bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II trial of paclitaxel, ifosfamide, and cisplatin (TIP) for previously untreated patients (pts) with intermediate- or poor-risk germ cell tumors (GCT).
Authors: Feldman Darren Richard , Hu James , Dorff Tanya B. , Patil Sujata , Van Alstine Lindsay Joy , Momen Lamia , Carousso Maryann , Hughes Amanda , Snively-Solomon Jolie , Ketchens Charlean , Sheinfeld Joel , Bains Manjit S. , Bajorin Dean F. , Bosl George J. , Motzer Robert John , Quinn David I. 
Published: February 2017

336 Background: Durable progression-free survival (PFS) rates for pts with intermediate- and poor-risk GCT approximate only 75% and 50%, respectively with standard BEP chemotherapy. This phase II study investigated first-line TIP in this population. Methods: Pts age ≥18 with previously untreated poor-risk or modified intermediate-risk (LDH ≥3x upper limit of normal [ULN]) GCT were eligible. Four cycles of TIP were given every 21 days, consisting of paclitaxel 120mg/m2 on days 1-2; ifosfamide 1200mg/m2 (with mesna support) on days 1-5; and cisplatin 20mg/m2on days 1-5. Peg-filgrastim was given on day 6 and levofloxacin on days 7-13 for prevention of neutropenic fever. The primary endpoint was the complete response (CR) rate; secondary endpoints included PFS and toxicity. A Simon’s two-stage design was used: if ≥11 CRs were observed in the first 18 pts, a total of 41 evaluable pts would be accrued with the trial considered positive if ≥27 CRs were achieved. Results: Of 44 men (median age 27 [range 18-56]) enrolled; 38 had nonseminoma and 6 had seminoma; 29 were poor-risk and 15 intermediate-risk. Primary site was testis in 30, mediastinum in 11, retroperitoneum in 3. Most pts had lung (n=31) and abdomen/pelvis (n=29) metastasis, and 14, 6, and 1 had liver, bone, and brain metastasis, respectively. Markers were elevated in 42 pts. Forty pts received all 4 TIP cycles; 3 pts were withdrawn after 2 cycles for allergic reactions to paclitaxel and were inevaluable for response, and 1 pt completed only 3 cycles in order to undergo surgery for growing teratoma syndrome (evaluable). Of 41 evaluable pts, 29 (72%, 90% CI: 60% – 78%) achieved a CR and 5 (all seminoma) achieved a PR with negative markers (PR-); 7 pts had incomplete responses and 2 pts relapsed from PR- or CR. With a median follow-up of 2.1 years, estimated 1-year PFS was 79% (95% CI: 64% – 89%) and 3-year overall survival 97% (95% CI: 83% – 100%). There were no toxic deaths. Grade 3/4 toxicities were primarily hematologic but only 7 (16%) pts developed neutropenic fever. Conclusions: TIP demonstrated promising efficacy and was tolerable in intermediate- and poor-risk GCT pts. A randomized trial of TIP versus BEP is being planned. Clinical trial information: NCT00470366.
Outcomes of patients with sarcomatoid renal cell carcinoma: The Mayo Clinic experience.
Authors: Costello Brian Addis , Zhang Ben , Lohse Christine M. , Boorjian Stephen A. , Cheville John , Leibovich Bradley C. , Thompson Robert Houston 
Published: February 2017

359 Background: Sarcomatoid renal cell carcinoma (RCC) is an aggressive form of RCC and is associated with a poor prognosis. Standard therapies tend to be less effective in this subset of patients. Methods: Using the Mayo Clinic Nephrectomy Registry, 206 patients with sarcomatoid RCC treated with partial or radical nephrectomy were identified. These patients were characterized based on extent of disease, treatment response and survival. Results: Of these 206, there was no evidence of distant metastases in 110 patients at the time of surgery and the estimated distant metastases-free survival at one year was 44%. The estimated cancer-specific survival rate at one and five years was 56% and 20%, respectively. Compared to patients with grade 4 RCC without sarcomatoid features, those with sarcomatoid RCC were more likely to develop distant metastases following surgery (hazard ratio 1.49). Considering those with metastatic sarcomatoid RCC, 96 patients had metastases at the time of surgery and 77 with no metastases at the time of surgery subsequently developed distant metastases (n=173). Of these, 156 died at a mean of 1.0 years from time of first evidence of distant metastases with a median cancer-specific survival of 0.6 years. Estimated cancer-specific survival rates from time of first metastases at one year and five years were 34% and 4%, respectively. The most common metastatic sites: lung (46%), bone (15%), liver (13%), non-regional lymph nodes (9%), and brain (5%). Patients who received targeted systemic therapy (10%) with either sunitinib (n=14), sorafenib (2) or pazopanib (1) for their first occurrence of distant metastases had an estimated cancer-specific survival rate at one year of 69%, compared to 30% for patients who did not. Median cancer-specific survival for those receiving targeted therapy as first-line was 2.2 years compared to 0.6 years for those patients who did not. Conclusions: Sarcomatoid RCC is an aggressive subtype of kidney cancer as evidenced by poor survival rates. The patients in this registry with metastatic sarcomatoid RCC who received targeted therapy as first-line treatment had improved cancer-specific survival rates.
Pulmonary complications with the use of mTOR inhibitors in targeted cancer therapy: A systematic review and meta-analysis.
Authors: Gartrell Benjamin Adam , Ying Jian , Sivendran Shanthi , Agarwal Neeraj , Boucher Kenneth M. , Choueiri Toni K. , Sonpavde Guru , Oh William K. , Galsky Matt D. 
Published: February 2017

362 Background: mTOR inhibitors are approved in several malignancies including renal cell carcinoma (RCC). While pulmonary toxicities are a recognized adverse effect associated with this drug class, the frequency and risk of these side effects have not been well characterized. Methods: Clinical trials of mTOR inhibitors in solid tumors were identified through a search of PubMed and ASCO abstracts. Prospective studies of temsirolimus, everolimus, and ridaforolimus in solid tumors were evaluated for inclusion. 22 eligible phase II and phase III trials that included 4,242 patients were identified and included in a systematic review and meta-analysis. Adverse event data was extracted for pulmonary complications including pneumonitis, dyspnea, and cough. The incidence rate and the incidence rate ratios were determined for these pulmonary adverse events. Results: Based on our analysis of the 20 trials that reported pneumonitis, the incidence rate of any grade pneumonitis in patients with solid tumors treated with mTOR inhibitors is 0.11 (95% CI, 0.06-0.17). The incidence rate of grade 3 or 4 pneumonitis is 0.03 (95% CI, 0.01-0.04). The incidence rate ratio of any grade pneumonitis with mTOR inhibitors relative to controls is 18.9 (95% CI, 6.5-55.1), and the incidence rate ratio for the development of grade 3 or 4 pneumonitis is 7.9 (95% CI, 2.6-24.0). The incidence rates of any grade cough and dyspnea were found to be 0.23 (95% CI, 0.20-0.27) and 0.15 (95% CI, 0.10-0.21), respectively. The incidence rates of grade 3 or 4 cough and dyspnea are found to be 0.01 (95% CI, 0.00-0.01) and 0.03 (95% CI, 0.02-0.04), respectively. There was a statistically significant, but modest increase in risk of developing any grade cough (incidence rate ratio of 1.9 [95% CI, 1.6-2.4]) and grade 3 or 4 dyspnea (incidence rate ratio of 2.0 [95% CI, 1.2-3.3]) with mTOR inhibitors relative to controls. Conclusions: This study confirms that mTOR inhibitors are associated with pulmonary adverse events and provides a quantitative estimation of the risk of these adverse events in solid tumor patients treated with these drugs. The majority of pulmonary adverse events are low grade.
Adjuvant versus neoadjuvant androgen deprivation with radiation therapy for prostate cancer: Does sequencing matter?
Authors: Weller Michael A. , Tendulkar Rahul D. , Reddy Chandana A. , Stephans Kevin L. , Kupelian Patrick 
Published: February 2017

37 Background: Androgen deprivation therapy (ADT) is typically given neoadjuvantly and concurrently with radiation therapy (RT) rather than adjuvantly in the management of intermediate and high risk prostate cancer. Our objective is to compare outcomes between patients who receive adjuvant ADT (ADJ), i.e. immediately after the completion of RT, with those who receive a neoadjuvant and concurrent regimen (NEO). Methods: From 1995-2002, 515 patients with CaP were definitively treated with RT and ADT. ADT was given for a duration of 6 months in all cases. NEO was given 2-3 months prior to the start of RT. ADJ was initiated immediately following the completion of RT. ADT sequencing was NEO in 311 (60%) and ADJ in 204 (40%). The distribution by NCCN risk classification for NEO was high in 67%, intermediate in 26%, and low in 7%. The risk group distribution for ADJ was high in 69%, and intermediate in 31%. RT dose was either 78 Gy at 2 Gy/fx (n=168) or 70 Gy at 2.5 Gy/fx (n=347). Kaplan-Meier analysis was used to calculate biochemical relapse free survival (bRFS, Phoenix definition), distant metastasis free survival (DMFS) and overall survival (OS). Cox proportional hazards regression was used to examine the impact of ADT timing on outcomes. Results: The median follow up for all patients was 8 years. For the entire cohort, the 10-yr bRFS, DMFS and OS rates were 61%, 80% and 66%, respectively. The 10-yr bRFS rates for ADJ vs. NEO were 63% vs. 60% (p=0.98). The 10-yr DMFS rates for ADJ vs. NEO were both 80% (p=0.60). The 10-yr OS rates for ADJ vs. NEO were 65% vs. 67% (p=0.98). There were no statistically significant differences in bRFS, DMFS or OS between the two groups after accounting for patient, tumor and treatment characteristics on both univariate and multivariate analyses. Conclusions: There is no difference between neoadjuvant vs. adjuvant ADT in the setting of dose-escalated RT for localized prostate cancer. This suggests that the synergy between radiation therapy and androgen deprivation is independent of the sequencing of both modalities and that the initiation of RT does not need to be delayed for a course of neoadjuvant ADT.
Impact of bone and liver metastases (BM, LM) in patients with metastatic renal cell carcinoma (mRCC) treated with molecularly targeted agents (MTAs): Results from the International mRCC Database Consortium (IMDC).
Authors: McKay Rana R. , Kroeger Nils , Xie Wanling , Lee Jae-Lyun , Knox Jennifer J. , Bjarnason Georg A. , MacKenzie Mary J. , Wood Lori , Srinivas Sandy , Vaishampayan Ulka N. , Rha Sun Young , Pal Sumanta Kumar , Donskov Frede , Tantravahi Srinivas , Rini Brian I. , Heng Daniel Yick Chin , Choueiri Toni K. 
Published: February 2017

394 Background: The skeleton and liver are frequently involved sites of metastases in patients with mRCC. Their impact on survival outcomes of patients treated with currently approved MTAs is largely unknown. The purpose of this study was to analyze patient outcomes based on the presence or absence of BM and/or LM in the era of MTAs. Methods: We conducted a review from the IMCD of 2,027 patients with mRCC treated from April 2003 to August 2012. Statistical analyses were performed using Cox regression and the Kaplan-Meier method. Results: Median follow-up was 21 months. 1,978 were treated with first-line VEGF targeted therapy and 49 were treated with first-line mTOR inhibitors. Presence of BM was 34% overall and 27%, 33%, and 43% in favorable, intermediate, and poor-risk disease, respectively, by IMDC criteria (p < 0.001). Presence of LM was 19% overall and higher in poor-risk patients (23%) compared to favorable (20%) or intermediate-risk groups (16%) (p = 0.003). Other sites of metastases include lung, lymph node, adrenal, soft tissue, and/or brain. Among patients with a single metastatic site, those with BM or LM had a worse overall survival (OS) when compared to metastases at other sites (Table). Among patients with ≥ 2 sites of metastases, those with BM and LM had a shorter time to treatment failure (4.2 vs. 7.3 months, p < 0.0001) and worse OS (Table) when compared to patients with metastases at other sites. In multivariable analyses adjusting for IMDC criteria, BM and LM independently predicted poorer survival (HR=1.38 for BM vs. other metastases, 1.37 for LM vs. other metastases, and 1.82 for concomitant BM and LM, respectively, p < 0.0001). Conclusions: BM and LM in mRCC patients have significant clinical relevance and may possibly be used for risk-stratification of patients with mRCC. [Table: see text]
Metastatic non–clear cell renal cell carcinoma (nccRCC) treated with targeted therapy agents: Applying the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic model to predict outcomes.
Authors: Kroeger Nils , Xie Wanling , Lee Jae-Lyun , Bjarnason Georg A. , Knox Jennifer J. , MacKenzie Mary J. , Wood Lori , Srinivas Sandy , Vaishamayan Ulka N. , Rha Sun Young , Pal Sumanta Kumar , Donskov Frede , Agarwal Neeraj , Kollmannsberger Christian K. , Tan Min-Han , North Scott A. , Rini Brian I. , Choueiri Toni K. , Heng Daniel Yick Chin 
Published: February 2017

396 Background: The International mRCC Database Consortium (IMDC) Prognostic Model (Heng, et al. model, JCO, 2009) was defined and validated in a patient cohort that was comprised of RCC of all histological-subtypes. Clear-cell RCC (ccRCC) accounts for ~80% of RCC cases, and thus it is unknown if this model is reliable in patients with non-ccRCC (nccRCC). Therefore, we sought to evaluate the reliability of the model separately in ccRCC and nccRCC. Methods: Data on 2,215 (1,963 ccRCC/252 n-ccRCC) patients treated with 1-st line VEGF-and mTOR targeted therapies were collected from the IMDC. nccRCC included papillary, chromophobe, and other histologies. Patients were assigned to favorable, intermediate, and poor prognosis groups according to the ICDM prognostic model. The discrimination ability for overall survival (OS) was evaluated by C-index. Results: The median OS of the entire cohort was 20.9 months. nccRCC patients were of younger age (p < 0.0001), more often presented with low Hb (p = 0.014) and elevated neutrophils (p = 0.0001), but displayed otherwise similar clinicopathological features compared to ccRCC. OS (22.3 vs. 12.8 months; p < 0.0001), and TTF (7.8 vs. 4.2 months; p < 0.0001) were worse in nccRCC compared to ccRCC. The hazard ratio for death (OS) and treatment failure (TTF) when adjusted for the prognostic factors was 1.41 (95%CI 1.19, 1.67, p < 0.0001) and 1.54 (95% CI 1.33, 1.79, p < 0.0001), respectively. The IMDC prognostic model reliably discriminated three risk groups to predict OS and TTF in nccRCC; the median OS and TTF of favorable, intermediate, and poor prognosis groups were 31.4, 16.1, and 5.1 months (p < 0.0001) and 9.6, 4.9, and 2.1 months (p < 0.0001), respectively. The C-indices for OS were 0.66 and 0.64 for the IDCM and MSKCC criteria, respectively. Conclusions: Patients with nccRCC treated with targeted therapies have a significantly worse outcome than ccRCC patients. The IMDC prognostic model reliably predicts OS and TTF in nccRCC and ccRCC.
Predicting survival in metastatic RCC on sunitinib using MASS criteria: Evaluation of a large multicentered prospective phase III trial.
Authors: Smith Andrew D. , Zhang Haowei , Souza Frederico , Roda Manohar , Penman Alan 
Published: February 2017

407 Background: The objective of this study is to predict progression-free survival (PFS) and overall survival (OS) in metastatic RCC on sunitinib therapy using initial post-therapy CT imaging changes as a biomarker. Methods: An IRB-approved HIPAA-compliant analysis of CT imaging and survival data from 213 randomly selected patients on sunitinib therapy from a prospective phase III trial of metastatic RCC treated with sunitinib (N=375) versus interferon-alpha (N=375) was performed. Up to 5 target lesions were identified, and response per RECIST 1.1, Choi Criteria, Modified Choi Criteria, and MASS Criteria were made in comparison with the baseline images, while blinded to clinical data. Imaging responses on the first post-therapy CT were associated with PFS and OS by log-rank test, descriptive statistics, and cox proportional hazards models. Results: All criteria had predictive capacity for PFS and OS (log-rank p < 0.0004 each). Only hazard ratios (HRs) of the best and worst response for Modified-Choi (0.60/2.60) and MASS Criteria (0.46/14.8) were both significantly different from the middle category for predicting PFS (p = 0.002/p = 0.008 and p < 0.001/p < 0.001). Only HRs of the best and worst response for RECIST (0.46/9.78) and MASS Criteria (0.56/7.18) were both significantly different from the middle category for predicting OS (p = 0.007/p < 0.001 and p = 0.001/ p <0.001). The overall accuracy for detecting a good clinic outcome (PFS > 250 days) was 51% for RECIST, 62% for Choi Criteria, 67% for Modified Choi Criteria, and 76% for MASS Criteria. The overall accuracy for detecting a poor clinical outcome (PFS<250 days) was 58% for RECIST, 57% for Choi Criteria, 58% for Modified Choi Criteria, and 58% for MASS Criteria. Conclusions: MASS Criteria had the best overall accuracy for predicting PFS and OS in metastatic RCC on sunitinib therapy.
Association of partial nephrectomy with a long-term survival advantage in patients between age 20 and 44 with renal cell carcinomas ≤ 4 cm: An analysis of the SEER database.
Authors: Daugherty Michael R. , Bratslavsky Gennady 
Published: February 2017

408 Background: PN decreases the risk of developing chronic kidney disease as opposed to RN. While prior studies have demonstrated the survival advantage of PN in older patients, they have been criticized by selection bias in procedure selection due to comorbidities. We hypothesized that the long-standing effects of renal preservation would manifest in a survival advantage of a younger patient population, where this selection bias is minimized. Methods: The SEER 18-registries database was queried for patients between the ages of 20 to 44 that were surgically treated with either PN or RN for RCC between 1993 and 2003. We have excluded patients with metastatic or locally advanced disease and included patients with localized tumors ≤4 cm with known grade. The histologies selected were clear cell, papillary, chromophobe, sarcomatoid, collecting duct, and renal cell. The final cohort consisted of 222 and 494 subjects treated with PN and RN respectively. Chi-square analysis compared tumor variables and patient characteristics. Cancer-specific and overall survival rates were compared at 5 and 10 years using Kaplan-Meier analyses. Results: There were no differences between patients treated by PN or RN in demographics or tumor characteristics. Additionally, there was no difference in cancer-specific survival between the two groups at 5 or 10 years (p= 0.34 and p = 0.1 respectively). While there was no difference in 5-year overall survival (98.2% vs. 95.5%, p = 0.07), the patients treated with PN had an advantage in 10-year overall survival compared to patients treated with RN (94% vs. 89.7%, p = 0.025). Conclusions: Present SEER analyses demonstrate that when compared to RN, PN results in improved overall survival in patients treated for small, localized RCC. As expected, the survival advantage is observed late and supports the importance of long-term renal functional preservation. The present study of a younger patient population allows for minimizing selection bias in choosing surgical procedure due to comorbidities and provides further support for maximal renal preservation in patients with a life expectancy of 10 years or more.
First-in-human study of AMG 208, an oral MET inhibitor, in adult patients (pts) with advanced solid tumors.
Authors: Hong David S. , Rosen Peter J. , Lockhart A. Craig , Fu Siqing , Janku Filip , Kurzrock Razelle , Khan Rabia , Amore Benny , Caudillo Isaac , Deng Hongjie , Hwang Yuying C. , Loberg Robert D. , Shubhakar Poornima , Zoog Stephen , Beaupre Darrin M. , Lee Peter 
Published: February 2017

41 Background: AMG 208 is a small molecule MET inhibitor that suppresses proliferation and induces apoptosis in human tumor xenografts. This first-in-human study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of AMG 208. We report data from the dose escalation part of the study. Methods: Key eligibility criteria: ≥ 18 yr, advanced solid tumors, ECOG ≤ 2, and evaluable/measurable disease. Using a modified Fibonacci design, 3–9 pts were enrolled into 1 of 7 sequential dose cohorts (25, 50, 100, 150, 200, 300, and 400 mg) of AMG 208. Pts received AMG 208 orally on days 1 and 4–28 once daily. If no dose limiting toxicity (DLT) was seen on days 1–28, pts received AMG 208 once daily starting at day 36 provided pts showed no evident disease progression. In cohorts 1–3, a standard 3+3 design was followed. In cohorts 4–7, a modified 3+3+3 design was followed. Results: As of July 16 2012, 54 pts (25 mg [n=6], 50 mg [n=4], 100 mg [n=4], 150 mg [n=3], 200 mg [n=16], 300 mg [n=10], and 400 mg [n =11]) had received ≥ 1 dose of AMG 208. 67% were men; 19% had prostate cancer (PC). Median (range) age: 61 (39–80) yr. ECOG 0/1: 52%/48%. 6 DLTs were seen: a grade (G) 3 increased AST (200 mg), a G3 thrombocytopenia (200 mg), a G4 acute myocardial infarction (300 mg), a G3 prolonged QT (300 mg), and two G3 hypertensions (400 mg). The maximum tolerated dose was not reached. 83% of pts had tx-related adverse events (AE). Tx-related AE occurring in > 10 pts: fatigue (n=24), nausea (n=18), hypertension (n=12), and diarrhea (n=11). 24% of pts had grade ≥ 3 tx-related AE. AMG 208 was orally bioavailable with a 30–35 hr mean half-life in plasma. Exposure increased linearly with dose; accumulation at day 28 was 2.7-fold across cohorts. Of the 42 pts with available tumor response data for site reads, 1 had complete response on bone scan (PC 300 mg) while 2 had partial responses (PR; PC 400 mg and kidney cancer 200 mg; both had -33% tumor shrinkage), and 29 had stable disease (SD); 1 other PC pt had PR after data cutoff. Of the 35 pts with available tumor response data for central reads, 26 had SD. FLT and biomarker data will be presented. Conclusions: AMG 208 up to 400 mg daily had manageable toxicities and showed evidence of antitumor activity, especially in prostate cancer. Clinical trial information: NCT00813384.