bluuebunny/crossref_metadata_2025 huggingface dataset:
Cabazitaxel in patients with metastatic castrate-resistant prostate cancer previously treated with a docetaxel-containing regimen: A single U.K. cancer center's experience using Early Access Programme and Cancer Drugs Fund.
Authors: Kelly Claire L. S. , Hague Christina J. , Cornthwaite Stephanie A. , Birtle Alison J.
Published: February 2017

224

Background: The TROPIC Trial demonstrated improved overall survival in patients with mCRPC who progressed during or after treatment with docetaxel. The trial established cabazitaxel as a tolerable and viable second line treatment option in these patients. We report our experience with cabazitaxel in patients receiving treatment within the Early Access Programme (EAP) and via the Cancer Drugs Fund (CDF). Methods: Retrospective review of patients receiving cabazitaxel chemotherapy from 1st January 2011 to 1st January 2012. Chemotherapy administration was corroborated via the electronic prescribing system. Patient records provided documentation regarding disease response and treatment toxicities. For patients within the EAP, data was confirmed and supplemented via the Trials Office. Results: 22 patients were identified, of which 20 received cabazitaxel. 12 were treated within the EAP and 8 via the CDF. Median age was 68.5 years (59-83) within the EAP group and 70 years (52-78) within the CDF group, whilst median number of cycles was 6 (1-10) and 5.5 (1-8) respectively. 83.3% of EAP patients received full dose throughout, compared with 62.5% of the CDF patients. Primary GCSF was used in 91.6% of EAP patients and 75% of CDF patients, with secondary GCSF in 8.3% and 12.5% respectively. 3/20 patients had treatment discontinued due to progressive disease (after a minimum of 3 cycles). 13/20 patients had a positive biochemical and/or clinical response. 15/20 patients (Gleason score ≥ 8, 7 of 15) remain alive with a mean survival of 12.1 months (3.4-19.4). There were no treatment related deaths. Treatment related adverse events are shown in the Table. Conclusions: Our results are comparable with the TROPIC data, suggesting cabazitaxel offers demonstrable response rates and meaningful survival with an acceptable toxicity profile. [Table: see text]
Incidental prostate cancer in patients with radical cystectomy for bladder cancer.
Authors: Djaladat Hooman , Bruins Max H. , Skinner Eila C. , Miranda Gus , Cai Jie , Ahmadi Hamed , Daneshmand Siamak
Published: February 2017

225

Background: Radical cystectomy is the gold standard surgical treatment for invasive bladder cancer. Prostate adenocarcinoma is often found incidentally in the cystoprostatectomy specimen. The clinical significance of this type of cancer has not been well characterized. We reviewed the cohort of male patients with bladder cancer who underwent radical cystectomy and found to have incidental prostate adenocarcinoma. Methods: 1,964 patients with primary transitional cell carcinoma of bladder underwent radical cystectomy between 1971 and 2008 with a median follow-up of 12.1 yrs (0.1-36) at USC. 1553 of them were male (79%) and 559 (36%) had incidental pathologic prostate adenocarcinoma (PC-group). Prostate and bladder cancer characteristics, recurrence and overall survival (OS) in the cohort of PC-group are reviewed. Results: Median age in the PC-group was 69 yo (35-92). The incidental PC was organ confined (OC) in 527 patients (94%). 32 (6%) had non-OC prostate cancer, treated by adjuvant radiation (5), hormone ablation (3) with a median follow-up of 3.9 yrs (0.1-16). Median pre-op PSA was 1.66 (0.01-83) in PC-group and 1.31 (0.01-33.2) in non-PC group. Gleason score was ≤ 6 in 458 (82%), 7 in 78 (14%) and ≥ 8 in 12 (2%) cases. Reviewing bladder cancer in the PC vs. non-PC group, 84 and 83% had high-grade cancer, 63 and 58% had associated CIS, 41 and 36% had multifocal disease and 29 and 27% had LVI respectively (P > 0.05). Incidental PC did not have significant effect on recurrence (P=0.3) and OS (P=0.4) after cystectomy for bladder urothelial cancer. No patient died of PC. 5-year OS rate was 60 ± 2% in both PC and non-PC groups. 10-year OS rate was also comparable at 42 ± 2% in PC and 44 ± 2% in non-PC-group. Conclusions: Incidental prostate adenocarcinoma is reported in more than one third of patients who undergo radical cystectomy for bladder cancer. It is organ confined in most of the cases and has no correlation with bladder cancer stage. Outcome of patients with incidental prostate adenocarcinoma at the time of radical cystectomy relies exclusively on the bladder cancer.
Characteristics and outcomes of elderly patients with systemic prostate cancer (PCa) treated with peripheral androgen blockade (PAB).
Authors: Kilari Deepak , Pandya Chintan , Fung Chunkit , Sahasrabudhe Deepak M. , Brasacchio Ralph Anthony , Messing Edward M. , Sievert Lynn , Mohile Supriya Gupta
Published: February 2017

226

Background: The side effect profile of androgen deprivation (ADT) warrants exploration of alternative options for elderly patients with systemic PCa. In phase 2 trials, the combination of anti-androgen and 5 alpha reductase inhibitor (PAB) demonstrated efficacy with low morbidity in the fit population. The objective of this retrospective study was to evaluate the characteristics and outcomes of elderly patients treated with PAB in lieu of ADT. Methods: We reviewed records of patients ≥65 yrs who received PAB in the geriatric oncology program from 2007-2012. Patients were evaluated with a validated comprehensive geriatric assessment (CGA) prior to PAB. Descriptive statistics were used to evaluate PAB type, characteristics of patients and their cancers, as well as PCa –specific and overall outcomes Results: Twenty-one asymptomatic PCa patients received PAB (bicalutamide alone-57%, or bicalutamide and finasteride-43%) in lieu of ADT. Indications for treatment were metastatic disease (53%) or biochemical relapse with PSA doubling time≤ 6 months (47%). Median age at the initiation of PAB was 86 years (range 65-94) and 76 % had ECOG PS≥ 2. By CGA, 57 % were vulnerable, 33% frail and 10% fit. 76% had contraindications for standard ADT (e.g., dementia, falls, etc.); the rest declined ADT due to concern about adverse effects (AE). The median PSA at PAB initiation was 14.78 (range 0.9-165.8). PSA nadir (i.e. 1st of 3 consecutive PSA levels where values were within 90%) was reached in 57% of patients at the time of analysis with the remainder demonstrating a continuing decline. Median PSA at nadir was 0.86(range 0.02-11.24). The median follow up time was 11 months (range 1-30). The median time to PSA nadir was 5 months; (range 1-19). PSA nadir was maintained for median of 10.5 months (range 3-24).The median % decline in PSA was 92 % (range 13-99%).No patients reported AE or required treatment interruption. Two fit patients of the 4 who progressed on PAB responded to subsequent ADT. Conclusions: These results provide evidence that PAB is feasible, active and well tolerated in patients for whom ADT may be contraindicated. A prospective phase II study for an older vulnerable patient population is planned.
Postdocetaxel treatment for castrate-resistant prostate cancer: The sequential use of abiraterone and cabazitaxe.
Authors: Fackrell David Gareth , James Nicholas David , Ford Daniel
Published: February 2017

234

Background: Large phase III trials have shown both abiraterone (Abi) and cabazitaxel (Cbz) to have a survival benefit in patients with metastatic castrate resistant prostate cancer (mCRPC). They are now used routinely throughout the UK in this setting. The mechanisms of resistance of these drugs remain unclear and therefore, their sequential use is less recognised. We present data from patients who have been exposed to both therapies. Methods: In this retrospective study, we searched our own pharmacy databases to identify all patients that had been exposed to both Abi and Cbz. All patients were treated between April 2009 and October 2012. A total of 21 patients were reviewed and clinical data was collected. SPSS software was used to create Kaplan Meier curves. Results: 17 of the 21 patients received Abi before Caz. Median progression free survival for patients on the sequential regimes was 16.9 months (95% Confidence interval: 10.5-23.3). Reviewing the drugs individually found progression free survival was 5.1 months (4.4-6.0 months) with Abi and 7.1 months (5.1-9.1) with Cbz. Conclusions: In a select group of patients who are fit enough to receive both drugs, superior progression free survival is seen than can be expected on one drug alone. The data compares favourably to that seen in the TROPIC study where time to progression on Cbz was 2.8 months. Furthermore, lack of response to one drug did not preclude worthwhile response to the other agent. These findings are consistent with the drugs having separate mechanisms. At this stage the series is not mature enough to draw conclusions on survival benefit. An updated series, involving larger patient numbers, will be presented at the meeting.
Age at diagnosis and treatment for prostate cancer (PC) in two distinct integrated health care systems.
Authors: Cross Deanna S. , Islam Rezwan , Jacobson Crystal , Ritter Mark A. , Mullins C. Daniel , Nallu Anitha , Hussain Arif
Published: February 2017

240

Background: An older age at diagnosis may affect the stage at which PC is diagnosed as well as the treatment decisions made by the providers and/or the patients. Here we compare two geographically and ethnically distinct PC cohorts to determine whether age affects treatment decisions. Methods: Populations- Marshfield Clinic (MC): individuals were included in the cohort if they were diagnosed with PC between January, 2005 and December, 2010 and enrolled in a population based biorepository. Veterans Affairs (VA):– cohort included individuals diagnosed with PC between January, 2010 and December, 2010 within the Baltimore VA Medical Center (BVAMC). Retrospective chart review using electronic abstraction from the EMR was performed at each site. Statistical analysis was performed using the chi-square test for categorical variables or Fisher's exact test if the cell size was under 5. Results: Compared to the MC population, the VA population had a younger median age at diagnosis (63 vs. 68), more African American men (63% vs. 0.5%) and exhibited higher median PSA at diagnosis (7.92 vs 5.78 ng/dL). Seventy nine percent of VA and 87% of MCpatientswere stage 1 or 2 at diagnosis (p=0.03). Stage was not associated with older age (age >/= 75) in either population. Individuals in the VA system were more likely to receive radiation (48% vs. 16%) and less likely to receive surgery than the MC population (18% vs. 59%). There were also several similarities in treatment decisions amongst these different populations. For instance, individuals with an older age (>/= 75 vs. other age categories) at diagnosis were more likely to receive non-aggressive treatments such as hormonal therapy or no treatment (>67% vs. <15% p=0.0001). Because the stage at diagnosis may affect treatment decisions, we also investigated treatments for stage 2 disease; in this category, individuals >/= 75 were still more likely to receive less aggressive treatment at both MC and BVAMC (>29% versus <3.4%, p=0.0001). Conclusions: This initial analysis suggests that individuals with an older age at diagnosis are more likely to receive non-aggressive treatment even when the stage of disease is the same as that of a younger individual across two distinct patient populations.
Novel definition of BCG failure to enhance recruitment into clinical trials.
Authors: Willis Daniel Levi , Lee Eugene K. , Dickstein Rian J. , Anderson Roosevelt , Pretzsch Shanna M. , Nogueras-Gonzalez Graciela M. , Grossman H. Barton , Dinney Colin P.N. , Kamat Ashish M.
Published: February 2017

246

Background: Designing clinical trials after BCG failure can be problematic without a reasonable control arm. Thus, there is a need for early identification of BCG failure relevant to clinical trial design which allows one arm to continue on BCG. Here we present a definition of BCG failure based on FISH profile at 6th week of induction BCG that would facilitate such trials. Methods: The definition presented is based on findings from our IRB-approved, prospective clinical trial where Urovysion FISH assays were performed serially during the normal course of BCG therapy (SWOG protocol) at various time points (pre-BCG, 6 weeks, 3 and 6 mo.). Herein we incorporated the FISH analysis at 6 weeks in patients with a negative 3 month cystoscopy and correlated the result with recurrence and progression rates at 24 months. A novel definition of BCG failure was proposed by focusing the analysis on 84 patients with high grade disease (cTa: 33, cT1: 44, cTis 7). The 6 week FISH was selected as this would allow the control arm to proceed with BCG maintenance in a timely fashion, taking into account the time required for obtaining FISH results, registration of patients, and randomization. Results: Of the 36 patients with a positive FISH at 6 weeks (and no tumor at 3 months), 17 recurred (PPV = 47%) and 11 progressed (PPV = 31%), while among those with a negative FISH, 5 recurred (NPV = 90%) and 4 progressed (NPV = 92%) (p<0.001). Kaplan Meier estimates of recurrence free survival with a positive 6 week FISH were 67% and 52%, and for progression free survival were 75% and 52%, at 1 and 2 years respectively. Therefore, if patients with a positive 6 week FISH (and negative 3 month cystoscopy) were considered as "molecular" BCG failures, a prospective clinical trial with 101 patients in the control (i.e. BCG maintenance) and experimental arms to detect a 20% difference in recurrence rates (α=0.05) with 80% power. Conclusions: Using the FISH status of patients at the 6 week interval on BCG therapy would allow a clinical trial design that incorporates one arm with continued BCG therapy, while enriching for events of interest, namely recurrence and progression. This would allow meaningful comparisons while negating any ethical concerns regarding a lack of “standard treatment” in BCG failure studies.
The role of post-cystectomy radiation in treatment of squamous cell carcinoma of the bladder: A combined retrospective analysis.
Authors: Li Baoqing , Stessin Alexander Michael , Nori Dattatreyudu
Published: February 2017

259

Background: Squamous cell carcinoma (SCC) is the most common nonurothelial histology in bladder cancers. Given the high locoregional recurrence as the primary cause of death, radiation therapy (RT) is often recommended in the post-operative setting. Large-scale randomized trials that are dedicated to bladder SCC would be difficult to accrue to adequate numbers. Therefore, we utilized the Surveillance, Epidemiology, and End Results (SEER) database. Methods: The SEER (1998-2007) was queried for patients with muscle-invasive (stage II-IV) squamous cell carcinoma of the urinary bladder who underwent complete cystectomy. Kaplan-Meier survival analysis and Cox regressions were used to assess survival outcomes. Additionally, records were reviewed for patients treated at New York Presbyterian Hospital-Weill Cornell Medical College (NYP-WCMC) between 1991 and 2010. Results: A total of 331 patients from the SEER were included in the analysis; Majority were received cystectomy alone (n=297), while 10% (n=34) received post-operative RT. Factors associated with post-operative RT were younger age (p=0.03) and more advanced stage at diagnosis (p<0.001). Median survival was 40 months for patients treated with surgery alone and 18 months for post-operative RT (p<0.05). In the institutional record review, 17 patients underwent cystectomy; of these, 5 received post-cystectomy RT. Those who underwent post-operative RT had better performance status (80% vs 25%) and a higher rate of positive surgical margins (67% vs 20%). Median survival was 38 months for patients treated with surgery alone and 22 months for post-op RT. Conclusions: RT has been employed as a post-operative treatment for some patients with muscle-invasive SCC of the urinary bladder. Younger age, better performance status, advanced stage, and positive margins may prompt the use of post-operative RT. However, both SEER and single institution retrospective analyses failed to show any survival advantage associated with the use of post-operative therapy. Further studies are needed to identify any subsets of patients with bladder SCC who may benefit from post-cystectomy radiation.
Augmentation of urothelial cancer cells' response to gemcitabine and cisplatin by a Smac mimetic.
Authors: Lee Eugene K. , Gerald Jinesh , Laing Naomi , Choi Woonyoung , McConkey David James , Kamat Ashish M.
Published: February 2017

261

Background: Cisplatin-based chemotherapy is considered the gold standard for patients with advanced bladder cancer. Despite initial response, many patients will relapse; therefore, novel salvage treatment strategies are desperately needed. Herein, we studied a mechanism based treatment combination using a Smac mimetic with standard chemotherapy. Methods: A panel of 10 urothelial cancer cell lines was exposed to gemcitabine and cisplatin, a Smac mimetic, and the combination. Sensitivity was determined using a DNA fragmentation assay. Constitutive expression of select members of the IAP family (XIAP, cIAP-1, cIAP-2, Survivin), the BCL family (BCL-2, BCLXL, BAX) and Smac were evaluated by gene expression profiling and Western blotting. Changes in protein expression under treatment conditions were examined using Western blotting. TNF-a blocking antibody was used to explore the contribution of autocrine TNF-a in cellular death. Lastly, a mouse model of bladder cancer was used to determine the effectiveness of the drug combination. Results: UMUC-3, UMUC-13 and RT4v6 were considered sensitive to the combination of gemcitabine and cisplatin based on an apoptosis assay. Three additional cell lines were sensitized to gemcitabine and cisplatin with the addition of the Smac mimetic (UMUC-6, UMUC-12, UMUC-18). The constitutive RNA and protein expression of SMAC, select members of the IAP family, and members of the BCL family did not correlate to drug sensitivity. Autocrine TNF-a demonstrated a partial contribution to cell death in UMUC-12. In an in vivo mouse model, the Smac mimetic alone and in combination with gemcitabine and cisplatin resulted in decreased tumor volume and increased apoptosis compared to the chemotherapy treatment alone. The combination resulted in decreased cellular proliferation and decreased microvessel density. Conclusions: Smac mimetic is able to augment the activity of gemcitabine and cisplatin based chemotherapy in vitro and in vivo. This may be an effective treatment strategy in patients with urothelial carcinoma and warrants further investigation.
A novel phase I trial design featuring a two-dimensional dose-finding algorithm optimizing the dose of gemcitabine and doxorubicin with bortezomib in metastatic urothelial carcinoma (UC).
Authors: Siefker-Radtke Arlene O. , Wen Sijin , Shen Yu , Stigall Kristi , McConkey David James , Millikan Randall E.
Published: February 2017

263

Background: Preclinical studies suggested that bortezomib (B) enhanced the activity of gemcitabine and doxorubicin (GA) in UC; thus we sought to define possible combinations of bortezomib with this doublet. We employed a novel phase I trial design systematically exploring doses in 2 dimensions. The method estimates an isotoxic curve allowing not only a combination with approximately equal (with respect to single component MTD) contributions of the two components to be found, but also combinations emphasizing one component or the other. Methods: Since 11/06, 74 patients with previously treated metastatic cancer were enrolled (70 UC, 3 prostate, 1 renal). GA was treated as a single component and given in a fixed ratio to a maximum of 900 and 50 mg/m2, and B to a maximal dose of 1.6 mg/m2 IV, with dosing every 14 days. After determining the MTD along the diagonal, we then decreased the dose of B, increasing GA, and vice versa, exploring doses along an isotoxic curve aiming for ≤ 30% dose limiting toxicity (DLT) in cycle 1. The objective response rate (ORR) includes PR or CR, and excludes SD. Results: The MTD along the diagonal for GAB was 756, 42, and 1.4 mg/m2, respectively. Doses maximizing the GA (900, 50) required reduction of B to 1.2 mg/m2. Likewise, doses maximizing B (1.6) required reduction of GA to 559 and 33 mg/m2. The most common DLT were thrombocytopenia 14%, neutropenic fever 5%, and mucositis 1%. There was minimal activity at the on-diagonal MTD with an ORR 1/10. Of the tolerable doses along the isotoxic curve, the greatest activity was seen when maximizing B (1.5-1.6 mg/m2, ORR 7/12 (58%)). The ORR when maximizing GA was 4/10. The most frequent ≥ G3 toxicities include: thrombocytopenia (26%), neutropenia (26%), anemia (24%), fatigue (8%), and neutropenic fever or infection (12%). Treatment was tolerable in poor renal function; 36 patients (49%) had a GFR < 50 ml/min. Conclusions: The combination of GAB has promising activity at doses maximizing proteosome inhibition, despite relatively low doses of GA. Traditional phase I design dosing to the MTD "along the diagonal" would have lead to the incorrect conclusion that there was minimal activity. Clinical trial information: NCT00479128.
Sequential chemotherapy with gemcitabine plus carboplatin followed by additional docetaxel for older patients with advanced bladder cancer.
Authors: Yoneyama Takahiro , Sugiyama Naoki , Suzuki Yuuichirou , Okamoto Akiko , Yamamoto Hayato , Imai Atsushi , Hatakeyama Shingo , Hashimoto Yasuhiro , Koie Takuya , Ohyama Chikara
Published: February 2017

266

Background: We retrospectively evaluated the feasibility and effectiveness of a sequential chemotherapy wihtout cisplatin for the patients 70 years or older with advanced bladder cancer. Methods: Fourty-seven patients with advanced bladder cancer (33 men and 14 women) with the age of 70 years or older were enrolled. They were treated at our clinic between August 2004 and December 2010. Their average age was 80.0 years old (70–86), average Ccr was 37.0 ml/min (14.5–113.0), and an average follow-up period was 17.4 months (10–55). There were 15 recurrent cases after radical surgery and 32 inoperable cases (T4b or metastatic). As for prior chemotherapy, 6 underwent MVAC therapy. The therapeutic regimen consisted of 2 lines: gemcitabine/carboplatin (GCarbo) therapy as the first line, with two courses as a set; GCarbo/docetaxel (GCarboD) therapy as the second line if the response in the first line was insufficient. If this regimen was effective, another 2 courses of GCarbo was performed. Treatment efficacy was checked every 2 course according to the RECIST version 1.1. Results: Of the 47 subjects who had undergone the GCarbo therapy, the response rate was 38.3% (CR+PR) with 5 and 12 subjects exhibiting a complete response (CR) and a partial response (PR), respectively; the average response duration was 15.7 months (2–42). Of the subjects with MVAC resistance, 1 exhibited a CR and 3 showed a PR. The response rates of 9 instances of GCarboD was 11.1%; the overall median survival was 15.0 months throughout the sequential chemotherapy. Adverse events (AE) of grade 3 or higher occurred in 30 of those who had undergone the GCarbo therapy (63.8%). Conclusions: Although the present study is small and preliminary, the present sequential chemotherapy is safe and active for advanced bladder cancer of the patients seventy years or older. GCarbo regimen achieved acceptable response rate (38.3%) in advanced bladder cancer including M-VAC-resistant case. The median overall survival of 15 months is acceptable when average age of 80 year for the subjects is took into consideration. However, GCarboD had limited effectiveness for non-responder of GCarbo.
Different effects of sunitinib, sorafenib, and pazopanib on inducing cancer cell death: The role of autophagy.
Authors: Santoni Matteo , Amantini Consuelo , Morelli Maria Beatrice , Farfariello Valerio , Nabissi Massimo , Liberati Sonia , Bonfili Laura , Mozzicafreddo Matteo , Eleuteri Anna Maria , Burattini Luciano , Berardi Rossana , Cascinu Stefano , Santoni Giorgio
Published: February 2017

270

Background: Tyrosine kinase inhibitors (TKI), such as sunitinib, sorafenib and pazopanib, have replaced immunotherapy as the standard of care for metastatic renal cell carcinoma (mRCC). However, their use in sequential or combined strategies is limited by the lack of evidences on the ability of TKIs to induce cell death in cancer cells. Aim of our study was to evaluate the different mechanisms responsible of the cytotoxic effects induced in vitro by µM doses of sunitinib, sorafenib and pazopanib in 5637 and J82 bladder cancer (BC) cell lines. Methods: The viability of BC cell lines were tested by MTT assay. Autophagy was evaluated by western blot analysis with the anti-LC3 and anti-p62 antibodies, acridine orange staining and cytofluorimetric analysis. Necrosis and apoptosis, (ΔΨm) dissipation and ROS generation were determined by Annexin-V/PI, JC-1 and DCFDA staining, respectively and cytofluorimetric analysis. The cathepsin B activity was evaluated by ELISA. Finally, by mRNA estraction and RT-PCR array the pazopanib-induced gene profile expression was evaluated. Results: We found that treatment of 5637 and J82 BC cells with the three TKI agents markedly reduced cell viability. Treatment for 24 h with sunitinib and sorafenib at 20 µM dose, triggers an incomplete autophagy of BC cells. In addition, inhibition of autophagy induced by sunitinib and sorafenib triggers cell death of BC cells. Thus, sunitinib by imparing the cathepsin B activity induces lysosomal-dependent necrosis. Similarly, sorafenib by defective lysosomial degradation triggers ROS- and mitochondrial-dependent apoptosis. As regard to pazopanib, we first demonstrate that treatment of BC cells for 72 hrs (20 µM) induces autophagic Type II cell death, which was markedly reversed in a dose-dependent manner by 3MA and chloroquine autophagic inhibitors. Finally, pazopanib upregulates the mRNA expression of α-glucosidase (GAA) and TP73 belonging to the p53 tumor suppressor genes. Conclusions: Overall, our results showing different TKI-induced cell death mechanisms provide the rationale for the sequential use of these agents and the biological basis for novel molecularly targeted approaches.
Long-term efficacy and safety outcomes of the modified (simplified) combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) as front-line therapy for unresectable or metastatic urothelial cancer (UC).
Authors: Necchi Andrea , Mariani Luigi , Giannatempo Patrizia , Raggi Daniele , Farè Elena , Pizzocaro Giorgio , Piva Luigi , Biasoni Davide , Torelli Tullio , Catanzaro Mario , Stagni Silvia , Milani Angelo , Gianni Alessandro M. , De Braud Filippo G. , Nicolai Nicola , Salvioni Roberto
Published: February 2017

284

Background: MVAC and cisplatin-gemcitabine (CG) are the established standard of care for untreated patients (pts) with locally advanced-metastatic UC. CG is the preferred choice in most cases due to the better toxicity profile. Modifying MVAC by reducing side-effects may have the potential to improve efficacy. Methods: Data relative to unresectable T/N+/M+ pts entering sequential single-institution trials were collected. Chronologically, these changes to classic MVAC were provided: deletion of day 22 and administration of 25 mg/m2CDDP d2-5 (modified MVAC [mMVAC]); deletion of day 22 only, and deletion of days 15 and 22 in a 3-week schedule (simplified [s]MVAC1 and 2). 4-6 cycles were provided. Multivariable analysis was undertaken for recognized clinical variables. ITT analysis was applied. Results: From 09/86 to 04/12, 157 pts were treated (25 mMVAC, 72 sMVAC1, 60 sMVAC2). 84% had a bladder primary, 70% had distant metastases, 53% and 36% had nodal and visceral mets, respectively. 43.9% had a Bajorin score 1-2. 65.8% attained a complete (19.1%) or partial response (46.7%), 24.3% a stable disease, with no difference among regimens. After a median follow up of 87 mos (IQR 37-161), median (95% CI) PFS was 10.2 mos (8.4-10.8) and median OS was 19.5 mos (16.3-24.1). 2yr (95% CI) PFS and 5yr OS were 30.9% (23.8-40.1) and 25.3% (18.8-34.1). Responses were mainly seen in nodal mets (OR: 2.48, 95%CI, 1.12-5.54). Presence of visceral (HR: 2.42, 95%CI, 1.37-4.30), nodal mets (HR: 1.70, 95%CI, 1.07-2.69) and mMVAC regimen (HR: 1.73, 95%CI, 1.02-2.92) were negative prognostic factors for OS. G3-4 toxicities were similar among regimens and were 36% neutropenia, 14% thrombocytopenia, 12% anemia, 10% mucositis, and 4% renal toxicity. 2 pts died for toxicity. Conclusions: Simplifying MVAC schedule may result in improved activity and efficacy while reducing toxicity. Though retrospective, the combined results of MVAC modification would claim a benefit over either classic/dose-dense MVAC or CG in terms of efficacy and safety. A reappraisal of the upfront management of advanced/metastatic UC is warranted.
High-risk prostate cancer treated with pelvic radiotherapy and 36 versus 18 months of androgen blockade: Results of a phase III randomized study.
Authors: Nabid Abdenour , Carrier Nathalie , Martin André-Guy , Bahary Jean-Paul , Souhami Luis , Duclos Marie , Vincent François , Vass Sylvie , Bahoric Boris , Archambault Robert , Lemaire Céline
Published: February 2017

3

Background: Radiotherapy (RT) and long term androgen blockade (AB) is standard treatment for patients with high risk prostate cancer. However, the optimal duration of AB is not yet defined. The purpose of this randomized study was to compare outcomes between 36 vs. 18 months of AB in high risk prostate cancer treated with RT (PCS IV trial, Clinical Trials.gov, #NCT00223171). Methods: PCS IV randomized patients with node negative high risk prostate cancer (T3-4, PSA >20 ng/ml or Gleason score >7), to pelvic RT (whole pelvis 44 Gy/4 ½ weeks, prostate 70 Gy/7 weeks) and 36 (arm 1) vs. 18 months (arm 2) of AB (neo adjuvant, concomitant, adjuvant). AB consisted of bicalutamide 50 mg for one month plus goserelin 10.8 mg every three months for 36 vs. 18 months. Overall survival was the primary end point. Overall and cancer specific survival rates were compared between arms with Kaplan-Meier log rank test and Cox regression. Results: From October 2000 to January 2008, 310 patients were randomized to arm 1 and 320 to arm 2. Patients’ characteristics were well balanced between the two arms (median age 71 years, median PSA 16 ng/ml, median Gleason score 8). Most patients had T2-3 disease. At a median follow-up of 77 months, 71/310 patients (22.9%) in arm 1 and 76/320 (23.8%) in arm 2 had died (p=0.802). Overall, 116 patients died of causes other than prostate cancer. Overall and cancer specific survival hazard ratios were 1.15 (0.83-1.59), p=0.398 and 1.13 (0.61-2.08), p=0.153, respectively. 5 year overall and disease specific survival rates were 92.1% (89.1-95.1) vs. 86.8% (83.0-90.6), p=0.052 and 97.6% (95.9-99.4) vs. 96.4% (94.2-98.6), p=0.473 and 10 year overall and disease specific survival rates were 63.6% (55.7-71.5) vs. 63.2% (54.7-71.7), p=0.429 and 87.2% (81.0-93.3) vs. 87.2% (80.9-93.6), p=0.838 for arm 1 and arm 2, respectively. There were no significant differences in the rates of biochemical, regional or distant failure between arms. Conclusions: Our study shows that long term AB can be safely reduced from 36 to 18 months without compromising outcomes. Analysis of treatment impact on quality of life is now under review. Source of Funding: AstraZeneca Pharmaceuticals Grant. Clinical trial information: Clinical Trials.gov, #NCT00223171.
A comparison of toxicity of gemcitabine versus platinum-based combined chemoradiation for muscle-invasive bladder cancer: The Memorial Sloan-Kettering experience.
Authors: Baliga Sujith , Pei Xin , Bajorin Dean F. , Rosenberg Jonathan E. , Bochner Bernard , Kollmeier Marisa
Published: February 2017

313

Background: The optimal radiosensitizer for chemoradiation therapy for bladder cancer is unknown. We compared toxicities of concurrent platinum (plat) vs gemcitabine (gem) in this setting. Methods: 88 patients with muscle invasive bladder cancer (MIBC) who underwent concurrent platinum (n=26) or gemcitabine (n=62) chemotherapy with definitive external beam radiotherapy (median dose= 64.8Gy) were included in this analysis. Gem was delivered biweekly and platinum-based (cisplatin or carboplatin) chemotherapy given weekly or every 3 weeks. Treatment interruptions, cycle delays, and dose reductions were recorded. Acute (<90 days) and late (≥90 days) toxicity was graded using CTCAE v4.0. Chi-square and fisher’s exact tests were used to compare groups with respect to stage, nodal status, tumor size, baseline urinary medication and Charlson co-morbidity index (CCMI). Results: Median follow-up was 18.5 mos. Mean age was 77 years (range 35-91). Gem patients were older (76 vs 63 years; p<0.01) and had higher CCMI (p<0.01). There were no significant differences in treatment interruption (8% vs 4%; p=0.67), cycle delays (52% vs 36%; p=0.24) or dose reductions (27% vs 12%; p=0.16) in the gem vs plat cohorts respectively. Hematologic toxicity was the most common reason in both groups. Acute and late grade ≥2 GU toxicity in the gem and plat cohorts were 30% vs 8% (p=0.03) and 8% vs 8%, respectively. More gem patients were on a baseline urinary medication (21% v 8%; p=0.22). Six patients developed urinary incontinence (all in gem cohort). One patient in the plat cohort developed late grade 3 hemorrhagic cystitis. Acute and late grade ≥2 GI toxicity in the gem and plat cohorts were 16% vs 12% (p=0.75) and 4% vs 3% (p=1), respectively. 2 patients (one in each cohort) developed acute grade 3 GI toxicity. Conclusions: Chemoradiation for MIBC with gemcitabine or platinum-based chemotherapy is generally well tolerated. In our series, despite older age and higher CCMI in the gem cohort, most (>90%) completed treatment. Higher acute GU toxicity was noted in the gem cohort. Late grade 3 GU/GI toxicity was low and comparable amongst the two radiosensitizers.
Prediction of relapse in stage I nonseminomatous germ cell tumors (NSGCT) by CXCL12: Results from the MRC TE08 and TE22 clinical trials.
Authors: Gilbert Duncan Charles , Thway Khin , Chandler Ian , Al-Saadi Reem , Gabe Rhian , Stenning Sally P. , Shipley Janet , Huddart Robert Anthony
Published: February 2017

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Background: Stage I NSGCT harbor occult metastatic disease in up to 50% of patients and undergo surveillance with chemotherapy at relapse or adjuvant treatment with excellent survival but concern around subsequent toxicity. Better prediction of relapse would minimize exposure to unnecessary treatments. Previous data suggested CXCL12 aided assessment of relapse risk (Gilbert DC, et al. J Pathol. 2009 Jan;217:94-102). MRC TE08 (Rustin GJ, et al. J Clin Oncol. 2007 Apr 10;25:1310-1315) and TE22 (Huddart RA, et al. J Clin Oncol. 2007 Jul 20;25:3090-3095) were clinical trials incorporating surveillance in stage I NSGCT. Methods: Tumor samples from patients enrolled in TE08 and TE22 were obtained with ethical approval and subjected to immunohistochemical staining for CXCL12. These were scored and CXCL12 analysed as a prognostic factor for relapse independently of vascular invasion (VI - the only currently validated marker). Results: Samples were obtained from 182/466 eligible patients. The 2-year relapse-free rate (RFR) was 76.4%. In CXCL12 moderate/strong cases this was 80.1% (95% CI 73.4-86.8). In CXCL12 absent/weak cases (<1% cells staining moderately or strongly) this was 64.9% (49.6-80.2); hazard ratio 0.54 (95% CI 0.28-1.04). CXCL12 intensity was independently prognostic, p=0.006 (logrank test stratified by VI). Absent/weak CXCL12 expression was significantly associated with embryonal histology (p=0.001). In multivariate analysis including clinical and pathological features, only CXCL12 (HR 0.43, 95%CI 0.22-0.83) and VI (HR 4.77, 95%CI 2.49-9.13) were predictive of relapse. Conclusions: CXCL12 intensity is prognostic for relapse independently of VI. This additional prognostic information can identify groups at very low and very high risk of relapse with potential clinical utility. Acknowledgements: Supported by MRC Biomarkers Grant G0801477 and the NCRI Testis Cancer Clinical Studies Group. [Table: see text]
Postchemotherapy retroperitoneal lymph node dissection for advanced germ cell tumors at a Japanese single high-volume center.
Authors: Nakamura Terukazu , Kimura Yasunori , Ueda Takashi , Naya Yoshio , Hongo Fumiya , Miki Tsuneharu
Published: February 2017

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Background: Post chemotherapy lymph node dissection (PCRPLND) plays important role in the management of advanced germ cell tumors (GCTs). Guidelines recommend performing PCRPLND for advanced GCT with tumor marker normalization. The aim of this study is to assess efficacy and preserve antegrade ejaculation at Japanese single high volume center. Methods: One hundred and eleven patients who had PCRPLND at Kyoto Prefectural University of Medicine between June 1998 and August 2011 were studied. Five cases of desperation RPLND and 6 cases of laparoscopic RPLND were also included. Results: Median age was 30 years old (17-68y.o.). Seminoma was 11 cases and nonseminoma was 100 cases at primary site. Good, intermediate and poor prognosis group of International Germ Cell Cancer classification was 48, 35 and 20 cases, respectively. Seventy-four cases were treated after induction chemotherapy and 41 cases were done after salvage chemotherapy. median operation time was 590 min. and median blood loss was 1650ml. Nerve-sparing procedure were performed for 90 cases. Antegrade ejaculation was preserved in 83.5% of this cohort. Especially, antegrade ejaculation was preserved in 93.3% of the patients with bilateral nerve sparing. Necrosi/fibrosis, teratoma only and viable cancer were detected in 54.4%, 32.5% and 13.1%, respectively. Additional procedure such as nephrectomy was performed in 12 cases. Five-year overall survival was 95.1%. In the desperation group, only one case is alive without disease. Conclusions: The results of PCRPLND at high volume center could be satisfied and preservation of antegrade ejaculation could be obtained. On the other hand, indication of desperation RPLND had to be carefully considered.
Treatment patterns for patients with localized (T1-T2) penile squamous cell carcinoma in the United States.
Authors: Barbosa Brittney Diane , Hendrix Laura H. , Pearlstein Kevin Alexander , Chen Ronald C.
Published: February 2017

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Background: The standard treatment for patients with localized penile squamous cell carcinoma is penectomy, which is associated with high psychosocial morbidity. Organ preservation using radiation therapy is an alternative. To our knowledge, this is the first population-based patterns of care study in this disease for a modern cohort of men. Methods: Caucasian (CA, N=1,270) and African American (AA, N=139) patients diagnosed with localized cancer from 2000-2009 were included from the Surveillance, Epidemiology and End Results (SEER) database. Treatments were categorized into ablative therapies (e.g. laser, electrocautery), surgical resection, or radiation therapy (including external beam and brachytherapy). Multivariate logistic regression assessed factors associated with receipt of radiation therapy as primary treatment. Results: 57% of patients were married. The vast majority of patients receive surgical resection, with about 1% receiving primary radiation therapy (Table). Patterns of care were not significantly different among AA and CA patients (p=.95). Multivariable analysis including diagnosis year, marital status, age, race and SEER region did not show any covariate significantly associated with receipt of primary radiation treatment. Conclusions: Surgical resection is the predominant treatment for patients with localized penile cancer in the United States, with very few patients receiving primary radiation therapy. [Table: see text]
Incidence of testicular cancer in the United States from 1992 to 2009.
Authors: Nigam Manas , Aschebrook-Kilfoy Brisa , Shikanov Sergey , Eggener Scott E.
Published: February 2017

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Background: The incidence of testicular cancer (TC) increased in the US through 2003. However, little is known about these trends after 2003. We sought to determine trends in TC incidence based on race, ethnicity and tumor characteristics. Methods: TC incidence and tumor characteristic data from 1992-2009 were extracted from the Surveillance, Epidemiology, and End Results-13 (SEER) registry. Trends were determined using JoinPoint. Results: TC incidence in the US increased from 1992 (5.7/100,000) to 2009 (6.8/100,000) with annual percentage change (APC) of 1.1% (p < 0.001). TC rates were highest in non-Hispanic white men (1992: 7.5/100,000; 2009: 8.6/1000) followed by Hispanic men (1992: 4.0/100,000; 2009: 6.3/100,000) and lowest among non-Hispanic black men (1992: 0.7/100,000; 2009: 1.7/100,000). Significantly increasing incidence rates were observed in non-Hispanic white men (1.2%, p < 0.001) but most prominently among Hispanics, especially from 2002-2009 (5.6%, p < 0.01). A significant increase was observed for localized TC (1.21%, p < 0.001) and metastatic TC (1.43%, p < 0.01). Increased incidence occurred in localized tumors for non-Hispanic white men (1.56%, p <0.001), while Hispanic men experienced an increase in localized (2.6%, p < 0.001), regionalized (16.5% from 2002-09, p < 0.01), and distant (2.6%, p < 0.01) disease. Conclusions: Through 2009, testicular cancer incidence continues to increase in the United States, most notably among Hispanic men. [Table: see text]
Surveillance for the management of small renal masses: Utilization and outcomes in a population-based cohort.
Authors: Huang William C. , Pinheiro Laura C. , Russo Paul , Lowrance William Thomas , Elkin Elena B.
Published: February 2017

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Background: Small renal masses (SRM) are comprised of a heterogeneous group of tumors with some having malignant potential. Although surgery is the standard treatment for SRMs, emerging data suggests that surgery in the elderly or morbidly ill patients may be unnecessary and may adversely impact non-oncologic outcomes. We analyzed a population-based cohort of patients to identify predictors of surveillance and assess the impact of surveillance on overall survival, kidney cancer-specific survival and cardiovascular (CV) events, compared with surgery. Methods: From surveillance, epidemiology, and end results (SEER) cancer registry data linked with Medicare claims, we performed a retrospective cohort study of patients 66 years of age or older who received surgery or surveillance for SRM (< 4 cm) diagnosed between 2000 to 2007. Propensity score methods were used to control for potential confounders in multivariable analysis. Results: Of 8,317 patients, 5,706 (70%) underwent surgery and 2,611 (31%) underwent surveillance. The use of surveillance increased from 25% in 2000 to 37% in 2007 (p < 0.001). During a median follow-up of 58 months, 2,053 (25%) patients had at least one CV event and 2,078 (25%) patients died, including 277 (3%) who died of kidney cancer. Compared with surgery, surveillance was associated with a significantly lower risk of death from any cause (hazard ratio [HR], 0.84; CI, 0.75-0.94) and of suffering a CV event (HR, 0.79; CI 0.70-0.89), controlling for patient and disease characteristics. Kidney cancer-specific survival did not differ by treatment approach (HR, 0.89; CI, 0.66-1.21). Conclusions: There is increasing utilization of surveillance as an initial treatment strategy for patients with SRMs. For older patients with SRM, surveillance does not appear to adversely affect kidney cancer-specific survival, while surgery may be associated with CV complications and an increased risk of death from any cause. Surveillance should be considered an option for patients with SRM who are not otherwise acceptable candidates for surgical treatment.
Incidence and risk of infections in renal cell cancer (RCC) and non-RCC patients treated with everolimus and temsirolimus: A meta-analysis of randomized control trials.
Authors: Kaymakcalan Marina , Je Youjin , Sonpavde Guru , Galsky Matt D. , Nguyen Paul Linh , Schutz Fabio , Heng Daniel Yick Chin , Richards Christopher J. , Choueiri Toni K.
Published: February 2017

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Background: Everolimus and temsirolimus are mammalian target of rapamycin (mTOR) inhibitors used in a variety of malignancies including renal cell carcinoma (RCC). These targeted agents have been associated with a unique set of adverse events including infections. We performed an up-to-date meta-analysis of published clinical trials to further characterize the risk of infections in cancer patients treated with mTOR inhibitors. Methods: Pubmed and oncology conference proceedings were searched for studies from January 1966 to June 2012. Eligible studies were limited to phase II and III randomized controlled trials (RCTs) of everolimus or temsirolimus that reported on patients with cancer of any tumor type including RCC and with adequate safety profiles. Summary incidence, RR, and 95% CIs were calculated using random- or fixed-effects models based on the heterogeneity of the included studies. Results: A total of 2,990 patients from 8 RCTs were included. The incidence of all-grade infections due to mTOR inhibitor treatment was 35.7% (95% CI, 28.8-43.3) and that of high-grade infections was 4.2% (95% CI, 2.1-8.4). The relative risk of all-grade infection due to mTOR inhibitors was 1.95 (95% CI, 1.67-2.29, p<.001) and that of high-grade infection was 1.91 (95% CI, 1.09-3.35, p=.024). Subgroup analysis found no difference in the incidence or risks of infections between everolimus and temsirolimus or between different tumor types (RCC vs. non RCC). Infections included respiratory tract (38.0%), urinary tract (17.1%), skin/soft tissue (3.6%), others (2.6%), and infection/not specified (38.7%). No evidence of publication bias was observed. Conclusions: Treatment with mTOR inhibitors, everolimus and temsirolimus, is associated with a significant increase in risk of infection in RCC and non-RCC patients.