M1 Pts Research Articles

MP11-13 CLINICAL FRACTURE INCIDENCE IN METASTATIC HORMONE-SENSITIVE PROSTATE CANCER (mHSPC) AND RISK-REDUCTION FOLLOWING ADDITION OF ZOLEDRONIC ACID TO ANDROGEN DEPRIVATION THERAPY (ADT) WITH OR WITHOUT DOCETAXEL (DOC): LONG-TERM RESULTS FROM 2 PHASE 3 TRIALS FROM THE STAMPEDE PLATFORM PROTOCOL

You have accessJournal of UrologyCME1 Apr 2023MP11-13 CLINICAL FRACTURE INCIDENCE IN METASTATIC HORMONE-SENSITIVE PROSTATE CANCER (mHSPC) AND RISK-REDUCTION FOLLOWING ADDITION OF ZOLEDRONIC ACID TO ANDROGEN DEPRIVATION THERAPY (ADT) WITH OR WITHOUT DOCETAXEL (DOC): LONG-TERM RESULTS FROM 2 PHASE 3 TRIALS FROM THE STAMPEDE PLATFORM PROTOCOL Craig Jones, Ashwin Sachdeva, Laura Murphy, Macey Murray, Louise Brown, Eugene McCloskey, Janet Brown, Gerhardt Attard, Mahesh Parmar, Nicholas James, Matthew Sydes, and Noel Clarke Craig JonesCraig Jones More articles by this author , Ashwin SachdevaAshwin Sachdeva More articles by this author , Laura MurphyLaura Murphy More articles by this author , Macey MurrayMacey Murray More articles by this author , Louise BrownLouise Brown More articles by this author , Eugene McCloskeyEugene McCloskey More articles by this author , Janet BrownJanet Brown More articles by this author , Gerhardt AttardGerhardt Attard More articles by this author , Mahesh ParmarMahesh Parmar More articles by this author , Nicholas JamesNicholas James More articles by this author , Matthew SydesMatthew Sydes More articles by this author , and Noel ClarkeNoel Clarke More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003226.13AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Long-term ADT is recommended for men with mHSPC: bone loss and increased fracture risk are known complications. The STAMPEDE trial compared ADT±docetaxel (Doc)±zoledronic acid (ZA): adding ZA did not improve overall survival (OS) but long-term effects of bisphosphonate treatment on skeletal health was not formally collected as part of the trial. Accessible, high quality, routinely-collected healthcare data (RCHD) enables analysis of outcome data beyond standard trial follow-up to evaluate long-term treatment toxicity and clinical efficacy of ZA as a bone protective agent in mHSPC. The Hospital Episode Statistics (HES) database provides RCHD for patients in England and Wales. METHODS: HES data up to 2018 were obtained for patients (pts) randomised 2:1 between ADT (Arm A) and ADT+ZA (Arm B), or ADT+Doc (Arm C) or ADT+Doc+ZA (Arm E). ZA (4 mg) was six 3-weekly cycles, then 4-weekly for 2 years. Clinical fracture events were identified using a bespoke pre-specified coding framework of International Classification of Diseases (ICD 10) diagnosis and Classification of Interventions and Procedures (OPCS 4) procedure codes. Multivariate Cox regression models were developed to adjust for age, N stage, WHO performance status, Gleason score and NSAID use to determine impact of ZA on fracture risk. RESULTS: Connected datasets were available for 2,145 eligible pts (796 M0, 1,349 M1) of 2,962 (72%). Overall, 5-year fracture incidence was 6.4%; higher in M1 pts (9.6% in M1 vs 2.1% in M0, p<0.0001), and lower amongst M1 pts allocated ZA (4.55% with ZA vs 12.9% without ZA, p<0.0001) (Figure 1). ZA significantly reduced fracture risk in M1 pts (HR 0.36, 95% CI 0.22-0.57, p<0.0005) but not in M0 pts (HR 0.67, 95% CI 0.32-1.39, p=0.28). CONCLUSIONS: By accessing RCHD, we evaluated long-term fracture events amongst patients in STAMPEDE. Fracture rates were clinically notable in M1 and reduced significantly in pts allocated ZA with ADT±Doc. These data support using bone protective agents to reduce clinically significant fractures in mHSPC. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e129 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Craig Jones More articles by this author Ashwin Sachdeva More articles by this author Laura Murphy More articles by this author Macey Murray More articles by this author Louise Brown More articles by this author Eugene McCloskey More articles by this author Janet Brown More articles by this author Gerhardt Attard More articles by this author Mahesh Parmar More articles by this author Nicholas James More articles by this author Matthew Sydes More articles by this author Noel Clarke More articles by this author Expand All Advertisement PDF downloadLoading ...

Efficacy of enzalutamide (ENZA) plus androgen deprivation therapy (ADT) in men with de novo (M1) metastatic hormone-sensitive prostate cancer (mHSPC) versus progression to mHSPC (M0): Post hoc analysis of the phase III ARCHES trial.

102 Background: In ARCHES (NCT02677896) ENZA + ADT reduced the risk of radiographic progression-free survival (rPFS) events, primary endpoint, and improved key secondary endpoints vs PBO + ADT in men with mHSPC (also known as metastatic castration-sensitive PC). Given the progressive nature of PC, this exploratory analysis evaluated efficacy of ENZA + ADT in patients (pts) who progressed to M1 HSPC following initial diagnosis (M0) vs pts who presented with de novo mHSPC at diagnosis (M1). Methods: mHSPC pts (n=1150) were randomized 1:1 to ENZA (160 mg/day) + ADT or PBO + ADT, stratified by disease volume and prior docetaxel use. In this post hoc analysis, pts previously centrally categorized as MX/unknown metastasis at initial diagnosis (n=213) were adjudicated as either M0 or M1 disease following review of their medical profiles; efficacy outcomes were compared according to M0 vs M1 disease at initial diagnosis. Results: In this analysis, 246 pts (ENZA n=117; PBO n=129) had M0 and 890 pts (ENZA n=448; PBO n=442) had M1 disease at initial diagnosis; metastatic status of 14 pts (ENZA n=9; PBO n=5) were unknown (data not shown). Baseline characteristics were generally comparable between treatment arms; however, a greater proportion of M1 pts had high disease volume (n=606; 68.1% vs n=116; 47.2% [M0]) and prior docetaxel (n=173, 19.4% vs n=29, 11.8% [M0]). ENZA + ADT improved rPFS vs PBO + ADT irrespective of M0 or M1 disease at diagnosis; similar improvements were observed for secondary endpoints including prostate-specific antigen (PSA) and objective responses, time to PSA progression, time to new antineoplastic therapy (Table). Safety profiles were generally similar between subgroups and the overall population; exceptions include higher fatigue in M0 ENZA and PBO treatment arms. Conclusions: This post hoc analysis demonstrates clinical benefit of ENZA + ADT vs PBO + ADT based on rPFS and secondary endpoints in men who progressed from M0 to M1 HSPC and those with de novo M1 HSPC. Clinical trial information: NCT02677896. [Table: see text]

844O - Docetaxel for hormone-naïve prostate cancer: Results from long-term follow-up of metastatic (M1) patients in the STAMPEDE randomised trial (NCT00268476) and sub-group analysis by metastatic burden

844O - Docetaxel for hormone-naïve prostate cancer: Results from long-term follow-up of metastatic (M1) patients in the STAMPEDE randomised trial (NCT00268476) and sub-group analysis by metastatic burden

Multidisciplinary osteoncologic approach to bone metastases: Analysis of a large, mono-institutional cohort.

159 Background: Bone metastases are responsible for high morbidity in patients (pts) with a strong clinical impact. Recently, a new multidisciplinary approach called osteoncology has benn develped. No data on multidisciplinary management of large series of patients (pts) with bone cancer disease are available. Methods: We reviewed clinical data of all the consecutive pts evaluated from Apr 2013 to Dec 2016 in the multidisciplinary Osteoncology clinic of Istituto Oncologico Veneto. We collected clinical data on primary diasease, sites of disease, pain, bone clinical and radiological situation, assesment and medical decision taken in a multidisciplinary team. Results: 481 pts (303 F, 63%) have been evaluated by a multidisciplinary team composed by medical and clinical oncologist, pain specialist, endocrinologist, radiologist and ortopedic surgeon. Totally, 444 visits and 340 discussione have been performed. 422 pts (88%) had bone metastases, median age 65 years (range 34-89). 388 pts (92%) had vertebral metastases, 167 (39%) had pelvic bone disease, 201 (47%) had other site of bone disease including extremities. 186 (39%) pts had pain. We have prescribed a corset for 151 (31%) pts, radiation therapy for 202 (42%) pts with a median time from prescription to delivery of 15 days. Vertebroplastic has been prescribed in 66 (14%) pts with a median time for delivery of 7.5 days. 33 (7%) pts received indication to orthopedic surgery with a median waiting time of 15 days. For 115 pts data on pain at visit and 30 days later were available: 41 pts had no change in NRS, 11 pts had a worst paint (median NRS Δ = +2), 63 pts had a pain reduction (median NRS Δ = -3). 301 pts received a diagnosis of SRE. Median OS (mOS) was 80.9 months; at 2 yrs 91% of M0 pts vs 75.8% of M1 pts was alive (p = 0.0018); mOS for pts with a SRE was 70 vs 89.5 mos in pts without SRE (p = 0.033); among M1 pts, there was no significant difference from having or not a SRE. Conclusions: To our knowledge this is the first reported series of pts evalutated by an osteoncologic team. OS confirms that pts with SRE had a poorer outcome. Median time from prescrition to care delivery is shorter from data available in literature, conferming the positive impact for pts from multidisciplinary approach.

Small cell carcinoma of the bladder (SCCB): Clinical, histopathologic, and genomic predictors of clinical outcomes.

294 Background: SCCB is a rare, aggressive subtype of bladder cancer. We reviewed our center’s experience in SCCB management and investigated potential markers of clinical outcomes. Methods: SCCB cases were identified and re-reviewed for confirmation by detailed histologic evaluation. A subset of SCCB was sequenced with MSK-IMPACT ( &gt; 279 genes) (Cheng et al J Mol Diagn 2015). Clinical stage, treatment response and proportion of neuroendocrine component (%NE) were correlated with progression-free (PFS) and overall survival (OS), calculated from the time of cystectomy. Distribution of somatic alterations (alts) was compared between responders ( ≤ ypT1pN0) and nonresponders. Results: Between 1985 and 2015, 214 SCCB patients (pts) were identified. Median age was 68 years (range: 38 – 94) and 78% were male. Of 199 pts with sufficient data, 147 (74%) were nonmetastatic (M0) and 52 pts (26%) had metastatic disease (M1). 14 pts did not receive SCCB-directed therapies. Of M0 pts, 108 underwent cystectomy: 71 received neoadjuvant (NAC), 14 received adjuvant, 14 had definitive chemoradiotherapy and 23 did not receive chemotherapy. Of M1 pts, 47 received chemotherapy. Cystectomy only pts were older than NAC pts (76 vs 67 years, p &lt; .01). NAC improved PFS and OS compared to cystectomy only (HR 0.55, p = .04 and HR 0.41, p &lt; .01) although only OS remains significant after adjusting for age (p = .01). For NAC pts, pT0pN0 and ≤ pT1pN0 rates were 38% and 48%, respectively. Responders had superior PFS (HR 0.26 p &lt; .01) and OS (HR 0.32 p = .02). Median %NE was 100 (range: 10 – 100) and did not correlate with NAC response. %NE ≥ 95 is more prevalent among M1 pts (85% vs 68%, p = .04). Genomic data were available for 31 NAC pts (44%). Responders were enriched with alts in ERBB2 (33% vs. 0%, p = .02), PI3K pathway ( PIK3CA, PTEN, AKT1, TSC1, TSC2) (33% vs. 6%, p = .02) and histone acetyltransferases (60% vs. 25%, p = .07). Of 22/31 tumors sequenced with a larger gene set (n = 341), ERCC2 and RBM10 alts were enriched in responders (54% vs. 11%, p = .07) and nonresponders (44% vs. 0%, p = .02), respectively. Conclusions: In SCCB, NAC improves survival and response might be characterized by specific somatic alts. M1 pts had higher %NE but it is not predictive of outcome.

Abstract S6-05: Characterization of male breast cancer: First results of the EORTC10085/TBCRC/BIG/NABCG International Male BC Program

Abstract Intro: Male BC is a rare disease (&amp;lt;1% male tumors); knowledge is limited and management extrapolated from female BC. An international consortium, coordinated by EORTC and TBCRC, was created to better characterize and manage this disease, with 3 parts: 1) retrospective joint analysis 2) prospective registry 3) clinical trial(s). We report 1st results of part 1. Methods: Joint analysis of male BC pts with available FU &amp; FFPE samples, treated in 1990-2010, in 23 centers from 9 countries. Clinical data, long term outcomes, local pathology were centrally analyzed at EORTC. FFPE samples were analyzed at 3 central labs (UK, NL, US) for histology, grade, ER, PR, AR, HER-2, Ki67. Cut-off for positivity: Allred score ≥ 3 for ER/ AR/PR; 20% for Ki67; ASCO-CAP for HER2. Outcome data (OS &amp; RFS) analyzed per Kaplan Meier, p-values correspond to logrank test, CI’s by Brookmeyer &amp; Crowley. Reported % use number of non-missing values as denominator. Results: 1822 pts enrolled; 349 (19%) ineligible (no valid central lab assessment); of 1473 eligible pts (1384 from EU, 89 from US) 63% diagnosed in 2001-2010. Median age at diagnosis (Dx) was 68.5 ys. Of pts with known M status at Dx, 56 (5.1%) were M1; of 1046 M0 cases, 60% were N0 and 51% had T1 tumors at Dx; 4% of pts had BCS and 18% had SLNB; half received adjuvant RT. (Neo)adjuvant CT was used in 30% of M0 pts, most (44%) anthracycline-only; 77% of M0 pts received adjuvant ET, most tamoxifen (88.4%). Central pathology: 697 cases with central histology &amp; grade (full series ongoing): 87% ductal, 53% grade 2. In 1473 pts, at least 1 biomarker centrally assessed; 92% ER highly+ (Allred 7-8), PR had wider variation (35% highly+); 87% AR highly+; 25% Ki67 high; 5% HER2pos. Using IHC surrogates: 58% Luminal A-like, 35% LuminalB-like/HER2neg, 6% LuminalB-like/HER2pos; 0.1% HER2pos/non-Luminal; 1% TNBC (16% not classified). Outcome: For 1046 M0 pts, median FU was 5.7 yrs (0-19.2); 63% alive at analysis; in 88% cause of death was reported, mainly 33% non-cancer and 28% progression(PD)/toxicity. Significant OS improvement over time is seen. 75% (42/56) M1 pts died, mainly due PD. In M0 pts, median OS (yrs) was significantly correlated with ER+ p=0.001 [Allred 0-2: 3.9 (0.1, 6.0); 3-6: 7.1 (4.7, 11.7); 7-8: 8.8 (8.3, 10.0)] &amp; with PR+ p=0.022 [Allred 0-2: 7.3 (6.1, 10.3), 3-6: 8.0 (7.0, 9.3), 7-8: 9.5 (8.4, 12.8)]; less correlation for AR; no major differences for HER2 or Ki67. Median OS &amp; grade (394 cases; full series ongoing): Grade1: 12.8 yrs (6.1-15.6); Grade2: 7.9 (6.5-10.7); Grade3: 9.3 (4.9-21.1). Median OS for IHC surrogates: 8.7 (7.8-9.7) for Luminal A; 8.3 (6.9-9.4) for Luminal B/HER-2neg; 9.3 years (5.9-21.1) for Luminal B/HER-2+. Similar results were seen for RFS. ER/PR/AR using histoscores will be presented. Conclusions: a) 56% pts had T1 tumors at Dx but only 4% had BCS; b) ER was highly + in &amp;gt;90% but adjuvant ET given in only 77% pts; c) Male BC is usually ER+, PR+ &amp; AR+ and of Luminal A-like subtype (5% HER2pos &amp; 1% TNBC); d) Significant improvement in OS over time; e) ER and PR (Allred) are prognostic (high expression/better prognosis), less for AR, not for Ki67 nor IHC surrogates; f) In-depth characterization of samples is ongoing. Funding: BCRF, EBCC Council, Pink Ribbon NL, BRO. Citation Format: Fatima Cardoso, John Bartlett, Leen Slaets, Carolien van Deurzen, Elise van Leewen-Stok, Peggy Porter, Barbro Linderholm, Ingrid Hedenfalk, Carolien Schroder, John Martens, Jane Bayani, Christi van Asperen, Melissa Murray, Clifford Hudis, Lavinia Middleton, Joanna Vermeij, Stephanie Peeters, Judith Fraser, Monica Nowaczyk, Isabel Rubio, Stefan Aebi, Catherine Kelly, Kathryn Ruddy, Eric Winer, Cecilia Nilsson, Lissandra Dal Lago, Larissa Korde, Kim Benstead, Danielle Van Den Weyngaert, Oliver Bogler, Theodora Goulioti, Nicolas Dif, Carlo Messina, Konstantinos Tryfonidis, Jan Bogaerts, Sharon Giordano. Characterization of male breast cancer: First results of the EORTC10085/TBCRC/BIG/NABCG International Male BC Program [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 S6-05.

794P - Real World Data Analysis of Incident Metastatic (M1) Prostate Cancer (Pc) Patients (Pts): Us Claims Database Analysis

ABSTRACT Aim: Newly diagnosed (dx) M1 PC pts have a poor prognosis (median survival 3.7 yrs [Hussain, NEJM 2013]), and their characterization is mainly based on clinical trial data. We conducted a retrospective analysis to characterize newly dx M1 pts in a real world setting. Methods: The Truven Health Analytics MarketScan® US claims database from 2000-2013 was used to identify pts with an index PC dx. M1 pts were identified by diagnosis codes of metastasis to bone, visceral, distant lymph node, and nonspecific sites within 90 days of PC dx. Prior to index PC dx, pts had ≥ 180 days without any PC dx and up to 5 yrs without any other primary malignancy. Medical/surgical castration and prostatectomy/radiation (RP/RT) were identified by NDC and CPT4 codes. Progression to metastatic castration-resistant PC (mCRPC) was identified by exposure to ≥ 1 approved mCRPC drugs: docetaxel, abiraterone acetate, cabazitaxel, enzalutamide, sipuleucel-t, mitoxantrone, estramustine, and radium-223. Results: 326,907 pts (median age 64 yrs) with an index PC dx were identified. 2.8% (9199) had M1 disease (median age 68 yrs) with a median follow-up of 1.7 yrs. 2244 pts (24%) had only nonspecified metastasis. The remaining 6955 pts had metastasis to bone (77%; 53% of these with > 1 site), any viscera (38%), or any lymph node (21%); 5% had metastasis to all 3 sites. 51% of M1 pts underwent castration; 16% localized therapy (mainly RT [75%]); 18% single-agent therapy (bicalutamide or steroid); 15% did not receive any of these treatments. Median time to castration was 33 days; 78% of these pts underwent castration within 90 days. Median time to RP/RT was 72 days. 65% of pts with any bone metastasis underwent castration, 35% of pts with visceral only metastasis received single-agent therapy, and 98% of pts with metastasis to all 3 sites received treatment. 22% of pts who underwent castration progressed to mCRPC; median time from initial dx with M1 disease to mCRPC treatment was 404 days. Conclusions: Acknowledging limitations to claims data analyses due to variations in coding practices, these findings suggest that management of newly dx M1 pts is more diverse than recommended US treatment guidelines. Further research to validate these findings is warranted. Disclosure: T. Flaig: is an employee of and has intellectual property interests with Aurora Oncology, has served as a consultant with GTx, and has received research funding from BNIT, Dendreon, Genentech, GTx, Janssen, Medivation, Novartis, Sanofi, and Exelixis; M. Mehra: is an employee of Janssen and owns stock in Johnson & Johnson; R. Potluri: is an employee of SmartAnalyst and has served as a consultant/advisor to Janssen. Y. Ng: is an employee of Janssen and holds stock in Johnson & Johnson; M. Todd: is an employee of Janssen and owns stock in Johnson & Johnson; C. Higano: has served as a consultant/advisor for Astellas/Medivation, Bayer, Dendreon, and Johnson & Johnson and received research funding from Algeta, Aragon, Astellas/Medivation, Dendreon, and Sanofi.

Study to explore the willingness of patients (pts) to undergo biopsy at the time of breast cancer (BC) recurrence.

1102 Background: Physicians (MDs) may not request a biopsy (BX) when metastatic (M1) diagnosis is certain, however, there is increasing awareness of the value of tissue for cancer discovery. In addition, biomarkers can change from initial BC to M1 in 20%, affecting treatment. With ethics approval we investigated under what conditions BC pts would agree to a BX of recurrent cancer, to guide MD practice. Methods: Consenting English speaking pts with M1, or at least 3 months post adjuvant therapy, were asked to complete a survey (at home or with research assistant) about willingness to undergo BX at M1. Demographic and disease information was collected. The BX scenarios increased in inconvenience/discomfort and decreased in direct benefit to pt. Results: Among 204 participants, mean age was 60 (29-92), 71% were caucasian, 73% completed more than high school, 84% lived within 1 hour of the cancer centre. 87 (43%) pts had no relapse (M0) and 116 (57%) had M1 (including 20 [17%] with local relapse only, 21 [18%] de novo M1). 82 (71%) of M1 pts reported having had a BX for M1. When it required only image guidance and minimal discomfort (eg ultrasound guided liver BX), 86% of M1 pts would have a BX to join a trial and 81% would for pure research; 69% and 76% of M0 pts would have a BX to join a trial, or for research only, respectively. The Table shows the responses for the most invasive BX. Conclusions: Two thirds of BC pts would undergo the most invasive/inconvenient BX to join a trial, and half would for pure research. This demonstrates a large degree of altruism in this BC population. Willingness increased as direct benefit increased and the pain/inconvenience decreased. This data suggests MDs should not be hesitant to ask BC pts for a BX at M1. This study was limited to English speaking pts and most were well educated, thus it may not reflect all cultural attitudes toward BX. [Table: see text]

A national treatment survey on the chemotherapy (CTX) treatment for patients (Pts) with metastatic breast cancer (MBC) in Germany.

e17544 Background: The optimal CTX regimens and their sequence is the subject of ongoing debates esp. on the use of anthracycline/taxane (AT)-based adjuvant therapy (tx). Methods: Since 2004 a biennial survey is performed to evaluate routine CTX practice in MBC A total of 1,966 German sites were contacted. From 515 (26.2%) patient data were used for evaluation in order to achieve a representative sample for a chart review between June and August 2012. The current analysis is based on data from 291 sites on characteristics and tx of 741 pts undergoing first (1L), second (2L) or third (3L) line CTX for MBC in May 2012. Results: Data from 417 pts in 1L, 203 pts in 2L, and 121 pts in 3L were evaluated. Median age was 60 years (yrs). Patient characteristics were: 74% hormone receptor positive, 24% HER2-positive at primary diagnosis, 67% premenopausal, 60% had metastases in ≥ 2 organs, 66% had visceral disease. Prior tx (excluding M1 pts) was: no systemic tx 10%, endocrine tx only 13%, adjuvant CTX 58% (40% A and 44% AT-based), neoadjuvant CTX 20% (12% A and 75% AT-based). Median time from primary diagnosis to start of any treatment for MBC was 4.5 yrs for node-negative and 2.1 yrs for node-positive disease. Median time from primary diagnosis to current CTX was 4.9 yrs in 1L, 5.1 yrs in 2L and 5.8 yrs in 3L. Combination CTX was given in 21% of 1L, 12% of 2L and 9% of 3L pts, and its use decreased with increasing age. Agents used most frequently in 1L were taxanes in 61% (paclitaxel (P) 52%, docetaxel (D) 6%, nab-paclitaxel (Nab) 3%), capecitabine (X) 21%, vinorelbin (V) 19%, Epirubicin 6%, carboplatin 5%. 1L taxane tx was given to 73% of pts with prior A-based and 46% of pts with prior AT-based (neo-)adjuvant tx. Agents used most frequently in 2L were X 31%, P 20%, V 20%, gemcitabine (G) 7%, Nab 6% and in 3L V 27%, X 22%, eribulin 15%, Nab 12% P 7%, G 5%. Targeted tx was given in 54% of pts (20% trastuzumab, 4% lapatinib, and 30% bevacizumab), additional tx were bisphosphonates in 58%, and radiotherapy in 20%. Conclusions: The survey showed a high concordance of routine treatment and the existing national guidelines regarding CTX. Taxanes still dominate CTX in MBC including a significant amount of taxane rechallenge after their use in (neo-)adjuvant tx.

Daunorubicin or Not During the Induction Treatment of Childhood Standard-Risk B-Cell Precursor Acute Lymphoblastic Leukemia (SR-BCP-ALL): The Randomized Fralle 2000-A Protocol

AbstractAbstract 135▪▪This icon denotes a clinically relevant abstractFrom December 2000 to June 2010, 1201 children with SR-BCP-ALL (age: 1–9 years, WBC<50 G/L, CNS-, no MLL rearrangement, no BCR-ABL, no Down syndrome) were included in the FRALLE 2000-A multicenter protocol. At a MFU of 60 months, 1195 patients are evaluable. An ETV6-RUNX1 fusion transcript was documented in 28% of the pts (329 out of 1173 evaluable pts). Induction regimen: prednisone prephase +IT MTX, dexamethasone (DEX) 6 mg/m2/d, vincristine (VCR), native E.coli L-asparaginase ASPA: 6000 IU/m2 × 9 infusions). Response was assessed at D8 (blood, good if < 1000 blasts/mm3), D21 (bone marrow morphology, good if less than 5% blasts, so-called M1) and end of induction D35 (bone marrow morphology and DNA-based PCR for Ig/TCR rearrangements MRD). A D21 M1 marrow was observed in 1132 pts (94.7%). Out of these, 1128 pts were randomized to receive daunorubicin (DNR; 40 mg/m2 at D22 and D29) [560 DNR(+) pts] or not [568 DNR(-) pts]. Pts with D21 M2/M3 marrow (n= 61; 5%) were not randomized and received two infusions of DNR. Two pts died before D21. Pts with D21 M1 marrow (A1 group) received after induction a 12 week-consolidation based on VCR, DEX, mercaptopurine (6-MP) and oral methotrexate (MTX), followed by a 1st delayed intensification (reduced “Protocol II”, including a total of 75 mg/m2 of doxorubicin), an interphase therapy (VCR, DEX, 6-MP, MTX), and a triple drug only-2nd delayed intensification (DI°2) (VCR, MTX 100 mg/m2, ASPA 20000 IU/m2; 4 cycles). A 24-month maintenance was then applied, including 12 VCR-DEX pulses the first year. A total of 18 intrathecal injections of MTX was given. Only the rare patients with D21 M3 marrow and/or EOI MRD level ≥1% (n= 47, 4%)(A3 group) received an intensified treatment after CR with 3 block-consolidation, intensified interphase with 6 cycles of MTX 5 g/m2 and a second DI (“reduced protocol II”). No pt received CNS irradiation.Results: 1. Overall efficacy:No leukemic induction failure was observed; 4 induction deaths (0.3%) occurred leading to a 99.7% CR rate. Only 30 out 1097 evaluable pts (2.7%) had a decisional EOI MRD ≥ 1%. Eighty-two relapses have been observed (BM: 47, CNS+: 24, BM+CNS: 9, testis: 2). For the whole population 5-year EFS is 91.5% (95%CI: 89.8–93.3), 5-year OS is 97.4% (95%CI: 96.4–98.4). 5-yr EFS and OS for the A1 and A3 groups are 93.1% vs. 61.2% (p<0.0001), and 98.3% vs. 84.2% respectively (p<0.0001). Five-year DFS of the 30 pts with MRD ≥1% is 58.8% (95%CI: 41.7–82.8). Five-year EFS of the children with ETV6-RUNX1 fusion transcript is 96.6% (95%CI: 94.4–98.8). 2. Overall toxicity:5 non leukemic deaths have been observed after CR (0.4%). Other main toxicities were attributable to ASPA (CNS thrombosis: 1.5%, grade 3–4 pancreatitis: 0.8%, allergic reaction-all grades- during DI °2: 70%). Six cases of secondary neoplasms were observed (AML: 5 pts, astrocytoma: 1 pt). 3. Randomization:5y EFS and OS from randomization was 92.9% and 97.2% for D21 M1 pts DNR(+) versus 93.3% and 98.2% for D21 M1 DNR(-) pts (p= 0.89 and p= 0.85, respectively). Interestingly EOI MRD levels in the two arms were not different at the sensitivity cut-off of 10−2 (p=0.93) or 10−3(p= 0.74). 4. Prognostic factors:For the whole population, age < 6 years, WBC < 20.000/mm3, ETV6-RUNX1 positivity, as well as D21 marrow M1 and EOI MRD levels of 10−2 and 10−3 were all associated to EFS in univariate analysis. In multivariate analysis remain only WBC < 20.000/mm3 (p=.001), ETV6-RUNX1 positivity (p=.02), EOI MRD levels ≤ 10−3 (p=1.4×10−5). Considering only randomized pts (D21M1 pts) age <6 (p=.004), WBC < 20.000/mm3 (p=.04), ETV6-RUNX1 positivity (p=.01), EOI MRD levels ≤ 10−3(p=.002) remain as independent prognostic factors in multivariate analysis. Conclusions:Very good results were obtained with this VCR-DEX-ASPA oriented protocol. SR-BCP ALL pts which represents around 55 % of all children with ALL can be cured with a modest dose of anthracyclin (75 mg/m2). A further decrease in therapy based on the identified prognostic factors could be proposed. Intensification of the chemotherapy for the rare SR pts with a very high MRD has salvaged half of these pts but the addition of new drugs and/or HSCT is now to be evaluated. Disclosures:No relevant conflicts of interest to declare.

1509P - Chemotherapy is Effective in Primitive Neuroectodermal Tumor (PNET) / Ewing Sarcoma (EWS) of The Kidney

ABSTRACT Background PNET/EWS is a rare tumor that occurs most commonly in bone and soft tissues of children and young. PNET/EWS arise rarely as a primary renal neoplasm and exhibits highly aggressive biological behavior. Since its first description in 1975, less than 100 cases of EWS/PNET have been published in medical literature. We aim to collect and to analyze clinical and pathological features of this tumor. Patient and methods All cases reports of PNET/EWS published from 1975 to February 2012 were collected. When available, clinical and pathological data were extracted for each case such as previously reported (Iacovelli et al. BJU Int 2012). Survivals were estimated with Kaplan-Meier method and compared with log-rank test with 95% CI. Results A total of 117 cases were found, 55% were male and the median age was 28.0 y (IQR: 20.0 – 42.0). All patients (pts) had clinical symptoms as first presentation of disease such as pain (54%), hematuria (29%) and bulky renal mass (28%); whereas dysuria, fever, weight loss fatigue and abdomen swelling were reported rarely. 66% of pts had stage IV at diagnosis and the main sites of metastases were lung (60%), liver (37%), abdominal lymph-nodes (20%), bone and local relapse ( Conclusions PNET/EWS is a rare aggressive tumor with a well defined genetic profile. It affects principally young people with a poor prognosis for M1 pts; chemotherapy is an effective strategy in M1 and probably also in M0 pts. Disclosure All authors have declared no conflicts of interest.

Comparison of incidence and patterns of recurrence in colon cancer (Cca) treated by sentinel lymph node (SLN) mapping (M) versus conventional surgery.

3619 Background: Recurrence of Cca patients (pts) depends on the initial stage at diagnosis. SLNM upstages more pts than conventional surgery (Conv. Surg.) for nodal metastasis, this might have an impact on the incidence and pattern of recurrence. Hence comparative study was undertaken for recurrence in Cca pts undergoing SLNM Vs Conv.Surg. Methods: Group (Gp) A pts underwent SLNM with 1% Lymphazurin. The first 1-4 blue nodes were marked as SLNs followed by standard oncologic resection. Gp B pts underwent Conv. Surg. Data was collected for, TNM staging, Recurrence sites and follow up treatment. Minimum follow up of all pts was 12 month, with mean follow up period 44 months for both Gps. Results: There were 357 pts in GpA and 466 pts in GpB. For GpA pts, SLNM was successful in 99.6% of pts with average (Avg.) SLN was 2.8/pts. Avg. no. of LNs in GpA was 15.4/pts vs. 12.8/pt in GpB (p=0.001). For GpA pts, 46% was LN +ve vs 34% in GpB . Excluding T0, Tis and M1 pts at diagnosis, recurrence was calculated for 313 pts in GpA vs. 314 pts in GpB. An overall recurrence was 7.9% in GpA vs 22.2% (p=0.001) in GpB with distant mets being most common in both Gps. Recurrence of LN +ve and LN –ve pts also were significantly lower in GpA vs GpB (Table). The pattern of recurrence between the two Gps is shown in the Table. Conclusions: SLNM upstages significantly more pts in Cca than conv. surg. Even though pattern of recurrence was similar in both Gps, better staging may have resulted in better treatment, reducing the recurrence in SLNM Gp. Hence SLNM may be beneficial for Cca surgery. [Table: see text]

Correlation of bone marrow micrometastasis to TNM stage of colorectal tumors

e15039 Background: Bone marrow (BM) micrometastasis(M) has been shown to be an important prognostic factor in Breast Cancer. However, there is paucity of data for BMM in Colorectal Cancer(CrCa). Hence a study was undertaken to find any correlation between TNM staging with BMM in CrCa patients(pts). Methods: A total of 155 consecutive patients(pts) from March 2004-October 2008 with CrCa were included in the study. Prior to resection of the primary tumor, pts underwent bilateral posterior-superior-iliac spine BM aspiration and samples were examined for presence of micrometastasis by Automated Cellular Imaging System using Chroma Vision Cytokeratin Detection Kit to detect cells expressing CK 8 as defined by CAM 5.2 monoclonal antibody. BMM and TNM staging were recorded and analyzed for correlations. Results: Of 155 CrCa pts, 11.6%(18/155) were found to have BMM. BMM was positive(+ve) in 50%(9/18) bilaterally and 50%(9/18) unilaterally. BMM was +ve in 11.5%(13/113) of colon pts and 12%(5/42) of rectal pts. When analyzed by T stage in colon pts, BMM was present in 10.5%(2/19) of T1 pts, 16.6%(2/12) of T2 pts, 14% (6/42) of T3 pts, 37.5%(3/8) of T4 pts, and 16%(5/31) of M1 pts. Upon analyzing rectal cancer pts data, BMM was found in 8.3%(1/12) of T1 pts, 16.6%(3/18) of T3 pts and 16.6% (3/18) of M1 pts. Of 113 total Colon pts, 27%(31/113) had nodal disease without distant metastasis(stage III); 13%(4/31) of these pts had BMM with 60% (3/5) unilaterally and 40%(2/5) bilaterally. In the Rectal group, 16%(7/42) had stage 3 disease; 14% (1/7) of stage 3 rectal pts had BMM. Conclusions: BMM did not correlate with tumor size, nodal status or distant metastasis. This discrepancy between tumor stage and BMM suggests BMM to operate independently of TNM staging. Further studies correlating prognosis and disease free survival in +ve BMM pts are needed to examine the significance of BMM in CrCa. [Table: see text] No significant financial relationships to disclose.

High-Dose Methotrexate Seems to Benefit Only to Standard-Risk BCP-ALL Patients with Good Early Response to Chemotherapy: Final Analysis of the FRALLE93B Study

From 06/93 to 12/99, 1395 children and adolescents were included in the FRALLE 93 protocol: group A (Very Low Risk): 182, B (Standard risk): 672 and C (High risk including T-ALL): 541. The median FU is 9.5 yr. Inclusion criterias in group B were: age between 1 and 15 yr, WBC< 100,000, BCP phenotype and no poor-prognosis cytogenetic feature (MLL rearrangement or Ph1). Group B pts were randomised in a 2-steps schedule: at inclusion: daunorubicin (DNR: 40 mg/m2 × 2) vs idarubicin (IDA: 8 mg/m2 × 2), and at consolidation: high-dose IV methotrexate (HD-MTX): 4 × 8g/m2 at D1, D15, D29 and D42, vs low-dose po MTX (LD-MTX): 4 × 25 mg/m2; the number of triple IT was the same for both arms (N = 18). Pts with CNS leukemia were not randomized for MTX. During induction, pts were also classified on D21 bone marrow aspiration according to the level of residual blasts: M1 (< 5%): n=555, M2 (6–25%): n=71 and M3 (> 25%): n=41; M2/M3 pts received 1 more antracyclin infusion at D22 and M3 pts were subsequently treated according to the HR group and not randomized for MTX. Both M1 and M2 pts who reached CR were randomized for MTX. The overall group B EFS, DFS and OS were respectively 80±2, 81±2, and 91±1%. Globally there is no statistically significant impact of 1st or 2nd randomization on the outcome of patients. When we look at the outcome according to the D21 status, the EFS are very different: M1: 84±2%, M2: 63±6% and M3: 74±7%. The very poor EFS of M2 pts, who can not actually be classified as SR pts, and the fact that M1 pts represent 90% of pts randomized for MTX led us to analyse separately M1 pts. For M1 pts there is no interaction between 1st and 2nd randomization for survival, EFS and relapse rate (Gail and Simon test, p = 0.51); therefore pts were pooled for 2nd randomization analysis. Among M1 pts, 271 pts were randomized for HD-MTX and 264 for LD-MTX; there is no difference regarding age or leucocytosis between the 2 arms. Results are as follows:5-yr EFSRelapses CIiBM relapses CIOther relapses CI5-yr OSHD-MTX87.82±1.99%0.12±0.047.01±0.025.17±0.0295.20±1.30LD-MTX79.92±2.47%0.20±0.0610.6±0.039.10±0.0388.64±1.95Testlog-rankGrayGrayGraylog-rankp value0.0280.0370.160.180.07(EFS: event-free survival, CI: cumulative incidence, iBM: isolated bone-marrow, OS: overall survival)At the contrary, among M2 pts there is no difference in EFS for pts treated with HD-MTX (61±7%) and LD-MTX (65±9%)Conclusion:HD-MTX seems to benefit to pts with standard-risk BCP-ALL and good early response to chemotherapy, and the benefit is associated with a reduction in the number of relapses.No benefit is demonstrated in M2 pts with SER who have a very poor outcome and do require a more intensive treatment; the better EFS of M3 patients treated with double delayed intensification is in favour of this hypothesis.

Minimal Residual Disease (MRD) at the End of Induction (EOI) after a Three or Four-Drug Induction Regimen for Childhood Standard-Risk B-Cell Precursor Acute Lymphoblastic Leukemia (SR-BCP-ALL): Interim Results of the FRALLE 2000-A Protocol.

From Dec 2000 to Dec 2003, 390 children with SR-BCP-ALL (age: 1–9, WBC<50 G/L, CNS-, no MLL-R, no BCR-ABL) were included in the FRALLE 2000 -A protocol. Induction regimen is: prednisone prephase for 7 days (60 mg/m2/d) +IT MTX, dexamethasone 6 mg/m2 (D8–D28), vincristine 1.5mg/m2(D8, D15, D22, D29), L-asparaginase 6000 U/m2 (9 infusions). Good marrow responders at D21(M1 pts) are randomized to receive or not daunorubicin (DNR) 40 mg /m2 at D22 and D29. D21 M2/M3 pts are not randomized and given DNR. MRD at EOI is determined by DNA-based PCR for Ig/TCR rearrangements. Two methods are used for quantification (competitive PCR with GeneScan analysis -sensitivity: 0.5x 10-3-, RQ-PCR with clone-specific probes- sensitivity range: 10-3-10-5). EOI MRD data are evaluable for 343 pts with D21 M1 response (DNR+= 169/ DNR−= 173/ not randomized = 1) and for 20 pts M2M3 ; two pts died during induction and thus are NE. MFU of these 365pts is 22m (3–39). Median age is 4.1y(1.1–9.9), median WBC is 7.47 G/L (.9–47). MRD results are classified for analysis either in three categories (negative, weakly +ve if < 10−3, highly positive if > 10−3, or according to the exact level of positivity.Results: 1) 15% (51/336 pts) of the SR-BCP ALL have a detectable MRD at EOI 2) As expected, whatever the threshold, pts with D21 M2/M3 marrow are more likely to have a detectable MRD (p=.0017). But 43/316 M1 pts (14%) have a highly +ve (n=19;6%) or weakly +ve MRD (n=24 ; 8%). Surprisingly, only 1 out 20 M2M3 pts had a MRD > 10−2 while it is the case for 8 out 316 M1 pts (p=NS). If only pts receiving DNR are considered (DNR+ M1 pts and all M2/M3 pts), again pts with D21 M2/M3 marrow are more likely to have a detectable MRD (p=.0015). 3) If we compare the MRD levels in the 2 arms (DNR+ve or neg) in the 315/343 M1 pts evaluable for MRD: 136 pts in each arm had no detectable MRD; 16 and 8 have a weak positivity in the DNR− and DNR+ arm respectively while 10 and 9 have a weak positivity in the DNR− and DNR+ arm respectively: p= .29). If the exact level is considered, this absence of difference remains at all levels considered.Conclusions: 15% of the SR-BCP ALL have a detectable MRD at EOI after a three or four-drug induction. D21 M2/M3 pts are more likely than M1 pts to have a detectable MRD at EOI but 14% of the D21 M1 pts have a high (> 10−3) or very high MRD (> 10−2) which confirms the added value of MRD detection to classical morphology. The MRD level at EOI is not different in SR-BCP-ALL after a three or four-drug induction regimen. This is of paramount importance since EOI MRD is a surrogate marker for probability of relapse.