OBJECTIVE:To evaluate the effect of margin status and radiation dose in patients treated with radiation therapy (RT) for vulvar cancer. Clinical outcomes included vulvar recurrence (VR), relapse-free survival (RFS) and overall survival (OS). METHODS:We retrospectively reviewed the records of 300 patients with Stage I-IVA vulvar cancer treated between 1988 and 2009. Slides were reviewed and margin status was scored as negative (≥ 1 cm), close (<1cm) or positive after formalin fixation. Cox proportional hazards models were constructed to determine significant prognostic factors for vulvar relapse. RESULTS:Of 205 eligible patients, 69 (34%) had negative surgical margins, 116 (56%) had close margins and 20 (10%) had positive margins. Median follow-up time was 49 months. The 4-year RFS rate was 53% and OS was 73%. Of 78 recurrences, 62 had the vulva as the first site of recurrence. The 4-year rates of freedom from vulvar recurrence were 82%, 63% and 37% for those with negative, close and positive margins, respectively (p for trend=0.005). On multivariate analysis, close margins (HR=3.03, 95% CI 1.46-6.26) and positive margins (HR=7.02, 95% CI 2.66-18.54) were associated with a significantly increased risk of vulvar relapse. Those who received a dose ≥ 56 Gy had a lower risk of relapse than those who received ≤ 50.4 Gy (p<0.05). Though recurrences were noted with margins up to 9 mm, the highest risk of vulvar recurrence was associated with margins ≤ 5 mm (p=0.002). CONCLUSIONS:Close or positive margins were associated with a significantly increased risk of vulvar recurrence. Radiation with a dose ≥ 56 Gy may decrease the risk of vulvar recurrence.

Objective. To compare outcomes in patients with squamous cell carcinoma (SCC) of the vulva treated with radiation (RT) and concurrent weekly platinum-based or every-3-4-week regimens containing 5-fluorouracil (5-FU).Methods. Records of 44 patients with vulvar SCC treated with concurrent chemotherapy and radiation (chemoRT) from 1988 to 2008 were reviewed. Rates of disease-free survival (DFS), overall survival (OS), locoregional recurrence (LRR), and distant metastases (DM) were estimated using the Kaplan-Meier method.Results. The median age was 63 years (range, 44-90), 84.1% of patients had ECOG performance status 0-1, and patients had FIGO Stage II (n = 6), III (n = 31), or IVA (n = 7) disease. Patients were treated preoperatively (n = 10), postoperatively (n = 10), or without surgery (n = 24). The median RT dose to the vulva was 50.2 Gray (range, 22-75). Concurrent chemotherapy regimens included weekly platinum (n = 16) or every 3-4 week regimens with 5-FU as the backbone (n = 28). With a median follow-up of 31.5 months, there was no significant difference in 2-year OS (74.5% vs. 70.0%; p = 0.65), DFS (61.9% vs. 56.0%; p = 0.85), LRR (31.3% vs. 32.9%; p = 0.93), or DM (6.3% vs. 10.6%; p = 0.81) between the weekly platinum and every-3-4-week 5-FU regimens. Twenty patients (45.4%) recurred: 16 LRR, 2 DM, and 2 with both. The clinical and pathologic complete response rates were 58.8% (20/34), and 53.8% (14/26), respectively. There was a higher proportion of grade 3 or higher acute non-skin toxicities in patients receiving every-3-4-week 5-RI (46.1% vs. 13.3%; p = 0.07), but more grade 3 or higher skin toxicity in patients receiving weekly platinum (62.5% vs. 32.0%; p = 0.01).Conclusion. OS, response rates, and recurrence rates were not significantly different after RT with concurrent weekly platinum-based versus every-3-4-week regimens containing 5-FU for vulvar SCC. (C) 2010 Elsevier Inc. All rights reserved.

To analyze the importance of lymph node ratio (the percentage of positive nodes [%LN+]) as a predictor of progression-free (PFS) and overall (OS) survival in uterine papillary serous carcinoma (UPSC). We retrospectively identified 89 patients with UPSC who underwent TAH/BSO and lymph node sampling/dissection at Brigham and Women's Hospital/Dana Farber Cancer Institute from 1983 to 2006. The FIGO stage distribution was 1A–1C (31), II (8), IIIA (23), IIIB (1), IIIC (20), IVA (5) and IVB (1). Adjuvant RT was delivered to the pelvis (31), whole abdomen (23) or vaginal vault only (6). 46 patients received adjuvant chemotherapy, most commonly carboplatin (41), taxol (42) and/or doxorubicin (16). Kaplan-Meier PFS and OS rates were compared using the log–rank test. Cox multivariate regression (MVA) was used to analyze predictors of survival. The median follow-up time was 17.1 months for all patients and 22.7 months for survivors. The median age was 68 years (range, 53–84); median tumor size, 3 cm (range, 0–12); and median depth of myometrial invasion, 25% (range, 0–100%). Lymphovascular invasion (LVI) was present in 33 patients (38%) and positive peritoneal cytology in 27 (31%). The median number of recovered nodes was 4 (range, 1–30). A total of 63 patients had no LN+, 11 had between 1 and 50% LN+, and 15 patients had >50% LN+. The 5-year PFS rates for 0%, 1%–50%, and >50% LN+ were 46%, 47%, and 13% (p = 0.018). The corresponding 5-year OS rates were 62%, 44%, and 17% (p = 0.005). On univariate analysis, stage, LVI and %LN+ were significant predictors of OS. On MVA, having >50% LN+ was the only independent predictor of overall survival compared to the node-negative group (HR 3.6, p = 0.003). Age, use of radiation, and adjuvant chemotherapy did not predict either PFS or OS. Grade 3 GI toxicity was reported in 2 patients who received whole abdomen RT. UPSC is an aggressive subtype of uterine cancer that portends a poor prognosis. Patients with more than 50% positive nodes have a 5-year overall survival rate that is significantly lower than that of node-negative patients and those with <50% positive nodes. The percentage of positive lymph nodes, or lymph-node ratio, is an important prognostic factor among patients of all stages with UPSC.

To evaluate the effect of margin status on vulvar recurrence (VR) and overall survival (OS) in patients with vulvar cancer. We retrospectively reviewed the records of 178 patients with vulvar cancer treated surgically at Brigham and Women's Hospital/Dana-Farber Cancer Institute between 1998 and 2004. Exclusion criteria included no surgery (18), unknown margin status (2), and non-squamous/non-adenocarcinoma histology (6). Stages for 152 patients were I (2%), IA (11%), IB (27%), II (37%), III (20%), IVA (3%), and IVB (1%). Median age was 70 years (range: 27-94). Treatment included: surgery alone (104), RT alone (36), chemo alone (2) or either sequential or concurrent chemo-RT (10). Twenty-seven patients received RT to the vulva with a median dose of 45 Gy (range: 4-59.6). Seventy-one patients (47%) had negative margins, 72 (47%) had close (<1 cm) margins, 7 (4%) had positive margins, and 2 (1%) had carcinoma-in-situ (CIS) at the margin. Fifteen (13%) were LVI-positive. Kaplan-Meier 5-year OS and VR rates were calculated and a Cox regression model was performed. With a median follow-up of 31 months (range: 1.5-180), 52 patients (34%) presented with recurrent disease. Median time to recurrence was 16.7 months (range: 2.0-123). The vulva was the most frequent site of first (24%) and any recurrence (26%). There was VR in 19% (3/16) of Stage IA, 24% (10/41) of Stage IB, 29% (16/56) of Stage II, 27% (8/30) of Stage III, and 40% (2/5) of Stage IVA. Five-year actuarial VR by margin status was 23% for negative margins, 41% for close margins, and 72% for positive margins. There was a statistically significant increase in VR in patients with close and positive margins compared to negative margins (77% vs. 55%, p = 0.046). Of 106 patients treated without RT, the crude rate of VR was 20% (11/55) with negative, 28% (12/43) with close, and 50% (3/6) with positive margins. Of 27 patients treated with RT to the vulva, the VR rate was 20% (2/10) with negative, 31% (5/16) with close, and 0% (0/1) with positive margins. Neither of the patients with CIS at the margin received vulvar RT, and 1 developed a VR. Five of 6 patients treated with RT to the vulva who subsequently developed VR received ≤50 Gy. Actuarial 5-year OS by margin status was 65% for negative, 66% for close, and 43% for positive margins (p = 0.47). OS was significantly correlated with positive nodal status (p = .006), but not presence of LVI (p = .09). Depth of invasion, tumor size, LVI, or inguinal nodal status were not predictive of VR. This is the largest retrospective series to date and demonstrates an increased risk of VR but no decrement in OS in patients with close or positive compared to negative margins. Patients treated to the vulva with ≤50 Gy may be at increased risk for VR. Patients with CIS at the margin may have an increased risk of VR.

Objectives. Patients with high-grade clinically localized disease often have disease beyond the prostate and, if so, are unlikely to benefit from radical prostatectomy in the long-term. The objective of this study was to assess whether use of other known prognostic factors could be helpful in defining which men with Gleason 8 to 10 prostate cancer are most likely to benefit from surgical management.Methods. A retrospective analysis was performed on men with biopsy Gleason 8 to 10 prostate cancer who underwent radical prostatectomy at two major university centers. No patients received hormonal therapy as part of initial treatment or adjuvant radiation therapy. Surgery was performed using a retropubic approach, and lymph node dissection was performed in all patients. Risk groups were defined based on prostate-specific antigen (PSA) value and percent positive biopsy cores (%PBC). A Cox proportional hazards analysis was performed to assess for differences in pretreatment prognostic factors. Kaplan-Meier curves were generated for each group, and then comparisons between groups were performed using log-rank analysis to assess for differences in 5-year actuarial freedom from biochemical failure.Results. Radical prostatectomy was performed on 196 patients between 1987 and 2002, of whom 168 had sufficient data for analysis. Median follow-up was 18 months (range, I to 130 months), with 31 patients at risk for more than 5 years. Patients with a PSA value of less than 10 ng/mL and %PBC of less than 50% had a 5-year actuarial biochemical control rate of 67% versus 23% for all other patients (P = 0.0001).Conclusions. PSA value and %PBC are useful in selecting patients with high-grade prostate cancer most likely to benefit by radical prostatectomy.

Purpose: To identify an association between perineural invasion (PNI) and cancer-specific survival in patients With prostate cancer after standard-dose external beam radiation therapy (RT).Methods and Materials: A total of 517 consecutive patients who underwent RT (median dose, 70.5 Gy) between 1989 and 2003 for low-risk or intermediate-risk prostate cancer were studied. A genitourinary pathologist (AAR) scored presence or absence of PNI on all prostate needle-biopsy specimens. A Cox regression multivariable analysis was performed to assess whether the presence of PNI was associated with risk of prostate cancer-specific mortality after RT when the recognized risk-group variables were factored into the model. Estimates of cancer-specific mortality were made using a cumulative incidence method. Comparisons of survival were made using a two-tailed log-rank test.Results: At a median follow-up of 4.5 years, 84 patients (16%) have died, 15 of 84 (18%) from prostate cancer. PNI was the only significant predictor of prostate cancer-specific mortality after RT (p = 0.012). The estimated prostate cancer-specific mortality was 14% at 8 years for PNI + patients vs. 5% for PNI- patients (p = 0.0008).Conclusions: Patients with low- or intermediate-risk prostate cancer who have PNI on prostate needle biopsy have a significantly higher rate of prostate cancer-specific mortality after standard-dose radiation therapy than patients without PNI. Although this analysis is retrospective, this association argues for consideration of the use of more aggressive therapy, such as hormonal therapy with RT or dose escalation, in these select patients. (c) 2006 Elsevier Inc.

OBJECTIVES:To evaluate the risk of acute urinary retention (AUR) and sequelae after urethra-sparing magnetic resonance imaging (MRI)-guided prostate brachytherapy. METHODS:Between 1997 and 2003, MRI-guided prostate brachytherapy was performed after external beam radiotherapy (n = 60) or as monotherapy (n = 188) following a diagnosis of low-risk prostate adenocarcinoma. The median prostate gland volume was 40 cm3 (range 16 to 184). Of the 248 patients, 88 (35%) had prostate gland volumes greater than 45 cm3. The median follow-up was 40 months. RESULTS:Of the 248 patients, 18 (7%) developed AUR. Of the 248 patients, 2% (3 of 160), 6% (3 of 49), 28% (8 of 29), and 40% (4 of 10) of patients experienced AUR if the prostate gland volume was less than 45, 45 to 60, 60 to 90, or greater than 90 cm(3), respectively (P <0.0001). Retention requiring intermittent self-catheterization resolved in one half of the patients by 2 weeks and had resolved in all patients by 6 weeks. At 1, 3, and 6 months after implantation, 100%, 57%, and 29% of patients who experienced AUR, respectively, used Flomax (P <0.0001). The mean Flomax dose used decreased from 0.9 mg at 1 month to 0.53 mg at 1 year. CONCLUSIONS:AUR after urethral-sparing MRI-guided prostate brachytherapy is volume dependent and is self-limited despite very large prostate gland volumes.

BACKGROUND. To determine whether a delay in initiating external beam radiation therapy (RT) following diagnosis could impact prostate-specific antigen (PSA) outcome for patients with localized prostate cancer, 460 patients, who received 3D conformal RT to a median dose of 70.4 Gy for clinically localized prostate cancer between 1992 and 2001, were studied.METHODS. The primary endpoint was PSA failure (American Society for Therapeutic Radiology and Oncology definition). Estimates of PSA control were made using the Kaplan-Meier method. Delay was defined as the time between diagnosis and the start of RT. Risk groups were defined based on known predictors of PSA outcome, namely, baseline PSA level, clinical T-category, Gleason score, and percentage of biopsy cores positive for tumor. Cox multivariate regression analysis was used to determine the ability of treatment delay to predict time to PSA failure after adjusting for the other known predictors.RESULTS. Treatment delay independently predicted time to PSA failure following diagnosis for high-risk (Adjusted Hazard Ratio = 1.08 per month; P = 0.029) but not low-risk patients (P = 0.31). Patients with high-risk disease (n = 240) had 5-year estimates of PSA failure-free survival of 55% versus 39% (Plog-rank = 0.014) for those with delay < 2.5 months versus 2.5 months respectively. The median delay was 2.5 months.CONCLUSIONS. Treatment delay adversely affected PSA outcome for high-risk patients but not for low-risk patients following RT. (c) 2005 American Cancer Society.

Objectives. To determine the preoperative and postoperative predictors of a short prostate-specific antigen (PSA) doubling time (PSADT) after radical prostatectomy for patients diagnosed during the PSA era.Methods. Between 1989 and 2003, 1785 men underwent radical prostatectomy for 2002 American Joint Committee on Cancer (AJCC) Stage T1c or T2 prostate cancer. Of these men, 205 had documented PSA failure. The PSADT was calculated by assuming first-order kinetics and using a minimum of two detectable postoperative PSA measurements after a previous undetectable level. Multivariable logistic regression analyses were performed to determine the significant preoperative and postoperative predictors of a PSADT of less than 6 months.Results. Patients with a greater biopsy Gleason score (P = 0.006), greater preoperative risk group (P = 0.002), greater prostatectomy Gleason score (P = 0.0006), greater 2002 AJCC pathologic stage (P = 0.01), or shorter time to postoperative PSA failure (P = 0.04) were more likely to have a shorter PSADT. Using multivariable analysis, high-risk disease (P = 0.0001) was the only preoperative factor that remained an independent significant predictor of a PSADT of less than 6 months. Of the postoperative factors, a prostatectomy Gleason score of 8 to 10 (P = 0.002), 2002 AJCC pathologic Stage T3b (P = 0.03), and time to PSA failure of less than 2 years (P = 0.05) remained significant independent predictors of a PSADT of less than 6 months.Conclusions. High-risk disease preoperatively and a prostatectomy Gleason score of 8 to 10, seminal vesicle invasion, or a time to PSA failure of less than 2 years postoperatively were significant independent indicators of developing a postoperative PSADT of less than 6 months. For these men, trials studying systemic therapy in addition to radical prostatectomy are needed. (c) 2005 Elsevier Inc.

Purpose: This study was performed to define the rectal dose constraint that would predict late rectal bleeding requiring argon plasma coagulation (APC) following prostate brachy mono-therapy.Methods and materials: Between February 1999 and April 2002, 91 patients with low risk prostate cancer underwent permanent 1 1 25 radioactive seed implantation without the use of supplemental external beam radiation or androgen suppression therapy. Patients received both CT and MRI scans 6 weeks postimplant for evaluation of dosimetry. The CT and MRI scans were fused. Rectal volumes were contoured on the T2 weighted MR images. For those patients requiring APC, the date on which a patient reported rectal bleeding was recorded. A Cox regression analysis was performed to assess whether there was a significant association between the rectal volume (continuous) exceeding 100 Gy time rectal bleeding. Comparisons of estimates of rectal bleeding requiring APC were made using a 2-sided log rank test.Results: There was a significant association (hazard ratio = 5.6 [95% confidence interval: 1.3, 23.8]; P = 0.002) between the rectal volume exceeding 100 Gy and rectal bleeding requiring APC. After a median follow-up of 4.25 (1-6) years, no patient with less than a median value of 8 cc of rectum exceeding 100 Gy required APC, whereas 20% (P = 0.004) were estimated to require APC within 3 years following treatment.Conclusions: Keeping the rectal volume receiving more than 100 Gy below 8 cc will minimize the risk of rectal bleeding requiring APC following I-125 permanent prostate brachy mono-therapy. Published by Elsevier Inc.

Purpose/Objective: To estimate the late gastrointestinal (GI) and genitourinary (GU) toxicity rates and early prostate-specific antigen (PSA) control following salvage prostate brachytherapy. Materials/Methods: Between October 2000 and December 2004, 20 men were enrolled on an IRB-approved Phase II salvage prostate brachytherapy (SBT) protocol. Biopsy-proven local recurrence was documented in the setting of a slowly rising PSA (PSA doubling time > 9 months) following radiation therapy (RT). PSA failure was defined using the 1997 ASTRO consensus criteria. Late Toxicity was defined according to the 1997 Modified RTOG and Late Effects Normal Tissue Task Force criteria. Cox regression was used to assess whether pre-treatment clinical factors were significantly associated with a complication requiring surgical intervention. Kaplan Meier method was used to estimate freedom from PSA failure and freedom from late Grade 3 or 4 GI and/or GU toxicity. Results: Median PSA doubling time (PSADT) was 14 months (range: 9–38). At a median follow up of 2.3 years (range: 0.3–4.4), 88% of patients were estimated to remain free from PSA failure 3 years following SBT. By 3 years following salvage therapy, 80% of patients were free of a Grade 3 or 4 GI and/or GU complication requiring surgery. Fifteen percent of men required non-surgical management of moderate RT proctopathy treated with therapeutic argon plasma coagulation, while 50% of men experienced urinary hesitancy adequately managed by alpha 1a-blockers. No urinary retention was observed. Surgical intervention required to correct a late GI and/or GU complication was significantly associated with the time interval between the initial RT and SBT (p = 0.04). Specifically, all 3 complications requiring surgery were observed in men for whom this time interval was less than 4.5 years. Conclusions: In carefully selected patients with both a long PSADT and interval between the initial and SBT, salvage brachytherapy can be performed with avoidance of surgery-requiring complications and excellent short-term PSA control. The overall toxicity profile of this approach appears favorable when compared with those reported from the salvage radical prostatectomy or cryosurgery literature.

Purpose: Algorithms have been developed to predict time to biochemical failure (BF) following radical prostatectomy (RP) for patients with clinically localized prostate cancer. The purpose of this study was to validate an algorithm based on prostatectomy findings and to evaluate whether the preoperative serum prostate specific antigen (PSA) enhances the predictive ability of the algorithm.Materials and Methods: Between 1988 and 2002, 2417 patients underwent RP for clinically localized prostate cancer at one of 2 large university hospitals. Patients were retrospectively stratified into 4 risk groups based upon prostatectomy grade, stage, and margin status, and were then dichotomized by the preoperative PSA level (cut point 10 ng/mL). Cox regression multivariable analyses were performed to evaluate the ability of the risk group and preoperative PSA level to predict time to BF (PSA more than 0.2 ng/mL) following RP.Results: The preoperative PSA level (P < 0.0001) and risk group (P < 0.0001) were significant predictors of time to BF following RP. Estimates of the BF rates 7 years following RP were 13%, 30%, 51%, and 72% for groups 1-4, respectively (pairwise P values <= 0.0002). Further stratification within each risk group using the preoperative PSA level with a cut point at 10 ng/mL revealed BF rates of 8% versus 35%, 25% versus 54%, 31% versus 73%, and 63% versus 86% for risk groups 1-4, respectively (all P values < 0.0001).Conclusions: An algorithm to predict BF based on prostatectomy findings has been validated, and the addition of the preoperative PSA level improved its ability to identify high risk patients who may benefit from entry into adjuvant treatment trials. (c) 2005 Elsevier Inc. All rights reserved.

Objectives To determine which preoperative and postoperative factors were predictive of the time to prostate-specific antigen (PSA) failure after radical retropubic prostatectomy (RRP) for patients with seminal vesicle invasion (SVI). SVI by prostate cancer is associated with high PSA failure rates after RRP and subsequent distant metastases. Methods Between 1988 and 2002, 1697 patients with prostate cancer underwent RRP at Brigham and Women's Hospital, of whom 103 (6%) had SVI. Cox regression multivariable analysis was used to determine whether the preoperative PSA level, prostatectomy Gleason score, margin status, or presence of extraprostatic extension was predictive of the time to postoperative PSA failure. Estimates of PSA outcome were made using the actuarial method of Kaplan and Meier for patients who had none, all, or at least one of the factors that predicted for the time to postoperative PSA failure. Results The statistically significant categorical predictors of the time to PSA failure after RRP in patients with SVI included prostatectomy Gleason score of 4+3 or greater (P = 0.009), preoperative PSA level greater than 20 ng/dL when evaluated as a categorical or as a continuous variable (P = 0.002 and P = 0.001, respectively), and margin positivity (P = 0.075) which was of borderline significance. The 3-year estimate of PSA control was 52% to 100%, 28%, and 0% for patients with negative margins, preoperative PSA less than 20 ng/dL, and prostatectomy Gleason score of 3+4 or less versus having one to two or all three predictors of the time to postoperative PSA failure. Conclusions The PSA outcome after RRP for patients with SVI varies depending on the preoperative PSA level, prostatectomy Gleason score, and margin status.

Purpose: This study examined the impact that seminal vesicle invasion (SVI), observed on endorectal magnetic resonance imaging (erMRI), had on prostate-specific antigen (PSA) outcome after external beam radiation therapy (EBRT) for patients with clinically localized prostate cancer.Methods and Materials: The study cohort was comprised of 250 patients who received 3D conformal radiation therapy without hormones for clinically localized prostate cancer between 1992 and 2001. The primary end point was PSA failure, defined using the American Society for Therapeutic Radiology and Oncology consensus definition. Cox regression multivariable analysis was used to determine the ability of the pretreatment risk group and erMRI SVI to predict for time to PSA failure after EBRT.Results: Both risk group (p(Cox) = 0.001) and erMRI SVI (p(Cox) = 0.003) were independent and significant predictors of time to PSA failure. For patients beyond low risk, 4-year estimates of PSA failure-free survival for erMRI SVI-negative vs. erMRI SVI-positive patients were 68% vs. 33% (Plog-rank = 0.0014), respectively.Conclusion: Patients with clinically localized disease and PSA >10 or biopsy Gleason score greater than or equal to7 or clinical T category T2b or T2c who also have erMRI evidence of SVI have PSA outcomes similar to patients with locally advanced prostate cancer after EBRT monotherapy. Consideration should be given to combining EBRT with hormonal therapy in these patients. (C) 2004 Elsevier Inc.