EORTC Guidelines Research Articles

Febrile Neutropenia Risk Assessment and Granulocyte-Colony Stimulating Factor Support in Patients with Diffuse Large B Cell Lymphoma Receiving R-CHOP Regimens.

Abstract 107 BACKGROUND:ASCO and EORTC guidelines recommend granulocyte colony-stimulating factor (G-CSF) primary prophylaxis for cancer patients with a ≥20% overall risk of febrile neutropenia (FN), and to support delivery of dose-dense regimens. CHOP-like regimens (with rituximab [R]) are the current standard of care for the management of aggressive non-Hodgkin lymphoma (NHL), but they are often associated with significant myelosuppression. Neutropenic events, particularly febrile neutropenia (FN), can be life-threatening and may lead to dose delays or reductions that compromise the efficacy of chemotherapy. In IMPACT NHL, we evaluated current practice in FN risk assessment and use of G-CSF prophylaxis in patients receiving (R)CHOP. METHODS: IMPACT NHL is a retrospective and prospective observational study conducted in 14 European countries and Australia. Physicians assessed the overall FN risk of NHL patients and their need for G-CSF prophylaxis. This analysis focuses on patients with diffuse large B-cell lymphoma (DLBCL) receiving either 2-weekly R-CHOP-14 or 3-weekly R-CHOP-21. FN risk was assessed according to EORTC guidelines (i.e. the total risk from the chemotherapy regimen plus individual patient risk factors). The primary outcome measure was the proportion of patients assessed as being at ≥20% risk of FN and who were planned to receive primary prophylaxis with a G-CSF (defined as G-CSF initiation within days 1-7 of cycle 1). RESULTS: Data were available for 1829 patients who initiated chemotherapy between 01/2005 and 08/2008; 1136 had DLBCL. The mean age±SD of patients receiving R-CHOP-21 (N=704) was 62.6±13.8 years, 51% were aged ≥65 years and 53% had Stage III-IV disease. For R-CHOP-14 patients (N=409), the mean age was 58.4±14.7 years, 41% were ≥65 years and 59% had Stage III-IV disease. In total, 434 R-CHOP-21 patients were assessed as being at high risk for FN and 47% of them actually received G-CSF primary prophylaxis (with either pegfilgrastim or daily G-CSF) (see Table). Furthermore, almost a fifth of patients assessed as being at <20% FN risk received G-CSF primary prophylaxis. Across all cycles, 29% of R-CHOP-21 patients had an unplanned hospitalization, with neutropenia/FN being the main reason. Subsequently, 67% of patients achieved a relative dose intensity (RDI) of ≥90% of their planned treatment (with respect to cyclophosphamide, doxorubicin, and vincristine). In the R-CHOP-14 group, 16% of patients did not receive G-CSF primary prophylaxis; 32% had an unplanned hospitalization and 59% of patients achieved '90% of their planned RDI.TableFN risk assessment, G-CSF support and FN outcomes in patients receiving R-CHOP-21 or R-CHOP-14R-CHOP-21R-CHOP-14Overall FN risk assessment≥20%<20%N/AN434266409G-CSF PP recommended per guidelinesYesNoYes (dose dense)G-CSF PP planned237 (55%)46 (17%)348 (85%)G-CSF PP given205 (47%)47 (18%)345 (84%)FN* in any cycle89 (21%)43 (16%)81 (20%)FN* in cycle 145 (10%)17 (6%)24 (6%)RCHOP: rituximab, cyclophosphamide, doxorubicin, vincristine, prednisonePP: primary prophylaxis*FN defined as absolute neutrophil count <0.5 × 109/L (or <1.0 × 109/L and predicted to fall <0.5) and fever CONCLUSIONS:Half of R-CHOP-21 patients assessed as high risk for FN did not receive G-CSF primary prophylaxis despite physicians' awareness of elevated risk, while primary G-CSF support was not given to almost one fifth of R-CHOP-14 patients, contrary to guideline recommendations. Both R-CHOP-14 and R-CHOP-21 resulted in significant myelotoxicity (with substantial FN even in those evaluated as being at lower risk), and only around two-thirds of patients received optimal chemotherapy RDI. Our data suggest that improvements in neutropenia management are required. More consistent use of G-CSF primary prophylaxis may further reduce FN and assist in optimal chemotherapy delivery.Sponsored by Amgen Disclosures:Salar:Amgen: Honoraria. Haioun:Roche: Research Funding; Amgen: Other, Research Funding; Celgene: Other, Research Funding; Mundipharma: Research Funding. Pettengell:Amgen: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau; Bayer: Honoraria, Speakers Bureau. Jaeger:Amgen: Research Funding. Schwenkglenks:Amgen: Honoraria, Research Funding. Bacon:Amgen: Employment, Equity Ownership. Bendall:Amgen: Employment.

A Prospective Observational Study Exploring the Impact of Iron Status On Response to Darbepoetin Alfa in Patients with Chemotherapy Induced Anemia.

Abstract 2007Poster Board I-1029 Background:Chemotherapy-induced anemia (CIA) is a complication of cancer therapy. Erythropoiesis Stimulating Agents (ESA) increase hemoglobin (Hb) concentration, if folate, vitamin B12 and iron levels are sufficient. Patients and Methods:This multicenter, prospective observational study explored response to darbepoetin alfa (DA) (Aranesp®) 500 μg Q3W or 300 μg Q2W in correlation with iron status in cancer patients with CIA. Secondary objectives were: safety and Hb outcome, Hb concentration at treatment initiation, and prescription behavior of physicians. All anemic patients foreseen to receive DA were enrolled in a registry. Data on baseline (BL) characteristics were collected. Subsequently, patients with normal vitamin B12 and folate were eligible for follow-up (FU). Results:481 adult cancer patients with CIA (defined as Hb <11 g/dL as per EORTC guidelines (2007) and DA label at time of recruitment), treated in 26 oncology and hematology centers in Belgium and Luxemburg between December 2006 and April 2008, were enrolled in the registry. Mean ±SD age was 63.7±11.5 years; 42.5% of patients were male. Most patients (87.5%) had a solid tumor, mainly NSCLC, breast and colorectal cancer, and 54.4% were metastatic. DA treatment was initiated before the 4th cycle of chemotherapy in 82.5% of patients, planned to be synchronised with chemotherapy in 73.5% of patients and DA 500 μg Q3W was the most prescribed dose schedule (76.8%) in patients with solid and hematological tumors. Of the 481 enrolled subjects, 414 subjects were eligible for FU (396 subjects with available Hb data, and 379 subjects with available iron data). For patients with available Hb data (n=396), the mean ±SD Hb was 9.9±0.7 g/dL (range: 9.8-10) at inclusion and 10.9±1.7 g/dL (range: 10.7-11.1) at end of treatment. Hb target (≥11 g/dL) was reached by 87.4% (KM estimate; 95% CI: 81.2-92.3) of patients after a median time of 39.0 days (KM est.; 95%CI: 29.0-42.0). Iron deficiency was defined as having a Ferritin <100 ng/ml and/or TSAT <20% at inclusion or at any time on study. Of the 396 patients, 170 (42.9%) were iron deficient (ID) at inclusion. Hb target was achieved by 85.9% (KM est; 95%CI: 75.8-93.3) of patients with ID at inclusion vs 87.8% (KM est; 95%CI: 79.1-94.2) of patients without ID at inclusion. Among these iron deficient patients 20% received DA + iron. Hb target was reached more often (KM est: 100%) in these patients than in those not receiving iron treatment (KM est: 75.9%; 95% CI: 62.7-87.1) and the median time to target was also shorter (KM est: 28.5 days; 95% CI: 21.0-43.0) with iron than without (KM est: 42.0 days; 95% CI: 34.0-56.0). For patients with available iron FU data (n=379), the number of patients with ID at any time on study was 197 (52%). Thirty-six of these patients received DA + iron and reached Hb target after a median time of 28.5 days (KM est; 95% CI: 21.0-42.0) compared to 47.0 days (KM est; 95% CI: 35.0-62.0) for subjects not receiving iron. Among patients who were never iron-deficient during the study (101/379), 16 were given iron supplement and reached Hb target faster (KM est. median time: 21.0 days; 95% CI: 9.0-21.0, vs. 32.0 days; 95% CI: 21.0-55.0) than those not supplemented. The number of patients needing blood transfusion was similar regardless of iron deficiency at inclusion (KM est: 32.0% for ID vs. 35.5% for non ID). The DA treatment was safe: 5 patients reported moderate adverse drug reaction, none of them being serious. Conclusions:DA administered to cancer patients with CIA increased their Hb levels. Iron supplementation in iron deficient patients improved DA effectiveness although additional investigation is needed to draw any firm conclusions. Disclosures:Beguin:Amgen: Research Funding. Bosly:Amgen: Research Funding.

CHOICE, an international, observational study to examine current practice use of darbepoetin alfa in the management of chemotherapy-induced anaemia

Introduction In February 2008, the European product label for darbepoetin alfa (DA) in the treatment of chemotherapy-induced anaemia (CIA) was changed to stipulate target haemoglobin (Hb) values between 10 and 12 g/dL. EORTC guidelines on ESA use state similar Hb target levels. The primary aim of this study is to assess adherence to the recommended Hb target range in patients (pts) receiving DA in routine clinical practice. Methods This prospective, multicenter, observational study evaluated the routine clinical practice use of DA in 11 European countries in pts with various non-myeloid malignancies (breast, colorectal, ovarian and lung cancer) at any time during chemotherapy treatment. Key outcome measures were Hb levels and the requirement for red blood cell (RBC) transfusions. Results 336 (mean±SD age 61.8±10.9 years) out of 1300 pts were included in this interim analysis. 80 pts had breast, 57 colorectal, 131 lung (33 small cell lung and 98 non-small cell lung cancer) and 68 ovarian cancer. 25% and 61% of pts had stage 3 and 4 disease at baseline, respectively. At baseline, 60% of all pts (53% of breast cancer and 62% of lung cancer pts) had a baseline Hb value of At week 9, Hb values for 243 pts (72%) were available. Of these, 136 pts (56%) had Hb levels between 10 and 12 g/dL, 59 pts (24%) had a Hb value > 12 g/dL and for 48 pts (20%), a Hb value below 10 g/dL was reported. The Kaplan-Meier percentage of pts with Hb levels ⩾10 g/dL was 89% (see table). The Kaplan-Meier percentage of pts requiring RBC transfusions from week 5 to end of treatment period was 17% (see table). A median DA dose of 500 μg was administered 3 times (median). Additional efficacy outcomes are presented in the table below. A treatment related non-serious adverse drug reaction (back pain) was reported for one patient only. Table 1Efficacy outcomes Total Breast cancer Lung cancer n (%) 336 (100) 80 (24) 131 (39) Hb (g/dL )at baseline, mean (SD) 9.8 (0.8) 9.9 (0.7) 9.7 (0.9) Hb (g/dL)at EOTP, mean (SD) 10.8 (1.6) 11.2 (1.4) 10.5 (1.7) K-M Hb⩾10 (g/dL) from wk 1 to EOTP, % (95% CI), na 89 (84, 95), 202 91 (82,101), 42 94 (85,102), 81 K-M RBC transfusions from wk 1 to EOTP, % (95% CI), n 26 (20, 31), 336 19 (8, 29), 80 37 (27, 46), 131 K-M RBC transfusions from wk 5 to EOTP, % (95% CI), nb 17 (12, 23), 208 12 (2, 22), 50 24 (14, 35), 72 CI, confidence interval; Hb, haemoglobin; EOTP, end of treatment period; K-M, Kaplan-Meier; RBC, red blood cell; wk, week.aOnly patients with Hb Conclusions This interim analysis suggests that the majority of pts were treated according to the European product label for DA and EORTC guidelines and did not surpass Hb levels of 12 g/dL. Furthermore, only 17% needed RBC transfusions from week 5 to end of treatment period. These data further support the effectiveness of DA for the treatment of pts with CIA. Sponsored by Amgen GmbH.

P45 Clinical impact and QoL in older colon cancer patients after chemotherapy

P45 Clinical impact and QoL in older colon cancer patients after chemotherapy

Use of analysis of iron metabolism with CRP-dependent ferritin index and reticulocyte hemoglobin to determine treatment strategy for chemotherapy-related anemia

e20510 Background: Intravenous iron (IV Fe) can increase the efficacy of erythropoiesis stimulating agents (ESA). However it is still unsettled whether all patients (pts) do so. We conducted a phase II trial to analyze various parameters for the addition of IV Fe to ESA in chemotherapy treated anemic cancer pts. Methods: Pts with an indication for ESA following the EORTC guidelines and a serum ferritin (SF) level ≥20ng/ml were screened in a central laboratory. Those with a C-reactive protein (CRP)-dependent ferritin index (FI = soluble transferrin receptor (sTFR)/log ferritin ratio) above threshold (* FI ≥3.2 if CRP &lt;5mg/l, or FI &gt;2.0 if CRP ≥5 mg/l) were treated with iron only. Those with a sub-threshold FI received Epoetin beta (Epo) 30.000E/wk sc., and from these, those with a reticulocyte hemoglobin (Hb) content (CHr) ≤28pg/ml additionally received Fe-saccharat 200mg/wk iv up to 1g. Results: 11 centers recruited 303 pts (median age 65y, male 41%) from 10/04 to 10/06; 230 (76%) had a sub threshold FI (group Q I+IV), of whom 23 (8%, Q IV) had a CHr ≤28pg. 73 pts (24%) had an increased FI (Q II+III), indicating relative iron deficiency, of whom 27 (9%, Q III) had a CHr ≤28pg. There was no correlation between assignment to one of the groups (Q I-IV) and age, gender, body-mass-index, type or stage of tumor, endogenous Epo level, and hematokrit. In 265 pts evaluable for response Hb on d1 was 9.8 ±1.2 g/dl (mean ± SD) and 10.7 ±1.3 g/dl in 4th week. Mean increase of Hb from d1 to 8th week was 1.4 ± 1.7 g/dl. 36% pts received a transfusion within 12 weeks and 18% after the 4th week. The table shows response according to groups. Conclusions: At study onset we expected nearly all pts to receive Epo and searched for those who might have a benefit from additional IV Fe. However, we conclude in synopsis with other studies, that all pts might have a benefit from IV Fe but only 76%, those with a sub-threshold FI, have a benefit from Epo. [Table: see text] [Table: see text]

Validation of the Mexican-Spanish version of the EORTC QLQ-C15-PAL questionnaire for the evaluation of health-related quality of life in patients on palliative care

e20557 Background: Health-related quality of life (HRQL) is a fundamental outcome in oncology and this is particularly important in the palliative care setting. Our aim was to validate the Mexican-Spanish version of the EORTC QLQ-C15-PAL questionnaire, which is a brief version of QLQ-C30, for the measure of HRQL in terminal patients with cancer. Methods: Patients attending the Palliative Care Unit at the Hospital from July to October 2008 with terminal cancer, diagnosed by biopsy and without any active anti-neoplasic treatment were included in this study. Mexican-Spanish version of the EORTC QLQ-C15-PAL questionnaire was used to measure HRQL. Linear transformation of scale scores were done after EORTC guidelines. Correlation analysis was done obtaining the Spearman correlation coefficient and the Cochran alpha. Association of clinical parameters and scale scores were analyzed using one-way ANOVA and Chi-squared test. Test-retest comparison was tested using ANOVA for repeated measurements. Survival analysis was performed using the Kaplan-Meier and Cox's methods. Results: Eighty-three patients were enrolled in this study (mean age of 61.2 years). Compliance rates were high; all patients answered the questionnaire in less than 20 minutes and it was well-accepted. Five missing values in five different items were found. Scales in the QLQ-C15 distinguished between other clinically distinct groups of patients. Multi-trait scaling analysis demonstrated good convergent and discriminant validity. Cronbach's alpha coefficients were &gt;0.7 in three of four multi-item scales. Test-retest scores were obtained from 25 patients and scores were consistent. Emotional function, Dyspnea, Insomnia and Appetite scales demonstrated an important association with overall survival by multivariate analysis (p&lt;0.05). Conclusions: The Mexican-Spanish version of EORTC QLQ-C15-PAL questionnaire is reliable and valid for HRQL measurement in terminal patients with cancer, and appropriate for its use in clinical trials in Mexican patients. No significant financial relationships to disclose.

Managing cancer-related anaemia in congruence with the EORTC guidelines is an independent predictor of haemoglobin outcome: Initial evidence from the RESPOND study

Purpose To model the relationship between scores for practicing in congruence (CSs; 0–10) with EORTC guidelines for erythropoietic proteins (EPs) and haemoglobin (Hb) outcomes observed in the validation study of the RESPOND system. Methods Thirty four patient pairs matched on cancer type and chemotherapy in pre- (retrospective; clinicians not using RESPOND) and post-cohorts (prospective; clinicians using RESPOND) followed over 4 months following EP treatment initiation. CSs quantify the extent that care was guideline-adherent. Linear and logistic regressions controlling for cohort examined Hb outcomes as a function of CSs. Results A one-point increase in CS was associated with 0.60 g/dL increase in Hb at month 4 ( R 2 = 0.40) and 0.56 g/dL increase in Hb change from month 1–4 ( R 2 = 0.33). Each one-point increase in CS increased the odds of reaching Hb ⩾ 11 g/dL by 3.14 ( R 2 = 0.42) and Hb ⩾ 12 g/dL by 2.77 ( R 2 = 0.45). Conclusion Guideline-adherent EP treatment may improve Hb outcomes but specifically designed outcomes studies are necessary.

Analysis of Hypochromic Reticulocytes and Ferritin Index as a Rationale for An Effective Therapy of Cancer- and Chemotherapy-Associated Anemia

Introduction: In most cancer patients anemia will be attributable to the mechanisms of chronic disease compounded by the myelotoxic effect of chemotherapy. Nevertheless it is important to exclude alternative explanations such as iron deficiency before starting therapy with erythropoiesis stimulating agents (ESA). Recently Thomas et al. (Clin Chem 2002; 48:1066-76) combined the reticulocyte hemoglobin (Hb) content (CHr) with the C-reactive protein (CRP)-dependent ferritin (Fer) index (FI: soluble transferrin receptor/ log Fer ratio) in a diagnostic plot (DP). We conducted a prospective phase II trial to analyze the diagnostic value of CHr, FI and the DP in anemic chemotherapy treated cancer patients (pts).Methods: Informed consenting pts with an indication for ESA therapy as per EORTC guidelines and a ferritin level ≥20ng/ml were screened with the DP in a central laboratory. DP classifies pts in 1 of 4 quadrants (Q1 – Q4). Those with FI values above threshold (FI ≥3.2 if CRP < 5mg/l, or FI > 2.0 if CRP ≥5 mg/l) were assigned to Q2 (CHr > 28 pg) or Q3 (CHr ≤ 28 pg), and those with sub threshold FI values to Q1 (CHr > 28 pg) or Q4 (CHr ≤ 28 pg). Pts in Q1 received Epoetin beta (Epo) 30.000E/wk sc., those in Q4 additionally Fe-saccharat 200mg/wk iv up to 1g. Pts in Q2 + 3 were treated with oral or iv iron only.Results: 11 centers recruited 303 pts (median age 65 y, male 41%) from 10/04 to 10/06; 230 (76%) had a sub threshold FI (Q1+4), of whom 23 (8%) had a CHr ≤28pg (Q4). 63 pts (21%) fell in Q2+3 with an increased FI, indicating relative iron deficiency, of whom 27 (9%) had a CHr ≤28pg (Q3). There was no correlation between assignment to Q1−4 and age, gender, body-mass-index, type or stage of tumor, measurable metastasis, bonemarrow infiltration, performance status, endogenous epo level, and haematocrit. However, Hb was lower and CRP was higher in Q4. RBC were higher in Q2+3, as leucocytes and thrombocytes were in Q3+4 and transferrin saturation in Q1. In 265 pts. evaluable for response Hb on d1 was 9.8 ± 1.2 g/dl (mean ± SD) and 10.7 ± 1.3 g/dl in 4th week. Mean increase of Hb from d1 to 8th week was 1.4 ± 1.7 g/dl. 36% pts. received a transfusion within 12 weeks and 18% after the 4th week. The table shows response according to Q1−4.Conclusions: Overall response rate was comparable to other ESA studies. However pre therapeutic analysis of hypochromic reticulocytes and ferritin index in the diagnostic plot identifies about a quarter of pts, which were classified in Q2/3 due to elevated FI and had a good response receiving iron only. 8% pts with hypochromic reticulocytes and a sub threshold FI (Q4) had the best Hb-response with epo + iv iron.Table: Response to treatment per quadrant in the diagnostic plotN 265FI < threshold *<threshold*<=?=” ?=”” ??=”/” span=””></threshold*<=?=”>FI ≥ threshold *CHr >28 pg therapy Hb g/dl mean ± SD d1 4thweek Δ Hb 8th wk-d1 mean ± SD median g/dl (Quartile) % pts. with transfusions within 12 weeks after 4th weekQ1 N 194 (73%) Epo only9.9 ± 1 10.7 ± 1.3 1.3 ± 1.5 1.1 (0.3–2.1) 41% 22%Q2 N 31 (12%) Iron only9.6 ± 2 10.4 ± 1.3 1.6 ± 2.4 1.5 (−0.1–2.4) 19% 3%CHr ≤ 28 pg therapy Hb g/dl mean ± SD d1 4thweek ΔHb 8th wk-d1mean ± SD median g/dl (Quartile) % pts. with transfusions within 12 weeks after 4th weekQ4 N 21 (8%) Epo + iv iron9.2 ± 1 10.6 ± 1.4 2.3 ± 2 2.2 (0.3–4.1) 33% 19%Q3 N 19 (7%) Iron only 9.2 ± 1.1 10.9 ± 1.1 1.5 ± 1.5 2 (0.1–2.6) 16% 5%* FI ≥2.0 if CRP <5 mg/l, or FI >3.2 if CRP ≥5 mg/l

Diagnosis of invasive aspergillosis using Galactomannan assay in pediatric patients with cancer

20522 Background: Invasive aspergillosis (IA) is an important cause of increased mortality and morbidity in immunocompromised patients. Early diagnosis is difficult as microbiological culture techniques have low sensitivity and the radiological tools have low specificity. Some adult studies have concluded that serial determination of Galactomannan by sandwich Elisa (GM Assay) is a sensitive tool for the diagnosis of IA in patients at risk. Due to the paucity of data in the pediatric age group we evaluated utility of GM Assay in diagnosis of IA in pediatric cancer patients. Methods: This is a prospective study, which included high-risk pediatric cancer patients admitted with fever at Sir Ganga Ram Hospital from Oct 2006 to Dec 2007. They were receiving chemotherapy for malignancy with neutropenia <500 neutrophils/mm3 for >10 days, bone marrow transplant - allogeneic/autologous, relapsed acute lymphoblastic leukemia and acute myeloid leukemia. GM assay was done twice weekly in each episode. GM assay index >1.0 was taken as positive. CT chest/sinus and Broncho-alveolar lavage (BAL) was performed as per protocol. IA was classified as Proven, Probable, Possible and No fungus as per EORTC Guidelines. Results: A total of 95 serum samples for GM Assay were collected during 34 episodes of fever (Febrile neutropenia - 23 episodes). 34/95 (36%) GM assay serum samples were positive. 4 had proven IA, 6 had Probable IA, 3 had Possible IA and 21 had No fungus as per EORTC guidelines. 11 patients had evidence of suspected IA in CT Chest. BAL was done in 6 episodes, out of which 2 episodes had evidence of Aspergillus. The GM Assay conducted in this study had a sensitivity of 90% and specificity of 80%. It had a positive predictive value of 64% and negative predictive value of 95%. GM assay was negative in 2 episodes where Piperacillin-Tazobatum was used. Conclusion: Serial GM Assay is highly sensitive for diagnosis of IA in high-risk pediatric cancer patients. This test has a good negative predictive value in ruling out IA in immunosuppressed children. Results of GM Assay of episodes with Proven, Probable, Possible and No IA Patient case category Positive GM Negative GM Total episodes Proven IA 3 1 4 Probable IA 6 0 6 Possible IA 2 1 3 No Fungus 2 19 21 Total 13 21 34 No significant financial relationships to disclose.

Evidence-based management of anemia in cancer patients: Validity of RESPOND, a web-based clinical guidance system based on the EORTC guidelines

20573 Background: The EORTC has published evidence-based guidelines for the management of anemia using erythropoiesis- stimulating agents (ESA). We previously described background/validation methodology (Van Erps et al, ASCO 2007 abstr 19633) and content validity results (Foubert et al, ASCO 2007 abstr 19676) for the RESPOND system. Concurrent, discriminant, and predictive validity are reported here. Methods: 68 patients (2x34) matched by gender, cancer type, and treatment, and managed prior to (pre-cohort) and after introduction of the EORTC guidelines (post-cohort). Endpoint: congruence score (CS) with EORTC guidelines. Results: See Table 1 for CS results. Mean CS for the pre-cohort was 3.0 (SD=1.5; 95% CI 2.5–3.5), for the post-cohort 8.2 (SD=1.4, 95% CI 7.7–8.7). Concurrent validity was inferred from the high mean CS for post-cohort. Discriminant validity was inferred from the statistically significant difference between M±SD CSs for both cohorts (p<.00001) and higher likelihood of the post-cohort to have Hb ≥11g/dL (OR=3.6, 95% CI 1.1–11.8) and ≥12g/dL (OR=2.9, 95% CI 1.1–8.1). Predictive validity was inferred from significant Hb differences at each of the 4 visits and HbΔ from visit 1 to 4 (all at least p<.03), interaction effect for time and cohort (p=.006), regression slope coefficient of 0.3g/dL HbΔ increase for every 1 CS point increase, and CS predicting likelihood of Hb ≥11g/dL (OR=1.5, 95% CI 1.2–2.0) and ≥12g/dL (OR=1.5, 95% CI 1.2–1.8). Conclusions: RESPOND has now been shown to have content, concurrent, discriminant, and predictive validity. This validation study identified areas where web-based clinical guidance can improve guideline-adherent anemia management: ruling out or treating other causes of anemia, initiating ESA treatment, setting Hb target range, fixed initial dosing per ESA evidence, and achieving target range at 4–8wks; and where good practice is reinforced in terms of managing starting Hb levels at <9g/dL or between 11.0–11.9g/dL. Congruence scores (0-10) for pre-cohort and post- cohort Rule out/treat iron deficiency, bleeding, nutritional deficits, hemolysis 0.25 each 0% 85–100% p<.0001 ESA Rx initiated at Hb 9–11g/dL 1 6% 100% p<.0001 If Hb<9g/dL: patient considered for blood transfusion; or: not applicable 1 80% 88% p=ns If Hb 11.0–11.9g/dL: pt individually considered for ESA Rx; or: not applicable 1 100% 100% p=ns Target Hb range set at 12–13g/dL 1 0% 100% p<.0001 Initial ESA dose: 40K alfa Q1W; 30K beta Q1W; darbepoetin Q1W or Q3W 1 41% 100% p<.0001 Initial ESA dose fixed 1 3% 100% p<.0001 Target achieved at 4–8wks; if not: individualized dose escalation 1 21% 53% p=.006 Hb maintained at 12–13g/dL up to 8 weeks .125/wk 21% 38% p=ns ESA discontinued if Hb≥13g/dL (or 12–23g/dL at end of study) 1 29% 50% p=ns Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Roche Roche Roche

Response evaluation by CT and FDG-PET/CT in malignant pleural mesothelioma

11098 Background: To evaluate the prognostic value of response evaluation by CT and FDG - PET in patients with malignant pleural mesothelioma undergoing chemotherapy. Methods: Patients with malignant mesothelioma were prospectively recruited and evaluated by FDG - PET/CT before and after three cycles of chemotherapy with pemetrexed and cisplatin or carboplatin. Patients with talc pleurodesis within 6 months prior were excluded. The response assessments were: Conventional CT-response using modified RECIST (<- 30%; -30% - +25%; >+25%), mean and maximum standardized uptake value (SUVmax/mean) using the EORTC guidelines (<-25%; -25% - +25% >+25%). Volume based analysis was done by total lesion glycolysis (TLG) and total glycolysis volume (TGV). Reduction of TLG and TGV was grouped in <-80%; -80% - -40%; >-40%. The prognostic value of PET and CT data was evaluated using the Cox Regression Model. Results: 37 patients with a mean age of 63 years (44 - 74 years) were included in the study between February 2002 and June 2004. Median survival after the first PET/CT scan was 491.4 days. All patients died within the observation period. Follow up CT using modified RECIST after three cycles of chemotherapy showed partial response in 9 patients, stable disease in 27 patients and progressive disease in 1 patient. Follow up PET showed partial response in 13 patients, stable disease in 20 patients and progressive disease in 4 patients using EORTC criteria. RECIST response in the CT scan correlated with overall survival (p=0.0037). Change of SUVmax according to EORTC was not a significant predictor of survival (p=0.69). Reduction of TLG and TGV according to the defined groups correlated with overall survival (TLG p=0.0095; TGV p=0.0054). The Cox Regression showed the best correlation with survival in combining response criteria of TLG, TGV and modified CT RECIST criteria (p=0.0014). Conclusions: Morphological response using modified RECIST criteria in CT and functional volume based response in FDG-PET both have prognostic value in patients treated with combined pemetrexed and platin chemotherapy. Our data suggest an advantage of combining morphological CT and functional imaging. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Eli Lilly

Development of a European Organization for Research and Treatment of Cancer Module to Assess the Quality of Life of Patients With Proctitis After Pelvic Radiotherapy for Malignancy

To describe the development of a proctitis-specific quality-of-life module to supplement the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). The module was developed according to EORTC guidelines, which consisted of an extensive literature review to identify previously described issues and interviews conducted with seven health professionals and 10 patients to rationalize the item list for construction into a provisional module. The module developed was then pretested with 28 patients and five health professionals. The final module contains 21-items that are suitable to obtain information about the patients' quality of life after high-dose pelvic irradiation. The questionnaire has now been translated into four languages and commenced field testing in late 2007. The EORTC QLQ-C30, supplemented by EORTC QLQ-PRT21, will enable health professionals to more accurately monitor the side effects that patients experience after pelvic irradiation.

Erythropoiesestimulierende Substanzen: günstiges Sicherheitsprofil bei indikationskonformer Anwendung

Several studies with erythropoiesis-stimulating agents (ESAs) have raised a number of safety issues. Therefore, a discussion of available data in light of the current EORTC guidelines 2006 on the use of ESAs in anemic patients is warranted. Literature is reviewed with respect to experimental and clinical data on the effect of ESA therapy on tumor growth both in the preclinical setting and on patient survival. Studies showing an adverse effect of ESA therapy on patient survival generally exhibit considerable methodological deficiencies. Moreover, they investigated treatment situations for which ESAs are not approved and/or did not involve recommended baseline ("intervention") or target hemoglobin levels. When used as indicated, ESAs are valuable and safe drugs for the treatment of anemia and do not negatively affect patient survival. In particular, the data situation confirms the importance and correctness of the EORTC guidelines 2006 and their recently updated version. It is therefore recommended that these guidelines continue to be strictly followed in the treatment of chemotherapy-induced anemia.

EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer: 2006 update

EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer: 2006 update

IVB.4 EORTC guidelines on anaemia: adapting to senior adults

The treatment of relapsed and refractory plasma cell myeloma is a real challenge, especially in case of resistance to proteasome inhibitors and immunomodulatory drugs (IMiDs). The situation is complicated by the lack of commonly accepted therapeutic guidelines. This study summarizes therapeutic strategies used to treat recurrent plasma cell myeloma in Polish population before 2015, when bortezomib has become available in the first-line therapy. We focused mainly on the use of IMiDs and proteasome inhibitors. To analyze the situation medical records of patients treated in 21 Polish hematological centers have been reviewed. In total data on 400 patients were analyzed and extrapolated to the national level to obtain data on 7293 patients (400/7293). Mean number of applied therapies was 1.7. Half of the patients were treated with two or more chemotherapy regimens. Second-line therapy most commonly included: VD, PAD, thalidomide in monotherapy and MP regimen. Combinations of two drugs, namely lenalidomide, thalidomide or bortezomib with dexamethasone, were most often used in third-line therapy. Fourth-line treatment most commonly consisted of MPT regimen and dexamethasone monotherapy. At least PR was observed in 73%, 82%, and 50% of patients treated with II, III and IV-line therapy, respectively. Complications were observed in at least half of the patients regardless the type of treatment. Polyneuropathy and myelotoxicity were the most common adverse events.The outcome of recurrent plasma cell myeloma treatment in Polish patients was relatively good, probably because of rare use of bortezomib and lenalidomide in first-line therapy.

Early vs. late treatment with darbepoetin alfa in patients with genitourinary tumors during chemotherapy

18583 Background: Anemia is a common complication in patients who receive anticancer therapy. We evaluated the efficacy of darbepoetin alfa in early vs. late treatment in patients with genitourinary tumors undergoing chemotherapy. We wanted to investigate whether an early onset of treatment with darbepoetin alfa reduces frequency of red blood cell transfusion and increases patients’ QoL. Methods: Patients on chemotherapeutic treatment for a urogenital neoplasia and a hemoglobin between 10–12 g/dl were randomized between an immediate start of treatment with darbepoetin alfa 150 μg sc weekly (group A) and a Hb below 10 g/dl or clinical symptoms (group B). Results: 52 patients out of 68 (76.5%) completed the trial, 7/40 patients (17%) in group A and 9/28 patients (32%) in group B withdraw from the study. An intent to treat analysis was performed and showed a significant superiority (p = 0.023, log-rank test) for the early treatment. In group A, only 12.5% of patients (5/40) received at least one red blood cell transfusion compared to group B, where 39% of the patients (11/28) received a transfusion. In group A the mean Hb level increased steadily, starting with a baseline value of 11.0 g/dl. In week 21 a mean Hb level of 12.8 g/dl was reached, resulting in an overall increase in Hb of 1.8 g/dl. In group B, which had a comparable baseline Hb level of 10.9 g/dl, the mean Hb value decreased initially during the first 4 weeks to 10.0 g/dl. In week 21 a level of 11.4 g/dl was reached, resulting in a total Hb-increase of 0.5 g/dl. When anemia treatment was initiated early, the mean Hb level always remained in the range of 11 to 13 g/dl from the beginning of the study, in the B group the mean level of 11 g/dl was first achieved after 12 weeks. 35% in group A compared to 54% in group B (p = 0.13) experienced a dose doubling. The mean values (EORTC-QLQ-C30) of all symptom scales in group A were markedly below those in group B with the highest difference for dyspnea, 29.1 points (p &lt; 0.001). Conclusions: Early treatment with darbepoetin alfa in patients with urogenital cancer results in optimal hemoglobin levels according to EORTC guidelines and consequently in a reduction of red blood cells transfusion. Furthermore, in patients with earlier initiation of treatment a clinically significant improvement of dyspnea can be observed. [Table: see text]

EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphomas and solid tumours

Chemotherapy-induced neutropenia is not only a major risk factor for infection-related morbidity and mortality, but is also a significant dose-limiting toxicity in cancer treatment. Patients developing severe (grade 3/4) or febrile neutropenia (FN) during chemotherapy frequently receive dose reductions and/or delays to their chemotherapy. This may impact on the success of treatment, particularly when treatment intent is either curative or to prolong survival. The incidence of severe or FN can be reduced by prophylactic treatment with granulocyte-colony stimulating factors (G-CSFs), such as filgrastim, lenograstim or pegfilgrastim. However, the use of G-CSF prophylactic treatment varies widely in clinical practice, both in the timing of therapy and in the patients to whom it is offered. While several academic groups have produced evidence-based clinical practice guidelines in an effort to standardise and optimise the management of FN, there remains a need for generally applicable, European-focused guidelines. To this end, we undertook a systematic literature review and formulated recommendations for the use of G-CSF in adult cancer patients at risk of chemotherapy-induced FN. We recommend that patient-related adverse risk factors such as elderly age (⩾65 years), be evaluated in the overall assessment of FN risk prior to administering each cycle of chemotherapy. In addition, when using a chemotherapy regimen associated with FN in >20% patients, prophylactic G-CSF is recommended. When using a chemotherapy regimen associated with FN in 10–20% patients, particular attention should be given to patient-related risk factors that may increase the overall risk of FN. In situations where dose-dense or dose-intense chemotherapy strategies have survival benefits, prophylactic G-CSF support is recommended. Similarly, if reductions in chemotherapy dose intensity or density are known to be associated with a poor prognosis, primary G-CSF prophylaxis may be used to maintain chemotherapy. Finally, studies have shown that filgrastim, lenograstim and pegfilgrastim have clinical efficacy and we recommend the use of any of these agents to prevent FN and FN-related complications, where indicated.

Early change in glucose metabolic rate (MRGlu) measured using FDG-PET in patients with high grade glioma (HGG) and correlation with response to temozolomide, and temozolomide + radiotherapy

1532 Background: Temozolomide plus radiotherapy should now be the standard of care for patients with HGG (Stupp et al 2004; J Clin Oncol 22, 14S:2). We have previously shown that PET measurements of MRGlu can predict temozolomide response (Brock et al 2000; Br J Cancer 82:608–615). In this study, we compared the ability of PET to predict response to temozolomide vs temozolomide plus radiotherapy. Methods: 19 patients with HGG were studied. Patients with recurrent glioma received temozolomide 75mg/m2 daily for 7 weeks (n=8). Newly diagnosed patients received temozolomide 75mg/m2 daily plus radiotherapy 60Gy/30# over 6 weeks, followed by 6 cycles of adjuvant temozolamide (n=11). FDG PET scan and MRI were performed at baseline, and 7 and 19 weeks following initiation of treatment. Changes in MRGlu and MRI response were correlated with patient survival. Results: In patients receiving temozolomide alone, we confirmed our previous finding that early changes in MRGlu predicted response. Patients who survived >26 weeks vs ≤26 weeks showed a greater reduction in MRGlu measured at 7 weeks with median reductions of -34% and -4%, respectively (p=0.02). PET responders, defined as a reduction in MRGlu ≥25% (EORTC Guidelines 1999 Eur J Ca 35:1773–1782), had a longer survival than non-responders with mean survival times of 75 wks [95% CI 34–115] vs 20 wks [95% CI 14–26] (p=0.0067). In the small group of patients studied, there was no relationship between MRI response and survival (p=0.52). For patients receiving radiotherapy, there was no difference in survival between PET responders and non-responders (p=0.32). However, when PET response was measured 19 weeks following the initiation of treatment, there was a trend for increased survival in PET responders compared with non-responders (n=11, p=0.16). Conclusions: Early changes in MRGlu predict response to temozolomide, but not temozolomide plus radiotherapy. This may be due to the infiltration of tumours by glycolytic inflammatory cells following radiotherapy. FDG-PET assessment of radiotherapy response should be made later than for chemotherapy. No significant financial relationships to disclose.

EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer

Anaemia is frequently diagnosed in patients with cancer, yet it is difficult to identify a single cause due to its multifactorial aetiology. We conducted a systematic literature review (1996–2003) to produce evidence-based guidelines on the use of erythropoietic proteins in anaemic patients with cancer (see Table 4). Level I evidence exists for a positive impact of erythropoietic proteins on haemoglobin (Hb) levels when administered to patients with chemotherapy-induced anaemia or anaemia of chronic disease, when used to prevent cancer anaemia, in patients undergoing cancer surgery and following allogeneic bone marrow transplantation. The Hb level at which erythropoietic protein therapy should be initiated is difficult to determine as it varied between studies; a large number of Level I studies in patients with chemotherapy-induced anaemia or anaemia of chronic disease enrolled patients with a Hb concentration ⩽105 g/L, but none compared the effect of different baseline Hb levels on the response to treatment. Similarly, several studies defined the target Hb concentration as 120–130 g/L following treatment with erythropoietic proteins, but none specifically addressed the correlation between target Hb level and clinical benefit in a randomised fashion. Level I evidence shows that red blood cell (RBC) transfusion requirements are significantly reduced with erythropoietic protein therapy in patients with chemotherapy-induced anaemia or when used to prevent cancer anaemia (approximately 20% reduction compared with controls). We found indirect Level I and III evidence that patients with chemotherapy-induced anaemia or anaemia of chronic disease initially classified as non-responders to standard doses proceed to respond to treatment following a dose increase (absolute increases in response rate ranged from 8% to 18%). However, none of these studies examined the effect on response rates of a longer treatment period at the lower dose, or performed a randomised comparison of a dose increase versus an unchanged dose. There is Level I evidence to show that quality-of-life (QOL) is significantly improved in patients with chemotherapy-induced anaemia and in those with anaemia of chronic disease, particularly in patients achieving a Hb response to erythropoietic protein therapy. There are insufficient data to determine the effect on survival following treatment with erythropoietic proteins in conjunction with chemotherapy or radiotherapy. There is Level I evidence that dosing of erythropoietic proteins less frequently than three times per week (TIW) is efficacious when used to treat chemotherapy-induced anaemia or prevent cancer anaemia. There is Level III evidence that initial doses of erythropoietic proteins considered to be higher than current standard practice produce higher haematological responses in patients with chemotherapy-induced anaemia or anaemia of chronic disease. Level I evidence demonstrates that several baseline patient parameters (e.g., low endogenous erythropoietin [EPO] concentration, age <60 years, Hb concentration ⩾90 g/L) impact upon the response to erythropoietic proteins when used to treat chemotherapy-induced anaemia or prevent cancer anaemia. Evidence indicates that endogenous EPO concentration impacts on response in patients with lymphoproliferative malignancies, but is not a valid parameter in patients with solid tumours. There is Level I evidence that fixed doses of erythropoietic proteins can be used at the start of therapy to treat patients with chemotherapy-induced anaemia, but maintenance doses should be titrated individually. There is no evidence that pure red cell aplasia (PRCA) occurs following treatment with erythropoietic proteins in patients with chemotherapy-induced anaemia or when used prophylactically in patients with cancer. There is Level I evidence that the risk of thromboembolic events and hypertension are slightly elevated in patients with chemotherapy-induced anaemia receiving erythropoietic proteins. Level I evidence supports the effectiveness of erythropoietic proteins to prevent anaemia in non-anaemic cancer patients receiving chemotherapy or radiotherapy or in those undergoing cancer surgery. However, these are non-licensed indications and we do not currently recommend the prophylactic use of erythropoietic proteins to prevent anaemia in patients who have normal Hb values at the start of treatment. Additional trials are warranted, especially on the issues of iron replacement and cost-effectiveness of erythropoietic protein therapy, as well as on tumour response/progression and survival.

EORTC Guidelines show in which patients erythropoietin works

EORTC Guidelines show in which patients erythropoietin works