The Volume of PET-Defined, Active Bone Marrow Spared Predicts Acute Hematologic Toxicities in Anal Cancer Patients Receiving Concurrent Chemoradiation Therapy

Abstract

Up to 60% of the body’s hematopoietic tissues reside within pelvis. Patients with anal cancer (AC) receiving chemoradiation are at high risk for hematologic toxicity (HT), with rates of grade 3-4 toxicity as high as 60%. Radiation dose to the PET-defined active pelvic bone marrow (APBM) has been evaluated in gynecologic cancers; however optimal dosimetric parameters are unknown in AC. Much like the liver, bone marrow is a synthetic organ with functional subunits arranged in parallel. This study evaluates whether the volume of APBM spared or pelvic bone marrow (PBM) spared are better predictors of grade 3+ HT compared to conventional dosimetric parameters. Eighteen patients with AC who received concurrent chemoradiotherapy with 5-Fu and mitomycin were retrospectively reviewed. PBM was defined as the contoured volumes of L4, L5, proximal femur to lesser trochanter, ilium, sacrum, ischium, and pubis using total bone as a surrogate for bone marrow. The APBM was defined as regions of pelvic bone with FDG uptake greater than the total body mean SUV. Receiver Operating Characteristic (ROC) curves were used to assess dosimetric parameters (mean dose, V10, V20, V40) to PBM and ABM as well as volume (cc) of PBM and ABM spared 10, 20, and 40 Gy. The toxicity endpoint was grade 3+ HT using the Common Terminology Criteria for Adverse Events (CTCAE) for Hb, platelets, WBC count, and neutrophils. All patients received IMRT according to RTOG 0529. Fifty-eight percent of the patients had T3 or T4 disease at diagnosis. Of the patients treated, 44% developed grade 3+ HT. The volume of APBM ranged from 291 to 1486 cc and the fraction of PBM composed of APBM ranged from 24% to 90%. The mean dose, V10, V20, and V40 to APBM or PBM did not predict for grade 3+ HT. The volume of PBM spared did not predict for grade 3+ HT; However, the volume of APBM spared 20 Gy (216 cc; AUC 0.788, p=0.015), volume of APBM spared 40 Gy (564 cc; AUC 0.788, p=0.016), and baseline volume of APBM (954 cc; AUC 0.788, p =0.017) all predicted for grade 3+ HT. In patients with < 564 cc of APBM spared 40 Gy, 86% (6/7) developed grade 3+ HT compared to 18% (2/11) of patients with > 564 cc spared 40 Gy (p=0.0128). HT in AC patients undergoing chemoradiation is dependent on the total volume of APBM in the pelvis and the volume of APBM spared 20 Gy and 40 Gy. The volume of APBM and the fraction of APBM was heterogeneous across patients. Sparing greater than 564 cc of APBM 40 Gy was more predictive of HT than conventional dosimetric constraints. This may be a useful parameter for minimization of HT in AC patients undergoing definitive chemoradiation and should be further evaluated in additional cohorts.