Levent Türkeri

Final Results of an EORTC-GU Cancers Group Randomized Study of Maintenance Bacillus Calmette-Guérin in Intermediate- and High-risk Ta, T1 Papillary Carcinoma of the Urinary Bladder: One-third Dose Versus Full Dose and 1 Year Versus 3 Years of Maintenance

BACKGROUND The optimal dose and duration of intravesical bacillus Calmette-Guérin (BCG) in the treatment of non-muscle-invasive bladder cancer (NMIBC) are controversial. OBJECTIVE To determine if a one-third dose (1/3D) is not inferior to the full dose (FD), if 1 yr of maintenance is not inferior to 3 yr of maintenance, and if 1/3D and 1 yr of maintenance are associated with less toxicity. DESIGN, SETTING, AND PARTICIPANTS After transurethral resection, intermediate- and high-risk NMIBC patients were randomized to one of four BCG groups: 1/3D-1 yr, 1/3D-3 yr, FD-1 yr, and FD-3 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The trial was designed as a noninferiority study with the null hypothesis of a 10% decrease in the disease-free rate at 5 yr. Times to events were estimated using cumulative incidence functions and compared using the Cox proportional hazards regression model. RESULTS AND LIMITATIONS In an intention-to-treat analysis of 1355 patients with a median follow-up of 7.1 yr, there were no significant differences in toxicity between 1/3D and FD. The null hypotheses of inferiority of the disease-free interval for both 1/3D and 1 yr could not be rejected. We found that 1/3D-1 yr is suboptimal compared with FD-3 yr (hazard ratio [HR]: 0.75; 95% confidence interval [CI], 0.59-0.94; p=0.01). Intermediate-risk patients treated with FD do not benefit from an additional 2 yr of BCG. In high-risk patients, 3 yr is associated with a reduction in recurrence (HR: 1.61; 95% CI, 1.13-2.30; p=0.009) but only when given at FD. There were no differences in progression or survival. CONCLUSIONS There were no differences in toxicity between 1/3D and FD. Intermediate-risk patients should be treated with FD-1 yr. In high-risk patients, FD-3 yr reduces recurrences as compared with FD-1 yr but not progressions or deaths. The benefit of the two additional years of maintenance should be weighed against its added costs and inconvenience. TRIAL REGISTRATION This study was registered at ClinicalTrials.gov, number NCT00002990; http://clinicaltrials.gov/ct2/show/record/NCT00002990.

EORTC Nomograms and Risk Groups for Predicting Recurrence, Progression, and Disease-specific and Overall Survival in Non-Muscle-invasive Stage Ta-T1 Urothelial Bladder Cancer Patients Treated with 1-3 Years of Maintenance Bacillus Calmette-Guérin.

BACKGROUND There are no prognostic factor publications on stage Ta-T1 non-muscle-invasive bladder cancer (NMIBC) treated with 1-3 yr of maintenance bacillus Calmette-Guérin (BCG). OBJECTIVE To determine prognostic factors in NMIBC patients treated with 1-3 yr of BCG after transurethral resection of the bladder (TURB), to derive nomograms and risk groups, and to identify high-risk patients who should be considered for early cystectomy. DESIGN, SETTING, AND PARTICIPANTS Data for 1812 patients were merged from two European Organization for Research and Treatment of Cancer randomized phase 3 trials in intermediate- and high-risk NMIBC. INTERVENTION Patients received 1-3 yr of maintenance BCG after TURB and induction BCG. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Prognostic factors for risk of early recurrence and times to late recurrence, progression, and death were identified in a training data set using multivariable models and applied to a validation data set. RESULTS AND LIMITATIONS With a median follow-up of 7.4 yr, 762 patients recurred; 173 progressed; and 520 died, 83 due to bladder cancer (BCa). Statistically significant prognostic factors identified by multivariable analyses were prior recurrence rate and number of tumors for recurrence, and tumor stage and grade for progression and death due to BCa. T1G3 patients do poorly, with 1- and 5-yr disease-progression rates of 11.4% and 19.8%, respectively, and 1- and 5-yr disease-specific death rates of 4.8% and 11.3%. Limitations include lack of repeat transurethral resection in high-risk patients and exclusion of patients with carcinoma in situ. CONCLUSIONS NMIBC patients treated with 1-3 yr of maintenance BCG have a heterogeneous prognosis. Patients at high risk of recurrence and/or progression do poorly on currently recommended maintenance schedules. Alternative treatments are urgently required. PATIENT SUMMARY Non-muscle-invasive bladder cancer patients at high risk of recurrence and/or progression do poorly on currently recommended bacillus Calmette-Guérin maintenance schedules, and alternative treatments are urgently required. TRIAL REGISTRATION Study 30911 was registered with the US National Cancer Institute clinical trials database (protocol ID: EORTC 30911). Study 30962 was registered at ClinicalTrials.gov, number NCT00002990; http://clinicaltrials.gov/ct2/show/record/NCT00002990.

EAU Guidelines on Urethral Trauma.

CONTEXT These guidelines were prepared on behalf of the European Association of Urology (EAU) to assist urologists in the management of traumatic urethral injuries. OBJECTIVE To determine the optimal evaluation and management of urethral injuries by review of the worlds literature on the subject. EVIDENCE ACQUISITION A working group of experts on Urological Trauma was convened to review and summarize the literature concerning the diagnosis and treatment of genitourinary trauma, including urethral trauma. The Urological Trauma guidelines have been based on a review of the literature identified using on-line searches of MEDLINE and other source documents published before 2009. A critical assessment of the findings was made, not involving a formal appraisal of the data. There were few high-powered, randomized, controlled trials in this area and considerable available data was provided by retrospective studies. The Working Group recognizes this limitation. EVIDENCE SYNTHESIS The full text of these guidelines is available through the EAU Central Office and the EAU website (www.uroweb.org). This article comprises the abridged version of a section of the Urological Trauma guidelines. CONCLUSIONS Updated and critically reviewed Guidelines on Urethral Trauma are presented. The aim of these guidelines is to provide support to the practicing urologist since urethral injuries carry substantial morbidity. The diversity of urethral injuries, associated injuries, the timing and availability of treatment options as well as their relative rarity contribute to the controversies in the management of urethral trauma.

Impact of the expression of epidermal growth factor, transforming growth factor alpha, and epidermal growth factor receptor on the prognosis of superficial bladder cancer

OBJECTIVES To investigate the correlation of epidermal growth factor receptor (EGFR) expression and its ligands EGF and transforming growth factor-alpha (TGF-alpha) with disease outcome in a cohort of patients with superficial bladder cancer. METHODS Tumor samples of 21 patients with transitional cell carcinoma of the bladder were analyzed by immunohistochemistry for expression of EGFR, EGF, and TGF-alpha. Disease-related events were recorded during a routine clinical follow-up and analyzed for possible correlation with the expression status of the above-mentioned proteins. RESULTS All Stage pT1 transitional cell carcinomas expressed EGFR, and 10 of 21 (48%) tumors showed focal areas of strong EGF and/or TGF-alpha expression. Of these, 80% with EGF positivity (8 of 10) had recurrences, whereas only 9% of patients without EGF staining (1 of 11) did so. The same pattern was observed with TGF-alpha. A strong association was confirmed between EGF/TGF-alpha positivity and tumor recurrence (P <0.005). We also found that EGF and TGF-alpha were expressed in stroma and/or around the vessels of tumor tissue in 48% and 38% of the tumors, respectively. No association was found between the recurrence rate/vascular invasion and the stromal/vascular wall expression of the growth factors. CONCLUSIONS Expression of EGF and TGF-alpha is correlated with tumor recurrence. Also, there is the ability of vessel walls to express EGF and TGF-alpha in superficial bladder cancer. Further clarification of the impact of this expression on angioinvasion of tumor cells may be helpful in understanding the nature of local invasion and metastasis.

Is There a Role for Bladder Preserving Strategies in the Treatment of Muscle-Invasive Bladder Cancer?

Single modality bladder sparing therapy for muscle-invasive bladder cancer, including transurethral resection, systemic chemotherapy or radiotherapy have been demonstrated to result in insufficient local control of the primary tumor as well as decreased long-term survival of the patients when compared to radical cystectomy. Therefore, multimodality treatment protocols that aim at bladder preservation and involve all of the aforementioned approaches have been established. Arguments for combining systemic chemotherapy with radiation are to sensitize tumor tissue to radiotherapy and to eradicate occult metastases that have already developed in as many as 50% of patients at the time of first diagnosis. It has been shown that the clinical outcome observed with this approach approximates that after radical cystectomy. Additionally, a substantial number of patients survive with an intact bladder. However, bladder preserving approaches are costly, and require close co-operation between different clinical specialists as well as very close follow-up. The good long-term results obtained after cystectomy and creation of an orthotopic neobladder make the possible advantage of a bladder preservation strategy questionable in consideration of quality of life issues. Additionally, side effects related to bladder sparing therapy may result in an increased morbidity and mortality in those patients who in fact need to undergo surgery due to recurrent or progressive disease. Multimodality bladder sparing treatment is a therapeutic option that can be offered to the patient at centres that have a dedicated multidisciplinary team at their disposal. However, radical cystectomy remains the standard of care for muscle-invasive bladder tumors.

Prevention of Hemorrhagic Cystitis Following Allogeneic Bone Marrow Transplant Preparative Regimens With Cyclophosphamide and Busulfan: Role of Continuous Bladder Irrigation

High dose cyclophosphamide and/or busulfan conditioning treatment of recipients of bone marrow transplants proved to be highly effective but associated with substantial and sometimes life threatening hemorrhagic cystitis. To prevent this complication, a prophylactic continuous bladder irrigation program was instituted in patients receiving cyclophosphamide and/or busulfan in preparation for bone marrow transplantation. Retrospective analysis of 199 patients who underwent allogeneic bone marrow transplantation revealed that continuous bladder irrigation significantly decreased the frequency of hemorrhagic cystitis in patients receiving busulfan and cyclophosphamide (continuous bladder irrigation 23% versus no bladder irrigation 53%, p < 0.004). There was no difference in the frequency of hemorrhagic cystitis between the different preparative regimens in patients who underwent continuous bladder irrigation. There was no relationship between the incidence of hemorrhagic cystitis and the severity of graft-versus-host disease or the time to engraftment. The duration of hemorrhagic cystitis and overall survival rates were similar in both groups, and there was no increase in complications related to catheterization. In general, continuous bladder irrigation was well tolerated, decreased the incidence of hemorrhagic cystitis and may be useful in bone marrow transplant patients.

Erectile dysfunction following radiotherapy and brachytherapy for prostate cancer: pathophysiology, prevention and treatment

ObjectivesAlthough detrimental impact on sexual function following radiotherapy (RT) and brachytherapy decreases the quality of life of prostate cancer survivors, the etiology, pathophysiology, prophylaxis and treatment of this condition has not yet been fully clarified. We reviewed the published literature in terms of etiology, treatment and possible prevention of erectile dysfunction (ED) following RT and/or brachytherapy.MethodWe have reviewed the literature through a MEDLINE search. Prostate cancer, erectile dysfunction, radiotherapy, brachytherapy, treatment and quality of life were used as keywords.ConclusionBoth RT and brachytherapy result in high rates of ED. Although arterial damage seems to be the main cause of ED after RT, exposure of neurovascular bundle to high levels of radiation dose has been also implicated in some studies with brachytherapy. The radiation dose received by the corpora cavernosa at the crurae of the penis may also be important in the etiology of ED. The most important predictive factor of ED following RT is the treatment modality. Intensity-modulated radiotherapy and vessel-sparing prostate radiotherapy are new techniques but those treatments may not guarantee complete preservation of the erectile function. Patients need to be correctly informed on the possible sequela of radiation-based treatments on their sexual well-being while planning their treatment. Patients should also be informed about the possible treatment modalities for ED, which may develop in due course.

PSA bouncing after external beam radiation for prostate cancer with or without hormonal treatment.

OBJECTIVES The purpose of this study was to find out the frequency of PSA bouncing and the factors effecting PSA bounce after external beam radiation treatment (EBRT) with or without hormonal treatment (HT) for prostate cancer and to identify any possible relationship with biochemical control. METHODS Between March 1997 and November 2000, 72 consecutive patients with clinically localised prostate cancer were treated by EBRT with or without HT. All patients had a pretreatment PSA level, at least six post-treatment PSA levels and minimum two years of follow-up. Median follow-up for all patients was 51 months (range 25-69 months). Median radiation dose given to the center of the prostate was 70Gy (range 63-74Gy). Fifty-nine patients (82%) received adjuvant HT with median duration of six months. PSA bounce was defined as a minimal rise of 0.4ng/ml over six months (monthly rise > or =0.07 ng/ml), followed by any decrease. Biochemical failure was defined in accordance with the ASTRO consensus guidelines. RESULTS Seventeen patients (24%) experienced at least one PSA bounce. PSA bounces were more frequent in patients with T1-2 stage, pretreatment PSA <10 ng/ml, small field irradiation, radiation dose < or =70 Gy, PSA nadir > or =0.2 ng/ml and without HT. PSA bounce occurred in 54% of patients treated by EBRT only, and 17% of patients treated by EBRT and HT. Logistic regression model for multivariate analysis revealed the radiation field size as the only independent predictive factor for PSA bounce. Five-year biochemical control rates were 82% for non-bouncers and 88% for bouncers (p=0.5). CONCLUSIONS PSA bouncing occurs in approximately a quarter of patients treated with EBRT with or without HT. It is associated with pretreatment and treatment characteristics, but we did not observe any relationship with biochemical failure.

Differential Diagnosis of Smooth Muscle Tumors Utilizing p53, pTEN and Ki-67 Expression with Estrogen and Progesterone Receptors

Background/Aim: To investigate the expression and value for diagnosis of the genes, p53 and pTEN, the protein, Ki-67, and the receptors, estrogen and progesterone, in differentiating smooth muscle tumors of the uterus. Material and Method: Seventeen samples of leiomyosarcoma, 2 smooth muscle tumors with uncertain malignant potential (STUMP), 9 atypical myomas and 15 leiomyomas were stained immunohistochemically. The χ2 test was used for the statistical analysis of the data. Results: The malignant side of the spectrum was strongly stained for Ki-67 and p53 while uniformly decreasing toward the benign tumors. The results were found to be statistically significant (p < 0.0001). The staining for progesterone receptor was also statistically significant, but the tumors that were considered benign, such as leiomyoma and atypical myoma, were the ones strongly stained (p = 0.005). The expression of estrogen receptor was significant in these tumors, but the p value was very close to the cut-off value (p = 0.07). As the degree of differentiation of the tumor increased, the trend showed stronger staining for estrogen receptor. However, no difference was detected in the staining properties of the tumors for pTEN (p = 0.2457). Conclusion: The expression of Ki-67, p53 and progesterone receptors is promising in immunodifferentiation of smooth muscle tumors of the uterus with malignant potential.

Presence of high grade tertiary Gleason pattern upgrades the Gleason sum score and is inversely associated with biochemical recurrence-free survival

OBJECTIVES Tumor heterogeneity is a common finding and led to realization of a tertiary Gleason component (TGC) in prostate cancer. In an attempt to further investigate its prognostic value, we analyzed the association of tertiary Gleason pattern in Gleason score ≤ 7 tumors with pathologic stage and biochemical disease-free survival. MATERIAL AND METHODS A total of 331 radical prostatectomy specimens were analyzed retrospectively. The primary, secondary, and the tertiary patterns were evaluated by reviewing all of the pathologic slides. TGC was defined as Gleason grade pattern 4 or 5 for Gleason score < 7 tumors and Gleason grade pattern 5 for Gleason score 7 tumors. The pathologic prognostic factors, (extraprostatic extension, seminal vesicle and lymph node invasion, surgical margin status) of Gleason score < 7, 3+4, and 4+3 tumors with or without TGC were compared. Biochemical recurrence-free survival (BRFS) was calculated using Kaplan-Meier method with log rank test, and the influence of TGC was assessed in a Cox regression model. RESULTS TGC observed more frequently with higher Gleason scores (21% of the GS < 7 cases, 23% of the GS 3+4 cases, and 58% of the GS 4+3 cases). In terms of adverse pathologic prognostic factors and BRFS, GS < 7 tumors with TGC behaved significantly worse than GS < 7 tumors without TGC (P = 0.01 and P = 0.001, respectively) with properties similar to GS 3+4 tumors without TGC. Gleason score 3+4 and 4+3 tumors without TGC were statistically similar and had better features than corresponding tumors of same Gleason score with TGC. Furthermore, Gleason score 7 tumors with TGC had similar features with GS 8-10 tumors. During follow-up, 73 (22%) subjects had PSA recurrence. In the Cox regression model TGC was an independent variable for BRFS (HR = 2.63, 95% CI = 1.39-4.98, P = 0.003). CONCLUSION According to the present study, 3 different prognostic groups were observed; good prognostic group: GS < 7, intermediate prognostic group: GS < 7+TGC, GS 3+4, and GS 4+3, and finally bad prognostic group: GS (3+4)+TGC, GS (4+3)+TGC, GS > 7. Presence of a TGC appears to upgrade the total score and adjuvant treatment decisions may further be refined by considering the tertiary pattern.