Purpose To investigate the impact of treatment-related toxicity on health-related quality of life (HRQoL) among patients with head and neck squamous cell carcinoma treated with radiotherapy either alone or in combination with chemotherapy or surgery. Patients and Methods The study sample was composed of 425 disease-free patients. Toxicity was scored according to the European Organisation for Research and Treatment of Cancer (EORTC)/Radiation Therapy Oncology Group (RTOG) late radiation-induced morbidity scoring system. HRQoL was assessed using the EORTC Quality of Life Questionnaire C30. These assessments took place at 6, 12, 18, and 24 months after completion of radiotherapy. The analysis was performed using a multivariate analysis of variance. Results Of the six RTOG scales investigated, two significantly affected self-reported HRQoL, salivary gland (RTOGxerostomia) and esophagus/pharynx (RTOGswallowing). Although RTOGxerostomia was reported most frequently, HRQoL was most affected by RTOGswallowing, pa...

Impact of Late Treatment-Related Toxicity on Quality of Life Among Patients With Head and Neck Cancer Treated With Radiotherapy

Dysphagia disorders in patients with cancer of the oropharynx are significantly affected by the radiation therapy dose to the superior and middle constrictor muscle: a dose-effect relationship.

There is considerable interest in the use of bioorthogonal covalent chemistry such as “click” chemistries to label small molecules located on live or fixed cells.[1] Such labeling has been used for the visualization of glycans, activity based protein profiling, site-specific tagging of proteins, detection of DNA and RNA synthesis, revealing the fate of small molecules in plants, and detection of post-translational modification in proteins.[2-4] Most reported applications rely on either the copper catalyzed azide-alkyne cycloaddition, which is limited to in vitro application due to the cytotoxicity of copper, or the elegant strain-promoted azide-alkyne cycloaddition, which permits live cell and in vivo application use but is hindered by relatively slow kinetics and often difficult synthesis of cyclooctyne derivatives.[4-5] New bioorthogonal reactions that do not require catalyst and show rapid kinetics are therefore of interest for different molecular imaging applications at the cellular level. In this report we demonstrate the use of inverse electron demand Diels-Alder cycloaddition between a serum stable 1,2,4,5 tetrazine and a highly strained trans-cyclooctene to covalently label live cells. This chemistry has been applied to the pretargeted labeling of Cetuximab (Erbitux) tagged epidermal growth factor receptor (EGFR) on A549 cancer cells. We find that the tetrazine cycloaddition to trans-cyclooctene labeled cells is fast and can be amplified by increasing the loading of dienophile on the antibody. This results in a highly sensitive targeting strategy that can be used to label proteins using nanomolar concentrations of a secondary agent for short durations of time.

Fast and Sensitive Pretargeted Labeling of Cancer Cells through a Tetrazine/trans-Cyclooctene Cycloaddition†

Cancer is a major threat to human health. Diagnosis and treatment using precision medicine is expected to be an effective method for preventing the initiation and progression of cancer. Although anatomical and functional imaging techniques such as radiography, computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) have played an important role for accurate preoperative diagnostics, for the most part these techniques cannot be applied intraoperatively. Optical molecular imaging is a promising technique that provides a high degree of sensitivity and specificity in tumor margin detection. Furthermore, existing clinical applications have proven that optical molecular imaging is a powerful intraoperative tool for guiding surgeons performing precision procedures, thus enabling radical resection and improved survival rates. However, detection depth limitation exists in optical molecular imaging methods and further breakthroughs from optical to multi-modality intraoperative imaging methods are needed to develop more extensive and comprehensive intraoperative applications. Here, we review the current intraoperative optical molecular imaging technologies, focusing on contrast agents and surgical navigation systems, and then discuss the future prospects of multi-modality imaging technology for intraoperative imaging-guided cancer surgery.

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Intraoperative Imaging-Guided Cancer Surgery: From Current Fluorescence Molecular Imaging Methods to Future Multi-Modality Imaging Technology

BACKGROUND:

Changing trends in head and neck cancer (HNC) merit an understanding of the late effects of therapy, but few studies examine dysphagia beyond 2 years of treatment.



METHODS:

A case series was examined to describe the pathophysiology and outcomes in dysphagic HNC survivors referred for modified barium swallow (MBS) studies ≥5 years after definitive radiotherapy or chemoradiotherapy (January 2001 through May 2011). Functional measures included the penetration-aspiration scale (PAS), performance status scale–head and neck (PSS-HN), National Institutes of Health Swallowing Safety Scale (NIH-SSS), and MBS impairment profile (MBSImp).



RESULTS:

Twenty-nine patients previously treated with radiotherapy (38%) or chemoradiotherapy (62%) were included (median years posttreatment, 9; range, 5-19). The majority (86%) had oropharyngeal cancer; 52% were never-smokers. Seventy-five percent had T2 or T3 tumors; 52% were N+. The median age at diagnosis was 55 (range, 38-72). Abnormal late examination findings included: dysarthria/dysphonia (76%), cranial neuropathy (48%), trismus (38%), and radionecrosis (10%). MBS studies confirmed pharyngeal residue and aspiration in all dysphagic cases owing to physiologic impairment (median PAS, 8; median NIH-SSS, 10; median MBSImp, 18), whereas stricture was confirmed endoscopically in 7 (24%). Twenty-five (86%) developed pneumonia, half requiring hospitalization. Swallow postures/strategies helped 69% of cases, but no patient achieved durable improvement across functional measures at last follow-up. Ultimately, 19 (66%) were gastrostomy-dependent.



CONCLUSIONS:

Although functional organ preservation is commonly achieved, severe dysphagia represents a challenging late effect that may develop or progress years after radiation-based therapy for HNC. These data suggest that novel approaches are needed to minimize and better address this complication that is commonly refractory to many standard dysphagia therapies. Cancer 2012. © 2012 American Cancer Society.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/cncr.27631

Late dysphagia after radiotherapy‐based treatment of head and neck cancer

Objectives: Dysphagia is commonly associated with head and neck cancer treatment. Traditional dysphagia management strategies focus on post-treatment therapy. This study evaluated the utility of pretreatment swallowing exercises in improving post-treatment swallowing quality of life (QOL).

Study Design: Prospective cohort study and cross-sectional QOL analysis.

Methods: This study includes 37 patients who underwent primary radiation or combined chemoradiation treatment for newly diagnosed hypopharyngeal, laryngeal, or oropharyngeal primary tumors at the University of Alabama at Birmingham. Of the 37, 25 patients underwent swallowing exercises beginning 2 weeks prior to the start of radiation. The M.D. Anderson Dysphagia Inventory (MDADI) was administered an average of 14 months after treatment to assess the success of the protocol. Analysis of QOL scores related to gender, primary site, stage, and race were obtained.

Results: Patients who performed pretreatment swallowing exercises (n = 25) showed improvement in the overall MDADI score (P = .0002) compared to the control population (n = 12) who underwent post-treatment therapy. Furthermore, a separate analysis of individual domains of the MDADI (global, emotional, functional, and physical) demonstrated improved quality of life.

Conclusions: Implementation of pretreatment swallowing education and exercise may improve dysphagia-specific QOL in head and neck cancer patients undergoing radiation and/or chemoradiation therapy.

Pretreatment, preoperative swallowing exercises may improve dysphagia quality of life.

Purpose: To determine whether Cy5.5-labeled antiepidermal growth factor (EGFR) antibody could be used to detect head and neck squamous cell carcinoma (HNSCC) xenografts in vivo.



Methods: AntiEGFR antibody (cetuximab) was labeled with Cy5.5, a fluorophore with emission in the near infrared range. The cetuximab-Cy5.5 conjugate was systemically administered in subtherapeutic doses (50 μg) to mice bearing orthotopically xenografted HNSCC cell lines (SCC1, CAL27, and FaDu). As a control, isotype-matched human immunoglobulin (Ig)G1k antibody labeled with Cy5.5 was systemically injected in parallel experiments. All tumor regions (n = 6) were imaged by fluorescent stereomicroscopy at 0, 6, 24, 48, or 72 hours. Tumor size was measured by high-frequency ultrasonography at 72 hours. Transcervical partial and near-total resections were then performed with stereomicroscopic imaging after each resection. The mandible and associated structures were then resected, paraffin embedded, and then serial sectioned for analysis.



Results: Tumors could be clearly visualized by near infrared fluorescent stereomicroscopy at 48 and 72 hours after systemic administration of cetuximab-Cy5.5 but not after administration with the labeled isotype control antibody, IgG1k-Cy5.5. Ultrasound measurement of tumors (n = 5) correlated with fluorescent measurements of tumor (Spearman's coefficient, 0.92, P ≤ .01). When fluorescent stereomicroscopic findings were correlated with histologic findings in near-total resections, this technique could accurately identify residual tumor less than 1 mm in size.



Conclusion: Fluorescent immunoguided neoplasm detection may be used as a diagnostic tool and to guide surgical therapy by providing real-time imaging information about the extent of disease or the presence of residual disease.

In vivo detection of head and neck cancer orthotopic xenografts by immunofluorescence.

Objectives To determine whether fluorescently labeled anti–epidermal growth factor (EGFR) antibody could be used to detect residual disease and to guide surgical resections by comparing the sensitivity and specificity of optical fluorescence imaging with the sensitivity and specificity of histopathologic evaluation. Design A preclinical model of head and neck squamous cell carcinoma. Subjects Mice xenografted with SCC-1 tumor cells. Interventions The mice underwent systemic injection with anti-EGFR antibody (cetuximab) conjugated to an optically active fluorophore (Cy5.5). Both a subcutaneous flank model (n = 18) and an orthotopic murine model (n = 15) were used to assess for the presence of residual disease by fluorescent stereomicroscopy after subtotal resections of tumors. Histologic analysis was performed to confirm the presence or absence of disease. Results In the subcutaneous flank model, a diagnostic dose (50 μg) and therapeutic dose (250 μg) of fluorescent-labeled anti-EGFR were administered. When a diagnostic dose was given, the sensitivity was 86%, which was less than the 91% sensitivity when the higher dose was given. Tumor biopsy specimens in which disease was detected by histologic analysis but not by fluorescence (false-negative result) averaged 166 cells (range, 50-350 cells). The specificity of optical fluorescence to predict the presence of tumor in both groups was 100%. In the floor of the mouth model, we demonstrated a sensitivity of 81% and a specificity of 100%. False-negative results were obtained in a tumor fragment measuring less than 0.5 mm in diameter. Conclusion These data support further investigation of fluorescently labeled anti-EGFR antibody to detect disease in the surgical setting.

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Sensitivity and specificity of fluorescent immunoguided neoplasm detection in head and neck cancer xenografts.

Objective: Combining the therapeutic and diagnostic properties of targeted antibodies may improve clinical assessment of disease with limited added toxicity during treatment. Methods: Mice (n=10) were xenografted with SCC-1 tumor cells and then treated with radiation, cisplatin, and cetuximab. Brightfield and fluorescent imaging was performed after systemically injecting fluorescently labeled cetuximab prior to treatment and at 6 or 10 weeks after initiation of treatment. The relative fluorescence intensity was determined for each image. Results: The tumor luminosity measured before (week 0), during (week 6) and after treatment (week 10) did not significantly change. Actual tumor measurement corresponded to fluorescent measurements of tumors both before treatment and after treatment. Complete response to therapy occurred in one animal, where resolution of the tumor correlated with loss of fluorescent activity. Conclusions: This preclinical data suggests combining the diagnostic and therapeutic properties ...

Fluorescently labeled cetuximab to evaluate head and neck cancer response to treatment

Objective To assess the use of genetic testing by pediatric otolaryngologists in evaluating a child with prelingual sensorineural hearing impairment (SNHI). Design Questionnaire on the use of genetic testing in the evaluation of prelingual SNHI was made available to pediatric otolaryngologists through the American Society of Pediatric Otolaryngology (ASPO) Web site (http://www.aspo.us). Each ASPO member was invited by e-mail to complete the questionnaire. Participants Sixty-three ASPO members. Results Forty-two (69%) of 61 respondents indicated that they use genetic testing of the connexin 26 (Cx26) gene ( GJB2 ) as an initial test in their workup of prelingual SNHI, and 30 (71%) of 42 reported that they provide genetic counseling for their patients and their families. However, 17 (45%) of 38 respondents answered questions regarding recurrence risks incorrectly or stated that they did not know the correct response. In addition, 7 (12%) of 60 respondents reported that they do not use DNA-based testing at any point in their workup. Conclusions Many pediatric otolaryngologists use DNA-based testing in their evaluation of prelingual SNHI. However, many pediatric otolaryngologists do not have an adequate knowledge of the implications of genetic testing. Because it will take on an increasingly large role in clinical practice, pediatric otolaryngologists must be familiar with current genetic testing, counseling, and treatment recommendations. As these results demonstrate, such knowledge is still lacking in this physician population.

https://jamanetwork.com/journals/jamaotolaryngology/articlepdf/484680/ooa60148_231_236.pdf

Ryan D. Duncan

Papers

Pretreatment, preoperative swallowing exercises may improve dysphagia quality of life.

In vivo detection of head and neck cancer orthotopic xenografts by immunofluorescence.

Sensitivity and specificity of fluorescent immunoguided neoplasm detection in head and neck cancer xenografts.

Fluorescently labeled cetuximab to evaluate head and neck cancer response to treatment

Pediatric otolaryngologists' use of genetic testing