Canagliflozin mediates tumor suppression alone and in combination with radiotherapy in non-small cell lung cancer (NSCLC) through inhibition of HIF-1α.

Non-small cell lung cancer (NSCLC) has a poor prognosis, and effective therapeutic strategies are lacking. The diabetes drug canagliflozin inhibits NSCLC cell proliferation and the mammalian target of rapamycin (mTOR) pathway, which mediates cell growth and survival, but it is unclear whether this drug can enhance response rates when combined with cytotoxic therapy. Here, we evaluated the effects of canagliflozin on human NSCLC response to cytotoxic therapy in tissue cultures and xenografts. Ribonucleic acid sequencing (RNA-seq), real-time quantitative PCR (RT-qPCR), metabolic function, small interfering ribonucleic acid (siRNA) knockdown, and protein expression assays were used in mechanistic analyses. We found that canagliflozin inhibited proliferation and clonogenic survival of NSCLC cells and augmented the efficacy of radiotherapy to mediate these effects and inhibit NSCLC xenograft growth. Canagliflozin treatment alone moderately inhibited mitochondrial oxidative phosphorylation and exhibited greater antiproliferative capacity than specific mitochondrial complex-I inhibitors. The treatment downregulated genes mediating hypoxia-inducible factor (HIF)-1α stability, metabolism and survival, activated adenosine monophosphate-activated protein kinase (AMPK) and inhibited mTOR, a critical activator of hypoxia-inducible factor-1α (HIF-1α) signaling. HIF-1α knockdown and stabilization experiments suggested that canagliflozin mediates antiproliferative effects, in part, through suppression of HIF-1α. Transcriptional regulatory network analysis pinpointed histone deacetylase 2 (HDAC2), a gene suppressed by canagliflozin, as a key mediator of canagliflozin's transcriptional reprogramming. HDAC2 knockdown eliminated HIF-1α levels and enhanced the antiproliferative effects of canagliflozin. HDAC2-regulated genes suppressed by canagliflozin are associated with poor prognosis in several clinical NSCLC datasets. In addition, we include evidence that canagliflozin also improves NSCLC response to chemotherapy. In summary, canagliflozin may be a promising therapy to develop in combination with cytotoxic therapy in NSCLC.

A two-center experience: The impact of COVID-19 on two brachytherapy programs in Ontario - virtual care, service suspension and radiation therapy workflow.

INTRODUCTION: Most brachytherapy (BT) procedures require general anesthesia and are therefore considered aerosol generating medical procedures (AGMPs). The COVID-19 pandemic impacted BT as services were prioritized by balancing the harm associated with COVID-19 infection versus the effect of delay of potentially curative treatment. This article summarizes the impact of the pandemic on BT programs in two cancer centers in a Canadian province. METHODS: As part of a quality assurance project, a retrospective study was conducted for the first five months of the pandemic (March 1 to July 31, 2020). Chart review and COVID-19 related mitigation strategies were identified by BT Clinical Specialist Radiation Therapists (bCSRT) in each center using electronic medical records, departmental reports, policies and procedures. RESULTS: Impact included start of virtual care (VC), shortened fractionation, suspension of services and workflow changes.  Both centers implemented VC strategies to reduce clinic visits: "same-day size and treat" strategy for post-operative endometrial cancer patients and virtual patient education for all patients. BT services that were suspended were low-dose-rate and high-dose-rate (HDR) prostate treatments (Center 1), lung and esophagus HDR treatments (Center 2).  Workflow changes that affected staff and patients in both centers included COVID-19 screening and the use of personal protective equipment. The centers were marginally different in workflow adjustments for AGMP procedures.  Those considered high-risk AGMP and low-risk cancer were suspended temporarily with alternate treatment strategies sought for some patients. Others had temporizing treatment such as androgen deprivation therapy to facilitate oncological safe deferral of procedures. CONCLUSION: Both BT programs delivered treatment to most patients with minimal delays and cancellations, where feasible. Some of the pandemic workflow changes continued to the current state of the pandemic. Long-term follow-up is needed to assess the impact of COVID-19 and treatment interruptions on oncologic outcomes.

Malignant transformation of a solitary tracheal papilloma in the absence of human papillomavirus infection in a patient with 48, XYYY syndrome: case report.

The diagnosis and management of tracheobronchial papilloma is challenging due to its rarity, and non-specific presenting symptoms. Small percentage undergoes malignant transformation. Herein, we report an unusual case of tracheal papilloma initially misdiagnosed as chronic obstructive pulmonary disease (COPD) in 36-year-old male with triple Y syndrome. It was successfully treated with local debridement and brachytherapy. To the best of our knowledge, this is the first description of brachytherapy for such a condition.

BRACHY: A Randomized Trial to Evaluate Symptom Improvement in Advanced Non-Small Cell Lung Cancer Treated With External Beam Radiation With or Without High-Dose-Rate Intraluminal Brachytherapy.

PURPOSE: Uncontrolled studies suggest that the addition of high-dose-rate intraluminal brachytherapy (HDRIB) to external beam radiation therapy (EBRT) may improve palliation for patients with advanced non-small cell lung cancer (NSCLC). The purpose of this study was to evaluate the potential clinical benefit of adding HDRIB to EBRT in a multicenter randomized trial. METHODS AND MATERIALS: Patients with symptomatic stage III or IV NSCLC with endobronchial disease were randomized to EBRT (20 Gy in 5 daily fractions over 1 week or 30 Gy in 10 daily fractions over 2 weeks) or the same EBRT plus HDRIB (14 Gy in 2 fractions separated by 1 week). The primary outcome was the proportion of patients who achieved symptomatic improvement in patient-reported overall lung cancer symptoms on the Lung Cancer Symptom Scale (LCSS) at 6 weeks after randomization. Secondary outcomes included improvement in individual symptoms, symptom-progression-free survival, overall survival, and toxicity. The planned sample size was 250 patients based on detection of symptomatic improvement from 40% to 60% with a 2-sided α of .05 and 80% power. RESULTS: A total of 134 patients were randomized over 4.5 years: 67 to each arm. The study closed early owing to slow accrual. The mean age was 69.8 years, and 67% of patients had metastatic disease. At 6 weeks, 19 patients (28.4%) in the EBRT arm and 20 patients (29.9%) in the EBRT plus HDRIB arm experienced an improvement in lung cancer symptoms (P = .84). When limited to patients who completed the LCSS, percentages were 40.4% versus 47.6%, respectively (P = .49). Between group differences in mean change scores (0.3-0.5 standard deviations) in favor of EBRT plus HDRIB were observed for overall symptoms, but only hemoptysis was significantly improved (P = .03). No significant differences were observed in progression-free or overall survival. Grade 3/4 toxicities were similar between groups. CONCLUSIONS: Small to moderate improvements were seen in symptom relief with the combined therapy, but they did not reach statistical significance. Further research is necessary before recommending HDRIB in addition to EBRT for palliation of lung cancer symptoms.

The role of brachytherapy in treatment of stage I esophageal cancer: A systematic review.

PURPOSE: Despite advancements in the early detection of esophageal cancer, optimal radiotherapy methods for treatment of early disease have not yet been determined. Moreover, the benefit of intraluminal brachytherapy on local control or survival remains controversial. We performed a systematic review to establish the role of brachytherapy as boost therapy in stage I esophageal squamous cell carcinoma, and to evaluate associated survival outcomes. METHODS AND MATERIALS: A systematic search of three bibliographic databases from January 1950 to January 2019 was conducted. All studies investigating brachytherapy for curative intent were included and palliative treatment was excluded. Primary outcomes included overall survival and disease-free survival (DFS). Secondary outcomes included loco-regional control (LRC) and toxicity grades and/or complications. Two reviewers independently abstracted data and evaluated study quality using grading of recommendations assessment, development, and evaluation, pooled results were presented through risk ratios. RESULTS: A total of 12 retrospective studies met inclusion criteria. The overall quality of evidence yielded a Grade 1C rating (strong recommendation, low quality evidence). Of 525 included patients, 325 patients received both external beam radiation (EBRT), and brachytherapy, 132 underwent EBRT only, and 68 received brachytherapy with and/or without chemoradiation. For patient group treated with EBRT and brachytherapy, 5-year mortality, DFS and LRC were: 43% (27-59%), 63% (49-76%) and 72% (63-80%) respectively. Rates of complications reported included 82.1% Grade 1 esophagitis for a combined external beam radiation and brachytherapy cohort, 12.3% ulcerations, and 3.3% fistulae. CONCLUSIONS: Brachytherapy as a combined modality is encouraging, given its relative safety and effectiveness. Further prospective analysis using higher quality evidence is warranted to evaluate oncologic outcomes and survival advantage.

Review of brachytherapy complications - Upper gastrointestinal tract.

While brachytherapy applications are not widely used for cancer diagnoses in the upper GI tract (including the esophagus, liver, stomach, and pancreas), they have a clear role in palliation and symptom management and occasionally definitive locoregional treatment. With the increasing use of image-guided techniques, the incidence of side effects and complications has shown to be lower than many other alternative treatment modalities, making brachytherapy approaches a preferred treatment option. This review examines procedural complications and acute and chronic adverse effects from radiation associated with esophageal, hepatobiliary, and pancreatic brachytherapy and their management.

Low-dose non-targeted radiation effects in human esophageal adenocarcinoma cell lines.

PURPOSE: To investigate non-targeted radiation effects in esophageal adenocarcinoma cell lines (OE19 and OE33) using human keratinocyte and colorectal cancer cell reporters following γ-ray exposure. MATERIALS AND METHODS: Both clonogenic assays and ratiometric calcium endpoints were used to check for the occurrence of bystander signals in reporter cells. RESULTS: We report data suggesting that γ-irradiation increases cell killing over the expected linear quadratic (LQ) model levels in the OE19 cell line exposed to doses below 1 Gy, i.e. which may be suggestive to be a low hyper-radiosensitive (HRS) response to direct irradiation. Both EAC cell lines (OE19 and OE33) have the ability to produce bystander signals when irradiated cell conditioned medium (ICCM) is placed onto human keratinocyte reporters, but do not seem to be capable of responding to bystander signals when placed on their autologous reporters. Further work with human keratinocyte reporter models showed statistically significant intracellular calcium fluxes following exposure of the reporters to ICCM harvested from both EAC cell lines exposed to 0.5 Gy. CONCLUSION: These experiments suggest that the OE19 and OE33 cell lines produce bystander signals in human keratinocyte reporter cells. However, the radiosensitivity of the EAC cell lines used in this study cannot be enhanced by the bystander response since both cell lines could not respond to bystander signals.

Prospective comparison of rectal dose reduction during intracavitary brachytherapy for cervical cancer using three rectal retraction techniques.

PURPOSE: To compare three rectal retraction methods on dose to organs at risk, focusing on rectal dose, in cervix cancer patients treated with high-dose-rate intracavitary brachytherapy. METHODS AND MATERIALS: A prospective study was conducted on patients with cervical carcinoma treated with chemoradiotherapy, including external beam radiation and four fractions of high-dose-rate intracavitary brachytherapy prescribed to Point A using a ring and tandem applicator under conscious sedation. Rectal retraction methods included: a rectal retractor blade (RR), vaginal gauze packing (VP), and a tandem Foley balloon (FB). All three methods were used in all patients. The RR was used first, and the following applications were randomly assigned to VP or FB. CT planning was used to calculate D2cc for rectum, sigmoid, small bowel, and bladder. The Wilcoxon signed rank test was used to determine if the median dose differences between methods were statistically significant. RESULTS: In these 11 patients, median dose (min, max) in cGy to the rectum using RR, FB, and VP was 131 (102, 165), 199 (124, 243), and 218 (149, 299), respectively. The RR demonstrated lower median intrapatient doses to rectum compared with FB and VP (-55 cGy; p = 0.014 and -76 cGy; p = 0.004, respectively). The RR also resulted in lower sigmoid doses. No differences in dose were observed between the VP and FB methods. CONCLUSION: The rectal retractor significantly reduced the dose to rectum and sigmoid compared with FP and VP. In patients treated under conscious sedation, the RR method provides the best rectal sparing. There were no significant differences in dose observed between the FB and VP techniques.

A Phase II Trial of Erlotinib and Concurrent Palliative Thoracic Radiation for Patients With Non-Small-Cell Lung Cancer.

BACKGROUND: The downstream signaling pathways of the epidermal growth factor receptor might influence radiation resistance. Data from preclinical work support the hypothesis that erlotinib concurrent with radiation therapy (RT) might increase cancer cell killing. The present trial was designed to examine the efficacy and toxicity of combined erlotinib and palliative chest thoracic RT in non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: Patients with newly diagnosed stage III-IV (American Joint Committee on Cancer, version 6) or recurrent NSCLC received 3 weeks of erlotinib at a dose of 150 mg daily, starting 1 week before palliative thoracic RT to 30 Gy in 10 fractions within 2 weeks. The primary outcome was a change in the quality of life, as measured by the Lung Cancer Symptom Scale (LCSS) question on the "symptoms of lung cancer" from baseline to 4 weeks after treatment. RESULTS: A total of 40 patients were recruited from 2 institutions. Of the 40 patients, 22 (55%) were men, with an average age of 71 years, and 60% had stage IV disease. A total of 26 patients (65%) completed the full course of erlotinib, and 35 (88%) completed the planned RT. Twenty-five patients (62.5%) reported LCSS scores at 4 weeks after treatment, with an average change (improvement) of -12.5 U (95% confidence interval, -23.0 to -1.9; 2P = .023). This was less than the a priori hypothesis of a change of -17.5 U. The median overall and progression-free survival was 5.2 and 3.2 months, respectively. CONCLUSION: The present single-arm, phase II trial did not demonstrate additional symptomatic benefit from concurrent erlotinib therapy with standard palliative thoracic RT for patients with locally advanced or metastatic NSCLC.

Assessing patient characteristics and radiation-induced non-targeted effects in vivo for high dose-rate (HDR) brachytherapy.

PURPOSE: To test whether blood, urine, and tissue based colony-forming assays are a useful clinical detection tool for assessing fractionated treatment responses and non-targeted radiation effects in bystander cells. MATERIALS AND METHODS: To assess patients' responses to radiation treatments, blood serum, urine, and an esophagus explant-based in vivo colony-forming assay were used from oesophageal carcinoma patients. These patients underwent three fractions of high dose rate (HDR) intraluminal brachytherapy (ILBT). RESULTS: Human keratinocyte reporters exposed to blood sera taken after the third fraction of brachytherapy had a significant increase in cloning efficiency compared to baseline samples (p < 0.001). Such results may suggest an induced radioresistance response in bystander cells. The data also revealed a clear inverse dose-rate effect during late treatment fractions for the blood sera data only. Patient characteristics such as gender had no statistically significant effect (p > 0.05). Large variability was observed among the patients' tissue samples, these colony-forming assays showed no significant changes throughout fractionated brachytherapy (p > 0.05). CONCLUSION: Large inter-patient variability was found in the urine and tissue based assays, so these techniques were discontinued. However, the simple blood-based assay had much less variability. This technique may have future applications as a biological dosimeter to predict treatment outcome and assess non-targeted radiation effects.

A prospective analysis of high-dose-rate endobronchial brachytherapy in the palliation of obstructive symptoms in lung cancer patients: A single-institution experience.

PURPOSE: Obstructive symptoms that affect quality of life (QOL) are commonly caused by endobronchial disease in many patients with locally advanced, inoperable lung cancer. High-dose-rate endobronchial brachytherapy (HDREBBT) has been used to palliate these symptoms, yet its role is not well defined in the literature. METHODS AND MATERIALS: Ninety-eight patients with locally advanced, inoperable lung cancer received HDREBBT. They were prospectively followed for survival, QOL, and toxicity endpoints. QOL measures were captured using the Quality of Life Questionnaire-Lung Cancer 30 and -Lung Cancer 13. RESULTS: At 1-year follow-up, no significant toxicities were seen. Overall survival was 13.4% at 12 months (mean 192 days). Performance status, additional treatment after HDREBBT and treatment intent affected overall survival on univariate analysis (p < 0.05). Mean hemoptysis-free survival for all patients was 232.3 days, cough-free survival was 140.3 days, and dyspnea-free survival was 173.5 days. There was no impact of any treatment- or patient-related factors of these outcomes on multivariate analysis, including additional treatment modalities and HDREBBT dose. CONCLUSIONS: HDREBBT is a safe and effective way to palliate endobronchial symptoms. Additional external-beam radiation therapy, chemotherapy, or chemoradiation after HDREBBT improves survival, but does not affect QOL measures.

Endotracheal brachytherapy alone: An effective palliative treatment for tracheal tumors.

BACKGROUND: Tracheal tumors are rare. They are usually unresectable and treated primarily with external beam radiation. The use of palliative endotracheal brachytherapy (ETBT) alone in treating patients with tracheal tumors has not been reported. METHODS: Using a prospective database, demographic, treatment, and outcome data of patients with tracheal tumors treated palliatively with ETBT from 2006 to 2014 were analyzed. Tumor and symptom responses were evaluated based on response evaluation criteria in solid tumors criteria. Survival, in-field disease control, symptom response, and duration of symptom responses were evaluated using descriptive analyses. RESULTS: Sixteen ETBT (median, 2) treatments were delivered to 8 patients. Median age was 63.4 years old. Common symptoms were hemoptysis, cough, and dyspnea. Tracheal lengths of 3.5-11 cm were treated with 5-7 Gy/fraction, using 1-3 fractions. The mean overall survival was 5 months and symptom-free survival was 6.8 months, respectively. After ETBT, 88% of patients experienced symptomatic improvement (hemoptysis [n = 3/3], cough [n = 6/7], and dyspnea [n = 4/4]). One patient developed Grade 1 stenosis that did not require intervention. CONCLUSIONS: This is among the largest series of tracheal tumors treated palliatively with ETBT alone. ETBT provided effective palliation with symptom improvement and minimal toxicity.

Surface mold brachytherapy for nonmelanoma skin cancer: Canadian patterns of practice.

PURPOSE: We sought to describe the use of surface mold brachytherapy (SMBT) for nonmelanoma skin cancer in Canada. METHODS AND MATERIALS: A list of Canadian Association of Radiation Oncologists membership and provincial registries were used for a preliminary survey to identify radiation oncologists and physicists involved in the practice of SMBT. A detailed survey was sent electronically to individuals involved in treating with SMBT. RESULTS: Of 41 centers in Canada, 39 responded, with 7 centers indicating use of SMBT. Seven radiation oncologists and 5 physicists from 6 of 7 treating centers responded to the detailed survey, with an overall 75% individual response rate (12/16). General agreement was found regarding indications for SMBT which included irregular or curved surfaces, avoidance of deep structures, and requirement for small fields. There was consensus regarding some contraindications for SMBT such as tumor depth and size. Hypofractionated schedules were used in 5 of 6 centers and doses ranged from 50 Gy in 5 fractions once per week to 30 Gy in 10 fractions twice a day over 5 days. The most common dosimetric parameters for plan evaluation included D90, D95, D100, and maximum skin dose. CONCLUSIONS: A minority of Canadian centers practice SMBT. In centers practicing SMBT, general agreement exists on general indications for its use. Given the wide variation in dose and fractionation used and the rarity of the indication a phase 2 Canadian protocol would be invaluable.

The involvement of serum serotonin levels producing radiation-induced bystander effects for an in vivo assay with fractionated high dose-rate (HDR) brachytherapy.

PURPOSE: The primary goal of this investigation was to observe whether measurable levels of bystander factor(s) can be detected in esophageal carcinoma patients' urine samples taken after undergoing high dose rate (HDR) intraluminal brachytherapy (ILBT). However, a small pilot study was developed to evaluate whether serotonin [5-Hydroxytryptamine (5-HT)] serum levels play an active role in the mechanisms of radiation-induced bystander effects (RIBE) at high doses. MATERIALS AND METHODS: In the present study, a colony-forming in vivo assay was developed and used for the detection of non-targeted effects. Samples of urine were collected from five esophageal carcinoma patients undergoing fractionated HDR-ILBT. To observe whether 5-HT modulates the bystander effect at higher doses, different batches of foetal bovine serum (FBS) and 5-HT were tested on the same urine samples before and after brachytherapy. RESULTS: Some of our data suggests statistically significant evidence for serotonin playing an active role as a signalling molecule at higher doses when patients underwent HDR-ILBT. CONCLUSION: However, a more thorough investigation, with a larger sample size, is warranted before serotonin can be known to play a role in bystander effects at this particular dose range and treatment regime.

Palliative thoracic radiotherapy in lung cancer: An American Society for Radiation Oncology evidence-based clinical practice guideline.

PURPOSE: To provide guidance to physicians and patients with regard to the use of external beam radiotherapy, endobronchial brachytherapy, and concurrent chemotherapy in the setting of palliative thoracic treatment for lung cancer, based on available evidence complemented by expert opinion. METHODS AND MATERIALS: A Task Force authorized by the American Society for Radiation Oncology (ASTRO) Board of Directors synthesized and assessed evidence from 3 systematic reviews on the following topics: (1) dose fractionation in thoracic external beam radiotherapy (EBRT); (2) clinical utility of initial and salvage endobronchial brachytherapy (EBB); and (3) use of concurrent chemotherapy (CC) with palliative thoracic radiotherapy. Practice guideline recommendations were produced and are contained herein. RESULTS: Studies suggest that higher dose/fractionation palliative EBRT regimens (eg, 30 Gy/10 fraction equivalent or greater) are associated with modest improvements in survival and total symptom score, particularly in patients with good performance status. As these improvements are associated with an increase in esophageal toxicity, various shorter EBRT dose/fractionation schedules (eg, 20 Gy in 5 fractions, 17 Gy in 2 weekly fractions, 10 Gy in 1 fraction), which provide good symptomatic relief with fewer side effects, can be used for patients requesting a shorter treatment course and/or in those with a poor performance status. No defined role for EBB in the routine initial palliative treatment of chest disease has been demonstrated; however, EBB can be a reasonable option for the palliation of endobronchial lesions causing obstructive symptomatology including lung collapse, or for hemoptysis after EBRT failure. The integration of concurrent chemotherapy with palliative intent/fractionated radiotherapy is not currently supported by the medical literature. CONCLUSION: This Guideline is intended to serve as a guide for the use of EBRT, EBB, and CC in thoracic palliation of lung cancer outside the clinical trial setting. Further prospective clinical investigations with relevant palliative endpoints into the respective roles of EBB and CC/targeted therapy in the thoracic palliation of lung cancer are warranted, given the current state of the medical literature in these areas.

Adding external beam to intra-luminal brachytherapy improves palliation in obstructive squamous cell oesophageal cancer: a prospective multi-centre randomized trial of the International Atomic Energy Agency.

BACKGROUND: Whether the combination of high dose-rate brachytherapy (HDRBT) and External Beam Radiation Therapy (EBRT) is superior to HDRBT alone for the palliation of oesophageal cancer has only been explored in a previous IAEA pilot randomized trial. METHODS: Two hundred and nineteen patients were randomized to adding EBRT or not, after receiving two fractions of HDRBT within 1 week. Each HDRBT consisted of 8 Gy prescribed at 1cm from source centre. Patients randomized to EBRT received 30 Gy in 10 fractions. The primary outcome was dysphagia-relief experience (DRE). Additional outcomes included various scores, performance status, weight and adverse events. A majority of charts, imaging and radiotherapy plans were externally audited. RESULTS: Median follow-up was 197 days, with a median OS of 188 days and an 18% survival rate at 1 year. DRE was significantly improved with combined therapy, for an absolute benefit of +18% at 200 days from randomization (p=0.019). In longitudinal regression analyses, scores for dysphagia (p=0.00005), odynophagia (p=0.006), regurgitation (p=0.00005), chest pain (p=0.0038) and performance status (p=0.0015) were all significantly improved. In contrast, weight, toxicities and overall survival were not different between study arms. CONCLUSION: Symptom improvement occurs with the addition of EBRT to standard HDRBT. The combination is well tolerated and relatively safe.

Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival.

BACKGROUND: Previous results from our phase 3 randomised trial showed that adding cetuximab to primary radiotherapy increased overall survival in patients with locoregionally advanced squamous-cell carcinoma of the head and neck (LASCCHN) at 3 years. Here we report the 5-year survival data, and investigate the relation between cetuximab-induced rash and survival. METHODS: Patients with LASCCHN of the oropharynx, hypopharynx, or larynx with measurable disease were randomly allocated in a 1:1 ratio to receive either comprehensive head and neck radiotherapy alone for 6-7 weeks or radiotherapy plus weekly doses of cetuximab: 400 mg/m(2) initial dose, followed by seven weekly doses at 250 mg/m(2). Randomisation was done with an adaptive minimisation technique to balance assignments across stratification factors of Karnofsky performance score, T stage, N stage, and radiation fractionation. The trial was un-blinded. The primary endpoint was locoregional control, with a secondary endpoint of survival. Following discussions with the US Food and Drug Administration, the dataset was locked, except for queries to the sites about overall survival, before our previous report in 2006, so that an independent review could be done. Analyses were done on an intention-to-treat basis. Following completion of treatment, patients underwent physical examination and radiographic imaging every 4 months for 2 years, and then every 6 months thereafter. The trial is registered at www.ClinicalTrials.gov, number NCT00004227. FINDINGS: Patients were randomly assigned to receive radiotherapy with (n=211) or without (n=213) cetuximab, and all patients were followed for survival. Updated median overall survival for patients treated with cetuximab and radiotherapy was 49.0 months (95% CI 32.8-69.5) versus 29.3 months (20.6-41.4) in the radiotherapy-alone group (hazard ratio [HR] 0.73, 95% CI 0.56-0.95; p=0.018). 5-year overall survival was 45.6% in the cetuximab-plus-radiotherapy group and 36.4% in the radiotherapy-alone group. Additionally, for the patients treated with cetuximab, overall survival was significantly improved in those who experienced an acneiform rash of at least grade 2 severity compared with patients with no rash or grade 1 rash (HR 0.49, 0.34-0.72; p=0.002). INTERPRETATION: For patients with LASCCHN, cetuximab plus radiotherapy significantly improves overall survival at 5 years compared with radiotherapy alone, confirming cetuximab plus radiotherapy as an important treatment option in this group of patients. Cetuximab-treated patients with prominent cetuximab-induced rash (grade 2 or above) have better survival than patients with no or grade 1 rash. FUNDING: ImClone Systems, Merck KGaA, and Bristol-Myers Squibb.

Endoscopic brachytherapy for obstructive colorectal cancer.

PURPOSE: Palliation of obstructive colon cancer is often challenging. Treatment options include Yttrium aluminum garnet (YAG) laser, stent placement, and surgical intervention. High-dose-rate intraluminal brachytherapy (HDRILBT) has been used to relieve obstructive symptoms due to rectal, bronchial, and esophageal cancers. In this case report, we document the combined use of YAG laser and HDRILBT for the palliation of obstructive colon cancer at the hepatic flexure, not previously reported in the literature. METHODS AND MATERIALS: The patient in this case report had a large colonic tumor at the hepatic flexure causing near complete obstruction. Stent insertion and surgery were not feasible. YAG laser was used once and 11 days later, two fractions of HDRILBT were given 1 week apart. Under endoscopic vision and fluoroscopic guidance, a 150-cm Teflon catheter was passed through the lumen of the partially obstructed bowel for purposes of HDRILBT. A total dose of 10Gy was delivered at 1cm from the center of the source axis using a high-dose-rate afterloader. RESULTS: After treatment with the first fraction of HDRILBT, the tumor size decreased and the colonic lumen was significantly more patent. The patient's symptoms were significantly relieved after two fractions. Her weight increased and she was medically fit enough to undergo further chemotherapy. Further HDRILBT was not indicated. The calculated biological effective dose for the total HDRILBT treatments was well below the dose tolerances for acute effects for normal colonic tissue. CONCLUSION: HDRILBT should be considered as a possible treatment option for obstructive colon cancers when stent placement or surgery is not possible.

Motexafin gadolinium combined with prompt whole brain radiotherapy prolongs time to neurologic progression in non-small-cell lung cancer patients with brain metastases: results of a phase III trial.

PURPOSE: To determine the efficacy of motexafin gadolinium (MGd) in combination with whole brain radiotherapy (WBRT) for the treatment of brain metastases from non-small-cell lung cancer. METHODS AND MATERIALS: In an international, randomized, Phase III study, patients with brain metastases from non-small-cell lung cancer were randomized to WBRT with or without MGd. The primary endpoint was the interval to neurologic progression, determined by a centralized Events Review Committee who was unaware of the treatment the patients had received. RESULTS: Of 554 patients, 275 were randomized to WBRT and 279 to WBRT+MGd. Treatment with MGd was well tolerated, and 92% of the intended doses were administered. The most common MGd-related Grade 3+ adverse events included liver function abnormalities (5.5%), asthenia (4.0%), and hypertension (4%). MGd improved the interval to neurologic progression compared with WBRT alone (15 vs. 10 months; p = 0.12, hazard ratio [HR] = 0.78) and the interval to neurocognitive progression (p = 0.057, HR = 0.78). The WBRT patients required more salvage brain surgery or radiosurgery than did the WBRT+MGd patients (54 vs. 25 salvage procedures, p < 0.001). A statistically significant interaction between the geographic region and MGd treatment effect (which was in the prespecified analysis plan) and between treatment delay and MGd treatment effect was found. In North American patients, where treatment was more prompt, a statistically significant prolongation of the interval to neurologic progression, from 8.8 months for WBRT to 24.2 months for WBRT+MGd (p = 0.004, HR = 0.53), and the interval to neurocognitive progression (p = 0.06, HR = 0.73) were observed. CONCLUSION: In the intent-to-treat analysis, MGd exhibited a favorable trend in neurologic outcomes. MGd significantly prolonged the interval to neurologic progression in non-small-cell lung cancer patients with brain metastases receiving prompt WBRT. The toxicity was acceptable.