Methotrexate, Vinblastine, Adriamycin, Cisplatin Research Articles

Neoadjuvant chemotherapy and radical cystectomy in patients with bladder cancer

Background. Bladder cancer is the ninth most common malignant neoplasm worldwide. Hidden metastases at the time of diagnosis are the main reason muscle-invasive bladder cancer has poor prognosis. Even after radical cystectomy, muscleinvasive bladder cancer mostly progresses within 2 years with a recurrence rate of over 50 %. At stages II–IV of the disease, drug treatment is indicated before radical cystectomy. The main goal of neoadjuvant chemotherapy is to affect micrometastases, which may be present at the beginning of disease development. The response to ongoing chemotherapy can serve as a predictor of long-term survival.Aim. To increase effectiveness of bladder cancer treatment.Materials and methods. A total of 231 patients with bladder cancer were included in the study. The main contingent consisted of men over 60 years old with locally advanced tumors at stage Т2–Т4. Drug therapy was carried out in neoadjuvant mode before surgical treatment. Standard regimens were used: cisplatin + gemcitabine and MVAC (methotrexate, vinblastine, adriamycin, cisplatin). After four courses of neoadjuvant chemotherapy, the results were evaluated. With complete normalization of a patient’s condition, the issue of surgical treatment – radical cystectomy with one of the types of urinary diversion – was decided.Results and conclusion. The follow-up period for patients after treatment was 62 months. In patients who underwent neoadjuvant chemotherapy, the median overall survival was 44.9 months, in patients without neoadjuvant treatment – 36.8 months with improvement in recurrence-free survival from 32.5 to 39.8 months (p = 0.08). Overall survival after neoadjuvant chemotherapy improved by 8.1 months (p = 0.09).

Clinical and therapeutic factors associated with adverse pathological outcomes in clinically node-negative patients treated with neoadjuvant cisplatin-based chemotherapy and radical cystectomy.

Several disease characteristics have been identified as potential predictors for pathological node involvement (pN+) following radical cystectomy (RC). However, these have not been assessed in patients treated with neoadjuvant chemotherapy (NAC). We endeavored to assess factors predicting adverse pathology in clinically node-negative patients treated with NAC and RC. Patients from four North American institutions with cT2-4aN0M0 UC who received three or four cycles of NAC followed by RC were selected. Logistic regression was used to predict pN+, <pT2 and pT4 disease. One hundred and ninety-six patients were included. The clinical stage was cT2 in 115 (61%), cT3 in 62 (33%) and cT4 in 12 (6%) cases. NAC regiments were gemcitabine-cisplatin (GC)-4 cycles 57 (29%), GC-3 cycles 77 (39%), methotrexate, vinblastine, adriamycin, cisplatin (MVAC)-3 cycle 22 (11%) and MVAC-4 cycles 40 (21%). pN+ was seen in 35 (18%) patients. In the logistic regression analysis, cT4 stage (OR 7.50; 95% CI 1.58-33.3) and three compared to four cycles of GC (OR 3.44; 95% CI 1.09-10.9) were significant predictors of pN+ status. Additionally, when controlling for clinical stage, three cycles of GC, compared to four, were significantly associated with higher rates of pT4 disease and lower rates of downstaging to non-muscle-invasive disease. The results suggest that four cycles of neoadjuvant GC may be superior to three cycles, and the latter regimen may be associated with adverse pathological findings. Although this would require validation in a prospective trial, it does encourage the completion of the conventional four cycles GC whenever possible.

Quimioterapia neoadyuvante con gemcitabina-cisplatino vs metotrexato-vinblastina-adriamicina-cisplatino en pacientes con carcinoma urotelial vesical llevados a cistectomía radical: metaanálisis

Background and objectivesBladder urothelial carcinoma is a frequent cause of death among genitourinary tumours in Colombia. Radical cystoprostatectomy is the standard management of muscle invasive bladder urothelial carcinoma (CUMI). Unfortunately, 5-year survival is around 50%, therefore neoadjuvant chemotherapy regimens have been suggested. It has been demonstrated that using neoadjuvant chemotherapy increases overall and disease-free survival. This systematic review included CUMI patients, who received neoadjuvant chemotherapy and subsequent radical cystectomy. Overall mortality and disease-free survival were compared between CUMI patients treated with gemcitabine-cisplatin (GC) or methotrexate-vinblastine-adriamycin-cisplatin (MVAC) neoadjuvant regimens. Materials and methodsThis systematic review was performed using the available literature from 1980 to 2014 to identify clinical studies. Studies had to include patients with muscle invasive bladder urothelial carcinoma, who underwent radical cystoprostatectomy, and that compare overall mortality and disease-free survival of GC neoadjuvant versus MVAC scheme. Bias assessment and data extraction was performed by independent evaluators. Meta-analysis techniques were performed where possible, depending on the observed heterogeneity. The data were processed using Stata version 12 statistical program. ResultsSix non-randomised clinical studies were included. There were 184 patients assigned to a GC scheme and 228 patients in the MVAC group. No significant statistically differences were found in overall mortality with OR: 2.23 (95%CI: 0.87-5.67), cancer specific mortality for GC was 50% compared to MVAC 61% (P=.48), and complete disease response, OR: 1.34 (95%CI: 0.79-2.29). Higher relapse likelihood among patients with GC scheme was found, OR: 2.73 (95%CI: 1.1-6.75). ConclusionsThe available evidence comparing neoadjuvant regimes such as gemcitabine-cisplatin vs methotrexate-vinblastine-adriamycin-cisplatin is limited and lacks randomised studies. The evidence provides similar results with both cancer neoadjuvant chemotherapy regimens.

Malignant Urothelial Carcinoma of Urinary Bladder in a Young Child: A Rare Case Report

We present a rare case report of a malignant, high-grade, urothelial bladder carcinoma in a 4-year-old boy. The tumor recurred quickly after resection. The recurrence was treated with partial cystectomy plus MVAC (methotrexate, vinblastine, Adriamycin, cisplatin). This is the first reported use of the MVAC regimen for a pediatric bladder tumor.

Risk factors for refractory febrile neutropenia in urological chemotherapy

During chemotherapy, patients are more susceptible to infectious complications as a result of bone marrow suppression, leading to neutropenia. The purpose of this study is to investigate risk factors for refractory febrile neutropenia (FN) during urological chemotherapy. Our method for suppressing FN is to use granulocyte colony-stimulating factor and prevent upper respiratory infection by masking and gargling. We studied 47 episodes of FN in 39 patients that occurred during urological chemotherapy for urothelial cancer, testicular cancer, and prostate cancer. Among our cases, there were 5 patients with refractory FN; we set risk factors for refractory FN and performed statistical analyses. The average age of the 39 patients was 60.6 years (range, 18-80 years). In 47 FN episodes, the chemotherapy regimen before the occurrence of FN included 15 (31.9%) MVAC (methotrexate, vinblastine, adriamycin, cisplatin) for urothelial cancer, 5 (10.6%) DE (docetaxel, estramustin) for prostate cancer, and 3 (6.4%) TIP (paclitaxel, ifosfamide, cisplatin) for testicular cancer. The antibiotics used to treat FN included 17 (36.3%) meropenem and 23 (49.0%) cefepime, and the average duration of antibiotics was 4.4 days (range, 1-12). We investigated risk factors for refractory FN and showed a significant relationship between refractory FN and indwelling urinary catheter or smaller Multinational Association for Supportive Care in Cancer score by multivariate analysis. A future prospective study is needed for further evaluation for risk factors and establishing treatment protocols and guidelines for FN.

Examining the management of muscle-invasive bladder cancer (MIBC) by medical oncologists (MO).

298 Background: Neoadjuvant chemotherapy (NC) for the treatment of MIBC remains underutilized in the United States despite evidence supporting its use. The aim of this project is to examine the current management of MIBC by MO to move towards standardization of practice. Methods: An electronic 26 question survey was emailed to 92 MO belonging to the Bladder Cancer Advocacy Network or the American Society of Clinical Oncology, and posted on the US Oncology portal for 8 wks. The study was approved by the Office of Management and Budget (0925-0046). Percentages are based on the fraction that responded to a given question. Results: Of the 83 respondents: 48% were non-academic. 51% were general oncologists and 45% focused on GU malignancies. The majority of MIBC referrals came from urologists (79%). Initial CT staging with abd/pelvis was required by 88%, CT chest by only 72% and PET by 21%. NC is offered by 79% of MO to all MIBC pts and by 45% to all pts with high grade upper tract urothelial carcinoma. Adjuvant chemotherapy (AC) was offered by 46% to all MIBC pts and by 41% to pts with upper tract disease. NC was not offered if ECOG performance status (PS) was &gt;3 (49%), in T2 disease without lymphovascular invasion (29%), or with GFR of &lt;50 ml/min (35%). Chemotherapy regimens used for NC included gemcitabine/cisplatin (90%); methotrexate/vinblastine/adriamycin/cisplatin (MVAC) (30%), dose dense MVAC (20%); gemcitabine/carboplatin (36%); single-agent gemcitabine (10%), other regimens described include carboplatin/paclitaxel and ifosfamide/doxorubicin/gemcitabine. Response to NC was assessed by CT abd/pelvis (82%), CT chest (39%), cystoscopy (30%) and PET (12%). Pts with pathologic residual disease (&gt;pT2 or positive LN) after NC were generally observed (74%). Conclusions: The majority of MO do offer perioperative chemotherapy for MIBC pts with a trend towards increased use of NC over AC, which follows best evidence. The main reason for not offering perioperative chemotherapy was poor PS. The majority offer cisplatin-based combination therapy by preference. Increasing the rate of referrals of MIBC pts to MO, will result in more pts receiving perioperative cisplatin-based chemotherapy and may lead to better outcomes in this disease.

Efficacy and Safety of Gemcitabine Monotherapy in Patients with Transitional Cell Carcinoma after Cisplatin-Containing Therapy: A Japanese Experience

In Japan, the standard chemotherapy for advanced transitional cell carcinoma (TCC) of the urothelium is MVAC (methotrexate, vinblastine, adriamycin, cisplatin). However, a second-line therapy is still required for patients with recurrent TCC who discontinued MVAC because of toxicity or have MVAC refractory tumors. We evaluated gemcitabine monotherapy in patients with advanced TCC who were previously treated with a platinum-based regimen. Gemcitabine (1000 mg/m2) was given once a week for three consecutive weeks followed by a week of rest. This cycle was repeated at least three times, or until disease progression or intolerable adverse events were observed. Of the 46 patients entered into this study, 44 received gemcitabine. Performance status (PS) at study entry was: PS 0 (30 patients), PS 1 (12 patients) and PS 2 (2 patients). Stages III/IV were observed in 1/9 patients; the other 34 patients had relapsed after surgery. All 44 patients had been previously treated with a platinum-based regimen. The overall response rate was 25%, 1-year survival rate 52.3%, median survival time 12.6 months and median progression free survival 3.1 months. The major grade 3/4 hematological toxicity was neutropenia (47.7%), and the major grade 3/4 non-hematological toxicity was anorexia (9.1%). All adverse drug reactions seen in the study were manageable. Gemcitabine monotherapy is a sufficiently active and well-tolerated therapy for patients who have previously undergone chemotherapy with a platinum-based regimen.

The Comparison of the Efficacy and Side Effects between M-VAC and GC Chemotherapy for Advanced or Metastatic Urothelial Carcinoma Patients with a Good Performance Status

Purpose: We wanted to compare the efficacy and toxicity of chemotherapy with methotrexate, vinblastine, adriamycin, cisplatin (M-VAC) versus gemcitabine and cisplatin (GC) for patients with advanced or metastatic urothelial carcinoma. Materials and Methods: Forty-nine patients diagnosed with advanced urothelial cell carcinoma and who were started on chemotherapy were divided into two groups. All of them had a 0-1 Eastern Cooperative Oncology Group performance status. 19 patients received M-VAC chemotherapy and 30 patients received the GC regimen. Among them, the subjects who completed more than 3 cycles of their recommended formula (13/19 for M-VAC, 28/30 for GC) were included in this study. They were evaluated for their overall response rate, the 5-year survival rate, toxicities and the drop-out rate. Results: The overall response rate and median survival period of the M-VAC and G-C groups were 38% (5/13 cases) and 46% (13/28 cases), and 16.7 months and 43.9 months, respectively. The 5-year survival rates in the two groups were 10% in the M-VAC group and 46% in the G-C treated group (p=0.013). The main hematologic complication was leukopenia and this occurred in 10/19 patients and more than grade 3 leukopenia was noted in 4/10 patients in the M-VAC group and in 19/30 patients and more than grade 3 was noted in 10/19 patients in the GC group. The common non-hematologic side effects between the two groups were nausea/vomiting (84.2% vs 47.7%), alopecia (47.4% vs 26.7%), diarrhea (15.8% vs 16.7%), and nephrotoxicity (15.8% vs 6.7%), respectively. The drop-out rates were 31.6% in the M-VAC group and 6.7% with the GC group. Conclusions: For patients with a good performance status with advanced or metastatic urothelial carcinoma, GC chemotherapy is more effective and it has more tolerable toxicities than does the M-VAC regimen. (Korean J Urol 2007;48:1229-1235) 󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏

The role of paclitaxel in chemosensitive urological malignancies: current strategies in bladder cancer and testicular germ-cell tumors.

Recent results demonstrate an emerging role for paclitaxel in patients with urothelial-tract cancer and in patients with testicular cancer. Yielding response rates in the range of 40-50% as a single agent, paclitaxel is one of the most active drugs in metastatic bladder cancer. Ongoing trials of paclitaxel combination chemotherapy with cisplatin or cisplatin and ifosfamide demonstrate substantial objective remission rates above 70% and, in addition, a high range of complete responses. Thus, paclitaxel appears to be an important drug when used as part of first-line combination chemotherapy for metastatic bladder cancer. Ongoing clinical trials focus on the combination of paclitaxel with cisplatin, ifosfamide, gemcytabine, and carboplatin. Furthermore, paclitaxel administration has been demonstrated to be easily applicable to patients with reduced renal function, requiring no dose reduction and producing no increase in toxicity. Future strategies will have to compare the most active paclitaxel combination regimen with first-line MVAC (methotrexate, vinblastine, adriamycin, cisplatin) chemotherapy. Finally, the role of paclitaxel combination regimens needs to be explored in the adjuvant and neoadjuvant setting in patients with bladder cancer. In testicular cancer, paclitaxel has initially been tested in patients with cisplatin-refractory disease. Among 4 consecutive trials involving a total of 83 patients a response rate of 26% has been observed using dose schedules varying from 3-h to 24-h infusions and doses ranging from 175 to 250 mg/m2. The major toxicities of paclitaxel include neutropenia, neurotoxicity, and fatigue syndrome. Currently, combinations of paclitaxel with cisplatin +/- ifosfamide are used as first- or second-line salvage therapy in patients with relapsed metastatic testicular cancer. The German Testicular Cancer Study Group uses a paclitaxel (Taxol, ifosfamide, cisplatin; TIP) combination regimen as salvage treatment. Following the TIP regimen and the application of granulocyte colony-stimulating factor (G-CSF), peripheral blood stem cells (PBSC) are harvested and the patients subsequently receive high-dose chemotherapy with PBSC rescue. Since only a few drugs have demonstrated substantial activity in cisplatin-refractory disease, paclitaxel will be used in early salvage strategies and, possibly, as first-line chemotherapy as a part of platinum-based combination regimens in patients with testicular cancer. Further trials confirming the important role of paclitaxel in this highly curable malignancy and a thorough investigation of its acute and long-term toxicity will be the future tasks.

Optimal way of administration of granulocyte colony stimulating factor in the treatment of urological cancer

Granulocyte-Colony Stimulating Factor (G-CSF) was administered to patients with bladder cancer, ureteral cancer and testicular cancer following chemotherapy. Chemotherapy included 23 courses of M-VAC (Methotrexate, Vinblastine, Adriamycin, Cisplatin) therapy to patients with bladder cancer or ureteral cancer and 10 courses of EP (Etoposide, Cisplatin) therapy to patients with testicular cancer. During M-VAC chemotherapy, about a half of the patients experienced leukopenia below 3000/mm3 until the 11th day. Leukopenia failed to improve promptly when G-CSF was started after leukocytes decreased below 3000/mm3. On the other hand, 5-days of prophylactic administrations of G-CSF from the 9th day of M-VAC therapy were able to increase leukocytes promptly. In EP chemotherapy against testicular tumor, G-CSF was started on the 9th day and continued for 5 days. Leukocytes increased immediately and the average duration of leukopenia below 3000/mm3 was only 1.2 day. These results indicate that a short term of prophylactic administration of G-CSF following these chemotherapies is able to accelerate a recovery from leukopenia and decrease a risk of bacterial infection. G-CSF is proposed to be enrolled in the treatment of urological cancer for the improvement of safety and the outcome of therapy.