Iran’s National Lung Cancer Guideline Fails Key Quality Tests, AGREE II Appraisal Reveals

Lung cancer kills more people than any other malignancy, claiming roughly 1.8 million lives each year out of approximately 2.5 million new cases worldwide. Although it ranks third globally in incidence by age-standardized rate, at 23.6, it holds the highest age-standardized mortality rate of any cancer, at 16.8, a grim reflection of its aggressive clinical course and the persistent difficulty of catching it early. About 85 percent of these tumors fall into the non-small cell lung cancer category, encompassing adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Despite advances in screening and targeted therapies, prognosis remains poor because a large proportion of patients are diagnosed only at an advanced stage. High-income countries have introduced organized screening programs and public health interventions, but many low- and middle-income countries still face rising incidence and mortality, largely due to delayed diagnosis and unequal access to care.

In Iran, the disease is a growing concern. The country reports 10,934 new lung cancer cases and 9,895 deaths annually, with non-small cell lung cancer constituting the majority of these cases. Iran ranks fourth in incidence and second in mortality among all cancers, and a recent study from northern Iran documented a consistent increase in lung cancer mortality rates from 2013 to 2021. Evidence supporting the cost-effectiveness of low-dose computed tomography screening, documented delays between symptom onset, diagnosis, and treatment, and regional disparities in cancer survival all underscore the need for more effective early-detection and care pathways. Against this backdrop, the quality of the clinical practice guidance that Iranian clinicians actually follow becomes a matter of life and death, which is precisely why a team of Iranian researchers set out to scrutinize the country’s national guideline for diagnosing and treating non-small cell lung cancer.

Clinical practice guidelines are structured tools that synthesize high-quality evidence to inform clinical decision-making, improve patient outcomes, and reduce variation in care. Their utility is particularly critical in complex diseases like non-small cell lung cancer, where therapeutic options evolve rapidly. Major international oncology societies publish comprehensive guidelines, each with distinct strengths. The American Society of Clinical Oncology emphasizes evidence grading and multidisciplinary input, though its update frequency may lag behind emerging therapies. The European Society for Medical Oncology provides strong methodological rigor and online access, although its recommendations are primarily tailored to European regulatory environments. The National Comprehensive Cancer Network is widely recognized for real-time updates closely aligned with FDA approvals, but has been critiqued for limited methodological transparency in development. Iran’s Ministry of Health issued its own national clinical practice guideline for the diagnosis and treatment of non-small cell lung cancer in 2018, yet until now its methodological rigor, transparency, and clinical utility remained largely unexamined.

The new study, published in the open-access journal Heliyon, applied the Appraisal of Guidelines for Research and Evaluation II instrument, an internationally validated framework for assessing clinical guidelines, to Iran’s 2018 national document. Four expert clinicians, two board-certified pulmonologists and two hematology-oncology specialists, each with experience in guideline development or clinical research, independently evaluated the guideline in September 2020 without consulting one another. Before the assessment, they were provided with the AGREE II user manual and a brief orientation on scoring procedures to ensure consistent understanding. The investigators conducted a renewed targeted search of publicly accessible Iranian Ministry of Health repositories and university treatment portals, last updated in July 2026, and found no publicly accessible comprehensive national revision or document explicitly superseding the 2018 guideline. More recent drug-specific prescribing documents relevant to selected targeted therapies and immunotherapies were identified, but because these address individual treatments rather than the full diagnostic and therapeutic pathway, they were not considered comprehensive replacements.

The AGREE II instrument consists of 23 individual items grouped into six domains, each scored on a 7-point Likert scale ranging from strongly disagree to strongly agree, with final domain scores expressed as percentages from 0 to 100. Scope and Purpose assesses whether the guideline’s objectives, health questions, and target population are clearly defined. Stakeholder Involvement evaluates the extent to which the guideline represents the views of its intended users and relevant professionals. Rigor of Development, the largest domain with eight items, focuses on the process of evidence gathering, recommendation formulation, and update procedures. Clarity of Presentation measures the clarity, specificity, and structure of the recommendations. Applicability examines potential barriers and facilitators for implementation, resource implications, and monitoring strategies. Editorial Independence evaluates the independence of guideline content from funding bodies and the management of conflicts of interest. Because the instrument does not prescribe universal cut-off values for defining high-, moderate-, or low-quality guidelines, the researchers based their final assessment on the two direct AGREE II overall assessment items completed independently by each appraiser.

The results revealed an uneven methodological quality profile. The highest standardized domain score was observed for Clarity of Presentation, at 83.3 percent, indicating that the guideline recommendations were generally specific, unambiguous, and easily identifiable. This was followed by Stakeholder Involvement at 75.0 percent and Scope and Purpose at 70.8 percent, while Editorial Independence received a standardized score of 62.5 percent. In stark contrast, Rigor of Development had the lowest standardized score, at just 29.2 percent, highlighting major limitations in the evidence-search strategy, formulation of recommendations, linkage between evidence and recommendations, and updating procedures. Individual item ratings tell the story in granular detail: the item asking whether systematic methods were used to search for evidence drew ratings of only 2 or 3 from each appraiser, the item on clearly describing the strengths and limitations of the body of evidence drew ratings as low as 1, and the item on whether a procedure for updating the guideline is provided drew a total of just 6 out of a possible 28. Applicability was the second-lowest-scoring domain at 30.2 percent, reflecting inadequate consideration of implementation barriers and facilitators, practical implementation tools, resource implications, and monitoring or auditing criteria.

Inter-rater reliability was evaluated using intraclass correlation coefficients estimated with a two-way mixed-effects model and an absolute-agreement definition. Across all 23 items, overall reliability was high, with a single-measures ICC of 0.897 and an average-measures ICC of 0.972, with a 95 percent confidence interval of 0.943 to 0.998. Domain-specific estimates varied: Rigor of Development and Editorial Independence showed excellent agreement, with average-measures ICCs of 0.936 and 0.987 respectively, while Scope and Purpose and Stakeholder Involvement showed good agreement. The Clarity of Presentation domain yielded ICC estimates of 0.000, but the researchers caution that this result does not indicate perfect or uniform agreement; rather, the between-item and residual mean squares were identical, producing a zero numerator in the ICC calculations. Because the Clarity of Presentation and Applicability domains contained only three and four items and their confidence intervals were wide, these domain-specific estimates should be interpreted cautiously. Friedman tests showed no statistically significant differences in item ratings among the four appraisers within any individual domain, and an exploratory weighted composite analysis, using domain-specific weights derived from published regression coefficients, produced a mean exploratory weighted score of 4.21 with a standard deviation of 0.26, though no inferential test was performed on these totals.

The mean direct overall guideline quality rating was 5.25 on the 7-point scale, with individual ratings ranging from 5 to 6, and all four appraisers independently selected the same recommendation for use: yes, with modifications. The researchers emphasize that this comparison was descriptive and was not treated as an official AGREE II classification threshold. The findings place the Iranian guideline in international context. In a systematic review of 22 non-small cell lung cancer guidelines, Cortés-Jofré and colleagues reported high scores for Scope and Purpose at 90.7 percent, Clarity of Presentation at 89.8 percent, and Editorial Independence at 91.7 percent, whereas Applicability was the weakest domain, with a median score of 46.5 percent. Similarly, Applicability was one of the two lowest-scoring domains in the Iranian appraisal. A Korean study assessing 27 national guidelines found that Stakeholder Involvement averaged only 53.4 percent, pointing to a broader global issue in ensuring participatory development, while a systematic review of PET/CT oncology guidelines found that Editorial Independence frequently underperformed, with an average score of 50.6 percent. A Spanish study found that although 84.8 percent of oncology guidelines were deemed high quality, only one exceeded 60 percent in Applicability, underscoring that the Iranian weaknesses in practical implementation are part of a global pattern.

The low Rigor of Development score reflects the lack of transparent procedures for systematic evidence review, formal grading of evidence, and mechanisms for guideline revision and updating, elements that are essential to trustworthy guideline development. Even internationally recognized guidelines such as those issued by the NCCN have faced criticism for insufficient documentation of their evidence synthesis processes. Resource-stratified oncology guideline initiatives have emphasized that recommendations developed in maximal-resource settings may require adaptation to local infrastructure, workforce, technology, affordability, and access constraints before they can be implemented in resource-limited settings. The RIGHT-3 study on Italian oncology guidelines revealed that although treatment recommendations were commonly adopted, there were persistent gaps in the implementation of diagnostic and supportive care components, findings that align with the Iranian context, where the lack of guidance on monitoring, cost considerations, and practical execution likely contributed to the lower Applicability scores. The researchers also note the temporal context of the appraisal: the study assessed the 2018 national guideline using ratings collected in September 2020, and the present findings should be interpreted as an assessment of the methodological quality and reporting of the 2018 comprehensive guideline rather than as confirmation of the current clinical appropriateness of every recommendation it contains.

From a policy standpoint, the researchers argue that implementing centralized oversight mechanisms and mandatory use of validated appraisal tools such as AGREE II could elevate the quality, transparency, and consistency of future Iranian guidelines. Moreover, the use of international recommendations should be accompanied by a structured process of contextualization. The GRADE-ADOLOPMENT framework provides a transparent approach for adopting, adapting, or developing recommendations by considering local evidence, values and preferences, resource requirements, feasibility, and health-system context. Future appraisals should predefine any locally selected quality thresholds and clearly distinguish such thresholds from the official AGREE II scoring framework. Investments in training for evidence synthesis, participatory methodology, and implementation science are also essential to overcome the recurring limitations observed both locally and internationally. Further research should promote meaningful inclusion of patient and caregiver input, since stakeholder engagement and editorial transparency remain weak points, with some cancer pain guidelines scoring as low as 32.6 percent and 35.0 percent in these domains. Incorporating AGREE-REX, a validated instrument specifically designed to assess the clinical credibility and implementability of guideline recommendations, could complement future AGREE II assessments in Iran, while exploring the impact of structured training on guideline development may help improve scores in critical domains like Rigor and Applicability.

The study has limitations worth noting. Although four appraisers are consistent with the preferred number recommended for AGREE II appraisal, the small number limits broader generalizability, and domain-specific ICC estimates were based on only two to eight items and consequently had wide confidence intervals. The study evaluated only one national guideline, limiting comparison to other clinical guidelines, and the absence of stakeholder interviews and implementation data prevented triangulation of the AGREE II findings with real-world clinical use. Despite these limitations, the study provides a transparent item-level appraisal and identifies clear priorities for future guideline development and revision. Future versions should prioritize transparent evidence-synthesis methods, explicit updating procedures, implementation tools, resource considerations, monitoring criteria, and clearer conflict-of-interest reporting. For a country where lung cancer mortality is rising and the national health system bears an increasing burden, the message is unambiguous: a guideline that reads well is not enough. It must be built on evidence that can be traced, updated on a schedule that keeps pace with rapidly evolving oncology, and equipped with the practical tools that turn recommendations into care. The absence of a clearly identifiable comprehensive update since 2018 only reinforces the urgency of establishing an explicit, transparent, and regularly implemented updating procedure for future national guidelines.

Subject of Research: Health

Article Title: Quality appraisal of Iran's clinical guideline for diagnosis and treatment of non-small cell lung cancer (NSCLC) using the AGREE II instrument

Article References: Mohseni Ahangar, R., Ebrahimi, P., Pakdaman, K., Ghanei, M., & Ghazvini, A. (2026). Quality appraisal of Iran's clinical guideline for diagnosis and treatment of non-small cell lung cancer (NSCLC) using the AGREE II instrument. Heliyon, 12(16), Article e45598. https://doi.org/10.1016/j.heliyon.2026.e45598

Image Credits: AI Generated

DOI: 10.1016/j.heliyon.2026.e45598

Keywords: clinical guidelines, lung cancer, NSCLC, AGREE II, Iran, health policy, oncology, Quality, appraisal, Iran's, clinical, guideline