Comorbidities and cancer Applications to non small cell lung cancer Pr A. Vergnenègre Dr H. Le Caer CHU Limoges CH Draguignan 1
Comorbidities and cancer Why? 2
Epidemiology elderly among lung cancer 2010-2014 2005-2009 2000-2004 49 520 53 114 55 090 Source Framcim 43,2% 44,7% 44,9% 1995-1999 1990-1994 1985-1989 36 284 44 328 38 317 40,7% 43,0% 39,4% 1980-1984 1975-1979 33 674 27 276 39,4% 42,5% 0 20 000 40 000 60 000 80 000 100 000 120 000 140 000 males < 70 y 70 y 3
Epidemiology elderly among lung cancer 2010-2014 19 955 Source Framcim 45,1% 2005-2009 16 445 49,5% 2000-2004 13 228 52,4% 1995-1999 10 363 52,7% 1990-1994 8 110 52,6% 1985-1989 7 249 55,6% 1980-1984 6 067 57,5% 1975-1979 5 100 55,9% Females 0 10 000 20 000 30 000 40 000 50 000 < 70 y 70 y 4
Background Comorbidities = prognosis factor for cancer Consequences on patient s clinical pathway diagnosis ----> treatment Ex : - severe COPD limitation to thoracic surgery - severe congestive heart failure limitation to the use of some cytotoxic drugs 5
Clinical pathway Ambulatory care Evaluation Treatment Follow up End of life Process Screening Specialists Treatments Consultations Procedures Terminal care Result Detection Stage of disease Response Toxicity Relapse Controlled disease Survival without progression Death Death du to intercurrent event 6
Comorbidities and cancer Are there good tools for comorbidities assessment? 7
Charlson comorbidity index, CCI Charlson ME, et al : J Chron Dis 1987;40:5,373-83 19 diseases with weight from 1 to 6, prédictive of death +++ Comorbidity Score Myocardial infarction Congestive heart failure 1 1 Arteritis (peripheral vascular) 1 Cerebral diseases (except hemiplegia) 1 Dementia 1 Chronic obstructive pulmonary diseases 1 Systemic diseases 1 Gastro-duodenal ulcer 1 Hepatic failure (mild) 1 Diabetes mellitus without complication 1 Diabetes mellitus with another involved organ 2 Hemiplegia 2 Renal failure (moderate to severe) 2 Other solid tumors without metastasis 2 Leucemia 2 Lymphoma or Myeloma 2 Hepatic failure (moderate to severe) 3 VIH infection 6 TOTAL 8
Charlson comorbidity index, CCI Overall survival according to CCI, p<0,001 9
Charlson s age comorbidity index Charlson ME, et al : J Clin Epidemiol 1994;47:1245-51 gage Score 50-59 1 60-69 2 70-79 3 80-89 4 90-99 5 Global score: age + comorbidities 10
Charlson s age comorbidity index Age-Comorbidity score 0 1 2 3 4 5 6 7 8 Estimated relative risk 1.00 1.45 (1.25, 1.68) 2.10 (1.57, 2.81) 3.04 (1.96, 4.71) 4.40 (2.45, 7.90) 6.38 (3.07, 13.24) 9.23 (3.84, 22.20) 13.37 (4.81, 37.22) 19.37 (6.01, 62.40) 11
Charlson s age comorbidity index Overall survival for patients >75 according to CCI Comorbidity score : 0 1 2 3 0 2 4 6 8 4 > 4 12
EVALUATION Other index : adult comorbidity evaluation 27 (27 conditions) Simplified comorbidity score SCS: Colinet et al. Br J Cancer 2005;93:1098-1105 Tabacco (7), diabetes mellitus (5), Renal failure (4), Resp diseases, cancer, heart failure, alcoholism (1) 13
Adult comorbidity evaluation 27 Read, JCO 2004;22:3099-103 11 558 cancers. Adult index 27 Prognosis according to severity Lung colon prostate breast Relationship to stage but important variable for analysis 14
Adult comorbidity evaluation 27 Impact of comorbidities according to cancer type 15
Comorbidity scores Other index : adult comorbidity evaluation 27 (27 conditions) Simplified comorbidity score SCS: Colinet et al. Br J Cancer 2005;93:1098-1105 Tobacco (7), diabetes mellitus (5), renal failure (4), Resp diseases, cancer, heart failure, alcoholism (1) 16
Simplified comorbidity score SCS: Colinet et al. Br J Cancer 2005;93:1098-1105 Comorbidity Tobacco consumption Diabetes mellitus Renal insufficiency Respiratory comorbidity Cardiovascular comorbidity Neoplastic comorbidity Alcoholism Weighting 7 5 4 1 1 1 1 17
Simplified comorbidity score SCS: Colinet et al. Br J Cancer 2005;93:1098-1105 P<0,01 18
Comorbidity tools weaknesses : - hypothesis : each item has the same accuracy for any disease - some items refer to the studied disease (eg : cancer, weight loss, anemia, ) 19
Data recording Clinical Patient s Retrospective Administrative Register trials cohorts data claims Severity ++ +++ +++ + ++ Comorbidities ++ +++ +++ + + Cancer s data ++++ +++ +++ - +++ Patient s characteristics (PS, social) ++ +++ + +/- +/- Generalisation + ++ ++ ++++ ++++ costs + ++++ ++ + + 20
Comorbidities and cancer Applications to Non small cell Lung Cancer (NSCLC) 21
Epidemiology 80% NSCLC 75 % stage III or IV Comorbidities : étude IFCT 1540 patients >70 y : 52.6% COPD 37% hypertension 18.6% ischemial heart disease 17.6% arteritis 14;2% diabetes 7.7% stroke Quoix, IASLC 2005, P382 S215 22
Survival in elderly lung cancer Follow up 12 months* : 1509 patients Death 811 (53,7%) Cancer 645 (79.5%) Comorbidities 114 (14.1%) Toxicities 40 (4.9%) Unknown 12 (1.5%) * 139 withdrawal data Quoix, IASLC 2005, P382 S215 23
Elderly patients are more frequently untreated 1648 patients, Median 76 y [70-96] Treatement 70-74 y 75-79 y 80-84 y > 85 y P BSC (%) 11 11.9 27.1 51 <0.0001 Surgery (%) 27.9 26.8 18.6 8.3 0.005 Mediastinal radiotherapy (%) 19.3 22.8 22.7 41.7 0.039 Palliatie cerebral radiotherapy (%) 4.2 4.7 3.8 4.2 0.94 Chemotherapy (%) 75.2 68.3 64.4 54.2 0.001 E. Quoix, IASLC 2005, P-382 S215 24
Impact of comorbidities in elderly patients 1255 patients, with 481 patients in the ACT trial and 774 patients in the ANSCLC trial Median age: 61.2 years (34.2-88.7); 428 patients were 65 years 391 (31%): other medical conditions (besides NSCLC) 310 (25%): CCI score of 1, 81 (6%) CCI score of 2 or higher Comorbidity rates were higher in : older patients, male, squamous histology Comorbidity rates were lower in : Patients with weight loss 5% (31% vs 37%, p = 0.04) Patients with time from diagnosis to randomization < 6 months (p=0.004) Asmis, PAsco 2006,abstr 7117 25
Impact of comorbidities in elderly patients Dose intensity Age and comorbidity were associated with lower total dose in the ANSCLC trial while only age predicted for a lower total dose in the ACT trial Toxicity (univariate analysis) * Comorbidities associated with more grade 3-5 infection (p=0.03) and GI toxicity (p=0.022), pain (p=0.01), nausea (p=0.04) * Age 65 was associated with grade 3-5 neurologic toxicity (p<0.0001), GI toxicity (p=0.03), fatigue (p=0.01) Asmis, PAsco 2006,abstr 7117 26
Impact of comorbidities in elderly patients Multivariate analysis (overall survival) Variable H R (95% C.I.) P value C C I 1 1.21 (1.02-1.42) 0.03 C C I 2 0.96 (0.72-1.27) 0.75 Age 65 0.97 (0.84-1.13) 0.72 Female 0.79 (0.67-0.92) 0.004 ECOG 2+ 2.24 (1.70-2.95) <0.0001 ECOG 1 1.25 (1.06-1.46) 0.006 Hgb < 12 1.30 (1.08-1.56) 0.006 Inc Alk Phos 1.25 (1.06-1.48) 0.007 Asmis, PAsco 2006,abstr 7117 27
Impact of comorbidities in elderly patients % survival Score 0 Score =1 Score > 1 100 80 60 CCI 1 : p = 0.003 HR 1.28 (95% CI 1 0.9-1.5) CCI 2+ : p = 0.52 HR 1.09 (95% CI 0 8.3-1.44) 40 20 0 0 20 40 60 80 100 120 Months Asmis, PAsco 2006, abstr 7117 28
Impact of comorbidities in elderly patients Comorbidity is common in patients with NSCLC, and occurs in 42% of patients over the age of 65 Males, in general, had more comorbidity than females (35% vs 21%, p<0.0001) While the elderly received less chemotherapy, they derive the same benefit as younger patients in terms of overall survival and they should not be excluded from clinical trials. However, the presence of comorbidity is associated with a poorer outcome. Asmis, PAsco 2006,abstr 7117 29
Comorbidities and lung cancer Surgical patients : stage I NAPC D. Moro-Sibilot, ERJ 2005;26:480-6 Charlson 0 : 47% 3-4 : 8% 1-2 : 43,7% : 0,8% Charlson 2 survival prognosis factor : OR 1,81 (1,25; 2,63) 30
Comorbidities and lung cancer A multicenter phase II study of docetaxel/gemcitabine weekly in advanced non-small cell lung cancer (NSCLC) in elderly and/or poor performans status patients : preliminary results of the 02 02 Groupe Français de Pneumo-Cancérologie (GFPC) study H.LeCaer, C.Gimenez, C.Chouaid, H.Jullian, J. Le Treut, P. Bombaron, L. Gérinière, S. Hominal, P. Dominique, J. Auliac Lung Cancer 2005, 49:S262 31
Comorbidities and cancer Inclusion criteria according age, CCI, PS Age [Charlson] Comorbidities Charlson score PS Treatment 60-69 [2] 0-2 [2-4] 0-1 Non eligible 0-2 [2-4] 2 D + G 3-4 [5-6] 0-1 D + G 3-4 [5-6] 2 D 5-6 [7-8] 0-2 D 0-1 [3-4] 0-1 D + G 70-79 [3] 0-1 [3-4] 2 D 2-5 [5-8] 0-2 D 80-89 [4] 0 [4] 0-1 D + G 1-4 [5-8] 0-1 D 32
Comorbidities and cancer Phase II trial, 32 french hospitals; Primary objective: efficacy: OR after 3 chemotherapeutic cycles: Arm A docetaxel 30mg/m² weekly 6 weeks followed by two rest weeks Arm B docetaxel 30mg/m² plus gemcitabine 900mg/m² (G only at D1,8,22,29) followed by two rest weeks Secondary objectives: toxicity, TTP,QoL, survival. 33
Patients characteristics Arm A (D) Arm B (D+G) Age mean 76.6 73.7 (years) [70-84] [64-82] ECOG 0 22% 42% PS 1 46% 54% 2 32% 4% Charlson mean 1,9 0,8 [0-5] [0-4] Comorbidities mean 5.1 3.7 Age + Charlson [3-8] [2-6] Weight loss >10% 22% 23.9% 34
Toxicity Arm A (D) Arm B (D+G) N 50 50 Delivered cycles (n) 53 81 All grades (n) 145 271 Grades 3/4 Tox 30 (20.6%) 71 (26,1%) Anemia 2 6 Neutropenia 0 16 Thrombopénie 0 3 Thrombocyemia 0 1 Fever 0 1 Fatigue 15 16 Diarrhea 1 2 Constipation 1 3 Nausea/Vomiting 1 2 Bleeding 0 1 Infection 3 4 Congestive heart failure 1 2 Pulmonary 4 2 Neurological 1 3 Vascular 1 3 Pain 0 1 Alopecia 0 5 Red cell transfusions 4 pts (8%) 7 pts (14,9%) 35
Results ARM A (D) ARM B (D+G) Eligible Pts n (%) 50 (100) 50 (100) Evaluable Pts n (%) 39 (78) 42 (84) Partial response n (%) 5 (12,8) 17 (40,5) Stable n (/%) 14 (35,9) 18 (42,8) Controled diseases 19 (48,7%) 32 (83,3%) Progression n (%) 20 (51,3) 7 (16,6) TTP (jours) 65 138 Median survival (month) 4,33 6,6 Median number of cycles 1 ( 8 weeks) 1,6 (12.8 weeks) 36
Quality of life assessment MEAN INITIAL SCORE ARM A (D) ARM B (D+G) LCSS SCORE (0-10) N=44 N=44 ANOREXIA 3,58 3,15 FATIGUE 4,14 3,53 COUGH 2,7 1,89 DYSPNEA 3,44 3,1 HEMOPTYSIS 0,74 0,43 PAIN 2,46 2,35 SYMPTOM score 2,84 2,40 CONSEQUENCES ON DAILY ACTIVITY 3,62 3,28 GLOBAL QoL 3,31 3,16 SPITZER SCORE (0-10) N=44 N=43 GLOBAL SCORE 7 7 No difference at initial score between progressive and controled patients in each arm. No difference in each arm between initial score and at the end of the treatment. 37
Comorbidities and cancer ITTpatients Symptom score Treatment A 38
Comorbidities and cancer ITTpatients Symptom score Treatment B 39
Comorbidities and cancer new tool : Lecaer, Balas (CHU Nice) Elderly description: geriatric index Denutrition Mental assessment ADL, IADL Associated to precedent results 40
Relationships between PS, charlson index and geriatric assessment Dujon et al, Rev Mal Resp 2006, in press 41
Relationships between PS, charlson index and geriatric assessment Dujon et al, Rev Mal Resp 2006, in press 42
Comorbidities and cancer Inclusion criteria 43
Comorbidities and cancer Inclusion criteria AGE(CHARLSON) IADL ADL GROUPE <<VULNERABLE>> SYNDROMES GERIATRIQUES COMORBIDITE CHARLSON PS TRAITEMENT 1 0 0 0--2 2--4 0-1 1 0 0 0--2 2--4 2 INCLUSION 65-69 [2] <2 0 0 3--4 5--6 0-1 INCLUSION <2 0 0 3--4 5--6 2 INCLUSION 1 0 0 0--1 3--4 0--1 INCLUSION 70-79[3] <2 0 0 0--1 3--4 2 INCLUSION <2 0 0 2--4 5--6 0--2 INCLUSION 80-89[4] 1 0 0 0 4 0--1 INCLUSION <2 0 0 1--2 5--6 0--2 INCLUSION 44
Quality of life (IRIS scale) 45
Cognitives and sensorial functions 46
DISCUSSION 47
Group 1 : independant patient - No severe cardiac or pulmonary comorbidity (grade >2) - No untreated comorbidity - ADL > 4/6 et IADL > 4/6 - Age < 80 - Weight loss <15 % of body weight -Clocktest = 2/2 - No fall within the last 3 months - Creatinin clearance > 50 ml/min 48
Group 2 : vulnerable patient - 1 or 2 not controlled or not treated comorbidities - ADL < 4/6 or IADL< 4/6 - Age > 80 - Fall within the last 3 months - Positive depression test - Weight loss between 15-25 % of body weight - Creatinin clearance < 50 ml /min -Clocktest <2 49
Group 3: frailed and dependant patients - More than 2 comorbidities not controlled or not treated -ADL < 4 - IADL abnormal on 3 evaluable items or more - Weight loss >35 % of body weight - Creatinin clearance< 30 ml/min 50
Comorbidities and cancer Patient s refusal Or non proposition of treatment Interest of observational studies according to non diagnosed or non recorded diseases (dementia) 51
Conclusion Comorbidities: major item for cancer Clinical pathway: comorbidities have major impact on management Severity is a very important dimension Major role for elderly 52
Conclusion Future : Patient: center of strategy management Geriatric oncology associated with multi disciplinary staff Clinical research with social dimension 53