Volume 2, Number 4 • July 2005
Key words: Geriatric assessment, Nausea, Opioids, Pain management, Prophylactic treatment
Supportive Care of Elderly Patients with Cancer Lodovico Balducci
Abstract The majority of cancers are more prevalent in individuals aged ≥ 65 years than in younger patients, and supportive care is the key to treatment tolerance and quality of life for these individuals. This article examines the management of common complications of chemotherapy and pain in older patients with cancer. In accordance with the National Cancer Center Network guidelines, it is recommended that individuals aged ≥ 65 years be treated prophylactically with filgrastim or pegfilgrastim for the prevention of neutropenic infections when challenged by chemotherapy of dose intensity comparable to that of CHOP (cyclophosphamide/ doxorubicin/vincristine/prednisone) and that the levels of circulating hemoglobin be kept at ≥ 12 g/dL. In addition, it is recommended that the dose of cytotoxic agents be adjusted to renal function and that low-toxicity treatment (ie, capecitabine in lieu of 5-fluorouracil [5-FU], pegylated liposomal doxorubicin in lieu of doxorubicin) be used when feasible and indicated. For the management of pain, the following principles are established: age is not an absolute hindrance to pain assessment; a number of instruments and the observation of pain behaviors are reliable even in patients with dementia; cyclooxygenase (COX)–2 inhibitors are preferable to COX-1 inhibitors for individuals with bleeding diathesis, peptic ulcer, and Helicobacter pylori gastritis; and opioids should be slowly titrated because the effectiveness and toxicity become less predictable with age. In conclusion, with individualized supportive care, the survival and quality of life of older patients with cancer may be improved.
Age and Cytotoxic Chemotherapy
Approximately 60% of all cancers occur in individuals aged ≥ 65 years, and this percentage is expected to increase with the aging of the population.1 Older and younger individuals benefit to the same extent from chemotherapy of common neoplasms, but aging is associated with increased risk of short- and long-term complications of treatment and of cancer itself. Hence, supportive care is essential to allow the administration of effective treatment and to preserve the function and the quality of life of older cancer survivors.
Aging may be construed as a progressive decline in the functional reserve of multiple organ systems, which enhances the susceptibility to stress and increases the risk of functional deterioration. For example, not only are older patients at increased risk for neutropenic infections,1-5 but the consequent hospitalization is more prolonged than in younger individuals and is more likely to compromise the mobility and the independence of the elderly patient.6,7 Likewise, chemotherapy-induced nausea and vomiting and cancer-
Address for correspondence: Lodovico Balducci, MD, University of South Florida College of Medicine, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dri, Tampa, FL 33612-9416 Fax: 813-972-8359; e-mail: [email protected]
H. Lee Moffitt Cancer Center and Research Institute, University of South Florida College of Medicine, Tampa
Submitted: Aug 5, 2004; Revised: Aug 30, 2004; Accepted: Aug 30, 2005 Supportive Cancer Therapy, Vol 2, No 4, 225-228, 2005
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effective forms of assessment are explored, including homemailed questionnaires, screening questionnaires aimed to identify patients who benefit from a full assessment, and simple tests of physical performance whose results appear correlated with life expectancy and risk of functional decline.2,10,11 Of special interest, some laboratory tests, including measurement of the concentration of interleukin-6 and D-dimer in the circulation, appear predictive of mortality and functional deterioration.12 Given the evolution of the field, the NCCN does not recommend any specific instrument, as long as the form of geriatric evaluation selected has been validated. A decrease in glomerular filtration rate with age is almost universal.13 The adjustment of the doses of cyclophosphamide and methotrexate in response to kidney function has reduced the risk of treatment complications without compromising the effectiveness of treatment in women aged ≥ 65 years with metastatic breast cancer.14 Dose adjustment should include drugs whose parent compounds are eliminated from the kidneys (eg, methotrexate, carboplatin, cisplatin, bleomycin, and capecitabine) as well as those that give origin to active or toxic metabolites eliminated by the kidneys (eg, idarubicin, daunorubicin, and cytarabine in high doses).
NCCN Guidelines for the Management of Cancer in Older Patients2
1. Patients aged ≥ 70 years should undergo some form of geriatric assessment. 2. The first dose of chemotherapy should be adjusted to the renal function of older patients; if no toxicity is seen, subsequent doses should be increased. 3. Patients aged ≥ 65 years should receive prophylactic treatment with filgrastim or pegfilgrastim when receiving chemotherapy regimens of dose intensity comparable to CHOP. 4. Hemoglobin levels should be maintained at ≥ 12 g/dL. 5. Capecitabine should be used in lieu of intravenous fluorinated pyrimidines when feasible.
Prophylactic Treatment Prophylactic treatment of patients aged ≥ 65 years with filgrastim or pegfilgrastim is supported by 3 lines of consideration: 1. The risk of neutropenia and neutropenic infections as well as the duration of hospitalization for neutropenic infections increase at ages ≥ 65 years and is greater for patients treated with CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) and CHOP-like regimens. In some studies, the infection-related mortality rate was as high as 10%.2-5 Filgrastim may reduce the risk of neutropenia and neutropenic infections by 50%-75% according to 5 randomized and controlled studies.15-19 2. The alternative strategy to reduce the doses of chemotherapy has been associated with inferior results, at least in cases of non-Hodgkin’s lymphomas and adjuvant chemotherapy of breast cancer. This approach may be reasonable, however, in the case of palliative chemotherapy for metastatic cancer.20-23 3. Current studies of cost effectiveness show that prophylactic treatment with growth factors is cost effective if the risk of neutropenic infections during the first course of treatment is ≥ 20%.24 This is certainly the case for CHOP in patients aged ≥ 65 years. Additional considerations include the risk and cost of functional dependence and the deterioration of quality of life in older individuals undergoing hospitalization. The European Organisation for the Research and Treatment of Cancer (EORTC), in its guidelines for the management of
related pain may precipitate functional dependence in older individuals by restricting their mobility, and may mandate prolonged and expensive rehabilitation. Aware of this characteristic of aging, the National Cancer Center Network (NCCN) has issued a number of evidencebased guidelines aimed to ameliorate the complications and improve the benefits of cancer treatment in the elderly patient population (Table 1).2
Geriatric Assessment The aim of geriatric assessment is 3-fold: • To estimate the life expectancy and the risk of therapeutic complications of older patients with cancer; these may vary greatly among individuals in the same age group. • To identify reversible conditions that may interfere with cancer treatment. These include depression, anemia, poorly controlled comorbid conditions, memory disorders, malnutrition, polypharmacy, and lack of a competent home caregiver. • To institute a common language in the classification of older individuals. The classical geriatric assessment is a multidimensional instrument to evaluate function, comorbidity, cognition, mood, social conditions, nutrition, and pharmacy.8,9 More cost-
Volume 2, Number 4 • July 2005
cancer in elderly patients, has issued recommendations similar to those of the NCCN. While acknowledging that prophylactic filgrastim is indicated in individuals aged ≥ 65 years who are receiving curative treatment, the EORTC recommend a risk-adjusted approach.5 The American Society of Clinical Oncology (ASCO) has also studied this issue, and final recommendations on this topic are expected.
Pain is also a major problem for older individuals with and without cancer. Like nausea and vomiting, pain may limit the activity of these patients and cause functional deterioration.28 Basic principles related to pain management include the following. • Pain assessment in older individuals is generally reliable, even in those with cognitive impairment. Special strategies to evaluate pain include the use of vertical instead of horizontal pain scales, figurative pain scales, verbal pain descriptions, pain maps, and observation of pain behavior. • COX-2 inhibitors are preferable to COX-1 inhibitors in the presence of gastritis, recent hemorrhage, and increased risk of bleeding. • Older individuals are at increased risk of complications from opioids as a result of reduced excretion of morphine-6-glucuronide and morphine-3-glucuronide and the possibly changed ratio of μ- and δ-opioid receptors in the central nervous system. Treatment with opioids should be slowly titrated, and treatment with intrathecal morphine infusion should be considered in patients with a life expectancy of ≥ 3 months. • The home caregiver should be available in times of emergency and be able to provide timely transportation to the treatment center.29 Caregiving for the older patient with cancer may be distressful and costly. It benefits the health care provider to prevent caregiver “burnout” with proper education and support.
Anemia Anemia is a risk factor for myelotoxicity, as the majority of antineoplastic agents are bound to red blood cells. Anemia then causes increased concentration of free drug in the circulation and enhanced risk of toxicity. There are other good reasons to correct anemia in older individuals.25 Anemia has been associated with fatigue and increased prevalence of functional dependence, with increased risks of mortality, congestive heart failure, coronary death, and the possibly of dementia. Although treatment with epoetin or darbepoetin is expensive, this treatment is not more expensive than blood transfusion and may prevent the cost of management of dependent older individuals. The EORTC and ASCO are studying the issue of managing anemia in older patients with cancer.
Risk of Mucositis The risk of mucositis, which is mainly a complication of intravenous fluorinated pyrimidines, increases with age.26 In older individuals, this complication may become rapidly lethal as a result of limited reserve. Unfortunately, no antidote to mucositis is available, but the substitution of capecitabine for 5-FU and fluorodeoxyuridine may ameliorate the risk and severity of this complication. Capecitabine is a prodrug, activated in the liver and neoplastic tissue, with the result of minimizing the exposure of the normal tissues to the active compound.27 The NCCN guidelines represent a frame of reference that may accommodate new information, as the understanding of cancer and aging is rapidly evolving. Other aspects of supportive care that need to be dealt with emergently include the prevention of nausea and vomiting, the management of pain, and the choice of a home caregiver.
Conclusion Age is not a contraindication to proper cancer management; however, age is associated with increased risk of shortand long-tem complications. The NCCN guidelines for the management of older patients with cancer have been partly endorsed by the EORTC and provide a framework of reference for ameliorating the complications of cancer and cancer treatment and for accommodating emerging information in this rapidly evolving field.
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Nausea and Vomiting Even though the risk of nausea and vomiting does not seem to increase with age, the long-term consequences of this complication are of concern. These may include immobilization for fear of exacerbating the symptom and functional decline. The anti–neurokinin-1 agent aprepitant and the long-lasting serotonin inhibitor palonosetron offer a new opportunity to prevent nausea and vomiting in older individuals, and studies of these new compounds are needed.
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