Статья посвящена сравнительному анализу методов лечения рака печени, осложненного (или являющегося следствием) цирроза печени

Median disease-free survival for the resection and LT groups was 15.5 months (range: 0.2–67.4) and 29 months (range: 0.3–105), respectively. TACE patients were considered to have remnant tumor since no pathological evidence of clear margins or complete tumor necrosis could be produced. One, 3-, and 5-year cumulative disease-free survival among resection and LT patients was 73%, 50%, 15% and 90%, 84%, 77%, respectively (Table 2). There was a significant difference (Fig. 3) favoring the LT group (P = 0.002).

Fig. 3 Cumulative proportion of disease-free surviving (Kaplan–Meier curves) for the resection and transplantation groups



Analysis of Prognostic Factors for Overall and Disease-Free Survival

We performed a univariate analysis for each group, taking into account age, gender, MELD score, AFP, cause of cirrhosis, tumor grade, lymphatic invasion, microvascular invasion, resection margin status, UICC stage, tumor multifocality, maximum tumor diameter, meeting or exceeding the Milan criteria, and postoperative complications. Resection margins status (P = 0.024), tumor multifocality (P = 0.012), and complications (P = 0.007) were significant predictors of survival in the resection group. MELD score (P = 0.0006), maximum tumor diameter (P = 0.05), and Milan criteria (P = 0.02) reached statistical significance for TACE. AFP level (P = 0.04), tumor grade (P = 0.007), lymphatic invasion (P = 0.05), tumor multifocality (P = 0.05), maximum tumor diameter (P = 0.023), Milan criteria (P = 0.048), and complications (P = 0.05) gained significance in cases of LT.

A further multivariable analysis followed considering only predictors that reached significance in univariate analysis. The only independent predictor of survival in the resection group was the presence of complications (P = 0.004), MELD score (P = 0.0003), and maximum tumor diameter (P = 0.05) in the TACE group, and tumor grade (P = 0.01) and complications (P = 0.004) in the LT group.

In order to document a difference in the 5-year survival rate among the resection group (23%), TACE group (10%), and LT group (59%), we applied a two-sided survival log-rank test under power analysis with a type I error (alpha) of 0.05 and a power of 0.95. Forty-one patients per treatment arm would be sufficient to detect a difference in survival rates among the three groups. This prerequisite is fully covered by our data.

Discussion

The management of patients with HCC in cirrhosis constitutes a matter of discussion and disputation among physicians all over the world [30–37]. The great variety of therapeutic options allows on the one side the search for the most convenient/cost effective therapy for each center, but on the other side, emphasizes the loss of the optimal option, which could be available and applicable in most cases [38–44]. However, some agreement was reached in the past years, i.e., that LT is recognized as the best therapy option for these patients under the presupposition that the HCC does not exceed certain pre-established criteria and the candidate has an acceptable surgical risk [28, 45–48]. The institution of this treatment modality, however, is limited by the current scarcity of organs that allows only for a limited number of candidates to be transplanted at specialized centers [49]. Our status as a combined hepatobiliary and transplant specialty center offering all potential treatment options allowed us to evaluate the three most frequently recommended treatments for HCC in the setting of cirrhosis, i.e., resection, TACE, and LT. Although data were prospectively recorded to our data base, this was not a prospective, randomized study, something difficult to perform in this special era of clinical medicine, since it is ethically very difficult to deny the LT opportunity to HCC patients otherwise eligible for transplantation. However, although the choice of the appropriate treatment followed an algorithm, i.e., firstly resection, secondly LT, and thirdly TACE being evaluated, resulting in some primary patient selection, statistical methods and data analysis from different points of view allow us to make some comparison and to discuss our results more deeply. Furthermore, power analysis of the data proved that the study volume was sufficiently large to detect significant differences among the three groups, having approximately 20 patients over the required minimum per arm.

Independent predictors of survival by multivariable Cox proportional hazard regression analysis were the presence of complications in the resection group, MELD score, and maximum tumor diameter in the TACE group, and tumor grade and complications in the LT group.

In a specific statistical study of the presence of postoperative/post-interventional complications among the three groups, none of the eight variables evaluated gained statistical significance as an independent predictor for the presence of complications. Even the extension of liver resection (hemihepatectomy versus segmentectomy in the resection group) or the transplant procedure (full-size deceased donor versus living donor LT in the LT group), although they gave the clinical feeling that they were combined with higher morbidity in cases of hemihepatectomy and living donor LT, respectively, were not characterized by statistically significant differences concerning the presence of complications. However, it is remarkable that the high morbidity of 38% in the resection group was followed by a correspondingly high 30-day mortality of 23%, although the correspondingly high morbidity of 38% in the LT group was combined with a lower 30-day mortality of 8%.

The Milan criteria are the most applicable tool in evaluating treatment strategies for patients with HCC in cirrhosis. Evaluating our institutional experience with monotherapy for HCC in cirrhosis, 5-year survival was 44% for patients meeting the Milan criteria and 22% for patients exceeding them (P = 0.03524, Fig. 4). As most hepatobiliary/transplant centers have the policy to offer the possibility of transplant to HCC patients within these criteria, a further statistical analysis in our series was performed (Fig. 4), despite the fact that the Milan criteria did not gain significance as a predictor of patient survival in the multivariable model. This univariate analysis according to Gehan’s Wilcoxon test showed statistically improved survival for patients meeting the criteria only for the TACE (P = 0.04105) group and the LT (P = 0.03792) groups (P = 0.72 for the resection group). Five-year survival for patients within the Milan criteria was 26% for the resection group, 37% for the TACE group, and 66% for the LT group, respectively. There is an obvious survival benefit for HCC patients within the Milan criteria who undergo LT, and a simultaneous disadvantage for not transplanted HCC patients, who according to the Milan criteria could be eligible for LT, but because of other co-morbidities (age, poor physical and medical condition, high levels of AFP) and of the organ scarcity underwent resection or TACE. On the other hand, data analysis for patients outside the Milan criteria provides very interesting results. Four-year survival for patients outside the Milan criteria (no resection patient reached 5 years) was 30% for the resection group (for n = 35 patients), 7% for the TACE group (for n = 54 patients), and 53% for the LT group (for n = 34 patients), respectively. These apparent but politically very dangerous findings seem to imply that LT provides the best oncological long-term therapy for HCC patients, even for those beyond the currently recommended listing criteria! Of note is the fact that such cases beyond the Milan criteria are not open-ended, since for these three categories of monotherapy, a kind of patient selection is already performed, and patients with extrahepatic liver disease or macrovascular invasion are not considered. This observation is also explained by the fact that LT offers the chance for “cure” for both pathologies, i.e., malignancy and end-stage liver disease, whereas the role of liver resection and TACE is limited only to the oncological HCC pathology. Besides, performance of liver resection or TACE in the cirrhotic liver may further deteriorate the underlying liver function and diminish the long-term outcome.

LT is undoubtedly the best treatment option for patients with HCC in cirrhosis. LT provides not only the best survival and recurrence-free rates, but it also represents the most “curative” option for these patients, since it provides the longest recurrence-free survival. In our series, the 5-year recurrence-free survival was as high as 77% after LT, compared to 20% after resection (P = 0.00236). The question that rises is about the alternative options, i.e., resection and TACE. In our series, there were no significant differences between resection and TACE groups for the parameters age, MELD score, AFP levels, and etiology of liver disease. Statistically significant differences were detected for the parameters presence of complications, ICU stay, hospital stay, and Milan criteria. Based on our data, 5-year survival for the resection and TACE groups was 23% and 10% (P = 0.754), respectively. Statistical significance was achieved only after the exclusion of 30-day mortality (P = 0.006). Hence, a more restrictive patient selection for the resection group could result in lower morbidity/30-day mortality rates and potentially in better long-term survival rates. From the transplant point of view, analysis of these data according to the Milan criteria give us 5-year survival rates for the resection and TACE group of 26 and 37% for patients within the criteria, respectively. Four-year survival rates were 30% for the resection group and 6% for the TACE group for patients outside the Milan criteria. Our findings suggest that patients with HCC and cirrhosis who are not candidates for LT could undergo TACE if their tumors are within the Milan criteria or liver resection if the lesions exceed them. In the case of patients within the Milan criteria, TACE provides local control with no exposure to operative morbidity/30-day mortality and avoids a rapid tumor recurrence in a regenerating precancerous cirrhotic liver. In the case of patients outside the Milan criteria, where local control is limited with TACE, resection could offer a survival benefit if the surgical morbidity/30-day mortality is improved.

Contrary to these observations, liver resection constitutes the best treatment option in the instances of HCC in the non-cirrhotic liver [50–52], where the absence of cirrhosis is combined with a very different physical history of the disease.

LT represents the best therapy option for patients with HCC in the setting of cirrhosis and in the absence of extrahepatic disease and/or macrovascular invasion, even for patients exceeding the Milan criteria. From the transplant point of view, restricted HCC criteria have to be applied for LT, given the scarcity of available organs in order to provide the same long-term outcomes as for patients transplanted for non-tumor indications. From the oncological point of view, HCC criteria have to be more liberal for LT, since LT itself provides the longest overall and recurrence-free survival to these patients. The best alternative seems to be liver resection, itself hampered by postoperative morbidity and mortality, at least in the western world. TACE, with a low rate of complications, remains an option especially in cases of cirrhotic patients within the Milan criteria. In such cases, it may even be superior to liver resection.

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