Melissa Brouwers

AGREE II: advancing guideline development, reporting and evaluation in health care

Clinical practice guidelines, which are systematically developed statements aimed at helping people make clinical, policy-related and system-related decisions,[1][1],[2][2] frequently vary widely in quality.[3][3],[4][4] A strategy was needed to differentiate among guidelines and ensure that those

American Society of Clinical Oncology Recommendations on Adjuvant Chemotherapy for Stage II Colon Cancer

PURPOSE To address whether all medically fit patients with curatively resected stage II colon cancer should be offered adjuvant chemotherapy as part of routine clinical practice, to identify patients with poor prognosis characteristics, and to describe strategies for oncologists to use to discuss adjuvant chemotherapy in practice. METHODS An American Society of Clinical Oncology Panel, in collaboration with the Cancer Care Ontario Practice Guideline Initiative, reviewed pertinent information from the literature through May 2003. RESULTS A literature-based meta-analysis found no evidence of a statistically significant survival benefit of adjuvant chemotherapy for stage II patients. Recommendations The routine use of adjuvant chemotherapy for medically fit patients with stage II colon cancer is not recommended. However, there are populations of patients with stage II disease that could be considered for adjuvant therapy, including patients with inadequately sampled nodes, T4 lesions, perforation, or poorly differentiated histology. CONCLUSION Direct evidence from randomized controlled trials does not support the routine use of adjuvant chemotherapy for patients with stage II colon cancer. Patients and oncologists who accept the relative benefit in stage III disease as adequate indirect evidence of benefit for stage II disease are justified in considering the use of adjuvant chemotherapy, particularly for those patients with high-risk stage II disease. The ultimate clinical decision should be based on discussions with the patient about the nature of the evidence supporting treatment, the anticipated morbidity of treatment, the presence of high-risk prognostic features on individual prognosis, and patient preferences. Patients with stage II disease should be encouraged to participate in randomized trials.

Does Delay in Starting Treatment Affect the Outcomes of Radiotherapy? A Systematic Review

PURPOSE The objective of this study was to synthesize what is known about the relationship between delay in radiotherapy (RT) and the outcomes of RT. METHODS A systematic review of the world literature was conducted to identify studies that described the association between delay in RT and the probability of local control, metastasis, and/or survival. Studies were classified by clinical and methodologic criteria and their results were combined using a random-effects model. RESULTS A total of 46 relevant studies involving 15,782 patients met our minimum methodologic criteria of validity; most (42) were retrospective observational studies. Thirty-nine studies described rates of local recurrence, 21 studies described rates of distant metastasis, and 19 studies described survival. The relationship between delay and the outcomes of RT had been studied in diverse situations, but most frequently in breast cancer (21 studies) and head and neck cancer (12 studies). Combined analysis showed that the 5-year local recurrence rate (LRR) was significantly higher in patients treated with adjuvant RT for breast cancer more than 8 weeks after surgery than in those treated within 8 weeks of surgery (odds ratio [OR] = 1.62, 95% confidence interval [CI], 1.21 to 2.16). Combined analysis also showed that the LRR was significantly higher among patients who received postoperative RT for head and neck cancer more than 6 weeks after surgery than among those treated within 6 weeks of surgery (OR = 2.89; 95% CI, 1.60 to 5.21). There was little evidence about the impact of delay in RT on the risk of metastases or the probability of long-term survival in any situation. CONCLUSION Delay in the initiation of RT is associated with an increase [corrected] in LRR in breast cancer and head and neck cancer. Delays in starting RT should be as short as reasonably achievable.

Cancer Care Ontario and American Society of Clinical Oncology Adjuvant Chemotherapy and Adjuvant Radiation Therapy for Stages I-IIIA Resectable Non–Small-Cell Lung Cancer Guideline

PURPOSE To determine the role of adjuvant chemotherapy and radiation therapy in patients with completely resected stage IA-IIIA non-small-cell lung cancer (NSCLC). METHODS The Cancer Care Ontario Program in Evidence-Based Care and the American Society of Clinical Oncology convened a Joint Expert Panel in August 2006 to review the evidence and draft recommendations for these therapies. RESULTS Available data support the use of adjuvant cisplatin-based chemotherapy in completely resected NSCLC; however, the strength of the data and consequent recommendations vary by disease stage. Adjuvant radiation therapy appears detrimental to survival in stages IB and II, with a possible modest benefit in stage IIIA. CONCLUSION Adjuvant cisplatin-based chemotherapy is recommended for routine use in patients with stages IIA, IIB, and IIIA disease. Although there has been a statistically significant overall survival benefit seen in several randomized clinical trials (RCTs) enrolling a range of people with completely resected NSCLC, results of subset analyses for patient populations with stage IB disease were not significant, and adjuvant chemotherapy in stage IB disease is not currently recommended for routine use. To date, very few patients with stage IA NSCLC have been enrolled onto RCTs of adjuvant therapy; adjuvant chemotherapy is not recommended in these cases. Evidence from RCTs demonstrates a survival detriment for adjuvant radiotherapy with limited evidence for a reduction in local recurrence. Adjuvant radiation therapy appears detrimental to survival in stage IB and II, and may possibly confer a modest benefit in stage IIIA.

Adjuvant Therapy for Stage II Colon Cancer: A Systematic Review From the Cancer Care Ontario Program in Evidence-Based Care’s Gastrointestinal Cancer Disease Site Group

PURPOSE To develop a systematic review that would address the following question: Should patients with stage II colon cancer receive adjuvant therapy? METHODS A systematic review was undertaken to locate randomized controlled trials comparing adjuvant therapy to observation. RESULTS Thirty-seven trials and 11 meta-analyses were included. The evidence for stage II colon cancer comes primarily from a trial of fluorouracil plus levamisole and a meta-analysis of 1,016 patients comparing fluorouracil plus folinic acid versus observation. Neither detected an improvement in disease-free or overall survival for adjuvant therapy. A recent pooled analysis of data from seven trials observed a benefit for adjuvant therapy in a multivariate analysis for both disease-free and overall survival. The disease-free survival benefits appeared to extend to stage II patients; however, no P values were provided. A meta-analysis of chemotherapy by portal vein infusion has also shown a benefit in disease-free and overall survival for stage II patients. A meta-analysis was conducted using data on stage II patients where data were available (n = 4,187). The mortality risk ratio was 0.87 (95% CI, 0.75 to 1.01; P =.07). CONCLUSION There is preliminary evidence indicating that adjuvant therapy is associated with a disease-free survival benefit for patients with stage II colon cancer. These benefits are small and not necessarily associated with improved overall survival. Patients should be made aware of these results and encouraged to participate in active clinical trials. Additional investigation of newer therapies and more mature data from the presently available trials should be pursued.

American Society of Clinical Oncology/American Society of Hematology Clinical Practice Guideline Update on the Use of Epoetin and Darbepoetin in Adult Patients With Cancer

PURPOSE To update American Society of Clinical Oncology/American Society of Hematology recommendations for use of erythropoiesis-stimulating agents (ESAs) in patients with cancer. METHODS An Update Committee reviewed data published between January 2007 and January 2010. MEDLINE and the Cochrane Library were searched. RESULTS The literature search yielded one new individual patient data analysis and four literature-based meta-analyses, two systematic reviews, and 13 publications reporting new results from randomized controlled trials not included in prior or new reviews. RECOMMENDATIONS For patients undergoing myelosuppressive chemotherapy who have a hemoglobin (Hb) level less than 10 g/dL, the Update Committee recommends that clinicians discuss potential harms (eg, thromboembolism, shorter survival) and benefits (eg, decreased transfusions) of ESAs and compare these with potential harms (eg, serious infections, immune-mediated adverse reactions) and benefits (eg, rapid Hb improvement) of RBC transfusions. Individual preferences for assumed risk should contribute to shared decisions on managing chemotherapy-induced anemia. The Committee cautions against ESA use under other circumstances. If used, ESAs should be administered at the lowest dose possible and should increase Hb to the lowest concentration possible to avoid transfusions. Available evidence does not identify Hb levels ≥ 10 g/dL either as thresholds for initiating treatment or as targets for ESA therapy. Starting doses and dose modifications after response or nonresponse should follow US Food and Drug Administration-approved labeling. ESAs should be discontinued after 6 to 8 weeks in nonresponders. ESAs should be avoided in patients with cancer not receiving concurrent chemotherapy, except for those with lower risk myelodysplastic syndromes. Caution should be exercised when using ESAs with chemotherapeutic agents in diseases associated with increased risk of thromboembolic complications. Table 1 lists detailed recommendations.

How can we improve guideline use? A conceptual framework of implementability

BackgroundGuidelines continue to be underutilized, and a variety of strategies to improve their use have been suboptimal. Modifying guideline features represents an alternative, but untested way to promote their use. The purpose of this study was to identify and define features that facilitate guideline use, and examine whether and how they are included in current guidelines.MethodsA guideline implementability framework was developed by reviewing the implementation science literature. We then examined whether guidelines included these, or additional implementability elements. Data were extracted from publicly available high quality guidelines reflecting primary and institutional care, reviewed independently by two individuals, who through discussion resolved conflicts, then by the research team.ResultsThe final implementability framework included 22 elements organized in the domains of adaptability, usability, validity, applicability, communicability, accommodation, implementation, and evaluation. Data were extracted from 20 guidelines on the management of diabetes, hypertension, leg ulcer, and heart failure. Most contained a large volume of graded, narrative evidence, and tables featuring complementary clinical information. Few contained additional features that could improve guideline use. These included alternate versions for different users and purposes, summaries of evidence and recommendations, information to facilitate interaction with and involvement of patients, details of resource implications, and instructions on how to locally promote and monitor guideline use. There were no consistent trends by guideline topic.ConclusionsNumerous opportunities were identified by which guidelines could be modified to support various types of decision making by different users. New governance structures may be required to accommodate development of guidelines with these features. Further research is needed to validate the proposed framework of guideline implementability, develop methods for preparing this information, and evaluate how inclusion of this information influences guideline use.

Development of the AGREE II, part 1: performance, usefulness and areas for improvement

Background: We undertook research to improve the AGREE instrument, a tool used to evaluate guidelines. We tested a new seven-point scale, evaluated the usefulness of the original items in the instrument, investigated evidence to support shorter, tailored versions of the tool, and identified areas for improvement. Method: We report on one component of a larger study that used a mixed design with four factors (user type, clinical topic, guideline and condition). For the analysis reported in this article, we asked participants to read a guideline and use the AGREE items to evaluate it based on a seven-point scale, to complete three outcome measures related to adoption of the guideline, and to provide feedback on the instrument’s usefulness and how to improve it. Results: Guideline developers gave lower-quality ratings than did clinicians or policy-makers. Five of six domains were significant predictors of participants’ outcome measures (p < 0.05). All domains and items were rated as useful by stakeholders (mean scores > 4.0) with no significant differences by user type (p > 0.05). Internal consistency ranged between 0.64 and 0.89. Inter-rater reliability was satisfactory. We received feedback on how to improve the instrument. Interpretation: Quality ratings of the AGREE domains were significant predictors of outcome measures associated with guideline adoption: guideline endorsements, overall intentions to use guidelines, and overall quality of guidelines. All AGREE items were assessed as useful in determining whether a participant would use a guideline. No clusters of items were found more useful by some users than others. The measurement properties of the seven-point scale were promising. These data contributed to the refinements and release of the AGREE II.

Development of the AGREE II, part 2: assessment of validity of items and tools to support application.

Background: We established a program of research to improve the development, reporting and evaluation of practice guidelines. We assessed the construct validity of the items and user’s manual in the β version of the AGREE II. Methods: We designed guideline excerpts reflecting high-and low-quality guideline content for 21 of the 23 items in the tool. We designed two study packages so that one low-quality and one high-quality version of each item were randomly assigned to each package. We randomly assigned 30 participants to one of the two packages. Participants reviewed and rated the guideline content according to the instructions of the user’s manual and completed a survey assessing the manual. Results: In all cases, content designed to be of high quality was rated higher than low-quality content; in 18 of 21 cases, the differences were significant (p < 0.05). The manual was rated by participants as appropriate, easy to use, and helpful in differentiating guidelines of varying quality, with all scores above the mid-point of the seven-point scale. Considerable feedback was offered on how the items and manual of the β-AGREE II could be improved. Interpretation: The validity of the items was established and the user’s manual was rated as highly useful by users. We used these results and those of our study presented in part 1 to modify the items and user’s manual. We recommend AGREE II (available at www.agreetrust.org) as the revised standard for guideline development, reporting and evaluation.

American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer

PURPOSE To update American Society of Hematology/American Society of Clinical Oncology recommendations for use of erythropoiesis-stimulating agents (ESAs) in patients with cancer. METHODS An Update Committee reviewed data published between January 2007 and January 2010. MEDLINE and the Cochrane Library were searched. RESULTS The literature search yielded one new individual patient data analysis and four literature-based meta-analyses, two systematic reviews, and 13 publications reporting new results from randomized controlled trials not included in prior or new reviews. RECOMMENDATIONS For patients undergoing myelosuppressive chemotherapy who have a hemoglobin (Hb) level less than 10 g/dL, the Update Committee recommends that clinicians discuss potential harms (eg, thromboembolism, shorter survival) and benefits (eg, decreased transfusions) of ESAs and compare these with potential harms (eg, serious infections, immune-mediated adverse reactions) and benefits (eg, rapid Hb improvement) of RBC transfusions. Individual preferences for assumed risk should contribute to shared decisions on managing chemotherapy-induced anemia. The Committee cautions against ESA use under other circumstances. If used, ESAs should be administered at the lowest dose possible and should increase Hb to the lowest concentration possible to avoid transfusions. Available evidence does not identify Hb levels ≥ 10 g/dL either as thresholds for initiating treatment or as targets for ESA therapy. Starting doses and dose modifications after response or nonresponse should follow US Food and Drug Administration-approved labeling. ESAs should be discontinued after 6 to 8 weeks in nonresponders. ESAs should be avoided in patients with cancer not receiving concurrent chemotherapy, except for those with lower risk myelodysplastic syndromes. Caution should be exercised when using ESAs with chemotherapeutic agents in diseases associated with increased risk of thromboembolic complications. Table 1 lists detailed recommendations.