bluuebunny/crossref_metadata_2025 huggingface dataset:
Survival in patients with esophageal cancer treated with surgery after chemoradiotherapy.
Authors: Shridhar Ravi , Freilich Jessica , Hoffe Sarah , Fulp William J. , Chuong Michael , Almhanna Khaldoun , Karl Richard C. , Meredith Kenneth
Published: February 2017

98

Background: Chemoradiotherapy (CRT) followed by surgical resection is the standard of care for treating advanced esophageal cancer. However, the role of surgery has come into question in recent studies. The purpose of this study is to compare outcomes of patients treated with CRT with or without surgery. Methods: An IRB-approved database was queried to identify esophageal cancer patients treated with CRT with or without surgical resection between 2000 and 2011. Overall survival (OS) and disease-free survival (DFS) were calculated by the Kaplan-Meier method and log-rank analysis. Multivariate analysis for OS and DFS were calculated with a Cox proportional hazard ratio model. Results: We identified 232 patients treated with CRT (122 without surgery, 110 with surgery). Surgery was associated with a significant increase in OS and DFS. Median and 5 year OS for surgical versus nonsurgical patients was 42.2 months, and 42.3% versus 20.4 months and 29%, respectively (p = 0.0003). Median and 5 year DFS for surgical versus nonsurgical patients was 16.8 months and 29% versus 8.4 months and 22.8% (p < 0.001). MVA for OS revealed that lower stage (p = 0.0098), tumor length <5 cm (p = 0.0059), and surgery (p<0.0001) were prognostic for significantly decreased mortality, while age, gender, histology, tumor location, radiation dose, and radiation technique were not prognostic. MVA for DFS showed that tumor length <5 cm (p = 0.0112), radiation technique (p = 0.0023), and surgery (p = 0.0007) were prognostic for significantly decrease mortality, while lower stage (p = 0.069) and squamous histology (p = 0.055) were trending for decreased mortality. Age, gender, radiation dose, and tumor location were not prognostic for DFS. Conclusions: Surgery after CRT is strongly associated with increased OS and DFS in our esophageal cancer patient population. While we highly recommend surgical resection as part of trimodality treatment, it should only be performed in high volume centers. Longer followup in the already conducted randomized trials involving squamous cell carcinomas are needed to better qualify the initial negative results and randomized trials are need to address the role of surgery for adenocarcinomas.
Risk assessment for severe hypocalcemia requiring hospitalization with denosumab.
Authors: Autio Karen A. , Farooki Azeez , Glezerman Ilya , Chan Amelia , Barr Hallie C. , Seyboth Brian M. , Schneider Coursen Walker , Heller Glenn , Scher Howard I. , Morris Michael J.
Published: February 2017

115

Background: Skeletal-related events (SRE) pose clinical risks to patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) that can be mitigated with denosumab. Hypocalcemia is a side effect, however risk factors are not well described. Methods: An IRB waiver was obtained to review medical records for all mCRPC pts receiving denosumab at MSKCC between March-August 2011 for baseline labs, calcium (ca) and vitamin D nadirs, details of hospitalizations, concurrent therapies, and comorbidities. Comparisons between groups were made using Fisher’s exact test and the Wilcox rank sum test. Results: Nine of sixty pts (15%) treated with 1-2 doses of denosumab developed severe symptomatic hypocalcemia (median nadir 6.5 mg/dL) requiring hospitalization for intravenous (IV) ca replacement. Ca/Vitamin D was recommended to all pts. Ca recovered in 17 days in those who did return to baseline levels (n=5). However, four of nine (44%) pts required repeated hospitalizations for IV ca, never recovered to baseline ca levels, and died of advanced disease within 3 months. Median vitamin D 25-OH was 22.5 ng/ml for hospitalized pts, and PTH was 198 pg/ml at ca nadir. Conclusions: Denosumab was associated with severe hypocalcemia sufficient to require hospitalizations for IV ca replacement in 15% of pts with mCRPC. PSA, Ca, Alk Phos, and current chemotherapy were associated with severe hypocalcemia requiring hospitalization for IV ca. Clinicians are cautioned regarding potential risk factors including advanced disease, vitamin D insufficiency, and possibly comorbidities affecting calcium absorption. [Table: see text]
Concurrent treatment with everolimus (RAD001) and hormonoradiotherapy in high-risk locally advanced prostate cancer: Results of a phase I trial.
Authors: Azria David , Rebillard Xavier , Coux Nathalie , Jarlier Marta , Thuret Rodolphe , Llacer-Moscardo Carmen , Charissoux Marie , Culine Stephane
Published: February 2017

150

Background: Everolimus is able to stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving everolimus together with hormonotherapy and radiation therapy may kill more tumor cells. Methods: We conducted a phase I trial to evaluate the impact of everolimus (RAD001), an mTOR inhibitor, in patients treated concurrently with radiotherapy (RT) and ablative androgen treatment in high-risk locally advanced prostate cancer. Inclusion criteria were high-risk locally advanced non metastatic prostate cancer defined as clinical stage ≥ T3 or Gleason score ≥ 8 or PSA ≥ 20. The week before the beginning of RT, RAD001 was administered at different dose levels, twice daily, until the last day of irradiation. A nonsteroid antiandrogen was also given for 1 month at the beginning of RT. Prostate and seminal vesicle were irradiated up to 74Gy in 37 fractions of 2Gy with concomitant long-term LHRH analogue. The starting dose of RAD001 was 5mg/d with subsequent dose levels of 7.5 and 10 mg/d. The primary endpoint was the determination of the maximum tolerated dose (MTD). Dose escalation was implemented according to the continual reassessment method (CRM). Results: Fifteen patients were enrolled and 14 were assessable for toxicity and response. Significant toxicities were demonstrated at the 7.5 and 10 mg/d dose levels. Dose-limiting toxicity (DLT) occurred in two patients at dose level 7.5 mg/d and characterized by a grade 3 diarrhea and a grade 3 hydronephrosis due to dehydration and kidney lithiasis. DLT also occurred in two patients at dose level 10 mg/d (grade 3 diarrhea and grade 3 laryngopharyngeal infection). The MTD was reached at 7.5 mg/day (dose-level II). The recommended dose of RAD001 was 5 mg/d. After a median follow-up of 22 months, 12 patients are alive, 1 is dead (not related to cancer) and 2 patients had relapsed. Conclusions: Concomitant hormone-radiotherapy and everolimus is well-tolerated with mucositis, hypercholesterolemia, and urinary disorders. The recommended phase-II trial dose of everolimus in this combined setting is 5 mg/day. Clinical trial information: NCT00943956.
Arachidonic acid drives amoeboid transendothelial invasion through ligand independent activation of EphA2.
Authors: Brown Mick D. , Tawadros Thomas , Hart Claire , Clarke Noel W.
Published: February 2017

221

Background: We have previously shown that the omega-6 poly unsaturated fatty acid arachidonic acid is a potent stimulator of prostate epithelial transendothelial migration across the bone marrow endothelium and can completely restore the invasive stimulatory capacity of adipocyte depleted human bone marrow stroma. Arachidonic acid induces of EphA2 ligand independent signaling via pAkt with subsequent downstream activation of FAK and Src. Here we present further characterization of the arachidonic acid induced EphA2 pathway. Methods: Transendothelial migration of PC-3 cells across the bone marrow endothelial cell line BMEC was followed by time lapse microscopy and by SEM with or without amoeboid or mesenchymal inhibitors. Western blot analysis of the PC-3 cells or their lipid raft (LR) components post AA stimulation was conducted and signaling pathways validated by siRNA knockdown. Results: Initial studies demonstrated a requirement of PC-3 cells to undergo a mesenchymal to amoeboid switch for transendothelial migration towards bone marrow stroma. The mesenchymal to amoeboid switch was also induced by direct treatment with arachidonic acid as characterized by induction of the Rho/Rock pathway and phosphorylation of myosin light chain. Knockdown of EphA2 by siRNA blocked the induction of the mesenchymal to amoeboid switch and prevented transendothelial invasion. Conclusions: Malignant prostate epithelial cells undergo a switch from mesenchymal to amoeboid movement in response to arachidonic acid in order to cross the bone marrow endothelial barrier.
PSA outcomes in patients with adenocarcinoma of the prostate with presenting PSA > 20 ng/ml.
Authors: Shasha Daniel , Debenham Brock John , Salant Robert , Harrison Louis Benjamin
Published: February 2017

241

Background: Optimal treatment of prostate cancer with presenting PSA >20 ng/mL is debated within and between specialties, as reflected by variable PSA outcomes reported. We present our clinical outcomes in irradiated patients for this population. Methods: With IRB approval, we analyzed patient, disease, treatment, and PSA data of 149 patients with presenting PSA > 20 ng/mL radiated with curative intent 1997-2012 by a single physician (DS) at Beth Israel Medical Center (New York City). External beam radiation therapy (EBRT) was delivered first to prostate, seminal vesicles (SV) and draining pelvic lymph nodes to 45 Gy, then 5.4 Gy cone down, then a boost with either brachytherapy (BT) or 30.6 Gy conformal EBRT. BT was withheld in large volume of SV invasion by either DRE or by MRI. Hormonal therapy (HT) consisted of LHRH agonist +/- antiandrogen therapy. PSA was checked every 6 mos. Biochemical Failure (BF) was defined as post-treatment PSA nadir + 2 ng/mL. Results: 41% of patients were African American, 27% Hispanic, 21% Caucasian, and 6% Asian. The median patient age, Gleason score (GS), PSA, and T stage were 68 yrs (range 42-87), 30 ng/mL (range 20–280), 7 (range 5-10) and stage II (8% Tx, 29% T1, 32% T2, 22% T3a/b, 8% T3c). Combined EBRT and BT (CMT) were used in 70% (N=104); EBRT alone in 28% (N=42); BT alone in 2% (N=3). HT was given to 87% (N=129), (median duration 25 mos). Of CMT patients, 77% (N=81) had I-125 permanent seed implant, 22% (N=23) had Pd-103 implant, and 1% (N=1) had HDR temporary Ir-192 implant. With a minimum follow-up (FU) 2 years and median FU 4.9 years (range 2.0-14.1), overall BF was 18% (N=27), and median time to failure was 4 yrs (range 0.4–9.3). Of failures, median age was 64 (range 48-83), and 40% were African American; median pre-treatment PSA was 40 ng/mL (range 20–238), median stage was 3. BF occurred in 17/104 (16.3%) CMT patients (13/17 I-125 and 3/17 Pd-103), 9/42 (21.4%) EBRT patients, and 1/3 (33%) BT alone patients (1/1 I-125). All patients who failed received HT. Conclusions: Excellent overall biochemical outcomes in patients with presenting PSA > 20 ng/ml are reported, with only approximately 18% experiencing BF at a median FU of 4.9 years. Of all treatments analyzed, CMT yielded superior biochemical control.
Randomized phase III study of adjuvant versus progression-triggered treatment with gemcitabine (G) after radical cystectomy (RC) for locally advanced bladder cancer (LABC) in patients not suitable for cisplatin-based chemotherapy (CBC) (AUO-trial AB22/00).
Authors: Lehmann Jan , Kuehn Michael , Fischer Claus , Volkmer Bjoern , von Rundstedt Friedrich , Albers Peter , Becht Eduard , Bannowsky Andreas , Hofmann Rainer , Langbein Sigrun , Retz Margitta , Stoeckle Michael
Published: February 2017

250

Background: Cisplatin-based chemotherapy (CBC) has been widely used in trials of adjuvant therapy for LABC after RC. A high proportion of patients are unfit for CBC after RC for LABC. We therefore performed a prospective randomized phase III trial on G-monotherapy administered as adjuvant therapy (G-adj) vs in case of progression (G-prog) in pts not suitable for CBC. Methods: Between 7/2000 and 12/2008 120 of 178 planned pts with LABC unfit for CBC were randomized between 6 adjuvant cycles of G (q3w) starting within 12 wks after RC and G in case of disease progression. The primary endpoint of the trial was progression-free survival (PFS). Secondary endpoints included cancer-specific (CSS) and overall survival (OS) as well as treatment related toxicity. Results: The trial of 178 planned pts was closed early due to slow accrual. Of 120 randomized pts from 29 centers 114 were eligible for analysis. Median age of 81 male and 33 female pts was 72 (45-82) years. Lymph-node positive disease was found in 52/114 (47%) of pts at the time of surgery. The intention-to-treat analysis demonstrated a 10% difference in PFS after 3 years 50% (G-adj) vs 40% (G-prog) with a median PFS of 23 mo (G-adj) vs 17 mo (G-prog). The difference in PFS was not statistically significant (nss) (p= 0.335; HR 1.375, 95%CI 0.719 - 2.627). CSS at 3ys: 56% (G-adj) vs 50% (G-prog) with a median CSS of 49 mo (G-adj) vs 38 mo (G-prog). The difference in CSS was nss (p= 0.622; HR 1.166, 95%CI 0.632 - 2.149). OS at 3ys: 49% (G-adj) vs 48% (G-prog) with a median OS of 32 mo (G-adj) vs 31 mo (G-prog). The difference in OS was nss (p= 0.426; HR 1.225, 95%CI 0.743 - 2.018). Treatment with G was usually well tolerated, with less than 15% grade 3/4 toxicities..There was one treatment related death in the G-adj arm. Conclusions: The study-hypothesis of a 15% difference in PFS after 3 years in favor of G-adj vs G-prog could not be confirmed. Nevertheless a marked difference in survival in favor of G-adj was shown by Kaplan-Meier plots regarding PFS, CSS and OS within the first 24 months after RC. Clinical trial information: NCT00146276.
Association of hospital readmission following cystectomy with omission of postoperative chemotherapy in patients with urothelial carcinoma of the bladder.
Authors: Smaldone Marc C. , Uzzo Robert G. , Kutikov Alexander , Handorf Elizabeth , Wong Yu-Ning , Armstrong Katrina , Bekelman Justin E.
Published: February 2017

254

Background: Hypothesizing that complications after radical cystectomy requiring hospital re-admission may preclude subsequent systemic treatment, our objective was to test the association between readmission within 30 days of surgery and receipt of post-operative chemotherapy in Medicare beneficiaries. Methods: Using 1995-2007 linked Surveillance, Epidemiology, and End Results (SEER)-Medicare data, all patients undergoing cystectomy for pathologic stage III-IV urothelial carcinoma were identified. Univariate and multivariate logistic regression analyses were used to test the association between hospital readmission within 30 days and receipt of post-operative chemotherapy (defined ≤9 months from surgery) adjusting for demographic, clinical, hospital, and procedural characteristics. Results: We identified 4,034 patients undergoing radical cystectomy for urothelial carcinoma, of which 1,498 met final inclusion criteria (mean age 75.9±6.3 years, 62.7% male). 563 patients (37.6%) were readmitted within 30 days of surgery (7.5% with ≥2 readmissions). Postoperative chemotherapy was administered in 26.1% of candidates who were readmitted, compared to 35.4% who were not readmitted following surgery (p<0.001). Following adjustment, the odds of receiving chemotherapy were 30% less in patients readmitted to the hospital (OR 0.70 [CI 0.53-0.92]) when compared to patients who were not readmitted. Stratified by number of readmissions, the odds of receiving chemotherapy in patients with 1 and ≥2 readmissions were 26% (OR 0.74 [CI 0.56-0.99]) and 54% (OR 0.46 [CI 0.27-0.79]) less when compared to patients not readmitted. Use of a more restrictive 6 month post operative chemotherapy definition did not significantly impact our findings (OR 0.66 [CI 0.47-0.93]). Conclusions: In a cohort of Medicare beneficiaries undergoing cystectomy, hospital readmission within 30 days is associated with omission of post-operative chemotherapy in patients with Stage III-IV urothelial carcinoma. These data inform treatment planning decisions and strengthen the argument supporting chemotherapy utilization in the neoadjuvant setting.
Efficacy and safety of zoledronic acid in men with castration-sensitive prostate cancer and bone metastases: Results of CALGB 90202 (Alliance).
Authors: Smith Matthew Raymond , Halabi Susan , Ryan Charles J. , Stadler Walter Michael , Hussain Arif , Vogelzang Nicholas J. , Hauke Ralph J. , Sanford Ben L. , Small Eric Jay ,   Alliance
Published: February 2017

27

Background: Zoledronic acid (ZA) decreases risk of skeletal-related events (SREs) in men with castration-resistant prostate cancer (CRPC) and bone metastases. This phase III study evaluated efficacy and safety of earlier treatment with ZA in men with castration-sensitive metastatic prostate cancer. Methods: CALGB 90202 was a randomized, double-blinded, placebo-controlled phase III trial in men with castration-sensitive prostate cancer and bone metastases who had initiated androgen deprivation therapy within six months of study entry. Subjects were randomized 1:1 in blinded manner to receive ZA (4 mg intravenously every 4 weeks) or placebo (P). After progression to CRPC, all patients crossed over to open-label ZA. The primary endpoint was time to first SRE. Target sample size was 680. Time to SRE was defined as interval between date of randomization and date of first SRE (radiation to bone, or clinical fracture, or surgery to bone, or death due to prostate cancer). With 470 SRE events, the log-rank test has 88% power to detect a 23% decrease in hazard rate of SRE event assuming a one-sided type I error rate of 0.05. The study was discontinued prematurely after the corporate supporter withdrew study drug supply. Primary analysis was based on the stratified log-rank statistic adjusting on the stratification factors following observation of 284 SREs (60% of total events). Results: Between June 2004 and April 2012, 645 patients were randomly assigned to ZA or P. Median time to first SRE was 32.5 months in the ZA group and 29.8 months in the P group (hazard ratio (HR) 0.96 [0.76-1.22]; stratified log-rank P=0.74). A total of 271 deaths were observed; median follow-up time for surviving patients was 24.4 months (20.6, 28.3). Overall survival was similar between groups (HR= 0.89 [0.70-1.14]; stratified P=0.34). Rates of grade 3 or higher adverse events were similar between groups (15% vs. 12% in ZA and P). Conclusions: In men with castration-sensitive prostate cancer and bone metastases, early treatment with zoledronic acid was not associated with lower risk for SREs or death. Early termination limited statistical power of the study. Clinical trial information: NCT00079001.
Effectiveness and safety of valrubicin in non–muscle-invasive bladder cancer following reintroduction: Results from a medical chart review study.
Authors: Cookson Michael S. , Lihou Christine Francis , Harper Samira Q. , Li Thomas , Chitra Surya , Tutrone Ronald
Published: February 2017

296

Background: Valrubicin was approved in the United States in 1998, removed from the market in 2002 because of manufacturing issues, and reintroduced in 2009. We report secondary outcomes and concomitant medication use from a US multicenter, observational, retrospective study. Methods: Medical records of adult patients with non–muscle-invasive bladder cancer (NMIBC) who used valrubicin were abstracted (March–September 2011). Kaplan-Meier analyses were performed for disease-free survival (DFS), progression-free survival (PFS), worsening-free survival (WFS), cystectomy-free survival (CFS), and time to cystectomy. Results: 113 patients (mean age, 73.7 years) received intravesical valrubicin (median, 6 instillations [range, 2–18]). 107 patients (94.7%) received >3 instillations; 97 (85.8%) completed the full course of therapy (≥6 instillations). DFS was 51.6% (95% CI, 40.9%–61.3%) at 3 months, 30.4% (95% CI, 20.4%–41.1%) at 6 months, and median DFS was 3.5 months (95% CI, 2.5–4.0). PFS was 97.6% (95% CI, 90.9%–99.4%) at 3 months, 87.2% (95% CI, 75.4%–93.5%) at 6 months, and median PFS was 18.2 months (95% CI, 17.2–19.0). WFS was 47.4% (95% CI, 37.2%–57.0%) at 3 months and 28.1% (95% CI, 18.8%–38.2%) at 6 months. CFS was 98.0% (95% CI, 92.2%–99.5%) at 3 months and 93.7% (95% CI, 85.2%–97.4%) at 6 months. Median CFS was not reached; only 13.3% of patients underwent radical cystectomy after starting valrubicin. 56 patients (49.6%) experienced ≥1 local adverse reaction; the most common were hematuria and pollakiuria (both 17.7%), micturition urgency (15.9%), and bladder spasm (14.2%). 55 patients (48.7%) used ≥1 concomitant medication for local adverse reactions; the most commonly used were urinary antispasmodics (21.2%), fluoroquinolones (14.2%), and other urologicals (14.2%). Conclusions: In patients with NMIBC treated with intravesical valrubicin, median DFS and PFS were 3.5 and 18.2 months, respectively, and median CFS was not reached as only 13% of patients underwent radical cystectomy. Valrubicin was well tolerated, and most patients received the full course of 6 instillations. Funding: Research and abstract were supported by Endo Pharmaceuticals Inc.
A 10-year retrospective review of germ cell tumors not cured with cisplatin-based chemotherapy.
Authors: O'Donnell Elizabeth , Gray Kathryn P. , Hirsch Michelle S. , Ravi Praful , Beard Clair , Sweeney Christopher
Published: February 2017

325

Background: In 2011, there were about 8260 cases of Germ Cell Tumor (GCT) diagnosed in the US, of those, 350 or 4% will die of their disease. We sought to review our experience with a 10-year cohort of 819 patients treated for GCT at Dana-Farber and synthesize the cumulative findings of those who died from their disease specifically looking for different sub-types of incurable GCTs. Methods: Retrospective review of 819 germ-cell tumors treated in our center between 2000 and 2010 to identify patients not cured with cisplatin-based chemotherapy. Inclusion criteria were men over the age of 18 treated for malignant germ cell tumor between 2000 and 2010 at the Dana-Farber Cancer Institute that died from their disease. The outcomes of interest were smoking history, extent of disease at diagnosis, primary site of disease, histology, presence of lymphovascular invasion, outcomes to first- and second-line therapies, treatment with high dose chemotherapy (HDC), late relapse, brain metastases, and presence or absence of transformed teratoma as cause of death. Results: 38 men were identified. Median age 35. More than half had a smoking history. 3 presented with clinical stage 1 disease, 8 good-risk metastatic disease, 4 intermediate-risk and 22 poor-risk at diagnosis. The majority (28) had testicular primaries, 7 mediastinal, one pituitary, one retroperitoneal and one unknown. 21 of 48 had complete responses to first-line therapy. 4 received HDC for relapsed disease. 10 relapsed after 2 years of disease-free survival. 7 died of transformed teratoma. 63% progressed directly through cisplatin-based chemotherapy and died as a result of non-teratomatous germ cell tumor burden. 18% died from unresectable or transformed teratoma and 26% died after suffering a late relapse of disease. Conclusions: Within the cohort of patient who died from their GCTs there are three distinct biological subtypes – the majority is platinum-refractory germ cell tumor while unresectable/transformed teratoma and late relapse make up the remainder. Understanding the unique biology of these disease states compared with curable disease may provide informative insights into chemotherapy resistance for cancer in general.
Inguinal lymph node dissection for penile carcinoma: Postoperative complications using a validated classification system.
Authors: Jayaratna Isuru Sampath , Mitra Anirban Pradip , Dedhia Raj , Asbaghi Steven , Teruya Kara K. , Tygenhof Eric , Schuckman Anne K.
Published: February 2017

326

Background: Inguinal lymph node dissection (ILND) is the gold standard for evaluating for locoregional disease in penile squamous cell carcinoma (PSCC), however, it has been previously described to have a high morbidity rate. We describe our postoperative complications using a validated classification system and examine possible associations with clinicopathologic factors. Methods: We retrospectively identified patients with a diagnosis of PSCC that underwent ILND at our institution from 1995 to 2012. Postoperative complications were characterized by the highest grade complication achieved by patients using the Clavien-Dindo classification system during the first 90 days after their surgery. Clavien-Dindo scores of 2 or less were defined as low grade, and scores of 3 or greater were defined as high grade. Univariate Cox regression analysis was performed to examine associations between complications and clinicopathologic factors. Results: We identified 36 patients who underwent ILND during this period, with 29 that had complete clinical, pathological and complication data. For the 50 ILNDs performed in our cohort, we report a 46% total complication rate, with a 36% low grade and a 10% high grade complication rate. Of the low grade complications, 39% were wound dehiscences that required wound packing, and 28% were wound infections that required antibiotic treatment. The highest grade of complications achieved was 3A, all of which were lymphoceles that required percutaneous drainage for resolution. We were unable to demonstrate any association of complications with age, ethnicity, tumor stage, tumor grade, AJCC stage, presence of palpable lymphadenopathy or pathologic nodal stage. Conclusions: While ILND still remains an operation with high morbidity, our findings show that the most common low grade complications can be managed with medications and dressing changes, and the relatively modest high grade complication rate consists entirely of percutaneous drain placement. The inability to show associations with clinicopathologic variables is likely due to our low sample size. These findings support the continued use of ILND for staging in PSCC.
Antitumor activity of brentuximab vedotin in CD30 positive refractory germ cell tumors.
Authors: Albany Costantine , Feldman Darren Richard , Garbo Lawrence E. , Einhorn Lawrence H.
Published: February 2017

327

Background: Brentuximab Vedotin (BV) is a novel antibody drug conjugate that combines the agent mono-methyl auristatin E (MMAE) to a CD-30 specific monoclonal antibody by a protease-cleavable linker. It is approved by the FDA for treatment of relapsed Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (ALCL). In addition to HL and ALCL, CD-30 expression has been reported on malignant tumors of non-lymphoid origin including testicular embryonal carcinoma (EC). Here we report our initial experience in three heavily pre-treated patients with CD30-positive EC who were treated as part of an ongoing phase 2 open-label multicenter study designed to evaluate the antitumor activity of BV in patients with CD30-positive non-lymphomatous malignancies. Methods: Three men with relapsed or refractory, histologically confirmed CD-30 positive testicular cancer received BV until progression or toxicity. CD-30 expression was assessed by immunohistochemistry. All 3 patients were dosed at 1.8 mg/kg IV every 21 days and followed for response at cycles 2, 4. Results: Three patients were enrolled at 2 sites in the US. Median age was 26 years (range 24-33). All 3 patients progressed after high dose chemotherapy with peripheral blood stem cell transplant. Two patients received BV as 4th line and 1 patient as 3rd line therapy. Tumor sites included lungs, liver, retroperitoneal, mediastinal and supraclavicular lymph nodes. The first patient baseline hCG was 5571. After 2 cycles of therapy, hCG nadir was 45 with a radiologic partial response (PR) by RESICT that lasted 2 months. He then had serologic and radiographic progression in the liver while on therapy. Patient 2 was serologic marker negative and had a radiographic PR by RECIST in lung and mediastinum after cycle 2 and continues on therapy. Patient 3 had a baseline hCG of 10400, with nadir at 110 after 2 doses and continues to have serologic response. By RECIST he currently has stable disease. The treatment was well tolerated in all 3 patients with no grade 3-4 toxicities. Conclusions: All 3 patients with heavily pretreated CD-30 positive EC had clinical benefit after treatment with brentuximab vedotin. The treatment was well tolerated. The enrollment is ongoing in this Phase 2 study. Clinical trial information: NCT01461538.
Surface applicator high-dose-rate fractionated brachytherapy for conservative definitive management of extramammilary Paget’s disease of the penis, scrotum, and mons pubis.
Authors: Devlin Phillip M.
Published: February 2017

333

Background: This case is of a 70 yo Asian male who had suffered for many years from a painful eroding, oozing, bleeding lesion that started on the mons and over time had spread the full length of the penis and onto the anterior scrotum. A surface mold applicator fractionated computer-optimized high-dose rate (HDR) brachytherapy to 50Gy given in 2 Gy/day 5 days/week for 5 weeks. Methods: For the mons and the anterior scrotum a flat plate of aquaplast was molded with an aperture through which to pass the penis. For the penis a soft wrap, make of two layers of 5mm superflab was created with 15 truguide catheters embedded between. The wrapped penis was then supported with towels and tapes. Using radio-opaque dummy markers a CT was generated and an optimized treatment plan using Oncentra Brachytherapy. Because of the need for daily setups and the intrinsically elastic nature of the penis and scrotum, effort was made to keep the dwell times even so as to minimize any effect from day to day variation in set up. The prescription isodose line was manually adjusted so that where possible there was sparing of deep tissue of the urethra, bladder and testes. When QA was approved the patient began with daily treatments and successfully completed 25 without a treatment break. Results: Sustained local control was observed. Discussion: Surface mold applicator brachytherapy provides the most conformal of radiation therapy to complex superficial targets. For these targets it compares most favorably with all external beam approaches including electron, photon, IMRT and proton therapy. Conclusions: This modality optimally treated these lesions. The depth of the dose can be modulated. The treatment plan can be adapted to deal with swelling late in the course of therapy. The chance of a geographic miss of therapy is low because of the direct application to the affected area.
Long-term outcomes of cisplatin-based chemotherapy in patients with stage II-III germ cell tumors: Center 30-year experience of a single center.
Authors: De Velasco Guillermo , Castellano Daniel E. , Sepúlveda Juan Manuel , Villacampa Felipe , Pascual Tomas , Manneh Ray , Parrilla Lucia , Farfán Carlos A. , Cortes-Funes Hernan
Published: February 2017

338

Background: We retrospectively assessed long-term outcomes of cisplatin-based chemotherapy for stage II/IIII germ cell tumors (GCTs) at Medical Oncology Department of 12 Octubre University Hospital, Madrid (Spain). Methods: Two hundred fourteen (214) consecutive males with advanced GCTs of the testis or extragonadal origin who received standard cisplatin-based chemotherapy regimens between 1982 and 2012 were analyzed. Results: Demographic features: Median age 26.4 years (range 14- 72 years). Right and left testicular tumor present in 71 (37%) and 78 (41%) patients respectively and cryptorchidism in 11 (5%). Histology: 12% of the patients had seminomatous and 88% non-seminomatous histology. Stage distribution (TNM): Stage II 105p (49%), Stage III 109 p (51%). Twenty-five primary (11%) were extragonadal. Risk assessment according to IGCCCG - good 115 p (54%) intermediate 34 p (16%) and poor 62 p (29%). All patients received chemotherapy with cisplatin (BEP-73%, EP-15%, BOPM-EPI 5%, PVB 6%, others 1%). Survival analysis: The median follow-up period was 117 months (0 - 329). Totally, 158 patients (74%) achieved complete remission (CR). CR was achieved in 128 p (60%) after induction therapy (first line chemotherapy). Salvage treatment: surgery +/-chemotherapy was given to 72 (33%) and 85 (39%) patients respectively. High-dose chemotherapy (with carboplatin based- schemes at dosage (AUC20) as salvage therapy was performed in 65 patients (30%). Of them 35 p (53.4%) had complete remission of disease without relapse and the median progression free survival was of 47.2 months. Severe AEs were < to 5%, and classically already described renal impairment, ototoxicity and neurophaty with non chemotherapy-related toxic deaths. Conclusions: Improvement of medical management and survival during platinum-based chemotherapy and the development of several regimens for salvage chemotherapy seemed to contribute to improving outcomes of patients with advanced GCTs even for patients with platinum-refractory disease. However, we continue to investigate in the search for genetic and molecular mechanisms that help us change it.
Treatment of metastatic penile cancer in the adjuvant setting with ifosfamide, paclitaxel, and cisplatin: A single institution experience.
Authors: O'Reilly Aine , O'Keeffe Margaret , Aherne Paul , Mayer Nicholas J. , Sweeney John P. , Power Derek G.
Published: February 2017

340

Background: Surgery alone rarely results in long-term disease-free control in patients with N2 or N3 (stage III or IV) metastatic penile cancer. Five-year overall survival rarely exceeds 40% in this group of patients. Ifosfamide, paclitaxel, and cisplatin chemotherapy (ITP) has been reported in the neoadjuvant setting in a phase II trial. The evidence supporting adjuvant chemotherapy after inguinal lymph node dissection (LND) is poor. We report our experience of ITP chemotherapy given in the adjuvant setting after bilateral inguinal LND for stage III and IV penile cancer Methods: In our regional cancer center we performed a retrospective analysis of a prospectively maintained database of all patients between May 2008 and February 2012 who received adjuvant chemotherapy for regional metastatic penile cancer. Results: Four patients received chemotherapy in the adjuvant setting. One patient completed 4 cycles of cisplatin and 5-Fluorouracil after bilateral inguinal LND (pT1N2). There is no evidence of disease recurrence at 20 months post completion of chemotherapy. Three patients received adjuvant chemotherapy with paclitaxel 175 mg/m2 on day 1; ifosfamide 1,200 mg/m2 on days 1-3; and cisplatin 20 mg/m2on days 1-3 (ITP). All pts received 4 X 3 weekly cycles with no significant toxicity. The first two patients underwent inguinal LND for pT3N2 (stage IIIB) disease followed by 4 cycles of ITP. In both patients surveillance imaging showed no evidence of disease recurrence 28 and 50 months, respectively, post completion of chemotherapy. The third patient underwent inguinal LND for pT1bN3 (stage IV) disease followed by 4 cycles of ITP. Surveillance imaging at 6 months post completion of chemotherapy showed no evidence of local or distant recurrence. Conclusions: Multimodality treatment of regional metastatic penile cancer offers the best chance of long-term disease-free and overall survival. The ITP regimen is relatively nontoxic and well-tolerated. We propose that this regimen should be further investigated in the adjuvant or peri-operative settings.
Clinical activity and safety of antiprogrammed death-1 (PD-1) (BMS-936558/MDX-1106/ONO-4538) in patients (pts) with previously treated, metastatic renal cell carcinoma (mRCC): An updated analysis.
Authors: McDermott David F. , Drake Charles G. , Sznol Mario , Choueiri Toni K. , Powderly John D. , Smith David C. , Wigginton Jon M. , Kollia Georgia , Gupta Ashok Kumar , Atkins Michael B.
Published: February 2017

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Background: BMS-936558 is a fully human monoclonal antibody that blocks the PD-1 coinhibitory receptor expressed by activated T cells. In the initial portion of a phase I study (CA209-003), BMS-936558 showed promising activity in pts with various solid tumors, including mRCC. Accrual was expanded to better characterize antitumor, safety, and dose effects. Methods: Pts with RCC were treated with BMS-936558 IV q2wk at 10 mg/kg initially, followed by additional pts at 1 mg/kg. Pts received up to 12 cycles (4 doses/cycle) of treatment or until unacceptable toxicity, confirmed progressive disease, or complete response (CR). Clinical activity was assessed by RECIST v1.0. Results: As of July 3, 2012, 34 mRCC pts had been treated at 1 mg/kg (n=18) or 10 mg/kg (n=16). ECOG performance status was 0 in 13 pts and 1 in 21 pts. More than 40% of study patients received ≥3 prior therapies, >70% received prior antiangiogenic therapy, and >50% received prior immunotherapy. Sites of metastatic disease included lung (n=30), lymph node (n=28), bone (n=10), and liver (n=9). The incidence of grade 3-4 related adverse events was 21% and included hypophosphatemia (6%) and respiratory disorders (6%); there were no drug-related deaths among mRCC pts. Ongoing durable clinical responses were observed at both 1 and 10 mg/kg doses (Table) with some continuing off treatment. Three pts demonstrated nonconventional response patterns and were not categorized as responders by conventional RECIST. Current median duration of response was 12.9 months for both 1 and 10 mg/kg doses. Conclusions: BMS-936558 is tolerable and exhibits ongoing durable clinical activity in pts with previously treated mRCC. Clinical trial information: NCT00730639. [Table: see text]
Prolonged survival with personalized immunotherapy (AGS-003) in combination with sunitinib in unfavorable risk metastatic RCC (mRCC).
Authors: Amin Asim , Dudek Arkadiusz , Logan Theodore , Lance Raymond S. , Holzbeierlein Jeffrey M. , Master Viraj A. , Pal Sumanta Kumar , Knox Jennifer J. , Karsh Lawrence Ivan , Plessinger Doug , Nicolette Charles A. , Figlin Robert A.
Published: February 2017

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Background: During the past decade, VEGF targeted therapies have become standard treatment for advanced RCC. While targeted therapies have yielded improved efficacy, durable remissions are rare, particularly in unfavorable risk subjects. In a pivotal trial, treatment with sunitinib yielded a median OS of 5.3 months for poor risk and 20.7 months for intermediate risk subjects. Similarly, the validation dataset for the Heng risk model (ASCO 2011) revealed a median OS of 8 months for poor risk and 21 months for intermediate risk patients treated with VEGF targeted therapies. Durable responses have been elicited by immunotherapy in RCC. We report an update on patients with mRCC treated with combined VEGF TKI (sunitinib) plus autologous immunotherapy (AGS-003). Methods: In this phase II study, subjects with unfavorable prognosis mRCC (poor and intermediate risk) were treated with sunitinib plus autologous dendritic cell immunotherapy (AGS-003). Treatment consisted of standard 6-week cycles of sunitinib plus AGS-003 (once every 3 weeks x5 doses, then every 12 weeks until PD). Tumor response was assessed per RECIST and subjects were followed for PFS and OS. Immune monitoring samples were taken at screening, baseline and after the third and fifth doses of AGS-003 and analyzed by multiparametric flow cytometry. Results: 21 subjects were treated. As previously reported, the median overall PFS was 11.2 months and the final median OS was 30.2 months. When analyzed by baseline Heng risk status, the median PFS was 19.4 months for intermediate (n=11) and 5.8 months for subjects with poor risk features (n=10) at baseline. The median OS is 39.5+ months for intermediate and 9.1 months for subjects with poor risk. Conclusions: The results from this single-arm phase II study represent a near doubling of expected PFS and OS for unfavorable risk subjects treated with AGS-003 plus sunitinib. Updated survival and immunologic findings will be presented, as 8 of 21 subjects are still alive and continue to be followed. These results support the ongoing phase III ADAPT study, which is designed to validate these encouraging clinical and immunologic findings. Clinical trial information: NCT00678119.
MicroRNA as novel blood-based biomarkers in clear cell renal cell carcinoma.
Authors: Hakimi A. Ari , Jacobsen Anders , Mikkilineni Nina , Fiegoli Brandon , Blass Sara , Grigoryev Yevgeniy , Viale Agnes , Socci Nicholas D. , Voss Martin Henner , Motzer Robert John , Reuter Victor E. , Coleman Jonathan A. , Russo Paul , Hsieh James
Published: February 2017

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Background: MicroRNAs (miRNA) are short, non-coding RNAs involved in post-transcriptional gene regulation. Several reports have assessed their role as blood based biomarkers given their tissue and cancer-specific expression. Using an integrative approach we sequenced the miRNA transcriptome of the plasma of several clear cell renal cell carcinoma (ccRCC) patients both before and after surgery as well as several controls. Methods: We performed next generation miRNA sequencing (miRNAseq) on eight pairs (pre- and post-operative plasma samples) and four non-cancer controls to identify potential biomarker candidates. We further integrated our data with the miRNAseq tumor data from the Cancer Genome Atlas (TCGA) study to determine whether plasma miRNA levels are representative of tumor miRNA expression in ccRCC. Results: Overall, 930 unique miRNAs were detected, including 272 at greater than or equal to 10 read counts. There was a global shift of miRNA expression toward the non-cancer controls in the postoperative samples compared to preoperative. We further identified several stably expressed miRNAs across all samples and controls including miR-16, miR-191, and miR-103. We also identified several potential biomarker candidates by looking at differential expression both in terms of preoperative and postoperative status, as well as tumor vs. control including miR-378 and miR-660. Intriguingly, the plasma miRNA expression patterns showed no relationship to the tumor expression patterns using the TCGA samples. Conclusions: Plasma miRNA expression patterns are consistently altered in ccRCC and, following surgery, globally revert to the non-cancerous levels of the controls. Several biomarker candidates have been identified and a panel is undergoing validation in larger cohorts. Plasma miRNA levels do not appear to reflect tumor levels in ccRCC.
Randomized phase II trial of docetaxel (Doc) and prednisone (Pred) with or without AZD2171 (cediranib), in chemotherapy-naive, metastatic castrate-resistant prostate cancer (mCRPC) (NCI 7451).
Authors: Heath Elisabeth I. , Mannuel Heather Dorothy , Liu Glenn , Lara Primo , Monk J. P. , Flaig Thomas W. , Zurita Amado J. , Vaishampayan Ulka N. , Stella Philip J. , Smith Daryn W. , Dobson Kimberlee , Hussain Arif , Al-Janadi Anas , Ivy S. Percy , Heilbrun Lance K.
Published: February 2017

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Background: Cediranib + Doc were shown in a phase I trial to be feasible, with early evidence for efficacy in mCRPC patients (pts). A multi-center randomized Phase II screening trial of Cediranib+Doc+Pred (Arm A) vs. Doc+Pred (Arm B) was initiated in mCRPC pts. Methods: mCRPC pts with no prior chemotherapy were eligible. All received Doc at 75 mg/m2IV q 3 weeks and Pred 5 mg po bid. Cycle length was 21 days. Arm A pts also received Cediranib at 30 mg po daily. The primary endpoint was 6-month progression-free survival (PFS). We hypothesized 6-month PFS rates of 0.70 on Arm A and 0.50 on Arm B. Secondary endpoints included toxicity, PSA response, and RECIST response. Here we report the toxicity and PSA response data. Results: Of 58 pts enrolled, 57 were treated (29 Arm A, 28 Arm B). Median age = 68 years (range 51-84); 33% African-American, 63% Caucasian; median baseline PSA136 ng/mL (range 0.12 – 3,650); 57% had Gleason grade 8-10; and 40% had both bone/ visceral disease. Median nadir PSA was 10.5 ng/mL (range 0.10 – 1,484) in Arm A, and 25.9 ng/mL (range 0.00 – 2,076) in Arm B. Median number of cycles (range): Arm A = 9 (0 - 31); Arm B = 6.5 (1-39 ). 68% pts in Arm A required a dose reduction of at least one Cediranib dose level. Doc dose was reduced in 45% pts on Arm A and in 18% pts on Arm B. Primary grade 4 toxicity was neutropenia (11 [38%] pts A; 5 [18%] pts B), which prompted Cediranib dose reduction. Grade 3 toxicities included fatigue (9 (31%) A, 1 (4%) B); hypertension (8 (28%) A, 1 (4%) B); anemia (6 (21%) A, 2 (7%) B); neutropenia (4 (14%) A; 6 (21%) B); diarrhea (3 (10%) A, 1 (4%) B); deep vein thrombosis (2 (7%) A, 1 (4%) B); and pulmonary embolism (1 (3%) A). An amendment reduced Cediranib to 20 mg daily dose. PSA decrease ≥ 90% at nadir occurred for 13/29 = 45% on Arm A, and 6/28 = 21% on Arm B. PSA decrease ≥ 50% at nadir occurred for 19/29 = 66% on Arm A, and 17/28 = 61% on Arm B. Clinical partial response rates were 8/15 = 53% on Arm A and 3/9 = 33% on Arm B. Conclusions: The addition of Cediranib to Doc/Pred has increased toxicity but may be associated with higher rates of PSA response and clinical response in mCRPC patients. PFS results will be reported. Clinical trial information: NCT00527124.
Clinical evaluation of 2-(18F) fluoro-2 deoxy-D-glucose PET/ CT in hereditary leiomyomatosis and renal cell carcinoma.
Authors: Shuch Brian , Asher Kevin P. , Chen Clara , Lin Kelly , Bratslavsky Gennady , Linehan W. Marston , Srinivasan Ramaprasad
Published: February 2017

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Background: 2-(18F) fluoro-2 deoxy-D-glucose (FDG) PET/CT is a useful tool in the staging of malignancies. In patients with kidney cancer, the role of FDG is limited in those with clear-cell histology and remains to be evaluated with other subtypes. Kidney cancer associated with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is characterized by a defect in the Krebs cycle rendering these tumors highly dependent on aerobic glycolysis (the ‘Warburg effect’) with high glucose uptake to fulfill their energy requirements; we hypothesized that FDG PET/CT may have excellent sensitivity for staging in this condition. Methods: We retrospectively reviewed patients with HLRCC kidney cancer that underwent FDG PET/CT in conjunction with anatomic imaging at our institution. The ability of FDG PET/CT to detect malignant lesions (defined using pathologic or radiologic criteria) was evaluated. Results: A total of 30 patients underwent 42 PET /CTs. Conventional imaging identified a total of 107 lesions. Both patient and lesion-based analyses were performed. A total of 90 lesions, including ten renal lesions, were classified as malignant. 76 of 80 extra-renal lesions were correctly identified as malignant by PET/CT (sensitivity, 95%, CI 88-98%). In contrast, only 4 of 10 renal lesions were correctly identified as malignant (sensitivity, 40%, CI 17-69%). 11 of 12 histologically confirmed extra-renal lesions were PET avid (sensitivity, 92%, CI-64-98%). 10 of 12 (83%) benign lesions associated with HLRCC including uterine/cutaneous leiomyomas and adrenal nodules were PET avid. In a patient based analysis, all 18 patients with extra-renal spread of kidney cancer were correctly identified (sensitivity 100%, CI 82-100%). Conclusions: FDG PET/CT is a highly sensitive diagnostic modality for identifying metastatic kidney cancer associated with HLRCC. Prospective studies evaluating the utility of PET/CT imaging to characterize response to systemic therapy are currently underway.