bluuebunny/crossref_metadata_2025 huggingface dataset:
Salvage chemotherapy with irinotecan and nedaplatin for cisplatin refractory germ cell tumors
Authors: Nakamura T. , Nonomura N. , Mikami K. , Shiraishi T. , Takaha N. , Okuyama A. , Miki T.
Published: August 2020

e16022

Background: Only 20 - 30 % of patients with cisplatin (CDDP) refractory germ cell tumor (GCT) will remain continuously disease-free with salvage chemotherapy. The present study investigated the combination chemotherapy with irinotecan (Ir) and nedaplatin (CDGP), the second generation derivative of CDDP developed in Japan, as salvage chemotherapy for CDDP-refractory GCT. Methods: Between June 1998 and December 2007, 39 CDDP refractory GCT patients treated with irinotecan and CDGP (IrN therapy) were assessed retrospectively. IrN therapy consisted of Ir: 100–150 mg/m2 on day 1, 15 or 200–300 mg/m2 on day 2, CDGP: 100 mg/m2 on day 1 every four weeks with oral administration of Chinese-herb ‘Hange-shashinto’ and sodium bicarbonate for diarrhea. After tumor marker normalization, residual masses were resected and chemotherapy was continued in the case of without marker normalization. Results: The median age was 31 years old (range; 17–48). The median number of cycles of prior chemotherapy was 6 (range; 2–30). The median number of cycles of IrN therapy was 3 (range: 1–9). The response rate was 30.8% ( CR: 0%, PRm−: 15.4%, PRm+: 15.4% ) and the outcome was no evidence of disease (NED) 46.2%, alive with disease (AWD) 25.6% and dead 28.2%, respectively. Twenty-five patients with IrN therapy as 2nd (17 cases) and 3rd (8 cases) line salvage therapy showed that the response rate was 48% (CR: 0%, PRm−: 16.0%, PRm+: 16.0, NCm−: 16.0%) and the outcome was as follows; NED 64%, AWD 16% and dead 20%, respectively. On the other hand, 14 pts who had the treatment as fourth-line or more showed less response rate (PR: 28.5%) and worse outcome (NED 14.2%). Major adverse events more than grade 3 were neutropenia and thrombocytopenia. These adverse events were manageable. Grade 4 diarrhea which was major adverse event of CPT-11 was observed in only one case and there was no treatment related death. Conclusions: This study demonstrates that combination chemotherapy with CPT-11 and CDGP showed significant anticancer activity for patients with CDDP-refractory GCT without severe adverse events. These findings suggest that salvage IrN therapy may be one of the options as second- or third-line therapy.

No significant financial relationships to disclose.
Association of therapy with sunitinib and treatment-related hyperparathyroidism in renal cell carcinoma
Authors: Gruenwald V. , Fenner M. , Varvenne M. , Reuter C. , Ganser A. , Ivanyi P.
Published: August 2020

e16023

Background: Targeted therapies have been thought to combine high potency with high specifity. With increasing experience with multitargeted tyrosine kinase inhibitors (MTKI) recent findings suggest various interactions with physiological organ functions. Here, we report on abnormalities of the mineral metabolism in patients with renal cell carcinoma (RCC) treated with MTKI. Methods: We identified a total of 61 patients with metastatic RCC and evaluable markers of bone metabolism, which were either treated at our institution (N=53) or followed (N=8) during March 2005 and December 2008. Chemistry and parathyroid hormone (PTH) tests were assessed retrospectively. Patients received either sunitinib (4 weeks on/2 weeks off schedule) or sorafenib (continuous dosing) for metastatic disease. PTH, calcium and phosphate were either determined prior to, during and in some cases after completion of therapy with MTKI. Statistical analyses included either student's t-test or one-way ANOVA. Results: Of 61 evaluable patients, 47 received sunitinib, 6 sorafenib, and 8 patients follow-up only. Mean phosphate levels significantly decreased during treatment from 1.151 (CI 1.077–1.224) to 0.9264 (CI 0.844–1.008) (P<0.0001), whereas mean calcium levels remained unchanged (2.37; CI 2.30–2.44 and 2.36; CI 2.28–2.43 mmol/l, respectively). Treatment with MTKI resulted in increased mean levels of PTH (118.3; CI 91.37–145.2), when compared to baseline 43.52 (CI 30.94–56.10) (P<0.0001). In 4 patients additional values after end of therapy were evaluable, which showed reversible PTH increase (42.7; CI 7.473–77.93). Increase of PTH remained significant for treatment with either sorafenib or sunitinib (P0.05). Conclusions: Treatment with MTKI is associated with dysregulated parathyroid axis, which may have clinical implications in a number of patients and therefore should be monitored throughout the treatment. The mechanism for hormone disturbances remains elusive, but may involve the PDGFR, which plays a major role in transmitting signaling of the bone metabolism.

[Table: see text]
The significance of urine NMP22 in the screening of urothelial cancer (comparison of ELISA and immunochromatography method)
Authors: Ikeda H. , Ishida Y. , Dejima T. , Nomura M. , Sanefuji H.
Published: August 2020

e16024

Background: The early diagnosis of urothelial cancer allows for effective local treatment and optimizes the success of surgical therapy. Urine nuclear matrix protein 22 (NMP22) was introduced for the detection of transitional cell carcinoma. Add to old NMP22 (ELISA), new NMP22 (immunochromotography method : BladderChek) can be available from 2004. The objective of this study is to determine whether there are any correlation between urine NMP22 (two methods) and the grade or stage of urothelial cancer, and whether it can serve as a biochemical marker of urothelial cancer. Methods: A total of 246 patients with hematuria or followed up after TUR-BT, from March 2007 to December 2007,visited our hospital and subsequently underwent cystoscopy. The 246 patients provided voided urine samples. We immediately examined urine cytology and NMP22 (two methods). We set the cut off value on 12.0U/ml for NMP22 (ELISA). NMP22 (BladderChek) was judged by qualitative analysis. We decided that in urine cytology, classI,II,III were negative, while IV,V were positive by Papanicolaou classification. Results: Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) were 66.7 %, 98.3 %, 81.8 %, 96.3 % in urine cytology, 40.7 %, 75.9 %, 16.2 %, 91.8 % in NMP22 (ELISA), 59.3 %, 79.3 %, 24.6 %, 94.5 % in NMP22 (BladderChek). In 9 cases with false negative of urine cytology, 4 cases were picked up by NMP22 (ELISA), and 5 cases by NMP22 (BladderChek). Sensitivity of grade 1 was 33.3 % in urine cytology, while 66.7 % in NMP22 (BladderChek). By adding NMP22 (BladderChek) to urine cytology, sensitivity rose about 18 %. Conclusions: The sensitivity of urine cytology was unexpectedly high. NMP22 (BladderChek) is more useful than NMP22 (ELISA) because of higher sensitivity, specificity and advantage of simplicity, rapidity. It seems that the addition of NMP22 (BladderChek) to urine cytology is beneficial.

No significant financial relationships to disclose.
Phase II study of aflibercept (VEGF-Trap) in patients (pts) with recurrent or metastatic transitional cell carcinoma (TCC) of the urothelium: A California Cancer Consortium trial
Authors: Twardowski P. , Stadler W. M. , Frankel P. , Lara P. N. , Ruel C. , Chatta G. , Heath E. I. , Quinn D. I. , Gandara D. R.
Published: August 2020

e16030

Background: The role and efficacy of subsequent systemic therapies for advanced TCC following failure of frontline platinum-based chemotherapy is unclear. There is evidence that vascular endothelial growth factor (VEGF) is important in the pathophysiology of TCC. Aflibercept is a recombinant fusion protein that binds and neutralizes multiple VEGF isoforms. Methods: Pts with measurable, metastatic or locally advanced urothelial TCC previously treated with one platinum-containing regimen were entered. Aflibercept was given at 4 mg/kg IV q 2 weeks. Response rate (RR) and progression free survival (PFS) were assessed in a 2-stage accrual design (22+18). A maximum of 40 pts were to be accrued to rule out a null hypothesized RR of 4% and PFS of 3 months versus alternative of 15% RR and 5.4 months PFS with α=0.12 and β=0.19. Results: 22 pts were accrued between 11/06–2/08. Pt characteristics: M/F 15/7; Median age 67 years (45–79); 18 had bladder primary. One partial response (4.5% RR) was seen in a pt with nodal metastasis. Median PFS was 3.5 months (95% CI: 1.8–4.1). Attributable grade 3 toxicities included: hypertension (2), proteinuria (1), pulmonary hemorrhage (1), back pain (1), upper GI bleed (1), hyponatremia (1), anorexia (1) and fatigue (1). There were no attributable grade 4+ toxicities Conclusions: Aflibercept was well tolerated with toxicities similar to those seen with other VEGF pathway inhibitors, however it has limited single agent activity in platinum-pretreated TCC pts.

[Table: see text]
Erlotinib with sirolimus for advanced renal cell carcinoma: Preliminary efficacy results
Authors: Flaig T. W. , Costa L. , Breaker K. , Schultz M. , Crighton F. , Kim F. J. , Drabkin H. A.
Published: August 2020

e16037

Background: The mammalian target of rapamycin (mTOR) is an important therapeutic target in the treatment of renal cell carcinoma (RCC). Temsirolimus, an analog of rapamycin, prolongs survival when used to treat high-risk RCC patients and is approved for the treatment of advanced RCC. Oral rapamycin (sirolimus/Rapamune) is less expensive than temsirolimus and plasma levels can be routinely monitored. Pre-clinical data indicate that the combined inhibition of the epidermal growth factor receptor (EGFR) and mTOR results in enhanced anti-cancer activity, especially in cell lines with wt-VHL. Methods: All patients on this study had metastatic or unresectable renal cell carcinoma with progression despite sunitinib and/or sorafenib. Treatment was started with erlotinib (Tarceva) 150 mg po daily. On day 8, sirolimus was begun with a single 6 mg loading dose and then given as 2 mg daily. Radiographic assessments were performed every 8 weeks. Results: The current data set was obtained through July of 2008. Enrollment started in July of 2006 with the last patient accrued in March 2008; 25 patients have been treated. The median subject age was 60 years with an average of 2.6 previous medical treatments. The unconfirmed median progression free survival (PFS) was 12 weeks (range 2–52) with 4 patients remaining on active treatment and included in this analysis. No confirmed complete or partial responses were observed, but meaningful stable disease (SD) (e.g., > 6 months) was noted in a small group of patients. The most common adverse events were rash and diarrhea with the majority of these observed as a grade 1 event. Grade 3 and 4 toxicities included rash, mucositis, neurological motor weakness, dehydration, worsening cardiac function, non-ST elevation MI, and anemia. Additional efficacy, toxicity and pharmacokinetic data will be presented. Conclusions: The combination of erlotinib and sirolimus produces a median PFS of 12 weeks in a significantly pretreated RCC population, which is not dissimilar to recent results with other mTOR inhibitors in this setting. The toxicity profile of this combination is consistent with the expectations of this pre-treated patient population with advanced RCC.

[Table: see text]
Predictors of renal function in nephron sparing surgery for renal cell carcinoma in solitary kidneys
Authors: Wosnitzer M. , Lee D. J. , Hirsch A. J. , McKiernan J. M.
Published: August 2020

e16045

Background: Partial nephrectomy (PN) is an effective option for the treatment of renal cell carcinoma (RCC) in patients who need to preserve renal function. However, the oncologic safety and functional outcome after PN in solitary kidneys have not been fully examined. We assessed the outcomes after PN, and evaluated predictors of post-operative renal function. Methods: A retrospective analysis of the Columbia Urologic Oncology database found 1327 patients were treated for RCC from 1988 - 2008, of whom 38 consecutive patients underwent PN on a solitary kidney. Glomerular filtration rate (GFR) was estimated with the Modification of Diet in Renal Disease (MDRD) equation. Severe chronic kidney disease (CKD) and renal failure were defined as GFR of 15–30 cc/min/1.73m2 and GFR<15, respectively. Cox proportional hazards regression methods were used. Results: The study group included 30 men and 8 women with unilateral RCC. The mean age was 63.2 years (range 35–83). The mean estimated blood loss was 465cc, the mean tumor diameter was 3.9cm, and 6 (17%) of the patients had a positive surgical margin. 9 patients (30%) had recurrence of RCC at a mean of 23 months postoperatively. Recurrence occurred in the kidneys of 4 patients, lung in 3 patients, bone in 3 patients, and the ipsilateral adrenal gland in one patient. The mean preoperative GFR was 55.6, and the GFR decreased postoperatively by an average of 14.2%. No patients required postoperative hemodialysis. Preoperative GFR (HR=1.01, p<0.01) and the volume of kidney removed (HR=0.93, p=0.01) were associated with severe CKD and renal failure on a univariate Cox regression analysis, but were not independent predictors after adjusting for age, race, tumor stage and grade. Preoperative GFR, volume removed, age, tumor stage or grade were not independent predictors of RCC recurrence. Conclusions: PN in solitary kidneys pose difficult challenges for surgical and clinical management. Nephron sparing surgery for the treatment of RCC is feasible with acceptable morbidity and renal function outcome. The volume of renal parenchyma removed and the preoperative GFR are associated with renal function loss several months after surgery, and may be useful in predicting long-term renal function.

No significant financial relationships to disclose.
Aberrant promoter methylation in serum of prostate cancer patients and controls
Authors: Singal R. , Navarro L. , Gordian E. , Ramachandran K. , Reis I. , Manoharan M. , Soloway M.
Published: August 2020

e16046

Background: The current screening method for prostate cancer (PC), which is based on prostate specific antigen (PSA) level lacks specificity and sensitivity. Previous studies have reported that increased levels of free circulating DNA (fcDNA) and hypermethylation of genes are associated with several cancers. In this study we evaluated the use of fcDNA level and aberrant promoter methylation of 4 genes in serum as biomarkers for PC. Methods: 89 PC patients, 59 with prostatitis (PT) and 104 with benign prostatic hyperplasia (BPH) were enrolled. Serum DNA was analyzed for methylation of GSTPi, RARB, RASSF1A and ECAD by methylation-specific PCR. FcDNA level was analyzed by quantitative PCR. We examined the effect of methylation and fcDNA on PC risk by fitting two logistic regression models, one comparing PC vs BPH and PT vs BPH and the other comparing PC vs PT+BPH. Models were adjusted for age, race, and log2PSA, and tested for variation in effect of methylation by race. Similar analyses assessed the effect of fcDNA as continuous variable, after log2 transformation, and as dichotomous variable with cutpoint near the upper quartile for BPH controls. Results: When adjusted for age and log2PSA, positive GSTPi methylation was associated with increased risk of PC in whites (OR = 6.11, p < 0.001, PC vs BPH; OR = 3.93, p = 0.001, PC vs BPH + PT). Methylation of RARB was associated with PT independent of race (OR = 2.85, p = 0.032, PT vs BPH). Patients with fcDNA ≥180ng/ml were at twice the risk of PC compared to those with levels <180ng/ml, and this result did not vary by race. Models including both GSTPi and fcDNA confirmed the independent effect of these two factors in whites (high fcDNA OR = 3.77, p = 0.002, positive GSTPi methylation OR = 5.41, p < 0.001, PC v. BPH + PT). Although high fcDNA also increased risk of PC in blacks, the effect was not statistically significant (OR = 1.91, p = 0.189, PC vs BPH + PT). Conclusions: Our results suggest that aberrant promoter methylation of GSTPi in serum is a potential biomarker for prostate cancer in whites. Level of fcDNA in serum also appears to be an independent diagnostic marker in whites.

No significant financial relationships to disclose.
A phase I study of intravesical Ad-IFN in superficial bladder cancer patients
Authors: Dinney C. P. , Benedict W. F. , Cutler D. L. , Fisher M. F. , O'Donnell M. A.
Published: August 2020

e16048

Background: Intravesical BCG (Bacillus Calmette-Guérin) is the gold standard for treatment of superficial bladder cancer. Recurrence is a significant problem. Intravesical interferon α (IFN) demonstrated complete response (CR) in ∼40% patients with most relapsing <1 year. Intravesical Ad-IFN takes advantage of the bladder to allow prolonged exposure to high concentrations of IFN; this is expected to potentiate durable therapeutic responses. Syn3 is an excipient used to increase adenoviral vector (Ad) transfection. Methods: The phase I study is a nonrandomized, open-label, rising-dose, multi-center study of Ad-IFN in patients with papillary bladder cancer, or carcinoma in situ refractory to BCG. Patients with T1 were not enrolled unless they refused cystectomy. A minimum of 3 subjects were enrolled at each dose level. Adverse events and lab abnormalities were graded according to CTC version 3 criteria. The occurrence of treatment-related Grade 3 or Grade 4 toxicity is considered dose-limiting toxicity (DLT). The maximum tolerated dose is defined as the dose which results in DLT in ≤1/6 subjects. Urine from pre-treatment, posttreatment days 0–7, 10, 14, and 28 were tested for IFN, Syn3, Ad-IFN DNA, and research biomarkers. Blood was assayed for IFN, Syn3, Ad-IFN DNA, anti- adenovirus and anti-IFN antibodies. Results: Intravesical administration of 3×109, 1×1010, 3x1010, 1×1011, or 3×1011 particles/ml of Ad-IFN (75ml) in 1mg/ml Syn3 is safe with only minor initial urgency controlled with anticholinergic medication. Of the 13 evaluable patients, 6 are CR, defined as a negative cytology and biopsy at 3 months. CR patients were offered a second dose. Response duration is variable with longest >1 year. Urinary IFN was seen for all patients in a dose-dependent fashion. TRAIL, IP-10, M65, and M30 were also seen. Conclusions: Initial safety and response activity justify further clinical development.

[Table: see text]
Impact of age at diagnosis on survival of hormone-refractory prostate cancer (HRPC) patients
Authors: Humphreys M. R. , Ma C. , Sridhar S. S.
Published: August 2020

e16050

Background: Conflicting data exist for age as a determinant of overall survival (OS) in pts with HRPC. We hypothesize that young (<55) HRPC pts represent a more aggressive biological phenotype and therefore have a decreased OS. Methods: A retrospective chart review was conducted on 334 consective HRPC pts treated between 1995–2005. Summary statistics for demographic and clinical factors were generated, and Kaplan-Meier (KM) OS curves were created. Bivariate Cox Proportional-Hazards regression was used to test the association of age at diagnosis while adjusting for a covariate, with significant covariates entered into multivariate models. Results: Overall median survivals in the age stratified categories (<55, ≥55–65, ≥65–75, ≥75) were 5.5, 6.9, 7.9, and 4.3 yrs, with 5 yr survivals 51.9%, 67.4%, 67.0%, and 34.9%, respectively. KM curves showed divergence with an overall significant log-rank test (p < 0.0001). Compared to pts ≥65–75, the hazard ratios (HR) for HRPC pts <55 and ≥75 were 1.40 (95% CI 0.90–2.60) and 2.52 (95% CI 1.67–3.82), respectively. However, following multivariate analysis HRs for HRPC pts <55 and ≥75 were 1.60 (95% CI 0.98–2.62) and 1.25 (95% CI 0.71–2.20). Pts <55 and ≥75 presented with advanced stage at diagnosis and progressed to bone metastasis earlier. Pts ≥75 had decreased performance status, more comorbidities, higher PSA at diagnosis, shorter duration of hormone sensitive disease, and were less likely to receive chemotherapy than pts <75. The percentage of rapid PSA doubling times was highest in the <55 cohort. In multivariate analysis with age as a categorical variate, ECOG 3–4 (HR 2.65), time from diagnosis to both HRPC (HR 0.78) and bone metastasis (HR 0.80), and duration of response to androgen ablation (HR 0.86) remained highly predictive. Conclusions: Age at diagnosis influences OS in HRPC with a bimodal survival curve. Pts <55 and ≥75 present with more aggressive disease, translating into reduced median and 5 yr survivals. Other covariates, especially ECOG status, likely account for the decreased OS in the ≥75 cohort. Conversely, pts <55 had an adjusted HR of 1.60 (p = 0.06). Our study supports a growing body evidence that suggests a poor prognosis in younger men; correlating these differences at the molecular level could lead to better targeted therapies.

No significant financial relationships to disclose.
Phase II study of sorafenib and docetaxel in men with metastatic castration resistant prostate cancer (mCRPC)
Authors: Cetnar J. P. , Rosen M. A. , Vaughn D. J. , Haas N. B. , Troxel A. B. , Song H. , Adluru G. , Flaherty K. T. , O'Dwyer P. J. , Amaravadi R. K.
Published: August 2020

e16055

Background: Previous trials of the antiangiogenic kinase inhibitor sorafenib in mCRPC have reported PSA elevation accompanying radiographic response, and evidence that sorafenib may potentiate docetaxel (dxl) myelosuppression. To assess the safety, antivascular effects, and activity of sorafenib and dxl in mCRPC, a phase II trial with dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) was conducted. Methods: Eligible men had mCRPC and no prior chemotherapy. Treatment consisted of dxl 75 mg/m2(day 1) and sorafenib (days 2–19) of a 21 day cycle. Patients received 7 days of sorafenib before cycle 1. Six patients received sorafenib 200mg BID and remaining patients received sorafenib 400 mg BID if <4/6 patients had grade 4 neutropenia. DCE-MRI was performed at baseline, days 8 and 28. The primary endpoint was PSA response rate (>50% PSA decline). Secondary endpoints were vascular response rate (>20% decline in area under the gadolinium curve [AUC60]), toxicity rates, and time to progression (TTP). PSA-only progression (2 consecutive PSA rises) was confirmed by a third PSA rise or radiographic progression after a 21-day drug holiday. Sample size of 69 patients in 1 stage was designed to maximize detection of significant correlations between DCE-MRI and clinical outcomes. Results: Six of 13 enrolled patients (46%) had a PSA response. A median PSA increase of 37% was observed in 73% of patients after 1 week of sorafenib. The median TTP was 8+ months. Two patients had complete disappearance of bone lesions. Grade 3 adverse events were neutropenia (77%), hand-foot syndrome (23%), anemia (15%), nausea (8%), and rash (8%). A median AUC60 decline of 40% from baseline was observed after 7 days of sorafenib, and only a 6% decline on day 28 during a scheduled sorafenib holiday. Conclusions: Sorafenib 400 mg po bid and dxl 75 mg/m2 are tolerable in men with mCRPC. Elevated PSA values in men treated with sorafenib and dxl does not always reflect disease progression. DCE-MRI can capture sorafenib's impairment of tumor vasculature in osseous metastases and rebound angiogenesis during drug holidays. Bone responses and TTP data provide evidence of encouraging activity.

No significant financial relationships to disclose.
CT response assessment combining reduction in size and arterial enhancement correlates with time to progression in metastatic renal cancer patients treated with TKIs
Authors: Nathan P. D. , Vinayan A. , Stott D. , Goh V.
Published: August 2020

e16062

Background: Targeted therapy is now the standard of care in advanced Renal Carcinoma (RCC). Response assessment by RECIST criteria is insensitive as treated tumours often have only a modest change in size despite the induction of significant necrosis and does not correlate with time to progression (TTP). The Choi criteria (10% size reduction or 15% contrast enhancement reduction) are routinely used in the assessment of GIST tumours treated with targeted agents. We report the use of combined size and density assessment in RCC metastases treated with either sunitinib or cediranib. Methods: CT scans from 32 patients with metastatic RCC treated with either sunitinib (18) or cediranib (14) were assessed. Scans from 10 patients were not evaluable as non-contrast enhanced scans were performed due to impaired renal function. Scans from a further 2 patients were excluded as they ceased treatment due to toxicity rather than progression. Scans from 20 evaluable patients at baseline and 12 weeks on treatment were assessed using RECIST, Choi, and modified criteria in which both a 10% decrease in size and 15% decrease in enhancement in the arterial phase were required to define a response (PR). A total of 60 lesions were assessed. Response assessment was performed using each of the three methods and correlated with time to disease progression (itself RECIST defined). Statistical analysis was performed using the Mann-Whitney U test. Results: There was no difference in TTP between RECIST defined PR (346.8 days) and SD (328.5 days) (P=0.965). TTP in Choi defined PR (358.4 days) and SD (189.6 days) groups showed improved but non-significant separation of TTP duration (P=0.266). TTP in PR (421.5 days) and SD (200.3 days) groups defined by a combined assessment of reduction in size and enhancement showed greatly improved separation (P=0.064). Conclusions: A combined reduction in both size and arterial phase enhancement of RCC metastases treated with TKIs correlates with time to progression. RECIST and standard Choi criteria appear inferior.

No significant financial relationships to disclose.
Prognostic factors of clear renal cell carcinoma in pT1a cases
Authors: Nishikimi T. , Tsuzuki T. , Fujita T. , Sassa N. , Araki H. , Fukatsu A. , Katsuno S. , Yoshino Y. , Hattori R. , Gotoh M.
Published: August 2020

e16064

Background: The proportion of clear cell renal cell carcinoma (CRCC) cases diagnosed at pT1a is known to be increasing significantly. Although their prognosis is excellent in general, some cases show distant metastasis. Most of proposed prognostic factors are based on mainly large sized CRCC data. The prognostic factors for small sized CRCC, especially for pT1a cases, aren't well described. Methods: Three hundred three pT1a CRCC cases were retrieved from authors’ institution files. All cases were reviewed by the single uropathologist (T. Tsuzuki). For each case, the following pathological parameters were analyzed: patient age, tumor location (upper, middle, low), Furhman grade, presence of capsule, presence of lympho-vascular invasion, growth pattern (expansive or infiltrating), presence of scar, presence of hemorrhage, and presence of necrosis. Results: Male to female ratio was 4.4. Patient's age ranged from 21 to 85 years (median: 59 years). Follow up duration ranged from one to 225 months (median: 59 months). 35 cases showed distant metastasis. The 5-year and 10-year cause specific survival rate were 96.9%, 93.0%. The 5-year and 10-year recurrence free survival rate were 91.8%, 83.9%. Furhman grade (grade 1+2+3 vs. 4), presence of lympho-vascular invasion, infiltrating growth pattern, and presence of necrosis were statistical significant (p < 0.0001). Conclusions: Furhman grade (less than 3 vs. 4), presence of lympho-vascular invasion, growth pattern, and presence of necrosis can be prognostic factors in CRCC in pTa cases. Growth pattern, which is unrecognized concept for prognosis, can be a new prognostic factor in CRCC.

No significant financial relationships to disclose.
External validation of a nomogram predicting survival in men with metastatic hormone-refractory prostate cancer
Authors: Gravis G. , Walz J. , Bagattini S. , Esterni B. , Mimoun C. , Salem N. , Marcy M. , Brunelle S. , Viens P. , Bladou F.
Published: August 2020

e16066

Background: Armstrong et al. (Clin Cancer Res. 2007;13:6396–403) recently published a nomogram predicting the probability of survival in patients with hormone-refractory prostate cancer. The initial report showed a predictive accuracy of 0.69. So far, this nomogram was not yet externally validated. We validated this nomogram in a cohort of patients with hormone-refractory prostate cancer participating in five phase II trials. Methods: In our institution, 84 patients received chemotherapy for metastatic symptomatic hormone-refractory prostate cancer from September 1999 to November 2006. Follow-up was stopped in March 2008 and median follow up for all patients was 15.7 month. 75% of patients received docetaxel based chemotherapy. At the time of inclusion, median age was 69.0 years, median PSA was 40ng/ml, 93% had known bone metastases and 19% had visceral metastases. The area under the receiver operating characteristics curve was used to estimate the predictive accuracy of the nomogram and calibration plots were used for comparison between predicted and observed probabilities. Results: Of all patients, median survival was 15.5 month. The nomogram predicted median survival was 19.9 month, overestimating the true survival by roughly 30%. The predictive accuracy of the predictions at 1 year, 2 years and 5 years was 0.76, 0.69 and 0.64, respectively. The calibration plots showed departures from ideal predictions at 1 year (up to 20% of over estimation of true survival) and 5 years ( up to 19% of under estimation of true survival), whereas the predictions at 2 years showed almost perfect calibrations. Conclusions: The Armstrong et al1 nomogram provides accurate survival predictions in patients with hormone-refractory prostate cancer. The current external validation of this nomogram provides evidence that the nomogram might generally be applied to those patients in daily practice.

No significant financial relationships to disclose.
Impact of VEGF and CgA as new predictive tools in management of elderly hormone-refractory prostate cancer (HRPC) patients
Authors: Carreca I. , Bellomo F. , Burgio S. , D'Alia P. , Piazza D. , Russo S. , Balducci L.
Published: August 2020

e16070

Background: Prostate cancer is one of the most frequent malignancy in men of the Western countries. The identification of new predictive factors of drug activity is crucial for elderly cancer patients, who need a particular selection according to prediction of efficacy and safety by pre-treatment parameters. Several prostate cancers show focal neuroendocrine (NE) spots and CgA seems to be associated to NE phenotype both in tissue and in circulation. VEGF expression in NE cells is corelated with clinical characteristics and disease-specific survival. Somatostatin analogues induce a decrease in plasma CgA and could have also anti-angiogenic activity by inhibition of VEGF, bFGF and GH/IGF-I axis. Methods: elderly patients, median age 75 (range: 65–83), were selected for hormone-refractory disease, previously treated with CAB. Serum PSA and plasmatic CgA and VEGF were evaluated in all pts at baseline (T0) and at 4 months (T4) and 8 months (T8) after therapy. Pts were treated with docetaxel 75 mg/m2 every 3 weeks for 6 cycles and octreotide acetate 20 mg administered intramuscularly every 4 weeks until progression. Clinical and biochemical response, progression- free survival and toxicity were also evaluated. A correlation of basal CgA and VEGF with biochemical response, clinical response and clinical benefit was also investigated. Results: Median duration of follow-up was 18 months (range: 8–32). Patients evaluable for response were 22. PSA response rate (RR) was observed in 10/22 (45%); clinical objective RR was 33% (7/22). Clinical benefit was observed in 19/22 pts (86%). Only mild toxicities was observed in both groups. CgA and VEGF were both strongly reduced after therapy. Lower CgA values correlated with clinical benefit, lower VEGF values also correlated with biochemical and clinical response. Conclusions: This combination treatment showed a good toxicity profile. The most relevant data in this study refer to the role of serum CgA and VEGF levels, for prediction of tumour response. If these findings were confirmed, it could be sufficient to measure these markers levels for identification of those HRPC patients who have more probability of obtaining clinical benefit from a docetaxel-based treatment in combination with a somatostatin analogue.

No significant financial relationships to disclose.
Complications of postchemotherapy residual tumor resection in patients with germ cell cancer
Authors: Albers P. , Bingöl C. , Witthuhn R. , de Geeter P.
Published: August 2020

e16077

Background: Residual tumor resection (RTR) is mandatory in all patients with advanced germ cell tumors and visible residual disease after chemotherapy. Full bilateral RTR is the proposed standard of care. However, in lately published series, the rate of nerve-sparing procedures was only 40%. Stage-related RTR may decrease surgical complications, enhance the rate of postoperative antegrade ejaculations and may not compromise oncological efficacy. Methods: A retrospective analysis of 98 patients in a tertial referral center with RTR (2003–2008) was performed using the RTR database and patients´ charts to correlate the extent of surgery to complications and outcome. Results: 49% of patients initially had IGCCCG intermediate and poor prognosis features. In 34%, residual tumor diameter was >5 cm. With a median age of 33 yrs (17–65), the median time of surgery was 210 min (90–604) with a median blood loss of 500 cc (50–5000). In 25 of 98 patients a full bilateral RTR was necessary to remove all residual tumors. The median residual tumor diameter in patients with full bilateral RTR without nerve-sparing was 10.9 cm (1.5–30) as opposed to 4.3 cm (0.5–20) in patients with modified template and/or nerve-sparing approaches (not significant). In 10 pts a nephrectomy and in 9 pts a resection of the vena cava was necessary. Only 2 of each had a bilateral RTR. All CTCAE grade III/VI complications like intraoperative hemorrhage (n=25, 11/25 bilateral RTR), postoperative lymphocele (n=8, 6/8 bilateral RTR), and retrograde ejaculation (15% with modified template and/or nerve-sparing, 100% with bilateral RTR) were significantly correlated with the residual tumor size and with the field of resection. Four patients relapsed, one had an in-field relapse after a template resection. One patient died due to a postoperative aorto-duodenal fistula. Conclusions: The complication rate of RTR is strongly related to the median residual tumor size and the extent of surgery. A full bilateral resection in all patients may result in unnecessary complications in a considerable cohort of patients. The field of resection should be adapted to the primary localization of disease and full bilateral resections should be performed only in patients with bilateral disease.

No significant financial relationships to disclose.
Cisplatin (C) and gemcitabine (G) chemotherapy with concurrent irradiation (XRT), for the conservative treatment of invasive transitional bladder cancer (ITBC) patients: Clinical outcome and long-term follow-up in a monoinstitutional experience
Authors: Caffo O. , Fellin G. , Graffer U. , Mussari S. , Caldara A. , Murgia V. , Valduga F. , Tomio L. , Galligioni E.
Published: August 2020

e16081

Background: C and G have synergistic activity when used in combination and are both potent radiosensitizers. In a dose finding trial, conducted in our hospital on ITBC patients using C and G with concurrent XRT, after maximum transurethral resection (TUR), the maximum tolerated dose of G was 400 mg/sqm (IJROBP 2003). On this basis, we have designed a phase II trial, which was prematurely closed, due to low accrual. We are presenting the long-term clinical outcome of the 16 patients involved in the dose-finding trial, together with that of the 9 pts enrolled in the phase II study. Methods: From June 1999 to December 2004, we have treated in our institution a consecutive series of 25 T2–4 N0 ITBC pts (median age 67 yrs, range 51–80). After macroscopically radical TUR, all pts received XRT (54 Gy in 30 fractions over 6 weeks) and concurrent C (100 mg/sqm, days 1, 22). In dose finding study G was given weekly from 200 to 500 mg/sqm: since unacceptable toxicity was observed in 2 cases (one death for toxicity) at the higher dose level, the recommended G dose for phase II trial was 400 mg/sqm on day 1,8 q 21 for 2 courses together with C and XRT. A cystoscopic re-evaluation was scheduled 6–8 weeks after treatment. Results: Except the pt died during treatment for toxicity, all the remaining 24 pts were microscopically disease free at cystoscopic re-evaluation. Seven local and 2 distant relapses have been observed so far, at a median follow-up of 66 mos. Presently, 16 pts (67%) is alive and disease-free, with 1 patient died for lung cancer. All pts alive have retained their bladder, with a normal organ function, in absence of any relevant long-term toxicity. The median survival has not been reached yet, while the OS at 7 years is 66%. The 5-year DFS, local DFS and survival without cystectomy, were 62%, 70%, and 95%, respectively. Conclusions: In our experience G + C with concurrent XRT in ITBC pts, appears encouraging, even at a long-term follow-up. Considering the 100% of complete response observed, this combination could be of interest to explore a possible enhancement of the disease control of C plus XRT, that is today the treatment of choice in the conservative therapy of ITBC.

No significant financial relationships to disclose.
High-dose chemotherapy and stem cell support in the management of metastatic germ cell cancer: A quantitative review
Authors: Bozcuk H. S. , Ozdogan M. , Coskun H. S. , Mutlu H. , Kargi A. , Uysal M. , Savas B.
Published: August 2020

e16094

Background: To analyze the independent associates of outcome in metastatic germ cell cancer (MGCC) patients treated with high dose chemotherapy (HDC) and stem cell rescue. Methods: Thirty-two published patient cohorts with MGCC (encompassing 2176 patients; 510 patients treated upfront and 1666 at relapse) were identified from PUBMED and Cochrane Registry of Clinical Trials. Weighed Regression Analyses of these trials were conducted to define prognosticators. Results: Correlate of overall survival (OAS) and survival with no evidence of disease (NED) in upfront HDC trials was number of chemotherapeutics in HDC (OAS with 2 agents: 60% vs. 3 or more agents: 72%, p = 0.047, survival with NED with 2 agents: 47% vs. 3 or more agents: 64%, p = 0.009). In trials of HDC at relapse, independent associates of OAS with multivariate analysis were line of chemotherapy index, an indicator of line of chemotherapy utilization (p = 0.004), and median age (≤30: 42%, >30: 49%, p = 0.023), whereas independent correlates of better survival with NED were again number of chemotherapeutics in HDC (2 agents: 54% vs. 3 or more agents: 33%, p = 0.001), and seminoma fraction (seminoma fraction ≤9%: 28% vs. seminoma fraction >9%: 49%, p < 0.001 ). Toxic mortality of HDC regimens employed in these trials ranged between 0% and 17%. Conclusions: HDC can cure patients with MGCC both as initial or salvage therapies. However, this study shows that type and setting of HDC, as well as patient age, and seminoma fraction all appear to be linked with benefit from HDC in MGCC. Future trials should continue to address the usage of tandem HDC cycles with multiagent protocols in high risk patients with MGCC.

No significant financial relationships to disclose.
Cancer testis antigen expression and immune responses by prostate cancer patients: Implications for prognosis and immunotherapy
Authors: von Boehmer L. , Wild P. , Keller L. , Hermanns T. , Provenzano M. , Sais G. , Jaeger E. , Stenner F. , Moch H. , Knuth A.
Published: August 2020

e16101

Background: Prostate cancer (PC) is the most frequent malignancy in men and it continues to be one of the most common fatal cancers. Treatment options in advanced castration-resistant prostate cancer (CRPC) are limited. Cancer testis (CT) antigens are expressed in a variety of human cancers, but not in normal tissues except for MHC deficient spermatogonia, and represent promising targets for immunotherapy. Little is known about CT antigen expression in relation to disease progression. The aim of this study was to investigate which CT antigens are expressed and immunogenic and hence represent promising targets for patients with prostate cancer and correlate these findings with clinicopathological characteristics. Methods: To determine the expression of 6 CT antigens in prostate cancer immunohistochemistry was performed on tissue micro arrays. We investigated 6 CT antigens (NY-ESO.1, MAGE-C1, MAGE-C2, GAGE, MAGE-A1 and MAGE-A4) in benign hyperplasia (n=45), early (n=388) and late stage (n=71) prostate cancer. To determine the occurrence of spontaneous antibodies against cancer testis antigens, ELISA and Western blot was performed for NY-ESO-1, MAGE-C1 and MAGE-C2 with sera from prostate cancer patients. Results: CT antigens are increasingly expressed in late stage prostate cancers. As an exception we found MAGE-C2 to be expressed early in the course of disease, frequently inducing MAGE-C2 specific antibodies. In later stage metastatic prostate cancer patients NY-ESO-1 is more often expressed, inducing NY-ESO-1 specific antibodies. Conclusions: Cancer testis (CT) antigens are prognostic markers, frequently inducing immune responses and may be suitable for immunotherapeutic intervention in patients with prostate cancer.

No significant financial relationships to disclose.
Down-staging of locally advanced prostate cancer with anti-CTLA-4 monoclonal antibody prior to radical prostatectomy
Authors: Granberg C. , Thompson R. H. , Quevedo J. F. , Karnes R. J. , Frank I. , Kwon E. D. , Blute M. L.
Published: August 2020

e16103

Background: At present, androgen ablation (AA) therapy ± radiation therapy represents a first-line treatment for patients with unresectable locally advanced prostate cancer (CAP), typically resulting in palliative disease control. Immunotherapy, in the form of CTLA-4 blockade, has been shown to potentiate T-cell responses, representing a potential antitumoral immunotherapy for treating CAP. Here, we discuss the outcomes of 5 locally advanced CAP patients treated with the monoclonal antibody MDX-CTLA-4 (MDX-010) + AA who subsequently underwent radical prostatectomy (RP), 2 of whom exhibited striking down-staging of their disease. Methods: A Phase II trial testing AA + MDX-010 therapy for treatment of locally or systemically advanced CAP is currently ongoing at our institution. To date, 5/85 patients have electively opted for off-study RP with extended pelvic lymphadenectomy after documentation of robust treatment response by PSA, staging digital rectal exam, and 3-D imaging. Results: All men had unresectable, locally advanced disease (stage T2c-T4) prior to treatment with AA + MDX-010 and subsequently underwent RP. Median blood loss was 400mL (400–900). All patients had negative surgical margins. Of the 5 patients, 2 exhibited dramatic and indisputable down-staging of their disease. These two patients presented with 80% of biopsies involved with cancer, extraprostatic extension, seminal vesicle (SV) invasion, and bladder base involvement. On final pathology, both exhibited extensive treatment effect, remission of SV involvement, and robust disaggregation of solid tumors resulting in only microscopic, non-contiguous foci of residual intraprostatic cancer. Both had T4 disease pre-treatment, and had stage T2c on final pathology. One patient is free of disease with undetectable PSA for 19 months following adjuvant radiation treatment but no further therapy, while the other patient is awaiting follow-up. Conclusions: We have been able to demonstrate true down-staging of locally advanced prostate cancer with neoadjuvant AA + MDX-010 therapy. This therapeutic modality exhibits significant promise for men with unresectable disease and may provide durable and potentially curative cancer control.

No significant financial relationships to disclose.
Predictive factors associated with clinical outcome and safety in Korean patients with metastatic renal cell carcinoma treated with sunitinib
Authors: Hong M. , Jeung H. , Chung H. , Ahn J. , Roh J. , Noh S. , Rha S.
Published: August 2020

e16111

Background: Sunitinib has become a standard treatment for metastatic renal cell carcinoma (RCC). The research for identifying patients who are more likely to benefit from this agent is quite limited, especially in Asian patients. Methods: In total, 81 histologically proven metastatic RCC patients who were treated with sunitinib were reviewed between Jan 2006 and Dec 2008. Tumor response was evaluated according to the RECIST criteria, and safety was assessed by NCI-CTC (version 3.0). Primary endpoint was progression-free survival (PFS) and secondary endpoints included overall survival (OS), overall response rate (ORR), disease control rate (DCR), and toxicities. Clinical features associated with clinical outcome were identified by univariate analysis; then, a stepwise modeling approach based on Cox's proportional hazards regression was used to identify independent prognostic factors to these endpoints. Results: Median age was 58 years (range, 29 to 73), and 33 patients received sunitinib as first-line systemic treatment. Clear cell type was predominant (85%). Patient distribution was 12% for favorable, 78% for intermediate, and 10% for poor group according to the MSKCC risk group. With the median follow-up of 26 months, median PFS was 16 months (95% CI, 8 –24) and median OS was 24 months (95% CI, 18 –30). ORR was 30% (95% CI, 19–40%) and DCR was 80% (95% CI, 70–89%). The most common grade 3/4 adverse events of sunitinib was thrombocytopenia (32%). Other severe toxicity included neutropenia (21%), anemia (19%), leucopenia (14%), fatigue (10%), stomatitis (10%). In multivariate analysis, the previous exposure to immunotherapy was related to longer PFS (P<.012). Performance status (ECOG 0–1) and corrected Ca level (8.5∼10.5 mg/dl) were associated with favorable ORR (P=.038) and DCR (p=0.008), respectively. Predictive factors for grade 3/4 thrombocytopenia were corrected Ca level (P=.018), poor MSKCC risk group (P=.025), and low WBC count (<4500/ul, P=.041). Conclusions: Compared to western reports, our data demonstrated comparable clinical efficacy in Asian patients, but different safety profile, especially in hematologic toxicities. This approach provides a tailored approach to predictive factors for targeted agents.

No significant financial relationships to disclose.