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1.  Impact of Bone-targeted Therapies in Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer Patients Treated with Abiraterone Acetate: Post Hoc Analysis of Study COU-AA-302 
European urology  2015;68(4):570-577.
Background
Metastatic castration-resistant prostate cancer (mCRPC) often involves bone, and bone-targeted therapy (BTT) has become part of the overall treatment strategy.
Objective
Investigation of outcomes for concomitant BTT in a post hoc analysis of the COU-AA-302 trial, which demonstrated an overall clinical benefit of abiraterone acetate (AA) plus prednisone over placebo plus prednisone in asymptomatic or mildly symptomatic chemotherapy-naïve mCRPC patients.
Design, setting, and participants
This report describes the third interim analysis (prespecified at 55% overall survival [OS] events) for the COU-AA-302 trial.
Intervention
Patients were grouped by concomitant BTT use or no BTT use.
Outcome measurements and statistical analysis
Radiographic progression-free survival and OS were coprimary end points. This report describes the third interim analysis (prespecified at 55% OS events) and involves patients treated with or without concomitant BTT during the COU-AA-302 study. Median follow-up for OS was 27.1 mo. Median time-to-event variables with 95% confidence intervals (CIs) were estimated using the Kaplan-Meier method. Adjusted hazard ratios (HRs), 95% CIs, and p values for concomitant BTT versus no BTT were obtained via Cox models.
Results and limitations
While the post hoc nature of the analysis is a limitation, superiority of AA and prednisone versus prednisone alone was demonstrated for clinical outcomes with or without BTT use. Compared with no BTT use, concomitant BTT significantly improved OS (HR 0.75; p = 0.01) and increased the time to ECOG deterioration (HR 0.75; p < 0.001) and time to opiate use for cancer-related pain (HR 0.80; p = 0.036). The safety profile of concomitant BTT with AA was similar to that reported for AA in the overall intent-to-treat population. Osteonecrosis of the jaw (all grade 1/2) with concomitant BTT use was reported in <3% of patients.
Conclusions
AA with concomitant BTT was safe and well tolerated in men with chemotherapy-naïve mCRPC. The benefits of AA on clinical outcomes were increased with concomitant BTT.
Patient summary
Treatment of advanced prostate cancer often includes bone-targeted therapy. This post hoc analysis showed that in patients with advanced prostate cancer who were treated with abiraterone acetate and prednisone in combination with bone-targeted therapy, there was a continued trend in prolongation of life when compared with patients treated with prednisone alone.
Trial registration
ClinicalTrials.gov NCT00887198.
doi:10.1016/j.eururo.2015.04.032
PMCID: PMC5056561  PMID: 25985882
Abiraterone acetate; Bone-targeted therapy; Chemotherapy-naïve; Metastatic castration-resistant prostate cancer
2.  Lung Adenocarcinoma with Anaplastic Lymphoma Kinase (ALK) Rearrangement Presenting as Carcinoma of Unknown Primary Site: Recognition and Treatment Implications 
Drugs - Real World Outcomes  2016;3:115-120.
Background
Molecular cancer classifier assays are being used with increasing frequency to predict tissue of origin and direct site-specific therapy for patients with carcinoma of unknown primary site (CUP).
Objective
We postulated some CUP patients predicted to have non-small-cell lung cancer (NSCLC) by molecular cancer classifier assay may have anaplastic lymphoma kinase (ALK) rearranged tumors, and benefit from treatment with ALK inhibitors.
Methods
We retrospectively reviewed CUP patients who had the 92-gene molecular cancer classifier assay (CancerTYPE ID; bioTheranostics, Inc.) performed on tumor biopsies to identify patients predicted to have NSCLC. Beginning in 2011, we have tested these patients for ALK rearrangements and epidermal growth factor receptor (EGFR) activating mutations, based on the proven therapeutic value of these targets in NSCLC. We identified CUP patients with predicted NSCLC who were subsequently found to have ALK rearrangements.
Results
NSCLC was predicted by the molecular cancer classifier assay in 37 of 310 CUP patients. Twenty-one of these patients were tested for ALK rearrangements, and four had an EML4-ALK fusion gene detected. The diagnosis of lung cancer was strongly suggested in only one patient prior to molecular testing. One patient received ALK inhibitor treatment and has had prolonged benefit.
Conclusions
We report on patients with lung adenocarcinoma and ALK rearrangements originally diagnosed as CUP who were identified using a molecular cancer classifier assay. Although ALK inhibitors treatment experience is limited, this newly identifiable group of lung cancer patients should be considered for therapy according to guidelines for stage IV ALK-positive NSCLC.
doi:10.1007/s40801-016-0064-7
PMCID: PMC4819469  PMID: 27073764
3.  Lung Adenocarcinoma with Anaplastic Lymphoma Kinase (ALK) Rearrangement Presenting as Carcinoma of Unknown Primary Site: Recognition and Treatment Implications 
Drugs - Real World Outcomes  2016;3(1):115-120.
Background
Molecular cancer classifier assays are being used with increasing frequency to predict tissue of origin and direct site-specific therapy for patients with carcinoma of unknown primary site (CUP).
Objective
We postulated some CUP patients predicted to have non-small-cell lung cancer (NSCLC) by molecular cancer classifier assay may have anaplastic lymphoma kinase (ALK) rearranged tumors, and benefit from treatment with ALK inhibitors.
Methods
We retrospectively reviewed CUP patients who had the 92-gene molecular cancer classifier assay (CancerTYPE ID; bioTheranostics, Inc.) performed on tumor biopsies to identify patients predicted to have NSCLC. Beginning in 2011, we have tested these patients for ALK rearrangements and epidermal growth factor receptor (EGFR) activating mutations, based on the proven therapeutic value of these targets in NSCLC. We identified CUP patients with predicted NSCLC who were subsequently found to have ALK rearrangements.
Results
NSCLC was predicted by the molecular cancer classifier assay in 37 of 310 CUP patients. Twenty-one of these patients were tested for ALK rearrangements, and four had an EML4-ALK fusion gene detected. The diagnosis of lung cancer was strongly suggested in only one patient prior to molecular testing. One patient received ALK inhibitor treatment and has had prolonged benefit.
Conclusions
We report on patients with lung adenocarcinoma and ALK rearrangements originally diagnosed as CUP who were identified using a molecular cancer classifier assay. Although ALK inhibitors treatment experience is limited, this newly identifiable group of lung cancer patients should be considered for therapy according to guidelines for stage IV ALK-positive NSCLC.
doi:10.1007/s40801-016-0064-7
PMCID: PMC4819469  PMID: 27073764
4.  Early Relapse of Follicular Lymphoma After Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Defines Patients at High Risk for Death: An Analysis From the National LymphoCare Study 
Journal of Clinical Oncology  2015;33(23):2516-2522.
Purpose
Twenty percent of patients with follicular lymphoma (FL) experience progression of disease (POD) within 2 years of initial chemoimmunotherapy. We analyzed data from the National LymphoCare Study to identify whether prognostic FL factors are associated with early POD and whether patients with early POD are at high risk for death.
Patients and Methods
In total, 588 patients with stage 2 to 4 FL received first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Two groups were defined: patients with early POD 2 years or less after diagnosis and those without POD within 2 years, the reference group. An independent validation set, 147 patients with FL who received first-line R-CHOP, was analyzed for reproducibility.
Results
Of 588 patients, 19% (n = 110) had early POD, 71% (n = 420) were in the reference group, 8% (n = 46) were lost to follow-up, and 2% (n = 12) died without POD less than 2 years after diagnosis. Five-year overall survival was lower in the early-POD group than in the reference group (50% v 90%). This trend was maintained after we adjusted for FL International Prognostic Index (hazard ratio, 6.44; 95% CI, 4.33 to 9.58). Results were similar for the validation set (FL International Prognostic Index–adjusted hazard ratio, 19.8).
Conclusion
In patients with FL who received first-line R-CHOP, POD within 2 years after diagnosis was associated with poor outcomes and should be further validated as a standard end point of chemoimmunotherapy trials of untreated FL. This high-risk FL population warrants further study in directed prospective clinical trials.
doi:10.1200/JCO.2014.59.7534
PMCID: PMC4879714  PMID: 26124482
5.  Efficacy of octreotide long-acting repeatable in neuroendocrine tumors: RADIANT-2 placebo arm post hoc analysis 
Endocrine-Related Cancer  2015;22(6):933-940.
Somatostatin analogues (SSA) have demonstrated antiproliferative activity in addition to efficacy for carcinoid symptom control in functional neuroendocrine tumors (NET). A post hoc analysis of the placebo arm of the RAD001 In Advanced Neuroendocrine Tumors-2 (RADIANT-2) study was conducted to assess the efficacy of octreotide long-acting repeatable (LAR) on progression-free survival (PFS) and overall survival (OS) estimated using the Kaplan–Meier method. Out of 213 patients randomized to placebo plus octreotide LAR in RADIANT-2, 196 patients with foregut, midgut, or hindgut NET were considered for present analysis. Of these, 41 patients were SSA-treatment naïve and 155 had received SSA therapy before study entry. For SSA-naïve patients, median PFS by adjudicated central review was 13.6 (95% CI 8.2–22.7) months. For SSA-naïve patients with midgut NET (n=24), median PFS was 22.2 (95% CI 8.3–29.5) months. For patients who had received SSA previously, the median PFS was 11.1 (95% CI 8.4–14.3) months. Among the SSA-pretreated patients who had midgut NET (n=119), the median PFS was 12.0 (95% CI 8.4–19.3) months. Median OS was 35.8 (95% CI 32.5–48.9) months for patients in the placebo plus octreotide LAR arm; 50.6 (36.4 – not reached) months for SSA-naïve patients and 33.5 (95% CI 27.5–44.7) months for those who had received prior SSA. This post hoc analysis of the placebo arm of the large phase 3 RADIANT-2 study provides data on PFS and OS among patients with progressive NET treated with octreotide therapy.
doi:10.1530/ERC-15-0314
PMCID: PMC4609826  PMID: 26373569
neuroendocrine tumors; octreotide LAR; progression-free survival; somatostatin analogues
6.  Updated Interim Efficacy Analysis and Long-term Safety of Abiraterone Acetate in Metastatic Castration-resistant Prostate Cancer Patients Without Prior Chemotherapy (COU-AA-302) 
European urology  2014;66(5):815-825.
Background
Abiraterone acetate (an androgen biosynthesis inhibitor) plus prednisone is approved for treating patients with metastatic castration-resistant prostate cancer (mCRPC). Study COU-AA-302 evaluated abiraterone acetate plus prednisone versus prednisone alone in mildly symptomatic or asymptomatic patients with progressive mCRPC without prior chemotherapy.
Objective
Report the prespecified third interim analysis (IA) of efficacy and safety outcomes in study COU-AA-302.
Design, setting, and participants
Study COU-AA-302, a double-blind placebo-controlled study, enrolled patients with mCRPC from April 2009 to June 2010. A total of 1088 patients were stratified by Eastern Cooperative Oncology Group performance status (0 vs 1).
Intervention
Patients were randomised 1:1 to abiraterone 1000 mg plus prednisone 5 mg twice daily by mouth versus prednisone.
Outcome measurements and statistical analysis
Co–primary end points were radiographic progression-free survival (rPFS) and overall survival (OS). Median times to event outcomes were estimated using the Kaplan-Meier method. Hazard ratios (HRs) and 95% confidence intervals (CIs) were derived using the Cox model, and treatment comparison used the log-rank test. The O’Brien-Fleming Lan-DeMets α-spending function was used for OS. Adverse events were summarised descriptively.
Results and limitations
With a median follow-up duration of 27.1 mo, improvement in rPFS was statistically significant with abiraterone treatment versus prednisone (median: 16.5 vs 8.2 mo; HR: 0.52 [95% CI, 0.45–0.61]; p < 0.0001). Abiraterone improved OS (median: 35.3 vs 30.1 mo; HR: 0.79 [95% CI, 0.66–0.95]; p = 0.0151) but did not reach the prespecified statistical efficacy boundary (α-level: 0.0035). A post hoc multivariate analysis for OS using known prognostic factors supported the primary results (HR: 0.74 [95% CI, 0.61–0.89]; p = 0.0017), and all clinically relevant secondary end points and patient-reported outcomes improved. While the post hoc nature of the long-term safety analysis is a limitation, the safety profile with longer treatment exposure was consistent with prior reports.
Conclusions
The updated IA of study COU-AA-302 in patients with mCRPC without prior chemotherapy confirms that abiraterone delays disease progression, pain, and functional deterioration and has clinical benefit with a favourable safety profile, including in patients treated for ≥24 mo.
Trial registration
Study COU-AA-302, ClinicalTrials.gov number, NCT00887198.
doi:10.1016/j.eururo.2014.02.056
PMCID: PMC4418928  PMID: 24647231
Abiraterone acetate; Chemotherapy-naive; Efficacy; Metastatic castration-resistant prostate cancer; Safety
7.  Paclitaxel/carboplatin with or without sorafenib in the first-line treatment of patients with stage III/IV epithelial ovarian cancer: a randomized phase II study of the Sarah Cannon Research Institute 
Cancer Medicine  2014;4(5):673-681.
This trial compared the efficacy and toxicity of standard first-line treatment with paclitaxel/carboplatin versus paclitaxel/carboplatin plus sorafenib in patients with advanced ovarian carcinoma. Patients with stage 3 or 4 epithelial ovarian cancer with residual measurable disease or elevated CA-125 levels after maximal surgical cytoreduction were randomized (1:1) to receive treatment with paclitaxel (175 mg/m2, 3 h infusion, day 1) and carboplatin (AUC 6.0, IV, day 1) with or without sorafenib 400 mg orally twice daily (PO BID). Patients were reevaluated for response after completing 6 weeks of treatment (two cycles); responding or stable patients received six cycles of paclitaxel/carboplatin. Patients receiving the sorafenib-containing regimen continued sorafenib (400 PO BID) for a total of 52 weeks. Eighty-five patients were randomized and received treatment.Efficacy was similar for patients receiving paclitaxel/carboplatin/sorafenib versus paclitaxel/carboplatin: overall response rates 69% versus 74%; median progression-free survival 15.4 versus 16.3 months; 2 year survival 76% versus 81%. The addition of sorafenib added substantially to the toxicity of the regimen; rash, hand–foot syndrome, mucositis, and hypertension were significantly more common in patients treated with sorafenib. The addition of sorafenib to standard paclitaxel/carboplatin did not improve efficacy and substantially increased toxicity in the first-line treatment of advanced epithelial ovarian cancer. Based on evidence from this study and other completed trials, sorafenib is unlikely to have a role in the treatment of ovarian cancer.
doi:10.1002/cam4.376
PMCID: PMC4430260  PMID: 25556916
Carboplatin; first-line therapy; ovarian cancer; paclitaxel; sorafenib
8.  Molecular Profiling in Unknown Primary Cancer: Accuracy of Tissue of Origin Prediction 
The Oncologist  2010;15(5):500-506.
The authors evaluated the accuracy of tissue-of-origin prediction by molecular profiling in patients with carcinoma of unknown primary site. They found the Cancer Type ID assay (bioTheranostics, Inc.) to be reliable in predicting the primary site in patients with carcinoma of unknown primary, and suggest that this could form the basis for more successful site-directed therapy when used in concert with clinicopathologic data.
Introduction.
This retrospective, multi-institutional study evaluated the accuracy of tissue-of-origin prediction by molecular profiling in patients with carcinoma of unknown primary site (CUP).
Methods.
Thirty-eight of 501 patients (7.6%) with CUP, seen in 2000–2008, had their latent primary site tumor subsequently identified during life. Twenty-eight of these patients (73.7%) had adequate initial tissue biopsies available for molecular profiling with a reverse transcriptase-polymerase chain reaction (RT-PCR) assay (Cancer Type ID; bioTheranostics, Inc., San Diego, CA). The assay was performed on formalin-fixed paraffin-embedded biopsy specimens in a blinded fashion, and the assay results were compared with clinicopathologic data and the actual latent primary sites.
Results.
Twenty of the 28 (71.4%) RT-PCR assays were successfully completed (eight biopsies had either insufficient tumor or poorly preserved RNA). Fifteen of the 20 assay predictions (75%) were correct (95% confidence interval, 60%–85%), corresponding to the actual latent primary sites identified after the initial diagnosis of CUP. Primary sites correctly identified included breast (four patients), ovary/primary peritoneal (four patients), non-small cell lung (three patients), colorectal (two patients), gastric (one patient), and melanoma (one patient). Three predictions were incorrect (intestinal, testicular, sarcoma) in patients with gastroesophageal, pancreatic, and non-small cell lung cancer, respectively, and two were unclassifiable in patients with non-small cell lung cancer. Clinicopathologic findings were helpful in suggesting the correct primary site in some patients and appear to complement the molecular assay findings.
Conclusions.
These data validate the reliability of this assay in predicting the primary site in CUP patients and may form the basis for more successful site-directed therapy, when used in concert with clinicopathologic data.
doi:10.1634/theoncologist.2009-0328
PMCID: PMC3227979  PMID: 20427384
Carcinoma of unknown primary site; Molecular profiling; Reverse transcriptase-polymerase chain reaction; Site-directed therapy
9.  High-Dose Etoposide: From Phase I to a Component of Curative Therapy 
Journal of Clinical Oncology  2008;26(33):5310-5312.
doi:10.1200/JCO.2008.19.0892
PMCID: PMC2661465  PMID: 18838698
10.  Lenalidomide in combination with gemcitabine as first-line treatment for patients with metastatic carcinoma of the pancreas 
Cancer Biology & Therapy  2013;14(4):340-346.
Objectives: To evaluate the 6-mo overall survival, safety and tolerability of lenalidomide in combination with standard gemcitabine as first-line treatment for patients with metastatic pancreatic cancer. Methods: Eligibility included: previously untreated metastatic adenocarcinoma of the pancreas with metastases incurable by surgery/radiation therapy; ECOG PS 0–2; adequate organ function; prophylactic anticoagulation for venous thromboembolic events (VTEs). Patients received lenalidomide 25 mg PO (days 1–21) and gemcitabine 1,000 mg/m2 IV (days 1, 8 and 15) each 28-day cycle, with response evaluations every eight weeks. Results: Between 5/2009–4/2010, 72 patients (median age 64 years; 68% male; 42% ECOG PS 0) were enrolled in this multicenter, community-based study. Six-month OS was 37% (95% CI 26–48%). Median PFS and OS were 2.3 (95% CI 1.9–3.5) and 4.7 (95% CI 3.4–5.7) months, respectively. Eight partial responses (11%) were documented. Thirty-nine patients (54%) experienced thrombocytopenia (2 patients, 3% grade 4). Hematologic toxicities resulted in dose modifications for the majority of patients. Twenty patients (28%) developed VTEs during treatment. Conclusions: The observed 6-month OS (37%) of lenalidomide with gemcitabine does not suggest improvement compared with historical results with gemcitabine alone. Toxicities and dose modifications likely limited dose intensity. Further development of this regimen in pancreas cancer is not recommended.
doi:10.4161/cbt.23625
PMCID: PMC3667874  PMID: 23358470
pancreas cancer; lenalidomide; phase II; gemcitabine combination
11.  Abiraterone and Increased Survival in Metastatic Prostate Cancer 
The New England journal of medicine  2011;364(21):1995-2005.
BACKGROUND
Biosynthesis of extragonadal androgen may contribute to the progression of castration-resistant prostate cancer. We evaluated whether abiraterone acetate, an inhibitor of androgen biosynthesis, prolongs overall survival among patients with metastatic castration-resistant prostate cancer who have received chemotherapy.
METHODS
We randomly assigned, in a 2:1 ratio, 1195 patients who had previously received docetaxel to receive 5 mg of prednisone twice daily with either 1000 mg of abiraterone acetate (797 patients) or placebo (398 patients). The primary end point was overall survival. The secondary end points included time to prostate-specific antigen (PSA) progression (elevation in the PSA level according to prespecified criteria), progression-free survival according to radiologic findings based on prespecified criteria, and the PSA response rate.
RESULTS
After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate–prednisone group than in the placebo–prednisone group (14.8 months vs. 10.9 months; hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P<0.001). Data were unblinded at the interim analysis, since these results exceeded the preplanned criteria for study termination. All secondary end points, including time to PSA progression (10.2 vs. 6.6 months; P<0.001), progression-free survival (5.6 months vs. 3.6 months; P<0.001), and PSA response rate (29% vs. 6%, P<0.001), favored the treatment group. Mineralocorticoid-related adverse events, including fluid retention, hypertension, and hypokalemia, were more frequently reported in the abiraterone acetate–prednisone group than in the placebo–prednisone group.
CONCLUSIONS
The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy. (Funded by Cougar Biotechnology; COU-AA-301 ClinicalTrials.gov number, NCT00638690.)
doi:10.1056/NEJMoa1014618
PMCID: PMC3471149  PMID: 21612468
12.  Follicular Lymphoma in the United States: First Report of the National LymphoCare Study 
Journal of Clinical Oncology  2009;27(8):1202-1208.
Purpose
Optimal therapy of follicular lymphoma (FL) is not defined. We analyzed a large prospective cohort study to identify current demographics and patterns of care of FL in the United States.
Patients and Methods
The National LymphoCare Study is a multicenter, longitudinal, observational study designed to collect information on treatment regimens and outcomes for patients with newly diagnosed FL in the United States. Patients were enrolled between 2004 and 2007. There is no study-specific prescribed treatment regimen or intervention.
Results
Two thousand seven hundred twenty-eight subjects were enrolled at 265 sites, including the 80% of patients enrolled from nonacademic sites. Using the Follicular Lymphoma International Prognostic Index (FLIPI), three distinct groups independent of histologic grade could be defined. Initial therapeutic strategy was: observation, 17.7%; rituximab monotherapy, 13.9%; clinical trial 6.1%; radiation therapy, 5.6%; chemotherapy only, 3.2%; chemotherapy plus rituximab, 51.9%. Chemotherapy plus rituximab regimens were: rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone, 55.0%; rituximab plus cyclophosphamide, vincristine, and prednisone, 23.1%; rituximab plus fludarabine based, 15.5%; other, 6.4%. The choice to initiate therapy rather than observe was associated with age, FLIPI, stage, and grade (P < .01). Significant differences in treatment (P < .01) across regions of the United States were noted. Contrary to practice guidelines, treatment of stage I FL frequently omits radiation therapy.
Conclusion
Widely disparate therapeutic approaches are utilized for FL. Initial therapy is deferred in a small subset of patients. There is no single standard of care for the treatment of de novo FL, although antibody use is ubiquitous when therapy is initiated. These disparate approaches to the initial care of patients with FL render a heterogeneous group of patients at relapse.
doi:10.1200/JCO.2008.18.1495
PMCID: PMC2738614  PMID: 19204203
13.  Safety of rituximab in the treatment of B cell malignancies: implications for rheumatoid arthritis 
Arthritis Research & Therapy  2003;5(Suppl 4):S12-S16.
The chimeric anti-CD20 monoclonal antibody rituximab has been used extensively in the treatment of B cell malignancies, and more recently it has emerged as a potential treatment for rheumatoid arthritis (RA), via selective B lymphocyte depletion. Experience in oncology shows that rituximab is well tolerated in a variety of settings, with mild-to-moderate infusion related reactions following the first infusion being the most common adverse event. Current data suggest that the safety profile of rituximab in patients with RA is similar to that in oncology, but that the adverse events are less frequent and less severe in patients with RA.
doi:10.1186/ar1008
PMCID: PMC2833440  PMID: 15180892
B cell depletion; oncology; rheumatoid arthritis; rituximab; safety

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