P16-positive Disease Research Articles

Impact of positive margins on outcomes of oropharyngeal squamous cell carcinoma according to p16 status.

Currently, positive surgical margins in head and neck cancer are considered to be an indicator for postoperative chemoradiotherapy (CRT) over radiotherapy (RT) alone. However, there are less data regarding the impact of margin status on human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (SCC). We performed a retrospective review of 55 patients with oropharyngeal SCC undergoing primary surgical treatment. The impact of margin status on disease-specific survival (DSS) was studied according to p16 status. Twenty-one patients had positive margins. Adjuvant treatment in these cases was CRT (n = 6), RT alone (n = 14), and none (n = 1). Among p16-negative patients, positive margins and dysplasia at margins predicted significantly worse DSS. Among patients with p16-positive disease, margin status had no impact on DSS. Patients with p16-positive oropharyngeal SCC and positive margins after excision maintain a low risk of recurrence despite most receiving RT alone as adjuvant treatment. These findings raise questions regarding the additional benefit of postoperative CRT in this group.

Prognostic importance of p16 status for women with vulvar squamous cell carcinoma (SCC) treated with radiotherapy.

5599 Background: To evaluate the association between p16 status and in-field recurrence (IFR), progression-free (PFS) and overall (OS) survival in patients with vulvar SCC treated with radiation (RT) with or without surgical resection. Methods: In a multi-institutional retrospective cohort study, we identified 105 women with vulvar SCC who received RT between 1985-2011. Immunostaining for p16 was performed on archival tumor tissue using the Leica Bond III staining platform. Histopathology and p16 stains were reviewed by pathologists with expertise in gynecologic cancer; the intensity and extent of p16 staining in tumor cells were classified as negative (focal, weak, patchy) or positive (moderate or strong diffuse linear positive). Actuarial estimates of PFS, OS and IFR were calculated using the Kaplan-Meier method and compared by the logrank test. Multivariable analysis (MVA) was performed using the Cox proportional hazards model. Results: Patients with p16-positive disease were significantly younger at diagnosis (median 67 vs. 77 years) and were more likely to be current smokers (51% vs. 0%) and to have received concurrent chemotherapy (68% vs. 47%, all p<0.05). FIGO stage distribution, RT intent and median RT doses were similar by p16 status. With a median follow-up of 61 months, 5-year PFS and OS rates were 35% and 40%, respectively. Women with p16-positive tumors had significantly better 5-year PFS and OS rates than those with p16-negative tumors (61% and 23%, p<0.01 and 64% and 29%, p=0.01, respectively). The 5-year IFR rate was also lower for those with p16-positive disease (17% vs. 65%, p<0.01). On univariate analysis, use of concurrent chemotherapy was not associated with PFS (p=0.5), OS (p=0.3) or IFR (p=0.8). On MVA adjusted for age and stage, p16 positivity was significantly associated with better PFS (HR 0.57, 95% CI 0.33-0.97) and lower IFR (HR 0.24, 95% CI 0.09-0.6). Conclusions: In a multi-institutional setting, women with p16-positive vulvar SCC treated with RT had a lower IFR rate and longer survival than those with p16-negative disease. The magnitude of prognostic importance of p16 status is similar to that seen in oropharyngeal, anal and cervical cancers treated with RT.

Investigation of p16 status, chemotherapy regimen, and other nutrition markers for predicting gastrostomy in patients with head and neck cancer.

The purpose of this study was to determine if p16 status, chemotherapy regimen, or other nutrition markers could improve protocol accuracy in predicting proactive gastrostomy in patients with head and neck cancer. Patients who received curative treatment from July 2010 to June 2011 were included (n = 269). Associations among dependent variables (age, sex, tumor site, staging, treatment, p16 status, albumin, and Malnutrition Screening Tool [MST] score), the protocol risk rating, and requirement for proactive gastrostomy were examined. Current protocol correctly identified 81 of 88 high-risk patients (92%) for gastrostomy, but incorrectly classified 32 of 181 low-risk patients (18%). Analysis of low-risk patients with oral or oropharyngeal cancers, found p16-positive disease had 4.4 times greater odds (p = .049), and those at risk of malnutrition had 4.5 times greater odds (p = .019) of requiring gastrostomy. Malnutrition risk and p16 status could be used to identify further patients who may benefit from proactive gastrostomy. © 2017 Wiley Periodicals, Inc. Head Neck 39: 868-875, 2017.

Impact of comorbidity and anemia in patients with oropharyngeal cancer primarily treated with surgery in the human papillomavirus era.

Comorbidity and anemia strongly influence treatment and outcome of oropharyngeal squamous cell carcinomas (SCCs), but respective data are frequently lacking in clinical studies. We evaluated 149 cases of oropharyngeal SCC primarily treated with surgery regarding the impact of these factors on disease-free survival (DFS) and overall survival (OS). Data were recorded during treatment and follow-up visits. Human papillomavirus (HPV) association of oropharyngeal SCC was detected by p16 immunohistochemistry. Patients with p16-positive disease were significantly less comorbid and anemic, and treated more aggressively. Comorbidity and anemia, but not p16 status, significantly influenced DFS and had more impact on OS than p16 status. In our study, p16-positive seems a good surrogate marker for healthier patients. Patients with p16-positive disease showed improved survival, but this was limited to none/mild comorbid and/or nonanemic individuals in this group. On the basis of our results, we strongly suggest the inclusion of these factors in risk stratification for clinical studies. © 2016 Wiley Periodicals, Inc. Head Neck 39: 7-16, 2017.

Total Mucosal Irradiation with Intensity-modulated Radiotherapy in Patients with Head and Neck Carcinoma of Unknown Primary: A Pooled Analysis of Two Prospective Studies

AimsTo determine the clinical outcomes of an intensity-modulated radiotherapy technique for total mucosal irradiation (TM-IMRT) in patients with head and neck carcinoma of unknown primary (HNCUP). Materials and methodsA single-centre prospective phase II trial design was used in two sequential studies to evaluate TM-IMRT for HNCUP. Patients were investigated for primary tumour site using examination under anaesthetic and biopsies, computed tomography ± magnetic resonance imaging (MRI) or 18-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT). Patients received IMRT to the potential primary tumour sites and elective cervical nodes. Concomitant chemotherapy was used in patients who received primary radiotherapy or those with nodal extracapsular extension. ResultsThirty-six patients with HNCUP were recruited; 72% male. Twenty-five patients (69.4%) had p16-positive disease. Two year mucosal and local nodal control rates were 97.1% (95% confidence interval 91.4–100) and 89.8% (78.4–100), respectively. One mucosal primary was detected 7.3 months after TM-IMRT and three patients died from recurrent/metastatic squamous cell carcinoma of the head and neck. Twelve patients (33%) developed grade 3 (Late Effects in Normal Tissue-Subjective, Objective, Management and Analytical; LENT-SOMA) dysphagia with a 1 year enteric tube feeding rate of 2.7%. The high-grade subjective xerostomia rate (LENT-SOMA) at 24 months after IMRT was 15%. ConclusionsAt a median follow-up of 36.1 months, the use of TM-IMRT was associated with good local control. Toxicity was comparable with previously reported TM-IMRT regimens encompassing similar mucosal volumes.

Prognostic value of FDG-PET volumetric parameters in patients with p16-positive oropharyngeal squamous cell carcinoma who received curative resection followed by postoperative radiotherapy or chemoradiotherapy.

The purpose of this study was to determine whether pretreatment 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) volumetric parameters add more prognostic information to p16-positive oropharyngeal squamous cell carcinoma (SCC). We retrospectively analyzed 86 patients with p16-positive oropharyngeal SCC who underwent surgery and postoperative radiotherapy (RT) or chemoradiotherapy (CRT). Maximum standardized uptake value (SUVmax ), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were measured. Higher total MTV (tMTV), nodal MTV (nMTV), and tumor TLG (tTLG) were significantly associated with lower disease-free survival (DFS) (all p < .05) and higher distant metastasis rates (all p < .05). Multivariate analysis of DFS revealed that tMTV (p = .032), nMTV (p = .004), and tTLG (p = .018) were independently significant prognosticators. Patients with p16-positive disease with high metabolic tumor burden were associated with higher distant metastasis rates, translating into worse survival. These patients may not be optimal candidates for treatment deintensification. © 2016 Wiley Periodicals, Inc. Head Neck 38: First-1524, 2016.

Squamous Cell Cancer of an Unknown Primary Head and Neck Site: Is Upfront Neck Dissection Still Relevant in the Era of Chemoradiation?

(NPM) is commonly used but often results in incomplete pain control and is associated with its own side effects. Single-institution retrospective reports have provided evidence that prophylactic gabapentin (GP) may reduce the need for NPM in patients undergoing RT, however the ideal dosing schedule is unknown. The purpose of this study was to evaluate whether the use of 300 mg 3 times daily (TID) of GP in a community oncology center will result in reduced need for NPM or reduced weight loss (WL) in patients undergoing RT with or without chemotherapy for oropharyngeal cancer. Materials/Methods: We performed a retrospective chart review of all patients treated with RT for oropharyngeal cancer in our clinic over the last 33 months. From these data, we stratified patients by the use of GP and compared the amount of NPM, the time to initiation of NPM, and the amount of WL between patients who did and did not receive GP. Two-tailed t tests were used to determine significance with a for significance set at P .05. Results: From November 2012 through July 2015, 64 patients with oropharyngeal cancer completed their prescribed RT course and at least 1 month of post-RT follow-up at our institution. Thirty-one patients received GP (at least 300 mg TID) within the first 2 weeks of RT. Patients who received GP had less unintentional WL (9.03 vs 15.82 lbs, PZ.004) and initiated NPM later in their RT course (34.6 vs 22.3 days, P<.001). On subset analysis, patients who underwent upfront surgery and patients with p16-positive disease had less unintentional WL with the use of GP. Oropharyngeal subsite did not influence the effect of GP. No adverse effects were attributed to GP. Conclusion: Patients who initiated at least 300 mg TID of GP within the first 2 weeks of RT for oropharyngeal cancer experienced less WL and a longer time to initiation of NPM compared to those that did not initiate GP. These differences were independent of oropharyngeal subsite. No adverse effects were attributed to GP. Patients who underwent upfront surgery and patients with p16-positive disease derived the greatest benefit from the use of GP. These data support continued exploration of GP use in this patient population. Our institution intends to continue to explore the effect of higher GP dosing in future patients to elucidate potential dose-response relationships. Author Disclosure: T. Dong: None. A. Reed: None. G.C. Jones: None. D. Scoble: None. J. Deeken: None. G.K. Bajaj: None.

Hybrid Capture 2 human papillomavirus testing of fine needle aspiration cytology of head and neck squamous cell carcinomas.

Human papillomavirus (HPV) positive head and neck squamous cell carcinoma (HNSCC) accounts for 25% of HNSCCs and frequently presents with neck lymph node metastases. We investigated utilizing cytology needle rinse material for HPV DNA testing by Hybrid Capture 2 molecular testing (HC2) as an alternative to p16 immunohistochemistry. Twenty-two cases of HNSCC presenting with neck lymph node metastasis were prospectively identified by assessment of Diff Quik stained cytology smears. An aliquot of the needle rinse material from the lymph node was analyzed for HPV status using standard HC2 protocol. P16 status was determined with immunohistochemistry on the cell block and/or surgically obtained tumor. The mean age of patients with p16 negative HNSCC was 7 years older than p16 positive disease (Table ). Primary tumor subsites were as follows: 17 oropharynx, 1 hypophayrnx, 3 larynx, and 1 oral cavity (Table ). All ten p16 negative patients had a history of smoking compared with 33% of p16 positive. Only 3 (25%) of p16 positive tumors demonstrated keratinization, whereas 90% of the p16 negative tumors keratinized (Fig. 1). Twelve of 22 HNSCC cases (55%) were p16 positive, of which 7 (58%) tested positive for HPV by HC2. Ten cases (45%) were negative for p16, all of which were negative for HPV by HC2 (Table ). Molecular testing for HPV using HC2 on needle rinse material of FNA of HNSCC is a useful method of determining HPV status in HNSCC.

PO-115: Limited value of MRI for response evaluation of the neck after radiotherapy ñ especially in p16-positive disease

PO-115: Limited value of MRI for response evaluation of the neck after radiotherapy ñ especially in p16-positive disease

1018O - Safety and Efficacy of Cisplatin Plus 5-Fu and Cetuximab in HPV-Positive and HPV-Negative Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck (R/M SCCHN): Analysis of the Phase III Extreme Trial

ABSTRACT Background Tumor human papillomavirus (HPV) status is a strong predictor of survival and response to treatment in patients (pts) with early and locally advanced oropharyngeal cancer, but its effects in R/M SCCHN remain to be clarified. This retrospective analysis of data from the EXTREME trial assessed the role of tumor HPV status in pts with R/M SCCHN receiving cisplatin + 5-FU chemotherapy (CT) alone or in combination with cetuximab. Material and methods: Immunohistochemical detection of p16INK4A was used to determine HPV status: p16-positive and p16-negative disease is referred to as HPV-positive (HPV+) and HPV-negative (HPV-) disease, respectively. Results 196/222 (88%) pts in the CT + cetuximab and 185/220 (84%) pts in the CT arm had tissue evaluable for p16. Of these, 91% and 88%, respectively, had HPV- tumors. Among HPV- pts, CT + cetuximab (n = 178) improved overall survival (OS), progression-free survival (PFS) and overall response rate (ORR), compared with CT (n = 162) (Table). A similar pattern was observed among HPV+ pts, between CT + cetuximab (n = 18) and CT (n = 23) for OS, PFS and ORR. Interaction tests between treatment and HPV status for OS and PFS confirmed that the treatment effect of CT + cetuximab vs CT was independent of tumor HPV status (p = 0.482 and p = 0.430, respectively: no significant interaction was noted). Within the CT + cetuximab and CT arms, HPV (p16) expression is associated with a more favorable outcome than HPV- (Table). In the CT + cetuximab arm, the overall incidence of grade 3/4 adverse events was slightly higher among HPV+ than HPV- pts. Conclusions Although the number of HPV+ pts in this analysis was low, the results suggest that in R/M SCCHN pts in the EXTREME trial, the survival benefits ofCT + cetuximab vs CT are independent of tumor HPV status and HPV (p16) expression is associated with a more favorable outcome than HPV-. Table: 1018O: Tumor HPV status: effects on prognosis and efficacy of CT + cetuximab and CT in R/M SCCHN. Population Comparison OS PFS ORR CT + cetuximab vs CT HPV- (n = 340) Median (months)/rate (%) 9.7 7.3 5.7 3.1 37 17 HR/odds ratio 95% CI p 0.822 (0.647–1.043) 0.1064 0.486 (0.376–0.628) 2.753 (1.655–4.579) HPV+ (n = 41) Median (months)/rate (%) 12.6 9.6 5.6 3.6 50 22 HR/odds ratio 95% CI p 0.628 (0.295–1.338) 0.2241 0.730 (0.363–1.469) 0.3761 3.600 (0.929–13.953) 0.0614 HPV+ vs HPV- CT + cetuximab (n = 196) Median (months)/rate (%) 12.6 9.7 5.6 5.7 50 37 HR/odds ratio 95% CI p 0.592 (0.319–1.098) 0.0925 1.172 (0.685–2.005) 0.5624 1.738 (0.657–4.600) 0.2620 CT (n = 185) Median (months)/rate (%) 9.6 7.3 3.6 3.1 22 17 HR/odds ratio 95% CI p 0.827 (0.504–1.355) 0.4492 0.871 (0.529–1.434) 0.5870 1.329 (0.455–3.880) 0.6025 Data are medians and hazard ratios (HR) for PFS and OS and rates and odds ratios for ORR. p: log-rank test for OS/PFS; Cochran-Mantel-Haenszel test for ORR. Disclosure B. De Blas: The author is an employee of Merck KGaA. I. Celik: The author is an employee of Merck KGaA J.B. Vermorken: I have participated in advisory boards of Merck-Serono, Amgen, Boehringer-Ingelheim, Genentech and Sanofi-aventis and have lectured (compensated) for Merck-Serono, Amgen, Bristol-Myers Squibb and Sanofi-aventis All other authors have declared no conflicts of interest.

Prognostic significance of p16 in locoregionally advanced head and neck cancer treated with concurrent 5-fluorouracil, hydroxyurea, cetuximab and intensity-modulated radiation therapy

A phase II trial was conducted to evaluate the tolerability and efficacy of incorporating cetuximab and simultaneous integrated boost intensity-modulated radiation therapy (SIB-IMRT) into a well-described 5-fluorouracil (5-FU) and hydroxyurea (HU)-based chemoradiation regimen. Patients with stage IVa-IVb or high-risk stage III squamous cell carcinomas were enrolled. Prior organ-conserving surgery or induction chemotherapy was allowed. IMRT was administered in 1.5 Gy fractions twice daily on days 1-5 of weeks 1, 3, 5, 7±9 for a total dose of 60-73.5 Gy. Concurrent systemic therapy consisted of 5-FU (600 mg/m2), HU (500 mg BID) and cetuximab (250 mg/m2). p16INK4A expression was assessed by immunohistochemistry. From January 2007 to January 2010, 65 patients (61 with stage IV disease; 31 with oropharyngeal primaries) were enrolled. At a median follow-up of 28 months, 2-year locoregional control, distant control, progression-free survival, event-free survival and overall survival were 79, 83, 72, 63 and 80%, respectively. In 48 patients with available pre-treatment tissue, p16 overexpression was associated with significantly increased distant control (p=0.03), progression-free survival (p=0.02), event-free survival (p=0.007) and overall survival (p=0.03). The most common grade 3-4 toxicities were mucositis (46%), leukopenia (18%), anemia (18%) and dermatitis (17%). Concurrent 5-FU, HU, cetuximab and SIB-IMRT is a highly active regimen, particularly in patients with p16-positive disease.