Oral chemotherapy agents were initially developed to relieve some of the patient stressors associated with intravenous chemotherapy. These agents can reduce the number of office visits required and avoid the pain and invasiveness of intravenous delivery. The availability of oral agents has made some aspects of receiving cancer treatment much easier, but it has created some patient management issues for primary care providers.
Oral chemotherapy agents are not necessarily more convenient than traditional intravenous chemotherapy, nor are they necessarily easier to administer. A common misconception is that oral chemotherapy agents have minimal side effects. All oral chemotherapy and biotherapy agents have the same potential dangers as intravenous chemotherapy.
The side effects of oral agents are related to their mechanism of action and the dosage of the drug. As side effects worsen for any given patient, adherence lessens. Patients who do not take oral chemotherapy medication as prescribed are less likely to receive the benefit of longer survival or improved outcome. This article provides information on the kinase inhibitors imatinib (Gleevec), pazopanib (Votrient), sorafenib (Nexavar) and sunitinib (Sutent), which target solid tumors.
Imatinib is approved for the treatment of KIT-positive unresectable and/or malignant metastatic gastrointestinal stromal tumors, completely resected KIT-positive GI stromal tumors, Philadelphia chromosome-positive chronic myeloid leukemia and several rare cancers.1 The drug is a small-molecule inhibitor of multiple tyrosine kinases, including BCR-ABL, and it inhibits proliferation and induces apoptosis.1
Pazopanib is approved for the treatment of advanced renal cell carcinoma, advanced soft tissue sarcoma and recurrent or metastatic progressive differentiated thyroid carcinoma that is refractory to radioactive iodine treatment.2 It is a small-molecule, multiple tyrosine kinase inhibitor of vascular endothelial growth factor receptor and a platelet-derived growth factor receptor.2
Sorafenib is approved for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma.3 Sorafenib is a kinase inhibitor that decreases tumor cell proliferation and works at multiple intracellular and cell surface kinases.3
Sunitinib is also a small-molecule multiple receptor kinase inhibitor. It is approved for the treatment of metastatic renal cell carcinoma, gastrointestinal stromal tumors and pancreatic neuroendocrine tumors.4 Specifically, it inhibits platelet-derived growth factor receptors, vascular endothelial growth factor receptors and several other kinases.4
Prior to Chemotherapy
Prior to initiation of chemotherapy treatment, the patient's medications are reviewed by the oncologist and oncology nurse to ensure the patient is taking no medications that may interact with the selected oral chemotherapy. The patient receives verbal and written instructions about how to take the chemotherapy, not to replace missed doses or ever double a dose, possible side effects, and interventions for side effects. Patients and caregivers are taught to recognize and report side effects early so that any side effects can remain minimal. Maintaining side effects at a tolerable level is key to adherence. Although primary management of the chemotherapy agents will be handled in the oncology office, the patient may bring side effects to the attention of the primary care provider.
Some oral chemotherapy medications can cause a degree of cardiac toxicity. Imatinib and sunitinib can cause severe heart failure and left ventricular dysfunction.1,4 Most patients who experience these side effects have other risk factors for cardiac disease.1,4 Pazopanib and sunitinib have been associated with QT prolongation and torsades de pointes.1,2
Providers must be careful when prescribing other medications that may also cause prolonged QT. Sorafenib can increase the incidence of cardiac ischemia and infarction.3 Although the number of patients who experience cardiac side effects is low, any patient with cardiac complaints or findings should immediately stop their medication and have further cardiac workup.
Blood Pressure Effects
Hypertension is a common side effect of pazopanib and sunitinib.1,4 Hypertensive crisis is an uncommon side effect of sorafenib.3 Blood pressure should be well controlled before the start of therapy with these medications.1,3,4
The primary care provider may be the first to become aware of increases in blood pressure. Hypertension should be controlled with antihypertensive medications. Initiating or changing the antihypertensive regimen should be done in collaboration with the oncology team because the chemotherapy dose may need to be interrupted or reduced.
Kinace inhibitors have many of the same gastrointestinal side effects as most intravenous chemotherapies. Most often, the patient experiences some degree of diarrhea, constipation, nausea, vomiting, anorexia and mucositis.1-4 All of these can be easily handled with early interventions involving lifestyle changes, antidiarrheals, antiemetics and good oral hygiene.
Pazopanib and sorafenib have been associated with gastrointestinal perforation.2,3 Pazopanib can also cause fistula formation.2 Patients with new or unexplained abdominal pain should be evaluated in the emergency department.
Much like intravenous chemotherapy, oral agents produce a high rate of fatigue. Patients may also experience fever or flu-like symptoms while taking oral chemotherapy.
Many causes of cancer- and treatment-related fatigue exist, but few effective medical interventions are known. Lifestyle changes are necessary to lessen the effects of fatigue. Maintaining good nutrition and hydration is important. Regular moderate exercise is the best defense against fatigue related to chemotherapy and cancer. Patients who exercise daily feel much better and have fewer constitutional side effects associated with their treatment.
Imatinib, sorafenib and sunitinib cause dermatologic toxicities that may be the initial complaint that brings the patient to the primary care provider's office.1,3,4 These include rash, hand-foot syndrome, skin discoloration, dry skin and pruritus.1,3,4 In most cases, rash, dry skin and pruritus can be treated with nonprescription lotions and oral or topical antihistamines. Severe rashes may require topical antibiotics. If infection is suspected, either in the form of a rash or from scratching pruritic skin, oral antibiotics may be necessary. Always assess for and treat skin infections early.
Hand-foot syndrome, or palmar plantar erythrodysesthesia, requires activity modifications such as reducing exposure to friction and heat. Patients should avoid washing dishes or taking hot showers and baths, as well as activities that increase pressure on the palms of the hands or soles of the feet. Instruct them to apply lotions but avoid aggressive rubbing. Pain medications may be necessary. Drug interruption may be necessary until the hand-foot syndrome resolves.
Imatinib causes a periorbital edema. Although it is concerning to the patient, it typically does not require intervention.1 If the edema is bothersome or is worsening, short-term use of oral diuretics is beneficial.
The primary care provider may discover various laboratory abnormalities in patients who take oral chemotherapy, including decreased white blood cells, lymphocytes, platelets and hemoglobin, increased liver enzymes, decreased kidney function, and alterations in electrolytes.1-4 It is important to discuss any alterations with the oncology team because lab changes may require modification of the chemotherapy dose or regimen.
It is important for the primary care provider to have an ongoing relationship with the patient's oncology staff. Encourage the patient to report any ongoing or unusual side effects to the oncology team. Do not allow the patient to be the go-between for you and his or her oncology team. Initiate ongoing interaction with them as you feel necessary. Always feel free to contact the oncology team with any questions you may have.
Patients with a cancer diagnosis should be asked about their cancer medications at every primary care visit. Oral chemotherapy medications are not obtained from the local pharmacy and may not have been paid for under the patient's regular insurance benefit. Therefore, these medications may not show in their prescription history when downloaded to the electronic medical record. Have patients bring all medication bottles to primary care visits.
The increased utilization of oral chemotherapy agents creates the need for accurate monitoring and management of side effects and closer collaboration between primary care providers and oncology providers.
Marilyn Garcia is a nurse practitioner at Texas Oncology in Dallas. She has completed a disclosure statement and reports no relationships related to this article.
1. Drucker BH, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344(14):1031-1037.
2. Sonpavde G, et al. Pazopanib: A novel multitargeted tyrosine kinase inhibitor. Curr Oncol Rep. 2007;9(2):115-119.
3. Escudier B, et al. Sorafenib for treatment of renal cell carcinoma: Final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol. 2009;27(20):3312-3318.
4. Hutson TE, et al. Phase III randomized trial of sunitinib malate (SU11248) versus interferon-alfa as first-line systemic therapy for patients with metastatic renal cell carcinoma. J Clin Oncol. 2006;24(Suppl 18).