Search

Purpose: To investigate the use of plasma and urine DNA mutation analysis for predicting neoadjuvant chemotherapy (NAC) response and oncological outcome in patients with muscle-invasive bladder cancer. Experimental Design: Whole-exome sequencing of tumor and germline DNA was performed for 92 patients treated with NAC followed by radical cystectomy (RC). A custom NGS-panel capturing approximately 50 mutations per patient was designed and used to track mutated tumor DNA in plasma and urine. A total of 447 plasma samples, 281 urine supernatants, and 123 urine pellets collected before, during, and after treatment were analyzed. Patients were enrolled from 2013 to 2019, with a median follow-up time of 41.3 months after RC. Results: We identified tumor DNA before NAC in 89% of urine supernatants, 85% of urine pellets, and 43% of plasma samples. Tumor DNA levels were higher in urine supernatants and urine pellets compared with plasma samples (P < 0.001). In plasma, detection of circulating tumor DNA (ctDNA) before NAC was associated with a lower NAC response rate (P < 0.001). Detection of tumor DNA after NAC was associated with lower response rates in plasma, urine supernatant, and urine pellet (P < 0.001, P = 0.03, P = 0.002). Tumor DNA dynamics during NAC was predictive of NAC response and outcome in urine supernatant and plasma (P = 0.006 and P = 0.002). A combined measure from plasma and urine supernatant tumor DNA dynamics stratified patients by outcome (P = 0.003). Conclusions: Analysis of tumor DNA in plasma and urine samples both separately and combined has a potential to predict treatment response and outcome.

PURPOSE This study aimed to assess long-term follow-up after chemoresection with mitomycin (MMC), a nonsurgical treatment modality for recurrent nonmuscle invasive bladder cancer (NMIBC). At the time of recurrence, chemoresection has previously been shown to reduce the number of patients requiring a procedure (transurethral resection of bladder tumors [TURBT] or office biopsy) by more than 50%. This study investigated the number of patients requiring a procedure during initial treatment and 2-year follow-up in patients treated with short-term, intensive chemoresection with MMC compared with patients undergoing standard surgical treatment of recurrent NMIBC. METHODS A randomized, controlled trial was conducted in two urological departments in Denmark from January 2018 to August 2021. In total, 120 patients with a history of Ta low- or high-grade NMIBC were included upon recurrence. The intervention group received intravesical MMC (40 mg/40 mL) three times a week for 2 weeks and TURBT or office biopsy only if the response was incomplete. The control group received TURBT or office biopsy and 6 weekly adjuvant instillations. The primary outcome was the number of patients undergoing a procedure within 2 years from inclusion, which was compared between groups using the chi-squared test. Recurrence-free survival was analyzed using the Kaplan-Meier method. RESULTS Significantly fewer patients were in need of a procedure in the intervention group than in the control group: 71% (95% CI, 57 to 81) and 100% (95% CI, 94 to 100), P < .001. The 12-month recurrence-free survival was 36% (95% CI, 24 to 50) and 43% (95% CI, 30 to 56) in the intervention and control groups, respectively ( P = .5). CONCLUSION Short-term intensive chemoresection is an effective treatment strategy for recurrent NMIBC that leads to a reduced number of required procedures without compromising long-term oncological safety.

BackgroundThis phase 1b study (NCT02323191) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of colony-stimulating factor-1 receptor-blocking monoclonal antibody (mAb) emactuzumab in combination with the programmed cell death-1 ligand (PD-L1)-blocking mAb atezolizumab in patients with advanced solid tumors naïve or experienced for immune checkpoint blockers (ICBs).MethodsEmactuzumab (500–1350 mg flat) and atezolizumab (1200 mg flat) were administered intravenously every 3 weeks. Dose escalation of emactuzumab was conducted using the 3+3 design up to the maximum tolerated dose (MTD) or optimal biological dose (OBD). Extension cohorts to evaluate pharmacodynamics and clinical activity were conducted in metastatic ICB-naive urothelial bladder cancer (UBC) and ICB-pretreated melanoma (MEL), non-small cell lung cancer (NSCLC) and UBC patients.ResultsOverall, 221 patients were treated. No MTD was reached and the OBD was determined at 1000 mg of emactuzumab in combination with 1200 mg of atezolizumab. Grade ≥3 treatment-related adverse events occurred in 25 (11.3%) patients of which fatigue and rash were the most common (14 patients (6.3%) each). The confirmed objective response rate (ORR) was 9.8% for ICB-naïve UBC, 12.5% for ICB-experienced NSCLC, 8.3% for ICB-experienced UBC and 5.6% for ICB-experienced MEL patients, respectively. Tumor biopsy analyses demonstrated increased activated CD8 +tumor infiltrating T lymphocytes (TILs) associated with clinical benefit in ICB-naïve UBC patients and less tumor-associated macrophage (TAM) reduction in ICB-experienced compared with ICB-naïve patients.ConclusionEmactuzumab in combination with atezolizumab demonstrated a manageable safety profile with increased fatigue and skin rash over usual atezolizumab monotherapy. A considerable ORR was particularly seen in ICB-experienced NSCLC patients. Increase ofCD8 +TILs under therapy appeared to be associated with persistence of a TAM subpopulation.

Overtreatment with cisplatin-based chemotherapy is a major issue in the management of muscle-invasive bladder cancer (MIBC), and currently none of the reported biomarkers for predicting response have been implemented in the clinic. Here we perform a comprehensive multi-omics analysis (genomics, transcriptomics, epigenomics and proteomics) of 300 MIBC patients treated with chemotherapy (neoadjuvant or first-line) to identify molecular changes associated with treatment response. DNA-based associations with response converge on genomic instability driven by a high number of chromosomal alterations, indels, signature 5 mutations and/or BRCA2 mutations. Expression data identifies the basal/squamous gene expression subtype to be associated with poor response. Immune cell infiltration and high PD-1 protein expression are associated with treatment response. Through integration of genomic and transcriptomic data, we demonstrate patient stratification to groups of low and high likelihood of cisplatin-based response. This could pave the way for future patient selection following validation in prospective clinical trials., There are currently only a few biomarkers to predict the response of muscle invasive bladder cancer to therapy. Here, the authors analyse 300 tumors using exome and RNA sequencing and find that tumors with a high degree of genomic instability and a non-basal/squamous gene expression subtype are most likely to respond to treatment.

Intravesical immunotherapy with Calmette-Guerin bacillus (BCG) have been used since decades for the treatment of non-muscle invasive bladder cancer and is a proof of principle that immunotherapy works for this malignancy. Since 2016, immune checkpoint inhibitors (ICI) demonstrated clinical benefits in locally advanced or metastatic bladder cancer, providing potentially durable tumor control in first line therapy or upon relapse after standard treatments. Ongoing clinical trials aim to demonstrate the efficiency of ICI for the treatment of localized disease.

Background Previous quality of life (QoL) literature in bladder cancer (BC) patients has focused on finding the preferred urinary diversion while little is known about the QoL of patients in medical oncological treatment (MOT). We performed a systematic review to assess the existing literature on QoL in patients with muscle-invasive BC (MIBC) undergoing MOT. Methods A systematic search of Pubmed and Embase was performed. Inclusion criteria were studies containing QoL data for patients undergoing chemo- and/or radiotherapy. We extracted all QoL scorings at different time intervals and on the six most prevalent domains: overall QoL, urinary, bowel sexual symptoms, pain and fatigue. The study was carried out according to PRISMA guidelines for systematic reviews and GRADE was used to rate the quality of evidence from the included studies. Results Of 208 papers reviewed, 21 papers were included. Twenty-one different QoL instruments were applied. The only data on QoL during chemotherapy was from patients in clinical trials investigating new treatments. No studies were found for patients in neoadjuvant treatment. The level of evidence at each time point was graded as very low to moderate. From the studies included the overall QoL seemed inversely related to the organ-specific impairment from sexual and urinary symptoms and increased with decreasing organ-specific symptoms for long term survivors > 6 months after treatment. Conclusions Collection of data on QoL from patients with MIBC disease undergoing MOT has been sparse and diverse. The present data can act as a summary but prompts for more prospective collection of QoL data from BC patients. Electronic supplementary material The online version of this article (10.1186/s12955-018-1077-6) contains supplementary material, which is available to authorized users.

This retrospective study was performed to evaluate real-world oncological outcomes of patients treated with chemo-based therapy for muscle-invasive or metastatic bladder cancer (MIBC/mBC) and compare results to data from RCTs and other cohorts. Among 1578 patients diagnosed, 470 (30%) had MIBC/mBC. Median overall survival (mOS) for RC alone (47 months), first-line (13 months) and second-line (7 months) chemotherapy, and chemotherapy for recurrent disease (8 months) were similar to literature. Treatment with neoadjuvant and induction chemotherapy (NAIC) was only utilized in 9% of patients, and often in patients with poor disease status, resulting in a lower mOS compared to literature (35 and 20 months, respectively). Patients treated with chemotherapy had many adversities to treatment, with only 50%, 13%, 18% and 7% of patients in NAIC, first-line, salvage after RC, and second-line setting completing the full pre-planned chemotherapy treatment. Real-world data shows NAIC before RC is underutilized. Adversities during chemotherapy treatment are frequent, with many patients requiring dose reduction or early treatment termination, resulting in poor treatment response. Although treatment efficacy between RCTs and real-world patients is quite similar, there are large differences in baseline characteristics and treatment patterns. Possibly, results from retrospective studies on real-world data can deliver missing evidence on efficacy of chemotherapy treatment on older and ‘unfit’ patients.

Vinflunine is to date the only registered agent for second-line treatment of metastatic urothelial cell carcinoma (UCC) in Europe. However, the effect is modest. Pemetrexed has demonstrated some single-agent activity in this disease entity. In order to improve treatment possibilities for UCC patients, a phase I trial (VINTREX) was undertaken to assess the safety of vinflunine and pemetrexed in metastatic UCC patients. A dose escalation design was planned to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of a vinflunine/pemetrexed combination. Pemetrexed was added to vinflunine dosed at 280 mg/m2 on day 1 of a 21-day cycle. Three levels of pemetrexed were planned starting at 400 mg/m2. Four patients were enrolled with a mean age of 66 years and with a mean number of prior GC-cycles of 6,8. Two DLT's were observed at the lowest dose-level in cohort 1. One patient experienced grade 4 thrombocytopenia and a second demonstrated hepatobiliary toxicity grade 3 with an increase in alanine aminotransaminase. Most common grade 3 and 4 adverse events were anemia, thrombocytopenia and neutropenia. Three out of four patients received 3 cycles of pemetrexed and vinflunine, all had progressive disease. Based on these observations and due to protocol design, the study was interrupted at dose level 1 for safety reasons. The combined therapy of vinflunine (Javlor®, Pierre Fabre Pharma) and pemetrexed (Alimta®, Eli Lilly) is poorly tolerated in metastatic UCC patients. The combination cannot be recommended for further investigations in metastatic UCC. Vinflunine is to date the only registered agent for second-line treatment of metastatic urothelial cell carcinoma (UCC) in Europe. However, the effect is modest. Pemetrexed has demonstrated some single-agent activity in this disease entity. In order to improve treatment possibilities for UCC patients, a phase I trial (VINTREX) was undertaken to assess the safety of vinflunine and pemetrexed in metastatic UCC patients. A dose escalation design was planned to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of a vinflunine/pemetrexed combination. Pemetrexed was added to vinflunine dosed at 280 mg/m2 on day 1 of a 21-day cycle. Three levels of pemetrexed were planned starting at 400 mg/m2. Four patients were enrolled with a mean age of 66 years and with a mean number of prior GC-cycles of 6,8. Two DLT's were observed at the lowest dose-level in cohort 1. One patient experienced grade 4 thrombocytopenia and a second demonstrated hepatobiliary toxicity grade 3 with an increase in alanine aminotransaminase. Most common grade 3 and 4 adverse events were anemia, thrombocytopenia and neutropenia. Three out of four patients received 3 cycles of pemetrexed and vinflunine, all had progressive disease. Based on these observations and due to protocol design, the study was interrupted at dose level 1 for safety reasons. The combined therapy of vinflunine (Javlor®, Pierre Fabre Pharma) and pemetrexed (Alimta®, Eli Lilly) is poorly tolerated in metastatic UCC patients. The combination cannot be recommended for further investigations in metastatic UCC.

low grade, low stageの膀胱移行上皮癌患者59例に対してBLM, CQ, ADMの膀胱内注入療法を施行し57%の抗腫瘍効果を認めた.乳頭状腫瘍においては非乳頭状腫瘍におけるよりも高い抗腫瘍効果を認めた.3年以内の観察期間では, 注入療法施行群の再発率は34%であり, 注入非施行群に比してあきらかな再発予防効果を認めた.抗癌剤の膀胱内注入療法は, 表在性膀胱癌患者に対して有効な治療法の1つであると同時に再発予防効果もある, The effect of intravesical chemotherapy on superficial urinary bladder cancer was analysed. Fifty-nine patients with low-staged, low-grade bladder cancer were treated with intravesical instillation of three anticancer drugs (adriamycin, carbazilquinone and bleomycin). Complete response (CR) was observed in 15 out of 42 patients and partial response (PR) in 9 patients. Overall, a better response rate was observed with adriamycin and carbazilquinone than with bleomycin. Papillary tumors responded well to these intravesical chemotherapies compared to the non-papillary tumors . Intravesical recurrence of tumors was evaluated in 68 patients who received intravesical instillation of these three drugs after TUR of tumors. The actuarial recurrence rate of 68 patients was 11, 22 and 34% within 1, 2 and 3 years, respectively. These rates were significantly lower than that of TUR therapy alone. No serious side effect was seen in these patients. From these results, it is noted that intravesical chemotherapy is a useful approach for controlling superficial urinary bladder cancer.

UFTを腎細胞癌7例, 膀胱癌5例, 前立腺癌4例に投与した.1)抗腫瘍効果は, complete response (CR) 2例, partial response (PR) 2例, NC 12例で, PDはみとめず, 有効率は16例中4例であった.2)腎細胞癌では7例中CR 1例, PR 1例, 膀胱癌では5例中CR 1例, PR 1例であったが, 前立腺癌4例はすべてNCであった.3)副作用は, 600 mg/日投与6例中3例に, それぞれ食欲不振, 嘔気と嘔吐, 口内炎をみたが, 300 mg/日投与例に消化器症状はみなかった.4)骨髄機能の抑制や, 肝, 腎機能障害はみなかった, Clinical study of UFT which was a mixture of FT and uracil, was conducted on 16 patients with urogenital malignancies. Seven patients had renal cell carcinoma, 5 patients had bladder cancer and 4 patients had prostatic cancer. UFT was continuously administrated at doses of 300 mg or 600 mg per day. One of the patients with renal cell carcinoma and 1 of the patients with bladder cancer showed a complete response, and 1 patient with each cancer showed a partial response, but none of the 4 patients with prostatic cancer responded. In total, complete or partial responses were obtained in 4 of the 16 patients, given an effective rate of 25.0%. Concerning side effects, 3 of the 16 patients complained of anorexia, nausea and vomiting, and stomatitis, but no hepatic or renal disorders, or marrow depression was observed.

The safety of prolonged administration of UFT in which tegafur and uracil were mixed in a ratio of 1:4 in molar fraction was studied in 44 cases of bladder cancer and 10 cases of renal cell carcinoma. Daily doses of UFT were 300-600 mg, and average total doses administered were 102.0 g for bladder cancer and 116.6 g for renal cell carcinoma cases. Incidence of adverse effects were 25.0% in bladder cancer and 18.5% in renal cell carcinoma cases. Anorexia, nausea, vomiting and decrease in WBC were observed, but rates of having discontinued the administration of UFT were very low, being 9.1% in bladder cancer and 10.0% in renal cell carcinoma. Thus, UFT was considered to be tolerable during prolonged use in bladder cancer and renal cell carcinoma and also a drug in which more usefulness is expected in multidisciplinary treatments in future.

1)膀胱腫瘍20例(TaNxMo 8例, T1NxMo 5例, T2NxMo 3例, T3aNxMo 1例, T3bN2Mo 1例, T3bNxMo 1例, T4NxMo 1例)に750 mg Tegafur坐剤1個を連日23～161日(平均47.45日)を投与した.投与総量は17.25～120.75g(平均34.45g)であった.2)斉藤・小山班の固形がん化学療法直接効果判定基準にもとづき効果判定をおこなうと, CR0例(0%), PR5例(25%), MR3例(15%), NC 10例(50%), PD2例(10%)で, Response rate(奏効率)は25.0%であった.3) 20例中6例(30%)になんらかの副作用が認められた.すなわち全身倦怠感4例(20%), 食欲不振3例(15%), 下痢1例(5%), 浮腫1例(5%), 貧血2例(10%), GOT・GPT上昇1例(5%)および血小板減少1例(5%)が認められた.これら副作用も投薬の休止および保存的療法にて消褪した, A Tegafur suppository of 750 mg was administered daily to 20 patients with bladder tumors, whose ages ranged from 43 to 84 years (average age 63.7). Histological study revealed transitional cell papilloma in 6 cases, transitional cell carcinoma in 12 cases, squamous cell carcinoma in 1 case and malignant tumor with extensive necrosis in 1 case. The result of staging and grading was as follows: 8 cases of pTa, 5 cases of pT1, 9 cases of pT2, 1 case of pT3a, 2 cases of pT3b and 1 case of T4; an, 6 cases of G0, 6 cases of G1, 5 cases of G2, 2 cases of G3 and 1 case of unknown grade. According to Saitoh and Koyama's criteria, no cases showed complete response (0%), 5 cases partial response (25%), 3 cases minor response (15%), 10 cases no change (50%) and 2 cases progressive disease, making the total effective rate 25.0%. Some side effects were observed in 6 of the cases (30%): General malaise in 4 cases (20%), loss of appetite in 3 cases (15%), diarrhea in 1 case (5%), edema in 1 case (5%), anemia in 2 cases (10%), an elevation of both GOT and GPT in 1 case (5%) and thrombocytopenia in 1 case (5%). A recovery from these side effects was achieved after discontinuing the use of Tegafur suppositories.

7機関より得た多発性表在性膀胱腫瘍111症例について, CAおよびCAとMMCまたはNCSまたはCQとの併用による治療効果を検討した.1) CA 400 mg投与29例の有効率は48.3%, CA 200 mgおよびMMC 20 mg併用投与25例の有効率は84.0%, CA 200 mgおよびNCS 4, 000 U併用28例は71.4%, CA 200 mgおよびNCS 6, 000 U併用22例は95.5%, CA 200 mgおよびCQ 10 mg併用7例は100%の有効率を示し, いずれの場合も併用療法がCA単独よりよい結果である.2)初発症例, 再発症例別にみた有効率にはほとんど差をみとめない.3)副作用はいずれも局所刺激症状で, 全身障害を示すものはない.CA単独の場合は3.4%, CAにCQを併用した場合がもっとも高く71.4%である.MMCとの併用では40.0%, NCS 4, 000 Uとの併用は3.6%, NCS 6, 000 Uとの併用の場合は22.7%であった, The effect of instillation therapy using CA alone or in combination with MMC, NCS or CQ was examined in 111 patients (92 males and 19 females, aged 32-87 years old with an average age of 66 years) with multiple superficial bladder tumors. The response rate of 29 patients given CA 400 mg alone was 48.3%, that of 25 patients given combination therapy of CA 200 mg and MMC 20 mg was 84.0%, that of 28 patients given combination therapy of CA 200 mg and NCS 4, 000 U was 71.4%, that of 22 patients given combination therapy of CA 200 mg and NCS 6, 000 U was 95.5% and that of 7 patients given combination therapy of CA 200 mg and CQ 10 mg was 100%. The response rates of the patients given any of the combination therapies were higher than that of the patients given CA alone. But because MMC, NCS and CQ were not administered singly, combination therapy cannot be concluded to be superior to single therapy. There was little difference between the response rate of primary cases and that of follow up cases. The side effects were all symptoms of local irritation, and were not indicative of systemic damage. Side effects were seen in 3.4%, 71.4%, 40.0% and 3.6% of the patients given CA alone, CA + CQ combination therapy, CA + MMC combination therapy and CA + NCS (4, 000) therapy, respectively, combination therapy of CA and CQ producing the highest percentage of side effects.

Small cell carcinoma of the urinary bladder is an extremely aggressive and rare tumor. Even though small cell carcinoma most commonly arises from the lungs there are several reports of small cell carcinoma in extrapulmonary sites. Due to its low frequency there is no well-established management for this disease. We report the case of a 61 year-old man with small cell carcinoma of the bladder who underwent radical cystectomy following neoadjuvant chemotherapy. We also reviewed the literature for the optimal treatment strategy. Keywords: Urinary bladder neoplasms/drug therapy; Carcinoma, small cell/drug therapy; Cystectomy/methods; Case reports