The extraction of groundwater can generate land subsidence by causing the compaction of susceptible aquifer systems, typically unconsolidated alluvial or basin-fill aquifer systems comprising ...aquifers and aquitards. Various ground-based and remotely sensed methods are used to measure and map subsidence. Many areas of subsidence caused by groundwater pumping have been identified and monitored, and corrective measures to slow or halt subsidence have been devised. Two principal means are used to mitigate subsidence caused by groundwater withdrawal—reduction of groundwater withdrawal, and artificial recharge. Analysis and simulation of aquifer-system compaction follow from the basic relations between head, stress, compressibility, and groundwater flow and are addressed primarily using two approaches—one based on conventional groundwater flow theory and one based on linear poroelasticity theory. Research and development to improve the assessment and analysis of aquifer-system compaction, the accompanying subsidence and potential ground ruptures are needed in the topic areas of the hydromechanical behavior of aquitards, the role of horizontal deformation, the application of differential synthetic aperture radar interferometry, and the regional-scale simulation of coupled groundwater flow and aquifer-system deformation to support resource management and hazard mitigation measures.
Squamous cell carcinoma of an unknown primary (SCCUP) of the head and neck is a rare disease. As a diagnosis of exclusion, the manner in which it is assigned merits consideration. Despite the ...development and refinement of several techniques designed to locate an occult tumor, including cross-sectional anatomic imaging, functional imaging, and transoral surgical techniques, delineating SCCUP remains an active clinical problem. Its relative rarity has prevented prospective study of the entity. Hence, investigators must rely on retrospective analyses to understand the disease and its appropriate treatment. The current understanding of SCCUP differs substantially from when it was initially described decades ago. The most common site of a small primary tumor initially thought to represent SCCUP is the tonsil or base of the tongue, and an increasing percentage are associated with human papilloma virus. Modern treatment of SCCUP by neck dissection alone, neck dissection followed by radiation with or without concurrent chemotherapy, or primary chemoradiation according to initial nodal disease burden produces extraordinarily low recurrence rates. Whether the potential mucosal primary site and/or the contralateral neck should be electively treated is controversial. Efficacy data seem to be similar; therefore, an evaluation of the toxicity of both treatment paradigms is warranted.
Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma have high survival when treated with radiotherapy plus cisplatin. Whether replacement of cisplatin with ...cetuximab—an antibody against the epidermal growth factor receptor—can preserve high survival and reduce treatment toxicity is unknown. We investigated whether cetuximab would maintain a high proportion of patient survival and reduce acute and late toxicity.
RTOG 1016 was a randomised, multicentre, non-inferiority trial at 182 health-care centres in the USA and Canada. Eligibility criteria included histologically confirmed HPV-positive oropharyngeal carcinoma; American Joint Committee on Cancer 7th edition clinical categories T1–T2, N2a–N3 M0 or T3–T4, N0–N3 M0; Zubrod performance status 0 or 1; age at least 18 years; and adequate bone marrow, hepatic, and renal function. We randomly assigned patients (1:1) to receive either radiotherapy plus cetuximab or radiotherapy plus cisplatin. Randomisation was balanced by using randomly permuted blocks, and patients were stratified by T category (T1–T2 vs T3–T4), N category (N0–N2a vs N2b–N3), Zubrod performance status (0 vs 1), and tobacco smoking history (≤10 pack-years vs >10 pack-years). Patients were assigned to receive either intravenous cetuximab at a loading dose of 400 mg/m2 5–7 days before radiotherapy initiation, followed by cetuximab 250 mg/m2 weekly for seven doses (total 2150 mg/m2), or cisplatin 100 mg/m2 on days 1 and 22 of radiotherapy (total 200 mg/m2). All patients received accelerated intensity-modulated radiotherapy delivered at 70 Gy in 35 fractions over 6 weeks at six fractions per week (with two fractions given on one day, at least 6 h apart). The primary endpoint was overall survival, defined as time from randomisation to death from any cause, with non-inferiority margin 1·45. Primary analysis was based on the modified intention-to-treat approach, whereby all patients meeting eligibility criteria are included. This study is registered with ClinicalTrials.gov, number NCT01302834.
Between June 9, 2011, and July 31, 2014, 987 patients were enrolled, of whom 849 were randomly assigned to receive radiotherapy plus cetuximab (n=425) or radiotherapy plus cisplatin (n=424). 399 patients assigned to receive cetuximab and 406 patients assigned to receive cisplatin were subsequently eligible. After median follow-up duration of 4·5 years, radiotherapy plus cetuximab did not meet the non-inferiority criteria for overall survival (hazard ratio HR 1·45, one-sided 95% upper CI 1·94; p=0·5056 for non-inferiority; one-sided log-rank p=0·0163). Estimated 5-year overall survival was 77·9% (95% CI 73·4–82·5) in the cetuximab group versus 84·6% (80·6–88·6) in the cisplatin group. Progression-free survival was significantly lower in the cetuximab group compared with the cisplatin group (HR 1·72, 95% CI 1·29–2·29; p=0·0002; 5-year progression-free survival 67·3%, 95% CI 62·4–72·2 vs 78·4%, 73·8–83·0), and locoregional failure was significantly higher in the cetuximab group compared with the cisplatin group (HR 2·05, 95% CI 1·35–3·10; 5-year proportions 17·3%, 95% CI 13·7–21·4 vs 9·9%, 6·9–13·6). Proportions of acute moderate to severe toxicity (77·4%, 95% CI 73·0–81·5 vs 81·7%, 77·5–85·3; p=0·1586) and late moderate to severe toxicity (16·5%, 95% CI 12·9–20·7 vs 20·4%, 16·4–24·8; p=0·1904) were similar between the cetuximab and cisplatin groups.
For patients with HPV-positive oropharyngeal carcinoma, radiotherapy plus cetuximab showed inferior overall survival and progression-free survival compared with radiotherapy plus cisplatin. Radiotherapy plus cisplatin is the standard of care for eligible patients with HPV-positive oropharyngeal carcinoma.
National Cancer Institute USA, Eli Lilly, and The Oral Cancer Foundation.
Human papillomavirus-associated oropharyngeal cancer (HPV-OPC) is a distinct clinical entity with a favorable prognosis compared with non-HPV-OPC. Surgery and radiotherapy (RT) result in adverse ...effects, and negative quality of life or functional outcomes, which impact a significant proportion of HPV-OPC survivors. Ongoing studies aim to reduce these negative treatment effects while maintaining high cure rates through deintensified therapy typically use either a primary surgical or RT approach. A single-day curative surgery will remain relevant for many patients with early-stage disease. However, the average patient with HPV-OPC will have indications for adjuvant therapy. A primary RT approach to deintensified therapy has more available data from patients on prospective multi-institutional trials, provides broader patient selection, and may be more cost-effective. Anticipated results from an active phase II/III NCTN trial will help guide the standard of care using primary RT. Next generation trials will help further refine patient selection and/or radical deintensification (30-50 Gy).
To assess the impact of radiation treatment time (RTT) in head and neck cancers on overall survival (OS) in the era of chemoradiation.
Patients with diagnoses of tongue, hypopharynx, larynx, ...oropharynx, or tonsil cancer were identified by use of the National Cancer Database. RTT was defined as date of first radiation treatment to date of last radiation treatment. In the definitive setting, prolonged RTT was defined as >56 days, accelerated RTT was defined as <47 days, and standard RTT was defined as 47 to 56 days. In the postoperative setting, prolonged RTT was defined as >49 days, accelerated RTT was defined as <40 days, and standard RTT was defined as 40 to 49 days. We used χ
tests to identify predictors of RTT. The Kaplan-Meier method was used to compare OS among groups. Cox proportional hazards model was used for OS analysis in patients with known comorbidity status.
19,531 patients were included; 12,987 (67%) had a standard RTT, 4,369 (34%) had an accelerated RTT, and 2,165 (11%) had a prolonged RTT. On multivariable analysis, accelerated RTT (hazard ratio HR 0.84; 95% confidence interval CI 0.73-0.97) was associated with an improved OS, and prolonged RTT (HR 1.25; 95% CI 1.14-1.37) was associated with a worse OS relative to standard RTT. When the 9,200 (47%) patients receiving definitive concurrent chemoradiation were examined, prolonged RTT (HR 1.29; 95% CI 1.11-1.50) was associated with a worse OS relative to standard RTT, whereas there was no significant association between accelerated RTT and OS (HR 0.76; 95% CI 0.57-1.01).
Prolonged RTT is associated with worse OS in patients receiving radiation therapy for head and neck cancer, even in the setting of chemoradiation. Expeditious completion of radiation should continue to be a quality metric for the management of head and neck malignancies.
To estimate the overall survival (OS) impact from increasing time to treatment initiation (TTI) for patients with head and neck squamous cell carcinoma (HNSCC).
Using the National Cancer Data Base ...(NCDB), we examined patients who received curative therapy for the following sites: oral tongue, oropharynx, larynx, and hypopharynx. TTI was the number of days from diagnosis to initiation of curative treatment. The effect of TTI on OS was determined by using Cox regression models (MVA). Recursive partitioning analysis (RPA) identified TTI thresholds via conditional inference trees to estimate the greatest differences in OS on the basis of randomly selected training and validation sets, and repeated this 1,000 times to ensure robustness of TTI thresholds.
A total of 51,655 patients were included. On MVA, TTI of 61 to 90 days versus less than 30 days (hazard ratio HR, 1.13; 95% CI, 1.08 to 1.19) independently increased mortality risk. TTI of 67 days appeared as the optimal threshold on the training RPA, statistical significance was confirmed in the validation set (P < .001), and the 67-day TTI was the optimal threshold in 54% of repeated simulations. Overall, 96% of simulations validated two optimal TTI thresholds, with ranges of 46 to 52 days and 62 to 67 days. The median OS for TTI of 46 to 52 days or fewer versus 53 to 67 days versus greater than 67 days was 71.9 months (95% CI, 70.3 to 73.5 months) versus 61 months (95% CI, 57 to 66.1 months) versus 46.6 months (95% CI, 42.8 to 50.7 months), respectively (P < .001). In the most recent year with available data (2011), 25% of patients had TTI of greater than 46 days.
TTI independently affects survival. One in four patients experienced treatment delay. TTI of greater than 46 to 52 days introduced an increased risk of death that was most consistently detrimental beyond 60 days. Prolonged TTI is currently affecting survival.
•Positive margins in oral cavity carcinoma lower 5-year survival by 11–15%.•Radiation alone does not change survival outcomes.•Re-resection or chemoradiotherapy should be pursued in positive margin ...patients.
Positive margins are known to impact survival in oral cavity squamous cell carcinoma (OCSCC). We aimed to determine the impact of positive margins on survival and whether radiation improves survival following positive margins.
Data was obtained from the National Cancer Database and included patients with cT1T2N0 OCSCC.
Survival outcomes were assessed via log-rank test. Cox-regression analysis was performed to determine if positive margins or radiation, when applicable, correlated with survival after accounting for covariates.
Positive margin patients had worse overall survival compared to negative margin control (HR = 1.76, p < 0.001) and reduced survival by 13%. On multivariate analysis, positive margins correlated with survival (HR = 1.60, p < 0.001). Radiation did not improve survival in positive margin patients (HR = 0.99, p = 0.55).
Patients with positive margins have an 11–15% worse overall survival. Radiation does not appear to impact survival in patients with a positive margin.
To characterize the cosmetic outcomes and local recurrence (LR) rates of various hypofractionated radiation therapy (RT) regimens for skin basal and squamous cell cancers (BCCs/SCCs).
A ...PICOS/PRISMA/MOOSE selection protocol was performed to identify 344 articles published between 1985–2016 evaluating patients with T1–2 N0 SCCs/BCCs treated with definitive RT. Biologically equivalent doses with α/β=3 (BED3s) were calculated. The primary endpoint was post-treatment cosmesis. Mixed effects regression models were used to estimate weighted linear relationships between BED3 and cosmetic outcomes.
A total of 21 studies were identified detailing the treatment of 9729 skin BCC/SCC patients, across seven countries, with external beam RT (n=9255) or brachytherapy (n=474). Median follow-up was 36months (range: 12–77). Median dose was 45Gy/11 fractions (interquartile range: 37.5Gy/6–55Gy/18) at 4Gy/fraction (interquartile range: 2.5–6Gy); most hypofractionated 18.75Gy/1. There was a trend to decreased “good” cosmesis with higher total dose: −3.4% “good” cosmesis/10Gy BED3, p=0.01. Similarly, there was a trend to increased “fair” cosmesis with higher dose: +3.8% “fair” cosmesis/10Gy BED3,p=0.006. At a BED3 of 100Gy, the expected rate of “good” cosmesis is 79% (95% confidence interval: 70%, 88%). Hypofractionated schedules produced similar cosmesis to conventionally fractionated schedules, at the same BED3. Fewer than 8% of patients experienced “poor” cosmesis, independent of dose or fractionation regimen.
Hypofractionated RT has favorable cosmesis for patients with skin BCCs/SCCs. We recommend clinicians consider these commonly-used regimens, which all have BED3 of ∼100Gy: 50Gy/15 fractions, 36.75Gy/7 fractions, or 35Gy/5 fractions, as they result in “good” cosmesis in 80% of patients.
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