Nick chen ppt presentation metronomic chemotherapy 2015
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Metronomic chemotherapy provides several advantages over conventional chemotherapy: - It is associated with lower toxicity due to more frequent lower doses, allowing better treatment consistency. - It has enhanced anti-cancer effects through anti-angiogenesis and improved immune response against tumors. - Targeting both the tumor and tumor microenvironment makes it less likely to encounter chemo-resistance.
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Nick chen ppt presentation metronomic chemotherapy 2015
- 1. Advantages of metronomic chemotherapy in an integrated cancer treatment setting Nick N. Chen, M.D., Ph.D. Medical Director Seattle Cancer Treatment and wellness Center nicknchenmd@gmail.com
- 2. What is metronomic chemotherapy? • low doses of chemotherapy administered more frequently and regularly, such as weekly or daily • In contrast, conventional chemotherapy is given at maximum tolerated dose (MTD) every 3weeks at doses just below what would cause over 50% of patients to experience severe or dose-limiting toxicity
- 3. • Generally associated with Lower chemotherapy side effects than high-dose treatment, therefore is associated with improved treatment consistency, duration and outcome. • Enhanced anti-cancer effect due to: • Anti-angiogenesis • Improvement of anti-cancer immune response by suppressing immune regulatory cells (Treg). • Killing more chemosensitive cycling cancer cells • Less tumor cell recovery time between treatments • Less likely to encounter tumor chemo-resistance due to its targeting of both tumor and the more stable tumor microenvironment Advantages of metronomic chemotherapy (over conventional chemotherapy)
- 4. Anti-angiogenesis effect of metronomic chemotherapy day 1 Day 14day 7 Day 21 Vascular endothelial cell Conventional Chemotherapy Metronomic Chemotherapy
- 5. Conventional vs. metronomic schedule in the induction of endothelial and tumour cell apoptosis Browder T et al. Cancer Res 2000;60:1878-1886 ©2000 by American Association for Cancer Research
- 6. Conventional vs. metronomic cyclophosphamide in treatment of drug-resistant Lewis lung carcinoma Browder T et al. Cancer Res 2000;60:1878-1886 ©2000 by American Association for Cancer Research
- 7. Metronomic chemotherapy can upregulate anti-tumor immune responses Metronomic Chemotherapy Treg T- effector Conventional Chemotherapy Treg Anti-tumor immune responses T- effectorTreg
- 8. Dose Dense (DD) chemotherapy exhibited better therapeutic efficacy against cisplatin-resistant tumour via immune-mediated mechanism Chang C et al. Cancer Res 2013;73:119-127 ©2013 by American Association for Cancer Research Immune-competent mice Nude mice
- 9. Host response to MTD chemotherapy accelerates metastasis growth Gingis-Velitski S et al. Cancer Res 2011;71:6986-6996 ©2011 by American Association for Cancer Research
- 10. Metronomic chemotherapy and the Norton-Simon hypothesis • tumor grows faster when it’s small and its growth slows significantly when its volume reaches a plateau • the rate of cancer cell death in response to treatment is directly proportional to the tumor growth rate at the time of treatment. • tumors given less time to grow between treatments (before its growth slows down with increasing volume) are more likely to be eradicated. • CLAGB 974 trial: dose dense chemo schedule reduced annual breast cancer recurrence by 26% and death by 31% compared to conventional q3 week chemotherapy
- 11. Conventional (CM) vs. Metronomic (MC) Chemotherapy Week 1 Week 2 Week 3 Tissue tolerance Tumor tolerance Druglevel Stem cell G1/G2 phase cells Chemo-insensitive S/M phase cells Chemo-sensitive CM MC Stem cells Un-dividing cells Dividing cells
- 12. Synergy of metronomic chemotherapy with naturopathic therapies metronomic • Lower chemo toxicity • Enhance anti-tumor immune response • Anti-angiogenesis • Causes less inflammation naturopathic • Reduce chemo toxicity • Enhance overall immune response • Anti-angiogenesis • Anti-inflammatory • higher chemo toxicity • suppress anti-tumor immune response • No consistent Anti- angiogenesis • Causes significant inflammation Conventional MTD
- 13. Clinical Outcomes of Breast Cancer Treatment in an Integrative Oncology Setting • Patient characteristics: • 112 patients with various stages of breast treated solely by me and integrated team at SCTWC were identified retrospectively through searching medical records. • 75 patients had early stage breast cancer( 19% stage I, 45% stage II, 36% stage III) • 37 patients had advanced stage IV breast cancer (35% HER-2 positive, 17% triple negative, 26% with brain mets, 43% with liver mets, and 74% with lung mets.) Nick Chen, M.D., Best overall poster presentation at Society of Integrative Oncology conference, Vancouver, B.C., Oct. 2013
- 14. Clinical Outcomes of Breast Cancer Treatment in an Integrative Oncology Setting • Treatment modalities: • Metronomic chemotherapy: weekly paclitaxel/carboplatin based chemotherapy regimen with or without anti-VEGF agent bevacizumab (Avastin) or anti-HER2 agent Trastuzumab (Herceptin) • Naturopathic therapies: • Core supplements: melatonin, Vitamin D3, Fish oil, green tea extract, multi-nutrients • Additional supplements: L-glutamine, co-enzyme Q10, turmeric, mushroom extract, high-dose Vitamin C intravenously
- 15. Clinical Outcomes of Patients with Early Stage Breast Cancer after Integrative Therapy Median F/U(y) Distant Relapse Local Relapse Relapse Free survival Survival (NCDB*) Stage I (14) 4 1(7.4%) 0(0%) 92.6% 100%(92) Stage IIA(18) 6 0(0%) 0(0%) 100% 100%(81) IIB(11) 6 1(9%) 1(9%) 82% 100%(74) Stage IIIA(11) 6 2(18%) 1(9%) 73% 100%(67) IIIB (7) 4 1(14%) 3(43%) 43% 86% (49) IIIC (9) 5 0 (0%) 0(0%) 100% 100% (49) *Data from National Cancer Data Base (NCDB)
- 16. Clinical Outcomes of Advanced Stage Breast Cancer Overall response rate: 89% Complete response: 43% Partial response: 46% Mixed response: 11% Progression-free survival (PFS): 1.2 years 5-year Survival: 53% Median Overall Survival: 5.8 years
- 17. Observed 5-year Survival of Patients with Stage IV Breast Cancer 0 20 40 60 80 100 120 1 2 3 4 5 PercentSurvival Years Since Diagnosis SCTWC NCDB
- 18. 48 y/o pre-menopausal woman Dx with meatastaic inflammatory breast cancer on 7-13-10 Path: Right breast invasive ductal carcinoma, nottingham grade of 8-9/9, ER-/PR-, Her-2/neu 3+ PET/CT on 9-30-10 showed large R breast mass measured 8.5 X 7.1 X 6.1 cm with inflammatory involvement of dermis and skin and multiple, hypermetabolic cervical, supraclavicular, axillary, internal mammary lymph nodes. Additionally, hypermetabolic large R-sided pleural effusion and distant to R posterior ilium were found. Copyright Rising Tide, KFT Metronomic Chemotherapy in Inflammatory Breast Cancer
- 19. 10-04-10 – started metronomic weekly chemotherapy with Taxol/Carbo/Herceptin. Completed 12 tx’s on 12- 23-10 Also started on wkly 25 gm IV Ascorbate immediately prior to each chemotherapy Completed 6 more wkly treatments with IVC/Taxol/Carbo/Herceptin on 2-17-11 Started wkly IV Glutathione on 1-5-11 to help with peripheral neuropathy Copyright Rising Tide, KFT Metronomic Chemotherapy in inflammatory breast cancer
- 20. 9/2010 Before RX
- 22. Prolonged metronomic chemotherapy leads to high response rate and long term survival in patients with NSCLC Nick Chen, poster presentation at 9th International Congress of lung cancer, Maui, H.I. 2008 • 14 consecutive patients with advanced NSCLC (stageIIIb or IV) • First line chemotherapy with weekly Taxol/carbo with or without Avastin • RR 100% • Medium OS 36 months • 5-year survival 25% • Well tolerated with mostly mild grade1-2 AE 1 14 11 12 13 10 9 8 17 6 5 4 3 2
- 23. • 75 y/o female non-smoker presented with stage IV lung adenocarcinoma widely metastatic to cervical supraclavicular and mediastinum lymph nodes and adrenal gland • Treated with metronomic weekly Taxane and carboplatin and had CR • Placed on maintenance Tarceva • Recurrences at 5 years and 10 years both successfully with metronomic chemotherapy with CR and PR respectively • She has now survived over 12 years since her initial diagnosis Long-term survival of a stage IV lung cancer patient treated with metronomic chemotherapy
- 24. Continuous improvement of advanced lung cancer with prolonged metronomic chemotherapy Before chemotherapy 6 months after chemotherapy 12 months after chemotherapy 5 years after treatment
- 25. Continuous improvement with prolonged metronomic chemotherapy • 67 y/o female past smoker with stage IIIb lung adenocarcinoma • Received 40 weeks of weekly taxol and carboplatin and had near complete remission • Placed on Tarceva as maintenance • No radiation therapy received • Remained in complete remission for over 5 years, passed away with COPD
- 26. Case report: Metronomic weekly cisplatin and irinotecan as 3rd line salvage treatment for extensive stage small cell lung cancer • 69 y/o male smoker from Idaho diagnosed of extensive stage small cell lung cancer • Presented with extensive disease with numerous mediastinal lymphadenopathies and multiple hepatic lesions. • First line therapy : Carboplatin+etopside q3wks, temporary improvement then progressed in 3 months. • Palliative radiotherapy for RLL obstruction • 2nd line chemotherapy: Topotecan with further disease progression and was told that he had no more treatment options left. • Treated with weekly cisplatin and CPT-11 (Irinotecan) at SCTWC for 18 weeks and had near complete remission. • Only low grade hematological and GI toxicity were encountered throughout the treatment.
- 29. Weekly paclitaxel, oxaliplatin, 5-FU and leucovorin (POLF) in the treatment of stage IV pancreatic cancer. Ben Chue and Nick Chen, Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 14146
- 30. Case report: Metronomic POLF treatment reversed chemo- resistance to FOLFOX in metastatic pancreatic cancer • 63 y/o female from Oregon diagnosed of metastatic adenocarcinoma of the head of pancreas in 5/09 after developing obstructive jaundice • She had diffuse mesenteric, retroperitoneal and mediastinal lymphadenopathy and numerous lung nodules in addition to head of pancreas mass. PET-CT scan and biopsy of a subcrinal node confirmed the metastasis.
- 31. Case report: Metronomic POLF treatment reversed chemo- resistance to FOLFOX in metastatic pancreatic cancer • 1st line therapy: Gemcitabine plus Axitinib, DC’d due to toxicity • 2nd line Gemcitabine alone: disease progression 5 months later. • 3rd line FOLFOX-4 regimen Q2 weeks: progression after 2 cycles • 4th line metronomic POLF protocol. Her CA 19-9 decreased from 23845 before treatment to 625 3 months later and her abdominal pain resolved. • Repeated PET-CT scan showed substantial regression of retroperitoneal lymphadenopathy and lung nodules. • She remained in remission for about 2 ½ years out from her initial diagnosis
- 32. Tumor marker CA 19-9 changes following standard FOLFOX and metronomic POLF treatment 0 5000 10000 15000 20000 25000 30000 w k1 FO LFO Xw k4 FO LFO X w k4 PO LF w k8 PO LF w k12 PO LF w k16 PO LF CA 19-9
Notas do Editor
- Immunofluorescence analysis of tumor cell and endothelial cell apoptosis in drug-resistant Lewis lung carcinoma. a, endothelial cell versus tumor cell apoptosis in cyclophosphamide-resistant Lewis lung carcinoma treated on the conventional schedule (white arrows). Endothelial cell apoptosis (○, dashed line) precedes and subsides before peak drug-resistant tumor cell apoptosis (•, solid line). Tumors were analyzed on days 1, 3, 5, 7, 10, 13, 17, and 21. Day 0 reflects the analysis of two control tumors harvested at tumor volumes of 100–200 mm3. Note that tumor cell apoptosis falls to background levels just as similar tumors begin to regrow on the conventional schedule (see Fig. 1 <$REFLINK> a, inset). b, endothelial cell versus tumor cell apoptosis in cyclophosphamide-resistant Lewis lung carcinoma treated on the antiangiogenic schedule (black arrows). Endothelial cell (○, dashed line) apoptosis precedes drug-resistant tumor cell (•, solid line) apoptosis after each of four cycles of cyclophosphamide delivered on the antiangiogenic schedule. Tumors were analyzed on days 1, 2, 4, 6, 6.5, 7, 8, 10, 12, 14, 16, 19, and 21. Day 0 reflects the analysis of two control tumors harvested at tumor volumes of 100–200 mm3. In contrast to one broad wave on the conventional schedule, the antiangiogenic schedule of cyclophosphamide induces repetitive waves of drug-resistant tumor cell apoptosis, and this schedule prevents net drug-resistant tumor growth for 36 days (see Fig. 1a <$REFLINK> ). Note that from day 13 through day 21, the antiangiogenic schedule results in a nearly 3-fold increase in drug-resistant tumor cell apoptosis over the background level in tumors treated on the conventional schedule (a). The second cycle (days 6–12) shows that endothelial apoptosis occurs within 12 h (day 6.5) of a dose of cyclophosphamide on the antiangiogenic schedule and precedes maximum drug-resistant tumor cell apoptosis by 3.5 days (on day 10). c, representative immunofluorescence (von Willebrand factor/TUNEL) of drug-resistant Lewis lung carcinoma from control (left panel, day 0), 12 h (middle panel, day 6.5), and 4 days (right panel, day 10) after cyclophosphamide administration on the antiangiogenic schedule. Microvessels are stained fluorescent red, and apoptotic tumor cell nuclei are stained fluorescent green. The white arrow marks an apoptotic endothelial cell nucleus (yellow).
- a, antiangiogenic versus conventional scheduling of cyclophosphamide for drug-resistant Lewis lung carcinoma. ▵, control saline; ○, conventional schedule [150 mg/kg every other day for three doses (white arrows, total 450 mg/kg) every 21 days]; •, antiangiogenic schedule (170 mg/kg every 6 days, CTX, thin black arrows); ▪, antiangiogenic schedule of cyclophosphamide and TNP-470 (170 mg/kg cyclophosphamide and 12.5 mg/kg TNP-470 administered on the same day of the 6-day cycle for seven cycles, CTX + TNP, thick black arrows). The inset (top right) has magnified axes for the first 21 days of therapy (n = 6 mice/group). All control and conventional schedule-treated mice died with large tumor burdens. Therapy was discontinued on the antiangiogenic schedule of cyclophosphamide alone after two of six mice died with pulmonary inflammation, accompanied by high peripheral leukocyte counts. No mouse on either schedule had visibly detectable pulmonary metastases at time of death. Therapy was discontinued on the antiangiogenic schedule of cyclophosphamide plus TNP-470 after seven cycles, three cycles beyond the point at which tumors were no longer visible. This graph depicts the long-term survival of five of six mice treated with the antiangiogenic schedule of cyclophosphamide and TNP-470 in one of five separate experiments. The arrow and Note on the graph reflect the recurrence of one of six drug-resistant tumors at 18 days off therapy in this experiment. b, antiangiogenic versus conventional scheduling of cyclophosphamide for drug-sensitive Lewis lung carcinoma. ▵, control saline; ○, conventional schedule [150 mg/kg every other day for 3 doses (white arrows, total 450 mg/kg) every 21 days]; •, antiangiogenic schedule (170 mg/kg every 6 days, thin black arrows). The inset (top right) reveals magnified axes for the first 21 days of therapy (n = 6 mice/group). Therapy on the antiangiogenic schedule was discontinued after seven cycles, three cycles beyond the point at which tumors were no longer visible. Three separate experiments produced similar results. Two mice from two separate experiments were reinoculated with Lewis lung carcinoma >500 days after the eradication of the original tumor. The growth of these second Lewis lung carcinomas was similar to that of tumors in untreated mice, an outcome not consistent with immune-mediated regression of the primary Lewis lung tumor by cyclophosphamide.
- DD chemotherapy exhibited better therapeutic efficacy against cisplatin-resistant tumor R HM-1. To mimic the treatment of ovarian cancer in a clinical setting, we designed 2 treatment protocols for a mouse ovarian cancer model to which DD or MTD chemotherapies were administered. A, DD chemotherapy exhibited better antitumor effect in mice bearing R HM-1 cell tumor. R HM-1 cells (1 × 106) were injected s.c. into the female (C57BL/6, C3H/He) F1 mice (5 in each group, day 0). On day 4, mice started chemotherapy with paclitaxel and cisplatin delivered i.p. in either DD (5 mg/kg paclitaxel plus 3 mg/kg cisplatin in a 3-day interval for 7 courses) or MTD (12 mg/kg paclitaxel plus 7 mg/kg cisplatin in a10-day interval for 3 courses) regimen. Control group mice were treated with PBS in 3-day interval. Significant therapeutic efficacy was noted in mice treated by DD chemotherapy (#, P = 0.017, control vs. DD), which was better than that of MTD (P = 0.039, MTD vs. DD). B, the specific antitumor effect of DD chemotherapy on R HM-1 cells was abolished in nude mice, suggesting that host immunity might be involved in the tumor elimination. Cisplatin-resistant HM-1 cells (1 × 106) were injected s.c. into female athymic nude mice (5 in each group, day 0). On day 4, mice began intraperitoneal administration of paclitaxel and cisplatin chemotherapy given in either DD (5 mg/kg paclitaxel plus 3 mg/kg cisplatin in a 3-day interval for 7 courses) or MTD (12 mg/kg paclitaxel plus 7 mg/kg cisplatin in a10-day interval for 3 courses) format. Control group mice were treated with PBS in a 3-day interval. There is no difference in the tumor size between the different groups of immune-deficient mice.
- Host response to chemotherapy accelerates metastasis growth. A–D, eight- to 10-week old C57BL/6 mice were treated with chemotherapy (n = 5 mice per group). After 24 hours, 2.5 × 104 GFP+ LLC cells were injected intravenously, and 45 days later, the lungs were removed for (A) the evaluation of metastasis lesions in lung sections (tumor cells in green), per ×100 objective field, (B) the percentage of GFP+ cells in lung tissue quantified by flow cytometry, and (C) the number of lesions counted in randomized fields of lung sections (n > 15 fields per group). D, survival of treated mice. E, the survival rate of mice intravenously injected with 2.5 × 104 GFP+ LLC cells that were exposed for 24 hours to plasma from chemotherapy-treated mice (n = 5 mice per group). F, six-week-old CB.17 SCID mice were implanted in the mammary fat pad with 2 × 106 LM2-4 cells. When tumors reached a size of 250 to 350 mm3, they were removed, and 3 cycles of MTD chemotherapy were initiated after 48 hours from primary tumor resection (n = 5–6 mice per group). The survival rate of mice from all treated groups is presented. *, P < 0.05; **, P < 0.01; ***, P < 0.001.