bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term outcomes of intensity-modulated radiation therapy combined with neoadjuvant hormonal therapy for Japanese patients with non-metastatic prostate cancer.
Authors: Aizawa Rihito , Takayama Kenji , Nakamura Kiyonao , Inoue Takahiro , Kobayashi Takashi , Akamatsu Shusuke , Yamasaki Toshinari , Ogawa Osamu , Mizowaki Takashi
Published: February 2018

49

Background: This study aimed to evaluate long-term outcomes of intensity-modulated radiation therapy (IMRT) combined with neoadjuvant (NA) hormonal therapy (HT) in Japanese patients with non-metastatic prostate cancer (NMPC). Methods: We retrospectively analyzed the data of 485 patients with T1-T4N0M0 adenocarcinoma of the prostate treated with IMRT combined with NA-HT. Of these patients, 32, 113, 250, and 90 patients were categorized into the low-, intermediate-, high-, and very high-risk groups, respectively, according to the NCCN risk classification. NA-HT was administered over a median duration of 6 months. In principle, 74 or 78 Gy in 2 Gy per-fraction were delivered to the prostate and seminal vesicles according to the risk. We did not administer adjuvant HT (A-HT) for any patient following the completion of IMRT. Salvage HT (S-HT) commenced when prostate-specific antigen (PSA) values exceeded 4 ng/mL. Results: The median follow-up period was 103.4 months, and the median PSA value at the initiation of S-HT was 5.1 ng/mL. In the low-risk group, the 8-year biochemical relapse-free survival, prostate cancer-specific survival, overall survival, and S-HT-free (SHTF) rates were 89.7%, 100.0%, 100.0%, and 96.7%, respectively. Those were 83.7%, 100.0%, 96.0%, and 94.3% for the intermediate-risk group, 64.5%, 97.8%, 87.0%, and 79.4% for the high-risk group, and 47.7%, 96.6%, 89.7%, and 53.3% for the very high-risk group, respectively. The estimated 8-year cumulative incidence rates of late gastrointestinal and genitourinary (grades 2–3) toxicity were 7.2% and 21.8%, respectively. We observed no grade 4 or higher toxicity. Conclusions: High-dose IMRT, combined with NA-HT and without A-HT under the early S-HT policy, achieved excellent survival outcomes with acceptable morbidities for a Japanese cohort with NMPC. Moreover, especially for high, and very high-risk patients, this approach could be a viable alternative to the uniform provision of long-term A-HT because more than the half of the patients maintained SHTF status over a period of 8-year after IMRT. Prospective trials are warranted to validate the findings of this study.
Discordance rate of PD-L1 expression between primary and metastatic lesions in urothelial carcinoma (UC).
Authors: Burgess Earle Frederick , Naso Caroline , Doherty Shannon , Guerrieri Renato , Livasy Chad , Hartman Aaron , Robinson Myra M. , Symanowski James Thomas , Grigg Claud , Graham David L. , Osei-Boateng Kwabena , Riggs Stephen Boyd , Clark Peter , Raghavan Derek
Published: February 2018

493

Background: Immune checkpoint inhibitors (ICI) targeting PD-1 or PD-L1 are effective in select patients with advanced UC. High PD-L1 expression enriches for response to ICIs; however, the predictive value of PD-L1 expression is limited, which may be due in part to dynamic expression of PD-L1 in the tumor environment. We sought to characterize PD-L1 expression in primary UC and paired metastatic lesions to gain insight into the potential temporal discordance of tumor PD-L1 expression during the metastatic process. Methods: Immunohistochemical (IHC) staining for PD-L1 using the SP-142 antibody was performed on primary tumors and matched metastatic specimens in 83 patients with advanced UC. IHC staining was scored for the percentage of cells positive ( < 5%, ≥5%) in tumor cell (TC) and immune cell (IC) compartments. Correlation of PD-L1 expression in TCs and ICs was estimated using Spearman’s correlation coefficients (ρ). Cohen’s kappa statistics (κ) were utilized to assess the agreement in PD-L1 expression between groups. Results: High (≥5%) PD-L1 expression in primary and metastatic biopsies, respectively, was observed in 6.1% and 14.6% of TCs and in 7.8% and 11.7% of ICs. High co-expression of PD-L1 in both TC and IC compartments was infrequent in primary and metastatic lesions (3.6% and 2.6%, respectively). PD-L1 expression in TCs was positively correlated with PD-L1 expression in ICs in primary tumors (ρ = 0.47) and in metastatic lesions (ρ = 0.27). TC PD-L1 expression in primary tumors was correlated with TC PD-L1 expression in paired metastatic lesions (ρ = 0.44) but there was minimal agreement in high expression rates between primary and metastatic lesions in the TC compartment (κ = 0.147). IC PD-L1 expression in primary tumors was not correlated with IC PD-L1 expression in paired metastatic lesions (ρ = 0.05) and there was poor agreement in high expression rates between primary and metastatic lesions in the IC compartment (κ = 0.086). Conclusions: High PD-L1 IC expression is temporally discordant between primary and metastatic UC lesions. Future studies of PD-1/PD-L1 targeted therapies in patients with metastatic UC should utilize recent biopsies of metastatic lesions to define PD-L1 expression when feasible.
Comparative effectiveness of non-cisplatin (cis)-based first-line (1L) regimens in patients with metastatic urothelial carcinoma (mUC): Veterans Affairs control cohorts vs. IMvigor210.
Authors: Vander Velde Nancy S. , Guerin Annie , Ionescu-Ittu Raluca , Shi Sherry , Wu Eric , Lin Shih-Wen , Hsu Ling-I , Saum Kai-Uwe , De Ducla Sabine , Wang Jingjing , Li Shi , Derleth Christina Louise , Liu Shuqian , Shi Lizheng , Leppert John
Published: February 2018

496

Background: For mUC patients (pts) ineligible for cis, 1L carboplatin (carbo)-based regimens and checkpoint inhibitors are recommended, but comparative data are lacking. We assessed OS in pts given 1L atezolizumab (atezo; anti–PD-L1) from Ph 2 study IMvigor210 and Veterans Affairs (VA) mUC pts treated with carbo standards. Methods: Carbo-based control cohorts were derived from the VA Health Care Network databases (diagnosed 2006-2017), with treatment (tx) defined per NCCN guidelines V2.2005. IMvigor210 eligibility criteria were used to refine non-cis VA cohorts. Prespecified OS predictors were balanced between VA and IMvigor210 pts using entropy (e)-balance weighting. OS was evaluated by Kaplan-Meier (KM) and Cox regression (weighted). Sensitivity analyses used stabilized inverse probability weighting (sIPW) and statistical adjustments. Results: Of 2056 VA pts included, 926 received carbo-based tx, of whom 380 received carbo+gemcitabine [CarboGem]; after IMvigor210 exclusion criteria, the carbo-based cohort included 282 pts, of whom 120 had CarboGem. Non-proportional hazards were seen with KM curves crossing at ≈ 5 (CarboGem) and 9 mo (carbo based). OS data are in the table. Weighted analyses showed OS benefit for atezo vs CarboGem and delayed benefit vs carbo-based tx. HRs from sensitivity analyses were consistent in direction and significance. Conclusions: We compared OS in mUC pts receiving 1L non-cis regimens in VA (carbo) and IMvigor210 (atezo) mUC cohorts. A lower risk of death was seen for atezo vs carbo, manifesting after a few months of tx. Randomized studies may validate these 1L mUC tx trends. Clinical trial information: NCT02951767. [Table: see text]
Vascular and tumor cell expression of VEGFR2 and molecular subtyping: An innovative biomarker approach in bladder cancer.
Authors: Nasir Aejaz , Falcon Beverly L , Wang Dan , Holzer Timothy R. , Nonte Elizabeth M , Chen Mia Yang , Fulford Angie D , Carter Julia H , Douglass Larry E , Pytowski Bronislaw , Bell-McGuinn Katherine M , Walgren Richard A. , Schade Andrew E , Chaudhry Aafia
Published: February 2018

497

Background: Treatment approaches combining anti-angiogenic therapy with chemotherapy have shown promising clinical results in metastatic bladder cancer (BC). In order to interrogate the potential clinico-pathologic and molecular basis of these findings, we evaluated VEGFR2, vascular density and molecular subtyping in a series of BC patients. Methods: A custom-TMA with primary BC tissues from 117 patients (mean age 71 yrs; range 38-99 yrs; M:F = 83:34) treated at a single institution, was stained and scored (0-3) for CD34 (vascular density) and for VEGFR2 on tumor vessels and cells. CK5/6 and GATA3 IHC was scored by a pathologist to identify main molecular classes of BC. The association between clinico-pathologic variables, VEGFR2, CD34 and molecular subtypes was analyzed by Fisher’s exact test and ANOVA. Univariate and multivariate Cox proportional models were used for survival analysis. Results: Of 112 analyzable BC tissues, 41% were muscle-invasive (MIBC) vs. 56% non-muscle invasive (NMIBC) and 3% undetermined. Compared to NMIBC patients those with MIBC had shorter overall survival (p < 0.001). The main molecular subtypes included basal (11%), mixed baso-luminal (28%) and luminal (61%). Compared to luminal and baso-luminal subtypes, the majority of basal BCs were muscle invasive (p = 0.036). VEGFR2 expression was higher in tumor vessels but variable in tumor cells. 74% of BCs showed high-medium levels of VEGFR2 (scores 3-2) in tumor vessels and 88% had high-medium levels of tumor vascular density. Within basal, luminal and baso-luminal subtypes, 58%, 78% and 71% had high-medium levels of vascular VEGFR2 (p = 0.52), while 83%, 91% and 82% had high-medium levels of tumor vascular density (p = 0.08). Survival analyses showed increasing patient age, higher stage and lower VEGFR2 levels as independent predictors of shorter survival. Conclusions: Given the observed complexity of BC regarding VEGFR2 expression and vascular density across molecular subtypes, further investigation is warranted to understand how the frequent expression of VEGFR2 on tumor vasculature and variable expression in tumor cells relates to the efficacy of anti-angiogenic agents across these subtypes in bladder cancer.
Defining the DNA damage repair (DDR) genomic landscape of urothelial carcinoma of the bladder (UCB).
Authors: Dason Shawn , McPherson Victor , Teo Min Yuen , Isharwal Sumit , Audenet François , Bagrodia Aditya , Cha Eugene K. , Berger Michael F. , Zehir Ahmet , Schultz Nikolaus , Bajorin Dean F. , Rosenberg Jonathan E. , Al-Ahmadie Hikmat , Bochner Bernard H. , Pietzak Eugene J. , Solit David B. , Iyer Gopa
Published: February 2018

502

Background: Impaired DDR is associated with response to platinum-based chemotherapy. Several genomically directed trials have been proposed using DDR alteration status for enrolment. In this study, we characterized the deleterious DDR alteration (DDRa) landscape of UCB across various clinical states. Methods: Targeted exon capture and sequencing of at least 341 cancer-associated genes was performed prospectively on 451 UCB specimens (MSK-IMPACT assay). We assessed sequencing data for deleterious alterations in 34 genes representing canonical DDR pathways. Deleterious alterations included truncating mutations, homozygous deletions, and functionally validated missense mutations. Results: Table 1. In NMIBC, deleterious DDRa were enriched in high-grade disease ([39/136, 28.7%] high grade vs. low-grade [2/28, 7.1%]; p=0.02). The frequency of deleterious DDRa in chemo-naïve MIBC was enriched relative to unmatched post-neoadjuvant chemotherapy (NAC) residual MIBC ([33/112, 29.5%] vs. [8/55, 14.5%]; p=0.01). Patients with metastatic disease had similar rates of deleterious DDRa to MIBC ([31/116, 26.7%] vs. [33/112, 29.5%]). The percentage of patients having any type of DDR alteration was similar across states. The proportion of patients with a deleterious DDRa relative to any DDRa was 41/77 (53.2%) in NMIBC, 33/65 (50.8%) in chemo-naïve MIBC, 8/27(29.6%) in post-NAC residual MIBC, and 31/68 (45.6%) in metastatic disease. Conclusions: DDRa are found across the UCB disease spectrum. ERCC2 and ATM are the most common DDRa although alterations were seen in most other DDR genes. Many alterations are of unknown significance and further characterization is needed to develop genomically directed treatment. [Table: see text]
Self-reported burden in patients with localized prostate cancer treated with stereotactic body radiation therapy (SBRT).
Authors: Pepin Abigail , Aghdam Nima , Johnson Colin , Danner Malika , Ayoob Marilyn , Yung Thomas M. , Lei Siyuan , Collins Brian Timothy , Dritschilo Anatoly , Suy Simeng , Lynch John , Collins Sean P.
Published: February 2018

51

Background: Retaining quality of life in patients treated with SBRT for prostate cancer remains paramount. As such, balancing the benefits of treatment against the effects of therapy on patients is essential. The quality of life is influenced by the disease and treatment related burden. The EORTC QLQ-ELD14 (ELD14) is a validated questionnaire that can assess burden. This study reports burden trends in patients with prostate cancer treated with SBRT. Methods: All patients with localized prostate cancer treated with SBRT at Georgetown University Hospital from 2007 to 2016 were eligible for inclusion in this cross-sectional cohort. The ELD14 questionnaire was used to assess self-reported patient quality of life at time points before and following treatment. Initially, 267 patients (Median age of 70) responded to the ELD14 questionnaire. Approximately 30% received ADT. The specific questions reviewed for this study were focused on burden of disease and treatment. The responses to these questions were grouped into three clinically relevant categories (not at all, a little and quite a bit to very much). Results: Number of patients reporting quite a bit or very much burden from prostate cancer declined over time from 13% prior to treatment to 8% at 36 months post-SBRT. This was highest at one month post-SBRT (15%) and resolved to baseline by 6 months. Treatment burden similarly decreased over time from 10% to 3%. Patients treated with androgen deprivation therapy (ADT) experienced greater burden than others. At initial consult, 19% of patients on ADT reported quite a bit or very much burden from their illness. At one month post-SBRT, this had increased to 27% and subsequently decreased to 16% at 36 months. Of those not receiving ADT, 12% reported having quite a bit or very much burden from illness initially, 9% at one month and 6% at 36 months. Conclusions: This cross-sectional study suggests that the burden of clinically localized prostate and its treatment with SBRT improves over time. Increased burden was noted in patients receiving ADT. These findings can inform decision making in improving quality of life for patients with prostate cancer treated with SBRT.
Costs and of treating Gleason score 9 and 10 prostate cancer vary widely based on need for adjuvant therapy: A critical assessment into the long-term cost implications of additional treatment modalities.
Authors: Laviana Aaron Alan , Saigal Christopher , Resnick Matthew J. , Reiter Robert Evan , King Christopher R. , Demanes David Jeffrey , Steinberg Michael L. , Horwitz Eric M. , Kishan Amar Upadhyaya
Published: February 2018

53

Background: The costs of treating localized, Gleason score 9 and 10 prostate cancer remain poorly described, especially when the particularly aggressive nature of the disease often requires a multimodal approach. We report the results of time-driven activity-based costing to assess the long-term costs of treating this subset of patients with either RALP, high-dose EBRT, or EBRT with a high-dose rate brachytherapy (BT) boost. Methods: Based on a multi-institutional cohort of 487 patients with Gleason score 9-10 prostate cancer, we generated process maps for each phase of care from the initial urologic visit through a median follow-up of 3.76 years, incorporating all prostate cancer treatment over this horizon. Costs were calculated per unit time, and the proportion of capacity for each step was determined. TDABC was defined as the sum of its resources. Results: Substantial cost variation was demonstrated between treatment modalities with an estimated median cost of $49,681 for EBRT, $35,140 for RALP, and $31,647 for EBRT + BT at 3.76 years. The primary driver in cost variation was the use of ADT. RALP (170 pts) ranged from $18,896 (29.5%) for no postoperative therapy to $63,270 for immediate long-term ADT (5.3%). EBRT (230 pts) had the greatest cost variation [Table 1]. Finally, EBRT + BT (336 pts) ranged from $26,522 for EBRT + BT alone (12.6%) to $37,834 for EBRT + BT + salvage ADT + HIFU (1.2%). Conclusions: Characterizing the costs associated with the distribution of treatments for men with high-risk prostate cancer is essential as we move towards health care accountability. There is substantial long-term cost variation between treatments in this subset of patients, and understanding these differences may affect treatment implications as we shift toward accountable payment models.[Table: see text]
Sentinel node biopsy in clinical stage I testicular cancer.
Authors: Blok Joost Marijn , Meijer Richard Paul , Kerst Jan M. , Vegt Erik , Bosch Ruud , Bex Axel , Van Der Poel Henk , Horenblas Simon
Published: February 2018

550

Background: Approximately 20 – 30% of patients with testicular germ cell tumors (TGCTs) in clinical stage I (CS I) have occult metastatic disease at the time of presentation and will relapse under surveillance. The availability of a sentinel node procedure would enable early identification of patients with occult metastases. We report the long-term results of the sentinel node approach in CS I testicular tumor patients in our facility. Methods: Between 2001 and 2015, patients suspected of CS I TGCT in our third echelon referral center were asked to participate. SNs were identified using SPECT/CT and/or lymphoscintigraphy. Participants underwent laparoscopic retroperitoneal SN excision together with inguinal orchiectomy. Patients with a SN positive for occult metastases were treated with adjuvant chemotherapy. Follow-up was according to then current guidelines and consisted of clinical examination, tumor markers, abdominal/thoracic CT-scanning and chest X-rays. Results: Twenty-seven patients were included. In two patients, no sentinel nodes were visualized on scintigraphy. In twenty-five patients, a median of 3 SNs (range 1 – 4) per patient were removed. Two patients showed no malignancy on histopathologic examination of the testis. Of the 23 patients diagnosed with TGCT, three (13.0%) had occult metastatic disease. All 23 patients were without evidence of disease at a median follow-up of 62.2 months (range 22.3 – 143.4). Conclusions: The SN procedure enables early identification of patients with occult metastatic disease in CS I TGCT. Clinical trial information: M00LMT.
Comparative genomic profiling (CGP) of refractory/metastatic penile (mPSCC) and non-penile cutaneous squamous cell carcinoma (mCSCC).
Authors: Jacob Joseph M , Shapiro Oleg , Ferry Elizabeth Kate , Gay Laurie M. , Elvin Julia Andrea , Vergilio Jo-Anne , Suh James , Ramkissoon Shakti , Ali Siraj Mahamed , Schrock Alexa Betzig , Chung Jon , Miller Vincent A. , Stephens Philip J. , Bratslavsky Gennady , Ross Jeffrey S.
Published: February 2018

552

Background: mPSCC is an aggressive malignancy with limited treatment options. Using CGP, we compared the therapy impacting genomic alterations (GA) between mPSCC and cutaneous mCSCC. Methods: DNA was extracted from 40 microns of FFPE samples from 78 cases of mPSCC and 338mCSCC.Comprehensive genomic profiling (CGP) was performed using a hybrid-capture, adaptor ligation based next generation sequencing assayto a mean coverage depth of > 500X. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Results: mPSCC patients were younger than mCSCC (Table). Both tumors types feature high CDKN2A, TERT and FAT1 GA frequencies. NOTCH1 and PTCH1 GA are also more common in mCSCC than mPSCC. CD274 ( PD-L1) amplification was rare in both tumor types. Targeted therapy opportunities in mPSCC included alterations in kinase pathways ( EGFR GA in 6%; FGFR3 and ERBB2 GA in 4%); MTOR pathway ( NF1 GA in 7% and PTENGA in4%) and DNA repair pathway ( BRCA2and ATMGA in 7%). TMB was significantly higher in the UV light exposed mSCC than mPSCC with both tumor types having potential for responsiveness to immunotherapies. MSI-High status was extremely rare for both mPSCC and mCSCC. HPV viral DNA was identified in 29% on mPSCC but only in 5% of mCSCC. TP53 GA were significantly more frequent in HPV- than HPV+ mPSCC and mCSCC respectively (P < 0.0001 for both). Clinical outcomes of selected patients will be presented. Conclusions: mPSCC is a unique subtype of SCC with distinctive genomic features that contrast with those identified in mCSCC of non-penile UV light exposed skin. Given the potential opportunities for targeted therapies and immunotherapies that can be uncovered, continued study of CGP for the guidance of treatment for patients with mPSCC appears warranted.[Table: see text]
The clinical presentation, diagnosis, treatment and long term outcome of germ cell tumor in 85 patients with Down syndrome.
Authors: Weatherford Emma , Wang Jue
Published: February 2018

554

Background: The main objective of this study was to determine the clinical features, treatment, clinical outcome and prognosis of Down's syndrome (DS) patients with germ cell tumor (GCT). Methods: Literature search based on PubMed search was performed using the following keywords: “Germ cell tumor (GCT)” and “Down's syndrome”. A total of 85 cases of GCT in DS patients published in literature between January 1985 and October 2017 were identified. Results: Our final cohort of GCT in DS include 44 cases of testicular germ cell tumor (TGCT); 22 intracranial GCT, 2 primary mediastinal GCT, 3 gastrointestinal GCT, 9 retroperitoneal GCT, and 5 cases of ovarian GCT. The median age of forty-four testicular GCT was 30 years (range 2 years – 50 years). In most cases, cancer was diagnosed following the discovering of swelling by care provider or found incidentally (either painless or painful) in the region of the testes, although abdominal pain was a symptom in a few cases. 29 (66%) patients were diagnosed with seminoma and 15 (34%) with non-seminoma. In the seminoma group, 18 (62%) patients were diagnosed with stage I , 9 (31%) with stage II and 2 (7%) with stage III. In the non-seminoma group, 4 (27%) patients were diagnosed with stage I, 5 (33%) with stage II and 6 (40%) with stage III. Nearly all patients (94%) underwent orchiectomy. 52% patients received chemotherapy, with BEP being the most common administered regimen. 7 patients had retroperitoneal lymph node dissection ( RPLND). In the seminoma group, there were 5 deaths, 3 related to disease progression, 2 related to comorbidities, 1 died during chemotherapy. In the non-seminoma group, there were 2 deaths, 1 related to disease progression, 1 died during chemotherapy. The overall survival at 5 years for stage I was 100%, 76% for stage II and 68% for stage III. Conclusions: In this largest cohort of GCT in DS, we found TGCTs are often diagnosed at stage II or III. In addition, delayed diagnosis, comorbidities likely contributed to the inferior outcome in stage II/III TGCTs in patients with DS. Emphasis on education, better communication, early screening and detection, are needed to improve the outcome in this population.
A longitudinal assessment of health-related quality of life in patients undergoing active surveillance for early prostate cancer in Japan (PRIAS-JAPAN).
Authors: Kato Takuma , Sugimoto Mikio , Hirama Hiromi , Kakehi Yoshiyuki , Yamaguchi Akito , Abe Takashige , Maruyama Satoru , Mitsuzuka Koji , Arai Yoichi , Fukuhara Hiroshi , Sasaki Hiroshi , Egawa Shin , Ninomiya Iku , Hashine Katsuyoshi ,   PRIAS-JAPAN Investigators
Published: February 2018

56

Background: There are few reports of the health-related quality of life (HRQOL) of Asian prostate cancer patients who choice active surveillance. We evaluate HRQOL in participants of the Prostate Cancer Research International Active Surveillance study (PRIAS-JAPAN). Methods: The participants’ general HRQOL was assessed longitudinally using the Short Form 8 Health Survey (SF-8) at enrollment and annually thereafter until discontinuation of active surveillance (AS). We compared the quality of life and baseline score of participants with that of the general population (Norm-based scoring [NBS] 50) using paired t-test and the mixed models. Age-adjusted logistic regression was applied to the 3-year AS remaining rate. Results: The SF-8 questionnaire was administered to 570 patients (median age, 68 [range, 45–87] years). We evaluated 484, 328, 140, 84, and 68 patients at enrollment and 1, 2, 3, and 4 years thereafter. At enrollment, the mean physical component summary (PCS) score and all subscales revealed better HRQOL than NBS. No significant difference was noted in mental component summary (MCS) compared to NBS at enrollment. However, MCS at 1, 2, and 4 years was higher than the NBS. PCS slightly diminished in 4 years, whereas MCS at all time points showed no change. Age-adjusted logistic regression showed an OR of 1.66 (95% CI: 1.047–2.632, P = 0.0313) on 3-year AS remaining rate in favor of patients with above median MCS at enrollment. Conclusions: Men who were enrolled into the PRIAS-JAPAN study had better HRQOL than that of NBS. PCS decreased but MCS did not. The AS remaining rate was influenced by baseline MCS.
Safety and efficacy of nivolumab in metastatic renal cell carcinoma (mRCC): Results from the NIVOREN GETUG-AFU 26 study.
Authors: Albiges Laurence , Negrier Sylvie , Dalban Cécile , Gravis Gwenaelle , Chevreau Christine , Oudard Stephane , Laguerre Brigitte , Barthelemy Philippe , Borchiellini Delphine , Gross-Goupil Marine , Geoffrois Lionnel , Brihoum Meryem , Escudier Bernard ,   GETUG
Published: February 2018

577

Background: Nivolumab (N) has been approved for the treatment of mRCC after failure of 1 or 2 tyrosine kinase inhibitors (TKI) based on the results of Checkmate 025 study. Right after approval, we initiated the NIVOREN GETUG-AFU 26 study (NCT03013335), a French multicenter prospective study to evaluate safety and efficacy of N in a “real world setting”. Methods: Patients (pts) with clear cell mRCC could be enrolled if they had received at least one TKI. Compared with the pivotal trial, inclusion criteria allowed patients with more than 2 previous lines of treatment, including previous mTOR inhibitors, ECOG PS 2, asymptomatic brain metastases (BM) or impaired renal function. The primary objective of the study was the safety of N, efficacy being the main secondary objective. Between February 2016 and June 2017, 729 pts have been enrolled. We report the results from the first 528 pts. Results: All pts had clear cell mRCC, median age was 64, 77.2% were male. ECOG PS was > 1 in 73 pts (14.7%), 27.5% pts had received prior everolimus, 29.7% pts had received more than 2 previous lines, IMDC risk groups were 19%/54.9%/26.1% for good/intermediate and poor risk respectively; 69 (14%) pts had BM at screening. With a median follow up of 13.1 months, median duration of treatment was 4.1 months [0-15.6], with 31.4% of pts still on therapy. Treatment discontinuation due to adverse event (AE) occurred in (48) 13.3% pts . 64 serious related AE have been reported in 52 pts (9.9%) including 7 renal failures and 6 pneumonitis. Median PFS was 4.4 months 95%CI[3;4.6] . At the time of this analysis, 170 pts have died and 12 months OS rate was 66.4% 95%CI[ 61.7; 70.7]. In subgroups analysis, ECOG-PS > 1 (Hazard Ratio (HR) = 2.450 [1.704;3.523]), more than 2 previous lines (HR = 1.442 [1.059;1.963]) and prior use of everolimus (HR = 1.704 [1.250;2.322]) were associated with reduced OS in univariate analysis. Conclusions: We report the first analysis of the largest prospective real world setting study of N in mRCC. NIVOREN study demonstrates that N safety and efficacy in a “real world” prospective study are comparable to the pivotal study. Clinical trial information: NCT03013335.
Cytoreductive nephrectomy in metastatic papillary renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).
Authors: Graham Jeffrey , Wells Connor , Donskov Frede , Lee Jae-Lyun , Fraccon Anna Paola , Pasini Felice , Porta Camillo , Bowman I. Alex , Bjarnason Georg A. , Ernst D. Scott , Rha Sun Young , Beuselinck Benoit , Hansen Aaron Richard , North Scott A. , Kollmannsberger Christian K. , Wood Lori , Vaishampayan Ulka N. , Pal Sumanta K. , Choueiri Toni K. , Heng Daniel Yick Chin
Published: February 2018

581

Background: There is evidence that cytoreductive nephrectomy (CN) may be beneficial in metastatic renal cell carcinoma (mRCC), but the role of CN in patients with papillary histology is unclear. Methods: Using the IMDC database, a retrospective analysis was performed on patients with papillary mRCC treated with or without CN. Baseline characteristics and IMDC risk factors were collected. Median overall survival (OS) was determined for both patient groups. Multivariable Cox regression analysis was performed to control for imbalances in individual IMDC risk factors. Results: In total, 353 patients with papillary mRCC with (n = 75) or without (n = 278) a component of clear cell histology were identified. Median follow-up time was 57.1 months (95% CI 32.9-77.8) and the OS from the start of first-line targeted therapy for the entire cohort was 13.2 months (95% CI 12.0-16.1). Baseline characteristics are in Table 1 and patients who had CN were more likely to be younger, with better KPS, and have sarcomatoid histology. Median OS in patients with CN was 16.3 months (95% CI 13.1-19.2), compared to 8.6 months (95% CI 6.1-12.2; p < 0.0001) in the no CN group. When adjusted for individual IMDC risk factors, the hazard ratio (HR) of death for CN was 0.62 (95% CI 0.45-0.85; p = 0.0031). Conclusions: The use of CN in patients with mRCC and papillary histology appears to be associated with improved survival when compared to no CN after adjustment for risk criteria. A clinical trial in this rare population may not be possible but this data does corroborate with clear cell literature. [Table: see text]
Utilization and survival implications of a delayed approach to targeted therapy for metastatic renal cell carcinoma: A nationwide cancer registry study.
Authors: Woldu Solomon L. , Matulay Justin T. , Clinton Timothy N , Singla Nirmish , Freifeld Yuval N , Sanli Oner N , Krabbe Laura-Maria , Hutchinson Ryan C , Lotan Yair , Hammers Hans J. , Hannan Raquibul , Brugarolas James , Bagrodia Aditya , Margulis Vitaly
Published: February 2018

586

Background: Targeted therapy (TT) is the first-line option for metastatic renal cell carcinoma (mRCC) however, it is not curative and associated with a high-cost and adverse events. Preliminary data suggests TT may be safely delayed in appropriately selected patient, however the utilization and impact of delayed TT has not been evaluated on larger-scale. Methods: The National Cancer Database (NCDB) was queried from 2006-2012 for patients with mRCC treated with cytoreductive nephrectomy and TT. Time to initiation of TT was defined as ‘early’ (within 2 months), ‘moderately delayed’ (2-4 months), and ‘delayed’ (4-6 months), and ‘late’ ( > 6 months) based on time from diagnosis to initiation of therapy. Multivariable logistic regression was performed to determine factors associated with delayed TT. The impact time to initiation of TT on OS was estimated by Kaplan-Meier and Cox multivariable survival analysis. Results: For2,716 patients in the analysis, the median (interquartile range [IQR]) follow-up was 18.8 (9.1-32.9) months, and 71.8% of patients had died at last follow-up. The median (IQR) time from diagnosis to initiation of TT was 2.1 (1.3-3.23) months, with the longest delay being 20.1 months. 1,255 patients (46.2%) had early TT, 1,072 patients (39.5%) had moderately delayed TT, 284 patients (10.5%) had delayed TT, and 105 patients (3.9%) had late TT. Delay in TT was not found to be a predictor of mortality in multivariable analysis; early TT (reference), moderately delayed TT (HR 0.98, p = 0.74), delayed TT (HR 0.95, p = 0.51), and late TT (HR 0.86, p = 0.20). Time from diagnosis to initiation of TT and time from initiation of TT to patient death were not correlated after control for covariates ( r= 0.04, p = 0.08). Conclusions: Delay in initiation of TT for mRCC was not an independent predictor of worse OS. Although this study is subject to limitations of observation study design and selection bias, the results are consistent with the notion that in carefully selected patients, outcomes might not be compromised with initial observation. Prospective, randomized evaluation is warranted.
Impact of metastatic local treatment in the strategy of metastatic renal cell carinoma including sterotactic radiotherapy, surgery, and radiofrequency in an expert center.
Authors: Salabert Laura , Gross-Goupil Marine , Haaser Thibaud , Bernhard Jean-Christophe , Palussière Jean , Ravaud Alain
Published: February 2018

596

Background: Standard treatment of metastatic renal clear cell carcinoma is based upon nephrectomy, and systemic treatment with targeted agents. These drugs induce frequent side effects that may compromise observance and quality of life. Considering a focal treatment of one or more metastases can lead to a drug-holidays, or allow to postpone systemic treatment start in oligometastatic disease. Such focal treatment techniques are surgery, radiofrequency ablation (RFA) or stereotactic radiotherapy (SRT). Methods: In this retrospective, monocentric and analytic study, we analyzed progression-free survival (PFS) and overall survival (OS) after a focal treatment in a cohort of patients from Bordeaux University Hospital, involving similar staff members along time. We have also reported local control, complications and potential predictive factors associated with a better outcome. Results: Seventy-one patients with 78 focal treatments (23 RFA, 47 metastasectomy and 8 SRT) have been included in our study. For 44 patients, the disease was oligometastatic, (1 to sites, less than 5 metastases) including 15 patients with a partial response to systemic treatment before the focal approach, and 12 patients with a dissociated response to systemic treatment. Progression post focal treatment occurred in 53 (74.6 %) of patients. Median PFS was 14 months (95 % confidence interval [CI], - 8-16 months); and median OS was 77 months (95 % CI, 41 months-not reach). Local control rate was 83.3 %, and complication rate was 36.3 % due to local treatments, without death related to iatrogenic events. A diagnosis of metachrone metastases and a disease-free interval between the first diagnosis and the occurrence of the metastases of at least one year seemed to be associated with better outcomes. Conclusions: Data observed in our study are consistent with those reported in literature. The prolonged OS and PFS post focal treatment should encourage clinical oncologists to discuss this multimodal approach (association of systemic and focal treatments). This approach should be also evaluated in the context of the immunocheckpoint inhibitor in the future.
The perineural invasion paradox: Is perineural invasion an independent prognostic indicator of biochemical recurrence risk in patients with pT2N0 prostate cancer?
Authors: Kraus Ryan , Cheng Nathan , Ji Lingyun , Jennelle Richard Lester Stephen , Groshen Susan G. , Ballas Leslie
Published: February 2018

6

Background: Perineural invasion is a histologic feature present in approximately 19% of patients with prostate cancer. The prognostic significance of perineural invasion is controversial with recent studies yielding contradictory results. This study aims to assess whether perineural invasion on surgical pathology of patients with pT2N0 disease is an independent prognostic indicator of the risk of biochemical recurrence. Methods: We identified 201 patients with non-metastatic pT2N0 prostate cancer at our institution between 1/1/2008-12/31/2014. We reviewed the electronic medical record of these patients and identified whether the patient had biochemical recurrence (defined as PSA > 0.2 after surgery). A multivariable analysis was then performed using clinical and histological data for each patient to assess the association between perineural invasion and biochemical recurrence. Results: Of the 201 patients identified, 68.1% (137/201) had perineural invasion and 14% (28/201) had biochemical recurrence. Perineural invasion was associated with pT2c disease (p < 0.001), an increased number of positive cores on biopsy (p < 0.001), and a higher surgical Gleason score (p < 0.001). 19% of patients with perineural invasion had disease recurrence compared to 3.1% without perineural invasion (p = 0.001, Hazard ratio of 6.2). After performing a multivariable analysis and accounting for pathologic tumor staging and Gleason score, perineural invasion had a trend towards a significant association with recurrence (p = 0.085, Hazard ratio of 3.2). Conclusions: Perineural invasion may be an indicator of unfavorable histology such as a high Gleason score or more widespread disease rather than an independent prognostic indicator of the risk of biochemical recurrence.
Improved survival rates in kidney cancer patients with brain metastases treated with modern multidisciplinary approaches.
Authors: Bowman I. Alex , Bent Alisha , Le Tri , Christie Alana , Wardak Zabi , Mickey Bruce , Timmerman Robert D. , Hannan Raquibul , Brugarolas James
Published: February 2018

601

Background: Brain metastases (BM) in RCC have been associated with poor overall survival. Systemic targeted and immunotherapy and the increasing use of stereotactic radiosurgery (SRS) is likely to improve outcomes. Methods: A retrospective database of mRCC patients treated at our institution between 2006 and 2015 was compiled and patients with BM identified. Overall survival (OS) was analyzed by the Kaplan-Meier method. BM patients were compared to non-BM patients after adjusting for the timing of BM diagnosis, either prior to or during 1st line systemic therapy (ST). Results: 56 of 248 mRCC patients (22.6%) were diagnosed with BM, 35 (62.5%) prior to and 21 (37.5%) during 1st line ST. 43/56 (77%) received definitive local therapy for BM (surgery 10, SRS 26, or both 7). 9 received WBRT only and 4 had no CNS-directed therapy. All patients received ST. The median OS for ST-naïve BM patients compared with non-BM patients was 19.5 vs. 28.7 months (p = 0.012). Survival for patients developing BM on 1st-line therapy was not significantly different from patients without BM progressing on 1st line ST (11.8 vs. 17.8 months, p = 0.66). BM patients with poor risk mRCC by IMDC criteria did worse than those without BM regardless of line of therapy. Conclusions: Survival for patients with BM and favorable or intermediate risk mRCC is significantly better than historical reports and similar to non-BM patients in our population which was heavily treated with both systemic and local therapies. Patients with BM and poor risk RCC had significantly worse survival, suggesting that risk group should be considered when counseling on prognosis and selecting treatment. [Table: see text]
Prognostic and predictive role of fumarate hydratase in metastatic clear cell renal cell carcinoma.
Authors: Vernieri Claudio , Fucà Giovanni , Massa Simona , Ratta Raffaele , Verzoni Elena , Grassi Paolo , Calareso Giuseppina , Pruneri Giancarlo , Minucci Saverio , de Braud Filippo , Colecchia Maurizio , Procopio Giuseppe
Published: February 2018

617

Background: Metabolic disruption is frequent in renal cell carcinoma (RCC). Loss of the mitochondrial fumarate hydratase (FH) enzyme is associated with enhanced glycolytic metabolism, angiogenesis and clinical aggressiveness in type 2 papillary RCC. However, FH expression has never been evaluated in clear cell RCC (ccRCC). In this study, we investigated the impact of FH expression on the outcomes of patients (pts) with metastatic ccRCC (mccRCC). Methods: We included pts with mccRCC, for whom formalin-fixed, paraffin embedded (FFPE) tissue from the primary tumor had been obtained before initiation of systemic treatment. FH levels were evaluated by immunohistochemistry (IHC), and were defined as “normal” if FH expression in most cancer cells was comparable to the adjacent normal tubular cells and “low” in the opposite case. We evaluated the association between FH levels and clinico-pathological characteristics through the chi-squared or Fisher’s exact test. The log-rank test was used to compare survival between patient subgroups. Results: We evaluated 49 mccRCC pts, of whom 36 (73.5%) had synchronous metastases. FH levels were normal in 29 (59.2%) pts and low in 20 (40.8%) pts. FH expression was not associated with patient age (p = 0.5), sex (p = 0.34), tumor grade (p = 0.66), T stage (p = 0.38), N stage (p = 0.88), metastatic disease at the time of diagnosis (p = 0.4), number of metastatic sites (p = 1) or sarcomatoid morphology (p = 0.36). 44 pts received first-line therapy with tyrosine kinase inhibitors (TKIs). In pts with low as compared to normal FH levels, median progression free survival (mPFS) during any first-line treatment was 34 and 10.1 months, respectively (HR 0.39, 95% CI 0.18-0.85; p = 0.014), while mPFS during first-line TKI therapy was 34 and 8.42 months, respectively (HR 0.4, 95% CI 0.17-0.94; p = 0.03). Median overall survival (OS) was not reached in pts with FH-low tumors, while it was 22.9 months in normally expressing ones (HR 0.14, 95% CI 0.032-0.63; p = 0.028). Conclusions: In mccRCC pts, low FH expression in primary tumors is associated with longer PFS during any first-line or TKI treatment, and also with better OS. This is the first study to reveal a prognostic and predictive role of FH levels in mccRCC.
The EVERPRO study: Final results of a non-interventional study (NIS) evaluating the quality of life (QoL) in second-line treatment of metastatic renal cell carcinoma (mRCC) with everolimus.
Authors: Goebell Peter-Juergen , Herrmann Edwin , Kube Ulrich , Doehn Christian , Marschner Norbert Walter , Dietel Anja , Blumenstengel Klaus , Grimm Marc-Oliver , Scheffler Michael Thomas , Rogler Anja , Bergmann Lothar
Published: February 2018

631

The EVERPRO study: Final results of a non-interventional study evaluating QoL in second-line treatment of mRCC with everolimus Background: Although the prognosis of mRCC patients remains poor, median overall survival has improved since 2006, probably due to the introduction of TKIs. Everolimus treatment following first-line VEGFR-TKI was demonstrated to be efficacious and safe and is recommended by current guidelines. Assuring an adequate QoL has become a major therapy goal, especially in the 2nd line. Hence, QoL and the implication of time effort of everolimus treatment were the major objectives assessed in this study. Methods: Adult patients scheduled for in-label everolimus treatment after 1st line VEGFR-TKI or bevacizumab were eligible. QoL was assessed by means of the NCCN-FACT FKSI-19 questionnaire. Additionally, time needed for therapy and limitations thereof were evaluated based on a particularly developed questionnaire (including total treatment duration and treatment type). Results: 202 patients were evaluable for analyses. Median treatment duration was 19.1 weeks [95% CI: 16.4 – 23.0] and median time to progression was 26.0 weeks [95% CI: 23.3 – 32.6]. The FKSI-19 median total score remained stable during treatment. The median time effort spent on total therapy was 20 hours per patient. Most of the patients stated to have ‘no’, ‘a little’ or ‘moderate’ limitations in their daily, social and professional life. Two months after treatment start, 65 patients reported none or a little time burden due to therapy. 167 patients experienced 804 adverse events (AEs) in total. The most commonly reported AEs related to everolimus were dyspnoea, fatigue and anaemia (all grade). Conclusions: QoL was maintained during everolimus therapy and limitations as well as time effort were acceptable for most patients. The observed safety profile is consistent with previous data and does not implicate changes on the benefit-risk balance of everolimus. This study supports previously published data demonstrating that everolimus is an effective and safe treatment option following a VEGF(R)-targeted drug. Clinical trial information: 2284.
Carcinomas of the renal medulla: A comprehensive genomic profiling (CGP) study.
Authors: Bratslavsky Gennady , Jacob Joseph M , Shapiro Oleg , Elvin Julia Andrea , Vergilio Jo-Anne , Suh James , Ramkissoon Shakti , Ali Siraj Mahamed , Schrock Alexa Betzig , Miller Vincent A. , Stephens Philip J. , Gay Laurie M. , Bourboulia Dimitra , Mollapour Mehdi , Ross Jeffrey S.
Published: February 2018

640

Background: Collecting duct carcinoma (CDC) and renal medullary carcinoma (RMC) represent rare tumors that arise in the renal medulla are therapy resistant tumors that progress rapidly. Methods: DNA was extracted from 40 microns of FFPE specimen from refractory CDC (46 cases) and RMC (24 cases). CGPwas performed using a hybrid-capture, adaptor ligation based next generation sequencing assayto a mean coverage depth of > 800X. Tumor mutational burden (TMB) was calculated from a minimum of 1.11 Mb of sequenced DNA as previously described and reported as mutations/Mb. Microsatellite instability status (MSI) was determined on 114 loci. Results: All CDC patients were older and more frequently male (Table). Sickle cell trait was identified in both CDC and RMC, but far more frequently associated with RMC. All (100%) of CDC and RMC were clinically advanced Stage III and IV tumors with the primary tumor used for CGP in 70% of cases and a metastasis biopsy was sequenced in 30%. All (100%) CDC and RMC were intermediate (Grade 3) or high grade (Grade 4). In both tumor types, the GA/tumor was relatively low and there were no (0%) VHL GA. SMARCB1 GA were significantly more frequent in RMC than CDC but common in both tumors. Targeted therapies for kinase ( EGFR, RET) and MTOR ( NF2, TSC2) pathways were more frequent in CDC than RMC. At 1.8 mut/Mb, the median TMB was low for both tumor types with no (0%) of cases showing≥20 mut/Mb. No (0%) of the CDC or RMC cases featured MSI-high status. Conclusions: In addition to their histologic differences, the frequencies and types of GA seen in CDC differ significantly from that seen in RMC. The opportunities for biomarker driven targeted therapies for bothCDCand RMC appear limited with rare opportunities to target GA in TKGFR and MTOR pathways for CDC. Similarly, the relatively low TMB and absence of MSI-High status in CDC and RMCalso predicts that these tumors may be resistant to immunotherapies.[Table: see text]