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. 2006 Jul 21;132(11):745–755. doi: 10.1007/s00432-006-0138-0

Hepatic intraarterial chemotherapy with gemcitabine in patients with unresectable cholangiocarcinomas and liver metastases of pancreatic cancer: a clinical study on maximum tolerable dose and treatment efficacy

Thomas J Vogl 1,✉, Wolfram Schwarz 1, Katrin Eichler 1, Kathrin Hochmuth 1, Renate Hammerstingl 1, Ursula Jacob 2, Albert Scheller 2, Stephan Zangos 1, Matthias Heller 1
PMCID: PMC12161034  PMID: 16858591

Abstract

Purpose

To define the maximum tolerated dose (MTD) of hepatic intraarterial chemotherapy with gemcitabine, administered with and without starch microspheres, in patients with inoperable intrahepatic cholangiocarcinomas and liver metastases of pancreatic carcinomas.

Methods

Gemcitabine was administered on days 1 and 8 with intervals of 2 weeks between the cycles. In group A the initial gemcitabine dose of 1,000 mg/m2 (without microspheres) was increased in 200-mg/m2 steps up to a maximum dose of 2,000 mg/m2. In group B the MTD with microspheres was assessed by giving an additional microsphere dose according to tumor extent and body weight, increasing gemcitabine starting from a dose-step below the MTD with microspheres. The MTD was evaluated via clinical and laboratory findings.

Results

Twenty-four patients were enrolled (12 males, 12 females, mean age 59.17 years; intrahepatic cholangiocarcinoma: n = 17, liver metastases of pancreatic carcinoma: n = 7). The MTD of gemcitabine without microspheres was reached at 1,400 mg/m2, and of gemcitabine with microspheres at 1,800 mg/m2. The comparative evaluation revealed statistically significant better data for the time to progression (p < 0.01) and survival for the group with microspheres (6.8 and 20.2 months) in comparison to the group without microspheres (4.2 and 13.5 months).

Conclusion

This clinical study indicates that the intraarterial application of gemcitabine with doses higher than the recommended 1,000 mg/m2 is well tolerated if combined with microspheres, and yields respectable results in patients who do not respond to systemic chemotherapy.

Keywords: Liver metastases, Intraarterial chemotherapy, Gemcitabine, Cholangiocarcinomas

Introduction

Liver malignancies are among the most common neoplasms worldwide. The main primary hepatic malignancies are hepatocellular and cholangiocarcinoma with an incidence rate of 3–4 men and 1–2 women /100,000 per year (Bosch et al. 1999; Bosch and Ribes J 2000; Yu et al. 2000, 2006; Srivatanakul et al. 2004; Tannapfel and Wittekind 2004; Gronbaek et al. 2006). Besides, the liver is the most affected target for metastases of numerous types of primary tumors (Bengmark et al. 1988). Surgical resection or, in some rare cases, liver transplantation is the only potentially curative treatment. However, when the tumor-associated symptoms arise, the tumor is already at an advanced stage; surgical treatment is not possible due to insufficient function of the nonresected liver parts or due to liver cirrhosis (Nakajima et al. 2001; Cenusa 2005; Llovel 2005; Margarit et al. 2006). Besides, only 5% of all liver metastases are resectable with a curative intention, with a 5-year survival rate of 25–35% (Ringe et al. 1994; Lamesch et al. 1997; Hanack et al. 1999; Lorf et al. 2000; Uenishi et al. 2000; Sasson and Sigurdson 2002; Pawlik et al. 2004; Malhi and Gores 2006). Local recurrences occur in 40–60% of the patients after curative surgery (Jones and Roh 2001; Huang et al. 2004; Tarcoveanu et al. 2005; Asthana et al. 2006). In cases of irresectability palliative local and regional treatments are available such as injection of alcohol, thermocoagulation, regional chemoperfusion, and chemoembolization (Gores 2000; Price 2001; Martin and Jarnagin 2003; Yalcin 2004). Systemic treatment consists of chemotherapy and supportive care. Hepatic malignancies normally have a large number of supplying arterial blood vessels drawing blood from the hepatic artery. Intraarterial chemoperfusion and chemoembolization have been suggested for reduction and devascularization with palliative and in some cases with neoadjuvant intentions (Al-Bassam et al. 1999; Sakaguchi et al. 2001; Tarazov 2001; Xiao et al. 2005). Superselective intraarterial injection can deliver high doses of chemotherapeutic agents in the tumor vessels causing increased regional levels with more effectiveness and lower systemic side effects. The additional application of embolic particles can reduce the intratumoral circulation. One of the chemotherapeutic agents beside epirubicin or cisplatin used is the relatively new antimetabolite gemcitabine. In several studies it has shown some limited response rates in a large variety of solid tumors especially in hepatic metastases of pancreatic carcinoma and cholangiocarcinoma (Hui and Reitz 1997; Barton-Burke 1999; Geffen and Man 2002; Toschi et al. 2005). Several clinical studies have shown the advantages and superiority of gemcitabine over other chemotherapeutic regimes especially regarding tumor response and clinical benefit with positive effects on the tumor-associated symptoms (Pawlik et al. 2004). Gemcitabine has a mildly toxic profile and the side effects are quite controllable. In recent years relevant publications have described the process of transarterial chemoperfusion in combination with embolization as an alternative effective treatment. While via the intraarterial administration of floxuridine (FUDR) a high level of hepatic extraction is achieved, other drugs such as 5-FU and mitomycin present a much more limited extraction. Hepatic intraarterial chemotherapy is currently the subject of controversy (Klapdor et al. 1999; Spagnuolo et al. 1999; Weissmann and Ludwig 1999; Brasiuniene et al. 2003; Vogl et al. 2003) and there are no data-driven recommended doses for gemcitabine. The aim of this clinical study was to evaluate the maximum tolerated dose (MTD) of gemcitabine, without and in combination with microspheres, for an intraarterial locoregional transcatheter chemoperfusion in cholangiocarcinomas and liver metastases of pancreatic carcinomas.

Materials and methods

Inclusion and exlusion criteria and baseline evaluation

This study was approved by the Institutional Review Board of the university and the German government authorities. The patients’ complete clinical history was evaluated. Adult patients ( > 18 years) with histologically confirmed solid inoperable hepatic malignancies such as cholangiocarcinoma and liver metastases of pancreatic cancer who had not responded to the usual antitumoral treatment, but with a life expectancy of more than 12 weeks according to the Karnofsky index, were consecutively included. We selected the groups of cholangiocarcinomas and liver metastases of pancreatic cancer due to their similar histopathology and the documented therapy response for the chemodrug gemcitabine. The malignant lesion had to be radiologically measurable in two dimensions. Other criteria consisted of a Karnofsky index of more than 70 and an adequate hematological profile (granulocyte count > 2.0 × 109/l and platelet count > 100 × 109/l), appropriate renal function (serum creatinine level < 1.5 times the upper limit of reference range) and hepatic function (bilirubin serum level < 1.5 times the upper limit of reference range). The patients were informed of the potential hazards to the fetus if they or their partners became pregnant during the treatment. Finally, a written informed consent was obtained from them. Pretreatment baseline imaging measurement consisted of plain and contrast-enhanced MRI and MRA with T1- and T2-weighted sequences and T1-weighted GE sequences followed by a post contrast dynamic series. Protocols used were True Fisp, HASTE, TSE, FLASH-2D in- and opposed phase and FLASH-2D dynamic sequences. Additionally, a contrast-enhanced multiphase helical CT of the abdomen was performed.

Exclusion criteria were as follows: prior application of chemotherapy within the last 4 weeks; presence of brain metastases and active infections; pregnancy or breast-feeding as well as reluctance to use appropriate birth control; and participation in other studies. General exclusion criteria for TACE were evaluated such as a tumor load of more than 75%, portal vein thrombosis, clinically relevant heart failure and extrahepatic mainifestation of disease.

Twenty-four patients (12 males, 12 females) were evaluated for the study endpoints. The patients were divided into two groups. Nine men and three women with a median age of 57 years were treated in the group without spherex (group A); three men and nine women with a median age of 62 years were treated in the group with spherex (group B). All patients had received a systemic chemotherapy with different chemotherapeutic agents in the past, which either did not show any effects or had to be stopped after progressive diseases. Seventeen patients suffered from an intrahepatic cholangiocarcinoma and seven patients had liver metastases of pancreatic carcinoma. An exact overview is shown in Table 1. In the CCC group the mean lesion per patient was x = 1.3 intrahepatic tumors with a range from 1 to 6 lesions, the medium size was 5 ± 4 cm in diameter. In the group with liver metastases of pancreatic carcinoma the mean number of intrahepatic lesions was x = 5.7 ± 4, the size varying between 5 and 60 mm.

Table 1.

Baseline demography of the study population

  Group without spherex Group with spherex
No % No %
Number of patients 12 100 12 100
Age
 Mean 57.38 62.17
 Range 41–72 41–75
Sex (m/f) 9/3 3/9
Karnofsky index
 70–80 6 50 4 33.3
 80–90 3 25 6 50
 >90 3 25 2 16.7
Disease stage at study entry
CC patients (cholangiocarcinoma)
 Total 9 75 8 66.7
 Primary inoperable 4 41.7 5 41.7
 Recurrence 5 33.3 3 25
 T2N0M1 0 0 2 16.7
 T3N0M1 0 0 2 16.7
 T3N1M1 5 41.7 5 41.7
 T4N0M0 1 8.3 0 0
 T4N0M1 2 15 0 0
 T4N1M1 1 8.3 0 0
Previous cancer treatment
 Surgery 5 41.7 2 16.7
 Chemotherapy 9 75 8 66.7
 Radiotherapy 0 0 1 8.3
Patients with hepatic metastasis of pancreatic carcinoma
 Total 3 25 4 33.3
 Primary hepatic metastasis 1 8.3 0 0
 Metastasis after curative treatment 3 25 4 33.3
 T2N0M1 1 8.3 0 0
 T2N1M1 1 8.3 4 33.3
 T3N1M1 1 8.3 0 0
 T4N1M1 1 8.3 0 0
Previous cancer treatment
 Whipple surgery 3 25 4 33.3
 Chemotherapy 3 25 4 33.3
 Radiotherapy 1 8.3 0 0
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Treatment plan

Group A

Three patients were treated per dose level. The initial dose was 1,000 mg/m2 body surface with a maximum of 6 cycles; one cycle consisted of two applications between days 1 and 8 with intervals of 2 weeks between the cycles. Dose steps were 200 mg/m2 up to a maximum dose of 2,000 mg/m2. As a precaution before each treatment a brief physical examination was performed, clinical laboratory values were assessed, and intercurrent diseases due to chemotherapeutic toxicity and adverse events were evaluated. WHO grade 3 and 4 symptoms meant the termination of the treatment for the patient. However, if two or all of the three patients showed grade 3 or 4 symptoms in the first cycle, the MTD without spherex was reached. The evaluated relevant side effects included hematological, gastrointestinal, renal, pulmonary, cardiac, and neurological criteria as well as allergic reactions.

Group B

In this group a microsphere dose was additionally given according to tumor extent and body weight increasing gemcitabine starting from a dose-step below the found MTD without microspheres using the same criteria for toxicity to evaluate the MTD. Again, dose steps were 200 mg/m2 up to a maximum dose of 2,000 mg/m2. After each application, imaging including plain MRI of the liver was performed in both groups for control purposes.

Drug administration

The intervention was performed using digital subtraction angiography (DSA) procedures: first, under local anesthesia the femoral artery was punctured in the inguinal area followed by catheterization using the Seldinger technique. First, a diagnostic angiography of the upper abdomen was performed using a pigtail catheter. This was followed by selective positioning of a Cobra or Sidewinder catheter (4 French diameter; Terumo, Frankfurt, Germany) in the right and left liver artery with angiographic representation of the tumor-supplying vessels and possible collateral circulations. Before injection of the chemotherapeutic agent a systemic hydration was administered. During intervention, supportive medication such as sedatives, antiemetics, and analgesics was used if necessary.

The chemoperfusion was then performed using the following regime: Two-thirds of gemcitabine was applied in the right liver artery by a perfusion pump and one-third was infused in the left liver artery within 20 min. In the group with microsphere application an intraarterial degradable starch microspheres (DSM) application of microspheres (EmboCept, PharmaCept GmbH, Berlin, Germany) in a dose of 80 mg/kg b.w. was applied directly after the end of the local chemotherapy. EmboCept was directly applied into the tumor feeding artery depending on the localization of the CCC or liver metastases. The DSM are produced from hydrolyzed potato starch with a polymeric matrix. In the diluted solution a starch microsphere concentration of about 30 mg/ml was used. After the intervention the catheter system was removed and a pressure bandage was applied for 24 h. A bed rest was necessary for 6 h, and then the patients were dismissed.

Evaluation of the endpoints

The primary endpoint was the evaluation of the MTD of intraarterial locoregionally applied gemcitabine first without and then with spherex. The MTD was reached when two or all three patients of one dose group had a WHO grade 3 or 4 myelosuppression or nonhematologic toxicity or side effects during cycle 1. The objective tumor response was defined as a secondary endpoint and was assessed in percentage in the total tumor mass in relation to the baseline measurements. Secondary endpoints included the time to response and the number of applications to the onset of the tumor response. The duration of response and the patients’ survival were further endpoints. Therefore, before each cycle a contrast-enhanced multiphase helical CT of the abdomen was performed as an imaging evaluation method. The tumor mass was assessed via volumetric measurements and responses were rated due to WHO definitions as follows: progressive disease was defined as an increase of 25% or more of the tumor mass at any time within the study. Stable disease was defined as a decrease of less than a 50% or an increase of less than 25%. Partial response was defined as a decrease of at least 50% but less than 100%. Complete response meant a decrease of 100%. Only partial and complete responses were defined to be objective tumor responses while stable and progressive diseases were defined as nonresponses.

To assess the clinical benefit in groups A and B, the presence and severity of common symptoms reported by the patients (i.e., pain, anorexia, weight loss, fatigue, ascites, and jaundice) were evaluated by a questionnaire as well. Clinical benefit response was defined according to Burris et al. (1997) (Fig. 1). For statistical methods and biometrical analysis the following variables were evaluated: the MTD of adminstered gemcitabine with and without spherex; the response of treated tumors; the time until onset and duration of response in correlation to the applied dosage; the time to progression in correlation to the applied dose; and patient survival. Presence and severity of side effects and common tumor symptoms were protocolled.

Fig. 1.

Fig. 1

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Assessment of the clinical benefit

Results

Group without application of microspheres

In the patient group without microspheres a total of 78 chemoperfusions with a mean of six perfusions per patient were performed. One severe adverse event occurred with an allergic or toxic lung edema immediately after the application, and the patient had to be transferred to the intensive care unit for one night. The MTD of gemcitabine was reached at 1,400-mg/m2 due to WHO grade 3 myelosuppressive side effects in two of three patients in the 1,600-mg/m2 dose group. We observed no complete remissions, no partial responses, 75% (n = 9) stable diseases and 25% (n = 3) progressive diseases. In the standardized questionnaire 75% (n = 9) of the patients showed a clinical response benefit. 75% (n = 9) of the patients showed an increase in weight. 75% (n = 9) of the patients showed a significant reduction in pain and took less analgesics for at least 4 weeks. 50% (n = 6) of the patients showed an increase in the Karnofsky index by at least 10%. However, 25% (n = 3) of the patients showed a decrease in weight, and 25% (n = 3) of the patients showed a significant increase in pain and took more analgesics for at least 4 weeks. 50% (n = 6) of the patients showed a stable or decreased Karnofsky index by at least 10%. The mean time to progression was 4.2 months and we observed a mean survival time of 13.5.

Group with application of microspheres

In the patient group with spherex there was a total of 110 chemoembolizations with a mean of 9.2 embolizations per patient (Fig. 2). No severe adverse event occurred. The MTD of gemcitabine was reached at 1,800 mg/m2 due to WHO grade 3 myelosuppressive side effects in two of three patients in the 2,000-mg/m2 dose group. We observed no complete remissions, no partial responses, 92% (n = 11) stable diseases and 8% (n = 1) progressive diseases. In the standardized questionnaire, 83% (n = 10) of the patients showed a clinical response benefit: 83% (n = 10) of the patients showed an increase in weight. 75% (n = 9) of the patients showed a significant reduction of pain and took less analgesics for at least 4 weeks. 50% (n = 5) of the patients showed an increase in the Karnofsky index by at least 10%. However, 16.7 % (n = 2) of the patients showed a decrease in weight, and 25% (n = 3) of the patients showed a significant increase in pain and took more analgesics for at least 4 weeks. The mean time to progression was 6.8 months, and we observed a mean survival time of 20.2 months with 8.3% (n = 1) of the patients still alive (Tables 2, 3). Examples for selective intraarterial chemotherapy application and imaging of tumor developments are shown in Figs. 3, 4, 5 and 6.

Fig. 2.

Fig. 2

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Tumor development under study conditions

Table 2.

Results and tumor development under therapy–survival times stated in months

  Group without spherex Group with spherex
No % No %
Mean number of cycles 6 9.2
Mean time to progression (months) 4.23 6.81
Mean survival time (months)
Starting from the beginning of the study 13.50 ± 2.50 20.20 ± 2.95
Patients evaluable 12 100 12 100
Complete response 0 0 0 0
Partial response 0 0 0 0
Stable disease 9 75 11 91.7
Progressive disease 3 25 1 8.3
Clinical benefit 9 75 10 83.3
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Table 3.

Overview of the most observed side effects and serious adverse

WHO Grade Group without spherex Group with spherex
No % No %
Anemia
 1–2 7 58.3% 6 50.0%
 3–4 0 0% 0 0%
Thrombopenia
 1–2 8 66.7% 6 50.0%
 3–4 0 0% 0 0%
Leukopenia
 1–2 11 91.7% 9 75.0%
 3–4 1 8.3% 2 16.7%
ALT rising
 1–2 10 83.3% 9 75.0%
 3–4 1 8.3% 1 8.3%
AST rising
 1–2 10 83.3% 11 91.6%
 3–4 1 8.3% 1 8.3%
AP rising
 1–2 9 75.0% 9 75.0%
 3–4 1 8.3% 1 8.3%
Vomiting
 1–2 5 41.7% 5 41.7%
 3–4 0 0% 0 0%
Nausea
 1–2 5 41.7% 7 58.3%
 3–4 0 0% 0 0%
Anorexia
 1–2 7 58.3% 7 58.3%
 3–4 0 0% 0 0%
Allergic reactions
 1–2 3 25.0% 3 25.0%
 3–4 1 8.3% 0 0%
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Fig. 3.

Fig. 3

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a Survival data in the group without microspheres and b survival data in the group with microspheres

Fig. 4.

Fig. 4

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a Contrast-enhanced CT scan: initial imaging of a 67-year-old patient suffering from a multilocal intrahepatic cholangiocarcinoma primary located in liver segments 5–8 with metastases in liver segment 3 and b after six locoregional applications the tumors show a size reduction of 20% in all involved liver segments with no new metastases

Fig. 5.

Fig. 5

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a Contrast-enhanced CT scan: initial imaging of a 49-year-old patient with liver metastases of a pancreatic carcinoma after previous pancreatic resection. Confluent liver metastases in segments 8 and 4 and b contrast-enhanced CT scan: after five applications the multiple liver lesions showed a reduction in size with no new liver metastases. In total, a volume reduction of 25% was calculated (stable disease)

Fig. 6.

Fig. 6

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Hepatic multinodular liver metastases. The MR imaging control under regional therapy protocol. a Pretreatment evalulation with high tumor volume, b posttreatment 3-month control with a reduction in size and c posttreatment 6-month control with further reduction as partial response

The comparative evaluation of the survival data for the group with microspheres revealed a stastitically significant better time to progression (p < 0.01) and survival (p < 0.01). A possible bias could be the higher number of performed HAI sessions in the microsphere group. With regard to other parameters such as the number of achieved stable disease, Karnofsky index and others, no statistically significant difference was calculated.

Discussion

The liver is one of the organs most affected by tumors. This is true for primary liver tumors as well as for the development of intrahepatic metastases of other tumors. So far surgical resection has been the only curative therapy option. However, for some time minimal invasive therapy methods such as laser-induced thermotherapy, radiofrequency, and cryotherapy have also been used for curative treatment. These techniques, however, are limited by anatomically unfavorable tumor localization and local tumor spreading. The majority of the patients with primary and secondary liver malignancies have a poor prognosis. In most cases, these tumors are diagnosed at an advanced stage due to the lack of early symptoms. Only a minority of patients are suitable for surgical resection. Thus, palliative therapy measures are becoming more important. These mainly consist of the application of systemic chemotherapy. Recent therapy options are concerned with regional chemotherapy, the rationale of which corresponds to the blood supply of liver tumors and to the intratumoral accumulation of agents.

The liver seems the ideal organ for regional therapy due to its dual supply via the portal and the hepatic vein. It is well known that in contrast to normal liver parenchyma, primary liver tumors as well as metastases are almost exclusively supplied via the arteries. Some of these tumors obtain up to 95% of their blood supply via the liver arteries, whereas in normal healthy liver tissue it is 75% via portal veins, and 25% via arteries.

Selective arterial administration of chemotherapeutic agents is performed to achieve a high local chemotherapeutic concentration in the tumorous liver tissue; this has a more lasting effect than systemic administration. Concentrations 10–100 times greater than those of systemic administration can be achieved. Several studies showed that an intraarterial administration is significantly superior to a systemic application with regard to response rates (Falconi et al. 1999; Kemeny et al. 1999; Zaloudik et al. 1997).

However, currently this method is not the standard procedure but is applied only if systemic chemotherapy fails, as one of the main problems in patients treated with chemotherapy is the availability of inpatient beds. Since the regional chemotherapy has a better toxicity profile than the systemic especially given on an outpatient basis it might overcome this and would allow older patients to be treated. The regimen used by us does not significantly extend the survival, but in comparison to systemic chemotherapy patients do not suffer from loss in quality of life. We also observed a significant reduction of the two associated symptoms pain and the influence on the Karnofsky index. Intraarterial therapy seems preferable only in order to control or, ideally, reduce isolated hepatic metastases or a primary liver tumor without distant metastases. The combination of local chemotherapy with additional dosage of embolization particles is an effective additional therapy (Starkhammer et al. 1987; Stuart K 2003). The rationale of this therapy option is based on an arterial occlusion in combination with local chemotherapy. The aim of chemoembolization is to achieve an arterial devascularization, thereby inducing intratumorally a relative ischemia or hypoxia while minimizing further damage to the healthy liver tissue and decelerating the passage of the chemotherapeutic agents. If these particles are administered together with chemotherapeutic agents, this results in long-lasting highly effective concentrations in the tumor tissue with subsequent formation of tumor necrosis. Additionally, as the highest cytostatic concentrations are found in the tumor margins another positive effect is that most liver tumors are predominantly hypervascular in the margins. Formerly, 5-FU was the most popular chemotherapeutic agent. In several studies, gemcitabine, which has been available since the mid-1990s, showed a significant superiority with regard to response rates and total survival rates especially in liver metastases of pancreatic carcinoma. Due to the mild toxicity profile, Gemcitabine seems to be an ideal option for elderly patients. In comparison to systemic chemotherapy regimens Gemcitabine lacks some of the classical toxicities of chemotherapeutics, i.e., alopecia, severe nausea and vomiting, and mucositis. The toxicity profile of gemcitabine in combination with targeted drugs such as trastuzumab, tyrosine kinase inhibitors, angiogenesis inhibitors, and others makes it an attractive agent to assess. Ongoing studies will reveal the role of gemcitabine in combination with these agents.

In a few studies this cytostatic agent was also administered in cholangiocarcinoma with reasonable results. In palliative therapy the concept of clinical benefit seems to be of increasing importance. Sometimes it is used as a parameter for therapeutic success, as an improvement of symptoms occurs much earlier than image morphological tumor response. Moreover, gemcitabine has less severe side effects. The main effect is bone marrow depression, which is quickly reversible especially in therapy-free intervals so that serious side effects such as severe infection due to myelosuppression or bleeding are quite seldom.

In several studies it has been shown that gemcitabine has synergetic activity with a variety of other chemotherapeutic compounds such as cisplatin, Irinotecan, Paclitaxel, Etoposide, Vinorelbine, and many others (Barton-Burke 1999). The results of these studies show that combined therapies have superior effects over the single use of gemcitabine in a first line systemic chemotherapy nonrefractory setting. But only a few studies discuss the regional therapy options in a refractory second line setting. Therefore, it does not seem meaningful to compare the results of these studies with our results and our results will stand as an option in a refractory second line situation with less comparable studies.

At present, gemcitabine is applied in several tumors, mainly pancreatic carcinoma, breast carcinoma, urinary bladder carcinoma, head and neck tumors, nonsmall cell bronchial carcinoma and several gastrointestinal tumors (Sandler et al. 2000; Gitlitz et al. 2003; Guarneri and Conte 2004; Raguse et al. 2005). As the intrahepatic cholangiocarcinoma is morphologically related to the pancreatic carcinoma, the application of gemcitabine is justifiable at least in experimental studies (Verderame et al. 2000; Kubicka et al. 2001; Tsavaris et al. 2004). The recommended dosage for the intravenous and intraarterial application of gemcitabine is 1,000 mg/m2. In the clinical application in mono or combination therapy doses from 1,000 to 1,500 mg/m2 are administered. Individual studies, which deal with a dose increase in systemic application, are available (Bourgeois et al. 2004; Reid et al. 2004). However, these studies show significant differences in their study design, and normally they were designed as escalation studies as part of a combination therapy. Studies with intravenous gemcitabine did not show any clear advantage, when doses greater than 1,000 mg/m² were given. At present, the studies of the intraarterial dosage are still in their initial stages. Dose-finding studies with regard to chemoembolization do not exist. Due to the small amount of data available a comparison of our results does not seem reasonable. In our study it was shown that much higher doses than the recommended 1,000 mg/m2 can be repeatedly applied intraarterially and are tolerated well. Another important point is that in chemoembolization an increased dosage can be tolerated as compared to local chemoperfusion. This may be due to the fact that the systemic side effects are smaller during the slow, fractional discharge of gemcitabine in the blood flow and do not occur until higher doses are applied. The superiority of chemoembolization to chemoperfusion might be due to the fact that the cytostatic agents are in the affected region for a longer time, particularly as the hypoxia arising due to the embolization sensitizes the tumor tissue even further for the cytostatic agents. The rates of complete and partial remissions as well as the high number of stable diseases do not seem to favor this method; however, it should be kept in mind that all patients had already received a systemic chemotherapy, which resulted in a progressive disease. Thus, the potential application area of transarterial chemoperfusion/chemoembolization can be seen, namely with regard to palliation in therapy failure of systemic chemotherapy.

The low side effects and the high rate of clinical benefit even up to the MTD should be considered. In contrast to the data published by other groups our data prove a relevant improvement of the time to progression and survival data in the group without and with microsphere application. A mean survival time with 20.2 months in the latter group is slightly better than the data already published by other groups (Weissmann and Ludwig 1999; Kubicka et al. 2001). Achieving stable disease with good life quality for quite a long time is a preferred therapy outcome to temporarily inducing a partial remission with finally lethal outcome.

The time until tumor progress or the cumulative survival time of the patients treated with high-dose gemcitabine shows a tendency to higher dosage ideally as part of the chemoembolization. Additionally, our data underline that this method can be performed repetitively and, above all, on an outpatient basis. The combination therapy of intraarterial high-dose gemcitabine with further cytostatic agents has to be tested in further studies.

In summary, this clinical study indicates that the intraarterial application of gemcitabine with doses higher than the recommended 1,000-mg/m2 is well tolerated, in particular, if combined with microspheres, and yields respectable results in patients who do not respond to systemic chemotherapy.

Footnotes

Albert Scheller has recently died.

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