bluuebunny/crossref_metadata_2025 huggingface dataset:
Results from ARQ 197-209: A global randomized placebo-controlled phase II clinical trial of erlotinib plus ARQ 197 versus erlotinib plus placebo in previously treated EGFR inhibitor-naive patients with locally advanced or metastatic non-small cell lung cancer (NSCLC).
Authors: Schiller J. H. , Akerley W. L. , Brugger W. , Ferrari D. , Garmey E. G. , Gerber D. E. , Orlov S. V. , Ramlau R. , Von Pawel J. , Sequist L. V.
Published: February 2017

LBA7502

Background: Orally administered ARQ197 is a selective, non-ATP competitive inhibitor of c-MET (MET), a receptor TK implicated in cancer cell migration, invasion, and proliferation. Dual EGFR-MET inhibition is a promising strategy for overcoming MET-mediated resistance to EGFR inhibitors. A prior phase I trial demonstrated the safety of ARQ197 plus erlotinib and suggested activity in patients (pts) with advanced NSCLC.

Methods: This is a global, randomized, placebo-controlled, double-blind trial comparing erlotinib plus ARQ197 (E+A) versus erlotinib plus placebo (E+P). Archival tissue was collected for all pts for k-RAS, EGFR, and MET analyses. The primary endpoint was PFS; secondary endpoints included safety, ORR, OS, and subgroup analyses.

Results: 167 pts were randomized to E+A (84 pts) or E+P (83 pts). Mean age was 63 yrs and baseline characteristics were well balanced for sex (39%/41% F); race (93%/96% white) and smoking history (20%/22% never smoker). Imbalances were seen among treatment arms in NSCLC histology (54%/64% adeno) and predictive molecular genotypes: EGFR mutations (7%/13%) and k-RAS mutations (12%/6%). Final PFS was prolonged with E+A (median = 16.1 wks) vs E+P (9.7 wks) among ITT pts (HR 0.81 [95% CI 0.57, 1.15]; p=0.23). Planned multivariable Cox regression model adjusting for prognostic factors (including histology, genotype) yielded PFS HR 0.68 (95% CI 0.47, 0.98; p<0.05). PFS improvement was particularly prominent among pts with nonsquamous histology, EGFR wild-type status, and k-RAS mutations. Preliminary safety analysis revealed no major differences between arms with AEs (≥10% of pts; all grades) including rash (64%/52%); diarrhea (48%/53%); fatigue (33%/37%); nausea (26%/26%); and anemia (14%/13%). OS, ORR, and final safety data will be analyzed at study conclusion.

Conclusions: Combined with erlotinib in the treatment of second/third-line EGFR-inhibitor naïve NSCLC, ARQ-197 is well-tolerated and prolongs PFS. Particular benefit is observed among pts with non-squamous histology, k-RAS mutations, and EGFR wild-type status.

[Table: see text]
Efficacy and safety of PF299804 versus erlotinib (E): A global, randomized phase II trial in patients (pts) with advanced non-small cell lung cancer (NSCLC) after failure of chemotherapy (CT).
Authors: Boyer M. J. , Blackhall F. H. , Park K. , Barrios C. H. , Krzakowski M. J. , Taylor I. , Liang J. Q. , Denis L. J. , O'Connell J. P. , Ramalingam S. S.
Published: February 2017

LBA7523

Background: PF299804, a potent, irreversible inhibitor of human epidermal growth factor receptor (HER)-1/EGFR, -2, and -4 tyrosine kinases (TK), is active in E-sensitive and -resistant preclinical models. PF299804 had clinical activity in phase I/II trials in EGFR TK inhibitor (TKI)-refractory NSCLC; a phase III trial is ongoing (BR26). The current trial compared efficacy and safety of PF299804 vs.E in pts with NSCLC after CT failure.

Methods: Eligible pts (any histology, ECOG performance status [PS] 0–2, 1/2 CT regimen failures, no prior E, available tumor tissue) were randomized 1:1 to oral PF299804 45 mg or E 150 mg once daily and treated until progression/toxicity. Endpoints included progression-free survival (PFS; primary), overall survival (OS), objective response rate (ORR), safety, and KRAS/EGFR mutation (mu) status.

Results: 188 pts (median age 60 years, 87% PS 0/1, 41% female, 65% adenocarcinoma (adeno), 25% East Asian, 21% non-smoker, 16% EGFR mu, 16% KRAS mu) were randomized. Baseline characteristics were balanced between arms except for PS 2 ( PF299804 , 20; E, 3 pts). Mu status determination rates were high (KRAS, 81%; EGFR, 77%). Median follow-up was 12 weeks. PF299804 showed significantly longer PFS vs. E in the overall population (p=0.017), with benefit consistent across several subgroups (SG) including EGFR wild type (wt). ORR favored PF299804 (17% vs. 4%; p=0.008). Frequent treatment-related adverse events (TRAEs) for PF299804 vs. E (grade, any/3 or 4): diarrhea (71%/11% v 48%/3%), acne (53%/7% vs. 34%/5%), and rash (26%/4% vs. 37%/2%). Eight pts discontinued due to TRAEs: PF299804 , 6; E, 2 pts.

Conclusions: PF299804 showed significant improvement in PFS (primary endpoint) vs. E in all enrolled pts with NSCLC. Common EGFR TKI AEs were more frequent with PF299804.

[Table: see text]

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Busulphan-melphalan as a myeloablative therapy (MAT) for high-risk neuroblastoma: Results from the HR-NBL1/SIOPEN trial.
Authors: Ladenstein R. L. , Poetschger U. , Luksch R. , Brock P. , Castel V. , Yaniv I. , Papadakis V. , Laureys G. , Malis J. , Balwierz W. , Ruud E. , Kogner P. , Schroeder H. , Forjaz De Lacerda A. , Beck Popovic M. , Bician P. , Garami M. , Trahair T. , Pearson A. D. , Valteau Couanet D.
Published: February 2017

2

Background: The HR-NBL1 trial of the European SIOP Neuroblastoma Group randomised 2 MAT regimens with the primary aim to demonstrate superiority based on event free survival (EFS). Methods: At randomisation closure, 1,577 high-risk neuroblastoma patients (944 males) had been included since 2002; with INSS stage 4 disease (1,369 pts) > 1 year, infants (65 pts) and stage II and III (143 pts) of any age with MYCN amplification. Response eligibility criteria prior to randomisation after Rapid COJEC Induction (J Clin Oncol, 2010) ± 2 courses of TVD (Cancer, 2003) included complete bone marrow remission and ≤ 3, but improved, mIBG positive spots. The MAT regimens were BuMel (oral busulfan till 2006, 4x150mg/m2 in 4 equal doses, or after 2006 intravenous use according to body weight and melphalan 140mg/m2/day) and CEM (carboplatin ctn. infusion [4xAUC 4.1mg/ml.min/day], etoposide ctn. infusion [4x338mg/m2day or 4x200mg/m2/day*], melphalan [3x70mg/m2/day or 3x60mg/m2/day*. *reduced if GFR<100ml/min/1.73m2]). A minimum of 3x10E6 CD34/kgBW PBSC were requested. VOD prophylaxis included ursadiol, but not prophylactic defibrotide. Local control included surgery and radiotherapy of 21 Gy. A total of 598 patients were randomised (296 BuMel, 302 CEM). The median age at randomisation was 3 years (1-17.2) with a median follow up of 3 years. Results: At the last analysis, the Peto rule of p<0.001 was met. A significant difference in EFS in favour of BuMel (3-years EFS 49% vs 33%) was observed as well as for overall survival (3-years OS 60% vs 48%, p=0.004). This difference was mainly related to the relapse and progression incidence, which was significantly (p<0.001) lower with BuMel (48% vs 60%). The severe toxicity rate up to day 100 (ICU and toxic deaths) was below 10%, but was significantly higher for CEM (p=0.014). The acute toxic death rate was 3% for BuMel and 5% for CEM (NS). The acute MAT toxicity profile favours the BuMel regimen in spite of a total VOD incidence of 18% (grade 3:5%). Based on these results and following advice from the DMC, the randomisation was closed early. Conclusions: BuMel was demonstrated to be superior to CEM and hence is recommended as standard treatment.
Personalized medicine in a phase I clinical trials program: The M. D. Anderson Cancer Center Initiative.
Authors: Tsimberidou A. M. , Iskander N. G. , Hong D. S. , Wheler J. J. , Fu S. , Piha-Paul S. A. , Naing A. , Falchook G. S. , Janku F. , Luthra R. , Wen S. , Kurzrock R.
Published: February 2017

CRA2500

Background: We initiated a personalized medicine program hypothesizing that tumor molecular analysis and use of targeted therapy to counteract the effects of specific aberrations would improve the outcomes of affected patients. Methods: Molecular analysis was performed in the M. D. Anderson CLIA-certified pathology laboratory. Patients whose tumors had an aberration were treated in the Phase I Program with a matched targeted agent, when available. Results: Tumor molecular analysis was feasible in 852 (89%) of 955 consecutive patients with advanced cancer. Of 852 patients (median, age 56 yrs; prior therapies 4), 354 (41.5%) had ≥ 1 aberration: 10% of patients had a PIK3CA mutation; 19% KRAS; 8% NRAS; 19% BRAF; 3% EGFR; and 2% had a CKIT mutation; 21% had PTEN loss. Results are shown in the table. Median time to treatment failure (TTF) in 161 patients with 1 aberration treated with matched targeted therapy was 5.3 months (95%CI: 4.1, 6.6) vs 3.2 months (95%CI: 2.9 – 4.0) for their prior systemic antitumor therapy (prior to referral to phase I) (p= .0003). For patients with 1 aberration, the CR+PR rate was 29% with matched targeted therapy vs. 8% without matching (p = .0001). The CR+PR rate was 6% in 438 patients without molecular testing treated on the same studies. Conclusions: Preliminary results suggest that in early clinical trials matching patients with targeted drugs based on their molecular profile results in (a) longer TTF compared to their prior therapy and (b) higher rates of response, survival and TTF compared to those seen in patients treated without molecular matching. Support: 3UL1 RR024148 04 S1 and IPCT.

[Table: see text]
Twelve versus 36 months of adjuvant imatinib (IM) as treatment of operable GIST with a high risk of recurrence: Final results of a randomized trial (SSGXVIII/AIO).
Authors: Joensuu H. , Eriksson M. , Hatrmann J. , Sundby Hall K. , Schutte J. , Reichardt A. , Schlemmer M. , Wardelmann E. , Ramadori G. , Al-Batran S. , Nilsson B. E. , Monge O. , Kallio R. , Sarlomo-Rikala M. , Bono P. , Leinonen M. , Hohenberger P. , Alvegard T. , Reichardt P.
Published: February 2017

LBA1

Background: Adjuvant IM administered for 12 months (mos) after surgery improves recurrence-free survival (RFS) of patients (pts) diagnosed with operable GIST. We compared 12 vs 36 mos of adjuvant IM as treatment of pts with a high risk for GIST recurrence after surgery. Methods: Pts with histologically diagnosed KIT-positive GIST were entered to this prospective, open-label, multicenter, randomized Phase III study (identifier NCT00116935 ). The risk of recurrence was estimated according to the modified Consensus Criteria. The primary objective was RFS. The secondary objectives included survival (OS) and treatment safety. The key exclusion criteria were ECOG PS >2, metastatic or inoperable GIST, and >12 wks from surgery to the study entry. IM was administered orally 400 mg/d. The sample size (n =200 in each group to obtain ≥110 events) was estimated by simulating log-rank tests assuming an overall hazard ratio (HR) of 0.44, a 20% drop-out rate, 2-sided type-I error rate of .05 and power 0.80. Analysis was based on the intention-to-treat population (ITT). Tumor histology was centrally reviewed. Results: 400 pts were entered to the study from Feb 2004 to Sep 2008. Three pts were excluded due to lack of consent from the ITT, which includes 15 pts who did not have GIST at a central review. The median FU time was 54 mos. RFS was longer in the 36-mo group compared to the 12-mo group (HR 0.46, 95% CI 0.32-0.65; p <.0001; 5-y RFS 65.6% vs 47.9%, respectively). Pts assigned to 36-mo of IM had longer OS (HR 0.45, 0.22-0.89; p =.019; 5-y OS 92.0% vs 81.7%). IM was generally well tolerated. The proportion of pts who discontinued IM during the assigned treatment period for reasons other than GIST recurrence was 25.8% in the 36-mo group and 12.6% in the 12-mo group. Exploratory efficacy subgroup analyses including KIT and PDGFRA mutation analysis data from 366 tumors will be presented. Conclusions: IM administered for 36 mos improves RFS and OS compared to 12 mos of administration as adjuvant treatment of GIST pts who have a high estimated risk of recurrence after surgery.
PALETTE: A randomized, double-blind, phase III trial of pazopanib versus placebo in patients (pts) with soft-tissue sarcoma (STS) whose disease has progressed during or following prior chemotherapy—An EORTC STBSG Global Network Study (EORTC 62072).
Authors: Van Der Graaf W. T. , Blay J. , Chawla S. P. , Kim D. , Bui Nguyen B. , Casali P. G. , Schöffski P. , Aglietta M. , Staddon A. P. , Beppu Y. , Le Cesne A. , Gelderblom H. , Judson I. R. , Araki N. , Ouali M. , Marreaud S. , Hodge R. , Dewji M. , Dei Tos A. P. , Hohenberger P.
Published: February 2017

LBA10002

Background: Pazopanib, a multi targeted angiogenesis inhibitor, has demonstrated single-agent activity in pts with advanced STS. The efficacy and safety of pazopanib versus placebo as second or later line treatment were evaluated in pts with metastatic STS in a multi-center, international, double-blind, placebo-controlled phase III trial. Methods: Pts ≥18 years of age with angiogenesis inhibitor-naïve, histologically proven, metastatic STS, who failed at least one anthracycline containing regimen, could enter the study. They should have ≥1 measurable baseline lesion (per RECIST v1.0), WHO PS 0-1, adequate bone marrow, coagulation, hepatic and renal function, no poorly controlled hypertension, no bleeding diathesis, and no CNS involvement. The study has been conducted by EORTC and GSK in collaboration with 72 sarcoma centers worldwide. Pts were randomized 2:1 to receive either pazopanib 800 mg once daily or placebo until tumor progression, unacceptable toxicity, death, or pt’s request. Results: A total of 369 randomized pts (246 pazopanib, 123 placebo), median age of 56 years, participated in the study (EORTC 45 %, other 55%). Median duration of follow-up at clinical cut-off date is 15 months. The primary endpoint of progression-free survival (PFS) per independent review is significantly prolonged with pazopanib (median: 20 vs 7 weeks; HR=0.31, 95% CI 0.24-0.40 ; P<0.0001). The interim analysis for overall survival shows a statistically non-significant improvement of pazopanib vs placebo (median: 11.9 vs 10.4 months, HR=0.83, 95% CI 0.62-1.09). Main on-therapy grade 3-4 toxicities in the pazopanib vs placebo arm respectively: fatigue (13%, 6%), hypertension (7%, nil), anorexia (6%, nil), and diarrhea (5%, 1%). Similarly, thromboembolic events (grade 3-5 ) (3%, 2%), LVEF drop of >15% (8%, 3%). Median relative dose intensity of pazopanib was 768 mg daily. Conclusions: Pazopanib is an active drug in anthracycline pretreated metastatic STS pts with an increase in median PFS of 13 weeks.
NCIC-CTG MA.20: An intergroup trial of regional nodal irradiation in early breast cancer.
Authors: Whelan T. J. , Olivotto I. , Ackerman I. , Chapman J. W. , Chua B. , Nabid A. , Vallis K. A. , White J. R. , Rousseau P. , Fortin A. , Pierce L. J. , Manchul L. , Craighead P. , Nolan M. C. , Bowen J. , McCready D. R. , Pritchard K. I. , Levine M. N. , Parulekar W.
Published: February 2017

LBA1003

Background: Randomized trials have demonstrated that locoregional radiation after mastectomy reduces locoregional recurrence and improves overall survival (OS) in women with node positive breast cancer treated with adjuvant systemic therapy. MA.20 evaluated the addition of regional nodal irradiation (RNI) to whole breast irradiation (WBI) following breast conserving surgery (BCS). Methods: Women with high risk node-negative or node-positive breast cancer treated with BCS and adjuvant chemotherapy and/or endocrine therapy were stratified by positive nodes, axillary nodes removed, chemo- and endocrine therapy and randomized to WBI (50Gy in 25 fractions +/- boost irradiation) or WBI plus RNI (45Gy in 25 fractions) to the internal mammary, supraclavicular, and high axillary lymph nodes. The primary outcome was OS. The Data Safety Monitoring Committee approved the analysis plan for the protocol specified interim analysis of relapse patterns, survival and toxicity at 5 years. Upon review of the data, they recommended release of the results. Results: Between March 2000 to March 2007, 1,832 women were randomly assigned to WBI+RNI (916) or WBI (916). Median follow-up was 62 months. Characteristics of the study population were: mean age, 53.3 years; node negative, 10%; 1-3 positive nodes, 85%; > 4 positive nodes, 5%; adjuvant chemotherapy, 91%; and adjuvant endocrine therapy, 71%. WBI+RNI in comparison to WBI alone was associated with an improvement in isolated locoregional disease free survival (DFS; HR=.59, p=.02, 5 year risk: 96.8% and 94.5% respectively), distant DFS (HR=.64, p=.002, 5 year risk: 92.4% and 87.0% respectively), DFS (HR=.68, p=.003, 5 year risk: 89.7% and 84.0% respectively) and OS (HR=.76, p=.07, 5 year risk: 92.3% and 90.7% respectively). WBI+RNI in comparison to WBI was associated with an increase in grade 2 or greater pneumonitis (1.3% and 0.2% respectively, p=.01), and lymphedema (7.3% and 4.1% respectively, p=.004). Conclusions: The majority of women with node positive breast cancer are now managed by BCS followed by WBI and adjuvant systemic therapy. Results from MA.20 demonstrate that additional RNI reduces the risk of locoregional and distant recurrence, and improves DFS with a trend in improved OS.
Phase III study of gemcitabine/oxaliplatin (GEMOX) with or without erlotinib in unresectable, metastatic biliary tract carcinoma.
Authors: Lim H. Y. , Lee J. , Chang H. , Kim J. S. , Choi H. J. , Lee M. A. , Jang J. , Jeung H. , Kang J. H. , Lee H. W. , Shin D. , Jang H. J. , Sun J. , Park S. H. , Park J. O. , Park Y. , Kang W. K.
Published: February 2017

LBA4032

Background: Currently, there is no standard regimen for palliative chemotherapy in metastatic, unresectable biliary tract cancer (BTC). A phase II trial of erlotinib monotherapy showed a promising anti-tumor activity in BTC with tolerable toxicity. Additionally, gemcitabine + erlotinib demonstrated superior efficacy when compared to gemcitabine alone in pancreatic cancer. Hence, we conducted a phase III trial to compare between GEMOX vs GEMOX+erlotinib (Tarceva [T]) (GEMOX/T) as first-line chemotherapy in unresectable, metastatic BTC. Methods: Eligible patients were as follows: histologically confirmed adenocarcinoma of biliary tract (CCC), ampulla of vater (AOV) or gall bladder (GB); unresectable or metastatic; ECOG performance status of 0~2; adequate marrow, hepatic, renal and cardiac functions; no prior chemotherapy. The primary endpoint was progression free survival (PFS). The study regimen was gemcitabine 1,000mg/m2, oxaliplatin 100mg/m2, erlotinib 100mg qd daily q 2 weeks. Results: From February 2009 to August 2010, 268 pts were randomized, 133 patients to GEMOX arm and 135 patients to GEMOX/T arm. Patient characteristics: median age 61 yrs (range 30-82); male (63.4%); CCC (n=180, 67.2%), GB (n=82, 30.6%), and AOV (n=6, 2.2%). With a median follow-up of 13.9 months (range, 6.7 – 25.0), median PFS was 5.8 months (95% CI, 4.6 - 7.0) in GEMOX/T arm and 4.2 months (95% CI, 2.7 - 5.7) in GEMOX arm (P=0.080). In subgroup analysis (CCC, n=180), however, median PFS was significantly longer in GEMOX/T arm (5.9 months) when compared with GEMOX arm (3.0 months, P=0.049). The overall response rate was significantly higher in the GEMOX/T arm when compared with GEMOX arm. There was no significant difference in overall survival between the two arms (GEMOX/T: 9.5 months, 95% CI, 7.6 – 11.4; GEMOX: 9.5 months, 95% CI, 7.5 – 11.5; P=0.611). The EGFR mutation testing results in correlation to responsiveness to erlotinib will be presented at the meeting. Conclusions: This phase III represents the first multicenter, randomized trial to compare GEMOX vs GEMOX/T in unresectable, metastatic BTC. Although PFS was not prolonged in GEMOX/T, there was a significant benefit in terms of PFS in GEMOX/T arm for CCC patients.
Silver in situ hybridization compared with immunohistochemistry in assessing HER2/neu status in fine-needle aspiration cytology.
Authors: Nofech-Mozes S. , Saad R. S. , Noy S. , Hanna W. , Ghorab Z.
Published: February 2017

10

Background: Fine needle aspiration (FNA) cytology is a common diagnostic tool in breast cancer used to establish diagnoses of primary, metastatic or recurrent lesions. In these settings, knowledge of the HER2/neu status is vital for optimal therapeutic decision. We examined the accuracy of HER2/neu testing in alcohol-fixed malignant aspirates.

Methods: FNAs with known HER2/neu status on concurrent/subsequent surgical specimen were retrospectively identified to select a study group of malignant aspirates in cell blocks (CB) from 38 breast and 18 axillary lymph nodes. This group was enriched for HER2/neu positive cases. Sequential sections were studied by IHC using rabbit monoclonal antibody 4B5 and SISH INFORM HER2 DNA and Chromosome 17 (both by Ventana Medical Systems, Tucson AZ, USA). IHC and SISH were evaluated by two pathologists according to 2007 ASCO/CAP criteria and results were compared with HER2/neu status of paired concurrent/subsequent surgical specimen.

Results: HER2/neu IHC on CB yielded 17/56 (30.6%) positive, 30/56 (53.6%) negative and 9/56 (16.1%) equivocal cases. HER2/neu SISH on CB revealed 25/56 (44.6%) amplified, 30/56 (53.6%) not amplified cases. In one case the test was uninterpretable. HER2/neu status on available on 54 surgical specimens (combined IHC and ISH results) was positive in 26 cases and negative in 28. The concordance between negative or positive IHC and SISH on cell blocks was 93.6%. SISH on cell blocks could predict the HER2/neu status in 98.2% of surgical specimens whereas after exclusion of equivocal results, IHC on cell clocks could predict it in only 91.1%. Of the 26 cases with positive HER2/neu status, IHC-CB revealed 3 cases that scored 1+ and one case that scored 0 on cell block. These cases would have been misclassified if HER2/neu was tested on CB by IHC alone.

Conclusions: SISH is a reliable methodology for testing HER2/neu in alcohol fixed cytology specimens and is superior to IHC in its ability to accurately predict the final HER2/neu status. Alternatively, cases can be first tested with IHC and further tested with in situ hybridization when the score is under 3+ to avoid false negative results.
Correlation between preoperative T1 breast cancer staging and final pathologic analysis.
Authors: Gass J. S. , Wiggins D. L. , Dizon D. S.
Published: February 2017

101

Background: Contemporary breast surgery is exploring less invasive techniques for the treatment of breast cancer and recent approaches such as ablative therapy have shown promise in early trials. Caution is required prior to adopting of these techniques, however, as ablative treatment may hinder interpretation of final pathology, which might impact adjuvant recommendations. To address this concern, we evaluated the concordance between preoperative core needle biopsy and postoperative final pathology, to determine whether the biopsy findings predicted final pathology.

Methods: A retrospective chart review was performed of women diagnosed with breast cancers less than 2 cm on radiographic evaluation between 1997 and 2004. Concordance between preoperative assessment (by imaging and core needle biopsy) and final pathology results was analyzed based on tumor size, grade, lymphovascular space invasion, and in situ component. Kappa analysis was performed to characterize agreement.

Results: We identified 56 women from our institution for analysis. The median age was 56 (range, 38-94) and the majority had presented with an abnormal mammogram (61%). The vast majority also underwent breast-conserving surgery (95%). Agreement was moderately accurate between preoperative and final assessment of grade (weighted κ 0.536) and size (weighted κ 0.464). It was not accurate in the assessment of lymphovascular invasion (weighted κ 0.123) and the presence of DCIS (weighted κ 0.197).

Conclusions: Information from preoperative evaluation is insufficiently accurate for the evaluation of breast tumors, which may be important for adjuvant decision making. This information must be taken in to account when assessing new technologies, which may impact on the assessment of histologic criteria in excised breast cancers.
Case-cohort study to determine the value of therapeutic touch in preventing radiation dermatitis.
Authors: Younus J. , Lock M. , Malec J. , Vujovic O. , Yu E.
Published: February 2017

103

Background: Therapeutic touch (TT) is a noninvasive healing technique. There is evidence of value in various clinical areas, but not during radiotherapy (RT) for breast cancer. The TT Cohort was designed to assess the acceptability, compliance, and side effects of TT. The Control Cohort was used compare the impact of TT in preventing radiation dermatitis.

Methods: Early breast cancer patients scheduled to undergo post-conservative surgery RT were selected. TT was administered three times per week during RT. Feasibility was defined a priori as 15 of 17 patients completing all treatments. The effectiveness of TT was evaluated by the NCIC CTC V3 dermatitis scale and EORTC Cosmetic Rating. The quality of life (QOL), mood, and fatigue were assessed by EORTC QLQ C30, POMS, and BFI, respectively. These were assessed at baseline and weekly during treatment.

Results: 17 stage I/II breast were prospectively identified for the TT Cohort and 31 patients were prospectively assessed in the Control Cohort. Median age was 63 years (47-79). TT was considered feasible as all 17 patients completed treatment. In the TT Cohort, the worst grade of radiation dermatitis was grade II in 9 patients. One patient did not develop any dermatitis. Median time to develop the worst grade was 20 days. QOL, mood and energy, and fatigue levels were consistent with the previous published studies. In the Control Cohort, the worst grade of radiation dermatitis was grade III in 1 patient. The most common toxicity grade was II in 15 patients. Three patients did not develop any dermatitis. Median time to develop the worst grade was 29 days. There was no statistical difference in the overall cosmetic score and grade II/III toxicity. There was a statistically significant difference in skin pigmentation and edema.

Conclusions: This study represents the first evaluation of TT in patients with EBC using objective measures. TT is a feasible addition for the management of dermatitis to a tertiary clinic. TT neither improved overall cosmesis nor grade II/III toxicity.
Comparison of locoregional recurrence in triple-negative and HER2-positive breast cancer subtype after breast-conserving therapy and modern systemic therapy.
Authors: Takita C. , Reis I. M. , Miao F. , LaFave K. E. , Gunaseelan V. , Hurley J. , Silva O. E. , Avisar E. , Wright J. L.
Published: February 2017

112

Background: Triple-negative (basal) and HER2+ subtypes have been associated with increased risk of locoregional recurrence (LRR) in earlier studies of breast-conserving therapy (BCT), in which fewer patients received systemic therapy compared with recent standards, including HER2-targeted therapy. We analyzed whether basal and HER2+ subtypes are independent prognostic factors for LRR in BCT patients treated with modern systemic therapy.

Methods: We retrospectively studied 415 patients with invasive breast cancer who received BCT from 1992 to 2009. Axillary surgery was done in 404 patients (97%). Forty eight percent of patients received chemotherapy (anthracycline/taxane 34%, trastuzumab-containing 4%, other 10%). Hormone therapy was given in 67%. Progression-free survival (PFS) and OS were estimated by the Kaplan-Meier method. Rate of LRR was estimated by the method of cumulative incidence allowing for competing risks. The effect of prognostic factors was examined by Fine and Gray’s test.

Results: Median follow-up was 60 months. Median age was 54 (26–86). Stage: T1 70%, T2 26.3%, T3 8%; N0 75%, N1 23.5%, N2 1.7%. Receptor status was available in 301 patients to approximate subtypes: 66% Luminal A, 9% Luminal B, and 5% HER2+, and 20% Basal. Overall, there were 11 LRR, 15 distant metastasis, and 20 deaths. The 10-year PFS and OS were 85.4% and 90.5%, respectively. The 5 and 10-year cumulative incidence of LRR were 2.8% (95%CI: 1.4–5.2) and 4.5% (95%CI: 2.2–8.2) respectively. On univariate analysis, Basal vs. Luminal A (HR: 9.12, p<0.001) and tumor size >2cm vs. ≤2cm (HR: 4.00, p=0.022) were significant prognostic factors for LRR as first failure. On multivariate analysis, only basal subtype (HR: 6.29, p=0.011) retained significance; others effects, including luminal B/HER2 combined subtypes, were not significant.

Conclusions: Long-term clinical outcomes were excellent in this cohort of breast cancer patients treated with BCT and modern systemic therapy, with 10-year LRR 4.5% and OS 90.5%. Basal subtype was an independent predictor for LRR. Conversely, HER2+ subtype was not associated with increase in LRR, in this cohort treated with BCT and trastuzumab.
Evidence-based indications for post-mastectomy radiation after neoadjuvant chemotherapy for stage II-III breast cancer.
Authors: Mayadev J. , Fowble B. , Einck J. P. , Kim D. , McCloskey S. , Yashar C. M. , Chen S. L. , Hwang S. E. ,   ATHENA Breast Health Network
Published: February 2017

114

Background: There are no established guidelines to define the role of post-mastectomy radiation therapy after neoadjuvant chemotherapy. We sought to identify a cohort of women with stage II-III breast cancer in whom radiation may be omitted based on the risk of local-regional failure (LRF).

Methods: Seven breast cancer physicians participating in the multi-campus University of California (UC) Athena Breast Health Network identified, reviewed and abstracted the available literature (from MEDLINE and Cochrane databases), formulated evidence tables (endpoints LRF, disease-free, and overall survival) and developed a risk assessment table of women undergoing mastectomy after neoadjuvant chemotherapy. We created 18 hypothetical clinical case scenarios, and using the American College of Radiology appropriateness criteria methodology, assigned appropriateness ratings for post-mastectomy radiation for each scenario based on our literature review.

Results: 23 of 24 studies identified were retrospective from single institutions. Consensus (80% agreement in a category) in the appropriateness rating was achieved for 78% of the clinical scenarios. Distinct LRF risk categories emerged. Patients who presented with clinical stage II (T1-2N0-1) ER(+) disease with age at diagnosis ≥35-40 years who had either a pathologic complete response (pCR) or 0-3 positive nodes without LVI or ECE were identified as having ≤10% risk of LRF without radiation. Limited data support pCR stage IIIA patients as being low risk.

Conclusions: In the absence of randomized trial data, we identified existing data to guide the use of PMRT in the neoadjuvant chemotherapy setting. Using this data and the appropriateness ratings, we found a high concordance of treatment recommendations for PMRT in our clinical scenarios and were able to identify a cohort of women with a low risk of LRF without radiation. These women will form the basis for future clinical studies in the UC Athena Breast Health Network.
Risk of breast fibrosis following irradiation using a breast-specific SBRT system compared with conventional APBI.
Authors: Husain Z. A. , Feigenberg S. J. , Nichols E. , Zhang J. , Yu C. , Prado K. , Yi B. , D'Souza W. , Mutaf Y.
Published: February 2017

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Background: To determine the dosimetric characteristics and risk of breast fibrosis using a normal tissue complication probability (NTCP) model in conjunction with a novel preoperative stereotactic radiotherapy system called the GammaPod. Results are compared with linac based post-lumpectomy APBI plans for the same cohort.

Methods: The GammaPod breast SBRT system consists of a Co-60 irradiation unit in combination with an immobilization device with embedded fiducials. Eight patients were enrolled in an IRB-approved protocol and underwent CT scans in the prone position with breast immobilization. A preoperative target (GTV) was synthesized to match the tumor location and volume reported in imaging studies obtained prior to surgery (0.3-2.4 cc). The GTV was expanded by 1.5 cm to create a CTV, and a PTV was created using an additional 0.3 cm margin. The PTV was prescribed 25.5 Gy in 3 fx, which is radiobiologically equivalent to conventional APBI doses of 38.5 Gy in 10 fx. Following the radioablative experience in NSCLC, we also planned to deliver 60.0 Gy to the GTV+0.3 cm as a simultaneous boost in conjunction with the 25.5 Gy PTV prescription dose. For comparison, linac-based treatment plans were created for the same cohort following NSABP B-39 guidelines. Whole breast dosimetry was analyzed in terms of biologically equivalent dose (BED) and Lyman NTCP analysis was performed.

Results: The volume of ipsilateral breast receiving 10, 20, 50, and 100% of the prescribed dose was substantially smaller in GammaPod vs. APBI plans, with cohort averages of 19.3, 13.0, 7.1 and 4.0% vs. 75.8, 67.3, 48.1 and 27.6% respectively (p<0.001). Even though the PTV equivalent uniform BED (EUD) was substantially higher in GammaPod plans (87.9 Gy vs. 57.3 Gy), the ipsilateral breast EUD was still smaller in these plans, 18.9 ± 5.0 Gy vs. 47.2 ± 3.2 Gy (p<0.001). Corresponding NTCP predictions for breast fibrosis rates following GammaPod and APBI treatments were 0.2 ± 0.1% vs. 2.8 ± 0.8% (p<0.001), respectively.

Conclusions: The GammaPod system improves upon traditional post-lumpectomy linac-based APBI by decreasing dose to the ipsilateral breast as well as the predicted rates of breast fibrosis.
Dosimetric comparison of radiotherapy plans for left-sided breast cancer patients in rolled versus supine body position.
Authors: Tao M. L. , Mikolajczyk N. , Martyn B. , Botnick L. E.
Published: February 2017

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Background: Left-sided breast cancer patients receiving whole breast radiation therapy (WBRT) are potentially at increased risk for cardiac morbidity. We evaluated heart sparing of left-sided breast cancer patients when placed in the rolled vs. the standard supine body position for WBRT.

Methods: Ten patients with left-sided breast cancer underwent planning CT scans in 2 different positions: supine and rolled to the right to allow for the heart to drop away from the chest wall. Patients were immobilized using vacuum cradles. The left lung, opposite breast, stomach, heart, left ventricle (LV), and left anterior descending coronary artery (LAD) were defined as organs at risk (OARs). Comparison 3D conformal tangential field plans were generated for each patient. Dose-volume histograms (DVHs) of the planning target volume (PTV) and OARs were examined.

Results: All plans met PTV dose coverage and homogeneity criteria of V95 > 95% and maximal dose < 108. Median V105 for PTV was 12.75% (range, 2.5-16%). None of these parameters differed either statistically or clinically between plans done with the patient supine or rolled. The maximal doses to the opposite breast and stomach were also not significantly different between the 2 positions. The right lung V20 was similar for the 2 positions, 11.1% and 12%. Although there were no significant differences in the mean and max doses to the heart or LV, the mean heart dose decreased by 18-70% in 6 patients in the rolled vs. supine position and increased by 2.7-31.5% in 4 patients. The mean dose to the LAD and the LAD V10 and V15 were significantly decreased when the patient was rolled: 17.1 vs. 29.5 Gy, 41.1% vs. 62.6% and 40% vs. 66.7% (p < .05), respectively. Six patients had superior plans when in the rolled position with substantial differences in the mean and/or max doses and/or DVHs for the heart, LV and LAD. The remaining 4 patients had no overall improvement or worsening of the plan when the patient was rolled vs. supine.

Conclusions: For patients with left-sided breast cancer receiving WBRT, the rolled position potentially reduces dose to the heart and its substructures without compromising the coverage and homogeneity of the PTV, hence limiting the need for IMRT.
Planning the boost in early-stage breast carcinoma: Comparison of two methods.
Authors: Krakobsky V. , Gwirc D.
Published: February 2017

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Background: When it comes to breast-conserving surgery the boost volume becomes a critical target because it has the highest risk of residual cancer cells. At our institution the most common methods to contour the tumor bed are: the scar-based planning guided by fluoroscopy (2DP) and the one that relies on the visualization of the seroma under CT (3DP). We evaluated the accuracy of the breast boost volume treated with clinical mark-up compared with the volume delineated with CT planning. Additionally, we evaluated whether or not the lumpectomy scar is a suitable landmark to define the tumor bed.

Methods: 20 patients diagnosed with breast cancer stage I-IIA underwent tumor bed boost planning using two techniques: 2DP and 3DP. All the information concerning to the 2DP was reproduced in a radiotherapy planning system. Statistical analysis: the match pair t-test and the coefficient of variation were used to test for an association among the two planning techniques for tumor bed coverage. The D95, D90, V15, volume, medium lung dose and geographic miss were analyzed. Pearson correlation analysis was used to assess the relationship between CVS, date of surgery, age and previous chemotherapy treatment. Other items taken into account were the match between the scar and the seroma, and how good the visualization of the seroma was by using the CVS.

Results: 2DP was inaccurate: the mean D95, D90 and V15 were 3.12 Gy, 4.6 Gy and 29% respectively (variation coefficient: 135%, 107% and 65% respectively). The difference between the mean 2DP D95 and 3DP D95 was 11 Gy (95% CI, 9 Gy to 13 Gy, p< 0.001). The difference between the mean 2DP V15 and 3DP V15 was 59% (95% CI, 49% to 69%, p < 0.001).The percentage of geographic miss was: 80% (95% CI, 63% to 97%). All the seromas were finely visualized There was no correlation between CVS, age, prior chemotherapy and date of surgery. The volumes and the medium lung dose were larger for the 3D method: 373.1 cm3 vs. 248.8 cm3 and 0.27Gy vs. 0.14 Gy respectively. Only 45% of the lumpectomy scars matched the seroma.

Conclusions: CT-based planning allows for optimal tumor bed coverage compared with scar-based planning which carries a significant risk of missing the target. The lumpectomy scar is often a poor indicator of the tumor bed.
Outcomes of patients diagnosed with DCIS with isolated tumor cells or micrometastases on sentinel lymph node biopsy.
Authors: Moscol G. , Morginstin M. S.
Published: February 2017

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Background: Ductal carcinoma in situ of the breast (DCIS) is considered a precancerous condition. Nevertheless, 6 to 13% of cases will present cancerous cells in the sentinel lymph node biopsy (SNB) when analyzed using immunohistochemistry (IHC). Current guidelines do not specify if patients with isolated tumor cells (ITC, staged as N0[i+] for clusters <0.2mm) or with micrometastases (micromets, staged as N1mic for clusters between 0.2mm and 2 mm) would benefit from radiation or systemic therapy. We compared the clinical outcomes of patients diagnosed with DCIS and found to have ITC or micromets on SNB to those of patients diagnosed with DCIS without SNB analysis.

Methods: Retrospective study. Medical records from patients diagnosed with DCIS at the Cancer Center of AEMC between 01/01/97 and 12/31/08 were reviewed and the SNB status assessed. Other pertinent data (receptor status, type of recurrence and time to recurrence) was collected. The primary outcomes were recurrence/distant metastasis rate (RR) confirmed by biopsy and the time to recurrence (TTR). Descriptive statistics, chi-square and Mann-Whitney U tests were used to analyze the data.

Results: Of the patients diagnosed with DCIS between 1997 and 2008 (N=743), 145 were lost to follow up; 598 charts were analyzed. Only 22% of patients had a SNB. Those that underwent the SNB showed a higher RR as compared to those w/o a SNB (9.2% vs 3.6%, p=0.018). The average TTR between groups showed a wide distribution and no statistically significant difference (SNB mean= 2163 days, S.D=1664; w/o SNB mean= 1300 days, S.D. =819, p=0.180). Subgroup analysis in the SNB group showed that patients w/o IHC exam showed the highest rate of recurrence (6 cases, 13.6%), as compared to those with negative findings (5 cases, 7.6%), those with isolated tumor cells (1 case, 5.9%) and those with micromets (0 cases) (p=0.597).

Conclusions: Patients with SNB had a higher RR when compared to those w/o SNB. Among patients with SNB, those w/o IHC had a higher RR as compared to those with SNB and IHC (although p > 0.05), possibly due to unidentified ITC/micromets. These results are limited due to the small number of cases with SNB and short follow up interval for patients with SNB and performed IHC.
Impact of dose intensity chemotherapy, in geriatric population with locally advanced breast cancer treated in neoadjuvant setting at the National Cancer Institute, Mexico City.
Authors: Arce Salinas H. C. , Ramirez-Morales R. , Aguila C. , Alvarado Miranda A. , Santamaria-Galicia J. , Cantu D.
Published: February 2017

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Background: Breast cancer in older women has a tendency to increase its incidence; the prevalence and their clinical course are not reported. This group of patients is usually considered to be fragile; they receive dose levels of chemotherapy below standards. Objective: To compare the association of dose intensity with complete pathological response (cPR) in older women.

Methods: This is a retrospective analysis of patients treated with neoadjuvant anthracyclines, taxanes, or combination regimen from 2005 to 2008. Pathologic response was evaluated in the surgical specimen.

Results: We analyzed 801 cases, 694 (86.6%) patients were younger than 65 years-old and 107 (13.3%) were older than 65 years-old. Clinical stage, histological type and HER2 status were similar in both groups. High-grade lesions were more common in the younger group (61% vs. 41% p>0.05). ER+/PR+ were more frequent for the group >65 years-old (57.5/47% vs. 79.5/50%) p=NS. Triple-negative were 154 cases (22%) for younger patients and 14 cases (13%) for elderly women (p=0.02). Optimal dose intensity was above 80% of planned dose. For anthracycline-based regimen, older patients had more dose reduction (27.8%) in comparison to the younger group 2.1% (p= 0.00001), for the taxane regimen dose intensity was less than the standard in 8.8% of young population vs. 17.6% for older women (p = 0.03). The rate of cPR in younger patients was 20.3% vs. 11.1% in the older group (p<0.001). Toxicity profile was statistically similar in both groups.

Conclusions: Breast cancer has the same presentation in younger and in older patients. Older patients receive less dose intense chemotherapy. This is associated with a lesser rate of cPR. Therefore, older patient should be treated with full doses taking into account the toxicity profile of the chemotherapeutic regimens as well as the physical and medical conditions of the patient.
Survival after locoregional recurrence in patients after breast cancer surgery.
Authors: Osako T. , Nishimura R. , Okumura Y. , Tashima R. , Toyozumi Y. , Arima N.
Published: February 2017

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Background: The purpose of this study was to investigate factors for survival after locoregional recurrence in patients who underwent mastectomy or breast-conserving therapy (BCT) for primary breast cancer in our hospital.

Methods: Out of 3,332 patients operated on from 1989 to 2008, 50 patients had chest wall recurrences after mastectomy (CWR), 40 patients had regional nodal recurrences (RNR), and 24 patients had ipsilateral breast tumor recurrences (IBTR) from 1997 to 2008. To investigate the prognostic factors for survival after locoregional recurrence, we conducted uni- and multivariate analyses of these cases.

Results: The median follow-up time was 49.2 months. The 5-year survivals after recurrence of the patients with CWR, RNR and IBRT were 52%, 28%, and 68%, respectively. And the 10-year survivals were 15%, 0%, and 62%, respectively. Furthermore, the 5-year distant metastasis-free survivals were 24%, 13%, and 59%, respectively. In a multivariate analysis of the patients with CWR, type of recurrent nodules (diffuse/single, RR 21.0, p= 0.001), pT (T3 or 4 /T1, RR 11.4, p=0.01), pN (N3/N0, RR 15.5, p= 0.03), Ki67 of primary tumor (>50%/<20%, RR6.7, p=0.02) and ER of the primary tumor (+ / -, RR 2.6, p = 0.02) were independent prognostic factors. In a multivariate analysis of RNR, the method of first line salvage therapy (local /local + systemic, RR 16.1, p = 0.01) was only an independent prognostic factor. In the cases of IBTR, there were no independent prognostic factors for survival after recurrence.

Conclusions: Although CWR developed distant metastases within 5 years, the survival depended upon the several biological factors. RNR developed distant metastases within a few years and provided poor prognosis. These suggested that RNR would be the first appearance of systemic metastasis not local disease. In contrast, IBTR provided better prognosis and a salvage treatment cured about 60% of the patients.
Patterns of reconstruction after unilateral and bilateral mastectomies.
Authors: Erb K. M. , Julian T. B.
Published: February 2017

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Background: A trend for the increased usage of mastectomy to treat breast cancer and for prophylaxis has been reported. Postmastectomy reconstruction (PMR) may improve body image and quality of life for breast cancer survivors. This prompted an investigation of the current pattern of PMR in our breast surgery practice.

Methods: An IRB-approved retrospective chart review of women who had mastectomies performed by dedicated breast surgeons from 2006 through 2009 was completed. Data collected included age, unilateral (ULM) or bilateral mastectomy (BLM), type and timing of reconstruction, BRCA status, presence of an in-breast tumor recurrence (IBTR). Two-sided Fisher exact test and t-test were used in comparing groups.

Results: From 2006 to 2009, 231 patients ranging in age from 27 to 91 years had ULM (n=155) or BLM (n=76). 38% of the patients had PMR. Patients <50 years old were more likely to undergo PMR than those >50 (67.5% versus 22.7%, p< 0.0001). 4 patients >70 years old had PMR. PMR followed ULM 27.7% of the time and BM 57.9% (p < 0.0001). Only 6 patients underwent delayed PMR. 30 patients had mastectomies after IBTR with 36.7% having PMR and 36.7% opting for BLM. These rates were not significantly different from women with a unilateral de novo breast cancer (33.1% and 21.3%, respectively). In 15 patients with a BRCA mutation, one had ULM. The 14 having BLM were more likely to have BMR than BLM patients without a mutation (92.9% versus 50.0%, respectively, p=0.0029) and were younger (44.6 versus 52.3 years, respectively, p=0.0166). Types of reconstructions were divided between tissue expander/implant (TE/I)(70%) and autologous tissue flaps (AT) techniques. After BLM, TE/I was employed more frequently than after UM (84% versus 56%, respectively, p=0.005). From 2006 to 2009, there was no significant change in type or frequency of PMR.

Conclusions: From this data it appears that a majority of women do not have PMR and few women return for a delayed PMR. Fewer women seek PMR after ULM. Rates and types of PMR have not changed over this time period. Further investigation to determine if women feel informed about PRM and to identify factors influencing their choices may be helpful in improving a PMR program.