Should chemotherapy be performed in elderly patients?

Tuncay Göksel

Ege University

Dept. of Pulmonary Medicine

No

Subject of the debate

• The role of chemotherapy in SCLC is clear, so it is not subject today

• The subject is NSCLC

• The debate will be done about the role of chemotherapy in elderly patients with advanced stage NSCLC

American College of Chest PhysiciansChest 2007; 132; 277-289

• In patients who have stage IV NSCLC and are elderly (> 70 to 79 years old), single-agent chemotherapy is recommended for most. Grade of recommendation, 1A

• However, in patients who have stage IV NSCLC, are elderly (> 70 to 79 years old), have good PS, and lack significant comorbidities, two-drug combination chemotherapy is recommended as an option. Grade of recommendation, 1B

• In patients who have stage IV NSCLC and are > 80 years old, the benefit of chemotherapy is unclear and should be decided on the basis of individual circumstances. Grade of recommendation, 2C

American Society of Clinical OncologyJ Clin Oncol 2009; 27:6251-6266

• Recommendation A4: The evidence does not support the selection of a specific first-line chemotherapy drug or combination based on age alone.

• 2003 recommendation. For elderly patients or patients with an ECOG/Zubrod PS of 2, available data support the use of single agent chemotherapy.

• In summary, clinical trial data since the 2003 update reinforce the recommendation that age alone should not be used to select chemotherapy for patients with stage IV NSCLC. Older patients may experience more toxicity from cytotoxic chemotherapy than younger patients but may garner an equal amount of benefit.

European Respiratory Monograph 2009; 44, 271–83

• In elderly patients the recommended first-line chemotherapy is a single agent, the most extensively studied being vinorelbine and gemcitabine.

National Comprehensive Cancer Network(NCCN 2009)

• Single agent therapy or platinum-based combinations are reasonable alternative in PS 2 patients or the elderly

“Erderly” age?65? or 70?

• In epidemiological studies >65 years

J Clin Oncol 2001; 19: 1064-70

• In most clinical trials >70 yearsLung Cancer 2004; 46: 61–76

What is the problem in age?

• Aging is inextricably associated with physiologic changes in functional status, organ function, and drug pharmacokinetics.

• Aging is associated with decreases in marrow reserve, drug clearance, and lean body mass.

• Furthermore, concomitant comorbidities that affect functional status, general health, and tumor symptoms are frequently present in this patient population.

Gridelli, J Clin Oncol 2007; 25:1898-907

So we expect more toxicities in elderly patients during treatment

Platin-based chemotherapy in elderly patients

• More myelotoxicity

• Greater risk of chemotherapy-related death Kubota et al: Cancer Chemother Pharmacol 1997; 40:469-74

Langer et al: J Natl Cancer Inst 2002; 94:173-81

Elderly patients in clinical trials

• Elderly patients are under-represented in almost all clinical cancer research (also lung cancer)

• In current practice, the elderly are often excluded from participation in clinical trials and receive untested or inadequate treatment based on the long-held

Hutchins et al: N Engl J Med 1999; 341: 2061-7

Lewis et al: J Clin Oncol 2003; 21: 1383-9

Yee et al: J Clin Oncol 2003; 21:1618-23

Gridelli et al: Clin Oncol 2007; 25:1898-907

The ratio of elderly and chemotherapy

• Approximately two thirds of patients with NSCLC are 65 years old, and approximately 40% are 70 years old

SEER Data, Semin Surg Oncol 1994; 10:21–30

• The rate of patients who are 70 years old is closer to 50%SEER Data, J Clin Oncol 2004; 22: 4971–8

• Elderly patients are generally underrepresented on clinical trials; participation of elderly patients with advanced disease in national clinical trials has ranged 15% -29%. The highly selected population is not representative of the general population

• A much lower rate of chemotherapy use than expected for the overall population in elderly patients – More comorbidities – A higher rate of functional compromise

• January 1, 1994, and December 31, 1999, SEER Data• 14,875 patients; 49.8% stage III and 50.2% stage IV

CT 33%

Co-m 44%

SEER Study, Ramsey et al. J Clin Oncol; 22:4971-4978 2004

SEER Study, Ramsey et al. J Clin Oncol; 22:4971-4978 2004

Median survival No chemotherapy 5 months (Poor performans patients)

Chemotherapy 8 months (P .01)

SEER Study, Ramsey et al. J Clin Oncol; 22:4971-4978 2004

SEER Study, Ramsey et al. J Clin Oncol; 22:4971-4978 2004

Phase III trials of advanced NSCLC in elderly patients

ELVIS trial 1999

Vinorelbine vs BSC

De Marinis 1999

Lonidamine vs Vindesine vs Lonidamine+Vindesine vs BSC

Frasci

2000

Vinorelbine vs Vinorelbine+Gemcitabine

Gridelli

2003

Vinorelbine vs Gemcitabine vs Vinorelbine+Gemcitabine

Takeda

2005

Vinorelbine vs Docetaxel

The Elderly Lung Cancer Vinorelbine Italian Study Group(ELVIS) çalışması

J Natl Cancer Inst 1999;91: 66–72

– 70 years of age or older,– Stage IV or IIIB NSCLC– Performance status of 0–2

Vinorelbin vs BSC

ELVIS,

J Natl Cancer Inst 1999;91: 66–72

ELVIS

J Natl Cancer Inst 1999;91: 66–72

Median survival • Vinorelbine arm: 28 week• Control arm: 21 week (p=0.03). ONLY: 7 weeks

The objective response rate: 19.7%

ELVIS, J Natl Cancer Inst 1999;91: 66–72

Toxicity• 93% of patients were assessed for toxicity.

(Grade1-4)• Treatment was stopped in five patients because

of severe toxic events

ELVIS, J Natl Cancer Inst 1999;91: 66–72

De Marinis et al, lonidamine vs vindesine vs

lonidamine+vindesine vs BSC in elderly NSCLC Tumori. 1999 May-Jun;85(3):177-82.

• Stage IV: 40%

• Stage III: 60%

• Early discontination – 8.7% progressed early– 9.5% died early– 9.4% refused treatment continuation because

of poor compliance

De Marinis et al, lonidamine vs vindesine vs

lonidamine+vindesine vs BSC in elderly NSCLC Tumori. 1999 May-Jun;85(3):177-82.

• Overall response– lonidamine: 1/30 – lonidamine + vindesine arm: 2/33

• Toxicity (all treated patients)– Leukopenia (grade 1-3): 30%– Myalgia: 70% – Fatigue 55-83%– Testicular pain: 40%

• The overall median survival was 170 days, with no significant impact on survival of either lonidamine or vindesine.

MILES study, J Natl Cancer Inst 2003;95:362–72]

• A randomized phase III trial in elderly patients with advanced NSCLC (older 70 years)– Vinorelbine – Gemcitabine – Vinorelbine plus gemcitabine

MILES study, J Natl Cancer Inst 2003;95:362–72]

MILES study, J Natl Cancer Inst 2003;95:362–72]

No chemotherapy (poor performans patients): 5 months SEER Study, Ramsey et al. J Clin Oncol; 22:4971-4978 2004

MILES study, J Natl Cancer Inst 2003;95:362–72]

MILES study, J Natl Cancer Inst 2003;95:362–72]

Frasci et al, Gemcitabine Plus Vinorelbine Versus Vinorelbine Alone in Elderly Patients

J Clin Oncol 2000 18:2529-2536

Frasci et al, Gemcitabine Plus Vinorelbine Versus Vinorelbine Alone in Elderly Patients

J Clin Oncol 2000 18:2529-2536

Frasci et al, Gemcitabine Plus Vinorelbine Versus Vinorelbine Alone in Elderly Patients

J Clin Oncol 2000 18:2529-2536

No chemotherapy (poor performans patients): 5 months SEER Study, Ramsey et al. J Clin Oncol; 22:4971-4978 2004

Frasci et al, Gemcitabine Plus Vinorelbine Versus Vinorelbine Alone in Elderly Patients

J Clin Oncol 2000 18:2529-2536

Frasci et al, Gemcitabine Plus Vinorelbine Versus Vinorelbine Alone in Elderly Patients

J Clin Oncol 2000 18:2529-2536

Frasci et al, Gemcitabine Plus Vinorelbine Versus Vinorelbine Alone in Elderly Patients

J Clin Oncol 2000 18:2529-2536

Takeda et al, Phase III study of docetaxel versus vinorelbine for elderly patients with NSCLC

J Clin Oncol 2005; 23 (16S): 623s (Abstr 7009).

• Single-agent docetaxel vs vinorelbine in 180 elderly patients with good PS

• Objective response rate – Docetaxel: 22.7%– Vinorelbine: 9.9% (p = 0.019)

• Survival– Docetaxel: 13.9 months – Vinorelbine: 9.9 months (p = 0.038)

• Major toxicity: grade 3–4 neutropenia – Docetaxel: 83.0%– Vinorelbine: 69.2% (p = 0.031)

Retrospective Subset Analyses of Elderly Patients in Randomized Trials of Platinum-based Chemotherapy

CHEST 2007; 132: 277S–289S

Phase II single-agent chemotherapy studies for elderly patients with NSCLC CHEST 2005; 128: 947–957

Phase II Trials of Non–Platinum-Based Combination Chemotherapy

CHEST 2005; 128: 947–957

Phase II Trials of platin and 3. generation chemotherapy agent CHEST 2005; 128: 947–957

Summary

• There is no enough randomized phase III trial, so the available data is not enough

• To make a decision according to phase II or retrospective analysis can be wrong

• The rate of toxicity is high• The rate of continuing of treatment is low

It is not performed routinely It can be made a decision based on patient

Summary

• If it will be performed– Patients with good performance (0-1)– Patients without severe underlying disease – Third generation single-agent chemotherapy

should be preferred