While I invite and strongly encourage people to read the article (though you need to have the right mindset to tackle it) and participate in the discussion on that thread, there is one topic that we haven’t touched on thus far in the thread that is an interesting point covered in the article.  Dr. Gawande refers to a study in which the insurance company Aetna allowed patients to receive palliative care without them being disqualified from receiving further anti-cancer therapies and found that they fared much better in many different aspects, including ability to communicate about their diagnosis and end of life wishes, and they were far less likely to end up having many visits to the emergency room and admissions to the hospital than people who had to choose between focusing on symptom control and managing their cancer proactively.

    This concept is remarkably similar to a presentation at this past American Society for Clinical Oncology (ASCO)Annual Convention, in which Dr. Jennifer Temel and colleagues at Massachusetts General Hospital compared patients who had palliative care integrated early in their treatment to patients who were referred for palliative care after they had exhausted anti-cancer treatments.  Dr. Nathan Pennell and I discussed this study, among others, in a recent webinar in which we reviewed ASCO highlights in lung cancer, noting the very striking findings.  Here is the transcript and figures from our discussion several weeks ago of this presentation:

 —————————————————————————-

Dr.  Pennell:   I think that this is one of my favorite presentations from ASCO, and this is something that you normally do not see in the oral presentations of the lung cancer section at ASCO, which is a trial of palliative care in lung cancer patients. Jennifer Temel is a lung cancer oncologist with a focus in palliative care who designed this randomized phase III trial to try to propose a new potential care model for patients with lung cancer, and really my guess will be that this would be applicable to almost any patient with cancer.

If you look at what Dr. Temel considers the current care model, and I don’t think I can argue with this, true palliative care, specialty palliative care is typically only instituted once the patients have already exhausted their potentially curative or life-prolonging treatments, and patients are transitioned into hospice and symptom control, somewhere relatively close to their death.  What Dr. Temel is proposing as a better model is starting symptom control and active palliative care at the initial time of diagnosis, and doing it in parallel with the curative and life-prolonging treatment allowing a smoother transition near the end of life and potentially improving the quality of life throughout the course of their illness.

 (click on image to enlarge)

This particular design was very straightforward, 150 patients.  These were consecutive new consults at Massachusetts General Hospital, were randomized to either standard care, which is meeting with the palliative care team only if their doctor requested it, or if the patient and family requested it, or in the experimental care arm, patients in addition to meeting with their oncologist and getting their treatment plan would also meet with a palliative care team within three weeks of signing consent, and then met with them essentially once a month afterwards.

Now, one of the criticism of the study is that there was really no firm description of exactly what the palliative care intervention was, because it was up to the team to devise an individual plan for each patient.  However, in general, they always tried to help improve the patient’s understanding of their illness and education about their treatment goals.  Obviously a big part of it was symptom management: dealing with pain, pulmonary symptoms, fatigue, mood is a big issue with depression and anxiety, helping the patients with decision-making, especially when it came to talking about transition near the end of life, and just helping the patient and family coping with their life-threatening illness.

In fact, on the standard care arm, 87% of patients actually never met with the palliative care team, so although this was billed as early palliative care versus standard palliative care, in fact, it was really more like early palliative care compared to no specific designated palliative care.  And just to show that it also was quite effective, most of the patients had at least three or more visits with the palliative care team.  The effect on psychological distress and depression was significantly better in those with the early palliative care intervention, was much less than in the standard arm, although there didn’t appear to be much of an impact on anxiety.

The primary outcome of this study was improved quality of life, using something called the FACT-Lung or the Trial Outcome Index, which is a subset of questions from the FACT-Lung.  This is a very well-established, very well-validated tool to measure quality of life, and there was a statistically significant improvement in the quality of life as measured by this tool, both in the TOI and in the FACT-Lung. This magnitude of benefit is what is considered to be a clinically significant improvement in symptoms as well, so most of this is symptoms when we’re talking about quality of life.

Another thing that is something we as physicians and as the health care system need to pay a lot of attention to is quality of care at the end of life.  So what ASCO defines as poor quality care at the end of life? Patients who die without being referred to hospice  or who are enrolled in hospice in less than or equal to three days before death, or who are given a chemotherapy treatment within two weeks of their death — this is considered to be overly aggressive care.

What Dr. Temel’s study showed was that the early palliative care team had a statistically significantly less aggressive end of life care, with only 33% of patients having one of these measures, versus 54% of patients in the standard care arm; also with fewer admissions to the hospital, more days on hospice, although again only 11 days on average on hospice, I think is pretty poor; and more patients had a documented resuscitation preference, so that their wishes on what to do when they were dying was upheld.

Now, here is a slide that was a bit of a shock and was kind of thrown in at the end of the talk. 

Apparently, the people at MGH were also surprised when they saw this.  This is the survival curves between the two arms.  This is not something that was originally designed into the trial but was looked at kind of on a whim and turned out that there was a statistically significant greater survival in the arm that received early palliative care compared to those who received standard care with 11.6 median of months compared with 8.9 months in the standard care arm which was statistically significant.

This was not a planned analysis, and I don’t know that there is a terrific underlying rationale for why this might be true.  According to Dr. Temel, there were no differences in utilization of chemotherapy or lines of therapy between these two arms.  We do know that patients who are depressed seem to have a worse survival, so perhaps treatment of symptoms and treatment of the mood disorders might have allowed patients to get more effective treatment and to do better. But this is certainly very intriguing if this is true, because this is a completely non-toxic intervention.

So my conclusion from this is that I think if you have access to a palliative care team, which is not actually widely available in the community, based on this study I think it would be very reasonable to consider getting them involved early on in the care of your patients, because I think the quality of the life of the patients or symptom control was clearly better when these professional symptom control experts were involved.  This is a very resource-heavy strategy: obviously not just the physician themselves, but also an entire team of palliative care specialists need to be involved.  This is not something that is necessarily financially viable in a lot of places.  But there really is no downside to it if you already have it.  From a research perspective, I think it should be replicated again, probably in a multi-center setting, because this was only done at one spot.

And the other thing that’s missing is really detailing exactly what they did.  If I want to go out now and have my palliative care team do something that’s going to potentially impact these patients and even potentially their survival, it’s unclear to me exactly what I should tell them they should be doing based on this.  So it’s a little amorphous, and hopefully the final publication will have more details about this intervention.  Jack, what did you think?

Dr.  West:       I thought it was really impressive and surprising.  I agree it was puzzling – I mean, nobody can really provide a good explanation.  I would have thought that perhaps if people were not getting detrimental therapies when patients were too ill to handle them, going beyond that point could be harmful, but apparently that wasn’t really what the evidence suggests.  The patients on early palliative care didn’t receive less treatment, at least not significantly so.

It’s a not large study, and it’s from a single institution,  but it’s extremely provocative in showing that there’s certainly no penalty for this and that we are probably not doing a great service by creating some gulf between what we consider to be the main conventional therapy that oncologists do and then a transition to supportive care being some line in the sand.  This suggests that they should really be intertwined, and perhaps just attending to things like bowel care and pain control and all these other things that are symptomatic are actually good for a person’s physiology, too.  But there’s certainly a lot more to be learned about it.

Dr.  Pennell:   Yeah, we talk about how in addition to giving chemotherapy, our job is also to provide best supportive care, and in fact I think many oncologists don’t provide the  best supportive care because they probably don’t have time. In a busy private practice, you see a lot of patients, and you don’t have a lot of time to sit and address the patient’s mood, how are they coping with it.  You might miss that they’re constipated or that their pain is not as well controlled as it could be.

And while all of us would like to think that we are good at symptom control, that isn’t really our main focus when we’re talking to patients, and having experts who are doing nothing but focusing on that aspect of thingsis great if you have something like that available.  And if you don’t, maybe paying a little more attention to that aspect of things could be beneficial.

Related posts:

1. Palliative What?    What

Related posts brought to you by Yet Another Related Posts Plugin.

These data, presented in the Plenary Session of our ASCO Annual Conference, were really not controversial, except for the question of whether crizotinib should be approved by the FDA (and potentially by other similar regulators in countries around the world) based on these overwhelmingly positive results, in a limited population.  The larger studies are ongoing that I think are exceptionally likely to lead to its official FDA approval, but in the meantime, there is no question that many patients will miss the opportunity to benefit from it while it remains available in only very selected settings around the world.  There will also be less awareness of the test for ALK rearrangements and the benefits of crizotinib in the appropriate target patients while it is not commercially available and marketed.

The biggest problem of all, though, is that having a very effective treatment for a limited segment of the population creates a whole new set of problems that we’ll see more and more.  In many ways, we are fortunate to have found the right target for the right targeted therapy here.  If crizotinib had been tested in a broad NSCLC population, as is the ritual default paradigm for our treatments, it would likely be just one more drug with a 3-4% response rate that would be discarded rather than progressing through additional clinical testing.  How many other crizotinibs are there that just haven’t had their appropriate targets identified and remain undeveloped by a drug company because they appear to be minimally active in an overly broad population? We should also remember that many, many agents have now been tested in too broad a population and had safety problems.  Many of the anti-angiogenic agents have been shown to have increased mortality compared with placebo in patients with squamous NSCLC; in fact, it’s easy to imagine that Avastin (bevacizumab) would be tainted as the drug that regularly kills people by hemoptysis if investigators hadn’t identified the problem early in its development in lung cancer (as reviewed in this post) and excluded patients with squamous NSCLC in the larger phase III studies that led to its ultimate approval.

But we should also be concerned that pharmaceutical and biotech companies will do the calculations of offering treatment to a smaller population and find that it isn’t worth their costs and efforts to pursue therapies for a small subset of patients.  Here is one of the first slides from Dr. Pennell’s excellent podcast on molecular therapies for NSCLC, showing that until 10 years ago, NSCLC was essentially viewed as one entity with a market of 60-70,000 patients with advanced disease (and smaller numbers with other stages as well) in the US each year:

(click on image to enlarge)

Treatments were given in this way, and in the second half of the 1990s, carbo/taxol (paclitaxel) was the overwhelmingly used doublet in first line therapy, and the company making it (Bristol-Myers Squibb) was like the British Empire of oncology.  There was little question of the value of having a large stake in that market.

Dr. Pennell, toward the end of his podcast, contrasted that old view with a more current perspective and future projection of the field, which is far more segmented.  In fact, his 2020 projection includes no large populations, but rather molecularly defined small groups that presumably can achieve greater benefits than today by receiving a more personalized treatment approach.

This new oncologic world order of smaller populations achieving greater benefits, however, has no blockbuster treatments.  We can only hope that there are enough incentives for pharma/biotech companies to develop agents that will be ideal treatments for populations of mere thousands or perhaps even only hundreds of patients instead of tends of thousands.  Perhaps companies will seek approval for their drugs based on a limited subset and hope that oncologists will also offer it to broader populations once it’s commercially available.

It would certainly help if the FDA changes its requirements for getting drugs approved in smaller populations.  Agents that may be very helpful in populations that amount to only hundreds or a few thousand patients per year can’t feasibly be tested in proper randomized prospective phase III studies (see here for review of basics of drug development and types of trials).  A shorter and less arduous drug approval process will greatly help reduce the costs and other disincentives for a company to bring a novel agent to market for a relatively small target population/market.

Reaching the right patients when they are uncommon to rare and geographically dispersed creates other challenges.   All of these molecularly defined therapies are predicated on having tumor tissue available for testing, far more than we’ve routinely sought just to make a diagnosis.  And the onus may be much more on patients to stay on top of opportunities and travel to pursue trials that are seeking their particular cancer subtype.

More than ever before, the pace of clinical research and drug approvals may depend on having a knowledgeable, empowered patient population who can help identify the best trial opportunities for themselves.

I welcome your thoughts.

No related posts.

Related posts brought to you by Yet Another Related Posts Plugin.

Insomnia is defined by the American Academy of Sleep Medicine as having difficulty initiating sleep (sleep onset takes longer than 30min), maintaining sleep, waking too early, or sleep that is poor in quality.   This is in the context of efforts and opportunities to sleep adequately (versus people who are sleep deprived by their own volition).   Along with difficulty with sleep, insomnia includes daytime symptoms as well, at least one of the following: fatigue or malaise, attention/concentration/memory problems, impaired function socially or vocationally, tendency towards errors at work, moodiness/irritability, daytime sleepiness, decreased energy, stress-related symptoms (GI, headache) due to lack of sleep, and worries about sleep.

Why is it so hard for patients with cancer to get good sleep?  There are a multitude of reasons, but often it is a combination of factors.   The cancer itself can cause a myriad of symptoms that keep patients awake or interrupt sleep, including but not limited to physical symptoms like pain, cough, trouble breathing as well as depression, anxiety, and stress.   Pain can be exacerbated by sleep deprivation and vice versa, so you can imagine how this can become a vicious cycle.   There is a significant interplay between the symptoms of cancer-related fatigue, insomnia, and depression, making it challenging at times to determine which may be the culprit. I would also add that the cancer itself can have systemic effects on the body’s circadian rhythms due to cancer-related cytokines (markers of inflammation, hormone-like substances), and research in shift workers has found that they have an increased risk of developing cancer, suggesting a relationship between sleep disturbances and cancer.   This relationship has not been elucidated, but underscores the importance of healthy sleep.   Cancer treatments can also cause sleep disturbances—consider the use of steroids which for some cancers is primary therapy.  Steroids are notorious for causing insomnia—up to 50-70% of patients taking prednisone complain of this.   Anti-nausea medications such as compazine or zofran can also cause insomnia as a side effect.

Treatment
There have not been studies on the treatment of sleep disorders in cancer patients specifically, but in general the treatment of insomnia is to primarily treat the underlying cause of insomnia, if possible (depression, anxiety, breathing problems, pain, etc).   For treatment of the insomnia symptoms, the approach includes both behavioral therapy and medication.

Prior to initiating medication for sleep, it is helpful to see if more simple sleep hygiene modification can help.   Good sleep hygiene consists of what may appear to be some good old common sense, but has been demonstrated to improve sleep.   This includes avoiding alcohol and smoking right before going to bed, avoiding caffeine after lunch, keeping a regular sleep schedule, and maintaining a sleeping environment with decreased stimuli.   Addressing sources of stress through counseling can also help.  More specialized cognitive behavioral therapy for sleep has also been demonstrated to improve sleep as well, should sleep hygiene alone not be adequate. Other non-medication-based techniques include relaxation, stimulus control, and sleep restriction (limiting time in bed to sleep only to improve sleep efficiency).

Medication therapy for insomnia consists of several major types: benzodiazepine-type medications, non-benzodiazepine sedatives, and melatonin agents.   I will focus here on those that have some evidence supporting their effectiveness in treating insomnia.

Benzodiazepines include halcion (triazolam), pro-som (estazolam), ativan (lorazepam), restoril (temazepam), dalmane (flurazepam), and doral (quazepam).   Choosing an agent depends on the insomnia pattern — if the problem is falling asleep (and maintaining sleep is normal), then a short-acting medication will help.   If the problem is maintenance of sleep, then a longer-acting medication will be more effective.   Halcion is the most short-acting of this class; dalmane and doral are the longest-acting.

Non-benzodiazepine medications include sonata (zaleplon), ambien (zolpidem), and lunesta (eczopiclone)—this is a newer class of drug for insomnia.   These medications act on the same receptors as the benzodiazepines, but are more specific.   Sonata is the shortest-acting of this group and lunesta is the longest-acting.

Rozerem (ramelteon) is a new medication that acts on the melatonin receptor instead of the benzodiazepine receptor, so it has fewer side effects associated with benzodiazepines.   It is very short-acting and so is appropriate primarily for sleep onset problems.

Anti-depressants are also used for the treatment of insomnia related to depression, but are not recommended in patients who are not depressed, as they have multiple side effects and often do not have long-lasting sedating effects.

For more information, check out these web pages:

http://www.sleepeducation.com/
http://www.sleepeducation.com/Disorder.aspx?id=6

For now, though, it’s late…time to get to bed.

Related posts:

1. Anxiety in Cancer: Not Just the Jitters Anxiety is

Related posts brought to you by Yet Another Related Posts Plugin.

What causes anxiety in cancer?
As mentioned, the diagnosis of cancer itself can act as a stressor to induce symptoms of anxiety, as well as uncontrolled symptoms such as pain or nausea.  Other medical conditions unrelated to the cancer can cause symptoms of anxiety, including heart disease, thyroid disease, emphysema and asthma, neurologic disorders, as well as metabolic imbalances (hypercalcemia, for example).  Certain medications used in cancer treatment can cause side
anxiety as a side effect—medication like antipsychotics, anti-emetics (reglan or compazine, for example), and steroids.  The withdrawal of certain medications like benzodiazepines or opioids can also precipitate anxiety.

Treatment strategies
Similar to depression, the most effective treatment strategies for anxiety include a psychotherapy component and a medication component.  Psychotherapy in anxiety, similar to depression, focuses on supportive strategies and coping.

Behavioral interventions have also demonstrated efficacy in controlling symptoms of anxiety, including relaxation techniques and guided imagery.  One study compared the use of a relaxation technique (muscle relaxation) to xanax (alprazolam) and found that both were effective in reducing cancer-related anxiety, though xanax had a faster onset of action than the use of muscle relaxation.

There are two major classes of medications used in the treatment of anxiety: benzodiazepines and anti-depressants.  Benzodiazepines are anti-anxiety medications such as ativan (lorazepam), valium (diazepam), or klonopin (clonazepam).  They act on GABA-receptors in the brain which are responsible for modulating mood, sleep, anxiety, and seizures.  They are used as first-line medication therapy for intermittent anxiety or mild chronic anxiety.

Ativan is most commonly used in this class: it is short-acting and effective for controlling intermittent anxiety.  The challenge with the short-acting benzodiazepines, like ativan or xanax, is that patients can experience breakthrough anxiety with frequent use; these patients may benefit form the use of longer-acting benzodiazepines such as valium or klonopin.  Several of the benzodiazepines come in rapid-dissolve forms, such as ativan tablets, which can be taken sublingually or klonopin wafers (rapid-dissolving), which are useful in achieving quick control
of anxiety symptoms and also when patients are nauseous or having trouble swallowing.

The major class of anti-depressants used for anxiety is the selective serotonin reuptake inhibitor (SSRI) class — this includes medications like paxil (paroxetine) or celexa (citalopram).  They are the drug of choice in patients with anxiety and depression together.  Their disadvantage is their slow onset of action (usually 3-6 weeks) so the benzodiazepines are preferred for immediate symptom management.  Buspirone is another medication (also works on serotonin receptors as well as dopamine receptors in the brain) used for chronic anxiety—its onset of action is 5-10 days (still not immediate).

Other medications
While antipsychotic medications are primarily used in cancer for symptoms of delirium, they can be helpful in cases of anxiety that are accompanied by hallucinations or other psychotic symptoms or when benzodiazepines are not adequate to control severe anxiety symptoms.  These include haldol, olanzapine, and mellaril (thioridazine).  For patients with anxiety and pain, the antihistamine atarax (hydroxyzine) has been used for the anxiety symptoms.

I welcome your questions and comments.

Related posts:

1. Getting Your Z’s with Cancer Sleep is a

Related posts brought to you by Yet Another Related Posts Plugin.

What is depression? It is a clinical condition that is marked by one of two major symptoms, depressed mood and loss of interest in most activities (called anhedonia), as well as at least 4 other symptoms. These could include feelings of hopelessness, helplessness, worthlessness, guilt, and thoughts of suicide as well as physical symptoms such as fatigue, anorexia (loss of appetite), sleep problems (too little or too much), and weight loss. If those physical symptoms sound familiar, it’s because they can also occur due to cancer itself; as a result, the physical symptoms are not as helpful in identifying clinical depression.

To complicate things further, both patients and clinicians often mistake clinical depression as a “normal” emotional reaction to the cancer. There is indeed an expected emotional response to this diagnosis, including sadness, and while patients with cancer may have initially difficulty with their normal functioning and social interactions, patients who aren’t depressed are able to adapt. A patient with clinical depression won’t be able to do normal daily functioning on an ongoing basis. They will also persistently not be able to enjoy activities or experience pleasure. Their thought processes will be affected and consumed by helplessness, guilt and low self-esteem as well as hopelessness. A despondency accompanies the hopelessness, as opposed to a patient who feels hopeless due to discovering their cancer is incurable but can re-direct hope to something else (life prolongation, good quality of life). Actively seeking an early death is more indicative of clinical depression, in the absence of poorly controlled symptoms or inadequate social support.

Who’s at risk for depression?
The incidence of depression amongst cancer patients is thought to be 15-25% based on a systematic review of the literature. Certain types of cancers have an increased incidence of clinical depression, including lung, pancreas, breast, and head & neck. Risk factors include a prior history of depression or suicide attempt, a family history of depression, history of drug or alcohol abuse, and poorly controlled symptoms, particularly pain. This underscores the importance for managing and controlling symptoms, both from the cancer itself as well as from treatment side effects. Young age at diagnosis is also considered a risk factor for depression. Interestingly, these risk factors vary somewhat from those for suicide; a recent 2008 Harvard study found that older aged patients with cancer had an increased risk for suicide.

Treatment
In general, the most effective treatment strategy is a combination of psychotherapy and medication. There is a larger body of literature looking at this combination approach that demonstrates its superiority in the general population and smaller studies in cancer-specific trials. I will also comment here that social support (family, friends, patient-only networks) has not been studied in formal trials (hard to randomize patients to social support vs. no social support), but lack of social support and social isolation is a considerable risk factor for suicide in depressed patients.

Psychotherapy
Psychotherapy alone has been demonstrated to improve depressive symptoms in multiple studies, though the number of randomized control trials is small. It can occur either in individual sessions or in professionally led groups; both have demonstrated efficacy. In general, this therapy focuses on crisis intervention and cognitive behavioral therapy. Crisis intervention aims to alleviate the immediate distress of stressful situations, i.e. the cancer diagnosis, life changes due to the cancer, etc. Cognitive behavioral therapy works to provide new coping skills and strategies for correcting the irrational thoughts in depression.

Medications
Antidepressants are the primary group of medications used; I know this sounds like a no-brainer, but there are other classes of medications that are used as well. There are two main categories of antidepressants used: the tricyclic antidepressants, or TCAs, and the selective serotonin reuptake inhibitors, or SSRIs.

The TCAs are much older but better studied—these include elavil (amitriptyline), pamelor (nortriptyline), tofranil (imipramine), and norpramin (desipramine). They are also used in the treatment of neuropathic pain and can be of added benefit for patients suffering from pain. However, they tend to have more side effects than some of the newer antidepressants and more drug interactions, which are important factors to consider with ongoing cancer treatment. Their side effects include sedation, dry mouth, constipation, and nausea, among others. You can see why they are not considered the most ideal for patients with cancer if there are better alternatives.

The SSRIs include medications like prozac (fluoxetine), paxil (paroxetine), zoloft (sertraline), and celexa (citalopram). They do not have as many side effects as the TCAs and are better tolerated; they are the preferred antidepressant to initially treat depression in cancer patients. However, their onset of action is quite slow; it usually takes 3-6 weeks for the full therapeutic benefit.

Other antidepressants include wellbutrin (bupropion), effexor (venlafaxine), remeron (mirtazapine), and trazodone. These are not as commonly used as first-line in cancer patients with depression, and they each have a different mechanism of action. I would highlight that remeron has the particular side effect of weight gain and can be particularly helpful for a patient who has depression and weight loss. One of the newest antidepressants is cymbalta (duloxetine); it has garnered attention for its use in the treatment of pain as well as depression and is being used instead of TCAs for patients with both depression and pain.

Psychostimulants are an additional class of medication to consider for depression and are more “activating.” They include ritalin (methylphenidate), dexedrine (dextroamphetamine), and provigil (modafinil). They are used to promote alertness and improve energy and mood; they’re also used to mediate the sedating effects of opioids for some patients. One of their main advantages is their rapid onset of action—they work quickly and are short-acting (dosed multiple times during the day). This is particularly helpful if 3-6 weeks will be too long for a patient to wait for relief or if their prognosis is limited to weeks.

This post is certainly not exhaustive, but rather is a broad overview of a big and important topic. I welcome your comments and questions.

No related posts.

Related posts brought to you by Yet Another Related Posts Plugin.

   The World Health Organization (WHO) defines palliative care now as:
   “…an approach that improves the quality of life of patients and their families facing the problems associated with life-threatening illness through the prevention and relief of suffering by means of early identification and impeccable assessment of pain and other problems—physical, psychosocial, and spiritual.” 

   In the WHO definition, there is no mention of death and dying, because a patient does not have to be dying to receive palliative care.  The overall philosophy of palliative care is the relief of suffering and the enhancement of quality of life.  Most commonly, palliative care is practiced with a multidisciplinary team approach and focuses on the patient and the family as the unit of care.  In the US, palliative care programs initially started out as hospital-based, or inpatient, programs but are now growing in the outpatient realm with clinics and other outpatient programs. 

Why Palliative Care?

   Palliative care has grown into a full-blown medicine specialty over the last several decade; few programs existed before the 1990s.  In 1995, there was a large study called the SUPPORT trial of over 9000 patients at multiple hospitals that evaluated how well we care for seriously ill, hospitalized patients.  It revealed that for half of the conscious patients who passed away in the hospital, 50% were in moderate to severe pain for the majority of the time.  It also showed that clinicians were not doing a good job determining the preferences of patients with advanced illness and their families for aggressive, hospital-based interventions.  This study highlighted the need for palliative care and for the improvement of our care for patients with life-limiting illnesses.  Between 1996 and 2006, the number of palliative care programs in the U.S. grew from just a handful to over a thousand.  In 2006, the American Board of Medical Specialties recognized palliative care as a new medical subspecialty, as 10 different specialty boards — including internal medicine, pediatrics, and surgery — sponsored and supported it.

   While palliative care initially grew out of the modern hospice movement, it is no longer synonymous with hospice.  However, its growth reflects the value of an approach to care that focuses on quality of life.  Palliative care has also developed an additional focus on communications and decision-making, particularly in transitions of care. 

Myths about Palliative Care

Myth #1: Palliative care means end-of-life care.

   This is the most common myth, and there is good reason for its existence.  The term “palliative care” was originally coined as a synonym for hospice and end-of-life care in the 1970s.  It has developed over the last several decades in its definition to encompass more.  Certainly palliative care clinicians are trained in end-of-life care, but have additional expertise in overall symptom management and the improvement of quality of life. 

Myth #2: A patient cannot have curative care and palliative care at the same time.

   This stems from myth #1, as hospice care and curative care are not usually concurrent.  However, palliative care can complement curative care to provide symptom relief so that curative treatments are better tolerated.  Palliative care clinicians care for patients at all stages of disease, from diagnosis to transplant to end-stage.

Palliative care and Oncology

   Oncology and palliative care have had a close relationship, and much of this stems from supportive care.  Supportive care is a term used in oncology referring to all of the non-cancer-focused treatments such as transfusions or growth factors (neupogen, epogen) and derives from its use in research for cancer treatments (a new cancer drug gets tested against “best supportive care”).  There is considerable overlap with palliative care, but traditionally supportive care has not focused on the psychosocial and spiritual issues as seen in palliative care.  The term “palliative” is also used in oncology for cancer-directed treatments that are not curative, but can improve the burden of the cancer.     

How to find palliative care near you

Oncologists and other clinicians practice palliative care on a daily basis by providing treatment for symptoms and offering support to their patients; palliative care is not exclusive to palliative care specialists.  However, it can be helpful to see a specialist in palliative care to augment the care you already receive from your primary physician.  In general, palliative care programs operate with a multidisciplinary team approach—physicians, nurses, social workers, etc—providing additional resources for patients and their families.  Here are few websites for patients and families looking for more information:

www.getpalliativecare.org

www.palliativedoctors.org

   I welcome your questions and comments.

Related posts:

1. Is Palliative Care “Giving Up”, or Can It Be Genuinely Helpful?   GRACE m

Related posts brought to you by Yet Another Related Posts Plugin.

For this, we can start by looking at results from a recent study of the anti-angiogenic agent sorafenib (nexavar) in renal cell carcinoma (kidney cancer).  Here, patients were classified according to whether they demonstrated evidence of a high blood pressure, which was defined as a systolic blood pressure (the higher number) of 140 or greater, and/or a diastolic blood pressure (the lower number) of 90 or greater over the course of their treatment with sorafenib. The 441 of 534 (83%) who had hypertension had a remarkably higher response rate (54% vs. 10%, p < 0.0001), and a significantly longer median progression-free survival (12.5 vs. 2.5 months, p < 0.0001) and median overall survival (30.5 vs. 7.8 months, p < 0.0001) than the patients with advanced RCC who didn’t have hypertension on the study:

Interestingly, and importantly, the study showed that it didn’t seem to matter much whether patients were treated with a dose reduction of sorafenib, started anti-hypertensive (blood pressure) medicines, or both; the only people who seemed to do poorly were those who never developed high pressure.

Perhaps that’s a fluke, but the same trend has been seen in lung cancer, although without as striking a difference.  In a retrospective analysis from the ECOG 4599 trial of carbo/taxol alone or combined with avastin (bevacizumab), patients with high blood pressure on avastin (in this case defined by a much higher bar of a BP above 150 systolic and 100 diastolic) had a median progression-free survivalof 8.0 vs. 4.5 months for those with hypertensive events, while the median overall survival was 14 months, vs. 11.3 months (neither statistically significant).  And in a review of a global registry of over 2000 patients receiving avastin in advanced lung cancer that was presented by Dr. Nick Thatcher at the World Conference on Lung Cancer in San Francisco earlier this year (abstract not available), the median overall survival was 18.8 months for those with hypertension, compared with 12. 9 months for those who didn’t show significantly elevated blood pressure.

These are still early reports and represent a small minority of the work being done with anti-angiogenic agents in cancer.  Nevertheless, it’s intriguing to see the same trends applying to patients being treated with different anti-angiogenic agents for different cancers, and in several different studies.  This issue certainly merits further study and raises the question of whether modifying the dose of anti-angiogenic agents in an attempt to develop high blood pressure, possibly as a biomarker that the drug is acting as intended, may possibly be beneficial.  This is not the standard approach right now, but we should see more information about the association of blood pressure and survival with various anti-angiogenic agents in oncology in the coming years.

No related posts.

Related posts brought to you by Yet Another Related Posts Plugin.

A couple have been the subject of trials that were negative, showing no benefit for the investigational agent, including the radioprotectant amifostine, the calcium channel blocker nimodipine, and some others.

A few have had some mixed and some positive results.  Among these, vitamin E has been suggested in trials to reduce the frequency and severity of CIPN, but as an anti-oxidant, there is some concern that it may compromise the effectiveness of chemotherapy.  Others that have looked favorable in small studies have included glutamine, glutathione, N-acetylcysteine, and calcium and magnesium infusions, though the last have raised some questions about being associated with reducing the efficacy of chemotherapy.   Overall, with most of these being such small trials, and without establishing that prevention of neuropathy occurs without a compromise of the effectiveness of the chemotherapy, none of these has become a standard treatment.   In the meantime, there are ongoing trials looking at whether certain approaches prevent CIPN, including acetyl-L-carnitine, vitamins B6 and B12, and alpha lipoic acid.

Beyond attempts at prevention, there are no agents that are established and FDA-approved as treatments for CIPN once it has developed.  However, there are several treatments that are used for the “positive” symptoms of pain and hypersensitivity, though none is felt to be effective for the “negative” symptoms of numbness and weakness (here, positive refers to symptoms of something superimposed on top of what is normal, and negative refers to something missing from what is normal).  The agents most commonly used here are Neurontin (gabapentin), Lyrica (pregabalin), opioids like oxycodone or morphine or Ultram (tramadol), a local anesthetic like Lidoderm (lidocaine) patches, or antidepressants like Cymbalta (duloxetine) or Elavil (amitriptyline), though these haven’t all been shown to be extremely effective in trials.  The links go to representative studies that support their use for neuropathy.   In general, these are started at low doses and titrated upwards gradually, and these are sometimes combined.

Finally, there are even approaches using electrical nerve stimulation, often with an implanted device.  These approaches typically entail the involvement of specialist in managing chronic pain.

Obviously, this is a very large topic, and many of the drugs covered here could be the subject of their own post about their possible role in managing neuropathy, though this work is really also outside of my range, or that of most oncologists.  For now, there are certainly several treatments that may be tried, and it’s important to note that larger trials are being conducted that we hope may lead to results that could allow us to mitigate the unfortunate effects of several of our more important and effective chemo agents.

Related posts:

1. Chemotherapy-Induced Peripheral Neuropathy Peripheral
2. Neuropathy in Cancer: That Tingling Feeling That Isn’t Love Neuropathy

Related posts brought to you by Yet Another Related Posts Plugin.

The classical side effect of chemo-inducted peripheral neuropathy is sensory and symmetric, affecting both sides of the body relatively similarly, unlike nerve compression, which affects a single nerve and is not symmetric.  Because neuropathy preferentially affects the longest nerves of the body first, and these are the nerves that run from the spinal cord to the tips of the feet and hands, a neuropathy in a stocking-glove distribution is what is typically seen.

The typical pattern of onset is that it gradually increases in severity over ongoing treatment with the offending agent(s) and is dose-dependent.  One interesting pattern is coasting, which is the observation that the neuropathy can sometimes worsen for several weeks to months after the chemotherapy has been discontinued.

Among our anti-cancer treatments, the most common offenders are the platinums (cisplatin far more than carboplatin, and oxaliplatin can also do this but especially causes a severe cold sensitivity), the taxanes, navelbine (vinorelbine) and other “vinca alkaloid” drugs in the same class, thalidomide, and a few others.

Most commonly, symptoms improve with time off of these treatments, but the improvement may be over a course of days or may persist for several months, and sometimes people can have permanent deficits.   Accordingly, there have been efforts to both prevent/protect against the onset of neuropathy and also to treat established neuropathy, and we’ll turn to the work on potential treatments next.

Related posts:

1. Neuropathy in Cancer: That Tingling Feeling That Isn’t Love Neuropathy
2. Highlights of Attempts at Prevention and Treatment of Chemo-Induced Peripheral Neuropathy Chemothera

Related posts brought to you by Yet Another Related Posts Plugin.

It is a very common problem, seen in about 3-4% of people, and it’s particularly common in people over 55.  About one third of cases are due to diabetes, and another third are termed idiopathic, a fancy sounding term just meaning that we can’t determine that cause of the problem (though a medical school professor of mine uncharitably suggested that it came from the idea that your doctor is an idiot, and that’s pathetic).  The remaining third are from a range of identified causes such as chemotherapy or other medications, autoimmune diseases, infections, nutritional deficiencies, metabolic disorders, or genetic-mediated nerve damage.

Neuropathy is most colloquially noted to represent numbness and tingling, but it can range from a slight hint of numbness to debilitating neurologic problem that makes it difficult or impossible to ambulate and can be associated with chronic pain.  Sensory neuropathy is often described as numbness and tingling that can lead to difficulty in walking, dropping things, inability to turn pages,  pick up small objects, button a button, etc., and sometimes a general feeling like a person is wearing gloves or walking on hot sand or a shag carpet all the time.  Autonomic neuropathy involving the internal organs can lead to constipation or diarrhea, low blood pressure and lightheadedness, or even difficulty with breathing.

In patients with cancer, the most common causes of neuropathy are:

• directly caused by chemo, radiation, or surgery
• cancer directly pressing on nerves (such as spinal cord compression from expansile vertebral metastases)
• metabolic disorders
• paraneoplastic (such as hormone- or antibody-mediated) neurologic disorders
• infections
• nutritional deficiencies

We’ll cover some details of chemotherapy-induced neuropathy next.

Related posts:

1. Chemotherapy-Induced Peripheral Neuropathy Peripheral
2. Highlights of Attempts at Prevention and Treatment of Chemo-Induced Peripheral Neuropathy Chemothera

Related posts brought to you by Yet Another Related Posts Plugin.