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.
This analysis demonstrates that the 10‐pack‐year rule may not apply to all early human papillomavirus–positive oropharynx cancers, particularly for former smokers.
•Patients with metastatic HPV+ SCC-OP may be appropriate candidates for MDT.•Trials evaluating the benefit of MDT generally enrich for indolent phenotypes.•In our study, patients with 1 metastatic ...lesion survived 41.2 months after DM.•Patients with no smoking history survived 37.6 months after DM.•These factors should be used as stratification variables for such clinical trials.
Patients with human papillomavirus (HPV) associated squamous cell carcinoma of the oropharynx (SCC-OP) have improved overall survival (OS) after distant metastasis (DM) compared to HPV negative patients. These patients may be appropriate candidates for enrollment on clinical trials evaluating the efficacy of metastasis-directed therapy (MDT). This study seeks to identify prognostic factors associated with OS after DM, which could serve as enrollment criteria for such trials.
From an IRB approved multi-institutional database, we retrospectively identified patients with HPV/p16 positive SCC-OP diagnosed between 2001 and 2018. Patterns of distant failure were assessed, including number of lesions at diagnosis and sites of involvement. The primary outcome was OS after DM. Prognostic factors for OS after DM were identified with Cox proportional hazards. Stepwise approach was used for multivariable analysis.
We identified 621 patients with HPV-associated SCC-OP, of whom 82 (13.2%) were diagnosed with DM. Median OS after DM was 14.6 months. On multivariable analysis, smoking history and number of lesions were significantly associated with prolonged OS. Median OS after DM by smoking (never vs ever) was 37.6 vs 11.2 months (p = 0.006), and by lesion number (1 vs 2–4 vs 5 or more) was 41.2 vs 17.2 vs 10.8 months (p = 0.007).
Among patients with newly diagnosed metastatic HPV-associated SCC-OP, lesion number and smoking status were associated with significantly prolonged overall survival. These factors should be incorporated into the design of clinical trials investigating the utility of MDT, with or without systemic therapy, in this population.
Background
To evaluate plan quality using volumetric‐modulated arc therapy (VMAT) and step‐and‐shoot intensity‐modulated radiation therapy (SS‐IMRT) techniques and for patients treated for ...oropharyngeal squamous cell carcinoma (OPSCC).
Methods
Treatment plans for patients treated definitively for stages I‐IVb, OPSCC between December 2009 and August 2015 were retrospectively reviewed. Dosimetric endpoints of involved organs‐at‐risk (OARs) were retrieved from clinical plans. Common Terminology Criteria for Adverse Events scores of acute toxicities were compared.
Results
Two‐hundred twenty‐two patients were identified with 134 and 88 receiving SS‐IMRT and VMAT with median follow‐up time of 23.0 and 7.9 months, respectively. The dosimetric endpoints of the OARs were significantly improved in VMAT cohort, which translated into significantly lower rates of grade 2 or higher acute dysphagia and xerostomia.
Conclusion
Improvements in stages I‐IVb, oropharyngeal cancer plan quality are associated with reduced grade ≥ 2 acute dysphagia and xerostomia.
Background
The role of smoking among patients with human papillomavirus (HPV)‐positive oropharyngeal squamous cell carcinoma (OPSCC) is unclear.
Methods
A retrospective cohort study of patients with ...HPV(+) OPSCC from 2001 to 2015 at a tertiary‐care institution was conducted. The primary outcome was overall survival (OS).
Results
Among 484 included patients, 94 (19.4%) were active smokers, 226 (46.7%) were former smokers, and 164 (33.9%) never smoked. Among active smokers, 82 patients (87.2%) had a ≥10 pack‐year and 69 (73.4%) had a ≥20 pack‐year smoking history. After adjusting for covariates, active smoking was a significant predictor of inferior OS (HR 2.28, P < .001) and PFS (HR 2.26, P < .001). When including pack‐years as the covariate, ≥20 pack‐years predicted a decreased effect‐size for inferior OS and PFS.
Conclusions
For patients with HPV(+) OPSCC, active smoking at diagnosis is the most powerful covariate capturing smoking history to predict OS and PFS.
•Sparing of the SMG when targeting the level Ib nodes was feasible.•Sparing of the SMG reduced mean dose to the SMG.•Sparing of the SMG did not result in increased level 1b nodal failure rates.
...Submandibular gland (SMG) metastases are extremely rare in head and neck cancer, even in the presence of level Ib lymph node (LN) involvement. In recent years, we have contoured the SMG and specifically attempted to limit its dose exposure even in patients in whom the level Ib LN station is targeted. This study reports our preliminary feasibility and safety experience with selective submandibular gland sparing.
Patients with squamous cell cancer (SCC) of the oral cavity or oropharynx with T1-2, N0-3, M0 disease in whom at least a single level Ib lymph node region was included in the target volume were identified. All patients were treated from 2009 to 2014 with definitive or postoperative IMRT with or without chemotherapy. Patients with recurrent disease, previous radiation or treated palliatively were excluded.
A total of 174 patients met criteria for inclusion. Among the 185 level Ib LN stations that were deliberately targeted in the clinical treatment volume, 32 submandibular glands were contoured, excluded from the target volume and avoided during treatment planning. Mean dose to the spared SMG were reduced by 12% (66.6 Gy vs. 58.9 Gy, p < .001). None of these patients experienced any level 1b LN failures.
Selective sparing of the submandibular gland when targeting the level 1b nodes in oral cavity and oropharynx cancer is feasible, reduces the mean dose to submandibular glands and does not result in increased level 1b nodal failure rates. Additional studies with larger cohorts are needed to validate this preliminary observation.
Objectives/Hypothesis
Patients with human papillomavirus (HPV)–induced cancer of unknown primary (CUP) are generally excluded from clinical trials, despite surgical series reporting detection rates ...of occult oropharynx primaries of >80%. We performed a matched‐pair analysis to compare outcomes between T0N1‐3M0 HPV+ CUP and T1‐2N1‐3M0 HPV+ oropharynx known primary (OPX).
Study Design
Retrospective cohort study at a single institution.
Methods
Patients with early T stage, node positive HPV+ OPX or CUP treated with curative intent between 1998 and 2016 were identified. For a subgroup of CUP patients with an unknown HPV status, we imputed HPV status and included patients with a >80% probability of being HPV+. Cohorts were matched based on patient demographics using a nearest neighbor propensity technique. After matching, patients were grouped according to either a favorable or unfavorable risk stratification designations per current NRG Oncology clinical trial enrollment criteria. Disease‐free survival (DFS) and overall survival (OS) were calculated using Kaplan‐Meier analysis.
Results
Of 298 patients with T1‐2N1‐3 OPX, 48 were matched to 48 HPV+ CUP patients (32 with confirmed and 16 imputed HPV status). Median follow‐up for CUP (34.1 months) and OPX (27.8 months) patients were similar (P = .23).There were no significant differences between the CUP and OPX groups for 3‐year DFS (89% vs. 85%, P = .44), and 3‐year OS (91% vs. 91%, P = .11), respectively.
Conclusions
Patients with T0N+M0 HPV‐induced CUP have similar survival outcomes to matched patients with T1‐2N+M0 HPV+ OPX. These patients can reasonably be included in clinical trials investigating the role of treatment deintensification and risk stratified similar to patients with early‐stage known primary OPX cancer.
Level of Evidence
4. Laryngoscope, 128:1379–1385, 2018
Late toxic effects are common after definitive radiotherapy and chemoradiotherapy for oropharynx cancer and are considered a significant contributor to decreased quality of life for survivors. The ...incidence of severe late toxic effects may be reduced by modern narrow-margin image-guided intensity-modulated radiotherapy (IG-IMRT), current supportive care improvements, and the changing epidemiology of oropharynx cancer.
Assess the incidence of severe late toxic effects after modern definitive non-operative treatment for oropharynx cancer.
For this single-institution retrospective review, 156 patients with stage I-IVB squamous cell carcinoma of the oropharynx treated between April 2009 and February 2015 at a tertiary-referral academic multidisciplinary head and neck practice were recruited.
Definitive narrow-margin IG-IMRT to a dose of 66 Gy (to convert milligray to rad, multiply by 0.1) or higher with or without concurrent cisplatin.
The primary outcome was the prospectively collected 2-year cumulative incidence of severe late toxic effects (Common Terminology Criteria for Adverse Events grade 3 or higher) occurring 3 months or more after radiotherapy. Toxic effect end points investigated included esophageal stricture requiring dilation, aspiration pneumonia hospitalization, vocal dysfunction, delayed feeding tube insertions, and osteoradionecrosis. Feeding tube dependence at 1 year was also considered a severe late toxic effect. Secondary outcomes collected include physician-reported grade 2 or higher neck fibrosis and xerostomia. The competing risks of recurrence and death were accounted for using the Gray method.
One-hundred fifty-six patients (median range age, 58 37-96 years) were identified; 130 patients (83%) were HPV positive. Concurrent cisplatin was delivered in 131 patients (84%) and 5 patients (3%) underwent an adjuvant neck dissection. The median (range) follow-up for survivors was 22 (4-73) months from diagnosis. The projected 2-year locoregional control was 93% (95% CI, 88.4%-97.6%) and overall survival was 88% (95% CI, 82.2%-94.0%). Thirty-eight patients (23%) required a feeding tube during treatment. The cumulative incidence of severe late toxic effects adjusted for competing risks at 2-year posttreatment was 2.3% (95% CI, 0%-5.6%). One patient required free-flap reconstruction for grade 3 osteoradionecrosis at 47 months. At 1 year, 2 patients (1%) experienced grade 2 neck fibrosis and 38 patients (23%) experienced grade 2 xerostomia.
These results suggest that severe late toxic effects after modern definitive IG-IMRT, with or without cisplatin, for oropharynx cancer is likely uncommon. The importance of late toxic effect reduction in current and future investigational strategies, including clinical trials, should be considered.
This Article analyzes a recent Supreme Court case, Lorenzo v. Securities and Exchange Commission, and explains why it provides a valuable window into the Court’s future now that Justice Kennedy has ...retired and his seat filled by Justice Brett Kavanaugh. Lorenzo is an important case that raises fundamental interpretative questions about the reach of federal securities statutes. But most significant is its unique procedural posture: when the Supreme Court issues its decision on Lorenzo in 2019, Justice Kavanaugh will be recused while the other eight Justices rule on a lower court opinion from the D.C. Circuit in which he wrote separately in an extensive dissent.
That dissent is quite remarkable. It contains a scathing assessment of securities fraud enforcement and adjudication at the SEC, the majority opinion’s interpretation of deceptive financial conduct under Rule 10b-5, and the SEC’s overall role in the development of federal securities law doctrine. Judge Kavanaugh’s dissent also goes on to identify how the legal deficiencies specific to Lorenzo motivate his broader skepticism towards the constitutional legitimacy of the administrative and regulatory state as a whole; a view that represents his signature contribution as a federal judge. Thus, in Lorenzo, the defining judicial philosophy of the newest Supreme Court Justice is on full display.
More broadly, this Article demonstrates that the deeper import of Lorenzo is not what it reveals about the views of Justice Kavanaugh. Rather, it is in the reception those views will meet from the other eight Justices on the Court. In addressing the argument set forth in the Lorenzo dissent, the current members of the Court will be confronting the positions of their newest peer and colleague. By necessity, they will also signal their openness to be-ing persuaded by Justice Kavanaugh on the issues where he speaks with greatest authority and can be expected to act as forceful advocate for his vision of the law at the Court. Lorenzo can therefore be seen as a bellwether for Justice Kavanaugh’s influence as judicial entrepreneur on behalf of his trademark theory of the Constitutional separation of powers in administrative law. Most importantly, the case bears directly on the area of administrative law where the stakes are highest of all—the role that Justice Kavanaugh may play in the demise of the Chevron doctrine and the collapse of judicial deference toward the administrative state.
This Article concerns the recent Supreme Court case, Leidos, Inc. v. Indiana Public Retirement System (Leidos), and examines the broader issues that it raised for securities law. The consensus among ...scholars and practitioners is that Leidos presented a direct conflict among the circuit courts over a core question of securities law-when a failure to comply with the SEC's disclosure requirements can constitute fraud under Rule 10b-5. This Article provides a much different interpretation of the case. It begins by demonstrating that the circuit split which is presumed to have brought Leidos to the Supreme Court does not in fact exist. It then shows that, rather than being riddled with disagreement, the leading judicial analysis in this area of the law instead reflects a shared set of misconceptions about how the securities regulation architecture works. By unraveling the underlying sources of the Leidos mix-up, this Article makes three contributions. First, it identifies overlooked aspects of the disclosure rules at issue in Leidos, and provides a novel analysis of how the case should have been decided. Second, it explains how errors in leading interpretations of the legal authorities implicated in Leidos carry over to other prominent portions of the regulatory framework, namely Sections 11 and 12 of the 1933 Securities Act. Third, it demonstrates that a central yet ill-defined securities doctrine -- the duty to disclose -- functions primarily to obscure rather than clarify the legal questions at issue in disclosure fraud claims. Taken together, these points suggest that Leidos was a more unusual case than has been appreciated, and stands at a remarkable confluence of legal and scholarly confusions, many of which implicate fundamental principles of securities law.
Mounting evidence from field and laboratory observations coupled with atmospheric model analyses shows that primary combustion emissions of organic compounds dynamically partition between the vapor ...and particulate phases, especially as near-source emissions dilute and cool to ambient conditions. The most recent version of the Community Multiscale Air Quality model version 5.2 (CMAQv5.2) accounts for the semivolatile partitioning and gas-phase aging of these primary organic aerosol (POA) compounds consistent with experimentally derived parameterizations. We also include a new surrogate species, potential secondary organic aerosol from combustion emissions (pcSOA), which provides a representation of the secondary organic aerosol (SOA) from anthropogenic combustion sources that could be missing from current chemical transport model predictions. The reasons for this missing mass likely include the following: (1) unspeciated semivolatile and intermediate volatility organic compound (SVOC and IVOC, respectively) emissions missing from current inventories, (2) multigenerational aging of organic vapor products from known SOA precursors (e.g., toluene, alkanes), (3) underestimation of SOA yields due to vapor wall losses in smog chamber experiments, and (4) reversible organic compounds–water interactions and/or aqueous-phase processing of known organic vapor emissions. CMAQ predicts the spatially averaged contribution of pcSOA to OA surface concentrations in the continental United States to be 38.6 and 23.6 % in the 2011 winter and summer, respectively. Whereas many past modeling studies focused on a particular measurement campaign, season, location, or model configuration, we endeavor to evaluate the model and important uncertain parameters with a comprehensive set of United States-based model runs using multiple horizontal scales (4 and 12 km), gas-phase chemical mechanisms, and seasons and years. The model with representation of semivolatile POA improves predictions of hourly OA observations over the traditional nonvolatile model at sites during field campaigns in southern California (CalNex, May–June 2010), northern California (CARES, June 2010), the southeast US (SOAS, June 2013; SEARCH, January and July, 2011). Model improvements manifest better correlations (e.g., the correlation coefficient at Pasadena at night increases from 0.38 to 0.62) and reductions in underprediction during the photochemically active afternoon period (e.g., bias at Pasadena from -5.62 to -2.42 µg m-3). Daily averaged predictions of observations at routine-monitoring networks from simulations over the continental US (CONUS) in 2011 show modest improvement during winter, with mean biases reducing from 1.14 to 0.73 µg m-3, but less change in the summer when the decreases from POA evaporation were similar to the magnitude of added SOA mass. Because the model-performance improvement realized by including the relatively simple pcSOA approach is similar to that of more-complicated parameterizations of OA formation and aging, we recommend caution when applying these more-complicated approaches as they currently rely on numerous uncertain parameters. The pcSOA parameters optimized for performance at the southern and northern California sites lead to higher OA formation than is observed in the CONUS evaluation. This may be due to any of the following: variations in real pcSOA in different regions or time periods, too-high concentrations of other OA sources in the model that are important over the larger domain, or other model issues such as loss processes. This discrepancy is likely regionally and temporally dependent and driven by interferences from factors like varying emissions and chemical regimes.
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