Patients Receiving Combination Chemotherapy Research Articles

Safety and efficacy of PEG-rhG-CSF as primary prophylaxis against neutropenia induced by combination chemotherapy regimens involving oral chemotherapy agents in gastrointestinal cancer patients: A prospective, exploratory, non-randomized controlled study.

e24107 Background: The safety and efficacy of PEGylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) for prevention of chemotherapy-induced neutropenia (CIN) in patients undergoing oral chemotherapy remain unclear. This study investigated the safety and efficacy of PEG-rhG-CSF as primary prophylaxis against CIN in gastrointestinal (GI) cancer patients receiving combination chemotherapy regimens involving oral chemotherapy agents. Methods: This is a prospective, single-center, open-label, exploratory, non-randomized controlled study. GI cancer patients receiving two consecutive cycles of IV oxaliplatin (150mg/m2 on day 1) combined with oral capecitabine 1000mg/m2 or tegafur gimeracil oteracil potassium capsule 40-60mg twice daily on days 1-14 every 3 weeks. PEG-rhG-CSF (6mg) was administered subcutaneously 24 hours post-oxaliplatin treatment in the PEG-rhG-CSF group, while the control group did not receive it. The primary endpoint was safety, and secondary endpoints included CIN incidence and neutropenic complications. The study was registered with the Chinese Clinical Trial Registry (registration number ChiCTR2100054854). Results: Between March 2022 and January 2023, a total of 49 patients was screened, and 43 patients completed the treatment (26 in PEG-rhG-CSF group and 17 in control group). The average age was 61.4 years, with 90.7% males and 83.7% having gastric cancer. Baseline characteristics were similar between the two groups. The overall adverse events (AE) did not differ statistically (88.5% vs. 88.2%, p = 1.000), with grade £2 fatigue and nausea being the most common AEs. Grade 3 platelet reduction showed no significant difference between the two groups (7.69% vs. 17.65%, p = 0.432). Four cases of bone pain (15.4%) and five cases of injection site reactions below grade 3 (19.2%) were observed in the PEG-rhG-CSF group. Grade ≥2 CIN was significantly lower in the PEG-rhG-CSF group (3.84% vs. 58.82%, p < 0.001). One case in the PEG-rhG-CSF group required antibiotic treatment due to febrile neutropenia. Regarding neutropenic complications, the PEG-rhG-CSF group exhibited lower proportion of chemotherapy delay (3.85% vs. 35.29%, p < 0.001) and dose reduction (1.92% vs. 23.53%, p = 0.002). Rescue treatment with rhG-CSF for grade 3/4 CIN was significantly less frequent in the PEG-rhG-CSF group (1.92% vs. 23.53%, p = 0.002). Conclusions: Primary prophylaxis with PEG-rhG-CSF in GI cancer patients undergoing oral capecitabine/tegafur gimeracil oteracil potassium may be safe, without an increased chemotherapy-related AEs, and is associated with a reduced grade ≥2 CIN. Clinical trial information: ChiCTR2100054854.

Meiotic susceptibility for induction of sperm with chromosomal aberrations in patients receiving combination chemotherapy for Hodgkin lymphoma

Improvements in survival rates with gonad-sparing protocols for childhood and adolescence cancer have increased the optimism of survivors to become parents after treatment. Findings in rodents indicate that chromosomal aberrations can be induced in male germ cells by genotoxic exposures and transmitted to offspring and future generations with effects on development, fertility and health. Thus, there is a need for effective technologies to identify human sperm carrying chromosomal aberrations to assess the germ-line risks, especially for cancer survivors who have received genotoxic therapies. The time-dependent changes in the burden of sperm carrying structural chromosomal aberrations were assessed for the first time in a cancer setting, using the AM8 sperm FISH protocol which simultaneously detects abnormalities in chromosomal structure and number in sperm. Nine Hodgkin lymphoma (HL) patients provided 20 semen samples before, during, and after NOVP therapy (Novantrone, Oncovin, Velban and Prednisone) and radiation therapy that produced scattered gonadal doses from <0.05 to 0.6 Gy. Late meiosis was found to be the most sensitive to NOVP treatment for the production of sperm with chromosomal abnormalities, both in structure and number. Earlier stages of spermatogenesis were less sensitive and there was no evidence that therapy-exposed stem cells resulted in increased frequencies of sperm with abnormalities in chromosomal structure or number. This indicates that NOVP therapy may increase the risks for paternal transmission of chromosomal structural aberrations for sperm produced 32 to 45 days after a treatment with these drugs and implies that there are no excess risks for pregnancies conceived more than 6 months after this therapy. This clinical evaluation of the AM8 sperm FISH protocol indicates that it is a promising tool for assessing an individual’s burden of sperm carrying chromosomal structural aberrations as well as aneuploidies after cancer therapy, with broad applications in other clinical and environmental situations that may pose aneugenic or clastogenic risks to human spermatogenesis.

Addressing the variation in adjuvant chemotherapy treatment for colorectal cancer: Can a regional intervention promote national change?

Analysis of routine population-based data has previously shown that patterns of surgical treatment for colorectal cancer can vary widely, but there is limited evidence available to determine if such variation is also seen in the use of chemotherapy. This study quantified variation in adjuvant chemotherapy across both England using cancer registry data and in more detail across the representative Yorkshire and Humber regions. Individuals with Stages II and III colorectal cancer who underwent major resection from 2014 to 2015 were identified. Rates of chemotherapy were calculated from the Systemic Anticancer Treatment database using multilevel logistic regression. Additionally, questionnaires addressing different clinical scenarios were sent to regional oncologists to investigate the treatment preferences of clinicians. The national adjusted chemotherapy treatment rate ranged from 2% to 46% (Stage II cancers), 19% to 81% (Stage III cancers), 24% to 75% (patients aged <70 years) and 5% to 46% (patients aged ≥70 years). Regionally, the rates of treatment and the proportions of treated patients receiving combination chemotherapy varied by stage (Stage II 4%-26% and 0%-55%, Stage III 48%-71% and 40%-84%) and by age (<70 years 35%-68% and 49%-91%; ≥70 years 15%-39% and 6%-75%). Questionnaire responses showed significant variations in opinions for high-risk Stage II patients with both deficient and proficient mismatch repair tumours and Stage IIIB patients aged ≥70 years. Following a review of the evidence, open discussion in our region has enabled a consensus agreement on an algorithm for colorectal cancer that is intended to reduce variation in practice.

Mobilization of Hematopoietic Stem Cells into Peripheral Blood for Autologous Transplantation Seems Less Efficacious in Poor Mobilizers with the Use of a Biosimilar of Filgrastim and Plerixafor: A Retrospective Comparative Analysis.

IntroductionBiosimilars of granulocyte colony-stimulating factors (G-CSF) have shown similar efficacy to originator filgrastim (Neupogen® [NEU]; Amgen Inc.) as prophylaxis in neutropenia and in the mobilization of stem cells in patients receiving combination chemotherapy with G-CSF.MethodsThis was a retrospective study in which the characteristics of stem cell mobilization treated with a G-CSF alone were compared in 216 patients and 56 donors. The two G-CSF compared were NEU and the biosimilar filgrastim Zarzio® (Sandoz GmbH) (referred to hereafter as BIO). Primary objectives were mobilization rate (minimum of 10 × 103/ml CD34+ on day 4 of treatment [day +4]) and use of the immunostimulant plerixafor (PLEX) in each group.ResultsThe general characteristics of the patients receiving NEU (n = 138) and those receiving BIO (n = 78) did not differ significantly. PLEX was used in 24% of BIO patients and in 25.7% of NEU patients. The median CD34+ cell count on day +4 was significantly lower in BIO patients who needed PLEX than in those who did not (2.4 vs. 4.8 × 103/ml; p = 0.002), as was the final CD34+ cell count (2.5 vs. 3.3 × 106/kg; p 0.03). Mobilization failure rate was higher in the BIO group than in the NEU group (20 vs. 0%; p = 0.01). With respect to donors, more than one apheresis was needed in three BIO donors, one of them with PLEX. The use of BIO was the only risk factor for mobilization failure in patients who needed PLEX (hazard ratio 10.3; 95% confidence interval 1.3–77.8).ConclusionThe study revealed that BIO had a lower efficacy for stem cell mobilization when the only treatment was G-CSF, especially in poor mobilizers needing PLEX.

Homologous recombination deficiency (HRD) scoring in pancreatic ductal adenocarcinoma (PDAC) and response to chemotherapy.

741 Background: Whole genome sequencing (WGS) can reveal patterns of substitution base signatures and structural variation consistent with tumours deficient in homologous recombination repair. We evaluated the published HRDetect score and a novel HRD hallmark score (HS) in patients receiving combination chemotherapy (cCT) on the COMPASS trial for advanced PDAC. Methods: The HRD-HS incorporates 10 genomic characteristics of HRD-PDAC with a score ≥ 4 defining HRD. HRD-HS and an HRDetect score ≥0.7 were applied to WGS data and overall survival (OS) and response (ORR) evaluated. Sensitivity and specificity were ascertained. Results: As of 05/19, 205 eligible patients (pts) were enrolled and 186 received cCT including modified FOLFIRINOX n = 108 (58%) or cisplatin/gemcitabine n = 2 (1%) and gemcitabine/nab-paclitaxel n = 76 (41%). HRD-HS had a sensitivity of 87.5% and specificity of 100% in detecting HRD-PDAC. In contrast, HRDetect (≥0.7) had sensitivity of 51.9% and specificity of 100%; sensitivity increased to 73.7% when using a cutoff score of ≥0.99. 23/186 (12%) pts were classified as HRdetecthi and median OS was 15.3months (mo) vs 8.7mo in HRDetectlo pts (HR 0.44 95% CI 0.27-.70, p = 0.009). In platinum treated pts, median OS was 18.1mo (HRDetecthi) vs 9.3mo (HRDetectlo) (HR 0.38 95%CI 0.21-0.69, p = 0.02). HRD-HS predicted the longest median OS for platinum of 21.0mths. ORR in HRDetecthi was not different to HRDetectlo pts treated with cCT, however in those receiving platinum the ORR was 50% vs 19% respectively (p &lt; 0.001). Of the false positives by HRDetect, 46% had a non-BRCA1 tandem duplicator phenotype (TDP). The TDP group comprised 8% of all patients enrolled. HRD-PDAC was caused by inactivation of BRCA1/2, PALB2, RAD51C and XRCC2; all germline variants were pathogenic. Pathogenic ATM and CHEK2 germline variants were present in 3 pts with evidence of a second somatic hit or LOH, none of these identified as HRD by either classifier nor considered a TDP. Conclusions: HRD-HS most correctly identified HRD-PDAC however the HRDetect score classifies additional patients sensitive to cCT, especially platinum. The TDP cohort may be responsive to DNA damaging agents warranting further evaluation. Clinical trial information: NCT02750657.

Role of chemotherapy in dedifferentiated liposarcoma of the retroperitoneum: defining the benefit and challenges of the standard

Benefit from chemotherapy for well-differentiated/de-differentiated (WD/DD) liposarcomas has been reported to be minimal, however traditional response criteria may not adequately capture positive treatment effect. In this study, we evaluate benefit from first-line chemotherapy and characterize imaging response characteristics in patients with retroperitoneal (RP) WD/DD liposarcoma treated at The University of Texas MD Anderson Cancer Center. Response was assessed using RECIST (Response Evaluation Criteria in Solid Tumors) and an exploratory analysis of vascular response was characterized. Among 82 patients evaluable for response to first-line therapy, 31 patients received neoadjuvant chemotherapy for localized/locally advanced disease; 51 received chemotherapy for unresectable recurrent/metastatic disease. Median overall survival from the start of chemotherapy was 29 months (95% CI 24–40 months). Response rates by RECIST: partial response (PR) 21% (17/82), stable disease (SD) 40%, and progression (PD) 39%. All RECIST responses were in patients receiving combination chemotherapy. A qualitative vascular response was seen in 24 patients (31%). Combination chemotherapy yields a response rate of 24% and a clinical benefit rate (CR/PR/SD > 6 months) of 44%, higher than previously reported in DD liposarcoma. A higher percentage of patients experience a vascular response with chemotherapy that is not adequately captured by RECIST in these large heterogeneous tumors.

Predictors of non-sentinel lymph node metastasis in patients with positive sentinel lymph node (SLN) in endometrial cancer

histology (Grade 3, Type I vs. Type II), depth of invasion, and lymphovascular space invasion. Group B cases were older (65.5 ± 9.2 vs. 63.0 ± 10.9 years, P= 0.02) and had more pelvic LNs harvested (26.4 ± 10.5 vs. 18.8 ± 8.5, P b 0.0001). Aortic LN yields were identical (9.0 ± 5.6 vs. 9.0 ± 6.0). More pelvic LN metastases were detected in Group B (30.3% vs. 13.6%, P b 0.0001). Group B had more Stage IIIC1 cases (19.3% vs. 6.0%, P b 0.0001), fewer Stage IIIA cases (0.8% vs. 6.6%, P b 0.01), more GOG high-risk cases (32.8% vs. 19.8%, P b 0.01), fewer low-risk cases (21.8% vs. 36.3%, P b 0.01), and more patients receiving combination chemotherapy + radiation (28.6% vs. 16.3%, P b 0.003). A total of 18/36 (50%) Group B cases with LNmetastases were isolated to the SLN, and 12/18 (66.7%) of these were micrometastases or isolated tumor cells that were missed on hematoxylin-and-eosin pathology. These 12 upstaged cases would have been considered GOG low-risk (n= 4), low-intermediate risk (n= 2), and high-intermediate risk (n= 6) without SLN mapping. Conclusions: This study suggests that compared to traditional pelvic lymphadenectomy, the addition of SLN mapping identifies more pelvic lymph node metastases and shifts GOG lowand intermediate-risk cases to high-risk cases, possibly resulting in administration of more postoperative chemotherapy and radiation therapy.

Evaluation Of Circulating Cell-Free VDJ DNA As a Marker For Monitoring Patients With Multiple Myeloma (MM) During Treatment With Carfilzomib, Lenalidomide and Dexamethasone,

BackgroundHuman plasma routinely contains measureable quantities of cell free DNA (cf-DNA). Some is generated directly within the vascular space, and some is presumably transported into the circulation from cells dying at extravascular sites. Recent studies using highly sensitive and specific detection methods demonstrate that tumor-derived circulating cf-DNA can be a powerful predictor of total body tumor burden in patients with colon and breast carcinoma. While cf-DNA monitoring is clearly a promising new approach, its general applicability in tracking other malignancies, which may vary widely in their patterns of distribution, vascularity, and cell turnover, remains to be determined. We conducted a pilot study to address the utility of cell free tumor DNA in monitoring disease burden in myeloma patients receiving combination chemotherapy. MethodsAll patients were enrolled in NIH protocols for treatment using carfilzomib, lenalidomide, and dexamethasone (CRd) combination chemotherapy. Molecular studies were performed using DNA from bone marrow (BM) aspirates obtained before and after CRd treatment, and cf-DNA extracted from 0.5-1 ml samples of plasma and/or serum obtained before each CRd cycle. The frequency and immunophenotype of myeloma cells in BM and blood was assessed using an 8-color flow cytometric panel to analyze >3 x106 events (sensitivity of 1 x 10-5).Clonal VDJ products were identified in pretreatment BM DNA using Biomed 2 primer “cocktails” targeting framework 1, 2, and 3 of the IgH chain and the variable region of the IgK light chain. Monoclonal VDJ or VJ products identified by capillary electrophoresis were cloned into pCR2.1 plasmid and sequenced. Quantitative rt-PCR assays employing patient-specific primer/Taqman probe combinations and linearized VDJ-plasmid DNA as a standard were used to measure VDJ in BM and cf-DNA. VDJ levels in BM DNA were normalized based on total actin copy number and expressed as % VDJ DNA. Cell free VDJ levels (cf-VDJ) were expressed in copies/ml of plasma or serum. ResultsTo date, 6 patients with newly diagnosed multiple myeloma (NDMM) and 3 with smoldering myeloma (SMM) have been studied. BM infiltration with CD138+ plasma cells varied from 15% to 60% and VDJ DNA levels in BM varied from 13% to 61% in this group. Circulating cf-VDJ levels before therapy were >50 copies/ml in 3 patients (444, 200, and 70 copies), detectable but <50 copies/ml in 4 patients, and undetectable in 2 patients. Cf-VDJ levels, where measurable, decreased rapidly in parallel with the decline in monoclonal M-protein concentration after CRd therapy. Unlike M-protein concentrations, which were often more persistent, cf-VDJ levels became undetectable in all cases within 1-2 cycles. By comparison, VDJ levels in BM DNA often remained detectable at low levels even in patients with complete remission by conventional clinical and laboratory criteria.Of interest, there was no correlation between the pretreatment level of cf-VDJ and disease burden estimated based on the % CD138+ plasma cells in BM, the proportion of VDJ DNA in BM, or the M-protein concentration in blood/urine. There was however, a statistically significant relationship between the level of cf-VDJ and the number of circulating myeloma cells in peripheral blood. ConclusionsIn this pilot study, cf-VDJ is detected in the blood of many patients with untreated myeloma and levels fall precipitously in patients responding to highly effective CRd therapy. In some untreated patients, cf-VDJ copy numbers in peripheral blood are low, limiting assay sensitivity. Our observation of a statistical association between the level of cf-VDJ and the number of circulating myeloma cells in peripheral blood (defined by flow cytometry) suggests that circulating myeloma cell lysis potentially accounts for, at least a portion of, the observed levels of cf-VDJ. Future studies are needed to assess the potential of cf-VDJ DNA in peripheral blood and VDJ DNA in BM for tracking disease before and after anti-myeloma therapy. Disclosures:Off Label Use: The abstract discussess off-label use of carfilzomib and lenalidomide.

Value of Magnetic Resonance Diffusion‐Weighted Imaging for the Prediction of Radiosensitivity in Nasopharyngeal Carcinoma

The effectiveness of radiotherapy in nasopharyngeal carcinoma (NPC) is closely related to the radiosensitivity of the carcinoma; however, there is currently no effective method to predict radiosensitivity in NPC. We explored the predictive value of magnetic resonance diffusion-weighted imaging (MR-DWI) for radiosensitivity in NPC. Study Design Prospective cohort study. Setting Single hospital. Patients with NPC who received intensity-modulated radiotherapy (IMRT) with or without chemotherapy were enrolled from April 2010 through November 2011. Primary tumor apparent diffusion coefficient (ADC) was measured before treatment (ADC0) and 2 weeks after the start of IMRT (ADC1). ADC change (ΔADC) was calculated as (ADC1 - ADC0)/ADC0 * 100%. Three months after the end of radiotherapy, the short-term effect of radiotherapy was assessed using the World Health Organization's response evaluation criteria in solid tumors. Of 134 eligible NPC patients, 121 received combination chemotherapy. Three months after radiotherapy, residual local tumors were detected in 23 (17.2%) cases, and no residual tumors were detected in 111 (82.8%) cases. There was no significant difference in the residual tumor rates of patients receiving combination chemotherapy vs those who did not (P = 1.000). There were no significant differences in the ADC0 or ADC1 values of patients with and without residual tumors (P = .083 and .262). The ΔADC values of patients with (49.77% ± 31.02%) and without (68.35% ± 34.22%) residual tumors were significantly different (t = -2.406, P = .017). Logistic regression analysis indicated that ΔADC was an independent prognostic factor for the short-term effect of IMRT in NPC. Magnetic resonance diffusion-weighted imaging may potentially have value for predicting radiosensitivity in NPC.

First-line clinical trials and metastatic colorectal cancer: How selected are clinical trial participants?

524 Background: Guidelines recommend that oncology patients have the opportunity to participate in a clinical trial wherever possible. It is purported that as trial participants are often younger and fitter, data extrapolation from trial outcomes to patients seen in routine care may be difficult. We compared characteristics of patients with metastatic colorectal cancer (mCRC) participating in a first-line clinical trial with those treated in routine care. Methods: The TRACC (Treatment of Recurrent and Advanced Colorectal Cancer) database, a clinician-designed mCRC comprehensive database, was used to identify patients treated on a first-line trial compared with those receiving combination chemotherapy; single-agent therapy; or no chemotherapy. Data collection began in June 2009 and is ongoing at 15 Australian centres to date. Results: Of 671 patients, 49 (7.3%) participated in a first-line clinical trial. Patients on trial were significantly younger, with 49% (n=24) trial participants being under 60 years, compared with 33% (n=128) receiving combination chemotherapy off study (p=0.047), 13% (n=13) single-agent therapy (p&lt;0.0001) and 10% (n=15) no treatment (p&lt;0.0001). All trial participants were ECOG performance status 0-1, compared with 87% (n=335) of non-trial patients receiving combination chemotherapy (p&lt;0.0001), 80% (n=82) receiving single-agent therapy (p&lt;0.0001) and 52% (n=76) no treatment (p&lt;0.0001). Similarly, Charlson comorbidity score was significantly lower in trial participants, with 88% (n=43) having a score 0-3 (less comorbidity) versus 71% (n=272) receiving combination chemotherapy, 39% (n=40) receiving single-agent therapy and 25% (n=36) no treatment. Preliminary analysis suggests significant overall survival benefit for the clinical trial cohort. Conclusions: Consistent with available literature, trial participants with mCRC are significantly younger, fitter and of better performance status than those who receive similar chemotherapy off-trial or no treatment. The impact of trial participation on survival may be thus subject to multiple factors biasing for a better outcome, including the contributing benefit of younger age and less comorbidity.

Evaluation of the Patient-Generated Subjective Global Assessment (PG-SGA) as a predictor of febrile neutropenia in gynecologic cancer patients receiving combination chemotherapy: A pilot study

ObjectiveDetermine if pre-treatment Patient-Generated Subjective Global Assessment (PG-SGA) predicts febrile neutropenia (FN) in gynecologic cancer patients receiving primary combination chemotherapy. MethodsFollowing IRB approval, clinicopathologic variables, pre-treatment laboratory values and PG-SGA were recorded from eligible patients. Bone marrow toxicity (CTC 3.0) divided groups of patients: (1) No grade 3 or 4 neutropenia, (2) grade 3 or 4 neutropenia, (3) FN. Statistical analysis with Kruskal–Wallis one-way analysis of variance and a receiver operating characteristic (ROC) curve were performed. Results58 patients met study inclusion: 25 in group 1, 28 in group 2, and 5 in group 3. Mean age was 61 and the majority, 42 (72%), had ovarian cancer. Median PG-SGA scores were: 6 (group 1) vs. 7 (group 2) vs. 14 (group 3) (p=0.019). Both median albumin: (1) 4.2 vs. (2) 4.0 vs. (3) 3.4g/dl (p=0.041), and hemoglobin: (1) 12.1 vs. (2) 11.75 vs. (3) 10.6g/dl (p=0.05) differed between the groups. The overall AUC of the ROC curve for PG-SGA was 0.831±0.064 (95% CI=0.706 to 0.956, p=0.015). Using the ROC, selecting a PG-SGA score of 7.5 to be predictive of febrile neutropenia yields a sensitivity of 100% and a specificity of 60%. When the cutoff value is set at 12.5, the specificity improves to 81% while decreasing sensitivity to 80%. ConclusionsPG-SGA scores were higher for patients experiencing FN and may be a reasonably predictive marker of FN in patients receiving multi-agent primary chemotherapy and likely benefactors of prophylactic GCSF.

Fluoxetine Disposition in Patients with Chronic Hepatitis C Treated with Interferon-α

Combination therapy with interferon-α and ribavirin is considered the treatment of choice for chronic hepatitis C. However, interferon-α may induce severe depression. It has been suggested that interferon-α is able to modify cytochrome P450 (CYP) 1A2 and 2D6 activity. We therefore decided to study the effects of the interferon-α-2b pegylated derivative on fluoxetine disposition in patients receiving combination chemotherapy for chronic hepatitis C. After approval by the institutional ethics committee, 20 adult patients with chronic hepatitis C, but with no history of other liver diseases, were prospectively admitted to the study, which included phenotyping by means of a dextromethorphan test and evaluation of fluoxetine and norfluoxetine pharmacokinetic parameters (the area under the serum concentration-time curve, maximum serum concentration, time to reach the maximum serum concentration and terminal elimination half-life) before and after 2 months of continuous peginterferon-α-2b therapy. The only statistically significant difference we observed was a significant reduction in the terminal elimination half-life of fluoxetine (from 47.30 to 33.23 hours; p = 0.014) after peginterferon-α-2b treatment. These data suggest that interferon-α may induce, rather than inhibit, the biotransformation of fluoxetine.

The prognosis and treatment of acquired hemophilia: a systematic review and meta-analysis

The inhibition of factor VIII by autoantibody development, or acquired hemophilia, occurs in approximately one person per million each year and can cause life-threatening bleeding. Due to the disease rarity, there are no randomized studies addressing prognostic features and treatment. The goal of this study is to identify prognostic indictors in acquired hemophilia to guide treatment choices. MEDLINE and EMBASE search from 1985-2008 retrieved 32 studies with detailed clinical information on five or more patients with acquired hemophilia. Univariate and multivariate analysis of the effects of age, sex, underlying condition, inhibitor titer, and treatment regimen were evaluated with regards to complete remission and death. A total of 32 studies containing 359 patients with acquired hemophilia were included in the analysis. The all-cause mortality rate in this cohort was 21%. Multivariate analyses revealed that patients more likely to die are the elderly [odds ratio (OR) 2.4, 95% confidence interval (CI) 1.32-4.36] and those with underlying malignancy (OR 2.76, CI 1.38-5.50). Early achievement of complete remission resulted in improved survival. Complete remission occurred in 94% of patients receiving combination chemotherapy, 82% receiving dual therapy, and 68% receiving steroids alone. Patients receiving immunosuppression had reduced odds of persistent hemophilia, with combination chemotherapy being the most efficacious (OR 0.04, CI 0.01-0.23) and steroid therapy alone being the least (OR 0.38, CI 0.14-0.94). In acquired hemophilia, increased age, underlying malignancy, and lack of complete remission are risk factors for death. Although the included studies were not randomized, patients treated with combination chemotherapy had the greatest odds of remission and the lowest odds of death.

Evaluation of combined docetaxel and nedaplatin chemotherapy for recurrent esophageal cancer compared with conventional chemotherapy using cisplatin and 5-fluorouracil: a retrospective study

This retrospective study evaluated the safety and efficacy of combination chemotherapy using docetaxel and nedaplatin in an outpatient setting compared with those of chemotherapy using cisplatin (CDDP) and 5-Fu under hospitalization. Subjects comprised 21 patients who had been diagnosed with recurrent esophageal squamous cell carcinoma (ESCC), with 10 patients receiving combination chemotherapy comprising CDDP and 5-fluorouracil (5-Fu) under hospitalization (FP group; n = 10), and 11 patients receiving combination chemotherapy comprising docetaxel and nedaplatin in an outpatient setting (Doc/Ned group; n = 11). In the Doc/Ned group, patients received 30 mg/m(2) of docetaxel over a 1-h infusion on day 1, followed by 40 mg/m(2) of nedaplatin over a 2-h infusion on day 1 in an outpatient setting. In the Doc/Ned group, complete response was observed in two patients (18.1%), one with liver metastasis and one with abdominal lymph node metastasis, and two (18.1%) achieved partial response. In contrast, no complete responses were obtained in the FP group, and partial response was observed in only one patient (10.0%) with local recurrence. Response rates were thus 36.3% for the Doc/Ned group and 10.0% for the FP group. With a median follow-up of 234 days in the Doc/Ned group and 279 days in the FP group, median survival time (MST) was 234 days in the Doc/Ned group and 378 days in the FP group. No significant differences in MST were identified between groups. Thus regimen based on docetaxel and nedaplatin allows administration on an outpatient basis and appears feasible for recurrent ESCC as a second-line chemotherapy.

Neoadjuvant Treatment of Colorectal Cancer with Bevacizumab: The Perioperative Angiogenic Balance Is Sensitive to Systemic Thrombospondin-1 Levels

Colorectal cancer patients receiving neoadjuvant treatment with bevacizumab, a monoclonal antibody neutralizing vascular endothelial growth factor (VEGF), may suffer from wound healing complications after surgery as the antibody persists in patient blood. We characterized the systemic angiogenic balance in the perioperative period to evaluate its effect on physiologic angiogenesis. Nineteen patients receiving combination chemotherapy and bevacizumab for six neoadjuvant cycles were compared with 14 patients receiving chemotherapy without bevacizumab. Plasma from perioperative days -1, +1, +7, and +21 was analyzed for VEGF, thrombospondin-1 (TSP-1), and PD-ECGF concentrations. The angiogenic capacity was further tested in an in vitro assay of endothelial cell proliferation and migration. On day +1, the onset of wound healing was reflected in a change of balance, i.e., an increase of proangiogenic factors VEGF and platelet-derived endothelial cell growth factor compared with low TSP-1 inhibitor levels in both treatment groups. Patients with bevacizumab therapy showed significantly higher blood levels of total VEGF throughout the evaluation period. However, most VEGF molecules were inactive, i.e., complexed with antibody. Nevertheless, the capacity to stimulate endothelial growth was higher for these plasma samples and was reflected in low TSP-1 levels and an altered TSP-1 sensitivity. When purified TSP-1 protein was added, plasma samples of the bevacizumab but not the chemotherapy group showed reduced endothelial growth. Feedback mechanisms of bevacizumab therapy are not restricted to VEGF expression but seem to involve additional factors, such as TSP-1, which influences the systemic angiogenic balance and permits endothelial growth.

Frequency of Febrile Neutropenia in Breast Cancer Patients Receiving Epirubicin and Docetaxel/Paclitaxel with Colony-Stimulating Growth Factors: A Comparison of Filgrastim or Lenograstim with Pegfilgrastim

Objective: Recombinant granulocyte colony-stimulating factors (G-CSF) have been shown to be effective in reducing the risk of infections associated with antitumour chemotherapy. This report describes a single-centre experience of the efficacy of pegfilgrastim compared with filgrastim or lenograstim in reducing the incidence of febrile neutropenia in patients receiving combination chemotherapy with taxane and epirubicin in a neoadjuvant and adjuvant setting. Methods: A total of 118 patients with breast cancer were treated with either epirubicin 75 mg/m² and docetaxel 75 mg/m² or epirubicin 90 mg/m² and paclitaxel 200 mg/m² every 3 weeks; 88 received G-CSF support with daily filgrastim or lenograstim and 30 with pegfilgrastim once per cycle. Results: Eight patients (9.1%) with prophylactic filgrastim or lenograstim support developed febrile neutropenia, as well as 1 patient (3.3%) in the pegfilgrastim group (p = 0.445). Febrile neutropenia occurred in 13 (2.7%) of 476 filgrastim or lenograstim supported chemotherapy cycles and in 2 (1.2%) of 172 cycles with pegfilgrastim support (p = 0.376). The frequency of chemotherapy delays and dose reductions was not significantly different between the two G-CSF treatment groups. Conclusion: These data show a trend towards superiority of pegfilgrastim over filgrastim or lenograstim in reducing the frequency of febrile neutropenia in patients treated with taxane and epirubicin chemotherapy regimens for breast cancer.

A phase II study of gefitinib as first line treatment for good performance advanced or metastatic non-small cell lung cancer in East Asian patients

7167 Background: Gefitinib is an effective treatment for chemotherapy-treated nonsmall cell lung cancer (NSCLC) in East Asian patients. There were only limited prospective studies on the use of gefitinib in chemonaive advanced or metastatic NSCLC patients. Methods: Eligibility included histological or cytological proven chemonaive stage IIIB/IV NSCLC, measurable disease, ECOG performance status of 0–2, good organ functions and candidate for platinum-based chemotherapy. Patients were treated with 250mg gefitinib per day. Tumor assessments were performed every two months by RECIST criteria. Responding patients were treated until progression. Patients with stable disease more than 2 months may continue treatment or shift to chemotherapy. The primary objective of this study was overall response rate of patients. Secondary objectives included 1-year progression-free survival, overall survival, and ancillary biomarker studies. Simon’s two-stage design was used to aim at a response rate more than 20%. Forty-four patients were planned in stage one and the study will be terminated if 5 or less patients responded to the treatment. A total of 106 patients are planned. Results: The planned interim analysis on the first 44 patients is reported here. There were 13 male and 31 female, median age was 63 (range 39–86), ECOG performance status of 0/1/2 were 0/40/4. 33 patients were nonsmokers. 39 patients had adenocarcinoma. The side effects of the treatment were mild and well accepted by patients. There were 24/9/10/1 patients with PR/SD/PD/NE. Overall response rate was 54.5% and disease control rate was 75%. The response rates for female / adenocarcinoma / nonsmoker were 58%/59%/61% respectively. The response rates for male / non-adenocarcinoma / smoker patients were 46%/20%/36%. The median time to progression for all patients was 6.3 months. Conclusions: Gefitinib is a very effective treatment for East Asian chemonaive advanced or metastatic NSCLC patients. Although the patients’ number was small, the response rates for patients with one unfavorable predictive factor were comparable to the response rates of patients receiving combination chemotherapy. The response rates and duration for 106 patients will be presented in the meeting. [Table: see text]

Evaluation of the prognostic factors in gastric cancer: the effect of chemotherapy on survival.

This is a retrospective review of 328 consecutive patients with histologically confirmed gastric adenocarcinoma diagnosed in one centre between 1974 and 1984. Of these patients, 128 (39 per cent) had a curative resection, 32 (9.8 per cent) had a palliative resection, 33 (10.0 per cent) had a gastro-enterostomy, 26 (7.9 per cent) had a Celestin tube inserted, 58 (17.7 per cent) had a laparotomy alone, and 51 (15.5 per cent) had no surgical procedure. The 5 year survival was 11 per cent but all long term survivors were patients who had a curative resection. Using multivariate analysis the best predictor of survival after curative resection was the presence or absence of serosal involvement (P = 0.0004). Patients with a long history of presenting symptoms (greater than 6 months) survived longer than those with a short history (P = 0.001). The impact of chemotherapy on the survival of 202 patients with advanced gastric cancer was analysed by multivariate analysis. The median survival of the 50 patients receiving combination chemotherapy was better than that of the 152 who did not (median survivals 160 versus 71 days; P less than 0.001). When deaths occurring within 14 days of diagnosis were excluded, the significance value dropped to P = 0.02. Comparison of the groups treated between 1974 and 1979, when 8 per cent of 92 patients received chemotherapy, with 1980-1984, when 45 per cent of 110 patients received chemotherapy, showed no significant difference in survival.

Multiple myeloma

Multiple myeloma (MM) is an incurable plasma cell dyscrasia that remains fatal. Despite efforts over the past 3 to 4 decades, the median survival of patients with MM does not exceed 3 to 4 years. Although patients receiving combination chemotherapy have higher response rates compared with those receiving oral melphalan and prednisolone, they have no survival advantage. High-dose chemotherapy followed by autologous stem cell transplantation has documented benefit over conventional treatment and is currently the accepted mode of treatment for symptomatic MM. Allogeneic transplantation is associated with high complete remission rates, but at the cost of high therapy-related mortality. Maintenance treatment with interferon-alpha shows benefit, albeit in a small fraction of MM patients. The use of bisphosphonates in patients with MM has clearly demonstrated benefit and reduced morbidity associated with bone disease. All of these measures have improved remission rates and survival, but all patients with MM ultimately relapse and succumb to their disease. Novel therapeutic strategies are therefore required to improve outcome of MM patients. The responses noted to thalidomide in MM are encouraging. Immune-based strategies, including both adoptive immunotherapy and vaccinations, are currently being investigated in the preclinical and clinical setting, with the goal of enhancing autologous and allogeneic anti-MM immunity for therapeutic applications.

Cost-minimization analysis of CHOP, fludarabine and rituximab for the treatment of relapsed indolent B-cell non-Hodgkin's lymphoma in the U.K.

The optimal therapy for patients with relapsed indolent B-cell non-Hodgkin's lymphoma is unclear. Combination chemotherapy such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) or purine analogues including fludarabine are frequently used and the anti-CD20 monoclonal antibody rituximab has recently been licensed for use. However, no comparative studies of these therapies have been reported. Since relapsed indolent B-cell NHL is generally regarded as incurable with current therapies, the place of each of these therapies is likely to be determined by their relative efficacy, toxicity and cost. We undertook a literature review and a retrospective analysis of patients receiving combination chemotherapy for relapsed indolent B-cell NHL at our institution to determine the response rates and the duration of response when treated with CHOP or fludarabine. Reported response rates and median response duration for these regimens are similar, and similar to those reported in phase II studies of rituximab. A cost minimization analysis was therefore conducted. The per patient costs for the treatment of drug-related adverse events were pound 5049 for CHOP, pound 2953 for fludarabine and pound 109 for rituximab. When costs of a full course of each treatment were compared, the costs per patient for CHOP, fludarabine and rituximab were pound 7210 (pound 5975-8445), pound 10022 (pound 8917-11126) and pound 6080 (pound 5892-6267) respectively. In this preliminary analysis, rituximab appeared to have a similar efficacy rate to CHOP and fludarabine, but had significantly fewer adverse events and a lower total cost per patient. These data require confirmation in a prospective randomized study with formal assessment of cost-effectiveness.