Hematologic Toxicity and Bone Marrow-Sparing Strategies in Chemoradiation for Locally Advanced Cervical Cancer: A Systematic Review
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Search Strategy
2.2. Search Terms
2.3. Eligibility Criteria
2.4. Data Extraction and Analysis
2.5. Quality Assessment
3. Results
3.1. Search Results
3.2. Population Characteristics
3.3. Therapy Regimens
3.4. Hematologic Toxicity
3.5. Pelvic Bone
3.5.1. Delineation Methods
3.5.2. Correlation between Dose Received by the Bone Marrow (Pelvic Bone) and HT Grades
Whole Bone
Substructures
Correlation between Active Bone Marrow and HT
Low-Density Bone Marrow Spaces
Recommended Cut-off Values
4. Discussion
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
3D: | three-dimensional conformal radiotherapy |
[18F]FDG-PET: | 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography |
ABM: | active bone marrow |
ANC: | absolute neutrophil count |
AP/PA: | anterior–posterior/posterior–anterior |
BM: | bone marrow |
BMS: | bone marrow sparing |
BSA: | body surface area |
BT: | brachytherapy |
CRT: | chemoradiotherapy |
CT: | computed tomography |
CTCAE: | Common Terminology Criteria for Adverse Events |
CTx: | chemotherapy |
Cy: | cycles |
FB: | femoral bone |
FU: | follow-up |
GI: | gastrointestinal |
GU: | genitourinary |
Gy: | Gray |
Hb: | hemoglobin |
HPV: | human papillomavirus |
HT: | hematologic toxicity |
IBM: | inactive bone marrow |
IC: | iliac crest |
IL: | os ilium |
IMRT: | intensity-modulated radiation therapy |
IS: | os ischium |
LKP: | leukopenia |
LPB: | lower pelvic bone |
LPBM: | lower pelvic bone marrow |
LS: | lumbar spine |
LSS: | lumbosacral spine |
LSSBM: | lumbosacral spine marrow |
LYM: | lymphocytes |
LYP: | lymphopenia |
NLR: | neutrophil-to-lymphocyte ratio |
NTP: | neutropenia |
OAR: | organ at risk |
PABM: | pelvic active bone marrow |
PB: | pelvic bone |
PBM: | pelvic bone marrow |
PBMS: | pelvic bone marrow sparing |
PLT: | platelets (thrombocytes) |
PTV: | planning target volume |
RCT: | randomized controlled trial |
RT: | radiation therapy |
SB: | sacral bone |
SUV: | standardized uptake value |
Tc-99m SPET: | technetium-99m sulfur colloid single-photon emission tomography |
TOMO: | tomotherapy |
VMAT: | volumetric modulated arc therapy |
WB: | whole body |
WBC: | white blood cells |
WPB: | whole pelvic bone |
Vx: | volume receiving x Gy |
WPBM: | whole pelvic bone marrow |
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Inclusion Criteria | Exclusion Criteria |
---|---|
Patients with cervical cancer who received (chemo)radiation therapy | Letters, reviews, abstracts and editorials |
Studies reporting on the correlation between hematologic toxicity and the radiation dose received by the pelvic bone marrow | Studies published in languages other than English or German |
Studies with a minimum of 10 patients | Mixed histologies that cannot be analyzed separately |
Publications from 2006 onwards | Studies before the year 2006 |
Both pre- and postoperative settings considered |
Author and Year | Number of Patients | Study Design | RT Intention | Dose Prescription | RT Technique | Chemotherapeutic Regimen | CTx Cycles (Patients in %) |
---|---|---|---|---|---|---|---|
Mell, 2006 [21] | 37 | Retrospective case series | Definitive (91.9%)/postoperative (8.1%) | 39.6–50.4 Gy | IMRT + BT | Cisplatin 40 mg/m2 weekly | 6 cy: 2.7%, 5 cy: ≈46%, 4 cy: ≈35% |
Rose, 2011 [22] | 81 | Retrospective case series and validation cohort | definitive | 39.6–50.4 Gy | IMRT + BT | Cisplatin 40 mg/m2 weekly | 4 cy: 20%, 5 cy: 34%, 6 cy: 25%, 55% at least 1 cy |
Albuquerque, 2011 [23] | 40 | Retrospective case series | Definitive | 45 Gy | 3D | Cisplatin 40 mg/m2 weekly | Not mentioned |
Klopp, 2013 [24] | 40 | Prospective cohort study | Postoperative | 50.4 Gy | IMRT | Cisplatin 40 mg/m2 weekly | 5 cy ≥ 83%, 4 cy ≥ 90%, 4 cy < 7.5% |
Zhu, 2015 [25] | 102 | Retrospective cohort study | Postoperative/definitive | 39.6–50.4 Gy | IMRT (97.1%)/3D (2.9%) +BT | Cisplatin 40 mg/m2 weekly | 6 cy: 20%, 5 cy: 38%, 4 cy: 22%, 3 cy: 11%, 2 cy: 5%, 1 cy: 4% |
Chang, 2016 [26] | 100 | Retrospective case series/cohort study | Definitive | 50.4–56 Gy | 3D (32%)/IMRT (37%)/ IMRT (RapidArc; 31%) + BT | Cisplatin 25 mg/m2 | 3–6 cy |
Li, 2016 [12] | 100 | Retrospective case series | Postoperative | 40–50 Gy | 2D (AP/PA: 77%)/IMRT (23%) | 52% received CT (paclitaxel/nedaplatin). Concomitantly: 15%; induction CT: 47%. | 6 cy ≥ 4%, 5 cy: 1%, 4 cy: 5%, 3 cy: 4%, 2 cy: 17%, 1 cy: 21% |
Bosque, 2018 [27] | 59 | Retrospective cohort study | Not mentioned | 45–50.4 Gy | 3D + BT | Cisplatin (93.2%)/carboplatin (6.7%) weekly | 5 cy ≥ 22%, 5 cy < 77.9% |
Ajayakumar, 2018 [28] | 47 | Prospective observational study | Definitive | 45–50.4 Gy | 3D (53.2%)/IMRT (46.8%) + BT | Cisplatin 40 mg/m2 weekly | Not mentioned |
Zhang, 2023 [29] | 117 | Retrospective case series | Definitive | 50.4 Gy | IMRT (24.79%)/VMAT (75.21%) + BT | Induction CT: (paclitaxel/cisplatin; 78.63%). Concomitant CT: cisplatin 25 mg/m2 weekly | 5 cy: 43.6%, 3–4 cy: 56.4% |
Chen, 2023 [30] | 69 | Retrospective case series | Definitive (36.2%)/postoperative (63.8%) | 45–50.4 Gy | IMRT +BT | Cisplatin 40 mg/m2 weekly | 3–4 cy: 62.3%, 5–6 cy: 37.7% |
Sun, 2023 [31] | 40 | Prospective observational study | Postoperative | 50 Gy | IMRT (50%) and PBMS-IMRT (50%) | Cisplatin 35–40 mg/m2 weekly | Not mentioned |
Mahantshetty, 2012 [32] | 47 | Retrospective case series | Definitive | 50 Gy | IMRT + BT | Cisplatin 40 mg/m2 weekly | 4 cy ≥ 95%, 2 cy ≤ 5% |
Lewis, 2018 [33] | 75 | Retrospective case series | Postoperative | 50 Gy | IMRT (TOMO) | Cisplatin 40 mg/m2 (98.7%)/carboplatin (1.3%) weekly | 6 cy: 1.3%, 5 cy: 69.3%, 4 cy: 24%, 3 cy: 1.3%, 2 cy: 2.7%, 1 cy: 1.3% |
Kumar, 2019 [34] | 114 | Retrospective case series | Definitive | 45 Gy (+Boost up to 60 Gy) | 3D (75.4%)/IMRT (24.6%) + BT | Cisplatin 40 mg/m2 (89.5%) or carboplatin AUC2 (10.5%) weekly in case of renal impairment | 5 cy: 76.3%, 4 cy: 19.3%, 4 cy < 4.4% |
Huang, 2020 [35] | 164 | Prospective RCT | Definitive | 50.4 Gy | IMRT + BT | Cisplatin 40 mg/m2 weekly | PBMS group: 6 cy: 48.8%, 5 cy: 40.2%, 4 cy: 8.5%, 2 cy: 1.2%, 1 cy: 1.2% Control group: 6 cy: 45.1%, 5 cy: 37.8%, 4 cy: 17.1% |
Singareddy, 2021 [36] | 34 | Prospective observational study | Definitive | 50 Gy | IMRT (VMAT) + BT | Cisplatin 40 mg/m2 weekly | 5 cy: 85.2%, 4 cy: 11.8%, 3 cy: 2.9% |
Rose, 2012 [37] | 26 | Retrospective case series | Definitive 81%; postoperative 19% | 45–50.4 Gy (+ Boost up to 60–66 Gy) | IMRT + BT | Cisplatin 40 mg/m2 weekly | 6 cy: 27%, 5 cy: 35%, 4 cy: 15%, 3 cy: 15%, 1 cy: 8% |
Elicin, 2014 [38] | 17 | Retrospective case series | Definitive | 45–50.4 Gy (+ Boost up to 60 Gy) | IMRT (TOMO) + BT | Cisplatin 40 mg/m2 weekly | 5 cy: 100% |
Khullar, 2017 [39] | 21 | Retrospective case series | Definitive | 45–50.4 Gy | 3D (76%)/IMRT (14%)/both (9%) | Cisplatin | 2–7 cy; ≥5 cy: 61.9% |
Yan, 2018 [40] | 38 | Retrospective case series | Definitive | 45 Gy (+ Boost up to 55–60 Gy) | 3D/IMRT + BT | Cisplatin 40 mg/m2 weekly | Not mentioned |
Zhou, 2018 [41] | 31 | Retrospective case series | Definitive/postoperative | 45–68 Gy | 3D (58%)/IMRT (42%) | Cisplatin 40 mg/m2 weekly | 0 cy: 29%, 1–3 cy: 19%, 4–5 cy: 32%, 6–7 cy: 19% |
Wang, 2019 [42] | 39 | Prospective cohort study | Definitive | 45 Gy (+ Boost 10–20 Gy) | IMRT (VMAT) + BT | Cisplatin 30–40 mg/m2 weekly | 5 cy: 84.6%, 4 cy: 15.4% |
Williamson, 2022 [43] | 101 | Prospective | Definitive | 45–50.4 Gy (+ Boost up to 59.4 Gy) | IMRT + BT | Cisplatin 40 mg/m2 weekly | ≥5 cy > 80% |
Author and Year | HT Assessment Method | HT Assessment Frequency | Blood Components Analyzed | HT Incidence |
---|---|---|---|---|
Mell, 2006 [21] | RTOG | Weekly during CRT | WBC, ANC, Hb, PLT | G2+ LKP 43.2%, NTP 18.9% |
Rose, 2011 [22] | RTOG | Weekly during CRT | WBC, ANC, Hb, PLT | G2+ LKP 74%, NTP 48% |
Albuquerque, 2011 [23] | CTCAE 3.0 | During CRT | WBC, ANC, Hb, PLT | G2+ HT 67.5% |
Klopp, 2013 [24] | CTCAE 3.0 | Not mentioned | Not mentioned | G2+ HT 58%, G3+ HT 25% |
Zhu, 2015 [25] | Not mentioned | Weekly during CRT | WBC, ANC, Hb, PLT | Not mentioned |
Chang, 2016 [26] | Not mentioned | Weekly during CRT | WBC, ANC, Hb, PLT | G2+ LKP: 3D/IMRT/RapidARC: 100%/78.4%/80.6% G3+ LKP: 78.1%/40.5%/48.4% G2+ NTP: 93.7%/64.9%/67.7% G3+ NTP: 65.6%/27.0%/29.0% |
Li, 2016 [12] | RTOG | Weekly and 120 days after start of RT | WBC, ANC, Hb, PLT | G2+ HT 47% |
Bosque, 2018 [27] | RTOG | Not mentioned | WBC, ANC, Hb, PLT | G2+ HT 50.8% |
Ajayakumar, 2018 [28] | RTOG | Weekly during CRT | Not mentioned | G2+ 38.3% (3D: 72.2%/IMRT: 27.8%) |
Zhang, 2023 [29] | CTCAE 4.0 | Baseline, weekly during CRT and at 1 mo FU | LYM | G3+ LYP 68.38% |
Chen, 2023 [30] | RTOG | Weekly during CRT | LYM, ANC, Hb, PLT | G2+ NTP: 50.7%, Anemia: 21.7%, Thrombocytopenia: 24.6%. |
Sun, 2023 [31] | Not mentioned | Until 3-month FU | Not mentioned | IMRT: G2+ 45% vs. PBMS-IMRT:G2+ 25%. (p = 0.038). |
Mahantshetty, 2012 [32] | RTOG | Weekly during CRT | WBC, ANC, Hb, PLT | G2+ LKP 53%, NTP 29.8% |
Lewis, 2018 [33] | CTCAE 3.0 | Weekly during CRT | WBC, ANC, Hb, PLT | G2+ 57.4%, G3+ HT 14.7% |
Kumar, 2019 [34] | CTCAE 4.0 | Baseline, weekly during CRT and at least once within 2 weeks FU | WBC, LYM, ANC, Hb, PLT | G4+ LKP 2.6%, LYM 12.3% |
Huang, 2020 [35] | RTOG | Weekly during CRT | WBC, ANC, Hb, PLT | G2+ HT 50% |
Singareddy, 2021 [36] | RTOG | Baseline and weekly during CRT | WBC, Hb, PLT | G2+ HT 50% |
Rose, 2012 [37] | RTOG | Weekly during CRT | WBC, ANC, Hb, PLT | G3+ LKP 38.5%, NTP 23.1% |
Elicin, 2014 [38] | RTOG | 1 week before and weekly during CRT 3 months after CRT, and at last FU | WBC, ANC, Hb, PLT | G3+ LKP 35%, NTP 35% |
Khullar, 2017 [39] | CTCAE 4.0 | Weekly to 6 weeks after end of CRT | Not mentioned | G3+ HT 71.4% |
Yan, 2018 [40] | CTCAE 4.0 | Weekly during RCT | WBC, ANC, Hb, PLT | G3+ HT 50% |
Zhou, 2018 [41] | CTCAE 4.0 | Weekly and one week after CRT | WBC, ANC, Hb, PLT | G3+ HT 77% |
Wang, 2019 [42] | CTCAE 3.0 | Weekly to two weeks after CRT | WBC, ANC, Hb, PLT | G3+ LKP 46.2%, NTP 2.5% |
Williamson, 2022 [43] | Not mentioned | Not mentioned | LYM, ANC, Hb, PLT | PET-BMS-IMRT vs. IMRT: significantly reduced G3+ neutropenia (13% vs. 35%) |
Author and Year | Bone Marrow Delineation Method | Bone Marrow Substructure Definition | Bone Marrow Dose Constraint during Treatment Planning | Distinction between ABM and IBM | Extended-Field RT (Para-Aortic) | Dosimetric Predictors |
---|---|---|---|---|---|---|
Mell, 2006 [21] | CT-based PB contour | yes (LSS, IL, LPB) | no | no | no | PB-V10, V20 |
Rose, 2011 [22] | CT-based PB contour | no | no | no | no | PB V10, V20 |
Albuquerque, 2011 [23] | CT-based PB contour | yes (LSS, IL, LPB, PB+IL+LPB, WPB+LSS) | no | no | no | PB-V20 |
Klopp, 2013 [24] | CT-based PB contour | no | no | no | no | PB-V40, Dmean |
Zhu, 2015 [25] | CT-based PB contour | Yes (LSS, IC, LPB) | individual | no | no | PB-Dmean, V20, V30, V40, LSS-V10, V40, LPB-V20, V30 |
Chang, 2016 [26] | CT-based PB contour | no | no | no | no | PB-V20, V40 |
Li, 2016 [12] | CT-based PB contour | Yes (WPB, LSS)) | no | no | no | LSS-V5-40 and LPB-V5-40 |
Bosque, 2018 [27] | CT-based PB contour | no | no | no | not mentioned | none |
Ajayakumar, 2018 [28] | CT-based PB contour | Yes (WPB, LSS) | yes | no | no | PBM: V20, 30, 40. LSSBM: V40 |
Zhang, 2023 [29] | CT-based PB contour | no | no | no | not mentioned | PB V5, V10, V20 and V30 |
Chen, 2023 [30] | CT-based PB contour | Yes (IL, LPB, LSS) | no | no | no | Hb: R(elative)-LPB-V10, R-LPB-V25, R-LPB-V50, R-LPB-mean, A(bsolute)-LPB-V15, A-LPB-V25 and A-LPB-V30. PLT: R-LPB-V40. ANC: R-IL-V15 and R-IL-V50 and A-LPB-V50. NLR: R-LPB-V15 and A-PBM-mean |
Sun, 2023 [31] | CT-based PB contour | no | yes (V20 < 76% and V40 < 35% in the PBMS group) | no | no | none |
Mahantshetty, 2012 [32] | CT-based PB contour + BM defined as the low-density regions within the corresponding bones | yes (SB, IL, IS, LPB, LSS, WPB) | no | no | not mentioned | PBM-V40 |
Lewis, 2018 [33] | CT-based PB contour + BM defined as the low-density regions within the corresponding bones | yes (WPB+LS, LS, SB, IL, IS, FB, WPB, LPB) | no | no | not mentioned | Ilium-PB V20 |
Kumar, 2019 [34] | CT-based PB contour + BM defined as the low-density regions within the corresponding bones | yes (LSS, IC, LPB) | no | no | yes (13.2%) | PB-V20, LPB-V5,20, Iliac crest-Dmean |
Huang, 2020 [35] | CT-based PB contour + BM defined as the low-density regions within the corresponding bones | yes (WPB, LSS) | yes | no | no | PB: PB-V40, LSS-V10, Dmean; PBM: PBM-V40, LSSBM -V10, V20, V40, Dmean |
Singareddy, 2021 [36] | CT-based PB contour + BM defined as the low-density regions within the corresponding bones | no | no | no | no | WPBM-V20,30,40 and Dmean |
Rose, 2012 [37] | CT-based PB contour, [18F]FDG-PET based ABM (≥SUVmean WPB) | no | no | yes | yes (23%) | PABM Dmean |
Elicin, 2014 [38] | CT-based PB contour, [18F]FDG-PET based ABM (≥SUVmean WPB) | no | no | yes | yes (23.5%) | none |
Khullar, 2017 [39] | CT-based PB contour, [18F]FDG-PET based ABM (≥SUVmean WB) | no | no | yes | not mentioned | PABM volume, PABM-V40 |
Yan, 2018 [40] | CT-based PB contour, [18F]FDG-PET based ABM (≥SUVmean WPB) | no | no | yes | yes (100%) | PB-V20, V30, V45, Dmean; PABM-V10,20,30,45, Dmean |
Zhou, 2018 [41] | CT-based PB contour, [18F]FDG-PET ABM (≥SUVmean WB) | no | no | yes | not mentioned | PB-V10; PABM V10, 20,40 Gy |
Wang, 2019 [42] | CT-based PB contour, Tc-99m SPET (≥SUVmean WB) | no | no | yes | no | PABM volume, PABM-V30, V40 |
Williamson, 2022 [43] | CT-based PB contour, [18F]FDG-PET-based ABM (≥SUVmean WPBM) | no | yes (PBM and ABM mean doses were constrained to <27 Gy and <28.5 Gy; V10 <90% and V20 <75%) | yes | no | none |
Parameter | Recommended Dose Constraints |
---|---|
Whole Pelvic Bone (Marrow) | |
V10 | <90%, <95% |
V20 | ≤65%, <71.7%, <76%, <78.6%, <79.4%, <86.6% |
V30 | <47.1%, <49.7%, <57% |
V40 | <22.8%, <28%, <29%, ≤37%, <40% |
V45 | < 20.4% |
Dmean | <28.8 Gy, <30.3 Gy, ≤34.2 Gy, <39.0 Gy, |
Volume spared 10 Gy | ≥230 cc |
Substructures (Bone Marrow) | |
LPB-V5 | ≤95% |
LSS-V10 | <87% |
LPB-V20, IL-PB-V20 | ≤45%, ≤90% |
LSS-V40 | <50.9% |
Dmean IC | ≤31 Gy |
Pelvic Active Bone Marrow | |
V10 | <95.5% |
V20 | <80.5% |
V30 | <46.5%, <59.6% |
V40 | <23.5% |
V45 | <31.7% |
Dmean | <26.8 Gy, <32.4 Gy |
Baseline PABM volume | >387.5 cc, ≥1201 cc |
Volume spared (V10, V20, V40) | ≥179 cc, ≥186 cc, ≥738 cc |
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Konnerth, D.; Gaasch, A.; Zinn, A.; Rogowski, P.; Rottler, M.; Walter, F.; Knoth, J.; Sturdza, A.; Oelmann, J.; Grawe, F.; et al. Hematologic Toxicity and Bone Marrow-Sparing Strategies in Chemoradiation for Locally Advanced Cervical Cancer: A Systematic Review. Cancers 2024, 16, 1842. https://doi.org/10.3390/cancers16101842
Konnerth D, Gaasch A, Zinn A, Rogowski P, Rottler M, Walter F, Knoth J, Sturdza A, Oelmann J, Grawe F, et al. Hematologic Toxicity and Bone Marrow-Sparing Strategies in Chemoradiation for Locally Advanced Cervical Cancer: A Systematic Review. Cancers. 2024; 16(10):1842. https://doi.org/10.3390/cancers16101842
Chicago/Turabian StyleKonnerth, Dinah, Aurelie Gaasch, Annemarie Zinn, Paul Rogowski, Maya Rottler, Franziska Walter, Johannes Knoth, Alina Sturdza, Jan Oelmann, Freba Grawe, and et al. 2024. "Hematologic Toxicity and Bone Marrow-Sparing Strategies in Chemoradiation for Locally Advanced Cervical Cancer: A Systematic Review" Cancers 16, no. 10: 1842. https://doi.org/10.3390/cancers16101842