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The NCCN Guidelines for Head and Neck Cancers address tumors arising in the oral cavity (including mucosal lip), pharynx, larynx, and paranasal sinuses. Occult primary cancer, salivary gland cancer, and mucosal melanoma (MM) are also addressed. The specific site of disease, stage, and pathologic findings guide treatment (eg, the appropriate surgical procedure, radiation targets, dose and fractionation of radiation, indications for systemic therapy). The NCCN Head and Neck Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding management of HPV-positive oropharynx cancer and ongoing research in this area.
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Head and Neck Neoplasms , Head and Neck Neoplasms/diagnosis , Head and Neck Neoplasms/therapy , HumansABSTRACT
Patients with small cell lung cancer (SCLC) are at significant risk of developing brain metastases during their disease course. Prophylactic cranial irradiation (PCI) has been incorporated into SCLC treatment guidelines to diminish the risk of developing brain metastases. In 2007, a randomized trial suggested that PCI decreases the incidence of brain metastases and prolongs overall survival (OS) in patients with extensive-stage SCLC (ES-SCLC) who have responded to initial therapy. However, this study did not include modern central nervous system imaging with CT or MRI prior to randomization. A more recent Japanese trial with MRI staging and surveillance demonstrated that PCI diminished the incidence of brain metastases but did not improve survival. This review examines the largest clinical studies, controversies, and future directions of PCI in patients with ES-SCLC.
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Brain Neoplasms , Lung Neoplasms , Small Cell Lung Carcinoma , Brain Neoplasms/prevention & control , Brain Neoplasms/radiotherapy , Cranial Irradiation/adverse effects , Cranial Irradiation/methods , Humans , Lung Neoplasms/etiology , Lung Neoplasms/prevention & control , Lung Neoplasms/radiotherapy , Magnetic Resonance Imaging/methods , Small Cell Lung Carcinoma/prevention & control , Small Cell Lung Carcinoma/radiotherapyABSTRACT
INTRODUCTION: For patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) periodic reassessment of prognostic factors provides valuable information that can aid in patient stratification. PATIENTS AND METHODS: This post hoc analysis included all patients with R/M HNSCC enrolled in the ECOG-ACRIN E1305 phase III clinical trial who received first-line treatment with platinum-containing chemotherapy doublet with or without bevacizumab. Overall survival (OS) was estimated using the Kaplan-Meier method. Prognostic factors for OS were identified using univariate and multivariable analyses. A new prognostic model for OS was built retaining the prognostic factors which were significant in the final multivariable analysis (P < 0.05). RESULTS: All 403 study participants were included in the analysis. The median OS in the whole study cohort was 11.8 months (90% confidence intervals [CI], 10.6-13.2). The new prognostic model for OS comprised four risk factors (ECOG performance status [1 versus 0], primary tumor location [other versus oropharynx], presence of bone or liver metastasis, and prior radiation to the head and neck); patients with ≤ 2 (n = 249) and > 2 risk factors (n = 154) had a median OS of 15.2 and 7.6 months, respectively (Hazard ratio, 2.14; 95% CI, 1.73-2.66; P < 0.0001). CONCLUSIONS: The new proposed model includes 4 clinical prognostic factors that can be readily assessed at baseline. Similar models have the potential to improve trial design and optimize stratification of patients with R/M HNSCC.
Subject(s)
Head and Neck Neoplasms , Neoplasm Recurrence, Local , Humans , Prognosis , Squamous Cell Carcinoma of Head and Neck/drug therapy , Neoplasm Recurrence, Local/pathology , Head and Neck Neoplasms/drug therapy , Risk Factors , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Retrospective StudiesABSTRACT
OBJECTIVES: To investigate and describe the patterns of regional metastases and recurrences after surgical treatment of oropharyngeal squamous cell cancer (OPSCC). MATERIALS AND METHODS: Retrospective study of patients diagnosed with OPSCC from 2006 to 2021 at a tertiary referral center. Only patients treated with surgery including a neck dissection were included. Patients with unknown human papillomavirus (HPV) status, prior head and neck cancer, distant metastases, or synchronous head and neck cancer were excluded. RESULTS: A total of 928 patients were included. 89% were males, the average age was 58.6 years (range: 25.2-87.5), 874 (94%) were HPV(+), and 513 (55.3%) had a tonsil cancer. Among cN + patients, the most commonly involved levels at presentation were level II (85.2%), level III (33.3%), and level IV (9.4%). In cN0 patients, metastases were only observed in level II (16.2%) and level III (9.2%). Nodal recurrence occurred in 48 (5.2%) patients after a median time of 1.0 years (interquartile range: 0.6-2.0). Nodal recurrence incidence was similar in HPV(+) and HPV(-) patients (5.0% vs. 7.4%, p = 0.44). The most common levels for regional recurrence were ipsilateral level II (45.8%), contralateral level II (43.8%), and ipsilateral level V (25.0%). Multivariable analysis revealed that pN was a significant predictor for regional recurrence (p = 0.02). CONCLUSION: There is no difference in the distribution of regional metastases and recurrences in HPV(+) and HPV(-) OPSCC patients. Our findings align with the established understanding that regional metastases predominantly manifest in the ipsilateral level II-IV at presentation. Moreover, the data support the clinical recommendation to restrict elective neck dissection in cN0 patients to ipsilateral levels IIa and III, excluding level IIb. Regional recurrence is significantly associated with pN status.
Subject(s)
Carcinoma, Squamous Cell , Head and Neck Neoplasms , Oropharyngeal Neoplasms , Papillomavirus Infections , Male , Humans , Middle Aged , Female , Squamous Cell Carcinoma of Head and Neck/pathology , Retrospective Studies , Carcinoma, Squamous Cell/pathology , Papillomavirus Infections/pathology , Lymphatic Metastasis , Head and Neck Neoplasms/pathology , Neck Dissection , Neoplasm StagingABSTRACT
INTRODUCTION: Intensity-modulated proton therapy (IMPT) has the potential to reduce radiation dose to normal organs when compared to intensity-modulated radiation therapy (IMRT). We hypothesized that IMPT is associated with a reduced rate of cardiopulmonary toxicities in patients with Stage III NSCLC when compared with IMRT. METHODS: We analyzed 163 consecutively treated patients with biopsy-proven, stage III NSCLC who received IMPT (n = 35, 21%) or IMRT (n = 128, 79%). Patient, tumor, and treatment characteristics were analyzed. Overall survival (OS), freedom-from distant metastasis (FFDM), freedom-from locoregional relapse (FFLR), and cardiopulmonary toxicities (CTCAE v5.0) were calculated using the Kaplan-Meier estimate. Univariate cox regressions were conducted for the final model. RESULTS: Median follow-up of surviving patients was 25.5 (range, 4.6-58.1) months. Median RT dose was 60 (range, 45-72) Gy [RBE]. OS, FFDM, and FFLR were not different based on RT modality. IMPT provided significant dosimetric pulmonary and cardiac sparing when compared to IMRT. IMPT was associated with a reduced rate of grade more than or equal to 3 pneumonitis (HR 0.25, P = .04) and grade more than or equal to 3 cardiac events (HR 0.33, P = .08). Pre-treatment predicted diffusing capacity for carbon monoxide less than equal to 57% (HR 2.8, P = .04) and forced expiratory volume in the first second less than equal to 61% (HR 3.1, P = .03) were associated with an increased rate of grade more than or equal to 3 pneumonitis. CONCLUSIONS: IMPT is associated with a reduced risk of clinically significant pneumonitis and cardiac events when compared with IMRT without compromising tumor control in stage III NSCLC. IMPT may provide a safer treatment option, particularly for high-risk patients with poor pretreatment pulmonary function.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Pneumonia , Proton Therapy , Radiotherapy, Intensity-Modulated , Humans , Radiotherapy, Intensity-Modulated/adverse effects , Proton Therapy/adverse effects , Carcinoma, Non-Small-Cell Lung/pathology , Radiotherapy Dosage , Lung Neoplasms/pathology , Neoplasm Recurrence, Local/etiology , Pneumonia/etiology , Radiotherapy Planning, Computer-AssistedABSTRACT
Rebeccamycin analog (RA) is an antitumor antibiotic with both topoisomerase I and II inhibiting activity. Topoisomerase inhibitors have demonstrated synergy with platinum agents. We performed a phase I trial of combination RA with oxaliplatin in patients with refractory solid tumors. RA was administered as a 1-hour infusion daily on days 1-5 with oxaliplatin administered on day 5. Cycles were repeated every 21 days. A total of 17 patients were enrolled. The MTD for RA was 80 mg/m(2)/d for five days along with oxaliplatin 130 mg/m(2) on day 5. Myelosuppression was a common occurrence but was mild except in one instance. Dose limiting toxicities included atrial fibrillation and hypophosphatemia. There was evidence of antitumor activity including 3 partial responses in patients with esophageal, gallbladder and hepato-cellular carcinoma; 5 additional patients had stable disease. Thus, the combination of RA and oxaliplatin is both tolerable and has evidence of clinical activity, but given the lack of significant activity for single agent RA across a variety of disease sites, it is unlikely to proceed to phase II development.
Subject(s)
Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carbazoles/therapeutic use , Drug Resistance, Neoplasm , Glucosides/therapeutic use , Neoplasms/drug therapy , Organoplatinum Compounds/therapeutic use , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carbazoles/administration & dosage , Carbazoles/adverse effects , Dose-Response Relationship, Drug , Female , Glucosides/administration & dosage , Glucosides/adverse effects , Humans , Male , Middle Aged , Organoplatinum Compounds/administration & dosage , Organoplatinum Compounds/adverse effects , OxaliplatinABSTRACT
STUDY DESIGN: Cross-sectional. OBJECTIVE: The aim of this study was to describe the self-experienced trunk appearance in individuals with and without idiopathic scoliosis. SUMMARY OF BACKGROUND DATA: Idiopathic scoliosis is the most common spinal deformity. A large scoliotic deformity increases the risk of back pain and pulmonary dysfunction. The deformity has also a psychological impact. METHODS: The pictorial part of the spinal appearance questionnaire (pSAQ) was administered to 1416 individuals with idiopathic scoliosis (386 untreated, 529 brace treated, 501 surgically treated) and 272 individuals without scoliosis from the general population. Comparisons were made between individuals with and without scoliosis, between treatment groups and sex in the scoliosis group. RESULTS: Mean (95% confidence interval) age of the individuals with scoliosis was 36.2 (35.5-36.9) years and for the individuals without scoliosis 40.2 (37.9-42.4). pSAQ total was 12.3 (12.1-12.5) for individuals with scoliosis and 7.4 (7.3-7.6) for individuals without scoliosis (Pâ<â0.001, adjusted for age and sex). pSAQ total was 11.5 (11.1-11.9) for untreated, 13.0 (12.6-13.3) for brace treated, and 12.3 (11.9-12.6) for surgically treated individuals (Pâ<â0.001, adjusted for sex and curve size). The pSAQ total between males and females with idiopathic scoliosis did not differ (Pâ=â0.22 adjusted for age and curve size). CONCLUSION: This study shows that individuals with idiopathic scoliosis have more concern about their body appearance than individuals without scoliosis. Untreated individuals are not as bothered of their spinal appearance as treated individuals. Males and females with scoliosis do not differ significantly in the perception of their spinal appearance. LEVEL OF EVIDENCE: 3.
Subject(s)
Body Image/psychology , Scoliosis/psychology , Self-Assessment , Surveys and Questionnaires , Adult , Braces/trends , Cross-Sectional Studies , Female , Humans , Male , Quality of Life/psychology , Scoliosis/diagnostic imaging , Scoliosis/therapy , Spine/diagnostic imaging , Torso/diagnostic imagingABSTRACT
AIMS: Idiopathic scoliosis is the most common spinal deformity in adolescents and children. The aetiology of the disease remains unknown. Previous studies have shown a lower bone mineral density in individuals with idiopathic scoliosis, which may contribute to the causation. The aim of the present study was to compare bone health in adolescents with idiopathic scoliosis with controls. METHODS: We included 78 adolescents with idiopathic scoliosis (57 female patients) at a mean age of 13.7 years (8.5 to 19.6) and 52 age- and sex-matched healthy controls (39 female patients) at a mean age of 13.8 years (9.1 to 17.6). Mean skeletal age, estimated according to the Tanner-Whitehouse 3 system (TW3), was 13.4 years (7.4 to 17.8) for those with idiopathic scoliosis, and 13.1 years (7.4 to 16.5) for the controls. Mean Cobb angle for those with idiopathic scoliosis was 29° (SD 11°). All individuals were scanned with dual energy x-ray absorptiometry (DXA) and peripheral quantitative CT (pQCT) of the left radius and tibia to assess bone density. Statistical analyses were performed with independent-samples t-test, the Mann-Whitney U test, and the chi-squared test. RESULTS: Compared with controls, adolescents with idiopathic scoliosis had mean lower DXA values in the left femoral neck (0.94 g/cm2 (SD 0.14) vs 1.00 g/cm2 (SD 0.15)), left total hip (0.94 g/cm2 (SD 0.14) vs 1.01 g/cm2 (SD 0.17)), L1 to L4 (0.99 g/cm2 (SD 0.15) vs 1.06 g/cm2 (SD 0.17)) and distal radius (0.35 g/cm2 (SD 0.07) vs 0.39 g/cm2 (SD 0.08; all p ≤ 0.024), but not in the mid-radius (0.72 g/cm2 vs 0.74 g/cm2; p = 0.198, independent t-test) and total body less head (1,559 g (SD 380) vs 1,649 g (SD 492; p = 0.0.247, independent t-test). Compared with controls, adolescents with idiopathic scoliosis had lower trabecular volume bone mineral density (BMD) on pQCT in the distal radius (184.7 mg/cm3 (SD 40.0) vs 201.7 mg/cm3 (SD 46.8); p = 0.029), but not in other parts of the radius or the tibia (p ≥ 0.062, Mann-Whitney U test). CONCLUSION: In the present study, idiopathic scoliosis patients seemed to have lower BMD at central skeletal sites and less evident differences at peripheral skeletal sites when compared with controls. Cite this article: Bone Joint J 2020;102-B(2):268-272.
Subject(s)
Absorptiometry, Photon , Bone Density , Bone Diseases, Metabolic/diagnostic imaging , Scoliosis/diagnostic imaging , Adolescent , Bone Diseases, Metabolic/complications , Child , Female , Femur Neck/diagnostic imaging , Humans , Male , Radius/diagnostic imaging , Scoliosis/etiology , Tibia/diagnostic imaging , Tomography, X-Ray Computed , Young AdultABSTRACT
AIM: To investigate the inter- and intra-rater reliability of the vertebral fracture classifications used in the Swedish fracture register. METHODS: Radiological images of consecutive patients with cervical spine fractures (n = 50) were classified by 5 raters with different experience levels at two occasions. An identical process was performed with thoracolumbar fractures (n = 50). Cohen's kappa was used to calculate the inter- and intra-rater reliability. RESULTS: The mean kappa coefficient for inter-rater reliability ranged between 0.54 and 0.79 for the cervical fracture classifications, between 0.51 and 0.72 for the thoracolumbar classifications (overall and for different sub classifications), and between 0.65 and 0.77 for the presence or absence of signs of ankylosing disorder in the fracture area. The mean kappa coefficient for intra-rater reliability ranged between 0.58 and 0.80 for the cervical fracture classifications, between 0.46 and 0.68 for the thoracolumbar fracture classifications (overall and for different sub classifications) and between 0.79 and 0.81 for the presence or absence of signs of ankylosing disorder in the fracture area. CONCLUSION: The classifications used in the Swedish fracture register for vertebral fractures have an acceptable inter- and intra-rater reliability with a moderate strength of agreement.
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PURPOSE: We evaluated the addition of bevacizumab, a humanized monoclonal antibody that targets vascular endothelial growth factor, to platinum-based chemotherapy in recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Patients with chemotherapy-naïve (or with prior platinum as part of multimodal therapy completed ≥ 4 months earlier) recurrent or metastatic SCCHN were randomly assigned to receive a platinum-based chemotherapy doublet with or without bevacizumab 15 mg/kg given intravenously every 3 weeks until disease progression. Chemotherapy could be discontinued after six cycles if a maximum response was achieved. RESULTS: The study randomly assigned 403 patients. Median overall survival (OS) was 12.6 months with bevacizumab plus chemotherapy (BC) and 11.0 months with chemotherapy alone (hazard ratio, 0.87; 95% CI, 0.70 to 1.09; P = .22). At 2, 3, and 4 years, the OS rates were 25.2% v 18.1%, 16.4% v 10.0%, and 11.8% v 6.4% for BC versus chemotherapy, respectively. In an analysis of 365 eligible patients who started treatment, the hazard ratio was 0.82 (95% CI, 0.65 to 1.04; P = .10), with a median OS of 14.2 months on BC v 11.1 months on chemotherapy. Median progression-free survival with BC was 6.0 months v 4.3 months with chemotherapy (P = .0014). Overall response rates were 35.5% with BC and 24.5% with chemotherapy (P = .016). There was increased toxicity, including a higher rate of treatment-related grade 3 to 5 bleeding events (6.7% v 0.5%; P < .001) and treatment-related deaths (9.3% v 3.5%; P = .022) with BC versus chemotherapy. CONCLUSION: The addition of bevacizumab to chemotherapy did not improve OS but improved the response rate and progression-free survival with increased toxicities. These results encourage biomarker-driven studies of angiogenesis inhibitors with better toxicity profiles in select patients with SCCHN.
Subject(s)
Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Bevacizumab/administration & dosage , Head and Neck Neoplasms/drug therapy , Neoplasm Recurrence, Local , Squamous Cell Carcinoma of Head and Neck/drug therapy , Aged , Antineoplastic Agents, Immunological/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bevacizumab/adverse effects , Disease Progression , Drug Administration Schedule , Female , Head and Neck Neoplasms/mortality , Head and Neck Neoplasms/pathology , Humans , Male , Progression-Free Survival , Squamous Cell Carcinoma of Head and Neck/mortality , Squamous Cell Carcinoma of Head and Neck/secondary , Time Factors , United StatesABSTRACT
OBJECTIVES: Fine needle aspiration (FNA) biopsy of thyroid nodules provides cytologic specimens whose interpretation can direct patients toward either thyroidectomy or observation. Approximately 20% of FNA specimens yield an indeterminate result. Recent studies have characterized differences in gene expression between benign and malignant conditions, most often using whole tissue. Our goal was to determine the feasibility of quantitative polymerase chain reaction (qPCR)-based gene expression analysis in cytologic samples. For five genes shown to be over-expressed in thyroid carcinomas (fibronectin, galectin-3, Met/HGFR, MUC1, and GA733-precursor), we compared expression among pathologic states. STUDY DESIGN: Prospective laboratory analysis of 20 thyroidectomy specimens. METHODS: Routine microscopy was performed. Cytologic samples were obtained from the dominant nodules, and RNA was extracted. Preliminary analysis using fluorometry and reverse-transcriptase (RT)-PCR was performed. Expression levels of the test genes in nodules and from control samples were measured by real-time qPCR. Fold changes in gene expression were compared. RESULTS: Only one specimen did not yield sufficient intact RNA for gene expression analysis. RT-PCR revealed satisfactory RNA recovery in all other specimens. qPCR showed significant over-expression of fibronectin in the papillary carcinomas compared with the goiters (P = .0013), follicular adenomas (P = .0014), and follicular carcinomas (P = .0001). Differences in both fibronectin and MUC1 expression between the follicular carcinomas and the follicular adenomas were also significant (P = .025 and .045, respectively). CONCLUSIONS: Cytologic specimens were a satisfactory source of tissue for qPCR-based gene expression analysis. Both fibronectin and MUC1 were differentially expressed in follicular adenomas and follicular carcinomas, and fibronectin expression differed in papillary carcinomas compared with the other lesions. These results may form the basis of a clinical predictor for lesions with indeterminate or suspicious cytology.
Subject(s)
Thyroid Nodule/pathology , Adenocarcinoma, Follicular/pathology , Adenoma/pathology , Antigens, Neoplasm/analysis , Biomarkers, Tumor/analysis , Biopsy, Fine-Needle , CD3 Complex/analysis , Carcinoma, Papillary/pathology , Cell Adhesion Molecules/analysis , Epithelial Cell Adhesion Molecule , Feasibility Studies , Fibronectins/analysis , Galectin 3/analysis , Gene Expression Regulation, Neoplastic/genetics , Goiter/pathology , Humans , Molecular Biology , Mucin-1/analysis , Polymerase Chain Reaction , Prospective Studies , Protein-Tyrosine Kinases/analysis , Proto-Oncogene Proteins/analysis , Proto-Oncogene Proteins c-met , Receptors, Growth Factor/analysis , Reverse Transcriptase Polymerase Chain Reaction , Thyroid Neoplasms/pathologyABSTRACT
BACKGROUND: Prospective data on health-related quality of life in patients with idiopathic scoliosis treated surgically as adults is needed. We compared preoperative and 1- and 2-year follow-up data in surgically treated adults with idiopathic scoliosis with juvenile or adolescent onset. Results were compared to untreated adults with scoliosis and population normative data. METHODS: A comparison of preoperative and 1- and 2-year follow-up data of 75 adults surgically treated for idiopathic scoliosis at a mean age of 28 years (range 18 to 69) from a prospective national register study, as well as a comparison with age- and sex-matched data from 75 untreated adults with less severe scoliosis and 75 adults without scoliosis, was made. Outcome measures were EuroQol-5 dimensions (EQ-5D) and Scoliosis Research Society (SRS)-22r questionnaire. RESULTS: In the surgically treated, EQ-5D and SRS-22r scores had statistically significant improvements at both 1- and 2-year follow-ups (all p < 0.015). The effect size of surgery on EQ-5D at 1-year follow-up was large (r = -0.54) and small-medium (r = -0.20) at 2-year follow-up. The effect size of surgery on SRS-22r outcomes was medium-large at 1- and 2-year follow-ups (r = -0.43 and r = -0.42 respectively). At the 2-year follow-up, the EQ-5D score and the SRS-22r subscore were similar to the untreated scoliosis group (p = 0.56 and p = 0.91 respectively), but lower than those in the adults without scoliosis (p < 0.001 for both comparisons). CONCLUSIONS: Adults with idiopathic scoliosis experience an increase in health-related quality of life following surgery at 2-year follow-up, approaching the health-related quality of life of untreated individuals with less severe scoliosis, but remain lower than normative population data.
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BACKGROUND: The purpose of this study was to establish the efficacy and toxicities of concurrent erlotinib and docetaxel with intensity-modulated radiotherapy (IMRT) for locally advanced head and neck squamous cell carcinoma (HNSCC). METHODS: Patients received daily erlotinib for 2 weeks, followed by daily IMRT with concurrent weekly docetaxel and daily erlotinib, followed by daily erlotinib for up to 2 years. The primary objective was disease-free survival (DFS). Secondary objectives included overall survival (OS), patterns of failure, and toxicities. Forty-three patients were recruited for this study. RESULTS: With a median follow-up of 48.7 months, the 3-year DFS, OS, locoregional failure-free survival, and distant metastasis-free survival was 69.5%, 81%, 82.4%, and 83.7%, respectively. The most common grade III/IV local toxicities were dysphagia, dermatitis, and mucositis. Patients with p16-positive tumors had significantly better outcomes. CONCLUSION: The regimen is tolerable and effective. It is worthy of further investigation in selected patients and may be useful in patients who cannot tolerate cisplatin. © 2016 Wiley Periodicals, Inc. Head Neck 38: E1770-E1776, 2016.
Subject(s)
Carcinoma, Squamous Cell/therapy , Chemoradiotherapy , Erlotinib Hydrochloride/therapeutic use , Head and Neck Neoplasms/therapy , Radiotherapy, Intensity-Modulated , Taxoids/therapeutic use , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols , Cisplatin , Disease-Free Survival , Docetaxel , Female , Humans , Male , Middle AgedABSTRACT
BACKGROUND: Chemoradiotherapy results in excellent outcomes in locally advanced head and neck squamous cell carcinoma (HNSCC). This trial compared 2 chemoradiotherapy regimens. METHODS: Patients with locally advanced HNSCC were treated with radiation (70-74.4 Gy), and randomized to arm A: cisplatin 100 mg/m(2) on radiotherapy (RT) days 1, 22, and 43, or arm B: cisplatin (20 mg/m(2) /day) and 5-fluorouracil (5-FU; 1000 mg/m(2) /day) continuous 96-hour infusions on RT weeks 1 and 4. The primary endpoint was relapse-free survival (RFS). RESULTS: Between February 2008 and October 2011, 69 patients were enrolled in this study. The study prematurely closed when a scheduled interim analysis showed superior outcomes in both arms and futility of continuation. Eighty-three percent of patients had oropharyngeal cancer, of these, 86% were human papillomavirus (HPV)/p16+. The 3-year Kaplan-Meier outcome estimates (median follow-up, 41 months) for arms A and B were: RFS 87% versus 80% (p = .24), overall survival 97% versus 85% (p = .013), locoregional control 96% versus 94% (p = .52), and distant metastatic control 91% versus 87% (p = .9). CONCLUSION: Multiagent was not superior to single-agent chemoradiotherapy. Overrepresentation of HPV/p16+ patients resulted in better than expected outcomes.
Subject(s)
Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/therapy , Chemoradiotherapy/methods , Cisplatin/administration & dosage , Head and Neck Neoplasms/mortality , Head and Neck Neoplasms/therapy , Adult , Aged , Carcinoma, Squamous Cell/pathology , Disease-Free Survival , Drug Administration Schedule , Female , Follow-Up Studies , Head and Neck Neoplasms/pathology , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasm Invasiveness/pathology , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/therapy , Neoplasm Staging , Radiotherapy Dosage , Risk Assessment , Statistics, Nonparametric , Survival Analysis , Treatment OutcomeABSTRACT
BACKGROUND: Anaplastic thyroid cancer (ATC) is a rare but highly aggressive malignancy with a median survival of 3-5 months. The BRAF oncogene is mutated to its active form in up to 24% of ATC cases. Sorafenib is a tyrosine kinase inhibitor that acts on the RAF-1 serine/threonine kinase. In preclinical mouse models, sorafenib inhibits the growth of ATC xenografts and improves survival. No study of sorafenib in ATC has been conducted. We conducted a multi-institutional phase II trial of sorafenib in patients with ATC who had failed up to two previous therapies. METHODS: The primary endpoint of the trial was the Response Evaluation Criteria In Solid Tumors (RECIST)-defined imaging response rate. Twenty patients with ATC were treated with sorafenib 400 mg twice daily. RESULTS: Two of the 20 patients had a partial response (10%) and an additional 5 of 20 (25%) had stable disease. The duration of response in the two responders was 10 and 27 months, respectively. For the patients with stable disease, the median duration was 4 months (range 3-11 months). The overall median progression-free survival was 1.9 months with a median and a 1-year survival of 3.9 months and 20%, respectively. Toxicity was manageable and as previously described for sorafenib, including hypertension and skin rash. CONCLUSION: Sorafenib has activity in ATC, but at a low frequency and similar to our previous experience with fosbretabulin. One patient with a response had previously progressed on fosbretabulin. Toxicities were both predictable and manageable.
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma/drug therapy , Niacinamide/analogs & derivatives , Phenylurea Compounds/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-raf/antagonists & inhibitors , Thyroid Gland/drug effects , Thyroid Neoplasms/drug therapy , Adult , Aged , Antineoplastic Agents/adverse effects , Carcinoma/pathology , Drug Eruptions/etiology , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Female , Follow-Up Studies , Humans , Hypertension/chemically induced , Male , Middle Aged , Neoplasm Staging , Niacinamide/adverse effects , Niacinamide/therapeutic use , Phenylurea Compounds/adverse effects , Protein Kinase Inhibitors/adverse effects , Sorafenib , Survival Analysis , Thyroid Carcinoma, Anaplastic , Thyroid Gland/pathology , Thyroid Neoplasms/pathologyABSTRACT
Methoxyamine (MX) is the first DNA base-excision-repair (BER) inhibitor evaluated in humans. This work described the development and validation of an LC-MS/MS method for quantitative determination of MX in human plasma. In this method, MX and its stable isotope methoxyl-d(3)-amine (MX-d3 as internal standard) were directly derivatized in human plasma with 4-(N,N-diethylamino)benzaldehyde. The derivatized MX and IS were extracted by methyl-tert-butyl ether, and separated isocratically on a Xterra C18 column (2.1 mm × 100 mm) using an aqueous mobile phase containing 45% acetonitrile and 0.4% formic acid at a flow rate of 0.200 ml/min. Quantitation of MX was carried out by multiple-reaction-monitoring (MRM) mode of positive turbo-ion-spray tandem mass spectrometry. This method has been validated according to FDA guidelines for bioanalytical method. The linear calibration range for MX was 1.25-500 ng/ml in human plasma with a correlation coefficient≥0.9993. The intra- and inter-assay precision (%CV) at three concentration levels (3.50, 45.0 and 450 ng/ml) ranged 0.9-1% and 0.8-3%, respectively. The stability studies showed that MX met the acceptable criteria under all tested conditions. The method developed had been applied to the determination of plasma MX concentrations in the first-in-human phase I clinical trial, and PK data were presented.
Subject(s)
Chromatography, Liquid/methods , Clinical Trials, Phase I as Topic/methods , Hydroxylamines/pharmacokinetics , Neoplasms/metabolism , Tandem Mass Spectrometry/methods , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Benzaldehydes/chemistry , Dacarbazine/administration & dosage , Dacarbazine/analogs & derivatives , Drug Stability , Humans , Hydroxylamines/administration & dosage , Hydroxylamines/blood , Hydroxylamines/isolation & purification , Linear Models , Liquid-Liquid Extraction , Neoplasms/blood , Neoplasms/drug therapy , Reproducibility of Results , Sensitivity and Specificity , TemozolomideABSTRACT
PURPOSE: To determine the pattern and risk factors for distant metastases in head-and-neck squamous cell carcinoma (HNSCC) after curative treatment with intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: This was a retrospective study of 284 HNSCC patients treated in a single institution with IMRT. Sites included were oropharynx (125), oral cavity (70), larynx (55), hypopharynx (17), and unknown primary (17). American Joint Committee on Cancer stage distribution includes I (3), II (19), III (42), and IV (203). There were 224 males and 60 females with a median age of 57. One hundred eighty-six patients were treated with definitive IMRT and 98 postoperative IMRT. One hundred forty-nine patients also received concurrent cisplatin-based chemotherapy. RESULTS: The median follow-up for all patients was 22.8 months (range, 0.07-77.3 months) and 29.5 months (4.23-77.3 months) for living patients. The 3-year local recurrence-free survival, regional recurrence-free survival, locoregional recurrence-free survival, distant metastasis-free survival, and overall survival were 94.6%, 96.4%, 92.5%, 84.1%, and 68.95%, respectively. There were 45 patients with distant metastasis. In multivariate analysis, distant metastasis was strongly associated with N stage (p = 0.046), T stage (p < 0.0001), and pretreatment maximum standardized uptake value of the lymph node (p = 0.006), but not associated with age, gender, disease sites, pretreatment standardized uptake value of the primary tumor, or locoregional control. The freedom from distant metastasis at 3 years was 98.1% for no factors, 88.6% for one factor, 68.3% for two factors, and 41.7% for three factors (p < 0.0001 by log-rank test). CONCLUSION: With advanced radiation techniques and concurrent chemotherapy, the failure pattern has changed with more patients failing distantly. The majority of patients with distant metastases had no local or regional failures, indicating that these patients might have microscopic distant disease before treatment. The clinical factors identified here should be incorporated in future clinical trials.
Subject(s)
Carcinoma, Squamous Cell/radiotherapy , Carcinoma, Squamous Cell/secondary , Head and Neck Neoplasms/radiotherapy , Radiotherapy, Intensity-Modulated/methods , Adult , Aged , Aged, 80 and over , Analysis of Variance , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/mortality , Combined Modality Therapy , Disease-Free Survival , Female , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/mortality , Head and Neck Neoplasms/pathology , Humans , Male , Middle Aged , Neoplasm Staging , Radiotherapy Dosage , Retrospective StudiesABSTRACT
PURPOSE: Combining cytotoxic agents with bevacizumab has yielded significant benefits in a number of solid tumors. Combining small-molecule kinase inhibitors of VEGFR with chemotherapy has yet to demonstrate clinical benefit. The dose, schedule and agents used may be critical to the development of this combinatorial therapy. METHODS: We performed a phase I trial of sunitinib and gemcitabine in patients with advanced solid tumor malignancies based on strong preclinical rationale. RESULTS: Two different MTDs were determined. The schedule of gemcitabine 800 mg/m(2) on days 1, 8, 15 and sunitinib 25 mg daily was considered to be a MTD. However, omission of day 15 gemcitabine was common, and thus, a second MTD of gemcitabine of 675 mg/m(2) on days 1 and 8 with sunitinib 25 mg daily was determined to be the recommended phase II dose. Grade 4 neutropenia and thrombocytopenia occurred in 33 and 6 %, respectively. Grade 3/4 non-hematological toxicities were uncommon. Four of 33 patients had a partial response. Another 11 patients had stable disease ranging from 3 to 36 months. Thus, the recommended phase II dose of this combination is gemcitabine 675 mg/m(2) on days 1 and 8 on an every 21-day schedule along with sunitinib 25 mg continuous daily. CONCLUSIONS: This combination is well-tolerated and has significant clinical activity.