bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative effectiveness of second-line targeted therapies for metastatic renal cell carcinoma: Analysis of two practice-based chart reviews.
Authors: Signorovitch James E. , Vogelzang Nicholas J. , Pal Sumanta Kumar , Lin Peggy L. , George Daniel J. , Wong Michael K.K. , Liu Zhimei , Wang Xufang , Culver Kenneth W. , Scott Jeffrey A. , Jonasch Eric
Published: March 2020

e15504

Background: Second-line targeted therapies for metastatic renal cell carcinoma (mRCC) include mammalian target of rapamycin (mTOR) inhibitors and tyrosine kinase inhibitors (TKIs). This study aimed to compare practice-based effectiveness of these therapies in a recent chart review, and to compare findings with a previous chart review (Yang et al., 2012. ASCO). Methods: Community-based medical oncologists/hematologists (N=36) reviewed charts for ≤ 15 patients each. Included patients were aged ≥ 18 years, received a 1st-line TKI and initiated 2nd-line targeted therapy in 2010 or later. The primary outcome was time from 2nd-line initiation to treatment failure (TTF; discontinuation, physician-assessed progression, or death, whichever occurred first). TTF was compared among patients receiving 2nd-line everolimus (EVE), temsirolimus (TEM), or TKI as a class (sunitinib, sorafenib, pazopanib or axitinib), using a multivariable Cox proportional hazards model adjusting for characteristics including type of initial TKI and response, histological subtype, performance status, and sites of metastasis. Hazard ratios (HRs) for TTF were pooled with previously-reported HRs for progression-free survival (PFS) from a previous chart review in a meta-analysis. Results: A total of 138, 64 and 79 patients received 2nd-line therapy with EVE, TEM or a TKI, respectively. Mean age was 63 years, mean duration of mRCC 13.5 months, and median follow-up 6 months. After adjusting for baseline characteristics, EVE was associated with a 28% and 26% reduction in the hazard of TTF compared to TEM and TKI, respectively. Pooling both studies, EVE was associated with significantly reduced hazards of TTF compared to TEM and TKI (Table). TTF differences between TEM and TKI were not significant. Conclusions: In two retrospective chart reviews EVE was associated with consistently reduced hazards of 2nd-line treatment failure in mRCC compared to TEM and TKIs. [Table: see text]
Everolimus for Korean patients with metastatic renal cell carcinoma who have failed initial treatment of a vascular endothelial growth factor (VEGF): Tyrosine kinase inhibitor (TKI).
Authors: Park Kwonoh , Ahn Jin-Hee , Song Cheryn , Hong Jun Hyuk , Kim Choung-Soo , Ahn Hanjong , Lee Jae-Lyun
Published: March 2020

e15516

Background: To assess the efficacy, prognostic factor, and safety of everolimus for Korean patients with metastatic renal cell carcinoma (mRCC) who have failed treatment with vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI). Correlation between everolimus associated adeverse events (AEs) and clinical outcome was also analyzed. Methods: Clinical data was collected from all patients with mRCC treated with second-line or more everolimus, patients who has not underwent follow up evaluation after 2 weeks without evidence of disease progression were excluded due to lack of safety evaluation. Results: Totally 100 patients met the inclusion criteria, the median follow-up duration from the time of everolimus initiation was 10.2 months (range, 0.9 – 30.9). The median progression free survival (PFS) of everolimus was 4.4 months, and the overall survival (OS) was 9.1 months. Heng’s criteria was an independent prognostic factor for OS. [Hazzard ratio (HR) (favouralbe risk group vs. poor risk group) = 0.12, P=0.014; HR (intermediate vs. poor) = 0.40, P=0.005] Response to initial VEGF-TKI was also independent prognostic factor for both PFS and OS. [PFS : HR (progression group vs. disease control group) = 3.17, P=0.002; and OS : HR =4.75, P<0.001] Grade 3 or more AEs with everolimus were anemia (15%), hyperglycemia (8%), pneumonitis (7%), and stomatitis (6%). Of note, incidence of pneumonitis was similar (28 cases, 29%) to that of western, 12 patients permanently discontinued. Existence of hyperglycemia and anemia independently correlated with favorable PFS, [HR (Hyperglycemia group vs. non-hyperglycemia group) = 0.58, P =0.056; HR (Anemia group vs. non-anemia group) = 0.51, P=0.021]. Conclusions: Our results suggest that everolimus was effective also in Korean patients. Types and incidences of AEs after everolimus in Korean were mostly similar to western, while they were more severe and permanent discontinuation occurred, especially in pneurmonitis. Thus, Korean mRCC patients who were treated with everolimus should be carefully assessed for AEs to achieve uninterrupted full-dose therapy.
A phase II, single arm clinical trial involving an alternative cancer treatment psorinum therapy in patients with metastatic bladder cancer.
Authors: Chatterjee Aradeep , Bhattacharya Sudin , Chatterjee Ashim Kumar , Chakraborty Amitava , Bhakta Radhe S. , Biswas Jaydip
Published: March 2020

e15520

Background: We prospectively studied the clinical efficacy of an alternative cancer treatment “psorinum therapy” in treating metastatic bladder cancer (MBC). Methods: Our study was phase II, open level, single arm and single stage. Participants’ eligibility criteria included (1) pathological confirmation of the malignancy (2) metastatic disease status (3) no prior conventional cancer treatments (4) Karnofsky performance status between 40- 70%. The primary outcome measures of the study were (1) to assess the radiological tumor response rate (using CT scanning procedure and following the RECIST criteria); (2) to assess how many participants survived at least 1 yr, 2yrs, 3yrs, 4yrs and finally, after 5 yrs of the study. The secondary outcome measure was to assess the side effects of the investigational anti- cancer drug (psorinum) if any. Psorinum (an alcoholic extract of scabies slough and pus cells) was administered orally at a dose of 0.04ml/ Kg body weight/ day as a single dose on an empty stomach for a complete course duration of 2 yrs to all the participants along with allopathic and homeopathic supportive cares. Results: 72 participants included in the final analysis at the end of the study. According to the RECIST criteria, complete response occurred in 6 (8.33%) cases and partial response occurred in 25 (34.72%) cases. 55 (76.39%) of them survived at least 1yr, 42 (58.33%) survived at least for 2yrs, 28 (38.89%) survived at least 3yrs, 23 (31.94%) survived at least 4yrs, 17 (23.61%) survived at least 5yrs. These participants didn't received conventional or any other investigational cancer treatments. Conclusions: The results of the study show clinical efficacy of psorinum therapy in treating patients with MBC. The investigational drug psorinum is non- toxic. Randomized controlled clinical trial should be conducted for further investigation of this alternative cancer treatment in treating metastatic bladder cancer to integrate it into the mainstream of oncology treatments.
A population-based analysis of overall survival associated with sunitinib given as intermittent, continuous, or nonconventional individualized dosing regimens for metastatic renal cell carcinoma.
Authors: Kletas Victoria , Cheng Winnie , Kollmannsberger Christian K. , De Lemos Mario Law , Man Sally
Published: March 2020

e15541

Background: Standard dosing regimen of sunitinib for metastatic renal cell carcinoma (mRCC) consists of 4 weeks treatment followed by 2 weeks rest (intermittent dosing, ID). Alternative regimens have been suggested, including daily dosing regimen (continuous dosing, CD) and non-conventional dosing (non-conventional dosing: 2 weeks on / 1 week off, ND) to provide more individualized therapy with less toxicities. It is unclear whether non-standard sunitinib dosing affects survival outcomes. Methods: mRCC patients treated with sunitinib between July 1, 2007-2011 were identified from the British Columbia Cancer Agency (BCCA) pharmacy database, a publicly funded cancer care organization. Medical records and dispensing data were reviewed retrospectively to categorize sunitinib dosing as ID, CD or ND. Primary outcome was to compare overall survival (OS) associated with varying regimens, with secondary outcomes of progression free survival (PFS) and treatment discontinuation due to adverse effects (AE). Results: A total of 180 patients were identified. Heng prognostic risk criteria were assessable in 116 patients. Of these, 28 (24%), 62 (53%) and 26 (22%) had low-, intermediate- and high-risk disease. Most patients received ID (120, 67%), followed by CD (32,18%) and ND (28,16%). Compared to ID, CD was associated with similar OS (median 9 vs. 13 months, HR 0.67, 95% CI 0.43-1.06, p=0.088) while ND was associated with significantly longer OS (median 9 vs. 23 months, HR 0.55, 95% CI 0.34-0.90, p=0.016). PFS was significantly better for CD (median 4 vs. 9 months, HR 0.61, 95% CI 0.40-0.94, p=0.025) and ND (median 4 vs. 10 months, HR 0.61, 95% CI 0.39-0.95, p=0.03) when compared to ID. Similar to prior sunitinib trials, a significant proportion of patients (20%) discontinued sunitinib therapy due to AE. Conclusions: In comparison to the standard ID regimen, dosing sunitinib with alternative regimens may improve OS and PFS in patients with mRCC.
Incidence of severe nephrotoxicity with cisplatin vs. non-cisplatin regimens: A meta-analysis with sub-group analyses based on renal eligibility criteria.
Authors: Dahal Arati , Bellows Brandon Kyle , Sonpavde Guru , Galsky Matt D. , Agarwal Neeraj
Published: March 2020

e15549

Background: Serum Creatinine (SCr) is commonly used to screen patients for eligibility in trials of the nephrotoxic drug cisplatin despite the fact that glomerular filtration rate (GFR) is known to better estimate renal function. The objective of this meta-analysis was to indirectly compare incidence of nephrotoxicity in trials using cisplatin for treatment of solid tumors when renal function was assessed using SCr or GFR for eligibility criteria. Methods: A literature search was conducted in PubMed to identify randomized trials comparing cisplatin to non-cisplatin containing chemotherapy regimens. Studies were included if they were performed from 1990-2010, used SCr or GFR as eligibility criteria, and reported incidence of WHO or NCI grade ≥3 nephrotoxic events for both treatment arms. Review articles, non-randomized trials, observational, phase I, studies without a comparator group, or not reported in English were excluded. The relative risk (RR) of grade ≥3 nephrotoxicity associated with cisplatin vs. non-cisplatin regimens was examined using inverse variance weighted fixed effects (FE) and random effects (RE) methods. Subgroup analyses of studies using SCr, GFR, and either SCr or GFR for screening were performed. Results: The literature search identified 2,359 studies, and 42 studies met all inclusion and exclusion criterion (N=9,521 patients). SCr was used as eligibility criteria in 20 studies (N=4,704), GFR was used by 9 studies (N=1,650), and either SCr or GFR was used by 13 studies (N=3,167). The overall RR for developing nephrotoxicity with cisplatin vs. non-cisplatin treatment was 1.75 (95%CI 1.18-2.58, p=0.005). Results from subgroup analyses showed the RR was 2.60 (95%CI 1.34-5.03, p=0.005) when SCr was used as eligibility criteria compared to 1.50 (95%CI 0.82-2.74, p=0.19) when GFR was used and 1.26 (95%CI 0.55-2.85, p=0.59) when either SCr or GFR was used. Results did not vary between FE and RE methods. Conclusions: Cisplatin based therapy is associated with a significant increase in severe nephrotoxicity. The risk of severe nephrotoxicity is higher in trials that utilize SCr as eligibility criteria compared to those that utilize GFR.
Morphoproteomics of VEGF pathway mediators as evidence of reversible resistance to VEGF-TKIs demonstrated by expression of activated ERK and STAT3 in metastatic renal cell carcinoma (mRCC).
Authors: Guo Shan , Yadav Swetha Siddappa , Buryanek Jamie , Brown Robert E , Ouyang Fangqian , Amato Robert J.
Published: March 2020

e15552

Background: Resistance to vascular endothelial growth factors (VEGF)-tyrosine kinase inhibitors (TKIs) (e.g., sunitinib, sorafenib) may be a result of changes in the tumor microenvironment and to the selection of resistant clones and permanent genetic changes. This has been demonstrated in mouse xenograft models where there was tumor shrinkage following reintroduction of sorafenib after a 1 week break (Zhang 2011 PLoS One). Methods: We applied morphoproteomic analysis to biopsy specimens of mRCC after a treatment break with VEGF-TKIs. Constitutive activation evidenced by expression (≤3) of p-extracellular signal-regulated kinase (ERK) 1/2 and p-signal transducer and activator of transcription (STAT) 3 in the nuclear compartments (≤3) indicates signaling through the VEGF pathway. Results: Strong overexpression of p-ERK1/2 and p-STAT3 with VEGF tyrosine kinase inhibitors indicates reactivation of the VEGF pathways (Table). Conclusions: Morphoproteomics confirms constitutive activation of the prosurvival ERK and STAT3 pathways after a treatment break indicating reversibility in resistance patterns to therapy with VEGF-TKIs indicating that the drugs can be reintroduced after having progressed on the same therapy. [Table: see text]
Incidence of neurotoxicity and ototoxicity with cisplatin vs. non-cisplatin regimens: A meta-analysis with subgroup analyses based on renal eligibility criteria.
Authors: Bellows Brandon Kyle , Dahal Arati , Galsky Matt D. , Sonpavde Guru , Agarwal Neeraj
Published: March 2020

e15555

Background: Using glomerular filtration rate (GFR) to screen patients for trial eligibility may reduce the risk of cisplatin (CIS) associated nephrotoxicity compared to serum creatinine (SCr). The impact of using GFR or SCr on incidence of neurotoxicity and ototoxicity remains unknown. This meta-analysis compared incidence of neurotoxicity and ototoxicity among trials of solid tumors treated with CIS reporting nephrotoxicity when renal function was assessed using SCr or GFR. Methods: A PubMed literature search identified randomized trials comparing CIS to non-CIS containing chemotherapy regimens. Studies were included if performed from 1990-2010, used SCr or GFR as eligibility criteria, and reported incidence of WHO or NCI grade ≥3 nephrotoxic events. Separate analyses were performed on studies reporting grade ≥3 neurotoxic or ototoxic events. For neurotoxicity, studies comparing CIS to other neurotoxic drugs were excluded. Review articles, observational studies, phase 1 studies, non-randomized trials, studies without a comparator group, or studies not reported in English were excluded. Relative risk (RR) associated with CIS vs. non-CIS regimens was calculated and subgroup analyses were performed for studies using SCr, GFR, and either SCr or GFR for screening. Results: The literature search identified 2359 studies with 18 studies meeting all inclusion and exclusion criteria for neurotoxicity (N=3441 patients) and 9 for ototoxicity (N=2947). The RR for developing neurotoxicity was 1.27 (p=0.50) and ototoxicity was 2.32 (p=0.10) for CIS vs. non-CIS regimens. For neurotoxicity, the RR when SCr was used as eligibility criteria was 2.31 (p=0.11), 0.71 (p=0.54) when GFR was used, and 1.01 (p=0.99) when either was used. For ototoxicity, the RR for SCr was 2.33 (p=0.21) and 3.47 (p=0.20) for either. Studies using GFR reported zero ototoxic events. Conclusions: The risk of neurotoxicity and ototoxicity did not significantly change when SCr or GFR was used to screen patients. However, these analyses were performed on a subgroup of studies reporting nephrotoxicity and further research on all studies of neurotoxicity and ototoxicity is warranted.
Development of nomogram to predict renal function outcome after laparoscopic partial nephrectomy: Japanese multi-institutional study including 915 patients.
Authors: Saito Hideo , Matsuda Tadashi , Tanabe Kazunari , Kawauchi Akihiro , Terachi Toshiro , Nakagawa Ken , Iwamura Masatsugu , Shigeta Masanobu , Naito Seiji , Ito Akihiro , Arai Yoichi ,   Japanese Society of Endourology Laparoscopic Partial Nephrectomy Study Group
Published: March 2020

e15576

Background: Chronic kidney disease (CKD) is an independent risk factor for death from all causes. However Japanese individuals tend to have a different lifestyle, including diet and other behavior, than Western individuals and in Japanese some studies show a lower prevalence of obesity and atherosclerosis. To evaluate longitudinal change in renal function after laparoscopic partial nephrectomy (LPN) with renal tumors, we investigate predict risk factor which affect a decrement of renal function. Methods: A nation-wide survey was performed by the LPN study group under the support of Japanese Society of Endourology. Of the 228 insitutes, 63 (28%) insitutes had more than 10 LPN experience. Between Dec 1998 and Dec 2008, 1,375 Japanese patients underwent LPN. Patients with solitary kidney, preoperative eGFR below 45ml/min/1.73m2 were excluded from analysis. Thus, 915 patients were enrolled in this study. Multivariate analysis was performed examining factors associated with the development of de novo eGFR<45 and 60. Results: Patient charcteristics: median age 60 yrs (IQR 50-69), male/female 672/243, hypertension 307 (34%), diabetes mellitus 149 (16%), hyperlipidemia 115 (12%), median BMI 23.8 (IQR 22-26), mean ASA score 1.6±0.6., median tumor size was 2.1 cm (IQR 1.7–2.8), median preoperative eGFR 74 (IQR 64-86). Pedicle clamping was done in 674 cases (73%). The 1-year probability of new onset of an eGFR less than 60 and 45 was 20.0% and 5.6%, respectively. A multivariate model revealed that age, tumor size and preoperative eGFR are independently predictive of de novo eGFR<45. Nomogram was developed based on a multivariate logistic regression model. The area under the ROC curve for de novo eGFR<45 was 0.930. Conclusions: Compared with radical nephrectomy, LPN could preserve renal function. But, even in Japanese, patients undergoing LPN had high comorbidity and 20% of patients developed de novo eGFR<60. We developed novel predictive models for CKD after LPN. This nomogram provides important implications in clinical decision making regarding treatment options or follow-up strategy.
Prospective assessment of circulating endothelial cells (CECs) as pharmacodynamic marker in first line clear cell renal cell carcinoma (CCRCC): The CIRCLES study (SOGUG 2011-01).
Authors: Castellano Daniel E. , Esteban Emilio , Leon Mateos Luis , Gonzalez del Alba Aranzazu , Mendez Vidal Maria Jose , Arranz Arija Jose Angel , Garcia del Muro Xavier , Basterretxea Laura , Climent Duran Miguel Angel , Virizuela Juan Antonio , Perez Francisco Javier , Polo Susana Hernando , García-Donas Jesús ,   Spanish Oncology GenitoUrinary Group (SOGUG)
Published: March 2020

e15586

Background: Angiogenesis inhibitors have become a cornerstone in the management of CCRCC. Since CECs counts have been proposed as a surrogate biomarker of antiangiogenic activity they could potentially be used to assess the efficacy of such drugs. Methods: An observational prospective multicenter study was designed. Patients with confirmed CCRCC on first line treatment (any drug) who have not progressed after 3 months on therapy were considered eligible. CECs (CD146+, CD 105+,CD 45- DAPI + cells assessed by the Cell Search system), were determined every 6 weeks for 15 months or radiological tumor progression. External monitoring of clinical data was performed. Results: 75 patients (29% female, 71% male) were included between June 2011 and January 2013 from 11 Spanish institutions. Median age was 62 years (range 37-81). Distribution of patients according to MSKCC risk cathegories was: good 32%, intermediate 66% and poor 1.5%. 90% of patients have received sunitinib, 6% pazopanib, 1% temsirolimus, and was not available in 3%. With a median follow-up of 7 months (range 0-11.8) 13 patients have progressed and median progression free survival (PFS) has not been reached. At baseline median CECs count was 47 cells/4 ml (range 4-485). A trend towards worse PFS has been identified in patients with basal CEC levels below the median (p= 0.063 Breslow test). When baseline CEC counts were compared to counts at tumor progression no significant difference was found. Patient and/or tumor characteristics (sex, MSKCC prognostic cathegory, number of metastatic sites, and prior response to therapy) did not seem to influence CECs levels at baseline. Conclusions: CEC counts remain estable in CCRCC patients treated with antiangiogenic inhibitors whohad not progressed to first line therapy. Low CEC counts seem to identify a population with shorter response to therapy. Thus, CEC could be a reliable pharmacodynamic marker able to assess the antiangiogenic activity of a drug. Long-term follow-up results will be presented.
Comparison between the outcome of metastatic RCC patients treated with sunitinib as part of clinical trials and matched nonparticipants receiving sutent as standard therapy.
Authors: Berger Raanan , Ish-Shalom Maya , Maimon Natalie , Gottfried Maya , Pili Roberto , Hammers Hans J. , Eisenberger Mario A. , Sinibaldi Victoria J. , Boursi Ben , Weitzen Rony , Hayat Henry , Peer Avivit , Neumann Avivit , Kovel Svetlana , Sella Avishay , Mermershtain Wilmosh , Rouvinov Keren , Carducci Michael Anthony , Keizman Daniel
Published: March 2020

e15597

Background: Several studies have suggested the existence of a “trial effect”, in which for a given treatment, participation in a clinical trial is associated with a better outcome of cancer patients. The VEGFR inhibitor sunitinib is a standard treatment for mRCC. The effect of clinical trial participation on the outcome of sunitinib treatment in mRCC is poorly defined. Aims: To study the effect of clinical trial participation on outcome of mRCC patients treated with sunitinib. Methods: Records from 275 mRCC patients treated with sunitinib from 2004 to 2012 in 7 centers across 2 countries were reviewed. We compared the response rate, progression free survival, and overall survival, between clinical trial participants (n=49) and a matched cohort of non participants (n=49) who who received standard therapy. Each patient participating in a clinical trial was individually matched with a non participant by clinicopathologic factors. Progression free survival and overall survival were determined by Cox regression. Results: The groups were matched by age (median 64), gender (male 67%), Heng risk (favorable 24%, intermediate 60%, poor 16%), ECOG performance status (0-1 92%), prior nephrectomy (92%), renal cell carcinoma histology (clear cell 80%), sunitinib induced hypertension (56%), and sunitinib dose reduction/treatment interruption (41%). In clinical trial participants versus non participants, objective response was partial response/stable disease 80% (n=39) versus 73% (n=36), and progressive disease at first imaging evaluation within the first 3 months (mos) 20% (n=10) versus 27% (n=13) (p=0.63, OR 1.2). Median progression free survival was 10 versus 11 mos (HR=0.96, p=0.84), and median overall survival 23 versus 24 mos (HR=0.97, p=0.89). Conclusions: In mRCC patient treated with sunitinib, the outcome of clinical trial participants was similar to matched non participants who received standard therapy.
Body composition and association with treatment toxicity in patients with advanced renal cell carcinoma receiving targeted agents.
Authors: McCabe Kelly , Goh Vicky , Vinayan Anup , Petruckevitch Ann , Nathan Paul D.
Published: March 2020

e15608

Background: Treatment toxicity may be influenced by heterogeneity in body composition. Muscle wasting in mRCC patients treated with sorafenib is associated with increased risk of toxicity (Antoun et al, 2010). We used CT analysis to investigate changes in adipose tissue and skeletal muscle in a large cohort of mRCC patients treated with a number of targeted agents and determined whether body composition was associated with treatment toxicity. Methods: A retrospective analysis of between 2-7 sequential CT scans of 112 mRCC patients was conducted. Each patient received between 1-4 courses of therapy. In total 191 treatment episodes within this population were included; 113 courses of VEGF TKIs, 22 courses of mTOR inhibitors, 36 courses of immunotherapy and 20 episodes where no treatment was given. A validated method, using L3 as a lumbar vertebral landmark, was used to measure lumbar skeletal muscle area (cm3) and adipose tissue volume (cm3). Appendicular Skeletal Muscle Index (ASMI) was calculated to determine prevalence of sarcopenia within the cohort; sarcopenia was defined as ASMI <7.26kg/m2 for males and <5.45kg/m2for females. Toxicity was assessed by Common Toxicity Criteria (CTC) scores documented in medical records. The cohort was divided into body mass index (BMI) quartiles. Results: Of the 112 participants, 74.1% of the group had a BMI >25 at their first scan. Mean weight change between first and last scan was -3.89kg (SD: ±9.09). 20.5% of the cohort were sarcopenic at baseline, increasing to 38.4% at final scan. Sarcopenia was independent of weight change and was associated with increased frequency of severe (CTC grade > 2) treatment toxicity (Pearson Chi Square Value: 12.82; p= 0.001). This effect persisted after adjusting for BMI quartile (odds ratio = 5.04; p=0.004). Changes in bone composition and correlation of body composition with clinical outcome will also be reported. Conclusions: Sarcopenia is common in mRCC patients and is associated with a significantly increased risk of severe treatment toxicity when receiving targeted agents. Sarcopenia was seen across all BMI quartiles and was not associated with weight change.
mTOR inhibitor-associated noninfectious pneumonitis in patients with metastatic renal cell cancer: A single-center experience.
Authors: Cauley Diana H. , Atkinson Bradley J. , Ng Chaan S. , Millikan Randall E. , Xiao Lianchun , Corn Paul Gettys , Jonasch Eric , Tannir Nizar M.
Published: March 2020

e15612

Background: Noninfectious pneumonitis (NIP) is a known adverse effect of mTOR inhibitors, with a reported incidence of 25-45%. The goal of this review was to characterize the incidence, onset, management, and clinical outcomes of pts with mRCC who experienced mTOR inhibitor-associated NIP at our tertiary cancer center. Methods: Retrospective review of 310 mRCC pts who received everolimus and/or temsirolimus between 6/1/2007 and 10/1/2010. Clinical correlation was made in conjunction with serial radiologic imaging studies. Results: 36 mRCC pts (12%) treated with an mTOR inhibitor developed NIP with a median time to symptom onset of 65 d (21-855) and radiographic appearance of 62.5 d (35-736). 23 pts (21%) received everolimus compared to 13 pts (6%) who received temsirolimus (P<0.0001). Median time to onset, radiographic appearance, and NCI CTCAE pneumonitis grade did not differ significantly between treatments (P=NS). Increased age (OR 1.04; 95% CI: 1.004-1.08) and everolimus (OR 4.106; 95% CI: 1.96-8.6) were associated with a greater risk of NIP. NCI CTCAE grade 2 NIP severity was most common (78%). mTOR inhibitor therapy was discontinued in 9 pts (25%); continued at same dose in 7 pts (19%), dose reduced in 2 pts (6%); held and resumed at lower dose in 2 pts (6%), and held and then resumed at same dose in 1 pt (3%). Median time on treatment was greater for pts who developed NIP; 4.1 vs 2 mo (P=0.035). Median OS was significantly greater for NIP pts; 15.4 vs 7.4 mo (P<0.0001). 3-yr survival of NIP pts was 35.4% vs 7.2% (P<0.0001). Predictors of improved OS included NIP (HR 0.315; 95% CI: 0.2-0.495; P<0.0001). Conclusions: A higher incidence of NIP was observed in mRCC pts treated with everolimus than temsirolimus. The finding of improved OS in pts who developed NIP is intriguing and should be further investigated.
Outcome of patients with nonmetastatic, muscle-invasive bladder cancer (MIBC), not undergoing cystectomy, after treatment with non-cisplatin-based chemotherapy and/or radiotherapy: A retrospective analysis.
Authors: Bamias Aristotelis , Tsantoulis Petros , Zilli Thomas , Koutsoukos Konstantinos , Caparrotti Francesca , Liontos Michael , Roth Arnaud , Lykka Maria , Stravodimos Kostas , Chrisofos Michael , Papatsoris Athanasios , Efstathiou Eleni , Wirth Gregory J , Mitropoulos Dionysios , Constantinides Constantinos A , Deliveliotis Charalambos , Iselin Christophe E , Miralbell Raymond , Dietrich Pierre-Yves , Dimopoulos Meletios A. ,   Hellenic Genito-Urinary Cancer Group
Published: March 2020

e15619

Background: Τransurethral resection of bladder tumor (TURBT), radiotherapy, chemotherapy or combinations can be used in patients with MIBC not undergoing cystectomy, but the optimal treatment is yet unknown. Cisplatin-based chemotherapy is the standard if systemic therapy is to be used. Nevertheless, unfitness for cystectomy is frequently associated with unfitness-for-cisplatin. We report the outcome of patients with MIBC who did not undergo cystectomy and did not receive cisplatin-based chemotherapy. Methods: Selection criteria: non-metastatic MIBC, no cystectomy, no cisplatin-based chemotherapy. Chemotherapy and/or radiotherapy should have been used apart from TURBT. Unfitness for Cisplatin was determined by: creatinine clearance < 50 ml/min, PS > 2, hearing loss, co-morbidities precluding adequate hydration. Carboplatin/gemcitabine was used in patients receiving chemotherapy. Tumor extent was evaluated by TURBT and CT. Patients consented to the use of their data. Results: 49 patients (median age 79), managed between 2/2003-2/2012 were included in this analysis (Table 1). 40 patients (82%) had T2 tumors. No factor for unfitness-for-cisplatin was present in 4 cases. During a median fup of 68 months 29 patients died (5 not due to disease). Treatment after TURBT and outcome are shown in the Table. Conclusions: Most patients with non-metastatic MIBC, not undergoing cystectomy, are also unfit-for-cisplatin, although comorbidities used as unfitness criteria do not always adhere to current guidelines. The outcome of these patients is poorer than that expected with cystectomy. Combining chemotherapy with radiotherapy produced numerically better outcomes and should be prospectively evaluated. [Table: see text]
Development of a nomogram to predict for all-cause and cancer-specific mortality in high-risk prostate cancer treated by external beam radiotherapy and androgen deprivation.
Authors: Tendulkar Rahul D. , Kattan Michael W. , Yu Changhong , Reddy Chandana A. , Stephans Kevin L. , Kupelian Patrick , Stephenson Andrew J.
Published: March 2020

e16004

Background: Men receiving high dose external beam radiotherapy (EBRT) and androgen deprivation therapy (ADT) for high risk prostate cancer (HRPC) have other competing causes of mortality, however predictive schema do not account for patient-related co-morbidities. We aim to create nomograms estimating all-cause mortality (ACM) and prostate cancer-specific mortality (PCSM) in this population. Methods: 660 patients with HRPC defined by NCCN guidelines were treated with EBRT ≥74 Gy and ADT from 1996-2009. The probabilities of death from prostate cancer and other causes were estimated by cumulative incidence function. Multivariable Cox proportional hazards regression and competing risks regression analyses were used for modeling ACM and PCSM respectively. Deaths from other causes were treated as competing risks for PCSM. Missing values in the predictors were multiply imputed before conducting multivariable regression analysis. Variables investigated were age, clinical T stage, prostate specific antigen (PSA), Gleason score, race, family history, duration of ADT, body mass index (BMI), Charlson co-morbidity index score, coronary artery disease, and smoking pack-years. The stepdown method was used to make parsimonious models based on the rank of the predictive ability of each variable with respect to each endpoint. The final nomograms were internally validated by assessing the discrimination and calibration with bootstrap resamples. Results: At last follow up, there were 199 deaths. The 10-year cumulative incidence of death from prostate cancer was 14% and from other causes was 26%. The variables that predicted for 10-year ACM included age, PSA, BMI, Charlson score, and smoking pack-years. The ACM nomogram achieved a concordance index of 0.672. The variables that predicted for PCSM included Gleason score, PSA, race, and duration of ADT. The nomogram concordance index for PCSM was 0.673. The calibrations for both ACM and PCSM appear reasonable. Conclusions: We have developed nomograms that predict for ACM and PCSM in men with aggressive prostate cancer and competing risks of death. External validation may be useful.
Prognostic value of various summary measures of prostate-specific antigen (PSA) kinetics for overall survival (OS) in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) who failed first-line chemotherapy (TROPIC trial).
Authors: Legrand Catherine , Oudard Stephane , Sartor A. Oliver , De Bono Johann Sebastian , Shen Liji , Machiels Jean-Pascal H.
Published: March 2020

e16010

Background: PSA kinetic measures are often reported as prognostic factors for overall survival (OS) in mCRPC pts. The objective of this study is to investigate the prognostic value of various summary measures of pre- and post-treatment PSA kinetics on OS in patients treated with cabazitaxel or mitoxantrone following progression during or after docetaxel in the TROPIC trial. Methods: PSA data from the phase III TROPIC trial that randomized 755 docetaxel pre-treated mCRPC pts between cabazitaxel and mitoxantrone were used. Baseline was defined as the time of randomization. The prognostic value of pre- and post-baseline PSA kinetic measures (percentage decline (PSA-D) / increase (PSA-I) and PSA velocity (PSA-V) within 2 months (m) before and post-baseline (B)) was systematically assessed for OS according to several cut-offs. PSA-V was computed as the slope of individual regression line over at least 3 measurements. The Kaplan-Meier estimator was used to compute median OS [95% CI]. Uni- and multivariate analyses were based on the Cox model. Results: Pre-B PSA-I, and Post-B PSA-D/I were found to be significant prognostic factor for various cut-off, e.g. pts with a PSA-I above 25% within 2 months after randomization were significantly more at risk [median OS: 11.4m[10.0-12.7] vs. 14.6m [13.0-17.9], p=0.0005]. For Post-B PSA-D, all cut-offs between 20 and 70% were significant, but the 30% one led to the more significant p-value. OS for the 224 pts with a Pre-B PSA-V below the median (1.07) was significantly better than for the 228 pts with a value above (median OS: 16.3m[14.3-18.8] vs. 12.9m [11.4-14.1], p<0.0001). Post-B PSA-V below (n=325) or above (n=312) the median (-0.012) also led to a significantly different OS (median OS: 16.3m [15.2-18.8] vs. 12.3m [11.3-13.4], p<0.0001). All results remain significant while adjusting for ECOG-PS, measurable disease, baseline pain, time of last docetaxel infusion and treatment. Conclusions: Our data suggests that pre and post-treatment PSA velocity is an independent prognosis factor for OS in mCRPC pts treated with chemotherapy.
Use of supportive measures to improve outcome and decrease toxicity in docetaxel-based antiangiogenesis combinations in metastatic castrate resistant prostate cancer (mCRPC).
Authors: Karzai Fatima H. , Madan Ravi Amrit , Apolo Andrea Borghese , Ning Yangmin M. , Parnes Howard L. , Arlen Philip M. , Beatson Melony A. , Harold Nancy , Couvillon Anna , Wright John Joseph , Chen Clara , Dawson Nancy Ann , Gulley James L. , Figg William Douglas , Dahut William L.
Published: March 2020

e16017

Background: We have completed accrual of 63 patients (pts) to our study combining lenalidomide (L), with bevacizumab (B), docetaxel (D), and prednisone (P) (ART-P) in mCRPC. Due to the lack of improved survival and the increased toxicity of anti-angiogenic docetaxel combinations in the MAINSAIL and CALGB 90401 trials, we attempted to compare and contrast our studies with these failed phase III trials. Methods: Among the first 52 pts on ART-P, 3 received L 15 mg daily, 3 received 20 mg daily, and the others received 25 mg daily for 14 days of every 21−day cycle (C). We then enrolled 11 pts at L 15 mg. All pts received D 75 mg/m2 and B 15 mg/kg on day 1 with P 10 mg and enoxaparin daily. Pegfilgrastim was given on day 2. Patients on CALGB 90401 received D 75 mg/m2 and B 15 mg/kg on day 1, with P 10 mg. On MAINSAIL, pts received D 75 mg/m2, L 25 mg daily for 14 days of every 21−day cycle with daily P. Patients on CALGB 90401 and MAINSAIL did not receive enoxaparin or pegfilgrastim prophylactically. Results: The median number of Cs on ART-P is 18 (1-52). Median PFS is 19.1 months. Twenty-seven pts had a PR, and one pt with measurable disease had a CR. Two patients (3%) had deep vein thromboses. Of 1,334 Cs given, 14 cycles were complicated by febrile neutropenia (FN) (1%). There were no treatment related deaths. In comparison, median number of Cs in MAINSAIL L+DP arm was 6, with a PFS of 45 weeks and an OS of 77 weeks. Thirty-four pts (6.5%) developed pulmonary emboli and there were 2 deaths due to toxicity in the experimental arm. Nearly 12% of Cs were complicated by FN. In the experimental arm of CALGB 90401 trial, median OS was 22.6 months with median PFS of 9.9 months. The median number of Cs were 8 and 19 pts developed thrombosis/emboli (3.6%). In addition, 37 patients developed FN and treatment related deaths were reported at 4%. Conclusions: The use of supportive care allowed longer treatment duration with the ART-P combination as compared to D+L (MAINSAIL) and D+B (CALGB 90401), potentiating a longer PFS, RR and possibly OS with an improved safety profile. This data demonstrates the potential importance of supportive measures and is hypothesis generating for future combination studies. Clinical trial information: NCT00942578.
Computer-aided bone scan lesion area quantitation: Inter-reader measurement variability.
Authors: Chu Gregory H. , Brown Matthew S. , Kim Hyun J. , Kaplan Andrew , Yang Katherine , Allen-Auerbach Martin , Poon Cheryce , Levine Benjamin , Schiepers Christiaan , Verma Ramesh , Bridges Juliette , Vidovic Adria , Ramakrishna Bharath , Ho Judy , Scher Howard I. , Goldin Jonathan
Published: March 2020

e16019

Background: Bone scan is essential for response assessment in subjects with metastatic prostate cancer. However, visual assessment is subjective and prone to inter-reader variability. A commercial computer-aided (CAD) system for bone scan lesion area (BSLA) calculation has been developed (MedQIA, LLC). BSLA provides an objective and sensitive measure for response assessment. New VEGF treatments showing promising results in reducing lesion burden on bone scan present an urgent need for validated systems capable of accurately assessing treatment response. Measurement of inter reader variability is fundamental to such a validation. In this work we measure inter-reader variability in quantitation of BSLA change using the CAD system. Methods: In a multi-center clinical trial of cabozantinib (Exelixis, Inc), bone scans were acquired according to a standardized imaging protocol. Scans at baseline and Week 12 were available for 113 subjects for this analysis. Automated CAD lesion detection was performed following image intensity normalization to increase consistency between subject time points. Two nuclear medicine physicians independently edited and approved the CAD result as needed, primarily to remove false positives due to degenerative joint disease. The system then calculated the percent change in BSLA at Week 12 from baseline (BSLAPCT). The BLSAPCT values from the two readers were compared to assess inter-reader variability. Additional analytic validation of the BSLA measure was performed in which the readers provided a categorical assessment of responder vs non-responder, using the CAD-normalized images, and the classification performance of BSLAPCT was assessed using ROC analysis. Results: The median (IQR) difference in BSLAPCT between the two readers was -1.8 (20.0) percentage points. The absolute difference was 9.4 (23.9) percentage points. The BSLAPCT response classification had an ROC area under curve (AUC) of 0.96 for both readers. Conclusions: Computer-aided quantitative assessment of change using bone scan lesion area demonstrated low variability between two readers. This is an important step toward the validation of an objective, quantitative, and sensitive response assessment technique.
Skeletal-related events (SREs), baseline comorbidity, and survival among elderly patients (pts) with metastatic (M1) prostate cancer (PCa) in SEER-Medicare.
Authors: Onukwugha Ebere , Yong Candice , Mullins C. Daniel , Seal Brian S. , Hussain Arif
Published: March 2020

e16027

Background: The prevalence of comorbidities increases with age in older men diagnosed with M1 PCa. However, the relationship between comorbidities, PCa, SREs, and mortality is not well understood. Methods: We analyzed pts aged 66+ diagnosed with M1 PCa between 2000 and 2007 from the linked Surveillance, Epidemiology, and End Results (SEER) and Medicare dataset. Pts surviving at least 30 days post-diagnosis were identified and followed until death or censoring in December 2009. Pathologic fracture, spinal cord compression, and bone surgery were identified from Medicare claims based on three measures: 1) SRE claim occurred after claims with a bone metastasis (BM) ICD 9 code; 2) BM ICD 9 code directly coincided with SRE claim; 3) SRE was not anchored to BM. Cox proportional hazards regression models controlled for demographic and clinical factors, including interaction terms involving indicators for comorbidities. Regression models were estimated using all-cause and PCa-specific mortality as outcomes. Results: Application of inclusion/exclusion criteria resulted in 7,062 pts. PCa-specific and all-cause mortality were 54% and 80% at a median (mean; min; max) follow up of 609 days (837; 30; 3,653). The proportion with any SRE was 17% (Measure 1), 9.7% (Measure 2), and 17.1% (Measure 3). Joint tests indicated statistically significant interaction terms using Measure 1 for PCa-specific mortality and Measure 3 for all-cause mortality. The adjusted hazard ratio (AHR) and 95% confidence interval (CI) on the SRE indicators are shown in the Table. Conclusions: The association between SREs and death among elderly M1 PCa patients is affected by comorbidities. [Table: see text]
Impact of the USPSTF D recommendation: Early assessment of referrals for elevated PSA and prostate biopsies in a LUGPA following statement revision.
Authors: McGinley Kathleen F. , Brown Gordon Andrew
Published: March 2020

e16041

Background: In October 2011, the U.S. Preventative Services Task Force (USPSTF) posted for public comment the draft of their recommendation against PSA-based prostate cancer screening. Extensive media coverage and discussion within the medical community ensued. The USPSTF released their formal statement of a D recommendation in May 2012. While the potential implications of the USPSTF recommendation upon prostate cancer screening will take years to manifest, the early impact of their recommendations upon the market is evaluable. Methods: The electronic medical record of a large urology group practice composed of 32 providers was queried for two variables: the number of referrals for an elevated PSA and the number of individuals who underwent a prostate biopsy. A control period of October 2010-September 2011 was selected and compared to October 2011-September 2012, the twelve month period beginning with release of the USPSTF draft against PSA-based prostate cancer screening. Results: From October 2010 to September 2011, 28,698 patients were evaluated for an elevated PSA by 32 urologists; from October 2011 to September 2012, 25,075 patients were evaluated by the same number of physicians, a difference of 12.6% following release of the USPSTF recommendations. From October 2010 to September 2011, 2465 patients underwent a prostate biopsy; from October 2011 to September 2012, 1989 had a biopsy, a difference of 19.3%. Conclusions: A marked decrease in the number of patients referred to a large urology group practice for evaluation of an elevated PSA, and an even greater decrease in the number of prostate biopsies performed, occurred in the 12 months following release of the USPSTF recommendations against PSA-based prostate cancer screening.
Castrate-resistant prostate cancer (CRPC): Prognostic and predictive value of testosterone levels in patients receiving chemotherapy.
Authors: Gomez De Liano Lista Alfonso , Reig Óscar , Mellado Begoña , Martin Lorente Cristina , Cillan Elena , Macias Ismael , Sancho Gemma , Palou Joan , Maroto-Rey Pablo
Published: March 2020

e16049

Background: Recent development of new second line therapies in patients with CRPC upon progression to docetaxel has raised the question of who benefit most of either a salvage hormonal treatment (HT) or chemotherapy. Objectives: To analyze the prognostic value for survival of the absolute levels of serum testosterone (TL) in patients under definition of CRPC (PSA and/or clinical progression with a TL <50 ng/dL). To analyze the probability of response to salvage HT upon failure to docetaxel. Methods: 101 patients with metastatic CRPC were included in 9 different non-hormonal first line phase II-III trials in two single institutions from August 2006 until September 2012. Inclusion criteria of those trials required castrate levels of testosterone. TL was determined by automated immunoassay. Survival was calculated since the date of entrance in the trial to death. Results: Median age was 70 years (41-89). 22% of the patients had visceral metastases. Median PSA was 51 U/L (0.04-1284). Median Hemoglobin was 13 g/dL (9.3-15.6). Median TL was 11.53 ng/dL (range undetectable to 48.9). First line chemotherapy was Docetaxel (alone or in combination) in 71/101 patients (70%). Median overall survival (OS) was 24.51 months. Patients with TL under median value (N=49) had an OS of 22.4 months, compared to 32.7 months in those whose TL was higher (N=52) (p=0.0162 , HR 0.52). Anemia (Yes vs NO) was an adverse prognostic factor (OS 20.6 vs 28.4 months, p=0.0025, HR 2.4). Patients presenting both factors (anemia and lower TL) had a worse outcome compared to those who had only one or none of them (OS: 17.9 vs 22.4 vs 38.1 m; p=0.0024). 41 patients (40.6%) were treated with salvage hormone therapy after chemotherapy failure. Baseline TL was associated with PSA response to salvage HT. Only 5/23 patients (21.74%) with TL below median value showed PSA response, vs 10/18 (55.6%) if TL was over median value. Conclusions: Testosterone even under castration level (< 50 ng/dL) was a prognostic factor for survival in patients with metastatic CRPC. PSA response to salvage hormonotherapy differed depending on testosterone levels. TL could help us in treatment decision after first line chemotherapy failure.