Optimal Dosing Strategy for Fluorescence-Guided Surgery with Panitumumab-IRDye800CW in Head and Neck Cancer

Purpose

To identify the optimal dosing strategy for fluorescence-guided surgery in patients with head and neck squamous cell carcinoma, we conducted a dose-ranging study evaluating the anti-epidermal growth factor receptor (EGFR) therapeutic antibody, panitumumab, that was fluorescently labeled with the near-infrared dye IRDye800CW.

Procedures

Patients (n?=?24) received either 0.5 or 1.0 mg/kg panitumumab-IRDye800CW in the weight-based dosing group or 25 or 50 mg panitumumab-IRDye800CW in the fixed dosing group. Following surgery, whole primary specimens were imaged in a closed-field device and the mean fluorescence intensity (MFI) and tumor-to-background ratio (TBR) were assessed. Clinical variables, including dose, time of infusion-to-surgery, age, unlabeled dose, gender, primary tumor site, and tumor size, were analyzed to evaluate the factors affecting the fluorescence intensity in order to identify the optimal dose for intraoperative fluorescence imaging.

Results

A total of 24 primary tumor specimens were imaged and analyzed in this study. Although no correlations between TBR and dose of panitumumab-IRDye800CW were found, there were moderate–strong correlations between the primary tumor MFI and panitumumab-IRDye800CW dose for fixed dose (mg) (R²?=?0.42) and for dose/weight (mg/kg) (R²?=?0.54). Results indicated that the optimal MFI was at approximately 50 mg for fixed dose and 0.75 mg/kg for dose/weight. No significant differences were found for the primary tumor MFI and TBRs between the weight-based dosing and the fixed dosing groups. MFIs significantly increased when the infusion-to-surgery window was reduced to within 2 days (vs. 3 days or more, p?<?0.05).

Conclusions

Antibody-based imaging for surgical resection is under investigation in multiple clinical trials. Our data suggests that a fixed dose of 50 mg is an appropriate diagnostic dose for successful surgical fluorescence imaging.

     

Optical Glucose Analogs of Aminolevulinic Acid for Fluorescence-Guided Tumor Resection and Photodynamic Therapy

Purpose

We have developed and tested a novel conjugation of the clinically used prodrug aminolevulinic acid with 2-deoxyglucosamine as a novel probe (ALA-2DG) for fluorescence imaging and photodynamic therapy.

Procedures

ALA-2DG was successfully synthesized, and the mechanisms of probe uptake, PpIX synthesis, and photodynamic therapy efficacy were evaluated in vitro and in vivo.

Results

ALA-2DG led to PpIX synthesis in tumor cells in vitro and in tumor in vivo. Competitive and inhibitory assays in vitro showed a reduction of this PpIX synthesis that was not observed when cells were incubated with ALA itself, indicating that intracellular uptake of ALA-2DG occurs by GLUT-mediated active transport. Initial photodynamic therapy studies confirmed the efficacy of ALA-2DG as a photodynamic sensitizer.

Conclusions

The in vitro assays suggest that ALA-2DG is taken up by cells via glucose transporters. Initial studies in oral cancer demonstrated the applicability of ALA-2DG for in vivo imaging and its potential as an alternative to ALA-PpIX-based fluorescence diagnostics and photodynamic therapy, providing higher tumor specificity.     

头颈部肿瘤放射治疗对甲状腺功能的影响

报道５５例头颈部肿瘤放射治疗（放疗）后甲状腺功能发生的变化。其中１６例放疗后促甲状腺激素（ＴＳＨ）水平高于正常，８例Ｔ_４水平下降，但临床上出现甲状腺功能减退（甲减）者仅２例，多数病人处于亚临床表现。提示临床不能忽视放疗对甲状腺功能的影响。     

Preclinical Comparison of Near-Infrared-Labeled Cetuximab and Panitumumab for Optical Imaging of Head and Neck Squamous Cell Carcinoma

Purpose

Though various targets have been proposed and evaluated, no agent has yet been investigated in a clinical setting for head and neck cancer. The present study aimed to compare two fluorescently labeled anti-epidermal growth factor receptor (EGFR) antibodies for detection of head and neck squamous cell carcinoma (HNSCC).

Procedures

Antigen specificities and in vitro imaging of the fluorescently labeled anti-EGFR antibodies were performed. Next, immunodeficient mice (n?=?22) bearing HNSCC (OSC-19 and SCC-1) tongue tumors received systemic injections of cetuximab-IRDye800CW, panitumumab-IRDye800CW, or IgG-IRDye800CW (a nonspecific control). Tumors were imaged and resected using two near-infrared imaging systems, SPY and Pearl. Fluorescent lymph nodes were also identified, and all resected tissues were sent for pathology.

Results

Panitumumab-IRDye800CW and cetuximab-IRDye800CW had specific and high affinity binding for EGFR (K _D?=?0.12 and 0.31 nM, respectively). Panitumumab-IRDye800CW demonstrated a 2-fold increase in fluorescence intensity compared to cetuximab-IRDye800CW in vitro. In vivo, both fluorescently labeled antibodies produced higher tumor-to-background ratios compared to IgG-IRDye800CW. However, there was no significant difference between the two in either cell line or imaging modality (OSC-19: p?=?0.08 SPY, p?=?0.48 Pearl; SCC-1: p?=?0.77 SPY, p?=?0.59 Pearl; paired t tests).

Conclusions

There was no significant difference between the two fluorescently labeled anti-EGFR monoclonal antibodies in murine models of HNSCC. Both cetuximab and panitumumab can be considered suitable targeting agents for fluorescent intraoperative detection of HNSCC.     

非常规分割放疗治疗头颈部肿瘤的系统评价

目的系统评价非常规分割放疗治疗头颈部肿瘤的疗效和副反应,为临床实践提供证据。方法计算机检索CENTRAL、MEDLINE、EMbase、CBMdisc和VIP数据库,并手工检索10种中文医学期刊,纳入非常规分割放疗与常规分割放疗比较,或非常规分割放疗 同步化疗与单纯非常规分割放疗比较治疗头颈部肿瘤的随机对照试验(RCT)。由两位研究者进行资料提取和质量评价,并采用RevMan4.2.8软件进行Meta分析。结果共检索到551篇文献,最终纳入23个RCT,包含8411例患者。其中13个是高质量研究,其余为低质量研究。Meta分析结果显示:①非常规分割放疗与常规分割放疗比较,仅分段加速超分割放疗(S-HART)与连续加速放疗(CAIR)组的完全缓解率较高,其RR分别为1.21[95%CI(1.02,1.44)]和3.31[95%CI(1.03,1.57)];随访2年时,仅超分割放疗(HRT)可提高2年总生存率[RR=1.32,95%CI(1.13,1.54)];随访5年时,总生存率差异无统计学意义;大多数非常规分割放疗会增加急性放射性副反应的发生率,但均不会增加晚期放射性副反应的发生率;②非常规分割放疗 同步化疗与单纯非常规分割放疗比较,仅连续超分割放疗(C-HRT)组的完全缓解率较高[RR=1.58,95%CI(1.18,2.11)];随访2年时,非常规分割放疗 同步化疗组提高了2年总生存率[RR=1.35,95%C(I1.18,1.54)];随访5年时,仅C-HRT组提高5年总生存率[RR=1.57,95%CI(1.19,2.07)];两组急性和晚期放射性副反应的发生率差异均无统计学意义。结论本系统评价由于例数偏少,尚不能证明非常规分割放疗可以提高头颈部肿瘤患者的完全缓解率和总生存率;但与同步化疗联合时,可以在不增加急性和晚期放疗并发症的同时取得更好的疗效,其中HRT和C-HRT的作用尤其值得关注。     

Effect of Formalin Fixation for Near-Infrared Fluorescence Imaging with an Antibody-Dye Conjugate in Head and Neck Cancer Patients

Purpose

This study evaluated the effect of formalin fixation for near-infrared (NIR) fluorescence imaging of an antibody-dye complex (panitumumab-IRDye800CW) that was intravenously administered to patients with head and neck squamous cell carcinoma (HNSCC) scheduled to undergo surgery of curative intent.

Procedures

HNSCC patients were infused with 25 or 50 mg of panitumumab-IRDye800CW followed by surgery 1–5 days later. Following resection, primary tumor specimens were imaged in a closed-field fluorescence imaging device, before and after formalin fixation. The fluorescence images of formalin-fixed specimens were compared with images prior to formalin fixation. Regions of interest were drawn on the primary tumor and on the adjacent normal tissue on the fluorescence images. The mean fluorescence intensity (MFI) and tumor-to-background ratios (TBRs) of the fresh and formalin-fixed tissues were compared.

Results

Of the 30 enrolled patients, 20 tissue specimens were eligible for this study. Formalin fixation led to an average of 10 % shrinkage in tumor specimen size (p?<?0.0001). Tumor MFI in formalin-fixed specimens was on average 10.9 % lower than that in the fresh specimens (p?=?0.0002). However, no statistical difference was found between the TBRs of the fresh specimens and those of the formalin-fixed specimens (p?=?0.85).

Conclusions

Despite the 11 % decrease in MFI between fresh and formalin-fixed tissue specimens, the relative difference between tumor and normal tissue as measured in TBR remained unchanged. This data suggests that evaluation of formalin-fixed tissue for assessing the accuracy of fluorescence-guided surgery approaches could provide a valid, yet more flexible, alternative to fresh tissue analysis.

Trial Registration

NCT02415881

     

Hypnosis for Postradiation Xerostomia in Head and Neck Cancer Patients: A Pilot Study

Xerostomia, the sensation of dry mouth, affects almost all patients who undergo radiotherapy for cancer in the head and neck area. Current therapies for xerostomia are inadequate, and the condition negatively impacts the quality of life. This prospective observational pilot study aimed to evaluate whether hypnosis could improve salivation and decrease xerostomia. Twelve patients with xerostomia after radiotherapy for head and neck cancer were assessed for severity of xerostomia symptoms and sialometry. They then received a single hypnosis session with specific suggestions to increase salivation. The session was recorded on a compact disk (CD), and the participants were instructed to listen to it twice a day for one month. Sialometry was repeated immediately after hypnosis. Validated xerostomia questionnaires were completed at one, four, and 12 weeks after hypnosis. A substantial overall improvement was reported by eight patients at 12 weeks (66%). The saliva flow rate increased on sialometry in nine patients following hypnosis (75%). There was no correlation between the magnitude of changes in the measured saliva flow rate and changes in subjective measures (Spearman's correlation coefficient r = 0.134). Symptomatic improvement significantly correlated with the number of times the patients listened to the hypnosis CD (r = 0.714, P = 0.009). No adverse events were reported. The data from this small observational trial suggest that hypnosis may be an effective treatment for xerostomia. Confirmation in a larger randomized and controlled investigation is warranted.     

头颈部肿瘤放疗中口腔黏膜反应的治疗

目的探讨2种漱口液治疗肿瘤患者在放射治疗过程中急性上口腔黏膜炎的疗效。方法将87例头颈部肿瘤患者按随机数字表法分为2组,自制漱口液组（n=43例）和口泰漱口液组（n=44例）。2组在放疗过程中分别采用自制漱口液和口泰漱口液含漱,每次10mL,4～5次.d-1,自放射治疗开始后1周内使用,连续使用7周。根据RTOG/EORTC急性放射性黏膜炎分级标准对2组患者的疗效及口腔黏膜损伤情况进行比较。结果自制漱口液组有效率高于口泰漱口液组、Ⅲ级急性放射性黏膜炎发生率低于口泰漱口液组（均P〈0.05）。结论头颈部肿瘤患者在放疗过程中口腔黏膜反应是不可避免的,自制漱口液配制简单、价格便宜、疗效确定,在头颈部肿瘤患者放射治疗过程中可作为预防和治疗用药。     

Developing an Adaptive Radiotherapy Technique for Virally Mediated Head and Neck Cancer

BackgroundVirally mediated head and neck cancers (VMHNC) often present with nodal involvement and are highly radio responsive, meaning that treatment plan adaptation during radiotherapy (RT) in a subset of patients is required. This study sought to determine potential risk profiles and a corresponding adaptive treatment strategy for these patients.MethodologyOne hundred twenty-one patients with virally mediated, node positive nasopharyngeal (Epstein-Barr virus positive) or oropharyngeal (human papillomavirus positive) cancers who were receiving curative intent RT were reviewed. The type, frequency, and timing of adaptive interventions, including source-to-skin distance (SSD) corrections, rescanning, and replanning, were evaluated. Patients were reviewed based on the maximum size of the dominant node to assess the need for plan adaptation.ResultsForty-six patients (38%) required plan adaptation during treatment. The median fraction at which the adaptive intervention occurred was 26 for SSD corrections and 22 for replanning CTs. A trend toward three risk profile groupings was discovered: (1) low risk with minimal need (<10%) for adaptive intervention (dominant pretreatment nodal size of ≤35 mm), (2) intermediate risk with possible need (<20%) for adaptive intervention (dominant pretreatment nodal size of 36–45 mm), and (3) high risk with increased likelihood (>50%) for adaptive intervention (dominant pretreatment nodal size of ≥46 mm).ConclusionsIn this study, patients with VMHNC and a maximum dominant nodal size of >46 mm were identified at a higher risk of requiring replanning during a course of definitive RT. Findings will be tested in a future prospective adaptive RT study.     

Symptom Clusters in Head and Neck Cancer: A Systematic Review and Conceptual Model

ObjectiveThe two approaches to symptom-cluster research include grouping symptoms and grouping patients. The objective of this systematic review was to examine the conceptual approaches and methodologies used in symptom-cluster research in patients with head and neck cancer.Data sourcesArticles were retrieved from electronic databases (CINAHL, MEDLINE via Ovid, APA PsycINFO, Scopus, Embase, and Cochrane Central Register of Controlled Trials-CENTRAL), five grey literature portals, and Google Scholar. Seventeen studies met the eligibility criteria. Eight studies grouped symptoms to identify symptom clusters, of which two used qualitative methods. The number of symptom clusters ranged from two to five, and the number of symptoms in a cluster ranged from 2 to 11. Nine studies grouped patients based on their experiences with multiple symptoms. Cluster analysis and factor analysis were most commonly used. Despite variable names and composition of symptom clusters, synthesis revealed three prominent symptom clusters: general, head and neck cancer-specific, and gastrointestinal. Being female and quality of life were significantly associated with high symptom group or cluster severity. Biological mechanisms were sparsely examined.ConclusionSymptom cluster research in head and neck cancer is emerging. Consensus on nomenclature of a symptom cluster will facilitate deduction of core clinically relevant symptom clusters in head and neck cancer. Further research is required on understanding patients’ subjective experiences, identifying predictors and outcomes, and underlying mechanisms for symptom clusters.Implications for Nursing PracticeIdentification of clinically relevant symptom clusters would enable targeted symptom assessment and management strategies, thus improving treatment efficiencies and patient outcomes.     

Sensorineural Hearing Loss after Treatment for Head and Neck Cancer: A Review of the Literature

BackgroundDefinitive cisplatin-based chemoradiation is increasingly delivered as the treatment of choice for patients with head and neck cancer. Sensorineural hearing loss is a significant long-term side effect of cisplatin-based chemoradiation and is associated with potential major quality of life issues for patients. The purpose of this article was to review the mechanism behind sensorineural hearing loss in patients treated with cisplatin-based chemoradiation, including incidence, the contributions of radiotherapy and cisplatin to sensorineural hearing loss, and the impact of the toxicity on patient quality of life.MethodsDatabase searches were conducted through PubMed (National Centre for Biotechnology Information) and OvidSP Medline via the Queensland University of Technology Library website. General article searches were conducted through the online search engine Google Scholar. Articles were excluded if the full text was unavailable, they were not in English, or if they were published before 1990. Key words included hearing loss, ototoxicity, cancer, quality of life, cisplatin, and radiotherapy.Results/DiscussionThe total number of journal articles accessed was 290. Because of exclusion criteria, 129 articles were deemed appropriate for review. Findings indicated that sensorineural hearing loss is a significant, long-term complication for patients treated with cisplatin-based chemoradiation. Current literature recognizes the ototoxic effects of cisplatin and cranial irradiation as separate entities; however, the impact of combined modality therapy on sensorineural hearing loss is seldom reported. Multiple risk factors for hearing loss are described; however, there are contradictory opinions on incidence and severity and the exact radiation dose threshold responsible for inducing hearing loss in patients receiving combined modality therapy. Sensorineural hearing loss creates a subset of complexities for patients with head and neck cancer and these patients face significant quality of life impairment.ConclusionsThe literature review identified that sensorineural hearing loss is a major quality of life issue for patients treated with cisplatin-based chemoradiation for head and neck cancer. Further investigation evaluating the contribution of cisplatin-based chemoradiation to sensorineural hearing loss and the subsequent effect on patient quality of life is warranted.