Severe lymphopenia during chemoradiation is often associated with higher risk of death, disease progression and distant metastases. Recent data has shown that head and neck cancer (HNC) patients with lymphopenia has a decreased 5-year overall survival of 70 vs 90%. While both radiation and chemotherapy have been associated with lymphopenia, the mechanism of action remains unclear. Here, we propose a spatially-defined model that evaluates the combined effects of lymphotoxic radiation doses to head and neck organs-at-risk (HN-OARs) which include the cervical bone marrow and the circulating blood pool. Our objective is to investigate the spatial dose relationships related to treatment-related lymphopenia (TRL) in HNC patients.We have identified a prospectively acquired dataset of 40 HNC patients treated at our institution with 31 oropharynx, 3 oral cavity, 4 nasopharynx and 2 larynx cases. Weekly lymphocyte counts were extracted at baseline and for 8 weeks since initiation of radiotherapy. Chemotherapy timing, dosage and regimens were documented. HN-OARs were manually contoured on CT simulation scans. To generate the spatially-defined linear regression model, we included these inputs (x): internal jugular veins (IJVs), carotid arteries (CAs), capillary bed (CB) and vertebral bodies (VBs). The output (y) is defined by % decrease between baseline and nadir lymphocyte counts. Then, we segmented VBs by vertebral levels, and other HN-OARs by disease laterality (ipsilateral vs contralateral). IJVs and CAs are further segmented by anatomic zones (zone 1: C1 to hyoid, zone 2: hyoid to cricoid, and zone 3: cricoid to C7). Stepwise selection was used to identify influential HN-OARs. Finally, we proposed spatial dose parameters associated with high risk lymphopenia (defined as ≥70% decrease) and performed sensitivity/specificity (Se/Sp) analyses.Using stepwise (forward) selection, we identified IJVs as potential targets to spare low dose bath parameters Dmin and D90 (P-values 0.028 to 0.056), and VBs as potential targets to spare point max doses Dmax and D10 (P-values < 0.001 to 0.020). To avoid overfitting, we also performed backward selection with a more liberal P-value criterion of 0.50 which showed similar results. Key anatomic zones for potential dose sparing include C1-3 VBs and contralateral zone 1 IJVs. Overall, we proposed these dose parameters to limit TRL risks: Dmax ≤ 60 Gy for VBs (Se/Sp: 76%/86%, AUC 0.84) and D90 ≤ 13 Gy for contralateral IJVs (Se/Sp: 72%/86%, AUC 0.79).The risk of treatment-related lymphopenia (TRL) appears to be spatially related to radiation doses to the VBs and IJVs. Better understanding of the spatial dose relationship with HN-OARs may lead to insights in reducing TRL risks and improving oncologic outcomes, especially as we consider the benefits of recent dose de-escalation studies (to reduce point max doses) and proton treatment techniques (to reduce low dose baths) in the management of head and neck cancers.
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