R.G.C.C. International GmbH CTCs & CSCs Analysis: Practical - - PowerPoint PPT Presentation
R.G.C.C. International GmbH CTCs & CSCs Analysis: Practical model AUTHOR-PRESENTER: DR. IOANNIS PAPASOTIRIOU THIS PRESENTATION CONSIDERED RGCC LTD INTELECTUAL PROPERTY AND THE USE OF A PART OR ALL RESENTATION FOR GENERATION OF ANOTHER
CTCs & CSCs Analysis: Practical model
AUTHOR-PRESENTER: DR. IOANNIS PAPASOTIRIOU
THIS PRESENTATION CONSIDERED RGCC LTD INTELECTUAL PROPERTY AND THE USE OF A PART OR ALL RESENTATION FOR GENERATION OF ANOTHER MATERIAL OR ADVERTISEMENT PRIOR RGCC’s CONCENT, WILL BE A VIOLATION OF A LAW
INDUCTION CONSOLIDATION MAINTENANCE ???? : TIMING OF FOLLOW-UP :ONCOSTAT (former TUP)
ONCOTRACE ONCOSTAT -PLUS SNiP IMMUNOSTAT SCORE ECOG
PERFORMANCE SCORE ECOG GOOD PERFORMANCE ECOG 0-2 POOR PERFORMANCE ECOG 3-4 SUPPORT THERAPY STAGE OF THE DISEASE (ONCOTRACE) MRD IMMUNOSTAT+METASTAT
CONSIDER THE OPTION FOR IMMUNOTHERAPY (DCs & MOAB) OR METRONOMIC THERAPY
ONCOSTAT EXTRACT
ADVANCE PD (ONCOSTAT PLUS) PK (SNiP)
HYPERTHERMIA CHEMICAL AGENTS NATURAL SUBSTANCES RADIOTHERAPY TARGETED THERAPIES
FOLLOW UP
ONCOTRAIL ONCOCOUNT IN HIGH RISK REASSESMENT IN LOW RISK CONTINUE REASSESS PERFORMANCE
ALGORITHM FOR PATIENTS WITH THE PRESENCE OF THE DISEASE
WHICH AGENTS ARE EFFECTIVE TO CANCER CELLS? (Pharmacodynamic-PD) HOW EFFICIENTLY THE BODY TRANSPORMS THE AGENTS TO THEIR ACTIVE FORM? (Pharmacokinetic-PK)
TREATMENT PLAN
Pharmacodynamic analysis Oncostat plus Conventional agents
Natural substances 1. Class I (cytotoxic affect)
2. Class II (growth factor inh.)
3. Class III (immunomodulators)
Pharmakinetic analysis ChemoSNiP Conventional agents
Natural substances 1. Class I (cytotoxic affect)
2. Class II (growth factor inh.)
3. Class III (immunomodulators)
Therapy options for clinical use Conventional agents
Natural substances 1. Class I (cytotoxic affect)
2. Class II (growth factor inh.)
3. Class III (immunomodulators)
1.
The agents are chosen one from each group in order to achieve synchronization and maximum effect.
2.
Besides the alkyliating agents all the rest are active in specific point of the cells cycle.
topoisomerase I & II inhibitors
epothilones
1.
One agent from each class is chosen for application for one month (the one with the most high efficacy)
2.
Shift to the next more efficient agent from each class in order to avoid secondary resistance)
1.
The TKI or the Moab are chosen by the markers
anaphase prophase metaphase telophase G1 phase S phase G2 phase G0 phase taxanes Alcaloid of vinca Antibiotics Antimetabolites Topoisomerase I Topoisomerase II
FUNCTION CLINICAL RISK MARKERS RESULTS OUTCOME Migration- invasion HIGH RISK MMPs 0>= LOW RISK KISS-1-r 0<= LOW RISK Nm23 0> HIGH RISK Angiogenesis LOW RISK VEGFr FGFr PDGFr MECHANISM CLINICAL RISK MARKERS RESULTS OUTCOME Signal transduction pathways HIGH PROLIFERATI VE SIGNAL Ras/raf/MEK/Erk 1-2 >0 HIGH mTOR =<0 LOW Growth factor receptors LOW PROLIFERATI VE SIGNAL EGFr TGF-β1/2 c-erb-B2 Hormone receptors HORMONE DEPENDED Estrogen Receptor Progesterone Receptor NC3R4 NC3R4 Cell cycle rate RAPID P27 >0 SLOW P16 >0 RAPID P53 >0 RAPID
MARKERS RESULTS OUTCOME PHENOTYPE Dnmt1 >0 RESISTANT RESISTANT PHENOTYPE DNA demethylase O6 akyltransferase HAT Histone deacetylase Marker Result (%) Clinical outcome per marker Clinical
HSP90
SENSITIVE SENSITIVE HSP72 NOT SENSITIVE HSP27 15 NOT SENSITIVE
Patients with present macroscopic disease
1. In order to identify active substances and drug against the disease the following test are recommended
2. In order to identify whether each patient is able to metabolize normaly each agent and receive the biological benefit from it the following test is recommended
3. For following up and monitor the patient the following test are recommended
4. Time interval for the follow-up tools
Patients with minimal residual disease
PERFORMANCE STATUS
PERFORMANCE SCORE ECOG GOOD PERFORMANCE ECOG 0-2 POOR PERFORMANCE ECOG 3-4 SUPPORT THERAPY STAGE OF THE DISEASE (ONCOTRACE) MRD IMMUNOSTAT+METASTAT
CONSIDER THE OPTION FOR IMMUNOTHERAPY (DCs & MOAB) OR METRONOMIC THERAPY
ONCOSTAT EXTRACT
ADVANCE PD (ONCOSTAT PLUS) PK (SNiP)
HYPERTHERMIA CHEMICAL AGENTS NATURAL SUBSTANCES RADIOTHERAPY TARGETED THERAPIES
FOLLOW UP
ONCOTRAIL ONCOCOUNT IN HIGH RISK REASSESMENT IN LOW RISK CONTINUE REASSESS PERFORMANCE
(ONCOSTAT PLUS)
Non cell cycle depended S phase of cell cycle Metaphases Alkyliating agents Inhibitors of topoisomerase I Inhibitors of topoisomerase II antimetabolites Inhibitors of tubulin polymerization Spindle poisoning agents
GEMCITABINE VINORELBIN ABRAXAN Moab (Monoclonal Antibodies) SMW (Small Molecular Weight molecule) ANASTROZOL TEMSIROLIMUS ERLOTINIB Class I
(cytotoxic agents)
Class II
(growth factors inhibitors)
Class III
(immuno-modulatory effect)
ARTEMISININ QUERCETINE MISTELTOE VITAMIN C GENISTEIN VITAMIN D Marker Result (%) Clinical outcome per marker Clinical
HSP90
SENSITIVE SENSITIVE HSP72 NOT SENSITIVE HSP27 15 NOT SENSITIVE
Sensitive-effective area Partial sensitive area No sensitive area
Natural-biological substances
1.
They include all natural extract from plants or cells which may have direct on indirect therapeutic (anticancer) activity.
2.
Mainly in cancer therapy almost the majority of natural substances they have an unknown mechanism of action or they have multiple interference in many point and pathways.
3.
Additionally they composed from a large number of substance with potent anticancer activity. Generally their anticancer activity can be categorized as follows
1.
Direct anticancer-cytotoxic effect (without a known mechanism of action)
2.
Block of growth factors
3.
Stimulation of immune system and activation of immune cells.
Sensitive-effective area
(ONCOSTAT PLUS)+(CHEMO-SNIPS)
Non cell cycle depended S phase of cell cycle Metaphases Alkyliating agents Inhibitors of topoisomerase I Inhibitors of topoisomerase II antimetabolites Inhibitors of tubulin polymerization Spindle poisoning agents
GEMCITABINE VINORELBIN ABRAXAN Moab (Monoclonal Antibodies) SMW (Small Molecular Weight molecule) ANASTROZOL TEMSIROLIMUS ERLOTINIB Class I
(cytotoxic agents)
Class II
(growth factors inhibitors)
Class III
(immuno-modulatory effect)
ARTEMISININ QUERCETINE MISTELTOE VITAMIN C GENISTEIN VITAMIN D Marker Result (%) Clinical outcome per marker Clinical
HSP90
SENSITIVE SENSITIVE HSP72 NOT SENSITIVE HSP27 15 NOT SENSITIVE
RAPID METABOLIZER
RADIATION HYPERTHERMIA SENSITIVE
PERFORMANCE SCORE ECOG GOOD PERFORMANCE ECOG 0-2 POOR PERFORMANCE ECOG 3-4 SUPPORT THERAPY STAGE OF THE DISEASE (ONCOTRACE) MRD IMMUNOSTAT+METASTAT
CONSIDER THE OPTION FOR IMMUNOTHERAPY (DCs & MOAB) OR METRONOMIC THERAPY
ONCOSTAT EXTRACT
ADVANCE PD (ONCOSTAT PLUS) PK (SNiP)
HYPERTHERMIA CHEMICAL AGENTS NATURAL SUBSTANCES RADIOTHERAPY TARGETED THERAPIES
FOLLOW UP
ONCOTRAIL ONCOCOUNT IN HIGH RISK REASSESMENT IN LOW RISK CONTINUE REASSESS PERFORMANCE
(TREATMENT OPTIONS) CONVENTIONAL GEMCITABINE AND VINORELBINE TARGETED ANASTROZOLE AND TEMSIROLIMUS NATURAL ARTEMISININE VITAMIN C VITAMIN D QUERCETINE GENISTEIN MISTELTOE OTHERS RADIOTHERAPY OR HYPERTHERMIA (local or general) PRINCIPLES
from the higher performance substance to the less active.
schedule in order to avoid secondary resistances
PATIENT FOLLOW ONCOSTAT PLUS WITH CTC IN 18.3 CELLS/7,5ML (CUT OFF 5CELL/7,5ML)
PERFORMANCE SCORE ECOG GOOD PERFORMANCE ECOG 0-2 POOR PERFORMANCE ECOG 3-4 SUPPORT THERAPY STAGE OF THE DISEASE (ONCOTRACE) MRD IMMUNOSTAT+METASTAT
CONSIDER THE OPTION FOR IMMUNOTHERAPY (DCs & MOAB) OR METRONOMIC THERAPY
ONCOSTAT EXTRACT
ADVANCE PD (ONCOSTAT PLUS) PK (SNiP)
HYPERTHERMIA CHEMICAL AGENTS NATURAL SUBSTANCES RADIOTHERAPY TARGETED THERAPIES
FOLLOW UP
ONCOTRAIL ONCOCOUNT IN HIGH RISK REASSESMENT IN LOW RISK CONTINUE REASSESS PERFORMANCE
(FOLLOW UP) CONVENTIONAL GEMCITABINE AND VINORELBINE TARGETED ANASTROZOLE AND TEMSIROLIMUS NATURAL ARTEMISININE VITAMIN C VITAMIN D QUERCETINE GENISTEIN MISTELTOE OTHERS HYPERTHERMIA (general) PRINCIPLES
(breast oncotrail) . Otherwise the usage of Oncotrace is recommended
Oncotrail/Oncotrace will be replace by oncocount in sequential model. After the second year continue in a semester time interval.
Are related with high risk of relapse.
PATIENT FOLLOW THE PLAN BELOW FOR 4 CYCLES FOR CONVENTIONAL DRUGS
malignancies (above that level considered as high risk
1.
Breast carcinoma: 5cells/7.5ml
2.
Lung carcinoma: 10cells/ml
3.
Prostate: 20cells/ml
4.
Colon: 5cells/ml
5.
Sarcoma: 15cells/6.5ml
6.
Others: 5cells/ml
The second but most important parameter is the phenotype of the CTCs.
worse the prognosis.
a.
Nanog
b.
Sox-2
c.
Oct ¾
d.
CD133
e.
CD44
NOTICE: CTCs phenotype prevails to the number of CTCs as risk factor.
(FOLLOW UP) 1 breast oncotrail (3m)
8,1cell/7.5ml
5 breast oncotrail (15m)
4cell/7.5ml
2 oncocount (6m)
5,4cell/7.5ml
6 oncocount (18m)
3.8cell/7.5ml
3 breast oncotrail (9m)
4,8cell/7.5ml
7 breast oncotrail (21m)
4.3cell/7.5ml
4 oncocount (12m)
4,3cell/7.5ml
8 oncocount (24m)
4.1cell/7.5ml
PATIENT RECEIVES CONVENTIONAL AGENTS FOR 6 CYCLES AND THEN REASSESSED
5 10 15 20 PATIENTS (CELLS/7.5ML) CUT OFF MARKERS ON ONCOTRAILS CD133: + OCT3/4: - CD44: +/- C-MET: - NANOG: + SOX-2: -
PERFORMANCE SCORE ECOG GOOD PERFORMANCE ECOG 0-2 POOR PERFORMANCE ECOG 3-4 SUPPORT THERAPY STAGE OF THE DISEASE (ONCOTRACE) MRD IMMUNOSTAT+METASTAT
CONSIDER THE OPTION FOR IMMUNOTHERAPY (DCs & MOAB) OR METRONOMIC THERAPY
ONCOSTAT EXTRACT
ADVANCE PD (ONCOSTAT PLUS) PK (SNiP)
HYPERTHERMIA CHEMICAL AGENTS NATURAL SUBSTANCES RADIOTHERAPY TARGETED THERAPIES
FOLLOW UP
ONCOTRAIL ONCOCOUNT IN HIGH RISK REASSESMENT IN LOW RISK CONTINUE REASSESS PERFORMANCE
(REASSESSMENT)
PATIENT AFTER TWO YEARS WITH NO SIGNS OF MACROSCOPIC DISEASE CONSIDERED AS CANDIDATE FOR IMMUNOTHERAPY IN MDR STAGE AFTER ASSESSMENT WITH IMMUNOSTAT & METASTAT Metastasis location Marker
Sample levels Ct Normal levels Ct Results General TGF-β R2
15,13 9,38
↓ ITGB-4 R
17,25
17,08
CCR6
20,55 12,26
↓ Mesothelin
CCR7
15,46 10,09
↓ Lung IGF-R2
17,74 11,71
↓ Phospho-ERK1/2
19,79 15,39
↓ Bone BMPR 1a/1b/2
17,46 13,93
↓ CXCR4
18,43 12,58
↓ RANK
17,74
15,96 12,04
↓ Liver CXCR4
18,43 12,58
↓ TRAIL-R2
15,84 9,66
↓ FAS R
15,26 8,20
↓ HGFR
24,15
Phospho-STAT-3
14,15 8,09
↓ CX3CR1
14,31 7,03
↓ DSC-2
(REASSESSMENT)
PATIENT AFTER TWO YEARS WITH NO SIGNS OF MACROSCOPIC DISEASE CONSIDERED AS CANDIDATE FOR IMMUNOTHERAPY IN MDR STAGE AFTER ASSESSMENT WITH IMMUNOSTAT & METASTAT
Hematopoiet ic cells Cell type Markers/cytokines control Result
CD45 positive cells B cells Plasma cells CD19 ↑ Naïve B cells CD20 − Memory cells CD28 − T cells CD8 (Cytotoxic T Lymphocytes, CTLs) CD62L − CD4 (T helper cells, TH) Th1 (cell mediated immunity) IFN-γ (interferon gamma) ↑ Th2 (humoral immunity) IL-4 (Interleukin 4) ↑ IL-6 (Interleukin 6) ↑ IL-2 (Interleukin 2) ↑ Th3 (suppresse d immunity) TNF-α (Tumor Necrosis Factor alpha)
regulatory cells (Tregs) CD25 − CTLA4
CD28 − Antigen Presenting Cells (APCs) Dendritic cells (DCs) CD80 ↑ CD86 ↑
POTENCY FOR IMMUNE PRIMING
PERFORMANCE SCORE ECOG GOOD PERFORMANCE ECOG 0-2 POOR PERFORMANCE ECOG 3-4 SUPPORT THERAPY STAGE OF THE DISEASE (ONCOTRACE) MRD IMMUNOSTAT+METASTAT
CONSIDER THE OPTION FOR IMMUNOTHERAPY (DCs & MOAB) OR METRONOMIC THERAPY
ONCOSTAT EXTRACT
ADVANCE PD (ONCOSTAT PLUS) PK (SNiP)
HYPERTHERMIA CHEMICAL AGENTS NATURAL SUBSTANCES RADIOTHERAPY TARGETED THERAPIES
FOLLOW UP
ONCOTRAIL ONCOCOUNT IN HIGH RISK REASSESMENT IN LOW RISK CONTINUE REASSESS PERFORMANCE
(FOLLOW UP) 9 breast oncotrail (27m)
3,9cell/7.5ml
13th breast oncotrail (39m)
2.8cell/7.5ml
10 oncocount (30m)
3,5cell/7.5ml
14th oncocount (42m)
2.7cell/7.5ml
11thbreast oncotrail(33m)
3.3cell/7.5ml
15th breast oncotrail (45m)
2.9cell/7.5ml
12th oncocount (36m)
3cell/7.5ml
16th oncocount (48m)
2.6cell/7.5ml
PATIENT RECEIVES PRIMED DCs FOR CTCs ANTIGENS AS MAINTENANCE THERAPY
5 10 15 20 PATIENTS (CELLS/7.5ML) CUT OFF
DCs THERAPY
MARKERS ON ONCOTRAILS CD133: + OCT3/4: - CD44: +/- C-MET: - NANOG: + SOX-2: -
Patient: Ch, O, D.O.B. 13.10.73
Diagnosis: Hodgkin's disease, nodular sclerotic type
Past history:
01/00 Diagnosis of Hodgkin's disease, nodular sclerotic type
04/00-08/00 Chemotherapy with BMOP (Bleomycin, etoposide, methotrexate, vincristine and prednisolone) alternating weekly with cyclophosphamide and adriamycin, with partial remission.
Mantle field radiotherapy commenced but ceased after second dose due to severe side effects
09/00-10/00 Progressive disease. No chemotherapy, using alternative medicines
02/01 Progressive disease, chemotherapy with ESHAP (etoposide, cisplatin, cytarabine, prednisolone) but without remission
03/01 Change of chemotherapy to Gemzar, Navelbine and betamethasone, with partial remission
06/01 High dose chemotherapy with BEAM with autologous PBSC, with full remission on gallium scan and CT scan
02/02-03/02 Progressive disease – right axillary lymph node, treated with radiotherapy with remission
08/02 Progressive disease – bilateral hilar and mediastinal lymph nodes, symptomatic treatment
01/04 Further progressive disease, controlled trial treatment with CD-30 antibodies with no effect
05/04 Markedly progressive disease – mediastinal, hilar, retroperitoneal and vena portae lymph nodes, confirmed on PET 06/04
06/04-07/04 Gemzar x3, with no effect
08/04-12/04 Commenced treatment at our clinic, initially with high dose prednisolone then chemotherapy with Vinblastin (40mg) in combination with Procarbacin, x4 cycles, together with CD20 antibody Mabthera plus bilateral hilar mediastinal radiotherapy (total 72 Gy). Local chemotherapy. Hyperthermia.
12/04 Restaging, with full remission in both PET and MRI
11/07 CTC 7,3 cells/ml
2/08 Mabthera
CTC 10,4 cells/ml
PET CT 20.2.2008 – complete remission (‘unremarkable whole body PET CT, no suggestion of recurrence or secondary malignancy’)
4/08 Mabthera
12/08 Mabthera
CTC 6,2 cells/ml
1/09 Mabthera,
10/10 CTC 3,7 cells/ml
Now Remains in full remission
2 4 6 8 10 12 01/10/2007 01/01/2008 01/04/2008 01/07/2008 01/10/2008 01/01/2009 01/04/2009 01/07/2009 01/10/2009 01/01/2010 01/04/2010 01/07/2010 01/10/2010
CTC
CTC 0,5 1 1,5 2 2,5 01/10/2007 01/12/2007 01/02/2008 01/04/2008 01/06/2008 01/08/2008 01/10/2008 01/12/2008
ß-microglobulin
ß- microglobulin
History D.F. 28.1.1947 2006: Abnormal mammogram then MRI diagnosed stage IV breast cancer with bone, liver and lymph node metastases. Therapy – bilateral mastectomy (ER+, HER2 –ve) then monthly Zometa, Femara 2008: Hepatic recurrence, therapy changed from Femara to Xeloda plus Herceptin (now HER2 +) 2009: Progressive disease. Xeloda increased. Tycarb commenced with initial beneficial effect but then further progression. Therapy changed to Abraxane plus Carboplatin (but reduced blood count) 9/2010 Markedly progressive disease on CT with massive increase in hepatic tumour mass, therapy changed to Abraxane, Zometa and Herceptin with partial remission (In this clinic) 29.9.10-4.11.10 Chemosensitivity test performed Local therapy – chemoperfusion/chemoembolisation (Prof Vogl, Uniklinik Frankfurt), x3 (28.9.2010 Mitomycin C + Avastin, 12.10.2010 Mitomycin C + Avastin, 29.10.2010 Gemcitabine + Avastin), initial MRI shows massive hepatic infiltration Systemic chemotherapy – 2.10.2010 Navelbine 50 mg (with whole body hyperthermia) Antibody therapy – Thalidomide Other – Faslodex, Zometa, Bondronate, whole body hyperthermia (x3),
Ongoing therapy at home – Navelbine, Thalidomide, Faslodex, Bondronate, Lektinol, 25.1.2011-7.2.2011 Local therapy – chemoembolisation/chemoperfusion (Prof Vogl, Uniklinik Frankfurt) with Mitoycin C + Avastin (31.1.2011) Systemic chemotherapy 27.1.2011 Navelbine 50 mg (together with whole body hyperthermia) Antibody therapy – Thalidomide (ceased 25.1.2011) replaced with Herceptin (3 weekly) Other therapies – Faslodex, Zometa, Bondronate, Artesunate, Lektinol, whole body hyperthermia x2 Ongoing therapy at home - Navelbine, Herceptin, Faslodex, Bondronate, Lektinol,
10.3.2011- 8.4.2011 Local therapy – chemoembolisation/chemoperfusion (Prof Vogl, Uniklinik Frankfurt) with Mitoycin C + Avastin (14.3.2011) Antibody therapy – Removab 16.3.2011 (5 mcg), 21.3.2011 (10 mcg), 28.3.2011 (10 mcg) Other therapies – Faslodex, Zometa, Artesunate, Lektinol Staging – PET CT – 6.4.2011 – total remission in bones and lungs, good partial remission in liver Ongoing therapy at home - Navelbine, Herceptin, Faslodex, Lektinol 20.5.2011-28.5.2011 Local therapy – chemoembolisation/chemoperfusion (Prof Vogl, Uniklinik Frankfurt) with Mitoycin C + Avastin (19.5.2011) Systemic chemotherapy 27.1.2011 Navelbine 50 mg (together with whole body hyperthermia) Anti-hormone therapy – Faslodex; Other therapies – Zometa, Bondronate Supportive therapies – whole body hyperthermia (23.5.2011), Artesunate, Lektinol
Ongoing therapy at home - Navelbine, Herceptin, Faslodex, Lektinol , Bondronate 10.9.2011-6.10.2011 Local therapy – chemoembolisation/chemoperfusion (Prof Vogl, Uniklinik Frankfurt) with Mitoycin C + Avastin (13.9.2011) and 23.9.11 (with Gemcitabine) – MRI shows progressive hepatic disease Antibody therapy – Removab (5 mcg 18.9.11, 10 mcg 28.9.11) Anti-hormone therapy – Faslodex, changed to Tamoxifen 22.9.11 Other therapies – Zometa, Bondronate, whole body hyperthermia (x2), Artesunate, DCA, Lektinol Staging PET CT (5.10.11) – single minimal residual hepatic lesion only
1 2 3 4 5 6 7
CTC (cells/7,5 ml)
CTC (cells/7,5 ml) 500 1000 1500 2000 2500 3000 CEA CA15-3 CA27,29 CA125
M,M 29.7.1968
Diagnosis: Lennerts lymphoma (Hodgkins disease), stage IV, CD20 positive, CD30 negative
First diagnosed 7/2008 after biopsy of cervical lymph node (left)
10.7.2008 PET CT multiple hypermetabolic mediastinal, abdominal and retroperitoneal lymph nodes as well as hepatosplenomegaly
16.9-23.10.08 BEA COPP-14 scheme, x3 cycles (Bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine plus prednisone), then Mabthera x1 cycle with good remission
16.9.08 Chemosensitivity test
30.10.2008 PET CT shows full remission
18.11-12.12.08 Maintenance chemotherapy (reduced dose) plus second cycle of Mabthera 600mg (to be continued every 6 weeks for 12 months),
24.11.2008 CT shows multiple small, not pathologically enlarged lymph nodes in cervical and para-aortic regions
27.2-13.3.09 PET CT 27.2 shows full remission
Chemosensitivity test on 9.3.09 shows 3,7 cells, with greatest sensitivity to Bleomycin, Etoposide,and vincristine plus rituximab, bortezomib and bevacizumab plus quercetin, c- statin, poly MVA and vitamin C
Therapy with Mabthera 600 mg, (and continuing 6 weekly to 8/09), plus Thalidomide 100 mg nocte
17.8.2009 Chemosensitivity test shows 2,9 cells, greatest sensitivity for etoposide and vincristine plus rituximab, bortezomib and bevacizumab plus thalidomide plus quercetin, c-statin and vitamin C
30.9.2009 CTC shows 2,2 cells
7.12-17.12.09 PET CT 7.12.09 shows full remission
Therapy with DCA, whole body hyperthermia
1.5-10.5.10 CTC shows no tumour cells
PET CT on 30.4.10 shows questionable metabolic activity in a small right inguinal lymph node, however subsequent surgical review and ultrasound found no suspicious node
Supportive therapy
3.11-10.11.10 PET CT full remission, the right inguinal lymph node is no longer visible
CTC shows no malignant cells
Supportive therapies
14.10-16.10.11 CTC shows <1 cell/ml
Supportive therapies
0,5 1 1,5 2 2,5 3 3,5 4 01/03/2009 01/06/2009 01/09/2009 01/12/2009 01/03/2010 01/06/2010 01/09/2010 01/12/2010 01/03/2011 01/06/2011
CTC (cells/ml)
CTC (cells/ml) 2 4 6 8 10 12 14 01/09/2008 01/12/2008 01/03/2009 01/06/2009 01/09/2009 01/12/2009 01/03/2010 01/06/2010 01/09/2010 01/12/2010 01/03/2011 01/06/2011 01/09/2011 Thymidine kinase (<7) β-2 microglobulin (0,7- 1,8)
Patient: Q, D, D.O.B. 11.06.47 Diagnosis: Adenoid cystic tracheal cancer, first diagnosed in 01/99 (NSCLC) Lung metastases, confirmed in 2002 Past history: 07/98 Increasing dyspnoea 01/99 First diagnosis of adenoid cystic carcinoma of trachea, at carinal level 03/99 Surgical resection, with free margins, followed by 05/99 Radiotherapy (650 rd over 6 weeks) 10/01 CT showed tiny lung ‘specks’ – considered not definitely malignant 06/02 CT scan showed 32 pulmonary metastases, bilaterally. Treated with 3 wedge resections (upper lobe left lung and lower lobe left lung x2), with histology confirming adenoid cystic carcinoma Chemosensitivity testing revealed no expected efficacy for chemotherapy 07/03-03/07 Sutent (with varying dosage regimes) 01/07 Restaging by PET (cf PET 04/06) and CT chest/abdomen showed stable disease for bilateral pulmonary metastases and no evidence of abdominal metastatic disease Treated with Carboplatin/Gemzar with no apparent effect (per pt)
8/07 Change to Tarceva Dendritic cell vaccination 11-12/07 Chemoperfusion of right lung 13.11.07 with Gemzar 1400 mg, Mitomycin 12,5 mg then left lung on 19.11.07 with and Oxaliplatin 60 mg, also antibody therapy with Tarceva (after chemosensitivity testing 11/07) Chemosensitivity testing Therapy at home with Tarceva, 01/08 Chemoembolisation (right lung 9.1.08, left lung 16.1.08 with Gemcitabine 1400mg plus Mitomycin 10mg)with MRI after second showing stable disease to partial
Therapy at home with Tarceva PET CT (27.2.08) numerous bilateral hypermetabolic pulmonary parenchymal nodules consistent with metastases. New in comparison with previous PET of 23.11.04 16.3-2.4.08 Chemoperfusion left lung 18.3.08, Oxaliplatin 60 mg then right lung 19.3.08 with Gemcitabine 1000 mg plus Mitomycin C 10 mg Tarceva ceased, Chemosensitivity test 31.3.08 Therapy at home with Tarceva,
PET CT shows ?pelvic lymph node, otherwise stable disease CTC 24.6.08 showed 4,7 cells/ml, CEA reduced Chemotherapy with Cisplatin and Alimta (Cisplatin ceased due to side effects), also antibody therapy with Avastin and Erbitux, also Xeloda Therapy at home Tarceva, 18.9.08 PET CT (US) shows ‘Increasing metabolic activity is fairly uniformly present throughout all of the previously identified hypermetabolic lung metastases.’ 10/08 Chemoperfusion right lung on 8.10.09 then left lung on 21.10.09 (both Avastin 400 mg, MRI on 21.10.08 shows stable disease by RECIST criteria), chemosensitivity test then therapy with Alimta and Tarceva, also Artesunate 26.8.08 chemosensitivity test shows greatest sensitivity to cisplatin, pemetrexed and topotecan plus cetuximab, bortezomib, 5-azacytidine and bevacizumab plus quercetin, artesunate, mistletoe, c- statin and vitamin C Dendritic cell vaccination 17.10.09 Therapy at home with Alimta 900 mg (3 weekly), Tarceva 150 mg second daily, 18.12.08 PET CT ‘relatively stable pattern of bilateral pulmonary parenchymal hypermetabolic, metastatic foci’ 19.3.2009 PET CT shows minimal progression (‘mixed but overall stable pattern of hypermetabolic lung metastases’) 03-04/09 Chemoperfusion (1.4.09 left lung Avastin 400 mg then 3.4.09 right lung Avastin 400mg, Taxotere 20 mg). CT thorax shows stable disease by RECIST criteria Chemosensitivity test shows 10 cells/ml with greatest sensitivity to cisplatin, pemtrexed and docetaxel plus cetuximab, bortezomib, 5-azacytidine and bevacizumab plus
Chemotherapy with low dose Cisplatin (50 mg as 5 day pump), antibody therapy with Vidaza, also Tarceva, Zometa, Artesunate Therapy at home with Alimta plus Cisplatin plus Vidaza 21.7.09 PET CT (US) Interval mild increase in hypermetabolic activity seen within multiple lung metastases 5.10.2009 PET CT (US) Numerous hypermetabolic pulmonary nodules, relatively unchanged in size, but slightly increased in hypermetabolic activity compared with the previous exam 10-11/09 Progressive disease with, treated with trifunctional antibody Removab (against EpCam) with good response, also Vidaza Chemosensitivity test 13.10.09, with 6,7 cells/ml. Greatest sensitivity to cisplatin and docetaxel plus cetuximab, bortezomib, 5-azacytidine and bevacizumab plus artesunate and vitamin C, Artesunate, DCA, PET 19.11.09 shows several metastases in right and left lungs, no mediastinal or hilar lesions. There is significant reduction in intensity and number of metastases compared to the previous examination of 5.10.09 Therapy continued at home with Vidaza 3.9.2010 PET stable disease, partial remission of pulmonary metastases 24.1.2011 PET CT (US) shows ‘Numerous hypermetabolic pulmonary nodules without significant change in activity, size or number from the prior exam’
2 4 6 8 10 12 01/06/2008 01/09/2008 01/12/2008 01/03/2009 01/06/2009 01/09/2009 01/12/2009 01/03/2010 01/06/2010 01/09/2010
CTCs (cells/ml)
CTCs (cells/ml) 5 10 15 20 25 01/11/2007 01/01/2008 01/03/2008 01/05/2008 01/07/2008 01/09/2008 01/11/2008 01/01/2009 01/03/2009 01/05/2009 01/07/2009 01/09/2009
CEA (<3,4)
CEA (<3,4)
INDUCTION CONSOLIDATION MAINTENANCE ???? :ONCOSTAT (former TUP)
In low risk watch and wait or Immunotherapy (primed DCs or personalized Moab)
In high risk Metronomic therapy
:FOLLOW-UP :METASTAT :CHEMOSNIP :IMMUNOSTAT
CR PR SD PD Complete Response (CR): 6 (7%) Partial Response (PR): 39 (47%) Stable Disease (SD): 11 (13,2%) Progress of Disease (PD): 27 (32,8%)
CR PR SD PD Complete Response (CR): 4 (11%) Partial Response (PR): 19 (51,5%) Stable Disease (SD): 5 (13,5%) Progress of Disease (PD): 9 (24%)
CR PR SD PD Complete Response (CR): 2 (6,8%) Partial Response (PR): 12 (41,2%) Stable Disease (SD): 7 (24%) Progress of Disease (PD): 8 (28%)
DUTH-Professor K. Chlichlia & prof. R Sandaltzopoulos (molecular Biology and genetics)-GR UCL-professor Edith Chan (synthesis-retrosynthesis-drug design)- UK Westminster-professor Pamela Greenwell-(department of life sceience)-UK Nottingham University –QMC & City hospital (professor Anna Grabowska)-UK Matrin Luther Univaersitaet Klinikum Halle/Saale (MLU) – Pharmakologie & Haematologie/Onkologie Abteilung –(Professor Paschke & professor H J Schmoll/Tidow-DE
System Biologie AG-Switzerland Nerium corporation-USA Biobites-UK PRECOS-PREclinical Oncology Systems-UK ZAMED-Zentrum Fuer Adwendische MEDizin (Centre for applicable medicines)-already validate a conjugated form of cisplatinum with THP-12 in human cancer cell cultures- DE Boehringer Ingelhein AG (Ulm)-assess new TKI in clinical samples for detecting & validate CTCs as pilot study before and after application of the candidate drug.
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