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Journal of Clinical Oncology

Journal of Clinical Oncology RSS feed - Early Release
Journal of Clinical Oncology









Purpose

Findings on the association between risk of cardiovascular disease (CVD) and the duration and type of androgen-deprivation therapy (ADT) in men with prostate cancer (PCa) are inconsistent.

Methods

By using data on filled drug prescriptions in Swedish national health care registers, we investigated the risk of CVD in a cohort of 41,362 men with PCa on ADT compared with an age-matched, PCa-free comparison cohort (n = 187,785) by use of multivariable Cox proportional hazards regression models.

Results

From 2006 to 2012, 10,656 men were on antiandrogens (AA), 26,959 were on gonadotropin-releasing hormone (GnRH) agonists, and 3,747 underwent surgical orchiectomy. CVD risk was increased in men on GnRH agonists compared with the comparison cohort (hazard ratio [HR] of incident CVD, 1.21; 95% CI, 1.18 to 1.25; and orchiectomy: HR, 1.16; 95% CI, 1.08 to 1.25). Men with PCa on AA were at decreased risk (HR of incident CVD, 0.87; 95% CI, 0.82 to 0.91). CVD risk was highest during the first 6 months of ADT in men who experienced two or more cardiovascular events before therapy, with an HR of CVD during the first 6 months of GnRH agonist therapy of 1.91 (95% CI, 1.66 to 2.20), an HR of CVD with AA of 1.60 (95% CI, 1.24 to 2.06), and an HR of CVD with orchiectomy of 1.79 (95% CI, 1.16 to 2.76) versus the comparison cohort.

Conclusion

Our results support that there should be a solid indication for ADT in men with PCa so that benefit outweighs potential harm; this is of particular importance among men with a recent history of CVD.




Purpose

Mercaptopurine (MP) is the mainstay of curative therapy for acute lymphoblastic leukemia (ALL). We performed a genome-wide association study (GWAS) to identify comprehensively the genetic basis of MP intolerance in children with ALL.

Patients and Methods

The discovery GWAS and replication cohorts included 657 and 371 children from two prospective clinical trials. MP dose intensity was a marker for drug tolerance and toxicities and was defined as prescribed dose divided by the planned protocol dose during maintenance therapy; its association with genotype was evaluated using a linear mixed-effects model.

Results

MP dose intensity varied by race and ethnicity and was negatively correlated with East Asian genetic ancestry (P < .001). The GWAS revealed two genome-wide significant loci associated with dose intensity: rs1142345 in TPMT (Tyr240Cys, present in *3A and *3C variants; P = 8.6 x 10–9) and rs116855232 in NUDT15 (P = 8.8 x 10–9), with independent replication. Patients with TT genotype at rs116855232 were exquisitely sensitive to MP, with an average dose intensity of 8.3%, compared with those with TC and CC genotypes, who tolerated 63% and 83.5% of the planned dose, respectively. The NUDT15 variant was most common in East Asians and Hispanics, rare in Europeans, and not observed in Africans, contributing to ancestry-related differences in MP tolerance. Of children homozygous for either TPMT or NUDT15 variants or heterozygous for both, 100% required ≥ 50% MP dose reduction, compared with only 7.7% of others.

Conclusion

We describe a germline variant in NUDT15 strongly associated with MP intolerance in childhood ALL, which may have implications for treatment individualization in this disease.


Purpose

In metastatic or recurrent cervical cancer, cisplatin-based chemotherapy is standard. The JCOG0505 randomized phase III trial evaluated the clinical benefits of carboplatin-based regimen.

Patients and Methods

Eligible patients had metastatic or recurrent cervical cancer and had ≤ one platinum-containing treatment and no prior taxane. Patients were randomly assigned either to conventional paclitaxel plus cisplatin (TP; paclitaxel 135 mg/m2 over 24 hours on day 1 and cisplatin 50 mg/m2 on day 2, repeated every 3 weeks) or paclitaxel plus carboplatin (TC; paclitaxel 175 mg/m2 over 3 hours and carboplatin area under curve 5 mg/mL/min on day 1, repeated every 3 weeks). Primary end point was overall survival (OS). Planned sample size was 250 patients to confirm the noninferiority of TC versus TP with the threshold hazard ratio (HR) of 1.29.

Results

Between February 2006 and November 2009, 253 patients were enrolled. The HR of OS was 0.994 (90% CI, 0.79 to 1.25; noninferiority P = .032 by stratified Cox regression). Median OS was 18.3 months with TP versus 17.5 months with TC. Among patients who had not received prior cisplatin, OS was shorter with TC (13.0 v 23.2 months; HR, 1.571; 95% CI, 1.06 to 2.32). One treatment-related death occurred with TC. Proportion of nonhospitalization periods was significantly longer with TC (P < .001).

Conclusion

TC was noninferior to TP and should be a standard treatment option for metastatic or recurrent cervical cancer. However, cisplatin is still the key drug for patients who have not received platinum agents.


Purpose

Three small retrospective studies have suggested that patients undergoing continuous androgen deprivation (CAD) have superior survival and time to progression if lower castrate levels of testosterone (< 0.7 nmol/L) are achieved. Evidence from prospective large studies has been lacking.

Patients and Methods

The PR-7 study randomly assigned patients experiencing biochemical failure after radiation therapy or surgery plus radiation therapy to CAD or intermittent androgen deprivation. The relationship between testosterone levels in the first year and cause-specific survival (CSS) and time to androgen-independent progression in men in the CAD arm was evaluated using Cox regression.

Results

There was a significant difference in CSS (P = .015) and time to hormone resistance (P = .02) among those who had first-year minimum nadir testosterone ≤ 0.7, > 0.7 to ≤ 1.7, and ≥ 1.7 nmol/L. Patients with first-year nadir testosterone consistently > 0.7 nmol/L had significantly higher risks of dying as a result of disease (0.7 to 1.7 nmol/L: hazard ratio [HR], 2.08; 95% CI, 1.28 to 3.38; > 1.7 nmol/L: HR, 2.93; 95% CI, 0.70 to 12.30) and developing hormone resistance (0.7 to 1.7 nmol/L: HR, 1.62; 95% CI, 1.20 to 2.18; ≥ 1.7 nmol/L: HR, 1.90; 95% CI, 0.77 to 4.70). Maximum testosterone ≥ 1.7 nmol/L predicted for a higher risk of dying as a result of disease (P = .02).

Conclusion

Low nadir serum testosterone (ie, < 0.7 mmol/L) within the first year of androgen-deprivation therapy correlates with improved CSS and duration of response to androgen deprivation in men being treated for biochemical failure undergoing CAD.


Purpose

Both presence of minimal residual disease (MRD) and achievement of complete remission (CR) with incomplete platelet recovery (CRp) rather than CR after induction therapy predict relapse in acute myeloid leukemia (AML). These results suggest a correlation between response (peripheral count recovery) and MRD at the time of morphologic remission. Here we examine this hypothesis and whether MRD and response provide independent prognostic information after accounting for other relevant covariates.

Patients and Methods

We retrospectively analyzed data from 245 adults with AML who achieved CR, CRp, or CR with incomplete blood count recovery (CRi) after induction therapy. Bone marrow samples were collected on or closest to the first date of blood count recovery, and MRD was determined by 10-color multiparameter flow cytometry.

Results

The 71.0% of patients who achieved CR had MRD less frequently and had lower levels of MRD than the 19.6% of patients achieving CRp and 9.4% achieving CRi. Although pretreatment covariates such as cytogenetics, monosomal karyotype, relapsed or refractory rather than newly diagnosed AML, and FLT3 internal tandem duplication were associated with relapse, their prognostic effect was much lower once MRD and response were taken into account, the univariable statistical effect of which was not materially affected by inclusion of pretreatment covariates.

Conclusion

Our data indicate that post-therapy parameters including MRD status and response are important independent prognostic factors for outcome in patients with AML achieving remission. MRD status and type of response (CR v CRp or CRi) should play important, and perhaps dominant, roles in planning postinduction therapy.


Purpose

To evaluate the prognostic factors in locally advanced cervical cancer limited to the pelvis and develop nomograms for 2-year progression-free survival (PFS), 5-year overall survival (OS), and pelvic recurrence.

Patients and Methods

We retrospectively reviewed 2,042 patients with locally advanced cervical carcinoma enrolled onto Gynecologic Oncology Group clinical trials of concurrent cisplatin-based chemotherapy and radiotherapy. Nomograms for 2-year PFS, five-year OS, and pelvic recurrence were created as visualizations of Cox proportional hazards regression models. The models were validated by bootstrap-corrected, relatively unbiased estimates of discrimination and calibration.

Results

Multivariable analysis identified prognostic factors including histology, race/ethnicity, performance status, tumor size, International Federation of Gynecology and Obstetrics stage, tumor grade, pelvic node status, and treatment with concurrent cisplatin-based chemotherapy. PFS, OS, and pelvic recurrence nomograms had bootstrap-corrected concordance indices of 0.62, 0.64, and 0.73, respectively, and were well calibrated.

Conclusion

Prognostic factors were used to develop nomograms for 2-year PFS, 5-year OS, and pelvic recurrence for locally advanced cervical cancer clinically limited to the pelvis treated with concurrent cisplatin-based chemotherapy and radiotherapy. These nomograms can be used to better estimate individual and collective outcomes.


Purpose

Secondary acute myeloid leukemia (sAML), defined as AML arising after a prior myelodysplastic syndrome or after antineoplastic therapy, responds poorly to current therapies. It is often associated with adverse karyotypic abnormalities and overexpression of proteins that mediate drug resistance. We performed a phase III trial to determine whether induction therapy with cytarabine and amonafide L-malate, a DNA intercalator and non–ATP-dependent topoisomerase II inhibitor that evades drug resistance mechanisms, yielded a superior complete remission rate than standard therapy with cytarabine and daunorubicin in sAML.

Patients and Methods

Patients with previously untreated sAML were randomly assigned at a one-to-one ratio to cytarabine 200 mg/m2 continuous intravenous (IV) infusion once per day on days 1 to 7 plus either amonafide 600 mg/m2 IV over 4 hours on days 1 to 5 (A + C arm) or daunorubicin 45 mg/m2 IV over 30 minutes once per day on days 1 to 3 (D + C arm).

Results

The complete remission (CR) rate was 46% (99 of 216 patients) in A + C arm and 45% (97 of 217 patients) in D + C arm (P = .81). The 30- and 60-day mortality rates were 19% and 28% in A + C arm and 13% and 21% in D + C arm, respectively.

Conclusion

Induction treatment with A + C did not improve the CR rate compared with D + C in patients with sAML.


Purpose

To evaluate the efficacy of maintenance sunitinib after chemotherapy for small-cell lung cancer (SCLC).

Patients and Methods

The Cancer and Leukemia Group B 30504 trial was a randomized, placebo-controlled, phase II study that enrolled patients before chemotherapy (cisplatin 80 mg/m2 or carboplatin area under the curve of 5 on day 1 plus etoposide 100 mg/m2 per day on days 1 to 3 every 21 days for four to six cycles). Patients without progression were randomly assigned 1:1 to placebo or sunitinib 37.5 mg per day until progression. Cross-over after progression was allowed. The primary end point was progression-free survival (PFS) from random assignment for maintenance placebo versus sunitinib using a one-sided log-rank test with α = .15; 80 randomly assigned patients provided 89% power to detect a hazard ratio (HR) of 1.67.

Results

One hundred forty-four patients were enrolled; 138 patients received chemotherapy. Ninety-five patients were randomly assigned; 10 patients did not receive maintenance therapy (five on each arm). Eighty-five patients received maintenance therapy (placebo, n = 41; sunitinib, n = 44). Grade 3 adverse events with more than 5% incidence were fatigue (19%), decreased neutrophils (14%), decreased leukocytes (7%), and decreased platelets (7%) for sunitinib and fatigue (10%) for placebo; grade 4 adverse events were GI hemorrhage (n = 1) and pancreatitis, hypocalcemia, and elevated lipase (n = 1; all in same patient) for sunitinib and thrombocytopenia (n = 1) and hypernatremia (n = 1) for placebo. Median PFS on maintenance was 2.1 months for placebo and 3.7 months for sunitinib (HR, 1.62; 70% CI, 1.27 to 2.08; 95% CI, 1.02 to 2.60; one-sided P = .02). Median overall survival from random assignment was 6.9 months for placebo and 9.0 months for sunitinib (HR, 1.28; 95% CI, 0.79 to 2.10; one-sided P = .16). Three sunitinib and no placebo patients achieved complete response during maintenance. Ten (77%) of 13 patients evaluable after cross-over had stable disease on sunitinib (6 to 27 weeks).

Conclusion

Maintenance sunitinib was safe and improved PFS in extensive-stage SCLC.


Purpose

Legislation mandating disclosure of breast density (BD) information has passed in 21 states; however, actual awareness of BD and knowledge of its impact on breast cancer detection and risk are unknown.

Methods

We conducted a national cross-sectional survey administered in English and Spanish using a probability-based sample of screening-age women, with oversampling of Connecticut, the only state with BD legislation in effect for > 1 year before the survey.

Results

Of 2,311 women surveyed, 65% responded. Overall, 58% of women had heard of BD, 49% knew that BD affects breast cancer detection, and 53% knew that BD affects cancer risk. After multivariable adjustment, increased BD awareness was associated with white non-Hispanic race/ethnicity (Hispanic v white non-Hispanic: odds ratio [OR], 0.23; P < .001), household income (OR, 1.07 per category increase; P < .001), education (OR, 1.19 per category increase; P < .001), diagnostic evaluation after a mammogram (OR, 2.64; P < .001), and postmenopausal hormone therapy (OR, 1.69; P = .002). Knowledge of the masking effect of BD was associated with higher household income (OR, 1.10; P < .001), education (OR, 1.22; P = .01), prior breast biopsy (OR, 2.16; P < .001), and residing in Connecticut (Connecticut v other states: OR, 3.82; P = .003). Connecticut residents were also more likely to have discussed their BD with a health care provider (67% v 43% for residents of other US states; P = .001).

Conclusion

Disparities in BD awareness and knowledge exist by race/ethnicity, education, and income. BD legislation seems to be effective in increasing knowledge of BD impact on breast cancer detection. These findings support continued and targeted efforts to improve BD awareness and knowledge among women eligible for screening mammography.








Purpose

Trastuzumab emtansine (T-DM1), an antibody–drug conjugate comprising the cytotoxic agent DM1, a stable linker, and trastuzumab, has demonstrated substantial activity in human epidermal growth factor receptor 2 (HER2) –positive metastatic breast cancer, raising interest in evaluating the feasibility and cardiac safety of T-DM1 in early-stage breast cancer (EBC).

Patients and Methods

Patients (N = 153) with HER2-positive EBC and prechemotherapy left ventricular ejection fraction (LVEF) ≥ 55% received (neo)adjuvant doxorubicin plus cyclophosphamide or fluorouracil plus epirubicin plus cyclophosphamide followed by T-DM1 for four cycles. Patients could then receive three to four cycles of optional docetaxel with or without trastuzumab. T-DM1 was then resumed with optional radiotherapy (sequential or concurrent) for 1 year (planned) of HER2-directed therapy. The coprimary end points were rate of prespecified cardiac events and safety.

Results

Median follow-up was 24.6 months. No prespecified cardiac events or symptomatic congestive heart failures were reported. Four patients (2.7%) had asymptomatic LVEF declines (≥ 10 percentage points from baseline to LVEF < 50%), leading to T-DM1 discontinuation in one patient. Of 148 patients who received ≥ one cycle of T-DM1, 82.4% completed the planned 1-year duration of HER2-directed therapy. During T-DM1 treatment, 38.5% and 2.7% of patients experienced grade 3 and 4 adverse events, respectively. Approximately 95% of patients receiving T-DM1 plus radiotherapy completed ≥ 95% of the planned radiation dose with delay ≤ 5 days.

Conclusion

Use of T-DM1 for approximately 1 year after anthracycline-based chemotherapy was feasible and generally well tolerated by patients with HER2-positive EBC, providing support for phase III trials of T-DM1 in this setting.


Purpose

Younger patients with acute myeloid leukemia (AML) harboring NPM1 mutations without FLT3–internal tandem duplications (ITDs; NPM1-positive/FLT3-ITD–negative genotype) are classified as better risk; however, it remains uncertain whether this favorable classification can be applied to older patients with AML with this genotype. Therefore, we examined the impact of age on the prognostic significance of NPM1-positive/FLT3-ITD–negative status in older patients with AML.

Patients and Methods

Patients with AML age ≥ 55 years treated with intensive chemotherapy as part of Southwest Oncology Gorup (SWOG) and UK National Cancer Research Institute/Medical Research Council (NCRI/MRC) trials were evaluated. A comprehensive analysis first examined 156 patients treated in SWOG trials. Validation analyses then examined 1,258 patients treated in MRC/NCRI trials. Univariable and multivariable analyses were used to determine the impact of age on the prognostic significance of NPM1 mutations, FLT3-ITDs, and the NPM1-positive/FLT3-ITD–negative genotype.

Results

Patients with AML age 55 to 65 years with NPM1-positive/FLT3-ITD–negative genotype treated in SWOG trials had a significantly improved 2-year overall survival (OS) as compared with those without this genotype (70% v 32%; P < .001). Moreover, patients age 55 to 65 years with NPM1-positive/FLT3-ITD–negative genotype had a significantly improved 2-year OS as compared with those age > 65 years with this genotype (70% v 27%; P < .001); any potential survival benefit of this genotype in patients age > 65 years was marginal (27% v 16%; P = .33). In multivariable analysis, NPM1-positive/FLT3-ITD–negative genotype remained independently associated with an improved OS in patients age 55 to 65 years (P = .002) but not in those age > 65 years (P = .82). These results were confirmed in validation analyses examining the NCRI/MRC patients.

Conclusion

NPM1-positive/FLT3-ITD–negative genotype remains a relatively favorable prognostic factor for patients with AML age 55 to 65 years but not in those age > 65 years.


Purpose

Bisphosphonates are common medications used for the treatment of osteoporosis and are also used to reduce metastases to bone in patients with cancer. Several studies, including the Women's Health Initiative (WHI), have found that use of bisphosphonates is associated with reduced risk of developing breast cancer, but less is known about associations with other common malignancies. This study was aimed at examining the effects of bisphosphonates on the risk of endometrial cancer.

Methods

We evaluated the relationship between use of oral bisphosphonates and endometrial cancer risk in a cohort of 89,918 postmenopausal women participating in the WHI. A detailed health interview was conducted at baseline, and bisphosphonate use was ascertained from an inventory of regularly used medications at baseline and over follow-up. All women had an intact uterus at the time of study entry.

Results

During a median follow-up of 12.5 years, 1,123 women were diagnosed with incident invasive endometrial cancer. Ever use of bisphosphonates was associated with reduced endometrial cancer risk (adjusted hazard ratio, 0.80; 95% CI, 0.64 to 1.00; P = .05), with no interactions observed with age, body mass index, or indication for use.

Conclusion

In this large prospective cohort of postmenopausal women, bisphosphonate use was associated with a statistically significant reduction in endometrial cancer risk.


Purpose

Fixed-dose rate gemcitabine plus docetaxel achieves objective response in 35% of patients with uterine leiomyosarcoma (uLMS). This study aimed to determine whether the addition of bevacizumab to gemcitabine-docetaxel increases progression-free survival (PFS) in uLMS.

Patients and Methods

In this phase III, double-blind, placebo-controlled trial, patients with chemotherapy-naive, metastatic, unresectable uLMS were randomly assigned to gemcitabine-docetaxel plus bevacizumab or gemcitabine-docetaxel plus placebo. PFS, overall survival (OS), and objective response rates (ORRs) were compared to determine superiority. Target accrual was 130 patients to detect an increase in median PFS from 4 months (gemcitabine-docetaxel plus placebo) to 6.7 months (gemcitabine-docetaxel plus bevacizumab). Treatment effects on PFS and OS were described by hazard ratios (HRs), median times to event, and 95% CIs.

Results

In all, 107 patients were accrued: gemcitabine-docetaxel plus placebo (n = 54) and gemcitabine-docetaxel plus bevacizumab (n = 53). Accrual was stopped early for futility. No statistically significant differences in grade 3 to 4 toxicities were observed. Median PFS was 6.2 months for gemcitabine-docetaxel plus placebo versus 4.2 months for gemcitabine-docetaxel plus bevacizumab (HR, 1.12; P = .58). Median OS was 26.9 months for gemcitabine-docetaxel plus placebo and 23.3 months for gemcitabine-docetaxel plus bevacizumab (HR, 1.07; P = .81). Objective responses were observed in 17 (31.5%) of 54 patients randomly assigned to gemcitabine-docetaxel plus placebo and 19 (35.8%) of 53 patients randomly assigned to gemcitabine-docetaxel plus bevacizumab. Mean duration of response was 8.6 months for gemcitabine-docetaxel plus placebo versus 8.8 months for gemcitabine-docetaxel plus bevacizumab.

Conclusion

The addition of bevacizumab to gemcitabine-docetaxel for first-line treatment of metastatic uLMS failed to improve PFS, OS, or ORR. Gemcitabine-docetaxel remains a standard first-line treatment for uLMS.


Purpose

Survivors of cervical cancer experience quality-of-life (QOL) disruptions that persist years after treatment. This study examines the effect of a psychosocial telephone counseling (PTC) intervention on QOL domains and associations with biomarkers.

Patients and Methods

We conducted a randomized clinical trial in survivors of cervical cancer, who were ≥ 9 and less than 30 months from diagnosis (n = 204), to compare PTC to usual care (UC). PTC included five weekly sessions and a 1-month booster. Patient-reported outcomes (PROs) and biospecimens were collected at baseline and 4 and 9 months after enrollment. Changes in PROs over time and associations with longitudinal change in cytokines as categorical variables were analyzed using multivariable analysis of variance for repeated measures.

Results

Participant mean age was 43 years; 40% of women were Hispanic, and 51% were non-Hispanic white. Adjusting for age and baseline scores, participants receiving PTC had significantly improved depression and improved gynecologic and cancer-specific concerns at 4 months compared with UC participants (all P < .05); significant differences in gynecologic and cancer-specific concerns (P < .05) were sustained at 9 months. Longitudinal change in overall QOL and anxiety did not reach statistical significance. Participants with decreasing interleukin (IL) -4, IL-5, IL-10, and IL-13 had significantly greater improvement in QOL than those with increasing cytokine levels.

Conclusion

This trial confirms that PTC benefits mood and QOL cancer-specific and gynecologic concerns for a multiethnic underserved population of survivors of cancer. The improvement in PROs with decreases in T-helper type 2 and counter-regulatory cytokines supports a potential biobehavioral pathway relevant to cancer survivorship.


Purpose

The American College of Surgeons Commission on Cancer has mandated implementation of a systematic protocol for psychosocial distress screening and referral as a condition for cancer center accreditation beginning in 2015. Compliance with standards requires evidence that distress screening protocols are carried out as intended and result in appropriate referral and follow-up when indicated. The purpose of this study was to examine the fidelity of distress screening protocols at two tertiary cancer treatment centers.

Methods

A retrospective review and analysis of electronic medical records over a 12-week period examined clinic adherence to a prescribed distress screening protocol and responsiveness to patients whose scores on the National Comprehensive Cancer Network Distress Thermometer (DT) indicated clinically significant levels of distress requiring subsequent psychosocial contact. A weekly online survey assessed clinician perspectives on the acceptability of the protocol.

Results

Across clinics, rates of adherence to the distress screening protocol ranged from 47% to 73% of eligible patients. For patients indicating clinically significant distress (DT score ≥ 4), documentation of psychosocial contact or referral occurred, on average, 50% to 63% of the time, and was more likely to occur at one of two participating institutions when DT scores were high (DT score of 8 to 10). Clinician assessments of the protocol's utility in addressing patient concerns and responding to patient needs were generally positive.

Conclusion

Systematic tracking of distress screening protocols is needed to demonstrate compliance with new standards of care and to demonstrate how well institutions are responding to their clinical obligation to address cancer patients' emotional and psychosocial needs.


Purpose

We have previously reported that radiotherapy (RT) added to androgen-deprivation therapy (ADT) improves survival in men with locally advanced prostate cancer. Here, we report the prespecified final analysis of this randomized trial.

Patients and Methods

NCIC Clinical Trials Group PR.3/Medical Research Council PR07/Intergroup T94-0110 was a randomized controlled trial of patients with locally advanced prostate cancer. Patients with T3-4, N0/Nx, M0 prostate cancer or T1-2 disease with either prostate-specific antigen (PSA) of more than 40 μg/L or PSA of 20 to 40 μg/L plus Gleason score of 8 to 10 were randomly assigned to lifelong ADT alone or to ADT+RT. The RT dose was 64 to 69 Gy in 35 to 39 fractions to the prostate and pelvis or prostate alone. Overall survival was compared using a log-rank test stratified for prespecified variables.

Results

One thousand two hundred five patients were randomly assigned between 1995 and 2005, 602 to ADT alone and 603 to ADT+RT. At a median follow-up time of 8 years, 465 patients had died, including 199 patients from prostate cancer. Overall survival was significantly improved in the patients allocated to ADT+RT (hazard ratio [HR], 0.70; 95% CI, 0.57 to 0.85; P < .001). Deaths from prostate cancer were significantly reduced by the addition of RT to ADT (HR, 0.46; 95% CI, 0.34 to 0.61; P < .001). Patients on ADT+RT reported a higher frequency of adverse events related to bowel toxicity, but only two of 589 patients had grade 3 or greater diarrhea at 24 months after RT.

Conclusion

This analysis demonstrates that the previously reported benefit in survival is maintained at a median follow-up of 8 years and firmly establishes the role of RT in the treatment of men with locally advanced prostate cancer.


Purpose

There is evidence from nonrandomized studies that a proportion of ipilimumab-treated patients with advanced melanoma experience long-term survival. To demonstrate a long-term survival benefit with ipilimumab, we evaluated the 5-year survival rates of patients treated in a randomized, controlled phase III trial.

Patients and Methods

A milestone survival analysis was conducted to capture the 5-year survival rate of treatment-naive patients with advanced melanoma who received ipilimumab in a phase III trial. Patients were randomly assigned 1:1 to receive ipilimumab at 10 mg/kg plus dacarbazine (n = 250) or placebo plus dacarbazine (n = 252) at weeks 1, 4, 7, and 10 followed by dacarbazine alone every 3 weeks through week 22. Eligible patients could receive maintenance ipilimumab or placebo every 12 weeks beginning at week 24. A safety analysis was conducted on patients who survived at least 5 years and continued to receive ipilimumab as maintenance therapy.

Results

The 5-year survival rate was 18.2% (95% CI, 13.6% to 23.4%) for patients treated with ipilimumab plus dacarbazine versus 8.8% (95% CI, 5.7% to 12.8%) for patients treated with placebo plus dacarbazine (P = .002). A plateau in the survival curve began at approximately 3 years. In patients who survived at least 5 years and continued to receive ipilimumab, grade 3 or 4 immune-related adverse events were observed exclusively in the skin.

Conclusion

The additional survival benefit of ipilimumab plus dacarbazine is maintained with twice as many patients alive at 5 years compared with those who initially received placebo plus dacarbazine. These results demonstrate a durable survival benefit with ipilimumab in advanced melanoma.


Purpose

To evaluate the breast cancer screening efficacy of mammography, ultrasound, and magnetic resonance imaging (MRI) in a high-risk population and in various population subgroups.

Patients and Methods

In a single-center, prospective, nonrandomized comparison study, BRCA mutation carriers and women with a high familial risk (> 20% lifetime risk) for breast cancer were offered screening with mammography, ultrasound, and MRI every 12 months. Diagnostic performance was compared between individual modalities and their combinations. Further comparisons were based on subpopulations dichotomized by screening rounds, mutation status, age, and breast density.

Results

There were 559 women with 1,365 complete imaging rounds included in this study. The sensitivity of MRI (90.0%) was significantly higher (P < .001) than that of mammography (37.5%) and ultrasound (37.5%). Of 40 cancers, 18 (45.0%) were detected by MRI alone. Two cancers were found by mammography alone (a ductal carcinoma in situ [DCIS] with microinvasion and a DCIS with < 10-mm invasive areas). This did not lead to a significant increase of sensitivity compared with using MRI alone (P = .15). No cancers were detected by ultrasound alone. Similarly, of 14 DCISs, all were detected by MRI, whereas mammography and ultrasound each detected five DCISs (35.7%). Age, mutation status, and breast density had no influence on the sensitivity of MRI and did not affect the superiority of MRI over mammography and ultrasound.

Conclusion

MRI allows early detection of familial breast cancer regardless of patient age, breast density, or risk status. The added value of mammography is limited, and there is no added value of ultrasound in women undergoing MRI for screening.


Treatment of glioblastoma (GBM), the most common primary malignant brain tumor in adults, remains a significant unmet need in oncology. Historically, cytotoxic treatments provided little durable benefit, and tumors recurred within several months. This has spurred a substantial research effort to establish more effective therapies for both newly diagnosed and recurrent GBM. In this context, antiangiogenic therapy emerged as a promising treatment strategy because GBMs are highly vascular tumors. In particular, GBMs overexpress vascular endothelial growth factor (VEGF), a proangiogenic cytokine. Indeed, many studies have demonstrated promising radiographic response rates, delayed tumor progression, and a relatively safe profile for anti-VEGF agents. However, randomized phase III trials conducted to date have failed to show an overall survival benefit for antiangiogenic agents alone or in combination with chemoradiotherapy. These results indicate that antiangiogenic agents may not be beneficial in unselected populations of patients with GBM. Unfortunately, biomarker development has lagged behind in the process of drug development, and no validated biomarker exists for patient stratification. However, hypothesis-generating data from phase II trials that reveal an association between increased perfusion and/or oxygenation (ie, consequences of vascular normalization) and survival suggest that early imaging biomarkers could help identify the subset of patients who most likely will benefit from anti-VEGF agents. In this article, we discuss the lessons learned from the trials conducted to date and how we could potentially use recent advances in GBM biology and imaging to improve outcomes of patients with GBM who receive antiangiogenic therapy.












Purpose

Nonadherence to adjuvant hormonal therapy is common and is associated with increased prescription copayment amount and black race. Studies suggest that household wealth may partly explain racial disparities. We investigated the impact of net worth on disparities in adherence and discontinuation.

Patients and Methods

We used the OptumInsight insurance claims database to identify women older than age 50 years diagnosed with early breast cancer, from January 1, 2007, to December 31, 2011, who were using hormonal therapy. Nonadherence was defined as a medication possession ratio of ≤ 80% of eligible days over a 2-year period. We evaluated the association of demographic and clinical characteristics, annual household income, household net worth (< $250,000, $250,000 to $750,000, or > $750,000), insurance type, and copayments (< $10, $10 to $20, or > $20) with adherence to hormonal therapy. Logistic regression analyses were conducted by sequentially adding sociodemographic and financial variables to race.

Results

We identified 10,302 patients; 2,473 (24%) were nonadherent. In the unadjusted analyses, adherence was negatively associated with black race (odds ratio [OR], 0.76; P < .001), advanced age, comorbidity, and Medicare insurance. Adherence was positively associated with medium (OR, 1.33; P < .001) and high (OR, 1.66; P < .001) compared with low net worth. The negative association of black race with adherence (OR, 0.76) was reduced by adding net worth to the model (OR, 0.84; P < .05). Correcting for other variables had a minimal impact on the association between race and adherence (OR, 0.87; P = .08). The interaction between net worth and race was significant (P < .01).

Conclusion

We found that net worth partially explains racial disparities in hormonal therapy adherence. These results suggest that economic factors may contribute to disparities in the quality of care.


Purpose

The addition of bevacizumab to fluorouracil-based chemotherapy is a standard of care for previously untreated metastatic colorectal cancer. Continuation of bevacizumab beyond progression is an accepted standard of care based on a 1.4-month increase in median overall survival observed in a randomized trial. No United States–based cost-effectiveness modeling analyses are currently available addressing the use of bevacizumab in metastatic colorectal cancer. Our objective was to determine the cost effectiveness of bevacizumab in the first-line setting and when continued beyond progression from the perspective of US payers.

Methods

We developed two Markov models to compare the cost and effectiveness of fluorouracil, leucovorin, and oxaliplatin with or without bevacizumab in the first-line treatment and subsequent fluorouracil, leucovorin, and irinotecan with or without bevacizumab in the second-line treatment of metastatic colorectal cancer. Model robustness was addressed by univariable and probabilistic sensitivity analyses. Health outcomes were measured in life-years and quality-adjusted life-years (QALYs).

Results

Using bevacizumab in first-line therapy provided an additional 0.10 QALYs (0.14 life-years) at a cost of $59,361. The incremental cost-effectiveness ratio was $571,240 per QALY. Continuing bevacizumab beyond progression provided an additional 0.11 QALYs (0.16 life-years) at a cost of $39,209. The incremental cost-effectiveness ratio was $364,083 per QALY. In univariable sensitivity analyses, the variables with the greatest influence on the incremental cost-effectiveness ratio were bevacizumab cost, overall survival, and utility.

Conclusion

Bevacizumab provides minimal incremental benefit at high incremental cost per QALY in both the first- and second-line settings of metastatic colorectal cancer treatment.


Purpose

To test whether combining bevacizumab, an anti–vascular endothelial growth factor treatment, with endocrine therapy (ET) could potentially delay the emergence of resistance to ET.

Patients and Methods

A multicenter, randomized, open-label, phase III, binational (Spain and Germany) study added bevacizumab (15 mg/kg every 3 weeks) to ET (ET-B; letrozole or fulvestrant) as first-line therapy in postmenopausal patients with human epidermal growth factor receptor 2 (HER2) –negative and hormone receptor–positive advanced breast cancer. We compared progression-free survival (PFS), overall survival (OS), overall response rate (ORR), response duration (RD), time to treatment failure (TTF), clinical benefit rate (CBR), and safety.

Results

From 380 patients recruited (2007 to 2011), 374 were analyzed by intent to-treat (184 patients on ET and 190 patients on ET-B). Median age was 65 years, 270 patients (72%) had Eastern Cooperative Oncology Group performance status of 0, 178 patients (48%) had visceral metastases, and 171 patients (46%) and 195 patients (52%) had received prior chemotherapy or ET, respectively. Median PFS was 14.4 months in the ET arm and 19.3 months in the ET-B arm (hazard ratio, 0.83; 95% CI, 0.65 to 1.06; P = .126). ORR, CBR, and RD with ET versus ET-B were 22% versus 41% (P < .001), 67% versus 77% (P = .041), and 13.3 months versus 17.6 months (P = .434), respectively. TTF and OS were comparable in both arms. Grade 3 to 4 hypertension, aminotransferase elevation, and proteinuria were significantly higher in the ET-B arm. Eight patients (4.2%) receiving ET-B died during study or within 30 days of end of treatment.

Conclusion

The addition of bevacizumab to ET in first-line treatment failed to produce a statistically significant increase in PFS or OS in women with HER2-negative/hormone receptor–positive advanced breast cancer.