Research Spotlight

Hussain, M., C. M. Tangen, I. M. Thompson, Jr., G. P. Swanson, D. P. Wood, W. Sakr, N. A. Dawson, N. B. Haas, T. W. Flaig, T. B. Dorff, D. W. Lin, E. D. Crawford, D. I. Quinn, N. J. Vogelzang and L. M. Glode (2018). “Phase III Intergroup Trial of Adjuvant Androgen Deprivation With or Without Mitoxantrone Plus Prednisone in Patients With High-Risk Prostate Cancer After Radical Prostatectomy: SWOG S9921.” J Clin Oncol: May 20;36(15):1498-1504. Epub 2018 Apr 6.

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Purpose: Patients with high-risk prostate cancer after radical prostatectomy are at risk for death. Adjuvant androgen-deprivation therapy (ADT) may reduce this risk. We hypothesized that the addition of mitoxantrone and prednisone (MP) to adjuvant ADT could reduce mortality compared with adjuvant ADT alone. Methods: Eligible patients had cT1-3N0 prostate cancer with one or more high-risk factors after radical prostatectomy (Gleason score [GS] >/= 8; pT3b, pT4, or pN+ disease; GS 7 and positive margins; or preoperative prostate-specific antigen [PSA] > 15 ng/mL, biopsy GS score > 7, or PSA greater than 10 ng/mL plus biopsy GS > 6. Patients with PSA less than or equal to 0.2 ng/mL after radical prostatectomy were stratified by pT/N stage, GS, and adjuvant radiation plan and randomly assigned to ADT (bicalutamide and goserelin for 2 years) or ADT plus six cycles of MP. The primary end point was overall survival (OS). Median OS was projected to be 10 years in the ADT arm, requiring 680 patients per arm to detect a hazard ratio of 1.30 with 92% power and one-sided alpha = .05. Results: Nine hundred sixty-one eligible intent-to-treat patients were randomly assigned to ADT or ADT + MP from October 1999 to January 2007, when the Data Safety Monitoring Committee recommended stopping accrual as a result of higher leukemia incidence with ADT + MP. Median follow-up was 11.2 years. The 10-year OS estimates were 87% with ADT (expected 50%) and 86% with ADT + MP (hazard ratio, 1.06; 95% CI, 0.79 to 1.43). The 10-year estimate for disease-free survival was 72% for both arms. Prostate cancer was the cause of death in 18% of patients in the ADT arm and 22% in the ADT + MP arm. More patients in the MP arm died of other cancers (36% v 18% in ADT alone arm). Conclusion: MP did not improve OS and increased deaths from other malignancies. The DFS and 10-year OS in these patients treated with 2 years of ADT were encouraging compared with historical estimates, although a definitive conclusion regarding value of ADT may not be made without a nontreatment control arm.

Hachem, R. R., M. Kamoun, M. M. Budev, M. Askar, V. N. Ahya, J. C. Lee, D. J. Levine, M. S. Pollack, G. S. Dhillon, D. Weill, K. B. Schechtman, L. E. Leard, J. A. Golden, L. Baxter-Lowe, T. Mohanakumar, D. B. Tyan and R. D. Yusen (2018). “Human Leukocyte Antigens Antibodies after Lung Transplantation: Primary Results of the HALT Study.” Am J Transplant. Apr 24. [Epub ahead of print].

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Donor-specific antibodies (DSA) to mismatched human leukocyte antigens (HLA) are associated with worse outcomes after lung transplantation. To determine the incidence and characteristics of DSA early after lung transplantation, we conducted a prospective multicenter observational study that used standardized treatment and testing protocols. Among 119 transplant recipients, 43 (36%) developed DSA: 6 (14%) developed DSA only to class I HLA, 23 (53%) developed DSA only to class II HLA, and 14 (33%) developed DSA to both class I and class II HLA. The median DSA mean fluorescence intensity (MFI) was 3197. We identified a significant association between the Lung Allocation Score and the development of DSA (HR = 1.02, 95% CI: 1.001-1.03, P = .047) and a significant association between DSA with an MFI ≥ 3000 and acute cellular rejection (ACR) grade ≥ A2 (HR = 2.11, 95% CI: 1.04-4.27, P = .039). However, we did not detect an association between DSA and survival. We conclude that DSA occur frequently early after lung transplantation, and most target class II HLA. DSA with an MFI ≥ 3000 have a significant association with ACR. Extended follow-up is necessary to determine the impact of DSA on other important outcomes.

Haase, V. H., G. M. Chertow, G. A. Block, P. E. Pergola, E. M. deGoma, Z. Khawaja, A. Sharma, B. J. Maroni and P. A. McCullough (2018). “Effects of vadadustat on hemoglobin concentrations in patients receiving hemodialysis previously treated with erythropoiesis-stimulating agents.” Nephrol Dial Transplant. Apr 16. [Epub ahead of print].

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Background: Vadadustat, an inhibitor of hypoxia-inducible factor prolyl-4-hydroxylase domain dioxygenases, is an oral investigational agent in development for the treatment of anemia secondary to chronic kidney disease. Methods: In this open-label Phase 2 trial, vadadustat was evaluated in 94 subjects receiving hemodialysis, previously maintained on epoetin alfa. Subjects were sequentially assigned to one of three vadadustat dose cohorts by starting dose: 300 mg once daily (QD), 450 mg QD or 450 mg thrice weekly (TIW). The primary endpoint was mean hemoglobin (Hb) change from pre-baseline average to midtrial (Weeks 7-8) and end-of-trial (Weeks 15-16) and was analyzed using available data (no imputation). Results: Overall, 80, 73 and 68% of subjects in the 300 mg QD, 450 mg QD, and 450 mg TIW dose cohorts respectively, completed the study. For all dose cohorts no statistically significant mean change in Hb from pre-baseline average was observed, and mean Hb concentrations-analyzed using available data-remained stable at mid- and end-of-trial. There was one subject with an Hb excursion >13 g/dL. Overall, 83% of subjects experienced an adverse event (AE); the proportion of subjects who experienced at least one AE was similar among the three dose cohorts. The most frequently reported AEs were nausea (11.7%), diarrhea (10.6%) and vomiting (9.6%). No deaths occurred during the study. No serious AEs were attributed to vadadustat. Conclusions: Vadadustat maintained mean Hb concentrations in subjects on hemodialysis previously receiving epoetin. These data support further investigation of vadadustat to assess its long-term safety and efficacy in subjects on hemodialysis.

Goyal, N. G., B. J. Levine, K. J. Van Zee, E. Naftalis and N. E. Avis (2018). “Trajectories of quality of life following breast cancer diagnosis.” Breast Cancer Res Treat 169(1): 163-173.

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PURPOSE: Although quality of life (QoL) improves over time for most breast cancer survivors (BCS), BCS may show different patterns of QoL. This study sought to identify distinct QoL trajectories among BCS and to examine characteristics associated with trajectory group membership. METHODS: BCS (N = 653) completed baseline assessments within 8 months of diagnosis. QoL was assessed by the Functional Assessment of Cancer Therapy-Breast (FACT-B) at baseline and 6, 12, and 18 months later. Finite mixture modeling was used to determine QoL trajectories of the trial outcome index (TOI; a composite of physical well-being, functional well-being, and breast cancer-specific subscales) and emotional and social/family well-being subscales. Chi-square tests and F tests were used to examine group differences in demographic, cancer-related, and psychosocial variables. RESULTS: Unique trajectories were identified for all three subscales. Within each subscale, the majority of BCS had consistently medium or high QoL. The TOI analysis revealed only stable or improving groups, but the emotional and social/family subscales had groups that were stable, improved, or declined. Across all subscales, women in “consistently high” groups had the most favorable psychosocial characteristics. For the TOI and emotional subscales, psychosocial variables also differed significantly between women who started similarly but had differing trajectories. CONCLUSIONS: The majority of BCS report good QoL as they transition from treatment to survivorship. However, some women have persistently low QoL in each domain and some experience declines in emotional and/or social/family well-being. Psychosocial variables are consistently associated with improving and/or declining trajectories of physical/functional and emotional well-being.

Felius, J. and S. A. Hall (2018). “Employment status at the time of heart transplant listing.” J Heart Lung Transplant 37(5): 575-576.

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For those living with a chronic illness, employment status can be seen as a proxy for both functional status and quality of life. In solid-organ transplantation, it has been established that work status immediately before transplantation is associated with clinical outcomes and with the probability of returning to work post-transplantation. Although previous research has established beneficial outcomes linked to work status after heart transplantation, it was heretofore unknown whether work status at the time of transplant listing (as well as in the pre-operative period) is associated with outcomes after transplantation. Although it may be challenging to tease apart the effects of employment during the pre-operative period on clinical outcomes after heart transplantation from potential confounders, such as age, socioeconomic status, and comorbidities, it may prove very useful indeed if employment status per se could be identified as a modifiable risk factor . . . Ravi et al present an analysis of 23,228 adult heart transplant recipients in the United States over the period from 2001 to 2014 through the United Network for Organ Sharing (UNOS) database in their assessment of the relationships between work status before/after transplantation and short, intermediate, and long-term survival . . . The authors concluded that recipients who were working at the time of transplant listing showed better long-term (5- and 10-year) survival, but the differences in 30-day and 1-year survival did not reach statistical significance. Recipients who were working at the time of transplantation showed better post-transplant survival at each time-point. (Excerpts from text; no abstract available.)