Title: Breathing New Life Into Lung Cancer Treatment: Recent Advances
1Breathing 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
2Outline
- I. Prognosis/background of lung cancer
- II. Current platinum chemotherapy
- III. New chemotherapeutic agents
- a. pemetrexed
- b. gefitinib
- c. topotecan
3Incidence of Cancerin Canada 2003
Patients
Canadian Cancer Society http//www.cancer.ca
Accessed Nov 2003
4Incidence of Cancer in BC 2003
Patients
Canadian Cancer Society http//www.cancer.ca
Accessed Nov 2003
5Lung Cancer Summary
6Lung 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
7Lung Cancer Staging
- NSCLC
- stage I, II, IIIA
- resectable
- stage IIIA, IIIB, IV
- chemo mainstay
- SCLC
- chemo for all
- ? survival
8Lung Cancer Chemotherapy
9Lung Cancer Chemotherapy
10Chemotherapy 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 200234692-98
11Contenders for Second Line and Beyond
- Non-small cell lung cancer
- pemetrexed
- gefitinib
- Small cell lung cancer
- topotecan
12Pemetrexed
13Pemetrexed 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
14Pemetrexed Mechanism of Action
AMP
RNA DNA Synthesis
PRPP Gln
IMP
GMP
Membrane
10-CHO-FH4
pemetrexed
pemetrexed
5, 10-CH2-FH4
Folate Carriers
FH4
dUMP
Cell
DHFR (MTX)
TS (5-Fu)
FH2
dTMP
DNA Synthesis
15Pemetrexed vs Docetaxel in Recurrent NSCLC
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
Previously treated patients 95 1 previous
chemo Stage III/IV Randomized
Pemetrexed 500mg/m2 iv q21 days dex, vitamin
B12, folic acid
Docetaxel 75mg/m2 q 21 days dex
Proc Am Soc Oncol 200322622, Ab 2503
16Pemetrexed 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
17Gefitinib
18Gefitinib Pharmacokinetics
- bioavailability 50
- t1/2 27-41 hours
- hepatically metabolism
- cytochrome P450 3A4
- excreted in feces
19Gefitinib Drug Interactions
- CYP3A4 inducers
- rifampin
- ?gefitinib levels
- CYP3A4 inhibitors
- itraconazole
- ?gefitinib levels
- lt 500mg dose
- does not induce/inhibit CYP450
20Gefitinib Mechanism of Action
EGF/TGFa
R
R
Extracellular
Membrane
Intracellular
K
K
EGFR-TKI
EGFR-TKI
Cell survival (anti-apoptosis)
Proliferation
Signalling
DNA
Growth factors
Angiogenesis
Chemotherapy/ radiotherapy sensitivity
Metastasis
R, epidermal growth factor receptor
21IDEAL IRESSA Dose Evaluation in Advanced Lung
Cancer Phase II Trials
- IDEAL- 1
- 250mg vs 500mg
- Response rate
- 18.4 (11.5-27.3)
- 19.0(12.1-27.9)
- Progression free survival
- 2.7 vs 2.8 months
- overall survival
- 7.6 vs 8 months
- -----------------------
- IDEAL 2
- 250mg vs 500mg
- Response rate
- 11.8(6.2-19.7)
- 8.8 (4.3-15.5)
- Overall survival
- 6.1 vs 6.0 months
IDEAL-1 (N210) 1-2 previous platinumchemo
regimens
Gefitinib 250mg Po daily
- R, DB
- Locally
- advanced
- or metastatic
IDEAL-2 (N216) Âł2 previous chemo regimens
including platinum and docetaxel
Gefitinib 500 mg Po daily
Continue gefitinib until diseaseprogression or
intolerable toxicity
22INTACT 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-naĂŻve R,DB, PC INTACT -1
n1093 Chemo gem/cis INTACT -2 n1037 Chemo
carbo/paclitaxel
500 mg gefitinib
23Gefitinib Toxicity
- diarrhea
- loperamide
- hydration
- skin rash
- topical steroids
- antibiotics
- antihistamines
- ?LFTs
- interstitial pneumonitis
- lt 1 incidence
24SummaryNSCLC Second Line Therapy
25Topotecan
26Topotecan Pharmacokinetics
- t1/22-3 hours
- little hepatic metabolism
- renal and biliary elimination
27Topotecan Mechanism of Action
Topotecan binds topoisomerase I, inhibits DNA
replication and prevents cell proliferation
28Topotecan versus Cyclophosphamide, Doxorubicin,
Vincristine (CAV)
response rate topotecan vs CAV 24.3
(16.2-32.4) 18.3(10.8-25.7) median survival
(months) 6.3 vs 6.2 Improved sx () Dyspnea
27.9vs 6.6 Anorexia 32.1v15.8 Hoarse 32.5 v
13.2 Daily living activities 26.9v11.1
SCLC Randomized previous chemo gt 6 months
prior n211
Topotecan 1.5mg/m2 X 5 days q21 days
Cyclophos 1, 000mg/m2 doxo 45mg/m2
vincristine 2mg q21 days
JCO 199917(2)658-667
29Topotecan Toxicity
- Neutropenia
- Thrombocytopenia
- Grade Âľ 30 topotecan vs 5 CAV
- Anemia
- Infection
- Nausea
- Alopecia
- Diarrhea
30SummarySCLC Second Line Therapy
31Conclusions Current Chemotherapy
- New agents
- Second/third line
- Similar efficacy to standard of practice
- Different toxicity profiles
32Conclusion No Substitute for Quitting Smoking
- 1 in 5 smokers will develop lung cancer
- gt 90 of lung cancer cases are related to smoking
- prevention is key
- its 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,S3S18-9
33Conclusion