is there a role for chemotherapy in elderly patients? – yes

Is there a role for chemotherapy in elderly patients? – YES

Rudolf M. Huber

PneumologyUniversity of Munich

Istanbul, 7. 5. 2010

2

Age and gender distribution of lung cancer

HuberIstanbul, 7. 5. 2010

Germany 2002

GEKID Gesellschaft der epidemiologischen Krebsregister in Deutschland e. V. in Zusammenarbeit mit dem Robert Koch Institut. Krebs in Deutschland, Häufigkeiten und Trends. 5. überarbeitete, aktualisierte Ausgabe. Saarbrücken: GEKID, 2006

3

Chemotherapy in Elderly Patients


Patients aged > 65 yrs represent about 50% of all patients with lung cancer and patients > 70 yrs about 30%.Elderly patients are under represented in clinical trials making any statement about the best treatment according to geriatric status very difficult

Quoix E: Chemotherapy in advanced NSCLC. In Spiro SG, Huber RM, Janes SM (eds.): Thoracic malignancies: Eur Respir Mon, 2009, 44, 271–283.

4

What does “elderly” mean?


Generally refers to a period of accelerated decline in physical functioning. Definitions currently in use

– Age > 70 years– Age > 65 years (East-Asian literature)

– Elderly < 75 years– Very elderly > 75 years– The oldest old > 85 years

5

Infections

Gastro-enterology

Hematology

NephrologyCrCl

ultrasound

PneumologyAge

GenderBMI

NeurologyCNSPNP

Cardio-vascular

Organ Systems

Reduced drug metabolism and organ reserveSmoking and age cause damage to many organs

Istanbul, 7. 5. 2010 Huber

6


NSCLC – first-line– monotherapy– non-platinum doublets– platinum-based doublets

NSCLC – second-line SCLC Age vs. comorbidity

7

Elderly* Lung Cancer Vinorelbine Italian Study Group (ELVIS)

a6422

J Natl Cancer Inst 91 (1999)

* > 70 years old

vinorelbine 30 mg/m2 d 1 and 8


8

BSC vs BSC plus vinorelbine for elderly advanced NSCLC: the ELVIS study


J Natl Cancer Inst. 1999; 91: 66–72

BSC vs. vinorelbineMedian survival:

21 wks vs. 28 wks;Survival at 6/12 months:

41/14% vs. 55/32%

With vinorelbine significant improvement in QoL

9

Chemotherapy in Elderly NSCLC Patients

Gemcitabine is the second most studied drug in elderly patients with quite a number of phase II studies demonstrating its efficacy in this subpopulation of patients.


Shepherd FA ea. Semin Oncol 1997; 24: Suppl. 7, S7-50–S7-55.Ricci S ea. Lung Cancer 2000; 27: 75–80.Quoix E ea. Lung Cancer 2005; 47: 405–412.

10

Docetaxel vs. Vinorelbine in Elderly Patients (> 70 years old)

Kudoh et al. J Clin Oncol. 2006;24:3657-3663.

Docetaxel60 mg/m2 d 1, 22

Vinorelbine 25 mg/m2

d 1, 8, 22, 29

Stratification:

Institution

Stage IV/IIIB

PS 0-1/2*

Elderly Patients withAdvanced NSCLC

N=181

Both treatments were repeatedover 4 cycles to disease progression

*ECOG 0-1 98,9 vs 93,4%

median 76 years, range 70 – 86 y


11

Docetaxel vs. Vinorelbine in Elderly Patients: Response and Survival

Kudoh et al. J Clin Oncol. 2006;24:3657-3663.

OutcomeDocetaxel

N=90Vinorelbine

N=91p-value

ORR, % 22.7 9.9 0.019

Median OS, mo 14.3 9.9 0.138

Median PFS, mo 5.5 3.0 <0.001

1-Y survival, % 58.6 36.7

Neutropenia G3/G4 26,1 / 56,8 % 30,8 / 38,5 % 0,031

Febrile Neutropenia G3 12,5 % 11,0 %

Anemia G3&G4 3,4 % 9,9 %


12

Kudoh, S. et al. J Clin Oncol; 24:3657-3663 2006

Overall survival for patients treated with docetaxel (n = 89) or vinorelbine (n = 91)

median progression-free survival (5.5 vs 3.1 months; P < .001)

Docetaxel vs. Vinorelbine in Elderly Patients (> 70 years old)


13

Forest plot of odds ratio for global quality of life (QoL) and disease-related symptoms analyses

Kudoh S ea. J Clin Oncol; 24:3657-3663 2006

Phase III Study of Docetaxel (n = 89) Compared With Vinorelbine (n = 91) in Elderly Patients With Advanced NSCLC

b6502Huber

14

Single-agent vs. Non-platinum based doublet

The South Italian Cooperative Oncology Group (SICOG) Phase III trial of vinorelbine (30 mg/m2; d 1 and 8, every 21 days) vs. vinorelbine/ gemcitabine doublet (vinorelbine: 30 mg/m2; gemcitabine 1200 mg/m2; both drugs on d 1 and 8, every 21 days)


Frasci G ea. J Clin Oncol 2000; 18: 2529–2536

15

Single-agent vs. Non-platinum based doublet


Frasci G ea. J Clin Oncol 2000; 18: 2529–2536Frasci G ea. Lung Cancer 2001; 34 (4 Suppl): S65–S69.

Prematurely terminated at interim analysis Significant survival benefit for combination:– Median OS 29 wks vs 18 wks– Estimated 6-month and 1-year survival:56/30 compared with 32/13% (P < 0.01).– Multivariate Cox analysis, after adjustments:Risk of death in the combination arm 0.48 (95% CI 0.29 to 0.79; P < 0.01) Symptoms and QoL deterioration more likely with monotherapy

16

Chemotherapy in Elderly NSCLC PatientsMILES

The combination of vinorelbine and gemcitabine versus monotherapy with either of these two agents did not provide any benefit (n = 700 patients).


Gridelli C, Perrone F, Gallo C, et al. Chemotherapy for elderly patients with advanced non-small cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst 2003; 95: 362–372.

17

Vinorelbine, Gemcitabine or Vinorelbine+ Gemicitabine (MILES)


Gridelli C ea. J Natl Cancer Inst 2003; 95: 362–372.

18

Gemcitabine with either paclitaxel or vinorelbine vs paclitaxel or gemcitabine

alone for elderly or unfit advanced NSCLC


Comella P ea. British Journal of Cancer (2004) 91, 489–497

19

Gemcitabine with either paclitaxel or vinorelbine vs paclitaxel or gemcitabine alone for elderly or unfit advanced NSCLC


Comella P ea. British Journal of Cancer (2004) 91, 489–497

Actuarial survival

20

Gemcitabine mono vs gemcitabine 3rd-generation doublet

Meta-analysis of a gemcitabine third-generation agent doublet versus single-agent treatment in elderly NSCLC patients Significantly higher overall response rate: combination vs. single agent; OR 0.65; P < 0.001 Trend toward higher survival in favor of combination treatment (OR 0.78; P = 0.169) Similar toxicity, except thrombocytopenia


Russo A ea. Cancer 2009; 115: 1924–1931.

21

Taiwan: cisplatin plus weekly paclitaxel or vinorelbine


Median survival times 15 months in the younger patients (n=70) and 11.7 months in the elderly patients (n=70; p=0.598)Chen Y-M ea. CHEST 2005; 128:132–139

22

NSCLC – platinum-based doublets


Okamoto I ea. Jpn J Clin Oncol 2005;35(4)188–194

Twenty-five patients aged >70 years (median, 76; range, 70–83) with chemotherapy-naive advanced NSCLC were enrolled between January 2001 and July 2003. Patients received carboplatin at an AUC of 5 mg/ml/min and paclitaxel at 180 mg/m2 on the first day of consecutive 3 week periods.

23

NSCLC – platinum-based doublets


Okamoto I ea. Jpn J Clin Oncol 2005;35(4)188–194

Treatment response and toxicity according to patient age

24

Chemotherapy in Elderly NSCLC Patients


Pujol JL ea. J Thorac Oncol 2006; 1: 328–334.

Combined carboplatin and paclitaxel was found to be highly effective and safe in a phase II study. This approach is now being investigated in a randomised trial comparing single agent therapy (vinorelbine or gemcitabine) with carboplatin and paclitaxel (French Intergroup of Thoracic Oncology).

25

Paclitaxel plus carboplatin versus single-agent paclitaxel


Lilenbaum RC ea. J Clin Oncol 2005; 23: 190–196.

Subgroup analysis of a study comparing paclitaxel monotherapy to paclitaxel/ carboplatin doublet Elderly patients benefitted from the combination regimen

median OS for monotherapy vs doublet:5.8 versus 8.0 months; P = nonsignificant

Lack of statistical significance likely due to the small numbers

26

Single agent versus platinum-based doublet (JCOG0207)

Randomized controlled trial comparing docetaxel (D)-cisplatin (P) combination with D alone in elderly with advanced NSCLC Pts ≥70 years old received either D/ P(D 20 mg/m2, P 25 mg/m2, d 1, 8, 15) or D (25 mg/m2, on the same schedule). Prematurely closed after only 63 patients per arm (interim analysis showed possible benefit with doublet in the 70–74 year subgroup).


Tsukada H ea. Proc Am Soc Clin Oncol 2007; 25: (Abstr 7629)

27

Gemcitabine plus carboplatin versus single-agent gemcitabine A preplanned subgroup analysis of elderly patients (n = 121): both young and elderly patients showed benefit in OS when treated with the combination regimen. Elderly patients experienced more hematological toxicity when compared with younger patients.


Sederholm C ea. J Clin Oncol 2005; 23: 8380–8388.

28

Comparison of platinum-doublets

Two doublets were evaluated in 159 elderly (aged ≥ 70 years) NSCLC patients:

– cisplatin/gemcitabine– cisplatin/ vinorelbine

Both doublets were shown to be feasible and active in elderly patients.


Gridelli C ea. J Clin Oncol 2007; 25: 4663–4669.

29

NSCLC – platinum-based doublets No elderly-specific platinum-based prospective phase III trials have been conducted Retrospective age-specific subgroup analyses of several phase III trials indicate outcome measures, namely response rate, PFS and OS, do not differ significantly between age groups Regarding severe toxicity (grade ≥ 3), some studies report a higher incidence in elderly patients, while others do not


Pallis AG ea. Ann Oncol 21: 692–706, 2010

30

NSCLC – second-line

Age-specific subgroup analysis of a randomized phase III trial comparing pemetrexed with docetaxel in pretreated patients with NSCLC. The original trial randomized 571 patients. Eighty-six of those (15%) were ≥70 years old.


Weiss GJ ea. J Clin Oncol 2006; 24: 4405–4411

31

NSCLC – second-line

Objective response rates, median PFS and OS were not significantly different between younger and elderly patients. Elderly pts had a median OS of 9.5/7.7 months for pemetrexed / docetaxel arms In younger pts the OS was 7.8/8.0 months for pemetrexed/docetaxel arms No significant difference between younger and elderly patients regarding toxicity


Weiss GJ ea. J Clin Oncol 2006; 24: 4405–4411

32

Efficacy and safety of pemetrexed in elderly cancer patients


Kulkarni PM ea. Crit Rev Oncol/Hematol (2008)

33

Efficacy and safety of pemetrexed in elderly cancer patients

HuberIstanbul, 7. 5. 2010Kulkarni PM ea. Crit Rev Oncol/Hematol (2008)

Non-haematological toxicities: no significant differences

34

Erlotinib second-line in elderly

Subgroup analysis of BR.21 study 163 (22% of the original cohort; 112 on erlotinib, 51 on placebo), pts ≥70 years old No significant difference between young and elderly pts in RR, PFS and OS (erlotinib: 6.4/ 7.6 mo.; P = 0.85) Elderly patients experienced significantly more ≥ grade 3 toxic effects (35% vs. 18% for elderly vs. young patients; P < 0.001)


Wheatley-Price P ea. J Clin Oncol 2008; 26: 2350–2357.

35

NSCLC – second-line Individual data from nine randomised trials of 2nd-line treatment in advanced NSCLC were analysed. Primary end-point was overall survival. 1197 pts (97%) had complete data sets. Prognosis of pts eligible for 2nd-line treatment of advanced NSCLC is significantly dependent on gender, PS, histology, stage, previous use of platinum and response to first-line.


Di Maio M ea. Eur J Cancer (2009), doi:10.1016/j.ejca.2009.12.013

36

2009 ASCO Recommendations

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

• Recommendation B2. The evidence does not support the selection of a specific second-line chemotherapy drug or combination based on age alone.


37

NCCN Practice Guidelines

Advanced NSCLC: Fit elderly merit appropriate treatment Single agent therapy or platinum-based combinations are a reasonable alternative in PS 2 patients or the elderly Unfit of any age (performance status 3 – 4) do not benefit from cytotoxic treatment


NCCN Practice Guidelines 2008

38

Chemotherapy in Elderly NSCLC Patients In patients with stage IV NSCLC who are elderly (> 70 to 79 years) single-agent chemotherapy is recommended for most patients. Grade of recommendation, 1A

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

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

ACCP 2007Huber

39

NSCLC elderly patients – recommendations


Older age should not exclude patients from a treatment modality (chemotherapy, radiotherapy, surgery). Comorbidity is more relevant (Level C).

German Society of Pneumology. Pneumologie 2010; 64, Supplement 2: e1– e164

40

SCLC


Approximately 40% of SCLC cases are diagnosed in patients older than 70 years, and this proportion continues to rise in contrast to the continued decline in incidence of SCLC among the general population. In the United States 10% are diagnosed in patients older than 80 years.

Owonikoko TK ea. JNCCN 2008;6:333–344

41

SCLC – extensive disease

Prospective trials have specifically addressed elderly patients with SCLC, and carboplatin plus etoposide is the most investigated regimen (Quoix E 2001, Larive S 2002) The same chemotherapy as used in younger patients induces reasonable activity, albeit with increased toxicity, in the elderly.


Gridelli C ea. J Clin Oncol 25 (2007):1898-1907

42

SCLC – extensive disease (etoposide phosphate and carboplatin)


Quoix E ea. Ann Oncol 12:957-962, 2001

Main issues according to age

43Davidoff AJ ea. J Clin Oncol; 28:2191-2197 2010

First-line: Distribution by type of chemotherapy

USA: Chemotherapy and Survival Benefit in Elderly (> 65 yrs) With Advanced NSCLC

Source: Surveillance, Epidemiology and End Results–Medicare, 1997-2002.


44

Adjusted survival benefit of chemo-therapy for elderly advanced NSCLC

Davidoff AJ ea. J Clin Oncol; 28:2191-2197 2010

Source: Surveillance, Epidemiology and End Results–Medicare, 1997-2002.

Chemo vs BSC: A: Proportional hazards; B: nonproportional hazards

Platinum-doublet vs single-agent: C: proportional hazards


45

Effect of comorbidity on treatment and prognosis of elderly with NSCLC

All patients with NSCLC diagnosed between 1995 and 1999 in the southern part of the Netherlands (n = 4072) were included In patients with non-localised NSCLC the proportion receiving chemotherapy was considerably higher for those aged less than 60 years (24%) than in those aged 80 or older (2%).


Janssen-Heijnen MLG ea. Thorax 2004;59:602–607

46

Treatment of non-localised NSCLC according to age, and comorbidity


Janssen-Heijnen MLG ea. Thorax 2004;59:602–607

47

Chrischilles EA ea. J Clin Oncol; 28:620-627 2010

Adverse Events Among the Elderly Receiving Chemotherapy for Advanced NSCLC

Of 1,371 patients, 58% received chemotherapy and 35% had AEs.

– Age < 55 years: 72% received chemotherapy

– Age > 75 years: 47% received chemotherapy

Platinum-based therapies were less common in the older-age groups.


48

Chrischilles EA ea. J Clin Oncol; 28:620-627 2010

Adverse Events Among the Elderly Receiving Chemotherapy for Advanced NSCLC*

Pretreatment medical event rates:– 18.6% for pts < 55 yrs– 9.2% for pts ≥ 75 yrs (adjusted rate ratio 0.49)

Older pts were more likely to have AEs during chemotherapy. Adjusted rate ratios compared with < 55 yrs

– 1.70 for 65- to 74-yr-olds– 1.34 for those ≥75 yrs


*Cancer Care Outcomes Research and Surveillance Consortium

49

Age and Comorbidity As Independent Prognostic Factors in NSCLC Therapy

Two large, prospectively randomized Canadian trials of systemic chemotherapy (adjuvant/palliative setting) for NSCLC. 1,255 patients were included The median age was 61 yrs (range: 34 - 89 yrs); 34% of patients were elderly (>= 65 yrs) 31% had comorbid conditions.


Asmis TR ea. J Clin Oncol 26 (2008):54-59.

50

Age and Comorbidity As Independent Prognostic Factors in NSCLC Therapy

Although age did not influence overall survival, the CCIS appeared prognostic (CCIS 1 v 0; hazard ratio 1.28; 95%CI, 1.09 to 1.5; P=.003). In these large, randomized trials, the presence of comorbid conditions (CCIS ≥ 1), rather than age more than 65 years, was associated with poorer survival.



51

Age and Comorbidity as Independent Prognostic Factors in NSCLC Therapy



Overall survival by Charlson comorbidity index (CCI) score

Overall survival by age

52


Shrink the tumour faster than the patient There is a clear need for treatment Data demonstrate a benefit Toxicity is an issue More age-specific therapies needed Don’t mix up age with comorbidity and geriatric disorders


53HuberIstanbul, 7. 5. 2010

Adjuvante Therapie des NSCLC

Thank you for your attention

is there a role for chemotherapy in elderly patients? – yes

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