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The journal Cancer has an article by Loberg et al that describes the lethal phenotype of cancer (free pdf!). While the article does get into the molecular level it keeps a pretty steady course and is very approachable for the 'non-bench research' physician. The article abstract highlights the key reason this is important for most palliative care practitioners to read:

While these studies describe the cellular events of the lethal phenotype of cancer in detail, how these events result in the common clinical syndromes that kill the majority of cancer patients is not well understood. It is clear that the central step that makes most cancers incurable is metastasis. Understanding the traits that a cancer acquires to successfully grow and metastasize to distant sites gives insight into how tumors produce multiple factors that result in multiple different clinical syndromes that are lethal for the patient.

Starting from the molecular level, the authors do a good job of linking research findings with the syndromes most palliative care practitioners are familiar with: anorexia-cachexia, thrombosis, bone pain and dyspnea. The figures and tables are informative and make for good presentation slides. Like the following one:









A)
Getting PubMed alerts by email always turns up interesting things. Like this article which highlights 'Survivin' a protein that inhibits apoptosis in cancer cells. What a great name for a protein. You don't even have to put the apostrophe on the end and drop the g, as if you were talking in a hip manner.

B)
And it is not only the US media who confuses the semantic differences among euthanasia, physician-assisted suicide, withdrawing/withholding medical treatments, and appropriate palliative care. Even in Japan, the newspaper mixes-up the terms causing the general public to think they are committing euthanasia when life support is discontinued in accordance with the patient's wishes. Here is the headline:


Kind of grabs your attention doesn't it?! But then the rest of the article mentions nothing about euthanasia, only withdrawal of medical technologies at the end of life. Pallimed offers its services to any media outlet wishing to double check the appropriate use of any medical terms at the end-of-life for the good of the public understanding about these complex issues.

C)
St. Oswald's Hospice in the UK is getting on the blog train by offering blogs/forums for patients to post about their experience with the hospice. (Adult blogs here / Peds blogs here) Does anyone know of any other hospice or palliative medicine programs that do this? If you start one let us know. (via the UK News Guardian)

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3 on heart failure...

1)
Journal of the American College of Cardiology has a trial looking at left-ventricular assist devices (LVADs) as destination therapy in patients with advanced heart failure. LVADs, in the simplest terms, are implantable devices which augment the pumping of a failing heart; they are relatively well accepted as a temporizing measure while people are awaiting heart transplants. They have also been controversially proposed for people who are ineligible for heart transplantation - as 'destination therapy.' The current study is a non-randomized, observational study of this. The patients (37 in the LVAD group, 18 in the medical management group) had Class IV heart failure symptoms (rest symptoms), severe systolic dysfunction, and had 'failed' inotrope weaning at least twice. They were then offered LVADs - most received them; those that didn't either declined them, had 'inadequate identifiable financial resources' to receive one, or had a mechanical aortic valve replacement (which was identified as a contraindication to LVAD placement). So, yes, the control group had different inclusion/exclusion criteria than the treatment group.

As you'd expect from an uncontrolled trial the control group was different than the treatment group. They were sicker: higher BUN and lower serum sodium levels (significant) and trends toward worse creatinine and wedge pressures. The LVAD group's survival was poor but substantially better than the control group: 6 month was 46% vs 22% and 12 month was 27% vs 11%. The authors mention quality of life was better in the LVAD group but don't present that data or baseline quality of life information.

The authors not only conclude that LVADs look a lot better than medical management for this patient population but suggest it is now no longer ethical to do a randomized study because one cannot reasonably argue there might be equipoise with medical management. The first statement seems reasonable: based on these data LVADs may prolong life (and we are reassured improve quality of life although those data weren't deemed important enough to actually present). While there's reason to doubt this; most notably due to the fact that the control group patients were sicker, had different inclusion/exclusion criteria, and it's probable that there's significant confounding in the decision to receive an LVAD or not (patient 'choice' and not having financial resources...when was the last time you saw that in a treatment trial as a reason not to receive the therapy?), the magnitude of the effect is pronounced (survival was doubled). But to say that these data, with all their associated problems (& I didn't even mention the small numbers), are sufficient to forever exclude an actual controlled trial on ethical grounds (lack of equipoise) seems a stretch.

My sniping aside, we are almost certain to see more of LVADs in the future, and they will further complicate the already complicated decision-making in heart failure, and should be a challenge we are ready for. And if there's one thing this study does clearly demonstrate it's the extraordinarily high mortality of these most-advanced heart failure patients: a prime patient population for palliative care priorities. To this end, I'd love to see the quality of life data...assuming they're legit (particularly that they suggest a clinically and not just statistically important improvement in QOL) this will highlight that for heart failure (perhaps more than many other terminal illnesses...?) distinguishing between life-prolonging interventions and quality of life interventions is often impossible. They're the same thing, insofar as getting the heart to pump better generally makes people feel better! The implications of this for hospice care and hospice's financial model will be interesting.

(Related editorial here.)

Full-sized LVAD image (& further discussion) at WebMD, or click on the image above.

2)
Annals of Internal Medicine has systematic review of implantable cardioverter defibrillators for people with systolic dysfunction, which concludes they reduce mortality in patients with class II & III symptoms but there are inconclusive data for the healthiest and sickest patients (classes I & IV). Absolute risk reductions and numbers-needed-to-treat are absent from the analysis.

The authors also noted these concerns, despite the mortality benefits of ICDs, and despite my argument in #1 above:

"However, our data on patient and device-related complication rates highlight the perhaps underappreciated risks of ICDs, particularly in light of 3 findings. First, three quarters to two thirds of ICD recipients in the observational studies received no therapeutic ICD discharges, and only 5% to 12% of trial participants received an appropriate shock per year. Second, the frequency of inappropriate shocks was surprisingly high, and at least 1 study has demonstrated that inappropriate shocks are associated with an increase in risk for death (hazard ratio, 1.97 [CI, 1.29 to 3.01] in the Sudden Cardiac Death in Heart Failure Trial). Third, although the studies we reviewed infrequently report quality-of-life outcomes, some studies have shown that quality of life declines in many ICD recipients, especially those who experience frequent ICD firings. Not unexpectedly, patient anxiety and psychological distress scores increase substantially after an ICD shock or after publicity about device recalls."

(Annals also has an analysis of how quickly systematic reviews become outdated for those of you who are interested. Answer: pretty quickly.)

3)
Heart has a qualitative study looking at palliative care needs of heart failure patients, their caregivers, and their health care providers. It's based on focus group-type interviews. The themes you'd expect emerge did emerge: patients not conceiving as their disease as terminal; cardiologists never 'running out' of disease-modifying interventions to try, and not being comfortable talking about mortality, particularly in light on the difficulties prognosticating for an individual patient; and so discussions about end of life concerns & care rarely occurring. What perplexes me about this is that while it's near impossible to prognosticate with any precision for most patients - more than "likely to live many years" or "not likely to live many years" - for those patients who are not likely to live many years what is likely to happen to them in that period of time is generally clear: ups and downs but with overall progressive functional decline, punctuated by episodes of critical illness, with each episode carrying high risk for death. Preparations for crisis and discussions of goals & treatment limitations in light of functional decline seem very pertinent, despite not being able to put a 'number' on the prognosis.

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#1)
The Journal of Clinical Oncology recently published an ambitious study by Gripp and colleagues looking at clinical prediction of survival (CPS) objective prognostic factors, and the psychological impact of coping. 216 consecutive patients receiving palliative radiation treatments consented to the study (adjuvant and curative patients were excluded). The CPS was divided into 3 groups:

• less than 1 month - 15% died
  
• 1-6 months - 36% died
  
• >6 months - 49% died

The study has some great analysis of prognostic accuracy comparing pooled physician estimates (average years of experience 1.7!), tumor board estimates, and a single experienced physician. The correct predicted survival range was in the 55-62% range for each of the 3 groups of physicians, with the poorest accuracy coming with predicting those with less than 1 month to live. That level of accuracy is not bad considering diagnostic accuracy may have rates in the 85% range and we have much more research into diagnostic tests and acumen.

When comparing the accuracy of the various lab test and functional indices, they find that certain cutoffs are statistically significant, but it was not clear if they picked those levels before testing them or kept parsing the data until they found what was significant for decreased survival. Of course, what is missed here is that lab values may associate with a higher mortality but how do you get that into clinically useful information that can be communicated. "You have brain mets and only 28% of patients with brain mets are alive at 180 days. What that means for you? I don't know." Therefore future research needs to translate these multiple objective factors into communicable data otherwise it will never be used, patients will be left with no structure to plan their treatment. I really hope we are on the cusp of a prognostic research avalanche. (That's a good kind of avalanche.)

The authors do gloss over the association they found (p<.0001) that use of morphine was associated with increased mortality. It only receives one sentence in the discussion, but obviously there may be much more to this discussion. I would hope the authors go into more detail in analyzing this in a future article. I was surprised they did not use some of the prognostic scoring systems out there already. It would have been nice to have a head to head trial of some of these to see how they stack up with the same patients. One sentence in the discussion was slightly over the top is that 'disclosing prognosis to patients and relatives is a matter of controversial debate.' The authors are from Germany and it may be debated in Düsseldorf, but the paper they cite is from Boston, MA (Jen Mack) and is about pediatric patients. When you get down to it, good informed consent requires disclosure of prognosis to some extent as it involves expected and avoidable outcomes based on the therapy chosen. Take this and you may live, don't take this and you may not live, etc.

While the study really did not get into a focused analysis of the coping issue, the prognostic analysis makes for a great article for the teaching file. If you are interested in prognosis, pick it up. (no free pdf, too bad.)

(Note: Drew blogged on this at the end of July. I thought it sounded familiar, but I only looked at the August posts when I checked this, since the article is from August 1)

#2)
A couple of news outlets are reporting on an AP analysis of DEA data. Pain medication use/sales is rising, almost 90% in 8 years. Here is a quote that attempts to quantify the problem using social math (poorly):

More than 200,000 pounds of codeine, morphine, oxycodone, hydrocodone and meperidine were purchased at retail stores during 2005, the most recent year represented in the data. That is enough to give more than 300 milligrams of painkillers to every person in the country.

The problem with this quote is that it treats all opioids the same. 300mg of morphine is not the same as 300mg of codeine or meperidine. It makes people imagine, "Oh my gosh 300mg of morphine that is a lot of drugs! I can't imagine if everyone took 300mg of morphine. This really is a problem." Since we are calling opioids 'painkillers', lets make sure we stop saying diuretics and only say 'fluid squeezing pills' and instead of anti-arrhythmics, lets call them 'heart slower-downers.' No one calls their band or a song 'heart slower downers,' but their are a lot of musical references to painkiller. (Also, is it pain killer or painkiller? Maybe we could be hip and write it PainKiller)

Anyone know why is meperidine on there? Aren't most hospitals/clinics/doctors trying to inhibit its use secondary to the poor side effect profile, and low potency compared to other opioids?

The articles reasons for the increase:

• aging population - (check)
• increased drug marketing - (hmmm...not so sure on this one. Yes big pharma advertising (DTC and DTP) has increased, but I do not recall the last time I saw Fentora, Oxycontin or Lortab being hawked on the national evening news. Now Flomax, sure.)
• major change in pain management philosophy - (check - more pain clinics, more interventional pain doctors, more palliative medicine doctors, more hospice services as none of these are mentioned individually)

The article then covers some of the high profile prosecutions of physicians for prescribing pain medications in high quantities. I am still holding my breath for the article that says pain control is not too hot or too cold but just right.

-Addendum (8/23/07)
After seeing some comments on this part of the post, I found a graph associated with this study, that tells a very interesting story, the article fails to note.

Here is the picture:
From 55 tons (groan...tons) to 104 tons. Over eight years as the article says. But wait the period is the full years from Jan 1 1997 to Dec 31, 2005. That is actually 9 full years. Count them. 97, 98, 99, 00, 01, 02, 03, 04, 05. Actually even over 9 years, it really is not a major change. A growth rate in use of about 10% per year. Nothing shocking.

The article uses the following words to describe this rise:
"Painkiller use rising at an alarming rate"
"reflecting a surge in use"

That surge sounds alarmist when the graph (especially when ignoring that 2000 dip) really shows a gradual change.

Also the article notes that oxycodone use jumped 6 fold over those 8 (actually 9) years. Well Oxycontin was introduced to the US market in 1995, so you would expect that a new extended release opioid (where there had only been MS Contin), might be prescribed more frequently. And even take off rapidly, regardless of diversion.

Speaking of diversion, the article quotes a 2004 'Government study' that notes 2-3 million doses (oxycodone, hydrocodone, codeine) are stolen from pharmacies annually. let's do some more social math like the AP did.

11 tons would be a conservative estimate. So the larger story here, that is missed, is that diverted and illegally obtained opioids is equal to 10-30% of what is legally prescribed.

*Lowest dose of oxycodone = 5mg
Lowest dose of codeine = 10mg
Lowest dose of hydrocodone = 5mg

The reason I am so passionate about this is that often times we (palliative professionals) have to try and reverse this stigma because patients who truly do have pain, don't want to be like 'all the people' they read about in the news who are addicted. Addiction, diversion, and abuse are surely problems that need to be dealt with in a fair and rational manner and I do not want to trivialize any impact that they can have on an individual, a family or on public health. But not to the point that those who earn the right to have good pain control end up suffering because of media/public stigma, and fear of health care professionals to do good symptom control.

--back to the original post--


#3)
The British are planting more poppies to produce diamorphine (aka heroin, legal in the UK for pain treatment) to make sure they don't get to reliable on outside sources in case of a flu pandemic. This is really surprising thinking ahead, but it is nice to see that if we had a major pandemic with many many deaths, that some of the palliative care needs would be addressed. Obviously the Afghan poppies-to-pills program I blogged about earlier would not work for this particular case. I have not heard if the US gov't is thinking of such a plan. An interesting stat from the article:

Hectacres of poppies planted (according to the International Narcotics Control Board):

• UK 166,000
• Turkey 70,000
• Hungary 13,000
• France 6,000
• US ??

(via Avian Flu Diary)

#4)
The National Cancer Institute is offering the newly made EPEC-O materials for free. If you are not familiar with the EPEC materials, they are of very good quality. These CD's include PowerPoints and video vignettes. You may also want to attend one of the Train the Trainer sessions too. Now there are other places where you can pay to get some similar high quality materials so if you have the budget go support some of these projects, but if money is tight and you want to teach some oncologists some palliative care principles go see the NCI.

Image 1 - Dusseldorf, Germany, courtesy of flickr.com user Mareen Fischinger
Image 2 - Poppy (non-opioid), courtesy of flickr.com user ToniVC

PS
Woo-hoo!!!!! I fixed the stupid line spacing problem after inserting a quote! Thank you Med Journal Watch! That was really bugging me.
PPS
We are now adhere to the Healthcare Blogger Code of Ethics. Always had (just had not applied for the rights)

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Cancer cachexia and then several things in brief...

1)
Head & Neck has an interesting trial of celecoxib for cancer cachexia. This was a small, randomized, placebo-controlled, and blinded trial of 11 patients with recently diagnosed head/neck/or upper GI cancers, 5% unintentional weight loss, no mechanical GI obstruction, and who were awaiting curative-intent cancer treatment (despite the fact that most of the patients had stage IV disease??); none were on other appetite modulators or anti-inflammatories (glucocorticoids, megestrol, NSAIDs etc.). They received 200mg bid of celecoxib or placebo for 3 weeks and a bunch of metabolic, inflammatory, and nutritional parameters were measured.

Despite the fact that that only 11 patients were involved & the study only lasted 21 days, celecoxib actually appeared to have some measurable and statistically significant effects: mean weight and body mass index increased (by 1kg and 0.3kg/m^2 in the treatment group - weight decreased by 1.3kg in the placebo group), health-related QOL improved a little in the treatment group as well. Laboratory measures of inflammation (CRP, IL-6, etc.) and other things like resting energy expenditure and lean body mass didn't differ between groups. Usually it's a good thing when small (but randomized and controlled) trials show treatment benefit (it's an indication that the effect is pretty robust if you only need 50-100 people to show an effect exists as opposed to, say, 10,000 patients in a hormone replacement therapy trial). This one, with so few people, however seems to swing in the opposite direction and one wonders if this is all chance - that the 4 (yes, 4) people who happened to get celecoxib were unique in some unmeasured way.

On the other hand we have a small, brief, trial of a drug with a well-defined risk profile which showed an effect that isn't anything to sneeze at: 2.3kg difference in just 3 weeks. And unlike the seeming hundreds of uncontrolled open-label trials out there this one can't be as easily dismissed. Longer term trials with many more people are obviously needed - do these trajectories in weight gain/loss continue for longer than a few weeks? Is lean body mass gained/preserved or (like with megestrol) is just fat gained? And does any of this translate into people feeling better or living longer? (Recent post on cachexia research here.)

2)
Annals of Oncology has a review on the use of quality of life/symptom control as end points in advanced cancer trials (of chemotherapy and other anti-cancer treatments). Symptoms and QOL as primary endpoints was rare; few studies discussed powering for QOL/symptoms; methodologic quality (choice of instruments, measuring patient compliance with QOL/symptom measurement, etc.) was poor but, notably, improving since 2000. Most interesting were the authors recommendations for improving symptom/QOL measurement and reporting in such trials, particularly with and eye to helping clinicians better understand and communicate QOL risks/benefits of a treatment:

"More than 80% of the studies reported changes [in symptoms or QOL scores] in group means or medians, with an average determined at baseline for each group, and then at one or more pre-defined times of follow-up. This strategy is sub-optimal for assessment of QoL or symptoms in clinical trials. QoL is the property of an individual and not of a group; it will improve in some patients and decline in others, and will do so at variable rates, so that average values may have little meaning. A strategy that leads to marked improvement in QoL in 50% of patients with an advanced malignancy, while QoL declines in the other 50% due to progression of disease, would represent substantial therapeutic effect, but a comparison of mean QoL scores with baseline might show no difference. Also, some patients will drop out (usually those who are doing poorly), and comparison of a reduced sample at varying times on treatment with the whole sample at baseline, or with the averaged score at baseline for the patients that remain on study, leads to bias that confounds interpretation. The above problems can be overcome by defining criteria for ‘palliative response’ for individual patients and determining the proportion of patients that satisfy it."

3)
Annals of Internal Medicine has a review on new CPR guidelines which looks at some of the debates in the field as well as reviews the evidence which underlies the current recommendations. Despite general acknowledgment of the dismal outcomes for most people suffering cardiac arrests there is zero mention in the paper about cessation of resuscitative efforts, let alone not beginning them, or medical decision making of any form outside of the treatment protocols themselves.

4)
For fellow EBM nerds out there JAMA had a recent commentary on EBM and practice (particularly institution-wide) change. I learned a new acronym (actually this includes elements both of an acronym and an abbreviation): "EBMgt" for evidence based management. (If anyone knows a linguist or similar such person please comment and let us know what such hybrid foreshortenings are called.) I read the commentary and wondered to myself 'well what does this have to do with palliative care?' as most of it was about beta blockers for heart failure etc. However the standardization of evidence based practices is a reality now and demands to 'EB' everything we do will continue. The provision of palliative care services will likely not be exempted from proving such services benefit patients (or, to be cynical, saves someone money) and it's in our benefit to make sure this happens in a reasonable way (see similar concerns in my last post).

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(Monday August 20, 2007: somehow sections #2 & #3 of this post became merged and some of the text was lost - I have tried to restore it by filling in the text as best as I can remember it. This post as it now stands is different that my original version but unless anyone can supply that to me this is how it's going to remain. Sorry about any confusion - Drew.)

1)
JAMA has a commentary on the use of mortality as a measure of hospital quality. The context of the commentary is the increased reporting of hospital mortality rates as supposed measures of quality, etc. The authors examine this, point out some problems, and suggest some solutions. I certainly can't say anything about this better than the authors themselves, so I'll quote them:

"Absent from these discussions is a more fundamental question: what is the quality of care for the 1.16 million individuals who die each year in US hospitals (over 40% of all US deaths)? Deaths from errors and deaths after deliberate decisions not to pursue unwanted life-prolonging treatments are polar opposite outcomes. Conflating the 2 may have unintended consequences of undermining expert palliation of dying patients and rewarding overly aggressive treatment when it is not desired or beneficial."

"Taken alone, short-term mortality measures essentially treat death as a medical failure and reinforce avoiding death at all costs. As a result, short-term mortality measures do not acknowledge the naturalness of death, disproportionately reinforce treatments that prolong life, and potentially discourage palliative care. In addition, the absence of cancer-related mortality measures and the increasing number of mortality measures for noncancer conditions reinforces the erroneous assumption that patients with cancer are expected to die and patients with non-cancer diagnoses are expected to live."

"A major challenge will be to better distinguish patients who are not supposed to die from those dying of advanced chronic illness. This distinction will be best informed not by studying decedents, but by following seriously ill patients over time and determining patient, physician, and system factors contributing to how and when individuals die, including the circumstances that the improved coordination, communication, and symptom control may improve quality of care, but have mixed effects on mortality. This is particularly relevant given the findings that more frequent use of acute care services during the last 6 months of life may be associated with overall worse health outcomes."

2)
Somewhat consonant with the above mortality<-?->quality quandary....

The New England Journal of Medicine has an article about prophylactic whole brain irradiation for patients with extensive stage small-cell lung cancer. The context here is that prophylactic WBI is generally accepted as a good thing for people with limited stage small cell lung cancer but it's less clearly helpful for those with extensive small-cell. This was a randomized, international, multicenter trial of WBI for people with extensive stage small cell lung cancer who had 'responded' (this was poorly defined in the trial) to initial chemotherapy, had good performance statuses, and did not have known brain metastases. They were randomized to receive WBI (various protocols were used) or not. There was no standardization of imaging before randomization or even at baseline staging after diagnosis; nor were people imaged in any standard way after treatment - only if they developed symptoms.

Findings: mortality outcomes, as expected for small cell cancer, were dismal but better in the WBI group. Median survival difference was a little over a month (6.7 months vs. 5.4 months) and 1-year survivals were 27 vs. 13% in the WBI and control groups, respectively. Symptoms were worse in the WBI groups (fatigue, hair loss, appetite loss, nausea/vomiting, leg weakness) but overall quality of life/global health status scores were similar between groups, as measured by the EORTC QLQ-C30. (These were all secondary outcomes in the study and so it's unknown if the study was adequately powered to show QOL differences.) So WBI seems to improve survival by a little over a month but doesn't improve QOL (and worsens some symptoms). The authors conclude that prophylactic WBI should become the standard of care for all extensive stage small cell patients who respond to chemo but given the lack of standardization in this trial (of protocols, of scanning, and even of defining 'response to chemotherapy'), and lack of improvement in QOL, I'm not convinced.

3)
American Journal of Gastroenterology has a controlled trial of long-term polyethylene glycol (PEG 3350 or 'MiraLAX') laxative use for constipation. The 600+ patients were healthy adults who had chronic idiopathic constipation (2 or fewer BM's a week plus either straining, hard stools, or sensation of incomplete evacuation at least 25% of the time, and not caused by drugs or a medical condition). They were randomized to either 17gm daily of PEG or placebo and followed for 6 months. The primary outcome was defined as >50% of weeks patients had 3 or more BM's, no use of rescue meds (bisacodyl), and no more than one of the associated straining/hard stools/incomplete evacuation symptoms). So, basically, the outcome was did PEG increase people from 2 or fewer tough stools a week to 3 or more decent stools a week at least half the time? We're not exactly talking catharsis here.

They found that PEG was much more effective than placebo (with minimal side effects including electrolyte abnormalities) - 52% of the PEG subjects achieved the primary endpoint as compared to 11% of the placebo patients.

Why am I mentioning this article at all? To be honest it's because I'm having a rare moment of pedantry because, at least where I practice, PEG seems to be the most widely misused laxatives. Notably, I see the above dosing scheme (17gm daily) frequently used as monotherapy for severely medically ill patients who do not have chronic/idiopathic constipation: it's drug induced (opioids, anticholinergics, chemo, etc.), or from general debility (bedbound, sick patients), or multifactorial. Nevertheless patients receive this drug/dose which was designed to get PEG 3350 a FDA indication so that it can be marketed to healthy adults who poop twice weekly to get them to poop thrice weekly. My sense is that because it's PEG which at higher (hundreds of grams at a time) can cause catharsis and is used for bowel preps for colonoscopy etc. that some people assume it's a 'big gun' and don't realize 17gm is 'gentle.' Certainly PEG has a role along with other osmotic laxatives in treating constipation in the medically ill (I've not seen it studied in this population - however I've yet to look) but it's role is not as a monotherapy and not at 17gm a day. Despite this I have seen it used more and more as monotherapy for even opioid-induced constipation and I've been devoting more time to 'discussing' this with housestaff, etc.

I desperately try to avoid coming off as pedantic on this blog, so I apologize, but I hope many of Pallimed's readers can appreciate the passion that is sometimes needed to prevent and ameliorate one of our patients' most frequent and troublesome symptoms.

4)
And finally - the AAHPM's new CEO, Steve Smith, has started on the job, per this announcement. The same announcement also notes candidates for the AAHPM board election - all around a very strong list - that includes my friend, collaborator, and all around good guy Dr. Christian Sinclair who's running for for a Director-at-Large spot. Good luck Christian. If anyone wants to talk with Christian as to why he's running leave a comment or email him at ctsinclair at gmail dot com and I'm sure he'll get back to you.

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The July issue of Pediatrics has an article about NICU decision making for terminally ill newborns. In the past few years there has been a bit of a media sensation because of the Dutch tackling the very tough issue of medicines and technology potentially prolonging the life or death of newborns that are unlikely to survive. It started when a NICU in the Netherlands came up with euthanasia guidelines for terminally ill newborns. For most readers of Pallimed, it should be well known that euthanasia and physician-assisted suicide are considered legal and acceptable medical practice in the Netherlands. I give credit to Dr. Verhagen and his colleagues in studying end-of-life decision making in the NICU. This is an area that palliative care has really not addressed as a profession in a systematic way. I would love to see more literature on this subject, because without discussion in an open forum, we risk compromising care and ethics.

The study examined 30 deaths at 2 NICU's over 6 months in early 2005 (out of 423 admissions; mortality rate of 7.1%). The date is actually important for this study because it was started only a few months after much of the media attention about euthanasia in newborns. (An interesting socialized medicine point. Only 10 NICU's are allowed in Holland by law to concentrate specialists and treatments. No ECMO at either, no heart surgery at one.)

The study was a retrospective chart review, complemented with interviews with the physicians at an unspecified amount of time after the death. 28 of the 30 deaths were after withholding or withdrawal of life support measures. 2 deaths were with maximal curative treatment. No deaths were considered to be due to the administration of medications with the intent of hastening death, although 5 patients did receive paralytics (neuromuscular blockers).

In the discussion section the authors do discuss the use of neuromuscular blockers to prevent gasping in the infant and the emotional trauma to the parents. The parents had actually requested a medication to prevent gasping from occurring in 3 of the cases. The authors make the reasoning that despite this being a possible scenario for hastened death, that if the request is persistent it should be granted. I find this contrary to most medical ethical judgments. Just because someone is persistent does not change the ethics of the situation. The basic bioethical principles are not autonomy, beneficence, non-maleficence and persistence. They also did not classify these deaths as hastened deaths, which I think could be open for debate, although the degree or the time frame which they contributed to death could be arguable as well.

The authors did look at time from decision to withhold or withdraw life support and actual orders placed, as well as the dynamic process of decision making in the ICU. They illustrate how EOL decisions actually start with withholding treatment and then move to withdrawing treatment, and all decisions can make an impact on the final outcome.

For neonatologists and pediatric palliative care colleagues, I think this is a very important article to bring to journal club and to discuss the many ethical challenges in pediatric/neonatal palliative care.
Pallimed Tidbits (aka Potpourri or maybe Pal-pourri?)

-Grand Rounds for Medical Blogs has a few good posts on caring for the dying patient. Topics include: GSW in the OR, death of a family friend, and death in the ED. If you do read these posts, feel free to leave a supportive, educational, empathetic comment or just even a 'thanks for posting this'. It could be one of the many nice things you did today.

-You can even find palliative care mentioned in the most unique situations, for example this blogger who is dealing with considering palliative care options for the family hamster. Sometimes the definition of family can be very broad.

-I don't ever think I have seen such a high service rate for a hospice. 55% of the deaths in the community served are helped by a single hospice. That is pretty impressive when you often hear the 30% range for hospice services of all dying patients. Any Pallimed readers know of a higher percent service rate?

-And lastly, for any Wikipedia fans out there (especially contributors). There is currently a debate about why the Hospice page redirects to the Palliative Care page. Some Wikipedians are trying to create a page dedicated to Hospice and seperate out the two concepts. If you want to hop on over and write an article for little credit or recognition, but realize that many, many people will read it, sign up to be a Wikipedia contributor.

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Back when I was a novice nurse, in 1980, I worked at a community hospital in Washington, DC. The favorite analgesic of one of our oncologists was Levo-Dromoran (levorphanol). The reason was that it was a little more potent than morphine, but more importantly it had a longer duration of action. I have only a vague recollection of how frequently we dosed it, but I think it was every 6 hours.

I moved on from that hospital after 3 years, and haven’t seen levorphanol ordered in all those intervening years (of course, extended release morphine became available in the ‘80’s). In 2003 there was an article in NEJM titled “Oral opioid therapy for chronic peripheral and central neuropathic pain.” (Free full text of older research articles; must register) Kathy Foley had an accompanying editorial extolling the trial results for demonstrating opioid responsiveness in neuropathic pain. If you didn’t read the article, you wouldn’t know that the study drug was levorphanol. At the time I remember thinking, “Why the heck would they select levorphanol for this study? Nobody uses the stuff!” (I guess somebody must, otherwise it wouldn’t still be on the market). Recently, however, there have been 2 articles on levorphanol in major palliative care journals. Are we about to see this drug resurrected?

Eric Prommer reviewed the pharmacology of levorphanol in Supportive Care in Cancer and suggested that it shouldn’t be overlooked as a step three analgesic. McNulty presented a case series in the Journal of Palliative Medicine in which levorphanol was used successfully as a rescue analgesic when other opioids, including methadone, were ineffective or produced unacceptable side effects [McNulty’s paper has an odd title. “Intractable” and “refractory” are sometimes used interchangeably, although I tend to think of intractable as worse than refractory. I’ve never before seen one of these terms used as an adjective for the other.]

In a very small nutshell, the advantages and disadvantages of levorphanol:

• Has been shown to be responsive in both peripheral and central neuropathic pain syndromes (small number of central pain patients, with response not much higher than would be expected from placebo); no studies comparing levorphanol with other opioids
  


• Multiple analgesic mechanisms: strong affinity for mu, delta, and kappa receptors; NMDA antagonist; serotonin & norepinephrine reuptake inhibitor
  


• 4-8 times more potent than morphine (per Prommer: suggested starting dose when switching from another opioid: 15:1 – 12:1, based on oral morphine equivalents [OME]); (per McNulty: 25:1 – 12:1 based on OME, using a table of decreasing ratios as OME increases, similar to methadone tables [examples here])
  


• Oral to parenteral ratio of 2:1
  


• Can be administered via oral, intravenous, subcutaneous, and intramuscular routes; not sublingual
  


• Not metabolized via cytochrome system, so relatively smaller risk of drug-drug interactions, especially compared to methadone

• Relatively long acting, dosing every 6 hours, possibly longer in some patients
  


• Accumulates, so all the usual precautions, including waiting 3 days between dose changes

• Anticholinergic properties similar to morphine
  

• Neurotoxic 3-glucuronide metabolite with symptoms (sedation, irritability) seen in the higher dose ranges
  


• Relatively slow onset, so not a good choice for breakthrough pain
  

I have a couple of concerns about levorphanol making a comeback, and they have little to do with the drug itself, at least directly. The first is that this is another relatively unique opioid which could be dangerous in inexperienced hands. The second is that there is a very, very small clinical research basis for using levorphanol. I suspect that widespread use could reveal additional warts as well as benefits.

I’d be interested to hear from our readers about any clinical experiences you may have with levorphanol.

Analgesic trivia:
What was the first oral sustained-release morphine product? Most people would say MS Contin, but that’s because Perdue Frederick had good marketing folks. MS Contin came out shortly after Roxane’s Oramorph, but MS Contin was color coded (all dose sizes of Oramorph are white) and quickly eclipsed Roxane’s just-as-good and less expensive product (yeah, I’m old enough to remember all that)

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Two from the latest Journal of Clinical Oncology & one from Lancet Oncology.

1)
First is a randomized controlled trial of donepezil for cancer fatigue. I briefly mentioned these results as they were presented at ASCO, but will look at them closer here. The trial involved ~110 advanced cancer patients (average age 56 years, women with breast cancer predominated, median ECOG performance status 2, median fatigue 7/10) who reported fatigue of at least 4/10 on a 0-10 scale; they were randomized to 5mg of donepezil daily for 7 days. Results: patients improved modestly after a week with both placebo and active treatment - there were no differences between the groups for any outcome as well as side effects. Highlighting the power of the placebo effect (or perhaps these patients' desperation to feel better) almost all patients in both groups elected to continue donepezil in an open labeled fashion at the end of the trial.

As a side note this study was a pleasure to read and I wish more trials were presented like this: succinct intro & discussion, straightforward assessment scales, results focus on the primary outcome and don't present 5 tables of difficult to interpret secondary outcomes. One doesn't have to slog through 2 pages of results to figure out what's important - many papers seem to present every scrap of data (tabulated different ways) and are annoying to read.

The one major concern I have with the findings are that one week and 5mg may not be sufficient. While doubtful, it's conceivable that 10mg daily for 3 weeks would be effective - in using donepezil for dementia it can take some time to determine efficacy. Anyone out there using this (I'm not)?

This study was from the MD Anderson palliative group & this is the second controlled trial they've published in as many years that found negative results for interventions which looked good in open-labeled trials. It reminds me of link #3 below about cancer cachexia research moving slowly - part of the reason there may be a perception that the field is moving so slowly is because there are dozens of open-labeled "trials" which have exciting, "promising" results which don't stand up to the rigors of randomization and control. All hype, no pay-off.

2)
There's also a study looking at cancer patients' attitudes towards potential conflicts of interest in their physicians (while in phase I trials). It involves survey results of adults receiving chemotherapy trials at the University of Chicago and was interesting to me for a couple of reasons. The main findings - patients care about both financial and intrinsic (the researcher's career, peer respect, etc.) conflicts of interest and generally feel they should be disclosed but also generally feel that this wouldn't change their decision to enroll in a trial - seem pretty straight-forward.

What was notable was the patients' general perceptions of research: nearly half believed patients in research received better medical care and nearly a quarter believed their physician cared more about the research than them! You could interpret this in a lot of ways but one wonders if there's a subset of patients enrolling in trials because they feel they'll get better/more attentive care (the ugly flip side of this being their fear their doctor won't provide proper care for them if they disappoint him or her by not enrolling). Is this the case? I don't know, although it seems reasonable to think that fear drives people to enroll in phase I trials (particularly the first-in-humans ones) as much as hope or a desire to help others by furthering science....

(And for you fellow armchair EBM pundits there's also an all too believable article about how common underpowered research is presented at meetings, usually without comment.)

3)
Lancet Oncology has a news article about why progress in treating cancer cachexia has been so slow. It reviews the dismal state of the science now and summarizes in a manner much more eloquently that I've been able to on this blog my thoughts about megestrol:

"The only other choices we currently have are megestrol acetate or glucocorticoids”, says Marks. Both drugs improve appetite and energy intake but have severe toxic effects. Furthermore they do not restore muscle mass, so any effect on quality of life is short lived. In fact, they both increase muscle proteolysis, and any weight gain is caused by accumulation of fat or oedema. As Tisdale observes, “megestrol acetate is the most used approach to clinical management and therapy for cachexia, not because it works, but because there is nothing else”.

...As well as some of the barriers to cachexia research (including a general lack of funding in supportive cancer research in general).

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An appeals court decision in DC has setup the potential for a very important Supreme Court hearing on the rights of the terminally ill. The court ruled 8-2 against the Abagail Alliance which supports the rights for dying patients to get access to experimental medications. The FDA is opposed to this measure. The finding by the judges stated that the constitution does not guarantee access to experimental drugs that have not been studied enough to be deemed safe and effective. (Read the court brief here.)

One of the cases cited in support of the decision was Washington v. Glucksberg, which is the Supreme Court Decision on the right to assisted suicide case from 1997, that challenged the Oregon law on PAS. The basic result from that decision was no federal/constitutional right exists but that this is a state matter. The Cruzan case is also referenced.

The FDA has a few programs that allow early access to medications before full clinical trials (Phase I, II, III) have been completed. These programs are not deemed to be adequate by the Abigail Alliance given the many hurdles and time needed to get these medications approved. The crux of the argument is that dying patients don't have time to go through a lengthy approval processes, and they are willing to take the risk for potential improvement, so what do they have to lose?

The FDA has argued the 'Pandora's Box phenomena.' Once more access to poorly tested drugs is achieved, proper clinical trials would not be done, and this would put more patients at risk and unsafe drugs would come to market. You have to feel a little sorry for the FDA. On one hand they are getting dunked on the issue of releasing medications to early to market before safety test are done or scrutinized appropriately and they are also getting shelled for not releasing medications fast enough. You can't please all of the people all of the time.

The footnotes are very interesting legal reading, such as how the argument may have different merit if you are arguing 'to save someone's life' or 'to have access to experimental drugs.' Some of the interesting quotes on drug regulation history:

Henry VI’s royal decree in 1447 that gave grocers the power to inspect “anis, wormseed, rhubarb, scammony, spikenard, senna and all sort of drugs belonging to medicine, so as not,
in the buying of these to be hurt in their bodily health.”

“[W]hen the Society of Apothecaries was chartered independently ([in] 1617), its master and wardens were empowered to inspect any pharmacy and to burn before the offender’s door all drugs and preparations they deemed corrupt or unwholesome.”

The judges make a clear point in changing the terms from 'access to life-saving drugs' to 'access to potentially life-saving drugs' which is key in a situation when trials have not concluded efficacy.

In these cases it is always interesting who files aimci curae on behalf of which party. ASCO and the National Organization for Rare Disorders sided with the FDA.

(via WSJ Health Blog)

And a couple of quick ones:

Sid Schwab at Surgeonsblog has three wonderfully written pieces 'On Death.' Take 15 minutes and read them at your leisure. Bring them to your team meeting and read them, discuss them, or just keep them to yourself.

Morphine gets some good press, and some bad press, and its own song. The lyrics to the song 'Lips Like Morphine' has the curious line that seems to contradict the treatment of dyspnea:

I want a girl with lips like morphine,
Blow a kiss that leaves me gasping.

And as of this post we have 400 readers. Thanks to all of you for reading, and subscribing and making Pallimed a great place to post.

Another Pallimed Quiz:

Sorry I missed this very important anniversary, but can anyone tell me what is so important about July 22 in the history of US Hospice and Palliative Care? Shiny silver quarter to anyone who posts the answer in the comments. (PS that was a hint not a promise of a coin)

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It's August, it's hot, I'm jealous of Tom Quinn who has seemed to be on an endless vacation (please give us the details when you get back), my little boy is about to take his first steps, I know all the secrets of the Harry Potter series, and my wee brain isn't working well, so I'm just going to touch on the interesting items cluttering my inbox this week.

1)
The latest issue of the Journal of Supportive Oncology has several notable articles (table of contents here; JSO is always available free online). There's a review on endoscopic procedures for malignant bowel obstructions (both small and large), particularly focusing on the use of self-expanding metal stents. It contains, among other things, a narrative review of the research surrounding SEMS use, and makes a good place to start for those who aren't familiar with their use. Two associated editorials are here & here.

The other article I wanted to mention was another trial looking at fentanyl buccal tablets for breakthrough cancer pain. It was an industry funded placebo controlled trial of opioid tolerant patients (median daily oral morphine equivalent dose of 180mg) which found, shockingly, that FBT provided more pain relief than placebo! What was interesting was that this trial provided further evidence that, at least with buccal fentanyl, baseline opioid dose does not correlate well with effective FBT breakthrough dose (i.e. the more opioids one is on at baseline does not mean one will need a higher breakthrough dose) and all patients need to go through a dose titration phase to find the right dose. Previous posts looking at the same question are here.

Oh and there's also a letter/case series on inhaled lidocaine for intractable cough; not a ringing endorsement of the practice.

2)
The American Journal of Health System Pharmacy has a review on long term trends in long-acting opioid prescribing in hospitalized cancer patients. It's from MD Anderson and, among other things, examines trends before & after their palliative care team was established in 1999. Basically what they found was that after the palliative care team was established, patients were prescribed more long acting opioids, but most of this increase was due to increased methadone prescribing, and overall costs went down because methadone is dirt cheap.

3)
JAGS has a study looking at the natural history of 'frailty' in older men. It is data from a large, multicenter, prospective study which followed ~6000 elderly community dwelling men (mostly in their 70's and 80's). Frailty was defined as: "A man was considered frail if three or more of the following five criteria were present: shrinking/sarcopenia, low activity, weakness, slowness, or low energy...." These criteria were each defined more objectively. 4% of the subjects were frail at baseline and these individuals had a strikingly different course than the 'robust' men: got sicker and died more. By the end of the study (mean follow up 4.7 years) 42% of the frail men had died compared to only 7% of the robust men and frailty was a very strong predictor of mortality (hazard ratio 2.05). Sounds like a perfect target population for early, palliative-care oriented, interventions.

4)
Nature and many news outlets have been reporting about the man in a minimally conscious state who has shown dramatic improvements after implantation of a thalamic stimulator (Nature article - actually it's a letter, Nature news story 1, Nature news story 2, NY Times story). The patient was 38 year old man who had been in a MCS for over 6 years after a traumatic head injury; he occasionally showed some awareness and attempts to communicate but was mostly stuporous. He is now alert much of the time, can verbalize appropriately at times, and can eat orally. He appears to have anterograde amnesia. There's a lot of neuro/MRI chatter in the case report that is too technical for me but it seems he showed imaging evidence of functioning cortex but his arousal system (including the thalamus) was not functioning - thus the apparent success of electrically stimulating his thalamus.

This is just one patient and the wider applicability of this technology may be be small, not to mention how unclear the long term outcomes are at this point. However it seems reasonable to assume we're moving into an era in which long term cognitive impairment (e.g. post strokes and anoxic and traumatic brain injuries) may be treatable (i.e. at least partially reversible with medical interventions other than supportive care & waiting to see if people get better with time which has been pretty much the only available options until now). This may make prognostic uncertainty even more difficult for these patients which will be a challenge and one for which we should be prepared as a profession. Talking through options, weighing uncertainties, identifying values and goals and hopes and helping people make decisions in light of them - these are our strengths in palliative care and as 'disease-modifying' options proliferate for even the sickest of patients these skills will become even more valuable. I hope.

(Image from the Cleveland Clinic's deep brain stimulation patient page.)