Treating cancer in older and oldest old patients.

The so-called "silver tsunami" is a metaphor that the individuals 65 and older represent the most rapidly growing segment of the Western world population. Aging is an ongoing process that leads to the loss of functional reserve of multiple organ systems, increased susceptibility to stress, it is associated with increased prevalence of chronic disease, and functional dependence. Determined by a combination of genetic and environmental factors, this process is highly individualized and poorly reflected in chronologic age. The heterogeneity and the complexity of the older old population represent the main challenge to the treatment of cancer in those patients. We should discern "fit" elderly in whom standard cancer treatment appears to be comparable to a younger population and "unfit" or "frail" elderly, in which the risks of the treatment may overwhelm potential benefits. There are many aspects that have to be assessed before treating an elderly patient, or before to choose the treatment itself. In our review we will try to explain and describe the meaning and the most important aspects related to the oldest old complex patients, and how to manage those patients.

Screening tools for multidimensional health problems warranting a geriatric assessment in older cancer patients: an update on SIOG recommendations†.

BACKGROUND: Screening tools are proposed to identify those older cancer patients in need of geriatric assessment (GA) and multidisciplinary approach. We aimed to update the International Society of Geriatric Oncology (SIOG) 2005 recommendations on the use of screening tools. MATERIALS AND METHODS: SIOG composed a task group to review, interpret and discuss evidence on the use of screening tools in older cancer patients. A systematic review was carried out and discussed by an expert panel, leading to a consensus statement on their use. RESULTS: Forty-four studies reporting on the use of 17 different screening tools in older cancer patients were identified. The tools most studied in older cancer patients are G8, Flemish version of the Triage Risk Screening Tool (fTRST) and Vulnerable Elders Survey-13 (VES-13). Across all studies, the highest sensitivity was observed for: G8, fTRST, Oncogeriatric screen, Study of Osteoporotic Fractures, Eastern Cooperative Oncology Group-Performance Status, Senior Adult Oncology Program (SAOP) 2 screening and Gerhematolim. In 11 direct comparisons for detecting problems on a full GA, the G8 was more or equally sensitive than other instruments in all six comparisons, whereas results were mixed for the VES-13 in seven comparisons. In addition, different tools have demonstrated associations with outcome measures, including G8 and VES-13. CONCLUSIONS: Screening tools do not replace GA but are recommended in a busy practice in order to identify those patients in need of full GA. If abnormal, screening should be followed by GA and guided multidisciplinary interventions. Several tools are available with different performance for various parameters (including sensitivity for addressing the need for further GA). Further research should focus on the ability of screening tools to build clinical pathways and to predict different outcome parameters.

MAX2--a convenient index to estimate the average per patient risk for chemotherapy toxicity; validation in ECOG trials.

Cancer patients, especially the elderly, present with a highly variable susceptibility to toxicity from chemotherapy. To estimate correctly a patient's risk for toxicity, both the average toxicity of a chemotherapy regimen and patient-related variables need to be assessed. However, treatment toxicities are typically reported item by item, not summarised per patient. We tested an index derived from a pilot study, the MAX2, on the ECOG database. Studies including 20 or more patients aged 70 years and older per arm were selected. Four studies were identified, representing 2526 patients, 410 (16%) being elderly. The association of the MAX2 index with the per patient incidence of grade 4 haematological and/or grade 3 or 4 non-haematological toxicity was highly significant, both for the overall group and for the elderly subgroup. The MAX2 index is a convenient and reproducible way of comparing the average per patient risk for toxicity from chemotherapy across several regimens.

Predictors of tolerance to chemotherapy in older cancer patients: a prospective pilot study.

Few data are available to help predict which older cancer patient is at risk of developing chemotherapy-related toxicity. This study was a pilot for a project designing a predictive risk score. Chemotherapy patients aged 70 years and older were prospectively enrolled. Chemotherapies were adjusted for their published toxicity. 60 patients were enrolled, 59 were evaluable. Mean dose-intensity was 90.3%, range 33.3-129.0%. 47% of the patients experienced grade 4 haematological and/or grade 3-4 non-haematological toxicity. Published toxicity (MAX2), diastolic blood pressure, marrow invasion and lactate dehydrogenase (LDH) were all associated with toxicity (P<0.1); Body Mass Index, previous chemotherapy, red blood cells, platelets, polymedication with dose-intensity; and polymedication with FACT-G change. After adjustment for the published toxicity, the variables retained their significance, except for LDH and polymedication (for dose-intensity). Although the size of this pilot study imposes a cautious interpretation, patient-related and chemotherapy-related variables correlated independently with toxicity. Designing a composite predictive score to use in assessing the toxicity of multiple chemotherapy regimens therefore appears to be a valid undertaking.

Management of breast cancer in the older woman.

BACKGROUND: Approximately half of all breast cancer cases occur after age 65. Several aspects for the treatment of early breast cancer may be influenced by patient age, including postoperative irradiation after partial mastectomy, axillary lymphadenectomy, primary medical treatment of early breast cancer, and adjuvant chemotherapy. METHODS: The authors review the literature regarding age-specific issues in the management of breast cancer, and they report their own experience in treating older women with breast cancer. RESULTS: In terms of survival and disease-free survival, tamoxifen alone in primary breast cancer is inferior to surgical treatment followed by adjuvant tamoxifen. Tamoxifen alone should be reserved for patients with absolute contraindications to mastectomy. Adjuvant chemotherapy is beneficial to women with hormone receptor-poor tumors. In those with hormone receptor-rich tumors, adjuvant chemotherapy is beneficial for HER2-positive tumors, and the regimen should contain an anthracycline. CONCLUSIONS: Although the risk of local recurrence after partial mastectomy declines with increasing age, the decision to forego radiation therapy is individualized based on risk of recurrence and on patient desires and resources. The advent of lymph node mapping obviates the need for lymphadenectomy in most patients. The benefits and risks of adjuvant chemotherapy should be individually assessed according to tumor stage, life expectancy, comorbidity, and expected tolerance of treatment.

Validity and reliability of the FACT-G scale for use in the older person with cancer.

This project was designed to evaluate the Functional Assessment of Cancer Therapy General Scale (FACT-G) for use in the older patient with cancer. Subjects were administered the MOS Short Form Health Survey (SF-36) and the FACT-G scale. Subscale and total scores were compared using the Pearson product correlation test. FACT-G total and subscores were compared with the mixed aged cancer patient normative group of Cella et al. (1993). Good correlations were found between total and subscores of the SF-36 and the FACT-G in all areas except vitality. The mean total FACT-G score was 82.2 +/- 16.2 SD for the patients with cancer, and 92.3 +/- 11.8 SD for community-dwelling elderly (CDE). The FACT-G was able to discriminate between patients that received cancer care and CDE (p < 0.002). Subjects who scored higher on the FACT-G were found to have higher Eastern Cooperative Oncology Group Performance Status (PS). Subjects with a PS of 0 had a mean total FACT-G score of 87.9 +/- 14.4 SD. Subjects with a PS of 3 had a mean score of 59.0 +/- 23.2 SD. The FACT-G is a valid and reliable instrument for use in the older patient with cancer. The FACT-G is not an age-biased instrument.

Measurement and impact of comorbidity in older cancer patients.

As the world population ages, oncologists are increasingly confronted with the problem of comorbidity in cancer patients. This has stemmed an increasing interest into approaching comorbidity in a systematic way, in order to integrate it in treatment decisions. So far, data on the subject have been widely scattered through the medical literature. This article is aimed at reviewing the available data on the interaction of comorbidity and prognosis. This overview should provide an accessible source of references for oncological investigators developing research in the field. Various methods have been used to sum comorbidity. However, a major effort remains to be done to analyze how various diseases combine in influencing prognosis. The main end-point explored so far is mortality, with which comorbidity globally is reliably correlated. A largely open challenge remains to correlate comorbidity with treatment tolerance, and functional and quality of life outcomes, as well as to integrate it in clinical decision-making.

Management of cancer in the older person: a practical approach.

The management of cancer in the older aged person is an increasingly common problem. The questions arising from this problem are: Is the patient going to die with cancer or of cancer? Is the patient able to tolerate the stress of antineoplastic therapy? Is the treatment producing more benefits than harm? This article explores a practical, albeit evolving, approach to these questions including a multidimensional assessment of the older person and simple pharmacologic interventions that may ameliorate the toxicity of antineoplastic agents. Age may be construed as a progressive loss of stress tolerance, due to decline in functional reserve of multiple organ systems, high prevalence of comorbid conditions, limited socioeconomic support, reduced cognition, and higher prevalence of depression. Aging is highly individualized: chronologic age may not reflect the functional reserve and life expectancy of an individual. A comprehensive geriatric assessment (CGA) best accounts for the diversities in the geriatric population. The advantages of the CGA include:Recognition of potentially treatable conditions such as depression or malnutrition, that may lessen the tolerance of cancer treatment and be reversed with proper intervention; Assessment of individual functional reserve; Gross estimate of individual life expectancy; and Adoption of a common language to classify older cancer patients. The CGA allows the practitioner to recognize at least three stages of aging:People who are functionally independent and without comorbidity, who are candidates for any form of standard cancer treatment, with the possible exception of bone marrow transplant. People who are frail (dependence in one or more activities of daily living, three or more comorbid conditions, one or more geriatric syndromes), who are a candidate only for palliative treatment; and People in between, who may benefit from some special pharmacological approach, such as reduction in the initial dose of chemotherapy with subsequent does escalations. The pharmacological changes of age include decreased renal excretion of drugs and increased susceptibility to myelosuppression, mucositis, cardiotoxicity and neurotoxicity. Based on these findings, the proposal was made that all persons aged 70 and older, treated with cytotoxic chemotherapy of dose intensity comparable to CHOP, receive prophylactic growth factor treatment, and that the hemoglobin of these patients be maintained >/=12 gm/dl.

What threshold for adjuvant therapy in older breast cancer patients?

PURPOSE: To consider the question of when to prescribe adjuvant treatment for elderly breast cancer patients, particularly when comorbidities are present. Knowledge of the threshold relapse risks above which adjuvant treatment is worth prescribing would enhance decision making. PATIENTS AND METHODS: A Markov analysis of data from the medical literature was conducted. Patients aged 65 to 85 years were considered, along with three levels of comorbidity. The threshold risk of relapse at 10 years (RR10), at which time treatment provides absolute reduction or reduction of an absolute 1% in relapse or mortality, was evaluated. RESULTS: The threshold RR10 for an absolute reduction in mortality risk by adjuvant treatment was low through the age of 85 years. However, for an absolute 1% reduction, the effect of treatment on relapse and the effect of treatment on mortality increasingly diverged. The threshold RR10 for an absolute 1% reduction in relapse risk remained fairly low (5% to 6% for tamoxifen, 12% to 19% for chemotherapy). The threshold RR10 for an absolute 1% reduction in mortality risk, although starting close to the RR10 for an absolute 1% reduction in relapse risk, rose sharply. For tamoxifen, the difference between the two was 4% for an average 65-year-old, 6% at the age of 75 years, and 15% at the age of 85 years. For chemotherapy, the differences were 6%, 12%, and 30%, respectively. Similarly, thresholds increased with increasing comorbidity. In older and sicker patients, the maximum benefit was reached after 5 years rather than 10 years. CONCLUSION: Older breast cancer patients can expect a reduction in relapse that is fairly similar to that of younger patients. However, the effect on mortality diverges markedly, and attention should be paid to this difference in clinical decision making. Comorbidity should be considered in recommendations for adjuvant treatment, including clinical practice guidelines.

Management of the frail person with advanced cancer.

The frail population is increasing: currently, approximately 400,000 frail persons have cancer in the USA. Although the frail person is not a candidate for aggressive life-prolonging antineoplastic treatment, he/she is a candidate for aggressive symptom palliation. Most common symptoms include pain, especially bone pain, anemia, and fatigue. Destruction of cancer with antineoplastic treatment is pivotal to symptom palliation. A number of cytotoxic agents including gemcitabine, taxanes in low doses, vinorelbine, oral fluorinated pyrimidine, appear suitable for the management of metastatic cancer in the frail patient and should be tested in clinical trials.

Measuring comorbidity in older cancer patients.

The aim of this article was to provide oncology researchers with adequate tools and practical advice to integrate comorbidity into clinical studies. Open research questions are also discussed. Commonly used comorbidity indexes were identified and a detailed literature search was done by MEDLINE and cross-referencing. Expert opinion was sought on each index. A common scheme exploring the description of the index, clinical experience, metrological performance, easiness of use, cross-compatibility and preservation of data was followed. The actual indexes are included in the Appendix. Four commonly used indexes were identified: the Charlson Comorbidity Index (Charlson), the Cumulative Illness Rating Scale (CIRS), the Index of Coexistent Disease (ICED), and the Kaplan-Feinstein index. The Charlson is the most commonly used whereas the performance of the first two indexes is best characterised. Most studies are retrospective and focus on mortality as an outcome and a base of grading. All indexes are easy to use and require a maximum of 10 min to be filled. Inter-rater and test-retest reliability is generally good. Little is known about other outcomes and the way various diseases cumulate in influencing prognosis. Thus, several reliable indexes are available to measure comorbidity in cancer patients. They show that globally comorbidity is a strong predictor of outcome. Since little is still known about the importance of individual comorbidities for various outcomes and the way comorbidity cumulates in influencing cancer treatment, a wide integration of comorbidity in prospective studies is essential.

Cancer and aging. An evolving panorama.

This article illustrates how the nosology of cancer evolves with the patient's age. If the current trends are maintained, 70% of all neoplasms will occur in persons aged 65 years and over by the year 2020, leading to increased cancer-related morbidity among older persons. Cancer control in the older person involves chemoprevention, early diagnosis, and timely and effective treatment that entails both antineoplastic therapy and symptom management. These interventions must be individualized based on a multidimensional assessment that can predict life expectancy and treatment complications and that may evaluate the quality of life of the older person. This article suggests a number of interventions that may improve cancer control in the aged. Public education is needed to illustrate the benefits of health maintenance and early detection of cancer even among older individuals, to create realistic expectations, and to heighten awareness of early symptoms and signs of cancer. Professional education is needed to train students and practitioners in the evaluation and management of the older person. Of special interest is the current initiative of the Hartford Foundation offering combined fellowships in oncology and geriatrics and incorporating principles of geriatric medicine in medical specialty training. Prudent pharmacologic principles must be followed in managing older persons with cytotoxic chemotherapy. These principles include adjusting the dose according to the patient's renal function, using epoietin to maintain hemoglobin levels of 12 g/dL or more, and using hemopoietic growth factors in persons aged 70 years and older receiving cytotoxic chemotherapy of moderate toxicity (e.g., CHOP). To assure uniformity of data, a cooperative oncology group should formulate a geriatric package outlining a common plan for evaluating function and comorbidity. This article also suggests several important areas of research items: Molecular interactions of age and cancer Host-tumor interactions in the older tumor host Chemoprevention of cancer and aging Laboratory evaluation of aging Development of shorter forms of geriatric assessment Management of the frail cancer patients Clinical trials of tumor-specific issues.

Assessment of the older cancer patient.

The correct assessment of a cancer patient is a key step in the treatment process. In older people, this assessment entails not only the patient's basic medical history and the standard cancer staging, but also much more comprehensive evaluation of the various facets of the patient's health and environment that may interfere with his or her therapy. Patient fitness for elective surgery, radiation therapy, and chemotherapy must be considered. Geriatricians have defined the relevant aspects of the general evaluation of the older person, and now this work is being adapted to cancer patients. This article reviews the various aspects of a comprehensive assessment applicable to the cancer patient in settings such as academic oncology programs, cooperative group studies, and private oncology practice.

Immunologic nonresponsiveness to tumors.

Over the past several years it has become clear that malignant cells express a variety of tumor associated antigens, and T cells reactive to these antigens have been identified. However, the T cells are not effective in rejecting tumors. In general, T cells that are not tolerized within the thymus have the potential to be rendered tolerant by one of three mechanisms. Immune deviation occurs when regulatory T cells which share a common precursor differentiate away from the phenotype required to effect a particular immune response. Anergy induction occurs when a T cell is stimulated through its T cell receptor in the absence of costimulation. Activation-induced cell death (AICD) is apoptosis of activated T cells upon subsequent encounter with antigen. There is emerging information that some of these mechanisms can be responsible for the lack of T cell responsiveness to tumor cells. Also, tumor cells can acquire attributes that interfere with an immune response, including down-regulation of MHC molecules or other molecules involved in antigen processing; secretion of the immunosuppressive cytokine TGFbeta; and expression of the apoptosis-inducing surface molecule, Fas ligand. An expansion in our understanding of how tumor cells evade a T cell mediated death will provide insight into potential strategies to improve immunotherapeutic approaches to cancer patients.

Relationship between cleaved L-selectin levels and the outcome of acute myeloid leukemia.

High plasma levels of the shed form of L-selectin (sL-selectin) are frequently detectable in acute myeloid leukemia (AML). sL-selectin can inhibit blast cell adhesion to vascular endothelium and may thereby influence the phenotype of AML. In this study, we have investigated the relationship between sL-selectin levels and clinical presentation or disease outcome in 100 patients with AML. Fifty-eight patients were found to have sL-selectin levels >/=3.12 microgram/mL (>/=3 SD above the mean of healthy controls: "increased"). Patients with extramedullary disease such as lymphadenopathies, splenomegaly, hepatomegaly, and/or muco-cutaneous infiltration had significantly increased sL-selectin levels (P < .001). sL-selectin levels were significantly heterogeneous in the French-American-British subtypes (P = .0003). Patients with "normal" sL-selectin levels had higher probability of achieving complete remission (CR) than with "increased" levels: 81% versus 64%, respectively (P = .06). When adjusting for clinically relevant covariates predictive for CR (sex, age, Auer rods), "normal" sL-selectin levels were significantly associated with CR (odds ratio, 3.08; 95% confidence interval [CI], 1.10 to 8.58; P = .03). Moreover, patients with "increased" sL-selectin levels (>/=3.12 microgram/mL) had shorter event-free survival (EFS) (median 7.3 v 12 months, P = .008) and overall survival (median 1 v 2.05 years, P = .03) than patients with sL-selectin <3.12 microgram/mL. Multivariate statistical analysis (adjusted for age and presence of Auer rods) indicated that sL-selectin was an independent prognostic factor for EFS (hazard ratio [HR], 1.96; 95% CI, 1.21 to 3.17, P = .006) and overall survival (HR, 1.80; 95% CI, 1.09 to 2.98; P = .02). Thus, plasma sL-selectin may be a useful prognostic marker in the evaluation of AML at diagnosis.

Comorbidity and functional status are independent in older cancer patients.

PURPOSE: Comorbidity is a frequent and often therapeutically limiting problem in older cancer patients. However, to date, there is no standard measure of the comorbidity burden available for these patients. We tested the performance of two comorbidity scales and their relationship with functional status. PATIENTS AND METHODS: The Cumulative Illness Rating Scale-Geriatric (CIRS-G) was compared with the Charlson scale in 203 patients who received a comprehensive geriatric assessment (CGA) in our Senior Adult Oncology Program (SAOP). Study end points were variability, reliability, correlation with Eastern Cooperative Oncology Group (ECOG) performance status (PS), Activities of Daily Living (ADL), and Instrumental Activities of Daily Living (IADL). The relative weight of comorbidity versus tumor stage in the correlations with functional status was assessed. RESULTS: Median age was 75 years (range, 63 to 91). Sixty-four percent of patients scored 0 on the Charlson scale versus 6% on the CIRS-G. The correlation between the Charlson and CIRS-G was fair (p = 0.25 to 0.39). CIRS-G grade 3/4 had a fair correlation with ADL (p = 0.27). Otherwise, there was low or no correlation between comorbidity and functional status across the measures. Tumor stage was not correlated with functional status either. Correlation of ECOG PS with ADL (p = 0.51)c and IADL (p = 0.61) was moderate. Interrater and test-retest correlations were good or very good for both the Charlson and CIRS-G. CONCLUSION: Comorbidity needs to be assessed independently from functional status. Both the Charlson and CIRS-G scales are reliable tools for use in trials of older cancer patients. Both can be tested in further studies as predictors of outcomes such as toxicity of treatment, changes in functional status, or survival.