Screening for HPV-related oropharyngeal, anal, and penile cancers in middle-aged men: Initial report from the HOUSTON clinical trial.

BACKGROUND: The Human papillomavirus (HPV)-related Oropharyngeal and Uncommon Cancers Screening Trial of Men (HOUSTON) was designed to determine the prevalence of IgG antibodies to HPV type 16 E proteins (HPV16EAbs), to screen for persistence of HPV and/or detect HPV-related premalignancies and cancers, and to assess acceptance of screening among middle-aged men. METHODS: HOUSTON consists of a cross-sectional study and a longitudinal cohort study of men aged 50-64 years. Serologic HPV16EAb status and oral rinse HPV16 status were determined. All HPV16EAb-positive (HPV16EAb+) men and a matched cohort of HPV16EAb-negative (HPV16EAb-) men as well as all oral rinse HPV16-positive (HPV16+) men were included in the longitudinal study (blinded to their results) and underwent oropharyngeal screening every 6 months as well as one-time anal and penile screening. RESULTS: Of 553 men enrolled in the cross-sectional study, six (1.1%) were HPV16EAb+ (two were also oral rinse HPV16+), and 41 (7.4%) were HPV16EAb- but oral rinse HPV16+. These 47 men, along with five matched controls, were invited to participate in the longitudinal study, and 42 (81%) agreed and completed baseline in-person screening, with 93% and 90% completeing 6-month and 12-month follow-up visits. One HPV16EAb+ (also oral rinse HPV16+) man, who declined participation in the longitudinal study, presented 4 months after enrollment with an early-stage HPV16-related pharyngeal cancer. Additionally, one HPV16EAb+ (oral rinse HPV16-) man and two oral rinse HPV16+ (HPV16EAb-) men were diagnosed with oncogenic HPV-associated anal dysplasia. CONCLUSIONS: This biomarker panel deserves further prospective study to explore potential utility for HPV-related cancer screening among men.

Patient reported dry mouth: Instrument comparison and model performance for correlation with quality of life in head and neck cancer survivors.

PURPOSE: To identify a clinically meaningful cut-point for the single item dry mouth question of the MD Anderson Symptom Inventory-Head and Neck module (MDASI-HN). METHODS: Head and neck cancer survivors who had received radiation therapy (RT) completed the MDASI-HN, the University of Michigan Hospital Xerostomia Questionnaire (XQ), and the health visual analog scale (VAS) of the EuroQol Five Dimension Questionnaire (EQ-5D). The Bayesian information criteria (BIC) were used to test the prediction power of each tool for EQ-5D VAS. The modified Breiman recursive partitioning analysis (RPA) was used to identify a cut point of the MDASI-HN dry mouth score (MDASI-HN-DM) with EQ-5D VAS, using a ROC-based approach; regression analysis was used to confirm the threshold effect size. RESULTS: Two-hundred seven respondents formed the cohort. Median follow-up from the end of RT to questionnaire completion was 88 months. The single item MDASI-HN-DM score showed a linear relationship with the XQ composite score (ρ = 0.80, p < 0.001). The MDASI-HN-DM displayed improved model performance for association with EQ-5D VAS as compared to XQ (BIC of 1803.7 vs. 2016.9, respectively). RPA showed that an MDASI-HN-DM score of ≥6 correlated with EQ-5D VAS decline (LogWorth 5.5). CONCLUSION: The single item MDASI-HN-DM correlated with the multi-item XQ and performed favorably in the prediction of QOL. A MDASI-HN-DM cut point of ≥6 correlated with decline in QOL.

Symptom burden and dysphagia associated with osteoradionecrosis in long-term oropharynx cancer survivors: A cohort analysis.

OBJECTIVE: The purpose is to examine the relationship between mandibular osteoradionecrosis (ORN) and chronic dysphagia in long-term oropharynx cancer (OPC) survivors, and to determine the perceived symptom burden associated with ORN. MATERIALS AND METHODS: Medical records of 349 OPC patients treated with bilateral IMRT and systemic therapy were reviewed. ORN was graded using a published 4-point classification schema. Patients were considered to have chronic dysphagia if they had aspiration pneumonia, stricture or aspiration detected by fluoroscopy or endoscopy, and/or feeding tube dependence in long-term follow-up ⩾1year following radiotherapy. MD Anderson Symptom Inventory - Head and Neck Module (MDASI-HN) scores were analyzed in a nested cross-sectional survey sample of 118 patients. RESULTS: 34 (9.7%, 95% CI: 6.8-13.3%) patients developed ORN and 45 (12.9%, 95% CI: 9.6-16.9%) patients developed chronic dysphagia. Prevalence of chronic dysphagia was significantly higher in ORN cases (12/34, 35%) compared to those who did not develop ORN (33/315, 11%, p<0.001). ORN grade was also significantly associated with prevalence of dysphagia (p<0.001); the majority of patients with grade 4 ORN requiring major surgery (6 patients, 75%) were found to have chronic dysphagia. Summary MDASI-HN symptom scores did not significantly differ by ORN grade. Significantly higher symptom burden was reported, however, among ORN cases compared to those without ORN for MDASI-HN swallowing (p=0.033), problems with teeth and/or gums (p=0.016) and change in activity (p=0.015) item scores. CONCLUSIONS: ORN is associated with excess burden of chronic dysphagia and higher symptom severity related to swallowing, dentition and activity limitations.

Long-term patient reported outcomes following radiation therapy for oropharyngeal cancer: cross-sectional assessment of a prospective symptom survey in patients ≥65 years old.

BACKGROUND: Given the potential for older patients to experience exaggerated toxicity and symptoms, this study was performed to characterize patient reported outcomes in older patients following definitive radiation therapy (RT) for oropharyngeal cancer (OPC). METHODS: Cancer-free head and neck cancer survivors (>6 months since treatment completion) were eligible for participation in a questionnaire-based study. Participants completed the MD Anderson Symptom Inventory-Head and Neck module (MDASI-HN). Those patients ≥65 years old at treatment for OPC with definitive RT were included. Individual and overall symptom severity and clinical variables were analyzed. RESULTS: Of the 79 participants analyzed, 82% were male, 95% white, 41% T3/4 disease, 39% RT alone, 27% induction chemotherapy, 52% concurrent, and 18% both, and 96% IMRT. Median age at RT was 71 yrs. (range: 65-85); median time from RT to MDASI-HN was 46 mos. (2/3 > 24 mos.). The top 5 MDASI-HN items rated most severe in terms of mean (±SD) ratings (0-10 scale) were dry mouth (3.48 ± 2.95), taste (2.81 ± 3.29), swallowing (2.59 ± 2.96), mucus in mouth/throat (2.04 ± 2.68), and choking (1.30 ± 2.38) reported at moderate-severe levels (≥5) by 35, 29, 29, 18, and 13%, respectively. Thirty-nine % reported none (0) or no more than mild (1-4) symptoms across all 22 MDASI-HN symptoms items, and 38% had at least one item rated as severe (≥7). Hierarchical cluster analysis resulted in 3 patient groups: 1) ~65% with ranging from none to moderate symptom burden, 2) ~35% with moderate-severe ratings for a subset of classically RT-related symptoms (e.g. dry mouth, mucus, swallowing) and 3) 2 pts. with severe ratings of most items. CONCLUSIONS: The overall long-term symptom burden seen in this older OPC cohort treated with modern standard therapy was largely favorable, yet a higher symptom group (~35%) with a distinct pattern of mostly local and classically RT-related symptoms was identified.

Concordance of oral HPV prevalence between patients with oropharyngeal cancer and their partners.

BACKGROUND: Human papilloma virus (HPV) is a known causative factor in oropharyngeal squamous cell cancer (OPC). In this prospective study, we sought to define the risk of HPV transmission between OPC patients and their sexual partners by performing HPV genotyping on oral cytology brushings. METHODS: Newly diagnosed OPC patients and their sexual partners underwent oral mouth swabs and answered a risk factor questionnaire. Patient tumor samples and oral swabs from both the patient and partner were assessed for HPV status and genotyped using Easy-Chip HPV Blot PCR. RESULTS: We enrolled 227 patient-partner pairs and obtained sufficient analyzable DNA from both members in 198 pairs. Of 144 patients with available OPC tumor tissue, 128 (89 %) had HPV-positive tumors by either in situ hybridization or p16 immunohistochemical analysis (104 or 121, respectively). In total, there were 28 patients and 30 partners who were HPV positive by oral swab. The prevalence rate of oral HPV in partners was 15 %. There were 39 patient-partner pairs who had one or both members returning positive for HPV in the oral swab, and 49 % of these pairs were concordant for their HPV-genotype. Female partners had a higher oral HPV prevalence (16 %) than did male partners (11 %). Patients who were non-white were also found to have a higher oral prevalence of HPV (p = 0.032) by mouth swab. CONCLUSIONS: Partners of OPC patients may have a higher prevalence of oral HPV and should be studied prospectively to understand their OPC risk. Additional future research is needed to identify oral HPV persistence in partners to OPC patients and to determine the optimal sampling methods and technologies to screen patients at high risk for HPV-related disease.

Favorable patient reported outcomes following IMRT for early carcinomas of the tonsillar fossa: Results from a symptom assessment study.

BACKGROUND: A questionnaire-based study was conducted to assess long-term patient reported outcomes (PROs) following definitive IMRT-based treatment for early stage carcinomas of the tonsillar fossa. METHODS: Participants had received IMRT with or without systemic therapy for squamous carcinoma of the tonsillar fossa (T1-2 and N0-2b) with a minimum follow-up of 2years. Patients completed a validated head and neck cancer-specific PRO instrument, the MD Anderson Symptom Inventory-Head and Neck module (MDASI-HN). Symptoms were compared between treatment groups of interest and overall symptom burden was evaluated. RESULTS: Of 139 participants analyzed, 51% had received ipsilateral neck IMRT, and 62% single modality IMRT alone (no systemic therapy). There were no differences in mean severity ratings for the top-ranked individual symptoms or symptom interference for those treated with bilateral versus ipsilateral neck IMRT alone. However, 40% of those treated with bilateral versus 25% of those treated with ipsilateral neck RT alone reported moderate-to-severe levels of dry mouth (p=0.03). Fatigue, numbness/tingling, and constipation were rated more severe for those who had received systemic therapy (p<0.05 for each), but absolute differences were small. Overall, 51% had no more than mild symptom ratings across all 22 symptoms assessed. CONCLUSIONS: The long-term patient reported symptom profile in this cohort of tonsil cancer survivors treated with definitive IMRT-based treatment showed a majority of patients with no more than mild symptoms, low symptom interference, and provides an opportunity for future comparison studies with other treatment approaches.

Osteoradionecrosis and radiation dose to the mandible in patients with oropharyngeal cancer.

PURPOSE: To determine the association between radiation doses delivered to the mandible and the occurrence of osteoradionecrosis (ORN). METHODS AND MATERIALS: We reviewed the records of 402 oropharyngeal cancer patients with stage T1 or T2 disease treated with definitive radiation between January 2000 and October 2008 for the occurrence of ORN. Demographic and treatment variables were compared between patients with ORN and those without. To examine the dosimetric relationship further, a nested case-control comparison was performed. One to 2 ORN-free patients were selected to match each ORN patient by age, sex, radiation type, treatment year, and cancer subsite. Detailed radiation treatment plans for the ORN cases and matched controls were reviewed. Mann-Whitney test and conditional logistic regression were used to compare relative volumes of the mandible exposed to doses ranging from 10 Gy-60 Gy in 10-Gy increments. RESULTS: In 30 patients (7.5%), ORN developed during a median follow-up time of 31 months, including 6 patients with grade 4 ORN that required major surgery. The median time to develop ORN was 8 months (range, 0-71 months). Detailed radiation treatment plans were available for 25 of the 30 ORN patients and 40 matched ORN-free patients. In the matched case-control analysis, there was a statistically significant difference between the volumes of mandible in the 2 groups receiving doses between 50 Gy (V50) and 60 Gy (V60). The most notable difference was seen at V50, with a P value of .02 in the multivariate model after adjustment for the matching variables and dental status (dentate or with extraction). CONCLUSIONS: V50 and V60 saw the most significant differences between the ORN group and the comparison group. Minimizing the percent mandibular volume exposed to 50 Gy may reduce ORN risk.

Phase II trial of induction chemotherapy followed by surgery for squamous cell carcinoma of the oral tongue in young adults.

BACKGROUND: We conducted a phase II clinical trial of induction chemotherapy followed by surgery ± radiotherapy for squamous cell carcinoma of the oral tongue (SCCOT) in young adults. METHODS: From September 2001 to October 2004, 23 patients aged 18 to 49 years with clinical T2-3 N0-2 M0 SCCOT and no prior radiotherapy, chemotherapy, or neck dissection underwent induction chemotherapy (paclitaxel, ifosfamide, and carboplatin) followed by glossectomy and neck dissection ± radiotherapy and chemotherapy. RESULTS: On final surgical pathology, 9 patients (39%) had a complete/major (2 complete) histologic response at the primary tumor site; 8 patients (35%) had no response or progression. Similarly, 9 patients (39%) had a complete response in the neck or remained node negative; 6 patients (26%) had an increase in nodal category. No treatment-associated deaths occurred, and toxicity was modest. At a median follow-up from the end of treatment of 52 months (minimum, 23 months), 10 patients (43%) developed recurrence, and all 10 died of cancer. Crude recurrence/cancer death rates were associated with ≤ a partial response at the tongue (p = .029), poor histologic differentiation (p = .012), and multiple adverse features on final surgical pathology (p = .040). CONCLUSION: Response rates and overall survival with this induction chemotherapy regimen were limited, but complete/major response at the tongue was associated with excellent prognosis. Additionally, improved patient selection and predictive tumor biomarkers will be needed for induction chemotherapy to be routinely incorporated into the treatment of oral tongue cancer in young adults.

Osteosarcoma of the jaw/craniofacial region: outcomes after multimodality treatment.

BACKGROUND: The current study was performed to evaluate outcomes in patients with osteosarcoma of the head and neck (OHN) who were treated with surgery with or without radiotherapy (RT). METHODS: Between 1960 and 2007, 119 patients with OHN underwent macroscopic total resection with or without RT. The median age of the patients was 33 years (range, 7-77 years). Of these 119 patients 92 (77%) underwent surgery alone whereas 27 (23%) patients were treated with combined modality treatment (CMT) comprised of surgery and RT (median dose, 60 Gray [Gy]; range, 50-66 Gy). RESULTS: The median follow-up was 5.8 years. Overall survival (OS) rates at 5 years and 10 years were 63% and 55%, respectively. Corresponding disease-specific survival (DSS) rates were 67% and 61%, respectively. Stratified analysis by resection margin status demonstrated that CMT compared with surgery alone improved OS (80% vs 31%; P = .02) and DSS (80% vs 35%; P = .02) for patients with positive/uncertain resection margins. Multivariate analysis indicated that CMT for patients with positive/uncertain resection margins improved OS (P < .0001). A total of 44 (37%) patients experienced local disease recurrence (LR) and 25 (21%) developed distant metastases (DM). There was no difference noted with regard to DSS if disease recurrence was isolated (LR vs DM: 26% vs 29%, respectively, at 5 years; P = .48) The use of CMT versus surgery alone improved local control (LC) (75% vs 24%; P = .006) for patients with positive/uncertain resection margins. The rate of surgical complications was 28% at 5 years. The rates of RT-associated complications were 40% and 47% at 5 years and 10 years, respectively. CONCLUSIONS: The results of the current study indicated that RT in addition to surgery improves OS, DSS, and LC for patients with OHN who have positive/uncertain resection margins.

Squamous cell carcinoma of the head and neck in never smoker-never drinkers: a descriptive epidemiologic study.

BACKGROUND: While the attributed risk factors for the vast majority of patients with squamous cell carcinoma of the head and neck (SCCHN) are smoking and alcohol abuse, there appears to be a rising proportion of SCCHN patients who report no significant smoking or drinking history. This study reports the demographic and potential risk factors of a large series of never smoker-never drinker (NSND) patients. METHODS: All subjects were participants in a prospective epidemiologic study of incident SCCHN. We obtained demographic data, clinical characteristics, and potential etiologic factors for 172 NSND patients and 1131 ever smoker-ever drinker (ESED) patients. RESULTS.: NSND patients were more likely to be female and to present at extremes of age, but overall were significantly younger than ESED patients. NSND patients had a higher proportion of oral cavity and oropharyngeal cancers than ESED patients had. Eleven percent of NSND patients (17% of NSND men) reported regular use of noncigarette tobacco products or marijuana, 41% (45% of NSND women) reported regular environmental exposure to tobacco smoke, 24% (36% of NSND men) reported regular occupational exposures to carcinogens/toxins, and 30% had a history of gastroesophageal reflux disease. More than half the NSND patients with an oropharyngeal primary were serologically positive for human papillomavirus type 16. CONCLUSION: NSND patients with SCCHN are commonly young women with oral tongue cancer, elderly women with gingival/buccal cancer, or young to middle-aged men with oropharyngeal cancer. While several exposures studied may be important to the etiology of a subset of these cancers in NSND patients, it is likely that no single known factor is responsible for a majority of SCCHN in NSNDs.

Postirradiation osteosarcoma of the mandible with heterologous differentiation.

Heterologous differentiation in osteosarcoma is rare, with only 17 cases previously described in the literature. We report a case of a mandibular osteoblastic osteosarcoma with rhabdomyosarcomatous differentiation in a 45-year-old man who had a history of Hodgkin lymphoma that was treated with chemotherapy and radiation. Radiographs showed a destructive osteoblastic tumor of the mandible that was proven by biopsy to be osteosarcoma. After the patient underwent neoadjuvant chemotherapy, the tumor was resected. It contained a high-grade osteosarcoma composed of osteoblastic and chondroblastic elements that had no definitive response to therapy. Within the center of the lesion was a discrete focus of pleomorphic cells with rhabdomyosarcomatous differentiation that was confirmed by immunohistochemical stains for desmin, myogenin, and myogenic differentiation antigen 1. The patient received additional chemotherapy and radiation therapy but developed lung, brain, and spinal metastases and died 7 months after surgery. To our knowledge, this is the first report of osteosarcoma of the mandible with heterologous differentiation.

Neoadjuvant chemotherapy for squamous cell carcinoma of the oral tongue in young adults: a case series.

BACKGROUND: Squamous cell carcinoma of the oral tongue (SCCOT) in the young population has emerged as a growing worldwide health problem. Standard therapies, consisting primarily of surgery with possible adjuvant radiotherapy, have resulted in only modest improvements in survival in recent decades, whereas the treatments for SCCOT continue to impair oral function. With the increased use and improved functional results of neoadjuvant chemotherapy in the treatment of squamous cell carcinoma of other upper aerodigestive tract sites, we have reviewed our experience with neoadjuvant chemotherapy in young patients with SCCOT. METHODS: A retrospective review was conducted of all patients younger than 45 years (N = 49) with previously untreated SCCOT evaluated at a comprehensive cancer center from July 1995 to August 2001. Charts were reviewed to obtain demographic data, comorbidities, nutritional status, tumor status, treatment and response information, and follow-up data. RESULTS: Fifteen patients were identified who received neoadjuvant chemotherapy with taxane-based regimens before undergoing glossectomy and neck dissection. Thirteen of these patients (87%) exhibited stage III or IV disease at presentation, and all exhibited at least a partial response at the primary site. Pathologically positive nodes were identified in only six patients (40%), although 13 (87%) had clinically or radiographically suspicious nodes at presentation. Adjuvant radiation therapy was administered to seven patients (47%). With a median follow-up of 39 months, no patient has had local or regional recurrence, although three patients (20%) have had distant metastases develop; one patient with an isolated distant metastasis was successfully salvaged with radiation. By comparison during the same period, 34 young adult patients with SCCOT were treated with surgery with or without postoperative radiotherapy but without the use of chemotherapy. Although these patients had lower T classifications (18% vs 67% T3/T4; p = .0007), incidence of nodal metastases (15% vs 87% N+; p < .0001), and overall disease stage (24% vs 87% stage III/IV; p < .0001) than the neoadjuvant chemotherapy group, the overall survival (82%), disease-specific survival (88%), and recurrence-free survival (82%) of the surgery-first group was similar to that of the neoadjuvant chemotherapy group (87%, 87%, and 80%, respectively). CONCLUSIONS: This retrospective investigation demonstrates that neoadjuvant chemotherapy with taxane-based regimens may play a role in the successful treatment of SCCOT in young adult patients. Ultimately, this treatment plan may lead to improved functional outcomes in young patients with SCCOT by allowing function-sparing surgery and avoiding postoperative radiotherapy, without sacrificing disease control and survival, but a prospective trial is needed. We have initiated a prospective clinical trial to further investigate the impact of neoadjuvant chemotherapy in patients younger than 50 with SCCOT.