Southwest Oncology Group Clinical Trials Research Articles

Geographic Distribution and Survival Outcomes for Rural Patients With Cancer Treated in Clinical Trials

Studies showing that patients with cancer from rural areas have worse outcomes than their urban counterparts have relied on cancer population data and did not account for differences in access to care. Clinical trial patients receive protocol-directed care by design, so large clinical trial databases are ideal for examining the impact of rural vs urban residency on outcomes. To compare the geographic distribution and survival outcomes for rural vs urban patients with cancer treated in clinical trials. In this comparative effectiveness retrospective cohort analysis, 36 995 patients from all 50 states enrolled in 44 phase 3 and phase 2/3 SWOG (formerly the Southwest Oncology Group) treatment trials from January 1, 1986, to December 31, 2012, were examined. Seventeen different cancer-specific analysis cohorts were constructed. Data through January 30, 2018, were analyzed. Rural vs urban residency was defined using the Rural-Urban Continuum Codes developed by the US Department of Agriculture. Multivariate Cox regression was used to estimate the association of residency with overall survival, progression-free survival, and cancer-specific survival, controlling for major disease-specific prognostic factors and demographic variables and stratifying by study. Different definitions of rurality were examined. The distribution of rural vs urban patients by geographic region was described. Overall, 27.7% of patients were 65 years or older (range across 17 cohort analyses, 7.8%-74.5%), 40.3% were female in the non-sex-specific analyses (range across 17 cohort analyses, 28.1%-45.9%), and 10.8% were black (range across 17 cohort analyses, 1.9%-22.4%). Overall, 19.4% of patients (7184 of 36 995) were from rural locations. Rural patients were more likely to be aged 65 years or older (rural, 30.7% aged ≥65 years vs urban, 27.0% aged ≥65 years; difference, 3.7%; 95% CI, 2.5%-4.9%; P < .001), were less likely to be black (rural, 5.4% vs urban, 12.1%; difference, 6.7%; 95% CI, 6.1%-7.3%; P < .001), were similar with respect to sex (rural, 40.4% female vs urban, 39.7% female; difference, 0.6%; 95% CI, -1.4% to 2.6%; P = .53), and were well represented within major US geographic regions (West, Midwest, South, and Northeast). Clinical prognostic factors were similar. In multivariable regression, rural patients with adjuvant-stage estrogen receptor-negative and progesterone receptor-negative breast cancer had worse overall survival (hazard ratio, 1.27; 95% CI, 1.06-1.51; P = .008) and cancer-specific survival (hazard ratio, 1.26; 95% CI, 1.04-1.52; P = .02). No other statistically significant differences for overall, progression-free, or cancer-specific survival were found. Results were consistent regardless of the definition of rurality. Rural and urban patients with uniform access to cancer care through participation in a SWOG clinical trial had similar outcomes. This finding suggests that improving access to uniform treatment strategies for patients with cancer may help resolve the disparity in cancer outcomes between rural and urban patients.

Association of Cardiovascular Risk Factors With Cardiac Events and Survival Outcomes Among Patients With Breast Cancer Enrolled in SWOG Clinical Trials.

Background Cardiovascular disease is the primary cause of death among patients with breast cancer. However, the association of cardiovascular-disease risk factors (CVD-RFs) with long-term survival and cardiac events is not well studied. Methods We examined SWOG (formerly the Southwest Oncology Group) breast cancer trials from 1999 to 2011. We identified baseline diabetes, hypertension, hypercholesterolemia, and coronary artery disease by linking trial records to Medicare claims. The primary outcome was overall survival. Patients with both baseline and follow-up claims were examined for cardiac events. Cox regression was used to assess the association between CVD-RFs and outcomes. Results We identified 1,460 participants older than 66 years of age from five trials; 842 were eligible for survival outcomes analysis. At baseline, median age was 70 years, and median follow-up was 6 years. Hypertension (73%) and hypercholesterolemia (57%) were the most prevalent conditions; 87% of patients had one or more CVD-RF. There was no association between any of the individual CVD-RFs and overall survival except for hypercholesterolemia, which was associated with improved overall survival (hazard ratio [HR], 0.73; 95% CI, 0.57 to 0.93; P = .01). With each additional CVD-RF, there was an increased risk of death (HR, 1.23; 95% CI, 1.08 to 1.40; P = .002), worse progression-free survival (HR, 1.12; 95% CI, 1.00 to 1.25; P = .05), and marginally worse cancer-free survival (HR, 1.15; 95% CI, 0.99 to 1.34; P = .07). The relationship between baseline CVD-RFs and cardiac events was analyzed in 736 patients. A strong linear association between the number of CVD-RFs and cardiac event was observed (HR per CVD-RF, 1.41; 95% CI, 1.17 to 1.69; P < .001). Conclusion Among participants in clinical trials, each additional baseline CVD-RF was associated with an increased risk of cardiac events and death. Efforts to improve control of modifiable CVD-RFs are needed, especially among those with multiple risk factors.

Comorbidities and Risk of Chemotherapy-Induced Peripheral Neuropathy Among Participants 65 Years or Older in Southwest Oncology Group Clinical Trials.

Neuropathy is a debilitating toxicity associated with various chemotherapy agents. We evaluated the association between common comorbid conditions and the development of peripheral neuropathy in patients treated with taxane-based chemotherapy. We examined the Southwest Oncology Group database to identify phase II and III trials that included taxane therapy from 1999 to 2011. We linked the Southwest Oncology Group clinical records to Medicare claims data according to Social Security number, sex, and date of birth. The following disease conditions potentially associated with peripheral neuropathy were evaluated: diabetes, hypothyroidism, hypercholesterolemia, hypertension, varicella zoster, peripheral vascular disease, and autoimmune diseases. Multivariate logistic regression was used to model the odds of experiencing grade 2 to 4 neuropathy. A total of 1,401 patients from 23 studies were included in the analysis. Patients receiving paclitaxel were more likely to experience grade 2 to 4 neuropathy compared with docetaxel (25% v 12%, respectively; OR, 2.20; 95% CI, 1.52 to 3.18; P < .001). The inclusion of a platinum agent was also associated with greater neuropathy (OR, 1.68; 95% CI, 1.18 to 2.40; P = .004). For each increase in age of 1 year, the odds of neuropathy increased 4% (P = .006). Patients with complications from diabetes had more than twice the odds of having neuropathy (OR, 2.13; 95% CI, 1.31 to 3.46; P = .002) compared with patients with no diabetes. In contrast, patients with autoimmune disease were half as likely to experience neuropathy (OR, 0.49; 95% CI, 0.24 to 1.02; P = .06). The other conditions were not associated with neuropathy. We found that in addition to drug-related factors, age and history of diabetes were independent predictors of the development of chemotherapy-induced peripheral neuropathy. Interestingly, we also observed that a history of autoimmune disease was associated with reduced odds of neuropathy. Patients with diabetic complications may choose to avoid paclitaxel or taxane plus platinum combination therapies if other efficacious options exist.

Early mortality in acute myeloid leukemia

The Southwest Oncology Group (SWOG) described the expected early mortality rate (EMR) for patients with non-M3 AML by age enrolled in clinical trials, but it is unclear how generalizable this data is. We sought to compare SWOG's reported EMR to that of the general population by utilizing the case listing session of SEER 18 matched to the accrual periods of the SWOG studies. 26,272 patients were identified within SEER compared to 968 in the SWOG cohort with mortality data. The EMR was 26.7% (7022 events) in the SEER cohort versus 12.2% (116) in the SWOG cohort. The EMR was higher in the SEER cohort in every studied age group and definition of EMR. Stepwise logistic regression analysis identified increasing age, black race (OR 1.15, CI 1.03-1.29, p<0.01), and monocytic differentiation (OR 1.55, CI 1.27-1.89, p<0.01) as predictors of higher EMR. This study demonstrates that EMR in patients with non-M3 AML is higher in the general patient population than reported in SWOG clinical trials.

Enhancing Nurse Contributions to SWOG Clinical Trials

To review nursing research contributions and future opportunities for nurses in cooperative oncology group research in SWOG (formerly Southwest Oncology Group). Peer-reviewed journal articles, grant submissions, professional manuals, research policy reports, and meeting minutes. Nurses and nurse researchers have had active roles in SWOG research involving quality of life, symptom management, recruitment and adherence, and data quality. There are opportunities for nurses to make greater contributions to cooperative group research, particularly in cancer survivorship, health outcomes, and quality of life. Nursing science and evidence-based practice will be enhanced by conducting nursing research in the multi-site cooperative group setting.

Influence of residual normal metaphases in acute myeloid leukemia patients with monosomal karyotype

Influence of residual normal metaphases in acute myeloid leukemia patients with monosomal karyotype

Genetic Polymorphisms In Oxidative Stress-Related Genes Correlated with Outcome Following Anthracycline-Based Therapy for Aggressive B-Cell Non-Hodgkin Lymphomas

AbstractAbstract 321Gene expression profiling of newly diagnosed diffuse large B-cell lymphomas shows a correlation between the expression of oxidative stress-related genes and patient prognosis following chemotherapy. Anthracyclines and cyclophosphamide used in lymphoma therapy are known to work, at least in part, through oxidative stress. We hypothesized that single nucleotide polymorphisms (SNPs) in oxidative stress-related genes may contribute to clinical outcomes and/or the development of hematologic toxicities for patients treated with curative intent anthracycline-based therapies for aggressive B-cell Non-Hodgkin lymphomas. Our study involved 473 patients enrolled in 7 prior Phase II or Phase III Southwest Oncology Group clinical trials. DNA for the SNP analyses was obtained from banked, paraffin-embedded diagnostic tissue. Genotyping was performed for 72 SNPs in 33 oxidative stress-related genes. After excluding pathologically or clinically ineligible patients and those with SNP call rates <85%, 345 patients were included in the analysis. All analyses were stratified on clinical trial and adjusted by IPI score. We found polymorphic alleles in aldo-keto reductase family 1 member C3 (AKR1C3), inducible nitric oxide synthase (NOS2) and myeloperoxidase (MPO) were associated with patient outcomes (see table below). AKR1C3 is a member of a superfamily of oxidoreductases. The diverse reactions catalyzed by these enzymes include the conversion of steroid hormones (e.g., glucocorticoids) to more potent forms and the repair of oxidative damage to proteins and lipids. The AKR1C3 SNP rs10508293, located in intron 4 of the gene, is of unknown functional significance. NOS2 produces nitric oxide, which is an important signaling molecule. However, nitric oxide can also increase oxidative stress by reacting with superoxide to produce the potent oxidant, peroxynitrite. The NOS2 polymorphism rs1060826 relevant to this study is located in exon 22. It does not change the amino acid sequence in the protein. MPO is found in neutrophils and macrophages where it produces hypochlorous acid. This enzyme can also activate xenobiotics and its products can cause protein oxidation. For our analysis of the MPO gene, we chose the -764A/G SNP (rs2243828) as a proxy for the -463G/A SNP (rs2333227). The latter polymorphism affects the transcription rate of the gene. Importantly, it has been linked to survival rates for breast cancer patients treated with cyclophosphamide. The -764A/G SNP was used due to technical difficulty genotyping the -463G/A SNP. There is 100% genotype concordance between these two SNPs. We found that patients with at least 1 copy of the AKR1C3 T allele had better overall and progression-free survival than those with the CC genotype. We also found that patients who were homozygous for the NOS2 G allele had better overall and progression-free survival than those with the AA genotype. In complete agreement with the study of breast cancer patients, the MPO GG genotype was associated with worse overall and progression-free survival, as compared to the AA genotype. Our additional tests for polymorphisms associated with hematologic toxicity identified the -212A/G SNP (rs1883112) in NCF4. This gene encodes p40-phox, a regulatory subunit of NAD(P)H oxidase. The NCF4 GG genotype has previously been linked to a two-fold reduction in the risk of anthracycline-induced cardiotoxicity among Non-Hodgkin lymphoma patients. We now report a similar reduction in hematologic toxicity for patients homozygous for the G allele, as compared to those with the AA genotype (hazard ratio, 0.48; 95% confidence interval, 0.19–0.95; unadjusted P = 0.038). This is the first report linking polymorphisms in AKR1C3, NOS2, MPO and NCF4 with outcome in aggressive lymphomas. Further work is needed to elucidate the mechanism(s) by which the SNP genotypes would influence treatment outcome. Disclosures:No relevant conflicts of interest to declare.

Fc Gamma Receptor 3a Genotype Predicts Overall Survival for Follicular Lymphoma Patients Treated On Southwest Oncology Group Trials with Combined Monoclonal Antibody Plus Chemotherapy but Not Chemotherapy Alone.

Abstract 111▪▪This icon denotes an abstract that is clinically relevant.Background: Fc gamma receptor (FCGR) polymorphisms have previously been linked to outcome in follicular lymphoma (FL) patients treated with the anti-CD20 monoclonal antibody (mAB), rituximab, as a monotherapy. This is thought to be due to differences in binding affinity of host effector cells for the therapeutic antibody between individuals with different genotypes. In particular, the R/R genotype of FCGR2A and the F/F genotype of FCGR3A have been correlated with a less favorable outcome compared to the higher affinity FCGR genotypes H/H and V/V, respectively. Previous studies have had relatively low statistical power and have used consecutive series of patients and the prognostic significance remains largely untested. Therefore, we questioned whether this association would hold up in the context of a chemotherapy regimen combined with a monoclonal antibody in a larger set of patients treated on Southwest Oncology Group (SWOG) clinical trials. Specifically, we wished to test whether the genotypes were predictive of survival following all treatment regimens, or just the regimens containing mAB.Methods: Excess paraffin embedded tissue from 146 patients previously treated on SWOG clinical trials with chemotherapy alone (protocol S8809, N=70) or combined chemotherapy and mAB (anti-CD20 antibodies rituximab or I-131 tositumomab on protocols S9800 and S9911, N=33 and 43 respectively) were analyzed. DNA was extracted using the Qiagen RNA/DNA kit, then assayed for the R131H polymorphism (rs1801274) in FCGR2A and the V158F polymorphism (rs396991) for FCGR3A using a TaqMan SNP assay. Stratified Cox regression was used to assess marker associations with overall survival (OS).Results: Patients in each clinical trial had similar IPI and FLIPI scores. Overall frequencies of the FCGR2A genotypes were 27% H/H, 54% R/H, 16% R/R. Frequencies of the FCGR3A genotypes were 36% FF, 41% VF, and 8% VV. There were no differences in genotype frequencies between trials and no associations between genotypes. Neither FCGR 2A nor 3A were associated with survival in S8809 (chemotherapy only). In S9800 and S9911 (chemotherapy + mAb), having at least 1 FCGR2A H allele was weakly associated with improved OS vs R/R (hazard ratio [HR] 0.42, 95% confidence interval [CI] 0.16–1.12, p=0.06), and having at least 1 FCGR3A V allele was more strongly associated with improved OS vs F/F (HR 0.28, 95% CI 0.10–0.80, p=0.02), with 5 year OS of 72% for F/F, 97% for V/F, and 100% for V/V. The interaction term between antibody usage and FCGR3A genotype was significant (p=.01), suggesting that the effect of this marker may be truly different in 9800/9911 than in 8809. All survival analyses held up after adjustment for IPI score.Summary: Overall, we found an association of FCGR3A genotype with overall survival in patients treated with chemo + mAB (rituximab or I-131 tositumomab). An association with survival was not identified in patients treated with chemotherapy alone. Interestingly, in the analysis of the overall dataset we found significant evidence of an interaction between mAb therapy (S9800/S9911 vs. S8809) and FCGR3A. This study suggests that FCGR3A polymorphism status may be predictive of survival in FL patients given mAB-containing treatment as opposed to any treatment in general. Therefore, FCGR3A polymorphism status may be an important factor to consider in designing new FL trials with mAB-containing regimens. Disclosures:Persky:Millennium, The Takeda Oncology Company: Consultancy, Research Funding. Dornan:Genentech, Inc.: Employment, Equity Ownership. Fisher:Genentech: Honoraria, Speakers Bureau. Maloney:Genentech, Biogen Idec, GSK: Membership on an entity's Board of Directors or advisory committees. Miller:Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Research Funding; Milleneum: Consultancy. Rimsza:Genentech: Research Funding.

Review: Cooperative group trials — Southwest Oncology Group (SWOG) innovations in advanced prostate cancer

The major goals of the SWOG-GU committee in the area of advanced prostate cancer are to improve the survival and quality of life of patients with advanced prostate cancer. SWOG trials have examined the role of combined androgen blockade, intermittent androgen deprivation, and the early application of chemotherapy in castration-naïve disease. In addition, they have contributed to advancing the current chemotherapy standard of docetaxel plus prednisone, and ongoing trials seek to improve upon that standard. Finally, surrogate endpoints have been identified and markers of treatment response or resistance with novel technology are under active investigation. This review highlights findings from recent SWOG clinical trials for advanced prostate cancer, emphasizing the clinical impact and future applications of the data.

Nitric oxide synthase variants and disease-free survival among treated and untreated breast cancer patients in a Southwest Oncology Group clinical trial.

Numerous chemotherapeutic agents are cytotoxic through generation of reactive species, and variability in genes related to oxidative stress may influence disease-free survival (DFS). We examined relationships between DFS and variants in NOS3, as well as NQO1, NQO2, and CBR3, among treated and untreated breast cancer patients in a Southwest Oncology Group clinical trial (S8897). In the parent trial, women were assigned according to prognostic features; the high-risk group was randomized to cyclophosphamide, i.v. methotrexate, and 5-fluorouracil or to cyclophosphamide, i.v. doxorubicin, and 5-fluorouracil +/- tamoxifen, and the low-risk group did not receive adjuvant therapy. We extracted DNA from normal lymph node tissue and examined functional polymorphisms in NOS3, NQO1, NQO2, and CBR3, in relation to DFS, using Cox proportional hazard model. There were significant interactions between DFS, adjuvant therapy, and NOS3 Glu298Asp and -786 polymorphisms, alone and in combination (P for interaction = 0.008). When NOS3 genotypes were combined, women with genotypes encoding for lower nitric oxide who received chemotherapy had a >2-fold increase in hazard of progression (hazard ratio, 2.32; 95% confidence interval, 1.26-4.25), whereas there was reduced risk for those who did not receive adjuvant therapy (hazard ratio, 0.42; 95% confidence interval, 0.19-0.95). There were no associations between the other genotypes and DFS in either group. Variants encoding lower activity of NOS3 may affect outcomes in breast cancer patients, with the direction of risk differing depending on chemotherapy status. These results may mirror the known dual functions of nitric oxide and nitric oxide synthase, depending on oxidative environment.

Polymorphisms in DNA repair genes and therapeutic outcomes of AML patients from SWOG clinical trials

AbstractRepair of damage to DNA resulting from chemotherapy may influence drug toxicity and survival in response to treatment. We evaluated the role of polymorphisms in DNA repair genes APE1, XRCC1, ERCC1, XPD, and XRCC3 in predicting therapeutic outcomes of older adults with acute myeloid leukemia (AML) from 2 Southwest Oncology Group (SWOG) clinical trials. All patients received standard chemotherapy induction regimens. Using logistic and proportional hazards regression models, relationships between genotypes, haplotypes, and toxicities, response to induction therapy, and overall survival were evaluated. Patients with XPD Gln751C/Asp312G (‘D‘) haplotype were more likely to have complete response (OR = 3.06; 95% CI, 1.44-6.70) and less likely to have resistant disease (OR = 0.32; 95%CI, 0.14-0.72) than patients with other haplotypes. ERCC1 polymorphisms were significantly associated with lung (P = .037) and metabolic (P = .041) toxicities, and patients with the XRCC3 241Met variant had reduced risk of liver toxicity (OR = 0.32; 95%CI, 0.11-0.95). Significant associations with other toxicities were also found for variant XPD genotypes/haplotypes. These data from clinical trials of older patients treated for AML indicate that variants in DNA repair pathways may have an impact on both outcomes of patients and toxicities associated with treatments. With validation of results in larger samples, these findings could lead to optimizing individual chemotherapy options.

Very Late Antigen-4 (VLA-4) Expression by AML Blasts: Correlation of VCAM-1 Binding to Overall Survival.

Adhesion of acute myeloid leukemia (AML) blasts in the bone marrow (BM) microenvironment is known to protect the cells from chemotherapy-induced apoptosis. Understanding the mechanisms of blast cell adhesion and adhesion-mediated chemotherapy resistance may be critical to improving response to chemotherapy. One study in AML patients (pts) proposed that expression of the adhesion receptor, VLA-4, is associated with chemotherapy resistance, leading to reduced survival (Matsunaga et al. 2003). VLA-4, composed of α4 and β1, binds to both the CS-1 domain of fibronectin (Fn) and vascular cell adhesion molecule-1 (VCAM-1), and has a major role in retaining stem/progenitor cells within the BM. We examined frozen BM samples from 175 AML pts (age 18–80, median 48) who underwent induction chemotherapy with anthracycline and cytarabine on Southwest Oncology Group clinical trials. Thawed samples were incubated in serum containing media with IL-3 and SCF for 16h prior to analysis. To assess the effect of freezing and thawing, we examined VLA-4 expression by cell lines and fresh versus frozen AML BM samples treated similarly, and found no difference in % expression. Flow cytometry was performed with gating on blasts by both forward vs. side scatter and CD45 vs. side scatter, and on viable cells by exclusion of 7-AAD. Both % positive cells and mean fluorescence intensity were measured. VLA-4 expression varied widely, with mean expression 60.6% (range 6.2–99.6%) for α4. VLA-4 functional adhesion was also measured. An in vitro cell adhesion assay to Fn peptide CH-296, performed on 20 randomly selected samples, revealed that pts with low α4 expression (<40% by flow cytometry) had virtually no adherent cells. The mean % of bound soluble VCAM-1 examined in 102 patient samples was 28.2%. Interestingly, overall survival (OS; p=0.028) and perhaps complete response (p=0.065) increased with increasing level of bound soluble VCAM-1. Estimated 5-yr OS was 29% (95% CI 12–46%) in 29 pts with VCAM-1 binding ≥40%, compared to 11% (CI 4–19%) in 79 pts with lower binding. Expression of the β1 activation dependent epitope 9EG7 was examined in 24 randomly selected samples before and after treatment with activating antibody 8A2, revealed pts expressed, on average, 57.5% of their maximum potential level of functional activation (range 6.0–100%). VLA-4 expression was also measured by real-time quantitative RT-PCR in 23 randomly selected pts. A significant correlation (Spearman's R=0.44, p=0.037) was found between molecules VLA-4/μg RNA and α4 expression by flow cytometry. Fourteen pts with high levels of α4 (≥40% by flow cytometry) had a mean of 2.34x104 molecules VLA-4/μg RNA, compared to 1.68x104 in pts with lower α4. In these 175 pts, VLA-4 expression was not significantly associated with response to chemotherapy, or with disease free or OS. However, we found a significant correlation between functional status of α4, as indicated by soluble VCAM-1 binding, and longer OS. These data may suggest an adverse effect of functionally inactive α4 v. physiological response of α4+ cells to the BM microenvironment. Disruption of this and other binding interactions may enhance susceptibility to chemotherapy. These approaches need to be prospectively evaluated.

Stability of Phosphoprotein as a Biological Marker of Tumor Signaling

The purpose of the study was to evaluate the stability of phosphoprotein as a marker of signaling activity in human tumors using clinical samples and xenografts. The expression of phospho-Ser473-Akt (p-Akt) was assessed by immunohistochemistry in paraffin-embedded samples from patients enrolled in a Southwest Oncology Group clinical trial of gastroesophageal junction tumors and by immunohistochemistry and Western blotting in human colon tumor xenografts at various times after removal from the animal. Clinical samples had evaluable p-Akt staining only when obtained as biopsies (9 of 13) and no staining was observed in tumors obtained as surgically resected samples (0 of 15). In HT-29 colon cancer xenografts, p-Akt staining was present in fresh sample but not in tissue that had been allowed to stand for 30 minutes at room temperature. Western blotting of HT-29 tumor xenografts at room temperature showed a slow decrease in total Akt with a half-life of 180 minutes and a rapid decrease in p-Akt with a half-life of 20 minutes. Caution should be used when using phosphoprotein levels in human tumor specimens to measure intrinsic signaling activity or drug effects because of the potential for rapid dephosphorylation. Rapid processing of biopsies is essential and postoperative surgical samples may be of limited value because of the time to fixation.

Bronchioloalveolar carcinoma: a model for investigating the biology of epidermal growth factor receptor inhibition.

Bronchioloalveolar carcinoma (BAC) is a previously uncommon subset of non-small cell lung cancer (NSCLC) with unique epidemiology, pathology, clinical features, radiographic presentation, and natural history compared with other NSCLC subtypes. Recent data suggest that the incidence of BAC is increasing, notably in younger nonsmoking women. Despite reports of prolonged survival after repeated surgical resection of multifocal lesions and slow growth kinetics, advanced bilateral or recurrent diffuse BAC remains incurable, with the vast majority of patients dying of respiratory failure or intercurrent pneumonia within 5 years. Limited data suggest that chemotherapy may yield poor results in BAC. However, anecdotal reports of prolonged complete response to tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR), a member of the human epidermal growth factor receptor (erbB) family, have raised considerable interest in studying this NSCLC subset. Here we present clinical data and preliminary results of correlative science studies analyzing human epidermal growth factor receptor pathways from the following two prospective Southwest Oncology Group clinical trials performed in advanced stage BAC: S9714 testing a 96-h continuous infusion of paclitaxel (Taxol) and S0126 evaluating the small molecule EGFR inhibitor gefitinib (ZD1839 or Iressa). These studies provide a biological rationale for investigating BAC as a model of predictive markers of EGFR inhibition.

Tumor origin and CD20 expression in posttransplant lymphoproliferative disorder occurring in solid organ transplant recipients: implications for immune-based therapy.

Posttransplant lymphoproliferative disorder (PTLD) is a potentially fatal complication of transplantation for which new therapies are being explored, including cytotoxic T-cell infusion and anti-CD20 antibody. Whether the PTLD is of donor cell or recipient cell origin influences the type of cytotoxic T-cell therapy, in view of the MHC-restricted nature of the immune response. The efficacy of anti-CD20 therapy, on the other hand, depends on CD20 expression by neoplastic cells. Only limited prior data exist regarding either of these parameters. Materials for this study were obtained in part from a Southwest Oncology Group clinical trial of solid organ transplant patients with PTLD. Tumor tissue from 21 patients (15 heart, 4 lung, and 2 kidney recipients) was evaluated for donor versus recipient origin by analyzing DNA at multiple polymorphic microsatellites. Twenty tumors (95%) were of recipient origin. Anatomically separate tumors from a given patient had the same origin. A single PTLD of donor origin arose in donor lung. Epstein-Barr virus (EBV), as assessed by EBER and LMP1 histochemical stains, was present in 16 of 17 tumors. CD20, evaluated immunohistochemically, was expressed diffusely in 12 of 17 tumors and focally in 3 and was undetectable in 2 tumors. PTLD after solid organ transplantation is frequently EBV-related and of recipient origin, implying that therapeutic EBV-specific T cells must be matched to the HLA type of the recipient, not that of the donor, in most cases of PTLD. Variable CD20 expression among tumors suggests that in some patients anti-CD20 therapy might be more effective in combination with other therapies.

Economic Analysis of Granulocyte Colony Stimulating Factor as Adjunct Therapy for Older Patients with Acute Myelogenous Leukemia (AML): Estimates from a Southwest Oncology Group Clinical Trial

Considerable morbidity, mortality, and economic costs result during remission induction therapy for elderly patients with acute myeloid leukemia (AML). In this study, the economic costs of adjunct granulocyte colony stimulating factor (G-CSF) are estimated for AML patients >55 years of age who received induction chemotherapy on a recently completed Southwest Oncology Group study (SWOG). Clinical data were based on Phase III trial information from 207 AML patients who were randomized to receive either placebo or G-CSF post-induction therapy. Analyses were conducted using a decision analytic model with the primary source of clinical event probabilities based on in-hospital care with or without an active infection requiring intravenous antibiotics. Estimates of average daily costs of care with and without an infection were imputed from a previously reported economic model of a similar population. When compared to AML patients who received placebo, patients who received G-CSF had significantly fewer days on intravenous antibiotics (median 22 vs. 26, p = 0.05), whereas overall duration of hospitalization did not differ (median 29 days). The median cost per day with an active infection that required intravenous antibiotics was estimated to be $1742, whereas the median cost per day without an active infection was estimated to be $1467. Overall, costs were $49,693 for the placebo group and $50,593 for the G-CSF patients. G-CSF during induction chemotherapy for elderly patients with AML had some clinical benefits, but it did not reduce the duration of hospitalization, prolong survival, or reduce the overall cost of supportive care. Whether the benefits of G-CSF therapy justify its use in individual patients with acute leukemia for the present remains a matter of clinical judgment.

Southwest Oncology Group clinical trials of chemosensitizers in non-Hodgkinʼs lymphomas

Southwest Oncology Group clinical trials of chemosensitizers in non-Hodgkinʼs lymphomas

Data monitoring committees for Southwest Oncology Group clinical trials.

A monitoring committee policy was established by the Southwest Oncology Group in 1985 to address documented problems in study conduct. Committees consisting of the study coordinators, disease committee chair, study statistician, Group chair, Group statistician, an uninvolved Southwest Oncology Group clinician, an NCI representative, and a representative from each involved group for intergroup studies have been appointed for each phase III study. Business is conducted largely through the mail and through conference calls. Since then, problems identified in older studies have been largely resolved. Appropriate and timely decisions are being made at modest additional expense to the Group.

Quality of life end points in cancer clinical trials: review and recommendations.

In this presentation, issues that influenced the development of policies for inclusion of quality of life end points in certain Southwest Oncology Group clinical trials are reviewed. The key policies recommended by us and adopted by the Cancer Control Research Committee of the Southwest Oncology Group are as follows: (a) Begin assessment of quality of life in specific types of phase III protocols. (b) Always measure physical functioning, emotional functioning, symptoms (general and protocol specific), and global quality of life separately. (c) Include measures of social functioning and additional protocol-specific measures if resources permit. (d) Use patient-based questionnaires with psychometric properties that have been documented in published studies. In this review, we also recommend specific questionnaires. Our recommendations may prove useful for other cancer clinical trials groups and for multi-institution trials of treatment for chronic diseases.

Involvement of the central nervous system by non-Hodgkin's lymphoma: the Southwest Oncology Group experience.

Fifty (5%) of 1039 patients with non-Hodgkin's lymphomas registered on two Southwest Oncology Group clinical trials between 1972 and 1977 developed evidence of central nervous system (CNS) lymphoma. Thirty-nine patients (3.7%) had leptomeningeal involvement, 10 patients (1%) had focal cerebral involvement and 2 patients (0.1%) had spinal cord compression. Cytologic examination of the cerebrospinal fluid (CSF) was the most reliable diagnostic technique. Patients with diffuse histologies and those with nodular histiocytic lymphoma had the highest incidence of CNS disease. Diffuse histiocytic lymphoma accounted for 22 patients with CNS involvement. Lymphoblastic lymphoma, convoluted type, was found in 6 patients, although in none was the diagnosis established prospectively. Patients who developed CNS lymphoma usually had extranodal disease and systemic symptoms at initial staging (90% stage IV, 54% “B” symptoms). The most commonly involved extranodal sites included the bone marrow (56%), gastrointestinal tract (26%), skin (18%), and lung (14%). CNS lymphoma was observed at all times during the clinical course but was most common in patients with active, poorly controlled disease. In 13 patients (26%), however, CNS lymphoma was the first sign of relapsing lymphoma. Median survival after recognition of CNS lymphoma was 2 months. The incidence of CNS disease was similar for 5 remission induction regimens employed, but maintenance chemotherapy with vincristine, prednisone and parenteral cytosine arabinoside appeared to substantially reduce the incidence of late CNS relapse (1 of 90 patients) compared to maintenance treatment with oral cyclophosphamide in place of cytosine arabinoside (9 of 90 patients, p = 0.02). This study indicates that there is a subgroup of patients with readily identifiable clinical and pathologic features who might benefit from prophylactic therapy to prevent CNS lymphoma.