Inclusion Criteria For Clinical Trials Research Articles

Outcomes of Salvage Autologous Stem Cell Transplant (ASCT) in Multiple Myeloma Patients Relapsed After An Initial ASCT and Refractory to Bortezomib and Immunomodulatory Agents

Abstract 4484 Background:Although the prognosis for patients with multiple myeloma (MM) has improved with the use of immunomodulatory drugs thalidomide and lenalidomide, as well as with the proteasome inhibitor bortezomib, eventually all patients relapse and become refractory to all available treatments. The prognosis for MM patients refractory to these two novel classes of therapies is dismal, with estimated progression free survival (PFS) and overall survival (OS) of only 5 and 9 months respectively (Kumar et al, ASH 2010). (Of note, only 60% of these patients had received prior stem cell transplants (SCT)). While clinical trials would be ideal for these patients, many have cytopenias (often due to heavy marrow replacement) that fail to meet standard inclusion criteria for clinical trials. Since autologous stem cells remain viable for many years, we have been performing intermediate or high dose chemotherapy with autologous stem cell transplant (ASCT) as a disease temporizing measure and also as a possible bridge to clinical trial participation. Although the safety and efficacy of salvage ASCT in relapsed MM has been reported (Olin et al, BMT 2009 and Qazilbash et al, Cancer 2006), no studies have focused on the novel agent refractory population. We review here the outcomes of salvage ASCTs in 63 patients with heavily pre-treated, relapsed, and novel agent refractory MM. Methods:Of the patients with MM who underwent ASCT between 1999 to 2010 at St Vincent's hospital, we first identified those patients who had a second autologous stem cell infusion at least 12 months after the first (i.e. non tandem SCTs). Of the 435 patients who met this criteria, 63 were found to have not only progressed on bortezomib containing regimens but also were refractory to IMids (thalidomide or lenalidomide). Results:The median age at time of salvage ASCT was 60 years [range 36–75] at a median of 5.6yrs [range 1.5 to 15.9] since the diagnosis of MM. Patients had a median of 5 lines of prior treatment [range 2–9] and a median of 58 months since the first auto SCT[range 12–164]. The median PFS in 59 evaluable patients after the initial ASCT was 21.6 months [range 4.5–76.8]. Of 58 evaluable patients, 56 patient were treated with a mephalan based conditioning regimen for the salvage ASCT including 11 at 200 mg/m2, 10 at 140 mg/m2, 24 at 100 mg/m2, and 11 who received 50–75 mg/m2. 27 of these patients received bortezomib with the melphalan conditioning and 3 patients received BCNU with melphalan. 2 other patients received VDT-PACE. 26 of these patients received their chemotherapy and stem cells in the outpatient setting. Of the available data, adverse effects included diarrhea in 3 patients, with grade 2 being the worst grade. Three patients had mucositis, one with grade 3.Of the 58 patients evaluable for response at day 100 post salvage SCT, 7 had a CR, 3 near CR, 5 VGPR, and 16 PR for an overall response rate of 53% by IMWG criteria. An additional 2 patients had SD. 25 patients had PD including 3 patients who died of PD within 30 days. The median PFS was 5.5 months [1.1–36 months] in 32 evaluable patients and median OS in 59 evaluable patients was 8.5 months [8 days-60 months]. 6 patients remain alive at a median of 16 months [7.7 – 53 months].Of 23 patients with baseline ANC < 1500 or plt < 50k making them ineligible for most clinical trials prior to salvage auto SCT, 20 (87%) exceeded those cut-offs at day 100 whereas 3 patients did not. Two of these patients died of PD at 3.1 and 6.4 months. The third had delayed platelet recovery and died of PD at 29 months. Results of univariate and multivariate analysis will be presented at the annual meeting. Conclusions:In a heavily pretreated population of patients with MM (median 5 lines of prior therapy) refractory to bortezomib and IMIDs, salvage auto SCT was associated with an overall response rate of 53%, a median OS of 8.5 months and PFS 5.5 months. Importantly, 87% of patients with cytopenias precluding clinical trial participation demonstrated hematologic recovery post salvage ASCT. This study demonstrates a continuing role for salvage ASCT in cytopenic, heavily pretreated, novel agent refractory patients with MM as a possible bridge to clinical trials. Disclosures:Chari:Millenium Takeda:; Celgene:. Jagannath:Celgene: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees.

Choix thérapeutique en fonction du contexte clinique

The choice of therapy in psoriasis is a complex multidimensional process based on both patient-related and disease-related factors. Standardisation of inclusion criteria for clinical trials leads to the exclusion of large numbers of patients with special forms of psoriasis or presenting comorbidities that must nevertheless be dealt with in real-life situations. The main patient-related factors affecting choice of therapy are age, pregnancy for women and the desire to father children for men, renal and hepatic failure, the risk of infection and neoplasia, metabolic and both cardiovascular and psychiatric comorbidities, as well as compliance and lifestyle. Disease-related factors affecting choice of therapy include unstable lesions, acral sites (palms, soles, nails, face and scalp), erythrodermic psoriasis, pustular psoriasis, guttate psoriasis and associated psoriatic rheumatism. The therapeutic recommendations set out in this study are based upon a critical analysis of the literature and upon the actual therapeutic practice of the experts.

Patient Recruitment into Acute Spinal Cord Injury Clinical Trials of Early Therapeutic Interventions: How Many Patients Can Really Be Enrolled?

Introduction While there is a desperate need for effective treatments for acute spinal cord injury (SCI), the clinical validation of novel therapeutic interventions is severely hampered by the need to recruit relatively large numbers of patients into clinical trials for sufficient statistical power. While a centre might annually admit 100 acute SCI patients, only a fraction may satisfy the basic inclusion criteria for an acute clinical trial, which typically requires patients of a certain injury severity (eg ASIA A), within a specific time window (eg. 12 hours from injury), and without other major injuries or conditions that would cloud the baseline neurologic assessment. This study was conducted to define that “fraction” of SCI patients that would theoretically satisfy standard inclusion criteria of an acute clinical trial. Methods Using a local database, we reviewed patients admitted to our Level 1 trauma center with a complete (ASIA A) or an incomplete (ASIA B, C and D) acute SCI involving bony spinal levels between C0 and sacrum. All patients admitted over the 4 year period from 2005 to 2009 were reviewed. Demographic information and data about the patients9 SCI and other injuries were reviewed. We then determined how many of the total number of SCI patients would be eligible for enrolment into a hypothetical acute clinical trial that required a valid baseline assessment of neurologic impairment, and an enrolment window of either 12 hours, 24 hours, or 48 hours. Results 408 acute traumatic SCI patients were admitted over the 4 year period. 253 of 408 (62%) patients presented within 12 hours of injury, 60 (15%) between 12–24 hours, and 28 (7%) between 24–48 hours. 42% of patients were ASIA A, 13% B, 18% C and 27% D. The number of patients who presented with injuries or other conditions that would exclude them from enrolment was relatively high: 4% had penetrating injuries, 12% had illicit drug use, and 20% had either alcohol intoxication or head injuries which precluded a valid baseline neurologic examination. Conclusions Out of a total of 408 patients admitted over 4 years, the number who would have been optimistically eligible for an acute neuroprotective trial was disappointingly small. Given that acute clinical trials are increasingly interested in cervical ASIA A patients (in whom segmental motor recovery can be assessed), the number of such patients who would actually be eligible for an acute intervention was surprisingly low. Given that additional inclusion/exclusion criteria would also be applicable in a real clinical trial, the true number of “eligible” or “recruitable” patients is conservatively even lower. This study is the first to quantify this challenging aspects of conducting acute SCI clinical trials, and provides valuable information for those planning such initiative

Acute renal artery occlusion: making the case for renal artery revascularization

Atherosclerotic renal artery disease is a common disease entity that may be identified in patients with difficult-to-control hypertension and/or chronic kidney disease but is probably underdiagnosed. Current evidence from both observational and randomized studies offers mixed results regarding the support for renal artery revascularization. There is lack of equipoise with regard to the efficacy of renal artery revascularization among the interventional and renal communities, as well as disagreements on the appropriate endpoints to measure in clinical trials, which have led to selection bias confounding the scant available data. We report a patient who does not fit any clinical trial inclusion criteria with acute on chronic kidney injury and new-onset heart failure whose symptoms and renal function improved significantly after renal artery intervention.

Evidence‐based Community Consultation for Traumatic Brain Injury

The objective was to determine if geospatial techniques can be used to inform targeted community consultation (CC) and public disclosure (PD) for a clinical trial requiring emergency exception from informed consent (EFIC). Data from January 2007 to December 2009 were extracted from a Level I trauma center's trauma database using the National Trauma Registry of the American College of Surgeon (NTRACS). Injury details, demographics, geographic codes, and clinical data necessary to match core elements of the clinical trial inclusion criteria (Glasgow Coma Scale [GCS] 3-12 and blunt head injury) were collected on all patients. Patients' home zip codes were geocoded to compare with population density and clustering analysis. Over a 2-year period, 179 patients presented with moderate to severe traumatic brain injury (TBI). Mapping the rate and frequency of TBI patients presenting to the trauma center delineated at-risk populations for moderate to severe head injury. Four zip codes had higher incidences of TBI than the rest, with one zip code having a very high rate of 80 per 100,000 population. Geospatial techniques and hospital data records can be used to characterize potential subjects and delineate a high-risk population to inform directed CC and public disclosure strategies.

Canadian Recommendations for Clinical Trials of Pharmacologic Interventions in Rheumatoid Arthritis: Inclusion Criteria and Study Design: Table 1.

Current clinical trial designs for pharmacologic interventions in rheumatoid arthritis (RA) do not reflect the innovations in RA diagnosis, treatment, and care in countries where new drugs are most often used. The objective of this project was to recommend revised entry criteria and other study design features for RA clinical trials. Recommendations were developed using a modified nominal group consensus method. Canadian Rheumatology Research Consortium (CRRC) members were polled to rank the greatest challenges to clinical trial recruitment in their practices. Initial recommendations were developed by an expert panel of rheumatology trialists and other experts. A scoping study methodology was then used to examine the evidence available to support or refute each initial recommendation. The potential influence of CRRC recommendations on primary outcomes in future trials was examined. Recommendations were finalized using a consensus process. Recommendations for clinical trial inclusion criteria addressed measures of disease activity [Disease Activity Score 28 using erythrocyte sedimentation rate (DAS28-ESR) > 3.2 PLUS ≥ 3 tender joints using 28-joint count (TJC28) PLUS ≥ 3 swollen joint (SJC28) OR C-reactive protein (CRP) or ESR > upper limit of normal PLUS ≥ 3 TJC28 PLUS ≥ 3 SJC28], functional classification, disease classification and duration, and concomitant RA treatments. Additional recommendations regarding study design addressed rescue strategies and longterm extension. There is an urgent need to modify clinical trial inclusion criteria and other study design features to better reflect the current characteristics of people living with RA in the countries where the new drugs will be used.

Effect of the Application of Trial Inclusion Criteria on the Efficacy of Adalimumab Therapy in a Rheumatoid Arthritis Cohort

To evaluate the influence of inclusion criteria used in rheumatoid arthritis (RA) trials with adalimumab on clinical outcome and response. The different inclusion criteria of published trials of adalimumab in RA were separately applied to a large prospective cohort of patients with RA treated with adalimumab (AdRA cohort), thereby mimicking patient selection for a clinical trial. Clinical response and outcome in the resulting 11 projection groups were compared using the 28-joint Disease Activity Score (DAS28) and time-averaged DAS28 as outcome measures of efficacy. Thirteen trials (n = 54-799) with 11 different sets of entry criteria were identified, resulting in 11 projection groups (n = 22-168). The DAS28 at baseline was similar in the original trial and each projection group based on this trial (5.1-6.4, total AdRA cohort 5.1). After 28 weeks, the efficacy varied substantially among the 11 projected groups (change from baseline DAS28: -1.65 to -2.65, time-averaged DAS28 3.67-4.53). Expressed as outcome (DAS28 at 28 weeks), the efficacy was much more similar for almost all projection groups (3.5-4.0) and thus appeared to be mostly independent of disease activity at baseline. We observed that different inclusion criteria for clinical trials can have a marked effect on the expected response, i.e., improvement from baseline. A novel finding is that final disease activity appeared much less dependent on initial disease activity. Our study suggests that for daily practice, one can assume that adalimumab treatment will on average result in a DAS28 between 3.5 and 4.0 after 28 weeks of treatment, regardless of baseline disease activity.

Treatment Options for Patients with Advanced Pompe Disease

Clinical trials of Myozyme® have demonstrated efficacy in carefully selected cohorts of patients with Pompe disease. Post-licensing, the drug is now being used in patients who have more advanced disease and would not have met the inclusion criteria for clinical trials. Real-life experience in infants has shown that cardiac disease responds well to enzyme replacement therapy (ERT), but babies who are already ventilator-dependent at initiation of therapy are unlikely to become ventilator-independent. In infants, advanced disease is severe disease and prognosis is likely to be correspondingly poor. In adults, even those who are wheelchair-bound or ventilator-dependent can show real improvements in performance with ERT, although these may be difficult to quantify. In adults diagnosed before ERT was available, we see a full spectrum of disease severity. Severity is related to age at symptom onset and older patients may have mild, moderate or severe disease. Adults with advanced disease get real benefit from ERT, although this may be difficult to quantify.

Comparison of 12 current staging systems for advanced hepatocellular carcinoma not amendable to locoregional therapy as inclusion criteria for clinical trials.

2567 Background: The life expectancy of patients with advanced hepatocellular carcinoma (HCC) enrolled in clinical trials should be at least 3 month to test drug response. However, the prognosis of these patients was poor with median overall survival (OS) shorter than 3 months. This study was aimed to evaluate different prognosis score systems for HCC in predicting prognosis and 3-month OS of patients with advanced HCC. Methods: From November 2008 to April 2010, a total of 208 patients with advanced HCC who were not amendable to locoregional therapy were included in this study. Data were collected to classify patients according to Japan Integrated Staging scoring system, TNM stage by liver Cancer Study Group of Japan criteria, National Comprehensive Cancer Network Stage system, Cancer of the liver Italian Program scoring system for hepatocelluar carcinoma (CLIP), Advanced Liver Cancer Prognostic System (ALCPS), model of end-stage liver disease, French scoring system, Chinese University Prognostic Index staging system for HCC (CUPI), OKUDA score system, Tokyo score system, Barcelona Clinic Liver Cancer staging for hepatocelluar carcinoma at diagnosis. OS and 3-month OS were the end points used in the analysis. Survival analysis, Cox regression, relative operating characteristic (ROC), and logistic regression were utilized to access the prognostic value of each score system. Results: ROC analysis confirmed that ALCPS was the best prognostic system for 3-month OS. The cut-off point for ALCPS was 14 with sensitivity of 81.82% and specificity of 79.01%, which was reinforced by the survival variation on the two subgroups divided by ROC analysis generated cutoff point. CLIP and CUPI presented no statistical difference in prognostic discrimination with ALCPS, however, with relatively lower accuracy. Conclusions: ALCPS was the best score system in prediction of OS and 3-month OS among the 12 systems analyzed and a proper inclusion criteria for clinical trials for Chinese advanced HCC patients.

Adopting new enrollment criteria for pharmaceutical trials in constipation: look before leaping

In this issue Dr Camilleri provides an important critique of the use of the Rome III criteria for functional constipation as inclusion criteria for clinical trials of new drugs or other therapies for chronic constipation. He points out that the Rome criteria for functional constipation require the presence of any two of six symptoms, some of which are suggestive of slow transit (e.g. less than three stools per week, hard or lumpy stools) and some of which are suggestive of evacuatory dysfunction (e.g. straining, sensation of anorectal blockage, and manual maneuvers to facilitate defecation). He reminds us that recent studies suggest that patients with evacuation disorders show a poor response to laxatives and suggests that, consequently, the use of inclusion/exclusion criteria that do not distinguish among subtypes of constipation may lead to an underestimation of the efficacy of new therapeutic agents with a mechanism of action similar to laxatives and to an overestimation of the sample sizes required to adequately power clinical trials. He ends by proposing alternative symptom criteria for clinical trials based on the presence of key symptoms of infrequent stools and hard or lumpy stool consistency, combined with the absence of excessive straining and manual maneuvers to facilitate defecation. This is a valid concern: inclusion criteria based only on the Rome III criteria for functional constipation will inevitably result in the inclusion of a heterogeneous group of patients with constipation. However, one should be cautious about embracing new symptom criteria before evaluating their sensitivity and specificity for discriminating patients with disordered defecatio from patients with other types of chronic constipation. The comments below begin with an explanation of the rationale behind the Rome III symptom criteria for functional constipation, including comments on why the Rome criteria for functional constipation are different for children and adolescents compared with adults. Then we summarize published evidence suggesting that the new symptom criteria proposed by Dr Camilleri have only modest sensitivity and specificity and may require further testing to make sure they will achieve the objective of reducing the heterogeneity of study populations in clinical trials.

Inclusion criteria for pharmacodynamic and clinical trials in chronic idiopathic constipation: pitfalls in using Rome III for functional constipation

Selection of the appropriate patients to take part in any pharmacodynamic or clinical trial is essential for the context and relevance of the trial and to realistically assess the efficacy and safety of an experimental treatment for the condition of interest. There is continued interest in the development of medications for chronic idiopathic constipation or constipation resulting from use of opiates.

SPP1 genotype is a determinant of disease severity in Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is the most common single-gene lethal disorder. Substantial patient-patient variability in disease onset and progression and response to glucocorticoids is seen, suggesting genetic or environmental modifiers. Two DMD cohorts were used as test and validation groups to define genetic modifiers: a Padova longitudinal cohort (n = 106) and the Cooperative International Neuromuscular Research Group (CINRG) cross-sectional natural history cohort (n = 156). Single nucleotide polymorphisms to be genotyped were selected from mRNA profiling in patients with severe vs mild DMD, and genome-wide association studies in metabolism and polymorphisms influencing muscle phenotypes in normal volunteers were studied. Effects on both disease progression and response to glucocorticoids were observed with polymorphism rs28357094 in the gene promoter of SPP1 (osteopontin). The G allele (dominant model; 35% of subjects) was associated with more rapid progression (Padova cohort log rank p = 0.003), and 12%-19% less grip strength (CINRG cohort p = 0.0003). Osteopontin genotype is a genetic modifier of disease severity in Duchenne dystrophy. Inclusion of genotype data as a covariate or in inclusion criteria in DMD clinical trials would reduce intersubject variance, and increase sensitivity of the trials, particularly in older subjects.

A Scoring System to Predict the Risk of Prolonged Air Leak After Lobectomy

Prolonged air leak (PAL) remains a frequent complication after lung resection. Perioperative preventative strategies have been tested, but their efficacy is often difficult to interpret due to heterogeneous inclusion criteria. The objective of this study was to develop and validate a practical score to stratify the risk of PAL after lobectomy. Six hundred fifty-eight consecutive patients were submitted to pulmonary lobectomy (2000 to 2008) in center A and were used to develop the risk-adjusted score predicting the incidence of PAL (> 5 days). Exclusion criteria were chest wall resection and postoperative assisted mechanical ventilation. No sealants, pleural tent, or buttressing material were used. To build the aggregate score numeric variables were categorized by receiver operating curve analysis. Variables were screened by univariate analysis and then used in stepwise logistic regression analysis (validated by bootstrap). The scoring system was developed by proportional weighing of the significant predictor estimates and was validated on patients operated on in a different center (center B). The incidence of PAL in the derivation set was 13% (87 of 658 cases). Predictive variables and their scores were the following: age greater than 65 years (1 point); presence of pleural adhesions (1 point); forced expiratory volume in one second less than 80% (1.5 points); and body mass index less than 25.5 kg/m(2) (2 points). Patients were grouped into 4 risk classes according to their aggregate scores, which were significantly associated with incremental risk of PAL in the validation set of 233 patients. The developed scoring system reliably predicts incremental risk of PAL after pulmonary lobectomy. Its use may help in identifying those high-risk patients in whom to adopt intraoperative prophylactic strategies; in developing inclusion criteria for future randomized clinical trials on new technologies aimed at reducing or preventing air leak; and for patient counseling.

Use of genomic signatures to predict response to histone deacetylase inhibitors and correlation with tumor subtypes and molecular pathways.

e13596 Background: Histone deacetylase (HDAC) inhibitors are a promising class of cancer drugs. The ability to predict which tumors are likely to respond helps in planning clinical trials and delivering treatment. Methods: We developed gene expression signatures using cell lines before and after treatment with valproic acid (VPA), trichostatin A (TSA), and suberoylanilide hydroxamic acid (SAHA). Gene expression signatures for pathway activation were developed using induction of genes regulating epigenetic processes (HDAC1, HDAC4, SIRT1, DNMT2, and EZH2). Using logistic regression we predicted drug sensitivity and epigenetic signaling pathways in subtypes of cancers using data from 32 public datasets. Prediction of pathway activity and drug responsiveness was validated using human tumor cells grown in 3D culture or mouse xenografts. Results: Pathway activation patterns and drug sensitivity vary across tumor types and subtypes. Thyroid and GI cancers and mesothelioma are predicted to have highest response to HDAC inhibitors (p<0.0001). There were significant differences in HDAC pathway activity and drug response within tumor subtypes. For example, glioblastoma, particularly Freije class HC2A and HC2B, are more likely to be sensitive to HDAC inhibitors than lower grade gliomas, which have lower HDAC4 and EZH2 activation (p<0.0001). Basal and HER2-positive breast tumors have higher HDAC4 activity and sensitivity to HDAC inhibitors than ER-positive tumors (p<0.0005). We saw correlation between components of the epigenetic machinery. HDAC inhibitor sensitivity correlates with MYC and EZH2 activation, particularly in ovarian tumors, mesotheliomas, basal breast cancer, and gliomas (p<0.001). Preclinical drug studies in cell lines and patient tumors grown in 3D culture and orthotopic models validate our genomic analyses. Conclusions: Epigenetic pathway activity and sensitivity to epigenetic modifiers vary across tumor types and subtypes. High-throughput expression profiling can impact cancer drug selection. Pre-identification of patient response may improve response rates and assist in identifying optimal inclusion criteria for clinical trials. No significant financial relationships to disclose.

Histologic evaluation of metastases in renal cell carcinoma with sarcomatoid transformation and its implications for systemic therapy

Sarcomatoid features in renal cell carcinoma may represent an aggressive subclone arising from the primary tumor. The patterns of metastases for these tumors were evaluated to determine if sarcomatoid features were retained at metastasis and whether the percentage of sarcomatoid features in the primary tumor influenced spread. All patients with sarcomatoid features found at nephrectomy with synchronous or metachronous resection of metastases were evaluated. The histology, grade, and percentage of sarcomatoid features in the primary and metastatic site were recorded. The association between percentage of sarcomatoid features, grade, histology, and pattern of metastases was evaluated. Thirty-two patients were identified with sarcomatoid features and resected metastases. Fifty-two metastatic sites were evaluated. A single histologic appearance (sarcomatoid or carcinomatoid) was present in 50 of 52 sites (96%). Thirty sites (58%) demonstrated only a sarcomatoid pattern, whereas 20 (38%) contained only a carcinoma pattern. Histology and carcinoma grade did not influence metastatic pattern; however, greater percentage of sarcomatoid features was associated with the presence of distant sarcomatoid histology. A cutoff of 30% sarcomatoid features in the primary tumor was useful in predicting systemic sarcomatoid histology. Sarcomatoid elements are frequently observed in the metastases of primary tumors with sarcomatoid features, and these metastases generally contain a solitary pattern supporting the subclone hypothesis. However, both components can metastasize in the same patient. The percentage of sarcomatoid features influences the pattern of spread, and patients with >30% sarcomatoid features in the primary tumor frequently have distant sarcomatoid histology. This cutpoint may be helpful for inclusion criteria for future clinical trials.

Taxanes: optimizing adjuvant chemotherapy for early-stage breast cancer

Taxanes are among the most widely used chemotherapy agents for advanced breast cancer. Results are now available from 21 trials that randomly allocated nearly 36,000 women with early-stage breast cancer to receive first-generation taxane-based adjuvant chemotherapy versus non-taxane-based adjuvant regimens. Three recent meta-analyses suggest that taxanes are beneficial in the adjuvant setting, irrespective of the patient's age, lymph-node involvement, hormone-receptor expression, and HER2 status. Nevertheless, the optimal role for taxanes in the adjuvant management of early-stage breast cancer remains controversial. We review the results of the first-generation taxane trials and discuss possible explanations for the differences observed in these studies, including variation in the 'strength' of anthracycline therapy in the control arms; suboptimal timing, dosing, or schedule of the taxane regimen; a masking effect of trials that included patients with relatively chemotherapy-insensitive luminal A disease; and decreased representation of the putative taxane-sensitive disease subset. Inclusion criteria for future clinical trials must be revised to account for the molecular heterogeneity of breast cancer and further optimize the role of adjuvant taxane therapy in early-stage disease.

Clinical guidelines for interstitial cystitis and hypersensitive bladder syndrome

A clinical guideline and algorism for interstitial cystitis and hypersensitive bladder syndrome has been developed by a group of East Asian urologists as a revised form of the Japanese guideline for interstitial cystitis. The guideline defines interstitial cystitis (IC) as a disease of the urinary bladder diagnosed by 3 requirements; 1) a characteristic complex of lower urinary tract symptoms, 2) bladder pathology such as Hunner's ulcer and bladder bleeding after overdistension, and 3) exclusions of confusable diseases. The characteristic symptom complex is termed as hypersensitive bladder syndrome (HBS), which is defined as bladder hypersensitivity, usually associated with urinary frequency, with or without bladder pain. For the definite diagnosis of IC, cytoscopy or hydrodistension is crutial; HBS is the diagnosis when IC is suspected but not confirmed by the 3 requirements. Numerous therapeutic options are available; however, most of them lack in high level of evidence, leaving a few as recommended therapies. Etiology of IC are multifactorial; the interaction among nervous, immune and endocrine factors forms a vicious cycle, provocating and maintaining inflammatory reactions in the bladder. The inclusion and efficacy criteria for clinical trials should be standardized to enhance the clinical research for this disabling disease, which has proved to be more prevalent than previously believed.

Tolerability and efficacy of first-line bevacizumab (B) plus chemotherapy (CT) in elderly patients with advanced breast cancer (aBC): Subpopulation analysis of the MO19391 study

1032 Background: Limited data exist on the efficacy and safety of biological agents in elderly patients with aBC. This is essentially due to the lack of studies specifically targeting the older population and to strict inclusion criteria in clinical trials. B significantly improved the efficacy of 1st-line taxane therapy in two large, randomized phase III trials, E2100 and AVADO. Methods: In study MO19391, 1st-line B 10mg/kg q2w or 15mg/kg q3w + CT (primarily but not exclusively taxane monotherapy) was investigated in a broader, large aBC patient population, with the aim of understanding safety and efficacy in patients seen in routine clinical practice, including elderly patients. Results: A total of 2,027 patients were enrolled. Median age was 54 years (range 21–93); 359 patients (17.7%) were aged ≥65 years and 169 (8.3%) were ≥70 years. Baseline characteristics and safety and efficacy results according to age are shown below (Table). Conclusions: Treatment with B is feasible in elderly patients. Hypertension was the only grade 3 B-related side effect reported more frequently in the older than in the younger cohort. Efficacy was similar in the two subgroups. These results suggest that the combination of B with 1st-line CT shows a similar therapeutic index regardless of age. Data on compliance according to the different CT regimens, the impact of comorbidities on safety, and analyses in the subgroup of patients ≥70 years will be presented. [Table: see text] [Table: see text]

Efficacy and toxicity of sunitinib in patients with metastatic renal cell carcinoma (mRCC) with severe renal impairment or on haemodialysis

5109 Background: Sunitinib is currently a standard of care for the treatment of mRCC. Due to the inclusion criteria of clinical trials, no studies of sunitinib have enrolled patients with severe renal impairment or those undergoing haemodialysis, and thus further investigation of the effect of sunitinib in this population is required. Methods: Clinical databases were used to identify all patients with mRCC treated with sunitinib in five institutions internationally. Medical records were searched to identify only those patients with a creatinine clearance (CLcr) of &lt;30ml/min or who had end stage renal disease (ESRD) requiring haemodialysis. Baseline characteristics, toxicity data and progression free survival (PFS) were collected. Results: 21 patients met inclusion criteria with 9 (43%) undergoing haemodialysis. Baseline characteristics include a median age of 62 years (range 44–80); 90% of patients had ECOG PS of 0 or 1; 38% of patients had &gt; 2 metastatic sites and 86% had prior nephrectomy. The estimated median PFS of this cohort was 38 weeks (range 2–120) although progression has not yet been reached in 8 (38%) patients. PR or SD was observed as best response in 17 (81%) patients. The most common treatment-related adverse events (AEs) included fatigue, diarrhoea, hand foot skin reaction (HFSR), nausea and vomiting and rash. Grade 3 treatment related AEs including fatigue, HFSR, diarrhoea and rash occurred in a total of 7 (33%) of patients. Only one patient experienced grade IV toxicity (HFSR). Conclusions: These data suggest that patients treated with sunitinib who have severe renal impairment, or ESRD on haemodialysis, have a PFS that is comparable to patients with normal renal function. In addition sunitinib appears to be reasonably well tolerated in this group of patients. These preliminary results warrant confirmation in a larger cohort of patients. [Table: see text]

Pegylated liposomal doxorubicin (CAELYX®) in patients with advanced ovarian cancer: results of a German multicenter observational study

Pegylated liposomal doxorubicin (PLD, CAELYX) has demonstrated activity in several phase-III trials and has been approved for the therapy of relapsed ovarian cancer after platinum treatment. Aim of this observational study was to analyze the efficacy and toxicity profile of PLD under routine clinical conditions and without the general restrictions of defined inclusion and exclusion criteria of clinical trials. Between 2003 and 2005, a total of 190 patients with relapsed ovarian cancer were enrolled. 183 patients were available for evaluation; dose-intensity, modifications, treatment duration, toxicities and response were systematically analyzed. The median patient age was 62 years (range 23-86 years). 45.4% of the patients received PLD as second-line therapy and a median of four courses per patient were administered. The median dose of PLD was 40 mg/m(2), most frequently used every 4 weeks (68.8%). Grade 3 Leucopenia (1.6%) and grade 3 and 4 thrombocytopenia (0.5%) were the most frequent hematological toxicities. The most frequent non-hematological toxicities were skin toxicity, pain and nausea, which were observed in 38.8, 41 and 45.9% of the patients, respectively. Twenty-seven percent of the patients showed a response to therapy with 6.9% achieving complete remission and 20.1% achieving partial remission. 37.7% achieved a stable disease. The median duration of response for all patients was 4.8 months (range 0-51.8 months). Median progression-free interval and overall survival were 5.8 months (95% CI 5.1-6.6 months) and 16.6 months (95% CI 13.9-22.6 months), respectively. PLD is safe and effective in patients with relapsed ovarian cancer, even after numerous previous treatment regimens. A dose of 40 mg/m(2) every 28 days seems to be an effective and well-tolerated therapeutic option in advanced ovarian cancer with a low incidence of hematological toxicities and acceptable non-hematological toxicities.