Jacqueline R. Kelly

Treatment de-intensification strategies for head and neck cancer

Increasingly, squamous cell carcinoma of the oropharynx (OPSCC) is attributable to transformation resulting from high-risk human papillomavirus (HPV) infection. Such cancers are significantly more responsive to treatment than traditional tobacco- and alcohol-associated squamous cell cancers of the head and neck. Conventional management with definitive chemoradiation, surgery and adjuvant radiation, or radiation given with altered fractionation schemes, while effective, incurs long-term morbidity that escalates with treatment intensity and significantly impairs quality of life. Recent trials have suggested that less intensive treatment regimens may achieve similar efficacy with decreased toxicity. In this article, we review the primary strategies used for de-escalation of treatment, which include the reduction of radiation dose, substitution and/or elimination of concurrent radiosensitising chemotherapy, and the use of minimally invasive surgery. We discuss the rationale behind these approaches and the preliminary data demonstrating the success of de-escalation, as well as potential considerations raised by treatment de-intensification in HPV-associated OPSCC.

The prognostic value of extranodal extension in human papillomavirus-associated oropharyngeal squamous cell carcinoma

Extranodal (or extracapsular) extension (ENE) is an adverse prognostic factor in patients with head and neck cancers who undergo primary surgery. However, the significance of ENE in human papillomavirus (HPV)‐positive oropharyngeal squamous cell carcinoma (OPSCC) is not well established, and single‐institution studies have not established that ENE predicts inferior outcome. The authors investigated the prognostic value of ENE in HPV‐positive patients who underwent primary surgery and whether adjuvant chemoradiation improved overall survival (OS) compared with radiation alone in ENE‐positive patients.

Adjuvant chemotherapy and overall survival in adult medulloblastoma

Background Although chemotherapy is used routinely in pediatric medulloblastoma (MB) patients, its benefit for adult MB is unclear. We evaluated the survival impact of adjuvant chemotherapy in adult MB. Methods Using the National Cancer Data Base, we identified patients aged 18 years and older who were diagnosed with MB in 2004-2012 and underwent surgical resection and adjuvant craniospinal irradiation (CSI). Patients were divided into those who received adjuvant CSI and chemotherapy (CRT) or CSI alone (RT). Predictors of CRT compared with RT were evaluated with univariable and multivariable logistic regression. Survival analysis was limited to patients receiving CSI doses between 23 and 36 Gy. Overall survival (OS) was evaluated using the Kaplan-Meier estimator, log-rank test, multivariable Cox proportional hazards modeling, and propensity score matching. Results Of the 751 patients included, 520 (69.2%) received CRT, and 231 (30.8%) received RT. With median follow-up of 5.0 years, estimated 5-year OS was superior in patients receiving CRT versus RT (86.1% vs 71.6%, P < .0001). On multivariable analysis, after controlling for risk factors, CRT was associated with superior OS compared with RT (HR: 0.53; 95%CI: 0.32-0.88, P = .01). On planned subgroup analyses, the 5 year OS of patients receiving CRT versus RT was improved for M0 patients (P < .0001), for patients receiving 36 Gy CSI (P = .0007), and for M0 patients receiving 36 Gy CSI (P = .0008). Conclusions This national database analysis demonstrates that combined postoperative chemotherapy and radiotherapy are associated with superior survival for adult MB compared with radiotherapy alone, even for M0 patients who receive high-dose CSI.

Comparison of Survival Outcomes Among Human Papillomavirus-Negative cT1-2 N1-2b Patients With Oropharyngeal Squamous Cell Cancer Treated With Upfront Surgery vs Definitive Chemoradiation Therapy: An Observational Study.

Importance Human papillomavirus (HPV)-negative oropharyngeal squamous cell carcinoma (OPSCC) has shown resistance to conventional concurrent chemoradiation (CRT) therapy and carries a relatively poor prognosis in comparison with HPV-positive disease, with decreased locoregional control and overall survival (OS). In the present analysis, we examine whether upfront surgical resection improves overall survival in a large national sample. Objective To compare survival outcomes among patients with newly diagnosed cT1-2 N1-2b HPV-negative OPSCC when treated with primary surgical resection vs CRT. Design, Setting, and Participants This was an observational study of factors associated with primary treatment modality were identified using multivariable logistic regression. Overall survival was compared using Kaplan-Meier analysis with log-rank tests, multivariable Cox regression, and propensity score matching. Statistical tests were 2-sided. Patients newly diagnosed as having cT1-2 N1-2b pathologically confirmed HPV-negative OPSCC in 2010 to 2012 were identified using the National Cancer Data Base, which includes more than 70% of patients newly diagnosed as having cancer in the United States. Exposures Primary surgical resection vs definitive CRT. Main Outcomes and Measures Overall survival. Results We identified 1044 patients, among whom 460 (44.1%) received upfront surgery and 584 (55.9%) received CRT. Median age was 59 years (range, 25-90 years); 812 patients were male (77.8%), 232 were female (22.2%). Median follow-up was 30 months. Approximately 59% of surgical patients received adjuvant CRT. On multivariable Cox regression, upfront surgery was not associated with increased OS when compared with CRT (adjusted hazard ratio [HR], 1.01; 95% CI, 0.74-1.39; P = .93). Propensity score-matching identified a cohort of 822 patients and redemonstrated equivalent OS (HR, 1.14; 95% CI, 0.81-1.62; P = .46). Lack of OS benefit with upfront surgery persisted in a subset analysis of patients with margin-negative resection (HR, 0.97; 95% CI, 0.66-1.45; P = .88). Conclusions and Relevance In this observational study, OS was similar for patients with HPV-negative OPSCC when treated with primary surgery vs CRT. Most surgical patients received trimodal therapy with adjuvant CRT. Our data may have implications for future research focusing on optimal patient selection for surgery.

Brachytherapy Boost Utilization and Survival in Unfavorable-risk Prostate Cancer

BACKGROUND There are limited comparative survival data for prostate cancer (PCa) patients managed with a low-dose rate brachytherapy (LDR-B) boost and dose-escalated external-beam radiotherapy (DE-EBRT) alone. OBJECTIVE To compare overall survival (OS) for men with unfavorable PCa between LDR-B and DE-EBRT groups. DESIGN, SETTING, AND PARTICIPANTS Using the National Cancer Data Base, we identified men with unfavorable PCa treated between 2004 and 2012 with androgen suppression (AS) and either EBRT followed by LDR-B or DE-EBRT (75.6-86.4Gy). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Treatment selection was evaluated using logistic regression and annual percentage proportions. OS was analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards, and propensity score matching. RESULTS AND LIMITATION We identified 25038 men between 2004 and 2012, during which LDR-B boost utilization decreased from 29% to 14%. LDR-B was associated with better OS on univariate (7-yr OS: 82% vs 73%; p<0.001) and multivariate analyses (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.64-0.77). Propensity score matching verified an OS benefit associated with LDR-B boost (HR 0.74, 95% CI 0.66-0.89). The OS benefit of LDR-B boost persisted when limited to men aged <60 yr with no comorbidities. On subset analysis, there was no interaction between treatment and age, risk group, or radiation dose. Limitations include the retrospective design, nonrandomized selection bias, and the absence of treatment toxicity, hormone duration, and cancer-specific outcomes. CONCLUSIONS Between 2004 and 2012, LDR-B boost utilization declined and was associated with better OS compared to DE-EBRT alone. LDR-B boost is probably the ideal treatment option for men with unfavorable PCa, pending long-term results of randomized trials. PATIENT SUMMARY We compared radiotherapy utilization and survival for prostate cancer (PCa) patients using a national database. We found that low-dose rate brachytherapy (LDR-B) boost, a method being used less frequently, was associated with better overall survival when compared to dose-escalated external-beam radiotherapy alone for men with unfavorable PCa. Randomized trials are needed to confirm that LDR-B boost is the ideal treatment.

The risk of level IB nodal involvement in oropharynx cancer: Guidance for submandibular gland sparing irradiation

PURPOSE Xerostomia remains a common side effect of head and neck irradiation. Conflicting data exist regarding the likelihood of level IB involvement for patients with oropharyngeal squamous cell cancer (OPSCC), and data are limited on this risk in patients with human papillomavirus-positive disease. This study examined surgically treated OPSCC to determine the risk of pathologic level IB nodal involvement and to identify a cohort of patients in whom ipsilateral level IB radiation therapy may be safely omitted. METHODS AND MATERIALS A total of 102 submandibular nodal dissections were identified (92 ipsilateral and 10 contralateral) in 92 patients from 2010 to 2016 in those undergoing primary surgical treatment and dissection of ipsilateral level IB lymph nodes. Radiographically positive cases were excluded. Retrospective chart review was used for data collection, and the rate of pathologic level IB involvement was determined. RESULTS The ipsilateral level IB nodal station had negative imaging and pathologically positive nodes at rates of 4.3% in OPSCC and 5.3% in human papillomavirus-positive OPSCC. Positive node burden in the ipsilateral neck at stations other than IB appeared to correlate with the risk of pathologic positive IB (pIB+) nodes: 50% of pathologically IB-negative patients had 2 or more positive nodes versus 75% of pIB+ patients who had 4 or more positive nodes. CONCLUSIONS Our data indicate a low risk of pathologic level IB involvement in early-stage OPSCC. High positive node burden in stations near level IB may be associated with a higher chance of pathologic level IB involvement.

Pretreatment Identification of Head and Neck Cancer Nodal Metastasis and Extranodal Extension Using Deep Learning Neural Networks

Identification of nodal metastasis and tumor extranodal extension (ENE) is crucial for head and neck cancer management, but currently only can be diagnosed via postoperative pathology. Pretreatment, radiographic identification of ENE, in particular, has proven extremely difficult for clinicians, but would be greatly influential in guiding patient management. Here, we show that a deep learning convolutional neural network can be trained to identify nodal metastasis and ENE with excellent performance that surpasses what human clinicians have historically achieved. We trained a 3-dimensional convolutional neural network using a dataset of 2,875 CT-segmented lymph node samples with correlating pathology labels, cross-validated and fine-tuned on 124 samples, and conducted testing on a blinded test set of 131 samples. On the blinded test set, the model predicted ENE and nodal metastasis each with area under the receiver operating characteristic curve (AUC) of 0.91 (95%CI: 0.85–0.97). The model has the potential for use as a clinical decision-making tool to help guide head and neck cancer patient management.

Incidence of Radiographically Occult Nodal Metastases in HPV+ Oropharyngeal Carcinoma: Implications for Reducing Elective Nodal Coverage

PURPOSE Initial deescalation studies for human papilloma virus (HPV)-positive driven oropharyngeal squamous cell carcinomas (HPV+ OPSCC) altered radiation therapy dose or the systemic agent used. Newer trials examine the disease control achieved with a reduced elective nodal field. We examined patterns of nodal involvement in patients with HPV+ OPSCC with a focus on implications for radiation field design for treatment deescalation. METHODS AND MATERIALS Records of patients with HPV+ OPSCC with preoperative imaging (computed tomography or fludeoxyglucose positron emission tomography/computed tomography) who underwent neck dissection without neoadjuvant therapy from 2010 to 2017 were retrospectively reviewed. The number and location of clinically positive lymph nodes on preoperative imaging were compared with those documented on pathology. These data were then used to establish the probability of missing nodal disease in 3 modified radiation field designs. RESULTS One hundred patients were included. The median time between imaging and surgery was 22 days. The most common clinical N stage was cN2a (35%), whereas the most common pathologic N stage was pN2b (45%). The median number of radiographically and pathologically involved nodes was 1 (range, 0-6) and 2 (range, 0-11), respectively. Forty-three percent of patients had more pathologically involved nodes than predicted on imaging, whereas 21% had pathologic involvement at an additional nodal level not predicted on imaging. Of the 21 patients with additional pathologically involved nodal levels, 14 had involvement of a directly adjacent station, 4 were patients with a cN0 hemineck with pathologically positive level II disease, and 3 had pathologic involvement of level 2 echelons removed from that predicted on imaging. CONCLUSION Our study suggests that radiation fields encompassing only clinically involved nodes or levels has an unacceptably high likelihood of missing subclinical disease. Alternatively, treating the first uninvolved echelon nodes in addition would cover pathologic sites of disease in 97% of patients. This approach merits further study in prospective trials.

Upfront surgery versus definitive chemoradiotherapy in patients with human Papillomavirus-associated oropharyngeal squamous cell cancer

OBJECTIVES Currently, human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV-A OPC) is managed with either primary surgery or definitive chemoradiotherapy (CRT), despite the lack of supporting randomized prospective data. We therefore assessed the outcomes of each treatment strategy using the National Cancer Database (NCDB). METHODS The NCDB was used to identify patients diagnosed with cT1 N2a-2b or cT2 N1-2b HPV-A OPC from 2010 to 2013 who underwent treatment with primary surgery or CRT. Demographic and clinicopathologic predictors of treatment were analyzed by the chi-square test and logistic regression. Overall survival (OS) was evaluated using multivariable Cox proportional hazard regression, Kaplan-Meier, log-rank test, and propensity score-matched analysis. RESULTS We identified 3063 patients; 1576 (51.5%) received CRT and 1487 (48.5%) underwent primary surgery. Median follow up was 32 months. 972 (65.4%) surgical patients received adjuvant CRT. On multivariable Cox regression, 3-year OS was comparable between surgery and CRT (hazard ratio [HR] 1.08, 95% confidence interval [CI] 0.83-1.41, P = 0.58). Inferior OS was significantly associated with increasing clinical T and N stage, older age, and non-private insurance. Propensity score-matching yielded a 2526 patient cohort and redemonstrated similar OS (HR, 1.09; 95% CI 0.81-1.47; P = 0.55). Comparable outcomes persisted in a subset analysis of patients with margin-negative resection, with 3-year OS 90.8% in CRT patients vs. 93.6% in surgery patients (log-rank P = 0.27). CONCLUSIONS Upfront surgery and CRT yielded comparable 3-year OS outcomes in this cohort. In this national sample, 65.4% of surgical patients received trimodal therapy with adjuvant CRT, highlighting the need for improved patient selection for primary surgery.

Patterns of failure in high-metastatic node number human papillomavirus-positive oropharyngeal carcinoma

BACKGROUND The 8th edition American Joint Committee on Cancer staging system for resected HPV-positive oropharynx carcinoma (HPV+ OPC) highlights high node number as a critical determinant of survival. We sought to characterize outcomes and patterns of failure in patients with high pathologically involved node number oropharynx cancer. METHODS We retrospectively identified 116 HPV+ OPC patients sequentially treated with neck dissection and either resection or intraoperative brachytherapy of the primary tumor between 2010 and 2016. External beam radiation was given based on the pathologic findings. Cox proportional hazards regression was used for multivariate analysis. RESULTS With a median follow-up of 27 months, the 3-year overall survival and progression free survival (PFS) were 89% and 81%, respectively. On multivariate analysis, ≥5 involved lymph nodes was significantly associated with worse PFS (hazard ratio 4.3, 95% confidence interval (CI) 1.5-12.0, P = 0.001). Rates of 3-year locoregional recurrence (LRR) in patients with ≤4 vs ≥5 were 6% and 22% (log-rank P = 0.12). Rates of 3-year distant metastases (DM) were 12% and 53% between ≤4 and ≥5 (log-rank P < 0.001). CONCLUSION Our findings confirm that patients with 5 or more involved lymph nodes appear to have substantially worsened rates of disease recurrence. While these patients appear to be at high risk of both LRR and DM, the predominant mechanism of failure is distant, and the rate of DM in this group was over 50%. Dedicated clinical trials in this patient population are warranted with a focus on mitigating the high DM rate.