Redefinirea momentului inițierii îngrijirilor paliative în cancerul avansat și metastatic: de la praguri prognostice la integrare concomitentă ghidată de nevoi pe parcursul traiectoriei terapeutice

Introduction

In contemporary oncology, palliative care is increasingly defined as an integral and longitudinal component of the management of patients with cancer, recommended for early initiation and concurrent integration with active antineoplastic therapies^(1-3). This reconceptualization moves beyond the traditional paradigm centered exclusively on terminal phases and positions palliative care as a complementary intervention aimed at limiting overall suffering, preserving functional status and facilitating a coherent therapeutic trajectory adapted to the individual clinical profile. The literature published after 2020 highlights an expansion of the role of palliative care beyond the control of refractory symptoms, encompassing systematic monitoring of treatment-related toxicities, early intervention for adverse effects and support for clinical decision-making within a context characterized by evolving uncertainty and therapeutic variability^(3,4,7). In advanced and metastatic cancer, symptom burden frequently results from the interaction between disease progression and the cumulative toxicities of systemic or locoregional treatments^(7-10). Pain, dyspnea, fatigue and psycho-emotional distress directly affect functional autonomy and quality of life, requiring repeated assessment and adaptive interventions^(8,11,15).

Within this framework, palliative care is increasingly utilized as a mechanism of clinical stabilization, without competing with active oncologic strategies^(1,3). Recent consensus documents and international guidelines emphasize its needs-based and function-oriented character, independent of rigid prognostic thresholds^(1,2). Consequently, practical attention shifts from questioning the necessity of palliative care to identifying the optimal timing and operational criteria that justify its initiation.

Nevertheless, delays in referral remain frequent. In real-world practice, many patients are directed to palliative services only after episodes of symptomatic decompensation, unplanned hospitalizations or advanced functional decline, circumstances in which the potential to influence the overall clinical trajectory is reduced^(6,9,12). Although palliative intervention remains essential for alleviating suffering, its longitudinal impact is more limited compared with early and concurrent integration^(4-6). 

Accordingly, recent literature describes a conceptual transition from models dependent on temporal benchmarks or prognostic estimates toward approaches guided by clinical needs and concrete triggering indicators. These include persistently insufficiently controlled symptoms, recurrent toxicities requiring repeated therapeutic adjustments, progressive deterioration of functional status, unplanned use of healthcare services and decisional uncertainty during critical therapeutic transitions^(3,4,13,14). This model supports anticipatory oncology-palliative integration, with a proactive role in maintaining functional status and ensuring continuity of care^(4,7).

Aim

The objective of this narrative review is to critically examine the literature published between 2020 and 2025 concerning the timing of palliative care initiation in patients with advanced locoregional or metastatic cancer. The analysis focuses on the relationship between the temporal positioning of palliative intervention and clinically relevant outcomes, including symptom control, management of treatment-related toxicities, preservation of functional status and prevention of episodes of clinical instability^(3-6,9).

In particular, the review aims to identify clinically actionable reference points that may support needs-based and appropriately timed integration. These reference points include disease extent and dynamics, functional performance status, transitions between therapeutic lines and periods of vulnerability associated with systemic or locoregional therapies. Additionally, contemporary models of oncology-palliative integration described in recent literature are examined in order to highlight operational approaches to the implementation of concurrent care^(4,7-9,14).

The analysis seeks to clarify the mechanisms through which early initiation and concurrent integration of palliative care may enhance the cumulative benefit of intervention along the therapeutic trajectory and reduce the frequency of delayed referrals that limit its impact on clinical evolution and the decision-making process.

Methodology

This manuscript is designed as a narrative review with the aim of providing a clinically oriented, critically integrated synthesis of recent evidence regarding the optimal timing of palliative care initiation in oncology. The narrative format allows contextual interpretation in a field characterized by conceptual heterogeneity, differences in the definition of “integrated palliative care” and organizational variability dependent on available resources and patient population characteristics^(4,6).

Publications issued between 2020 and 2025 were included, encompassing international guidelines and consensus documents, randomized clinical trials, observational studies and real-world analyses. The selection process targeted studies explicitly addressing the temporality of palliative care initiation and outcomes of direct clinical relevance: symptom burden, functional status, phases of oncologic treatment, healthcare utilization, continuity of care and treatment tolerability^(3-7,12,14). The analytical framework focused on identifying periods of vulnerability along the clinical trajectory in which palliative intervention may exert a preventive and stabilizing role, rather than functioning solely as a late-stage intervention. Particular attention was given to evidence supporting the transition from predominantly prognosis-based referral models to integration strategies guided by clinical needs and operational trigger indicators^(4,7-9).

Results

1. Conceptual reframing of palliative care in oncology

Recent literature documents a substantial shift in the paradigm of palliative care in oncology. Modern consensus definitions and updates of international guidelines mark the transition from a model reserved for end-of-life stages to an integrated approach delivered concurrently with active anticancer treatments^(1-3). In this new conceptual framework, palliative care is described as an active, flexible, needs-based clinical intervention that does not imply abandonment of therapeutic intent. The integration models discussed below further reinforce the complementary role of palliative care in improving treatment tolerability, preventing functional decline and supporting decision-making along a dynamic clinical pathway^(3,4,7). This reframing supports a shift in emphasis from justifying the need for palliative care to identifying the optimal timing for its initiation.

2. Contemporary models of oncology-palliative care integration

The analysis highlights a range of organizational models, while effective approaches share two common elements: early identification of needs and longitudinal monitoring^(4,6). Specialist palliative consultation “on demand” remains widely used; however, its effectiveness is substantially enhanced when the initial assessment is followed by scheduled follow-up visits, particularly for patients with high symptom burden or cumulative toxicities^(4,7). In this context, follow-up facilitates early interventions for pain and other treatment-related symptoms, consistent with current management recommendations⁽¹⁵⁾. Co-location of palliative services within oncology clinics reduces fragmentation of care and enables intervention before symptoms become refractory^(4,7). The shared-care model expands access by developing core palliative competencies within the oncology team, with escalation to specialist palliative care for complex cases^(6,10). An increasingly pragmatic direction in the recent literature is initiation based on trigger indicators and risk criteria: persistent symptoms, recurrent toxicities, repeated treatment adjustments, unplanned hospitalizations or progressive functional decline^(3,4,13,14). Embedding these signals into standardized referral algorithms reduces decisional variability and limits exclusively reactive integration^(4,6,9). Overall, these models reflect a transition toward anticipatory palliative care focused on stabilizing the clinical course and aligning care with patients’ goals^(3,4,7).

3. Integration of palliative care according to disease stage

The timing of initiation varies by clinical context and disease stage. In early-stage disease, palliative care is not routinely indicated, but may be introduced selectively when toxicities or symptoms disproportionately impair functioning^(3,4). In locoregionally advanced disease, early integration enables systematic monitoring of tolerance to intensive therapies and adaptive interventions before functional decline occurs, supporting continuity of the oncology strategy^(4,7,15). In metastatic disease, concurrent initiation with systemic treatment provides longitudinal support and enables anticipation of symptom complications, reducing the perception of palliative care as limited to terminal phases^(3,4,7,9,11). In settings of severe clinical deterioration, palliative care remains essential for refractory symptom control and decision support; however, its capacity to influence the overall trajectory is generally reduced compared with anticipatory integration^(4-6,9,12).

4. Needs-guided initiation and trigger indicators

Recent literature supports a shift from models dependent on chronological benchmarks or prognostic estimates toward approaches centered on clinical needs^(1-3). Operational trigger indicators include inadequately controlled symptoms, recurrent toxicities requiring repeated treatment adjustments, progressive functional decline, unplanned hospitalizations and decisional uncertainty during critical therapeutic moments^(3,4,13,14). Repeated assessment of symptoms, their impact on daily activities and psychological distress facilitates the identification of patients entering a potentially preventable phase of vulnerability^(8,11,14). Systematic integration of these signals into clinical workflows reduces delays and decisional variability^(4,6,9).

5. Impact of early integration: clinical evidence

Data from randomized and observational studies indicate that early integration yields benefits extending beyond isolated symptom relief, contributing to clinical stabilization and improved coordination of care^(3-5,7). Early initiation has been associated with lower levels of inadequately controlled symptoms and better adaptation to oncologic treatments at stages when the therapeutic plan remains adjustable^(3,9,11). Real-world evidence further demonstrates reduced unplanned health care utilization and improved continuity of care when palliative care is integrated early^(6,12). In contrast, late referral restricts the scope of intervention and diminishes its influence on the overall clinical trajectory^(6,9,12).

6. Functional status as an operational determinant of initiation timing

Functional status is consistently recognized as a major indicator of prognosis and treatment tolerance, and it is increasingly recommended as a practical benchmark for initiating palliative care^{(3,4,6,10,13)}. Although instruments such as the ECOG performance status have traditionally been used for prognostic stratification, recent literature supports expanding their role beyond outcome estimation, proposing their use as early signals to trigger palliative interventions^(4,14). Observational and implementation data suggest more consistent benefits when palliative care is introduced before the onset of severe functional decline, compared with delayed referral^(4,9,12). When patients retain partial autonomy and decision-making capacity, interventions may contribute to preserving functionality, reducing frailty and optimizing tolerance to oncologic therapies^(7,11).

Functional decline often follows a progressive course, reflecting the interaction between disease progression and cumulative treatment toxicities. Early integration of palliative care enables multidisciplinary interventions capable of slowing deterioration, limiting symptom escalation and stabilizing functional performance. Early measures – including symptom control, nutritional support and psychosocial interventions – may prolong periods of relative autonomy and support adaptation to treatment^(8,14,15). Conversely, the initiation in the context of profound functional impairment confines intervention predominantly to refractory symptom control and comfort care. Although clinically and ethically indispensable, its capacity to influence the overall trajectory becomes more limited. This supports framing functional status not as a late eligibility threshold, but as an active determinant of optimal timing for integration^(4,6,9).

7. Functional status and oncology-palliative care concurrency in optimizing the therapeutic trajectory

In contemporary oncology, functional status may be interpreted as an integrative indicator of the balance among disease burden, treatment intensity and the patient’s biological reserve. Beyond its prognostic value, it directly influences treatment tolerance, recovery after toxicities and engagement in decision-making. Subtle functional changes often precede overt clinical deterioration and may signal the opportunity for anticipatory palliative integration^(4,7,10). Repeated functional assessment – whether through standardized tools or longitudinal clinical monitoring – facilitates early detection of vulnerabilities at a stage when interventions may prevent accelerated frailty. From this perspective, palliative care is not deferred until loss of autonomy, but it is employed to preserve functionality and reduce the risk of decompensation. Initiation at a stage when the patient retains decisional capacity supports treatment adaptation and enhances alignment of therapeutic goals^(3,4,7).

The therapeutic trajectory includes periods of heightened vulnerability, such as initiation of systemic treatment, escalation of therapeutic regimens, transitions between treatment lines or cumulative toxicities. During these phases, functional decline may be abrupt, and the integration of palliative care in proximity to such events enables prevention of complications and timely adjustment of the oncologic strategy before toxicities become dose-limiting^(4,7,12).

Oncology-palliative concurrency represents a strategy to reduce the cumulative burden generated by both disease and treatment. Palliative interventions – including management of emerging symptoms, nutritional support, fatigue management and psychosocial care – enhance tolerability and decrease the likelihood of treatment interruptions or premature dose reductions^(4,7,15). Early integration also influences the toxicity profile through systematic monitoring and rapid intervention for incipient adverse effects. This approach facilitates differentiation between disease progression and treatment-related toxicity and enables proportional, appropriately timed adjustments. By preventing escalation to severe toxicity grades, palliative care may reduce hospitalizations and limit the need for major modifications to the oncologic plan^(4,12). Concurrent integration additionally impacts psychological distress associated with oncologic therapy. Anxiety, depression and uncertainty may amplify symptom perception and diminish treatment tolerance even in the absence of objectively severe toxicities. Early psychological and educational interventions can mitigate this distress and enhance coping capacity^(8,11). Through these interconnected mechanisms, integrated palliative care indirectly supports continuity of oncologic treatment, facilitating progression through planned therapeutic lines within a more stable and less reactive framework. In contrast, initiation in the setting of advanced functional decline restricts intervention primarily to symptom control and comfort care, with modest influence on the global therapeutic trajectory^(4-6,9). Overall, aligning functional assessment with key therapeutic milestones and implementing concurrent palliative integration reflects the transition from a late, reactive model toward an anticipatory strategy focused on preserving functionality and ensuring continuity of care^(3,4,7).

Discussion and clinical implications

1. Timing as a modifiable clinical variable

Literature published after 2020 increasingly supports the view that the timing of palliative care initiation is not merely an organizational issue, but a clinical determinant with direct impact on the trajectory of patients with advanced or metastatic disease^(3,4,6,7). The difference between early and late integration does not lie exclusively in the severity of symptoms treated, but in the presence or absence of a window of opportunity in which problems can be anticipated, monitored, and prevented. When palliative care is introduced before the escalation of toxicities and episodes of instability, there is room for proportional adjustments and adaptive interventions. In contrast, the initiation in the context of major functional decline implies intervention against a background of diminished biological reserve and restricted decisional options, with a more limited impact on overall evolution^(4-6,9,12).

2. The limits of prognostic thresholds in modern oncology

A recurrent element in recent studies is the limited effectiveness of strictly prognostic criteria in the context of modern oncologic therapies and heterogeneous trajectories. Survival estimation remains imprecise, and the use of rigid temporal thresholds may delay access to palliative care precisely during the period in which it could prevent functional deterioration and intensification of toxicities or unplanned use of healthcare services^(4,7,12). Consequently, a needs-oriented initiation model is emerging, correlated with disease stage, functionality and vulnerable treatment moments^(3,4,6,10). Within this framework, palliative care functions as a mechanism of stabilization and continuity; when introduced in a crisis context, the intervention often remains limited to acute symptom control, without accumulation of longitudinal benefits^(6,9,12).

3. Functionality and toxicity: a bidirectional relationship

Evidence supports the central role of functional status in the decision-making process, as it reflects biological reserve and the patient’s capacity to tolerate both disease and treatment simultaneously^(4,7). Functional declines may signal an emerging imbalance between therapeutic benefit and clinical burden, even in the absence of evident imaging or biological changes^(4,10). Toxicity directly contributes to this imbalance: acute or cumulative adverse reactions may accelerate decline, while functional frailty increases vulnerability to toxicity. Palliative integration, through continuous monitoring and adaptive interventions, may interrupt the toxicity-functional decline cycle and support treatment tolerability^(4,7,15). Within this paradigm, initiation of palliative care does not represent a signal of oncologic failure, but an anticipatory intervention when the ratio between treatment intensity and tolerance capacity becomes precarious^(3,4,7). 

4. Quality of clinical decisions

The timing of initiation directly influences the quality of dialogue regarding goals of care. When the patient has sufficient functional and emotional resources, discussions about the benefit-risk ratio can be structured, progressive and better aligned with individual preferences^(4,7,11). In contrast, late referral shifts these conversations into contexts dominated by instability and distress, reducing real options and increasing the likelihood of reactive decisions^(4,6,9).

5. Integration models: facilitators and barriers

Recent literature describes integration models influenced by resource availability. Although specialized palliative care remains essential for complex cases, limited access may determine initiation at a moment dictated by capacity rather than clinical necessity^(4,6,7). The development of basic competencies within oncology teams (primary palliative care) is reported as a pragmatic solution for reducing delays^(6,10). Implementation data suggest that this model accelerates initiation and reduces dependence on late referral^(9,13). Hybrid models are effective when supported by clear operational criteria and stable communication channels; in their absence, integration remains episodic^(4,6,9). 

6. Major practical and clinical implications

The planned and early integration of palliative care into the management of advanced or metastatic cancer represents an evidence-supported clinical intervention^(3,4), and its timing should be regarded as a modifiable parameter with direct impact on symptom control, preservation of functional status, and the quality of therapeutic decision-making. Early identification of patients at risk of cumulative toxicities, incipient functional decline or psychosocial distress – and the initiation of palliative care prior to the onset of symptomatic refractoriness – enable optimization of oncologic treatment tolerability and reduction of unplanned healthcare utilization^(4,7,11,15).

Functional status should be interpreted as an early clinical warning signal of a potential imbalance between treatment intensity and adaptive capacity. Referral should therefore be guided by objective indicators of clinical need (persistent symptoms, repeated treatment adjustments, unplanned hospitalizations, decisional uncertainty), rather than relying exclusively on rigid prognostic thresholds. Longitudinal integration, supported by systematic screening tools and telemedicine solutions in resource-limited settings^(12,14), distinguishes a preventive strategy – aimed at maintaining stability and therapeutic continuity – from a delayed, predominantly reactive intervention in the context of severe clinical decline^(4,6,9). 

7. Organizational and policy relevance

Implementation studies show that standardization of palliative care initiation is associated with reduced unplanned hospitalizations, shorter length of stay and fewer emergency department visits, without compromising oncologic objectives^(6,9,12,13). Therefore, early integration has not only clinical but also organizational implications. At the policy level, inclusion of palliative care in standardized oncology care pathways and its integration into quality indicators are proposed as strategies to reduce inequalities and variability of practice^(2,4,6,10).

Limitations

The comparability of studies is limited by heterogeneity in definitions of “early palliative care,” diversity of interventions and differences among analyzed populations^(4,6,9). The effects on survival are context-dependent and cannot be uniformly extrapolated across tumor types or therapeutic scenarios^(7,12). Differences in resources across systems may influence the magnitude of reported benefits^(6,9). By its nature, the narrative review prioritizes conceptual integration and clinical translation over procedural exhaustiveness; the robustness of conclusions relies on convergence of evidence from independent sources^(4-6,8,13).

Future directions

Implementation studies are needed to test standardized initiation algorithms integrated into the oncologic workflow, including disease stage, functionality, therapeutic moments and trigger indicators^(6,10,13).

Analyses by tumor subgroups and evaluations in the context of emerging therapies, characterized by different toxicity profiles, are also necessary^(7,12). Screening tools require continuous validation to reduce variability and increase equity of access⁽¹⁴⁾. Direct comparisons between early and late integration should use endpoints centered on functionality, toxicities, coordination and resource utilization, in order to allow translation of recommendations into algorithms applicable in real-world practice^(9,12,13).

Key message

In contemporary oncology, the timing of palliative care initiation must be understood as a modifiable clinical variable, with direct impact on the stability of the therapeutic trajectory. Converging evidence supports the transition from models predominantly based on prognostic thresholds toward strategies of concurrent integration guided by clinical needs, functionality and therapeutically vulnerable moments. Early integration, at a stage in which symptomatology and toxicities are still susceptible to anticipation and adjustment, allows proportional interventions, maintenance of autonomy and optimization of oncologic treatment tolerability. Within this framework, palliative care does not represent a stage of therapeutic withdrawal, but a mechanism of stabilization and continuity of care. Correlating functional assessment with indicators of instability and with therapeutic transitions provides an operational model applicable in real-world practice, capable of reducing decisional variability and preventing the exclusively reactive use of palliative care. Thus, redefining the timing of initiation becomes not only a procedural adjustment, but a paradigm shift oriented toward maintaining functionality, coherence of clinical decisions, and efficient use of resources throughout the entire course of the disease.

Conclusions with clinical relevance

1. The clinical impact of palliative care is maximal when integration occurs within a time interval in which symptomatology and toxicities remain susceptible to anticipation and influence, not exclusively to late manage­ment, after the installation of significant functional decline.

2. In the context of contemporary oncology, the exclusive use of prognostic criteria for referral to palliative care is insufficient. The variability of disease trajectories and the limits of survival prediction may delay access to an intervention with preventive and stabilizing potential.

3. Functional status must be considered a central reference point in the initiation decision. Early performance changes may reflect an emerging imbalance between treatment intensity and individual tolerance capacity, justifying anticipatory palliative integration.

4. Cumulative toxicities and therapeutic instability – manifested through repeated dose adjustments, treatment interruptions or unplanned presentations – constitute relevant operational indicators for including palliative care as a mechanism for stabilizing the clinical course.

5. Therapeutic transitions such as the initiation of a new line of treatment, disease progression or modification of therapeutic intent represent periods of increased vulnerability in which longitudinal palliative integration is particularly appropriate.

6. Independent of the organizational model adopted, structures that include periodic reassessment and longitudinal monitoring are associated with superior symptom control and reduced risk of premature discontinuation of oncologic treatment.

7. Through multidimensional interventions – symptom control, nutritional support and psychosocial approach –, palliative care initiated early may improve treatment tolerability and prevent escalation of toxicities that would impose major modifications of the therapeutic strategy.

8. Real-world data suggest more efficient resource utilization when palliative care is integrated before advanced functional decline, evidenced by reduction of unplanned hospitalizations and emergency department presentations, without compromising oncologic objectives.

9. Early integration creates a favorable framework for structured discussions regarding patient goals and preferences, whereas late initiation shifts the decisional process into contexts dominated by instability and optional constraints.

10. Standardization of initiation criteria – including functionality, toxicity profile, clinical instability and key therapeutic moments – into explicit referral algorithms may reduce practice variability and prevent the use of palliative care exclusively as a last-resort intervention.   

Author contributions: All authors contributed equally to the development of this study.

Corresponding author: Anda-Elena Crișan E-mail: anda_crisan2005@yahoo.com

Conflict of interest: none declared.

Financial support: none declared.

This work is permanently accessible online free of charge and published under the CC-BY licence.