Docetaxel (DTX) combined with cisplatin and 5-fluorouracil has been used as induction chemotherapy for head and neck squamous cell carcinoma (HNSCC). However, the development of acquired resistance remains a major obstacle to treatment response. Tumor-associated macrophages are associated with chemotherapeutic resistance. In the present study, increased infiltration of macrophages into the tumor microenvironment (TME) was significantly associated with shorter overall survival and increased resistance to chemotherapeutic drugs, particularly DTX, in patients with HNSCC. Macrophage coculture induced expression of intercellular adhesion molecule 1 (ICAM1), which promotes stemness and the formation of polyploid giant cancer cells, thereby reducing the efficacy of DTX. Both genetic silencing and pharmacological inhibition of ICAM1 sensitized HNSCC to DTX. Macrophage secretion of IL-1β was found to induce tumor expression of ICAM1. IL-1β neutralization and IL-1 receptor blockade reversed DTX resistance induced by macrophage coculture. IL-1β activated superoxide dismutase 2 and inhibited catalase, thereby modulating intracellular levels of ROS and inducing ICAM1 expression. Arsenic trioxide (ATO) reduced macrophage infiltration into the TME and impaired IL-1β secretion by macrophages. The combinatorial use of ATO enhanced the in vivo efficacy of DTX in a mouse model, which may provide a revolutionary approach to overcoming acquired therapeutic resistance in HNSCC.

Background: Phase 3 studies suggest that induction chemotherapy (ICT) of cisplatin and 5-fluorouracil plus docetaxel (TPF) is effective but toxic for patients with squamous-cell carcinoma of the head and neck (SCCHN). Dose-dense chemotherapy may yield favorable outcomes compared with standard-dose chemotherapy, yet the optimal induction regimen remains undefined. We assessed the efficacy and tolerability of biweekly dose-dense TPF ICT in patients with SCCHN. Methods: In this prospective phase II study, We enrolled patients with stage III/IV (AJCC 7th edition) unresectable squamous cell carcinoma of head and neck cancer. Patients received dose-dense TPF (ddTPF) with cisplatin and docetaxel 50 mg/m2 on day 1, leucovorin 250 mg/m2 on day1, followed by 48-h continuous infusion of 2500 mg/m2 of 5-fluorouracil on day 1 and 2, every 2 weeks for 6 cycles followed by radiotherapy. The primary endpoint was the response rate (RR) after ICT. Results: Fifty-eight patients were enrolled from June 2014 to September 2015. Overall RR after ICT was 89.6% [complete response (CR), 31%; partial response (PR), 58.6%]. Grade 3/4 neutropenia, mucositis, and diarrhea incidences were 25.9, 1.7, and 1.7%, respectively. 94.8% of patients completed all treatment courses of ICT without dose reduction. The 3-year overall survival (OS) was 54.3% (95%CI: 39.7 to 66.8%) and progression-free survival (PFS) was 34.3% (95%CI: 22.0 to 46.9%). Multivariate analysis showed that CR after ICT is an independent prognostic factor for OS and PFS. Conclusions: Six cycles of ddTPF is an active, well-tolerated induction regimen for patients with SCCHN. The presence of CR after ICT predicted long-term survival. Trial registration: ClinicalTrials.gov Identifier: NCT04397341, May 21, 2020, retrospectively registered.

Taxanes, particularly docetaxel (DTX), has been widely used for combination therapy of head and neck squamous cell carcinoma (HNSCC). For locally advanced unresectable HNSCC, DTX combined with cisplatin and 5-fluorouracil as a revolutionary treatment revealed an advantage in the improvement of patient outcome. In addition, DTX plus immune check inhibitors (ICIs) showed low toxicity and an increased response of patients with recurrent or metastatic HNSCC (R/M HNSCC). Accumulated data indicate that taxanes not only function as antimitotics but also impair diverse oncogenic signalings, including angiogenesis, inflammatory response, ROS production, and apoptosis induction. However, despite an initial response, the development of resistance remains a major obstacle to treatment response. Taxane resistance could result from intrinsic mechanisms, such as enhanced DNA/RNA damage repair, increased drug efflux, and apoptosis inhibition, and extrinsic effects, such as angiogenesis and interactions between tumor cells and immune cells. This review provides an overview of taxanes therapy applied in different stages of HNSCC and describe the mechanisms of taxane resistance in HNSCC. Through a detailed understanding, the mechanisms of resistance may help in developing the potential therapeutic methods and the effective combination strategies to overcome drug resistance.

The present retrospective study aimed to examine the outcomes of stage II‑IV upper‑tract urothelial carcinoma (UTUC) and determine whether adjuvant chemotherapy is a beneficial treatment for patients with locally advanced UTUC (specifically, stage III‑IV). The analysis included 126 patients with muscle‑invasive UTUC who were treated between June 2003 and June 2012. All patients underwent laparoscopic or open nephroureterectomy and bladder cuff excision. Overall survival (OS), disease‑free survival (DFS), distant metastasis‑free survival (DMFS) and locoregional recurrence‑free survival (LRFS) were assessed. Outcomes were compared between groups of patients with stage II (high‑stage localized) disease, stage III‑IV (high‑stage locally advanced) disease treated with chemotherapy, and stage III‑IV disease not treated with chemotherapy. Among patients with high‑stage locally advanced UTUC (stage III‑IV), those who received adjuvant chemotherapy had significantly better rates of OS (67.1 vs. 33.7%; P=0.004), DFS (70.2 vs. 46.0%; P=0.030) and DMFS (86.3 vs. 65.2%; P=0.048) at 5‑years compared with those who did not undergo adjuvant chemotherapy. However, there was no significant difference between the 5‑year LRFS rates in these two groups (78.2 vs. 62.5%; P=0.525). Importantly, the survival curve of patients with high‑stage UTUC who received adjuvant chemotherapy was similar to that of patients with low‑stage UTUC who underwent surgery only. Multivariate analysis revealed that adjuvant chemotherapy was an independent risk factor for OS [without adjuvant chemotherapy vs. with adjuvant chemotherapy: Hazard ratio (HR), 0.29; 95% confidence interval (CI), 0.129‑0.654; P=0.003] and DFS (without adjuvant chemotherapy vs. with adjuvant chemotherapy: HR, 0.381; 95% CI, 0.168‑0.865; P=0.021). In conclusion, adjuvant chemotherapy may improve the outcome for patients with high‑stage locally advanced UTUC.

Background: The treatment of recurrent or metastatic head and neck squamous-cell carcinoma (R/M HNSCC) remains challenging. Preclinical studies revealed that B cell depletion could modulate the microenvironment and overcome chemoresistance. We conducted a phase I study to evaluate the feasibility and safety of B cell depletion using the anti-CD20 antibody rituximab to treat HNSCC. Methods: Ten patients were enrolled in two protocols. The first four patients treated using protocol 1 received rituximab 1000 mg on days −14 and −7, followed by gemcitabine/cisplatin every 3 weeks, and rituximab was administered every 6 months thereafter. Because of disease hyperprogression, protocol 1 was amended to protocol 2, which consisted of the concomitant administration of rituximab 375 mg/m² and gemcitabine/cisplatin every 3 weeks. Another six patients were enrolled and treated using protocol 2. Results: Three patients treated using protocol 1 exhibited rapid disease progression, and the remaining patient could not undergo evaluation after rituximab treatment. Conversely, no unpredicted harm was observed in the six patients treated using protocol 2. Among these patients, one achieved complete response, and two had partial responses. The disease-free durations in these patients were 7.0, 6.2, and 7.1 months, respectively. Immune cell analysis revealed a higher ratio of cytotoxic T cells to regulatory T cells in responders than in non-responders. Conclusions: B cell depletion using rituximab alone in patients with HNSCC can cause hyperprogressive disease. Contrarily, the co-administration of rituximab and cisplatin/gemcitabine was feasible and safe. Trial registration: ClinicalTrials.gov Identifier: NCT04361409, 24 April 2020, retrospectively registered