Impact of Chemotherapy Regimens on Normal Tissue Complication Probability Models of Acute Hematologic Toxicity in Rectal Cancer Patients Receiving Intensity Modulated Radiation Therapy With Concurrent Chemotherapy From a Prospective Phase III Clinical Trial.

Yikan Cheng,Lei Wang,Yan Ma,Xiaolin Pang,Yewei Li,Haiyang Chen,Xiangbo Wan,Xueqin Wang,Fang He,Jianping Wang,Hua Deng,Jian Zheng

doi:10.3389/fonc.2019.00244

Abstract

Purpose: To determine whether there are differences in bone marrow tolerance to chemoradiotherapy (CRT) between two chemotherapy regimens according to FOWARC protocol and how chemotherapy regimens affect radiation dose parameters and normal tissue complication probability (NTCP) modelings that correlate with acute hematologic toxicity (HT) in rectal cancer patients treated with intensity modulated radiation therapy (IMRT) and concurrent chemotherapy.Materials and Methods: One hundred and twenty-eight rectal cancer patients who received IMRT from a single institution were recruited from Chinese FOWARC multicenter, open-label, randomized phase III trial. We assessed HT in these patients who were separated into two groups: Oxaliplatin (L-OHP) + 5- fluorouracil (5FU) (FOLFOX, 70 of 128) and 5FU (58 of 128). The pelvic bone marrow (PBM) was divided into three subsites: lumbosacral spine (LSS), ilium (I), and lower pelvic (LP). The endpoint for HT was grade ≥3 (HT3+) and grade ≥2 (HT2+) leukopenia, neutropenia, anemia and thrombocytopenia. Logistic regression was used to analyze the association between HT2+/HT3+ and dosimetric parameters. Lyman-Kutcher-Burman (LKB) model was used to calculate NTCP.Results: Sixty-eight patients experienced HT2+: 22 of 58 (37.9%) 5FU and 46 of 70 (65.7%) FOLFOX (p = 0.008), while twenty-six patients experienced HT3+: 4 of 58 (6.9%) 5FU and 22 of 70 (31.4%) FOLFOX (p = 0.016). PBM and LP dosimetric parameters were correlated with HT2+ in the 5FU group but not in the FOLFOX group. No PBM dosimetric parameters were correlated with HT3+ in both groups. For PBM, NTCP at HT3+ was 0.32 in FOLFOX group relative to 0.10 in 5FU subset (p < 0.05).Conclusion: Patients receiving FOLFOX have lower BM tolerance to CRT than those receiving 5FU. Low-dose radiation to the PBM is predictive for HT2+ in patients who received 5FU. NTCP modeling in FOLFOX group predicts much higher risk of HT3+ than 5FU group.

Highlights

Rectal cancer is a common malignancy in the world [1]
Bone marrow (BM) tolerance to pelvic CRT in rectal cancer patients is poorly understood, several studies indicated a correlation between low-dose radiation parameters to the pelvic BM (PBM) and acute hematologic toxicity (HT) in cervix [8,9,10,11] and anal cancer [12, 13] patients receiving intensity-modulated radiation therapy (IMRT)
While prior studies have shown both clinical and dosimetric predictors for HT in rectal cancer patients undergoing pelvic IMRT concurrent 5FU chemotherapy [7, 17], it is unclear which predictors correlate with HT in FOLFOX regimen and how different chemotherapy agents impact normal tissue complication probability (NTCP) modeling of PBM in rectal cancer

Summary

Introduction

Several randomized trials have demonstrated that preoperative radiotherapy (RT) combined fluorouracil (FU)-based chemotherapy improves locoregional control (LRC) in patients with locally advanced rectal cancer [2,3,4,5]. Bone marrow (BM) tolerance to pelvic CRT in rectal cancer patients is poorly understood, several studies indicated a correlation between low-dose radiation parameters to the pelvic BM (PBM) and acute HT in cervix [8,9,10,11] and anal cancer [12, 13] patients receiving intensity-modulated radiation therapy (IMRT). Results from LymanKutcher-Burman (LKB) normal tissue complication probability (NTCP) modeling of PBM in anal and cervix cancer are consistent with a parallel-like structure of the PBM [10, 13]. NTCP modeling of PBM for acute HT still remains unclear in rectal cancer

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