Mary W. Redman

Phase III Trial of Irinotecan/Cisplatin Compared With Etoposide/Cisplatin in Extensive-Stage Small-Cell Lung Cancer: Clinical and Pharmacogenomic Results From SWOG S0124

PURPOSE 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/m(2) on days 1, 8, and 15; cisplatin 60 mg/m(2) day 1, every 4 weeks) or EP (etoposide 100 mg/m(2) on days 1 through 3; cisplatin 80 mg/m(2) day 1, every 3 weeks). Blood specimens for genomic DNA analysis were collected before random assignment in 169 patients. RESULTS 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. CONCLUSION 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.

Incidence of Suicide in Persons With Cancer

PURPOSE 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. METHODS 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. RESULTS 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. CONCLUSION 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.

Finasteride Does Not Increase the Risk of High-grade Prostate Cancer: A Bias-adjusted Modeling Approach

Finasteride taken for 7 years in the Prostate Cancer Prevention Trial (PCPT) reduced the risk of prostate cancer by 25%, but with an apparent increased risk of high-grade disease. Subsequent analyses found that finasteride biases toward improved prostate cancer detection and accuracy in prostate cancer grading at biopsy. In our first analysis of the present study, we accounted for these biases in estimating the effect of finasteride on the risk of overall and high-grade prostate cancer. This analysis used PCPT data that included 3-month longer collection of endpoints than in the original report with observed prostate cancer rates of 22.9% (4.8% with high grade; placebo) versus 16.6% (5.8% with high grade; finasteride). Based on these updated results, the bias-adjusted prostate cancer rates are estimated to be 21.1% (4.2% high grade; placebo) and 14.7% (4.8% high grade; finasteride), a 30% risk reduction in prostate cancer [relative risk (RR), 0.70; 95% confidence interval (95% CI), 0.64-0.76; P < 0.0001] and a nonsignificant 14% increase in high-grade cancer (RR, 1.14; 95% CI, 0.96-1.35; P = 0.12) with finasteride. We then estimated rates of high-grade prostate cancer based on an analysis that incorporated grading information from radical prostatectomies in 500 subjects diagnosed with cancer. The resulting estimates were high-grade cancer rates of 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. Our third analysis examined the impact of biopsy sensitivity on the relative risk of high-grade prostate cancer and found that differential sensitivity of biopsy between the treatment arms can have a significant impact on risk ratio estimates. These collective results suggest that the observed, unadjusted higher risk of high-grade disease with finasteride seems to have been due to facilitated diagnosis resulting primarily from increased biopsy sensitivity with finasteride. Therefore, men undergoing regular prostate cancer screening or who express an interest in cancer prevention should be informed of the opportunity to take finasteride for preventing prostate cancer.

Disease control rate at 8 weeks predicts clinical benefit in advanced non-small-cell lung cancer: Results from Southwest Oncology Group randomized trials

PURPOSE Tumor shrinkage categorized as complete response (CR) or partial response (PR) is a fundamental efficacy measure for new cancer treatments and often considered a surrogate for overall survival. However, for any given treatment, many more patients typically achieve stable disease (SD) or have progressive disease (PD) than achieve response. We hypothesized that PD (or its converse, disease control rate [DCR], consisting of CR, PR, SD) is a stronger predictor of survival than response alone in advanced non-small-cell lung cancer (NSCLC), and that this determination might be assessable early on during therapy. PATIENTS AND METHODS Data from 984 NSCLC patients entered onto three randomized Southwest Oncology Group trials of platinum-based chemotherapy were pooled and subjected to Landmark survival analysis. Patients were categorized according to proportions alive at weeks 8, 14, and 20 after registration, as well as response status. Elements were fitted into a Cox proportional hazards model. RESULTS Tumor response (CR, PR) was seen in 260 patients (27%). Median time to response, time to progression, and survival time were 2.0, 4.3 and 8.9 months, respectively. Median survival times among patients with CR/PR, SD, or PD were 13.5, 8.4, and 3.1 months, respectively. Of 892 patients alive at week 8, DCR was 62%. Although CR/PR at week 8 was associated with longer survival (hazard ratio [HR] = 0.61; P < .001), DCR was superior in predicting survival (HR = 0.45; P < .0001). CONCLUSION DCR at week 8 is a more powerful predictor of subsequent survival than is the traditional tumor response rate in advanced NSCLC and provides an early assessment of subsequent outcome.

Health-Related Quality of Life Results in Pathologic Stage C Prostate Cancer From a Southwest Oncology Group Trial Comparing Radical Prostatectomy Alone With Radical Prostatectomy Plus Radiation Therapy

PURPOSE To compare short- and long-term effects of adjuvant treatment versus observation after surgery on health-related quality of life (HRQL) of prostate cancer patients. PATIENTS AND METHODS The Southwest Oncology Group (SWOG) intergroup trial compared radical prostatectomy (RP) plus observation versus RP plus adjuvant radiation therapy (RT). Two-hundred seventeen of 425 therapeutic trial patients were eligible and registered to the HRQL study. Patients completed the SWOG Quality of Life Questionnaire (emotional, physical, social, and role function; general symptom status; treatment/disease-specific symptoms; and global HRQL [GHRQL]) at baseline, 6 weeks, 6 months, and annually for 5 years. Prespecified outcomes were three genitourinary symptoms (bowel function tenderness, frequent urination, and erectile dysfunction [ED]) and measures of physical and emotional function. Adjustments were made for the baseline score. RESULTS Patients receiving adjuvant RT reported worse bowel function (through approximately 2 years) and worse urinary function. There were no statistically significant differences for ED. GHRQL was initially worse for the RP+RT arm but improved over time and was better at the end of the period than the GHRQL reported for RP alone (treatment arm x time interaction, P = .0004). Symptom distress was significantly worse for the RP+RT arm compared with the RP alone arm, but the treatment arms did not differ with respect to other general measures of HRQL. CONCLUSION The addition of RT to surgery resulted in more frequent urination, as well as early report of more bowel dysfunction, although bowel function differences disappeared over the 5-year period. The addition of RT did not negatively impact ED.

Equal Plasma Viral Loads Predict a Similar Rate of CD4± T Cell Decline in Human Immunodeficiency Virus (HIV) Type 1- and HIV-2-Infected Individuals from Senegal, West Africa

Human immunodeficiency virus (HIV) type 2 infection is characterized by slower disease progression to acquired immunodeficiency syndrome than results from HIV-1 infection. To better understand the biological factors underlying the different natural histories of infection with these 2 retroviruses, we examined the relationship between HIV RNA and DNA levels and the rate of CD4(+) T cell decline among 472 HIV-1- and 114 HIV-2-infected individuals from Senegal. The annual rate of CD4(+) T cell decline in the HIV-2 cohort was approximately one-fourth that seen in the HIV-1 cohort. However, when the analysis was adjusted for baseline plasma HIV RNA level, the rates of CD4(+) T cell decline per year for the HIV-1 and HIV-2 cohorts were similar (a rate increase of approximately 4% per year for each increase in viral load of 1 log(10) copies/mL). Therefore, plasma HIV load is predictive of the rate of CD4(+) T cell decline over time, and the correlation between viral load and the rate of decline appears to be similar among all HIV-infected individuals, regardless of whether they harbor HIV-1 or HIV-2.

Lung Master Protocol (Lung-MAP)-A Biomarker-Driven Protocol for Accelerating Development of Therapies for Squamous Cell Lung Cancer: SWOG S1400

The Lung Master Protocol (Lung-MAP, S1400) is a groundbreaking clinical trial designed to advance the efficient development of targeted therapies for squamous cell carcinoma (SCC) of the lung. There are no approved targeted therapies specific to advanced lung SCC, although The Cancer Genome Atlas project and similar studies have detected a significant number of somatic gene mutations/amplifications in lung SCC, some of which are targetable by investigational agents. However, the frequency of these changes is low (5%–20%), making recruitment and study conduct challenging in the traditional clinical trial setting. Here, we describe our approach to development of a biomarker-driven phase II/II multisubstudy “Master Protocol,” using a common platform (next-generation DNA sequencing) to identify actionable molecular abnormalities, followed by randomization to the relevant targeted therapy versus standard of care. Clin Cancer Res; 21(7); 1514–24. ©2015 AACR.

Lower Osteopontin Plasma Levels Are Associated With Superior Outcomes in Advanced Non–Small-Cell Lung Cancer Patients Receiving Platinum-Based Chemotherapy: SWOG Study S0003

PURPOSE 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. RESULTS 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). CONCLUSION Pretreatment plasma levels of OPN are significantly associated with patient response, progression-free survival, and overall survival in chemotherapy-treated patients with advanced NSCLC.

Phase II Study of Cediranib in Patients with Malignant Pleural Mesothelioma: SWOG S0509

Introduction: Malignant pleural mesothelioma (MPM) tumors express vascular epithelial growth factor (VEGF) and VEGF receptors. We conducted a phase II study of the oral pan-VEGF receptor tyrosine kinase inhibitor, cediranib, in patients with MPM after platinum-based systemic chemotherapy. Methods: Patients with MPM previously treated with a platinum-containing chemotherapy regimen and a performance status 0 to 2 were eligible for enrollment. Cediranib 45 mg/d was administered until progression or unacceptable toxicity. The primary end point was response rate. Tumor measurements were made by RECIST criteria, with a subset analysis conducted using modified RECIST. A two-stage design with an early stopping rule based on response rate was used. Results: Fifty-four patients were enrolled. Of 47 evaluable patients, 4 patients (9%) had objective responses, 16 patients (34%) had stable disease, 20 patients (43%) had disease progression, 2 patients (4%) had symptomatic deterioration, and 1 patient (2%) had early death. The most common toxicities were fatigue (64%), diarrhea (64%), and hypertension (70%); 91% 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. Conclusion: Cediranib monotherapy has modest single-agent activity in MPM after platinum-based therapy. However, some patient tumors were highly sensitive to cediranib. This study provides a rationale for further testing of cediranib plus chemotherapy in MPM and highlights the need to identify a predictive biomarker for cediranib.

Scientific advances in lung cancer 2015

ABSTRACT Lung cancer continues to be a major global health problem; the disease is diagnosed in more than 1.6 million new patients each year. However, significant progress is underway in both the prevention and treatment of lung cancer. Lung cancer therapy has now emerged as a “role model” for precision cancer medicine, with several important therapeutic breakthroughs occurring during 2015. These advances have occurred primarily in the immunotherapy field and in treatments directed against tumors harboring specific oncogenic drivers. Our knowledge about molecular mechanisms for oncogene‐driven tumors and about resistance to targeted therapies has increased quickly over the past year. As a result, several regulatory approvals of new agents that significantly improve survival and quality of life for patients with lung cancer who have advanced disease have occurred. The International Association for the Study of Lung Cancer has gathered experts in different areas of lung cancer research and management to summarize the most significant scientific advancements related to prevention and therapy of lung cancer during the past year.