bluuebunny/crossref_metadata_2025 huggingface dataset:
Primary colon cancer site as a predictor of bevacizumab effectiveness in metastatic colon cancer patients.
Authors: Islam R. , Chyou P. , Ege H. , Deedon A. , Burmester J. K.
Published: February 2017

574

Background: Bevacizumab has been approved by the FDA for first-line treatment in combination with chemotherapy for metastatic colon cancer. Although bevacizumab extends progression free survival and overall survival for many metastatic colon cancer patients, primary cancer site has not been examined as a predictor of its effectiveness.

Methods: Data regarding bevacizumab treatment for colorectal cancer were abstracted from the medical record of 175 patients treated at a large multi-specialty clinic. Data were collected regarding demographics, body mass index, weight loss, lifestyle variables (smoking status, drinking habit), history of colon polyps, family history of cancer, primary site of tumor in the colon, tumor stage, lymph node involvement, metastasis, tumor grade of metastasis, cancer cell type, symptoms related to the cancer, and other comorbidities (cardiovascular disease, diabetes mellitus, Crohn's disease, diverticulitis, and irritable bowel syndrome).Tumor response was measured by radiologic and biochemical markers. Univariate and multivariate analyses were performed using Fisher's exact test, Wilconox rank sum test, and unconditional logistic regression modeling.

Results: Univariate analysis demonstrated that positive tumor response was positively correlated with blood in stool (p=0.0301), advanced lymph node stage (p=0.048), and adenocarcinoma cancer cell type (p=0.0387), but negatively correlated with chemotherapy treatment of the primary tumor (p=0.0387) and primary site of the colon cancer (p=0.0328). Multivariate stepwise logistic regression analysis demonstrated that patients with primary tumor located in the transverse or descending/sigmoid colon were more likely (odds ratio=5.88, 95% confidence interval: 1.72–20.00; p=0.0046) to have a positive tumor response than patients whose primary tumor site was cecal/ascending colon.

Conclusions: Primary site of metastatic colon cancer may influence the effectiveness of bevacizumab therapy. Future randomized, controlled trials are needed to examine the primary site as a predictor of tumor response in metastatic colon cancer patients using bevacizumab therapy.

No significant financial relationships to disclose.
Colorectal cancer in elderly patients: A single-center experience.
Authors: Resch G. , Poetscher M. , Schauer W. , Hoebling W. , Mayrbaeurl B. , Burgstaller S. , Thaler J.
Published: February 2017

576

Background: In Austria more than 40% of cancers occur in adults over the age of 75 years. As the current population ages and more people live longer, the incidence of cancer in elderly patients (pts) is expected to rise. Several studies have shown that cancer treatment is beneficial for elderly pts in adjuvant and palliative setting. However, elderly pts with cancer have been underrepresented in clinical trials and there is little literature on this pts group. We now want to present our own experience in the treatment of elderly pts with colorectal cancer (CRC).

Methods: Since July 2006 all pts with new diagnosed CRC were recorded in a tumor registry at the Klinikum Wels- Grieskirchen. Patients were followed for treatment decision, progression free survival and overall survival. In this retrospective analysis elderly pts >75 years diagnosed with CRC have been evaluated.

Results: Overall, 165 pts >75 years (range 75-92) with a diagnosis of CRC stage I-IV were recorded from July 2006-July 2010 in our registry. Seventy-six (46.1%) and 89 (53.9%) out of these pts were men and women. Stage I has been diagnosed in 25 pts (15.2%), stage II in 57 pts (34.5%), stage III in 47 pts (28.5%) and stage IV in 36 pts (21.8%). 30.7 % (51 pts) had a tumor located in the rectum and 69.3% had colon cancer. 154 out of 165 pts underwent surgery (tumorectomy or colectomy). In one patient with stage II and in 11 pts with stage IV surgery was not possible because of poor performance status. Adjuvant chemotherapy was given in 8 pts with stage II and in 25/47 pts with stage III CRC. 11/36 pts were treated with palliative chemotherapy in stage IV CRC. 17 pts with stage I-III develop distant metastases and 11 out of these pts have been treated with palliative chemotherapy. Hemihepatectomy and lobectomy has been performed in 7 and 1 pts. Overall 13 pts (7.9%) were treated within a clinical trial for CRC. Chemotherapy regimens, progression free survival and overall survival data will be presented.

Conclusions: Although elderly pts often have comorbidities and poor performance status, age alone should not determine treatment options and person's eligibility in clinical trials. A careful discussion of treatment risks and benefits, especially in elderly pts, needs to be considered in the therapy decision.

No significant financial relationships to disclose.
Outcomes of definitive chemoradiation for squamous cell carcinoma of the anus and the effect of radiation technique on hematologic parameters.
Authors: Novak C. J. , Golden D. W. , Liauw S. L.
Published: February 2017

580

Background: Chemotherapy-radiation (CRT) is an established therapy for squamous cell carcinoma of the anus. A limiting factor in the successful completion of CRT is bone marrow toxicity. The effect of intensity modulated radiation therapy (IMRT) on marrow toxicity is not well defined. We evaluated the effect of IMRT on the severity of cytopenias for patients receiving CRT. We also explored the influence of cytopenias on disease outcome both pre-CRT or during CRT.

Methods: 43 patients were treated with CRT between 1994-2010. The median delivered dose was 50.4 Gy (range, 32.4-59.4). 31 patients (72%) were treated with IMRT. All patients received concurrent chemotherapy, usually 5FU and mitomycin-C (n = 34, 79%). White blood cell (WBC), hemoglobin (Hg), and platelet counts were recorded pre- CRT, weekly during CRT, and within 7 days post-CRT. Hematologic values were analyzed according to type of RT and for association with treatment outcome.

Results: 2-year locoregional failure (LRF) and distant failure were 14% and 14%, respectively. 21 patients required a treatment break due to any cause. In 9 (43%) patients the break was due to hematologic toxicity. 34 patients had complete blood values available. IMRT did not affect the rate of ≥ grade 2 cytopenia (p = 0.64) or median treatment nadirs; Hg (9.1 vs. 8.3 g/dL, p = 0.24), WBC (1.7 vs. 1.2 K/uL, p = 0.95), or platelets (90.5 vs. 61.5 k/uL, p = 0.88). Median time to nadir was not different for WBC (7 vs. 7 days, p = 0.36) or Hg (36 vs. 22 days, p = 0.29), but patients treated with IMRT did have a delayed platelet nadir (33 vs. 14 days, p = 0.01). Hg nadir ≤ 9 g/dL was associated with a higher rate of 2- year LRF (> 9 g/dL 100% vs. ≤ 9 g/dL 73%, p = 0.03). No other hematologic values were associated with LRF.

Conclusions: In this cohort of patients, nearly 50% of patients required a treatment break, which was related to a cytopenia 43% of the time. IMRT did not appear to have significant impact on acute marrow toxicity, although sample size may limit our power to detect a difference. Low Hg during CRT appears to influence LRF. More detailed dose volume histogram analysis will be useful to further explore how IMRT might influence acute hematologic toxicity, and therefore treatment outcomes.

No significant financial relationships to disclose.
Current perceptions and practice patterns of oncologists in managing patients with gastric cancer.
Authors: Williamson J. C.
Published: February 2017

60

Background: The management of gastric cancer is evolving with advances in the development of targeted therapies. This study was conducted to assess the current practice patterns in the management of patients with gastric cancer and identify gaps that may be addressed through educational initiatives.

Methods: A survey composed of patient case vignettes designed to elicit practice pattern information on testing and treating patients with gastric cancer, and questions regarding attitudes towards gastric cancer management, was distributed electronically to medical oncologists currently practicing in the U.S. in March 2010; 126 were completed and included for analysis.

Results: A lack of confidence was identified in appropriately staging, selecting appropriate treatment, or staying up-to-date with new therapies for gastric cancer with 44%-48% rating confidence as 7 or less on a 10 point confidence scale. Even more (66%) lack confidence in using molecular markers for treatment selection. Perceived levels of familiarity with these topics were rated similarly. In a case vignette of a patient with metastatic gastric cancer, most oncologists (84%) included HER2 testing to help inform treatment. However, a majority (54%) use HER2 testing for their patients with advanced gastric cancer infrequently (50% of the time or less). Also, almost half (44%) would not include H. pylori testing in an initial work-up for a patient whose biopsy confirmed gastric adenocarcinoma. In another case vignette, oncologists were more likely to select a surgery (61%) rather than a preoperative chemotherapy (39%) as supported by current evidence. Late detection is perceived as a significant barrier by 72% of oncologists in managing patients with gastric cancer.

Conclusions: With the confidence and familiarity gaps of oncologists in managing patients with gastric cancer, the infrequent HER2 testing patterns, and lack of preoperative chemotherapy treatment, continued education in the latest evidence is needed.

No significant financial relationships to disclose.
Care by Kampo medicine for toxicities of colorectal cancer chemotherapy: Effect of goshajinkigan (TJ-107) and powdered processed aconite root (TJ-3023) on oxaliplatin-related neurotoxicity, and effect of hangeshashinto (TJ-14) on CPT-11-related diarrhea.
Authors: Shindo Y. , Andoh H. ,   Akita University Graduate School of Medicine
Published: February 2017

601

Background: FOLFOX is standard therapy of advanced-stage colorectal cancer. Sensory neurotoxicity (SN) with oxaliplatin is its dose-limiting toxicity. We decided to use goshajinkigan (TJ-107) for prevention of oxaliplatin-related SN. We think that the main action is the one with powdered processed aconite root (TJ-3023). FOLFIRI is standard therapy too. But watery diarrhea is severe side effect. We decided to use hangeshashinto (TJ-14) for prevention of CPT-11-related watery diarrhea.

Methods: The subjects were 66 patients with advanced-stage colorectal cancer. All 66 patients take TJ-107 (7.5g/day) every day from first oxaliptatin infusion day. Patients profiles were: Male/Female: 29/37, median age 69 years old (42∼84), PS0/1/2/3: 57/9/0/0, clinical stage IIIC/IV: 14/52. Oxaliplatin (85mg/m2) was given as FOLFOX4 (27case), mFOLFOX6 (34) and CapeOx (5). When SN was increased, TJ-3023 was added. TJ-3023 is ingredient of TJ-107. 12 patients had severe watery diarrhea due to FOLFIRI regimen. All 12 patients take TJ-14 (7.5g/day) from appearance of watery diarrhea. Patients profiles were: Male/Female: 8/4.

Results: Total course number of FOLFOX/CapeOX was 595/21, and average number of FOLFOX/CapeOX was 8.46/4.2. Relative dose intensity of oxaliplatin were 37.6mg/m2/week. Medicine compliance of TJ-107 was 89%. 20 patients had grade 3 toxcity (neutropenia 18, thrombocytopenia 2). TTP is 8.14 months. Response Evaluation Criteria is CR/PR/SD/PD/NE:1/36/11/5/13. SN occurred in 43 patients (65.1%). TJ-3023 was added to 10 patients. SN was slightly decreased by TJ-3023. There was no neurotoxicity case with functional impairment in this study. By TJ-14, all 12 patients have a change for the better from grade 2 to grade 1 or 0 of diarrhea. There was no constipation cases.

Conclusions: TJ-107 seem to prervent acute oxaliplatin-induced SN. TJ-3023 may be related to SN prervention mechanism. TJ-14 seem to prevent CPT-11-induced diarrhea. The continuance of chemotherapy for colorectal cancer can be expected by these Kampo medicine.

No significant financial relationships to disclose.
Locally advanced rectal cancer (LARC): A 12-year experience of multimodality approach.
Authors: Bertolini F. , Scarabelli L. , Del Giovane C. , Zironi S. , De Marco G. , Fontana A. , Depenni R. , Bertoni F. , Luppi G. , Conte P. F.
Published: February 2017

607

Background: Main objective of the report is to review retrospectively a 12 years experience of pre-operative chemo-radiotherapy (CRT) in patients (pts) with LARC at the University Hospital of Modena and to correlate clinical variables with outcome.

Methods: Between 1998 and 2010, 275 consecutive pts with stage II, III and IV (oligometastatic in lung or liver) LARC who underwent neo-adjuvant CTR were identified from a single institution. All pts received fluoropyrimidine-based chemotherapy (alone or in combination) and RT (50-50.4 Gy).

Results: On 275 pts, 166 were males (61%) and 109 females (39%); median age: 65.9 years (range: 26-84). Rectal primary site (on 260 pts): 112 low (43%), 91 medium (35%) and 57 high (22%). Stage at diagnosis (on 245): 2 cT2N0 (0.8%), 8 cT2N+ (3.3%), 68 cT3N0 (27.8%), 134 cT3N1 (54.7%), 11 cT4N0 (4.5%), 22 cT4N1 (8.9%). Pre-operative treatment (on 268 pts): 168 pts (62.6%) received 5fluorouracil (5FU) in continuous infusion, 37 (13.9%) capecitabine, 36 (13.5%) FU+oxaliplatin and 27 (10%) 5FU+cetuximab (clinical trial). On evaluable 177 pts, only 25 (14%) developed G3 toxicity and subsequent treatment interruption. No grade 4 toxicity was recorded. 252 pts underwent surgery (18 pts are still ongoing; 5 did not receive surgery for multiple distant metastases at pre-operative staging): 189 anterior resection (75%), 59 abdominal-perineal amputation (23.4%) and 4 endoscopic resection (1.6%). On 235 pts, 148 obtained a T and/or N downstaging (63%). Dworak tumor regression grade (TRG) was (on 209 pts): TRG4 (pathological complete response) 38 (18.3%), TRG3 37 (17.8%), TRG2 67 (32%), TRG1 63 (30%) and TRG0 4 (1.9%). 5 y-disease free survival (DFS) and overall survival (OS) are 75% and 73%, respectively. Down-staging, TRG 3-4 and histological features like the positivity for radial margins and vascular invasion correlate with both DFS and OS.

Conclusions: Pre-operative CRT is well tolerated; downstaging, TRG and histological features such as radial margins and vascular invasion are the strongest predictors of survival.

No significant financial relationships to disclose.
Randomized phase III study of S-1 alone versus S-1 plus docetaxel (DOC) in the treatment for advanced gastric cancer (AGC): The START trial.
Authors: Kim Y. H. , Koizumi W. , Lee K. H. , Kishimoto T. , Chung H. C. , Hara T. , Cho J. Y. , Nakajima T. , Kim H. , Fujii M. ,   Japan Clinical Cancer Research Organization (JACCRO) and Korean Cancer Study Group (KCSG) Inter-Group Study
Published: February 2017

7

Background: S-1/cisplatin is regarded as one of the standard regimens in Japan by the SPIRITS trial, but cisplatin needs in-hospital treatment for hydration. Phase II data of S-1/DOC showed long survival by outpatient basis. Then we hypothesized that S-1/DOC can be the standard regimen for AGC as outpatient basis.

Methods: This is a prospective, multinational randomized phase III study in pts with AGC. Arm A: pts receive S-1 (40mg/m2) twice daily 14 days followed by 7 days rest plus DOC (40 mg/m2) iv on day 1. Arm B: pts receive S-1 28days followed by 14 days rest. Eligibility criteria included measurable/nonmeasurable AGC, age 20–79 and no prior chemotherapy. Primaryendpoint was OS, secondary endpoints were TTP, RR and safety. Based on planned sample size of 628 pts, the trial was designed tohave 90% power to detect an improvement in OS from 300 to 400 days. The accrual period was 3 years with 2 years follow up.

Results: 639 pts (Arm A/B, 316/323) were registered and the eligible pts were 635 (314/321).The MST for Arm A was 386 and for Arm B was 327days. The OS for Arm A was not superior to Arm B (log-rank p = 0.1595, HR: 0.88). The TTP for Arm A was 160 and for Arm B was 126 days. The TTP for Arm A was significantly superior to Arm B (log-rank p < 0.0003, HR: 0.74). RR of Arm A was significantly higher than Arm B (36.0%/ 24.4%, p = 0.01). By subset analysis of OS in pre-stratified nonmeasurable AGC, the MST for Arm A was significantly superior to for Arm B (523/335, log-lank p = 0.018). Most common grade 3/4 toxicities were: neutropenia, 31.4% vs. 4.4%; leucopenia, 22.1% vs. 2.5% and anorexia; 15.4% vs. 12.1%.

Conclusions: The combination ofS-1/DOC did not meet primary endpoint of OS, but of OS in nonmeasurable group and TTP of the S-1/DOC was significantly superior to that of the S-1 alone. We supposed that recent development of the second-line chemotherapy was influenced to our results. This regimen can be regarded as one of the standard treatments for AGC as outpatient basis.

[Table: see text]
Chemoradiation with FOLFOX plus cetuximab in locally advanced cardia or esophageal cancer: Final results of a GERCOR phase II trial (ERaFOX).
Authors: Lledo G. , Michel P. , Dahan L. , Mineur L. , Galais M. , Dupuis O. , Abdiche S. , Jovenin N. , Chibaudel B. , De Gramont A. ,   GERCOR
Published: February 2017

8

Background: Chemoradiotherapy (CRT) for locally advanced cardia and esophageal cancer is based on 5-FU combined with cisplatin, which could be favorably replaced by oxaliplatin (Ox). Cetuximab (C) has demonstrated synergism with both radiotherapy (RT) and platinum-based chemotherapy. ERaFOX trial was evaluating the safety and efficacy of the addition of C to CRT with FOLFOX.

Methods: Main inclusion criteria were: stage III squamous cell or adenocarcinoma of the esophagus or gastroesophageal junction; WHO PS 0-1; age 18-80 years; weight loss <15% in the last 6 months. Patients (pts) received 2 cycles of FOLFOX induction therapy (Ox 85 mg/m2/d1, folinic acid 400 mg/m2/d1, 5-FU 2,400 mg/m2/d1-2, q2w) plus C (first infusion 400 mg/m2 then 250 mg/m2, q1w), then RT 50.4 Gy (1.8Gy/d x 28 fractions) with FOLFOX plus C (same doses, except 5-FU 1,800mg/m2/d1-2). Tumor evaluation was performed at the end of CRT (RECIST and endoscopic ultrasonography). The primary endpoint was overall response rate (ORR), with a 50% threshold for efficacy (Simon Minimax two-stage design).

Results: From Nov 2007 to Feb 2010, 80 pts were enrolled in 12 centers. The characteristics of the 79 eligible pts were (1 ineligible pt for stage IV disease): male/female 60/19, median age 63 (23-79), PS 0/1/ND 47/31/1, squamous/adenocarcinoma/undifferentiated 53/25/1; esophagus/cardia 74/5; median daily caloric intake 1,720 Kcal (550-3160). 74 pts were treated by CRT (5 pts experienced anaphylaxis during the first cetuximab infusion). ORR (ITT) was achieved in 61 pts (77.2%), 6 pts (7.6%) had stable disease, and 9 pts (11.4%) had disease progression (3 pts were not evaluable). Grade 3-4 toxicities induction therapy/CRT were (%): neutropenia: 7.6/28.4; febrile neutropenia: 0.0/2.7; vomiting: 1.3/4.0; mucositis: 1.3/5.4; diarrhea: 3.8/2.7; dysphagia-esophagitis: 1.3/13.5; rash: 7.6/10.8; allergy 8.9/0.0. One toxic death (1.3%) occurred after CRT related to esophagitis with GI bleeding.

Conclusions: Threshold for efficacy was reached with an ORR of 77.2%. Chemoradiotherapy with FOLFOX plus cetuximab is active and has an acceptable toxicity profile in patients with locally advanced cardia or esophageal cancer.

No significant financial relationships to disclose.
Patient-reported fatigue and overall survival in locally advanced esophageal cancer: A Mayo Clinic Esophageal Adenocarcinoma and Barrett's Esophagus Registry Consortium study.
Authors: Stauder M. C. , Romero Y. , Kabat B. , Atherton P. J. , Fredericksen M. B. , Deschamps C. , Jatoi A. , Sloan J. A. , Botros M. , Miller R. C.
Published: February 2017

9

Background: We examined patient-reported fatigue scores and overall survival (OS) in patients with esophageal cancer (EC) enrolled in the Mayo Clinic Esophageal Adenocarcinoma and Barrett's Esophagus Registry (EABE).

Methods: 1,481 patients enrolled in the EABE between September 2001 and January 2009 returned a baseline quality of life questionnaire including a Linear Analog Self Assessment (LASA) fatigue score which was scored on a 0-10 scale, with 0 as the most extreme fatigue. Patients were categorized as having clinically deficient fatigue (DF) if they reported a score of ≤ 5 and clinically non-deficient fatigue (nDF) if they reported a score of > 5. Kaplan-Meier methodology and Cox models explored OS in relation to fatigue scores in patients with EC.

Results: A total of 667 patients with EC were included in the EABE, of which 659 returned a registry questionnaire with a valid LASA fatigue score recorded. Median age at the time of registry entry was 65 years (range 23-92). A total of 392 (59%) and 267 patients (41%) reported DF and nDF, respectively. On univariate analysis, patients with nDF had improved 5-year survival compared to patients with DF. In patients having esophagectomy prior to LASA, those reporting nDF had improved survival compared to patients with DF. Similarly, in patients having no esophagectomy prior to LASA, those with nDF had improved survival compared to those with DF. Among the 368 patients with locally advanced EC (LAEC), those reporting nDF had improved 5-year overall survival compared to patients with DF (28% vs 17%, HR = 0.67, p = 0.003). This remained significant on multivariate analysis (HR = 0.71, p = 0.015).

Conclusions: Patient-reported fatigue is associated with overall survival in patients with LAEC. As a result, fatigue scores should be considered as a stratification factor in future clinical trial design.

[Table: see text]

No significant financial relationships to disclose.
Evolution of multimodality management of gastrointestinal stromal tumors of the stomach.
Authors: Bilimoria K. Y. , Merkow R. P. , Wayne J. D. , Abbott D. E. , Cormier J. N. , Feig B. W. , Hunt K. , Pisters P. W. , Pollock R. E. , Bentrem D. J.
Published: February 2017

94

Background: Gastrointestinal stromal tumor (GIST) treatment has changed considerably with introduction of imatinib in 2001, initiation of ACOSOG adjuvant trial in 2002, and FDA adjuvant approval in 2008. However, little is known about how imatinib has been incorporated over time. Our objective was to examine the evolution of multimodality management of GISTs.

Methods: Patients coded specifically as gastric GISTs were identified (n = 4,508; 443 hospitals) from the National Cancer Data Base (2001-2007). Changes over time were assessed with chi-squared test for trend. Separate multivariable regression models were developed to examine factors associated adjuvant and neoadjuvant practices.

Results: Gastric GISTs reported to NCDB steadily increased: 463 in 2001 to 831 in 2007. 3,289 underwent resection: 78% partial/wedge, 6% total/near-total, and 14% multivisceral. From 2001 to 2007, use of adjuvant therapy increased from 29% to 47% (p < 0.001), although patients were less likely to get adjuvant therapy if older, tumors < 3cm, low grade, negative margins, or treated at low-volume hospitals (p < 0.01). Adjuvant systemic therapy for lesions < 3 cm also increased (17% to 25%, p = 0.001). For GISTs > 6 cm, use of adjuvant therapy increased from 41% to 49% overall, with increases of 45% to 70% at high-volume centers and of 39% to 48% at low-volume centers (all p < 0.001). Neoadjuvant therapy increased from 0% to 15% (p < 0.001) with patients more likely to receive neoadjuvant treatment if size > 6 cm, treated at high-volume centers, or treated in 2006-2007 (p < 0.001). Multivisceral resections decreased over time (19% to 12%, p < 0.001). The proportion of patients treated at high-volume centers increased slightly over time (22.2% to 26.9%, p = 0.006).

Conclusions: Adjuvant systemic therapy use for GISTs was increasing and widespread prior to FDA approval of adjuvant imatinib, suggesting contemporaneous advances in advanced GIST management were being translated into the adjuvant setting more than expected. As relatively costly therapies are integrated into practice, more robust tracking systems are needed to follow and guide the incorporation of new treatments.

No significant financial relationships to disclose.
Prostate-specific antigen (PSA) progression-free survival (PFS): A comparison of degarelix versus leuprolide in patients with prostate cancer.
Authors: Shore N. D. , Moul J. W. , Crawford E. , van der Meulen E. , Olesen T. , Persson B.
Published: February 2017

12

Background: Comparative effectiveness of the gonadotropin-releasing hormone (GnRH) blocker, degarelix, vs the GnRH agonist, leuprolide, was evaluated during a 1-year phase III trial (CS21); data have been presented. We now report long-term data from an ongoing 5-year extension study (CS21A).

Methods: In CS21, patients with prostate cancer (all stages) were randomized to degarelix (240 mg for 1 month, then monthly maintenance doses of 80 mg [n=207] or 160 mg [n=202]), or leuprolide 7.5 mg/month (n=201). Leuprolide patients could receive bicalutamide. Of the 504 patients who completed the 1-year trial, 384 chose to continue in an extension study; those on leuprolide were re-randomized to degarelix 240/80 mg or 240/160 mg. PSA PFS was defined as time to first PSA failure (two consecutive increases in PSA of 50% and ≥5 ng/mL above nadir) or death. Time for 25% of patients to experience PSA PFS (TTP25%) was analyzed using Weibull estimates.

Results: Up to 1 year, the risk of PSA PFS was significantly lower with degarelix 240/80 mg vs leuprolide (p=0.05, log-rank). At 27.5 months' median follow-up, hazard rate of PSA PFS significantly decreased in leuprolide patients switched to degarelix compared with before the switch (0.20 vs 0.08; p=0.003). Similar improvements occurred in patients with baseline PSA >20 ng/mL. During the first year, TTP25% for patients with baseline PSA >20 ng/mL was numerically longer with degarelix vs leuprolide (407 vs 303 days; p=0.085); the difference was even greater when degarelix data were analyzed beyond 1 year (514 vs 303 days; p=0.01).

Conclusions: Patients receiving degarelix had a significantly lower risk of PSA failure or death vs leuprolide during the first year of treatment. After switching to degarelix, patients who initially received leuprolide experienced a significantly lower rate of PSA failure or death. In patients with baseline PSA >20 ng/mL, TTP25% was significantly longer for degarelix patients. These data support the durability of the significant PSA PFS benefit of degarelix vs monthly leuprolide observed during the first year and the use of degarelix as first-line androgen deprivation therapy.

[Table: see text]
Know when to say when: Serial assessment of apoptosis and lymphocyte infiltrates with combined intraprostatic autologous dendritic cell immunotherapy/radiation therapy in high-risk prostate cancer.
Authors: Finkelstein S. E. , Gabrilovich D. , Rodriguez F. A. , Chuang T. , Kang L. , Torres-Roca J. , Heysek R. , Pow-Sang J. M. , Antonia S. , Fishman M. N. ,   Immunotherapy Research Group
Published: February 2017

149

Background: Previous work suggested combining local radiotherapy (XRT) with intratumoral syngeneic dendritic cell (DC) injection could result in apoptosis/cell death mediated induction of cytotoxic T lymphocytes (CTL) based anti-tumor immunity. However, the presence, timing, and effectiveness of effector CTL prior, during, and following combined XRT/intratumoral autologous DC injection in humans is unknown.

Methods: Herein, we report on timing concerns of intraprostatic DC injection in vivo, in human; five HLA-A2+, high risk localized prostate cancer patients were treated on protocol using androgen suppression therapy (AS), external beam radiation therapy (EBRT, 45 Gy) followed by brachytherapy permanent interstitial implant with addition of autologous intraprostatic DC injections during EBRT, after fractions 5, 15, and 25 of 25. Multiple serial prostate biopsies were collected before initiation of treatment, during EBRT and at 3, 12, 24 and 36 months after completion of treatment. Biopsies were stained for CD3, CD4, CD8, and cleaved caspase 3, and evaluated in a blinded manner. Specific anti-tumor immunity was assessed via ELISpot IFN-gamma production by CTL stimulated by HLA-A2 peptides derived from sequences of proteins associated with prostate cancer.

Results: Apheresis, DC injections, and biopsies were well tolerated. The pattern of distribution of CD8+ cells was consistent with prostate cancer antigen targeting, rather than non-specific organ infiltration. There was not immediate obvious intraprostratic infiltrate by CTL after DC injection in vivo, in humans. Measurable, induced increases in ELISpot titers in peripheral blood CTL were observed for some subjects and for some antigens, but non-specific immunity fluctuated.

Conclusions: This initial translational experience demonstrates safety and timing of DC injection coordinated with combined AS and XRT. Design of future trials employing combination XRT and DC will consider timing concerns to match therapy-induced apoptosis/cell death.

No significant financial relationships to disclose.
Characterization of antigen-specific T-cell activation and cytokine expression induced by sipuleucel-T.
Authors: Sheikh N. A. , Wesley J. D. , Chadwick E. , Perdue N. , dela Rosa C. P. , Frohlich M. W. , Stewart F. P. , Urdal D. L.
Published: February 2017

155

Background: Sipuleucel-T (Provenge) is an autologous cellular immunotherapy designed to stimulate an immune response in men diagnosed with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer. This study examined the role of GM-CSF in T cell activation and cytokine production in sipuleucel-T from men enrolled in phase III clinical trials (D9902B – IMPACT and P07-2 - PROACT).

Methods: Sipuleucel-T is manufactured from peripheral blood mononuclear cells (PBMCs) isolated every two weeks by leukapheresis. PBMCs are cultured with PA2024, a recombinant human antigen consisting of prostatic acid phosphatase (PAP) and granulocyte macrophage-colony stimulating factor (GM-CSF), for two days and cultured cells are then infused into patients. After each leukapheresis, a proportion of the PMBCs were cultured ex vivo for two days with GM-CSF (sargromostim). The GM-CSF cultures were compared to sipuleucel-T for their T cell activation profiles, cytokine production, and upregulation of CD54 and CD86 using flow cytometry and MesoScale Discovery technologies.

Results: Sipuleucel-T had increased APC activation-associated cytokines (IL-1a, IL-10, IL-12p70, IFNg and TNFa) and T cell activation- associated cytokines (IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, IFNg and TNFa) with each treatment. In contrast, GM-CSF-cultured cells had lower levels of these cytokines. Both PA2024- and GM-CSF-cultured cells had upregulated CD54 and CD86. T cell (CD4+ and CD8+) activation-markers were increased upon PA2024 restimulation, as measured by CD134 (OX40), CD137 (4-1BB), CD278 (ICOS), and CD279 (PD-1) expression. Cells from PA2024-cultures, but not GM-CSF-cultures, displayed a generalized pattern of enhanced expression of the T cell activation markers at the second infusion compared to the first and third.

Conclusions: These data indicate that T cell activation and enhanced cytokine expression are a consequence of priming after the first infusion. These effects are not driven by GM-CSF, as T cell activation and enhanced cytokine production were only observed in PA2024 cultures.

[Table: see text]
A randomized phase II study of pazopanib in castrate-sensitive prostate cancer: A University of Chicago phase II consortium/DoD Prostate Cancer Clinical Trials Consortium study.
Authors: Ward J. E. , Limvorasak S. , Karrison T. , Chatta G. S. , Hussain M. , Shevrin D. H. , Szmulewitz R. Z. , Stadler W. M. , Posadas E. M.
Published: February 2017

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Background: Intermittent androgen suppression (IAS) has been studied as a way of minimizing toxicity from long term androgen deprivation therapy (ADT). Based on previous studies with similar agents, we hypothesized that inhibition of VEGFR would result in prolonged time to PSA progression (TTPP) and allow for longer periods off ADT.

Methods: Men with biochemically recurrent, progressive prostate cancer and no evidence of macroscopic metastases were enrolled. They received 6 months of ADT. If at the end of that time the PSA was <0.5 ng/mL (with castrate testosterone levels), they were randomized to pazopanib 800 mg/d or observation. The primary outcome was TTPP, defined as time to a PSA >4.0 ng/mL, at which time they were restarted on ADT.

Results: 37 pts met randomization criteria. 18 were randomized to pazopanib. Only 4 pts met the endpoint criteria of TTPP, whereas 13 (72%) pts went off study for other reasons with 1 pt on treatment at study closure. Reasons for discontinuation included drug toxicity (grade 1/2, 9 pts) and patient preference (2 pts). No grade 3/4 toxicity was noted. 1 pt was removed due to pulmonary embolus, 1 pt due to MD discretion and 1 pt due to noncompliance. 19 pts were randomized to observation of which 12 were off treatment when the study was stopped. Only 5 pts met criteria for TTPP, whereas 7 of 12 (58%) dropped out for other reasons, including the frequency of protocol related blood draws and visits (3 pts) and randomization to observation (2 pts), 1 pt was removed per MD discretion and 1 pt transferred care. Due to high dropout rates in both arms, accrual was halted as the primary endpoint could not be measured robustly.

Conclusions: Minimizing the long term toxicities of ADT is an unmet need in prostate cancer therapy. Hence clinical interventions in concert with IAS represent an attractive area for drug development. This trial has outlined several barriers that exist in studying this patient population and might help to optimize future studies. Future trial design in this arena should investigate drugs with minimal toxicity and employ a design that maximizes patient convenience while anticipating the low threshold for patient drop out.

No significant financial relationships to disclose.
Assessment of two prognostic risk group methods to predict outcomes with docetaxel-based therapy in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Pond G. R. , Armstrong A. J. , Wood B. A. , Brookes M. , Leopold L. H. , Burke J. M. , Caton J. R. , Fleming M. T. , Sonpavde G.
Published: February 2017

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Background: Threeprognosticrisk groups have been identified in men with mCRPC (good [GR]/intermediate [IR]/poor [PR]) based on 0-1, 2 or 3-4 factors (visceral disease, pain, anemia, bone scan progression). Prostate Cancer Working Group (PCWG)-2 defines clinical subtypes with visceral disease, bone metastases ± nodal metastases and nodal disease only. The prognostic ability of risk grouping or PCWG2 subtypes was evaluated in a large, independent phase II trial.

Methods: A randomized phase IItrial of 221 men with mCRPC that received docetaxel-prednisone (DP) + AT-101 (Bcl-2 inhibitor) or DP + placebo was retrospectively analyzed using Cox regression and χ2 tests. Additional outcomes, tests and measures of discriminatory ability were assessed and will be presented. Patients from both groups were combined for analysis, as no significant differences in outcomes were observed.

Results: 93, 81 and 38 men had GR, IR and PR disease. GR men were more likely than IR/PR men to be ECOG-PS 0 (48%, 27%, 21%) and had a lower median baseline PSA (63, 85, 193 ng/ml). Significant differences between risk groups were observed for progression-free survival (PFS, p=0.009) and overall survival (OS, p<0.001), while PCWG2 subtypes did not discriminate for these outcomes. Both risk groups and PCWG2 subtypes inconsistently predicted PSA declines (table).

Conclusions: Prognostic risk groups significantly distinguished between outcomes in men with mCRPC receiving DP-based therapy, while PCWG2 subtypes did not. Risk groups may enhance stratification of patients in randomized trials and enable tailored drug development. Prognostic models that incorporate tumor molecular features may improve discriminatory ability.

[Table: see text]

[Table: see text]
The effect of pulmonary function testing on bleomycin dosing in germ cell tumors.
Authors: Houghton B. B. , Grimison P. S. , Toner G. C. , Chatfield M. , Thomson D. B. , Friedlander M. , Gebski V. , Rosenthal M. , Gurney H. , Stockler M.
Published: February 2017

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Background: Lung function testing (LFT) during chemotherapy with bleomycin is controversial. We describe the impact of LFT on bleomycin dosing in a phase II trial of accelerated BEP for advanced germ cell tumors.

Methods: Patients had measurable disease and were stratified with the International Germ Cell Cancer Consensus Classification (IGCCC). The planned number of weekly bleomycin doses was 12 for intermediate risk (IR) and poor risk (PR) disease, and 9 for good risk (GR) disease. Clinical assessments, CXR, DLCO corrected for haemoglobin, and FVC were done 2-weekly. Bleomycin was to be stopped for: predefined clinical or CXR evidence of pulmonary toxicity; or a >25% reduction in DLCO or FVC; or GFR <35mL/min. We determined bleomycin doses planned, received, and omitted; and, patients receiving all, ≥2/3, or <2/3 of their planned bleomycin doses.

Results: The first 30 patients had a median age of 28 (range 19-39) and 10 with lung metastases. 80% (259/324) of planned bleomycin doses were received; 75 doses (20%) were omitted in 15 pts, all for >25% reduction in DLCO. 16 patients had a 10 to 24% reduction in DLCO but none had >35%. In all patients the decline in FVC was < 10%. No patient developed other evidence of pulmonary toxicity. Patients with lung metastases were 2.5 times as likely to have a >25% reduction in DLCO (50% vs 20%, p=0.15), and 4 times as likely to receive <2/3 of their planned doses (40% v 10%, p=0.14).

Conclusions: Asymptomatic reductions in DLCO caused 20% of bleomycin doses to be omitted and 20% of patients to receive < 2/3 of their planned doses. A 25% reduction in DLCO may be too cautious a threshold, particularly in those with lung metastases.

[Table: see text]

No significant financial relationships to disclose.
Defining “cisplatin ineligible” patients with metastatic bladder cancer.
Authors: Galsky M. D. , Hahn N. M. , Rosenberg J. E. , Sonpavde G. , Oh W. K. , Dreicer R. , Vogelzang N. J. , Sternberg C. N. , Bajorin D. F. , Bellmunt J. ,   Cisplatin Ineligibility in Bladder Cancer Working Group
Published: February 2017

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Background: Cisplatin-based chemotherapy is standard first-line treatment for patients (pts) with metastatic urothelial carcinoma (UC). However, a large proportion of pts with UC are considered “unfit” for cisplatin, leading to clinical trials designed specifically for cisplatin-ineligible pts, with substantial variability in eligibility criteria. A clear and consistent definition of pts “unfit” for cisplatin-based therapy will aid in the development of standard eligibility criteria.

Methods: We assembled a panel of GU medical oncologists and followed a three-fold approach. First, we surveyed 120 international GU medical oncologists. Subsequently, we reviewed the literature regarding ‘cisplatin ineligibility‘ in solid tumors. Finally, the panel reconciled the survey results and available literature and generated a consensus definition.

Results: Responses were received from 65/120 (54%) of those surveyed. The survey results are shown in the Table . Reconciling the survey results with the available literature, the panel recommended the following be used to consistently define pts with metastatic UC “unfit” for cisplatin-based chemotherapy for clinical trial purposes: (1) ECOG performance status of 2 and/or (2) creatinine-clearance < 60 ml/min and/or (3) CTCAE Gr ≥ 2 hearing loss and/or (4) CTCAE Gr ≥ 2 neuropathy.

Conclusions: Substantial variability exists in investigators' definitions of pts with metastatic UC “unfit” for cisplatin. A consensus definition is proposed for standardization of eligibility criteria.

[Table: see text]

No significant financial relationships to disclose.
Results of a phase II study of single-agent nab-paclitaxel in platinum-refractory second-line metastatic urothelial carcinoma (UC).
Authors: Sridhar S. S. , Canil C. M. , Mukherjee S. D. , Winquist E. , Elser C. , Eisen A. , Reaume M. N. , Zhang L. , Ko Y.
Published: February 2017

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Background: There is currently no standard second-line chemotherapy for platinum- refractory UC. Both paclitaxel and docetaxel are commonly used but response rates are < 20% and no survival advantage has been shown. In this multi-institutional phase II study, we evaluated the efficacy and tolerability of a new albumin-bound nanoparticle formulation of paclitaxel, known as Abraxane (ABI-007) as a single agent in patients with platinum-refractory metastatic UC.

Methods: Patients with measurable UC, progressing on or after first-line platinum-based chemotherapy were enrolled onto this two-stage trial. ABI-007 was given at 260 mg/m2 IV q3weekly until progression. Clinical evaluation, CBC and blood chemistries were performed every cycle with restaging CT scans every 2 cycles.

Results: Accrual is now complete with 48 patients enrolled. Baseline characteristics: Male: Female 40:8; median age 68; ECOG Performance Status 0:1:2, 15:24:8. 248 cycles were delivered: median 5.5 cycles/pt with 17/48 pts (35%) requiring dose reductions. Most frequent adverse events (AE) were alopecia (12%), fatigue (12%), pain (12%), neuropathy (9%) and nausea (4%). The most frequent grade 3+ AE were pain (45%), hypertension (14%), fatigue (8%), joint stiffness (5%), neuropathy (4%) and weakness (4%). Forty patients are evaluable for response: 1 (2.5%) complete response (CR), 11 (28%) partial responses (PR), 9 (23%) stable disease (SD) and 20 (49%) progressive disease. One patient was inevaluable for response, 7 patients are too early for evaluation.

Conclusions: Single-agent ABI-007 was well tolerated with a response rate (CR+PR) of 33% (12/36) and a clinical benefit rate (CR+PR+SD) of 58% (21/36), representing one of the highest reported response rates to date in the second-line UC setting. These results suggest further study of ABI-007 in urothelial carcinoma is warranted.

No significant financial relationships to disclose.
Phase II study of single-agent volasertib (BI 6727) for second-line treatment of urothelial cancer (UC).
Authors: Stadler W. M. , Vaughn D. J. , Sonpavde G. , Vogelzang N. J. , Tagawa S. T. , Rosen P. J. , Lin C. , Mahoney J. F. , Zhao C. , Carducci M. A.
Published: February 2017

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Background: Polo-like kinase 1 (Plk1) controls multiple essential steps of mitosis. Volasertib (BI 6727) is a first-in-class, selective inhibitor of Plk1. In vitro, Plk1 depletion in cancer cells leads to activation of the mitotic checkpoint, prolonged mitotic arrest, and eventually apoptosis. No standard therapy exists for metastatic urothelial cancer (UC) progressing after initial chemotherapy. Thus, there is an urgent need for novel treatment options. Interim efficacy and tolerability results are presented from an open-label, single-arm, multi-center phase II trial of volasertib in patients (pts) with previously treated advanced UC.

Methods: Pts progressing after one prior systemic chemotherapy for locally advanced or metastatic UC or relapsing within 2 years of adjuvant/ neoadjuvant treatment received 300 mg volasertib (2-hour intravenous infusion) on day 1 every 21 days. If well tolerated, dose escalation to 350 mg in cycle 2 was encouraged. Primary endpoint was objective tumor response, defined by RECIST. The trial follows a modified Gehan-two-stage design with an early stopping rule based on the observed response rate of the first 20 pts receiving up to 4 courses of treatment. A minimum response rate of 10% (2/20) was required to recommend additional study.

Results: This trial is ongoing: 31 pts (median age 67) were treated between December 2009 and August 2010. All pts were eligible for interim safety/efficacy analysis. As of August 2010, 6 pts (19%) demonstrated a partial response, 7 pts (23%) had stable disease and 16 (52%) progressed between 3-6 weeks after study initiation. Thirteen (42%) pts remain on trial between 13-41 weeks (median time on trial 5 months) without disease progression. Major grade 3 or 4 adverse events (irrespective of drug relatedness) were neutropenia (10 pts, 32%), thrombocytopenia (7 pts, 23%), anemia (5 pts, 16%), hyponatremia (3 pts, 10%), dehydration (2 pts, 7%), and urinary tract infection (2 pts, 7%).

Conclusions: Single-agent volasertib was well tolerated and demonstrates clinical activity in the second-line treatment of pts with advanced UC. The early signs of clinical benefit allows proceeding per protocol to the second stage of the trial.

[Table: see text]
Effect of recombinant human endostatin on antitumor efficacy of paclitaxel/gemcitabine/cisplatin (TGP) chemotherapy in the treatment of advanced urothelial carcinoma.
Authors: Guo J. , Sheng X. N. , Cui C. L. , Si L. , Chi Z. H.
Published: February 2017

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Background: Rh-endostatin is a new recombinant human endostatin that can inhibit tumor endothelial cell proliferation, angiogenesis, and tumor growth in the pre-clinical studies. A phase III study revealed that rh-endostatin in combination with chemotherapy shows a synergic activity in advanced NSCLC patients. This study aims to evaluate the response, median progression-free survival (PFS), overall survival time (OS), and safety of the regimen, paclitaxel/gemcitabine/cisplatin (TGP) plus rh-endostatin, in patients with advanced urothelial transitional carcinoma.

Methods: The phase II trial included 35 patients with histologically diagnozed advanced or metastatic urothelial carcinoma, ECOG performance status 0-1, and GFR>60ml/min. TGP chemotherapy plus rh-endostatin as a first line treatment included: paclitaxel (80 mg/m2, d1&8), gemcitabine (1000 mg/m2, d1&8), cisplatin (30 mg/m2, d1 to 3) and rh-endostatin (15mg, d1 to 14, every 21d). For every 2 cycles, patients were evaluated for progression or response. Patients who had achieved an objective response (complete or partial) or who had stable disease were further treated for two cycles.

Results: The overall objective response rate was 62.8% (95% confidence interval [CI, 46.8% to 78.8%]), including 4 (11.4%) complete response (CR) and 18 (51.4%) partial responses (PRs). Six patients (17.1%) had stable disease (SD), and 7 (20.0%) had progression disease (PD). The disease control rate was 80.0%. The median progression-free survival and overall survival have not been reached. The most common adverse events included gastrointestinal reaction, alopecia, and myelosuppression. Grade 3/4 adverse events, including thrombocytopenia in 42.9% (15/35) of patients and leucopenia in 34.3% (12/35) of patients, were observed.

Conclusions: The addition of rh-endostatin to TGP regimen for advanced urothelial carcinoma patients might have higher response rate. Rh-Endostatinin combination with TGP chemotherapy showed a synergic activityand a favorable toxic profile in advanced urothelial carcinoma patients.

No significant financial relationships to disclose.