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Walter Stadler

Publications and source records attributed to Walter Stadler.

17 recordsLinked to original sources
PubMed2006

Activities and accomplishments of the cancer and leukemia group B genitourinary committee.

The Cancer and Leukemia Group B Genitourinary (GU) Committee has developed a multidisciplinary approach to treatment of GU cancer and has integrated correlative science research into the major research themes of the GU Committee. In localized prostate cancer, trials have evaluated novel approaches in radiation therapy. For patients with recurrence after local therapy, a trial evaluating local recurrence with salvage prostatectomy and a study of systemic therapy with "peripheral androgen blockade" were undertaken. Major contributions have been made in developing and testing therapeutics for advanced, androgen-independent prostate cancer (ketoconazole, suramin, estramustine/docetaxel, and docetaxel/bevacizumab), and in developing predictive markers and algorithms to assess prognosis in these patients. Contributions in kidney cancer have included the development of novel trial methodology, such as the randomized discontinuation trial design, and the testing of antiangiogenics. In addition to these areas, future work of the committee will include further development of therapy for earlier-stage prostate cancer patients and bladder cancer patients.

Antineoplastic Agents↗
PubMed2006

Sorafenib.

PURPOSE OF REVIEW: Sorafenib is an oral, multikinase inhibitor that was recently approved for use in metastatic renal cancer. It is currently undergoing investigation in locally advanced renal cancer and in other tumor types. RECENT FINDINGS: Sorafenib was initially developed as an inhibitor of Raf kinase; however, it has broad spectrum activity against multiple tyrosine kinases, including angiogenic factors VEGFR and PDGFR. Common toxicities experienced with sorafenib include hypertension, hand-foot syndrome, rash, diarrhea and fatigue. Early clinical trials suggested that sorafenib acts as a cytostatic agent, as many patients experienced prolonged disease stabilization but insufficient tumor shrinkage to meet RECIST criteria for response. To assess whether sorafenib's growth inhibition translated into a clinical benefit, a phase II randomized discontinuation trial was designed. This trial demonstrated that sorafenib increased progression-free survival in patients with metastatic renal cell cancer; the phase II data were confirmed in a large international phase III trial. SUMMARY: In this review, we will discuss the clinical development of sorafenib and its role in the treatment of renal cancer. Additionally, we will highlight critical methods of clinical trial design and biomarker development that contribute to the development of sorafenib.

Antineoplastic Agents↗
PubMed2005

A molecular classification of papillary renal cell carcinoma.

Despite the moderate incidence of papillary renal cell carcinoma (PRCC), there is a disproportionately limited understanding of its underlying genetic programs. There is no effective therapy for metastatic PRCC, and patients are often excluded from kidney cancer trials. A morphologic classification of PRCC into type 1 and 2 tumors has been recently proposed, but its biological relevance remains uncertain. We studied the gene expression profiles of 34 cases of PRCC using Affymetrix HGU133 Plus 2.0 arrays (54,675 probe sets) using both unsupervised and supervised analyses. Comparative genomic microarray analysis was used to infer cytogenetic aberrations, and pathways were ranked with a curated database. Expression of selected genes was validated by immunohistochemistry in 34 samples with 15 independent tumors. We identified two highly distinct molecular PRCC subclasses with morphologic correlation. The first class, with excellent survival, corresponded to three histologic subtypes: type 1, low-grade type 2, and mixed type 1/low-grade type 2 tumors. The second class, with poor survival, corresponded to high-grade type 2 tumors (n = 11). Dysregulation of G1-S and G2-M checkpoint genes were found in class 1 and 2 tumors, respectively, alongside characteristic chromosomal aberrations. We identified a seven-transcript predictor that classified samples on cross-validation with 97% accuracy. Immunohistochemistry confirmed high expression of cytokeratin 7 in class 1 tumors and of topoisomerase IIalpha in class 2 tumors. We report two molecular subclasses of PRCC, which are biologically and clinically distinct and may be readily distinguished in a clinical setting.

Adult↗
PubMed2005

Phase II study of the efficacy and safety of oral GD0039 in patients with locally advanced or metastatic renal cell carcinoma.

Seventeen patients with locally advanced or metastatic renal cell carcinoma (RCC) were enrolled in this phase II trial. The purpose of the trial was to assess the efficacy of the administration of oral GD0039, and to further assess the pharmacokinetics and pharmacodynamics of this drug. Patients were given an initial dose of 37.5 micro g/kg b.i.d for 3 weeks followed by one week off in each cycle, with the treatment continuing until disease progression or adverse effects. All 17 patients discontinued treatment due to disease progression or toxicity. Adverse events such as fatigue, nausea and diarrhea were common but generally mild. No evidence of anti-tumor activity of GD0039 was seen in this study.

Administration, Oral↗
PubMed2004

Quality of life impact of three different doses of suramin in patients with metastatic hormone-refractory prostate carcinoma: results of Intergroup O159/Cancer and Leukemia Group B 9480.

BACKGROUND: Research has suggested that men with hormone-refractory prostate carcinoma have a lower quality of life (QOL) compared with men who have hormone-sensitive prostate carcinoma and that quality of life (QOL) steadily declines over the last year of life for men with prostate carcinoma. The primary purpose of the current study was to evaluate whether there was evidence of palliative effects associated with suramin at any of the three doses administered in the original clinical trial. METHODS: Patients with histologically confirmed advanced hormone-refractory adenocarcinoma of the prostate were randomized to receive suramin at a low dose (n = 129; median age, 69 years), an intermediate dose (n = 129; median age, 71 years), or a high dose (n = 127; median age, 70 years) as part of the Intergroup 0159/Cancer and Leukemia Group B 9480 trial. Patients completed a battery of assessment tools, including the Functional Assessment of Cancer Therapy (FACT)-Prostate, the Center for Epidemiological Studies-Depression Scale (CES-D), the Brief Pain Inventory, and an opioid medication log, at baseline, on Day 1 of the sixth week of active therapy, during the second week after treatment termination, and 3 months after administration of the final suramin dose. RESULTS: Patients who received low-dose suramin reported improvement in QOL (FACT-General: P < 0.01; FACT-Treatment Outcome Index: P < 0.01) and decreased levels of depression (CES-D: P < 0.0006) during treatment compared with patients in the intermediate- and high-dose arms. After treatment, all groups experienced equal decreases in FACT and CES-D scores. CONCLUSIONS: The pattern of results suggests that the lowest dose of suramin administered had a palliative effect in terms of improvement in QOL and decreased levels of depression and that this effect was lost once suramin was discontinued.

Adenocarcinoma↗
PubMed2004

Androgen ablation adjuvant to postprostatectomy radiotherapy: complication-adjusted number needed to treat analysis.

OBJECTIVES: To quantify the benefits and harm of androgen ablation (AA) adjuvant to radiotherapy in the postprostatectomy setting. AA is commonly used in the management of prostate cancer. METHODS: A literature review was performed to estimate the absolute biochemical control advantage for the use of AA concomitant with postprostatectomy external beam radiotherapy. Additionally, a model was developed, with supporting published data, to estimate the utility-adjusted survival detriment due to the side effects of AA, using the number needed to treat (NNT) technique. Using these data, the unadjusted NNTs and the utility-adjusted NNTs for the addition of AA were computed. In all cases, the sign and magnitude of the NNTs obtained were used to gauge the effects of AA. RESULTS: The unadjusted NNT analysis demonstrated very low values (far less than 20), suggesting a strong benefit for the use of AA, in both adjuvant and salvage radiotherapy settings. Even after adjustment for hormone-induced functional loss, a significant advantage of AA was demonstrated. CONCLUSIONS: Using the complication-adjusted NNT method, AA appears to be advantageous in both adjuvant and salvage postprostatectomy radiotherapy settings. The results of the present investigation demonstrated the significant role of the NNT technique for uro-oncologic management decisions when treatment complications need to be considered and balanced against the beneficial effects of the treatment.

Androgens↗
PubMed2003

Disease-associated expression profiles in peripheral blood mononuclear cells from patients with advanced renal cell carcinoma.

Expression profiling has demonstrated that transcriptomes of primary malignancies differ from those in normal tissue. It is unknown, however, whether there exist "surrogate" transcriptional markers in peripheral blood mononuclear cells (PBMCs) of patients with solid tumors. We identified transcripts expressed differentially between PBMCs from renal cell carcinoma patients and normal subjects, some of which appear to reflect specific immune responses of circulating cells. We also identified small sets of predictor genes distinguishing PBMCs from renal cell carcinoma patients and normal volunteers with high accuracy. The present findings have important implications for diagnosis and future clinical pharmacogenomic studies of antitumor therapies.

Adult↗
PubMed2003

Androgen receptor mutations in androgen-independent prostate cancer: Cancer and Leukemia Group B Study 9663.

PURPOSE: The mechanisms responsible for prostate cancer androgen independence are diverse. Mutations of the androgen receptor (AR) gene that broaden ligand specificity have been implicated. Bone marrow specimens containing prostate tumor were obtained from men undergoing antiandrogen withdrawal for AR sequence analysis and clinical correlation. MATERIALS AND METHODS: Eligible men enrolled on a trial of antiandrogen withdrawal had a minimum prostate-specific antigen (PSA) level of 5 ng/dL that was increasing on castration therapy including an antiandrogen. With informed consent, marrow biopsies were obtained to collect prostate tumor. Additional samples were obtained from men enrolled on chemotherapy trials. AR cDNA or DNA was polymerase chain reaction-amplified, cloned, and sequenced. The AR CAG repeat length was recorded. RESULTS: One hundred eighty-four bone marrow biopsies were obtained, and 48 had prostate tumor detected by light microscopy. The ARs from these 48 samples were sequenced. Overall, five (10%) of 48 tumors had mutated ARs. AR point mutations were detected in the hormone-binding domain involved in transcription factor binding. Three mutations were novel in prostate cancer. One tumor sample had a CAG repeat length of 21, compared with germline length of 22 repeats. There was no association between detectability of AR mutations and antiandrogen withdrawal response or survival. CONCLUSION: These data suggest that AR mutations are present in approximately 10% of patients with prostate cancer who experience treatment failure with hormone therapy that included an antiandrogen. Mutations in the AR likely confer a growth advantage for a subset of progressive prostate cancers. Correlation of AR mutation with antiandrogen withdrawal response or survival could not be made.

Adenocarcinoma↗
PubMed2003

Angiogenesis inhibitors in genitourinary cancers.

Despite much enthusiasm, no clear clinical benefit to any antiangiogenic agent has yet been demonstrated. Phase I trials demonstrate that endostatin, an endothelial cell toxin, can be administered safely, but no obvious anti-tumor effects were observed. Certain matrix metalloproteinase inhibitors appear ineffective, but later generation inhibitors with less systemic toxicity continue to be investigated. There are occasional responses to thalidomide either singly or in combination, but its pharmacology and mechanism of action remain unclear. A randomized study with the anti-VEGF antibody bevacizumab suggests that VEGF pathway is an important target in renal cell cancer. VEGF receptor tyrosine kinase inhibitors continue to be developed, but one of the first compounds SU5416 has had minimal clinical effects. Clinical trial designs that address the stable disease endpoint should thus be investigated and the randomized discontinuation design has already been tested. Pharmacodynamic markers that reflect antiangiogenic drug effect also need to be developed, but the putative ones, including circulating proangiogenic factors, tumor microvessel density, and dynamic contrast MRI have not yet proven to be useful.

Angiogenesis Inhibitors↗
PubMed2002

Randomized discontinuation design: application to cytostatic antineoplastic agents.

PURPOSE: Propose a phase II study design to evaluate the activity of a putative cytostatic agent, acknowledging heterogeneity of tumor growth rates in the population of patients. METHODS: In the setting of renal cell carcinoma, some patients' tumors will grow slowly naturally. An appropriate design has to distinguish antiproliferative activity attributable to the novel agent from indolent disease. We propose a randomized discontinuation design that initially treats all patients with the study agent (stage 1) and then randomizes in a double-blind fashion to continuing therapy or placebo only those patients whose disease is stable (stage 2). This design allows the investigators to determine if apparent slow tumor growth is attributable to the drug or to selection of patients with naturally slow-growing tumors. RESULTS: By selecting a more homogeneous population, the randomized portion of the study requires fewer patients than would a study randomizing all patients at entry. The design also avoids potential confounding because of heterogeneous tumor growth. Because the two randomly assigned treatment groups each comprise patients with apparently slow growing tumors, any difference between the groups in disease progression after randomization is more likely a result of the study drug and less likely a result of imbalance with respect to tumor growth rates. Stopping rules during the initial open-label stage and the subsequent randomized trial stage allow one to reduce the overall sample size. Expected average tumor growth rate is an important consideration when deciding the duration of follow-up for the two stages. CONCLUSION: The randomized discontinuation design is a feasible alternative phase II study design for determining activity of possibly cytostatic anticancer agents.

Antineoplastic Agents↗
PubMed2002

Randomized study of three different doses of suramin administered with a fixed dosing schedule in patients with advanced prostate cancer: results of intergroup 0159, cancer and leukemia group B 9480.

PURPOSE: To test the hypothesis that the efficacy and toxicity of suramin in the treatment of patients with hormone-refractory prostate cancer was dose dependent. PATIENTS AND METHODS: Patients were randomized with equal probability to receive low-, intermediate-, or high-dose suramin (total doses 3.192, 5.320, and 7.661 g/m(2), respectively). Overall survival, time to progression, and response rate (prostate-specific antigen [PSA] and objective) for each treatment arm were compared. Relationships between plasma suramin concentrations and response, toxicity, and survival were also evaluated. RESULTS: Three hundred ninety patients were randomized. For the low-, intermediate-, and high-dose arms, the median survival time was 16, 14, and 13 months, respectively (P =.49). The objective response rate was 9%, 7%, and 15%, respectively (P =.10). PSA response rates were 24%, 28%, and 34%, respectively (P =.082). Landmark analyses of a 50% decline in PSA at 20 weeks showed a significant correlation with survival. There was a dose-response relationship between dose and toxicity. After adjusting for treatment arm, the measured suramin concentration was not associated with clinical response, PSA response, survival, or toxicity. CONCLUSION: Although high-dose suramin was associated with higher objective and PSA response rates, these were not statistically significant. Overall, no dose-response relationship was observed for survival or progression-free survival, but toxicity was increased with the higher dose. Patients treated with the low-dose level experienced modest toxicity, making it the preferred arm on this study. The lack of a dose-response relationship and the toxicity profile observed raise questions regarding the utility of suramin, particularly high-dose suramin, as administered on this schedule.

Aged↗
PubMed2002

New trial designs to assess antitumor and antiproliferative agents in prostate cancer.

The discovery of multiple putative therapeutic targets and multiple putative agents for these targets in prostate cancer in the coming years poses significant challenges for clinical trial design. This is especially true for cytostatic agents that are not expected to lead to frank tumor shrinkage or declines in the PSA. The most promising agents will need to be identified early in their development. Since surrogate biologic markers are likely to play a critical role, the identification and validation of these markers is discussed. A number of non-traditional phase I and phase II clinical trial designs, including pre-operative dosing for assessing drug effect on a marker and the randomized discontinuation phase II design, are also discussed in detail. Use of such designs as well as surrogate marker validation will likely be required to efficiently choose appropriate agents for definitive study in the phase III setting.

Antineoplastic Agents↗
PubMedDate not supplied

9-Nitrocamptothecin as second line chemotherapy for men with progressive, metastatic, hormone refractory prostate cancer: Results of the CALGB 99901.

BACKGROUND: Institution of early hormone therapy in the PSA era coupled with demonstration of clinical benefit with chemotherapy in hormone refractory prostate cancer (HRPC) and acceptance of PSA decline as a surrogate for response has resulted in introduction of chemotherapy earlier in the natural history of disease. There now exists a need to identify, effective agents for second line chemotherapy. 9-nitrocamptothecin (9-NC) a novel, oral camptothecin analogue was tested as second line chemotherapy for patients with progressive hormone refractory prostate cancer. PATIENTS AND METHODS: Eligible patients had metastatic hormone refractory prostate cancer with performance status (0-1) following progression on at least 1 prior cytotoxic chemotherapy. 9-NC was administered orally at the dose of 1.5 mg/m2/d for 5 days each week for 3 weeks, followed by rest for 1 week. Response was evaluated after 2 cycles according to the guidelines set forth for Phase II trials in HRPC by the PSA working group. RESULTS: Thirty-five patients were recruited to the study within a period of 6 months; 33 were evaluable for analysis. No patients had a >50% decline in PSA levels. Two out of 8 (25%) patients with measurable disease and 5/25 (20%) patients with nonmeasurable disease showed stable disease. The median time to disease and PSA progression was 2 months [95% confidence interval (CI), 0.9-2.8]. The median overall survival was 10 months (95% CI = 5-12). Seven patients are alive after a median follow-up of 23 months. CONCLUSIONS: 9-nitrocamptothecin failed to elicit clinical or PSA responses. Further study in pretreated HRPC patients is not warranted.

Administration, Oral↗