Closing the evidence gap in older adults with extensive-stage small-cell lung cancer: a CGA-guided,risk-adapted treatment framework

The representation gap in evidence-based medicine

In current oncological practice, a unified definition of the “elderly” population remains elusive. ¹² Although clinical trials frequently utilize chronological age cutoffs of 65 or 70 years, there is a consensus that chronological age is a poor surrogate for a patient’s functional reserve and biological frailty. ¹³ This reliance on arbitrary age thresholds has perpetuated a consistent underrepresentation of the elderly within RCTs. ¹⁴ Data indicate that while patients aged ⩾65 years constitute 66.6% of the real-world SCLC population, they account for merely 42.9% in pivotal RCTs. This “evidence gap” is particularly pronounced in the oldest-old, with a staggering disparity between real-world and trial proportions for those aged ⩾75 years (27.5% vs 8.5%). Such exclusionary criteria severely compromise the external validity of RCT data, implying that the efficacy and safety of standard first-line regimens (e.g., immunotherapy plus EP) in elderly ES-SCLC lack generalizable evidentiary support. ¹⁵ Given the scarcity of high-quality prospective data, clinical decision-making is reduced to navigating a precarious balance between potential benefits and toxicity risks, where slight deviations can lead to either undertreatment or treatment-related morbidity.^6,14,16

Multidimensional physiological heterogeneity and therapeutic tolerance

Elderly ES-SCLC patients exhibit unique physiological heterogeneity, where therapeutic complexity arises from the interplay of multidimensional pathophysiological factors rather than chronological aging alone. Foremost, comorbidity burden and polypharmacy create a complex pharmacological landscape. ¹⁷ Epidemiological data suggest that approximately 66% of elderly SCLC patients present with at least one chronic condition ⁸ ; long-term smoking history induces systemic vascular endothelial injury and chronic inflammation, fundamentally compromising the body’s physiological reserve.^18,19 Concurrently, drug-drug interactions driven by polypharmacy may significantly alter the pharmacokinetics of antineoplastic agents. ²⁰

Furthermore, functional decline and sarcopenia serve as core predictors of treatment tolerance. ²¹ Although the Eastern Cooperative Oncology Group performance status (ECOG PS) score is a classic prognostic factor, approximately 60% of elderly patients present with a PS ⩾2 at diagnosis, and PS alone often underestimates occult frailty—a functional limitation resulting from the synergistic effects of cancer cachexia and age-related sarcopenia.^22–24 Physiologically, elderly patients are often characterized by reduced hepatic and renal blood perfusion and diminished bone marrow hematopoietic reserve. ²⁵ These changes precipitate decreased clearance and prolonged half-life of cytotoxic drugs (e.g., etoposide), which significantly narrows the therapeutic index for myelosuppression and mucosal toxicity.^20,26 Therefore, the development of treatment regimens for geriatric patients necessitates a paradigm shift from standardized dosing models to individualized dose adjustments based on organ function. For etoposide, dose modification should be quantitatively guided, with renal function serving as the central metric. For patients with creatinine clearance of 15–50 mL/min, an initial 25% dose reduction, corresponding to 75% of the planned dose, is generally recommended. ²⁷ In Vulnerable patients without overt renal impairment but with impaired Instrumental Activities of Daily Living (IADL), sarcopenia, borderline marrow reserve, hypoalbuminemia, or prior grade ⩾3 hematologic toxicity, a pragmatic initial etoposide reduction of approximately 20%–25% may be considered, followed by cycle-by-cycle titration according to hematologic recovery and non-hematologic toxicity. ²⁸ Furthermore, in patients with markedly deteriorated renal function, recurrent severe toxicity, or those classified as Frail by CGA, more substantial dose reduction up to 50% or extension of the dosing interval should be considered.^28,29 It should be emphasized that dose attenuation in Vulnerable patients is not intended as a universal dose-reduction strategy, but rather as an initial risk-adapted approach for patients with impaired functional reserve, borderline organ function, or high predicted chemotherapy toxicity; subsequent dose escalation may be considered if cycle-1 tolerance is favorable.

Consequently, treatment planning for older adults with ES-SCLC must transcend chronological age thresholds and shift toward individualized decision-making based on functional status, comorbidity burden, and pharmacokinetic vulnerability.

Immunosenescence and remodeling of the tumor microenvironment

The efficacy of ICIs is contingent upon the integrity of the host immune system; however, immunosenescence may significantly alter the benefit-risk profile in elderly ES-SCLC patients. ²¹ Mechanistically, thymic involution precipitates a decline in naïve T-cell output and restriction of T-cell receptor diversity, thereby impairing the capacity for neoantigen recognition and clonal expansion. ³⁰ Concurrently, age-related “inflammaging”—characterized by chronic low-grade systemic inflammation—facilitates the recruitment of immunosuppressive populations such as myeloid-derived suppressor cells and regulatory T cells (Tregs), fostering an immunosuppressive tumor microenvironment (TME).^21,31 These biological alterations may predispose certain elderly cohorts to primary resistance against programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade.

Importantly, immunosenescence does not preclude immunotherapy; rather, it underscores the complexity of clinical phenotypes. Immune-related adverse events (irAEs) in this population are often clinically subtle, exhibit protracted recovery, and may mimic underlying comorbidities.^32,33 Therefore, this biological context mandates a strategic shift from “reactive management” to “proactive surveillance,” leveraging intensified baseline immune and frailty assessments to identify potential beneficiaries and optimize risk stratification.^34,35

PD-L1 inhibitors combined with chemotherapy: Validation of the first-line standard

The IMpower133 trial, the pioneering phase III study to demonstrate a survival benefit with chemoimmunotherapy, established atezolizumab plus etoposide-carboplatin as a standard of care. Long-term follow-up data revealed that in the subgroup aged ⩾65 years, the atezolizumab arm exhibited superior survival benefits (median OS 14.4 vs 9.6 months); notably, the magnitude of benefit (hazard ratio (HR) = 0.59) was numerically superior to that of the younger subgroup, with no unexpected geriatric-specific toxicity observed. This preliminarily supports the feasibility of this modality in the geriatric population.^4,15

Subsequent analyses from CASPIAN further supported the benefit of durvalumab combined with etoposide plus cisplatin/carboplatin in older patients. In the most recent formally published age-specific analysis, which used a cutoff of ⩾70 years, mOS was 12.0 versus 10.2 months, with an OS HR of 0.74 (95% confidence interval (CI) 0.49–1.11), indicating that the survival benefit remained directionally consistent in selected older patients.^41,42 Furthermore, the CAPSTONE-1 study, conducted in a Chinese cohort to evaluate adebrelimab, also suggested a survival benefit in older patients, although subgroup-specific mOS data have not yet been formally published. ⁴³ Together, these findings support the broader clinical relevance of PD-L1 inhibitor-based chemoimmunotherapy in older adults with ES-SCLC, while also underscoring the need for more complete age-specific outcome reporting.

Expansion of PD-1 inhibitors and statistical interpretation of subgroup data

As the therapeutic landscape evolves, PD-1 inhibitors combined with chemotherapy offer additional therapeutic options for older adults with ES-SCLC, but interpretation of age-specific subgroup findings remains challenging. In ASTRUM-005, serplulimab plus chemotherapy established a strong OS signal in the overall population, and the ⩾65 subgroup showed prolonged progression-free survival (PFS), supporting meaningful disease control in older patients.^38,44 However, subgroup-specific mOS data for older patients have not yet been formally reported. A similar issue applies to other recent phase III studies. In RATIONALE-312, although the overall population derived clear benefit, the HR for the ⩾65 subgroup (HR = 0.74, 95% CI: 0.53–1.03) crossed unity, which may reflect limited statistical power rather than true absence of benefit. ⁴⁵ Likewise, the EXTENTORCH study confirmed overall efficacy, but more granular age-specific survival reporting remains limited. ⁴⁰ Therefore, for several recent first-line phase III trials, available elderly subgroup HRs should be interpreted cautiously in the absence of formally published subgroup-specific mOS data.

Real-world evidence: Bridging the gap in poor PS

While RCTs have confirmed benefits in strictly selected elderly subgroups, a vast number of elderly patients with poor PS (ECOG PS ⩾2) in real-world settings are often excluded from the evidence base due to “enrollment bias,” resulting in a clinical evidence gap. ⁶ A retrospective real-world study from the Mayo Clinic has partially bridged this gap by including elderly patients with PS 2–3 who are typically ineligible for RCTs. The results indicated that following chemoimmunotherapy, the median OS of the PS 2–3 subgroup (9.3 months) showed no statistically significant difference from that of the PS 0–1 subgroup (10.6 months; p = 0.2718). ⁴⁶ This finding challenges the conventional paradigm of making treatment decisions based solely on PS scores, suggesting that select elderly patients with compromised PS may still derive benefit from immunotherapy. Nevertheless, given the inherent selection bias and sample size limitations of retrospective studies, and the high burden of complex comorbidities in this population, future prospective, real-world studies targeting the “old and frail” cohort are imperative to precisely delineate the therapeutic index of immunotherapy.^6,47

Vascular normalization and remodeling of the immune microenvironment

Aberrant activation of the vascular endothelial growth factor (VEGF) pathway not only drives tumor angiogenesis but also fosters a highly suppressive immune microenvironment by inhibiting dendritic cell maturation and promoting the infiltration of Tregs.^51,52 Consequently, blocking the VEGF pathway facilitates vascular normalization and enhances intratumoral immune cell infiltration, theoretically generating synergistic antitumor effects with ICIs. ³⁹

The ETER701 study, utilizing a “four-drug combination” of benmelstobart, anlotinib, and EP chemotherapy, significantly extended mOS to 19.3 months (HR = 0.61), setting a new survival benchmark. However, caution is warranted regarding generalizability to the elderly: the median age of participants was only 62 years, and the incidence of Grade ⩾3 treatment-related adverse events (TRAEs) reached 93.1%. Given that elderly patients prevalently exhibit age-related vascular stiffness and impaired hemodynamic regulation, the risks of hypertension and hemorrhage induced by small-molecule tyrosine kinase inhibitors (TKIs) may be significantly exacerbated when superimposed with chemotherapy toxicity. ³⁹ Therefore, when considering such “full-dose intensification” regimens in the geriatric population, cardiovascular reserve must be prioritized as a core screening metric rather than solely focusing on survival extension.^53,54

Conversely, a “chemo-free” maintenance strategy may offer a superior therapeutic index for frail elderly patients. Retrospective data indicate that for patients achieving stable disease after first-line chemotherapy, adopting anlotinib combined with PD-1/PD-L1 inhibitors for maintenance can yield a median PFS of 6 months with a manageable safety profile. ⁵⁵ This suggests that for elderly patients intolerant to the cumulative toxicity of long-term chemotherapy, a sequential maintenance strategy of immunotherapy plus anti-angiogenesis provides a viable, low-toxicity alternative pathway.^56,57

Radio-immunotherapy synergy: From cytotoxic control to immunomodulation

With chemoimmunotherapy established as the first-line standard, the role of radiotherapy is undergoing a paradigm shift from purely local control to systemic immunomodulation. Its core mechanism lies in inducing immunogenic cell death to release tumor-associated antigens, thereby priming a systemic antitumor immune response (i.e., the abscopal effect).^57,58 Consequently, the safety and efficacy of sequential thoracic consolidative radiotherapy (cTRT) in the immunotherapy era have emerged as a critical area of investigation.

Retrospective data indicate that ES-SCLC patients receiving sequential cTRT after induction chemoimmunotherapy can achieve a median PFS of 12.8 months; furthermore, under strict constraints on normal lung dosimetry (e.g., Lung V20), no prohibitive toxicities were observed, confirming feasibility. ⁵⁹ However, elderly patients frequently present with comorbidities such as COPD and pulmonary fibrosis, and their diminished pulmonary reserve renders them extremely sensitive to radiation-induced injury. ⁶⁰ Clinicians must exercise heightened vigilance regarding the overlapping toxicity of radiation pneumonitis and checkpoint inhibitor pneumonitis; once Grade ⩾2 pneumonitis occurs, the complexity of management and mortality risk increase significantly in the elderly.^61,62 Therefore, the implementation of cTRT must adhere to principles of “adaptive dosing” and “precision targeting.”

Concurrently, low-dose radiotherapy (LDRT) is gaining attention as an emerging immunomodulatory strategy. Distinct from traditional high-dose cytotoxic radiation, LDRT aims to remodel the stromal microenvironment and promote the infiltration of effector T cells into the tumor parenchyma. ⁶³ For elderly ES-SCLC patients with poor PS who cannot tolerate radical radiation doses, LDRT may provide a “toxicity-sparing” microenvironmental sensitizing approach, although its optimal dose-fractionation regimen warrants further validation through prospective studies.^64–66

Transcriptional regulators: The safety advantage of lurbinectedin

Lurbinectedin, a novel selective oncogenic transcription inhibitor, possesses a dual mechanism of action: it induces tumor cell apoptosis by inhibiting active transcription while simultaneously modulating the stimulator of interferon genes (STING)-interferon (IFN) pathway within the TME to reactivate antitumor immunity.^69,70 This unique profile positions it as the first novel agent approved by the U.S. Food and Drug Administration for SCLC since the era of topotecan. Key basket trials have validated its second-line efficacy: at a dose of 3.2 mg/m², it achieved an ORR of 35.2% and extended mOS to 9.3 months. ⁵⁸ More critically, recent data from phase III clinical trials (e.g., the IMforte study) demonstrated that lurbinectedin combined with atezolizumab as maintenance therapy significantly outperformed single-agent controls in both median PFS and OS, with no unexpected safety signals observed. For elderly ES-SCLC patients, the core advantage of lurbinectedin lies in its favorable hematologic safety profile. ⁷¹

Real-world data indicate that even in the subgroup aged ⩾65 years, efficacy remains comparable to the overall population, while the incidence of Grade 3–4 febrile neutropenia is significantly lower than that of topotecan, substantially reducing reliance on prophylactic granulocyte colony-stimulating factor. ⁷² This “hematologic-sparing” profile renders it an optimal choice for elderly patients with marginal PS or intolerance to high-intensity chemotherapy. ⁷³ Furthermore, studies such as LUPER are exploring its combination with ICIs; preliminary results suggest it holds promise for overcoming first-line immune resistance via remodeling of the TME, offering a new strategy of “chemo-immune resensitization” for later-line therapy. ⁷⁴

Delta-like ligand 3-targeting BiTE: Therapeutic potential and geriatric management challenges

Delta-like ligand 3 (DLL3), an inhibitory ligand of the Notch signaling pathway, exhibits aberrant high expression on the surface of approximately 85% of SCLC cells while remaining minimally expressed in normal adult tissues.^75,76 This exceptional tumor-specificity renders it a compelling target for precision immunotherapy. Tarlatamab, a first-in-class half-life extended BiTE, functions by bridging T cells and tumor cells to form a lytic synapse, thereby directly mediating the specific lysis of DLL3-positive tumor cells in a major histocompatibility complex (MHC)-independent manner. ⁷⁷

The DeLLphi series of studies have redefined treatment standards for second-line and later-line settings. The phase II DeLLphi-301 study confirmed durable responses in heavily pretreated patients. ⁷⁸ Subsequently, the confirmatory phase III DeLLphi-304 study demonstrated that, compared to standard second-line chemotherapy, tarlatamab significantly extended mOS to 13.6 months (vs 8.3 months), corresponding to a 40% reduction in the risk of death. Subgroup analyses revealed consistent survival benefits regardless of platinum sensitivity or prior immunotherapy exposure. ⁷⁹ Such broad efficacy is clinically significant for elderly patients with relapsed disease who otherwise face a paucity of effective options.

However, the application of BiTE therapy in the elderly population entails unique safety challenges, necessitating vigilance against the interplay between cytokine release syndrome (CRS) and age-related physiological decline. Primarily, transient hypotension or hypoxemia induced by CRS can precipitate severe hemodynamic decompensation in elderly patients with comorbid coronary artery disease or heart failure. ⁸⁰ Secondly, increased blood-brain barrier permeability and diminished baseline cognitive reserve in the elderly may lead to earlier and more severe manifestations of immune effector cell-associated neurotoxicity syndrome (ICANS); these symptoms can be easily confounded with geriatric delirium, leading to delayed diagnosis. ⁸¹ Therefore, while tarlatamab spares patients from severe myelosuppression, clinical practice mandates a risk-adapted monitoring strategy: this includes intensive cardiac monitoring during the initial dosing period, early differentiation of neurotoxicity from delirium, and a lower threshold for corticosteroid intervention, ensuring that survival benefits are balanced against the preservation of the elderly patient’s functional reserve.^79,82

Antibody-drug conjugates: Precision payload delivery and investigational development

Antibody-drug conjugates (ADCs) combine a tumor-directed monoclonal antibody, a chemical linker, and a cytotoxic payload to enable antigen-directed drug delivery.^83,84 This design provides a mechanistic rationale for increasing intratumoral payload exposure while reducing nonspecific systemic exposure compared with conventional chemotherapy; however, whether this strategy translates into a consistently wider therapeutic index in ES-SCLC, particularly in older adults, remains unproven.^83,84 At present, the clinical evidence supporting ADCs in ES-SCLC is derived mainly from early-phase studies, and no ADC has yet been approved for ES-SCLC at the time of this revision.^85,86 Among current ADC candidates, the B7 homolog 3 (B7-H3)-directed DXd ADC ifinatamab deruxtecan (I-DXd) has generated the most clinically advanced evidence in previously treated ES-SCLC, with encouraging antitumor activity reported in the phase II IDeate-Lung01 trial. ⁸⁶ Nevertheless, ADCs should not be regarded as inherently toxicity-sparing. Hematologic adverse events and interstitial lung disease (ILD)/pneumonitis remain clinically relevant safety concerns, and these risks may be amplified in older patients with limited marrow reserve, impaired pulmonary function, or comorbid chronic lung disease.^86,87 Therefore, in older adults with ES-SCLC, ADCs should be presented as emerging investigational treatment candidates whose efficacy, tolerability, and functional impact require further validation in prospective studies, rather than as established strategies that widen the therapeutic index.

Chimeric antigen receptor T-cell therapy

While chimeric antigen receptor T-cell (CAR-T) therapy has transformed the landscape of hematologic malignancies, its translation to solid tumors like SCLC faces significant biological and clinical barriers.^95,96 Despite the attractive target profile of DLL3 in SCLC, the application of CAR-T in elderly patients is impeded by unique physiological and technical challenges.

First, immunosenescence constitutes a fundamental bottleneck: the senescent phenotype and diminished diversity of peripheral T cells in elderly patients compromise the efficacy of leukapheresis, ex vivo expansion potential, and in vivo persistence post-infusion. ²¹ Second, the toxicity of lymphodepleting conditioning regimens presents a major hurdle. Standard CAR-T protocols require fludarabine/cyclophosphamide-based pretreatment to suppress host immune rejection; this poses prohibitive risks to elderly patients with diminished hematopoietic reserve, potentially precipitating prolonged pancytopenia and severe infections. ⁹⁶

Finally, regarding safety signals, elderly patients often present with limited cardiopulmonary reserve, rendering them vulnerable to the hemodynamic instability associated with CRS and the neurological sequelae of ICANS. ⁹⁷ Consequently, excluding the development of “off-the-shelf” allogeneic CAR-T products or toxicity-sparing strategies, this modality remains largely investigational rather than a viable standard of care for the geriatric SCLC population in the near term. ⁹⁸

From single scores to multidimensional assessment: Establishing a CGA-based stratified decision system

At present, in the management pathway of elderly patients with ES-SCLC, the establishment of a decision-making framework centered on CGA constitutes the cornerstone for maximizing therapeutic efficacy while minimizing TRAEs. ⁹⁹ Clinical practice should abandon the traditional model that relies solely on PS scoring. ¹⁰⁰ In practical implementation, a standardized CGA should encompass at least the following core domains, and the use of internationally recognized assessment instruments is recommended to ensure homogeneity and comparability of evaluations: (1) Functional status: assessed using the Katz Index of Activities of Daily Living (ADL) and the Lawton–Brody IADL scale^101–103; (2) Comorbidities: quantified using the Charlson Comorbidity Index (CCI) or the Cumulative Illness Rating Scale for Geriatrics (CIRS-G)^101,102; (3) Cognitive function: screened using the Mini-Mental State Examination or the Montreal Cognitive Assessment (MoCA)^104,105; (4) Nutritional status: identified using the Mini Nutritional Assessment–Short Form (MNA-SF)^106–108; (5) Psychological status: evaluated using the 15-item Geriatric Depression Scale. ¹⁰⁹ Polypharmacy and medication appropriateness should also be routinely reviewed as part of CGA, particularly in older patients with multimorbidity. In routine practice, CGA may be performed at baseline before treatment initiation and repeated at key treatment milestones to guide dynamic adjustment of therapeutic intensity and supportive interventions.

Based on the integrated findings of the CGA, patients should be precisely stratified into three categories—Fit, Vulnerable, and Frail (Figure 2, Table 3)—to determine the appropriate gradation of treatment intensity. ¹⁰⁰ For Fit patients who are independent in ADL/IADL, have limited comorbidities, and demonstrate preserved cognitive function, physiological reserve is considered adequate, and standard-intensity immunotherapy combined with platinum-based doublet chemotherapy may be considered in pursuit of maximal therapeutic benefit. ¹¹⁰ For Vulnerable patients with potentially reversible impairments in one to two CGA domains, priority should be given to dose-adjusted chemotherapy regimens, sequential or maintenance immunotherapy strategies, accompanied by proactive prevention of treatment-related toxicities.^111–113 In contrast, for Frail patients with severe multidimensional impairments (e.g., marked dependence in ADL and a high burden of comorbidities), the therapeutic objective should be shifted toward best supportive care or symptom-directed management, with emphasis on improving quality of life.^100,113

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Figure 2.

Proposed algorithm for CGA-guided holistic management and stratified treatment in elderly ES-SCLC. The flowchart illustrates the core decision-making pathway centered on CGA. Step 1: Patients undergo CGA to determine functional reserve. Step 2 (Stratification): Patients are categorized into “Fit,” “Vulnerable,” or “Frail” subgroups. Step 3 (Intervention):

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Table 3.

Proposed framework for CGA-based stratified management in elderly ES-SCLC.

Functional category	CGA characteristics	Therapeutic goal	Recommended first-line strategy	Supportive care and prehabilitation focus
Fit	• ADL independent	Maximize survival and preserve functional status	Standard-intensity chemoimmunotherapy with platinum-etoposide plus a PD-L1/PD-1 inhibitor, accompanied by CGA-informed toxicity monitoring.	Standard monitoring; patient education on immune-related adverse events.
	• No significant comorbidities
	• Normal cognitive function
Vulnerable	• Mild dependence in IADL	Survival benefit with tolerance optimization	Intensity-adapted strategy:	“Prehabilitation”:
	• Controlled comorbidities		• Full dose with G-CSF support OR	• Polypharmacy deprescribing.
	• Mild cognitive impairment		• Initial dose attenuation may be considered, such as carboplatin AUC 4–5 combined with etoposide at 75%–80% of the standard dose; for patients with CrCl 15–50 mL/min, etoposide 75% dosing is preferred. Subsequent escalation or further reduction should be guided by cycle-1 toxicity, hematologic recovery, renal function, and CGA reassessment.	• Nutritional support for sarcopenia.
				• Close monitoring of renal/cardiac function.
Frail	• Dependence in ADL	Symptom control/quality of life	Palliative approach:	Palliative care integration:
	• Major uncontrolled comorbidities		• BSC.	• Symptom management (pain, dyspnea).
	• Significant geriatric syndromes (falls, dementia)		• Consideration of monotherapy or dose-attenuated chemotherapy only if highly symptomatic.	• Advance care planning.
				• Caregiver support.

ADL, activities of daily living; AUC, area under the curve; BSC, best supportive care; CGA, comprehensive geriatric assessment; CrCl, creatinine clearance; ES-SCLC, extensive-stage small-cell lung cancer; G-CSF, granulocyte colony-stimulating factor; IADL, instrumental activities of daily living; OR, odds ratio; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1.

Concurrently, longitudinal management requires clinicians to implement precise interventions throughout the entire treatment continuum, including rigorous medication reconciliation and deprescribing in accordance with the Beers Criteria ¹¹⁴ ; enhancement of muscle reserve and physical performance through nutritional support and exercise-based rehabilitation for patients in whom deficits are identified by MNA-SF or ADL/IADL assessments ¹¹⁵ ; timely management of cardiovascular and metabolic comorbidities based on CCI or CIRS-G evaluation results; and early recognition and prompt management of irAEs, which may present more insidiously in elderly patients.^116,117

Optimization of the chemotherapy backbone: Balancing platinum selection and dose intensity

Although chemoimmunotherapy has established its first-line status, cytotoxic chemotherapy remains an essential backbone of systemic treatment for ES-SCLC. Given the physiological characteristics of elderly patients, such as declined glomerular filtration rate and increased susceptibility to ototoxicity and neurotoxicity, the formulation of chemotherapy regimens must strike a balance between “dose intensity” and “organ protection.” ¹³ Existing evidence strongly supports carboplatin as the preferred platinum agent for elderly ES-SCLC. A meta-analysis comprising 663 SCLC patients indicated that carboplatin is non-inferior to cisplatin regarding OS benefits but exhibits a significantly superior safety profile ¹¹⁸ ; real-world evidence from the SEER database further corroborates that the carboplatin-etoposide regimen significantly reduces treatment-related renal and neurological toxicities without compromising OS.^119,120 Consequently, the use of cisplatin should be restricted to a highly select minority of “Fit” elderly patients with intact organ function. ¹¹⁸ Furthermore, dosing flexibility is a critical clinical strategy. A retrospective study suggests that a “toxicity-guided” dose adjustment strategy—dynamically adjusting doses or extending cycle intervals based on patient tolerance—may compromise short-term ORRs but significantly lowers treatment-related mortality, ultimately improving OS by preserving treatment continuity. ¹²¹ This implies that in the geriatric population, maintaining the integrity of treatment cycles is more critical than adhering to peak dose intensity.

Bridging the evidence gap: Translation of novel therapies and pragmatic trials

Novel immunotherapeutic combinations, such as ADCs and bispecific antibodies, bring therapeutic potential to ES-SCLC, yet the “evidence gap” remains the primary bottleneck restricting their precise implementation in the elderly. ⁶ Due to the prevalence of physiological aging, multiple comorbidities, and declined organ reserve, the pharmacokinetic parameters and maximum tolerated dose established in younger populations often cannot be directly extrapolated to the elderly. ¹²² Therefore, filling this void is an urgent priority, and future research paradigms must undergo fundamental transformation. First, traditional RCTs should mandate the incorporation of CGA-based stratification factors and actively recruit “Vulnerable” and “Frail” subgroups to comprehensively assess safety boundaries under real physiological conditions. ¹²² Second, “Pragmatic Clinical Trials (PCTs)” and adaptive designs should be prioritized, relaxing comorbidity restrictions to better mirror real-world clinical scenarios. ¹²³ Finally, a geriatric-specific pharmacovigilance system should be constructed utilizing real-world data, focusing on monitoring occult risks such as ADC-induced pulmonary toxicity and immunotherapy-related myocarditis.^124,125 By constructing a closed-loop evidence system of “RCT confirmation + RWE supplementation,” the field can ultimately achieve the precise, safety-optimized, and individualized application of novel antitumor therapies in elderly ES-SCLC patients.