bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sunitinib in metastatic renal cell carcinoma (mRCC): Preliminary assessment of toxicity in an expanded access trial with subpopulation analysis
Authors: Gore M. E. , Porta C. , Oudard S. , Bjarnason G. , Castellano D. , Szczylik C. , Mainwaring P. N. , Schöffski P. , Rini B. I. , Bukowski R. M. 
Published: March 2020

5010 Background: Sunitinib is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs and PDGFRs, approved multinationally for advanced RCC. The primary aim of this international, open-label trial was to provide sunitinib to mRCC pts who failed =1 prior systemic therapy and were ineligible for other sunitinib trials or had no access to sunitinib before regulatory approval in their country. Methods: Eligibility criteria were minimized to broaden the enrolment population. Pts who were 18 yrs of age or older with histologically-confirmed mRCC received oral sunitinib 50 mg/day in 6-wk cycles (4 wks on Tx, 2 wks off). Physical exam, safety and concomitant meds were assessed every 4 wks. Results: As of Sept 1, 2006, 4,000 pts were enrolled from 181 sites in 36 countries; 2,158 pts (median age, 59 [19- 85]; male/female, 74%/26%) were included in this analysis. Baseline demographics included 106 pts (5%) with non-clear cell histology; 173 pts (8%) with brain mets; 158 pts (7%) with prior antiangiogenic Tx; and 288 pts (13%) with ECOG PS =2. Median Tx duration was 128 days (range 1- 2444) with interruptions in 17% of pts and dose reductions in 30%; 672 pts (31%) discontinued, of which 80 pts (12%) discontinued due to AEs. The median Tx duration was similar to the overall population regardless of age or site of metastatic disease at baseline (brain, bone, lung, liver, lymph nodes or other), but was longer in pts with ECOG PS 0/1 (154 days, range 1–2,444) than with ECOG PS =2 (83 days, range 1–449). The most common treatment-related AEs were diarrhea (39% any grade, 3% grade 3/4), fatigue (35%, 7%) and nausea (33%, 2%), the incidences of which were similar in pts regardless of age or site of baseline metastatic disease; overall, they occurred more frequently in pts with ECOG PS 0/1 vs. ECOG PS =2 (42% vs. 21%, 38% vs. 23%; and 34% vs. 25%, respectively), but differences in grade 3/4 severity were not observed. Median overall survival has not been reached; 19% of pts have died, the lowest incidence among pts with ECOG PS 0/1 (15%) and highest in pts with ECOG PS =2 (43%) and brain mets (34%). Conclusions: Preliminary observations suggest that sunitinib is associated with acceptable tolerability in an expanded access trial regardless of age or site of baseline metastatic disease. [Table: see text]
Randomised prospective study of intermittent versus continuous androgen suppression in advanced prostate cancer
Authors: Miller K. , Steiner U. , Lingnau A. , Keilholz U. , Witzsch U. , Haider A. , Wachter U. , Rüssel C. , Altwein J. 
Published: March 2020

5015 Background: Based on results of animal experiments intermittent androgen blockade was suggested to delay progression of advanced prostate cancer to the hormone refractory stage. We conducted a prospective randomized study to compare intermittent with continuous androgen suppression. Methods: This was a multi-centre, randomised, two-arm study comparing treatment with goserelin + bicalutamide (intermittent, group A) vs. goserelin + bicalutamide (continuous, group B). The primary endpoint was time to clinical and/or biochemical progression of the disease despite androgen suppression. Secondary enpoints were survival time, patient’s quality of life (QoL) and toxicity. Patients eligibility criteria were: histologically confirmed adenocarcinoma of the prostate in clinical stage T1–4N1–3M0 or T1–4N0–3M1 (D1 oder D2). After an induction phase of 24 weeks with MAB, 335 patients whose PSA decreased under 4 ng/ml or = 90% from baseline were randomized. Results: About two-thirds of the patients of both the intermittent and the continuous therapy arm (65% versus 66%, ITT population) experienced a clinical and/or biochemical disease progression due to any reason during this study. The median time to disease progression was longer for patients randomised to the intermittent therapy arm (16.6 months) compared with patients randomised to the continuous therapy arm (11.5 months). This difference however was not statistically significant (log rank test, p=0.1758). The median time to death from any cause was 51.4 month in the intermittent arm compared and 53.8 months in the continuous therapy arm (p = 0.658). There were no differences in the incidence of patients with AEs or SAEs or in any other safety parameter between patients treated intermittently and patients treated continuously. Patients’ self-assessment of their overall health and of their sexual activity appeared to be favourable in the intermittent compared with the continuous therapy arm. 88% of all patients treated intermittently experienced more than 50% of the number of treatment days as treatment-free days. Conclusions: Intermittent therapy in D1 and D2 prostate cancer patients appears to be safe and feasible. Off treatment periods are > 40 % and attribute to patients quality of life. No significant financial relationships to disclose.
A phase II trial of intra-patient dose-escalated sorafenib in patients (pts) with metastatic renal cell cancer (MRCC)
Authors: Amato R. J. , Harris P. , Dalton M. , Khan M. , Alter R. , Zhai Q. , Brady J. R. , Jac J. , Hauke R. , Srinivas S. 
Published: March 2020

5026 Background: Sorafenib has demonstrated activity with limited toxicity at a dose of 400 mg bid in MRCC pts. This presents an opportunity to explore a more intensive drug administration. This study allowed individual pt titration designed to evaluate the ability for pts to dose escalate. Response rate (RR), time to progression (TTP) and overall survival (OS) will be assessed. Methods: Eligibility included; pathologic diagnosis of a component of clear cell, progressive measurable MRCC, no more than 1 prior therapy, karnofsky performance status (KPS) = 70%, adequate organ/marrow function and no active CNS involvement. Initial dose 400 mg bid, daily. Dose escalation defined in the table below: Re-evaluation is performed every 8 weeks. RECIST criteria is utilized. Results: 46 patients have been enrolled. 44 are evaluable. 37 male/7 female, median age 50 years (43–79). 19 pts received prior therapy. 39 pts had a KPS of 100%, 5/90%. Sites of disease included; lung, nodal, liver, bone, adrenal, pancreas and kidney. 26 pts 1 metastatic site, 12 /2, 6/3 or more. 22 pts continue to receive sorafenib therapy; 2/800 mg, 7/1,200 mg, and 13/1,600 mg. 8 pts complete response (CR), 14 pts/partial response (PR) and 14 pts stable for 3+ months. Median duration of therapy is 6+ (range 0.2+ - 12+) months. 2 pts have not been reevaluated. Treatment related adverse events to-date; hand/foot syndrome, skin rash, diarrhea, alopecia, fatigue, hypertension, hypophosphatemia, and elevated amylase/lipase. Conclusion: 91% of pts were escalated to 1,200 mg or 1,600 mg per day. Dose escalated sorafenib has promising anti-tumor activity in pts with MRCC as demonstrated by a 52% CR/PR rate. Anti-tumor activity is further suggested by prolonged TTP = 3 months for 33% of pts. Independent radiology review is in progress. Intra-patient dose escalation data in association with anti-tumor activity and toxicity will be presented. [Table: see text] [Table: see text]
Correlation of survival with tumor histology, age, and prognostic risk group for previously untreated patients with advanced renal cell carcinoma (adv RCC) receiving temsirolimus (TEMSR) or interferon-alpha (IFN)
Authors: Dutcher J. P. , Szczylik C. , Tannir N. , Benedetto P. , Ruff P. , Hsu A. , Berkenblit A. , Thiele A. , Strahs A. , Feingold J. 
Published: March 2020

5033 Background: Temsirolimus is a novel mTOR inhibitor and has demonstrated significantly longer overall survival (OS, P=0.0069) and progression-free survival (PFS, P=0.0001) vs IFN for patients (pts) with previously untreated adv RCC with poor-risk features (Hudes et al. ASCO 2006). Planned and post-hoc analyses were performed to assess the influence of tumor histology (clear- cell vs other), age (<65 y vs =65 y), and prognostic-risk groups (intermediate vs poor; Motzer et al. JCO 20:289) on survival in pts treated with TEMSR or IFN. Methods: Pts received IFN 3 million units [MU] subcutaneously 3x weekly, escalating to 18 MU; TEMSR 25-mg intravenous infusion weekly; or TEMSR 15-mg infusion plus IFN 6 MU. Kaplan-Meier analysis and a Cox proportional hazards model were used to analyze OS and PFS for pt subsets. Histologies were reported by investigators. Results: The proportion of pts with different histologies was balanced across the 2 arms (81% clear-cell; 13% indeterminate, 6% non-clear-cell). Of those with additional subtype data, 75% were papillary. For pts with clear-cell tumors, median OS and PFS were longer for TEMSR vs IFN with hazard ratios (HR) of 0.82 and 0.76, respectively ( Table ). For pts with other tumor histologies, median OS and PFS also were longer for TEMSR vs IFN with HR of 0.49 and 0.38, respectively. Among pts <65 y, median OS and PFS were longer for TEMSR than for IFN (OS: TEMSR [n=145] 12.0 mo; IFN [n=142] 6.9 mo; HR=0.62 [95% CI, 0.47, 0.82]; PFS: TEMSR 5.6 mo; IFN 3.1 mo; HR=0.61 [0.47, 0.79]). There was no difference in OS or PFS for pts =65 y treated with TEMSR or IFN but TEMSR had a better side effect profile than IFN. OS and PFS for pts with intermediate- or poor-risk features will be reported. Conclusions: TEMSR benefits pts with clear-cell RCC and other histologies as well as younger and older pts. [Table: see text] No significant financial relationships to disclose.
The Advanced Renal Cell Carcinoma Sorafenib (ARCCS) expanded access trial: Safety and efficacy in patients (pts) with non-clear cell (NCC) renal cell carcinoma (RCC)
Authors: Stadler W. M. , Figlin R. A. , Ernstoff M. S. , Curti B. , Pendergrass K. , Srinivas S. , Canfield V. , Weissman C. , Poulin- Costello M. , Bukowski R. M. 
Published: March 2020

5036 Background: A phase III trial showed that sorafenib (SOR) doubled progression-free survival (PFS) in previously treated pts with clear cell RCC. Activity of SOR in pts with NCC RCC has not been previously reported. Methods: Pts eligible for this open-label, nonrandomized trial in North America were not eligible for other SOR clinical trials, had recovered from prior treatment-related toxicity, and had advanced RCC; ECOG PS of 0–2; age =15 yrs; no treatment with other investigational drugs within 4 wks; life expectancy >2 mos; no active coronary artery disease, ischemia or hypertension; and no severe renal impairment requiring dialysis. In the US, ARCCS enrollment ended with SOR approval in 12/05, and pts were transitioned to commercial drug with NCC pts being eligible for an additional 6-mo follow-up in an extension protocol (EP), which was designed to better assess PFS in NCC. Tumor assessments and radiological evaluations were conducted every 4 wks in the main protocol and every 8 wks in the EP. Results: Of 2,488 pts valid for safety in ARCCS, 212 (8.5%) had NCC RCC classified as papillary, chromophobe, collecting duct, or oncocytoma, of whom 24 enrolled in the EP. Baseline characteristics and efficacy are shown in the table . Grade 3 and 4 adverse events (AEs) with > 2% incidence across all histologies included fatigue 7.1%, hand-foot skin reaction 6.6%, rash/ desquamation 6.2%, hypertension 4.7%, abdominal pain 3.8% dyspnea 3.8%, pleural effusion 3.3%, nausea 3.8%, vomiting 2.4%, and ascites 2.4%. Grade 3 and 4 serious AEs were reported in 20% of patients. Of those enrolled in the EP with NCC, median PFS was 34.5 wks (65.2% censored). Conclusions: SOR was well tolerated among pts with NCC RCC. Within the limitations of no central pathologic review, SOR toxicity in NCC RCC was similar to that in the broader ARCCS population and SOR may have antitumor activity in papillary and chromophobe subtypes. [Table: see text] [Table: see text]
Differences in treatment in stage III breast cancer in African American women
Authors: Rizzo M. , Reisman N. , Gabram S. G. , Bumpers H. L. , Okoli J. , Brawley O. W. , Lund M. 
Published: March 2020

504 Background: Stage III breast carcinomas account for about 6–7% of all invasive breast cancers diagnosed annually in the US. Locally advanced breast cancer (Stage IIIA) and inflammatory breast cancer (Stage IIIB T4d) are now recognized as two distinct clinical pathologic entities, characterized by different prognostic factors profiles. The aim of this study was to compare differences in treatment in women with Stage III breast cancer in an inner city Cancer Center serving a large African American population. Methods: Retrospective review was performed on all Stage III primary breast cancers diagnosed and or treated from 2000 to 2005. Results: Of the 684 primary invasive breast cancers, 96 (14%) were Stage III (45 were Stage IIIA, 33 were Stage IIIB and 12 were inflammatory breast cancer) and 83 of the 96 (86%) were among African American women. The 6 Stage IIIC cases were excluded from analyses. To all patients was offered a combination of chemotherapy, surgery and radiation therapy. All patients with primary or residual tumors ≥ 5 cm or ≥ 3 positive axillary nodes were considered for chest wall and axillary radiation therapy; 48 of 74 received radiotherapy. Stage IIIA patients were less likely to receive neoadjuvant chemotherapy and were more likely to have ≥ 3 positive axillary nodes. Nineteen patients refused chemotherapy. The table summarizes our findings. Conclusions: In this predominantly African American female population, Stage III breast cancers were about twice as prevalent as observed nationally and a high number of these Stage III patients refused adjuvant and neoadjuvant chemotherapy. The benefit of chemotherapy and radiotherapy in improving prognosis for Stage III breast cancers is well established. Thus, reasons for refusal of chemotherapy and lack of radiotherapy need further investigation. [Table: see text] No significant financial relationships to disclose.
Use of carbonic anhydrase IX (CAIX) expression and Von Hippel Lindau (VHL) gene mutation status to predict survival in renal cell carcinoma
Authors: Pantuck A. J. , Trinh Q. , Karakiewicz P. I. , Fergelot P. , Rioux-Leclercq N. , Figlin R. , Said J. , Belldegrun A. , Patard J. 
Published: March 2020

5042 Background: VHL gene mutations induce the expression of CAIX, and previous studies have shown that low CAIX results in worse prognosis for RCC. We attempt to further describe the relationship between CAIX expression, VHL gene mutations and tumor characteristics. Methods: Radical nephrectomy was performed in 100 patients at 2 centers. Genomic DNA was extracted from frozen tumor samples using the QIAmp DNA mini kit. Four amplimers covering the whole coding sequence of the VHL gene were synthesized by PCR and sequenced by Big Dye. Mutation bearing sequences were confirmed by a second round of sequencing. The monoclonal antibody M75 was used to score the expression of the CAIX protein. Life table, Kaplan-Meier and Cox regression analyses addressed RCC-specific mortality (RCC-SM). Results: VHL mutations were identified in 58 patients (58%) and CAIX tumor expression ranged from 0% to 100%. Low CAIX expression (<85%) was associated with absence of VHL mutation (p=0.02), larger tumors (p=0.002), higher T stage (p=0.007), nodal metastases (p=0.001) and higher Fuhrman grade (p=0.006). Absence of VHL mutation was associated with worse ECOG (p=0.005), higher T stage (p=0.01) and presence of nodal (p=0.03) and distant metastases (p=0.02). Categorically-coded, CAIX was a statistically significant predictor of RCC-SM (p=0.002), while VHL mutation approached statistical significance (p=0.08) and a trend was observed for worse survival when VHL was not mutated. Patients with both high CAIX and VHL mutation had better survival (95.9% 1 year and 6 year median survival) than their counterparts with low CAIX expression and absence of VHL mutation (62.9% 1 year and 1.5 year median survival) (p<0.001). In Cox regression analyses, neither CAIX (p=0.06) nor VHL (p=0.4) achieved independent predictor status, when adjusted for age, gender, TNM stage, tumor size, Fuhrman and ECOG. Conclusions: Low CAIX expression is associated with the absence of VHL mutation and aggressive tumor characteristics, and is a statistically significant predictor of poor prognosis in patients with clear cell RCC. No significant financial relationships to disclose.
Thyroid function test (TFT) abnormalities in patients (pts) with metastatic renal cell carcinoma (RCC) treated with sorafenib
Authors: Tamaskar I. R. , Unnithan J. , Garcia J. A. , Dreicer R. , Wood L. , Iochimescu A. , Bukowski R. , Rini B. 
Published: March 2020

5048 Background: Sorafenib is an orally bioavailable VEGF receptor inhibitor with anti-tumor activity in metastatic RCC. Sunitinib, another VEGF receptor inhibitor, induces biochemical hypothyroidism in 85% of metastatic RCC pts, the majority of whom have signs or symptoms of hypothyroidism (Rini BI et al. JNCI 2007 99(1):81–83). Thus, the incidence of TFT abnormalities in pts with metastatic RCC receiving sorafenib was investigated. Methods: The medical records of pts with metastatic RCC receiving sorafenib in one of five clinical trials at the Cleveland Clinic Taussig Cancer Center were reviewed. TFTs (TSH, T4, FTI and T3), patient demographics and clinical outcomes were recorded. Results: Between February 2004 and November 2006, 71 pts (49 males, 22 females) were treated with sorafenib. Baseline pt characteristics included a median age of 62 years (range, 35–87), 87% of pts had clear cell histology and 97% had prior nephrectomy. Forty-two pts had TFTs measured while receiving sorafenib and 19/42 pts (45%; 95% CI: 30–61%) had abnormal TFTs. The TFT abnormalities were consistent with hypothyroidism (13 pts), euthyroid sick syndrome (2 pts) or hyperthyroidism (4 pts). The median values in pts with abnormal TFTs were: TSH-7 μU/ml, T3–79 ng/dl, T4–12.7 μg/dl, FTI- 5.4; these values are just outside the normal laboratory ranges. The majority of pts did not have clinical signs or symptoms that could be attributed solely to thyroid dysfunction; only one pt (2%) received thyroid hormone replacement. The estimated progression free survival for pts with normal TFTs is 7.5 months vs. 6.1 months for pts with abnormal TFTs (p=0.79). Conclusion: Mild biochemical TFTs abnormalities are common in pts with metastatic RCC treated with sorafenib. However, severe TFT abnormalities and/or clinical signs/symptoms of thyroid dysfunction are not seen, and thyroid replacement therapy is not often indicated. In contrast to sunitinib, where the high incidence and clinical relevance of thyroid dysfunction requires routine monitoring, pts with metastatic RCC receiving sorafenib should have TFTs monitored only if clinically indicated. [Table: see text]
A multivariate prognostic nomogram incorporating PSA kinetics in hormone-refractory metastatic prostate cancer (HRPC)
Authors: Eisenberger M. , Garrett-Mayer E. S. , Ou Yang Y. , de Wit R. , Tannock I. , Armstrong A. J. 
Published: March 2020

5058 Background: To develop a prognostic model and nomogram using baseline clinical variables to predict death among men with metastatic hormone-refractory prostate cancer (HRPC). Methods: TAX 327 was a clinical trial that randomized 1,006 men with metastatic HRPC to receive 3-weekly or weekly docetaxel or mitoxantrone, each with prednisone. Of these, 635 men had baseline data that included PSA kinetics, with 518 mortality events recorded as of November 2006. We developed a multivariate Cox model and nomogram to predict survival at two, three, and five years. Results: Ten independent prognostic factors were identified in multivariate analysis and include: 1) presence of liver metastases (HR 1.64, p=0.02), 2) number of metastatic sites (HR 1.58 if =2 sites, p=0.001), 3) clinically significant pain at baseline (HR 1.46, p<0.0001), 4) Karnofsky Performance Status (HR 1.42 if =70, p=0.01), 5) type of progression at baseline (HR 1.40 for measurable disease progression and 1.28 for bone scan progression, p=0.002 and 0.014 respectively), 6) pretreatment PSA doubling time (PSADT, HR 1.20 if <55 days, p=0.048), 7) baseline PSA (HR 1.17 per log rise, p<0.0001), 8) tumor grade (HR 1.18 for high grade, p=0.076), 9) alkaline phosphatase (HR 1.26 per log rise, p<0.0001), and 10) hemoglobin (HR 1.10 per unit decline, p=0.006). A PSADT <55 days (median value for this dataset) was associated with other adverse prognostic factors, but was independently associated with shortened overall survival. Men with a PSA less than the median of 114 ng/ml and longer PSADT (=55 days) had a median survival of 24.7 months, while those with higher PSA and shorter PSADT had a median survival of 13.8 months. A nomogram was developed based on this Cox multivariate model and validated internally using bootstrap methods, with a concordance index of 0.69. Conclusions: This multivariate model identified several prognostic factors in men with metastatic HRPC including PSADT, and led to the successful development of a clinically applicable nomogram. External prospective validation may support the wider use of this prognostic baseline model for men with HRPC treated with chemotherapy. No significant financial relationships to disclose.
Androgen deprivation therapy (ADT) for node postive prostate cancer
Authors: Wong Y. , Freedland S. , Hudes G. , Mitra N. , Montagnet C. , Armstrong K. 
Published: March 2020

5061 Background: The role of ADT for men with node positive prostate cancer following radical prostatectomy (RP) is unclear. One randomized trial has shown a survival advantage for men treated with immediate adjuvant (adj) ADT compared treatment at onset of clinical metastases. However, benefit of immediate therapy is less clear in the PSA era when ADT can initiated at the time of biochemical relapse. Methods: We used linked Surveillance, Epidemiology and End Results-Medicare Data to identify a cohort of men who underwent RP between 1991–1999 and were found to have positive regional lymph nodes. We searched Medicare claims to identify men with claims for ADT (hormonal therapy or orchiectomy) within 3 years of diagnosis. We excluded men who received ADT prior to RP. We classified men as receiving adj ADT if they received treatment within 120 days of RP and compared them to men who had not received adj ADT. We used propensity scores to balance potential confounders of receiving adj ADT (age, tumor characteristics, extent of nodal disease, demographics). We used Cox proportional hazard methods to estimate the impact of adj ADT on overall survival (OS) adjusting for propensity score. We conducted a sensitivity analysis using 90, 150, 180 and 365 days as the time limit for adj ADT. Results: 719 men were identified, of whom 190 received adjuvant ADT within 120 days of RP. There was no statistically significant difference in overall survival between the men who did or did not receive adj ADT (HR 0.96 95% CI 0.70–1.32) The results were similar for men who received ADT within 90 and 150 days. However, when the definition of adj ADT was moved to 180 days (HR 1.08 (0.80–1.47)) and 365 days (HR 1.24 (0.92–1.65)) the men receiving adj ADT had a slightly higher risk of death, suggesting some in the adj ADT groups using these later definitions may have received therapy as salvage therapy for progressive disease. Conclusions: This observational study suggests that in the PSA era when men can be started on ADT at the time of biochemical recurrence, overall survival may not be significantly compromised by deferring immediate ADT in men with positive lymph nodes following RP. Further clinical research is needed to better understand which patients are likely to benefit from immediate ADT, and which men can be spared the long term toxicities. [Table: see text]