Ibrahim SM, Mulcahy MF, Lewandowski RJ, et al. (2008) Treatment of unresectable cholangiocarcinoma using yttrium-90 microspheres: results from a pilot study. Cancer, 113(8):2119-2128
Introduction
Traditional systemic chemotherapies have been relatively unsuccessful in treating patients with advanced disease.5,6. The results of recent phase 2 studies using gemcitabine as a single agent only rarely improved survival in advanced biliary tract cancers.6
Materials & Methods
Patients: Twenty-four patients were treated at a single institution with 90Y radioembolization therapy. Our Institutional Review Board approved the study protocol, and all patients signed informed consent allowing the use of their data. Patients were referred for treatment by medical oncology and/or were discussed at our multidisciplinary tumor board and were deemed acceptable candidates for this procedure. Patient selection criteria included: 1) histologically proven diagnosis of ICC; 2) unresectable tumor; 3) an Eastern Cooperation Oncology Group (ECOG) performance status of 0, 1, or 2; 4) adequate hematology, including an absolute neutrophil count >1.5 3 109/L, a platelet count >50 3 109/L, renal function with creatinine level <2.0 mg/dL, and adequate liver function with bilirubin <2.0 mg/dL; and 5) able to undergo angiography and selective visceral catheterization. Patients were excluded if 1) flow to the gastrointestinal tract was not correctable by coil embolization on visceral angiography or 2) estimated radiation doses to the lungs exceeded 30 Gray (Gy) in a single administration or 50 Gy over multiple administrations.
Yttrium-90 Device: Investigators are directed to published US Food and Drug Administration (FDA) guidelines on the use of this device in patients that deviate from the approved indication.16
Treatment Protocol: 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. 90Y treatment was administered in a lobar or segmental fashion.Patients with bilobar disease were treated on the contralateral side 30 to 60 days after the first treatment. Patients were evaluated at 1 month, 3 months, and every 3 months after treatment. At each follow-up visit, patients were assessed for clinical and biochemical toxicities. Imaging response was assessed using computed tomography (CT) or magnetic resonance imaging (MRI).
Data collection & Statisitcal Analysis: All medical, laboratory, clinical, and imaging data were acquired prospectively. Biochemical toxicities that occurred any time after treatment, without time cutoff, were reported.The primary endpoints of this study were safety and toxicity. Secondary endpoints included tumor response and preliminary overall survival. Table I
Results
Baseline Patients Characteristics: Table II
Dosimetry: All patients were treated on an outpatient basis and were discharged from 2 to 6 hours after the procedure. The study population underwent a total of 48 90Y treatments in which 9 patients received 1 treatment, 9 patients received 2 treatments, and 6 patients received 3 treatments.
Biochemical and Clinical Toxicity after Treatment: Biochemical follow-up was available for all patients
Tumor Response and Imaging Findings: An overall objective tumor response (any decrease in size) was observed in 19 patients (86%): The mean tumor reduction was 35%.Examples of pretreatment and post treatment CT and positron emission tomography studies.
Survival: At the time of this writing, 11 patients (46%) remained alive, and 13 patients (54%) had succumbed to their disease.The median follow-up was 17.7 months. The median survival for patients with previous exposure to systemic chemotherapy (n=7) versus patients who were chemotherapy-naive (n=17) before treatment was 4.4 months and 31.8 months, respectively (P=0.0274)
Discussion
ICC is the second most common primary liver malignancy. It accounts for 10% to 20% of all primary liver tumors.22 The age-adjusted incidence rate for ICC in the US is estimated at 0.85 per 100,000 population.23 Of the anatomically distinct cholangiocarcinomas, therapies for ICC have been the least reported in literature.Long-term survival in patients with ICC is poor, even after they undergo operative resection.28-30
In general, the vast majority of patients present with unresectable disease, and surgical resection is not an option. Because a global consensus does not exist for treating advanced ICC, various palliative therapies have attempted to improve the survival and quality of life. These therapies include external beam radiation therapy (EBRT), systemic chemotherapy, radiofrequency ablation (RFA), and TACE.
Despite this drawback, several small studies investigating the utility of radiotherapy for the treatment of locally advanced cholangiocarcinoma have reported median survival from 10 months to 12 months.32,33 In a prospective study, Pitt et al failed to demonstrate any survival benefit in patients who received postoperative radiation.34
Given the absence of large phase 3 clinical trials, combined with the relatively ineffective drugs currently available, no standard-of-care chemotherapy exists for the treatment of ICC.13Several antineoplastic agents have been studied in small, uncontrolled studies with generally poor results. Early studies comparing 5- Fluorouracil either alone or in combination with other agents produced objective response rates from 0% to 40% and a median survival from 2 months to 12 months.35 In 2002, gemcitabine received FDA approval for treating cholangiocarcinoma based on preliminary phase 2 investigations. The results of several studies combining gemcitabine with other agents produced response rates from 9% to 37% and an overall median survival from 5 months to 15 months.36-39 Considering the limited responses and survival benefits achieved by chemotherapeutic agents, minimally invasive liver-directed therapies such as TACE and RFA have been reported in treating ICC.
RFA theoretically represents another possible cytoreductive therapy for focal cholangiocarcinoma. It is currently a treatment option for patients with small hepatic tumors who otherwise are ineligible for surgical cure. This modality recently was reported in treating unresectable ICC.The limited studies available for treating ICC with RFA, coupled with the lack of reported survival benefits, makes comparison with other locoregional therapies difficult.
Although it has been demonstrated that TACE reduces systemic toxicity and increases the local effects of the chemotherapeutic agent in liver cancer, the use of differing chemotherapeutic and embolic agents between series limits the ability to make direct comparisons. Furthermore, Herber et al reported mean survival rather than median survival, whereas Burger et al used the date of diagnosis rather than date of first treatment when measuring outcome. This makes interpretation and comparison between studies difficult. In addition, the vast majority of patients in each of the aforementioned TACE studies were managed medically for the commonly associated postembolization syndrome, which consists of right upper quadrant pain, nausea, and vomiting. This is a distinctly different entity than the postradioembolization syndrome observed after 90Y treatments. After radioembolization, patients commonly complain of fatigue and transient, vague abdominal pain that does not require medical intervention. All patients are observed for 2 to 6 hours and are discharged the day of treatment.
Under a phase 2 paradigm, 90Y radioembolization has demonstrated significant promise in treating primary and metastatic cancers of the liver. To our knowledge, however, there has been no study to date assessing this modality in the treatment of ICC. Twenty-nine percent of these patients had undergone previous systemic chemotherapy and were referred for radioembolization after failure of first and second-line chemotherapies. Hence, therapy was offered both to patients with rapidly deteriorating ECOG status as a palliative procedure and to those with advanced disease as primary therapy. Unlike the intra-arterial therapies that induce tumor ischemia by significantly occluding hepatic arteries, 90Y radioembolization is minimally embolic and has demonstrated safety and efficacy in patients with PVT. We observed that the safety profile of 90Y therapy was acceptable. The most common treatment-related symptoms in this cohort were fatigue (75%).42,43 Other symptoms included transient abdominal pain (42%), anorexia (8%), vomiting (8%), and nausea (4%)
To fully elucidate the survival benefits derived from any given liver-directed therapy, parameters of importance include 1) ECOG performance status, 2) failure on systemic chemotherapy, 3) morphologic variant of ICC, and 4) PVT. In addition, investigators should adhere to survival reporting standards: Median survival should be reported rather than mean survival (unless normally distributed data), and survival should be reported from the date of first treatment rather than from the date of diagnosis.44. Without standardization, it becomes difficult to draw firm conclusions regarding outcomes as they relate to other therapies, including surgery, ablation, TACE, and chemotherapy.
The current study had several important limitations. First, posttreatment imaging studies were not available for 2 patients as a result of 2 30-day mortalities. Second, this study represents the experience from a single institution and requires independent verification. Third, the small cohort of patients, combined with the rarity of this disease, makes drawing generalizations or absolute conclusions from this or any other small-scale study difficult. Fourth, survival data presented herein are preliminary. Further confirmatory trials with an appropriate control arm are warranted to determine the efficacy of this procedure.
90Y radioembolization appears to be a safe and effective therapeutic option for selected patients with unresectable ICC. In this report, we present 90Y therapy-associated toxicities, tumor response, and preliminary survival. The survival benefits are highly dependent on baseline characteristics, such as the presence or absence of cancer-related symptoms, morphologic tumor type, and the presence or absence of PVT. Our study produced favorable outcomes in patients without cancer-related symptoms, without PVT, and with peripheral tumor patterns. Although our results are encouraging, controlled investigations with larger trials are warranted.
Questions/ Thoughts
Introduction
Traditional systemic chemotherapies have been relatively unsuccessful in treating patients with advanced disease.5,6. The results of recent phase 2 studies using gemcitabine as a single agent only rarely improved survival in advanced biliary tract cancers.6
Materials & Methods
Patients: Twenty-four patients were treated at a single institution with 90Y radioembolization therapy. Our Institutional Review Board approved the study protocol, and all patients signed informed consent allowing the use of their data. Patients were referred for treatment by medical oncology and/or were discussed at our multidisciplinary tumor board and were deemed acceptable candidates for this procedure. Patient selection criteria included: 1) histologically proven diagnosis of ICC; 2) unresectable tumor; 3) an Eastern Cooperation Oncology Group (ECOG) performance status of 0, 1, or 2; 4) adequate hematology, including an absolute neutrophil count >1.5 3 109/L, a platelet count >50 3 109/L, renal function with creatinine level <2.0 mg/dL, and adequate liver function with bilirubin <2.0 mg/dL; and 5) able to undergo angiography and selective visceral catheterization. Patients were excluded if 1) flow to the gastrointestinal tract was not correctable by coil embolization on visceral angiography or 2) estimated radiation doses to the lungs exceeded 30 Gray (Gy) in a single administration or 50 Gy over multiple administrations.
Yttrium-90 Device: Investigators are directed to published US Food and Drug Administration (FDA) guidelines on the use of this device in patients that deviate from the approved indication.16
Treatment Protocol: 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. 90Y treatment was administered in a lobar or segmental fashion.Patients with bilobar disease were treated on the contralateral side 30 to 60 days after the first treatment. Patients were evaluated at 1 month, 3 months, and every 3 months after treatment. At each follow-up visit, patients were assessed for clinical and biochemical toxicities. Imaging response was assessed using computed tomography (CT) or magnetic resonance imaging (MRI).
Data collection & Statisitcal Analysis: All medical, laboratory, clinical, and imaging data were acquired prospectively. Biochemical toxicities that occurred any time after treatment, without time cutoff, were reported.The primary endpoints of this study were safety and toxicity. Secondary endpoints included tumor response and preliminary overall survival. Table I
Results
Baseline Patients Characteristics: Table II
Dosimetry: All patients were treated on an outpatient basis and were discharged from 2 to 6 hours after the procedure. The study population underwent a total of 48 90Y treatments in which 9 patients received 1 treatment, 9 patients received 2 treatments, and 6 patients received 3 treatments.
Biochemical and Clinical Toxicity after Treatment: Biochemical follow-up was available for all patients
Tumor Response and Imaging Findings: An overall objective tumor response (any decrease in size) was observed in 19 patients (86%): The mean tumor reduction was 35%.Examples of pretreatment and post treatment CT and positron emission tomography studies.
Survival: At the time of this writing, 11 patients (46%) remained alive, and 13 patients (54%) had succumbed to their disease.The median follow-up was 17.7 months. The median survival for patients with previous exposure to systemic chemotherapy (n=7) versus patients who were chemotherapy-naive (n=17) before treatment was 4.4 months and 31.8 months, respectively (P=0.0274)
Discussion
ICC is the second most common primary liver malignancy. It accounts for 10% to 20% of all primary liver tumors.22 The age-adjusted incidence rate for ICC in the US is estimated at 0.85 per 100,000 population.23 Of the anatomically distinct cholangiocarcinomas, therapies for ICC have been the least reported in literature.Long-term survival in patients with ICC is poor, even after they undergo operative resection.28-30
In general, the vast majority of patients present with unresectable disease, and surgical resection is not an option. Because a global consensus does not exist for treating advanced ICC, various palliative therapies have attempted to improve the survival and quality of life. These therapies include external beam radiation therapy (EBRT), systemic chemotherapy, radiofrequency ablation (RFA), and TACE.
Despite this drawback, several small studies investigating the utility of radiotherapy for the treatment of locally advanced cholangiocarcinoma have reported median survival from 10 months to 12 months.32,33 In a prospective study, Pitt et al failed to demonstrate any survival benefit in patients who received postoperative radiation.34
Given the absence of large phase 3 clinical trials, combined with the relatively ineffective drugs currently available, no standard-of-care chemotherapy exists for the treatment of ICC.13Several antineoplastic agents have been studied in small, uncontrolled studies with generally poor results. Early studies comparing 5- Fluorouracil either alone or in combination with other agents produced objective response rates from 0% to 40% and a median survival from 2 months to 12 months.35 In 2002, gemcitabine received FDA approval for treating cholangiocarcinoma based on preliminary phase 2 investigations. The results of several studies combining gemcitabine with other agents produced response rates from 9% to 37% and an overall median survival from 5 months to 15 months.36-39 Considering the limited responses and survival benefits achieved by chemotherapeutic agents, minimally invasive liver-directed therapies such as TACE and RFA have been reported in treating ICC.
RFA theoretically represents another possible cytoreductive therapy for focal cholangiocarcinoma. It is currently a treatment option for patients with small hepatic tumors who otherwise are ineligible for surgical cure. This modality recently was reported in treating unresectable ICC.The limited studies available for treating ICC with RFA, coupled with the lack of reported survival benefits, makes comparison with other locoregional therapies difficult.
Although it has been demonstrated that TACE reduces systemic toxicity and increases the local effects of the chemotherapeutic agent in liver cancer, the use of differing chemotherapeutic and embolic agents between series limits the ability to make direct comparisons. Furthermore, Herber et al reported mean survival rather than median survival, whereas Burger et al used the date of diagnosis rather than date of first treatment when measuring outcome. This makes interpretation and comparison between studies difficult. In addition, the vast majority of patients in each of the aforementioned TACE studies were managed medically for the commonly associated postembolization syndrome, which consists of right upper quadrant pain, nausea, and vomiting. This is a distinctly different entity than the postradioembolization syndrome observed after 90Y treatments. After radioembolization, patients commonly complain of fatigue and transient, vague abdominal pain that does not require medical intervention. All patients are observed for 2 to 6 hours and are discharged the day of treatment.
Under a phase 2 paradigm, 90Y radioembolization has demonstrated significant promise in treating primary and metastatic cancers of the liver. To our knowledge, however, there has been no study to date assessing this modality in the treatment of ICC. Twenty-nine percent of these patients had undergone previous systemic chemotherapy and were referred for radioembolization after failure of first and second-line chemotherapies. Hence, therapy was offered both to patients with rapidly deteriorating ECOG status as a palliative procedure and to those with advanced disease as primary therapy. Unlike the intra-arterial therapies that induce tumor ischemia by significantly occluding hepatic arteries, 90Y radioembolization is minimally embolic and has demonstrated safety and efficacy in patients with PVT. We observed that the safety profile of 90Y therapy was acceptable. The most common treatment-related symptoms in this cohort were fatigue (75%).42,43 Other symptoms included transient abdominal pain (42%), anorexia (8%), vomiting (8%), and nausea (4%)
To fully elucidate the survival benefits derived from any given liver-directed therapy, parameters of importance include 1) ECOG performance status, 2) failure on systemic chemotherapy, 3) morphologic variant of ICC, and 4) PVT. In addition, investigators should adhere to survival reporting standards: Median survival should be reported rather than mean survival (unless normally distributed data), and survival should be reported from the date of first treatment rather than from the date of diagnosis.44. Without standardization, it becomes difficult to draw firm conclusions regarding outcomes as they relate to other therapies, including surgery, ablation, TACE, and chemotherapy.
The current study had several important limitations. First, posttreatment imaging studies were not available for 2 patients as a result of 2 30-day mortalities. Second, this study represents the experience from a single institution and requires independent verification. Third, the small cohort of patients, combined with the rarity of this disease, makes drawing generalizations or absolute conclusions from this or any other small-scale study difficult. Fourth, survival data presented herein are preliminary. Further confirmatory trials with an appropriate control arm are warranted to determine the efficacy of this procedure.
90Y radioembolization appears to be a safe and effective therapeutic option for selected patients with unresectable ICC. In this report, we present 90Y therapy-associated toxicities, tumor response, and preliminary survival. The survival benefits are highly dependent on baseline characteristics, such as the presence or absence of cancer-related symptoms, morphologic tumor type, and the presence or absence of PVT. Our study produced favorable outcomes in patients without cancer-related symptoms, without PVT, and with peripheral tumor patterns. Although our results are encouraging, controlled investigations with larger trials are warranted.
Questions/ Thoughts
No comments:
Post a Comment