Saxena A, Bester L, Chua TC, Chu FC, Morris DL (2009) Yttrium-90 radiotherapy for unresectable intrahepatic cholangiocarcinoma: a preliminary assessment of this novel treatment option. Ann Surg Oncol, 17(2):484-491
Abstract: Patients were assessed at 1 month and then at 3-month intervals after treatment. Clinical and biochemical toxicities were prospectively recorded. No patient was lost to follow-up.
Introduction
Recent epidemiologic studies have shown that although ICC remains rare in developed countries, its age adjusted incidence has increased rapidly from .32 per 100,000 in 1975–1979 to .85 per 100,000 in 1995–1999.1–3. These patients with unresectable disease have a poor prognosis, with a median survival of 6 to 12 months from the time of diagnosis.3
Traditional systemic chemotherapies have shown poor results in treating patients with advanced ICC.7,8 The use of gemcitabine as a single agent or in combination with other chemotherapeutic agents is also of uncertain benefit in patients with advanced biliary tract cancers.9–11. Regional chemotherapy in the form of ransarterial chemoembolization (TACE) has been used in several small, uncontrolled trials of ICC with median survival ranging widely from 9 to 21 months.12–14.There are also few data demonstrating survival benefit from radiofrequency ablation, liver transplantation, or external-beam radiotherapy 1,5,15–18
Clearly, the optimal management strategy for patients with unresectable ICC remains to be defined.
However, to date, only one small series, by Ibrahim and colleagues, has examined the safety and efficacy of this treatment for unresectable ICC.20 The results of this study were promising, with a median survival of 14.9 months for the entire cohort and acceptable level of clinical and biochemical toxicity. However, more data are clearly required to determine the value of this treatment. We report our experience with 90Y radioembolization for ICC to determine the safety and clinical efficacy of this treatment modality in a subgroup of patients with unresectable disease.
Materials and Methods
This prospective investigation was approved by a local institutional review board. Inclusion criteria were as follows: (1) histologically proven diagnosis of ICC; (2) unresectable tumor; (3) age 18 to 85 years; (4) ability to undergo angiography and selective visceral catheterization; (5) Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2; and (6) adequate hematology (granulocyte count C 1.5 9 109/l, platelets C 50 9 109/l), renal function (creatinine level B 2.0 mg/dl), and hepatic function (bilirubin level B 2.0 mg/dl). Patients were deemed to have unresectable tumor on the basis of multiple intrahepatic lesions, distant metastasis, peritoneal carcinomatosis, extensive vascular involvement, or severe liver cirrhosis in patients who required major liver resection. Patients with limited extrahepatic disease, which at the time of treatment was less clinically important than the liver disease (from a tumor burden and symptom standpoint) and not immediately life-threatening, were not excluded. Patients who had prior treatment for ICC were not excluded.
Liver function tests, complete blood count, coagulation profiles, and albumin and total bilirubin levels were obtained on the first day of 90Y treatment for all patients. All patients underwent a pretreatment triple-phase computed tomographic (CT) imaging scan of the liver.
All patients were treated on an outpatient basis and were discharged from 2 to 6 hours after the procedure. Patients were initially followed up after 1 month and then at 3-month intervals until death. Clinical toxicity, blood, and biochemical markers in addition to abdominal CT scans were obtained and assessed at each follow-up visit.
Study Methods: We prospectively collected and reviewed patient clinicopathologic and treatment-related data. The primary outcome of this study was overall survival and radiological hepatic tumor response. Radiologic hepatic tumor response was assessed by an experienced interventional radiologist (L.B.) in accordance with the Response Criteria in Solid Tumors (RECIST) guidelines by comparison of each follow up examination with the baseline examination.25 In brief, a complete response was defined as disappearance of lesions; partial response as a >30% decrease in the sum of the longest diameter of the index lesions; stable disease as a <30% decrease or <20% increase in the sum of the longest diameter of the index lesions; and progressive disease as a C 20% increase in the sum of the longest diameter of the index lesions or appearance of new lesions. Secondary outcomes included clinical and serologic toxicity and were assessed by the National Cancer Institute’s Common Toxicity Criteria for adverse events (version 3).
Statistical Analysis: Survival data from time of the first radioembolization procedure were assessed by the Kaplan-Meier method with the last date of contact or death used for censoring. Clinicopathologic and treatment-related variables were analyzed for an association with overall survival by the log rank test. Categorical variables were compared by v2 analysis of Fisher’s exact test where appropriate. All statistical analyses were performed by SPSS for Windows, version 17.5 (SPSS GmbH, Munich, Germany). A statistically significant difference was defined as P<.05
Results
Clinicopathologic and Treatment Related Data: Between January 2004 and May 2009, a total of 25 patients with ICC underwent 90Y radioembolization. Table 1 summarizes the patient characteristics.
Seven patients (28%) underwent treatment with systemic chemotherapy after 90Y radioembolization.
Overall Survival: No patient was lost to follow-up. Eighteen patients (72%) had died at the last time of follow-up.
Biochemical and Clinical Toxicity: Clinical toxicities included fatigue in 16 patients (64%); nonspecific self-limiting abdominal pain in 10 patients (40%); nausea in 4 patients (16%); anorexia in 4 patients (16%); vomiting in 2 patients (8%); and shortness of breath in 2 patients (8%)
Discussion
Only one previous study20 has examined the safety and efficacy of this treatment for unresectable ICC. We report herein what is to our knowledge the largest single-institution experience of 90Y radioembolization for unresectable ICC to further assess the value of this treatment.
The overall median survival from the time of diagnosis was 20.4 months, which is higher than the reported 6- to 12-month survival in patients who were palliatively managed.3 These results must not be viewed in isolation. It must be noted that 68% of these patients had disease progression on previous systemic chemotherapy, and 40% presented with widespread disease despite a previous liver resection. Ibrahim and colleagues reported the only other data on 90Y radioembolization for unresectable ICC.20 Twenty-four patients were treated with glass-based 90Y microspheres over a 4-year period. In contrast to the current study, patients with bilobar disease were treated with two separate administrations of 90Y microspheres provided 30 to 60 days apart. Tumor response was assessed by the World Health Organization imaging criteria and showed partial response and stable disease in 95% of patients with follow-up imaging. The median survival in this cohort was 14.9 months. Both studies provide preliminary evidence that 90Y radioembolization is efficacious treatment for unresectable ICC.
The current study identified two factors associated with an improved survival. First, patients with an excellent performance status (ECOG performance status 0) had a better prognosis than patients whose daily activities were compromised by disease progression (ECOG performance status 1 and 2) (P\.001). Given the late clinical presentation of ICC, it is likely this finding simply reflects more advanced disease in patients with impaired performance status. Second, patients with mass-forming (peripheral) tumors had a superior median survival than patients with periductal-infiltrating (infiltrative) tumors (P = .004). The association of infiltrative tumors with a guarded prognosis has been extensively reported.20,26,27 This may be partially explained by the fact that infiltrative tumors represent a more biologically aggressive disease. Various studies have shown an association between infiltrative tumors and negative histopathologic prognostic factors including perineural invasion, vascular invasion, and lymph node metastases.26,28–30
Unfortunately, although the current study is the largest to date, the small patient sample does not allow identification of all important prognostic variables. For example, extrahepatic metastases would be expected to correlate with a poorer survival. In the current study, the median survival in patients with extrahepatic metastases was substantially lower than patients without extrahepatic metastases (16.3 vs. 4.8 months), but this was not statistically significant (P = .140). Clearly, a larger study is necessary to clearly identify the relevant prognostic variables.
The incidence of ICC has rapidly increased in developed countries worldwide. Shaib and colleagues showed a 165% increase in the age-adjusted incidence of ICC in the United States from .32 per 100,000 in 1975–1979 to .85 per 100,000 in 1995–1999.3. The authors argued that this was a true increase independent of improved detection or reclassification of other hepatobiliary malignancies, given that that the proportions of early stage disease, tumor size,and microscopic confirmation remained unchanged with time. Epidemiological studies from Europe, Japan, and Australia have reported similar findings.7 There are several hypotheses for the increased incidence, but the cause is currently unclear.1,7 Regardless, this factor has contributed to a renewed focus in the oncology community toward finding effective treatments for unresectable ICC.
Several treatment options have been explored for unresectable ICC. External-beam radiotherapy has shown minimal survival benefit.17,18 Results of liver transplantation for ICC are discouraging, with 5-year survival rates of 0% to 18%.1,5,16 Although radiofrequency ablation theoretically represents a cytoreductive therapy for ICC, there is a paucity of literature demonstrating any survival benefit. 15 Various systemic chemotherapy regimens have been assessed in small and nonrandomized studies, with generally poor and highly variable results.9–11,20,31 Regional chemotherapy in the form of TACE has been used in several small, uncontrolled, and heterogenous trials.12–14. The largest study, by Gusani and colleagues, reported on 42 patients treated with gemcitabine-based TACE.14 All patients had peripheral ICC and an ECOG performance status of 0 or 1. In the patients who were evaluated, tumor response according to RECIST showed stable disease and progressive disease in 57% and 43% of patients, respectively. The authors reported a median survival of 9.1 months from the time of first treatment. Another disadvantage of TACE is that a high proportion of patients develop postembolization syndrome and subsequently require medical management.12–14
In contrast to TACE, 90Y radioembolization has been shown to have a minimal embolic effect and an acceptable safety profile.20,32,33 Our data correlate with these findings even with the inclusion of the two patients who died within 1 month of treatment. Given that the current study showed a poor prognosis in patients with a poor performance status and advanced, infiltrative disease, it is likely that the risks of 90Y radioembolization in these patients outweigh any potential benefit. Conversely, 90Y radioembolization is likely to be safe and efficacious in patients with a good performance status and low disease burden. Therefore, our data suggest that judicious patient selection involving careful evaluation of a patient’s performance status and disease status can improve the safety profile and clinical efficacy of this treatment. In line with previous series, the most common treatment-related symptoms were fatigue (64%), transient abdominal pain (40%), and nausea (16%).20,32,33 One patient (4%) developed a duodenal ulcer, but this was self limiting. Five grade III biochemical toxicities were observed (two albumin, two bilirubin, one alkaline phosphatase). No other severe adverse events were observed.
Despite its rarity, ICC is a cancer of increasing incidence and importance. Our study provides preliminary evidence that 90Y radioembolization may be an efficacious and safe treatment option for unresectable ICC. In the absence of any other effective treatment for unresectable ICC and the growing global importance of this disease, the results of this study warrant further prospective investigation.
Abstract: Patients were assessed at 1 month and then at 3-month intervals after treatment. Clinical and biochemical toxicities were prospectively recorded. No patient was lost to follow-up.
Introduction
Recent epidemiologic studies have shown that although ICC remains rare in developed countries, its age adjusted incidence has increased rapidly from .32 per 100,000 in 1975–1979 to .85 per 100,000 in 1995–1999.1–3. These patients with unresectable disease have a poor prognosis, with a median survival of 6 to 12 months from the time of diagnosis.3
Traditional systemic chemotherapies have shown poor results in treating patients with advanced ICC.7,8 The use of gemcitabine as a single agent or in combination with other chemotherapeutic agents is also of uncertain benefit in patients with advanced biliary tract cancers.9–11. Regional chemotherapy in the form of ransarterial chemoembolization (TACE) has been used in several small, uncontrolled trials of ICC with median survival ranging widely from 9 to 21 months.12–14.There are also few data demonstrating survival benefit from radiofrequency ablation, liver transplantation, or external-beam radiotherapy 1,5,15–18
Clearly, the optimal management strategy for patients with unresectable ICC remains to be defined.
However, to date, only one small series, by Ibrahim and colleagues, has examined the safety and efficacy of this treatment for unresectable ICC.20 The results of this study were promising, with a median survival of 14.9 months for the entire cohort and acceptable level of clinical and biochemical toxicity. However, more data are clearly required to determine the value of this treatment. We report our experience with 90Y radioembolization for ICC to determine the safety and clinical efficacy of this treatment modality in a subgroup of patients with unresectable disease.
Materials and Methods
This prospective investigation was approved by a local institutional review board. Inclusion criteria were as follows: (1) histologically proven diagnosis of ICC; (2) unresectable tumor; (3) age 18 to 85 years; (4) ability to undergo angiography and selective visceral catheterization; (5) Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2; and (6) adequate hematology (granulocyte count C 1.5 9 109/l, platelets C 50 9 109/l), renal function (creatinine level B 2.0 mg/dl), and hepatic function (bilirubin level B 2.0 mg/dl). Patients were deemed to have unresectable tumor on the basis of multiple intrahepatic lesions, distant metastasis, peritoneal carcinomatosis, extensive vascular involvement, or severe liver cirrhosis in patients who required major liver resection. Patients with limited extrahepatic disease, which at the time of treatment was less clinically important than the liver disease (from a tumor burden and symptom standpoint) and not immediately life-threatening, were not excluded. Patients who had prior treatment for ICC were not excluded.
Liver function tests, complete blood count, coagulation profiles, and albumin and total bilirubin levels were obtained on the first day of 90Y treatment for all patients. All patients underwent a pretreatment triple-phase computed tomographic (CT) imaging scan of the liver.
All patients were treated on an outpatient basis and were discharged from 2 to 6 hours after the procedure. Patients were initially followed up after 1 month and then at 3-month intervals until death. Clinical toxicity, blood, and biochemical markers in addition to abdominal CT scans were obtained and assessed at each follow-up visit.
Study Methods: We prospectively collected and reviewed patient clinicopathologic and treatment-related data. The primary outcome of this study was overall survival and radiological hepatic tumor response. Radiologic hepatic tumor response was assessed by an experienced interventional radiologist (L.B.) in accordance with the Response Criteria in Solid Tumors (RECIST) guidelines by comparison of each follow up examination with the baseline examination.25 In brief, a complete response was defined as disappearance of lesions; partial response as a >30% decrease in the sum of the longest diameter of the index lesions; stable disease as a <30% decrease or <20% increase in the sum of the longest diameter of the index lesions; and progressive disease as a C 20% increase in the sum of the longest diameter of the index lesions or appearance of new lesions. Secondary outcomes included clinical and serologic toxicity and were assessed by the National Cancer Institute’s Common Toxicity Criteria for adverse events (version 3).
Statistical Analysis: Survival data from time of the first radioembolization procedure were assessed by the Kaplan-Meier method with the last date of contact or death used for censoring. Clinicopathologic and treatment-related variables were analyzed for an association with overall survival by the log rank test. Categorical variables were compared by v2 analysis of Fisher’s exact test where appropriate. All statistical analyses were performed by SPSS for Windows, version 17.5 (SPSS GmbH, Munich, Germany). A statistically significant difference was defined as P<.05
Results
Clinicopathologic and Treatment Related Data: Between January 2004 and May 2009, a total of 25 patients with ICC underwent 90Y radioembolization. Table 1 summarizes the patient characteristics.
Seven patients (28%) underwent treatment with systemic chemotherapy after 90Y radioembolization.
Overall Survival: No patient was lost to follow-up. Eighteen patients (72%) had died at the last time of follow-up.
Biochemical and Clinical Toxicity: Clinical toxicities included fatigue in 16 patients (64%); nonspecific self-limiting abdominal pain in 10 patients (40%); nausea in 4 patients (16%); anorexia in 4 patients (16%); vomiting in 2 patients (8%); and shortness of breath in 2 patients (8%)
Discussion
Only one previous study20 has examined the safety and efficacy of this treatment for unresectable ICC. We report herein what is to our knowledge the largest single-institution experience of 90Y radioembolization for unresectable ICC to further assess the value of this treatment.
The overall median survival from the time of diagnosis was 20.4 months, which is higher than the reported 6- to 12-month survival in patients who were palliatively managed.3 These results must not be viewed in isolation. It must be noted that 68% of these patients had disease progression on previous systemic chemotherapy, and 40% presented with widespread disease despite a previous liver resection. Ibrahim and colleagues reported the only other data on 90Y radioembolization for unresectable ICC.20 Twenty-four patients were treated with glass-based 90Y microspheres over a 4-year period. In contrast to the current study, patients with bilobar disease were treated with two separate administrations of 90Y microspheres provided 30 to 60 days apart. Tumor response was assessed by the World Health Organization imaging criteria and showed partial response and stable disease in 95% of patients with follow-up imaging. The median survival in this cohort was 14.9 months. Both studies provide preliminary evidence that 90Y radioembolization is efficacious treatment for unresectable ICC.
The current study identified two factors associated with an improved survival. First, patients with an excellent performance status (ECOG performance status 0) had a better prognosis than patients whose daily activities were compromised by disease progression (ECOG performance status 1 and 2) (P\.001). Given the late clinical presentation of ICC, it is likely this finding simply reflects more advanced disease in patients with impaired performance status. Second, patients with mass-forming (peripheral) tumors had a superior median survival than patients with periductal-infiltrating (infiltrative) tumors (P = .004). The association of infiltrative tumors with a guarded prognosis has been extensively reported.20,26,27 This may be partially explained by the fact that infiltrative tumors represent a more biologically aggressive disease. Various studies have shown an association between infiltrative tumors and negative histopathologic prognostic factors including perineural invasion, vascular invasion, and lymph node metastases.26,28–30
Unfortunately, although the current study is the largest to date, the small patient sample does not allow identification of all important prognostic variables. For example, extrahepatic metastases would be expected to correlate with a poorer survival. In the current study, the median survival in patients with extrahepatic metastases was substantially lower than patients without extrahepatic metastases (16.3 vs. 4.8 months), but this was not statistically significant (P = .140). Clearly, a larger study is necessary to clearly identify the relevant prognostic variables.
The incidence of ICC has rapidly increased in developed countries worldwide. Shaib and colleagues showed a 165% increase in the age-adjusted incidence of ICC in the United States from .32 per 100,000 in 1975–1979 to .85 per 100,000 in 1995–1999.3. The authors argued that this was a true increase independent of improved detection or reclassification of other hepatobiliary malignancies, given that that the proportions of early stage disease, tumor size,and microscopic confirmation remained unchanged with time. Epidemiological studies from Europe, Japan, and Australia have reported similar findings.7 There are several hypotheses for the increased incidence, but the cause is currently unclear.1,7 Regardless, this factor has contributed to a renewed focus in the oncology community toward finding effective treatments for unresectable ICC.
Several treatment options have been explored for unresectable ICC. External-beam radiotherapy has shown minimal survival benefit.17,18 Results of liver transplantation for ICC are discouraging, with 5-year survival rates of 0% to 18%.1,5,16 Although radiofrequency ablation theoretically represents a cytoreductive therapy for ICC, there is a paucity of literature demonstrating any survival benefit. 15 Various systemic chemotherapy regimens have been assessed in small and nonrandomized studies, with generally poor and highly variable results.9–11,20,31 Regional chemotherapy in the form of TACE has been used in several small, uncontrolled, and heterogenous trials.12–14. The largest study, by Gusani and colleagues, reported on 42 patients treated with gemcitabine-based TACE.14 All patients had peripheral ICC and an ECOG performance status of 0 or 1. In the patients who were evaluated, tumor response according to RECIST showed stable disease and progressive disease in 57% and 43% of patients, respectively. The authors reported a median survival of 9.1 months from the time of first treatment. Another disadvantage of TACE is that a high proportion of patients develop postembolization syndrome and subsequently require medical management.12–14
In contrast to TACE, 90Y radioembolization has been shown to have a minimal embolic effect and an acceptable safety profile.20,32,33 Our data correlate with these findings even with the inclusion of the two patients who died within 1 month of treatment. Given that the current study showed a poor prognosis in patients with a poor performance status and advanced, infiltrative disease, it is likely that the risks of 90Y radioembolization in these patients outweigh any potential benefit. Conversely, 90Y radioembolization is likely to be safe and efficacious in patients with a good performance status and low disease burden. Therefore, our data suggest that judicious patient selection involving careful evaluation of a patient’s performance status and disease status can improve the safety profile and clinical efficacy of this treatment. In line with previous series, the most common treatment-related symptoms were fatigue (64%), transient abdominal pain (40%), and nausea (16%).20,32,33 One patient (4%) developed a duodenal ulcer, but this was self limiting. Five grade III biochemical toxicities were observed (two albumin, two bilirubin, one alkaline phosphatase). No other severe adverse events were observed.
Despite its rarity, ICC is a cancer of increasing incidence and importance. Our study provides preliminary evidence that 90Y radioembolization may be an efficacious and safe treatment option for unresectable ICC. In the absence of any other effective treatment for unresectable ICC and the growing global importance of this disease, the results of this study warrant further prospective investigation.
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