Supportive Care of Elderly Patients with Cancer

Supportive Care of Elderly Patients with Cancer

Volume 2, Number 4 • July 2005 Comprehensive Review Key words: Geriatric assessment, Nausea, Opioids, Pain management, Prophylactic treatment Suppo...

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Volume 2, Number 4 • July 2005

Comprehensive Review

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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Supportive Cancer Therapy

Supportive Therapy in Elderly Patients

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).

Table 1

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

Lodovico Balducci

Pain Management

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.

References 1. Balducci L. Geriatric oncology. Clin Rev Oncol Hematol 2003; 46:211-220. 2. Balducci L. Guidelines for the management of the older cancer patient. J Natl Compr Cancer Network 2004. In press. 3. Balducci L, Repetto L. Increased risk of myelotoxicity in elderly patients with non-Hodgkin’s lymphoma. Cancer 2004; 100:6-11. 4. Extermann M, Balducci L, Optimizing cancer care in the elderly: progresses in geriatric oncology. Cancer Control 2003; 10:440-452. 5. Repetto L, Biganzoli L, Koehne CH, et al. Cancer in the elderly. Task force guidelines for the use of growth factors in elderly patients with cancer. Eur J Cancer 2003; 39:2264-2272. 6. Morrison V, Picozzi V, Scott S, et al. The impact of age on delivered dose intensity and hospitalization for febrile neutropenia in patients with intermediate-grade non-Hodgkin’s lymphoma receiving initial CHOP chemotherapy: a risk factor analysis. Clin Lymphoma 2001; 2:47-56.

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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Supportive Therapy in Elderly Patients

7. Chrischilles E, Brink L, Scott S, et al. Factors associated with early termination of CHOP therapy and impact on survival of elderly patients with chemosensitive large cell non-Hodgkin’s lymphoma. Cancer Control 2002; 9:203-211. 8. Cohen HJ, Feussner JR, Weinberger M, et al. A controlled trial of inpatient and outpatient geriatric evaluation and management. N Engl J Med 2002; 346:905-912. 9. Extermann M, Overcash J, Lyman GH, et al. Comorbidity and functional status are independent in older cancer patients. J Clin Oncol 1998; 16:1582-1587. 10. Saliba D, Elliott M, Rubenstein LZ, et al. The Vulnerable Elders Survey: a tool for identifying vulnerable older people in the community. J Am Geriatr Soc 2001; 49:1691-1699. 11. Gill M, Baker DI, Gottschalk M, et al. A program to prevent functional decline in physically frail elderly persons who live at home. N Engl J Med 2002; 347:1068-1074. 12. Cohen HJ, Harris T, Pieper CF. Coagulation and activation of the inflammation pathway in the development of functional decline and mortality in the elderly. Am J Med 2003; 114:180-187. 13. Cova D, Balducci L. Chemotherapy in the older cancer patient. In: Balducci L, Lyman GH, Ershler WB. Comprehensive Geriatric Oncology. Amsterdam: Harwood Academic Publishers, 2004. 14. Gelman RS, Taylor SG. Cyclophosphamide, methotrexate and 5-fluorouracil chemotherapy in women more than 65 year old with advanced breast cancer: the elimination of age trends in toxicity by using doses based on creatinine clearance. J Clin Oncol 1984; 2:1406-1414. 15. Zinzani PL, Storti S, Zaccaria A, et al. Elderly aggresive-histology nonHodgkin’s lymphoma: first line VNCOP-B regimen experience on 350 patients. Blood 1999; 94:33-38. 16. Osby E, Hagberg H, Kvaloy S, et al. CHOP is superior to CNOP in elderly patients with aggressive lymphoma while outcome is unaffected by filgrastim treatment: results of a Nordic Lymphoma Group randomized trial. Blood 2003; 101:3840-3848. 17. Bertini M, Freilone R, Vitolo U, et al. The treatment of elderly patients with aggressive non-Hodgkin’s lymphomas: feasibility and efficacy of an intensive multidrug regimen. Leuk Lymphoma 1996; 22:483-493. 18. Zagonel V, Babare R, Merola MC, et al. Cost-benefit of granulocyte

colony-stimulating factor administration in older patients with nonHodgkin’s lymphoma treated with combination chemotherapy. Ann Oncol 1994; 5(suppl 2):127-132. 19. Doorduijn JK, Van der Holt B, Van der Hem KG, et al. Randomized trials of granulocyte-colony stimulating factor (G-CSF) added to CHOP in elderly patients with aggressive non-Hodgkin’s lymphoma (NHL). Blood 2000; 96:133a (Abstract #575). 20. Tirelli U, Errante D, Van Glabbeke M, et al. CHOP is the standard regimen in patients ≥ 70 years of age with intermediate and high grade non-Hodgkin’s lymphoma: results of a randomized study of the European organization for the Research and Treatment of Cancer Lymphoma Cooperative Study. J Clin Oncol 1998; 16:27-34. 21. Bastion Y, Blay JY, Divine M, et al. Elderly patients with aggressive non-Hodgkin’s lymphoma: Disease presentation, response to treatment and survival. A Groupe d’Etude des Lymphomes de l’Adulte Study on 453 patients older than 69 years. J Clin Oncol 1997; 15:2945-2953. 22. Dixon DO, Neilan B, Jones SE, et al. Effect of age on therapeutic outcome in advanced diffuse hisiocytic lymphoma: the Southwest Oncology Group experience. Clin Oncol 1986; 4:295-305. 23. Meyer RM, Browman GP, Samosh M, et al. Randomized phase II comparison of standard CHOP with weekly CHOP in elderly patients with non-Hodgkin’s lymphoma. J Clin Oncol 1995, 13:2386-2393. 24. Lyman GH, Kuderer N, Greene J, et al. The economics of febrile neutropenia: implications for the use of colony-stimulating factors. Eur J Cancer 1998; 34:1857-1864. 25. Balducci L. Anemia, cancer and aging. Cancer Control 2003: 10:478486. 26. Jacobson SD, Cha S, Sargent DJ, et al. Tolerability, dose intensity and benefit of 5FU based chemotherapy for advanced colorectal cancer (CRC) in the elderly: a North Central Cancer Treatment Group study. Proc Am Soc Clin Oncol 2001; 20:384a (Abstract #1534). 27. Balducci L, Carreca I. Oral chemotherapy in older cancer patients. Crit Rev Oncol Hematol 2003; 48(suppl):S65-S70. 28. Balducci L. Management of pain in the older cancer patient: J Support Oncol 2003; 1:175-191. 29. Haley WE. The cost of family caregiving: implications for geriatric oncology. Crit Rev Oncol Hematol 2003; 48:151-158.