bluuebunny/crossref_metadata_2025 huggingface dataset:
Intergroup randomized phase III study of androgen deprivation therapy (ADT) plus radiation therapy (RT) in locally advanced prostate cancer (CaP) (NCIC-CTG, SWOG, MRC-UK, INT: T94-0110; NCT00002633).
Authors: Warde P. R. , Mason M. D. , Sydes M. R. , Gospodarowicz M. K. , Swanson G. P. , Kirkbride P. , Kostashuk E. , Hetherington J. , Ding K. , Parulekar W. ,   NCIC CTG PR.3/MRC PRO7/SWOG JPR3 Investigators
Published: February 2017

CRA4504

Background: The impact of radiotherapy on overall survival (OS) in men with locally advanced CaP is unclear. The SPCG-7 trial recently showed a benefit to RT for CaP specific mortality. Our primary objective was to assess the effect of RT on OS when added to lifelong ADT in men with locally advanced CaP.

Methods: Patients with T3/T4 (1057) or T2, PSA > 40 μ g/l (119) or T2 PSA > 20 μ g/l and Gleason ≥ 8 (25) and N0 /NX, M0 prostate adenocarcinoma were randomized to lifelong ADT (bilateral orchiectomy or LHRH agonist) with or without RT (65-69 Gy to prostate ± seminal vesicles with or without 45Gy to pelvic nodes). The primary endpoint was OS and secondary endpoints included disease specific survival (DSS), time to disease progression and quality of life.

Results: 1205 patients were randomized from 1995 to 2005, 602 to ADT and 603 to ADT+RT (well balanced with respect to baseline characteristics). A protocol specified second interim analysis on OS was performed in Aug 2009 (data cut-off Dec 31 2008). The DSMC recommended release of the results to the Trial Committee for publication. The median follow-up is 6.0 years and 320 patients have died (175 ADT and 145 ADT+RT). 10% of patients had no follow-up data beyond 2006. The addition of RT to ADT significantly reduced the risk of death (hazard ratio [HR] 0.77, 95% CI 0.61-0.98, p=0.033). 140 patients died of disease and/or treatment (89 on ADT and 51 on ADT+RT) The disease specific survival HR was 0.57 (95% CI 0.41-0.81, p=0.001) favoring ADT+RT. The 10 year cumulative disease specific death rates were estimated at 15% with ADT+ RT and 23% with ADT alone. Grade ≥2 late GI toxicity rates were similar in both arms (proctitis, 1.3% ADT alone, 1.8% ADT+RT).

Conclusions: The trial results indicate a substantial overall survival and disease specific survival benefit for the combined modality approach (ADT+RT) in the management of patients with locally advanced prostate cancer with no significant increase in late treatment toxicity. In view of this data combined modality therapy (ADT+RT) should be the standard treatment approach for these patients. Supported by NCI-US Grant #5U10CA077202-12, CCSRI Grant #15469.

No significant financial relationships to disclose.
Phase III trial of sunitinib (SU) in combination with capecitabine (C) versus C in previously treated advanced breast cancer (ABC).
Authors: Crown J. , Dieras V. , Staroslawska E. , Yardley D. A. , Davidson N. , Bachelot T. D. , Tassell V. R. , Huang X. , Kern K. A. , Romieu G.
Published: February 2017

LBA1011

Background: Recent trials support combining an antiangiogenic agent with chemotherapy (CT) in pretreated patients (pts) with metastatic BC (MBC). SU, an oral multitargeted tyrosine kinase inhibitor demonstrated single-agent activity (11% ORR) in heavily pretreated pts with MBC. Antitumor activity with SU+C was reported in pts with advanced solid tumors. This multicenter, randomized, phase III trial (SUN 1099) compared the efficacy and safety of SU + C vs. C in pts with ABC.

Methods: Eligibility criteria were: age ≥18 yrs, ECOG PS ≤1, measurable HER2-positive (FISH+, CISH+ or IHC3+) or -negative ABC, no brain metastases, prior treatment (tx) with an anthracycline and taxane in the (neo)adjuvant or metastatic setting, and ≤2 prior CT regimens for advanced disease. Prior C tx was not permitted. Pts were randomized (1:1) to combination tx with C 2,000 mg/m2/d po days 1–14 every q3w + SU 37.5 mg/d po daily, or to C 2,500 mg/m2/d days 1–14 q3w. Pts with progressive disease per RECIST on the C arm were offered single-agent SU (37.5 mg/d). Endpoints included PFS (primary), ORR, OS, QoL, and safety. Stratified and unstratified log-rank tests compared PFS between arms.

Results: At the data cutoff (December 15, 2009), the ITT population comprised 442 pts: 221 in each arm with baseline characteristics well balanced between arms. The trial did not meet its primary endpoint of prolonging PFS based on the independent radiologic assessment nor secondary endpoint of longer OS (final analysis March 10, 2010). Median PFS was 5.5 mos (95% CI 4.5–6.0) in the SU+C arm vs. 5.9 mos (95% CI 5.4–7.6) in the C arm (HR 1.224). Median OS was 16.4 mos (95% CI 13.6–18.4) for the SU+C arm and 16.5 mos (95% CI 14.2–18.6) for the C arm (HR 0.995). ORR was 18.6% for the SU+C arm and 16.3% for the C arm. The most common all causality grade 3/4 AEs (≥10%) were neutropenia (32%), hand–foot syndrome (HFS; 16%), thrombocytopenia (17%), asthenia (12%), fatigue (10%) in the SU+C arm and HFS (24%) and diarrhea (10%) in the C arm. Intended drug delivery for each arm was >80%. Discontinuations due to an AE were more frequent in the SU+C arm vs. the C arm. Discontinuations by drug in the SU+C arm: SU 39%, C 42%, SU and C 33%; in the C arm: 18%.

Conclusions: Data from this randomized phase III trial do not support use of SU+C for therapy of patients with ABC.

[Table: see text]
A prospective, randomized, open-label, phase III clinical trial of NovoTTF-100A versus best standard of care chemotherapy in patients with recurrent glioblastoma.
Authors: Stupp R. , Kanner A. , Engelhard H. , Heidecke V. , Taillibert S. , Lieberman F. S. , Dbalý V. , Kirson E. D. , Palti Y. , Gutin P. H.
Published: February 2017

LBA2007

Background: The NovoTTF is a portable, medical device delivering low intensity, intermediate frequency, alternating electric fields by means of noninvasive, disposable scalp electrodes. These tumor treatment fields (TTF) physically interfere with cell division and assembly of organelles.

Methods: Adult pts (KPS≥70%) with recurrent GBM were randomized (stratified by surgery for recurrence and center) to either NovoTTF administered continuously (20-24h/day, 7 days/week) or the best standard chemotherapy (BSC) at each physicians’ discretion. Number of prior therapies was not limited. Primary endpoint was overall survival (OS). The study was powered (80%) to detect a 60% increase in OS with a two tailed a of 0.05.

Results: 237 pts were randomized (28 centers in the United States and Europe) to either TTF alone (120 pts) or BSC (117 pts). Patient characteristics were balanced, median age was 54 years (range 23-80), median KPS 80% (50-100). All had prior TMZ/RT, and the majority at least one prior therapy for recurrence. One-quarter had surgery for recurrence. Mean treatment duration was 4.4 mo (0-40) vs. 2.3 mo (0-15), median OS was 6.6 vs. 6.0 months for TTF and BSC, respectively (p=0.23, hazard ratio 0.84 [95% CI 0.63-1.12]), the 1-year survival rate 23.6% versus 20.8% (ns). PFS6 was 17.6% in both groups. Time to treatment failure favored the TTF group (HR 0.76 [0.57-1.02], p=0.07). Objective responses were more common in the TTF arm (12%) versus the BSC (6%). Related adverse events were mild-to-moderate skin rash beneath the electrodes in 17% of TTF treated pts. Hematological and other toxicities were observed at a significantly higher incidence in the BSC arm depending on the type of chemotherapy, no treatment-related deaths occurred. Treatment compliance with TTF was excellent with a median duration 20 hours/day.

Conclusions: This is the first phase III, controlled clinical trial testing TTF, an entirely novel treatment modality. TTF had minimal toxicity, long-term treatment proved feasible. TTF as a single modality showed a higher response rate and longer time to treatment failure compared to best available chemotherapy. Overall survival also favored TTF, but did not reach statistical significance. In view of the above, TTF should be considered a valid novel treatment modality.

[Table: see text]
Gemcitabine plus erlotinib (GE) followed by capecitabine (C) versus capecitabine plus erlotinib (CE) followed by gemcitabine (G) in advanced pancreatic cancer (APC): A randomized, cross-over phase III trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO).
Authors: Boeck S. H. , Vehling-Kaiser U. , Waldschmidt D. , Kettner E. , Märten A. , Winkelmann C. , Klein S. , Kojouharoff G. , Jung A. , Heinemann V.
Published: February 2017

LBA4011

Background: Gemcitabine plus erlotinib (GE) is regarded as one standard of care for patients (pts) with APC and CE as an all-oral regimen could be a feasible option in this population. To date, the value of a prospectively defined second-line treatment is unclear in APC.

Methods: Within a prospective multicenter phase III trial, 281 pts with histologically confirmed APC and adequate organ function were randomly assigned to first-line treatment with either C (2,000 mg/m2/d, d1-14 q3w) plus E (150 mg/d, arm A) or G (1,000 mg/m2 over 30 min weekly x 7, then d1, 8, 15 q4w) plus E (150 mg/d, arm B). In case of treatment-failure (e.g. disease progression or toxicity, TTF1), pts were "crossed-over" to second-line treatment with the comparator cytostatic drug without E. The primary study endpoint was time to treatment failure of second-line therapy (TTF2); secondary endpoints included TTF1, objective response, overall survival (OS) and toxicity.

Results: Of 279 eligible pts, 60% were male and median age was 64 years; 47 pts had locally advanced and 232 metastatic disease, 141 pts (51%) received second-line chemotherapy. Objective response rate (CR+PR, ITT) to first-line treatment was 5% (A) vs. 13% (B). Currently, TTF2 is estimated with 4.4 months (mo) in arm A and 4.2 mo in arm B (HR 0.98, p=0.43), median OS is 6.9 mo (A) and 6.6 mo (B), respectively (HR 0.96, p=0.78). TTF1 was significantly prolonged in arm B (2.4 mo vs 3.4 mo; HR 0.69, p=0.0036). Hematological toxicity was more frequent with G-containing regimens, skin rash > grade 1 during E treatment occurred in 31% pts in arm A and in 43% pts in arm B. Tissue tumor samples are available from 204 pts; 123 tumors (70%) harboured a somatic KRAS mutation (mut). Pts with KRAS wildtype (wt, n=53) had an improved OS (wt: 8.0 mo vs. mut: 6.6 mo; HR 1.62, p=0.011).

Conclusions: TTF2 and OS were comparable in both arms; GE was superior compared to CE with regard to TTF1. Wt KRAS status was associated with an imprved OS in pts with APC.

[Table: see text]
A randomized phase III trial of denosumab versus zoledronic acid in patients with bone metastases from castration-resistant prostate cancer.
Authors: Fizazi K. , Carducci M. A. , Smith M. R. , Damião R. , Brown J. E. , Karsh L. , Milecki P. , Wang H. , Dansey R. D. , Goessl C. D.
Published: February 2017

LBA4507

Background: Bone metastases from hormone-refractory (castration-resistant) prostate cancer (CRPC) are associated with RANKL-mediated osteoclast activation resulting in bone destruction and skeletal-related events (SRE). Denosumab is a fully human monoclonal antibody against RANKL. This phase III, randomized, double-blind, active-controlled trial compared the efficacy and safety of denosumab vs. zoledronic acid (ZA) in patients with metastatic CRPC.

Methods: Patients (n = 1,901) with CRPC and at least 1 bone metastasis, but no prior IV bisphosphonate use, received either SC denosumab 120 mg and IV placebo (n = 950), or SC placebo and IV ZA 4 mg (n = 951) adjusted for creatinine clearance every 4 weeks. All patients were instructed to take supplemental calcium and vitamin D. The primary endpoint was time to first on-study SRE, defined as pathologic fracture, radiation or surgery to bone, or spinal cord compression.

Results: Denosumab significantly delayed the time to first on-study SRE compared with ZA, (HR 0.82 ; 95% CI: 0.71, 0.95 ; p = 0.008.) The median time to first on-study SRE was 20.7 mo denosumab vs. 17.1 mo ZA, a difference of 3.6 months. Denosumab also significantly delayed the time to first and subsequent on-study SRE (multiple event analysis) (HR 0.82 ; 95% CI: 0.71, 0.94 ; p = 0.004). Greater suppression of the bone turnover markers uNTx and BSAP occurred in denosumab patients compared with ZA (p < 0.0001 for both). Overall, adverse event (AE) rates (97% each) and serious AEs (63% denosumab, 60% ZA) were similar, irrespective of potential relationship to study drugs. AEs of hypocalcemia were reported in 13% and 6% of denosumab and ZA patients. Osteonecrosis of the jaw occurred in 22 (2.3%) denosumab compared with 12 (1.3%) ZA patients (p = 0.09). Overall survival (HR 1.03 ; 95% CI: 0.91, 1.17 ; p = 0.65) and time to cancer progression (HR 1.06; 95% CI: 0.95, 1.18; p = 0.30) were similar between treatment arms.

Conclusions: Denosumab demonstrated superiority over ZA in delaying or preventing SREs in patients with bone metastases from CRPC. Adverse events were consistent in both treatment groups with those previously reported in advanced cancer populations.

[Table: see text]
Safety and efficacy of targeted intraoperative radiotherapy (TARGIT) for early breast cancer: First report of a randomized controlled trial at 10-years maximum follow-up.
Authors: Baum M. , Joseph D. J. , Tobias J. S. , Wenz F. K. , Keshtgar M. R. , Alvarado M. , Bulsara M. , Eiermann W. , Williams N. R. , Vaidya J. S. ,   on behalf of the TARGIT Trialists’ Group
Published: February 2017

LBA517

Background: After breast conserving surgery, 90% of local recurrences (LR) occur within the index quadrant. Hence, restricting the radiation therapy to the immediate area around the tumour bed after removal of the primary tumour may be adequate (Vaidya JS, et al. Br Cancer.1996;74:820-4)

Methods: Having safely piloted a new technique of partial breast irradiation (Vaidya JS, Baum M, Tobias JS et al Ann Oncol 2001;12:1075-80) we launched the TARGIT-A trial in March 2000 comparing TARGIT vs. standard whole breast external beam radiotherapy (EBRT) after breast conserving surgery in patients ≥45 years with invasive duct carcinoma. LR was the primary outcome measure (core protocol: www.thelancet.com/protocol-reviews/99PRT-47 ). Trial accrual from 31 international centers is complete (n=2232), with 80% power to detect a difference in relapse rate of 2.5% - the non-inferiority margin.

Results: Median age was 63 (IQR 57-69), median tumor size 13mm (IQR 9-18mm), lymph nodes 17%+ve. Median follow-up is 24.6 months (max 10 years). Wound breakdown or delayed healing were reported in 28 of the TARGIT group and 20 in the EBRT group (p=0.24). RTOG grade 3 toxicity (nil grade 4) was seen in 6 vs. 21 (p=0.004) respectively. Overall local toxicity was equivalent (34/1092 TARGIT v. 41/1096 EBRT, p=0.42). The Kaplan-Meier estimate of LR in the breast, was 0.31% (CI 0.08-1.26) for TARGIT versus 0.29% for EBRT (CI 0.07-1.16) at 24 months.

Conclusions: In the TARGIT group, the radiotherapy toxicity was significantly lower than in the EBRT group, while the increase in wound complications was not statistically significant. This analysis suggests that at a median follow-up of 24 months the local control with TARGIT is comparable to EBRT. Longer term follow-up is essential and accrual in similar studies is encouraged.

[Table: see text]
Results of a randomized, phase III trial of nab-paclitaxel (nab-P) and carboplatin (C) compared with cremophor-based paclitaxel (P) and carboplatin as first-line therapy in advanced non-small cell lung cancer (NSCLC).
Authors: Socinski M. A. , Bondarenko I. N. , Karaseva N. A. , Makhson A. , Vynnichenko I. , Okamoto I. , Hon J. K. , Hirsh V. , Bhar P. , Iglesias J.
Published: February 2017

LBA7511

Background: Platinum-based doublet therapy in NSCLC, regardless of the combination used, reached a therapeutic plateau. PC produced 15-25% overall response (ORR, Kelly 2001; Sandler 2006; Schiller 2002). Albumin-bound paclitaxel, nab-P, utilizes the albumin receptor (gp60)/caveolin-1 (CAV1) pathway achieving high intratumoral paclitaxel accumulation (Desai 2006), which may have contributed to a 48% ORR observed with nab-PC in NSCLC (Stroyakovsky, 2009). This phase III trial studied the efficacy of nab-PC vs. PC in advanced NSCLC of all histologic types.

Methods: First-line stage IIIB or IV NSCLC pts (ECOG 0/1) were randomized to C AUC6 q3w and either nab-P 100 mg/m2 qw w/o premed (n = 521) or P 200 mg/m2 q3w with premed (n = 531). Primary endpoint: ORR by independent radiologic review (IRR).

Results: Baseline and histologic characteristics were well balanced. Dose intensity of paclitaxel was higher in nab-PC vs. PC (82 vs. 65 mg/m2/wk). nab-PC was superior to PC both by IRR (33 vs. 25%, p=0.005), a 31% improvement (1.31 response ratio [RR], 95% CI: 1.08, 1.59), and by investigator review (37 vs. 30%, p=0.008), a 26% improvement (1.26 RR, CI: 1.06, 1.50). Histologic analysis showed significantly improved ORR for nab-PC (n = 228) vs. PC (n = 221) in squamous cell carcinoma (SQC) pts (41 vs. 24%, p<0.001, IRR), a 67% improvement (1.67 RR, CI: 1.26, 2.21). nab-PC was as effective as PC in nonSQC pts (ORR 26 vs. 25%). nab-PC was well tolerated, with significantly improved safety profile vs. PC despite higher paclitaxel dose delivered (1,338 vs. 1,100 mg/m2).

Conclusions: The primary endpoint was met, with significantly improved ORR and safety profile of nab-PC vs. PC as first-line therapy for advanced NSCLC. nab-PC was highly active in the SQC subset, which may in part be attributed to the aberrant CAV1 overexpression in SQC (Yoo 2003) and the high intratumoral accumulation of nab-P via the gp60-CAV1 pathway.

[Table: see text]

[Table: see text]
Comparison of high-dose methotrexate (HD-MTX) with Capizzi methotrexate plus asparaginase (C-MTX/ASNase) in children and young adults with high-risk acute lymphoblastic leukemia (HR-ALL): A report from the Children’s Oncology Group Study AALL0232.
Authors: Larsen E. C. , Salzer W. L. , Devidas M. , Nachman J. B. , Raetz E. A. , Loh M. L. , Heerema N. A. , Carroll A. J. , Gastier-Foster J. M. , Borowitz M. J. , Wood B. L. , Willman C. L. , Winick N. J. , Hunger S. , Carroll W. L.
Published: February 2017

3

Background: Although EFS continues to improve for children and young adults with HR-ALL, central nervous system (CNS) disease has become an increasing site of treatment failure. AALL0232 was designed to test the safety and efficacy of interventions targeted to enhance CNS control including comparisons of HD-MTX versus Capizzi escalating methotrexate plus PEG asparaginase (C-MTX/ASNase) during interim maintenance-1 (IM-1) and dexamethasone (DEX) versus prednisone (PRED) during Induction. Methods: AALL0232 was a Phase III, randomized trial for patients 1-30 years old with newly diagnosed NCI high risk B-precursor ALL that utilized a 2 x 2 factorial design with an augmented intensity Berlin-Frankfurt-Münster (BFM) backbone. Patients were randomized to receive DEX versus PRED during induction and HD-MTX (5gm/m2 biweekly x 4) versus C-MTX/ASNase during IM-1. To date 2104/3156 AALL0232 patients have completed IM-1. Results: Planned interim monitoring showed 5-year EFS for patients randomized to receive HD-MTX (N=1,209) was 82 + 3.4% versus 75.4 + 3.6% for the C-MTX/ASNase (N=1,217) regimen, p=0.006. Because this difference crossed a pre-defined boundary, enrollment was halted and patients were crossed over from C-MTX/ASNase to HD MTX when feasible. There were fewer marrow and CNS relapses in the HD-MTX versus C-MTX/ASNase arms (42 and 22 versus 68 and 32). The incidence of febrile neutropenia was lower with HD-MTX compared to the C-MTX; 5.2% vs 8.2%, respectively, p=0.005. There were no statistically significant differences in acute neurotoxicity, osteonecrosis, or other clinically relevant toxicities between the two regimens. Conclusions: HD-MTX administered in place of C-MTX, during the IM-1 phase of augmented BFM therapy is associated with superior EFS, with no increase in acute toxicity, in children and young adults with HR-ALL.
Randomized double-blind placebo-controlled international trial of abago-vomab maintenance therapy in patients with advanced ovarian cancer after complete response to first-line chemotherapy: The Monoclonal Antibody Immunotherapy for Malignancies of the Ovary by Subcutaneous Abago-vomab (MIMOSA) trial.
Authors: Pfisterer J. , Berek J. S. , Casado A. , Cwiertka K. , Pinter T. , Pluzanska A. , Pujade-Lauraine E. , Scambia G. , Vermorken J. B. , Simonelli C. , Bertolotti M. , Capriati A. , Sabbatini P. ,   AGO-OVAR, COGI, GEICO, GINECO
Published: February 2017

LBA5002

Background: Abagovomab, a murine monoclonal anti-idiotypic antibody directed against CA125, has been shown to induce an active immune response against CA125 tumor-associated antigen in advanced ovarian cancer patients. Methods: Abagovomab (A) has been tested in a randomized (2:1) double-blind, placebo (P) controlled, multicenter phase II/III trial in patients with FIGO stage III/IV ovarian cancer after complete response to platinum-taxane first-line chemotherapy. A (2 mg/1 ml) or P was given subcutaneously every 2 weeks for 6 weeks (induction phase); then every 4 weeks (maintenance phase) until recurrence, or up to 21 months after the last patient had been randomized. Primary endpoint is progression-free survival (PFS); secondary endpoints are OS and immunological response. An estimated 870 patients, with a mean follow-up of 18 months, were needed to observe at least 535 recurrences, which provides a power >90% in rejecting the null hypothesis of equality between A and P on PFS according to a hazard ratio (HR) of 1.33, in which median P PFS time is 18 months, significance level (a) 5% (two-sided), and the overall dropout rate 10%. Primary analysis was run on PFS in the ITT population. The design included a prospective stratification in randomization for the following prognostic factors: FIGO stage (III-IV); tumor size after debulking (residual tumor <1 cm, >1 cm); and CA125 serum level after the third cycle (<35 U/ml, >35 U/ml). The Cox proportional hazards model was used for adjusting the primary analysis. Results: 888 patients were enrolled by December 2008, 593 in A arm and 295 in P arm. The median follow-up was 28.1 months and the mean number treatment administrations was 18. Baseline characteristics were balanced between arms. Overall tolerability profile was consistent with previous A studies. Median (95% CI) PFS was 13.24 (10.612-13.602) months for A arm and 13.21 (10.612-16.000) months for P arm; HR=1.099 (0.919-1.315); p=0.301. Conclusions: Treatment with A did not translate into a prolonged PFS.
Surgical and oncologic outcomes in patients with breast cancer undergoing tattooing prior to neoadjuvant chemotherapy.
Authors: Lannin D. R. , Grube B. J. , Killelea B. K. , Horowitz N. , Harris L.
Published: February 2017

100

Background: Neoadjuvant chemotherapy for breast cancer increases the breast preservation rate, but also increases the rate of local recurrence, probably because there is no standard technique to determine the amount of breast tissue to be removed. In 2007 we described a technique where the surgeon maps the extent of a breast tumor, plans a surgical incision, and tattoos the breast prior to the patient receiving neoadjuvant chemotherapy. After the chemotherapy, digital photographs are retrieved that allow the surgeon to precisely reconstruct where the margins of the original tumor were in the breast, and to proceed with a planned operation to remove the entire tumor bed but minimal surrounding breast tissue. The purpose of this study is to describe a series of patients treated with this technique and to evaluate the surgical and oncologic outcomes obtained.

Methods: Data were collected from a prospective breast cancer database and from chart review on all patients treated with this technique at a single institution. Most patients receiving neoadjuvant chemotherapy underwent the tattooing, unless they knew beforehand that they were going to undergo a mastectomy.

Results: Between June 2005 and January 2011, 87 patients underwent breast tattooing followed by chemotherapy. Of patients who have completed subsequent definitive therapy, the initial surgery was mastectomy in 31 and lumpectomy in 53. Most patients’ tumors became nonpalpable following the therapy, and the pathologic complete and partial response rates were 22% and 64% respectively. Of patients who underwent an initial lumpectomy, 5/53 (9%) had positive margins and underwent further surgery (2 mastectomy and 3 wider lumpectomy). With a median follow-up of 36 months, only 1 patient has had an in-breast local recurrence.

Conclusions: These early results clearly show a lower rate of re-excision and a lower rate of local recurrence than commonly reported in the literature for breast preservation following neoadjuvant chemotherapy. The technique warrants wider application and further study.
Study of sentinel lymph node biopsy after preoperative chemotherapy in patients with breast cancer.
Authors: Kinoshita T. , Hojo T. , Asaga S. , Suzuki J. , Jimbo K. , Tamura N.
Published: February 2017

104

Background: Despite the increasing use of both sentinel lymph node biopsy (SLNB) and preoperative chemotherapy (PST) in patients with operable breast cancer, there is still limited information on the feasibility and accuracy of SLNB following PST. In this study, the feasibility and accuracy of SLNB for breast cancer patients with clinically negative lymph nodes after PST were investigated. In addition, conditions that may affect SLN biopsy detection and false-negative rates with respect to clinical tumor response and clinical tumor/nodal status before PST were analyzed.

Methods: Between 2003 and 2008, 200 patients with stage II and III breast cancer previously treated with PST were enrolled in this study. The eligible criteria for PST were (a) primary tumor > 3cm or (b) positive axillary lymph node status on initial examination. FNA biopsy was performed for clinically or ultrasonographically suspicious axillary lymph nodes. The patients then underwent SLNB, which involved a combination of intradermal injection over the tumor of radiocolloid and subareolar injection of blue dye. This was followed by Level I/II axillary lymph node dissection (ALND).

Results: The median patient age was 49 years, and the median primary tumor size was 4.9 cm. The overall SLN identification rate was 94.5% (189 of 200). In 178/189 patients (94%) the SLN accurately predicted the axillary status. Eleven patients had a false-negative SLN biopsies, yielding a false-negative rate of 12.9%. There were no significant differences in the SLN identification rate according to tumor classifications before PST, the clinical nodal status before PST, the clinical tumor response after PST, or pathological response of the tumor after PST, although the SLN identification rate tended to be lower in patients with a T4 primary tumor.

Conclusions: Our data and some reports suggested that SLNB was feasible method for axillary staging in breast cancer patients who received PST even in patients who initially with lymph node positive disease. However, false-negative rate of SLNB in patients with clinical and pathological complete tumor response tended to be higher than other group.
Locoregional recurrence risk factor and indications for postmastectomy radiotherapy in Japanese patients with tumors 5 cm or larger.
Authors: Nagao T. , Kinoshita T. , Tamura N. , Hojo T. , Morota M. , Kagami Y.
Published: February 2017

127

Background: Locoregional recurrence (LRR) after mastectomy reduces the patient’s quality of life and survival. There is a consensus that postmastectomy radiotherapy (PMRT) helps achieve locoregional control and reduces LRR. However, in patients with large tumors, the question of which variables affect the likelihood of LRR and the role of PMRT has been the subject of substantial controversy. This study investigated what are risk factors for LRR and the efficacy of PMRT in this Japanese patient population.

Methods: This study examined 589 cases of invasive breast carcinoma with tumors 5 cm or larger from 1998 to 2008. We divided the study population into 3 groups: patients with negative nodes, 1-3 positive nodes, and ≥4 positive nodes. The relationship between various clinicopathological variables and LRR was examined and the relationship between LRR and PMRT was estimated.

Results: During the median follow-up was 44.2 months, 38 (6.5%) patients experienced LRR. In the multivariate analysis, independent predictors of LRR include pectoral invasion in patients with 1-3 positive nodes, and severity lymphatic invasion, estrogen receptor-negative status, and nodal ratio of positive/excised nodes ≥ 0.50 in patients with ≥4 positive nodes. In patients without positive nodes, none of the examined variables were significantly associated with LRR. PMRT did not improve the outcome of the patients at highest risk who had these variables.

Conclusions: The efficacy of PMRT in patients with large tumors was not shown. In the context of systemic therapy and adequate lymph node dissection, PMRT by itself had a limited role in providing locoregional control. Due to the very low incidence of LRR observed, PMRT was not necessary for patients with large tumors without lymph node metastasis. The indication for PMRT in patients with metastatic nodes remains controversial.
Toxicity of hypofractionated adjuvant radiation after breast-conserving surgery for DCIS.
Authors: Blakaj D. , Fox J. L. , Manzerova J. , Hannan R. , Hong L. , Mehta K. J. , Kalnicki S.
Published: February 2017

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Background: Traditional fractionation for whole breast radiation therapy after breast-conserving surgery has been 50Gy in 25 fractions over a 5-week period, with or without a 10 Gy boost. Hypofractionation has recently been adapted for early-stage invasive breast cancer, typically treating with 42.5 Gy in 16 daily fractions. This approach has been shown to have equivalent efficacy as the more traditional schedule. Its application to patients with DCIS has been an extrapolation of these data, and warrants further examination. This retrospective analysis reviews toxicity outcomes in women with DCIS treated with hypofractionation at our institution.

Methods: 59 women with DCIS treated with lumpectomy and hypofractionated radiotherapy with or without boost between 2006 and 2010 at the Einstein-Montefiore Cancer Center were identified. Median age was 65 (39-85). Median follow-up was 13.7 months (2–37.6). Surgical margin status was negative in 55, positive in 1, and unknown in 3. Thirteen patients had high-grade DCIS, 17 intermediate-grade, and 13 low-grade nuclear features, and 16 did not have grade delineation. 68% of patients (40 women) had disease that was positive both for ER and PR receptors, 2 women were simultaneously positive for ER and PR, 5 women had ER-only positive disease, 2 women had HER2-neu-only positive disease, 1 woman was positive for both ER and HER2-neu receptors, 1 woman was positive only for PR receptors, and 6 women were negative for all receptors; receptor status of specimens from 2 patients is not known. All women were treated with whole-breast hypofractionated therapy (42.4 Gy, in 16 fractions of 2.65 Gy each). 49 women received a boost to the lumpectomy cavity consisting of 10Gy in 5 fractions or 9.6 Gy in 4 fractions at the physician’s discretion.

Results: With this regimen, no patient experienced acute RTOG grade 3 or higher skin, or other toxicity. No treatment breaks were required due to toxicity. The most common side effects were grade 1 dermatitis, followed by grade 2 dermatitis with mild edema of the treated breast.

Conclusions: Our results suggest that postoperative hypofractionated radiation to the breast is well tolerated by women with DCIS and does not result in untoward acute toxicity.
Early evidence of increasing national mastectomy rates for the treatment of breast cancer.
Authors: Mahmood U. , Hanlon A. L. , Koshy M. , Buras R. , Chumsri S. , Tkaczuk K. H. , Cheston S. , Regine W. , Feigenberg S. J.
Published: February 2017

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Background: The use of mastectomy for the treatment of breast cancer has declined since initial randomized trials demonstrated equivalent survival with breast conservation therapy. Recent single institution series, however, have reported increasing mastectomy rates within the past decade.

Methods: In order to verify these findings at the national level, we analyzed data from the Surveillance, Epidemiology, and End Results database, including women diagnosed with T1-2 N0-3 M0 breast cancer from 2000 to 2007. We evaluated therapeutic mastectomy rates by the year of diagnosis and performed a multivariable logistic regression analysis to determine predictors of mastectomy as the treatment choice.

Results: A total of 228,240 patients met the entry criteria. The proportion of women treated with mastectomy decreased from 40.3% to 35.6% between 2000 and 2005. Subsequently, the mastectomy rate increased to 37.9% in 2007 (p < 0.0001). The mastectomy rate in 2007 was the highest since 2002 (38.6%). A reversal in previously declining mastectomy rates was noted in nearly all cohorts, but was most pronounced among younger women. Multivariable analysis found that age, race, marital status, geographic location, involvement of multiple regions of the breast, lobular histology, increasing tumor size, lymph node positivity, increasing grade, negative hormone receptor status, and synchronous diagnosis of an ipsilateral or contralateral breast cancer were independent predictors of mastectomy. Additionally, multivariable analysis confirmed that women diagnosed in 2007 were more likely to undergo mastectomy than women diagnosed in 2005 (HR = 1.14, CI: 1.09 to 1.18, p < 0.0001).

Conclusions: There is evidence of a reversal in the previously declining national mastectomy rates, with the mastectomy rate reaching a nadir in 2005 and subsequently rising. Further follow-up to confirm this trend and investigation to determine the underlying cause of this trend and its impact on outcomes are warranted.
Prognostic classification of ipsilateral breast tumor recurrence (IBTR).
Authors: Eladoumikdachi F. G. , Jones M. , Shidfar A. , Helenowski I. B. , Franz J. M. , Scholtens D. , Sullivan M. E. , Bethke K. P. , Hansen N. M. , Jeruss J. S. , Khan S. A.
Published: February 2017

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Background: IBTR after breast conservation encompasses true recurrence (TR) and new primary cancer (NP). No clear criteria distinguish TR from NP, but there is agreement that NP tumors have better outcomes than TR. Prior studies have used distance of IBTR from index cancer (IC), time to IBTR, histological, immunohistochemical (IHC) and genetic differences, but all data are not often available. We have examined IBTR patterns with the goal of identifying the simplest, most robust determinants of outcomes following IBTR.

Methods: We reviewed records of breast cancer patients diagnosed with IBTR at the Lynn Sage Breast Center from 8/1992 to 6/2010. Data for the IBTR and IC were reviewed for histology, IHC, location, time between IC and IBTR, follow-up status, and cause of death. Parameters were scored as 1 if IBTR and IC were similar, and 0 if different (location=1 if ≤3cm; IHC=1 if hormone receptors and HER2 similar; interval=1 if ≤ 4 years). Univariate and multivariate proportional hazard models were used to determine impact on overall survival (OS), disease-specific survival (DSS), recurrence-free survival (RFS), distant recurrence free survival (DRFS) and local recurrence (LR). The multivariate model included significant univariate parameters.

Results: We identified 161 patients with IBTR and complete data on ≥3 parameters; post-IBTR median follow up was 25 months. Data were missing on location in 13%, histology in 9%, IHC in 26%, and time interval in 0%. In univariate analysis, short interval to IBTR significantly decreased OS (HR 2.56, p=0.04), DSS (HR 4.31, p=0.009), RFS (HR 2.25, p=0.01), DRFS (HR 2.53, p=0.02), LR (HR 2.28, p=0.02); close location of IBTR decreased OS (HR 2.68, p=0.04). Histology and receptor status had no significant impact on the outcomes. Multivariate analysis included time and location, time ≤ 4 years was shown to decrease DSS (HR 4.00, p= 0.04), RFS (HR 2.32, p=0.03) and LR (HR 2.41, p=0.03).

Conclusions: A short time interval between IC and IBTR is the most important prognostic parameter; location of IBTR within 3 cm of the IC also increases HR of subsequent events. These are the most easily available parameters when evaluating patients with IBTR, and therefore the most useful for distinction of TR versus new primary.
A nomogram to predict nonsentinel lymph node involvement in breast cancer patients with sentinel lymph node metastases.
Authors: Kojima Y. , Tsugawa K. , Enokido K. , Iwata H. , Ohno S. , Akiyama F. , Motomura K. , Watanabe C. , Nakamura S.
Published: February 2017

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Background: Several nomograms have been described as predictors of non-sentinel axially lymph node (non-SN) metastases in breast cancer with positive sentinel nodes (SN). However, all these predicting models were based on data from western countries. The purpose of this study was to examine predictive factors of non-SN status among SN metastatic patients, in order to develop a nomogram based on Japanese large data set.

Methods: This research was analyzed by using a clinical database of 11,228 Japanese breast cancer patients who registerd to cohort study as SN biopsy between March 2008 and Octover 2009 in Japan. We reviewed data retrospectively to extract patients with SN metastases who underwent complementary axillary lymph node dissection. In this cohort, we examined predictive factors of non-SN metastases. All clinical and pathologic features were analyzed to predict the non-SN status, by using univariate and multivariate logistic regression model. A receiver operating characteristic curve was constructed and the area under the curve (AUC) was calculated.

Results: Among the database, SN metastases were found in 1,029 patients, and 345 (33.5%) were non-SN positive. Univariate analysis showed a significant association between non-SN involvement and primary tumor size (p<0.001), histologic grade (p=0.011), lymphatic invasion (p<0.001), venous invasion (p=0.005) and the number of involved SNs among all identified SNs (p<0.001). Tumor size (p<0.001), lymphatic invasion (p<0.001), and the size of SN metastasis (p<0.001) were associated with non-SN metastasis in multivariate analysis. Based on the multivariate analysis, we developed a scoring system to predict the likelihood of non-SN metastases in breast cancer patients with SN involvement. The discriminatory ability of our nomogram, as measured by the AUC, was 0.752.

Conclusions: In patients with invasive breast cancer and a positive SN, primary tumor size, lymphatic invasion, and the size of SN metastases among all identified SNs were independently predictive of non-SN involvement, and used for a nomogram. Validation study will be performed in the future investigation.
Prognosis and non-sentinel lymph node status of the breast cancer patients with micrometastatic sentinel lymph nodes.
Authors: Takahashi M. , Jinno H. , Hayashida T. , Hirose S. , Mukai M. , Kitagawa Y.
Published: February 2017

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Background: Sentinel lymph node biopsy (SLNB) is a more sensitive and accurate nodal staging procedure than axillary lymph node dissection (ALND). Because of detailed pathologic evaluation in SLNs, more nodal micrometastases have been identified. However, it remains controversial whether to perform ALND for patients with micrometastases in SLNs and their prognostic significance is also a matter of debate. The purpose of this study is to determine the non-sentinel lymph node (NSLN) status and prognosis of the patients with micrometastatic SLNs.

Methods: A prospective database of 1,012 clinically node-negative, T1-T2 breast cancer patients, who underwent SLNB from January 2002 to Dec 2010 at Keio University Hospital was analyzed. SLNs were detected using a combined method of isosulfun blue dye and small-sized technetium-99m-labeled tin colloid. Intraoperative frozen examination was performed with hematoxylin and eosin (HE) staining. SLNs, fixed and embedded in paraffin, were additionally diagnosed with HE staining and immunohistochemical (IHC) analysis.

Results: Micrometastases in SLNs were found in 69 (6.8%) of 1,012 patients. Thirty eight (55.1%) of 69 patients with micrometastatic SLNs underwent immediate or delayed ALND and revealed no NSLN metastasis. Among 31 (44.9%) patients with micrometastatic SLNs who omitted ALND and axillary radiation therapy, no axillary lymph node recurrence has been observed after a median follow-up of 50 months, although 29 patients (93.5%) in these 31 patients received adjuvant systemic therapy. There is no significant difference in recurrence free survival between the patients with micrometastatic and negative SLNs (98.0% vs. 95.7%, respectively).

Conclusions: These date suggested that it may not be necessary to perform ALND for the patients with micrometastatic SLNs and the presence of micrometastases in SLNs may not worsen prognosis with proper systemic therapy.
Utilizing BRCA1/2 mutation status to select patients for breast cancer clinical trials: Experience from a prospective phase II trial.
Authors: Schackmann E. A. , Vinayak S. , Kurian A. W. , Ford J. M. , Telli M. L.
Published: February 2017

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Background: Information from BRCA1/2 mutation testing is used to guide cancer screening and risk reduction strategies. More recently, BRCA1/2 mutation status is being used to select patients for breast cancer (BC) clinical trials employing new targeted therapies, such as PARP inhibitors. There is concern that current testing practices do not produce results within the timeframe necessary for clinical trial eligibility assessment.

Methods: We analyzed BRCA1/2 mutation testing patterns in the context of a prospective phase II neoadjuvant study of gemcitabine, carboplatin and BSI-201 (iniparib) for women with Stage I-IIIA triple-negative or BRCA1/2 mutation-associated BC. Specifically, we analyzed: 1) the proportion of participants who met BRCA1/2 mutation testing criteria per NCCN Guidelines v1.2011 and 2) the proportion who had the Myriad Genetics Single Site, Multisite 3 (Ashkenazi Panel), BRACAnalysis and Comprehensive Rearrangement tests performed and their results. For patients without a known BRCA1/2 mutation prior to BC diagnosis who met testing criteria, we assessed the length of time from BC diagnosis to receipt of test results.

Results: Sixty-four patients between the ages of 26 and 73 were enrolled. Results are summarized below. For patients who had BRCA1/2 testing after BC diagnosis, the median number of days from BC diagnosis to receipt of results was 42.

Conclusions: The frequency of BRCA1/2 mutations in this cohort is high (20%), though nearly half of these mutations were found after patients provided trial consent. Current standard processes for testing women with newly diagnosed BC for BRCA1/2 mutations do not occur expeditiously enough for many to guide clinical trial selection.

[Table: see text]
Comparison of hypnotherapy versus gabapentin in the treatment of hot flashes: A pilot study.
Authors: MacLaughlan S. , Salzillo S. , Bowe P. , Scuncio S. , Malit B. , Raker C. , Gass J. S. , Granai C. O. , Dizon D. S.
Published: February 2017

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Background: The purpose of this study is to compare the efficacy of hypnotherapy versus gabapentin for the treatment of hot flashes in women with an increased risk or personal history of breast cancer.

Methods: In a prospective trial, eligible women were randomized to receive gabapentin (control arm) or hypnotherapy (experimental arm). Eligibility was defined by a personal history of breast cancer or an increased risk of developing breast cancer in women who reported at least one daily hot flash. The duration of participation was eight weeks, and women were asked to keep a daily journal of the number and severity of their hot flashes. The primary endpoints were number of daily hot flashes and hot flash severity score (HFSS). The secondary endpoint was quality of life, measured using the Hot Flash Related Daily Interference Score (HFRDIS).

Results: Twenty-seven women were enrolled (n=14 gabapentin, n=13 hypnotherapy) and 15 (56%) were considered evaluable for the primary endpoint (n=8 gabapentin, n=7 hypnotherapy). The median number of daily hot flashes at enrollment was 4.5 in the gabapentin arm, and 5 in the hypnotherapy arm. HFSS scores were 7.5 in the gabapentin arm and 10 in the hypnotherapy arm. After eight weeks, the median number of daily hot flashes was reduced by 33.3% among women in the gabapentin arm, and 80% in the hypnotherapy arm. The median HFSS was reduced by 33.3% in the gabapentin arm, and 85% in the hypnotherapy arm. HFRDIS scores improved by 51.6% in the gabapentin group and 55.2% in the hypnotherapy group.

Conclusions: Hypnotherapy and gabapentin both demonstrate efficacy in improving hot flashes in women with an increased risk or personal history of breast cancer. Complementary and alternative medicine (CAM) therapies are preferable to many women over hormone therapy due to the perceived risk of breast cancer, but objective data have been lacking comparing its use to conventional therapies. This pilot study provides evidence supporting the use of hypnotherapy for the treatment of hot flashes and emphasizes the need to perform further studies aimed at defining evidence-based recommendations for CAM.
Risk factor for axillary lymph node metastases in microinvasive breast cancer.
Authors: Ahn S.
Published: February 2017

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Background: Sentinel lymph node biopsy (SLNB) in patients with ductal carcinoma in situ (DCIS) was controversial. Usually we didn’t SLNB when we performed conserving operation with small sized DCIS. But sometimes we can find DCIS with microinvasive breast cancer (MIC) after operation. Must do reoperation in all patients? We determined the incidence of positive axillary lymph node (ALN) in patients with MIC and the predictive factors of ALN metastases in these patients.

Methods: Between July 1989 and December 2008, 9.635 patients had operation on invasive breast cancer in Asan Medical Center. Among these patients 319 patients had MIC. The research conducted on the 293 patients except who didn’t performed axillary lymph node dissection or SLN biopsy. We retrospectively checked clinical and pathologic variables.

Results: There were 22 cases of ALN metastases identified in this group of patients (7.5%). Lymphatic invasion (p<0.001) and positive estrogen receptor status (p=0.03) were independent significant predictors of axillary metastases.

Conclusions: Microinvasive breast cancer is associated with a low rate of lymph node metastases. Some breast cancer patients with MIC at low likelihood of lymph node metastases may be spared lymph node evaluation.