bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety Profile of Nivolumab Monotherapy: A Pooled Analysis of Patients With Advanced Melanoma
Authors: Weber Jeffrey S. , Hodi F. Stephen , Wolchok Jedd D. , Topalian Suzanne L. , Schadendorf Dirk , Larkin James , Sznol Mario , Long Georgina V. , Li Hewei , Waxman Ian M. , Jiang Joel , Robert Caroline
Published: February 2017

Purpose

We conducted a retrospective analysis to assess the safety profile of nivolumab monotherapy in patients with advanced melanoma and describe the management of adverse events (AEs) using established safety guidelines.

Patients and Methods

Safety data were pooled from four studies, including two phase III trials, with patients who received nivolumab 3 mg/kg once every 2 weeks. We evaluated rate of treatment-related AEs, time to onset and resolution of select AEs (those with potential immunologic etiology), and impact of select AEs and suppressive immune-modulating agents (IMs) on antitumor efficacy.

Results

Among 576 patients, 71% (95% CI, 67% to 75%) experienced any-grade treatment-related AEs (most commonly fatigue [25%], pruritus [17%], diarrhea [13%], and rash [13%]), and 10% (95% CI, 8% to 13%) experienced grade 3 to 4 treatment-related AEs. No drug-related deaths were reported. Select AEs (occurring in 49% of patients) were most frequently skin related, GI, endocrine, and hepatic; grade 3 to 4 select AEs occurred in 4% of patients. Median time to onset of select AEs ranged from 5 weeks for skin to 15 weeks for renal AEs. Approximately 24% of patients received systemic IMs to manage select AEs, which in most cases resolved. Adjusting for number of doses, objective response rate (ORR) was significantly higher in patients who experienced treatment-related select AEs of any grade compared with those who did not. ORRs were similar in patients who did and patients who did not receive systemic IMs.

Conclusion

Treatment-related AEs with nivolumab monotherapy were primarily low grade, and most resolved with established safety guidelines. Use of IMs did not affect ORR, although treatment-related select AEs of any grade were associated with higher ORR, but no progression-free survival benefit.
Reduced CD62L Expression on T Cells and Increased Soluble CD62L Levels Predict Molecular Response to Tyrosine Kinase Inhibitor Therapy in Early Chronic-Phase Chronic Myelogenous Leukemia
Authors: Sopper Sieghart , Mustjoki Satu , White Deborah , Hughes Timothy , Valent Peter , Burchert Andreas , Gjertsen Bjørn T. , Gastl Günther , Baldauf Matthias , Trajanoski Zlatko , Giles Frank , Hochhaus Andreas , Ernst Thomas , Schenk Thomas , Janssen Jeroen J.W.M. , Ossenkoppele Gert J. , Porkka Kimmo , Wolf Dominik
Published: February 2017

Purpose

Immunologic surveillance of minimal residual disease in chronic myelogenous leukemia (CML) may be relevant for long-term control or cure of CML. Little is known about immune-modulatory effects of nilotinib in vivo, potentially predicting response to therapy.

Patients and Methods

A prospective and comprehensive flow cytometry–based immunomonitoring program paralleled the ENEST1st clinical study, investigating 52 nilotinib-naïve patients with chronic-phase CML. Data were verified in independent validation cohorts.

Results

T cells of patients with CML at diagnosis expressed low l-selectin (CD62L) levels, which was not a result of proportional aberrations of T-cell subsets. Low numbers of CD62L-expressing CD4+ and CD8+ T cells correlated with higher Sokal score, increased spleen size, and high leukocyte and peripheral-blood blast counts. At month 6 during nilotinib therapy, CD62L expression returned to levels of healthy individuals. The level of CD62L loss on T cells directly correlated with the extent of soluble CD62L (sCD62L) elevation. In parallel, the proteolytic activity of tumor necrosis factor α–converting enzyme (TACE; ADAM17, CD156b), the metalloproteinase shedding CD62L, was increased at diagnosis and significantly decreased during nilotinib treatment. High CD62L+ expression on both CD4+ and CD8+ T cells and, vice versa, low sCD62L levels at CML diagnosis were linked to superior molecular responses. These findings were corroborated in independent validation cohorts.

Conclusion

We demonstrate the prognostic impact of CD62L shedding from T cells and increased sCD62L plasma levels at CML diagnosis on molecular response to tyrosine kinase inhibitor therapy in early chronic-phase CML. Functionally, decreased CD62L may be a consequence of increased TACE-mediated CD62L cleavage and potentially impairs immune-cell function. Larger prospective studies are ongoing to confirm the prognostic relevance of this finding.
Impact of Extent of Resection on Local Control and Survival in Patients From the COG A3973 Study With High-Risk Neuroblastoma
Authors: von Allmen Daniel , Davidoff Andrew M. , London Wendy B. , Van Ryn Collin , Haas-Kogan Daphne A. , Kreissman Susan G. , Khanna Geetika , Rosen Nancy , Park Julie R. , La Quaglia Michael P.
Published: February 2017

Purpose

This analysis of patients in the Children’s Oncology Group A3973 study evaluated the impact of extent of primary tumor resection on local progression and survival and assessed concordance between clinical and central imaging review–based assessments of resection extent.

Patients and Methods

The analytic cohort (n = 220) included patients who had both central surgery review and resection of the primary tumor site. For this analysis, resection categories of < 90% and ≥ 90% were used, with data on resection extent derived from operating surgeons’ assessments (all patients), as well as blinded central imaging review of computed tomography scans for a subset of 84 patients; assessment results were compared for concordance. Treatment outcomes included event-free survival (EFS), overall survival (OS), and cumulative incidence of local progression (CILP).

Results

Surgeon-assessed extent of resection was ≥ 90% in 154 (70%) patients and < 90% in 66 (30%). Five-year EFS, OS, and CILP (± SE) were 43.5% ± 3.7%, 54.9% ± 3.7%, and 11.9% ± 2.2%, respectively. EFS was higher with ≥ 90% resection (45.9% ± 4.3%) than with < 90% resection (37.9% ± 7.2%; P = .04). Lower CILP ( P = .01) was associated with ≥ 90% resection (8.5% ± 2.3%) compared with < 90% resection (19.8% ± 5.0%). On multivariable analysis, ≥ 90% resection was associated with longer EFS after adjustment for MYCN amplification or diploidy but had no significant effect on OS. Concordance between surgeons’ assessments of resection extent and central image–guided review was low, with agreement of 63% (< 90% v ≥ 90%; simple κ = −0.0301).

Conclusion

Despite discordance between clinical assessment of resection extent and assessment via central imaging review, a surgeon-assessed resection extent ≥ 90% was associated with significantly better EFS and lower CILP. Improving OS, however, remains a challenge in this disease. These findings support continued attempts at ≥ 90% resection of the primary tumor in high-risk neuroblastoma.
American Society of Clinical Oncology Obesity Initiative: Rationale, Progress, and Future Directions
Authors: Ligibel Jennifer A. , Wollins Dana
Published: February 2017

Obesity is increasingly being linked to the risk of developing and dying from cancer. In recognition of the growing contribution of obesity to cancer risk and outcomes, ASCO made obesity and cancer one of its core initiatives in 2014. The goals of this initiative included raising awareness of the relationship between obesity and cancer, providing tools and resources to oncology providers and patients to help encourage conversations regarding weight management in cancer survivors, fostering a robust research agenda, and advocating for access to evidence-based weight management programs for cancer survivors. Efforts to date have included developing patient and provider toolkits focused on weight management and physical activity, publishing a policy statement outlining ASCO’s initiatives in this area, and hosting a summit focused on obesity research in cancer populations. As ASCO has defined its priorities in the area of obesity and cancer, it has become increasingly clear that obesity is a problem that extends far beyond its impact on cancer risk and outcomes. Many groups, including those focused on heart disease, diabetes, and endocrinology, have been developing, testing, and implementing obesity prevention and treatment strategies for years. As ASCO moves forward with its obesity initiative, the next steps will focus on forging collaboration with groups working on obesity-related initiatives both within and outside of the field of cancer to learn from their efforts and to partner with them on efforts to increase the education of medical professionals; raising awareness in lay populations regarding the negative health consequences of obesity and effective strategies to foster weight loss; developing collaborative research initiatives; and working together to advocate for the societal changes that will be needed to combat the obesity epidemic in the United States and beyond.
Obesity and Cancer Mechanisms: Tumor Microenvironment and Inflammation
Authors: Iyengar Neil M. , Gucalp Ayca , Dannenberg Andrew J. , Hudis Clifford A.
Published: February 2017

Purpose

There is growing evidence that inflammation is a central and reversible mechanism through which obesity promotes cancer risk and progression.

Methods

We review recent findings regarding obesity-associated alterations in the microenvironment and the local and systemic mechanisms through which these changes support tumor growth.

Results

Locally, hyperadiposity is associated with altered adipose tissue function, adipocyte death, and chronic low-grade inflammation. Most individuals who are obese harbor inflamed adipose tissue, which resembles chronically injured tissue, with immune cell infiltration and remodeling. Within this distinctly altered local environment, several pathophysiologic changes are found that may promote breast and other cancers. Consistently, adipose tissue inflammation is associated with a worse prognosis in patients with breast and tongue cancers. Systemically, the metabolic syndrome, including dyslipidemia and insulin resistance, occurs in the setting of adipose inflammation and operates in concert with local mechanisms to sustain the inflamed microenvironment and promote tumor growth. Importantly, adipose inflammation and its protumor consequences can be found in some individuals who are not considered to be obese or overweight by body mass index.

Conclusion

The tumor-promoting effects of obesity occur at the local level via adipose inflammation and associated alterations in the microenvironment, as well as systemically via circulating metabolic and inflammatory mediators associated with adipose inflammation. Accurately characterizing the obese state and identifying patients at increased risk for cancer development and progression will likely require more precise assessments than body mass index alone. Biomarkers of adipose tissue inflammation would help to identify high-risk populations. Moreover, adipose inflammation is a reversible process and represents a novel therapeutic target that warrants further study to break the obesity-cancer link.
Use of Medications for Treating Anxiety and Depression in Cancer Survivors in the United States
Authors: Hawkins Nikki A. , Soman Ashwini , Buchanan Lunsford Natasha , Leadbetter Steven , Rodriguez Juan L.
Published: February 2017

Purpose

This study used population-based data to estimate the percentage of cancer survivors in the United States reporting current medication use for anxiety and depression and to characterize the survivors taking this type of medication. Rates of medication use in cancer survivors were compared with rates in the general population.

Methods

We analyzed data from the National Health Interview Survey, years 2010 to 2013, identifying cancer survivors (n = 3,184) and adults with no history of cancer (n = 44,997) who completed both the Sample Adult Core Questionnaire and the Adult Functioning and Disability Supplement.

Results

Compared with adults with no history of cancer, cancer survivors were significantly more likely to report taking medication for anxiety (16.8% v 8.6%, P < .001), depression (14.1% v 7.8%, P < .001), and one or both of these conditions combined (19.1% v 10.4%, P < .001), indicating that an estimated 2.5 million cancer survivors were taking medication for anxiety or depression in the United States at that time. Survivor characteristics associated with higher rates of medication use for anxiety included being younger than 65 years old, female, and non-Hispanic white, and having public insurance, a usual source of medical care, and multiple chronic health conditions. Survivor characteristics associated with medication use for depression were largely consistent with those for anxiety, with the exceptions that insurance status was not significant, whereas being widowed/divorced/separated was associated with more use.

Conclusion

Cancer survivors in the United States reported medication use for anxiety and depression at rates nearly two times those reported by the general public, likely a reflection of greater emotional and physical burdens from cancer or its treatment.
Obesity and Cancer Mechanisms: Cancer Metabolism
Authors: Hopkins Benjamin D. , Goncalves Marcus D. , Cantley Lewis C.
Published: February 2017

Obesity is a risk factor for cancer development and is associated with poor prognosis in multiple tumor types. The positive energy balance linked with obesity induces a variety of systemic changes including altered levels of insulin, insulin-like growth factor-1, leptin, adiponectin, steroid hormones, and cytokines. Each of these factors alters the nutritional milieu and has the potential to create an environment that favors tumor initiation and progression. Although the complete ramifications of obesity as it relates to cancer are still unclear, there is convincing evidence that reducing the magnitude of the systemic hormonal and inflammatory changes has significant clinical benefits. This review will examine the changes that occur in the obese state and review the biologic mechanisms that connect these changes to increased cancer risk. Understanding the metabolic changes that occur in obese individuals may also help to elucidate more effective treatment options for these patients when they develop cancer. Moving forward, targeted clinical trials examining the effects of behavioral modifications such as reduced carbohydrate intake, caloric restriction, structured exercise, and/or pharmacologic interventions such as the use of metformin, in obese populations may help to reduce their cancer risk.
CpG Methylation Signature Predicts Recurrence in Early-Stage Hepatocellular Carcinoma: Results From a Multicenter Study
Authors: Qiu Jiliang , Peng Baogang , Tang Yunqiang , Qian Yeben , Guo Pi , Li Mengfeng , Luo Junhang , Chen Bin , Tang Hui , Lu Canliang , Cai Muyan , Ke Zunfu , He Wei , Zheng Yun , Xie Dan , Li Binkui , Yuan Yunfei
Published: February 2017

Purpose

Early-stage hepatocellular carcinoma (E-HCC) is being diagnosed increasingly, and in one half of diagnosed patients, recurrence will develop. Thus, it is urgent to identify recurrence-related markers. We investigated the effectiveness of CpG methylation in predicting recurrence for patients with E-HCCs.

Patients and Methods

In total, 576 patients with E-HCC from four independent centers were sorted by three phases. In the discovery phase, 66 tumor samples were analyzed using the Illumina Methylation 450k Beadchip. Two algorithms, Least Absolute Shrinkage and Selector Operation and Support Vector Machine-Recursive Feature Elimination, were used to select significant CpGs. In the training phase, penalized Cox regression was used to further narrow CpGs into 140 samples. In the validation phase, candidate CpGs were validated using an internal cohort (n = 141) and two external cohorts (n = 191 and n =104).

Results

After combining the 46 CpGs selected by the Least Absolute Shrinkage and Selector Operation and the Support Vector Machine-Recursive Feature Elimination algorithms, three CpGs corresponding to SCAN domain containing 3, Src homology 3-domain growth factor receptor-bound 2-like interacting protein 1, and peptidase inhibitor 3 were highlighted as candidate predictors in the training phase. On the basis of the three CpGs, a methylation signature for E-HCC (MSEH) was developed to classify patients into high- and low-risk recurrence groups in the training cohort ( P < .001). The performance of MSEH was validated in the internal cohort ( P < .001) and in the two external cohorts ( P < .001; P = .002). Furthermore, a nomogram comprising MSEH, tumor differentiation, cirrhosis, hepatitis B virus surface antigen, and antivirus therapy was generated to predict the 5-year recurrence-free survival in the training cohort, and it performed well in the three validation cohorts (concordance index: 0.725, 0.697, and 0.693, respectively).

Conclusion

MSEH, a three-CpG–based signature, is useful in predicting recurrence for patients with E-HCC.
Beyond Positive Margins and Extracapsular Extension: Evaluating the Utilization and Clinical Impact of Postoperative Chemoradiotherapy in Resected Locally Advanced Head and Neck Cancer
Authors: Trifiletti Daniel M. , Smith Andrew , Mitra Nandita , Grover Surbhi , Lukens John N. , Cohen Roger B. , Read Paul , Mendenhall William M. , Lin Alexander , Swisher-McClure Samuel
Published: February 2017

Purpose

To examine recent utilization and survival outcomes associated with use of adjuvant chemoradiotherapy (CRT) for patients with resected locally advanced head and neck cancer (LAHNC) with negative surgical margins (SM negative) and no extracapsular extension (ECE).

Materials and Methods

We conducted a retrospective observational cohort study using the National Cancer Database evaluating patients diagnosed in 2004 to 2012 with AJCC stage III to IVB squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx treated with definitive surgery and adjuvant radiotherapy (RT) or CRT. We identified a subset of patients with SM negative and no ECE (n = 10,870). We determined factors associated with CRT use and examined overall survival of patients receiving CRT versus RT. We further evaluated survival outcomes by number of lymph nodes involved to assess whether this was associated with benefit from CRT.

Results

Among patients with resected LAHNC with SM negative and no ECE, 47% received adjuvant CRT. The use of CRT varied substantially according to several factors, including patient age, contralateral/bulky neck disease, increasing number of positive lymph nodes, and lower neck disease. CRT was associated with a statistically significant improvement in overall survival compared with RT alone (hazard ratio, 0.90; 95% CI, 0.86 to 0.94; P < .001). Survival benefits of CRT versus RT alone increased in patients with multiple positive lymph nodes.

Conclusion

The use of adjuvant CRT in patients with resected LAHNC with SM negative and no ECE is common. Substantial practice variation as well as the survival differences observed in this study support the conduct of additional research to guide personalized treatment approaches in this setting. The number of positive lymph nodes seems to be an appropriate selection factor for further investigation of CRT in such patients.
Economic Burden of Chronic Lymphocytic Leukemia in the Era of Oral Targeted Therapies in the United States
Authors: Chen Qiushi , Jain Nitin , Ayer Turgay , Wierda William G. , Flowers Christopher R. , O’Brien Susan M. , Keating Michael J. , Kantarjian Hagop M. , Chhatwal Jagpreet
Published: February 2017

Purpose

Oral targeted therapies represent a significant advance for the treatment of patients with chronic lymphocytic leukemia (CLL); however, their high cost has raised concerns about affordability and the economic impact on society. Our objective was to project the future prevalence and cost burden of CLL in the era of oral targeted therapies in the United States.

Methods

We developed a simulation model that evaluated the evolving management of CLL from 2011 to 2025: chemoimmunotherapy (CIT) as the standard of care before 2014, oral targeted therapies for patients with del(17p) and relapsed CLL from 2014, and for first-line treatment from 2016 onward. A comparator scenario also was simulated where CIT remained the standard of care throughout. Disease progression and survival parameters for each therapy were based on published clinical trials.

Results

The number of people living with CLL in the United States is projected to increase from 128,000 in 2011 to 199,000 by 2025 (55% increase) due to improved survival; meanwhile, the annual cost of CLL management will increase from $0.74 billion to $5.13 billion (590% increase). The per-patient lifetime cost of CLL treatment will increase from $147,000 to $604,000 (310% increase) as oral targeted therapies become the first-line treatment. For patients enrolled in Medicare, the corresponding total out-of-pocket cost will increase from $9,200 to $57,000 (520% increase). Compared with the CIT scenario, oral targeted therapies resulted in an incremental cost-effectiveness ratio of $189,000 per quality-adjusted life-year.

Conclusion

The increased benefit and cost of oral targeted therapies is projected to enhance CLL survivorship but can impose a substantial financial burden on both patients and payers. More sustainable pricing strategies for targeted therapies are needed to avoid financial toxicity to patients.
Obesity and Breast Cancer Prognosis: Evidence, Challenges, and Opportunities
Authors: Jiralerspong Sao , Goodwin Pamela J.
Published: February 2017

Purpose

To summarize the evidence of an association between obesity and breast cancer prognosis.

Methods

We reviewed the literature regarding overweight and obesity and breast cancer survival outcomes, overall and with regard to breast cancer subtypes, breast cancer therapies, biologic mechanisms, and possible interventions. We summarize our findings and provide clinical management recommendations.

Results

Obesity is associated with a 35% to 40% increased risk of breast cancer recurrence and death and therefore poorer survival outcomes. This is most clearly established for estrogen receptor–positive breast cancer, with the relationship in triple-negative and human epidermal growth factor receptor 2–positive subtypes less well established. A range of biologic mechanisms that may underlie this association has been identified. Weight loss and lifestyle interventions, as well as metformin and other obesity-targeted therapies, are promising avenues that require further study.

Conclusion

Obesity is associated with inferior survival in breast cancer. Understanding the nature and mechanisms of this effect provides an important opportunity for interventions to improve the diagnosis, treatment, and outcomes of obese patients with breast cancer.
Multidisciplinary Approach to Novel Therapies in Cardio-Oncology Research (MANTICORE 101–Breast): A Randomized Trial for the Prevention of Trastuzumab-Associated Cardiotoxicity
Authors: Pituskin Edith , Mackey John R. , Koshman Sheri , Jassal Davinder , Pitz Marshall , Haykowsky Mark J. , Pagano Joseph J. , Chow Kelvin , Thompson Richard B. , Vos Larissa J. , Ghosh Sunita , Oudit Gavin Y. , Ezekowitz Justin A. , Paterson D. Ian
Published: February 2017

Purpose

The primary toxicity of trastuzumab therapy for human epidermal growth factor receptor 2–overexpressing (HER2-positive) breast cancer is dose-independent cardiac dysfunction. Angiotensin-converting enzyme inhibitors and β-blockers are recommended first-line agents for heart failure. We hypothesized that angiotensin-converting enzyme inhibitors and β-blockers could prevent trastuzumab-related cardiotoxicity.

Patients and Methods

In this double-blinded, placebo-controlled trial, patients with HER2-positive early breast cancer were randomly assigned to receive treatment with perindopril, bisoprolol, or placebo (1:1:1) for the duration of trastuzumab adjuvant therapy. Patients underwent cardiac magnetic resonance imaging at baseline and post–cycle 17 for the determination of left ventricular volumes and left ventricular ejection fraction (LVEF). Cardiotoxicity was evaluated as the change in indexed left ventricular end diastolic volume and LVEF.

Results

Thirty-three patients received perindopril, 31 received bisoprolol, and 30 received placebo. Baseline demographic, cancer, and cardiovascular profiles were similar between groups. Study drugs were well tolerated with no serious adverse events. After 17 cycles of trastuzumab, indexed left ventricular end diastolic volume increased in patients treated with perindopril (+7 ± 14 mL/m2), bisoprolol (+8 mL ± 9 mL/m2), and placebo (+4 ± 11 mL/m2; P = .36). In secondary analyses, trastuzumab-mediated decline in LVEF was attenuated in bisoprolol-treated patients (−1 ± 5%) relative to the perindopril (−3 ± 4%) and placebo (−5 ± 5%) groups ( P = .001). Perindopril and bisoprolol use were independent predictors of maintained LVEF on multivariable analysis.

Conclusion

Perindopril and bisoprolol were well tolerated in patients with HER2-positive early breast cancer who received trastuzumab and protected against cancer therapy–related declines in LVEF; however, trastuzumab-mediated left ventricular remodeling—the primary outcome—was not prevented by these pharmacotherapies.
Cetuximab Plus Chemoradiotherapy in Immunocompetent Patients With Anal Carcinoma: A Phase II Eastern Cooperative Oncology Group–American College of Radiology Imaging Network Cancer Research Group Trial (E3205)
Authors: Garg Madhur K. , Zhao Fengmin , Sparano Joseph A. , Palefsky Joel , Whittington Richard , Mitchell Edith P. , Mulcahy Mary F. , Armstrong Karin I. , Nabbout Nassim H. , Kalnicki Shalom , El-Rayes Bassel F. , Onitilo Adedayo A. , Moriarty Daniel J. , Fitzgerald Thomas J. , Benson Al B.
Published: February 2017

Purpose

Squamous cell carcinoma of the anal canal (SCCAC) is characterized by high locoregional failure (LRF) rates after sphincter-preserving definitive chemoradiation (CRT) and is typically associated with anogenital human papilloma virus infection. Because cetuximab enhances the effect of radiation therapy in human papilloma virus–associated oropharyngeal squamous cell carcinoma, we hypothesized that adding cetuximab to CRT would reduce LRF in SCCAC.

Methods

Sixty-one patients with stage I to III SCCAC received CRT including cisplatin, fluorouracil, and radiation therapy to the primary tumor and regional lymph nodes (45 to 54 Gy) plus eight once-weekly doses of concurrent cetuximab. The study was designed to detect at least a 50% reduction in 3-year LRF rate (one-sided α, 0.10; power 90%), assuming a 35% LRF rate from historical data.

Results

Poor risk features included stage III disease in 64% and male sex in 20%. The 3-year LRF rate was 23% (95% CI, 13% to 36%; one-sided P = .03) by binomial proportional estimate using the prespecified end point and 21% (95% CI, 7% to 26%) by Kaplan-Meier estimate in a post hoc analysis using methods consistent with historical data. Three-year rates were 68% (95% CI, 55% to 79%) for progression-free survival and 83% (95% CI, 71% to 91%) for overall survival. Grade 4 toxicity occurred in 32%, and 5% had treatment-associated deaths.

Conclusion

Although the addition of cetuximab to chemoradiation for SCCAC was associated with lower LRF rates than historical data with CRT alone, toxicity was substantial, and LRF still occurs in approximately 20%, indicating the continued need for more effective and less toxic therapies.
Weight Loss Randomized Intervention Trials in Female Cancer Survivors
Authors: Chlebowski Rowan T. , Reeves Marina M.
Published: February 2017

Purpose

Observational study evidence has associated overweight/obesity with decreased survival in women with breast cancer and with several other cancers. Although full-scale, definitive weight loss adjuvant intervention trials with cancer end points remain to be conducted, a number of randomized controlled trials have evaluated weight loss interventions in survivors of cancer in women. Findings from these trials in breast, endometrial, and ovarian cancer are reviewed.

Methods

A systematic review of randomized controlled clinical trials evaluating weight loss interventions was updated (for studies published 2013 to 2016), and clinical trials registers were searched for ongoing trials.

Results

Six new randomized trials in breast cancer survivors and two randomized trials in endometrial cancer survivors were identified. Evidence from these trials and the 10 earlier randomized trials in female cancer survivors provide support for the feasibility of recruiting women closer to the cancer diagnosis and efficacy for achieving weight loss, in particular with telephone-based interventions, and have identified the challenge of achieving significant weight loss in African American cancer survivors and of maintaining weight loss in any cancer survivor group. Seven ongoing randomized trials are evaluating the influence of weight loss interventions on cancer end points (five in breast cancer, one in ovarian cancer, and one in endometrial cancer).

Conclusion

After a decade of preliminary studies, ongoing randomized, controlled clinical trials will potentially provide definitive assessment of whether weight loss can improve breast cancer clinical outcome. Longer-term interventions (> 2 years’ duration) may be needed to optimize weight loss maintenance and any potential benefits on cancer end points.
Effectiveness of Adjuvant Chemotherapy After Radical Nephroureterectomy for Locally Advanced and/or Positive Regional Lymph Node Upper Tract Urothelial Carcinoma
Authors: Seisen Thomas , Krasnow Ross E. , Bellmunt Joaquim , Rouprêt Morgan , Leow Jeffrey J. , Lipsitz Stuart R. , Vetterlein Malte W. , Preston Mark A. , Hanna Nawar , Kibel Adam S. , Sun Maxine , Choueiri Toni K. , Trinh Quoc-Dien , Chang Steven L.
Published: February 2017

Purpose

There is limited evidence to support the use of adjuvant chemotherapy (AC) after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). Against this backdrop, we hypothesized that such treatment is associated with overall survival (OS) benefit in patients with locally advanced and/or positive regional lymph node disease.

Patients and Methods

Within the National Cancer Database (2004 to 2012), we identified 3,253 individuals who received AC or observation after RNU for pT3/T4 and/or pN+ UTUC. Inverse probability of treatment weighting (IPTW) –adjusted Kaplan-Meier curves and Cox proportional hazards regression analyses were used to compare OS of patients in the two treatment groups. In addition, we performed exploratory analyses of treatment effect according to age, gender, Charlson comorbidity index, pathologic stage (pT3/T4N0, pT3/T4Nx and pTanyN+), and surgical margin status.

Results

Overall, 762 (23.42%) and 2,491 (76.58%) patients with pT3/T4 and/or pN+ UTUC received AC and observation, respectively, after RNU. IPTW-adjusted Kaplan-Meier curves showed that median OS was significantly longer for AC versus observation (47.41 [interquartile range,19.88 to 112.39] v 35.78 [interquartile range, 14.09 to 99.22] months; P < .001). The 5-year IPTW-adjusted rates of OS for AC versus observation were 43.90% and 35.85%, respectively. In IPTW-adjusted Cox proportional hazards regression analysis, AC was associated with a significant OS benefit (hazard ratio, 0.77 [95% CI, 0.68 to 0.88]; P < .001). This benefit was consistent across all subgroups examined (all P < .05), and no significant heterogeneity of treatment effect was observed (all Pinteraction > .05).

Conclusion

We report an OS benefit in patients who received AC versus observation after RNU for pT3/T4 and/or pN+ UTUC. Although our results are limited by the usual biases related to the observational study design, we believe that the present findings should be considered when advising post-RNU management of advanced UTUC, pending level I evidence.
Addressing the Role of Obesity in Endometrial Cancer Risk, Prevention, and Treatment
Authors: Onstad Michaela A. , Schmandt Rosemarie E. , Lu Karen H.
Published: February 2017

In sharp contrast to many other cancer types, the incidence and mortality of endometrial cancer continue to grow. This unfortunate trend is, in no small part, a result of the worldwide obesity epidemic. More than half of endometrial cancers are currently attributable to obesity, which is recognized as an independent risk factor for this disease. In this review, we identify the molecular mechanisms by which obesity and adipose tissue contribute to the pathogenesis of endometrial cancer. We further discuss the impact of obesity on the clinical management of the disease and examine the development of rational behavioral and pharmaceutical interventions aimed at reducing endometrial cancer risk, improving cancer outcomes, and preserving fertility in an increasingly younger population of patients with endometrial cancer.
Association of Obesity-Related Metabolic Disruptions With Cancer Risk and Outcome
Authors: Lohmann Ana Elisa , Goodwin Pamela J. , Chlebowski Rowan T. , Pan Kathy , Stambolic Vuk , Dowling Ryan J.O.
Published: February 2017

Over the past 40 years, the prevalence of obesity has increased epidemically worldwide, which raises significant concerns regarding public health and the associated economic burden. Obesity is a major risk factor for several conditions including cardiovascular disease and type 2 diabetes, and recent evidence suggests that obesity negatively affects cancer risk and outcome. The relationship between obesity and cancer is complex and involves multiple factors both at the systemic and cellular level. Indeed, disruptions in insulin metabolism, adipokines, inflammation, and sex hormones all contribute to the adverse effects of obesity in cancer development and progression. The focus of this review will be the impact of these systemic obesity-related factors on cancer biology, incidence, and outcome. Potential therapeutic interventions and current clinical trials targeting obesity and its associated factors will also be discussed.
Cardiac Toxicity After Radiotherapy for Stage III Non–Small-Cell Lung Cancer: Pooled Analysis of Dose-Escalation Trials Delivering 70 to 90 Gy
Authors: Wang Kyle , Eblan Michael J. , Deal Allison M. , Lipner Matthew , Zagar Timothy M. , Wang Yue , Mavroidis Panayiotis , Lee Carrie B. , Jensen Brian C. , Rosenman Julian G. , Socinski Mark A. , Stinchcombe Thomas E. , Marks Lawrence B.
Published: February 2017

Purpose

The significance of radiotherapy (RT) –associated cardiac injury for stage III non–small-cell lung cancer (NSCLC) is unclear, but higher heart doses were associated with worse overall survival in the Radiation Therapy Oncology Group (RTOG) 0617 study. We assessed the impact of heart dose in patients treated at our institution on several prospective dose-escalation trials.

Patients and Methods

From 1996 to 2009, 127 patients with stage III NSCLC (Eastern Cooperative Oncology Group performance status, 0 to 1) received dose-escalated RT to 70 to 90 Gy (median, 74 Gy) in six trials. RT plans and cardiac doses were reviewed. Records were reviewed for the primary end point: symptomatic cardiac events (symptomatic pericardial effusion, acute coronary syndrome, pericarditis, significant arrhythmia, and heart failure). Cardiac risk was assessed by noting baseline coronary artery disease and calculating the WHO/International Society of Hypertension score. Competing risks analysis was used.

Results

In all, 112 patients were analyzed. Median follow-up for surviving patients was 8.8 years. Twenty-six patients (23%) had one or more events at a median of 26 months to first event (effusion [n = 7], myocardial infarction [n = 5], unstable angina [n = 3], pericarditis [n = 2], arrhythmia [n = 12], and heart failure [n = 1]). Heart doses (eg, heart mean dose; hazard ratio, 1.03/Gy; P = .002,), coronary artery disease ( P < .001), and WHO/International Society of Hypertension score ( P = .04) were associated with events on univariable analysis. Heart doses remained significant on multivariable analysis that accounted for baseline risk. Two-year competing risk–adjusted event rates for patients with heart mean dose < 10 Gy, 10 to 20 Gy, or ≥ 20 Gy were 4%, 7%, and 21%, respectively. Heart doses were not associated with overall survival.

Conclusion

Cardiac events were relatively common after high-dose thoracic RT and were independently associated with both heart dose and baseline cardiac risk. RT-associated cardiac toxicity after treatment of stage III NSCLC may occur earlier than historically understood, and heart doses should be minimized.
Minimal Loss of Lifetime for Patients With Diffuse Large B-Cell Lymphoma in Remission and Event Free 24 Months After Treatment: A Danish Population-Based Study
Authors: Jakobsen Lasse Hjort , Bøgsted Martin , Brown Peter de Nully , Arboe Bente , Jørgensen Judit , Larsen Thomas Stauffer , Juul Maja Bech , Schurmann Lene , Højberg Linda , Bergmann Olav Jonas , Lassen Therese , Josefsson Pär Lars , Jensen Paw , Johnsen Hans Erik , El-Galaly Tarec Christoffer
Published: February 2017

Purpose

The general outlook for patients with diffuse large B-cell lymphoma (DLBCL) in first remission is important information for patients and for planning post-treatment follow-up. The purpose of this study was to evaluate the survival of patients with DLBCL in remission compared with a matched general population.

Methods

A total of 1,621 patients from the Danish Lymphoma Registry who were newly diagnosed with DLBCL between 2003 and 2011 were included in this study. All patients were ≥ 16 years of age at diagnosis and had achieved complete remission or complete remission unconfirmed after first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or R-CHOP–like therapy.

Results

The 5-year post-treatment DLBCL survival was inferior to survival in the matched general population (78%; 95% CI, 76 to 80; v 87%; standardized mortality ratio, 1.75; P < .001). Excess mortality was present but reduced for patients achieving post-treatment event-free survival for 24 months (pEFS24; standardized mortality ratio, 1.27; P < .001). In age-stratified analyses, the survival of patients < 50 years of age was normalized to the general population after achieving pEFS24 ( P = .99). During the first 8 years after pEFS24, the average loss of lifetime was 0.31 mo/y (95% CI, 0.11 to 0.50 mo/y). Excess mortality diminished when analyzing death from lymphoma as competing event to death from other causes, suggesting that early and late relapse is responsible for increased mortality in patients with DLBCL.

Conclusion

Although this population-based study does not support complete normalization of survival for patients with DLBCL achieving pEFS24, the estimated loss of residual lifetime was low for patients in continuous remission 2 years after ending treatment. Therefore, pEFS24 is an appealing and relevant milestone for patient counseling and could be a surrogate end point in clinical trials.
Integration of Palliative Care Into Standard Oncology Care: American Society of Clinical Oncology Clinical Practice Guideline Update
Authors: Ferrell Betty R. , Temel Jennifer S. , Temin Sarah , Alesi Erin R. , Balboni Tracy A. , Basch Ethan M. , Firn Janice I. , Paice Judith A. , Peppercorn Jeffrey M. , Phillips Tanyanika , Stovall Ellen L. , Zimmermann Camilla , Smith Thomas J.
Published: February 2017

Purpose

To provide evidence-based recommendations to oncology clinicians, patients, family and friend caregivers, and palliative care specialists to update the 2012 American Society of Clinical Oncology (ASCO) provisional clinical opinion (PCO) on the integration of palliative care into standard oncology care for all patients diagnosed with cancer.

Methods

ASCO convened an Expert Panel of members of the ASCO Ad Hoc Palliative Care Expert Panel to develop an update. The 2012 PCO was based on a review of a randomized controlled trial (RCT) by the National Cancer Institute Physicians Data Query and additional trials. The panel conducted an updated systematic review seeking randomized clinical trials, systematic reviews, and meta-analyses, as well as secondary analyses of RCTs in the 2012 PCO, published from March 2010 to January 2016.

Results

The guideline update reflects changes in evidence since the previous guideline. Nine RCTs, one quasiexperimental trial, and five secondary analyses from RCTs in the 2012 PCO on providing palliative care services to patients with cancer and/or their caregivers, including family caregivers, were found to inform the update.

Recommendations

Inpatients and outpatients with advanced cancer should receive dedicated palliative care services, early in the disease course, concurrent with active treatment. Referral of patients to interdisciplinary palliative care teams is optimal, and services may complement existing programs. Providers may refer family and friend caregivers of patients with early or advanced cancer to palliative care services.
Reversion of BRCA1/2 Germline Mutations Detected in Circulating Tumor DNA From Patients With High-Grade Serous Ovarian Cancer
Authors: Christie Elizabeth L. , Fereday Sian , Doig Ken , Pattnaik Swetansu , Dawson Sarah-Jane , Bowtell David D.L.
Published: February 2017

Purpose

Germline BRCA1 or BRCA2 mutations in patients with high-grade serous ovarian cancer (HGSC) are associated with favorable responses to chemotherapy. However, secondary intragenic (reversion) mutations that restore protein function lead to clinically significant rates of acquired resistance. The goal of this study was to determine whether reversion mutations could be found in an unbiased manner in circulating cell-free DNA (cfDNA) to predict treatment response in HGSC.

Patients and Methods

Plasma and tumor samples were obtained from 30 patients with HGSC with either BRCA1 or BRCA2 germline mutation. Two cohorts were ascertained: patients with a malignancy before undergoing primary HGSC debulking surgery (n = 14) or patients at disease recurrence (n = 16). Paired tumor and plasma samples were available for most patients (24 of 30). Targeted amplicon, next-generation sequencing was performed using primers that flanked germline mutations, whose design did not rely on prior knowledge of reversion sequences.

Results

Five patients were identified with intragenic mutations predicted to restore BRCA1/2 open reading frames, including two patients with multiple independent reversion alleles. Reversion mutations were only detected in tumor samples from patients with recurrent disease (five of 16) and only in cfDNA from patients with a tumor-detected reversion (three of five). Findings from a rapid autopsy of a patient with multiple independent reversions indicated that reversion-allele frequency in metastatic sites is an important determinant of assay sensitivity. Abundance of tumor-derived DNA in total cell-free DNA, as measured by TP53 mutant allele frequency, also affected assay sensitivity. All patients with reversions detected in tumor-derived DNA were resistant to platin- or poly ADP ribose polymerase inhibitor-based chemotherapy.

Conclusion

Reversion mutations can be detected in an unbiased analysis of cfDNA, suggesting clinical utility for predicting chemotherapy response in recurrent HGSC.
Effects of Early Integrated Palliative Care in Patients With Lung and GI Cancer: A Randomized Clinical Trial
Authors: Temel Jennifer S. , Greer Joseph A. , El-Jawahri Areej , Pirl William F. , Park Elyse R. , Jackson Vicki A. , Back Anthony L. , Kamdar Mihir , Jacobsen Juliet , Chittenden Eva H. , Rinaldi Simone P. , Gallagher Emily R. , Eusebio Justin R. , Li Zhigang , Muzikansky Alona , Ryan David P.
Published: February 2017

Purpose

We evaluated the impact of early integrated palliative care (PC) in patients with newly diagnosed lung and GI cancer.

Patients and Methods

We randomly assigned patients with newly diagnosed incurable lung or noncolorectal GI cancer to receive either early integrated PC and oncology care (n = 175) or usual care (n = 175) between May 2011 and July 2015. Patients who were assigned to the intervention met with a PC clinician at least once per month until death, whereas those who received usual care consulted a PC clinician upon request. The primary end point was change in quality of life (QOL) from baseline to week 12, per scoring by the Functional Assessment of Cancer Therapy-General scale. Secondary end points included change in QOL from baseline to week 24, change in depression per the Patient Health Questionnaire-9, and differences in end-of-life communication.

Results

Intervention patients ( v usual care) reported greater improvement in QOL from baseline to week 24 (1.59 v −3.40; P = .010) but not week 12 (0.39 v −1.13; P = .339). Intervention patients also reported lower depression at week 24, controlling for baseline scores (adjusted mean difference, −1.17; 95% CI, −2.33 to −0.01; P = .048). Intervention effects varied by cancer type, such that intervention patients with lung cancer reported improvements in QOL and depression at 12 and 24 weeks, whereas usual care patients with lung cancer reported deterioration. Patients with GI cancers in both study groups reported improvements in QOL and mood by week 12. Intervention patients versus usual care patients were more likely to discuss their wishes with their oncologist if they were dying (30.2% v 14.5%; P = .004).

Conclusion

For patients with newly diagnosed incurable cancers, early integrated PC improved QOL and other salient outcomes, with differential effects by cancer type. Early integrated PC may be most effective if targeted to the specific needs of each patient population.
Myeloablative Versus Reduced-Intensity Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes
Authors: Scott Bart L. , Pasquini Marcelo C. , Logan Brent R. , Wu Juan , Devine Steven M. , Porter David L. , Maziarz Richard T. , Warlick Erica D. , Fernandez Hugo F. , Alyea Edwin P. , Hamadani Mehdi , Bashey Asad , Giralt Sergio , Geller Nancy L. , Leifer Eric , Le-Rademacher Jennifer , Mendizabal Adam M. , Horowitz Mary M. , Deeg H. Joachim , Horwitz Mitchell E.
Published: February 2017

Purpose

The optimal regimen intensity before allogeneic hematopoietic cell transplantation (HCT) is unknown. We hypothesized that lower treatment-related mortality (TRM) with reduced-intensity conditioning (RIC) would result in improved overall survival (OS) compared with myeloablative conditioning (MAC). To test this hypothesis, we performed a phase III randomized trial comparing MAC with RIC in patients with acute myeloid leukemia or myelodysplastic syndromes.

Patients and Methods

Patients age 18 to 65 years with HCT comorbidity index ≤ 4 and < 5% marrow myeloblasts pre-HCT were randomly assigned to receive MAC (n = 135) or RIC (n = 137) followed by HCT from HLA-matched related or unrelated donors. The primary end point was OS 18 months post–random assignment based on an intent-to-treat analysis. Secondary end points included relapse-free survival (RFS) and TRM.

Results

Planned enrollment was 356 patients; accrual ceased at 272 because of high relapse incidence with RIC versus MAC (48.3%; 95% CI, 39.6% to 56.4% and 13.5%; 95% CI, 8.3% to 19.8%, respectively; P < .001). At 18 months, OS for patients in the RIC arm was 67.7% (95% CI, 59.1% to 74.9%) versus 77.5% (95% CI, 69.4% to 83.7%) for those in the MAC arm (difference, 9.8%; 95% CI, −0.8% to 20.3%; P = .07). TRM with RIC was 4.4% (95% CI, 1.8% to 8.9%) versus 15.8% (95% CI, 10.2% to 22.5%) with MAC ( P = .002). RFS with RIC was 47.3% (95% CI, 38.7% to 55.4%) versus 67.8% (95% CI, 59.1% to 75%) with MAC ( P < .01).

Conclusion

OS was higher with MAC, but this was not statistically significant. RIC resulted in lower TRM but higher relapse rates compared with MAC, with a statistically significant advantage in RFS with MAC. These data support the use of MAC as the standard of care for fit patients with acute myeloid leukemia or myelodysplastic syndromes.