Version May 2024
INTRODUCTION — People 65 years or older are the fastest growing segment of the population in the United States [1]. By 2030, this group will comprise about 20 percent of the total population, and among older adults, the percentage of patients >75 and >85 years old will increase disproportionately. A similar aging of the population is present in Western Europe and Japan.
The importance of this demographic increase in the number of older adults is magnified by the sharp rise in the incidence of most types of cancer after age 60 years. Currently, approximately 50 percent of all cancers and 70 percent of cancer deaths occur in those ≥65 years old, and this fraction is expected to increase [1,2].
Despite the frequency with which cancer occurs in the older-adult population, this group is significantly underrepresented in clinical trials [3-5]. Older-adult patients who are enrolled in clinical trials represent a carefully selected subset. A systematic review of 345 cooperative group trials found no evidence of poorer survival or increased treatment-related mortality with experimental treatments compared with younger patients, despite concerns about an increased risk of toxicity [4].
Even when substantial numbers of older patients are included, the results cannot be extrapolated to the entire older-adult population. Patients with a poor performance status or renal, hepatic, or bone marrow dysfunction generally have been excluded, thus raising questions about the general applicability of data derived from such trials. This is particularly true for patients over 80 years.
Challenges specific to older patients with advanced cancer and the treatment of common malignancies in the older-adult population will be reviewed here. Detailed discussions of the therapy of specific malignancies are presented separately, and additional information on specific chemotherapy drugs can be found in the UpToDate drug database. Considerations regarding choice of therapy, including targeted therapies and immunotherapy, are found in other topics. Toxicity of other anticancer therapies is discussed elsewhere:
●(See "Toxicities associated with immune checkpoint inhibitors".)
●(See "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents".)
●(See "Nephrotoxicity of molecularly targeted agents and immunotherapy".)
●(See "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents".)
●(See "Immune checkpoint inhibitor colitis".)
●(See "Rheumatologic complications of checkpoint inhibitor immunotherapy".)
CHALLENGES SPECIFIC TO OLDER-ADULT PATIENTS — The essential principles of treating advanced cancer in older adults are the same as in younger patients. However, older patients, who may have age-related organ function decline and medical comorbidity, require special attention to the risks of chemotherapy (both treatment-related toxicity and quality of life [QOL] issues), particularly in the context of estimated life expectancy.
The following age-related changes should be considered when assessing the risk of systemic chemotherapy.
Age-related organ function decline — Aging is commonly accompanied by a decline in the function of critical organ systems, and this declining organ function probably underlies age-related loss of physiologic reserve. Older patients with little reserve are at risk for decompensation upon exposure to severe stresses such as chemotherapy. This has several implications for older-adult patients undergoing chemotherapy.
Chronologic age may not correlate with physiologic impairment and decline in functional reserve, both of which vary substantially between individuals. Thus, treatment of cancer in older adults should focus on the extent of comorbidity and functional status rather than chronologic age.
Liver — Aging is associated with a decline in hepatic volume and hepatic blood flow [6,7]. As a result, drug metabolism and elimination may be slowed, potentially exposing patients to higher drug concentrations for longer periods of time. (See 'Liver function and metabolism' below.)
Patients with a large burden of liver metastases may have a greater than expected degree of hepatic decompensation. In the setting of decreased volume of normal hepatic parenchyma, careful monitoring of liver function is recommended in older patients, particularly when drugs metabolized by the liver are being used. In addition, comorbidities such as alcohol abuse or a history of viral hepatitis may be relevant considerations in treatment decisions. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Conventional cytotoxic agents", section on 'Impact of preexisting liver disease'.)
Kidney — Renal function, as measured by the glomerular filtration rate (GFR), falls with age. However, age-related loss of muscle mass makes the serum creatinine concentration alone less reliable as a marker of GFR in older patients. Estimation equations have been derived to estimate GFR. (See 'Kidney function and drug excretion' below.)
Because of the diminished renal reserve in older-adult patients, volume depletion can lead to exaggerated reductions in renal function [6]. Thus, careful attention should be paid to fluid management in patients who develop chemotherapy-associated vomiting or diarrhea.
Bone marrow function — Bone marrow reserve diminishes as a part of normal aging, placing older patients at greater risk for severe and prolonged chemotherapy-related cytopenias [7]. Dose reduction and/or delay may be necessary; another alternative is the use of hematopoietic growth factor support during treatment. (See 'Bone marrow' below.)
Heart — Normal aging is associated with an increasing risk of coronary artery disease, an increased frequency and severity of valvular heart disease, and a decrease in ventricular compliance [6]. The possibility of exacerbating age-related abnormalities should be considered when potentially cardiotoxic drugs are being used. (See "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity" and "Cardiotoxicity of trastuzumab and other HER2-targeted agents" and "Fluoropyrimidine-associated cardiotoxicity: Incidence, clinical manifestations, mechanisms, and management" and "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines".)
Muscle — Sarcopenia, increased age, and inactivity may all contribute to loss of muscle mass. Unlike cachexia, sarcopenia, which is defined by loss of skeletal muscle mass two standard deviations below sex-specific normal values for young adults [8], does not require the presence of weight loss. Whereas most people with cachexia are sarcopenic, most sarcopenic individuals are not considered cachectic. Muscle loss in the setting of obesity is known as sarcopenic obesity, which is prevalent in older adults [9,10] and is also noted in advanced cancer. The causes of sarcopenia are multifactorial and can include disuse; changing endocrine function; chronic diseases; inflammation; insulin resistance; nutritional deficiencies; some forms of cancer treatment, notably sorafenib and androgen deprivation therapy; and specific cancers, notably non-small cell lung cancer. (See "Assessment and management of anorexia and cachexia in palliative care", section on 'Definitions'.)
Loss of muscle mass places older individuals at risk for further muscle wasting associated with the effects of the malignancy and chemotherapy, which in turn reduces mobility and functional status.
Comorbid conditions — Older-adult patients, particularly those over the age of 75 years, often have multiple other medical conditions at the time of diagnosis of cancer [11]. The most common conditions are anemia (often from occult blood loss related to the primary tumor), hypertension, gastrointestinal diagnoses, and heart disease [12].
For seriously ill patients with severe comorbid illness that results in a short life expectancy (particularly one year or less), the risks of chemotherapy often outweigh its benefits. Most of these patients should receive supportive care rather than chemotherapy, with attention to palliation of symptoms. Available prognostic tools for use in clinical decision-making for older adults are available through http://eprognosis.ucsf.edu/. (See "Communication of prognosis in palliative care", section on 'The science of estimating prognosis'.)
On the other hand, palliative chemotherapy is reasonable for older-adult patients with metastatic cancer who have chronic conditions that are not imminently life threatening.
Quality of life issues — Quality of life (QOL) is a crucial component of decision-making when treating older cancer patients. The available data suggest that older patients are just as willing to try chemotherapy as their younger counterparts, but less willing to endure severe treatment-related side effects [13].
There are few data about how chemotherapy affects QOL in older patients [14]. A major unanswered issue is whether the higher response rates and generally longer survival seen with modern combination regimens (as compared with a strategy of sequential single agents) are outweighed by the greater likelihood of side effects and adverse impact on QOL. (See "Systemic therapy for metastatic colorectal cancer: General principles", section on 'Available agents'.)
PHARMACOKINETICS — The aging process can significantly alter the pharmacokinetics of chemotherapy agents. These pharmacokinetic differences may be caused by alterations in excretion, metabolism, distribution, and absorption.
Kidney function and drug excretion — There is a gradual decline in kidney function with age in most people, including those without hypertension or known renal disease. This decline results in a significant percentage of the older-adult population with a calculated glomerular filtration rate (GFR) <60 mL/min per 1.73 m2. Impaired renal function can result in higher peak drug levels and more prolonged exposure to chemotherapy, causing excessive toxicity with agents that are dependent upon renal excretion for their clearance (eg, methotrexate, cisplatin), particularly when they are combined with other agents that also are associated with renal dysfunction (eg, nonsteroidal anti-inflammatory drugs [NSAIDs]).
The serum creatinine is not a reliable indicator of renal function in older-adult patients, since a reduction in the GFR may be obscured by a simultaneous loss of muscle mass [15-17]. Various equations are used to estimate the creatinine clearance; these are based upon measurement of a stable serum creatinine, as well as age and body weight. A calculator is available to calculate the creatinine clearance based upon the ideal body weight and the serum creatinine level (calculator 1). (See "Assessment of kidney function", section on 'Glomerular filtration rate'.)
Estimates of the creatinine clearance rather than the serum creatinine should be used to determine the dosing for chemotherapy drugs that are excreted by the kidneys. General guidelines for the use of chemotherapy agents in patients with compromised renal function are discussed in detail elsewhere. (See "Nephrotoxicity of molecularly targeted agents and immunotherapy" and "Nephrotoxicity of chemotherapy and other cytotoxic agents".)
Liver function and metabolism — Two major pathways are utilized by the liver to detoxify and excrete drugs (figure 1). (See "Drugs and the liver: Metabolism and mechanisms of injury".)
●In phase I reactions, polar groups are added to drugs by oxidation, reduction, or hydrolysis to facilitate water-solubility. This group of reactions is catalyzed predominantly by the cytochrome P450 enzymes. Many common chemotherapy agents are metabolized through the cytochrome p450 system, and the specific isoenzymes responsible for their metabolism are summarized in the individual drug monographs.
●In phase II reactions, the drug or its metabolite is conjugated to a large water-soluble polar group, such as glucuronide, sulfate, or acetate. This more polar compound is then excreted, either in the bile or by the kidneys.
Although liver size and hepatic blood flow are decreased with aging [18], these changes are not of sufficient magnitude to require routine dose modification in older adults. However, concurrent hepatic impairment, due to the malignancy or other comorbid conditions, may necessitate dose adjustments.
Distribution — The distribution of drugs is affected by body composition [19]. In the older-adult population, the fat content doubles from approximately 15 to 30 percent of body weight, while intracellular water decreases (33 versus 42 percent in the average 25 year old) [18,19]. These changes increase peak blood concentrations of more polar drugs while decreasing peak concentrations but lengthening half-lives of lipid-soluble drugs. In addition, decreases in plasma albumin and red blood cell concentration are often present with aging, and this can affect the pharmacokinetics of agents that are bound to albumin or erythrocytes [20].
These pharmacokinetic alterations in drug distribution in the older-adult population have not been shown to necessitate dose modifications based upon age.
Absorption — Atrophy of the intestinal mucosa and decreases in gastrointestinal motility, splanchnic blood flow, and secretion of digestive enzymes all can contribute to a decreased rate of drug absorption in older adults [19]. Although absorption of orally administered drugs such as capecitabine and temozolomide may be affected by changes in the gastrointestinal tract, the magnitude of such changes does not justify dose modification based upon age. Furthermore, the emphasis on oral therapy makes compliance an important issue in treatment, as a significant number of patients fail to take oral anticancer therapy as prescribed [21-23].
COMORBIDITY AND FUNCTIONAL STATUS — In patients ≥65 years receiving chemotherapy, according to guidelines by the American Society of Clinical Oncology, geriatric assessment should be used to identify vulnerabilities that are not routinely captured in oncology assessments [24]. Evidence supports, at a minimum, assessment of function, comorbidity, falls, depression, cognition, and nutrition. (See "Comprehensive geriatric assessment for patients with cancer".)
Aging is a highly individualized, multidimensional process. Chronologic age does not reliably predict physiologic decline. The process of aging has been represented as a continuum ranging from functional independence to pre-death [25]. At one end of this spectrum, a healthy older individual has no significant limitations in activity and only minimally reduced functional reserve. With progressive increase in comorbidity, an individual becomes more vulnerable and has a decreased functional reserve. This physiologic decline results in significant limitations, although there may be the ability for some recovery. Frailty, the far end of the spectrum, is characterized by severe limitations with little or no ability to withstand treatment or serious illness.
Chronologic age alone is not an indication for a change in therapeutic plan or drug dosing in older adults. If renal function is normal and there is no significant comorbidity, most chemotherapy agents can be given in full doses. However, dose modifications or a change in the agents used is often required when drug toxicity overlaps with comorbid conditions or there is an increased susceptibility to complications.
Comorbid conditions — Examples of comorbid conditions that can affect treatment with chemotherapy agents include the following.
Impaired renal function — Chemotherapy agents that are primarily excreted by the kidneys must be used with extreme care in the older-adult population, because of the high incidence of occult renal impairment [15,26]. However, for patients with renal insufficiency but good performance status, chemotherapy may be administered with dosing adjustments, without compromising disease outcomes or resulting in excess toxicity. Guidelines for the use of chemotherapy agents in patients with compromised renal function are discussed in detail elsewhere. (See "Nephrotoxicity of chemotherapy and other cytotoxic agents" and "Nephrotoxicity of molecularly targeted agents and immunotherapy".)
In a study of 619 patients age ≥65 years with early-stage breast cancer treated with cyclophosphamide/doxorubicin (AC), cyclophosphamide/methotrexate/fluorouracil (CMF), or single-agent capecitabine, with dosing adjustments of methotrexate and capecitabine made based on pretreatment renal function, there was no relationship for any regimen between pretreatment renal function and toxicity, progression-free survival, or overall survival [27].
Hepatic disease — Patients with moderate or severe hepatic dysfunction, due to either comorbidity or tumor, may not be able to metabolize or excrete drugs that are normally handled by the liver, thereby increasing the risk for systemic toxicity. In addition, patients with preexisting liver disease may be susceptible to chemotherapy-induced hepatotoxicity. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Conventional cytotoxic agents", section on 'General aspects of chemotherapy-induced hepatotoxicity'.)
General guidelines for dose modifications in patients with liver disease are shown in the following table (table 1). (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Conventional cytotoxic agents", section on 'Specific cytotoxic agents'.)
Ascites and pleural effusion — Extreme caution is indicated with the use of methotrexate in patients with ascites or pleural effusions, both in older-adult and younger patients. Methotrexate accumulates in such third-space fluid collections, which then act as a reservoir for slow distribution into the plasma, thereby increasing systemic exposure and the risk of toxicity.
Decreased functional reserve — Decreased functional reserve can increase the susceptibility to chemotherapy-related complications. Examples of conditions potentially leading to increased toxicity in older adults include the following.
Bone marrow — Bone marrow stem cell reserve may decrease with aging. This can contribute to increased hematologic toxicity with myelosuppressive agents, resulting in neutropenia and/or anemia [28].
The incidence of severe neutropenia is increased in older adults compared with younger patients with a variety of chemotherapy regimens [29-32]. Severe neutropenia may result in infectious complications, hospitalizations, and a higher mortality.
Under most circumstances, decreased doses, rather than white blood cell growth factors, are used to avoid severe neutropenia. Guidelines from the American Society of Clinical Oncology (ASCO) support the use of hematopoietic growth factors when the risk of febrile neutropenia is approximately 20 percent or higher [33]. Guidelines from the National Comprehensive Cancer Network (NCCN) recommend the use of such growth factors for all older-adult patients who are being treated with potentially curative regimens such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) [34]. (See 'Non-Hodgkin lymphoma' below and "Use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation".)
Anemia, which can impair functional status, is commonly seen in patients with cancer as a complication of both the illness and its treatment with chemotherapy [35-37]. The incidence of anemia increases significantly with age, both in males and females [35].
The erythropoiesis-stimulating agents (ESAs) epoetin alfa and darbepoetin alfa have been extensively evaluated in cancer patients. The utility of ESAs in patients with nonhematologic malignancies appears to be restricted to those patients in whom the anemia is due to chemotherapy, and there is some evidence that these agents may be harmful in patients with nonhematologic malignancies and anemia not due to chemotherapy. These agents are not indicated for patients being treated with curative intent. (See "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer".)
Heart disease — Preexisting occult heart disease is more frequent in older as opposed to younger patients. The presence of such heart disease can increase the risk of heart failure associated with anthracycline-like agents and trastuzumab or coronary artery vasospasm due to fluoropyrimidines. (See "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Cardiotoxicity of trastuzumab and other HER2-targeted agents" and "Fluoropyrimidine-associated cardiotoxicity: Incidence, clinical manifestations, mechanisms, and management".)
The potential risks associated with cardiotoxic chemotherapy in the older-adult population were illustrated by a Surveillance, Epidemiology, and End Results (SEER) Medicare database study of 9438 patients with diffuse B-cell non-Hodgkin lymphoma [38]. The risk of subsequently developing heart failure was increased 29 percent in those whose treatment included doxorubicin, and this increased risk was particularly prominent when anthracyclines were administered to those with hypertension.
The risks of cardiotoxicity in older adults need to be balanced against the benefits of chemotherapy, and newer methods need to be developed to prevent or treat such toxicity [39].
Polypharmacy — Older ambulatory patients use approximately three times as many medications as younger patients [40]. At least 90 percent of older patients used at least one medication, and the average is at least four medications per patient. The use of large numbers of medications by older patients increases the likelihood of harmful drug interactions, particularly for agents that are metabolized through the cytochrome P450 system [41,42]. Details about specific interactions may be obtained by using the drug interactions program included within UpToDate. Furthermore, due to the large number of medications used by older adults, compliance with therapy is an important issue [21-23,42,43].
Medications that inhibit cytochrome P450 enzymes (particularly CYP3A4) have the potential to increase the toxicity of chemotherapy drugs either by reducing their conversion to nontoxic metabolites or by increasing their conversion to toxic metabolites. On the other hand, agents that induce enzymes in the P450 pathway (eg, dexamethasone, anticonvulsants, alcohol) can decrease the therapeutic effectiveness of a chemotherapy agent by increasing the metabolism of active drug. Other medications that can interact with chemotherapy because of their metabolism by or inhibition of CYP3A4 are shown in the following table (table 2). (See "Drugs and the liver: Metabolism and mechanisms of injury".)
Drug-drug interactions may also be present with herbal remedies and other alternative medications. Details about specific interactions may be obtained by using the drug interactions program included within UpToDate. (See "Overview of complementary, alternative, and integrative medicine practices in oncology care, and potential risks and harm", section on 'Interactions of CAIM with conventional treatment'.)
Assessments of physical function and reserve — Older-adult patients may experience more frequent adverse events during chemotherapy than younger patients, independent of comorbidity [44]. However, a "fit older-adult" individual may tolerate standard doses and schedules of chemotherapeutic medications and thus may obtain the same benefit. By contrast, a "frail older-adult" patient has an increased risk of toxicity, and thus may not be able to tolerate a full course of treatment. In this situation, treatment may need to focus more heavily on improving quality of life (QOL), rather than prolonging survival [25,45-48].
The previously described age-related changes in physical health vary widely among individuals. Chronologic age is a poor marker of a patient's functional status. Careful assessment of these parameters is required [34]. Several methods of functional assessment are available.
Performance status — The most common method to measure physiologic reserve and functional status in cancer patients is the clinician-estimated performance status (PS). There are two widely used scales, Karnofsky Performance Status (KPS) (table 3) and the Eastern Cooperative Oncology Group (ECOG) scale (table 4).
Both the ECOG PS and KPS are useful to assess a patient's ability to tolerate chemotherapy and to assess short-term prognosis. Regardless of age, patients with a poor PS (eg, ECOG PS >2, KPS <60) usually tolerate chemotherapy poorly and have a short median overall survival. However, PS tends to underrepresent the degree of functional impairment in the older patient [49].
Activities of daily living — A more comprehensive understanding of an older patient's functional state can be obtained by use of Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) scales. ADL refers to the skills that are necessary for basic living, and include feeding, grooming, transferring, and toileting. IADL refers to the skills required to live independently in the community, including shopping, managing finances, housekeeping, preparing meals, and the ability to take medications.
Comprehensive geriatric assessment — Assessment of functional status with the ADL and IADL scales is a component of the comprehensive geriatric assessment (CGA) that is used by geriatricians to identify frail older patients at high risk of adverse outcomes such as falls, hospitalization, and death. (See "Frailty".)
Incorporating a more thorough geriatric assessment of function using the CGA can aid treatment decision-making in older cancer patients. As an example, in one report, formal evaluation using a CGA influenced therapeutic decision-making in 82 percent of 161 patients referred for geriatric oncology consultation [20].
There is no uniform CGA measurement tool, but all include some multidisciplinary assessment of the following domains: physical function, comorbid conditions, psychological state, social support, cognitive function, nutrition, and polypharmacy (table 5) [50]. (See "Comprehensive geriatric assessment for patients with cancer".)
Guiding treatment decisions by assessment of physical function — There is general agreement that frail older adults, those with significant functional impairment or an ECOG PS of 3 to 4 (table 4), should be supported with palliative measures aimed at maintaining QOL [51]. There is also general agreement that active, fit, older patients without comorbidity should be treated in the same fashion as younger patients with cancer (table 4).
The patients who are neither frail nor fit are the patients in whom treatment decision-making is most complex. Their treatment requires excellent communication and individualized care.
Models predicting chemotherapy toxicity and early death — Models have been developed to predict chemotherapy toxicity that are based upon geriatric assessment [52-56]. (See "Comprehensive geriatric assessment for patients with cancer", section on 'Potential benefits'.)
As examples:
●Investigators from the City of Hope developed the Cancer and Aging Research Group (CARG) model, which can be useful in predicting which patients are at increased risk of developing severe or fatal toxicity from chemotherapy (table 6 and figure 2) [54]. Parameters included within this model include age, type of cancer, the proposed chemotherapy regimen, renal and hematologic function, hearing, and activity levels from the CGA (ability to take medications, physical activity, social activity). This approach was significantly better than the clinician assessment of KPS for predicting chemotherapy toxicity (table 7). In an independent validation cohort including 250 patients ≥65 years, CARG score correlated with frequency of toxicities, with 37 percent of patients with low CARG scores experiencing chemotherapy-related toxicities versus 62 of those with medium and 70 percent of those with high CARG scores [57].
•More recently, the CARG-Breast Cancer (CARG-BC) was developed to predict toxicity from chemotherapy specifically in older adults with early breast cancer (figure 3) (calculator 2), with better prediction than either KPS or the more general CARG in this subset [58]. Like the general CARG, it considers anemia, falls, limited mobility, and social factors, but also includes cancer stage, regimen, planned treatment duration, and liver function to refine its predictive ability. Further discussion on management of older adults with early breast cancer is found elsewhere. (See "Overview of the approach to early breast cancer in older women".)
●European investigators studying predictors of early death in older patients treated with first-line chemotherapy for cancer identified advanced disease, a low score on the mini-nutritional assessment, and long Get Up And Go test as being parameters associated with a higher risk of early death (within six months) after initiation of chemotherapy [59].
●Investigators at the Moffitt Cancer Center developed a Chemotherapy Risk Assessment Scale for High age (CRASH) score to predict the risk of chemotherapy-related hematologic and nonhematologic toxicity in older persons [53]. This model takes into account the specific chemotherapy regimen to be used as well as laboratory values (creatinine, albumin, hemoglobin, lactate dehydrogenase [LDH], liver function tests) and assessments of functional, mental, and nutritional status.
SPECIFIC MALIGNANCIES — Patient age influences the biologic behavior of some malignancies. As examples, acute myeloid leukemia (AML) and aggressive non-Hodgkin lymphoma (NHL) have a poorer prognosis in older adults compared with younger individuals. By contrast, breast cancer tends to be somewhat more indolent.
Breast cancer — Systemic treatment for breast cancer, both as an adjuvant and for metastatic disease, can be used successfully in older patients. Such treatment needs to consider both the patient's overall status and potential differences in the natural history of the disease [60].
The Cancer and Aging Research Group-Breast Cancer (CARG-BC) was developed to predict toxicity from chemotherapy specifically in older adults with early breast cancer (figure 3) (calculator 2) [58]. (See 'Models predicting chemotherapy toxicity and early death' above.)
Adjuvant therapy — Both systemic hormonal therapy and chemotherapy can have an important role in the management of early breast cancer in older adults. In addition to the patient's expected survival, comorbidity, and functional status, a knowledge of the status of regional lymph nodes, primary tumor size, histopathology, estrogen and progesterone receptor status, and whether or not there is expression of human epidermal growth factor receptor 2 (HER2)/neu all must be considered in making specific recommendations.
Issues surrounding the use of adjuvant therapy for breast cancer in older-adult patients are discussed separately. (See "Overview of the approach to early breast cancer in older women".)
Metastatic disease — Management of metastatic breast cancer in patients >65 years old follows the same principles as in younger patients, with a few exceptions. Like younger patients, older patients are unlikely to be cured of metastatic disease, and the goal of therapy is palliation rather than cure.
Because of the higher frequency of hormone receptor expression and the tendency toward more indolent tumor growth, older patients with an unknown hormone receptor status and without life-threatening or rapidly progressive disease should receive a trial of endocrine therapy. If there is a response or a prolonged period of stable disease with the initial endocrine treatment, several different endocrine agents should be tried in succession to maximize quality of life (QOL) for the longest period of time. (See "Treatment of metastatic breast cancer in older women", section on 'HER2-negative disease'.)
Chemotherapy may be considered when a tumor becomes refractory to endocrine therapy or as first-line therapy if life-threatening or rapidly progressive disease is present. Sequential single-agent therapy is often chosen rather than combination chemotherapy in older patients with metastatic breast cancer. Osteoclast inhibition significantly reduces the risk of skeletal-related events in patients with bone metastases; the choice of agent (ie, a bisphosphonate or denosumab) depends on many factors. (See "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors".)
Colorectal carcinoma — Approximately 70 percent of cases of colorectal cancer occur in individuals >65 years old. Chemotherapy regimens that incorporate fluorouracil (FU) or capecitabine are used both as an adjuvant following surgery and for palliation of metastatic disease.
Care must be taken in patients with significant cardiovascular disease because of the potential cardiotoxicity of fluoropyrimidines. (See "Fluoropyrimidine-associated cardiotoxicity: Incidence, clinical manifestations, mechanisms, and management".)
The possibility of enterotoxicity from these agents should also be considered in older-adult patients who have undergone bowel surgery and/or radiation therapy, and these patients may have altered bowel function. (See "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'Fluorouracil' and "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'Capecitabine'.)
Adjuvant therapy — Adjuvant chemotherapy is underused in patients >65 years old, despite the significant reduction in recurrence and death associated with adjuvant chemotherapy. Although individual trials have provided little information on chemotherapy effectiveness in this population, pooled analyses of data indicate that older patients derive as much benefit from FU-based adjuvant chemotherapy as do younger patients, although the incremental benefit from oxaliplatin may be less. Treatment-related toxicity is not necessarily worse when close attention is paid to regimen selection. These results are discussed separately. (See "Adjuvant therapy for resected colon cancer in older adult patients".)
Metastatic disease — In older-adult patients with metastatic colorectal cancer, pooled results indicate that antitumor efficacy of chemotherapy is similar to that in younger individuals, although there may be a slightly higher rate of hematologic toxicity. Based upon these results, standard FU-based chemotherapy regimens that include either oxaliplatin or irinotecan are a reasonable option for older-adult patients. (See "Therapy for metastatic colorectal cancer in older adult patients and those with a poor performance status".)
In older-adult patients, irinotecan is associated with an increased incidence of delayed diarrhea, due to intestinal accumulation of SN-38, the active metabolite of irinotecan. For this reason, irinotecan should be started at reduced doses in patients >70 years old [61,62].
Most older-adult patients can tolerate the addition of bevacizumab to these regimens for first-line therapy, although concerns about the potential for thromboembolic complications have tempered enthusiasm for this approach. (See "Therapy for metastatic colorectal cancer in older adult patients and those with a poor performance status", section on 'Bevacizumab and biosimilars'.)
Non-small cell lung cancer — Slightly more than one-half of patients diagnosed with non-small cell lung cancer (NSCLC) are >70 years old. About one-third present with metastatic (stage IV) disease and a majority are not able to undergo potentially curative surgical resection.
Chemotherapy is used as an adjuvant after surgical resection for early-stage disease, as a component of multimodality therapy for stage III disease, and in first- and second-line therapy to palliate advanced disease.
Adjuvant therapy — Adjuvant chemotherapy clinical trials in NSCLC have primarily focused upon younger patients. Subset analyses of one trial suggest that adjuvant chemotherapy is as effective in carefully selected older-adult patients as it is in those who are younger. (See "Systemic therapy in resectable non-small cell lung cancer", section on 'Older adult patients'.)
Stage III disease — Randomized trials have established the superiority of concurrent administration of chemotherapy and radiotherapy compared with sequential chemotherapy and radiation therapy, and concurrent chemoradiotherapy has become the preferred approach for most unresected patients with pathologic stage III disease. (See "Management of stage III non-small cell lung cancer", section on 'Preferred approach: Chemoradiotherapy, followed by durvalumab'.)
Although concurrent chemoradiotherapy in older-adult patients with stage III NSCLC is associated with an increased incidence of severe toxicity, subset analyses have shown that survival at two and five years is similar to that in younger patients. However, older-adult patients managed with chemoradiotherapy may be at increased risk of cardiac disorders even if they were free of such problems prior to the diagnosis of NSCLC [63].
Some evidence suggests that comprehensive geriatric assessment (CGA) is prognostic and may also predict those at highest risk of toxicities from treatment. For example, in a prospective study of 85 patients at least 75 years old with inoperable, locally advanced NSCLC who underwent CGA and the Vulnerable Elders Survey (VES-13), those classified as fit or medium-fit by CGA were administered concurrent platinum-based chemoradiotherapy, while unfit patients received best supportive care [64]. Fit and medium-fit patients had longer median overall survival than unfit patients (23.9 and 16.9 months, respectively, versus 9.3 months). Among patients receiving chemoradiotherapy, higher scores on the VES-13 were associated with shorter overall survival and higher risk of serious toxicity. Geriatric assessment in cancer patients is discussed in more detail elsewhere. (See "Comprehensive geriatric assessment for patients with cancer".)
Palliative chemotherapy — Clinical trials have shown that systemic therapy can improve both survival and QOL in older-adult as well as young patients. The approach to older patients with advanced lung cancer is discussed in more detail elsewhere. (See "Overview of the initial treatment of advanced non-small cell lung cancer", section on 'Older adult patients'.)
Small cell lung cancer — Approximately one-third of patients with small cell lung cancer (SCLC) are ≥70 years old. Standard chemotherapy regimens have caused increased toxicity in this population, although survival was similar to younger patients. By contrast, single-agent chemotherapy or dose attenuation caused less toxicity but resulted in inferior survival. Thus, older-adult patients should be treated with the same doses and regimens as a younger population if their overall medical condition is satisfactory [65]. (See "Extensive-stage small cell lung cancer: Initial management", section on 'Older adult patients or those with poor performance status'.)
Non-Hodgkin lymphoma — For older-adult patients with aggressive NHL, combination chemotherapy using the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone) remains the standard approach because of its curative potential (table 8). Rituximab is added to CHOP for older-adult patients with lymphomas that are positive for CD20. Although this regimen has significant toxicity, less intense regimens do not appear to be as effective. (See "Initial treatment of advanced stage diffuse large B cell lymphoma" and "Initial treatment of peripheral T cell lymphoma" and "Treatment protocols for lymphoma", section on 'Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone with 21 days between cycles (R-CHOP-21)'.)
American Society of Clinical Oncology (ASCO) guidelines recommend that white blood cell growth factors be given to patients ≥65 years of age with diffuse aggressive lymphoma to permit the administration of full doses of potentially curative chemotherapy [33]. Although the cost-effectiveness of primary as compared with secondary prophylaxis in this setting has been questioned [66], we still agree with the ASCO guidelines and consider that individuals over the age of 65 represent a high-risk group for treatment-related myelosuppression. (See "Use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation".)
Recurrent NHL in the older-adult population is particularly difficult to treat. If a patient cannot tolerate standard salvage chemotherapy, regimens designed particularly for older-adult patients may be tried. Alternatively, single-agent therapy with anthracyclines, cytarabine, or alkylating agents may be used for symptom palliation. (See "Diffuse large B cell lymphoma (DLBCL): Second or later relapse or patients who are medically unfit", section on 'Medically unfit, but not frail'.)
The long natural history of indolent NHLs and the lack of symptoms at diagnosis have fostered close observation as the initial approach for many of these patients, although chemotherapy options should be considered in selected patients. This approach may be particularly attractive in older patients. (See "Initial treatment of stage I follicular lymphoma".)
Hodgkin lymphoma — Hodgkin lymphoma (HL) has a bimodal age distribution with one peak in young adults, and another in older adults (approximately 65 years of age). (See "Hodgkin lymphoma: Epidemiology and risk factors", section on 'Age and race'.)
The treatment of older adults with HL has not been well studied, and older adults should be encouraged to participate in clinical trials, whenever possible. Older adults are more likely to have comorbidities that can limit treatment options and increase the risk of toxicity, but they should be offered curative therapy such as that used for younger adults whenever possible. Although doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) is the regimen most often offered to older patients with HL, there are increasing data that older patients are particularly vulnerable to the toxicity of bleomycin, which can be severe. Some have advocated omitting bleomycin in older patients. (See "Initial treatment of advanced (stage III-IV) classic Hodgkin lymphoma", section on 'Older adults' and "Bleomycin-induced lung injury", section on 'Age' and "Bleomycin-induced lung injury", section on 'Hodgkin lymphoma' and "Bleomycin-induced lung injury", section on 'Risk factors'.)
Acute myeloid leukemia — Acute myeloid leukemia (AML) has a poorer prognosis in older compared with younger patients. However, otherwise healthy, older patients with AML, especially those with favorable cytogenetic features, should be offered curative chemotherapy with standard regimens. (See "Acute myeloid leukemia: Management of medically unfit adults".)
For older-adult patients with indolent AML, severe comorbidity, or high risk and unfavorable prognostic factors, intensive chemotherapy may not be the most appropriate choice. In these settings, supportive care with transfusions and control of leukocytosis should be considered. (See "Acute myeloid leukemia: Management of medically unfit adults", section on 'Supportive care'.)
SUMMARY AND RECOMMENDATIONS
●Introduction – Although there are important differences in the treatment of advanced cancer in the older-adult population, the same principles used in younger patients can be applied if appropriate precautions are taken into account.
●Kidney function and dose modification – Pharmacokinetic differences in chemotherapy drug handling in older adults potentially can contribute to increased toxicity. Particular attention should be given to dosages of drugs that are excreted by the kidneys. Dosages should be modified based upon the calculated creatinine clearance and not the serum creatinine (table 9). (See 'Kidney function and drug excretion' above.)
●Assessment of functional status – There are accumulating data that some form of assessment is critical to the decision-making process for older patients with cancer.
Extent of comorbidity and functional impairment should be assessed prior to the initiation of treatment and should be incorporated into the overall treatment plan. A comprehensive geriatric assessment can be particularly useful. (See 'Comorbidity and functional status' above and 'Comprehensive geriatric assessment' above.)
Predictive tools such as the Cancer and Aging Research Group (CARG) or Chemotherapy Risk Assessment Scale for High age (CRASH) risk scores can be useful to identify those patients who are at high risk for chemotherapy-related toxicity and mortality. (See 'Models predicting chemotherapy toxicity and early death' above.)
●Approach to the healthy older-adult patient – For the healthy older-adult patient with minimal comorbidity and near-normal functional reserve, aggressive treatment including full doses of chemotherapy is warranted, especially in the potentially curative setting, and can yield results that are similar to those in younger patients. (See 'Breast cancer' above and 'Colorectal carcinoma' above and 'Non-small cell lung cancer' above and 'Small cell lung cancer' above and 'Non-Hodgkin lymphoma' above.)
•The use of white blood cell growth factors may permit the clinician to maintain dose intensity and avoid severe neutropenia. (See 'Bone marrow' above and 'Non-Hodgkin lymphoma' above.)
•Erythropoiesis-stimulating agents may be useful to treat chemotherapy-induced anemia. However, there is controversy about use of these agents in patients being treated with curative intent because of concerns about inferior disease outcomes in some but not all studies. This subject is addressed in detail elsewhere. (See 'Bone marrow' above and "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer".)
●Approach to the frail older-adult patient – For the frail older-adult patient, therapeutic goals may need to focus primarily on quality of life and symptom palliation, rather than prolonging survival. (See 'Comorbidity and functional status' above.)
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