Fighting diagnostic and therapeutic nihilism in the elderly with cancer

Fighting diagnostic and therapeutic nihilism in the elderly with cancer—why?

Geriatric oncology

Geriatric oncology is a new field of medicine, with a rapidly growing importance, providing designated approaches to elderly oncological patients (1). It is especially aiming at providing a higher quality, both in patients under an active cancer or a palliative treatment. In addition to the corresponding adaptation of cancer treatment, the targeted treatment of age-related comorbidities is one of important focuses.

Advanced age is the main risk factor for cancer (2,3). Thus, the majority of oncological patients are already older at the time of diagnosis, so that the neoplasm is often not the only disease, but there are various preexisting, usually chronic comorbidities and with varying frequency, polypharmacy, as well as not well treatable problems, such as sarcopenia, malnutrition due to in appetite or cognitive decline, drowsiness, gait deceleration and social problems, such as loss of independence and participation in life (4). Due to this enormous complexity and the great interindividual variance, caring for older patients with cancer is a challenge in daily practice. In this heterogeneous patient collective, the thoroughly diagnostic work up—including the cancer diagnosis and the age-related changes, the careful selection of therapeutic measures, and adequate concomitant therapy are crucial. Thus, geriatric oncology requires a team work of a multidisciplinary, multi-professional team in various venues, e.g., geriatricians, surgical/medical/radiation oncologists, internists, palliative care specialists at local oncology practices, ambulances, clinics and centers. The goal is to provide recommendations of a therapeutically concept that is individually adapted to the pre-existing conditions and situation of the patient, ensuring a better therapy tolerance and better quality of life during that therapy (5).

Geriatric syndromes in old-age cancer patients are not only to be considered in oncological therapy decisions, but also directed to a targeted management. If a geriatric complex treatment can be realized, functional improvements are expected (6). Thus, despite being there for a short period of time, geriatric oncology data already show that the assessment and subsequent interventions can reduce toxicity and mortality through specific therapy and improve quality of life (7).

Aging and cancer—epidemiology, demography, cancer as disease of old age

The National Institute on Aging recently described the phenomenon of demographic development as a “silver tsunami”. Approximately 50% of newly diagnosed cases occur in elderly over 65 years and this percentage is expected to increase to 70% by 2030. Cancer incidence is 12 to 36 times higher in individuals over 65 years of age as compared to younger adults. Despite the high incidence rate in this population, older patients are mostly underrepresented in practice-changing clinical trials (8).

Some specialists claim that if people were to live up to 150 years of age, we would probably almost all get cancer or die due to cancer. The advances of medicine in other fields allow people to reach high age, which has however a positive correlation to cancerogenesis: the constant regeneration of human organism through mitosis and miosis leads to inevitable mistakes, repair failure and mutations in oncogenes (9,10). With age, the damage accumulates and the body's repair tools lose their effect (11-13). Many cancers never appear clinically and would only be detected on autopsies, e.g., in 100 years old men, 85% have prostate cancer (14). Pre-forms of leukemia are also found in 20 percent of older people (15). Clearly, also the lifestyle (smoking, alcohol, physical inactivity) and the nutrition of the last decades lead to a significant increase in cancer incidence. However, it is crucial to also consider the component of screening and early diagnosis, which improved and is greatly available in developed countries—the relative number of cancer cases may not be objectively higher, but the actual diagnosis number (16-18).

Another theory linking aging and genes is the shortening of telomeres. Shortening of the telomeres could be associated with the aging process (19). In the group of over-60s, those with shorter telomeres were three times more likely to die from heart disease and eight times more likely to die from infectious diseases. Many neoplasms are associated with shortened telomeres, for example in the pancreas, the bones, the prostate and bladder, the lungs, the kidneys, the head and neck (20-22). A common feature of human cancers is the overexpression of telomerase, a ribonucleoprotein complex that is responsible for maintaining the length and integrity of chromosome ends. The extremely hypermitotic cancer cells need this protective mechanism (23,24). A prospective study reported measured telomere length in 787 healthy participants, 92 of which developed cancer within ten years. The cancer rate was 60% higher than the average for those with short telomeres and five times higher than in participants with long telomeres (25).

It was long not known whether telomere shortening is simply a sign of aging or is it actively contributing to the aging process (26). According to the recent research from Australia, it is rather telomeres’ health (structure of the DNA segment) than the length (27). Telomeres usually form a loop structure in which the ends of the chromosomes are hidden. As the telomere loops unfold, the end of the chromosome is exposed and the cell perceives it as broken DNA. The telomere loop can only be formed with difficulty by shortening it. While in cancer cells, this can actually be a therapeutic target, since telomeres can alter their structure in response to chemotherapy, making them more susceptible.

Overall, it is most likely that a combination of various physiological processes contributes to aging and carcinogenesis: oxidative stress, glycation, telomere shortening, and others (12,28).

What role does biological age play?

The aspect of biological age is very controversial. It is difficult to set a strict limit to categorize old, oldest old and elderly, since the physiological and mental decline of health is individual (29). While some cases of hardship can be described as retirees with a good conscience, many oldest old patients look and act much less senile than the chronological age indicates.

Partially, the (further below) multi-dimensional geriatric assessment are framing these aspects and help to discriminate between biologically old and still elderly patients. These assessments examine the life situation regardless of age, including mobility, cognition, emotional mood, social environment etc., to be included in the therapy decision.

Oldest old—lack of care due to lack of evidence

Oncologists are faced with the challenge of customizing treatment adjustment that would be optimal for each individual older patient, while taking into consideration the heterogeneity of comorbidities, functional status, disabilities and geriatric conditions. This constitutes a barrier of enrollment into RCTs that are mostly performed on middle-aged patients who have just one disease and therefore focus on monopathology. The difficulty of dealing with old patients in trials is mainly attributed to high prevalence of comorbidities and treatment-related toxicity in older population, but also due to a number of ethical issues (free will, informed consent etc.) and drop out or lost-to-follow up rates. As a result, there is limited evidence-based information as well as inadequate guideline on the risk/benefit ratio that specifically address the evaluation and treatment for elderly (30,31).

Some professional societies have already set up sections dedicated to the needs of older people, which provide a list of tools for physicians to optimize therapy and adjust to patients’ wishes and needs, exceeding the purely medical needs. Nevertheless, so far apart from several general recommendations (32,33), there are no stringent guidelines that would support or lead the physicians in their decision making (Table 1). This is because most RCT and bigger studies exclude elderly and oldest old patients (34-36). If one transfers these results to old, often chronically ill and multimorbid patients, that is on the one hand often not scientific ally founded and possibly even risky. Due to the poor evidence, there are still no S3 (as it is the case for dementia or diabetes in oldest old patients), albeit they are urgently needed, since the majority of patients are diagnosed with cancer beyond the age of 65 or higher (the age itself is not the crucial point, but rather the comorbidities), while they represent only 36% of RCT participants (37). Since this group is massively underrepresented, subgroup analyzes from larger studies are currently the most powerful evidence, although they cannot answer many questions. In addition, they con only provide answers for a population matching to the included group of patients. This tremendous inadequacy in study situation leads to an inadequate care: old patients receive regimes of anti-tumor therapies without a proper knowledge of the potential multimorbidity-adjusted side effects, whether a dose-adjustment is effective and whether an alternative management would be more beneficial.

Table 1 List of SIOG guideline and recommendations
Full table

Recently, a study of breast cancer patients reports that in fact a lower dosage of cyclophosphamide (plus anti-HER2) are superior to docetaxel in terms of geriatric-oriented outcomes of ADL (Activities of Daily Living) and IADL (Instrumental ADL). Controversies arise since these end points are not the most valid and representative assessment tools, as well as because the sample only contained 80 patients (38,39).

Another study from the USA confirmed that for most palliative patients (mean age 69), chemotherapy has no discernible influence on risk of death. While for patients with ECOG Performance Status 2 or 3 at baseline, chemotherapy did not bring any quality of life benefits one week before death, for those of ECOG 0 and 1, it significantly worsened the quality of life (40). These findings urge to reconsider the standard treatment advise towards a better balance between the quality and quantity of life in specific patient groups—those who are fit, but approaching death, as not to spend the last weeks or months of a lifetime on largely ineffective therapies and their side effects. As a general timeframe, 6 months prior to death were mentioned (40). The leading physician is however always required to conduct a clear discussion about prognosis, goals, fears and sustainable compromises (41).

Oldest old cancer patients’ special needs

One of the biggest challenges for physicians is to establish a report with the patient and find a difficult balancing act to weigh together carefully what do older patients need to consider when choosing cancer therapies. Concomitant diseases can significantly influence the course of therapy and since the physical conditions in older cancer patients vary greatly, the effect of the medication is much more difficult to predict (42). However, besides of these concerns, frequently, the patients themselves express the desire for age-appropriate or no treatment in order to avoid the renunciation of exhausting therapies. In cases of early diagnoses of slowly growing tumors, e.g., prostate cancer, the decision to refrain from interventions is reasonable (43). In palliative cases, this rationale is not applicable and requires a high level of personalized approach.

Another important element for geriatric cancer patients is the special in- and outpatient care. Most patients require longer and more frequent hospitalizations, leading to decline in cognitive functions, sarcopenia and muscle wasting, logically requiring an intensive follow-up in outpatient setting, including support in everyday life, rehabilitation etc. (44,45). The recovery is usually of a slow progress, so the patients (and caregivers) should be prepared for what to expect after the therapy as to organize support before the therapy starts. Depression following radical surgeries, such as mastectomy, should also be considered (46).

Clinical challenges and pitfalls in palliative care of geriatric cancer patients

The public often perceives the value of cancer treatment in terms of survival, yet for geriatric patients, it is necessary to address independence, quality of life and the avoidance of toxic side effects due to the remaining lifetime (32).

Besides of the heterogeneity in old age and difficult decision of an appropriate tumor therapy in old age, further challenging situations that require convincing arguments, are present. When determining a therapy goal, ethical issues and the relevance of preserving of human dignity are arbitrative. Informed consents (ICs) of affected parties are only effective if they meet certain requirements of data protection law. The IC is only effective if the person concerned knows exactly to what he/she agrees to. Especially the voluntary basis must be clearly and understandably explained. It must be pointed out to the person concerned that his/her consent is entirely of free-will, that is why he/she can refuse it or revoke it without implications. In case of geriatric patients, however, this might be problematic to assess to what extent the comprehension of the person concerned can be ensured so that the effectiveness of the consent is guaranteed. Many are simply overwhelmed by the flood of information or are cognitively impaired (which is not always obvious at the consultation). To give consent, patients must have legal and clinical capacity (47-50). Doctors who wish to receive informed consent must be able to provide qualified information and to provide comprehensive information on both the risks and benefits of the intervention and to answer appropriate questions. From an ethical and legal perspective, it is imperative that physicians are committed to ensuring that patients are aware of the current state of health, including the probable course if no treatment is given, potentially helpful treatments, including a description and explanation of the potential risks and benefits, assessment of the doctor about the best alternative etc. Physicians, families, patients, nurses and further health professionals have to be aware of that and have a sufficient ethical competence, as they have to often face autonomy conflict in over- or under-treatment or end-of-life situations, where discontinuing or refraining from therapies is being agreed upon. Single experiences of even somnolent patients receiving chemotherapy, resulting in a temporary bettering and thus a chance for a last farewell, provide a base for entrusting that not every tumor therapy in palliative stage is futile.

Furthermore, therapy limitation is frequently misunderstood as a complete therapy cessation. However, comfort therapy can also include active substances, such as electrolyte substitution for alleviating thirst, benzodiazepines for anxiety etc. (51).

Last but not least, aged individuals have an already developed individual personality, as well as crystallized their priorities, goals and purposes in life. On this background, it is important to promote the active competence with an affirmative attitude.

Trust of the patient in the physicians aim to seek for the best treatment for him/her, is the cornerstone of a good care. In some patients this might be active cancer treatment, in others the best treatment can be not to provide active cancer treatment. In every patient, standard palliative care should be included in any case.

Undertreatment of geriatric cancer patients

Despite tremendous advancements in the medical care options, geriatric cancer patients are still not optimally diagnosed and/or treated. This is based—besides of the lack of data as described above—on various preconceptions and mostly the fear (of both patients and physicians) of unwanted side effects of the therapy. Ultimately, the life expectancy of patients is underestimated (52).

Several registry studies confirmed that there is a severe underdiagnosis and undertreatment for this specific population—an almost ironic seeing strong efforts in various disciplines towards choosing wisely and “less is more”.

In colorectal cancer, no or almost no patients over 80 received adjuvant therapy, despite the fact that the life expectancy is higher than time-to-recurrence (53). Newer insights suggest that 5FU-based adjuvant therapies are indeed not beneficial, however, other regiments such as UFT (Tegafur/Uracil) and oral capecitabine were favorable (54-56). An US cohort study actually confirmed that chronic diseases, which are mostly a barrier to application of adjuvant colorectal cancer therapies, are not significant and the adjuvant treatment leads to a better survival (median patients’ age 76) (57). This report was contradictory to an earlier study based on a SEER data extraction (58). Thus, some insecurity about of whether to apply standard protocols for geriatric patients is advisable or not, remains controversial. However, one has to consider the rapid progress of treatment management and be critical to studies from before the last decade. Similar information has been gathered for NSCLC, encouraging clinicians to apply adjuvant chemotherapies in elderly as they have a similar safety profile and lead to a survival benefit (48,59,60). Due to their common co-morbidities, less platinum-based regimens are used, but fit patients may also receive a standard regimen adapted to their kidney function. The additional administration of bevacizumab has similar advantages in the elderly patients as in the younger ones in both tumor entities, when considering patients included into clinical trials (61-63).

Fighting diagnostic and therapeutic nihilism in the elderly with cancer—how to?

Early and late onset palliative care

A significant feature of this specific discipline is that it provides a venue for doctors to discuss patient’s preference and treatment goal so that the treatment plan reflects these essential aspects of care. Palliation is often misunderstood as end-of-life care in terminal phases or as pain/symptom management only. Meanwhile, palliative care, especially in older patients, is aimed to exculpate families or caregivers, as well as in avoid unnecessary hospitalizations.

A recent metanalysis reported an overall benefit in quality of life for cancer patients who are under early palliative care treatment, despite an increased pain occurrence and loss of appetite. There was no impact on depression or survival (64). However, these results need to be validated in a bigger cohort, which is still not available. For a general population (not only geriatric patients), similar outcomes, but including a survival benefit, have been reported in the North America and Belgium (65-67). Some authors claimed that an early palliative intervention is not only beneficial in terms of symptomatic treatment, but actually reduces mortality and morbidity in cancer patients (68,69). Nevertheless, the results have been widely discussed and attention has been pointed to an attentive interpretation of these, because of numerous confounders (70). Oorschot et al. recently evaluated the effects of integrated palliative care in newly diagnosed stage 4 pulmonary and GI tumor patients, looking at the change in quality of life, depression score and consulted end-of-life care preferences within 12 and 24 weeks (T2), reporting a clear benefit in all aspects (71). These reports are more imminent based on the fact that for elderly cancer patients, pain management is the cornerstone of palliative care. The Hospitalized Elderly Longitudinal Project (HELP) showed that one third of patient subjects experienced severe pain in the last months of their lives (72). However, the evaluation of pain has always been and remains a challenge for clinicians due to its both physical and emotional component (73,74). Existing evaluations of pain evaluation are mainly based on patients' self-report, which is particularly problematic in geriatric patients, especially in individuals with cognitive impairment (75-77). Validation of effective pain assessment system relying on behaviors observation is urgently needed (78).

Although elderly account for approximately 50% of all cancer patients, their pain management is often neglected, even in Western countries. A study from Italy analyzed the underlying causes of this neglect, pointing to an underestimation of patients’ sensitivity to pain, the overestimation of pain tolerance and their benefit from opioids (79-81).

Geriatric assessments

As mentioned before, most geriatric old tumor patients can benefit from a cytotoxic treatment. The basis for the treatment decision must be scientifically valid and allow to select the appropriate treatment protocols.

Over the last decades, oncologists and geriatricians developed such instruments, which allow to capture comprehensive patient factors to aid in clinical management, individualized intervention plan, and optimized decision-making process—geriatric assessments. Therefore, we can observe an increasing call of experts for a new concept for the integration of these simple tools in order to assess the geriatric risk profile of the patients.

The cancer-specific geriatric assessments evaluate the individual’s functional status, comorbidities, cognition, psychological status, social functioning, support, and nutritional status. Information gained serves as the basis for treatment planning and anticipating the possible consequences of cancer and its treatment on an older adult cancer survivor (31,32,82).

One study conducted a comparison of the G8 and Triage Risk Screening Tool (fTRST).

In patients ≥70 years of age with a newly diagnosed malignancy. Both scales showed a high sensitivity (86.5% to 91.3%), moderate negative predictive value (61.3% to 63.4%) and strong prognostic value for functional decline on ADL and IADL, and the OS. They are simple and useful instruments in older patients with cancer for identifying patients with a and have a strong prognostic value for functional decline and OS (83).

CRASH study provided further insights assessments of this specific population. It identified several predictors, such as hemoglobin, creatinine clearance, self-esteem for one’s own health, the CIRS-G-index for the cancer stage and comorbidities, the performance, the Mini-Mental Status Examination (MMSE), the Mini Nutritional Assessment (MNA) for non-hematologic toxicity and albumin, LDH and diastolic blood pressure for hematological toxicity (84).

Applying geriatric assessments has already been recommended by national and international professional societies in order to identify deficiencies and plan targeted support, as well as to ensure better compliance.

A further focus is on cross-sectorial collaboration, so that the patient can follow on a competent outpatient care after inpatient therapy.

Current research focus on the approach to base interventions on the results of geriatric assessment, which is standard in general geriatric medicine, however not yet in geriatric oncology. Currently at least four RCTs are on the way to demonstrate, that geriatric assessment based geriatric interventions improve outcome in elderly cancer patients.

Conclusions and perspectives

While ageism is still one of the main reasons for discrimination of geriatric patients, there is a need for an increasing awareness of geriatric oncology among patients and health professionals. Special divisions of palliative care need to be understood as centers for more than end-of-life and hospice care. Especially early palliative management of geriatric patients should aim to relieve physical and psychological symptoms, while also providing closeness, hope, security and comfort for relatives. Symptomatic treatment might include interventions and active anti-tumor therapies. The individual assessments of risks and benefits, as well as a considerate judgment and integration of patient’s wishes should be prioritized in decision making. Sometimes, advocacy can improve life (quality over quantity) and appropriate training should be offered to crucial actors, also with regards to their interactions and team work (nurses, palliative/oncology/internal medicine/GP/geriatrics health professionals, caregivers etc.) With the rapid progress in precision and personalized medicine, there are new perspectives opening for geriatric cancer patients.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Jan Gaertner, Charles B. Simone II and Fiona Lim) for the series “Clinical Challenges and Pitfalls in Early Palliative Care: Practical Knowledge and Guidance from other Medical Specialties” published in Annals of Palliative Medicine. The article was sent for external peer review organized by the Guest Editors and the editorial office.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/apm.2019.08.03). The series “Clinical Challenges and Pitfalls in Early Palliative Care: Practical Knowledge and Guidance from other Medical Specialties” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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