Reported Response Rates Research Articles

Review article: Hepatitis B and dialysis

The incidence of hepatitis B virus (HBV) infection in dialysis populations has declined over recent decades, largely because of improvements in infection control and widespread implementation of HBV vaccination. Regardless, outbreaks of infection continue to occur in dialysis units, and prevalence rates remain unacceptably high. For a variety of reasons, dialysis patients are at increased risk of acquiring HBV. They also demonstrate different disease manifestations compared with healthy individuals and are more likely to progress to chronic carriage. This paper will review the epidemiology, modes of transmission and diagnosis of HBV in this population. Prevention and treatment will be discussed, with a specific focus on strategies to improve vaccination response, new therapeutic options and selection of patients for therapy.

Monitoring the 2001 Declaration of Commitment on HIV/AIDS

This article describes the development of the international reporting system to monitor the implementation of the Declaration of Commitment on HIV/AIDS that resulted from the 2001 United Nations General Assembly Special Session on HIV/AIDS (UNGASS). The UNGASS reporting system is based on the biennial submission of Country Progress Reports. These include data on a set of core indicators and are prepared and submitted by Member States using a transparent collaborative process. This article reviews the evolution of the system and analyzes the quality and completeness of data from the most recent 2008 reporting round. Over the course of 3 rounds of reporting response rates increased from 54% to 77%. This increase occurred alongside an increase in the completeness of the reported data. Increases in reporting are consistent across countries regardless of the severity of the HIV epidemic. UNGASS reporting has resulted in an unparalleled body of evidence on the response to HIV. Data from 147 countries are now available on the patterns of HIV epidemics, the behaviors related to them, and the programmatic responses that have been mounted by countries. The ultimate goal is for national governments and their civil society partners to achieve ownership of the reporting process. The reporting system has provided a catalyst for the development of national systems for monitoring and evaluating HIV programs and for guiding more effective, efficient, and sustainable responses to the HIV epidemic.

Oral Beclomethasone Dipropionate Monotherapy as An Initial Treatment for Stage 1-2 Gastrointestinal Tract Acute Graft-Versus-Host Disease Following Unrelated Cord Blood Transplantation.

Abstract 1153Poster Board I-175 IntroductionSystemic corticosteroid has been used as initial treatment for gastrointestinal tract acute graft-versus-host disease (GI-aGVHD) following allogeneic hematopoietic stem cell transplantation (HSCT). However, the response remains far from satisfactory, and adverse events caused by prolonged immunosuppression are significant problem. Oral beclomethasone dipropionate (BDP) is a topically active corticosteroid with low bioavailability. Although several studies demonstrated that BDP as monotherapy or in combination with systemic corticosteroid is safe and effective for treatment of GI-aGVHD, there has been not much data available regarding this issue in unrelated cord transplantation (UCBT). Design and MethodsThis study was approved by the institutional review board and started since January 2006. BDP was administered as a single agent in patients who developed stage 1-2 GI-aGVHD following UCBT, were able to swallow the drug, and gave written informed consent. BDP was administered orally as one enteric-coated cellulose capsule and an aqueous suspension every 6h for a total daily dose of 8mg. Response was evaluated on days 3, 7, 14, 21, and 28 after the beginning of BDP treatment. Patients who had worsening GI symptoms at day 3, or who had no improvement at day 7 were classified as nonresponders, and systemic corticosteroid was started. ResultsForty patients were included in this analysis from Jan 2006 through April 2009. Median age was 53.5 years (range 22-82). Twenty-eight (70%) had advanced disease (relapse or refractory disease), and 12 (30%) had history of prior transplantation. All but one patient received fludarabine-based preparative regimen. GVHD prophylaxis consisted of tacrolimus plus mycophenolate mofetil in 27, and tacrolimus alone in 13. Single cord blood units, matched at 4/6 in 35, 5/6 in 3, and 6/6 in 2, were infused. GI-aGVHD developed at a median of 32.5 days (range, 8-80 days) post-transplant. Twenty-five (62.5%) had stage 1 and 15 had stage 2 GI-aGVHD. Twenty (50%) had only GI involvement and the others had mild skin involvement. BDP was started at a median of 36 days (range, 8-86 days) post-transplant. Thirty-three (82.5%) responded to BDP treatment. Response occurred at a median of 4 days (range, 2-7 days) after BDP treatment. Response rate was suggestively higher in patients with stage 1 GI-aGVHD (88%) compared with those with stage 2 (73%), although not statistically significant (P=0.1). The median duration of BDP treatment was for 51 days (range, 7-343 days). Three patients progressed and 4 patients did not respond. Twenty-seven (67.5%) developed infectious episodes during BDP treatment; bacterial sepsis in 9, CMV reactivation in 10, CMV gastroenteritis in 2, Fungal pneumonia in 3, and others in 3 patients. Two patients developed symptomatic adrenal insufficiency during BDP treatment, and required systemic steroid hormone replacement. Transplant-related mortality was 15% at 100 days post-transplant. Three patients died due to sepsis associated with GVHD, 2 died from idiopathic pneumonia syndrome, and 1 died from invasive fungal infection. At median follow-up of 475 days (range, 132-1368 days), overall survival at 2 years was 35.7%. Conclusions: In this study, we evaluated the efficacy and safety of BDP as a single agent in a series of patients with stage 1-2 GI-aGVHD following UCBT. The response rate was 82.5%, which compares favorably with previously reported response rate using BDP as monotherapy or in combination with systemic corticosteroid after allogeneic HSCT. Furthermore, BDP treatment was not associated with the increased risk of severe opportunistic infections. We conclude that BDP as a single agent could become an ideal therapeutic approach for stage 1-2 GI-aGVHD following UCBT DisclosuresNo relevant conflicts of interest to declare.

Signaling pathways in adenoid cystic cancers: Implications for treatment

Adenoid cystic cancers (ACC) in the head and neck are rare yet present a clinical dilemma. Although 5 year survivals are excellent, their have a propensity for late recurrences. Most of these cancers are initially treated with surgery followed by radiation. When recurrences happen, treatment options are limited both by the morbidity and low efficacy of re-irradiation and repeated surgical resection. Reported response rates to chemotherapy are low and targeted therapies may be one option. We, therefore, investigated signaling pathways that may be active in adenoid cystic cancers. Tissues from the last 9 ACC patients resected at the University of Iowa were immunohistochemically stained with antibodies for EGFR, phosphorylated (P) Akt, and P-MAPK in order to molecularly characterize these tumors. An ACC cell line (ACC3) was also characterized by Western blot. We found that seven of the 9 tumor samples had strong expression of P-Akt and 5/9 had P-MAPK. None of them had EGFR expression. In the ACC3 cell line, similar data was found in that there was P-Akt and P-MAPK but no EGFR expression. We tested the HIV protease inhibitor nelfinavir (NFV) which has been shown to inhibit Akt signaling to see its effect on ACC3 cells. Both P-Akt and P-MAPK were inhibited with NFV in ACC3 cells and this resulted in growth inhibition and clonogenic death. In patients where re-irradiation or further surgery is not an option, a trial of NFV may be warranted.

8004 Effectiveness of multiple lines of chemotherapy in platinum-resistant ovarian cancer: the Christie experience

Carboplatin and paclitaxel, delivered on a 3-weekly basis, is the historical standard for the management of advanced epithelial ovarian cancers (EOC). Increased dose intensity, the inclusion of additional active cytotoxic agents and lengthening treatment duration have failed to improve the outcomes seen with standard doses of carboplatin and paclitaxel in the treatment of EOC. Dose-dense (i.e. weekly) delivery of paclitaxel may exploit anticancer mechanisms such as anti-angiogenesis and the induction of apoptosis. Tumour regrowth may be more effectively impaired by the dose-dense delivery of paclitaxel. Non-randomised studies of dose-dense chemotherapy in EOC have been promising, particularly in heavily pretreated and platinum-resistant disease, with reported response rates as high as 60%. Dose-dense paclitaxel also seems to be well tolerated. These observations led to a number of comparative trials of dose-dense paclitaxel chemotherapy, three have been reported and four are ongoing. This review explores the rationale behind dose-dense delivery of paclitaxel and evaluates the results of completed phase III trials.

Dysfonction érectile après prostatectomie totale : physiopathologie, évaluation et traitement

Radical prostatectomy (RP) is the gold standard treatment for localized prostate cancer; yet erectile dysfunction (ED) in selected series is still reported as high as 80% after this surgery. Patient selection and surgical technique (i.e., preservation of neurovascular bundles) are the major determinants of postoperative ED. Pharmacological treatment of postoperative ED, using either oral or local approaches, is effective and safe. Thus, most men need adjuvant treatments to be sexually active following RP. These include intracorporeal injections of vasoactive drugs, vacuum constriction devices and transurethral dilators, all of which have reported response rates of 50 to 70%. Unfortunately, long-term compliance is sub-optimal, with a discontinuation rate of nearly 50% at 1year. These non-oral options should be offered on an individual basis to patients who have failed oral therapy (IPDE5) since efficacy and compliance vary. Also, these options should be considered in the early postoperative period to enhance sexual activity and penile oxygenation, which may prevent corporeal fibrosis. Early penile rehabilitation with intracavernosal injections is the gold standard for partients over 60years old and those who underwent non-sparing surgery. In younger patients and/or when preservation of nerve tissue was feasible, oral IPDE5 may be effective in promoting an earlier return of erectile function. Recent studies have shown that pharmacological prophylaxis early after RP can significantly improve the rate of erectile function recovery after surgery. Use of on-demand treatments for treatment of ED in patients subjected to RP has been shown to be highly effective, especially in cases of properly selected young patients treated with a bilateral nerve-sparing approach by experienced urologists.

Publication Outcomes of Phase II Oncology Clinical Trials

Translation of evidence-based medicine into oncology practice depends on timely and full publication of clinical trials. We investigated publication outcomes of Phase II trial abstracts from the annual meetings of the American Society of Clinical Oncology (ASCO). We searched the 1997, 1999, and 2001 ASCO annual meeting proceedings and identified all Phase II trials, excluding those that reported preliminary results. Literature search was performed using PubMed, EMBASE, and Google for corresponding publications in peer-reviewed journals. We attempted to contact authors of all unpublished trials. Only 60.8% of t he 559 trials identified were published, with a median time to publication of 41 months. At 5 years, 65.9%, 62.7%, and 57.0% of studies from 1997, 1999, and 2001, respectively, were published. Studies with larger samples were associated with a shorter time to publication, as were oral and poster presentations versus print only (P < 0.001). Common reasons for not publishing were uninteresting results, lack of time, and relocation of authors. Among abstracts reporting response rates, 37.7% showed different results in subsequent publications. Though not statistically significant, over the 5-year period, abstracts presented at later years had a lower rate of publication, longer time to publication, and a higher likelihood of showing a better tumor response. Almost half of Phase II trials presented at ASCO annual meetings within the last 10 years remain unpublished. Over one-third of published trials reported results different from those presented in abstracts. Like Phase I and III trials, Phase II trials often are unpublished.

In vitro chemoresponse assay results and population chemotherapy response rates in endometrial cancer

5503 Background: While a number of potentially active chemotherapeutic agents are available for the treatment of endometrial cancer, some therapies may not be effective in all women. An in vitro assay performed before therapy initiation to identify the drug(s) most likely to be effective for the individual patient would have clinical utility. The primary objective of this study was to determine whether the results from an in vitro chemoresponse assay are similar to the published population response rates for endometrial cancer. Methods: Tumor specimens were collected from Dec 1, 2007 to July 15, 2008 from 405 consecutive patients with endometrial carcinoma and were tested in vitro for a response by using the ChemoFx assay. Tumors were categorized prospectively as responsive (R), intermediately responsive (IR) or nonresponsive (NR) to each drug or combination tested. The in vitro response rates were compared to reported response rates from clinical trials. Results: FIGO stage distribution was 171 stage I patients, 32 stage II patients, 106 stage III patients, 57 stage IV patients, 37 recurrent patients, and 2 unknown patients. The assay was successfully completed for 360 (89%) cases. The majority of tumors (73%) exhibited varying degrees of responsiveness to different drug(s). No significant difference in response rate was observed between primary and recurrent tumors or between stage I/II and III/IV tumors. Conclusions: In vitro tumor response rates were similar to reported treatment response rates for all treatments except single-agent carboplatin. A drug response marker can provide clinically useful information to optimize individual chemotherapy regimens for women with endometrial cancer. [Table: see text] [Table: see text]

5-azacytidine treatment results in myelodysplastic syndrome

e18003 Background: Myelodysplastic syndrome (MDS) is a clonal disease of hematopoiesis characterized by dysplasia in one or more series. 5-azacytidine (5-AZA) which is one of the methyl transferase inhibitors, targets the epigenetic changes in MDS and has been used for the last few years. Phase III studies which compare 5-AZA with supportive therapies report response rates up to 60%. Methods: In this study the aim was to retrospectively analyze the response rates of 26 MDS patients who were treated with 5-AZA between years 2002–2008. The patients were; median age 58 (21–84); male/female = 16/10; RAEB-I (7 patients); RAEB-II (18 patients); ve CMML (1 patient); secondary MDS (2 patients). According to an international prognostic scoring system, 6 patients were intermediate-1; 9 patients were intermediate-2; and 11 patients were high risk. Nine patients received 5-AZA as first-line therapy. The median leukocyte counts, absolute neutrophil counts (ANC), hemoglobin values, and thrombocyte counts at the begining of the cycles were; 2.4 (0.5–23)x10e9/L, 0.7 (0.1–16.5)x10e9/L, 8.6(5.3–11.4) gr/dl, 41(4–35)x10e9/L, respectively. The karyotype analysis revealed del5q in 3 patients; -7/del7q in 6 patients; trisomy 8 in 7 patients, del20q, del11q and complex karyotype (del7q+del5q+delY) in 1 patient each. The median cycles completed were 2 (1–6). Results: Seven patient were not elligible for response evaluation. Nine patients (47%) did not respond to the therapy and 8 of them were lost. Ten patients (53%) responded to the therapy with complete remission (n=4), partial remission (n = 2) and hematological improvement (n = 4). The responders and non-responders were similar in terms of median age, sex and pretreatment leukocyte, ANC and hemoglobin levels. However, there was statistically significant difference in terms of initial thrombocyte counts, total number of cycles received and serum ferritin levels. The patients who received 5-AZA as first line therapy had beter response than others (71% versus 29%). Conclusions: The observed response to 5-AZA therapy was similar to the reported rates in the literature. The most important factors for response were initial thrombocyte counts, total number of cycles, other therapies received before 5-AZA and the serum ferritin levels. No significant financial relationships to disclose.

Is There a Taxane-Free Interval That Predicts Response to Taxanes as a Later-Line Treatment of Recurrent Ovarian or Primary Peritoneal Cancer?

Taxanes have reported response rates of 20% to 40% in recurrent ovarian cancer (ROC) but are less well studied as a later-line treatment. We reviewed our experience with taxanes in ROC to determine (1) if a taxane-free interval is associated with response rates in women with ROC and (2) if the use of intervening therapy (IT) affects subsequent response rates to taxanes. We retrospectively identified women who received first- or second-line platinum-taxane therapy and later received a single-agent taxane. Demographics, intervening regimens, and follow-up and survival data were collected. Responses were characterized by cancer antigen 125 levels based on the Gynecologic Cancer InterGroup serologic response definitions. We identified 46 women who met the eligibility criteria. The median age was 57 years (range, 39-78 years). The median interval between taxanes was 25.8 months (range, 2.9-85.5 months), with 10 (21%) of the women were treated 12 months or less from their last taxane and 37 (79%) treated more than 12 months. The median number of IT was 2 (range, 0-5). Forty patients (87%) received paclitaxel; 6 (13%) received docetaxel. All patients treated 12 months or less from their last taxane responded (P = 0.02). The number of IT was associated with a better response; all women (100%) treated who had no IT, 7 (54%) of 13 women with 1 to 2 ITs, and 7 (39%) of 18 women with 3 ITs or more responded. The overall survival was 13.4 months in responders versus 10.6 months in nonresponders (P = 0.27). Taxanes maintain an activity as a later-line agent, even with 3 or more intervening therapies. However, the highest responses were seen if taxanes were used within 12 months of the last platinum-based combination. The lack of an increased response with aprolonged taxane-free interval is likely related to the number of IT, consistent with the emergence of multidrug resistance.

Optimizing Regional Therapy for Melanoma

In this issue of Annals of Surgical Oncology, Kroon et al. describe the toxicity of isolated limb infusion with melphalan and actinomycin D in their experience with 185 patients over 15 years. This work continues to expand on the group’s notable contributions to regional chemotherapeutics for extremity melanoma including their initial description and utilization of isolated limb infusion (ILI) in the early 1990s. ILI has been explored as a minimally invasive alternative to hyperthermic isolated limb perfusion (HILP) for advanced extremity melanoma whereby placement of percutaneously placed catheters allows delivery of regional chemotherapy to an isolated limb. In the current study, ILI was found to be a safe alternative to HILP with less long-term morbidity than HILP. Previously, the Sydney Melanoma Group has reported response rates that are less than traditional response rates to HILP but certainly not outside the range of reported studies of HILP. Due to the safety and efficacy of the treatment as well as disappointing results of a multicenter HILP trial, ILI is now utilized at several major US centers and has been demonstrated to be a well-tolerated treatment alternative for patients with advanced extremity melanoma. As with any new regional treatment, the goal should be to define the procedure’s therapeutic index, which balances the treatment’s toxicity with its ability to control disease. Results of the current study suggest that there may be additional methods to reduce toxicity from ILI by altering modifiable factors which were found to be predictive of higher grades of toxicity. In addition this study’s results further support a role for ILI as a safe treatment in the armamentarium of therapeutic options for patients with advanced extremity melanoma. ILI is essentially a low-flow HILP performed by insertion of percutaneous catheters in the contralateral limb, in contrast to HILP where open surgical cannulation of the artery and vein are performed. ILI is performed attempting to achieve temperatures in the range 37–38.5 C and the blood is not oxygenated, leading to hypoxia and acidosis in the limb. The hypoxia and acidosis of ILI have previously been suggested to be beneficial in terms of response. In HILP, the catheters are connected to a cardiopulmonary bypass circuit which maintains physiologic oxygenation and pH. Temperatures in HILP generally range from 38.5 C to 40 C. While hyperthermia is well documented to increase the cytotoxicity induced by melphalan, excessive heat can also increase the toxicity of melphalan to normal tissue. ILI also differs from HILP in that ILI uses less melphalan per liter of extremity treated, circulates blood in an isolated extremity at a much slower rate than HILP (50– 100 mL/min in ILI versus 350–1,000 mL/min in HILP), and treatment is only for 30 min as compared with 60 min in HILP. These differences in the method of drug delivery are important to consider when comparing toxicity and response between the two procedures. In both ILI and HILP, there appears to be no relationship between significant limb toxicity and response to treatment. As such, minimizing toxicity from these procedures as discussed by the authors should be a goal of therapy. In the current study, high-grade limb toxicity (Wiberdink toxicity C grade 3) occurred in 42% (n = 77) of patients. Only 3% (n = 5) of patients had grade IV toxicities and there were no grade V toxicities (grade V toxicity is a toxicity necessitating amputation). Systemic toxicities were minimal and melphalan was detected in the systemic circulation in only 6% of patients. There were no systemic effects clearly associated with leakage of the small amounts of melphalan into the systemic circulation. Low circulating volumes seen in ILI were not related to increased limb toxicity. Overall toxicity from this study is in a similar range to the spectrum of toxicity after HILP. However, as the authors point out, long-term morbidity and severe toxicity (grade V) appear to be less with ILI. In a Society of Surgical Oncology 2009

Dismal Response To High Dose Methylprednisolone (MP) After Failure To Respond To Standard Dose In Pediatric Hematopoietic Stem Cell Transplantation (HSCT) Patients With Acute Graft-Versus-Host-Disease (aGVHD)

Introduction: Corticosteroids remain the primary therapy for aGVHD. The reported response rate to standard treatment (IV MP 2mg/kg/day for 14 days then tapered) is 70%. Patients who are refractory to standard treatment may be treated with high dose MP. We evaluated the response to high dose MP in children with aGVHD refractory to standard dose MP.

Individual patient data analysis to assess modifications to the RECIST criteria

Background After the initial RECIST 1.0 were published in 2000, the criteria were widely implemented in the scientific oncology community. Since then, the RECIST working group has identified several issues to examine further. Two key issues that required careful, data-based assessment were the maximum number of lesions that should be assessed at each evaluation and the added value of requiring confirmation of response. Methods To address these questions, data were obtained from 16 clinical trials in metastatic cancer, with patients enrolled between 1993 and 2005. A total of 6512 patients were included in the primary analysis dataset, accounting for over 18,000 potential target lesions. Nine percent of the included patients ( n = 585) had six or more reported target lesions. The response and progression outcomes in the database were calculated using an adjusted RECIST methodology with a maximum of 5 (or 3) target lesions with/without confirmation and this was compared to the original RECIST version 1.0 which required up to 10 target lesions plus confirmation of response. Results Assessment of 5 lesions per patient led to a difference in best overall response assignment for an estimated 209 (3.2%) patients as compared to RECIST version 1.0. However, these changes did not affect the overall response rate. Progression-free survival was only minimally affected by measuring fewer lesions. In contrast, removing the requirement for response confirmation led to a significant increase in the numbers of patients classified as responders, resulting in a relative increase of approximately 19% in response rate. An algorithm using a maximum of three target lesions shows high concordance with the 10 lesions requirement in terms of response and TTP assignment. Concern that appropriate assessment of disease within an organ requires two lesions to be followed per organ suggests the approach of following two target lesions per organ, up to a maximum of five target lesions overall. Both strategies seem reasonable based on the data warehouse. The requirement of response confirmation in trials where this is a primary end-point is recommended to be maintained as its removal would substantially increase reported response rates.

Efficacy of a Two Day Induction Regimen for De Novo and Secondary AML with Intermediate and Adverse Cytogenetic Profiles

Background: Cytogenetic data remains one of the most powerful prognostic factors for predicting response and survival in adult AML patients. The relationship between cytogenetics and induction response to the standard “7+3” regimen has been analyzed in the past. In a CALGB study, patients with favorable cytogenetics achieved a complete remission (CR) rate of 88%, those with intermediate cytogenetics achieved a 67% CR rate and those with adverse cytogenetics had a 32% CR rate (Byrd et al. Blood 100: 4325, 2002). We present a retrospective analysis of the correlation between the hierarchical cytogenetic groups and complete remission rate following induction of AML using a novel induction regimen. This regimen was developed based on the concept of timed sequential therapy. The first pulse of chemotherapy recruits leukemic cells into the cell cycle while the second pulse is given at a time of peak cell recruitment. It utilizes two highly active anti-leukemic drugs: cytarabine, a cell cycle-specific drug, and mitoxantrone, which has a favorable cardiac toxicity profile.Patients and Methods: One hundred four patients with AML were treated with two days of chemotherapy given 96 hours apart from April 1997 to April 2008. Each day consisted of two doses of cytarabine 2gm/m2 (at t=0 and t=12) followed by one dose of mitoxantrone 30 mg/m2 administered after the second cytarabine dose (t=15). Bone marrow biopsies were performed for assessment of leukemia-free state (day 14) and to document remission response. Cytogenetic results were classified into favorable, intermediate, and unfavorable categories based on CALGB data. Responses were defined per the Revised IWG Recommendations (Cheson et al, J Clin Onc 21: 4642, 2003).Results: Median age of the 104 patients was 57 years [range 17–79]. There were 47 males and 57 females. Forty-two patients (40%) were 60 years of age and older, and the remaining 62 patients (60%) were younger than 60. Sixty-four patients (61.5%) had de novo AML. Five patients had favorable cytogenetics with 100% of them achieving CR. All of the patients with favorable cytogenetics were less than 60 years of age. For the 61 patients with intermediate cytogenetics, the ORR was 83.6% with a CR of 61%. In patients younger than 60, the ORR was 83.8%% (26 CR, 3 CRi, 2 CRp) with CR of 70%. For patients 60 years and older, the ORR was 83.3% (11 CR, 3 CRi, 5 CRp, 1 RMDS). In the 38 patients with unfavorable cytogenetics, the ORR was 57.9% with CR of 37%. For patients younger than 60 and 60 years and older, the overall responses were 75% and 38.8%, respectively.Of the 40 patients with secondary AML due to pre-existing MDS, the ORR was 65% with CR of 27.5%. In patients with de novo AML, the ORR was 81% with CR of 70%. Patients with prior MDS were more likely to have CRi (20% vs 1.5%), TF due to refractory disease (25% vs 15.6%) or aplasia (7.5% vs 1.5%) as compared to patients without MDS. The rates of CRp (10% vs 9%) were similar for both groups. MDS patients with intermediate cytogenetics had an ORR of 77.7% as compared to 54.5% in those with unfavorable cytogenetics. De novo patients with intermediate cytogenetics had ORR of 86% and those with unfavorable cytogenetics had ORR of 62.5%.Conclusion: Our data reflects the overall effectiveness of high dose cytarabine and mitoxantrone for induction therapy of AML. In the favorable cytogenetic group, the CR rate was higher than previously reported response rates; however, the number of patients was small. In the intermediate and unfavorable cytogenetic groups, the response rates for de novo AML compare favorably to historic controls. Patients with secondary AML respond equally well as compared to those with de novo AML; though, the influence of cytogenetics was similar to that seen in de novo AML. This regimen is very effective in producing a high response rates across cytogenetic categories.

Radioimmunotherapy (RIT) with 90y-Ibritumomab Tiuxetan (Zevalin) in Relapsed or Refractory Aggressive Lymphoma Previously Treated with Rituximab Containing Regimens

Introduction: The addition of antibody monoclonal anti CD20 Rituximab to CHOP chemotherapy resulted in improved CR, progression free survival and overall survival rates for patients with diffuse large B cell lymphoma (DLBCL). RIT with Zevalin, as single agent, has been shown to be effective in the treatment of relapsed refractory elderly DLBCL, namely in Rituximab naïve patients. However, in patients pretreated with Rituximab the reported response rate was lower. The aim of this study was to evaluate the efficacy and safety of Zevalin in a group of patients with relapsed or refractory aggressive lymphoma, all heavily pretreated with Rituximab containing regimens.Patients and methods: Inclusion criteria were as follows: age over 18 yrs; relapsed or refractory CD20+ aggressive lymphoma (follicular grade IIIb, PML or DLBCL); WHO performance status of 0 to 2; stage II bulky, III or IV; bone marrow involvement <25 %; written informed consent approved in accordance with institutional guidelines. All patients were previously treated with ≥ 2 lines of Rituximab containing regimens. Patients with pre-treatment platelet counts of > 150 × 109/l received Zevalin at 0.4 mCi/kg whereas those with platelets < 150 109/l received 0.3 mCi/kg.Results: 24 patients were treated with RIT. Five patients had stage II, and 19 stage III/IV; bone marrow involvement was present in 11/24. Nine patients had grade IIIb follicular, 14 DLBCL and one mantle cell lymphoma. Eighteen patients received 0.4 mCi/kg and six patients 0.3 mCi/kg. Eleven patients were treated with RIT alone, six received RIT after standard salvage chemoimmunotherapy and seven were treated with RIT in combination with BEAM and subsequent autologous stem cell transplantation (ASCT). Status of disease before Zevalin treatment was: progressive disease (PD) in 14; complete response (CR) and partial response (PR) after salvage chemoimmunotherapy in 4 and 6 patients respectively. All patients in CR before RIT (4/24) maintained a continous CR after treatment. Overall response rate (ORR) after RIT for patients not in CR (20/24) was: 4 patients (20%) achieved a CR, 7 patients (35%) a PR and 9 patients experienced no response/progression (ORR 11/20 patients 55%). Six of seven patients treated with RIT + BEAM + ASCT achieved a response (CR 4 patients and PR 2 patients), one patient progressed immediately after the end of program. ORR in 11 patients treated with RIT alone and in six patients treated with chemotherapy + RIT were 46% and 50% respectively. With a median follow up of 32 months, OS and PFS rates were 67% and 52%. Eight patients died, all because of lymphoma. The most common grade 3–4 adverse events were neutropenia and thrombocytopenia.Discussion: the results of this study suggest that RIT with 90Y-Ibritumomab Tiuxetan is a safe and effective treatment for patients with relapsed/refractory aggressive lymphoma even if they were pretreated with Rituximab containing chemotherapy.

Radiotherapy and Hyperthermia for Treatment of Primary Locally Advanced Cervix Cancer: Results in 378 Patients

To report response rate, pelvic tumor control, survival, and late toxicity after treatment with combined radiotherapy and hyperthermia (RHT) for patients with locally advanced cervical carcinoma (LACC) and compare the results with other published series. From 1996 to 2005, a total of 378 patients with LACC (International Federation of Gynecology and Obstetrics Stage IB2-IVA) were treated with RHT. External beam radiotherapy (RT) was applied to 46-50.4 Gy and combined with brachytherapy. The hyperthermia (HT) was prescribed once weekly. Primary end points were complete response (CR) and local control. Secondary end points were overall survival, disease-specific survival, and late toxicity. Patient, tumor, and treatment characteristics predictive for the end points were identified in univariate and multivariate analyses. Overall, a CR was achieved in 77% of patients. At 5 years, local control, disease-specific survival, and incidence of late toxicity Common Terminology Criteria for Adverse Events Grade 3 or higher were 53%, 47%, and 12%, respectively. In multivariate analysis, number of HT treatments emerged as a predictor of outcome in addition to commonly identified prognostic factors. The CR, local control, and survival rates are similar to previously observed results of RHT in the randomized Dutch Deep Hyperthermia Trial. Reported treatment results for currently applied combined treatment modalities (i.e., RT with chemotherapy and/or HT) do not permit definite conclusions about which combination is superior. The present results confirm previously shown beneficial effects from adding HT to RT and justify the application of RHT as first-line treatment in patients with LACC as an alternative to chemoradiation.

Rethinking Satisfaction Surveys

The Minute Survey uses 2 questions to assess patient's satisfaction. The first question asks the patient to rate overall satisfaction with the care. The second question asks the patient to explain what worked well and what needed improvement. The Minute Survey reduces cost of conducting satisfaction surveys by (1) reducing cost of printing, (2) reducing cost of handling and mailing, (3) increasing response rate and thus reducing the need for follow-up reminder, and (4) by relying on time to dissatisfied patient as opposed to percent of dissatisfied patients. We report response rate of 34% to 77% to minute surveys. The combination of Minute Survey and analysis of time to dissatisfied patient may reduce the cost of conducting satisfaction surveys by 89% compared with Consumer Assessment of Healthcare Providers and Systems survey suggested for use by Centers for Medicare and Medicaid.

The Challenges of Conducting Research to Improve the Health of American Indians and Alaska Natives

Research to improve the health of American Indians and Alaska Natives (AI/AN) is subject to many special challenges. To that end, the merits and barriers of health disparities research was a central discussion topic by the editorial advisory board members for this special issue when they met in the fall of 2006. This discussion reflected that the comparison of AI/AN and non-Hispanic white health issues has limited value when limited ability exists to control contextual differences. These differences include the AI/AN history, level of poverty, culture, living environment, and the ability to access quality health services. Therefore, the board agreed to give priority to research papers that focused on measures for improving AI/AN health. AI/AN are dispersed in large cities such as New York City and Los Angeles and in small cities like Anchorage and Tulsa. In addition, they live in relatively isolated tribal reservations and villages disproportionately located in the 30% of U.S. counties that are sparsely populated and located at a great distance or travel time from the closest significant service center or market (Fig. 1). Most AI/AN live west of the Mississippi River. The National Center for Frontier Communities has described the challenges of economic development in these areas. We included papers that demonstrate the diversity of AI/AN with respect to their place of residence, as well as critical health issues. We cannot adequately represent the geographic and other diversity of the federally recognized 562 tribes who live on reservations or in urban areas. Assisting AI/AN in developing their own public health interventions will require knowledge and sensitivity to a multitude of variations. Maternal and child health practice research among AI/ AN is plagued by low response rates that limit generalization of specific findings. Response rates are often available for the overall survey, but not for AI/AN. In this issue, low reported response rates included 51% for inner city youth in two Oklahoma cities, 54% overall in the National Survey of Child Health [1] and 63% among AI in the Pregnancy Risk Assessment Systems (PRAMS) [2]. The median AI/AN response rates for Behavioral Risk Factor Surveys declined from 63% in 1997 to 50% in 2000 [3]. Kim noted that the 2000 US Census had an overall response rate from AI of 67%, with only 8.5% of tribes having a response rate of 70% or higher [4]. On the positive side, Kim documented that non-response in PRAMS was chiefly due to inability to contact the desired respondent. Once contacted, AI/AN responded as often as non-Hispanic whites. Conducting valid research to improve the health of AI/ AN may require more resources than research on the general population. Methods to increase research validity may include oversampling, face-to-face (rather than telephone) interviews; large record-linkage studies; identifying county code of residence of birth mothers for local area analysis; and the engagement of communities and their leaders in developing health assessment and practice methods. Moreover, educational resources should be devoted to developing more AI/AN researchers who can lead in achieving relevant research to improve the health of AI/AN mothers and children. R. Rochat (&) Hubert Department of Global Health, Rollins School of Public Health, STE 768, Emory University, 1518 Clifton Road NE, Atlanta, GA 30322, USA e-mail: rrochat@sph.emory.edu 1 http://www.frontierus.org/geography.htm

Clinical benefits and risks of phase I oncology trials: experience from a single institution

6572 Background: The majority of published series of phase I oncology trials has reported response rates between 4 to 6 percent. A recent meta-analysis of phase I studies showed a higher response rate of 10.6%. Few reports on single-institution phase I experience have been published. Methods: Results from phase I trials conducted at our institution from 1999 to 2007 were reviewed. Data including clinical responses to treatment, toxic events, and treatment-related deaths were recorded. Results: Data from 33 phase I studies [cytotoxic agents (50%), biologic agents (40%), and both (10%)] involving 491 patients (pts) were analyzed. Primary diagnoses included colorectal (25%), ovarian (20%), breast (8.5%), and lung (7%) cancer. 391 pts were assessable for response and the overall response rate (RR) was 8.2% (complete response rate of 1.5%). Patients with documented response had a lower baseline LDH (234 vs 342 U/l, p=0.04), platelet count (167,000 vs 209,000/μl, p=0.03) and serum protein (6.97 vs 7.23 gm/dl, p=0.06) than patients with stable or progressive disease. Notably, patients with a response had a lower mean CTC pain grade while on study (1.1 vs 1.45, p=0.08) than patients with lack of response. Seven of the 32 responses (22%) were observed below the maximum tolerated dose. The rate of stable disease was 39.4%. The mean and median duration on study were 79 days and 53 days, respectively. The treatment-related mortality rate was 1.2%. The rates of hematologic and non-hematologic grade 4 toxic events were 16.7% and 4.3%, respectively. Conclusions: This is one of the largest single-institution series of phase I oncology trials. Our response rate of 8.2% is comparable to that reported in a recently published multi- institution series. This RR falls within the 95% confidence interval of the RR of a majority of third line (and greater) chemotherapy for solid malignancy, and the concept of phase I studies as being ‘non-therapeutic‘ is called into question. No significant financial relationships to disclose.

Treatment of recurrent thyroid cancers – is there a light in the horizon?

Thyroid cancer is a rare tumour. In spite of this, its incidence is increasing faster than any other tumour. The reported response rates of recurrent thyroid cancer to chemotherapy are generally poor. Molecular studies have provided some information on their biology and have identified new targets with therapeutic potential. Ever since the seventies, no major breakthrough has been achieved in terms of chemotherapy in advanced/recurrent thyroid cancer. Anaplastic thyroid cancer, for instance, has not shown any improvement in overall survival during the past 40 years. Several agents are currently being tested that target molecular signalling and cancer cell biology, and will be reviewed in this paper. Some of these new targeted approaches hold promise for our future ability to treat patients with advanced thyroid cancer unresponsive to traditional therapy. The success of these molecular-targeted agents is dependent on the molecular abnormalities involved in carcinogenesis as well as on well designed clinical trials to study these new agents.