The major toxicity of many traditional chemotherapeutic agents remains myelosuppression, leading to anemia, neutropenia, and thrombocytopenia.
The risk of infection increases with the magnitude and the duration of neutropenia, which typically occurs 5 to 15 days after chemotherapy administration. Serious infectious complications are more likely when the absolute neutrophil count is below 500/µL (0.5 × 109/L) and the expected duration is more than 7 days. Fever in a patient with neutropenia is an emergency, as patients can become septic quickly. Prompt evaluation is critical and should include blood count; other appropriate cultures; and administration of an empiric, broad-spectrum antibiotic. The antibiotic is typically an antipseudomonal β-lactam agent such as cefepime; a carbapenem, such as meropenem or imipenem-cilastatin; or piperacillin-tazobactam. Other antimicrobials, such as aminoglycosides, fluoroquinolones, or vancomycin, can be used in combination with piperacillin-tazobactam if antimicrobial resistance is suspected or for management of complications, such as hypotension or pneumonia. Selected patients without significant comorbidities who are medically stable and adherent, and in whom a short duration of neutropenia is anticipated, can be treated on an outpatient basis with intravenous or oral antibiotics.
The prophylactic use of granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor reduces the risk of febrile neutropenia. These medications may be given to patients receiving regimens associated with a high risk of this complication or as secondary prophylaxis in patients with a previous episode of neutropenic fever. Growth factors are not used in the treatment of patients with neutropenic fever unless the patient has either persistent fever despite antibiotic treatment or severe neutropenia (absolute neutrophil count less than 100/µL [0.1 × 109/L]) expected to last more than 7 days.
Anemia in patients with cancer may be multifactorial, related to chronic inflammation, bone marrow suppression, blood loss, and chemotherapy. Anemia contributes significantly but not solely to the fatigue patients with cancer endure. Erythrocyte transfusions and erythropoietin administration are sometimes required. The enthusiasm for erythropoietin has been tempered by studies suggesting that symptom improvement is achieved at a cost of more rapid cancer progression and increased risk of venous thromboembolism. This concern has prompted increased regulation and a significant decrease in the use of erythropoietin therapy in patients with cancer, particularly for those receiving curative or adjuvant treatments. For this reason, erythropoiesis-stimulating agents (ESAs) should not be prescribed for patients with chemotherapy associated anemia whose cancer treatment is curative in intent. With the exception of certain patients with myelodysplasia, ESAs should not be used to treat most patients whose anemia is not related to cancer chemotherapy.
Thrombocytopenia is generally managed with platelet transfusions, when needed, and appropriate dose reductions and delays.
Although nausea and vomiting are still common side effects of chemotherapy, their incidence and severity have been markedly reduced by antiemetic medications. Delayed nausea (more than 1 day after treatment), especially with cisplatin regimens, has not been as effectively prevented. Chemotherapy agents can be separated into mild, moderate, and severe emetogenic effect categories. For patients receiving moderate to severely emetogenic drugs, administration of serotonin receptor antagonists (such as ondansetron or the longer-acting palonosetron) in combination with high-dose glucocorticoid therapy is standard. Improvement in both acute and delayed nausea and vomiting is seen with the addition of neurokinin 1 receptor blockers (such as aprepitant and netupitant). Further benefit has been reported with the antipsychotic agent olanzapine.
Cutaneous toxicities vary in frequency, severity, and type. Alopecia is the most common but does not occur with all chemotherapy agents. Almost all drugs have the potential to cause allergic reactions; examples of severe reactions include toxic epidermal necrolysis and Stevens-Johnson syndrome. Fluoropyrimidines (5-fluorouracil and capecitabine) are associated with palmar-plantar erythrodysesthesia (“hand-foot syndrome”), described as redness, peeling, and tenderness of the palms and soles. Small-molecule epidermal growth factor receptor (EGFR) inhibitors, such as erlotinib and gefitinib, used to treat EGFR-mutated lung cancer, are associated with pustular acneiform eruptions and other skin changes, including dryness. Monoclonal antibodies against EGFR (cetuximab and panitumumab) are associated with a similar and often more severe acneiform eruption. See MKSAP 18 Dermatology for further discussion of dermatologic chemotherapy reactions.
A wide variety of chemotherapy agents can be associated with pulmonary injury, likely from various mechanisms. Bleomycin, nitrosoureas, and gemcitabine may have the strongest associations with pulmonary toxicity, but many others have toxicity potential. In addition, various monoclonal antibodies and targeted therapies can be associated with pulmonary toxicities, including rituximab, trastuzumab, cetuximab, and erlotinib.
Radiation therapy can be associated with a pneumonitis, typically occurring within 1 to 3 months of treatment, and may lead to the development of radiation fibrosis. See MKSAP 18 Pulmonary and Critical Care Medicine for further discussion of disorders of pulmonary function related to chemotherapy.
Several chemotherapy agents can affect kidney function. Cisplatin is the most common agent and is associated with acute tubular necrosis. The risk is reduced with the use of aggressive hydration. Ifosfamide can be associated with kidney disease and significant tubular toxicity, with long-term potassium, magnesium, and bicarbonate wasting. Both ifosfamide and cyclophosphamide, in high doses, may cause a hemorrhagic cystitis. Hemolytic uremic syndrome is associated with various chemotherapy agents, most commonly with mitomycin and gemcitabine. Kidney failure can occur with tumor lysis syndrome.
Peripheral neuropathy is a common toxicity of several chemotherapy agents, most commonly occurring with platinums, taxanes, and vinca alkaloids, as well as with newer agents, such as bortezomib. Oxaliplatin causes a transient hypersensitivity to cold—patients must avoid eating, drinking, or even touching cold items for several days after infusions—as well as a non–temperature-dependent persistent peripheral neuropathy that may be more problematic in the long term. Therapies are sometimes continued with appropriate dose reductions if there are only mild sensory symptoms. However, when patients develop significant symptoms with dysfunction, pain, and motor weakness, therapies are discontinued. Although symptoms may alleviate over time, some patients are left with significant deficits. Medications such as gabapentin and duloxetine may help alleviate discomfort but no definitive neuroprotective agents or strategies have proved to reliably prevent or resolve these symptoms.
Rituximab, along with other immunosuppressive agents, rarely has been associated with progressive multifocal leukoencephalopathy. 5-Fluorouracil and high-dose cytosine arabinoside are associated with cerebellar toxicity. The reversible posterior encephalopathy syndrome, consisting of headache, visual disturbances, delirium, and seizures associated with characteristic white matter edema in the posterior brain, has been linked to chemotherapy that targets vascular endothelial growth factor, such as bevacizumab or sunitinib.
Whole brain radiation can cause impairment of cognitive function. In some situations, this toxicity can be reduced by the use of focused high-dose radiation (gamma knife or stereotactic radiosurgery) to identified lesions. See MKSAP 18 Neurology for further discussion of disorders of peripheral neuropathy related to chemotherapy.
With the increasing use of checkpoint inhibitors for various tumors, patients with cancer are at risk for toxicities associated with the induction of autoimmunity. Antibodies such as ipilimumab (anti–cytotoxic T-lymphocyte associated protein 4 [CTLA4]), pembrolizumab and nivolumab (anti–programmed death receptor-1 [PD-1]), and atezolizumab (anti–programmed death ligand-1 [PDL1]), are associated with immune-related toxicities, including colitis, pneumonitis, hepatitis, dermatitis, hypophysitis, thyroiditis, and adrenalitis. These toxicities occur in a small but significant minority of patients and require prompt recognition and often glucocorticoid therapy as well as hormone replacement, if indicated.
As patients with cancer live longer, being either cured or surviving for more extended periods, survivorship issues have assumed greater importance. Survivorship embodies the care that follows patients on completion of their treatments, including screening for recurrence and secondary malignancies; monitoring for late organ dysfunction; and helping patients cope with the psychological, sexual, vocational, and other effects of treatment. An initial treatment plan for cancer may be based not only on providing the highest probability of cure but also on a strategy to reduce the risk of long-term complications.
Bone loss occurs at an increased rate in female cancer survivors who have taken long-term glucocorticoids; those who have undergone surgical, radiation, or chemotherapy-induced premature menopause; and those taking aromatase inhibitors for breast cancer. Men treated for prostate cancer with androgen deprivation therapy may also develop osteoporosis. Multiple myeloma, in addition to causing lytic bone disease, can be associated with generalized bone loss. Assessment of bone density and treatment or prophylaxis should be considered to reduce the risk of fracture. Treatment commonly includes routine supplements of vitamin D and calcium (while monitoring serum calcium levels) and bisphosphonates or denosumab (a receptor activator of nuclear factor κB ligand monoclonal antibody). Vigilance for complications with these agents, which can include osteonecrosis of the jaw and atypical subtrochanteric spiral fractures of the femur, is required for patients on these agents.
Radiation therapy to the heart can lead to valvular disease, myocardial and pericardial disease, and coronary disease. These risks have been reduced owing to advances in dosing, treatment planning, and modern radiation techniques. Doxorubicin and other anthracyclines can cause irreversible cardiomyopathy; the risk for this increases with cumulative dosing. Trastuzumab can also induce non-dose-dependent cardiomyopathy; the risk increases when trastuzumab is combined with anthracyclines. Fluoropyrimidines (5-fluorouracil and capecitabine) have been associated with a risk of coronary spasm and ischemia during administration.
Newer-generation tyrosine kinase inhibitors for treatment of chronic myeloid leukemia have been associated with cardiovascular morbidity, nilotinib and ponatinib are associated with coronary insufficiency, and dasatinib is associated with pulmonary hypertension. The anti–vascular endothelial growth factor antibody bevacizumab is associated with an increased risk of coronary and other vascular events, both arterial and venous.
Monitoring for and management of cardiac complications in cancer survivors is discussed in MKSAP 18 Cardiovascular Medicine.
Surgery, radiation, and chemotherapy all have the potential to affect sexual function and fertility of both men and women. Altered body image after breast surgery or other radical resection and the generalized fatigue associated with most radiation or chemotherapy may reduce libido. Anxiety and depression further diminish interest in sex. Individual counseling and support groups may be helpful.
In women, premature menopause and infertility can result from both pelvic radiotherapy and chemotherapy, particularly with alkylating agents. Risk factors for infertility relate to the dose and duration of chemotherapy as well as patient age, with older women being at greater risk for premature menopause. Consultation with experts in fertility should be considered in younger women who desire future childbearing; egg and embryo harvests may be options. Fertility evaluations can often be done on an emergency basis so delay in the initiation of definitive cancer treatment is minimized. Men may be offered the option of semen cryopreservation.
Hormonal therapy for women with breast cancer, including tamoxifen, aromatase inhibitors, and ovarian suppression, may cause menopausal symptoms, decreased libido, and vaginal dryness. Men with prostate cancer commonly suffer from erectile dysfunction after surgery, radiation, and androgen suppression therapy.
Short-term and long-term declines in cognitive function are now recognized as a complication after cancer therapy. It remains unclear whether cancer and its treatment unmasks preexisting cognitive impairment that was not yet manifest, whether the decline represents a sign of more rapid aging, or whether there is a more specific neurotoxic effect. Symptoms may include impairment of multitasking and executive function, memory, and verbal ability. Behavioral therapy may be beneficial. Patients with cancer who complain of a decline in cognitive function should have their experience acknowledged and validated, and behavioral therapy should be offered.
Patients with cancer go through distinct phases of management, beginning with the initial therapy and any maintenance or adjuvant treatment needed to achieve and prolong remission. Once in remission, these patients go through a phase of surveillance for disease recurrence. Whereas the duration of the surveillance phase and the extent of active assessment through physician examination and diagnostic imaging differs based on the underlying cancer, patients eventually reach the “survivor” phase, wherein disease recurrence becomes unlikely.
Providing patients with a prescription for survivorship is an important responsibility of oncologists. Patients are given a formal document summarizing their diagnosis, stage, and treatment details, along with recommended follow-up by the oncologist as they return to their internist. Recommendations can include surveillance for cancer recurrence; lifestyle modifications, such as diet, exercise, and avoiding tobacco and alcohol to reduce the risk of a second malignancy; and a discussion of the late effects of cancer treatment that may occur and any strategies for preventing or reducing them.
Cancer survivors should, at a minimum, have age- and gender-appropriate cancer screening. Secondary malignancies may develop in cancer survivors owing to a preexisting genetic predisposition, a “field” effect from previous carcinogen exposure, or late effects of previous cancer treatments. Patients with BRCA gene mutations have an increased risk of breast and ovarian cancer. Patients with smoking-related head and neck cancer are prone to second head and neck cancers, as well as lung and esophageal cancers. Patients exposed to chemotherapy with alkylating agents have an increased risk of myelodysplastic syndromes and acute leukemia. Radiation to the neck can be associated with the development not just of hypothyroidism but also of thyroid cancer years later. Women receiving radiation to the mediastinum for Hodgkin lymphoma and other cancers have a marked increase of breast cancer, particularly if they were treated in adolescence and early adulthood, with the increased risk beginning within 8 years of treatment. Screening MRI, mammography, or a combination of both modalities is recommended for these patients beginning at age 25 years or 8 years after completion of radiation therapy, whichever occurs last.