Impact of Tumour Hypoxia on Evofosfamide Sensitivity in Head and Neck Squamous Cell Carcinoma Patient-Derived Xenograft Models.

Tumour hypoxia is a marker of poor prognosis and failure of chemoradiotherapy in head and neck squamous cell carcinoma (HNSCC), providing a strategy for therapeutic intervention in this setting. To evaluate the utility of the hypoxia-activated prodrug evofosfamide (TH-302) in HNSCC, we established ten early passage patient-derived xenograft (PDX) models of HNSCC that were characterised by their histopathology, hypoxia status, gene expression, and sensitivity to evofosfamide. All PDX models closely resembled the histology of the patient tumours they were derived from. Pimonidazole-positive tumour hypoxic fractions ranged from 1.7-7.9% in line with reported HNSCC clinical values, while mRNA expression of the Toustrup hypoxia gene signature showed close correlations between PDX and matched patient tumours, together suggesting the PDX models may accurately model clinical tumour hypoxia. Evofosfamide as a single agent (50 mg/kg IP, qd × 5 for three weeks) demonstrated antitumour efficacy that was variable across the PDX models, ranging from complete regressions in one p16-positive PDX model to lack of significant activity in the three most resistant models. Despite all PDX models showing evidence of tumour hypoxia, and hypoxia being essential for activation of evofosfamide, the antitumour activity of evofosfamide only weakly correlated with tumour hypoxia status determined by pimonidazole immunohistochemistry. Other candidate evofosfamide sensitivity genes-MKI67, POR, and SLFN11-did not strongly influence evofosfamide sensitivity in univariate analyses, although a weak significant relationship with MKI67 was observed, while SLFN11 expression was lost in PDX tumours. Overall, these data confirm that evofosfamide has antitumour activity in clinically-relevant PDX tumour models of HNSCC and support further clinical evaluation of this drug in HNSCC patients. Further research is required to identify those factors that, alongside hypoxia, can influence sensitivity to evofosfamide and could act as predictive biomarkers to support its use in precision medicine therapy of HNSCC.

Parotid and cervical nodal status predict prognosis for patients with head and neck metastatic cutaneous squamous cell carcinoma.

BACKGROUND AND OBJECTIVES: The appreciation of parotid involvement being an independent prognostic factor for metastatic cutaneous squamous cell carcinoma (SCC) is relatively new. A more comprehensive clinical staging system that separates parotid (P) from neck (N) disease, and further stratifies the N category has been proposed [O'Brien et al., Head Neck 2002; 24: 417-422]. This paper presents the clinical outcome of patients with head and neck metastatic cutaneous SCC treated at the four major head & neck surgical oncology centers in New Zealand and tests the proposed staging system, with modifications for pathological staging. METHODS: Patients treated with a curative intent from 1990 to 2005 were identified and re-staged. Survival rates were calculated using the Kaplan-Meier method, and curves were compared with the log-rank test. Multivariate analysis using the Cox regression model was performed to assess the impact of each proposed P and N sub-group, and other parameters. RESULTS AND CONCLUSIONS: One hundred and seventy patients were identified. The 5-year disease-specific survival rate was 69%, and the loco-regional recurrence rate was 36%. The presence of parotid (P < 0.01) or neck (P = 0.01) disease, immunosuppression (P < 0.01) and the uptake of radiotherapy (P < 0.01) impacted significantly on survival. Increasing P or N category worsened the prognosis significantly.

Evofosfamide for the treatment of human papillomavirus-negative head and neck squamous cell carcinoma.

Evofosfamide (TH-302) is a clinical-stage hypoxia-activated prodrug of a DNA-crosslinking nitrogen mustard that has potential utility for human papillomavirus (HPV) negative head and neck squamous cell carcinoma (HNSCC), in which tumor hypoxia limits treatment outcome. We report the preclinical efficacy, target engagement, preliminary predictive biomarkers and initial clinical activity of evofosfamide for HPV-negative HNSCC. Evofosfamide was assessed in 22 genomically characterized cell lines and 7 cell line-derived xenograft (CDX), patient-derived xenograft (PDX), orthotopic, and syngeneic tumor models. Biomarker analysis used RNA sequencing, whole-exome sequencing, and whole-genome CRISPR knockout screens. Five advanced/metastatic HNSCC patients received evofosfamide monotherapy (480 mg/m2 qw × 3 each month) in a phase 2 study. Evofosfamide was potent and highly selective for hypoxic HNSCC cells. Proliferative rate was a predominant evofosfamide sensitivity determinant and a proliferation metagene correlated with activity in CDX models. Evofosfamide showed efficacy as monotherapy and with radiotherapy in PDX models, augmented CTLA-4 blockade in syngeneic tumors, and reduced hypoxia in nodes disseminated from an orthotopic model. Of 5 advanced HNSCC patients treated with evofosfamide, 2 showed partial responses while 3 had stable disease. In conclusion, evofosfamide shows promising efficacy in aggressive HPV-negative HNSCC, with predictive biomarkers in development to support further clinical evaluation in this indication.

Quality of life after parotid and temporal bone surgery for cancer.

OBJECTIVES: The purposes of this study were to examine the quality of life (QL) of patients who received treatment for cancer of the parotid or temporal region, and to identify factors contributing to it. The relationships between clinician-based measures of treatment outcome and the patient-based counterparts were also evaluated. METHODS: A retrospective, cross-sectional study was conducted on 23 patients who had received either a temporal bone resection or a combination of parotidectomy and radiotherapy. The QL survey involved both global QL and measures of the appearance, communication, hearing, physical, psychological, and social domains. Patients were assessed clinically for their performance status, facial nerve function, disfigurement, and hearing and the results were compared with patient-rated QL. Correlation between the QL variables and global QL was identified using Spearman correlation tests. RESULTS: Ongoing physical symptoms, communication difficulties, and social disturbances were associated with poorer global QL (P <.05). No correlation was detected between global QL and objective disfigurement, facial function, and measures of hearing loss. With the exception of hearing testing, clinical assessments generally did not correlate well with patient ratings. CONCLUSION: QL measures provide insight into patients' perceptions of the treatment outcome but do not necessarily correlate with the clinicians' views. The use of a global QL measure overcomes the difficulty of extrapolating the impact of symptom scores or observational measures on patients' overall quality of survival.

Endovascular treatment of epistaxis.

AIM: Embolization of external carotid vessels in the treatment of intractable epistaxis is not well documented in Australasia. The aim of the present retrospective study was to audit our experience with the technique, and to compare it with other centres. METHODS: Retrospective review. RESULTS: Twenty-nine embolizations were performed in 28 patients. Embolization was successful in 24 out of 28 patients (86%). Three patients required ligation of the anterior ethmoidal arteries, one of whom subsequently underwent successful repeat embolization. There were minor complications in 6/29 procedures (21%), and no major complications. CONCLUSION: Our outcomes compare favourably with those of larger centres. Embolization is an effective tool in the management of patients with intractable epistaxis.

Comparison of the use of endoscopic and radiologic gastrostomy in a single head and neck cancer unit.

BACKGROUND: Head and neck cancer patients frequently require gastrostomy feeding. Different insertion techniques have been described. The aim of the present study was to compare clinical results of percutaneous endoscopic and radiological gastrostomies in patients treated in a regional head and neck cancer unit. METHODS: The records of patients who received either percutaneous endoscopic gastrostomy (PEG) or percutaneous radiological gastrostomy (PRG) between August 1997 and February 2001 were reviewed retrospectively. Documented complications (leak, infection, nausea and vomiting, ileus, bleeding, peritonitis) were recorded, compared and evaluated. RESULTS: There were 74 patients (56 PEG, 18 PRG), most with stage III and IV head and neck malignancy. There was a significantly lower incidence of complications in PEG than PRG (11% vs 44%, P = 0.004). There was a delay of feeding due to tube placement in 4% of PEG and 22% of PRG (P < 0.025). Major complications occurred in 3.6% and 5.6% of PEG and PRG, respectively. Generally the complication rate for either form of gastrostomy was comparable with other studies. No procedure-related deaths occurred. CONCLUSION: Selection bias, technique and tube type appeared to influence the complication rate in the present review. Percutaneous endoscopic gastrostomy will remain the authors' preferred method while PRG will be reserved for those cases for whom endoscopic placement is deemed to be impractical.

Parotid metastatic disease from cutaneous squamous cell carcinoma: prognostic role of facial nerve sacrifice, lateral temporal bone resection, immune status and P-stage.

BACKGROUND: Recognized prognostic indicators for metastatic cutaneous squamous cell carcinoma (SCC) of the head and neck include facial nerve involvement, immune status, and "parotid" staging system (P-stage). We sought to examine the impact of lateral temporal bone resection (LTBR) on prognosis. METHODS: We conducted a retrospective analysis of 160 patients with metastatic cutaneous SCC to the parotid. All patients had parotidectomy and neck dissection; 27% had additional LTBR when the tumor was adherent to the temporal bone. RESULTS: Overall 5-year survival was 48%, disease-specific survival 77%, and locoregional control 83%. Corresponding results for immunocompetent versus immunocompromised were 55%, 86%, and 87% versus 12%, 48%, and 64%. On Cox regression analysis, only immunocompromised status (ie, lymphoproliferative disorder, organ-transplant patient) was prognostically significant (p < .001). CONCLUSION: More radical resection that may include LTBR mitigates the poorer prognosis with advanced disease in our series. Treatment must be individualized in immunocompromised patients who have shortened overall survival.

Acinic cell carcinoma of the parotid gland: Auckland experience and literature review.

Acinic cell carcinoma is an uncommon malignancy of the salivary glands and as such it has been difficult to accurately delineate its natural history. The aim of this study is to assess the behaviour of acinic cell salivary cancer of the parotid gland presenting to a single head and neck surgical unit in Auckland. The study is a structured review of cases of acinic cell carcinoma of the parotid gland presenting from 2000 to 2006 to the Head and Neck Unit at Auckland Hospital, those identified from the pathology database and the Otobase head and neck database. Case records and pathology reports were reviewed. Fifteen patients were identified, 9 men and 6 women. The mean age was 67.2 years, with range 50-85 years. The mean follow up was 4.4 years and range 1.1-7 years. There was one case of local recurrence during study period and no deaths. Five of 15 patients received postoperative radiotherapy. Postoperative complications consisted of one wound haematoma and two cases of marginal mandibular weakness (one transient and one permanent). Current management strategies are obtaining appropriate rates of recurrence and postoperative complications within the Auckland population.

Effect of immunocompromise on metastatic cutaneous squamous cell carcinoma in the parotid and neck.

BACKGROUND: Our aim was to examine the effect of a compromised immune state on the outcomes in patients treated for metastatic cutaneous squamous cell carcinoma (SCC). METHODS: A retrospective analysis of patients with metastatic cutaneous SCC to the parotid and neck treated at Greenlane Hospital between 1992 and 2002 was conducted. Outcomes were compared between immune-competent and immunocompromised patients. A logistic regression analysis of likely risk factors for poor outcome was done. RESULTS: Forty-nine patients were identified, nine of whom were immunocompromised. All patients were treated by parotidectomy and/or neck dissection. The facial nerve was sacrificed in 42% of the patients. Thirty-seven patients underwent postoperative radiotherapy (76%). Recurrence was significantly more common in the immunocompromised group (56% vs 28%), with higher rates of local and distant recurrence. Survival at 1 and 2 years was reduced. CONCLUSION: Immunocompromise has a significant impact on the outcome of metastatic cutaneous SCC to the parotid and neck, affecting recurrence and survival.