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ORIGINAL ARTICLE
Year : 2021  |  Volume : 58  |  Issue : 4  |  Page : 583-589
 

Predictors of chemotherapy tolerance and survival benefit in a geriatric patient population with advanced solid tumors


Department of Oncology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, People's, Republic of China

Date of Submission20-Jan-2021
Date of Decision20-Mar-2021
Date of Acceptance23-Mar-2021
Date of Web Publication31-Dec-2021

Correspondence Address:
Yong-Qiang Zhang
Department of Oncology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences
Republic of China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_88_21

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 » Abstract 


Background: It is challenging to identify robust elderly patients suitable for systemic chemotherapy. The goal of this study was to ascertain clinical characteristics that may best predict the most benefit of systemic chemotherapy for geriatric patients (aged ≥80 years) with advanced solid tumors.
Methods: A retrospective cohort study was conducted of advanced solid tumors patients treated with systemic chemotherapy. We divided the patients into chemotherapy tolerant and intolerant groups. We assessed the efficacy, adverse reactions, progression-free survival, and overall survival of patients treated with chemotherapy. We accounted for comorbidities, Eastern Cooperative Oncology Group performance status (PS), activities of daily living (ADL), and routine serologic lab metrics. We compiled survival curves for the two groups, and Cox regression univariate and multivariate analyses were used to identify factors that influenced survival.
Results: We included 84 patients in the analyses. Comorbidities ≤3, medications ≤4, ADL score ≥90, and PS score ≤1 were associated with chemotherapy tolerance (P < 0.05). Normal D-Dimer and serum albumin concentrations were associated with chemotherapy tolerance (P < 0.05). The median overall survival was 15.0 months (95% confidence interval [CI]: 12.8 - 17.2) in the tolerant group and 7.0 months (95% CI: 4.3 - 9.7) in the intolerant group (P < 0.05). Thus, most tolerant patients (79.6%) benefited from chemotherapy. PS, ADL, normal albumin, and chemotherapy tolerance were statistically correlated with overall survival (P < 0.05).
Conclusion: Some clinical characteristics were associated with chemotherapy tolerance. The overall survival time of elderly patients with good tolerance to chemotherapy was longer.


Keywords: Chemotherapy safety, chemotherapy tolerability, geriatrics, survival benefits
Key Message The basic state and laboratory examination may predict the chemotherapy tolerance of elderly patients with advanced solid tumors. The overall survival time of elderly patients with good tolerance was longer


How to cite this article:
Xu Y, Ding L, Zhang YQ. Predictors of chemotherapy tolerance and survival benefit in a geriatric patient population with advanced solid tumors. Indian J Cancer 2021;58:583-9

How to cite this URL:
Xu Y, Ding L, Zhang YQ. Predictors of chemotherapy tolerance and survival benefit in a geriatric patient population with advanced solid tumors. Indian J Cancer [serial online] 2021 [cited 2022 Jan 19];58:583-9. Available from: https://www.indianjcancer.com/text.asp?2021/58/4/583/334639



 » Introduction Top


Men and women aged 70 years and older are one-third and one-quarter more likely to develop cancer.[1] China has an annual 5% rate of increase in the population of geriatric patients (aged ≥80 years).[2] As expected, this increase is associated with an increase in the number of older adults diagnosed with advanced malignancies. Elderly persons often have compromised organ function due to natural aging and non-cancer related comorbidities; aging and comorbidities make elderly individuals more vulnerable to toxicity of conventional cytotoxic agents.[3] Less than 10% of patients enrolled in National Cancer Institute (NCI) Cooperative Group Clinical Trials was aged 75 years or older.[4] Frequently, patients aged ≥ 80 years are excluded from clinical trials.[5] Recent retrospective data suggest that chemotherapy may be feasible for cancer patients aged ≥80 years, provided they receive careful clinical assessment.[6] However, despite frequent dose modifications, these patients are at high risk for hospitalization and treatment discontinuation due to the toxicity of chemotherapy agents.[7]

How do oncologists make treatment decisions for older cancer patients, especially patients aged 80 years and older? Can these patients benefit from chemotherapy? Most decisions about which robust elderly patients are suitable for systemic chemotherapy rely on clinical gestalt and anecdotal experience. In the year of precision medicine, we must strive to be precise not only with treatment selection for actionable mutations (such as EGFR gene mutation) but also with patient selection in the aging population.[7]

We conducted a retrospective cohort study of patients aged 80+ years who received systemic chemotherapy. We assessed the efficacy, adverse reactions, progression-free survival (PFS), and overall survival (OS) of the patients. Our goal was to investigate the tolerance to chemotherapy in this cohort and determine whether any clinical or serologic laboratory values were associated with tolerance. Those associations will inform decisions about which geriatric patients should receive chemotherapy.


 » Methods Top


A retrospective cohort study was conducted of all patients with advanced solid tumors treated with systemic chemotherapy at our hospital, which is a multispecialty tertiary hospital, from January 2012 to September 2019. Inclusion criteria required patients to be ≥80 years old at the time of their first cycle of chemotherapy. All patients had pathologically confirmed advanced solid tumors. Patients must have received at least one cycle of chemotherapy to be included in this study. Patients were excluded if they received only supportive care, hormonal therapy, targeted therapy, and immunotherapy. Eighty-four patients met the above criteria and were included in our analysis.

Data were extracted from electronic medical records. We collected baseline data of age, sex, eastern cooperative oncology group (ECOG) performance status (PS), activities of daily living (ADL, Barthel index), body mass index (BMI), baseline number of prescription medications prior to initiation of chemotherapy, comorbidities (the number of comorbidities documented), cancer type, chemotherapy planned (regimen, dose adjustment prior to the first cycle), and baseline serologic parameters [complete blood count (CBC), albumin, hepatic and renal function, and coagulation function].

We divided the patients into chemotherapy tolerant and chemotherapy intolerant groups. Chemotherapy intolerance was defined as patients who required a dose reduction, dose delay (>1 week), or discontinuation due to toxicity. Otherwise, patients were classified as chemotherapy tolerant. Differences between chemotherapy tolerant and intolerant individuals were analyzed based on baseline characteristics before chemotherapy.

We assessed the efficacy, adverse reactions, PFS, and OS of patients with chemotherapy to find the survival benefits between chemotherapy tolerance group and intolerance group. We drew the survival curve of the two groups and found the factors influencing the survival through univariate and multivariate survival analysis.

Statistical analysis

The baseline data before chemotherapy were compared by chi-square test test between chemotherapy tolerant and intolerant groups. We plotted Kaplan-Meier survival curves to compare overall survival between the two groups, and we used Cox regression univariate and multivariate survival analysis to identify factors that influenced survival.


 » Results Top


Basic characteristics

We searched records of all patients with advanced solid tumors at our hospital from January 2012 to September 2019. There were 1230 patients aged >70 years, of which 278 were greater than 80 years old. Eighty-four patients were included in the analysis (see Methods for criteria). Most of the patients (75, 89.3%) had tumor metastasis, and most of the patients received only palliative intent chemotherapy (78, 92.9%). (Treatment regimens were shown in the [Supplement Table 1].) Forty-nine (58.3%) patients were chemotherapy tolerant, and 35 (41.7%) patients were chemotherapy intolerant [Table 1]. One-third of the patients were women, and the median age of all patients was 81 (range: 80–90 years). Most patients had lung cancer (36, 42.8%), followed by colorectal cancer (23, 27.4%).

Table 1: Characteristics of the patients with efficacy and adverse reactions to chemotherapy

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In terms of tumor subtypes, patients with urothelial cancer (6/6, 100%) and colorectal cancer (17/23, 73.9%) were most tolerant of chemotherapy. Patients with lung cancer (17/36, 47.2%) and gastric cancer ( 5/10, 50%) were least tolerant. We compared lung cancer and colorectal cancer, the two cancers with the largest number of patients in our cohort. The 47.2% tolerance of lung cancer patients was significantly lower than the 73.9% tolerance of colorectal cancer patients (P = 0.043).

Efficacy and adverse reactions of chemotherapy

All patients received a median of four courses of chemotherapy (range: 1–16) (Treatment regiments are shown in [supplement Table 1]). Of 84 patients, three patients did not have imaging evaluation because the disease progressed rapidly after treatment, and the progress was judged according to clinical manifestations. Two patients were judged by bedside chest radiograph, and the rest patients were evaluated by computer tomography (CT) or magnetic resonance imaging (MRI). Overall objective response rate (ORR) was 25.0% including complete response and partial response, and disease control rate (DCR) was 72.6% including complete response, partial response and stable disease. In the tolerant group, the ORR and DCR were 32.7% and 79.6%, respectively. In the intolerant group, the ORR and DCR were 14.3% and 62.8%, respectively. The most common adverse reaction was hematologic toxicity (35, 41.7%). Among the patients in the intolerant group, 24 (68.6%) had hematologic toxicity, and 15 (42.8%) were in the third degree or greater of hematologic toxicity (Grading according to Common Terminology Criteria Adverse Events (CTCAE) v5.0).

Factors influencing chemotherapy tolerance

[Table 2] shows that the patients with more than three comorbidities and more than four medications were intolerant to chemotherapy, and a high ADL score (≥90) and low PS score (≤1) were associated with chemotherapy tolerance (P < 0.05). In the chemotherapy intolerant group, the proportion of dose adjustment before chemotherapy was greater, but there was no statistically significant difference compared with the tolerant group.
Table 2: Factors that influenced chemotherapy tolerance

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We found some factors may affect patients' chemotherapy tolerance, such as decreased hemoglobin, elevated aminotransferase, transpeptidase, and elevated creatinine showing a trend of intolerance, but there were no statistically significant differences, except D-Dimer and serum albumin concentrations, which were associated with chemotherapy tolerance (P < 0.05).

Survival analysis

During the follow-up of survival information, two patients lost contact and did not get the follow-up survival status. Eighty-two patients were followed to survival time. The median PFS was 7 (95% confidence interval [CI]: 5.8 - 8.2) months in the tolerant group and 5.8 (95% confidence interval [CI]: 4.3 - 5.7) months in the intolerant group; the difference was not significant (P = 0.448). The median overall survival was 15 (95% confidence interval [CI]: 12.8 - 17.2) months in the tolerant group and 7 months (95% confidence interval [CI]: 4.3 - 9.7) in the intolerant group, a difference of 8.0 months [P = 0.029; [Table 1] and [Figure 1]]. The one-year survival was 46.3% (36/82), and it was 55.3% versus 34.3% for the tolerant and intolerant groups.Univariate survival analysis showed that PS, ADL, normal albumin, and tolerance were correlated with OS [P < 0.05; [Table 3]]. But in multivariate survival analysis, none of these features was an independent prognostic factor [Table 4].
Figure 1: Overall survival; OS: overall survival; CI: confidence interval; HR: hazard ratio

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Table 3: Univariate survival analysis

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Table 4: Multivariate survival analysis

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 » Discussion Top


The growth of the aging Chinese population has accelerated. In 2015, the estimated yearly increase in cancer cases was 21.9% for individuals aged 75 years and older.[8] Although molecularly targeted agents and immunotherapies are changing the treatment landscape, chemotherapy remains the standard of care, including care of geriatric patients. There are a few studies on systemic chemotherapy for Asian patients aged 80 years and greater. In clinical practice, there is a lack of objective measures that predict chemotherapy tolerance in the geriatric population. We found that older patients can tolerate chemotherapy, but selectively. We could select the tolerant patients according to comorbidities, medications, PS, and ADL score. Nearly 80% of tolerant patients can benefit from chemotherapy, and they survive longer compared with patients who are not tolerant of chemotherapy.

Patients with a few comorbidities (≤3), a few medications (≤4), high ADL scores (≥90), and low PS scores (≤1) were more likely to be chemotherapy tolerant (P < 0.05). Many comorbidities may necessitate many medications. Sud et al.[7] reported that having a small number of baseline prescription medications was beneficial for patients to tolerate chemotherapy, and investigators reported a higher frequency of dose delays and dose reductions in patients with many comorbidities.[9],[10] Polypharmacy is associated with chemotherapy toxicities.[11] Popa et al.[12] found that potential drug interactions from polypharmacy were associated with chemotherapy tolerance by older cancer patients, and drug interactions increased the risk of non-hematological toxicity.

The ECOG scale of performance status describes a patient's level of functioning in terms of their ability to care for themselves, daily activity, and physical ability.[13] However, Dong et al.[14] found that, as a primary driver of treatment decisions for elderly cancer patients, PS may not reflect the comprehensive status of geriatric cancer patients. ADL scores may be a better assessment of the global function of geriatric patients. Caillet et al.[15] reported that ADL scores were more sensitive than ECOG PS in older cancer patients, and some studies suggest that comprehensive geriatric assessment scores and patient baseline prescription medications can help screen patients likely to be tolerant to chemotherapy.[5],[7] Our study was retrospective; thus, we did not have geriatric assessment data. There are several chemotherapy-risk prediction calculators available. The Chemotherapy Risk Assessment Scale for high-age patients (CRASH) is recommended to obtain estimates of chemotherapy toxicity risk.[16] In CRASH score, ADL and ECOG score can predict chemotherapy toxicity, which is similar to our results.

In this study, we found that patients with normal D-Dimer concentration were more tolerant to chemotherapy (P < 0.001). Thrombosis in cancer patients can cause significant morbidity, and thrombosis is the leading cause of mortality long before a malignancy becomes directly life-threatening.[17] Anticancer chemotherapy may affect liver function and decrease the synthesis of both pro- and anticoagulation factors. Although the side effects of chemotherapy are reversible, endothelial lesions may persist for many years after the anticancer treatment.[18]

We found that patients with normal serum albumin concentrations were more tolerant to chemotherapy (P < 0.001). Serum albumin abundance may reflect nutritional status; a reduction in albumin concentration may indicate poor nutritional status and lead to chemotherapy intolerance. Aging predisposes elderly persons to a high prevalence of undernutrition.[19] Malnutrition is widespread among elderly cancer patients, and malnutrition is associated with poor prognosis (losing more than five percent of weight, increases the risk of death). Paccagnella et al.[20] found that poor nutrition reduced tolerance to chemotherapy, caused high susceptibility to infection, provoked treatment complications, and diminished quality of life. Supplementation with parenteral nutrition for patients with advanced colorectal cancer reduced chemotherapy-related side effects.[21] Future studies should include a more comprehensive nutritional assessment tool in the evaluation of chemotherapy tolerance.

We found that the overall survival time of elderly patients with better tolerance to chemotherapy was longer compared with patients who could not tolerate chemotherapy (15.0 months versus 7.0 months, P = 0.029), and the efficacy was better. Most patients (79.6%) benefited from chemotherapy. There are a few studies of chemotherapy for patients greater than 80 years old. Choi et al.[3] disclosed that the one-year survival rate was 48% for solid tumor patients aged 80 years or older who received chemotherapy. Stage of disease was the only statistically significant factor that predicted survival. This finding is similar to the one-year survival rate (46.3%) that we found, but the tolerant group (55.3%) had better results than in the previous study.[3] Oncologists may differ greatly in their decisions about chemotherapy for older patients. Evidence-based assessment and management of geriatric-related diseases can provide information for chemotherapy decision-making and improve prognosis.[16]

Our study had some limitations. The heterogeneity of disease was an important shortcoming. Different chemotherapy regimens for different tumor species lead to differences in chemotherapy tolerance. We found that the tolerance of lung cancer patients was significantly lower than that of colorectal cancer patients. In addition, there are many tools to assess cognitive function, depression, and social factors for elderly cancer patients, but the retrospective nature of our research precluded the use of these tools.

We need a further prospective investigation of chemotherapy tolerance by elderly patients. Many geriatric assessment tools for elderly patients with tumors should be employed to screen patients who may benefit from systemic chemotherapy.


 » Conclusion Top


Some clinical characteristics were associated with chemotherapy tolerance in a geriatric patient population. The overall survival time of elderly patients with good tolerance to chemotherapy was longer. Most tolerant patients could benefit from chemotherapy.

Ethical statement

The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the ethics committee of Beijing Hospital. (Number: 2020BJYYEC-213-01).

The authors thank AiMi Academic Services (www.aimieditor.com) for English language editing and review services.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

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Kvolik S, Jukic M, Matijevic M, Marjanovic K, Glavas-Obrovac L. An overview of coagulation disorders in cancer patients. Surg Oncol 2010;19:e33-46. doi: 10.1016/j.suronc. 2009.03.008.  Back to cited text no. 18
    
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21.
Hasenberg T, Essenbreis M, Herold A, Post S, Shang E. Early supplementation of parenteral nutrition is capable of improving quality of life, chemotherapy-related toxicity and body composition in patients with advanced colorectal carcinoma undergoing palliative treatment: Results from a prospective, randomized. Colorectal Dis 2010;12:e190-9. doi: 10.1111/j. 1463-1318.2009.02111.x.  Back to cited text no. 21
    


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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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