Patients with locally advanced cervical cancer (LACC) treated with chemoradiation often experience hematologic toxicity (HT), as chemoradiation can induce bone marrow (BM) suppression. Studies on the relationship between BM dosimetric parameters and clinically significant HT might provide relevant indices for developing BM sparing (BMS) radiotherapy techniques. This systematic review studied the relationship between BM dose and HT in patients with LACC treated with primary cisplatin-based chemoradiation. A systematic search was conducted in Embase, Medline, and Web of Science. Eligibility criteria were treatment of LACC-patients with cisplatin-based chemoradiation and report of HT or complete blood cell count (CBC). The search identified 1346 papers, which were screened on title and abstract before two reviewers independently evaluated the full-text. 17 articles were included and scored according to a selection of the TRIPOD criteria. The mean TRIPOD score was 12.1 out of 29. Fourteen studies defining BM as the whole pelvic bone contour (PB) detected significant associations with V10 (3/14), V20 (6/14), and V40 (4/11). Recommended cut-off values were V10 > 95-75%, V20 > 80-65%, and V40 > 37-28%. The studies using lower density marrow spaces (PBM) or active bone marrow (ABM) as a proxy for BM only found limited associations with HT. Our study was the first literature review providing an overview of articles evaluating the correlation between BM and HT for patients with LACC undergoing cisplatin-based chemoradiation. There is a scarcity of studies independently validating developed prediction models between BM dose and HT. Future studies may use PB contouring to develop normal tissue complication probability models.

External beam radiation therapy (EBRT) with concurrent chemotherapy followed by brachytherapy is a very effective treatment for locally advanced cervical cancer (LACC). However, treatment-related toxicity is common and reduces the patient’s quality of life (QoL) and ability to complete treatment or undergo adjuvant therapies. Intensity modulated proton therapy (IMPT) enables a significant dose reduction in organs at risk (OAR), when compared to that of standard intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (VMAT). However, clinical studies evaluating whether IMPT consequently reduces side effects for LACC are lacking. The PROTECT trial is a nonrandomized prospective multicenter phase-II-trial comparing clinical outcomes after IMPT or IMRT/VMAT in LACC. Thirty women aged >18 years with a histological diagnosis of LACC will be included in either the IMPT or IMRT/VMAT group. Treatment includes EBRT (45 Gy in 25 fractions of 1.8 Gy), concurrent five weekly cisplatin (40 mg/m²), and 3D image (MRI)-guided adaptive brachytherapy. The primary endpoint is pelvic bones D_mean and mean bowel V_15Gy. Secondary endpoints include dosimetric parameters, oncological outcomes, health-related QoL, immune response, safety, and tolerability. This study provides the first data on the potential of IMPT to reduce OAR dose in clinical practice and improve toxicity and QoL for patients with LACC.

Women with locally advanced cervical cancer (LACC) undergoing primary platinum-based chemoradiotherapy and brachytherapy often experience toxicities. Normal-tissue complication probability (NTCP) models quantify toxicity risk and aid in optimizing radiation therapy to minimize side effects. However, it is unclear which predictors to include in an NTCP model. The aim of this systematic review was to provide an overview of the identified predictors contributing to gastrointestinal (GI), genitourinary (GU), and vaginal toxicities and insufficiency fractures for LACC. A systematic search was performed and articles evaluating the relationship between predictors and toxicities in women with LACC treated with primary chemoradiation were included. The Quality In Prognosis Studies tool was used to assess risk of bias, with high-risk studies being excluded from further analysis. Relationships between dose-volume parameters, patient and treatment characteristics, and toxicity endpoints were analyzed. Seventy-three studies were identified. Twenty-six had a low or moderate risk of bias and were therefore included. Brachytherapy-related dose-volume parameters of the GI tract, including rectum and bowel equivalent dose in 2 Gy fractions (EQD2) D2 cm³, were frequently related to toxicities, unlike GU dose-volume parameters. Furthermore, (recto)vaginal point doses predicted toxicities. Few studies evaluated external beam radiation therapy dose-volume parameters and identified rectum EQD2 V30 Gy, V40 Gy, and V55 Gy, bowel and bladder EQD2 V40 Gy as toxicity predictors. Also, total reference air kerma and vaginal reference length were associated with toxicities. Relationships between patient characteristics and GI toxicity were inconsistent. The extent of vaginal involvement at diagnosis, baseline symptoms, and obesity predicted GU or vaginal toxicities. Only 1 study evaluated insufficiency fractures and demonstrated lower pretreatment bone densities to be associated. This review detected multiple candidate predictors of toxicity. Larger studies should consider insufficiency fractures, assess dose levels from external beam radiation therapy, and quantify the relationship between the predictors and treatment-related toxicities in women with LACC to further facilitate NTCP model development for clinical use.

Objective. A dynamic model is developed to predict the impact of radiotherapy on circulating lymphocyte counts in women with locally advanced cervical cancer (LACC). This study aims to compare the effects of photon and proton therapy, as well as the influence of bone marrow sparing (BMS) techniques, on relative lymphocyte preservation over time. Approach. A dynamic lymphocyte flow model was developed to simulate the migration of lymphocytes based on seven compartments. Biological cell death and lymphocyte production were integrated across compartments. The lymphocyte flow model was applied to 19 LACC patients. Volumetric modulated arc therapy (VMAT) and intensity modulated proton therapy (IMPT) treatment plans were created for each patient without BMS and with BMS. The model calculated radiation dose to lymphocytes to estimate radiation-induced cell death over time. The output of the model was the relative lymphocyte count relative to baseline (RLC) over time and the RLC nadir in the blood and total body. Main results. According to the model, IMPT resulted in lower doses to lymphocyte and higher RLC nadirs compared to VMAT for all 19 patients. The total RLC nadir (mean ± SD) was 48.4% ± 4.0% for VMAT and 62.5% ± 5.1% for IMPT. In the blood compartment, the RLC nadir was 32.7% ± 3.5% for VMAT and 47.7% ± 5.9% for IMPT. The RLC nadir in the blood compartment improved with 3 Gy BMS from 32.7% ± 3.5% to 33.0% ± 3.5% , while it decreased for IMPT from 47.7% ± 5.9% to 46.6% ± 6.0%. Total RLC nadir decreased with BMS for VMAT from 48.4% ± 4.0% to 48.2% ± 3.9% and for IMPT from 62.5% ± 5.1% to 60.9% ± 5.3%. Significance. By incorporating a dynamic flow model, we predicted the RLC over time. The model predicted a substantial sparing effect IMPT has on the lymphocytes compared to VMAT. This sparing was both present in the blood and the total body. Sparing the bone marrow showed only a minimal effect on the RLC.

Gastrointestinal (GI) side effects are common after radiotherapy for gynecological cancers. Normal tissue complication probability (NTCP) models providing individual risk estimates for GI adverse events in gynecological cancers are not yet available. The aim of this study was to develop NTCP models for GI toxicity after postoperative (chemo)radiotherapy for cervical cancer. Data from the phase-III PARCER trial (NCT01279135) was used. Tested variables included patient- and treatment-related characteristics and dosimetric parameters of small, large, and total individual bowel loops, and bowel bag as peritoneal space. NTCP endpoints included acute and late ≥G2 diarrhea and GI toxicity (CTCAEv3.0) and late persistent GI toxicity defined with the Cumulative-Month and Severity Score (C-MOSES). Logistic or Cox regression were used for multivariable models, selecting variables with Least Absolute Shrinkage and Selection Operator. Internal model performance was evaluated with area-under-the-curve (AUC) or C-index. The median follow-up of the 283 included patients was 43 months. Volumes of the bowel receiving 30 Gy (V30Gy) and 40 Gy (V40Gy) were associated with acute and late ≥G2 diarrhea and persistent GI toxicity. IMRT reduced risk of late ≥G2 and persistent GI toxicity, whereas radical hysterectomy with bilateral lymphadenectomy increased it. AUC/C-indices ranged from 0.588 (persistent GI toxicity) to 0.761 (late ≥ G2 diarrhea). NTCP models for acute and late diarrhea and persistent GI toxicity after postoperative radiotherapy for cervical cancer included bowel V30Gy and V40Gy. Furthermore, 3DCRT and more extensive surgery increased risks. Further studies should explore additional variables to improve model performance, reach consensus on bowel delineation methods, and validate models externally.

Chemoradiotherapy is immunosuppressive in women with locally advanced cervical cancer (LACC). Both advanced external-beam radiation therapy (EBRT) and bone marrow sparing (BMS) radiotherapy techniques might lower bone marrow dose and therefore reduce the impact on the immune system. In this study, immune composition and function changes in the blood of women with LACC were evaluated for BMS volumetric-modulated arc therapy (VMAT) and exploratively compared with a historical cohort of women with LACC who underwent non-BMS radiotherapy (RT) with older EBRT techniques. Women were treated with chemoradiotherapy followed by brachytherapy according to EMBRACE-II protocol (BMS VMAT) or with 46–52.5 Gy in 23–30 fractions (non-BMS RT). Blood samples for immunomonitoring were collected at set timepoints. Statistical analyses were performed using linear mixed-effects models. Eighteen and eleven women received BMS VMAT and non-BMS RT, respectively. Although BMS VMAT reduced mean pelvic bone dose by 8.1 Gy, it did not prevent treatment-induced leukopenia and lymphopenia. Chemoradiotherapy mainly reduced CD4+ T helper cells and B cells, leaving CD8+ T-cell and natural killer-cell frequencies untouched. T-cell reactivity to common pathogens was decreased, despite sustained T-cell proliferative capacity, and coincided with increased numbers of regulatory T cells. The potential to activate immune cells remained intact, with small increases in dendritic cells, decreases in myeloid-derived suppressor cells, and preserved capacity of myeloid cells to present antigen and activate T cells. Our study provided insight in the dynamic immune changes following chemoradiotherapy in LACC. As immunosuppression occurred with BMS VMAT, optimizing BMS and exploring other techniques is warranted.