Low dose chemotherapy with insulin (Insulin Potentiation Therapy) in combination with hormone therapy for treatment of castration resistant prostate cancer D-r Christo Damyanov, D-r Desislava Gerasimova, D-r Ivan Maslev, D-r Veselin Gavrilov Medical center “Integrative medicine”

Sofia 2012 Medical center “Integrative medicine”

Introduction In spite of the efficacy of standard androgen deprivation therapy for metastasis tumors of prostate gland, almost all of the patients progress with their disease In spite of the efficacy of standard androgen deprivation therapy for metastasis tumors of prostate gland, almost all of the patients progress with their disease Despite obvious efforts for revealing the reasons for hormonal resistance after androgen deprivation the treatment remains a challenge. Despite obvious efforts for revealing the reasons for hormonal resistance after androgen deprivation the treatment remains a challenge. Up to 1990 the results after chemotherapy for hormone- resistant tumors of prostate gland are disappointing. Up to 1990 the results after chemotherapy for hormone- resistant tumors of prostate gland are disappointing. In 2004 two trials registered and prolonged survival after using Docetaxel. In 2004 two trials registered and prolonged survival after using Docetaxel. At this moment the treatment with Docetaxel in combination with Prednisone is accepted as standard of care for metastatic castration resistant prostate tumors [5,6]. At this moment the treatment with Docetaxel in combination with Prednisone is accepted as standard of care for metastatic castration resistant prostate tumors [5,6]. According to our previous experience in implementation of IPTLD in different tumors including castration resistant prostate tumors we conducted a research for new possibilities where our main target was to improve the quality of life. According to our previous experience in implementation of IPTLD in different tumors including castration resistant prostate tumors we conducted a research for new possibilities where our main target was to improve the quality of life. This study is focusing on the potential of IPTLD in combination with hormone therapy for treatment of patients with castration resistant prostate tumors. This study is focusing on the potential of IPTLD in combination with hormone therapy for treatment of patients with castration resistant prostate tumors.

Patients and method Between April 2006 to May 2011 a total 406 patients with diverse tumors were treated with IPTLD and 21 out of them were with prostate cancer. Sixteen of them were with advanced prostate cancer (Stage III – Stage IV and nodal, bone or visceral secondary) and cynically apparent hormonal independence entered the study. Between April 2006 to May 2011 a total 406 patients with diverse tumors were treated with IPTLD and 21 out of them were with prostate cancer. Sixteen of them were with advanced prostate cancer (Stage III – Stage IV and nodal, bone or visceral secondary) and cynically apparent hormonal independence entered the study. The patients were divided into two groups: The patients were divided into two groups: Group A - 8 patients treated with Еpirubicine, Vinblastine, Cyclophosphamide in combination with LHRH agonist (Goserelin depot 3,6mg). Group B another 8 patients were treated with Docetaxel in combination with LHRH agonist (Goserelin depot 3,6mg).

Patients and method Clinical characteristics of the treated patients Clinical parameters Group A Group B Total number of patients 8 8 Age Median64 66 Range Karnovsky Performance Scale (mean) Median68 74 Range Beretta score bifor treatment Median24 24 Range Glison score Unknown0 2

Patients and method Clinical characteristics of the treated patients Tumor stage Stage III 0 0 Stage IV 8 8 Extend of disease(nr.) With local metastases 3 (8) With distant metastases 7(8) 7 ( 8) Previous therapy Surgical orchiectomy 6 (8) 5 (8) Antiandrogens 8 (8) 7 (8) Palliative radiotherapy 4 (8) 0 PSA(ng/ml) Median389,6 1511,2 Range 63, , Al. phosphatase mg/ml Median Range

Patients and method Pre-treatment evaluation of the patients Pre-treatment evaluation of the patients Control lab exams Control lab exams Objective response Objective response Quality of life Quality of life

Patients and method Self Compilation Questionnaire for Determination of Subjective Status according to G.Beretta

Treatment Insulin potentiation therapy (IPT): Insulin potentiation therapy (IPT): 1.Group A - Insulin i.v. ( 0,4 UI/kg.) in combination with Cyclophosphamide (0,10-0,15 g /m2 ) / Epirubicine (3 mg /m2 ); Vinblastine (0,5mg /m2 ) i.v. in 8 patients; 2.Group B – Insulin i.v. (0,4 UI/kg. ) in combination with Docetaxel (3,6 mg /m2) i.v. in 8 patients. Length one scan treatment – 6 applications in every 5 days interval, then sustaining treatment in gradual increasing intervals (four applications in 10 days, 2, 3 and more weeks). Length one scan treatment – 6 applications in every 5 days interval, then sustaining treatment in gradual increasing intervals (four applications in 10 days, 2, 3 and more weeks). In the interval: Dexamethason – 20 mg., Cyclophosphamide - 50 mg. p.o., Doxycyclin-100 mg, Legalon 3 x 140 mg., Celebrex 2 x 7,5 mg., antioxidants and ozone therapy. In the interval: Dexamethason – 20 mg., Cyclophosphamide - 50 mg. p.o., Doxycyclin-100 mg, Legalon 3 x 140 mg., Celebrex 2 x 7,5 mg., antioxidants and ozone therapy. Maintaining treatment consists of no more than 24 IPT applications. Maintaining treatment consists of no more than 24 IPT applications.

Treatment results Treatment results (after 6 IPT) Group A Group B Overall nnn(%) Complete respons 000 Partial respons 5 (8) 3 (8) 8 /16 (50) Stabile disease 2 (8) 4 /16 (25) Progressive disease 1 (8) 3 (8) 4 /16 (25)

Treatment results Treatment results (after 10 IPT) Group A Group B Overall nnn(%) Complete respons 1 (5) 2 (4) 3/9 (33) Partial respons 0 (5) 1 (4) 1/9 (11) Stabile disease 2 (5) 0 (4) 2/9 (22) Progressive disease 2 (5) 1 (4) 3/9 (33)

Treatment results The mean values of PSA Group A Before treatment After 6th (course of treatment) IPT After the 10th course 256, 7 ng/ml 94,6 ng/ml. 36,3 ng/ml. Group B Before treatment After 6th (course of treatment) IPT After the 10th course 2215,3 ng/ml 956,2 ng/ml 4,9 ng/ml

Treatment results - Subjective improvement Quality of life assessment according to Berreta Symptoms Index, after the 6 th IPТ course for Group А

Treatment results - Subjective improvement Quality of life assessment according to Berreta Symptoms Index, after the 6 th IPТ course for Group B

Discussion The theoretical conception for the mechanisms of action of IPT The theoretical conception for the mechanisms of action of IPT Problems of the treatment of hormone-resistant prostate tumors. Problems of the treatment of hormone-resistant prostate tumors. In search of a new method for lowering the toxicity of the chemotherapy for treating oncological diseases we began in 2006 to implement IPTLD combined with LHRH agonist Gosrelin depot 3,6 mg. In search of a new method for lowering the toxicity of the chemotherapy for treating oncological diseases we began in 2006 to implement IPTLD combined with LHRH agonist Gosrelin depot 3,6 mg. Despite the advanced stage of disease in patients treated by us the treatment is well tolerated without any serious side effects. Despite the advanced stage of disease in patients treated by us the treatment is well tolerated without any serious side effects. Quality of life after the second IPTLD application is significantly improved, and this applies even to patients with treatment failure in terms of PSA criteria. Quality of life after the second IPTLD application is significantly improved, and this applies even to patients with treatment failure in terms of PSA criteria.

Conclusion Our present experience with IPTLD (in more than 400 treated patients) with various tumors, as well as the practical experience of the growing number of doctors practicing the method gives us a reason to assume that IPTLD method provides a real opportunity for resolving one of the most serious problems of toxicity associated with chemotherapy using maximum tolerated doses. Our present experience with IPTLD (in more than 400 treated patients) with various tumors, as well as the practical experience of the growing number of doctors practicing the method gives us a reason to assume that IPTLD method provides a real opportunity for resolving one of the most serious problems of toxicity associated with chemotherapy using maximum tolerated doses. A certain advantage of the method along with its effectiveness is the significantly improved quality of life of the treated patients. A certain advantage of the method along with its effectiveness is the significantly improved quality of life of the treated patients. In spite of the small number of patients treated by us with castrate resistant prostate tumor, the preliminary results are promising and this gives us hope and expectations for future serious researches on the potential of widespread clinical use of IPTLD. In spite of the small number of patients treated by us with castrate resistant prostate tumor, the preliminary results are promising and this gives us hope and expectations for future serious researches on the potential of widespread clinical use of IPTLD.

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