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•Carotid stenosis incidence was high, rising over time after head and neck radiation.•Diabetes was predictive of time to carotid stenosis on multivariate analysis.•Carotid dose ...parameters were not significantly associated with carotid stenosis.
Head and neck radiotherapy (RT) is a risk factor for cerebrovascular disease. We performed a retrospective cohort study to evaluate carotid artery stenosis (CAS) incidence in head and neck cancer (HNC) patients undergoing RT, characterizing associated risk factors.
Records were retrospectively reviewed for HNC patients undergoing carotid ultrasound screening after definitive or adjuvant RT between January 2000 and May 2016. CAS was defined as ≥50% stenosis on imaging, stroke, or transient ischemic attack. Actuarial CAS rates were calculated by Kaplan-Meier method. Univariate and multivariate analyses predicted CAS risk based on carotid dosimetric and clinical parameters.
366 patients met inclusion criteria. Median time from RT completion to last follow-up was 4.1 yr. Actuarial risk for CAS was 29% (95% CI 22–36%) at 8 years. Univariate analysis showed that smoking (HR 1.7; 95% CI 1.1–2.7), hyperlipidemia (HR 1.6; 95% CI 1.03–2.6), diabetes (HR 2.8; 95% CI 1.6–4.8), coronary artery disease (HR 2.4; 95% CI 1.4–4.2), and peripheral artery disease (HR 3.6; 95% CI 1.1–11.6) were significantly associated with increased CAS. In multivariate analysis, diabetes was predictive of time to CAS (HR 1.9; 95% CI 1.1–3.4). Carotid dose parameters were not significantly associated with CAS.
CAS incidence is high after head and neck radiotherapy, gradually rising over time. No clear dose-response effect between carotid dose and CAS was identified for HNC patients. Carotid artery screening and preventative strategies should be employed in this high-risk patient population.
Purpose
This study investigated the prognostic potential of intra‐treatment PET radiomics data in patients undergoing definitive (chemo) radiation therapy for oropharyngeal cancer (OPC) on a ...prospective clinical trial. We hypothesized that the radiomic expression of OPC tumors after 20 Gy is associated with recurrence‐free survival (RFS).
Materials and Methods
Sixty‐four patients undergoing definitive (chemo)radiation for OPC were prospectively enrolled on an IRB‐approved study. Investigational 18F‐FDG‐PET/CT images were acquired prior to treatment and 2 weeks (20 Gy) into a seven‐week course of therapy. Fifty‐five quantitative radiomic features were extracted from the primary tumor as potential biomarkers of early metabolic response. An unsupervised data clustering algorithm was used to partition patients into clusters based only on their radiomic expression. Clustering results were naïvely compared to residual disease and/or subsequent recurrence and used to derive Kaplan‐Meier estimators of RFS. To test whether radiomic expression provides prognostic value beyond conventional clinical features associated with head and neck cancer, multivariable Cox proportional hazards modeling was used to adjust radiomic clusters for T and N stage, HPV status, and change in tumor volume.
Results
While pre‐treatment radiomics were not prognostic, intra‐treatment radiomic expression was intrinsically associated with both residual/recurrent disease (P = 0.0256, χ2 test) and RFS (HR = 7.53, 95% CI = 2.54–22.3; P = 0.0201). On univariate Cox analysis, radiomic cluster was associated with RFS (unadjusted HR = 2.70; 95% CI = 1.26–5.76; P = 0.0104) and maintained significance after adjustment for T, N staging, HPV status, and change in tumor volume after 20 Gy (adjusted HR = 2.69; 95% CI = 1.03–7.04; P = 0.0442). The particular radiomic characteristics associated with outcomes suggest that metabolic spatial heterogeneity after 20 Gy portends complete and durable therapeutic response. This finding is independent of baseline metabolic imaging characteristics and clinical features of head and neck cancer, thus providing prognostic advantages over existing approaches.
Conclusions
Our data illustrate the prognostic value of intra‐treatment metabolic image interrogation, which may potentially guide adaptive therapy strategies for OPC patients and serve as a blueprint for other disease sites. The quality of our study was strengthened by its prospective image acquisition protocol, homogenous patient cohort, relatively long patient follow‐up times, and unsupervised clustering formalism that is less prone to hyper‐parameter tuning and over‐fitting compared to supervised learning.
Acute mucositis is a dose-limiting toxicity of concurrent chemoradiotherapy regimens for locally advanced head and neck cancer. Palifermin (a recombinant human keratinocyte growth factor; ...DeltaN23-KGF) stimulates the proliferation and differentiation of mucosal epithelium to reduce mucositis in patients receiving intensive therapy for hematologic cancers. This study assessed the efficacy and safety of palifermin in patients receiving concurrent chemoradiotherapy for advanced head and neck squamous cell carcinoma.
In a phase II trial, standard radiotherapy was delivered in daily 2-Gy fractions to 70 Gy, or hyperfractionated radiotherapy was delivered in 1.25-Gy fractions twice daily to 72 Gy, over 7 weeks. Chemotherapy included cisplatin 20 mg/m(2) for 4 days and continuous-infusion fluorouracil 1,000 mg/m(2)/d for 4 days on weeks 1 and 5 of irradiation. Patients were randomly assigned 2:1 to palifermin 60 microg/kg or placebo once weekly for 10 doses. A follow-up trial evaluated long-term survival.
Sixty-seven patients received palifermin and 32 received placebo. The median duration of grade >or= 2 mucositis was 6.5 and 8.1 weeks in the palifermin and placebo groups, respectively (P = .157). Palifermin appeared to reduce mucositis, dysphagia, and xerostomia during hyperfractionated radiotherapy (n = 40) but not standard radiation therapy (n = 59). Adverse events were similar between treatment groups. Palifermin did not alter tumor response or survival.
Ten once-weekly doses of palifermin at 60 microg/kg were well tolerated. Most patients completed treatment, but palifermin did not reduce the morbidity of concurrent chemotherapy and radiotherapy. Future studies should evaluate higher palifermin doses with longer and more standardized assessment of acute mucositis.
The concept of the therapeutic ratio (TR) is central to understanding the rationale for using radioprotectors. The TR relates tumor control probabilities and normal tissue complication probabilities ...to one another. An ideal radioprotector will reduce the latter without compromising the former. It should also be minimally toxic itself. Radioprotective strategies can be classified under the categories of protection, mitigation, and treatment. Protectors are administered before radiotherapy (RT) and are designed to prevent radiation-induced injury. Amifostine is the prototype drug. Mitigants are administered after RT but before the phenotypic expression of injury and are intended to ameliorate injury. Palifermin can be considered as the prototype mitigant. Treatment is a strategy that is predominantly palliative and supportive in nature. Pharmacologic radioprotective strategies should be integrated with physical strategies such as intensity-modulated radiotherapy to realize their maximum clinical potential.
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers provide treatment recommendations for cancers of the lip, oral cavity, pharynx, larynx, ethmoid and ...maxillary sinuses, and salivary glands. Recommendations are also provided for occult primary of the head and neck (H&N), and separate algorithms have been developed by the panel for very advanced H&N cancers. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding the increase in human papillomavirus-associated oropharyngeal cancer and the availability of immunotherapy agents for treatment of patients with recurrent or metastatic H&N cancer.
Radiotherapy for head and neck cancer causes acute and chronic xerostomia and acute mucositis. Amifositine and its active metabolite, WR-1065, accumulate with high concentrations in the salivary ...glands. This randomized trial evaluated whether amifostine could ameliorate these side effects without compromising the effectiveness of radiotherapy in these patients.
Patients with previously untreated head and neck squamous cell carcinoma were eligible. Primary end points included the incidence of grade > or =2 acute xerostomia, grade > or =3 acute mucositis, and grade > or =2 late xerostomia and were based on the worst toxicity reported. Amifostine was administered (200 mg/m(2) intravenous) daily 15 to 30 minutes before irradiation. Radiotherapy was given once daily (1.8 to 2.0 Gy) to doses of 50 to 70 Gy. Whole saliva production was quantitated preradiotherapy and regularly during follow-up. Patients evaluated their symptoms through a questionnaire during and after treatment. Local-regional control was the primary antitumor efficacy end point.
Nausea, vomiting, hypotension, and allergic reactions were the most common side effects. Fifty-three percent of the patients receiving amifostine had at least one episode of nausea and/or vomiting, but it only occurred with 233 (5%) of 4,314 doses. Amifostine reduced grade > or =2 acute xerostomia from 78% to 51% (P<.0001) and chronic xerostomia grade > or = 2 from 57% to 34% (P=.002). Median saliva production was greater with amifostine (0.26 g v 0.10 g, P=.04). Amifostine did not reduce mucositis. With and without amifostine, 2-year local-regional control, disease-free survival, and overall survival were 58% versus 63%, 53% versus 57%, and 71% versus 66%, respectively.
Amifostine reduced acute and chronic xerostomia. Antitumor treatment efficacy was preserved.
To test the effects of a novel Mn porphyrin oxidative stress modifier, Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin (MnBuOE), for its radioprotective and radiosensitizing properties ...in normal tissue versus tumor, respectively.
Murine oral mucosa and salivary glands were treated with a range of radiation doses with or without MnBuOE to establish the dose-effect curves for mucositis and xerostomia. Radiation injury was quantified by intravital near-infrared imaging of cathepsin activity, assessment of salivation, and histologic analysis. To evaluate effects of MnBuOE on the tumor radiation response, we administered the drug as an adjuvant to fractionated radiation of FaDu xenografts. Again, a range of radiation therapy (RT) doses was administered to establish the radiation dose-effect curve. The 50% tumor control dose values with or without MnBuOE and dose-modifying factor were determined.
MnBuOE protected normal tissue by reducing RT-mediated mucositis, xerostomia, and fibrosis. The dose-modifying factor for protection against xerostomia was 0.77. In contrast, MnBuOE increased tumor local control rates compared with controls. The dose-modifying factor, based on the ratio of 50% tumor control dose values, was 1.3. Immunohistochemistry showed that MnBuOE-treated tumors exhibited a significant influx of M1 tumor-associated macrophages, which provides mechanistic insight into its radiosensitizing effects in tumors.
MnBuOE widens the therapeutic margin by decreasing the dose of radiation required to control tumor, while increasing normal tissue resistance to RT-mediated injury. This is the first study to quantitatively demonstrate the magnitude of a single drug's ability to radioprotect normal tissue while radiosensitizing tumor.
Hypoxia shifts the balance of cellular energy production toward glycolysis with lactate generation as a by-product. Quantitative bioluminescence imaging allows for the quantitation of lactate ...concentrations in individual tumors. We assessed the relationship between pretreatment tumor lactate concentrations and subsequent development of metastatic disease in patients with newly diagnosed head-and-neck cancer.
At the time of biopsy of the primary site, a separate specimen was taken and flash-frozen for subsequent quantitation of lactate concentration using a luciferase bioluminescence technique. The two-dimensional spatial distribution of the bioluminescence intensity within the tissue section was registered directly using a microscope and an imaging photon counting system. Photon intensity was converted to distributions of volume-related tissue concentrations (micromol per gram wet weight). Treatment consisted of either surgery and postoperative radiotherapy or primary radiotherapy, based on presenting disease stage and institutional treatment policies. The subsequent development of metastatic disease constituted the primary clinical endpoint.
Biopsies obtained from 40 patients were evaluable in 34. The larynx was the most frequent primary site (n = 25). Other sites included oropharynx (n = 5), hypopharynx (n = 3), and oral cavity (n = 1). Most patients (74%) presented with an advanced stage T3 or T4 primary tumor. Nodal involvement was present in 19 (54%) patients. The median tumor lactate concentration was 7.1 micromol/g. Tumors were classified as having either low or high lactate concentrations according to whether these values were below or above the median. The median follow-up time for surviving patients is 27 months. Two-year actuarial survival was 90% for patients with low-lactate-concentration tumor vs. 35% for patients with high-lactate-concentration primaries (<0.0001). Two-year metastasis-free survival was adversely influenced by high tumor lactate concentrations (90% vs. 25%, p < 0.0001). The median lactate concentration for tumors that subsequently metastasized was 12.9 micromol/g vs. 4.8 micromol/g for patients who remained continuously free of disease (p < 0.005). Lactate concentration was not correlated with presenting T stage or N stage.
Elevated tumor lactate concentrations are associated with the subsequent development of nodal or distant metastases in head-and-neck cancer patients. This more aggressive malignant phenotype is probably associated with hypoxia-mediated radioresistance and the upregulation of metastasis-associated genes.
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