Jeffrey S. Moyer

Intensity-Modulated Chemoradiotherapy Aiming to Reduce Dysphagia in Patients With Oropharyngeal Cancer: Clinical and Functional Results

PURPOSE To assess clinical and functional results of chemoradiotherapy for oropharyngeal cancer (OPC), utilizing intensity-modulated radiotherapy (IMRT) to spare the important swallowing structures to reduce post-therapy dysphagia. PATIENTS AND METHODS This was a prospective study of weekly chemotherapy (carboplatin dosed at one times the area under the curve [AUC, AUC 1] and paclitaxel 30 mg/m(2)) concurrent with IMRT aiming to spare noninvolved parts of the swallowing structures: pharyngeal constrictors, glottic and supraglottic larynx, and esophagus as well as the oral cavity and major salivary glands. Swallowing was assessed by patient-reported Swallowing and Eating Domain scores, observer-rated scores, and videofluoroscopy (VF) before therapy and periodically after therapy through 2 years. RESULTS Overall, 73 patients with stages III to IV OPC participated. At a median follow-up of 36 months, 3-year disease-free and locoregional recurrence-free survivals were 88% and 96%, respectively. All measures of dysphagia worsened soon after therapy; observer-rated and patient-reported scores recovered over time, but VF scores did not. At 1 year after therapy, observer-rated dysphagia was absent or minimal (scores 0 to 1) in all patients except four: one who was feeding-tube dependent and three who required soft diet. From pretherapy to 12 months post-therapy, the Swallowing and Eating Domain scores worsened on average (+/- standard deviation) by 10 +/- 21 and 13 +/- 19, respectively (on scales of 0 to 100), and VF scores (on scale of 1 to 7) worsened from 2.9 +/- 1.5 (mild dysphagia) to 4.1 +/- 0.9 (mild/moderate dysphagia). CONCLUSION Chemoradiotherapy with IMRT aiming to reduce dysphagia can be performed safely for OPC and has high locoregional tumor control rates. On average, long-term patient-reported, observer-rated, and objective measures of swallowing were only slightly worse than pretherapy measures, representing potential improvement compared with previous studies.

Tobacco Use in Human Papillomavirus–Positive Advanced Oropharynx Cancer Patients Related to Increased Risk of Distant Metastases and Tumor Recurrence

Purpose: The goal of this study was to examine the effect of tobacco use on disease recurrence (local/regional recurrence, distant metastasis, or second primary) among patients with human papillomavirus (HPV)–positive squamous cell carcinoma of the oropharynx (SCCOP) following a complete response to chemoradiation therapy. Experimental Design: Between 1999 and 2007, 124 patients with advanced SCCOP (86% with stage IV) and adequate tumor tissue for HPV analysis who were enrolled in one of two consecutive University of Michigan treatment protocols were prospectively included in this study. Patients were categorized as never-, former, or current tobacco users. The primary end points were risk of disease recurrence and time to recurrence; secondary end points were disease-specific survival and overall survival. Results: One hundred and two patients (82.3%) had HPV-positive tumors. Over two thirds (68%) of patients with HPV-positive tumors were tobacco users. Among HPV-positive patients, current tobacco users were at significantly higher risk of disease recurrence than never-tobacco users (hazard ratio, 5.2; confidence interval, 1.1-24.4; P = 0.038). Thirty-five percent of HPV-positive ever tobacco users recurred compared with only 6% of HPV-positive never users and 50% of HPV-negative patients. All HPV-negative patients were tobacco users and had significantly shorter times to recurrence (P = 0.002), and had reduced disease-specific survival (P = 0.004) and overall survival (P < 0.001) compared with HPV-positive patients. Compared with HPV-positive never-tobacco users, those with a tobacco history showed a trend for reduced disease-specific survival (P = 0.064) but not overall survival (P = 0.221). Conclusions: Current tobacco users with advanced, HPV-positive SCCOP are at higher risk of disease recurrence compared with never-tobacco users. Clin Cancer Res; 16(4); 1226–35

Cancer Stem Cell Vaccination Confers Significant Antitumor Immunity

Most studies of cancer stem cells (CSC) involve the inoculation of cells from human tumors into immunosuppressed mice, preventing an assessment on the immunologic interactions and effects of CSCs. In this study, we examined the vaccination effects produced by CSC-enriched populations from histologically distinct murine tumors after their inoculation into different syngeneic immunocompetent hosts. Enriched CSCs were immunogenic and more effective as an antigen source than unselected tumor cells in inducing protective antitumor immunity. Immune sera from CSC-vaccinated hosts contained high levels of IgG which bound to CSCs, resulting in CSC lysis in the presence of complement. CTLs generated from peripheral blood mononuclear cells or splenocytes harvested from CSC-vaccinated hosts were capable of killing CSCs in vitro. Mechanistic investigations established that CSC-primed antibodies and T cells were capable of selective targeting CSCs and conferring antitumor immunity. Together, these proof-of-concept results provide a rationale for a new type of cancer immunotherapy based on the development of CSC vaccines that can specifically target CSCs.

Early Prediction of Outcome in Advanced Head-and-Neck Cancer Based on Tumor Blood Volume Alterations During Therapy: A Prospective Study

PURPOSE To assess whether alterations in tumor blood volume (BV) and blood flow (BF) during the early course of chemo-radiotherapy (chemo-RT) for head-and-neck cancer (HNC) predict treatment outcome. METHODS AND MATERIALS Fourteen patients receiving concomitant chemo-RT for nonresectable, locally advanced HNC underwent dynamic contrast-enhanced (DCE) MRI scans before therapy and 2 weeks after initiation of chemo-RT. The BV and BF were quantified from DCE MRI. Preradiotherapy BV and BF, as well as their changes during RT, were evaluated separately in the primary gross tumor volume (GTV) and nodal GTV for association with outcomes. RESULTS At a median follow-up of 10 months (range, 5-27 months), 9 patients had local-regional controlled disease. One patient had regional failure, 3 had local failures, and 1 had local-regional failure. Reduction in tumor volume after 2 weeks of chemo-RT did not predict for local control. In contrast, the BV in the primary GTV after 2 weeks of chemo-RT was increased significantly in the local control patients compared with the local failure patients (p < 0.03). CONCLUSIONS Our data suggest that an increase in available primary tumor blood for oxygen extraction during the early course of RT is associated with local control, thus yielding a predictor with potential to modify treatment. These findings require validation in larger studies.

The pattern of failure after reirradiation of recurrent squamous cell head and neck cancer: implications for defining the targets.

PURPOSE Reirradiation (re-RT) of recurrent head and neck cancer (HNC) may achieve long-term disease control in some patients, at the expense of high rates of late sequelae. Limiting the re-RT targets to the recurrent gross tumor volume (rGTV) would reduce the volumes of reirradiated tissues; however, its effect on tumor recurrence pattern is unknown. METHODS AND MATERIALS This is a retrospective review of 66 patients who underwent curative-intent re-RT for nonresectable recurrent or second primary mucosal squamous cell HNC. Treatment was delivered with three-dimensional conformal (3D) RT or intensity-modulated RT (IMRT). The targets in all patients consisted of the rGTVs with tight (0.5-cm) margins, with no intent to treat prophylactically lymph nodes or subclinical disease in the vicinity of the rGTVs. The sites of locoregional failures (LRFs) were determined using imaging at the time of failure and were compared with the rGTVs. RESULTS Median re-RT dose was 68 Gy. Forty-seven patients (71%) received concomitant chemotherapy, and 31 (47%) received hyperfractionated, accelerated RT. At a median follow-up of 42 months, 16 (23%) were alive and disease-free. Fifty patients (77%) had a third recurrence or persistent disease, including 47 LRFs. All LRFs occurred within the rGTVs except for two (4%) (95% confidence interval, 0-11%). Nineteen patients (29%) had Grade > or = 3 late complications, mostly dysphagia (12 patients). CONCLUSIONS Almost all LRFs occurred within the reirradiated rGTVs despite avoiding prophylactic RT of tissue at risk of subclinical disease. These results support confining the re-RT targets to the rGTVs to reduce reirradiated tissue volumes.

HPV-Positive/p16-Positive/EBV-Negative Nasopharyngeal Carcinoma in White North Americans

Human papillomavirus (HPV) has been detected in keratinizing nasopharyngeal carcinomas (NPCs); however, the relationship between HPV and Epstein–Barr virus (EBV) among whites with nonkeratinizing NPCs remains unclear. The HPV, p16, and EBV status was examined in current University of Michigan patients with NPC.

Infiltrating lymphocytes and human papillomavirus-16–associated oropharyngeal cancer†‡§

Human papillomavirus‐16 (HPV‐16)–associated carcinoma of the oropharynx has a favorable prognosis. Such patients have elevated CD8+ T‐lymphocyte levels that correlate with response to chemotherapy and survival. Tumor‐infiltrating lymphocyte (TIL) subpopulations were assessed in pretreatment biopsies from a prospective patient cohort to determine if TIL subsets differed by HPV status, clinical factors, or patient outcome or correlated with peripheral blood T‐cell levels.

Correlation of Cellular Immunity With Human Papillomavirus 16 Status and Outcome in Patients With Advanced Oropharyngeal Cancer

OBJECTIVE to determine whether the favorable outcome associated with human papillomavirus (HPV) 16-positive oropharyngeal cancer is related to a patients adaptive immunity. SETTING academic medical center. PATIENTS forty-seven of 66 previously untreated patients (6 of 20 patients with stage III and 41 of 46 with stage IV cancer) in a prospective clinical trial of chemoradiotherapy. INTERVENTION all patients were treated with a single course of neoadjuvant chemotherapy followed by either surgery (for nonresponders) or chemoradiotherapy. MAIN OUTCOME MEASURES pretreatment levels (percentages and absolute counts) of CD3, CD4, CD8, natural killer, and B cells and overall white blood cell counts were measured by flow cytometry. Correlations of subsets with HPV-16 status, tumor subsite, cancer stage, T class, N class, smoking status, performance status, sex, response to chemoradiotherapy, p53 mutation type, epidermal growth factor receptor expression, and disease-specific and overall survival were determined. RESULTS after a median follow-up of 6.6 years, improved survival was associated with an elevated percentage of CD8 cells (P = .04), a low CD4:CD8 ratio (P = .01), low epidermal growth factor receptor expression (P = .002), and HPV status (P = .02). The percentage of CD8 cells was significantly higher (P = .04) and the CD4:CD8 ratio was significantly lower (P = .02) in HPV-16-positive patients. A higher percentage of CD8 cells was associated with response to induction chemotherapy (P = .02) and complete tumor response after chemoradiotherapy (P = .045). CONCLUSION these findings confirm previous correlations of outcome with circulating CD8 cell levels and support the conjecture that improved adaptive immunity may play a role in the favorable prognosis of patients with HPV-16-positive cancers.

High-Risk Human Papillomavirus Detection in Oropharyngeal, Nasopharyngeal, and Oral Cavity Cancers Comparison of Multiple Methods

IMPORTANCE Human papillomaviruses are now recognized as an etiologic factor in a growing subset of head and neck cancers and have critical prognostic importance that affects therapeutic decision making. There is no universally accepted gold standard for high-risk HPV (hrHPV) assessment in formalin-fixed, paraffin-embedded (FFPE) tissue specimens, nor is there a clear understanding of the frequency or role of hrHPV in sites other than oropharynx. OBJECTIVE To determine the optimal assessment of hrHPV in FFPE head and neck tumor tissue specimens. DESIGN, SETTING, PARTICIPANTS In the setting of a large Midwestern referral center, assessment of hrHPV by p16 immunohistochemical staining, in situ hybridization, and polymerase chain reaction (PCR)-MassArray (PCR-MA), with L1 PGMY-PCR and sequencing to resolve method discordance, was conducted for 338 FFPE oropharyngeal, nasopharyngeal, and oral cavity tumor tissue specimens. Relative sensitivity and specificity were compared to develop a standard optimal test protocol. Tissue specimens were collected from 338 patients with head and neck cancer treated during the period 2001 through 2011 in the departments of Otolaryngology, Radiation Oncology, and Medical Oncology. INTERVENTION Patients received standard therapy. MAIN OUTCOMES AND MEASURES Optimal hrHPV identification, detection, and activity in head and neck cancers. RESULTS Using combined PCR-MA with L1 PGMY-PCR and sequencing for conclusive results, we found PCR-MA to have 99.5% sensitivity and 100% specificity, p16 to have 94.2% sensitivity and 85.5% specificity, and in situ hybridization to have 82.9% sensitivity and 81.0% specificity. Among HPV-positive tumors, HPV16 was most frequently detected, but 10 non-HPV16 types accounted for 6% to 50% of tumors, depending on the site. Overall, 86% of oropharynx, 50% of nasopharynx, and 26% of oral cavity tumors were positive for hrHPV. CONCLUSIONS AND RELEVANCE PCR-MA has a low DNA (5 ng) requirement effective for testing small tissue samples; high throughput; and rapid identification of HPV types, with high sensitivity and specificity. PCR-MA together with p16INK4a provided accurate assessment of HPV presence, type, and activity and was determined to be the best approach for HPV testing in FFPE head and neck tumor tissue specimens.

Matted nodes: Poor prognostic marker in oropharyngeal squamous cell carcinoma independent of HPV and EGFR status

Despite better prognosis, there is a group of oropharyngeal squamous cell carcinoma (SCC) human papillomavirus (HPV)+ patients who experience treatment failure and succumb to distant metastasis.