Rethinking the 10-pack-year rule for favorable human papillomavirus-associated oropharynx carcinoma: A multi-institution analysis.

BACKGROUND: De-intensified treatment strategies for early human papillomavirus-positive (HPV+) oropharynx cancer (OPC) rely on selecting patients with an excellent prognosis. The criterion for enrollment in current de-intensification trials is ≤10 pack-years. More nuance to the pack-year criteria may expand enrollment, improve patient outcomes, and prevent overtreatment. It was hypothesized that patients with more than 10 pack-years may experience favorable outcomes if smoking cessation has been achieved. METHODS: From an institutional review board-approved database, patients with HPV+ oropharyngeal squamous carcinoma treated definitively with radiation with or without chemotherapy were retrospectively identified. Patients with a history of smoking who were eligible for national de-intensification trials were included (cT1-2N1-2b or T3N0-2b [American Joint Committee on Cancer, seventh edition]). Cox regression with penalized smoothing splines was used to evaluate nonlinear effects of cessation. Recursive partitioning analysis (RPA) was used to objectively search for relationships between the 2 colinear variables (pack-years and time since cessation). RESULTS: Among 330 patients meeting the inclusion criteria, 130 (40%) were never smokers, 139 (42%) were former smokers, and 61 (18%) were current smokers. With standard therapy, all former smokers achieved a progression-free survival (PFS) rate higher than 91%, regardless of pack-year exposure. Nonlinear Cox regression demonstrated that more recent cessation was associated with significantly worse PFS even among those with ≤20 pack-years. RPA demonstrated that only current smokers experienced a 2-year PFS rate lower than 91%; former smokers, regardless of pack-years, experienced a 2-year PFS rate higher than 91%. CONCLUSIONS: The 10-pack-year rule may not apply to all early HPV+ OPCs, particularly for former smokers. Future randomized de-intensification trials should consider a broader and more nuanced approach until the predictive role of smoking status is established.

Cost-effectiveness analysis of endocrine therapy alone versus partial-breast irradiation alone versus combined treatment for low-risk hormone-positive early-stage breast cancer in women aged 70 years or older.

PURPOSE: We performed a cost-effectiveness analysis of three strategies for the adjuvant treatment of early breast cancer in women age 70 years or older: an aromatase inhibitor (AI-alone) for 5 years, a 5-fraction course of accelerated partial-breast irradiation using intensity-modulated radiation therapy (APBI-alone), or their combination. METHODS: We constructed a patient-level Markov microsimulation from the societal perspective. Effectiveness data (local recurrence, distant metastases, survival), and toxicity data were obtained from randomized trials when possible. Costs of side effects were included. Costs were adjusted to 2019 US dollars and extracted from Medicare reimbursement data. Quality-adjusted life-years (QALY) were calculated using utilities extracted from the literature. RESULTS: The strategy of AI-alone ($12,637) was cheaper than both APBI-alone ($13,799) and combination therapy ($18,012) in the base case. All approaches resulted in similar QALY outcomes (AI-alone 7.775; APBI-alone 7.768; combination 7.807). In the base case, AI-alone was the cost-effective strategy and dominated APBI-alone, while combined therapy was not cost-effective when compared to AI-alone ($171,451/QALY) or APBI-alone ($107,932/QALY). In probabilistic sensitivity analyses, AI-alone was cost-effective at $100,000/QALY in 50% of trials, APBI-alone in 28% and the combination in 22%. Scenario analysis demonstrated that APBI-alone was more effective than AI-alone when AI compliance was lower than 26% at 5 years. CONCLUSIONS: Based on a Markov microsimulation analysis, both AI-alone and APBI-alone are appropriate options for patients 70 years or older with early breast cancer with small cost differences noted. A prospective trial comparing the approaches is warranted.

Increased pathologic upstaging with rising time to treatment initiation for head and neck cancer: A mechanism for increased mortality.

BACKGROUND: Time to treatment initiation (TTI) is increasing and is associated with worsening survival. In the current study, the authors sought to identify a mechanism for this relationship by assessing the effect of TTI on clinical-to-pathologic upstaging in patients with head and neck squamous cell carcinoma (HNSCC). METHODS: Using the National Cancer Data Base, the authors analyzed patients receiving definitive surgery for SCC of the oral cavity, oropharynx, larynx, and hypopharynx from 2005 through 2014. The primary outcome was T, N, or stage group upstaging, defined as higher pathologic stage than clinical stage. TTI was defined as the time between diagnosis and surgery. Multivariable logistic and Cox proportional hazards regression modeled upstaging and survival, respectively. RESULTS: Cohorts of 60,194 patients, 51,380 patients, and 52,980 patients, respectively, with complete T, N, and stage group data were included. N upstaging was most common (18.6%), followed by stage group (17.4%) and T (12.1%) upstaging; all types were predicted by TTI. Compared with a TTI of 1 to 6 days, TTIs as short as 7 to 13 days (odds ratio, 1.20; P = .038) or ≥ 70 days (odds ratio, 2.04; P < .001) were found to predict T upstaging, a finding that is consistent for N and stage group upstaging. Using restricted cubic splines, relative odds of T and stage group upstaging escalated to 2.25 and 1.93, respectively, at a TTI of 365 days. In survival analyses, T (hazard ratio [HR], 1.53), N (HR, 1.88), and stage group (HR, 1.69) upstaging all predicted mortality (P < .001), whereas TTI only predicted mortality after 70 days (HR, 1.11; P = .023). CONCLUSIONS: Tumor progression, measured by clinical-to-pathologic upstaging, increases mortality for patients with HNSCC experiencing treatment delays. Cancer 2018;124:1400-14. © 2018 American Cancer Society.

The risk of radiation necrosis following stereotactic radiosurgery with concurrent systemic therapies.

To investigate late toxicity among patients with newly-diagnosed brain metastases undergoing stereotactic radiosurgery (SRS) with concurrent systemic therapies with or without whole-brain radiation therapy (WBRT). Patients with newly-diagnosed brain metastasis who underwent SRS at a single tertiary-care institution from 1997 to 2015 were eligible for inclusion. The class and timing of all systemic therapies were collected for each patient. The primary outcome was the cumulative incidence of radiographic radiation necrosis (RN). Multivariable competing risks regression was used to adjust for confounding. During the study period, 1650 patients presented with 2843 intracranial metastases. Among these, 445 patients (27%) were treated with SRS and concurrent systemic therapy. Radiographic RN developed following treatment of 222 (8%) lesions, 120 (54%) of which were symptomatic. The 12-month cumulative incidences of RN among lesions treated with and without concurrent therapies were 6.6 and 5.3%, respectively (p = 0.14). Concurrent systemic therapy was associated with a significantly increased rate of RN among lesions treated with upfront SRS and WBRT (8.7 vs. 3.7%, p = 0.04). In particular, concurrent targeted therapies significantly increased the 12-month cumulative incidence of RN (8.8 vs. 5.3%, p < 0.01). Among these therapies, significantly increased rates of RN were observed with VEGFR tyrosine kinase inhibitors (TKIs) (14.3 vs. 6.6%, p = 0.04) and EGFR TKIs (15.6 vs. 6.0%, p = 0.04). Most classes of systemic therapies may be safely delivered concurrently with SRS in the management of newly-diagnosed brain metastases. However, the rate of radiographic RN is significantly increased with the addition of concurrent systemic therapies to SRS and WBRT.

Use of systemic therapy with definitive radiotherapy for elderly patients with head and neck cancer: A National Cancer Data Base analysis.

BACKGROUND: The purpose of this study was to investigate the use of systemic therapy along with definitive radiotherapy for elderly patients with head and neck cancer. METHODS: Patients who were 71 years old or older with stage III to IVB squamous cell carcinoma of the nasopharynx, oropharynx, larynx, or hypopharynx treated with definitive radiotherapy with or without systemic therapy were identified from the National Cancer Data Base. Patterns of systemic therapy use before or during definitive radiotherapy were investigated. The association between systemic therapy use and overall survival was investigated with a multivariate, inverse probability-weighted propensity score-adjusted Cox proportional hazards model. RESULTS: Elderly patients treated between 2004 and 2012 (n = 4165) were identified, and 80.4% received systemic therapy. The median follow-up was 26 months (range, 1.8-125 months), and the 3-year overall survival rate was 51.6% (95% confidence interval, 50.0%-53.2%). During the study period, there was an increase in the frequency of systemic therapy use from 64% in 2004 to 86% in 2012. The use of systemic therapy was associated with improved overall survival in the multivariate model (hazard ratio, 1.456; 95% confidence interval, 1.308-1.620; P < .0001). A threshold age above which the use of systemic therapy was not associated with improved overall survival in select patients was not identified. CONCLUSIONS: In contrast to the available prospective evidence, the majority of elderly patients with locoregionally advanced head and neck cancer treated with definitive radiotherapy also receive systemic therapy. The use of systemic therapy is associated with improved overall survival and should be a patient-specific decision in all age groups. Cancer 2016;122:3472-3483. © 2016 American Cancer Society.

The impact of an enhanced recovery after surgery protocol for major head and neck oncologic surgery on postoperative complications and adjuvant treatment delivery.

OBJECTIVE: The Commission on Cancer (CoC) recently introduced a quality metric to optimize time between major head and neck surgery and adjuvant treatment (TAT) ≤6 weeks, as TAT delay adversely impacts patient survival. This study evaluates whether enhanced recovery after surgery (ERAS) for this population reduces the rate of postoperative complications, length of stay (LOS), and TAT. METHODS: Patients undergoing larynx or oral cavity resection with free flap reconstruction, ERAS, and adjuvant treatment after 2018 were compared to a historical pre-ERAS cohort. Patients underwent surgery at a single-institution tertiary referral center for complex head and neck oncology. Differences between groups were compared by chi-square, Fisher's exact, or Wilcoxon rank-sum test. TAT >6 weeks was evaluated with univariate and multivariable logistic regression. RESULTS: Thirty-nine pre-ERAS patients were compared to 39 ERAS patients. No demographic differences existed between groups. LOS was improved with ERAS (p = 0.005). ERAS patients were discharged to home and returned to their activities of daily living (ADL) earlier (p = 0.004, 0.001). ADL recovery was associated with on-time TAT ≤42 days on univariate analysis (OR 1.36, 95% CI 1.13-1.63, p = 0.001). TAT delay was less frequent with ERAS (51.3% vs. 69.2%), but this was not significant after multivariable logistic regression (p = 0.11). CONCLUSION: ERAS decreases LOS and returns advanced head and neck cancer patients to their ADL sooner. Postoperative ADL recovery independently predicts on-time adjuvant treatment. Still, compliance beyond 50% with the TAT ≤6 weeks CoC quality metric remains a major treatment barrier.

Weekly Versus Bolus Cisplatin Concurrent With Definitive Radiation Therapy for Squamous Carcinoma of the Head and Neck: A Systematic Review and Network Meta-Analysis.

PURPOSE: The schedule of cisplatin concurrent with definitive radiation for squamous carcinoma of the head and neck remains controversial. Most institutions deliver either a high-dose "bolus" schedule once every 3 weeks or a low-dose weekly schedule. We compared these 2 schedules via a simplified network meta-analysis with a common comparator. METHODS AND MATERIALS: We performed a PRISMA-concordant systematic review to identify randomized controlled trials comparing cisplatin with cetuximab for nonmetastatic, locoregionally advanced squamous carcinoma of the head and neck treated with definitive radiation. Trials incorporating primary surgery or induction therapy were excluded. Patient survival times were extracted on a per-event basis from the published curves using a digitizer and validated against published point estimates and hazard ratios (HRs). Survival was compared using random effects Cox regression under a frequentist framework. Toxicity and secondary endpoints were analyzed qualitatively. The Cochrane method assessed the risk of bias. The analysis plan was preregistered with the Open Science Foundation. RESULTS: Five randomized trials were identified, including 1678 patients. There was no statistical difference in overall survival between weekly and bolus regimens (HR, 0.90; 95% CI, 0.53-1.52, P = .345). This Cox model suggested that for the average patient in the cohort, the absolute difference in 5-year overall survival between weekly and bolus regimens was +1.2% (95% CI, -6.1%-+5.9%, P = .345). Secondary endpoints and toxicity were not obviously different by regimen, qualitatively. CONCLUSIONS: The cetuximab trials provide indirect data suggesting that the differences between cisplatin schedules are subtle.

Unplanned Emergency Department or Inpatient Acute Care Within 1 Week After Administration of Peptide Receptor Radionuclide Therapy: Frequency of Occurrence and Standard Operating Procedures for Radioprotection in These Situations.

Peptide receptor radionuclide therapy (PRRT) is a rapidly developing treatment modality. These treatments are indicated for patients who are either heavily pretreated and/or may have neurohormonal active disease, increasing risk of acute adverse effects and the need for unplanned acute care. The goals of this report were to characterize the frequency of unplanned acute care utilization after PRRT infusion and to detail a comprehensive standard operating procedure (SOP) for radioprotection during unplanned post-PRRT acute care. The records of patients treated with PRRT were reviewed. The event of interest was emergency department (ED) utilization and/or inpatient admission within 7 days of PRRT infusion. A multidisciplinary group developed a radioprotection SOP for all phases of unplanned acute care including the clinical infusion space, emergency medical services (EMS) transport to the ED, within the ED, and on the inpatient floor. A total of 232 patients received 814 infusions of PRRT, with 134 (58%) receiving Lutathera and 98 (42%) receiving Pluvicto. Nineteen patients received unplanned acute care at an ED within 7 days of PRRT infusion (8% of patients, 2% of infusions), of which 10 received Lutathera (8% of patients, 2% of infusions). Two patients (2% of patients, 0.5% of infusions) experienced carcinoid crises within 24 hours of Lutathera infusion. The median and average interval between infusion and ED visit was 0.5 days and 1.3 days, respectively. Nine patients received Pluvicto (9% of patients, 3% of infusions). The median and average interval between infusion and ED visit was 4 days and 4.7 days, respectively. Emergency room utilization and/or inpatient admission after PRRT administration are relatively infrequent events, but not unexpected. Centers that administer PRRT should have a comprehensive SOP in place to effectively care for radioactive patient emergencies while maximizing medical staff protection.

Imaging and Biomarker Surveillance for Head and Neck Squamous Cell Carcinoma: A Systematic Review and American Radium Society Appropriate Use Criteria Statement.

Surveillance for survivors of head and neck cancer (HNC) is focused on early detection of recurrent or second primary malignancies. After initial restaging confirms disease-free status, the use of surveillance imaging for asymptomatic patients with HNC is controversial. Our objective was to comprehensively review literature pertaining to imaging and biomarker surveillance of asymptomatic patients treated for head and neck squamous cell carcinoma and to convene a multidisciplinary expert panel to provide appropriate use criteria for surveillance in representative clinical scenarios. The evidence base for the appropriate use criteria was gathered through a librarian-mediated search of literature published from 1990 to 2022 focused on surveillance imaging and circulating tumor-specific DNA for nonmetastatic head and neck squamous cell carcinoma using MEDLINE (Ovid), Embase, Web of Science Core Collection, and the Cochrane Central Register of Controlled Trials. The systematic review was reported according to PRISMA guidelines. Using the modified Delphi process, the expert panel voted on appropriate use criteria, providing recommendations for appropriate use of surveillance imaging and human papillomavirus (HPV) circulating tumor DNA. Of 5178 studies identified, 80 met inclusion criteria (5 meta-analyses/systematic reviews, 1 randomized control trial, 1 post hoc analysis, 25 prospective, and 48 retrospective cohort studies [with ≥50 patients]), reporting on 27,525 patients. No large, randomized, prospective trials examined whether asymptomatic patients who receive surveillance imaging or HPV circulating tumor DNA monitoring benefit from earlier detection of recurrence or second primary tumors in terms of disease-specific or quality-of-life outcomes. In the absence of prospective data, surveillance imaging for HNC survivors should rely on individualized recurrence-risk assessment accounting for initial disease staging, HPV disease status, and tobacco use history. There is an emerging surveillance role for circulating tumor biomarkers.

An Estimate of Local Failure in the TARGIT-A Trial of Pre-pathology Intraoperative Radiation Therapy for Early Breast Cancer.

PURPOSE: TARGIT-A was a pragmatic randomized noninferiority trial including women with early-stage breast cancer treated postlumpectomy with either external beam radiation therapy (EBRT) or 50 kV x-rays delivered intraoperatively with or without EBRT, as indicated. The long-term update of the pre-pathology cohort did not include a 10-year estimate of the primary endpoint of local failure (although tabular 5-year data was provided). Here, we used the data from the pre-pathology manuscript to estimate the cumulative incidence of local failure. METHODS AND MATERIALS: Using digitizer software and the published survival curves, we extracted the Kaplan-Meier rate of local recurrence-free survival and overall survival. The extracted data were calibrated to the published point-estimates to within ±0.5%. The data were then fit to parametric survival models, and overall survival and local recurrence-free survival curves were subtracted to give the estimate of local failure in the presence of the competing risk of death. Bootstrap resampling was used to assess for parameter uncertainty in the modeling process. RESULTS: Our analysis estimated that the risk of local failure at 10 years in the TARGIT-A pre-pathology cohort is approximately 1.7% with EBRT (95% confidence interval [CI], 0%-4.3%) and 5.5% in the pragmatic risk-adapted TARGIT strategy (95% CI, 2.9%-8.0%). A weighted average estimate suggests that the risk of local failure in low-risk women treated with TARGIT alone is approximately 6.6% at 10 years (95% CI, 3.3%-10.0%), with an estimated difference of 4.9% (95% CI, 0.6%-9.2%) compared with EBRT. CONCLUSIONS: These data allow for contextualization and informed decisions when considering megavoltage EBRT, kilovoltage intraoperatively, or omission of radiation therapy entirely.

Cost-Effectiveness Analysis of Ultra-Hypofractionated Whole Breast Radiation Therapy Alone Versus Hormone Therapy Alone or Combined Treatment for Low-Risk ER-Positive Early Stage Breast Cancer in Women Aged 65 Years and Older.

PURPOSE: The optimal management of early-stage, low-risk, hormone-positive breast cancer in older women remains controversial. Recent trials have shown that 5-fraction ultrahypofractionated whole-breast irradiation (U-WBI) has similar outcomes to longer courses, reducing the cost and inconvenience of treatment. We performed a cost-utility analysis to compare U-WBI to hormone therapy alone or their combination. METHODS AND MATERIALS: We simulated 3 different treatment approaches for women age 65 years or older with pT1-2N0 ER-positive invasive ductal carcinoma treated with lumpectomy with negative margins using a Markov microsimulation model. The strategies were U-WBI performed with a 3-dimensional conformal technique over 5 fractions without a boost ("radiation therapy [RT] alone"), adjuvant hormone therapy (anastrozole for 5 years) without RT ("aromatase-inhibitor [AI] alone"), or the combination of the 2. The combination strategy was calibrated to match trial results, and the relative effectiveness of the RT alone and AI alone strategies were inferred from previous randomized trials. The primary endpoint was the cost-effectiveness of the 3 strategies over a lifetime horizon as measured by the incremental cost-effectiveness ratio (ICER), with a value of $100,000/quality-adjusted life-year deemed "cost-effective." RESULTS: The model results compared with the prespecified target outcomes. On average, RT alone was the least expensive strategy ($14,775), with AI alone slightly more ($14,998), and combination therapy the costliest ($19,802). RT alone dominated AI alone (the incremental cost-effectiveness ratio [ICER] -$5089). Combination therapy, compared with RT alone, was slightly more expensive than our definition of cost-effective (ICER $113,468) but was cost-effective compared with AI alone (ICER $54,451). Probabilistic sensitivity analysis demonstrated RT alone to be cost-effective in 50% of trials, with combination therapy in 36% and AI alone in 14%. CONCLUSIONS: U-WBI alone appears the more cost-effective de-escalation strategy for these low-risk patients, compared with AI alone. Combining U-WBI and AI appears more costly but may be preferred by some patients.

Radiation therapy for cT1-2 carcinoma of the palatine tonsil diagnosed via a simple tonsillectomy: Dosimetry and patterns of care in the IMRT era.

OBJECTIVE: Small carcinomas of the palatine tonsil are often diagnosed via simple tonsillectomy, a maneuver with non-therapeutic intent. Herein, practice patterns for this unique situation are evaluated. PATIENTS AND METHODS: A retrospective review was performed across 10 facilities to identify patients with cT1-2 squamous carcinomas of the tonsil diagnosed by simple tonsillectomy between 2010 and 2018. Patients who received curative-intent intensity modulated radiotherapy (IMRT) without additional surgery were included. Target volumes were reviewed, and cumulative incidences of local failure and severe late dysphagia were calculated. RESULTS: From 638 oropharyngeal patients, 91 were diagnosed via simple tonsillectomy. Definitive IMRT with no additional surgery to the primary site was utilized in 57, and three with gross residual disease were excluded, leaving 54 for analysis. Margins were negative in 13%, close (<5 mm) in 13%, microscopically positive in 61%, and not reported in 13%. Doses typically delivered to gross disease (68-70.2 Gy in 33-35 fx or 66 Gy/30 fx) were prescribed to the tonsil bed in 37 (69%). Sixteen patients (29%) received doses from 60 to 66 Gy (≤2 Gy/fx) and one received 50 Gy (2 Gy/fx). No local failures were observed. One late oropharyngeal soft tissue ulcer occurred, treated conservatively (grade 2). At five years, the cumulative incidence of severe late dysphagia was 17.4% (95% CI 6.1-28.8%). CONCLUSION: Small tonsil carcinomas diagnosed by simple tonsillectomy represent a niche subset with favorable oncologic outcomes. Regardless, radiation oncologists tend to deliver full-dose to the tonsil bed. The necessity of this routine could be questioned in the modern era.

Oncologists' Perspective on Dental Care Around the Treatment of Head and Neck Cancer: A Pattern of Practice Survey.

PURPOSE: Patients with head and neck cancer are at risk of long-term dental complications. Proper dental assessment pre- and post-treatment can improve outcomes but is logistically challenging. We surveyed oncologists to better understand their perspectives surrounding dental care in this unique population. METHODS: We surveyed oncologists at institutions associated with an ongoing national study of oral health after treatment of head and neck cancer. Seventeen questions were used to assess provider characteristics, patterns of practice, patterns of referral, barriers to referral, and willingness to apply fluoride varnish in the oncology clinic. RESULTS: Ninety-seven oncologists were invited from six institutions, of whom 40 (41%) responded. Surgeons represented 45% of the sample, followed by radiation oncologists (40%) and medical oncologists (15%). Both generalists and subspecialists were included. All practiced in a metropolitan area with an academic dental practice, and many felt that this improved access to care. Despite this, most oncologists thought that financial factors were a significant barrier to obtaining timely dental care. Most oncologists performed a dental assessment during visits. Oncologists felt qualified to identify the most significant complications of treatment, such as exposed bone, but felt underqualified to identify early changes in need of intervention. When asked if the oncology clinic could apply fluoride varnish during follow-ups, most stated that this seemed feasible but would require education and financial support. CONCLUSION: Oncologists often perform limited dental evaluations during their routine visits. Given the challenges associated with access to proper dental care for this population, these oncology visits may provide a window for preventative intervention.

The economic impact of circulating tumor-tissue modified HPV DNA for the post-treatment surveillance of HPV-driven oropharyngeal cancer: A simulation.

PURPOSE: Following treatment of HPV-driven oropharynx cancer, surveillance nasopharyngoscopy and imaging are often performed but are expensive and frequently ineffective. A novel plasma circulating tumor-tissue modified viral HPV DNA (TTMV-HPV-DNA) assay accurately detects recurrences. We modeled the cost of the new assay. METHODS: We designed and validated a partitioned survival model which replicated the results of the RTOG 1016 study and calculated cumulative surveillance costs from the payer's perspective. Two strategies were considered: a standard of routine endoscopy with imaging as needed and an alternative strategy which omitted scopes and imaging but obtained serial TTMV-HPV-DNA samples. No difference in effectiveness (QALY or LY) was assumed in the base case. A 5-year horizon was used, costs were reported in 2020 U.S. dollars discounted by 3%. Seven scenarios tested model assumptions and practice variation. Deterministic and probabilistic sensitivity analyses assessed parameter uncertainty. RESULTS: In the base case, at the list TTMV-HPV-DNA price, the cumulative cost of surveillance was $11,674 for the standard strategy and $20,756 for the TTMV-HPV-DNA strategy (+$9082 over 5 years). Probabilistic sensitivity analysis demonstrated the cost difference ranged from $4917-$12,047. The TTMV-HPV-DNA strategy was most likely to be either cost saving or cost-effective if future data demonstrate small improvements in quality or quantity of life (approximately 33 quality-adjusted life-days), if the assay reduces utilization of imaging, and if the periodicity of TTMV-HPV-DNA draws could be reduced from that on clinical trials. CONCLUSIONS: This data informs providers seeking to design more accurate, accessible, and economical post-treatment surveillance strategies.

Defining targets to improve care delivery for T4 larynx squamous cell carcinoma.

Objective: United States oncology trends consistently demonstrate that nearly half of T4a larynx carcinoma patients are treated with larynx preservation, despite national guidelines favoring laryngectomy. This study identifies clinical decision-making drivers and defines patient subsets that should become targets for care improvement. Methods: Retrospective analysis of patients with cT4 squamous cell carcinoma of the larynx from US National Cancer Database 2005-2016. Demographic data and survival rates between clinical pathways were compared. Survival was estimated by Kaplan-Meier method with statistical comparisons assessed by log-rank test. Results: Of 11,556 patients with cT4 disease, laryngectomy (TL) was the initial treatment for 4627 (40%) patients. Larynx preservation via chemoradiation (CRT) occurred for 4307 patients. TL and CRT patients had similar Charlson-Deyo comorbidity indices and insurance status. TL patients had higher total tumor size, lower N3 rates and were more often seen at academic institutions (p < .0001). N0 surgery patients with adjuvant treatment demonstrated superior median survival (MS) compared to CRT (surgery + radiation MS: 69 months, surgery + chemoradiation MS: 66, CRT MS: 37.7), p < .0001. MS for N1/N2 disease patients was 56.5 months for surgery + radiation and 35.5 months for surgery + CRT, superior to CRT, MS 30.8 months, p < .0001. Tri-modality N3 patients with up front surgery had similar MS compared to CRT (surgery + chemoradiation 21.3 months vs. CRT 16.1), p = .95. Conclusion: National quality improvement initiatives are needed to promote guideline adherence and improve survival in advanced larynx cancer. Targets for such initiatives should be patients with limited or no nodal disease burden, that meet clear T4a imaging criteria. Level of Evidence: Level IV, non-randomized controlled cohort.

Volumetric Modulated Arc Therapy (VMAT) Craniospinal Irradiation (CSI) for Children and Adults: A Practical Guide for Implementation.

PURPOSE: Volumetric modulated arc therapy (VMAT) craniospinal irradiation (CSI) has been shown to have significant dosimetric advantages compared to 3-dimensional conformal therapy but is a technically complex process. We sought to develop a guide for all aspects of the VMAT CSI process and report patient dosimetry results. METHODS AND MATERIALS: We initiated VMAT CSI in 2017 and have regularly revised our standard operating procedure for this process since then. Herein, we report a detailed template for the entire VMAT CSI process from initial patient setup and immobilization at time of computed tomography (CT) simulation to contouring and treatment planning, quality assurance, and therapy delivery. The records of 12 patients who were treated with VMAT CSI were also retrospectively reviewed. RESULTS: Patient age ranged from 2 to 59 years with 5 pediatric patients (age <18 years), 5 young adults (age 18-35 years), and 2 older adults (age >35 years). The majority of patients (67%) had medulloblastoma. CSI dose ranged from 21.6 to 36 Gy, with a median of 36 Gy. The median CSI planning target volume was 2383 cc with a median V95% of 99.8% and median 0.03 cc hotspot of 112.5%. The average V107% was 7.4% and the average conformality index was 1.01. CONCLUSIONS: VMAT CSI has potentially significant dosimetric and acute toxicity advantages compared to 3-dimensional conformal. However, proper procedures need to be in place throughout the process in order to be able to realize these potential advantages. We herein describe our detailed standard operating procedure for VMAT CSI. Recognizing the scarcity of proton beam centers in many areas, VMAT CSI represents a feasible treatment with more widespread availability.

Survivorship Care Plans Improve the Identification of Post-radiation Hypothyroidism After Head and Neck Cancer Treatment.

BACKGROUND/AIM: Survivorship care programs (SCPs) educate patients on post-treatment side-effects, which may lead to earlier identification and mitigation of their impact. This study assessed the impact of SCP on identification and management of post-treatment hypothyroidism in a head and neck cancer population and evaluated socio-demographic factors in the effectiveness of SCPs. PATIENTS AND METHODS: A retrospective analysis was performed of sociodemographic and clinical characteristics of patients with head and neck cancer treated with radiation therapy between January 2011 and January 2019 at a large community cancer institution. Development of hypothyroidism was defined as elevated thyroid-stimulating hormone (TSH) or initiation of supplementation post-treatment. Cumulative incidence of hypothyroidism was analyzed with Gray's method. RESULTS: Of 608 patients, 483 (79%) had post-treatment TSH surveillance. A total of 203 (42%) of those patients developed hypothyroidism; 53 (11%) patients completed SCPs. The median follow-up was 1.4 (interquartile range=0.7-2.6) years with a median time until diagnosis of hypothyroidism of 1.2 (interquartile range=0.7-2.1) years. The median time to diagnosis was 12.0 months with SCP versus 14.2 months without. Race and insurance status were not associated with differences in thyroid surveillance. Patients with laryngeal cancer were at greatest risk of developing hypothyroidism (hazard ratio=1.92, confidence interval=1.44-2.56; p<0.077). Cumulative incidence of post-treatment hypothyroidism was higher in patients managed with SCP, 65.4% at 4 years, compared to those without (49.0%). Receipt of SCP was independently associated with an increased incidence of hypothyroidism detection (hazard ratio=1.51, confidence interval=1.04-2.20; p=0.030). CONCLUSION: In our experience, SCP utilization was independently associated with a diagnosis of hypothyroidism. This study supports implementation of a survivorship program for identification and management of post-treatment sequelae.

Retreatment of Recurrent or Second Primary Head and Neck Cancer After Prior Radiation: Executive Summary of the American Radium Society Appropriate Use Criteria.

Retreatment of recurrent or second primary head and neck cancers occurring in a previously irradiated field is complex. Few guidelines exist to support practice. We performed an updated literature search of peer-reviewed journals in a systematic fashion. Search terms, key questions, and associated clinical case variants were formed by panel consensus. The literature search informed the committee during a blinded vote on the appropriateness of treatment options via the modified Delphi method. The final number of citations retained for review was 274. These informed 5 key questions, which focused on patient selection, adjuvant reirradiation, definitive reirradiation, stereotactic body radiation, and reirradiation to treat nonsquamous cancer. Results of the consensus voting are presented along with discussion of the most current evidence. This provides updated evidence-based recommendations and guidelines for the retreatment of recurrent or second primary cancer of the head and neck.

Dissolved rubidium to strontium ratio as a conservative tracer for wastewater effluent-sourced contaminant inputs near a major urban wastewater treatment plant.

Municipal wastewater (MWW) effluent discharges can introduce contaminants to receiving waters which may have adverse impacts on local ecosystems and human health. Conservative chemical constituents specific to the MWW effluent stream can be used to quantify and trace wastewater effluent-sourced contaminant inputs. Gadolinium (Gd), a rare earth element used as a contrasting agent in medical magnetic resonance imaging, can be found in urban MWW streams. Dissolved anthropogenic Gd has been shown to be an indicator and potential conservative tracer for MWW effluent in receiving waters. Like other known MWW tracers, it can be difficult and expensive to measure. Dissolved rubidium (Rb) to strontium (Sr) ratio enrichment in biological materials such as blood and urine can lead to enriched Rb/Sr values in MWW effluent relative to natural waters. This ratio is relatively easy and inexpensive to measure and represents a promising additional indicator for MWW effluent in receiving waters in urbanized freshwater systems. In July 2015 and 2016 surface water samples were collected from sites in the tidal-fresh Potomac River in the vicinity of the Blue Plains Advanced Wastewater Treatment Plant (BPAWWTP) outfall near Washington, DC USA along with treated MWW effluent samples from the BPAWWTP. Dissolved Rb/Sr ratios were measured in these waters and compared to dissolved Gd concentrations in order to demonstrate the potential of the dissolved Rb/Sr ratio as a conservative indicator for MWW effluent. Results suggest the dissolved Rb/Sr ratio represents a simple and cost-effective indicator and conservative tracer for MWW effluent. It can be used with, or in place of, other proven tracers to investigate wastewater impacts in highly-urbanized, anthropogenically-impacted freshwater systems like the tidal fresh Potomac River and perhaps in a wider range of geologic settings than previously thought. A case study is presented as an example to demonstrate the potential of using dissolved Rb/Sr ratios to trace MWW-sourced nutrient inputs from a major WWTP like BPAWWTP to the receiving waters of tidal-fresh Potomac River.