Southwest Oncology Group Research Articles

Study changes how physicians treat metastatic prostate cancer

Study changes how physicians treat metastatic prostate cancer

Chemotherapy Outcomes by Histologic Subtypes of Non–Small-Cell Lung Cancer: Analysis of the Southwest Oncology Group Database for Antimicrotubule-Platinum Therapy

ObjectiveHistologic subtyping has been advocated to select chemotherapy for patients with advanced-stage non–small-cell lung cancer (NSCLC). To determine whether histologic subtype was associated with efficacy for the commonly used antimicrotubule (AMT) agents, paclitaxel, docetaxel, and vinorelbine plus a platinum compound, we examined the Southwest Oncology Group (SWOG) lung cancer database. MethodsData from 4 randomized trials (S9308, S9509, S9806, and S0003) administering an AMT agent plus platinum in patients receiving first-line treatment for advanced-stage NSCLC were analyzed. Overall survival (OS) and progression-free survival (PFS) comparisons were performed using Cox proportional hazard regression, adjusting for sex. Median survival times were estimated by Kaplan–Meier. ResultsOf 1146 patients included in this analysis, 640 had adenocarcinoma (56%), 220 had squamous cell carcinoma (19%), 121 had large cell carcinoma (11%), and 165 had NSCLC not otherwise specified (NOS) (14%). Median OS times by histologic subtypes were 8.5, 8.4, 8.2, and 9.6 months, respectively, and median PFS times were 4.2, 4.3, 4.3, and 4.6 months, respectively. No difference in OS or PFS was observed by histologic subtype and, specifically, between nonsquamous and squamous histologies. ConclusionsThis pooled analysis from 4 SWOG trials using an AMT-platinum regimen did not show a difference in survival outcomes by histologic subtype. Because the majority of patients with advanced NSCLC continue to receive chemotherapy, defining molecular-based predictive markers of responsiveness is warranted.

Five-year outcome of concurrent radiotherapy and chemotherapy in Saudi women with locally advanced cervical cancer: single-institution experience

BACKGROUND AND OBJECTIVESWe aimed to evaluate long-term treatment outcomes and toxicity profile of combined radiotherapy and chemotherapy in Saudi women with locally advanced cervical cancer.DESIGN AND SETTINGSRetrospective study in a tertiary care cancer center in Riyadh, Saudi Arabia.METHODS AND MATERIALSThe medical records of patients with histopathologically proven, locally advanced cervical cancer were analyzed. These patients received three-dimensional conformal radiotherapy with concurrent chemotherapy followed by high dose rate brachytherapy in our center between July 2007 and April 2012. The data regarding the safety profile, response rates, occurrence of locoregional or distant failure, disease-free survival, and overall survival rates were recorded.RESULTSThe median follow-up period was 60 months (range, 8–66) for 74 patients. The median age of study population was 52.3 years (32–78), and the stage IIB was the predominant stage (49 patients [66.2%]). A total of 45 patients (60.9%) had radiologic-positive pelvic ± para-aortic lymphadenopathy. The 5-year locoregional and distant control rates were 84.3% and 78.5%, respectively. The 5-year disease-free and overall survival rates were 75.7% and 64.5%, respectively. Stage, nodal status, and hemoglobin levels were found to be important prognostic factors for locoregional and distant control. Acute grade 3 hematological and nonhematological toxicities were seen in 4 (5.4%) and 4 (5.4%) patients. Late toxicities were mild, and only 1 (1.4%) patient presented with subacute intestinal obstruction.CONCLUSIONConcurrent chemoradiation in Saudi women with locally advanced cervical cancer showed better locoregional and distant control and survival rates with minimal toxicity.

Pancoast tumor

Pancoast tumors, also known as superior sulcus tumors, to this day remain a complex and challenging condition. This review will explore the evolution of the treatment of these tumors over the better part of a century. It will illustrate how with a multidisciplinary approach and the use of trimodality therapy this entity has evolved from a universally fatal disease to one that is treatable with outcomes similar to those of other stage-matched nonsmall cell lung cancers. The Southwest Oncology Group 9416 Intergroup 0160 trial reported in 2007 By Rusch et al. culminated years of research showing that trimodality therapy with chemotherapy, radiation and surgery provided optimal outcomes. Since that time, there have been studies corroborating these outcomes and utilization of novel surgical approaches including Video-assisted thoracoscopic surgery; however, no change in survival has been reported. The treatment of tumors of the superior sulcus has evolved over the years, so that outcomes approach those of other stage-matched nonsmall cell carcinomas. In the future, new approaches, perhaps the detailed genetic analysis of tumors and guided treatments, will have a positive impact on nonsmall cell carcinomas. The tumors of the superior sulcus will hopefully follow suit in their improved outcomes.

Declining rates of treatment-related mortality in patients with newly diagnosed AML given ‘intense’ induction regimens: a report from SWOG and MD Anderson

Less-intense remission induction regimens for adults with newly diagnosed acute myeloid leukemia (AML) aim to reduce treatment-related mortality (TRM), here defined as death within 4 weeks after starting induction therapy. This assumes that TRM rates are similar to the 15-20% observed 20 years ago. Herein we test this assumption. We examined TRM rates in 1409 patients treated on SWOG (Southwest Oncology Group) trials and 1942 patients treated at MD Anderson (MDA) from 1991 to 2009. Eighty-eight percent of SWOG patients received '3+7' or regimens of similar intensity while 92% of the MDA patients received ara-C at 1.5-2.0 g/m(2) daily × 3-5 days+other cytotoxic agents. We examined the relationship between time and TRM rates after accounting for other covariates. TRM rates between 1991 and 2009 decreased from 18-3% in SWOG and 16-4% at MDA. Multivariate analyses showed a significant decrease in TRM over time (P=0.001). The decrease in TRM was not limited to younger patients, those with a better performance status or a lower white blood cell count. Though our observations are limited to patients treated with intensive therapy at SWOG institutions and MDA, the decrease in TRM with time emphasizes the problem with historical controls and could be considered when selecting AML induction therapy.

Gemtuzumab ozogamicin in acute myeloid leukemia: a remarkable saga about an active drug

AbstractDespite living in an era of unprecedented progress in the understanding of the genetic and molecular biology of acute myeloid leukemia (AML), this has not translated into significant advances in therapy. Never before have so many potential targets been studied. Yet most have not advanced beyond the phase 1 and, occasionally, phase 2 studies. The few ongoing phase 3 studies seem unlikely to have more than a marginal benefit, if at all. Thus, it is not surprising that in past few decades almost no new drugs for AML have received regulatory approval. In 2000, gemtuzumab ozogamicin (GO) was granted accelerated approval by the US Food and Drug Administration based on promising phase 2 data in relapsed older adults with AML. GO held promise as a new agent that also could be efficacious in newly diagnosed AML with acceptable toxicity. Several phase 3 studies were designed to test GO in this setting. The results of a randomized study by the Southwest Oncology Group led in 2010 to the voluntary withdrawal of this agent when improved efficacy could not be demonstrated and toxicity appeared excessive. Since then, 4 randomized studies have been completed that, in aggregate, strongly support the efficacy of this agent in newly diagnosed AML with acceptable toxicity. There is a very plausible explanation for this discrepancy, making a compelling case for reapproval of GO in AML.

Autologous peripheral blood stem cell transplantation with granulocyte colony-stimulating factor combined conditioning regimen as a postremission therapy for acute myelogenous leukemia in first complete remission

We retrospectively analyzed the outcomes of 81 patients with non-M3 acute myelogenous leukemia (AML) in first complete remission (CR1) who were treated with high-dose chemotherapy (HDCT) and autologous peripheral blood stem cell transplantation (Auto-PBSCT) by the Fukuoka Blood and Marrow Transplantation Group between 1989 and 2005. Cytogenetically, 16 patients were defined as good risk, 56 as intermediate risk, and nine as poor risk, following the Southwest Oncology Group criteria. The pre-transplant conditioning regimen consisted of high-dose busulfan, etoposide, and cytarabine (BEA regimen), combined with priming by granulocyte colony-stimulating factor (G-CSF). Disease-free survival (DFS) and overall survival at 5years were 64.0% (95% CI 52.5-73.4) and 66.4% (95% CI 54.9-75.6) after Auto-PBSCT at a median follow-up time of 103months (range 3-240months), respectively. Two patients died of transplant-related pulmonary complications 6months after Auto-PBSCT without relapse. The 5-year DFS rates of patients in the genetically good-, intermediate-, and poor-risk groups were 80.8, 64.3, and 33.3%, respectively, but there was no significant difference statistically among the risk groups (log-rank p=0.0579). These observations suggest that HDCT supported by Auto-PBSCT with the BEA regimen combined with G-CSF priming is a therapeutic option for postremission therapy of AML in CR1.

PFS: The Endpoint We Love and Love to Hate

One of the major challenges in oncology drug development is the identification of appropriate endpoints that indicate direct benefit to the patient. The U.S. Food and Drug Administration (FDA) has clearly defined meaningful clinical benefit as improvement in patient-reported symptomatology or improvement in survival and has considered these patient-directed endpoints in clinical trials as the basis for registration of new agents (1). However, the FDA has also recognized that such endpoints may be difficult to obtain and so has allowed the establishment of surrogates that may substitute for the above endpoints, often then requiring later confirmation through further clinical study. The most widely used and perhaps the most controversial surrogate is progression-free survival (PFS), which measures the amount of time from study enrollment to a prespecified point at which a tumor is no longer considered to be affected by the administered therapy, generally a 20% increase in tumor size above the starting value or an achieved nadir. Interpretation of PFS remains a challenge despite its use as an endpoint in oncology for over 40 years, illustrated in the 1969 Moertel and colleagues PFS plot (Fig. 1; ref. 2). Parenthetically, it should be noted that this 20% cutoff has never been proven to actually indicate treatment failure, as the boundary may be crossed despite ongoing tumor growth delay—efficiently termed a “cytolentic,” or cell-slowing effect. More widely discussed is the point that the determination of progression is susceptible to multiple sources of error. Those errors can introduce missing or incomplete data in randomized trials. Missing data, in turn, can cause informative censoring. This CCR Focus section delves deeply into PFS measurement with John J. Crowley, former Director of the Statistical Center of SWOG (previously known as the Southwest Oncology Group), as Guest Editor. Experts in the field identify sources of error in PFS determination, propose strategies to limit the error, and introduce two new approaches in clinical trial methodologies. These approaches, embracing an audit strategy to reduce missing data events in randomized trials, and using a new phase II/III trial design, should expedite drugs through the development pipeline and deserve a close look. As with every edition of CCR Focus, it is hoped that these articles will stimulate discussion among colleagues, inspire those already working in drug development, and inform those desiring a more in-depth understanding of this important challenge in oncology.Susan E. BatesDeputy Editor, CCR FocusNational Cancer Institute

Modeling the relationship between progression-free survival and overall survival: the phase II/III trial.

The standard phase II trial design has changed dramatically over the past decade. Randomized phase II studies have essentially become the standard phase II design in oncology for a variety of reasons. The use of these designs is motivated by concerns about the use of historical data to determine if a new agent or regimen shows promise of activity. However, randomized phase II designs come with the cost of increased study duration and patient resources. Progression-free survival (PFS) is an important endpoint used in many phase II designs. In many clinical settings, changes in PFS with the introduction of a new treatment may represent true benefit in terms of the gold standard outcome, overall survival (OS). The phase II/III design has been proposed as an approach to shorten the time of discovery of an active regimen. In this article, design considerations for a phase II/III trial are discussed and presented in terms of a model defining the relationship between OS and PFS. The design is also evaluated using 15 phase III trials completed in the Southwest Oncology Group (SWOG) between 1990 and 2005. The model provides a framework to evaluate the validity and properties of using a phase II/III design. In the evaluation of SWOG trials, three of four positive studies would have also proceeded to the final analysis and 10 of 11 negative studies would have stopped at the phase II analysis if a phase II/III design had been used. Through careful consideration and thorough evaluation of design properties, substantial gains could occur using this approach.

Toward a Science of Research Prioritization? The Use of Value of Information by Multidisciplinary Stakeholder Groups

In this issue of Medical Decision Making, Carlson and others describe the process of convening an external group of diverse stakeholders to identify 3 high-priority cancer genomics tests for further research and to rank these in order of priority for conducting further research. The external multidisciplinary stakeholder advisory group involved 13 members, including patient advocates, payers, test developers, a regulator, policy makers, and practicing oncologists. This group committed to meet over 2 years to help the South West Oncology Group (SWOG) leadership and investigators identify and prioritize future research areas and to help assess where scarce research funds would be best spent. The stakeholder group began by identifying 3 topics for research from a larger number of possible options in the area of cancer genomic tests. They were provided with a landscape review, and they developed priority-setting criteria in collaboration with the SWOG investigators to undertake this process. They identified 3 genomic tests for which further research would be useful: 1) ERCC1 expression testing for platinum-based adjuvant therapy in fully resected earlystage non–small cell lung cancer (NSCLC); 2) epidermal growth factor receptor (EGFR) mutation testing for erlotinib maintenance therapy after firstline chemotherapy in advanced NSCLC, and 3) breast cancer tumor markers (BC markers) for detection of recurrence after primary breast cancer therapy. The stakeholder group was subsequently provided with value of information (VOI) analyses to quantify the value of conducting further research on each of these genomic tests. More specifically, they were provided with expected value of perfect information (EVPI) analyses, which estimate the upper level dollar value of reducing the uncertainty about which strategy is the optimal intervention. Providing the stakeholder group with these analyses involved a number of complex steps: developing simulation models for each genomic test, calculating the EVPI, training the external group of stakeholders in understanding what these results mean and how to use them, and discussing the results and reranking their choices based on what they may have learned from the VOI analyses. Indeed, Carlson and colleagues describe how the stakeholder group ranking of the tests changed from 1) ERCC1, 2) EGFR, 3) BC markers to 1) ERCC1, 2) BC markers, 3) EGFR. The BC markers ranked higher relative to EGFR compared with the initial prioritization vote in part because the VOI analyses helped the stakeholders appreciate the benefits of studying a technology associated with high uncertainty. Of the stakeholders, 69% reported finding these analyses helpful and 53% reported that they changed their priority ranking because of the information provided by the VOI results. The science of research prioritization has made important advances over the past 20 years. Research prioritization has moved from an approach largely based on convening groups of experts for unstructured discussions to a scientific process that studies who and how to engage in priority-setting decisions and provides measurements of the value provided Received 11 March 2013 from Patient Centered Outcomes Research Institute (RLF); Department of Medicine, Department of Economics, and the Harris School of Public Policy Studies at the University of Chicago (DOM). Accepted for publication 20 March 2013.

Clarifying the role of salvage radiotherapy

In this issue of CUAJ, the Genito-Urinary Radiation Oncologists of Canada (GUROC) group addresses several very important issues relating to salvage radiotherapy following biochemical relapse after radical prostatectomy.1 With the published results from the EORTC (European Organisation for Research and Treatment of Cancer) 229112 and SWOG (Southwest Oncology Group) 8794 (NCIC PR-2)3 studies and the recent update of the latter trial showing metastasis-free and overall survival benefit for adjuvant radiotherapy for pT3 disease,4 the questions relating to salvage radiotherapy deserve more discussion. A fundamental issue is the attitude of urologists toward the use of local salvage radiotherapy. There is a wide range of opinions among practitioners in various countries about whether radiotherapy should be recommended for prostate-specific antigen (PSA) relapse after radical prostatectomy, with those in favour ranging from 13% to 91%. A safe assumption is that the Canadian position is more moderate and intermediate. The dichotomy in practice pattern stems largely from the lack of evidence from randomized controlled trials. The GUROC consensus meeting included a discussion on 2 retrospective multi-institutional analyses by Stephenson and colleagues5,6 that revealed some surprising results. The 6-year progression-free probability was 32% for all participants, and even the most unfavourable group (those with a Gleason score of 8–10, negative margins or a serum PSA level doubling time of < 10 mo, i.e., those with a high probability of distant metastatic disease) had a 1 in 5 chance of achieving sustained progression-free response provided the local salvage radiotherapy was delivered when the serum PSA level was less than 2.0 μg/L. Remarkably, when such patients were treated when the serum PSA level was less than 0.5 μg/L, 41% were disease-free at 6 years. These findings have led to the very reasonable recommendation by the GUROC for much earlier referral for salvage radiation consideration, even for patients with high-risk features. Another potential consequence of earlier radiotherapy may be obviation or deferral of androgen ablation (demonstrated in the SWOG 8794, NCIC PR-2 adjuvant radiotherapy trial3,4), with the inherent benefits of avoiding hormonal therapy. Although multivariable analysis from the retrospective multicentre study suggested a benefit for neoadjuvant androgen ablation6 the role of adjunctive hormonal therapy with salvage radiotherapy remains unsettled. The upcoming MRC (Medical Research Council) (NCIC PR-13) study hopes to answer some of the questions, including the timing and duration of hormonal therapy. The trial design appears somewhat complicated and imposing at first glance, but is in fact very logical and straightforward, and by providing an opportunity for most radical prostatectomy patients to participate at some point in the variable clinical course, the MRC will hopefully maximize accrual and eventually provide some valuable answers. Sia and colleagues referred to the potential role of endorectal magnetic resonance imaging in guiding and planning salvage radiotherapy. Another imaging modality is the ProstaScint (Cytogen Corporation) capromab pendetide scan.7 More promising would be the fusion or coregistration of ProstaScint with another imaging modality such as CT.8,9 Ongoing studies with newer imaging techniques will assist radiation oncologist with making decisions about and fine-tuning salvage radiotherapy for the patient with biochemical relapse after radical prostatectomy. The recommendations by GUROC, with acceptance and participation from urologists, should clarify the role of salvage radiotherapy after radical prostatectomy.

Cytoreductive nephrectomy: a treatment of the past

Cytoreductive nephrectomy: a treatment of the past

SWOG S0353: Phase II Trial of Intravesical Gemcitabine in Patients with Nonmuscle Invasive Bladder Cancer and Recurrence after 2 Prior Courses of Intravesical Bacillus Calmette-Guérin

Prior phase II studies of intravesical gemcitabine have shown it to be active and well tolerated, but durable responses in patients with nonmuscle invasive bladder cancer who have experienced recurrence after bacillus Calmette-Guérin treatment are uncommon. We performed a multi-institutional phase II study within the SWOG (Southwest Oncology Group) cooperative group to evaluate the potential role of gemcitabine induction plus maintenance therapy in this setting. Eligible patients had recurrent nonmuscle invasive bladder cancer, stage Tis (carcinoma in situ), T1, Ta high grade or multifocal Ta low grade after at least 2 prior courses of bacillus Calmette-Guérin. Patients were treated with 2 gm gemcitabine in 100 cc normal saline intravesically weekly × 6 and then monthly to 12 months. Cystoscopy and cytology were performed every 3 months, with biopsy at 3 months and then as clinically indicated. Initial complete response was defined as negative cystoscopy, cytology and biopsy at 3 months. A total of 58 patients were enrolled in the study and 47 were evaluable for response. Median patient age was 70 years (range 50 to 88). Of the evaluable patients 42 (89%) had high risk disease, including high grade Ta in 12 (26%), high grade T1 in 2 (4%) and carcinoma in situ in 28 (60%) with or without papillary lesions. At the initial 3-month evaluation 47% of patients were free of disease. At 1 year disease had not recurred in 28% of the 47 patients, all except 2 from the high risk group, and at 2 years disease had not recurred in 21%. Intravesical gemcitabine has activity in high risk nonmuscle invasive bladder cancer and offers an option for patients with recurrence after bacillus Calmette-Guérin who are not suitable for cystectomy. However, less than 30% of patients had a durable response at 12 months even with maintenance therapy.

Significance of FAB subclassification of “acute myeloid leukemia, NOS” in the 2008 WHO classification: analysis of 5848 newly diagnosed patients

AbstractThe World Health Organization (WHO) classifies acute myeloid leukemia (AML) via genetic, immunophenotypic, biological, and clinical features. Still, “AML, not otherwise specified (NOS)” is further subdivided based on morphologic criteria similar to those of the French-American-British (FAB) classification. We analyzed the relevance of this practice in patients with newly diagnosed “AML, NOS” with available FAB information undergoing curative-intent therapy in trials of 3 cooperative study groups (Dutch-Belgian Cooperative Trial Group for Hematology/Oncology [HOVON], UK Medical Research Council/National Cancer Research Institute [MRC/NCRI], and the US cooperative group Southwest Oncology Group [SWOG]) or at MD Anderson Cancer Center. Ignoring information on NPM1 and CEBPA, 5848 patients met criteria for “AML, NOS.” After multivariate adjustment, FAB M0 was independently associated with significantly lower likelihood of achieving complete remission and inferior relapse-free and overall survival as compared with FAB M1, M2, M4, M5, and M6, with inconclusive data regarding M7. However, restricting attention to known NPM1neg patients, FAB M0 was no longer associated with worse outcomes; restricting attention to patients known to be NPM1neg/CEPBAneg (ie, honoring the provisional entities of “AML with mutated NPM1” and “AML with mutated CEBPA”) did not affect this result. In conclusion, in the 2008 WHO classification scheme, FAB subclassification does not provide prognostic information for “AML, NOS” cases if data on NPM1 and CEBPA mutations are available.

The clinical characteristics and prognostic significance of MN1 gene and MN1-associated microRNA expression in adult patients with de novo acute myeloid leukemia

This study aimed to determine the clinical characteristics and prognostic significance of the meningioma 1 (MN1) gene and MN1-associated microRNA expression in Chinese adult de novo acute myeloid leukemia (AML) patients. The expression level of MN1, microRNA-20 (miR-20a), and microRNA-181b (miR-181b) in bone marrow mononuclear cells was measured in 158 newly diagnosed AML patients and 20 cases of normal healthy donors by real-time quantitative reverse transcriptase polymerase chain reaction. All AML patients significantly overexpressed MN1 at the level of 0.01983 (P < 0.001) compared with normal controls. High MN1 expression was associated with spleen involvement (P = 0.037), NPM1 wild type (P = 0.001), lower miR-20a expression levels (P = 0.015), and higher miR-181b expression levels (P = 0.035). MiR-20a (P = 0.029) and miR-181b (P = 0.017) overexpressed in the bone marrow cells of patients with certain subtypes of AML compared with healthy donors. High MN1 expressers had lower complete remission (CR) rates and shorter overall survival (OS) within the Southwest Oncology Group classification. In multivariable models, high MN1 expression was associated with worse CR rates (P = 0.01), relapse-free survival (RFS; P = 0.02), and OS (P = 0.02); high miR-20a expression was associated with higher CR rates (P = 0.008) and longer OS (P = 0.04), whereas high miR-181b expression was associated with lower CR rates (P = 0.03), and shorter RFS (P = 0.045) and OS (P = 0.017). High MN1 expression confers worse prognosis in Chinese adult patients with de novo AML. MN1 gene and MN1-associated microRNAs provide clinical prognosis of AML patients and may refine their molecular risk classification.

Randomized Phase III Trial of ABVD Versus Stanford V With or Without Radiation Therapy in Locally Extensive and Advanced-Stage Hodgkin Lymphoma: An Intergroup Study Coordinated by the Eastern Cooperative Oncology Group (E2496)

Although ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) has been established as the standard of care in patients with advanced Hodgkin lymphoma, newer regimens have been investigated, which have appeared superior in early phase II studies. Our aim was to determine if failure-free survival was superior in patients treated with the Stanford V regimen compared with ABVD. The Eastern Cooperative Oncology Group, along with the Cancer and Leukemia Group B, the Southwest Oncology Group, and the Canadian NCIC Clinical Trials Group, conducted this randomized phase III trial in patients with advanced Hodgkin lymphoma. Stratification factors included extent of disease (localized v extensive) and International Prognostic Factors Project Score (0 to 2 v 3 to 7). The primary end point was failure-free survival (FFS), defined as the time from random assignment to progression, relapse, or death, whichever occurred first. Overall survival, a secondary end point, was measured from random assignment to death as a result of any cause. This design provided 87% power to detect a 33% reduction in FFS hazard rate, or a difference in 5-year FFS of 64% versus 74% at two-sided .05 significance level. There was no significant difference in the overall response rate between the two arms, with complete remission and clinical complete remission rates of 73% for ABVD and 69% for Stanford V. At a median follow-up of 6.4 years, there was no difference in FFS: 74% for ABVD and 71% for Stanford V at 5 years (P = .32). ABVD remains the standard of care for patients with advanced Hodgkin lymphoma.

Editorial Comment: Safety of bronchovascular reconstructions after induction therapy

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Cooperative Group Clinical Trials in General Thoracic Surgery: Report From the 2012 Robert Ginsberg Clinical Trials Meeting of the General Thoracic Surgical Club

At the 25th Annual General Thoracic Surgical Club meeting in March 2012, the major cooperative groups presented updates on clinical trials at the Robert Ginsberg Clinical Trials Meeting. There were 57 members in attendance. Representatives from the Radiation Treatment Oncology Group (RTOG), American College of Surgeons Oncology Group (ACOSOG), Cancer and Leukemia Group B (CALGB), Southwest Oncology Group (SWOG), National Cancer Institute of Canada Clinical Trials Group (NCIC), and the Eastern Cooperative Oncology Group (ECOG) presented an overview of trials currently accruing or in development. These include oncologic trials that thoracic surgeons are currently accruing patients to in North America. The purpose of this review is to centralize the information to assist surgeons enrolling patients into oncologic clinical trials in thoracic surgery.

2-weekly versus 3-weekly docetaxel for prostate cancer

In the early 1990s, a phase 1 trial of docetaxel administered in 2-weekly and 3-weekly schedules showed that a suitable dose for study in phase 2 trials was 100 mg/m2 every 3 weeks. 1 Extra JM Rousseau F Bruno R Clavel M Le BN Marty M Phase I and pharmacokinetic study of Taxotere (RP 56976; NSC 628503) given as a short intravenous infusion. Cancer Res. 1993; 53: 1037-1042 PubMed Google Scholar The 2-weekly schedule was associated with unacceptable side-effects when doses were greater than 55 mg/m2. By 2000, 3-weekly docetaxel-based regimens had become the standard of care for patients with castration-resistant prostate cancer. 2 Petrylak DP Docetaxel (Taxotere) in hormone-refractory prostate cancer. Semin Oncol. 2000; 27: 24-29 PubMed Google Scholar Beer and colleagues 3 Beer TM Pierce WC Lowe BA Henner WD Phase II study of weekly docetaxel in symptomatic androgen-independent prostate cancer. Ann Oncol. 2001; 12: 1273-1279 Crossref PubMed Scopus (180) Google Scholar reported that weekly docetaxel alone was potentially equally active and less toxic than 3-weekly combined regimens. TAX 327 4 Tannock IF de Wit R Berry WR et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004; 351: 1502-1512 Crossref PubMed Scopus (4876) Google Scholar assessed 75 mg/m2 3-weekly docetaxel or 30 mg/m2 weekly docetaxel administered in 5 of every 6 weeks, combined with prednisone and compared these regimens with a standard chemotherapy regimen of prednisone and mitoxantrone. In TAX 327, 3-weekly docetaxel was associated with a significant improvement in survival compared with mitoxantrone, whereas weekly docetaxel was not. In the Southwest Oncology Group 9916 trial, 60 mg/m2 3-weekly docetaxel combined with estramustine was compared with mitoxantrone. 5 Petrylak DP Tangen CM Hussain MH et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004; 351: 1513-1520 Crossref PubMed Scopus (3254) Google Scholar The docetaxel dose was escalated to 70 mg/m2 in patients without grade 3 or higher toxic effects in the first cycle. Estramustine seemed to add no benefit. The US Food and Drug Administration, therefore, the approved dose of 75 mg/m2 docetaxel every 3 weeks in combination with oral prednisone based on these two phase 3 randomised trials. 2-weekly versus 3-weekly docetaxel to treat castration-resistant advanced prostate cancer: a randomised, phase 3 trialAdministration of docetaxel every 2 weeks seems to be well tolerated in patients with castration-resistant advanced prostate cancer and could be a useful option when 3-weekly single-dose administration is unlikely to be tolerated. Full-Text PDF

A randomized controlled Alzheimer's disease prevention trial's evolution into an exposure trial: The preadvise trial

To summarize the ongoing Prevention of Alzheimer’s Disease (AD) by Vitamin E and Selenium (PREADViSE) trial as an ancillary study to SELECT (a large prostate cancer prevention trial) and to present the blinded results of the first year as an exposure study. PREADViSE was designed as a double blind randomized controlled trial (RCT). SELECT terminated after median of 5.5 years of exposure to supplements due to a futility analysis. Both trials then converted into an exposure study. In the randomized component PREADViSE enrolled 7,547 men age 62 or older (60 if African American). Once the trial terminated 4,246 of these men volunteered for the exposure study. Demographics were similar for both groups with exposure volunteers having baseline mean age 67.3 ± 5.2 years, 15.3 ± 2.4 years of education, 9.8% African Americans, and 22.0% reporting a family history of dementia. In the RCT men were randomly assigned to either daily doses of 400 IU of vitamin E or placebo and 200 µg of selenium or placebo using a 2×2 factorial structure. In the RCT, participants completed the Memory Impairment Screen (MIS), and if they failed, underwent a longer screening (based on an expanded Consortium to Establish a Registry in AD [CERAD] battery). CERAD failure resulted in visits to their clinician for medical examination with records of these examinations forwarded to the PREADViSE center for further review. In the exposure study, men are contacted by telephone and complete the telephone version of the memory impairment screen (MIS-T) screen. If they fail the MIS-T, a Modified Telephone Interview of Cognitive Status (TICS-M) exam is given. A failed TICS-M exam also leads to a visit to their clinician for an in-depth examination and forwarding of records for a centralized consensus diagnosis by expert clinicians. A subgroup of the men who pass the MIS-T also take the TICS-M exam for validation purposes. While this ancillary trial was open to all 427 SELECT clinical sites, only 130 (30.0%) of the sites chose to participate in PREADViSE. Staff turnover at the sites presented challenges when training persons unfamiliar with cognitive testing procedures to conduct the memory screens. In the RCT few participants (1.6%) failed the MIS screen and among those who passed this screen a significant practice effect was encountered. In the exposure study 3,581 men were reached by phone in year 1, 15.7% could not be reached after 5 calls, and of those contacted 6.0% refused the screen even after consenting to the procedures at their clinical site. Most notable is that the failure rate for the MIS-T increased fourfold to 7.2%. Of the 257 men who took the TICS-M, 84.0% failed and were asked to contact their physicians for a more detailed memory assessment, and approximately half of these had some form of dementia or cognitive impairment. Several of these dementia cases are not AD. Partnering with SELECT led to an AD prevention trial conducted at a very reasonable cost by taking advantage of the experience and efficient clinical trial management found in a cancer cooperative group (Southwest Oncology Group or SWOG). Once unblinded, the RCT and exposure study data have the potential to yield new information on long term exposure to antioxidant supplements under controlled conditions.