Cardiovasc Intervent Radiol (2007) 30:1156–1165 DOI 10.1007/s00270-007-9032-7
Transarterial Chemoembolization (TACE) for Inoperable Intrahepatic Cholangiocarcinoma S. Herber Æ G. Otto Æ J. Schneider Æ N. Manzl Æ I. Kummer Æ S. Kanzler Æ A. Schuchmann Æ J. Thies Æ C. Du¨ber Æ M. Pitton
Received: 27 March 2007 / Revised: 27 March 2007 / Accepted: 28 March 2007 / Published online: 17 May 2007 Springer Science+Business Media, LLC 2007
Abstract The aim of this retrospective study was to determine the safety and efficacy of chemoembolization (TACE) as palliative treatment for patients with unresectable intrahepatic cholangiocarcinoma (CCA) and to compare the results with those in the literature. Fifteen patients with histology-proven CCA (5 men, 10 women) had received palliative treatment with TACE over a 6year period. The treatment protocol comprised repeated TACE at a minimum of 8-week intervals. TACE was performed with a mixture of 10 ml Lipiodol and 10 mg mitomycin C injected into the tumor-supplying vessels. Follow-up investigations after 8–10 weeks comprised contrast-enhanced multislice spiral CT and laboratory control. Statistical evaluation included survival analysis using the Kaplan-Meier method. During the investigation period 58 TACEs (3.9 ± 3.8; 1–15) were performed in 15 patients. Mean tumor size was 10.8 ± 4.6 cm (range, 2.0–18.0 cm). Unifocal tumor disease was diagnosed in eight patients, and multifocal disease in seven. Mean survival was 21.1 months (95% CI, 9.4–32.5 months). At the end of the investigation period 3 patients are still alive, and 12 patients have died. The 1-, 2-, and 3-year survival rate was 51.3%, 27.5%, and 27.5% respectively.
S. Herber (&) J. Schneider N. Manzl I. Kummer C. Du¨ber M. Pitton Department of Diagnostic and Interventional Radiology, University of Mainz, Langenbeckstr. 1, 55131 Mainz, Germany e-mail:
[email protected] G. Otto J. Thies Department of Hepatobiliary Surgery, University of Mainz, Mainz, Germany S. Kanzler A. Schuchmann I. Medical Clinic, University of Mainz, Mainz, Germany
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According to RECIST criteria interim best response to therapy was stable disease in 9 of 15 patients, a partial response in 1 of 15 patients, and tumor progression in 4 of 15 patients. No deaths and no acute liver failure occurred under TACE therapy. Major complications were observed in two patients, comprising anaphylactic shock owing to contrast medium administration in one and gastric ulceration due to lipiodol displacement in the second patient. These results demonstrate that TACE is a safe procedure with a moderate number of complications for patients suffering from inoperable CCA. According to recently published data on i.v. chemotherapy we suggest that TACE might be able to prolong survival in selected patients who would succumb under other palliative treatment modalities. Keywords TACE Chemoembolization Cholangiocarcinoma Survival Kaplan-Meier Mitomycin C Lipiodol
Introduction Cholangiocarcinoma (CCA) is an uncommon neoplasm with a poor prognosis. The 5-year survival rate, including resected patients, is actually between 5% and 18% [1–3]. The tumor, first described by Durand-Fardel in 1840, arises from biliary epithelial cells, and more than 90% of CCAs are adenocarcinomas. Almost 60%–70% of CCAs occur at the hepatic duct bifurcation, and the remainder occur either in the distal part of the common bile duct (20%30%) or, very rarely, within the liver (5%–15%) [1–3]. Whereas the incidence of extrahepatic tumors is declining, several studies have shown an increasing incidence and mortality for intrahepatic CCA. Its incidence is estimated to be 1–2
S. Herber et al.: TACE for Inoperable Intrahepatic Cholangiocarcinoma
cases per 100,000, with a peak age over 65 years and a slight male preponderance [2]. Owing to the usually late diagnosis, untreated CCA represents a rapidly fatal process. Even if surgical resection is the only potentially curative treatment, disease is already unresectable at presentation in the majority of patients [2, 4]. Only a minority of patients with extrahepatic proximal or distal CCA may be candidates for liver transplantation, whereas patients with intrahepatic CCAs are commonly not eligible [5]. Those patients frequently show multifocal tumor growth or bilobar tumor or lymphatic tumor spread so that alternative therapeutic modalities are required. Systemic chemotherapy has provided disappointing results in the past and photodynamic therapy is not feasible in larger tumors [1–5]. However, recently published reports have focused on the value of TACE and chemoperfusion in the treatment of unresectable CCA. Even if TACE is well established in the palliative treatment of hepatocellular carcinoma (HCC), its effectiveness for CCA is not yet known [6–8]. To address this issue, we retrospectively analyzed patients with intrahepatic CCA who had been treated by means of TACE over the past 6 years. The aim of the work is to demonstrate our results with respect to the literature and to evaluate the safety and efficacy of this treatment concept in intrahepatic CCA.
Patients and Methods During a 6-year period between October 2000 and June 2006 we treated 15 patients with histologically confirmed CCA by TACE. In each case, diagnosis was confirmed by either needle biopsy, laparoscopy, or open laparotomy. The decision for TACE was made by an interdisciplinary tumor board in each individual case. Approval for TACE as palliative treatment for inoperable liver cancer was granted by the institutional investigation and ethics committee. The treatment protocol called for repeated TACE treatment with a minimum interval of 8 weeks between procedures using a mixture of mitomycin C and Lipiodol (Lipiodol ultra fluid; Andre Guerbet, Aulnaysous-Bois, France). Patients were excluded from TACE treatment if one of the following was found: decompensated liver disease (ChildPugh class C, Okuda stage III, massive ascitis, serum bilirubin >3 mg/dl), bacterial infection, extrahepatic tumor spread, or any contraindication for an arterial procedure (impaired clotting test, platelet count 50%
4
Capsule infiltration Absent
12
Present
3
Central necrosis
58 (3.9 ± 3.8; 1–15)
Additional therapy
2–5 lesions
Tumor mass 10 (miliary Periportal adenopathy tumor)
Chemotherapy; PTCD pre-TACE Chemotherapy
38.7
F; 65.3
8 · 7.5/left lobe 16 · 10/both lobes
9 10
F; 56.3
4
Stable/dead
12 · 9/both lobes
1
PTCD pre-TACE
9.2
11
M; 46.7
2
Stable/dead
2.5
F; 60.4
3
Progression/ dead
>10 Miliary Nausea, vomiting, fever tumor 2 Periportal adenopathy
Chemotherapy
12
2 · 2/both lobes 14 · 7/right lobe
—
4.5
13
F; 67.4
1
Stable/dead
13 · 7/both lobes
1
Resection postTACE
14
M; 77.7
1
Stable/dead
15
F; 76.1
1
Stable/alive
18x16/right 1 Portal vein thrombosis lobe 12x9/both lobes >10 Miliary Portal vein thrombosis tumor
Hilar infiltration, cholestasis
Portal vein thrombosis
3.3
19.2
—
3.5
—
7.0
Note. Chemotherapy was carried out with gemcitabine prior to TACE in each case
Discussion We present the results for patients treated at a single center with TACE for intrahepatic CCA. The tumors in all patients were rated as unresectable by an interdisciplinary tumor board due to the extensive tumor spread and the infiltration or encasement of intrahepatic vessels or due to severe limiting comorbidity. Four of 15 patients were admitted to TACE because of substantial tumor progression under gemcitabine chemotherapy. TACE was offered to those patients as perhaps the last alternative treatment approach. In the remaining patients TACE was given as first-line therapy. This proceeding was based, on one hand, on the disappointing results that systemic chemotherapy has shown in the past. The median survival for patients treated with systemic chemotherapy ranges even in modern phase II trials only between 6.5 and 11.5 months [13–16]. On the other hand, the decision for TACE was influenced
by the positive experiences that we have collected in the past decade in treating patients with HCC [17, 21, 22]. However, whereas the value of palliative TACE in patients with HCC has been confirmed by recent randomized trials [6, 7], to our knowledge only a few rare case series have dealt with the effect of chemoembolization or chemoperfusion in patients with CCA [8, 23–24]. Although the majority of CCAs are hypovascular and therefore they might appear not to be suitable for an arterial embolization, the arterial supply of the biliary tree arises from branches of the hepatic artery. Accordingly it should be possible to target intrahepatic CCAs much more selectively by chemoembolization than by systemic chemotherapy [8]. But there is no consensus about the ideal i.v. chemotherapy in CCA; however, there is even less agreement about the chemotherapeutics for locoregional treatment. In addition to mitomycin C, which has been used for several years in the treatment of HCC and CCA,
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S. Herber et al.: TACE for Inoperable Intrahepatic Cholangiocarcinoma
Fig. 2 (A–C) Patient 4, a 57-year-old woman. Histologically confirmed CCA, tumor grade G3, with large infiltration of the right and left (segment 4) liver lobe. Contrast-enhanced helical spiral CT (A) shows a 10 · 8.5-cm, centrally hypodense tumor with a hypervascularized peripheral rim (arrows). After chemoembolization
(B) postinterventional CT demonstrates peripheral Lipiodol accumulation (arrows), with only a slight enhancement in the central parts (star). After the 12th TACE (C) and a 2.5-year course, the arterial phase reveals complete peripheral devascularization and a moderate decrease in tumor size
gemcitabine, cisplatin, and doxorubicin are used for chemoembolization either as monotherapy or in combination with other chemotherapeutics [8, 18–20, 23–25, 28– 31]. At our institution TACE was performed with a mixture consisting of a fixed dose of mitomycin C as a single chemotherapeutic drug and 10–20 ml of Lipiodol at 8week intervals. Instead of this, Burger et al. used a combination therapy of doxorubicin, cisplatin, and mitomycin C, with subsequent particulate embolization [8]. In contrast to Burger and to other authors, we did not administer permanently or even temporarily occluding agents due to the potential danger of irreversible vessel occlusion that might prevent further TACE treatments [8, 23, 24]. According to this Kirchhoff et al. reported an unintentional vessel occlusion in four of eight patients following particulate embolization [23]. Therefore, only a median of 2.0 TACE could be performed in each patient. Kirchhoff et al. reported that follow-up angiography revealed progressive rarefication of the intrahepatic arteries. They suggested that this finding might be related either to the toxicity of the chemotherapeutic agent and subsequent arteritis or, and this appears more appropriate, to ischemic reactions that could have been aggravated by the use of
particulate embolization [23]. If we consider that 75% tumor necrosis is the best one can achieve in half of the treated patients, even with the use of an aggressive regimen as presented by Burger et al., the role of occluding agents in CCA should be discussed critically [8]. When further treatment sessions are required the approach to the segmental, tumor-supplying vessels should not be aggravated by particulate embolization. In our cohort treatment did not have to terminated in any patient because of premature vessel occlusion, which may be related to the fact that we refrained from using particles. So far we have performed a mean of 3.9 TACEs in each patient. Vogl et al. presented a dose-increase study in 2006 dealing with chemoembolization in patients with hepatic malignancies [24]. They administered gemcitabine as intraarterial monotherapy or in combination with starch microspheres. Although only 12 patients were included in each group, they found some benefit for patients treated with chemoembolization compared to the study group, which received only chemoperfusion. For assessment of therapeutic success they used contrast-enhanced helical spiral CT in follow-up investigations, as we did. Actually multislice detector CT revealed a peripheral hypervascularized
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S. Herber et al.: TACE for Inoperable Intrahepatic Cholangiocarcinoma Table 5 Side effects and complications No complications
9 of 15 pts
Complications
6 of 15 pts
Complications (total no.)
Number
Classification
14
12 minor/2 major
Nausea/vomiting
4
Minor B
Abdominal pain
6
Minor B
Spasm of hepatic arteries
2
Minor B
Lipiodol displacement
1
Major D
Anaphylactic shock
1
Major D
Death (30 ± 3 days)
0
—
Note. A total of 12 minor and 2 major complications were registered in six patients owing to simultaneous occurrence of vomiting and abdominal pain in four patients
zone in most cases, and accordingly, the majority of tumors presented a ring-like pattern of Lipiodol accumulation in the tumor periphery in postinterventional CT controls. [8, 26, 27]. But even though the local Lipiodol enhancement facilitated the depiction of the tumor and its borders, one should be aware that owing to the use of Lipiodol, the portion of viable tumor and the degree of necrosis could not be assessed reliably. Therefore, treatment success or failure was not proved by the assessment of tumor necrosis but by evaluation of the tumor size that was determined according to the RECIST criteria [10]. The objective response rate, i.e., partial or complete response, was strictly disappointing [8]. In only one single patient did analysis of our CT data indicate a significant decrease in tumor size rated as a partial response. In this patient the maximum tumor size decreased by almost 40% after five TACE procedures. The patient is still alive 13.5 months after diagnosis of a large CCA with a maximum diameter of 12 cm in the cross-sectional image. Due to progressive deterioration of liver function, TACE was suspended after the partial response since the time of writing. Meanwhile liver function has stabilized and the patient is still in fair condition. The mean overall survival in our cohort was 21.1 months, with a median survival of 16.3 months. The 95% confidence interval was 9.4 to 32.5 months. This result is comparable to those reported by Burger et al. and Vogl et al. [8, 24]. In their recently published studies, they reported a survival of 23.0 and 20.2 months, respectively. The 1- and 3-year survival in our cohort calculated by the Kaplan-Meier method was 54.5% and 27.3%, respectively. According to this Tanaka et al. reported quite similar results for a chemoperfusion study in 2002 [25]. They implanted arterial ports with access to the hepatic artery and performed chemoperfusion of the intrahepatic CCA. Their mean number of treatment cycles was an astonishing 51.
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Thereby they reached a mean survival of 26 months with a >50% response rate [25]. Whereas our regimen was similar to those of Burger et al. and Vogl et al., the study by Kirchhoff and colleagues included, besides TACE, systemic chemotherapy with intravenous application of gemcitabine. They reported a median survival of only 12 months and, as mentioned above, attributed this fair result to the high rate of premature vessel occlusions [23]. Which patients profit from this treatment? TACE failed to improve survival in patients suffering from a military-type tumor with disseminated nodules and giant tumors with multiple satellites. In those patients the mean survival was disappointing, at 3.4 months. TACE did not prolong survival or improve the quality of life, and in retrospect, the indication has to be questioned very critically. Death in those patients was attributed to rapid tumor progression combined with tumor cachexia. In contrast, patients with a more focal tumor disease that was ideally limited to a single liver lobe showed the best outcome. The mean survival in these cases was 27.5 months, which is superior to most of the historical data for i.v. chemotherapy [29, 32–34]. In particular, four patients showed a favorable course of disease with a long-term survival of >18 months. In seven others we achieved some improvement, with survival of between 9.0 and 17.3 months. As mentioned at the beginning, systemic chemotherapy with gemcitabine was carried out in four patients prior to TACE. Comparable to Burger et al., who reported a benefit of TACE in three patients in whom systemic chemotherapy had failed, two patients in our cohort potentially benefited from the TACE treatment and one showed a 9.0-month survival after the last TACE, although the intrahepatic tumor growth could not be stopped. The other patient was a woman who showed tumor progression under systemic chemotherapy and was therefore referred for TACE as the last therapeutic option. She showed a very favorable course of disease, with survival of >3 years, but finally died as a result of extrahepatic tumor spread with peritoneal carcinomatosis and tumor consumption. In patients suffering from HCC, TACE has been shown its ability to substantially shrink carcinomas and to enable either operation or locoregional thermoablation therapy [15, 16]. So far in the cohort of Burger et al., operation was enabled due to TACE treatment in two patients who converted from inoperable to operable status [8]. In our small cohort TACE therapy was performed in one patient prior to extended right hemihepatectomy. The follow-up CT 3 months after TACE revealed a stable tumor size but there was no evidence of tumor shrinkage. So far we cannot claim that our treatment regimen is of value in terms of downsizing the tumor or giving a curative therapy option such as surgery.
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The limitations of the present study are obvious. First, this evaluation was carried out retrospectively, which implicates all the disadvantages associated with retrospective work. Second, this study had to contend with the same problems shared by most recently published studies: a small cohort of patients owing to the uncommon disease being studied. Therefore, the results have to be interpreted with caution, and a bias due to a natural positive course that might be present in an individual patient has to be taken into consideration.
Conclusion In patients with intrahepatic CCA, TACE has been suggested to be a safe method with a moderate and tolerable frequency of complications, considering the dismal prognosis for these patients. Compared to the scant literature on transarterial chemoembolization in the field of CCA, our results emphasize the potential benefit and the prolongation of life in certain patients suffering from CCA. However, the fatal outcome of patients with a miliary disease and giant tumors cannot be influenced by TACE.
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