The rigour of CPG development needs to be improved in the future
The rigour of development could be an important domain for measuring the credibility of guidelines. The most effective CPGs should incorporate the current best evidence and place it in the context of local settings. Failure to use SRs to support their recommendations or to make explicit links between the supporting evidence and the recommendation still existed in some guidelines.
If recommendations were made, the strength is linked directly to the consideration of benefit and harm. Research for intervention safety should be conducted and safety outcomes should be set as key outcomes to balance benefit and harm. A transparent process for reaching consensus is vital for guideline validity, and it is also necessary to record details of all processes by which evidence was appraised and how recommendations were formulated.
Consumer involvement in cancer-related guidelines
Consumers are broadly defined as recipients of health care who provide a layperson’s perspective and can help in reaching consensus regarding the appropriate rating, presenting recommendations in ways that are understandable to patients and respectful of their needs and acting as a safeguard against conflicts of interests .
For example, a patient might consider that the potential benefits in terms of survival might not be worthwhile in view of the potential important, even life-threatening side effects, of a given treatment. Therefore, it is important to consider patient views and expectations in cancer-related treatment recommendations.
BCG instillation has more noticeable side effects than chemotherapy, so the balance between benefit and harm it should be given special attention when making recommendations, especially when attributing the SOR.
The need to improve the implementation of guidelines during the development process
The score of the applicability domain was disturbingly low, indicating that guideline panels considered the development and implementation of the guidelines as separate activities and did not pay enough attention to the potential facilitators and barriers to the guideline dissemination .
To facilitate implementation, guideline panels should consider the publication types and format when reporting the guidelines. Some derivative products were specifically tailored for the target users, including summaries, algorithms and wall charts . Some other resources, such as commissioning support, including audit, measurement and bench marking tools, might be needed as well .
Furthermore, disparities in available resources for health care were enormous and shocking. Most included CPGs were developed for situations having full resources so incurring the maximal level of costs, making the applicability of limited utility. Cost-effectiveness analyses were needed for a sensible recommendation especially for developing countries. Economic evaluation should start during scoping of the guidelines. A reliable health economist shall be available to give advice on which questions are likely to require an assessment, and conduct the assessment and then report the results prior to the formulation of recommendations .
Recommendations varied in detail for a variety of reasons
Although most CPGs recommended TURBT and intravesical therapy, they differed in some details such as indications for re-TURBT and the use of chemotherapy agents and BCG in intermediate and high risk NMIBC.
The reasons for offering different recommendations were undoubtedly multifactorial, which might in part be explained by the fact that the guidelines were produced by organizations from different contexts and settings. It could be possible that some discrepancy in guidelines arose through limitations in the current evidence for guideline panels to support their recommendations. In addition, the lack of a transparent process for recommendation formulation resulted in the risk of current evidence having been interpreted differently, because of the different weighting given to certain outcomes during decision making process.
Notably, the recommendations were mostly based on low and moderate quality evidence, whereas the SOR results rated strong plus moderate accounted for a higher proportion. The lack of high-quality evidence might have increased the role that the decision-makers’ opinion had to play in framing the recommendations. Apart from the methodology of guideline development, guideline panels need to focus more on the growing body of evidence.
Issues that need to be resolved to optimize the treatment
Although the recommendations covered most areas for managing NMIBC patients, some issues that need to be resolved for optimizing treatment have been indicated in some guidelines.
The first important item was whether the second TURBT should be performed after the intravesical therapy followed by the TURBT and whether intravesical therapy should be offered before pathology reports are available. The ESMO guidelines described re-TURBT as a reasonable option in high-risk NMIBC tumours after intravesical therapy, whereas the grade of the recommendation was rated low at III.8 The need for further research was obvious.
Such an acknowledged item was which BCG strain is the safest and most effective option [3, 10, 12,13,14]. Different BCG strains have been implicated in determining responses to BCG, and some strains could influence antitumour immune responses as has been suggested by clinical studies comparing different BCG strains . However, the trial did not reach statistical significance for progression free survival, and none of the CPGs could offer related recommendations. Further evaluation using prospective trials might be needed [12, 23].
Different drug combinations of BCG, chemotherapeutic agents and interferon have been evaluated in various studies, such as interferon plus BCG , interferon plus epirubicin , BCG plus MMC , or BCG plus isoniazid . While CPGs don’t really recommended an optimal combination option, probably because of insufficient evidence, no significant different decrease in recurrence and progression could be found for any of these combination therapies [3, 9, 10, 12, 14].
Despite the disappointing results of combination therapy to date, device-assisted therapies have shown some promising data. Several studies have evaluated the efficacy of hyperthermia to improve the penetration of chemotherapy agents into the bladder wall, thus potentially improving outcomes . The use of electromotive drug administration (EMDA) has been demonstrated to reduce recurrence rates and prolong disease-free intervals . The definitive conclusion, however, needs additional studies to further validate their efficacy as first- and second-line treatments [10, 12].
Limitations and strengths
Our study might have some potential limitations. First, various grading systems to rate the LOE and SOR make it difficult to compare LOE and SOR among guidelines. Second, recommendations about BCG relapse and radical cystectomy have not been extracted from guidelines, causing the presentation and synthesis of recommendations on the management of NMIBC to be potentially incomplete.
Nonetheless, our present study was reliable and helpful. First, a systematic literature search was conducted for screening eligible CPGs. Second, the reviewers applied AGREE II quality criteria to each CPG and achieved excellent interrater agreement. Furthermore, this is the first attempt to systematically synthesize and appraise CPGs for NMIBC management.