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Dose-volume histogram analysis of acute gastrointestinal toxicity for gynecologic patients receiving intensity-modulated whole pelvic radiotherapy
Proceedings of the 43rd Annual ASTRO Meeting
221
While BM suppression is not typically significant following WPRT alone, it is common in patients who receive chemotherapy. Recent data have demonstrated that intensity-modulated WPRT (IM-WPRT) significantly reduces the volume of small bowel, bladder and rectum receiving the prescription dose in gynecology patients. The purpose of this study is to evaluate IM-WPRT as a means to reduce the volume of pelvic BM irradiated. Materials and Methods: Ten women with cervical or endometrial cancer previously treated using IM-WPRT were selected for this analysis. Using the treatment planning computed tomography scan, the clinical target volume (CTV) was defined to encompass the gross tumor, parametrial tissues, uterus (if present) and the regional lymph nodes. The CTV was expanded by a 1 cm margin to form the planning target volume (PTV). The bladder, rectum, small bowel were delineated in each patient. BM in the iliac crests was also contoured since studies have shown that the majority of the pelvic BM is located in these sites. Two plans were created for each patient: a standard 4-field WPRT plan with apertures shaped to the PTV in each beam’s-eye view, and an IM-WPRT plan designed to conform dose to the PTV while minimizing the dose to the normal tissues including the BM. Dose volume histograms (DVHs) for the PTV, small bowel and BM were compared for each patient. Results: For each of the ten patients, IM-WPRT treatment plans demonstrated a significant reduction of the volume of the BM receiving greater than 30% of the prescription dose (13.5 Gy). The attached table shows the average volume of the BM in the iliac crests receiving the specified dose (or greater) for the 4-field WPRT and the BM-sparing IM-WPRT plans. On average, IM-WPRT resulted in a 50% reduction in the volume of BM irradiated to doses greater than 22.5 Gy (p ⬍ 0.001), and more than 60% reduction of the BM irradiated to doses greater than 31.5 Gy (p ⬍ 0.001). Furthermore, as expected, the BM-sparing IM-WPRT plans resulted in significant sparing of all other normal tissues that was comparable to the original IM-WPRT that did not specifically consider BM as a constraint. In all ten cases, the BM-sparing treatment plan did not result in any significant differences in the PTV and small bowel DVHs. Conclusion: IM-WPRT significantly reduces the volume of pelvic BM irradiated compared to conventional WPRT. In addition, BM-sparing IM-WPRT did not compromise the improvements previously seen in IM-WPRT treatment plans that did not consider BM. Currently patients are being treated with this BM-sparing technique to determine if the dosimetric improvements seen here translate into clinical benefits.
Dose Gy (%)
WPRT (% BM Volume)
BM-Sparing IM-WPRT (% BM volume)
p-value
9.0 (20%) 13.5 (30%) 22.5 (50%) 31.5 (70%) 40.5 (90%) 45.0 (100%)
95.8% 92.3% 87.0% 52.8% 42.5% 33.0%
98.5% 90.4% 43.7% 25.9% 12.1% 4.5%
⬍ 0.001 0.35 ⬍ 0.001 ⬍ 0.001 ⬍ 0.001 ⬍ 0.001
1086
Dose-Volume Histogram Analysis of Acute Gastrointestinal Toxicity for Gynecologic Patients Receiving Intensity-Modulated Whole Pelvic Radiotherapy
J.C. Roeske, A.E. Lujan, U. Krishnamachari, A.J. Mundt Radiation and Cellular Oncology, The University of Chicago, Chicago, IL Purpose: Gastrointestinal (GI) sequelae are among the most common side effects in gynecologic patients receiving whole pelvic radiotherapy (WPRT). Recently, it has been reported that intensity-modulated whole pelvic radiotherapy (IMWPRT) reduces the volume of the small bowel and rectum irradiated in these women. However, since introducing IM-WPRT in our clinic, we have noted a broad range of acute GI toxicities. To better understand and minimize these sequelae, the goal of this study is to correlate acute GI toxicity with features of the small bowel and rectal dose-volume histograms (DVHs). Materials and Methods: Thirty-two patients treated with IM-WPRT were evaluated, all of who received a prescribed dose of 45 Gy. Patients were divided into 2 groups based on the severity of acute GI toxicity: Group A (22 patients) had no or only mild symptoms requiring infrequent anti-diarrheal medications and Group B (10 patients) had moderate to significant symptoms requiring frequent medications. DVHs of the small bowel and rectum were averaged within each group. Using a Monte Carlo simulation code, a permutation analysis was performed to assess the statistical difference in DVH areas. This simulation involved randomly re-assigning individual DVHs to Group A or Group B with the constraint that the total number within each group remain the same (22 and 10 patients, respectively). The average DVHs for the random samplings within each group were computed and the difference in area between the average DVHs was compared to the actual observed value. A p-value was calculated as the frequency in which this difference exceeded the observed clinical outcome. A total of 10,000 simulations were performed. In addition, a multivariate analysis was performed to control for confounding variables (age, co-morbid disease, chemotherapy, and normal tissue volumes). Results: The area under the average small bowel DVH was significantly larger in Group B than Group A (p ⫽ 0.02). A comparison of the small bowel volume irradiated at various isodose levels is summarized in the attached table. There were no statistical differences in the areas of the average rectal DVHs, or in the absolute rectal and small bowel volumes amongst these groups. Dosimetric variables remained statistically significant after controlling for clinical factors on multivariate analysis. Conclusion: Our results demonstrate that the severity of acute GI toxicity is correlated with the volume of small bowel irradiated. As IMRT software requires the treatment planner to specify individual tissue DVHs, this analysis will aid in the design of future IM-WPRT plans that minimize the severity of acute GI toxicity.
222
I. J. Radiation Oncology
● Biology ● Physics
Volume 51, Number 3, Supplement 1, 2001
Percent Dose
Group A (% volume)
Group B (% volume)
p-value
25 50 75 90 100 105
99.2 88.0 57.5 42.1 31.0 17.7
99.1 90.1 66.4 52.5 42.0 27.0
0.82 0.31 0.04 0.03 0.02 0.04
1087
Measurement of Tumor Volume by PET to Evaluate Prognosis in Patients with Cervical Cancer
T.R. Miller, P.W. Grigsby Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO Purpose: Positron emission tomography using 18F-fluorodeoxyglucose (FDG-PET) is highly effective in patients with cervical cancer. The primary tumor is readily seen and lymph nodes and distant metastases are accurately identified. To extend the usefulness of FDG-PET in evaluating prognosis, the tumor volume was computed and correlated with recurrence and survival and compared to FIGO stage and lymph node status in patients undergoing treatment by radiation therapy and chemotherapy. Materials and Methods: Fifty-one patients with a new diagnosis of cervical cancer with FIGO stage Ib2 or greater underwent PET imaging 40 – 90 min after injection of 10 – 15 mCi (370 – 555 MBq) of 18F-FDG. The patients were then treated exclusively by irradiation and concurrent cisplatin-based chemotherapy. The radiation treatment consisted of six weeks of external beam irradiation with two intracavitary treatments. A technique was developed to measure the volume of the primary tumor three-dimensionally from the PET images. A simple thresholding algorithm was used to define the tumor margin at 40% of the peak activity within the tumor. Volume was then determined from the total number of voxels inside the tumor multiplied by the volume of a voxel. The edge detector was validated by correlation with CT scans in 13 patients. Kaplan-Meier survival analysis employing the Cox Proportional Hazards model was used to correlate the pre-treatment tumor volume with progression-free survival (PFS) and overall survival (OS). Tumor volume was also correlated with FIGO stage and the presence of lymph nodes on the PET study. Results: The patients varied in age from 24 to 87 yr (mean 49 yr) and were followed for 0.2 – 2.4 yr (mean 1.4 yr). Tumor volume ranged from 0 – 216 cm3 (mean 60 cm3). The left panel in the figure shows the Kaplan-Meier graph for PFS with patients separated by volume ⱕ 60 cm3 (n⫽34) and volume ⬎ 60 cm3 (n⫽17). The difference in recurrence was significant (p⫽0.01). The graphs for OS with volume separation were similar and also statistically significant (p⫽0.004). FIGO stage was not predictive of PFS (p⫽0.11) or OS (p⫽0.07), and stage did not contribute significantly when included with volume in the Cox model. For patients with (n⫽32) and without (n⫽19) lymph node disease by PET, the volumes were 63 ⫾ 48 cm3and 56 ⫾ 52 cm3, respectively (p⫽n.s.). The Kaplan-Meier graph is shown in the right panel for a subset of patients (Group I, n⫽14) who had small tumor volumes (ⱕ 60 cm3) and no abnormal nodes compared to those with either larger volumes, lymph node involvement, or both (Group II, n⫽37). None of the Group I patients experienced recurrence or death over a follow-up period of 415 - 783 days, while 17 (46%) patients in Group II had recurrence or death, with 17 (recurrence) and 15 (death) in fewer than 415 days (p⬍0.01). Conclusion: This study in patients with cervical cancer treated by combined irradiation and chemotherapy shows that: 1) Tumor volume separates patients with a good prognosis from those with a much poorer prognosis; 2) A subset of patients with relatively small tumors and no lymph node disease have a markedly superior survival; 3) Tumor volume measured by PET does not correlate with FIGO stage or the presence of disease in lymph nodes. Thus, FDG-PET with measurement of tumor volume identifies patients with a poor prognosis who may require more aggressive initial treatment.
221
While BM suppression is not typically significant following WPRT alone, it is common in patients who receive chemotherapy. Recent data have demonstrated that intensity-modulated WPRT (IM-WPRT) significantly reduces the volume of small bowel, bladder and rectum receiving the prescription dose in gynecology patients. The purpose of this study is to evaluate IM-WPRT as a means to reduce the volume of pelvic BM irradiated. Materials and Methods: Ten women with cervical or endometrial cancer previously treated using IM-WPRT were selected for this analysis. Using the treatment planning computed tomography scan, the clinical target volume (CTV) was defined to encompass the gross tumor, parametrial tissues, uterus (if present) and the regional lymph nodes. The CTV was expanded by a 1 cm margin to form the planning target volume (PTV). The bladder, rectum, small bowel were delineated in each patient. BM in the iliac crests was also contoured since studies have shown that the majority of the pelvic BM is located in these sites. Two plans were created for each patient: a standard 4-field WPRT plan with apertures shaped to the PTV in each beam’s-eye view, and an IM-WPRT plan designed to conform dose to the PTV while minimizing the dose to the normal tissues including the BM. Dose volume histograms (DVHs) for the PTV, small bowel and BM were compared for each patient. Results: For each of the ten patients, IM-WPRT treatment plans demonstrated a significant reduction of the volume of the BM receiving greater than 30% of the prescription dose (13.5 Gy). The attached table shows the average volume of the BM in the iliac crests receiving the specified dose (or greater) for the 4-field WPRT and the BM-sparing IM-WPRT plans. On average, IM-WPRT resulted in a 50% reduction in the volume of BM irradiated to doses greater than 22.5 Gy (p ⬍ 0.001), and more than 60% reduction of the BM irradiated to doses greater than 31.5 Gy (p ⬍ 0.001). Furthermore, as expected, the BM-sparing IM-WPRT plans resulted in significant sparing of all other normal tissues that was comparable to the original IM-WPRT that did not specifically consider BM as a constraint. In all ten cases, the BM-sparing treatment plan did not result in any significant differences in the PTV and small bowel DVHs. Conclusion: IM-WPRT significantly reduces the volume of pelvic BM irradiated compared to conventional WPRT. In addition, BM-sparing IM-WPRT did not compromise the improvements previously seen in IM-WPRT treatment plans that did not consider BM. Currently patients are being treated with this BM-sparing technique to determine if the dosimetric improvements seen here translate into clinical benefits.
Dose Gy (%)
WPRT (% BM Volume)
BM-Sparing IM-WPRT (% BM volume)
p-value
9.0 (20%) 13.5 (30%) 22.5 (50%) 31.5 (70%) 40.5 (90%) 45.0 (100%)
95.8% 92.3% 87.0% 52.8% 42.5% 33.0%
98.5% 90.4% 43.7% 25.9% 12.1% 4.5%
⬍ 0.001 0.35 ⬍ 0.001 ⬍ 0.001 ⬍ 0.001 ⬍ 0.001
1086
Dose-Volume Histogram Analysis of Acute Gastrointestinal Toxicity for Gynecologic Patients Receiving Intensity-Modulated Whole Pelvic Radiotherapy
J.C. Roeske, A.E. Lujan, U. Krishnamachari, A.J. Mundt Radiation and Cellular Oncology, The University of Chicago, Chicago, IL Purpose: Gastrointestinal (GI) sequelae are among the most common side effects in gynecologic patients receiving whole pelvic radiotherapy (WPRT). Recently, it has been reported that intensity-modulated whole pelvic radiotherapy (IMWPRT) reduces the volume of the small bowel and rectum irradiated in these women. However, since introducing IM-WPRT in our clinic, we have noted a broad range of acute GI toxicities. To better understand and minimize these sequelae, the goal of this study is to correlate acute GI toxicity with features of the small bowel and rectal dose-volume histograms (DVHs). Materials and Methods: Thirty-two patients treated with IM-WPRT were evaluated, all of who received a prescribed dose of 45 Gy. Patients were divided into 2 groups based on the severity of acute GI toxicity: Group A (22 patients) had no or only mild symptoms requiring infrequent anti-diarrheal medications and Group B (10 patients) had moderate to significant symptoms requiring frequent medications. DVHs of the small bowel and rectum were averaged within each group. Using a Monte Carlo simulation code, a permutation analysis was performed to assess the statistical difference in DVH areas. This simulation involved randomly re-assigning individual DVHs to Group A or Group B with the constraint that the total number within each group remain the same (22 and 10 patients, respectively). The average DVHs for the random samplings within each group were computed and the difference in area between the average DVHs was compared to the actual observed value. A p-value was calculated as the frequency in which this difference exceeded the observed clinical outcome. A total of 10,000 simulations were performed. In addition, a multivariate analysis was performed to control for confounding variables (age, co-morbid disease, chemotherapy, and normal tissue volumes). Results: The area under the average small bowel DVH was significantly larger in Group B than Group A (p ⫽ 0.02). A comparison of the small bowel volume irradiated at various isodose levels is summarized in the attached table. There were no statistical differences in the areas of the average rectal DVHs, or in the absolute rectal and small bowel volumes amongst these groups. Dosimetric variables remained statistically significant after controlling for clinical factors on multivariate analysis. Conclusion: Our results demonstrate that the severity of acute GI toxicity is correlated with the volume of small bowel irradiated. As IMRT software requires the treatment planner to specify individual tissue DVHs, this analysis will aid in the design of future IM-WPRT plans that minimize the severity of acute GI toxicity.
222
I. J. Radiation Oncology
● Biology ● Physics
Volume 51, Number 3, Supplement 1, 2001
Percent Dose
Group A (% volume)
Group B (% volume)
p-value
25 50 75 90 100 105
99.2 88.0 57.5 42.1 31.0 17.7
99.1 90.1 66.4 52.5 42.0 27.0
0.82 0.31 0.04 0.03 0.02 0.04
1087
Measurement of Tumor Volume by PET to Evaluate Prognosis in Patients with Cervical Cancer
T.R. Miller, P.W. Grigsby Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO Purpose: Positron emission tomography using 18F-fluorodeoxyglucose (FDG-PET) is highly effective in patients with cervical cancer. The primary tumor is readily seen and lymph nodes and distant metastases are accurately identified. To extend the usefulness of FDG-PET in evaluating prognosis, the tumor volume was computed and correlated with recurrence and survival and compared to FIGO stage and lymph node status in patients undergoing treatment by radiation therapy and chemotherapy. Materials and Methods: Fifty-one patients with a new diagnosis of cervical cancer with FIGO stage Ib2 or greater underwent PET imaging 40 – 90 min after injection of 10 – 15 mCi (370 – 555 MBq) of 18F-FDG. The patients were then treated exclusively by irradiation and concurrent cisplatin-based chemotherapy. The radiation treatment consisted of six weeks of external beam irradiation with two intracavitary treatments. A technique was developed to measure the volume of the primary tumor three-dimensionally from the PET images. A simple thresholding algorithm was used to define the tumor margin at 40% of the peak activity within the tumor. Volume was then determined from the total number of voxels inside the tumor multiplied by the volume of a voxel. The edge detector was validated by correlation with CT scans in 13 patients. Kaplan-Meier survival analysis employing the Cox Proportional Hazards model was used to correlate the pre-treatment tumor volume with progression-free survival (PFS) and overall survival (OS). Tumor volume was also correlated with FIGO stage and the presence of lymph nodes on the PET study. Results: The patients varied in age from 24 to 87 yr (mean 49 yr) and were followed for 0.2 – 2.4 yr (mean 1.4 yr). Tumor volume ranged from 0 – 216 cm3 (mean 60 cm3). The left panel in the figure shows the Kaplan-Meier graph for PFS with patients separated by volume ⱕ 60 cm3 (n⫽34) and volume ⬎ 60 cm3 (n⫽17). The difference in recurrence was significant (p⫽0.01). The graphs for OS with volume separation were similar and also statistically significant (p⫽0.004). FIGO stage was not predictive of PFS (p⫽0.11) or OS (p⫽0.07), and stage did not contribute significantly when included with volume in the Cox model. For patients with (n⫽32) and without (n⫽19) lymph node disease by PET, the volumes were 63 ⫾ 48 cm3and 56 ⫾ 52 cm3, respectively (p⫽n.s.). The Kaplan-Meier graph is shown in the right panel for a subset of patients (Group I, n⫽14) who had small tumor volumes (ⱕ 60 cm3) and no abnormal nodes compared to those with either larger volumes, lymph node involvement, or both (Group II, n⫽37). None of the Group I patients experienced recurrence or death over a follow-up period of 415 - 783 days, while 17 (46%) patients in Group II had recurrence or death, with 17 (recurrence) and 15 (death) in fewer than 415 days (p⬍0.01). Conclusion: This study in patients with cervical cancer treated by combined irradiation and chemotherapy shows that: 1) Tumor volume separates patients with a good prognosis from those with a much poorer prognosis; 2) A subset of patients with relatively small tumors and no lymph node disease have a markedly superior survival; 3) Tumor volume measured by PET does not correlate with FIGO stage or the presence of disease in lymph nodes. Thus, FDG-PET with measurement of tumor volume identifies patients with a poor prognosis who may require more aggressive initial treatment.