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CT Tumor Measurement for Therapeutic Response Assessment: Comparison of Unidimensional, Bidimensional, and Volumetric Techniques—Initial Observations¹

¹ From the Department of Radiology, Massachusetts General Hospital and Harvard Medical School, 32 Fruit St, White 270-E, Boston, MA 02114 (S.R.P., K.S.J., S.S., P.F.H., E.F.H.); and WorldCare, Cambridge, Mass (J.E.S). Received September 28, 2001; revision requested December 5; revision received February 7, 2002; accepted April 15. Address correspondence to S.S. (e-mail: ssaini@partners.org).

	ABSTRACT

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PURPOSE: To compare unidimensional, bidimensional, and volumetric techniques for evaluation of treatment response in patients with liver metastases from breast cancer in a phase III clinical trial.

MATERIALS AND METHODS: Helical computed tomographic (CT) studies in 38 patients with liver metastases from breast cancer who were enrolled in a phase III clinical trial were evaluated before treatment and at 6 months after treatment. Two subspecialty radiologists measured all lesions on transverse CT scans with use of electronic calipers according to both unidimensional and bidimensional criteria. Volumetric measurements were made by tracing individual lesions. Measurements of individual lesions were summed to obtain patient response, which was categorized as complete response, disappearance of lesions; partial response, greater than 30% decrease in tumor diameter (unidimensional), greater than 50% reduction in tumor area (bidimensional), or greater than 65% reduction in tumor volume (volumetric); disease progression, greater than 20% increase in tumor diameter, greater than 25% increase in tumor area, or greater than 73% increase in tumor volume: or stable disease (size response other than that of complete response, partial response, or disease progression).

RESULTS: In 37 patients, there was concordant treatment response with use of unidimensional and bidimensional techniques. Volumetric measurement produced results different from those of the unidimensional and bidimensional techniques in 12 and 13 patients, respectively. In six patients with partial response per unidimensional and bidimensional criteria, the response based on the volumetric technique was stable disease. In two patients with stable disease per bidimensional and unidimensional criteria, the response was partial response by volumetric measurement. In four patients with disease progression per bidimensional and unidimensional criteria, the response was stable disease per volumetric criteria.

CONCLUSION: Volumetric measurement of tumor burden gives different results for treatment response compared with that of the unidimensional or bidimensional technique in a considerable proportion of patients.

© RSNA, 2002

Index terms: Breast neoplasms, metastases, 761.3320 • Liver neoplasms, CT, 761.12115 • Liver neoplasms, secondary, 761.332 • Liver neoplasms, staging • Liver neoplasms, therapy

	INTRODUCTION

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Quantification of tumor burden with computed tomography (CT) and magnetic resonance (MR) imaging is being used with increasing frequency to assess the effectiveness of cytotoxic anticancer drugs (1). As a result, radiologic evaluation of tumor size during clinical trials of anticancer pharmaceuticals has evolved into a surrogate marker of therapeutic response, potentially allowing expedited approval (2).

Since 1979, World Health Organization (WHO) guidelines have been used for radiologic tumor response evaluation (3,4). According to WHO methodology, each tumor is measured in two dimensions: its maximum diameter in the transverse plane and its largest perpendicular diameter on the same image. These diameters are multiplied to yield a cross product. Pretreatment and posttreatment cross products are compared to categorize treatment response into one of four categories. These consist of complete response, indicating tumor disappearance; partial response, indicating greater than 50% reduction in cross product; disease progression, indicating greater than 25% increase in cross product; or stable disease, representing less than 50% reduction to less than 25% increase in cross product. For patients with multiple lesions, the cross product of several indicator lesions is added to categorize the patient’s response. For the entire trial, overall response rate is based on the proportion of subjects classified as having a complete or partial response.

In 1994, the European Organization for Research and Treatment in Oncology, the National Cancer Institute of the United States, and the National Cancer Institute of Canada Clinical Trials Group set up a task force to review tumor measurement techniques in view of the advances in imaging technologies. The revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines advocated that unidimensional measurement alone (largest diameter in the transverse plane) be used for quantifying tumor burden (5). Furthermore, they proposed that measurements should be limited to an arbitrary five lesions per organ and up to 10 lesions per patient in patients with tumors in multiple organs (5). For the unidimensional measurement approach, the criteria for treatment response categorization were also modified, with partial response being defined as greater than 30% reduction in tumor diameter, stable disease being less than 30% reduction to less than 20% increase in diameter, and disease progression being greater than 20% increase in tumor diameter (5). The criterion for complete response was total tumor disappearance.

Recent advances in CT technology, specifically volumetric data acquisition and image processing, permit volumetric tumor burden quantification (6,7). We hypothesized that such quantification would result in a different response assessment compared with those of the unidimensional and bidimensional techniques. The purpose of our study therefore was to compare unidimensional, bidimensional, and volumetric techniques for evaluation of treatment response in patients with liver metastases from breast cancer in a multicenter phase III clinical trial.

	MATERIALS AND METHODS

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In a multicenter, open-label, randomized phase III clinical trial to compare the efficacy of docetaxel monotherapy vis-a-vis capecitabine-docetaxel combination therapy (Hoffman-La Roche, Nutley, NJ), patients with metastatic breast carcinoma underwent contrast material–enhanced abdominal CT at various clinical sites. Approval of the institutional review boards and patient informed consent have been obtained at the local sites involved in the study. The images were forwarded to a central reading facility where tumor size was measured on digitized images with use of electronic calipers (Cheshire; Hayden Image Processing, Boulder, Colo). Off-site tumor measurements were performed by independent experienced radiologists (including S.S.) who ensured that the same lesion was being evaluated on pretreatment and follow-up scans and that the measurement technique was uniform with respect to anatomic level, angle of measurement, and inclusion of tumor rim. Electronic recording (as overlays) of the measurements facilitated the measurements on follow-up studies.

For this analysis, two subspecialist radiologists (S.R.P., K.S.J.) worked together in consensus to identify patients with multiple liver metastases who had been examined with a helical (spiral) CT scanner and in whom the entire liver had been imaged in a single breath hold. Thirty-eight patients satisfied the criteria. All tumor measurements were made by these two radiologists working together in consensus at the off-site facility. Up to five indicator liver lesions were chosen for measurement in each patient to assess treatment response. The indicator lesions were chosen with consensus of the two radiologists to include large, well-defined lesions. This was done to provide a reasonable tumor burden estimate while measuring five lesions according to unidimensional criteria (5). As per the RECIST guidelines, lesions measuring less than 1 cm were not considered as indicator lesions for linear tumor measurements (5).

Three tumor measurement techniques were used. Bidimensional tumor measurements were made at baseline and at 6 months after treatment, and patients were categorized into four treatment response groups—complete response, partial response, stable disease, and disease progression—according to the WHO guidelines (3,4). The longest diameter was extracted from the bidimensional measurements, and the patients were reclassified according to the revised unidimensional criteria. In addition, volume determinations were performed with a Cheshire workstation (Hayden Image Processing) by tracing all lesions at baseline and at the 6-month follow-up examination. The sum of the areas from each section was multiplied by the reconstruction interval on contiguous sections to obtain tumor volumes. Treatment response was evaluated by using the unidimensional criteria extrapolated to volumes. Thus, complete response indicated tumor disappearance, partial response indicated greater than 65% reduction in tumor volume, disease progression indicated greater than 73% increase in tumor volume, and stable disease represented less than 65% reduction to less than 73% increase in tumor volume (Table).

	RESULTS

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Results of treatment response were concordant between the bidimensional and unidimensional criteria in 37 (97%) of the 38 patients, whereas the volumetric assessment produced a discordant result from the unidimensional criteria in 12 (32%; 95% CI: 17.5%, 48.7%) of 38 patients and from the bidimensional criteria in 13 (34%; 95% CI: 19.6%, 51.4%) of 38 patients. In six patients with partial response based on unidimensional and bidimensional criteria, the response based on the volumetric technique was changed to stable disease. In two patients with stable disease per bidimensional and unidimensional criteria, the response was reclassified as partial response per volumetric measurement. In four patients with disease progression per bidimensional and unidimensional criteria, the response was changed to stable disease per volumetric criteria. Thus, in six patients, the response to treatment was worse using the volumetric criteria, and in six patients the treatment response was better using the volumetric criteria, showing no difference in overall response rate. In the single patient with discordant results between bidimensional and unidimensional criteria, the volumetric and unidimensional responses were similar, showing partial response, whereas the bidimensional response was stable disease.

Review of the images showed that most lesions were predominantly spherical with well-defined margins. No clear trends in lesion morphology were seen to correlate with discordance in results among measurement techniques. Discordant results were obtained in patients with multiple liver metastases that showed differential response to chemotherapy (Figure). Treatment response categorizations were discordant when there was asymmetrical tumor growth or shrinkage.

View larger version (116K): [in this window] [in a new window] [Download PPT slide]   Figure a. Discordance of results between linear and volumetric tumor measurement techniques owing to differential tumor response to chemotherapy in a patient with multiple liver metastases from breast cancer. (a) Baseline transverse CT scan shows multiple well-defined lesions in the right posterior lobe (arrowhead) and in the left lateral lobe (arrows). (b) Six-month follow-up CT scan shows that the lesion in the right posterior lobe (arrowhead) is stable and lesions in the left lateral lobe (arrows) have grown considerably.

View larger version (109K): [in this window] [in a new window] [Download PPT slide]   Figure b. Discordance of results between linear and volumetric tumor measurement techniques owing to differential tumor response to chemotherapy in a patient with multiple liver metastases from breast cancer. (a) Baseline transverse CT scan shows multiple well-defined lesions in the right posterior lobe (arrowhead) and in the left lateral lobe (arrows). (b) Six-month follow-up CT scan shows that the lesion in the right posterior lobe (arrowhead) is stable and lesions in the left lateral lobe (arrows) have grown considerably.

	DISCUSSION

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Recent advances in imaging parallel development of anticancer agents. Radiologic assessment of tumors with use of volumetric imaging technologies such as helical CT and MR imaging before and after start of therapies permits accurate quantification of tumor burden (6,7). Volumetric image acquisition with modern-day MR imagers and helical CT scanners allows precise three-dimensional measurement of tissue volumes.

Our results show that in patients with hepatic metastases, there was almost complete agreement in treatment response between bidimensional and unidimensional criteria. However, the volumetric assessment produced different results in one-third of patients when compared with unidimensional and bidimensional techniques. We believe that volumetric measurement provides better representation of tumor burden and may be superior to conventional tumor measurement techniques. However, correlation with clinical outcome is needed for confirmation. We were unable to do so in the current study owing to the 6-month period being too short to determine clinical outcome and to the overall low availability of helical (spiral) CT scans in the clinical trial.

The value of volumetric tumor measurements is controversial. Authors of some preliminary studies support the use of three-dimensional measurement techniques for assessing tumor size (10,11). Others did not find significant added benefit of volumetric tumor measurement for evaluating therapeutic response when compared to unidimensional and bidimensional measurements (12,13). However the results of a study by Hopper et al (14) showed considerable interobserver variation among radiologists in CT linear tumor measurement, especially for ill-defined and irregular lesions. Volumetric measurement would overcome difficulty in estimating the size of lesions that are confluent and irregular. An important theoretic advantage of volumetric measurements is that it permits measurement of overall tumor burden in an organ, thereby eliminating the arbitrary guideline of measuring five indicator lesions per organ.

The tumor volume measurement technique may have certain disadvantages. Tracing individual tumor margins is time consuming. In addition, the software for accurate tumor volume estimation needs to be installed, and different formulas for volume estimation need to be applied when considering nonspherical tumors. However, with advances in image processing, the outlining of lesions may become more automated, leaving the radiologist the simpler task of refining the outlined tumor margin (15).

Our study has several limitations, foremost of which is the modest sample size. In theory, a larger data sampling could permit more comprehensive testing of the hypothesis and could yield a different outcome among the three techniques. Again, with a larger test population, it may be possible to test the effect of different measurement techniques in different organs. In addition, owing to the off-site data analysis methodology, we were unable to correlate the radiologic response assessment with patient outcome to determine which criteria correlated best with clinical results. Another limitation of our study was that the tumor measurements were performed on scanned images; measurements on soft-copy images might have been more accurate. Most of the patients in our study cohort had spherical metastases with well-defined margins. Therefore, our results may not apply when quantifying tumor burden of irregular or ill-defined lesions and/or lesions that surround normal structures.

In conclusion, compared with unidimensional and bidimensional criteria for evaluating treatment response of liver metastases, the volumetric measurement technique gives different results. The value of volumetric measurement for assessment of treatment response needs to be confirmed by large studies in different patient populations, along with correlation with clinical outcomes.

	FOOTNOTES

 
Abbreviations: RECIST = Response Evaluation Criteria in Solid Tumors, WHO = World Health Organization

Author contributions: Guarantors of integrity of entire study, S.R.P., S.S., K.S.J.; study concepts, S.R.P.; study design, S.S., S.R.P., K.S.J.; literature research, S.R.P., S.S.; clinical studies, S.R.P., K.S.J., J.E.S.; data acquisition, S.R.P., K.S.J.; data analysis/interpretation, S.R.P., K.S.J., E.F.H.; statistical analysis, E.F.H.; manuscript preparation and definition of intellectual content, S.S., S.R.P.; manuscript editing, S.S., P.F.H.; manuscript revision/review, S.S., P.F.H., J.E.S.; manuscript final version approval, S.S., P.F.H.

	REFERENCES

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 

1. Hopper KD, Singapuri K, Finkel A. Body CT and oncologic imaging. Radiology 2000; 215:27-40.[Abstract/Free Full Text]
2. Saini S. Radiologic measurement of tumor size in clinical trials: past, present, and future. AJR Am J Roentgenol 2001; 176:333-334.[Free Full Text]
3. World Health Organization. WHO handbook for reporting results of cancer treatment. WHO offset publication no. 48 Geneva, Switzerland: World Health Organization, 1979.
4. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981; 47:207-214.[CrossRef][Medline]
5. Therasse P, Arbuk SG, Eisenhauer EA, et al. New guidelines to evaluate response to treatment in solid tumors. J Natl Cancer Inst 2000; 92:205-216.[Abstract/Free Full Text]
6. Zeman RK, Fox SH, Silverman PM, et al. Helical (spiral) CT of the abdomen. AJR Am J Roentgenol 1993; 160:719-725.[Abstract/Free Full Text]
7. Touliopoulos P, Costello P. Helical (spiral) CT of the thorax. Radiol Clin North Am 1995; 33:843-861.[Medline]
8. Guidance for industry. FDA approval of new cancer treatment uses for marketed drug and biological products. U.S. Department of Health and Human Services, Food and Drug Administration Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). December 1998; Clin 7.
9. Pazdur R. Response rates, survival, and chemotherapy trials. J Natl Cancer Inst 2000; 92:1552-1553.[Free Full Text]
10. Van Hoe L, Van Cutsem E, Vergote I, et al. Size quantification of liver metastases in patients undergoing cancer treatment: reproducibility of one-, two-, and three-dimensional measurements determined with spiral CT. Radiology 1997; 202:671-675.[Abstract/Free Full Text]
11. Hopper KD, Kasales CJ, Eggli KD, et al. The impact of 2D versus 3D quantification of tumor bulk determination on current methods of assessing response to treatment. J Comput Assist Tomogr 1996; 20:930-937.[CrossRef][Medline]
12. Dachman AH, MacEneaney PM, Adedipe A, Carlin M, Phillip L. Tumor size on computed tomography scans. Cancer 2001; 91:555-560.[CrossRef][Medline]
13. Sohaib SA, Turner B, Hanson JA, Farquharson M, Oliver RT, Reznek RH. CT assessment of tumour response to treatment: comparison of linear, cross-sectional and volumetric measures of tumour size. Br J Radiol 2000; 73:1178- 1184.[Abstract]
14. Hopper KD, Kasales CJ, Van Slyke MA, Schwartz TA, TenHave TR, Jozefiak JA. Analysis of interobserver and intraobserver variability in CT tumor measurements. AJR Am J Roentgenol 1996; 167:851-854.[Abstract/Free Full Text]
15. Schwartz LH, Ginsberg MS, DeCorato D, et al. Evaluation of tumor measurements in oncology: use of film-based and electronic techniques. J Clin Oncol 2000; 18:2179-2184.[Abstract/Free Full Text]

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