Hoffmann RT, Paprottka PM, Schon A, et al. (2011) Transarterial Hepatic Yttrium-90 Radioembolization in Patients with Unresectable Intrahepatic Cholangiocarcinoma: Factors Associated with Prolonged Survival. Cardiovasc Intervent Radiol
Abstract: Radioembolization (RE) using yttrium-90 (90Y) microspheres is an accepted therapy for patients with hepatocellular-carcinoma or metastatic liver tumors. However, there are limited data on the value of RE in patients with ICC and few data on factors influencing prognosis.
Introduction
Intrahepatic cholangiocarcinoma (ICC) is a rare disease with approximately 3,000 cases diagnosed every year in the United States; increasing incidence and mortality rates have been reported [16, 24].In contrast to other gastrointestinal and liver malignancies, the molecular pathogenesis remains poorly understood [10]. There is no recognized standard palliative treatment for advanced or metastatic cholangiocarcinoma. Several chemotherapeutic regimens have been tested in mostly small studies in biliary tract cancers with limited success [6]. Recently, the first randomized phase III clinical study comparing gemcitabine versus gemcitabine plus cisplatin has been published [32]. In this study, combination treatment resulted in a median overall survival of 11.7 months compared with 8.1 months in the gemcitabine group. Locoregional therapies, such as radiofrequency ablation [31, 35] and transarterial chemoembolization [3, 9], have been proposed, but, in contrast to their role in hepatocellular cancer (HCC) [2], they are currently not regarded as a standard of care in locally advanced intrahepatic cholangiocarcinomas.
To date, two small series have examined the safety and efficacy of RE with 90Y [11, 27]. The median survival of patients with unresectable disease has been reported to be 6–12 months [28]. The median survival reported for RE was 14.9 and 9.3 months, respectively [11, 27]. The objective of our study was to identify patients who benefit most from RE. We report data on clinical and biochemical toxicities, treatment response, and patient outcomes.
Materials and Methods
Patient Selection: Thirty-three consecutive patients with unresectable cholangiocellular carcinoma or chemotherapy-refractory liver metastases from cholangiocellular carcinoma who were treated between April 2007 and January 2010 with yttrium-90 resin-microspheres were retrospectively analyzed.
Although strict inclusion criteria were not defined, the study population was comprised by patients with the following characteristics, as determined to the extent possible for a retrospective study:
Discussion
Long-term survival in patients with ICC is poor, even after surgical resection [23].Due to the fact that a whole-liver dose of[40 Gy often is associated with severe side effects, including life-threatening radiation-induced liver disease (RILD) [4] EBRT is restricted to those patients with a small and focal tumor burden, where a sufficient volume of the liver remains untreated. Despite this constraint, there are some case series and studies reporting a median survival between 10 and 12 months [7,33]. More recent developments, such as single-session radiosurgery (24 Gy) using robotic image-guided real-time tumor tracking for selected patients with a small number and size of colorectal liver metastases have reported encouraging results [29, 30].
Several chemotherapeutic regimens mostly based on 5-fluorouracil or gemcitabine alone or in combination with other agents have been tested in mostly small studies in biliary tract cancers with limited success [6].Recently, a randomized phase III clinical study was published that compared gemcitabine versus gemcitabine plus cisplatin in 410 patients with locally advanced or metastatic cholangiocarcinoma, gallbladder cancer, or ampullary cancer [32]. In this study, the gemcitabine–cisplatin combination resulted in a significantly prolonged median overall survival of 11.7 months compared with 8.1 months in the gemcitabine group. Our very encouraging outcome results for patients without previous chemotherapy (median survival, 22.7 months) are highly indicative for the prominent efficiency of 90Y treatment in this cancer type (despite the retrospective caveats), because patient selection should not have been stricter than in the chemotherapy study.
To date, the published results of RFA include only case reports or small case series, and therefore lacking the proof of a significant improvement of survival compared with treated patients [22].
During the past few years, there have been a number of case series published on TACE in patients with ICC [3, 8, 9]. However, these studies differ significantly in quality; only one study reported median survival (13.8 months) posttreatment [8]. Other studies reported only mean survival or survival from initial diagnosis but not from the first TACE procedure.
Although radioembolization with 90Y microspheres is a relatively novel treatment for otherwise untreatable tumors or metastases of the liver, there is now a large body of evidence reporting very encouraging results in treatmentrefractory patients with liver metastases of different tumor types [14, 17, 20, 21] and in patients with HCC, as a treatment option instead of TACE or in patients who are not ideally suited to TACE [12, 26].
For patients with ICC, there are few data on radioembolization, and there is only one prospective and one retrospective study published at present [11, 27] reporting on smaller numbers of patients. Therefore, we report what is to the best of our knowledge the largest single institution experience of RE of ICC and we tried to evaluate prognostic factors for the success of the therapy. In our retrospective analysis of 33 patients suffering from ICC treated with 90Y-radioembolization, we were able to show that RE enables a formidable outcome compared with published chemotherapy data in terms of local tumor control rate, time to progression, and overall survival in patients who are not eligible for surgery at a very good toxicity rate. Our data showed partial response or stable disease in 85% of patients, and the median survival from the first treatment was 10 months and from time of diagnosis it was 30.2 months, which is much higher than historical data reporting 6–12 months for patients with best supportive care only [28]. Our data should not be seen in isolation because 79% of patients had previous chemotherapy, 37% of patients had surgery, and 18% had RFA, TACE, or EBRM before radioembolization. The results of our study suggest a longer survival in the chemotherapy naı¨ve subgroup (14.2 months) than in the group of patients previously treated with chemotherapy (11 months) and in the group of patients not having undergone previous surgery (11.9 vs. 9.6 months). This finding supports data of one of the previous SIRT studies, where chemotherapy-naı¨ve patients survived significantly longer after 90Y-radioembolization [11]. However, patients with previous chemotherapy or surgery had a longer time span since first diagnosis in our study than patients with no previous treatment had and therefore these results seems not to be indicative for better survival for this patient cohort.
It is of general importance in the planning of oncologic therapies to identify those patients likely to have a less favorable outcome, to avoid treating patients with an expensive therapy with the potential risk of harming them. Our study identified three factors associated with a better survival. Patients with an excellent performance status (ECOG performance status 0) had a significantly better prognosis than patients with an impaired performance status, depending whether they had an ECOG 1 or ECOG 2 performance status. This result is in good correlation with the results published by Saxena et al. [27], which described a median survival of 18.3 months for ECOG 0 and 2.4 months for ECOG 1 or 2. Beside the performance status, tumor burden and response after 3 months was a reliable prognostic factor in our study, showing a significant better survival in patients with stable disease or partial response, whereas patients with progressive disease had no better outcome than patients who underwent best supportive care. Other factors included in our analysis, such as patient age, gender, or tumor-to-liver ratio, did not have an impact on patient outcome. However, it needs to be taken into account that due to the small patient cohort our analyses concerning prognostic factors are limited.
Our findings substantiate preliminary reports that 90Yradioembolization is an efficacious and safe treatment for unresectable ICC. Unfortunately, even though our study includes the highest number of patients available at the moment, the relatively small number of patients does not allow identification of all the prognostic factors that influenced patient outcome. In addition, the questions of how far extrahepatic metastases influence survival, whether patients benefit from radioembolization as a first-line therapy, or which tumor markers can predict outcome need to be addressed by larger studies in the future. Therefore, a prospective and randomized study and pooling of the data from multiple centers as a combined retrospective analysis of multicenter data is mandatory.
Abstract: Radioembolization (RE) using yttrium-90 (90Y) microspheres is an accepted therapy for patients with hepatocellular-carcinoma or metastatic liver tumors. However, there are limited data on the value of RE in patients with ICC and few data on factors influencing prognosis.
Introduction
Intrahepatic cholangiocarcinoma (ICC) is a rare disease with approximately 3,000 cases diagnosed every year in the United States; increasing incidence and mortality rates have been reported [16, 24].In contrast to other gastrointestinal and liver malignancies, the molecular pathogenesis remains poorly understood [10]. There is no recognized standard palliative treatment for advanced or metastatic cholangiocarcinoma. Several chemotherapeutic regimens have been tested in mostly small studies in biliary tract cancers with limited success [6]. Recently, the first randomized phase III clinical study comparing gemcitabine versus gemcitabine plus cisplatin has been published [32]. In this study, combination treatment resulted in a median overall survival of 11.7 months compared with 8.1 months in the gemcitabine group. Locoregional therapies, such as radiofrequency ablation [31, 35] and transarterial chemoembolization [3, 9], have been proposed, but, in contrast to their role in hepatocellular cancer (HCC) [2], they are currently not regarded as a standard of care in locally advanced intrahepatic cholangiocarcinomas.
To date, two small series have examined the safety and efficacy of RE with 90Y [11, 27]. The median survival of patients with unresectable disease has been reported to be 6–12 months [28]. The median survival reported for RE was 14.9 and 9.3 months, respectively [11, 27]. The objective of our study was to identify patients who benefit most from RE. We report data on clinical and biochemical toxicities, treatment response, and patient outcomes.
Materials and Methods
Patient Selection: Thirty-three consecutive patients with unresectable cholangiocellular carcinoma or chemotherapy-refractory liver metastases from cholangiocellular carcinoma who were treated between April 2007 and January 2010 with yttrium-90 resin-microspheres were retrospectively analyzed.
Although strict inclusion criteria were not defined, the study population was comprised by patients with the following characteristics, as determined to the extent possible for a retrospective study:
- Nonresectable cholangiocellular carcinoma, as determined by experienced liver surgeons in an interdisciplinary tumor board.
- Chemotherapy-refractory liver metastasis from cholangiocellular carcinoma.
- Absence of significant extrahepatic disease. Only patients with stable intraabdominal lymph nodes were included, and progression of lymph nodes or other kind of metastases was considered significant.
- Failure to respond to other types of medical, surgical, or local ablative treatment modalities.
- Patent portal vein: patients with an occlusion of any portion of the portal vein were excluded.
- Adequate biochemical and hematological function (total bilirubin\2 mg/dL, sufficient coagulation, albumin, and pseudocholinesterase within normal range (according to common criteria used).
- <20% arteriovenous shunting to the lung vascular bed.
- Tumor burden\50%; volume of the liver metastases divided by total liver volume (Software OncoTreat , MeVis ).
- No severe comorbidities (e.g., chronic obstructive or chronic restrictive pulmonary disease, including dyspnea at rest from any cause, heart failure, malignant hypertension).
- Written, informed consent.
Radiation Source: In this study, only 90Y resin-microspheres (SIRSpheres , Sirtex Medical Limited, LaneCove, Australia) were used. The typical prescribed activity of 90Y resinmicrospheres is 1.5–2 GBq, which contain approximately 35 million microspheres (range, 20–50 million), each microsphere containing 50 Bq activity.
Radioembolization procedure: Arteriography for 90Y-microsphere therapy planning is described elsewhere in detail [13, 15, 25]
Follow-up: Response, Toxicity, Survival
Most recent history was taken for side effects during follow- up
Statistical Analysis: Continuous survival data are displayed as mean ± standard deviation and as proportions for binary data.
Results
The mean period from the date of disease-specific diagnosis and radioembolization was 21.2 months (median 20.2 months/SD 18.8 months).No patient had to abandon treatment and no reduction in the calculated radioactivity due to extensive shunting of the microspheres to the lung was observed.Table 1. Table 3. Fig1. Contrast-enhanced axial CT and MRI images were available in all patients.
The mean follow-up time was 13.5 months (median, 10 months; range, 3.1–44 months), with 15 of 33 patients still alive at the end of this study. There were no significant differences in survival or TTP according to previous chemotherapy and surgery Table 5. No radiation-induced liver disease was noted.
Discussion
Long-term survival in patients with ICC is poor, even after surgical resection [23].Due to the fact that a whole-liver dose of[40 Gy often is associated with severe side effects, including life-threatening radiation-induced liver disease (RILD) [4] EBRT is restricted to those patients with a small and focal tumor burden, where a sufficient volume of the liver remains untreated. Despite this constraint, there are some case series and studies reporting a median survival between 10 and 12 months [7,33]. More recent developments, such as single-session radiosurgery (24 Gy) using robotic image-guided real-time tumor tracking for selected patients with a small number and size of colorectal liver metastases have reported encouraging results [29, 30].
Several chemotherapeutic regimens mostly based on 5-fluorouracil or gemcitabine alone or in combination with other agents have been tested in mostly small studies in biliary tract cancers with limited success [6].Recently, a randomized phase III clinical study was published that compared gemcitabine versus gemcitabine plus cisplatin in 410 patients with locally advanced or metastatic cholangiocarcinoma, gallbladder cancer, or ampullary cancer [32]. In this study, the gemcitabine–cisplatin combination resulted in a significantly prolonged median overall survival of 11.7 months compared with 8.1 months in the gemcitabine group. Our very encouraging outcome results for patients without previous chemotherapy (median survival, 22.7 months) are highly indicative for the prominent efficiency of 90Y treatment in this cancer type (despite the retrospective caveats), because patient selection should not have been stricter than in the chemotherapy study.
To date, the published results of RFA include only case reports or small case series, and therefore lacking the proof of a significant improvement of survival compared with treated patients [22].
During the past few years, there have been a number of case series published on TACE in patients with ICC [3, 8, 9]. However, these studies differ significantly in quality; only one study reported median survival (13.8 months) posttreatment [8]. Other studies reported only mean survival or survival from initial diagnosis but not from the first TACE procedure.
Although radioembolization with 90Y microspheres is a relatively novel treatment for otherwise untreatable tumors or metastases of the liver, there is now a large body of evidence reporting very encouraging results in treatmentrefractory patients with liver metastases of different tumor types [14, 17, 20, 21] and in patients with HCC, as a treatment option instead of TACE or in patients who are not ideally suited to TACE [12, 26].
For patients with ICC, there are few data on radioembolization, and there is only one prospective and one retrospective study published at present [11, 27] reporting on smaller numbers of patients. Therefore, we report what is to the best of our knowledge the largest single institution experience of RE of ICC and we tried to evaluate prognostic factors for the success of the therapy. In our retrospective analysis of 33 patients suffering from ICC treated with 90Y-radioembolization, we were able to show that RE enables a formidable outcome compared with published chemotherapy data in terms of local tumor control rate, time to progression, and overall survival in patients who are not eligible for surgery at a very good toxicity rate. Our data showed partial response or stable disease in 85% of patients, and the median survival from the first treatment was 10 months and from time of diagnosis it was 30.2 months, which is much higher than historical data reporting 6–12 months for patients with best supportive care only [28]. Our data should not be seen in isolation because 79% of patients had previous chemotherapy, 37% of patients had surgery, and 18% had RFA, TACE, or EBRM before radioembolization. The results of our study suggest a longer survival in the chemotherapy naı¨ve subgroup (14.2 months) than in the group of patients previously treated with chemotherapy (11 months) and in the group of patients not having undergone previous surgery (11.9 vs. 9.6 months). This finding supports data of one of the previous SIRT studies, where chemotherapy-naı¨ve patients survived significantly longer after 90Y-radioembolization [11]. However, patients with previous chemotherapy or surgery had a longer time span since first diagnosis in our study than patients with no previous treatment had and therefore these results seems not to be indicative for better survival for this patient cohort.
It is of general importance in the planning of oncologic therapies to identify those patients likely to have a less favorable outcome, to avoid treating patients with an expensive therapy with the potential risk of harming them. Our study identified three factors associated with a better survival. Patients with an excellent performance status (ECOG performance status 0) had a significantly better prognosis than patients with an impaired performance status, depending whether they had an ECOG 1 or ECOG 2 performance status. This result is in good correlation with the results published by Saxena et al. [27], which described a median survival of 18.3 months for ECOG 0 and 2.4 months for ECOG 1 or 2. Beside the performance status, tumor burden and response after 3 months was a reliable prognostic factor in our study, showing a significant better survival in patients with stable disease or partial response, whereas patients with progressive disease had no better outcome than patients who underwent best supportive care. Other factors included in our analysis, such as patient age, gender, or tumor-to-liver ratio, did not have an impact on patient outcome. However, it needs to be taken into account that due to the small patient cohort our analyses concerning prognostic factors are limited.
Our findings substantiate preliminary reports that 90Yradioembolization is an efficacious and safe treatment for unresectable ICC. Unfortunately, even though our study includes the highest number of patients available at the moment, the relatively small number of patients does not allow identification of all the prognostic factors that influenced patient outcome. In addition, the questions of how far extrahepatic metastases influence survival, whether patients benefit from radioembolization as a first-line therapy, or which tumor markers can predict outcome need to be addressed by larger studies in the future. Therefore, a prospective and randomized study and pooling of the data from multiple centers as a combined retrospective analysis of multicenter data is mandatory.
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