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1.  Age most significant predictor of requiring enteral feeding in head-and-neck cancer patients 
Background
A significant number of patients treated for head and neck squamous cell cancer (HNSCC) undergo enteral tube feeding. Data suggest that avoiding enteral feeding can prevent long-term tube dependence and disuse of the swallowing mechanism which has been linked to complications such as prolonged dysphagia and esophageal constriction. We examined detailed dosimetric and clinical parameters to better identify those at risk of requiring enteral feeding.
Methods
One hundred patients with advanced stage HNSCC were retrospectively analyzed after intensity-modulated radiation therapy (IMRT) to a median dose of 70 Gy (range: 60-75 Gy) with concurrent chemotherapy in nearly all cases (97%). Patients with significant weight loss (>10%) in the setting of severely reduced oral intake were referred for placement of a percutaneous endoscopic gastrostomy (PEG) tube. Detailed DVH parameters were collected for several structures. Univariate and multivariate analyses using logistic regression were used to determine clinical and dosimetric factors associated with needing enteral feeding. Dichotomous outcomes were tested using Fisher’s exact test and continuous variables between groups using the Wilcoxon rank-sum test.
Results
Thirty-three percent of patients required placement of an enteral feeding tube. The median time to tube placement was 25 days from start of treatment, after a median dose of 38 Gy. On univariate analysis, age (p = 0.0008), the DFH (Docetaxel/5-FU/Hydroxyurea) chemotherapy regimen (p = .042) and b.i.d treatment (P = 0.040) (used in limited cases on protocol) predicted need for enteral feeding. On multivariate analysis, age remained the single statistically significant factor (p = 0.003) regardless of other clinical features (e.g. BMI) and all radiation planning parameters. For patients 60 or older compared to younger adults, the odds ratio for needing enteral feeding was 4.188 (p = 0.0019).
Conclusions
Older age was found to be the most significant risk factor for needing enteral feeding in patients with locally advanced HNSCC treated with multimodal treatment. Pending further validation, this would support maximizing early nutritional guidance, targeted supplementation, and symptomatic support for older adults (>60) undergoing chemoradiation. Such interventions and others (e.g. swallowing therapy) could possibly delay or minimize the use of enteral feeding, thereby helping avoid tube dependence and tube-associated long-term physiologic consequences.
doi:10.1186/s13014-015-0408-6
PMCID: PMC4404131  PMID: 25896830
Head-and-neck cancer; Radiotherapy; Enteral feeding; Swallowing dysfunction
2.  A feasibility study incorporating a pilot randomised controlled trial of oral feeding plus pre-treatment gastrostomy tube versus oral feeding plus as-needed nasogastric tube feeding in patients undergoing chemoradiation for head and neck cancer (TUBE trial): study protocol 
Background
There are 7000 new cases of head and neck squamous cell cancers (HNSCC) treated by the NHS each year. Stage III and IV HNSCC can be treated non-surgically by radio therapy (RT) or chemoradiation therapy (CRT). CRT can affect eating and drinking through a range of side effects with 90 % of patients undergoing this treatment requiring nutritional support via gastrostomy (G) or nasogastric (NG) tube feeding.
Long-term dysphagia following CRT is a primary concern for patients. The effect of enteral feeding routes on swallowing function is not well understood, and the two feeding methods have, to date, not been compared to assess which leads to a better patient outcome.
The purpose of this study is to explore the feasibility of conducting a randomised controlled trial (RCT) comparing these two options with particular emphasis on patient willingness to be randomised and clinician willingness to approach eligible patients.
Methods/design
This is a mixed methods multicentre study to establish the feasibility of a randomised controlled trial comparing oral feeding plus pre-treatment gastrostomy versus oral feeding plus as required nasogastric tube feeding in patients with HNSCC. A total of 60 participants will be randomised to the two arms of the study (1:1 ratio). The primary outcome of feasibility is a composite of recruitment (willingness to randomise and be randomised) and retention. A qualitative process evaluation investigating patient, family and friends and staff experiences of trial participation will also be conducted alongside an economic modelling exercise to synthesise available evidence and provide estimates of cost-effectiveness and value of information. Participants will be assessed at baseline (pre-randomisation), during CRT weekly, 3 months and 6 months.
Discussion
Clinicians are in equipoise over the enteral feeding options for patients being treated with CRT. Swallowing outcomes have been identified as a top priority for patients following treatment and this trial would inform a future larger scale RCT in this area to inform best practice.
Trial registration
ISRCTN48569216
doi:10.1186/s40814-016-0069-8
PMCID: PMC5154009  PMID: 27965848
Nasogastric tube; Gastrostomy; Swallow outcome; Chemoradiation therapy; Head and neck cancer
3.  Epidermal growth factor receptor targeted therapy in stages III and IV head and neck cancer 
Current Oncology  2010;17(3):37-48.
Question
What are the benefits associated with the use of anti–epidermal growth factor receptor (anti-egfr) therapies in squamous cell carcinoma of the head and neck (hnscc)? Anti-egfr therapies of interest included cetuximab, gefitinib, lapatinib, zalutumumab, erlotinib, and panitumumab.
Perspectives
Head-and-neck cancer includes malignant tumours arising from a variety of sites in the upper aerodigestive tract. The most common histologic type is squamous cell carcinoma, and most common sites are the oral cavity, the oropharynx, the hypopharynx, and the larynx. Worldwide, hnscc is the sixth most common neoplasm, and despite advances in therapy, long-term survival in hnscc patients is poor. Primary surgery followed by chemoradiation, or primary chemoradiation, are the standard treatment options for patients with locally advanced (stages iii–ivb) hnscc; however, meta-analytic data indicate that the benefit of concurrent platinum-based chemotherapy disappears in patients over the age of 70 years.
Cetuximab is a monoclonal antibody approved for use in combination with radiation in the treatment of patients with untreated locally advanced hnscc and as monotherapy for patients with recurrent or metastatic (stage ivc) hnscc who have progressed on platinum-based therapy.
Given the interest in anti-egfr agents in advanced hnscc, the Head and Neck Cancer Disease Site Group (dsg) of Cancer Care Ontario’s Program in Evidence-Based Care (pebc) chose to systematically review the literature pertaining to this topic so as to develop evidence-based recommendations for treatment.
Outcomes
Outcomes of interest included overall and progression-free survival, quality of life, tumour response rate and duration, and the toxicity associated with the use of anti-egfr therapies.
Methodology
The medline, embase, and Cochrane Library databases, the American Society of Clinical Oncology online conference proceedings, the Canadian Medical Association InfoBase, and the National Guidelines Clearinghouse were systematically searched to locate primary articles and practice guidelines. The reference lists from relevant review articles were searched for additional trials. All evidence was reviewed, and that evidence informed the development of the clinical practice guideline. The resulting recommendations were approved by the Report Approval Panel of the pebc, and by the Head and Neck Cancer dsg. An external review by Ontario practitioners completed the final phase of the review process. Feedback from all parties was incorporated to create the final practice guideline.
Results
The electronic search identified seventy-four references that were reviewed for inclusion. Only four phase iii trials met the inclusion criteria for the present guideline. No practice guidelines, systematic reviews, or meta-analyses were found during the course of the literature search.
The randomized controlled trials (rcts) involved three distinct patient populations: those with locally advanced hnscc being treated for cure, those with incurable advanced recurrent or metastatic hnscc being treated with first-line platinum-based chemotherapy, and those with incurable advanced recurrent or metastatic hnscc who had disease progression despite, or who were unsuitable for, first-line platinum-based chemotherapy.
Practice Guideline
These recommendations apply to adult patients with locally advanced (nonmetastatic stages iii–ivb) or recurrent or metastatic (stage ivc) hnscc.
Platinum-based chemoradiation remains the current standard of care for treatment of locally advanced hnscc.
In patients with locally advanced hnscc who are medically unsuitable for concurrent platinumbased chemotherapy or who are over the age of 70 years (because concurrent chemotherapy does not appear to improve overall survival in this patient population), the addition of cetuximab to radical radiotherapy should be considered to improve overall survival, progression-free survival, and time to local recurrence.
Cetuximab in combination with platinum-based combination chemotherapy is superior to chemotherapy alone in patients with recurrent or metastatic hnscc, and is recommended to improve overall survival, progression-free survival, and response rate.
The role of anti-egfr therapies in the treatment of locally advanced hnscc is currently under study in large randomized trials, and patients with hnscc should continue to be offered clinical trials of novel agents aimed at improving outcomes.
Qualifying Statements
Chemoradiation is the current standard of care for patients with locally advanced hnscc, and to date, there is no evidence that compares cetuximab plus radiotherapy with chemoradiation, or that examines whether the addition of cetuximab to chemoradiation is of benefit in these patients. However, five ongoing trials are investigating the effect of the addition of egfr inhibitors concurrently with, before, or after chemoradiotherapy; those trials should provide direction about the best integration of cetuximab into standard treatment.
In patients with recurrent or metastatic hnscc who experience progressive disease despite, or who are unsuitable for, first-line platinum-based chemotherapy, gefitinib at doses of 250 mg or 500 mg daily, compared with weekly methotrexate, did not increase median overall survival [hazard ratio (hr): 1.22; 96% confidence interval (ci): 0.95 to 1.57; p = 0.12 (for 250 mg daily vs. weekly methotrexate); hr: 1.12; 95% ci: 0.87 to 1.43; p = 0.39 (for 500 mg daily vs. weekly methotrexate)] or objective response rate (2.7% for 250 mg and 7.6% for 500 mg daily vs. 3.9% for weekly methotrexate, p > 0.05). As compared with methotrexate, gefitinib was associated with an increased incidence of tumour hemorrhage (8.9% for 250 mg and 11.4% for 500 mg daily vs. 1.9% for weekly methotrexate).
PMCID: PMC2880902  PMID: 20567625
Head-and-neck cancer; epidermal growth factor receptor; egfr inhibitors; overall survival; progression-free survival; tumour response rate
4.  Nutritional management in head and neck cancer: United Kingdom National Multidisciplinary Guidelines 
The Journal of Laryngology and Otology  2016;130(Suppl 2):S32-S40.
Nutritional support and intervention is an integral component of head and neck cancer management. Patients can be malnourished at presentation, and the majority of patients undergoing treatment for head and neck cancer will need nutritional support. This paper summarises aspects of nutritional considerations for this patient group and provides recommendations for the practising clinician.
Recommendations
• A specialist dietitian should be part of the multidisciplinary team for treating head and neck cancer patients throughout the continuum of care as frequent dietetic contact has been shown to have enhanced outcomes. (R)
• Patients with head and neck cancer should be nutritionally screened using a validated screening tool at diagnosis and then repeated at intervals through each stage of treatment. (R)
• Patients at high risk should be referred to the dietitian for early intervention. (R)
• Offer treatment for malnutrition and appropriate nutrition support without delay given the adverse impact on clinical, patient reported and financial outcomes. (R)
• Use a validated nutrition assessment tool (e.g. scored Patient Generated–Subjective Global Assessment or Subjective Global Assessment) to assess nutritional status. (R)
• Offer pre-treatment assessment prior to any treatment as intervention aims to improve, maintain or reduce decline in nutritional status of head and neck cancer patients who have malnutrition or are at risk of malnutrition. (G)
• Patients identified as well-nourished at baseline but whose treatment may impact on their future nutritional status should receive dietetic assessment and intervention at any stage of the pathway. (G)
• Aim for energy intakes of at least 30 kcal/kg/day. As energy requirements may be elevated post-operatively, monitor weight and adjust intake as required. (R)
• Aim for energy and protein intakes of at least 30 kcal/kg/day and 1.2 g protein/kg/day in patients receiving radiotherapy or chemoradiotherapy. Patients should have their weight and nutritional intake monitored regularly to determine whether their energy requirements are being met. (R)
• Perform nutritional assessment of cancer patients frequently. (G)
• Initiate nutritional intervention early when deficits are detected. (G)
• Integrate measures to modulate cancer cachexia changes into the nutritional management. (G)
• Start nutritional therapy if undernutrition already exists or if it is anticipated that the patient will be unable to eat for more than 7 days. Enteral nutrition should also be started if an inadequate food intake (60 per cent of estimated energy expenditure) is anticipated for more than 10 days. (R)
• Use standard polymeric feed. (G)
• Consider gastrostomy insertion if long-term tube feeding is necessary (greater than four weeks). (R)
• Monitor nutritional parameters regularly throughout the patient's cancer journey. (G)
• Pre-operative:
○ Patients with severe nutritional risk should receive nutrition support for 10–14 days prior to major surgery even if surgery has to be delayed. (R)
○ Consider carbohydrate loading in patients undergoing head and neck surgery. (R)
• Post-operative:
○ Initiate tube feeding within 24 hours of surgery. (R)
○ Consider early oral feeding after primary laryngectomy. (R)
• Chyle Leak:
○ Confirm chyle leak by analysis of drainage fluid for triglycerides and chylomicrons. (R)
○ Commence nutritional intervention with fat free or medium chain triglyceride nutritional supplements either orally or via a feeding tube. (R)
○ Consider parenteral nutrition in severe cases when drainage volume is consistently high. (G)
• Weekly dietetic intervention is offered for all patients undergoing radiotherapy treatment to prevent weight loss, increase intake and reduce treatments interruptions. (R)
• Offer prophylactic tube feeding as part of locally agreed guidelines, where oral nutrition is inadequate. (R)
• Offer nutritional intervention (dietary counselling and/or supplements) for up to three months after treatment. (R)
• Patients who have completed their rehabilitation and are disease free should be offered healthy eating advice as part of a health and wellbeing clinic. (G)
• Quality of life parameters including nutritional and swallowing, should be measured at diagnosis and at regular intervals post-treatment. (G)
doi:10.1017/S0022215116000402
PMCID: PMC4873913  PMID: 27841109
5.  De-escalation of radiation dose for human papillomavirus-positive oropharyngeal head and neck squamous cell carcinoma: A case report and preclinical and clinical literature review 
Oncology Letters  2015;11(1):141-149.
Traditionally, head and neck squamous cell carcinoma (HNSCC) has been considered to be a relatively homogeneous disease. However, recent data have demonstrated that human papillomavirus (HPV)-positive and HPV-negative disease are two different clinical entities associated with different outcomes. Preclinical and clinical studies have reported a divergence in treatment strategies as well as prognostic outcomes for HNSCCs that are HPV-positive versus HPV-negative. The present study describes the case of a 52-year-old man who presented with stage IVB cT2N3M0 right tonsillar HPV-positive squamous cell carcinoma. Induction chemotherapy with docetaxel, cisplatin and 5-fluorouracil (TPF), followed by chemoradiation therapy with carboplatin and 70 Gray (Gy) radiation in daily fractions was recommended. The patient completed the TPF and carboplatin treatment; however, he was unable to tolerate the radiation course, receiving a final dose of 46 Gy. A 60-day follow-up right neck salvage dissection was subsequently performed. Despite having received a partial radiation treatment of 46 Gy, the patient had no pathological evidence of disease at 60 days post radiation treatment. Repeat positron emission tomography-computed tomography at 32 months after the right neck dissection revealed no evidence of disease. The present study also discusses the current preclinical in vitro and in vivo targets for HPV-positive HNSCC and the obstacles presented in advancing clinical treatment modalities. Previous preclinical models investigating radiation sensitivity have yielded mixed results. Thus, it is important to understand and establish representative preclinical models for studying HPV and HNSCC to improve clinical research and therapeutic development. This review may guide future understanding of the role of HPV in HNSCC.
doi:10.3892/ol.2015.3836
PMCID: PMC4727039  PMID: 26870181
human papillomavirus; de-escalation; radiation; oropharyngeal; head and neck squamous cell carcinoma
6.  Management of neck metastases in head and neck cancer: United Kingdom National Multidisciplinary Guidelines 
The Journal of Laryngology and Otology  2016;130(Suppl 2):S161-S169.
This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. A rational plan to manage the neck is necessary for all head and neck primaries. With the emergence of new level 1 evidence across several domains of neck metastases, this guideline will identify the evidence-based recommendations for management.
Recommendations
• Computed tomographic or magnetic resonance imaging is mandatory for staging neck disease, with choice of modality dependant on imaging modality used for the primary site, local availability and expertise. (R)
• Patients with a clinically N0 neck, with more than 15–20 per cent risk of occult nodal metastases, should be offered prophylactic treatment of the neck. (R)
• The treatment choice of for the N0 and N+ neck should be guided by the treatment to the primary site. (G)
• If observation is planned for the N0 neck, this should be supplemented by regular ultrasonograms to ensure early detection. (R)
• All patients with T1 and T2 oral cavity cancer and N0 neck should receive prophylactic neck treatment. (R)
• Selective neck dissection (SND) is as effective as modified radical neck dissection for controlling regional disease in N0 necks for all primary sites. (R)
• SND alone is adequate treatment for pN1 neck disease without adverse histological features. (R)
• Post-operative radiation for adverse histologic features following SND confers control rates comparable with more extensive procedures. (R)
• Adjuvant radiation following surgery for patients with adverse histological features improves regional control rates. (R)
• Post-operative chemoradiation improves regional control in patients with extracapsular spread and/or microscopically involved surgical margins. (R)
• Following chemoradiation therapy, complete responders who do not show evidence of active disease on co-registered positron emission tomography–computed tomography (PET–CT) scans performed at 10–12 weeks, do not need salvage neck dissection. (R)
• Salvage surgery should be considered for those with incomplete or equivocal response of nodal disease on PET–CT. (R)
doi:10.1017/S002221511600058X
PMCID: PMC4873907  PMID: 27841133
7.  Prevalence of swallowing and speech problems in daily life after chemoradiation for head and neck cancer based on cut-off scores of the patient-reported outcome measures SWAL-QOL and SHI 
The objective of this study is to assess swallowing and speech outcome after chemoradiation therapy for head and neck cancer, based on the patient-reported outcome measures Swallowing Quality of Life Questionnaire (SWAL-QOL) and Speech Handicap Index (SHI), both provided with cut-off scores. This is a cross-sectional study. Department of Otolaryngology/Head and Neck Surgery of a University Medical Center. Sixty patients, 6 months to 5 years after chemoradiation for head and neck squamous cell carcinoma. Swallowing Quality of Life Questionnaire (SWAL-QOL) and SHI, both validated in Dutch and provided with cut-off scores. Associations were tested between the outcome measures and independent variables (age, gender, tumor stage and site, and radiotherapy technique, time since treatment, comorbidity and food intake). Fifty-two patients returned the SWAL-QOL and 47 the SHI (response rate 87 and 78 %, respectively). Swallowing and speech problems were present in 79 and 55 %, respectively. Normal food intake was noticed in 45, 35 % had a soft diet and 20 % tube feeding. Patients with soft diet and tube feeding reported more swallowing problems compared to patients with normal oral intake. Tumor subsite was significantly associated with swallowing outcome (less problems in larynx/hypopharynx compared to oral/oropharynx). Radiation technique was significantly associated with psychosocial speech problems (less problems in patients treated with IMRT). Swallowing and (to a lesser extent) speech problems in daily life are frequently present after chemoradiation therapy for head and neck cancer. Future prospective studies will give more insight into the course of speech and swallowing problems after chemoradiation and into efficacy of new radiation techniques and swallowing and speech rehabilitation programs.
doi:10.1007/s00405-015-3680-z
PMCID: PMC4899484  PMID: 26071622
Swallowing; Speech; Patient-reported outcomes; Quality of life; Head and neck cancer; Chemoradiation
8.  Development and Validation of a Prediction Model for Tube Feeding Dependence after Curative (Chemo-) Radiation in Head and Neck Cancer 
PLoS ONE  2014;9(4):e94879.
Background
Curative radiotherapy or chemoradiation for head and neck cancer (HNC) may result in severe acute and late side effects, including tube feeding dependence.
The purpose of this prospective cohort study was to develop a prediction model for tube feeding dependence 6 months (TUBEM6) after curative (chemo-) radiotherapy in HNC patients.
Patients and Methods
Tube feeding dependence was scored prospectively. To develop the multivariable model, a group LASSO analysis was carried out, with TUBEM6 as the primary endpoint (n = 427). The model was then validated in a test cohort (n = 183). The training cohort was divided into three groups based on the risk of TUBEM6 to test whether the model could be extrapolated to later time points (12, 18 and 24 months).
Results
Most important predictors for TUBEM6 were weight loss prior to treatment, advanced T-stage, positive N-stage, bilateral neck irradiation, accelerated radiotherapy and chemoradiation. Model performance was good, with an Area under the Curve of 0.86 in the training cohort and 0.82 in the test cohort. The TUBEM6-based risk groups were significantly associated with tube feeding dependence at later time points (p<0.001).
Conclusion
We established an externally validated predictive model for tube feeding dependence after curative radiotherapy or chemoradiation, which can be used to predict TUBEM6.
doi:10.1371/journal.pone.0094879
PMCID: PMC3988098  PMID: 24736318
9.  Human Papillomavirus Infection as a Prognostic Factor in Oropharyngeal Squamous Cell Carcinoma Patients Treated in a Prospective Phase II Clinical Trial 
Anticancer research  2009;29(5):1467-1474.
Background
Human papillomvirus (HPV)-16 is associated with an improved prognosis in a subset of patients with head and neck squamous cell carcinoma (HNSCC). Cervical carcinoma models have also demonstrated that HPV oncoproteins, E6 and E7, can induce VEGF and HIF-1 gene expression. The purpose of this study was to 1) determine the presence of high-risk HPV 16 in patients with HNSCC enrolled in a prospective phase II clinical trial, 2) assess the impact of HPV status on treatment response and survival in this select cohort treated with combined modality therapy, and 3) identify the differences between HIF/VEGF expression in HPV-positive and -negative tumors.
Experimental Design
The effect of HPV status on treatment response and outcome was prospectively evaluated in a single-institution phase II clinical trial. Patients had resectable untreated stage III, IV HNSCC of the oral cavity, oropharynx, hyopharynx, or larynryx, and stage II cancer of the base of tongue, hypopharynx, and larynx. All patients received neoadjuvant chemotherapy with two course of docetaxel (T) 60 mg/m2, then a 96-hour infusion of cisplatin (P) 25mg/m2/d, 5-fluorouracil (F) 700 mg/m2/d, and leucovorin (L) 500 mg/m2/d (TPFL). Those with at least a partial response received a third course. Responding patients then underwent surgery including modified lymph node dissection followed by adjuvant radiation or chemoradiation. Patients who progressed during neoadjuvant chemotherapy proceeded directly to surgery. HPV status was determined by conventional PCR in fresh frozen biopsy samples and Taqman PCR assay on formalin-fixed, paraffin-embedded specimens. HIF-1a and VEGF-A expression were assessed by immunohistochemistry (IHC) and quantitative real-time PCR (RT-PCR). Multivariate Cox proportional hazards regression analysis of time to disease progression or death was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for HPV-positive status.
Results
Of the 24 evaluable cases, HPV16 DNA was detected in 14 specimens, 13 of which were oropharyngeal tumors. HPV18 was not detected in any of the specimens. Treatment compliance was similar between both groups. There was no difference in either the response rates seen after NCT (85.7% vs. 90%), or the pathologic complete response rate for surgical patients (38.5% vs. 42.9%) for the HPV-positive and –negative tumors, respectively. After a median follow-up time of 52.9 months, there was a trend toward better progression-free (HR 0.15; p = 0.06) and overall survival (HR 0.14; p = 0.10), but this was not statistically significant. There was no difference in the level of VEGF expression at the protein level, however, in a subset of 13 fresh frozen tissue samples, quantitative RT-PCR revealed a statistically significant increase in VEGF mRNA transcript in the HPV-positive tumors (p < 0.01). No difference was seen for HIF-1a expression.
Conclusions
HPV-positivity portended a better prognosis in patients with oropharyngeal SCC treated with induction chemotherapy and adjuvant radiation in a prospective clinical trial although the benefit did not reach the level of statistical significance due to the small patient number. The level of VEGF mRNA was up-regulated in HPV16-positive tumors possibly by a HIF-1 independent manner.
PMCID: PMC3582681  PMID: 19443352
10.  High XRCC1 Protein Expression Is Associated with Poorer Survival in Patients with Head and Neck Squamous Cell Carcinoma 
Purpose
We evaluated X-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1) protein in head and neck squamous cell carcinoma (HNSCC) patients in association with outcome.
Experimental Design
XRCC1 protein expression was assessed by immunohistochemical (IHC) staining of pretreatment tissue samples in 138 consecutive HNSCC patients treated with surgery (n = 31), radiation (15), surgery and radiation (23), surgery and adjuvant chemoradiation (17), primary chemoradiation (51), and palliative measures (1).
Results
Patients with high XRCC1 expression by IHC (n = 77) compared with patients with low XRCC1 expression (n = 60) had poorer median overall survival (OS; 41.0 months vs. OS not reached, P = 0.009) and poorer progression-free survival (28.0 months vs. 73.0 months, P = 0.031). This association was primarily due to patients who received chemoradiation (median OS of high- and low-XRCC1 expression patients, 35.5 months and not reached respectively, HR 3.48; 95% CI: 1.44–8.38; P = 0.006). In patients treated with nonchemoradiation modalities, there was no survival difference by XRCC1 expression. In multivariable analysis, high XRCC1 expression and p16INK4a-positive status were independently associated with survival in the overall study population (HR = 2.62; 95% CI: 1.52–4.52; P < 0.001 and HR = 0.21; 95% CI: 0.06–0.71; P = 0.012, respectively) and among chemoradiation patients (HR = 6.02; 95% CI: 2.36–15.37; P < 0.001 and HR = 0.26; 95% CI: 0.08–0.92, respectively; P = 0.037).
Conclusions
In HNSCC, high XRCC1 protein expression is associated with poorer survival, particularly in patients receiving chemoradiation. Future validation of these findings may enable identification of HNSCC expressing patients who benefit from chemoradiation treatment.
doi:10.1158/1078-0432.CCR-10-1604
PMCID: PMC3725262  PMID: 21908577
11.  Acupuncture for Dysphagia after Chemoradiation Therapy in Head and Neck Cancer: A Case Series Report* 
Integrative cancer therapies  2010;9(3):284-290.
Background
Dysphagia is a common side effect following chemoradiation therapy (CRT) in head and neck cancer (HNC) patients.
Methods
In this retrospective case series, ten HNC patients were treated with acupuncture for radiation-induced dysphagia and xerostomia. All patients were diagnosed with stage III/IV squamous cell carcinoma. Seven of 10 patients were percutaneous endoscopic gastrostomy (PEG) tube-dependent when they began acupuncture. Manual acupuncture and electroacupuncture were used once a week.
Results
Nine of 10 patients reported various degrees of subjective improvement in swallowing functions, xerostomia, pain and fatigue levels. Six (86%) of 7 PEG tube-dependent patients had their feeding tubes removed after acupuncture, with a median duration of 114 days (range 49–368) post CRT. One typical case is described in detail.
Conclusions
A relatively short PEG tube duration and reduced symptom severity following CRT were observed in these patients. Formal clinical trials are required to determine the causality of our observations.
doi:10.1177/1534735410378856
PMCID: PMC3014053  PMID: 20713374
acupuncture; chemoradiation therapy; radiation therapy; head and neck cancer; dysphagia; percutaneous endoscopic gastrostomy (PEG) tube
12.  Treatment-Related Toxicities in Older Adults with Head and Neck Cancer: A Population-Based Analysis 
Cancer  2015;121(12):2083-2089.
Background
Despite advantages in terms of cancer control and organ preservation, the benefits of chemoradiation (CTRT) may be offset by potentially severe, treatment-related toxicities particularly in older patients. Our objectives were to assess the type and frequency of toxicities in older adults with locally or regionally advanced, head and neck squamous cell carcinoma of the (HNSCC) receiving either primary CTRT or RT alone.
Methods
Using SEER cancer registry data linked with Medicare claims, we identified patients aged 66 years or older with locally advanced HNSCC, diagnosed 2001–2009, who received CTRT or RT alone. We examined differences in the frequency of toxicity-related hospital admissions and emergency room (ER) visits as well as feeding tube use and estimated the impact of chemotherapy on the likelihood of toxicity, controlling for demographic and disease characteristics.
Results
Of patients who received CTRT (N=1,502), 62% had a treatment-related toxicity, compared with 46% of patients who received RT alone (N=775). Controlling for demographic and disease characteristics, CTRT patients were twice as likely to experience an acute toxicity compared with their RT only peers. Fifty-five percent of CTRT patients had a feeding tube placed during or after treatment compared with 28% of the RT-only group.
Conclusions
In this population-based cohort of older adults with HNSCC, the rate of acute toxicities and feeding tube use in patients receiving CTRT was considerable. It is possible that for certain older patients, the potential benefit of adding CT to RT does not outweigh the harms of this combined modality therapy.
doi:10.1002/cncr.29262
PMCID: PMC5018230  PMID: 25728057
head and neck cancer; toxicity; radiotherapy; chemoradiation; SEER; Medicare
13.  The effect of neck dissection on quality of life after chemoradiation 
Objective
To determine differences in QOL between head and neck cancer patients receiving chemoradiation versus chemoradiation and neck dissection.
Methods
A prospective cohort study was conducted at 2 tertiary otolaryngology clinics and a VA. Sample: 103 oropharyngeal Stage IV SCCA patients treated via chemoradiation +/− neck dissection. Intervention: self-administered health survey collecting health, demographic, and QOL information pretreatment and 1 year later. Main outcome measures: QOL via SF-36 and HNQoL. Descriptive statistics were calculated for health / clinical characteristics, demographics, and QOL scores. T-tests evaluated changes in QOL over time.
Results
65 patients received chemoradiation and 38 chemoradiation + neck dissection. Only the pain index of the SF-36 showed a significant difference between groups (p<.05) with the neck dissection group reporting greater pain.
Conclusions
After post-treatment neck dissection, patients experience statistically significant decrement in bodily pain domain scores, but other QOL scores are similar to those of patients undergoing chemoradiation alone.
doi:10.1016/j.otohns.2008.07.007
PMCID: PMC2840712  PMID: 18922336
14.  Post-radiotherapy neck dissection improves control at non-regional disease sites after definitive chemoradiation for squamous cell carcinoma of the head and neck 
Importance
After chemoradiation for head and neck cancer, over ninety percent of patients who achieved a complete response by imaging were regionally controlled without post-radiotherapy neck dissections (PRND). Since several groups have reported that lymph node involvement also predicted failure at both primary and distant sites, it remains unclear the extent to which PRND impacts non-regional sites of disease.
Objective
Here, we evaluated how PRND impacted local and distant control in patients who achieved a clinical complete response.
Design
We retrospectively reviewed patients treated for stage III/IV disease with definitive chemoradiation between 1990 to 2012.
Setting
University of Illinois at Chicago.
Participants
287 patients were treated with definitive CRT, of whom seventy-four underwent PRND. Median follow up was 25.4 months.
Interventions
Chemoradiation followed by lymph node dissection or observation.
Main Outcomes and Measures
Endpoints evaluated included local control (LC), regional control (RC), freedom from distant metastasis (FFDM), progression free survival (PFS) and overall survival (OS) using first-failure analysis.
Results
Patients with advanced nodal disease (≥N2b; n=176) had improved PFS (74.6% vs. 39.1%; P<.001) while patients with lesser nodal disease had similar PFS. For patients with advanced nodal disease, PRND improved 2-year LC (85.5 vs. 53.5%; p<.001), locoregional control with PRND (78.9% vs. 45.7%; P<.001), FFDM (79.5% vs. 67.5%%; P=.03) and OS (84.5% vs. 61.7%; P=.004) but not RC (96.9% vs. 90.1%; P=.21) The benefit in LC (87.4% vs. 66.2%; P=.02) and PFS (80.7% vs. 53.4%; P=.01) persisted for those with negative post-treatment imaging who underwent PRND. On univariate analysis, PRND, alcohol use, nodal stage and chemoradiation significantly impacted 2 year LC and/or PFS. On multivariate analysis, PRND remained strongly prognostic for 2 year LC (HR 0.22; P=.0007) and PFS (HR 0.42; P=.002).
Conclusions and Relevance
PRND improved control of non-regional sites of disease in patients with advanced nodal disease who achieved a complete response after chemoradiation. Thus, PRND may impact the control of non-nodal sites through possible mechanisms such as clearance of incompetent lymphatics and prevention of re-seeding of the primary and distant sites.
Trial Registration
None.
doi:10.1001/jamaoto.2013.5754
PMCID: PMC4662541  PMID: 24263403
15.  FUNCTIONAL OUTCOMES AFTER TORS FOR OROPHARYNGEAL CANCER: A SYSTEMATIC REVIEW 
OBJECTIVE
Summarize functional outcomes after transoral robotic surgery (TORS) ± adjuvant therapy for oropharyngeal cancer (OPC).
STUDY DESIGN
A systematic review was conducted. The MEDLINE database was searched (MeSH terms: transoral robotic surgery, pharyngeal neoplasms, oropharyngeal neoplasms).
METHODS
Peer-reviewed human subject papers published through December, 2013 were included. Exclusion criteria were: 1) case report design (n<10), 2) review article, or 3) technical, animal or cadaver studies. Functional outcomes extracted included feeding tube dependence, swallow examination findings, speech ratings, velopharyngeal insufficiency, pneumonia, and oral intake measures.
RESULTS
Twelve papers comprising 441 patients with OPC treated with TORS ± adjuvant therapy were included. Feeding tube rates were the most commonly reported functional outcome. Excluding prophylactic placement, 18% to 39% of patients required gastrostomy placement, typically during adjuvant therapy. Chronic gastrostomy dependence ranged from 0% to 7% (mean follow-up: 11–26 months), regardless of disease stage. Composite MD Anderson Dysphagia Inventory (MDADI) scores ranged from 65.2 to 78 (89 patients, 3 series, mean follow-up: 12–13 months). Videofluoroscopic swallowing studies were not systematically reported. Incidence of postoperative pneumonia was 0% to 7%. Predictors of swallowing function included baseline function, T-stage, N-stage, tongue base primary tumors, and adjuvant chemoradiation. Rates of transient hypernasality were 4% to 9%. A single study suggested dose-dependent effects of adjuvant therapy (none, radiation alone, chemoradiation) on diet scores at 6- and 12-months.
CONCLUSIONS
Crude endpoints of functional recovery after TORS ± adjuvant therapy suggest promising swallowing outcomes, depending on the functional measure reported.
doi:10.1007/s00405-014-2985-7
PMCID: PMC4169348  PMID: 24643851
Transoral robotic surgery; Oropharyngeal cancer; Functional outcome; Swallowing
16.  Transoral Robotic Surgery for Oropharyngeal Cancer: Long Term Quality of Life and Functional Outcomes 
Objective
To determine swallowing, speech and quality of life (QOL) outcomes following transoral robotic surgery (TORS) for oropharyngeal squamous cell carcinoma (OPSCC).
Design
Prospective cohort study.
Setting
Tertiary care academic comprehensive cancer center.
Patients
81 patients with previously untreated OPSCC.
Intervention
Primary surgical resection via TORS and neck dissection as indicated.
Main Outcome Measures
Patients were asked to complete the Head and Neck Cancer Inventory (HNCI) pre-operatively and at 3 weeks as well as 3, 6 and 12 months post-operatively. Swallowing ability was assessed by independence from a gastrostomy tube (G-Tube). Clinicopathological and follow-up data were also collected.
Results
Mean follow-up time was 22.7 months. HNCI response rates at 3 weeks and 3, 6, and 12 months were 79%, 60%, 63%, 67% respectively. There were overall declines in speech, eating, aesthetic, social and overall QOL domains in the early post-operative periods. However, at 1 year post-TORS scores for aesthetic, social and overall QOL remained high. Radiation therapy was negatively correlated with multiple QOL domains (p<0.05), while age > 55 years correlated with lower speech and aesthetic scores (p<0.05). HPV status did not correlate with any QOL domain. G-Tube rates at 6 and 12 months were 24% and 9%, respectively. The extent of TORS (> 1 oropharyngeal site resected) and age > 55 years predicted the need for a G-Tube at any point after TORS (p<0.05).
Conclusions
Patients with OPSCC treated with TORS maintain a high QOL at 1 year after surgery. Adjuvant treatment and advanced age tend to decrease QOL.
doi:10.1001/jamaoto.2013.2747
PMCID: PMC4274181  PMID: 23576186
Transoral robotic surgery; oropharyngeal cancer; health related quality of life
17.  Swallowing Function Following post Chemoradiotherapy Neck Dissection – Review of Findings and Analysis of Contributing Factors 
Objective
This study assesses swallowing function following chemoradiotherapy and neck dissection in head and neck cancer patients and investigates clinical, treatment and neck dissection factors associated with dysphagia.
Study Design
Case series with chart review
Setting
Tertiary Care Center
Subjects and Methods
88 patients undergoing neck dissection after chemoradiotherapy for advanced head and neck cancer were reviewed. Dysphagia outcome measures included weight loss, diet, gastrostomy tube-dependency and video swallow findings of aspiration or stenosis. Additionally we created a Diet/GT Scale, score 1–5. Univariate and multivariate analysis of clinical, treatment or neck dissection factors potentially associated with dysphagia outcome measures was undertaken.
Results
Peak mean weight loss was 17% at 6 months after chemoradiotherapy. At 12 months a soft/regular diet was taken by 78/88 (89%) and only 1/88 (1%) of patients were nil per os. Gastrostomy tube-dependence at 6, 12, 24 months was 53%, 25%, and 10%. Diet/GT score was 5 (gastrostomy tube removed and soft/regular diet) for 47% at 6 months, 74% at 12 months and 89% at 24 months. Multivariate analyses revealed that higher tumor stage was associated with a lower Diet/GT score at 12 months (p=0.02) and gastrostomy-dependence at 12 (p=0.01) and 24 months (p=0.04).
Conclusion
Despite the addition of neck dissection to chemoradiotherapy, nearly all patients took a soft or regular diet, reached a Diet/GT score of 5 and only 1% remained nil per os. A higher tumor stage is associated with a lower Diet/GT score and gastrostomy tube-dependency beyond 12 months.
doi:10.1177/0194599811403075
PMCID: PMC3434459  PMID: 21493276
18.  Concurrent Chemoradiation with Low-Dose Weekly Cisplatin in Locally Advanced Stage IV Head and Neck Squamous Cell Carcinoma 
Purpose
Concurrent chemoradiation (CRT) with 3-weekly doses of cisplatin is a standard treatment for loco-regionally advanced head and neck squamous cell carcinoma (HNSCC). However, treatment with 3-weekly doses of cisplatin is often associated with several adverse events. Therefore, we conducted this retrospective analysis to determine the efficacy and tolerance of CRT with a low weekly dose of cisplatin in stage IV HNSCC patients.
Materials and Methods
Medical records of patients who were diagnosed with stage IV HNSCC and received concurrent CRT were analyzed. All patients were treated weekly with cisplatin at 20-30 mg/m2 until radiotherapy was completed.
Results
A total of 35 patients were reviewed. Median follow up was 10.7 months (range, 1.7 to 90.5 months), the median radiation dose was 7,040 cGy, and the median dose of cisplatin received was 157 mg/m2. Eleven patients received docetaxel combination chemotherapy. Overall, 25 patients (71.4%) achieved complete response (CR), eight (22.9%) showed partial response. The median overall survival was 42.7 months, the 3-year survival rate was 51.2% and the 3 year disease-free survival rate was 72.8%. Overall survival was improved in patients who achieved CR relative to others (59.7 months vs. 13.4 months; p=0.008). There were significant differences in survival between patients who received docetaxel combination and cisplatin alone (51.8 months vs. 7.9 months; p=0.009). Grade 3-4 adverse events included stomatitis (82.9%), dermatitis (22.9%), infection (11.4%), dysphagia (8.6%), and neutropenia (5.7%).
Conclusion
CRT with low dose weekly cisplatin is likely effective and tolerable, even in patients with locally advanced-stage IV HNSCC.
doi:10.4143/crt.2013.219
PMCID: PMC4506097  PMID: 25672576
Head and neck neoplasms; Chemoradiotherapy; Cisplatin
19.  Planned neck dissection following chemo-radiotherapy in advanced HNSCC 
Background
Neck dissection has traditionally played an important role in the management of patients with regionally advanced head and neck squamous cell carcinoma (HNSCC) treated with radical radiotherapy alone. However, with the incorporation of chemotherapy in the therapeutic strategy for advanced HNSCC and resultant improvement in outcome the routine use of post chemo-radiotherapy neck dissection is being questioned.
Methods
Published data for this review was identified by systematically searching MEDLINE, CANCERLIT & EMBASE databases from 1995 until date with restriction to the English language.
Results
There is lack of high quality evidence on the role of planned neck dissection in advanced HNSCC treated with chemo-radiotherapy. A systematic literature search could identify only one small randomized controlled trial (Level I evidence) addressing this issue, albeit with major limitations. Upfront neck dissection followed by chemo-radiotherapy resulted in better disease-specific survival as compared to chemoradiation only. Several single arm prospective and retrospective reports were also identified with significant heterogeneity and often-contradictory conclusions.
Conclusions
Planned neck dissection after radical chemo-radiotherapy achieves a high level of regional control, but its ultimate benefit is limited to a small subset of patients only. Unless there are better non-invasive ways to identify residual viable disease, the role of such neck dissection shall remain debatable. A large randomized controlled trial addressing this issue is needed to clarify its role and provide evidence-based answers.
doi:10.1186/1477-7800-1-6
PMCID: PMC520831  PMID: 15377383
chemo-radiotherapy; HNSCC; and neck dissection
20.  The evolution of surgery in the management of neck metastases 
Summary
In spite of advancement in science, molecular medicine and target therapies, surgical treatment of metastases using different techniques, from selective neck dissection to extended radical neck dissections, form a major part in the management of neck metastases. This is due to the fact that, so far, there is no treatment more effective for resectable neck metastases, than surgery. Since most head and neck cancer patients die due to loco-regional progression of disease, and a very large majority of them do not live long enough to develop distant metastases, the status of neck lymph nodes remains the single most important prognostic factor, in these cases. In the 100 years since George Washington Crile described Radical Neck Dissection, we now have a much better understanding of the biological and clinical behaviour of neck metastases. This has ultimately led to the conservative approaches of selective neck dissections depending on the primary site of the tumour, type of tumour and the characteristic features of the metastases themselves. A search of the literature on neck lymph nodes and neck dissections, on the internet and in old publications, not available in the electronic media, has been carried out. Using this as the basis, we arranged, in sequence, the dates of various landmarks in the treatment of head and neck cancer related to neck dissections to emphasize the overall process of evolution of neck dissection thereby showing how the field of head and neck surgery has travelled a long way from radical neck dissection to its modifications and further to selective neck dissections and sentinel node biopsies. The present understanding of the patterns of neck metastases enables us not only to adequately treat the neck metastases, but also to diagnose metastases from unknown primaries. Therefore, depending on the site of the primary tumour, it is now easy to predict the most probable route of metastatic spread and vice versa. This has enabled us to adopt modified and selective neck dissections which have ultimately led to a dramatic reduction in morbidity and almost eliminated mortality due to neck dissection. In the near future, molecular diagnostics and targeted therapies for treating metastases should be able to further reduce the burden of head and neck cancer.
PMCID: PMC2639986  PMID: 17633149
Neck; Lymph nodes; Neck dissection; Classification; History; Evolution
21.  Phase 1 Trial of Bevacizumab With Concurrent Chemoradiation Therapy for Squamous Cell Carcinoma of the Head and Neck With Exploratory Functional Imaging of Tumor Hypoxia, Proliferation, and Perfusion 
Purpose
A phase 1 trial was completed to examine the safety and feasibility of combining bevacizumab with radiation and cisplatin in patients with locoregionally advanced squamous cell carcinoma of the head and neck (HNSCC) treated with curative intent. Additionally, we assessed the capacity of bevacizumab to induce an early tumor response as measured by a series of biological imaging studies.
Methods and Materials
All patients received a single induction dose of bevacizumab (15 mg/kg) delivered 3 weeks (±3 days) before the initiation of chemoradiation therapy. After the initial dose of bevacizumab, comprehensive head and neck chemoradiation therapy was delivered with curative intent to 70 Gy in 33 fractions with concurrent weekly cisplatin at 30 mg/m2 and bevacizumab every 3 weeks (weeks 1, 4, 7) with dose escalation from 5 to 10 to 15 mg/kg. All patients underwent experimental imaging with [18F]fluorothymidine positron emission tomography (FLT-PET) (proliferation), [61Cu]Cu-diacetyl-bis(N4-methylthiosemicarbazone) PET (Cu-ATSM-PET) (hypoxia), and dynamic contrast-enhanced computed tomography (DCE-CT) (perfusion) at 3 time points: before bevacizumab monotherapy, after bevacizumab monotherapy, and during the combined therapy course.
Results
Ten patients were enrolled. All had stage IV HNSCC, all achieved a complete response to treatment, and 9 of 10 remain alive, with a mean survival time of 61.3 months. All patients experienced grade 3 toxicity, but no dose-limiting toxicities or significant bleeding episodes were observed. Significant reductions were noted in tumor proliferation (FLT-PET), tumor hypoxia (Cu-ATSM-PET), and DCE-CT contrast enhancement after bevacizumab monotherapy, with further decreases in FLT-PET and Cu-ATSM-PET during the combined therapy course.
Conclusions
The incorporation of bevacizumab into comprehensive chemoradiation therapy regimens for patients with HNSCC appears safe and feasible. Experimental imaging demonstrates measureable changes in tumor proliferation, hypoxia, and perfusion after bevacizumab monotherapy and during chemoradiation therapy. These findings suggest opportunities to preview the clinical outcomes for individual patients and thereby design personalized therapy approaches in future trials.
doi:10.1016/j.ijrobp.2014.11.029
PMCID: PMC4580235  PMID: 25659884
22.  Success of Endoscopic Pharyngoesophageal Dilation after Head and Neck Cancer Treatment 
The Laryngoscope  2013;123(12):3066-3073.
Objective
To assess clinical success and safety of endoscopic pharyngoesophageal dilation after chemoradiation or radiation for head and neck cancer and to identify variables associated with dilation failure.
Study Design
Case series with chart review
Methods
Between 2000 and 2008 one hundred and eleven patients treated with chemoradiation or radiation for head and neck cancer with subsequent pharyngoesophageal stenosis requiring endoscopic dilation were identified. Patients were evaluated for endoscopic dilation technique, severity of stenosis, technical and clinical success and intra and post operative complications. The Diet/GT Score, range 1–5, was utilized to measure swallow success. Variables associated with dilation failure were analyzed by univariate and multivariate logistic regression.
Results
271 dilations were analyzed, with 42 combined antegrade retrograde dilations, 208 dilations over a guidewire and 21 dilations without guidewire. Intraoperative patency and successful dilation of the stenotic segment was achieved in 95% of patients. A Diet/GT score of 5 (gastrostomy tube removed and soft/regular diet) was attained in 84/111 (76%) patients. Safety analysis showed complications occurred in 9% of all dilations. Perforations were noted in 4% of all procedures with only two esophageal perforations requiring significant intervention. Multiple dilations were associated with an increased risk for perforations. Further logistic regression analyses revealed that the number of dilations was indicating a poor outcome and low Diet/GT score.
Conclusion
Pharyngoesophageal stenosis, occurring after chemoradiation and radiation treatment, can be successfully and safely treated with endoscopic dilation techniques. Patients with restenosis, requiring multiple dilations, have a higher risk of persistent dysphagia.
Level of Evidence
2b individual retrospective cohort study
doi:10.1002/lary.24268
PMCID: PMC3844120  PMID: 23775806
esophageal stenosis; pharyngoesophageal stenosis; dysphagia; esophageal dilation; head and neck cancer; CARD
23.  Long term results of TAX324, a randomized phase III trial of sequential therapy with TPF versus PF in locally advanced squamous cell cancer of the head and neck 
The Lancet. Oncology  2011;12(2):153-159.
Background
With a minimum follow up of 2 years, the TAX324 study demonstrated a significant survival benefit of induction chemotherapy (IC) with docetaxel, cisplatin and 5FU (TPF) versus cisplatin and 5fluorouracil (PF) followed by chemoradiotherapy with carboplatin delivered as sequential therapy (ST) in locally advanced head and neck cancer (LAHNC). We report the long term results with 5 years minimum follow-up.
Methods
TAX324 was a randomized, open-label phase 3 trial comparing three cycles of TPF IC (docetaxel 75 mg/m2 of body-surface area, followed by intravenous cisplatin 100 mg/m2 and 5fluorouracil 1000 mg/m2 per day administered as a continuous 24-hour infusion for 4 days) with three cycles of PF (intravenous cisplatin 100 mg/m2, followed by fluorouracil 1000 mg/m2 per day as a continuous 24-hour infusion for 5 days). Both regimens were followed by 7 weeks of chemoradiotherapy with concomitant weekly carboplatin (AUC1.5). Randomization was performed centrally with the use of a biased-coin minimization technique. At study entry, patients were stratified according to the site of the primary tumor, nodal status (N0 or N1 vs. N2 or N3), and institution. For this long term analysis, data was gathered retrospectively. Overall survival (OS) and progression-free survival (PFS) were the primary endpoints. Data as of December 1, 2008 were analyzed. Tracheostomy and gastric feeding tube dependence were used as surrogates for treatment related long term toxicity. The median follow-up was 72.2 months (mo) (IQR for TPF =33 mo, PF =34 mo and for all pts =34 months). The analysis was based on data from all 501 patients. 61 patients were lost to follow-up and their data as of the initial analysis in 2005 was used.
Findings
OS was significantly better with TPF versus PF (HR=0.74, 95%CI: 0.58–0.94), with an estimated 5-yr survival rate of 0.52 and 0.42 in the TPF and PF arms, respectively. Median survival time was 70.6 mo (95%CI: 49.0–89.0 mo) with TPF versus 34.8 mo (the 95%CI: 22.6–48.0 mo) in the PF group (p=0.014). PFS was also significantly better with TPF (38.1 mo; 95%CI 19.3–66.1 mo vs. 13.2 mo, 95%CI 10.6–20.7 mo; HR= 0.75, 95%CI: 0.60–0.94). Subjects with hypopharyngeal and laryngeal cancer had significantly superior PFS with TPF (HR=0.68, the 95%CI: 0.47–0.98). No significant difference for dependence on gastric feeding tubes and tracheotomies was detected between the treatment groups. In the TPF arm 3 out of 91 patients (3%) remained feeding tube dependent (no information in 40 cases) while 8 out of 71 (10%) patients required feeding tubes in the PF arm (no information in 30 cases). 6 out of 92 (7%) patients had tracheostomies (no information in 39) versus 8/71 (13%) (no information in 30) in the TPF and PF groups, respectively.
Interpretation
IC with TPF provides long term survival benefit compared to PF in LAHNC. Patients who are candidates for IC should be treated with TPF.
doi:10.1016/S1470-2045(10)70279-5
PMCID: PMC4356902  PMID: 21233014
24.  Quality of life, functional outcome, and voice handicap index in partial laryngectomy patients for early glottic cancer 
Background
In this study, we aim to gather information about the quality of life issues, functional outcomes and voice problems facing early glottic cancer patients treated with the surgical techniques such as laryngofissure cordectomy, fronto-lateral laryngectomy, or cricohyoidopexi. In particular, consistency of life and voice quality issues with the laryngeal tissue excised during surgery is examined. In addition, the effects of arytenoidectomy to the life and voice quality are also studied.
Methods
29 male patients were enrolled voluntarily in the study. The average age was 53.9 years. Three out of 10 patients with laryngofissure cordectomy also had arytenoidectomy. 11 patients had fronto-lateral laryngectomy with Tucker reconstruction, two of which also had arytenoidectomy. There were eight patients with cricohyoidopexi and bilateral functional neck dissection. Three of these patients also had arytenoidectomy. In bilateral functional neck dissection cases, spinal accessory nerve was preserved and level V of the neck was not dissected. None of the patients had neither radiotherapy nor voice therapy. Cordectomy patients never had a temporary tracheotomy or were connected to a feeding tube. Data was collected for 13 months for the cordectomy group, 14 months for fronto-lateral laryngectomy and cricohyoidopexi groups on average post-operatively. Statistical analysis in this study was carried out using the one-way analysis of variance, and the Post-Hoc group comparisons were made after Bonferroni and Scheffé-procedures.
In order to determine the effects of arytenoidectomy, a regression analysis is carried out to see if there are statistical differences in answers given to the survey questions among patients who were arytenoidectomized during their surgeries.
Results
There was a statistically significant difference between cordectomy and cricohyoidopexi group in answers to the University of Washington- Quality of Life- Revised survey part 1. (p = 0). A statistically significant difference was also established between cordectomy and fronto-lateral laryngectomy groups, as well as between cordectomy and cricohyoidopexi groups in answers to the University of Washington- Quality of Life- Revised survey part 2. (p = 0,036 and p = 0.009, respectively). Cricohyoidopexi group has given the lowest scores and the cordectomy group has given the highest scores in three survey questions representing the quality of life, performances and new voices. These ranges are also consistent with the laryngeal tissue excised during surgery (cricohyoidopexi > fronto-lateral laryngectomy > cordectomy). There was no statistically significant difference between groups in Performance Status Scale for Head and Neck cancer patients instrument. The difference between the Voice Handicap Index and Voice Handicap Index (functional); Voice Handicap Index (physical) and Voice Handicap Index (emotional) scores in three patient groups was not significant either. All of the patients evaluated that their new voices have similar functional, physical and emotional impact on their life. Decanulation and oral feeding times of cricohyoidopexi and fronto-lateral laryngectomy patients are found to be significantly longer than cordectomy patients. Lastly, the removal of arytenoid does not have any significant adverse effects on the quality of life, the functional outcomes, or the quality of voice.
Conclusion
In the present study, all patients with early glottic cancer, treated with different surgical technics reported fairly good quality of life outcomes, functional results and voice qualities. This study also finds that the removal of arytenoid does not have any adverse effects on the quality of life and voice from the patients' point of view.
doi:10.1186/1472-6815-5-3
PMCID: PMC1142310  PMID: 15890067
25.  Patterns of recurrence after selective postoperative radiation therapy for patients with head and neck squamous cell carcinoma 
BMC Cancer  2016;16:192.
Background
The radiation field for patients with postoperative head and neck squamous cell carcinoma is narrower in our institution than in Western countries to reduce late radiation related toxicities. This strategy is at a risk of loco-regional or distant metastasis. However, because patients are more closely checked than in Western countries by every 1 to 2 months intervals and it is supposed that regional recurrences are identified and salvage surgeries are performed more quickly. Therefore, it is considered that patient survival would not be compromised with this strategy. The aim of this study was to investigate the feasibility of this strategy retrospectively.
Methods
Patients who underwent neck dissection with close or positive margin, extra-capsular spread (ECS), multiple regional lymph node metastasis, pT4, with or without primary tumor resection were treated with postoperative radiation therapy. The volume of radiation field, especially the coverage of prophylactic regional lymph node area, was discussed among head and neck surgeons and radiation oncologists taking into account the clinical factors including patient’s age, performance status, number of positive lymph nodes, size of metastatic lymph nodes, extension of primary tumor beyond the midline, and existence of ECS.
Results
Seventy-two patients were identified who were treated with postoperative radiation therapy for head and neck squamous cell carcinoma between November 2005 and December 2014. There were 20 patients with oropharynx, 19 with hypopharynx, 7 with larynx, 23 with oral cavity, and 3 with other sites. Thirty eight patients had their neck irradiated bilaterally and 34 unilaterally. Median follow-up period for patients without relapse was 20.7 months (5.1–100.7). Thirty two patients had disease relapse after treatment including 22 loco-regional recurrence and 14 distant metastases. Among 22 loco-regional recurrence, seven patients underwent salvage surgery and one of them was no relapse at the time of the analysis. Among patients without bilateral neck lymph node metastasis who were treated with unilateral neck irradiation, patients with oral cavity or recurrent disease had significantly lower DFS compared with those without (2-y DFS 41.7 % vs 88.2 %, p = 0.017).
Conclusions
In patients without bilateral neck lymph node involvement, the postoperative unilateral neck irradiation is a reasonable treatment strategy for patients with the exception of oral cavity or recurrent disease.
doi:10.1186/s12885-016-2229-x
PMCID: PMC4782319  PMID: 26951089
Head and neck squamous cell carcinoma; Postoperative radiation therapy; Patterns of recurrence; Selective neck irradiation

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