Failure-free Interval Research Articles

Impact of ITV/GTV Ratio on Local Failure in Early Stage Non-Small Cell Lung Cancer Patients Receiving Stereotactic Ablative Radiation Therapy

The free-breathing internal target volume (ITV) approach is a popular motion management strategy that covers the gross tumor volume (GTV) throughout respiration during stereotactic ablative radiation therapy (SABR) for lung cancer. A large ITV/GTV ratio suggests significant tumor motion during the respiratory cycle relative to the tumor's volume which may result in increased risk of geographic miss and local failure. We hypothesized that higher ITV/GTV ratio is associated with higher rates of local failure following SABR for early stage non-small cell lung cancer (NSCLC).Patients with early stage NSCLC archived in a prospective, IRB-approved tumor registry were identified and reviewed for treatment failure following SABR. All SABR plans utilized the ITV approach with a free-breathing 4DCT to account for tumor motion. Treatment failure was based on two criteria: persistent tumor growth on CT and evidence of tumor viability (confirmed by biopsy or FDG PET revealing uptake consistent with malignancy). Failure was categorized as primary at the treatment site, lobar if within the treated lobe (excluding primary site), or local if either primary or lobar. GTV, ITV, target min/mean/max doses, histology, T stage, lobe involved, and the use of abdominal compression were recorded. ITV/GTV ratio was calculated for each case. The effect of ITV/GTV on local failure was assessed using the Cox proportional hazard model. The effects of ITV/GTV on primary and lobar failure were assessed using the Kaplan-Meier method and log-rank test. Significance was set at P < 0.05 for each comparison.A total of 305 patients with complete dosimetric data were treated from 10/2005 to 3/2015 with a median follow up of 19.5 months (range, 0-168 months). Local, primary, and lobar failure were observed in 12.8%, 6.2%, and 6.6% of patients, respectively. No dosimetric or clinical factor, including the ITV/GTV ratio, was significantly associated with local failure on univariate Cox analysis. ITV/GTV ratio > 1.37 (median value) demonstrated a trend toward longer failure-free interval at the primary site (22.2 vs 18.1 months, P = 0.08) while no trend was observed between ITV/GTV ratio and lobar failure.In this cohort, the ITV/GTV ratio was not significantly associated with local failure; however, ITV/GTV ratio > 1.37 demonstrated a trend toward longer failure-free interval at the primary site on subgroup analysis. This is the inverse of our initial hypothesis and suggests that capturing the entire motion envelope within the free-breathing ITV may be important for optimizing primary tumor control. Further investigation of the ITV/GTV ratio and its association with local failure is warranted in a larger cohort with a greater number of failures to allow for more comprehensive analysis of the primary and lobar components.

Combined homologous recombination repair deficiency and immune activation analysis for predicting intensified responses of anthracycline, cyclophosphamide and taxane chemotherapy in triple-negative breast cancer

BackgroundTriple-negative breast cancer (TNBC) is a clinically aggressive disease with abundant variants that cause homologous recombination repair deficiency (HRD). Whether TNBC patients with HRD are sensitive to anthracycline, cyclophosphamide and taxane (ACT), and whether the combination of HRD and tumour immunity can improve the recognition of ACT responders are still unknown.MethodsData from 83 TNBC patients in The Cancer Genome Atlas (TCGA) was used as a discovery cohort to analyse the association between HRD and ACT chemotherapy benefits. The combined effects of HRD and immune activation on ACT chemotherapy were explored at both the genome and the transcriptome levels. Independent cohorts from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and Gene Expression Omnibus (GEO) were adopted to validate our findings.ResultsHRD was associated with a longer ACT chemotherapy failure-free interval (FFI) with a hazard ratio of 0.16 (P = 0.004) and improved patient prognosis (P = 0.0063). By analysing both HRD status and ACT response, we identified patients with a distinct TNBC subtype (ACT-S&HR-P) that showed higher tumour lymphocyte infiltration, IFN-γ activity and NK cell levels. Patients with ACT-S&HR-P had significantly elevated immune inhibitor levels and presented immune activation associated with the increased activities of both innate immune cells and adaptive immune cells, which suggested treatment with immune checkpoint blockade as an option for this subtype. Our analysis revealed that the combination of HRD and immune activation enhanced the efficiency of identifying responders to ACT chemotherapy (AUC = 0.91, P = 1.06e−04) and synergistically contributed to the clinical benefits of TNBC patients. A transcriptional HRD signature of ACT response-related prognostic factors was identified and independently validated to be significantly associated with improved survival in the GEO cohort (P = 0.0038) and the METABRIC dataset (P < 0.0001).ConclusionsThese findings highlight that HR deficiency prolongs FFI and predicts intensified responses in TNBC patients by combining HRD and immune activation, which provides a molecular basis for identifying ACT responders.

Preoperative chemoradiotherapy to improve overall survival in pancreatic cancer: Long-term results of the multicenter randomized phase III PREOPANC trial.

4016 Background: Preoperative chemoradiotherapy (CRT) may improve overall survival in resectable pancreatic cancer (RPC) and borderline resectable pancreatic cancer (BRPC). Long term results are presented. Methods: In this multicenter phase III trial, patients with RPC or BRPC were randomized between preoperative CRT, (gemcitabine 1000 mg/m2 weekly for 7 of 10 weeks, and 15x2.4 Gy radiotherapy in week 4 to 6), followed by surgery and four cycles of adjuvant gemcitabine (1000 mg/m2 weekly for 3 of 4 weeks), or immediate surgery followed by 6 cycles of adjuvant gemcitabine (1000 mg/m2 weekly for 3 of 4 weeks). Primary endpoint was overall survival by intention-to-treat (ITT). Results: From April 2013 to July 2017, 246 eligible patients were accrued by 16 Dutch centers and randomized, 119 to preoperative CRT and 127 to immediate surgery. After a median follow up of 56 months (35.3-92.0 months), 210 patients have died, 93 (78%) in the preoperative CRT arm and 117 (92%) in the immediate surgery arm. Three- and five-year overall survival ITT was 27.7% and 20.5% after preoperative CRT versus 16.5% and 6.5% after immediate surgery (HR 0.73; 95% CI 0.56 to 0.96; p = 0.025). In addition, disease-free survival (HR 0.70; p = 0.009) locoregional failure-free interval (HR 0.57; p = 0.004) and distant metastases free interval (HR 0.74; p = 0.071) improved after preoperative CRT. Also in the stratified subsets RPC and BRPC, preoperative CRT improved OS: RPC (n = 133, HR 0.79; 95% CI 0.54 to 1.16; P = 0.23). BRPC (n = 113, HR 0.67; 95% CI 0.45 to 0.99; p = 0.045). We could not demonstrate a difference in treatment effect between these subsets (interaction test p = 0.56). Conclusions: Preoperative gemcitabine-based CRT for RPC or BRPC improves long term overall survival compared to immediate surgery with adjuvant gemcitabine. Clinical trial information: NTR3709.

Treating the primary in low burden metastatic prostate cancer: Where do we stand?

On the basis of endocrine therapy for patients with low burden metastatic prostate cancer (LBMP), the clinical efficacy and quality of life were compared between prostate-only directed radiotherapy (PODT) and prostate and metastasis radiotherapy (PMRT).From November 2009 to November 2015, total 91 patients newly diagnosed with LBMP were retrospectively analyzed, of which 52 patients received PODT and 39 patients received PMRT. The biochemical failure free interval (IBF), prostate specific survival (PCSS), and overall survival (OS) time were compared between the 2 groups, and expanded prostate cancer index composite (EPIC) scale was used to evaluate the difference in quality of life between the 2 groups.The median IBF of the PODT group was 31 months, which was significantly lower than the 39 months of the PMRT group (P < .05); the 5-year OS and PCSS were 58.9%, 65.3% in PODT group, and 58.9%, 71.79% in PMRT group, respectively. There was no significant between the 2 groups (P > .05); the side effects of acute radiotherapy in PMRT group were significantly higher than PODT group (P < .05), especially in bone marrow suppression and gastrointestinal reactions; The scores of urinary system function and intestinal system function in PMRT group were significantly higher than PODT group at the end of radiotherapy, 3 months after radiotherapy, and 6 months after radiotherapy (P < .05). The score of sexual function in PMRT group was significantly lower than that in PODT group after radiotherapy (P < .05), and higher than that in PORT group at other follow-up time points (P < .05). The hormone function was decreased at each follow-up time point in 2 groups, and there was no significant difference between the 2 groups (P > .05).Patients with LBMP receiving PMRT can improve IBF, but cannot increase PCSS and OS, and increase the incidence of acute radiation injury.

MP60-03 THE EFFECTIVENESS AND SAFETY OF SURGICAL PROCEDURES FOR STRESS URINARY INCONTINENCE IN PATIENTS WITH NEUROGENIC STRESS INCONTINENCE

You have accessJournal of UrologyTrauma/Reconstruction/Diversion: Urethral Reconstruction (including Stricture, Diverticulum) II (MP60)1 Apr 2020MP60-03 THE EFFECTIVENESS AND SAFETY OF SURGICAL PROCEDURES FOR STRESS URINARY INCONTINENCE IN PATIENTS WITH NEUROGENIC STRESS INCONTINENCE Min Soo Choo*, Bahaa Malaeb, John Park, Paholo Barboglio-Romo, J Quentin Clemens, Anne Cameron, and John T Stoffel Min Soo Choo*Min Soo Choo* More articles by this author , Bahaa MalaebBahaa Malaeb More articles by this author , John ParkJohn Park More articles by this author , Paholo Barboglio-RomoPaholo Barboglio-Romo More articles by this author , J Quentin ClemensJ Quentin Clemens More articles by this author , Anne CameronAnne Cameron More articles by this author , and John T StoffelJohn T Stoffel More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000929.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: We evaluated the effectiveness and safety of 3 surgical procedures (Artificial Urinary Sphincter, Suburethral Sling, Urethral Bulking agents) for treating stress urinary incontinence in patients with neurogenic lower urinary tract dysfunction. METHODS: We used CPT and ICD-9 codes between 2012 – 2019 to identify patients with neurogenic bladder dysfunction who underwent urethral bulking injection (UBI), sling, or artificial urethral sphincter (AUS) for treatment of stress urinary incontinence (SUI). Failure of procedure was defined as stress incontinence > 50% from pre operative baseline (pad number, review of symptoms) at any follow up visit and/or additional surgical intervention for SUI. Time to failure was compared between procedures and risk factors for failure assessed. RESULTS: Of the consecutive 1138 patients reviewed, 68 procedures in 51 patients (37 male) with neurogenic SUI were included. There were 39, 15, and 14 cases of UBI, sling, and AUS, respectively. The median age was 37 years (IQ: 15-56). Spinal cord injury and spina bifida were the most common diagnoses (33 patients). The median follow-up was 256 days (IQ: 108-717). AUS had the longest failure free interval, followed by sling, and UBI (Figure 1). AUS had 46% failure rate at 2700 days post implantation and sling and UBI had 50% failure rates at 760 and 369 days, respectively (log-rank, p = 0.037). Age< 19 years was a significant factor for failure of any procedure in multivariable analysis (OR 0.088, p=0.020). Failure was particularly prevalent in patients < age 19 treated with UBI (90% failure). Sex and cause of neurogenic bladder were not associated with failure. No Clavien IV-V complications were noted in any procedure and there were no differences in overall complication rates. CONCLUSIONS: Neurogenic stress incontinence can be safely treated with artificial urinary sphincter, sling or bulking agent. Artificial sphincter had the longest failure free interval and urethral bulking agents demonstrated the most rapid time to failure. Since the durability is different between each procedure, shared decision making between patient and physician is necessary to match expectations and outcomes. Source of Funding: none © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e889-e890 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Min Soo Choo* More articles by this author Bahaa Malaeb More articles by this author John Park More articles by this author Paholo Barboglio-Romo More articles by this author J Quentin Clemens More articles by this author Anne Cameron More articles by this author John T Stoffel More articles by this author Expand All Advertisement PDF downloadLoading ...

Androgen deprivation and high-dose radiotherapy for oligometastatic prostate cancer patients with less than five regional and/or distant metastases

Background. Substantial survival may be observed with oligometastatic prostate cancer. Combining androgen deprivation (AD) and high-dose external beam radiotherapy (RT) to isolated regional or distant lesions may be proposed for these patients and the outcome of this strategy is the purpose of the present report. Material and methods. From 2003 to 2010, 50 prostate cancer patients were diagnosed with synchronous (n = 7) or metachronous (n = 43) oligometastases (OM). Among the relapsing patients, the recurrence occurred after radical prostatectomy in 33 patients and curative RT (± AD) in 10 patients. The median age at diagnosis was 63 years (range, 48–82). All patients underwent a bone scan and 18F-choline or 11C-acetate PET-CT at the time of diagnosis or relapse, showing regional and/or distant nodal and bone and/or visceral metastases in 33 and 17 patients, respectively. The median delivered effective dose was 64 Gy. All but one patient received neo-adjuvant and concomitant AD. Results. After a median follow-up of 31 months (range, 9–89) the three-year biochemical relapse-free survival (bRFS), clinical failure-free survival, and overall survival rates were 54.5%, 58.6% and 92%, respectively. No grade 3 toxicity was observed. Improved bRFS was found to be significantly associated with the number of OM. The three-year bRFS was 66.5% versus 36.4% for patients with 1 and > 1 OMs (p = 0.031). A normalised total dose (NTD in 2 Gy/fraction, alpha/beta = 2 Gy) above 64 Gy was also correlated with a better three-year bRFS compared to lower doses: 65% vs. 41.8%, respectively (p = 0.005). On multivariate analysis, only the NTD > 64 Gy retained statistical significance (HR: 0.37, 95% CI 0.15–0.93). Conclusion. Oligometastatic patients may be successfully treated with short AD and high-dose irradiation to the metastatic lesions. High dose improves bRFS. Such a treatment strategy may hypothetically succeed to prolong the failure-free interval between two consecutive AD courses.

Local control in resectable and borderline resectable pancreatic cancer (PCa) treated with preoperative chemoradiation using IMRT or chemotherapy alone.

282 Background: The primary objective is to review local control and failure patterns in PCa patients treated with preoperative chemoradiation (chemoXRT) using IMRT compared to patients treated with chemotherapy alone. Methods: All patients with resectable and borderline resectable PCa treated between 1/1/2009 -11/1/2011 were reviewed. During the study period, 68 patients (40 borderline resectable, 28 resectable) were treated with preoperative chemoXRT (50.4 Gy [1.8 Gy/fx] with concurrent gemcitabine [n=59] or capecitabine [n=7]). 12 patients with resectable tumors received gemcitabine based chemotherapy alone and did not receive radiation therapy due to enrollment on chemotherapy only protocols (n=10) or to patient preference (n=2). Radiation was delivered to a CTV that includes the primary mass, the SMA and SMV, +/- the celiac axis. A 4D-CT and daily image guidance were used in all patients. The local failure free interval was defined as the time from surgical resection to local failure or last documented CT scan of the abdomen with no evidence of local disease progression. Results: Following preoperative chemoXRT, 48/68 patients underwent resection with 47(98%) R0 resections. 11/12 patients in the No XRT group undwerent resection with 10 (91%) R0 resections. In the No XRT group, 8/11 (73%) patients failed locally at the SMA/SMV or resection bed as a component of first failure compared to 1/48 (2%) patients who received preoperative chemoXRT (p&lt;0.001). Local failure was the sole site of first failure in 5/11 patients in the No XRT group and 0/48 patients who received preoperative chemoXRT. The actuarial rate of local failure 1 year from surgery was 5% in the preoperative chemoXRT group vs 27% in the No XRT group (p&lt;0.001). All local failures in the No XRT group would have been encompassed using the CTV target volumes used in patients treated with preoperative chemoXRT. Conclusions: IMRT-based, conformal, preoperative chemoXRT for resectable and borderline resectable PCa may facilitate margin negative resection and increase local control. Omission of radiation therapy may result in high rates of local failures at the SMA/SMV vasculature or in the pancreatic bed.

Clinical outcome of gamma knife (GK) radiotherapy for central nervous system (CNS) metastases from renal cell carcinoma (RCC).

e15071 Background: Current treatment modalities for RCC CNS metastases include resection, GK and whole-brain radiotherapy. Existing series describing treatment outcomes include a mix of tumor types, and thus provide little insight into CNS metastasis response by tumor type. Although RCC has historically been considered radioresistant, GK is increasingly being applied to RCC CNS metastases. Methods: RCC pts with brain metastases treated with GK between 1996 and 2010 were retrospectively identified. Pt, GK and systemic therapy characteristics were recorded. Pts were followed radiographically at 30 days post GK and every 3-6 months thereafter with MRI scans. Local failure was defined as treated tumor progression after GK and distant failure was defined as new CNS metastases not in the GK field. Results: One hundred sixty-six patients were identified: 75% male, median age 60, 55% performance status 0, 21% received systemic therapy within 30 days of GK and 97% clear cell histology. Two hundred thirty-three GK procedures were performed on a total of 487 CNS lesions, most commonly in the frontal lobe (32%), parietal lobe (17%), cerebellum (12%), occipital lobe (11%) and temporal lobe (9%). The median interval from diagnosis of RCC to first GK was 20 months (range, 0.1-310). The majority of pts (65%) received a GK dose of 24 Gy with a mean of 1.8 targets per GK procedure. 76% of pts received 1 GK and 24% received multiple GK procedures. Considering all GK procedures, local control was 87%, with an additional 38% of patients having distant CNS failure. The median time to local or distant failure was 9.9 months (range, 5.9-12.9). Local control and failure-free interval of a second GK procedure was not different from the first GK procedure (p=.31, sign test). Potential predictors of CNS failure were examined, and only age >60 (p=.07) and number of targets > 2 (p=.09) approached significance. Prognostic variables, GK treatment characteristics or systemic targeted therapy within 30 days of GK did not predict for subsequent CNS relapse. Conclusions: GK is a common treatment modality for RCC CNS metastases, providing excellent local control and freedom from CNS relapse for several months.

In Patients Experiencing Biochemical Failure After Radiotherapy, Pretreatment Risk Group and PSA Velocity Predict Differences in Overall Survival and Biochemical Failure-Free Interval

To characterize the demographics and survival outcomes of localized prostate cancer patients who developed biochemical failure (BF) according to a prostate-specific antigen (PSA) nadir plus 2 ng/mL. We identified 375 prostate cancer patients who had undergone external beam radiotherapy without androgen deprivation therapy but with sufficient PSA data to study PSA kinetics. Of these patients, we identified 82 with BF. The pretreatment PSA velocity was calculated for each patient. For the BF cohort, 26% were low-risk and 74% were intermediate- or high-risk patients. Of the 82 BF patients, 16 (20%) were noted to have both low-risk disease and a pretreatment low PSA velocity of < or =2 ng/mL/y (termed "low-risk low-velocity" [LRLV]). The remaining BF patients had either intermediate- or high-risk features or a high PSA velocity >2 ng/mL/y (termed "higher risk" [HR]). For patients who had BF, the LRLV group had a delayed median time to BF of 55 months compared with 33 months for the HR patients (p = 0.04). With a median clinical follow-up of 112 months, the 5-year overall survival rate was 100% for the LRLV BF patients vs. 84% for the HR patients (p = 0.02). We observed that LRLV BF patients represent a sizeable proportion of all patients with treatment failure. However, when comparing LRLV BF with HR BF patients, the former had significantly better overall survival and a longer interval to BF. This suggests that not all BF events are equivalent and emphasizes the challenges associated with using BF alone as a surrogate for a survival endpoint.

Prognostic Impact of Cytogenetic Abnormalities in Elderly Patients with Acute Myeloid Leukemia (AML) Enrolled in the ALFA-9803 Trial.

We have recently reported the superiority of prolonged ambulatory versus short intensive post-remission therapy in 416 patients with AML aged 65 years or more (median age, 72 years) selected to be treated intensively in the ALFA-9803 trial (C. Gardin et al. Blood 2007). We report here on the prognostic value of cytogenetic abnormalities in 339 of these patients with available karyotype (27 not done, 50 failures). When classical endpoints (CR rate, DFS, OS) were used, we were only able to identify one very unfavorable subgroup of 14% patients (N=49 with −7, abnormalities of both chromosomes 5 and 7, 3q abnormality, or complex karyotype with 5 abnormalities or more; CR rate, 30%). No significant differences in outcome were found between patients with any other abnormality and the 171 patients with a normal karyotype/−Y (overall CR rate, 62%). When cumulative incidences of AML-related events (primary refractory AML, relapses) were used as endpoints with induction deaths and deaths in first CR as competing events, three distinct subsets were more easily identified:1.14% very unfavorable-risk patients, as detailed above;2.59% standard-risk patients (N=200 with t(8;21), inv(16), normal karyotype/−Y, or isolated +8; CR rate, 65%); and3.27% unfavorable-risk patients (N=90 with other abnormalities, including notably 5q− and 7q−; CR rate, 58%).Median failure-free interval (Fig 1; P<.001, by the Gray test) and relapse-free interval (Fig 2; P<.001, by the Gray test) were 2.3, 12.4, and 8.1 months and 4.2, 15.0, and 10.5 months in these three subsets, respectively. Interestingly, prolonged ambulatory post-remission therapy was associated with longer DFS and OS in the standard-risk subset only. The results demonstrate that despite their poor general outcome, older patients with AML may be subdivided in three meaningful cytogenetic subgroups. This 3-subgroup classification should help to optimize disease management decisions such as intensive versus non-intensive or investigational therapies for induction or consolidation. [Display omitted] [Display omitted]

Final results of a Phase I/II dose escalation trial in non–small-cell lung cancer using three-dimensional conformal radiotherapy

The aim of this study was to determine the maximum tolerated dose (MTD) delivered within 6 weeks in patients with non-small-cell lung cancer (NSCLC). The impact of tumor volume and delivered dose on failure-free interval (FFI) and overall survival (OS) were also studied. A Phase I/II trial was performed including inoperable NSCLC patients. According to the relative mean lung dose (rMLD), five risk groups with different starting doses were defined: Group 1, rMLD 0.0 to 0.12; Group 2, rMLD 0.12 to 0.18; Group 3, rMLD 0.18 to 0.24; Group 4, rMLD 0.24 to 0.31; and Group 5, rMLD 0.31 to 0.40. Patients underwent irradiation with 2.25 Gy per fraction and a fixed overall treatment time of 6 weeks. The dose was escalated with 6.75 Gy after 6 months follow-up without dose-limiting toxicity. If more than 30 fractions were prescribed, twice-daily irradiation was performed with at least a 6-h interval. A total of 88 patients were included. Tumor Stage I or II was found in 53%, IIIA in 31%, and IIIB in 17%. The MTD was not achieved in risk Group 1 (reached dose, 94.5 Gy). For risk Groups 2 and 3 the MTD was 81 Gy. The 74.3-Gy dose was determined to be safe for Group 4 and the 60.8-Gy dose for Group 5. In 2 patients (5%) an isolated nodal relapse occurred. Based on multivariable analysis, higher doses significantly increased the FFI (p = 0.02) for the total group. The OS was increased in the lower risk groups (p = 0.05) but not in the higher risk groups (p = 0.4). Dose escalation is safe up to 94.5 Gy in 42 fractions in 6 weeks in patients with an MLD 13.6 Gy or less. Higher doses are associated with a better FFI and OS for smaller tumor volumes. Involved-field irradiation results in a low percentage of isolated nodal relapses.

Nodal downstaging predicts survival following induction chemotherapy for stage IIIA (N2) non-small cell lung cancer in CALGB protocol #8935

CALGB 8935 was a phase II protocol for mediastinoscopically staged IIIA (N2) non-small cell lung cancer. Induction cisplatin/vinblastine chemotherapy was followed by surgical resection, adjuvant cisplatin/vinblastine, and radiotherapy. We now evaluate the prognosis of pathologic nodes. Failure-free survival was calculated from a landmark 3 months after resection to account for heterogeneity in adjuvant therapy. Nine of 42 (21%) resected patients had no residual N2 disease. This subset of 9 had a median failure-free interval of 47.8 months from landmark, whereas the 33 patients (79%) with persistent N2 disease had a median failure-free survival of 8.2 months from landmark (P=0.01). Although 21/42 (50%) had an incomplete resection (positive highest resected node and/or margin), completeness of resection did not influence failure-free survival. There were 3 distant and no local recurrences among the N2 negative group, and 12 local recurrences among patients with residual N2 disease (P=0.041). These data suggest: (1) persistent N2 disease following induction chemotherapy is unfavorable; (2) patients downstaged to N2 negative may benefit from surgical resection; however, (3) 33% of N2 negative patients suffered disease relapse.

Transactors

We introduce transactors , a fault-tolerant programming model for composing loosely-coupled distributed components running in an unreliable environment such as the internet into systems that reliably maintain globally consistent distributed state. The transactor model incorporates certain elements of traditional transaction processing, but allows these elements to be composed in different ways without the need for central coordination, thus facilitating the study of distributed fault-tolerance from a semantic point of view. We formalize our approach via the τ-calculus, an extended lambda-calculus based on the actor model, and illustrate its usage through a number of examples. The τ-calculus incorporates constructs which distributed processes can use to create globally-consistent checkpoints . We provide an operational semantics for the τ-calculus, and formalize the following safety and liveness properties: first, we show that globally-consistent checkpoints have equivalent execution traces without any node failures or application-level failures, and second, we show that it is possible to reach globally-consistent checkpoints provided that there is some bounded failure-free interval during which checkpointing can occur.

Widening eligibility to phase II trials: constant arcsine difference phase II trials

This paper presents a method for undertaking Phase II trials in which not all patients are considered equally likely to respond to treatment. In ovarian cancer, for example, it has been shown that response is less likely in patients who have failed the previous treatment after only a short interval compared to those who have a protracted failure-free interval [Gynecol. Oncol. 36 (1990) 207]. The method is analogous to those used in phase III trials which estimate relative rather than absolute effects; a constant odds ratio, for example, encompasses multiple relationships between response rates. Phase II trials commonly test the null hypothesis H 0: P≤ p 0 against the alternate hypothesis H 1: P≥ p 1, where the response rate p 1 is the minimum required level of efficacy and p 0 the highest level which would indicate that the treatment is of no further interest. This approach can be extended by using the arcsine transformation to allow p 0 and p 1 to vary between patients, thus for the ith patient p 0 i =(sin c i ) 2 and the efficacy level is set to p 1 i =(sin ( c i + b)) 2. The value of the arcsine parameter b therefore determines efficacy and the test for efficacy in the trial then becomes a test of the null hypothesis H 0: B≤0 against the alternate hypothesis H 1: B≥ b. The value of b is determined by considering representative values of p 0 and p 1 and setting b=(sin −1√ p 1−sin −1√ p 0); b is thus the constant arcsine difference (CAD) between p 0 i and p 1 i . The variance of B is 1/4 n, which is independent of P, trial designs are therefore independent of P, implying that all patients for whom this difference is identical can be entered into the same trial. This paper considers single-stage and two-stage CAD Phase II trials.

Prognostic indices in ovarian cancer. Their significance in treatment planning.

Ovarian cancer exhibits a wide spectrum of behavior, the effectiveness of therapies varies and the circumstances of patients differ. Better outcomes will require more selective treatment strategies considerate of these variables. 1. The need for treatment As long as outcome is affected more by disease than by treatment, survival will be determined by the bulk and growth-rate of residual tumor-prognostic factors reflect these. They indicate the need for treatment, but not whether benefit is likely. FIGO stage is the international standard, but this alone is inadequately predictive. Grade reflects virulence, but subjectivity has limited its usefulness. Newer quantitative pathology techniques (such as DNA ploidy) more reproducibly reflect behavior. Prognostic factors can be used to define subsets of patients at differing degrees of disease risk. 2. Efficacy of treatment No response predictors are yet of practical use in selecting primary chemotherapy on an individual basis. Generally, response is more likely if the tumor is less extensive and if dose and treatment frequency are higher. Monitoring biomarkers can more quickly identify those with a suboptimal response who may require a change or discontinuation of treatment. Re-laparotomy has limited usefulness. Response predictors for second-line treatment (e.g. the failure-free interval) are available and also have implications for new drug testing. 3. Suitability of treatment Advanced age or serious additional illness may render intensive treatment inappropriate. The informed patient's wishes are of prime importance. An evolving strategy of selective management is described.

The ?failure free interval? defines the likelihood of resistance to carboplatin in patients with advanced epithelial ovarian cancer previously treated with cisplatin: relevance to therapy and new drug testing

An earlier phase II trial of second-line carboplatin in patients (n= 46) with epithelial ovarian carcinoma previously treated with cisplatin was re-analyzed using the period from initial diagnosis to the first evidence of progression (the ‘failure free interval’) as a predictor of the probability of response to carboplatin. The rationale was to try to improve our ability to define resistant patients. No responses were seen if the failure free interval was less than 24 months (0/32) whilst 63% (9/14) responded if it was more than 24 months (6 complete and 3 partial responses).