bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular dissection of primary mediastinal germ cell tumors.
Authors: Nappi Lucia , Annala Matti , Vandekerkhove Gillian , Fazli Ladan , Gleave Martin , Chi Kim N. , Kollmannsberger Christian K. , Wyatt Alexander William
Published: March 2017

417

Background: Mediastinal non-seminomas (M-NS) have a poor prognosis compared to non-M-NS germ cell tumours (GCT) (i.e. primary gonadal or mediastinal seminomas (PG-S and M-S) and primary gonadal non-seminoma (PG-NS). M-NS tumors, while having pathological and serological similarity to other nonseminomas, are clinically and biological distinct and are considered IGCCC poor risk. In this study we aimed to evaluate the somatic mutation rate and prevalence of actionable/informative mutations in M-NS compared to M-S and primary GCT to inform consideration of targeted/precision therapy in these patients. Methods: Pre-treatment formalin fixed paraffin embedded specimens were collected from eleven patients with mediastinal and primary GCT patients (4 M-NS, 2 M-S, 3 PG-NS and 2 PG-S). High-density tumor areas were selected for DNA extraction and targeted sequencing of 578 established pan-cancer genes was performed (Roche Nimblegen SeqCaP EZ Comprehensive Cancer Design). Results: Consistent with the known landscape of testicular cancer, we identified five tumors with amplification of chromosome 12p, as well as hotspot mutations in KIT (n = 2) and KRAS (n = 1). Three of the 4 M-NS tumors had a non-synonymous mutation rate > 1 per Mb, which is higher than the primary TGCT and M-S sequenced here (range 0-0.5 per Mb) and the established low mutation rate for TGCT of 0.3-0.9 mutations/Mb. Mutations in TP53 (n = 2) and PTEN (n = 1) were only identified in patients with M-NS. The 2 patients with a TP53 mutation had a high non-synonymous mutation rate (1.3/Mb and 7.3/Mb), extensive metastatic disease with liver metastasis and high tumor markers (β-HCG: 1281 IU/L and α-FPT: 8500 ng/ml) at diagnosis. Both died of their disease and were the only patients in the cohort to have died. Conclusions: This study suggests that M-NS GCTs harbour more somatic alterations than non-M-NS GCTs, potentially underlying their poor prognosis. Our data are consistent with previous reports of an association between TP53 mutations and poor outcomes. Confirmation of our findings could lead to multi-center studies of targeted/precision therapies in patients with M-NS.
Oncologic outcomes of radiation therapy following active surveillance for low- and intermediate-risk localized prostate cancer.
Authors: Ahmad Ardalan , Chua Melvin , Murgic Jure , Raziee Hamid Reza , Hosni Ali , Moraes Fabio Ynoe De , Timilshina Narhari , Bristow Robert G. , Berlin Alejandro , Finelli Antonio
Published: March 2017

42

Background: To evaluate the oncologic outcomes and potential impact of delayed radical treatment in the form of radiotherapy (RT), in men with localized prostate cancer progressing after active surveillance (AS). Methods: We identified patients on AS subsequently treated with state-of-the-art RT (either dose-escalated image-guided intensity modulated radiotherapy [IG-IMRT] or low-dose-rate brachytherapy [LDR-BT]). Based on the clinical characteristics at time of AS progression, we compared the oncologic outcomes to matched patients treated with upfront RT after diagnose. One to two matching patients per AS case were identified from existing RT databases based on: age (+/- 3 years), clinical prognostic factors (NCCN risk group; PSA +/- 2ng/mL; cT category; primary and secondary Gleason score; percentage of diagnostic cores involved dichotomized at < or > 50%), and treatment modality (IG-IMRT or LDR-BT). We aimed to determine whether patients on AS have potentially compromised outcomes. Results: We identified 215 patients (out of 1070 AS cohort) undergoing RT after a median of 26 months (IQR 16-52.5) on AS. Median follow-up post RT was 4.8 years (IQR 2.9-7.2). No patient died of prostate cancer. At 5-years, the biochemical relapse free-, metastases free- and overall-survival rate were respectively 98.6%, 99.1%, 98.6% in the AS cohort. Matched cohort comprised 400 patients treated with IG-IMRT (71%) or LDR-BT (29%). Adequate matching was confirmed. The median follow-up post RT was 8.2 years (IQR 4.7-10). At 5-years, biochemical relapse free-, metastases free- and overall-survival rates of 98.5%, 98.7%, 93.7% respectively, which were not statistically different compared to those patients treated upon AS progression. Conclusions: Curative-intent radiotherapy (i.e. dose-escalated IG-IMRT or LDR-BT) after a period of AS renders excellent oncologic outcomes at 5 years. Moreover, the delay of therapy after a period of AS does not appear to result in inferior oncologic outcomes compared to patients with similar risk characteristics undergoing upfront radical radiotherapy.
Squamous cell carcinoma of the posterior urethra: Outcomes following radical surgery and adjuvant chemo-radiotherapy.
Authors: Castiglione Fabio , Christodoulidou Michelle , Nigam Raj , Malone Peter , Mitra Anita , Muneer Asif
Published: March 2017

425

Background: Squamous cell carcinoma (SCC) of the posterior urethra is rare and is associated with sexually transmitted infections, urethritis, chronic strictures or urethral surgery. Unlike anterior urethral SCC, the presentation of posterior urethral SCC is often late and there are currently no standardised treatment protocols. We present our series of posterior urethral SCC treated by radical surgery and bladder preservation by performing a pan-urethrectomy, radical prostatectomy with a bladder neck closure and chemoradiotherapy. Methods: We retrospectively collected data from patients diagnosed with posterior urethral SCC from a penile cancer database. Data including patient age, histological subtypes, surgical management, post-operative complications, chemo-radiotherapy and survival rates were recorded. Results: A total of 10 cases with histologically proven posterior urethral SCC were treated in a single centre. Median follow-up was 19 months (SD±10 months). Mean age at presentation was 49 years (SD±6.44) and usual type SCC (80%) was the most prevalent histological subtype followed by NOS and condylomatous SCC. The majority of cases were poorly differentiated SCC (70%), stage ≥ T3 and required radical surgery with total urethrectomy and radical prostatectomy. Complications included post-operative ileus (30%), wound infection (20%), sepsis (10%), perioperative transfusion was required in one patient. Lymphovascular invasion was present in 90% of cases and local recurrence occurred in 60% of patients. Only one patient was suitable for neo-adjuvant chemo-radiotherapy (cisplatin/5-FU) and a further 5 required adjuvant chemoradiotherapy following surgery. 60% of patients developed metastatic disease and 60% died with a median survival of 9.6 months (SD±5.3) from diagnosis to death. Conclusions: Posterior urethral SCC is rare and the late presentation means that neoadjuvant chemoradiotherapy is often not possible. Radical surgery requires a pan-urethrectomy and urinary diversion. Despite adjuvant chemoradiotherapy, posterior urethral SCC is associated with significant mortality with a median survivial of less than one year.
Patterns of relapse and second malignancy after adjuvant external beam radiation therapy for stage I-II seminoma.
Authors: Anderson Erik Steven , Folkert Michael Ryan , Zelefsky Michael J. , Alektiar Kaled M. , McBride Sean Matthew , Feldman Darren R. , Sheinfeld Joel , Kollmeier Marisa
Published: March 2017

428

Background: To determine relapse rate, patterns of relapse and risk of second malignancy (SM) from a large single institution experience of adjuvant external beam radiation therapy (RT) for stage I-II seminoma. Methods: 463 patients with clinical stage I (n = 339) and II (n = 124) seminoma underwent adjuvant RT (median 25.5Gy) between 2/1990 and 11/2015. Data was gathered by retrospective chart review. Patients with > 5 years of follow-up (n = 312) were included in analysis of SM risk. Of stage II patients, 72% (89/124) received a boost to gross disease (median 4.5Gy). Field design was para-aortic nodal region only (n = 96), para-aortic and ipsilateral pelvic nodal region (n = 351) or para-aortic and bilateral pelvic nodal region (n = 8). Field design was not available for 8 patients. Patients were followed with clinical exam, serial imaging, and tumor markers. Relapse and SM were confirmed pathologically. Results: At median follow-up of 7.9 years, there were 20 relapses (median 13.2 months; range 2.5-55.3 months). There were 9 and 11 relapses in stage I and II patients, respectively, with 7/20 (35%) occurring > 2 years after RT. Relapses were identified by clinical symptoms (n = 7), imaging (n = 9), or elevated serum markers (n = 4). Sites of relapses included the lung/mediastinum (n = 10), retroperitoneum/pelvis (n = 5), bone (n = 3) and inguinal nodes (n = 2). 15 (3 pelvic) occurred after para-aortic and ipsilateral pelvic lymph node RT, while 5 (2 pelvic) occurred after para-aortic RT alone. 19/20 patients received cisplatin-based chemotherapy for relapse and were without evidence of disease at last follow-up (median 123 months). Of 35 total non-testicular SM (33 patients), 17 (48.6%) were in the RT field, 4 (11.4%) were marginal and 14 (40%) were out of field. Common SM were prostate (10), lymphoma (4), bladder (3) and kidney (3). The 5 and 10 year overall survival for the cohort is 99.2% and 97.9%, respectively. Conclusions: Stage I-II seminoma patients have a low risk of relapse and SM following adjuvant RT. Relapse is less common in patients treated with para-aortic and pelvic fields. More than 1/3 of relapses occur more than 2 years after adjuvant RT, necessitating long term clinical, radiographic and biochemical follow-up.
Intermediate-term outcomes from the DISSRM registry: A prospective analysis of active surveillance in patients with small renal masses.
Authors: Alam Ridwan , Patel Hiten D. , Riffon Mark F. , Trock Bruce J. , Uzosike Akachimere , Chang Peter , Wagner Andrew J. , McKiernan James M. , Allaf Mohamad , Pierorazio Phillip M.
Published: March 2017

430

Background: Active surveillance is an alternative to primary intervention aimed at reducing the overtreatment of small renal masses, defined as solid renal masses ≤4.0 cm (clinical stage T1a). Methods: Since 2009, the Delayed Intervention and Surveillance for Small Renal Masses (DISSRM) registry prospectively enrolled 615 patients with small renal masses who chose to undergo primary intervention or active surveillance. Intervention was recommended to patients for masses with an elevated growth rate (>0.5 cm/year) or increased tumor diameter (>4.0 cm). Primary outcomes were cancer-specific survival and overall survival; secondary outcomes included progression-free survival. Progression was strictly defined as growth rate >0.5 cm/year, greatest tumor diameter >4.0 cm, metastatic disease, or elective crossover. Outcomes were evaluated using Kaplan-Meier survival analysis and comparisons were performed using the log-rank test. Results: Of the 615 enrolled patients, 298 (48.5%) chose primary intervention and 317 (51.5%) chose active surveillance. From the active surveillance cohort, 45 (14.2%) patients underwent delayed intervention. Median follow-up time for the entire registry was 2.9 years, with 203 (33.0%) patients followed for 5 years or more. At baseline, patients who chose active surveillance were older (p < 0.001) and had higher comorbidity status (p < 0.001) than those who chose primary intervention. There was no difference in cancer-specific survival at 7 years between primary intervention and active surveillance (99.0% vs. 100%, respectively, p = 0.3). However, overall survival was higher in patients with primary intervention when compared to active surveillance at 5 years (93.0% vs. 80.2%, respectively) and 7 years (91.7% vs. 65.9%, respectively, p = 0.002). The 5-year and 7-year progression-free survival rate in the active surveillance cohort was 76.7% and 48.4%, respectively. Conclusions: In the intermediate-term, active surveillance appears to be as safe as primary intervention for carefully selected patients with small renal masses. As the registry matures, further studies will elucidate the effectiveness of active surveillance in the long-term. Clinical trial information: NCT02346435.
Cryoablation of cT1 renal masses in the “healthy” patient: Early outcomes from Mayo Clinic.
Authors: Zaid Harras B. , Atwell Thomas D. , Schmit Grant , Boorjian Stephen A. , Parker William P. , Cheville John C. , Leibovich Bradley C. , Thompson Robert Houston
Published: March 2017

433

Background: Current guidelines suggest that percutaneous thermal ablation (PTA) can be utilized in those with significant comorbidity who are unable to tolerate surgery (radical or partial nephrectomy). However, the use of PTA in healthy patients, who are otherwise candidates for surgery, has been limited. Here, we reviewed our institutional experience in healthy patients electing to undergo PTA, specifically cryoablation. Methods: We identified patients ≤65 years undergoing percutaneous cryoablation for solitary, non-metastatic renal masses <7cm (cT1). We further limited our cohort to patients with an ASA score of 1 or 2, and in whom pre-operative eGFR was >60. Clincopathologic characteristics and recurrence patterns (local recurrence within the kidney versus metastatic disease) were evaluated. Results: Between March 2003 and December 2015, 705 patients underwent cryoablation, of whom 43 (6.1%) were deemed to be “healthy”. Median age of this cohort was 57 years (IQR 52−62), with pre-ablation eGFR of 75.6 (IQR 69.0-86.3). Seven patients (16.3%) had a prior partial nephrectomy, and 5 (11.6%) had a solitary kidney. The majority (40, 93.0%) of ablated masses were cT1a, with 3 (7.0%) being cT1b. Median tumor size was 2.0 cm. 27 masses (63.7%) were biopsy-proven renal cell carcinoma (RCC) and 6 (13.6%) were benign; histology was unknown in 10 (22.7%). Follow-up imaging was available for 37 patients. Median radiological follow-up was 22 months (IQR 9-42), during which time 2 patients developed metastatic disease and 1 developed local recurrence; all events were in patients with biopsy-proven RCC. No patients died from RCC during this time period. Conclusions: In this single institution cohort of “healthier” patients with cT1 solitary renal masses, cryoablation offered reasonable short term oncologic control. While longer follow-up data are needed to evaluate for durability, cryoablation in healthy patients, particularly those with challenging surgical anatomy, warrants further study.
Expression of tyrosine kinase AXL receptor in patients with metastatic renal cell carcinoma treated with sunitinib and its association with clinical and pathological outcomes.
Authors: Zucca Luis Eduardo Rosa , Carcano Flavio Mavignier , Scapulatempo Cristovam , Oliveira Renato , Morini Mariana Andozia , Ribeiro Guilherme , Viana Cristiano Ribeiro , Reis Rui Manuel
Published: March 2017

439

Background: Renal cell carcinoma (RCC) represents 2 to 3% of all cancers of the Western countries. Currently, sunitinib, an anti-receptor tyrosine kinase (RTK), particularly of PDGFR and VEGFR, is the first-line therapy for metastatic RCC (mRCC), with significant improvement in clinical outcome. However, there is a lack of predictive biomarkers of sunitinib response. Recently, we and others have suggested that the RTK AXL may modify the response to sunitinib. Objective: To study the expression of AXL in a series of mRCC patients treated with sunitinib and to correlate it with patient’s clinico-pathological features and therapeutic response. Methods: Sixty four mRCC patients (51 clear cell carcinomas and 13 non-clear cell carcinomas) were evaluated and AXL expression was assessed by immunohistochemistry in TMAs. Results: AXL positivity was observed in 47% of cases. The multivariate survival analysis showed that AXL expression was a poor prognostic factor in patients with mRCC (HR 2.007, 1.006 - 4.006, p=0.048). In addition to the positivity for AXL, other prognostic factors were absence of nephrectomy, more than one site of metastasis, and bone metastasis. Considering only the clear cell subtype, the univariate analysis showed that AXL expression was statistically associated with a poor prognosis, with a median overall survival of 13 months vs. 43 months in patients with negative AXL. In this subtype, along with the AXL positivity, other prognostic factors were absence of nephrectomy, KPS, more than one site of metastasis, and liver metastasis. Moreover, AXL expression was associated with shorter progression to sunitinib. Conclusions: AXL expression was correlated with worse clinical outcome and may be an important prognostic biomarker in sunitinib-treated metastatic renal cell carcinoma patients.
Combined abiraterone, salvage prostate bed radiotherapy and LH-RH agonists (CARLHA) in biochemically-relapsing prostate cancer patients following prostatectomy: A phase I study of the GETUG/GEP.
Authors: Supiot Stephane , Campion Loic , Pommier Pascal , Dore Melanie , Racadot Severine , Rio Emmanuel , Milano Gerard A. , Mahier - Ait Oukhatar Celine , Carrie Christian
Published: March 2017

45

Background: Salvage radiotherapy (RT) plus 6 months LH-RH therapy (ADT) improves biochemical relapse free survival in men with rising PSA following prostatectomy. Abiraterone acetate (Aa) increases overall survival in metastatic prostate cancer. We aimed to establish the toxicity of adding Aa combined with salvage RT and 6 months goserilin (Gos). Methods: We enrolled pT2-pT4a pN0 prostate cancer patients (pts) with rising PSA (0.2 to <2.0 μg/l) following radical prostatectomy. The primary endpoint was to determine the Maximum Tolerated Dose and recommended dose of Aa during RT plus Gos, two dose levels tested : 1 (750mg) and 2 (1000 mg). Two different schemes were explored: Sheme A: Aa (1000 mg) and predisone (10 mg) were given orally during 1 month to salvage IMRT (66 Gy in 33 fractions). The first day of irradiation, Aa is reduced to level 1 or 2 and 10.8 mg Gos is injected (sc). In sheme B, Gos is injected the first day (1 month before starting RT). Results: We recruited 9 + 9 pts in scheme A and B respectively. In scheme A, Testosterone (Tst) levels declined to castration level (<0.5ng/ml) after 10 days . Two/9 pts did not achieve castration levels at 30 days. Median LH levels increased to 10.4 (D10) and 12.5 IU/l (D20). At dose level 1, 4/9 pts (44%) experienced grade 3 hepatitis, occurring prior to RT or during RT (8 Gy, 36 and 54 Gy). We hypothesized that this unexpected liver toxicity was related to the LH increase during the first month (Aa administration without Gos). Therefore, we modified LH-RH administration (scheme B) and recruited 9 more pts. Tst levels dropped to undetectable at day 6, while median LH levels decreased to 6.1 (D10) and 1.7 IU/l (D20). At dose level 1 (3 + 3 pts), no grade 3 liver toxicity was reported. No other grade 3 toxicity was recorded. At dose level 2, 2/3 pts had grade 3 hepatitis occurring during RT. CYP17 polymorphism did not correlate with liver toxicity. Conclusions: The recommended dose of Aa combined to short-term androgen deprivation and salvage RT is 750 mg. Aa alone did lead to castration levels in 22% of pts.An unexpected high frequency of grade 3 liver toxicity was observed. Clinical trial information: NCT01780220.
Neutrophil lymphocyte ratio (NLR) as a clinical biomarker predictive of outcomes with immune checkpoint inhibitor therapy in genitourinary cancers.
Authors: Jeyakumar Ghayathri , Bumma Naresh , Kim SeongHo , Landry Craig , Kim Heejin , Silski Cynthia , Suisham Stacey , Dickow Brenda , Heath Elisabeth I. , Fontana Joseph A. , Vaishampayan Ulka N.
Published: March 2017

453

Background: Immune checkpoint inhibitors (ICI) have been approved in genitourinary cancers (GU) such as renal cell carcinoma (RCC) and urothelial carcinoma (UC). There is an unmet need to determine factors predictive of response, to guide therapeutic selection in these cancers. We evaluated NLR as a predictor of response, progression free survival (PFS), and overall survival (OS) in patients treated with ICI. Other known prognostic clinical factors assessed were age, race, and smoking status and for RCC the prognostic score per MSKCC (Memorial Sloan Kettering) and Heng criteria. Methods: Regulatory approval was obtained. A retrospective chart review of RCC and URC patients at Karmanos Cancer Institute, treated with ICI based therapy was conducted. Data was collected on demographics, smoking status, prognostic scoring, NLR pretherapy, and post 4 doses of ICI. Correlation with clinical PFS and OS was conducted by univariable and multivariable analyses. Log-rank test was used to compare PFS and OS. Results: 57 pts were evaluated with median age 62 yrs (range, 24-85). 11 (19%) were African American (AA) and 31 (54%) were smokers. Pretherapy NLR<4 and ≥4 was seen in 38 (67%) and 19 (33%) pts respectively. 13 (31%) RCC pts were treated with > 1 VEGF therapy and 24(57%) pt were treated for > 6 mths and 14/15 UC pts were pretreated. RCC pts treated with > 6 mths and > 12 mths of VEGF therapy had a shorter PFS (HR =2.31, p= 0.028; HR = 2.075, p= 0.051 respectively). AA had shorter PFS and OS with ICI in RCC but not in UC (HR=3.72, p=0.001; HR= 40.8; p=0.001; HR=0.49, p=0.5; HR=0.85, p=0.88, respectively). Conclusions: Pretherapy NLR ≥4 was a statistically significant predictor of shorter PFS and OS with ICI therapy in RCC. NLR is an easily applicable clinical predictive factor that can help guide therapy, after validation of these findings in a larger population dataset. [Table: see text]
Sunitinib dose escalation after disease progression in metastatic renal cell carcinoma.
Authors: Raphael Jacques , Thawer Alia , Bjarnason Georg A.
Published: March 2017

458

Background: Previous pharmacologic studies demonstrated that higher sunitinib ( S) exposure is associated with improved clinical outcomes in metastatic renal cell carcinoma (mRCC) patients. We aimed to assess the efficacy and toxicity of S dose escalation in mRCC patients progressing on the standard 50mg dose. Methods: A single institution retrospective review was conducted on mRCC patients, treated outside trials with a 50 mg S dose given on an individualized schedule between October 2009 and January 2016, who subsequently progressed on imaging. At progression, patients were dose escalated to 62.5 and 75mg on an individualized schedule if toxicity permitted. Median Progression and Overall Survival (PFS, OS) were analyzed using the Kaplan Meier method. PFS1 and 2 were defined as the time between the start of sunitinib and first progression and the time between dose escalation and second progression respectively. Results: Twenty-five eligible patients were identified, with a median follow-up of 40.3 months (11.1-66.6) and a mean age of 54 years (12.4). The majority of patients underwent cytoreductive surgery (92%) and were men (88%). Thirty two percent, 44%, and 24% had a good, intermediate, and poor prognostic Heng score respectively. At the 50 mg doses, 60% and 16% of patients had a partial response (PR) and stable disease (SD) respectively with a median time to progression (TTP) of 11.4 months (95% CI, 3-20.7). After progression, 36% and 28% had PR and SD on higher doses of S respectively with a TTP of 7.8 months (95% CI, 6.3-12.4). Three patients with progressive disease as best response on a 50 mg S dose achieved SD (2/3) or PR (1/3) after dose escalation. The median PFS1, PFS2, and OS were 6.1 months (95% CI, 2.3-19.4), 6.7 months (95% CI, 3.1-8.4), and 63.7 months (95% CI, 26-not reached) respectively. The most common adverse events after dose escalation were fatigue (56%), diarrhea (40%), and skin toxicity (28%). Conclusions: Patients with mRCC who progress on a 50 mg S dose, may derive a clinical benefit and prolonged survival from dose escalation with acceptable toxicity profiles. These results need to be confirmed in well-designed prospective studies with the aim to optimize the duration of benefit from S therapy.
Eligibility criteria and endpoints in metastatic renal cell carcinoma trials.
Authors: Wong Sarah , Quinn David I. , Bjarnason Georg A. , North Scott A. , Sridhar Srikala S.
Published: March 2017

465

Background: Treatments for metastatic renal cell carcinoma (mRCC) are often compared across trials, but trial eligibility criteria and endpoints differ. In Sept 2015, DATECAN published recommendations for time-to-event endpoints in mRCC trials. The success of their efforts to harmonize endpoints has not yet been assessed. Methods: We assessed eligibility criteria and endpoints from 18 Phase III mRCC trials starting from 2003 onwards. We also assessed 4 Phase III trials submitted after Sept. 2015 for compliance with DATECAN recommendations. Results: Among the 18 trials, consistent criteria were: absolute neutrophil count ≥1,500/µL, platelet count ≥100,000/µL, and bilirubin ≤1.5xULN. However, the following differed in requirements and measures used: see table.The 4 newer trials did not entirely follow DATECAN’s recommendations. Although their primary endpoint is progression free survival (PFS) as recommended, 3/4 trials do not define PFS, and the one that does includes death from any cause instead of DATECAN’s “death from kidney cancer.” Conclusions: Key eligibility criteria were somewhat inconsistent across phase III mRCC trials, and newer trials’ endpoints did not align with DATECAN’s recommendations. Not only is greater standardization needed to facilitate meta-analyses and cross-trial comparisons, but as evident from lack of adherence to DATECAN’s recommendations, greater promotion and enforcement of recommendations is needed to harmonize trial design and improve comparability.[Table: see text]
The SUNPAZ study: Results of an open label, single arm trial to evaluate patients with mRCC treated with everolimus after failure of first line therapy with sunitinib or pazopanib.
Authors: Schostak Martin , Nusch Arnd , de Geeter Patrick , Decker Thomas , Resch Anna , Weiss Claudia , Schmitz Stephan H.
Published: March 2017

473

Background: The VEGFR-TKIs Sunitinib and Pazopanib are the currently recommended 1st line agents for the treatment of renal cell carcinoma (RCC). Everolimus is a well-established treatment option after failure of a prior VEGFR-TKI. However, few prospective clinical data exist on the efficacy and safety of Everolimus after failure of a single line of VEGFR-TKI therapy and no clinical data exists on the efficacy and safety of Everolimus following Pazopanib treatment. Methods: This phase IV clinical trial investigated Everolimus 10 mg daily in patients who have progressed on or after 1st line treatment with Sunitinib or Pazopanib. Adult patients with advanced clear cell RCC and an ECOG 0-1 were included. The primary endpoint was the rate of patients progression-free after 6 months of treatment. Results: 16 and 13 patients who received prior Sunitinib and Pazopanib, respectively, have been enrolled at 13 German sites. The median age was 65 years in the Sunitinib (SUN) group and 74 years in the Pazopanib (PAZ) group. After 6 months of Everolimus treatment, 11/12 (92%) patients in the SUN group showed disease progression, whereas 6/13 (46%) patients in the PAZ group remained progression-free (FAS population). The median OS was 14.8 months in the SUN group (95% CI 9.4 – not reached (NR)) and 20.4 months in the PAZ group (95% CI 11.7 – NR). The most common adverse events (AE) regardless of any relation to study drug included anemia (31.1% (SUN group) vs. 53.8% (PAZ group)), nausea (25.0 vs. 46.2%), stomatitis (12.5 vs. 61.5%), peripheral edema (12.5 vs. 53.8%), and dyspnea (12.5 vs. 46.2%). Conclusions: Patients in the PAZ group showed a lower rate of tumor progression within 6 months and a longer PFS as compared to the SUN group. The results confirm Everolimus as an effective 2nd line treatment option with a favorable safety profile, especially following Pazopanib, and the sequence Pazopanib - Everolimus as effective treatment option for mRCC patients. However, due to the small number of patients enrolled in the study, results have to be interpreted with caution. The types of observed AE are consistent with the well-known toxicity profile of Everolimus. Clinical trial information: NCT01514448.
Long term overall survival (OS) in patients with primary metastatic kidney cancer: An analysis of 1468 patients from the Austrian National Cancer Registry (ANCR).
Authors: Marszalek Martin , Karim-Kos Henrike E , Madersbacher Stephan , Rauchenwald Michael , Hackl Monika
Published: March 2017

489

Background: The introduction of thyrosinkinase inhibitors (TKI) changed the treatment of metastatic kidney cancer fundamentally. To elaborate the potential impact of TKI therapies, we studied trends in OS for patients with primary metastatic kidney cancer between 1998 and 2014 in Austria. Methods: All patients with primary metastatic kidney cancer aged ≥18 years, diagnosed from 1998-2009 were derived from the ANCR (n=2134). Patients diagnosed from 2004-2006 (n=316) were excluded (transition period of systemic therapies). To evaluate differences in OS between patients treated in preTKI-era and TKI-era, two periods were defined: 1998-2003 (before the introduction of Sunitinib in Austria, P1; n=926) and 2006-2009 (P2; n=542). Follow-up was complete until December 31st, 2014. OS rates were estimated by using the Kaplan-Meier method. The Cox proportional hazard model was used to calculate hazard ratios (HR). Results: A total 1468 patients was included in the analysis. The median age of the study population was 70 yrs (sd ±12) and did not differ between the two eras. The incidence of T1 tumors increased from 6.6% in P1 to 10% in P2 while T4 tumors decreased from 15% to 6.5% (p<0.001). Surgery rate remained stable at 48% (p=0.14). Five-year OS for patients undergoing surgery slightly increased from 16% in P1 to 20% in P2, although not significant (p=0.11). For patients without surgery 5-year OS improved from 4.3% in P1 to 7.9% in P2 (p=0.02). Apart from surgery, survival gain was observed for younger patients (<75 yrs) of 4% (p=0.04) and for T3/T4 tumors of 7% (p=0.008). The risk of death (HR) for patients treated in the TKI-era was reduced compared to the preTKI-era (HR 0.83, 95% CI 0.74-0.93) adjusted for sex, age, T-stage, and surgery. Survival advantage for patients undergoing surgery remained significant (HR: 0.50, 95% CI 0.45-0.57) after adjustment for TKI-era, sex, age, and T-stage. Conclusions: Patients with primary metastatic kidney cancer treated in the TKI era show improved OS compared to the cytokine era. Most benefit was observed in non-surgical patients, younger patients, and for T3/T4 disease. Surgery remains as an important therapy for additional survival benefit.
Do CT perfusion measures predict early clinical response in patients with advanced renal cell carcinoma?
Authors: Fan Alice C. , Kino Aya , Schmiedeskamp Heiko , Sundaram Vandana , Srinivas Sandy , Chen Viola , Imae Yori , Desai Manisha , Kamaya Aya
Published: March 2017

496

Background: We need biomarkers of response to guide treatment decisions in RCC. Our pilot study uses perfusion CT to assess early changes in tumor vascularity in response to targeted therapies. We will determine if perfusion CT measurements can help predict response to therapy after 1 week of treatment in patients with metastatic RCC. Methods: Nine patients with metastatic renal cell carcinoma treated with targeted therapy have been enrolled to date. CT perfusion measures were collected: (1) prior to treatment, (2) 7-10 days after start of treatment, and (3) 12 weeks after start of treatment. At each time point, 5 measures were analyzed: (1) blood volume (BV), (2) blood flow (BF), (3) mean transit time (MTT), (4) flow extraction product (FEP), and (5) tumor size. Clinical response was determined based on RECIST criteria. Univariate and multivariate logistic regression analyses were conducted to determine the association of the CT perfusion measures and clinical response. The relationship between clinical response and individual measure at each time point, change in each measure at each time point, and the rate of change over the measure across all time points (slope) were evaluated in each patient. Results: We found that two blood volume measurements are associated with outcome. 5/9 (56%) patients had stable disease and 4/9 (44%) had progressive disease. Decrease in blood volume from time prior to treatment to 7-10 days after start of treatment was significantly associated with decreased odds of having stable disease (OR 0.63 (0.4-0.99), p=0.04). When examining the rate of change, the slope of blood volume was significantly associated with decreased odds of having stable disease (OR 0.52 (0.27-1.01), p=0.05). Univariable logistic regression for each individual CT measure, FEP prior to treatment (OR 1.07 (0.99-1.15), p=0.08) and 12 weeks after treatment (OR 1.13 (0.99-1.29), p=0.06) were not significantly associated with stable disease. Conclusions: Changes in blood volume including absolute difference as well as rate of change of blood volume were statistically significantly different between patients with stable disease versus progressive disease. Clinical trial information: NCT01926990.
The role of cytoreductive nephrectomy in elderly patients with metastatic renal cell carcinoma in an era of targeted therapy.
Authors: Uprety Dipesh , Bista Amir , Vallatharasu Yazhini , Marinier David E.
Published: March 2017

499

Background: The role of cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) has not been clearly understood after the approval of new targeted therapies, particularly in an elderly population. We therefore conducted this study to evaluate survival difference (CN vs. no CN) among elderly patients with mRCC in targeted era. To limit the heterogeneity in use of targeted agents we define targeted era as February 2006 to December 2011, as sunitinib got FDA approval for use in RCC in January 2006. Methods: We utilized Surveillance, Epidemiology, and End Results (SEER-18) database to identify elderly (≥ 65 years) patients with mRCC, as first primary malignancy, who were diagnosed between February 2006 and 2011. Kaplan-Meier curve and log rank test were used to compare overall survival (OS) and cancer-specific survival (CSS) between patients receiving CN and not receiving CN. Cox proportional hazard model was used for multivariate analysis. Results: Out of 3,365 patients, 1088 (32.3%) received CN. There was a significant survival benefit for those who received CN vs. those who did not (Median OS: 22 months vs. 5 months, p< 0.001; Median CSS: 25 months vs. 6 months, p<0.001). After adjusting for age, sex, race, T-stage, N-stage, histology types, and year of diagnosis, patient receiving CN had significantly better 3-year OS and 3-year CSS compared to patients not receiving CN with HR of 0.37, 95% CI of 0.34 to 0.41; p<0.001 and HR of 0.37, 95% CI of 0.34 to 0.42, p <0.001 respectively. Among patients who received CN, younger age at diagnosis, other races (other than Caucasian and African American), and N0 stage were found to be independent factors predicting better survival. Conclusions: SEER database lacks individual patient’s information. One may argue that the non-surgical group may have larger proportion of patients with poor performance status. Despite this limitation, our study showed that CN has significant survival benefit and should be a serious consideration in elderly patients if they have good performance status.
National predictors and trends for androgen deprivation therapy use in low-risk prostate cancer.
Authors: Yang David , Muralidhar Vinayak , Mahal Brandon Arvin Virgil , Nezolosky Michelle Daniel , Vastola Marie , Labe Shelby , Orio Peter F. , Martin Neil E. , King Martin T. , Trinh Quoc-Dien , Sweeney Christopher , Choueiri Toni K. , Nguyen Paul L.
Published: March 2017

50

Background: Androgen deprivation therapy (ADT) is not recommended for low-risk prostate cancer due to its known harms and lack of benefits. We evaluated the incidence and predictors of ADT use in men with low-risk prostate cancer. Methods: We identified 197,980 patients in the National Cancer Database (NCDB) with low-risk prostate cancer (Gleason 3+3 = 6, PSA < 10ng/mL, and cT1-T2a) diagnosed from 2004 to 2012 with complete demographic and treatment information. We determined the incidence of ADT use and utilized multiple logistic regression to evaluate predictors of ADT use. Results: ADT use in low-risk prostate cancer patients declined steadily from 2004 to 2012 (17.6% vs. 3.5%). 80.6% of these patients underwent radiation, and 10.0% received ADT as primary therapy. Among 82,354 low-risk disease patients treated with radiation, demographic and treatment factors associated with increased likelihood of ADT use include older age (adjusted odds ratio [AOR] 1.04 per year, p < 0.001); Hispanic vs. non-Hispanic white ethnicity (18.9% vs. 17.8%, AOR 1.26, p < 0.001); having Medicare at age < 65 (15.3%, AOR 1.14, p = 0.008) or Medicare at age ≥ 65 (21.5%, AOR 1.11, p < 0.001) vs. private insurance (13.9%); having bottom quartile vs. top quartile income (19.4% vs. 16.3%, AOR 1.26, p < 0.001); being treated in a community cancer program (22.0%, AOR 1.60, p < 0.001) or a comprehensive community cancer program (18.7%, AOR 1.38, p < 0.001) vs. an academic/research cancer program (13.9%); and receiving brachytherapy vs. external beam radiation therapy (19.3% vs. 15.5%, AOR 1.32, p < 0.001). Increasing distance from the treatment facility was associated with decreased likelihood of receiving ADT (AOR 0.97 for every 100 miles, p = 0.001). Conclusions: Among men with low-risk prostate cancer, increasing age, Hispanic ethnicity, Medicare insurance, lower income level, treatment in a non-academic/research cancer program, and brachytherapy use were all associated with increased odds of receiving ADT. Given the lack of evidence supporting ADT use in low-risk disease and increasing evidence of its many side-effects, it is critical to understand why low-risk prostate cancer patients are still receiving ADT so that this practice may be reduced.
Meta-analysis of upfront VEGF targeted therapy prior to nephrectomy in metastatic clear cell renal cancer.
Authors: Wimalasingham Akhila Ganeshi , Gomez De Liano Lista Alfonso , de Bruijn Roderick , Haanen John B. A. G. , Szabados Bernadett , Hall Peter , Blank Christian U. , Chowdhury Simon , Hopkins Thomas , Powles Thomas , Bex Axel
Published: March 2017

514

Background: The safety and efficacy of upfront VEGF targeted, before nephrectomy in metastatic clear cell renal cancer (mCCRC) has not been robustly evaluated. Methods: In this study we performed a meta-analysis of 3 studies (NCT) with an almost identical design and included a single institution experience (which adopted this approach as a standard). Patients with newly diagnosed mCCRC had 12-18 weeks of sunitinib or pazopanib therapy prior to planned cytoreductive nephrectomy (CN). Results: 224 patients were included in this analysis (54% had sunitinib and 46% pazopanib). Overall, 73% had MSKCC intermediate risk and 23% poor risk disease. 20% of patients had an ECOG performance status of 0.84% of patients obtained stable disease or a response to therapy (by RECIST) before surgery. The median reduction of size of the primary tumour was 14%. 60% of patients had CN. The commonest reason for not performing CN was progression of disease. Progression free survival (PFS) and overall survival (OS) was 6.2 (95% CI 5.7-6.7) and 13 (95% CI: 10.2-15.7) respectively. Patients with MSKCC poor risk disease had a poor outcome irrespective of CN (OS = 7.5 months 95% CI 5.8-9.2). A comparison of sunitinib and pazopanib showed no significant difference in median PFS 7.1 (95% CI, 6.0-9.2) and 6.0 (95% CI: 5.1-6.8) or surgical complications (p<0.05). Conclusions: Outcomes with this approach are in line with expected survival for this population. Results with sunitinib and pazopanib were similar. This approach is attractive for patients with MSKCC intermediate risk disease.
Brain metastases (BM) from renal cell carcinoma treated with nivolumab: Evidence of early brain flare?
Authors: Albiges Laurence , Flippot Ronan , Arfi-Rouche Julia , Caramella Caroline , Ruatta Fiorella , Derosa Lisa , Louvel Guillaume , Maroun Pierre , Bossi Alberto , Escudier Bernard J.
Published: March 2017

520

Background: Brain metastases (BMs) are associated with poor prognosis in metastatic renal cell carcinoma (mRCC). Patients with BM were excluded from pivotal studies of nivolumab in mRCC. Therefore, activity of nivolumab in BM is currently unknown. Methods: Data from mRCC patients with BMs, treated at Gustave Roussy with nivolumab, were collected. RECIST 1.1 assessments of both BM and metastatic sites outside the brain have been prospectively centrally reviewed. Treatment for BM: surgery, stereotactic radiation therapy (SBRT), whole brain radiotherapy (WBRT), and systemic treatment were collected. Results: Between February 2016 and September 2016, 62 consecutive patients have been treated with nivolumab in 2nd/3rdline at Gustave Roussy as part of the GETUG-AFU-26 NIVOREN trial (EudraCT 2015-004117). Among those, 8 patients (13%) had baseline non symptomatic BM, either untreated (n=6), or after SBRT (n=2). Among the 8 patients, median follow up from study enrollment is 8.1 months (range: 3.7-8.5). All 8 patients are alive at the time of analysis, only one still receiving nivolumab. 6/6 patients previously untreated required focal therapy to the brain due to early symptomatic disease progression to the brain: SBRT=5; surgery=1; WBRT=1 (one patient had SBRT +WBRT). Disease progression of BM was symptomatic in 8/8 patients and required steroid use as well as nivolumab discontinuation in 7/8 patients due to either brain and/or systemic disease progression. Conclusions: To our knowledge,this is the first experience evaluating BMs from mRCC treated with nivolumab. Our report suggests that BM from mRCC may not derive benefit from nivolumab and that prior focal therapy to the brain may be discussed in patients before nivolumab start. This finding is currently being investigated in the entire GETUG-AFU-26 NIVOREN trial population (n=499 patients, from 27 centers), which included 54 patients (11%) with BM at treatment start, to be presented at ASCO GU.[Table: see text]
Cryotherapy and thermal ablation for renal malignancy over 3cm: Comparative analysis of survival with small renal masses.
Authors: Jones Alex , Dinino Megan , Wakefield Mark , Murray Katie , Pokala Naveen
Published: March 2017

531

Background: Ablative treatments achieve good oncological outcome for renal parenchymal tumors 3 cm or smaller. Larger renal malignancies are increasingly being treated with ablation. This comparative study determines the survival following ablation in these large renal masses. Methods: Patients undergoing cryotherapy or thermal ablation (Procedure codes 13, 15, or 23) for renal tumors were identified from SEER database (1998-2013). Exclusions: T stage not recorded, more than one primary, metastatic, or node positive disease. Demographics, stage, and overall (OS) and cancer specific survival (CSS) were analyzed. T1a tumors were compared to T1b or T2 tumors. Tumors 3 cm or less were compared to greater than 3 cm. Results: 4886 patients were identified, and 2340 patients met inclusion criteria. The mean age was 66.5 years, 1943 were white, 243 were black, and 1419 were male. The stage distribution included T1a (n=2159), T1b (n=172), and T2 (n=9). 1186 tumors had right sided, 1149 had left ,and the others were bilateral or not specified. 2326 patients had the size recorded and 1637 patients had 3 cm or smaller tumors and 689 tumors were larger than 3 cm. The OS in T1a tumors was 84.4% at 5 years and 69.2% at 9 years. The patients with T1b tumors had 62% at 5 years and 38% at 9 years. The T2 tumors had an OS of 64.8% at 57 months. The 5 yr CSS was 97.4% in the whole group, 97.9% in T1a, and 97.4% in the T1b group. The corresponding 9 yr CSS was 96.9, 97.5, and 96.9%. Comparative CSS in patients with T1a tumors was 98% at 5 years and 97.5% at 9 years. In T1b or greater tumors the 5 and 9 year survival was 90.2%. All patients that survived beyond 5 years were alive at 9 years of follow-up. On analysis by size, tumors 3 cm or less had a 98.4 5-yr and a 98.2 9-yr CSS and tumors that were greater than 3 cm had 95% 5-yr and a 93.9 9-yr survival. On univariate analysis both T1a tumors and tumors smaller than 3 cm had significantly better survival (p=0.001). Conclusions: Ablative therapies for small renal masses can achieve excellent CSS at 97% at 9 years. This study demonstrates that reasonable CSS can be achieved in masses larger than 3 cm and patients with T1b or larger tumors. Further studies are required to address the role of ablative therapies for larger renal masses.
Outcomes of patients (pts) with renal cell carcinoma and sarcomatoid dedifferentiation (sRCC) treated with nephrectomy (Nx) and systemic therapies (T) over three decades: The MD Anderson Cancer Center (MDACC) experience.
Authors: Keskin Sarp K. , Msaouel Pavlos , Hess Kenneth R. , Matin Surena F. , Jonasch Eric , Wood Christopher G. , Karam Jose A. , Tannir Nizar M.
Published: March 2017

534

Background: Pts with sRCC historically have had a poor prognosis. We determined the overall survival (OS) and prognostic factors of pts treated with Nx and T in the cytokine and targeted therapy eras. Methods: This is a retrospective study of pts with sRCC who had Nx and received T at MDACC in the cytokine era (1987-2005) or the targeted therapy era (2006-2015). OS was measured from time of diagnosis until death of any cause or last follow-up. OS times were estimated by Kaplan-Meier plots and were compared using the log-rank test. Cox regression models were used to determine the association of covariables with OS. Results: Among 199 pts with sRCC (80.9% clear-cell) identified, 167 pts (83.9%) have died at a median follow-up of 8.8 years (median OS 16.5 months; 95% CI: 15.2, 20.9). The 1-year, 2-year, and 5-year OS rates were 67%, 38%, and 14%, respectively. There was no significant difference in OS between pts with clear-cell vs. those with non-clear cell histology. Pts with metastatic disease at initial diagnosis had a significantly shorter OS compared with pts with localized disease (median 12.1 months vs. 23.3 months; p=0.0064). Biopsy of the primary tumor or a metastatic site was able to detect the presence of sarcomatoid features in only 7% of cases. The % of sarcomatoid component (<10%, 10-40%, >40%) in the primary tumor did not impact OS. For first-line (1L) therapy, 77 pts (39%) received targeted agents, and 122 pts (61%) received chemotherapy or cytokines. Although a significant improvement in OS rate was observed at 1 year for pts treated in the targeted therapy era (p = 0.011), this effect was attenuated at year 2 and disappeared at years 3-5 after diagnosis. Conclusions: Pts with sRCC still have poor prognosis with no clear long-term benefit of targeted therapy, underscoring the need to develop more effective systemic therapies for these patients.