Amygdalar activity measured using FDG-PET/CT at head and neck cancer staging independently predicts survival.

IMPORTANCE: The mechanisms underlying the association between chronic stress and higher mortality among individuals with cancer remain incompletely understood. OBJECTIVE: To test the hypotheses that among individuals with active head and neck cancer, that higher stress-associated neural activity (ie. metabolic amygdalar activity [AmygA]) at cancer staging associates with survival. DESIGN: Retrospective cohort study. SETTING: Academic Medical Center (Massachusetts General Hospital, Boston). PARTICIPANTS: 240 patients with head and neck cancer (HNCA) who underwent 18F-FDG-PET/CT imaging as part of initial cancer staging. MEASUREMENTS: 18F-FDG uptake in the amygdala was determined by placing circular regions of interest in the right and left amygdalae and measuring the mean tracer accumulation (i.e., standardized uptake value [SUV]) in each region of interest. Amygdalar uptake was corrected for background cerebral activity (mean temporal lobe SUV). RESULTS: Among individuals with HNCA (age 59±13 years; 30% female), 67 died over a median follow-up period of 3 years (IQR: 1.7-5.1). AmygA associated with heightened bone marrow activity, leukocytosis, and C-reactive protein (P<0.05 each). In adjusted and unadjusted analyses, AmygA associated with subsequent mortality (HR [95% CI]: 1.35, [1.07-1.70], P = 0.009); the association persisted in stratified subset analyses restricted to patients with advanced cancer stage (P<0.001). Individuals within the highest tertile of AmygA experienced a 2-fold higher mortality rate compared to others (P = 0.01). The median progression-free survival was 25 months in patients with higher AmygA (upper tertile) as compared with 36.5 months in other individuals (HR for progression or death [95%CI], 1.83 [1.24-2.68], P = 0.001). CONCLUSIONS AND RELEVANCE: AmygA, quantified on routine 18F-FDG-PET/CT images obtained at cancer staging, independently and robustly predicts mortality and cancer progression among patients with HNCA. Future studies should test whether strategies that attenuate AmygA (or its downstream biological consequences) may improve cancer survival.

Double trouble: Synchronous and metachronous primaries confound ctHPVDNA monitoring.

BACKGROUND: Human papillomavirus-associated head and neck squamous cell carcinoma (HPV + HNSCC) occurs in the oropharynx (HPV + OPSCC), sinonasal cavity (HPV + SNSCC), and nasopharynx (HPV + NPC). Circulating tumor HPV DNA (ctHPVDNA) is an accurate tool for diagnosis, treatment monitoring, and recurrence detection. An emerging challenge with ctHPVDNA is that ~7.4% of HPV + HNSCC patients develop synchronous or metachronous HPV+ primaries, which could confound ctHPVDNA monitoring. METHODS: We describe a 65-year-old patient with T2N1M0 HPV16 + OPSCC and a 55-year-old patient with T2N2M0 HPV16 + OPSCC. Both patients were enrolled in our prospective observational ctHPVDNA study with longitudinal blood collections throughout treatment. Both patients developed multiple HPV+ primaries. RESULTS: Detailed discussion of the patients' treatment courses, the subsequent diagnoses of their second HPV+ primaries, and their ctHPVDNA monitoring is presented. CONCLUSIONS: As ctHPVDNA use becomes more prevalent, it is important to recognize that an increase in ctHPVDNA can come not only from the primary tumor or metastatic clones, but also from synchronous or metachronous second primaries.

Large anatomical changes in head-and-neck cancers - A dosimetric comparison of online and offline adaptive proton therapy.

Purpose: This work evaluates an online adaptive (OA) workflow for head-and-neck (H&N) intensity-modulated proton therapy (IMPT) and compares it with full offline replanning (FOR) in patients with large anatomical changes. Methods: IMPT treatment plans are created retrospectively for a cohort of eight H&N cancer patients that previously required replanning during the course of treatment due to large anatomical changes. Daily cone-beam CTs (CBCT) are acquired and corrected for scatter, resulting in 253 analyzed fractions. To simulate the FOR workflow, nominal plans are created on the planning-CT and delivered until a repeated-CT is acquired; at this point, a new plan is created on the repeated-CT. To simulate the OA workflow, nominal plans are created on the planning-CT and adapted at each fraction using a simple beamlet weight-tuning technique. Dose distributions are calculated on the CBCTs with Monte Carlo for both delivery methods. The total treatment dose is accumulated on the planning-CT. Results: Daily OA improved target coverage compared to FOR despite using smaller target margins. In the high-risk CTV, the median D98 degradation was 1.1 % and 2.1 % for OA and FOR, respectively. In the low-risk CTV, the same metrics yield 1.3 % and 5.2 % for OA and FOR, respectively. Smaller setup margins of OA reduced the dose to all OARs, which was most relevant for the parotid glands. Conclusion: Daily OA can maintain prescription doses and constraints over the course of fractionated treatment, even in cases of large anatomical changes, reducing the necessity for manual replanning in H&N IMPT.

The Prediction of Cardiac Events Using Contemporary Risk Prediction Models after Radiation Therapy for Head and Neck Cancer.

This study aims to evaluate the efficacy of the Pooled Cohort Equation (PCE), U.S. Preventative Services Task Force (USPSTF), and Framingham Risk Score (FRS) models in predicting ASCVD events among patients receiving radiation therapy (RT) for head and neck cancer (HNCA). From a large cohort of HNCA patients treated with RT, ASCVD events were adjudicated. Observed vs. predicted ASCVD events were compared. We compared rates by statin eligibility status. Regression models and survival analysis were used to identify the relationship between predicted risk and post-RT outcomes. Among the 723 identified patients, 274 (38%) were statin-eligible based on USPSTF criteria, 359 (49%) based on PCE, and 234 (32%) based on FRS. During follow-up, 17% developed an ASCVD, with an event rate of 27 per 1000 person-years, 68% higher than predicted (RR 1.68 (95% CI: 1.02, 2.12), p < 0.001). In multivariable regression, there was no difference in event rates by statin eligibility status (p > 0.05). Post-RT, the observed event rate was higher than the predicted ASCVD risk across all grades of predicted risk (p < 0.05) and the observed risk of an ASCVD event was high even among patients predicted to have a low risk of ASCVD. In conclusion, current ASCVD risk calculators significantly underestimate the risk for ASCVD among patients receiving RT for HNCA.

Unusual presentation of HPV-positive squamous cell carcinoma of the nasolacrimal duct as carcinoma of unknown primary.

Most human papillomavirus (HPV)-positive carcinomas of unknown primary (CUP) in the cervical lymph nodes are ultimately found to arise from the oropharynx, which has by far the highest prevalence of HPV-positivity among head and neck tumors. However, HPV is also detected in a subset of tumors from other sites. In this case report, we describe the first reported instance of a lacrimal sac carcinoma presenting as an HPV-positive CUP. A 64-year-old male presented with isolated right-sided neck swelling, found on core biopsy to be HPV-positive squamous cell carcinoma (SCC). Initial diagnostic workup did not reveal a primary site, and he was treated for T0N1M0 oropharyngeal SCC with chemoradiation. Shortly afterwards he developed epiphora and was found to have an FDG-avid lesion along his inferior right orbit. Biopsy revealed HPV-positive SCC, presumed to be the true primary site of his previously diagnosed CUP. He was treated with surgical resection, proton-beam radiation, and carboplatin-paclitaxel. He had an excellent outcome with no evidence of disease 18 months following treatment completion. This case underscores the importance of continued vigilance and thorough investigation for a primary tumor site even when cervical nodal metastases are HPV-positive. While the vast majority of HPV-positive head and neck tumors arise in the oropharynx, other anatomical sites may also harbor HPV-positive malignancies.

Cell-free human papillomavirus DNA kinetics after surgery for human papillomavirus-associated oropharyngeal cancer.

BACKGROUND: New ultrasensitive methods for detecting residual disease after surgery are needed in human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV+OPSCC). METHODS: To determine whether the clearance kinetics of circulating tumor human papillomavirus DNA (ctHPVDNA) is associated with postoperative disease status, a prospective observational study was conducted in 33 patients with HPV+OPSCC undergoing surgery. Blood was collected before surgery, postoperative days 1 (POD 1), 7, and 30 and with follow-up. A subcohort of 12 patients underwent frequent blood collections in the first 24 hours after surgery to define early clearance kinetics. Plasma was run on custom droplet digital polymerase chain reaction (ddPCR) assays for HPV genotypes 16, 18, 33, 35, and 45. RESULTS: In patients without pathologic risk factors for recurrence who were observed after surgery, ctHPVDNA rapidly decreased to <1 copy/mL by POD 1 (n = 8/8). In patients with risk factors for macroscopic residual disease, ctHPVDNA was markedly elevated on POD 1 (>350 copies/mL) and remained elevated until adjuvant treatment (n = 3/3). Patients with intermediate POD 1 ctHPVDNA levels (1.2-58.4 copies/mL) all possessed pathologic risk factors for microscopic residual disease (n = 9/9). POD 1 ctHPVDNA levels were higher in patients with known adverse pathologic risk factors such as extranodal extension >1 mm (P = .0481) and with increasing lymph nodes involved (P = .0453) and were further associated with adjuvant treatment received (P = .0076). One of 33 patients had a recurrence that was detected by ctHPVDNA 2 months earlier than clinical detection. CONCLUSIONS: POD 1 ctHPVDNA levels are associated with the risk of residual disease in patients with HPV+OPSCC undergoing curative intent surgery and thus could be used as a personalized biomarker for selecting adjuvant treatment in the future. LAY SUMMARY: Human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV+OPSCC) is increasing at epidemic proportions and is commonly treated with surgery. This report describes results from a study examining the clearance kinetics of circulating tumor HPV DNA (circulating tumor human papillomavirus DNA [ctHPVDNA]) following surgical treatment of HPV+OPSCC. We found that ctHPVDNA levels 1 day after surgery are associated with the risk of residual disease in patients with HPV+OPSCC and thus could be used as a personalized biomarker for selecting adjuvant treatment in the future. These findings are the first to demonstrate the potential utility of ctHPVDNA in patients with HPV+OPSCC undergoing surgery.

Visualizing dynamic changes in PD-L1 expression in non-small cell lung carcinoma with radiolabeled recombinant human PD-1.

PURPOSE: Tumor heterogeneity limits the predictive value of PD-L1 expression and influences the outcomes of the immunohistochemical assay for therapy-induced changes in PD-L1 levels. This study aimed to determine the predictive value of PD-L1 for non-small cell lung carcinoma (NSCLC), thereby developing imaging agents to non-invasively image and examine the effect of the therapeutic response to PD-L1 blockade therapy. METHODS: A cohort of 102 patients with lung cancer was analyzed, and the prognostic significance of PD-L1 expression level was investigated. Recombinant human PD-1 ECD protein (rhPD1) was expressed, purified, and labeled with 64Cu for the evaluation of PD-L1 status in tumors. Mice subcutaneously bearing PD-L1 high-expressing tumor HCC827 and PD-L1 low-expressing tumor A549 were used to determine tracer-target specificity and examine the effect of therapeutic response to PD-L1 blockade therapy. RESULTS: PD-L1 was proved to be a good prognosis marker for NSCLC, and its expression was correlated with the histology of NSCLC. PET imaging revealed high tumor accumulation of 64Cu-NOTA-rhPD1 in HCC827 tumors (9.0 ± 0.5%ID/g), whereas it was 3.2 ± 0.4%ID/g in A549 tumors at 3 h post-injection. The lower tumor uptake (3.1 ± 0.3%ID/g) of 64Cu-labeled denatured rhPD1 in HCC827 tumors at 3 h post-injection (p < 0.001) demonstrated the target specificity of 64Cu-NOTA-rhPD1. Furthermore, PET showed that 64Cu-NOTA-rhPD1 sensitively monitored treatment-related changes in PD-L1 expression, and seemed to be superior to [18F]FDG. CONCLUSION: We identified PD-L1 as a good prognosis marker for surgically resected NSCLC and developed the PET tracer 64Cu-NOTA-rhPD1 with high target specificity for PD-L1.

Cell-Free HPV DNA Provides an Accurate and Rapid Diagnosis of HPV-Associated Head and Neck Cancer.

PURPOSE: HPV-associated head and neck squamous cell carcinoma (HPV+HNSCC) is the most common HPV-associated malignancy in the United States and continues to increase in incidence. Current diagnostic approaches for HPV+HNSCC rely on tissue biopsy followed by histomorphologic assessment and detection of HPV indirectly by p16 IHC. Such approaches are invasive and have variable sensitivity. EXPERIMENTAL DESIGN: We conducted a prospective observational study in 140 subjects (70 cases and 70 controls) to test the hypothesis that a noninvasive diagnostic approach for HPV+HNSCC would have improved diagnostic accuracy, lower cost, and shorter diagnostic interval compared with standard approaches. Blood was collected, processed for circulating tumor HPV DNA (ctHPVDNA), and analyzed with custom ddPCR assays for HPV genotypes 16, 18, 33, 35, and 45. Diagnostic performance, cost, and diagnostic interval were calculated for standard clinical workup and compared with a noninvasive approach using ctHPVDNA combined with cross-sectional imaging and physical examination findings. RESULTS: Sensitivity and specificity of ctHPVDNA for detecting HPV+HNSCC were 98.4% and 98.6%, respectively. Sensitivity and specificity of a composite noninvasive diagnostic using ctHPVDNA and imaging/physical examination were 95.1% and 98.6%, respectively. Diagnostic accuracy of this noninvasive approach was significantly higher than standard of care (Youden index 0.937 vs. 0.707, P = 0.0006). Costs of noninvasive diagnostic were 36% to 38% less than standard clinical workup and the median diagnostic interval was 26 days less. CONCLUSIONS: A noninvasive diagnostic approach for HPV+HNSCC demonstrated improved accuracy, reduced cost, and a shorter time to diagnosis compared with standard clinical workup and could be a viable alternative in the future.

Brain-Specific Relative Biological Effectiveness of Protons Based on Long-term Outcome of Patients With Nasopharyngeal Carcinoma.

PURPOSE: Uncertainties in relative biological effectiveness (RBE) constitute a major pitfall of the use of protons in clinics. An RBE value of 1.1, which is based on cell culture and animal models, is currently used in clinical proton planning. The purpose of this study was to determine RBE for temporal lobe radiographic changes using long-term follow-up data from patients with nasopharyngeal carcinoma. METHODS AND MATERIALS: Five hundred sixty-six patients with newly diagnosed nasopharyngeal carcinoma received double-scattering proton therapy or intensity modulated radiation therapy at our institutions. The 2 treatment cohorts were well matched. Proton dose distributions were simulated using Monte Carlo and compared with those obtained from the proton clinical treatment planning system. Late treatment effect was defined as development of enhancement of temporal lobe on T1-weighted magnetic resonance imaging, with or without accompanying clinical symptoms. The tolerance dose was calculated with receiving operator characteristic analysis and the Youden index. Tolerance curves, expressed as a cumulative dose-volume histogram, were generated using the cutoff points. RESULTS: With a median follow-up period >5 years for both cohorts, 10% of proton patients and 4% of patients undergoing intensity modulated radiation therapy developed temporal lobe enhancement in unilateral temporal lobe. There was no significant difference in dose distributions between the Monte Carlo method and treatment planning system. The tolerance dose-volume levels were V10 (26.1%), V20 (21.9%), V30 (14.0%), V40 (7.7%), V50 (4.8%), and V60 (3.3%) for proton therapy (P < .03). Comparison of the two tolerance curves revealed that tolerance doses of proton treatments were lower than that of photon treatments at all dose levels. The dose tolerance at D1% was 58.56 Gy for protons and 69.07 Gy for photons. The RBE for temporal lobe enhancement from proton treatments were calculated to be 1.18. CONCLUSIONS: Using long-term clinical outcome of patients with nasopharyngeal carcinoma, our data suggest that the RBE for temporal lobe enhancement is 1.18 at D1%. A prospective study in a large cohort would be necessary to confirm these findings.

Individualization of Clinical Target Volume Delineation Based on Stepwise Spread of Nasopharyngeal Carcinoma: Outcome of More Than a Decade of Clinical Experience.

PURPOSE: Radiation-related toxicity in nasopharyngeal carcinoma (NPC) is common. There are no well-established guidelines for clinical target volume (CTV) delineation with long-term follow-up. Current consensus continues to rely heavily on bony landmarks and fixed margins around the gross tumor volume (GTV), an approach used to define fields in the conventional 2- and 3-dimensional radiation therapy era. METHODS AND MATERIALS: We retrospectively evaluated patients with newly diagnosed nonmetastatic NPC treated with definitive radiation therapy using a technique of CTV delineation based on individual tumor extent and the orderly stepwise pattern of tumor spread. Dosimetric comparisons were made between national protocol HN001 and our contouring strategies on a representative early- and advanced-stage NPC. The primary endpoints were patterns of failure and local control; secondary endpoints included regional control and survival, estimated using the Kaplan-Meier method. RESULTS: Between 1999 and 2013, 73 patients (88% with stage 3-4 disease) were treated with median follow-up of 90 months for surviving patients. Median dose to GTV was 70 Gy. Four patients developed local recurrence and 1 patient developed regional recurrence. All locoregional recurrences occurred within the high-dose GTV. The 5-year local control, regional control, and overall survival was 94% (95% confidence interval [CI], 85%-98%), 99% (95% CI, 90%-100%), and 84% (95% CI, 73%-91%), respectively. Compared with HN001, our contouring strategy resulted in 62% and 36% reduction in CTV for T1 and T4 disease, respectively. In the T1 tumor, the reduction of doses to the contralateral parotid, optic nerve, and cochlea were 54%, 50%, 34% respectively. In the T4 case, there was a decrease of optic chiasm dose of 46% and contralateral optic nerve of 37%. There were 10 grade 3 toxicities. There was no grade 2 or higher xerostomia and no grade 4/5 toxicity. CONCLUSIONS: Our long-term experience with individualized CTV delineation based on stepwise patterns of spread results in excellent local control, with no recurrence outside the GTV.

Impact of aeration change and beam arrangement on the robustness of proton plans.

This study determines the impact of change in aeration in sinonasal cavities on the robustness of passive-scattering proton therapy plans in patients with sinonasal and nasopharyngeal malignancies. Fourteen patients, each with one planning CT and one CT acquired during radiotherapy were studied. Repeat and planning CTs were rigidly aligned and contours were transferred using deformable registration. The amount of air, tumor, and fluid within the cavity containing the tumor were measured on both CTs. The original plans were recalculated on the repeat CT. Dosimetric changes were measured for the targets and critical structures. Median decrease in gross tumor volume (GTV) was 19.8% and correlated with the time of rescan. The median change in air content was 7.1% and correlated with the tumor shrinkage. The median of the mean dose Dmean change was +0.4% for GTV and +0.3% for clinical target volume. Median change in the maximum dose Dmax of the critical structures were as follows: optic chiasm +0.66%, left optic nerve +0.12%, right optic nerve +0.38%, brainstem +0.6%. The dose to the GTV decreased by more than 5% in 1 case, and the dose to critical structure(s) increased by more than 5% in three cases. These four patients had sinonasal cancers and were treated with anterior proton fields that directly transversed through the involved sinus cavities. The change in dose in the replanning was strongly correlated with the change in aeration (P = 0.02). We found that the change in aeration in the vicinity of the target and the arrangement of proton beams affected the robustness of proton plan.

Association of Estrogen Receptor Alpha Expression With Survival in Oropharyngeal Cancer Following Chemoradiation Therapy.

BACKGROUND: Oropharyngeal squamous carcinoma (OPSC) continues to increase in incidence secondary to human papillomavirus (HPV) infection. Despite the good overall prognosis for these patients, treatment with chemoradiation is associated with morbidity and treatment failure. Better predictors for disease outcome are needed to guide de-intensification regimens. We hypothesized that estrogen receptor α (ERα), a prognostic biomarker in oncology with therapeutic implications, might have similar utility in OPSC. METHODS: To investigate associations among ERα and demographics, HPV status, and survival, we analyzed ERα mRNA expression of head and neck squamous carcinomas (HNSC) from The Cancer Genome Atlas (TCGA) and immunohistochemistry (IHC) of pretreatment biopsy specimens from an independent group of 215 OPSC patients subsequently treated with primary chemoradiation (OPSC-CR). Associations among variables were evaluated with Fisher exact tests and logistic regression; associations with survival were evaluated with log-rank tests and Cox proportional hazards regression. RESULTS: Among 515 patients in TCGA, ERα mRNA expression was highest in HPV-positive OPSC. High ERα mRNA expression was associated with improved survival among those receiving chemoradiation (hazard ratio adjusted for HPV status = 0.44, 95% confidence interval = 0.21 to 0.92). In OPSC-CR, ERα was positive by IHC in 51.6% of tumors and was associated with improved overall, disease-specific, progression-free, and relapse-free survival (log-rank tests: P < .001, P < .001, P = .002, P = .003, respectively); statistically significant associations of ERα positivity with improved survival were maintained after adjusting for clinical risk factors including HPV status. CONCLUSION: In two independent cohorts, ERα is a potential biomarker for improved survival that also may represent a therapeutic target in OPSC.

Incidental Statin Use and the Risk of Stroke or Transient Ischemic Attack after Radiotherapy for Head and Neck Cancer.

BACKGROUND AND PURPOSE: Interventions to reduce the risk for cerebrovascular events (CVE; stroke and transient ischemic attack [TIA]) after radiotherapy (RT) for head and neck cancer (HNCA) are needed. Among broad populations, statins reduce CVEs; however, whether statins reduce CVEs after RT for HNCA is unclear. Therefore, we aimed to test whether incidental statin use at the time of RT is associated with a lower rate of CVEs after RT for HNCA. METHODS: From an institutional database we identified all consecutive subjects treated with neck RT from 2002 to 2012 for HNCA. Data collection and event adjudication was performed by blinded teams. The primary outcome was a composite of ischemic stroke and TIA. The secondary outcome was ischemic stroke. The association between statin use and events was determined using Cox proportional hazard models after adjustment for traditional and RT-specific risk factors. RESULTS: The final cohort consisted of 1,011 patients (59±13 years, 30% female, 44% hypertension) with 288 (28%) on statins. Over a median follow-up of 3.4 years (interquartile range, 0.1 to 14) there were 102 CVEs (89 ischemic strokes and 13 TIAs) with 17 in statin users versus 85 in nonstatins users. In a multivariable model containing known predictors of CVE, statins were associated with a reduction in the combination of stroke and TIA (hazard ratio [HR], 0.4; 95% confidence interval [CI], 0.2 to 0.8; P=0.01) and ischemic stroke alone (HR, 0.4; 95% CI, 0.2 to 0.8; P=0.01). CONCLUSIONS: Incidental statin use at the time of RT for HNCA is associated with a lower risk of stroke or TIA.

Human Papillomavirus Status and the Risk of Cerebrovascular Events Following Radiation Therapy for Head and Neck Cancer.

BACKGROUND: Radiation therapy (RT) is a standard treatment for head and neck cancer; however, it is associated with inflammation, accelerated atherosclerosis, and cerebrovascular events (CVEs; stroke or transient ischemic attack). Human papillomavirus (HPV) is found in nearly half of head and neck cancers and is associated with inflammation and atherosclerosis. Whether HPV confers an increased risk of CVEs after RT is unknown. METHODS AND RESULTS: Using an institutional database, we identified all consecutive patients treated with RT from 2002 to 2012 for head and neck cancer who were tested for HPV. The outcome of interest was the composite of ischemic stroke and transient ischemic attack, and the association between HPV and CVEs was assessed using Cox proportional hazard models, competing risk analysis, and inverse probability weighting. Overall, 326 participants who underwent RT for head and neck cancer were tested for HPV (age 59±12 years, 75% were male, 9% had diabetes mellitus, 45% had hypertension, and 61% were smokers), of which 191 (59%) were tumor HPV positive. Traditional risk factors for CVEs were similar between HPV-positive and -negative patients. Over a median follow-up of 3.4 years, there were 18 ischemic strokes and 5 transient ischemic attacks (event rate of 1.8% per year). The annual event rate was higher in the HPV-positive patients compared with the HPV-negative patients (2.6% versus 0.9%, P=0.002). In a multivariable model, HPV-positive status was associated with a >4 times increased risk of CVEs (hazard ratio: 4.4; 95% confidence interval, 1.5-13.2; P=0.008). CONCLUSIONS: In this study, HPV-positive status is associated with an increased risk of stroke or transient ischemic attack following RT for head and neck cancer.