Transarterial Chemoembolization

3-3 Combination of Cryosurgery with Transarterial Chemoembolization for Liver Cancer

ABSTRACT

1. Transarterial chemoembolization (TACE), by itself, is not associated with improved survival, however, can shrink the mass of liver cancer.
2. Combination of TACE and cryosurgery is expected to yield better therapeutic efficacy.
3. It is showed that sequential TACE-cryosurgery might improve outcome for the patients with liver cancer with the lower local recurrence rate at the ablation area and lower incidences of hepatic bleeding complication.

INTRODUCTION
Cryosurgery has been used for two decades for the treatment of many benign, malignant, and metastatic cancer [1-3]. More specifically, hepatocellular carcinoma (HCC) has been successfully treated either with cryosurgery alone or in combination with resection [4-6].

Transarterial chemoembolization (TACE), by itself, is not associated with improved survival when compared with that of an untreated control group[7], however, it has been proved to shrink the mass of liver cancer. It is shown that sequential TACE-resection might improve outcome for the patients with large HCC [8]. Therefore, combination of TACE and cryosurgery is expected to yield better therapeutic efficacy.

INDICATION
The combination of cryosurgery with TACE is mainly adaptable for larger liver cancer, including primary and metastatic.

TECHNIQUE
TACE
TACE was performed in an interventional radiology suite after cross-sectional images were reviewed[9]. A 6 French vascular sheath was placed into the femoral artery, and a 0.035 inch diameter Mickaelson catheter was advanced into the celiac and superior mesenteric arteries. Contrast was injected into the arteries during rapid-sequence radiographic imaging. Arterial branches supplying the
tumor were then located. The venous phase was carefully examined for patency of the portal veins. The vessels were analyzed for the presence of anatomic variation. A 0.018 inch diameter Tracker catheter was advanced through the Mickaelson catheter to the arterial
branches that supply the tumor. Doxorubicin (50 mg) and Mitomycin (10 mg) were mixed with Lipiodol (4-15 ml), and the mixture was injected into the arterial branches until hemostasis was achieved. If the tumor had no shrinking at 2 weeks after the procedure, the second TACE was performed.

Cryosurgery
Cryosurgery is performed with open ,laparoscopic and percutaneous approaches. Percutaneous cryosurgery is performed under guidance of real-time untrasound.

CLINICAL DATA
Clavien[9] evaluated in a prospective study the safety and efficacy of this combination in cirrhotic patients with unresectable hepatocellular carcinoma (HCC). Fifteen patients were included in this study. All but one patient underwent one or several sessions of TACE before cryosurgery. Cryoablation was successfully performed in each patient. The patient who did not undergo preoperative TACE required reoperation for hemorrhage. Another patient with Child class B cirrhosis died postoperatively of hepatic and multiorgan failure. At a mean follow-up of 2.5 years, three patients had recurrence of disease, and 13 of 15 patients were alive with the longest survival time being 5 years. The actuarial survival rate at 5 years was 79%.
Qian[10]reported thirty-four patients with histologically or clinically confirmed primary or metastatic hepatic carcinomas which were treated with TACE. One week to 1 month later, they were treated percutaneously under ultrasound guidance using cryosurgical system. All patients were followed up to determine serum tumor marker, CT scans, MRI images or ultrasound images. This therapy was performed in 34 patients including 32 patients with Child A, 2 patients with Child B and no patient with Child C. There were 28 patients with primary liver cancer and 6 patients with metastatic liver cancer. During the follow-up period of 3 to 15 months, 41.1% patients were recognized clinically cured because the serum tumor markers became normal, or CT scans and MRI images revealed that the lesion became completely necrotic. Forty-four percent of patients were recognized effectively treated.

We[11] reported their experience. From March 2001 to December 2006, a total of 980 patients with HCC received intraoperative or percutaneous cryosurgery in Fuda Cancer Hospital Guangzhou, China, among whom, 660 received TACE before cryosurgery. A retrospective study is to invest the results of 310 patients who were treated with sequential use of TACE-percutaneous cryosurgery, in comparison with 110 patients who received percutaneous cryosurgery alone. Results are as followings.

Survival
During a mean follow-up of 36±17 months (range from 24 to 60 months), 129 patients (30.7%) showed no evidence of disease, 98 (23.3%) were alive with recurrent disease, 170 (40.5%) died of disease recurrence or spread, and 23 (5.5%) died of other diseases (infection of respiratory system in 5 cases, heart disease in 12 cases, renal failure in 3 cases, and unknown etiology in 3 cases). The overall 1-,2-,3-,4-,and 5-year survival rates are 72%,57%, 47%, 39% and 31%, respectively. The survival rates between sequential group and cryo-alone group were statistically significant different at 4 and 5 years after treatment（p=0.04） (Table 3-3-1)(Figure 3-3-1).

Table 3-3-1. Survival and disease status of sequential TACE-cryoablation ?vs.cryo-alone groups

One-year survival rates were 71% for sequential therapy group and 73% for cryo-alone group (p=0.06), while 4- and 5-years survival were 49% and 39% in sequential group, respectively, which were higher than 29% and 23% (p=0.002) in cryo-alone group, respectively.

There were 18 patients with large HCC (>5cm) who underwent sequential treatment and had disease-free survival for more than 5 years, while no patient with large HCC had survival of more than 5 years. The CT of the liver for selected patients is illustrated in Figure 3-3-2 to 3-3-5.

Figure 3-3-2. Right liver lobe had tumor mass of 14X9 cm in size and was proved to be HCC by biopsy. Figure A-B showed the sequential changes of the mass until its eventually disappearance after sequential therapy. The patient is alive and has 72 months of disease recurrence- free survival.

Figure 3-3-3. The diagnoses of HCC was proved by histology. The figures showed the tumor mass at 3 mo (A) and 28 mo (B) after sequential therapy. The cryoablated mass had cavitiation formation. No cancer cells were identified by needle aspiration. The patient alive for 61 months.

Figure 3-3-4. The patient had HCC proved by biopsy and underwent sequential therapy. Figure A showed a space-occupying lesion. B and C showed the shrinkage of cryoablated lesion after sequential treatment. The patient had survival of 64 months.

?Figure 3-3-5. A female had a biopsy-proved HCC. The figures A showed a space-occupying lesion in right lobe of the liver after TACE and prior to the cryosurgery; B and C showed the cryoablated lesion at three months and three years, respectively, after TACE-cryoablation. C showed the liquefaction of the cryoablated lesion and no cancer cell was found by needle aspiration. D showed PET-CT of the cryoablated mass at 5 years after the therapy which showed no metabolic activity.

The local recurrence rate at the ablation area was 17% for all patients, and 11% and 23 % for sequential therapy and cryo-alone group, respectively (p=0.04).

Complication
The main complications were hepatic bleeding, liver rupture, liver failure, thrombocytopenia and/or clotting dysfunction, acute renal failure with myoglobinuria and pneumonia as shown in Table 3-3-2. The overall rate of complications was 24%, and there were 21% and 26.2 % of complication rate, respectively, for the sequential group and cryo-alone groups (p= 0.06).The latter group had more incidence of hepatic bleeding (p=0.02). Liver rupture was only seen in cryo-alone group. Liver failure was seen in 16 patients (3.8%), including 12 patients (4.1%) in sequential group and 4 patients (3.1%) in cryo-alone group (p>0.05). Peri-cryosurgery death occurred to 2 patients from the cryo-alone group, who died of liver crack and massive hepatic bleeding, respectively.

Table 3-3-2. Complication of sequential TACE-cryosurgery vs. cryo-alone groups

DISCUSSION

Because systemic chemotherapy and radiation therapy provide dismal results, TACE remains the sole approach to antagonizing the cancer growth in most patients with liver cancer. Although most tumors show an extensive necrosis after TACE, the beneficial effect on survival has not been properly substantiated, so that its application still remains a matter of debate. In most studies, TACE did not increase the survival of patients as compared with the palliative treatment. TACE is currently considered as a base of further radical treatment for unresectable HCC[12,13].
It is not known if TACE combined with other treatments is beneficial. PubMed search for all cohort and randomized trials (n=84) evaluating TACE combined with other therapies. A meta-analysis involving 4 RCTs showed a significant decrease in mortality favouring combination treatment (TACE plus percutaneous ablation) compared to monotherapy in patients with either small (<3cm) or large HCC nodules (>3cm) (p=0.046). TACE combined with local radiotherapy improved survival in patients with tumour thrombosis of the portal vein in 7 non-randomized studies. Two RCTs and 13 non-randomized studies showed that TACE prior to hepatic resection does not improve survival or tumour recurrence. Conversely, 2 RCTs and 5 comparative studies showed that transarterial injection of chemotherapeutic drugs mixed with lipiodol (TOCE) following hepatectomy confers survival benefit and less tumour recurrence. TACE before liver transplantation is safe and reduces drop-out rate from the waiting list, but there is no current evidence of improvement in subsequent survival or recurrence rate. The results showed that a combined approach involving TACE and percutaneous ablation improves survival. Adjuvant TOCE improves outcome after hepatectomy. TACE is useful to control tumours burden while on the waiting list for OLT. Multimodal treatment seems to be the best way to optimize TACE outcomes in HCC[13].
Kaibori[14] evaluated the effect of preoperative whole-liver chemolipiodolization. A retrospective comparison was performed between 36 patients with chemolipiodolization confined to the tumor (selective group) and 23 patients with chemolipiodolization also involving the noncancerous liver (whole-liver group). Tumor diameter was significantly greater in the selective group, but other pathological characteristics were comparable. The 5-year disease-free and overall survival rates for the selective and whole-liver groups were 11.9% and 33.0% (p=0.0191) and 44.9% and 73.2% (p=0.0121), respectively. These results indicate that preoperative whole-liver chemolipiodolization reduces postoperative recurrence and prolongs survival in patients undergoing resection of hepatocellular carcinoma.
Cryosurgery is similar to resection in term of elimination of cancerous tissue for liver cancer. Therefore, combination of TACE and cryosurgery is expected to yield better therapeutic efficacy. Current data suggests that the addition of TACE results in better long-term outcome. It is believed that the relatively good outcome is due to the use of TACE prior to cryosurgery. The efficacy of TACE has a possible increase in the rate of tumor ablation and reduction in postoperative bleeding.

Cryo-induced tumor cell destruction is influenced by several factors, among which, temperature is critical. Temperatures lower than -40? C are assumed necessary to ensure tumor ablation. Ice-balls larger than the target lesions are thus necessary for complete tumor ablation, because the temperature at the edge (few millimeter thickness) of an iceball is non-lethal [15-17]. An ice-ball encompassing the entire tumor mass and 1-cm beyond the tumor borders should be considered adequate for ablation. According to MRI-estimated three-dimensional temperature distribution in liver cryolesion provided by mala[16], the mean value of the distances calculated between the -40?C isotherm and the cryolesion edge was median 4.1 mm and the largest of these distances defined for each cryo-lesion was median 8.1mm. The largest distance defined between the tumoricidal part of the cryolesion and the cryolesion edge may be close to 1-cm for less than 25 cm3 of cryolesion volume, while for cryolesion larger than 25cm3 the 1-cm rim zone was not likely to ensure temperatures adequate for ablation in the entire volume enclosed by the rim zone. It is shown that tumor size influences the rate of tumor ablation. Lesions larger than 3 cm are more likely associated with a higher recurrence rate than smaller tumors[18].

Therefore, the smaller the tumor, the more effective the cryoablation, and the lower the recurrence rate. TACE is proved to shrink masses of liver cancer. Obviously, TACE performed prior to cryoablation may be expected to increase the efficacy of the cryoablation for liver cancer, and to decrease the local recurrence at the ablation area. This fact is of special significance for the large tumor close to large vessel, because it is unlikely for the edge zone of the cryolesion to reach the temperature of less than -40°C due to blood warming effect[19].

Experimental study showed that selective occlusion of vascular inflow, i.e., ischemia, increases the volume of tissue destruction [20,21]. In clinical practice, additional Pringle maneuver (vascular occlusion) is introduced with the idea of increasing the volume and effectiveness of the cryosurgical procedure.

The major complications of cryosurgery are hemorrhage and liver crack [22,23]. It is likely that TACE may reduce the risk of hemorrhage and liver crack after cryosurgery.

It is suggested that TACE before cryosurgery may increase cryoablation efficacy and decrease the adverse effects, especially bleeding complication, and accordingly, raise the survival rate of the patients with liver cancer receiving cryosurgery.

Question is whether percutaneous cryosurgery could replace open cryosurgery for the treatment of liver cancer. A prospective randomized study between the two modes of cryosurgery will ultimately be necessary to determine the value of each mode in the treatment of HCC. Nevertheless, for the patients with liver cancer who often have liver cirrhosis and compromised hepatic reserve, percutaneous cryosurgery, a mini-invasive modality, should be more appropriate than open cryosurgery, a more invasive procedure. Moreover, along with developed imaging techniques which are used for the guidance of cryosurgery and accumulation of clinical experience, the percutaneous mode will be practical for achieving effective ablation for tumor.

TACE before operative resection has been proved to be a good strategy for large liver cancer. The use of TACE prior to percutaneous cryosurgery, therefore, might be applied to the treatment of unresectable liver cancer.
Apart from use of TACE, it is showed that preoperative use of portal vein embolization (PVE) enables surgical resection in liver cancer patients with small future liver remnant volume and improves patient survival compared with TACE[24]. Whether the strategy is adaptable for cryosurgery is subject to further study.

CONCLUSION
A combined approach involving TACE and perctaneous cryosurgery has been shown to improve survival of patients with liver cancer. TACE is useful to control tumors burden. Sequential use of TACE and cryosurgery seems to be the best way to improve outcome in unresectable liver cancer, especially larger liver tumors.

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