Keywords
Chemotherapy - elderly - hematologic - nonhematologic - toxicity
Introduction
Aging has been defined as a loss of “entropy and fractality.”[1] Aging is not homogeneous across the elderly population and ranges from high-functioning
fit adults to the elderly being bedridden. Cancer is a disease of aging, with the
majority falling in the age group of above 65 years.[2]
[3]
Indian perspective
Between 2010 and 2050, the share of 65 years and older is expected to increase from
5% to 14%, while the share in the oldest age group (80 and older) will triple from
1% to 3% (UN 2011).[4] The nexus of cancer and aging presents some unique issues for older cancer patients
and their caregivers (familial and professional).[5] Age-related physiological changes due to both genetic (e.g., organ and systems functional
reserve) and environmental influences (e.g., disease, physical and emotional stresses,
lifestyle, and carcinogenic exposures) involve a progressive loss of the body’s ability
to cope with stress. This may affect the growth rate of the tumor, the pharmacokinetics
of drugs, and the risk of drug-related toxicity.[6]
Chemotherapy
Trials in the elderly have established that older individuals may benefit from chemotherapy
to the same extent as younger individuals (as long as the chemotherapy is administered
in an adequate dose intensity) but also that older individuals were more vulnerable
to the complications of cytotoxic chemotherapy, especially myelotoxicity, mucositis,
and cardiotoxicity.[7]
[8]
[9] Appropriate supportive care to manage the toxicity of chemotherapy, such as the
use of growth factors, is particularly important in older patients, who are at greater
risk for the toxicity associated with chemotherapy.[10]
Although the elderly patient is prototype for cancer, very few clinical trials focus
on the therapeutic decisions most directly facing older adults. Historically, older
adults have been underrepresented in cancer clinical trials.[11] Moreover, data are limited on the occurrence and outcomes of chemotherapy toxicity
in elderly. It was with this aim of analyzing chemotherapy toxicity in the elderly
cancer patients that this study was taken up.
Subjects and Methods
This study was conducted at a tertiary care hospital, Department of Medical Oncology.
This study was a prospective, observational cohort study. The study commenced in October
2014 after obtaining the clearance from the hospital ethics and protocol committee.
Patients were enrolled with effect from October 2014 as per Type 1 progressive censoring
scheme. Enrollment was completed in May 2016. The cutoff date for the last follow-up
was September 30, 2016.
A total of 100 patients were included in the study. All patients were of age ≥65 years,
had malignancy, and were planned to be started with chemotherapy only. Informed consent
was obtained from all patients as per the Institute Ethics Committee. A patient information
sheet was provided to all patients. All patients were subjected to a thorough history
taking and physical examination, a systematic review of records, treatment received,
and other clinical information.
Toxicity of the chemotherapy regimen was graded as per Common Terminology Criteria
for Adverse Events (CTCAE) adverse events criteria Version 4.0 Published: May 28,
2009. Development of Grade 3/4/5 nonhematologic (NH) or Grade 4/5 hematologic (H)
toxicities was taken as the development of severe toxicity. Patients recruited for
the study had solid-organ malignancy of various primary sites.
More than 20 types of chemotherapy regimens differing in dose and schedule were administered.
The details of the toxicity were collected and recorded. The reason for discontinuation
of chemotherapy was toxicity, disease progression, or completion of planned treatment.
Patients were followed throughout chemotherapy until a minimum of 1 month after the
last cycle. The observations were recorded in a standard pro forma for detailed analysis
and data were analyzed.
The quantitative variables were expressed as a mean ± standard deviation and compared
using unpaired t-test. Further, they were grouped and expressed in terms of contingency
tables wherein Chi-square test was used to assess the associations. P < 0.05 was considered
statistically significant. SPSS Version 16.0 (IBM) software was used for statistical
analysis. Descriptive statistics for continuous variables and frequency distribution
with their percentages were calculated wherever required.
Results
The study design included 100 elderly patients (44 females and 56 males) who satisfied
the designated inclusion criteria. The mean age of the population was 68.46 ± 4.3
years. Twenty-four out of these 56 male patients experienced chemotherapy toxicity
(39.2%). Among females, 22 out of 44 enrolled experienced toxicity (50%) P = 0.28.
Tumor characteristics
We enrolled oncology patients with varied primary diagnosis into our study [Table 1]. Among females, the majority of patients were those of carcinoma ovary – including
primary peritoneal carcinomatosis (21 out of 44) followed by carcinoma breast (14
out of 44). Among males, the most common cancer was carcinoma lung (13 patients).
Most of the patients fell in Stage 4 groups (69 out of 100).
Table 1
Various tumor types enrolled in the study
|
Diagnosis
|
n
|
|
PPC – Primary peritoneal carcinoma; NHL – Non-Hodgkin lymphoma; DLBCL – Diffuse large
B cell lymphoma
|
|
Gastrointestinal
|
27
|
|
Carcinoma ovary (including PPC)
|
21
|
|
Breast carcinoma
|
14
|
|
Carcinoma lung
|
13
|
|
NHL (DLBCL)
|
8
|
|
Genitourinary cancer
|
8
|
|
Head-and-neck cancer
|
7
|
|
Synovial sarcoma
|
2
|
|
Total
|
100
|
Adjuvant chemotherapy was planned in 22 patients and neoadjuvant chemotherapy in five
patients. Immunochemotherapy for diffuse large B-cell lymphoma was given in eight
patients. Sixty-five of them received palliative chemotherapy. Twenty-nine different
chemotherapy regimens and schedule were used. Weekly paclitaxel and carboplatin was
the most favored regime (26 out of 100 patients). The incidence of chemotherapy toxicity
was maximum (75%) among the subset who had chemotherapy twice before. This group was
small, consisting of only eight patients, but still it points toward the cumulative
chemotherapy toxicity and vulnerability of this population toward adverse effects
(P = 0.234).
More than three-fourth (77%) of the patients received prophylactic granulocyte colony
stimulating factor (GCSF) support, and among them, 16.8% patients developed H toxicity.
On the other side, none of the patients suffered from H toxicity with no GCSF support.
It can be inferred that patients planned for more toxic chemotherapy are more likely
to receive growth factor support and thus are also at more risk for H toxicity (P = 0.035). Three-fourth of the patients had ECOG PS ≤2 (76 out of 100). Twenty-four
percent of patients had PS of 3. Furthermore, as anticipated, 91% of patients with
PS 3 developed toxicity in comparison to 23.3% in patients with PS 1. The correlation
between performance status and development of toxicity was found to be statistically
significant (P < 0.05).
Two-third of the patient’s cohort had one or more comorbidity. Chemotherapy-related
toxicity was 51.2%, 27.5%, and 50% in patients with none, one, or more than one comorbidity.
There was no association between the presence of comorbidity and occurrence of toxicity
in the study population (P = 0.107).
Chemotherapy toxicity
Chemotherapy toxicity was graded as per CTCAE version 4.0.
Overall, 64 (64%) patients were able to complete their prescribed treatment. Twelve
patients stopped or changed to another chemotherapy regimen due to disease progression
and 24 patients stopped the treatment due to toxicity. Two patients were lost to follow-up,
and their data were censored. The overall survival was calculated as per the response
of the patient as on September 30, 2016. The mean number of days of follow-up was
266.04 ± 142.38. Patients who developed chemotherapy toxicity received less chemotherapy
cycles (median number of cycles 4.5) compared to patients who never had any severe
chemotherapy-related toxicity (median number of cycles 6).
Totally 3 patients (3%) died within 1 month of starting treatment. Forty-four patients
(44%) of our study cohort experienced Grade 4 H or Grade 3 or 4 NH toxicity, 13 patients
(13%) had Grade 4 “H” toxicity, and 42% (42 patients) had Grade 3 or 4 “NH.” [Figure 1] shows the incidence of chemotherapy toxicity.
Figure 1: Chemotherapy toxicity in the study cohort
The most common H Grade 4 toxicities were neutropenia (6%) followed by thrombocytopenia
(5%). The most common NH toxicity were fatigue (18%) followed by infection (10%) and
cardiac abnormalities (4%) which included coronary artery disease and left ventricular
dysfunction. This has been shown in [Table 2].
Table 2
Occurrence of chemotherapy-related toxicity
|
Toxicity type (n=100)
|
n (%)
|
|
*The symptoms are not due to disease progression but chemotherapy toxicity. ANC –
Absolute neutrophil count; SAIO – Sub acute intestinal obstruction; GTCS – Generalized
tonic clonic seizures
|
|
Any (hematologic or nonhematologic)
|
44 (44)
|
|
Hematologic (13)
|
Grade 4/5 (13)
|
|
Neutropenia
|
6 (6)
|
|
Thrombocytopenia
|
5 (5)
|
|
Sepsis with neutropenia
|
3 (3)
|
|
Nonhematologic (42)
|
Grade 3/4/5 (42)
|
|
Fatigue
|
18(18)
|
|
Sepsis with normal ANC
|
10 (10)
|
|
Cardiac
|
4 (4)
|
|
GTCS*
|
1 (1.0)
|
|
Dyspnea
|
2 (2.0)
|
|
Mucositis
|
2 (2.0)
|
|
SAIO*
|
3 (3.)
|
|
Anorexia*
|
3 (3)
|
|
Ascites*
|
2 (2)
|
|
Hyponatremia
|
1 (1.0)
|
|
Psychosis
|
1 (1.0)
|
|
Diarrhea
|
1 (1.0)
|
|
Vomiting
|
1 (1.0)
|
|
Neuropathy
|
1 (1.0)
|
|
Hematologic and nonhematologic (both)
|
11 (11)
|
Among 44 patients who developed chemotherapy toxicity, the time range to suffer adverse
effects of chemotherapy was 6–216 days. The median time taken to develop toxicity
was 39.5 days. Therefore, one needs to be very careful during the early course of
chemotherapy.
Discussion
The life expectancy in our country has doubled since independence.[12] The elderly constitutes (>65 years) 5.5%–7% of the total population of India. Eight
to ten lakhs cancer patients are being diagnosed every year in India.[13] Cancer in the elderly is usually undertreated in our country due to various barriers
such as financial, social, emotional, educational, and physical. It is a general assumption
that the incidence and severity of side effects are greater in the elderly population.
It has been proved beyond doubt that elderly also obtain benefits similar to younger
patients with administration of chemotherapy.[14] This study was a prospective, observational hospital-based study in the department
of medical oncology at a tertiary cancer care center which is catering to a large
number of cancer patients from across the Delhi/NCR and adjoining states. This study
evaluated the profile of chemotherapy toxicity in the elderly population (>65 years).
The study profile included the demographic, biochemical, and clinical profile of the
patients in the study.
The data for treatment in elderly are sparse due to limited representation in clinical
trials.[11] Few studies have been conducted in elderly cancer population in our country. Head-and-neck
cancer is the most common type of cancer in males in India (GLOBOCAN India, 2012[15]) The same is shown by Patil et al.[16] in their study from rural districts of Kerala. In our study, there were few head-and-neck
cancer patients as our study was concentrating on chemotherapy only and excluded patients
receiving radiation or concurrent chemoradiation. Hence, this may explain the discrepancy
between our study and other similar studies. Carcinoma lung is the second most common
site of cancer in India. It was also found to be the most common in the study by Goyal
et al.[17] In our study also, lung cancer was the leading primary site of cancer in males.
Carcinoma cervix is one of the leading sites of cancer in females in India.[15] However, since a combination of chemotherapy and radiotherapy is often employed
for Ca Cervix, our study excluded such patients.
Carcinoma breast is the most common site of cancer among females in India (GLOBOCAN
2012 India)[15]. In our study also, carcinoma breast was among the top three sites of cancer in
females.
Sarkar and Shahi et al.[18] reported treatment-related Grade 3 or 4 toxicity in elderly as 10.2% (4 out of 39
patients). It includes adverse effect due to surgery, radiation or chemotherapy. As
per our knowledge, there is no Indian data available on the occurrence of chemotherapy
toxicity in elderly. Thus, comparison of chemotherapy toxicity is done with studies
all over the globe. It may be seen that the incidence of toxicity observed in different
tumors may range from 27.7% (observed in Carcinoma ovary by Freyer et al.[19]) to as high as 64% (in various cancers by Extermann et al.[20]).
In both of the studies conducted by Hurria et al.,[21]
[22] more than half of the patients had chemotherapy-related Grade 3–5 toxicity. In our
data, the overall incidence of chemotherapy-related toxicity was lower (44%) than
that observed by all the above-quoted studies. The observed difference in the incidence
of toxicity between our study and the others could be, because our sample size was
small, confined to only one hospital and not representative of the Indian population
at large.
Hematologic toxicity was observed in 13% of patients and NH in 42% in our study. The
difference in H toxicity may be explained by use of primary prophylaxis growth factors
in 77% of our study patients. Our study population was younger (mean age <70 years)
than the comparative studies mentioned above leading to less incidence of toxicity
(mean age >75 years).[20]
[21]
[22]
When scrutinized, the patients in metastatic setting have higher incidence of toxicity,
that is, 49.2%. This shows the higher burden of the disease and poor performance status
in these patients and affects their tolerance for treatment.
The spectrum of chemotherapy toxicity among different tumor types is affected by patient,
tumor and treatment-related factors. Chemotherapy toxicity was observed in 44% of
our patients compared to 63% of patients in Extermann et al.[20] group. The incidence of neutropenia, febrile neutropenia, and mucositis is similar
across the studies. Among NH toxicity, fatigue not relieved on sleep and interfering
with activities of daily living was the most common (16.4%). Sepsis without neutropenia
was also important chemotherapy toxicity across studies. Our patient cohort represented
the privileged class in India. They had better support system in terms of financial
and social field.
The toxicities across the studies are variable, and it depends on amalgamation of
heterogeneous patient, tumor, and chemotherapy-related factors.
Studies show that most of the patients develop toxicity during the first cycle of
chemotherapy.[23]
[24] Crawford et al.[23] took a heterogeneous population and observed that most (58.9%) H toxicity events
occurred in the first cycle. Similarly, Lyman et al.[24] studied the timing of H toxicity in patients receiving CHOP chemotherapy in non-Hodgkin
lymphoma. Fifty percent of H toxicity happened in the first cycle. In our study, the
range to suffer adverse effects of chemotherapy was 6–216 days. The median time taken
to develop toxicity was 39.5 days. The median time to develop toxicity was 22 days
in Extermann et al.[20] study. This corresponds to the period between second and third chemotherapy cycle.
The period of concern is 1st month of starting chemotherapy as maximum number of events
(45.4%) occurred during this timeframe. We also noted that around 50% of patients
would manifest chemotherapy-related toxicity between cycles 2–3 of chemotherapy. Based
on these observations, we suggest close and frequent monitoring after first and second
cycle of chemotherapy to avert or to ameliorate the development of adverse effects.
Conclusions
For any elderly patient, the occurrence of chemotherapy-related toxicity is a matter
of concern. In our study, it was noted that 64% of patients were able to complete
the prescribed treatment with <50% of patients experiencing severe chemotherapy-related
toxicity (H and NH). The first 30 days of treatment are most important as 45% of patients
experienced toxicity in this time frame. The development of chemotherapy toxicity
makes an individual likely to receive less (4.5 vs. 6) number of chemotherapy cycles.
We reported only Grade 3–5 toxicity; however, some Grade 2 toxicities (diarrhea, neuropathy)
may also be pertinent to the geriatric population.
We suggest that large-scale, prospective studies with a greater sample size must be
undertaken to describe more accurately the incidence of chemotherapy-related toxicity
and that future studies also document the development of Grade 2 toxicities in elderly,
which are often underrecognized.
