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Herein, a series of 2,3-dihydrobenzofurans have been developed as highly potent bromo and extra-terminal domain (BET) inhibitors with 1000-fold selectivity for the second bromodomain (BD2) over the first bromodomain (BD1). Investment in the development of two orthogonal synthetic routes delivered inhibitors that were potent and selective but had raised in vitro clearance and suboptimal solubility. Insertion of a quaternary center into the 2,3-dihydrobenzofuran core blocked a key site of metabolism and improved the solubility. This led to the development of inhibitor 71 (GSK852): a potent, 1000-fold-selective, highly soluble compound with good in vivo rat and dog pharmacokinetics.

Purpose Stereotactic body radiation therapy (SBRT) is an emerging option for localized prostate cancer. However, there are no standard dosimetric guidelines, and normal tissue tolerances for extreme hypofractionation are not well defined. We analyzed dosimetric correlations with patient-reported urinary and bowel quality of life (QOL) on a prospective trial. Methods and Materials Patients with low- or intermediate-risk prostate cancer from 18 institutions were enrolled on a phase 2 trial from 2007 to 2012 and treated using robotic SBRT to 38 Gy in 4 fractions on consecutive days. No androgen deprivation was used. Patients received simulation with Foley catheter for urethral delineation. The clinical target volume was prostate (low-risk patients) or prostate plus 1 cm of proximal seminal vesicles (intermediate-risk patients). Multiple dosimetric measures for urethra, bladder, and rectum were prospectively recorded. QOL using the Expanded Prostate Cancer Index Composite was assessed before and after treatment at protocol-specific time points. Linear regression was used to assess factors associated with QOL at 1 month and 2 years. Results A total of 259 patients were enrolled. QOL data were available for 98%, 96%, and 84% at baseline, 1 month, and 2 years, respectively. Median age was 69 years. Prior transurethral resection of the prostate and clinical target volume size were associated with 2-year urinary incontinence. There was a trend toward worse 2-year obstruction/irritation in older patients on multivariable analysis. Bladder and urethral doses were not associated with either 1-month or 2-year urinary QOL. In contrast, rectum maximum dose was associated with both 1-month and 2-year bowel QOL. At 2 years, the proportion with moderate or big overall bowel problems (as defined by Expanded Prostate Cancer Index Composite-26) was significantly higher in patients with rectum maximum dose greater than versus less than the median 37.4 Gy (11% vs 2%, Fisher's exact test P = .008). Conclusions These results provide novel data that contribute to a better understanding of patient and dosimetric factors associated with adverse QOL effects from prostate SBRT.

Background Stereotactic body radiation therapy is an emerging treatment for prostate cancer (PC), with potential biological and oncologic advantages. A well-established radiation dosing schedule (38Gy in 4 fractions) has shown excellent long-term efficacy in high-dose-rate (HDR) brachytherapy. Objective To report 5-yr efficacy, toxicity, and quality-of-life (QOL) outcomes of a novel 4-d SBRT regimen. Design, setting, and participants This was a single-arm prospective phase 2 trial involving 259 patients with low- or intermediate-risk PC treated at 18 US centers from December 2007 to February 2012. The median follow-up was 5yr (interquartile range 37–85mo). Intervention SBRT with 38Gy in four fractions; radiation plans mimicked HDR brachytherapy dosimetry. Outcome measurements and statistical analysis We measured freedom from biochemical recurrence (BCR) and assessed toxicities using the Common Terminology Criteria for Adverse Events v3.0 and QOL using the Expanded Prostate Cancer Index Composite. Results and limitations The 5-yr BCR-free rates were 100% and 88.5% for patients with low- and intermediate-risk PC, respectively. The cumulative 5-yr grade 2, 3, and 4 toxicity rates were 12.4%, 1.9%, and 0.4% for urinary, and 3.4%, 0%, and 0% for gastrointestinal toxicities, respectively. The median baseline prostate-specific antigen (PSA) level of 5.12ng/ml decreased to 0.1ng/ml by ≥42mo. QOL scores decreased at 1mo but returned to baseline by 6mo, with a later decline (≥24mo) in the urinary continence domain (pad use was 2% at baseline and 10% at 5yr), and lower sexual potency over time. Comparative outcomes versus other types of radiotherapy are difficult because the trial was not randomized. Conclusions This regimen yields a high rate of BCR-free survival, with a very low median PSA nadir suggesting prostate ablation. For properly selected patients with low- or intermediate-risk PC who choose SBRT, this treatment regimen is effective. Patient summary This potent four-treatment stereotactic body radiotherapy regimen appears to be effective for patients with early prostate cancer.

Introduction: Stereotactic radiosurgery and radiotherapy (SRS-SRT) is a valuable treatment for brain metastases (BMs) due to its specificity to the patient and reduction of toxic effects compared to whole brain radiation. Immune checkpoint inhibition (ICI) is also an important treatment option utilizing anti-cytotoxic T-lymphocyte-associated protein 4 and anti-programed cell death protein 1 receptors in cancer cells. However, few published studies are available describing how combined immunotherapy and SRS-SRT affect patient outcomes. The purpose of this study was to retrospectively analyze how SRS-SRT given in combination with immunotherapy affects toxicity and survivorship in patients with metastatic brain tumors. Methods: A retrospective review was completed of patients with BMs treated with linac-based SRS-SRT and ICI from 2010-2019 at a community cancer program. IRB exempt status was established. Timing of ICI in relation to SRS-SRT was characterized as prior (ended 6 months before), concurrent (delivered within 2 weeks before or during), and following (initiated more than 3 months) after radiation. Total radiation dose, fractionation, number of BMs treated, and conformality index (CI) in relation to ICI drug(s) and incidence of acute and delayed toxicities via RTOG criteria, were analyzed to identify predictors of toxicity and tumor control. Progression free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier survival curves and Cox proportional hazards models were used for multivariate analysis. Brain MRI with contrast was completed every 3 months post-radiation. Patients were evaluated via ROS and physical exam q2-3 months until death. Results: The final sample consisted of 417 patients, 178M, 239F, with the mean age of 62.6 years (range 17-90). Primary tumor sites of BMs were lung (NSCLC and SCLC) 56%, Other 16.6%, breast 12.9%, melanoma 8.8%, and colon 5.5%. There were a total of 986 BMs treated, median dose was 2000 cGy in 3 fractions. A total of 71 pts (17%) received ICIs concurrent with SRS-SRT. Median RTOG toxicity score was 0.73, (SD 1.049). Neurotoxicity grade 3 occurred in 6.2% of all patients. Concurrent use of either Ipilimumab or Pembrolizumab with SRS-SRT showed significantly increased acute RTOG toxicity scores compared to either pre or post radiation ICI use of any drug. No grade 4 or 5 toxicities occurred. PFS and OS were not significantly associated with use of concurrent ICI with radiotherapy. Conclusions: The use of ICI prior to, during or after SRS-SRT for BMs appears to be safe in both acute and delayed toxicity evaluation. However a small but statistically significant increase in acute toxicities was observed when concurrent Ipilimumab or Pembrolizumab were given. Citation Format: Sonal Khedkar, Andrew S. Kennedy, D Edward Hunt, James Gray, Melissa L. Johnson, Casey Chollet-Lipscomb, Meredith McKean, Brian J. Stevens, David Spigel. Impact of immune checkpoint inhibition combined with stereotactic radiotherapy in treatment of brain metastases [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6502.

Purpose To report a patient with bilateral uveal metastases secondary to previously quiescent prostate adenocarcinoma with a 22-month follow-up. Methods Retrospective chart review was performed for this patient. Results Androgen deprivation therapy and external beam radiation therapy were shown to manage ocular symptoms in a sixty-nine-year-old man previously diagnosed with adenocarcinoma of the prostate. Conclusion Uveal metastases can be the first site of systemic metastasis even long after initial diagnosis and treatment of prostate adenocarcinoma; the 17 years between this patient's treatment for adenocarcinoma and commencement of his ocular symptoms is the longest interval reported. Hormonal therapy, in conjunction with radiation therapy, can successfully reduce tumor burden in these patients and improve visual symptoms over time.

Summary Background Data available regarding patient perspectives on ulcerative colitis (UC) and their preferences and satisfaction with therapy are limited. Aims To examine the preferences of UC patients to understand better what they look for in a therapy when managing their disease, as this may influence overall medication adherence. Methods The study surveyed 100 Canadian UC patients on topics including educational resources used to learn about the disease, medication attributes that are most valued and preferred by the patient and satisfaction with current therapy. Results Overall, efficacy- and safety-related medication attributes were rated by patients to be more important than those related to dosing regimen (e.g. dosing frequency, number of pills), cost and formulary coverage. In pair-wise comparisons of specific medication attributes, UC patients rated speed of symptom relief and few side effects as the most important factors when considering a UC medication (preferred on average 84% and 74% of the time respectively). Conclusion This study provides insight into UC patient preferences and satisfaction with therapy that may be important when counselling on treatment options, and generates relevant discussions on adherence. Larger studies may be warranted to examine further how these findings can be extrapolated to broader UC populations.

Summary Background In 2003, British Columbia’s PharmaCare programme implemented a drug reimbursement policy called Therapeutic Substitution, which required patients with acid-related diseases, primarily gastro-oesophageal reflux disease (GERD), to make a medically unnecessary switch from their prescribed proton pump inhibitor (PPI) to the cheapest available brand name PPI (Pariet, rabeprazole sodium), comprising a different (nongeneric) chemical. Aim To evaluate the independent effects of PPI Therapeutic Substitution on individual healthcare utilization among those complying with the policy. Methods We used the BC Ministry of Health Services’ individual-level linked data, allowing isolation of healthcare utilization for the entire population of PPI consumers from 2002 to 2005. Results After controlling for individual case variation in age, gender and a proxy for pre-existing health status, regression analysis revealed statistically significant greater overall use of PPIs, physician services and hospital services independently associated with patients who complied with Therapeutic Substitution. Over the 3-year period 2003–2005, this represented net healthcare expenditures totalling approximately C$43.51 million (C$9.11 million in total PPI drug expenditures, C$24.65 million for physician services and C$9.75 million for hospital services). Conclusion Medically unnecessary drug switching caused by compliance with Therapeutic Substitution policy appears to be independently associated with higher overall healthcare utilization.

According to the processing-efficiency hypothesis (Eysenck, Derakshan, Santos, & Calvo, 2007), anxious individuals are thought to require greater activation of brain systems supporting cognitive control (e.g., dorsolateral prefrontal cortex; DLPFC) in order to maintain equivalent performance to nonanxious subjects. A recent theory of cognitive control (Braver, Gray, & Burgess, 2007) has proposed that reduced cognitive efficiency might occur as a result of changes in the temporal dynamics of DLPFC recruitment. In this study, we used a mixed blocked/ event-related fMRI design to track transient and sustained activity in DLPFC while high- and low-anxious participants performed a working memory task. The task was performed after the participants viewed videos designed to induce neutral or anxiety-related moods. After the neutral video, the high-anxious participants had reduced sustained but increased transient activation in working memory areas, in comparison with low-anxious participants. The high-anxious group also showed extensive reductions in sustained activation of “default-network” areas (possible deactivation). After the negative video, the low-anxiety group shifted their activation dynamics in cognitive control regions to resemble those of the high-anxious group. These results suggest that reduced cognitive control in anxiety might be due to a transient, rather than sustained, pattern of working memory recruitment. Supplementary information for this study may be found at www.psychonomic.org/archive.

PURPOSE This prospective randomized study compared overall survival (OS) in patients with previously untreated advanced non–small-cell lung cancer (NSCLC) when treated with the platinum agent–based triple drug combination of paclitaxel/carboplatin/gemcitabine (PCG) versus the nonplatinum agent–based doublet drug combination of gemcitabine/vinorelbine. PATIENTS AND METHODS Advanced (stages IIIB, IV, and recurrent) chemotherapynaive patients with NSCLC and performance status 0-2 were randomly assigned to the PCG arm (paclitaxel 200 mg/m 2 on day 1, carboplatin area under the concentration-time curve of 5 on day 1, and gemcitabine 1000 mg/ m 2 on days 1 and 8, every 21 days) or to the gemcitabine/vinorelbine arm (gemcitabine 1000 mg/m 2 on days 1, 8, and 15 and vinorelbine 25 mg/m 2 on days 1, 8, and 15, every 28 days). RESULTS A total of 337 patients were randomly assigned to the 2 arms. The median time to progression was 6 months for PCG and 3.9 months for gemcitabine/vinorelbine with 1- and 2-year progression-free survival rates of 13% and 2% versus 14% and 4% ( P = .324 log rank). Median OS for PCG was 10.3 months versus 10.7 months for gemcitabine/vinorelbine with 1-, 2-, and 3-year OS rates of 38%, 12%, and 2% versus 45%, 12%, and 6%, respectively ( P = 0.269 log rank). Grade 3/4 thrombocytopenia, nausea/vomiting, myalgia/arthralgia, and neuropathy were significantly greater in the PCG arm. CONCLUSION There was no difference in OS or progression-free survival when comparing PCG and gemcitabine/vinorelbine, and gemcitabine/vinorelbine was significantly less toxic. Gemcitabine/vinorelbine is a reasonable nonplatinum agent–based doublet therapy for patients with advanced NSCLC.

This study was designed to evaluate the efficacy and toxicity of a novel preoperative combined-modality regimen in patients with locally advanced non-small-cell lung cancer (NSCLC). Patients with clinical stage IIB, IIIA, or IIIB NSCLC received preoperative combined-modality therapy with concurrent radiation therapy (RT) and weekly paclitaxel/carboplatin for 5 consecutive weeks. After this treatment, patients believed to have resectable disease by standard surgical criteria underwent thoracotomy. Patients whose disease remained unresectable after initial therapy received further RT with concurrent paclitaxel/carboplatin. Of 107 patients entered into this clinical trial, only 20 patients (19%) were considered to have surgically resectable disease at the time of study entry. Ninety-eight patients (92%) completed preoperative combined-modality therapy. Forty-nine patients (46%) underwent thoracotomy and 34 patients had definitive resection. Fourteen patients (13%) had pathologic complete response (pCR). Thirteen of 18 patients (72%) with clinical stage T3 N0 (IIB) tumors had definitive resections, and 33% had pCR. After a median follow-up of 32 months, the 1- and 2-year actuarial survival rates for the entire group are 64% and 42%, respectively. Favorable-prognosis subgroups included patients who had definitive resection and patients with clinical stage T3 N0 tumors (2-year survival rates of 67% for both subgroups). Preoperative therapy with RT and weekly paclitaxel/carboplatin showed activity in this patient population; however, disease in the majority of patients with extensive involvement of mediastinal nodes remained unresectable after this treatment. Results in patients who initially had unresectable disease do not appear different than results achieved with concurrent RT/chemotherapy approaches. Postoperative complications associated with this preoperative combined-modality regimen were more frequent than expected with resection alone.

PURPOSE: To provide long-term follow-up on the survival of patients with advanced non–small-cell lung cancer treated with paclitaxel/carboplatin-based regimens in a multicenter, community-based setting. PATIENTS AND METHODS: Between March 1995 and April 1998, 321 patients with newly diagnosed stage IIIB or IV non–small-cell lung cancer were treated on sequential phase II trials with the following combination regimens: paclitaxel/carboplatin, paclitaxel/carboplatin/gemcitabine, and paclitaxel/carboplatin/vinorelbine. Details of these three regimens and patient populations have been previously reported. Responding and stable patients continued treatment until tumor progression or for a recommended six treatment courses. RESULTS: After a median follow-up of 58 months (minimum follow-up, 40 months), the median survival for the entire group of patients was 8.6 months, with actual 1-, 2-, and 3-year survival rates of 40%, 19%, and 7%, respectively. The actuarial 4-year survival rate for the entire group was 4%. No statistically significant differences in survival were seen among the three regimens. Administration of all three regimens was feasible in a community-based setting; however, myelosuppression and hospitalizations for treatment of neutropenia/fever were more frequent with the three-drug regimens. CONCLUSION: Paclitaxel/carboplatin-based regimens, in addition to prolonging median survival and improving 1-year survival, result in substantial improvements in the 2-year survival of patients with advanced non–small-cell lung cancer when compared retrospectively with supportive care or traditional cisplatin-based regimens. In these sequential phase II trials, we did not demonstrate any advantages of three-drug regimens when compared with paclitaxel/carboplatin. Because few patients remain alive after 4 years with any of these chemotherapy regimens, future treatment improvements will require the introduction of novel agents.

BACKGROUND The objective of this study was to determine the feasibility and toxicity of paclitaxel and carboplatin given in the adjuvant setting alone for patients with resected Stage IB disease and combined with radiotherapy for patients with resected Stages II and IIIA disease and selected patients with Stage IIIB and IV disease (Revised International System for Staging of Lung Cancer). METHODS One hundred two patients with resected nonsmall cell lung carcinoma were treated in the postoperative period with 3 courses of paclitaxel 200 mg/m2 intravenously (i.v.) over 1 hour and carboplatin area under the curve of 6 i.v. every 3 weeks for 3 courses. Patients with Stage IB received no further therapy, and those with higher stages also subsequently received radiotherapy plus concurrent weekly paclitaxel and carboplatin over 6 weeks. The median age was 61 years, with 56 men and 46 women, and the predominant histologic type was adenocarcinoma. Twenty pneumonectomies, 80 lobectomies, and 2 other procedures were performed. Ninety percent of the patients (92 of 102) received all 3 courses of adjuvant paclitaxel and carboplatin (84% received full doses). Seventy-three percent received full doses of radiotherapy and concurrent weekly chemotherapy (49 of 67 patients), and 14 others received greater than 75% of the radiotherapy and concurrent chemotherapy. RESULTS Toxicity of the chemotherapy was mild with only three hospitalizations for neutropenia and fever and no treatment-related deaths. Severe hypersensitivity occurred in six patients (6%). Concurrent radiation therapy and weekly chemotherapy also was well tolerated with the exception of Grade 3–4 esophagitis observed in 27% (17 of 67 patients). Follow-up was short with a median of 10 months, and 65% of all patients remained progression free. CONCLUSIONS Three courses of paclitaxel and carboplatin is tolerable, feasible, and can be delivered in most patients in the adjuvant setting. Subsequently, in higher stage patients, concurrent postoperative radiation therapy and weekly paclitaxel and carboplatin is well tolerated and delivered in most patients. Definitive prospective randomized Phase III adjuvant trials are warranted. Cancer 2001;92:2142–7. © 2001 American Cancer Society.

INTRODUCTION Effective hand-washing is essential for reducing the spread of infection in hospitals. We aimed to evaluate hand-washing performance of hospital personnel and to determine if this could be improved by education. MATERIALS AND METHODS A total of 55 personnel working in the orthopaedic department were asked to clean their hands using an alcohol gel containing a clear fluorescent substance. They were unaware of the assessment method. Performance was assessed by examining their hands under UV light to identify areas that had been neglected. Subjects could visualise which areas they had missed and were then educated regarding hand-washing technique and retested after 7 days. RESULTS Of the 55 subjects, 53 completed the study. Individual performance varied widely. Following a simple educational intervention, 49 out of 53 subjects improved from an average of 7.8% to 2.3% area missed (P < 0.001). CONCLUSIONS We suggest that hand-washing effectiveness needs to be improved and that a simple educational intervention can be effective.

PURPOSE In two sequential phase II studies, we evaluate the feasibility and efficacy of adding paclitaxel to a standard platinum/etoposide regimen in the first-line treatment of small-cell lung cancer. PATIENTS AND METHODS One hundred seventeen patients with small-cell lung cancer were treated between June 1993 and July 1996. The first 38 patients received a lower-dose regimen: paclitaxel 135 mg/m2 by 1-hour infusion, carboplatin at an area under the concentration-time curve (AUC) of 5.0, and etoposide 50 mg alternating with 100 mg orally on days 1 to 10. When only mild myelosuppression was observed, doses of paclitaxel and carboplatin were increased in the subsequent 79 patients (paclitaxel 200 mg/m2 by 1-hour infusion and carboplatin at an AUC of 6.0). All patients received four courses of treatment, administered at 21-day intervals. Patients with limited-stage small-cell lung cancer also received thoracic radiation therapy (1.8 Gy/d; total dose, 45 Gy) administered concurrently with courses 3 and 4 of chemotherapy. RESULTS Seventy-two of 79 patients (91%) who receive the higher-dose regimen had major responses. Thirty-two of 38 (84%) with extensive-stage disease responded (21% complete response rate); median survival was 10 months for this group. With limited-stage disease, the overall response rate was 98%, with 71% complete responses; the median survival time has not been reached at 16 months. Median survival in extensive-stage patients was longer in patients who received the higher-dose regimen (10 months) than in the previous group treated with lower doses (7 months; P = .008). The higher-dose regimen was well tolerated, with myelosuppression being the major toxicity. Compared with the lower-dose regimen, grade 3/4 neutropenia increased from 8% to 38% of courses, but the incidence of hospitalization for neutropenia and fever did not increase. Other nonhematologic toxicities were uncommon, and did not increase substantially with the higher-dose regimen. CONCLUSION Paclitaxel can be added at full dose (200 mg/m2) to a carboplatin/etoposide combination while maintaining a tolerable toxicity profile. Median survival times in both extensive- and limited-stage patients compare favorably with other reported regimens. This regimen merits further investigation, and a randomized trial to compare this regimen with a standard carboplatin/etoposide combination is underway.

PURPOSE The addition of combination chemotherapy to standard radiation therapy has improved treatment for locally unresectable non-small-cell lung cancer. In this phase II study, we evaluated the toxicity and efficacy of a novel chemotherapy regimen that included paclitaxel, cisplatin, and etoposide plus concurrent radiation therapy in this group of patients. PATIENTS AND METHODS Thirty-three patients with previously untreated, unresectable stage III non-small-cell lung cancer (stage IIIA, 11 patients; stage IIIB, 22 patients) initially received two courses of chemotherapy, which included paclitaxel 135 mg/m2 by 1-hour infusion on day 1, cisplatin 60 mg/m/ intravenously (i.v.) on day 2, and etoposide 100 mg/m2 i.v. on days 1, 2 and 3. On week 6, radiation therapy (60 Gy in 30 fractions) was initiated in conjunction with two additional courses of chemotherapy: paclitaxel 135 mg/m2 i.v. by 1-hour infusion on day 1, cisplatin 5 mg/m2 i.v. on days 2- to 10, and etoposide 25 mg/m2 on days 1 to 10. RESULTS This combined modality program was feasible and well tolerated by most patients. During the two courses of induction chemotherapy, grade 3 or 4 myelosuppression occurred in only six patients (18%). Esophagitis was common during combined modality therapy (grade 3, 10 patients; grade 4 five patients). Forty-two percent of patients had partial response after two courses of induction therapy, and 82% of patients had an objective response at completion of therapy. Twelve patients (36%) had a complete response. Nineteen patients remain progression-free at a median of 8 months; the median survival time has not been reached. CONCLUSION This paclitaxel-containing combined modality therapy is feasible and highly active in patients with inoperable stage III lung cancer. Esophagitis is the most common severe toxicity with this program. Further studies with paclitaxel-containing combination regimens in patients with stage III non-small-cell lung cancer are indicated.

35 Background: SBRT is an emerging treatment for prostate cancer, but long-term reporting remains sparse. We present a prospective Phase II trial with 90% treated in community facilities. Methods: 14 institutions enrolled 259 patients - 112 low-risk; 147 intermediate-risk. The regimen emulated a high-dose rate brachytherapy (HDR) regimen - 38 Gy/4 fractions delivered by robotic SBRT. Androgen deprivation therapy was not allowed. HDR-like heterogeneous prostate dosing was used (Dmax >57 Gy). Toxicities were assessed by CTCAE v3.0 and quality of life assessed by Expanded Prostate Cancer Index Composite (EPIC). Biochemical recurrence was defined by Phoenix criteria. Results: Median follow-up is 5 years. 5-yr Grade 2 GU toxicity was 13.7% and GI toxicity 4.5%, with Grade 3 rates of 3% (GU) and 0% (GI) (one Gd 4 GU event). 5-yr median PSA was 0.1 ng/mL with further subsequent decrease (7 y = 0.035 ng/mL). 5-yr biochemical disease-free survival (bDFS) = 100% for low-risk and 88.5% for int-risk. 6 patients developed distant metastasis and one died of disease. Median EPIC GU obstruction and GI scores were similar at baseline vs. 5 years. 2% of patients had baseline GU incontinence requiring pad use vs 10% at 5 yrs. Of baseline potent men, 46% remained so at 5 yrs (66.7% for those age ≤65 vs. 37.1% age >65 at treatment). Conclusions: This is the first report of 5-year median follow-up outcomes post heterogeneous dosing SBRT for early prostate cancer. This treatment produces a low PSA nadir vs other forms of radiotherapy, with a favorable long-term result that appears reproducible in the community. Clinical trial information: 00643617. [Table: see text]

Studies by the US Geological Survey (USGS) of uranium mill tailings (UMT) have focused on characterizing the forms in which radionuclides are retained and identifying factors influencing the release of radionuclides to air and water. Selective extraction studies and studies of radionuclide sorption by and leaching from components of UMT showed alkaline earth sulfate and hydrous ferric oxides to be important hosts of radium-226 (226Ra) in UMT. Extrapolating from studies of barite dissolution in anerobic lake sediments, the leaching of226Ra from UMT by sulfate-reducing bacteria was investigated; a marked increase in226Ra release to aqueous solution as compared to sterile controls was demonstrated. A similar action of iron(III)-reducing bacteria was later shown. Ion exchangers such as clay minerals can also promote the dissolution of host-phase minerals and thereby influence the fate of radionuclides such as226Ra. Radon release studies examined particle size and ore composition as variables. Aggregation of UMT particles was shown to mask the higher emanating fraction of finer particles. Studies of various ores and ore components showed that UMT cannot be assumed to have the same radon-release characteristics as their precursor ores, nor can226Ra retained by various substrates be assumed to emanate the same fraction of radon. Over the last decade, USGS research directed at offsite mobility of radionuclides from uranium mining and milling processes has focused on six areas: the Midnite Mine in Washington; Ralston Creek and Reservoir, Colorado; sites near Canon City, Colorado; the Monument Valley District of Arizona and Utah; the Cameron District of Arizona; and the Puerco River basin of Arizona and New Mexico.

We describe 129 patients with disabling instability of the knee due to deficiency of the anterior cruciate ligament. They were treated by replacement of the ligament with a Leeds-Keio prosthesis supplemented by an extra-articular MacIntosh lateral substitution reconstruction. After an average period of 71 months a satisfactory outcome was found in only 60% of knees. Nine had required revision because of recurrent instability and the pivot-shift sign had become positive in 40% of patients. In our opinion the long-term results are unsatisfactory when compared with those obtained using a graft from the medial third of the patellar tendon supplemented with a MacIntosh extra-articular tenodesis.

Endothelial cell and platelet function were measured in 15 Marfan's syndrome patients and 15 age-, sex- and smoking-matched normal control subjects. The Marfan's syndrome patients had significantly increased factor VIII von Willebrand factor antigen (fVIIIvVVFAg) levels (median = 147%, inter-quartile ranges [IQRs] 117–174%) and thrombomodulin levels (median = 7.7 ng/ml, IQRs 6.1–9.1 ng/mg) compared to the control subjects (median = 82%, IQRs 64–134%), wherep = 0.007Mann-Whitney U test and (median = 2.6 ng/ml, IQRs 2.3–3.1 ng/ml), p = 0.001 Mann-Whitney U test respectively.The major complication of Marfan's syndrome is aortic dissection which is due to an inherited intrinsic defect of aortic wall structure. We postulate that the increased fVIIIvWFAg and thrombomodulin levels which were detected in the Marfan's syndrome patients are secondary to endothelial injury caused by the impaired tensile strength of blood vessels in Marfan's syndrome.

Purpose Preoperative chemoradiotherapy is a primary treatment option for patients with resectable esophageal cancer. Combination regimens using newer agents may improve patient outcomes. This multicenter community-based phase I/II trial examined a modern triplet regimen comprised of oxaliplatin, docetaxel, and capecitabine (ODC) combined with radiation therapy (RT). Patients and Methods The primary end point was the pathologic complete response (pCR) rate. Eligibility criteria included resectable stage I to III cancer of the mid-/distal-esophagus or gastroesophageal junction, measurable disease, and Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1. Treatment included oxaliplatin 40 mg/m2, docetaxel 20 mg/m2 (intravenous, weekly × 5); capecitabine 1,000 mg/m2 orally twice daily on days 1 to 7, 15 to 21, and 29 to 35; and concurrent RT (45 Gy). Resection was performed during weeks 9 to 12. ODC and RT safety was determined in a phase I portion (n = 10) preceding phase II. Results Fifty-nine patients were enrolled (September 2005 to February 2008; phase I/cohort 1, 10 patients; phase I/cohort 2/phase II, 49 patients). Baseline characteristics included median age of 63 years; 84% male; ECOG PS 0 and 1, 51% and 49%, respectively; adenocarcinoma and squamous cell, 69% and 18%, respectively; stage I, II, and III, 12%, 41%, and 45%, respectively. Phase I revealed no dose-limiting toxicity. Responses: pCR rate, 49%; objective response rate, 61% (24 complete and six partial responses); stable disease, 6%; and progressive disease, 2%. Sixty-nine percent of patients underwent surgery. Survival: median follow-up, 116 weeks; median disease-free survival (DFS) and overall survival (OS) were 16.3 and 24.1 months, respectively. Two-year DFS and OS were 45.1% and 52.2%, respectively. Most common (≥ 5%) grade 3 to 4 nonhematologic toxicities were anorexia (20%), dehydration (16%), diarrhea (8%), dysphagia (10%), esophagitis (20%), fatigue (12%), hyperglycemia (6%), nausea (16%), pulmonary symptoms (14%), sepsis (6%), and vomiting (16%). All other grade 3 to 4 hematologic and nonhematologic toxicities were uncommon (< 5%). Conclusion Preoperative ODC plus RT is active and relatively safe in patients with locoregional esophageal cancer. Importantly, this therapy can be administered within 8 weeks. This regimen warrants additional study in this setting and in combination with newer biologic agents.

The authors studied the cigarette and alcohol use of 243 patients with adenocarcinoma of the cardia or lower esophagus, including 66 with Barrett's metaplasia (esophagocardia group). They compared results of that investigation with the cigarette and alcohol use of 303 patients with squamous carcinoma of the esophagus, a cancer in which an etiologic association is proven, and of 338 patients with stomach cancer not involving the cardia, a cancer in which there is little or no association with cigarettes or alcohol. Controlled for other variables, patients with squamous cancer used more cigarettes and alcohol than the other two groups. There was no significant difference in cigarette or alcohol use between patients with esophagocardia and stomach cancer or between those in the esophagocardia group with or without Barrett's metaplasia. Because cigarette and alcohol use was not greater in patients with esophagocardia than in those with stomach cancer, the authors do not think that such factors explain the increasing incidence of adenocarcinoma of the cardia or lower esophagus.

Fluorophotometry was carried out in 19 eyes with no pathology except for the presence of advanced cataracts. The age range was 60–75 and there was no evidence of systemic disorders such as diabetes mellitus or hypertension. The scanning fluorometer used (Fluorotron Master) was modified in order to improve depth resolution (0.585 mm). Corneal endothelial permeability (Pac) was calculated before surgery (Pac: 3.14 ± 0.60 × 10 -4 cm/min). In 11 eyes, corneal endothelial permeability was again measured one week after planned extracapsular cataract extraction and intraocular lens (IOL) implantation. The corneal endothelial permeability increased after surgery and this increase correlated well with duration of surgery. Longer surgical procedures (>20 min) were associated with greater increases in corneal endothelial permeability.

To compare health care workers' hand surface coverage using two different volumes of alcohol gel for hand disinfection.and methods. A total of 84 members of staff in our hospital were studied. Subjects were asked to disinfect their hands with alcohol gel containing a clear fluorescent substance. Performance was assessed by using UV light to identify areas which had been missed, and the total surface area missed was calculated. A total of 42 subjects received 3.5 ml of alcohol gel, and 42 age-, sex-, and job-matched subjects received 1.75 ml of alcohol gel.Significantly less area was missed when hand disinfecting with double the volume of alcohol gel; 1.23 versus 6.35% surface area was missed (P0.001).Doubling the volume of alcohol gel used for hand disinfection significantly improves the efficiency of coverage of the hands with alcohol gel. This may result in lower bacterial count on the hands and may reduce the spread of nosocomial infections including that of methicillin-resistant Staphylococcus aureus.

Purpose This phase II study was designed to determine the feasibility, toxicity, and therapeutic efficacy of a novel outpatient combined-modality preoperative regimen in patients with localized esophageal cancer. Patients and methods One hundred twenty-nine eligible patients with previously untreated, potentially resectable, clinical stage I-III carcinoma of the esophagus were treated between July 1995 and July 1999. Combined-modality treatment included: paclitaxel, 200 mg/m2, 1-hour i.v. infusion, days 1 and 22; carboplatin, an area under the concentration time curve 6.0 i.v., days 1 and 22; 5-fluorouracil, 225 mg/m2/day, continuous i.v. infusion, days 1-42; and radiation therapy, 45 Gy, 1.8-Gy single daily fractions 5 days weekly, beginning day 1. All patients underwent surgical resection 4-8 weeks after completion of the preoperative therapy. Results One hundred twenty-three patients (95%) completed preoperative therapy, 105 patients (81%) underwent attempted resection, and 96 patients (74%) had definitive resection. A pathological complete response was achieved in 47 of 123 evaluable patients (38%); an additional 30 patients (24%) had only microscopic residual tumor. With a median follow-up of 45 months, the median survival is 22 months (95% CI = 15-32 months), with actuarial 1-, 2-, and 3-year survivals of 71%, 47%, and 41%, respectively. The most frequent grade 3/4 toxicities of the neoadjuvant program were leukopenia (73%) and esophagitis (43%). Although 73 patients (57%) required brief hospitalizations during preoperative therapy, there were no treatment-related deaths, and 94% of patients remained candidates for resection after the completion of treatment. Six patients (6%) died after surgery. Conclusions This novel combined-modality regimen is highly active in the treatment of locoregional esophageal cancer, producing an actuarial 3-year survival of 41%. Although this preoperative regimen produced moderate acute toxicity, there were no treatment-related deaths and the large majority of patients were able to undergo subsequent esophageal resection. These results, obtained in a community-based setting and involving multiple surgeons, radiation oncologists, and medical oncologists, compare favorably with those of previous single-center and multicenter results. Further evaluation of novel combined-modality programs is warranted, as is the incorporation of epidermal growth factor receptor antagonists or other targeted agents.

BACKGROUND The authors compared the toxicity, response rate, and progression free survival of four chemotherapy regimens for patients with advanced (Stage IIIB and IV) nonsmall cell lung carcinoma. METHODS A total of 267 patients entered this randomized Phase II trial on one of four arms: paclitaxel, carboplatin, and gemcitabine (Arm A); paclitaxel, carboplatin, and vinorelbine (Arm B); paclitaxel and gemcitabine (Arm C); and gemcitabine and vinorelbine (Arm D). Patient characteristics were similar in all treatment arms. At the time of tumor progression, patients were removed from study and were treated at the discretion of their physician. RESULTS Patients received a median of four courses of chemotherapy in all arms, and there was no difference in the dose delivered. There were no statistical differences in response rates (range, 32–45%), median progression free survival (range, 4.9–6.6 months), or progression free survival at 1 year (range, 8–19%). Actuarial survival in all four arms was not different, with a median survival ranging from 8.7 months to 10.7 months and a 1-year survival rate of 38–44%. Each arm was compared with a historic control with a median survival of 8 months. Arm D (gemcitabine and vinorelbine) approached significance at the 0.05 level. CONCLUSIONS Two-drug combinations containing the newer drugs without a platinum drug were less toxic than three-drug, platinum-based regimens. There were no significant differences in objective response rates or progression free survival when the four regimens were compared. The two-drug combination of gemcitabine and vinorelbine was the least toxic and, thus, may be superior. A Phase III trial comparing combined gemcitabine and vinorelbine with combined paclitaxel, carboplatin, and gemcitabine is ongoing. Cancer 2002;95:1279–85. © 2002 American Cancer Society. DOI 10.1002/cncr.10810

The objective of this study was to determine the feasibility and toxicity of paclitaxel and carboplatin given in the adjuvant setting alone for patients with resected Stage IB disease and combined with radiotherapy for patients with resected Stages II and IIIA disease and selected patients with Stage IIIB and IV disease (Revised International System for Staging of Lung Cancer).One hundred two patients with resected nonsmall cell lung carcinoma were treated in the postoperative period with 3 courses of paclitaxel 200 mg/m(2) intravenously (i.v.) over 1 hour and carboplatin area under the curve of 6 i.v. every 3 weeks for 3 courses. Patients with Stage IB received no further therapy, and those with higher stages also subsequently received radiotherapy plus concurrent weekly paclitaxel and carboplatin over 6 weeks. The median age was 61 years, with 56 men and 46 women, and the predominant histologic type was adenocarcinoma. Twenty pneumonectomies, 80 lobectomies, and 2 other procedures were performed. Ninety percent of the patients (92 of 102) received all 3 courses of adjuvant paclitaxel and carboplatin (84% received full doses). Seventy-three percent received full doses of radiotherapy and concurrent weekly chemotherapy (49 of 67 patients), and 14 others received greater than 75% of the radiotherapy and concurrent chemotherapy.Toxicity of the chemotherapy was mild with only three hospitalizations for neutropenia and fever and no treatment-related deaths. Severe hypersensitivity occurred in six patients (6%). Concurrent radiation therapy and weekly chemotherapy also was well tolerated with the exception of Grade 3-4 esophagitis observed in 27% (17 of 67 patients). Follow-up was short with a median of 10 months, and 65% of all patients remained progression free.Three courses of paclitaxel and carboplatin is tolerable, feasible, and can be delivered in most patients in the adjuvant setting. Subsequently, in higher stage patients, concurrent postoperative radiation therapy and weekly paclitaxel and carboplatin is well tolerated and delivered in most patients. Definitive prospective randomized Phase III adjuvant trials are warranted.

Emotional states might selectively modulate components of cognitive control. To test this hypothesis, the author randomly assigned 152 undergraduates (equal numbers of men and women) to watch short videos intended to induce emotional states (approach, neutral, or withdrawal). Each video was followed by a computerized 2-back working memory task (spatial or verbal, equated for difficulty and appearance). Spatial 2-back performance was enhanced by a withdrawal state and impaired by an approach state; the opposite pattern held for verbal performance. The double dissociation held more strongly for participants who made more errors than average across conditions. The results suggest that approach-withdrawal states can have selective influences on components of cognitive control, possibly on a hemispheric basis. They support and extend several frameworks for conceptualizing emotion-cognition interactions.

The long term survival and toxicity associated with the chemotherapy combination of paclitaxel, carboplatin, and extended-schedule etoposide used for the treatment of patients with metastatic carcinoma of unknown primary site were evaluated.Seventy-one patients were treated between March 1995 and November 1996 with paclitaxel, carboplatin, and oral etoposide every 21 days. Stable or responding patients received four to eight courses of therapy. The following histologies were represented: well differentiated adenocarcinoma (34 patients); poorly differentiated adenocarcinoma or poorly differentiated carcinoma (30 patients); poorly differentiated neuroendocrine carcinoma (6 patients); and squamous cell carcinoma (1 patient).Forty-eight percent of assessable patients had major responses to therapy (95% confidence interval, 39%-55%), and 10 patients (15%) had complete responses. There were no response differences among the major histologic types. The median survival for all 71 patients was 11 months, and the 1-year, 2-year, and 3-year survival rates were 48%, 20%, and 14%, respectively. The minimum follow-up period was 34 months (range, 34-50 mos). The regimen was tolerated well with no treatment-related deaths and only 12 hospitalizations for neutropenia and fever. There was no serious long term toxicity.In this large Phase II trial, the combination of paclitaxel, carboplatin, and oral etoposide produced major responses or stable disease status in nearly 80% of patients who had carcinoma of unknown primary site. The median survival and 1-year, 2-year, and 3-year survival rates were noteworthy. The current study obtained similar or superior results to those seen with chemotherapy for many other groups of patients, such as those who had well defined advanced malignancies, those who were considered to have responsive tumors, and those who had obtained substantial benefits from cytotoxic therapy. Although the regimen reported in the current study can become an attractive option for many patients with carcinoma of unknown primary site, there remains a need for further clinical trials.

We evaluated the ability of both static electric and static magnetic fields to enhance the in vivo action of a chemotherapeutic agent, adriamycin, against transplanted mammary tumors in mice. Female B6C3F1 mice with transplanted mammary adenocarcinoma were divided into four randomized groups and injected with 10 mg/kg adriamycin on day 7 of the study. Three of the groups were then exposed to nonuniform static electric or static magnetic fields. The resulting tumor regression in each group was measured four times during the remaining 13 days of the 20 day study. Two-sided statistical tests revealed all of the static field exposed groups achieved significantly greater (P/=.05) tumor regression than the group treated with adriamycin only, with P-values in a range as low as. 0001. There is an almost universal need in disease treatment to increase the efficacy and delivery of bioactive agents against target cells. The technology demonstrated here may result in improved use of therapeutic materials ranging from drugs to genetic agents. In addition, our findings point to possible hazards from the in vivo enhancing action of static fields on administered or environmentally encountered chemicals.

Summary Purpose To evaluate the toxicity, response rate and short-term survival associated with the chemotherapy combinations of docetaxel plus cisplatin or carboplatin when used for the treatment of patients with metastatic carcinoma of unknown primary site. Patients and methods Twenty-six patients were treated with docetaxel 75 mg/m2 i.v. and cisplatin 75 mg/m2 i.v. given every three weeks (study A) and subsequently, 47 patients were treated with docetaxel 65 mg/m2 and carboplatin (AUC dose = 6) every three weeks (study B). Stable or responding patients received a maximum of eight courses of therapy. Patients who were known to be in treatable subset groups were excluded from these trials. The majority of patients had two or more sites of metastasis; about 45% had adenocarcinoma and 50% poorly differentiated carcinoma. Results In study A, 6 of 23 (26%) assessable patients had a major response to therapy. The median survival was eight months and one-year survival 42%. Seven patients were removed from the study early for grade 3 or 4 nausea and vomiting. In study B, 9 of 40 assessable patients (22%) had a major response to therapy. Median survival was eight months and one-year survival 29%. Toxicity associated with this regimen was predominantly myelosuppression. Comparisons of the two sequential trials showed no differences in response rates or survivals (P= 0.75). Conclusions Docetaxel and cisplatin (study A) is an active combination in carcinoma of unknown primary site, but associated with substantial gastrointestinal toxicity. A combination of docetaxel plus carboplatin (study B) is better tolerated and produced a similar response rate, median survival and one-year survival. Comparative phase III trials will be necessary to unequivically prove a survival advantage for any form of therapy in these patients. However, the survival for patients with carcinoma of unknown primary site receiving docetaxel-based chemotherapy is comparable to the survivals for several other groups of advanced cancer patients, such as non-small cell lung cancer, receiving various types of chemotherapy.

To evaluate the feasibility, toxicity, and therapeutic efficacy of 1-hour paclitaxel, carboplatin, continuous low-dose infusional 5-fluorouracil, and concurrent radiation therapy administered preoperatively in patients with localized esophageal cancer.Forty-nine patients with localized esophageal cancer, of either squamous cell carcinoma or adenocarcinoma histology, were enrolled into this phase II trial. All patients were candidates for surgical resection and received the following neoadjuvant therapy: paclitaxel, 200 mg/m2, 1 hour IV on days 1 and 22; carboplatin, AUC 6.0, IV on days 1 and 22; 5-fluorouracil, 225 mg/m2/day, continuous IV infusion on days 1 to 42; and radiation therapy, 45 Gy, administered by 1.8-Gy daily fractions beginning on day 1 of chemotherapy. Upon completion of this neoadjuvant regimen, patients were reevaluated, and all responding patients were resected within 6 weeks of completing neoadjuvant treatment.Administration of this combined modality regimen was associated with moderate toxicity and was tolerated by most patients. Leukopenia (65%) and esophagitis (31%) were the most common toxicities. Most patients did not require nutritional support. There were no treatment-related deaths during neoadjuvant therapy; however, three patients (9%) experienced postoperative death. Preliminary assessment of treatment efficacy is encouraging, with 17 of 37 evaluable patients (46%) achieving pathologic complete remission and an additional 11 patients (30%) having only microscopic residual disease.This novel, combined-modality neoadjuvant approach for the treatment of localized esophageal carcinoma is feasible and can be administered with toxicity that compares favorably to previously reported neoadjuvant regimens containing high-dose cisplatin. Preliminary assessment of efficacy is also encouraging, with 46% of patients having pathologic complete response. Further follow-up and larger numbers of patients are required to assess efficacy more definitively.

This periodic meeting of individuals with oncologic expertise represents the best that modern medicine can be: a true multidisciplinary approach to patient care. Nowhere else in healthcare will you find a better example of combining different expertise for the express purpose of improving the delivery of care for an individual patient.

During the first 2 weeks following imaginal ecdysis, the wingbeat frequency of Locusta migratoria doubles, and the activity of the forewing stretch receptor (fSR), in response to wing elevation, increases. We examined the three-dimensional structure of the centrally projecting axon of the fSR during adult maturation to determine if there are changes in the branching geometry. We found that changes occur in the mesothoracic projection (IISR Meso). Here, there was a significant increase in the volume of the projection from 2.3 x 10(4) +/- 0.2 x 10(4) microns 3 in immature locusts to 6.0 x 10(4) +/- 1.2 x 10(4) microns 3 in mature locusts. There were also significant increases in the total length, the number of branch points, the number of axonal swellings, and the diameters of first- and second-order branches of the projection. No significant changes were observed in the prothoracic projection (IISR Pro), and the only significant change observed in IISR Meta was negative allometric growth relative to IISR Meso. These results demonstrate that during adult maturation, growth of the fSR axon is heteromorphic between different ganglionic projections and that there is a potential increase in the connectivity of IISR Meso to other flight neurons in the mesothoracic ganglion. We suggest that this may be a mechanism for maintaining the efficacy of afferent input to flight interneurons that are also growing during maturation.

Summary Fourteen patients with Marfan syndrome, defined according to present criteria, had bone mineral content of the distal forearm measured by single photon absorptiometry. Patients were matched for age and sex with a large local group of healthy volunteers. While further work is needed with other methods of densitometry with measurements at other sites, our results provide no evidence that there is an increased incidence of osteoporosis in Marfan syndrome. Previous reports of an association were probably due to incorrect clinical diagnosis or confusion with clinically similar syndromes known to cause osteoporosis.

Finding the proper balance between too much and not enough immunosuppression is just as important in the late posttransplant period as it is during the first year after transplantation. In general, too much immunosuppression leads to an increase in patient mortality, whereas inadequate immunosuppression can lead to an inordinately high rate of allograft failure (Fig 5). In the late posttransplant period, patient and allograft survival are both critically dependent on the degree of immunosuppression and on the long-term side effects of the agents used to achieve this immunosuppression. Adequate immunosuppression is important in treating and preventing the acute allograft rejection episodes that are common during the first year after transplantation (Fig 6). Some data suggest that the severity of early acute rejection episodes may influence the development of chronic rejection, the most common cause of graft failure in the late posttransplant period. Otherwise, the role of immunosuppression in treating and preventing chronic rejection is unclear. The discontinuation of immunosuppression by noncompliant patients is a major cause of late graft failure. Whether the nephrotoxicity of CsA will also result in graft failure in the very late posttransplant period is still unknown. The agents used to achieve immunosuppression, along with decreased graft function and proteinuria, contribute to hypercholesterolemia, hypertension, and hyperglycemia. These and other risk factors have a negative impact on both graft and patient survival. Thus, immunosuppression is directly, or indirectly linked to most of the common causes of death and graft failure after renal transplantation. Although potent new immunosuppression protocols have increased the rate of short-term patient and allograft survival after renal transplantation, future advances in long-term survival after renal transplantation will depend on improvements that are effective in the late posttransplant period. Currently, the best approach to preventing complications in the late posttransplant period is to maintain a vigilant, comprehensive program of on-going medical care. The minimal amount of immunosuppression required to prevent allograft rejection should be used, while adhering to the principle that it is better to lose the graft than to lose the patient.

17000 Background: Topotecan IV weekly produces significantly less myelotoxicity than the standard 5-day IV schedule and appears as active in patients (pts) with relapsed ovarian cancer. Topotecan 5-day IV schedule is the standard for second-line therapy for pts with sensitive relapse SCLC. Methods: The primary endpoints were to determine the response rate and toxicity of weekly topotecan IV in pts with previously untreated extensive stage SCLC who were elderly, with poor performance status (PS), or severe coexistent medical illness. Topotecan 4mg/m2 IV over 30 minutes for 12 consecutive weeks was planned. Dose modifications were made based on toxicity. Pts were evaluated for response after 4 weeks; at least 3 weekly treatments were required to be eligible. Results: 39 pts were enrolled: 21 men, 18 women; age range 60–90 (median 71); PS 0 = 2, 1 = 18, 2 = 19). 31 pts were evaluable by WHO criteria for response. 4 pts had partial responses (13%, 95% CI 4%-30%); 20 pts (65%) had stable disease (4 had minor responses with tumor shrinkage of 29%, 19%, 12%, and 5%); 7 pts had progressive disease (22%). 15 pts completed 12 weeks of therapy. Grade 3/4 neutropenia/thrombocytopenia was seen in 11 pts and 3 pts; grade 3 infection 4 pts; grade 3/4 fatigue 12 pts. A total of 225 weeks of therapy was administered with 32 weeks of treatment delay and 10% required dose reduction. There were no treatment-related deaths. The median and 1-year survival of PR/stable pts were 5.6 months and 24%. Conclusions: Topotecan IV weekly has activity and was relatively well tolerated as first-line therapy in this very poor prognostic group of pts with extensive stage SCLC. The therapeutic index is improved with weekly topotecan IV schedule in contrast to the 5-day IV schedule. Additional study of weekly topotecan in combination with other agents in SCLC is warranted. [Table: see text]

5543 Background: Concurrent chemotherapy/radiation therapy (RT) improves treatment outcome in pts with locally advanced unresectable squamous cancers of the head and neck. We previously reported a 51% 3-year disease-free survival with induction paclitaxel/carboplatin/5-FU followed by concurrent paclitaxel/carboplatin/RT. In this phase II trial, we added gefitinib, an EGFR inhibitor, to a similar chemoradiation regimen. Methods: All pts had squamous carcinoma of the head and neck, with at least one of the following: N1-N3 disease, T3 or T4 primary lesion, nasopharynx primary (except T1N0M0). Additional eligibility: no previous therapy, ECOG PS 0 or 1, adequate bone marrow, kidney, liver function; informed consent. All pts received initial docetaxel 60mg/m2 D1, 22; carboplatin AUC 5.0 D1, 22; 5-FU 200mg/m2, 24-hour CI, D1–43; gefitinib 250mg PO qd, D1–43. Beginning week 8, pts received RT, 1.8Gy single daily dose to total 68.4 Gy, and concurrent docetaxel 20mg/m2 weekly × 6 doses + gefitinib 250mg PO daily. At completion of therapy, pts were reevaluated with CT scans and endoscopy. Results: 45 pts entered this trial between 8/04 and 8/05. Pertinent clinical characteristics: clinical T3/T4, 17; N2/N3, 23. 42 pts (93%) completed induction chemotherapy. 34 pts (76%) have completed combined modality therapy and have been restaged. Response to treatment: 11 CR (32%); 18 PR (53%); 5 stable/progression (15%). After median follow-up 7 months, 9 patients (20%) have developed progressive cancer. Actuarial PFS and OS at 1 year are 68% and 86%, respectively. Grade 3/4 myelosuppression was common, and grade 3/4 mucositis occurred in all pts during combined modality therapy. One pt had a treatment-related death during combined modality therapy. The addition of gefitinib did not substantially increase toxicity. Conclusions: This combined modality regimen was feasible and produced high response rates in pts with locally advanced head and neck cancer. Toxicity was consistent with other effective combined modality regimens for these pts. Further follow-up is needed to better assess the benefit of this approach. [Table: see text]

7083 Background: Topotecan IV weekly produces significantly less myelotoxicity than the standard 5-day IV schedule and appears as active as the 5-day schedule in patients (pts) with relapsed ovarian cancer. Topotecan 5-day IV schedule is the standard for second-line therapy for sensitive relapse SCLC. Methods: The primary endpoints of this phase II trial were to determine the response rate and toxicity of topotecan IV weekly as second-line therapy in patients with sensitive relapse (SR) and resistant relapse (RR) SCLC. Topotecan 4mg/m2 IV over 30 minutes for 12 consecutive weeks was planned. Dose modifications were made based on toxicity. Pts were evaluated for response after 4 weeks; at least 3 weekly treatments were required to be evaluable. Results: A total of 103 pts (59 SR; 44 RR) were enrolled: 56 men, 48 women; age range 42–86 (median 65); performance status 0=18, 1=69, 2=16, 3=1. 47 pts with SR and 34 pts with RR were evaluable for response by WHO criteria. For SR, 3 pts had partial response (6.4%, 95% CI 1.3%-17.5%), 17 pts had stable disease (7 had minor responses with tumor shrinkage of 39%, 27%, 21%, 20%, 20%, 7%, and 3%, respectively). Using RECIST criteria 5 pts had PR (13%, 95% CI 6%-25%). For RR, 1 pt had a CR (3%, 95% CI 0.1%-15.3%), 6 pts had stable disease (2 had minor responses with 36%, 5% tumor shrinkage). Grade 3/4 neutropenia/thrombocytopenia was seen in 17 and 22pts, grade 3 infection 6 pts; grade 3/4 fatigue 16 pts. There was 1 treatment-related death. Median and 1-year survival for all patients was 4.5 months (SR = 5.6 months; RR 3.2 months, p = 0.05) and 19% (SR = 22%; RR = 10%). There was no difference in survival for PR versus stable pts, and PR/stable had 1-year survival of 46% compared to PD of 9% (p < 0.0001). Conclusions: Topotecan IV weekly has similar activity to the standard 5-day IV schedule in SR SCLC, and considerably less myelotoxicity. These data support the weekly schedule for standard therapy of SR SCLC, and further study of weekly topotecan as a component of combination therapy for SCLC. [Table: see text]