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Pain Management: Opioid Adherence in Cancer Patients

This week, Real World Health Care speaks with Salimah H. Meghani, PhD, MBE, RN, FAAN. Dr. Meghani is an associate professor and term chair in Palliative Care at the University of Pennsylvania School of Nursing. She is also associate director, NewCourtland Center for Transitions and Health. Her main research interest involves palliative care, specifically understanding and addressing sources of disparities in symptom management and outcomes among vulnerable patients.

We asked her about her study on analgesic adherence and health care utilization in outpatients with cancer pain, recently published in Patient Preference and Adherence. We also discussed the role of non-pharmacological approaches in treating cancer pain.

Opioid Adherence Patterns

Real World Health Care: Last year, you published an article: Patterns of analgesic adherence predict health care utilization among outpatients with cancer pain. Can you provide a brief summary of the article and talk about the study’s implications for cancer patients with pain management issues?

Salimah H. Meghani, University of Pennsylvania School of Nursing

Salimah Meghani: This is the first study to understand how opioid adherence patterns, over time among cancer patients, relate to health care utilization outcomes. We used objective measures of adherence (Medication Event Monitoring System – MEMS) and novel adaptive methods recently validated by the co-author, Dr. George Knafl from UNC-Chapel Hill. We found that inconsistent adherence patterns of analgesics over time was significantly associated with hospitalization over a 3-month observation period. The interaction of inconsistent adherence and strong opioids (WHO step 3 opioids) was one of the strongest predictors of health care use. It should be noted that this was a serendipitous finding. We did not plan to study adherence patterns and health care utilization. It therefore needs validation in hypothesis-driven study.

RWHC: Are you currently involved in any new research programs studying pain management in cancer patients? If yes, can you briefly describe?

SM: Yes, I am studying outcomes of opioid adherence and adherence patterns among cancer outpatients. This is an important topic as few recent U.S. based studies exist on the topic despite all the recent guideline contentions (e.g., CDC guidelines for managing chronic pain including chronic cancer pain and ASCO response) and national policy debates on opioids.

How Patients Manage Cancer Pain

RWHC: What do you think are the biggest challenges facing researchers studying pain management in cancer patients? How can those challenges be addressed?

SM: One of the biggest challenges is that we know very little about how patients manage their cancer pain. We know that opioids are widely prescribed, but we also know that there is poor adherence to prescribed opioids. Other treatments such as acupuncture are not consistently covered by health insurance or lack data on clinical effectiveness. There is a need to understand how patients are managing their cancer pain and what health care systems can do better to address the great burden on unrelieved cancer pain. Future work should also include improving access to effective non-opioid treatments for cancer patients. My previous research has also documented racial and ethnic disparities in cancer pain treatment for African Americans, which requires continued attention.

Safe Opioid Use

RWHC: What do you think are the biggest challenges facing clinicians treating pain in cancer patients? How can those challenges be addressed?

SM: There is a lot of confusion among clinicians about the role of opioids and the safe and rational use of opioids among cancer patients. Unfortunately, there is little empirical evidence base about the outcomes of opioid treatment among cancer patients. A look at the recent CDC guidelines on managing chronic pain would indicate that cancer patients frequently, if not invariably, have been excluded from the studies of the outcomes of chronic opioid therapy. More empirical evidence is needed to help clinicians develop comfort in opioid prescriptions.

Non-Opioid Treatments

RWHC: What do you think is the role of non-pharmaceutical pain management therapies for cancer patients? How can clinicians integrate both pharmaceutical and non-pharma therapies for cancer patients?

SM: I think access to non-pharmacological treatments is the biggest problem. While the NCCN guidelines for cancer pain identify a number of non-pharmacological modalities, they are not readily accessible to cancer patients. I have argued this in a recent letter to JAMA Oncology about the CDC opioid guideline that recommends that non-opioid treatments should be the first line therapy for chronic pain. This paradigm assumes easy and consistent access to non-opioid treatments. Also, access to effective non-pharmacological treatments are very different among poor, minorities, those with limited literacy.

Global Disparities

RWHC: What initially attracted you to this field? What continues to inspire you about it?

SM: My original research interest was global disparities in opioid availability for cancer pain management and the role of the International Narcotics Control Board. After migrating to the United States, I became familiar with racial and ethnic disparities in pain care and the toll it has for patients and families. This work continues to inspire me.

Multiple Sclerosis: Overcoming Pain

Real World Health Care continues our series on pain management by speaking with Dawn Ehde, PhD, Department of Rehabilitation Medicine, University of Washington School of Medicine. Dr. Ehde serves as a clinical psychologist and professor at UW. She conducts research evaluating the efficacy of various behavioral, exercise, and pharmacological interventions for chronic pain, depression, and/or fatigue in adults with multiple sclerosis (MS) and other acquired neurological conditions.

Dr. Ehde discusses some of her recent clinical and research work on cognitive-behavioral interventions for MS-related pain.

Living with MS and Pain

Real World Health Care: In 2015, you published an article: Utilization and Patients’ Perceptions of the Effectiveness of Pain Treatments in Multiple Sclerosis. Can you summarize the key results of your study and the implications for patients with MS?

Dawn Ehde, PhD, University of Washington School of Medicine

Dawn Ehde: We conducted this survey to learn more about pain management from the perspective of people living with MS and pain. We found that people with MS and pain try a lot of different treatments to manage pain, but few treatments provide adequate pain relief.

Nonprescription medications such as nonsteroidal anti-inflammatories and physical modalities such as massage were some of the most common methods used. Many use more than one treatment to manage pain. Some of the treatments that individuals rated as most helpful, such as hypnosis, were infrequently used. In fact, we found that very few people surveyed had tried or accessed behavioral pain treatments such as training in mindfulness meditation, cognitive behavioral self-management, or self-hypnosis. This was the case even though there is good evidence that these types of treatments are beneficial to many people with chronic pain, including MS, and have few or no negative side effects. This study highlighted for me the need to improve access to these types of non-pharmacological pain management.

Integrated Care Approach

RWHC: Are you currently involved in any other research relating to pain management in MS patients?

DE: We have several studies in various stages that address pain management in MS. We recently published a study that found that an eight-session telephone-delivered self-management intervention was effective in reducing pain (both its severity and its interference with activities) and fatigue. It also was effective in improving mood, quality of life, and resilience. The benefits were maintained at 6- and 12-month follow ups. Patient satisfaction with the treatment was high as well.

The study I am most excited about is the MS Care study, which is a comparative effectiveness trial that evaluated the benefits of an integrated care approach to pain and depression management in the clinic called “collaborative care.” The MS version, called “MS Care,” aims to improve the quality of pain care in the clinic by adding an MS Care manager to coordinate care, deliver brief behavioral treatments, initiate or adjust other medical treatments, and ensure patients do not slip through the cracks. We also offer patients the choice of getting their care management by phone or in person. Seventy-five percent chose the phone. We found that patients with chronic pain and/or depression randomly assigned to MS Care had significantly improved pain and depression symptoms, including less severe pain, less interference, less disability, and less fatigue. Additional details on the results are available at http://www.uwmscare.org/background.

Opportunities in MS Pain Research

RWHC: What are some of the biggest challenges facing researchers who are studying pain management in MS patients? How can those challenges be overcome?

DE: I actually see a lot of opportunities as an MS pain researcher. The MS community is interested in improving pain management and supporting research in this area. For example, the National MS Society has named pain as one of its research priorities. We also often find people with MS are willing participants in our research, both as participants as well as stakeholders who guide us in our research. For example, we used stakeholders to guide our MS Care study. At times, we have had to work hard to convince potential funders that pain is an issue that warrants funding and study, but that has improved in the time that I’ve been doing research. We have come a long way since I first started in this area, when pain was not always recognized as an important problem deserving attention in MS.

Challenges for MS Clinicians

RWHC: What are some of the biggest challenges facing clinicians who are treating MS patients with pain management problems?

DE: MS presents many different symptoms to manage, and thus both patients and clinicians have a lot to discuss and manage in the typical clinic appointment. One challenge is that pain management is often only one of several issues being addressed. As such, it may be difficult to fully manage a complex issue like chronic pain. I think these challenges may be overcome by rethinking how we approach and deliver pain care. We need to look at harnessing technology — including telehealth technologies — to improve care. We also need to empower patients and the MS community to recognize that pain management is something that requires active self-management and multimodal strategies.

Pain Management Therapies

RWHC: What do you see as the most promising pharmaceutical therapies for treating pain in MS patients? What are the caveats that must be understood by clinicians when prescribing such therapies?

DE: As a psychologist, I’m less able to speak to promising pharmaceutical therapies on the horizon. However, I think there are promising practices for how we deliver pain care, including medications and other rehabilitation interventions. We did manage medications in our MS Care study, and our goal within that was to promote the appropriate and effective use of pain medications and other medications that can benefit pain management, such as some of the antidepressants which have analgesic benefits. We know from our research that too often, patients get started on a treatment, perhaps at a “low dose,” and for whatever reason, they don’t have adequate follow up to adjust, intensify, or change treatment plan. In the MS Care study, we closely and quickly followed patients’ pain and adjusted treatments to optimize their benefits or switched treatments if needed. We also know that physical activity — whether it is physical therapy or encouraging physical activity — benefits people with MS and likely helps with pain management.

RWHC: Do you see a role for non-pharmaceutical pain management therapies in treating pain in patients with MS?

DE: Certainly. This is where I’ve spent most of my energy, not only because I am a psychologist, but also because many people with MS want to use non-pharmacological therapies and strategies. The people with MS I know and our stakeholders are eager to advance our understanding and use of non-pharmacological treatments such as mindfulness meditation, relaxation, and cognitive behavioral coping skills.

Partnering with Patients

RWHC: What initially got you interested in this field? What continues to inspire you?

DE: I have had family and friends with MS, and thus was drawn to learning more about MS. I started out conducting chronic pain research in people where chronic pain such as headaches was the primary problem. When I started working with patients with MS clinically, I was struck by how little we knew about MS pain management and how people with MS pain were not accessing care we knew was helpful in other pain populations.

I’ve been inspired and continue to be inspired by the people with MS whom we’ve partnered with to conduct our research. Our best research has resulted from partnering with people living with MS. They’ve also taught me a lot about resiliency. Although MS can present many challenges like pain, many people with MS and pain live full, meaningful and happy lives.

I also have been fortunate to have training grants from the National MS Society, which have allowed me to train postdoctoral fellows in MS and rehabilitation research. They represent the next generation of clinical researchers in pain and symptom management in MS.

Pain Management for Cancer Survivors

This week, Real World Health Care continues our series on Pain Management by speaking with Judith A. Paice, PhD, RN, who is the lead author for the American Society of Clinical Oncology’s guideline, Management of Chronic Pain in Survivors of Adult Cancer. Dr. Paice is Research Professor of Medicine, Hematology/Oncology, at Northwestern University’s Feinberg School of Medicine and a full member of the Robert H. Lurie Comprehensive Cancer Center. Dr. Paice’s clinical work focuses on the management of cancer-related pain, and her research focuses on the study of chemotherapy-induced peripheral neuropathy. We spoke about the ASCO guideline and the need for clinicians to balance pharmaceutical and non-pharmaceutical approaches to pain management.

Real World Health Care: Why did ASCO issue a guideline for the management of pain in survivors of adult cancer?

Judith A. Paice, Feinberg School of Medicine, Northwestern University

Judith Paice: The oncology field has evolved tremendously in recent years. Not only are people living longer with cancer, but they’re being cured of their disease thanks to some fantastic treatments. These treatments provide good clinical responses, but they can also cause significant toxicity, some of which may lead to chronic pain syndromes. The goal of the guideline was to alert oncologists to the presence of these long-term, persistent pain syndromes. A secondary goal was to provide support for chronic pain syndrome treatment.

Clinician Guidance

RWHC: What are the most important take-aways for clinicians?

JP: First are ASCO’s recommendations for screening and assessment. Second are recommended treatment options, both pharmacological and, equally important, non-pharmacological treatments. The guideline also provides insights and risk mitigation strategies for clinicians around the long-term use of opioids.

Today’s oncologists are faced with a very different pain management phenomenon than they were 20 years ago, when opioids were primarily used at end of life. Opioids are now being used for patients with a much longer survival trajectory — 20 to 30 years or more. As clinicians, we need to ask if such long-term use of opioids is appropriate and safe. How do we go about determining that? The guideline helps oncologists with those types of assessments and decision making.

RWHC: What do you feel are the biggest challenges facing oncologists in managing chronic pain in cancer patients, and how is ASCO helping clinicians manage those challenges?

JP: Our society is facing a serious public health problem in the opioid abuse and misuse epidemic. As a result of this problem, we’ve seen regulations at both the state and federal level that are having a chilling effect on the availability of opioids, even for those in desperate need of these medications. ASCO has a position paper on protecting access to treatment for cancer-related pain that I encourage all clinicians to read. ASCO also advocates for better third-party reimbursement for physical therapy, occupational therapy, cognitive behavioral therapy and mental health counseling. These are crucial therapies for patients facing the “new normal” of cancer survivorship, yet most third party payers provide little or no support for these treatments. As clinicians, we need to help our patients maintain function and cope with the fact that their lives are going to be very different. For patients, it’s more than surviving cancer. It’s about finding their own inner strength in survivorship.

New Pain Management Treatments

RWHC: Where do the biggest opportunities lie for new pharmaceutical pain management treatments?

JP: Several new findings in the laboratory may lead to novel agents that do not produce opioid related adverse effects. This is promising, assuming the findings can be translated into a clinical setting. There have also been numerous compounds that proved effective in animal models of pain, but when moved into the clinical setting, they either had adverse effects that weren’t seen in animals, or they didn’t have the efficacy they presented in the lab. It is very difficult to develop a model of cancer pain in animals.

Unfortunately, there haven’t been many completely new drugs. Most of the agents approved recently are slight variations of existing compounds or an update in the delivery method: a spray instead of a tablet, for example. The industry has been more focused recently on abuse-deterrent compounds. This is a somewhat controversial area because while such formulations prevent people from crushing, snorting or injecting the drugs, they don’t keep people from taking more than what is prescribed.

Non-Pharmacologic Therapies

RWHC: What should the role be for non-pharmaceutical pain management therapies in treating cancer patients?

JP: For quite a long time, there was a tendency in medicine to rely only on pharmaceutical therapies. This made sense when patients did not have long-term survival prospects and when managing pain meant helping the patient get from their bed to a chair. Today, cancer patients are living longer. They want to get back to work and function safely without the risk of falls and other complications.

We’ve seen good data around the usefulness of physical therapy, occupational therapy and cognitive behavioral therapy for many chronic pain situations, including cancer-related pain. These non-pharmacologic therapies must go hand-in-hand with pharmaceutical therapies.

Part of the challenge with non-pharmacologic therapies is limited reimbursement. The other big challenge is getting buy-in from patients. Most of us want a quick fix. Redefining expectations can be difficult. Physical and occupational therapy can be demanding, and access to specialists who understand the special needs of those surviving cancer are in short supply. Also, there remains a stigma attached to seeing a mental health counselor. It’s important for cancer patients to know that they aren’t “weak” if they need support to help them cope with the physical and emotional challenges of being a cancer survivor. Our field needs to do a better job educating our patients about the importance of including non-pharmacologic therapies as part of our pain management repertoire.

Calling for an Integrative Approach to Pain Management

This week, Real World Health Care continues our series on pain management with an interview with Bob Twillman, PhD, FAPM, Executive Director of the Academy of Integrative Pain Management. Dr. Twillman is responsible for overseeing federal and state pain policy developments and advocating for those supporting an integrative approach to pain management. He also serves as chair of the Prescription Monitoring Program Advisory Committee for the Kansas Board of Pharmacy. Dr. Twillman previously served as a faculty member at the University of Kansas School of Medicine, where he founded and directed the inpatient pain management program and was a co-founder of the hospital’s Palliative Care Team.

Improving People’s Lives

Bob Twillman, PhD, Executive Director, Academy of Integrative Pain Management

Real World Health Care: Can you describe the mission of the Academy of Integrative Pain Management?

Bob Twillman: Our mission is to improve the lives of people with pain by advancing a person-centered, integrative model of pain care through evidence-guided education, credentialing, and advocacy. In essence, we want to promote an integrative, multimodal, multidisciplinary approach to pain management because we believe such an approach is more effective and more cost-effective in treating all types of pain, both chronic and acute. Our educational opportunities teach clinicians how to provide this kind of care, and our advocacy efforts — which are unparalleled in the pain management sphere — promote policies that encourage provisions of this type of care.

Clinician Training & Challenges

RWHC: Why is it important for clinicians to be well-versed in integrative pain management?

BT: The traditional biomedical approach to pain management doesn’t always work well for a good number of people with pain. We know — and it’s been confirmed by the Institute of Medicine and in the recently-issued National Pain Strategy — that pain is a complex biopsychosocial phenomenon, and that an integrative approach is the only safe and sane way to care for people with pain. The only way to achieve the best possible pain control for every person with pain is to use an integrative approach that addresses all aspects of this complex phenomenon, as they play out for each individual person. There is no cookbook for pain care, and one size doesn’t even fit most, so we need to use an integrative approach that permits maximum flexibility in providing care.

RWHC: What are some of the biggest challenges that clinicians face in dealing with patients’ pain management issues?

BT: Undoubtedly, access to all the treatments we need in order to provide integrative pain care is our biggest challenge. Access to integrative non-pharmacological treatments such as acupuncture, massage therapy, biofeedback and others has never been good because insurance reimbursement is poor, causing people with pain to have to pay out of pocket for these treatments — something many of them can’t do. Adjunctive treatments such as physical therapy and behavioral health care might be more readily available, but they also are subject to inadequate insurance coverage that makes true access less than optimal. And now, even the medications that have been so ubiquitous as primary treatments of pain are under fire and both insurers and policymakers are restricting access to those as well. It’s really challenging to provide the kind of care that even key governmental agencies like the CDC have been calling for.

RWHC: How is the Academy addressing these challenges?

BT: AIPM continues to advocate for appropriate access to all of the treatments we need in order to provide comprehensive integrative pain care. Often, that means we have to battle inappropriate restrictions on pain medications, but we also advocate extensively for policies that promote improved access to non-pharmacological pain treatments. Recently, we have been advocating for enhanced Medicare and Medicaid coverage of integrative pain treatments, while also advocating for more opportunities to carry out Medicaid demonstration projects that we believe will show how much can be gained if those treatments were covered. And of course, we continue to educate clinicians about ways they can provide integrative pain care even if they don’t have a large multi-disciplinary staff and insurance coverage for all the treatments they need.

Pain Management Therapies

RWHC: What are the most promising non-pharmaceutical approaches for pain management and why are they important?

BT: Consider what the pain management experts at the Department of Defense and the Department of Veterans Affairs have listed as the five evidence-based, non-pharmaceutical approaches they think every current and former service member with chronic pain should be able to access: chiropractic and osteopathic manipulations, acupuncture, massage therapy, biofeedback, and yoga. And it’s important to note here, in follow up to my previous comment on inadequate coverage, that only some types of chiropractic and osteopathic manipulation are covered by Medicare, and only for some diagnoses. None of the rest of this list of five are covered.

Additionally, we know that many people with pain benefit from physical and occupational therapy and from behavioral health interventions. If we had full access with adequate insurance coverage for these treatments, we would be delighted. Being able to get these treatments for people with pain would mean that more of them would have less pain, better functioning in a number of areas, improved quality of life, and increased likelihood of being able to work. Plus, we would spend less money achieving those improved outcomes.

Opioid Addiction

RWHC: How is the rising opioid addiction issue in America changing how clinicians address and treat their patients’ pain?

BT: For much of the past two decades, pain treatment has been primarily associated with opioid prescribing. While I think increased opioid prescribing was a well-intended attempt by the medical profession to provide better pain care, it may have been misguided due to lack of evidence, lack of access to alternatives, and the influence of a number of market forces and cultural beliefs. Now that this increased prescribing has been implicated in the parallel and sharp increase in overdose deaths involving prescription opioids, policymakers are extraordinarily active in pushing legislation and regulation intended to reduce excessive prescribing. Unfortunately, this is happening in the context of the non-pharmaceutical treatment access problems I outlined previously, without concomitant attempt to improve that access. All of that leaves primary care clinicians, who deliver the majority of pain care in this country, struggling to figure out what to do.

We are hearing from people with pain that some clinicians are responding by either setting an arbitrary dose limit for opioids, or by establishing policies that they will not prescribe opioids, regardless of the circumstances. That may be harming people who benefit from those medications, in service of benefitting those who use opioids inappropriately and in a harmful manner. I think it’s going to be a while before all of this shakes out and we can arrive at a balanced approach that maximizes the benefits and minimizes the harms for everyone.

Pharmaceutical Industry Efforts

RWHC: What should be the role of the pharmaceutical industry in addressing the rising opioid addiction issue in America? How can they work with clinicians and groups like the Academy?

BT: The pharmaceutical industry has been engaged in efforts to make their products safer, by developing abuse-deterrent opioids. These medications make it much harder to abuse prescription opioids by means of altering them to permit snorting or injecting the opioid medication. This is an important step, because it will protect people who misuse these medications — the vast majority of whom are not people with pain. If we are able to do that, then perhaps we won’t see as much of a reactionary backlash that causes people with a legitimate medical need for prescription opioids to have their prescriptions denied or taken away.

The industry can also help us by increasing funding for our education and advocacy efforts. We have so many needs for education — both for new clinicians who are now in school and for experienced clinicians who are in practice — that meeting the need is an enormous and extremely expensive task. Due to mandates for Risk Evaluation and Mitigation Strategies (REMS) education imposed by FDA, much of this funding has been redirected away from organizations like ours that can provide integrative pain management education — and without discernible benefit. We desperately need FDA to revise the REMS program blueprints so we can teach clinicians about more than just the pharmacology of opioids and so we can teach about non-pharmacological approaches to pain care. It’s really challenging for the industry to adhere to FDA mandates and to go beyond those, but we need to find a way to encourage that to happen.

Assessing Chronic Pain

Our series on Pain Management continues this week with insight on how clinicians assess chronic pain. We spoke with Bryan Jensen, PhD, a clinical health psychology postdoctoral fellow at the VA Salt Lake City Health Care System, where he treats inpatients and outpatients with chronic pain as well as facilitates primary care chronic pain recovery groups. Dr. Jensen recently graduated with his doctorate in clinical psychology from Virginia Commonwealth University, where he focused his clinical and research work serving patients with chronic disease in both inpatient and primary care populations, most notably underserved patient populations and those with high levels of co-morbidities.

Bryan Jensen, PhD, VA Salt Lake City Health Care System

We asked him about his recent Translational Behavioral Medicine article on chronic pain assessment within a translational framework and the challenges facing researchers and clinicians who are studying and treating chronic pain.

Real World Health Care: Can you provide a summary of your recent article in Translational Behavioral Medicine?

How Chronic Pain is Assessed

Bryan Jensen: As researchers and clinicians seek to treat pain, we first need to understand if we are assessing pain accurately. The article is a review of how pain is assessed across the translational continuum. It starts by exploring the basic science of animal models of pain and the types of methods used in that setting to assess pain. Clearly, these methods are not the same methods we use in clinical practice — a rat is not the same as a human — but they must translate. We are starting to understand that older models of pain assessment may no longer be adequate, so we are looking at newer models and seeking to determine a more accurate definition of pain across clinical and research settings. Other translational issues are outlined with a focus on how providers are using pain assessment tools and how they can implement newer evidence-based tools for more evidence based assessment.

The article points to three main areas that hold promise to bridge current gaps. One is using computer adapted technologies to obtain self-reported measures of pain. Because we can’t take a “thermometer reading” of pain, we rely on patients’ assessments. But pain is multi-dimensional, and asking patients to go through a 100-question survey is daunting and time-consuming, so scientists have developed computer programs that evaluate how patients respond to clinicians’ questions and adapt those responses so clinicians can more efficiently and effectively get the information they need. The NIH has been rolling out these tools over the past decade.

The second promising area is lab-based, for example, using a blood draw to look for proxy measures of pain. This is more of a downstream method to assess the patient. These tools still require further research to understand how to directly translate into clinical practice.

The third promising area is observational. In animal models, we poke a rat and watch its response. With very few exceptions — such as needle prick tests for diabetic neuropathy — we’re not going to go poking human patients. But there are observation-based methods that allow clinicians to accurately measure pain and pain behaviors. For example, the University of Alabama at Birmingham developed a pain behavior scale. Unfortunately, it isn’t widely used, even though it has demonstrated excellent validity in terms of helping providers easily and quickly measure pain and pain behaviors like grimacing, holding one’s back, and limping. It really does an excellent job giving a complete picture of a patient’s experience.

Effective Pain Treatment

RWHC: What are some of the important implications for patients and for the field of pain management?

BJ: The whole point of accurate pain assessment is to allow for more effective treatment. If patients are more aware of various pain assessment methods, they can advocate for themselves and request clinicians to widen their scope of assessment. Informed patients always help the clinical process.

The goals are improved assessment and treatment, which would lead to better patient care, higher patient satisfaction, and a reduced burden on patients, their families, and our nation. Economically, the cost of chronic pain is over $600 billion a year. If we can chip away at that, we would be making a huge impact.

Challenges and Opportunities

RWHC: What are the biggest challenges facing researchers when it comes to studying pain assessment, and how can those challenges be overcome?

BJ: From a research perspective, there’s less emphasis on assessing pain than there is on treating pain. The main challenge is a financial one, with fewer research dollars dedicated to studying pain measurement. Another challenge is a theoretical one. There’s been some exciting, cutting-edge research on neurological measures, focused on neurosignatures that act as a thermometer to measure pain, but there’s been some discord in the field as to whether this is a useful pursuit. We also need better uniformity across the literature in terms of methods and measurement. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) has been working for well over a decade to develop consensus and establish best practices for measuring pain in clinical trials, but these best practices aren’t always followed.

RWHC: What are the biggest challenges facing clinicians in assessing pain, and how can those challenges be overcome?

BJ: Making clinicians aware of the latest research is a big challenge. I hear lots of clinicians express that they don’t have the training to fully assess and treat pain — especially chronic pain. Many providers approach treating someone with chronic pain with some trepidation as we have seen political, societal, and clinical swings in the use of opiates and other pain medications. Many clinicians will opt to not treat chronic pain or to seek out clinics with non-opiate policies. This is problematic, because the fact is that some patients do benefit from opiates.

We need more focus on early medical training. Medical schools are just starting to employ an integrated approach to pain, by combining the fields of primary care, psychology, pharmacy and social work. Trainees and residents are now being exposed to a broad-based perspective on how to approach and treat chronic pain, but additional course work is needed.

Clinicians also have a practical challenge. Most cases of pain are managed in primary care practices, and these clinicians are time-strapped. They default to the model of assessing pain by asking patients what their pain is on a scale of one to ten without looking at how pain impacts a patient’s functionality and quality of life. Those quality of life measures, like being able to get back to work or play with your kids, are important goals for treatment.

RWHC: What initially attracted you to this field and what continues to inspire you?

BJ: I initially became interested in the field of pain assessment when my daughter was born. She had an early medical condition — which fortunately turned out to be benign— and I was struck by the integrated team at the Shriner’s hospital who cared for her and our family. Since then, I’ve had wonderful opportunities to do clinical work with chronic pain patients. I continue to be inspired by my patients and the impact pain has on their lives. It’s gratifying to help them go from being essentially disabled to the point where they can regain their lives and take part in meaningful activities.

 

A Big Pain

Editor’s Note: This article in our pain management series originally appeared in Biotech Primer Weekly. For more of the science behind the headlines, please subscribe.

The Science Behind Opiods

Emily Burke, BiotechPrimer.com

The opioid addiction epidemic gained attention at the highest levels of U.S. policy circles this past year, as presidential candidates that disagreed on nearly everything else vowed to make fighting the problem a priority if elected. In July, the U.S. Senate overwhelmingly approved a bill to strengthen prevention, treatment, and recovery efforts. And no wonder – according to the Center for Disease Control, opioid overdose deaths are at an all-time high – a stark reality that highlights the dark side of a class of treatments serving a vital need. Opioid pain medications manage the severe short-term or chronic pain of millions of Americans. While these medications mitigate needless suffering, joining forces are the government, corporations, and medical community to battle against opioid abuse and addiction.

We wonder: what is the science behind the headlines? So, let’s talk about how pain medications work, the different types on the market, and the approaches to developing less addictive versions of opioid drugs.

Opiods vs. NSAIDS

There are two main categories of pain medications, opioids and non-steroidal anti-inflammatory drugs (NSAIDs). Although these two categories of drugs work differently, they do share one thing in common: both are derivatives of natural products. The NSAID Aspirin is a synthetic version of an extract from willow tree bark, and opioids are synthetic versions of opium and morphine, which come from poppy flowers.

Aspirin works by inhibiting an enzyme called cyclooxyrgenase 1 (COX-1). Once stopped, COX-1 is no longer able to produce signaling molecules, called prostaglandins and thromboxanes. Prostaglandins and thromboxanes have a wide variety of functions, including mediating aspects of inflammation (fever and swelling) as well as promoting neuronal response to pain. Other NSAIDs, such as ibuprofen and naproxen, also work by inhibiting COX-1 or its sister enzyme COX-2.

Opioid pain medications, such as Oxycontin and Percocet, work by binding to mu receptor proteins on the surface of cells in the central nervous system (CNS) —think brain and spinal cord. While the CNS is tasked with relaying pain signals, opioids decrease the excitability of nerve cells delivering the message, resulting in pain relief—along with a feeling of euphoria in some users. 

Lessening the Pain

Short term medical used of opioid pain killers rarely leads to addiction—when properly managed. Due to the euphoria-inducing effects of the drugs, long-term regular use, or use in the absence of pain, may lead to physical dependence and addiction. And because regular use increases drug tolerance, higher doses are required to achieve the same effect, leading abusers to consume pain pills in unsafe ways such as crushing and snorting or injecting the pills. According to the Centers for Disease Control, 44 Americans die every day due to prescription painkiller overdose. At the same time, chronic pain is also a serious problem, affecting approximately 100 million U.S. adults, while millions of others suffer acute pain due to injury or surgery. The medical need for these drugs is very real despite the dark side.

The answer to developing less addictive drugs may be found in a drug that blocks pain without inducing euphoria. These new drugs will need a different mechanism of action than traditional opioid drugs, which bind to the mu receptors of cells inside the CNS. Drugs under development include those that bind to a different type of opioid receptor, the kappa opioid receptor. These receptors are present on sensory nerves outside of the CNS.

Preclinical studies suggest that targeting these receptors could be effective at reducing pain without driving addictive behaviors. A lead candidate, CR845, is currently in Phase 3 clinical testing for post-operative pain and pruritus (severe itching), and in Phase 2 clinical testing for chronic pain. Also under development are compounds that selectively activate cannabinoid (CB) receptors outside of the CNS. CB receptors inside the CNS are linked to the psychoactive qualities of marijuana; those outside the brain are found on white blood cells and have been shown to be involved in decreasing pain and inflammation. A lead CB receptor activator, CR701, is in preclinical development.

Also under development are small molecule inhibitors of ion channels – proteins on the surface of nerve cells that help to transmit pain signals by allowing positively charged calcium ions to enter the nerve. This plays a critical role in sending the pain signal to the brain, yet because it works on nerves outside of the brain, it has less of a potential for addiction.  Phase 1 clinical studies are currently underway of HX-100 for the treatment of painful diabetic neuropathy.

Another development is a derivative of capsaicin, a naturally-occurring compound found in chili peppers. Capsaicin has pain relieving properties and has been used as a natural remedy. The lead candidate, CNTX-4975, is a highly potent, synthetic form of capsaicin designed to be administered via injection into the site of pain. CNTX-4975 targets the capsaicin receptor, an ion channel protein on the surface of nerve cells. When CNTX-4975 binds the capsaicin receptor, the influx of calcium ions results in desensitization of the nerves, making them unresponsive to other pain signals. This effect can last for months, and only affects nerves near the site of injection. CNTX-4975 is currently in Phase 2b clinical studies for knee osteoarthritis, and Phase 2 clinical studies for Morton’s neuroma, a sharp pain in the foot and toe caused from a thickening of the tissue around one of the nerves leading to the toes.

Earlier this year, researchers at Tulane University published a paper that shows great promise for the development of effective yet non-addictive pain medications. They have developed a compound that is derived from the endogenous opioid endomorphin. Endogenous opioids are chemicals produced naturally by the body that bind to and activate the mu opioid receptors, resulting in pain relief and mild euphoria without the detrimental side effects associated with opioid drugs such depressed respiration, motor impairment, and addiction. Scientist have tried before to develop safer pain medications based on endogenous opioids, but have not been successful, due to the instability of these molecules. The Tulane team created a derivative of endomorphin that is stable and binds to the mu receptor in such a way that pain relief occurs, but not the negative side effects listed above. Clinical testing is expected to begin by the end of 2017.

An Antidote to an Overdose

Overdosing can be fatal since respiratory failure occurs at high blood concentration levels of opioids. If an overdose is suspected, the individual should be treated as quickly as possible with naloxone—a “competitive antagonist” of the mu opioid receptor. Simply put, a competitive antagonist binds the receptor without activating it. Since naloxone doesn’t activate the receptor, it doesn’t have any pain-relieving or euphoria-inducing qualities; rather, it prevents the opioid drugs from binding. It may also displace opioids that have already bound the mu receptor, aiding in the stoppage of an overdose.

Cocktail Fodder: Runner’s High

Some folks love to run; others avoid it at all costs. This might be explained by inherent differences in sensitivity to the natural opioids called endorphins that are released during exercise. Not everyone experiences the “runner’s high” — feelings of calm and mild euphoria – just like not everyone experiences euphoric feelings from pain medications. These differences may help to explain why some people enjoy exercise and others don’t, and why some people get addicted to opioids—while others can take them or leave them.

 

New Real World Health Care Series to Focus on Pain Management

I remember visiting my grandmother in the hospital in late 1989.  She was in the final stages of pancreatic cancer; her hospitalization was primarily meant to keep her comfortable until her passing.  She had a “button” that added morphine into her IV line.  Although the machine was programmed to deliver only so much morphine within a certain timeframe, she could push that button whenever she needed pain relief.  She never stopped pushing that button.

Krista Zodet, President, HealthWell Foundation

Over twenty-seven years later, the pain associated with and caused by cancer is still a challenge.  In fact, pain seems to accompany many of the diseases we help with at HealthWell and we certainly hear so from our patients.  Even in life outside of HealthWell, I hear from friends and family members stricken with chronic pain related to surgery or an injury and their struggles to manage it productively.

Their stories are powerful and many put into words a pain that I cannot fathom trying to cope with day in and day out.  From minor headaches and injuries, to the effects of major surgeries and chronic disease, pain is an unfortunate fact of life for millions of Americans. It affects more Americans than diabetes, heart disease and cancer combined, according to the American Academy of Pain Medicine.

In a 2011 report, the Institute of Medicine estimated that 100 million adult Americans experience chronic pain every year, costing the nation between $560 billion and $635 billion annually. Much of this pain is preventable or could be better managed, according to the committee that wrote the report, which called on health care providers, insurers and the public to have a greater understanding about pain: Although pain is universal, it is experienced uniquely by each person and care often requires a combination of therapies and coping techniques. It is more than a physical symptom and is not always resolved by curing the underlying condition.

We at the HealthWell Foundation agree with the authors of the IOM report in believing that successful treatment, management and prevention of pain requires an integrated approach that responds to all the factors that influence pain.

We also share the growing concern about the role of opioids in treating pain. In its Guideline for Prescribing Opioids for Chronic Pain, the CDC notes that opioid pain medication use presents serious risks, including overdose and opioid use disorder. CDC estimate that nearly 2 million Americans age 12 or older either abused or were dependent on prescription opioids in 2014.

Over the next couple of months, we will be focusing on the issue of pain management, including traditional pharmaceutical approaches and non-traditional alternative therapies. We’ll be interviewing top researchers in the field as well as leaders of clinical organizations dedicated to helping patients manage pain.

We invite you to check back to learn more about what’s working in the field of pain control and the challenges researchers and clinicians continue to face, especially in light of the growing issue of opioid addiction. You can also sign up to receive email alerts when new interviews are posted. Just enter your email address under the sign-up message to the right.

NSCLC: The Emerging Role of Liquid Biopsies

Real World Health Care concludes its series on non-small cell lung cancer by speaking with Erica Carpenter, MBA, PhD, Research Assistant Professor in the Department of Medicine at the Perelman School of Medicine at the University of Pennsylvania. Dr. Carpenter also serves as Director of the Circulating Tumor Material Laboratory in the Division of Hematology/Oncology at the Abramson Cancer Center.

Dr. Carpenter served as senior author on a recent study that suggests for patients with advanced lung cancer, a non-invasive liquid biopsy may be a more effective and suitable alternative to the gold standard tissue biopsy to detect clinically relevant mutations and help guide the course of treatment.

Real World Health Care: Explain your role at the Perelman School of Medicine.

carpenter_erica_businessErica Carpenter: I am Director of the Circulating Tumor Material Laboratory and an Assistant Professor in the Division of Hematology-Oncology at the Perelman School of Medicine. My lab focuses on the identification, capture, and analysis of Circulating Tumor Cells (CTCs) and cell-free DNA (cfDNA), exosomes and other material shed from cancer patient tumors.  Blood, bone marrow, pleural effusions, and other non-invasively captured patient samples are used to detect biomarkers which will allow: early detection of disease as well as post-therapy monitoring of minimal residual disease, an efficient means of determining clinical and biological response to therapy and, thus, clinical decision making, and cancer genetic phenotyping to drive personalized medicine that obviates the need for serial biopsies in a population of patients for whom these procedures can be difficult, risky, and insufficient.

RWHC: Can you give us an overview of your recent research as it relates to non-small cell lung cancer and liquid biopsies?

EC: While the work described in the Clinical Cancer Research paper is the only NSCLC liquid biopsy study we have completed, we have several studies currently enrolling, including studies on the use of liquid biopsies to monitor and predict response of patients receiving a form of immunotherapy known as checkpoint inhibitors, and characterization of the tumor cells and circulating tumor DNA found in the pleural effusions (excess fluid that sometimes builds up in patients’ lungs) of lung cancer patients as another method for monitoring without an invasive biopsy.

RWHC: Just a few months ago, the FDA approved the first liquid biopsy test for patients with metastatic NSCLC. Why is this an important development?

EC: This is important for a number of reasons. First, the cobas test detects mutations in a gene called EGFR that can be targeted with specific drugs that have been shown to be effective in NSCLC patients with these specific mutations. In addition, liquid biopsies in general can greatly improve sensitivity of mutation detection in metastatic patients. Metastatic disease means that a patient has tumors in multiple sites in the body, and this can make surgical biopsy or fine needle aspirate very difficult to perform without great discomfort to the patient. Metastases can sometimes occur in places like the bone or brain where it is impossible to invasively obtain tumor tissue. Moreover, the genetic profile of a tumor tends to evolve over the course of a patient’s therapy, and it is not unusual for a metastatic patient to exhibit mutational heterogeneity where not all mutations are expressed in all tumor locations. In these cases, it is thought that a liquid biopsy will detect all or most mutations as all tumor sites, whether primary or metastatic, are thought to shed DNA into the blood. Finally, when a next-generation sequencing panel, such as the one used in our study, is applied to a liquid biopsy, comprehensive and clinically actionable data can be obtained with a single blood test, including mutations in multiple genes associated with therapy resistance.

RWHC: Do you think that liquid biopsies will become a standard of care for NSCLC patients? Will they, or should they replace tissue biopsy? Why or why not?

EC: Liquid biopsies are already becoming a routine part of care for NSCLC and other cancer patients here at the Abramson Cancer Center at Penn Medicine. These tests can be incorporated into the blood draw procedure for other standard of care monitoring blood tests and performed at already scheduled outpatient visits, thus causing no additional pain or inconvenience to the patient. We are working to better understand the different ways in which liquid biopsies can be used to better manage the care of these patients. However, while I expect liquid biopsy use for NSCLC and other cancer patients to continue to expand, I do not expect that they will replace tissue biopsy. Next-generation sequencing of circulating tumor DNA cannot provide crucial phenotypic information, such as information about the physical characteristics of the tumor, that are essential for initial diagnosis. Tissue biopsies can also play a unique role in monitoring of patients for the development of neuroendocrine disease, which can be associated with therapy resistance but is not detectable using ctDNA.

RWHC: What challenges need to be overcome to make them a standard of care?

EC: More studies need to be done, and this is an area of active focus for us, to measure whether the use of liquid biopsies has a positive effect on patient outcomes. In addition, clinical ctDNA tests tend to be ordered for detection of mutations that can be therapeutically targeted, or the emergence of mutations that signal the development of therapy resistance. To become a larger part of the standard of care for NSCLC and other cancer patients, we must better understand whether liquid biopsies can be used to effectively monitor patients receiving other important forms of therapy, including recently approved types of immunotherapy.

RWHC: This approved liquid biopsy test detects a specific type of gene mutation that is present in about 10-20 percent of NSCLC patients. Do you think other liquid biopsy tests will eventually be able to do the same for the remaining 80-90 percent of NSCLC patients? If yes, where does the biggest opportunity exist? If no, why not?

EC: In our study, we detected 275 mutations in 45 different genes, with at least one alteration found in the liquid biopsy for 84 percent of patients. Further underscoring the clinical utility of such a comprehensive liquid biopsy approach, 70 percent of patients were deemed to have a relevant clinical trial available on the basis of their ctDNA result, 55 percent of patients had an off-label targeted therapy that could possibly be used, and 31 percent of patients had an FDA-approved therapy available. So, I would say that liquid biopsy tests are already providing meaningful results for the majority of NSCLC patients.

RWHC: Beyond detecting the gene mutation responsible for NSCLC, how can liquid biopsies be used to monitor the progression of the disease?

EC: As I mentioned earlier, circulating tumor DNA tests for NSCLC patients are typically used to detect driver mutations and/or mutations that indicate the development of therapy resistance, some of which can also be therapeutically targeted. However, sometimes the physical characteristics of the tumor, including the number of circulating tumor cells in blood and expression of certain protein markers, can be measured by liquid biopsy and used to monitor disease progression. For instance, an increase or decrease in the number of circulating tumor cells (CTCs) detected in a tube of blood can be an indication of disease progression or response to therapy, respectively. Moreover, these CTCs can be isolated and gene expression measured to detect signatures associated with sensitivity or resistance to certain forms of chemotherapy in other cancers. CTCs can also be used to non-invasively assess expression of a protein known as PDL-1 which has been shown to be associated with a response to a form of immune therapy known as checkpoint inhibitors.

RWHC: How can NSCLC liquid biopsy tests be used to help increase the length of NSCLC patient survival?

EC: This is an area of active study for us. We will seek to measure whether repeat, non-invasive liquid biopsies can be used to detect therapeutic targets when a tissue biopsy isn’t possible, thus possibly enhancing the chance of a clinical response to therapy. Others have shown that a liquid biopsy can detect therapy resistance weeks or even months before standard of care imaging. It will be important to determine whether such early detection, especially when used to guide re-stratification of the patient onto a different therapy, has a positive effect on outcomes. Additionally, one of the most significant predictors of prognosis in NSCLC is the stage of disease at presentation, and our lab is actively focused on determining whether liquid biopsies can be utilized to identify patients with early stage disease.

Non-Small Cell Lung Cancer: EGFR Mutations and Targeted Therapies

Continuing our series on non-small cell lung cancer, this week Real World Health Care speaks with Lecia V. Sequist, MD, MPH, Associate Professor of Medicine at Harvard Medical School and the Mary B. Soltonstall endowed chair in oncology at Massachusetts General Hospital. Dr. Sequist’s research focuses on studying novel targets and targeted agents for lung cancer treatment, particularly those that target the epidermal growth factor receptor (EGFR) and in detecting and studying the significance of tumor cells circulating in the bloodstream.

Real World Health Care: Tell us about what you do at Massachusetts General Hospital, especially in relation to research and treatment of non-small cell lung cancer.

Lecia V. Sequist, MD, MPH, Harvard Medical School

Lecia V. Sequist, MD, MPH, Harvard Medical School

Lecia Sequist: I’m a medical oncologist with a busy practice, seeing and treating patients with lung cancer. I also conduct clinical and translational research on new drugs, looking at the molecular aspects of tumors and biopsies as patients go through various forms of treatment. My focus is on personalizing treatment for each patient.

RWHC: Can you share some highlights of your recent research in non-small cell lung cancer?

LS: Most of my recent research has revolved around EGFR mutations. One of the biggest advances in lung cancer in recent years is that we’ve come to understand lung cancer is not one disease. It’s many diseases. We can now tell the difference between one cancer and another by looking at the tumor genetics. These are not the genes we inherit from our parents, rather they are genes that reside only in cancer cells. These genes are at the core of what causes cancer. By identifying these genes in a lung cancer patient’s tumor, we can be more successful with treatments that target those genes and the proteins they produce.

EGFR mutations were first discovered here at Mass General, right around the time I started in oncology. It was a very exciting time, and ushered in a new era of personalized treatment for cancer. Since those early days, we’ve done a tremendous amount of research with patients who have the EGFR mutation, and we’ve found treatments that work better than standard chemotherapy.

RWHC: What are some of the biggest challenges you face as a researcher studying non-small cell lung cancer?

LS: I think of the challenges in two categories: scientific and societal. From the scientific point of view, we can’t currently identify mutations in every lung cancer, though we’re constantly working to uncover more of them. The group of lung cancer patients who have no identifiable mutation, or who have a mutation with no matching drug therapies at this time, are effectively left out of the “molecular revolution.” For those groups, the challenge is to find alternative approaches. Luckily some of the newer immunotherapies may work particularly well in such patients. Then down the road, we know that targeted therapies eventually “wear off,” in the sense that cancer cells get smart and find ways to work around the roadblocks we put in their path. For example, we saw this with the first generation of tyrosine kinase inhibitors (TKIs) developed to target EGFR mutations. Most patients initially responded, but subsequently developed a resistance after about a year, because they developed a second mutation that prevents the TKIs from binding to the cancer cells. Last year, a new EGFR drug was FDA approved that is able to effectively target this second mutation. Now we’re racing trying to learn how the cancers may get around the newer drug and also looking at strategies to prevent resistance.

From a societal standpoint, one of our biggest challenges in the lung cancer research community is the stigma that still exists around lung cancer. In the United States, we were fortunate to have had a very successful public health campaign around the dangers of smoking over the last generation. Those dangers are important to understand, but one of the unexpected consequences of this was to popularize the opinion that lung cancer is a self-inflicted disease and therefore patients carry some degree of blame. Not only does this end up negatively affecting individual patients, it also cuts into research funding. The fact is, some smokers get lung cancer while others don’t. And more importantly, many lung cancer patients have never smoked. No one deserves lung cancer and research must push forward to stop this, the deadliest of all cancers.

RWHC: What are some of the biggest challenges you face as a clinician treating patients with non-small cell lung cancer?

LS: There are promising treatments being studied in clinical trials, but many patients don’t have access to those treatments because the trials are concentrated in academic centers. Even if patients have geographic access to research studies, clinical trials have fairly high thresholds for eligibility, so if a patient has other medical conditions — which many lung cancer patients have — or if their cancer has certain characteristics, they won’t be eligible for the trial. We need to keep pressure on the pharmaceutical industry to include broader groups of patients in trials so all patients can get access to promising new treatments.

RWHC: What do you think are some of the biggest opportunities for advancement in how we research non-small cell lung cancer and treat people with the disease?

LS: Immunotherapy has really changed the paradigm for non-small cell lung cancer. Years of failed vaccine studies led us to believe that it wasn’t possible to affect the human immune system in meaningful ways against lung cancer. Now that we’ve hit upon a different way to activate the immune system, new discoveries are tumbling out the door every day. Unlike past treatments, immunotherapy has true promise for long-term disease control. There are already three FDA-approved lung cancer immune therapy treatments over the last year and likely many more to come. I think someday we’ll look back on this time and say that this is when the needle really started to move.

RWHC: Why did you get into this field of research? What continues to inspire you?

LS: I was initially drawn to studying lung cancer when I was in training by the doctors who were mentoring me and the patients I met. At the time, there weren’t many treatments available for non-small cell lung cancer, so there was a lot of room for improvement. This was attractive to me as a clinician and a researcher and it has remained a vibrant and ever-changing field. I enjoy being involved in the exponentially increasing number of treatments available and how these new treatments can bring hope to patients. It has ended up being an intellectually stimulating and extremely fulfilling career and I continue to be inspired by the patients I meet every day.

NSCLC: Targeting What Drives People’s Cancer

This week, Real World Health Care talks with Edward B. Garon, M.D., Associate Professor of Medicine at the David Geffen School of Medicine at UCLA Health. He specializes in hematology and oncology, with an interest in lung cancer and chest malignancies.

Dr. Garon’s research focuses on the testing and development of targeted therapies and immunotherapies in the treatment of non-small cell lung cancer (NSCLC), including the development of a class of drugs known as PD-1 (programmed cell death-1) inhibitors, which allow immune cells to eliminate cancer. We spoke with Dr. Garon about checkpoint inhibitors, immunotherapies and targeted therapies for NSCLC.

Real World Health Care: Describe your role at UCLA’s David Geffen School of Medicine, especially as it relates to research of non-small lung cancer.

Edward Garon, MD, UCLA Health

Edward Garon, MD, UCLA Health

Edward Garon: I serve as director of thoracic oncology and conduct both clinical and laboratory research with a focus on translational research to determine lung cancer patient subgroups that are most likely to respond to certain therapies. Instead of looking at NSCLC as one disease, it’s important to personalize therapy and give people the therapies that are appropriate, not just for the disease site origin, but for a disease that’s driven by a particular set of molecular events.

RWHC: What do you think are the biggest challenges relating to NSCLC research and how are those challenges being addressed?

EG: We’ve seen some real progress in NSCLC research, especially in terms of immune checkpoint inhibitors, which unleash a patient’s own T cells to kill tumors. But we’re not yet where we want to be. One of the biggest priorities is identifying more people who will respond to therapies and connecting the right research with the right patient population, especially since targeted therapies currently only apply to a small percentage of the patient population. Although early-phase lung cancer studies in non-metastatic patients have hinted at the potential to use biomarkers to select patients, data from clinical studies have tempered expectations.

RWHC: What do you think are the biggest challenges relating to current NSCLC treatment and how are those challenges being addressed?

EG: In the past 10 years, there has been a push to individualize care for NSCLC, to evaluate individual tumors on individual patients and determine if there are molecular changes or abnormalities in the tumor itself that can dictate whether there are certain therapies that are more or less likely to be effective in any given patient. Treatments for NSCLC have improved somewhat over time, but in patients whose tumors have progressed during or after their initial therapy, the outcomes for additional treatment have been quite poor.

Another challenge for clinicians is the emergence of checkpoint inhibitors, immunotherapies and targeted therapies. We currently have two PD-1 inhibitors available for treating advanced NSCLC, both of which are well-tolerated among patients. The quality and duration of responses to anti-PD-1 therapy can be profound in NSCLC, but some clinicians are not overly familiar with them and how to use them. Much of the experience with these drugs is concentrated in select academic centers. We need wider clinician awareness of which patients are most likely to benefit from therapy, when therapy should be stopped and how toxicity should be managed.

RWHC: Where do you think the biggest opportunities for future advances in NSCLC research and treatment lie?

EG: We will soon see a tremendous amount of data on the combination of checkpoint inhibitors and additional agents. It will be interesting to see both what the data from randomized studies show and how researchers interpret that data in terms of what constitutes a signal and what doesn’t. Careful selection of patients, doses of each agent, and information supporting strategies — concomitant or sequential — is still needed. Another exciting avenue is the potential incorporation of immunotherapy in early-stage disease, locally advanced disease and in first-line therapy for metastatic disease. These agents could become the frontline choice for select patients with stage IV disease versus standard chemotherapy.

RWHC: Why did you get into this field and what continues to inspire you about it?

EG: I became involved in lung cancer as a young physician coming from fellowship training. While there was not a lot of excitement in the field at that exact moment, I saw a good opportunity to be on the leading edge of therapy development. I am fortunate here at UCLA to be part of many of the studies of new drugs that have changed the course of patients’ disease and don’t have the toxicity associated with many chemotherapies. It’s certainly been gratifying to see how new therapies can positively impact patients. Just a few short years ago, NSCLC was seen as a disease that wasn’t particularly immunogenic. Ten years from now, I hope to look back on this exciting time and realize that we have come much farther still.