Advantages of metronomic chemotherapy in an integrated

cancer treatment settingNick N. Chen, M.D., Ph.D.

Medical Director

Seattle Cancer Treatment and wellness Center

nicknchenmd@gmail.com

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

• 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)

Anti-angiogenesis effect of metronomic chemotherapy

day 1 Day 14day 7 Day 21

Vascular endothelial cell

Conventional Chemotherapy

Metronomic Chemotherapy

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

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

Metronomic chemotherapy can upregulate anti-tumor immune responses

Metronomic Chemotherapy

TregT-

effector

Conventional Chemotherapy

Treg

Anti-tumor immune responses

T-effectorTreg

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

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

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

Conventional (CM) vs. Metronomic (MC) Chemotherapy

Week 1 Week 2 Week 3

Tissue tolerance

Tumor tolerance

Dru

g level

Stem cell G1/G2 phase cells

Chemo-insensitive

S/M phase cells

Chemo-sensitive

CM

MC

Stem cells Un-dividing cells Dividing cells

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

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

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

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)

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

Observed 5-year Survival of Patients with Stage IV Breast Cancer

0

20

40

60

80

100

120

1 2 3 4 5

Pe

rce

nt

Surv

ival

Years Since Diagnosis

SCTWC

NCDB

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

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 Ascorbateimmediately 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

9/2010 Before RX

3/2011 RESPONSE TO RX

Prolonged metronomic chemotherapy leads to high response rate and long term survival in patients with NSCLCNick 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/carbowith or without Avastin

• RR 100%

• Medium OS 36 months

• 5-year survival 25%

• Well tolerated with mostly mild grade1-2 AE

1

14

1112

13

10

98

17

6

5

4

3

2

• 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

Continuous improvement of advanced lung cancer with prolonged metronomic chemotherapy

Before chemotherapy

6 months after chemotherapy

12 months after chemotherapy

5 years after treatment

Continuous improvement with prolonged metronomic chemotherapy

• 67 y/o female past smoker with stage IIIb lung adenocarcinoma

• Received 40 weeks of weekly taxoland 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

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.

Before chemo

12 weeks after chemo

18 weeks After chemo

Before chemo

12 week after chemo

18 weeks after chemo

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

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.

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

Tumor marker CA 19-9 changes following standard FOLFOX and metronomic POLF treatment

0

5000

10000

15000

20000

25000

30000

wk1

FOLFO

X

wk4

FOLFO

X

wk4

POLF

wk8

POLF

wk12

PO

LF

wk16

PO

LF

CA 19-9

Chemotherapy…..Don’t Abandon it,Improve it!