Gestione

del paziente unfit/frail

Dal punto di vista dell’oncologo

Cristina MasiniS.C. Oncologia

IRCCS, Arcispedale Santa Maria Nuova di Reggio Emilia

Frailty is an irreversible condition that induces susceptibility

to acute illnesses, disability, dependence,

institutionalization and death

Frailty based on

-weakness

-low grip strength

-low energy

-slow gait speed

-low activity levels

Frailty is diagnosed if 3 or more criteria are present, whereas pre-

frailty or vulnerability is diagnosed if 1 or 2 criteria are present

The American Journal of the Medical Sciences , July 2013

There are no specific guidelines for frail

patients and particulary…

no reliable predictors of fragility have

been identified so far

Outcomes of patients with mRCC that don’t meet

elegibility criteria for clinical trials

The number of patients that are

ineligible for clinical trials is

substantial and their outcomes

are inferior

Outline

1) kidney cancer in the elderly

2) Targeted therapies in mRCC elderly

3) Targeted therapies and renal impairment

4) Targeted Therapies in mRCC pts undergoingdialysis

5) Active surveillance in unfit/vulnerablepatients

Assessment and treatment of elderly patients with cancer

ENDPOINTS

The most serious threat � loss of indipendence

one of the main purposes of the treatment of the elderly in oncology is the

extension of the "Active life expectancy"

.

Adapted from Balducci L, et al. Surg Oncol. 2010

Increase PFS and OS

Palliation of symptoms

Kidney cancer in the elderly

• >60% of cases occur in patients older than 60 years and

> 20% in those 75 years and older

• Up to 30% of patients are metastatic at the time of

diagnosis

• Elderly patients were often excluded from clinical trials

because they exhibit comorbities coupled with poorer PS

and less tolerance from treatment

• These patients frequently have comorbidities requiring

other medical agents, with an increased risk of drug

interaction

Zustovich F. et al. Expert Rev. Anticancer Ther. 2013

Amandine Quivy et al. Clinical Interventions in Aging, 2013

Comprehensive geriatric assessment (CGA) � CGA is a multidimensional, interdisciplinary diagnostic process to

determine the medical, psychological, and functional capabilities of a

frail elderly person in order to develop a coordinated and integrated plan

for treatment and long-term follow-up

� This evaluation includes :

- comorbid conditions and disease severity

- medication review

- nutritional status

- basic activities of daily living

- instrumental activities of daily living (IADL)

- psychological assessment with mental status testing (Mini-Mental

Status)

- mood testing using the geriatric depression scale, social assessment,

and environmental assessment

Amandine Quivy et al. Clinical Interventions in Aging, 2013

Specific considerations

for the elderly patients with mRCC

Amandine Quivy et al. Clinical Interventions in Aging, 2013

Outline

1) kidney cancer in the elderly

2) Targeted therapies in mRCC elderly

3) Targeted therapies and renal impairment

4) Targeted Therapies in mRCC pts undergoing dialysis

5) Active surveillance in unfit/vulnerable patients

Comparison between % of incidence of RCC

in elderly in real world and % of elderly enrolled

in clinical trials

Zustovich F. et al. Expert Rev. Anticancer Ther. 2013

PFS benefit of target therapies in elderly and

younger patients enrolled in phase III clinical trials

Favours targeted therapy Favours alternative therapy

< 65 years Sorafenib

0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6

Hazard ratio (PFS)

>= 65years Sorafenib

< 65 years Temsirolimus

>= 65 years Temsirolimus

>= 65 years Sunitinib

< 65 years Bevacizumab plus IFN

>= 65 years Bevacizumab plus IFN

< 65 years Everolimus

>= 65 years Everolimus

< 65 years Axitinib

>= 65 years Axitinib

< 65 years Sunitinib

< 65 years Pazopanib

>= 65 years Pazopanib

Adapted from Porta C. et al. Cancer Treatment Reviews 2010

Final results of the European Advanced RCC

Sorafenib (EU-ARCCS) EAP

Baseline patient characteristics Drug-related adverse events by age

Beck J, Ann Oncol 2011

Sorafenib tolerability in elderly patients with

advanced RCC: results from a large pooled analysis

� Database: 6 clinical trials and 2 expanded-access studies

� Sorafenib treatment duration was 30% shorter in the ≥75-

years subgroup

� There were no substantial differences in any-grade DRAEs

with sorafenib between subgroups

� Drug-related adverse events and dose modifications due to

DRAEs tended to occur in months 0–3 and declined

thereafter

Procopio G et al, BJC 2013

Safety and efficacy of sunitinib for mRCC elderly pts:

an expanded-access trial

Gore ME, Lancet Oncol 2009

AE significantly less common in younger vs older patients,:

� fatigue (60% vs 69%)

� cough (20% vs 29%)

� peripheral edema (17% vs 27%)

� anemia (18% vs 25%)

� decreased appetite (13% vs 29%)

� thrombocytopenia (16% vs 25%)

Hand–foot syndrome was more common in younger patients (32% vs 24%)

Efficacy and safety of sunitinib in elderly patients

with mRCC: 1059 patients in 6 trials

Hutson TE, et al. BJC 2014

Comparison of activity data of Sunitinib from

different studies: randomized trial, EAP, a phase

II trial, retrospective cohorts

Adapted from Brunello et al. Ann of Oncology 2013

Motzer

et al.

EAP Tomita

et al.

Choueri

et al.

Ansari

et al.

Hutson et

al.

Brunello et

al.

De Giorgi et

al.

N 375 4564 51 57 56 202 68 185

Median age

(years)

62 59 56.6 58 61 73 74 74

N elderly (%) 275

(36.7%)

> 65 years

1418

(32%)

> 65 years

NR 7 (35%)

> 60 years

NR 202 (100%)

> 70 years

68 (100%)

> 70 years

185 (100%)

> 70 years

Clinical

benefit

(CR+PR+SD)

77% 77% 52.9% 82% 78%

(PR+SD)

NR 83.3% 68%

PFS (months) 11 11.3 12.2 15.3 12.2 10.9 13.6 11

OS (months) 26.4 18.2 33.1 35.8 18.2 23.7 18.3 25.5

Standard vs Adapted Sunitinib Regimen in Elderly pts

With mRCC: Results From a Large Retrospective Analysis

� 123 pts (66.5%) received a standard 50 mg/d for a 4 weeks on/2 weeks off regimen

(SR), and 62 pts (33.5%) received an AR (37.5 mg/d 4 weeks on/2 weeks off or 25

mg/d)

� Grade 3-4 toxicities occurred in 87 of 123 SR (70.7%) and 32 of 62 AR (51.6%),

respectively; dose reductions were required in 82 SR (66.7%) and 26 AR (41.9%)

� Discontinuations because of therapy-related adverse events occurred in 25 SR (20.3%)

and 15 AR (24.2 %)

The optimal treatment of frail patients with mRCC remains to be established

PFS 11 months OS 25.5 monthsDe Giorgi U. et al. Clin Gen Cancer 2013

Lymphopenia and clinical outcome of elderly patients

treated with sunitinib for metastatic renal cell cancer

� 181 patients with mRCC aged ≥70 years treated with first-line sunitinib

� Twenty-nine (16%) patients had a baseline lymphocyte count <1000/μL (group

A) and 152 (84%) patients had a lymphocyte count ≥1000/μL (group B)

� No differences between the two groups were reported in terms of overall

response rate (P = 0.207), dose reductions (P = 0.740), discontinuation due to

adverse events (P = 0.175) or overall incidence of grade 3–4 toxicities (P = 0.112)

De Giorgi U. et al. Journal of Geriatric Oncology 2014

Lymphocyte count is an independent prognostic

factor for overall survival

in elderly patients with mRCC treated

with first-line sunitinib

Use of Pazopanib in Elderly Patients

A phase III, placebo-controlled trial evaluated pazopanib in

patients with locally advanced and/or metastatic RCC

Adverse events (AEs) were not analyzed by subgroup populations

Sternberg CN, et al. J Clin Oncol 2010

A phase III, noninferiority trial evaluated the use of

pazopanib vs sunitinib as first-line therapy in patients

with mRCC of clear cell histology (COMPARZ)

�In pts ≥65 years of age, the most commonly reported AEs were fatigue (63%), diarrhea

(60%), nausea (46%), decreased appetite (43%), hypertension (41%), and increased ALT

(31%)

�There was a higher incidence of serious AEs in pts ≥65 years of age in both treatment

arms compared to pts <65 years

In the pazopanib arm���� 50% and 36% in pts ≥65 years of age and <65 years of

age, respectively

In the sunitinib arm ���� 51% and 34% in pts ≥65 years of age and <65 years of

age, respectively

Data on File. Study VEG105192. 2008. Available at: http://www.gsk-clinicalstudyregister.com/

patients ≥65 yr

patients ≥70 yr

� Everolimus was generally well

tolerated in elderly patients, and most

adverse events were grade 1 or 2 in

severity

� The toxicity profile of everolimus was

generally similar in older patients and

the overall population

� Peripheral edema, cough, rash, and

diarrhea were reported more

frequently in the elderly regardless of

treatment

Porta C, et al. 2012

Outline

1) kidney cancer in the elderly

2) Targeted therapies in mRCC elderly

3) Targeted therapies and renal impairment

4) Targeted Therapies in mRCC pts undergoing dialysis

5) Active surveillance in unfit/vulnerable patients

• Up to 15% of patients with renal cell

carcinoma (RCC) present

moderate/severe impaired renal

function

• 10% required dialysis at some time

during symptom progression

Renal Cell Carcinoma and

Renal Impairment

Retrospective analysis on 529 pts with mRCC who received sunitinib (323 pts),

sorafenib (165 pts), or bevacizumab (41 pts) was performed.

Patient characteristics included: 74% male, median age 61 years, and median GFR 60.1

mL/min/1.73 m2 (range, 6.5-174.2)

Decreased GFR was not associated with inability

to receive VEGF-targeted therapy and did not have

an impact on ORR or OS

Macfarlane R, Cancer 2011

Safety and efficacy of molecularly targeted agents

in pts with mRCC with renal dysfunction

Gupta A, AntiCancer Drugs 2011

………….…….......….efficacy seems to be maintained in patient s with RI

Safety and efficacy of molecularly targeted agents

in pts with mRCC with renal dysfunction

In this retrospective study patients receiving any of the targeted agents seem to have

comparable response rates, but favorable TTP and OS, than patients with normal renal

function

It is unclear if this difference is related to longer plasma exposure of the drugs or its

metabolites in renal impairment patients

Gupta A, AntiCancer Drugs 2011

Outline

1) kidney cancer in the elderly

2) Targeted therapies in mRCC elderly

3) Targeted therapies and renal impairment

4) Targeted Therapies in mRCC pts undergoing dialysis

5) Active surveillance in unfit/vulnerable patients

Authors

n.

patient TKi

Dose reduction Response

(after 3 mos) Toxicity (G3-4)

Rey PM, 2008 1

1

Sunitinib

Sorafenib

No

yes

SD

SD

0

0

Ruppin S, 2008 1 Sorafenib no PR 0

Zastrow S, 2009 1

1

Sunitinib

“

yes

no

CR

SD

Amylase/lipase;

0

Ferraris E, 2009 1

1

Sorafenib

“

No

yes

PR

SD

No

Fatigue, dyspnea

Hilger RA, 2009 2 Sorafenib Yes NR NR

Vickers MM, 2009 1

1

Sunitinib

“

yes

no

PR

SD

Hypothyroidism, fatigue

Park CY, 2009 1 Sunitinib No CR 0

Reckova M, 2009 1 Sunitinib yes PR Thrombocytopenia, HTN, EF

Izzedine H, 2009 1

1

Sunitinib no

no

SD

NR

0

0

Castagneto B, 2010 1 Sorafenib Yes PR 0

Shinsako K, 2010 1 Sorafenib No SD 0

Sang Hyun Yoo, 2010 2 Sunitinib Yes PR 0

Park, 2010 6 Sunitinib Yes SD Mucositis, anorexia, fatigue

Josephs D, 2011 10 Sunitinib Yes PR Fatigue, stomatitis, HFS, diarrhea

Kennoki T, 2011 10 Sorafenib Yes CR, PR, SD subarachnoid hemorrhag, cerebellar

hemorrhage

Casper, 2011 21 Sunitinib Yes CR, PR, SD Asthenia, nausea, vomiting, diarrhoea,

thrombocytopenia, hypertension,

hypotension, left systolic ventricular

dysfunction

Masini C, 2012 24 Sunitinib

Sorafenib

no PR, SD Nasuea, diarrohea, fatigue,

thrombocytopenia, left systolic ventricular

dysfunction

Ibrahim Y, 2014 2 Sunitinib No PD Acute pulmonary edema, caused by

uncontrolled hypertension

TKi in mRCC patients on dialysis

PFS 10.3 mesi

11 mesi

5.5 mesi

Motzer RJ, et al N. England.J.Med. 2007

Escudier B, et al. N Engl J Med. 2007

Masini C, et a. BJUI 2012

Motzer RJ, et al N. England.J.Med. 2007

Escudier B, et al. N Engl J Med. 2007

Masini C, et a. BJUI 2012

OS 22.6 mesi

26.4 mesi

17.8 mesi

Temsirolimus in mRCC patients

on dialysis

Lunardi G., Clin Ther. 2009

After single-dose

administration

of temsirolimus 25 mg as

a 30-minute intravenous

infusion, neither

temsirolimus nor

sirolimus concentrations

were significantly

affected by hemodialysis

in these patients with

RCC compared with

those not receiving

dialysis

Everolimus in mRCC patients on dialysis

Authors Number

of pts

Primary

tumor

Dose

reduction

Toxicity G3/4

Thiery-Vuillemin et al,

Ann of Oncology 20122 kidney Yes Asthenia,

hyperglycemia,

Mucitis

J Syrios et al., BMC

Nephrology 20132 kidney No none

Hemodialysis does not affect everolimus

pharmacokinetics: two cases of patients with

metastatic renal cell cancer

� HD did not modify the blood

everolimus concentrations as

they were close to the

predialysis level

� No everolimus was detected

in the dialysate, confirming

its lack of adhesion to the

dialysis membrane

The toxic effects observed (Asthenia G2-3, diarrhea G2, hyperglycemia

G3, mucitis G2-3, pneumonitis G2) do not seem to be linked to an

overdose of everolimus

A. Thiery-Vuillemin et al, Ann of Oncology 2012

Safety and activity of Everolimus Treatment of Metastatic

Kidney Cancer patients on dialytic replacement therapy:

an Italian retrospective survey

0.00

0.25

0.50

0.75

1.00

0 5 10 15 20analysis time

Kaplan-Meier survival estimate

9.01 months (range 2.72 to 16.49

months)

0.0

00.

250.

500

.75

1.0

0

0 5 10 15 20 25analysis time

Kaplan-Meier survival estimate

14.36 months(range of 2.29 to

24.03)

Masini C, et al. submitted

PFS

OS

Outline

1) kidney cancer in the elderly

2) Targeted therapies in mRCC elderly

3) Targeted therapies and renal impairment

4) Targeted Therapies in mRCC pts undergoing dialysis

5) Active surveillance in unfit/vulnerable patients

Conclusions

� mRCC elderly patients do not experience more frequent or severe toxicity

� The efficacy of targeted agents seems to be the same in the

elderly patients as in younger patients

� Toxicity in the elderly even mild to moderate (grade 1 and 2) may induce

dose reductions or early interruptions of treatment

� The use of targetes therapies seem not contraindicated in patients with

mRCC and severe renal impairment or on dialysis

� The need to reduced dose of TKIs or mTORi was dictated by the little

experience of the clinician to avoid severe toxicity

� Caregiver is an important point for the outcome of treatment