Mistletoe extracts (Viscum album) as an adjuvant therapy concept in feline fibrosarcoma. Mistelextrakt (Viscum album) als ergänzendes Therapie- konzept beim ...
Mistletoe extracts (Viscum album) as an adjuvant therapy concept in feline fibrosarcoma Mistelextrakt (Viscum album) als ergänzendes Therapiekonzept beim felinen Fibrosarkom Ulrike BiegeI, Peter Klacke, Kotjo Ruess-Melzer, Borbora Koser-Hatz
Summary
A prospective observational study was conducted with 44 cats with feline fibrosarcoma (FFS) to prevent post-surgical recurrences by administration of per-oral oak mistletoe extracts. All cats received twice daily 0.5 ml of an l
aqueous dilution of 1 mg/ml- Viscum album Quercus equivalent to Iscador® (Hiscia and Weleda, ArIesheim). The median disease-free survival time (DFST) was 447 days (range from 31 to 983 days). Cats operated in a referral veterinary clinic showed a median DFST of 279 days compared to 472 days (not significant) in cats receiving surgery in a veterinary practice. Histologically confirmed completeness of surgery and number of surgeries did not affect survival time significantly. It can be concluded that disease-free survival time shows promising results. Controlled studies have to be conducted for detailed therapy efficacy assessment. Keywords: Fibrosarcoma, feline, cat, Viscum album therapy, survival, KaplanMeier Zusammenfassung
Das feline Fibrosarkom (FFS) stellt durch seine Malignität und seine extrem hohe Rezidivrate ein großes Problem in der Kleintierpraxis dar. Nahezu alle betroffenen Katzen werden einer chirurgischen Entfernung des Tumors unterzogen, entwickeln aber zu einem hohen Prozentsatz innerhalb kurzer Zeit Rezidive. Unterstützende Misteltherapieprotokolle mit Injektionspräparaten wer, den kritisch beurteilt, da FFS im Verdacht stehen, durch mechanische Insulte (Spritzen, Verletzungen) zu entstehen. Die orale Anwendung von Viscum album erscheint daher als mögliche Alternative in der adjuvanten Tumortherapie. In einer prospektiven Anwendungsbeobachtung 44 __ Katzen soll die rezidivproL_ _ ._ _ ,_".,,_._. ___ ."" __ ___ ._.__ _____ ._ _ _ _ _ ._ _ bei __ - ___ __ _ "_. __ _ _ _._.. _ _! 1 ~
~
._~
~
476
111. Klinische Anwendung und Prüfung
phylaktische Wirkung eines oralen Eichenmistelextraktes postoperativ geprüft
Adjuvant therapy concept in feline fibrosarcoma
477
Introduction
werden. Alle Tiere erhielten zweimal täglich 0,5 ml einer wässrigen Viscum Quercus Lösung (Viscum Quercus praeparatum 0,1 % Hiscia und Weleda, ArIesheim). Die mediane rezidivfreie Zeit (DFST, disease-free survival time) betrug 447 Tage (31 bis 983 Tage). Verglichen mit Literaturdaten liegt dieses Ergebnis höher als in Kollektiven ohne adjuvante Therapie (120 d bis ca. 300 d, Operationen ohne Amputation). Erstaunlicherweise zeigten die Katzen, die in einer Spezialklinik operiert worden waren, eine geringere DFST von 279 Tagen, verglichen mit 472 Tagen (nicht signifikant) der Tiere, die in einer allgemeinen Tierarztpraxis operiert worden waren. Weder die histologisch bestätigte komplette Exzision des Tumors, noch die Anzahl der vorausgegangenen Tumorbzw. Rezidivoperationen zeigten einen signifikanten Effekt auf die Überlebenszeit. Zur Bestätigung bzw. Absicherung des als positiv zu wertenden therapeutischen Effektes sind weitere kontrollierte Studien notwendig. Schlüsselwörter: Fibrosarkom, felines, Katze, Viscum album, Misteltherapie,
Überlebenszeit, Kaplan-Meier
Feline fibrosarcoma (FFS) is a malignant soft tissue tumor in cats. The recurrence rate is up to 75 %. Disease-free survival time (DFST) after surgical excision is only 3 to 3.5 months (Stiglmair-Herb 1987; Hershey et al. 2000). DFST increases from two months after surgery in a veterinary practice compared to nine months in a referral clinic. This strongly correlates to the extent of surgery (Hershey et al. 2000). But even complete rem oval of the tumor is no guarantee for success (Kobayashi et al. 2002). Due to frequent relapses and the aggressive nature of the tumor FFS is achallenge for practitioners (Barber et al. 2000). Because of high postsurgical recurrence rates, adjuvant therapy is necessary (Novosad 2003). The varying survival data depends on therapy type, success and extent of prior surgery. For example, post-surgical chemotherapy is associated with a median DFST of 388 days (Poirier et al. 2002), whereas irradiation plus chemotherapy shows various DFST of 66 to 661 days (Davidson et al. 1997; Hershey et al. 2000; Bregazzi et al. 2001; Cohen et al. 2001). The obviously best results could be achieved by extensive surgery and adjuvant irradiation and/or chemotherapy with DFST of 475-986 days (Bregazzi et al. 2001; Kobayashi et al. 2002; Spugnini et al. 2007) Over the past decades, a number of prospective and controlled clinical trials with mistletoe extract and isolated mistletoe ingredients have been conducted (Kienle et al. 2003; Kienle, Kiene 2007). For humans, efficacy of Viscum preparations concerning e. g. quality of life and survival time prolongation (Grossarth-Marticek, Ziegler 2006) as well as increased tolerability of chemotherapy (Piao et al. 2004) have been reported. The standard therapy of Viscum extracts is applied by sub-cutaneous injection. In cats, however, the FFS can be induced by injections such as vaccinations and other agents, respectively (Cohen et al. 2001). Chronic inflammation can lead to neoplastic transformation and formation of sarcomas (Macy, Hendrick 1996). Hence, for this study we used the orally applicable formula Viscum Quernls praeparatum Dilutio aquosa, which is equivalent to Iscador® Qu (oak mistletoe). We wanted to investigate the post-surgical prophylactic effects of Viscum album Quercus extracts in cats with feline fibrosarcoma (FFS).
478
111. Klinische Anwendung und Prüfung
Material and methods 50 cats with clinical confirmation of feline fibrosarcoma and subsequent tumor ex cis ion were enrolled in the study. Three cats were excluded due to surgery failure (recurrence within 30 days after surgery), one cat because of lung metastasis and two were lost to follow-up within 30 days. 44 cats with primary tumors or recurrences, histologically confirmed as feline fibrosarcoma (FFS) remained in the study. The patients were recruited from veterinarian practices (n = 30 from 18 different practice sites) or from a referral clinic (n = 14 from 7 different clinics). The study was conducted as a prospective, non-randomized, non-controlled, multicenter, observational study (case series). After excision and histological confirmation of FFS dia gnosis the treatment was started, which was within 0 to 150 days (median 25 days). An additional clinical evaluation by the veterinarian was conducted one month after the beginning of the Viscum therapy and every 2-3 months thereafter. Twice daily, cats received ten drops (0.5 ml = 0.5 mg) orally of an aqueous dilution of Viscum Quercus praeparatum Dilutio aquosa 1 mg x ml-l (equivalent to Iscador®; Institute Hiscia, Society for Cancer Research and Weleda AG, Arlesheim, Switzerland). Treatment failure was defined by clinically confirmed recurrences, metastasis or death due to FFS. The outcome was assessed by calculation of the disease-free survival time (DFST) which is defined by the period from surgery to treatment failure. The DFST median, 95 % confidence interval and range were calculated to describe the population's distribution of DFST. To study therapy effects depending on quality and completeness of surgery, tumors were assessed as completely excised or incompletely excised depending on histopathologic reports. An event leading to the censo ring of a patient was defined as death due to other reasons, discontinuation of therapy by owner decision, concomitant diseases, and lost to followup. Statistical analysis was performed using Kaplan-Meier survival function with DFST as the dependent variable (see Fig. 1). To identify prognostic factors, the following independed variables were included: sex, age « 10 and 10+ years), number of surgeries (once and more), surgery site (veterinary practice and clinic), and histological evaluation of complete and in-
Adjuvant therapy concept in feline fibrosarcoma
479
complete excision. Differences were tested using Log-Rank test. The median and range of DFST and event incidence per year was calculated. Statistical analysis was performed using the statistical software package R ver. 2.12. Significance level was set to a = .05. 0
rl
Vi" u..
e.
00
0
C'5 .~
...>
:l
Cf)
\D
0
(1) (1)
.:: d>
(J)
C1l
