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Breathing New Life Into Lung Cancer Treatment

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					Breathing New Life Into Lung Cancer Treatment: Recent Advances
BCCA Annual Cancer Conference November 29, 2003
Saira Mithani, BSc Pharm, Pharm D Clinical Pharmacy Specialist, Drug Information BC Cancer Agency

Outline
I. Prognosis/background of lung cancer II. Current platinum chemotherapy

III. New chemotherapeutic agents a. pemetrexed b. gefitinib c. topotecan

Incidence of Cancer in Canada 2003
25000

Patients

20000

15000 Lung Breast Prostate

10000

5000

0 Incidence Deaths

Canadian Cancer Society http://www.cancer.ca Accessed Nov 2003

Incidence of Cancer in BC 2003
3000 2500

Patients

2000 Lung Breast Prostate

1500

1000

500

0 Incidence Deaths

Canadian Cancer Society http://www.cancer.ca Accessed Nov 2003

Lung Cancer: Summary
NSCLC SCLC

Frequency Staging
Potential for early metastasis

80% Stage I, II, III, IV
Less likely

20% Limited, extensive
High

Progression
Response to chemo Surgery 5 years survival

Slower
Lower Potential for cure if caught early Stage 1,II: >40% (30-70%) Stage III, IV: <5-30% Distant mets <1%

Fast
High, potentially curable No role due to early mets Limited: 20-40% Extensive <1%

Lung Cancer: Staging
Goal:
• identify surgical candidates
– highest potential for cure

Prognostic factors:
• performance status • tumour stage

Overall Prognosis of lung cancer:
• untreated: 3-6 months survival • treated: 9-12 months

Lung Cancer: Staging
NSCLC • stage I, II, IIIA
– resectable

• stage IIIA, IIIB, IV
– chemo mainstay

SCLC • chemo for all •  survival

Lung Cancer Chemotherapy
doxorubicin
etoposide

vincristine
cyclophos

cisplatin

carboplatin

vinorelbine irinotecan

topotecan gemcitabine paclitaxel

docetaxel

Lung Cancer Chemotherapy
doxorubicin
etoposide

vincristine
cyclophos

cisplatin

carboplatin

vinorelbine irinotecan

topotecan gemcitabine paclitaxel

docetaxel

Chemotherapy Rules of Thumb
• first line
– cisplatin based regimen – usually two agents – comparable

• second line
– CAV, cisplatin, etoposide
• SCLC

– Docetaxel
• NSCLC

Shiller et al. N Engl J Med 2002;346:92-98

Contenders for Second Line and Beyond
• Non-small cell lung cancer – pemetrexed – gefitinib • Small cell lung cancer – topotecan

Pemetrexed

Pemetrexed: Pharmacokinetics
• t1/2 2-4 hours
– t1/2 plasma  long t1/2 in cells

• ~80% eliminated unchanged in the urine
–  renal clearance –risk of toxicity

Pemetrexed: Mechanism of Action
AMP

GARFT
PRPP + Gln
Membrane

IMP

RNA & DNA Synthesis

GMP

10-CHO-FH4
pemetrexed

pemetrexed
Folate Carriers

5, 10-CH2-FH4

FH4
dUMP

Cell

TS
(5-Fu)
dTMP DNA Synthesis

DHFR

FH2

(MTX)

Pemetrexed vs Docetaxel in Recurrent NSCLC
Previously treated patients 95% 1 previous chemo Stage III/IV Randomized Pemetrexed 500mg/m2 iv q21 days dex, vitamin B12, folic acid Pemetrexed vs docetaxel response rate 9.1% vs 8.8% HR 0.99 (0.8-1.2)

median survival 8.3 vs 7.9 mnths Grade III/IV toxicity 10% vs 24%

Docetaxel 75mg/m2 q 21 days dex

Proc Am Soc Oncol 200322:622, Ab 2503

Pemetrexed: Toxicity
• diarrhea (2%) • skin rash
– dexamethasone 4mg/day before, day of, day after therapy – reduce risk of skin rash

• neutropenia (5%)
– folic acid 400mcg daily
• begin 1-3 weeks before therapy

– vitamin B12 1000ug im q 9 weeks –  frequency of adverse reactions including:
• bone marrow suppression, diarrhea • no effect on cytotoxic activity

Gefitinib

Gefitinib: Pharmacokinetics
• bioavailability 50% • t1/2 27-41 hours • hepatically metabolism
– cytochrome P450 3A4

• excreted in feces

Gefitinib: Drug Interactions
• CYP3A4 inducers
– rifampin – ↓gefitinib levels

• CYP3A4 inhibitors
– itraconazole – ↑gefitinib levels
• < 500mg dose

• does not induce/inhibit CYP450

Gefitinib: Mechanism of Action
EGF/TGFα R R
Extracellular

Membrane
Intracellular EGFR-TKI

Proliferation

Signalling


DNA


K K

EGFR-TKI

Cell survival (anti-apoptosis)

Growth factors

Angiogenesis

Chemotherapy/ radiotherapy sensitivity

Metastasis
R, epidermal growth factor receptor

IDEAL = IRESSA Dose Evaluation in Advanced Lung Cancer: Phase II Trials
IDEAL- 1:
250mg vs 500mg Gefitinib 250mg Response rate: Po daily 18.4% (11.5-27.3) 1-2 previous platinum R, DB 19.0%(12.1-27.9) chemo regimens Locally Progression free survival: advanced 2.7 vs 2.8 months or metastatic Gefitinib 500 mg overall survival: IDEAL-2: (N=216) Po daily 7.6 vs 8 months ----------------------2 previous chemo IDEAL – 2: regimens including 250mg vs 500mg platinum and docetaxel Response rate: 11.8%(6.2-19.7) Continue gefitinib until disease 8.8% (4.3-15.5) progression or intolerable toxicity Overall survival: 6.1 vs 6.0 months

IDEAL-1 (N=210)

INTACT = IRESSA NSCLC Trial Assessing Combination Therapy: Phase III Trials
INTACT – 1 Placebo vs 250mg vs 500mg Overall survival: 11.1 months vs 9.9 vs 9.9months ---------------------INTACT-2 Placebo vs 250mg vs 500mg Overall survival: 9.9 vs 9.8 vs 8.7 months

Stage III/IV Chemo-naïve R,DB, PC

INTACT -1 n=1093 Chemo= gem/cis INTACT -2 n=1037 Chemo = carbo/paclitaxel

Chemotherapy x 6 cycles + 250 mg gefitinib

Chemotherapy x 6 cycles + 500 mg gefitinib
Chemotherapy x 6 cycles + Placebo

Gefitinib: Toxicity
• diarrhea
– loperamide – hydration

• skin rash
– topical steroids – antibiotics – antihistamines

• ↑LFTs • interstitial pneumonitis
– < 1% incidence

Summary: NSCLC Second Line Therapy
Best supportive care
Median survival (months) Toxicity 4.6

Docetaxel

Pemetrexed

Gefitinib

7.8

8.9

6-8

Neutropenia 40% Neutropenic fever 13% Thrombocytopenia <1% Neuropathy 8% Diarrhea 3% Rash 48% Dexamethasone

Neutropenia 5% Neutropenic fever 2% Thrombocytopenia 2% Neuropathy 3% Diarrhea <1% Folic acid, vit B12, dexamethasone Iv

Rash 46% Diarrhea 32% Elevated LFTs 10% Interstitial pneumonitis <1% none

Premeds

Route

Iv

po

Topotecan

Topotecan: Pharmacokinetics
• t1/2=2-3 hours • little hepatic metabolism • renal and biliary elimination

Topotecan: Mechanism of Action

Topotecan binds topoisomerase I, inhibits DNA replication and prevents cell proliferation

Topotecan versus Cyclophosphamide, Doxorubicin, Vincristine (CAV)
SCLC Randomized previous chemo > 6 months prior n=211 response rate topotecan vs CAV 24.3% (16.2-32.4) 18.3%(10.8-25.7) Topotecan 1.5mg/m2 X 5 days q21 days median survival (months) 6.3 vs 6.2

Cyclophos 1, 000mg/m2 + doxo 45mg/m2 + vincristine 2mg q21 days

Improved sx (%) Dyspnea 27.9vs 6.6 Anorexia 32.1v15.8 Hoarse 32.5 v 13.2 Daily living activities 26.9v11.1

JCO 1999;17(2):658-667

Topotecan: Toxicity
• Neutropenia • Thrombocytopenia
– Grade ¾ 30% topotecan vs 5% CAV

• • • • •

Anemia Infection Nausea Alopecia Diarrhea

Summary: SCLC Second Line Therapy
Best supportive care CAV Topotecan

Median survival (months)
Toxicity

3

6.2
Neutropenia 70% Thrombocytopenia 5% Anemia 20% Infection 26% Peripheral neuropathy Alopecia 22% Nausea 40% Cardiac toxicity Hemorrhagic cystitis

6.3
Neutropenia 70% Thrombocytopenia 30% Anemia 42% Infection 28% Alopecia 35% Nausea 39% Diarrhea 12%

Conclusions: Current Chemotherapy
• • • • New agents Second/third line Similar efficacy to standard of practice Different toxicity profiles

Conclusion: No Substitute for Quitting Smoking
• 1 in 5 smokers will develop lung cancer • > 90% of lung cancer cases are related to smoking
– prevention is key

• it’s never too late to quit
– before middle age, ↓ risk ~ risk of non-smoker – by 50 years old, ↓ risk by 50%

Burns, D. Lung Cancer 2003: 41,S3:S18-9

Conclusion


				
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