Computed tomography based assessment of treatment response in solid tumors

A “substantial evidence” of effectiveness is required for new cancer treatment regimens to be approved. Objective tumor shrinkage/enlargement has been adopted as an indicator of drugs efficacy. The change of tumor size is assessed and quantified by various radiological techniques; most commonly computed tomography (CT). A high accuracy and reproducibility is, for obvious reasons, necessary in order to achieve a meaningful evaluation of such studies. For that purpose, the World Health Organization criteria (WHO-criteria) were launched in 1979 followed by the Response Evaluation Criteria In Solid Tumors (RECIST) in 2000 and the updated version RECIST 1.1 in 2009. There are, however, still several steps that may deteriorate consistencies.

The purpose of this thesis was to investigate causes that may affect inconsistency in evaluation procedure according to RECIST (study I and II) and to explore the percentage of tumor size change at the first follow-up CT as the potential new surrogate indicators for OS in patient with metastatic colorectal cancer (mCRC) (study III) and in patient with metastatic breast cancer (MBC) (study IV).

The number of discordant cases increased gradually when assessing fewer target lesions. Measuring fewer than four target lesions might cause discrepancies when more than five target lesions were present (study I). Interobserver variation using RECIST and WHO-criteria were moderate: 0.53 (95%CI 0.33 - 0.72) and 0.60 (0.39 – 0.80), respectively. Intraobserver variation using RECIST and WHO-criteria were substantial to perfect that ranged between 0.76 – 0.96 and 0.86 – 0.91, respectively (study II).

The initial change in tumor size 8 weeks after initiation of chemotherapy was prognostic for PFS: Hazard Ratio (HR) 2.21, 95%CI 1.97 – 2.49, and OS: HR2.01, 95%CI 1.75 – 2.31, in mCRC (study III). The initial change in tumor size also correlated with OS in MBC (study IV). A marked difference in OS between patients with or without new lesion was demonstrated in mCRC: HR 3.77, 95%CI 2.08 – 6.83 (study III) and in MBC: HR 4.29, 95%CI 2.44 – 7.53 (study IV).

In conclusion, the current tumor response evaluation criteria are associated with several subjective steps that may cause inconsistent results. The initial change in tumor size at the first follow-up CT may provide an alternative surrogate outcome. The findings obtained in this thesis may improve the development of future response evaluation criteria.

List of scientific papers

I. Darkeh, M. H., Suzuki, C. & Torkzad, M. R. 2009. The minimum number of target lesions that need to be measured to be representative of the total number of target lesions (according to RECIST). Br J Radiol. 82, 681-6.
https://doi.org/10.1259/bjr/72829563

II. Suzuki, C., Torkzad, M. R., Jacobsson, H., Åström, G., Sundin, A., Hatschek, T., Fujii, H. & Blomqvist, L. 2010. Interobserver and intraobserver variability in the response evaluation of cancer therapy according to RECIST and WHO-criteria. Acta Oncol. 49, 509-14.
https://doi.org/10.3109/02841861003705794

III. Suzuki, C., Blomqvist, L., Sundin, A., Jacobsson, H., Bystrom, P., Berglund, A., Nygren, P. & Glimelius, B. 2012. The initial change in tumor size predicts response and survival in patients with metastatic colorectal cancer treated with combination chemotherapy. Ann Oncol. 23, 948-54.
https://doi.org/10.1093/annonc/mdr350

IV. Suzuki, C., Blomqvist, L., Hatschek, T.,Carlsson, L., Einbeigi, Z., Linderholm, B., Lindh, B., Loman, N., Malmberg, M., Rotstein, S., Söderberg, M., Sundquist, M., Walz, T., Åström, G., Fujii, H., Jacobsson, H., Glimelius, B. Impact of early response on overall survival in metastatic breast cancer patients treated with combination chemotherapy within a randomized phase III trial. [Submitted]

V. Appendix. Suzuki, C., Jacobsson, H., Hatschek, T., Torkzad, M. R., Boden, K., Eriksson-Alm, Y., Berg, E., Fujii, H., Kubo, A. & Blomqvist, L. 2008. Radiologic measurements of tumor response to treatment: practical approaches and limitations. Radiographics. 28, 329-44.
https://doi.org/10.1148/rg.282075068