The management of cancer in the older-aged person is an increasingly common problem, because the population is aging and cancer is largely a disease of aging. Aging involves a progressive loss in functional reserve of multiple organs and consequently increased susceptibility to the complications of cancer treatment. These are important for several reasons. First of all, they may cause discomfort, disease, and death. Second, they may prevent the administration of effective cancer treatment. Third, they may lead to functional dependence that is associated with poorer quality of life and higher management cost. In this chapter, the nonhematological complications of systemic cancer treatment are examined, including descriptions of both the acute and chronic complications of hormonal, cytotoxic, and targeted therapy. At the end of the chapter, the unsolved issues related to the management of cancer in the older-aged person are outlined and a research agenda to address these issues is proposed.
A 75-year-old woman is diagnosed with early-stage breast cancer. After lumpectomy and radiation, she meets with her medical oncologist who discusses adjuvant treatment; the decision is made to treat her with hormone therapy alone, and she is placed on an aromatase inhibitor. Two months later she visits her primary care provider stating that she seems to be tolerating her new medication, but asking for pain medications for her worsening arthritis. She also mentions that she had a fall about 2 weeks ago but luckily did not break any of her bones. However, the emergency department physician noted that she appeared to have some “bone weakness” on her x-ray.
Hormonal Treatment
Hormonal manipulations are the mainstay treatment of prostate and breast cancer. In this section the complications of luteinizing hormone-releasing hormone (LHRH) analogs, estrogen, aromatase inhibitors, and selective estrogen receptor modulators (SERMs) are addressed.
LHRH Analogs
For more than 20 years, these agents have been used to induce chemical castration in patients with prostate cancer. The definitive benefits of this treatment have been demonstrated in only two circumstances: in the presence of metastatic disease confirmed by imaging and in combination with radiation therapy for the management of locally advanced disease (stage C or III). The benefits of adjuvant hormonal treatment in patients at high risk of recurrence are controversial. Despite a lack of any evidence, it has become common practice to induce chemical castration in patients experiencing so-called chemical (PSA) recurrences.
In addition to loss of libido, chemical castration is complicated by hot flushes, fatigue, and possibly anemia. It is not clear whether it may also cause cognitive decline. Fatigue is particularly ominous, as it has been associated with an increased risk of functional dependence and of death in older individuals. Likewise, anemia has also been associated with death, functional dependence, and geriatric syndromes including falls and dementia.
The best established long-term complication of castration is osteoporosis. Treatment with LHRH analogs for longer than 1 year has been associated with increased risk of fracture that increases directly with treatment duration. Other potential complications include diabetes and increased incidence of coronary events in patients with a preexisting history of coronary artery disease.
The best management of complications from LHRH analogs is prevention, which includes avoiding the unwarranted use of these compounds. Hot flushes may respond to progesterone, to gabapentin, and to antidepressants, but these medications carry their own set of complications. Fatigue may be ameliorated with exercise. The benefit of provigil in these situations is controversial.
Bone loss may be reversed by bisphosphonates or RANK ligand inhibitors (denosumab). These compounds are recommended in patients who already have osteopenia and in those for whom treatment with LHRH analogs for longer than 1 year is planned.
A number of alternative approaches may also obviate some of the complications of LHRH analogs. These include: intermittent castration, use of androgen antagonists in lieu of LHRH analogs, LHRH inhibitors, and novel compounds such as abiraterone and more specific androgen antagonists.
Intermittent castration has become increasingly popular, though it has not been conclusively demonstrated that it is as effective as continuous castration. In one study, bicalutamide in high doses was found to be as effective as castration in patients with metastatic prostate cancer. This approach may allow some patients to preserve their libido, but it is expensive and associated with painful gynecomastia (that may be prevented by prophylactic breast irradiation). It is not clear whether long-term treatment with this compound may also lead to osteoporosis, diabetes, and coronary artery disease. Direct LHRH antagonists have only recently been introduced in the management of prostate cancer. Their main indication is in treatment of patients with critical metastases (such as impending spinal cord compression or urinary obstruction) for whom LHRH analogs are contraindicated. At least theoretically, the complications of these agents should be similar to those of LHRH analogs.
Two types of drugs appear particularly promising in the management of hormone-sensitive prostate cancer: abiraterone and highly selective androgen antagonists. Both types of compounds were found active in “hormone-refractory prostate cancer,” as they antagonize the effect of dihydrotestosterone synthesized within the cancer. Abiraterone is a selective inhibitor of androgen synthesis that prevents the synthesis of dihydrotestosterone within the gonads, the adrenals, and the tumor.
Estrogen
Though seldom used nowadays, estrogen may provide effective and inexpensive treatment of both prostate and breast cancers. In metastatic prostate cancer, diethylstilbestrol (DES) appears to be at least as effective as LHRH analogs. Unlike LHRH, estrogen does not cause loss of libido, osteoporosis, or hot flushes. Complications include painful gynecomastia and deep vein thrombosis. A never-solved controversy is whether DES in low doses (1 mg/daily) is as effective as and less risky than the most commonly used dose of 3 mg per day. Retrospective studies suggest that this may be the case. Despite low cost and safety, the use of estrogen in metastatic prostate cancer has almost disappeared in the USA as a result of the aggressive marketing of LHRH analogs.
In metastatic breast cancer, DES at high doses (15 mg daily) is as effective as tamoxifen and may prove effective in 15% of patients whose cancer progressed while they were receiving tamoxifen. The complications of this treatment include deep vein thrombosis, fluid retention, and congestive heart failure, and the risk of these increases with patient age.
Selective Estrogen Receptor Modulators (SERMs)
These include tamoxifen, toremifene, and raloxifene. Fulvestrant (Faslodex), although a pure estrogen antagonist, will also be discussed in this group.
Until recently, tamoxifen has been the mainstay treatment of hormone receptor-rich breast cancer. This agent has reduced by 40% the systemic recurrence of breast cancer after surgery. Recent pharmacogenomic studies showed that tamoxifen is effective in women who are rapid metabolizers, that is, women in whom the activity of CYP2D6 is increased, because this enzyme converts the inactive parent compounds into active metabolites. The concomitant prescription of tamoxifen and CYP2D6 inhibitors, such as paroxetine, should then be avoided. Toremifene has comparable activity as tamoxifen. Raloxifene is untested in the management of breast cancer. Tamoxifen and raloxifene reduce by approximately 50% the incidence of hormone receptor-rich breast cancer in women at risk. Other beneficial effects of SERMs include prevention of osteopenia and osteoporosis and decreased serum cholesterol levels. SERMs cause hot flushes, vaginal secretions, and deep vein thrombosis (DVT). In rare instances, tamoxifen and toremifene, but not raloxifene, cause endometrial cancer. Risk factors for DVT and endometrial cancer include age 70 or older and obesity.
Hot flushes may be ameliorated by antidepressants and gabapentin. The benefit of serial gynecologic exams for early diagnosis of endometrial cancer is controversial.
Being a pure antiestrogen, fulvestrant does not cause either DVT or endometrial cancer. The effect of this compound on the bone is not well understood, as it has not been studied in the adjuvant setting where long-term complications are expected.
Aromatase Inhibitors
These compounds have largely superseded SERMs in the treatment of breast cancer, in both the adjuvant and the metastatic setting. Like tamoxifen, they may cause hot flushes. An especially troublesome complication is arthralgias, whose pathogenesis is poorly understood. Arthralgia may represent a cause of functional limitations in older women. Unlike the SERMs, these compounds cause osteoporosis. Early treatment with bisphosphonates such as zoledronic acid did prevent bone loss in the Z-fast study but it has not been proven yet that this treatment prevents bone fractures. Current recommendations for the management of osteopenia and osteoporosis include assessment of bone density at the beginning of treatment and serially thereafter and institution of bisphosphonate therapy in the presence of bone loss. Prophylactic bisphosphonate treatment in all women receiving aromatase inhibitors is not recommended.
Aromatase inhibitors have also been associated with an increase in serum cholesterol, but there is no evidence that they cause increased incidence of coronary artery disease or stroke.
In conclusion, hormonal treatment is the safest form of systemic cancer therapy for older individuals. Osteoporosis and increased risk of bone fractures are common complications of chemical castration for prostate cancer and of aromatase inhibitors, but these complications may be offset by bisphosphonates or RANK ligand inhibitor. Except in its application for chemical castration in patients with a preexisting history of coronary artery disease, there is no proof that LHRH analogs may cause coronary death. Deep vein thrombosis complicates treatment with estrogen and to a lesser extent with SERMs. Age and obesity are risk factors for these complications. Aromatase inhibitor-associated arthralgia may be a cause of disability for some older women.
As is the case for any medications, hormonal treatment should not be used in conditions when the risks supersedes the benefits. That seems to be the case for chemical castration in presence of chemical recurrence of prostate cancer.
A 75-year-old woman is diagnosed with early-stage breast cancer. After lumpectomy and radiation, she meets with her medical oncologist who discusses adjuvant treatment; the decision is made to treat her with both adjuvant chemotherapy and hormone therapy. Prior to starting therapy, she visits her primary care provider with concerns about the side effects of chemotherapy, as one of her friends mentioned that it is bad for the brain and the heart. She wants to know whether she should go through with it and if there is anything that she can do to avoid these complications.
LHRH Analogs
For more than 20 years, these agents have been used to induce chemical castration in patients with prostate cancer. The definitive benefits of this treatment have been demonstrated in only two circumstances: in the presence of metastatic disease confirmed by imaging and in combination with radiation therapy for the management of locally advanced disease (stage C or III). The benefits of adjuvant hormonal treatment in patients at high risk of recurrence are controversial. Despite a lack of any evidence, it has become common practice to induce chemical castration in patients experiencing so-called chemical (PSA) recurrences.
In addition to loss of libido, chemical castration is complicated by hot flushes, fatigue, and possibly anemia. It is not clear whether it may also cause cognitive decline. Fatigue is particularly ominous, as it has been associated with an increased risk of functional dependence and of death in older individuals. Likewise, anemia has also been associated with death, functional dependence, and geriatric syndromes including falls and dementia.
The best established long-term complication of castration is osteoporosis. Treatment with LHRH analogs for longer than 1 year has been associated with increased risk of fracture that increases directly with treatment duration. Other potential complications include diabetes and increased incidence of coronary events in patients with a preexisting history of coronary artery disease.
The best management of complications from LHRH analogs is prevention, which includes avoiding the unwarranted use of these compounds. Hot flushes may respond to progesterone, to gabapentin, and to antidepressants, but these medications carry their own set of complications. Fatigue may be ameliorated with exercise. The benefit of provigil in these situations is controversial.
Bone loss may be reversed by bisphosphonates or RANK ligand inhibitors (denosumab). These compounds are recommended in patients who already have osteopenia and in those for whom treatment with LHRH analogs for longer than 1 year is planned.
A number of alternative approaches may also obviate some of the complications of LHRH analogs. These include: intermittent castration, use of androgen antagonists in lieu of LHRH analogs, LHRH inhibitors, and novel compounds such as abiraterone and more specific androgen antagonists.
Intermittent castration has become increasingly popular, though it has not been conclusively demonstrated that it is as effective as continuous castration. In one study, bicalutamide in high doses was found to be as effective as castration in patients with metastatic prostate cancer. This approach may allow some patients to preserve their libido, but it is expensive and associated with painful gynecomastia (that may be prevented by prophylactic breast irradiation). It is not clear whether long-term treatment with this compound may also lead to osteoporosis, diabetes, and coronary artery disease. Direct LHRH antagonists have only recently been introduced in the management of prostate cancer. Their main indication is in treatment of patients with critical metastases (such as impending spinal cord compression or urinary obstruction) for whom LHRH analogs are contraindicated. At least theoretically, the complications of these agents should be similar to those of LHRH analogs.
Two types of drugs appear particularly promising in the management of hormone-sensitive prostate cancer: abiraterone and highly selective androgen antagonists. Both types of compounds were found active in “hormone-refractory prostate cancer,” as they antagonize the effect of dihydrotestosterone synthesized within the cancer. Abiraterone is a selective inhibitor of androgen synthesis that prevents the synthesis of dihydrotestosterone within the gonads, the adrenals, and the tumor.
Estrogen
Though seldom used nowadays, estrogen may provide effective and inexpensive treatment of both prostate and breast cancers. In metastatic prostate cancer, diethylstilbestrol (DES) appears to be at least as effective as LHRH analogs. Unlike LHRH, estrogen does not cause loss of libido, osteoporosis, or hot flushes. Complications include painful gynecomastia and deep vein thrombosis. A never-solved controversy is whether DES in low doses (1 mg/daily) is as effective as and less risky than the most commonly used dose of 3 mg per day. Retrospective studies suggest that this may be the case. Despite low cost and safety, the use of estrogen in metastatic prostate cancer has almost disappeared in the USA as a result of the aggressive marketing of LHRH analogs.
In metastatic breast cancer, DES at high doses (15 mg daily) is as effective as tamoxifen and may prove effective in 15% of patients whose cancer progressed while they were receiving tamoxifen. The complications of this treatment include deep vein thrombosis, fluid retention, and congestive heart failure, and the risk of these increases with patient age.
Selective Estrogen Receptor Modulators (SERMs)
These include tamoxifen, toremifene, and raloxifene. Fulvestrant (Faslodex), although a pure estrogen antagonist, will also be discussed in this group.
Until recently, tamoxifen has been the mainstay treatment of hormone receptor-rich breast cancer. This agent has reduced by 40% the systemic recurrence of breast cancer after surgery. Recent pharmacogenomic studies showed that tamoxifen is effective in women who are rapid metabolizers, that is, women in whom the activity of CYP2D6 is increased, because this enzyme converts the inactive parent compounds into active metabolites. The concomitant prescription of tamoxifen and CYP2D6 inhibitors, such as paroxetine, should then be avoided. Toremifene has comparable activity as tamoxifen. Raloxifene is untested in the management of breast cancer. Tamoxifen and raloxifene reduce by approximately 50% the incidence of hormone receptor-rich breast cancer in women at risk. Other beneficial effects of SERMs include prevention of osteopenia and osteoporosis and decreased serum cholesterol levels. SERMs cause hot flushes, vaginal secretions, and deep vein thrombosis (DVT). In rare instances, tamoxifen and toremifene, but not raloxifene, cause endometrial cancer. Risk factors for DVT and endometrial cancer include age 70 or older and obesity.
Hot flushes may be ameliorated by antidepressants and gabapentin. The benefit of serial gynecologic exams for early diagnosis of endometrial cancer is controversial.
Being a pure antiestrogen, fulvestrant does not cause either DVT or endometrial cancer. The effect of this compound on the bone is not well understood, as it has not been studied in the adjuvant setting where long-term complications are expected.
Aromatase Inhibitors
These compounds have largely superseded SERMs in the treatment of breast cancer, in both the adjuvant and the metastatic setting. Like tamoxifen, they may cause hot flushes. An especially troublesome complication is arthralgias, whose pathogenesis is poorly understood. Arthralgia may represent a cause of functional limitations in older women. Unlike the SERMs, these compounds cause osteoporosis. Early treatment with bisphosphonates such as zoledronic acid did prevent bone loss in the Z-fast study but it has not been proven yet that this treatment prevents bone fractures. Current recommendations for the management of osteopenia and osteoporosis include assessment of bone density at the beginning of treatment and serially thereafter and institution of bisphosphonate therapy in the presence of bone loss. Prophylactic bisphosphonate treatment in all women receiving aromatase inhibitors is not recommended.
Aromatase inhibitors have also been associated with an increase in serum cholesterol, but there is no evidence that they cause increased incidence of coronary artery disease or stroke.
In conclusion, hormonal treatment is the safest form of systemic cancer therapy for older individuals. Osteoporosis and increased risk of bone fractures are common complications of chemical castration for prostate cancer and of aromatase inhibitors, but these complications may be offset by bisphosphonates or RANK ligand inhibitor. Except in its application for chemical castration in patients with a preexisting history of coronary artery disease, there is no proof that LHRH analogs may cause coronary death. Deep vein thrombosis complicates treatment with estrogen and to a lesser extent with SERMs. Age and obesity are risk factors for these complications. Aromatase inhibitor-associated arthralgia may be a cause of disability for some older women.
As is the case for any medications, hormonal treatment should not be used in conditions when the risks supersedes the benefits. That seems to be the case for chemical castration in presence of chemical recurrence of prostate cancer.
A 75-year-old woman is diagnosed with early-stage breast cancer. After lumpectomy and radiation, she meets with her medical oncologist who discusses adjuvant treatment; the decision is made to treat her with both adjuvant chemotherapy and hormone therapy. Prior to starting therapy, she visits her primary care provider with concerns about the side effects of chemotherapy, as one of her friends mentioned that it is bad for the brain and the heart. She wants to know whether she should go through with it and if there is anything that she can do to avoid these complications.
Cytotoxic Chemotherapy
The risk of both acute and long-term complications of cytotoxic chemotherapy increases with age. Acute complications include mucositis, cardiotoxicity, and peripheral neuropathy. Chronic complications include chronic subclinical cardiac dysfunction, peripheral neuropathy, acute leukemia, myelodysplasia, and, possibly, dementia and functional dependence.
Acute Complications
Mucositis
The risk of mucositis from fluorinated pyrimidines and anthracyclines increases with age. Mucositis may lead to volume depletion because of diarrhea and dysphagia. This complication is more rapid and more severe in older than in younger individuals because the total body water decreases with age. It is not clear why mucositis is more common and more severe in older individuals. A possible explanation is found in aging rodents, in whom the proliferation of cryptal cells increases with age while the reserve of mucosal stem cells is diminished. This condition would predispose to mucositis by a twofold mechanism. The increased proliferation would render the cryptal cells more susceptible to destruction by cycle-active agents while the depletion of mucosal stem cells would delay the repair of the mucosal damage.
In addition to age, other risk factors for mucositis include female sex, ethnic group, and genetics, including hereditary deficiency of enzymes involved in drug metabolisms. New insight in the pathogenesis of mucositis reveals that the administration of cytotoxic drugs leads to oxidative damage, activation of stress-response genes, and increased production of nuclear factor KB and inflammatory cytokines that maintain and amplify the mucosal damage. In addition, chemotherapy-induced alterations in the oral and intestinal flora may also play a role in the pathogenesis of mucositis.
The management of mucositis is unsatisfactory. The only medication that was proven to reduce the incidence and severity of mucositis in randomized controlled studies has been the keratinocyte growth factor. This compound has not received widespread acceptance, however, because it is expensive and requires administration over several days. Recently, oral spray of human intestinal trefoil factor has ameliorated the risk of mucositis in a double blind phase II randomized study. Physiologically, trefoil factor binds to mucin and prevents mucosal damage. It is produced by goblet cells, which are destroyed by cytotoxic chemotherapy.
The substitution of intravenous fluorinated pyrimidines with capecitabine has reduced the risk of mucositis, but capecitabine in full doses is not well tolerated for other complications, especially the hand-foot syndrome. Furthermore capecitabine is contraindicated in patients with renal insufficiency, which is an almost universal condition of age and is associated with interaction with drugs metabolized through the cytochrome p450 system. The use of these drugs, such as warfarin, increases with age.
Aggressive fluid resuscitation should be initiated without delay in patients who cannot drink because of diarrhea.
Neuropathy
Peripheral neuropathy is a common complication of alkaloids, epipodophyllotoxins, taxanes, epothilones, cisplatin, and oxaliplatin. The risk of this complication increases with age. In older patients, these complications are also longer-lasting and more debilitating. Loss of sensation in the fingers may prevent the performance of basic ADLs including dressing, feeding, and toileting. Loss of sensation in the toes is associated with ambulatory difficulties and falls.
No antidote to peripheral neuropathy is available. Early discontinuance of the offending medication is the only effective prevention. In general, docetaxel appears to cause less neuropathy that other taxanes, but it is more myelotoxic.
Cardiomyopathy
The incidence of this often irreversible anthracycline complication increases with age and with medication dose. The interaction of the medication with intracellular iron causes the production of free radicals that lead to a progressive damage of the cardiac sarcomeres. Cardiomyopathy may be prevented with the administration of doxorubicin by continuous intravenous infusion or with the administration of desrazoxane. This agent prevents the production of free radicals by chelating the cellular iron and preventing its interaction with the anthracyclines. Unfortunately, desrazoxane may reduce the antineoplastic effectiveness of doxorubicin and is associated with increased risk of mucositis and myelotoxicity, which also become more common with age. The substitution of doxorubicin with pegylated liposomal doxorubicin (PLD) may reduce the risk of cardiomyopathy and other anthracycline complications including nausea and vomiting, alopecia, and myelotoxicity. The cancers for which the effectiveness of PLD has been proven include multiple myeloma, metastatic breast cancer, ovarian cancer, and AIDS-associated Kaposi sarcoma. PLD is effective in lymphoma, although it is not clear whether it is as effective as doxorubicin. The most common strategy to prevent cardiomyopathy involves the discontinuance of doxorubicin when the patient ejection fraction decreases by at least 14% on the basis of serial measurements by MUGA or echocardiogram.
In the last few years, it has become clear that patients treated with anthracycline may experience a delayed subclinical cardiac dysfunction, whose incidence increases with age and is progressive in time. The Surveillance Epidemiology and End Result (SEER) data suggest that this complication may eventually lead to clinical cardiac insufficiency, because the diagnosis of congestive heart failure becomes more common with time among breast cancer patients who have received adjuvant chemotherapy than among those treated without chemotherapy. It is not clear at present whether this complication may be prevented.
Dementia
An important and yet unresolved question is whether the common complication known as “chemobrain” may lead to dementia in older individuals, whose cognitive reserve is more limited than that of younger people. Reviewing the SEER data, Henke et al. reported that the diagnosis of dementia increased among older women treated with adjuvant chemotherapy for breast cancer. Other authors failed to confirm these findings. Perhaps the most important question is not whether the diagnosis of dementia increases after chemotherapy but whether a degree of cognitive decline occurs that leads to functional dependence, and whether it may be prevented or ameliorated. This question can only be addressed with a prospective study.
Functional Dependence
In addition to the prolongation of survival, prolongation of active life expectancy is a major goal of geriatrics. Unfortunately, at present there are few data related to the functional consequences of cancer treatment. Studies conducted at the authors’ institution suggested that:
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Functional dependence was more common among older breast cancer survivors who had been treated with chemotherapy. 8,46-47
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Fatigue, which is almost universal in older cancer patients, may be an important harbinger of functional dependence. The interaction of fatigue and functional dependence has been reported in the geriatric population by other authors.
The issue is one of the most important in geriatric oncology and needs to be studied prospectively. The most urgent questions to address include:
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Does functional dependence increase with time in older individuals treated with chemotherapy?
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Is functional dependence reversible?
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Which intervention may prevent or reverse functional dependence?
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