bluuebunny/crossref_metadata_2025 huggingface dataset:
Reflection intensity waveform inversion
Authors: Liu Yike , He Bin , Zhang Zhendong , Zheng Yingcai , Li Peng
Published: March 2020

Traditional iteration-based full-waveform inversion (FWI) methods encounter serious challenges if the initial velocity model is far from the true model or if the observed data are lacking low-frequency content. As such, the optimization algorithm may be trapped in local minima and fail to go to a global optimal model. In addition, the traditional FWI method requires long-offset data to update the deep structure of a velocity model with diving waves. To overcome the disadvantages of traditional FWI under these circumstances, we have developed a reflection intensity waveform inversion method. This method aims to minimize the seismic intensity differences between the modeled reflection data and field data. Our method is less dependent on the starting model, and long-offset data are no longer required. The wave intensity, proportional to the square of the original data amplitude, can have a low-frequency band and a higher frequency band, even for waveforms without initial low-frequency content. Our multiscale intensity inversion starts from the low-frequency information in the intensity data, and it can largely avoid the cycle-skipping problem. Synthetic and field data examples demonstrate that our method is able to overcome cycle skipping in handling data with no low-frequency information.
Randomized Phase IIB Trial of Proton Beam Therapy Versus Intensity-Modulated Radiation Therapy for Locally Advanced Esophageal Cancer
Authors: Lin Steven H. , Hobbs Brian P. , Verma Vivek , Tidwell Rebecca S. , Smith Grace L. , Lei Xiudong , Corsini Erin M. , Mok Isabel , Wei Xiong , Yao Luyang , Wang Xin , Komaki Ritsuko U. , Chang Joe Y. , Chun Stephen G. , Jeter Melenda D. , Swisher Stephen G. , Ajani Jaffer A. , Blum-Murphy Mariela , Vaporciyan Ara A. , Mehran Reza J. , Koong Albert C. , Gandhi Saumil J. , Hofstetter Wayne L. , Hong Theodore S. , Delaney Thomas F. , Liao Zhongxing , Mohan Radhe
Published: March 2020

PURPOSE

Whether dosimetric advantages of proton beam therapy (PBT) translate to improved clinical outcomes compared with intensity-modulated radiation therapy (IMRT) remains unclear. This randomized trial compared total toxicity burden (TTB) and progression-free survival (PFS) between these modalities for esophageal cancer.

METHODS

This phase IIB trial randomly assigned patients to PBT or IMRT (50.4 Gy), stratified for histology, resectability, induction chemotherapy, and stage. The prespecified coprimary end points were TTB and PFS. TTB, a composite score of 11 distinct adverse events (AEs), including common toxicities as well as postoperative complications (POCs) in operated patients, quantified the extent of AE severity experienced over the duration of 1 year following treatment. The trial was conducted using Bayesian group sequential design with three planned interim analyses at 33%, 50%, and 67% of expected accrual (adjusted for follow-up).

RESULTS

This trial (commenced April 2012) was approved for closure and analysis upon activation of NRG-GI006 in March 2019, which occurred immediately prior to the planned 67% interim analysis. Altogether, 145 patients were randomly assigned (72 IMRT, 73 PBT), and 107 patients (61 IMRT, 46 PBT) were evaluable. Median follow-up was 44.1 months. Fifty-one patients (30 IMRT, 21 PBT) underwent esophagectomy; 80% of PBT was passive scattering. The posterior mean TTB was 2.3 times higher for IMRT (39.9; 95% highest posterior density interval, 26.2-54.9) than PBT (17.4; 10.5-25.0). The mean POC score was 7.6 times higher for IMRT (19.1; 7.3-32.3) versus PBT (2.5; 0.3-5.2). The posterior probability that mean TTB was lower for PBT compared with IMRT was 0.9989, which exceeded the trial’s stopping boundary of 0.9942 at the 67% interim analysis. The 3-year PFS rate (50.8% v 51.2%) and 3-year overall survival rates (44.5% v 44.5%) were similar.

CONCLUSION

For locally advanced esophageal cancer, PBT reduced the risk and severity of AEs compared with IMRT while maintaining similar PFS.
Phase II trial of the CDK4 inhibitor PD0332991 in CDK4-amplified liposarcoma.
Authors: Dickson Mark Andrew , Keohan Mary Louise , Tap William D. , Antonescu Cristina , Landa Jonathan , Qin Li-Xuan , Dohrenwend Eric Gerard , Rathbone Dustin , Ustoyev Yelena , Condy Mercedes M , Singer Samuel , Schwartz Gary K.
Published: March 2020

10002

Background: CDK4 is amplified in approximately 90% of well-differentiated/de-differentiated liposarcomas (WD/DDLS). The selective CDK4/CDK6 inhibitor PD0332991 (PD) inhibits growth and induces senescence in liposarcoma cell lines and xenografts. In a phase I trial of PD, several patients with progressive WD/DDLS had prolonged stable disease for several years. To determine the safety and efficacy of PD, a phase II study was performed. Methods: Participants were patients with advanced WD/DDLS. Eligibility criteria were age≥18 years, measurable WD/DDLS (RECIST 1.1), documented progression on at least one systemic therapy directly before enrollment, CDK4 amplification by fluorescence in situ hybridization and retinoblastoma protein (RB) expression by immunohistochemistry (≥1+). Pts received oral PD 200mg daily for 14 consecutive days in 21-day cycles. The primary endpoint was progression-free survival (PFS) at 12 weeks. Based on historical data, a promising result was defined as a 12-week PFS of ≥40% and not promising as ≤20%. The sample size was up to 28 evaluable patients. If 9 patients were progression free at 12 weeks, then PD would be considered to have activity in WD/DDLS. Results: Of 44 patients screened (42/44 CDK4 amplified; 41/44 RB+), 29 were enrolled and 27 were evaluable for the primary endpoint. Median age was 65 (range 37-83); 52% were male; ECOG scores were 0 (69%) or 1 (31%), and the median number of prior regimens was 1 (range 1-5). PFS at 12 weeks was 70% (19/27 patients; 90% CI 56-100%), and thus the study significantly exceeded its primary endpoint. At the data cutoff, the median PFS was 18 weeks. Seven patients remain on study with stable disease at 18-48 weeks of followup. Grade 3 and 4 events included anemia (grade 3, 14%), thrombocytopenia (grade 3, 17%; grade 4, 14%), neutropenia (grade 3, 41%; grade 4, 7%) and febrile neutropenia (3%). Dose reductions were required in 24% of patients. Conclusions: Among patients with WD/DDLS with CDK4 amplification and RB expression who had actively progressing disease despite prior systemic therapy, treatment with the CDK4 inhibitor PD0332991 was associated with improved PFS. A randomized phase 3 trial is planned.
A phase II multicenter study of the IGF-1 receptor antibody cixutumumab (A12) and the mTOR inhibitor temsirolimus (TEM) in patients (pts) with refractory IGF-1R positive (+) and negative (-) bone and soft tissue sarcomas (STS).
Authors: Schwartz Gary K. , Tap William D. , Qin Li-Xuan , Livingston Michael B. , Undevia Samir D. , Chmielowski Bartosz , Agulnik Mark , Schuetze Scott , Reed Damon R. , Okuno Scott H. , Ludwig Joseph A. , Hande Kenneth R. , Rietschel Petra , Kraft Andrew S. , Adkins Douglas , Brockstein Bruce , Yim Vincent , Bitas Christiana , Antonescu Cristina , Maki Robert G.
Published: March 2020

10003

Background: Preclinical studies demonstrate synergistic anti-tumor activity by inhibiting mTOR and IGF-1R. This study evaluated the safety and efficacy of A12 and TEM in 3 chemo-refractory cohorts: IGF-1R (+) STS (Arm A), IGF-1R (+) bone (Arm B), and IGF-1R (-) bone and STS (Arm C). Methods: An optimal Simon 2 stage design was used for each arm. The primary end-point was progression free survival (PFS) at 12 weeks. Based on historical data, a 40% PFS rate was considered promising and a 20% PFS non-promising (type I/ II error, 0.05/0.10). ≥5 PFSs at 12 weeks were required in the first 19 and ≥16 PFSs were required in a total of 54 pts to consider each arm positive. Key eligibility: measurable disease (RECIST 1.1), age ≥18, 1- 4 priors, ECOG status 0-1. A12 (6 mg/kg) and TEM (25 mg) were administered IV weekly. Pre and post treatment tumor biopsies and plasma for IGF-1 and IGFBP3 were obtained. 20 Sarcoma Centers participated. Results: Starting in 02/2010, 383 pts were tested for IGF-1R by immunohistochemistry (IHC; 54% +) and 171 were treated: mean age 47 (range: 18-80), mean # priors 2.2 (range: 1-4). Grade 3/4 toxicities ≥10%: lymphopenia (12%), mucositis (10%). By intent to treat (ITT) analysis, each arm of the study achieved its primary 12 week PFS end-point (≥16 PFSs): Arm A: 18/56 (32%), Arm B: 19/50 (38%) (4 too early), Arm C: 27/63 (43%). The one-sided 95% CI for 12-week PFS is (0.22, 1), (0.27, 1), and (0.32, 1), respectively. By ITT the median PFS (95% CI) in weeks for each arm is 6.3 (5.9, 12.0), 11.0 (8.0, 18.0) and 11.6 (9.0, 17.9), respectively, and for chondro (n=18), Ewing’s (n=24), and osteo (n=23) only it is 22.6 (5.7, 40.9), 10.4 (5.7, 17.9) and 6.0 (6.0, 18.0), respectively. Westerns on 32 matched pair tumor biopsies indicate inhibition of IGF-1R, pAKT and pS6. Of biopsies on 7 IGF-1R (-) IHC pts (Arm C), 5 were IGF-1R (+) by western. Plasma biomarkers did not correlate with PFS. Conclusions: A12 and TEM met its primary end-point of improved PFS in pts with metastatic sarcoma. This effect was independent of IGF-1R status by IHC. These results support further clinical development of this combination in bone and STS.
A first-in-human, phase Ib combination study to assess safety, pharmacokinetics (PK), and pharmacodynamics (PD) of a hedgehog inhibitor, GDC-0449, with a Notch inhibitor, RO4929097, in patients with advanced sarcoma.
Authors: Gounder Mrinal M. , Dickson Mark Andrew , Wu Nian , Ivy S. Percy , Carvajal Richard D. , D'Angelo Sandra P. , Keohan Mary Louise , Qin Li-Xuan , Erinjeri Joseph Patrick , Takebe Naoko , Tanner Lanier , Morales Rita , Condy Mercedes M , Ustoyev Yelena , Maki Robert G. , Tap William D. , Schwartz Gary K.
Published: March 2020

10004

Background: Aberrant Hedgehog and Notch signaling is seen in sarcoma and anti-tumor activity is enhanced by inhibiting both pathways. This first in man Phase Ib study evaluated safety and efficacy of the combination of GDC-0449 (G), a smoothened inhibitor with RO4929097 (R), a gamma-secretase/notch inhibitor. Methods: The study evaluated fixed dose G (150 mg qd) for 21 days followed by G + R at either 10 mg (level 1) or 15 mg (level 2) QD. At MTD pts were evaluated with G + R (without “lead in” G) or single agent R. Pre and post treatment tumor biopsies were obtained to assess notch and hedgehog inhibition. PK was assessed for each drug. Key eligibility: advanced sarcoma, ECOG ≤ 2, age ≥ 18 and prior therapies ≤ 4. RECIST response was assessed Q6 wks. Results: 34 pts had a median age of 53 yrs (23-78), median priors 3 and various histologies [liposarcoma (7), chondrosarcoma (7), leiomyosarcoma (4), osteosarcoma (2), GIST (2) and other (12)]. No DLT was seen. Common (≥10 %) grade ≤3 toxicity was hypophosphatemia (18%). Systemic exposure (AUC0-24 and Cmax) of G was similar to established studies (not shown). AUC0-24 and Cmax of R was significantly lower (~70%) when administered with G (Table). However, measurement of unbound, free drug (Cfree) of R showed comparable levels between single agent R and G + R, but not when G was a “lead in” (Table). Target inhibition of the notch pathway (cleaved notch) and pAkt was observed in matched tumor biopsies with both arms. Durable SD was seen in both arms: myxoid chondrosarcoma (56 wks), liposarcoma (24+ wks), clear cell (21+ wks), desmoid (17+ wks), spindle cell (15+ wks) and chondrosarcoma (13+ wks). Conclusions: The combination of G+R is well tolerated and the RP2D is G 150 mg qd and R 15 mg qd without a “lead in” G. Despite reduction in total levels of R in the combination, free drug was similar and inhibits target. Disease stability was seen with R and R + G. Further clinical development of notch and hedgehog inhibitors in sarcomas is warranted. [Table: see text]
Localized angiosarcomas (AS): Identification of prognostic factors (PF) and analysis of treatment impact—Series from the French Sarcoma Group (GSF/GETO).
Authors: Lindet Clothilde , Neuville Agnes , Penel Nicolas , Lae Marick , Michels Jean-Jacques , Trassard Martine , Terrier Philippe , Birtwisle-Peyrottes Isabelle , Valo Isabelle , Collin Francoise , Chateau Marie-Christine , Robin Yves Marie , Coindre Jean-Michel
Published: March 2020

10018

Background: AS represents less than 2% of all adult soft tissue sarcoma. PF and role of respective (neo)-adjuvant treatments in management of localized AS remain badly established. Methods: We have conducted a retrospective multicentre study (June 1980-October 2009) of 107 patients with localized AS. All cases have been centrally reviewed by pathologist expert. Univariate and multivariate analysis were conducted to identify independent PF. Overall survival (OS) and Local Recurrence Free Survival (LRFS) were estimated using the Kaplan-Meier method. Impact of treatments had been explored with Cox Model after adjustment to the PF. Results: The sex ratio was 18/89 (0.2). Median age was 71 years. 22% (24/107) and 62% (67/107) of patients developed AS in preexisting lymphoedema and in irradiated field, respectively. 71 cases (66%) were superficial. The most frequent primary locations were: limbs (35, 33%), chest wall (32, 29%) and breast (22, 20%). Grade was 1 in 21/103 (20%), 2 in 35/103 (34%) and 3 in 47/103 cases (46%). Treatments consisted in surgery, adjuvant radiotherapy and (neo)-adjuvant chemotherapy in, respectively, 95, 27 and 27 cases. R0 margin was obtained in 49 cases. The median OS and LRFS were, respectively, 38.8 months and 27 months. In multivariate analysis, the following PF influenced the OS: lymphedema (HR=2.02 [1.15-3.55]) and size>5 cm (HR=1.48 [1.01-2.45]). After adjustment to these PF, R0 margins was the sole treatment parameter improving the OS (HR=0.19 [0.05-0.73]). In multivariate analysis, the following PF influence the LRFS: Age>70 (HR=1.68 [1.02-2.76]) and pre-existing lymphedema (HR=2.07 [1.15-3.75]). After adjustment to these prognostic factors, R0 margins (HR=0.48 [0.38-0.69]) and adjuvant radiotherapy (HR=0.29 [0.10-0.83]) improved the LRFS. Conclusions: Pre-existing lymphedema, tumour size and age>70 are the major PF in patients with localized AS. The achievement of R0 margins is of major importance for improving the outcome whatever the endpoint (OS, LRFS) Adjuvant radiotherapy decreased the local recurrence. (Neo)-adjuvant chemotherapy does not influence survivals.
Tenosynovial giant cell tumor (TGCT)/pigmented villonodular synovitis (PVNS): Outcome of 313 patients before the era of kinase inhibitors.
Authors: Palmerini Emanuela , Pengo Stefano , Maki Robert G. , Staals Eric L. , Cioffi Angela , Alberghini Marco , Picci Piero , Ruggieri Pietro , Mapelli Sergio , Parafioriti Antonina , Morris Carol , Gronchi Alessandro , Casali Paolo Giovanni , Ferrari Stefano , Stacchiotti Silvia
Published: March 2020

10022

Background: Tenosynovial giant cell tumor (TGCT) is a rare, usually benign neoplasm of synovium and tendon sheath. TGCT is classified as localized or diffuse according to the extent of synovial involvement. Surgery is the primary treatment, but the recurrence rate is high, with possible multiple recurrences, joint function deterioration and decline in quality of life. Recent data suggest a role for TKIs in advanced disease. In order to identify prognostic factors for recurrence, a retrospective pooled analysis was carried out in three institutions (Istituto Ortopedico Rizzoli, Bologna, Italy; Istituto Nazionale Tumori, Milano, Italy; Memorial Sloan Kettering Cancer Center, New York, USA). Methods: Clinical charts and pathology reports of patients (pts) treated in the period 1998-2008 were examined. Results: The study included 313 pts, 177 F and 136 M; median age: 36 years (range: 11-89 years). Most (64%) pts had tumors in the knee (15% ankle, 11% hip, 10% other). Tumor size was: <2 cm in 24% of pts, 2-5 cm in 44%, >5 cm in 32%. A diffuse pattern was reported in 69% of pts. The resection status was available in 289 pts: 51% had R0 surgery, 28% R1 and 21% R2. No metastases were documented. Local recurrence was reported in 76 pts (median time to recurrence: 15.7 months). With a median follow-up of 4.2 years, 5-year local recurrence-free survival (LRFS) was 66% (95% CI: 59 - 73). Size (< 2 cm 80% vs. 2-5 cm 67% vs. >5 cm 62%, p=0.04), gender (F 73% vs. M 56%, p=0.02), type (localized 78% vs. diffuse 61%, p=0.02), and resection status (R0 76% vs. R1 55%, vs. R2 57%, p=0.002) influenced 5-year LRFS, whereas age, tumor location and bone involvement did not. The 5-year 2nd LRFS was 43% (95% CI: 28 - 59). Multiple (2 to 5) local recurrences were observed in 39% of relapsed patients. Conclusions: The study confirms TGCT propensity to multiple local recurrences. Diffuse type, suboptimal surgery, male gender and larger tumors increase the recurrence risk. In order to improve the probability of local control, studies addressing the role of TKIs could be considered in subsets of patients.
Cetuximab and EGFR inhibitors in patients with neurological symptoms due to chordoma.
Authors: Linden Ola , Ehinger Mats , Kinhult Sara , Relander Thomas , Lundgren Lotta , Engellau Jakob , Kjellén Elisabeth
Published: March 2020

10024

Background: Chordomas are rare tumours located along the neuraxis, showing limited sensitivity to radiotherapy and lack of response to chemotherapy. However, tyrosine kinase inhibitors (TKIs) have been reported to have an effect. Following the failure of single-agent treatment in a young patient using cetuximab, we decided to treat patients (pts) with neurological symptoms with dual targeting of the epidermal growth factor receptor (EGFR), based on a case report by Hof et al., who successfully used dual targeting of EGFR, and supporting in vitro data. Methods: Eight consecutive pts with neurological symptoms at referral were treated with cetuximab (250 mg/m2 weekly) and an EGFR signalling inhibitor (250 mg gefitinib or 150 mg erlotinib daily). The duration of treatment was not decided in advance. Results: EGFR expression on tumour cells was variable but present in all pts. Six pts were evaluable. One tetraplaegic pt died of an unknown cause and one pt on lithium carbonate discontinued treatment before the first follow-up due to renal toxicity. Four pts showed neurological improvement. Two of these regained and one improved the ability to walk, and a fourth, with a sacral tumour, improved his voiding ability. The fifth pt had clinically stable disease and, although the PET scan showed improvement, the treatment had to be discontinued due to skin toxicity. One pt showed progressive disease. In the four pts responding neurologically, improvement was noted already by the end of the third week. Three pts were retreated without failure while on treatment. The first pt who regained the ability to walk is still walking at 52+ months. This pt, while still responsive to cetuximab and erlotinib, has failed to respond to single-agent treatment with imatinib, sorafenib or everolimus. The second pt who regained walking ability had severe alcoholism and died while being treated. The third is still walking at 16+ months. All pts exhibited significant cutaneous side effects, in some cases necessitating intermittent interruption of therapy. Conclusions: Treatment with cetuximab and TKIs can thus achieve meaningful and long-lasting clinical improvement in pts with paresis due to chordoma, and is feasible in pts with limited comorbidities.
Lapatinib in advanced chordoma: A phase II study.
Authors: Stacchiotti Silvia , Tamborini Elena , Palassini Elena , Negri Tiziana , Marrari Andrea , Messina Antonella , Morosi Carlo , De Troia Beatrice , Longhi Alessandra , Palmerini Emanuela , Gronchi Alessandro , Pilotti Silvana , Casali Paolo Giovanni
Published: March 2020

10026

Background: To report on a prospective Phase II, investigator-driven, collaborative study to explore the activity of lapatinib, a dual EGFR and ErbB2 inhibitor, in EGFR-positive advanced chordomas. Methods: From December 2009 to December 2011, 19 advanced progressing chordoma patients entered this study (mean age: 59 yrs – range = 35-75; PS: 0-3 - ≥2 = 52%; site: sacrum = 68%, spine = 21%, skull base = 11%; disease extent: metastatic = 68%, locally advanced = 32%). EGFR expression was evaluated by immunohistochemistry in all patients. EGFR activation was detected in 15 of 17 evaluable cases by phospho-arrays and/or real-time PCR and/or fluorescence immunostaining. EGFR FISH analysis showed high level of gene gain in 4. HerB2 status is under evaluation. Patients received lapatinib 1500 mg/day (dose intensity in excess of 1250 mg/day), until progression or toxicity. The primary study end-point was response rate (RR) as for Choi criteria extended to MRI. Secondary end-points were RR by RECIST, PFS by Choi, OS, clinical benefit rate (CBR) (CR+PR+SD≥6mos), correlation between EGFR status and response. Results: 16 pts are evaluable for response (3 too early); 4 patients are still on treatment. 3 patients (19%) had a partial response (PR) and 8 (50%) a stable disease (SD) as their best Choi response, corresponding to RECIST SD in all cases. The 3 cases with a PR by Choi had a minor decrease in size; another patient had a mixed response. The CBR was 19%. Median PFS as for Choi was 5.5 (range = 2-12+) months, with 1 patient being progression-free at 18 months. Toxicity was as expected. In one case treatment was interrupted due to side effects. No correlation was observed between EGFR expression/activation and response. Conclusions: This Phase II study showed a modest activity of lapatinib in chordoma. EGFR expression was not predictive of response. The clinical relevance of EGFR targeting in chordoma needs to be further investigated.
A phase III, multicenter, randomized trial of maintenance versus observation after achieving clinical response in patients with metastatic breast cancer who received six cycles of gemcitabine plus paclitaxel as first-line chemotherapy (KCSG-BR 0702, NCT00561119).
Authors: Im Young-Hyuck , Park Yeon Hee , Jung Kyung Hae , Im Seock-Ah , Sohn Joo Hyuk , Ro Jungsil , Kim Sung-Bae , Ahn Jin-Hee , Oh Do Youn , Han Sae-Won , Lee Soohyeon , Park In Hae , Lee Keun-Seok , Kim Jee Hyun , Kang Seok Yun , Lee Moon Hee , Park Hee Sook , Ahn Jin Seok
Published: March 2020

1003

Background: Chemotherapy provides a survival benefit in patients with metastatic breast cancer (MBC), but the optimal duration of chemotherapy remains controversial. Primary purpose of the study was to evaluate whether the maintenance chemotherapy with gemcitabine/paclitaxel (GP), which is one of the two regimens which showed a survival gain from a randomized trial, is superior to observation in terms of progression free survival (PFS) in responding patients with MBC after 6 cycles of GP as first-line treatment. Methods: This study is a prospective, randomized, multi-center, phase III study. Patients who achieved response (CR+PR+SD) following 6 cycles of GP chemotherapy (gemcitabine 1250 mg/m2 on day 1 and 8 plus paclitaxel 175 mg/m2 on day 1 every 3 weeks) randomized to maintenance till progression or observation arm. The trial was conducted by the Korean Cancer Study Group (KCSG). Results: Among total 324 patients enrolled between 2007 and 2010 from 10 centers, 231 responding patients to were randomly assigned to maintenance chemotherapy (n=116) or observation (n=115). Median age was 49 (range 28-76). The numbers of hormone receptor (HR)+ve and HR-ve patients were 172 (74.5%) and 59 (25.5%), respectively. The median No. of chemotherapy cycles in maintenance group was 12 (range 6-32). During median 33 months of follow-up, median PFS was superior in maintenance than in observation (12.0 vs. 8.3 months, p=0.030). Patients < age 50 years (hazard ratio 0.50, p=0.001) and HR-ve patients (hazard ratio 0.52, p=0.019) received more benefit from maintenance chemotherapy in terms of PFS. Median OS was superior in maintenance than in observation (36.8 vs 28.0 months, p=0.047). Neurotoxicity (≥ grade 2) was more common in maintenance than in observation without statistical significance (41.7% vs 33.3%, p=0.210). Serial assessment of Quality of Life (QoL) did not show any significant difference between two groups. Conclusions: Maintenance GP chemotherapy for responding patients with MBC showed clinical benefit in terms of PFS and OS without impairment of QoL.
Efficacy of a phosphoinositol 3 kinase (PI3K) inhibitor in gastrointestinal stromal tumor (GIST) models.
Authors: Van Looy Thomas , Wozniak Agnieszka , Sciot Raf , Floris Giuseppe , Manley Paul W. , Debiec-Rychter Maria , Schöffski Patrick
Published: March 2020

10030

Background: PI3K signaling is crucial for GIST proliferation and survival. We assessed the efficacy of the PI3K inhibitor NVP-BEZ235 (BEZ), alone or in combination with imatinib (IM), in GIST xenografts. Methods: Nude mice were grafted bilaterally with human GIST, carrying either KIT exon 9 (GIST-BOE, dose-dependent IM resistant) or exon 11 (GIST-DFR, IM sensitive) mutations. Animals, randomized into four groups (n=8/group) were dosed orally for 2 weeks with either vehicle, IM (50mg/kg/bid), BEZ (10mg/kg/qd), or IM+BEZ. Treatment efficacy was assessed by tumor volume, histopathology and Western immunoblotting. Moreover tumor regrowth was evaluated for 3 weeks after treatment cessation. Results: As a single agent IM and BEZ stabilized tumor growth of both GIST-BOE and DFR. Moderate to significant tumor regression was observed in GIST-BOE under BEZ (by 27%), and IM+BEZ (66%), and also in GIST-DFR under IM (75%) and IM+BEZ (75%). In GIST-BOE significant reduction in mitotic index was observed under BEZ (8.5 fold) and IM+BEZ (8.5 fold) as compared to control. In GIST-DFR mitotic activity was virtually absent under all regimens. Apoptotic activity increased significantly after treatment with IM (5.5 fold) and IM+BEZ (14.0 fold) in GIST-DFR, whereas it was almost unaffected by BEZ as single agent, as well as in all treatment groups in GIST-BOE. By Western, PI3K signaling was incompletely inhibited in all groups in GIST-DFR, and after BEZ in GIST-BOE. Complete inhibition of PI3K signaling was observed only after combination treatment. After treatment cessation long-lasting growth-inhibition was observed in IM+BEZ treated GIST-DFR. Moreover, mitotic index after BEZ and BEZ+IM in GIST-DFR was lower than in control even after treatment withdrawal. Conclusions: BEZ shows significant efficacy in GIST xenografts. Furthermore, combination with IM shows synergistic and long-lasting effects even after treatment withdrawal, which is not the case with drugs routinely used for GIST treatment.
Clinical activity of mTOR inhibition in combination with cyclophosphamide in the treatment of recurrent nonresectable chondrosarcomas.
Authors: Merimsky Ofer , Bernstein-Molho Rinat , Kollender Yehuda
Published: March 2020

10043

Background: Chondrosarcomas (CS) represent a heterogeneous group of rare sarcomas, poorly responsive to chemotherapy or radiotherapy. When local therapies in recurrent or metastatic disease are exhausted, chemotherapy plays a marginal role. Different molecular pathways have been shown to be activated in CS. In this retrospective study we summarize our experience in treating a cohort of patients with recurrent nonresectable CS with a combination of sirolimus and cyclophosphamide. Methods: Nine consecutive patients with nonresectable CS were offered off-label treatment with sirolimus and cyclophosphamide between 2007-2011. Tumor response, progression-free survival (PFS), adverse events and other relevant clinical data were analyzed. Results: The median patients’ age was 52 (range, 35-68). Median disease-free interval (DFI) since the primary diagnosis was 24 months. Median time from the disease recurrence to initiation of sirolimus and cyclophosphamide treatment was 20.9 months due to additional local surgical treatments/excision of metastases/slow and asymptomatic progression. One (11%) objective response was observed and five (56%) patients had stabilization of disease for at least 6 months. One patient has been treated for only 3.5 months and reported symptomatic improvement at this stage, two patients had progressive disease. Median time to treatment failure (TTF) was 15 months (range, 2.8-30.3). No significant adverse events were observed. Conclusions: Although advanced CS remains an incurable disease, our experience suggests that a combination of sirolimus and cyclophosphamide is well-tolerated and has meaningful clinical activity with clinical benefit rate of 67%. Further prospective studies are warranted.
High-dose ifosfamide (HDI) in metastatic synovial sarcoma: The Institut Gustave Roussy experience.
Authors: Rahal Arslane Skander , Cioffi Angela , Rahal Chahinez , Domont Julien , Blesius Aurore , Patrikidou Anna , Bonvalot Sylvie , Le Pechoux Cécile , Terrier Philippe , Vilcot Laurence , Lanoy Emilie , Le Cesne Axel
Published: March 2020

10044

Background: Synovial sarcoma (SS) is one of the most chemo-sensitive histological subtypes of sarcoma but with a dismal prognosis. In metastatic setting, Anthracyclin/ifosfamide-containing chemotherapy (CT) regimen is the gold standard of treatment in front-line therapy. Patients (pts) with resistant diseases are candidates to investigational drugs or higher dose ifosfamide regimen in selected pts. Methods: Pts treated in our institution, with histological confirmation of advanced SS, adequate organ function and in good condition (PS≤2) were included in this retrospective analysis. Pts who progressed after 1–2 chemotherapy lines received High-dose ifosfamide (HDI) in the form of 4 g/m2 daily (over 24 hours CI) for 3 days for a total dose of 12 g/m2; cycles were given with growth factor support and were repeated every 3 weeks. The primary endpoints were PFS and overall response rate (ORR); the secondary endpoints OS and toxicity profile. AE were assessed by NCI-CTC v. 3.0. Results: 34 pts (21 males) with a median age of 39 years (range 19-66) received this HDI regimen. PS was 0-1 in 90%. 95% of pts received prior doxorubicin, ifosfamide or both, 7 patients had 2 prior lines. Grade III monophasic pattern was seen in 21 patients, grade II in 13. 171 cycles were delivered, median number of cycles was 4 (2-10). The objective responses were CR 0; PR 15; SD 14; PD 2; and NE 3, resulting in an ORR of 44%. The clinical benefit rate was 85%. Median PFS: 11.6 months (95% CI: 9-14). Eleven pts were amenable to a subsequent resection of residual disease. Common adverse events included grade III/IV neutropenia: 47%, febrile neutropenia: 12%, thrombocytopenia: 12%, cystitis: 3%, neurologic: 3%. There was no treatment related death. Conclusions: HDI demonstrated clinically meaningful efficacy with manageable toxicity in pts who failed previous standard Ifosfamide dose. Ifosfamide remains the most active agents in SS and high dose regimen have to be considered in pts previously treated with ifosfamide.
Does combined dose intensification radiotherapy improve disease control in resectable retroperitoneal sarcoma? Long-term results of a phase I/II trial.
Authors: Smith Myles JF , Ridgway Paul F , Catton Charles N , Cannell Amanda , O'Sullivan Brian , Mikula Lynn A , Jones Julia J , Swallow Carol Jane
Published: March 2020

10050

Background: Late failure is a challenging problem in retroperitoneal sarcoma (RPS) and reported 10 yr overall survival (OS) rates range from 20-30%. Use of preoperative external beam radiotherapy (XRT) in the management of RPS remains controversial. No RCT and very few prospective trials of any type have been completed. We investigated the effects of preop XRT plus dose escalation with early postop brachytherapy (BT) on long term survival and recurrence in RPS. Methods: From 06/96 to 10/00, 40 patients (25 female) with resectable RPS were entered onto a phase I/II trial of preop XRT (50 Gy) plus postop BT (20-25 Gy). As previously reported, BT to the upper abdomen was associated with significant grade III-V postop toxicity, and from 12/98 on, BT was applied only to cases where the “field at risk” excluded the upper abdomen. Kaplan Meier survival curves were constructed; OS and recurrence free survival (RFS) were compared by log rank (SPSS 19.0). Results: Median age at study entry was 58 (38-70) yrs. Twenty nine patients presented to our center with primary disease (73%), and 22 (55%) had high grade tumors. All patients had preop XRT and total gross resection, while half (n=19) received BT. As of 12/2011, median follow-up time is 108 mos. For the entire study cohort, OS at 5 and 10 yrs were 70% and 65%, respectively; RFS at 5 and 10 yrs were 65% and 58%, respectively. RFS at 5 yrs was reduced in high vs. low grade RPS (50% vs. 83%, p=0.028), but by 10 yrs. was similar in high and low grade tumors (50% vs. 67%, p=ns). RFS was reduced in patients who presented with recurrent vs. primary disease (27% vs. 69% at 10 yrs., p=0.018), as was OS (36% vs. 76% at 10 yrs., p=0.034). Neither OS nor RFS was improved in the cohort of patients who received BT compared to the cohort who did not: at 10 yrs. RFS was 53% +BT and 62% -BT, while OS was 53% and 76%, respectively, p=ns. Conclusions: In this prospective study with mature follow-up, long term OS and RFS in patients who underwent combined preop XRT plus resection of RPS compare favorably with those reported in retrospective institutional and population-based series. Postoperative BT did not contribute to disease control.
Risk factors leading to grading changes within 300 low-grade soft tissue sarcomas.
Authors: Koshrawipour Tanja , Stricker Ingo , Tannapfel Andrea , Steinstraesser Lars , Langer Stefan , Ring Andrej
Published: March 2020

10059

Background: Soft tissue sarcomas (STS) are rare, mesenchymal derived tumors. Based on malignancy, three grades are distinguished with G1 equaling low grade, G2 intermediate grade and G3 high grade, respectively. Studies have shown that some G1 tumors which underwent complete surgical resection reoccurred as lesions with a grading shift from G1 to higher malignancy. This grading change is referred to as up grading. Patients with grading changes were thoroughly examined in our study. Our aim was to find possible risk factors for up gradings, such as age, localization of tumor and tumor type. Methods: This retrospective case control study evaluated 333 Patients, who, between 1996 to 2011 were treated for G1 STS at Bergmannsheil Bochum, university clinic. These patients received complete initial surgical resection. Among our 333 patients, 9.9% (n=33) developed up gradings of their STS. These were then reviewed more closely in the aim of finding possible risk factors. We did not exclude any patients from our data or deliberately pick any grading changers and regard our collective as randomly sampled. The processed data includes age, gender, tumor type, tumor localization, occurrence of recidive and grading change. Results: Patients with up gradings were found to have a higher mean age of 4, 5 years than reference collective. The tumor type has a strong, statistically significant effect on grading change as patients with fibrosarcomas have a threefold risk of developing up gradings when compared to patients with other G1 STS. Conclusions: Our results indicate that age and tumor type play the key role in the development of up gradings in low malignant STS .Patients aged 60 and above diagnosed with fibrosarcomas are at a 3 times higher risk of developing a grading change as opposed to patients younger than 60 with other low grade STS than fibrosarcoma. We discussed the significance of these risk factors and argued whether, in addition to wide tumor resection, a short term postoperative radiotherapy should be applied for these patients to improve therapeutical outcome.
Treatment outcomes of primary mediastinal and intrathoracic great vessels sarcoma: Royal Marsden Hospital experience.
Authors: Lu Shir Kiong , Benson Charlotte , Ganguli Sushila , Scurr Michelle R. , Fisher Cyril , Khabra Komel , Al-Muhaderis Omar , Dunlop Alison , Saran Frank , Ross Gillian , Miah Aisha , Judson Ian Robert
Published: March 2020

10060

Background: Sarcoma of the mediastinum and great vessels remain a rare subgroup of soft tissue sarcoma and prognosis remains poor with patients (pts) often presenting with advanced disease. There is no standard treatment due to paucity of data hence its management relies on case series. To date this is the largest series of pts reported. Methods: Retrospective analysis of pts identified anonymously from a prospectively maintained database of the sarcoma unit. Results: 46 pts were included in the analysis. The median age at diagnosis was 45.9 with a male: female ratio of 1.2: 1. 60% of pts presented with localised disease. The most common histological subtype was spindle cell sarcoma followed by angiosarcoma. The heart (n=21), majority in the atria, was the commonest primary site. 28 pts presented with localised disease of which 21 had surgery and 16 received chemotherapy (CT). 4 pts received multi-modality treatment. 83% of pts with metastases had CT. 6 of them attained stable disease, 1 had partial response and 4 (Ewing’s, rhabdomyosarcoma and angiosarcoma) had complete response. 31 pts developed disease recurrence of which 58% had initial localised disease. 6 pts had metastectomy, 19 received palliative CT and 11 had palliative radiotherapy (RT). RT of 50-60Gy to the heart or mediastinum was delivered to 61% of pts with initial localized disease and 33% of pts with metastases. 2 pts had documented post-treatment cardiac complication. After a median follow up of 2.16 years, the median event-free survival was 0.97 years (95%CI 0.65-1.30), median overall survival (OS) was 1.7 years (95% CI 0.70-2.71) and 5 year OS was 17.9%. Conclusions: The optimal management in this disease is unclear. In this study, surgery was frequently implemented in both localised and metastatic settings but challenges remain in achieving clear margins. Chemotherapy has a role and it is key to identify chemosensitive subtypes. RT is offered as an adjunct following suboptimal resection. Despite aggressive treatments, this group of young pts had high recurrence rate and poor prognosis. Multi-modality treatment may have a role in selected pts but its efficacy and long-term cardiac sequelae need to be evaluated prospectively.
Bone metastases in soft tissue sarcoma patients: A survey of natural, prognostic value, and treatment.
Authors: Vincenzi Bruno , Santini Daniele , Schiavon Gaia , Frezza Anna Maria , Dileo Palma , Silletta Marianna , Bertoldo Francesco , Badalamenti Giuseppe , Baldi Giacomo G. , Zovato Stefania , Berardi Rossana , Tucci Marco , Whelan Jeremy , Tirabosco Roberto , Dei Tos Angelo Paolo , Tonini Giuseppe
Published: March 2020

10063

Background: Given the limited data currently available, we surveyed the natural history of bone metastases in patients affected by soft tissue sarcoma (STS). Methods: This retrospective, multicenter, observational study evaluated data from 135 patients with STS metastatic to the bone who presented between 2001 and 2011. For all patients, we recorded the primary tumor histological subtype, bone metastases characteristics (onset, site), type of treatment received (surgery, radiotherapy, zoledronic acid), type and frequency of skeletal related events (SRE) and disease outcome. Results: The most represented histological subtypes among the enrolled patients were leiomyosarcoma (27%), angiosarcoma (13%) and spindle cell sarcoma (8%). The spine was the most common site for bone involvement (51%), followed by hip/pelvis (20%), long bones (15%) and other sites (14%). In 27% of cases, bone metastases were present at the time of diagnosis. Fiftyfour patients (40%) developed SREs and the median time to first SRE (if developed) was 4 months. The most common SRE was the need for radiotherapy occurring in 28% of patients followed by pathologic fracture (22%). Patients survived for a median of 6 months after bone metastases diagnosis. The occurrence of a SRE was associated with a decreased overall survival (P=0.04). A subgroup analysis revealed that zoledronic acid significantly prolonged median time to first SRE (5 versus 2 months; P = 0.002). Conversely, It did not determine an improvement in terms of overall survival, even if favorable trend was identified (median, 7 versus 5 months, respectively; P = 0.105). Conclusions: This study illustrates the burden of bone disease from STS and supports the use of zoledronic acid in this setting.
Use of microRNA (miR) expression profiling to identify distinct subclasses of triple-negative breast cancers (TNBC).
Authors: Shapiro Charles L. , Cascione Luciano , Gasparini Pierluigi , Lovat Francesca , Carasi Stefania , Pulvirenti Alfredo , Ferro Alfredo , Huebner Kay ,   Ohio State University Medical Center and Comprehensive Cancer Center
Published: March 2020

1007

Background: TNBC is divided into basal and non-basal subclasses. To further subclassify TNBC we performed microRNA (miR) expression profiles and linked them to patient overall survival. Methods: During 1996-2005, 365 consecutive TNBC (phenotypically estrogen, progesterone and HER2 negative by immunohistochemistry [IHC]) were identified from the NCCN Breast Cancer Data Base/Tumor Registry at OSU Medical Center. One hundred fifty-eight (43%) formalin-fixed paraffin embedded (FFPE) breast cancer and 40 normal breast tissue blocks were available and tissue cores were obtained for RNA. RNA was isolated using the Ambion recoverall total nucleic acid isolation kit and the expression of ~700 miRs was assessed for each sample using the nanoString nCounter method. A consensus-clustering algorithm (ConsensusClusterPlus, Bioconductor www.bioconductor.org) was used to identify subclasses of TNBC and Kaplan-Meier overall survival curves were compared using the log-rank test. Censoring occurred at the date of death from causes other than breast cancer or at time of the last known follow-up, whichever occurred first. The median follow-up was 67 mo. (range 4-171 mo.). Results: The median age was 52 yrs. (range 20-84 yrs.); 81% white and 9% African-American; stages I, II, and III were 31%, 54% and 15%, respectively; and most patients received adjuvant anthracycline-based regimens with (25%) or without taxanes (75%). The algorithm identified 5 distinct subclasses; 1 clustering with normal breast miR expression whereas the other 4 each had a unique pattern of deregulated miRs. The median overall survivals were significantly different across the 5 cancer subclasses (log-rank p=0.028) (Table). Conclusions: miR expression profiling identifies and discriminates 5 TNBC subclasses, which do not coincide with those identified as basal and non-basal by IHC. Molecular analyses are ongoing to associate the miR-based subclasses with specific clinical features or the expression of specific pathways. [Table: see text]
Age as a prognostic factor in osteosarcoma: Survival analysis.
Authors: Pallotta Guadalupe Maria , Boggio Gaston Federico , Specterman Sergio , Lastiri Jose Maria , Lopez Lincuez Maria Emilia , Lupinacci Lorena , Makiya Monica , Streitenberger Patricia , Aponte Luis , Farfalli German , Ayerza MIguel Angel
Published: March 2020

10074

Background: Studies comparing survival between adult and paediatric population with osteosarcoma are scarce and contradictory. Generally adults were excluded from analysis in historical series. End Point: evaluate age as prognostic factor in ostosarcomas IIb treated exclusively by a multidisciplinary group in a single institution. Methods: 132/278 patients with histological diagnosis of osteosarcoma IIb were selected. All were treated exclusively in our hospital from July 1988 until December 2010. Patients 17 years old or younger were considered paediatric. They all received presurgical chemotherapy with the same scheme: ifosfamide + doxorrubicin + high dose methotrexate. Univariate analysis was made (Fischer exact test). Survival was calculated wih Kaplan-Meier actuarial method. Curves were compared with log rank test. Multivariate Cox analysis was made. Results: Median age was 19.6 years (std: 9,1; range 5-58). Adults: 77, children: 55. No differences were detected between the two age groups regarding: elevated alkaline phosphatase, kind of surgery (amputation vs. limb sparing), relapse site (lung, local, other), necrosis greater than 90% or number of lung resections. There was a tendency towards axial localization in adults (p=0.05). No paediatric patient had inadequate medical intervention, but it was present in 14.3% of adults (p=0.002). 5 year Overall survival (5y OS) in children was 85,2% compared with 61,8% in adults (p=0.005); Disease free survival (DFS) had a non significant tendency to be better in children (69.6% vs. 51,3%). Variables associated with worse OS were: axial location (p=0.01), elevated alkaline phosphatase (0.003), amputation (p=0.008), local relapse or systemic non-lung metastasis (p= 0.001), necrosis less than 90% (0.001). Multivariate Cox analysis showed association between OS and paediatric population (p=0.01) and necrosis greater than 90% (p=0.001), while DFS was associated with necrosis greater than 90% (p=0.01) and elevated alkaline phosphatase (p=0.05). Conclusions: Paediatric population presents better survival compared to adults in our institution. Differences in tumour biology and in the mode of presentation related to age may be the explanation.
Multimodality treatment of pediatric and adult patients with Ewing sarcoma: A single-institution experience.
Authors: Lorente David , Diaz Robert , Torres Barbara , Cañete Adela , Aparicio Jorge , Gimenez Alejandra , Reche Encarni , Rodrigo Esteban , Verdeguer Amparo , Montalar Joaquin
Published: March 2020

10082

Background: Treatment of Ewing sarcoma pts. usually follows pediatric protocols, both in children and in adults. However, older patients fare poorly in most series. We analyze our experience with the 2001 protocol of the Spanish Society of Pediatric Oncology. Methods: Retrospective analysis. Schema: 6 cycles (cy) of VIDE chemotherapy (CT: vincristine, ifosfamide, etoposide, doxorrubicin). If no progression, local treatment (surgery or RT) and consolidation adjusted to risk: VACx8 (vincristine, dactinomycin, ciclophosphamyde) in standard-risk pts; if increased risk (axial, complete response in lung metastases or non-pulmonary metastases) VACx1, high-dose CT (busulphan-melphalan) and autologous transplant (ATSP). Analysis: induction CT toxicity, pathological response rates, consolidation treatment, disease-free (DFS) and overall survival (OS) (Kaplan- Meier). Log-rank and Cox regression analysis of prognostic factors in OS. Results: 35 patients (01.2003-05.2011). 60% male. Median age 16 y (r 7-57). Axial (43%), extremities (34%), extra-osseous (18%) and ribs (9%). Metastases: 54% (lung 58%, bone 26%, others 12%). > 1 location: 29%. Induction CT: 83% received 6 cy. 6% early progressions and 3% toxic deaths. 196 cycles of CT. Dose reduction (etoposide) in 60%. Grade 3-4 toxicity: neutropenia 13%, anemia 14%, neutropenic fever 13%, diarrhoea-stomatitis 7%.Local treatment: surgery (49%), radiotherapy (29%), none (22%). In 17 resections, > 90% necrosis in 53%. Consolidation: VACx8 29%; VACx1-ATSP in 34%; 37% other treatments (progression). No ATSP-related mortality. Median follow-up: 36 m ( 5-101 m). Median DFS 25 m (16-34 m). Median OS 28 m (15-41 m), 3-year OS 40%. Median time to progression 7 m (0.4-15 m). Median OS from progression 7 m (0.4-15 m). Age < 15 years, a non-axial primary and no extra-pulmonary metastases were favourable prognostic factors in the univariate analysis. Conclusions: Induction CT with the VIDE regimen is feasible in most patients, with a low risk of early progression. Hematological toxicity is substantial but manageable. Adults patients have a worse prognosis compared to pediatric patients. Unfortunately, survival after progression is dismal.