Therapeutic equivalence in survival for hepatic arterial chemoembolization and yttrium 90 microsphere treatments in unresectable hepatocellular carcinoma

A Two-Cohort Study

Authors


Abstract

BACKGROUND:

Intrahepatic arterial yttrium 90 (90Y) microspheres have been proposed as a less toxic, less invasive therapeutic option to transhepatic arterial chemoembolization (TACE) for patients with surgically unresectable hepatocellular carcinoma (HCC). TACE has demonstrated the ability to prolong survival. However, long-term survival remains uncertain.

METHODS:

In a 2-cohort experience in the treatment of North American patients who had advanced, unresectable, biopsy-proven HCC, 691 patients received repetitive, cisplatin-based chemoembolization; and a separate cohort of 99 patients who had similar treatment criteria received a planned, single dose of 90Y. Over the study period, an additional 142 patients were followed without treatment (total, 932 patients).

RESULTS:

Overall survival was slightly better in the 90Y group compared with the TACE group (median survival, 11.5 months vs 8.5 months). However, the selection criteria indicated a small but significant bias toward milder disease in the 90Y group. By using stratification into a 3-tier model with patients dichotomized according to bilirubin levels <1.5 mg/dL, the absence of portal vein thrombosis (PVT), and low α-fetoprotein plasma levels (<25 U/dL), an analysis of survival in clinical subgroups indicated that the 2 treatments resulted in similar survival. In addition, patients who had PVT or high α-fetoprotein levels also had similar survival in both treatment groups.

CONCLUSIONS:

Given the current evidence of therapeutic equivalence in survival, 90Y and TACE appeared to be equivalent regional therapies for patients with unresectable, nonmetastatic HCC. Cancer 2010. © 2010 American Cancer Society.

The management of primary hepatocellular cancer (HCC) is evolving as new modalities of therapy are being evaluated. Advances have taken place for patients who present at early stages of tumor extent and include more aggressive approaches to surgical resection, radiofrequency ablation (RFA), and liver transplantation. However, the majority of patients who present with HCC in the absence of a surveillance program have surgically unresectable disease because of their tumor extent, the severity of their cirrhosis, or both, and the prognosis is poor for these patients.

There is now large experience with hepatic artery chemotherapy, with or without some form of embolization (transhepatic arterial chemoembolization [TACE]) to slow tumor growth,1, 2 although only 2 randomized controlled trials have demonstrated a survival advantage.3, 4 Compared with controls who receive no treatment, this approach appears to confer some palliative benefit to many patients, including tumor shrinkage (partial response) rates in the 10% to 60% range.1, 2, 4

More recently, internal hepatic irradiation with microspheres carrying yttrium 90 (90Y)5-8 or other radionuclides9-11 that are injected intra-arterially, has been proposed as an alternative approach to regional chemotherapy that often requires the administration of only a single dose and generally appears to be safe.5, 6 Currently, limited information is available on the efficacy of this approach. We recently reported the short-term acceptability of this approach in a phase 2, open-label trial of 65 patients using this strategy, but we did not report on long-term survival.7 Our clinical hypothesis was that, if survival after 90Y therapy was either equivalent or superior to chemotherapy in patients who received TACE, then outpatient 90Y may be a primary regional treatment of choice for patients with nonmetastatic HCC.

In this article, we report our extended, open-label experience of 90Y microspheres (TheraSpheres; MDS Nordion, Ottawa, Ontario, Canada) in a cohort of 99 patients who had biopsy-proven, unresectable HCC and compare that experience with 691 similar patients with HCC from a preceding cohort of patients who received a cisplatin-based TACE chemotherapy regimen and with an additional 142 patients who could not receive any treatment. The focus of this report is on survival. In this open-label comparison of 2 sequential patient cohorts, we have matched subgroups of HCC based on comparable baseline pretreatment criteria to evaluate tumor extension and residual hepatic function. Our objective was to determine whether there is a difference in survival advantage between therapeutic alternatives.

MATERIALS AND METHODS

Clinical Selection

This report includes consecutive series of all patients with biopsy-proven HCC who were seen at a single medical center; who were not candidates for surgical resection, RFA, or hepatic transplantation; and who received either conventional cisplatin-TACE from 1992 to 2000 or 90Y microspheres (TheraSpheres) from 2000 through 2005.

Baseline Evaluation

All patients had tumor biopsy proof of HCC as well as random biopsies from nonmalignant areas of the underlying liver to assess for the presence of cirrhosis. Baseline triphasic computed tomography (CT) scans of the abdomen and chest and laboratory blood tests were obtained that included a complete blood count, prothrombin time, liver function tests, and creatinine and α-fetoprotein (AFP) measurements. Exclusion criteria for either treatment was a bilirubin level >3.0 mg/dL, creatinine >2.0 mg/dL, platelets <60,000/μL, granulocytes <1500 μL, the presence of metastases at baseline, uncorrectable shunting of blood to the intestines or lungs, and an Eastern Cooperative Oncology Group performance score of 0 or 1. Specifically for 90Y, added exclusion criteria were the presence of aberrant vessels on an angiogram that fed the stomach or intestines and a lung shunt that delivered a calculated ≥16.5 mCi or 30 grays (Gy) of 90Y.

Chemoembolization therapy for hepatocellular carcinoma with cisplatin-transhepatic arterial chemoembolization

For intrahepatic arterial chemoembolization, we have used cisplatin. This is based on the finding that cisplatin has the ability to shrink tumors12-15 and has minimal myelosuppressive activity compared with most other agents. This is a useful property in the setting of portal hypertension and accompanying splenomegaly. It also is tolerated relatively well by the cirrhotic liver. Typically, it was given at a dose of 125 mg/m2 of body surface area in 1 mg/mL of normal saline and infused into the right or left hepatic artery over 30 minutes together with dexamethasone16 20 mg (in an attempt to limit hepatic inflammation), morphine sulfate 5 mg (for pain), and intravenous antibiotics (cefazolin or vancomycin) before TACE. A pressure pump was used to deliver the drug. Complete baseline arteriograms of the superior mesenteric artery and celiac axis were obtained using standard selective percutaneous catheterization techniques to identify all hepatic arterial blood supply, including any aberrant vessels. Catheterizations were accomplished using standard percutaneous 5-French catheters, such as the Cobra-2 and the Sos Omni catheter (Angiodynamics, Queensbury, NY). Angiograms were reviewed to ensure that there was complete visualization of all tumor vessels. If there was any discrepancy and all vessels could not be identified, then aortograms were obtained as needed to evaluate for any aberrant blood supply. Individual treatment sessions were limited to unilobar or segmental therapy to minimize the risk of TACE-induced hepatic failure. Selective catheterization of the right or left hepatic artery often was achieved using a microcatheter, such as the Renegade catheter (Boston Scientific, Natick, Mass) as needed.

Chemoembolization or TACE therapy with cisplatin was given on a protocol that was designed to minimize side effects of nausea, vomiting, pain, ototoxicity, nephrotoxicity, and neurotoxicity and to be completed over 24 hours. Most patients underwent treatment under conscious sedation. A combination of an anxiolytic agent, such as midazolam HCl, and pain medication with fentanyl citrate was used. A diuretic regimen was designed to prevent cisplatin-mediated nephrotoxicity. Two hundred fifty milliliters of 3% saline was given intravenously before chemotherapy. In addition, the patients were given aggressive intravenous hydration. This was done using D5 half-normal saline or just normal saline (for diabetics) with 20 millequivalents of KCl per L at 250 mL per hour for a minimum of 3 hours. Once the patient was in the vascular procedure room, the fluid rate was increased to 2 L over 2 hours immediately before the cisplatin infusion, together with immediate intravenous infusion of the diuretics, mannitol 12.5 g, and furosemide 40 mg during the cisplatin infusion. We also gave an intravenous bolus of sodium thiosulfate 9 g/m2 immediately before the chemotherapy and a 6-hour intravenous infusion of 1.5 g/m2 per hour afterward. This integrated management resulted in the essential disappearance of cisplatin-mediated ototoxicity, nephrotoxicity, and neurotoxicity. Intravenous hydration at 150 mL per hour was continued postchemotherapy until the patient was discharged from the hospital the following morning. Before cisplatin, a single intravenous dose of granisetron 1 mg or ondansetron 32 mg was given together with dexamethasone 4 mg. Aggressive anti-inflammatory and triple antiemetics over the 24 hours of the protocol, consisting of a combination of dexamethasone, raglan, and diphenhydramine (Benadryl; McNeil-PPC, Skillman, NJ), or granisetron all were given repetitively over the 24 hours of the protocol. After cisplatin, intravenous metoclopramide 2 mg/kg (Reglan; Schwarz Pharma AG, Monheim, Germany), Benadryl 25 mg, and dexamethasone 4 mg (Decadron; Merck & Company, Whitehouse Station, NJ) was given every 3 hours for the next 12 hours.

Initially, Gelfoam sponge particles (Pharmacia & Upjohn, Kalamazoo, Mich) were injected into the hepatic artery at the beginning of the administration of chemotherapy, halfway through the cisplatin infusion, and again at the end of the cisplatin administration. The objective of this approach was to cause vascular slowing (chemo-occlusion) but not complete occlusion. This partial embolization approach was used in an attempt at a greater safety margin, especially when portal vein thrombus was present. The arterial flow was monitored during the chemotherapy by regular bolus injections of angiographic dye after each insertion of Gelfoam to check the vascular flow. Then, the cisplatin in 150 mL to 250 mL saline was infused at a rate to allow the entire volume to be administered in 30 to 45 minutes. Gelfoam aliquots typically were given before, during, and at the end of the chemotherapy infusion.14

More recently, we substituted biospheres (Embospheres; BioSphere Medical, Rockland, Mass) at doses from 100 μm to 300 μm in prefilled syringes for Gelfoam for convenience and particle size consistency.17 The Embospheres were mixed with water-soluble contrast material (Optiray 320; Mallinckrodt, Hazelwood, Mo) according to the manufacturer's directions and were injected under fluoroscopic guidance. In most patients, embolization was performed to the point of visibly stagnant blood flow. Moderate antegrade slowing was used as the endpoint only in patients who had elevated serum bilirubin levels.

All patients had baseline CT scans obtained for the evaluation of tumor burden and location. Baseline liver function tests were obtained in addition to renal function tests and coagulation studies. A follow-up CT scan was obtained immediately before the next treatment. Thus, after Treatment 1, a CT scan was obtained immediately before Treatment 2; and, after Treatment 3, a CT scan was obtained immediately before Treatment 4. Complete blood count, prothrombin time, liver function tests, and creatinine and AFP measurements were obtained weekly throughout the treatment process. Cisplatin-TACE was repeated every 8 to 12 weeks, depending on hepatic tolerance; the tumor response; recovery of the white blood cells, platelets, bilirubin levels; and the time to clinical patient recovery (mainly tiredness).

Yttrium 90 microspheres protocol

The hepatic artery catheterization and 90Y delivery were performed in the angiography suite, as was the TACE procedure. The potential for radiation exposure to the stomach and intestines, which could result in nonhealing radiation ulcers, was minimized by a pretreatment planning celiac and hepatic angiogram. The potential for inducing radiation pneumonitis after portal-systemic shunting of microspheres delivered to the cirrhotic liver was minimized by obtaining a pretreatment technetium 99 macroaggregated albumin (99Tc MAA) scan after the radiotracer was injected into the hepatic artery; this was followed by single-photon emission CT scanning of the lung at the time of the planning angiogram and typically was obtained 2 or 3 weeks before the planned treatment date. The 99Tc MAA scan was used to exclude patients from this procedure who otherwise may have had >16.5 mCi of injected 90Y going to their lungs. TheraSphere treatment was given by rapid bolus injection over 1 to 5 minutes into the right or left hepatic artery with the intent to deliver from 135 to 150 Gy (13,500-15,000 rads) to the treated lobe, as described previously.8, 18

The protocol plan was to treat the patient with only a single dose of 90Y to the liver lobe that had the dominant disease burden and, in subsequent months, only to monitor the patient unless follow-up CT scans revealed progressive disease. In that situation, a second treatment was given to the hepatic lobe that had tumor progression. Otherwise, patients were followed during clinic visits every 2 months with physical examinations, laboratory tests, and follow-up CT scans. The reason for this plan, in contrast to the repeated treatments that are typical of TACE (and all other cancer chemotherapeutics), was to minimize the (unknown) toxicities of 90Y to the cirrhotic liver. TheraSphere therapy currently is approved for treatment of HCC under approval through a humanitarian device exemption. Individual institutional review board (IRB)-approved informed consent was obtained from each patient in this 90Y treatment group along with an IRB-approved data collection consent. The cisplatin-TACE group was not considered experimental; therefore, those patients signed a standard hospital treatment consent form for the hepatic arterial chemotherapy. The data were collected and analyzed under an IRB-approved data collection protocol. The time from patient referral to first treatment was about 2 weeks for the TACE group and about 4 weeks for the 90Y group because of the need in the latter group for a planning angiogram and the scheduling of 90Y shipments for each patient.

Tumor Responses

World Health Organization tumor response on CT scans or magnetic resonance images was determined for measurable lesions (>1 cm) by using the cross-product of the greatest perpendicular dimensions to assess the need for further cycles of therapy. Corresponding lesions from baseline and post-treatment scans were compared during venous and arterial contrast phases to assess tumor morphology and size changes. A “complete response” was defined as a change in the sum of the cross-products to zero (ie, a 100% reduction), a “partial response” was defined as a decrease ≥50% in the sum of cross-products, “stable disease” was defined as a decrease <50% in the sum of cross-products or an increase <25%, and “progression” was defined as an increase ≥25% in the sum of cross-products. Response Evaluation Criteria in Solid Tumors came into general use more than halfway through these treatments. Therefore, World Health Organization response criteria were used throughout this series, which began in 1992.

Statistical Methods

Overall survival was the only endpoint used and was defined as the time between the date of first treatment and date of death. A substantial investment of effort was made to identify the time of death in each patient to avoid issues involved with censorship from loss to follow-up, which would have introduced a bias to underestimate median values. The data used to relate to survival time were dichotomized. These included demographics, historic risk factors, clinical characteristics, conventional liver function tests, and CT scan results and were defined by the largest tumor size, the number of tumors, and CT evidence of tumor extension, including the presence or absence of portal vein thrombosis (PVT). These parameters were obtained at the time of initial clinical evaluation at our clinic. Univariate survival curves were estimated using the Kaplan-Meier method. Differences in the median and 95% confidence intervals (CIs) for each subgroup analysis in survival rates were compared by using the log-rank test. Hazard ratios were calculated using the Cox proportional regression model. Analyses were carried out using SAS 9.1 statistical software (SAS Institute, Inc., Cary, NC). Throughout the accompanying tables, although the data are shown for the TACE group, the 90Y group, and the no treatment group, the statistical analyses were applied only to comparisons between the 2 treatments (TACE and 90Y).

RESULTS

Patient Demographics

Nine hundred thirty-two patients with HCC who were considered unsuitable for resection, RFA, or liver transplantation were managed with chemoembolization (TACE; n = 691), with 90Y microspheres (n = 99), or with no treatment (n = 142). The no-treatment group included patients who were referred for treatment but, because of poor liver function or the presence of metastases, were deemed unlikely to be helped by either of these 2 intra-arterially delivered therapies. The demographic distribution of patients who received the 2 treatments is presented in Tables 1 and 2. Of these, most patients were men. However, there were similar proportions of men and women in each treatment category. Hepatitis C virus (HVC) alone was present in 19% of patients in the chemoembolization group and in 30% of patients in the 90Y group. Hepatitis B virus (HBV) alone as well as both HBV and HCV were present in similar proportions in each group (Table 1). Baseline radiologic assessment with abdominal CT scans indicated that there were similar proportions patients in each treatment group who had tumors that measured ≥5 cm, >5 tumors, bilobar disease, and elevated AFP. However, there was a slightly higher proportion of patients with PVT in the chemoembolization group compared with the 90Y group (42% vs 28%; P <.08). A greater proportion of patients in the chemoembolization (25%) had bilirubin levels ≥1.5 mg/dL than in the 90Y group (13%; P < .044) (Table 2).

Table 1. Demographic Variables in Patients With Unresectable Hepatocellular Carcinoma Who Received Transhepatic Arterial Chemoembolization, Yttrium 90, or No Treatment
VariableNo. of Patients (%)P
TACE90Y
  1. TACE indicates transhepatic arterial chemoembolization; 90Y, yttrium 90; NS, not significant; HBV, hepatitis B virus; HCV, hepatitis C virus.

Total group691 (100)99 (100) 
Men518 (75)70 (70)NS
Women173 (25)29 (30)NS
Alcohol217 (31)37 (37)NS
Tobacco101 (15)19 (19)NS
HBV only97 (14)9 (9)NS
HCV only132 (19)30 (30).057
Cirrhosis462 (66)80 (80)NS
Table 2. Clinical Variables in Patients With Unresectable Hepatocellular Carcinoma Who Received Either Transhepatic Arterial Chemoembolization, Yttrium 90, No Treatment
VariableNo. of Patients (%)P
TACE90Y
  1. TACE indicates transhepatic arterial chemoembolization; 90Y, yttrium 90; NS, not significant; PVT, portal vein thrombosis; AFP, α-fetoprotein.

Total group691 (100)99 (100) 
No. of tumors ≥5257 (37)26 (26)NS
Bilobar disease354 (51)43 (43)NS
PVT295 (42)28 (28).08
AFP ≥25 ng/mL465 (67)58 (58)NS
Bilirubin ≥1.5 mg/dL173 (25)13 (13).044
Albumin <3.5 g/dL449 (65)66 (66)NS

Hazard ratio analysis of survival between the 2 treatment groups

In the second step of the analysis, we undertook an analysis of hazard ratios (HRs) and 95% CIs in relation to the length of survival between risk factors observed in patients with HCC in each treatment group separately (TACE and 90Y) (Table 3). Men and patients with alcohol intake had a significantly increased HR in the TACE group but not the 90Y group. Patients who used tobacco had a comparatively higher HR in the 90Y group. With respect to concomitant liver disease, the presence of HBV was more hazardous to patients who received 90Y but less hazardous to patients who underwent TACE. The presence of cirrhosis was associated with increased risk in each group. Tumor size did not confer an increased HR. However, the presence of ≥5 tumors conferred risk only in the 90Y group. The presence of PVT and an elevated AFP level were risk factors in both groups. A bilirubin level ≥1.5 mg/dL and an albumin level <3.5 g/dL were associated with a significant HR in both treatment groups.

Table 3. Hazard Ratios and 95% Confidence Intervals for the Presence or Absence of Variables of Interest
VariableHR (95% CI)
TACE90Y
  1. HR indicates hazard ratio; CI, confidence interval; TACE, transhepatic arterial chemoembolization; 90Y, yttrium 90; HBV, hepatitis B virus; HCV, hepatitis C virus; PVT, portal vein thrombosis; AFP, α-fetoprotein.

Demographics  
 Men vs women1.29 (1.07-1.55)1.63 (0.99-2.69)
 Heavy alcohol use1.32 (1.08-1.63)1.72 (0.98-3.01)
 Heavy tobacco use1.20 (0.90-1.61)2.47 (1.17-5.25)
Concomitant liver disease  
 HBV only0.77 (0.61-0.98)2.75 (1.31-5.78)
 HCV only1.21 (0.98-1.57)1.28 (0.76-2.16)
 Cirrhosis, any cause1.50 (1.25-1.81)1.96 (1.02-3.69)
Tumor characteristics  
 Tumor size ≥5 cm1.17 (0.90-1.38)0.78 (0.41-1.50)
 No. of tumors ≥51.06 (0.88-1.3)1.8 (1.01-3.21)
PVT1.31 (1.11-1.54)2.13 (1.33-3.39)
AFP ≥25 ng/mL1.56 (1.30-1.88)1.71 (1.09-2.70)
Liver function  
 Bilirubin ≥1.5 mg/dL1.55 (1.29-1.86)2.69 (1.44-5.04)
 Albumin <3.5 g/dL1.48 (1.22-1.78)2.03 (1.25-3.31)

Liver function, tumor extent, and survival

Overall survival differed significantly between patients who underwent TACE compared with patients who received 90Y (P < .0146) (Fig. 1), with a modest sustained difference maintained over the 50 months of observation. The median survival was 8.5 months in the TACE group and 11.5 months in the 90Y group. Untreated patients had a median survival of 2 months. The median survival was compared between subsets of treated patients based on selected, dichotomized variables that had different HRs (see Table 4). In these analyses, the median survival was significantly longer in the 90Y group compared with the TACE group (11.5 months [95%CI, 8-16 months] vs 8.5 months [95%CI, 8-10 months]; P < .05). Although survival was poorer survival for men than for women, women who received 90Y survived significantly longer compared with women who underwent TACE (19 months [95%CI, 16-32 months] vs 12 months [95%CI, 10-15 months]; P < .05).

Figure 1.

Patient survival curves are shown dichotomized by treatment type. The 95% confidence intervals are presented as dotted lines. The numbers of patients at risk during each time interval are provided for the transhepatic arterial chemoembolization (TACE) and yttrium 90 (Y90) treatment groups. The top line represents TACE, and the bottom line represents Y90.

Table 4. Comparison of Survival (in Months) Between Patient Treatment Groups
VariableMedian Survival (95% CI), moPa
TACE90Y
  • CI indicates confidence interval; TACE, transhepatic arterial chemoembolization; 90Y, yttrium 90; NS, not significant; PVT, portal vein thrombosis; AFP, α-fetoprotein.

  • a

    aP value for the comparison between treatment groups.

Overall groups8.5 (8-10)11.5 (8-16)<.05
Sex   
 Men8 (7-10)10 (7-13)NS
 Women12 (10-15)19 (16-32)<.05
 P for sex<.001NS 
Cirrhosis   
 No cirrhosis12 (10-35)22 (16-40)NS
 Cirrhosis8 (8-9)10 (7-14)<.05
 P for cirrhosis<.0001<.05 
Tumor size, cm   
 <510 (9-12)8 (5-18)NS
 ≥58 (6-10)17 (7-40)<.05
 P for tumor sizeNSNS 
No. of tumors   
 <510 (8-13)14 (7-19)NS
 ≥58 (6-10)9 (5-13)NS
 P for no. of tumorsNS<.05 
PVT   
 Absent12 (10-14)16 (12-20)<.05
 Present7 (5-9)5 (4-9)NS
 P for the presence of PVT<.0001<.0001 
AFP, ng/mL   
 <2515 (14-18)18 (13-28)NS
 ≥257 (6-8)8 (6-13)NS
 P for elevated AFP<.0001<.05 
Bilirubin, mg/dL   
 <1.512 (10-13)13 (9-18)NS
 ≥1.55 (3-5)4 (2-10)NS
 P for elevated bilirubin<.0001<.0001 
Albumin, g/dL   
 ≥3.513 (10-15)22 (13-32)<.05
 <3.57 (6-9)8 (6-13)NS
 P for low albumin<.0001<.001 

The presence of cirrhosis resulted in a reduction in survival in each group. However, in the subset groups with cirrhosis, patients in the 90Y group had a marginally longer survival than patients in the TACE group (10 months [95%CI, 7-14 months] vs 8 months [95%CI, 8-9 months]; P < .05). Similarly, the presence of PVT was associated with decreased survival in each group. There was a modest increase in survival in the 90Y group compared with the TACE group in the subset without PVT (16 months [95%CI, 12-20 months] vs 12 months [95%CI, 10-14 months]; P < .05). Abnormal values for each of the biochemical indices identified in the HR analysis in Table 4 were associated with marked reductions in survival in each group, but only in the comparison of subsets with normal serum albumin was survival longer in the 90Y group than in the TACE group (22 months [95%CI, 13-32 months] vs 13 [95%CI, 10-15 months]; P < .05), as shown in Table 4.

Three-Tier Model

The lengths of survival indicate that each of the variables of tumor extent, liver function, and concomitant cirrhosis need to be taken into consideration simultaneously to create subgroups with comparable baseline characteristics before inferences can be drawn regarding differences in HCC treatment variables. Collectively, the univariate and bivariate analyses of individual risk factors, such as concomitant liver disease or the radiologic characteristics of the tumor, did not take into account variation in liver function. Conversely, the analysis using biochemical indices of liver function did not take into account the presence or absence of tumor extension. We considered the use of multivariate regression analysis. However, because the data elements are closely intertwined and nonparametric, we elected to take advantage of the large size of the study population and build a 3-tier pathophysiologic model based on subgroup analyses that account for each of the dominant variables.

In the first tier of this analysis, we choose a bilirubin level <1.5 mg/dL as an index of good liver function and a level ≥1.5mg/dL as an index of poor liver function. In this first tier of the 928 patients with data available for evaluation, 655 patients (70.2%) had a normal bilirubin levels (Fig. 2, left column; Tier 1). The patients who had elevated bilirubin levels (29.8%) had an extremely poor prognosis with a median survival of 3 months (95%CI, 2-4 months) in contrast to 11 months (95%CI, 10-13 months) in the patients with normal bilirubin levels (P < .0001). In the second tier, subdividing patients with good bilirubin into those with (n = 308) or without (n = 347) PVT resulted in 2 groups of substantial size, 37% and 33% of the original overall cohort, respectively. Within these 2 groups, the presence of PVT was associated with a 50% reduction in median survival (P < .0001) from a median of 15 months (95%CI, 13-17 months) down to 8 months (95%CI, 7-10 months) (Fig. 2, middle column; Tier 2). In the remaining cohort with elevated baseline bilirubin, the presence of PVT retained an its association with a >2-fold reduction in survival (P < .001) from 5 months (95%CI, 3-6 months) down to 2 months (95%CI, 1-3 months). Having created subgroups in which the heterogeneity of the overall group had been reduced by considering residual hepatic function and the presence or absence of PVT, next, we evaluated the impact of different types of treatment on survival. That analysis in the third tier revealed no significant treatment effect on survival (Fig. 2, right column; Tier 3). The no-treatment group was excluded from the third-tier analysis, which explains the difference in total patient numbers between Tier 2 and Tier 3. The P values for statistical significance to the right in each column of Figure 2 relate to a comparison of the 2 active treatment cohorts only and not to the no-treatment arm. A similar analysis evaluating the impact of elevated AFP is presented in Figure 3. Like in the analysis of PVT, high or low AFP levels had a marked impact on survival (Fig. 3, Tier 2). However, within the high AFP or low AFP cohorts, there was no statistically significant difference in survival for the 2 treatment arms (Fig. 3, Tier 3).

Figure 2.

This 3-tier model with patients dichotomized by bilirubin level, portal vein thrombosis (PVT), and treatment received shows the median survival (95% confidence interval) in months. The far right column provides a statistical analysis between the transhepatic arterial chemoembolization (TACE) and yttrium 90 (Y90) treatment groups. NS indicates not significant.

Figure 3.

This 3-tier model with patients dichotomized by bilirubin level, α-fetoprotein (AFP) level, and treatment received shows the median survival (95% confidence interval) in months. The far right column provides a statistical comparison of the transhepatic arterial chemoembolization (TACE) and yttrium 90 (Y90) treatment groups. NS indicates not significant.

Tumor Responses

Tumor responses (Table 5) were measured radiologically in all patients after 3 chemoembolization cycles, or 6 months after the first treatment, or at 6 months for the 90Y group. Complete response rates were similar and low for both modalities. The partial response rate was 55% and 33% for chemoembolization and 90Y, respectively, but stable disease was identified in 29% of patients versus 35% of patients in the chemoembolization group and the 90Y group, respectively. Thus, overall tumor control rate (all patients who attained a complete response, a partial response, and stable disease) was 89% for the chemoembolization group and 76% for the 90Y group. However, this was probably an underestimate of the 90Y tumor response benefits, because the pace of radiologic change differed between the 2 treatment modalities. Chemoembolization responses, when they occurred, typically were observed soon after the first treatment, with vascular responses occurring before size responses. 90Y responses occurred much more slowly, with vascular responses occurring within 2 months of treatment, but size responses (which were used for all response assessments in Table 5) often followed after many months (range, 6-18 months) and, for some patients, continued for >24 months after a single treatment. Patients in the chemoembolization group received an average of 2.5 treatments (range, 2-12 treatments), and patients in the 90Y group received a single, planned treatment, but 30% required a second treatment because of new, late appearing lesions.

Table 5. Tumor Responses to Treatment
ResponseTreatment: No. of Patients (%)
TACE90Y
  1. TACE indicates transhepatic arterial chemoembolization; 90Y, yttrium 90.

Total691 (100)99 (100)
Complete response37 (5)3 (3)
Partial response380 (55)38 (38)
Stable disease199 (29)35 (35)
Progressive disease75 (11)23 (23)

DISCUSSION

The management of HCC that is considered too extensive for surgical resection or RFA poses a difficult and unresolved dilemma in the role of therapeutic choices to assist in palliative care.1, 2, 19, 20 In recent years, a strategy of choice has been the direct delivery of chemotherapy through the hepatic artery directly to the tumor vasculature.2, 14, 15, 20 The current clinical experience was obtained in 2 sequential cohorts of patients with unresectable, advanced HCC. In the first group, we describe our overall experience of patients who were treated on a structured protocol of cisplatin infusion accompanied by Gelfoam or Embospheres arterial embolization, which was designed to reduce but not completely obstruct (embolize)14 the hepatic arterial blood flow and to minimize side effects (the TACE group). This regime recently underwent a suggested change in terminology, from TACE to “chemoembolization.”21 TACE is used in the current report merely as a convenience. In the second group, patients were received a rapid intrahepatic arterial injection of 90Y microspheres (90Y group), which was designed to deliver from 135 Gy to 150 Gy (13,500-15,000 rads) to the tumor site.

Our transition in elective choice of first-line therapy was a clinically based impression that the palliative benefit of 90Y treatment was greater than TACE and, in particular, required a smaller number of treatment hospitalizations.6-8 However, there was no previous evidence with which to compare the duration of survival from the time of the procedure. The observation in this cohort comparison is that, in the overall group, there was a small but statistically significant difference in survival, which was longer in the 90Y group (Fig. 1). This difference was observed immediately after the procedure, and the differences were sustained over time. However, we believe that this difference may be explained by the selection of patients who had milder disease in the 90Y group. When a tiered approach was used to stratify subsets, there was no residual difference in survival between the 2 therapeutic alternatives. Clearly, this subset strategy reduces the power of each observation; however, even if trends were supported in a larger series, the differences in median values would appear to be marginal.

The main toxicity of chemoembolization was tiredness and loss of appetite for 7 to 10 days after each treatment. The major inconvenience to the patients was the need for multiple treatments. Similar loss of appetite occurred in some 90Y patients. The identification of therapeutic equivalence in survival is helpful in clinical decision making, particularly because others previously demonstrated that the cisplatin/TACE combination used in our study has the ability to confer a survival advantage in a randomized controlled study.4 We recently reported in detail the early clinical consequences of 90Y treatment in a subset of 65 patients in this cohort.7 In that series, 2 patients had complete responses, 18 patients had partial responses, 27 patients had tumor stabilization, and 19 patients had tumor progression. The overall clinical appraisal in that report was that the efficacy data for tumor stabilization were encouraging, and the toxicity profile was qualitatively less than previous experience with chemotherapy. Therefore, we conclude that, in a risk-benefit analysis between the 2 treatment options, 90Y offers a superior option for palliative care, and we suggest that a randomized comparative trial with or without a control group may not be merited at this time.

We previously used this 3-tier strategy to identify elevated bilirubin as the strongest predictor of poor survival in this patient group with PVT and elevated AFP levels indicating high risk22 and being a women indicating low risk.23 An analogous tiered strategy previously used PVT to indicate differences in outcome after 90Y treatment.8 This observation raises the question of whether any intrahepatic arterial procedure should be offered in patients who have bilirubin levels that are as modestly elevated as 1.5 mg/dL if they have either PVT or an elevated AFP level, because their prognosis is so limited.

The study reported here, which was based on clinical outcome studies of 2 sequential patient treatment cohorts, raises the possibility of selection bias and changes what would be expected to occur over time and what would not be present in a conventional randomized clinical trial. We argue that, by using a tiered stratification, there is evidence of differences in selection with a bias toward less severe disease in the 90Y group. In considering change in management over time, the details of each therapeutic protocol are presented in detail, because they indicate a thoughtful, sustained attention to the overall process of each strategy. Even if the general care did improve at later times, the time-related bias would be expected to be an advantage to the 90Y group. However, the modest differences between groups already can be accounted for. Even if 90Y had a lesser response than TACE, the effect would be marginal and would not have an impact on the overall risk-benefit ratio. The patients who received no treatment were included for perspective only. They were different from the treated patients, usually because of extrahepatic cancer or because of the severity of their liver failure or poor performance status. Thus, comparison statistics were not analyzed for this group. However, the group clearly was heterogeneous. Although all patients died, not all patients had an equally bad prognosis, as scan be observed in those patients who had normal bilirubin levels, low AFP levels, or the absence of cirrhosis (Table 4).

The results of this study should be considered within the context of the US experience. It reflects a marked contrast to Japan, where screening has identified a much greater proportion of early cases in which the major consequence of the HCC is related to the location and size of the tumor.24 The clinical situation in advanced HCC is much more complex, because ≥2 concomitant disease processes progress as independently. In addition to the tumor characteristics, such as abnormal production of AFP or tumor extension into the portal vein, there is the potential for underlying hepatic predisposing disease (hepatitis or cirrhosis) as well as tumor replacement of viable liver. It is our impression that, in this late stage of disease, patients often die as a result of hepatic failure rather than as a consequence of tumor extension.25 We have not identified the cause of death in this overall cohort, but it is interesting to observe the differences in survival based on using a serum bilirubin level <1.5 mg/dL to identify conserved function and using the presence of either PVT or AFP as a measure of advanced tumor (Tables 2, 3; Figs. 2, 3). If these measures are considered surrogate biomarkers for the 2 processes, then loss of hepatic function is the most frequent life-limiting process.25 The literature on TACE for HCC is confusing, and there have been many noncomparable trials.1, 2 Thus, it has never been established whether 3 or 2 drugs are superior to 1 drug and, if so, which combination is optimal.15 Although lipiodol is used frequently, it has drawbacks, including difficulty in assessing subsequent CT scans.12, 15 Many different embolizing agents also have been reported from various institutions. These variables, together with the heterogeneity of patients in any trial and variations in patient selection or liver function in different trials, severely impede comparison of response results or survival results between different institutions.

In conclusion, in comparing the clinical outcomes of chemoembolization (TACE) versus 90Y strategies for palliative care of advanced, surgically unresectable HCC, the risk and inconvenience of repetitive inpatient TACE needs to be weighed against limited treatments in an outpatient setting for 90Y when the 2 approaches are equivalent therapeutically with respect to survival. Despite the limitations of study design in comparing sequential cohorts, the marginal advantage for the 90Y group can be explained on the basis of small but significant differences in selection bias toward milder disease. We also confirmed that, if a serum bilirubin level >1.5 mg/dL is used as a biomarker of impaired residual hepatic function, then such patients have a poor survival with either therapy (Fig. 2). We believe that the available information indicates that these 2 regional treatment strategies result in similar survival.

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Supported by grant NIH 5RO1DK05919-05.

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