gemma bruera medical oncology dpt. biotechnological and applied clinical sciences university of...

Gemma BrueraMedical OncologyDpt. Biotechnological and Applied Clinical SciencesUniversity of L'Aquila

Rome, October 19, 2012

Supportive and Palliative Care in the Elderly

Chemotherapy-related toxicity in the elderly

Gastro-intestinal toxicity

2

Decision-making according to patient fitness

Age

Comorbidities

Modulation of treatment according to patients’ fitness

Balance between intensification of medical treatment and

safety (gastro-intestinal toxicity)

Treatment of diarrhea

Gastrointestinal toxicity in elderly patientsOutline

3

Metastatic colorectal cancerIntegration between antitumoral treatment and supportive care

ANTITUMORAL

TREATMENT

SUPPORTIVE CARE

4

PS

COMORBIDITYADLIADL

NUTRITIONAL CONDITION

AGE

5

Elderly patients

Comorbidities

Nutritional conditions

Functional conditions and Performance Status

Metastatic colorectal cancerFunctional condition of the patient

6

Number of comorbidities

Severity of comorbidities

Comorbidity

Metastatic colorectal cancerFunctional condition of the patient

7

Metastatic colorectal cancerComorbidity index CIRS (Cumulative Illness Rating Scale)

8

Comorbidity index CIRS

9

Activities of daily living: ADL

10

Instrumentalactivities ofdaily living: IADL

11

Terminal

Unstable CIRS ( 3 cathegories or 1 severe cathegory) dependent IADL

Secondary

Stable CIRS (< 3 mild or moderate cathegories) dependent or independent IADL

Intermediate

Independent IADL (score 8) Absent or mild CIRS

PrimaryCharacteristicsStage

Metastatic colorectal cancerComorbidities index CIRS Making decision

12

Medical treatments 65-75 years >75 years Primary Standard Standard Intermediate Standard Modified Secondary Modified Modified Terminal - -

Metastatic colorectal cancerComorbidity index CIRS (Cumulative Illness Rating Scale)

13


Age

Comorbidities






14

Triplet chemotherapy: activity and efficacy data

Phase ORR(%)

PFS(months)

OS(months)

doublet triplet doublet triplet doublet triplet

FOLFOXIRI versus FOLFIRIFalcone, J Clin Oncol 2007

III 34 60* 6.9 9.8* 16.7 23.4*

FOLFOXIRI versus FOLFIRISouglakos, Br J Cancer 2006

III 33.6 43 6.9 8.4 19.5 21.5

FIr/FOxMorelli, Oncol Rep 2010

II 66.7 12 20

Abbreviations: ORR, objective response rate, PFS, progression-free survival, OS, overall survival, *, statistically significant difference.

Ficorella C, Bruera G et al, Clin Colorectal Cancer 2012 Epub Ahead of print

15

Triplet chemotherapy: projected/received dose-intensities

Phase irinotecan(mg/m2/week)

oxaliplatin(mg/m2/week)

5-fluorouracil(mg/m2/week)

pDI rDI %

pDI rDI%

pDI rDI %


III 82.5 67.6583

42.5 35.282

1600 131282


III 65 63.7585

32.5 27.384

1000 88088


II 80 65.682

40 3587.5

1800 147682

Abbreviation: pDI, projected dose-intensity; rDI, received dose-intensity.


16

Triplet chemotherapy: grade 3-4 toxicity (NCI-CTC version 3.0)

Phase Diarrhea(%)

StomatitisMucositis

(%)

Asthenia(%)

Neutropenia(%)

Febrile neutropenia

(%)

Neurotoxicity(%)

NCI-CTC, version 3.0 G3 G4 G3 G4 G3 G4 G3 G4 G3 G4


III 17 3 4 1 6 - 33 175

2 -


III 27.7 5 5.6 357

5.8


II 35 - - - 4 - 13-

4-

4 -

Abbreviation: NCI-CTC, National Cancer Institute-Common Toxicity Criteria; G, grade.


17

FOLFOXIRI versus FOLFIRI in the elderly MCRC patients

Patients’ features

Vamvakas L et al, Crit Rev Oncol Hematol 2010; 76(1):61-70

18


Age distribution of elderly patients


19


Median TTP and OS according to age in patients treated with FOLFIRI

TTP OS


20


Median TTP and OS according to age in patients treated with FOLFOXIRI

TTP OS


21


Forest Plot analysis for OS and TTP


22


Relative dose-intensities according to age in patients treated with FOLFIRI and FOLFOXIRI


23


Incidence of common toxicities according to age in patients treated with FOLFIRI and FOLFOXIRI


24


Incidence of common toxicities according to age in patients treated with FOLFIRI and FOLFOXIRI


25

MCRC: Intensive 4-drugs chemotherapyphase II studies: activity and efficacy

ORR(%)

PFS(months)

OS(months)

Triplet regimens

39.0-66.0 8.3-10.6 20.4-26.1

Triplet+Bev 77-82 12-13.1 28-30.9

Triplet+Cet 79 14 37

Abbreviation: Bev, Bevacizumab; Cet, Cetuximab; ORR, objective response rate; PFS, progression-free survival; OS, overall survival.

Bruera and Ricevuto, Expert Opin Biol Ther 2011; 11(6):821-4

26

Triplet chemotherapy plus target agent: activity and efficacy data

Phase ORR(%)

PFS(months)

OS(months)

FOLFOXIRI + bevacizumabMasi, Lancet Oncol 2010

II 77 13.1 30.9

FIr-B/FOxBruera, BMC Cancer 2010

II 82 12 28

Chrono-IFLO + cetuximabGarufi, Br J Cancer 2010

II 79 14 37

ERBIRINOXAssenat, The Oncologist 2011

II 80.9 9.5 24.7

Abbreviations: ORR, objective response rate, PFS, progression-free survival, OS, overall survival.


27

Triplet chemotherapy plus target agent: projected/received dose-intensities

Phase irinotecan(mg/m2/week)

oxaliplatin(mg/m2/week)

5-fluorouracil(mg/m2/week)

bevacizumab(mg/kg/week)

cetuximab(mg/m2/week)

pDI rDI pDI rDI pDI rDI pDI rDI

FOLFOXIRI + BEVMasi, Lancet Oncol 2010

II 82.5 70 42.5 36 1600 1344 2.5 2


II 80 66 40 32.5 1800 1500 2.5 2


II 65 55 40 28 1200 1100 250 250

ERNIRIXOXAssenat,The Oncologist 2011

II 90 77.4 42.5 36 1400 1288 250 235

Abbreviation: pDI, projected dose-intensity; rDI, received dose-intensity.


28

Triplet chemotherapy plus target agent: grade 3-4 toxicity (NCI-CTC version 3.0)

Phase Diarrhea(%)

Asthenia(%)

Neutropenia(%)

Febrile neutropenia

(%)

Hypertension(%)

Deep-veinthrombosis

(%)

CutaneousRash(%)

NCI-CTC, version 3.0

G3 G4 G3 G4 G3 G4 G3 G4 G3 G4 G3 G4

FOLFOXIRI + BEVMasi, Lancet Oncol 2010

II 14 - 7 - 25 252

9 2 7 - n.r. n.r.


II 28 - 6 - 10 - 2 - - - n.r. n.r.


II 35 1 12 - 6 - n.r. n.r. n.r. n.r. 15 -

ERBIRINOXAssenat,The Oncologist 2011

II 52.4 - 31.7 - 164.8

16 - - - - 14.4 -

Abbreviation: NCI-CTC, National Cancer Institute-Common Toxicity Criteria; G, grade.


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Toxicity requiring treatment modulation in triplet chemotherapy plus Bevacizumab reported regimens

NCI-CTC Grade 2-4 (%) FOLFOXIRI+Bevacizumab FIr-B/FOx

Number of patients 57 50

Nausea 37 36

Vomiting 28 16

Diarrhea 37 52

Stomatitis/mucositis 28 10

Asthenia 40 46

Neurotoxicity 44 10

Hypertension 21 10

Hypertransaminasemy n.r.

Anemia 44 8

Leucopenia n.r. 34

Neutropenia 68 38

Febrile neutropenia 2 -

Thrombocytopenia 3.5 2

Deep-vein thrombosis 9 -

Serious Adverse Events 10.5 -

Abbreviation: NCI-CTC, National Cancer Institute Common Toxicity Criteria; n.r., not reported.

Bruera and Ricevuto, Exper Opin Biol Ther 2011; 11(6):821-4

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Age

Comorbidities






31

Poker Schedule (FIr-B/FOx)

5-Fluorouracil (5-FU), time flat infusion of 12h, Irinotecan (CPT-11) / Bevacizumab (BEV), Oxaliplatin (l-OHP), as first line treatment of metastatic colorectal cancer:

fase II study.

Patients and methods Poker Schedule (FIr-B/FOx)

Bev 5 mg/kg Bev 5 mg/kg

Bruera G et al, BMC Cancer 2010;10:567

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Patients’ features Total N. (%)

No. of patients 50

Sex M/F 31/19

Age, years median range > 65 years

6340-73

24 (48)

WHO Performance Status 0 1-2

48 (96)2 (4)

Metastatic disease metacronous sincromous

15 (30)35 (70)

Primary tumor colon rectum

24 (48)26 (52)

Sites of metastases liver lung lymph nodes local Other

33 (66)10 (20)17 (34)10 (20)5 (10)

No. of involved sites 1 2

32 (64)18 (36)

Single metastatic site liver lung lymph nodes local

22 (44)3 (6)3 (6)4 (8)

Liver metastases single Multiple

11 (22)22 (44)

Previous adjuvant chemotherapy: FA/5-FU bolus Capecitabine Folfox4

9 (18) 4 (8)1 (2) 4 (8)

Previous radiotherapy: RT alone RT+CT (5-FU i.c.) RT+CT (XELOX)

6 (12)2 (4)3 (6)1 (2)

Abbreviation: WHO, Wordl Health Organization; c.i., continous infusion

Patients and methods Patients’ featuresBruera G et al, BMC Cancer 2010;10:567

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Activity and efficacy data

Results Activity and efficacy

Intent-to-treatAnalysis

As-treatedAnalysis

No % No %

Enrolled patients 50 100 50 100

Evaluable patients 49 98 43 86

Objective Response Partial Response Complete Response

40364

82 (CI±11)738

36324

84 (CI±11)759

Stable Disease 2 4 2 5

Progressive Disease 7 14 5 12

Median Progressio-free survival, months Range Progression events

123-69+

44 88

Median Overall Survival, months Range Deaths

283+-69+

33 66

Liver metastasectomies No/Overall patients (50) No/Patients with liver metastases (33) No/Patients with liver-only metastases (22)

13263954


34

Kaplan-Meier survival estimate. Phase II study population; median follow-up 28 months (1) Progression-Free Survival (2) Overall Survival

(1)

12 months (3-69+)

(2)

31 months (3+-69+)

Results Activity and Efficacy of FIr-B/FOx association

Bruera G et al, unpublished data

35

Dose-intensity

Results Dose-intensity

All patients Young-elderly patients

DI/cyclemg/m2(or Kg)/w


Projected DImg/m2(or Kg)/w

Median(Range)

Received DI (%)

Median(Range)

Received DI (%)

5-FU 1800 1487(480-1800)

82,6 1420(480-1800)

80

CPT-11 80 66,7(25-80)

83 61(25-80)

76

l-OHP 40 32(8-40)

80 31,5(8-40)

79

BEV 2,5 2,1(1-2,5)

84 2(1-2,5)

80

Abbreviation: DI, dose-intensity; 5-FU, 5-Fluorouracil; CPT-11, Irinotecan; l-OHP, Oxaliplatin; BEV, Bevacizumab.


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Cumulative toxicity

Results Toxicity

Patients Cycles

Number 50 247

NCI-CTC Grade 1 2 3 4 1 2 3 4

Nausea (%) 23 (46) 15 (30) 3 (6) - 81 (33) 23 (9) 4 (2) -

Vomiting (%) 10 (20) 6 (12) 2 (4) - 19 (8) 9 (4) 2 (1) -

Diarrhea (%) 20 (40) 12(24) 14 (28) - 76 (30) 28 (11) 15 (6) -

Hypoalbuminemia (%) 2 (4) 1 (2) - - 2 (1) 1 (0.5) - -

Constipation (%) 17 (34) 1 (2) - - 22 (9) 1 (0.5) - -

Stomatitis/mucositis (%) 16 (32) 2 (4) 3 (6) - 29 (12) 3 (1) 3 (1) -

Erythema (%) 1 (2) - 1 (2) - 3 (1) - 1 (0.5) -

Asthenia (%) 13 (26) 20 (40) 3 (6) - 48 (19) 38 (15) 3 (1) -

Neurotoxicity (%) 36(72) 5 (10) - - 126(51) 6 (2) - -

Hypertension (%) 15 (30) 4 (8) 1 (2) - 27 (11) 4 (2) 1 (0.5) -

Hypotension (%) 1 (2) - - - 1 (0.5) - - -

Hematuria (%) 2 (4) 1 (2) - - 3 (1) 1 (0.5) - -

Gengival recession/gengivitis (%) 7 (14) - - - 10 (4) - - -

Rhinitis (%) 38 (76) - - - 110(44.5) - - -

Epistaxis (%) 31 (62) 2 (4) - - 68 (27.5) 2 (1) - -

HFS (%) 2 (4) - - - 2 (1) - - -

Headache (%) 6 (12) - - - 9 (4) - - -

Hypokalemia (%) 3 (6) - 1 (2) - 3 (1) - 1 (0.5) -

Hypertransaminasemy (%) 3 (6) 2 (4) 1 (2) 1 (2) 9 (4) 6 (2) 1 (0.5) 1 (0.5)

Hyperpigmentation (%) 6 (12) 2 (4) - - 14 (6) 5 (2) - -

Fever without infection (%) 10 (20) - - - 10 (4) - - -

Alopecia (%) 5 (10) 9 (18) 3 (6) - 11 (4) 17 (7) 7 (3) -


37

Cumulative toxicity

Results Toxicity

Patients Cycles

Number 50 247

NCI-CTC Grade 1 2 3 4 1 2 3 4

Anemia (%) 7 (14) 4 (8) - - 16 (6) 4 (2) - -

Leucopenia (%) 13 (26) 17 (34) - - 49 (20) 26(10.5) - -

Neutropenia (%) 9 (18) 14 (28) 5 (10) - 35 (14) 32 (13) 8 (3) -

Trhombocitopeny (%) 7 (14) 1 (2) - - 16 (6) 1 (0.5) - -


38

Cumulative toxicity (young-elderly patients)

Results Toxicity

Patients Cycles

Number 24 119

NCI-CTC Grade 1 2 3 4 1 2 3 4

Nausea (%) 8 (33) 10 (42) 2 (8) - 39 (33) 16 (13) 2 (2) -

Vomiting (%) 6 (25) 3 (12.5) 2 (8) - 14 (12) 5 (4) 2 (2) -

Diarrhea (%) 11 (46) 7 (29) 6 (25) - 46 (39) 14 (12) 7 (6) -

Hypoalbuminemia (%) 1 (4) 1 (4) - - 1 (1) 1 (1) - -

Constipation (%) 11 (46) - - - 14 (12) - - -

Stomatitis/mucositis (%) 9 (37.5) 1 (4) 3 (12.5) - 18 (15) 2 (2) 3 (2.5) -

Erythema (%) - - 1 (4) - 1 (1) - 1 (1) -

Asthenia (%) 6 (25) 10 (42) 3 (12.5) - 21 (18) 22 (18) 3 (2.5) -

Neurotoxicity (%) 18 (75) 3 (12.5) - - 61 (51) 3 (2.5) - -

Hypertension (%) 5 (21) 2 (8) - - 9 (7.5) 2 (2) - -

Hypotension (%) 1 (4) - - - 1 (1) - - -

Hematuria (%) - 1 (4) - - - 1 (1) - -

Gengival recession/gengivitis (%) 4 (17) - - - 5 (4) - - -

Rhinitis (%) 20 (83) - - - 45 (38) - - -

Epistaxis (%) 17 (71) - - - 38 (32) - - -

HFS (%) - - - - - - - -

Headache (%) 5 (21) - - - 7 (6) - - -

Hypokalemia (%) 2 (8) - - - 2 (2) - - -

Hypertransaminasemy (%) 1 (4) 1 (4) - 1 (4) 1 (1) 2 (2) - 1 (1)

Hyperpigmentation (%) 3 (12.5) - - - 5 (4) - - -

Fever without infection (%) 6 (25) - - - 6 (5) - - -

Alopecia (%) 3 (12.5) 7 (29) 3 (12.5) - 8 (7) 14 (12) 7 (6) -


39

Cumulative toxicity (young elderly patients)

Results Toxicity

Patients Cycles

Number 24 119

NCI-CTC Grade 1 2 3 4 1 2 3 4

Anemia (%) 3 (12.5) 2 (8) - - 7 (6) 2 (2) - -

Leucopenia (%) 9 (37.5) 10 (42) - - 33 (38) 15 (13) - -

Neutropenia (%) 4 (17) 10 (42) 3 (12.5) - 25 (21) 23 (19) 3 (2.5) -

Trhombocitopeny (%) 4 (17) 1 (4) - - 6 (5) 1 (1) - -


40

Limiting toxicity syndromes (LTS): overall and in young-elderly patients

Results Toxicity

Overall Young-elderly

No % No %

Patients 50 100 24 100

Limiting Toxicity Syndromes (LTS) 22 44 11 46

LTS single-site (LTS-ss) 10 20 2 8

LTS multiple-sites (LTS-ms) 12 24 9 37.5

Single DLT plus G2-3 10 20 7 29

Double DLTs 2 4 2 8

Abbreviation: DLT, dose-limiting toxicity; G, grade


41

Limiting Toxicity Syndromes (LTS)

Results Toxicity

Patients#

Age(years) DLT

Associated Toxicity

DLT G2-G3

1 51 Diarrhea G3 - -





6 70 Asthenia G3 - -

7 62 Hypertension G3

8 51 Hypertransaminasemy G3 - -

9 55 Thrombocytopeny G1 for >2 weeks - -

10 63 Neutropenia G3 - -

11 68 Diarrhea G3 - Vomiting G3

12 59 Diarrhea G3 - Vomiting G2 Neurotoxicity G2

13 67 Diarrhea G3 - Nausea G3Asthenia G2

14 57 Diarrhea G3 - Nausea G3

15 67 Diarrhea G3 - Vomiting G2

16 65 Diarrhea G3 Epistaxis G2

17 40 Diarrhea G3 - Nausea G2

18 66 Diarrhea G3 - Stomatitis/mucositis G2Asthenia G2

19 67 Stomatitis/mucositis G3 - Asthenia G2

20 66 Hypertransaminasemy G4 - Diarrhea G2Nausea G2Anemia G2

21 71 Diarrhea G3 Stomatitis/mucositis G3 Hypoalbuminemia G2

22 66 Stomatitis/mucositis G3 Erythema G3 -

Abbreviation: DLT, dose-limiting toxicity; G, grade.


42

5-Fluorouracil (5-FU), time flat infusion of 12h, Irinotecan (CPT-11) / Cetuximab (Cet), Oxaliplatin (l-OHP), as first line treatment of metastatic colorectal cancer:

fase II study.

Poker-C Schedule (FIr-C/FOx-C)

Patients and methods Poker Schedule (FIr-C/FOx-C)

Medical Oncology, S. Salvatore Hospital, University of L'Aquila, Preliminary unpublished data

43

Dose-intensity

Results Dose-intensity

All patients Young-elderly patients



Projected DImg/m2(or Kg)/w

Median(Range)

Received DI (%)

Median(Range)

Received DI (%)

5-FU 1800 1440(214.25-1800)

80 977.5(675-1280)

54

CPT-11 80 60(20-80)

75 48(40-56)

60

l-OXP 40 32(10-40)

80 21(10-32)

52.5

Cet 250 200(93-287.5)

80 171.25(112.5-230)

58

Abbreviation: DI, dose-intensity; 5-FU, 5-Fluorouracil; CPT-11, Irinotecan; l-OHP, Oxaliplatin; Cet, Cetuximab.


44

Limiting toxicity syndromes (LTS): overall and in young-elderly patients

Results Toxicity

Overall Young-elderly

No % No %

Patients 9 100 2 100

Limiting Toxicity Syndromes (LTS) 7 78 1 50

LTS single-site (LTS-ss) - - - -

LTS multiple-sites (LTS-ms) 7 78 1 50

Single DLT plus G2-3 4 44 - -

Double DLTs 3 33 1 50

Abbreviation: DLT, dose-limiting toxicity; G, grade


45

Limiting Toxicity Syndromes (LTS)

Results Toxicity

Patients#

Age(years) DLT

Associated ToxicityDLT G2-G3

1 54 Skin rash G3 Stomatitis/mucositis G3 Asthenia G2Diarrhea G2

2 60 Diarrhea G3 - Constipation G2Asthenia G2

Neurotoxicity G2Hypotension G2

Stomatitis/mucositis G23 51 Diarrhea G3 - Stomatitis/mucositis G2

Asthenia G2Neurotoxicity G2

Rhinitis G24 56 Diarrhea G3 - Nausea G2

Anorexia G2Hypertension G2

Fever without infection G2Skin rash G2

Stomatitis/mucositis G25 59 Diarrhea G3 Deep vein thrombosis Dry skin G2

Erythema G26 72 Myocardial infarcion - Diarrhea G2

Vomiting G27 58 Diarrhea G3 Asthenia G3 Anorexia G3

Hypercreatininemia G2Hyponatriemia G3

Hypoalbuminemia G2 Abbreviation: DLT, dose-limiting toxicity; G, grade.

46


Age

Comorbidities






47

Patients without risk of complications:

I step: initial dose loperamide 4 mg + 2 mg after each

episode of diarrhea (maximum daily dose 16 mg)

II step, in case of diarrhea unchanged after 12-24 hours:

Loperamide 2 mg after each episode of diarrhea +

fluoroquinolone

III step, in case of diarrhea unchanged after 12-24 hours:

Octreotide 0.6 mg sc continuos infusion for 24 hours +

rehidration iv.

Diarrhea: treatment

Rosenoff Sh et al, J Support Oncol 2006; 4:289-294Alimonti A et al, Cancer Treat Rev 2004; 30:555-562

Benson AB et al, J Clin Oncol 2004; 22:2918-2926Rubenstein EB et al, Cancer 2004; 100(10):2026-2046

Javle MM et al, Clin Cancer Res 2007; 13:965-971Porzio G et al, La terapia dei sintomi in oncologia, SCTF, Oncologia Medica L’Aquila

48

Patients at risk of complications (G3-4 diarrhea, or G1-2 diarrhea

associated with nausea/vomito ≥G2, fever, neutropenia,

dehydration, comorbidity, liver failure, chronic renal failure,

diabetes, heart disease):

IV hydration

Antibiotic (fluoroquinolone iv)

I step: Octreotide 0.6 mg sc continuos infusion for 24 hours

II step: Octreotide 0.9 mg sc continuos infusion for 24 hours

III step: add atropine 0.5 mg sc every 4/6 hours (not in patients

with heart diseases or glaucoma) or atropine 2 mg sc continuos

infusion for 24 hours.

Diarrhea: treatment

Stein A et al, Ther Adv Med Oncol 2010; 2(1):51-63Peeters M et al, Acta Gastroenterol Belg 2010; 73:25-36

Cherny NI, J Pain Symptom Manage 2008; 36:413-423Gilbson RJ et al, Supp Care Cancer 2006; 14:890-900

Porzio G et al, La terapia dei sintomi in oncologia, SCTF, Oncologia Medica L’Aquila

49

Patients receiving chemotherapy with previous G3-4

diarrhea or G2-4 diarrea with concomitant diseases (liver

failure, chronic renal failure, diabetes, heart disease)

I step: octreotide LAR

30 mg im 14 days before day1 of therapy

30 mg im day1 of therapy

30 mg im every 28 days

II step: octreotide LAR 40 mg im + celecoxib 400 mg x2.

Diarrhea: prevention

Rosenoff Sh et al, J Support Oncol 2006; 4:289-294Alimonti A et al, Cancer Treat Rev 2004; 30:555-562

Benson AB et al, J Clin Oncol 2004; 22:2918-2926Rubenstein EB et al, Cancer 2004; 100(10):2026-2046

Javle MM et al, Clin Cancer Res 2007; 13:965-971Porzio G et al, La terapia dei sintomi in oncologia, SCTF, Oncologia Medica L’Aquila

50

Parameters to guarantee proper balance between

treatment efficacy and safety

Age (young-elderly, old-elderly)

Comorbidity (CIRS)

Cumulative toxicity

Limiting toxicity syndromes (individual toxicity)

Received dose-intensity

Activity and efficacy

Conclusions

gemma bruera medical oncology dpt. biotechnological and applied clinical sciences university of...

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