Concurrent Chemoradiotherapy Shows Long-Term Survival after Conversion from Locally Advanced to Resectable Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a major disease in Asian countries. Global cancer statistics showed this disease as the third most common cause of cancer-related deaths worldwide.1 Since HCC is unresectable in the majority of patients at the time of initial visiting, patients are frequently referred to non curative treatments. Based on the results of randomized clinical trials, sorafenib has become the first-line therapy for advanced Barcelona Clinic Liver Cancer (BCLC) stage C HCC.2, 3 However, BCLC stage C represents a variety of disease features, including metastasis, portal vein invasion, and performance 0-2. In this stage, National Comprehensive Cancer Network guidelines suggest that radiotherapy (RT) can be considered as an alternative to ablation/embolization techniques for unresectable HCC with category 2B level evidence. Lee and Seong4 reviewed the optimal indications for RT according to the BCLC staging system and the application of various RT modalities and prescription according to the extent of disease. Combining RT with radiosensitizers such as concurrent chemoradiotherapy (CCRT) is an also attractive strategy to increase the therapeutic ratio for these patients.5

Several studies reported downstaging or total necrosis of the tumor after non-surgical modalities, including transcatheter arterial chemoembolization (TACE), hepatic artery chemo-infusion, combined systemic chemotherapy, external radiation, and radioimmunotherapy.6, 7, 8, 9 Although tumor shrinkage was sufficient to allow salvage liver resection following therapy in only a small proportion of patients, the potential for curative therapy in responders also gives hope to patients with unresectable HCC.

In our institute, patients with locally advanced BCLC stage C were treated with CCRT when surgery was not feasible due to portal vein tumor thrombosis or inadequate non-tumor liver volume.10 Among them, some patients underwent surgical resection after showing a response to CCRT. In this study, we evaluated prognostic factors and long-term survival in patients who underwent hepatic resection after CCRT.

Surgical resection of tumors gives the best opportunity of a cure for patients with HCC. However, the resectability of HCC is low at initial diagnosis (10-30%). Among the unrectable patients, patients with poor general condition or decompensated liver disease could be candidates for tumor downstaging and salvage liver resection. The decision making for the unresectability of HCC include a large tumor volume with insufficient normal hepatic mass after liver resection, extensive and multifocal bilobar tumors, extrahepatic spread of the disease, and tumors with main portal vein/hepatic vein/inferior vena cava tumor thrombus. For Asian patients, 80-90% of cases of HCC develop in cirrhotic livers. Although a normal liver can permit up to 80% of resection of functional liver volume, cirrhotic liver is a major risk factor for the development of postoperative liver insufficiency, failure, and mortality. Even minor resection of a cirrhotic liver can result in post-resection liver failure. Therefore, the resection of liver that should be safely monitored according to the degree of cirrhosis, the functional reserve, and the regenerative response to the surgical intervention. A main vessels tumor thrombus usually occurs as a late complication of large or diffuse HCC, and is associated with a poor median survival of 2 months. Such tumors are therefore traditionally considered unsuitable for partial hepatectomy. However, the decision on whether or not a tumor is resectable is still largely subjective. This is a common criticism of studies on salvage surgery following tumor downstaging. In radiation oncologists' view, "locally advanced hepatocellular carcinoma" is defined as disease not acceptable to surgical resection or immediate liver transplantation. The extent of disease could be defined by BCLC(B) intermediate stage or BCLC (C) advanced stage without extrahepatic spread except for regional lymph node involvement.14 In our study, the resectability of tumors was determined at multidisciplinary HCC conferences before and after CCRT.

Recent reports have revealed that RT can be delivered at a high dose to the focal liver with acceptable complications.15, 16, 17, 18 Global experience with the use of a combination of RT and radiosensitizers in HCC treatment is limited.5 CCRT has shown excellent tumor responses with prolonged survival in selected series of HCC patients.19, 20, 21 However, there is a still risk of radiation induced toxicity. We previously reported that several factors, such as tumor size, pre-RT ICG-R15, and Child-Pugh class could be useful for predicting radiation hepatotoxicity in HCC patients treated with RT.22, 23, 24 Han, et al.10 reported the therapeutic effect of concurrent fluorouracil (5-FU) and RT followed by iA CTx in patients with locally advanced HCC with portal vein thrombosis. In most tumor sites, the majority of experience with radiation sensitizers is through systemically delivered agents. In HCC, however, there has been more experience with hepatic arterial regional chemotherapy delivered with RT.25, 26 The rationale for selective radiosensitization is that the exposure of non-tumor normal tissues to radiosensitizer is reduced, improving the therapeutic ratio and potentially leading to increased doses to the focal HCC, thereby increasing the tumor response. Regional perfusion of drugs with high hepatic extraction rates and short serum half-lives allow much higher drug doses to be delivered to focal HCCs. iA CTx alone or with TACE, takes advantage of this selective blood supply to HCC versus normal liver. In our study, all patients had Child Pugh A liver function. The objective response rate was 45% (18 of 40 patients). The actuarial 3-year OS rate was 24.1%, and the median survival time was 13.1 months from the start of RT. The results were better than a similar group of patients with a 4-6 months median survival.10 Following this treatment, the shrunken tumor as well as compensatory hyperplasia of the non-tumor liver allowed for surgical resection in a small portion of patients. According to the initial response after localized CCRT, patients with good response showed significantly improved survival (p=0.033). The median survival time of responders was 19.9 months, compared with 11.4 months for non-responders. In our study, 264 patients with HCC were treated with CCRT, and 18 patients (6.8%) underwent hepatic resection. These patients showed better 3-year OS (59.3%) than our previous results of our CCRT study (24.1%). However, this result was restricted from highly selected patients.

Tang, et al.6 reported residual disease in 69.7% of the surgical specimens resected after combination treatments. Majno, et al.7 described that downstaging or total necrosis of the tumor after TACE occurred in 62% of liver resected patients. A total necrosis after TACE was reported at 24 patients (50%). In liver transplantation cases, downstaging of tumors >3 cm (54% of patients) and total necrosis (28% of patients) were associated with superior disease-free survival (p=0.01 and p=0.03). Huang, et al.8 also mentioned that only a small portion of tumors showed complete necrosis after TACE. Total necrosis (100%) of tumor was observed in 11.1% of 117 patients. Fan, et al.9 showed that complete tumor necrosis occurred in 11 patients (16.9%). There were 6 patients who had undergone five TACE treatments each, but their percentage of necrotic area was only 60-90%. Choi, et al.12 reported six patients (12%) who had undergone TACE followed by RT showed total necrosis.

Since the waiting list is long and patients may drop out owing to tumor progression, radiation therapy may have a role in selected patients. There are several studies on using radiation therapy as a bridge to liver transplant. Sandroussi, et al.27 reported their experience with treating 10 patients with conformal radiotherapy as a novel bridge to liver transplantation. There was no complete tumor necrosis and 4 patients demonstrated a pathological response with the degree of necrosis ranging from 40% to 90%. The lack of complete necrosis may be related to the sublethal radiation dose, owing to concerns about radiation-induced liver disease. In a recent case report, the explant demonstrated complete histological necrosis of the lesion after external-beam radiotherapy in patients who were candidates for liver transplantation.28 O'Connor, et al.29 also reported that the explant pathology revealed no viable tumor in three of the 11 tumors they studied, resulting in a complete response rate of 27%. Our pathological review of resected specimens after CCRT showed a similar rate of complete necrosis (22.2%), and 7 patients (38.9%) showed 70-99% necrosis. For the patterns of failure, the number of patients with intrahepatic metastases was six (33.3%), and high necrosis (≥80%) indicated a low risk for extrahepatic metastasis. These results demonstrate that using radiation therapy as a bridge to liver transplant provided a clear advantage in terms of local tumor control. In several studies, vascular invasion, multiple tumors, a high value of AFP, and cirrhosis were shown to be significant prognostic factors for survival after resection of huge HCC.30, 31, 32 Tumor size is also an important predictor for disease free survival and overall survival after resection in patients with HCC. When the tumor size is bigger, the incidence of vascular invasion and intrahepatic metastasis also increases. Choi, et al.12 evaluated the surgical outcomes of 50 patients with ≥10 cm HCC. The 5 year-overall survival was 40.2%, and a multivariate analysis showed that the single nodular tumor type was the only significant prognostic factor for survival. These patients also had a more incidence of high AFP >1000 IU/mL, microscopic vascular invasion, and advanced stage tumors than patients with smaller tumors. Mean tumor size of the present study was 10.7 cm before CCRT, and histologic prognostic factors such as vessel invasion, capsular infiltration, resection margin positivity, and tumor size were also analyzed in this study. Vessel invasion was significant for OS and DFS, and capsular infiltration was significant for DFS in univariate analysis. In multivariate analyses, vessel invasion was a significant factor for OS, and capsule infiltration was significantly correlated with DFS. Patients who remained without evidence of disease for a long time also showed favorable pathologic findings (Table 6), and these results were similar to surgical studies.

In our previous results, we suggested CCRT followed by iA CTx to be a useful modality.10, 33, 34 This study described that CCRT could also achieved downstaging and conversion to operable status in selected patients with unresectable HCC. Our data suggest that there is hope for long-term survival through surgical resection. However, this study has limitations of a small sample size (18 patients) and the risk of type II error is high. Notwithstanding, the results are similar to those of other studies on TACE followed by downstaging surgery or other results for surgical outcomes for large HCC.9, 12 Our data suggest that long-term survival may be possible in total necrosis, as well as capsular and vessel invasion negative patients. Therefore, tailored strategies according to the pathologic findings after downstaging surgery after CCRT may be effective. However, more clinical experience and prospective studies are needed to determine the role of downstaging by CCRT. In selected patients, CCRT showed favorable response and locally advanced HCC converted into resectable tumor after CCRT. Long-term survivors showed the pathological features of near total necrosis, as well as negative capsule and vessel invasion.