A highly functional 83-year-old woman with early-stage breast cancer presents for follow-up. She has a history of controlled hypertension, and had coronary artery stents placed 3 years ago after an episode of unstable angina. Three months ago, routine mammography revealed a calcified lesion in her left breast. She underwent a biopsy that revealed invasive ductal adenocarcinoma. She had a lumpectomy and sentinel lymph node dissection, which revealed adenocarcinoma in 0 of 3 sentinel lymph nodes. On review of the pathology, her tumor was 1.3 cm, estrogen receptor (ER) positive, progesterone receptor (PR) positive, HER-2 positive, high nuclear grade, and moderately well-differentiated. She has no family history of breast cancer. She received radiation therapy to her left breast and is now ready to begin adjuvant treatment with an aromatase inhibitor and possibly trastuzumab. Cardiac evaluation consisted of an electrocardiogram showing nonspecific ST-T wave changes and an echocardiogram revealing an ejection fraction of 42% with segmental left ventricular wall motion abnormalities and mild mitral regurgitation. She is given a prescription for a 30-day supply of letrozole along with calcium and vitamin D supplements. It was decided to defer trastuzumab therapy because of the cardiac abnormalities. Three weeks later, she calls stating that she is completely out of medication. The pharmacy insists that she was given the correct number of pills. The patient uses a pill box which she herself fills weekly with her seven daily medications for hypertension, hypercholesterolemia, and hypothyroidism. It is unclear where the error occurred but there is significant concern that the patient may have consumed extra doses of the letrozole.
A 78-year-old man presented to his primary care physician complaining of weakness and fatigue. His physical examination was unremarkable except for guaiac-positive stools. The patient was referred for his first colonoscopy and was found to have a cecal mass; the biopsy showed adenocarcinoma. A CT scan revealed extensive pulmonary and liver metastases. His hemoglobin level was 8.9 gm/dL, with a ferritin level of 5 ng/mL. Past medical history was significant for hypertension. The patient had been hospitalized for a transient ischemic attack 3 months ago, which caused transient dysarthria. He is currently on aspirin. Because of extensive disease, he was started on systemic chemotherapy with FOLFOX (fluorouracil, leucovorin, oxaliplatin) and supplemental iron. Bevacizumab was deferred due to his recent arterial thrombotic event and hypertension.
Cancer is a disease of older adults, with approximately 60% of cancer diagnoses and 70% of cancer mortality occurring in individuals age 65 and older. As the population ages and life expectancy increases, there are more elderly adults with cancer and several unique challenges arise in caring for them. Specifically, the physiological changes associated with aging can affect the pharmacokinetics and pharmacodynamics of cancer therapies. Because the clinical trials that set the standards for oncology care have typically underrepresented the elderly and focused on a younger patient population, the effects of age-related changes on drug dosing and tolerance have been understudied. In this chapter, the means by which these age-related changes may affect the safety, tolerability, and efficacy of novel and targeted therapies in the elderly will be reviewed. The challenges of polypharmacy and nonadherence in this population will also be explored. Finally, existing evidence regarding the safety and efficacy of targeted agents in elderly cancer patients will be discussed.
Physiologic Changes with Aging
While aging is a heterogeneous process, there are some characteristic changes in physiology and organ function that can have an impact on the pharmacology and toxicity of anticancer therapy. Several reviews discuss the pharmacology of chemotherapy in older patients, and some of the key physiologic changes that occur with aging that may affect the pharmacokinetics and pharmacodynamics of anticancer therapies will be summarized ( Table 10-1 ).
| Organ/System | Physiologic Change |
|---|---|
| Renal | Decreased creatinine clearance |
Gastrointestinal
|
|
Bone marrow
|
|
Body composition
|
|
Renal Function
With increasing age, there is a decrease in renal mass and renal blood flow. While serum creatinine is often used to approximate renal function in younger adults, it is a poor indicator of renal function in older adults because of a decrease in muscle mass with age. On average, the glomerular filtration rate decreases by approximately 0.75 mL/min/year after age 40. However, this decrease is not universal and approximately one third of all patients will have no change in creatinine clearance with age. There are several equations that have been used to estimate glomerular filtration rate. The Cockcroft/Gault and Jeliffe formulas have primarily been validated in younger patients without renal diease. For elderly patients with a glomerular filtration rate over 50mL/min, the Wright formula is more accurate. For those with chronic renal disease, the modification of diet in renal disease (MDRD) formula is more accurate, as it takes into account age, sex, ethnicity, serum creatinine, blood urea nitrogen, and albumin.
Absorption and Metabolism
As people age, they experience a decrease in splanchnic blood flow, gastrointestinal motility, and secretion of digestive enzymes, all of which, along with the mucosal atrophy that occurs with age, can alter drug absorption. In addition, hepatic mass and cytochrome P450 content decrease with increasing age. However, the consequences of these changes remain controversial. As a result of changes in body composition involving an increase in body fat and decrease in total body water, the volume of distribution for drugs that are lipid-soluble increases and the volume of distribution decreases for water-soluble drugs. Many drugs are bound to albumin and, as a result, hypoalbuminemia can increase the volume of distribution of their bound drugs.
Bone Marrow
Bone marrow fat increases and bone marrow reserve decreases with increasing age. This decrease in reserve places older adults at increased risk for myelosuppressive complications from chemotherapy. The American Society of Clinical Oncology (ASCO) recommends primary prophylaxis with white blood cell growth factors for the prevention of febrile neutropenia in patients older than 65. ASCO had suggested use of erythropoietin-stimulating agents. However, their use will be limited because of recent data and FDA recommendations ( http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm109375.htm ). In addition, many drugs are bound to hemoglobin; anemia can therefore increase the volume of distribution of drugs, which in turn alters their metabolism.
Renal Function
With increasing age, there is a decrease in renal mass and renal blood flow. While serum creatinine is often used to approximate renal function in younger adults, it is a poor indicator of renal function in older adults because of a decrease in muscle mass with age. On average, the glomerular filtration rate decreases by approximately 0.75 mL/min/year after age 40. However, this decrease is not universal and approximately one third of all patients will have no change in creatinine clearance with age. There are several equations that have been used to estimate glomerular filtration rate. The Cockcroft/Gault and Jeliffe formulas have primarily been validated in younger patients without renal diease. For elderly patients with a glomerular filtration rate over 50mL/min, the Wright formula is more accurate. For those with chronic renal disease, the modification of diet in renal disease (MDRD) formula is more accurate, as it takes into account age, sex, ethnicity, serum creatinine, blood urea nitrogen, and albumin.
Absorption and Metabolism
As people age, they experience a decrease in splanchnic blood flow, gastrointestinal motility, and secretion of digestive enzymes, all of which, along with the mucosal atrophy that occurs with age, can alter drug absorption. In addition, hepatic mass and cytochrome P450 content decrease with increasing age. However, the consequences of these changes remain controversial. As a result of changes in body composition involving an increase in body fat and decrease in total body water, the volume of distribution for drugs that are lipid-soluble increases and the volume of distribution decreases for water-soluble drugs. Many drugs are bound to albumin and, as a result, hypoalbuminemia can increase the volume of distribution of their bound drugs.
Bone Marrow
Bone marrow fat increases and bone marrow reserve decreases with increasing age. This decrease in reserve places older adults at increased risk for myelosuppressive complications from chemotherapy. The American Society of Clinical Oncology (ASCO) recommends primary prophylaxis with white blood cell growth factors for the prevention of febrile neutropenia in patients older than 65. ASCO had suggested use of erythropoietin-stimulating agents. However, their use will be limited because of recent data and FDA recommendations ( http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm109375.htm ). In addition, many drugs are bound to hemoglobin; anemia can therefore increase the volume of distribution of drugs, which in turn alters their metabolism.
Polypharmacy
Polypharmacy means “many drugs” and is used to describe the use of more medication than is clinically indicated or warranted. While people older than 65 years represent approximately 15% of the population, they account for more than one third of all prescription drugs taken and an even larger percentage of nonprescription drugs. This often unnecessary use of many drugs can produce noxious results such as adverse drug reactions and drug-drug interactions and can lead to increased emergency room visits, hospitalizations, and nursing home admissions. A recent drug evaluation reported that three medications accounted for about one third of emergency department visits for adverse drug events in older adults: warfarin (17.3%), insulin (13.0%), and digoxin (3.2%). In addition, the elderly cancer patient often needs medications prescribed to treat possible side effects of other drugs.
Nonadherence
Adherence is defined by the World Health Organization (WHO) as the extent to which a person’s behavior corresponds with agreed-upon recommendations from a health care provider. Issues related to adherence are not well understood, and it is difficult to measure accurately. Generally, clinicians assume that patients are taking medications as prescribed and believe their patients when they say they are doing so. However, many studies have shown poor adherence with medications that have proven benefit when taken appropriately. A patient’s choice to follow the clinician’s advice is influenced by his or her assessment of risks and benefits. Some of the major risk factors for poor adherence include cognitive impairment, treatment of asymptomatic disease, inadequate follow-up, poor provider-patient relationship, adverse effects of medications, and patient’s lack of belief in the benefit of treatment. Poor adherence has long been acknowledged as an obstacle in improving patient care. With the recently passed health care legislation reform, there is a desire to create an infrastructure for improving health outcomes through improved adherence.
As many of the new anticancer targeted therapies are administered orally, they can be taken at home, eliminating the need for intravenous access; however, this shifts many of the responsibilities of managing the regimen from the oncologist to the patient. Even in clinical trials, a context in which the patients are highly motivated and receive extra supervision, adherence is quite variable, ranging from 20% to100%. In addition, a study of anastrozole therapy adherence in early-stage breast cancer reported that approximately one in four women was not optimally adherent. In 2009, at the San Antonio Breast Cancer Symposium, data from the British Columbia Cancer Agency, Vancouver, BC, Canada, were presented showing that only 40% of their population, all of whom receive medications free of charge, was compliant with hormonal therapy.
Despite the impressive efficacy of imatinib for chronic myelogenous leukemia (CML), treatment failure and suboptimal responses are seen and may be due to poor adherence. From a study in Belgium evaluating imatinib adherence for CML, one third of patients were nonadherent, and those with suboptimal responses showed significantly less adherence. Another prospective trial demonstrated a correlation between adherence to imatinib and major—and even complete—molecular responses.
Clearly, further research focusing on strategies to improve adherence in the oncology setting is needed. One effective step to ensure appropriate prescribing and improve adherence is medication reconciliation with review of all medications at every visit. Patient and family education is another critical element in achieving medication adherence. This is of particular importance in elderly patients, who often take multiple medications, and who may have difficulties managing complex regimens without assistance from caregivers.
Targeted Therapies
There are three major classes of target drug therapy: endocrine therapy, monoclonal antibodies, and signal transduction inhibitor. Each class of medications and each specific drug has its own adverse reactions and safety profile. For none of these medications does enough data exist to routinely recommend dose alterations in the elderly ( Table 10-2 ). However, many of these medications have specific side effects ( Table 10-3 ) that are potentially more significant in an elderly population given their comorbid conditions, the prescription medications they often take, and the physiological changes associated with normal aging.
| Drug | Elderly | Hepatic | Renal |
|---|---|---|---|
| Tamoxifen | No | No | No |
| Aromatase inhibitor | No | No, but not studied with severe impairment | No |
| Bevacizumab | No | No | No |
| Cetuximab | No | No | No |
| Rituximab | No | No | No |
| Trastuzumab | No | No | No, unless creatinine > 2 mg/dL |
| Imatinib | No | Yes, severe impairment | Yes |
| Erlotinib | No | Yes | No |
| Sorafenib | No | Yes | Yes |
| Sunitinib | No | Not studied with severe impairment, no adjustment with mild or moderate impairment | Not studied |
| Temsirolimus | No | Not studied | No |
| Lapatinib | No | Yes, severe impairment | No |
| Bortezomib | No | Yes, moderate impairment | No |
| Drug | Event |
|---|---|
| Tamoxifen | Thromboembolism, ischemic cerebrovascular events, endometrial hyperplasia, endometrial cancer, and cataract development |
| Aromatase inhibitor | Musculoskeletal symptoms and osteoporosis |
| Bevacizumab | Thrombosis, bleeding, neutropenic fever, hypertension, and gastrointestinal perforation |
| Cetuximab | Diarrhea |
| Rituximab | Infusion reaction |
| Trastuzumab | Cardiac toxicity |
| Imatinib | Edema, rash, fatigue |
| Erlotinib | Rash, diarrhea |
| Sorafenib | Cardiac toxicity |
| Sunitinib | Cardiac toxicity |
| Temsirolimus | Thrombocytopenia |
| Lapatinib | Cardiac toxicity |
| Bortezomib | Thrombocytopenia |
Endocrine Therapy
The oldest example of “targeted therapy” is perhaps the proposal of oophorectomy as a treatment for advanced breast cancer in 1889. Since then, drugs that inhibit estrogen signaling, whether by blocking the estrogen receptor, as with selective estrogen receptor modulators (SERM), or by inhibiting the production of estrogen, as with aromatase inhibitors, have become commonly used agents in the adjuvant and metastatic setting for older patients with hormone receptor-positive breast cancer. However, some data suggest that toxicities may vary within subgroups of older oncology patients and the impact of the different side effect profiles remains unclear.
Tamoxifen
Tamoxifen is a SERM that competes with estrogen for binding at the estrogen receptor. When used for 5 years in patients aged 70 or older with early-stage, ER-positive breast cancer, it has had a significant role in reducing the risk of breast cancer recurrence and death. However, because tamoxifen has partial estrogen-agonist effects, its use is associated with an increased risk of thromboembolism, ischemic cerebrovascular events, endometrial hyperplasia, endometrial cancer, and risk of cataract development. Notably, the increased risk of endometrial cancer is almost exclusively seen in patients older than 50 and the absolute risk remains low. Clearly, these risks may influence the safety and tolerability profile of tamoxifen in older women with breast cancer, especially those with other comorbid conditions.
Aromatase Inhibitors
Aromatase inhibitors (AIs) block the enzyme aromatase that is responsible for the peripheral conversion of androgenic substrates into estrogen. Several randomized trials demonstrated superior disease-free survival with AIs compared to tamoxifen for the adjuvant treatment of postmenopausal women with early-stage, hormone receptor-positive breast cancer. While AIs have been associated with an increased incidence of musculoskeletal symptoms and osteoporosis, there has been less endometrial cancer and hypercoagulability than with tamoxifen. Notably, in a study of 1,300 women aged 70 or older, they had significantly higher incidences of fracture, new osteoporosis, and heart disease relative to younger women but there was no treatment-related association. However, a meta-analysis of several randomized AI studies suggested an increased risk for grade 3 and 4 cardiovascular complications (RR 1.31, p = 0.007) compared to tamoxifen. There remains some ambiguity regarding specific toxicities in the elderly population, but for now the evidence favors use of aromatase inhibitors for hormone receptor-positive breast cancer in postmenopausal women.
Monoclonal Antibodies
Monoclonal antibodies are the most widely-used cancer immunotherapy. The first monoclonal antibodies were made entirely from mouse cells; this posed a problem when patients developed severe allergic reactions as their immune systems mounted attacks against the mouse antibodies because they were recognized as foreign. Over time, however, techniques have been developed to replace entire or significant portions of the mouse antibodies with human parts. These part-mouse and part-human antibodies are referred to as chimeric or humanized. Monoclonal antibodies function by either activating the immune systems of patients to recognize and then destroy cancer cells or by binding to parts of cancer cells or those cells that help them grow and blocking them from working.
Bevacizumab
Bevacizumab is a humanized monoclonal antibody that inhibits vascular endothelial growth factor (VEGF) from binding its receptor and thereby prevents downstream signaling events. It has been approved for use in multiple diseases. Rare but serious adverse reactions include hypertension, gastrointestinal perforation, and proteinuria. Patients also commonly experience pancytopenia, diarrhea, and fatigue. Several studies have shown improved progression-free and overall survival with the incorporation of bevacizumab into first-line therapy in advanced colorectal cancer. Relative to younger patients, grade 3 to 4 leukopenia was 5% higher in the elderly. In addition, a retrospective pooled analysis of five randomized studies in 1745 patients demonstrated an increased risk of arterial thromboembolic events in those aged 65 or older who received chemotherapy and bevacizumab. From a community-based registry of 1953 patients receiving bevacizumab, the safety and effectiveness of bevacizumab in patients aged 65 or older was similar to those younger than 65. In this cohort, age was not a significant factor in predicting targeted bevacizumab-related safety events. Additional studies have confirmed this finding. Another analysis of elderly colorectal patients at the Mayo Clinic demonstrated an increased incidence of adverse events in the population age 75 and older relative to the group 70 to 74 years of age. Thus, elderly patients appear to experience more adverse events but the nature of the association between these events and the addition of bevacizumab requires further study.
The role of bevacizumab in older patients with non-small cell lung cancer (NSCLC) has been examined. A retrospective analysis of the patients aged 70 and older showed a trend towards higher response rate and progression-free survival with the use of bevacizumab, but overall survival was similar. Elderly patients did have a greater incidence of grade 3 to 5 neutropenia, bleeding, and proteinuria with bevacizumab. Bevacizumab was, therefore, associated with a higher degree of toxicity but no improvement in overall survival. Bevacizumab is also approved for use in the first-line treatment of metastatic breast cancer in combination with paclitaxel. A retrospective study of patients older than 65 who received bevacizumab with chemotherapy for advanced breast cancer revealed an increased incidence of thrombosis, bleeding, neutropenic fever, and gastrointestinal perforation.
On the basis of the data, bevacizumab is beneficial as first-line treatment in elderly patients with advanced colorectal disease. However, its role in the treatment of elderly patients with NSCLC and breast cancer is less apparent, especially in patients with underlying cardiovascular disease.
Cetuximab and Panitumumab
Cetuximab is a chimeric monoclonal antibody directed to the exodomain of the epidermal growth factor receptor (EGFR), which blocks downstream signaling. Panitumumab is a fully humanized antibody also directed against EGFR. After failure of standard therapies, cetuximab and panitumumab have shown activity against metastatic colorectal cancer. However, retrospective subset analyses suggest that patients with KRAS mutations do not benefit from anti-EGFR therapy. When used in combination with irinotecan in irinotecan-resistant patients, there is also some evidence suggesting drug-resistance reversal. Cetuximab is also approved for the treatment of head and neck cancer in combination with radiotherapy.
Unfortunately, very few data are available regarding cetuximab use in elderly patients. Common side effects include fatigue, rash, abdominal pain, weakness, and diarrhea. A retrospective review of elderly patients who received cetuximab for metastatic colorectal carcinoma revealed that 75% experienced rash, 11% grade 3; and 80% experienced diarrhea, 20% grade 3-4. A prospective phase II study of first-line single-agent cetuximab in elderly patient with metastatic colorectal cancer, which excluded frail patients, demonstrated 12.2% grade 3 skin toxicity.
Rituximab
Rituximab is a chimeric murine and human monoclonal antibody directed against the CD20 antigen of B-lymphocytes, and is used alone and in combination with cytotoxic chemotherapeutic agents to treat lymphomas. Despite the large proportion of elderly patients in the lymphoma population, few studies have evaluated rituximab in the elderly. Most adverse reactions are infusion-related and are usually mild after the first dose. The combination of rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) appears well-tolerated and effective in those older than 60 years with aggressive non-Hodgkin lymphoma and, in fact, was first studied in the elderly population. In addition, the role of maintenance rituximab after CHOP chemotherapy with or without rituximab was investigated in patients aged 60 or older. Overall, nonhematological toxicity was the same in the two groups of patients. It therefore seems that the incorporation of rituximab into standard chemotherapy regimens for indolent and aggressive lymphoma in the elderly does not increase overall toxicity in a significant manner.
Trastuzumab
Trastuzumab is a humanized monoclonal antibody that targets the HER-2/neu receptor. In combination with chemotherapy, overall survival is improved in women with advanced and early-stage HER-2-amplified or overexpressed breast cancer. Cardiac toxicity is a significant side effect, especially in patients who received concomitant anthracycline-based chemotherapy. For those older than 60 years, the risk of cardiac toxicity is higher (21% in those older than 60 years versus 11% in those 60 years or younger), but the overall survival advantage is maintained. Because of the potential for cardiac toxicity, most patients with cardiac comorbidities were excluded from the adjuvant trials of trastuzumab. However, this restriction also eliminated many older patients, and thus the available data are limited regarding the benefit of adjuvant trastuzumab for women older than 60 years; at present, they suggest that the benefits outweigh the risks.
Signal Transduction Inhibitors
Signal transduction inhibitors block signals passed between molecules; these signals are often involved in many functions of the cells including death, growth, and division. Many drugs have been developed to block particular signals in the hope of precluding cancer cells from rapidly multiplying and invading other tissues.
Imatinib
Imatinib is an orally administered tyrosine kinase inhibitor metabolized by the cytochrome P450 isoenzyme 3A4. Common toxicities include edema, fatigue, rash, nausea, diarrhea, muscle cramps, and pancytopenia. Nearly all patients with CML in chronic phase treated with imatinib achieve a complete hematologic response, which is defined as normalization of the white blood cell count with no immature granulocytes and less than 5% basophils, platelet count less than 450,000/μL , and a nonpalpable spleen. Complete cytogenetic response, defined as no detectable Philadelphia chromosome-positive cells, occurs in 69% of those treated with imatinib for 12 months and 87% of those treated for 60 months. The use of imatinib in elderly patients with chronic phase CML or Philadelphia-positive acute lymphoblastic leukemia has been studied and has shown efficacy similar to that in younger patients.
Although gastrointestinal stromal tumors (GISTs) are resistant to conventional chemotherapy, they are extremely sensitive to therapy with imatinib. Approximately 90% of patients with GIST experience tumor control with imatinib and prolonged overall survival. In a phase III trial of imatinib in patients with advanced or metastatic GIST, only the nonhematologic toxicities of edema, rash, and fatigue correlated with advanced age.
Erlotinib
Erlotinib targets the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). Rare but serious events such as gastrointestinal perforation, bullous and exfoliative rash, and corneal perforation have been reported. Common side effects include fatigue, rash, and diarrhea. Extreme caution is used in patients with abnormal liver function tests. In the National Cancer Institute of Canada Clinic Trials Group (NCICCTG) BR.21 study, the use of erlotinib improved survival in patients who had experienced treatment failure with first- or second-line chemotherapy for non-small cell lung cancer. A retrospective analysis of elderly patients in this trial revealed more toxicity overall and more severe toxicity. In addition, tissue samples from participants in the BR.21 study were analyzed for EGFR mutations and EGFR copy number. Mutations and high copy number were predictive of a response to erlotinib and EGFR fluorescence, while EGFR fluorescence in situ hybridization (FISH) positivity and wild type were associated with a survival benefit from the use of erlotinib.
Despite the paucity of randomized prospective studies to confirm the efficacy and tolerance of erlotinib in elderly patients, it is often used as a single agent in frail patients or those with poor performance status. Notably, a phase II study of erlotinib as first-line therapy for patients aged 70 and older with advanced non-small cell lung cancer showed that 12% of patients required discontinuation of therapy compared with 5% of those in the erlotinib arm of the BR.21 trial. Additional open-label, nonrandomized studies have demonstrated tolerable toxicities with erlotinib use as first-line or subsequent therapy in elderly lung cancer patients. Erlotinib has also been studied in patients with end-organ dysfunction, which may be applicable in the elderly population where end-organ dysfunction is more common.
Erlotinib, in combination with gemcitabine, for patients with unresectable pancreatic cancer has also been shown to modestly improve progression-free survival compared to gemcitabine alone. Although this phase III trial did not focus specifically on elderly patients, the median age was 63.9 and ranged from 36.1-92.4. However, gemcitabine with erlotinib was associated with more toxicity including rash, death, and interstitial lung disease-like syndromes.
Sorafenib and Sunitinib
Sorafenib is an orally active multikinase inhibitor with effects on tumor cell proliferation and tumor angiogenesis. It has been shown to inhibit Raf kinase; vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptor; FMS-like tyrosine kinase 3; c-Kit protein; and RET tyrosine kinase. It has been approved for use in renal and hepatocellular carcinoma, but seems to have activity in several other malignancies. In a subgroup analysis of a phase III trial (TARGET), adverse events were independent of age. In addition, side effects caused by sorafenib were similar in both elderly and younger patients treated with the expanded access program in North America and commonly included fatigue, hand-foot syndrome, diarrhea, thrombocytopenia, and neutropenia.
Sunitinib is an orally-administered, multitargeted tyrosine kinase inhibitor of VEGF receptors, platelet-derived growth factor receptors, FLT-3, c-Kit, and RET that improves progression-free survival in patients with clear cell metastatic renal cell carcinoma. It is also used to treat imatinib-resistant GIST tumors. Common toxicities include hypertension, decreased left ventricular ejection fraction, fatigue, diarrhea, and pancytopenia. However, there are no data regarding the toxicity in elderly cancer patients.
Most concerning in the elderly population is the potential cardiac toxicity associated with these medications. Approximately one third of evaluable patients in a single observational study had a cardiac event while on these medications. All patients recovered and were able to continue treatment with a tyrosine kinase inhibitor, but almost 10% were seriously compromised and required escalation of care. The impact of this toxicity in the elderly population has not been examined.
Temsirolimus
Temsirolimus is an mTOR inhibitor that is approved for use in patients with advanced renal cell carcinoma (RCC). Because this drug is primarily metabolized in the liver, patients with moderate or severe hepatic dysfunction were excluded from clinical trials involving temsirolimus. In addition, most clinical studies of this drug have not included enough elderly patients to determine the safety and toxicity of this drug. Common toxicities include edema, rash, hyperglycemia, mucositis, nausea, anemia, neutropenia, and thrombocytopenia. Given the significantly increased amount of thrombocytopenia in a study of patients with non-Hodgkin lymphoma with a median age of 70, special consideration of this toxicity may be required in elderly patients. Notably, rare and sometimes fatal cases of bowel perforation, interstitial lung disease, and acute renal failure have occurred.
Lapatinib
Lapatinib is a dual HER-1 and HER-2 tyrosine kinase inhibitor that is approved in combination with capecitabine for the treatment of advanced HER-2-positive breast cancer after progression following trastuzumab-based chemotherapy. Common toxicities include fatigue, palmoplantar erythrodysesthesias, diarrhea, nausea, anemia, and neutropenia. In addition, rare but severe hepatoxicity, left ventricular dysfunction, and pulmonary toxicity have been reported. Dose reductions are recommended with severe hepatic compromise. There are no data regarding the effects of age on the pharmacokinetics of lapatinib, but thus far no differences in safety or effectiveness have been observed between patients older than 65 years and those 65 years and younger. There is also significant concern regarding the cardiac toxicity associated with this therapy. While the absolute incidence of cardiac toxicity is low at 1.6%, predictors of this toxicity include age older than 50, baseline cardiac dysfunction, and use of antihypertensive medications.
Bortezomib
Bortezomib is a proteasome inhibitor used to treat multiple myeloma, and requires dose adjustment with moderate hepatic impairment. It is also active in mantle cell lymphoma and approved for use in relapsed/refractory disease. Common toxicities include edema, nausea, thrombocytopenia, sensory neuropathy, and weakness. In a study of bortezomib in combination with melphalan and prednisone in elderly patients, overall toxicity was higher in patients aged 75 or older; however, this may have been related to the physical condition of these patients. In addition, it is possible that the increased incidence of hematologic toxicities was due to melphalan and not to bortezomib. When compared to elderly subgroups from previous trials, the rates of serious adverse events were similar and were generally manageable.
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