European Journal of Cardiovascular Medicine

The oncological armamentarium, though progressively fortified by advances in chemotherapeutic regimens, remains regrettably encumbered by the inexorable reality of off-target toxicities, which, while collateral to their anti-neoplastic intent, exact a grievous toll on neurological, cognitive, and cardiovascular homeostasis. Among these iatrogenic adversities, chemotherapy-induced peripheral neuropathy (CIPN), cognitive deterioration—popularly denominated "chemobrain"—and cardiotoxicity collectively form an insidious triad that profoundly undermines the therapeutic calculus, survivorship trajectory, and quality of life of afflicted individuals (1-5).

CIPN, an affliction that predominantly besieges sensory, motor, and autonomic neural conduits, frequently emanates from the neurotoxic predilections of platinum-based compounds, taxanes, vinca alkaloids, proteasome inhibitors, and select alkylating agents (6-9). Its clinical constellation—paraesthesia, allodynia, distal weakness, proprioceptive derangement—often compels dose attenuation or premature cessation of otherwise life-prolonging cytotoxic protocols (10-12). Paradoxically, while this neurotoxicity ostensibly targets peripheral circuits, an emerging corpus of literature implicates systemic chemotherapy in subtle yet discernible central nervous system derangements, manifested as cognitive attenuation, executive dysfunction, and impaired psychomotor integration (13-16). The nebulous construct of "chemobrain" has, in recent years, transcended anecdotal narratives, finding empirical corroboration through neuropsychological batteries, neuroimaging, and biomarker studies (17-19).

Concurrently, the cardiovascular axis is not impervious to the cytotoxic collateral, particularly in the context of anthracyclines, HER2-directed therapies, and select alkylating agents, which precipitate a spectrum of cardiotoxic insults ranging from asymptomatic left ventricular dysfunction to overt heart failure, arrhythmogenesis, and, in some instances, sudden cardiac death (20-24). The pathobiological underpinnings—oxidative stress, mitochondrial injury, endothelial dysfunction, and maladaptive remodelling—mirror, to a certain extent, the neurotoxic mechanisms, implicating shared molecular substrates and systemic vulnerability (25-27).

Despite burgeoning evidence delineating the individual domains of neurotoxicity, cognitive decline, and cardiotoxicity, a lacuna persists in comprehensively elucidating their interrelationship within a unified, prospective, and clinically applicable framework. Furthermore, the integration of affordable, reproducible clinical tools, biochemical indices, and accessible imaging modalities remains an unmet imperative, particularly within resource-constrained oncological settings.

This prospective observational study thus endeavours to delineate, with rigorous clinical, biochemical, and statistical scrutiny, the incidence, temporal trajectory, and correlative interplay of chemotherapy-induced neuropathy, cognitive decline, and cardiotoxicity in a cohort of 150 patients subjected to neuro- and cardiotoxic chemotherapeutic regimens, thereby furnishing an evidence-based scaffold for anticipatory surveillance and mitigative intervention.

Study Design and Population

A prospective, observational cohort study conducted from January 2023 to June 2024 at the Department of Radiation Oncology, Neurology, Cardiology, Biochemistry, Pathology & Pharmacology at a Tertiary Care Hospital, Kolkata.

Inclusion Criteria:

1. Adults aged 18–70 years
2. Diagnosed with solid malignancies (breast, lung, ovarian, colorectal)
3. Planned for chemotherapy regimens including platinum agents, taxanes, anthracyclines, or HER2-targeted therapies
4. Baseline LVEF ≥50%

Exclusion Criteria:

1. Pre-existing neuropathy or cognitive impairment
2. Known structural heart disease
3. Diabetes mellitus with peripheral neuropathy
4. CNS metastases

Sample Size Justification:

Assuming a 30% incidence of CIPN and 20% cardiotoxicity, with 95% confidence and 10% allowable error, the calculated minimum sample size was 138; 150 patients were enrolled to account for attrition.

Table 1 - Clinical Tools and Assessments

Follow-Up Schedule:

Baseline: Neurological assessment, cognitive testing, ECG, ECHO, blood parameters, CT brain

Every 3 months: Repeat assessments as above

Duration: 12 months

Statistical Analysis

1. Data were compiled in MS Excel 2021 and analysed using IBM SPSS Version 28.
2. Continuous variables: Expressed as mean ± SD; compared using paired/unpaired t-tests or ANOVA
3. Categorical variables: Expressed as percentages; compared using Chi-square or Fisher's exact test
4. Correlations: Pearson or Spearman correlation coefficients
5. Regression Analysis: Multivariate logistic regression for predictors of cardiotoxicity
6. Statistical Significance: p < 0.05

Demographic Profile

1. Mean age: 53.6 ± 8.9 years
2. Gender distribution: 82 females (54.7%), 68 males (45.3%)
3. Cancer types: Breast (44%), Lung (23.3%), Ovarian (18%), Colorectal (14.7%)

Incidence of Chemotherapy-Induced Neuropathy

1. CIPN diagnosed in 94 patients (62.7%)
2. Mean TNSc score at 6 months: 6.2 ± 2.1
3. Higher incidence with:
4. Platinum agents (cisplatin/oxaliplatin): 71% (p < 0.001)
5. Taxanes (paclitaxel/docetaxel): 68% (p < 0.001)
6. Nerve conduction studies: Reduced sensory nerve action potential in 61% of affected
7. Elevated serum NSE correlated with severe CIPN (r = 0.42, p = 0.002)

Cognitive Decline

1. MoCA score <26 in 57 patients (38%) at 6 months
2. Cognitive domains most affected: Executive function, Attention
3. CT brain:
4. Subcortical white matter hypoattenuation in 21%
5. No gross structural atrophy
6. Cognitive decline significantly associated with severe CIPN (TNSc >7, p < 0.001)

Cardiotoxicity Profile

1. Cardiotoxicity documented in 46 patients (30.7%)
2. Mean LVEF reduction: 11.4 ± 3.2%
3. Elevated hs-TnI (>0.04 ng/mL) in 33%
4. NT-proBNP elevated in 29%
5. Higher risk with:
6. Anthracyclines (OR 3.7, 95% CI: 2.1–6.4, p < 0.001)
7. HER2-targeted therapies (OR 2.9, 95% CI: 1.5–5.6, p = 0.001)
8. NYHA Class II or worse in 17%

Correlations

1. CIPN severity positively correlated with cognitive decline (r = -0.51, p < 0.001)
2. Both CIPN and cognitive decline independently predicted cardiotoxicity:
3. CIPN (OR 2.46, p = 0.002)

4.       Cognitive decline (OR 1.98, p = 0.015)

Table 2- Distribution of Chemotherapeutic Agents and Their Association with Toxicities (n = 150)

Table 3- Biochemical Marker Abnormalities in Relation to Clinical Toxicities

Table 4 - Multivariate Logistic Regression for Predictors of Cardiotoxicity

Table 5- Temporal Progression of Toxicities at 3, 6, and 12 Months

The findings of this meticulously orchestrated prospective inquiry underscore the formidable neuro-cardiovascular sequelae that beset patients undergoing chemotherapy, with an appreciable incidence of peripheral neuropathy (62.7%), cognitive attrition (38%), and cardiotoxicity (30.7%) documented within the study cohort. These figures resonate, albeit with nuanced variations, with prior epidemiological observations (4, 6, 9, 21, 22).

The preponderance of CIPN, particularly among recipients of platinum-based and taxane chemotherapeutics, aligns with established mechanistic paradigms implicating axonal degeneration, mitochondrial dysfunction, and calcium dysregulation in the genesis of sensorimotor derangement (7, 8, 11, 28). Moreover, the elevation of serum neuron-specific enolase (NSE) levels in severe CIPN subsets corroborates its emerging utility as a peripheral biomarker of neural injury, a premise substantiated in recent neuro-oncological literature (29, 30).

Cognitive decline, as objectively delineated by MoCA assessments and corroborated by subtle radiological aberrations on CT imaging, reaffirms the insidious cerebral ramifications of systemic chemotherapy (13, 15, 16, 17). The significant inverse correlation between CIPN severity and cognitive performance (r = -0.51, p < 0.001) lends credence to the hypothesis of a shared neurotoxic axis, potentially mediated via microvascular compromise, neuroinflammation, or peripheral-central neural axis dysregulation (31-34).

The cardiotoxic landscape delineated herein—characterised by LVEF diminution, biomarker perturbations (hs-TnI, NT-proBNP elevation), and functional compromise (NYHA deterioration)—mirrors canonical anthracycline and HER2-targeted therapy-induced cardiomyopathy, as extensively chronicled in prior meta-analytical treatises (20, 23, 24, 35). Intriguingly, the present study elucidates, for the first time within this demographic and methodological framework, that both CIPN and cognitive decline independently portend an elevated cardiotoxicity risk, a phenomenon hitherto underexplored in contemporaneous oncological literature (26, 27, 36).

The findings of this meticulously orchestrated prospective inquiry underscore the formidable neuro-cardiovascular sequelae that beset patients undergoing chemotherapy, with an appreciable incidence of peripheral neuropathy (62.7%), cognitive attrition (38%), and cardiotoxicity (30.7%) documented within the study cohort. These figures resonate, albeit with nuanced variations, with prior epidemiological observations (4, 6, 9, 21, 22).

The preponderance of CIPN, particularly among recipients of platinum-based and taxane chemotherapeutics, aligns with established mechanistic paradigms implicating axonal degeneration, mitochondrial dysfunction, and calcium dysregulation in the genesis of sensorimotor derangement (7, 8, 11, 28). Moreover, the elevation of serum neuron-specific enolase (NSE) levels in severe CIPN subsets corroborates its emerging utility as a peripheral biomarker of neural injury, a premise substantiated in recent neuro-oncological literature (29, 30).

Cognitive decline, as objectively delineated by MoCA assessments and corroborated by subtle radiological aberrations on CT imaging, reaffirms the insidious cerebral ramifications of systemic chemotherapy (13, 15, 16, 17). The significant inverse correlation between CIPN severity and cognitive performance (r = -0.51, p < 0.001) lends credence to the hypothesis of a shared neurotoxic axis, potentially mediated via microvascular compromise, neuroinflammation, or peripheral-central neural axis dysregulation (31-34).

The cardiotoxic landscape delineated herein—characterised by LVEF diminution, biomarker perturbations (hs-TnI, NT-proBNP elevation), and functional compromise (NYHA deterioration)—mirrors canonical anthracycline and HER2-targeted therapy-induced cardiomyopathy, as extensively chronicled in prior meta-analytical treatises (20, 23, 24, 35). Intriguingly, the present study elucidates, for the first time within this demographic and methodological framework, that both CIPN and cognitive decline independently portend an elevated cardiotoxicity risk, a phenomenon hitherto underexplored in contemporaneous oncological literature (26, 27, 36).

This intersectionality may plausibly emanate from a confluence of systemic inflammatory milieu, endothelial dysfunction, and oxidative stress, collectively orchestrating neural and myocardial injury (25, 28, 33, 37-39). Such mechanistic synergy accentuates the necessity for holistic, cross-disciplinary surveillance encompassing neurological, cognitive, and cardiovascular axes within chemotherapeutic paradigms.

The utilisation of accessible, cost-effective clinical instruments (TNSc, MNSI, MoCA, NYHA), biochemical surrogates (NSE, hs-TnI, NT-proBNP), and periodic imaging (CT, echocardiography) renders the surveillance algorithm proposed herein eminently translatable, particularly within resource-constrained settings endemic to developing economies (40-43). Nonetheless, this study is not impervious to limitations. The absence of advanced neuroimaging (MRI, PET), detailed neuropsychological batteries, and longitudinal follow-up beyond 12 months constrains the extrapolation of chronic neuro-cardiotoxic trajectories. Furthermore, the observational design precludes causal inferences, necessitating prospective interventional studies to validate mitigative strategies.

The findings emergent from the present scholastic undertaking indubitably delineate an ominous, multifactorial intersection of neurotoxicity, cognitive attrition, and cardiotoxicity that collectively besiege the oncological survivorship continuum, rendering the traditional compartmentalised appraisal of chemotherapy-induced sequelae grossly inadequate in both scope and profundity. This investigation, fortified by an assemblage of affordable yet diagnostically incisive clinical tools, biochemical surrogates, and imaging modalities, furnishes a methodologically robust paradigm through which the protean manifestations of chemotherapy-induced peripheral neuropathy (CIPN), cognitive impairment, and cardiotoxicity may be anticipated, detected, and stratified with commendable clinical precision.

Foremost, the preponderance of CIPN—documented in an appreciable 62.7% of the cohort—resonates with an expansive corpus of neuropathological evidence implicating cytotoxic perturbation of axonal integrity, mitochondrial dynamics, and neural microvasculature as central pathomechanisms. The corroborative elevation of neuron-specific enolase (NSE) as a peripheral biomarker of neural compromise introduces a pragmatic, biochemically grounded adjunct to clinical and electrophysiological evaluation—particularly germane within resource-constrained oncological settings endemic to the developing world.

Simultaneously, the discernible cognitive attenuation, affecting nearly 38% of participants and objectified via MoCA scoring and cerebral imaging, accentuates the stealthy neurocognitive toll exacted by systemic chemotherapy. The significant inverse correlation between neuropathy severity and cognitive performance—statistically corroborated herein—illuminates the insidious bidirectional crosstalk between peripheral neural injury and central neurocognitive dysfunction, a relationship hitherto insufficiently interrogated within the prevailing oncological literature.

Moreover, the cardiotoxic phenotype delineated—encompassing LVEF diminution, elevation of cardiac troponins, NT-proBNP derangement, and NYHA functional deterioration—affirms the cardiac vulnerability imposed by anthracyclines, HER2-directed therapies, and alkylating agents, mirroring global epidemiological trends. Crucially, this study elucidates, with unprecedented statistical clarity, the independent predictive valence of CIPN and cognitive decline vis-à-vis subsequent cardiotoxicity—thereby unveiling a novel, clinically actionable nexus that compels integrated, anticipatory surveillance beyond the myopic silos of traditional organ-specific toxicity appraisal.

Collectively, these revelations coalesce to demand an irrevocable paradigm shift within oncology practice—eschewing reductionist, unidimensional toxicity monitoring in favour of an integrative, cross-disciplinary surveillance architecture that holistically encapsulates the neural, cognitive, and cardiovascular axes as interdependent constituents of the patient’s systemic vulnerability landscape.

Whilst the methodological rigour and statistical robustness of the present inquiry augment its translational applicability, certain limitations—namely, the absence of advanced neuroimaging, granular neuropsychological batteries, and protracted longitudinal follow-up—preclude an exhaustive delineation of the chronic neuro-cardiovascular trajectory. Future investigative endeavours, preferably interventional in design, must seek to address these lacunae whilst validating mitigative strategies tailored to this vulnerable patient demographic.

In conclusion, this prospective, multimodal study constitutes an invaluable empirical scaffold upon which to architect more nuanced, anticipatory, and resource-sensitive strategies for the early detection, risk stratification, and holistic management of chemotherapy-induced neuropathy, cognitive decline, and cardiotoxicity within contemporary oncological practice.

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