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1.  Randomized Trial of Hyperfractionation versus Conventional Fractionation in T2 Squamous Cell Carcinoma of the Vocal Cord (RTOG 9512) 
To compare hyperfractionation versus standard fractionation for T2N0 vocal cord carcinoma in a randomized controlled trial.
Methods and Materials
Patients with T2 vocal cord cancer were stratified by substage (T2a vs. T2b) and randomly assigned to receive either hyperfractionation (HFX) to 79.2 Gy in 66 fractions of 1.2 Gy given twice a day, or standard fractionation (SFX) to 70 Gy in 35 fractions given once a day. The trial was designed to detect a 55% reduction in the local failure hazard rate with 80% statistical power.
Between April 1996 and July 2003, 250 patients were enrolled. Of 239 patients analyzable for outcomes, 94% were male, 83% had KPS 90-100, and 62% had T2a tumor. Median follow-up for all surviving patients was 7.9 years (range: 0.6 – 13.1). The 5-year local control (LC) rate was 8 points higher (but not statistically significant: p=0.14) for HFX (78%) vs SFX (70%), corresponding to a 30% hazard rate reduction. Five-year disease-free survival (DFS) was 49% vs 40% (p=0.13) and overall survival (OS) 72% vs 63% (p=0.29). HFX had higher rates of acute skin, mucosal, and laryngeal toxicity. Grade 3-4 late effects were similar with 5-year cumulative incidence of 8.5% (3.4-13.6%) after SFX and 8.5% (3.4-13.5%) after HFX.
Five-year local control was modestly higher with HFX compared to SFX for T2 glottic carcinoma, but the difference was not statistically significant. These results are consistent with prior studies of hyperfractionation showing a benefit in local control. Substaging by T2a vs T2b carries prognostic value for DFS and OS. For cost and convenience reasons other altered fractionation schedules have been adopted in routine practice.
PMCID: PMC4709016  PMID: 25035199
laryngeal cancer; fractionation; local control; organ preservation; clinical trial
2.  p16 Status, Pathologic and Clinical Characteristics, Biomolecular Signature, and Long Term Outcomes in Unknown Primary Carcinomas of the Head and Neck 
Head & neck  2014;36(12):1677-1684.
To report associations between p16 status, clinicopathologic characteristics, and outcomes for unknown primary head and neck squamous cell carcinoma (SCCUPS).
Specimens of SCCUPS were re-analyzed. HPV status was determined by p16 stain. A tissue microarray (TMA) was constructed to evaluate biomarkers potentially prognostic in HNSCC.
A majority of the population (n = 26, 74%) was p16+. Prognostic factors benefitting survival were p16+ status (p < 0.0001), absence of macroscopic extracapsular extension [ECE] (p = 0.004), younger age (p = 0.01), and higher grade (p = 0.007). The prognostic implication of worse OS with macroscopic ECE (p = 0.009) remained significant when limited to p16+ patients (p=0.002). Exploratory TMA between unknown primary and controls suggested a biomolecular difference between SCCUPS and known-primary cancer.
The majority of SCCUPS patients were p16+, indicative of HPV association. p16 staining and ECE appear to be the most prognostic features in SCCUPS.
PMCID: PMC3972378  PMID: 24115269
3.  Phase II Study of Cetuximab in Combination with Cisplatin and Radiation in Unresectable, Locally Advanced Head and Neck Squamous Cell Carcinoma: Eastern Cooperative Oncology Group Trial E3303 
Cisplatin or cetuximab combined with radiotherapy (RT) each yield superior survival in locally advanced squamous cell head and neck cancer (LA-SCCHN) compared to RT alone. E3303 evaluated the triple combination.
Patients with stage IV unresectable LA-SCCHN received a loading dose of cetuximab (400mg/m2) followed by 250mg/m2/week and cisplatin 75mg/m2 q 3 weeks x3 cycles concurrent with standard fractionated RT. In the absence of disease progression or unacceptable toxicity, patients continued maintenance cetuximab for 6–12 months. Primary endpoint was 2-year progression-free survival (PFS). Patient tumor and blood correlates, including tumor human papillomavirus (HPV) status, were evaluated for association with survival.
Sixty-nine patients were enrolled; 60 proved eligible and received protocol treatment. Oropharyngeal (OP) primaries constituted the majority (66.7%), stage T4 48.3% and N2–3 91.7%. Median RT dose delivered was 70 Gy, 71.6% received all 3 cycles of cisplatin and 74.6% received maintenance cetuximab. Median PFS was 19.4 months, 2-year PFS 47% (95%CI: 33–61%). 2-year overall survival (OS) was 66% (95%CI: 53–77%); median OS was not reached. Response rate was 66.7%. Most common grade ≥3 toxicities included mucositis (55%), dysphagia (46%) and neutropenia (26%); one attributable grade 5 toxicity occurred. Only tumor HPV status was significantly associated with survival. HPV was evaluable in 29 tumors; 10 (all OP) were HPV+. HPV+ patients had significantly longer OS and PFS (p=0.004 and p=0.036, respectively).
Concurrent cetuximab, cisplatin and RT were well-tolerated and yielded promising 2-year PFS and OS in LA-SCCHN with improved survival for patients with HPV+ tumors.
PMCID: PMC4184913  PMID: 25107914
4.  Papillary Thyroid Carcinoma Metastases Presenting as Ipsilateral Adrenal Mass and Renal Cyst 
Urology Case Reports  2015;3(6):221-222.
Metastatic spread of differentiated thyroid cancer to genitourinary organs is rare. Synchronous presentation of renal and adrenal thyroid metastasis is even less common, this case being only the 3rd reported. We describe a case of a 60-year-old male with oligometastatic thyroid cancer, where adrenal and renal metastases were the only extracervical sites of disease and triggered the patient's presentation.
PMCID: PMC4714304  PMID: 26793559
Thyroid cancer; Adrenal mass; Renal tumor; Oligometastasis
5.  Phospho-T356RB1 predicts survival in HPV-negative squamous cell carcinoma of the head and neck 
Oncotarget  2015;6(22):18863-18874.
Locally advanced squamous cell carcinoma of the head and neck (SCCHN) that is not associated with human papillomavirus (HPV) has a poor prognosis in contrast to HPV-positive disease. To better understand the importance of RB1 activity in HPV-negative SCCHN, we investigated the prognostic value of inhibitory CDK4/6 phosphorylation of RB1 on threonine 356 (T356) in archival HPV-negative tumor specimens from patients who underwent surgical resection and adjuvant radiation. We benchmarked pT356RB1 to total RB1, Ki67, pT202/Y204ERK1/2, and TP53, as quantified by automatic quantitative analysis (AQUA), and correlated protein expression with tumor stage and grade. High expression of pT356RB1 but not total RB1 predicted reduced overall survival (OS; P = 0.0295), indicating the potential relevance of post-translational phosphorylation. Paired analysis of The Cancer Genome Atlas (TCGA) data for regulators of this RB1 phosphorylation identified loss or truncating mutation of negative regulator CDKN2A (p16) and elevated expression of the CDK4/6 activator CCND1 (cyclin D) as also predicting poor survival. Given that CDK4/6 inhibitors have been most effective in the context of functional RB1 and low expression or deletion of p16 in other tumor types, these data suggest such agents may merit evaluation in HPV-negative SCCHN, specifically in cases associated with high pT356RB1.
PMCID: PMC4662460  PMID: 26265441
biomarkers; RB1; CDK4/6; E2F; head and neck cancer
6.  A pilot study of psychosocial functioning and vascular endothelial growth factor in head and neck cancer patients 
Head & neck  2013;36(8):1113-1119.
Psychosocial functioning is associated with vascular endothelial growth factor (VEGF) in various patient populations. This study examined whether psychosocial functioning in patients with head and neck squamous cell carcinoma (HNSCC) is associated with tumor VEGF expression, a protein that stimulates angiogenesis and is associated with poor prognosis.
Forty-two newly diagnosed patients completed assessments of psychosocial functioning (i.e. depressive symptoms, perceived stress, anxiety, social support) prior to surgery. Tumor samples were obtained for VEGF analysis and HPV-typing.
Poorer psychosocial functioning was associated with greater VEGF expression controlling for disease stage (OR=4.55, 95% CI = 1.72, 12.0, p < 0.01). When examined by HPV-status, the association between psychosocial functioning and VEGF remained significant among HPV-negative patients (OR=5.50, 95% CI = 1.68, 17.3, p < 0.01), but not among HPV-positive patients.
These findings inform our understanding of the biobehavioral pathways that may contribute to poor outcomes in non-HPV-associated HNSCCs.
PMCID: PMC4099415  PMID: 23804308
depressive symptoms; perceived stress; anxiety; social support; human papillomavirus
7.  Recommended Patient-Reported Core Set of Symptoms to Measure in Head and Neck Cancer Treatment Trials 
We identified a standard core set of patient-reported symptoms and health-related quality-of-life (HRQOL) domains to be assessed in head and neck (H&N) cancer clinical trials. The core symptom and HRQOL domain scores were used to guide recommendations by a working group of experts as part of a National Cancer Institute Symptom Management and HRQOL Clinical Trials Planning Meeting. A PubMed search was conducted using the search terms of “health-related quality of life” and “head & neck cancer,” limited to publications from January 1, 2000, to December 31, 2010. Fifty-four articles were used to guide the choice of recommendations. Twenty-nine symptoms and nine domains were identified, from which 12 H&N-specific core symptoms and HRQOL domains were recommended: swallowing, oral pain, skin changes, dry mouth, dental health, opening mouth/trismus, taste, excess/thick mucous/saliva, shoulder disability/motion, voice/hoarseness, social domain, and functional domain. This core set of 12 H&N-specific, patient-reported symptoms and HRQOL domains should be assessed in future H&N cancer clinical trials.
PMCID: PMC4192043  PMID: 25006189
8.  Baseline health perceptions, dysphagia and survival in head and neck cancer 
Cancer  2013;120(6):840-847.
Baseline dysphagia, more common than abnormalities on formal swallowing testing, is believed to predict survival in untreated head and neck cancer patients. We hypothesized that patient-reported dysphagia impacts multiple domains of quality of life and predicts disease recurrence and disease-related death.
The Swal-QOL, a dysphagia-specific measure, and the EuroQOL were administered to 159 patients prior to treatment with curative intent, in this prospective cross-sectional cohort study. Logistic regression evaluated associations among clinical and subjective measures. Multivariable competing risk regression tested the impact of clinical, tumor and patient-reported measures on survival.
Baseline dysphagia, pain and diminished patient-reported health state (PRHS) were more closely associated with weight loss prior to treatment and advanced T-classification, than any other clinical feature. However, only 56% (23/40) of patients reporting dysphagia had >5% weight loss. Dysphagia was associated with pain and/or diminished PRHS, independent of weight loss. Female patients were more likely to report pain and dysphagia, while males reported dysphagia alone. Dysphagia predicted recurrence and disease related death, adjusting for T and N classification, performance status, smoking and weight loss, and accounting for competing risks of death (RFS: HR 3.8 (95%CI 1.7–8.4), p=.001; DOD HR 4.2 (95%CI 1.04–5), p=.004).
Baseline dysphagia affects multiple domains of quality of life and general health perceptions in untreated head and neck cancer patients. A dysphagia measure captures the effort of maintaining nutrition with cancer, identifying patients with or at risk for weight loss, and predisposed to disease recurrence and disease-related death.
PMCID: PMC3951722  PMID: 24352973
9.  Bilateral granulosa cell tumors: a novel malignant manifestation of multiple endocrine neoplasia 1 syndrome found in a patient with a rare menin in-frame deletion 
Multiple endocrine neoplasia 1 (MEN1) is a cancer syndrome resulting from mutations of the MEN1 gene. The syndrome is characterized by neoplasia of the parathyroid and pituitary glands, and malignant tumors of the endocrine pancreas. Other manifestations include benign lipomas, angiofibromas, and carcinoid tumors commonly originating in the colon, thymus, and lung. This is the first report of MEN1 syndrome manifesting as bilateral granulosa cell ovarian tumors, and which is associated with a rare intronic mutation of the MEN1 gene.
Case report
A 41-year-old woman presented with abdominal pain, increasing abdominal girth, and dysmenorrhea. Ultrasound demonstrated enlarged ovaries and uterine fibroids. After an exploratory laparotomy, she subsequently underwent bilateral salpingo–oophorectomy with hysterectomy where the pathology revealed bilateral cystic granulosa cell tumors of the ovaries. Additional workup including computed tomography imaging discovered a thymic mass, which the pathology showed was malignant, along with a pancreatic mass suspicious for a neuroendocrine tumor. Hyperparathyroidism was also discovered and was found to be secondary to a parathyroid adenoma. Genetic testing revealed an exceedingly rare mutation in the MEN1 gene (c.654 + 1 G>A).
Mutations of the menin gene leading to MEN1 syndrome are classically nonsense or missense mutations producing a dysfunctional protein product. Recently, researchers described a novel mutation of MEN1 (c.654 + 1 G>A) in a male proband meeting the criteria for clinical MEN1 syndrome. Functional analysis performed on the stable mutant protein showed selective disruption of the transforming growth factor beta signaling pathway, yet it maintained its wild-type ability to inhibit nuclear factor kappa B and to suppress JunD transcriptional activity.
To our knowledge, this is the first report of MEN1 syndrome associated with bilateral granulosa cell malignancy. We postulate that this presentation may be due to the novel menin gene mutation recently described.
PMCID: PMC4337709  PMID: 25733923
menin gene; ovarian tumors; hyperparathyroidism
10.  Quantification of excision repair cross complementing group 1 (ERCC1) and survival in p16-negative squamous cell head and neck cancers 
Multimodality treatment for squamous cell carcinoma of the head and neck (SCCHN) often involves radiation (RT) and cisplatin-based therapy. Elevated activity of DNA repair mechanisms, such as the nucleotide excision repair (NER) pathway, of which ERCC1 is a rate-limiting element, are associated with cisplatin and possibly RT resistance. We have determined ERCC1 expression in HPV-negative SCCHN treated with surgery (+/− adjuvant RT/chemoradiation (CRT)).
Experimental Design
We assessed ERCC1 protein expression in archival tumors using automated, quantitative analysis (AQUA) immunohistochemistry (IHC) and three antibodies to ERCC1 (8F1 (2009, Lab Vision), FL297 (Santa Cruz) and HPA029773 (Sigma)). Analysis with Classification and Regression Tree Methods (CART) ascertained the cut-points between high/low ERCC1 expression. Multivariable analysis adjusted for age, T and N stage. Kaplan-Meier curves determined median survival. ERCC1 expression at initial tumor presentation and in recurrent disease were compared. Performance characteristics of antibodies were assessed.
ERCC1 low/high groups were defined based on AQUA analysis with 8F1/2009, FL297 and HPA029773. Among patients treated with surgery plus adjuvant RT/CRT, longer median survival was observed in ERCC1 low tumors versus ERCC1 high (64 vs. 29 months, p=0.02 (HPA029773)). Data obtained with HPA029773 indicated no survival difference among patients treated only with surgery. Recurrent cancers had lower ERCC1 AQUA scores than tumors from initial presentation. Extensive characterization indicated optimal specificity and performance by the HPA029773 antibody.
Using AQUA, with the specific ERCC1 antibody HPA029773, we found a statistical difference in survival among high/low ERCC1 tumors from patients treated with surgery and adjuvant RT.
PMCID: PMC4045641  PMID: 24088734
ERCC1; radiation; head and neck cancer; immunohistochemistry
11.  Dysplasia at the Margin? Investigating the Case for Subsequent Therapy in ‘Low-Risk’ Squamous Cell Carcinoma of the Oral Tongue 
Oral oncology  2013;49(11):1083-1087.
This is a retrospective analysis of the impact of moderate dysplasia at the resection margin for early stage cancer of the oral tongue.
Materials and Methods
Patients with T1-2N0 oral tongue cancer treated with surgery alone at Fox Chase Cancer Center (FCCC) from 1990 – 2010 were reviewed. Tumor and margin characteristics were abstracted from the pathology report.
Overall survival (OS), disease-free survival (DFS) and local control (LC) were calculated using the Kaplan Meier method. Predictors of LC, OS and DFS were analyzed.
126 patients met the inclusion criteria. Dysplasia was present at the final margin in 36% of the cases (severe: 9%, moderate: 15%, mild: 12%).
Median follow-up was 52 months. 3 and 5-year actuarial LC for the entire cohort was 77 and 73%, respectively. Actuarial 5-year LC and DFS were significantly worse for patients with moderate or severe dysplasia at the margin vs. none or mild dysplasia at the margin (49 v 82%, p = 0.005 and 49 v 80%, p = 0.008, respectively); 3-year comparisons were not significant. When analyzed separately, the detrimental local effect of moderate dysplasia at the margin persisted (p = 0.02) and the effect of severe dysplasia at the margin was approaching significance (p = 0.1). Mild dysplasia at the margin did not significantly impair LC or DFS.
Multivariate analysis demonstrated worse LC (HR: 2.99, p=0.006) and DFS (HR: 2.84, p=0.008) associated with severe or moderate dysplasia at the margin.
Both severe and moderate dysplasia at the margin appear to be correlated with inferior LC and DFS. Additional therapy may be justified, despite added morbidity.
PMCID: PMC4037753  PMID: 24054332
Oral tongue cancer; dysplasia; margin
12.  Extranodal Extension of Metastatic Papillary Thyroid Carcinoma: Correlation with Biochemical Endpoints, Nodal Persistence, and Systemic Disease Progression 
Thyroid  2013;23(9):1099-1105.
The impact of extranodal extension (ENE) of metastatic papillary thyroid carcinoma (PTC) on short- and long-term clinical outcomes, including biochemical testing, has not been reported.
This single-institution National Cancer Institute-designated Comprehensive Cancer Center cohort study included patients with macroscopic metastases and excluded patients with gross residual disease after surgery, distant disease, or poorly differentiated papillary carcinoma. A suppressed or stimulated thyroglobulin (Tg) <1 ng/mL, without suspicious imaging or anti-thyroglobulin antibodies, after radioactive iodine (RAI) treatment was termed an excellent or “complete biochemical response” (CR).
Of 89 subjects included, 60 previously untreated patients underwent total thyroidectomy and therapeutic neck dissection; 29 additional patients underwent a neck dissection for persistence or recurrence after prior surgery and RAI administration. ENE, identified in 29 patients (33%), was associated with T4 classification (p=0.02) and involvement of a greater number of nodes (median 11 vs. 5, p=0.03). ENE was associated with a 20% increased risk of nodal persistence necessitating additional surgery (p=0.02). In a multivariable analysis, ENE, T4 classification, and recurrence/persistence proved to be independent predictors of systemic disease progression (ENE: hazard ratio [HR] 4.3 [95% confidence interval (CI) 1.2–15], p=0.02; T4 classification: HR 4.2 [CI 1.3–14], p=0.01; recurrent/persistent status: HR 3.6 [CI 1.1–12], p=0.035). Nodal or systemic disease progression was rare after a biochemical CR; in contrast, in previously untreated patients, stimulated Tg levels (sTg) >50 ng/mL prior to initial RAI administration, heralded the progression of nodal disease, and also predicted the eventual development of systemic disease (p=0.0001). Of those with a sTg >50 ng/mL, over 70% underwent surgery for nodal persistence within five years. The presence of ENE diminished the odds of a biochemical CR (odds ratio 3.5% [CI 1.3–10], p=0.02), and increased the probability that the sTg levels after surgery will exceed 50 ng/mL (odds ratio 5 [CI 1.2–21], p=0.03). Following surgery for tumor persistence, 25% of those with ENE were rendered biochemically free of disease.
ENE diminishes the probability of a biochemical CR after treatment for regional metastatic PTC, and increases the probability of tumor persistence after initial resection, likely from abundant metastasis. ENE and nodal persistence independently predict eventual systemic disease progression.
PMCID: PMC3770240  PMID: 23421588
13.  Unilateral Neck Therapy in the Human Papillomavirus-Era: Virus Association does not Alter Accepted Regional Spread Patterns 
Head & neck  2012;35(2):160-164.
To determine whether the incidence of bilateral neck disease tonsil cancer is rising.
We reviewed tonsil cancer incidence data from the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute.
The annual incidence of advanced neck disease (≥N2) with small primary tonsil cancer is increasing (annual percent change (APC), p < 0.05) during two evaluable time frames (1988–2003 and 2004–2008). The increase for small primary tonsil cancer from 2004–2008 is associated with increased ipsilateral disease (ie, T1-2N2ab, APC 10.6%, p < 0.05) rather than bilateral neck disease (T1-2N2c, APC 5.9%, APC = NS). The increase in bilateral neck disease is less than the overall rise in T1-2 tonsil cancer (APC 7.2%, p < 0.05).
In the HPV era bilateral neck disease is increasingly common. This appears to be a consequence of increasing incidence of tonsil cancer rather than a new biologic behavior.
PMCID: PMC4037756  PMID: 22302641
Tonsil; SEER; HPV; Unilateral Therapy; Stage Migration
14.  Long-Term Results of RTOG 91-11: A Comparison of Three Nonsurgical Treatment Strategies to Preserve the Larynx in Patients With Locally Advanced Larynx Cancer 
Journal of Clinical Oncology  2012;31(7):845-852.
To report the long-term results of the Intergroup Radiation Therapy Oncology Group 91-11 study evaluating the contribution of chemotherapy added to radiation therapy (RT) for larynx preservation.
Patients and Methods
Patients with stage III or IV glottic or supraglottic squamous cell cancer were randomly assigned to induction cisplatin/fluorouracil (PF) followed by RT (control arm), concomitant cisplatin/RT, or RT alone. The composite end point of laryngectomy-free survival (LFS) was the primary end point.
Five hundred twenty patients were analyzed. Median follow-up for surviving patients is 10.8 years. Both chemotherapy regimens significantly improved LFS compared with RT alone (induction chemotherapy v RT alone: hazard ratio [HR], 0.75; 95% CI, 0.59 to 0.95; P = .02; concomitant chemotherapy v RT alone: HR, 0.78; 95% CI, 0.78 to 0.98; P = .03). Overall survival did not differ significantly, although there was a possibility of worse outcome with concomitant relative to induction chemotherapy (HR, 1.25; 95% CI, 0.98 to 1.61; P = .08). Concomitant cisplatin/RT significantly improved the larynx preservation rate over induction PF followed by RT (HR, 0.58; 95% CI, 0.37 to 0.89; P = .0050) and over RT alone (P < .001), whereas induction PF followed by RT was not better than treatment with RT alone (HR, 1.26; 95% CI, 0.88 to 1.82; P = .35). No difference in late effects was detected, but deaths not attributed to larynx cancer or treatment were higher with concomitant chemotherapy (30.8% v 20.8% with induction chemotherapy and 16.9% with RT alone).
These 10-year results show that induction PF followed by RT and concomitant cisplatin/RT show similar efficacy for the composite end point of LFS. Locoregional control and larynx preservation were significantly improved with concomitant cisplatin/RT compared with the induction arm or RT alone. New strategies that improve organ preservation and function with less morbidity are needed.
PMCID: PMC3577950  PMID: 23182993
15.  Head and Neck Sarcomas: A Comprehensive Cancer Center Experience 
Cancers  2013;5(3):890-900.
Head/neck sarcomas are rare, accounting for about 1% of head/neck malignancies and 5% of sarcomas. Outcomes have historically been worse in this group, due to anatomic constraints leading to difficulty in completely excising tumors, with high rates of local recurrence. We retrospectively analyzed cases of head/neck soft tissue sarcomas (STS) and osteogenic sarcomas managed in a multi-disciplinary setting at Fox Chase Cancer Center from 1999–2009 to describe clinicopathologic characteristics, treatment, outcomes, and prognostic factors for disease control and survival. Thirty patients with STS and seven patients with osteogenic sarcoma were identified. Most STS were high grade (23) and almost all were localized at presentation (28). Common histologies were synovial cell (6), rhabdomyosarcoma (5), angiosarcoma (4), liposarcoma (4) and leiomyosarcoma (3). The type of primary therapy and disease outcomes were analyzed. Cox proportional hazards regression analysis was performed to identify predictors of disease-free survival (DFS) and overall survival (OS). The HR and 95% CI for Cox model and median DFS/OS analyzed by Kaplan-Meier curves were calculated.
PMCID: PMC3795370  PMID: 24202325
head and neck sarcomas; soft tissue sarcomas; osteogenic sarcomas
16.  Informational Needs of Head and Neck Cancer Patients 
Health and technology  2012;2(1):57-62.
Treatment for head and neck squamous cell carcinoma (HNSCC) can lead to considerable functional impairment. As a result, HNSCC patients experience significant decrements in quality of life, high levels of emotional distress, deteriorations in interpersonal relations, and increased social isolation. Studies suggest that HNSCC patients may have extensive informational and psychosocial needs that are not being adequately addressed. However, few programs have been developed to address the needs of HNSCC patients. Therefore, we conducted a pilot study of HNSCC patients to: 1) characterize patients' informational needs; and 2) describe preferred formats and time points for receiving such information. The majority of participants desired additional information regarding treatment options, managing changes in swallowing and speaking, and staying healthy after treatment. Overall, patients with early-stage disease reported more informational needs compared to patients with advanced disease. Female patients were more likely to desire information about coping with emotional stress and anxiety than male patients. Younger patients (29–49 years) were more interested in receiving information about sexuality after cancer compared to their older (50+) counterparts. Although information was requested throughout the cancer trajectory, most patients preferred to receive such information at diagnosis or within 1–3 months post-treatment. The majority of patients reported having computer and Internet access, and they were most receptive to receiving information delivered via the Internet, from a DVD, or from pamphlets and booklets. The relatively high percentage of patients with computer and Internet access reflects a growing trend in the United States and supports the feasibility of disseminating health information to this patient population via Internet-based programs.
PMCID: PMC3327509  PMID: 22518350
Head and neck cancer; informational needs; Treatment side effects; Internet
17.  Psychological functioning of caregivers for head and neck cancer patients 
Oral Oncology  2011;48(1):18-25.
Patients with head and neck squamous cell carcinoma (HNSCC) often require assistance from family caregivers during the treatment and post-treatment period. This review article sought to summarize current findings regarding the psychological health of HNSCC caregivers, including factors that may be associated with poorer psychological health. Online databases (PUBMED, MEDLINE and PSYCINFO) were searched for papers published in English through September 2010 reporting on the psychological health of caregivers of HNSCC patients. Eleven papers were identified. Caregivers experience poorer psychological health, including higher levels of anxious symptoms, compared to patients and to the general population. Fear of patient cancer recurrence is evident among caregivers and is associated with poorer psychological health outcomes. The 6-month interval following diagnosis is a significant time of stress for caregivers. Greater perceived social support may yield positive benefits for the psychological health of caregivers. To date, there have been relatively few reports on the psychological health of caregivers of HNSCC patients. Well designed, prospective, longitudinal studies are needed to enhance our understanding of how caregiver psychological health may vary over the cancer trajectory and to identify strategies for improving caregiver outcomes.
PMCID: PMC3357183  PMID: 22154127
Caregiving; Psychological health; Emotional distress; Anxiety; Depression; Head and neck cancer
18.  Impact of neck dissection on long-term feeding tube dependence in head and neck cancer patients treated with primary radiation or chemoradiation 
Head & neck  2010;32(3):341-347.
The impact of post-treatment neck dissection on prolonged feeding tube dependence in head and neck squamous cell cancer (HNSCC) patients treated with primary radiation or chemoradiation remains unknown.
Retrospective cohort study using propensity score adjustment to investigate the effect of neck dissection on prolonged feeding tube dependence.
A review of 67 patients with node positive HNSCC (T1-4N1-3), treated with primary radiation or chemoradiation, with no evidence of tumor recurrence and follow-up of at least 24 months was performed. Following adjustment for covariates, the relative risk of feeding tube dependence at 18 months was significantly increased in patients treated with post-treatment neck dissection (RR 4.74, 95% CI 2.07-10.89). At 24 months, the relative risk of feeding tube dependence in the patients having undergone neck dissection increased further (RR 7.66, 95% CI 2.07-10.89). Of patients with feeding tubes two years after completing treatment, 75% remained feeding tube dependent.
Neck dissection may contribute to chronic oropharyngeal dysphagia in HNSCC patients treated with primary radiation or chemoradiation.
PMCID: PMC3457780  PMID: 19693946
19.  The Use of a Conventional Low Neck Field (LNF) and Intensity-Modulated Radiation Therapy (IMRT): No Clinical Detriment of IMRT to an Anterior LNF during the Treatment of Head and Neck Cancer 
Appropriate treatment of the lower neck when using IMRT is controversial. Our study tried to determine differences in clinical outcomes using IMRT or a standard LNF to treat low neck.
Methods and Materials
This is a retrospective, single institution study. Ninety-one patients with squamous cell carcinoma of head and neck cancer were treated with curative intent. Based on physician preference, some patients were treated with LNF (PTV3) field using a single anterior photon field matched to the IMRT field. Field junctions were not feathered. The endpoints were time to failure and use of PEG tube (as a surrogate of laryngeal edema causing aspiration) and analysis done with chi-square and the log-rank tests.
Median follow up 21 months (range 2 – 89). The median age 60 years. Thirty seven (41%) were treated with LNF, 84% were stage III or IV. PEG tube was required in 30% as opposed to 33% without the use of LNF. N2 or 3 neck disease was treated more commonly without a LNF (38% vs. 24%, p = 0.009). Failures occurred in 12 patients (13%). Only one patient treated with LNF failed regionally, 4.5 cm above the match line. The 3-year disease-free survival rate was 87%, 79% with LNF and without LNF respectively (p = 0.2) and the 3-year LR failure rate was 4%, 21% respectively, (p = 0.04).
Using LNF to treat the low neck did not increase the risk of regional failure “in early T& early N diseases” or decrease PEG tube requirements.
PMCID: PMC3339153  PMID: 20385457
IMRT; Head and Neck cancer; Low neck field; RT toxicities; PEG tube
20.  Sentinel Lymph Node Biopsy Accurately Stages the Regional Lymph Nodes for T1-T2 Oral Squamous Cell Carcinomas: Results of a Prospective Multi-Institutional Trial 
Journal of Clinical Oncology  2010;28(8):1395-1400.
The validity of sentinel lymph node biopsy (SLNB) for T1 or T2, clinically N0, oral cancer was tested by correlation of sentinel node pathologic status with that of nodes within the completion neck dissection.
This prospective, cooperative group trial involved 25 institutions over a 3-year period. One hundred forty patients with invasive oral cancers, stage T1 and T2, N0 including 95 cancers of the tongue, 26 of the floor of mouth, and 19 other oral cancers were studied. The study excluded lesions with diameter smaller than 6 mm or minimal invasion. Imaging was used to exclude nonpalpable gross nodal disease. Patients underwent injection of the lesion with 99mTc-sulfur colloid, nuclear imaging, narrow-exposure SLNB, and completion selective neck dissection. The major end point was the negative-predictive value (NPV) of SLNB.
In the 106 SLNBs, which were found to be pathologically and clinically node-negative by routine hematoxylin and eosin stain, 100 patients were found to have no other pathologically positive nodes, corresponding to a NPV of 94%. With additional sectioning and immunohistochemistry, NPV was improved to 96%. In the forty patients with proven cervical metastases, the true-positive rate was 90.2% and was superior for tongue tumors relative to floor of mouth. For T1 lesions, metastases were correctly identified in 100%.
For T1 or T2 N0 oral squamous cell carcinoma, SLNB with step sectioning and immunohistochemistry, performed by surgeons of mixed experience levels, correctly predicted a pathologically negative neck in 96% of patients (NPV, 96%).
PMCID: PMC2834497  PMID: 20142602
Detect tumor-related DNA using LigAmp in histologically clear margins and associate results with clinical outcome.
Experimental Design
Patients with head and neck cancer were registered for molecular analysis of surgical margins. Adequacy of resection was ensured using histologic margin analysis. Further margins were then harvested and DNA extracted. TP53 mutations in tumor were determined using Affymetrix p53 GeneChip. Margins were analyzed by Ligamp in comparison with standard curves for quantification of mutant DNA. Ligation employed 2 oligonucleotides to isolate DNA targeting the mutation. Ligated DNA was amplified using real-time PCR. The quantity of mutation in the margin was determined as percent of mutant species relative to plasmid (MRP) and relative to tumor (MRT). Cutpoints were identified and defined groups evaluated for local failure-free, cancer-specific, and overall survival. Study margins were examined for presence of tumor by light microscopy.
Tissue from 95 patients with common mutations was analyzed. Fifteen experienced local recurrence. Cutpoints of 0.15% for MRP and 0.5% for MRT were chosen as most selective of recurrent cases. LigAmp had slightly better area under the ROC curve (p=0.09) than light microscopy correctly predicting 9 of 15 recurrent tumors. There were 6 false negative cases and 26 false positive results. No statistically significant distinctions were observed in cancer-specific or overall survival in this limited cohort.
Ligamp provides quantifiable, sensitive detection of mutant DNA in histologically normal margins. Detection of mutant species in margins may identify patients at risk of local recurrence.
PMCID: PMC2842212  PMID: 19996217
22.  Early Postoperative Paclitaxel Followed by Concurrent Paclitaxel and Cisplatin With Radiation Therapy for Patients With Resected High-Risk Head and Neck Squamous Cell Carcinoma: Report of the Phase II Trial RTOG 0024 
Journal of Clinical Oncology  2009;27(28):4727-4732.
We sought to improve outcomes for patients with high-risk head and neck squamous cell cancer (HNSCC) after surgical resection by testing the feasibility and safety of early postoperative chemotherapy followed by concurrent chemoradiotherapy.
Patients and Methods
Eligible patients had resected, stages III to IV HNSCC with positive margins, extracapsular nodal extension, or multiple positive nodes. Paclitaxel (80 mg/m2) was given once weekly during postoperative weeks 2, 3, and 4 and was given before radiation therapy (RT). Paclitaxel (30 mg/m2) and cisplatin (20 mg/m2) were given once weekly during the last 3 weeks of RT (60 Gy over 6 weeks, beginning 4 to 5 weeks after surgery). The primary end points were treatment safety and tolerability compared with concurrent cisplatin (100 mg/m2 every 3 weeks) and RT, as tested in Radiation Therapy Oncology Group trial RTOG 9501.
The median follow-up time for the 70 patients enrolled was 3.3 years (range, 0.6 to 4.4 years) for surviving patients. Tolerability of all treatment components was comparable to that of RTOG 9501 treatment, which is the current standard of care (compliance rate, 75%; 95% CI, 63% to 85%). One patient died, and seven patients experienced grade 4 nonhematologic toxicities. Rates of locoregional control, disease-free survival, and overall survival exceeded those of RTOG 9501 after adjustment for important prognostic variables (ie, positive margins, extracapsular extension, primary site, and performance status).
Chemotherapy soon after surgery followed by concurrent chemoradiotherapy therapy was feasible; tolerance was in line with standard postoperative chemoradiotherapy; and this regimen led to excellent rates of locoregional control and disease-free survival.
PMCID: PMC2754914  PMID: 19720915
23.  Comparison of Clinical and Pathological Staging in Head and Neck Squamous Cell Carcinoma 
To compare the results of clinical and pathological staging for a large cohort of patients with head and neck squamous cell carcinoma (HNSCC) and to examine patterns and ramifications of the disparity between staging methods.
Prospective inception cohort (median follow-up, 7 years).
Multi-institutional cooperative group study (Eastern Cooperative Oncology Group 4393/Radiation Therapy Oncology Group 9614) involving 17 academic medical centers.
A total of 560 patients with new-onset or recurrent HNSCC enrolled during a 7-year period.
Surgical resection with curative intent with or without adjuvant or previous radiotherapy or chemotherapy.
Main Outcome Measures
Clinical staging and pathological staging and the component TN tumor categories were compared with overall and disease-specific survival. Association of survival with staging was derived by means of the proportional hazards model.
Of the 501 cases in which both clinical and pathological staging was available, a disparity was found between at least 1 component tumor category assigned by the 2 methods in almost 50% of cases. Both methods showed a strong association of stage with overall survival for the cohort at large. However, pathological nodal category was a superior predictor (P<.001 vs P=.005), whereas there was an advantage to pathological tumor category in predicting disease-specific survival (P=.01).
Both staging methods are useful in predicting survival, whereas information gained at neck dissection regarding nodal metastases provides some refinement in prognostic results. These findings demonstrate the need for enhanced methods of tumor assessment and apparent benefit of data gathered at neck dissection for accurate disease assessment and stratification.
PMCID: PMC2846171  PMID: 19770416
24.  Issues Related to Implementing a Smoking Cessation Clinical Trial for Cancer Patients1 
Cancer causes & control : CCC  2008;20(1):97-104.
Given high rates of smoking among cancer patients, smoking cessation treatment is crucial, yet limited data exist to guide integration of such trials into the oncologic context. To determine the feasibility of conducting smoking cessation clinical trials with cancer patients, screening and baseline data from a large randomized placebo-controlled pharmacotherapy trial were analyzed. Descriptive statistics and regression analyses were used to compare enrollees to decliners, describe program enrollees, and assess correlates of confidence in quitting smoking. Of 14,514 screened patients, 263 (<2%) were eligible; 43 (16%) refused enrollment. Among eligible patients, 220 (84%) enrolled. Enrollment barriers included: smoking rate, medical history/contraindicated medication, lack of interest, and language. Compared to enrollees, decliners were more likely to have advanced cancer. The trial enrolled a sample of 67 (>30%) African Americans; participants had extensive smoking histories; many were highly nicotine dependent; and participants consumed about 7 alcoholic beverages/week on average. Head and neck and breast cancer were the most common tumors. Fifty-two (25%) reported depressive symptoms. A higher level of confidence to quit smoking was related to lower depression and lower tumor stage. Integrating a smoking cessation clinical trial into the oncologic setting is challenging, yet feasible. Recruitment strategies are needed for patients with advanced disease and specific cancers. Once enrolled, addressing participant’s depressive symptoms is critical for promoting cessation.
PMCID: PMC2628415  PMID: 18758971
cancer patients; smoking cessation; confidence; feasibility data
25.  TP53 Mutations and Survival in Squamous-Cell Carcinoma of the Head and Neck 
The New England journal of medicine  2007;357(25):2552-2561.
The abrogation of function of the tumor-suppressor protein p53 as a result of mutation of its gene, TP53, is one of the most common genetic alterations in cancer cells. We evaluated TP53 mutations and survival in patients with squamous-cell carcinoma of the head and neck.
A total of 560 patients with squamous-cell carcinoma of the head and neck who were treated surgically with curative intent were enrolled in our prospective multicenter, 7-year study. TP53 mutations were analyzed in DNA from the tumor specimens with the use of the Affymetrix p53 chip and the Surveyor DNA endonuclease and denaturing high-performance liquid chromatography. Mutations were classified into two groups, disruptive and nondisruptive, according to the degree of disturbance of protein structure predicted from the crystal structure of the p53–DNA complexes. TP53 mutational status was compared with clinical outcome.
TP53 mutations were found in tumors from 224 of 420 patients (53.3%). As compared with wild-type TP53, the presence of any TP53 mutation was associated with decreased overall survival (hazard ratio for death, 1.4; 95% confidence interval [CI], 1.1 to 1.8; P = 0.009), with an even stronger association with disruptive mutations (hazard ratio, 1.7; 95% CI, 1.3 to 2.4; P<0.001) and no significant association with nondisruptive mutations (hazard ratio, 1.2; 95% CI, 0.9 to 1.7; P = 0.16). In multivariate analyses a disruptive TP53 alteration, as compared with the absence of a TP53 mutation, had an independent, significant association with decreased survival (hazard ratio, 1.7; 95% CI, 1.2 to 2.4; P = 0.003).
Disruptive TP53 mutations in tumor DNA are associated with reduced survival after surgical treatment of squamous-cell carcinoma of the head and neck.
PMCID: PMC2263014  PMID: 18094376

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