The association of clinical outcome to first-line VEGF-targeted therapy with clinical outcome to second-line VEGF-targeted therapy in metastatic renal cell carcinoma patients

There are many active drugs to treat metastatic renal cell carcinoma (mRCC) patients who progress through their first-line vascular endothelial growth factor (VEGF) inhibitor. Many clinicians choose a second-line VEGF inhibitor based on the type of response to first-line VEGF inhibitor, without data supporting this practice. This study was conducted to determine the association of response to second-line VEGF inhibitor with response to first-line VEGF inhibitor. All mRCC patients in participating centers of the International mRCC Database Consortium who were treated from January 2004 through June 2011 with a second-line VEGF inhibitor after failure of a different first-line VEGF inhibitor were retrospectively identified. The primary outcome is objective response rate (ORR) and the secondary outcome is progression-free survival (PFS) in each line of therapy. Of 1,602 total database patients, 464 patients received a first- and second-line VEGF inhibitor. The ORR to first-line therapy was 22 %, and the ORR to second-line therapy was 11 %. The ORR to second-line therapy was not different among patients achieving partial response versus stable disease versus progressive disease to first-line therapy (14 % vs. 10 % vs. 11 %, respectively; chi-squared trend test p?=?0.17). The median PFS on first-line VEGF-targeted therapy was 7.5 months (95 % CI, 6.6–8.1), and the median PFS on second-line VEGF inhibitor was 3.9 months (95 % CI, 3.6–4.5). There was no correlation between first-line and second-line PFS (Pearson correlation coefficient 0.025; p?=?0.59). The clinical response to a second-line VEGF inhibitor is not dependent on response to the first-line VEGF-inhibitor. Further studies are needed to define clinical parameters that predict response to second-line therapy to optimize the sequence of VEGF-targeted therapy in metastatic RCC patients.     

Adjuvant Chemo-/Hormonal Therapy Trials for Locally Advanced Prostate Cancer

Patients with clinical or pathologic locally advanced prostate cancer (LAPC) are at risk for systemic and local disease progression or relapse. Pre- and post-therapy predictors of risk include prostate-specific antigen (PSA) levels, clinical and pathologic stage, Gleason’s score (GS) of the biopsy and prostatectomy specimens, positive margins, and post-therapy PSA kinetics. Combined modality trials have been done predominantly in LAPC patients treated with radiation. The data indicate a local control and disease-free survival advantage to the use of androgen deprivation. Neoadjuvant hormonal therapy with radical prostatectomy (RP) has no proven role thus far; however, recent data on adjuvant hormonal therapy in patients with pathologic D1 disease treated with radical prostatectomy suggest a potential benefit. Chemotherapy trials are still in their infancy but present exciting opportunities for future research. The heterogeneity in the hormone responsiveness of prostate cancer, the availability of several active chemotherapy combinations, and the refinement in risk prediction have stimulated a series of adjuvant therapy trials which constitute the subject of this discussion. Emphasis on enrollment in clinical trials is thus imperative in LAPC.     

Development of a Prediction Tool for Exclusive Locoregional Recurrence After Radical Cystectomy in Patients With Muscle-Invasive Bladder Cancer

Background

Limited information is available about the pattern of relapse after perioperative chemotherapy with radical cystectomy (RC) vs. RC alone in muscle-invasive bladder cancer.

Combined modality therapy for esophageal squamous cell carcinoma

Of 55 patients with esophageal squamous cell carcinoma, 30 with localized disease were treated with a combined modality for curative intent. Treatment consisted of mitomycin C (10 mg/m2 day 1) and continuous infusion 5-FU (1000 mg/m2 day, days 1-4, 29-32) (CT), radiation (XRT) (3000 rad, days 1-21) with nutritional support, and surgery (days 49-64). Surgery consisted of celiotomy, esophagectomy and esophagogastrostomy +/- postoperative ventilatory support. Postoperative CT plus an additional 2000 rad XRT was restricted to patients with histologic positive tumor. Since five resected patients with subclinical metastatic tumor had an inferior survival equal to 25 patients treated essentially for palliation, pretreatment celiotomy seems warranted to identify patients with an inferior prognosis. Of 18 resected patients without disseminated tumor evaluable for this combined modality: six were tumor free, three had intramural and nine transmural tumor; the median survival is 76 weeks and five of six living patients are disease free at 95-190 weeks; and local recurrence occurred in two and in two of seven unresected patients. Since toxicity was minimal except for postoperative pneumonitis (13%) and local recurrence low (13%), two courses of chemotherapy and 5000 rad XRT perhaps obviates the need for resection.     

Further development of the case-only design for assessing gene-environment interaction: evaluation of and adjustment for bias

BACKGROUND: The case-only study for investigating gene-environment interactions provides increased statistical efficiency over case-control analyses. This design has been criticized for being susceptible to bias arising from non-independence between the genetic and environmental factors in the population. Given that independence is critical to the validity of case-only estimates of interaction, researchers frequently use controls to evaluate whether the independence assumption is tenable, as advised in the literature. Our work investigates to what extent this approach is appropriate and how non-independence can be accounted for in case-only analyses. METHODS: We provide a formula in epidemiological terms that illustrates the relationship between the gene-environment association measured among controls and the gene-environment association in the source population. Using this formula, we conducted sensitivity analyses to describe the circumstances in which controls can be used as proxy for the source population when evaluating gene-environment independence. Lastly, we generated hypothetical cohort data to examine whether multivariable modelling approaches can be used to control for non-independence. RESULTS: Our sensitivity analyses show that controls should not be used to evaluate gene-environment independence in the population, even when the baseline risk of disease is low (i.e. 1%), and the interaction and independent effects are moderate (i.e. risk ratio = 2). When the factors are associated, it is possible to remove bias arising from non-independence using standard statistical multivariable techniques in case-only analyses. CONCLUSIONS: Even when the disease risk is low, evaluation of gene-environment independence in controls does not provide a consistent test for bias in the case-only study. Given that control for non-independence is possible when the source of the non-independence can be conceptualized, the case-only design may still be a useful epidemiological tool for examining gene-environment interactions.     

A Review of Current and Future Treatment Options in Renal Cancer

Renal cancer is a malignancy that has been rising in incidence over the past 5 decades. The treatment of choice for localized cancer is radical nephrectomy, although nephron-sparing surgery can be considered in selected cases with small tumors. The risk of recurrence or metastatic disease ranges from 15 to 80%. Some of the factors predictive of prognosis are histology, stage, and grade of the cancer. Metastatic or stage IV disease is the major cause of mortality. The treatment of choice for metastatic disease is surgical resection of metastases, if feasible, as it can result in prolonged remissions in a small proportion of patients (10–20%). The results of randomized trials demonstrated a survival benefit with nephrectomy in metastatic disease. Consequently, this should be a consideration in patients with good functional status prior to immunotherapy. Adjuvant therapy has no proven role in renal cancer. The approved systemic immunotherapy is interleukin-2 (IL-2) with a reported overall response rate of 15% and durable remission rate of 7%. The wide application of IL-2 is limited by the severe toxicity profile. Thus, the use of IL-2 is restricted to patients with excellent performance status. Less toxic doses, schedules, and routes of administration of IL-2 have demonstrated responses in metastatic disease, but prolonged remission has not been clearly established. Cytotoxic chemotherapy has not shown promising results to date; however, novel cytotoxic agents and combinations are in the clinical evaluation phase. Biochemotherapy regimens, such as combinations of gemcitabine and capecitabine with IL-2 and interferon, have shown responses ranging from 15 to 40% with 10 to 15% complete remissions which, although favorable, have not resulted in major improvements in overall survival. In a preliminary study, allogeneic mini transplant produced responses in 10 of 19 patients with metastatic disease: three complete and seven partial remissions. However, the 10 to 20% treatment-related mortality associated with mini transplant, excellent performance status requirement, and low availability of matched donor, in this highly selected group of patients, indicates that this would be feasible in <10% of patients screened. Further follow-up and validation of the safety and efficacy of transplant are required. Targeted therapies such as tyrosine kinase inhibitors, epithelial growth factor inhibitors and monoclonal antibodies will be evaluated in the next few years. There is a strong rationale for the antiangiogenic strategy due to the hypervascular nature of this tumor type. The future promises improvement in tumor characterization techniques and advances in targeted therapies to enable effective, individually tailored treatment for metastatic renal cell carcinoma.     

Her-2/neu overexpression in muscle-invasive urothelial carcinoma of the bladder: prognostic significance and comparative analysis in primary and metastatic tumors.

PURPOSE: The prognostic significance of Her-2/neu overexpression in muscle-invasive urothelial carcinoma of the bladder is largely unknown. Accurate determination of Her-2/neu overexpression may have therapeutic importance. EXPERIMENTAL DESIGN: Eighty consecutive cases of muscle-invasive urothelial carcinoma of the bladder treated by radical cystectomy with available follow-up were analyzed. In each case, one representative section was stained with anti-Her-2/neu. Staining was graded as 1 = faint/equivocal, 2 = moderate, and 3 = strong and was considered positive if > or =2. In those cases with a metastasis, the stain was also performed in the metastatic tumor. Results were correlated with survival. RESULTS: Twenty-two (28%) cases were considered Her-2/neu-positive in the primary tumor, and 17 of 32 (53%) were considered Her-2/neu-positive in the lymph node metastasis. Median survival for Her-2/neu-positive primary tumors was 33 months, compared with 50 months for Her-2/neu-negative cases (P = 0.46). Similarly, Her-2/neu overexpression in the lymph node metastasis did not predict survival. Sixty metastatic urothelial carcinomas were further studied by comparing Her-2/neu expression in the primary tumor with that of the lymph node and/or distant metastasis. Forty-five percent of Her-2/neu-negative primary tumors had a Her-2/neu-positive lymph node metastasis, whereas only one case (8%) of Her-2/neu-positive primary tumors was Her-2/neu-negative in the lymph node metastasis (P = 0.009). Similarly, 67% of Her-2/neu-negative primary tumors had a Her-2/neu-positive distant metastasis, whereas no Her-2/neu-positive primary tumor was negative in the metastasis (P = 0.429). CONCLUSIONS: Her-2/neu overexpression in primary or metastatic tumor did not predict survival in this cohort of muscle-invasive tumors. Overexpression in the primary tumors consistently predicts overexpression in a distant or regional metastasis. However, some Her-2/neu-negative primary tumors may show overexpression in their corresponding metastasis. Her-2/neu analysis in a metastasis may be necessary to accurately determine Her-2/neu status in metastatic bladder urothelial carcinoma.