Results of modified M-VAC chemotherapy for advanced urothelial carcinoma

PURPOSE: We retrospectively evaluated the efficacy and toxicity of modified M-VAC therapy for locally advanced or metastatic urothelial carcinoma. PATIENTS AND METHOD: From 1993 October to 2005 February, 28 patients were treated with modified M-VAC therapy and 25 of 28 patients had lesions suitable for the evaluation. The modified regimen was the combination of methotrexate at a dose of 30 mg/m2 on day 1, vinblastine at a dose of 3 mg/m2 on day 2, doxorubicin at a dose of 30 mg/m2 on day 2, and cisplatin at a dose of 70 mg/m2 on day 2 with courses repeated every three weeks. RESULTS: The median number of cycle was 3 (1 to approximately 7 cycles). Six of 25 patients achieved complete response (CR) and six partial response (PR), resulting in a 48% response rate. With a median followup time of 65.6 months, the median survival was 9.3 months and the 1-year and 2-year survival rates were 33.5% and 9.6%, respectively. The median progression-free survival was 6.0 months. Grade 3 and 4 toxicities included neutropenia (84.4%), thrombocytopenia (40%), anemia (56%), febrile neutropenia (20%), nausea, vomiting (8%). CONCLUSION: Although response rate of modified M-VAC therapy was similar to classic M-VAC therapy, but modified M-VAC therapy had shorter response duration and more frequent toxicities. We were not able to find the benefits of modified M-VAC therapy.     

Clinical study of modified M-VAC therapy with one 21-day cycle for advanced urothelial cancer

Although M-VAC therapy is a standard chemotherapy for advanced transitional cell carcinoma, the treatment schedule has to be delayed or cancelled in many patients because of the toxicity. To reduce the toxicity we modified the treatment schedule of M-VAC treatment. The dosages of this simplified M-VAC therapy were 30 mg/m2 methotrexate (on day 1), 3 mg/m2 vinblastine (on day 2), 30 mg/m2 doxorubicin (on day 2) and 70 mg/m2 cisplatin (on day 2), with courses repeated every 21 days for four cycles as a principle. Seventeen patients with histologically proven advanced transitional cell carcinoma were treated with this simplified M-VAC therapy without dose modification or delay. The median number of cycles was 4. Neutropenia, anemia and thrombopenia (grade 4) was observed in 2, 1 and 2 patients respectively, but no drug-related deaths were observed. Complete response and partial response were achieved in 2 (12%) and 10 (59%) patients respectively. Of 2 complete responders one patient was alive without evidence of disease at 12 months and another patient died of the disease at 42 months. Of 10 partial responders 6 patients underwent the additional surgical resection of residual tumors. Of these 6 patients 3 patients are alive without evidence of disease at 6, 30 and 31 months. The remaining 3 developed recurrence and 2 died of the disease at 13 and 29 months. Five non-responders died of the disease at 5 months after the start of the therapy. Response rate of simplified M-VAC therapy was excellent and treatment duration was short. However, relapses were commonly observed as well as the original M-VAC treatment.     

Outcome of treatment with surgical resection of the remaining tumor after modified M-VAC treatment for advanced urothelial carcinoma

We retrospectively evaluated the effect of the surgical resection of the remaining tumor after modified M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) (m-M-VAC) treatment for locally advanced or metastatic urothelial carcinoma. In m-M-VAC therapy, methotrexate and vinblastine on 15 and 22 days were omitted from the classical M-VAC to avoid the discontinuation and the dose reduction, and duration of 1 course was shortened to 21 days from 28 days of the classical M-VAC. Seven patients with locally invasive or metastatic carcinoma of the renal pelvis, ureter, and bladder, 6 males and 1 female, with a median age 64.1 years, ranging from 49 to 77 years received m-M-VAC chemotherapy without severe side effects. In all patients, the residual viable carcinoma was completely resected and they achieved complete remission. The median survival time was 20 months (range, 7 to 61). Five of these 7 patients were still alive. Two patients had no recurrence and achieved long-term survival (survival duration; 61 and 39 months). Although further studies and long-term follow up are required, these results suggest that patients who present with locally advanced or metastatic urothelial carcinoma may benefit from surgical resection after m-M-VAC.     

Clinical evaluation of M-VAC chemotherapy (methotrexate, vinblastine, adriamycin and cisplatin) for advanced urothelial cancer

Combination chemotherapy with methotrexate, vinblastine, adriamycin and cisplatin (M-VAC regimen) was administered to 12 patients with advanced epithelial cancer of the urinary tract in a clinical trial undertaken to assess clinical efficacy of this multiagent therapy. This series comprised 11 males and 1 female ranging in age from 46 to 76 years (mean age: 63), with performance status (PS) being rated 0 in 2, 1 in 5, 2 in 2, 3 in 2 and 4 in 1 of these 12 patients. The site of primary lesion was bladder in 8, renal pelvis in 3 and ureter in 1. Histologically, these tumors were all identified as transitional cell carcinoma (grade 3) with the exception of 1 mixed type (transitional cell carcinoma plus squamous carcinoma). Nine of the patients had already their primary tumor resected surgically while the remaining 3 had undergone only biopsy. The site of metastasis was lung in 7, bone in 4 and lymph nodes in 3. In consideration of the patients' general condition, the dosages of the chemotherapeutic agents were set at 80% of those recommended by Sternberg. Of the 9 patients with primary tumor resected, 1 died of chemotherapy; of the remaining 9 patients, the M-VAC regimen brought about CR in 1 and PR in 4, hence with a response rate of 62.5%. The 4 patients showing PR underwent surgical resection of residual tumor and 2 of them achieved CR and have been free of a recurrence during a 33- or 29-month period of the chemotherapeutic regimen.(ABSTRACT TRUNCATED AT 250 WORDS)     

Combination chemotherapy for advanced squamous cell carcinoma of the head and neck

Fifty-one patients (32 previously untreated, 19 previously treated) with advanced squamous cell carcinoma of the head and neck received a single course of combination chemotherapy consisting of high dose cis-platinum (DDP), bleomycin (Bleo), +/- high dose methotrexate (MTX). Thirty-three (65%) patients responded to therapy; 5 (10%) of these patients had a complete response. Previously untreated patients and those who received the three drugs (DDP, Bleo and MTX) had the highest response rates. The duration of response was 8 to 12 weeks. Seven (15%) patients showed a two-year survival rate. All nonresponders were dead of disease within two years. Three (56%) of the five complete-response patients and 4 (21%) of the partial-response patients survived for two years. The role of preoperative chemotherapy in head and neck cancer is yet to be conclusively defined.     

Long-term results of M-VAC for the treatment of advanced urothelial cancer

Total of 37 patients with measurable lesions originating in advanced urothelial cancers received M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) combination chemotherapy and have been followed for a minimum of 12 months. The study included initial diagnoses of 24 bladder cancers and 13 upper urinary tract cancers in patients whose mean age was 62 years. The patients received a mean of three cycles of M-VAC. Clinical complete remission was observed in five of the 37 patients (13.5%) and partial remission was achieved in 10 patients (27.0%) after mean treatment of 2.4 and 2.1 cycles, respectively, for an over-all objective response rate of 40.5%. The mean duration of response was 11.6 +/- 7.1 months and 4.4 +/- 3.5 months for complete and partial remissions, respectively. A mean of 5.2 +/- 1.7 cycles of M-VAC was given for complete remissions and 3.5 +/- 1.4 cycles in partial remissions. An over-all survival rates after one and two years were 28.125% and 5.859%, respectively. Two of the five patients who had once marked complete remissions died after a mean survival time of 14.5 +/- 4.5 months and three survived with a mean duration of 20.3 +/- 5.4 months. Meanwhile, all of the patients who had achieved partial remissions died after a mean survival of 9.1 +/- 5.4 months except for one patient who survived more than 12 months. These results indicate that M-VAC combination chemotherapy for advanced urothelial cancer is extremely efficacious in initial responses.(ABSTRACT TRUNCATED AT 250 WORDS)     

M-VAC chemotherapy for patients with lymph node metastases and/or locally advanced bladder carcinoma

Sixteen patients with lymph nodes metastases and/or locally advanced bladder carcinoma were treated with a combination chemotherapy regimen consisting of methotrexate, vinblastine, adriamycin, and cisplatin (M-VAC) from November 1986 through September 1988. There were 14 men and 2 women. The median age was 61.9 years, with a range from 43 to 81 years. Complete response (CR) was observed in 6 of 16 patients (38%), partial response (PR) was confirmed in 5 of 16 patients (31%), and overall response rate was 69%. Median duration of response was 10.3 and 5.2 months in CR and PR patients, respectively. The myelosuppression with this regimen was tolerable. This study demonstrates that the M-VAC regimen is effective in the invasive bladder carcinoma with or without lymph nodes metastases. However, the duration of response is relatively short, and the true long-term benefits of this regimen remain to be determined.     

Clinical and fundamental study of a squamous cell carcinoma related antigen (SCC-RA) for esophageal squamous cell carcinoma

SCC-RA is one of the fractions of TA-4, extracted and purified from uterine cervical squamous cell carcinoma. I studied SCC-RA in order to evaluate its significance as a tumor marker for esophageal carcinoma. In 32 of 75 (42.7%) esophageal cancer patients, serum SCC-RA was positive. As compared with IAP and CEA, SCC-RA was the best marker to monitor esophageal cancer. SCC-RA positive patients tended to die earlier than negative ones, and it was considered to be one of the prognostic factors. In the immunohistochemical study using anti SCC-RA monoclonal antibody, both the normal epithelium and the carcinoma tissue reacted with SCC-RA. In the carcinoma tissue. SCC-RA reactivity was observed in 27 of 31 specimens (87%). However there was no correlation among the reactivity, the serum level and clinical stage. Furthermore, I studied the relationship between the tumor growth and the serum SCC-RA levels in the nude mice bearing human esophageal squamous cell carcinoma xenografts. The SCC-RA levels in mice sera gradually increased and they correlated well to the tumor volume. In conclusion, SCC-RA reflected the tumor volume and clinical stage, and SCC-RA is useful for monitoring esophageal cancer patients.     

HER2表达水平对化疗失败的转移性尿路上皮癌免疫治疗疗效的影响

目的:探讨HER2表达水平对既往化疗失败的转移性尿路上皮癌(UC)免疫治疗疗效的影响。方法:回顾性分析北京大学肿瘤医院2017年6月至2021年4月行免疫治疗的77例既往化疗失败的转移性UC患者的临床资料。男49例,女28例;中位年龄为62(29~79)岁;肿瘤原发于膀胱28例(36.4%),肾盂25例(32.5%),...     

Histopathologic changes of transitional cell carcinoma of bladder after M-VAC chemotherapy

Over the past several years, we have utilized methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) as definitive, neoadjuvant, and adjuvant therapy for various stages of transitional cell carcinoma with reduced toxicities. Currently, there is little information concerning the histopathologic changes after M-VAC therapy. We report on the histopathologic changes of bladder transitional cell carcinoma following M-VAC chemotherapy in our protocol for treatment of bladder cancer. The main histopathologic findings after M-VAC therapy are squamous metaplasia, necrosis, fibrosis, and persistent transitional cell carcinoma. In 2 cases, there were persistent adenocarcinoma and squamous cell carcinoma. The importance of these observations in terms of diagnostic and therapeutic implications is reviewed.     

Cure of undifferentiated small cell carcinoma of the urinary bladder with M-VAC chemotherapy

Small cell carcinoma (SCC) of the urinary bladder is a rare, aggressive malignancy with approximately 135 cases reported in the literature. Treatments have included chemotherapy, radical surgery, radiotherapy, and combinations of these. We present the apparent cure of a 73-year-old man who presented with clinical stage T2 SCC of the urinary bladder. He was treated with three cycles of methotrexate, vinblastine, Adriamycin (doxorubicin), and cisplatin (M-VAC) chemotherapy. Subsequent radical cystoprostatectomy revealed no pathologic evidence of tumor. The patient is alive and well with no evidence of recurrence 3 years post cystectomy. A brief review of the literature is also presented.     

Preoperative sequential chemotherapy in locally advanced squamous cell carcinoma of the head and neck

BACKGROUND: Induction chemotherapy may contribute to decreased local and distant recurrences in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) resectable for cure. METHODS: Patients with previously untreated locally advanced stage III-IV (N0-2, M0) SCCHN received a dose-dense sequential regimen combining cisplatin/5-fluorouracil followed by bleomycin/methotrexate/hydroxyurea. Induction chemotherapy was followed by locoregional surgery and/or radiation therapy. RESULTS: Among 37 patients, 23 (62%) had T4 primary tumors. Grade 3 to 4 asymptomatic hematologic toxicity occurred in less than 15% of patients. Nonhematologic toxicities were limited to grade 1 to 2 in less than 20% of patients. In the overall cohort (intent-to-treat; n = 35), 24 (68.5%) of 35 patients had objective clinical responses, including nine complete responses (25.7%). Fifty-seven percent of patients were free of disease at 2.5 years. CONCLUSIONS: Sequential induction chemotherapy is feasible and active in patients with locally advanced head and neck cancers and may further include recent compounds such as taxanes.     

Cisplatinum–epirubicin chemotherapy for advanced unresectable squamous cell carcinoma of the head and neck

Twenty-seven patients with locally advanced unresectable squamous cell carcinoma of the head and neck were offered three courses of cisplatinum and epirubicin. The purpose of this study was to evaluate the effectiveness of this chemotherapy regimen. Subsequent therapy included surgery when feasible and/or radiation therapy. Eighteen patients completed three courses of chemotherapy. Three had a complete response and 14 a partial response. Nine patients refused chemotherapy before treatment was completed. Overall response rate was 63%. Among responding patients, the initial favorable response to chemotherapy was apparent after the first course of chemotherapy. A moderate degree of nausea, vomiting, anorexia, and alopecia were the most common toxicities. Leukopenia grade 3 according to ECOG criteria (WBC 1,000–2,000/mm³) was found in 8(44%) of the 18 patients completing treatment. There was no cardiac toxicity. This regimen appears to be an effective induction chemotherapy for advanced unresectable head and neck cancer with acceptable side effects. Subsequent therapy with surgery and/or radiation can give long-term local control of disease in some patients. In a selected group of patients with smaller tumors, this treatment should have a better response rate and a favorable effect on survival. Phase III studies using this regimen should be carried out.     

Methotrexate, vinblastine, adriamycin and cisplatin (M-VAC) in advanced urothelial cancer--analysis of efficacy and toxicity]

Seventy-seven patients with advanced urothelial cancer were treated with methotrexate, vinblastine, adriamycin, and cisplatin (M-VAC). Of these 77 patients, 65 could be evaluated for response and 74 for toxicity. Response rates were 65% in the primary organs (62% in the renal pelvis and ureter, 67% in the bladder), 68% in the lymph nodes, 60% in the lung, 25% in the bone and 14% in the liver. Complete responses were noted in 11 patients (17%) and partial responses in 26 patients for an overall response rate of 57% (95% confidence limits 45 to 69%). The median durations of response were 11 months for complete response patients and 7 months for partial response patients. Of the 65 patients 20 (31%) are alive, and 1-, 2-, and 3-year survival rates were 65%, 37%, and 25%, respectively. While survival rates of responders were higher than those of nonresponders with a statistical significance until 15 months, no significant differences were observed in survival rates between these two groups in the subsequent period. The M-VAC regimen was used for 15 patients as a neoadjuvant chemotherapy. Of the 15 patients, 8 responded and primary organs were preserved in 6 of the 8 responders. Histological effects classified according to Oboshi-Shimosato's criteria were G.I in 9, G.IIA in 3, G.IIB in 1, and G.IVC in 2. There were no significant differences in survival rates according to responses and histological effects. Factors related to response were analyzed with a multiple logistic regression model on 54 patients treated with intravenous administration of drugs and whose histological type was transitional cell carcinoma. The analysis results indicate that the presence of distant metastases is an important factor in predicting poor efficacy. Sixteen of 74 patients (22%) had white blood cell count of less than 1,000 cells per mm3 in the first cycle, while the decrease of platelet count was mild in degree compared with that of the white blood cell count. Patients with elevations of serum creatinine, GOT, and GPT were low in frequency, and toxic symptoms were controllable. Factors significantly related to the occurrence of side effects were sex, performance status, prior radiotherapy, prior chemotherapy, and the method of drug administration. Among these factors, prior radiotherapy was related to severe decrease of white blood cell count. While an excellent overall response rate was provided with the M-VAC regimen, disadvantages of the present regimen were low effectiveness in the bone and liver, and short duration of response.(ABSTRACT TRUNCATED AT 400 WORDS)     

Clinical role of additional adjuvant chemotherapy in patients with locally advanced urothelial carcinoma following neoadjuvant chemotherapy and cystectomy

Purpose

Neoadjuvant chemotherapy (NAC) can downstage invasive bladder cancers prior to radical cystectomy (RC) and improve overall survival. However, the optimal management in patients with persistent non-organ confined disease (pT3–T4 and/or pN+) following RC has not been completely defined. The aim of this study was to describe outcomes associated with the use of adjuvant chemotherapy (AC) in patients with residual non-organ confined cancer at RC following NAC.

Materials and methods

Using data from a high-volume referral institution, pT3–T4 and/or pN+ patients who received NAC and then also RC were identified. Recurrence-free survival (RFS) and cancer-specific survival (CSS) were assessed with Kaplan–Meier analysis.

Results

From 2001 to 2013, 161 patients received NAC and then RC. Eighty-eight pT3–T4 and/or pN+ patients were identified. Twenty-nine (33 %) received AC. Adjuvant chemotherapy in the majority of patients was carboplatin-based (16), followed by cisplatin (8) and other, mainly taxane-containing regimens (5). The median RFS was 17.5 months in the AC and 13.7 months in the non-AC group (p = 0.78). AC remained an insignificant predictor for RFS after adjusting for pT, pN and margin status (HR 0.89, 95 % CI 0.48–1.68]). CSS was 23 and 22 months (p = 0.65) and remained insignificant after adjusting for pathologic confounders.

Conclusions

In our current study population, adjuvant conventional cytotoxic chemotherapy was not associated with significant improvements in RFS or CSS. The choice of AC regimens, and incorporation of newer treatments, may be the key for improving outcomes in this high-risk patient group.

     

Genomic landscape of locally advanced or metastatic urothelial carcinoma with squamous differentiation compared to pure urothelial carcinoma

BackgroundUrothelial carcinoma with squamous differentiation (UCS) is the most common variant differentiation of urothelial carcinoma (UC). Although treatment is usually similar to pure UC, there is paucity of data regarding its genomic landscape and putative molecular drivers. In this study, we compared the mutational profile of tumors with UCS and UC histology.MethodsIn this IRB-approved retrospective study, patients with advanced UCS and UC undergoing tumor based comprehensive genomic profiling from a CLIA-certified laboratory were included. An independent genitourinary pathologist reviewed all cases. Patients were determined to have UCS based on presence of any component of squamous differentiation. Patients with UC having any other secondary histology variant were excluded. Genes with alterations (GA) in less than 5% of patients and variants of unknown significance were excluded from the analysis. Chi-square test was used to compare gene aberration frequency and the p-values were adjusted for false using Benjamini-Hochberg (BH) correction.ResultsAmong the 87 eligible patients with UCS (n=31) and UC (n=56), patients with UCS were more likely to be female (32.3% vs. 14.3%, p=0.047) with no significant differences in other clinicopathological features. Most common genomic alterations seen in UCS were TP53 (67.7%), KMT2D (48.4%) and ARID1A (32.3%). KMT2D mutations were significantly enriched in UCS (48.4% vs. 0%, FDR adj p <0.001, p = <0.001) compared to UC. Prevalence of CUL4A mutations was numerically higher in UCS vs. UC (12.9% vs. 1.8%, FDR adj p = 0.43, p = 0.03). Tumor mutation burden and the number of genomic aberrations per patient were not significantly different between the two groups.ConclusionThese findings highlight significant enrichment of KMT2D mutations in UCS and potential role of chromatin remodeling genes as drivers and potential therapeutic targets.     

Experience with combination chemotherapy consisting of methotrexate, vinblastine, adriamycin and cisplatin (M-VAC) in advanced urothelial cancer

The M-VAC (methotrexate, vinblastine, adriamycin and cisplatin) regimen was used to treat 6 patients with metastatic transitional cell carcinoma of the urothelial tract. Three patients showed a partial response, all of them were made surgically disease free. Two of them are still alive 1 year and for 6 months after surgery with no evidence of disease and one other died of disease 11 months after surgery. The response in one case was no change and that in two others was a progressive disease. From our experience, we suggest that treatment with M-VAC is effective but that surgery after M-VAC appears essential for the successful management of the patients with metastatic transitional cell carcinoma of the urothelial tract.