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Predictors of Acute Hematologic Toxicity in Women Receiving Extended-Field Chemoradiation for Cervical Cancer: Do Known Pelvic Radiation Bone Marrow Constraints Apply?

Open AccessPublished:June 13, 2022DOI:https://doi.org/10.1016/j.adro.2022.100998

      Abstract

      Purpose

      Patients with cervical cancer who are at high risk for para-aortic lymphatic involvement may receive extended-field chemoradiation (EF-CRT), with inclusion of the para-aortic region. Increased radiation to bone marrow (BM) may heighten hematologic toxicity (HT) and affect timely delivery of chemoradiation. Factors associated with HT in this setting have not been well studied.

      Methods and Materials

      This study was a retrospective analysis of women treated with EF-CRT from 2012 to 2018 with platinum-based chemotherapy. Factors including age, body mass index (BMI), race, Charlson Comorbidity Index (CCI), and nadirs for white blood cell count, absolute neutrophil count, hemoglobin, and platelet count were collected. The BM metrics included V5Gy, V10Gy, V15Gy, V20Gy, V25Gy, V30Gy, V35Gy, V40Gy and V45Gy (VxGy was defined as the percentage of BM volume receiving x Gy). Hematologic toxicity was defined as grade ≥2 (Cooperative Group Common Toxicity Criteria) leukopenia, anemia, neutropenia, or thrombocytopenia. Univariate analysis (UVA) and multivariate analysis (MVA) were performed using the χ2 test, the Fisher exact test, and logistic regression. Previously published dosimetric BM constraints were examined as detailed in each respective study.

      Results

      Fifty-two women underwent EF-CRT with cisplatin. UVA showed no association between HT and age, BMI, or CCI. When accounting for race, V5Gy ≥98% was associated with grade ≥2 leukopenia (P = .02) and grade ≥2 HT (P = .05). Most previously described radiation metrics were not reproduced in our cohort, but a similar constraint, V20Gy <70%, was associated with reduced leukopenia of grade ≥2 on UVA (P = .02) and MVA (P < .05).

      Conclusions

      Acute HT in patients receiving EF-CRT was associated with large volumes of low-dose radiation to the BM and was also associated with race. Restricting the BM V20Gy to less than 70% to 75% may be beneficial in reducing HT, but other pelvic radiation BM constraints may not be applicable to this population.

      Introduction

      Cervical cancer is the third most common cancer in women worldwide.
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      Many of these patients present with advanced-stage disease, for which either postoperative or primary (definitive) chemoradiation (CRT) is required. Patients with para-aortic lymph node metastasis or who are at high risk for para-aortic lymph node involvement are frequently treated using extended-field radiation therapy (RT) with concurrent chemotherapy (EF-CRT).
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      However, these methods are associated with significant hematologic toxicity (HT). For example, more than 80% of women in RTOG 0116 experienced grade 3 or higher HT.
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      Moreover, 33% to 50% of patients who undergo EF-CRT treatment require cisplatin dose reductions or discontinuation, which leads to treatment interruptions or delays.
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      In the neoadjuvant setting, dose reductions and fewer cycles of chemotherapy have been associated with lower complete response rates.
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      In the concurrent setting, the importance of cisplatin dosing and treatment completion is less established. Ryu et al previously demonstrated that triweekly cisplatin concurrent chemoradiation was associated with better 5-year overall survival and a higher relative completion rate of scheduled chemotherapy cycles.
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      Similarly, recent meta-analyses demonstrated that triweekly cisplatin with concurrent RT was superior to weekly cisplatin with respect to local recurrence, treatment compliance, and anemia.
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      These data suggest that completion of concurrent, full-dose chemotherapy may be important for optimal treatment outcomes. Therefore, efforts to reduce treatment delay and interruptions should be investigated.
      Identifying factors that reduce HT may therefore have a significant effect on optimizing a patient's outcome. Previous studies suggested that several clinical factors are associated with HT in the setting of concurrent chemoradiation to the pelvis, including decreased body mass index (BMI), female sex, and lymph node positivity.
      • Mell LK
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      • et al.
      Dosimetric predictors of acute hematologic toxicity in cervical cancer patients treated with concurrent cisplatin and intensity-modulated pelvic radiotherapy.
      ,
      • Mell LK
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      • et al.
      Dosimetric comparison of bone marrow-sparing intensity-modulated radiotherapy versus conventional techniques for treatment of cervical cancer.
      Although valuable for risk assessment, these clinical factors are not modifiable. Dosimetric constraints to the bone marrow (BM) may provide an actionable means to guide treatment and reduce HT, given that approximately 60% of hematopoietic stem cells in adults are within the lumbar spine and pelvis and are particularly radiosensitive.
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      Multiple studies have evaluated the role of BM radiation dose on acute HT and provided dosimetric constraints to decrease HT.
      • Mell LK
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      • Roeske JC
      • et al.
      Dosimetric predictors of acute hematologic toxicity in cervical cancer patients treated with concurrent cisplatin and intensity-modulated pelvic radiotherapy.
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      • Albuquerque K
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      • Morrison C
      • et al.
      Radiation-related predictors of hematologic toxicity after concurrent chemoradiation for cervical cancer and implications for bone marrow-sparing pelvic IMRT.
      • Yan K
      • Ramirez E
      • Xie XJ
      • et al.
      Predicting severe hematologic toxicity from extended-field chemoradiation of para-aortic nodal metastases from cervical cancer.
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      • Lujan AE.
      Intensity-modulated radiation therapy in gynecologic malignancies.
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      Intensity-modulated radiotherapy as a means of reducing dose to bone marrow in gynecologic patients receiving whole pelvic radiotherapy.
      • Liang Y
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      • et al.
      Impact of bone marrow radiation dose on acute hematologic toxicity in cervical cancer: Principal component analysis on high dimensional data.
      • Rose BS
      • Aydogan B
      • Liang Y
      • et al.
      Normal tissue complication probability modeling of acute hematologic toxicity in cervical cancer patients treated with chemoradiotherapy.
      Mell et al demonstrated that intensity modulated RT (IMRT) can be used to decrease BM radiation dose compared with the traditional 3-dimensional conformal RT (3D-CRT) 4-field box technique.
      • Mell LK
      • Tiryaki H
      • Ahn KH
      • et al.
      Dosimetric comparison of bone marrow-sparing intensity-modulated radiotherapy versus conventional techniques for treatment of cervical cancer.
      The INTERTECC-2 phase 2/3 trial demonstrated that BM-sparing IMRT with concurrent cisplatin for cervical cancer reduced HT compared with historical standards.
      • Mell LK
      • Sirák I
      • Wei L
      • et al.
      Bone marrow-sparing intensity modulated radiation therapy with concurrent cisplatin for stage IB-IVA cervical cancer: An international multicenter phase II clinical trial (INTERTECC-2).
      ,
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      • Xu R
      • et al.
      Positron emission tomography-guided bone marrow-sparing radiation therapy for locoregionally advanced cervix cancer: Final results from the INTERTECC phase II/III trial.
      Similarly, a phase 2 trial from India demonstrated a reduction in rates of grade 2 neutropenia and HT with IMRT when comparing IMRT with 3D-CRT.
      • Kapoor AR
      • Bhalavat R
      • Chandra M
      • et al.
      Assessment of impact of bone marrow sparing for hematological and gastrointestinal toxicities in cervical cancer with external beam radiation therapy.
      However, these studies excluded patients receiving EF-CRT, which is associated with significantly greater HT.
      • Klopp AH
      • Moughan J
      • Portelance L
      • et al.
      Hematologic toxicity in RTOG 0418: A phase 2 study of postoperative IMRT for gynecologic cancer.
      ,
      • Wang X.
      Firth logistic regression for rare variant association tests.
      Recently, Yan et al found that in 38 patients treated with EFRT using conventional 4-field box or IMRT techniques, a mean total BM dose ≥30.3 Gy was correlated with grade 3 HT.
      • Yan K
      • Ramirez E
      • Xie XJ
      • et al.
      Predicting severe hematologic toxicity from extended-field chemoradiation of para-aortic nodal metastases from cervical cancer.
      The purpose of this study was twofold: to identify clinical and dosimetric factors associated with acute HT for patients treated with EF-CRT with an IMRT technique and concurrent cisplatin and to determine whether existing pelvic BM dosimetric constraints could successfully be extrapolated to the patient cohort treated with EFRT to predict for toxicity.

      Methods

      Study design and patient population

      We identified women with locally advanced cervical cancers treated at 2 urban, academic institutions from 2012 to 2018. This study was approved by the institutional review boards of both institutions. Only patients treated with extended-field chemoradiation using IMRT with platinum-based chemotherapy were included in this study, because IMRT has been associated with reduced HT toxicity compared with a 3D-CRT technique.
      • Mell LK
      • Sirák I
      • Wei L
      • et al.
      Bone marrow-sparing intensity modulated radiation therapy with concurrent cisplatin for stage IB-IVA cervical cancer: An international multicenter phase II clinical trial (INTERTECC-2).
      Patient demographics and clinical characteristics are summarized in Table 1. BMI, race (as self-reported in the medical record), Charlson Comorbidity Index (CCI) score, chemotherapy cycles delivered, and nadirs for white blood cell count, absolute neutrophil count, hemoglobin, and platelet count were obtained. Stage was defined using the International Federation of Gynecology and Obstetrics (FIGO) 2009 cervical cancer staging system.
      Table 1Patient and treatment characteristics
      CharacteristicPatients, No. (%) (N = 52)*
      Patients
       Age, median (IQR), y44.5 (39.3-58.8)
       BMI, median (IQR), kg/m225.1 (22.7-31.2)
       Race
       White13 (25)
       African American30 (58)
       Other9 (17)
      FIGO 2009 clinical stage
       I12 (23)
       II18 (35)
       IIIA19 (36)
       IV3 (6)
      Treatment
      Radiation technique
       Intensity modulated radiation therapy52 (100)
       3D conformal radiation therapy2 (3.9)
       Brachytherapy51 (98)
       Intracavitary brachytherapy35 (67.3)
       Interstitial brachytherapy17 (32.7)
       Declined1 (1.9)
      Dosimetric characteristics, median (IQR)
       V5Gy98 (94-100)
       V10Gy89 (85-93)
       V15Gy79 (73-87)
       V20Gy70 (65-76)
       V25Gy59 (54-64)
       V30Gy49 (44-53)
       V35Gy37 (32-42)
       V40Gy26 (21-32)
       V45Gy12 (9-17)
       Mean dose28.4 (26.4-30.2)
      Chemotherapy
       Cisplatin52 (100)
       Cycles of cisplatin, median (IQR), No.5 (4-5)
       Chemotherapy dose reduction
       Yes17 (33)
       No34 (67)
      Abbreviations: 3D = 3-dimensional; BMI = body mass index; FIGO = International Federation of Gynecology and Obstetrics; IQR = interquartile range; SD = standard deviation; VxGy = percentage of bone marrow volume receiving x Gy.
      *Data are presented as the number (percentage) of patients unless otherwise indicated.

      Radiation therapy

      Patients underwent individualized computed tomography–based planning before the beginning of treatment with immobilization in alpha cradles with their arms placed above their head. The BM contours were standardized across all patients and included vertebral bodies within the radiation treatment field, sacrum, coccyx, pelvic bones, and femurs from the top of the femoral head to the inferior border of the ischial tuberosities (Fig. 1). The extended-field RT clinical target volume (CTV) included treatment to the uterus, cervix, and primary mass; the paracervical, parametrial, and uterosacral regions; and at least the upper half of the vagina. The nodal CTV treatment volumes included the external iliac, hypogastric, obturator, and para-aortic lymph nodes with a 0.7- to 0.8-cm margin around the vessels minus anatomic subtraction as clinically indicated. The superior extent of the para-aortic field was defined by the renal vessels in all patients, with the exception of 1 patient who had high para-aortic nodal disease (Table B in the Supplement). The nodal planning target volume was uniformly expanded by 0.7 cm to produce the planning target volume. A cervix internal target volume was created using bladder-empty and bladder-full scans; this was expanded by 1.5 to 2.5 cm to account for organ motion. Similarly, a vaginal and parametrial internal target volume was created and expanded by 0.5 to 1.0 cm. In cases of urgent vaginal bleeding, radiation treatments used 3D-CRT for the first fractions to expedite treatment. These plans were subsequently incorporated into the composite dose calculations for IMRT treatment planning. Volumetric-modulated arc therapy or static-field IMRT were used to treat the volume to a total dose of 45 Gy in 1.8-Gy daily fractions, which was followed by a boost to gross nodal disease to a total dose of 55 to 60 Gy using either a sequential or simultaneous integrated boost technique. Organs at risk, including the rectum, bowel, and bladder, were contoured for radiation planning. The BM was contoured but was not used as an avoidance structure for IMRT planning until 2017. Patients were reassessed toward the end of external beam radiation treatment; they were given a parametrial boost if indicated and high-dose-rate intracavitary or interstitial brachytherapy. The boost treatment used iridium-192 with a dose of 28 to 30 Gy to the high-risk CTV, or point A, in 4 to 5 treatments. RT and brachytherapy were generally held if the absolute neutrophil count was less than 0.5 × 109/L or if the platelet count was less than 50 × 109/L.
      Fig 1
      Figure 1Representative contours. Green indicates bone marrow; purple, PTV45; and red, PTV55 lymph node boost. Abbreviation: PTV = planning target volume.

      Chemotherapy

      Patients received concurrent weekly chemotherapy with cisplatin (40 mg/m2). Doses were based on patient weight and surface area. Patients were planned to receive 5 to 6 cycles of chemotherapy concurrently with radiation. Cisplatin was generally held if an absolute neutrophil count was less than 1 × 10
      • Koh WJ
      • Abu-Rustum NR
      • Bean S
      • et al.
      Cervical cancer, Version 3.2019, NCCN clinical practice guidelines in oncology.
      /L and/or a platelet count was less than 100 × 10
      • Koh WJ
      • Abu-Rustum NR
      • Bean S
      • et al.
      Cervical cancer, Version 3.2019, NCCN clinical practice guidelines in oncology.
      /L, although this was at the discretion of the treating gynecologic oncologist. Any cisplatin dose reduction was also at the discretion of the treating physician.

      Dosimetry

      Contours and dose summation were completed on the Eclipse treatment planning system, version 15.5, and the Pinnacle treatment planning system, version 9.8. A cumulative plan was created from all external beam portions of the patient's treatment (if applicable), and a dose-volume histogram was generated for each contoured BM region for each patient. The brachytherapy dose was not included, given its minimal contribution to bony structures; however, a record of brachytherapy was notated. The BM metrics collection included the mean BM dose, V5Gy, V10Gy, V15Gy, V20Gy, V25Gy, V30Gy, V35Gy, V40Gy and V45Gy (VxGy was defined as the percentage of BM volume receiving x Gy). Specific dosimetric predictors of HT previously published in the literature for pelvic (nonextended-field) radiation were also evaluated in this patient cohort. These included V10Gy ≥90%, V20Gy ≥75%, and V40Gy >37%.
      • 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.
      ,
      • Rose BS
      • Aydogan B
      • Liang Y
      • et al.
      Normal tissue complication probability modeling of acute hematologic toxicity in cervical cancer patients treated with chemoradiotherapy.
      ,
      • Klopp AH
      • Moughan J
      • Portelance L
      • et al.
      Hematologic toxicity in RTOG 0418: A phase 2 study of postoperative IMRT for gynecologic cancer.
      A previously published dosimetric predictor in the extended-field setting (mean BM dose >30.3 Gy) was also evaluated in this patient cohort.
      • Yan K
      • Ramirez E
      • Xie XJ
      • et al.
      Predicting severe hematologic toxicity from extended-field chemoradiation of para-aortic nodal metastases from cervical cancer.

      Toxicity endpoints

      Toxicity grading was based on the Cooperative Group Common Toxicity Criteria. The HT endpoints included (1) any grade 2 or higher hematologic acute toxic effect, not including lymphopenia, and (2) grade 2 or higher leukopenia. These endpoints were chosen as a measure of toxicity because these may result in modifications to systemic or RT and were previously used as HT endpoints in RTOG 0418.
      • Klopp AH
      • Moughan J
      • Portelance L
      • et al.
      Hematologic toxicity in RTOG 0418: A phase 2 study of postoperative IMRT for gynecologic cancer.
      Previously published HT endpoints were used for examination of their respective published BM dosimetric constraints in this patient cohort, which included HT ≥2,
      • Klopp AH
      • Moughan J
      • Portelance L
      • et al.
      Hematologic toxicity in RTOG 0418: A phase 2 study of postoperative IMRT for gynecologic cancer.
      leukopenia ≥2,
      • 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.
      ,
      • Klopp AH
      • Moughan J
      • Portelance L
      • et al.
      Hematologic toxicity in RTOG 0418: A phase 2 study of postoperative IMRT for gynecologic cancer.
      neutropenia ≥2 (grade 2-4 neutropenia),
      • 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.
      HT ≥3 (grade 3-4 HT),
      • Yan K
      • Ramirez E
      • Xie XJ
      • et al.
      Predicting severe hematologic toxicity from extended-field chemoradiation of para-aortic nodal metastases from cervical cancer.
      and leukopenia ≥3 (grade 3-4 leukopenia).
      • Rose BS
      • Aydogan B
      • Liang Y
      • et al.
      Normal tissue complication probability modeling of acute hematologic toxicity in cervical cancer patients treated with chemoradiotherapy.

      Statistical analysis

      All statistical analyses were performed using STATA, version 17.0 (StataCorp LLC, College Station). Univariate analysis was performed using the χ2 test and logistic regression. The χ2 test or Fisher exact test was used to compare rates of hematologic adverse events for patients with a volume of BM irradiation from 5 to 45 Gy (V5Gy to V45Gy), dichotomized at the median, and to compare rates of hematologic adverse events for patients according to dichotomized patient characteristics (African American race vs other; CCI), as appropriate. Tests for normality were performed for age and BMI with the Shapiro-Wilk statistic, and these variables were transformed using the natural logarithm to eliminate skew. Logistic regression was used to test for associations between natural log-transformed age or natural log-transformed BMI and hematologic endpoints. Variables with a P value <.1 from univariate logistic models were included in the multivariate model. Multivariate analysis (MVA) was performed using logistic regression to correlate HT ≥2 and leukopenia ≥2 with patient or dosimetric characteristics. Firth's logistic regression was used in cases of rare events.
      • Wang X.
      Firth logistic regression for rare variant association tests.
      Previously published BM constraints from both the nonextended-field setting (V10Gy ≥90%, V20Gy ≥75%, and V40Gy ≥37%)
      • Mell LK
      • Tiryaki H
      • Ahn KH
      • et al.
      Dosimetric comparison of bone marrow-sparing intensity-modulated radiotherapy versus conventional techniques for treatment of cervical cancer.
      ,
      • Rose BS
      • Aydogan B
      • Liang Y
      • et al.
      Normal tissue complication probability modeling of acute hematologic toxicity in cervical cancer patients treated with chemoradiotherapy.
      ,
      • Klopp AH
      • Moughan J
      • Portelance L
      • et al.
      Hematologic toxicity in RTOG 0418: A phase 2 study of postoperative IMRT for gynecologic cancer.
      and the extended-field setting were evaluated (BM mean >V30.3Gy)
      • Yan K
      • Ramirez E
      • Xie XJ
      • et al.
      Predicting severe hematologic toxicity from extended-field chemoradiation of para-aortic nodal metastases from cervical cancer.
      as described in each respective publication, including covariates. Associations of hematologic endpoints with V5Gy ≥98% and V20Gy ≥70% were performed using the Fisher exact test.

      Results

      Patient, cancer, treatment, and toxicity characteristics

      Fifty-two patients with locally advanced cervical cancer treated with EF-CRT with concurrent cisplatin were identified (Table 1). All patients were treated using an IMRT technique: 21 (40.4%) with volumetric-modulated arc therapy and 31 (59.6%) with static-field IMRT. Two patients (3.9%) started treatment urgently with 3D-CRT (9 Gy in 5 fractions and 18 Gy in 10 fractions) owing to vaginal bleeding and were converted to IMRT plans. Fifty-one patients (98.1%) were treated with brachytherapy: 17 (32.7%) interstitial and 35 (67.3%) intracavitary. One patient (1.9%) declined brachytherapy. The median mean BM dose was 28.40 Gy (interquartile range [IQR], 26.4-30.2). Table 1 further details radiation dosimetric characteristics.
      All patients in the study received concurrent cisplatin, and 17 patients (33%) required dose reduction. The median number of cycles of cisplatin was 5 (IQR, 4-5). Forty-eight of the patients (92.31%) experienced HT ≥2 and 28 (53.85%) experienced HT ≥3 (Table 2).
      Table 2Distribution of hematologic toxicity
      Toxicity grading was based on the Cooperative Group Common Toxicity Criteria.
      Patients, No. (%)
      ToxicityGrade 0Grade 1Grade 2Grade 3Grade 4
      Any hematologic toxicity1 (1.92)3 (5.77)20 (38.46)19 (36.54)9 (17.31)
      Leukopenia3 (5.77)5 (9.62)21 (40.38)16 (30.77)7 (13.46)
      Neutropenia12 (24.00)8 (16.00)12 (26.00)13 (26.00)5 (10.00)
      Anemia6 (11.54)11 (21.15)25 (48.08)9 (17.31)1 (1.92)
      Thrombocytopenia27 (51.92)12 (23.08)8 (15.38)3 (5.77)2 (3.85)
      low asterisk Toxicity grading was based on the Cooperative Group Common Toxicity Criteria.

      Predictors of hematologic toxicity

      Supplemental Table A demonstrates univariate analysis of the association between clinical or dosimetric variables with any grade ≥2 HT and grade ≥2 leukopenia. African American race trended toward association with HT ≥2 (odds ratio [OR], 14.84; 95% CI, 0.75-292.62; P = .08) and leukopenia ≥2 (OR, 5.25; 95% CI, 0.79-57.25; P = .06) on univariate analysis. There was no significant association between any of the HT endpoints and age, BMI, or CCI (all P > .05). Among the BM metrics that were analyzed, V5Gy ≥98% (volume of BM receiving 5 Gy) was associated with leukopenia ≥2 (OR, 5.89; 95% CI, 1.10-472.72; P = .02; 96% vs 72%) and trended toward association with HT ≥2 (OR, 11.51; 95% CI, 0.59-225.67; P = .11; 100% vs 84%). V20Gy ≥70% was associated with increased rates of leukopenia ≥2 (OR, 9.21; 95% CI, 1.002-431.25; P = .02; 96% vs 73%).
      When accounting for race on MVA, V5Gy ≥98% was associated with leukopenia ≥2 (OR, 17.73; 95% CI, 1.71-183.56; P = .02) and HT ≥2 (OR, 21.76; 95% CI, 0.99-473.43; P = .05), whereas V20Gy ≥70% was associated with leukopenia ≥2 (OR, 9.43; 95% CI, 1.01-87.72; P < .05) (Table 3).
      Table 3Multivariate analysis of hematologic toxicity with models including (A) race and V5Gy and (B) race and V20 Gy using logistic regression
      V5Gy <98% vs ≥98%Race (African American vs others)
      Model AOR (95% CI)P valueOR (95% CI)P value
      Grade ≥2 hematologic toxicity21.76 (0.99-473.43).05*26.58 (1.21-578.25).04*
      Grade ≥2 leukopenia17.73 (1.71-183.56).029.76 (1.43-66.44).02
      V20Gy <70% versus ≥70%Race (African American vs others)
      Model BOR (95% CI)P valueOR (95% CI)P value
      Grade ≥2 hematologic toxicity2.31 (0.28-18.75).43*13.70 (0.70-268.09).08*
      Grade ≥2 leukopenia9.43 (1.01-87.72).0495.39 (0.89-32.55).07
      Abbreviations: CI = confidence interval; OR = odds ratio; VxGy = percentage of bone marrow volume receiving x Gy.
      *Denotes that Firth's logistic regression was used to account for rare events.
      Although previously described radiation metrics for pelvic radiation in the literature (V10Gy ≥90%, V20Gy ≥75%, or V40Gy >37%) and their respective HT endpoints were not exactly found to be associated in our extended-field patient cohort, the V20Gy metric was very similar to our findings
      • 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.
      ,
      • Rose BS
      • Aydogan B
      • Liang Y
      • et al.
      Normal tissue complication probability modeling of acute hematologic toxicity in cervical cancer patients treated with chemoradiotherapy.
      ,
      • Klopp AH
      • Moughan J
      • Portelance L
      • et al.
      Hematologic toxicity in RTOG 0418: A phase 2 study of postoperative IMRT for gynecologic cancer.
      (Table 4).
      Table 4Summary of existing published dosimetric bone marrow constraints for cervical cancer concurrent chemoradiation
      AuthorsSample sizeDatesRadiation fieldTechnique (IMRT vs 3D-CRT)Identified dosimetric constraintToxicity endpointValidatedValidated in the extended-field cohort (P value)
      Mell et al
      • 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.
      442000-2004PelvisIMRTBone marrow V10Gy ≥90%Grade 2 or worse leukopeniaYesNo (.19)
      Grade 2 or worse neutropeniaNoNo (.96)
      Bone marrow V20Gy ≥75%Grade 2 or worse leukopeniaYesNo (.45)
      Grade 2 or worse neutropeniaNoNo (.91)
      Rose et al
      • Rose BS
      • Aydogan B
      • Liang Y
      • et al.
      Normal tissue complication probability modeling of acute hematologic toxicity in cervical cancer patients treated with chemoradiotherapy.
      812000-2008Pelvis94% IMRTBone marrow V10Gy ≥95%Grade 3 or worse leukopeniaNoNo (.26)
      Bone marrow V20Gy ≥76%Grade 3 or worse leukopeniaNoNo (.26)
      Klopp et al
      • Klopp AH
      • Moughan J
      • Portelance L
      • et al.
      Hematologic toxicity in RTOG 0418: A phase 2 study of postoperative IMRT for gynecologic cancer.
      402006-2008PelvisIMRTBone marrow V40Gy >37%Grade 2 or worse hematologic toxicityNoNo (.85)
      Grade 2 or worse leukopeniaNoNo (.65)
      Yan et al
      • Yan K
      • Ramirez E
      • Xie XJ
      • et al.
      Predicting severe hematologic toxicity from extended-field chemoradiation of para-aortic nodal metastases from cervical cancer.
      382008-2015Extended-field71% IMRTMean dose to total bone marrow >30.3 GyGrade 3 or worse hematologic toxicityNoNo (.96)
      Mean dose to total bone marrowGrade 3 or worse hematologic toxicityNoNo (.43)
      Abbreviations: 3D-CRT = 3-dimensional conformal radiation therapy; IMRT = intensity modulated radiation therapy; VxGy = percentage of bone marrow volume receiving x Gy.
      *Each hematologic endpoint and dosimetric constraint were analyzed via the statistical methodology in each respective publication including covariates.
      V20Gy ≥70% was associated with grade ≥2 leukopenia in this study (P = .05).

      Discussion

      To our knowledge, this is the largest study to evaluate the dosimetric patterns specifically of extended-field IMRT with concurrent chemoradiation to predict HT in patients with cervical cancer with para-aortic lymph node metastasis.
      Our results showed that African American race was associated with leukopenia ≥2 (OR, 5.25; CI, 0.79-57.25; P = .04) and trended toward association with increased HT ≥2 (OR, 14.84; 95% CI, 0.75-291.62; P = .08) on univariate analysis. Race was also associated with HT ≥2 (OR, 26.58; 95% CI, 1.21-578.25; P = .04) and leukopenia ≥2 (OR, 9.76; 95% CI, 1.43-66.44; P = .02) on MVA when including V5Gy ≥98% in the model but trended toward significance when V20Gy ≥70% (HT ≥2: OR, 13.70; 95% CI, 0.70-268.09; P = .08; leukopenia ≥2: OR, 5.39; 95% CI, 0.89-32.55; P = .07) was included in the model (Table 4). Although studies have been published on the role of pharmaco-ethnicity,
      • Casal MA
      • Ivy SP
      • Beumer JH
      • Nolin TD.
      Effect of removing race from glomerular filtration rate-estimating equations on anticancer drug dosing and eligibility: A retrospective analysis of National Cancer Institute phase 1 clinical trial participants.
      the literature shows conflicting results with respect to differences in toxicity of systemic therapy among races.
      • Farley JH
      • Tian C
      • Rose GS
      • et al.
      Chemotherapy intensity and toxicity among Black and White women with advanced and recurrent endometrial cancer: A Gynecologic Oncology Group Study.
      Toxicity results in our cohort were focused solely on hematologic toxicity and did not encompass many of the other toxic effects that patients commonly experience during chemoradiation, including gastrointestinal and genitourinary adverse effects. Moreover, because socioeconomic information for this cohort was not available, the clinical implications of these results are limited.
      Our results do not demonstrate an association between BMI and HT for patients with cervical cancer treated with EF-CRT. This is in contrast to Yan et al, who found that nonobese patients (BMI <30 kg/m2) were more likely to experience HT during EF-CRT treatment for cervical cancer.
      • Yan K
      • Ramirez E
      • Xie XJ
      • et al.
      Predicting severe hematologic toxicity from extended-field chemoradiation of para-aortic nodal metastases from cervical cancer.
      Overall, previously published studies investigating the interaction between BMI and HT showed conflicting results.
      • Hourdequin KC
      • Schpero WL
      • McKenna DR
      • Piazik BL
      • Larson RJ.
      Toxic effect of chemotherapy dosing using actual body weight in obese versus normal-weight patients: A systematic review and meta-analysis.
      • Gutierrez F
      • Gonzalez-de-la-Fuente GA
      • Nazco GJ
      • Oramas J
      • Batista N.
      Hematological toxicity of carboplatin for gynecological cancer according to body mass index.
      • Meyerhardt JA
      • Catalano PJ
      • Haller DG
      • et al.
      Influence of body mass index on outcomes and treatment-related toxicity in patients with colon carcinoma.
      • Steinmeyer Z
      • Gérard S
      • Filleron T
      • et al.
      Low lean mass and chemotherapy toxicity risk in the elderly: The Fraction Study protocol.
      • Morrison VA
      • McCall L
      • Muss HB
      • et al.
      The impact of actual body weight-based chemotherapy dosing and body size on adverse events and outcome in older patients with breast cancer: Results from Cancer and Leukemia Group B (CALGB) trial 49907 (Alliance A151436).
      • 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 intensity-modulated radiotherapy.
      • Grabowski JP
      • Richter R
      • Rittmeister H
      • et al.
      Impact of body mass index (BMI) on chemotherapy-associated toxicity in ovarian cancer patients: A pooled analysis of the North-Eastern German Society of Gynecological Oncology (NOGGO) Databank on 1,213 patients.
      The differences in our findings regarding BMI may be owed to the small sample size of both of our study cohorts or to the significantly lower use of 3D-CRT in our study. Overall, the cohorts included in the current study and that by Yan et al are similar, with the exception of (1) a greater proportion of Hispanic patients in the study by Yan et al compared with a greater proportion of African American patients in our cohort and (2) a greater proportion of patients with stage 3B disease or higher in our cohort (43.9% vs 26.3%).
      In terms of dosimetric predictors, our study suggests that V5Gy and V20Gy are associated with acute HT in patients with locally advanced cervical cancer undergoing EF-CRT. When we assessed previously described radiation metrics specified for the nonextended-field setting (V10Gy ≥90%, V20Gy ≥75%, and V40Gy ≥37%), our results did not show an association with the primary endpoint studied (eg, grade 2 or higher leukopenia, grade 3 or higher leukopenia, etc) (Table 4).
      • 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.
      ,
      • Rose BS
      • Aydogan B
      • Liang Y
      • et al.
      Normal tissue complication probability modeling of acute hematologic toxicity in cervical cancer patients treated with chemoradiotherapy.
      ,
      • Klopp AH
      • Moughan J
      • Portelance L
      • et al.
      Hematologic toxicity in RTOG 0418: A phase 2 study of postoperative IMRT for gynecologic cancer.
      However, we found that a similar V20Gy metric that was previously found to be associated with leukopenia ≥2 in pelvic RT patients (V20Gy ≥75%) also applied to our patient population (V20Gy ≥70%).
      • 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.
      ,
      • Rose BS
      • Aydogan B
      • Liang Y
      • et al.
      Normal tissue complication probability modeling of acute hematologic toxicity in cervical cancer patients treated with chemoradiotherapy.
      Additionally, validation of the RTOG-identified BM constraint (V40Gy >37%)
      • Klopp AH
      • Moughan J
      • Portelance L
      • et al.
      Hematologic toxicity in RTOG 0418: A phase 2 study of postoperative IMRT for gynecologic cancer.
      is limited, because only 4 patients in the 52-patient cohort had a BM V40Gy >37%. All 4 of the patients in our cohort with V40 Gy >37% experienced both HT ≥2 and leukopenia ≥2. Of the 48 remaining patients with V40Gy ≤ 37%, 44 (92%) and 40 (83%) experienced HT ≥2 and leukopenia ≥2, respectively. Unsurprisingly, the HT ≥2 rates in our study of EF-CRT are much higher than the findings of Klopp et al, who reported that 40% of patients with V40Gy ≤ 37% experienced HT ≥2.
      • Klopp AH
      • Moughan J
      • Portelance L
      • et al.
      Hematologic toxicity in RTOG 0418: A phase 2 study of postoperative IMRT for gynecologic cancer.
      Overall, the inability to extrapolate this particular pelvic BM dosimetric constraint may be owed to the much larger radiation field used in EFRT, which extends up the spine, generally to T12 or L1. To that end, our results suggest that some previously published pelvic BM constraints may not be applicable to the extended-field radiation setting.
      When we evaluated the only other described radiation metric in the extended-field setting, mean BM >V30.3Gy, we similarly did not observe an association with HT.
      • Yan K
      • Ramirez E
      • Xie XJ
      • et al.
      Predicting severe hematologic toxicity from extended-field chemoradiation of para-aortic nodal metastases from cervical cancer.
      This may be owed to the almost exclusive use of IMRT in our study as compared with the cohort from Yan et al.
      • Yan K
      • Ramirez E
      • Xie XJ
      • et al.
      Predicting severe hematologic toxicity from extended-field chemoradiation of para-aortic nodal metastases from cervical cancer.
      However, the overall rate of HT ≥3 was similar between our study and that by Yan et al, at approximately 50%. This may be explained by the higher stage of disease of patients in our cohort (43% vs 26% were FIGO ≥III), with the caveat that the staging was based on FIGO 2009 staging. In our practice, most patients who receive IMRT receive a simultaneous integrated boost for any gross nodal involvement, which may further lead to variation in dosimetric patterns between 3D-CRT and IMRT planning.
      • Vargo JA
      • Kim H
      • Choi S
      • et al.
      Extended field intensity modulated radiation therapy with concomitant boost for lymph node-positive cervical cancer: Analysis of regional control and recurrence patterns in the positron emission tomography/computed tomography era.
      Another potential explanation is that physicians may have modified the systemic therapy regimen once hematologic cell lines were noted to decrease and depending on the timing of brachytherapy, which may differ between institutional practices. We postulate that differences in treatment planning, small patient numbers, physician behavior, and the patient population itself may have led to the differences observed between these 2 studies.
      Comparison with other published dosimetric pelvic BM constraints is unsurprisingly difficult given the small sample size (N <100) of each of the published cohorts.
      • 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.
      ,
      • Yan K
      • Ramirez E
      • Xie XJ
      • et al.
      Predicting severe hematologic toxicity from extended-field chemoradiation of para-aortic nodal metastases from cervical cancer.
      ,
      • Rose BS
      • Aydogan B
      • Liang Y
      • et al.
      Normal tissue complication probability modeling of acute hematologic toxicity in cervical cancer patients treated with chemoradiotherapy.
      ,
      • Klopp AH
      • Moughan J
      • Portelance L
      • et al.
      Hematologic toxicity in RTOG 0418: A phase 2 study of postoperative IMRT for gynecologic cancer.
      Given the high volume receiving 5 Gy that was noted in this study (V5Gy ≥98%), it is unclear whether the dosimetric constraint is clinically meaningful. Additionally, the V20Gy constraint was found to be important in both this study and a prior pelvic RT study.
      • 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.
      ,
      • Rose BS
      • Aydogan B
      • Liang Y
      • et al.
      Normal tissue complication probability modeling of acute hematologic toxicity in cervical cancer patients treated with chemoradiotherapy.
      Taken together, these findings suggest that heightened attention to volumetric low-dose spill to the BM may be beneficial to reduce rates of HT. From a radiobiological perspective, the exquisite radiation sensitivity of hematopoietic cells is well established and supports this low-dose importance conceptually.
      • Radford IR.
      Radiation response of mouse lymphoid and myeloid cell lines. Part I: Sensitivity to killing by ionizing radiation, rate of loss of viability, and cell type of origin.
      The general concept of the importance of low-dose radiation is consistent with other published series,
      • 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.
      ,
      • Rose BS
      • Aydogan B
      • Liang Y
      • et al.
      Normal tissue complication probability modeling of acute hematologic toxicity in cervical cancer patients treated with chemoradiotherapy.
      but the optimal cutoff from an inverse planning perspective has not been robustly identified in the extended-field radiation setting. Despite these limitations, the overall higher rates of HT in the extended-field setting compared with the treatment of the pelvis suggest that there should be further investigation into meaningful dose constraints for patients undergoing EF-CRT.
      Although a validated dose constraint for EF-CRT is needed, more stringent constraints may result in increased toxicity in other organs at risk.
      • Verma J
      • Sulman EP
      • Jhingran A
      • et al.
      Dosimetric predictors of duodenal toxicity after intensity modulated radiation therapy for treatment of the para-aortic nodes in gynecologic cancer.
      ,
      • George G
      • Lewis S
      • Chopra S
      • et al.
      A retrospective study of the dosimetric parameters and duodenal toxicity in patients with upper gastrointestinal and gynaecological cancers treated with radiation therapy.
      However, as suggested by the INTERTECC-II trial and a phase 2 study out of India, IMRT has the potential benefit to reduce both gastrointestinal and HT.
      • Mell LK
      • Sirák I
      • Wei L
      • et al.
      Bone marrow-sparing intensity modulated radiation therapy with concurrent cisplatin for stage IB-IVA cervical cancer: An international multicenter phase II clinical trial (INTERTECC-2).
      • Williamson CW
      • Sirák I
      • Xu R
      • et al.
      Positron emission tomography-guided bone marrow-sparing radiation therapy for locoregionally advanced cervix cancer: Final results from the INTERTECC phase II/III trial.
      • Kapoor AR
      • Bhalavat R
      • Chandra M
      • et al.
      Assessment of impact of bone marrow sparing for hematological and gastrointestinal toxicities in cervical cancer with external beam radiation therapy.
      Other methods of decreasing HT may include further investigation optimizing chemotherapy delivery and dosing. For instance, there is some suggestion that cisplatin administered every 3 weeks is associated with lower rates of HT.
      • Ryu SY
      • Lee WM
      • Kim K
      • et al.
      Randomized clinical trial of weekly vs triweekly cisplatin-based chemotherapy concurrent with radiotherapy in the treatment of locally advanced cervical cancer.
      Advances in imaging, radiation techniques, and improved patient selection of those who would benefit most from prophylactic para-aortic nodal radiation may assist in reducing the high rates of HT associated with EF-CRT.

      Limitations and future directions

      Aside from the retrospective nature of our study, we were principally limited by a small data set. However, to our knowledge, our study is the largest and only IMRT-exclusive cohort to describe HT in EF-CRT. In addition, our data set comprised patients from multiple treatment centers, which may have biased data by differences in practice patterns of oncologists or of the patient cohort. However, radiation treatment planning was performed using consistent extended-field radiation treatment fields and dosing schemes. Moreover, the multi-institutional nature of this study may improve generalizability. It is also unclear whether varying dose metrics would apply to different anatomic bone marrow regions. Perhaps the biggest limitation of the study was the lack of positron emission tomography (PET) or other functional imaging methods to predict areas of active BM to be used as avoidance structures.
      • McGuire SM
      • Menda Y
      • Ponto LL
      • et al.
      A methodology for incorporating functional bone marrow sparing in IMRT planning for pelvic radiation therapy.
      • Elicin O
      • Callaway S
      • Prior JO
      • et al.
      18)F]FDG-PET standard uptake value as a metabolic predictor of bone marrow response to radiation: Impact on acute and late hematological toxicity in cervical cancer patients treated with chemoradiation therapy.
      • 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.
      INTERTECC-2 specifically attempted to address this question in a prospective cohort and found that the use of functional image–guided RT to guide BM sparing techniques was associated with lower rates of neutropenia compared with standard IMRT for patients treated with nonextended-field chemoradiation.
      • Mell LK
      • Sirák I
      • Wei L
      • et al.
      Bone marrow-sparing intensity modulated radiation therapy with concurrent cisplatin for stage IB-IVA cervical cancer: An international multicenter phase II clinical trial (INTERTECC-2).
      ,
      • Williamson CW
      • Sirák I
      • Xu R
      • et al.
      Positron emission tomography-guided bone marrow-sparing radiation therapy for locoregionally advanced cervix cancer: Final results from the INTERTECC phase II/III trial.
      On the contrary, Yan et al did not find an added benefit to the use of functional imaging in identifying dosimetric predictors of HT in the extended-field setting.
      • Yan K
      • Ramirez E
      • Xie XJ
      • et al.
      Predicting severe hematologic toxicity from extended-field chemoradiation of para-aortic nodal metastases from cervical cancer.
      Active BM defined by PET was not included in our study because of the challenges in deformable registration of the PET scans to the treatment-planning computed tomography scans owing to the large fields involved. These technical factors may have contributed to the lack of benefit of functional imaging as observed by Yan et al. Moreover, areas of active BM are common among patients and primarily appear to be in the sacrum and thoracolumbar spine,
      • Li N
      • Noticewala SS
      • Williamson CW
      • et al.
      Feasibility of atlas-based active bone marrow sparing intensity modulated radiation therapy for cervical cancer.
      which may be difficult to meaningfully avoid with low-dose isodose lines when treating para-aortic disease burden. Overall, more work must be done to further explore methods to decrease HT for extended-field radiation therapy, including exploring the potential utility and feasibility of integrating functional imaging for BM sparing techniques, such as development of a standardized atlas that is inclusive of the para-aortic region.

      Conclusions

      In conclusion, our results demonstrate that there may be a role in dosimetric constraints to limit HT for patients undergoing EF-CRT. Acute HT in patients receiving EF-CRT was associated with BM radiation dose and race but not with age, BMI, or CCI. Limiting low-dose BM V5Gy to <98% and V20Gy to <70% to 75% may reduce rates of HT ≥2 and the subsequent need for chemotherapy reduction or treatment interruption. Given the limitation of sample size as well as the retrospective nature of the data, these findings are hypothesis generating, and future studies are needed to further validate these results. Overall, these data support the role of BM-sparing techniques to reduce HT for patients receiving EF-CRT.

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