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AM 68/89 (Resistocell™)
Clinical Research
Summaries of all relevant clinical reports AM 68/89 (Resistocell™) has been used in humans since 1968.
Numerous clinicians have reported their observations concerning welcomeand unwelcome effects of the application of AM 68/89.
The following studies have been chosen according to their systematism and scope and reflect the latest developments in research.
Dr. Blumenberg, Senior Consultant, Central X–ray and Radiotherapy Department, Protestant Hospital, D–Bonn–Bad Godesberg, reports observations from 1969 of 200 patients with advanced tumor diseases patients received the test drug at a point when there was a lack of tumorsensitivity to radiation (primary or secondary resistence) after variousattempts at therapy with radiation or cytostatic agents.
the preparation was always well tolerated.
no allergic reactions were observed.
the patients reported a feeling of well–being after the injections.
in isolated cases it was even possible to reduce the opiate dose.
normalisation of the toxically altered blood picture in some patients whohad been treated with cytostatic agents and radiotherapy, combined with areturn to normal of lymphocyte values, provided there was still somereactivity.
impression of a reduction of the risk of recurrences by regularly applyingthe preparation after successful radio- and cytostatic therapy.
in individual cases when applying the preparation together with radiationor cytostatic agents, response of tumors which had previously notresponded to either of the two therapies.
Application of the preparation considered to be of true therapeutic
value
Blumenberg F.-W.: Erste klinische Erfahrungen über die Zusatztherapie mit einemZellpräparat zur Strahlen- bzw. Zytostatika-Therapie; Die Heilkunst 84, 10,S. 287–289 (1971) Blumenberg F.-W.: Klinische Erfahrung über die Zusatztherapie mit einemZellpräparat zur Strahlen- beziehungsweise Zytostatika-Therapie; Ehk. 20, 8,S. 248–252 (1971) Prof. H. Renner, D-Nuremberg and Prof. Kh. Renner, Senior Consultant, Department of Radiotherapy and Specific Oncology, Hannover Medical School report on their treatment results in various AM 68/89 was administered to 57 patients suffering from breast cancerwith local, osseous or visceral metastases in addition to the SKIT scheme(combined interval chemoradiotherapy), developed by the authors. Eachpatient received 3 to 4 applications starting after the third or fourth thera-peutic cycle and afterwards at 4–weekly–intervals always at the end of atherapeutic cycle. The results were compared with the previous prospectivestudy, Hannover 1975, where the patients had been treated according to thesame scheme but without AM 68/89. Both groups had a balanced distri-bution of operative pretreatments and length of recurrence-free intervals.
The differences in age and recurrence type were taken into account byanalysing subgroups.
striking result of this study was a prolongation of the median survival timefrom 22.2 months (Hannover ’57) to 29.3 months (Hannover ’76).
Significance was only scarcely missed (p=0.056).
repetition of the study Hannover 1976 with identical procedure and 84patients.
median survival time of the patients treated with AM 68 additionally was30.0 months. This result was significant (p=0.009).
Comments on the studies carried out in Hannover
even when subdividing the patients in different risk groups according toage and type of metastases there is a striking correspondence between themedian survival of the patients observed in the studies Hannover 1976 andHannover 1978.
Patients 50- 60-years old and patients with local type metastases seem tobenefit most.
After 1.5 to 2 years the number of survivors in the group treated withAM 68/89 additionally to radio- and chemotherapy is considerably higherthan in the group treated without AM 68/89.
early mortality within the first year does not seem to change, though thefraction of long-term survivors increases, sometimes considerably, afterfour to five years.
Prof. H. Renner, Nuremberg and Prof. Kh. Renner, Hannover report on theirtreatment results in various studies (continuation): Retrospective study Nuremberg 1976–1985 48 patients with local recurrences, exclusively high- risk patients withearly recurrences or presenting fairly large residual tumors on the outerthorax or in the lymphatic nodes at the time of the therapy, were treatedaccording to the SKIT scheme; one subgroup received additional treatmentwith AM 68/89. In contrast to the Hannover study prednisone was notadministered and AM 68/89 was not given at the end of each therapeuticcycle but in the middle of the therapy–free interval. In isolated cases thefirst application of AM 68/89 was administered in the interval after thefirst cycle, with the total number of applications ranging from 3 to 18(mean value 6.5). 8 patients with inflammatory type recurrences wereexcluded from the evaluation, because they were not equally represented inboth groups.
median survival time of the group additionally treated with AM 68/89(n=22) was on average 61 months compared to 38 months in the groupwho did not receive this additional treatment (n=18).
it seems not only to improve long-term survival but also early mortality.
the number of patients is too small and therefore, despite the 23 monthsdifference, no significance is obtained.
Overall Assessment
The authors conclude by reporting that three different studies on advancedbreast cancer have shown a reproducible improvement of long–termsurvival and are of the opinion that further controlled studies are essential.
A worthwhile starting-point seems to have been reached.
Renner Kh., A. Emminger, R. Bendel, V. Bendel, J. Slomska, D. Gefeller, T.
Runge: Resistocell(R) als Adjuvans in der Therapie des fortgeschrittenenMamma-Carcinoms: Bericht über eine prospektive klinische Studie;Cytobiol.Rev. 7, 2, S. 60–67 (1983) Renner Kh.: Zusatzbehandlung mit ”Resistocell” bei fortgeschrittenem Mamma-karzinom; Krebsgesch. 18, 5, S. 123–128 (1986) Renner H. Kh. Renner: Die Therapie mit xenogenem, lyophilisierten Fetalgewebeals Adjuvans beim fortgeschrittenen Mammakarzinom; Akt.Onk. 32, S. 75–83,W. Zuckschwerdt, München Bern Wien (1986) Prof. Dr. G. Bastert, Managing Director of University Women’sHospital Heidelberg, comments on the clinical studies with AM 68/89carried out in his clinic pilot study with 77 patients with breast cancer, some of them treatedadjuvantly, the majority receiving palliative treatment.
the most striking aspects were the improvement of the activity index(Karnofsky) and the reduction of pain sensation.
further interesting aspects are the long–term survival of 4 patients withmetastasized breast cancer as well as that of 3 primary high-risk cases.
because of the results of the pilot study Prof. Kubli initiated a prospectiverandomised study on metastasized breast cancer, in which – due to lack ofpersonnel – the planned systemic ascertainment of quality of life couldhowever not be carried out [regarding the progression–free interval,median survival after recurrence and total survival after primary operation,no favorable but also no unfavorable effects of the additional treatmentwith AM 8/89 were observed].
the side–effects of an application of AM 68/89 were systematicallyrecorded [documentation of 3244 applications in 252 patients].
The submitted results should make possible a prospective multicentric
study, applying phase I and II criteria
Bastert G.: Kommentar zu Prof. Landsbergers ”Untersuchung bei sieben langzeit-überlebenden Mammakarzinompatientinnen mit AM 68/89 additiv zu konventio-neller Therapie”; dat. den 09.10 1990 Schmid H., M. Kaufmann, U. Abel, F. Kubli: Lyophilisiertes fetales Mesenchym(Resistocell™) beim metastasierten Mammakarzinom – prospektiv randomisierteStudie; TumorDiagnostik&Therapie 10, S. 115–118 (1989) Bestätigung der Dokumentation über unerwünschte Wirkungen von AM 68/89durch Dr. Hans Schmid, Leiter der Onkologischen Ambulanz derUniversitätsfrauenklinik Heidelberg, dat. den 17.01.92 Schmid H.: Stellungnahme zur Studie ”Lyophilisiertes fetales Mesenchym(Resistocell™) beim metastasierten Mamma-Carcinom – eine prospektivrandomisierte Studie;” dat. den 11.05.1993 Interpretation of the results concerning the quality of life of thewomen treated within the framework of the pilot study carried out atUniversity Women’s Hospital Heidelberg with AM 68/89 in additionto the standard therapy from the very beginning a distinct increase of activity as defined byKarnofsky was observed.
also a distinct reduction of disease–related pain.
the assessment made by the doctors in attendance is confirmed in the self-assessment of the patients.
only after 43 months does the trend reverse, but with the exception ofactivity.
on average the scores for the condition improved by 27 %, for complaintsby 19 % and for pain by 39 %, in patients with multilocular pain by even51 %. Activity index rises by an average of 2 points (10–point scale).
marked improvement of the activity index especially in patients who hadstarted with values of less than 5.
Overall Assessment
In summary, one can say that there was an improvement in the quality oflife of the patients with breast cancer additionally treated with AM 68/89.
This improvement can be seen in the first control examination, after onemonth, and lasts – with decreasing numbers of observed cases – for up to43 months. Patients with an initially harsh reduction in quality of life alsoexperienced an improvement, even a particularly obvious one University Women’s Hospital Heidelberg, D. Landsberger, M. Landsberger Selected results from the orientating prospective clinical study of the effectiveness of additional treatment with AM 68/89 of patients with breast cancer at University Women’s Hospital Heidelberg Quality of life of the patients, determined with the activity index as defined by Karnofsky
Mean values of the activity index (Karnofsky) 1 0 1 3 1 6 1 9 2 2 2 5 2 8 3 1 3 4 3 7 4 0 4 3 4 6 4 9 t(m) Mean values of the activity index before the first application of AM 68/89 (S) and during thestudy over 49 months. All patients for whom activity index data where available are included.
On the abscissa, the number of patients observed at each point is shown additionally.
Mean values of the relative individual index changes 1 0 1 3 1 6 1 9 2 2 2 5 2 8 3 1 3 4 3 7 4 0 4 3 4 6 4 9 t(m) In order to rule out the possibility that the improvement of the mean values is due to selectionof those patients who, initially or throughout, had a lesser reduction, the relative index changecompared with the initial value (S) was worked out for each individual and, on this basis, themean value for the total population was calculated. Presentation as above.
Pain sensation of the patients, determined and rated by the doctor in attendance
1 0 1 3 1 6 1 9 2 2 2 5 2 8 3 1 3 4 3 7 4 0 4 3 4 6 4 9 t(m) Mean values of pain sensation before the first application of AM 68/89 (S) and during the studyover 49 months. Scale ranging from 0 (no pain) to 4 (most severe pain). All patients who, at anypoint of the study, complained about having pain are included. On the abscissa, the number ofpatients observed at each point is shown additionally. In patients with multilocular pains detailsof the different locations of the pain were averaged.
1 0 1 3 1 6 1 9 2 2 2 5 2 8 3 1 3 4 3 7 4 0 4 3 4 6 4 9 t(m) Mean values of the relative individual changes of pain sensation In order to rule out the possibility that the improvement of the mean values is due to selectionof those patients who, initially or constantly, had less pain the relative change of pain sensationcompared to the initial value (S) was worked out for each individual and, on this basis, themean value for the total population was calculated. Presentation as above.

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