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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