Practical Radiation Oncology (2014) 4, 198–206
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Original Report
Lumbosacral spine and marrow cavity modeling of acute hematologic toxicity in patients treated with intensity modulated radiation therapy for squamous cell carcinoma of the anal canal Jason Chia-Hsien Cheng MD, PhD a, b , Jose G. Bazan MD, MS a , Jian-Kuen Wu MS b, c , Albert C. Koong MD, PhD a , Daniel T. Chang MD a,⁎ a
Department of Radiation Oncology, Stanford University, Stanford, California Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan c Institute of Electro-Optical Science and Technology, National Taiwan Normal University, Taipei, Taiwan b
Received 10 June 2013; revised 8 July 2013; accepted 16 July 2013
Abstract Purpose: To identify various dosimetric parameters of bone marrow cavity that correlate with acute hematologic toxicity (HT) in patients with anal squamous cell carcinoma treated with definitive chemoradiation therapy (CRT). Methods and materials: We analyzed 32 patients receiving CRT. The whole pelvic bone marrow (PBM) and the lumbosacral spine (LSS) subregion were contoured for each patient. Marrow cavities were contoured using the Hounsfield units (HUs) of 100, 150, 200, and 250 as maximum density threshold levels. The volume of each region receiving at least 5, 10, 15, 20, 30, and 40 Gy was calculated. The endpoint was grade ≥ 3 HT (HT3 +). Normal-tissue complication probability (NTCP) was evaluated with the Lyman-Kutcher-Burman (LKB) model. Maximal likelihood estimate was used to compare the parameter set. Logistic regression was used to test associations between HT and both dosimetric and clinical parameters. Results: Ten patients (31%) experienced HT3 +. While dose to both LSS and PBM significantly predicted for HT3 +, LSS was superior to PBM by logistic regression and LKB modeling. Constrained optimization of the LKB model for HT3 + yielded the parameters m = 0.21, n = 1, and TD50 = 32 Gy for LSS. The NTCP fits were better with the whole bone than with marrow cavity using any HU threshold. Mean LSS doses of 21 Gy and 23.5 Gy result in a 5% and 10% risk of HT3 +, respectively. Mean dose and low-dose radiation parameters (V5, V10, V15, V20) of whole bone or bone cavities of LSS were correlated most significantly with HT3 +. Conclusions: For predicting the risk of HT3 +, whole-bone contours were superior to marrow cavity and LSS was superior to PBM by LKB modeling. The results confirm PBM and LSS as parallel organs when predicting hematologic toxicity. Recommended dose constraints to the LSS are V10 ≤80%. An LSS mean dose of 23.5 Gy is associated with a 10% risk of HT. © 2014 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
Conflicts of interest: None. ⁎ Corresponding author. Department of Radiation Oncology, Stanford University Medical Center, 875 Blake Wilbur Dr, Stanford, CA 94305-5847. E-mail address: [email protected] (D.T. Chang). 1879-8500/$ – see front matter © 2014 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.prro.2013.07.011
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Introduction To preserve organ function, the standard of care for squamous cell carcinoma of the anal canal is concurrent chemoradiation therapy (CRT). 1 Two randomized trials demonstrated the superiority of CRT with 5-fluorouracil (5FU) and mitomycin C (MMC) over radiation therapy (RT) alone. 2,3 The Radiation Therapy Oncology Group 87-04 indicated that MMC was a necessary component of CRT. 4 Myelosuppression is a major common side effect of CRT that could lead to treatment interruptions. Intensity modulated radiation therapy (IMRT) has been used for anal cancer with improved treatment tolerability while preserving high rates of local control. 5 Although IMRT has been shown to reduce treatment breaks, acute skin toxicity, and acute gastrointestinal toxicity, a significant problem that remains is hematologic toxicity (HT). Mell et al 6 demonstrated a correlation between several pelvic bone marrow (PBM) dosimetric parameters with blood count nadirs, but not with grade ≥ 3 toxicity in patients with anal cancer. Data from cervix cancer suggest that lowdose radiation parameters are correlated with grade ≥ 2 HT. 7-9 We previously reported our results using normaltissue complication probability (NTCP) modeling and showed a significant association of PBM dose with HT. 10 Lumbosacral spine (LSS), a sub-site of PBM, contains a substantial amount of BM that can receive significant dose from current RT techniques for cervical or anal cancer due to its close proximity to the primary tumor and pelvic lymphatics. Our previous work showed that the dosimetric impact of LSS along with PBM was important in predicting HT. 10 Efforts have been made to reduce the dose of these structures through BM-sparing IMRT, 11 but the specific impact of LSS versus PBM has not been addressed. The whole bone is comprised of higher density cortical bone and lower-density trabecular bone, the latter of which contains the active marrow cavity. Thus, it would follow that the marrow cavity would correspond to the lower Hounsfield unit (HU) portions of the bone on computed tomography (CT). While our previous work showed that the PBM defined using the whole bone correlated with the risk of HT, the dose to the marrow cavity specifically may better predict this risk. This study aims to compare Lyman-Kutcher-Burman (LKB) NTCP modeling between PBM and LSS for acute HT, and to evaluate the usefulness of HU-based marrow cavity as a surrogate of bone marrow correlated with HT in patients treated with CRT for anal cancer.
Methods and materials Under an institutional review board-approved protocol, we conducted a retrospective review of the medical rec-
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ords of patients with squamous cell carcinoma of the anal canal treated with definitive CRT with IMRT at Stanford University between January 2003 and December 2010. Of 38 patients identified, 1 was excluded because we were unable to retrieve the treatment planning CT scan. Another 4 were excluded from the primary analysis because they were positive for the human immunodeficiency virus. Incomplete imaging data were found in 1 patient. The remaining 32 patients formed the study cohort.
Radiation therapy All patients received IMRT. Our methods for patient simulation and target volume delineation have been described previously. 5 Median radiation doses to the primary tumor and nodal regions are summarized in Table 1. While our practice has evolved over time, we currently treat the low-risk (common iliac, proximal internal iliac superior to the inferior aspect of the sacroiliac joint, presacral, external iliac, and uninvolved inguinal nodes) planning target volume to 40 Gy at 1.6 Gy per fraction, the intermediate-risk planning target volume (internal iliac inferior to the inferior aspect of the sacroiliac joint, involved inguinal, and perirectal nodes) to 45 Gy at 1.8 Gy per fraction, and the high-risk planning target volume (primary tumor and gross nodal disease) to 45 Gy with a sequential boost of 5.4 Gy for T1-2 tumors and 9 Gy to 14.4 Gy for T3-T4 tumors or node-positive patients.
Table 1
Patients’ characteristics (n = 32)
Characteristic
No.
Females/males (No.) Body mass index, median (range) Age, median (range) T stage, n (%) T1 T2 T3 T4 N stage, n (%) N0 N1 N2 N3 Tumor size, median (range) Chemotherapy (no.) MMC/5-FU Cisplatin-based 5-FU alone Radiation dose, median (range) Primary tumor Upper pelvic nodes Lower pelvic nodes Inguinal nodes
18/14 24.9 (17.3-45.6) kg/m 2 61 (45-88) y
5-FU, 5-fluorouracil; MMC, mitomycin.
3 (9%) 19 (60%) 7 (22%) 3 (9%) 25 (78%) 1 (3%) 4 (13%) 2 (6%) 4 cm (0.6-6 cm) 27 4 1 54 40 45 45
Gy (45-59.4) Gy (0-45) Gy (45-45) Gy (40-45)
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Chemotherapy All 32 patients received 5-FU-based chemotherapy (Table 1); 19 received capecitabine (825 mg/m 2) and 13 received infusional 5-FU (either 1000 mg/m 2 on days 1-4 and days 29-32 or 200-225 mg/m 2 intravenously daily during RT). Twenty-seven patients received MMC (10 mg/m 2 ) on day 1 and day 29 with 5-FU, 4 patients received concurrent platinum (3 patients cisplatin, 1 patient carboplatin), and 1 patient received capecitabine alone.
Bone marrow and cavity delineation For each patient, the external contour of all bones (whole bone) within the pelvis as well as the L5 vertebral body and the femoral heads down to the inferior extent of the lesser trochanter was used as a surrogate for PBM, and the PBM was further divided into 3 sub-sites, as described by Mell et al 8; ilium, lower pelvis, and LSS. To contour the marrow cavity in the PBM or LSS, the HUs of 100, 150, 200, and 250 were used as the thresholds by auto-segmented function to outline the low-density region of the bone. The dose-volume histogram (DVH) were then generated for each of these marrow cavity subregions as well as for the whole bone. The following parameters were recorded for each structure: mean dose and the volume of each region receiving at least 5, 10, 15, 20, 30, and 40 Gy (V5, V10, V15, V20, V30, V40, respectively).
Hematologic toxicity Hematologic toxicity was graded according to the Common Terminology Criteria for Adverse Events, version 3.0. 12 The highest-grade toxicity for white blood count, absolute neutrophil count, hemoglobin, and platelets were recorded, with HT of grade ≥3 noted as an event (HT3+).
Normal-tissue complication probability modeling We previously showed that the LKB model can be simplified to represent NTCP as a function of equivalent uniform dose using an exponential of a second-degree polynomial instead of the integral used in the Lyman formula. 13 The equivalent uniform dose reduces the DVH to a single value that for normal tissues represents the uniform dose that results in the same NTCP. The Lyman NTCP model was used as below: NTCP ¼ 1=b2π∫t−∞ exp −t 2 =2 dt t ¼ ðD‐TD50 ðvÞÞ=ðm TD50 ðvÞÞ V ¼ V=Vref where TD50(v) is the 50% tolerance dose for uniform irradiation of the partial volume v. The partial- and whole-
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organ radiation-tolerance doses are related by a powerlaw relationship: TDð1Þ ¼ TDðvÞ Vn ; where Vref is the volume of PBM or LSS. The parameter “n” is the volume-effect parameter, while the parameter “m” is the steepness of the dose-complication curve for a fixed partial volume. For uniform partial-organ irradiation, the effective volume method was used to provide estimates of equivalent dose and volume pairs from the DVHs summarizing the nonuniform irradiation. For the purposes of this study, as is the general practice for a protocol using conventional fractionation (ie, 1.8-2 Gy), no dose-per-fraction DVH modification was introduced. Thus, the DVH was not modified in accordance with a model of biologic effectiveness per fraction size (ie, α/β model). A set of calculations for m, n, and TD50 were performed, using the maximum likelihood estimation to compare the NTCP fitting between parameter sets and to determine the optimum m, n, and TD50 for best fitting of calculated NTCP to the clinical data with n constrained to lie between the limits, 0 b n ≤ 1.
Statistical analysis Age, body mass index (BMI), and dosimetric parameters were coded as continuous variables. Categorical variables included gender and dosimetric parameters (dichotomized by the median value). Univariate logistic regression was used to test the correlation between clinical and dosimetric parameters with HT3+. Multivariate logistic regression models controlling for age, gender, and BMI were then used to examine the effect of significant dosimetric parameters on HT3+. Given the small number of events for grade ≥3 hematologic toxicity, each dosimetric variable was combined with all clinical variables (4-variable model).
Results Baseline patient characteristics are shown in Table 1.
Dosimetric parameters for bony structures Table 2 summarizes the dosimetric parameters of PBM and LSS as well as the marrow cavities using the maximum-threshold HUs of 100, 150, 200, and 250. The median mean doses of the whole-bone PBM and LSS were 28.36 Gy and 28.14 Gy, respectively.
Hematologic toxicity The median nadirs in white blood count, absolute neutrophil count, hemoglobin and platelets were 2.6 k/μL (range, 0.8-7.1), 1.6 k/μL (range, 0.4-4.4), 10.7 g/dL (range,
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Table 2 Descriptive statistics of dosimetric parameters of bony structures Parameter Pelvic bone marrow (PBM) Volume (mL) Mean dose (cGy) V5 (%) V10 (%) V15 (%) V20 (%) V30 (%) V40 (%) PBM100 Volume (mL) Mean dose (cGy) V5 (%) V10 (%) V15 (%) V20 (%) V30 (%) V40 (%) PBM150 Volume (mL) Mean dose (cGy) V5 (%) V10 (%) V15 (%) V20 (%) V30 (%) V40 (%) PBM200 Volume (mL) Mean dose (cGy) V5 (%) V10 (%) V15 (%) V20 (%) V30 (%) V40 (%) PBM250 Volume (mL) Mean dose (cGy) V5 (%) V10 (%) V15 (%) V20 (%) V30 (%) V40 (%) Lumbosacral spine (LSS) Volume (mL) Mean dose (cGy) V5 (%) V10 (%) V15 (%) V20 (%) V30 (%) V40 (%)
Median value (range) 1213 2836 94 89 83 76 50 20
(868-2113) (706-3489) (38-99) (25-97) (20-95) (15-90) (6-79) (1-37)
271 2885 96 91 85 77 50 22
(106-547) (686-3626) (39-100) (26-99) (19-97) (15-94) (4-84) (0-41)
434 2846 95 89 84 76 49 21
(214-759) (676-3585) (38-100) (25-98) (19-96) (14-92) (5-82) (0-40)
577 2854 95 89 84 76 50 20
(345-953) (671-3552) (37-100) (25-98) (19-95) (14-91) (5-81) (1-39)
707 2864 95 89 84 76 51 20
(168-1126) (664-3523) (37-100) (24-98) (18-95) (14-91) (5-80) (1-39)
310 2814 88 82 76 73 57 26
(200-519) (29-4031) (1-100) (1-100) (0-100) (0-100) (0-92) (0-67)
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Table 2 (continued) Parameter LSS100 Volume (mL) Mean dose (cGy) V5 (%) V10 (%) V15 (%) V20 (%) V30 (%) V40 (%) LSS150 Volume (mL) Mean dose (cGy) V5 (%) V10 (%) V15 (%) V20 (%) V30 (%) V40 (%) LSS200 Volume (mL) Mean dose (cGy) V5 (%) V10 (%) V15 (%) V20 (%) V30 (%) V40 (%) LSS250 Volume (mL) Mean dose (cGy) V5 (%) V10 (%) V15 (%) V20 (%) V30 (%) V40 (%)
Median value (range) 93 (51-182) 3176 (53-4047) 94 (3-100) 89 (2-100) 86 (1-100) 83 (1-100) 67 (1-95) 26 (0-68) 138 (85-237) 3082 (45-4069) 92 (2-100) 87 (1-100) 83 (1-100) 80 (1-100) 64 (0-94) 28 (0-67) 180 (116-294) 3050 (43-4069) 91 (2-100) 85 (1-100) 81 (1-100) 78 (1-100) 63 (0-93) 28 (0-67) 214 (140-351) 3002 (40-4062) 91 (2-100) 85 (1-100) 81 (1-100) 77 (1-100) 62 (0-93) 28 (0-67)
LSS100-250, lumbosacral spine with the Hounsfield unit of no more than 100-250; PBM100-250, pelvic bone marrow with the Hounsfield unit of no more than 100-250.
6.5-13.2), and 111 k/μL (range, 18-235), respectively. Overall, 10 patients (31%) experienced HT3+, all related to white blood count and absolute neutrophil count toxicity.
Chemotherapy delivery Nine patients (28%) required dose reductions in chemotherapy, and 4 were unable to complete all cycles: 2 patients had infusional 5-FU held and 2 patients had the second cycle of MMC held. Nine (28%) patients required support with filgrastim, blood transfusions, or erythropoietin.
LKB NTCP modeling Constrained optimization (0 b n ≤ 1, with unrestricted variation of m and TD50) of the LKB model for HT3+ yielded
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the value n = 1, confirming the expectation that, over this restricted range characteristic of LKB tissue modeling, both PBM and LSS act like parallel organs. The maximum likelihood estimation optimizations yielded the parameters of m = 0.20 and TD50 = 31 Gy for PBM, and m = 0.21 and TD50 = 32 Gy for LSS. With this model, mean PBM doses of 20.5 Gy and 23 Gy and mean LSS doses of 21 Gy and 23.5 Gy result in a 5% and 10% risk of HT3+, respectively. The plots of NTCP by equivalent uniform dose of PBM and LSS are shown in Fig 1.
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Using maximum likelihood estimation to compare the different bone and cavity contours in LKB modeling, LSS was superior to PBM with either whole-bone or any HUbased marrow-cavity contour. The NTCP fittings were better for the whole-bone contour than any of the HUbased marrow-cavity contours for both PBM and LSS from 100 HUs to 250 HUs (Table 3). In addition, the NTCP fitting improved for the marrow cavities as the HU threshold increased from 100 to 250.
Figure 1 Lyman-Kutcher-Burman (LKB) normal-tissue complication probability (NTCP) model for HT3 + by (A) whole bone of pelvic bone marrow (PBM) and (B) whole bone of lumbosacral spine (LSS). The red squares represent patients with grade ≥ 3 hematologic toxicity (HT3 +), while the black stars represent patients without HT3 +. EUD, equivalent uniform dose.
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Table 3 Maximal likelihood estimate (MLE) of normal tissue complication probability parameter sets by whole bone or bone cavities of pelvic bone marrow (PBM) and lumbosacral spine (LSS)
Table 4 Univariate logistic regression analysis of factors associated with the development of grade ≥ 3 hematologic toxicity
Bone contours
Age Female vs male BMI Chemotherapy (MMC vs non-MMC) PBM Mean dose V5 V10 V15 V20 V30 V40 PBM100 Mean dose V5 V10 V15 V20 V30 V40 PBM150 Mean dose V5 V10 V15 V20 V30 V40 PBM200 Mean dose V5 V10 V15 V20 V30 V40 PBM250 Mean dose V5 V10 V15 V20 V30 V40 LSS Mean dose V5 V10 V15 V20 V30 V40 LSS100 Mean dose
PBM Whole bone PBM250 PBM200 PBM150 PBM100 LSS Whole bone LSS250 LSS200 LSS150 LSS100
MLE − 17.6670 − 17.6973 − 17.7859 − 18.0245 − 18.1501 − 16.1568 − 16.3776 − 16.5019 − 16.5235 − 17.0537
LSS100-250, lumbosacral spine with the Hounsfield unit of no more than 100-250; PBM100-250, pelvic bone marrow with the Hounsfield unit of no more than 100-250.
Predictors of hematologic toxicity On univariate analysis, age, gender, chemotherapy agent (MMC vs non-MMC), and BMI were not significantly associated with HT3 +. For LSS, the mean dose, V5, V10, V15, and V20 of whole bone and all other marrow cavities outlined by 100 to 250 HUs were significantly associated with HT3 +. The rate of HT3 + for the LSS was 6% (1 out of 17 patients) for V10 b 82% vs 60% (9 out of 15 patients) for V10 ≥ 82% (P = .01). For PBM, only the mean dose and V10 were consistently associated with HT3 + for the whole-bone contour and all marrow cavity subregions defined by the 100 to 250 HU thresholds (Table 4). These data are summarized in Table 4. On multivariate analysis, the mean dose and V10 of the whole bone or marrow cavities using any HU threshold retained statistical significance in association with HT3 +. The V30 of both whole-bone PBM and LSS were borderline significant (Table 5).
Discussion To our knowledge, this is the second study to use marrow-cavity contours as a surrogate for bone marrow for LKB modeling to predict acute HT in patients with anal cancer receiving CRT. The LKB model applied to our conventionally fractionated treatments confirmed the expectation that both PBM and LSS act like parallel organs. In addition, we found superior fitting of the NTCP model with LSS compared with PBM in predicting HT3 +, and that the whole-bone contour was better than any marrow-cavity contour using CT HU-maximum thresholds of 100 to 250. Several of the low-dose dosimetric parameters of either PBM or LSS were associated with
Parameter
Odds ratio 1.046 1.615 0.893 0.632
P value .226 .556 .218 .648
19.29 3.37 7.00 3.37 19.29 7.00 7.00
.010 .136 .032 .136 .010 .032 .032
7.00 7.00 7.00 7.00 3.37 7.00 3.37
.032 .032 .032 .032 .136 .032 .136
7.00 7.00 7.00 3.37 7.00 3.37 3.37
.032 .032 .032 .136 .032 .136 .136
19.29 7.00 7.00 3.37 7.00 3.37 3.37
.010 .032 .032 .136 .032 .136 .136
19.29 3.37 7.00 3.37 7.00 3.37 3.37
.010 .136 .032 .136 .032 .136 .136
19.29 19.29 19.29 19.29 19.29 7.00 1.80
.010 .010 .010 .010 .010 .032 .448
3.37
.136
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Table 4 (continued) Parameter
Odds ratio
P value
V5 V10 V15 V20 V30 V40 LSS150 Mean dose V5 V10 V15 V20 V30 V40 LSS200 Mean dose V5 V10 V15 V20 V30 V40 LSS250 Mean dose V5 V10 V15 V20 V30 V40
19.29 19.29 3.37 7.00 7.00 1.00
.010 .010 .136 .032 .032 1.000
19.29 19.29 19.29 19.29 infinity 7.00 1.80
.010 .010 .010 .010 .998 .032 .448
19.29 7.00 19.29 19.29 19.29 7.00 1.80
.010 .032 .010 .010 .010 .032 .448
19.29 7.00 19.29 19.29 19.29 19.29 1.80
.010 .032 .010 .010 .010 .010 .448
BMI, body mass index; F, female; M, male; LSS100-250, lumbosacral spine with the Hounsfield unit of no more than 100-250; MMC, mitomycin; PBM100-250, pelvic bone marrow with the Hounsfield unit of no more than 100-250.
clinically significant HT. The results again support the practical guideline of keeping the mean PBM or LSS dose as low as possible to minimize the risk of HT. There have been several studies, including ours, investigating the dosimetric parameters of PBM that correlate with the risk of HT on various pelvic malignancies. Mell et al 8 found in cervical cancer patients that PBM-V10 was associated with grade ≥ 2 leukopenia or neutropenia. Rose et al 9 found that PBM-V10 ≥ 95% and PBM-V20 N 76% were associated with increased grade ≥ 3 leukopenia in a similar patient cohort. Albuquerque et al 7 studied 40 women who received CRT to treat cervical cancer and found PBM-V20 ≥ 80% with the increased odds of developing grade ≥ 2 HT. For patients with anal cancer, Mell et al 6 demonstrated a relationship between PBM-V5, -V10, -V15, and -V20 with white blood count and absolute neutrophil count nadirs, but not grade ≥ 3 HT. All previous studies have used the whole bone as a surrogate for bone marrow; however, we assumed that only the low-density trabecular portion of the bone contains active marrow and sought to determine whether the marrow
Table 5 Multivariate logistic regression analysis of factors associated with the development of grade ≥ 3 hematologic toxicity Parameter
Odds ratio
P value
Age Female vs male BMI PBM Mean dose V10 V20 V30 V40 PBM100 Mean dose V5 V10 V15 V30 PBM150 Mean dose V5 V10 V20 PBM200 Mean dose V5 V10 V20 PBM250 Mean dose V10 V20 LSS Mean dose V5 V10 V15 V20 V30 LSS100 V5 V10 V20 V30 LSS150 Mean dose V5 V10 V15 V30 LSS200 Mean dose V5 V10 V15 V20 V30 LSS250
1.012-1.125 0.506-1.023 0.002-1.606
.109-.824 .083-.661 .102-.920
18.61 9.27 31.80 5.70 7.02
.017 .038 .019 .071 .048
17.41 5.32 22.29 15.94 8.87
.025 .091 .041 .052 .034
14.42 5.28 9.27 9.68
.032 .086 .038 .045
46.72 5.4 9.27 8.25
.013 .086 .038 .049
46.72 9.27 8.25
.013 .038 .049
25.39 15.18 19.00 17.13 17.13 7.72
.012 .023 .016 .024 .024 .073
18.31 27.35 7.72 10.90
.021 .024 .051 .029
39.34 18.31 17.34 1994.05 10.90
.008 .021 .023 .037 .029
25.39 5.71 17.34 37.48 37.26 10.90
.012 .074 .023 .024 .024 .029
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Table 5 (continued) Parameter Mean dose V5 V10 V15 V20 V30
Odds ratio
P value
25.39 5.71 17.34 37.26 37.26 46.62
.012 .074 .023 .024 .024 .008
Note: Given the small number of events for grade ≥ 3 hematologic toxicity, each dosimetric variable was combined with all clinical variables (4-variable model). The resulting ranges of clinical variables in odds ratios and upper or lower bounds of the P values are presented. BMI, body mass index; F, female; LSS100-250, lumbosacral spine with the Hounsfield unit of no more than 100-250; M, male; PBM100-250, pelvic bone marrow with the Hounsfield unit of no more than 100-250.
cavity defined by the lower-density subregions of the bone would better correlate with the risk of HT over the whole bone. One Indian study 14 on 47 cervical cancer patients treated with CRT investigated the dosimetric correlations between whole-bone and free-hand marrow-cavity contours with HT. The V40 of free-hand whole-pelvis contour was the only significant factor associated with grade 2 leukopenia and neutropenia. Yet, their marrow cavity was defined freehand and not based on a more systematic and objective threshold using CT HUs. In contrast, because of a lack of published data on the proper HU threshold to use, our study defined the marrow cavity testing various maximum HU thresholds of 100, 150, 200, and 250. While we were able to identify 1 Norwegian study that proposed an HU threshold of 600 to define the corticocancellous interface in cadaver femurs, 15 we found that this threshold produced marrow-cavity contours that were nearly identical to the whole bone. We therefore chose lower CT HU thresholds. We found a significant correlation with HT of whole-bone PBM (V15 and V20) and LSS (V5, V10, V15, and V20) and marrow cavities by 100 to 250 HUs; however, our data failed to show that any HU-based marrow cavity was better than the entire bone in predicting HT3 +, either by NTCP fitting or by logistic regression. We also found that the correlation with the risk of HT3+ successively improved with a higher HU maximum threshold. Magnetic resonance imaging (MRI) studies have suggested that the red marrow, which harbors the cells of hematopoiesis, does not necessarily localize to areas of low CT density. 16 Also, the low-density regions of bone may not all correspond to active bone marrow, and it is likely that nuclear imaging studies such as positron emission tomography (PET) may better define the active marrow. 17 Therefore, marrow-cavity contouring based on CT HU thresholds may not adequately define the active marrow. Few studies have found a relationship between radiation to specific sub-sites of PBM and the risk of HT. One study
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using nuclear medicine imaging showed that most active pelvic bone marrow resided in the LSS. 18 We previously reported a strong correlation of LSS with HT. 5 In addition, the current study found that all marrow cavity subregions of the LSS had a stronger correlation to HT compared with the PBM subregions. These data can have important implications in radiation therapy treatment planning for anal cancer. Because the larger PBM volume encircles the pelvic lymph node regions that are included in the target volume, strict dose constraints for the PBM will either necessarily reduce coverage of the target volume or likely cause increased heterogeneity and hotspots within the target volume or critical structures. We therefore propose that using LSS alone rather than PBM as a critical structure for IMRT planning is sufficient and preferred. This method should, however, be tested in a prospective study. Our study has several limitations. First, the data were generated from a single-institution retrospective review of a relatively small cohort with some heterogeneity in treatment. Our findings need to be validated in a larger, prospectively collected group of data. In addition, all patients were treated with IMRT, and the results may not be applicable to patients being treated with conventional radiation therapy techniques. Finally, we contoured the marrow cavities by CT-based HUs rather than other imaging tools (ie, PET, MRI) to delineate active marrow. This decision was made to determine a simple and practical method to define the active marrow that would be readily available to radiation therapy practices, as other imaging modalities such as PET and MRI may not be routinely used for treatment planning. However, given our inability to find a CT-based method to define the active marrow, we are currently exploring the use of PET for these purposes. One prospective trial is using both MRI and PET to define active marrow in IMRT planning for pelvic malignancies in an effort to spare BM. 19 In conclusion, LSS was superior to PBM, and whole bone was superior to marrow cavity, in predicting the risk of HT. Mean- and low-dose parameters V10-15 were associated with HT3 +. Mean LSS doses of 21 Gy and 23.5 Gy were associated with a 5% and 10% risk of HT3 +, respectively. These data can be used to reduce the risk of HT. Until further methods of defining active marrow are validated, we propose using the whole-bone LSS to represent the bone marrow, and we suggest limiting the V10 ≤ 80%, if feasible, while minimizing the mean dose to reduce the risk of serious HT.
References 1. Nigro ND, Vaitkevicius VK, Considine Jr B. Combined therapy for cancer of the anal canal: a preliminary report. Dis Colon Rectum. 1974;17:354-356. 2. Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. UKCCCR Anal Cancer Trial Working Party. UK Co-ordinating Committee on Cancer Research. Lancet. 1996;348:1049-1054.
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3. Bartelink H, Roelofsen F, Eschwege F, et al. Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups. J Clin Oncol. 1997;15:2040-2049. 4. Flam M, John M, Pajak TF, et al. Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study. J Clin Oncol. 1996;14:2527-2539. 5. Bazan JG, Hara W, Hsu A, et al. Intensity-modulated radiation therapy versus conventional radiation therapy for squamous cell carcinoma of the anal canal. Cancer. 2011;117:3342-3351. 6. Mell LK, Schomas DA, Salama JK, et al. Association between bone marrow dosimetric parameters and acute hematologic toxicity in anal cancer patients treated with concurrent chemotherapy and intensitymodulated radiotherapy. Int J Radiat Oncol Biol Phys. 2008;70: 1431-1437. 7. Albuquerque K, Giangreco D, Morrison C, et al. Radiationrelated predictors of hematologic toxicity after concurrent chemoradiation for cervical cancer and implications for bone marrow-sparing pelvic IMRT. Int J Radiat Oncol Biol Phys. 2011;79:1043-1047. 8. Mell LK, Kochanski JD, Roeske JC, et al. Dosimetric predictors of acute hematologic toxicity in cervical cancer patients treated with concurrent cisplatin and intensity-modulated pelvic radiotherapy. Int J Radiat Oncol Biol Phys. 2006;66:1356-1365. 9. Rose BS, Aydogan B, Liang Y, et al. Normal tissue complication probability modeling of acute hematologic toxicity in cervical cancer patients treated with chemoradiotherapy. Int J Radiat Oncol Biol Phys. 2011;79:800-807. 10. Bazan JG, Luxton G, Mok EC, et al. Normal tissue complication probability modeling of acute hematologic toxicity in patients treated with intensity-modulated radiation therapy for squamous cell
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carcinoma of the anal canal. Int J Radiat Oncol Biol Phys. 2012;84:700-706. Mell LK, Tiryaki H, Ahn KH, Mundt AJ, Roeske JC, Aydogan B. Dosimetric comparison of bone marrow-sparing intensity-modulated radiotherapy versus conventional techniques for treatment of cervical cancer. Int J Radiat Oncol Biol Phys. 2008;71:1504-1510. Trotti A, Colevas AD, Setser A, et al. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol. 2003;13:176-181. Luxton G, Keall PJ, King CR. A new formula for normal tissue complication probability (NTCP) as a function of equivalent uniform dose (EUD). Phys Med Biol. 2008;53:23-36. Mahantshetty U, Krishnatry R, Chaudhari S, et al. Comparison of 2 contouring methods of bone marrow on CT and correlation with hematological toxicities in non-bone marrow-sparing pelvic intensity-modulated radiotherapy with concurrent cisplatin for cervical cancer. Int J Gynecol Cancer. 2012;22:1427-1434. Aamodt A, Kvistad KA, Andersen E, et al. Determination of Hounsfield value for CT-based design of custom femoral stems. J Bone Joint Surg Br. 1999;81:143-147. Vande Berg BC, Malghem J, Lecouvet FE, Maldague B. Magnetic resonance imaging of normal bone marrow. Eur Radiol. 1998;8: 1327-1334. Murata Y, Kubota K, Yukihiro M, Ito K, Watanabe H, Shibuya H. Correlations between 18F-FDG uptake by bone marrow and hematological parameters: measurements by PET/CT. Nucl Med Biol. 2006;33:999-1004. Roeske JC, Lujan A, Reba RC, Penney BC, Diane Yamada S, Mundt AJ. Incorporation of SPECT bone marrow imaging into intensity modulated whole-pelvic radiation therapy treatment planning for gynecologic malignancies. Radiother Oncol. 2005;77:11-17. Liang Y, Bydder M, Yashar CM, et al. Prospective study of functional bone marrow-sparing intensity modulated radiation therapy with concurrent chemotherapy for pelvic malignancies. Int J Radiat Oncol Biol Phys. 2013;85:406-414.
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Original Report
Lumbosacral spine and marrow cavity modeling of acute hematologic toxicity in patients treated with intensity modulated radiation therapy for squamous cell carcinoma of the anal canal Jason Chia-Hsien Cheng MD, PhD a, b , Jose G. Bazan MD, MS a , Jian-Kuen Wu MS b, c , Albert C. Koong MD, PhD a , Daniel T. Chang MD a,⁎ a
Department of Radiation Oncology, Stanford University, Stanford, California Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan c Institute of Electro-Optical Science and Technology, National Taiwan Normal University, Taipei, Taiwan b
Received 10 June 2013; revised 8 July 2013; accepted 16 July 2013
Abstract Purpose: To identify various dosimetric parameters of bone marrow cavity that correlate with acute hematologic toxicity (HT) in patients with anal squamous cell carcinoma treated with definitive chemoradiation therapy (CRT). Methods and materials: We analyzed 32 patients receiving CRT. The whole pelvic bone marrow (PBM) and the lumbosacral spine (LSS) subregion were contoured for each patient. Marrow cavities were contoured using the Hounsfield units (HUs) of 100, 150, 200, and 250 as maximum density threshold levels. The volume of each region receiving at least 5, 10, 15, 20, 30, and 40 Gy was calculated. The endpoint was grade ≥ 3 HT (HT3 +). Normal-tissue complication probability (NTCP) was evaluated with the Lyman-Kutcher-Burman (LKB) model. Maximal likelihood estimate was used to compare the parameter set. Logistic regression was used to test associations between HT and both dosimetric and clinical parameters. Results: Ten patients (31%) experienced HT3 +. While dose to both LSS and PBM significantly predicted for HT3 +, LSS was superior to PBM by logistic regression and LKB modeling. Constrained optimization of the LKB model for HT3 + yielded the parameters m = 0.21, n = 1, and TD50 = 32 Gy for LSS. The NTCP fits were better with the whole bone than with marrow cavity using any HU threshold. Mean LSS doses of 21 Gy and 23.5 Gy result in a 5% and 10% risk of HT3 +, respectively. Mean dose and low-dose radiation parameters (V5, V10, V15, V20) of whole bone or bone cavities of LSS were correlated most significantly with HT3 +. Conclusions: For predicting the risk of HT3 +, whole-bone contours were superior to marrow cavity and LSS was superior to PBM by LKB modeling. The results confirm PBM and LSS as parallel organs when predicting hematologic toxicity. Recommended dose constraints to the LSS are V10 ≤80%. An LSS mean dose of 23.5 Gy is associated with a 10% risk of HT. © 2014 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
Conflicts of interest: None. ⁎ Corresponding author. Department of Radiation Oncology, Stanford University Medical Center, 875 Blake Wilbur Dr, Stanford, CA 94305-5847. E-mail address: [email protected] (D.T. Chang). 1879-8500/$ – see front matter © 2014 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.prro.2013.07.011
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Introduction To preserve organ function, the standard of care for squamous cell carcinoma of the anal canal is concurrent chemoradiation therapy (CRT). 1 Two randomized trials demonstrated the superiority of CRT with 5-fluorouracil (5FU) and mitomycin C (MMC) over radiation therapy (RT) alone. 2,3 The Radiation Therapy Oncology Group 87-04 indicated that MMC was a necessary component of CRT. 4 Myelosuppression is a major common side effect of CRT that could lead to treatment interruptions. Intensity modulated radiation therapy (IMRT) has been used for anal cancer with improved treatment tolerability while preserving high rates of local control. 5 Although IMRT has been shown to reduce treatment breaks, acute skin toxicity, and acute gastrointestinal toxicity, a significant problem that remains is hematologic toxicity (HT). Mell et al 6 demonstrated a correlation between several pelvic bone marrow (PBM) dosimetric parameters with blood count nadirs, but not with grade ≥ 3 toxicity in patients with anal cancer. Data from cervix cancer suggest that lowdose radiation parameters are correlated with grade ≥ 2 HT. 7-9 We previously reported our results using normaltissue complication probability (NTCP) modeling and showed a significant association of PBM dose with HT. 10 Lumbosacral spine (LSS), a sub-site of PBM, contains a substantial amount of BM that can receive significant dose from current RT techniques for cervical or anal cancer due to its close proximity to the primary tumor and pelvic lymphatics. Our previous work showed that the dosimetric impact of LSS along with PBM was important in predicting HT. 10 Efforts have been made to reduce the dose of these structures through BM-sparing IMRT, 11 but the specific impact of LSS versus PBM has not been addressed. The whole bone is comprised of higher density cortical bone and lower-density trabecular bone, the latter of which contains the active marrow cavity. Thus, it would follow that the marrow cavity would correspond to the lower Hounsfield unit (HU) portions of the bone on computed tomography (CT). While our previous work showed that the PBM defined using the whole bone correlated with the risk of HT, the dose to the marrow cavity specifically may better predict this risk. This study aims to compare Lyman-Kutcher-Burman (LKB) NTCP modeling between PBM and LSS for acute HT, and to evaluate the usefulness of HU-based marrow cavity as a surrogate of bone marrow correlated with HT in patients treated with CRT for anal cancer.
Methods and materials Under an institutional review board-approved protocol, we conducted a retrospective review of the medical rec-
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ords of patients with squamous cell carcinoma of the anal canal treated with definitive CRT with IMRT at Stanford University between January 2003 and December 2010. Of 38 patients identified, 1 was excluded because we were unable to retrieve the treatment planning CT scan. Another 4 were excluded from the primary analysis because they were positive for the human immunodeficiency virus. Incomplete imaging data were found in 1 patient. The remaining 32 patients formed the study cohort.
Radiation therapy All patients received IMRT. Our methods for patient simulation and target volume delineation have been described previously. 5 Median radiation doses to the primary tumor and nodal regions are summarized in Table 1. While our practice has evolved over time, we currently treat the low-risk (common iliac, proximal internal iliac superior to the inferior aspect of the sacroiliac joint, presacral, external iliac, and uninvolved inguinal nodes) planning target volume to 40 Gy at 1.6 Gy per fraction, the intermediate-risk planning target volume (internal iliac inferior to the inferior aspect of the sacroiliac joint, involved inguinal, and perirectal nodes) to 45 Gy at 1.8 Gy per fraction, and the high-risk planning target volume (primary tumor and gross nodal disease) to 45 Gy with a sequential boost of 5.4 Gy for T1-2 tumors and 9 Gy to 14.4 Gy for T3-T4 tumors or node-positive patients.
Table 1
Patients’ characteristics (n = 32)
Characteristic
No.
Females/males (No.) Body mass index, median (range) Age, median (range) T stage, n (%) T1 T2 T3 T4 N stage, n (%) N0 N1 N2 N3 Tumor size, median (range) Chemotherapy (no.) MMC/5-FU Cisplatin-based 5-FU alone Radiation dose, median (range) Primary tumor Upper pelvic nodes Lower pelvic nodes Inguinal nodes
18/14 24.9 (17.3-45.6) kg/m 2 61 (45-88) y
5-FU, 5-fluorouracil; MMC, mitomycin.
3 (9%) 19 (60%) 7 (22%) 3 (9%) 25 (78%) 1 (3%) 4 (13%) 2 (6%) 4 cm (0.6-6 cm) 27 4 1 54 40 45 45
Gy (45-59.4) Gy (0-45) Gy (45-45) Gy (40-45)
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Chemotherapy All 32 patients received 5-FU-based chemotherapy (Table 1); 19 received capecitabine (825 mg/m 2) and 13 received infusional 5-FU (either 1000 mg/m 2 on days 1-4 and days 29-32 or 200-225 mg/m 2 intravenously daily during RT). Twenty-seven patients received MMC (10 mg/m 2 ) on day 1 and day 29 with 5-FU, 4 patients received concurrent platinum (3 patients cisplatin, 1 patient carboplatin), and 1 patient received capecitabine alone.
Bone marrow and cavity delineation For each patient, the external contour of all bones (whole bone) within the pelvis as well as the L5 vertebral body and the femoral heads down to the inferior extent of the lesser trochanter was used as a surrogate for PBM, and the PBM was further divided into 3 sub-sites, as described by Mell et al 8; ilium, lower pelvis, and LSS. To contour the marrow cavity in the PBM or LSS, the HUs of 100, 150, 200, and 250 were used as the thresholds by auto-segmented function to outline the low-density region of the bone. The dose-volume histogram (DVH) were then generated for each of these marrow cavity subregions as well as for the whole bone. The following parameters were recorded for each structure: mean dose and the volume of each region receiving at least 5, 10, 15, 20, 30, and 40 Gy (V5, V10, V15, V20, V30, V40, respectively).
Hematologic toxicity Hematologic toxicity was graded according to the Common Terminology Criteria for Adverse Events, version 3.0. 12 The highest-grade toxicity for white blood count, absolute neutrophil count, hemoglobin, and platelets were recorded, with HT of grade ≥3 noted as an event (HT3+).
Normal-tissue complication probability modeling We previously showed that the LKB model can be simplified to represent NTCP as a function of equivalent uniform dose using an exponential of a second-degree polynomial instead of the integral used in the Lyman formula. 13 The equivalent uniform dose reduces the DVH to a single value that for normal tissues represents the uniform dose that results in the same NTCP. The Lyman NTCP model was used as below: NTCP ¼ 1=b2π∫t−∞ exp −t 2 =2 dt t ¼ ðD‐TD50 ðvÞÞ=ðm TD50 ðvÞÞ V ¼ V=Vref where TD50(v) is the 50% tolerance dose for uniform irradiation of the partial volume v. The partial- and whole-
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organ radiation-tolerance doses are related by a powerlaw relationship: TDð1Þ ¼ TDðvÞ Vn ; where Vref is the volume of PBM or LSS. The parameter “n” is the volume-effect parameter, while the parameter “m” is the steepness of the dose-complication curve for a fixed partial volume. For uniform partial-organ irradiation, the effective volume method was used to provide estimates of equivalent dose and volume pairs from the DVHs summarizing the nonuniform irradiation. For the purposes of this study, as is the general practice for a protocol using conventional fractionation (ie, 1.8-2 Gy), no dose-per-fraction DVH modification was introduced. Thus, the DVH was not modified in accordance with a model of biologic effectiveness per fraction size (ie, α/β model). A set of calculations for m, n, and TD50 were performed, using the maximum likelihood estimation to compare the NTCP fitting between parameter sets and to determine the optimum m, n, and TD50 for best fitting of calculated NTCP to the clinical data with n constrained to lie between the limits, 0 b n ≤ 1.
Statistical analysis Age, body mass index (BMI), and dosimetric parameters were coded as continuous variables. Categorical variables included gender and dosimetric parameters (dichotomized by the median value). Univariate logistic regression was used to test the correlation between clinical and dosimetric parameters with HT3+. Multivariate logistic regression models controlling for age, gender, and BMI were then used to examine the effect of significant dosimetric parameters on HT3+. Given the small number of events for grade ≥3 hematologic toxicity, each dosimetric variable was combined with all clinical variables (4-variable model).
Results Baseline patient characteristics are shown in Table 1.
Dosimetric parameters for bony structures Table 2 summarizes the dosimetric parameters of PBM and LSS as well as the marrow cavities using the maximum-threshold HUs of 100, 150, 200, and 250. The median mean doses of the whole-bone PBM and LSS were 28.36 Gy and 28.14 Gy, respectively.
Hematologic toxicity The median nadirs in white blood count, absolute neutrophil count, hemoglobin and platelets were 2.6 k/μL (range, 0.8-7.1), 1.6 k/μL (range, 0.4-4.4), 10.7 g/dL (range,
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Table 2 Descriptive statistics of dosimetric parameters of bony structures Parameter Pelvic bone marrow (PBM) Volume (mL) Mean dose (cGy) V5 (%) V10 (%) V15 (%) V20 (%) V30 (%) V40 (%) PBM100 Volume (mL) Mean dose (cGy) V5 (%) V10 (%) V15 (%) V20 (%) V30 (%) V40 (%) PBM150 Volume (mL) Mean dose (cGy) V5 (%) V10 (%) V15 (%) V20 (%) V30 (%) V40 (%) PBM200 Volume (mL) Mean dose (cGy) V5 (%) V10 (%) V15 (%) V20 (%) V30 (%) V40 (%) PBM250 Volume (mL) Mean dose (cGy) V5 (%) V10 (%) V15 (%) V20 (%) V30 (%) V40 (%) Lumbosacral spine (LSS) Volume (mL) Mean dose (cGy) V5 (%) V10 (%) V15 (%) V20 (%) V30 (%) V40 (%)
Median value (range) 1213 2836 94 89 83 76 50 20
(868-2113) (706-3489) (38-99) (25-97) (20-95) (15-90) (6-79) (1-37)
271 2885 96 91 85 77 50 22
(106-547) (686-3626) (39-100) (26-99) (19-97) (15-94) (4-84) (0-41)
434 2846 95 89 84 76 49 21
(214-759) (676-3585) (38-100) (25-98) (19-96) (14-92) (5-82) (0-40)
577 2854 95 89 84 76 50 20
(345-953) (671-3552) (37-100) (25-98) (19-95) (14-91) (5-81) (1-39)
707 2864 95 89 84 76 51 20
(168-1126) (664-3523) (37-100) (24-98) (18-95) (14-91) (5-80) (1-39)
310 2814 88 82 76 73 57 26
(200-519) (29-4031) (1-100) (1-100) (0-100) (0-100) (0-92) (0-67)
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Table 2 (continued) Parameter LSS100 Volume (mL) Mean dose (cGy) V5 (%) V10 (%) V15 (%) V20 (%) V30 (%) V40 (%) LSS150 Volume (mL) Mean dose (cGy) V5 (%) V10 (%) V15 (%) V20 (%) V30 (%) V40 (%) LSS200 Volume (mL) Mean dose (cGy) V5 (%) V10 (%) V15 (%) V20 (%) V30 (%) V40 (%) LSS250 Volume (mL) Mean dose (cGy) V5 (%) V10 (%) V15 (%) V20 (%) V30 (%) V40 (%)
Median value (range) 93 (51-182) 3176 (53-4047) 94 (3-100) 89 (2-100) 86 (1-100) 83 (1-100) 67 (1-95) 26 (0-68) 138 (85-237) 3082 (45-4069) 92 (2-100) 87 (1-100) 83 (1-100) 80 (1-100) 64 (0-94) 28 (0-67) 180 (116-294) 3050 (43-4069) 91 (2-100) 85 (1-100) 81 (1-100) 78 (1-100) 63 (0-93) 28 (0-67) 214 (140-351) 3002 (40-4062) 91 (2-100) 85 (1-100) 81 (1-100) 77 (1-100) 62 (0-93) 28 (0-67)
LSS100-250, lumbosacral spine with the Hounsfield unit of no more than 100-250; PBM100-250, pelvic bone marrow with the Hounsfield unit of no more than 100-250.
6.5-13.2), and 111 k/μL (range, 18-235), respectively. Overall, 10 patients (31%) experienced HT3+, all related to white blood count and absolute neutrophil count toxicity.
Chemotherapy delivery Nine patients (28%) required dose reductions in chemotherapy, and 4 were unable to complete all cycles: 2 patients had infusional 5-FU held and 2 patients had the second cycle of MMC held. Nine (28%) patients required support with filgrastim, blood transfusions, or erythropoietin.
LKB NTCP modeling Constrained optimization (0 b n ≤ 1, with unrestricted variation of m and TD50) of the LKB model for HT3+ yielded
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the value n = 1, confirming the expectation that, over this restricted range characteristic of LKB tissue modeling, both PBM and LSS act like parallel organs. The maximum likelihood estimation optimizations yielded the parameters of m = 0.20 and TD50 = 31 Gy for PBM, and m = 0.21 and TD50 = 32 Gy for LSS. With this model, mean PBM doses of 20.5 Gy and 23 Gy and mean LSS doses of 21 Gy and 23.5 Gy result in a 5% and 10% risk of HT3+, respectively. The plots of NTCP by equivalent uniform dose of PBM and LSS are shown in Fig 1.
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Using maximum likelihood estimation to compare the different bone and cavity contours in LKB modeling, LSS was superior to PBM with either whole-bone or any HUbased marrow-cavity contour. The NTCP fittings were better for the whole-bone contour than any of the HUbased marrow-cavity contours for both PBM and LSS from 100 HUs to 250 HUs (Table 3). In addition, the NTCP fitting improved for the marrow cavities as the HU threshold increased from 100 to 250.
Figure 1 Lyman-Kutcher-Burman (LKB) normal-tissue complication probability (NTCP) model for HT3 + by (A) whole bone of pelvic bone marrow (PBM) and (B) whole bone of lumbosacral spine (LSS). The red squares represent patients with grade ≥ 3 hematologic toxicity (HT3 +), while the black stars represent patients without HT3 +. EUD, equivalent uniform dose.
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Table 3 Maximal likelihood estimate (MLE) of normal tissue complication probability parameter sets by whole bone or bone cavities of pelvic bone marrow (PBM) and lumbosacral spine (LSS)
Table 4 Univariate logistic regression analysis of factors associated with the development of grade ≥ 3 hematologic toxicity
Bone contours
Age Female vs male BMI Chemotherapy (MMC vs non-MMC) PBM Mean dose V5 V10 V15 V20 V30 V40 PBM100 Mean dose V5 V10 V15 V20 V30 V40 PBM150 Mean dose V5 V10 V15 V20 V30 V40 PBM200 Mean dose V5 V10 V15 V20 V30 V40 PBM250 Mean dose V5 V10 V15 V20 V30 V40 LSS Mean dose V5 V10 V15 V20 V30 V40 LSS100 Mean dose
PBM Whole bone PBM250 PBM200 PBM150 PBM100 LSS Whole bone LSS250 LSS200 LSS150 LSS100
MLE − 17.6670 − 17.6973 − 17.7859 − 18.0245 − 18.1501 − 16.1568 − 16.3776 − 16.5019 − 16.5235 − 17.0537
LSS100-250, lumbosacral spine with the Hounsfield unit of no more than 100-250; PBM100-250, pelvic bone marrow with the Hounsfield unit of no more than 100-250.
Predictors of hematologic toxicity On univariate analysis, age, gender, chemotherapy agent (MMC vs non-MMC), and BMI were not significantly associated with HT3 +. For LSS, the mean dose, V5, V10, V15, and V20 of whole bone and all other marrow cavities outlined by 100 to 250 HUs were significantly associated with HT3 +. The rate of HT3 + for the LSS was 6% (1 out of 17 patients) for V10 b 82% vs 60% (9 out of 15 patients) for V10 ≥ 82% (P = .01). For PBM, only the mean dose and V10 were consistently associated with HT3 + for the whole-bone contour and all marrow cavity subregions defined by the 100 to 250 HU thresholds (Table 4). These data are summarized in Table 4. On multivariate analysis, the mean dose and V10 of the whole bone or marrow cavities using any HU threshold retained statistical significance in association with HT3 +. The V30 of both whole-bone PBM and LSS were borderline significant (Table 5).
Discussion To our knowledge, this is the second study to use marrow-cavity contours as a surrogate for bone marrow for LKB modeling to predict acute HT in patients with anal cancer receiving CRT. The LKB model applied to our conventionally fractionated treatments confirmed the expectation that both PBM and LSS act like parallel organs. In addition, we found superior fitting of the NTCP model with LSS compared with PBM in predicting HT3 +, and that the whole-bone contour was better than any marrow-cavity contour using CT HU-maximum thresholds of 100 to 250. Several of the low-dose dosimetric parameters of either PBM or LSS were associated with
Parameter
Odds ratio 1.046 1.615 0.893 0.632
P value .226 .556 .218 .648
19.29 3.37 7.00 3.37 19.29 7.00 7.00
.010 .136 .032 .136 .010 .032 .032
7.00 7.00 7.00 7.00 3.37 7.00 3.37
.032 .032 .032 .032 .136 .032 .136
7.00 7.00 7.00 3.37 7.00 3.37 3.37
.032 .032 .032 .136 .032 .136 .136
19.29 7.00 7.00 3.37 7.00 3.37 3.37
.010 .032 .032 .136 .032 .136 .136
19.29 3.37 7.00 3.37 7.00 3.37 3.37
.010 .136 .032 .136 .032 .136 .136
19.29 19.29 19.29 19.29 19.29 7.00 1.80
.010 .010 .010 .010 .010 .032 .448
3.37
.136
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Table 4 (continued) Parameter
Odds ratio
P value
V5 V10 V15 V20 V30 V40 LSS150 Mean dose V5 V10 V15 V20 V30 V40 LSS200 Mean dose V5 V10 V15 V20 V30 V40 LSS250 Mean dose V5 V10 V15 V20 V30 V40
19.29 19.29 3.37 7.00 7.00 1.00
.010 .010 .136 .032 .032 1.000
19.29 19.29 19.29 19.29 infinity 7.00 1.80
.010 .010 .010 .010 .998 .032 .448
19.29 7.00 19.29 19.29 19.29 7.00 1.80
.010 .032 .010 .010 .010 .032 .448
19.29 7.00 19.29 19.29 19.29 19.29 1.80
.010 .032 .010 .010 .010 .010 .448
BMI, body mass index; F, female; M, male; LSS100-250, lumbosacral spine with the Hounsfield unit of no more than 100-250; MMC, mitomycin; PBM100-250, pelvic bone marrow with the Hounsfield unit of no more than 100-250.
clinically significant HT. The results again support the practical guideline of keeping the mean PBM or LSS dose as low as possible to minimize the risk of HT. There have been several studies, including ours, investigating the dosimetric parameters of PBM that correlate with the risk of HT on various pelvic malignancies. Mell et al 8 found in cervical cancer patients that PBM-V10 was associated with grade ≥ 2 leukopenia or neutropenia. Rose et al 9 found that PBM-V10 ≥ 95% and PBM-V20 N 76% were associated with increased grade ≥ 3 leukopenia in a similar patient cohort. Albuquerque et al 7 studied 40 women who received CRT to treat cervical cancer and found PBM-V20 ≥ 80% with the increased odds of developing grade ≥ 2 HT. For patients with anal cancer, Mell et al 6 demonstrated a relationship between PBM-V5, -V10, -V15, and -V20 with white blood count and absolute neutrophil count nadirs, but not grade ≥ 3 HT. All previous studies have used the whole bone as a surrogate for bone marrow; however, we assumed that only the low-density trabecular portion of the bone contains active marrow and sought to determine whether the marrow
Table 5 Multivariate logistic regression analysis of factors associated with the development of grade ≥ 3 hematologic toxicity Parameter
Odds ratio
P value
Age Female vs male BMI PBM Mean dose V10 V20 V30 V40 PBM100 Mean dose V5 V10 V15 V30 PBM150 Mean dose V5 V10 V20 PBM200 Mean dose V5 V10 V20 PBM250 Mean dose V10 V20 LSS Mean dose V5 V10 V15 V20 V30 LSS100 V5 V10 V20 V30 LSS150 Mean dose V5 V10 V15 V30 LSS200 Mean dose V5 V10 V15 V20 V30 LSS250
1.012-1.125 0.506-1.023 0.002-1.606
.109-.824 .083-.661 .102-.920
18.61 9.27 31.80 5.70 7.02
.017 .038 .019 .071 .048
17.41 5.32 22.29 15.94 8.87
.025 .091 .041 .052 .034
14.42 5.28 9.27 9.68
.032 .086 .038 .045
46.72 5.4 9.27 8.25
.013 .086 .038 .049
46.72 9.27 8.25
.013 .038 .049
25.39 15.18 19.00 17.13 17.13 7.72
.012 .023 .016 .024 .024 .073
18.31 27.35 7.72 10.90
.021 .024 .051 .029
39.34 18.31 17.34 1994.05 10.90
.008 .021 .023 .037 .029
25.39 5.71 17.34 37.48 37.26 10.90
.012 .074 .023 .024 .024 .029
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Table 5 (continued) Parameter Mean dose V5 V10 V15 V20 V30
Odds ratio
P value
25.39 5.71 17.34 37.26 37.26 46.62
.012 .074 .023 .024 .024 .008
Note: Given the small number of events for grade ≥ 3 hematologic toxicity, each dosimetric variable was combined with all clinical variables (4-variable model). The resulting ranges of clinical variables in odds ratios and upper or lower bounds of the P values are presented. BMI, body mass index; F, female; LSS100-250, lumbosacral spine with the Hounsfield unit of no more than 100-250; M, male; PBM100-250, pelvic bone marrow with the Hounsfield unit of no more than 100-250.
cavity defined by the lower-density subregions of the bone would better correlate with the risk of HT over the whole bone. One Indian study 14 on 47 cervical cancer patients treated with CRT investigated the dosimetric correlations between whole-bone and free-hand marrow-cavity contours with HT. The V40 of free-hand whole-pelvis contour was the only significant factor associated with grade 2 leukopenia and neutropenia. Yet, their marrow cavity was defined freehand and not based on a more systematic and objective threshold using CT HUs. In contrast, because of a lack of published data on the proper HU threshold to use, our study defined the marrow cavity testing various maximum HU thresholds of 100, 150, 200, and 250. While we were able to identify 1 Norwegian study that proposed an HU threshold of 600 to define the corticocancellous interface in cadaver femurs, 15 we found that this threshold produced marrow-cavity contours that were nearly identical to the whole bone. We therefore chose lower CT HU thresholds. We found a significant correlation with HT of whole-bone PBM (V15 and V20) and LSS (V5, V10, V15, and V20) and marrow cavities by 100 to 250 HUs; however, our data failed to show that any HU-based marrow cavity was better than the entire bone in predicting HT3 +, either by NTCP fitting or by logistic regression. We also found that the correlation with the risk of HT3+ successively improved with a higher HU maximum threshold. Magnetic resonance imaging (MRI) studies have suggested that the red marrow, which harbors the cells of hematopoiesis, does not necessarily localize to areas of low CT density. 16 Also, the low-density regions of bone may not all correspond to active bone marrow, and it is likely that nuclear imaging studies such as positron emission tomography (PET) may better define the active marrow. 17 Therefore, marrow-cavity contouring based on CT HU thresholds may not adequately define the active marrow. Few studies have found a relationship between radiation to specific sub-sites of PBM and the risk of HT. One study
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using nuclear medicine imaging showed that most active pelvic bone marrow resided in the LSS. 18 We previously reported a strong correlation of LSS with HT. 5 In addition, the current study found that all marrow cavity subregions of the LSS had a stronger correlation to HT compared with the PBM subregions. These data can have important implications in radiation therapy treatment planning for anal cancer. Because the larger PBM volume encircles the pelvic lymph node regions that are included in the target volume, strict dose constraints for the PBM will either necessarily reduce coverage of the target volume or likely cause increased heterogeneity and hotspots within the target volume or critical structures. We therefore propose that using LSS alone rather than PBM as a critical structure for IMRT planning is sufficient and preferred. This method should, however, be tested in a prospective study. Our study has several limitations. First, the data were generated from a single-institution retrospective review of a relatively small cohort with some heterogeneity in treatment. Our findings need to be validated in a larger, prospectively collected group of data. In addition, all patients were treated with IMRT, and the results may not be applicable to patients being treated with conventional radiation therapy techniques. Finally, we contoured the marrow cavities by CT-based HUs rather than other imaging tools (ie, PET, MRI) to delineate active marrow. This decision was made to determine a simple and practical method to define the active marrow that would be readily available to radiation therapy practices, as other imaging modalities such as PET and MRI may not be routinely used for treatment planning. However, given our inability to find a CT-based method to define the active marrow, we are currently exploring the use of PET for these purposes. One prospective trial is using both MRI and PET to define active marrow in IMRT planning for pelvic malignancies in an effort to spare BM. 19 In conclusion, LSS was superior to PBM, and whole bone was superior to marrow cavity, in predicting the risk of HT. Mean- and low-dose parameters V10-15 were associated with HT3 +. Mean LSS doses of 21 Gy and 23.5 Gy were associated with a 5% and 10% risk of HT3 +, respectively. These data can be used to reduce the risk of HT. Until further methods of defining active marrow are validated, we propose using the whole-bone LSS to represent the bone marrow, and we suggest limiting the V10 ≤ 80%, if feasible, while minimizing the mean dose to reduce the risk of serious HT.
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