Treatment strategies for breast cancer

THE ONCOLOGY NURSE S ROLE IN THE CARE OF PATIENTS WITH BREAST CANCER * Carol S. Viele, RN, MS, CNS ABSTRACT Oncology nurses play a central role in the recognition and management of adverse events that are caused by medications used to treat metastatic breast cancer. Anemia and neutropenia are common side effects of many chemotherapeutic agents, especially in patients who are older, who have metabolic or nutritional deficits, receive radiation therapy, or have other risk factors for these conditions. Anemia typically develops after several chemotherapy cycles, whereas neutropenia may develop soon after treatment begins. Neuropathy may affect the sensory, motor, or autonomic nerves, and may cause several significant adverse effects, including changes in voluntary movement, muscle tone, reflexes, blood pressure, and sensations of pain, touch, and awareness of how the patient s body is positioned (proprioception). Neurologic assessment is important to establish a baseline level of function and to document treatment-related changes. Chemotherapy-induced nausea and vomiting (CINV) is a common side effect of cancer medications and is also influenced by several patient characteristics. A classification system developed by Hesketh et al in 1997 is used to rate the potential for CINV with different chemotherapy agents. *Based on a presentation by Ms Viele at a roundtable held in Boulder, Colorado, on July 20, 2007. Clinical Nurse Specialist, Hematology-Oncology-Bone Marrow Transplant, Associate Clinical Professor, Department of Physiological Nursing, University of California San Francisco, School of Nursing, San Francisco, California. Address correspondence to: Carol S. Viele, RN, MS, CNS, Clinical Nurse Specialist, Hematology-Oncology- Bone Marrow Transplant, Associate Clinical Professor, Department of Physiological Nursing, University of California San Francisco, School of Nursing, Box 0210, 505 Parnassus Avenue, Moffitt E&E, San Francisco, CA 94143. E-mail: carol.viele@ucsfmedctr.org. The adverse effects of chemotherapy create significant barriers to patient adherence to treatment. Oncology nurses can help to improve treatment adherence by asking patients about obstacles to adherence that they encounter and by helping patients develop strategies to remain adherent to therapy. (Adv Stud Nurs. 2007;5(3):91-96) Treatment strategies for breast cancer often involve combinations of therapies that produce significant adverse effects. Patients with breast cancer may receive various combinations of therapy including surgery, radiation, chemotherapy, and may be taking other medications for comorbid conditions, creating complex medication regimens that can be difficult for patients to tolerate. Anemia, neutropenia, neurotoxicity, nausea, and emesis are especially common side effects of therapy. Oncology nurses are often called on to recognize and help patients manage these adverse effects from a variety of cancer therapies. Strategies are available to help patients remain adherent to therapy despite the difficulties associated with treatment-associated toxicities. MANAGEMENT OF ADVERSE EVENTS ANEMIA AND NEUTROPENIA Several factors contribute to an increased risk of anemia in patients with breast cancer, including the use of chemotherapy or targeted therapy, bone marrow involvement, radiation therapy, older age, nutritional deficit, abnormal metabolism, and the use of concomitant medications. 1,2 Inadequate levels of circulating hemoglobin or red blood cells affect more than Johns Hopkins Advanced Studies in Nursing 91

50% of patients with cancer. 1,3 Red blood cell production by the bone marrow is regulated by the hormone erythropoietin, nearly all of which is produced by the kidneys. Normal erythrocyte life span is approximately 120 days, and anemia usually does not develop until after the third or fourth cycle of chemotherapy, 3,4 although it may occur earlier for patients with hematologic malignancies when bone marrow is involved. Anemia may be identified using several laboratory tests or clinical signs and symptoms, including hemoglobin concentration, hematocrit value, fatigue, dyspnea, palpitations, headaches, angina, difficulty sleeping, poor concentration, irritability, cold intolerance, anorexia, and pallor. Once anemia has been identified, the treatment team should identify and manage the underlying cause of anemia. Management strategies may include iron supplementation, transfusion of blood products, recombinant erythropoietin, and symptom management (eg, energy conservation and oxygen therapy). The risk factors for neutropenia are similar to those for anemia, and include older age, myelosuppressive therapy, bone marrow involvement, immune system dysfunction, hepatic or renal impairment, and malnutrition. 5,6 In contrast to erythrocytes, neutrophils have a life span of only a few hours, and chemotherapy may rapidly deplete circulating neutrophils. Most agents produce a nadir neutrophil count within 7 to 14 days, although the nadir may be delayed with some agents (eg, nitrosureas). 7,8 It should be noted that not all chemotherapy medications cause neutropenia. Symptoms of neutropenia may involve the gastrointestinal (GI) system (eg, mucositis and diarrhea), respiratory tract (eg, cough, dyspnea, and abnormal breath sounds), or urinary tract, along with complications from indwelling devices, or alteration of the skin and mucous membranes. Generalized symptoms include flu-like symptoms, fever, chills, and malaise. 9 However, it should be noted that patients with severe neutropenia may not manifest any specific symptoms, and the only signs of sepsis in these individuals may be fever and/or shaking chills. Due to the need for rapid intervention, patient education is especially important in the recognition and management of neutropenic fever. Patients should be instructed to seek medical attention immediately if they experience symptoms of fever and/or rigors. They should be reminded to perform meticulous hygiene and observation of their indwelling devices, and instructed where to call if they experience symptoms. It may be necessary to define terms such as fever and rigors for patients and to ensure that patients have a thermometer at home. PERIPHERAL NEUROPATHY Peripheral neuropathy is the injury, inflammation, or degeneration of the peripheral nerve fibers. Peripheral neuropathy may be hereditary or acquired, and is often difficult to diagnose. When the sensory nerves are affected, the person may experience changes in perception of pain, proprioception (awareness of limb position in space), temperature, and vibration. Neuropathy of the motor nerves may produce involuntary movement, changes in muscle tone and coordination, decreased reflexes, and weakness. Neuropathy of the autonomic nerves may cause decreased blood pressure, orthostatic changes, sexual dysfunction, and intestinal dysmotility. 10 It has been estimated that as many as 50% of patients with cancer experience peripheral neuropathy. 11 Common causes of peripheral neuropathy in individuals with cancer include cachexia-associated neuropathy, paraneoplastic sensorimotor neuropathy, and chemotherapy treatments that may cause or exacerbate neuropathy. Chemotherapy agents that are associated with doselimiting neuropathy effect include cisplatin, vincristine, and paclitaxel. 12,13 Patients with cancer also may have other medical conditions that increase their risk of neuropathy, including diabetes, vitamin B 12 deficiency, HIV infection, and the genetic disorder Charcot-Marie-Tooth disease. 10,13-15 Chemotherapy can cause neuropathy, or it may worsen neuropathy that is due to another cause. Neuropathy is often the dose-limiting toxicity for patients who are undergoing chemotherapy. 12,13,16 In general, chemotherapy-related neuropathy occurs soon after treatment (typically within a few days). An exception is cisplatin-related neuropathy, which may be delayed for weeks to months after cisplatin administration. Chemotherapy-related neuropathy often occurs in a stocking-glove pattern, with the symptoms occurring first at the tips of the fingers or toes and progressing toward the trunk. Chemotherapyinduced sensory neuropathy may affect the large nerve fibers (which carry information about touch and vibration) or small fibers (which carry information about pain and temperature). Loss of large-diameter fibers also causes the loss of deep tendon reflexes, and examination of these reflexes is an important part of the assessment of patients who undergo chemotherapy. 92 Vol. 5, No. 3 December 2007

Neuropathy may be irreversible and may persist even after successful completion of therapy. Taxanes cause axonal injury and demyelination by promoting microtubule polymerization and aggregation, resulting in mixed sensorimotor neuropathy. 13,17 Patient complaints usually involve changes in temperature, sensation, and pain. Paclitaxel-induced peripheral neuropathy is rare at doses lower than 200 mg/m 2, but is often severe at doses exceeding 300 mg/m 2. Neuropathy also is associated with the total cumulative dose of paclitaxel received: it is generally mild at total doses lower than 600 mg/m 2, moderate at doses between 600 and 1500 mg/m 2, and severe at doses higher than 1500 mg/m 2. 18 Neuropathy is less common with docetaxel. 19 Peripheral neuropathy has also been reported in clinical investigations of epothilones, such as ixabepilone. 20-22 Neurologic assessment is important for patients with breast cancer to establish baseline neurologic function, identify preexisting medical conditions that may affect sensory function, to alert the treatment team to the possibility of increased risk of neurologic complications, and to indicate the need for a change in the treatment regimen. Sensory assessment may be performed using several simple tests. Pain may be measured using a pinprick. Temperature sensation may be assessed by the application of hot or cold items. The use of extreme temperatures is not necessary. Proprioception may be assessed by moving the patient s digits and assessing ability to describe the location of a finger or toe with both eyes closed. Vibration is assessed by the application of a tuning fork, which is placed as far as possible from any bony prominences (eg, the bony prominence on the top of the middle finger or the last joint in the great toe). Potential strategies to reduce the severity of peripheral neuropathy include certain antidepressants (eg, amitriptyline), antiseizure medications (eg, carbamazepine), and glutamine. 23,24 NAUSEA AND EMESIS Chemotherapy-induced nausea and vomiting (CINV) is a common side effect experienced by patients with breast cancer. 25,26 The vomiting response involves complex interactions between the brain stem (especially a vomiting center within the medulla oblongata), the vagus nerve, and the GI tract. The vomiting center receives nerve signals from several different incoming pathways, including a chemoreceptor trigger zone (CTZ), the vestibular system, the pharynx, and the GI tract. The CTZ is located within a region of the brain known as the area postrema, which is not protected by the blood-brain barrier. 27 It is therefore more sensitive to toxins (including chemotherapy drugs) circulating in the bloodstream than the rest of the brain. Toxins are also detected by sensory receptors within the GI system. This information is communicated to the vomiting center via the vagus nerve and, to a lesser extent, the splanchnic nerves. Therefore, chemotherapy may induce CINV by at least 2 different mechanisms: local irritation or injury to the GI tract, or direct activation of neurotransmitter receptors in the CTZ by chemicals in the blood or the cerebrospinal fluid. The risk of CINV is influenced by chemotherapyrelated factors and patient-related factors. The most important predictor of acute CINV risk is the intrinsic emetic effect of the chemotherapy agent. Other factors include the dose, intravenous administration, rapid infusion, and repeated cycles of chemotherapy. 28-30 Patient characteristics that are associated with increased risk of CINV include low alcohol consumption (<10 drinks/week), age younger than 50 years, female sex, and a history of motion sickness. The most important predictor of delayed CINV is poor control of CINV during the acute phase of treatment. 28,31,32 A classification system has been developed by Hesketh et al to rate the potential for chemotherapy agents to produce emesis. 33 This system was based on a comprehensive review of the medical literature regarding the risk of emesis with chemotherapy agents, and included the potential effects of the dose, rate of infusion, and route of administration. As shown in Table 1, the authors classified emetic risk into 5 levels, increasing from Level 1 agents (which produce emesis in <10% of patients) to Level 5 agents (which produce emesis in >90% of patients). 33 PATIENT ADHERENCE TO CHEMOTHERAPY Because of the growing number of oral agents used in cancer therapy, the role of patients in ensuring correct treatment is greater than it has been in the past. The tendency of patients to continue their treatment may be defined in several ways (Table 2). 34 Most experts now emphasize patient adherence, rather than compliance, in maintaining a long-term treatment schedule. The use of the term compliance suggests that the patient is passively following the direction of the healthcare provider, whereas the term adherence emphasizes the importance of the patient s Johns Hopkins Advanced Studies in Nursing 93

Table 1. Frequency of Emesis with Chemotherapy Drugs Frequency of Level Emesis, % Agent 5 >90 Carmustine >250 mg/m 2 Cisplatin 50 mg/m 2 Cyclophosphamide >1500 mg/m 2 Dacarbazine Mechlorethamine Streptozocin 4 60 90 Carboplatin Carmustine 250 mg/m 2 Cisplatin <50 mg/m 2 Cyclophosphamide >750 mg/m 2 1500 mg/m 2 Cytarabine >1 g/m 2 Doxorubicin >60 mg/m 2 Methotrexate >1000 mg/m 2 Procarbazine (oral) 3 30 60 Cyclophosphamide 750 mg/m 2 Cyclophosphamide (oral) Doxorubicin 20 60 mg/m 2 Epirubicin 90 mg/m 2 Hexamethylmelamine (oral) Idarubicin Ifosfamide Methotrexate 250 1000 mg/m 2 Mitoxantrone <15 mg/m 2 2 10 30 Docetaxel Etoposide 5-fluorouracil <1000 mg/m 2 Gemcitabine Methotrexate >50 mg/m 2 <250 mg/m 2 Mitamycin Paclitaxel 1 <10 Bleomycin Busulfan Chlorambucil (oral) 2-chlorodeoxyadenosine Fludarabine Hydroxyurea Methotrexate 50 mg/m 2 L-phenylalanine mustard (oral) Thioguanine (oral) Vinblastine Vincristine Vinorelbine Note: Proportion of patients who experience emesis in the absence of effective antiemetic prophylaxis. Reprinted with permission from the American Society of Clinical Oncology, Hesketh et al. J Clin Oncol. 1997;15:103-109. 33 role in ensuring that treatment is used as prescribed. In most studies, approximately 60% to 75% of patients remain adherent to oral therapy (primarily tamoxifen) during 1 year of follow-up. 35 With longerterm treatment, adherence rates to oral therapies may be no higher than 40% to 50%, and are influenced by patient perceptions of risk, perception of benefits, and the cost of treatments. Other factors that influence treatment adherence include patient knowledge or understanding of the disease, the patient s beliefs about health and disease, the quality of the interaction between the patient and healthcare providers, the patient s social and financial resources, and other factors associated with the illness and its treatment. 36 Adherence may be improved by questioning the patient about obstacles to taking the treatment as required (Table 3). 37 Table 2. Definitions of Treatment Adherence Compliance is defined as the act or process of complying with a desire, demand, or coercion from another person Adherence, in contrast, implies participation in a treatment regimen that is agreed to by the patient or participant Concordance involves a negotiated agreement between the patient and the healthcare provider, and also implies patient involvement in the treatment process Persistence (also referred to as the continuation rate) is the percentage of patients who are still using their therapy as prescribed after some period of time (eg, the end of a treatment regimen; after 1 month) Table 3. Questions to Help Improve Treatment Adherence Do you have any questions as to why you are receiving this therapy? How many doses did you miss? Do you recall why you missed the dose(s)? Are you having any side effects? Are these side effects causing any difficulties for you? Are you having any problems paying for your prescription or meeting your co-pay? Are you able to get to the pharmacy to pick up your prescription? Are you aware of the specialty pharmacy mail-order option? Do you need a new prescription at this time? 94 Vol. 5, No. 3 December 2007

Several other tools may also help improve treatment adherence, including calendar blister packs, pill organizers, assessment of the patient s ability to pay for treatment, and asking patients to demonstrate that they are able to correctly identify their medications, open medication containers, and remove the correct dosage. CONCLUSIONS Breast cancer treatment produces several potentially serious adverse effects that are often difficult for patients to tolerate. Anemia generally develops after several cycles of therapy, whereas neutropenia often develops soon after the initiation of treatment. Peripheral neuropathy may involve sensory, motor, or autonomic nerves, and produces diverse symptoms that include pain, disturbances of sensation, and the loss of deep tendon reflexes. CINV is very common and is influenced by several patient-related and treatment-related factors. Although these and other adverse effects have the potential to significantly interfere with patient adherence to therapy, oncology nurses have many options to help manage adverse treatment effects and improve adherence to therapy. DISCUSSION Dr Gallucci: It is important for us to develop effective tools to assess neuropathy. Simple clinical measures can help us establish a baseline and assess neuropathy as the patient continues therapy. For example, can the patient pick up a coin or singlehandedly button a shirt? Ms Stein: It may also help us establish a risk factor profile for our patients receiving these cytotoxic agents, including factors such as prior exposure to neuropathic agents, diabetes, alcoholism, or other factors that may contribute to neuropathy. Ms Shivnan: This is an area where nurses really are the experts and have the responsibility to provide nonpharmacologic options for preventing symptoms, as well as referring appropriately for pharmacologic options, or to modify the treatment plan if needed. Nurses also have a clear role in promoting adherence to regimens, particularly the oral drugs. Many women who would benefit from hormonal therapy stop taking it, and the nurse has a major role in helping to encourage and keep women on medication regimens that they need. Dr Gallucci: There are also community resources for women with breast cancer. For example, Team Survivor involves women in physical activities and can help patients to share knowledge about managing some of these toxicities. For example, I have heard patients describe how a hot tub may help with neuropathy. We may also be able to participate in these groups to help direct the conversation, and it also helps us learn what helps patients. Ms Stein: Several pharmaceutical companies have case management programs to help with the adherence issues that are commonly seen. Some include a nurse who calls and checks on the patients and sees how they are doing and makes sure they are adhering to their programs. Ms Frye: Are there medication strategies that you use to prevent neuropathy? This seems to be an area of controversy. Ms Stein: Some studies have examined glutamine to try to prevent sensory neuropathy, and many of us use vitamin B 6. I am not sure if anyone knows the exact mechanism of action of these agents. Ms Viele: There are several studies in neuropathy looking at different medications to relieve the symptoms of the pain and burning. As mentioned, Dr Linda Vahdat has looked at the use of glutamine 10 gm 3 times a day in the paclitaxel population with some success. Vitamin B 6 (pyridoxine), as mentioned by Ms Stein, is usually dosed at 200 mg twice a day or 100 mg 3 times a day. In addition, the use of antiseizure medications, such as carbamazepine, gabapentin, and pregabalin, have all been tried with some success. If we are looking at an intervention that is both cost effective and efficacious in some patients, the use of amitriptyline has been utilized over many years. It has been met with some success. Each of the agents may be used, and it will be up to the patient and healthcare practitioner to determine which one works best and causes the least amount of bothersome side effects. All of these are usually taken in the evening so the patient may have a comfortable night s sleep. It has been my experience that patients symptoms are often noted to be worse in the evening so the side effects of sleepiness work well in this situation. Dr Gallucci: We should also mention fatigue. A good assessment of blood values, combined with an assessment of the patient s daily activities is important to help patients understand the most fatiguing activities that they do each day. For instance, taking a shower is one of the most fatiguing activities for patients. Johns Hopkins Advanced Studies in Nursing 95

We have to help patients learn how to conserve energy so that they are able to do those things that they want to do during the day. Also, research is showing that exercise helps relieve fatigue. Helping the individual learn to manage a low-impact exercise regimen whether it is just walking out to the mailbox and then walking to the end of the sidewalk can help with fatigue. And then maybe getting involved in something more structured, like Team Survivor, could help. Ms Viele: As Dr Gallucci points out, we need to address fatigue as it bothers a majority of patients, and we have no clear information for the patient on duration. All patients should be individually counseled on fatigue reduction techniques. Sometimes just restructuring a day in a patient s life can be helpful in this manner. REFERENCES 1. Gordon MS. Managing anemia in the cancer patient: old problems, future solutions. Oncologist. 2002;7:331-341. 2. Argiles JM, Busquets S, Moore-Carrasco R, et al. Targets in clinical oncology: the metabolic environment of the patient. Front Biosci. 2007;12:3024-3051. 3. Coiffier B, Guastalla JP, Pujade-Lauraine E, et al. Predicting cancer-associated anaemia in patients receiving non-platinum chemotherapy: results of a retrospective survey. Eur J Cancer. 2001;37:1617-1623. 4. Biondi C, Cotorruelo C, Ensinck A, et al. Senescent erythrocytes: factors affecting the aging of red blood cells. Immunol Invest. 2002;31:41-50. 5. Scott S. Identification of cancer patients at high risk of febrile neutropenia. Am J Health Syst Pharm. 2002;59:S16-S19. 6. Alexandre J, Gross-Goupil M, Falissard B, et al. Evaluation of the nutritional and inflammatory status in cancer patients for the risk assessment of severe haematological toxicity following chemotherapy. Ann Oncol. 2003;14:36-41. 7. Camp-Sorrell D. Myelosuppression. In: Itano JK, Taoka KN, eds. Core Curriculum for Oncology Nursing. St. Louis, MO: Elsevier Health Sciences; 2005:259-276. 8. American Cancer Society. What are the possible side effects of chemotherapy? Available at: http://www.cancer.org/docroot/eto/content/eto_1_4x_what_are_the _Side_Effects_of_Chemotherapy.asp?sitearea=ETO. Accessed August 14, 2007. 9. Oncology Nursing Society. Causes of neutropenia. Available at: http://www.cancersymptoms.org/neutropenia/causes.shtml. Accessed August 14, 2007. 10. Poncelet AN. An algorithm for the evaluation of peripheral neuropathy. Am Fam Physician. 1998;57:755-764. 11. Wilkes G. Peripheral neuropathy related to chemotherapy. Semin Oncol Nurs. 2007;23:162-173. 12. Quasthoff S, Hartung HP. Chemotherapy-induced peripheral neuropathy. J Neurol. 2002;249:9-17. 13. Lee JJ, Swain SM. Peripheral neuropathy induced by microtubule-stabilizing agents. J Clin Oncol. 2006;24:1633-1642. 14. Head KA. Peripheral neuropathy: pathogenic mechanisms and alternative therapies. Altern Med Rev. 2006;11:294-329. 15. Weimer LH, Podwall D. Medication-induced exacerbation of neuropathy in Charcot Marie Tooth disease. J Neurol Sci. 2006;242:47-54. 16. Wickham R. Chemotherapy-induced peripheral neuropathy: a review and implications for oncology nursing practice. Clin J Oncol Nurs. 2007;11:361-376. 17. Hagiwara H, Sunada Y. Mechanism of taxane neurotoxicity. Breast Cancer. 2004;11:82-85. 18. Hasheer F, Schilsky R, Bains S, et al. Diagnosis, management, and evaluation of chemotherapy-induced peripheral neuropathy. Semin Oncol. 2006;33:15-49. 19. Katsumata N. Docetaxel: an alternative taxane in ovarian cancer. Br J Cancer. 2003;89:S9-S15. 20. Ixabepilone [prescribing information]. Princeton, NJ: Bristol- Myers Squibb Company; 2007. 21. Cortes J, Baselga J. Targeting the microtubules in breast cancer beyond taxanes: the epothilones. Oncologist. 2007;12:271-280. 22. Denduluri N, Low JA, Lee JJ, et al. Phase II trial of ixabepilone, an epothilone B analog, in patients with metastatic breast cancer previously untreated with taxanes. J Clin Oncol. 2007;25:3421-3427. 23. Makino H. Treatment and care of neurotoxicity from taxane anticancer agents. Breast Cancer. 2004;11:100-104. 24. Eisenberg E, River Y, Shifrin A, Krivoy N. Antiepileptic drugs in the treatment of neuropathic pain. Drugs. 2007;67:1265-1289. 25. Wiser W, Berger A. Practical management of chemotherapy-induced nausea and vomiting. Oncology. 2005;19:637-645. 26. Grunberg SM, Hesketh PJ. Control of chemotherapyinduced emesis. N Engl J Med. 1993;329:1790-1796. 27. Miller AD, Leslie RA. The area postrema and vomiting. Front Neuroendocrinol. 1994;15:301-320. 28. Gralla RJ, Osoba D, Kris MG, et al. Recommendations for the use of antiemetics: evidence-based, clinical practice guidelines. American Society of Clinical Oncology. J Clin Oncol. 1999;17:2971-294. 29. Hesketh PJ. Defining the emetogenicity of cancer chemotherapy regimens: relevance to clinical practice. Oncologist. 1999;4:191-196. 30. de Wit R, Schmitz PI, Verweij J, et al. Analysis of cumulative probabilities shows that the efficacy of 5HT3 antagonist prophylaxis is not maintained. J Clin Oncol. 1996;14:644-651. 31. Osoba D, Zee B, Pater J, et al. Determinants of postchemotherapy nausea and vomiting in patients with cancer. Quality of Life and Symptom Control Committees of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1997;15:116-123. 32. Pisters KMW, Kris MG. Treatment-related nausea and vomiting. In: Berger A, Portenoy RK, Weissman DE, eds. Principles and Practice of Supportive Oncology. Philadelphia, PA: Lippincott-Raven Publishers; 1998:165-177. 33. Hesketh PJ, Kris MG, Grunberg SM, et al. Proposal for classifying the acute emetogenicity of cancer chemotherapy. J Clin Oncol. 1997;15:103-109. 34. Viele C. Managing oral chemotherapy: the healthcare practitioner s role. Am J Health-Sys Pharm. 2007;64:S25-S32. 35. Partridge AH, Wang PS, Winer EP, Avorn J. Nonadherence to adjuvant tamoxifen therapy in women with primary breast cancer. J Clin Oncol. 2003;21:602-606. 36. Cameron C. Patient compliance: recognition of factors involved and suggestions for promoting compliance with therapeutic regimens. Adv Nurs. 1996;24:244-250. 37. Kelly A et al. Oncology. 2006;20(10, Suppl 7):50-54. 96 Vol. 5, No. 3 December 2007