Melissa Fazzari

Long-Term Survival in Metastatic Transitional-Cell Carcinoma and Prognostic Factors Predicting Outcome of Therapy

PURPOSE The variation in reported survival of patients with metastatic transitional-cell carcinoma (TCC) treated with systemic chemotherapy may be a consequence of pretreatment patient characteristics. We hypothesized that a prognostic factor-based model of survival among patients treated with methotrexate, vinblastine, doxorubicin, and cisplatin chemotherapy could account for such differences and help guide clinical trial design and interpretation. PATIENTS AND METHODS A database of 203 patients with unresectable or metastatic TCC was retrospectively subjected to a multivariate regression analysis to determine which patient characteristics had independent prognostic significance for survival. Patients were assigned to three risk categories depending on the number of unfavorable characteristics. Patient selection in phase II studies was addressed by developing a table of expected median survival for patient cohorts that had varying proportions of patients from the three risk categories. RESULTS Two factors had independent prognosis: Karnofsky performance status (KPS) less than 80% and visceral (lung, liver, or bone) metastasis. Median survival times for patients who had zero, one, or two risk factors were 33, 13.4, and 9.3 months, respectively (P =.0001). The median survival time of patient cohorts could vary from 9 to 26 months simply by altering the proportion of patients from different risk categories. CONCLUSION The presence of baseline KPS less than 80% or visceral metastasis has an impact on survival. Reporting the proportion of patients with zero, one, and two risk factors will facilitate understanding of the relevance of the median survival in phase II trials. Phase III trials should stratify patients according to the number of risk factors to avoid imbalance in treatment arms.

Complementarity of Blue Dye and Isotope in Sentinel Node Localization for Breast Cancer: Univariate and Multivariate Analysis of 966 Procedures

Background: The hypothesis that sentinel lymph node (SLN) mapping in breast cancer patients is optimized by combining blue dye and isotope is reasonable and intuitive. Despite this, few studies examine in detail the factors contributing to the success of these techniques, either individually or in combination.Methods: During a time period of 21/2 years, 1000 consecutive patients at Memorial Sloan-Kettering Cancer Center had SLN mapping performed by using both blue dye and isotope, with preoperative lymphoscintigraphy (LSG). Among the 966 patients with invasive cancer, 12 variables were examined for their correlation with the success of SLN localization by blue dye, by isotope, and by the combined method, using univariate and multivariate models.Results: By univariate analysis, blue dye success was more frequent in association with: a positive LSG (P = .02), age ≤60 (P < .0005), a previous surgical biopsy (P = .03), and an outer quadrant tumor (P < .0005). Isotope success was more frequent with a positive LSG (P < .0005), age ≤60 (P = .004), and intradermal isotope injection (P < .0005). Combined (dye and/or isotope) success was more frequent when there was a positive LSG (P < .0005), age ≤60 (P = .006) and intradermal isotope injection (P < .0005).In multivariate analysis, blue dye success remained uniquely associated with outer quadrant tumor location (P < .0005), and isotope success was uniquely associated with intradermal isotope injection (P = .012). Combined success was more frequent with a positive LSG (P < .0005), age ≤60 (P = .033), and intradermal isotope injection (P = .003).Conclusions: The five variables associated with successful SLN localization by blue dye or by isotope overlap but are not identical. Only three of these, intradermal isotope injection, a positive LSG, and age <60, predicted success by the dye-isotope combination in the multivariate model. Dye and isotope complement each other, and SLN biopsy for breast cancer should use both.

Clinical categories of neuroblastoma are associated with different patterns of loss of heterozygosity on chromosome arm 1p.

Deletion of the short arm of chromosome 1 is frequently observed in neuroblastoma (NB). We performed loss of heterozygosity (LOH) analysis of 120 well characterized NB to better define specific regions of 1p loss and any association with clinical and biological prognostic features (DNA index, MYCN, age, and stage). All categories of disease were represented including 7 ganglioneuromas, 8 stage 4S, 33 local-regional (stages 1, 2, and 3), and 72 stage 4 NB according to the International Neuroblastoma Staging System. Patients were consistently treated with stage-appropriate protocols at a single institution. Sixteen highly informative, polymorphic loci mapping to chromosome 1 were evaluated using a sensitive, semi-automated, fluorescent detection system. Chromosome arm 1p deletions were detected in all categories of tumor except ganglioneuroma. Frequent LOH was detected at two separate regions of 1p and distinct patterns of losses were associated with individual clinical/biological categories. Clinically aggressive stage 4 tumors were predominantly diploid with extensive LOH frequently detected in the region of 1ptel to 1p35 (55%) and at 1p22 (56%). The shortest region of overlap for LOH at 1p36 was between D1S548 and D1S1592 and for 1p22 was between D1S1618 and D1S2766. Local-regional tumors were mostly hyperdiploid with short regions of loss primarily involving terminal regions of 1p36 (42%). Most spontaneously regressing stage 4S tumors (7/8) were hyperdiploid without loss of 1p36 or 1p22. These findings suggest that genes located on at least two separate regions of chromosome arm 1p play a significant role in the biology of NB and that distinct patterns of 1p LOH occur in individual clinical/biological categories.

The Phase II/III Transition: Toward the Proof of Efficacy in Cancer Clinical Trials

Few phase III investigations show a benefit for an experimental treatment when compared to a standard therapy or placebo. This illustrates the need for more reliable estimates of treatment effects from the phase II investigations used to design the more definitive phase III trials. In this manuscript, we examine four aspects of phase II clinical trial designs: (1) selecting endpoints; (2) defining the patient population for evaluation; (3) determining a level of activity that would justify a phase III trial; and (4) estimating sample sizes. In each area, problems with the conventional approaches are discussed and alternatives for the successful transition of phase II results to a phase III setting are suggested. An application of the design for patients with androgen-independent prostate cancer is illustrated.

Bone Metastases From Thyroid Carcinoma A Histopathologic Study With Clinical Correlates

CONTEXT Only limited information exists on the pathologic aspects of thyroid carcinomas with bone metastases, most large studies having concentrated mainly on their clinical features. OBJECTIVE To study in detail the morphologic features of thyroid carcinomas with skeletal metastases. DESIGN Seventy-nine cases of thyroid carcinoma with bone metastases treated at Memorial Sloan-Kettering Cancer Center, New York, NY, between 1964 and 1998 were investigated, with emphasis on the pathology of the primary and/or metastatic tumors and comparison of the morphologic features of the tumors at both the sites, wherever possible. The tumors were also compared for various clinical parameters. RESULTS The cohort consisted of 22 papillary, 17 follicular, 16 insular, 10 anaplastic, 9 Hürthle cell, and 5 medullary carcinomas. Of these cases, 68% had poorly differentiated or undifferentiated features in the primary and/or metastatic tumors. The metastatic tumors were better differentiated than the primary in one third of the cases (6 of 18). Only one case showed a less differentiated metastasis. The overall 5- and 10-year survival probabilities after the bone metastases were 29% and 13%, respectively (Kaplan-Meier method). Although both the tumor type and differentiation seemed to affect survivals after bone metastasis (P =.007 and.012, respectively) (log-rank test), this was primarily due to the much worse prognosis in the cases of anaplastic and medullary carcinoma. Cases of Hürthle cell carcinoma showed the longest median survival. There was no significant difference in survival among patients up to or older than 45 years at the time of metastases (P =.31). CONCLUSIONS Most thyroid carcinomas with bone metastases are of papillary type, and most have poorly differentiated or undifferentiated features. The influence of the microscopic tumor type and tumor differentiation on survival after bone metastasis primarily appears to be due to the much worse prognosis among anaplastic and medullary carcinomas. Age at diagnosis of bone metastases does not influence survivals.

Varying Features of Early Age-of-Onset "Sporadic" and Hereditary Nonpolyposis Colorectal Cancer Patients

PURPOSE: Although the criteria for clinical diagnosis of hereditary nonpolyposis colorectal cancer are not fully agreed on, young age seems to be a common trait. The purpose of this study is to identify clinicopathologic features of hereditary nonpolyposis colorectal cancer in early age-of-onset colorectal cancer patients stratified as a function of family cancer history. METHODS: Two hundred thirty consecutive colorectal cancer patients 40 years or older at time of diagnosis were registered into an ongoing database during a ten-year period. Accurate family history was obtainedvia medical records, telephone calls, and questionnaires on 146 patients. According to extent of family history of cancer, patients were stratified into seven groups: 1) fulfilling Amsterdam criteria, 2) fulfilling less strict criteria, 3) having at least one first-degree relative with colorectal cancer, 4) having at least one distant relative with colorectal cancer, 5) having at least one first-degree relative with any cancer, 6) having at least one distant relative with any cancer, 7) having no family history of cancer. RESULTS: Twenty-two of 146 patients fulfilled Amsterdam and less strict hereditary nonpolyposis colorectal cancer criteria (15 percent). These hereditary nonpolyposis colorectal cancer patients were significantly younger (31vs. 35 years;P=0.0003) and had more metachronous colorectal cancer (27 percentvs. 2 percent;P=0.007) and less colorectal cancer with nodal or metastatic spread than the non-hereditary nonpolyposis colorectal cancer patients (35 percentvs. 65 percent;P=0.01). CONCLUSION: Precise familial cancer assessment in early age-of-onset colorectal cancer increases the yield of hereditary nonpolyposis colorectal cancer diagnosis. Because of the frequent development of metachronous colorectal cancer and favorable prognosis, extensive rather than segmental surgery should be considered in early age-of-onset colorectal cancer patients belonging to hereditary nonpolyposis colorectal cancer families.

PD36-09 INSTITUTIONAL VOLUME IS ASSOCIATED WITH REDUCED 90 DAY MORTALITY RATES FOR BOTH OPEN AND ROBOTIC RADICAL CYSTECTOMY

The association between PBT and oncological outcomes, as well as OCM was assessed using Cox and logistic regression analyses. Imbalances in clinicopathological features of patients receiving PBT vs. patients not receiving PBT were mitigated using conventional adjusting as well as inverse probability of treatment weighting (IPTW). RESULTS: The final population consisted of 525 patients with a median follow-up of 26 months (IQR: 21-30 months) of whom 275 patients (52.4%) received PBT. The two groups (PBT vs. no PBT) differed significantly with respect to most clinicopathological features including perioperative blood loss (median: 1000ml; IQR: 650-1600ml vs. median: 570ml; IQR: 400-800ml). Independent predictors of receipt of PBT in multivariate logistic regression analysis were sex (odds ratio (OR)1⁄44.66; 95% confidence interval (CI)1⁄4[2.34-9.29]; p<0.001), body mass index (OR1⁄40.92; 95% CI1⁄4[0.87-0.97]; p1⁄40.003), type of urinary diversion (OR1⁄40.40; 95% CI1⁄4[0.22-0.75]; p1⁄40.004), estimated blood loss (OR1⁄41.29; 95% CI1⁄4 [1.21-1.39]; p<0.001), and any complication within 30 days (OR1⁄43.00; 95% CI1⁄4[1.75-5.15]; p<0.001). Unweighted and unadjusted survival analyses revealed a significant increase in cumulative incidences of CSM and OCM in the two groups (p1⁄40.017 and p<0.001, respectively). After IPTW-adjustment, those differences no longer held true. PBT was not associated with RFS (HR1⁄40.92; 95% CI1⁄4[0.53-1.59]; p1⁄40.76), OS (HR1⁄41.07; 95% CI1⁄4[0.56-2.04]; p1⁄40.84), CSM (sub-HR1⁄41.09; 95% CI1⁄4[0.62-1.93]; p1⁄40.76) and OCM (sub-HR1⁄41.02; 95% CI1⁄4[0.27-3.84]; p1⁄40.95) in IPTW-adjusted Cox regression and competing-risks regression analyses. The same held true in conventional multivariate Cox and competing-risks regression analyses, where pathological tumor stage and lymphovascular invasion were the only independent predictors of CSM (HR1⁄43.71, 95% CI1⁄4[2.06-6.68], p<0.001 and HR1⁄42.49, 95% CI1⁄4 [1.43-4.33], p<0.001) aswell as disease recurrence (HR1⁄44.48, 95%CI1⁄4 [2.45-8.16], p<0.001 and HR1⁄42.76, 95% CI1⁄4[1.56-4.87], p<0.001). CONCLUSIONS: This study could not determine an adverse impact of PBT on oncological outcome and overall survival after adjusting for differences in patient characteristics.

PD67-06 PATHOLOGIC METRICS OF SURGICAL QUALITY IN OPEN AND ROBOTIC RADICAL CYSTECTOMY IMPROVED AT HIGHER VOLUME AND ACADEMIC CENTERS

INTRODUCTION AND OBJECTIVES: Continent urinary diversion (CUD) can offer improved quality of life in select patients follow in radical cystectomy (RC). We aim to evaluate the rate of receipt of CUD in robotic assisted RC (RARC) and open RC (ORC) based on hospital volume and facility type in the National Cancer Data Base. METHODS: We divided all cystectomy cases into volume categories (defined as: 1-2.9, 3-4.9, 5-9.9, 10-19.9 and 20+ cystectomies/ year) and facility type (academic/research (AR), comprehensive community (CC) and other), type of surgery (ORC or RARC) to assess the patterns in the rate of receipt of CUD. To assess the relationship between facility characteristics and receipt of CUD, chi-square was used. Univariate and multivariable logistic regression models for CUD rates were used to adjust for patient, tumor and facility characteristics. RESULTS: 16,923 RC cases were identified (ORC 1⁄4 13,236, RARC1⁄43,687). Overall, 5.7% of ORC (754) and 7.1% of RARC (261) received CUD (p1⁄40.003). RARC had higher rates of receiving CUD compared to ORC in all volume categories except for the highest volume centers (10.2% vs 9.7%). Rates of receipt of CUD increased with increasing RC volume centers (p1⁄40.01); in the ORC group (2.8 vs. 10.2%), and in the RARC group by (5.7% vs. 9.7%; p for interaction1⁄40.10). In adjusted models, center volume remained a highly significant predictor of CUD receipt (p<0.001). Rates of receipt of CUD were higher in RARC vs. ORC in CC and other facility types, but were equal in AR facilities. The difference in the rate of CUD receipt between facility types was significant for ORC (p1⁄40.001) but not for RARC (p1⁄40.09). CUD receipt was observed to decrease linearly over time in both ORC (6.9% in 2010 vs. 4.7 in 2013; p1⁄40.001) and RARC (9.4% in 2010 vs. 6.0% in 2013; p1⁄40.06). CONCLUSIONS: Increasing facility cystectomy volume was associated with increased rates of receipt of CUD in both open and robotic cystectomy while facility type was only significant for open surgeries. The overall rate of receiving CUD was higher in RARC versus ORC surgeries but the overall rate of patients receiving continent diversions remains low and may be decreasing.