Response Evaluation of Gastrointestinal Stromal Tumors (GIST) Haesun Choi, M.D. Diagnostic Imaging The University of Texas MD Anderson Cancer Center, Houston, TX

Gastrointestinal Stromal Tumor (GIST) deadly disease therapeutic options

+ “KIT” receptor Tyrosine kinase receptor blocker Kinase domains Chris Corless, M.D. + Imatinib mesylate Tyrosine kinase receptor blocker

Thessasse et al. JNCI 92(3); 205, 2000 “Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) are the best currently available and most reproducible methods for measuring the target lesions …” the recent guidelines for response evaluation in solid tumors, published in 2000 Thessasse et al. JNCI 92(3); 205, 2000

Fluorine-18-fluorodeoxyglucose Positron Emission Tomography (FDG PET)

8/9/02 10/28/02

Pre-Treatment Pre-Treatment

Computed Tomography (CT) In general practice, CT remanins the modality of choice to monotor the disease.

Gastric GIST Metastatic GIST

Small bowel GIST Metastatic GIST

6/01 HU 63 3.3 cm 8/01 HU 38 2.3 cm 10/01 HU 32 1.9 cm

Pre-Treatment 2 Months Post

Pre-Treatment 5 Days Post

30 HU 43 HU Pre-Treatment 2 Months Post

Methods and Materials (I) CT vs. PET PET: EORTC1999 Tumor size (cm) Tumor density (HU) “Overall tumor status (OTS)” Total patients = 36 CT* and PET* = 29 *within a week of each other Total lesions = 173 Liver: 116 Peritoneum: 52 Pleura: 5

Subjective Tumor Response Evaluation: OTS Pre-Treatment Size + tumor vessels solid tumor nodules tumor density

Pre-Treatment 2 Months Post

Objective Tumor Response Evaluation Size Mean HU Mean SUVmax P = 0.0025, t-test P<0.0025, t-test Pre-treatment 8 Wks Post-treatment

No. of Patients by Changes in Size* Size vs. SUV No. Patients by Changes in SUVmax** No. of Patients by Changes in Size* Total No. of Patients PD SD PR CR Grade 1 2 Grade 2 1 5 6 Grade 3 Grade 4 15 4 20 Note. - The data were analyzed for the 29 patients who underwent both CT and FDG PET. * Based on RECIST ** Based on modified EORTC 1999 criteria

Methods and Data Analysis (II) Total patients = 40 CT and PET “Good Response” :Decrease in SUVmax >70% <2.5 Good Response: 33 (83%) 30 (75%): PET CR 3 (8%): 70 - 99% decrease, decrease to a value <2.5 Poor Response:7 (17%) 5 (12%): stable 2 (5%): increased SUVmax (Van den Abbeele AD, et al, ASCO 2002)

Changes in Size and HU on CT vs. Tumor Response on FDG PET Total number of patients = 40 Tumor response by PET Patients with  10% decrease in size (%)  15% decrease in HU (%)  10% decrease in size or  15% decrease in HU (%) Good (n=33) 31 (94) 27 (82) 32 (97) Poor (n=7) 0 (0) n – number of patients

Modified CT Criteria PET response: CT response: SUV < 2.5, 70% HU  -15%, Size  -10% 1 .9 .8 .7 .6 .5 .4 .3 .2 .1 1 .9 .8 .7 .6 .5 .4 .3 .2 .1 + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + P = 0.03 + + + + + + + + + + + + + + + + + + + + P = 0.03 + + + + + Responder Responder Non-responder Non-responder 30 27 24 21 18 15 12 9 6 3 30 27 24 21 18 15 12 9 6 3 Months Months Time to Progression by PET and modified CT criteria

Time to Progression: RECIST Response Rate 45%

Time to Progression: Modified CT Response Rate 83%

Surveillance

Progression Increase in tumor size Appearance of a new lesion at the site of primary tumor Appearance metastatic lesions

Pre-Treatment 2 Months Post 8 Months Post 11 Months Post

10 Months Post 17 Months Post 21 Months Post 27 Months Post

“Appearance of new intra-tumoral nodules” Progression in GIST “Increase in tumor size” Appearance of a new lesion at the site of primary tumor Appearance metastatic lesions “Appearance of new intra-tumoral nodules”

We do need FDG PET.

30 HU 43 HU Pre-Treatment 2 Months Post

Conclusions RECIST underestimates the tumor response. Subjective evaluation using changes in tumor nodules, density, tumor vessels, in addition to change in size is the best criteria on CT and is reproducible. CT density alone can be a good indicator in early, quantitative tumor response evaluation.

Conclusions Objective evaluation using a combination of tumor density (15% change) and modified tumor size criteria (10% change) is promising in early tumor response evaluation and has a prognostic value. FDG PET should be performed whenever the CT findings are inconclusive or inconsistent with the clinical presentation.

It's Time To Re-visit Tumor Response Criteria !!

Acknowledgements Chusilp Charnsangavej, M.D. Donald A. Podoloff, M.D. Division of Diagnostic Imaging: Chusilp Charnsangavej, M.D. Silvana C. Faria, M.D. Eric P. Tamm, M.D. Evelyn M. Loyer, M.D. Kazama Toshiki, M.D. Division of Nuclear Medicine: Donald A. Podoloff, M.D. Homer A. Macapinlac, M.D. Department of Sarcoma Medical Oncology: Robert S. Benjamin, M.D. Sarcoma Center Team Department of Biostatistics: Marcella M. Johnson, M.S.

Data Analysis: CT Variables Response Analysis Size (cm) RECIST* PD, SD, PR, CR Density (HU) Grade 1-4 (median:13% ) G1  -12% (worse) G2 -11% - 11% G3 12- 31% G4  32% (best) OTR** (size, density, vessels, nodules) G1 worse, G2 stable G3 better, G4 best **OTR – overall tumor response *JNCI 92(3); 205, 2000

No. Patients by Changes in OTS OTS vs. SUV P = 0.0001*, Chi-Square Test No. Patients by Change in SUVmax No. Patients by Changes in OTS Total No. of Patients Grade 1 Grade 2 Grade 3 Grade 4 2 6 1 4 15 20 horozontal vertical *Statistically significant. Note. - The data were analyzed for the 29 patients who underwent both CT and FDG PET.

No. Patients by Changes in HU HU vs. SUV P = 0.3088, Chi-Square Test No. Patients by Change in SUVmax No. Patients by Changes in HU Total No. of Patients Grade 1 Grade 2 Grade 3 Grade 4 1 2 4 6 10 20 Note. - The data were analyzed for the 29 patients who underwent both CT and FDG PET.

Reproducibility N = 35

Methods and Materials (II) Two radiologists who were not participated in initial analysis of CT images Overall Tumor Status (OTS) The results of two radiologists were compared with each other.

Mean HU Size Mean SUVmax Pre-treatment 8 Wks Post-treatment P < 0.0001, t-test P < 0.0001, t-test Mean SUVmax P < 0.0001, t-test Pre-treatment 8 Wks Post-treatment

P* = 0.0002, Chi-Square Test, rtau** = 0.5782 Reader A vs. B P* = 0.0002, Chi-Square Test, rtau** = 0.5782 Reader A Reader B Grade 1 Grade 2 Grade 3 Grade 4 1 2 11 12 7 There was a good agreement between the two readers through the grades. *Statistically significant. ** Kendall’s Tau correlation. Note – Grades are based on OTR at 8 wks post-treatment.

No. Patients by Changes in OTS OTS vs. SUV P = 0.0001*, Chi-Square Test No. Patients by Change in SUVmax No. Patients by Changes in OTS Total No. of Patients Grade 1 Grade 2 Grade 3 Grade 4 2 1 10 20 31 And also again the changes in ODS correlated well with the changes in SUVmax based on consensus. *Statistically significant. Note. - The data were analyzed for the 35 patients who underwent both CT and FDG PET.

Pre-Treatment 2 Months Post EatoEaton 411286 24 Months Post 27 Months Post

Discrepancy(?): HU vs. SUVmax Development of intratumoral hemorrhage Definition of ROI EORTC guideline

528671

Tyrosine Kinase Receptor Blocker “KIT” Receptor + Tyrosine Kinase Receptor Blocker

Conclusions RECIST underestimates the tumor response in GIST. Subjective evaluation using changes in tumor nodules, density, tumor vessels, in addition to change in size is the best criteria on CT and is reproducible.

Conclusions Objective evaluation using a combination of tumor density (15% change) and modified tumor size criteria (10% change) is promising in early tumor response evaluation and has a prognostic value. FDG PET should be performed whenever the CT findings are inconclusive or inconsistent with the clinical presentation.