Top Ten Tips Palliative Care Clinicians Should Know About Prognostication in Oncology,Dementia,Frailty,and Pulmonary Diseases

Abstract

Prognostication has been described as “Medicine's Lost Art.” Taken with diagnosis and treatment, prognostication is the third leg on which medical care rests. As research leads to additional beneficial treatments for vexing conditions like cancer, dementia, and lung disease, prognostication becomes even more difficult. This article, written by a group of palliative care clinicians with backgrounds in geriatrics, pulmonology, and oncology, aims to offer a useful framework for consideration of prognosis in these conditions. This article will serve as the first in a three-part series on prognostication in adults and children.

Introduction

Determining and sharing prognosis is widely considered one of the three primary functions of the medical profession. The overall goal of estimating and communicating prognosis is to improve patient-centered clinical decision making and, ultimately, ensure that patients' care matches their goals, values, and preferences.

In this article, we will focus on oncology, dementia, frailty, and pulmonary diseases. All palliative care (PC) clinicians should become familiar with these tools, understand their strengths and weaknesses, and use them appropriately. To do so, we draw upon a team of physicians and nurse practitioners with training in various backgrounds such as geriatrics, palliative medicine, oncology, ethics, psychiatry, and pulmonary medicine to shed light on those important topics in the following “Top 10” tips.

Tip 1: Accurate Prognostic Understanding, Which Can Be Framed Around Function, Time, or Uncertainty, Influences Patient/Family Decision Making and Use of Intensive Medical Care at the End of Life; Specifically, Patients Who Report Accurate Prognostic Understanding Are Less Likely to Receive Aggressive End-of-Life Care

A significant proportion of patients with advanced cancer hold inaccurate perceptions of prognosis and goals of treatment.¹ Patients with advanced cancer who have serious illness discussions about prognosis, goals, and values are more likely to receive care directed at symptom management and quality of life.² In contrast, patients who overestimate their prognosis are more likely to choose and receive intensive therapy at the end of life.³ Patients who have upstream discussions about prognosis, goals, and values are also more likely to receive goal concordant care.⁴ Thus, the importance of serious illness communication between patients with advanced cancer and their clinicians cannot be overstated.

Discussions about cancer prognoses that starts early in the trajectory of illness allow for an iterative and gentle approach to prognostic communication. Clinicians often fear the emotional impact of a time-based prognosis; recent work suggests that prognoses framed around future function or uncertainty are acceptable and feasible and can help guide decision making for patients and families.^5,6 Communication interventions to improve the frequency and timing of goals of care discussions or quality of communication comprise strategies to improve the delivery of primary PC by oncology clinicians.^6,7 However, there are not yet sufficient data to suggest that primary PC can replace PC specialists and more research is needed around how best to partner oncology and PC services to enhance the quality and timing of prognostic communication.

Tip 2: Novel Therapies Such as Immunotherapy Are Often Considered “Less Toxic” When Compared to Cytotoxic Chemotherapy by Patients and Clinicians Alike; Due to Difficulties Knowing Which Patients Will Enjoy an “Exceptional Response,” Immunotherapy Administered to Frail and Declining Patients May Serve as a Barrier to High Quality End-of Life-Care (i.e., Hospice Care)

A minority of patients will have an exceptional response to immunotherapy, and may have prolonged survival.⁸ However, prediction of exceptional responses to immunotherapy has become increasingly challenging. The most commonly used predictive biomarker for sensitivity to immune checkpoint inhibitors (ICIs), programmed death-ligand 1 (PDL-1), is at best an imperfect tool. In the last decade, there have been 45 approvals from the United States Food and Drug Administration (FDA) for ICIs across 15 cancer diagnoses.⁹

Among all immunotherapies approved during this time, PDL-1 was a predictive biomarker in <30% of cases, not predictive in ∼50% of cases, and not tested in about 18% of cases.⁹ The uncertainty of predictive capabilities has made prognostication even more challenging in the immunotherapy era. There is also uncertainty about the safety of ICIs in cohorts of patients who may be at higher risk for immune-related adverse events (transplant recipients on immunosuppressive medications, and underlying autoimmune conditions), and those patients who have other comorbid conditions leading to poor performance status.^8,10

There is a lack of consensus guidelines on risk stratification for immune related adverse events in these higher-risk populations, leaving individual clinicians to navigate these nuanced discussions. Additionally, there are data showing that immunotherapy in the last weeks of life among those with poor performance status is associated with worse survival, lower rates of hospice enrollment, and higher chance of in-hospital death.¹¹ These data suggest that immunotherapy administered to patients with advanced cancer and poor performance status may not result in high quality end-of-life care.

Tip 3: In Cancer Treatment, Marital or Partnered Status Correlates Positively with Survival While Acute Thromboembolic Events, Leptomeningeal Disease, and Hypercalcemia of Malignancy Correlate Negatively

Understanding positive and negative associations of outcomes of cancer treatment can help PC clinicians better identify who is more likely to benefit from therapy and how to prognosticate accordingly. Patients with optimized socioeconomic support tend to do best with treatment, and evidence suggests across a variety of tumor types that married or partnered status is protective and correlates with improved survival.

Other factors portend a worse prognosis and must be considered. Acute thromboembolic events remain a major issue in terms of cancer-related morbidity and mortality. Whether thrombosis is related to catheters, antineoplastics, or intrinsic hypercoagulability, and location of the thrombosis, may alter length of anticoagulation recommended and associated mortality risk. Given this complexity, National Comprehensive Cancer Network guidelines highlight the need to be aware of emerging evidence for prophylaxis and treatment of thromboembolism, including direct oral anticoagulants.¹²

Leptomeningeal disease (LMD) remains a marker of very poor overall prognosis. Regardless of cancer type, most antineoplastics cross the blood-brain barrier poorly limiting penetration. Patients with LMD often have advanced neurocognitive defects, which do not improve with treatment; radiation may worsen these effects. Intrathecal chemotherapy, whether intermittent with lumbar puncture or via Ommaya reservoir, does not appear to appreciably change overall prognosis and should be avoided. Even for diseases like breast cancer where marked improvement in systemic treatment options and overall survival have been observed, LMD still has a poor prognosis averaging three to four months.¹³ Considering all cancers, estimated prognosis in LMD is two to six months with treatment and lower (four to six weeks) with expectant management only. Foregoing palliative treatment may be reasonable unless markers of human epidermal growth factor receptor 2 (HER-2) expression, epidermal growth factor receptor (EGFR) mutation, or anaplastic lymphoma kinase (ALK)-gene rearrangements are noted.

Finally, hypercalcemia of malignancy is frequently encountered either from osseous metastatic lesions or humoral hypercalcemia of malignancy. Hypercalcemia in the setting of breast cancer and multiple myeloma may be observed in earlier stage or more treatable disease. However, patients with humoral hypercalcemia of malignancy who develop refractory hypercalcemia of malignancy have an overall poor prognosis, with 50% mortality risk within the first month from diagnosis.^14,15

Tip 4: Sometimes Prognosis Is Longer Than Would Be Predicted Based on Functional Status or Line of Chemotherapy; Those with Metastatic Breast Cancer, Newly Diagnosed Extensive Stage Small Cell Lung Cancer, and Tumors with Targetable Genetic Mutations Can Live Longer than Clinicians Expect

In the era before targeted therapy/immunotherapy, prognosis was based on response to cytotoxic therapy. Without effective treatment, the disease would take its course and lead to death. In melanoma, there was no agent that prolonged life substantially and in almost all metastatic cancers median survival was below two years.¹⁶ Cancers responsive to hormone therapy, such as breast or prostate cancer have had a substantially better prognosis.¹⁷

Immunotherapy led to a change of paradigm and to long lasting or ongoing therapeutic responses in some patients. Response rates can be over 50% and five-year survival over 20% even in the metastatic stage. However, signs of poor prognosis, such as very low performance status, are equally valid in those receiving immunotherapy.¹⁸

Specific predictors of response to immunotherapy are scarce. A substantial percentage will not respond to immunotherapy and will require end-of-life care and die. Therefore, prognostic uncertainty has increased for oncologists and palliative specialists.^19,20 The before/after model of oncology and PC (first tumor specific therapy, then symptomatic care) has ultimately lost its rationale.²¹ Therefore, it is necessary to offer PC to those in need, sometimes quite early in the disease trajectory. Dialog and mutual acknowledgement—signs of poor prognosis for the oncologists, dramatic responses in some patients for the PC physician—further quality-focused collaborative care.

Tip 5: Artificial Hydration and Blood Transfusions May Benefit Some Patients with Cancer Near the End of Life; However, Such Treatments Must Be Balanced Against Possible Drawbacks

Decisions about the provision or limitation of blood transfusions and/or artificial hydration in clinical practice often give rise to debates among health care professionals and with patients and their relatives. This discussion is not surprising, as blood transfusions and hydration carry considerable symbolic meaning. In addition, there is scant evidence regarding benefits and harms of these treatments.

In a recent review—not restricted to, but including studies on cancer patients—Kingdon et al.²² point out that there are not only different views on benefits and burdens around hydration at the end of life,^23,24 but also heterogeneous practices with regards to such treatments.²⁵ In a multicenter randomized clinical trial, Bruera et al. did not find any differences in symptoms of patients receiving 100 or 1000 mL of hydration.²⁶ At the same time, there are indications, though no confirmatory data, that during the last days of life, hydration may reduce frequency and severity of delirium while putting patients at risk of fluid retention symptoms.²³

Concerning the effects of blood transfusions, Preston et al. have summarized and critically appraised the evidence in a Cochrane review.²⁷ While some before/after studies show short-term benefits regarding fatigue, there is an overall lack of high quality studies. This lack of data also makes it impossible to determine possible harm associated with transfusions like fluid overload or increase of viscosity. In conclusion, decisions about hydration and blood transfusions are challenging due to lack of evidence and due to values and meanings attributed to these treatments. Accordingly, individualized approaches, taking into account uncertainty and heterogeneous values of patients, relatives, and health care professionals, are recommended.

Tip 6: Prognostication of Remaining Life Expectancy in Dementia Remains Difficult and Is Dependent on Dementia Type, Age, Comorbidities, and Other Variables

Besides prognostication of cognition, daily-life functioning, and time to institutionalization, prognostication of survival time is of fundamental importance for care planning in dementia. Overall, dementia is associated with high mortality. In a Dutch nationwide hospital-based cohort of patients with clinical diagnosis of dementia, one-year mortality was 38.3% in men and 30.5% in women—higher than in patients admitted for acute myocardial infarction, heart failure, or stroke.²⁸ Our ability for individual prognosis in dementia remains limited. However, a recent systematic review on mortality risk models for persons with dementia identified two models with reasonable applicability and risk of bias.²⁹

One of these models is based on nationwide data on persons with incident dementia in Sweden.³⁰ The median survival time from dementia diagnosis (at median age 81.6 years) was 5.1 years for women and 4.3 years for men. Higher age, male sex, higher comorbidity burden and lower cognitive function at diagnosis, a diagnosis of non-Alzheimer's dementia, living alone, and using more medications were associated with higher mortality. The model predicted three-year survival after dementia diagnosis with good accuracy. The original publication includes three-year survival probability tables that can be a helpful basis for clinical discussion.

The other model, the Advanced Dementia Prognostic Tool (ADEPT), is directed at nursing home residents with advanced dementia.³¹ It is based on Minimum Data Set variables, a routine assessment instrument employed by nursing homes in many countries. In the original sample, 40% of U.S. nursing home residents with advanced dementia died over 12 months. Based on 12 variables (length of stay, age, male sex, dyspnea, pressure ulcers, total functional dependence, bedfast, insufficient intake, bowel incontinence, body mass index, weight loss, and congestive heart failure), the model predicted six-month survival with moderate accuracy. In a prospective validation study, ADEPT was only modestly accurate for prediction of six-month survival, yet still more accurate than U.S. hospice eligibility criteria that include the Functional Assessment Staging scale.³² Ongoing difficulties with predicting six-month survival is one of the reasons for the ongoing debate on hospice care for patients with dementia in the United States.³³

Tip 7: Proxy Education About the Limited Life Expectancy in Advanced Dementia, Including Explicitly Naming That Dementia Is a Terminal Disease, May Help to Avoid Burdensome Medical Interventions

Nursing home residents with advanced dementia can be exposed to a substantial amount of burdensome medical interventions near end of life. In one study in Boston-area nursing homes, about 40% of residents underwent at least one potentially burdensome intervention (hospitalization, emergency room visit, parenteral therapy, or tube feeding).³⁴ Reducing such burdensome medical interventions is an integral part of PC for advanced dementia. Since persons with advanced themselves lack decision-making capacity, the determination of care goals and day-to-day decision making is taken over by proxies. Health care proxies' prognostic estimates of a person with advanced dementia may then be instrumental for avoiding burdensome but ultimately futile medical interventions. Indeed, proxy survival estimates were found to be moderately accurate and lower expectations of survival were associated with less burdensome interventions in two prospective studies in Boston-area nursing homes.³⁵

Strikingly, goals of care intervention with proxies of nursing home residents with advanced dementia appeared to be effective in reducing the hospital admission rate in this population.³⁶ In contrast, a proxy video intervention on advance care planning did not have an effect on care preferences, Do Not Hospitalize status, or burdensome treatments among nursing home residents with advanced dementia.³⁷ However, the video intervention did increase directives to withhold tube feeding. Taken together, educational interventions around limited life expectancy may help to avoid burdensome medical interventions in persons with advanced dementia. It remains unclear, however, how this can be done effectively on a larger scale.

Tip 8: Frailty, Independently Associated with Increased Risk of Disability, Hospitalization, and Mortality After Adjustment for Covariates, Is a Complex Multisystem Syndrome That Profoundly Alters a Patient's Capacity to Recover from an Acute Complication

Advanced age is associated with higher medical complexity and reduced life expectancy. However, chronological age is not a universal predictor of poor clinical outcome. Some older adults retain a substantial ability to recover from stress, while some young individuals lack significant physiologic reserve. The variable ability to recover from physiologic insults, independent of chronologic age, is best encapsulated within the concept of frailty.

Frailty is strongly associated with negative critical care outcomes, including mortality, health care utilization, and disability in addition to increased severity of illness at presentation.³⁸ The World Health Organization defines frailty as “a progressive age-related decline in physiological systems that results in decreased reserves of intrinsic capacity, which confers extreme vulnerability to stressors and increases the risk of a range of adverse health outcomes.”³⁹ The theoretical underpinnings of frailty emphasize the importance of screening older adults to determine baseline physical and mental capacities for the purpose of risk assessment, preventive intervention, and anticipatory care related to the eventual end of life. During, or better before, an acute complication, obtaining baseline frailty and cognitive measures is essential for accurate prognostication.⁴⁰

Recently, Hansen et al. evaluated the predictive value of a previously validated⁴¹ record-based multidimensional prognostic index (MPI) including data of the inpatient's electronic medical records to assess multidimensional frailty in a large cohort of 1190 medical inpatients aged ≥75 years.^42,43 The results demonstrated that the record-based MPI, assessed at discharge in hospitalized older patients, accurately predicted postdischarge mortality (after 90-days and one year) and hospital readmissions in a dose-dependent manner; additionally, the MPI value was associated with the hospital length-of-stay. These findings further support the idea that the MPI, though derived from different assessment scales in different settings, is able to express quantitatively the global health and functions to implement a multidimensional approach to the assessment of frailty in older people.^43,44 Indeed, the MPI is currently one of the most commonly used tools for evaluating frailty, both in primary care and hospital settings.⁴⁵ The inclusion of this information is a best practice in establishing goals of care early in subacute decline.

Tip 9: Lung Function Measurements Are Used to Grade Severity of Lung Disease, Though Individual Prognosis in Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis Are also Influenced by Key Demographic and Clinical Characteristics; Hospitalizations for Exacerbation Can Serve as an Inflection Point

Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) affect quality of life for millions of Americans through chronic and progressively debilitating breathlessness, cough, fatigue, and emotional symptoms. In both illness types, early specialist and primary PC are justified for symptom relief and to foster prognostic awareness among patients and their families. Beyond lung function measures that guide prognosis such as the forced expiratory volume in one second (FEV₁) in COPD and the forced vital capacity in IPF, individual prognosis in COPD and IPF are also influenced by several demographic and clinical characteristics. In COPD, these include rural residence and a rising mortality rate in women compared to men^46,47; in IPF, demographic characteristics include older age, male sex, and White race.^48,49

Clinical characteristics that influence mortality and yet are rarely addressed in COPD and IPF include weight loss,⁵⁰ anxiety, and depression.^51,52 Finally, hospitalizations in both COPD and IPF can serve as sentinel events. Approximately one in four adults hospitalized with COPD die in the year after hospitalization.⁵³ In IPF, the in-hospital mortality is nearly 50%; among those discharged, the median survival is only three to four months.⁵⁴ Given these statistics, hospitalizations for COPD and IPF should serve as inflection points that trigger clinicians to begin essential elements of primary PC and to engage specialist PC.

Tip 10: The Variable Progression Patterns and Unpredictable Illness Trajectories of COPD and IPF Make Prognostication Exceedingly Challenging and Are Major Barriers to Implementation of Early Palliative and Hospice Care

Patients with COPD typically fall into one of four global initiative for chronic lung disease severity stages of worsening FEV₁. Though lung function declines at predictable yearly rates with age and is accelerated with smoking, patients may not necessarily progress linearly through severity stages and instead progress very unpredictably.⁵⁵ Likewise, IPF is a progressive and fatal disease characterized by a highly variable and irreversible decline in lung function punctuated by acute exacerbations.⁴⁹ Some patients demonstrate a slow decline in lung function over time, especially in the presence of antifibrotic medications, while other patients may have a rapidly progressive disease course. Clinicians report that variable illness trajectories are a major barrier to implementing timely PC in COPD and IPF.⁵⁶

When illness trajectories become too difficult to predict, prognostic uncertainty can be reduced by using evidence-based scores to guide values-based conversations and trigger early specialist PC referral in such conditions. In COPD, the BODE index (Body Mass Index, Airflow Obstruction, Dyspnea, and Exercise tolerance) is a standard for mortality risk prediction.⁵⁷ In addition, the surprise question has been studied with good accuracy for predicting one-year mortality,⁵⁸ and wide variety of clinical characteristics have been consolidated into a list of potential referral criteria to hospice care.⁵⁹ Unfortunately, in IPF, such a score or clinical staging has not been validated. Regardless of the disease trajectory, individuals with COPD and IPF can experience symptom burden that affects quality of life long before the end of life, and early PC could confer significant benefit.

Conclusions

In clinical practice and training, estimating prognosis, the probability of an individual developing a particular outcome over a specific period, typically receives less attention than diagnosing and treating disease. Yet, many clinical decisions and patients' choices cannot be fully informed unless a patient's prognosis is considered.⁶⁰ As described here, a patient's prognosis does not just depend on their age and primary diagnosis, but also on the severity of their illness, their functional capacity both before and during the illness, and the number of comorbidities also suffered from.⁶¹ Palliative clinicians must consider prognosis in their decision making to enable guiding of clinical decisions that are aligned with their patients' values, preferences, and goals of care.

Footnotes

Funding Information

No funding was received for this article.

Author Disclosure Statement

No competing financial interests exist.

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