Phase 2 Multicenter Clinical Trial of Bone Marrow–Sparing Intensity Modulated Radiation Therapy With Concurrent Cisplatin for Stage IB-IVA Cervical Cancer

Abstract

SummaryWe performed an international phase II trial to test the Purpose: To test the hypothesis that intensity modulated radiation therapy (IMRT) reduces acute hematologic and gastrointestinal (GI) toxicity for patients with locoregionally advanced cervical cancer. hypothesis that intensity modulated radiation therapy (IMRT) would reduce the acute toxicity for locoregionally advanced cervical cancer. For the 83 patients enrolled, acute gastrointestinal toxicity was significantly reduced with both IMRT and positron emission tomography-guided bone marrow sparing IMRT (IG-IMRT) compared with historical controls. The incidence of neutropenia was significantly reduced in patients who underwent IG-IMRT. We conclude that IMRT reduces acute toxicity compared with standard treatment in this population and that IG-IMRT warrants testing in randomized trials.Methods and Materials: We enrolled patients with stage IB-IVA cervical carcinoma in a single-arm phase II trial involving 8 centers internationally. All patients received weekly cisplatin concurrently with once-daily IMRT, followed by intracavitary brachytherapy, as indicated. The primary endpoint was the occurrence of either acute grade !3 neutropenia or clinically significant GI toxicity within 30 days of completing chemoradiation therapy. A preplanned subgroup analysis tested the hypothesis that positron emission tomography-based image-guided IMRT (IG-IMRT) would lower the risk of acute neutropenia. We also longitudinally assessed patients' changes in quality of life. Results: From October 2011 to April 2015, 83 patients met the eligibility criteria and initiated protocol therapy. The median follow-up was 26.0 months. The incidence of any primary event was 26.5% (95% confidence interval [CI] 18.2%-36.9%), significantly lower than the 40% incidence hypothesized a priori from historical data (PZ.012). The incidence of grade !3 neutropenia and clinically significant GI toxicity was 19.3% (95% CI 12.2%-29.0%) and 12.0% (95% CI 6.7%-20.8%), respectively. Compared with patients treated without IG-IMRT (nZ48), those treated with IG-IMRT (nZ35) had a significantly lower incidence of grade !3 neutropenia (8.6% vs 27.1%; 2-sided c 2 PZ.035) and nonsignificantly lower incidence of grade !3 leukopenia (25.7% vs 41.7%; PZ.13) and any grade !3 hematologic toxicity (31.4% vs 43.8%; PZ.25). Conclusions: IMRT reduces acute hematologic and GI toxicity compared with standard treatment, with promising therapeutic outcomes. Positron emission tomography IG-IMRT reduces the incidence of acute neutropenia. Ó

Feasibility of bone marrow sparing volumetric modulated arc therapy to spare active bone marrow in cervical and vaginal cancer patients: a retrospective dosimetric analysis

“…The V10-20Gy has been optimised in prospective research, which have demonstrated reductions in HT. 14,16 We found that the V10Gy < 90%, V20Gy < 75% and V30Gy < 60% could be met in 100% of cases where VMAT margins were utilised (Table S1), suggesting that these objectives could be prioritised. The V40Gy < 37% was achieved in 83.3% of cases in our cohort; therefore, aiming to achieve this with a relatively low priority is feasible, until further prospective studies are available.…”

“…7,11 12 These studies are limited by their bone marrow delineation methods using CT only, and therefore, whether these objectives are applicable to functionally defined ABM cannot be determined. 14,16 More recent studies have focussed on correlations between HT and functionally defined bone marrow; however, results are also inconsistent. In these studies, there is a heterogeneity in image modality used for ABM delineation.…”

“…[7][8][9][10][11][12] Bone marrow sparing (BMS) techniques aim to reduce HT associated with CRT treatment, primarily focussing on pelvic sites. 8,[13][14][15][16][17] Proximity of the bone marrow to the planning target volume (PTV) can be technically challenging; however, with the use of techniques such as volumetric modulated arc therapy (VMAT), BMS techniques may be plausible in achieving bone marrow reductions.…”

“…Further uncertainty is enhanced by the inconsistency of bone marrow delineation across studies. 8,[13][14][15][16][17] Fluorodeoxyglucose positron emission tomography (FDG-PET) has been demonstrated to be superior to computerised tomography (CT), which cannot distinguish between active and inactive areas, in defining haematopoietically active bone marrow (ABM) for HT predictions. 9,16,18,19 Its use in other retrospective studies is limited, with BMS-VMAT (excluding intensity modulated radiotherapy (IMRT)) studies delineating bone marrow based on CT only.…”

“…13,17 Prospective trials in this area are few, with Mell et al conducting the only trial investigating FDG-PET-defined ABM specifically in cervical cancer (n = 83) reporting reductions in the rate of HT. 14 Despite the differences in ABM delineation, all studies demonstrated, dosimetrically, that dose to the ABM can be reduced without compromise of target coverage or organs at risk (OAR) dose.…”