- Email: [email protected]
Antiemetic guidelines: are they being used?
Essay
Antiemetic guidelines: are they being used? Rolf Kaiser Lancet Oncol 2005; 6: 622–25 Correspondence to: Dr Rolf Kaiser, Department of Clinical Pharmacology, University Medical Centre Georg-August University Göttingen, Robert Koch Strasse 40, D-37075 Göttingen, Germany [email protected]
Evidence-based guidelines are regarded as therapeutic standards for many medical interventions. However, implementation of such recommendations seems to be rather difficult. An international antiemetic guideline for the treatment of patients undergoing chemotherapy was issued by the Multinational Association of Supportive Care in Cancer in 1997 and has been in use ever since. However, for many reasons, the guideline has not been followed completely, despite the fact that if antiemetics are used in accordance with guidelines, efficacy is similar to that achieved in randomised controlled trials. Structural dificulties, patients characteristics, and other barriers, such as the individual acceptance of guidelines and education of physicians and nurses, could be crucial factors for successful implementation. Thus, better adherence to antiemetic guidelines can only be achieved through a complex and long-term process, consisting of efficient education, training, and monitoring of all individuals involved.
Clinical relevance
© Simon Fraser/Science Photo Library
During the past few decades, there have been substantial therapeutic advances in the treatment of malignant diseases, especially in the sphere of supportive care in cancer. However, cytostatic-drug-induced nausea and vomiting are adverse effects most feared by patients and can influence therapeutic outcome.1 Three forms of vomiting or nausea induced by cancer chemotherapy can be distinguished: acute emesis arising within 24 h of chemotherapy administration; delayed emesis arising after the first 24 h and lasting for up to 6 days; and anticipatory emesis.2 The acute type of emesis seems to be provoked predominantly by release of serotonin within the first 4–8 h after chemotherapy (particularly with cisplatin), leading to consecutive activation of serotonin 5-HT3 receptors on peripheral vagal fibres and central structures such as the area postrema and nucleus tractus solitarii.3–5 Thereafter, substance P, as well as serotonin and other neurotransmitters, seems to have an important role in the maintenance of acute and delayed
Figure 1: Putting guidelines into practice
622
emesis.6 The underlying biochemical mechanism of conditioned vomiting is yet to be clarified. The introduction of 5-HT3-receptor antagonists was a breakthrough in antiemetic treatment of patients with cancer. Whichever 5-HT3-receptor antagonist was given, more than 70% of patients receiving cisplatin responded to a combination of 5-HT3-receptor antagonists and a glucocorticoid in the acute phase of chemotherapyinduced nausea and vomiting compared with 38% of patients given metoclopramide.7–11
Antiemetic guidelines After a breakthrough such as that seen in antiemetic treatment, the results of controlled clinical trials should be translated quickly into routine clinical practice (figure 1). National and international organisations, such as the Multinational Association of Supportive Care in Cancer, the National Comprehensive Cancer Network, the American Society of Health-System Pharmacists, and the American Society of Clinical Oncology, have issued antiemetic guidelines for the treatment of patients undergoing chemotherapy.12–16 Although these guidelines should serve to harmonise antiemetic treatment, they differ to some extent. For example, guidelines by the American Society of Health-System Pharmacists and by the National Comprehensive Cancer Network distinguish five different grades of emetogenicity of chemotherapeutic agents, whereas the Multinational Association of Supportive Care in Cancer guidelines distinguishes four. Furthermore, in contrast to the guidelines of the American Society of Health-System Pharmacists and the American Society of Clinical Oncology, those of the National Comprehensive Cancer Network and the Multinational Association of Supportive Care in Cancer recommend administration of aprepitant, an antagonist of neurokinin receptor subtype 1 for the prevention of acute emesis in patients treated with highemetic-risk chemotherapy. The guidelines of the National Comprehensive Cancer Network offer a different antiemetic treatment algorithm for emetogenic stage five than for stages 3–4, whereas the American Society of Health-System Pharmacists recommends the same antiemetic treatment approach for these stages. http://oncology.thelancet.com Vol 6 August 2005
Essay
The reason for these differences could be due to a different interpretation of the antiemetic trials, different compositions of the respective committees, or differences in the timing of guideline updates. Guidelines are not, however, followed completely for many reasons, especially in the case of delayed emesis, although proper use of antiemetics has long been known to achieve efficacy similar to that recorded in randomised controlled trials. The problem of non-adherence is not restricted to the guidelines on antiemetic treatment but seems to apply generally to use of guidelines. Guidelines such as a red traffic light, which is simple, easy to understand, precise, uncontroversial, and target group-oriented, refers to an acute situation, and is based on the correlation of a higher risk for the road user not following it. However, like clinical guidelines, there are some people who have difficulty in implementing it.
physicians. Guidelines should focus on acute clinical problems, since compliance with guidelines that focus on acute care seems to be much better than that with those referring to chronic care.20–23 Furthermore, guidelines should be uncontroversial. A controversial or ambiguous guideline will be used incorrectly or not at all. Guidance needs to be in accordance with regulations in effect and with daily routine, and the recommendations should be easy to incorporate into routine clinical practice. For patients to accept a guideline, it needs to have a positive effect for the patient. And, of course, guidance must be set out clearly, must refer to the target group, and must be unambiguous and precise.20,21,24,25 Adoption of therapeutic guidelines is not only a specific problem of the antiemetic guidelines, it is a potential problem in different social and medical specialties.26–28
Non-adherence to clinical guidelines
Non-adherence to antiemetic guidelines
Guidelines are systematically developed statements to assist practioners and patients in decisions on appropriate healthcare in specific clinical circumstances.17 What is sought from guidelines depends on the different groups in the health-care system. These groups have differing attitudes towards the ultimate goal of the therapeutic guidelines applied. Thus, physicians and patients are mainly interested in improving treatment. Politicians, insurers, and clinical administrations are not so strongly focused on individual therapeutic outcome for the patients; their emphasis tends to be on reducing costs of the healthcare system or on the economic efficiency of their clinic. In surveys of attitudes to guidelines in general,18,19 more than 50% of physicians thought that guidelines are good educational tools, which are motivated by the desire to improve quality of life. However, they believed that guidelines have strong limitations, are too rigid to be applied to individual patients, and resemble cookbook medicine. Moreover, more than 60% of physicians replied that guidelines could be used for disciplinary actions against physicians and that most of the guidelines are motivated by the desire to reduce costs. However, 52% of physicians thought that the use of guidelines should improve the quality of patients’ care. But only 12% thought that guidelines would probably increase physicians’ satisfaction with the practice of medicine. For more than 40% of the physicians, guidelines were associated with a reduction in reimbursement and a rise in the total cost of healthcare.19 Confidence in guidelines depend on the type of organisations that issue them; specialists have greater confidence in guidelines issued by specialist medical organisations than in guidelines issue them by national or federal organisations.18,19 For therapeutic guidelines to be accepted, certain standards have to be included. For example, a guideline must be evidence-based for it to be accepted by
How effective is the transfer of antiemetic guidelines into routine clinical practice? In 1998, the Italian Group for Antiemetic Research carried out a prospective observational study on the use and efficacy of antiemetic drugs in 33 Italian departments of oncology, including over 2000 patients.29 More than 20% of the patients treated with highly emetogenic cytostatic agents did not receive the appropriate treatment for acute chemotherapyinduced nausea and vomiting. The proportion was even higher among patients treated with moderately emetogenic (58%) or low-emetogenic (63%) agents. The trend was similar for the treatment of delayed-typechemotherapy-induced nausea and vomiting. Furthermore, a high proportion of patients were overtreated; 48% of the patients treated with low-emetogenic cytostatics were given antiemetic treatment for the delayed-type and 15% were treated for acute-type vomiting, even though these treatments were not necessary. As expected, patients who received highly emetogenic chemotherapy and who had been treated according to the antiemetic recommendations had less vomiting than those who did not receive the appropriate treatment. Among patients who received low-emetogenic chemotherapy, the proportion of complete protection from acute vomiting was the same for those given an unecessary antiemetic treatment and for those not given any antiemetic treatment. Whether the unecessarily treated patients experienced more side-effects than the other patients could not be concluded from the data. 92% of patients given highly emetogenic cytostatic agents in centres with a background in antiemetic research received the correct antiemetic treatment compared with only 64% in centres without such a research background. The same pattern was reported for patients undergoing moderately emetogenic chemotherapy. The result of a further study was rather worrying. Only 56% of all patients received the appropriate antiemetic treatment for acute emesis and only 45% of the
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623
Essay
Knowledge
Attitudes
Knowledge
Lack of:
Lack of:
External factors:
Familiarity
Agreement
Patients
Awareness
Outcome-expectancy
Guidelines
Self-efficiency
Environment
Motivation
Time
Figure 2: Steps involved in changing physicians’ behaviour24,25,27
patients were treated appropriately for delayed-type vomiting. Patients treated with anthracyclines received better antiemetic treatment for acute chemotherapyinduced nausea and vomiting than patients treated with the combination of cyclophosphamide, methotrexate, and fluorouracil. As recorded in the previous study, the antiemetic treatment was of a better standard in centres that had a background in antiemetic research than in centres not experienced in this kind of treatment.30 We can speculate whether this difference arises because experience from clinical trials with antiemetic drugs leads to greater sensibility for this medical problem or because the investigators merely follow their own recommendations. In a further survey investigating the treatment of delayed-type chemotherapy-induced nausea and vomiting, only 43% of patients treated with highly emetogenic cytostatics, 64% treated with moderately emetogenic cytostatics, and 31% of the patients treated with low-emetogenic cytostatic agents received the correct antiemetic treatment for delayed-type vomiting. Moreover, 68% of the patients received unnecessary antiemetic treatment.31
Implementing guidelines more effectively Lack of adherence with guidelines is not restricted to antiemetic treatment but is widespread throughout medicine. The reasons could be related to the guideline itself or to the issuing organisation.18,19 The way in which guidelines are introduced could have an important role. Furthermore, compliance also depends on patients, nurses, and physicians. To change physicians’ behaviour is difficult and a long-term process (figure 2).21,25,27 Before a guideline can affect a patient’s outcome, it must first change the knowledge of the physician, then the attitudes towards or the acceptance of the guideline, and finally the clinical behaviour that could ultimately lead to a better therapeutic outcome for the patient. Crucial factors can affect this process at each stage; for example, the physician might not be aware of the guideline or 624
might disagree with it. Of course, the physician should be seeking knowledge, be experienced in therapeutic guidelines, and be open minded about applying new knowledge. There are different strategies for better implementation of guidelines in general.21,32–35 Passive dissemination of educational material is ineffective no matter how important the issue or how valid the methods. Successful implementation of therapeutic guidelines occurs through combined strategies by use of educational material, outreach visits, patient-mediated interventions, and a computerised decision-supportsystem. Finally, each guideline has to be investigated to see whether it can be implemented, and more importantly whether it will be accepted by the people involved.
Evidence that better implementation works Nolte and co-workers36 reported on the development, implementation, and assessment of antiemetic guidelines. Adherence to the guidelines rose from 73% in the first version to 98% in the third version of the guidelines. This increase in adherence was achieved by personal feedback when the antiemetic order did not follow the guideline and by introduction of a check box on the chemotherapy order sheet. Better adherence was accompanied by better antiemetic outcomes for patients and lower costs. However, the extent to which economic issues influenced this process of implementation cannot be concluded from the publication. In another survey, implementation of guidelines was improved by means of a multifaceted intervention programme that consisted guideline dissemination, use of opinion leaders, interactive educational workshops, therapeutic reminders, clinical interventions by pharmacists, physician audit, and feedback. Treatment of more than 88% of the patients met the guidelines in terms of appropriate indication, dose, and duration.37 However, a joint guideline development and distribution strategy had only a short-term effect on adherence.38 A subsequent lecture by a visiting professor, a renowned specialist in this sphere, also failed to improve the results. However, the presentation and discussion of the poor antiemetic outcome in patients who had not been treated according to the guidelines definitely changed the behaviour of the physicians.38 Thus, educational approaches for dissemination are not successful, but direct feedback on patients’ outcomes to the physician is very effective. Financial incentives or penalties could also serve as negative conditioning tools to improve the implementation of guidelines.32,38–40 However, whether negative reinforcements to change behaviour is really an intelligent approach is questionable.
Implications for policy and clinical practice 30–50% of patients do not receive appropriate antiemetic treatment. Thus, antiemetic guidelines must be better implemented. In general, guidelines should be precise, http://oncology.thelancet.com Vol 6 August 2005
Essay
easy to follow, evidence-based, refer to acute clinical problems, and be easily implemented into routine clinical practice. Only a long-term educational process with active participation of all individuals involved will improve antiemetic outcome for patients. Moreover, to improve adherence, antiemetic guidelines, issued by different organisations should be harmonised. Finally, the informed patient will have an increasingly important role in medical decision-making. Conflict of interest I declare no conflicts of interest. Acknowledgments I receive support from the German Ministry for Research and Technology (BMFT), grant 01GG9845/5. References 1 Stewart DJ. Cancer therapy, vomiting, and antiemetics. Can J Physiol Pharmacol 1990; 68: 304–13. 2 Andrews PL, Davis CJ. The mechanism of emesis induced by anticancer therapies. In: Andrews PL SG, ed. Emesis in anti-cancer therapy. London: Chapman and Hall, 1993: 113–61. 3 Tyers MB, Freeman AJ. Mechanism of the anti-emetic activity of 5-HT3 receptor antagonists. Oncology 1992; 49: 263–68. 4 Miller AD, Leslie RA. The area postrema and vomiting. Front Neuroendocrinol 1994; 15: 301–20. 5 Gregory RE, Ettinger DS. 5-HT3 receptor antagonists for the prevention of chemotherapy-induced nausea and vomiting: a comparison of their pharmacology and clinical efficacy. Drugs 1998; 55: 173–89. 6 Hesketh PJ, van Belle S, Aapro M, et al. Differential involvement of neurotransmitters through the time course of cisplatin-induced emesis as revealed by therapy with specific receptor antagonists. Eur J Cancer 2003; 8: 1074–80. 7 Gralla RJ, Itri LM, Pisko SE, et al. Antiemetic efficacy of high-dose metoclopramide: randomized trials with placebo and prochlorperazine in patients with chemotherapy-induced nausea and vomiting. N Engl J Med. 1981; 305: 905–09. 8 Cunningham D, Hawthorn J, Pople A, et al. Prevention of emesis in patients receiving cytotoxic drugs by GR38032F, a selective 5-HT3 receptor antagonist. Lancet 1987; 1: 1461–63. 9 Hesketh P, Navari R, Grote T, et al. Double-blind, randomized comparison of the antiemetic efficacy of intravenous dolasetron mesylate and intravenous ondansetron in the prevention of acute cisplatin-induced emesis in patients with cancer. J Clin Oncol 1996; 14: 2242–49. 10 Navari RM, Kaplan HG, Gralla RJ, et al. Efficacy and safety of granisetron, a selective 5-hydroxytryptamine-3 receptor antagonist, in the prevention of nausea and vomiting induced by high-dose cisplatin. J Clin Oncol 1994; 12: 2204–10. 11 Poli-Bigelli S, Rodrigues-Pereira J, Carides AD, et al. Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting: results from a randomized, double-blind, placebocontrolled trial in Latin America. Cancer 2003; 97: 3090–98. 12 Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer (MASCC). Prevention of chemotherapyand radiotherapy-induced emesis: results of Perugia Consensus Conference. Ann Oncol 1998; 9: 811–19. 13 Gralla RJ, Roila F, Tonato M, et al. The 2004 Perugia Antiemetic Consensus Guideline process: methods, procedures, and participants. Support Care Cancer 2005; 13: 77–79. 14 National Comprehensive Cancer Network. Guidelines for supportive care, antiemesis. http://www.nccn.org/professionals/ physician_gls/f_guidelines.asp?button=I+Agree#care. (accessed April 14, 2005). 15 American Society of Health-System Pharmacists. ASHP therapeutic guidelines on the pharmacologic management of nausea and vomiting in adult and pediatric patients receiving chemotherapy or radiation therapy or undergoing surgery. Am J Health Syst Pharm 1999; 56: 729–64.
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Gralla RJ, Osoba D, Kris MG, et al. Recommendations for the use of antiemetics: evidence-based, clinical practice guidelines. J Clin Oncol 1999; 17: 2971–94. Field MJ, Lohr KN. Clinical practice guidelines: directions of a new program. Washington, DC: National Academy Press, 1990. Tunis SR, Hayward RS, Wilson MC, et al. Internists’ attitudes about clinical practice guidelines. Ann Intern Med 1994; 120: 956–63. Borkowski NM, Allen WR. Does attribution theory explain physicians’ nonacceptance of clinical practice guidelines? Hosp Top 2003; 81: 9–21. Grilli R, Lomas J. Evaluating the message: the relationship between compliance rate and the subject of a practice guideline. Med Care 1994; 32: 202–13. Grol R, Dalhuijsen J, Thomas S, et al. Attributes of clinical guidelines that influence use of guidelines in general practice: observational study. BMJ 1998; 317: 858–61. Foy R, MacLennan G, Grimshaw J, et al. Attributes of clinical recommendations that influence change in practice following audit and feedback. J Clin Epidemiol 2002; 55: 717–22. Burgers J, Grol R, Zaat J, et al. Characterics of effective clinical guidelines for general practice. Br J Gen Pract 2003; 53: 15–19. Grol R, Grimshaw J. From best evidence to best practice: effective implementation of change in patients’ care. Lancet 2003; 362: 1225–30. Michie S, Johnston M. Changing clinical behaviour by making guidelines specific. BMJ 2004; 328: 343–45. Lomas J, Anderson GM, Domnick-Pierre K, et al. Do practice guidelines guide practice? The effect of a consensus statement on the practice of physicians. N Engl J Med 1989; 321: 1306–11. Cabana MD, Rand CS, Powe NR, et al. Why don’t physicians follow clinical practice guidelines? A framework for improvement. JAMA 1999; 282: 1458–65. Grol R. Successes and failures in the implementation of evidencebased guidelines for clincial practice. Med Care 2001; 39 (suppl 2): 46–54. The Italian Group for Antiemetic Research. Transferability to clinical practice of the results of controlled clinical trials: the case of antiemetic prophylactic treatment for cancer chemotherapy-induced nausea and vomiting. Ann Oncol 1998; 9: 759–65. Drug Utilization Review Team in Oncology (DURTO). Antiemetic prescription in Italian breast cancer patients submitted to adjuvant chemotherapy. Support Care Cancer 2003; 11: 785–89. Fabi A, Barduagni M, Lauro S, et al. Is delayed chemotherapyinduced emesis well managed in oncological clinical practice? An observational study. Support Care Cancer 2003; 11: 156–61. Davis DA, Thomson MA, Oxman AD, Haynes RB. Changing physician performance: a systematic review of the effect of continuing medical education strategies. JAMA 1995; 249: 700–05. Bero LA, Grilli R, Grimshaw JM, et al. Closing the gap between research and practice: an overview of systematic reviews of interventions to promote the implementation of research findings. BMJ 1998; 317: 465–68. Mazmanian PE, Davis DA. Continuing medical education and the physician as a learner: guide to the evidence. JAMA 2002; 288: 1057–60. Grimshaw JM, Eccles MP. Is evidence-based implementation of evidence-based care possible? Med J Aust 2004; 180: 50–51. Nolte MJ, Berkery R, Pizzo B, et al. Assuring the optimal use of serotonin antagonist antiemetics: the process for development and implementation of institutional antiemetic guidelines at Memorial Sloan-Kettering Cancer Center. J Clin Oncol 1998; 16: 771–78. Dranitsaris G, Leung P, Warr D. Implementing evidence based antiemetic guidelines in the oncology setting: results of a 4-month prospective intervention study. Support Care Cancer 2001; 9: 611–18. Mertens WC, Higby DJ, Brown D, et al. Improving the care of patients with regard to chemotherapy-induced nausea and emesis: the effect of feedback to clinicians on adherence to antiemetic prescribing guidelines. J Clin Oncol 2003; 21: 1373–78. Goldman L. Changing physicians’ behavior: the pot and the kettle. N Engl J Med 1990; 322: 1524–25. Greco PJ, Eisenberg JM. Changing physicians’ practices. N Engl J Med 1993; 329: 1271–74.
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Antiemetic guidelines: are they being used? Rolf Kaiser Lancet Oncol 2005; 6: 622–25 Correspondence to: Dr Rolf Kaiser, Department of Clinical Pharmacology, University Medical Centre Georg-August University Göttingen, Robert Koch Strasse 40, D-37075 Göttingen, Germany [email protected]
Evidence-based guidelines are regarded as therapeutic standards for many medical interventions. However, implementation of such recommendations seems to be rather difficult. An international antiemetic guideline for the treatment of patients undergoing chemotherapy was issued by the Multinational Association of Supportive Care in Cancer in 1997 and has been in use ever since. However, for many reasons, the guideline has not been followed completely, despite the fact that if antiemetics are used in accordance with guidelines, efficacy is similar to that achieved in randomised controlled trials. Structural dificulties, patients characteristics, and other barriers, such as the individual acceptance of guidelines and education of physicians and nurses, could be crucial factors for successful implementation. Thus, better adherence to antiemetic guidelines can only be achieved through a complex and long-term process, consisting of efficient education, training, and monitoring of all individuals involved.
Clinical relevance
© Simon Fraser/Science Photo Library
During the past few decades, there have been substantial therapeutic advances in the treatment of malignant diseases, especially in the sphere of supportive care in cancer. However, cytostatic-drug-induced nausea and vomiting are adverse effects most feared by patients and can influence therapeutic outcome.1 Three forms of vomiting or nausea induced by cancer chemotherapy can be distinguished: acute emesis arising within 24 h of chemotherapy administration; delayed emesis arising after the first 24 h and lasting for up to 6 days; and anticipatory emesis.2 The acute type of emesis seems to be provoked predominantly by release of serotonin within the first 4–8 h after chemotherapy (particularly with cisplatin), leading to consecutive activation of serotonin 5-HT3 receptors on peripheral vagal fibres and central structures such as the area postrema and nucleus tractus solitarii.3–5 Thereafter, substance P, as well as serotonin and other neurotransmitters, seems to have an important role in the maintenance of acute and delayed
Figure 1: Putting guidelines into practice
622
emesis.6 The underlying biochemical mechanism of conditioned vomiting is yet to be clarified. The introduction of 5-HT3-receptor antagonists was a breakthrough in antiemetic treatment of patients with cancer. Whichever 5-HT3-receptor antagonist was given, more than 70% of patients receiving cisplatin responded to a combination of 5-HT3-receptor antagonists and a glucocorticoid in the acute phase of chemotherapyinduced nausea and vomiting compared with 38% of patients given metoclopramide.7–11
Antiemetic guidelines After a breakthrough such as that seen in antiemetic treatment, the results of controlled clinical trials should be translated quickly into routine clinical practice (figure 1). National and international organisations, such as the Multinational Association of Supportive Care in Cancer, the National Comprehensive Cancer Network, the American Society of Health-System Pharmacists, and the American Society of Clinical Oncology, have issued antiemetic guidelines for the treatment of patients undergoing chemotherapy.12–16 Although these guidelines should serve to harmonise antiemetic treatment, they differ to some extent. For example, guidelines by the American Society of Health-System Pharmacists and by the National Comprehensive Cancer Network distinguish five different grades of emetogenicity of chemotherapeutic agents, whereas the Multinational Association of Supportive Care in Cancer guidelines distinguishes four. Furthermore, in contrast to the guidelines of the American Society of Health-System Pharmacists and the American Society of Clinical Oncology, those of the National Comprehensive Cancer Network and the Multinational Association of Supportive Care in Cancer recommend administration of aprepitant, an antagonist of neurokinin receptor subtype 1 for the prevention of acute emesis in patients treated with highemetic-risk chemotherapy. The guidelines of the National Comprehensive Cancer Network offer a different antiemetic treatment algorithm for emetogenic stage five than for stages 3–4, whereas the American Society of Health-System Pharmacists recommends the same antiemetic treatment approach for these stages. http://oncology.thelancet.com Vol 6 August 2005
Essay
The reason for these differences could be due to a different interpretation of the antiemetic trials, different compositions of the respective committees, or differences in the timing of guideline updates. Guidelines are not, however, followed completely for many reasons, especially in the case of delayed emesis, although proper use of antiemetics has long been known to achieve efficacy similar to that recorded in randomised controlled trials. The problem of non-adherence is not restricted to the guidelines on antiemetic treatment but seems to apply generally to use of guidelines. Guidelines such as a red traffic light, which is simple, easy to understand, precise, uncontroversial, and target group-oriented, refers to an acute situation, and is based on the correlation of a higher risk for the road user not following it. However, like clinical guidelines, there are some people who have difficulty in implementing it.
physicians. Guidelines should focus on acute clinical problems, since compliance with guidelines that focus on acute care seems to be much better than that with those referring to chronic care.20–23 Furthermore, guidelines should be uncontroversial. A controversial or ambiguous guideline will be used incorrectly or not at all. Guidance needs to be in accordance with regulations in effect and with daily routine, and the recommendations should be easy to incorporate into routine clinical practice. For patients to accept a guideline, it needs to have a positive effect for the patient. And, of course, guidance must be set out clearly, must refer to the target group, and must be unambiguous and precise.20,21,24,25 Adoption of therapeutic guidelines is not only a specific problem of the antiemetic guidelines, it is a potential problem in different social and medical specialties.26–28
Non-adherence to clinical guidelines
Non-adherence to antiemetic guidelines
Guidelines are systematically developed statements to assist practioners and patients in decisions on appropriate healthcare in specific clinical circumstances.17 What is sought from guidelines depends on the different groups in the health-care system. These groups have differing attitudes towards the ultimate goal of the therapeutic guidelines applied. Thus, physicians and patients are mainly interested in improving treatment. Politicians, insurers, and clinical administrations are not so strongly focused on individual therapeutic outcome for the patients; their emphasis tends to be on reducing costs of the healthcare system or on the economic efficiency of their clinic. In surveys of attitudes to guidelines in general,18,19 more than 50% of physicians thought that guidelines are good educational tools, which are motivated by the desire to improve quality of life. However, they believed that guidelines have strong limitations, are too rigid to be applied to individual patients, and resemble cookbook medicine. Moreover, more than 60% of physicians replied that guidelines could be used for disciplinary actions against physicians and that most of the guidelines are motivated by the desire to reduce costs. However, 52% of physicians thought that the use of guidelines should improve the quality of patients’ care. But only 12% thought that guidelines would probably increase physicians’ satisfaction with the practice of medicine. For more than 40% of the physicians, guidelines were associated with a reduction in reimbursement and a rise in the total cost of healthcare.19 Confidence in guidelines depend on the type of organisations that issue them; specialists have greater confidence in guidelines issued by specialist medical organisations than in guidelines issue them by national or federal organisations.18,19 For therapeutic guidelines to be accepted, certain standards have to be included. For example, a guideline must be evidence-based for it to be accepted by
How effective is the transfer of antiemetic guidelines into routine clinical practice? In 1998, the Italian Group for Antiemetic Research carried out a prospective observational study on the use and efficacy of antiemetic drugs in 33 Italian departments of oncology, including over 2000 patients.29 More than 20% of the patients treated with highly emetogenic cytostatic agents did not receive the appropriate treatment for acute chemotherapyinduced nausea and vomiting. The proportion was even higher among patients treated with moderately emetogenic (58%) or low-emetogenic (63%) agents. The trend was similar for the treatment of delayed-typechemotherapy-induced nausea and vomiting. Furthermore, a high proportion of patients were overtreated; 48% of the patients treated with low-emetogenic cytostatics were given antiemetic treatment for the delayed-type and 15% were treated for acute-type vomiting, even though these treatments were not necessary. As expected, patients who received highly emetogenic chemotherapy and who had been treated according to the antiemetic recommendations had less vomiting than those who did not receive the appropriate treatment. Among patients who received low-emetogenic chemotherapy, the proportion of complete protection from acute vomiting was the same for those given an unecessary antiemetic treatment and for those not given any antiemetic treatment. Whether the unecessarily treated patients experienced more side-effects than the other patients could not be concluded from the data. 92% of patients given highly emetogenic cytostatic agents in centres with a background in antiemetic research received the correct antiemetic treatment compared with only 64% in centres without such a research background. The same pattern was reported for patients undergoing moderately emetogenic chemotherapy. The result of a further study was rather worrying. Only 56% of all patients received the appropriate antiemetic treatment for acute emesis and only 45% of the
http://oncology.thelancet.com Vol 6 August 2005
623
Essay
Knowledge
Attitudes
Knowledge
Lack of:
Lack of:
External factors:
Familiarity
Agreement
Patients
Awareness
Outcome-expectancy
Guidelines
Self-efficiency
Environment
Motivation
Time
Figure 2: Steps involved in changing physicians’ behaviour24,25,27
patients were treated appropriately for delayed-type vomiting. Patients treated with anthracyclines received better antiemetic treatment for acute chemotherapyinduced nausea and vomiting than patients treated with the combination of cyclophosphamide, methotrexate, and fluorouracil. As recorded in the previous study, the antiemetic treatment was of a better standard in centres that had a background in antiemetic research than in centres not experienced in this kind of treatment.30 We can speculate whether this difference arises because experience from clinical trials with antiemetic drugs leads to greater sensibility for this medical problem or because the investigators merely follow their own recommendations. In a further survey investigating the treatment of delayed-type chemotherapy-induced nausea and vomiting, only 43% of patients treated with highly emetogenic cytostatics, 64% treated with moderately emetogenic cytostatics, and 31% of the patients treated with low-emetogenic cytostatic agents received the correct antiemetic treatment for delayed-type vomiting. Moreover, 68% of the patients received unnecessary antiemetic treatment.31
Implementing guidelines more effectively Lack of adherence with guidelines is not restricted to antiemetic treatment but is widespread throughout medicine. The reasons could be related to the guideline itself or to the issuing organisation.18,19 The way in which guidelines are introduced could have an important role. Furthermore, compliance also depends on patients, nurses, and physicians. To change physicians’ behaviour is difficult and a long-term process (figure 2).21,25,27 Before a guideline can affect a patient’s outcome, it must first change the knowledge of the physician, then the attitudes towards or the acceptance of the guideline, and finally the clinical behaviour that could ultimately lead to a better therapeutic outcome for the patient. Crucial factors can affect this process at each stage; for example, the physician might not be aware of the guideline or 624
might disagree with it. Of course, the physician should be seeking knowledge, be experienced in therapeutic guidelines, and be open minded about applying new knowledge. There are different strategies for better implementation of guidelines in general.21,32–35 Passive dissemination of educational material is ineffective no matter how important the issue or how valid the methods. Successful implementation of therapeutic guidelines occurs through combined strategies by use of educational material, outreach visits, patient-mediated interventions, and a computerised decision-supportsystem. Finally, each guideline has to be investigated to see whether it can be implemented, and more importantly whether it will be accepted by the people involved.
Evidence that better implementation works Nolte and co-workers36 reported on the development, implementation, and assessment of antiemetic guidelines. Adherence to the guidelines rose from 73% in the first version to 98% in the third version of the guidelines. This increase in adherence was achieved by personal feedback when the antiemetic order did not follow the guideline and by introduction of a check box on the chemotherapy order sheet. Better adherence was accompanied by better antiemetic outcomes for patients and lower costs. However, the extent to which economic issues influenced this process of implementation cannot be concluded from the publication. In another survey, implementation of guidelines was improved by means of a multifaceted intervention programme that consisted guideline dissemination, use of opinion leaders, interactive educational workshops, therapeutic reminders, clinical interventions by pharmacists, physician audit, and feedback. Treatment of more than 88% of the patients met the guidelines in terms of appropriate indication, dose, and duration.37 However, a joint guideline development and distribution strategy had only a short-term effect on adherence.38 A subsequent lecture by a visiting professor, a renowned specialist in this sphere, also failed to improve the results. However, the presentation and discussion of the poor antiemetic outcome in patients who had not been treated according to the guidelines definitely changed the behaviour of the physicians.38 Thus, educational approaches for dissemination are not successful, but direct feedback on patients’ outcomes to the physician is very effective. Financial incentives or penalties could also serve as negative conditioning tools to improve the implementation of guidelines.32,38–40 However, whether negative reinforcements to change behaviour is really an intelligent approach is questionable.
Implications for policy and clinical practice 30–50% of patients do not receive appropriate antiemetic treatment. Thus, antiemetic guidelines must be better implemented. In general, guidelines should be precise, http://oncology.thelancet.com Vol 6 August 2005
Essay
easy to follow, evidence-based, refer to acute clinical problems, and be easily implemented into routine clinical practice. Only a long-term educational process with active participation of all individuals involved will improve antiemetic outcome for patients. Moreover, to improve adherence, antiemetic guidelines, issued by different organisations should be harmonised. Finally, the informed patient will have an increasingly important role in medical decision-making. Conflict of interest I declare no conflicts of interest. Acknowledgments I receive support from the German Ministry for Research and Technology (BMFT), grant 01GG9845/5. References 1 Stewart DJ. Cancer therapy, vomiting, and antiemetics. Can J Physiol Pharmacol 1990; 68: 304–13. 2 Andrews PL, Davis CJ. The mechanism of emesis induced by anticancer therapies. In: Andrews PL SG, ed. Emesis in anti-cancer therapy. London: Chapman and Hall, 1993: 113–61. 3 Tyers MB, Freeman AJ. Mechanism of the anti-emetic activity of 5-HT3 receptor antagonists. Oncology 1992; 49: 263–68. 4 Miller AD, Leslie RA. The area postrema and vomiting. Front Neuroendocrinol 1994; 15: 301–20. 5 Gregory RE, Ettinger DS. 5-HT3 receptor antagonists for the prevention of chemotherapy-induced nausea and vomiting: a comparison of their pharmacology and clinical efficacy. Drugs 1998; 55: 173–89. 6 Hesketh PJ, van Belle S, Aapro M, et al. Differential involvement of neurotransmitters through the time course of cisplatin-induced emesis as revealed by therapy with specific receptor antagonists. Eur J Cancer 2003; 8: 1074–80. 7 Gralla RJ, Itri LM, Pisko SE, et al. Antiemetic efficacy of high-dose metoclopramide: randomized trials with placebo and prochlorperazine in patients with chemotherapy-induced nausea and vomiting. N Engl J Med. 1981; 305: 905–09. 8 Cunningham D, Hawthorn J, Pople A, et al. Prevention of emesis in patients receiving cytotoxic drugs by GR38032F, a selective 5-HT3 receptor antagonist. Lancet 1987; 1: 1461–63. 9 Hesketh P, Navari R, Grote T, et al. Double-blind, randomized comparison of the antiemetic efficacy of intravenous dolasetron mesylate and intravenous ondansetron in the prevention of acute cisplatin-induced emesis in patients with cancer. J Clin Oncol 1996; 14: 2242–49. 10 Navari RM, Kaplan HG, Gralla RJ, et al. Efficacy and safety of granisetron, a selective 5-hydroxytryptamine-3 receptor antagonist, in the prevention of nausea and vomiting induced by high-dose cisplatin. J Clin Oncol 1994; 12: 2204–10. 11 Poli-Bigelli S, Rodrigues-Pereira J, Carides AD, et al. Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting: results from a randomized, double-blind, placebocontrolled trial in Latin America. Cancer 2003; 97: 3090–98. 12 Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer (MASCC). Prevention of chemotherapyand radiotherapy-induced emesis: results of Perugia Consensus Conference. Ann Oncol 1998; 9: 811–19. 13 Gralla RJ, Roila F, Tonato M, et al. The 2004 Perugia Antiemetic Consensus Guideline process: methods, procedures, and participants. Support Care Cancer 2005; 13: 77–79. 14 National Comprehensive Cancer Network. Guidelines for supportive care, antiemesis. http://www.nccn.org/professionals/ physician_gls/f_guidelines.asp?button=I+Agree#care. (accessed April 14, 2005). 15 American Society of Health-System Pharmacists. ASHP therapeutic guidelines on the pharmacologic management of nausea and vomiting in adult and pediatric patients receiving chemotherapy or radiation therapy or undergoing surgery. Am J Health Syst Pharm 1999; 56: 729–64.
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