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1.  A phase I study of the safety and pharmacokinetics of trabectedin in combination with pegylated liposomal doxorubicin in patients with advanced malignancies 
Annals of Oncology  2008;19(10):1802-1809.
Background: To determine the maximum tolerated dose (MTD), safety, potential pharmacokinetic (PK) interactions, and effect on liver histology of trabectedin in combination with pegylated liposomal doxorubicin (PLD) for advanced malignancies.
Patients and methods: Entry criteria for the 36 patients included normal liver function, prior doxorubicin exposure <250 mg/m2, and normal cardiac function. A 1-h PLD (30 mg/m2) infusion was followed immediately by one of six trabectedin doses (0.4, 0.6, 0.75, 0.9, 1.1, and 1.3 mg/m2) infused over 3 h, repeated every 21 days until evidence of complete response (CR), disease progression, or unacceptable toxicity. Plasma samples were obtained to assess PK profiles.
Results: The MTD of trabectedin was 1.1 mg/m2. Drug-related grade 3 and 4 toxic effects were neutropenia (31%) and elevated transaminases (31%). Six patients responded (one CR, five partial responses), with an overall response rate of 16.7%, and 14 had stable disease (less than a 50% reduction and less than a 25% increase in the sum of the products of two perpendicular diameters of all measured lesions and the appearance of no new lesions) >4 months (39%). Neither drug had its PK affected significantly by concomitant administration compared with trabectedin and PLD each given as a single agent.
Conclusion: Trabectedin combined with PLD is generally well tolerated at therapeutic doses of both drugs in pretreated patients with diverse tumor types and appears to provide clinical benefit. These results support the need for additional studies of this combination in appropriate cancer types.
doi:10.1093/annonc/mdn363
PMCID: PMC2598415  PMID: 18497430
ET-743; ovarian cancer; pegylated liposomal doxorubicin (PLD); sarcomas; trabectedin
2.  A Phase I Study of the Safety and Pharmacokinetics of Trabectedin in Combination With Pegylated Liposomal Doxorubicin in Patients With Advanced Malignancies 
SUMMARY
Background
To determine the maximum tolerated dose (MTD), safety, potential pharmacokinetic (PK) interactions, and effect on liver histology of trabectedin in combination with pegylated liposomal doxorubicin (PLD) for advanced malignancies.
Patients and Methods
Entry criteria for the 36 patients included normal liver function, prior doxorubicin exposure <250 mg/m2, and normal cardiac function. A 1-hour PLD (30 mg/m2) infusion was followed immediately by 1 of 6 trabectedin doses (0.4, 0.6, 0.75, 0.9, 1.1, and 1.3 mg/m2) infused over 3 hours, repeated every 21 days until evidence of complete response (CR), disease progression, or unacceptable txicity. Plasma samples were obtained to assess PK profiles.
Results
The MTD of trabectedin was 1.1 mg/m2. Drug-related grade 3 and 4 toxicities were neutropenia (31%) and elevated transaminases (31%). Six patients responded (1 CR, 5 partial responses), with an overall response rate of 16.7%, and 14 had stable disease >4 months (39%). Neither drug had its PK affected significantly by concomitant administration compared to trabectedin and PLD each given as a single agent.
Conclusion
Trabectedin combined with PLD is generally well tolerated at therapeutic doses of both drugs in pretreated patients with diverse tumor types, and appears to provide clinical benefit. These results support the need for additional studies of this combination in appropriate cancer types.
doi:10.1093/annonc/mdn363
PMCID: PMC2598415  PMID: 18497430
trabectedin; ET-743; pegylated liposomal doxorubicin (PLD); sarcomas; ovarian cancer
3.  Assessment of HER2 gene amplification in adenocarcinomas of the stomach or gastroesophageal junction in the INT-0116/SWOG9008 clinical trial 
Annals of Oncology  2013;24(7):1754-1761.
Background
Trastuzumab has been approved for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric carcinoma; however, relatively little is known about the role of HER2 in the natural history of this disease.
Patients and methods
Patients enrolled in the INT-0116/SWOG9008 phase III gastric cancer clinical trial with available tissue specimens were retrospectively evaluated for HER2 gene amplification by FISH and overexpression by immunohistochemistry (IHC). The original trial was designed to evaluate the benefit of postoperative chemoradiation compared with surgery alone.
Results
HER2 gene amplification rate by FISH was 10.9% among 258 patients evaluated. HER2 overexpression rate by IHC was 12.2% among 148 patients evaluated, with 90% agreement between FISH and IHC. There was a significant interaction between HER2 amplification and treatment with respect to both disease-free survival (DFS) (P = 0.020) and overall survival (OS) (P = 0.034). Among patients with HER2-non-amplified cancers, treated patients had a median OS of 44 months compared with 24 months in the surgery-only arm (P = 0.003). Among patients with HER2-amplified cancers, there was no significant difference in survival based on treatment arm. HER2 status was not a prognostic marker among patients who received no postoperative chemoradiation.
Conclusion
Patients lacking HER2 amplification benefited from treatment as indicated by both DFS and OS.
Clinical trial
INT-0116/SWOG9008 phase III.
doi:10.1093/annonc/mdt106
PMCID: PMC3690906  PMID: 23524864
gastric cancer; HER2; FISH; immunohistochemistry; 5FU chemotherapy; radiation therapy
4.  Temsirolimus combined with sorafenib in hepatocellular carcinoma: a phase I dose-finding trial with pharmacokinetic and biomarker correlates 
Annals of Oncology  2013;24(7):1900-1907.
Background
Based upon preclinical evidence for improved antitumor activity in combination, this phase I study investigated the maximum-tolerated dose (MTD), safety, activity, pharmacokinetics (PK), and biomarkers of the mammalian target of rapamycin inhibitor, temsirolimus, combined with sorafenib in hepatocellular carcinoma (HCC).
Patients and methods
Patients with incurable HCC and Child Pugh score ≤B7 were treated with sorafenib plus temsirolimus by 3 + 3 design. The dose-limiting toxicity (DLT) interval was 28 days. The response was assessed every two cycles. PK of temsirolimus was measured in a cohort at MTD.
Results
Twenty-five patients were enrolled. The MTD was temsirolimus 10 mg weekly plus sorafenib 200 mg twice daily. Among 18 patients at MTD, DLT included grade 3 hand–foot skin reaction (HFSR) and grade 3 thrombocytopenia. Grade 3 or 4 related adverse events at MTD included hypophosphatemia (33%), infection (22%), thrombocytopenia (17%), HFSR (11%), and fatigue (11%). With sorafenib, temsirolimus clearance was more rapid (P < 0.05). Two patients (8%) had a confirmed partial response (PR); 15 (60%) had stable disease (SD). Alpha-fetoprotein (AFP) declined ≥50% in 60% assessable patients.
Conclusion
The MTD of sorafenib plus temsirolimus in HCC was lower than in other tumor types. HCC-specific phase I studies are necessary. The observed efficacy warrants further study.
doi:10.1093/annonc/mdt109
PMCID: PMC3690907  PMID: 23519998
hepatocellular carcinoma; mTOR; pharmacokinetics; sorafenib; temsirolimus
5.  Cruciferous vegetables consumption and the risk of female lung cancer: a prospective study and a meta-analysis 
Annals of Oncology  2013;24(7):1918-1924.
Background
Epidemiological studies evaluating the association between cruciferous vegetables (CVs) intake and female lung cancer risk have produced inconsistent results.
Patients and methods
This study followed 74 914 Chinese women aged 40–70 years who participated in the Shanghai Women's Health Study. CV intake was assessed through a validated food-frequency questionnaire (FFQ) at baseline and reassessed during follow-up. Hazard ratios (HRs) and 95% confidence interval (CIs) were estimated by using Cox proportional hazards models. Furthermore, we carried out a meta-analysis of all observational studies until December 2011.
Results
After excluding the first 2 years of follow-up, 417 women developed lung cancer over a mean of 11.1 years of follow-up. An inverse association of borderline statistical significance was observed between CV consumption and female lung cancer risk, with HR for the highest compared with the lowest quartiles of 0.73 (95% CI 0.54–1.00, P trend = 0.1607). The association was strengthened in analyses restricting to never smokers, with the corresponding HR of 0.59 (95% CI 0.40–0.87, P trend = 0.0510). The finding of an inverse association between CV intake and lung cancer risk in women was supported by our meta-analysis of 10 included studies.
Conclusions
Our study suggests that CV consumption may reduce the risk of lung cancer in women, particularly among never smokers.
doi:10.1093/annonc/mdt119
PMCID: PMC3690909  PMID: 23553059
cruciferous vegetable; lung cancer; meta-analysis; prospective study; women
6.  A phase II study of ixabepilone and trastuzumab for metastatic HER2-positive breast cancer 
Annals of Oncology  2013;24(7):1841-1847.
Background
A multicenter NCI-sponsored phase II study was conducted to analyze the safety and efficacy of the combination of ixabepilone with trastuzumab in patients with metastatic HER2-positive breast cancer.
Patients and methods
Two cohorts were enrolled: cohort 1 had received no prior chemotherapy or trastuzumab for metastatic disease and cohort 2 had received 1–2 prior trastuzumab-containing regimens for metastatic disease. Patients in both cohorts received ixabepilone 40 mg/m2 as a 3-h infusion and trastuzumab on day 1 of a 21-day cycle. Tumor biomarkers that may predict response to trastuzumab were explored.
Results
Thirty-nine women entered the study with 15 patients in cohort 1 and 24 patients in cohort 2. Across both cohorts, the overall RR was 44%, with a clinical benefit rate (CR + PR + SD for at least 24 weeks) of 56%. Treatment-related toxic effects included neuropathy (grade ≥2, 56%), leukopenia (grade ≥2, 26%), myalgias (grade ≥2, 21%), neutropenia (grade ≥2, 23%), and anemia (grade ≥2, 18%).
Conclusions
This represents the first study of the combination of ixabepilone with trastuzumab for the treatment of metastatic HER2-positive breast cancer. These results suggest that the combination has encouraging activity as first and subsequent line therapy for metastatic breast cancer.
doi:10.1093/annonc/mdt121
PMCID: PMC3690910  PMID: 23559151
breast; cancer; HER2; ixabepilone; trastuzumab
7.  Genome-wide discovery of genetic variants affecting tamoxifen sensitivity and their clinical and functional validation 
Annals of Oncology  2013;24(7):1867-1873.
Background
Beyond estrogen receptor (ER), there are no validated predictors for tamoxifen (TAM) efficacy and toxicity. We utilized a genome-wide cell-based model to comprehensively evaluate genetic variants for their contribution to cellular sensitivity to TAM.
Design
Our discovery model incorporates multidimensional datasets, including genome-wide genotype, gene expression, and endoxifen-induced cellular growth inhibition in the International HapMap lymphoblastoid cell lines (LCLs). Genome-wide findings were further evaluated in NCI60 cancer cell lines. Gene knock-down experiments were performed in four breast cancer cell lines. Genetic variants identified in the cell-based model were examined in 245 Caucasian breast cancer patients who underwent TAM treatment.
Results
We identified seven novel single-nucleotide polymorphisms (SNPs) associated with endoxifen sensitivity through the expression of 10 genes using the genome-wide integrative analysis. All 10 genes identified in LCLs were associated with TAM sensitivity in NCI60 cancer cell lines, including USP7. USP7 knock-down resulted in increasing resistance to TAM in four breast cancer cell lines tested, which is consistent with the finding in LCLs and in the NCI60 cells. Furthermore, we identified SNPs that were associated with TAM-induced toxicities in breast cancer patients, after adjusting for other clinical factors.
Conclusion
Our work demonstrates the utility of a cell-based model in genome-wide identification of pharmacogenomic markers.
doi:10.1093/annonc/mdt125
PMCID: PMC3690911  PMID: 23508821
gene expression; genome-wide association study; HapMap; SNP; tamoxifen
8.  Spin and bias: the tip of the iceberg 
Annals of Oncology  2013;24(7):1949.
doi:10.1093/annonc/mdt189
PMCID: PMC3697056  PMID: 23704199
9.  Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study 
Annals of Oncology  2013;24(7):1813-1821.
Background
This phase I/II study in patients with metastatic castration-resistant prostate cancer (mCRPC) explored ipilimumab as monotherapy and in combination with radiotherapy, based on the preclinical evidence of synergistic antitumor activity between anti-CTLA-4 antibody and radiotherapy.
Patients and methods
In dose escalation, 33 patients (≥6/cohort) received ipilimumab every 3 weeks × 4 doses at 3, 5, or 10 mg/kg or at 3 or 10 mg/kg + radiotherapy (8 Gy/lesion). The 10-mg/kg cohorts were expanded to 50 patients (ipilimumab monotherapy, 16; ipilimumab + radiotherapy, 34). Evaluations included adverse events (AEs), prostate-specific antigen (PSA) decline, and tumor response.
Results
Common immune-related AEs (irAEs) among the 50 patients receiving 10 mg/kg ± radiotherapy were diarrhea (54%), colitis (22%), rash (32%), and pruritus (20%); grade 3/4 irAEs included colitis (16%) and hepatitis (10%). One treatment-related death (5 mg/kg group) occurred. Among patients receiving 10 mg/kg ± radiotherapy, eight had PSA declines of ≥50% (duration: 3–13+ months), one had complete response (duration: 11.3+ months), and six had stable disease (duration: 2.8–6.1 months).
Conclusions
In mCRPC patients, ipilimumab 10 mg/kg ± radiotherapy suggested clinical antitumor activity with disease control and manageable AEs. Two phase III trials in mCRPC patients evaluating ipilimumab 10 mg/kg ± radiotherapy are ongoing.
ClinicalTrials.gov identifier: NCT00323882.
doi:10.1093/annonc/mdt107
PMCID: PMC3707423  PMID: 23535954
ipilimumab; metastatic castration-resistant prostate cancer; phase I/II trial; prostate-specific antigen and radiotherapy; immunotherapy
10.  Global, multicenter, randomized, phase II trial of gemcitabine and gemcitabine plus AGS-1C4D4 in patients with previously untreated, metastatic pancreatic cancer† 
Annals of Oncology  2013;24(7):1792-1801.
Background
We evaluated AGS-1C4D4, a fully human monoclonal antibody to prostate stem cell antigen (PSCA), with gemcitabine in a randomized, phase II study of metastatic pancreatic cancer.
Patients and methods
Patients with Eastern Cooperative Oncology Group (ECOG) performance status 0/1 and previously untreated, metastatic pancreatic adenocarcinoma were randomly assigned 1:2 to gemcitabine (1000 mg/m2 weekly seven times, 1 week rest, weekly three times q4weeks) or gemcitabine plus AGS-1C4D4 (48 mg/kg loading dose, then 24 mg/kg q3weeks IV). The primary end point was 6-month survival rate (SR). Archived tumor samples were collected for pre-planned analyses by PSCA expression.
Results
Between April 2009 and May 2010, 196 patients were randomly assigned to gemcitabine (n = 63) or gemcitabine plus AGS-1C4D4 (n = 133). The 6-month SR was 44.4% (95% CI, 31.9–57.5) in the gemcitabine arm and 60.9% (95% CI, 52.1–69.2) in the gemcitabine plus AGS-1C4D4 arm (P = 0.03), while the median survival was 5.5 versus 7.6 months and the response rate was 13.1% versus 21.6% in the two arms, respectively. The 6-month SR was 57.1% in the gemcitabine arm versus 79.5% in the gemcitabine plus AGS-1C4D4 arm among the PSCA-positive subgroup and 31.6% versus 46.2% among the PSCA-negative subgroup.
Conclusions
This randomized, phase II study achieved its primary end point, demonstrating an improved 6-month SR with addition of AGS-1C4D4 to gemcitabine among patients with previously untreated, metastatic pancreatic adenocarcinoma.
ClinicalTrials.gov identifier: NCT00902291.
doi:10.1093/annonc/mdt066
PMCID: PMC3716216  PMID: 23448807
chemotherapy; clinical trial; gemcitabine; metastatic disease; pancreatic cancer; prostate stem cell antigen
11.  Prospective evaluation of type 2 diabetes mellitus on the risk of primary liver cancer in Chinese men and women 
Annals of Oncology  2013;24(6):1679-1685.
Background
No prospective study has investigated the relationship between type 2 diabetes mellitus (T2DM) and the risk of primary liver cancer (PLC) in mainland China, and little is known about the effect of diabetes duration on PLC risk.
Design
Data from two population-based cohorts (the Shanghai Men's Health Study, SMHS, 2002–2006 and the Shanghai Women's Health Study, SWHS, 1996–2000) were thus used to assess the associations among T2DM, diabetes duration and PLC risk in Chinese population.
Results
During follow-up through 2009, 344 incident PLC cases were identified among 60 183 men and 73 105 women. T2DM is significantly associated with the increased risk of PLC in both men [hazard ratio (HR) = 1.63, 95% confidence interval (CI) 1.06–2.51] and women (HR = 1.64, 95% CI 1.03–2.61). The highest risk of incident liver cancer was observed in the first 5 years after diabetes diagnosis, and decreased substantially with the prolonged diabetes duration (Ptrend < 0.001). No synergistic interaction in the development of PLC was found between diabetes and other known risk factors.
Conclusions
T2DM is associated with the increased risk of subsequent liver cancer within 5 years after diagnosis in Chinese population, suggesting that hyperinsulinaemia rather than hyperglycaemia is more likely to be a primary mediator for this association.
doi:10.1093/annonc/mdt017
PMCID: PMC3660077  PMID: 23406734
China; cohort study; primary liver cancer; type 2 diabetes
12.  CYP2C8*3 increases risk of neuropathy in breast cancer patients treated with paclitaxel† 
Annals of Oncology  2013;24(6):1472-1478.
Background
Paclitaxel-induced neuropathy is an adverse event that often leads to therapeutic disruption and patient discomfort. We attempted to replicate a previously reported association between increased neuropathy risk and CYP2C8*3 genotype.
Patients and methods
Demographic, treatment, and toxicity data were collected for paclitaxel-treated breast cancer patients who were genotyped for the CYP2C8*3 K399R (rs10509681) variant. A log-rank test was used in the primary analysis of European-American patients. An additional independent replication was then attempted in a cohort of African-American patients, followed by modeling of the entire patient cohort with relevant covariates.
Results
In the primary analysis of 209 European patients, there was an increased risk of paclitaxel-induced neuropathy related to CYP2C8*3 status [HR (per allele) = 1.93 (95% CI: 1.05–3.55), overall log-rank P = 0.006]. The association was replicated in direction and magnitude of effect in 107 African-American patients (P = 0.043). In the Cox model using the entire mixed-race cohort (n = 411), each CYP2C8*3 allele approximately doubled the patient's risk of grade 2+ neuropathy (P = 0.004), and non-Europeans were at higher neuropathy risk than Europeans of similar genotype (P = 0.030).
Conclusions
The increased risk of paclitaxel-induced neuropathy in patients who carry the CYP2C8*3 variant was replicated in two racially distinct patient cohorts.
doi:10.1093/annonc/mdt018
PMCID: PMC3660078  PMID: 23413280
chemotherapy-induced peripheral neuropathy; cytochrome P450 2C8*3; paclitaxel; pharmacogenetics; race
13.  Bevacizumab use and risk of cardiovascular adverse events among elderly patients with colorectal cancer receiving chemotherapy: a population-based study 
Annals of Oncology  2013;24(6):1574-1579.
Background
Cardiovascular risk attributable to bevacizumab (Avastin®, BEV) for treatment of metastatic colorectal cancer (CRC) remains unclear. We conducted a population-based cohort study to assess the safety of BEV use among patients aged ≥65.
Patients and methods
We identified CRC patients diagnosed from 2005 to 2007 who received chemotherapy and were followed until 31 December 2009. Outcomes were 3-year risk of arterial thromboembolic events (ATEs), cardiomyopathy or congestive heart failure (CM/CHF), and cardiac death (CD) after chemotherapy initiation. We fitted Cox-proportional hazards (PHs) models with inverse-probability-of-treatment-weights and calculated hazard ratios (HRs) for the risk of adverse events.
Results
We identified 6803 CRC patients (median age: 73 years). Those with cardiac comorbidity were less likely to receive BEV (P < 0.0001). BEV is associated with an elevated risk of ATEs (HR = 1.82, 95% CI = 1.20–2.76, P < 0.001; rate difference: 3.5 additional cases/1000 person-years). We observed no association between BEV and CD or CM/CHF.
Conclusions
In general practice, the cardiovascular risk of BEV in elderly CRC is modest. The observed ATEs risk is lower than reported in clinical trials, which may be due to careful patient selection. Our findings may facilitate clinical decision-making of BEV use in elderly patients.
doi:10.1093/annonc/mdt019
PMCID: PMC3660079  PMID: 23429865
adverse events; arterial thromboembolic events; bevacizumab; cardiac death; congestive heart failure
14.  Incidence and risk of central nervous system metastases as site of first recurrence in patients with HER2-positive breast cancer treated with adjuvant trastuzumab 
Annals of Oncology  2013;24(6):1526-1533.
Background
Central nervous system (CNS) disease as the site of first relapse after exposure to adjuvant trastuzumab has been reported. We carried out comprehensive meta-analysis to determine the risk of CNS metastases as the first site of recurrence in patients with HER2-positive breast cancer who received adjuvant trastuzumab.
Methods
Eligible studies include randomized trials of adjuvant trastuzumab administered for 1 year to patients with HER2-positive breast cancer who reported CNS metastases as first site of disease recurrence. Statistical analyses were conducted to calculate the incidence, relative risk (RR), and 95% confidence intervals (CIs) using fixed-effects inverse variance and random-effects models.
Results
A total of 9020 patients were included. The incidence of CNS metastases as first site of disease recurrence in HER2-positive patients receiving adjuvant trastuzumab was 2.56% (95% CI 2.07% to 3.01%) compared with 1.94% (95% CI 1.54% to 2.38%) in HER2-positive patients who did not receive adjuvant trastuzumab. The RR of the CNS as first site of relapse in trastuzumab-treated patients was 1.35 (95% CI 1.02–1.78, P = 0.038) compared with control arms without trastuzumab therapy. The ratio of CNS metastases to total number of recurrence events was 16.94% (95% CI 10.85% to 24.07%) and 8.33% (95% CI 6.49% to 10.86%) for the trastuzumab-treated and control groups, respectively. No statistically significant differences were found based on trastuzumab schedule or median follow-up time. No evidence of publication bias was observed.
Conclusions
Adjuvant trastuzumab is associated with a significant increased risk of CNS metastases as the site of first recurrence in HER2-positive breast cancer patients.
doi:10.1093/annonc/mdt036
PMCID: PMC3660080  PMID: 23463626
breast cancer; central nervous system; hER2; meta-analysis; metastases; trastuzumab
15.  A phase II multicenter trial of hyperCVAD MTX/Ara-C and rituximab in patients with previously untreated mantle cell lymphoma; SWOG 0213 
Annals of Oncology  2013;24(6):1587-1593.
Background
Rituximab-hyper-CVAD alternating with rituximab-high-dose methotrexate and cytarabine is a commonly utilized regimen in the United States for mantle cell lymphoma (MCL) based on phase II single institutional data. To confirm the clinical efficacy of this regimen and determine its feasibility in a multicenter study that includes both academic and community-based practices, a phase II study of this regimen was conducted by SWOG.
Patients and methods
Forty-nine patients with advanced stage, previously untreated MCL were eligible. The median age was 57.4 years (35–69.8 years).
Results
Nineteen patients (39%) did not complete the full scheduled course of treatment due to toxicity. There was one treatment-related death and two cases of secondary myelodysplastic syndrome (MDS). There were 10 episodes of grade 3 febrile neutropenia, 19 episodes of grade 3 and 1 episode of grade 4 infection. With a median follow-up of 4.8 years, the median progression-free survival was 4.8 years (5.5 years for those ≤65 years) and the median overall survival (OS) was 6.8 years.
Conclusions
Although this regimen is toxic, it is active for patients ≤65 years of age and can be given both at academic centers and in experienced community centers.
doi:10.1093/annonc/mdt070
PMCID: PMC3660082  PMID: 23504948
dose-intensive; mantle cell; rituximab
16.  Statins and prostate cancer recurrence following radical prostatectomy or radiotherapy: a systematic review and meta-analysis 
Annals of Oncology  2013;24(6):1427-1434.
Background
In this meta-analysis, we evaluated associations between statins and recurrence-free survival (RFS) following treatment of localized prostate cancer, with attention to potential benefits among patients treated primarily with radiotherapy (RT) versus radical prostatectomy.
Patients and methods
We identified original studies examining the effect of statins on men who received definitive treatment of localized prostate cancer using a systematic search of the PubMed and EMBASE databases through August 2012. Our search yielded 17 eligible studies from 794 references; 13 studies with hazard ratios (HRs) for RFS were included in the formal meta-analysis.
Results
Overall, statins did not affect RFS (HR 0.90, 95% CI 0.74–1.08). However, in RT patients (six studies), statins were associated with a statistically significant improvement in RFS (HR 0.68; 95% CI 0.49–0.93); this benefit was not observed in radical prostatectomy patients (seven studies). Sensitivity analyses suggested that primary treatment modality may impact the effect of statins on prostate cancer recurrence.
Conclusions
Our meta-analysis suggests a potentially beneficial effect of statins on prostate cancer patients treated with RT but not among radical prostatectomy patients. Although limited by the lack of randomized data, these results suggest that primary treatment modality should be considered in future studies examining associations between statins and oncologic outcomes.
doi:10.1093/annonc/mdt077
PMCID: PMC3660083  PMID: 23508824
meta-analysis; prostate cancer; radical prostatectomy; radiotherapy; recurrence; statin
17.  Tetrathiomolybdate-associated copper depletion decreases circulating endothelial progenitor cells in women with breast cancer at high risk of relapse 
Annals of Oncology  2013;24(6):1491-1498.
Background
Bone marrow-derived endothelial progenitor cells (EPCs) are critical for metastatic progression. This study explores the effect of tetrathiomolybdate (TM), an anti-angiogenic copper chelator, on EPCs in patients at high risk for breast cancer recurrence.
Patients and methods
This phase 2 study enrolled breast cancer patients with stage 3 and stage 4 without evidence of disease (NED), and stage 2 if triple-negative. TM 100 mg orally was administered to maintain ceruloplasmin <17 mg/dl for 2 years or until relapse. The primary end point was change in EPCs.
Results
Forty patients (28 stage 2/3, 12 stage 4 NED) were enrolled. Seventy-five percent patients achieved the copper depletion target by 1 month. Ninety-one percent of triple-negative patients copper-depleted compared with 41% luminal subtypes. In copper-depleted patients only, there was a significant reduction in EPCs/ml by 27 (P = 0.04). Six patients relapsed while on study, of which only one patient had EPCs maintained below baseline. The 10-month relapse-free survival was 85.0% (95% CI 74.6%–96.8%). Only grade 3/4 toxicity was hematologic: neutropenia (3.1% of cycles), febrile neutropenia (0.2%), and anemia (0.2%).
Conclusions
TM is safe and appears to maintain EPCs below baseline in copper-depleted patients. TM may promote tumor dormancy and ultimately prevent relapse.
doi:10.1093/annonc/mds654
PMCID: PMC3707432  PMID: 23406736
breast cancer; endothelial progenitor cells; tetrathiomolybdate
18.  Improved survival outcomes with the incidental use of beta-blockers among patients with non-small-cell lung cancer treated with definitive radiation therapy 
Annals of Oncology  2013;24(5):1312-1319.
Background
Preclinical studies have shown that norepinephrine can directly stimulate tumor cell migration and that this effect is mediated by the beta-adrenergic receptor.
Patients and methods
We retrospectively reviewed 722 patients with non-small-cell lung cancer (NSCLC) who received definitive radiotherapy (RT). A Cox proportional hazard model was utilized to determine the association between beta-blocker intake and locoregional progression-free survival (LRPFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS).
Results
In univariate analysis, patients taking beta-blockers (n = 155) had improved DMFS (P < 0.01), DFS (P < 0.01), and OS (P = 0.01), but not LRPFS (P = 0.33) compared with patients not taking beta-blockers (n = 567). In multivariate analysis, beta-blocker intake was associated with a significantly better DMFS [hazard ratio (HR), 0.67; P = 0.01], DFS (HR, 0.74; P = 0.02), and OS (HR, 0.78; P = 0.02) with adjustment for age, Karnofsky performance score, stage, histology type, concurrent chemotherapy, radiation dose, gross tumor volume, hypertension, chronic obstructive pulmonary disease and the use of aspirin. There was no association of beta-blocker use with LRPFS (HR = 0.91, P = 0.63).
Conclusion
Beta-blocker use is associated with improved DMFS, DFS, and OS in this large cohort of NSCLC patients. Future prospective trials can validate these retrospective findings and determine whether the length and timing of beta-blocker use influence survival outcomes.
doi:10.1093/annonc/mds616
PMCID: PMC3629895  PMID: 23300016
beta-blockers; distant metastasis; non-small-cell lung cancer; radiation therapy
19.  Association between clinical complete response and pathological complete response after preoperative chemoradiation in patients with gastroesophageal cancer: analysis in a large cohort 
Annals of Oncology  2012;24(5):1262-1266.
Background
Chemoradiation followed by surgery is the preferred treatment of localized gastroesophageal cancer (GEC). Surgery causes considerable life-altering consequences and achievement of clinical complete response (clinCR; defined as postchemoradiation [but presurgery] endoscopic biopsy negative for cancer and positron emission tomographic (PET) scan showing physiologic uptake) is an enticement to avoid/delay surgery. We examined the association between clinCR and pathologic complete response (pathCR).
Patients and methods
Two hundred eighty-four patients with GEC underwent chemoradiation and esophagectomy. The chi-square test, Fisher exact test, t-test, Kaplan–Meier method, and log-rank test were used.
Results
Of 284 patients, 218 (77%) achieved clinCR. However, only 67 (31%) of the 218 achieved pathCR. The sensitivity of clinCR for pathCR was 97.1% (67/69), but the specificity was low (29.8%; 64/215). Of the 66 patients who had less than a clinCR, only 2 (3%) had a pathCR. Thus, the rate of pathCR was significantly different in patients with clinCR than in those with less than a clinCR (P < 0.001).
Conclusions
clinCR is not highly associated with pathCR; the specificity of clinCR for pathCR is too low to be used for clinical decision making on delaying/avoiding surgery. Surgery-eligible GEC patients should be encouraged to undergo surgery following chemoradiation despite achieving a clinCR.
doi:10.1093/annonc/mds617
PMCID: PMC3629896  PMID: 23247658
clinical complete response; esophageal cancer; multimodality therapy; pathologic complete response; prediction
20.  Guideline-discordant androgen deprivation therapy in localized prostate cancer: patterns of use in the medicare population and cost implications 
Annals of Oncology  2012;24(5):1338-1343.
Background
Androgen deprivation therapy (ADT) in localized prostate cancer improves overall survival and is recommended by National Comprehensive Cancer Network guidelines in certain situations. However, ADT is without benefit in other situations and can actually cause harm. This study examines recent trends in the ADT use and quantifies the cost of guideline-discordant ADT.
Patients and methods
Patients, aged 66–80 years, in the Surveillance Epidemiology and End Results-Medicare database with non-metastatic prostate cancer diagnosed between 2004 and 2007 were included for analysis. Prostate-specific antigen, Gleason score, and stage were used to define D'Amico risk categories. Logistic regression was used to examine factors associated with guideline-discordant ADT. Annual direct cost was estimated using 2011 Medicare reimbursement for ADT.
Results
Of 28 654 men included, 12.4% received guideline-discordant ADT. In low-risk patients, 14.9% received discordant ADT, mostly due to simultaneous ADT with radiation. Discordant use was seen in 7.3% of intermediate and 14.9% of high-risk patients, mostly from ADT as primary therapy. The odds of receiving guideline-discordant ADT decreased over time (2007 versus 2004; OR 0.69; 95% CI 0.62–0.76). The estimated annual direct cost from discordant ADT is $42 000 000.
Conclusion
Approximately one in eight patients received ADT discordant with published guidelines. Elimination of discordant use would result in substantial savings.
doi:10.1093/annonc/mds618
PMCID: PMC3629897  PMID: 23277483
drug costs; gonadotropin-releasing hormone; health services; prostatic neoplasms; SEER program
21.  Comparative outcomes of oncologic therapy in gastric extranodal marginal zone (MALT) lymphoma: analysis of the SEER-Medicare database 
Annals of Oncology  2013;24(5):1352-1359.
Background
Therapy for gastric marginal zone (MALT) lymphoma is largely based on single-arm trials. This observational study compared survival with radiotherapy, rituximab and combination chemoimmunotherapy in this disease.
Patients and methods
Gastric MALT lymphoma cases diagnosed between 1997 and 2007 were selected from the Surveillance, Epidemiology and End Results-Medicare database. Propensity score analysis and competing risk models were used to compare survival in patients with stage IE treated with radiation or chemotherapy, and in patients of all stages treated with rituximab alone or with chemoimmunotherapy.
Results
Among 1134 patients, 21% underwent radiation and 24% chemotherapy as initial treatment. In the balanced cohort of 347 patients with stage IE, radiotherapy alone was associated with a better cause-specific survival [hazard ratio (HR) 0.27, P < 0.001]. Patients receiving systemic therapy had better survival if it incorporated rituximab (HR 0.53, P = 0.017). After adjustment for confounding, the outcomes of those who received rituximab alone or combination chemoimmunotherapy were not statistically different (P = 0.14).
Conclusions
In elderly patients with stage IE gastric MALT lymphoma, radiotherapy was associated with lower risk of lymphoma-related death than chemotherapy. In those requiring systemic treatment, addition of cytotoxic chemotherapy to rituximab in the first-line regimen was not associated with improved survival.
doi:10.1093/annonc/mds644
PMCID: PMC3629899  PMID: 23348804
chemotherapy; gastric lymphoma; MALT; propensity score; rituximab; SEER-Medicare
22.  Regular recreational physical activity and risk of hematologic malignancies: results from the prospective VITamins And lifestyle (VITAL) study† 
Annals of Oncology  2012;24(5):1370-1377.
Background
Conflicting evidence exists on the relationship between physical activity (PA) and incident hematologic malignancies. Herein, we used a large cohort study to examine this association.
Patients and methods
Sixty-five thousand three hundred twenty-two volunteers aged 50–76 years were recruited from 2000 to 2002. Incident hematologic malignancies (n = 666) were identified through 2009 by linkage to the Surveillance, Epidemiology, and End Results cancer registry. Hazard ratios (HRs) for hematologic malignancies associated with PA averaged over 10 years before baseline were estimated with Cox proportional hazards models, adjusting for factors associated with hematologic cancers or PA.
Results
There was a decreased risk of hematologic malignancies associated with PA (HR = 0.66 [95% confidence interval, 95% CI 0.51–0.86] for the highest tertile of all PA, P-trend = 0.005, and HR = 0.60 [95% CI 0.44–0.82] for the highest tertile of moderate/high-intensity PA, P-trend = 0.002). These associations were strongest for myeloid neoplasms (HR = 0.48 [95% CI 0.29–0.79] for the highest tertile of all PA, P-trend = 0.013, and HR = 0.40 [95% CI 0.21–0.77] for the highest tertile of moderate/high-intensity PA, P-trend = 0.016). There were also significant associations between PA and chronic lymphocytic leukemia/small lymphocytic lymphoma or other mature B-cell lymphomas except plasma cell disorders.
Conclusions
Our study offers the strongest epidemiological evidence, to date, to suggest an association between regular PA and dose-dependent risk reduction for most hematologic malignancies, particularly myeloid neoplasms.
doi:10.1093/annonc/mds631
PMCID: PMC3629898  PMID: 23247659
cancer risk; epidemiology; hematologic malignancies; physical activity; prospective cohort study; VITamins And Lifestyle study
23.  Penile cancer: current therapy and future directions 
Annals of Oncology  2013;24(5):1179-1189.
Background
Penile cancer (PC) is a rare cancer in western countries, but is more common in parts of the developing world. Due to its rarity and the consequent lack of randomized trials, current therapy is based on retrospective studies and small prospective trials.
Design
Studies of PC therapy were searched in PubMed and abstracts at major conferences.
Results
PC is generally an aggressive malignancy characterized by early locoregional lymph node (LN) spread and later metastases in distant sites. Given the strong predictive value of LN involvement for overall survival, evaluating regional LNs is critical. Advanced LN involvement is increasingly being treated with multimodality therapy incorporating chemotherapy and/or radiation. A single superior cisplatin-based regimen has not been defined. Further advances may occur with a better collaboration on an international scale and comprehensive understanding of tumor biology. To this end, the preventive role of circumcision and understanding of the oncogenic roles of Human Papilloma Virus-16, and smoking may yield advances. Preliminary data suggest a role for agents targeting epidermal growth factor receptor and angiogenesis.
Conclusion
Advances in therapy for PC will require efficient trial designs, synergistic collaboration, incentives to industry and the efforts of patient advocacy groups and venture philanthropists.
doi:10.1093/annonc/mds635
PMCID: PMC4047287  PMID: 23293117
biologic agents; chemotherapy; combined modality therapy; molecular targets; penile cancer; radiotherapy
24.  Functional proteomics characterization of residual breast cancer after neoadjuvant systemic chemotherapy 
Annals of Oncology  2012;24(4):909-916.
Background
The purpose of this study was to determine the functional proteomic characteristics of residual breast cancer and hormone receptor (HR)-positive breast cancer after neoadjuvant systemic chemotherapy, and their relationship with patient outcomes.
Methods
Reverse phase protein arrays of 76 proteins were carried out. A boosting approach in conjunction with a Cox proportional hazard model defined relapse predictors. A risk score (RS) was calculated with the sum of the coefficients from the final model. Survival outcomes and associations of the RS with relapse were estimated. An independent test set was used to validate the results.
Results
Test (n = 99) and validation sets (n = 79) were comparable. CoxBoost revealed a three-biomarker (CHK1pS345, Caveolin1, and RAB25) and a two-biomarker (CD31 and Cyclin E1) model that correlated with recurrence-free survival (RFS) in all residual breast cancers and in HR-positive disease, respectively. Unsupervised clustering split patients into high- and low risk of relapse groups with different 3-year RFS (P ≤ 0.001 both). RS was a substantial predictor of RFS (P = 0.0008 and 0.0083) after adjustment for other substantial characteristics. Similar results were found in validation sets.
Conclusions
We found models that independently predicted RFS in all residual breast cancer and in residual HR-positive disease that may represent potential targets of therapy in this resistant disease.
doi:10.1093/annonc/mds530
PMCID: PMC3603436  PMID: 23139263
breast cancer; neoadjuvant chemotherapy; residual disease
25.  Disease volumes as a marker for patient response in malignant pleural mesothelioma 
Annals of Oncology  2012;24(4):999-1005.
Background
The goal of this study was to create a comprehensive model for malignant pleural mesothelioma patient survival utilizing continuous, time-varying estimates of disease volume from computed tomography (CT) imaging in conjunction with clinical covariates.
Patients and methods
Serial CT scans were obtained during the course of clinically standard chemotherapy for 81 patients. The pleural disease volume was segmented for each of the 281 CT scans, and relative changes in disease volume from the baseline scan were tracked over the course of serial follow-up imaging. A prognostic model was built using time-varying disease volume measurements in conjunction with clinical covariates.
Results
Over the course of treatment, disease volume decreased by an average of 19%, and median patient survival was 12.6 months from baseline. In a multivariate survival model, changes in disease volume were significantly associated with patient survival along with disease histology, Eastern Cooperative Oncology Group performance status, and presence of dyspnea.
Conclusions
Analysis of the trajectories of disease volumes during chemotherapy for patients with mesothelioma indicates that increasing disease volume was significantly and independently associated with poor patient prognosis in both univariate and multivariate survival models.
doi:10.1093/annonc/mds535
PMCID: PMC3603437  PMID: 23144443
chest CT; malignant pleural mesothelioma; therapy response assessment

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