bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical and pathologic factors associated with development of hepatocellular carcinoma in patients with hepatitis virus-related cirrhosis: A long-term follow-up study
Authors: Morales-Espinosa D. , Martínez-Velasco A. , Cerón-Lizárraga T. , Rosas-Camargo V. , Rodríguez-Díaz J. L. , Flores- Estrada D. , Gamboa-Domínguez A. , Arrieta O.
Published: March 2020

4646

Background: Hepatocellular carcinoma (HCC) represents >90% of primary liver neoplasms and develops mainly in patients with liver cirrhosis. Risk factor identification for development of HCC in patients with cirrhosis is of great relevance due to its high incidence and poor prognosis when detected at advanced stages. The aim of our study was to identify HCC development-associated risk factors in a cohort of patients with hepatitis virus-related chronic liver disease and cirrhosis. Materials and Methods: Patients with diagnosis of hepatitis virus-related cirrhosis from January 1980 to January 2000 were included. Patients were followed with abdominal US and determination of AFP levels, physical examination, and biochemical tests every 3–6 months. The endpoint in this study was defined as development of HCC. Liver histology was evaluated according to the METAVIR. Results: 282 patients met the inclusion criteria; most (86%) had a serologic diagnosis of hepatitis C virus, and only 14% had hepatitis B virus at the time of diagnosis of cirrhosis, while 56 and 37% were classified as Child A and B, respectively; only 7% as Child C. Histological activity was mild in 59% of patients; moderate and severe in 41%. Mean annual incidence was 1.87%; 22 and 35% of patients developed HCC at 10 and 15 years of follow-up, respectively. Diagnosis of HCC was made by histopathology in 37% and by tumoral lesion-associated AFP elevation confirmed by imaging studies in 63%. In multivariate analysis, 3 variables were associated with HCC: moderate to severe histological activity; platelet count <105 103/mm3, and alpha- fetoprotein >5 ng/mL. We divided patients into two groups according to regression coefficient: low and high-risk; patients assigned to the low-risk group showed 5, 10, and 15-year HCC incidences of 3.4, 6.4, and 6.4%, respectively, in contrast to patients from the high-risk group, who showed incidences of 17.8, 33.5, and 56.8%, respectively. Conclusions: We found three HCC-associated variables: histological activity; platelet count and alpha-fetoprotein levels. Patients considered as high-risk for developing hepatocellular carcinoma must be considered candidates for closer follow-up.

No significant financial relationships to disclose.
Tamoxifen, hot flashes, and breast cancer recurrence: Support for pharmacogenetics
Authors: Mortimer J. , Flatt S. , Parker B. , Gold E. , Pierce J. P.
Published: March 2020

500

Background:
Knowledge of the pharmacogenetics of the CYP2D6 enzyme has been shown to correlate with the efficacy of adjuvant tamoxifen. Women who are ‘extensive metabolizers” of CYP2D6 have an improved relapse free survival and experience more hot flashes than women who have impaired metabolism (Goetz, JCO 2005;23:9312–18). We hypothesized that the development of hot flashes on adjuvant tamoxifen was an indicator of drug metabolism and would correlate with a more favorable outcome than women who did not experience hot flashes.
Methods:
The WHEL trial enrolled 3,088 breast cancer survivors with stages I (T1c)-IIIA breast cancer, within 2–48 months of initial diagnosis, and age < 75 years to either a dietary intervention (n=1,537) or a control group (n=1,551). Data on the primary tumor, cancer treatment, disease status, and quality of life measures were collected at baseline and annually. Bivariate associations of vasomotor symptoms with age, race/ethnicity, menopausal status, cancer stage, ER and PR status, and time since diagnosis were tested using chi-square tests for categorical and t-tests for continuous variables. A left-truncated Cox proportional hazards model tested the association between recurrence-free survival and hot flashes, adjusting for tumor stage and grade and patient age. Women who died without a new breast cancer event were censored at their date of death; those without a new breast cancer event were censored at December 1, 2006 or the date of their most recent self-report of their breast cancer status.
Results:
The study sample includes 864 women treated with adjuvant tamoxifen 78% who reported hot flashes, and 69% of those reporting hot flashes also reported night sweats; 4% reported night sweats without hot flashes, and 18% reported neither hot flashes nor night sweats. A delayed entry Cox proportional hazards model adjusting for tumor stage and grade showed that those reporting hot flashes had a hazard ratio of 0.51 of recurrence during the follow-up period (95% CI 0.32–0.79) and that hot flashes were more predictive of outcome for tamoxifen treated patients than were age, grade, hormone receptor status, or stage II cancer.
Conclusions:
Our results contribute to the data that suggest tamoxifen side effects and efficacy may relate to an individual’s pharmacogenetics.

No significant financial relationships to disclose.
Concomitant and adjuvant androgen deprivation (ADT) with external beam irradiation (RT) for locally advanced prostate cancer: 6 months versus 3 years ADT—Results of the randomized EORTC Phase III trial 22961
Authors: Bolla M. , van Tienhoven G. , de Reijke T. M. , van den Bergh A. C. , van der Meijden A. P. , Poortmans P. M. , Gez E. , Kil P. , Piérart M. , Collette L. ,   EORTC Radiation Oncology and Genito-Urinary TractCancer Groups
Published: March 2020

5014

Background: After EORTC trial 22863, 3 years of endocrine treatment has become standard adjuvant treatment to RT for locally advanced prostate cancer. EORTC 22961 tests if similar survival can be achieved in patients who underwent EBRT (to 70 Gy) and 6 months of combined ADT without further ADT (SADT arm) as in patients with 2.5 years of further treatment with luteinizing hormone-releasing hormone agonist monotherapy (LADT arm). Methods: Eligible patients had T1c-2b N1–2 or pN1–2, or T2c-4 N0–2 (UICC 1992) M0 prostate cancer with PSA <150ng/ml. Non-inferior survival was defined as a morality hazard ratio (HR) = 1.35 for SADT vs LADT. Non inferiority at 80% power and 1-sided a=0.05 required 275 deaths. A stopping boundary was applied at 1-sided a=0.018. Results: 970 patients were randomized (483 SADT and 487 LADT). At 5.2 years median follow-up, 173 patients had died (100 vs 73). An Independent Data Monitoring Committee recommended disclosure of results based on an interim analysis showing futility. Patient characteristics were well balanced: median age 69 years, WHO PS 0 in 83.4%, most patients had T2c-T3 N0 disease. Progression (mostly biochemical and/or bone progression) occurred in 220 cases (159 on SADT vs 61 on LADT) and was treated by secondary hormonal manipulation. The 5-year overall survival rate was 85.3% on LADT and 80.6% on SADT (HR=1.43, 96.4% CI: 1.04–1.98), and failed to prove non-inferiority. The 5-year clinical progression-free survival rate was 81.8% on LADT versus 68.9% on SADT arm and the 5-year biochemical progression-free survival rate was 78.3% on LADT versus 58.9% on SADT, indicating inferiority of SADT with HR=1.93 and HR=2.29, respectively. Conclusions: The study was designed to demonstrate non-inferior survival with 6 months ADT compared to 3 years adjuvant ADT after irradiation for patients with locally advanced prostate cancer, but observed survival data indicate that non-inferiority cannot be confirmed. Progression-free survival was also shorter on SADT.

No significant financial relationships to disclose.
Results of a phase III randomized controlled trial of the safety and efficacy of atrasentan in men with nonmetastatic hormone-refractory prostate cancer (HRPC)
Authors: Nelson J. B. , Chin J. L. , Love W. , Schulman C. , Sleep D. , Qian J. , Steinberg J. , Hintzman P. , Dawson M. , Carducci M.
Published: March 2020

5018

Introduction: Atrasentan is a potent oral, selective endothelin A receptor antagonist with biological activity in patients with HRPC. This randomized phase III trial of atrasentan vs placebo was conducted in 941 men with nonmetastatic HRPC whose prostate-specific antigen (PSA) was rising despite adequate androgen suppression. Methods: 467 patients were randomized to receive atrasentan 10 mg and 474 patients were randomized to receive placebo daily. Primary efficacy endpoints were time to disease progression (TTP) and progression-free survival, with progression defined as the onset of metastases. Secondary endpoints were overall survival, time to PSA progression, change from baseline in bone alkaline phosphatase (BAP), and PSA doubling time (PSADT). Results: In the intent-to-treat population, median TTP was 764 days with atrasentan and 671 days with placebo (hazard ratio [HR], 0.915; G1,1 P=0.288). More placebo- treated patients (267, 56.3%) than atrasentan-treated patients (227, 48.6%) experienced disease progression. Overall, 278 patients (29.5%) discontinued before reaching a protocol-defined endpoint (155, 40.8% US vs 123, 21.6% non-US). More placebo-treated patients (210, 44.3%) than atrasentan-treated patients (169, 36.2%) experienced new skeletal lesions. Median survival was 1,477 days for the atrasentan group and 1,403 days for the placebo group (HR, 0.909; G1,1 P=0.176). Mean change from baseline to final BAP was -1.51 IU/L with atrasentan compared with +2.20 IU/L with placebo (P<0.001). PSADT was lengthened with atrasentan relative to placebo (P<0.031). The incidence of peripheral edema, nasal congestion, headache, dyspnea, anemia, and heart failure was significantly greater in the atrasentan group (P<0.05). Most of these events were mild and nonserious and did not result in study discontinuation. Conclusions: Data from this study did not show a statistically significant difference in time to progression between atrasentan and placebo. However, the high discontinuation rate, especially among US patients, may have compromised the ability of the study to accurately determine the treatment effect of atrasentan in this population.

No significant financial relationships to disclose.
Survival and secondary malignancy rates for adjuvant radiation therapy versus observation in stage I testicular seminoma: A Surveillance, Epidemiology, and End Results (SEER) analysis
Authors: Vudarla N. , Jawed I. , Kaya H. , Tward J. D. , Macdonald O. K. , Martincic D. , Gaffney D. K. , Shivnani A. T. , Odom- Maryon T. L. , Lee C. M.
Published: March 2020

5020

Background: The standard adjuvant treatment for men with stage I testicular seminoma remains controversial within the literature. We analyzed survival and secondary malignancy rates in men with stage I seminoma who underwent adjuvant radiation therapy (RT) or observation (OB) following orchiectomy. Methods: Data was obtained from the Surveillance, Epidemiology, and End Results program (SEER) of the U.S. National Cancer Institute from 1973 - 2003. The primary end points were overall survival (OS) and cause-specific survival (CSS). Multivariate Cox regression models were utilized to study the significance of clinical variables: age at diagnosis, laterality of primary disease, race (white, black, American Indian, Asian/pacific islander) and radiation group. Standardized incidence ratios (observed-to-expected [O/E] ratio) and absolute excess risks of secondary malignancies were also assessed for each subgroup. Results: Out of 6,764 patients eligible for analysis, 5,265 were treated with RT and 1,499 with OB. After a median follow up of 7.6 years, the 5-, 10- and 20- year OS rates for the RT versus OB were 97.9 vs. 95.0; 92.2 vs. 92.2; and 83.6 vs. 84.1 (p= 0.005), respectively. The CSS rates for the same time periods were 99.6 vs. 98.7; 99.2 vs. 98.7; and 99.2 vs. 98.7 (p= 0.002), respectively. Adjuvant RT was associated with improved CSS on multivariate analysis with HR 0.37 (CI 0.19–0.70, p= 0.002). Overall, 312 patients developed secondary malignancies which was significantly higher than the endemic rate (O/E 1.43, p<0.05). RT patients had an increased rate of secondary malignancies when compared with the OB population (O/E 1.93, p<0.05). RT population were at excess risk for contralateral testicular, pancreatic, and hematologic malignancies (p<0.05). Conclusions: Within this large United States population analysis, adjuvant RT was associated with improved CSS for men with stage I testicular seminoma. The incidence of secondary malignancies was also found to be significantly increased for the RT group. Further studies are needed to determine if modern RT techniques and field-size reductions may lead to improvements in the therapeutic ratio.

No significant financial relationships to disclose.
Sunitinib versus interferon-alfa (IFN-α) as first-line treatment of metastatic renal cell carcinoma (mRCC): Updated results and analysis of prognostic factors
Authors: Motzer R. J. , Figlin R. A. , Hutson T. E. , Tomczak P. , Bukowski R. M. , Rixe O. , Bjarnason G. A. , Kim S. T. , Chen I. , Michaelson D.
Published: March 2020

5024

Background: In a randomized phase III trial of patients (pts) with mRCC, sunitinib demonstrated a significant improvement in progression-free survival (PFS) and objective response rate (ORR) compared to IFN-a as first-line therapy (Proc ASCO 2006;24:2s [Abstract LBA3]). We present the most recent data from this trial and an analysis of prognostic factors. Methods: Untreated pts with clear-cell mRCC were randomized 1:1 to receive either sunitinib (repeated 6-week cycles of 50 mg/day orally for 4 weeks, followed by 2 weeks off treatment) or IFN-a (9 MU given subcutaneously three times weekly). The primary endpoint was PFS. Results: A total of 750 pts were randomized: 375 to sunitinib, 375 to IFN-a. The median duration of treatment is 11 months (range: <1–25) for sunitinib vs. 4 months (range: <1–22) for IFN-a. The updated ORR by investigator assessment is 44% (95% CI: 39, 49) for sunitinib vs. 11% (95% CI: 8, 15) for IFN-a (p <0.000001), including 4 complete responses for sunitinib and 2 for IFN-a. The median duration of response in the sunitinib group (n=165) is 12 months (95% CI: 10, 14) vs. 10 months (95% CI: 8, 17) in the IFN-a group (n=43). The median PFS is 11 months (95% CI: 10, 11) for sunitinib vs. 4 months (95% CI: 4, 5) for IFN-a. The median PFS for pts with 0 risk factors is 14 months (95% CI: 11, 16) for sunitinib vs. 8 months (95% CI: 7, 10) for IFN-a; 9 months (95% CI: 8, 11) vs. 4 months (95% CI: 4, 4), respectively, for pts with 1- 2 risk factors; 4 months (95% CI: 2, 10) vs. 1 month (95% CI: 1, 2), respectively, for pts with =3 risk factors. The sunitinib benefit in PFS extends across all MSKCC prognostic risk factor groups (HR=0.488; 95% CI: 0.406, 0.586). The baseline features that predict longer PFS (by investigator assessment) for the sunitinib group are hemoglobin =LLN (p=0.0043), corrected calcium =10 mg/dL (p=0.001), ECOG score of 0 (p=0.0005), number of metastatic sites 0 or 1 (p=0.0064), and time from diagnosis to treatment =1 yr (p=0.0002). Conclusions: Sunitinib is a reference standard for first-line treatment of mRCC, with significant improvement in PFS and ORR compared to IFN-a. The benefit of sunitinib extends across all subgroups of pts with mRCC. Previously defined MSKCC risk factors for mRCC predict longer PFS with sunitinib.

No significant financial relationships to disclose.
Randomized phase II trial of first-line treatment with sorafenib versus interferon in patients with advanced renal cell carcinoma: Final results
Authors: Szczylik C. , Demkow T. , Staehler M. , Rolland F. , Negrier S. , Hutson T. E. , Bukowski R. M. , Scheuring U. J. , Burk K. , Escudier B.
Published: March 2020

5025

Background: This trial investigated the efficacy and safety of sorafenib (SOR) vs interferon (IFN) in treatment-naïve patients with clear-cell renal cell carcinoma (RCC). Methods: Previously untreated patients with advanced RCC were randomized to continuous oral SOR 400 mg bid or IFN 9 million units tiw (part 1), with an option of dose escalation to SOR 600 mg bid or crossover from IFN to SOR 400 mg bid upon disease progression (part 2). The primary endpoint was progression-free survival (PFS). Results: Baseline characteristics (ITT, n=189) were similar in SOR (n=97) and IFN (n=92) groups. In the IFN arm, 90/92 patients received treatment; 56 had disease progression, of which 50 crossed to SOR. All 97 patients in the SOR arm received SOR 400 mg bid; 65 had disease progression, of which 44 were dose escalated to 600 mg bid. In part 1, 5% vs 9% patients had complete/partial response, disease control rate (complete/partial response + stable disease) was 79% vs 64%, and median PFS was 5.7 months (CI: 5.0–7.4 months) vs 5.6 months (CI: 3.7–7.4 months) for SOR vs IFN, respectively. Progression-free rates for SOR vs IFN were 90.0% vs 70.4%, 45.9% vs 46.5%, and 11.5% vs 30.4% at 3, 6, and 12 months, respectively. A total of 11% vs 15% of patients receiving SOR or IFN, respectively, discontinued due to adverse events. Overall, the incidence of adverse events was similar between both treatment arms, although skin toxicity (rash and hand-foot skin reaction) and diarrhea occurred more frequently in the SOR group, and flu-like syndrome occurred more frequently in the IFN group. In part 2, median PFS was 5.3 months (CI: 3.6–6.1 months) in patients (n=50) who crossed from IFN to SOR. The median PFS for patients (n=44) with dose escalation to 600 mg bid was 3.6 months (CI: 1.9–5.3 months). The 600 mg bid dose was well tolerated. Conclusions: Although the primary endpoint (PFS) was not reached, SOR showed activity in first-line treatment of RCC based on disease control rate. PFS benefit was observed in patients who crossed to SOR 400 mg bid after progression on IFN. Patients who were dose escalated to 600 mg bid after progression had disease stabilization for a further 3.6 months. Further analyses of possible benefit from SOR dose escalation are required in a larger number of patients.

[Table: see text]
Phase II trial of sunitinib in bevacizumab-refractory metastatic renal cell carcinoma (mRCC): Updated results and analysis of circulating biomarkers
Authors: George D. J. , Michaelson M. D. , Rosenberg J. E. , Bukowski R. M. , Sosman J. A. , Stadler W. M. , Margolin K. , Hutson T. E. , Rini B. I.
Published: March 2020

5035

Background: Sunitinib malate is an oral, multitargeted tyrosine kinase inhibitor with antiangiogenic and antitumor activity. This study evaluated the safety and activity of sunitinib in mRCC patients (pts) previously treated with the VEGF-neutralizing antibody, bevacizumab. Levels of angiogenic biomarkers, including plasma VEGF and soluble VEGFR-3 (sVEGFR-3), were assessed for predictive significance with clinical response. Methods: Pts were required to have mRCC with disease progression following bevacizumab- based therapy, measurable disease, ECOG performance status 0 or 1, and adequate organ function. Pts were treated with sunitinib 50 mg daily in 6-week cycles (4 weeks on, followed by 2 weeks off). The primary endpoint was objective response according to RECIST. Plasma VEGF and sVEGFR-3 levels were measured in pre-treatment samples and at multiple timepoints on study. Results: A total of 61 pts were enrolled. The objective partial response rate was 23% (95% CI: 13%, 36%); 35 pts (57%) demonstrated stable disease. The median duration of response was 36 weeks (95% CI: 26, NA) and progression-free survival was 30 weeks (95% CI: 18, 34). Plasma VEGF levels increased from baseline (3-fold mean elevation), while plasma sVEGFR-3 levels decreased from baseline (40% mean reduction). Pre-treatment VEGF levels were significantly higher in pts (n=34) with <10 weeks between cessation of bevacizumab and start of sunitinib (p<0.001); ELISA specificity suggests that detected VEGF is not bevacizumab-bound. Pre-treatment sVEGFR-3 levels were significantly lower at baseline in responding pts vs. non-responding pts (p<0.0318). A greater reduction in sVEGFR-3 levels was seen in responding pts vs. non-responding pts (p<0.10). Pretreatment VEGF and VEGF fold-changes did not differ according to clinical response. Conclusions: Sunitinib has significant antitumor activity in bevacizumab-refractory mRCC pts, suggesting absence of cross-resistance between bevacizumab and sunitinib. Biomarkers including plasma VEGF and sVEGFR-3 may have predictive potential in sunitinib-treated patients.

No significant financial relationships to disclose.
The Advanced Renal Cell Carcinoma Sorafenib (ARCCS) expanded access trial: Safety and efficacy in patients (pts) with prior bevacizumab (BEV) treatment
Authors: Drabkin H. A. , Figlin R. A. , Stadler W. M. , Hutson T. E. , Hajdenberg J. , Chu L. , Trent D. , Campos L. T. , Kelly F. , Bukowski R. M.
Published: March 2020

5041

Background: Sorafenib (SOR) is an oral multi-kinase inhibitor of tumor-cell angiogenesis and proliferation. Phase III (TARGETs) data have demonstrated prolonged progression-free survival in pts with advanced clear cell renal cell carcinoma (RCC) in whom prior therapy failed. Activity of SOR following treatment with BEV, an anti-vascular endothelial growth factor and antiangiogenic monoclonal antibody, has not been evaluated. Methods: A subset analysis was conducted to describe safety and efficacy in the SOR expanded access program in North America for pts receiving prior BEV. Inclusion criteria for this open-label, nonrandomized trial included advanced RCC; ineligibility for, or lack of access to, other SOR clinical trials; age =15 years; ECOG PS of 0–2; recovery from prior treatment; adequate prior treatment of brain metastases. Major exclusion criteria included life expectancy <2 months; active coronary artery disease, ischemia or hypertension; severe renal impairment requiring dialysis. Pts previously treated with BEV required =28 days from last dose, no =Grade 3 hemorrhagic episode during therapy, and no history of =Grade 2 hemorrhagic event 6 mos prior to BEV treatment. Results: Of the 2,488 pts in ARCCS valid for safety analysis, 289 pts had received prior BEV: 65% male with median age 61 yrs. Grade 3 and 4 toxicities occurring in >2% of prior BEV pts included hand-foot skin reaction 9.0%; fatigue 6.9%; hypertension 4.8%; dehydration, dyspnea, anorexia, and abdominal pain 3.1%; back pain, rash/desquamation, and mucositis 2.8%; pleural effusion and diarrhea 2.1%. Of the 195 BEV-pretreated pts evaluable for response, 152 (77.5%) had stable disease and 5 (2.5%) had confirmed partial responses (PR). There were 26 (13.3%) unconfirmed PRs reported according to RECIST, 4 of which missed a second scan due to US ARCCS enrollment ceasing upon FDA approval of SOR in 12/05. Conclusions: We observed activity of SOR following BEV therapy for advanced RCC. AEs in this subset were generally well tolerated and similar to those in the overall ARCCS population. Further investigation is warranted to elucidate mechanisms for response to SOR following prior antiangiogenic treatment.

[Table: see text]
Serum level of vascular endothelial growth factor (VEGF) as an independent prognostic factor in metastatic renal cell carcinoma (MRCC)
Authors: Negrier S. , Chabaud S. , Escudier B. , Ravaud A. , Chevreau C. , Blay J. Y. , Delva R. , Biota C. , Perol D. , Menetrier- Caux C. ,   Groupe Francais d’Immunotherapie
Published: March 2020

5044

Background: The French Immunotherapy Group previously showed that circulating interleukin-6 (IL-6) and VEGF correlate with survival in MRCC patients (pts) (Négrier JCO 2004). We aimed to confirm the prognostic value of IL-6 and VEGF, and to test that of macrophage colony-stimulating factor (M-CSF) and macrophage inflammatory protein 3-alpha (MIP-3a) for survival in MRCC pts of good and intermediate prognoses. Patients and Methods: Pre-treatment samples were obtained from 302 MRCC pts enrolled in 2 parallel multicenter randomized cytokine trials. Baseline serum levels of IL-6, M-CSF, VEGF, and MIP3a were determined by immunoassays; their prognostic value for progression-free survival (PFS) and overall survival (OS) was tested. Characteristics of pts with a 0.15 significance level in univariate analysis (ECOG PS, prior therapy, metastatic sites and biological parameters) were entered in a multivariate Cox model. A backward stepwise procedure discriminated non-influential variables at 0.05 level. Results: Median IL6, VEGF, M-CSF and MIP3a levels were respectively 7.3 (range 0–392 pg/mL), 0.5 (0–2.3 ng/mL), 406 (0–4,785 pg/mL) and 0 (0–1,705 ng/mL). IL6 or M-CSF and VEGF (p<0.0001), or IL6 and M-CSF (p=0.0005) were significantly correlated. Death occurred in 192/302 pts, with 20.9 month median OS. OS was highly correlated with IL6, VEGF and M-CSF (p <0.001) but not with MIP3a (p=0.06) in univariate analysis. Only VEGF remained independently prognostic for OS in multivariate analysis (39% increased probability of death if VEGF level doubled) after adjustment on PS, time from diagnosis to metastasis, number of metastatic sites, pleural metastasis, abnormal sedimentation rate, haemoglobin and LDH levels. Similar results were found for PFS, with a hazard ratio of 1.19 for a 2-fold VEGF increase. Conclusions: The independent prognostic value of serum IL6 level is not confirmed in our cohort that excluded pts with poor outcome, but serum VEGF level appears as an independent prognostic factor, thus supporting the therapeutic interest for these pts of newly available drugs targeting VEGF receptors.

No significant financial relationships to disclose.
Safety of VEGF-targeted tyrosine kinase inhibitors in patients (Pts) with metastatic renal cell carcinoma (mRCC) and central nervous system (CNS) metastases
Authors: Unnithan J. S. , Choueiri T. , Garcia J. , Dreicer R. , Laura W. , Bukowski R. , Rini B.
Published: March 2020

5047

Background: Hemorrhagic complications have been reported in pts treated with various angiogenesis inhibitors, however, reports of intracranial bleeding are rare. Intracranial hemorrhage has been reported during therapy with multitargeted tyrosine kinase inhibitors (TKIs) at higher dose levels during phase I evaluation. Given the occurrence of CNS metastases in RCC and the common use of TKIs, a review of the safety of TKIs in RCC pts with CNS metastases was undertaken. Methods: All pts with mRCC and CNS metastases who were treated with TKIs at the Cleveland Clinic Taussig Cancer Center were investigated. Results: Between 8/2005 and 10/2006, 23 pts with mRCC and CNS metastases were treated utilizing either sunitinib or sorafenib. 7/23 pts received sequential therapy with both TKIs. The median time to development of CNS metastases was 16.0 months (range: 0 - 288 months). Thirteen pts received sunitinib (50 mg daily, 4 out of 6 weeks) and 10 pts received sorafenib (400 mg BID continuously). All 23 pts had known CNS lesions at initiation of TKI treatment and had received prior therapy to the CNS. This consisted of either surgery and whole brain radiation therapy (WBRT; 4pts), WBRT alone (3 pts), conformal radiotherapy in the form or gamma knife or Intensity Modulated Radiation Therapy (13 pts), WBRT and gamma knife (2 pts) or surgical resection alone (1 pt). The median TKI treatment duration (including sequential TKI therapy), was 5.6 months (range: 0.3–20.3 months). No evidence of CNS intratumoral bleeding or other hemorrhagic complications have been observed. Three pts developed new metastatic foci in the brain while on sunitinib. Overall, the median time to progression was 6.5 months (0.9 - 20.3 months). Conclusions: These data suggest sunitinib or sorafenib can be safely administered to RCC pts with previously treated CNS metastases The safety of these agents in patients with untreated CNS lesions is unclear, and therefore pretreatment CNS imaging should be considered.

[Table: see text]
Comparison of quality-adjusted survival in patients with advanced renal cell carcinoma receiving first-line treatment with temsirolimus (TEMSR) or interferon-α (IFN) or the combination of IFN+TEMSR
Authors: Parasuraman S. , Hudes G. , Levy D. , Strahs A. , Moore L. , DeMarinis R. , Zbrozek A. S.
Published: March 2020

5049

Background: In a phase 3, randomized, 3-arm study of TEMSR or IFN or the combination of TEMSR + IFN in the first-line treatment of patients with advanced renal cell carcinoma (RCC) and poor-prognostic features, TEMSR improved overall survival (p=0.0069) and progression-free survival (p=0.0001) vs. IFN (Hudes et al. J Clin Oncol. 2006;24:LBA4). Quality-adjusted survival was a pre-defined endpoint and is reported. Methods: Quality-adjusted time without symptoms and toxicity (QTWiST) was estimated by partitioning overall survival into 3 distinct health states: time with serious toxicity, time with progression, and time without symptoms and toxicity (TWiST). Survival was value-weighted when patients completed quality of life questionnaires (EQ-5D) at weeks 12 and 32, when a grade 3 or 4 adverse event (AE) was reported, upon relapse or progression, or upon withdrawal from the study. Treatment group comparisons used restricted means analyses estimated from censored survival data. Restricted means were computed for duration of each health state by truncating data at median follow-up (17.9 months). Variance and covariance were estimated using bootstrap methods. Results: All 626 randomized patients in the study were included in computation of health state durations. EQ-5D questionnaires were obtained from 260/300 (87%) upon progression and 230/570 (40%) after a grade 3/4 AE. Patients receiving TEMSR alone had 38% greater TWiST than those receiving IFN alone (TEMSR=6.5 months vs. IFN=4.7 months, p=0.00048). There was no significant difference in TWiST between the combination arm and IFN alone (IFN+TEMSR=5.4 months vs. IFN=4.7 months, p=0.1288). Patients receiving TEMSR alone had 23% greater Q-TWiST than those receiving IFN alone (TEMSR=7.0 months vs. IFN=5.7 months; p=0.0015). There was no significant difference in Q-TWiST for the combination arm compared with IFN alone (IFN+TEMSR=6.1 months vs. IFN=5.7 months, p=0.3469). Conclusions: Patients with advanced RCC receiving TEMSR alone had significantly greater quality-adjusted survival than those receiving IFN alone.

No significant financial relationships to disclose.
Salvage chemotherapy with high-dose carboplatin and etoposide (HDCE) with peripheral blood stem cell transplant (PBSCT) in patients with relapsed seminoma
Authors: Herbert S. M. , Abonour R. , Einhorn M.D. L. H.
Published: March 2020

5054

Background: Patients with relapsed seminoma are treated with salvage chemotherapy. Current therapeutic options include cisplatin plus ifosfamide based regimens or high dose chemotherapy with PBSCT. At Indiana University HDCE was usually reserved for third line therapy for relapsed seminoma, unless there were visceral metastases or relapse within 3 months of initial chemotherapy. Methods: Retrospective review of 35 consecutive patients with pure seminoma (median 38 yrs; range 23–56 yrs) that received HDCE with PBSCT from 2/96–12/04. Cytoreductive chemotherapy with 0–2 courses of vinblastine, ifosfamide, and cisplatin (VeIP) preceeded HDCE. Carboplatin dosage was 700mg/m2 for 3 days plus etoposide 750mg/m2 for 3 days. A second course of therapy was given after hematopoietic recovery. Results: Treatment related mortality was seen only in patients that received two or more prior regimens (median age 45 yrs, range 27–56 yrs) and occurred in 4/35 (11%) patients. One man died of AML at 62 months (see table below). 26/35 (74%) are continuously NED (cNED). 15/35 patients received 1 prior regimen and 14/15 (93%) are cNED. 20/35 patients received =2 prior regimens and 12/20 (60%) are NED. 14/35 patients had prior XRT. 10/14 (71%) are cNED. 6/14 patients had prior XRT and =2 prior regimens and 3/6 (50%) are NED. Conclusions: HDCE with PBSCT has a high cure rate even when used as 3rd line or later therapy. Because of the 93% continuous NED rate when used as 2nd line therapy and the increased treatment related mortality when used as 3rd line therapy we now recommend HDCE as initial salvage therapy.

[Table: see text]

No significant financial relationships to disclose.
The Prostate Cancer Clinical Trials Working Group (PCCTWG) consensus criteria for phase II clinical trials for castration-resistant prostate cancer
Authors: Scher H. I. , Halabi S. , Tannock I. , Morris M. , Higano C. , Kelly W. , Sternberg C. , Eisenberger M. , Martin A. , Hussain M.
Published: March 2020

5057

Background: The clinical manifestations of castration-resistant metastatic prostate cancer pose challenges to the design of phase 2 trials. In 1999, PSAWG issued a consensus report to standardize phase 2 design and endpoint definitions. A reassessment is reported. Methods: At 4 meetings, and using electronic communication, PCCTWG is seeking consensus on the design and analysis of phase 2 trials that can inform decisions about proceeding to phase 3. Results: PCCTWG recognizes that trial objectives, and details of design and analysis depend on the agent under study. PCCTWG recommends: (i) A standard disease assessment that includes prior treatment history, bone scan, and CT of the chest, abdomen and pelvis; (ii) Revision of eligibility criteria to lower PSA thresholds and serum testosterone levels; (iii) Emphasis on time-to-event endpoints including clinical, biochemical (e.g. PSA) or radiologic progression, recognizing that molecular targeted agents may delay progression without influencing initial response. (iv) Independent reporting of biochemical, radiographic, and clinical outcomes, avoiding grouped categorizations of complete or partial response, or stable disease. (v) Treating for a minimum of 12 weeks before assessing disease status, as the onset of PSA declines are often delayed, verifying that an agent does not influence release of PSA from cells. (vi) RECIST criteria are appropriate for changes in measurable disease, separating nodal and visceral sites. (vii) Changes in bone scan should be reported as “new lesions” or “no new lesions”, confirming findings of progression on a second scan. (viii) Pain and analgesic intake should be assessed using validated scales. (ix) Due to inherent variability, randomization to experimental and control groups is preferred, and innovative designs, e.g. expanding selected arms of randomized phase 2 trials to phase 3. Conclusions: PCCTWG recommends increasing emphasis on time to event endpoints as decision aids in proceeding from phase 2 to phase 3 trials. The recommendations will evolve as data are generated from phase 3 studies on the ability of intermediate endpoints to predict for clinical benefit. Support: MSKCC SPORE (CA 92629), Prostate Cancer Foundation.

No significant financial relationships to disclose.
Tumor metabolism, blood flow changes, and prognosis by positron emission tomography: A prospective cohort of locally advanced breast cancer patients
Authors: Dunnwald L. , Gralow J. , Ellis G. , Livingston R. , Linden H. , Specht J. , Doot R. , Lawton T. , Barlow W. , Mankoff D.
Published: March 2020

506

Background: Breast cancer patients with locally advanced tumors receive preoperative chemotherapy to provide early systemic treatment and assess in-vivo tumor response. Positron emission tomography (PET) has been used to follow tumor response to therapy, as pathologic response is predictive of patient outcome. We evaluated the prognostic utility of serial quantitative PET tumor blood flow (BF) and metabolism measurements. Methods: Fifty-five women with a primary diagnosis of locally advanced breast carcinoma (LABC) underwent dynamic [18F]-FDG and [15O]-water PET scans prior to and at midpoint of neoadjuvant chemotherapy. The FDG metabolic rate (MRFDG), transport (K1), and flux (Ki) parameters were calculated, and tumor blood flow was estimated from the [15O]-water study. Associations between tumor BF and MRFDG measurements and disease-free survival (DFS) and overall survival (OS) were evaluated using the Cox proportional hazards model. Results: Patients that had an increase in BF and K1, from baseline to mid-therapy measurements, had elevated recurrence and mortality risks compared to patients that had reductions in BF and MRFDG values. In multivariate analysis, changes in BF and K1 remained independent prognostic indicators of DFS and OS survival. Conclusions: PET measurements of tumor response prior to completion of neoadjuvant chemotherapy were predictive of patient outcome. Patients that failed to have a decline in BF and K1 experienced higher risks of recurrence and mortality that was largely independent of clinical tumor characteristics assessed in this study. These results suggest that tumor perfusion, measured directly by [15O]-water or indirectly by dynamic FDG PET, is highly predictive of outcome in neoadjuvantly treated breast cancer.

No significant financial relationships to disclose.
The impact of the duration of adjuvant hormonal therapy in patients with unfavorable prognosis prostate cancer treated with radiotherapy: Secondary analysis of RTOG 85–31
Authors: Souhami L. , Bae K. , Pilepich M. V. , Sandler H.
Published: March 2020

5062

Background: RTOG 85–31 was a Phase III trial of androgen suppression for life as an adjuvant to radiotherapy. However not all patients continued on the protocol-mandated long-term hormonal therapy despite no evidence of recurrent disease. This analysis correlates duration of adjuvant hormonal therapy and outcomes among patients who prematurely discontinued long-term hormonal therapy. Methods: The protocol mandated pelvic radiotherapy (60–66 Gy) followed by goserelin 3.6 mg monthly given indefinitely or until disease progression. To avoid potential bias due to early progression/death, only patients who were alive with no evidence of disease at the time of cessation of hormonal therapy were included. There were 377 analyzable patients. Patients were divided in groups based on the hormonal therapy duration (HTD), as follows: = 1 year (27.3%), 1< and =2 years (11.4%), 2< and =4 years (13.3%), 4< and =6 years (10.6%) and > 6 years (37.4%). End-points were overall survival, disease-free survival, disease-free survival with PSA <1.5 ng/mL, disease-specific survival, local failure and distant failure. Cox-proportional hazards regression model was used to test the outcomes among the 5 groups. Results: The median follow-up time of surviving patients is 11.27 years. Pretreatment characteristics by hormone duration groups were well balanced except for age. The median duration of adjuvant hormonal therapy was 3.59 years. For each outcome, there are statistically significant differences among the 5 HTD groups in all outcomes without adjusting for other covariates. Pairwise comparisons show that HTD > 6 year group is significantly associated with having an improved survival and fewer failure events than all other HTD groups (HR < 1, p-value <0.0001). Adjusted for age and stratification variables, the HTD>6 year group remains the only group significantly associated with having fewer failure events in all outcomes. Conclusions: Prolonged HTD of > 6 years is significantly associated with improvements in all end-points studied. Based on these data, decreasing HTD to < 6 years may have a detrimental effect in patients with unfavorable prostate cancer.

No significant financial relationships to disclose.
Phase I evaluation of abiraterone acetate (CB7630), a 17 alpha hydroxylase C17,20-Lyase inhibitor in androgen-independent prostate cancer (AiPC)
Authors: Ryan C. J. , Rosenberg J. , Lin A. , Valiente J. , Kim J. , Small E. J.
Published: March 2020

5064

Background: Abiraterone acetate (Ab) is an oral inhibitor of 17 alpha hydroxylase and C17,20-Lyase, which are important in adrenal androgen synthesis. A phase I study was undertaken to define the maximum tolerated dose (MTD) of Ab in patients (pts) with AIPC, the need for corticosteroid replacement (CSR) and the effects of Ab on hormone levels. Methods: Eligible pts had progressive AIPC by consensus criteria and normal organ and adrenal function. Dose escalations both while fasting and with food range from 250 mg to a maximum planned dose of 2,000 mg per day. Single dose pharmacokinetic (pK) analysis was performed prior to the onset of continuous daily dosing. Results: Sixteen pts have been enrolled, 3 with non-metastatic AIPC and 13 with bone/soft tissue metastases. Median PSA and testosterone levels are 26.7 and 7.7 ng/dL, respectively. Fourteen of 16 received prior ketoconazole. CSR has been required during the first month in 1 pt at a dose level of 500 and in 1 pt in month 3. Two pts experienced syncopal events (grade 3) on Ab, one at 250 mg and one at 500 mg, both after starting CSR. Mineralocorticoid-induced hypertension (grade 2) developed in 4 pts and was treated with aldosterone antagonists. Grade 1 edema has occurred in 3 pts. Testosterone became undetectable in 4/9 pts with available data, the mineralocorticoid deoxycorticosterone rose by a median 6.7 fold on therapy (range 1.5–67 fold). PK suggest maximum concentrations of Ab are achieved within 2 hr post dose with a mean t 1/2 of 7.8 hr, and interpatient variability in AUC and Cmax of approximately 2.5 fold. A decline in PSA by >50% occurred in 7 of 14 patients (50%) completing the initial 28 days of treatment. Five of 9 pts with ketoconazole refractory disease experienced a >50% reduction in PSA. Conclusions: Abiraterone appears to have moderate activity in AIPC pts (including significant activity in pts treated previously with ketoconazole) and an acceptable toxicity profile. CSR has not been consistently required.

No significant financial relationships to disclose.
Phase III trial of docetaxel (D), estramustine (E), and prednisone versus docetaxel plus prednisone in patients with metastatic hormone-refractory prostate cancer (HRPC)
Authors: Machiels J. H. , Mazzeo F. , Clausse M. , Filleul B. , Marcelis L. , Honhon B. , D’Hondt L. , Dopchie C. , Bonny M. , Kerger J.
Published: March 2020

5067

Background: D alone or in combination with E improves survival of pts with metastatic HRPC. Whether E is necessary in combination with D is controversial. Preclinical data suggest a synergistic activity between D and E. Phase II as well as small randomized trials support this hypothesis, although indirect comparisons between the large phase III studies are not in favor of D/E combination. We conducted a randomized, prospective, multicentric study to compare D versus D/E. Methods: 150 metastatic HRPC were randomized (minimisation, stratification parameters: PSA level, ECOG, previous E use (38 pts), and center) between D (35 mg/m2 on day 2 and 9, every 3 wks) and D in combination with E (280 mg PO tid on days 1 to 5 and 8 to 12, coumadin 1mg/d). E was the only difference between the two treatment arms. All the pts received prednisone (10 mg/d). The primary endpoint was PSA response rate (decrease in PSA > 50% from baseline) and the study was powered to detect a 25% difference in PSA response rate. Results: No significant difference was found for PSA response (D/E: 50/68 (73%); D: 48/69 (69%)), time to PSA progression (median 205 days for D/E and 210 days for D), duration of PSA response (median 185 days for D/E and 220 days for D), progression-free survival (median 186 days for D/E and 195 days for D), response rate according to RECIST, and overall survival (median 617 days for D/E and 629 days for D). PSA < 4 ngr/mL occurred in 28/68 pts (41%) in D/E and in 17/69 (25%) in D (p=0.04). More pts had at least one grade 3/4 NCI-CTC toxicity in D/E (33/75 pts; 45%) compared to D (16/75 pts; 21%) (p=0.003). The main difference was grade 3/4 digestive toxicity (D/E:15% and D:4%; p=0.017). Serious adverse events were reported more frequently in D/E than D: 20 vs 9 (p=0.03). In D/E, the most frequent grade 3/4 toxicities were digestive (15%) and venous thrombosis (12%). In D, the most frequent grade 3/4 toxicity was anemia (9%) and venous thrombosis (8%). Conclusions: Our study did not show any clinically relevant advantage in term of efficacy for the addition of E to D. Both regimens were well-tolerated although the toxicity profile was in favor of D without E. Our study does not support the addition of E to D to treat pts with HPRC.

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Final results from a phase II trial of systemic chemotherapy in a small cell urothelial cancer: Evidence supporting neoadjuvant chemotherapy from the M.D. Anderson Cancer Center
Authors: Siefker-Radtke A. O. , Kamat A. M. , Grossman H. , Williams D. L. , Dinney C. P. , Millikan R. E.
Published: March 2020

5083

Background: Previously reported retrospective data supported a potential role for neoadjuvant chemotherapy in small cell urothelial cancer (SCUC). We now report final results from a phase II clinical trial in SCUC. Methods: Since 2001, 30 patients with biopsy proven SCUC received alternating doublet chemotherapy with Ifosfamide + Doxorubicin, and Etoposide + Cisplatin. Patients with surgically resectable disease (<=cT4aN0M0) received a total of 4 cycles followed by cystectomy, while those with unresectable disease (>=cT4b, N+, or M+) received 2 cycles beyond maximal response. Results: Neoadjuvant chemotherapy was given in 18 patients (cT2:14, cT3:4), while 12 patients were treated for metastatic SCUC. For those receiving neoadjuvant therapy, the median OS is 58 months, with a 5-year survival of 48%; 8 remain alive and NED beyond 2.5 years. There have been only 5 deaths for the neoadjuvant group (3 SCUC, 1 post-op infection, 1 AML). For those with metastatic disease, the median OS is 14 months. Two were rendered resectable with chemotherapy (cT4b:1,N+:1); 1 died of recurrent SCUC, while the other is currently undergoing therapy for TCC of the ureter. Brain metastases developed in 7 patients (cT3b:2, initial M+:5). Chemotherapy has been well-tolerated with only 2 G4 toxicities (catheter infection and neutropenia). The most frequent G3 toxicities include transfusion (10), neutropenic fever (7), infection (5), and vomiting (3). There was only one post-surgical death; a case of sepsis in a patient with diverticulitis and abscess requiring sigmoid colon resection. Conclusions: These prospective results, which are consistent with our previously reported retrospective review, provide additional support for 4 cycles of neoadjuvant chemotherapy in the setting of SCUC. Unfortunately, once metastases are present, the prognosis remains poor with few long-term survivors. These results may also predict a patient subset for which prophylactic cranial irradiation may be potentially beneficial.

No significant financial relationships to disclose.