Association Between Bone Marrow Dosimetric Parameters and Acute Hematologic Toxicity in Locally Advanced Rectal Cancer Patients Treated with Concurrent Weekly Irinotecan in Combination with Capecitabine-Based Chemoradiotherapy and Neoadjuvant IMRT

Abstract

To test the hypothesis that increased pelvic bone marrow (BM) irradiation is associated with increased hematologic toxicity (HT) in locally advanced rectal cancer (LARC) patients undergoing weekly irinotecan in combination with capecitabine-based neoadjuvant chemoradiotherapy. We analyzed 95 patients with clinical stage T3-4, N0-2 who were eligible for preoperative chemoradiotherapy and UGT1A1*28 6/6 genotype in Fudan University Shanghai Cancer Centre (FUSCC) from November 2015 to January 2018. The dose of weekly irinotecan was 80 mg/m2 for UGT1A1*28 6/6 genotype patients, whereas the dose of capecitabine was fixed at 625 mg/m2. Intensity-modulated radiation therapy (IMRT) was applied to the whole pelvis with total dose of 50 Gy in 25 fractions. Pelvic bone marrow (BM) was delineated as ilium (IL), lumbosacral (LS), lower pelvis (LP), and the relative DVHs were calculated. All patients underwent blood cell counts twice a week. The endpoint for hematologic toxicity was grade≥3 (HT3+) leukopenia, neutropenia, anemia or thrombocytopenia according to CTCAE V4.03. Logistic regression was used to analyze correlation between dosimetric parameters and grade≥3 hematologic toxicity. Linear regression models were used to test for correlation to nadir blood counts. Thirty of 95 (31.6%) patients achieved pathological complete response (PCR). Twenty of 95 (21.1%) patients experienced grade≥3 hematologic toxicity. On univariate and multivariate logistic regression, the dosimetric parameter V10 Gy to the lower pelvic BM (LP V10) was associated with grade≥3 hematologic toxicity. Increased LP V10 was associated with an increased grade≥3 hematologic toxicity (p=0.015). Patients with LP V10 ≥90% had higher rates of grade ≥3 hematologic toxicity than did patients with LP V10 <90% (33.3%, 14/42 vs. 11.3%, 6/53, p=0.01). Linear regression analysis showed iliac and lower pelvic BM dose metrics to associate with reduced nadir ANC and WCC. On multivariate analysis, only LP V10 remained associated with nadir ANC (p=0.022). These findings support the hypothesis that HT increases with increasing pelvic BM volume irradiated. Efforts to maintain LP V10 <90% may reduce grade ≥3 hematologic toxicity in LARC patients undergoing concurrent capecitabine combined with weekly irinotecan and pelvic intensity-modulated radiation therapy (IMRT).