Higher Relative Dose Research Articles

Clinical Significance of Increased Skeletal Muscle Mass During Nab-Paclitaxel Plus Gemcitabine Treatment in Patients With Advanced Pancreatic Cancer.

The clinical significance of increased skeletal muscle mass during nab-paclitaxel plus gemcitabine (AG) treatment in patients with advanced pancreatic cancer (APC) remains unknown. Therefore, we retrospectively investigated the characteristics of patients after AG treatment to evaluate the clinical significance of increased skeletal muscle mass during treatment. From January 2015 to August 2021, 67 patients with APC received AG as first-line chemotherapy at Higashiosaka City Medical Center. Of these patients, 39 received second-line (2L) chemotherapy after AG therapy, and 28 received best supportive care. Patients' characteristics at the end of AG treatment were compared retrospectively between these 2 groups, and the relevant factors at the end of first-line treatment for 2L chemotherapy induction were analyzed. A performance status of 0 to 1 and increased skeletal muscle mass during AG therapy were independently associated with 2L chemotherapy induction in multivariate analysis. A high relative dose intensity (≥50%) in the first 8 weeks of AG treatment was more frequently found in patients with increased skeletal muscle mass during treatment ( P = 0.037). Increased skeletal muscle mass during AG treatment might contribute to the higher prevalence of 2L chemotherapy induction in patients with APC.

Real-Life Efficacy and Safety of Vemurafenib Plus Rituximab (V+R) in Relapsed or Refractory Hairy Cell Leukemia: A Multi-Center Retrospective Study (HCL-PG03R)

BACKGROUND Hairy cell leukemia (HCL) is a BRAFV600E-mutated indolent B-cell neoplasm (Tiacci et al., NEJM 2011) often relapsing after chemotherapy with purine analogs. BRAF inhibition is very active in relapsed/refractory (R/R) HCL, but produces mostly partial remissions (PR) and never clears minimal residual disease (MRD) (Tiacci, Park, et al., NEJM 2015). In a recent phase-2 single-center study on 30 R/R patients (pts) with a median of 3 prior therapies, a short chemotherapy-free regimen of the BRAF inhibitor vemurafenib (V) + rituximab (R; Mabthera) led to 87% complete remissions (CR), 60% MRD-negativity and 85% relapse-free survival (RFS) at a median follow-up of 34 months, with a favorable toxicity profile (Tiacci et al., NEJM 2021). METHODS A multi-center retrospective study was conducted to validate in a real-world setting the off-label use of V+R in R/R HCL needing therapy due to cytopenia(s). RESULTS From 6/2019 to 12/2021, 35 pts (median age 56 years, range 42-80) were treated at 14 Italian centers with VR (V: 960 mg bid for 8 weeks; R: 375 mg/m2 every 2 weeks for 8 doses); biosimilar R was used in 89% of pts. Prior therapies (median 2; range 0-11) included chemotherapy with cladribine or pentostatin (94% of pts), interferon-alpha (29%), rituximab (31%), splenectomy (6%), BRAF inhibitor monotherapy (6%) and zanubrutinib (3%). Median blood counts across the 35 pts were: platelets 69000/mmc, neutrophils 860/mmc and hemoglobin 11.6 g/dl (with 20% of pts, i.e. 7/35, requiring transfusions). Eleven pts (31%) had active (n=3) or latent (n=8) infections, including: ongoing systemic atypical mycobacteriosis (n=1); ongoing miliary tuberculosis (n=1; a 80-year old pt who was the only one receiving V+R as first-line therapy); ongoing large cerebral abscess (n=1); HIV infection controlled by anti-viral therapy (n=1); and latent tuberculosis (n=1) or HBV (n=6) infections requiring anti-microbial prophylaxis. Toxicity was as expected, mostly of grade 1-2 and always reversible (Table), allowing high relative dose intensities (RDI) for both drugs (V, median 97%; interquartile range/IQR 73-100%; R, 100% in 85% of pts). Similarly, among the 33/35 (94%) pts who received V for a substantial duration (≥35 days), and were thus evaluable for dose density, 20 pts (61%) completed V without ever suspending the drug, including 14/33 pts (42%) without any dose reduction. Vemurafenib toxicities were mainly represented by cutaneous rash, asymptomatic liver and pancreatic laboratory abnormalities, arthralgia, warts and photosensitivity. Three pts (9%) were not evaluable for response as they died prematurely due to atypical mycobacteriosis, complications of neurosurgery for cerebral abscess and sudden death unrelated to study drugs. Recovery of platelets (≥100000/mmc), neutrophils (≥1500/mmc) and hemoglobin (≥ 11 g/dl) occurred quickly, after a median of 2, 4 and 7 weeks after starting treatment, respectively. A CR was observed in 30/32 evaluable cases (94%; or 86%, 30/35 pts, by intention to treat/ITT). CR was obtained in all evaluable cases refractory to chemotherapy (n=8) or rituximab (n=3), or previously splenectomized (n=2) or unable to reach CR with a prior BRAF inhibitor (n=2). The only 2 evaluable pts not achieving a CR (1 PR; 1 short-lived resolution of cytopenias) received V at only 16%/50% RDI and R at only 13%/34% RDI due to drug toxicities. Analysis of MRD by allele-specific PCR for BRAF-V600E in the bone marrow aspirate was performed in 30 pts and showed MRD clearance (<0.05% mutant alleles) at a high rate: 79% (22/28 CR pts; or 65%, 22/35 pts, by ITT), which raised to 82% (66% by ITT) when including 1 additional CR case untested by PCR which had negative bone marrow flow cytometry. At a median follow-up of 21 months after the end of treatment, RFS was high among the 31 responding pts, with just 1 relapse (3%) in the only case obtaining a PR post-therapy (Figure). CONCLUSIONS This study validates in a real-life context the high efficacy and tolerability of the V+R chemo-free regimen delivered to R/R HCL pts, including the cost-saving use of biosimilar rituximab.

The Impact of Pre-Chemotherapy Body Composition and Immunonutritional Markers on Chemotherapy Adherence in Stage III Colorectal Cancer Patients

Patients with colorectal cancer (CRC) often fail to complete full-course chemotherapy with a standard dose due to various reasons. This study aimed to determine whether body composition affects chemotherapy adherence in patients with CRC. The medical records of 107 patients with stage III CRC who underwent adjuvant folinic acid, fluorouracil and oxaliplatin (FOLFOX) chemotherapy at a single center between 2014 and 2018 were analyzed retrospectively. Blood test results for selected immunonutritional markers were analyzed and body composition was measured through computed tomography. Univariate and multivariate analyses were performed on low and high relative dose intensity (RDI) groups, based on an RDI of 0.85. In the univariate analysis, a higher skeletal muscle index was correlated with a higher RDI (p = 0.020). Psoas muscle index was also higher in patients with high RDI than in those with low RDI (p = 0.026). Fat indices were independent of RDI. Multivariate analysis was performed for the aforementioned factors and results showed that age (p = 0.028), white blood cell count (p = 0.024), and skeletal muscle index (p = 0.025) affected RDI. In patients with stage III CRC treated with adjuvant FOLFOX chemotherapy, a decrease in RDI was related to age, white blood cell count, and skeletal muscle index. Therefore, if we adjust the drug dosage in consideration of these factors, we can expect an increased treatment efficiency in patients by increasing chemotherapy compliance.

Clinical Impact of Primary Prophylactic Pegfilgrastim in Breast Cancer Patients Receiving Adjuvant Docetaxel-Doxorubicin-Cyclophosphamide Chemotherapy.

PurposeThe regimen including concurrent docetaxel, doxorubicin, and cyclophosphamide (TAC) has been categorized as an important risk factor for febrile neutropenia (FN). This comparative study examined the clinical impact of long-acting granulocyte colony-stimulating factor (G-CSF) (pegfilgrastim) during adjuvant TAC chemotherapy in Korean patients with advanced breast cancer.MethodsWe analyzed data from 239 patients who received 6 cycles of adjuvant TAC chemotherapy. We categorized patients into 2 groups according to the use of primary prophylactic pegfilgrastim and compared the incidence and risk of FN, hospital care costs, and survival in the 2 groups.ResultsThe incidence of FN decreased from 54.2% to 21.2% in all patients, after the use of pegfilgrastim. The analysis of a total of 1,432 chemotherapy cycles showed that the incidence of FN decreased from 36.1% to 9.1% after the use of pegfilgrastim. Moreover, the decrease in the incidence of FN with the use of pegfilgrastim resulted in a significant decrease in the mean duration of neutropenia (4.15 to 1.29 days), the risk of hospitalization (99.5% to 29.7%) and the mean total hospital care cost (USD 3,038 to USD 2,347). High relative dose intensity (RDI) in patients treated with pegfilgrastim than in those not treated with pegfilgrastim (99.18% vs. 93.85%) was associated with a better overall survival (p = 0.033).ConclusionsThe use of pegfilgrastim during adjuvant TAC chemotherapy was significantly associated with a decrease in the incidence and risk of FN, hospital care costs, and risk of death compared to the use of adjuvant TAC without primary prophylaxis.

Abstract 3284: Adiposity, muscle mass and delays and dose reductions on adjuvant, taxane-based chemotherapy for breast cancer

Abstract Introduction: Low muscle mass and excess adiposity are thought to increase the risk of chemotherapy toxicity, leading to dose reductions or delays. Yet, few studies of body composition and chemotherapy examine patients with breast cancer; prior studies have been small and looked mainly at toxicities. Here, we evaluate whether adiposity or muscle mass and radiodensity (a measure of intramyocellular lipid accumulation) are associated with risk of dose reductions or delays among nonmetastatic breast cancer patients receiving adjuvant taxane-based chemotherapy, and whether dose reductions are associated with cancer-specific survival. Methods: Our study included 1,403 patients with stage II-III breast cancer receiving taxane-based chemotherapy at Kaiser Permanente. We evaluated body composition from clinically-acquired CT scans at diagnosis. We defined dose reductions from infusion records as relative dose intensities <0.85 (delivered v. planned dose) while on taxane therapy, and dose delays as treatments received more than 3 days later than scheduled. We defined neuropathy from diagnosis codes and hematologic toxicities from laboratory values during chemotherapy. Logistic regression models adjusted for age and dosing body surface area (BSA). Cox proportional hazards models for cancer-specific survival adjusted for age, BSA, body composition and tumor characteristics. Results: Mean (standard deviation [SD]) age at diagnosis was 53 (10) years. Higher visceral adiposity was associated with a 20% increased risk of dose reductions and a 17% increased risk of dose delays on taxane-based chemotherapy (odds ratios of 1.20; 95%CI:1.02-1.42 and 1.17; 95%CI:0.99-1.39 per SD, respectively). Higher muscle radiodensity (indicating lower intramyocellular lipid infiltration, i.e., leaner muscle) was associated with a 13% lower risk of dose reductions and a 16% lower risk of dose delays (odds ratios of 0.87; 95%CI:0.75-1.00 and 0.84; 95%CI:0.72-0.98 per SD, respectively). Muscle mass and subcutaneous adiposity were not associated with dose reductions or delays, though lower muscle mass did increase risk of hematologic toxicity. Women who experienced dose reductions on taxane-based chemotherapy had a 37% increased risk of dying from breast cancer relative to those with higher relative dose intensities (hazard ratio 1.37; 95%CI:1.01-1.85; median follow-up 6 years, 203 breast cancer deaths). Conclusions: Excess visceral adiposity and lower muscle radiodensity were associated with dose reductions and delays among breast cancer patients receiving taxane-based chemotherapy, reducing the efficacy of these life-saving therapies: women who experienced dose reductions were at higher risk of dying from breast cancer. Body composition information assessed from clinically-acquired CT scans may help identify patients for supportive interventions to mitigate toxicity. Citation Format: Elizabeth M. Cespedes Feliciano, Valerie Lee, Wendy Y. Chen, Carla M. Prado, Shlomit S. Shachar, Stacey Alexeeff, Bette J. Caan. Adiposity, muscle mass and delays and dose reductions on adjuvant, taxane-based chemotherapy for breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3284.

Review of high-resolution peripheral quantitative computed tomography for the assessment of bone microstructure and strength

Trabecular microstructure is an important factor in determining bone strength and physiological function. Normal X-ray and computed tomography (CT) cannot accurately reflect the microstructure of trabecular bone. High-resolution peripheral quantitative computed tomography (HR-pQCT) is a new imaging technique in recent years. It can qualitatively and quantitatively measure the three-dimensional microstructure and volume bone mineral density of trabecular bone in vivo. It has high precision and relative low dose of radiation. This new imaging tool is helpful for us to understand the trabecular microstructure more deeply. The finite element analysis of HR-pQCT data can be used to predict the bone strength accurately. We can assess the risk of osteoporosis and fracture with three-dimensional reconstructed images and trabecular microstructure parameters. In this review, we summarize the technical flow, data parameters and clinical application of HR-pQCT in order to provide some reference for the popularization and extensive application of HR-pQCT.

Evaluation of relative dose intensity during the early phase of first-line sunitinib treatment using a 2-week-on/1-week-off regimen for metastatic renal cell carcinoma

Sunitinib treatment with a 2-week-on/1-week-off schedule (Schedule 2/1) is a common alternative regimen with high relative dose intensity (RDI) and superior tolerability for patients with metastatic renal cell carcinoma (mRCC). The prognostic impact of RDI is reported only in 4-week-on/2-week-off or mixed regimens. Herein, we evaluated the prognostic impact of RDI during early-phase sunitinib treatment using Schedule 2/1. Seventy-four patients who received first-line sunitinib treatment using Schedule 2/1 were evaluated. Endpoints were progression-free survival (PFS) and overall survival (OS). We assessed RDI within the initial two cycles (2c-RDI), and its prognostic impact. Predictive factors for 2c-RDI deterioration were also evaluated. The cut-off value of 2c-RDI was set at 65%. Based on this cut-off, 31 patients (42.0%) were classified into the low 2c-RDI group (< 65%). PFS and OS were significantly shorter in the low-2c-RDI patients, compared with the high 2c-RDI patients (median PFS: 6.15 vs. 18.4 months, p = 0.0005; OS 11.0 vs. 39.3 months, p = 0.0002). Furthermore, multivariate analyses showed that the development of dose-limiting toxicities (DLTs) within the initial two cycles, as well as low initial dose, were independent factors for low 2c-RDI (DLTs: OR 18.6, 95% CI 3.27-105.30, p = 0.0010; initial dose: OR 9.26, 95% CI 1.42-60.40, p = 0.020). The most common adverse event was thrombocytopenia (any grade: 24.3%; grade ≥ 3: 8.1%). More than 65% of 2c-RDI should be maintained for optimal therapeutic effect of sunitinib treatment using Schedule 2/1. To achieve the appropriate 2c-RDI, careful follow-up for patient tolerability is needed to avoid early DLT development.

Comparison of manual and inverse optimization for CT guided interstitial brachytherapy in locallyadvanced cervical cancer

Objective To investigate the dosimetric difference between inverse planning simulated annealing (IPSA) and manual optimized plan for isodose line in interstitial brachytherapy for locally advanced cervical cancer and to provide a better optimization method for clinical application. Methods A total of 104 patients with cervical cancer were enrolled in this study. They received pelvic external beam radiotherapy and interstitial brachytherapy in five fractions. Both IPSA and manual optimized plan for isodose line were used to optimize the dose in each fraction. Dose volume parameters of the two plans were compared to analyze the dosimetric outcome by paired t-test. Results There were no significant differences in mean D90 and D100 for high-risk clinical target volume (HR-CTV) and D90 for intermediate-risk clinical target volume (IR-CTV) between the two groups (P>0.05). The IPSA group had a significantly higher D100 for IR-CTV than the manual optimized group (58.36±2.06 Gy vs. 53.99±2.17 Gy, P=0.025). For organs at risk, the IPSA group had a significantly lower mean rectum D2cc and a significantly higher bladder D2cc than the manual optimized group (68.53±2.85 Gy vs. 71.77±1.79 Gy, P=0.002; 80.49±3.36 Gy vs. 78.71±2.64 Gy, P=0.034). There was no significant difference in sigmoid D2cc between the two groups (P>0.05). The IPSA group had significantly higher relative dose homogeneity index (HI) and conformity index (CI) of radiation dose for target volume than the manual optimized group (P<0.05), and there was no significant difference in overdose volume index (OI) between the two groups (P=0.107). Conclusions Compared with manual optimized plan for isodose line, IPSA can improve the dose distribution of tumor tissue, reduce mean rectum D2cc, and increase CI and HI, so it is a preferable optimized treatment planning method in clinical application. Key words: Cervical cancer; Interstitial brachytherapy; Inverse planning simulated annealing; Isodose manual optimized method; Dosimetr

The Charlson age comorbidity index predicts prognosis in patients with resected pancreatic cancer

BackgroundThe Charlson age comorbidity index (CACI) is a useful measure of comorbidity to standardize the evaluation of surgical patients and has been reported to predict postoperative mortality in various cancers. MethodA total of 379 patients who underwent R0/R1 resection for pancreatic cancer between 2003 and 2014 were enrolled in this study. According to the CACI, the age-adjusted comorbidity index was calculated by weighting individual comorbidities; CACI<4 was considered the low-CACI group, whereas CACI≥4 was considered the high-CACI group. The correlations between the CACI and clinicopathologic features and survival outcomes were statistically analyzed. ResultsThe patients with a high CACI were more likely to be old and had higher CA19-9 levels and lower incidences of portal vein resection and blood transfusion. The rate of patients who received chemotherapy was significantly higher in the low-CACI group than in the high-CACI group (87% vs. 69%, P < 0.0001). The overall survival (OS) rate was significantly higher in the low-CACI group than in the high-CACI group (P = 0.047). Multivariable analysis showed that a high CACI was a predictor of poor survival (P = 0.024). In the high-CACI group, patients with high relative dose intensity (RDI) for postoperative adjuvant chemotherapy had significantly better relapse-free survival (RFS) and OS than those with low RDI (both P < 0.0001). ConclusionsThe CACI was a significant independent predictor of prognosis and compliance for postoperative adjuvant chemotherapy in the resected pancreatic cancer.

The Charlson age comorbidity index to predict prognosis in patients with resected pancreatic cancer.

495 Background: The Charlson age comorbidity index (CACI) is a useful measure of comorbidity to standardize the evaluation of surgical patients and has been reported to predict postoperative mortality in various cancers. Methods: A total of 379 patients who underwent R0/R1 resection for pancreatic cancer between 2003 and 2014 were enrolled in this study. According to the CACI, the age-adjusted comorbidity index was calculated by weighting individual comorbidities; CACI &lt; 4 was considered the low-CACI group, whereas CACI ≥ 4 was considered the high-CACI group. The correlations between the CACI and clinicopathologic features and survival outcomes were statistically analyzed. Results: The patients with a high CACI were more likely to be old and had higher CA19-9 levels and lower incidences of portal vein resection and blood transfusion. The rate of patients who received chemotherapy was significantly higher in the low-CACI group than in the high-CACI group (87% vs. 69%, P&lt; 0.0001). There was no difference in relapse-free survival (RFS) between the low- and high-CACI groups; however, the overall survival (OS) rate was significantly higher in the low-CACI group than in the high-CACI group ( P= 0.047). Multivariable analysis showed that a high CACI was a predictor of poor survival. In the high-CACI group, patients with high relative dose intensity (RDI) for postoperative adjuvant chemotherapy had significantly better RFS and OS than those with low RDI (both P&lt; 0.0001). Conclusions: The CACI was a significant independent predictor of prognosis and compliance for postoperative adjuvant chemotherapy and could be clinically useful for decision-making in the treatment strategy for pancreatic cancer.

A prospective, real-world study of treatment patterns in early-stage breast cancer (ESBC) patients (pts) at high risk for febrile neutropenia (FN).

e21653Background: ESBC is commonly treated with myelosuppressive chemotherapy, and maintaining high relative dose intensity (RDI) is associated with improved survival. However, FN can result in red...

Abstract P3-13-09: Relative dose intensity of taxane-based chemotherapy in patients with stage IV breast cancer

Abstract Background: Maintaining high relative dose intensity (RDI) has been associated with improved disease-free survival, progression-free survival, and overall survival of patients with breast cancer treated in the adjuvant setting. Neutropenia and related complications, such as febrile neutropenia, are common side effects of myelosuppressive chemotherapy that can lead to dose delays, dose reductions, and reduced RDI. Primary prophylaxis with colony-stimulating factors (CSFs) can reduce the duration and severity of neutropenia and the incidence of febrile neutropenia, thereby supporting high RDI. For patients with stage IV breast cancer, dose delays and dose reductions are frequently used to manage toxicity associated with myelosuppressive chemotherapy. However, the prevalence and impact of reduced RDI in the metastatic disease setting is poorly understood. Objective: To estimate mean chemotherapy RDI and incidences of dose delays, dose reductions, RDI &amp;lt;85%, and primary CSF prophylaxis among women with stage IV breast cancer receiving first-line chemotherapy. Methods: Using the McKesson Specialty Health/US Oncology iKnowMed™ electronic health record (HER) database, we retrospectively identified adult women with stage IV breast cancer who initiated first-line, intravenous, myelosuppressive chemotherapy from January 2007 to December 2010 in community oncology practices in the US. Patients were assigned to chemotherapy cohorts based on myelosuppressive agents received in cycle 1 and planned regimen information in the database. Standard chemotherapy regimens were defined based on NCCN breast cancer guidelines and clinical studies. Mean RDI and incidences of dose delays ≥7 days, dose reductions ≥15%, and RDI &amp;lt;85% in any cycle during the course of chemotherapy were evaluated relative to the standard chemotherapy regimen. Primary CSF prophylaxis was defined as first receipt of CSF during the first 5 days of chemotherapy cycle 1. Patients were followed for up to 6 months after chemotherapy initiation. Results: This study included 1471 patients with stage IV breast cancer who received myelotoxic chemotherapy. The most common chemotherapy regimens in the metastatic setting were taxane-based, and endpoints for the three most common chemotherapy regimens (n = 307) are shown in the Table. Paclitaxel/ BevacizumabaAlbumin-bound PaclitaxelbPaclitaxelcN1767556Age, mean (SD) years58.2 (11.9)63.6 (12.4)61.8 (13.8)RDI, mean (SE)89.0% (1.9)89.1% (3.1)89.0% (3.2)RDI &amp;lt;85%37.5%41.3%26.8%Dose delays ≥7 days36.9%22.7%32.1%Dose reductions ≥15%40.9%61.3%8.9%CSF primary prophylaxis0%1.3%3.6%aPaclitaxel 80-90 mg/m2 on days 1, 8, and 15 and bevacizumab 10 mg/kg on days 1 and 15 (cycle length 28 days). Paclitaxel dose at cycle 1, day 1 was defined as the standard dose for this regimen; bAlbumin-bound paclitaxel 100 mg/m2 on days 1, 8, and 15 (cycle length 28 days); cPaclitaxel 80 mg/m2 (cycle length 7 days). Conclusions: Chemotherapy dose delays, dose reductions, and reduced RDI were common in patients with stage IV breast cancer. The impact of RDI on progression-free and overall survival is being evaluated and will be presented. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-13-09.

Oncological Outcomes of Metastatic Testicular Cancers under Centralized Management through Regional Medical Network

To investigate the dose intensity of induction chemotherapy and oncological outcomes of metastatic testicular cancer under centralized management through a regional medical network. We retrospectively analyzed the outcomes of 86 metastatic testicular cancer patients who were given induction chemotherapy at Tsukuba University Hospital and four branch hospitals between January 2000 and November 2010. Principally, management of patients with poor-prognosis disease and patients having risk factors for bleomycin, etoposide and cisplatin were referred to Tsukuba University Hospital before chemotherapy. For high-risk groups, etoposide and cisplatin or etoposide, ifosfamide and cisplatin was used as an alternative to bleomycin, etoposide and cisplatin. Overall, 56 and 30 patients were treated at Tsukuba University Hospital and branch hospitals, respectively. Forty-seven, 18 and 21 patients were classified with good-, intermediate- and poor-prognosis disease, respectively, according to the International Germ Cell Cancer Collaborative Group criteria. Eighteen of the 21 patients (86%) with poor-prognosis disease were treated at Tsukuba University Hospital from the beginning of induction chemotherapy. Induction chemotherapy with a high relative dose intensity was possible in most patients. The average relative dose intensity of each drug was >0.96. Treatment procedures other than induction chemotherapy were efficiently centralized; 74% of post-chemotherapy surgery and all second-line or subsequent chemotherapies were performed at Tsukuba University Hospital. The 5-year overall survival rates of the good-, intermediate- and poor-prognosis groups were 97, 93 and 84%, respectively. Induction chemotherapy with high relative dose intensity, post-chemotherapy surgery and salvage chemotherapy was accomplished efficiently through centralization of management. Oncological outcomes were excellent, especially in patients with poor-prognosis disease, whose 5-year OS reached 84%.

An Open-Label, Randomized Study of Bendamustine and Rituximab (BR) Compared with Rituximab, Cyclophosphamide, Vincristine, and Prednisone (R-CVP) or Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in First-Line Treatment of Patients with Advanced Indolent Non-Hodgkin's Lymphoma (NHL) or Mantle Cell Lymphoma (MCL): The Bright Study

AbstractAbstract ▪902▪This icon denotes a clinically relevant abstract BackgroundBendamustine (B) is an active agent for relapsed and refractory indolent NHL, both as monotherapy and combined with rituximab (R), results recently updated by the StiL study group. This study compared efficacy and safety of BR with standard treatment regimens of R-CHOP and R-CVP as first-line treatment for indolent NHL or MCL. MethodsPatients were randomized to 6–8 cycles of BR or R-CHOP/R-CVP (R-CHOP or R-CVP determined by investigator prior to randomization). BR regimen was B 90 mg/m2/day on days 1 and 2 plus R 375 mg/m2on day 1 of a 28-day cycle. Standard dosing and 21 day cycles were used for R-CHOP and R-CVP. Primary objective was to demonstrate noninferiority of complete response (CR) rate of BR vs standard treatment (noninferiority margin [ratio] 0.88). Secondary measures included overall response rate (ORR), progression-free survival, and overall survival. Tumor response was determined by a blinded independent review committee (IRC) using International Working Group revised response criteria for malignant lymphoma. Investigator assessments were compared with those of the IRC. ResultsOf 447 randomized patients, 436 received treatment (BR n=221; R-CHOP/R-CVP n=215 [R-CHOP n=99; R-CVP n=116]) and were evaluable for safety. Of these, 419 patients (BR n=213; R-CHOP/R-CVP n=206 [R-CHOP 97; R-CVP n=109]) were evaluable for efficacy. The randomized groups were well matched for age (median 60 and 58 years), sex (male, 61% and 59%), ECOG status (64% performance status 0, both groups), lymphoma type (83% indolent NHL, both groups), and Ann Arbor stage (62% stage IV, both groups).Among randomized patients and efficacy evaluable patients, the IRC-assessed CR rate was numerically higher for BR than R-CHOP/R-CVP and statistically noninferior (Table). In the randomized groups, CR rates for indolent NHL were numerically similar between BR and R-CHOP/R-CVP; however, in MCL, BR was statistically superior (P=0.018) (Table). Investigator-assessed response in randomized patients found superiority of BR vs R-CHOP/R-CVP (P=0.0013). IRC and investigator assessments differed mainly in quality of response (CR vs partial) rather than in whether a patient was a responder. For randomized patients, the ORR was 94% for BR and 84% for R-CHOP/R-CVP. Time-to-event data are immature and will be analyzed later. At time of data cut-off, 8% of the BR group had progressed, relapsed, or died, compared with 4% of R-CHOP/R-CVP group.Most patients completed 6 cycles (92% for BR and 91% for R-CHOP/R-CVP), with high relative dose intensity (>96%). Dose delays were more common for BR-treated patients (35% vs 19%), and dose reductions were less common (22% vs 29%).Most common AEs for BR and R-CHOP/R-CVP, respectively, were nausea (139 vs 102 patients), fatigue (113 vs 107), neutropenia (76 vs 85), constipation (65 vs 90), and alopecia (8 vs 74). Laboratory grade 3/4 hematologic toxicities for BR and R-CHOP/R-CVP were lymphopenia (137 vs 64), neutropenia (98 vs 151), leukopenia (84 vs 116), thrombocytopenia (16 vs 15), and anemia (6 vs 9), respectively. The most frequent investigator-reported nonhematologic grade 3/4 AEs for BR and R-CHOP/R-CVP were infusion-related reaction (13 vs 8 patients). Granulocyte colony stimulating factors were given at investigator discretion (per ASCO recommendations) to 29% of the BR group and 43% of the R-CHOP/R-CVP group. Fatal AEs occurred in 6 BR patients (pneumonia, respiratory failure, and sepsis; acute respiratory failure; cardiac arrest; pneumonia; chronic obstructive pulmonary disease; lung cancer) and 1 R-CHOP/R-CVP patient (sepsis). ConclusionIn patients with advanced indolent NHL and MCL, BR produces a CR rate that is noninferior to that of R-CHOP/R-CVP. In the subgroup of patients with MCL, BR produces a significantly higher CR rate (51% vs 24%). High ORRs were attained in both treatment groups. The AE profile of BR was distinct from that of R-CHOP/R-CVP.Support: Teva Pharmaceutical Industries Ltd.TableComplete Response RatesPopulation, AnalysisBR %R-CHOP/R-CVP %Ratio (95% Confidence Interval)P valueEvaluable, IRC31251.25 (0.93–1.73)0.0225aRandomized, IRC31231.34 (0.98–1.83)0.0084aRandomized, IRC NHL27231.16 (0.81–1.65)0.1289aRandomized IRC MCL51241.95 (1.01–3.77)0.0180bRandomized, investigator–assessment31181.60 (1.14–2.25)0.0013bIRC, independent review committee assessment.aTest for noninferiority;bTest for superiority. Disclosures:Flinn:Teva Pharmaceuticals : Research Funding. Off Label Use: Bendamustine is FDA-approved for adults with chronic lymphocytic leukemia or indolent B-cell non-Hodgkin's lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. Van der Jagt:Celgene: Consultancy, Research Funding, Sponsorship Other; Novartis: Consultancy, Research Funding, sponsorship, sponsorship Other; Roche: Consultancy, sponsorship, sponsorship Other; Cephalon: Consultancy, Research Funding; Incyte: Research Funding; Xanthus: Research Funding; Bristol-Myers Squibb : Consultancy. Kahl:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. MacDonald:Lundbeck: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Munteanu:Teva Pharmaceutical Industries Ltd.: Employment. Clementi:Teva Pharmaceutical Industries Ltd.: Employment. Chen:Teva Pharmaceutical Industries Ltd.: Employment. Burke:Spectrum Pharmaceuticals: Consultancy.

Current patterns of chemotherapy and supportive care for early-stage breast cancer (ESBC).

1062 Background: ESBC is commonly treated with myelosuppressive chemotherapy, and high relative dose intensity (RDI) correlates with improved overall survival. A retrospective analysis of patients with ESBC treated from 1997–2000 showed that 56% received an RDI &lt; 85% (Lyman et al. JCO. 2003;21:4524-4531). To determine current practice, we evaluated ESBC treatment patterns at 24 US community- and hospital-based oncology practices. Methods: Data were abstracted from medical records of 532 patients with ESBC treated from January 2007–December 2009. Inclusion criteria included surgically resected ESBC (stage I-IIIA); ≥ 18 years old; and completion of at least 1 standard chemotherapy cycle on an every 2 or 3 week schedule. The primary endpoint was RDI over planned cycles. Other endpoints were incidence of dose delays ≥ 7 days, dose reductions ≥ 15% from standard, grade 3/4 neutropenia (SN), febrile neutropenia (FN), FN-related hospitalization, granulocyte-colony stimulating factor (G-CSF) use, and antimicrobial therapy. Descriptive statistics were generated for all endpoints. Results: In this study, mean (range) age was 55 (29–85) years. Relative to previously published results, chemotherapy regimens have shifted from mainly doxorubicin + cyclophosphamide (AC) (previously 35%) to docetaxel + cyclophosphamide (TC; n = 221; 42%) and AC followed by paclitaxel (AC-T; n = 163; 31%). Mean RDI is now higher (93% for both TC and the most common AC-T schedule [dose dense AC-T; n = 84] vs 79% previously); the incidence of dose delays (16% vs 25% previously) and dose reductions (21% vs 37% previously) have decreased; and primary prophylactic use of G-CSF has increased (76% vs 3% previously). In this study, 40% of patients had SN, 3% had FN, 2% had an FN-related hospitalization, and 30% received antimicrobial therapy. These measures were not available in the previously published results. Conclusions: The observed changes between the two studies are noteworthy though inferential comparisons are limited by changes in treatments and other factors. RDI has improved over time, but 16% of patients in this study received an RDI &lt; 85%. Further evaluation is needed to identify factors associated with lower RDI and determine outcomes for these patients.

Gemcitabine and cisplatin after radical cystectomy for bladder cancer in an adjuvant setting: feasibility study from the Genito-Urinary Group of the French Federation of Cancer Centers

The impact of adjuvant chemotherapy in locally advanced bladder cancer is still not fully established. Between January 2000 and November 2001, 30 patients entered the trial to receive four cycles of a combination of gemcitabine 1,250 mg/m on day 1 and day 8 and cisplatin 70 mg/m on day 1, repeated every 3 weeks. Histologic diagnoses included pT2-pT3-pT4 tumors and/or pN1-pN2. Combination treatment with gemcitabine and cisplatin was considered feasible if 70% of the patients received a relative dose intensity of each drug of more than 90%. Twenty-seven patients received four cycles of combination treatment. The relative dose intensity of cisplatine and gemcitabine was 96 and 88%, respectively. No toxic death occurred. We conclude that giving four cycles of the gemcitabine-cisplatin regimen in the adjuvant setting after cystectomy is feasible with a manageable toxicity and a high relative dose intensity. Whether this approach may increase survival is currently assessed in a randomized trial.

Paclitaxel in Breast Cancer

Paclitaxel has emerged as an important agent in the treatment of breast cancer. The efficacy and tolerability of this agent, as well as its lack of cross-resistance with anthracyclines, have spurred intensive clinical investigation worldwide. Optimization of paclitaxel dose and scheduling and evaluation of the drug in combination regimens are a central focus of investigations. Recent clinical evidence suggests that optimal dose of single-agent paclitaxel by 3-h infusion is 175 mg/m&sup2;. Trials evaluating administration schedule have not found either a 24-h or 96-h infusion to be superior to a 3-h infusion. Weekly moderate-dose paclitaxel administration is also generating much interest, given the high relative dose intensity and dose density delivered, yet very modest myelosuppression and manageable neurotoxicity observed. As first-line therapy in metastatic disease, multiple studies have documented overall response rates in the range of 30%-60%. As second-line or salvage single-agent therapy in metastatic patients, paclitaxel generally affords an overall response rate of 20%-40%, even in anthracycline-resistant patients. The novel mechanism of action and manageable toxicity of paclitaxel has led to successful incorporation into combination chemotherapy regimens. The combination of paclitaxel and doxorubicin has been the most extensively studied, with the role of this regimen continuing to evolve. Other combination regimens that appear to hold substantial promise as first-line metastatic treatment are paclitaxel with carboplatin and paclitaxel with trastuzumab (anti-HER2 antibody). The favorable results obtained in the metastatic setting have prompted phase II and phase III investigations of paclitaxel in the adjuvant and neoadjuvant settings. In the adjuvant setting, a recent phase III study has indicated that the addition of sequential paclitaxel to standard therapy affords both disease-free and overall survival benefits. Current investigations with paclitaxel will continue to optimize the role of this agent in the treatment of early- and advanced-stage breast cancer, addressing not only response rates but also survival and quality-of-life issues. The use of paclitaxel on a weekly schedule or with new therapeutic modalities, such as monoclonal antibodies, is also receiving much attention. While it is clear that paclitaxel is a very active agent in the treatment of breast cancer, it is hoped that these innovative trials will further maximize the potential of this agent in patients with breast cancer.

Prostate brachytherapy. An overview.

Prostate brachytherapy represents one of the oldest techniques of using radiation therapy to treat prostate cancer. Over the past 10 years, there have been major changes in the types of prostate brachytherapy that can be performed with the introduction of new radioactive isotopes, new afterloading techniques, and an improved understanding of the radiobiology associated with differing dose rates. Prostate brachytherapy can be divided into temporary implantation using high activity sources such as iridium-192, or permanent brachytherapy using the interstitial implantation of iodine-125 or palladium-103 sources. There are various techniques that can be used to actually insert the radioactive material into the prostate. This can be done as an open or closed procedure and can be performed via a suprapubic or a perineal retropubic approach. The use of remote afterloading has substantially reduced the radiation protection problems associated with manually loaded radioactive sources. Results using brachytherapeutic isotopes in the treatment of prostate cancer have been variable, but it appears that using the higher dose rate sources and delivering a high relative integral dose to the prostate can result in improved histologic control of prostate cancer. In patients with aggressive prostate cancer, the use of iodine-125 permanent implantation has not been successful. The role of brachytherapy in the treatment of prostate cancer remains an exciting alternative in the management of prostate cancer. Its role is becoming more defined in the treatment of large, bulky prostatic neoplasms as a way of improving the dose distribution achieved between normal and tumor tissue.

Effects of dose relative to body weight in the national cooperative gallstone study: A fixed-dose trial

Most clinical trials of a drug employ total fixed doses (mg/day) but the results are also often analyzed according to doses relative to body weight (mg/kg/day). The latter corresponds to a subgroup analysis stratified by body weight. This paper describes the difficulty in interpreting such results as illustrated by the National Cooperative Gallstone Study (NCGS). The NCGS evaluated the efficacy and safety of chenodiol for the dissolution of gallstones using fixed dosage groups (750, 375, and 0 mg/day). Analyses are presented comparing those patients who received high vs. low relative doses by virtue of a low (≦62.5 kg) vs. high (>62.5 kg) body weight. Although a significantly higher proportion of those with a low body weight achieved partial (50% reduction in volume) or complete dissolution of gallstones, these subgroups also differed significantly in a variety of characteristics (sex, age, percent ideal body weight; and floating gallstones) which have been shown to be prognostic of dissolution with a fixed dose of chenodiol. Similarly, although the body weight subgroups differed in the proportions of patients experiencing clinically significant diarrhea, they also differed in the characteristic (sex) associated with diarrhea. After adjustment for these characteristics, the differences for dissolution and diarrhea between the high and low relative dose subgroups were not significant. Thus, an analysis by relative (mg/kg) doses of the results of a fixed dose clinical trial should be used only with caution to determine whether a high relative dose (mg/kg) of an agent would be more efficacious or less safe when applied to the general population.