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1.  A phase 2 cooperative group adjuvant trial using a biomarker-based decision algorithm in patients with stage I non-small cell lung cancer (SWOG-0720, NCT00792701) 
Cancer  2014;120(15):2343-2351.
This cooperative group adjuvant phase 2 trial in patients with completely resected stage I non-small cell lung cancer with tumor diameters measuring ≥ 2 cm was designed to assess the feasibility and preliminary efficacy of assigning patients to therapy or observation using a molecularly based decision algorithm.
At least a lobectomy and sampling of recommended mediastinal lymph node stations, good Zubrod performance status, adequate organ function, and a formalin-fixed and paraffin-embedded tumor specimen were required. Excision repair cross-complementing group 1 (ERCC1) and ribonucleotide reductase M1 (RRM1) were analyzed using immunofluorescence-based in situ automated quantitative image analysis and categorized as high or low using prespecified cutoff values. Patients with high ERCC1 and RRM1 were assigned to observation and all others to 4 cycles of cisplatin and gemcitabine. Feasibility was defined as treatment assignment within 84 days from surgery in > 85% of patients. Secondary objectives were to estimate the 2-year survival.
Treatment assignment met the feasibility criteria in 88% of eligible patients (71 of 81 patients). The collective 2-year disease-free and overall survival rates were 80% and 96%, respectively. Protein levels for RRM1 fell within the previously established range, ERCC1 levels were slightly lower than expected, and they were significantly correlated (correlation coefficient, 0.4). The rates of assignment of patients to observation (22%) and chemotherapy (78%) were as expected.
Gene expression analysis for treatment assignment is feasible. Survival results are encouraging and require future validation. Real-time performance of quantitative in situ ERCC1 and RRM1 analysis requires further development.
PMCID: PMC4140446  PMID: 24752945
lung cancer; adjuvant therapy; personalized medicine; ERCC1 (excision repair cross-complementing group 1); RRM1 (ribonucleotide reductase M1)
2.  Modeling the relationship between progression-free survival and overall survival: The phase 2/3 trial 
The standard phase 2 trial design has changed dramatically over the last decade. Randomized phase 2 studies have essentially become the standard phase 2 design in oncology for a variety of reasons. The use of these designs is motivated by concerns regarding the use of historical data to determine if a new agent or regimen shows promise of activity. However, randomized phase 2 designs come with the cost of increased study duration and patient resources. Progression-free survival (PFS) is an important endpoint used in many phase 2 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 2/3 design has been proposed as an approach to shorten the time to discovery of an active regimen. In this a paper design considerations for a phase 2/3 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 3 trials completed in SWOG between 1990 and 2005. The model provides a framework to evaluate the validity and properties of a employing a phase 2/3 design. In the evaluation of SWOG trials, 3 of 4 positive studies would have also proceeded to the final analysis and 10 of 11 negative studies would have stopped at the phase 2 analysis, if a phase 2/3 design had been used. Through careful consideration and thorough evaluation of design properties, substantial gains could occur using this approach.
PMCID: PMC4131693  PMID: 23669424
Progression-free survival; phase 2; phase 3; phase 2/3
3.  Phase II Trial of Carboplatin, Paclitaxel, Cetuximab and Bevacizumab Followed by Cetuximab and Bevacizumab in Advanced Non-Squamous Non-Small Cell Lung Cancer: SWOG S0536 
Cetuximab and bevacizumab have each been demonstrated to prolong survival when added to chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). However, the potential benefit of combining cetuximab and bevacizumab together with a platinum-based doublet had not been explored. We designed this phase II trial to evaluate the safety, tolerability and efficacy of the combination of carboplatin, paclitaxel, cetuximab and bevacizumab in chemotherapy-naïve patients with advanced, non-squamous NSCLC.
Patients received with up to six cycles of carboplatin (area under curve 6), paclitaxel (200 mg/m2), cetuximab (400 mg/m2 day 1 then 250 mg/m2 weekly) and bevacizumab (15 mg/kg) every 21 days. Patients with an objective response or stable disease received maintenance cetuximab (250 mg/m2 weekly) and bevacizumab (15 mg/kg every 21 days) until disease progression. The primary endpoint was safety as defined by the frequency and severity of hemorrhagic toxicities. Secondary endpoints included response rate (RR), progression-free survival (PFS), overall survival (OS), and toxicity. Molecular biomarkers were assessed in an exploratory manner.
The primary endpoint of grade 4 or higher hemorrhage of 2% (95% confidence interval: 0-7%) met prespecified criteria for safety. Oone hundred ten patients were enrolled. There were 4 treatment-related deaths including lung hemorrhage (2), infection (1), and unknown (1). Median progression-free survival was 7 months and median overall survival was 15 months. The RR was 56% with an overall disease control rate of 77%.
This regimen was safe, feasible and effective as frontline treatment of advanced NSCLC, providing the basis for the ongoing Phase III trial S0819.
PMCID: PMC4072123  PMID: 24189513
Non-small-cell lung cancer; Paclitaxel; Carboplatin; Cetuximab; Bevacizumab; Frontline
5.  The Effect of Pre-Transplant Distress on Immune Reconstitution among Adult Autologous Hematopoietic Cell Transplantation Patients 
Brain, behavior, and immunity  2012;30(Suppl):S142-S148.
Myeloablative hematopoietic cell transplantation (HCT) is a common treatment for hematological malignancy. Delayed immune reconstitution following HCT is a major impediment to recovery with patients being most vulnerable during the first month after transplant. HCT is a highly stressful process. Because psychological distress has been associated with down regulation of immune function we examined the effect of pre-transplant distress on white blood cell (WBC) count among 70 adult autologous HCT patients during the first 3 weeks after transplant. The participants were on average 38 years old; 93% Caucasian, non-Hispanic and 55% male. Pre-transplant distress was measured 2–14 days before admission using the Cancer and Treatment Distress (CTXD) scale, and the Symptom Checklist-90-R (SCL-90-R) anxiety and depression subscales. WBC count was measured during initial immune recovery on days 5 through 22 post-transplant. Linear mixed model regression analyses controlling for gender and treatment-related variables revealed a significant effect of the mean pre-transplant SCL Depression-Anxiety score on WBC recovery. We found no significant effect of pre-transplant CTXD on WBC recovery. In general, higher levels of pre-treatment depression and anxiety were associated with slower WBC recovery. Psychological modulation of WBC recovery during HCT suggests a unique mechanism by which psychological distress can exert influence over the immune system. Given that WBC recovery is essential to survival for HCT patients, these data provide a rationale for treating anxiety and depression in HCT patients.
PMCID: PMC3549315  PMID: 22910186
hematopoietic cell transplantation; immune reconstitution; cancer treatment-related distress; depression; anxiety; hematologic malignancy; cancer
6.  Impact of Disease Progression Date Determination on Progression-free Survival Estimates in Advanced Lung Cancer 
Cancer  2012;118(21):5358-5365.
Progression-free survival (PFS) based endpoints are controversial; however in advanced lung cancer, overall survival is largely influenced by the progression status. We thus evaluated the impact of progression date (PD) determination approach on PFS estimates.
Individual patient data from 21 trials (14 NCCTG; 7 SWOG) were used. Reported progression date (RPD) was defined as either the scan date or the clinical deterioration date. PD was determined using 4 methods (M): RPD (M1), one day after last progression-free scan (M2), midpoint between last progression-free scan and RPD (M3), and using an interval censoring approach (M4). PFS was estimated using Kaplan-Meier (M1, M2, M3), and maximum likelihood (M4). Simulation studies were performed to understand the impact of the length of time elapsed between the last progression-free scan and the PD on time to progression (TTP) estimates.
PFS estimates using RPD were the highest, with M2 being the most conservative. M3 and M4 were similar due to majority of progressions occurring during treatment (i.e., frequent disease assessments). M3 was less influenced by the length of the assessment schedules (%difference from true TTP <1.5%) compared to M1 (11% to 30%) and M2 (-8% to -29%). The overall study conclusion was unaffected by the method used for randomized trials.
The magnitude of difference in the PFS estimates is large enough to alter trial conclusions in advanced lung cancer. Standards for PD determination, use of sensitivity analyses, and randomized trials are critical when designing trials and reporting efficacy using PFS based endpoints.
PMCID: PMC3481159  PMID: 22434489
7.  Design of a phase III clinical trial with prospective biomarker validation: SWOG S0819 
The role of cetuximab for the treatment of advanced non-small-cell lung cancer (NSCLC) is currently unclear. The molecular target of cetuximab, epidermal growth factor receptor (EGFR), as measured by fluorescent in situ hybridization (FISH), has shown potential to be a predictive biomarker for cetuximab efficacy in NSCLC. SWOG S0819 is a Phase III trial evaluating both the value of cetuximab in this setting as well as EGFR FISH as a predictive biomarker. This paper describes the decision process for determining the design and interim monitoring plan for S0819. Six possible designs were evaluated in terms of their properties and the hypotheses that can be addressed within the design constraints. A subgroup-focused multiple-hypothesis design was selected for S0819 incorporating co-primary endpoints to assess cetuximab in both the overall study population and among EGFR FISH positive patients with the sample size determined based on evaluation in the EGFR FISH positive group. The interim monitoring plan chosen specifies interim evaluations of both efficacy and futility in the EGFR FISH positive group alone. The futility monitoring plan to determine early stopping in the EGFR FISH non-positive group is based on evaluation within the positive group, the entire study population, and the non-positive group. SWOG S0819 employs a design which addresses both the biomarker-driven and general efficacy objectives of this study.
PMCID: PMC3409929  PMID: 22592956
Clinical trial design; Molecular targeted therapies; cetuximab; interim monitoring; non-small cell lung cancer
8.  A Pilot Study (SWOG S0429) of Weekly Cetuximab and Chest Radiotherapy for Poor-Risk Stage III Non-Small Cell Lung Cancer 
Frontiers in Oncology  2013;3:219.
Purpose: Stage III non-small cell lung cancer (NSCLC) patients with poor performance status (PS) or co-morbidities are often not candidates for standard chemoradiotherapy (chemoRT) due to poor tolerance to treatments. A pilot study for poor-risk stage III NSCLC patients was conducted combining cetuximab, a chimeric monoclonal antibody targeting epidermal growth factor receptor (EGFR), with chest radiation (RT).
Methods: Stage III NSCLC patients with Zubrod PS 2, or Zubrod PS 0–1 with poor pulmonary function and co-morbidities prohibiting chemoRT were eligible. A loading dose of cetuximab (400 mg/m2) was delivered week 1, followed by weekly cetuximab (250 mg/m2)/RT to 64.8 Gy in 1.8 Gy daily fractions, and maintenance weekly cetuximab (250 mg/m2) for 2 years or until disease progression. H-score for EGFR protein expression was conducted in available tumors.
Results: Twenty-four patients were enrolled. Twenty-two were assessed for outcome and toxicity. Median survival was 14 months and median progression-free survival was 8 months. The response rate was 47% and disease control rate was 74%. Toxicity assessment revealed 22.7% overall ≥Grade 3 non-hematologic toxicities. Grade 3 esophagitis was observed in one patient (5%). The skin reactions were mostly Grade 1 or 2 except two of 22 (9%) had Grade 3 acne and one of 22 (5%) had Grade 3 radiation skin burn. Grade 3–4 hypomagnesemia was seen in four (18%) patients. One patient (5%) had elevated cardiac troponin and pulmonary emboli. H-score did not reveal prognostic significance. An initially planned second cohort of the study did not commence due to slow accrual, which would have added weekly docetaxel to cetuximab/RT after completion of the first cohort of patients.
Conclusion: Concurrent weekly cetuximab/chest RT followed by maintenance cetuximab for poor-risk stage III NSCLC was well tolerated. Further studies with larger sample sizes will be useful to establish the optimal therapeutic ratio of this regimen.
PMCID: PMC3755267  PMID: 24010120
cetuximab; stage III non-small cell lung cancer; EGFR; performance status; radiosensitization
9.  Phase II Study of AZD2171 in Patients with Malignant Pleural Mesothelioma: SWOG S0509 
Malignant pleural mesothelioma (MPM) tumors express VEGF and VEGF receptors. MPM patients have high circulating levels of VEGF, suggesting that tumor angiogenesis is a relevant therapeutic target for MPM. We conducted a phase 2 trial of the VEGFR1/2 TKI AZD2171 in patients with MPM after platinum-based systemic chemotherapy.
Patients and Methods
Patients (pts) with MPM previously treated with a platinum-containing chemotherapy regimen, good performance status, measureable disease and no significant bleeding diathesis or thrombotic history were eligible for enrollment. Pts were treated with AZD2171 45 mg/day on days 1-28 of each 28 day dosing cycle. Tumor measurements were made by RECIST criteria, with a subset analysis of modified RECIST. A two-stage design with a stopping rule based on number of patients with complete or partial response was utilized.
Fifty-four patients were enrolled on study between 11/05 and 4/08. For 47 evaluable patients, 4 patients (9%) had objective responses, including two patients who had 91% and 56% responses in bulky pleural tumor; 16 patients (34%) had stable disease, 20 pts (43%) had disease progression; 2 pts (4%) had symptomatic deterioration and 1 pt (2%) had early death. Four were not assessable for response and assumed to be non-responders. The most common AZD2171-attributable toxicities were fatigue (64%), diarrhea (64%) and hypertension (70%); the majority of patients required a dose reduction. Median overall survival was 9.5 months, 1-year survival was 36% and median progression-free survival was 2.6 months.
The anti-angiogenic AZD2171 has modest single agent activity in MPM. However, several patient tumors were exquisitely sensitive to AZD2171. The starting dose was not well tolerated in this setting. Tumor response by Modified RECIST available for a small subset of patients correlated well with tumor response by RECIST. This study provides a rationale for further testing of AZD2171 with chemotherapy in MPM.
PMCID: PMC3477852  PMID: 21964533
Phase 2; angiogenesis inhibitor; pleural mesothelioma
10.  Human Leukocyte Antigen (HLA) B*18 and Protection against Mother-to-Child HIV Type 1 Transmission 
Human leukocyte antigen (HLA) molecules regulate the cellular immune system and may be determinants of infant susceptibility to human immunodeficiency virus type 1 (HIV-1) infection. Molecular HLA typing for class I alleles was performed on infants followed in a Kenyan perinatal cohort. Early HIV-1 infection status was defined as infection occurring at birth or month 1, while late infection via breast milk was defined as first detection of HIV-1 after 1 month of age. Likelihood ratio tests based on a proportional hazards model adjusting for maternal CD4 T cell count and HIV-1 viral load at 32 weeks of gestation were used to test associations between infant allelic variation and incident HIV-1 infection. Among 433 infants, 76 (18%) were HIV-1 infected during 12 months of follow-up. HLA B*18 was associated with a significantly lower risk of early HIV-1 transmission [relative risk (RR) = 0.26; 95% confidence interval (CI) 0.04–0.82], and none of the 24 breastfeeding infants expressing HLA B*18 who were uninfected at month 1 acquired HIV-1 late via breast milk. We observed a trend toward increased early HIV-1 acquisition for infants presenting HLA A*29 (RR = 2.0; 95% CI 1.0–3.8) and increased late HIV-1 acquisition via breast milk for both Cw*07 and Cw*08 (RR = 4.0; 95% CI 1.0–17.8 and RR = 7.2; 95% CI 1.2–37.3, respectively). HLA B*18 may protect breast-feeding infants against both early and late HIV-1 acquisition, a finding that could have implications for the design and monitoring of HIV-1 vaccines targeting cellular immune responses against HIV-1.
PMCID: PMC3380108  PMID: 15307911
11.  Common arm comparative outcomes analysis of phase III trials of cisplatin + irinotecan vs. cisplatin + etoposide in extensive stage small cell lung cancer: Final patient-level results from JCOG 9511 and SWOG 0124 
Cancer  2010;116(24):5710-5715.
S0124 was a large North American phase III trial that failed to confirm a survival benefit for cisplatin/irinotecan over cisplatin/etoposide in patients with extensive stage small cell lung cancer (E-SCLC). These results were contrary to J9511, a phase III trial exclusively in Japanese patients. Since S0124 and J9511 used identical treatment regimens and similar eligibility criteria, patient-level data were pooled from both trials and a “common arm” analysis was performed to explore potential reasons for the divergent results.
Patients with documented E-SCLC and adequate end-organ function were randomized to intravenously receive either Cisplatin 60 mg/m2 day 1 + Irinotecan 60 mg/m2 days 1, 8, & 15 every 4 weeks or Cisplatin 80 mg/m2 day 1 + Etoposide 100 mg/m2 days 1-3 every 3 weeks. Demographics and outcomes data were compared among 805 patients enrolled in J9511 and S0124 receiving identical treatment using a logistic model adjusted for age, sex, and performance status (PS).
Of 671 patients in S0124, 651 eligible patients were included as were all 154 patients from J9511. Significant differences in sex and PS distribution as well as toxicity were seen between trials. There were also significant differences in response rates (87% vs. 60%, p<0.001) and median overall survival (12.8 vs. 9.8 months, p<0.001) when the cisplatin/irinotecan arms from both trials were compared.
Significant differences in patient demographics, toxicity, and efficacy were identified in the J9511 and S0124 populations. These results, relevant in the current era of clinical trials globalization, warrant: 1) consideration of differential patient characteristics and outcomes amongst populations receiving identical therapy; 2) utilization of the “common arm” model in prospective trials; and 3) inclusion of pharmacogenomic correlates in cancer trials where ethnic/racial differences in drug disposition are expected.
PMCID: PMC2994945  PMID: 20737417
12.  Phase II Selection Design Trial of Concurrent Chemotherapy and Cetuximab Versus Chemotherapy Followed by Cetuximab in Advanced-Stage Non–Small-Cell Lung Cancer: Southwest Oncology Group Study S0342 
Journal of Clinical Oncology  2010;28(31):4747-4754.
Randomized clinical trials failed to show a survival benefit for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors plus concurrent chemotherapy in patients with metastatic non–small-cell lung cancer (NSCLC), with preclinical data suggesting potential negative interactions. In contrast, pilot trials of the EGFR-targeted antibody, cetuximab, plus chemotherapy suggested enhanced antitumor activity. This randomized phase II trial was designed to select a cetuximab plus chemotherapy regimen for phase III evaluation.
Patients and Methods
Treatment-naive patients with advanced-stage NSCLC were randomly assigned to receive paclitaxel (225 mg/m2) and carboplatin (area under the curve, 6) every 3 weeks plus concurrent cetuximab (400 mg/m2 loading dose followed by 250 mg/m2 weekly) for four cycles followed by maintenance cetuximab or sequential paclitaxel-carboplatin for four cycles followed by cetuximab.
Of 242 patients enrolled, 224 were eligible and assessable for response (106 and 118 patients in the concurrent and sequential arms, respectively). With a median follow-up time of 32 months, the median overall survival was 10.9 months (95% CI, 9.2 to 13.0 months) for patients receiving concurrent therapy and 10.7 months (95% CI, 8.5 to 12.8 months) for patients receiving sequential therapy (P = .57); 1-year survival rates were 45% (95% CI, 36% to 54%) and 44% (95% CI, 35% to 53%), respectively. Response rates and progression-free survival times were similar in both arms, as was grade 3 rash, whereas sensory neuropathy was higher in the concurrent arm (15% v 5% in the sequential arm; P = .036).
Although both regimens met the efficacy criterion for continued evaluation, the concurrent regimen of paclitaxel/carboplatin plus cetuximab was chosen.
PMCID: PMC3020704  PMID: 20921467
13.  Pain and Emotional Well-Being Outcomes in Southwest Oncology Group–Directed Intergroup Trial S0205: A Phase III Study Comparing Gemcitabine Plus Cetuximab Versus Gemcitabine As First-Line Therapy in Patients With Advanced Pancreas Cancer 
Journal of Clinical Oncology  2010;28(22):3611-3616.
S0205 was a randomized clinical trial that compared the therapeutic impact of gemcitabine versus gemcitabine plus cetuximab. Study results for patient-reported health-related quality of life (HRQL) outcomes are reported.
Patients and Methods
Patients completed the Brief Pain Inventory and a measure of emotional well-being (each measured on a 0 to 10 scale) at baseline and at weeks 5, 9, 13, and 17 postrandom assignment. Worst pain status was classified as palliated (worst pain scores < 5 maintained for 2 consecutive cycles) or not palliated (remaining patients) and tested with a χ2 test. Change in emotional well-being and worst pain (exploratory analysis) were assessed over 17 weeks using generalized estimating equations with inverse probability of censoring weights.
Seven hundred twenty of 766 enrolled patients contributed baseline HRQL data. The two treatment arms did not differ statistically in the percentage of patients with successful worst pain palliation. Longitudinal analyses showed significantly improved emotional well-being for patients on both arms by weeks 13 and 17 (P < .01 and P < .001). An exploratory longitudinal analysis of worst pain showed significant decreases at all time points for both arms (P < .01 and P < .001). Significant treatment arm differences for either worst pain or emotional well-being were not observed at any of the assessment times.
We observed palliated pain and improved well-being for patients on this trial. However, these improvements were similar in both treatment arms, suggesting that the addition of cetuximab did not contribute to improvement in these HRQL outcomes.
PMCID: PMC2917316  PMID: 20606094
14.  Phase II Study of Tirapazamine, Cisplatin, and Etoposide and Concurrent Thoracic Radiotherapy for Limited-Stage Small-Cell Lung Cancer: SWOG 0222 
Journal of Clinical Oncology  2009;27(18):3014-3019.
A SWOG pilot study (S0004) showed that tirapazamine (TPZ) when combined with concurrent chemoradiotherapy yielded a promising median survival of 22 months in limited-stage small-cell lung cancer (LSCLC). We report results of the phase II study designed to confirm this result.
Patients and Methods
The concurrent phase consisted of two cycles of cisplatin, etoposide, and once-daily radiation to 61 Gy. TPZ was given at 260 mg/m2 on days 1, 29, and at 160 mg/m2 on days 8, 10, 12, 36, 38, and 40. Consolidation consisted of two cycles of cisplatin and etoposide. Complete responders received prophylactic cranial irradiation. Results were considered promising if the median survival time was at least 21 months and of no further interest if ≤ 14 months.
S0222 was closed early due to a report of excess toxicity for TPZ in a head and neck cancer trial elsewhere. Of planned 85 patients, 69 were accrued. In 68 assessable patients, 17 (25%) had grade 3 to 4 esophagitis and eight (12%) had grade 3 febrile neutropenia during the concurrent phase. There were three possible treatment-related deaths, two in concurrent phase (one progressive disease not otherwise specified within 30 days, one pericardial effusion) and one in consolidation phase (esophageal hemorrhage). At a median follow-up of 35 months, median progression-free survival was 11 months (95% CI, 10 to 13 months) and median overall survival was 21 months (95% CI, 17 to 33 months).
S0222 showed acceptable levels of toxicity and similar promising median survival as S0004. Further study of hypoxia-targeted therapy is warranted in LSCLC.
PMCID: PMC2702233  PMID: 19364954
15.  Does Finasteride Affect the Severity of Prostate Cancer? A Causal Sensitivity Analysis 
In 2003 Thompson and colleagues reported that daily use of finasteride reduced the prevalence of prostate cancer by 25% compared to placebo. These results were based on the double-blind randomized Prostate Cancer Prevention Trial (PCPT) which followed 18,882 men with no prior or current indications of prostate cancer annually for seven years. Enthusiasm for the risk reduction afforded by the chemopreventative agent and adoption of its use in clinical practice, however, was severely dampened by the additional finding in the trial of an increased absolute number of high-grade (Gleason score ≥ 7) cancers on the finasteride arm. The question arose as to whether this finding truly implied that finasteride increased the risk of more severe prostate cancer or was a study artifact due to a series of possible post-randomization selection biases, including differences among treatment arms in patient characteristics of cancer cases, differences in biopsy verification of cancer status due to increased sensitivity of prostate-specific antigen under finasteride, differential grading by biopsy due to prostate volume reduction by finasteride, and nonignorable drop-out. Via a causal inference approach implementing inverse probability weighted estimating equations, this analysis addresses the question of whether finasteride caused more severe prostate cancer by estimating the mean treatment difference in prostate cancer severity between finasteride and placebo for the principal stratum of participants who would have developed prostate cancer regardless of treatment assignment. We perform sensitivity analyses that sequentially adjust for the numerous potential post-randomization biases conjectured in the PCPT.
PMCID: PMC2880822  PMID: 20526381
Causal inference; principal stratification; treatment effects; selection bias
16.  Phase III Trial of Irinotecan/Cisplatin Compared With Etoposide/Cisplatin in Extensive-Stage Small-Cell Lung Cancer: Clinical and Pharmacogenomic Results From SWOG S0124 
Journal of Clinical Oncology  2009;27(15):2530-2535.
Irinotecan plus cisplatin (IP) improved survival over etoposide plus cisplatin (EP) in Japanese patients with extensive-stage small-cell lung cancer (E-SCLC). To confirm those results and discern the potential role of population-related pharmacogenomics (PG) in outcomes, we conducted a large randomized trial of identical design to the Japanese trial in North American patients with E-SCLC.
Patients and Methods
Patients were randomly assigned to IP (irinotecan 60 mg/m2 on days 1, 8, and 15; cisplatin 60 mg/m2 day 1, every 4 weeks) or EP (etoposide 100 mg/m2 on days 1 through 3; cisplatin 80 mg/m2 day 1, every 3 weeks). Blood specimens for genomic DNA analysis were collected before random assignment in 169 patients.
Of 671 patients, 651 were eligible (324 and 327 patients in the IP and EP arms, respectively). Response rates with IP and EP were 60% and 57%, respectively (P = .56). Median progression-free survival for IP and EP was 5.8 and 5.2 months, respectively (P = .07). Median overall survival for IP and EP was 9.9 and 9.1 months, respectively (P = .71). Severe diarrhea was more common with IP (19% v 3%); severe neutropenia and thrombocytopenia were higher with EP versus IP (68% v 33% and 15% v 4%, respectively). PG analysis showed that ABCB1 (C3435T)T/T (membrane transport) was associated with IP-related diarrhea; UGT1A1 (G-3156A)A/A (drug metabolism) was associated with IP-related neutropenia.
This large North American trial failed to confirm the previously reported survival benefit observed with IP in Japanese patients. Both regimens produced comparable efficacy, with less hematologic and greater gastrointestinal toxicity with IP. These results emphasize the potential importance of PG in interpreting trials of cancer therapy.
PMCID: PMC2684855  PMID: 19349543
17.  Finasteride Does Not Increase the Risk of High-grade Prostate Cancer: A Bias-adjusted Modeling Approach 
The Prostate Cancer Prevention Trial found that seven years of administration of finasteride reduced the risk of prostate cancer by 25% but with an apparent increased risk of high grade disease. Subsequent analyses found that finasteride affects cancer detection and improves accuracy of tumor grading at biopsy. We herein estimate the impact of finasteride on the risk of overall and high grade prostate cancer, accounting for these biases. Study endpoints (biopsy-proven cancer or a 7-year end-of-study biopsy) were available in 10,182 of 15,990 subjects assessable for 7-year status and grading information from 500 subjects diagnosed with cancer who underwent radical prostatectomy. Prostate cancer was observed in 22.9% (4.8% with high grade) in the placebo group versus 16.6% (5.8% with high grade) in the finasteride group. In this bias-adjusted analysis, the estimated rates are 21.1% (4.2%) and 14.7% (4.8%), respectively, a 30% risk reduction in prostate cancer (RR =0.70 (95% confidence interval (CI) =0.64-0.76, p<0.0001) and a non-significant 14% increase in high grade cancer (RR=1.14 (95% CI = (0.96-1.35), p=0.12) with finasteride. Incorporating the prostatectomy data, estimated rates of high grade cancers are 8.2% (placebo) versus 6.0% (finasteride), a 27% risk reduction (RR = 0.73 (95% CI=0.56-0.96, p=0.02)) with finasteride. While the observed risk of high grade disease is greater with finasteride, this appears to be through facilitated diagnosis, primarily due to increased biopsy sensitivity. Men undergoing regular prostate cancer screening or who express an interest in cancer prevention should be informed of this prevention opportunity.
PMCID: PMC2844801  PMID: 19138953
Prostate Cancer; Cancer Prevention; Finasteride; PSA; Inverse probability weighted estimation
18.  Lower Osteopontin Plasma Levels Are Associated With Superior Outcomes in Advanced Non–Small-Cell Lung Cancer Patients Receiving Platinum-Based Chemotherapy: SWOG Study S0003 
Journal of Clinical Oncology  2008;26(29):4771-4776.
S0003 was a phase III trial of carboplatin/paclitaxel with or without the hypoxic cytotoxin tirapazamine in patients with advanced or metastatic non–small-cell lung cancer (NSCLC). We investigated the relationship between clinical outcomes and plasma levels of the hypoxia-associated protein osteopontin (OPN) in patients on this protocol.
Patients and Methods
Baseline plasma was obtained from 172 patients. In 56 patients, sequential plasma was obtained after one or two cycles. Concentrations of OPN, as well as plasminogen activator inhibitor-1 (PAI-1) and vascular endothelial growth factor (VEGF), were measured using enzyme-linked immunosorbent assay. Tumor expression of OPN was assessed by immunohistochemistry in 61 matched archival specimens.
Patients with lower OPN levels (below the median) had a significantly superior overall survival compared with patients with higher levels, regardless of treatment arm (hazard ratio [HR] = 0.60, P = .002). A similar correlation was observed for progression-free survival (HR = 0.69, P = .02). When examined as a continuous variable, OPN maintained its significant association with both progression-free (HR = 1.05, P = .01) and overall survival (HR = 1.09, P < .0001). Patients with lower plasma OPN levels were significantly more likely to have tumor response (P = .03). No differences were observed between treatment arms. Tumor OPN levels did not correlate with patient outcomes or with plasma levels. No associations were observed between patient outcomes and VEGF or PAI-1 levels; however, plasma concentrations of these markers were significantly interrelated (P < .0001) and significantly decreased after treatment (P = .0002 and P = .03, respectively).
Pretreatment plasma levels of OPN are significantly associated with patient response, progression-free survival, and overall survival in chemotherapy-treated patients with advanced NSCLC.
PMCID: PMC2653139  PMID: 18779603
19.  Incidence of Suicide in Persons With Cancer 
Journal of Clinical Oncology  2008;26(29):4731-4738.
The purpose of this study was to characterize suicide rates among patients with cancer in the United States and identify patient and disease characteristics associated with higher suicide rates. Prior studies, mostly in Europe, have suggested that patients with cancer may be at increased risk for suicide, but large cohort studies comparing patients with cancer with the general population have not been performed in the United States.
Patients in the study were residents of geographic areas served by the Surveillance, Epidemiology, and End Results (SEER) program who were diagnosed with cancer from 1973 to 2002. Comparisons with the general US population were based on mortality data collected by the National Center for Health Statistics. This was a retrospective cohort study of suicide in persons with cancer.
Among 3,594,750 SEER registry patients observed for 18,604,308 person-years, 5,838 suicides were identified, for an age-, sex-, and race-adjusted rate of 31.4/100,000 person-years. In contrast, the suicide rate in the general US population was 16.7/100,000 person-years. Higher suicide rates were associated with male sex, white race, and older age at diagnosis. The highest suicide risks were observed in patients with cancers of the lung and bronchus (standardized mortality ratio [SMR] = 5.74; 95% CI, 5.30 to 6.22), stomach (SMR = 4.68; 95% CI, 3.81 to 5.70), oral cavity and pharynx (SMR = 3.66; 95% CI, 3.16 to 4.22), and larynx (SMR = 2.83; 95% CI, 2.31 to 3.44). SMRs were highest in the first 5 years after diagnosis with cancer.
Patients with cancer in the United States have nearly twice the incidence of suicide of the general population, and suicide rates vary among patients with cancers of different anatomic sites. Further examination of the psychological experience of patients with cancer, particularly that of patients with certain types of cancer, is warranted.
PMCID: PMC2653137  PMID: 18695257

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