Docstoc

Metronomic Chemotherapy

Document Sample
Metronomic Chemotherapy Powered By Docstoc
					Fellow Meeting

METRONOMIC CHEMOTHERAPY
R6 楊士弘 2007.8.3

Conventional Chemotherapy
Cell number (log)

chemotherapy
MTD

Log-kill hypothesis

Recovery

104~105
Classification Category Mechanism Alkylating agent DNA break, crosslink ifosfamide sarcoma Antimetabolites block DNA, RNA synthesis 5-FU gastric cancer

Immune surveillance Time Antimicrotubules inhibit mitosis, nutrient transport paclitaxel lung cancer Topoisomerase poisons block DNA replication, transcription irinotecan colon cancer

Example Utility

Limitation of Conventional CTx
 Imperfect log-kill model
 Heterogeneity of cancer cells  Multiple genetic changes  Multiple drug-resistance mechanisms  Therapy-induced genomic instability  Clonal evolution of cancer cells in metastasis

 Not targeting at the cross-talk between environment and cancer cells
 Growth factors, cytokines  Angiogenesis

 The rest period for toxicity
 Tumor re-growth
Lancet Oncol 2001; 2: 733–40

Angiogenesis

Nat Rev Drug Discov 2007; 6(4):273-86

Advantage of Endothelial Targeting

Lancet Oncol 2001; 2: 733–40

Lancet Oncol 2001; 2: 733–40

Anti-angiogenic

JCO 19:1195-1206,2001

Tumor Endothelium

 Normal and tumor endothelium are highly related.  TE is qualitatively different from NE.  TE-expressing genes also express in angiogenesis during

wound healing and corpus luteum formation.

Science 2000; 289: 1197–202

Antiangiogenic therapy
-no resistance

Induction of cancer dormancy -not mediated by immune response No resistance
Nature 1997; 390: 404–07

Endothelial Chemoresistance
-Survivin
ADR 1 μM; CDDP 20μM; Taxol 10nM; VBL 1 μM

 C/T or VEGF induces PI3K/Akt/survivin expression.  Chemoresistance: Survivin protects endothelial apoptosis from C/T.
Proc. Natl Acad. Sci. USA 99, 4349–4354 (2002)

J Clin Invest 2000; 105: 1045–47

“Metronomic”

Hanahan D, Bergers G, Bergsland E. Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice.

Metronomic VBL/DC101
SKN-MC and SK-N-AS: human NB cell lines 1 ng/ml

Giannoula Klement-J Clin Invest 2000; 105:15–24

TUNEL

DC101 alone

Edema

Detachement

Death

FITC-dextran fluorescence method

in vivo Matrigel plug angiogenesis assay

VBL 1mg/m2 (0.33mg/kg) ip q3d (D1,4,7) DC101 800 μg ip q3d (D1,4,7) Sacrifice on D10

VBL 1mg/m2 (0.33mg/kg) ip q3d DC101 800 μg ip q3d

VBL-CVI Phase I Trial
 In vitro cytotoxicity: ≧1 ng/ml  Method:
 Surgically-implanted infusion pump  Patient: N=24; cancer refractory to Tx or without

standard Tx  Schedule: 3 mg/m2 iv bolus (D0), CVI since D3
 0.5 mg/m2/d (13), 0.6 mg/m2/d (10), 0.7 mg/m2/d (1)  Median Tx: 12 weeks (2-36 weeks)  Dose escalation if acceptable toxicities

 Result:
 Mild toxicity at rate ≦ 0.65 mg/m2/d  Suggested phase II dose: 0.7 mg/m2/d  Monitor concentration < 1.5-2 ng/ml to avoid toxicity
CANCER RESEARCH 46, 4827-4830, September 1986

VBL-CVI Phase I Trial

CANCER RESEARCH 46, 4827-4830, September 1986

Antiangiogenesis-vinblastine
Apoptosis of HUVEC 0.25pM 1pM

HUVEC chemotaxis

Blood 1999; 94: 4143–55

Antiangiogenesis-vinblastine

NIH 3T3: fibroblast Namalwa: Burkitt’s lymphoma LIK: B-cell lymphoblastic leukemia CEM: T-cell lymphoblastic leukemia

 HUVEC is sensitive to very low-dose VBL.  Other cell types are not sensitive to very low

dose of VBL.
Blood 1999; 94: 4143–55

Metronomic-Therapeutic Window

MDA-MB-435: breast cancer T0.1: MDR(+)-MDA-MB-435 NHDF: Normal human dermal fibroblast HMVEC-d: Dermal Microvascular Endothelial Cell

Cancer Res. 62, 6938–6943 (2002)

Metronomic Therapy in Resistant Cancer Models

Timothy Browder-Cancer Res 2000; 60: 1878–86

PK of CTX in Human
 Single Dose    

a) Cytotoxic effects, IV/oral: 7 to 14 days (Reynolds, 1997). 2) Multiple Dose a) Cytotoxic effects: 1 to 3 days (Reynolds, 1997). CTX: a prodrug converted by hepatic microsomal enzymes to the active form A) Parent Compound: HALF-LIFE 1.3 to 16 hours B) Metabolites 1) Alkylating species 7.7 to 9.9 hours a) PHOSPHORAMIDE MUSTARD and ACROLEIN: elimination half-life of 9.9 hours following ORAL and 7.7 hours following IV administration 2) 4-hydroxycyclophosphamide: 2.5 to 5.5 hours
Micromedex

Effect of p53 status on tumor response to antiangiogenic therapy.
HCT116 colorectal carcinoma cells, SCID mice xenograft

Science 295, 1526–1528 (2002)

circulating endothelial progenitor cell

Nat Rev Cancer 2002;2:826-35

CEP -MTD vs Metronomic Dose
Namalwa-injected NOD/SCID mice Truly metronomic ?

Metronomic: 170 mg/kg q6d ip or 20 mg/kg/day po MTD: 75 mg/kg on days 3, 5 and 7, or 225 mg/kg/cycle of therapy repeated every 21 days

↑Dose => ↑CEP ? => CEP mobilization CEP  tumor growth
Cancer Res. 63, 4342–4346 (2003)

CEP & VEGF -conventional vs Metronomic Dose
 Patient:
 24 patients: adjuvant C/T for breast cancer or C/T for

lymphoma (Conventional group)  18 patients: metronomic trofosfamide ±celecoxib for advanced cancer (Metronomic group)

 Method:
 Blood sampling: before C/T, 10 and 21 days after

starting C/T.  PB CEP levels: flow cytometry (CD34- and VEGF-R2+)  VEGF plasma concentration: ELISA

 Results:
 CEP: a 2-fold increase 21 days after conventional C/T

but a significant decrease under metronomic C/T  VEGF: remained stable in metronomic C/T but significantly increased under conventional C/T

2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S , 2007: 14053

Metronomic-CTX-Immune Modulation
 Methods: 9 patients, metastatic solid tumors  Regimen: CTX 50 mg bid, 1 week on, and 1

week off, until PD or limiting toxicity.  Results:

Cancer Immunol Immunother (2007) 56:641–648

Metronomic Carboplatin/VP-16
PEX: fragment of recombinant human MMP-2

HD: 40 mg/kg of carboplatin i.p. (D1) plus 20 mg/kg of etoposide i.p. (D1-5); q3w LD: 6 mg/kg of carboplatin i.p. (D1) plus 4 mg/kg of etoposide i.p. (D1); then 2 mg/kg of carboplatin i.p. plus 2 mg/kg of etoposide i.p. (q3d) Truly “metronomic” ? HD: MS 45 days (2 cycles; C: 80; E 200), control 22 days LD: MS 30 days (11 cycles; C: 26; E 24) control 25 days Cancer Res. 61, 7501–7506 (2001)

Metronomic Carboplatin/VP-16

Cancer Res. 61, 7501–7506 (2001)

Metronomic-TSP-1 Effect

Proc. Natl Acad. Sci. USA 100, 12917–12922 (2003)

Metronomic-Antiangionenic Effect

Nat Rev Cancer 2004;4:423-36

Metronomic Therapy vs Cancer Stem Cell

CR 2007;67(8):3560-3564

Metronomic-Optimal Biologic Dose
OBD: dose causing maximum reduction in the tumor volume with no or minimal toxicity

MeWo: human melanoma Blood. 2005;106:3058-3061

MVB9: MDR expressing a variant of the human MDA-MB-231 breast cancer cell

Metronomic-Optimal Biologic Dose

CEPs determine/predict “OBD”.
Blood. 2005;106:3058-3061

Therapeutic Window

CCR 2002;8:221-232

Metronomic-mCRC
 Patient: 20; median prior C/T=3  Methods: CPT-11 CIF in pretreated mCRC  Dose level: 1.4, 2.8 and 4.2 mg/m2/day; (CIF MTD= 5.6 mg/m2/day)  Results:
 No toxicities of grade >1 NCI scale  No objective response, but 4 (20%) SD with a median

duration of 14 weeks  TSP-1 significantly increased after 1 week and remained higher than the baseline for >8 weeks.  VEGF levels did not significantly change  No statistical differences have been found for TSP-1 and VEGF concentrations among the three dose levels.
2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S, 2006: 13111

Breast cancer-CTX and MTX
 N=63, metastatic, PD after 1st C/T (32), PD after ≧2nd C/T (20)  Regimen: MTX 2.5mg (10am, 5pm) D1,2/wk + CTX 50mg (9am) qd  RR: 19% (2 CR, 10 PR)

Ann. Oncol. 13, 73–80 (2002)

Metronomic-Breast Cancer
 Patient: 23/26; prior 3 line C/T  Regimen: CAP (500 mg TID), CTX (50 mg QD),

Avastin (10 mg/Kg Q 2w)  Results:
 1 CRs (4.3%), 10 PRs (43.5%), 6 SD (26.1%), and 6 PD

(26.1%); RR 48%  Median PFS: 6 months (+)  Grade 3 side effects: 6 HTN , 1 leucopenia , 2 neutropenia , 2 transaminitis (both liver mets)

2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S, 2007: 11501

Metronomic-HCC
 Patient: 22 (BCLC: 5 pts = B; 17 pts = C; Child: 12 pts =A, 8=B, 2=C. 14 pts PVT)
 15 (front line), 7 (second line)

 first cycle: CAP (2000 mg/m2; D1-14/21d)
 Later: CAP (1300 mg) without interruption  Results:
 5 dismissed for liver failure during the standard CAP  2 discontinued CAP due to liver failure during the

metronomic Tx  10 accomplished at least the first month of metronomic Tx  6 evaluated for response: 2 PR (one second line), 3 SD (all in second line), 1 PD (second line)
2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S , 2007: 15163

Metronomic-HCC
 N=45, untreated, Child A  Tx: Xeloda 800mg/m2 bid d1-14 and Avastin

7.5mg/kg d1, q3w x6  Results: By 2006/12, 25 patients completed at least 6 months’ follow-up and were assessed  Result:
 RR: 16% and disease control 60%  MS: 10.7 months  PFS 4.1 months  Median cycle: 5 (1-6)  grade 3 toxicities: HFS (2), nail changes (1), diarrhea

(1), nausea/vomiting/hiccups (1), GU hemorrhage (1)
2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S , 2007: 15190

Metronomic- taxane-resistant HRPC
 Patient: 17
 Regimen: CTX (50 mg/d) and Dex (1 mg/d);

treatment continued until PD  Results:
 Median PSA at study entry: 134 ng/ml  9 PSA response (↓ ≧50%)  8 PSA progression  TTP:24 (responder) vs 60 weeks  No grade 3 and 4 toxicities

2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S , 2007: 15647

Metronomic- CTX and celecoxib (CEL)-HRPC
 Patient: 10

 Regimen: CEL 400 mg bid and CTX 50 mg qd
 Results:
 1 PR (PR duration 13 mos with PSA stabilization for

12 mos) and 1 prolonged stable PSA (7 mos) and prolonged stable disease (8 mos)  1 unconfirmed PR  One grade 3 hypertension  All other toxicities were grade ½.

2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S, 2007: 14046

Metronomic- NSCLC-second-line
 Patient: : 21, stage IV, one prior C/T (platinum 15, no platinum 6)  Regimen: docetaxel 25 mg/m2 (D1, 8, 15, q4w) + trofosfamide 50mg/d  Histologic: 8 SCC, 7 adenoca, 6 large cell  Result:
    

median cycle: 3 (1 - 8) RR 19% (1 CR, 2 PR); 9 SD (42.9%), 8 PD (38.1%). MS after Tx: 6.9 months 1-year survival 28.6%, 2-year survival 7.1% Hematological and non-hematological toxicities were mild. No grade 4 toxicity was observed.

2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S, 2007: 18105

Metronomic- Pancreatic cancer-POLF
 Patient: 9, metastatic  Regimen: weekly POLF (Paclitaxel: 60 mg/m2, OHP: 50mg/ m2, LV: 20 mg/m2, 5-FU: 425 mg/m2)

for 12 wk  1 patient with intermittent Cetuximab.  Results:
 3 PR  Patient D.P. (bil 27) patient L.C. (bil 9.6) normalized bil  Patient A.B. (ECOG 4) PD after 2 prior C/T alive and well

after 2 years since diagnosis with ECOG 0.  Toxicity: one grade 3 neurotoxicity and one grade 3 diarrhea  Median survival has not been reached (12+ weeks)
2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S ,2007: 15175

Metronomic-Melanoma
 Patient: 20 (M1c: 18); prior Tx 0/1/2/3+: 1/7/5/7  Regimen: paclitaxel 10 mg/m2 for 96 hrs weekly

by CIV and Celecoxib 400 mg bid  Metastasis: lung (13), LN (14), soft tissue (13), liver (9), bone (4), brain (6), other (11).  Result:
 grade 3-4 toxicities (line related) bacteremia (3),

DVT (3), PE (3); no grade 3-4 toxicities due to C/T  No responder; 6 (30%) SD  MS: 6 months
2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S, 2006: 8010

Metronomic-relapsed aggressive NHL
 Patient: N=32/35
 DLBCL (20), MCL(1), PTCL (2), transformed FL (4),

transformed SLL (1), ALCL (3), FL-large (1)  Prior regimens: 3 (1-6), prior autograft: 11

 Methods:
 CTX 50 mg qd + celecoxib 400 mg bid

 Results: 17 are evaluable for response.
 RR 37% (2 CR/CRu, 9 PR)  MS 14.4 months and PFS 4.7 months

 AE grade 3-4: ANC (2), PLT (5), fatigue (6), rash(2),

DVT (2), SVT (2)
CCR 2006; 12(17): 5190-98

Metronomic-SCCHN
 Patient: 13, failed platinum and taxane  Origin: 4 naso-, 6 oro- and 3 hypo-pharyngeal  Tx: 2.5 mg MTX qd + 400 mg celecoxib bid  Result:
 Median TTF: 161 days (10 - 385 days)  6 patients died of PD with median time of 91 days

after enrolment to the study (45 - 301 days)

Proc Am Soc Clin Oncol 22: 2003 (abstr 2066)

Thanks for your attention !