The State of Cancer Care in America: 2015

The State of Cancer Care in America: 2015
The U.S. cancer care system remains
in a state of transition.

In 2014, the United States made significant progress in cancer care as demonstrated by improvement in the five year cancer survival rate for many cancer types and a record
14.5 million cancer survivors, as well as by the availability of 10 new drugs and several new tests for the diagnosis, treatment, or management of cancer.1
At the same time, a growing demand for cancer services, turbulence in the cancer care delivery system, and growing concerns about cost of care are creating uncertainties about the system’s capacity to continue to provide high-quality care for all
patients with cancer. These factors have focused attention on the need for better definitions of value and meaningful ways to assess quality. In this second annual
State of Cancer Care in America report, the American Society of Clinical Oncology (ASCO) chronicles the challenges currently facing the U.S. cancer care system. The report provides background and context to help understand what is happening today
in cancer care and describes trends in the cancer care workforce and diverse practice environment that may affect cancer care in the coming years.

1. CANCER CARE IN AMERICA: A SHIFTING LANDSCAPE
The American population continues to grow and age, driving up demand for cancer services to previously unseen levels. This report includes updates on progress in the field of cancer care and on the state of cancer incidence and survival.
f
Progress in cancer care.
In 2014, the U.S. Food and Drug Administration (FDA) approved 10 new drugs and several
new tests for the diagnosis, treatment or management of cancer, and more than 771 promising therapies are in the development pipeline.2,3
Advances in treatment have produced improvements in the five-year survival rate
for many cancer types, and there are now 14.5 million Americans who are cancer survivors today a number that continues to grow with each passing year.

Rapidly growing demand.
An estimated 1.6 million new cancers were diagnosed in 2014, with growing numbers
expected in future years. Demand for cancer care is being driven by newly insured patients, an aging population and long-term care needs of survivors. In 2014 the first
year of the insurance mandate of the Affordable Care Act (ACA)nearly eight million Americans registered through new insurance exchanges and millions more are gaining access to insurance through the expansion of private and governmental programs.4
As ACA implementation progresses, these numbers are expected to increase ignificantly.

Persistent inequities.
The benefits of cancer screening and treatment advances have not been experienced
evenly across racial and ethnic groups, as evidenced by differences in incidence and mortality rates. Although the Affordable Care Act has successfully expanded
access to insurance and cancer care services, millions of Americans remain uninsured, while other individuals with public and private plans continue to lack sufficient
coverage for high-quality cancer care.

Emerging public health concerns.
This year, the ASCO report addresses two new issues with potential to influence demand for cancer services:

Obesity.
In the United States today, more than one third of adults and nearly one fifth of children are considered obese. Public health experts are concerned about a range of serious health consequences. There is mounting evidence that obesity leads to at least eight forms of cancer and affects survival.5
Obesity is responsible for more than 84,000 cancer cases annually, and this number is expected to rise substantially in future years 6,7 yet the link between obesity and cancer is largely unrecognized by the public.

Electronic cigarettes.
Electronic cigarettes are advertised to American consumers as a safe alternative
to smoking but these claims lack adequate scientific support. The U.S. Food & Drug Administration (FDA) currently only regulates electronic cigarettes marketed for therapeutic purposes, but it has proposed expanded regulations covering all electronic cigarettes. This authority is important because electronic cigarettes are becoming popular among smokers and non-smokers alike, including nearly two million U.S. adolescents.

For these reasons, ASCO and public health experts support the expansion of FDA’s authority and are calling for research to assess potential direct and indirect health effects of these devices.

2. THE ONCOLOGY WORKFORCE
ASCO regularly monitors the size, distribution and diversity of the U.S. oncology workforce to identify trends that could affect access to care. The Society’s latest analysis identified several key issues:

Number of oncologists constant despite growth in demand. In 2014, approximately 11,500 hematologists and/or medical oncologists provided care to U.S. patients with cancer, a modest 1.6 percent increase from the previous year.9
Altogether, more than 18,000 physicians provide oncology subspecialty patient care, including gynecologic oncology, pediatric hematology/oncology, radiation oncology, and surgical oncology.10

Additionally, more than three thousand advanced practice providers provide oncology care across the country, including nurse practitioners, doctors of nursing practice, and physician assistants. Advanced practice provider employment is growing rapidly, enhancing the pipeline of providers who might choose a career in oncology.

Aging workforce, declining interest in private or solo practice careers.
Consistent with last year’s report,oncologists are aging with oncologists ages 65 years and older continuing to outpace those entering the field (ages 40 years and younger). Women continue to increase their share of the workforce and occupy nearly
half (48 percent) of hematology/oncology fellowship slots.11

In contrast, the number of ethnic and racial minorities in oncology remains discouragingly low.

New to this edition of the report, ASCO covers practice decisions made by new entrants into the oncologist workforce. In a 2014 survey of medical oncology fellows, a majority (55.8 percent) of respondents indicated a preference for university-based clinical practice or research, whereas 36.8 percent indicated they were likely to choose non-academic community or private practice settings. Among oncologists presently working in a practice setting, young oncologists are more likely
to work in group practice and less likely to work in solo practice than their older colleagues.10

Rural settings underserved.
Oncology continues to experience uneven geographic distribution of its workforce. Relative to where Americans ages 55 and older reside (who account for the majority of new cancer cases), Washington, DC, and Massachusetts have the most oncologists, whereas Hawaii and Nevada have the fewest. For the more than 59 million Americans living in rural areas, a diagnosis of cancer can present unique challenges to obtaining high-quality care for their disease, including long travel distances and decreased access to specialists, and state-of-the-art diagnostics,treatments and technologies.12-14

ASCO’s 2014 analysis of oncology locations identified approximately 600 hematologists and medical oncologists (5.5 percent) practicing in rural care sites.9,15

States investing in outreach, monitoring workforce.
Two state-based research initiatives conducted in Iowa and Nebraska examined access in underserved areas and pointed to strategies that may serve to inform efforts in other communities across the United States. In Iowa, community hospitals and health centers in remote areas are offering cancer services by employing visiting oncologists, thereby significantly expanding patient access in the state.16

In nearby Nebraska, where 47 percent of residents live in rural areas and cancer is
the leading cause of death, researchers found that the number of oncologists increased by 3 percent and the number of oncology nurse practitioners and physician
assistants increased by more than a third (37 percent and 36.1 percent, respectively) from 2008—2012.17

These increases provided additional provider capacity within Nebraska although not in rural areas.

Burnout a continuing problem.
A recent survey of medical oncology fellows found that more than a third of respondents experienced high levels of burnout (at least one event a week)a rate similar to that reported among practicing oncologists.18

3. THE STATE OF ONCOLOGY PRACTICE
This report highlights findings from ASCO’s third annual census of U.S. oncology practices, conducted in 2014, along with related data from other sources.

ASCO Oncology Census: continuing practice adaptation.
Nearly 1,000 (n=974) U.S. oncology practices participated in this year’s census study, representing more than 10,000 individual oncologists. In a continuing trend toward consolidation, one quarter of community-based practices signaled the likelihood of pursuing hospital affiliation in the next twelve months.

Shifts in practice staffing and administration.
The number of practices reporting multi-specialty services remained high in 2014, especially among academic and hospital-based practices. A majority (52 percent)
of practices responding to the ASCO Oncology Census employed advanced practice providers, accounting for more than 2,700 advanced practice nurses and 1,100
physician assistants.

Practice financial health and management.
In 2014, cost and payer pressures persisted as the most pressing practice concerns, especially among physician-owned and hospital-based practices. Drug prices were also
a major concern among physician-owned practices. Academic practices were primarily concerned with clinical research issues and competitive pressures.

Preauthorization a growing concern.
The time clinicians and their staff spend dealing with insurance companies reduces the time available for patient care and remains a burden on practices. Preauthorization
the requirement that clinicians get prior approval from patients’ insurance providers before ordering certain tests or administering certain treatments is an area of
particular concern among oncology practices. A recent survey of ASCO state affiliate organizations found that preauthorization requirements increase demands on staff time, delay or interrupt patient care, decrease patient satisfaction, and complicate medical decision making.

Drug shortages in cancer care.
Drug shortages remain a relatively small but persistent pressure on practices.
According to a 2014 survey of oncology practices, policy changes enacted in 2011 and 2012 may have helped avert or mitigate drug shortages consistent with findings from several recent governmental analyses. Survey respondents reported that they often address shortages by recommending different treatment regimens, working directly with manufacturers to obtain available drugs, contracting or sharing drugs available
from other local providers, or contracting with other drug distributors.

Safe handling of chemotherapy drugs.
The regulation of chemotherapy safety often occurs at the state level, and several states have been active in recent years in developing new rules in this area. State-level efforts are typically informed by available guidelines and ecommendations. In 2014, the medical oncology community worked collaboratively to develop standards
and to help support communications and educational efforts with policymakers at the state level to ensure that regulations promote safety and are easily adopted
when applied to the day-to-day operations of practices.

340B Drug Pricing Program.
The 340B Drug Pricing Program requires drug manufacturers to provide price discounts to certain hospitals and other health care facilities that qualify as covered entities. Some have questioned the rapid expansion of the 340B Drug Pricing
Program in terms of both the number of eligible facilities and the number of eligible drug claims.19,20,21
This was a focus for both Congress and the Administration in 2014,but there has been no regulatory action to refine the program to date.10

4.QUALITY AND VALUE IN CANCER CARE
Defining and delivering high-value care was a key focus across the oncology community in 2014 and will continue to dominate health reform efforts in the year ahead. Cost
of care continues to drive practice and payment reform initiatives, quality measurement and improvement efforts, and a focus on data and transparency is more broadly viewed as a means of informing consumer choice.

Focus on cost.
In the last decade, the average monthly cost of cancer treatment has more than doubled to $10,000.22
A handful of treatments now cost more than $100,000 annually per patient, and as cancer therapy moves toward use of multiple such agents, concerns about cost have grown. Payers and policymakers are focused on strategies to better define value and engage patients in selecting high-value options.

Response to cost: targeting utilization.
Health insurers and policymakers have pursued a variety of strategies to control cost while preserving or enhancing quality.These include: administrative controls on utilization (e.g., preauthorization for costly therapies and clinical
pathways), development of alternative payment models, and quality monitoring. There has also been a strong emphasis on creating more informed and value conscious consumers.

Quality assessment and performance improvement.
Greater availability of metrics and tools to analyze clinical data are expanding the way that oncologists learn and improve care quality. Quality measurement and improvement are central elements in virtually every payment reform model proposed this year. Notably, the Centers for Medicare & Medicaid Services the single
largest payer for health services in the United States is increasingly expecting providers and practices to demonstrate their commitment to improving quality
of care. Other organizations are also advancing national quality measurement and methods to improve performance.

Big data.
The use of large and complex data sets to inform cancer treatment and care delivery is a growing focus. Numerous big data projects are underway among private and public organizations, including ASCO’s rapid learning system, CancerLinQ; data sharing among
pharmaceutical companies through Project Data Sphere; PCORnet by the Patient-Centered Outcomes Research Institute; and several initiatives of private companies
such as IBM and Optum

Groundbreaking Legislation to Accelerate Pace of Cures in Cancer Care

2015 ASCO Advocacy at Work: Groundbreaking Legislation to Accelerate Pace of Cures in Cancer Care

Major Congressional efforts are underway this year to bring forward legislation that will accelerate the discovery, development, and delivery of promising new treatments to patients. The House Energy and Commerce Committee released its much anticipated first draft of the 21st Century Cures Legislation. The Senate Health Education Labor and Pensions (HELP) Committee released “Innovation for Healthier Americans,” a white paper that identifies similar areas of need.

ASCO has weighed in heavily throughout this process and will continue to work closely with lawmakers in both the House and the Senate to build a legislative framework that is designed to quicken the discovery, development, and delivery of promising new treatments to patients.

This page will feature regular updates on Congressional developments and ASCO advocacy efforts to shape this far-reaching initiative.

U.S. House: 21st Century Cures

21st Century Cures Discussion Document Unveiled
ASCO Offers Input on 21st Century Cures PCAST White Paper
ASCO Provides Input on U.S. House Committee White Paper on Accelerating Progress in Care
21st Century Cures: ASCO Supports Congressional Effort to Accelerate Medical Progress

U.S. Senate: Innovation for Healthier Americans

ASCO Responds to Senate “Innovation for Healthier Americans” Discussion Document, Saying Any Legislation Should Protect Patients, Empower Physicians to Use Technology

Additional Resources

ASCO has shared the following reports with Congressional lawmakers. These reports lay out ASCO’s vision for the future of cancer care in the United States, including the growing role of big data and cancer panomics in cancer prevention, diagnosis, and treatment.

ASCO Response to Innovation for Healthier Americans (February 2015)
ASCO’s Comments to House Energy and Commerce Committee on Regulation of Laboratory Developed Tests (January 2015)
Shaping the Future of Oncology: Envisioning Cancer Care in 2030
Accelerating Progress Against Cancer: ASCO's Blueprint for Transforming Clinical and Translational Cancer Research
Blueprint Progress Report

Triple Negative Breast Cancer treatment.

Dramatic Changes Underway in TNBC Treatment Landscape | Page 1
Silas Inman @silasinman
Published Online: Wednesday, November 25, 2015
Dr. Kimberly L. Blackwell

Kimberly L. Blackwell, MD
The treatment paradigm for patients with triple-negative breast cancer (TNBC) is set to undergo a dramatic transformation, as standard chemotherapeutic approaches are perfected and novel antibody-drug conjugates (ADCs) are developed, according to Kimberly Blackwell, MD, at the 2015 Chemotherapy Foundation Symposium.

“I think we will see significant improvements in triple-negative breast cancer within the next few years,” said Blackwell, an oncologist at the Duke Cancer Institute. “There are two ADCs that I am fairly excited about that are in late stage development.”


Refining Chemotherapy for TNBC

In a phase III trial,1 labeled Study 301, eribulin mesylate was compared with capecitabine in previously treated patients with locally advanced or metastatic breast cancer. Patients were randomized to receive eribulin at 1.4 mg/m2 on days 1 and 8 (n = 554) or capecitabine at 1250 mg/m2 on days 1 to 14 (n = 548).

Across the full population of the study, eribulin was not found to be superior to capecitabine for the coprimary endpoints of overall survival (OS) and progression-free survival (PFS). However, in a preplanned subgroup analysis of those with TNBC, a distinct advantage was seen.

“The one thing where this study actually changed my practice was this planned subgroup analysis of those women with triple-negative metastatic breast cancer,” Blackwell said. “This study validates that IV chemotherapy might be valuable in this population of first-line triple-negative breast cancer.”

In patients with TNBC (n = 284), there was a 5-month improvement in OS with eribulin versus capecitabine. Median OS was 14.4 versus 9.4 months, for eribulin and capecitabine, respectively (HR, 0.702; 95% CI, 0.545-0.906).

“When you see an overall survival advantage in the setting of women facing metastatic or incurable disease, you have to sit up and take note,” said Blackwell. "This study actually did shape my practice quite a bit, in terms of triple-negative breast cancer."

In a second phase III study,2 labeled TNT, 376 patients with triple-negative or known BRCA1/2 mutation-positive metastatic breast cancer were treated with first-line docetaxel or carboplatin. Patients were randomized to receive carboplatin at AUC 6 every 3 weeks (n = 188) or docetaxel at 100 mg/m2 every 3 weeks (n = 188). Crossover was planned between the two arms following progression.

Across all patient groups, the objective response rate (ORR) with carboplatin was 31.4% compared with 35.6% for docetaxel (P = .44). Following crossover similar findings were demonstrated.

“The only real difference in this study—that was very intriguing but validated some of the things were had been thinking—is that for those women facing breast cancer in the setting of a BRCA 1 or 2 mutations, the response rate was double, in favor of carboplatin over docetaxel,” Blackwell said.

In those with BRCA1/2-mutant breast cancer, ORR with carboplatin was 68.0% compared with 33.3% for docetaxel (P = .03). In this same population, the median PFS with carboplatin was 6.8 versus 4.8 months with docetaxel. In the absence of BRCA1/2 mutations, the ORR with carboplatin was 28.1% versus 36.6% with docetaxel (P = .16).

“This is the second randomized trial that basically changed my practice, in that it really demonstrated a role for platinums versus taxanes in women harboring a deleterious BRCA1/2 mutations,” Blackwell said.

Novel Strategies in TNBC

A number of novel therapies are on the horizon for treating TNBC, specifically those utilizing ADC technology. The two agents in this class generating the most excitement are glembatumumab vedotin (CDX-011) and sacituzumab govitecan (IMMU-132), explained Blackwell.

Glembatumumab vedotin comprised of the gpNMB-targeted human IgG2 monoclonal antibody CR011 linked with the tubulin polymerization inhibitor MMAE. In a phase II study for patients with metastatic TNBC,3 glembatumumab vedotin demonstrated exciting findings in the setting of metastatic TNBC, Blackwell noted.

The ORR in 16 patients with high expression of gpNMB was 33% with glembatumumab vedotin compared with 0% with investigator's choice of chemotherapy. When considering those with stable disease, the disease control rate with glembatumumab vedotin was 75% compared with 25% for those treated with chemotherapy.

Median PFS with the ADC was 3.5 versus 1.5 months with chemotherapy (HR, 0.11). Additionally, administration of the ADC nearly doubled OS compared with chemotherapy (median 10.0 vs 5.5 months; HR, 0.14).

The phase II METRIC study is currently exploring glembatumumab vedotin versus capecitabine in patients with gpNMB overexpressing TNBC who have received ≤2 prior therapies. The study will be randomized in a 2:1 ratio favoring the ADC, with PFS as the primary endpoint (NCT01997333).

The second ADC mentioned by Blackwell, sacituzumab govitecan, is a humanized IgG antibody targeted against Trop-2 conjugated to SN-38, which is an active metabolite of the chemotherapy irinotecan.

Sacituzumab govitecan was explored in a phase I/II study in heavily pretreated patients with TNBC who had received a median of 4 prior therapies (range, 1-11).4 Patients were not selected based on Trop-2, which is expressed in more than 80% of tumors.

In 56 evaluable patients, the ORR with sacituzumab govitecan was 30%, which included a complete response for 2 patients. The disease control rate with the ADC was 46%. The median PFS was 7 months.

“Considering that these patients on average had received 4 lines of chemotherapy, these are pretty impressive results,” Blackwell said. “Many of us who are familiar with this data are excited about this compound moving forward.”

Androgen Receptor Signaling

The androgen receptor (AR) is frequently expressed on TNBC, suggesting that anti-androgen approaches could be successful. A phase II study examined this theory using the agent bicalutamide in metastatic AR-positive TNBC.5 At 24 weeks, the clinical benefit rate was 19% and the median PFS was 12 weeks.

Under the guise that enzalutamide is 8-fold more potent than bicalutamide, another phase II study was conducted looking at this second-generation anti-androgen agent in patients with TNBC with ≥1% AR expression.6 In evaluable patients (n = 75), the clinical benefit rate was 35% at 16 weeks and 29% by week 24. The ORR was 8%.

To further define a patient population most likely to response, a diagnostic test labeled PREDICT AR was developed based on the expression of 521 genes. Using this test, those who were positive experienced a significant extension in OS, when compared with the negative population. Based on these findings, studies have been launched in the United States and globally to further explore AR inhibition and the PREDICT AR test, Blackwell concluded.

Radical Prostatectomy Versus Radiation and Androgen Deprivation Therapy for Clinically Localized Prostate Cancer

Radical Prostatectomy Versus Radiation and Androgen Deprivation Therapy for Clinically Localized Prostate Cancer: How Good Is the Evidence?
Mack Roach III, MDcorrespondenceemail
, Tania L. Ceron Lizarraga, MD, Ann A. Lazar, PhD
Article has an altmetric score of 2
DOI: http://dx.doi.org/10.1016/j.ijrobp.2015.08.005 |

Purpose

The optimal treatment of clinically localized prostate cancer is controversial. Most studies focus on biochemical (PSA) failure when comparing radical prostatectomy (RP) with radiation therapy (RT), but this endpoint has not been validated as predictive of overall survival (OS) or cause-specific survival (CSS). We analyzed the available literature to determine whether reliable conclusions could be made concerning the effectiveness of RP compared with RT with or without androgen deprivation therapy (ADT), assuming current treatment standards.

Methods

Articles published between February 29, 2004, and March 1, 2015, that compared OS and CSS after RP or RT with or without ADT were included. Because the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system emphasis is on randomized controlled clinical trials, a reliability score (RS) was explored to further understand the issues associated with the study quality of observational studies, including appropriateness of treatment, source of data, clinical characteristics, and comorbidity. Lower RS values indicated lower reliability.

Results

Fourteen studies were identified, and 13 were completely evaluable. Thirteen of the 14 studies (93%) were observational studies with low-quality evidence. The median RS was 12 (range, 5-18); the median difference in 10-year OS and CSS favored RP over RT: 10% and 4%, respectively. In studies with a RS ≤12 (average RS 9) the 10-year OS and CSS median differences were 17% and 6%, respectively. For studies with a RS >12 (average RS 15.5), the 10-year OS and CSS median differences were 5.5% and 1%, respectively. Thus, we observed an association between low RS and a higher percentage difference in OS and CSS.

Conclusions

Reliable evidence that RP provides a superior CSS to RT with ADT is lacking. The most reliable studies suggest that the differences in 10-year CSS between RP and RT are small, possibly <1%.

Cranial irradiation significantly reduces beta amyloid plaques in the brain and improves cognition in a murine model of Alzheimer’s Disease

Cranial irradiation significantly reduces beta amyloid plaques in the brain and improves cognition in a murine model of Alzheimer’s Disease (AD)
Brian Marplescorrespondenceemail, Mackenzie McGee, Sean Callan, Scott E. Bowen, Bryan J. Thibodeau, Daniel B. Michael, George D. Wilson, Michael E. Maddens, James Fontanesi
, Alvaro A. MartinezDOI: http://dx.doi.org/10.1016/j.radonc.2015.10.019

Abstract

Background and purpose

To investigate if cranial X-irradiation reduces amyloid-β (Aβ) plaques and influences cognitive function in a transgenic mouse model of AD.
Methods and materials

B6.Cg-Tg (APPswePSEN1dE9)85Dbo/J AD-prone mice were given cranial X-irradiation. The number of Aβ plaques, along with expression of AD specific genes (84 genes: Mouse Alzheimer’s Disease RT2 Profiler™), radiation-associated cytokines (Milliplex® MAP Mouse Cytokine Chemokine Immunoassay) and immunohistochemistry (IL10, IL-1β, Iba1 CD45) was assessed. Behavioral testing was performed to relate changes in Aβ burden to cognitive function using a Morris water-maze task.

Results

Single X-ray doses reduced the number (p = 0.002) and size (p = 0.01) of Aβ plaques. Low-dose fractionation produced greater 50.6% (1 Gy × 10), 72% (2 Gy × 5) and 78% (2 Gy × 10) reductions. Irradiation was associated with gene (Pkp4, 1.5-fold, p = 0.004) and proteomic (MIP-2, 8-fold, p = 0.0024) changes at 24–48 h. Microglia increased at 4 weeks post-irradiation (p = 0.001). The reduction in Aβ burden (2 Gy × 5) was associated with cognitive improvement (p = 0.012).

Conclusion

This is the first report that a clinically relevant course of external beam irradiation (2 Gy × 5) produces a significant reduction in AD-associated amyloid-β plaques with a subsequent improvement in cognitive function. However, longer-term studies are needed to define the precise underlying mechanism and longevity of this response.

Treatment of Neuropatic Pain. Medscape

Abstract and Introduction
Abstract

Neuropathic pain is a common symptom associated with peripheral neuropathy and can be as or more disabling than the effects of nerve damage from the neuropathy. Though treatment of the underlying pathophysiology causing neuropathies may not be possible, treatment of neuropathic pain is. The author reviews the major medications used, dosing schedules, and data from randomized controlled trials.

Introduction

Neuropathic pain is a common symptom expressed by patients who have a variety of causes for their neuropathy. It is thought to be due to pathologic changes in, or damage to, neurons in the peripheral or central nervous system.[1]

This disrupts the normal pain signaling process and can cause sensitization or spontaneous neuronal activity in the nervous system. The neural activity is perceived as pain.
There are effective medications available for the treatment of neuropathic pain; however, many patients do not achieve a satisfactory response or experience intolerable side effects.
Several organizations have published guidelines for the pharmacologic management of neuropathic pain.[2–5]

These guidelines are fairly consistent and emphasize the importance of medication efficacy, patient comorbidities, potential side effects and drug interactions, abuse potential, and cost when considering a medication for the treatment of neuropathic pain.
The data for a large number of drugs used to treat neuropathic pain are reviewed and suggestions to optimize patient use and effect are provided. Several drugs will be discussed for off-label indications.

Calcium Channel Alpha-2-delta Ligands

Gabapentin (Neurontin®, Pfizer Pharmaceuticals) and pregabalin (Lyrica®, Pfizer Pharmaceuticals) are structurally similar to gamma-aminobutyric acid (GABA), although they do not bind to GABA receptors. They are thought to exert their beneficial effects on neuropathic pain by binding to the α-2-delta subunit of voltage-dependant calcium channels. This leads to reduction of the influx of calcium into neurons throughout the central nervous system (CNS).[3]
This in turn may decrease the release of glutamate, norepinephrine, and substance P.[5]

Gabapentin (Neurontin®)

Gabapentin is an antiepileptic drug (AED) studied for various types of neuropathic pain. It is FDA-approved for the treatment of PHN and as adjunct therapy for partial onset seizures.[11]
Clinical trials have shown positive results for the treatment of PHN and painful polyneuropathy, and mixed results for the treatment of painful diabetic neuropathy and phantom limb pain.
Gabapentin was not effective in studies of complex regional pain syndrome, chemotherapy-induced neuropathy, and HIV neuropathy.[6] Gabapentin is recommended as a first-line treatment option for painful polyneuropathies, postherpetic neuralgia, and central neuropathic pain by the AISP, EFNS, and CPS.[2–5]

Gabapentin can be initiated at doses of 100 to 300 mg at bedtime or 100 to 300 mg three times daily.
The dose should be titrated by 100 to 300 mg every 3 to 7 days as tolerated to a maximum dose of 3600 mg per day.
The usual effective dose is 1800 mg to 3600 mg per day, which may take several weeks to achieve. Because of the slow dose titration, an adequate trial may take more than 2 months.[5]
It has minimal drug interactions because it is not hepatically metabolized and does not inhibit or induce hepatic enzymes.
However, a dose reduction is required in patients with renal insufficiency. It may also help improve sleep.

Sedation is the most common dose-limiting side effect and is minimized by initiating with a lower dose and titrating more gradually.[6]
Somnolence and dizziness are the most common side effects, and can often be managed by a slow titration.
The elderly are more prone to these side effects and gabapentin may increase the risk of falls and worsen cognitive impairment in this patient population.[5]
The slow-dose titration and onset of action, three times daily dosing schedule and side effects of sedation, edema, dizziness, and weight gain may limit the use of gabapentin for some patients.

A Cochrane review[12] included trials of gabapentin for the treatment of different types of chronic pain.
This analysis included four placebo-controlled trials (281 patients) of gabapentin 900 to 3600 mg daily for the treatment of painful diabetic neuropathy.

The combined NNT for effective pain relief in these four studies was 4.3 (95% CI 3.5–5.7); that is, 64% of patients improved on gabapentin compared with 28% on placebo.
Three control studies comparing gabapentin to amitriptyline for the treatment of painful diabetic neuropathy were also reported.
One study of 25 patients showed similar efficacy with gabapentin (900–1800 mg per day) or amitriptyline (25–75 mg per day).
A second study of 25 patients concluded that gabapentin (1200–2400 mg per day) was superior to amitriptyline (30–90 mg daily), but these results were not statistically significant.
The third study included only seven patients who had benefit from gabapentin in a previous study. The results of this study were not evaluable.[12]

A recent crossover design study[13] compared nortriptyline (maximum dose of 100 mg daily), gabapentin (maximum dose of 3600 mg daily), and a combination of both in 56 patients with painful diabetic neuropathy or PHN.
Participants received each treatment for 6 weeks followed by a one week taper and a one-week washout phase.
Pain scores were significantly lower during the combination phase than for either treatment alone.
Gabapentin monotherapy and nortriptyline monotherapy were similarly effective. Dry mouth was more common with nortriptyline and difficulty concentrating was more common with gabapentin.

Pregabalin (Lyrica®)

Pregabalin is thought to have a mechanism of action similar to gabapentin. It is FDA-approved for the treatment of painful diabetic neuropathy, PHN, and fibromyalgia and as adjunct therapy for partial onset seizures.
Its efficacy is established in randomized controlled trials for the treatment of painful diabetic neuropathy and PHN; however, some trials in these conditions have also shown negative results.[6]

Pregabalin is initiated at a dose of 50 mg three times daily or 75 mg twice daily. The total daily dose can be titrated in increments of 150 mg every 3 to 7 days as tolerated to a maximum dose of 600 mg per day.
However, doses greater than 300 mg have not consistently shown additional benefit for the treatment of neuropathic pain conditions.[6] A lower initial dose and slower taper may help minimize sedation.
Pregabalin has a faster tolerable titration than does gabapentin and twice daily rather than three times per day dosing.
Pregabalin has minimal drug interactions and no hepatic metabolism. It can help with comorbidities such as insomnia and anxiety.[6]

The side effects associated with pregabalin also appear to be similar to those associated with gabapentin, including sedation, edema, dizziness, and weight gain and occur more frequently at higher doses.
A small percentage of patients reported euphoria when taking pregabalin, leading to its Schedule V Controlled Substance classification in the United States.[6]

A Cochrane review assessed the efficacy of pregabalin for chronic pain.
The NNT for greater than 50% pain relief over baseline with 600 mg/day was 5.0 (95% CI 4.0–6.6) for painful diabetic neuropathy (six studies, 1360 patients) and 5.6 (95% CI 3.5–14) for central neuropathic pain (two studies, 176 patients).

The NNT for greater than 50% pain reduction at a lower dose of 300 mg per day was 7.5 (95% CI 5.1–14) for painful diabetic neuropathy (two studies, 341 patients).
The results were similar when only studies of greater than 8-week duration were included.

The NNH causing discontinuation due to side effects with 600 mg/day was 8.8 (95% CI 6.8–12) in painful diabetic neuropathy trials (six studies, 1351 patients), and not significantly different from placebo in central neuropathic pain trials.
For a lower dose of 300 mg per day, the NNH was 16 (95% CI 9.9 to 37) for painful diabetic neuropathy (four studies, 823 patients).


Topical Lidocaine

Topical lidocaine is thought to reduce discharges of small afferent nerve fibers by blocking voltage-gated sodium channels.[3] It is available in gel and transdermal patch formulations. The transdermal patch is FDA approved for treatment of PHN.[14]

Lidocaine 5% transdermal patch was effective in randomized controlled trials of patients with allodynia due to PHN or peripheral neuropathies of other etiologies.[6]

A lidocaine gel formulation was effective in patients with PHN and allodynia, but can also be considered when the transdermal patch is not available, is not tolerated, or is too expensive.[5]

NeuPSIG recommends topical lidocaine as a first-line option for the treatment of localized peripheral neuropathic pain,[5] and the EFNS recommends it as first-line treatment of PHN with allodynia.

Topical lidocaine is considered a second-line treatment option for localized neuropathic pain by the CPS.[4]

A maximum of three patches can be applied to the painful area once every 24 hours and left in place for 12 hours.
Prior to removing the release liner, the patches can be cut to fit the affected area.[14]

Topical lidocaine is well tolerated and minimal systemic absorption occurs at the recommended dose.[5]
No dose titration is necessary to reach an effective dose.[6]

Lidocaine patches are effective only for the area where the patch is applied, and are not helpful for central neuropathic pain or to treat polyneuropathy that occurs over a large area.[6]
Application site irritation may occur.
Although systemic absorption is unlikely, topical lidocaine should be used with caution in patients with hepatic dysfunction, and those taking class I antiarrhythmic medications such as mexiletine.[5]

Increased absorption or drug accumulation may occur when the patch is applied for longer periods of time or over larger areas than recommended, in small patients, and in patients with kidney insufficiency.[14]


Opioid Analgesics

Randomized controlled trials have shown beneficial effects of opioids (including oxycodone, methadone, morphine, and levorphanol) for the treatment of DPN, PHN, painful polyneuropathy, and phantom limb pain.[6]

Comparative trials have shown similar benefit with opioids when compared with TCAs and gabapentin, but more frequent side effects occurred with opioids.[6] NeuPSIG recommends opioids as second-line medications when an adequate response is not achieved with first-line medications or as a first-line option when immediate pain relief is necessary and short-term for acute neuropathic pain.[5]

The EFNS recommends opioid medications as second- or third-line options for painful diabetic neuropathy, PHN, and central neuropathic pain because of limited trials assessing long-term safety and abuse potential.[2]

The Canadian Pain Society recommends opioids (excluding methadone) as third-line agents for the treatment of painful diabetic neuropathy, PHN, and other neuropathic pain conditions.

Methadone is considered a fourth-line agent because of limited clinical evidence, difficulty with titration, and regulatory status in Canada.[4]

The appropriate dose is widely variable from patient to patient and depends on prior opioid exposure.
The typical initial dose is 10 to 15 mg of morphine or equianalgesic dose every 4 hours or as needed.

After 1 to 2 weeks the total daily dose can be converted to an equianalgesic dose of a longer acting opioid medication such as transdermal fentanyl, extended release oxycodone, or extended release morphine.

A scheduled long-acting opioid is typically preferred. If pain is not improved after an adequate trial, the medication should be tapered and discontinued.[5]

Compared with other medications, opioids typically have a quick onset of pain relief. Opioid medications are particularly useful for short-term use to treat acute exacerbations or during the titration phase of a first-line medication.[5]

There are several disadvantages associated with the use of opioid medications.
They are often poorly tolerated. Common side effects include sedation, constipation, and nausea. Constipation typically does not improve over time and a bowel regimen may be required.
These medications can increase risk of falls and cognitive problems in elderly patients.
Rare but serious side effects include hypogonadism, immunologic changes, and hyperalgesia.

Opioids are associated with a risk of misuse or addiction of 5% to 50% in other chronic pain conditions. Risk factors for abuse include a history of or current substance abuse, major psychiatric disorders, and family history of substance abuse.[5]

A Cochrane review of 23 studies assessed the efficacy of opioid medications for the treatment of neuropathic pain.[15]

The majority of these studies assessed treatment for less than 24-hour duration, single doses, or intravenous (IV) administration, but nine studies were 8 to 70 days in duration and included 460 patients with various types of neuropathic pain (painful diabetic neuropathy, PHN, and phantom limb pain).

The opioid medications studied were morphine (four trials), oxycodone (three trials), methadone (two trials), and levorphanol (one trial).

The opioid medications were superior to placebo in all placebo-controlled studies. A meta-analysis of the seven studies with suitable data concluded that overall opioid medications were associated with a reduction in pain intensity of 13 points on a scale of 0 to 100.
The most common side effects were nausea, constipation, sedation, and vomiting. The NNH for drug discontinuation was 16.7 (95% CI 9.1–100).

Links and Oncology

Journal Of Clinical Oncology

New England Oncology

American Society of Clinical Oncology

British Journal of Cancer

Nature

Science

The Green Journal ESTRO

The Red Journal ASTRO

Sociedad Española de Oncología Médica

Bulletin du Cancer

European Society of Medical Oncology

Medscape

OncLive

National Center for Biotechnology Information

Clinical Care Options

Genetic Testing and Breast Cancer Treatment Decisions

How Genetic Testing Impacts Breast Cancer Treatment Decisions | Page 1
Steven J. Katz, MD, MPH and Reshma Jagsi, MD, DPhil
Published Online: Tuesday, November 10, 2015
University of MichiganSteven J. Katz, MD, MPH
Steven J. Katz, MD, MPH
Attending Physician, Breast Oncology
Georgetown Lombardi Comprehensive Cancer Center
MedStar Georgetown University Hospital
MedStar Montgomery Medical Center
Assistant Professor, Georgetown University
Washington, DC Reshma Jagsi, MD, DPhil
Reshma Jagsi, MD, DPhil
Associate Professor, Radiation Oncology
University of Michigan Medical School
Ann Arbor, MI
Dr. Catherine M. Diefenbach


As genetic testing becomes increasingly available, there will be a growing gap between the wide availability of testing and the relative importance of results to treatment decisions. In the current environment, there’s more promise in precision medicine than practical applications in the exam room. Multigene panel testing is increasingly available, but we don’t fully understand how to best incorporate results into treatment recommendations for patients with breast cancer.

As a result, patients newly diagnosed with breast cancer and their doctors face a conundrum in the exam room: how to efficiently incorporate increasingly complex clinical information into treatment decision making.

The demand is growing for genetic testing. More than a quarter of patients newly diagnosed with breast cancer undergo genetic testing now. That rate has been increasing, and recent studies suggest it could be even higher.

Our study of 1536 breast cancer survivors published this year in the Journal of Clinical Oncology found that 35% of patients had a strong desire for genetic testing.1 Many of the women who reported strong interest were at low risk of having a mutation and might not be typical candidates for a discussion about genetic testing.

Stepwise Approach Needed

But whether results of genetic testing show a mutation or not, what does it mean for physicians recommending treatment options to patients and for patients trying to understand complex treatment options and risk to decide how to treat their cancer? We need to change both the way genetic tests results are reported and, more importantly, how results are incorporated into treatment deliberation for patients newly diagnosed with breast cancer.

After diagnosis, patients face a rapid escalation of treatment decisions navigated by different specialists. We need to allow more time for deliberation and a better way to incorporate increasingly more complex genetic and genomic information into the process.

Germline genetic testing often requires discussions with genetic counselors. Patients need a stepwise approach to deliberation and ought not to rush the process. We don’t honor enough the process and time patients need for treatment decision making.
CPM Rates Illustrate Knowledge Gap


This can be seen in the recent uptick in women choosing contralateral prophylactic mastectomy (CPM). A 2014 study in JAMA Surgery found that 70% percent of women who have CPM have no clinical indications, such as a family history of breast or ovarian cancer or a mutation found on genetic testing.2 In fact, many of these women were candidates for breast conservation. It’s striking that so many women are receiving much more extensive surgery than needed to treat their disease.

Women diagnosed with breast cancer are naturally eager to do everything in their power to fight the disease. So many patients confide that they just want to do everything they can to be there for their children. It is up to us, as doctors, to make sure they understand which treatments are really going to do that, and which actions might seem heroic but are actually not expected to improve the outcomes for a typical woman with early-stage breast cancer.


Our team presented an abstract at the 2015 American Society of Clinical Oncology Annual Meeting that found nearly half of 1949 breast cancer survivors surveyed said they considered CPM.3 Of those who considered it, only 37% knew that the more aggressive procedure does not improve survival for women at average risk of a second cancer. Further, we found that women’s perceptions of their surgeon’s recommendation played a big role in the decision to have CPM. Only 4% of women who said their surgeon recommended against CPM had the procedure. But even among patients who did not have a genetic mutation or strong family history to motivate the decision for CPM, 23% who said their surgeon didn’t recommend for or against CPM went on to have the aggressive surgery.

This research indicates that patients are coming away with perceptions that really require adjustments. Doctors need to address the jaw-dropping gaps in patient knowledge of CPM benefits and the perception of what their surgeons told them.

Study Tackles Decision Making

The University of Michigan Comprehensive Cancer Center leads an interdisciplinary group of investigators from across the country seeking to understand and improve how patients and their providers communicate and make decisions about cancer treatments.
The Cancer Surveillance and Outcomes
Research Team (CanSORT) has a grant from the National Cancer Institute, part of which includes building a decision tool to help women with breast cancer fully understand their treatment options and the risks involved.

Part of the issue is in how different healthcare providers frame information about risk. Typically, genetics experts focus on the cumulative risk of another cancer over a lifetime. This doesn’t incorporate comorbid conditions, such as heart disease, diabetes, or even the present cancer diagnosis. Meanwhile, oncologists recommending treatment for the current cancer talk about 5- to 10-year survival rates and they do consider other health risks.

Patients are stuck in the middle, trying to make sense of it all. As healthcare professionals, we need to do a better job of framing this discussion in a patient-centered, coherent way. CanSORT investigators are currently in the midst of a survey called iCanCare, and are beginning to analyze responses from 7500 breast cancer survivors on issues related to treatment decision making. The team is also completing an agreement that would involve looking at patterns of genetic testing among a very large sample of patients with breast cancer. Going forward, we believe breast cancer will be the tracer condition to show how genetic testing can influence treatment decision making and improve patient health.

radiation therapy and palliative care

Advanced cancer patients have better quality of life and reduced health care costs when radiation therapy and palliative care are coordinated and based on patient-reported feedback

San Antonio, October 19, 2015


A collaborative, patient reported outcome (PRO)-based approach by palliative care and radiation oncology teams, results in better outpatient symptom management and a decrease in end-of-life hospitalizations and costs for late-stage cancer patients according to research presented today at the American Society for Radiation Oncology’s (ASTRO’s) 57th Annual Meeting. The data also showed that through the implementation of rapid palliative radiotherapy that includes shorter, higher doses of radiation therapy, many patients experience pain relief within one week of treatment.

Starting in 2012, researchers at the University of Virginia Health System developed an integrated patient care program for advanced cancer patients that utilized information from PROs to improve patients’ health and quality of life and reduce costs of care. The program emphasized reducing hospitalizations and improving outpatient management of patients. The collection of PRO assessments was initiated for all patients beginning in October 2013, following a pilot testing phase completed in February 2013.

A patient questionnaire that asked patients how they were doing emotionally and physically was incorporated into the facility’s electronic medical records system. A comprehensive assessment and rapid evaluation and treatment (CARE Track) palliative care team was alerted by the system to clinically significant reported changes in a patient’s status.

A total of 646 cancer patients were enrolled into the CARE Track program. End-of-life data of 368 CARE Track patients was compared to end-of-life data of 198 patients not enrolled in the CARE Track program (the control group). A total of 967 PRO surveys were completed by the 368 CARE Track patients.
The CARE Track patients had significantly fewer end-of-life hospitalizations, with 48.3 percent of patients being hospitalized in the final 90 days of life, compared to 64 percent from the control group.
Additionally, the CARE Track patients received more hospice care than the control group (69.6 percent compared to 47 percent), which resulted in fewer hospital deaths for the CARE Track group than the control group (8.4 percent vs. 38.5 percent).
This difference in end of life care resulted in a reduced mean total cost of $7,317 per patient in the last 90 days of life.

A multidisciplinary Supportive Care Tumor Board was also developed that met weekly to develop rapid and coordinated care plans for highly symptomatic patients.
To respond more quickly to pain control, the team developed STAT RAD—a more rapid workflow for palliative radiation therapy for patients with bone metastases with the goal of turning a common two-to-three week treatment course into a one-day treatment procedure with highly focused radiation treatment to reduce treatment-related toxicity.

The STAT RAD pilot clinical trial enrolled 28 patients. The patients each had between one and three painful bone metastases (37 target lesions) and received RT of 5 to 10 Gy per fraction, for between two and five fractions.
An average of 21.6 Gy in 3.1 fractions was administered. The pain response of patients in the STAT RAD program was assessed using the International Bone Metastasis Consensus Working Party; and the patients’ quality of life (QOL) was assessed using the Functional Assessment of Cancer Therapy - Bone Pain Scale.
Patients reported 80 to 90 percent partial or complete pain relief by three months and QOL was significantly improved for patients for a timeframe ranging from one week post STAT RT to 26 weeks post STAT RAD. A second clinical trial is still accruing patients and is exploring single fraction STAT RAD with dose escalation from 8 Gy to 15 Gy so that the entire course of simulation, planning, quality assurance, and treatment can be completed in a single 3-4 hour patient centric-procedure.

“If we listen to our patients carefully, talk to them about their changing medical and emotional needs and develop rapid and coordinated treatment plans we can improve their quality of life and reduce their need for hospitalization for symptom management at the end of life,” said Paul W. Read, MD, PhD, lead author of the study and professor of radiation oncology at the University of Virginia Health System.

“Integrating patient surveys to collect patient reported outcomes directly into electronic medical records, and incorporating them into routine clinical care can be done in most hospital systems. The concept of Tumor Boards for multi-specialty care planning of curative cancer patients is practiced throughout the country and extending this concept to palliative care management is easy and straightforward. Single fraction radiation therapy for palliation of bone metastases for advanced cancer patients with short life expectancies is an accepted national care guideline and has been studied for decades in clinical trials. Therefore, these programs can all be adopted into clinical practice at most health systems with minimal cost, training or education.”

The abstract, “Outcomes of a Re-engineered Palliative Care and Radiation Therapy Care Model” will be presented in detail during the clinical trials session at ASTRO’s 57th Annual Meeting at 3:15 p.m. Central time on Sunday, October 18, 2015. To speak with Dr. Read, please call or email Nancy Mayes in ASTRO’s Press Office at the Henry B. González Convention Center in San Antonio on October 18 – 21, 2015 at 210-258-8104 or 210-258-8105.

Pneumatic Compression and Post-Cancer Lymphedema

Pneumatic Compression Device Combats Post-Cancer Lymphedema
Patients with cancer-associated lymphedema may benefit from home care with an advanced pneumatic compression device

Date: 09 Oct 2015
Author: Lynda Williams, Senior medwireNews Reporter
Topic: Complications of Treatment / Surgery and/or Radiotherapy of Cancer

medwireNews: Advanced pneumatic compression device (APCD) use can reduce cellulitis and healthcare requirements arising from secondary lymphedema associated with cancer, US research suggests.

Pinar Karaca-Mandic, from University of Minnesota School of Public Health in Minneapolis, and team reviewed private insurance claims information for 374 affected individuals before and after they began using a specific pneumatic compressor device with or without calibrated gradient pressure at home.

The majority (75.9%) of patients had breast cancer, with the next most common sites being bone, connective tissue or skin, and the genitourinary organs.

As reported in JAMA Dermatology, the rate of cellulitis decreased by a significant 79% from 21.1% in the 12 months before the APCD was used to 4.5% in the 12 months after its purchase.

This decrease in skin infections was accompanied by a significant 30% reduction in the rate of manual therapy for lymphedema, from 35.6% to 24.9% and a significant 29% decline in the rate of outpatient hospital visits, from 58.6% to 41.4%.

These improvements significantly lowered lymphedema-related insurance costs, the authors emphasize, highlighting a 54% reduction in outpatient hospital care expenditure. This included a 50% reduction in the costs of physical and occupational therapy and a 42% lowering of costs associated with office visits.

Pinar Karaca-Mandic and team add that a second cohort of 344 patients with secondary lymphedema not associated with cancer also experienced a significant reduction in cellulitis, and the need for manual therapy and outpatient hospital care.

“While our findings are based on the outcomes from a specific device, it is possible other such devices may also reduce patient burden. This warrants explorations in future studies”, they say.

The authors of an accompanying editorial note that the role of PCDs has previously focused on limb volume and circumference or tissue elasticity and “largely ignored patient-centered outcomes, such as health-related quality of life and ability to perform daily activities.”

Peter Franks, from the University of Glasgow, UK, and Christine Moffatt, from the University of Nottingham, UK, therefore comment: “The consequences of a reduction in the incidence of cellulitis should not be ignored because this has other consequences, although much larger studies and longer follow-up than most of those identified in this article may be required for this to be a suitable outcome.”

Nevertheless, they conclude that although the “major clinical and health economic outcomes are impressive in cohort studies there is still a need to undertake [randomised controlled trials] to exclude bias” and now await clinical trials designed to compare different devices and compression parameters to determine the optimal treatment of lymphedema.

Reference

Karaca-Mandic P, Hirsch AT, Rockson SG, Ridner SH. The cutaneous, net clinical and health economic benefits of advanced pneumatic compression devices in patients with lymphedema. JAMA Dermatol 2015; Advance online publication 7 October. doi:10.1001/jamadermatol.2015.1895

Franks PJ, Moffatt CJ. Inermittent pneumatic compression devices in the management of lymphedema. JAMA Dermatol 2015; Advance online publication 7 October. doi:10.1001/jamadermatol.2015.1974

medwireNews (www.medwireNews.com) is an independent medical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2015

Olaparib and Metastatic Prostate Cancer

Olaparib ‘Highly Effective’ In DNA Repair-Deficient Metastatic Prostate Cancer


Date: 29 Oct 2015
Author: Shreeya Nanda, Senior medwireNews Reporter
Topic: Anti-Cancer Agents & Biologic Therapy / Prostate Cancer / Translational

medwireNews: Previously-treated metastatic prostate cancer patients with tumours harbouring mutations in DNA repair genes could benefit from treatment with the poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitor olaparib, findings indicate.

In the phase II trial reported in The New England Journal of Medicine, 50 patients with metastatic, castration-resistant disease who had progressed after up to two regimens of chemotherapy were given open-label olaparib 400 mg twice daily.

After a median follow-up of 14.4 months, 16 (33%) of 49 evaluable study participants achieved a response, defined as an objective response as per RECIST 1.1 criteria, a reduction of at least 50% in the prostate-specific antigen level or a confirmed reduction in the circulating tumour-cell count to below 5 cells per 7.5 mL of blood.

Whole-exome and transcriptome sequencing of fresh-frozen or archived (in six cases) biopsy samples showed that 16 patients had tumours with homozygous deletions, deleterious alterations or both in genes known to be involved in DNA repair, such as BRCA1,BRCA2,ATM and CHEK2.

Fourteen (88%) of the patients with DNA-repair defects had a response to the PARP inhibitor compared with just two (6%) of 33 mutation-negative patients, a significant difference, report Johann de Bono, from the Institute of Cancer Research and Royal Marsden NHS Foundation Trust in Sutton, UK, and fellow investigators of the TOPARP-A trial.

Radiological progression-free survival was also significantly improved in men with tumours harbouring compared with those lacking the relevant aberrations, at a median of 9.8 versus 2.7 months. And overall survival was longer in men with than in those without alterations, although the difference only tended to significance.

The most frequent grade 3 or 4 adverse event attributed to olaparib therapy was anaemia (20%), followed by fatigue (12%), leukopenia (6%), thrombocytopenia (4%) and neutropenia (4%). The olaparib dose was reduced in 13 participants, while three discontinued treatment as a result of unacceptable toxicity.

“Our trial marks a significant step forward in the treatment of prostate cancer, showing that olaparib is highly effective at treating men with DNA repair defects in their tumours”, Johann de Bono said in a press release.

“It also proves the principle that we can detect prostate cancers with specific targetable mutations using genomic sequencing to deliver more precise cancer care by matching treatment to those men most likely to benefit.

“I hope it won’t be long before we are using olaparib in the clinic to treat prostate cancer, or before genomic stratification of cancers becomes a standard in this and other cancers.”

Reference

Mateo J, Carreira S, Sandhu S,et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer.N Engl J Med2015; 373:1697–1708. doi: 10.1056/NEJMoa1506859

medwireNews (www.medwireNews.com) is an independent medical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2015

A Never-Ending Battle

Perspective
A Never-Ending Battle

Vyjeyanthi S. Periyakoil, M.D.

November 4, 2015DOI: 10.1056/NEJMp1505976


“Were you in the Army, Navy, Air Force, Marine Corps, or the `Guard'?” I asked as I admitted my patient, a 78-year-old veteran.

Mr. M. had florid heart failure, the result of multiple myocardial infarctions over years, each one taking a big bite out of his heart's pumping abilities and leaving his lungs and body waterlogged. His aging kidneys had slacked off, too, and despite maximal medical therapy he was now looking at a remaining lifespan of weeks. He was wheelchair-bound and tethered to his oxygen cylinder owing to profound air hunger.

He sketched me a mocking salute. “U.S. Army Cavalry Scout reporting for duty, Ma'am!”

“Have you seen combat?” I asked.

He idly gestured toward the combat veteran license plate on his scooter wheelchair.

“So what exactly did you do as a scout?”

“Just routine, boring stuff. Nothing fancy,” he said dismissively.

“He doesn't like to talk about the war,” his wife put in, trying gently to defuse her husband's abruptness.

“Your records show you have chest pain and trouble sleeping. Do you have post-traumatic stress disorder?” I asked.

He shook his head vehemently.

I turned to his wife. “Is he up a lot in the night? Does that bother your sleep?”

“I don't know,” she ventured reluctantly. “I sleep in the guest bedroom.”

“What about the pain?” I forged on. “Are you taking anything for it?”

“Don't you try and give me none of those narc pills, doc. I want nothing for my pain,” Mr. M. said, wincing as a wave of pain washed over him.

Soon after he'd come back from the war, his wife later told me, she woke up one night to find him in the throes of a nightmare, straddling her abdomen as he tried to choke her. Fortunately, she was able to shout and wake him up. Ever since, he refused to sleep in the same room as she did, saying he loved her too much and was afraid that he would harm her. When she suggested that he get help for PTSD, he refused so violently that she never had the nerve to bring it up again.

Even if the war they fought is long over, many veterans are perpetual prisoners of an ongoing inner war that rages silently in their heads. Men and women on active duty may be forced to commit actions that directly conflict with their ethical and moral beliefs. Their stoicism and “battlemind” may serve them well as long as their psychological defenses are intact. At the end of life, however, their previous coping strategies may crumble, especially if they're taking mind-altering medications to relieve pain. Many may even prefer to bear severe pain and avoid pain medications, which make them fuzzy-headed and can unleash war-related nightmares and flashbacks. Thus, I was not surprised that Mr. M. vehemently refused pain medications. Many veterans' war memories are so painful that they never discuss them, even with their loved ones or their doctors.

In the days that followed, Mr. M. and I established a reasonable working relationship. I ran some tests and fine-tuned his medications and started him on IV antibiotics for pneumonia. His little vice was shopping at the hospital gift store, where he enjoyed buying small, whimsical gifts for his family and the staff. He continued to soldier on through his pain, and as his breathing difficulties worsened, his skin took on a grayish hue. He continued to refuse the opioids that might have alleviated both his pain and his air hunger.

The nights were pretty bad for him. He was hyperalert but exhausted, and he often prowled the hospital hallways on his electric scooter all night long.

“Why don't you hold my pager tonight so I can get some sleep?” I joked late one evening as I examined the weeping ulcers in his ankles.

“You got it, V.J.,” he said. “It will be just like when I scouted around at night with my army buddies.” He smiled for a second and then sobered up. “Doc, it's hard to sleep when you know you're going to wake up in the trenches.”

“The trenches?” I echoed, preoccupied by a large ulcer with an angry reddish hue.

“I most remember the cooking smells. On warm nights, the smell of rice used to waft over from the villages. My buddy and I used to wander the fields at night.”

“What for?” I probed the ulcer's depths gently to see if I could hit bone.

“Recon,” he said. “The scout goes ahead of the platoon to scope out the enemy. Mostly it was pretty quiet. Sometimes we had to fight our way out. One time it was pretty bad.”

My ears pricked up, but I knew better than to seem overeager, which would make him shut down.

“This wound needs to be cleaned up,” I said. “It's going to sting a bit.” I grabbed the wound supplies and got to work. “So what happened? The time you said it got pretty bad — did you run into some hostiles?”

He didn't speak for several minutes, and I continued to work in silence.

“When you see an enemy,” he said finally, “it's one thing. When the enemy sees you, that's something entirely different. When you're seen by the enemy, you put your entire platoon at risk. You have to follow the protocol. You have no choice.”

I kept my silence.

“V.J., we were almost done with our shift, my buddy and I. Another 30 minutes, we would have been back at camp. My buddy heard a sudden soft noise, and we had to investigate.” Mr. M. was staring at the ceiling, his eyes unfocused. “We had our weapons drawn, ready for combat. Then we saw the woman a few feet away — actually, she looked like a teenager, and she was alone and looked pretty harmless. I signed to my buddy to stand down, and we tried to silently retreat before the girl could sight us. We almost made it, but something must have alerted her, because she looked up and saw us.”

Now his words were coming fast and furious.

“We knew what we had to do. I drew the short straw. I made sure that it was swift. It was over before she even knew was happening. We covered our tracks and returned to camp.”

I had stopped débriding the wound, chilled by his words as their meaning sank in.

Finally, Mr. M. looked straight into my eyes and said softly, “The girl was pregnant. I noticed it after . . . you know . . . as I was cleaning my knife. Whenever I close my eyes, I see her face, that split second when she understood what was about to happen. I cannot get it out of my head.”

The vault had finally opened, and I knew he had a lot more to say.

I got up quietly and filled two Styrofoam cups with stale hospital coffee. What would I have done if I had been in his shoes, I wondered. I could have let the girl go, but maybe the mission would have been compromised and my entire platoon would have been killed or taken prisoner of war. Or maybe I would have done exactly what Mr. M. did and would now be deep in the throes of moral distress.

As I handed him his coffee, it suddenly dawned on me that my patient was not a war veteran. He was a soldier, very much on active combat duty — just on a different battlefront. And he'll be in combat until he dies.

I sat at his bedside and started sipping my coffee. “I'll stay until your wife gets back from dinner,” I said. He nodded.

After several minutes of companionable silence, he asked, “V.J., am I going to hell for killing two innocents?” Without waiting for a response, he continued, “Well, I'm going to find out soon enough.”

A Delicate Balance — Pharmaceutical Innovation and Access NEJM

Perspective
A Delicate Balance — Pharmaceutical Innovation and Access

William W. Chin, M.D.

N Engl J Med 2015; 373:1799-1801November 5, 2015DOI: 10.1056/NEJMp1513227

Comments open through November 11, 2015


As an endocrinologist, a former dean at Harvard Medical School, and a one-time head of research and clinical investigation at a biopharmaceutical company, I've seen many encouraging advances in medicine, plenty of discouraging false starts, and myriad areas where answers remain unknown. But today, as chief medical officer and executive vice president of Pharmaceutical Research and Manufacturers of America (PhRMA), I am seeing a therapeutic golden age like no other in my four-plus decades in medicine.

I believe ongoing biopharmaceutical advances hold great promise for us all, and they lie at the center of a national debate over the cost and value of health care in general and new medicines in particular. This debate demands our attention, because whereas it is essential to accelerate scientific and medical progress, it's also critical to ensure that patients have affordable access to the care they need, want, and deserve. For the sake of patients, we need to strike a delicate balance in policies that achieve both biopharmaceutical innovation and access.

The study by Motzer et al. in this issue of the Journal (pages 1803–1813) provides a good example of current innovation, showcasing two important drugs that offer options to patients with renal-cell carcinoma and other cancers. More important, the study reflects a broader, deeper pattern that cuts across diseases. New therapeutic approaches such as immunooncology, for example, have helped increase the 5-year survival rate across all cancers by 42% since 1975, according to the National Cancer Institute. Hepatitis C is now curable in more than 90% of treated patients, and progress in endocrinology has expanded our arsenal of weapons against diseases such as diabetes, obesity, osteoporosis, and hypertension. Motzer and colleagues highlight just 2 of the more than 500 new medications that have been approved in the United States since 2000.

Yet even with these new options for treating or curing disease, the proportion of health care spending devoted to retail prescription medications remains about the same as it was in 1960. Moreover, despite the pipeline's promise, drug spending is projected to remain at about 14 cents out of every health care dollar between 2015 and 2024, even when nonretail medications, such as those administered by physicians, are included.1 Medications also generate benefits that cascade through our health care system, by improving patients' productivity and quality of life, extending lives, and averting more costly hospital and institutional care.

It's possible to deliver so many new medications to patients while still managing costs because the United States relies on competitive markets to set prices and encourage innovation — a system that, as I see it, is working well.

After approval by the Food and Drug Administration, a new medication enters a market that is increasingly characterized by competition from other brand-name and generic drugs in the same therapeutic class. This market then does its work. Payers demand demonstration of value and drive patients to the lowest-cost options using aggressive cost-containment strategies: tiered cost sharing, prior authorization, step therapy, and incentives for prescribers to adhere to preferred clinical pathways.

Drug purchasing is dominated by a few very large and sophisticated payers. By the end of 2015, the top four pharmacy benefit managers are expected to control more than 80% of all prescriptions.2 These payers bargain fiercely for rebates and other discounts (resulting in prices lower than a new drug's list price). The new breakthrough hepatitis C medications, with cure rates above 90%, are a good case study: within a year, competing medications entered the market, driving down prices by about half3 while broadening access to the long-term benefits these cures deliver to a heavily burdened health care system.

At the end of a brand-name medication's lifecycle, generic competitors enter the market, mostly capitalizing on innovative biopharmaceutical companies' prior work. The United States makes more efficient use of generics than other countries: nearly 90% of all U.S. prescriptions are filled with generics that are sold at a fraction of the price of the original brand-name medication, helping ensure long-term affordability. And the new biosimilars pathway is expected to deliver additional cost savings.

No other part of the health care system delivers this type of built-in savings. Our system recognizes the considerable challenges and expense of the research and development process and the need to reward innovation, and it balances these needs against access.

Recent history shows that we can find answers that bring value to our health care system. After all, in the 1980s there was no effective treatment for HIV–AIDS, and many observers warned that the disease would bankrupt the system as increasing numbers of patients began requiring acute end-of-life care. But instead of spiraling toward bankruptcy, we developed new medications, and today we can treat many more patients with HIV–AIDS, keep them out of the hospital and the costs of their care stable, and provide them with a near-normal lifespan. Rather than cutting off progress, we innovated and got more for our health care dollar and for patients.

Of course, this balanced U.S. system is by no means perfect. All of us in the health care system can do better for our patients so that they have access to affordable care while we add to our arsenal of medications. By working with other stakeholders, we can achieve both. It won't be easy. But if we can first agree that we all share a commitment to value, our next steps become clearer.

I recommend that we first close gaps in the evidence base across the continuum of care. Biopharmaceutical companies are committed to actively collaborating with government, academia, payers, physicians, and patients to fill these gaps (our participation in the Patient-Centered Outcomes Research Institute is just one example).
Second, the health care system can empower physicians and patients with the best available evidence through shared decision making, well-designed care pathways, and decision-support tools.
Third, as the Medicare Payment Advisory Commission, the National Academy of Medicine, and others have noted,4 we can refine our ability to measure care quality and performance — particularly clinical outcomes, consideration of patients' preferences, and quality of life. And we can do so in ways that are administratively feasible for physicians and that enhance, rather than impede, their interactions with patients.

We in the United States are fortunate to have biopharmaceutical product approval, lifecycle, and market-based–purchasing systems that work to balance cost and value, and our ongoing innovation benefits patients and society.
As we move forward, I believe we must recognize that what determines value is varied and individual, and any centralized government-purchasing model would probably result in drastically limited choices for physicians and patients.
In the United Kingdom, for example, use of a national cost-effectiveness standard has created barriers to patients' access to many important new cancer treatments. In fact, in 2013, the U.K.'s National Institute for Health and Care Excellence recommended against coverage of all six cancer medications it reviewed.5

As we strive to advance both innovation and access, I argue that we must also avoid creating new systems that would eliminate the very incentives that have fostered U.S. innovation for decades. After all, U.S. research and development has vastly outperformed that of former biopharmaceutical powerhouse countries such as Germany and Switzerland, which have instituted price controls that limit patient choice.

Meeting the health care challenges we face starts with a shared commitment to improving patients' lives and advancing value in a competitive health care market. I believe it requires payers, government, academia, health care providers, patients, and industry to pull in the same direction.
By doing so, we can improve the delivery of patient-centered, high-quality care, accelerate continued progress toward addressing unmet needs, and ensure continued access to affordable care. U.S. patients deserve nothing less, and industry is ready to help.

Peritoneal carcinomatosis and “Chemotherapy Bath”

Standardization Is Key to Future of “Chemotherapy Bath” | Page 1
Christina T. Loguidice
Published Online: Friday, October 30, 2015
Jesus Esquivel, MD

Jesus Esquivel, MD
An increasing number of patients are presenting with peritoneal carcinomatosis, or widespread metastasis of the peritoneum, which can result from a variety of tumors, including digestive and gynecologic malignancies. 1 The diagnosis is devastating, with treatment often limited to palliation of symptoms, but a combination of cytoreductive surgical resection (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC)—sometimes referred to as “hot chemotherapy bath”—has the potential to provide some patients with long-term survival.

HIPEC is administered after CRS, with CRS attempting to remove all visible disease from the abdomen and HIPEC targeting any microscopic disease. A variety of chemotherapeutic agents can be used, depending on tumor type. The selected agent is heated before it is infused into the abdominal cavity. The heat is thought to help the chemotherapeutic agent kill any residual cancer cells, and flooding the abdomen with the agent is thought to expose cancer cells to higher concentrations of the selected drug than can be achieved with systemic chemotherapy.

After the drug has been deemed to sufficiently circulate through the abdomen (30-120 minutes), it is drained from the body, anastomoses are performed, and the abdomen is closed.2 Patients may go on to receive systemic chemotherapy, particularly if they have more extensive or aggressive disease.

Although the procedure has been in use since the 1970s, HIPEC has been criticized for its lack of standardization, with the literature showing variations in the seven parameters used to characterize the procedure: (1) method, (2) inflow temperature, (3) perfusate volume, (4) drug used, (5) dosage, (6) timing of drug delivery, and (7) total perfusion time.2 Randomized controlled trials are still lacking to shed light on these issues; however, in 2009, the American Society of Peritoneal Surface Malignancies (ASPSM) was formed to improve the overall care of patients with peritoneal surface malignancies, and it set HIPEC standardization as its first goal.2

OncologyLive discussed this treatment in greater detail with Jesus Esquivel, MD, national director for HIPEC research, Department of Surgical Oncology, Cancer Treatment Centers of America, who has performed more than 500 such procedures and is also on ASPSM’s board of directors.

Q: Which patients with peritoneal carcinomatosis would be candidates for HIPEC, and would it always be paired with cytoreductive surgery?

The ideal patients would be those with limited amount of peritoneal carcinomatosis and with a diagnosis of a not very aggressive tumor, like mucionus tumors of the appendix, ovary, or colon. The results for more aggressive tumors, like pancreatic tumors, sarcomas, and gastric tumors, are not as good. For the most part, cytoreduction and HIPEC go together all the time. Sometimes HIPEC can be used without cytoreductive surgery as a palliative procedure for those patients with intractable ascites.

Q: One of the criticisms of HIPEC has been that there is no standardized approach— agents and methods can vary considerably. What approach do you apply? Is it the same for all patients or does it vary? If the latter, how do you decide?

In the past, there were tremendous variations on how HIPEC was delivered. Nowadays, most of us follow the recommendations published by the American Society of Peritoneal Surface Malignancies. The chemotherapy agent used will depend on the diagnosis of the patient. Mitomycin C is the most frequently used drug for gastrointestinal malignancies and a platinum agent would be the most commonly used for gynecological malignancies.

Q: Do you see HIPEC methods being standardized or improving in the future?

Absolutely. To be able to promote a therapy, there needs to be as much standardization as possible. There will always be some small variations that appear not to be clinically relevant, but even those will have to be standardized in the near future.

Q: Currently, it still seems to be a very taxing therapy, necessitating tube feedings for weeks after surgery. Has this been your experience?

As the selection criteria improve, I think the number of those cytoreductions that represent a heroic surgical effort will diminish. We need to work together with our medical oncologists to identify those patients who will benefit the most from a multidisciplinary therapy that includes systemic chemotherapy and cytoreductive surgery. The role of HIPEC will have to be demonstrated to make this procedure standard of care.

Q: What results have you seen with this treatment?
- See more at: http://www.onclive.com/publications/oncology-live/2015/october-2015/standardization-is-key-to-future-of-chemotherapy-bath/1#sthash.gCUnzfze.dpuf
The outcome of patients undergoing cytoreductive surgery and HIPEC is directly related to the burden of disease and the histology of the tumor. For patients with low-grade tumors, like pseudomyxoma peritonei of the appendix, this procedure can be done with curative intent in many patients. For patients with colon cancer with peritoneal carcinomatosis, the outcomes continue to improve as systemic chemotherapy gets better. Most series now report median survivals of about 3 or more years. A decade ago, the median survival for patients treated with only systemic chemotherapy was less than 12 months.

Q: What have you learned from your experience?

I have learned that our biggest challenge is to identify the timing and sequence of all currently available therapies. At this time, those therapies include systemic chemotherapy, cytoreductive surgery, and HIPEC.

Q: What should healthcare providers know about HIPEC?

Multidisciplinary care is the hallmark of cancer care in 2015. Therefore, patients with peritoneal carcinomatosis should be evaluated also by a cytoreductive surgeon. At the present time, more than 90% of patients with colorectal cancer who are candidates for cytoreductive surgery and HIPEC are being treated only with systemic chemotherapy.

Q: What about patients? Are they prepared for how grueling this therapy can be?

I think that the days of “grueling” cytoreductive surgeries and HIPEC are diminishing quickly. We need to focus on patients who will derive a good long-term benefit and at the same time focus on diminishing the morbidity while preserving quality of life. Current outcome data demonstrate that this is possible.

- See more at: http://www.onclive.com/publications/oncology-live/2015/october-2015/standardization-is-key-to-future-of-chemotherapy-bath/2#sthash.MvKCcZ5p.dpuf