Cisplatin, Ifosfamide, Methotrexate and Vinblastine Combination Chemotherapy for Metastatic Urothelial Cancer

Purpose

We investigated the activity of combination chemotherapy consisting of cisplatin, ifosfamide, methotrexate and vinblastine in patients with metastatic urothelial cancer.

Materials and Methods

A total of 32 consecutive patients was treated with 30 mg./m.² cisplatin on days 1 through 3, 1.5 gm./m.² ifosfamide with mesna on days 1 through 3, 30 mg./m.² methotrexate and 3 mg./m.² vinblastine on day 1 plus 5 micro g./kg. granulocyte colony-stimulating factor on days 7 through 11. Courses were repeated every 21 days for a maximum of 6 cycles.

Results

Major toxicity was granulocytopenia in 56% of patients, including 11 episodes of granulocytopenic fever. Anemia and thrombocytopenia developed in a third of the cases. No other significant toxicity or treatment related death was noted. An objective response was achieved in 20 patients (62.5%, 95% confidence interval 44 to 79). Median time to progression was 7 months and median survival was 13 months.

Conclusions

The cisplatin, ifosfamide, methotrexate and vinblastine regimen appeared active in patients with metastatic urothelial carcinoma. This regimen was associated with significant but manageable hematological toxicity and the incidence of mucositis or renal impairment was low. Prospective randomized studies are needed to assess whether the addition of ifosfamide to other active agents will improve the survival of patients with this disease.     

Immunotherapy for Urothelial Carcinoma: Current Evidence and Future Directions

Purpose of Review

Until recently, effective treatment options for patients with advanced urothelial carcinoma were limited to platinum-based chemotherapy. In the post-platinum setting and for patients ineligible for cisplatin, minimally effective second-line chemotherapy was used and outcomes were poor. The approval of immune checkpoint inhibitors has significantly changed the treatment landscape of urothelial carcinoma. Here, we review current data demonstrating their efficacy in advanced disease and ongoing trials investigating novel combination strategies.

Recent Findings

Since May 2016, five agents targeting the programmed cell death 1 (PD-1) pathways have been approved for use after progression on platinum-based chemotherapy. Further, atezolizumab and pembrolizumab are approved for use in cisplatin-ineligible patients with high programmed death-ligand 1 (PD-L1) expression. Preliminary studies have shown their safety and efficacy as neoadjuvant therapy in muscle-invasive bladder cancer. Several ongoing trials are investigating these agents in combination with radiation therapy, platinum-based chemotherapy, other immune checkpoint inhibitors, and targeted agents.

Summary

Immune checkpoint inhibitors have demonstrated durable efficacy in patients with advanced urothelial carcinoma as first- and second-line therapy. Ongoing studies will help define the optimal sequence, combination strategies, and predictive biomarkers of response.

     

Adjuvant Methotrexate, Vinblastine and Cisplatin Chemotherapy for Invasive Transitional Cell Carcinoma: Taiwan Experience

Purpose

The feasibility of adjuvant cisplatin, methotrexate and vinblastine chemotherapy was evaluated in Taiwanese patients with invasive transitional cell carcinoma at high risk for recurrence.

Materials and Methods

We assigned 56 patients with high risk transitional cell carcinoma (vascular or lymphatic invasion in the primary tumor, poorly differentiated stage P2, P3, P4 or N + and M0) to receive adjuvant chemotherapy after radical urological surgery. The chemotherapy consisted of 40 mg./m.² methotrexate and 4 mg./m.² vinblastine on days 1 and 8, and 100 mg./m.² cisplatin on day 2 given in 6 courses at 21-day intervals.

Results

Median followup was 44 months. An average of 4.63 cycles of chemotherapy was administered. The median actual survival was 44 months, and the 1 and 3-year survival probabilities were 92 percent and 50 percent, respectively. The median disease-free survival was 15.5 months, and the 1 and 3-year disease-free survival probabilities were 66 percent and 28 percent, respectively. Only 5 (9 percent) and 1 (2 percent) patients had grades 3 and 4 leukopenia, respectively, and none died of sepsis.

Conclusions

The use of adjuvant cisplatin, methotrexate and vinblastine chemotherapy in patients with invasive transitional cell carcinoma at high risk for recurrence is feasible with tolerable toxicity but randomized controlled trials will be required to assess the benefit.     

Primary Cisplatin, Methotrexate and Vinblastine Aiming at Bladder Preservation in Invasive Bladder Cancer: Multivariate Analysis on Prognostic Factors

Purpose

Although radical cystectomy is the standard therapy for invasive bladder cancer, cisplatin based multi-drug chemotherapy has proved to be effective for advanced transitional cell urothelial carcinoma. The potential for bladder preservation with neoadjuvant chemotherapy is currently under investigation.

Materials and Methods

A phase 2 protocol is presented for conservative treatment of muscle invasive transitional cell carcinoma of the bladder consisting of primary cisplatin, methotrexate and vinblastine chemotherapy followed by reevaluation for bladder sparing surgery and surveillance. A total of 61 patients completed the protocol with a mean followup of 41.4 months.

Results

Initial complete response to chemotherapy associated with tumor stage, size and configuration was noted in 20 patients (33 percent). Bladder preservation, intended only for the complete response group, was achieved in 16 patients (26 percent) but only 11 (18 percent) were alive with the bladder intact at study closure. Disease-free 5-year survival rate was 47 percent (95 percent confidence interval 65 to 26 percent). Tumor stage (p = 0.0007), size (p = 0.0003), response to chemotherapy (p = 0.002), patient age (p = 0.039) and tumor grade (p = 0.048) influenced survival. Multivariate analysis revealed response to chemotherapy (beta = 0.988, p = 0.034) and tumor size (beta = 0.978, p = 0.042) to be the only independent predictors.

Conclusions

Induction of cisplatin, methotrexate and vinblastine chemotherapy is helpful in identifying patients with a greater chance for survival among those with locally advanced bladder cancer. However, a bladder preservation strategy based on this therapy is only of limited success.     

Five-year Followup of a Prospective Trial of Radical Cystectomy and Neoadjuvant Chemotherapy: Nordic Cystectomy Trial 1

Purpose

Chemotherapy is widely used in patients with locally advanced bladder cancer but until now there has been no conclusive evidence that this therapy improves survival. The Nordic Cooperative Bladder Cancer Study Group conducted a randomized phase III study to assess the possible benefit of neoadjuvant chemotherapy in patients with bladder cancer undergoing radical cystectomy after short-term radiotherapy.

Materials and Methods

Our trial included 325 patients with locally advanced stage T1 grade 3 or stages T2 to T4aNXMO bladder cancer allocated randomly into a chemotherapy or no chemotherapy group (control). The chemotherapy schedule consisted of 2 cycles of 70 mg./m.² cisplatin and 30 mg./m.² doxorubicin with a 3-week interval between the cycles.

Results

After 5 years the overall survival rate was 59 percent in the chemotherapy group and 51 percent in the control group (p = 0.1). The corresponding cancer specific survival rate was 64 and 54 percent, respectively. In regard to treatment, no difference was observed for stages T1 and T2 disease, while there was a 15 percent difference in overall survival for patients with stages T3 to T4a disease (p = 0.03). In a multivariate analysis only chemotherapy and T category emerged as independent prognostic factors. The relative death risk for patients who received chemotherapy was 0.69 (95 percent confidence interval 0.49 to 0.98) compared to the control group after adjustment for the other tested factors.

Conclusions

Neoadjuvant chemotherapy seems to improve long-term survival after cystectomy in patients with stages T3 to T4a bladder carcinoma, while no survival benefit was found for stages T1 to T2 disease.     

Impact of C‐reactive protein kinetics on survival of patients with advanced urothelial carcinoma treated by second‐line chemotherapy with gemcitabine,etoposide and cisplatin

Study Type – Prognosis (cohort) Level of Evidence 2a What's known on the subject? and What does the study add? C‐reactive protein (CRP) level has been shown to be a significant prognostic factor for various malignancies, including urothelial carcinoma treated surgically. Apart from CRP level, several prognostic factors have been identified for advanced urothelial carcinoma patients receiving a second‐line chemotherapy. CRP could also be a significant prognostic factor for advanced urothelial carcinoma patients receiving a second‐line chemotherapy. CRP kinetics, the dynamic change of CRP concentration, has a strong impact on survival. Adding to the baseline CRP status at the start of treatment, the normalization of CRP during treatment is significantly associated with prognosis. The period with normalized CRP level was strongly correlated with survival period. Therefore, CRP could be a potential biomarker for advanced urothelial carcinoma patients.

OBJECTIVE

• ? To assess the impact of C‐reactive protein (CRP) kinetics, the effect of dynamic changes of CRP concentration on the survival of patients with locally advanced or metastatic urothelial carcinoma (UC) treated by single chemotherapeutic regimen including cisplatin was examined.

PATIENTS AND METHODS

• ? Eighty patients with advanced UC, who failed treatment of advanced UC with the first‐line chemotherapy or who received perioperative treatment of neoadjuvant or adjuvant settings, were treated with gemcitabine, etoposide and cisplatin (GEP) as second‐line chemotherapy.
• ? Patients were divided into three groups according to CRP kinetics based on baseline and nadir CRP concentrations. Patients whose baseline CRP levels were <5 mg/L, patients whose baseline CRP levels were ≥5 mg/L and normalized (<5 mg/L), and patients whose baseline CRP levels were ≥5 mg/L and never normalized were assigned to non‐elevated, normalized and non‐normalized CRP groups, respectively.
• ? The prognostic impact of CRP kinetics and the correlation between normalized CRP period and overall survival period were determined.

RESULTS

• ? In 46 (57%) of the 80 patients, CRP levels were elevated at the diagnosis of advanced UC. During treatment, after a median follow‐up period of 12 months CRP levels were normalized in 24 (71%) of 34 patients, whereas CRP levels remained elevated in the remaining 10 patients.
• ? Overall survival rates were significantly different between the non‐elevated, normalized, and non‐normalized CRP groups (P < 0.001), with 1‐year survival rates of 72, 51 and 14%, respectively. On multivariate analysis including Eastern Cooperative Oncology Group performance status, visceral metastasis, number of metastatic sites, previous definitive surgery, anaemia, baseline and nadir CRP levels (mg/L), and CRP kinetics status, CRP kinetics was an independent and significant factor for overall survival.
• ? The normalized CRP period was significantly correlated with the overall survival period in 52 patients who died.

CONCLUSIONS

• ? CRP kinetics is significantly associated with the prognosis and survival period of patients with advanced UC treated by chemotherapy.
• ? Although larger confirmatory studies are warranted to validate our results, CRP can potentially be a useful biomarker for patients with advanced UC.

     

GENITOURINARY SMALL CELL CARCINOMA: DETERMINATION OF CLINICAL AND THERAPEUTIC FACTORS ASSOCIATED WITH SURVIVAL

Purpose

We assessed the prognostic impact of genitourinary small cell carcinoma tumor and patient characteristics, and therapy.

Materials and Methods

We retrospectively reviewed the records of 180 patients with genitourinary small cell carcinoma in which patient and tumor characteristics, therapy, followup duration and survival status had been documented. Patient age, sex, primary site, histological features, tumor size, stage, locoregional therapy, systemic chemotherapy and hormonal manipulations were analyzed for association with survival.

Results

There were 106 cases of bladder, 60 prostatic, 8 renal and 6 ureteral small cell carcinoma. Median survival was 10.5 months overall, and 7 and 13 months for prostatic and bladder small cell carcinoma, respectively (p <0.0001 log rank analysis). In all cases metastatic disease at presentation (p <0.008, risk ratio 1.9) predicted poor survival on multivariate analysis. Radical surgery (p <0.0001, risk ratio 0.34) and cisplatin chemotherapy (p <0.0001, risk ratio 0.20) were the only factors that predicted improved survival on multivariate analysis. For prostatic small cell carcinoma primary surgical therapy (p <0.012, risk ratio 0.46) was the only parameter that predicted survival on univariate analysis. For bladder small cell carcinoma only cisplatin chemotherapy (p <0.0001, risk ratio 0.15) predicted survival on multivariate analysis.

Conclusions

Genitourinary small cell carcinoma has a poor prognosis, which is worse in prostatic than bladder disease. Patient and tumor characteristics were not determinants of survival when prostatic and bladder small cell carcinoma were analyzed individually. For prostatic disease only primary surgical therapy was associated with prolonged survival, while for bladder disease cisplatin chemotherapy was associated with a favorable prognosis. We recommend considering primary surgical therapy for prostatic and cisplatin based chemotherapy for bladder small cell carcinoma.     

Neoadjuvant and adjuvant chemotherapy use in upper tract urothelial carcinoma

Objective

To determine trends in neoadjuvant and adjuvant chemotherapy use for upper tract urothelial cancer and assess its effects on survival.

Feasibility of Pre- and Postoperative Gemcitabine-plus-Cisplatin Systemic Chemotherapy for the Treatment of Locally Advanced Urothelial Carcinoma in Kidney Transplant Patients

Objective

To investigate the feasibility of pre- and postoperative gemcitabine-plus-cisplatin (GC) adjuvant chemotherapy for the treatment of locally advanced urothelial carcinoma in kidney transplant patients.

Methods

Seven kidney transplant patients diagnosed with locally advanced urothelial carcinoma were treated with a pre- and postoperative GC adjuvant chemotherapy between January 2008 and March 2012. Gemcitabine (800 mg/m²) was administered at as an intravenous infusion on days 1 and 8. A total cisplatin dosage of 100 mg/cycle was administered on 2 days (50 mg/d on days 2 and 3) as an intravenous infusion. A single treatment cycle lasted 21 days. At the beginning of chemotherapy, the cyclosporine (CSA) dosage was reduced by 25 mg/d (on day 1 through day 8) if the blood CSA concentration was well maintained and did not fluctuate significantly. In addition, mycophenolate mofetil was reduced by 500 mg/d, while azathioprine was reduced by 25 mg/d (on day 1 through day 16). One cycle of GC neoadjuvant chemotherapy was given before operation, and several GC cycles were given after operation according to the patients' situation. Retrospective analysis was performed on the clinical data, chemotherapy regimen, chemotherapy efficacy, and side effects of the 7 patients.

Results

The 7 patients were all treated with 1 course of presurgical chemotherapy. The seven patients completed 24 treatment cycles of chemotherapy in total. The average GC medication period per patient was 3.4 cycles. The postsurgery follow-up was 6 to 36 months (average-22.1); all of the patients survived. There was 1 case of complete remission (14.5%), 2 of partial remission (28.5%), and 4 of stable disease (57%), with one case of T4N1M0 and three cases of T3N0M0. The overall efficacy was 43%. The toxicity and side effects associated with the GC regimen were largely associated with myelosuppression. The other side effects included reversible nephrotoxicity, gastrointestinal tract and skin reactions, as well as phlebitis. Hematologic toxic reactions included reversible leukopenia, thrombocytopenia, and anemia. There was 1 case of degree III anemia and 1 case of degree II; 5 cases of degree III and 1 of degree II leukopenia; and 3 of degree II thrombocytopenia. Gastrointestinal reactions included nausea, vomiting, and constipation. There were 2 cases of degree III and 4 cases of degree II nausea and vomiting as well as 2 cases of degree III and 3 cases of degree II constipation. There were 3 cases of degree I phlebitis (43%) and 2 cases of degree I skin erythema. The nephrotoxicity reactions were all reversible. Both liver function and grafted kidney function were not significantly altered after chemotherapy compared with prior to chemotherapy. None of the patients suffered renal allograft rejection after chemotherapy; none required additional antirejection drug treatments. The original antirejection treatment regimen was restored after the patients completed the chemotherapy treatment cycles.

Conclusion

We confirmed the efficacy of applying a GC regimen to treat locally advanced urothelial carcinoma in kidney transplant patients. The side effects were tolerable and reversible with minor impacts on graft function.     

Neoadjuvant docetaxel/estramustine prior to radical prostatectomy or external beam radiotherapy in high risk localized prostate cancer: A phase II trial

Background

Patients with locally advanced or organ confined, high risk, prostate cancer are at significant risk of having disease recurrence despite definitive local therapy. We evaluated the 2-year progression-free survival of subjects treated with chemotherapy administered prior to definitive therapy with surgery or radiation.

Patients and methods

Patients (n = 24) with locally advanced and high risk localized prostate cancer were treated with neoadjuvant docetaxel 36 mg/m2 i.v. weekly for 3 weeks and estramustine 140 mg orally 3 times daily for 3 consecutive days every 28 days prior to definitive treatment with prostatectomy or radiation.

Results

All evaluable patients, except 1, completed the proposed cycles of neoadjuvant chemotherapy with minimal dose reductions or delays. Of the 22 evaluable patients, 12 underwent radical prostatectomy and 10 underwent external beam radiation therapy. Twenty-one of 22 patients achieved a prostate-specific antigen (PSA) reduction > 25%. There were no pathologic complete responses. With a median follow-up of 24 months, the 2-year progression-free survival was 45%.

Conclusions

Our findings support the safety, tolerability, and efficacy of neoadjuvant chemotherapy in patients with men with high risk, locally advanced prostate adenocarcinoma, although the relative contributions of androgen deprivation therapy and docetaxel cannot be determined. The effectiveness of neoadjuvant chemotherapy in preventing prostate cancer relapses should be studied in a randomized trial.     

Outcome of metastatic urothelial carcinoma treated by systemic chemotherapy: Prognostic factors based on real-world clinical practice in Japan

Aim

To clarify prognostic factors of metatstatic urothelial carcinoma treated by systemic chemotherapy in real-world clinical practice in the Japanese population.

Neoadjuvant and adjuvant chemotherapy in muscle-invasive bladder cancer

Context

The use of neoadjuvant and adjuvant chemotherapy in the treatment of muscle-invasive bladder cancer is still controversial.

Objective

To determine the optimal use of chemotherapy in the neoadjuvant and adjuvant settings in patients with advanced urothelial cell carcinoma. Bladder preservation is also discussed.

Evidence acquisition

A critical review of the published literature on chemotherapy for patients with locally advanced bladder cancer was performed.

Evidence synthesis

The presence of occult micrometastases at the time of radical cystectomy leads to both distant and local failure in patients with locally advanced transitional cell carcinoma of the bladder. Both neoadjuvant and adjuvant therapies have been evaluated in patients with locally advanced bladder cancer. Studies evaluating adjuvant chemotherapy have been limited by inadequate statistical power to detect meaningful clinical answers as well as by experimental arms utilizing inadequate chemotherapy.

Conclusions

The aggregate of available evidence suggests that neoadjuvant cisplatin-based combination chemotherapy should be considered as a standard of care for patients with muscle-invasive or locally advanced operable bladder cancer. In patients who are either unfit for or refuse radical cystectomy, neoadjuvant chemotherapy with or without radiation can render bladder preservation possible for patients who attain an excellent clinical response. With the introduction of new cytotoxic drugs, there is a need for well-designed studies to address the optimal utility of perioperative therapy in high-risk patients with bladder cancer.     

ICUD-EAU International Consultation on Bladder Cancer 2012: Chemotherapy for Urothelial Carcinoma—Neoadjuvant and Adjuvant Settings

Context

We present a summary of the Second International Consultation on Bladder Cancer recommendations on chemotherapy for the treatment of bladder cancer using an evidence-based strategy.

Objective

To review the data regarding chemotherapy in patients with clinically localized and metastatic bladder cancer with a focus on its use for patients in the neoadjuvant and adjuvant settings.

Evidence acquisition

Medline databases were searched for original articles published prior to April 1, 2012, using the following search terms: bladder cancer, urothelial cancer, metastatic, advanced, neoadjuvant, and adjuvant therapy. Proceedings of major conferences from the last 5 yr also were searched. Novel and promising drugs currently in clinical trials were included.

Evidence synthesis

The major findings are addressed in an evidence-based manner. Prospective trials and important cohort data were analyzed.

Conclusions

Cisplatin-based combination chemotherapy for advanced and metastatic bladder cancer is an established standard, improving overall survival. In the advanced setting, cisplatin-ineligible patients may benefit from gemcitabine and carboplatin. Meta-analyses undertaken for neoadjuvant cisplatin-based combination chemotherapy show a 5% benefit in overall survival. Pathologic complete remission may be an intermediate surrogate for survival, but requires further validation. Use of neoadjuvant chemotherapy is low, and is attributable to patient and physician choice because of limited benefit, advanced age, and comorbidities including renal and/or cardiac dysfunction. Sufficient data to support adjuvant chemotherapy are lacking.     

The method of GFR determination impacts the estimation of cisplatin eligibility in patients with advanced urothelial cancer

Objectives

To determine GFR with different methods in patients with first-line chemotherapy for advanced urothelial cancer (UC) and to evaluate the impact of these methods on the estimation of cisplatin eligibility.

Methods

A database was built retrospectively containing all patients receiving first-line chemotherapy for UC between 2001 and 2012 in one German high-volume center. GFR was calculated with the methods by Cockcroft–Gault (CG), MDRD and CKD-EPI. Measurements of creatinine clearance with timed urine collections were registered.

Results

A total of 166 patients were included. All methods of renal function determination yielded consistent results in terms of cisplatin eligibility for 134 patients (80.7 %) and disagreeing results for 32 patients (19.3 %). Twenty-two of these 32 patients with borderline GFR received cisplatin-based chemotherapy. Fifteen of these 22 patients completed at least three cycles. The mean GFR in the mentioned 32 patients was 51.3, 56.2 and 54.2 ml/min with the method by CG, MDRD and CKD-EPI. Three, ten and four patients were estimated cisplatin-eligible with either method. There was a good correlation between MDRD and CKD-EPI (r ² = 0.92). CG tended to underestimate GFR compared to both MDRD and CKD-EPI. Measurements of creatinine clearance showed a wide distribution in comparison with MDRD (r ² = 0.002).

Conclusions

The method used to determine GFR influences the estimation of cisplatin eligibility in a subset of UC patients. MDRD and CKD-EPI formulas seem most valuable, while CG tends to underestimate renal function. Using a strict cutoff of 60 ml/min may unnecessarily preclude cisplatin in some patients.     

Concurrent Cisplatin and Radiotherapy for Patients with Muscle Invasive Bladder Cancer Who are not Candidates for Radical Cystectomy

Purpose

We assessed the results and prognostic factors in patients with bladder cancer treated conservatively with concurrent cisplatin and radiotherapy.

Materials and Methods

A total of 109 patients with localized muscle invasive bladder cancer who were not candidates for radical cystectomy underwent concomitant chemotherapy and radiation. Median patient age was 70 years. Of the patients 36 percent had stages T3B and 4 tumors, and 37 percent had benefited from prior macroscopically complete transurethral resection. Pelvic irradiation consisted of 40 to 45 Gy., and was followed by a boost to the bladder to a total dose of 55 to 60 Gy. Continuous infusion cisplatin (20 to 25 mg./m.² daily for 5 days) was delivered during weeks 2 and 5 of radiation therapy.

Results

Median followup was 54.8 months. The projected 4-year locoregional control rate was 47.6 percent for the 109 patients and 61.2 percent for 76 with a complete response. Projected overall 4-year survival was 41.9 percent for all patients and 51.4 percent for complete responders. Univariate analysis of prognostic factors was done for local control and survival. Local control was statistically better in patients with a good performance status, stages T2 and 3A disease, complete initial transurethral resection and without hydronephrosis. In terms of overall survival 4 factors were significant: 1) performance status, 2) T stage, 3) absence of hydronephrosis and 4) complete response. By multivariate analysis performance status, hydronephrosis and T stage were significant factors for local control, while T stage and complete response were the strongest determinants for survival.

Conclusions

Concurrent cisplatin and radiation therapy is a potentially curative and conservative treatment for patients with localized muscle invasive bladder cancer who are not candidates for radical surgery, particularly those with intravesical stages T2 and T3A tumors.     

Gemcitabine or gemcitabine plus oxaliplatin in the first-line treatment of patients with advanced transitional cell carcinoma of the urothelium unfit for cisplatin-based chemotherapy: a randomized phase 2 study of the French Genitourinary Tumor Group (GETUG V01)

Background

The optimal chemotherapy for patients with advanced transitional cell carcinoma of the urothelium who are not eligible for cisplatin remains to be defined.

Objective

To assess the activity of gemcitabine alone (GEM) or in combination with oxaliplatin (GEMOX) in a randomized phase 2 trial.

Design, setting, and participants

The primary end point was the objective response rate according to Response Evaluation Criteria in Solid Tumors criteria. The sample size was based on a two-stage Fleming design with p0 = 35% and p1 = 55%. At the end of the first stage designed to register 20 patients on each treatment arm, the observation of seven or more objective responses would have led to the inclusion of 30 more patients in each arm.

Results and limitations

From July 2004 to March 2009, 44 patients in 10 centers were randomly assigned into the GEM or the GEMOX arm, 22 on each treatment arm. The median age was 76 yr. Seven patients were included for a performance status (PS) of 2 only. The remaining 37 patients had an impaired renal function, 11 of whom also had a PS of 2. The median creatinine clearance was 45 ml/min (range: 30–80 ml/min). The trial was closed after the first part because the GEMOX arm did not reach the targeted objective response rate to proceed further.

Conclusions

Oxaliplatin does not add any significant activity (in terms of response rates) compared with gemcitabine alone in patients with advanced transitional cell carcinoma of the urothelium who are ineligible for cisplatin.     

A systematic review of neoadjuvant and adjuvant chemotherapy for muscle-invasive bladder cancer

Context

Muscle-invasive bladder cancer (MIBC) is a disease with a pattern of predominantly distant and early recurrences. Neoadjuvant cisplatin-based combination chemotherapy has demonstrated improved outcomes for MIBC.

Objective

To review the data supporting perioperative chemotherapy and emerging regimens for MIBC.

Evidence acquisition

Medline databases were searched for original articles published before April 1, 2012, with the search terms bladder cancer, urothelial cancer, radical cystectomy, neoadjuvant chemotherapy, and adjuvant chemotherapy. Proceedings from the last 5 yr of major conferences were also searched. Novel and promising drugs that have reached clinical trial evaluation were included.

Evidence synthesis

The major findings are addressed in an evidence-based fashion. Prospective trials and important preclinical data were analyzed.

Conclusions

Cisplatin-based neoadjuvant combination chemotherapy is an established standard, improving overall survival in MIBC. Pathologic complete response appears to be an intermediate surrogate for survival, but this finding requires further validation. Definitive data to support adjuvant chemotherapy do not exist, and there are no data to support perioperative therapy in cisplatin-ineligible patients. Utilization of neoadjuvant cisplatin is low, attributable in part to patient/physician choice and the advanced age of patients, who often have multiple comorbidities including renal and/or cardiac dysfunction. Trials are using the neoadjuvant paradigm to detect incremental pathologic response to chemobiologic regimens and brief neoadjuvant single-agent therapy to screen for the biologic activity of agents.     

Initial Evaluation of Cyfra 21-1 Diagnostic Performances as a Urinary Marker in Bladder Transitional Cell Carcinoma

Purpose

CYFRA 21-1, an immunoradiometric assay developed for the detection of a soluble cytokeratin 19 fragment, is evaluated for its diagnostic performance in urine of patients with transitional cell carcinoma.

Materials and Methods

CYFRA 21-1 was investigated in serum and urine of 128 patients, including 48 with bladder transitional cell carcinoma (group 1), 44 with other urological pathological conditions (group 2) and 36 free of urothelial disease (group 3). Urinary cytopathology was also performed.

Results

Mean urinary CYFRA was 123.5 +/− 53, 11.9 +/− 4.8 and 2.3 +/− 0.2 ng./ml. for groups 1 to 3, respectively, and was significantly different. From the receiver operating characteristics curve, the optimal combination of 96% sensitivity and 74% specificity was determined for a threshold value of 4 ng./ml. while overall cytopathology sensitivity was 43%.

Conclusions

Urinary CYFRA 21-1 may be a useful marker for diagnosing transitional cell carcinoma.     

Phase II study of paclitaxel and cisplatin for advanced urothelial cancer

PURPOSE: We examined the role of paclitaxel and cisplatin as first line therapy for metastatic urothelial cancer. MATERIALS AND METHODS: A total of 34 patients were enrolled in this study, and all were eligible for treatment and assessable for response. Patients received 135 mg./m.2 paclitaxel intravenously for 3 hours followed by 70 mg./m.2 cisplatin for 2 hours every 3 weeks to a maximum of 6 cycles. RESULTS: Of the patients 70% experienced a major response to treatment, which was partial/regression in 38% and complete in 32%. Toxicity was manageable with no episodes of grade 4 leukopenia or thrombocytopenia. Nonhematological toxicities included primarily nausea, anorexia and neuropathy, which rarely were severe. CONCLUSIONS: This regimen of paclitaxel and cisplatin is effective, safe and convenient to administer in an outpatient setting for advanced urothelial cancer.     

Epidermal growth factor expression as a predictor of chemotherapeutic resistance in muscle-invasive bladder cancer

Background

Epidermal growth factor receptor (EGFR) overexpression is believed to be associated with bladder cancer (BC) progression and poor clinical outcomes. In vivo studies have linked EGFR subcellular trafficking and chemo-resistance to cisplatin-based chemotherapies. This has not been studied in the clinical adjuvant setting. We aimed to investigate the prognostic significance of EGFR expression in patients receiving cisplatin-based adjuvant chemotherapy following radical cystectomy for advanced BC.

Methods

The database from the Urology and Nephrology Center at Mansoura University was reviewed. BC patients who were treated with radical cystectomy and adjuvant chemotherapy for adverse pathological features or node positive disease were identified. Patients who underwent palliative cystectomy, had histological diagnoses other than pure urothelial carcinoma, or received adjuvant radiotherapy were excluded from the study. Immunohistochemical staining for EGFR expression was performed on archived bladder specimens. The following in vitro functional analyses were performed to study the relationship of EGFR expression and chemoresponse.

Results

The study included 58 patients, among which the mean age was 57 years old. Majority of patients had node positive disease (n?=?53, 91%). Mean follow up was 26.61 months. EGFR was overexpressed in 25 cystectomy specimens (43%). Kaplan-Meier analysis revealed that EGFR over-expression significantly correlated with disease recurrence (p?=?0.021). Cox proportional hazard modeling identified EGFR overexpression as an independent predictor for disease recurrence (p?=?0.04). Furthermore, in vitro experiments demonstrated that inhibition of EGFR may sensitize cellular responses to cisplatin.

Conclusions

Our findings suggest that EGFR overexpression is associated with disease recurrence following adjuvant chemotherapy for advanced BC. This may aid in patient prognostication and selection prior to chemotherapeutic treatment for BC.