Keywords:
Geriatric assessment - Lung neoplasms - Frail elderly.
Descritores:
Avaliação geriátrica - Neoplasias pulmonares - Idoso frágil.
INTRODUCTION
In the coming decades the elderly population will make up about 20% of the total population
and the percentage of patients over 75 and over 85 will increase disproportionately.
The importance of this demographic trend is magnified by the sharp increase in the
incidence of most cancers after age 60. Currently, approximately 50 percent of all
malignancies and 70 percent of cancer deaths occur in those ≥65 years of age and this
fraction tends to increase.[1]
[2]
[3]
Older adult (OA) patients require special attention to the risks of chemotherapy (treatment-related
toxicities and quality of life issues). Aging is associated with decreased organ functions,
muscle wasting, multiple comorbidities, polypharmacy with likelihood of harmful drug
interactions and risk of adherence to therapy.[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16] For critically ill patients with severe comorbid disease that results in an estimated
short life span (particularly one year or less) the risks of chemotherapy often outweigh
their benefits. Older patients, then, are at risk for decompensation due to exposure
to severe metabolic stresses such as chemotherapy and most of these patients should
receive supportive care rather than chemotherapy, with attention to symptom palliation.[17]
Thus, age and comorbidities may limit the ability of full cancer treatment for advanced
non-small cell lung cancer (NSCLC). The median age of newly diagnosed NSCLC patients
in developed countries is approximately 68 years and up to 40% are aged ≥70 years
at diagnosis.[18] In addition, patients with limited or low performance status (PS) [ECOG≥2 or Karnofsky
Performance Status (KPS) ≥70] comprise 30 to 40 percent of patients with advanced
NSCLC.[19] About one third of patients with metastatic disease and most patients who are in
the other stages of the disease are not able to undergo a potentially curative surgical
resection.[20]
The most current first-line palliative treatment options for these patients comprise
oral target therapy, immunotherapy and chemotherapy combinations, all with robust
survival benefits when compared to chemotherapy alone.[21]
[22]
[23]
[24]
[25]
[26]
[27] Target therapies, tyrosine kinase inhibitor (TKI) against EGFR, ALK, ROS1, and NTRK,
require specific molecular tests to detect the mutations and predict response to these
drugs.[21]
[22]
[23]
[24] The indication of isolated or combined checkpoint inhibitors also requires specific
tests to evaluate expression of PD-L1.[25]
[26] And, once target TKI mutations or high PD-L1 expression are excluded, combinations
of chemotherapy with immunotherapy have become the standard treatment.[27] However, these treatments require specific tests that are not accessible and, in
fact, new less toxic therapies are very restricted for the vast majority of patients
in emerging countries, imposing the use of traditional chemotherapies or first-generation
target therapies as the only treatment option despite all the recent advances in lung
cancer therapies.
Regarding chemotherapy treatment for lung cancer in older patients, some studies show
that appropriately selected patients and those with borderline performance status
(PS 2), chemotherapy can improve overall survival without adversely affecting quality
of life compared to the best supportive care for advanced NSCLC.[28]
[29]
[30] The American Society of Clinical Oncology Guideline for Geriatric Oncology and a
panel of European experts have not definitively resolved the issue of combination
versus mono chemotherapy for patients with advanced NSCLC who are older or have low
PS.[31]
[32]
The aim of this study was to evaluate the clinical data and outcomes of an elderly
population with lung adenocarcinoma undergoing palliative treatment with chemotherapy
or first-generation target therapy after comprehensive geriatric assessment (GA) to
attempt to determine detectable prognostic factors in a scenario of scarce resources,
as is the case of most oncology services in emerging countries, which do not always
have access to molecular testing, lastgeneration TKI and/or immunotherapy.
METHODS
A retrospective analysis was performed by collecting clinical data from the electronic
medical records of patients with stage IIIB and IV lung adenocarcinoma aged 70 years
or older diagnosed and treated with chemotherapy or first- generation TKI in 1st or 2nd line between January 2007 to December 2015 in the AC Camargo Cancer Center undergoing
GA. The definition of GA for the study was evaluation of functional capacity, comorbidities,
polypharmacy, and nutritional status. As a basis for analysis, an evaluation table
was used containing epidemiological data (age, gender, ethnicity, and care network),
specific pathological data (staging, whether initial or relapsing, and number of metastasis
sites), known predictive and prognostic data (hemoglobin, ECOG, and presence of driver
mutation), comorbidities (smoking, cardiovascular disease, diabetes mellitus, chronic
kidney disease, neurological diseases, respiratory disease, smoking, incontinence
and fall, polypharmacy (≥ 5 medications), Charlson score index, and Katz and Lawton
functional assessments and nutritional status), cancer treatment (chemotherapies or
TKI used in 1st and 2nd palliative lines, response rates, and toxicities), and progression or death. Data
were tabulated and statistically analyzed to describe the population with frequencies,
means and medians. Overall survival (OS) was calculated according to the Kaplan-Meier
method, and we performed univariate and multivariate analysis using the Cox method
to describe potential prognostic factors for OS, with forced entry of functional capacity.
RESULTS
Between the periods from January 2007 to December 2015 in AC Camargo Cancer Center,
54 patients aged ≥70 years with pulmonary adenocarcinoma who underwent GA were treated
palliatively. Demographical data are presented in [Table 1].
Table 1
Demographic and clinical features of the study population
|
Age (interval)
|
median: 76 (71-88)
|
Nutritional status Eutrophic At risk / malnourished
|
17 (31.5%) 37 (68.5%)
|
|
Sex Male Female
|
27 (50%) 27 (50%)
|
Charlson comorbidity index ≥ 10 > 10
|
median: 10 36 (67%) 18 (33%)
|
|
ECOG 0-1 ≥ 2
|
42 (78%) 12 (22%)
|
Number of comorbidities ≥ 2 > 2
|
median: 2 33 (61%) 21 (39%)
|
|
Polypharmacy No Yes
|
28 (52%) 26 (48%)
|
Liver metastasis No Yes
|
49 (90.7%) 5 (9.3%)
|
|
Katz A Non-A
|
41 (76%) 13 (24%)
|
Number of metastatic sites < 2 ≥ 2
|
median: 1 28 (52%) 26 (48%)
|
|
Lawton 27 < 27
|
27 (50%) 27 (50%)
|
Treatment type Chemotherapy Target therapy
|
43 (79.6%) 11 (20.4%)
|
ECOG - Eastern Cooperative Oncology Group.
The median age was 76 years, ranging from 71 to 88 years. The distribution by gender
was equal. Regarding performance status, 22% had ECOG≥2 and all were functionally
classified according to activities of daily living (ADL) with 76% of patients classified
as Katz A and 50% as Lawton <27. In the assessment of nutritional status, 68.5% were
at risk of malnutrition or malnourishment (weight loss >5% during prior 6 months or
>2% for patients with low BMI or sarcopenia). The average age-adjusted Charlson comorbidity
index was 10, with 33% of the population studied above this average; 61% had at least
2 comorbidities and 48% had polypharmacy (≥5 drugs). Regarding cancer disease, 26
patients had at least 2 metastatic sites. The central nervous system (CNS) was affected
in 7.5% of cases and the liver in 9.3%. At treatment evaluation, 79.6% of patients
underwent chemotherapy and the others received TKI. After a 29-month follow-up, the
mean OS was 17.1 months (13.5-27.8 months). In the univariate analysis ([Table 2]), we observed significantly lower survival results for patients with ECOG≥2 (Hazard
Ratio [HR]=5.9; p<0.001), number of metastatic sites ≥2 (HR=2.0; p=0.04) and presence of liver metastasis (HR=12.6; p<0.001). In multivariate analysis ([Table 2]), male, ECOG≥2, more than 2 metastatic sites and the presence of liver metastases
were associated with higher risk of death. We did not observe any difference between
patients classified according to worse functional capacity (Katz non-A) in univariate
or multivariate analysis (HR=1,6; p=0,18 and HR=0,64; p=0,25, respectively).
Table 2
Prognostic factors for overall survival
|
Univariate
|
analysis
|
|
|
Multivariate
|
analysis
|
|
Variable Sex
|
HR
|
95% CI
|
P value
|
HR
|
95% CI
|
P value
|
|
Male
|
1.7
|
0.86-3.5
|
0.11
|
4.14
|
1.5-11.8
|
0.94
|
|
Female ECOG
|
1
|
-
|
|
1
|
-
|
|
|
0-1
|
1
|
-
|
|
1
|
-
|
|
|
≥ 2 Nutritional status
|
5.9
|
2.6-13.0
|
<0.001
|
10.6
|
1.9-59.5
|
0.18
|
|
Eutrophic
|
1
|
-
|
|
1
|
-
|
|
|
At risk / malnourished Katz
|
2.1
|
0.9-4.4
|
0.047
|
1
|
0.4-2.7
|
0.33
|
|
A
|
1
|
-
|
|
1
|
-
|
|
|
Non-A Liver metastasis
|
1.6
|
0.77-3.6
|
0.18
|
0.64
|
0.1-2.9
|
0.25
|
|
No
|
1
|
-
|
|
1
|
-
|
|
|
Yes Number of metastatic sites
|
12.6
|
3.6-48.8
|
<0.001
|
6.03
|
0.97-37.2
|
0.4
|
|
Number of metastatic sites
|
|
< 2
|
1
|
-
|
|
1
|
-
|
|
|
≥
|
2
|
2
|
1.01-3.9
|
0.04
|
2.2
|
0.9-5.4 0.59
|
CI - Confidence interval
DISCUSSION
Concerned about optimized NSCLC care in OA who does not have access to new diagnostic
tests involving PD-L1 expression, target mutations for TKI and new less toxic treatments,
such as immunotherapy and last-generation TKI, we made an assessment of survival outcomes,
to correlate them with prognostic factors to define how to continue cancer treatment
while offering the only accessible therapy, although outdated, respecting physiological
and morbid limitations of this more frail population, seeking to improve the general
situation with interventions and minimize toxicities and inadequacies of treatment
according to GA.
We note that most patients are at risk of malnutrition or are malnourished and half
of them have polypharmacy and do not have maximum independence for instrumental activities
of daily living (Lawton <27). In spite of that, comorbidities are not very prevalent
(only 40% had at least 2 comorbidities) and only a third of our patients received
a Charlson score above 10. The end result is that almost 80% of our population has
an ECOG 0 or 1. Even though this is not such a frail population, they was at a time
immediately preceding access to immunotherapy and the most modern tyrosine kinase
inhibitors. Unfortunately, this is still the very reality in most cancer treatment
sites in emerging countries. As a result, about 80% of these patients underwent palliative
treatment with single-drug or combination chemotherapy. Unlucky, we were unable to
obtain quality data regarding the toxicity of treatments that would allow better correlation
with survival outcomes.
In our study, we found that the main prognostic factors that negatively impacted the
OS on univariate analysis were ECOG≥2, more than 2 sites of metastasis and presence
of liver metastasis, which was present in a minority of the patients. This could explain
the beyond expected median survival of 17.1 months after a median follow-up of 29
months. In multivariate analysis, these factors plus male gender were associated with
higher risk of death. Malnutrition, although very prevalent in our sample, did not
impact survival. After all, the tumor biology and the effectiveness of chemotherapy
may have a higher prognostic impact when compared to clinical features that compose
GA.
We understand the limitations of this work such as the lack of formalization in the
quality of life assessment, the use of the less broad concept of GA, which could also
include psychological evaluation, geriatric, neuro-cognitive and socio-financial syndromes,
so called comprehensive geriatric assessment (CGA). Still, we found no prognostic
impact of functional capacity and this is in agreement with a multicenter, open-label,
phase III ESOGIA study that evaluated over four hundred patients ≥70 years with a
PS of 0 to 2 and stage IV NSCLC and randomly assigned them between chemotherapy allocation
based on performance status (standard arm) and age or CGA (carboplatin-based double
for fit patients, docetaxel for vulnerable patients, and best supportive care for
frail patients). This trial failed to show differences in treatment failure-free survival
(primary endpoint) and OS, but patients experienced significantly less toxicity across
all grades (85.6% vs. 93.4%; p=0.015) and fewer failures in treatment as a result of toxicity (4.8% vs. 11.8%; p=0.007) compared with patients in the standard arm.[33]
This results do not minimize the importance of GA and ideal patient care demand participation
of a multidisciplinary team attentive to the care of older cancer patients carrying
out a broader geriatric assessment, evaluating and taking care of patients' comorbidities
and nutrition, always taking into account the risks of polypharmacy, with dynamically
personalizing and individualizing treatment that can provide a better quality of life.[34]
Finally, since GA and CGA proved to be an insufficient tool for selecting systemic
treatment with more obsolete therapies against NSCLC, promoting broad access to new
prognostic and predictive tests and modern therapies could allow not only less toxicity
to this fragile population, but mainly gains in overall survival and quality of life.
Thus, we should observe a greater governmental effort in favor of this cause, with
investments in medical science, reducing the costs of new drugs, promoting greater
access to new diagnostic tests and investing in infrastructure of oncology centers
and in the training of its specialists. These measures would certainly advance the
care of older patients with metastatic lung cancer in emerging countries.
Bibliographical Record
Mauro Daniel Spina Donadio, Audrey Cabral F Oliveira, Luciana Leite Moura, Victor
Hugo Fonseca de Jesus, Tiago Cordeiro Felisimino, Aldo Lourenço Abbade Dettino. Real-world
data suggest that geriatric assessment fails to stratify risk in treating older adults
with lung cancer. Brazilian Journal of Oncology 2021; 17: e-20210030.
DOI: 10.5935/2526-8732.20210030
