Ralph W. Gilbert

Deintensification Candidate Subgroups in Human Papillomavirus-Related Oropharyngeal Cancer According to Minimal Risk of Distant Metastasis

PURPOSE To define human papillomavirus (HPV) -positive oropharyngeal cancers (OPC) suitable for treatment deintensification according to low risk of distant metastasis (DM). PATIENTS AND METHODS OPC treated with radiotherapy (RT) or chemoradiotherapy (CRT) from 2001 to 2009 were included. Outcomes were compared for HPV-positive versus HPV-negative patients. Univariate and multivariate analyses identified outcome predictors. Recursive partitioning analysis (RPA) stratified the DM risk. RESULTS HPV status was ascertained in 505 (56%) of 899 consecutive OPCs. Median follow-up was 3.9 years. HPV-positive patients (n = 382), compared with HPV-negative patients (n = 123), had higher local (94% v 80%, respectively, at 3 years; P < .01) and regional control (95% v 82%, respectively; P < .01) but similar distant control (DC; 90% v 86%, respectively; P = .53). Multivariate analysis identified that HPV negativity (hazard ratio [HR], 2.9; 95% CI, 2.0 to 5.0), N2b-N3 (HR, 2.9; 95% CI, 1.8 to 4.9), T4 (HR, 1.8; 95% CI, 1.2 to 2.9), and RT alone (HR, 1.8; 95% CI, 1.1 to 2.5) predicted a lower recurrence-free survival (RFS; all P < .01). Smoking pack-years > 10 reduced overall survival (HR, 1.72; 95% CI, 1.1 to 2.7; P = .03) but did not impact RFS (HR, 1.1; 95% CI, 0.7 to 1.9; P = .65). RPA segregated HPV-positive patients into low (T1-3N0-2c; DC, 93%) and high DM risk (N3 or T4; DC, 76%) groups and HPV-negative patients into different low (T1-2N0-2c; DC, 93%) and high DM risk (T3-4N3; DC, 72%) groups. The DC rates for HPV-positive, low-risk N0-2a or less than 10 pack-year N2b patients were similar for RT alone and CRT, but the rate was lower in the N2c subset managed by RT alone (73% v 92% for CRT; P = .02). CONCLUSION HPV-positive T1-3N0-2c patients have a low DM risk, but N2c patients from this group have a reduced DC when treated with RT alone and seem less suited for deintensification strategies that omit chemotherapy.

Refining American Joint Committee on Cancer/Union for International Cancer Control TNM Stage and Prognostic Groups for Human Papillomavirus–Related Oropharyngeal Carcinomas

PURPOSE To refine stage and prognostic group for human papillomavirus (HPV) -related nonmetastatic (M0) oropharyngeal cancer (OPC). METHODS All patients with nonmetastatic (M0) p16-confirmed OPC treated with radiotherapy with or without chemotherapy from 2000 to 2010 were included. Overall survival (OS) was compared among TNM stages for patients with HPV-related and HPV-unrelated OPC separately. For HPV-related OPC, recursive partitioning analysis (RPA) derived new RPA stages objectively. Cox regression was used to calculate adjusted hazard ratios (AHRs) to derive AHR stages. The performance of survival prediction of RPA stage and AHR stage was assessed against the current seventh edition TNM stages. Prognostic groups were derived by RPA, combining RPA stage and nonanatomic factors. RESULTS The cohort comprised 573 patients with HPV-related OPC and 237 patients with HPV-unrelated OPC, with a median follow-up of 5.1 years. Lower 5-year OS with higher TNM stage was evident for patients with HPV-unrelated OPC (stage I, II, III, and IV 5-year OS: 70%, 58%, 50%, and 30%, respectively; P = .004) but not for patients with HPV-related OPC (stage I, II, III, and IV 5-year OS: 88%, 78%, 71%, and 74%, respectively; P = .56). RPA divided HPV-related OPC into RPA-I (T1-3N0-2b), RPA-II (T1-3N2c), and RPA-III (T4 or N3; 5-year OS: 82%, 76%, and 54%, respectively; P < .001). AHR also yielded a valid classification, but RPA stage demonstrated better survival prediction. A further RPA (including RPA stage, age, and smoking pack-years [PYs]) derived the following four valid prognostic groups for survival: group I (T1-3N0-N2c_≤ 20 PY), group II (T1-3N0-N2c_> 20 PY), group III (T4 or N3_age ≤ 70), and group IVA (T4 or N3_age > 70; 5-year OS: 89%, 64%, 57%, and 40%, respectively; P < .001). CONCLUSION An RPA-based TNM stage grouping (stage I/II/III: T1-3N0-N2b/T1-3N2c/T4 or N3, with M1 as stage IV) is proposed for HPV-related OPC as a result of significantly improved survival prediction compared with the seventh edition TNM, and prognostication is further improved by an RPA-based prognostic grouping within the American Joint Committee on Cancer/Union for International Cancer Control TNM framework for HPV-related OPC.

Identification of a microRNA signature associated with progression of leukoplakia to oral carcinoma

MicroRNAs (miRs) are non-coding RNA molecules involved in cancer initiation and progression. Deregulated miR expression has been implicated in cancer; however, there are no studies implicating an miR signature associated with progression in oral squamous cell carcinoma (OSCC). Although OSCC may develop from oral leukoplakia, clinical and histological assessments have limited prognostic value in predicting which leukoplakic lesions will progress. Our aim was to quantify miR expression changes in leukoplakia and same-site OSCC and to identify an miR signature associated with progression. We examined miR expression changes in 43 sequential progressive samples from 12 patients and four non-progressive leukoplakias from four different patients, using TaqMan Low Density Arrays. The findings were validated using quantitative RT-PCR in an independent cohort of 52 progressive dysplasias and OSCCs, and five non-progressive dysplasias. Global miR expression profiles distinguished progressive leukoplakia/OSCC from non-progressive leukoplakias/normal tissues. One hundred and nine miRs were highly expressed exclusively in progressive leukoplakia and invasive OSCC. miR-21, miR-181b and miR-345 expressions were consistently increased and associated with increases in lesion severity during progression. Over-expression of miR-21, miR-181b and miR-345 may play an important role in malignant transformation. Our study provides the first evidence of an miR signature potentially useful for identifying leukoplakias at risk of malignant transformation.

PREDICTORS OF MORBIDITY FOLLOWING FREE FLAP RECONSTRUCTION FOR CANCER OF THE HEAD AND NECK

Free flap reconstruction of head and neck cancer defects is complex with many factors that influence perioperative complications. The aim was to determine if there was an association between perioperative variables and postoperative outcome.

Outcomes of HPV-related oropharyngeal cancer patients treated by radiotherapy alone using altered fractionation.

PURPOSE To report outcome of HPV-related [HPV(+)] oropharyngeal cancer (OPC) managed predominantly by altered-fractionation radiotherapy-alone (RT-alone). METHODS OPCs treated with RT-alone (n = 207) or chemoradiotherapy (CRT) (n = 151) from 2001 to 2008 were included. Overall survival (OS), local (LC), regional (RC) and distant (DC) control were compared for HPV(+) vs. HPV-unrelated [HPV(-)], by RT-alone vs. CRT, and by smoking pack-years (≤ 10 vs. >10). Multivariate analysis identified predictors. RESULTS HPV(+) (n = 277) had better OS (81% vs. 44%), LC (93% vs. 76%), RC (94% vs. 79%) (all p < 0.01) but similar DC (89% vs. 86%, p = 0.87) vs. HPV(-) (n = 81). HPV(+) stage IV CRT (n = 125) had better OS (89% vs. 70%, p < 0.01), but similar LC (93% vs. 90%, p = 0.41), RC (94% vs. 90%, p = 0.31) and DC (90% vs. 83%, p = 0.22) vs. RT-alone (n = 96). Both HPV(+) RT-alone (n = 37) and CRT (n = 67) stage IV minimal smokers had favorable OS (86% vs. 88%, p = 0.45), LC (95% vs. 92%, p = 0.52), RC (97% vs. 93%, p = 0.22), and DC (92% vs. 86%, p = 0.37). RT-alone and heavy-smoking were independent predictors for lower OS but not CSS in multivariate analysis. CONCLUSIONS Overall, HPV(+) RT-alone stage IV demonstrated lower survival but comparable disease control vs. CRT, but no difference was apparent among minimal smokers.

Merkel cell carcinoma of the head and neck: Is adjuvant radiotherapy necessary?

Controversy exists regarding the optimal management of patients with Merkel cell carcinoma. The primary aim of this study was to determine whether combined treatment with surgery and radiotherapy improves outcome in a multi‐institutional cohort of patients with Merkel cell carcinoma of the head and neck. The secondary aims were to determine by stage, which patients derive benefit from combined therapy and to identify predictors for survival on multivariable analysis.

Clinicopathologic and therapeutic risk factors for perioperative complications and prolonged hospital stay in free flap reconstruction of the head and neck

We aimed to determine predictors of morbidity in patients undergoing microvascular free flap reconstruction of the head and neck.

Morbidity After Flap Reconstruction of Hypopharyngeal Defects

Objectives: Laryngopharyngeal reconstruction continues to challenge in terms of operative morbidity and optimal functional results. The primary aim of this study is to determine whether complications can be predicted on the basis of reconstruction in patients undergoing pharyngectomy for tumors involving the hypopharynx. In addition, we detail a reconstructive algorithm for management of partial and total laryngopharyngectomy defects.

Correlation of tumor volume with local control in laryngeal carcinoma treated by radiotherapy.

An analysis of 37 patients with laryngeal carcinoma (T2 or greater) treated with radical radiotherapy, with surgery reserved for failure, was performed to determine if tumor volume, alone or in association with other prognostic factors, accurately predicted the probability of local control. Patient records were reviewed retrospectively and the following data extracted: Age, sex, laryngeal region and number of sites involved by tumor, T and N categories, and success or failure of radiotherapy. Tumor volume for each patient was calculated from pretreatment computed tomograms by summing the products of the cross-sectional tumor area on each CT cut and the interval in millimeters between sequential CT cuts. The mean tumor volume for patients failing radiotherapy was 21.8 cm3, and the mean volume for patients primarily controlled by radiotherapy was 8.86 cm3. Tumor volume significantly predicted disease-free interval (p = .045) and outcome with radiotherapy (p = .02). The study suggests that tumor volume is a significant factor in determining the outcome of primary radiotherapy in advanced laryngeal carcinoma.

Low prevalence of Human Papillomavirus in oral cavity carcinomas

BackgroundIncreasing evidence shows that Human Papillomavirus (HPV) is preferentially associated with some head and neck squamous cell carcinomas (HNSCCs), with variable infection rates reported.MethodsWe assessed HPV involvement in HNSCC using the Roche Linear Array HPV Genotyping Test, which can detect 37 different HPV types. We examined the prevalence of HPV infection in 92 HNSCCs (oropharynx, oral cavity, and other HNSCC sites).ResultsHPV was frequently detected in oropharyngeal cancers (OPCs) (16/22, 73%), but was uncommon in oral cavity cancers (2/53, 4%), and in other HNSCC subsites (1/17, 6%). HPV positive tumors were associated with patients that were 40-60 years old (p = 0.02), and node positive (p = < 0.0001). HPV 16 was the most prevalent type, but other types detected included 6, 18, 33, 35, 45, and 52/58.ConclusionOur results show that in contrast to oropharyngeal cancers, oral cancers and other HNSCCs infrequently harbor HPV.