Cancer Treatments / Symptoms & Support
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GRACE member and forum moderator Catharine started a forum thread and conversation that followed a great link to a difficult but thought-provoking article written by Dr. Atul Gawande in the New Yorker on the subject of the transition from aggressive anti-cancer therapy to a focus on palliating symptoms and focusing on quality of life. This is one of the most difficult topics in oncology, for patients, doctors, and society as a whole to confront.
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:
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Posted in: Pain and Symptom ManagementEarlier this week, I wrote about the very promising early work with the novel, still investigational agent crizotinib (PF-02341066) in treating the 4-5% of NSCLC patients with a tumor positive for an ALK rearrangement. For this minority of patients, the benefit was of a kind we don’t see enough in cancer and certainly not in lung cancer, with about 2/3 of patients showing a significant response in terms of tumor shrinkage, and 87% achieving at least stable disease; nearly 3 out of 4 remained on it without progression 6 months later, and many are on it now for much longer, with responses still ongoing.
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)
Sleep is a precious commodity. While sleep disturbances in cancer patients include both insomnia as well as other sleep disorders (like sleep apnea), I will focus primarily on insomnia and the lack of sleep in this post, as that is by far the most common problem. Sleep disorders are more prevalent in patients with cancer than the general population—33-40% versus 15-20%. This is due to multiple reasons, related to both the disease and treatments. Cancer patients tend to sleep more total hours on average, but have poorer sleep quality — i.e., the sleep is interrupted or there is not enough restorative sleep (deeper stages). A recent review of the literature on sleep disorders in cancer found lung cancer patients to have the highest incidence of sleep disturbances; this may be due to symptoms related to breathing at night, like coexisting lung conditions (emphysema) or troublesome coughing.
Posted in: Pain and Symptom ManagementAnxiety is common in patients with cancer and can develop as a result of cancer and its treatments. Symptoms of anxiety are seen in up to 48% of all cancer patients, often in the form of a “situational anxiety”—these symptoms include worry as well as physical symptoms like muscle tension, restlessness, palpitations, sweating, and shortness of breath. A smaller percentage of patients actually develop a formal anxiety disorder such as panic disorder, post-traumatic stress disorder, phobias, or generalized anxiety disorder. Typical anxiety symptoms include severe worry, feeling “on edge,” irritability as well as physical symptoms such as nausea/vomiting, diarrhea, shortness of breath, and palpitations. You can see that similar to depression, the physical symptoms of anxiety are similar to those of cancer and treatment side effects. Shortness of breath in particular gives me pause, as it is intimately linked with anxiety—the two can often trigger each other and cause a vicious cycle, making both the anxiety and the shortness of breath much worse.
Posted in: Pain and Symptom ManagementPeople often expect that having cancer would make anyone depressed, that it is “normal,” but clinical depression is anything but normal and is imminently treatable. The challenge is that cancer can often cause the same symptoms that are seen in depression, so that depression is under-recognized and consequently undertreated.
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.
Posted in: Pain and Symptom ManagementWhat is palliative care? I get this question at least once a day, not only from patients and families but also from other clinicians. While many GRACE members are familiar with palliative care, there still exists a lot of confusion out there about what palliative care exactly is. To be honest, back when I started medical school, I didn’t know what it was myself.
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.
Posted in: Cancer Treatments, Pain and Symptom ManagementOne of the most common side effects of many different anti-angiogenic agents, which are felt to decrease the tumor’s blood supply, is high blood pressure, also known as hypertension. The cause of this isn’t really known, but most patients develop some degree of high blood pressure. What is interesting is that there is growing evidence that this may not just be an unwanted side effect, but rather a marker of a probability of doing better, similar to the correlation of rash with longer survival in patients receiving EGFR inhibitors.
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:
Chemotherapy is a common contributor to peripheral neuropathy, and because of this, there have been efforts to both prevent and treat chemo-induced peripheral neuropathy (CIPN). However, much of the work in this field has been hampered by difficulty in measuring this, as well as trials that are pretty small.
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.
Posted in: Cancer Treatments, Pain and Symptom ManagementPeripheral neuropathy is a common complication of multiple widely used chemotherapy agents, and this symptom often limits our ability to have patients continue on the same treatment, even when it’s effectively treating the cancer. Typically, the symptoms are more sensory than motor, and the leading complaints are numbness and tingling, cold sensitivity, sometimes burning, electric, and sometimes normal pressure is perceived as painful. Diminished proprioception, the perception of a person’s body in space, can lead to balance problems and falls. And while dysfunction of autonomic nerves, which mediate the body’s automated body processes like temperature regulation, blood pressure and heart rate bowel fucntion, etc., is felt to be rare, this hasn’t been well studied. It’s possible that issues like difficulty regulating blood pressure, constipation, and urinary difficulties may in fact be related to neuropathy of autonomic nerve function.
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.
Neuropathy, also known as peripheral neuropathy, is a common medical problem caused by damage and dysfunction to one or more peripheral nerves, which are the nerves connecting the brain and spinal cord to the rest of the body. There are three different types of nerves: sensory, motor, and autonomic (controlling reflexive/automatic body processes like blood pressure, heart rate, temperature regulation, sweating, etc.).
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.
Posted in: Cancer Treatments, Pain and Symptom Management
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