Zusammenfassung
Ziel: Evaluation der lokoregionären transarteriellen Chemoperfusion (TACP) bei therapierefraktären
Lokalrezidiven und fortgeschrittenen Stadien des Pankreaskarzinoms bezüglich Tumoransprechens,
Überlebens und Schmerzentwicklung. Material und Methodik: Bei 40 Patienten (medianes Alter 62 Jahre, Bereich 36 - 79) wurden mindestens 3 (im
Mittel 6, Bereich 3 - 12) transarterielle Chemoperfusionen pro Patient in vierwöchigen
Abständen ambulant durchgeführt. Die Patienten zeigten in 28 Fällen ein fortgeschrittenes
Tumorstadium und in 12 Fällen ein Lokalrezidiv. Gemcitabine (1000 mg/m2 ) in Kombination mit Mitomycin C (8,5 mg/m2 ) wurde über 1 Stunde über einen im Truncus coeliacus platzierten Katheter appliziert.
Das Tumoransprechen (Durchmesser, Volumen) wurde mittels MRT oder CT bestimmt und
nach der RECIST-Klassifikation beurteilt. Als Ansprechen der Schmerzsymptomatik wurde
eine mehr als 50 %ige Reduktion der Schmerzstärke auf einer visuellen Analogskala
oder eine mehr als 50 %ige Reduktion des Schmerzmittelbedarfs oder ein Umsetzen auf
ein weniger potentes Analgetikum gewertet. Ergebnisse: Alle Patienten tolerierten das ambulante Therapiemanagement gut. Es kam zu keinen
Grad-III/IV-Nebenwirkungen nach CTC (Common Toxicity Criteria). Krankheitsassoziierte
Schmerzen konnten bei 20 / 32 (62,5 %) der Patienten verringert werden. Bezüglich
des radiologischen Ansprechens konnte bei 3 / 40 (7,5 %) der Patienten eine „complete
response”, bei 9 / 40 (22,5 %) eine „partial response”, bei 16 / 40 (40 %) eine „stable
disease” und bei 12 / 40 (30 %) eine „progressive disease” dokumentiert werden. Das
mediane Überleben seit Erstdiagnose lag bei 16,4 Monaten, seit Beginn der TACP bei
8,1 Monaten. Die Gruppe der Rezidivtumoren zeigte sowohl beim Tumoransprechen (41,7
% vs. 25 %) als auch bei den Überlebenszeiten (14,4 vs. 7 Monate) bessere, jedoch
nicht signifikante Ergebnisse als die Gruppe der fortgeschrittenen Tumorstadien. Patienten
mit Therapieansprechen (CR + PR) lebten signifikant länger als solche mit Tumorprogress
(13,0 vs. 6,0 Monate; p = 0,013). Schlussfolgerung: Die lokoregionäre TACP stellt ein minimalinvasives, ambulant einsetzbares Verfahren
zur palliativ-symptomatischen Therapie des therapierefraktären Pankreaskarzinoms dar.
Zielsetzung ist dabei die symptomatische Verbesserung lokaler tumorassoziierter Schmerzen
bis hin zum Erreichen einer verbesserten Überlebenszeit durch ein Tumoransprechen.
Abstract
Purpose: The purpose of this study was to evaluate local transarterial chemoperfusion (TACP)
in locally recurrent pancreatic carcinoma and advanced tumor stages which did not
respond to prior systemic chemotherapy. The tumor response, survival, and pain response
were retrospectively analyzed. Materials and Method: Forty outpatients (median age 62 years, range 36 - 79) were treated with a minimum
of 3 (mean 6, range 3 - 12) applications per patient in four-week intervals. Twenty-eight
patients were in advanced tumor stages, and 12 patients had locally recurrent tumors.
Gemcitabine (1,000 mg/m2 ) and mitomycin C (8.5 mg/m2 ) were administered within 1 hour through a celiac trunk catheter. The tumor response
(diameter, volume) was measured using MRI or CT and classified according to RECIST.
The pain response was defined as a reduction of pain intensity of more than 50 % on
a visual analog scale, or a reduction of more than 50 % in analgesics consumption,
or a switch to a less potent analgesic agent. Results: The treatment was tolerated well by all patients. No clinically relevant problems
or grade III or IV toxicity according to CTC (Common Toxicity Criteria) were observed.
Tumor-related pain was relieved in 20 / 32 (62.5 %) cases. Radiologically, “complete
response” was found in 3 / 40 (7.5 %), “partial response” in 9 / 40 (22.5 %), “stable
disease” in 16 / 40 (40 %), and “progressive disease” in 12 / 40 (30 %) of the patients.
The median survival period since initial diagnosis and first TACP was 16.4 months
and 8.1 months, respectively. Locally recurrent tumors showed better, but still not
significant results regarding tumor response (41.7 % vs. 25 %) as well as survival
(14.4 vs. 7 months) compared to advanced tumor stages. Responders (CR + PR) showed
a significant survival advantage compared to patients with tumor progression (13.0
vs. 6.0 months; p = 0.013). Conclusion: TACP is a minimally invasive outpatient treatment for therapy-resistant locally recurrent
pancreatic carcinoma and advanced tumor stages. It may be considered as an important
aspect in palliative symptomatic pain-relieving treatment, or may even result in improved
survival by achieving tumor response.
Key words
pancreatic carcinoma - transarterial chemoperfusion - Gemcitabine - Mitomycin
Literatur
1
Stieler J M, Oettle H.
Aktuelle Diagnostik und Therapie des fortgeschrittenen Pankreaskarzioms.
Dtsch Med Wochenschr.
2005;
130
2146-2148
2 Bruns C, Diebold J, Heinemann V. et al .Karzinome des exokrinen Pankreas und der
periampullären Region. Sendler A Tumorzentrum München: Manual Gastrointestinale Tumoren
- Empfehlung zur Diagnostik, Therapie und Nachsorge. 7. Auflage München, Wien, New
York; Zuckschwerdt Verlag 2006: 77-99
3
Delbeke D, Pinson C W.
Pancreatic tumors: role of imaging in the diagnosis, staging and treatment.
J Hepatobiliary Pancreat Surg.
2004;
11
4-10
4
Goldstein D, Carroll S, Apte M. et al .
Modern management of pancreatic carcinoma.
Intern Med J.
2004;
34
475-481
5
Ridwelski K, Meyer F.
Current options for palliative treatment in patients with pancreatic cancer.
Dig Dis.
2001;
19
63-75
6
Heinemann V, Wilkowski R.
Behandlung des fortgeschrittenen und metastasierten Pankreaskarzinoms.
Dtsch Arztebl.
2005;
102
2720-2725
7
Okusaka T, Kosuge T.
Systemic chemotherapy for pancreatic cancer.
Pancreas.
2004;
28
301-304
8
Aigner K R.
Intra-arterial infusion: overview and novel approaches.
Sem Surg Oncol.
1998;
14
248-253
9
Chen H SG, Gross J F.
Intra-arterial infusion of anticancer drugs: theoretic aspects of drug delivery and
review of responses.
Cancer Treat Rep.
1980;
64
31-40
10
Stephens F O.
Pharmacokinetics of intra-arterial chemotherapy.
Recent Results Cancer Res.
1983;
86
1-12
11
Dedrick R L.
Arterial drug infusion: pharmacokinetic problems and pitfalls.
J Natl Cancer Inst.
1988;
80
84-89
12
Müller H, Hilger R.
Curative and palliative aspects of regional chemotherapy in combination with surgery.
Support Care Cancer.
2003;
11
1-10
13
Therasse P, Arbuck S G, Eisenhauer E A. et al .
New guidelines to evaluate the response to treatment in solid tumors.
J Natl Cancer Inst.
2000;
92
205-216
14
Burris H A 3 rd, Moore M J, Andersen J. et al .
Improvements in survival and clinical benefit with gemcitabine as first-line therapy
patients with advanced pancreas cancer: a randomized trial.
J Clin Oncol.
1997;
15
2403-2413
15
Bramhall S R, Schulz J, Nemunaitis J. et al .
A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat
with gemcitabine and placebo as first line therapy in patients with advanced pancreatic
cancer.
Br J Cancer.
2002;
87
161-167
16
van Cutsem E, van de Velde H, Karasek P. et al .
Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo
in advanced pancreatic cancer.
J Clin Oncol.
2004;
22
1430-1438
17
Berlin J D, Catalano P, Thomas J P. et al .
Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine
alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology
Group Trial E 2297.
J Clin Oncol.
2002;
20
3270-3275
18
Rocha Lima C M, Green M R, Rotche R. et al .
Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine
monotherapy in patients with locally advanced or metastatic pancreatic cancer despite
increased tumor response rate.
J Clin Oncol.
2004;
22
3776-3783
19
Storniolo A M, Enas N H, Brown C A. et al .
An investigational new drug treatment program for patients with gemcitabine - results
for over 3000 patients with pancreatic carcinoma.
Cancer.
1999;
85
1261-1268
20
Colucci G, Giuliani F, Gebbia V. et al .
Gemcitabine alone or with cisplatin for the treatment of patients with locally advanced
and/or metastatic pancreatic carcinoma. A prospective, randomized phase III study
of the Gruppo Oncologica dell’Italia Meridionale.
Cancer.
2002;
94
902-910
21
Rougier P, Adenis A, Ducreux M. et al .
A phase II study: docetaxel as first-line chemotherapy for advanced pancreatic adenocarcinoma.
Eur J Cancer.
2000;
36
1016-1025
22
Androulakis N, Kourousis C, Dimopoulos M A. et al .
Treatment of pancreatic cancer with docetaxel and granulocyte colony-stimulating factor:
a multicenter phase II study.
J Clin Oncol.
1999;
17
1779-1785
23
Ryan D P, Kulke M H, Fuchs C S. et al .
A phase II study of gemcitabine and docetaxel in patients with metastatic pancreatic
carcinoma.
Cancer.
2002;
94
97-103
24
Ko A H, Tempero M A.
Systemic therapy for pancreatic cancer.
Sem Radiat Oncol.
2005;
15
245-253
25
Kindler H L, Friberg G, Singh D A. et al .
Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic
cancer.
J Clin Oncol.
2005;
23
8033-8040
26
Xiong H Q, Rosenberg A, LoBuglio A. et al .
Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in
combination with gemcitabine for advanced pancreatic cancer: a mulitcenter phase II
trial.
J Clin Oncol.
2004;
22
2610-2616
27
Chin K V, Ueda K, Pastan I. et al .
Modulation of activity of the promoter of the human MDR1 gene by ras and p53.
Science.
1992;
255
459-462
28
Lorenz M, Heinrich S, Staib-Sebler E. et al .
Regional chemotherapy in the treatment of advanced pancreatic cancer - is it relevant?.
Eur J Cancer.
2000;
36
957-965
29
Aigner K R, Gailhofer S, Kopp S.
Regional versus systemic chemotherapy for advanced pancreatic cancer: a randomized
study.
Hepato-Gastroenterol.
1998;
45
1125-1129
30
Han G H, Yin Z X, Meng X J. et al .
Prospective randomized clinical trial of two drug delivery pathway in the treatment
of inoperable advanced pancreatic carcinoma.
Chin J Dig Dis.
2006;
7
45-48
31
Link K H, Gansauge F, Görich J. et al .
Palliative and adjuvant regional chemotherapy in pancreatic cancer.
Eur J Surg Oncol.
1997;
23
409-414
32
Gebauer T, Ridwelski K, Fahlke J. et al .
Lokoregionäre und systemische Therapie beim fortgeschrittenen Pankreaskarzinom.
Langenbecks Arch Chir.
1998;
Suppl 2
1344-1347
33
Shibuya K, Nagata Y, Itoh T. et al .
Transcatheter arterial infusion therapy in the treatment of advanced pancreatic cancer:
a feasibility study.
Cardiovasc Intervent Radiol.
1999;
22
196-200
34
Cantore M, Pederzoli P, Cornalba G. et al .
Intra-arterial chemotherapy for unresectable pancreatic cancer.
Ann Oncol.
2000;
11
569-573
35
Muchmore J H, Preslan J E, George W J.
Regional chemotherapy for inoperable pancreatic carcinoma.
Cancer.
1996;
78
664-673
36
Muchmore J H, Carter R D, Preslan J E. et al .
Regional chemotherapy with hemofiltration: a rationale for a different treatment approach
to advanced pancreatic cancer.
Hepato-gastroenterol.
1996;
43
346-355
37
Homma H, Doi T, Mezawa S. et al .
A novel arterial infusion chemotherapy for the treatment of patients with advanced
pancreatic carcinoma after vascular supply distribution via superselective embolization.
Cancer.
2000;
89
303-313
38
Takamori H, Kanemitsu K, Tsuji T. et al .
5-Fluorouracil intra-arterial infusion combined with systemic gemcitabine for unresectable
pancreatic cancer.
Pancreas.
2005;
30
223-226
39
Kornmann M, Butzer U, Blatter J. et al .
Pre-clinical evaluation of the activity of gemcitabine as a basis for regional chemotherapy
of pancreatic and colorectal cancer.
Eur J Surg Oncol.
2000;
26
583-587
40
Shamseddine S I, Khalifeh M J, Mourad F H. et al .
Comparative pharmacokinetics and metabolic pathway of gemcitabine during intravenous
and intra-arterial delivery in unresectable pancreatic cancer patients.
Clin Pharmacokinet.
2005;
44
957-967
41
Vogl T J, Heller M, Zangos S. et al .
Transarterielle Chemoperfusion des inoperablen Pankreaskarzinoms und Lokalrezidivs.
Fortschr Röntgenstr.
2003;
175
695-704
42
Vogl T J, Schwarz W, Eichler K. et al .
Hepatic intraarterial chemotherapy with gemcitabine in patients with unresectable
cholangiocarcinoma and liver metastases of pancreatic cancer: a clinical study on
maximum tolerable dose and treatment efficacy.
J Cancer Res Clin Oncol.
2006;
132
745-55
43
Klapdor R, Seutter E, Lang-Polckow E M. et al .
Locoregional/systemic chemotherapy of locally advanced/metastasized pancreatic cancer
with a combination of mitomycin c and gemcitabine and simultaneous follow-up by imaging
methods and tumor markers.
Anticancer Res.
1999;
19
2459-2469
Prof. Thomas J. Vogl
Institut für Diagnostische und Interventionelle Radiologie, J. W. Goethe-Universität
Frankfurt
Theodor-Stern-Kai 7
60596 Frankfurt
Phone: ++ 49/69/63 01 72 77
Fax: ++ 49/69/63 01 72 58
Email: T.vogl@em.uni-frankfurt.de