343 Background: Biomarkers are needed to help select patients (pts) with muscle invading bladder cancer (MIBC) for bladder sparing chemotherapy and radiation treatment (CRT). Higher MRE11 expression has been identified as a potential RT response marker in MIBC. MRE11 protein is involved in the DNA double strand break repair mechanism. This analysis evaluates associations between MRE11 expression and outcome in pts from 6 NRG/RTOG bladder-sparing RT protocols. Methods: Archival tissue via TMA or unstained slides was used. Cases were stained with anti MRE11 antibody Rabbit mAb, clone EPR3471 (Epitomics at 1:1500 dilution). Slides were scanned on an Aperio FL instrument and analyzed via Automated Quantitative Image analysis (AQUA). MRE11 scores were determined within the nucleus and cytoplasm of urothelial cells and a ratio of nuclear to cytoplasmic (N/C) score calculated. A ratio was used to normalize scores and overcome pre-analytical variation. MRE11 N/C was analyzed by quartile cut points. Cumulative incidence was used to estimate disease-specific mortality (DSM; failure=bladder cancer death) and Fine-Gray models were used to evaluate associations between MRE11 and DSM. Cox models were used for overall survival (OS; death) and bladder-intact survival (BIS; cystectomy/death). Results: Out of 465 eligible pts, tissue was available and MRE11 N/C determined for 135. Analyzable pts were less likely to be white (p=0.0001) and more likely to be T2 (p=0.0003). Median MRE11 N/C was 2.41 (min-max: 0.69-6.03). Pts with MRE11 N/C ≤ 1.49 (lower quartile) were associated with significantly higher DSM (HR= 2, 95% CI: 1.1, 3.8, p=0.03). The 4-year DSM was 41% for pts with MER11 N/C ≤ 1.49 vs. 21% for pts with MER11 N/C was >1.49. MRE11 N/C was not associated with OS or BIS. Conclusions: AQUA analysis allows precise measurement of this marker in tissue samples. Low expression of MRE11 N/C (≤1.49) is associated with significantly higher DSM. This adds further evidence of MRE11 as a potential RT response biomarker for selection of pts most likely to respond to bladder-sparing CRT. Supported by NCI grants U10CA180868, U10CA180822, UG1CA189867,U24CA196067.

RTOG completed 4 protocols (8802, 8903, 9506, 9706) from 1988 to 1999 treating clinical T2 – 4a MIBC patients with selective bladder preservation using transurethral surgery (TURBT) plus cisplatin-containing induction and consolidation chemoradiation regimens with tumor response evaluation, reserving radical cystectomy for invasive tumor persistence / recurrence. We investigated molecular markers on the VEGF angiogenesis pathway as potential biomarkers. Long-term clinical outcomes – complete response (CR), local failure (LF) and distant failure (DF), bladder-intact survival (BIS), and overall survival (OS) of all 294 eligible patients were updated. Patients with paraffin blocks of the invasive MIBC from the entry TURBT were evaluated in the correlative analysis. Expression of ligands including VEGF (A – D) and receptors VEGFR1 and R2 were quantified and scored by HistoRx AQUA platform. Using the 0.05 significance level (two-sided), continuous variables were evaluated using the t test; discrete variables using Fisher's exact test; time-to-event outcomes with competing risks (LF, DF) using Gray's test and time-to-event outcomes (BIS, OS) using the log-rank test. Long-term clinical outcomes of all 294 eligible patients had a median follow-up of 5.4, and 8.8 years in the 92 surviving patients. The CR rate after induction cisplatin-containing chemotherapy concurrent with 40 Gy was 72%. The 5 and 10-year overall survival rates were 53 and 31%, bladder-intact survival rates, 42 and 31%; distant metastases rates, 33 and 37%, respectively. Increased nuclear and cytoplasmic VEGF-B levels (n = 35) were associated with increased DF hazard (p = 0.01/0.02 [dep. on per 10-unit HR]). Increased VEGF-B nuclear levels were not associated with bladder-intact or overall survival. Increased cytoplasmic levels were associated with death hazard (p = 0.03). Increased nuclear and cytoplasmic VEGF-C levels (n = 33) were associated with increased distant failure (p = 0.009/0.046) and death hazard (p = 0.011/0.002). Higher levels of nuclear VEGF-D (n = 37) were associated with increased distant failure hazard (p = 0.04). Increased expression levels of nuclear and cytoplasmic VEGF B and C in the initial TURBT specimen of tumor and stroma were associated with increased risk of distant dissemination of disease and risk of death in MICB patients treated by bladder preservation therapy. Expression profiles of VEGF (A – D) and receptors VEGFR1 and VEGFR2 were not associated with response of primary tumor following trimodality therapy. Future investigation of VEGF antagonists and possible correlation of levels of expression may be warranted.

Abstract Introduction: There have been biological findings alluding to the role of selective COX-2 inhibitors in reducing the risk of developing cancers including breast cancer. Epidemiological data suggest that COX-2 inhibitors may prevent the development of cancers, including colorectal, esophageal and lung cancer. To date, there exists no study that reported any relationship between their use and the risk of breast cancer recurrence. Thus, we investigated the associations between the use of COX-2 inhibitors and the risk of tumor recurrence among breast cancer patients. Methods: We reviewed the medical records of female patients diagnosed with stage II/III breast cancer in Albert Einstein Medical Center between 1999 and 2005 and later reached no evident disease (NED) stage. Follow up period was from 1999 to 2008 with mean and maximum being 4.4 years and 9.8 years, respectively. COX-2 inhibitor user was defined as patients taking the medication in NED stage for at least 6 months. Age, race, family history, smoking history, menopausal status, diabetes, HER2/Neu status, hormone receptor status, TNM stage, histology, and treatment received were compared between COX-2 inhibitor users and nonusers. The primary outcome was disease free survival. The secondary outcome was overall survival. Multivariate analyses were performed using Cox proportional hazard model. Results: Of 682 cancer patients, 7.3 % (n=50) were prescribed COX-2 inhibitor; 10.0 % (5/50) of patients developed recurrence among COX-2 inhibitor users, while 22.0% (139/632) did among nonusers (chi-square test: P<0.05). COX-2 inhibitor use was negatively associated with cancer recurrence (hazard ratio [HR], 0.41; 95% confidence interval[CI], 0.17-1.00; P=0.05). Variables associated with recurrence in multivariate model were race (Caucasian vs. non-Caucasian; adjusted hazard ratio [AHR], 1.83; 95% CI, 1.20-1.84; P<0.01) and number of nodes ≥3 (AHR, 2.22; 95% CI, 1.24-3.98; P<0.01). In multivariate analysis, the association between COX-2 inhibitor use and cancer recurrence only suggestive (AHR, 0.35; 95% CI; 0.11-1.12; P=0.07). Kaplan-Meier survival analysis revealed that COX-2 inhibitor use was related to disease-free survival benefit (log-rank test P<0.05). 5 year survival was 0.88 for COX-2 inhibitor users, and 0.77 for non-users. However, COX-2 inhibitor use was not associated with reduced overall mortality in breast cancer patients (AHR, 0.49; 95% CI: 0.15-1.58; P=0.23; log-rank test P=0.12) K-M Survival Curve of Breast Cancer Recurrence Conclusions: The use of COX-2 inhibitors seems to be related to a reduced risk of developing recurrence in patients with breast cancer. This result provides the clinical evidence, in accordance with existing biological data, that COX-2 inhibitor use in breast cancer patients may be inversely associated with tumor recurrence. However, prospective randomized trials are required to validate our finding. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-10-01.

e22060 Background: The contribution of inflammation to carcinogenesis has been reported. Allergic diseases are now recognized as a systemic inflammatory process. We investigated whether common allergic symptoms are associated with cancer risk. Methods: The Third National Health and Nutrition Examination Survey (NHANES III) is a stratified probability sample of the U.S. population collected during 1988–1994. The prevalence of cancer excluding skin cancer was obtained by personal medical interview. Allergic symptoms were categorized into three categories: no symptoms (NO), rhinitis/conjunctivitis without wheezing (RC), and wheezing (WZ). Other risk factors for cancer were defined by NHANES III questionnaire and results of physical examination. Multivariate logistic regression was used to obtain odds ratios of cancer according to the existence of allergic symptoms adjusted for other possible confounding variables considering complicated sampling methods and weights. Results: 4,558 female adults were selected out of 5076 female adults aged ≥40 years who participated in both interview and physical examination. Cancer was present in 7.41% (n=301). 36.3% (n=1,893) of subjects did not have any allergic symptoms (NO), 47.6% (n=1,979) showed RC, and 16.2% (n=726), WZ. The prevalence of cancer was 5.43% in NO, 7.63% in RC, and 11.23 in WZ (p=0.006). Unadjusted odds ratios of cancer were 1.44 (95% CI: 0.99–2.08, p=0.053) in RC and 2.20 (1.27–3.80, p=0.006) in WZ compared with NO. Odds ratios are 1.49 (1.00–2.22, p=0.048) in RC and 2.08 (1.11–3.89) in WZ adjusting for age, race, education, income, asthma, COPD, C-reactive protein, obesity, smoking, alcohol drinking, physical inactivity, and menopausal status. In subgroup analysis, adjusted odds ratios of breast cancer were 1.89 (1.04–3.42, p=0.037) in RC and 2.08 (0.90–4.78, p=0.084) in WZ, while other cancers showed no statistically significant associations. Conclusions: Common allergic symptoms, even symptoms of allergic rhinitis of conjunctivitis, may be associated with increased risk of cancer in female adults. It supports the hypothesis that systemic inflammation mediators may trigger or promote cancer development in all parts of the body. However, prospective studies are required to validate our findings. No significant financial relationships to disclose.

Infradiaphragmatic Hodgkin lymphoma (IDH) accounts for 4–13% of cases of stage I–II Hodgkin lymphoma (HD). It has been associated with distinct pre-treatment characteristics and outcomes when compared with supradiaphragmatic HD (SDH). The comparison of IDH vs SDH can only be made in early and intermediate stages (I–II), such a comparison is not possible for advanced stages (III–IV). This study retrospectively compared two groups of 1013 patients with stage I–II SDH and 101 patients with IDH (10%). These two sub-groups of patients were treated in 1988–1993 in 2 prospective randomized clinical trials in Germany for early and intermediate stages of Hodgkin lymphoma. IDH-patients were older (median 39 vs 31 years; p < 0.001), predominantly male (73% vs 52%; p < 0.001) and more often had involvement of ⩾ 3 lymph node areas (LNA) (80% vs 55%; p < 0.001). Histology in IDH was more likely to be mixed cellularity (46.5% vs 23.6%, p < 0.001) or lymphocyte predominant (20 vs 10%, p = 0.003) and less likely nodular sclerosis (25% vs 63%, p < 0.001). In early-stage unfavorable disease, IDH was associated with a higher treatment failure rate (unadjusted hazard ratio 2, 95% CI, 1.3–3.4; p = 0.003). After controlling for age, sex, stage, histology, B-symptoms and involvement of ⩾ 3 LNA, the adjusted hazard ratio was 1.25 (95% CI, 0.65–2.4; p = 0.51) so that IDH was no longer associated with a statistically significant treatment failure rate. Poorer outcomes with IDH as compared to SDH are attributable to its association with known adverse prognostic risk factors, but IDH, in itself, is not an independent adverse prognostic factor for treatment failure or survival.

Background: Syncytial Variant is a subtype of nodular sclerosis Hodgkin's disease (NSHD), reported to occur in younger patients (median age 25 years) who typically present with advanced disease and systemic symptoms.

PURPOSETo investigate differences in attitudes, preferences, and behaviors regarding end of life in terminally ill patients and their designated family caregivers.PATIENTS AND METHODS68 African-American and white patients with stage III-B or IV lung or stage IV colon cancer and 68 patient-designated family caregivers interviewed between December 1999 and May 2001.RESULTSWhite patients were more likely to have a durable power of attorney (34% v 8%, P =.01) and were more likely to have a living will (LW; 41% v 11%, P =.004) than were African-American patients. More African-American than white patients desired the use of life-sustaining measures (cardiopulmonary resusitation [CPR], mechanical ventilation, tube feeding) in their current condition (all P >.12). In a near-death condition, African-American patients were more likely than white patients to desire each of the life-sustaining measures (all P <.004). There was no patient-caregiver agreement beyond chance regarding preferences for initiation of CPR, tube feeding, or mechanical ventilation in the patient's current condition or in the near-death condition. In the near-death condition in patients without LWs, there was disagreement in 46% of patient-caregiver pairs about CPR, in 50% about mechanical ventilation, and in 43% about tube feeding.CONCLUSIONAlthough most patients and families endorse the primacy of the patient in decisions at end of life, the majority do not take supporting actions. Disagreements between patients and families about the use of life-sustaining measures in patients without LWs may result in patients' preferences being superseded at end of life.

We present the case of a 76 year old Asian male who presented with abdominal pain, weight loss and an abdominal mass. Further evaluation by histopathology revealed a squamous cell carcinoma (SqCC) of the pancreas. A review of the English literature confirms the rare occurrence of pure SqCC of the pancreas. We discuss the prevailing theories as to its etiology and the unusual radiographic appearance of our case.

PURPOSE:To assess the efficacy of neoadjuvant methotrexate, cisplatin, and vinblastine (MCV) chemotherapy in patients with muscle-invading bladder cancer treated with selective bladder preservation. PATIENTS AND METHODS:One hundred twenty-three eligible patients with tumor, node, metastasis system clinical stage T2 to T4aNXMO bladder cancer were randomized to receive (arm 1, n=61 ) two cycles of MCV before 39.6-Gy pelvic irradiation with concurrent cisplatin 100 mg/m2 for two courses 3 weeks apart. Patients assigned to arm 2 (n=62) did not receive MCV before concurrent cisplatin and radiation therapy. Tumor response was scored as a clinical complete response (CR) when the cystoscopic tumor-site biopsy and urine cytology results were negative. The CR patients were treated with an additional 25.2 Gy to a total of 64.8 Gy and one additional dose of cisplatin. Those with less than a CR underwent cystectomy. The median follow-up of all patients who survived is 60 months. RESULTS:Seventy-four percent of the patients completed the protocol with, at most, minor deviations; 67% on arm 1 and 81% on arm 2. The actuarial 5-year overall survival rate was 49%; 48% in arm 1 and 49% in arm 2. Thirty-five percent of the patients had evidence of distant metastases at 5 years; 33% in arm 1 and 39% in arm 2. The 5-year survival rate with a functioning bladder was 38%, 36% in arm 1 and 40% in arm 2. None of these differences are statistically significant. CONCLUSION:Two cycles of MCV neoadjuvant chemotherapy were not shown to increase the rate of CR over that achieved with our standard induction therapy or to increase freedom from metastatic disease. There was no impact on 5-year overall survival.

PURPOSE:This phase II study was designed to evaluate effectiveness and toxicity of a combined chemoradiotherapy program with selective bladder preservation in the management of patients with invasive bladder cancer.PATIENTS AND METHODS:Ninety-one eligible patients with invasive bladder cancer stages T2M0 to T4AM0 suitable for radical cystectomy received two courses of methotrexate, cisplatin, and vinblastine (MCV regimen) followed by radiotherapy with 39.6 Gy and concurrent cisplatin. After complete urologic evaluation, operable patients who achieved complete response were selected for bladder preservation and treated with consolidation cisplatin-radiotherapy.RESULTS:Of 91 eligible patients, 85 underwent complete urologic evaluation and 68 (75%; 95% confidence interval [CI], 59% to 84%) had documented complete responses. Fourteen operable patients with residual tumor underwent immediate cystectomy. Of 70 patients treated with consolidation cisplatin-radiotherapy, 36 subsequently developed bladder recurrences, 23 of which were invasive. Patients with invasive recurrence (n = 16), extensive noninvasive recurrence (n = 6), or severe treatment complications (n = 1) underwent salvage cystectomy. Thus, a total of 37 of 91 patients (40%) required cystectomy. The 4-year cumulative risk of invasive local failure (which includes induction failures) was 43% (95% CI, 33% to 53%). The 4-year actuarial risk of distant metastasis was 22% (95% CI, 13% to 31%). The 4-year actuarial survival rate of the entire group was 62% (95% CI, 52% to 72%). The 4-year actuarial rate of survival with bladder intact was 44% (95% CI, 34% to 54%).CONCLUSION:Initial results of this combined chemoradiotherapy program show that bladder preservation can be achieved in the majority of patients, and that overall survival is similar to that reported with aggressive surgical approaches. Long-term survival and quality-of-life assessments require longer follow-up study.

This study compared the efficacy and tolerability of oral ondansetron (8 mg twice daily [BID] for up to 3 days) with those of phenothiazine prochlorperazine (10 mg BID for up to 3 days) in 133 cancer patients receiving cyclophosphamide-based chemotherapy. In addition, the study evaluated the impact of these treatments on patients' health-related quality of life, measured with both the Functional Living Index—Cancer and the Functional Living Index—Emesis questionnaires. The first dose of study drug was administered 30 minutes before initiation of chemotherapy. Patients received a rescue antiemetic at their request or if the investigator deemed it necessary. There was a statistically significant difference in the number of patients with no emetic episodes over the 3-day study period: 60% in the ondansetron group compared with 21% in the prochlorperazine group. Twenty-five percent of ondansetron-treated patients compared with 68% of prochlorperazine-treated patients experienced three or more emetic episodes, rescue medication use, or withdrawal from the study due to adverse events or lack of efficacy of the study drug. Among patients with at least one emetic episode, the mean time to emesis was significantly longer (13 hours and 37 minutes) in the ondansetron group compared with the prochlorperazine group (9 hours and 30 minutes). Nausea and appetite scores did not differ significantly between groups. The score on the vomiting subscale of the Functional Living Index—Emesis was significantly more favorable in the ondansetron group compared with the prochlorperazine group, indicating better maintenance of health-related quality of life in ondansetron-treated patients. Both treatments were well tolerated. The most common potentially drug-related adverse event was headache, which occurred in significantly more (16%) ondansetron-treated patients compared with prochlorperazine-treated patients (3%). The results of this study demonstrate that oral ondansetron 8 mg BID for up to 3 days is more effective than prochlorperazine 10 mg BID for up to 3 days in the prevention of emesis associated with moderately emetogenic chemotherapy.

Pinover, Wayne D.O.; Pickens, Peter M.D.; Cohn, Jeffrey M.D.; Tester, William M.D.; Nieman, Roger E. M.D.; III, John Redmond M.D.; Auerbach, Herbert E. D.O. Author Information

PURPOSE:This Phase II study was designed to test the tolerance and effectiveness of concurrent cisplatin-radiotherapy in the treatment of invasive bladder cancer. Objectives were to determine toxicity, complete response rate, bladder preservation rate, and survival.METHODS AND MATERIALS:Patients with invasive bladder cancer, clinical Stages T2-4, NO-2 or NX, MO were treated with pelvic radiotherapy 40 Gy in 4 weeks and cisplatin 100 mg/m2 on days 1 and 22. Complete responders were given an additional 24 Gy bladder boost plus a third dose of cisplatin; patients with residual tumor after 40 Gy were assigned radical cystectomy.RESULTS:The complete remission rate following cisplatin and 40 Gy for evaluable cases was 31/47 (66%). Acute toxicity was acceptable with only two patients not completing induction therapy. Patients with poorly differentiated tumors were more likely to achieve complete remission. Of fully evaluable patients, 28/42 (67%) achieved complete remission with induction therapy, 11 remain continuously in remission, and eight have relapsed with bladder as the only site of failure. Five of these eight cases relapsed with noninvasive tumor. Of the 14 patients who failed to achieve complete remission, only three remain disease-free. Median survival is not reached, with 17/42 (19/48) deaths reported. Actuarial survival is 64% at 3 years.CONCLUSION:This combined cisplatin-radiotherapy regimen was moderately well-tolerated and associated with tumor clearance in 66% of patients treated. Isolated bladder recurrences with invasive carcinoma are infrequent. Better definition of pretreatment selection criteria is needed if combined modality treatment is to achieve disease control and organ preservation for patients with bladder cancer.