5 Pitfalls of Conventional Tumor Response Assessment
Major Pitfalls of the WHO and RECIST criteria.
The term “tumor response assessment” is well known in the medical community and frequently used in both the oncologic and radiologic literature. Numerous investigations of tumor response assessment have been carried out in different types of cancer, including lung cancer, using conventional and novel criteria for response assessment.
The introduction of the concept and the definitions of essential terminology contributed to standardize the ways tumor response was assessed and results of cancer treatment were documented in clinical oncology research. The standardization allowed effective comparisons among results of different cancer treatments, which has led to significant advances in cancer therapy.
The two most commonly used response assessment criteria in solid tumors are the World Health Organization (WHO) criteria, introduced in 1979, and the Response Evaluation Criteria in Solid Tumors (RECIST), published in 2000 and revised in 2009. The WHO criteria use bidimensional measurements, while RECIST utilizes the longest unidimensional diameters of target lesions.(Fig 1)
Although RECIST provides a standardized and practical method to assess response and define progression in solid tumors in general, pitfalls and limitations of RECIST have been noted in various clinical scenarios.
To complement such pitfalls and limitations of RECIST, several newer response criteria are being proposed for patients with specific types of cancer treated with specific therapeutic agents, and some of these criteria have been applied in oncology trials and practice.
5 Pitfalls of Conventional Tumor Response Assessment
1. Inaccurate Assumptions
These criteria rely on size measurement alone and assume that tumor volume is simply related to a planar measurement. However, significant intra-tumoral heterogeneity exists in rates and patterns of tumor growth.
In reality, heterogeneity can either be in terms of tumor growth within one lesion where only one portion of the lesion grows disproportionally while other portions remain essentially unchanged, or it can be in terms of tumor growth among multiple lesions within a patient, where some lesions grow significantly during therapy while others remain unchanged or decrease in size.
2. Lack of Consistency
Substantial intra- and interobserver measurement variability has been documented by using both WHO criteria and RECIST. Erasmus  studied the consistency of size measurements in 40 lung tumors assessed on CT scans and reported that the probability of misclassifying a tumor progression was 43% with WHO criteria and 30% with RECIST.
The findings indicate that, despite considerable variability, the measurements were reproducible within the partial response category. Moreover, the cutoff values for progression were within the range of measurement variability, indicating that some patients were unnecessarily placed in the progressive disease category.
3.Imperfect Assessment of Tumor Cavitation
One of the significant limitations of the WHO criteria and RECIST in lung cancer is the assessment of tumor cavitation. An alternative method of measurement of cavitary lesions excluding the area of cavitation has been proposed and has been shown to alter response assessment and the determination of time to progression in some patients. However, the impact of the method in prediction of outcomes remains to be investigated.
4. Flawed Assessment for EGFR-TKI Therapy
Progression by RECIST criteria may not warrant termination of therapy for genomically defined subsets of Non-Small Cell Lung Cancer (NSCLC) patients. In patients with EGFR-mutant NSCLC treated with EGFR-TKI, continued EGFR-TKI therapy may be indicated in those patients with progressive disease because these tumors grow slowly over many months and some tumor cells remain sensitive to EGFR-TKI.
A recent study of 56 NSCLC patients harboring EGFR mutations treated with first-line EGFR-TKI, ‘erlotinib’ or ‘gefitinib’, demonstrated that 88% of the patients continued EGFR-TKI therapy beyond progression according to RECIST, indicating that RECIST progression is no longer the determining factor to terminate TKI therapy. 
5. Unreliability for Immunotherapy Treatment
In patients with metastatic melanoma treated with immunotherapeutic agents such as ‘ipilimumab’, which work by enhancing anti-tumor immune responses rather than directly inducing cytotoxicity to tumor cells, clinical observations suggested that “stable disease” by RECIST or WHO criteria may be an indicator of meaningful therapeutic effect. 
Furthermore, response to immunotherapy was noted to occur after an increase in tumor burden characterized as progressive disease by RECIST or WHO criteria. These observations raised concern for relying solely on these conventional criteria in patients treated with immunotherapy.
- American Journal of Roentgenology. 2012;198: 737–745. 10.2214/AJR.11.7483
- Radiology Journal (RSNA). https://doi.org/10.1148/radiol.14122524
- Dr. Erasmus JJ, Dr. Gladish GW, Dr. Broemeling L, et al. Interobserver and intraobserver variability in measurement of non-small-cell carcinoma lung lesions: implications for assessment of tumor response. J Clin Oncol 2003;21(13):2574–2582. [CrossRef][ Medline]
- Dr. Nishino M, Dr. Cardarella S, Dr. Dahlberg SE, et al. Radiographic assessment and therapeutic decisions at RECIST progression in EGFR-mutant NSCLC treated with EGFR tyrosine kinase inhibitors. Lung Cancer 2013; 79(3):283–288. [CrossRef][ Medline]
- Dr.Hodi FS, Dr. O’Day SJ, Dr. McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711–723 [Crossref] [Medline]
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