RESUMO
Background: Urethral tumors are uncommon in canines, represented predominantly by transitional cell carcinoma, marked by aggressive behavior associated with short life expectancy. Definitive diagnosis is achieved by histopathological analysis. Surgery associated with chemotherapy is the main therapeutic alternative. The aim of this paper is to report a case of primary transitional cell carcinoma of the urethra in a bitch, submitted to surgical treatment associated with conventional adjuvant chemotherapy and metronomic chemotherapy, achieving survival of 21 months, to date. Case: A 12-year-old bitch mixed breed was admitted at the Veterinary Hospital of Federal Rural University of Rio de Janeiro (UFRRJ), manifesting hematuria and urinary incontinence for one month. Physical examination indicated that vital parameters were within normal limits. Laboratory tests of blood count and serum biochemistry, urinalysis, culture, urinary antibiogram, and abdominal ultrasound were performed. The ultrasound image suggested a neoplastic urethral process. Because of the suspicion of neoplasm, a thoracic X-ray was performed, showing no evidence of metastasis. Computed tomography (CT) of the abdominal region was performed, revealing an expansive lesion in the urethra with loss of definition of the walls and urethral lumen extending to the level of the pelvic floor, measuring about 2.9 x 1.4 x 1.2 cm. After preanesthetic exams, the animal underwent resection and surgical anastomosis of the affected urethral region. The sectioned tissue was sent for histopathological analysis, with diagnosis of transitional cell carcinoma. Adjuvant chemotherapy was performed using carboplatin at a dose of 250 mg/m², intravenously, every 21 days for 6 sessions. After completing the protocol, abdominal ultrasonography was performed again, which showed a cicatricial process in the urethral region of the surgical excision, with no sign of tumor recurrence. A metronomic chemotherapy protocol was then started with cyclophosphamide at a dose of 15 mg/m², daily for 6 months, with periodic oncological follow-up. At the end of the period, the animal remained under periodic follow-up with ultrasound exams performed at 2-month intervals, and has been free from recurrence for 21 months until now. Discussion: Urethral neoplasms account for 0.5 - 2% of all canine tumors, and are represented mostly by transitional cell carcinomas. Clinical signs of urinary obstruction and hematuria are the most common, as reported in the patient in question. The definitive diagnosis is by histopathological examination. However, imaging tests such as computed tomography are important in the initial investigation and surgical planning. The indicated treatment is surgical resection of the mass with subsequent adjuvant chemotherapy or radiotherapy. The chemotherapy protocol associating cisplatin and piroxicam can achieve remission rates of 70%, but this association has a high nephrotoxic effect. In the present case, cisplatin was replaced by carboplatin in order to reduce the nephrotoxic effects of chemotherapy. The metronomic protocol using cyclophosphamide was used as maintenance therapy, at the end of the conventional chemotherapy protocol. Survival achieved was longer than that described in the literature in cases of transitional cell carcinomas in the urethral region. Therefore, multimodal therapy using surgery associated with conventional and metronomic chemotherapy, is an option in canines with urethral carcinoma.
Assuntos
Animais , Feminino , Cães , Uretra/patologia , Carcinoma de Células de Transição/terapia , Carcinoma de Células de Transição/veterinária , Carboplatina/administração & dosagem , Neoplasias Uretrais/veterinária , Administração Metronômica/veterináriaRESUMO
BACKGROUND: Recent studies have observed an association between immune-related adverse events (irAE) and favorable clinical outcomes in the setting of cancer treatment with immune checkpoint inhibitors (ICI). However, results have been variable and inconclusive. Therefore, we have conducted a pan-cancer meta-analysis evaluating the relationship between irAEs and clinical outcomes. MATERIALS AND METHODS: The search included studies published in PubMed, Embase, and Web of Science from conception to 12.28.2019 as well as abstracts published in the ASCO and ESMO meetings from 2015 to 2019. Studies were included if ICI was used in advanced or metastatic cancer settings and excluded if data contained only combination therapy regimens or contained anti-CTLA-4. Raw data for overall response rate (ORR), hazard ratios (HR), number of patients (n), and p values for overall survival (OS) and progression-free survival (PFS) were extracted. Pooled sensitivity (SN), specificity (SP), positive (PPV) and negative predictive values (NPV), and odds ratios (ORs) were calculated using the 2 × 2 table and logit transformed proportions; and summary receiver operating curve (sROC) was generated using the bivariate approach for ORR. Pooled HRs were calculated using the means weighted by inverse of the variance for OS and PFS. Heterogeneity was assumed and random effects model was used throughout the analyses. RESULTS: Final analysis included 32 studies, among which ORR data were available in 15 studies, OS in 17, and PFS in 16. 17 studies evaluated non-small cell lung cancer (NSCLC), two studies melanoma, one study gastric cancer, three studies renal cell carcinoma (RCC), seven studies various cancer types, two studies urothelial carcinoma, and one study head and neck cancer (HNSCC). With respect to ORR, pooled SN, SP, PPV and NPV, and OR were 0.522 [0.423-0.619], 0.810 [0.771-0.844], 0.516 [0.413-0.618], 0.819 [0.764-0.864], and 4.59 [3.24-6.50], respectively. The area under the curve (AUC) derived from the sROC was 0.773. HR for OS and PFS were 0.47 [95% CI 0.37-0.60] and 0.46 [95% CI 0.37-0.56], respectively. Between-study publication bias was present for ORR, OS, and PFS; however, results remained significant after trim-fill analysis. CONCLUSION: irAEs predict OR, OS, and PFS across different types of cancer and may represent useful biomarkers in the clinical setting.
Assuntos
Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias/terapia , Área Sob a Curva , Antígeno B7-H1/antagonistas & inibidores , Viés , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/terapia , Carcinoma de Células de Transição/imunologia , Carcinoma de Células de Transição/mortalidade , Carcinoma de Células de Transição/terapia , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Renais/imunologia , Neoplasias Renais/mortalidade , Neoplasias Renais/terapia , Complexo Antígeno L1 Leucocitário/imunologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/terapia , Melanoma/imunologia , Melanoma/mortalidade , Melanoma/terapia , Neoplasias/imunologia , Neoplasias/mortalidade , Intervalo Livre de Progressão , Sensibilidade e Especificidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/terapia , Resultado do TratamentoRESUMO
Metastatic urothelial carcinoma of the bladder is a rarely curable disease. Patients receive systemic therapy with limited response rates and survival benefits. The rescue regimens of these patients who have failed first-line treatment had remained problematic until the recent advances. Several trials with novel regimens, including immune checkpoint inhibitors and targeted therapy, to salvage relapsed urothelial carcinoma of the bladder have recently been published. However, the choice of an optimal treatment regimen remains challenging in the absence of randomized trials comparing regimen sequences. Daily clinical cases provoke the question of whether there is a preferred second-line regimen. This paper provides an overview of recent trials and proposes a management algorithm based on subgroup analyses and prognostic features.
Assuntos
Algoritmos , Antineoplásicos/uso terapêutico , Carcinoma de Células de Transição/terapia , Terapia de Salvação/métodos , Neoplasias da Bexiga Urinária/terapia , Ensaios Clínicos como Assunto , HumanosRESUMO
PURPOSE: To determine the effectiveness and harms of bladder-preserving trimodal therapy (TMT) as a first-line treatment versus radical cystectomy (RC) plus radical pelvic lymphadenectomy in the treatment of muscle-invasive bladder cancer in terms of overall survival. METHODS: We included parallel clinical trials and prospective and retrospective cohort studies that included patients older than 18 years old, diagnosed with muscle-invasive bladder cancer, who underwent TMT compared with RC. The planned comparison was TMT versus RC plus pelvic lymphadenectomy as first-line treatment. The primary outcome was overall survival (OS) and secondary outcomes were salvage cystectomy and cancer-specific survival and progression-free survival. A search strategy was designed for MEDLINE, CENTRAL, Embase, and LILACS. We saturated information with conference abstracts, in progress clinical trials, literature published in non-indexed journals, and other sources of gray literature. Standardized tools assessed the risk of bias independently. We performed the statistical analysis in R v3.4.1 and effect sizes were reported in terms of hazard ratios (HR) and the corresponding 95% confidence intervals (95%CI). Accordingly, we used a random effect model due to the statistical heterogeneity found in included studies. RESULTS: We found 2682 records with the search strategies and, finally, 11 studies were included in the quantitative analysis. The summary HR for OS was 1.06 95%CI (0.85-1.31) I2 = 77%, showing no statistical difference. Regarding cancer-specific survival, the summary HR was 1.23 95%CI (1.04-1.46) I2 = 14%. On the other side, for the progression-free survival, the summary HR was 1.11 95%CI (0.63-1.95) I2 = 78%. Only one study described HR for adverse events (1.37 95%CI 1.16-1.59). CONCLUSION: We found no differences in overall survival and progression-free survival between these two interventions. Nonetheless, we found that cancer-specific survival favored patients who received radical cystectomy.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células de Transição/terapia , Músculo Liso/patologia , Terapia Neoadjuvante , Tratamentos com Preservação do Órgão , Radioterapia Adjuvante , Neoplasias da Bexiga Urinária/terapia , Carcinoma de Células de Transição/patologia , Quimioterapia Adjuvante , Cistectomia , Cistoscopia , Humanos , Excisão de Linfonodo , Invasividade Neoplásica , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Taxa de Sobrevida , Neoplasias da Bexiga Urinária/patologiaRESUMO
The goal of this article is to provide recommendations for the diagnosis and treatment of muscle-invasive and metastatic bladder cancer. The diagnosis of muscle-invasive bladder cancer is made by pathologic evaluation after transurethral resection. Recently, a molecular classification has been proposed. Staging of muscle-invasive bladder cancer must be done by computed tomography scans of the chest, abdomen and pelvis and classified on the basis of UICC system. Radical cystectomy and lymph node dissection are the treatment of choice. In muscle-invasive bladder cancer, neoadjuvant chemotherapy should be recommended in patients with good performance status and no renal function impairment. Although there is insufficient evidence for use of adjuvant chemotherapy, its use must be considered when neoadjuvant therapy had not been administered in high-risk patients. Multimodality bladder-preserving treatment in localized disease is an alternative in selected and compliant patients for whom cystectomy is not considered for clinical or personal reasons. In metastatic disease, the first-line treatment for patients must be based on cisplatin-containing combination. Vinflunine is the only drug approved for use in second line in Europe. Recently, immunotherapy treatment has demonstrated activity in this setting.
Assuntos
Carcinoma de Células de Transição/diagnóstico , Carcinoma de Células de Transição/terapia , Músculo Esquelético/patologia , Guias de Prática Clínica como Assunto , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/terapia , Carcinoma de Células de Transição/patologia , Carcinoma de Células de Transição/secundário , Humanos , Invasividade Neoplásica , Espanha , Neoplasias da Bexiga Urinária/patologiaRESUMO
Systemic therapy for metastatic urothelial carcinoma has seen minimal progress and no new approved therapies in the past 20 years. However, with the approval of the checkpoint inhibitor atezolizumab in May 2016, immunotherapy inserted itself into the standard clinical dogma. The emergence of systemic immunotherapies, heralded by drugs targeting immune checkpoint blockade, can provide durable remissions in a subset of patients with a favorable toxicity profile. With other similar agents showing promise in early-phase trials, more options may be on the way. Current and ongoing trials are investigating ways to increase response rates with rational combinations as well as to uncover predictive biomarkers to identify patients most likely to benefit. In this review, we present updated data regarding immunotherapeutic agents in clinical trials as well as ongoing studies investigating novel designs, intriguing combinations, and alternative immunotherapy strategies.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células de Transição/terapia , Imunoterapia , Terapia de Alvo Molecular , Neoplasias da Bexiga Urinária/terapia , Animais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Biomarcadores Tumorais , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Vacinas Anticâncer/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/imunologia , Cisplatino/administração & dosagem , Ensaios Clínicos como Assunto , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Humanos , Ipilimumab/uso terapêutico , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/imunologia , Nivolumabe , Terapia Viral Oncolítica , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Terapias em Estudo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/imunologia , GencitabinaRESUMO
OBJECTIVE: Ulceration is common in bladder tumors, but its prognostic role, although intuitive, is not established. We aim to explore the presence of gross ulceration and its relationship with other morphological and biological features classically associated with extravesical disease, in patients submitted to radical cystectomy. METHODS: Tumor size and morphology were noted on 101 cystectomy patients (2000-2010). Papillary, exophytic, and vegetant tumors were grouped as "papillary" and solid/nodular, ulcerated and infiltrative as "nonpapillary." Ulceration was noted grossly in every case as a binary parameter, regardless of morphology. Immunohistochemistry was performed for hypoxia (hypoxia-inducible factor-1α and vascular endothelial growth factor), and cell cycle proteins (pRb, p53, and cyclin D1). RESULTS: Mean age was 66.7 year, male:female ratio was 2:1, 20 patients received bacillus Calmette-Guerin and 10 neoadjuvant chemotherapy. Upstaging rate was 56.4%. Ulcerated lesions presented mostly as nonpapillary and nonorgan confined (nOC), whereas nonulcerated tumors were often papillary and organ confined (OC). Tumor size was smaller in nonpapillary tumors (P = 0.002), but did not associate with altered hypoxia or cell cycle expressions. pRb and cyclin D1 loss and p53 overexpression were more frequent in ulcerated and non-OC tumors as did the phenotype vascular endothelial growth factor-negative/hypoxia-inducible factor-1α-low (P<0.001). On a multivariate model, ulceration was an independent predictor of non-OC and extravesical disease. CONCLUSION: Patients with ulcerated tumors were often staged with extravesical disease, independent of other morphologic and biological features known to affect prognosis. Prospective studies are needed to confirm the predictive value of tumor ulceration at cystoscopy, which could improve patient stratification for neoadjuvant chemotherapy.
Assuntos
Carcinoma de Células de Transição/secundário , Cistectomia , Úlcera/etiologia , Neoplasias da Bexiga Urinária/patologia , Idoso , Antineoplásicos/uso terapêutico , Vacina BCG/uso terapêutico , Carcinoma de Células de Transição/química , Carcinoma de Células de Transição/complicações , Carcinoma de Células de Transição/terapia , Ciclo Celular , Hipóxia Celular , Terapia Combinada , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/análise , Excisão de Linfonodo , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Proteínas de Neoplasias/análise , Carga Tumoral , Úlcera/patologia , Neoplasias da Bexiga Urinária/química , Neoplasias da Bexiga Urinária/complicações , Neoplasias da Bexiga Urinária/terapia , Fator A de Crescimento do Endotélio Vascular/análiseRESUMO
We constructed recombinant Bacille Calmette-Guérin (rBCG) that secreted human interferon alpha 2b (hIFNα-2b), and investigated its antitumor effects on bladder cancer cells in vitro. The recombinant plasmid phIFN-α-2b was constructed using pMAO-4 and transformed into BCG. The supernatant was collected at various times and IFN-γ, interleukin (IL)-12, and tumor necrosis factor (TNF)-α were detected using an enzyme-linked immunosorbent assay. EJ cells were cultivated for 24, 48, and 72 h, together with rBCG, wild-type BCG (wBCG), or wBCG+IFN-α-2b. rBCG capable of secreting cytokine IFNα-2b was constructed. On the 4th day of culture, the IFNα-2b secreted by rBCG reached a maximum. wBCG and rBCG showed no significant difference on cell growth rate over 7 days of incubation in 7H9 medium. wBCG and rBCG were both positive for acid-fast staining, and showed mycobacterial characteristics of intercellular connection in clusters with no clear abnormalities. Higher levels of IFN-γ, TNF-α, and IL-12 were induced by rBCG compared with wBCG or MAO4-rBCG (P < 0.05). rBCG may induce lymphocyte proliferation; the proliferation ratio was higher than those induced by wBCG and wBCG+IFN. rBCG had direct anti-proliferative effects on EJ cells. An MTT assay showed that rBCG inhibited the proliferation of bladder cancer cells and had more activity compared with wBCG (P < 0.05). The highest anti-tumor activity of lymphocytes was stimulated by rBCG (20.31-51.22%). rBCG-IFNα-2b induces enhanced cytotoxicity against bladder cancer cells in vitro and may be used as an alternative to BCG for bladder cancer patients.
Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células de Transição/terapia , Interferon-alfa/farmacologia , Mycobacterium bovis/imunologia , Neoplasias da Bexiga Urinária/terapia , Apoptose , Carcinoma de Células de Transição/imunologia , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Fatores Imunológicos/farmacologia , Interferon alfa-2 , Mycobacterium bovis/metabolismo , Proteínas Recombinantes/farmacologia , Células Th1/metabolismo , Células Th1/fisiologia , Neoplasias da Bexiga Urinária/imunologiaRESUMO
PURPOSE: We aimed to determine the efficacy and the toxicity of low dose weekly gemcitabine with radiation therapy in medically unfit muscle-invasive bladder cancer patients. METHODS: Twenty-six patients were included into the retrospective analysis. Weekly gemcitabine was administered 75 mg/m(2) with a median dose of 63 Gy radiation therapy. Clinical target volume was defined as the urinary bladder only in conformal treatment planning. RESULTS: Median follow-up was 51 months (range 14-118 months). Complete response rate was 62.5 %. The 5-year local progression-free survival, disease-specific survival and overall survival rates were 40.6, 59.5 and 58.5 %, respectively. Concurrent chemotherapy was continued in 80.7 % of patients without any interruption. Gemcitabine was stopped due to grade 3 thrombocytopenia (n = 1), cardiac angina (n = 1), chronic obstructive pulmonary disease exacerbation (n = 1) or patients' reluctance (n = 2). CONCLUSIONS: Low dose weekly gemcitabine with concurrent radiotherapy is a tolerable regimen and have comparable outcomes with platinum-based combined treatments in muscle-invasive bladder cancer. Prospective randomized trials can help in understanding the safety and efficacy of this treatment specially in medically unfit patients.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Carcinoma de Células de Transição/terapia , Quimiorradioterapia/métodos , Desoxicitidina/análogos & derivados , Neoplasias da Bexiga Urinária/terapia , Idoso , Idoso de 80 Anos ou mais , Desoxicitidina/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Neoplasias da Bexiga Urinária/mortalidade , GencitabinaRESUMO
Nowadays in modern oncology there is a tendency towards therapies that target organ preservation. Organ preservation protocols have become standard in the treatment of laryngeal carcinoma, oesophageal cancer, breast carcinoma and soft tissue sarcomas. The three-combined therapy consisting of a transurethral resection of the bladder tumour followed by concomitant chemoradiotherapy has been shown to be an attractive alternative for bladder preservation in selected patients with muscle-invasive bladder cancer. In order to evaluate the organ preservation approaches in muscle-invasive bladder cancer we have conducted a comprehensive literature review. Data reported from the studies have shown that bladder preservation therapy with a trimodality approach is safe and effective. Moreover, such an approach provides patients with the opportunity to maintain an intact and functional bladder with a survival rate similar to that of radical cystectomy.