Impact Of Relative Dose Intensity Research Articles

Impact of relative dose intensity on bone marrow suppression induced by S-1: retrospective observational study

BackgroundS-1 (a combination of tegafur, gimeracil, and oteracil) is used to treat various cancers. Bone marrow suppression is a dose-limiting toxicity of S-1. The relationship between relative dose intensity (RDI) and bone marrow suppression has not been investigated. Hence, we aimed to elucidate the threshold for RDI to identify bone marrow suppression induced by S-1.MethodsIn this retrospective cohort study, patients who initiated S-1 treatment at Tokyo Women’s Medical University, Medical Center East between June 2015 and June 2017 were included. Bone marrow suppression induced by S-1 was assessed using Common Terminology Criteria for Adverse Events version 4.0. The relationships between grade 3 or higher bone marrow suppression induced by S-1 and RDIs (i.e., 70, 75, and 80%) were investigated using the multivariate Cox proportional hazard model.ResultsWe identified 143 patients in this study. The median RDI was 78.8%. Bone marrow suppression induced by S-1 developed in 19 (13.3%) patients. The multivariate Cox proportional hazard model revealed that grade ≥ 2 lymphocytopenia was associated with bone marrow suppression induced by S-1 regardless of the threshold for RDI. In addition, RDI > 75% [hazard ratio (HR) = 1.71, p < 0.05] and RDI > 80% (HR = 1.65, p < 0.05) were associated with bone marrow suppression induced by S-1.ConclusionsReduced dose of S-1 still has the risk of developing bone marrow suppression. Clinicians should assess RDI to identify high risk patients with bone marrow suppression induced by S-1.

O2-13-5 - Impact of relative dose intensity of R-CHOP on outcomes of patients with advanced follicular lymphoma

O2-13-5 - Impact of relative dose intensity of R-CHOP on outcomes of patients with advanced follicular lymphoma

A retrospective review of borderline resectable-locally advanced pancreatic adenocarcinoma (BR-LAPC) undergoing neoadjuvant chemotherapy followed by stereotactic body radiation therapy (SBRT) at the University of Colorado Cancer Center.

436 Background: Metastatic pancreatic chemotherapy regimens are often used as neoadjuvant treatment in the LAPC setting. The University of Colorado has a treatment paradigm for BR-LAPC which consists of 2-4 months of chemotherapy followed by SBRT then reevaluated for surgical resection. Methods: Retrospective analysis of patients with pathologically confirmed BR-LAPC who received all neoadjuvant treatment (chemotherapy and SBRT) with intention of undergoing surgical resection at the University of Colorado Cancer Center from 2012 to 2017. Baseline data collected includes demographics, comorbidities, disease characteristics and chemotherapy regimen FOLFIRINOX or Gemcitabine/Nab-Paclitaxel (GNP). The objective of the study is to describe the correlation of neoadjuvant regimens and clinical outcomes. Results: A total of 100 patients were identified with 40 patients collected for the interim analysis. Of these patients 82.5% (N = 33) received FOLFIRINOX and 17.5% (N = 7) received GNP. Patients who received FOLFIRINOX, 78.8% went for surgical resection compared to 85.7% in the GNP group. The number of patients who had a reported College of American Pathology (CAP) grade ≤1, representing no or minimal residual disease, was 3 for the FOLFIRINOX group and no patients in the GNP group. The percent of patients in the FOLFIRINOX group who achieved R0 resections was 90% compared to 83% for the GNP group. Mean initial CA 19-9 was 38.5U/ml, 386.7U/ml, and 1799.8U/ml in CAP grade 1, 2, 3 respectively, while percent reduction in CA 19-9 level during neoadjuvant was 33.3%, 69.7%, and 72.4% respectively. Assessment of the impact of relative dose intensity for each neoadjuvant regimen on clinical outcomes is ongoing. Conclusions: FOLFIRINOX neoadjuvant treatment was associated with improved surgical outcomes including an increased rate of R0 and CAP grade ≤1 resections. Low initial CA 19-9 levels were associated with favorable surgical and pathologic outcomes whereas absolute or relative CA 19-9 reductions with neoadjuvant were not. Final analysis of all 100 patients will be reported.

Impact of relative dose intensity in gemcitabine-cisplatin chemotherapy for metastatic urothelial carcinoma.

Objectives:To evaluate the impact of relative dose intensity for gemcitabine–cisplatin chemotherapy in patients with metastatic urothelial carcinoma.Methods:We retrospectively reviewed the medical records of 18 patients with metastatic urothelial carcinoma, who received gemcitabine–cisplatin regimen as the first-line chemotherapy between 2009 and 2015. The doses of gemcitabine and cisplatin were reduced or the intervals between treatment cycles were prolonged according to the treatment efficacy and adverse events during the first and second cycles. The individually optimal relative dose intensity was set as the actual dose per the standard dose in the first and second cycles. From the third course onward, patients received the gemcitabine–cisplatin chemotherapy with the same relative dose intensity. Overall survival was compared with the groups according to the value of relative dose intensity.Results:The median age was 72.5 (range, 56–79) years and 15 men and 3 women were enrolled in the study. The median number of cycles of first-line gemcitabine–cisplatin chemotherapy was 8 (range, 2–17), and the median survival time from initiation of first-line chemotherapy was 20.1 (range, 3.5–32.8) months. The total median relative dose intensity of gemcitabine–cisplatin chemotherapy was 56.1%. The median survival time of 10 patients in the group with the relative dose intensity of less than 60% was significantly longer than that of 8 patients in the group with the relative dose intensity of more than 60% (19.2 and 11.0 months, respectively, p = 0.04).Conclusion:Individual low relative dose intensity management in the first-line gemcitabine–cisplatin chemotherapy may be an acceptable option for patients with metastatic urothelial carcinoma.

Impact of relative dose intensity and G-CSF use in the adjuvant treatment of resected colon cancer.

752 Background: The benefits of adjuvant chemotherapy in stage III colon cancer (CC) are well established. However, the consequences of dose delays and modifications are not well established. Relative dose intensity (RDI) and dose scheduling have been shown to have prognostic significance in a number of cancers. We examine the effect of RDI, dose intensity (DI) and dose delays on disease free survival (DFS) and overall survival (OS) in stage III CC. Furthermore, we investigate the role of G-CSF in CC and its role in preserving RDI, and its effect on outcomes. Methods: A retrospective review was conducted for patients with stage III CC seen at a Canadian academic cancer center between 2006 and 2011. Patients who received at least three cycles of FOLFOX or at least two cycles capecitabine were included in the analysis. The RDI and DI were calculated and examined for correlation with DFS and OS. The influence of G-CSF on RDI and DI was also investigated. Results: FOLFOX was used more commonly than capecitabine, 64% vs. 36%. Within the FOLFOX regimen median RDI for oxaliplatin was 76.3%, and 83.5% for 5-FU. Median capecitabine RDI was 73.8%. Median DI were similar at 75.4%, 86.5%, and 69.1%, respectively. 60% of patients receiving FOLFOX got over 80% of their intended dose, while only 29% of patients receiving capecitabine achieved this DI. 3-year DFS was higher when RDI or DI was &gt; 80%, compared to ≤ 80%, for each chemotherapeutic, however the differences did not reach significance. 3-year OS trended towards being higher in patients with an RDI and DI &gt; than 80%, however there were limited events in these groups. Over half of patients on FOLFOX experienced a dose delay, 56.9%, most of whom then received G-CSF, 64.9%. Patients who received G-CSF had a higher DI than those who did not, 74.9% and 87.4% versus 66.5% and 76.8%, for the oxaliplatin and 5-FU components, respectively. 3-year DFS and OS was higher in patients who received G-CSF versus those who did not, 78.3% and 97.5% vs. 69.8% and 91.5%, respectively. Conclusions: In patients with stage III colon cancer an RDI or DI is associated with improved 3-year DFS and OS, although the difference did not reach significance in our review. G-CSF as secondary prophylaxis improves RDI, DI, DFS and OS.

High Risk Stage 2 and Stage 3 Colon Cancer, Predictors of Recurrence and Effect of Adjuvant Therapy in a Nonselected Population.

Patients with stage 2 and stage 3 colon cancer often are treated with adjuvant chemotherapy. However, patients seen in daily practice have more comorbidity than those enrolled in clinical trials. This study aims to evaluate prognostic factors for recurrence and to ascertain the benefit of adjuvant chemotherapy on recurrence-free survival (RFS) of patients in a nonselected population. Furthermore, the impact of relative dose intensity (RDI) of adjuvant therapy on RFS is examined. Chart review was performed for 243 consecutive patients diagnosed and treated at a single center for stage 2 and stage 3 colon cancer from 2002 to 2008. Adjuvant chemotherapy was administered to 66 patients. Median overall survival (OS) was 5.84 years and median RFS was 5.37 years. For stage 2 disease, patients treated with or without adjuvant therapy had a median RFS of 5.49 and 5.73, respectively (p = ns). For stage 3 disease, median RFS rates were 5.08 and 1.19, respectively (p = 0.084). Overall RDI of oxaliplatin based chemotherapy higher than median was associated with increased RFS (p = 0.045). In conclusion, adjuvant therapy did not significantly increase recurrence-free survival. This could be the result of comorbidity in patients. Relative dose intensity of oxaliplatin based therapy is associated with RFS.

The impact of dose/time modification in irinotecan- and oxaliplatin-based chemotherapies on outcomes in metastatic colorectal cancer

This study was designed to evaluate (1) the impact of relative dose intensity (RDI) on tumor response and survival outcomes and (2) the influence of dose reduction and schedule modification on outcomes in patients with metastatic colorectal cancer (mCRC). Pooled datasets from two previous phase II trials of FOLFIRI (CCOG-0502; n = 36) and mFOLFOX6 (CCOG-0704; n = 30) in patients with mCRC were analyzed retrospectively. The RDIs of irinotecan and oxaliplatin were compared to response rate (RR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). To assess the effects of dose reduction and schedule modification, the effects of dose index (DI) and time index (TI) on outcomes were evaluated. The median RDIs of irinotecan in FOLFIRI and oxaliplatin in mFOLFOX6 were 80 and 79 %, respectively. Higher RDI of irinotecan in FOLFIRI was associated with significant improvements in RR (65 vs. 6 %, p < 0.01), DCR (100 vs. 59 %, p < 0.01), PFS (9.9 vs. 5.6 months, p < 0.01) and OS (26.7 vs. 12.9 months, p = 0.01) and was the only independent factor associated with PFS [hazard ratio (HR) 8.48, p < 0.01). Higher RDI of oxaliplatin in FOLFOX was significantly associated with DCR (65 vs. 6 %, p < 0.01), and higher TI of oxaliplatin was the only independent factor associated with PFS (HR 2.74, p = 0.04). RDIs of irinotecan and oxaliplatin affected clinical outcomes. Dose reductions in irinotecan, as indicated by DI, and time delays in oxaliplatin, as indicated by TI, were the only independent prognostic factors predicting PFS in patients receiving FOLFIRI and FOLFOX6, respectively.

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.

Impact of relative dose intensity on the outcome of metastatic colorectal cancer.

508 Background: Relative dose intensity (RDI) is the ratio of delivered dose intensity of chemotherapy to standard dose intensity. There is established evidence supporting the significance of RDI in patients with various cancer, however data in patients with metastatic colorectal cancer (mCRC) are limited. In this study, we evaluate the significance of RDI of irinotecan and oxaliplatin-based chemotherapy on the outcome of mCRC. Methods: A retrospective analysis of mCRC patients entered into two prospective clinical trials, testing FOLFIRI (CCOG-0502) and mFOLFOX6 (CCOG-0704), was performed. RDI was calculated as the delivered dose intensity divided by standard dose intensity calculated for each regimen and compared to objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS). Results: The median RDI of irinotecan in FOLFIRI and oxaliplatin in mFOLFOX6 were 80% and 79%. ORRs In higher RDI (&gt;median) group and lower RDI (&lt;median) group were 64.7% and 5.9% of irinotecan (p=0.001), and 46.7% and 33.3% of oxaliplatin (p=0.456). DCRs in higher and lower group were 100% and 41.2% in FOLFIRI (p=0.003), and 100 and 73.3% in mFOLFOX6 (p=0.032). PFS in higher and lower group were 9.9 and 5.6 months in FOLFIRI (p=0.002), and 8.5 and 6.2 months in mFOLFOX6 (p=0.064). Conclusions: RDI of key cytotoxic agents is a significant predictor of disease control in patients with mCRC, especially in irinotecan-based regimen. Dose reductions and treatment delays could be minimized to achieve an RDI of at least 80%.

The economic value of primary prophylaxis using pegfilgrastim compared with filgrastim in patients with breast cancer in the UK

Febrile neutropenia (FN) is a serious adverse event associated with myelotoxic chemotherapy that predisposes patients to life-threatening bacterial infections. Prophylaxis with granulocyte colony-stimulating factors (G-CSFs) from the first cycle of chemotherapy is recommended by the 2006 American Society of Clinical Oncology, 2008 National Comprehensive Cancer Network and 2006 European Organisation for Research and Treatment of Cancer guidelines when the overall risk of FN is approximately 20% or higher. Once-per-cycle pegfilgrastim and daily filgrastim are two commonly used G-CSFs with different dosing schedules and associated costs. To evaluate the cost effectiveness of pegfilgrastim versus filgrastim primary prophylaxis in women with early-stage breast cancer receiving chemotherapy in the UK. A decision-analytic model was constructed from the UK NHS perspective with a lifetime study horizon. The model simulated three clinical scenarios: scenario 1 assumed that pegfilgrastim and filgrastim had differential impact on the risk of FN; scenario 2 assumed additional differential impact on FN-related mortality; and scenario 3 assumed additional differential impact on chemotherapy relative dose intensity (RDI) with long-term survival effects. The base-case population included 45-year-old women with stage II breast cancer receiving four chemotherapy cycles, with an FN risk of approximately 20% or higher. Model inputs, including FN risk, FN case-fatality, RDI, impact of RDI on survival and utility scores, were based on a review of the literature and expert panel validation. Using data from the literature, it was estimated that the absolute risk of FN associated with pegfilgrastim was 5.5% lower than with 11-day filgrastim (7% vs 12.5%), and 10.5% lower than with 6-day filgrastim (7% vs 17.5%). Costs were taken from official price lists or the literature and included drugs, drug administration, FN-related hospitalizations and subsequent medical costs. Breast cancer mortality and all-cause mortality were obtained from official statistics. The main outcome measures were the costs ( pound, year 2006 values) per percentage decrease in (absolute) FN risk, per FN event avoided, per life-year gained (LYG), and per QALY gained. Model robustness was tested using deterministic and probabilistic sensitivity analyses. Pegfilgrastim was cost saving compared with 11-day filgrastim ( pound 3196 vs pound 4315). Compared with 6-day filgrastim, pegfilgrastim was associated with a cost of pound 4200 per FN event avoided, or pound 42 per 1% decrease in absolute risk of FN, in scenario 1. In scenario 2, pegfilgrastim provided 0.055 more LYGs or 0.052 more QALYs at a minimal cost increase of pound 441 ( pound 3196 vs pound 2754) per person, yielding an incremental cost-effectiveness ratio (ICER) of pound 8075/LYG or pound 8526/QALY. In scenario 3, when all potential benefits of G-CSF were considered, the ICER became pound 3955/LYG or pound 4161/QALY. Results were most sensitive to the relative risk of FN for 6-day filgrastim versus pegfilgrastim. In this UK analysis, pegfilgrastim appears to dominate 11-day use of filgrastim. The value of pegfilgrastim versus 6-day filgrastim at pound 4161-8526/QALY was very favourable compared with the commonly used threshold in the UK. In this setting, primary prophylaxis with pegfilgrastim may be cost effective compared with filgrastim.

Impact of relative dose intensity (RDI) in CHOP combined with rituximab (R-CHOP) on survival in diffuse large B-cell lymphoma

BackgroundRecently, maintaining higher relative dose intensity (RDI) of chemotherapeutic drugs has become a widespread practice in an attempt to achieve better outcomes in the treatment of aggressive lymphoma. The addition of rituximab to chemotherapy regimens has significantly improved outcome in diffuse large B-cell lymphoma (DLBL). However, it is unknown if higher RDI in chemotherapy when combined with rituximab leads to a better outcome in aggressive B-cell lymphoma.MethodsWe retrospectively evaluated the impact of the RDI of initial chemotherapy (consisting of cyclophosphamide, doxorubicin, vincristine and prednisolone with rituximab (R-CHOP) on outcome in 100 newly diagnosed DLBL patients.ResultsA multivariate Cox regression model showed that RDI trended towards a significant association with mortality [hazard ratio per 0.1 of RDI = 0.8; 95% confidence interval 0.6–1.0; P = 0.08]. Additionally, on multivariate logistic analysis, advanced age was a significant factor for reduced RDI.ConclusionOur data suggest that in DLBL patients, mortality was affected by RDI of R-CHOP as the initial treatment, and the retention of a high RDI could therefore be crucial.

Adjuvant chemotherapy for breast cancer – prognostic impact of relative dose-intensity.

Abstract Abstract #4109 Introduction: Maintenance of adequate dose intensity (DI) is an important aim in the use of adjuvant chemotherapy for early breast cancer. Some studies report a decreased survival, if the DI is below 80% of the planned dose. We evaluated the rate of decreased DI and its prognostic impact for patients (pts.) treated in our institution between 1990 and 2004. During the long observation period a variety of regimens were used: CMF, normal dosed anthracycline (norA) based regimens (Epirubicin less than 35 mg/sqm*week) and higher dosed anthracyclines (hiA; Epirubicin doses of more than 45 mg/sqm*week).&amp;#x2028; Methods: All patient files were reviewed to calculate relative DI; cycles not applied were treated as a 100% dose reduction. Follow up-data were taken from our institutional prospective data base and the regional tumor registry. Excluded from the analysis were pts. with high dose chemotherapy with stem cell support, rare regimens (less than 10 cases / regimen), pts. switching institution during therapy and pts. progressing during chemotherapy.&amp;#x2028; Results: From 966 pts. receiving adjuvant chemotherapy, 887 matched the inclusion criteria. Mean follow up is 70 months with 260 distant progressions and 234 deaths. 193 pts. received CMF, 442 norA and 252 hiA, 302 pts. received taxanes. Preterm termination of chemotherapy occurred in 77 pts (8.7%), dose reductions in 36 pts. (4.1%). Pts. receiving hiA were at higher risk for dose reductions than with norA and CMF (7.5% vs. 2.9% vs. 2.1%, p=0.015). Mean dose delays were 12.7 days (CMF), 6.4 days (norA) and 5.7 (hiA) (p&amp;lt;0.01, Kruskal-Wallis-test). The mean rel. DI were 90% (CMF), 93% (norA) and 92% (hiA) and significantly different (p=0.01, Kruskal-Wallis-test).&amp;#x2028; In univariate analysis, 5 year-metastasis free survival (MFS, 74% vs. 55%, p=0.002) and overall survival (OAS, 80% vs. 65%, p=0.009) are significantly lower for pts. with a rel. DI of less than 80%. This effect seems more pronounced for norA (OAS 80% vs. 45%), than for CMF (OAS 74% vs. 74%) and hiA (OAS 85% vs. 77%). The adverse effect of low DI was independent of taxan-use. In a cox-regression analysis low DI was not identified as independent predictor for MFS and OAS.&amp;#x2028; Conclusions: Compared to DI reported from most prospective randomised trials the DI in this study seems lower, potentially reflecting patient selection. Dose reductions, delays and preterm termination are common findings, leading to impaired DI. In our study low DI is associated with adverse prognosis in univariate, but not in multivariate analysis. Nevertheless, unnecessary dose modifications should be avoided. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4109.

Cost-Effectiveness of Primary Prophylaxis with Pegfilgrastim Versus Filgrastim in Non-Hodgkin's Lymphoma Patients Receiving CHOP-21.

Prophylaxis with granulocyte colony-stimulating factors (G-CSFs) starting in the first and continuing in subsequent chemotherapy cycles when the risk of febrile neutropenia (FN) is ≥20% is recommended in the 2006 ASCO and EORTC clinical guidelines. Although the daily G-CSF filgrastim (Neupogen®, Amgen Inc.) and the long-acting G-CSF pegfilgrastim (Neulasta®, Amgen Inc.) are both commonly used, in practice filgrastim is often administered for shorter-than-recommended courses, eg, 6 days, which has been shown to be associated with less clinical efficacy. The purpose of this study was to evaluate the cost-effectiveness of primary prophylaxis using pegfilgrastim versus 6-day filgrastim in patients with aggressive non-Hodgkin's lymphoma (NHL) receiving CHOP-21. Without G-CSF support, CHOP-21 is associated with 17%-50% FN risk. We constructed a decision-analytic model from a payer perspective with a life-time study horizon. Outcomes were measured as incremental cost-effectiveness ratios (ICERs) including cost per FN event avoided, cost per life-year-gained (LYG), or cost per quality-adjusted-life-year (QALY) saved. Model inputs including FN risk, FN case-fatality, relative dose intensity (RDI) of chemotherapy, impact of RDI on survival, and utility scores were obtained from a comprehensive literature review. Drug and drug administration costs were obtained from Center for Medicare and Medicaid Services. Cost for FN-related hospitalizations and subsequent medical costs were obtained from the literature. NHL mortality rates and other-cause mortality were based on data from US Surveillance Epidemiology and End Results and National Vital Statistics Reports. Sensitivity analyses were conducted on key variables. Our model simulated 3 clinical scenarios: Scenario 1 included the impact of prophylaxis with pegfilgrastim or filgrastim on FN risk, Scenario 2 included the impact of a difference in FN risk on FN-related mortality, and Scenario 3 included a differential impact on RDI and long-term survival. Extrapolating from the results of a meta-analysis and observational studies, it was estimated that pegfilgrastim decreased the absolute risk of FN by 12% compared with 6-day filgrastim (13.1% versus 25.1%) for a baseline FN risk of approximately 27.9%. Our results showed that compared with 6-day filgrastim, pegfilgrastim was associated with an ICER of $2,133/FN event avoided in Scenario 1, $4,869/LYG or $5,476/QALY saved in Scenario 2, and $1,805/LYG or $2,029/QALY saved in Scenario 3 (Table 1). Key factors influencing ICER estimates included relative risk of FN, cost of pegfilgrastim and filgrastim, and baseline FN risk. Varying these variables within plausible ranges, the ICERs did not exceed $100,000/QALY saved, a commonly cited threshold for judging cost-effectiveness in oncology. Our study suggested that primary prophylaxis with pegfilgrastim is cost-effective compared with filgrastim used for 6 days in NHL patients receiving CHOP-21.Table 1:Cost-effectiveness of pegfilgrastim versus filgrastimCost ($)Scenario 1Scenario 2 (LY)Scenario 2 (QALY)Scenario 3 (LY)Scenario 3 (QALY)Pegfilgrastim15,60813.1%9.358.138.097.01Filgrastim15,35225.1%9.298.087.956.89ICER---$2,133 per FN event avoided$4,869/LY$5,476/QALY$1,805/LY$2,029/QALYICER, incremental cost-effectiveness ratio; LY, life-year; QALY, quality-adjusted life year; numbers may not match due to rounding errors

The Impact of Relative Dose Intensity (RDI) of CHOP on Outcome of Diffuse Large B-Cell Lymphoma: Results of a Single Center Study.

Introduction: The achievement of a clinical response to the first induction chemotherapy has been considered for predicting survival in patients (pts) with aggressive non-Hodgkin lymphoma (NHL). Reduced dose intensity of chemotherapy has been likely to compromise long-term outcome of the patients with aggressive NHL treated with a standard chemotherapy of cyclophosphamide (CY), doxorubicin (ADR), vincristine and prednisone (CHOP). In particular, recent studies have revealed the relevance of relative dose intensity (RDI) to clinical outcomes, with reduced RDI leading to a poor survival, as well as the impact of RDI<85% for aggressive NHL with detailed analysis of risk factors influencing reduce RDI<85% (Gary H. Lyman, J. Clin Oncol 22: 4302, 2004). This study was conducted to investigate the impact of RDI<85% of CHOP on outcomes of the pts with diffuse large B-Cell lymphoma (DLCL).Methods: Data were retrospectively collected on 100 pts with DLCL who had been initially treated with more than 3 courses of CHOP (n=70) or CHOP plus rituximab (CHOP-R, n=30) at our institution between 1995 and 2006. We evaluated whether RDI might affect clinical outcomes, including complete response (CR) and event free survival (EFS). The average RDI derived from CY and ADR (referred to as RDI-CY/ADR) was determined for each patient, with classified into 2 populations according to the differences from the value of 85%, including RDI-CY/ADR<85% (n=60), and RDI-CY/ADR≥85% (n=40).Results: The median age of the study population was 54 years (range, 17 to 76), with 36 pts older than 60 years (yrs) of age. According to International Prognostic Index (IPI) score, pts were classified into 2 groups of low/ low-intermediate (n=46) and high/ high-intermediate (n=54). The overall CR rate reached 62%, and the probability of overall survival (OS) or EFS at 5 years estimated 77% or 43%, respectively with a median follow-up of 13.3 months. Multivariate analysis identified RDI-CY/ADR<85%, as well as IPI score to be associated with CR rate and EFS. Thus, RDI-CY/ADR<85% and IPI score of high/ high-intermediate were significant factors for lower CR rate (as RDI-CY/ADR≥85%, HR=0.3, 95% CI 0.1 to 0.7, p=0.009, and HR=5.5, 95% CI 2.2 to 14, p<0.001, respectively), and for reduced EFS (HR=1.9, 95% CI 1.0 to 3.7, p=0.048, and as IPI score of low/ low-intermediate HR=0.3, 95% CI 0.2 to 0.6, p<0.001, respectively). Furthermore, logrank analysis revealed that CY/ADR-RDI<85% was the significant factor for reduced EFS in non elderly pts (≤60 yrs of age), or in pts with IPI score of low/ low-intermediate (p=0.01, p=0.02, respectively).Conclusion: These data thus suggested the impact of RDI-CY/ADR<85% in influencing outcomes of the pts with DLCL, in terms of CR rate and EFS. Further investigation is currently planned to confirm this promising results with longer follow-up in larger numbers of pts with NHL.

The Impact of Relative Dose Intensity on Response and Survival in a Series of 180 Newly Diagnosed Patients with Hodgkin's Lymphoma.

To improve ABVD results we first developed a protocol which adds G-CSF to the standard ABVD treatment. From March 1997 to May 2004 69 patients with HL were treated with ABVD+G-CSF and 22 with a standard ABVD. Recently we designed a new dose-dense and dose-intensity ABVD scheme (escABVD-21) for advanced HL; in this new schedule the adriamycin was escalated from 25 to 35 mg/m2 (cycles 1,2,3,4) and the inter-cycle period was shortened from 28 to 21 days (for all 6 cycles); primary G-CSF was administered from d3 to d8 and drugs were delivered at d10 and d21 of every cycle. From June 2004, 19 patients were treated with this protocol.Relative dose-intensity (RDI) was calculated for any of these 110 newly diagnosed HL patients treated with ABVD. The results were also compared with a historical group of 70 patients who had undergone hybrid MOPP/ABVD.HL patients received from 4 to 8 cycles of CT +/− IF-RT. Patients were divided in 4 groups according to the RDI. The first group included 20 (11%) pts with RDI less than 0.80; the 2nd group, 64 (36%) pts with RDI values between 0.80 and 0.95, the 3rd group, 74 (42%) pts with RDI values between 0.96 and 1.10 and, finally, the 4th group included pts with RDI values of more than 1.10. In Tab 2 we report the CR, EFS and OS rates according to the 4 levels of RDI. Figures 1 shows EFS curve according to Kaplan-Meyer.Response and survival rates of groups 1,2,3 and 4 were: 50%vs91%vs97% vs 100%, for CR (p<0.0001); 20%vs78%vs92%vs100% for EFS (p< 0.0001); and 25%vs91%vs99%vs100% for OS (p< 0.0001).The best progression rates of CR, EFS and OS were seen in patients with RDI >1.10. In particular, the new dose-dense and dose-intensity escABVD-21 protocol seems very promising in terms of complete response and toxicity profile: 19/19 pts (100%) obtained an early CR; (PET negative at the end of the 2nd cycle), and, as on 8th August 2005, all these19 patients were disease-free. The dose-escalation of adriamycin and the dose-density of the schedule were well-tolerated; toxicity was mild. These results show that subptimal RDI may compromise outcomes proportionally to the level of RDI reduction. On the contrary, Primary G-CSF permits to deliver dose-dense and dose intense schedules such as escABVD-21 maintaining the same profile of toxicity of standard ABVD, higher RDI levels, and consequently, a significant impact on complete response and survival rates.tab1Presentation featuresn. of ptsmale sexage>45 yrsadvanced stageE sites>1bulkyB symptomsIPI score ≥ 3180924314823808356%51%24%82%13%44%46%31%tab.2Response and Survival according to 4 RDI levelsRDI level (range 0.5–1.5)N. of pts. (%)CR rateFisher's Exact test (2-sided)EFS ratelog-rank statistic0S ratelog-rank statisticoverall180(100%)90%80%88%<0.8020 (11%)50%20%25%0.80–0.9564 (36%)91%28.39178%74.9991%96.760.96–1.1076 (42%)97%92%99%>1.1020 (11%)100%100%100%significance<0.0001<0.0001<0.0001 [Display omitted]