Using [18F]Fluorothymidine Imaged With Positron Emission Tomography to Quantify and Reduce Hematologic Toxicity Due to Chemoradiation Therapy for Pelvic Cancer Patients

Abstract

Purpose The purpose of this prospective clinical trial was to determine the efficacy of FLT identified active bone marrow sparing for pelvic cancer patients by correlating FLT uptake change during and after chemoradiation therapy to hematologic toxicity. Methods Simulation FLT PET images were used to spare pelvic bone marrow using IMRT (IMRT BMS) for 32 patients with pelvic cancer. FLT PET imaging taken after 1 and 2 weeks of chemoradiation therapy and 30 days and 1 year after chemoradiation therapy was complete were used to evaluate the acute and chronic dose response of pelvic bone marrow. CBCs were recorded at each imaging time point to correlate FLT uptake change to systemic hematologic toxicity. Results IMRT BMS plans significantly reduced dose to pelvic regions identified with FLT uptake when compared to control IMRT plans (p < 0.001 paired t-test). Radiation doses of 4Gy caused an ~50% FLT uptake decrease in pelvic bone marrow after either 1 or 2 weeks of chemoradiation therapy. Additionally, subjects with more FLT identified bone marrow exposed to ≥ 4 Gy after 1 week developed grade 2 leukopenia sooner (p < 0.05 Cox regression). Apparent bone marrow recovery at 30 days post therapy is not maintained 1 year after chemotherapy. FLT uptake in pelvic bone marrow regions that received > 35 Gy was 18.8 ± 1.8 % greater 30 days post therapy than 1-year post therapy. WBCs, platelets, lymphocytes, and neutrophils 1-year post therapy were all lower when compared to pretherapy levels (p < 0.05, paired t-test). Conclusions IMRT BMS plans reduced dose to FLT identified pelvic bone marrow for pelvic cancer patients, but reduction in hematologic toxicity is challenging due to acute radiation sensitivity (~4 Gy), and chronic suppression of bone marrow activity that receives radiation doses > 35 Gy as measured by FLT uptake change correlated to CBCs.

Impact of (chemo)radiotherapy on immune cell composition and function in cervical cancer patients

“…The extreme sensitivity of active pelvic bone marrow was recently demonstrated by McGuire et al. using [ 18 F]Fluorothymidine (FLT) imaging using positron emission tomography (FLT-PET) to identify active bone marrow before, during and after radiotherapy 29 . As little as a radiation dose of 4–5 Gy resulted in an approximately 50% decrease in FLT uptake and the suppression of bone marrow activity was measurable up to 1 y after radiotherapy, especially in pelvic cancer patients receiving radiation doses of more than 35 Gy 29 .…”

“…using [ 18 F]Fluorothymidine (FLT) imaging using positron emission tomography (FLT-PET) to identify active bone marrow before, during and after radiotherapy 29 . As little as a radiation dose of 4–5 Gy resulted in an approximately 50% decrease in FLT uptake and the suppression of bone marrow activity was measurable up to 1 y after radiotherapy, especially in pelvic cancer patients receiving radiation doses of more than 35 Gy 29 . Based on empirical experience, the use of daily fractions of 2 Gy to a total dose of approximately 46–50 Gy has evolved as a standard radiotherapy approach to control microscopic disease for most tumor types including cervical cancer.…”

Longitudinal Changes in Active Bone Marrow for Cervical Cancer Patients Treated With Concurrent Chemoradiation Therapy

“…Thus, BM-sparing techniques may be beneficial in improving tolerance to chemotherapy in the concurrent and potentially the adjuvant and salvage settings. McGuire et al (28) postulate that reducing the bone marrow volume receiving 10 or 20 Gy in total dose may delay the time to the occurrence of a hematologic toxicity event, which could result in the delivery of more chemotherapy. Also, we found that specific patient-related and treatment-related characteristics appear to play a role in the hematopoietic compensatory response.…”

Relative skeletal distribution of proliferating marrow in the adult dog determined using 3′‐deoxy‐3′‐[18F]fluorothymidine

“…Compared to other modern techniques like magnetic resonance imaging (MRI), which provides an anatomical approach to imaging marrow distribution based largely on its relative fat and water content (Sebag, Dubois, Tabet, Bonato, & Lallemand, ), PET/CT more directly interrogates marrow function by exploiting specific physiologic pathways that mediate the distribution of certain positron‐emitting radiopharmaceuticals. In particular, PET/CT using 3′‐deoxy‐3′‐[ 18 F]fluorothymidine ( 18 FLT) has gained attention in recent years as a powerful tool to analyse marrow proliferation (Agool et al, ; Agool, Schot, Jager, & Vellenga, ; Ballegeer et al, ; Hayman et al, ; McGuire et al, ; McGuire, Menda, Boles Ponto, et al, ; McGuire, Menda, Ponto, et al, ; Menda et al, ). As a substrate for the pyrimidine salvage pathway of DNA synthesis, 18 FLT enters proliferating cells and becomes trapped due to phosphorylation by thymidine kinase 1 (TK1) (Salskov, Tammisetti, Grierson, & Vesselle, ; Shields et al, ).…”