HCC is the fifth most common cancer and the second most frequent cause of cancer-related deaths globally. It represents about 90% of primary liver cancers and is considered a major world health problem [1]. In Egypt, HCC is a significant public health problem and is responsible for 33.63% and 13.54% of all cancers in males and females, respectively [12].
The AFP model was proposed as a prognostic tool which was designed in a French training cohort of HCC candidates for liver transplantation and tested further in an external, prospectively followed, validation set. It has been shown to be more accurate than the Milan criteria for selecting HCC candidates for liver transplantation in the French population, and as a result, it was adopted as an official selection tool by the French organization for organ sharing in 2013 [10, 13]. However, to our knowledge, the AFP model has not been tested as a prognostic tool for patients with HCC undergoing TACE (with respect to response to treatment, HCC recurrence, and survival). Therefore, the present study is the first to assess the prognostic value of the AFP model in patients with HCC after TACE.
The mean age in our patients was around 58 years with male predominance (77.3%). El-Zayadi et al. [14] reported that there was a slight shift in age distribution among Egyptian patients with HCC from > 60 years to the age group 40–60 years. The relatively younger age in the Egyptian patients can be explained by the high prevalence of HCV among Egyptians and the occurrence of the infection at a young age. This is in agreement with other Egyptian studies which showed a shift in age in Egyptian patients with HCC [15, 16]. Most of the patients included were HCV Ab–positive (89.4%). It is known that Egypt has a high prevalence of HCV infection with 92.5% of patients infected with genotype 4 [3,4,5,6].
According to the latest European Association for the Study of the Liver (EASL) guidelines with respect to the locoregional treatment of HCC, thermal ablation with radiofrequency is the standard of care for patients with BCLC 0 and A tumors not suitable for surgery. Thermal ablation in single tumors 2–3 cm in size is an alternative to surgical resection based on technical factors, location of the tumor, and hepatic and extrahepatic conditions. TACE is recommended for patients with BCLC stage B and should be carried out in a selective manner [1]. An Egyptian study concluded that unresectable HCC with segmental vascular invasion could be treated with TACE with favorable outcome [17]. A proportion of patients in each stage do not fulfill all the criteria for the treatment allocation. In these cases, the patient should be offered the next most suitable option within the same stage or the next prognostic stage. This is already known by the concept of treatment stage migration [18]. Most of our patients were Child A (90.2%). About 48.5% of the patients were BCLC A, and 47% were BCLC B. This is explained by the facts that some lesions were large (> 4 cm) and others were located near the main bile duct, the intestinal loop, or a blood vessel, so radio frequency ablation could not be done, and TACE was the second-best option for them. This is compatible with stage migration in the treatment of HCC as documented in EASL practice guidelines 2018 concerning the management of HCC [1].
In the current study, 81.1% achieved CR, and recurrence occurred in about 74.8% of patients. Median OS was 18 months, while the 1 and 3-year OS were 77% and 9.4%, respectively. The one and three-year RFS rates were 39% and 20%, respectively. Lencioni et al., [18] published a systematic review on conventional TACE, which included 101 articles, with 10,108 patients. The objective response rate defined as the sum of CR and PR was 52.5%, which is much less than that of the current study where the objective response rate was 97% (CR = 81.1%, PR = 15.9%). The OS was 70.3% at 1 year which is less than that of the current study (77%). The 3-year OS was also higher (40.4%) than that in our study (9.4%). The median OS was 19.4 months vs. 18 months in the current study. In a similar study [19], the tumor response in 129 patients with HCC was evaluated 3 months after the first TACE. In the conventional TACE group, the disease was controlled in 79.8% of patients, which is less than that of the current study where it was controlled in 98.5% of patients. CR was 23.1%, which is much less than that in the current study (81.1%). PR was 26.3% which was more than the current study (15.9%). SD was also higher than that in the current study (30.4% vs. 1.5%). PD occurred in 20.2% of the cases in contrast with the only 1.5% of the current study. Kloeckner et al. [20] reported that the median survival was 409 days (13.6 months) in the conventional TACE group, which is less than that of the current study (18 months).
In the current study, it was observed that the more the liver functions were impaired, the more the increase in the recurrence rate. Recurrence occurred in 73.2% of Child class A and in 90% of Child class B. The median OS was 17 months in Child class A and 15 months in Child class B. The 1- and 3-year OS were 77.9% and 10.3%, respectively, in Child class A, and 69.2% and 0%, respectively, in Child class B. This is compatible with an Egyptian study performed by Zeeneldin et al. [21] who studied 221 patients with HCC who underwent TACE in the period between January 2007 and December 2010 and reported that the median OS in Child A was 21 months, which is more than that of the current study (17 months), and 11 months in Child B, which is less than that of the current study (15 months). The results of the current study are close to that of Kloeckner et al. [20] who found that the median OS of the subgroup of Child A patients, was 602 days for conventional TACE, which is equal to 20 months. Moreover, the results of the current study are very close to that of Greten et al. [22], which had the same median OS in Child A patients as that of the current study (17 months), while patients with Child B had a lower median survival rate of 6 months vs. 14.5 months in the current study.
Prognosis after locoregional treatment is affected by many factors including degree of hepatic dysfunction, patient comorbidities, tumor biology, level of AFP, number of nodules, and size of largest nodule [8, 9]. Several studies used the AFP level alone as a prognostic factor for HCC post intervention like Riaz et al.’s [23] which studied 125 patients with baseline AFP higher than 200 ng/mL and found that a 50% decrease in AFP levels resulted in a better time to progression and OS in comparison with patients whose AFP levels failed to respond to treatment with TACE or trans arterial radioembolization; another study also evaluated the percentage decline in tumor marker levels after treatment (from pretreatment levels) in patients who underwent TACE [24]. The reductions in both AFP and PIVKA-II levels in patients exhibiting a CR or PR were significantly greater than that in those with SD or PD according to the mRECIST criteria. They also found significant differences in median OS times between tumor marker responders and nonresponders.
Several studies used the tumor size [25,26,27] and number of tumor nodules [28, 29] as predictors of response, recurrence, and survival for HCC after locoregional treatment. Others used the AFP level in combination with the size of nodules as prognostic factors like Lai et al [30] who suggested that the combination of the total tumor diameter ≤ 8 cm and an AFP level ≤ 400 ng/mL would result in favorable survival outcomes. The 5-year DFS rate was 74.4%.
Others used the AFP level in combination with the number of nodules to assess the outcome after locoregional treatment, like Shin et al. [31], who found that tumor size (≤ 5 cm) and single nodularity were predictive factors for CR, and multi-nodularity and elevated levels of AFP (> 20 ng/mL) were predictive factors for recurrence after CR in patients who underwent TACE as a first-line therapy. Another study of 357 patients with HCC who underwent radiofrequency ablation for primary HCC between 2001 and 2013 showed that male sex, AFP level (> 10 mg/mL), and multiple tumors were significantly correlated with a high rate of HCC recurrence after complete ablation [32].
The AFP model was used to predict recurrence after liver transplantation for patients with HCC. In general, recurrence was higher in high-risk patients than in low-risk patients. It was found that among 432 patients fulfilling the Milan criteria, the 5-year risk of recurrence was 12.8% in patients with a low-risk AFP model and 32.4% in patients with a high-risk AFP model. In the same study, of 142 patients beyond the Milan criteria, the risk of recurrence was 14.9% among patients with a low-risk AFP model and 58.9% in patients with a high-risk AFP model [13]. Further, another study assessed the AFP model as a predictor of recurrence in patients with HCC who underwent liver transplantation and found that low-risk patients showed 21.1% of 5-year recurrence rate, which was lower than that of high-risk patients who showed 57.7% of 5-year recurrence rate [33].
To our knowledge, no study evaluated the AFP model as a prognostic model for patients undergoing locoregional treatment for HCC. In the current study, we used the AFP model with its components: AFP level in combination with the size of the largest nodule and the number of nodules as a prognostic model for predicting response, recurrence, and survival in patients with HCC after TACE. In the current study, in low-risk patients according to the AFP model, recurrence was lower (71.2%) than in the high-risk group (78.2%). When we classified the cases, who underwent TACE with AFP level < 100 IU/mL according to the AFP model, recurrence was less in the low-risk group (37 patients (71.2%)) than it was in the high-risk group (13 patients (81.2%)). Jinsoo et al. also assessed the AFP model as predictor of survival in patients with HCC who underwent liver transplantation and found that low-risk patients had a 5-year survival rate higher than that of high-risk patients (76.2% vs. 52.2%, respectively) [33]. In our patients, the 3-year survival in the low-risk group was higher than that in the high-risk group (37.3% vs. 11.6%, respectively). Our study is the first that has tried to predict the response, recurrence, and survival after TACE depending on three parameters (level of AFP, number of nodules, and size of largest nodule collectively) in the form of the AFP model, which was recently validated for patients with HCC undergoing liver transplantation by the French group [10]. More studies are still needed with larger sample sizes to validate its use. Further comparative studies between the AFP model and other prognostic scores for patients with HCC who will perform TACE are needed to figure out the best predictors of response, recurrence, and survival. Further prospective studies are still needed on the efficacy of the AFP model in predicting recurrence and survival in patients with vascular invasion who are candidates for locoregional treatment.