Paul Sweeney

Integrated Therapy for Locally Advanced Bladder Cancer: Final Report of a Randomized Trial of Cystectomy Plus Adjuvant M-VAC Versus Cystectomy With Both Preoperative and Postoperative M-VAC

PURPOSE We conducted a phase III trial to investigate the timing of chemotherapy with respect to surgery for patients with resectable but high-risk urothelial cancer. The trial was also designed to evaluate the accuracy of clinical staging in patients with locally advanced cancer and the prognostic significance of chemotherapy-induced downstaging. PATIENTS AND METHODS A total of 140 uniformly evaluated patients with locally advanced urothelial cancer were studied. Planned treatment was five cycles of chemotherapy (M-VAC: methotrexate, vinblastine, doxorubicin, and cisplatin) plus radical cystectomy and pelvic lymph node dissection. Patients were randomly assigned to receive either two courses of neoadjuvant M-VAC followed by surgery plus three additional cycles of chemotherapy, or, alternatively, to have initial cystectomy followed by five cycles of adjuvant chemotherapy. RESULTS There were no significant differences in outcome between the two groups. By intent-to-treat, 81 patients (58%) remain disease-free, with median follow-up of 6.8 years. We confirmed a high rate of clinical understaging in this cohort, especially among patients showing lymphovascular invasion on biopsy. Patients with no residual muscle-invasive disease at cystectomy after neoadjuvant chemotherapy were likely to be cured. CONCLUSION These results lend further support to the impression from small randomized trials that, in a high-risk cohort, there is an improved cure fraction by the combination of multiagent chemotherapy and surgery, although we found no preferred sequence. Importantly, it is possible to select appropriate patients for such therapy on the basis of clinical staging information. These results establish a benchmark of outcome for this cohort.

Surgical management of renal cell carcinoma associated with complex inferior vena caval thrombi

The operative morbidity and mortality of radical nephrectomy are considerably higher when the vena cava is involved by the tumor. The prognostic significance of vena caval extension in this setting remains controversial. We reviewed our experience of vena caval thrombectomy specifically addressing prognostic factors. We retrospectively studied 96 patients treated at our institution between 1985 and 2001. The study population included 28 women and 68 men; (37 left- and 59 right-sided tumors). Twenty-seven patients had metastatic disease at presentation. Prognostic features (age, sex, race, side of tumor, embolization, tumor grade, tumor confinement by renal capsule, cephalic extent of thrombus, nodal status, and presence of distant metastasis) were evaluated using a Cox proportional hazards model (univariate and multivariate). These prognostic features were analyzed in the group as a whole and in the subgroup of patients who did not have metastatic disease at presentation and did not die perioperatively. There were 5 perioperative deaths. Extracapsular tumor extension and regional node involvement were present in 64% and 17% of the patients, respectively. Level of tumor thrombus were as follows: level I (41%), II (29%), III (7%), IV (15%). Fuhrmans grade was 2 in 17%, 3 in 45%, and 4 in 30% of the patients. For all 96 patients, median overall survival (OS) was 35 months. Five-year OS was 35%. The presence of distant metastasis at presentation did not significantly alter median OS (20 months with metastasis vs. 38 months without, P = 0.3), although this finding may have been confounded by selection. The presence of nodal metastasis was associated with decreased OS by multivariate analysis (P < 0.01). After exclusion of patients dying perioperatively and patients with metastasis at presentation, median OS and progression-free survival were 40 and 18 months, respectively (5-year OS was 40%). In the multivariate model, none of the factors examined were associated with OS, but age <58 years, and the presence of extracapsular tumor extension were associated with an increased risk of recurrence. In patients with renal tumors and extension of tumor thrombus into the vena cava, the level of propagation of the thrombus does not predict for OS. Selected patients with metastatic renal cancer may benefit from aggressive surgical resection of the primary tumor and associated tumor thrombus.

Biological Significance of C-met Over Expression in Papillary Renal Cell Carcinoma

PURPOSE Hereditary papillary renal cell carcinoma is associated with mutations of the c-met proto-oncogene. Similar aberrations have been described at a molecular level in up to 13% of sporadic papillary renal cell carcinomas. We assessed c-met expression in papillary renal cell carcinomas and evaluated the prognostic significance of c-met expression in patients with this tumor. MATERIALS AND METHODS We performed immunohistochemical testing to identify c-met expression in archival specimens of 55 papillary renal cell carcinomas in 51 patients. Only 1 patient reported a family history of renal malignancy. RESULTS We identified c-met protein expression in the cytoplasm and cell membrane of 80% and 56% of these tumors, respectively. c-met expression significantly correlated with higher stage tumors (p = 0.004) but it was not associated with Fuhrman nuclear grade (p = 0.157). A trend toward a higher overall survival rate was noted in patients in whom tumors did not express c-met but this association failed to achieve statistical significance (p = 0.07). CONCLUSIONS Our study indicates that c-met over expression may be associated with an aggressive phenotype in these tumors.

Ad5CMVp53 gene therapy for locally advanced prostate cancer - Where do we stand?

Abstract Despite the introduction of screening procedures and an increased public awareness of prostate cancer, a substantial number of patients present with locally advanced prostate cancer. Traditional therapies (such as radiation therapy or radical prostatectomy) applied either alone or in combination fail to control local disease in a large number of cases and have no effect on disseminated disease. Recent advances in molecular oncology and genetics have led to such novel therapies as p53 gene therapy, which we are currently evaluating in a clinical protocol in patients with locally advanced (nonmetastatic) prostatic cancer. Ad5CMVp53 (RPR/INGN 201) has previously shown promise in both patients with lung cancer and those with head and neck cancer. The traditional end points used to appraise prostate cancer preclude rapid evaluation of the patients disease and prevent modification of the therapeutic strategy, and we suggest that the pathologic stage after therapy be evaluated as an intermediate end point.