bluuebunny/crossref_metadata_2025 huggingface dataset:
First results of a phase III multicenter randomized controlled trial of intensity modulated (IMRT) versus conventional radiotherapy (RT) in head and neck cancer (PARSPORT: ISRCTN48243537; CRUK/03/005)
Authors: Nutting C. , A'Hern R. , Rogers M. S. , Sydenham M. A. , Adab F. , Harrington K. , Jefferies S. , Scrase C. , Yap B. K. , Hall E.
Published: February 2017

LBA6006

Background: Xerostomia is the most common late toxicity of RT to the head and neck. IMRT dose distributions reduce the dose delivered to parotid gland. PARSPORT investigated the role of IMRT in reducing xerostomia in patients with head and neck cancer. Methods: The PARSPORT trial compared two radiotherapy delivery methods in the treatment of patients with pharyngeal tumors (T1–4, N0–3, M0). Patients received 65Gy in 30 fractions over 6 weeks delivered using either CT planned parallel opposed lateral fields or parotid-sparing IMRT. Stratification was by site of tumor and center. The primary endpoint was incidence of LENT-SOMA ≥G2 xerostomia one year after treatment. Secondary endpoints included acute toxicities (CTCAE v3) and other late RTOG and LENT-SOMA radiation toxicities. Proportions of patients with ≥G2 toxicity were compared using exact tests. For secondary endpoints a significance level of 1% was used. Results: 94 patients (47 RT; 47 IMRT) were randomized between 2003 and 2007 from six UK centers. 80 patients had oropharyngeal tumors and 14 hypopharyngeal. Radiotherapy was given as primary treatment in 71 patients and post-operatively in 23. 22 patients had AJCC stage I/II disease. Median follow-up was 31.9 months (IQR: 26.6 –38.8). Twelve month LENT-SOMA ≥G2 xerostomia scores were observed in 74% (25/34) of RT and 40% (15/38) of IMRT patients (p=0.005). Corresponding values at 18 months were 71% (15/21) and 29% (9/31) (p=0.004). On the RTOG scale, 12 month ≥G2 xerostomia was reported in 64% (21/33) RT vs 41% (15/37) IMRT patients (p=0.06). The 18 month incidence was 81% 17/21 RT vs 20% (6/30) IMRT (p<0.001). Acute radiotherapy related ≥G2 fatigue was more prevalent in the IMRT group (76% vs 41% p=0.001). No differences in acute mucositis or pain scores were seen. At 12 months, no statistically significant differences were seen in other late toxicities. No differences were observed between overall survival and locoregional control rates. Conclusions: Sparing the salivary glands through use of IMRT significantly reduces the incidence of xerostomia in patients with pharyngeal tumors.

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Adjuvant radiotherapy and regional lymph node field control in melanoma patients after lymphadenectomy: Results of an intergroup randomized trial (ANZMTG 01.02/TROG 02.01)
Authors: Henderson M. A. , Burmeister B. , Thompson J. F. , Di Iulio J. , Fisher R. , Hong A. , Scolyer R. , Shannon K. , Hoesktra H. , Ainslie J.
Published: February 2017

LBA9084

Background: Adjuvant radiotherapy (RT) is an option for patients with isolated regional recurrence of melanoma considered to be at high risk of further regional recurrence after lymphadenectomy. This is the first completed study to assess the effects of RT on regional recurrence, survival, morbidity and quality of life (QOL) in these patients. Methods: Multicenter randomized study of patients with isolated regional recurrence at increased risk (>25%) of regional recurrence. Eligibile patients included ≥1 parotid, ≥ 2 cervical or axillary or ≥ 3 groin nodes or extra nodal spread of tumor or maximum metastatic node diameter ≥3cm in neck or axilla or ≥4cm in the groin. Patients were randomized to observation or regional nodal basin RT (48Gy in 20 fractions) after lymphadenectomy. Regional recurrence was the primary end point and morbidity, QOL, patterns of relapse, disease free and overall survival were secondary end points. The target sample size was 220 patients, which would enable a difference in 3 year regional relapse (cumulative incidence) rates of 30% versus 15% to be detected with a power of 80% (using a two sided logrank test at the 5% level of significance). Results: 250 pts were randomized from 16 centers from March 2002 to September 2007. There were 123 in the RT group and 127 in OBS group. 2 pts withdrew consent and 31 were excluded from analysis of the main objective following an independent blinded review of eligibility compliance by two reviewers. 227 pts were available for analysis of the main objective (109 RT, 108 OBS). Median follow-up was 27 mo. There was a statistically significant improvement in lymph node field control with radiotherapy, 20 RT pts and 34 OBS pts relapsed (HR 1.77 1.02–3.08 p=0.041). Median survival times were 2.6 years (RT) and 3.9 years (OBS) p=0.14. Conclusions: Adjuvant RT improved regional control in melanoma patients at high risk of regional relapse after lymphadenectomy. An effect on survival was not demonstrated.

No significant financial relationships to disclose.
ACOSOG Z0011: A randomized trial of axillary node dissection in women with clinical T1-2 N0 M0 breast cancer who have a positive sentinel node.
Authors: Giuliano A. E. , McCall L. M. , Beitsch P. D. , Whitworth P. W. , Morrow M. , Blumencranz P. W. , Leitch A. M. , Saha S. , Hunt K. , Ballman K. V.
Published: February 2017

CRA506

Background: Sentinel node biopsy (SNB) eliminates the need for axillary dissection (ALND) in patients whose sentinel node (SN) is tumor-free. However, completion ALND remains the gold standard for patients with a tumor-involved sentinel node. ALND achieves regional control, but its effect on survival remains controversial. The main objective of ACOSOG Z0011 was to compare outcomes of patients with hematoxylin and eosin (H&E) detected metastasis in SN managed with or without ALND and no axillary irradiation.

Methods: Clinically node-negative patients who underwent SN biopsy and had 1 or 2 SN with metastases detected by H&E were randomized to ALND or no further axillary specific treatment. All patients were treated with lumpectomy and opposing tangential field irradiation. Adjuvant systemic therapy was at the discretion of their physicians. Overall survival (OS), disease-free survival (DFS), and locoregional control were evaluated.

Results: 446 patients were randomized to SNB alone and 445 to SNB plus ALND. Patients treated with SNB alone were similar to those treated with SNB + ALND with respect to age, tumor size, Bloom-Richardson score, estrogen receptor status, adjuvant systemic therapy, tumor type, and T stage. Patients randomized to SNB alone had a median of two lymph nodes removed whereas patients randomized to ALND had a median of 17 lymph nodes removed. 17.6% of ALND patients had 3 or more involved nodes compared to 5.0% of SNB patients (p < 0.001). Median follow-up is 6.2 years. 5-year in breast recurrence after ALND was 3.7% compared to 2.1% for SNB (p = 0.16) while 5-year nodal recurrence was 0.6% compared to 1.3% (p = 0.44) respectively. The five-year OS for patients undergoing SNB + ALND is 91.9% compared to 92.5% for SNB alone (p = 0.24), and DFS is 82.2% compared to 83.8% respectively (p = 0.13).

Conclusions: Despite the widely held belief that ALND improves survival, no significant difference was recognized by this study of SN node-positive women. Although the study closed early because of low accrual/event rate, it is the largest phase III study of ALND for node-positive women, and it demonstrates no trend toward clinical benefit of ALND for patients with limited nodal disease.

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A phase I pharmacokinetic trial of sonic hedgehog (SHH) antagonist GDC-0449 in pediatric patients with recurrent or refractory medulloblastoma: A Pediatric Brain Tumor Consortium study (PBTC 25).
Authors: Gajjar A. J. , Stewart C. F. , Ellison D. W. , Curran T. , Phillips P. , Goldman S. , Packer R. , Kun L. E. , Boyett J. M. , Gilbertson R. J.
Published: February 2017

CRA9501

Background:Aberrant signaling in SHH pathway is implicated in causing medulloblastoma in approximately 20% of children with this disease. GDC-0449 is an orally active agent that binds to the SMO receptor and prevents downstream signaling through GLI. Preclinical murine models predict efficacy of an SMO antagonist to treat tumors dependent on the SHH pathway. Adult studies have documented the efficacy of this compound against recurrent medulloblastoma and basal cell carcinoma. A phase I pharmacokinetic trial of GDC 0449 was conducted in children with recurrent or refractory medulloblastoma to select, based on safety and pharmacokinetics, one of two dosages to recommend for a pediatric phase II trial. We also used immunonistochemistry (IHC) and in situ hybridization (ISH) on paraffin-embedded tissue to determine which tumors belonged to the SHH subtype.

Methods: GDC 0449 was administered once daily for 28 days dose levels of (1) 85 mg/m2/dose and (2) 170 mg/m2/dose. A course was defined as 28 days in duration. PK analysis was performed during the first course and steady-state concentrations were obtained prior to each subsequent course (day 21). MRI scans of the knees were obtained at baseline and 3 mos to assess abnormalities in bone development.

Results: To date 11 eligible patients have been enrolled on the trial (10 males, median age 11.6 years (range 4.4–20.9). All patients were fully evaluable for toxicity. 1 DLT, grade 3 gamma-Glutamyl transpeptidase, occurred in a patient enrolled at 170 mg/m2/dose. There were no grade 4 toxicities. The median (range) steady-state day 21 concentration at 85 mg/m2 (n=5) is 10.15 μ M (9.10–18.99 μ M) and at 170 mg/m2 (n=2) is 14.50 μ M (14.43–14.57 μ M). The steady-state GDC-0449 clearance (n=7) is 0.86 (0.44 – 1.17 L/h/m2). At steady state (day 21), the ratio of GDC-0449 CSF to plasma is 1.3%, which is an estimate of the CSF penetration of GDC-0449.

Conclusions: GDC 0449 is well-tolerated in children with recurrent or refractory medulloblastoma. The phase I study estimating the recommended phase II dose of GDC 0449 is ongoing; final results including medulloblastoma subgroup data will be presented.

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Glioblastoma (GBM) in elderly patients: A randomized phase III trial comparing survival in patients treated with 6-week radiotherapy (RT) versus hypofractionated RT over 2 weeks versus temozolomide single-agent chemotherapy (TMZ).
Authors: Malmstrom A. , Grønberg B. H. , Stupp R. , Marosi C. , Frappaz D. , Schultz H. P. , Abacioglu M. U. , Kinhult S. , Henriksson R.
Published: February 2017

LBA2002

Background: Despite treatment advances, survival of elderly GBM patients (pts) is usually < 12 months. Hypofractionated RT is advocated in order to shorten treatment time, and chemotherapy has been proposed as an alternative to RT. In a randomized trial we compared two different RT schedules with single-agent TMZ chemotherapy.

Methods: Newly diagnosed GBM pts age ≥ 60 years with PS 0-2, were randomized to either standard RT (60 Gy in 2 Gy fractions over 6 weeks) or hypofractionated RT (34 Gy in 3,4 Gy fractions over 2 weeks) or 6 cycles of chemotherapy with TMZ (200 mg/m2 day 1-5 every 28 days). Follow-up including quality of life, symptom checklist, and steroid dosing was completed at 6 weeks, 3 months, and 6 months after start of treatment. The primary study end point was overall survival (OS).

Results: A total of 342 pts were included. 291 pts were randomized between the 3 treatment options, 51 pts between hypofractionated RT and TMZ. Median age was 70 years (range 60-88), 59% were male and 72% had undergone tumor resection, the remaining 28% had a diagnostic biopsy only. Performance status was 0-1 for 75% of pts. Survival data are available for 334 pts (98%), with 11 pts (3%) being alive. There was no significant difference in OS between the three treatment arms, with median survival being 8 months for TMZ, 7.5 months for hypofractionated RT and 6 months for 6 weeks RT (p=0.14).

Conclusions: Elderly patients with GBM have a short survival. Time-consuming therapy that does not offer longer survival should therefore be avoided. Our study showed no advantage of standard 6 weeks RT compared to hypofractionated RT over 2 weeks or 6 cycles of TMZ chemotherapy. These results indicate that standard RT should no longer be offered to the elderly pt population with GBM. Exclusive TMZ chemotherapy may be an alternative to RT. Subgroup analyses and determination of molecular markers is ongoing. Whether outcome could be improved by concomitant chemoradiotherapy is subject of ongoing clinical trials.

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Phase III trial of induction gemcitabine (G) or paclitaxel (T) plus carboplatin (C) followed by elective T consolidation in advanced ovarian cancer (OC): Final safety and efficacy report.
Authors: Teneriello M. G. , Gordon A. N. , Lim P. , Janicek M.
Published: February 2017

LBA5008

Background: Safety and efficacy of GC or TC induction followed by elective T consolidation (Tcon) were evaluated.

Methods: Patients (pts) with stage IC-IV epithelial OC were randomized to GC: G 1,000 mg/m2 on days 1, 8 plus C AUC=5 on day 1; or TC: T 175 mg/m2 plus C AUC=6 on day 1 for a total of six 21-day cycles. Pts with a complete response (CR) could receive Tcon 135 mg/m2every 28 days for 12 cycles. Non-CR pts received single-agent crossover (CO) therapy (CO-T 175 mg/m2 on day 1 or CO-G 1,000 mg/m2 on days 1, 8) every 21 days until CR or progression of disease (PD). PD or death in 636 pts was required to compare GC and TC with 80% power for progression-free survival (PFS), the primary endpoint. Efficacy results were compared by log-rank test.

Results: The trial was stopped in 8/2009 after an ad hoc futility analysis showed low probability of a positive PFS result. Of 919 pts enrolled, 88 pts were excluded (clerical errors); 831 pts were entered; 820 pts had induction; 352 pts had Tcon (GC-Tcon=169, TC-Tcon=183); 155 pts had crossover (CO-T=77, CO-G=78); 313 pts discontinued after induction (GC=165, TC=148). Baseline pt characteristics were balanced across arms. Overall response and adverse events for induction regimens were similar to interim results (Gordon, Clin Ovar Cancer, 2009). For GC and TC, median PFS were 20.0 and 22.2 months; median overall survival (OS) were 43.8 and 57.3 months, respectively. There was no significant difference in PFS (p=0.199) comparing GC and TC. Despite high censorship (GC: 52.8%, TC: 61.4%), OS was greater for TC (p=0.013) compared to GC, but there was no statistical difference after adjusting for significant covariates. For pts with CR, median OS was 65.6 months with Tcon versus 51.4 months without Tcon (p=0.041). Median OS was not reached for TC-Tcon and was 56.1 months for GC-Tcon (p=0.035). For pts not receiving Tcon or receiving either CO-T or CO-G crossover, there was no difference in OS.

Conclusions: PFS was similar for GC and TC. Tcon improved OS. However, OS analysis was limited by study design and high censorship. GC does not offer an advantage over standard of care TC for first-line chemotherapy in advanced OC.

No significant financial relationships to disclose.
Phase III trial (EORTC 10994/BIG 00-01) assessing the value of p53 using a functional assay to predict sensitivity to a taxane versus nontaxane primary chemotherapy in breast cancer: Final analysis.
Authors: Bonnefoi H. R. , Bogaerts J. , Piccart M. , Mauriac L. , Fumoleau P. , Jassem J. , Becette V. , Cameron D. A. , Bergh J. , Iggo R. ,   on behalf of the EORTC, SweBCG, SAKK, and ACCOG Investigators
Published: February 2017

LBA503

Background: Predictive markers of response to chemotherapy are lacking. Preclinical data suggest that p53 mutated tumors are resistant to anthracyclines and sensitive to taxanes. However, clinical data are contradictory. Using a functional yeast assay to detect biologically important mutations, this study tested the hypothesis that docetaxel confers a greater advantage over anthracyclines in p53 mutated tumors (mut) than p53 wild type (wt).

Methods: Patients (pts) with locally advanced/inflammatory or large operable tumors were randomized to either a standard anthracycline regimen (arm A) or a taxane-based treatment (arm B). In arm A pts received 6 cycles of FEC 100, or tailored FEC + G-CSF (Swedish cohort). In arm B docetaxel (T) 100mg/m2 was given for 3 cycles, followed by 3 cycles of epirubicin 90mg/m2and T 75mg/m2 q3 weeks (T-ET). After chemotherapy, pts underwent surgery followed by radiotherapy. Endocrine therapy and/or trastuzumab were given according to each center's policy. Fresh frozen tumor biopsies were mandatory before starting chemotherapy: frozen sections were examined centrally and the p53 test was done when the invasive tumor cell content was > 20%. cDNA derived from tumor-extracted RNA was transfected into yeast (Flaman et al. PNAS 1995): tumors were deemed p53 wt when there were < 20% red colonies (background) and p53 mut > 20%. The three co-primary comparisons for the endpoint of progression-free survival (PFS) were between arms A and B in p53 mut, p53 wt, and the entire trial population, each at a p=0.02. The sample size gave sufficient power for an interaction test for outcomes between p53 mut and wt at p<0.05.

Results: From April 2001 to November 2006, 1,856 patients were included. A total of 386 pts (21%) were ineligible (including 292 pts with <20% tumor cells and 67 without sample). No unexpected toxicity was observed. At the time of analysis 675 events were registered after a median follow-up time of 57 months. The results are summarized below.

Conclusions: p53 is not a predictive factor of response or resistance to taxanes, although it is, as expected, prognostic (<0.001). PFS is not statistically significantly different between FEC and T-ET arms at the 2% cutoff level.

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A randomized phase II trial of mapatumumab, a TRAIL-R1 agonist monoclonal antibody, in combination with carboplatin and paclitaxel in patients with advanced NSCLC.
Authors: Von Pawel J. , Harvey J. H. , Spigel D. R. , Dediu M. , Reck M. , Cebotaru C. L. , Kumm E. , Gallant G. , Fox N. , Camidge D. R.
Published: February 2017

LBA7501

Background: Mapatumumab, a fully human agonist monoclonal antibody, targets and activates the death receptor TRAIL-R1. We conducted this randomized, controlled phase II trial to evaluate mapatumumab in combination with carboplatin and paclitaxel as first-line therapy in advanced non-small call lung cancer (NSCLC).

Methods: Patients were required to have histologically or cytologically confirmed Stage IIIB or IV advanced primary NSCLC with measurable disease by RECIST. Patients were randomly assigned to Arm A, paclitaxel 200 mg/m2 + carboplatin AUC 6.0 (PC); Arm B, PC + mapatumumab 10 mg/kg; or Arm C, PC + mapatumumab 30 mg/kg. Cycles were repeated every 21 days; patients completed up to 6 cycles in the absence of evidence of disease progression or unacceptable toxicity. Patients in Arms B and C could receive additional cycles of mapatumumab in the absence of disease progression. The co-primary endpoints were response rate (RR; complete response + partial response) and progression-free survival (PFS). Images were read by independent radiologists blinded to treatment group assignment, as well as locally.

Results: 111 patients were enrolled at 22 sites in 4 countries. Addition of mapatumumab to PC did not improve RR or PFS. RR and PFS, based on the independent read, and overall survival results are summarized below. The results based on local reading also showed no benefit from the addition of mapatumumab to PC. Adverse events were generally balanced across treatment groups; there was no evidence that mapatumumab exacerbated toxicities associated with PC.

Conclusions: The results do not support further evaluation of mapatumumab in combination with PC in patients with advanced NSCLC. Additional trials of mapatumumab in other indications are ongoing.

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Preoperative chemoradiotherapy and postoperative chemotherapy with 5-fluorouracil and oxaliplatin versus 5-fluorouracil alone in locally advanced rectal cancer: First results of the German CAO/ARO/AIO-04 randomized phase III trial.
Authors: Roedel C. , Becker H. , Fietkau R. , Graeven U. , Hohenberger W. , Hothorn T. , Lang-Welzenbach M. , Liersch T. , Staib L. , Christiansen H. , Wittekind C. , Sauer R. ,   German Rectal Cancer Study Group
Published: February 2017

LBA3505

Background: The German CAO/ARO/AIO-94 trial established preoperative chemoradiotherapy (CRT), surgery, and postoperative chemotherapy with 5-FU as standard treatment for locally advanced rectal cancer. With this approach local relapse rates are below 10%. The development of distant metastasis is the predominant mode of failure. Integrating more effective systemic treatment into combined modality therapy was the goal of CAO/ARO/AIO-04. Methods: Between 7/2006-2/2010, patients with rectal cancer within 12 cm from the anal verge and clinical evidence of perirectal fat or lymph node involvement were randomly assigned to receive preoperative CRT, surgery, and adjuvant chemotherapy with 5-FU according to CAO/ARO/AIO-94 (arm 1), or preoperative CRT (50.4 Gy in 28 fractions) with 5-FU (250 mg/m2/days 1-14 and 22-35) and oxaliplatin (50 mg/m2/days 1, 8, 22, 29), surgery, and 8 cycles of adjuvant chemotherapy according to modified FOLFOX6 regimen (arm 2). Disease-free survival was the primary endpoint. We present early secondary endpoints, including acute toxicity, treatment compliance, and pCR-rates. Results: 637 patients were randomly assigned to arm 1 and 628 to arm 2. Full dose preoperative RT and full dose concurrent chemotherapy was delivered in 97% and 74% of patients in both arms, respectively. Preoperative grade 3/4 toxicity occurred in 21.6% in arm 1 and in 22.9% in arm 2. The R0-resection rate was 95.4% in both arms, and abdominoperineal resections were limited to 11.9% and 12.2% in arms 1 and 2, respectively. Overall postoperative complications were not different between both arms (21.0% and 21.9%). The pCR rate (ypT0N0) was 13.1% in arm 1 and 17.6% in arm 2 (p = 0.033, Cochran-Mantel-Haenszel Chi-Squared Test without continuity correction for conditional independence of pCR rate in the two treatment arms in each stratum). Conclusions: Inclusion of oxaliplatin to 5-FU based CRT was well tolerated and associated with increased pCR-rates compared with 5-FU-CRT alone. Longer follow-up is necessary to evaluate the primary endpoint, disease-free survival.
Phase III randomized, open-label, multicenter trial (BRIM3) comparing BRAF inhibitor vemurafenib with dacarbazine (DTIC) in patients with V600EBRAF-mutated melanoma.
Authors: Chapman P. B. , Hauschild A. , Robert C. , Larkin J. M. G. , Haanen J. B. A. G. , Ribas A. , Hogg D. , O'Day S. , Ascierto P. A. , Testori A. , Lorigan P. , Dummer R. , Sosman J. A. , Garbe C. , Lee R. J. , Nolop K. B. , Nelson B. , Hou J. , Flaherty K. T. , McArthur G. A.
Published: February 2017

LBA4

Background: About 50% of melanomas have an activating V600EBRAF mutation which led to the hypothesis that inhibition of the mutated BRAF kinase may be of clinical benefit. Phase I and II trials with vemurafenib (previously PLX4032/RO5185426), an orally available inhibitor of oncogenic BRAF kinase, showed response rates (RR; CR+PR) >50% in V600EBRAF- mutated melanoma patients (pts). We conducted a phase III trial to determine if vemurafenib improved overall survival (OS) and progression-free survival (PFS) in melanoma pts with V600EBRAF mutation. Methods: Pts with previously untreated, unresectable stage IIIC or stage IV melanoma that tested positive for V600EBRAF mutation by the cobas 4800 BRAF V600 Mutation Test were randomized (1:1) to vemurafenib (960 mg po bid) or DTIC (1,000 mg/m2, IV, q3w). Randomization was stratified by PS, stage, LDH, and geographic region. Pts were assessed for tumor responses after weeks 6, 12, and then q9 weeks. Co-primary endpoints were OS and PFS on the intent-to-treat population; secondary endpoints included RR, response duration, and safety. Final analysis was planned at 196 deaths. Results: 675 pts were enrolled at 103 centers worldwide between Jan and Dec 2010. Treatment cohorts were well-balanced. At the pre-planned interim analysis (50% of deaths needed for final analysis), the hazard ratios for OS and PFS were 0.37 (95% CI 0.26 to 0.55; p<0.0001) and 0.26 (95% CI 0.20 to 0.33; p<0.0001), respectively, both in favor of vemurafenib. The confirmed RR was 48.4% and 5.5% to vemurafenib and DTIC, respectively, among the 65% of pts evaluable for RR to date. Benefit in OS, PFS, and RR was seen in all subgroups examined. Due to these data, the DTIC cohort has been allowed to cross over to vemurafenib. At the time of data analysis, 66% of vemurafenib pts and 25% DTIC pts were still on treatment. The most common toxicities of vemurafenib were: diarrhea, rash, alopecia, photosensitivity, fatigue, arthralgia, and keratoacanthoma/skin squamous cell carcinoma. Conclusions: Vemurafenib is associated with significantly improved OS and PFS compared to DTIC in pts with previously untreated, V600EBRAF-mutated metastatic melanoma.
Phase III randomized study of ipilimumab (IPI) plus dacarbazine (DTIC) versus DTIC alone as first-line treatment in patients with unresectable stage III or IV melanoma.
Authors: Wolchok J. D. , Thomas L. , Bondarenko I. N. , O'Day S. , Weber J. S. , Garbe C. , Francis S. , Ibrahim R. A. , Hoos A. , Robert C.
Published: February 2017

LBA5

Background: IPI monotherapy (3mg/kg) improved overall survival (OS) in a phase III study of previously treated, unresectable or metastatic melanoma. Current study in 1st line metastatic melanoma evaluates combination of DTIC (a global standard of care) plus IPI. Methods: In this double-blind phase 3 study, patients (pts) with metastatic melanoma, ECOG PS 0/1, and no prior therapy for advanced disease, were randomized 1:1 to IPI (10 mg/kg) + DTIC (850 mg/m2) or placebo + DTIC (850 mg/m2) at Wks 1, 4, 7, 10 followed by DTIC q3 wks through Wk 22 (induction). Eligible pts received IPI or placebo q12 wks as maintenance. Primary endpoint was OS; 2-sided log-rank test was performed, stratified by baseline M stage and ECOG PS. Results: Of 502 pts, 56% had M1c disease, 40% elevated LDH, and 26% adjuvant therapy. 37% in IPI + DTIC and 65% in DTIC alone arms received 4 induction doses. A significant improvement in OS (HR=0.72; P=0.0009) and higher estimated 1, 2 and 3 yr survival rates were seen with IPI + DTIC (Table). 56% in IPI +DTIC (n=247) and 27% in DTIC alone (n=251) arms had grade 3/4 adverse events (AEs, regardless of attribution), including: elevated ALT (22% vs 1%); diarrhea (4% vs 0%); rash (1% vs 0%). No intestinal perforations or hypophysitis were noted. There were no drug-related deaths in IPI + DTIC and one in DTIC alone arm [gastrointestinal (GI) hemorrhage]. Conclusions: IPI (10mg/kg) + DTIC significantly improved OS in 1st line metastatic melanoma vs DTIC alone; durable survival and objective responses were noted in some pts after follow-up for up to 4yrs. Type of AEs was consistent with prior IPI studies; however, frequencies of some AEs differed with a higher transaminitis and lower diarrhea/colitis/ GI perforation rates than expected. No drug-related deaths were noted in IPI arm. OS benefit of IPI is confirmed in treatment-naive metastatic melanoma.

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An international, randomized, placebo-controlled, double-blind phase III study (MONET1) of motesanib plus carboplatin/paclitaxel (C/P) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC).
Authors: Scagliotti G. , Vynnychenko I. , Ichinose Y. , Park K. , Kubota K. , Blackhall F. H. , Pirker R. , Galiulin R. , Ciuleanu T. , Sydorenko O. , Dediu M. , Papai-Szekely Z. , Martinez Banaclocha N. , McCoy S. , Yao B. , Hei Y. J. , Spigel D. R.
Published: February 2017

LBA7512

Background: This study evaluated whether motesanib (a selective oral inhibitor of VEGFR 1, 2 and 3; PDGFR and Kit) plus C/P improved overall survival (OS) compared with placebo + C/P in patients (pts) with nonsquamous NSCLC and in a subset of pts with adenocarcinoma. Methods: Pts had stage IIIB/IV or recurrent nonsquamous NSCLC and no prior systemic therapy for advanced NSCLC. The study initially enrolled all histologies but was amended to exclude pts with squamous NSCLC owing to a high rate of hemoptysis. Pts were randomized 1:1 to receive up to six 3-wk cycles of C (AUC 6 mg/mL·min) and P (200 mg/m2) with either motesanib 125 mg QD (Arm A) or placebo QD (Arm B) orally continuously. The primary endpoint was OS; secondary endpoints included progression-free survival (PFS), adverse events (AEs), objective response rate (ORR) and association between placental growth factor (PLGF) change and OS. OS was evaluated using a stratified Cox model and 2-sided log-rank test (α=0.03 for nonsquamous pts and α=0.02 for adenocarcinoma pts). Results: 1090 pts with nonsquamous NSCLC were randomized (Arm A/B, n=541/549); 890 had adenocarcinoma (n=448/442). 61% were men; median age was 60 years (range 21–87); 83% had stage IV disease. At the time of analysis, 753 pts had died (608 pts with adenocarcinoma). Median follow-up was 10.6 mo. OS was not significantly improved in Arm A compared with Arm B (Table). In Arm A, PLGF analysis did not show an association with OS. The incidence of grade ≥3 AEs in Arms A/B was 73/59%. Grade ≥3 AEs occurring more frequently in Arm A than B included neutropenia (22/15%), diarrhea (9/1%), hypertension (7/1%) and cholecystitis (3/0%). The incidence of grade 5 AEs was 14/9% in Arms A/B. Conclusions: In pts with advanced nonsquamous NSCLC, treatment with motesanib + C/P did not significantly improve OS compared with C/P alone.

[Table: see text]
The ultra-low molecular weight heparin (ULMWH) semuloparin for prevention of venous thromboembolism (VTE) in patients with cancer receiving chemotherapy: SAVE ONCO study.
Authors: Agnelli G. , George D. J. , Fisher W. , Kakkar A. K. , Lassen M. R. , Mismetti P. , Mouret P. , Chaudhari U. , Turpie A. G. G.
Published: February 2017

LBA9014

Background: Patients receiving chemotherapy for cancer are at increased risk for VTE; large randomized controlled trials (RCT) are needed to demonstrate benefit of antithrombotic prophylaxis. Semuloparin is a novel ULMWH with high anti-factor Xa and residual anti-factor IIa activities. We performed a multinational RCT to assess the efficacy and safety of semuloparin for VTE prevention in cancer patients receiving chemotherapy (SAVE-ONCO). Methods: This was a double-blind study in patients with metastatic or locally advanced cancer of lung, colon-rectum, stomach, ovary, pancreas, or bladder, initiating a new chemotherapy course. Patients were randomized to receive subcutaneous semuloparin, 20 mg od, or placebo, until change of chemotherapy. The primary efficacy outcome was the composite of any symptomatic deep vein thrombosis (DVT), non fatal pulmonary embolism (PE) and VTE-related death. Clinically relevant bleeding was the main safety outcome. Outcomes were adjudicated by an independent Committee. Results: Of 3,212 randomized patients, 68% had metastatic cancer; the majority had lung (37%) or colon-rectum (29%) cancer. Median treatment duration was ~3.5 months. Twenty of the 1,608 patients treated with semuloparin (1.2%) and 55 of the 1,604 patients treated with placebo (3.4%) had a thromboembolic event, representing a 64% risk reduction in such event rate (hazard ratio [HR]=0.36, 95% confidence interval [CI] 0.21–0.60, p<0.0001, intent-to-treat analysis). Treatment effect was consistent for DVT and PE, with a 59% risk reduction in PE rate (odds ratio 0.41, 95%CI 0.19–0.85). No heterogeneity in the benefit was observed for cancer type or stage. Nineteen of 1,589 patients (1.2%) in the semuloparin and 18 of the 1,583 patients (1.1%) in the placebo group had a major bleeding (HR=1.05, 95%CI 0.55 to 1.99). The rate of clinically relevant bleeding was 2.8% with semuloparin vs 2.0% with placebo (HR=1.40, 95%CI 0.89–2.21). Conclusions: We have demonstrated the benefit of thromboprophylaxis with semuloparin in patients receiving chemotherapy without increase in major bleeding. Such patients should be considered for thromboprophylaxis.
Multivariate analysis of predictors of positive or close margins in breast-conserving therapy.
Authors: Chokechanachaisakul A. , Wesen C. A. , Hall T. M. , Falk J. S.
Published: February 2017

105

Background: Local recurrence rates after breast-conserving therapy (BCT) are increased with positive or close margin lumpectomy. This group of patients usually requires a re-excision lumpectomy or a completion mastectomy, causing delays in systemic therapy, and a less desirable cosmetic outcome. The objectives of this study were to identify any predictive risk factors that might be associated with positive or close lumpectomy margins (<1mm), and thus have implications for the planning of appropriate primary surgical excision.

Methods: This was a retrospective cohort study of 195 consecutive patients from a prospectively collected, single-institution database. Patients who underwent primary lumpectomy for ductal carcinoma in situ (DCIS), invasive ductal carcinoma, and invasive lobular carcinoma from October 2007 to July 2010 were reviewed. Statistical analysis of the data was performed using Chi-squared analyses, multivariate logistic regression and Student’s t-test to identify significant predictors of a close or positive margin following lumpectomy.

Results: In this study, 53.8% had positive or close margins. Ninety-two percent of this group underwent re-excision (86.5%) and total mastectomy (13.5%). We also observed that 53.1% of patients who underwent second operation had no residual disease. Factors significantly associated with positive or close margins include a family history of breast cancer (OR=2.3, p=0.01), a non-palpable mass (OR=2.4, p=0.01), or an excisional biopsy (OR=6.02, p=0.022). Age, race, use of hormone replacement therapy, menopausal status, use of preoperative MRI or US, BIRAD, use of neoadjuvant chemotherapy, tumor size, staging, waiting time, histology, receptor status, and axillary status were not significantly correlated with positive or close margins.

Conclusions: For patients who were recommended to have a lumpectomy, an increased risk of a positive or close margin was significantly associated with a family history of breast cancer, a nonpalpable mass, or an excisional biopsy. These predictors should be weighed in the decision for attempting lumpectomy with the goal of a negative margin versus the ability to obtain a satisfactory cosmetic outcome.
Accelerated partial breast brachytherapy after lumpectomy as salvage treatment for local recurrences after conservative treatment of breast cancer: Eighteen-year results of a nonrandomized comparison with mastectomy.
Authors: Guix B. , Lejarcegui J. A. , Tello J. I. , Guix I. , Zanon G. , Quinzaños L. , Palombo P. , Del-Campo J. M. , Galdon G. , Espino M. , Milla A.
Published: February 2017

109

Background: To report the long-term results in a prospective group of patients (pts) treated for local recurrence after conservative treatment of breast cancer by a second conservative surgery or by total mastectomy.

Methods: Between 12/1990 and 10/2004, 85 pts with <3 cm, low-risk local recurrence after conservative treatment for breast cancer were offered total mastectomy. 48 of them refused it and were treated by a second lumpectomy followed by HDR brachytherapy implant to the tumor bed+margin. 30 Gy in 12 fractions in 5 days were given. Pts treated by mastectomy had no further radiotherapy. Postmenopausal pts with negative receptors had no systemic tx. The rest of the pts had chemo or hormones. No pts were lost for follow-up.

Results: All pts completed treatment. During the 17-year, 1-year minimum follow-up, in the second conservative group there were 8 pts who had regional (2 pts) or distant metastases (6 pts) as their first site of failure. Three of them experienced a differed local recurrence and 1 died from the disease. In the total mastectomy group, there were 2 local recurrences, 1 regional recurrence, and 5 distant metastases as first site of failure. One patient died from the disease. Actuarial results at 17-year for second conservative and total mastectomy were respectively: local control 84.2%-71.7%; disease free survival 65.4%-63.8%; and survival 90.7% and 88.2%. Cosmetic results were satisfactory in 89.4% treated conservatively. No patient experienced arm edema or grade 3-4 early or late complications. Between the 14 pts that were followed-up for at least 10-years, 13 of them were with their breast still in place.

Conclusions: Second conservative treatment by HDR brachytherapy was a safe and effective method of treatment for small-size, low-risk, local recurrence after local excision in conservatively treated pts. APBI with wide margins probed to be enough treatment, without significant side-effects in previously intesively irradiated patients. Lumpectomy and partial breast brachytherapy can be conidered the treatment of choice in selected patients with low-risk recurrent breast tumors.
Triple-negative breast cancer (TNBC) outcomes with partial breast irradiation and concurrent chemotherapy (PBI-CC) compared with whole breast irradiation and sequential chemotherapy (WBI-SC).
Authors: De Souza Lawrence L. M. , Shah A. , Stearns V. , Asrari F. , Frassica D. A. , Tsangaris T. N. , Fetting J. H. , Lange J. R. , Jacobs L. K. , Zellars R. C.
Published: February 2017

115

Background: TNBC (ER/PR/HER2-negative) is associated with worse locoregional recurrence (LRR), disease-free survival (DFS), and overall survival (OS) than non-TNBC. MSKCC/Harvard recently reported a 5-yr local recurrence rate of 33% in TNBC patients treated with PBI (Pashtan et. al. ASTRO 2010). Having completed two prospective trials of PBI-CC, one previously reported (Zellars et al. JCO 2009), we reviewed the outcomes of TNBC patients treated with PBI-CC and compared them to those treated with WBI-SC.

Methods: TNBC patients treated on 2 phase I/II PBI-CC protocols were compared to a cohort of TNBC patients treated at our institution with WBI-SC with respect to OS, DFS, LRR and in-breast tumor recurrence (IBTR). KM rates of local and distant recurrence, log-rank test of statistical significance are presented.

Results: Between 2004 and 2009, 16 patients were treated with PBI-CC and 32 with WBI-SC. PBI-CC was 40.5 Gy (2.7 Gy x 15 QD) to the lumpectomy bed only with cycle 1 of ddAC (60/600 mg/m2 every 14 days with growth factor support x 4 cycles). WBI-SC patients received a med. dose (+ boost) of 60.7 Gy, (42.5 – 66), 5/32 had nodal irradiation. 28/32 recieved AC, and 4/32 C, Docetaxel. Med. follow-up is 38.4 mo (9.2–65.5) and 40.5 mo (5.6–77.8), respectively. There is no statistically significant difference between groups with respect to T/N stage, median age, and menopausal status. No patients died. All 6 recurrences (1 nodal, 4 IBTR, 1 distant) were in the WBI-SC group. Med. time to recurrence was 14.4 months (0.8–38.6). DFS at 3 yr/5 yr were 100% vs. 84.4% (p=0.10) and 100% vs. 81.3%. (p=0.07) in the PBI-CC and WBI-SC groups respectively. There is a trend towards decreased LRR (0% vs. 15.6%, p=0.12) and IBTR (0% vs. 12.5% , p=0.16), in favor of PBI-CC.

Conclusions: Our results differ from earlier reports of a high rate of LRR in TNBC patients treated with PBI. This may be due to our use of concurrent chemotherapy with PBI or to undefined factors in our series of WBI-SC. Our data suggest improved DFS, LRR, and IBTR with PBI-CC when compared to retrospectively reviewed contemporary TNBC patients treated WBI-SC and should be externally confirmed.
Patterns of locoregional failure following radiotherapy for breast cancer.
Authors: Chen S. A. , Crocker I. R. , Fox T. , Liu T. , Whitaker D. , Godette K. D. , Torres M. A.
Published: February 2017

118

Background: To determine the influence of radiotherapy (XRT) technique on local control in breast cancer (BRCA) patients, we evaluated the relationship between PET/CT-identified locoregional recurrences (LRR) and prior definitive XRT treatment plans.

Methods: Twenty-two consecutive LRRs of BRCA were identified by PET/CT in 19 patients treated from 2004-2011 with definitive post-operative radiation for their BRCA. PET/CT and original XRT CT simulation images were fused using a B-spline deformable registration algorithm (VelocityAI, Velocity Medical Solutions, Atlanta, GA) to correct for posture and soft tissue changes. Prior XRT dose to the FDG avid LRR region was calculated. LRR was classified as in-field, marginal or out-of-field. In-field LRRs were defined as ≥95% of the LRR volume receiving ≥95% of the prescribed dose (45–50.4 Gy). Marginal misses were LRRs at the field edge and/or not receiving ≥95% of the prescribed dose. Out-of-field LRRs were LRRs intentionally not treated with the original XRT plan.

Results: Four LRRs were in-field, 8 were marginal and 10 were out-of-field, with two patients having both in-field and out-of-field LRRs and one having a marginal and out-of-field LRRs. Three in-field, 3 marginal and 6 out-of-field LRRs occurred simultaneously with distant metastasis (DM). In-field LRRs received a median dose of 48.4Gy (range 45-50Gy). Two in-field LRRs were marginal misses of the additional 15 Gy boost dose (median dose received 53.5 Gy); both patients had high grade, ER/PR-, and HER2 + tumors. In the 7 patients with triple negative tumors, there were 4 marginal, 4 out-of-field, and no in-field LRRs. Among marginal LRRs, a median dose of 33Gy (range 2–45.6Gy) was delivered. Out-of-field LRRs occurred in 5 supraclavicular and 5 internal mammary lymph nodes. With a median follow-up period of 3.7 yrs, the 5-yr disease-free survival (DFS) in patients with an isolated LRR is 55.6%, while in those recurring with DM, the DFS is 22.5%.

Conclusions: Our study is one of the first to systematically evaluate the influence of XRT technique over local control in BRCA. Due to the number of marginal and out-of-field LRRs, our data suggest that XRT field design and dose are important factors in preventing LRRs in addition to tumor biology.
Preliminary results of a prospective trial of image-guided 3D conformal accelerated partial breast irradiation (APBI).
Authors: Pham H. T. , Yao M. , Song G. , Badiozamani K. R. , Salcedo - Wasicek C. , Wechter D.
Published: February 2017

125

Background: External beam APBI is noninvasive and may offer better coverage of tumor sites in proximity to skin or chest wall than brachytherapy. To improve conformality and accuracy of treatment, we conducted a prospective IRB-approved clinical trial of APBI with implanted gold markers for image guidance. Cosmetic assessments through patient and physician questionnaires were collected. Adverse events were graded according to Common Terminology Criteria for Adverse Events v3.0. This is our preliminary report on toxicity and cosmetic outcomes.

Methods: Thirty-four pts were enrolled from 12/06 to 4/10. Eligibility criteria included age > 40, unifocal disease, ductal histology, tumor ≤ 3 cm, surgical margin ≥ 2 mm, and planning target volume: breast volume ratio < 0.2. Vascular invasion, positive axillary nodes, high-grade ductal carcinoma in situ, and extensive intraductal component were excluded. Three gold fiducials were sutured into the operative site at the time of partial mastectomy. The clinical target volume comprised the surgical cavity including all surgical clips and gold fiducials + 10-15 mm. Prescribed dose was 3.85 Gy b.i.d. to 38.5 Gy, using 4–5 non-coplanar beams. Special breathing technique and image guidance with electronic portal imaging were used.

Results: Median follow-up is 18 months (range 7-47 months). Most pts had mild acute reactions with only 6% grade 2 erythema. Late toxicities include hyperpigmentation (71% grade 1), fibrosis (26% grade 1, 32% grade 2), skin dimpling or indentation (38% grade 1, 3% grade 2), telangiectasias (12% grade 1), rib fractures in the treatment area (3% grade 2). The only grade 3 toxicity was a seroma requiring surgical excision in one pt. Cosmesis was rated by the pt versus (v.) physician as excellent/good in 85% v. 94%, 80% v. 90%, and 84% v. 85% of the pts at prior to treatment, 6 months, and one year respectively. Ninety-one percent of patients were “totally satisfied with the treatment and results.” No breast recurrences have been observed.

Conclusions: Image-guided APBI is well-tolerated, with high patient satisfaction. Early cosmesis results, as assessed by both pts and physicians, are comparable to whole-breast radiotherapy.
Concordance between the 21-gene recurrence score (RS) and the 70-gene profile (MP) in breast cancer (BC) patients (pts).
Authors: Denduluri N. , Rugo H. S. , Davis S. E. , Favret A. , Hong R. , Au A. , Moore D. H. , Esserman L.
Published: February 2017

13

Background: Genomic assays are increasingly incorporated into treatment planning for pts with early stage BC to provide prognostic and/or predictive information. MP is a validated predictor of recurrence risk (RR) in pts without any treatment and RS is a validated predictor of RR in pts treated with 5 years of hormonal therapy (HT). Because concordance between RS and MP is largely unknown, we analyzed concordance in untreated pts that had both tests performed.

Methods: Data are from 50 early stage BC pts treated at 4 US Oncology practices and the University of California, San Francisco. We used linear regression to test whether clinical features were related to discordance, measured as part of the gamma statistic.

Results: Median age was 52.5 years, 16% (8 pts) had micro or macroscopic nodal involvement, and 66%, 30%, and 4% of pts had stage I, II, and III disease, respectively. All pts had estrogen receptor positive disease and 2 pts had HER2 overexpression by IHC or FISH. Concordance of MP and RS is shown below. Clinical features, including tumor size, grade, and HER2 were not significantly related to discordance. Gamma concordance was 0.64 (95% CI 0.28 to 0.98, p=0.0013).

Conclusions: Concordance is high, mostly due to agreement in low risk scores. Five cases are truly discordant (MP low/RS intermediate or high) based on predicted outcomes. The 11 cases with high-risk MP with low risk RS may reflect endocrine sensitivity to 5 years of HT, or true discordance. Our identification of discordance should stimulate research to further clarify biology and elucidate the drivers of different types of risk. Large studies are underway to refine risk definition and treatment recommendations.

[Table: see text]