablative techniques include the avoidance of transhepatic puncture (reducing the risk of tract seeding, parietal injuries, or arterio-portal fistulas) and the ability to target lesions traditionally difficult for ablation (dome, caudate lobe, hepatic hilum, gallbladder). Also, since a sector of liver tissue is perfused using this technique, microsatellites surrounding the HCC may also be treated, resulting in a treatment margin, analogous to a surgical margin (Supporting Fig. 3). This is supported by the finding of all lesions exhibiting 90-100% necrosis at pathology explant. Among potential disadvantages, exposure to ionizing irradiation (although ablation is often performed with CT guidance) and cost should be mentioned. Costs associated with Y90 are now being addressed by the concept of same-day outpatient radioembolization.
While there are many studies looking at radiology-pathology in animal models, there is a paucity of data in the literature looking at ablation and ability to achieve CPN in human explants. There have been other studies reviewing pathology after ablation; these report CPN rates of 55%, 66%, and 74%.[28-30] As opposed to these three studies, our study was performed in lesions not amenable to RFA. Despite this limited ability to compare, CPN rates in this study using radiation segmentectomy in lesions not amenable to RFA were comparable to those reported in RFA studies.
Strengths and Limitations
This study faces some limitations. First, during follow-up assessment the treated volume was observed in a time-dependent manner, with enhancement from radiation dissipating with time. This possibly led to a slight overestimation of radiation dose. In addition, we also assumed uniform activity distribution in the treated volume; however, it has been shown that microsphere distribution (including with chemoembolization) is preferential to tumor when performing segmental injections. Unfortunately, Y90 microsphere cannot be imaged (except by positron emission tomography [PET]), limiting possibilities of posttreatment treated volume estimation. Future radioembolization materials such as holmium-loaded spheres will likely eliminate this shortcoming. Also, given the lack of macroembolic effect of Y90, imaging findings should not necessarily seek to achieve imaging CR.[24, 25] Finally, RECIST criteria were not used to document local progression since this would have necessitated the enlargement of the entire “radioablated” segment, as opposed to mRECIST, which focuses on the concept of enhancing tissue. Had we used only RECIST for progression analyses, a misleadingly prolonged TTP would have been observed.
There are strengths. First, our study reports on treatment of HCC when the recommended approach is not feasible (second line); robust data are lacking in the literature. The two centers combined have significant experience in Y90 for HCC. Inclusion criteria were very stringent, resulting in a homogenous population. Data analyses were very extensive (survival, laboratory [>2 years], imaging [until transplantation/death], dosimetry, adverse events). Gold standard pathology results were used for final determination of treatment efficacy. Given the growing trend for the use of mRECIST, we used this method with two readers and adjudication in the case of discordance; we believe the results would be similar to our previous work using the EASL concept. One advantage to the use of mRECIST we detected was to ensure that new nodules were only declared when >1 cm enhancing lesions with washout was noted; this prevented an overcall of progressive disease by labeling any new finding on imaging as a new lesion. The results and lessons from this study may serve as a basis for future randomized controlled trials comparing radiation segmentectomy to ablative techniques. This is one of few radiology-pathology studies comparing imaging and pathology tissue in humans; most of the literature reports on the ability of ablation to achieve necrosis in animal models. Finally, our study confirms our previous randomized study showing the lack or correlation between imaging findings and explant tissue.
In conclusion, radiation segmentectomy is a safe and efficacious technique providing excellent tumor response and CPN in solitary HCC ≤5 cm not amenable to RFA. These data support its use as a second choice if RFA or resection is not feasible. This is of particular interest in the bridge-to-transplantation perspective, where in some centers ablation is not recommended for concern of malignant tract seeding. Additional studies are required to further refine the role of radiation segmentectomy in solitary HCC. Several international randomized phase 3 studies are currently under way investigating the role of Y90 in HCC.