Dan Ou

Concurrent chemoradiotherapy with cisplatin or cetuximab for locally advanced head and neck squamous cell carcinomas: Does human papilloma virus play a role?

OBJECTIVES The optimal concurrent regimen, chemoradiotherapy (CRT) or bioradiotherapy (BRT), in locally advanced head and neck squamous cell carcinoma (LAHNSCC) remains controversial, especially in human papilloma virus-associated patients. MATERIAL AND METHODS Data of 265 patients with LAHNSCC treated with CRT (cisplatin, 100mg/m(2) every 3weeks, n=194) or BRT (weekly cetuximab, n=71), including 119 patients with known HPV/p16 status were analyzed. RESULTS Median follow-up was 54.5months. The 5-year progression-free survival (PFS) and locoregional control (LRC) were 51.7% vs. 36.9% (p=0.01) and 74.2% vs. 51.2% (p=0.002), both in favor of CRT. Multivariate analysis adjusted for p16 status continued to show improved outcomes (PFS and LRC) for CRT. The 5-year LRC was significantly better with CRT vs. BRT both in the p16+ subgroup (p=0.01) and in p16- or unknown subgroup (p=0.02), and 5-year PFS was of non-significant trend of improvement with CRT vs. BRT in both subgroups (p=0.07 in p16+ and p=0.09 in p16- or unknown, respectively). In the subset of oropharyngeal cancer patients with HPV/p16 status available (n=88), MVA after adjusted for other clinical co-variates showed a non-significant trend of improvement of LRC with CRT compared with BRT (HR=0.4, 95%CI, 0.1-1.0; p=0.06). CONCLUSION Our long-term results suggested better outcomes in LAHNSCC patients receiving concurrent cisplatin over cetuximab regardless of HPV/p16 status.

Induction chemotherapy with docetaxel, cisplatin and fluorouracil followed by concurrent chemoradiotherapy or chemoradiotherapy alone in locally advanced non-endemic nasopharyngeal carcinoma

OBJECTIVES To evaluate the efficacy of induction chemotherapy with docetaxel, cisplatin and fluorouracil (TPF) followed by concurrent chemoradiotherapy (IC+CCRT) or CCRT alone in non-endemic locally advanced nasopharyngeal carcinoma (NPC) patients. MATERIALS AND METHODS Data of 106 patients with NPC treated from January 1999 to June 2012 with IC+CCRT (n=58) or CCRT alone (n=48) were retrospectively reviewed. RESULTS Median follow-up was 6.4years. Distribution of age, performance status, stage and concurrent chemotherapy regimen were imbalanced between the two groups. The 5-year overall survival (OS) and progression-free survival (PFS) were not significantly different between IC+CCRT and CCRT groups (OS: 78.3% vs. 82.7%, p=0.77; PFS: 72.5% vs. 68.2%, p=0.81, respectively). There were less total cumulative incidence of grade 3-4 late radiation morbidity in the IC+CCRT group (44.8% vs. 70.8%, p=0.01). Five-year OS for patients with post-IC complete response (CR), partial response (PR) and stable disease (SD) sub-groups were 100%, 79.4% and 60%, respectively. CONCLUSION Compared with CCRT alone, IC (TPF regimen)+CCRT did not improve OS or PFS in patients with NPC, but less grade 3-4 late toxicities were observed. Responsiveness of IC may provide additional prognostic information.

Predictive and prognostic value of CT based radiomics signature in locally advanced head and neck cancers patients treated with concurrent chemoradiotherapy or bioradiotherapy and its added value to Human Papillomavirus status

OBJECTIVES To explore prognostic and predictive value of radiomics in patients with locally advanced head and neck squamous cell carcinomas (LAHNSCC) treated with concurrent chemoradiotherapy (CRT) or bioradiotherapy (BRT). MATERIALS AND METHODS Data of 120 patients (CRT vs. BRT matched 2:1) were retrospectively analyzed. A total of 544 radiomics features of the primary tumor were extracted from radiotherapy planning computed tomography scans. Cox proportional hazards models were used to examine the association between survival and radiomics features with false discovery rate correction. The discriminatory performance was evaluated using receiver operating characteristic curve analysis. RESULTS Multivariate analysis showed a 24-feature based signature significantly predicted for OS (HR=0.3, P=0.02) and progression-free survival (PFS) (HR=0.3, P=0.01). Combining the radiomics signature with p16 status showed a significant improvement of prognostic performance compared with p16 (AUC=0.78vs. AUC=0.64 at 5years, P=0.01) or radiomics signature (AUC=0.78vs. AUC=0.67, P=0.01) alone. When patients were stratified according to this combination, OS and PFS were significantly different according to the 4 sub-types (p16+ with low/high signature score; p16- with low/high signature score) (P<0.001). Patients with high signature score significantly benefited from CRT (vs. BRT) in terms of OS (P=0.004), while no benefit from CRT in patients with low signature score. CONCLUSION Our analysis suggests an added value of radiomics features as prognostic and predictive biomarker in HNSCC treated with CRT/BRT. Moreover, the radiomics signature provided additional information to HPV/p16 status to further stratify patients. External validation of such findings is mandatory given the risk of overfitting.

Clinical relevance of tumor infiltrating lymphocytes, PD-L1 expression and correlation with HPV/p16 in head and neck cancer treated with bio- or chemo-radiotherapy

ABSTRACT To investigate the prognostic value of tumor infiltrating lymphocytes (TILs: CD8+ and FoxP3+), and PD-L1 expression in patients with head and neck squamous cell carcinoma (HNSCC) treated with radiotherapy combined with cisplatin (CRT) or cetuximab (BRT). Immunohistochemistry for CD8, FoxP3 was performed on pretreatment tissue samples of 77 HNSCC patients. PD-L1 results were evaluable in 38 patients. Cox regression analysis was used to analyze the correlations of these biomarkers expression with clinicopathological characteristics and treatment outcomes. High CD8+ TILs level was identified in multivariate analysis (MVA) as an independent prognostic factor for improved progression-free survival with a non-significant trend for better overall survival (OS). High FoxP3+ TILs and PD-L1+ correlated with a favorable OS in the uni-variate analysis, respectively, but not in the MVA. In subgroup analysis, CD8+TILs appear to play a pivotal role, p16+/high CD8+TILs patients had superior 5-year OS compared with p16+/low CD8+TILs, p16-/ high CD8+TILs, and p16-/ low CD8+TILs patients. p16+/PD-L1+ patients had improved 3-year OS compared with p16+/PD-L1-, p16-/ PD-L1+, and p16-/ PD-L1- patients. In low CD8+ TILs tumors, 5-year loco-regional control of patients treated with CRT was improved vs. those with BRT (p = 0.01) while no significant difference in high CD8+ TILs was observed. CD8+ TILs correlated with an improved clinical outcome in HNSCC patients independent of Human papillomavirus status. The immunobiomarkers may provide information for selecting suitable patients for cisplatin or cetuximab treatment. Additionally, the impact of TILs and PD-L1 of deciphering among the p16+ population a very favorable outcome population could be of interest for patients tailored approaches.

Corrigendum to "Long-term results of a phase II study of gemcitabine and cisplatin chemotherapy combined with intensity-modulated radiotherapy in locoregionally advanced nasopharyngeal carcinoma" [Oral Oncol. 73 (2017) 118-123]

OBJECTIVES To evaluate long-term results of a phase II study of induction and adjuvant gemcitabine and cisplatin (GP) chemotherapy with intensity-modulated radiotherapy (IMRT) in locoregionally advanced nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS One hundred and twelve patients (Stage III: 65, IVA-B: 47) with locoregionally advanced NPC were enrolled in this study. All patients received induction chemotherapy consisting of 1000 mg/m2 gemcitabine on day 1 and 8, and cisplatin 25 mg/m2 on day 1-3, every 3 weeks for 2 cycles. Adjuvant chemotherapy for 2 cycles of the same regime was given 28 days after the end of IMRT. The IMRT technique was utilized for all patients. RESULTS In total, 97.3% patients completed 2 cycles of induction chemotherapy. The overall response rate (RR) of cervical lymph nodes was 89.0%. Acute toxicities were mainly grade 1-2 myleosuppression and vomiting. And 83.9% patients completed 2 cycles of adjuvant chemotherapy. All patients finished IMRT with RR at the end of IMRT for nasopharynx, lymph nodes of neck and retropharyngeal area being 99.1%, 97.9% and 97.7%, respectively. The 5-year local control, regional control, distant metastasis-free and overall survival rates were 93.2%, 92.3%, 89.0% and 82.1%, respectively. The 5-year overall survival of stage III and IVA-B were 87.0%, and 75.5%, respectively. The incidence of grade 3-4 acute radiotherapy-related mucositis was 28.6%. Severe late toxicities were uncommon. CONCLUSION IMRT combined with GP for locoregionally advanced NPC is well tolerated, effective, and convenient, and warrants further studies.

Influence of tumor-associated macrophages and HLA class I expression according to HPV status in head and neck cancer patients receiving chemo/bioradiotherapy

BACKGROUND AND PURPOSE To investigate the prognostic value of tumor-associated macrophages (TAM) and HLA class I expression according to HPV status in patients with head and neck squamous cell carcinoma treated with definitive radiotherapy combining cisplatin (CRT) or cetuximab (BRT). MATERIAL AND METHODS Ninety-five patients were enrolled. The density of CD68+ cells and CD68+ CD163+ cells (further referred as M2) in the intraepithelial and the stromal compartments, respectively, as well as HLA class I expression in tumor cells, were evaluated semi-quantitatively. Correlations between biomarker expression and treatment outcomes were analyzed. RESULTS Multivariate analysis showed that the intraepithelial macrophage density (IEMD) was prognostic for favorable progression-free survival (PFS) and there was a non-significant trend for improved overall survival (OS). HLA class I down-regulation was not an independent prognostic factor. Subgroup analysis showed that in p16+ population, patients with high IEMD had improved 5-year PFS vs. patients with low IEMD (81.2% vs. 25.0%, p < 0.001), while in p16- population, no difference was observed. Similarly, when stratified by primary tumor site, IEMD showed prognostic value in oropharyngeal cancer patients (OPC) but not non-OPC patients. Five-year PFS of patients with low stromal M2 macrophage density treated with CRT was significantly improved vs. those with BRT (54.5% vs. 36.1%, p = 0.03), while in tumors with high M2, there was no significant difference (50.3% vs. 42.9%, p = 0.67). CONCLUSIONS The prognostic role of TAM phenotype and distribution depends on HPV status and might predict treatment response. They prompt further validation in prospective studies.

Leukocytosis, prognosis biomarker in locally advanced head and neck cancer patients after chemoradiotherapy

Highlights • In locally advanced HNSCC, baseline leukocytosis predicts OS and PFS.• Respectively 24% and 20% patients displayed baseline leukocytosis or neutrophilia.• This independent biomarker could help identifying patients with high risk of tumor relapse.

Prognostic value of tissue necrosis, hypoxia-related markers and correlation with HPV status in head and neck cancer patients treated with bio- or chemo-radiotherapy

BACKGROUND AND PURPOSE The aim of the present study was to investigate the role of three hypoxia-related biomarkers in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) treated with concurrent chemoradiotherapy (3-weekly cisplatin) or bioradiotherapy (weekly cetuximab). MATERIAL AND METHODS In tumor tissue material from 100 patients with known HPV status, we evaluated the extent of tumor necrosis, the expression level of CA-IX and the microvascular density (MVD) measured as the density of CD34+ vascular structures. The correlations between biomarker expressions and clinicopathological characteristics and treatment outcomes were analyzed. RESULTS We found a significant correlation of MVD with UICC stage (p = 0.02) and T classification (p = 0.05), of CA-IX with UICC stage (p = 0.03) and N classification (p = 0.04) and a significant inverse correlation of MVD with CA-IX expression (r = -0.22, p = 0.03). Multivariate analysis showed that low MVD combined with high CA IX-expression was a significant independent prognostic factor for worse loco-regional control (HR = 2.6, 95%CI 1.1-5.0, p = 0.02) in the whole population but not in the p16+ subgroup. Patients treated with CRT had a better LRC than those with BRT independent of MVD or CA-IX expression. CONCLUSIONS The combination of MVD and CA-IX expression might give additional prognostic information in HNSCC patients with known HPV status.

Long-term results of a phase II study of gemcitabine and cisplatin chemotherapy combined with intensity-modulated radiotherapy in locoregionally advanced nasopharyngeal carcinoma

Objectives To evaluate long-term results of a phase II study of induction and adjuvant gemcitabine and cisplatin (GP) chemotherapy with intensity-modulated radiotherapy (IMRT) in locoregionally advanced nasopharyngeal carcinoma (NPC). Materials and methods One hundred and twelve patients (Stage III: 65, IVA-B: 47) with locoregionally advanced NPC were enrolled in this study. All patients received induction chemotherapy consisting of 1000 mg/m2 gemcitabine on day 1 and 8, and cisplatin 25 mg/m2 on day 1–3, every 3 weeks for 2 cycles. Adjuvant chemotherapy for 2 cycles of the same regime was given 28 days after the end of IMRT. The IMRT technique was utilized for all patients. Results In total, 97.3% patients completed 2 cycles of induction chemotherapy. The overall response rate (RR) of cervical lymph nodes was 89.0%. Acute toxicities were mainly grade 1–2 myleosuppression and vomiting. And 83.9% patients completed 2 cycles of adjuvant chemotherapy. All patients finished IMRT with RR at the end of IMRT for nasopharynx, lymph nodes of neck and retropharyngeal area being 99.1%, 97.9% and 97.7%, respectively. The 5-year local control, regional control, distant metastasis-free and overall survival rates were 93.2%, 92.3%, 89.0% and 82.1%, respectively. The 5-year overall survival of stage III and IVA-B were 87.0%, and 75.5%, respectively. The incidence of grade 3–4 acute radiotherapy-related mucositis was 28.6%. Severe late toxicities were uncommon. Conclusion IMRT combined with GP for locoregionally advanced NPC is well tolerated, effective, and convenient, and warrants further studies.