Although it has been shown that chemoradiotherapy may induce immunogenic cell death, which could trigger T-cell immunity mediated by high-mobility group box 1 protein (HMGB1) and calreticulin, there is still limited information to support this theory directly in a clinical setting. In the present study, we evaluated antigen-specific T-cell responses against six cancer-testis antigens in peripheral blood lymphocytes from patients with esophageal squamous cell carcinoma (ESCC) receiving chemoradiation. Expression of HMGB1 and calreticulin within tumor microenvironment was also analyzed in resected samples with and without chemoradiotherapy in relation to patients survival. Tumor antigen-specific T-cell responses were confirmed in six (38%) of 16 patients with ESCC after chemoradiotherapy coexisting with elevated serum HMGB1. In addition, HMGB1 within tumor microenvironment was significantly upregulated in patients with ESCC with preoperative chemoradiotherapy, but not in those without chemoradiotherapy, and the degree of HMGB1 positively correlated with patient survival (n ¼ 88). Both irradiation and chemotherapeutic drugs induced upregulation of HMGB1 and calreticulin in nine ESCC cell lines. Furthermore, HMGB1 was able to induce maturation of dendritic cells. Together, our findings indicate that chemoradiation induces tumor antigen-specific T-cell responses, and HMGB1 production is related to clinical outcome after chemoradiation. Cancer Res; 72(16); 3967-76. Ó2012 AACR.

Herein, we investigate the long-term clinical outcomes for cervical cancer patients treated with in-room computed tomography–based brachytherapy. Eighty patients with Stage IB1–IVA cervical cancer, who had undergone treatment with combined 3D high-dose rate brachytherapy and conformal radiotherapy between October 2008 and May 2011, were retrospectively analyzed. External beam radiotherapy (50 Gy) with central shielding after 20–40 Gy was performed for each patient. Cisplatin-based chemotherapy was administered concurrently to advanced-stage patients aged ≤75 years. Brachytherapy was delivered in four fractions of 6 Gy per week. In-room computed tomography imaging with applicator insertion was performed for treatment planning. Information from physical examinations at diagnosis, and brachytherapy and magnetic resonance imaging at diagnosis and just before the first brachytherapy session, were referred to for contouring of the high-risk clinical target volume. The median follow-up duration was 60 months. The 5-year local control, pelvic progression-free survival and overall survival rates were 94%, 90% and 86%, respectively. No significant differences in 5-year local control rates were observed between Stage I, Stage II and Stage III–IVA patients. Conversely, a significant difference in the 5-year overall survival rate was observed between Stage II and III–IVA patients (97% vs 72%; P = 0.006). One patient developed Grade 3 late bladder toxicity. No other Grade 3 or higher late toxicities were reported in the rectum or bladder. In conclusion, excellent local control rates were achieved with minimal late toxicities in the rectum or bladder, irrespective of clinical stage.

This study evaluated the efficacy of computed tomography (CT)-based three-dimensional (3D) dose-volume parameters of the rectum as predictor for late rectal complication (LRC) in cervical cancer patients treated with radiotherapy alone. Eighty-four patients treated with a combination of external radiotherapy and high-dose-rate intracavitary brachytherapy between January 2000 and December 2004 were retrospectively analyzed. Brachytherapy was prescribed with standard 2D planning. Patients underwent pelvic CT at brachytherapy. The external rectal wall was contoured on the CT images, and the minimum doses delivered to 0.1cc, 1cc, and 2cc of the most irradiated rectal volumes were calculated with dose-volume histograms. The International Commission of Radiation Units and Measurements (ICRU) rectal point dose was also calculated by conventional method. Total dose (external radiotherapy plus brachytherapy) to the rectum was transformed to the biologically equivalent dose in 2-Gy fractions with alpha/beta of 3 Gy (D(0.1cc), D(1cc), D(2cc) and D(ICRU)). The relationships between these dosimetric parameters and the incidence of LRC were analyzed. The 5-year overall actuarial rate of LRC was 26.4%. The values of D(0.1cc), D(1cc), and D(2cc) were significantly higher in patients with LRC than in those without (p < 0.001), but the difference in the values of D(ICRU) was not statistically significant (p = 0.10). The rate of LRC increased significantly with increasing D(0.1cc), D(1cc), and D(2cc) (p = 0.001). However, no positive dose-response relationship was observed between D(ICRU) and the rate of LRC (p = 0.42). The present study has suggested that CT-based 3D dose-volume parameters of the rectum may be effective for predicting LRC.