Susana Esteves

A Pilot Cost-Effectiveness Analysis of Treatments in Newly Diagnosed High-Grade Gliomas: The Example of 5-Aminolevulinic Acid Compared With White-Light Surgery

BACKGROUND: High-grade gliomas are aggressive, incurable tumors characterized by extensive diffuse invasion of the normal brain parenchyma. Novel therapies at best prolong survival; their costs are formidable and benefit is marginal. Economic restrictions thus require knowledge of the cost-effectiveness of treatments. Here, we show the cost-effectiveness of enhanced resections in malignant glioma surgery using a well-characterized tool for intraoperative tumor visualization, 5-aminolevulinic acid (5-ALA). OBJECTIVE: To evaluate the cost-effectiveness of 5-ALA fluorescence-guided neurosurgery compared with white-light surgery in adult patients with newly diagnosed high-grade glioma, adopting the perspective of the Portuguese National Health Service. METHODS: We used a Markov model (cohort simulation). Transition probabilities were estimated with the use of data from 1 randomized clinical trial and 1 noninterventional prospective study. Utility values and resource use were obtained from published literature and expert opinion. Unit costs were taken from official Portuguese reimbursement lists (2012 values). The health outcomes considered were quality-adjusted life-years, life-years, and progression-free life-years. Extensive 1-way and probabilistic sensitivity analyses were performed. RESULTS: The incremental cost-effectiveness ratios are below €10 000 in all evaluated outcomes, being around €9100 per quality-adjusted life-year gained, €6700 per life-year gained, and €8800 per progression-free life-year gained. The probability of 5-ALA fluorescence-guided surgery cost-effectiveness at a threshold of €20000 is 96.0% for quality-adjusted life-year, 99.6% for life-year, and 98.8% for progression-free life-year. CONCLUSION: 5-ALA fluorescence-guided surgery appears to be cost-effective in newly diagnosed high-grade gliomas compared with white-light surgery. This example demonstrates cost-effectiveness analyses for malignant glioma surgery to be feasible on the basis of existing data. ABBREVIATIONS: 5-ALA, 5-aminolevulinic acid ICER, incremental cost-effectiveness ratio LY, life-year PFLY, progression-free life-year QALY, quality-adjusted life-year

Clinical Outcomes of 217 Patients with Acute Erythroleukemia According to Treatment Type and Line: A Retrospective Multinational Study

Acute erythroleukemia (AEL) is a rare disease typically associated with a poor prognosis. The median survival ranges between 3–9 months from initial diagnosis. Hypomethylating agents (HMAs) have been shown to prolong survival in patients with myelodysplastic syndromes (MDS) and AML, but there is limited data of their efficacy in AEL. We collected data from 210 AEL patients treated at 28 international sites. Overall survival (OS) and PFS were estimated using the Kaplan-Meier method and the log-rank test was used for subgroup comparisons. Survival between treatment groups was compared using the Cox proportional hazards regression model. Eighty-eight patients were treated with HMAs, 44 front line, and 122 with intensive chemotherapy (ICT). ICT led to a higher overall response rate (complete or partial) compared to first-line HMA (72% vs. 46.2%, respectively; p ≤ 0.001), but similar progression-free survival (8.0 vs. 9.4 months; p = 0.342). Overall survival was similar for ICT vs. HMAs (10.5 vs. 13.7 months; p = 0.564), but patients with high-risk cytogenetics treated with HMA first-line lived longer (7.5 for ICT vs. 13.3 months; p = 0.039). Our results support the therapeutic value of HMA in AEL.

Abstract P1-15-03: Comparison of efficacy of primary prophylaxis with pegfilgrastim, filgrastrim and a biosimilar filgrastim in TAC regimen (docetaxel, doxorubicin and cyclophosphamide):

Background: Febrile neutropenia (FN) is a major toxicity of myelosupressive chemotherapy. Primary prophylactic use of granulocyte colony stimulating factors (G-CSF) is recommended in high risk FN regimens. The comparison of pegfilgrastim (Peg) and filgrastim (Fil) FN prophylactic effectiveness is still an issue of debate. Very recently Nivestim (Niv), a new biosimilar filgrastim, has also become commercially available. We aimed to compare the efficacy of the 3 mentioned types of G-CSF in the primary prophylaxis of FN. Methods: Single-center, retrospective study to evaluate the incidence of FN in women with breast cancer treated with adjuvant or neo-adjuvant TAC (FN risk ≥20%). Patients (Pt) were divided in 3 consecutive cohorts according to G-CSF primary prophylaxis (Fil, Peg and Niv) FN was defined as axillary temperature ≥38,3 °C and absolute neutrophil count Results: We included a total of 421 women (median age 51 y, 25–76) with Stage II (56%) and Stage III (44%) breast cancer. Age and stage distribution were similar in the 3 cohorts. A single dose of Peg was administered in all 767 cycles (cy). The standard dose of Fil and Niv was 7 daily injections, only in in 13% Fil pt and 10% Niv pt The incidence of FN per patient and per cycle is presented in Table 1. In all cohorts, approximately half of NF episodes occurred in the 1st cycle (48% Fil, 59% Peg, 42% Niv). Conclusions: No differences in terms of efficacy existed between Biosimilar Niv and original biological reference Fil. Seven daily injections of Fil and Niv seem equivalent to single dose Peg. Besides efficacy, questions like cost-effectiveness and convenience of administration should be taken into account when approaching this topic. Our data showed a predominance of events in the 1st cycle (regardless of the type of G-CSF). This has been consistently described in the literature and may support the necessity to recommend other NF preventive measures in this cycle. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-15-03.

Incidence and risk factors for Central Nervous System thrombosis in paediatric acute lymphoblastic leukaemia during intensive asparaginase treatment: a single-centre cohort study.

Central Nervous System (CNS) thrombosis is a complication of acute lymphoblastic leukaemia (ALL) treatment that is potentially associated with significant morbidity and neurological sequelae. Its presumably multifactorial aetiology is poorly characterized. We conducted a single‐centre, retrospective cohort study on 346 ALL paediatric patients (1–16 years old) treated with asparaginase intensive Dana Farber Cancer Institute (DFCI) protocols from 1998 to 2011. The incidence, risk factors and outcome of CNS thrombosis were evaluated. CNS thrombosis occurred in 3·8% (13/346) of the patients (95% confidence interval 2·0–6·3%). Twelve events were diagnosed during intensification, all of which resolved within 2 weeks without neurological sequelae or significant impact in survival. Obesity (body mass index above 95th percentile) and asparaginase formulation were the only factors associated with CNS thrombosis, with an increase in the odds of event in obese patients [odds ratio (OR) = 3·37; P = 0·064] and a reduction in patients receiving Erwinia asparaginase (OR = 0·12; P = 0·018). No association could be demonstrated for age, gender, DFCI risk‐group, ALL phenotype, steroid or doxorubicin use, central venous line use or CNS radiotherapy. CNS thrombosis is a rare but manageable adverse event without significant sequelae or detrimental effects in survival. Increased awareness is recommended in obese patients particularly during intensive asparaginase use.

Clinical outcomes of AML patients treated with Azacitidine in Portugal: A retrospective multicenter study

Retrospective data was collected from 77 elderly acute myeloid leukemia (AML) patients treated with Azacitidine (AZA) and 50 elderly AML patients treated with intensive chemotherapy (IC) from 4 Portuguese Hospitals. Median OS was 10.6 months in those receiving AZA as 1st line. Response (overall response rate 44%) had a significant impact on overall survival (p=<0.0001). Median OS of the comparator IC cohort was significantly inferior to that observed in the cohort treated with AZA in first line (p=0.0104). These results support the efficacy of AZA in AML in the elderly in any line of treatment.

Adjuvant chemotherapy with TAC (docetaxel, doxorubicin, and cyclophosphamide) in patients with breast cancer--incidence of neutropenic fever outside clinical trials.

To the Editor: In a phase III trial in node-positive breast cancer, adjuvant chemotherapy with TAC improved diseasefree and overall survival as compared to FAC (5FU, doxorubicin and cyclophosphamide) but with a high incidence of neutropenic fever (NF, 24.7% versus 2.5% of patients) (1). A subsequent trial showed that primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) reduces the incidence of NF with TAC from 24% to 6.5% of patients (2) but there are little data outside the clinical trials setting. Our aim was to assess the hematologic toxicity of TAC chemotherapy with primary prophylaxis with filgrastim, in patients treated in our referral cancer centre outside clinical trials. All consecutive women treated with adjuvant TAC chemotherapy for node-positive breast carcinoma at our Institution between October 2004 and April 2007 were included. Patients were identified through hospital pharmacy and day-hospital records. Clinical charts and pharmacy dispensing records were reviewed for collection of patient and disease characteristics, treatment administration, toxicity, and filgrastim prophylaxis administration. All patients had a blood cell count before day one of each cycle. No routine cell blood counts were done in between, unless determined by clinical events that led to nonprogrammed hospital visits. NF was defined as axillary temperature above 38 C associated with an absolute neutrophil count (ANC) below 500 ⁄lL, regardless of the need for hospital admission. Descriptive statistics are described as median and ranges. Two-sided 95% confidence intervals (CI) for sample proportions were estimated. This retrospective study included 147 female patients (median age 52 years, range 27–70 48% premenopausal) who had completed treatment at the time of analysis. The majority had T1 (40%) and T2 (56%) tumors; all but one had at least one positive axillary lymph node on pathologic examination (55% one to three, 29% four to nine and 16% ten or more positive nodes); 76% tumors were hormone-receptor positive; 29 tumors were HER-2 ⁄ neu positive and 108 were negative (10 undetermined ⁄ unknown). All patients had undergone primary surgery – breastconserving surgery in 57% and modified radical mastectomy in 43%. All patients received TAC as described by Martin et al. (1) but no prophylactic antimicrobials. Of the 147 patients, 134 received all six scheduled cycles while 12 received less due to prior neutropenic fever or infection (six), neurotoxicity (one), docetaxelhypersensitivity (four) and neutropenia without fever or infection (one); one patient received seven cycles of TAC. Overall, 840 cycles of TAC were administered, (median 6 per patient, range 1–7). There were 31 treatment delays and two dose reductions (Table 1). All patients received primary prophylaxis with filgrastim. Two patients switched to pegfilgrastim (Neulasta; Amgen, Thousand Oaks, CA) on the first and fifth cycles of chemotherapy, respectively. One hundred and thirty-one (89%) started filgrastim prophylaxis between cycle day 2 and 4 and 16 (11%) between days 5 and 9. Thirty patients (20%) received filgrastim for less than 7 days in at least one cycle. The duration of filgrastim administration was less than 7 days in 104 (12%) cycles and 7 days or more in 729 (87%) cycles; pegfilgrastim was given in seven cycles (1%). In some patients filgrastim treatment was continued beyond 7 days due to the development of NF, persistence of neutropenia or NF in a prior cycle. There were 27 NF episodes (3.2% of cycles; CI 2.2–4.7%). Twenty patients had one single episode, Address correspondence and reprint requests to: JL Passos-Coelho, MD, PhD, IPOLFG, Rua Professor Lima Bastos, 1099-023 Lisboa, Portugal, or e-mail: passoscoelho@sapo.pt.

Surgery vs. primary radiotherapy in early-stage oropharyngeal cancer

Background Early-stage oropharyngeal squamous cell carcinoma (OPSCC) can currently be treated by surgical resection or definitive radiotherapy (RT). The aim of this study is to review the outcomes of early-stage OPSCC submitted to surgery or primary RT. Preliminary results have shown similar overall survival (OS) and locoregional recurrence-free survival (LRFS). Material/Methods Retrospective study of patients with cT1-T2 cN0-N1 OPSCC, diagnosed between January 2009 and December 2014, treated with surgery or primary RT. Results 61 patients with cT1-T2 cN0-N1 OPSCC were included. Forty-two (69%) were submitted to surgical resection, of which 37 (88%) had adjuvant treatment (24 received RT and 13 chemoradiotherapy). Nineteen (31%) were treated with primary RT, and 3 of them had concurrent chemotherapy. RT was given with intensity-modulated radiation therapy (IMRT) (71%) or three-dimensional conformal radiation therapy (3D-CRT) (29%). At a median follow-up of 5.4 years, there were 3 tumor persistences, 5 local failures, 2 regional failures and no distant metastasis. The 3-year and 5-year OS were 77% and 71% in the RT group vs. 71% and 59% in the surgery group, respectively (HR 0.60, 95% CI 0.22–1.61; p = 0.30). The 3-year and 5-year LRFS were 71% and 64% in the RT group vs. 66% and 50% in the surgery group, respectively (HR 0.59, 95% CI 0.24–1.45; p = 0.24). Up to 34% had acute grade 3 toxicity and 11% had grade 4 osteoradionecrosis of the jaw. Conclusions Longer follow-up still does not show a significant difference in OS and LRFS between both treatments. Because most patients submitted to surgery required adjuvant RT and since its side-effects were not negligible, further studies are warranted to better suit the first treatment for each patient and to prevent the need for adjuvant treatment and the risk of toxicity.

Abstract P4-12-14: Distress as a measure of the psychological impact after disclosure of a BRCA1/2 positive test result

Introduction and objectives- A positive result after BRCA1/2 screening can represent a difficult psychological experience. Previous studies have shown that the psychological outcomes following BRCA1/2 testing vary according to the previous individual and family experiences of each person. Objectives of this study were to measure the distress caused by the disclosure of a positive BRCA1/2 test result and to analyse the degree of BRCA1/2 carriers retention of information, transmitted at the post-test counselling interview. Material and Methods-This is a prospective study. All consecutive individuals with a BRCA1/2 positive test were invited to participate, after the post-test counselling visit. Participation involved signing an informed consent form and agreeing to a structured post-test phone interview, one week and one month after disclosure of the test result. Phone interviews were done by nurses trained by the Psychological Unit of our centre. Measure instruments: 1) Emotional thermometer (ET) - analogical scale ranging from 0 (no distress) to 10 (maximum distress), measures distress during the previous week 2) Distress questionnaire (DQ)- 13 items to evaluate depression, anxiety and loss of emotional control, with a global score ranging from 3 (no distress) and 45 (maximum distress). 3) Knowledge of disease status and understanding of the individualized risk management plan- additional 4 items included at the end of DQ. Subgroup analysis was performed according to age, sex, previous cancer diagnosis and offspring existence using Wilcoxon rank sum test with continuity correction. Results-From 177 eligible carriers, 28 were not included (14 for logistical reasons; 2 deaths; 1 refused; 3 progressive symptomatic disease ). A total of 149 carriers were included: 120 women (81%) and 29 men (19%); median age 43 yrs (21-74); 67 (45%) with a previous cancer diagnosis and 82 (55%) healthy at risk; 42 (28%) had no offspring and 102 (68%) were professionally active. The mean distress scores were 3.07 (SD 2.72) and 20.13 (SD 7.88) for ET and DQ instruments, respectively. Using the NCCN (2013) guidelines for ET classification, we found that 95 (64%) of our carriers did not have clinically significant distress. For the DQ (using a cut-off Subgroup analysis: A statistically significant difference was found with both ET and DQ for higher distress levels in women than men (p=0.006 and p than 50yrs), previous cancer diagnosis or with vs no offspring. Levels of knowledge and understanding of individual risk management were high (average 18.7; maximum 20) and no correlation was found with distress levels. Twenty-eight (19%) carriers were found in need of specialized psychological/psychiatric support and were appropriately referred. Conclusions-In our BRCA1/2 carrier population clinically significant distress was not frequent and only 19% needed specialized psychological/psychiatric support. Distress was higher in women than in men. Retention of information given during counselling was high, and there was no correlation between information retention and distress levels. Citation Format: Joana Parreira, Susana Esteves, Fatima Vaz, Carla Simoes, Paula Rodrigues, Ana Luis, Ana Clara, Sandra Bento, Maria Jesus Moura. Distress as a measure of the psychological impact after disclosure of a BRCA1/2 positive test result [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-12-14.

1028PSINONASAL ADENOCARCINOMA (SNA) - EXPERIENCE OF AN ONCOLOGY CENTER

Introduction and Objectives: Sinonasal tumours represent only 3% of all head and neck cancers. Adenocarcinoma is the second most frequent histopathology type. Hardwood exposure has been considered a risk factor. Sinonasal adenocarcinoma grows silently which leads to a late diagnosis and low survival rates. The aim of this study was to present our experience in the management of the patients with sinonasal adenocarcinoma. Method: Retrospective medical records review of patients with sinonasal adenocarcinomas (1974 to 2009). Results: From 301 patients with sinonasal tumors, 67 had histology of adenocarcinoma. Patient average age was 60.1 ± 11.1 years (30 - 84 years). 83.6% were man. 65.7% had history of working with wood. 70.1% of the patients had advance disease. The most common treatment strategy was external surgery (lateral rhinotomy (47.8%), sublabial (17.9%) or cranio-facial resection (6%)) or endoscopic approaches with postoperative radiotherapy. The 3 and 5 years overall survival rate were 60% and 49%, respectively. Conclusions: Our group study showed similar epidemiologic characteristics than other series. We confirmed sinonasal adenocarcinomas tendency to late diagnosis and wood dust exposure relation. In our experience, the limited surgical treatment (without craniofacial resection) and postoperative radiotherapy has good survival rates results, similar to other departments who consider the craniofacial resection as the standard treatment.