T1b Disease Research Articles

Association of Statins with Biochemical Failure after Radiotherapy for Prostate Cancer

There has been growing interest in the potential anticancer activity of statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) based on preclinical evidence of their antiproliferative, proapoptotic, and radiosensitizing properties. This study was undertaken to determine whether statins enhance the efficacy of Radiation Therapy (RT) in prostate cancer patients. Between 1988 and 2006, 719 men (median age 69) with prostate adenocarcinoma were treated at the University of Chicago with curative-intent radiotherapy. All patients had intact prostates, no distant metastases, and minimum follow-up of 2 years. The majority (80%) had <T2b disease with a median Gleason Score of 6 and a median PSA of 8.4 ng/mL (range, 0.2 to 242). The median radiation dose was 72 Gy delivered using external beam RT (84%), brachytherapy (9%), or a combination of both (7%). A total of 59% received Androgen Deprivation Therapy (ADT) for a median of 4 months. One hundred nine patients (15%) were on statins at initial consult, and 35 (5%) were started on statins after completing radiotherapy. Lipid panels were available in 85 of the patients taking statins with median lipid panel date 3 months prior to radiation start. Type of statin and statin doses were recorded, and doses were normalized to simvastatin equivalents for dose response analysis. Median follow-up was 50 months after RT. A PSA relapse was defined according to the Phoenix (nadir + 2) definition. On univariate analysis, statin use was associated with favorable biochemical outcomes using both Phoenix and ASTRO definitions (p < 0.0001 and p = 0.0167, respectively). This effect was seen in D'Amico low and high-risk groups (p = 0.0314 and p = 0.0070, respectively) with a trend in intermediate-risk patients (p = 0.0750). Across risk categories, statin use was associated with biochemical outcome to a greater degree than ADT (low-risk, p = 0.3482; intermediate risk, p = 0.3183; high-risk, p = 0.0544). On multivariate analysis, statin use (p < 0.0002), pretreatment PSA ≤8.4 (p = 0.0016), Stage <T2b (p = 0.0171), Gleason score <7 (p = 0.0261), and dose ≥7,400 cGy (p = 0.0474) were associated with biochemical outcome whereas ADT (p = 0.6026) was not. There was no significant relationship between LDL (p = 0.1382), HDL (p = 0.4576), or triglyceride level (p = 0.4767) and biochemical failure. There was, however, a trend for improved biochemical control with lower total cholesterol levels (p = 0.0531). There was no relationship demonstrated between statin type (p = 0.3553), statin dose (low or high, p = 0.1942), or timing of RT (at consult or during follow-up, p = 0.1654) and biochemical outcome. Statin use was associated with a significantly decreased risk of biochemical failure. Randomized clinical trials are warranted to further investigate this effect.

The Impact of Prostate and Seminal Vesicle Motion during Prostate Cancer Radiotherapy on Planning Margins

The seminal vesicles (SVs) form part of the target in the radiotherapy (RT) treatment of prostate cancer, either because of their significant risk of involvement in locally advanced disease or because of overt clinical invasion. While prostate motion and appropriate margins have been documented, there is little information on SV motion. Movement of the SVs compared to the prostate, if uncorrected, can lead to geometrical target miss. The aim of this prospective study was to assess and compare SV motion with respect to prostate motion to ascertain the appropriate margins for each target. The study population consisted of 10 patients with locally advanced prostate cancer and considered to be at risk of SV invasion or with clinically T3b disease. The average age was 71 years, with average PSA and median Gleason scores of 10 μg/L and 8, respectively, and T stages from T2a to T3b. Following consent, 5 gold seeds were inserted trans-rectally into each patient. Of the 5 seeds, 3 were inserted into the prostate (right base, left mid gland, right apex), and 1 into each of the left and right SVs. All patients were treated to a dose of 78 Gy in 39 fractions with IMRT. Daily orthogonal 2D Electronic Portal Images (EPIs) were taken of each patient in treatment position prior to RT. Elekta I-View GT template matching software was used to verify EPIs with the reference image (CT-derived Digitally Reconstructed Radiograph). Online verification was performed for each fraction using the 3 prostate seeds. Matches of the left and right SV seeds were performed offline for each of the 39 fractions of all 10 patients. The total standard deviation (SD) of systematic errors (∑tot) and SD of random errors (σtot) were calculated, and the CTV-PTV margins for both the prostate and SVs were generated using a previously published formula (2.5∑tot + 0.7σtot). The average correctional shifts (with ranges) for the prostate and SVs in mm were: Prostate: Right-Left (RL) 0.9 (−4.6 to 6.5), Superior-Inferior (SI) −0.3 (−9.8 to 6.3), Anterior-Posterior (AP) −0.3 (−8.6 to 9.1) Left SV: RL 0.9 (−10.5 to 10.4), SI -1.4 (−10.8 to 8.8), AP -2.2 (−16.6 to 8.3) Right SV: RL 0.1 (−9.0 to 5.3), SI -1.1 (−9.4 to 6.3), AP -2.1 (−13.2 to 10.9). Required CTV-PTV margins in mm in the RL, SI and AP planes were: Prostate: 4.2, 6.1, 3.3 Left SV: 9.1, 5.4, 6.9 Right SV: 5.5, 5.4, 6.7. Positional variation of the prostate and SVs was observed during RT. We have found that SV motion is greater in the RL and AP directions than prostate motion. Consequently, the calculated PTV margins for the SVs were greater than the prostate margins, indicating that differential margins may be warranted.

The prognostic role of the pathological T2 subclassification for prostate cancer in the 2002 Tumour‐Nodes‐Metastasis staging system

To evaluate the prognostic role of the 2002 Tumour-Nodes-Metastasis (TNM) pT2 subclassification for biochemical recurrence (BCR) after radical prostatectomy (RP) for prostate cancer. The 1997 TNM staging system is based on one subdivision for organ-confined prostate tumours (T2a, unilateral; T2b, bilateral involvement). The 2002 TNM staging system subdivides unilateral involvement into T2a (half of one lobe or less) and T2b (more than one half of one lobe), while bilateral involvement is classified as T2c. In all, 542 patients were treated with RP at our institute; the RP specimens were completely embedded and histopathologically evaluated for Gleason grade, tumour volume and anatomical extent, and were staged according to the 2002 TNM staging criteria. Patients were followed for a median of 39.5 months. BCR was defined as two subsequent increasing prostate-specific antigen (PSA) levels of >0.10 ng/mL. Kaplan-Meier and proportional hazards regression analyses were used to evaluate the univariable and multivariable prognostic effect of tumour stage. According to the 2002 TNM staging system, 360 specimens were found to have pT2 tumours; 79 (22%) of the RP specimens were staged as pT2a and 281 (78%) as pT2c; no pT2b specimens were identified. Patients with unilateral involvement (pT2a) had a 5-year risk of BCR of 13%, while those with bilateral involvement (pT2c) had a risk of 23% (log rank test, P = 0.056). Patients with pT2c disease were more likely to have a larger tumour volume (Mann-Whitney U-test P < 0.001) and positive surgical margins (Fishers' exact test, P = 0.001)than those with pT2a tumours. Mann-Whitney U-tests showed no differences between the groups for preoperative PSA levels (P = 0.167). Also, the RP Gleason score was no different between groups (Pearson chi-square, P = 0.807). In the multivariable analyses, positive surgical margins appeared to increase the risk of BCR (hazard ratio 4.4, 95% confidence interval 2.5-7.9); pT2c vs pT2a had only a marginally (insignificant) additional effect (1.3, 0.6-2.7). The absence of a true unilateral pathological T2b tumour in a series of 360 pT2 RP specimens questions the relevance of substaging unilateral disease. The limited differences in BCR and in pathological features of unilateral vs bilateral pT2 prostate cancer justify modifying the TNM staging system to one with no subclassification of pT2 disease, or at most as only one subdivision into unilateral (T2a) and bilateral (T2b) disease, combining the T2b and T2c substages.

To compare the results of Adjuvant Online and Oncotype DX in estimating risk for relapse in hormone receptor positive stage I breast cancer patients

22069 Methods: Patients with Estrogen receptor positive, stage I, breast cancer that had Oncotype DX testing done were identified by retrospective review. 10 year relapse risk results obtained with Oncotype DX and Adjuvant Online were compared. The results were separated for T1b and T1c tumors. Cost comparison was done. Results: 30 patients with T1c and 8 patients with T1b disease were identified. All patients were females, age 29–73 years. Her 2 neu receptors were not over expressed in any case. T1c: For T1c tumors, 10 year tamoxifen adjusted relapse rate calculated from Adjuvant Online varied between 10.8–19.2%. Oncotype DX estimated rate of distant recurrence at 10 years in this group varied between 5–25%. 10 year relapse risk results calculated by these two methods were within 5 points of each other in 70% (21/30) cases, between 5–10 points in 23.3% (7/30) cases and > 10 point difference was seen in 6.7% (2/30) cases. Oncotype DX recurrence score identified 50% (15/30) patients in low risk group (Recurrence score < 18 and 10 yr relapse rate < 11), 40% in intermediate risk group (Recurrence score 18 - 30 and 10 yr relapse rate 11–21%), and 10% in high risk group (Recurrence score ≥ 31 and 10 yr relapse rate > 21%). Adjuvant Online results also showed three distinct groups with 26.6% patients in low risk group (10 yr relapse rate 10.8%), 63.3% in intermediate risk group (10 yr relapse rate 15%) and 10% in high risk group (10 yr relapse rate 19.2%). T1b: For T1b tumors, 10 yr relapse rate with Adjuvant Online varied between 9–15.6% and for Oncotype DX it varied between 10–23%. 10 yr relapse risk results calculated by two methods were within 5 points of each other in 62.5% (5/8) cases and difference was >10 points in 37.5% (3/8) cases. Oncotype DX testing assessed higher risk in 87.5% (7/8) cases. Cost Comparison: Oncotype DX cost $3,650 per test and total cost was $138,700. Adjuvant Online cost was 0. Conclusion: There was considerable variability in results of risk assessment provided by Oncotype DX testing and Adjuvant Online. Each method has been validated previously and there is need of a large longitudinal study to compare their risk assessment ability in cost effective fashion. No significant financial relationships to disclose.

Incidental carcinoma of the prostate: What’s the best procedure to discover residual disease?

16106 Background: Incidental prostate cancer (CaP) presents a highly different risk of progression for T1a and T1b disease (T1a: 10–26% at 7–10 years; T1b: up to 30 % at 2 years), even in more recent series. An incorrect definition of stage can strongly impact on patient’s survival, so we restaged our patients after transurethral resection of the prostate (TURP) by means of a second procedure, consisting of a repeated TURP plus ultrasound-guided biopsies (BxP). The study investigated prospectively these two diagnostic modalities with the aim to discover which one provides the best detection rate. Methods: Between January 1997 through January 2006, 50 T1a CaP were discovered in patients submitted to TURP (1021pts). Median prostate-specific antigen (PSA) before the operation was 5.25 ng/ml (range 0.6 - 17). After three months, prior PSA reevaluation, all patients underwent a second resection in conjunction with an ultrasound-guided transrectal biopsy (six cores). Results: After the first TURP median PSA was 1.35 ng/ml (range 0 - 4.02). Residual disease was demonstrated in 20 patients (40%) [median PSA 1.19 (range 0.4 - 4.02)], then treated surgically or not, depending on age or comorbidities. Among them, in 7 cases (14%) both re- TURP and BxP were positive; in 7 patients (14%) repeated TURP was positive and BxP negative (p n.s.), while in the remaining 6 (12%) repeated TURP was negative and BxP positive (p n.s.). Twelve out of 20 patients (median age 68) with persistent cancer underwent radical surgery and locally advanced disease was revealed in 3 (25%), with one patient having a Gleason score 9. Conclusions: In these series 40% of patients, initially diagnosed in stage T1a, revealed residual tumor after restaging. This high percentage warranted the discomfort and the costs of a second procedure. Either repeated TURP and BxP failed to demonstrate an advantage over each other in terms of “detection rate”. A 10% false negative rate for both prompts us to associate the two modalities instead of choosing between them, in order to discover a potentially lethal residual disease for which, in many cases, a definitive treatment is to be considered. No significant financial relationships to disclose.

Hand-Assisted Laparoscopic Nephrectomy for Renal Cell Cancer with Renal Vein Tumor Thrombus

To assess outcomes after hand-assisted laparoscopic nephrectomy (HALN) for renal cell cancer tumor thrombus confined to the renal vein and to compare outcomes with published series in this setting. Thirteen patients underwent HALN for radiologic T3b disease (tumor thrombus confined to the renal vein on preoperative computed tomography) under the care of three surgeons at two centers between 1997 and 2006. Median patient age was 69 years. Median duration of surgery was 176 minutes. Median blood loss was 250 mL. Median postoperative stay was 3 days. Two patients were converted to open surgery: 1 owing to unsuspected invasion of the subdiaphragmatic vena cava requiring vascular clamping with direct excision and suture, and 1 for control of bleeding. No patients suffered major morbidity associated with surgery, and there was one minor complication (aside from blood transfusion in 5 patients). After 2.7 years median follow-up, 3 of the 12 patients with pT3bN0 disease had metastases, but there were no local recurrences. These data demonstrate that HALN for renal cell cancer with tumor thrombus limited to the renal vein is feasible. Our outcomes compare favorably to published data on open surgical radical nephrectomy in this setting, and HALN should be considered in centers with experience with this technique.

What Is an Adequate Extent of Resection for T1 Gallbladder Cancers?

The purpose of this study was to analyze clinicopathologic and surgical features and to determine what should be an adequate extent of resection for T1 gallbladder cancers. Simple cholecystectomy offers adequate treatment for T1a cancers; however, it remains debatable whether T1b cancers should be treated by simple cholecystectomy or by radical resection. Two hundred ninety patients with gallbladder cancer underwent surgical resection. A retrospective analysis was conducted on 52 patients with pathologic stage T1 (27 [52%] with T1a and 25 [48%] with T1b). Clinicopathologic features, extents of resection, and survival rates were investigated retrospectively. No lymph node metastasis or lymphovascular or perineural infiltration was observed in those with T1a disease, but 2 of the 25 patients with T1b disease (3.8%) had lymph node metastasis and 1 patient (1.9%) had lymphatic infiltration. Twenty-one of the 52 study subjects (40.3%) underwent simple cholecystectomy. No peritoneal dissemination occurred regardless of the surgical method (laparoscopy or open surgery). Of the 23 radically resected patients (44.2%) in T1b group, 6 patients (11.5%) underwent cholecystectomy and hepatoduodenal lymph node dissection (CholeLN), and 17 patients (32.7%) underwent CholeLN combined with wedge resection of IVb and V segments of liver, common bile duct resection, or pancreaticoduodenectomy. No difference in locoregional recurrence, metastasis, or survival rate was observed regardless of combined resection of an adjacent organ. The overall survival rate for all patients was 96.2%, and for T1a and T1b these were 96.3% and 96%, respectively. When early gallbladder carcinoma is suspected on the basis of imaging findings, further evaluation of the depth of invasion by endoscopic ultrasonography or intraoperative frozen biopsy is advised. Then, if the disease stage is determined to be T1a, laparoscopic or open cholecystectomy alone is curative, and if T1b, cholecystectomy with hepatoduodenal lymph node dissection without combined resection of an adjacent organ is recommended.

Gallbladder cancer — A comprehensive review

Gallbladder cancer is the fifth most common cancer involving the gastrointestinal tract, but it is the most common malignant tumour of the biliary tract worldwide. The percentage of patients diagnosed to have gallbladder cancer after simple cholecystectomy for presumed gallbladder stone disease is 0.5-1.5%. This tumour is traditionally regarded as a highly lethal disease with an overall 5-year survival of less than 5%. The marked improvement in the outcome of patients with gallbladder cancer in the last decade is because of the aggressive radical surgical approach that has been adopted, and improvements in surgical techniques and peri-operative care. This article aims to review the current approach to the management of gallbladder cancer. A Medline, PubMed database search was performed to identify articles published from 1990 to 2007 using the keywords 'carcinoma of gallbladder', 'gallbladder cancer', 'gallbladder neoplasm' and 'cholecystectomy'. The overall 5-year survival for patients with gallbladder cancer who underwent Ro curative resection was reported to range from 21% to 69%. Laparoscopic cholecystectomy is absolutely contraindicated when gallbladder cancer is known or suspected pre-operatively. Patients with a pre-operative suspicion of gallbladder cancer should undergo open exploration and cholecystectomy after proper pre-operative assessment. For patients whose cancer is an incidental finding on pathological review, a second radical resection is indicated except for Tis and T1a disease. There is still controversy for the optimal management of T1b disease. Although the role of surgery for advanced disease remains controversial, patients with advanced gallbladder cancer can benefit from radical resection, provided a potentially curative Ro resection is possible. There is still no effective adjuvant therapy for gallbladder cancer.

Laparoscopic radical nephrectomy: long-term outcomes

Concurrent with the rise of laparoscopic radical nephrectomy as the gold standard for managing renal cell carcinoma, awareness has increased regarding the value of nephron-sparing surgery, even in the presence of a normal contralateral kidney. Therefore, whereas fewer radical nephrectomies will be performed for T1a tumors, there is a move towards handling more advanced pathology laparoscopically; that is, very large tumors, T3b disease, and limited lymph-node involvement. This review will highlight the long-term outcomes and recent developments in laparoscopic radical nephrectomy reported over the past year. There were several papers reiterating the excellent long-term outcomes of laparoscopic radical nephrectomy in the form of retrospective comparisons with cohorts of patients undergoing open radical nephrectomy. None of these studies demonstrated any differences in 5-year cancer-specific or overall survival. Surgeons continue to expand upon the current technique and indications. Long-term studies repeatedly support the superiority of laparoscopic radical nephrectomy over open radical nephrectomy for the majority of renal cell cancers due to equivalent oncologic control, low morbidity and shorter convalescence time. Experienced surgeons are able to manage more advanced pathologies laparoscopically without compromising cancer control or patient safety.

Revision surgery for incidental gallbladder cancer: factors influencing operability and further evidence for T1b tumours

Background and aim. There is a need to increase the available data on revision radical surgery for incidental gallbladder cancer and to determine factors influencing operability. We aimed to assess the impact of stage of disease (pT) and the type of primary surgery (laparoscopy versus open) on resectability rates. Material and methods. The data of 90 consecutive patients referred to the Tata Memorial Hospital between 1 January 2003 and 30 April 2007 for revision radical surgery for incidental gallbladder cancer were reviewed retrospectively. Results. Of the 90 patients who underwent revision surgery, accurate data on T-stage was available in 76, and of these 76 patients, 44 (57.8%) had prior laparoscopic simple cholecystectomy, while 32 (42.2%) had undergone open surgery. The median time interval between the two surgeries was 2 months (range 4 weeks to 11 months). By T-stage, 23 patients had T1b disease, while 33 and 20 patients had T2 and T3 disease, respectively. Successful revision surgery could be undertaken in 71% of patients (54/76) and 29.6% of these had residual disease confirmed by histopathological examination. Conclusions. T-stage is an important factor in determining operability as confirmed by our study. As the T-stage of the disease increased, the chances of finding residual disease increased, while operability decreased. Furthermore, the case for revision surgery is strengthened because the incidence of lymph nodal disease is high even for pT1b cancers. The type of primary surgery does not affect operability in patients undergoing revision radical surgery for incidental gallbladder cancer.

Pros and cons of radical cystectomy in the treatment of T1G3 bladder cancer

The management of T1G3 (or high-grade T1) bladder cancer poses a challenging clinical dilemma to the urologist. There are good data supporting bladder conservative therapy with repeat transurethral resection and administration of Bacille Calmette-Guérin (BCG) intravesical therapy but this must include maintenance regimens since only maintenance BCG has been shown to decrease tumor recurrence and progression. Concern over worse survival with a delay in definitive therapy has prompted many to recommend immediate cystectomy for T1G3 disease. Ultimately, the decision needs to be individualized and although certain pathologic factors (T1b disease, early recurrence or progression within three months of BCG therapy, lymphovascular invasion and variant histology) are prognostic of progressive disease, no definitive risk factors for tumor progression have been identified.

Histopathological analysis of T1 renal cell carcinoma: Does presentation matter?

Objectives:To study the differences in the clinico-pathological features of incidental and symptomatic T1 renal cell carcinoma (RCC) and to see, particularly in T1b RCC, if symptomatic presentation has adverse pathological features concerning the oncological safety of elective nephron-sparing surgery (NSS) in this subgroup.Materials and Methods:Of 278 patients who underwent radical nephrectomy for RCC from January 1995 to January 2005, 70 had tumor size up to 7 cm (T1). They were categorized as incidental or symptomatic and as T1a or T1b tumors. Clinico-pathological features were compared between incidental (IRCC) and symptomatic (SRCC) groups. Tumors were analyzed using the 1997 TNM staging and Fuhrman's grade.Results:Of the 70 with T1 tumors, 24 had T1a (IRCC, 12 and SRCC, 12) and 46 had T1b tumors (IRCC, 27 and SRCC, 19). Clear cell was the commonest histology. In T1a cancers, though no significant difference in histopathological pattern and grade was seen between the incidental and symptomatic groups, symptomatic tumors had more papillary, mixed histopathological pattern and higher nuclear grade. Among T1b tumors, 14 had papillary and mixed histology, 12 (86%) of which were symptomatic (P= <0.0001). In T1b, 15 (79%) symptomatic had higher nuclear grade (G2-3) while 22 (81%) incidental had lower Fuhrman′s grade (P= <0.0001).Conclusion:Symptomatic T1b RCCs had higher nuclear grade and papillary histology. This difference was statistically significant. This may be relevant when considering elective NSS in symptomatic T1b disease.

Long-Term Outcome Following Three-Dimensional Conformal/Intensity-Modulated External-Beam Radiotherapy for Clinical Stage T3 Prostate Cancer

ObjectiveTo report the long-term tumor control and survival outcomes after conformal external-beam radiotherapy for patients with clinical stage T3 prostate cancer. MethodsBetween 1988 and 2000, 296 patients with clinical stage T3 prostate cancer were treated with three-dimensional conformal radiotherapy and intensity-modulated radiotherapy. Of these, 130 patients (44%) had stage T3a (extracapsular extension without seminal vesicle involvement [SVI]) and 166 patients (56%) had stage T3b disease (SVI). Prior to radiotherapy, 189 patients (43%) were treated with short-course androgen-deprivation therapy (ADT). The median follow-up time was 8 yr. ResultsThe 5- and 10-yr prostate-specific antigen (PSA) relapse-free survival (PRFS) outcomes for stage T3a tumors were 69% and 44%, respectively. The corresponding PRFS outcomes for T3b tumors were 49% and 32% (p=0.005). Despite the presence of locally advanced disease, the 5- and 10-yr local progression-free survival (LPFS) outcomes for all patients were 87% and 83%. Among patients who received ≥8100 cGy and ADT, the 5- and 10-yr local control rates were 96% and 88%. The 5- and 10-yr distant metastases-free survival (DMFS) outcomes for stage T3a tumors were 85% and 73%. The corresponding DMFS outcomes for T3b tumors were 49% and 32% (p=0.005). Multivariate analysis demonstrated that ADT conferred a 7-fold risk reduction for local failure. Pretreatment PSA levels and the presence of SVI on clinical staging were important predictors of distant metastases. ConclusionsConformal radiotherapy for T3 prostate cancer is associated with excellent tumor control and survival outcomes. These results are at least comparable to reported outcomes from surgical series for T3 disease and substantiate the role of radiotherapy as the standard management option for locally advanced stage prostate cancer.

Is a Positive Bladder Neck Margin Truly a T4 Lesion in the Prostate Specific Antigen Era? Results From the SEARCH Database

Positive bladder neck margins after radical prostatectomy are currently designated as pT4 lesions. However, to our knowledge the prognostic significance of a positive bladder neck margin in the prostate specific antigen era is unknown. We examined the association between positive bladder neck margins and prostate specific antigen recurrence relative to other pathological findings. We examined 1,722 men from the Shared Equal Access Research Cancer Hospital Database who were treated with radical prostatectomy without lymph node metastases. Time to prostate specific antigen recurrence was compared in men with positive vs negative bladder neck margins using Cox proportional hazards models adjusted for multiple clinical and pathological features. A positive bladder neck margin in 79 patients (5%) was significantly associated with other poor prognostic features, including higher prostate specific antigen, higher pathological Gleason sum, extracapsular extension, seminal vesicle invasion and other positive margins. After adjusting for clinical and pathological characteristics positive bladder neck margins were associated with an increased risk of prostate specific antigen recurrence (HR 1.52, 95% CI 1.06-2.19, p = 0.02). Relative to organ confined margin negative disease a positive bladder neck margin associated with other positive margins showed a recurrence risk that was similar to that of seminal vesicle invasion (HR 4.14, 95% CI 2.55-6.73 and HR 4.22, 95% CI 3.08-5.78, respectively, each p <0.001). An isolated positive bladder neck margin was a rare event, noted in 15 patients (0.7%). In these men the recurrence risk was difficult to estimate due to the small number. However, the HR was similar to that in men with nonbladder neck positive margins or extracapsular extension (HR 2.65, 95% CI 0.97-7.25, p = 0.06 and HR 2.19, 95% CI 1.71-2.82, p <0.001, respectively). In the current study a positive bladder neck margin was frequently associated with other adverse features. When it was concomitant with other positive margins, a positive bladder neck margin was associated with a progression risk similar to that of seminal vesicle invasion (T3b disease). Although men with an isolated positive bladder neck margin had a more favorable pathological profile, there were too few of them to assess outcome reliably. However, the limited data suggest that they may best be categorized as having pT3a disease.

High-Dose-Rate Intracavitary Brachytherapy Boost for Early T Stage Nasopharyngeal Carcinoma{PRIVATE}

To investigate any possible therapeutic gain from dose escalation with brachytherapy for early T stage nasopharyngeal carcinoma (NPC). One hundred forty-five patients with T1-2b N0-3 NPC were boosted with high-dose-rate intracavitary brachytherapy after completion of two-dimensional external radiotherapy (ERT) during the period from 1999 to 2003. To compare the efficacy of brachytherapy boost, another 142 patients with T1-2b N0-3 disease who were treated with ERT alone during 1994 to 1999 were evaluated. All patients were treated with ERT to a total dose of 66 Gy in 6.5 weeks. The brachytherapy boost group was given 10-12 Gy in 2 weekly fractions. Dose escalation beyond 66 Gy with brachytherapy boost was shown to improve local control and survival. The 5-year actuarial local failure-free survival, regional failure-free survival, distant metastasis-free survival, progression-free survival, cancer-specific survival, and overall survival rates for the brachytherapy group and the control group were 95.8% and 88.3% (p = 0.020), 96% and 94.6% (p = 0.40), 95% and 83.2% (p = 0.0045), 89.2% and 74.8% (p = 0.0021), 94.5% and 83.4% (p = 0.0058), and 91.1% and 79.6% (p = 0.0062), respectively. The 5-year major-complication-free survival rate was 89.5% for the brachytherapy group and 85.6% for the control group (p = 0.23). For patients who are treated with two-dimensional treatment techniques, dose escalation with brachytherapy boost improves local control and overall survival of patients with T1-T2a and possibly non-bulky T2b disease.

Neoadjuvant docetaxel treatment for locally advanced prostate cancer

The objective of the current study was to determine the histologic and molecular changes that occurred in patients with high-risk, localized prostate cancer (PCa) after neoadjuvant docetaxel chemotherapy. Patients who had locally advanced PCa (serum preoperative [initial] prostate-specific antigen [iPSA] level >or=15 ng/mL, or clinical >or=T2b disease, or biopsy Gleason score [GS] >or=8) and no evidence of metastatic disease received 6 doses of intravenous docetaxel (40 mg/m(2)) administered weekly for 6 weeks followed by radical prostatectomy (RP). The Wilcoxon signed-rank test was used to compare pretreatment and posttreatment markers. Twenty-eight patients completed chemotherapy and underwent RP at the Cleveland Clinic; none achieved a pathologic complete response. Pretreatment diagnostic prostate biopsies (PBx) were reviewed in all patients, and unstained sections of formalin-fixed tissue were available from 11 patients. The median patient age was 62 years (range, 49-72 years), and the median iPSA was 6.8 ng/mL (range, 2.5-24 ng/mL). At a median follow-up of 49.5 months (range, 23-72 months), 12 patients (43%) remained clinically and biochemically free of disease with no additional therapy, and 16 patients (57%) had biochemical failure. The pretreatment GS was 6 in 2 patients (7%), 7 in 10 patients (36%), 8 in 11 patients (39%) and 9 in 5 patients (18%). Two patients (7.1%) had organ-confined disease, and 23 patients (82.1%) had extraprostatic extension. Four patients (14.3%) had positive lymph nodes, and 11 patients (39.3%) had seminal vesicle involvement. Immunohistochemical (IHC) staining for a panel of markers involved in various cellular functions (alpha-methylacyl-coenzyme A racemase [AMACR], beta-tubulin I, beta-tubulin III, cyclin D1, p27, p21, Ki-67, p53, Bcl-2, and an apoptosis detection kit [ApopTag]) was performed on a tissue microarray that contained the posttreatment (RP) tissue specimens and on the PBx specimens, if available. When the IHC staining patterns were compared between PBx and RP specimens using the Wilcoxon signed-rank test, only p53 expression (P = .017) and Bcl-2 expression (P = .014) were found to be increased significantly after neoadjuvant docetaxel treatment. However, after performing the Bonferroni adjustment, these differences were no longer significant (P > .005). Ki-67, ApopTag, beta-tubulin I, and beta-tubulin III expression levels also were increased after treatment; however, the differences were not found to be statistically significant. The expression levels of AMACR, p27, p21, and cyclin D1 were comparable in pretreatment and posttreatment specimens. The current results indicated that, although it will require longer follow-up studies and larger numbers of patients to ascertain the value of neoadjuvant treatment, the negative findings of the current study may explain the lack of clinical response in patients who received neoadjuvant docetaxel for PCa. Although the results were subject to interpretation limits based on the study size, the increased expression of p53 and Bcl-2 that was detected after treatment using the Wilcoxon signed-rank test suggested that the apoptotic pathway may be an important target for this drug, and further investigation is warranted.

Subclassification of Clinical Stage T1 Prostate Cancer: Impact on Biochemical Recurrence Following Radical Prostatectomy

We investigated biochemical outcomes following radical prostatectomy across subclassifications of clinical stage T1 prostate cancer. Of 8,658 men who underwent radical prostatectomy for clinical stage T1 prostate cancer 85, 156 and 8,417 had clinical stage T1a, T1b and T1c disease, respectively. Age, race, prostate specific antigen, year of surgery and preoperative Gleason scores were compared across clinical stage T1 subcategories. Time to prostate specific antigen recurrence was compared among groups using Kaplan-Meier and Cox hazards modeling. Patients with clinical stage T1a prostate cancer had more favorable postoperative pathological features, including lower prostatectomy Gleason scores (p <0.001), rates of extraprostatic extension (p <0.001), lymph node invasion (p <0.001) and positive surgical margins (p = 0.006). Patients with T1a cancer also showed significantly lower rates of biochemical recurrence on Kaplan-Meier analysis than men with T1b and T1c disease (log rank 0.006). Cox regression analysis adjusted for known predictors of biochemical recurrence demonstrated that clinical tumor stage in the subgroup of patients with T1 disease was not an independent predictor of biochemical recurrence (p = 0.321). Men with clinical stage T1a prostate cancer who undergo radical prostatectomy have significantly lower biochemical recurrence rates than men with stage T1b or T1c disease. However, subclassification of tumors in this group of patients was not an independent prognostic factor for biochemical recurrence after accounting for preoperative variables, including prostate specific antigen and Gleason score.

Randomized trial comparing cryoablation and external beam radiotherapy for T2C-T3B prostate cancer

The objective was to evaluate the relative efficacy of cryoablation (CRYO) versus external beam radiation (EBRT) for clinically locally advanced prostate cancer in a randomized clinical trial. Patients with histologically proven, clinically staged as T2C, T3A or T3B disease were randomized with 6 months of perioperative hormone therapy to one of the two procedures. Owing largely to a shift in practice to longer term adjuvant hormonal therapy and higher doses of radiation for T3 disease, only 64 out of the planned 150 patients were accrued. Twenty-one of 33 (64%) in the CRYO group and 14 of 31 (45%) in the EBRT-treated group who had met the ASTRO definition of failure were also classified as treatment failure. The mean biochemical disease-free survival (bDFS) was 41 months for the EBRT group compared to 28 months for the CRYO group. The 4-year bDFS for EBRT and CRYO groups were 47 and 13%, respectively. Disease-specific survival (DSS) and overall survival (OS) for both groups were very similar. Serious complications were uncommon in either group. EBRT patients exhibited gastrointestinal (GI) adverse effects more frequently. Taking into account the relative deficiency in numbers and the original trial design, this prospective randomized trial indicated that the results of CRYO were less favorable compared to those of EBRT, and was suboptimal primary therapy in locally advanced prostate cancer.

Prostate cancer‐specific mortality after radical prostatectomy or external beam radiation therapy in men with 1 or more high‐risk factors

Estimates of prostate cancer-specific mortality (PCSM) were determined after radical prostatectomy (RP) or radiation therapy (RT) in men with >or=1 high-risk factors. The study cohort comprised 948 men who underwent RP (N = 660) or RT (N = 288) for localized prostate cancer between 1988 and 2004 and had at least 1 of the following high-risk factors: a prostate-specific antigen (PSA) velocity >2 ng/mL/year during the year before diagnosis, a biopsy Gleason score of >or=7, a PSA level of >or=10 ng/mL, or clinical category T2b or high disease. Grays regression was used to evaluate whether the number and type of high-risk factors were associated with time to PCSM. Multiple determinants of high risk were found to be significantly associated with a shorter time to PCSM after RP (P < .001) or RT (P <or= .001). The solitary presence of a PSA velocity >2 ng/mL/year was associated with an increased risk of PCSM after RP (hazards ratio [HR] of 7.3; 95% confidence interval [95% CI], 1.0-59 [P = .05]) or RT (HR of 12.1; 95% CI, 1.4-105 [P = .02]) when compared with men with any other single high-risk factor. Men with a PSA velocity >2 ng/mL/year had a significantly higher risk of PCSM compared with men who had any other single high-risk factor. These men should be considered for randomized trials evaluating the impact on PCSM from adding systemic agents to standards of care for men with high-risk PC.

Prognostic Relevance of Tumour Size in T3a Renal Cell Carcinoma: A Multicentre Experience

ObjectiveTo evaluate the prognostic role of tumour size in pathological stage T3a renal cell carcinoma (RCC) with fat invasion only and to assess whether this subgroup maintains its relevance over the other pathological stages. MethodsWe retrospectively studied 2113 patients from eight international institutions who were treated by surgical resection for T2–4 RCC. Disease-specific survival (DSS) was evaluated with univariate and multivariate analyses. ResultsUnivariate analysis of patients with T3a RCC showed that tumour size was significantly associated with DSS (HR: 1.09, 95% CI: 1.05–1.12, p<0.001). An ideal cut-off of 7cm for these patients was identified with a scatter plot of Martingale residuals and tumour size. The two T3a groups were distinctly different with respect to clinicopathologic parameters (performance status, metastases, grade, histological subtype) and survival (p<0.001). Median survival time was not reached for patients with T2 and T3a≤7cm disease with a 5- and 10-yr DSS rate of 70% and 59% and 63% and 53%, respectively. Median survival time for patients with T3a>7cm, T3b, T3c, and T4 disease was 54, 46, 21, and 11 mo, respectively, with 5- and 10-yr DSS rates of 46% and 36%, 46% and 36%, 34% and 0%, and 16% and 14%, respectively. ConclusionsOur data indicate that tumour size is an important factor for predicting outcome of patients with T3a RCC with fat invasion only. Our findings should merit consideration during the next revision of the TNM classification.