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1.  Age most significant predictor of requiring enteral feeding in head-and-neck cancer patients 
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.
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.
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).
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.
PMCID: PMC4404131  PMID: 25896830
Head-and-neck cancer; Radiotherapy; Enteral feeding; Swallowing dysfunction
2.  Epidermal growth factor receptor targeted therapy in stages III and IV head and neck cancer 
Current Oncology  2010;17(3):37-48.
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.
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 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.
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.
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
3.  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.
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).
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).
We established an externally validated predictive model for tube feeding dependence after curative radiotherapy or chemoradiation, which can be used to predict TUBEM6.
PMCID: PMC3988098  PMID: 24736318
4.  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.
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.
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.
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
5.  High XRCC1 Protein Expression Is Associated with Poorer Survival in Patients with Head and Neck Squamous Cell Carcinoma 
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).
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).
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.
PMCID: PMC3725262  PMID: 21908577
6.  Acupuncture for Dysphagia after Chemoradiation Therapy in Head and Neck Cancer: A Case Series Report* 
Integrative cancer therapies  2010;9(3):284-290.
Dysphagia is a common side effect following chemoradiation therapy (CRT) in head and neck cancer (HNC) patients.
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.
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.
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.
PMCID: PMC3014053  PMID: 20713374
acupuncture; chemoradiation therapy; radiation therapy; head and neck cancer; dysphagia; percutaneous endoscopic gastrostomy (PEG) tube
7.  The effect of neck dissection on quality of life after chemoradiation 
To determine differences in QOL between head and neck cancer patients receiving chemoradiation versus chemoradiation and neck dissection.
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.
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.
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.
PMCID: PMC2840712  PMID: 18922336
8.  Transoral Robotic Surgery for Oropharyngeal Cancer: Long Term Quality of Life and Functional Outcomes 
To determine swallowing, speech and quality of life (QOL) outcomes following transoral robotic surgery (TORS) for oropharyngeal squamous cell carcinoma (OPSCC).
Prospective cohort study.
Tertiary care academic comprehensive cancer center.
81 patients with previously untreated OPSCC.
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.
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).
Patients with OPSCC treated with TORS maintain a high QOL at 1 year after surgery. Adjuvant treatment and advanced age tend to decrease QOL.
PMCID: PMC4274181  PMID: 23576186
Transoral robotic surgery; oropharyngeal cancer; health related quality of life
9.  Swallowing Function Following post Chemoradiotherapy Neck Dissection – Review of Findings and Analysis of Contributing Factors 
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
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.
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).
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.
PMCID: PMC3434459  PMID: 21493276
10.  Concurrent Chemoradiation with Low-Dose Weekly Cisplatin in Locally Advanced Stage IV Head and Neck Squamous Cell Carcinoma 
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.
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%).
CRT with low dose weekly cisplatin is likely effective and tolerable, even in patients with locally advanced-stage IV HNSCC.
PMCID: PMC4506097  PMID: 25672576
Head and neck neoplasms; Chemoradiotherapy; Cisplatin
11.  Planned neck dissection following chemo-radiotherapy in advanced HNSCC 
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.
Published data for this review was identified by systematically searching MEDLINE, CANCERLIT & EMBASE databases from 1995 until date with restriction to the English language.
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.
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.
PMCID: PMC520831  PMID: 15377383
chemo-radiotherapy; HNSCC; and neck dissection
12.  The evolution of surgery in the management of neck metastases 
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
13.  Success of Endoscopic Pharyngoesophageal Dilation after Head and Neck Cancer Treatment 
The Laryngoscope  2013;123(12):3066-3073.
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
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.
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.
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
PMCID: PMC3844120  PMID: 23775806
esophageal stenosis; pharyngoesophageal stenosis; dysphagia; esophageal dilation; head and neck cancer; CARD
14.  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.
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.
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.
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.
IC with TPF provides long term survival benefit compared to PF in LAHNC. Patients who are candidates for IC should be treated with TPF.
PMCID: PMC4356902  PMID: 21233014
15.  Quality of life, functional outcome, and voice handicap index in partial laryngectomy patients for early glottic cancer 
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.
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.
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.
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.
PMCID: PMC1142310  PMID: 15890067
16.  Prophylactic PEG placement in head and neck cancer: How many feeding tubes are unused (and unnecessary)? 
AIM: To determine the rate of use and non-use of prophylactic percutaneous endoscopic gastrostomy (PEG) tubes among patients with head and neck cancer (HNC) patients.
METHODS: All patients with HNC undergoing PEG between January 1, 2004 and June 30, 2006 were identified. Patients (or their next-of-kin) were surveyed by phone and all available medical records and cancer registry data were reviewed. Prophylactic PEG was defined as placement in the absence of dysphagia and prior to radiation or chemoradiation. Each patient with a prophylactic PEG was assessed for cancer diagnosis, type of therapy, PEG use, and complications related to PEG.
RESULTS: One hundred and three patients had PEG tubes placed for HNC. Thirty four patients (33%) could not be contacted for follow-up. Of the 23 (22.3%) patients with prophylactic PEG tubes, 11/23 (47.8%) either never used the PEG or used it for less than 2 wk. No association with PEG use vs non-use was observed for cancer diagnosis, stage, or specific cancer treatment. Non-use or limited use was observed in 3/6 (50%) treated with radiation alone vs 8/17 (47.1%) treated with chemoradiation (P = 1.0), and 3 of 10 (30%) treated with surgery vs 8 of 13 (62%) not treated with surgery (P = 0.21). Minor complications were reported in 5/23 (21.7%). One (4.3%) major complication was reported.
CONCLUSION: There is a high rate of unnecessary PEG placement when done prophylactically in patients with head and neck cancer.
PMCID: PMC3057142  PMID: 21448351
Head and neck cancer; Percutaneous gastrostomy tube; Prophylactic
17.  Protocol for a randomized controlled trial of early prophylactic feeding via gastrostomy versus standard care in high risk patients with head and neck cancer 
BMC Nursing  2014;13:17.
Patients with head and neck cancer are at high risk of malnutrition and dysphagia. Enteral tube feeding via a gastrostomy or nasogastric tube is often required in response to dysphagia, odynophagia or side effects of treatment that lead to dehydration and/or weight-loss. A recent systematic review concluded that the optimal method of tube feeding remains unclear; however prophylactic gastrostomy, placed in anticipation of its use during and after treatment, is common practice, following a number of demonstrated benefits. However the majority of these studies have been undertaken in patients receiving radiotherapy alone. More recent studies in patient populations receiving concurrent chemoradiotherapy are showing that despite prophylactic gastrostomy placement significant weight loss still occurs, placing the patient at risk of the consequences of malnutrition. Therefore we set out to investigate innovative prophylactic nutrition support via the gastrostomy to optimise the nutritional outcomes of patients with head and neck cancer.
Patients with head and neck cancer will be eligible for this single centre randomised controlled trial if they are identified for referral for a prophylactic gastrostomy using local guidelines. Patients will be excluded if they are: under the age of eighteen; pregnant; unable to give informed consent; or severely malnourished or moderately malnourished with significant dysphagia requiring a liquid or puree diet. All eligible patients who consent for the study will be allocated randomly to either the intervention or control group (usual care). The intervention group will commence prophylactic supplementary nutrition support via the gastrostomy immediately following placement compared to usual care where nutrition support is commenced via the gastrostomy when clinically indicated during treatment. Key outcome measures will be percentage weight loss, body composition, nutritional status and quality of life, measured at baseline and three months post treatment.
To our knowledge this is the first study to evaluate the effectiveness of early prophylactic tube feeding compared to commencement of feeding during treatment, as per current standard practice, in patients undergoing prophylactic gastrostomy prior to treatment for head and neck cancer.
Trial registration
This trial has been registered in the Australian New Zealand Clinical Trials registry as ACTRN12612000579897.
PMCID: PMC4083037  PMID: 25002833
Prophylactic; Gastrostomy; Head and neck cancer; Nutrition support; Enteral nutrition; Quality of life
Head & neck  2010;33(10):1387-1393.
The objective of this study was to determine the prognostic significance of viable tumor in post-chemoradiation neck dissection specimens in patients with squamous cell carcinoma of the laryngopharynx.
Retrospective analysis identified 181 patients treated with primary concurrent chemoradiation for carcinoma of the laryngopharynx at Memorial Sloan-Kettering Cancer Center between the years 1995 and 2005. Of these, 56 patients had a comprehensive neck dissection either as a planned or salvage procedure. Neck dissection specimens were analyzed by a single pathologist for the presence of viable tumor. The presence of viable tumor was correlated to the timing of neck dissection after chemoradiation and to tumor response. Overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) were determined by the Kaplan–Meier method, and correlation to tumor viability was determined with the log-rank test.
Nineteen (33%) patients had viable tumor in their neck dissection specimens. Viable tumor was higher in patients who had a less-than-complete response to chemoradiation compared with those who had a complete response (42% vs 25%, p = .1). There was no correlation to timing of neck dissection. The 5-year OS, DSS, and RFS were significantly lower in patients who had viable tumor in their neck dissection specimens (OS 49% vs 93%, p = .0005; DSS 56% versus 93%, p = .003; RFS 40% vs 75%, p = .004).
Patients with viable tumor in postchemoradiation neck dissection specimens had a poorer outcome compared with patients with no viable tumor.
PMCID: PMC3772770  PMID: 21928410
viable tumor; chemoradiation; neck dissection; prognosis
19.  Intra-tumor Genetic Heterogeneity and Mortality in Head and Neck Cancer: Analysis of Data from The Cancer Genome Atlas 
PLoS Medicine  2015;12(2):e1001786.
Although the involvement of intra-tumor genetic heterogeneity in tumor progression, treatment resistance, and metastasis is established, genetic heterogeneity is seldom examined in clinical trials or practice. Many studies of heterogeneity have had prespecified markers for tumor subpopulations, limiting their generalizability, or have involved massive efforts such as separate analysis of hundreds of individual cells, limiting their clinical use. We recently developed a general measure of intra-tumor genetic heterogeneity based on whole-exome sequencing (WES) of bulk tumor DNA, called mutant-allele tumor heterogeneity (MATH). Here, we examine data collected as part of a large, multi-institutional study to validate this measure and determine whether intra-tumor heterogeneity is itself related to mortality.
Methods and Findings
Clinical and WES data were obtained from The Cancer Genome Atlas in October 2013 for 305 patients with head and neck squamous cell carcinoma (HNSCC), from 14 institutions. Initial pathologic diagnoses were between 1992 and 2011 (median, 2008). Median time to death for 131 deceased patients was 14 mo; median follow-up of living patients was 22 mo. Tumor MATH values were calculated from WES results. Despite the multiple head and neck tumor subsites and the variety of treatments, we found in this retrospective analysis a substantial relation of high MATH values to decreased overall survival (Cox proportional hazards analysis: hazard ratio for high/low heterogeneity, 2.2; 95% CI 1.4 to 3.3). This relation of intra-tumor heterogeneity to survival was not due to intra-tumor heterogeneity’s associations with other clinical or molecular characteristics, including age, human papillomavirus status, tumor grade and TP53 mutation, and N classification. MATH improved prognostication over that provided by traditional clinical and molecular characteristics, maintained a significant relation to survival in multivariate analyses, and distinguished outcomes among patients having oral-cavity or laryngeal cancers even when standard disease staging was taken into account. Prospective studies, however, will be required before MATH can be used prognostically in clinical trials or practice. Such studies will need to examine homogeneously treated HNSCC at specific head and neck subsites, and determine the influence of cancer therapy on MATH values. Analysis of MATH and outcome in human-papillomavirus-positive oropharyngeal squamous cell carcinoma is particularly needed.
To our knowledge this study is the first to combine data from hundreds of patients, treated at multiple institutions, to document a relation between intra-tumor heterogeneity and overall survival in any type of cancer. We suggest applying the simply calculated MATH metric of heterogeneity to prospective studies of HNSCC and other tumor types.
In this study, Rocco and colleagues examine data collected as part of a large, multi-institutional study, to validate a measure of tumor heterogeneity called MATH and determine whether intra-tumor heterogeneity is itself related to mortality.
Editors’ Summary
Normally, the cells in human tissues and organs only reproduce (a process called cell division) when new cells are needed for growth or to repair damaged tissues. But sometimes a cell somewhere in the body acquires a genetic change (mutation) that disrupts the control of cell division and allows the cell to grow continuously. As the mutated cell grows and divides, it accumulates additional mutations that allow it to grow even faster and eventually from a lump, or tumor (cancer). Other mutations subsequently allow the tumor to spread around the body (metastasize) and destroy healthy tissues. Tumors can arise anywhere in the body—there are more than 200 different types of cancer—and about one in three people will develop some form of cancer during their lifetime. Many cancers can now be successfully treated, however, and people often survive for years after a diagnosis of cancer before, eventually, dying from another disease.
Why Was This Study Done?
The gradual acquisition of mutations by tumor cells leads to the formation of subpopulations of cells, each carrying a different set of mutations. This “intra-tumor heterogeneity” can produce tumor subclones that grow particularly quickly, that metastasize aggressively, or that are resistant to cancer treatments. Consequently, researchers have hypothesized that high intra-tumor heterogeneity leads to worse clinical outcomes and have suggested that a simple measure of this heterogeneity would be a useful addition to the cancer staging system currently used by clinicians for predicting the likely outcome (prognosis) of patients with cancer. Here, the researchers investigate whether a measure of intra-tumor heterogeneity called “mutant-allele tumor heterogeneity” (MATH) is related to mortality (death) among patients with head and neck squamous cell carcinoma (HNSCC)—cancers that begin in the cells that line the moist surfaces inside the head and neck, such as cancers of the mouth and the larynx (voice box). MATH is based on whole-exome sequencing (WES) of tumor and matched normal DNA. WES uses powerful DNA-sequencing systems to determine the variations of all the coding regions (exons) of the known genes in the human genome (genetic blueprint).
What Did the Researchers Do and Find?
The researchers obtained clinical and WES data for 305 patients who were treated in 14 institutions, primarily in the US, after diagnosis of HNSCC from The Cancer Genome Atlas, a catalog established by the US National Institutes of Health to map the key genomic changes in major types and subtypes of cancer. They calculated tumor MATH values for the patients from their WES results and retrospectively analyzed whether there was an association between the MATH values and patient survival. Despite the patients having tumors at various subsites and being given different treatments, every 10% increase in MATH value corresponded to an 8.8% increased risk (hazard) of death. Using a previously defined MATH-value cutoff to distinguish high- from low-heterogeneity tumors, compared to patients with low-heterogeneity tumors, patients with high-heterogeneity tumors were more than twice as likely to die (a hazard ratio of 2.2). Other statistical analyses indicated that MATH provided improved prognostic information compared to that provided by established clinical and molecular characteristics and human papillomavirus (HPV) status (HPV-positive HNSCC at some subsites has a better prognosis than HPV-negative HNSCC). In particular, MATH provided prognostic information beyond that provided by standard disease staging among patients with mouth or laryngeal cancers.
What Do These Findings Mean?
By using data from more than 300 patients treated at multiple institutions, these findings validate the use of MATH as a measure of intra-tumor heterogeneity in HNSCC. Moreover, they provide one of the first large-scale demonstrations that intra-tumor heterogeneity is clinically important in the prognosis of any type of cancer. Before the MATH metric can be used in clinical trials or in clinical practice as a prognostic tool, its ability to predict outcomes needs to be tested in prospective studies that examine the relation between MATH and the outcomes of patients with identically treated HNSCC at specific head and neck subsites, that evaluate the use of MATH for prognostication in other tumor types, and that determine the influence of cancer treatments on MATH values. Nevertheless, these findings suggest that MATH should be considered as a biomarker for survival in HNSCC and other tumor types, and raise the possibility that clinicians could use MATH values to decide on the best treatment for individual patients and to choose patients for inclusion in clinical trials.
Additional Information
Please access these websites via the online version of this summary at
The US National Cancer Institute (NCI) provides information about cancer and how it develops and about head and neck cancer (in English and Spanish)
Cancer Research UK, a not-for-profit organization, provides general information about cancer and how it develops, and detailed information about head and neck cancer; the Merseyside Regional Head and Neck Cancer Centre provides patient stories about HNSCC
Wikipedia provides information about tumor heterogeneity, and about whole-exome sequencing (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
Information about The Cancer Genome Atlas is available
A PLOS Blog entry by Jessica Wapner explains more about MATH
PMCID: PMC4323109  PMID: 25668320
20.  Metastatic squamous cell carcinoma to the brain: An unrecognized pattern of distant spread in patients with HPV-related head and neck cancer 
Journal of neuro-oncology  2013;112(3):449-454.
Head and neck squamous cell carcinoma (HNSCC) is notorious for local recurrence and metastatic spread to regional lymph nodes. Distant spread is uncommon, and brain involvement is rare. Over the past decade there has been a rising incidence of HPV-related HNSCC, but it is not known if this escalation has had any impact on trends relating to brain involvement.
Cases of metastatic squamous cell carcinoma (SCC) to the brain were identified from a computerized search of the surgical pathology files of The Johns Hopkins Hospital between 1985 and 2012. The medical records were reviewed to document primary site of tumor origin, treatment, and patient outcome. P16 immunohistochemistry and HPV in situ hybridization were performed on those metastases arising from the head and neck.
Of the 38 metastatic SCCs, 7 (18%) originated in the head and neck. HPV-16 was detected in 4 (57%) of the metastatic HNSCCs. All 4 HPV-positive metastases were from oropharyngeal primaries. The time from treatment of the primary to development of the brain metastasis ranged from 19–57 months (mean, 45). Following aggressive treatment (surgery and radiation), 2 patients died of disease progression (7 and 34 months), and 2 are alive with recurrent brain metastases (4 and 10 months).
Although HPV positivity is regarded as a favorable prognostic indicator, it does not safeguard from spread to the brain. In our experience, just over half of the HNSCCs that metastasized to the brain were HPV-related. The potential for developing a brain metastasis long after curative therapy argues for extended patient follow-up. The development of a brain metastasis is an ominous finding signaling rapid clinical deterioration.
PMCID: PMC3630253  PMID: 23408186
brain; metastasis; human papillomavirus (HPV); head and neck squamous cell carcinoma; p16; in situ hybridization
21.  Swallow Preservation Exercises during Chemoradiation Therapy Maintains Swallow Function 
To evaluate a swallow preservation protocol (SPP) in which patients received swallow therapy before, during, and after radiation treatment and its efficacy in maintaining swallowing function in head and neck cancer patients.
Case series with chart review.
Tertiary care academic medical center.
Subjects and Methods
Eighty-five patients who received radiation (RT) or chemoradiation (CRT) participated in the SPP from 2007 to 2012. Subjects were divided into 2 groups: compliant and noncompliant with SPP. At each SPP visit, the diet of each patient was recorded as regular (chewable), puree, liquid, or gastrostomy tube (G-tube) dependent, along with their compliance with the swallow exercises. Patients were stratified by age, gender, tumor stage, type of treatment, radiation dose, diet change, dysguesia, odynophagia, pain, and stenosis. Statistical analysis was performed comparing the 2 compliance groups in regards to swallowing-related outcomes at 1 month after completion of therapy.
Fifty-seven patients were compliant and 28 were non-compliant with SPP during treatment. The compliant group had a higher percentage of patients tolerating a regular diet (54.4% vs 21.4%, P = .008), a lower G-tube dependence (22.8% vs 53.6%, P = .008), and a higher rate of maintaining or improving their diet (54.4% vs 25.0%, P = .025) compared to noncompliant patients.
A swallow preservation protocol appears to help maintain or improve swallow function in head and neck cancer patients undergoing RT or CRT. Patients who are able to comply with swallow exercises are less likely to worsen their diet, receive a G-tube, or develop stenosis.
PMCID: PMC4312659  PMID: 23981953
swallow therapy; swallow preservation; radiation and swallow
22.  Refining Risk Stratification for Locoregional Failure after Chemoradiotherapy in Human Papillomavirus-Associated Oropharyngeal Cancer 
Oral oncology  2014;50(5):513-519.
To determine whether the addition of molecular and imaging biomarkers to established clinical risk factors could help predict locoregional failure (LRF) after chemoradiation in human papillomavirus (HPV)-related(+) oropharyngeal cancer (OPC) and improve patient selection for locoregional treatment de-intensification.
HPV status was determined for 198 consecutive patients with Stage III/IV OPC treated with definitive chemoradiation from 5/2003–10/2010. The impact of pre-therapy epidermal growth factor receptor (EGFR) overexpression; imaging biomarkers including primary tumor and nodal maximum standardized uptake values on FDG-PET, gross tumor volumes, and matted nodes; and clinical factors on LRF (including residual disease at adjuvant neck dissection) was assessed.
Primary tumors were HPV+ in 184 patients and HPV-negative in 14. EGFR overexpression was related to HPV-negative status and was univariately associated with LRF in the overall population, but was neither retained in the multivariate model after adjustment for HPV status, nor associated with LRF in HPV+ patients. Similarly, imaging biomarkers were univariately associated with LRF, but correlated with T-stage and/or N-stage and did not remain predictive in HPV+ patients after adjustment for T4- and N3-stages, which were the only significant predictors of LRF on multivariate analysis. Among HPV+ patients with non-T4- or N3-stages, only minimal smoking was associated with decreased LRF.
The prognostic impact of EGFR overexpression and imaging biomarkers on LRF was predominantly related to their association with HPV-negative status and T- or N-stage, respectively. . Among HPV+ OPC patients treated with uniform chemoradiation, only T4-stage, N3-stage, and smoking contributed to risk-stratification for LRF.
PMCID: PMC4086868  PMID: 24565983
23.  Wound healing following combined radiation and cetuximab therapy in ahead and neck cancer patients 
Journal of wound care  2011;20(4):166-170.
This study set out to determine if cetuximab treatment increases the risk of wound healing complications when combined with radiation therapy.
We performed a retrospective chart review of head and neck cancer patients who received salvage neck dissections between 1999 and 2007, at two academic tertiary care centres. Complications from wound healing were compared between radiation and combined therapy groups.
A total of 35 patients received radiation (n=20) or combined radiation and cetuximab therapy (n=15) prior to neck dissection. The treatment groups were similar in regard to demographic and primary tumour-related characteristics. The time between treatment and salvage neck dissection did not differ between the radiation (3.9 months) and combination treatment (3.0 months) groups (p=0.15). Wound healing complications occurred in 13% (2/15) of the patients treated with radiation and cetuximab and there were no complications in patients who received radiation alone (p=0.20).
Cetuximab did not significantly increase the risk of post-surgical wound complications, although a higher absolute number of wound complications was observed in the group treated with cetuximab and radiation therapy, compared with the group treated with radiation alone.
PMCID: PMC3951343  PMID: 21537303
Erbitux; cetuximab; neck dissection; head and neck cancer; radiation; EGFR
24.  Candidate Dosimetric Predictors of Long-Term Swallowing Dysfunction Following Oropharyngeal IMRT 
To investigate long-term swallowing function in oropharyngeal cancer patients treated with IMRT, and to identify novel dose-limiting criteria predictive for dysphagia.
Methods and Materials
Thirty-one patients with stage IV oropharyngeal squamous carcinoma enrolled on a phase II trial were prospectively evaluated by modified barium swallow studies at baseline, and 6, 12, and 24 months post-radiation. Candidate dysphagia-associated organs-at-risk (OARs) were retrospectively contoured into original treatment plans. Twenty-one (68%) cases were base of tongue, and 10 (32%) were tonsil. Stage distribution was T1 (12), T2 (10), T3 (4), T4 (2), and TX (3), and N2 (24), N3 (5), and NX (2). Median age was 52.8 years (Range: 42–78). Thirteen (42%) received concurrent chemotherapy during IMRT. Thirteen (42%) were former smokers. Mean dose to glottic larynx for the cohort was limited to 18 Gy (range: 6–39 Gy) by matching IMRT to conventional low neck fields.
Dose-volume constraints (V30 < 65% and V35 < 35% for anterior oral cavity and V55 < 80% and V65 < 30% for high superior pharyngeal constrictors) predictive for objective swallowing dysfunction were identified by univariate and multivariate analyses. Aspiration and feeding tube dependence were observed in only one patient at 24 months.
In the context of glottic laryngeal shielding, we describe candidate oral cavity and superior pharyngeal constrictor OARs and dose-volume constraints associated with preserved long-term swallowing function; these constraints are currently undergoing prospective validation. Strict protection of the glottic larynx via beam-split IMRT techniques promises to make chronic aspiration an uncommon outcome.
PMCID: PMC4034521  PMID: 20646872
Dysphagia; IMRT; radiation; head and neck cancer; dose-volume constraints; toxicity; swallowing
25.  Predictors of Poor Sleep Quality Among Head and Neck Cancer Patients 
The Laryngoscope  2010;120(6):1166-1172.
The objective of this study was to determine the predictors of sleep quality among head and neck cancer patients 1 year after diagnosis.
Study Design
This was a prospective, multisite cohort study of head and neck cancer patients (N = 457).
Patients were surveyed at baseline and 1 year after diagnosis. Chart audits were also conducted. The dependent variable was a self-assessed sleep score 1 year after diagnosis. The independent variables were a 1 year pain score, xerostomia, treatment received (radiation, chemotherapy, and/or surgery), presence of a feeding tube and/or tracheotomy, tumor site and stage, comorbidities, depression, smoking, problem drinking, age, and sex.
Both baseline (67.1) and 1-year post-diagnosis (69.3) sleep scores were slightly lower than population means (72). Multivariate analyses showed that pain, xerostomia, depression, presence of a tracheotomy tube, comorbidities, and younger age were statistically significant predictors of poor sleep 1 year after diagnosis of head and neck cancer (P < .05). Smoking, problem drinking, and female sex were marginally significant (P < .09). Type of treatment (surgery, radiation and/or chemotherapy), primary tumor site, and cancer stage were not significantly associated with 1-year sleep scores.
Many factors adversely affecting sleep in head and neck cancer patients are potentially modifiable and appear to contribute to decreased quality of life. Strategies to reduce pain, xerostomia, depression, smoking, and problem drinking may be warranted, not only for their own inherent value, but also for improvement of sleep and the enhancement of quality of life.
PMCID: PMC3721672  PMID: 20513034
Head and neck cancer; sleep; pain; xerostomia

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