JCO issue on supportive and palliative cancer care

Journal of Clinical Oncology recently devoted an entire issue to supportive and palliative cancer care (table of contents for the entire issue here). It is mostly a series of review articles about measuring and improving the quality of supportive/palliative & end of life care for cancer patients.

I wanted to highlight one paper in particular, about the use of aggressiveness of care at the end of life as a quality measure. This is an issue we've discussed before on the blog (most recently here). The current paper is written by some of the researchers who helped develop/define the concept in a research sense (i.e. how to measure 'aggressiveness' of care at the end of life - proportion of patients who initiate a new chemotherapy regimen within the last month of life, proportion of patients whose hospice lengths of stay are less than 3 days, those sorts of things) and the paper is a summary of their work and an overview of the field as a whole.

I was most interested in their discussion of the validity of these measures: are they actually reasonable quality measures? This is what they had to say:

To explore the validity of the measures, we sought to relate each of our measures to the outcome of family members’ satisfaction with quality of care near the end of life. We have examined data from a prospective cohort study looking at patient and family needs among women with hormone-refractory metastatic breast cancer treated at two Canadian regional cancer centers, and limited analysis to the patients who died during follow-up. Family members were asked to complete the FAMCARE instrument within 2 weeks of patient death. FAMCARE is a 20-question survey that asks about satisfaction with symptom control, psychosocial care, information provision, and availability of providers. Among 51 consecutive women who died and had a caregiver complete the FAMCARE instrument, there were trends toward less satisfaction with care when chemotherapy was continued within 14 days of death, death occurred in an acute care setting, or there was no or only a short ( 3 day) hospice involvement. These did not reach statistical significance, however, perhaps because of the small sample size. Interestingly, variability in scores appeared to be mostly driven by the "information giving" and "physical care" subscales of the FAMCARE instrument, suggesting that inadequate communication and symptom management may be associated with aggressive anticancer treatment. A larger validation study is underway in the National Cancer Institute–funded Cancer Care Outcomes Research and Surveillance (CanCORS) consortium comparing these measures with patient and family assessments of the overall quality of care patients with lung or colorectal cancer receive before death.

Well, I guess we'll look forward to the CanCORS results then. It of course seems intuitive that increased aggressiveness of care at the end of life for cancer patients is an indicator of 'poor' quality of care, but there are patients/families who would disagree with that, as well as some patients for whom treatment decisions to be 'aggressive' made sense/were appropriate at the time they were made despite the eventual 'poor outcome' and so defining the proportion of patients for whom aggressive care in the last month of life is inappropriate is going to be tough (10% emergency room visits in the last month good, 20% bad?).

Along these lines, death in an acute care setting is often proposed as a quality measure (increased hospital death implying worse care). One of the problems here is that rates of hospice use vary dramatically and at least partially by geography and hospice availability and I'm assuming that access to inpatient hospice facilities/hospice units is distributed unevenly as well. Given that, there are likely a certain number of dying patients for whom dying in the hospital is absolutely the best place to be (to get symptoms managed etc.). Higher rates of hospital deaths then may reflect more of a lack of access to hospice units (so it's a quality failure regarding equity in access to hospice care but not, for instance, a failure on the part of the patient's doctors/caregivers). In a general sense I'm sure higher rates of hospital deaths aren't a good thing, but the problem with quality measures is that once you create them people (e.g. Medicare, other payors, the JC, etc.) start using them (pay for performance etc.) with unintended consequences.

Anyway, it appears I began to ramble, and none of this is to suggest that this shouldn't be carefully investigated, and it's exciting to look at how people have operationalized this concept, and perhaps the CanCORS study will continue to clarify things.

Quality vs. quantity of life in CHF

The Journal of Heart and Lung Transplantation has a fascinating article looking at treatment preferences in CHF patients. It involved a convenience sample of ~90 patients with CHF (either class II or IV) at a single Canadian center, who were given hypothetical scenarios about treatment options (essentially best medical management, longer life, lingering death; vs. oral inotropes, 4 months of improved symptoms, sudden death; vs. LVAD, improved symptoms and survival, lots of care burdens, lingering death). The basis of this seems to be several trials of oral inotropes which were stopped earlier because of increased mortality in the patients receiving oral inotropes. Despite the increased mortality, patients receiving the inotropes apparently had improved health related quality of life over those receiving best medical care, so the researchers here asked themselves, "Well, is that a reason to stop these trials - maybe some patients would prefer improved symptoms even if it meant decreased survival?" Thus, the current study.

The major findings can be summarized as 1) many patients were happy to take shortened survival if it meant improved symptoms and a non-lingering death and 2) treatment preferences didn't seem to correlate with current CHF severity, symptom severity, or health-related quality of life. While it goes without saying that the scenarios presented to patients were somewhat artificial, the important point here is that there were a substantial number of patients for whom longevity was not the preeminent concern.

This is of course not a surprise, but this paper is written directly at a cardiac research and clinical community and argues research in this population which assume survival benefit as the preeminent treatment outcome is short-sighted, and encourages further scrutiny of oral inotropes as palliative therapy for those patients with quality of life-predominant treatment goals. (Are there any agents currently available? None of the ones they mentioned are commercially available as far as I know. I remember encountering oral inotropes as a resident in research trials but don't know of anything available off the top of my head....)

The other intriguing thing here of course is that preferences didn't seem to be related to current health status or symptoms (the authors had hypothesized that those with the current worse symptoms would be more inclined to receive life-shortening but symptom alleviating treatments). The study wasn't specifically powered to find such a relationship as far as I can tell, however if it exists it is probably not a very powerful interaction. Values may be the more powerful predictor of treatment preferences here.

BMJ series on qualitative research

BMJ has a series of articles about reading, understanding, and appraising qualitative research - a good set for the teaching file. BMJ has a complex online <-> print publishing system which I don't exactly understand and I can't exactly tell which issue these are from (the were all grouped together in a recent table of contents announcement from BMJ) - so here are the individual articles:

1. An introduction to reading and appraising qualitative research.
2. Grounded theory, mixed-methods, and action research.
3. Discourse analysis.
4. Why use theories in qualitative research?
   
5. Ethnography (from the text: "ethnography is the study of social interactions, behaviours, and perceptions that occur within groups, teams, organisations, and communities").
6. Critically appraising qualitative research.
   

Articles 1, 2, and 6 will likely be of most interest to readers of the blog and their trainees. Grounded theory comes up a lot in palliative care research, and I was hoping #2 would be illuminating, but is unfortunately a relatively brief introduction to it. Does anyone have a good overview of grounded theory research and how to interpret it (one that's written for clinicians, and not researchers, social scientists, etc.)?

Pall-pourri

1)
Archives of Internal Medicine has a literature review and discussion on relationship building and good communication skills, with a focus on what can be done in brief patient encounters. (It has a specific primary care focus.) To be sure, the literature is sparse, and this paper mostly discusses it in a narrative fashion, making some common-sense recommendations. I'm noting it because, as an educator, I'm constantly telling my residents/fellows/etc. that good communication does not necessarily mean a huge time commitment (and certainly, anecdotally, it can be a huge time saver - I believe this even though I have nothing to back it up), and so it's good to see a paper specifically addressing the time-issues involved in patient-centered communication.

2)
Journal of Pharmacy Practice has a review article on symptom management of non-motor symptoms in Parkinson's disease (GI symptoms, psychosis, pain, dysautonomias, etc.).

3)
JNCI has a commentary warning about the over-selling of epidemiological findings in cancer research. That is - findings that suggest X 'is associated with' Y, even though there is no experimental evidence to suggest there is a causal link (e.g. coffee consumption is associated with lower risk for liver cancer - findings like that). The article is mostly a critical overview of how, why, and when such associations turn out to be 'wrong' (not causal) and is a good one for the EBM teaching file. The topic is important for a variety of reasons, not least because our patients read sensationalistic (or at least over-sold, uncritical) accounts of these findings and they can create false hope or 'false-guilt' (I caused my cancer because I didn't do enough aerobic exercise, etc.).

Propensity scores in palliative research

Chest has an article about the effects of treatment limitations in ICU patients on prolonged survival. I'm not going to discuss the article itself much: it's also well discussed in the July 2008 PC-FACS (although you have to be an AAHPM member to access it) and in an accompanying editorial in Chest. Instead I wanted to focus on its use of propensity scores, as the article is a good introduction to them.

Some background on the article. It's a single institution retrospective cohort study which compared 60 day mortality between patients for whom there was some sort of order/decision to withhold a life-sustaining treatment in the ICU (e.g. vent, dialysis, pressors, CPR, etc.) and patients who had no such decision/order. Patients who had any such treatment withdrawn were excluded, as well as patients who wanted comfort-only care. There were ~2000 patients in the study; ~200 had a WLST decision. As you'd expect, the WLST patients were older, sicker, with a higher in-ICU and in-hospital mortality than the non-WLST patients (16% vs 2%, 30% vs 5%).

The authors then created a propensity score model to describe the likelihood of having a WLST decision. Propensity scores (PS) are a way to try to minimize confounding differences between groups in observational research. Clearly one cannot do a RCT of WLST decisions. Instead all you can do is watch what happens to those who have a WLST decision and those that don't. Of course there are likely many confounding variables in such observations (things that are associated both with having a WLST decision and with death like being older and sicker - it's not fair, say, to compare these older, sicker patients with the younger, healthier ones and conclude that the WLST decision was responsible for increased mortality). What PS try to do is to mimic a RCT by creating a model which predicts the likelihood of a subject getting an intervention (in this case WLST) then comparing outcomes between subjects who got the intervention or not but who had an equal chance of getting the intervention in the first place (i.e. as if they were randomized to the intervention or a control).

To clarify.... A multivariate model is created from as many data points (hopefully) that the researchers have. This model creates a score (PS) which describes a patient's likelihood - within the cohort - of receiving the intervention (in this case a WLST decision). In this paper it was a 69-variable model and included things like demographics, markers of illness severity, etc. - the model was derived from data from the subjects in this cohort, and, again, predicts a subject's likelihood (propensity) of getting the intervention in question. A simplified example could be: a 67 year old white male with Medicare admitted to the ICU on hospital day 4 with an APACHE II score of 30 and gram negative sepsis would have a PS of X. X being some number which means something to statisticians about how likely this patient is to have a WLST decision in this cohort. (A 53 yo woman with diabetic ketoacidosis and an APACHE II score of 14 would have a lower PS, for instance.) What you then do is take a patient with a WLST decision, derive their PS, then match them as closely as possible to a patient in your cohort who did not have a WLST decision but who has a nearly identical PS. The idea is, again, to mimic a RCT in the sense that - as much as your model is accurate - both of these patients had an identical 'chance' or 'risk' of having a WLST decision and it 'just so happens' that one did and one didn't; you then can fairly compare outcomes. You repeat this matching across your entire sample of WLST patients and you can then compare outcomes between the groups because, ideally, the patients in the WLST group and the non-WLST group had an equal 'chance' of receiving that 'intervention' and so it's fair to then compare the outcomes.

So, to keep things concrete, in this study they took their 200 WLST patients and matched them 1:1 with non-WLST patients with nearly identical PS and then compared outcomes between the groups (which now total 400 patients and not the original 2000). What they found is that despite the now very similar baseline characteristics between the groups (age, demographics, indices of illness severity) the WLST patients had higher mortality in-ICU, in-hospital, at 30 days, and at 60 days (16% vs 6%, 32% vs 12%, 42% vs 22%, 51% vs 26%). (The authors were surprised that the difference in mortality extended so long and there is some hand-wringing about whether or not we are causing 'premature' deaths by WLST - see the editorial mentioned above for some common sense reaction to this.)

The obvious problem with PS is that it all hinges on what is included in the multivariate analysis to derive the PS. Only things which are measured can be included, and so if there are important factors which aren't being measured or included, which could influence the outcome, the model breaks down. (For this study the editorialists points out that in this study clinicians' prediction of prognosis was not included).

Why am I rambling on about PS? They have been proposed and promoted within the palliative care research community as one 'get around' for the fact that controlled trials are often impossible or impractical for our patient population (like for instance this trial, or one looking at the effects of G-tube feedings in dementia, or the effects of early palliative care consultation on some outcome, etc.), and PS have some appeal because they approximate randomization (again, only as well as the models contain all relevant variables, which is a significant issue). They have been discussed in J Palliative Med here, and were the subject of a concurrent session at AAHPM last winter, and I've begun to see them used more often. I have been waiting for a good article to introduce into my program's palliative care-EBM curriculum about PS and this is the one I'm probably going to use (as it's relatively easy to understand and a little controversial which gets people excited and interested).

PS are not without controversy, not only because of the issues mentioned above, but there's some debate whether they actually add anything to 'routine' multivariate analysis; however this debate is quite statistical and well above my head. I haven't found any really good, simple (casually readable) summaries on PS: this one is OK.

The ProVent Prognostic Score: Helpful?

Palliative Care Nurse: "We got a new consult in the ICU. A 55 year old who has been on the vent for 4 weeks with platelets of 75, on levophed and hemodialysis."
Palliative Care Doctor: "Sounds pretty serious. I wonder how he is going to do?"

Have you ever faced this dilemma of prognostication? If so, there is a new prognostic test developed for just this situation. If you are asking yourself, "Where is the prognostic dilemma? I already have a pretty good idea of what is going to happen" then you can go to the head of the class.

A reader sent me a well-executed study demonstrating the development and validation of a prognostic scoring system. This NIH funded study from UNC, Duke, and ECU was completed over 4 years (3 for the development cohort of 200 patients and 1 for the validation cohort of 100 patients).

The researchers choose to study patients requiring prolonged mechanical ventilation (greater than 21 days), a population notable for a high mortality and symptom burden. The reason for the study was noble in trying to enable physicians to have an easy to use, highly specific prognostic score to encourage open discussions about prognosis with patients and surrogate decision makers. They cite two studies in the discussion for the severe lack of prognostic disclosure in critical care situations (12% and 40% (SUPPORT)). (Hint: get a palliative care consult)

They identify the four variables with the highest relative risk: Age older than 50y, vasopressors, platelets less than 150, and hemodialysis. Each is assigned one point to get your ProVent Score. (I give one point for cleverness on the name for the score!) A score of 3 or 4 indicates a roughly 95% one-year mortality risk and a 85% 3 month mortality risk. (Disclaimer:Read the study for more details before you take this information and apply it clinically.)

Do you find this score to be clinically relevant? Would you use it to inform your decisions/prognostic estimates? Would you quote it to the family or patient? How about discussing with other clinicians? Personally, I am not too sure it is clinically relevant. We rarely see patients on vents longer than 21d still in the hospital. They are often already at the long term acute care hospital. I plan to give it a try and see how it compares with my own clinical judgement and that of my peers.

The authors conclude:

"Simple clinical variables measured on day 21 of mechanical ventilation can identify patients at highest and lowest risk of death from prolonged ventialtion."

The best part about actually reading an article is you can come to completely different conclusions (beware quoting abstracts!). For me (and you if you have read this far) the take home points to this article are really hidden and have numerous implications:

for clinical care (to be further validated):

• 40-50% of patients on prolonged mechanical ventilation (more than 21d) will die in the hospital (i.e. consider a palliative care consult trigger to discuss prognosis)
• If you survive the hospital stay, your mortality is only 17% at one-year (Graph)
• If you have a ProVent score of 2 or more you have minimal chances at being alive and independent in all ADL's at one year.
  

for future prognostic studies:

• Obtain clinician estimates for survival as a measure to compare your calculated prognostic score. Otherwise you risk making a score that is no better than current practice (communicated or not).
• Condeming all clinical estimates of survival based on a small handful of poorly designed studies does not qualify statements like "we know that prediction of mortality by clinicians using clinical probability of ICU survival is not accurate." We have too much to learn about the practice of clinical prognostication to come to this conclusion.
  
• Inclusion of the prognostic score is vital as a core part of the research to be examined and discussed amongst peers.
• Clinically relevant prognostic time frames are important and are very situation dependent. Discussing the chance that someone may have a 90% chance of dying within 1 year or even 3 months is not typically being discussed in ICU palliative care family meetings. The range may be hours, days or maybe a couple of weeks.
  

and for ICU studies of mortality:

• Include palliative care consultation and decisions to withdraw or withhold key life support measures as baseline demographic or outcome variables. These two issues could have major repercussions on validity of data sets concerning mortality.
• Consider using the ProVent score to stratify different risk groups in this select patient population.
  

(HT: B. Arnold)
Carson, S.S., Garrett, J., Hanson, L.C., Lanier, J., Govert, J., Brake, M.C., Landucci, D.L., Cox, C.E., Timothy, S.C. (2008). A prognostic model for one-year mortality in patients requiring
prolonged mechanical ventilation. Critical Care Medicine, 36(7), 2061-2069. DOI: 10.1097/CCM.0b013e31817b8925

Making Sh*t Happen: Methylnaltrexone

Methylnatrexone has hit the big time with a very timely publication of a industry funded double-blinded RCT in the New England Journal of Medicine. If you have been in palliative care for the past few years, methylnatrexone has been one of the drugs with some 'buzz' around it at conferences and in publications. We have touched on MNTX a few times here at Pallimed before.

This new study does not add much to previous knowledge about the medicine, but the study is the largest and most comprehensive one to date. Other double-blinded RCT's have already been published (JPSM 2008, Clin Pharm Ther 2000, J Pharmacol Exp Ther 2002, JAMA 2000) showing efficacy versus placebo without affecting analgesia from opioids. The patients were from nursing homes, hospices or palliative care centers and 60-70% were ECOG/WHO 3 or 4 (confined to bed more than 50%)

The participants were already on stable opioid doses, and stable laxative regimens with less then 3 reported BM's in the past week. More than 50% rated their 'constipation related distress' as moderate to severe. This seems to be a somewhat broad inclusion criteria. Constipation can be a very distressing symptom, but there are two types of distress from constipation: psychological distress of not 'being regular' and physical distress from GI discomfort. Many patients with advanced illness may have decreased number of stools for many reasons besides just opioid constipation, and I would propose that a regular number of stools for those with anorexia-cachexia syndrome and decreased functional status may be less then 3 per week. In assessing constipation related distress, managing expectations is part of good clinical care.

Interestingly less then 30% were on stool softeners, but most were on 2 laxatives of some category (stool softener, enema, bulk producer, contact laxative, or osmotic agent). I thought the percentage would be much higher in this population.

Of interest to some will be the oral morphine equivalent doses (OMED) these patients were on. I always find this interesting when seeing studies about hospice and palliative care patients, because opioids have a wide range of therapeutic dosing. The mean OMED was 339mg (+/-1214 )(placebo) and 417mg(+/-787)(MNTX) with a wide range in the study (9-10,160mg of morphine equivalents per day). For those readers who have not worked in palliative care you did read that number right. 10,160mg of morphine equivalents per day. If you ask anyone in palliative care they will probably tell you about the one or two patients they have seen up in that range. Now that would be a case-series to figure out how someone is tolerating those doses.

Sidebar:
As far as drug names go, I find 'Relistor' pretty uninspiring. Methylnaltrexone is fun to say, MNTX is easy to write, Relistor...eh. To me it sounds like a drug to get you back on a transplant list-> Re-listor=Re-lister. Or was Wyeth going for being 'realistic' about your constipation or advanced illness. Maybe they were trying to stay away from names that were too scatological or associated with OTC meds. Relistor just is uninspiring. (Sorry for the sidetrack, I find drug names fascinating.)

BTW the logo is pretty bland too. Come on now another circular logo? Are they trying to replicate the millions of hospice logos with 'embracing circles/hugs?' I would think something coming out of something else would be more representative. Any graphic designers or wordsmiths want to help Wyeth out?
(end sidebar)

I am sure many in palliative care are glad this medication is available and we will probably go through the next few months trying to figure out where it fits in the bowel toolbox. Thomas and the rest of the authors (and Progenics) should be commended for a well-designed research study in a hospice-oriented patient population. It would be a good article to review in a journal club to see how the study was designed and carried out, especially with so many institutions.

Overall the study is a good one, but it should be noted it was industry funded, which is notably very transparent in the article: "Progenics Pharmaceuticals designed the protocol and collected and analyzed the data." Is this part of the beginning of more pharmaceutical industry-palliative care/hospice collaborations? I would be interested to hear from Pallimed readers about their thoughts on the field's collaboration with industry. Is this a new source for funding and advancement of our field? Or is this a 'bogeyman' that is relatively absent from our small but growing field?

Of note there are two good editorials (here and here - sub required) in the issue regarding opioids and constipation.

(Disclaimer: I get nothing from Wyeth. Neither does Pallimed.)

(Advanced apology for the near-swear in the title for those who might be offended)

(Image from same issue of NEJM - not Opioid Induced Constipation)

(I like parentheses.)

Reference:

Thomas, J., Karver, S., Cooney, G.A., Chamberlin, B.H., Watt, C.K., Slatkin, N., Stambler, N., Kremer, A., Israel, R. (2008). Methylnaltrexone for Opioid-Induced Constipation in Advanced Illness. New England Journal of Medicine, 358(22), 2232-2343.

Peaceful acceptance of cancer; Chemo neuropathy; 'Slow medicine'

Two from Cancer:

1)
First is a paper discussing a scale developed to measure peaceful acceptance of a cancer diagnosis. This comes from the Coping With Cancer Study (previous publication here) and the paper describes the development and some of the validation of their scale ('PEACE') which attempts to measure both 'peaceful acceptance' of an illness (e.g. asks things like To what extent do you feel you have made peace with your illness?) and 'struggle with an illness' (asks about what extent a patient feels their life is over as they now know it, what extent they feel it's unfair they have cancer, etc.). They also give some of the findings of the CWCS that I'll note.

First they found that answers to a single item on the peaceful acceptance subscale (to what extent do you believe a sense of inner peace and harmony?) strongly correlated to the entire peaceful acceptance score (i.e. it could be used as a quick and dirty substitute for it). They also report that patients' self-reported awareness of having a terminal illness (all patients in the study had advanced/incurable cancer) was not related to peaceful acceptance of their illness (peaceful acceptance scores were similar between those who acknowledged or didn't acknowledge being terminally ill). (This is similar to findings they reported in the prior publication I mentioned above.) They did find however that patients' reported 'struggle' with an illness was higher in those with a terminal illness acknowledgment (as were, interestingly, rates of advance care planning & living will completion). As you'd expect, reporting being strongly 'spiritual' had a protective effect all around. Higher symptom scores were associated with lower peaceful acceptance and higher struggle.

The conclusion I'd love to make from this is that we have it right in palliative care: honest disclosure of prognosis/terminally ill status doesn't 'hurt' people, symptoms do, so let's keep on telling the truth and treating symptoms. This is one study of course, and I shouldn't overplay these results, but I think from a didactic/rhetorical standpoint it is helpful/welcome to behold some data suggesting that knowing your prognosis doesn't affect your ability to feel peaceful about your condition/lot in life. (These were of course people who freely acknowledged/admitted to having a terminal illness - one wonders how many of them were told this or just figured it out for themselves.)

Of course there's more struggle, but of course there is, and one cannot take away the 'human condition part of the human condition,' so to speak. I think I've blabbed on this blog before that I think the CWCS is one of the most interesting recent research projects out there; it seems to me to be a big leap forward in this type of research (understanding how/why terminally ill patients understand, cope with (or not), their illness and how that affects the sort of care they get) and I hope there will be further publications from the study.

Mack, J.W., Nilsson, M., Balboni, T., Friedlander, R.J., Block, S.D., Trice, E., Prigerson, H.G. (2008). Peace, Equanimity, and Acceptance in the cancer experience (PEACE). Cancer DOI: 10.1002/cncr.23476

2)
Second is a randomized, controlled trial of lamotrigine for chemotherapy associated peripheral neuropathy. It involved 131 patients (mean age 61 years; about 2/3 had finished their chemotherapy) with painful chemotherapy induced peripheral neuropathy with at least 4/10 pain; they were started on lamotrigine (titrated to 150 mg bid over 8 weeks) or matching placebo and were followed for 10 weeks total (only two weeks on the max dose). The results weren't good for lamotrigine: pain was a little better in both groups and both primary and secondary pain outcomes were identical between groups. Lamotrigine had more side effects and more drop outs due to them (this approached but didn't reach statistical significance).

A couple things here: people weren't on the maximum dose of lamotrigine that has been studied and shown to be effective (at least 400mg), however there really was not even a hint of a dose response curve here - it's not that lamotrigine looked a little better but didn't achieve statistical significance - lamotrigine's curve never departed from placebo's (actually it looked a little worse for a bit). I don't use lamotrigine and I'm not sure if 2 weeks on the max dose is enough; however the total time on active treatment was 10 weeks without a hint of benefit (and if this drug takes more than 10 weeks to work is this something we'd want to use anway?).

This did get me thinking: what are people using out there as the 2nd line antiepileptic adjuvant (after gabapentin or pregabalin which I'm assuming most people are using - one or the other - as their 1st line AED adjuvants)? It also got me thinking: has anything been shown to be an effective therapy for painful CIPN (in a controlled trial)? EPERC recently published this Fast Fact about it and my recollection when I was editing it is that there's a dearth of controlled data.

3)
The New York Times has a story about 'slow medicine,' focusing on a care-model being developed at a nursing home in New Hampshire. 'Slow medicine' really means deliberately and pro-actively defining care-limitations up front in elderly patients in light of their goals and prognosis (i.e. it's also 'good medicine' and shares palliative care's ethos of 1) honesty about prognosis, 2) focusing on care goals, and 3) explicitly giving people all their care options including limitations on testing/hospital level care/etc.). This is a really telling excerpt:

Kendal begins by asking newcomers whether they want to be resuscitated or go to the hospital and under what circumstances. “They give me an amazingly puzzled look, like ‘Why wouldn’t I?’ “ said Brenda Jordan, Kendal’s second nurse practitioner.
She replies with CPR survival statistics: A 2002 study, published in the journal Heart, found that fewer than 2 percent of people in their 80s and 90s who had been resuscitated for cardiac arrest at home lived for one month. “They about fall out of their chairs when they find out the extent to which we’ll go to let people choose,” Ms. Jordan said.

"Fall out of their chairs...": apparently these patients weren't used to being offered options/choices about their care.

Thanks to Kathleen Jacobs, RN for alerting me to this article.

Evidence and palliative care; hydration reviewed, sort of; opioid antagonists for OBD

1)

Over here at Pallimed we’ve been having an off-line conversation about “evidence” for palliative care-related practices, and decided to bring it to our readers. The impetus for the discussion is the publication of two new Cochrane reviews, one on medical hydration in advanced illness and the other on mu-opioid antagonists for opioid-induced bowel dysfunction.

Regular readers of Pallimed will know that the three of us are strong proponents of increasing and improving the evidence base for palliative care. We are also very much aware of the difficulty of doing so, especially using the stricter definitions and methods of evidence-based medicine (EBM).

I will disclose that I am not a regular devotee of the Cochrane reviews, but “medically assisted hydration” caught my eye. I was disheartened, however to see that only 5 papers made the cut to be reviewed, and that the conclusion was “There are insufficient good quality studies to make any recommendations for practice with regard to the use of medically assisted hydration in palliative care patients.” It reminded me of a conversation a couple of years ago with a well-known pain physician and researcher. He told me that he doesn't even read Cochrane reviews anymore. "They all end with the same conclusion: there is insufficient evidence to make a recommendation about . . . " I don't think that is necessarily a bad thing, but they are super-strict in their criteria for selection. That makes it particularly difficult in palliative care, where doing the type of research one might do for approving a hypertension agent is almost impossible. The issue, of course, is that the assumed “highest” level of evidence is the randomized controlled trial (RCT). Some have argued that RCTs are not only difficult to design and conduct, but may be unethical in interventions for people with advanced disease where comfort, not cure or control, is the therapeutic goal. Others criticize the misuse of EBM, either attempting to apply broadly the results from a trial in a subset if patients, or conversely denying payment for a successful intervention for a specific individual because the RCT “proves” that the intervention doesn’t work. Fragile patients with advanced disease are usually excluded from RCTs, yet that is precisely the population most in need of evidence-based palliative interventions.

The phrase “perfect is the enemy of good” springs to mind. But the RCT is unlikely to ever be the “perfect” tool for symptom management, population-based or public health studies, and other complex beyond-the-physiology questions.

Carr, an early proponent, points out that EBM continues to evolve, has limits, and can easily be misused. Where applicable, the RCT should be used, but with the results interpreted judiciously for specific populations and individuals. Hallenbeck, Carr (specifically for pain medicine), Aoun & Kristjanson, and Devery are among those who have made reasoned criticisms of EBM, and suggested “other ways” of using EBM or of gaining knowledge. These include an “Equity-based evidence framework” (Aoun & Kristjanson), “narrative-based” evidence (Devery), or recognition that “lower” (not necessarily less rigorous) levels of evidence apply quite well to palliative care.

We’d like to hear how our readers use and interpret “evidence” in their practice of palliative care.

2)

Getting back to the Cochrane reviews:
Hydration: there was only one “high quality” study (2 RCTs) but over a very short duration (2 days) and very underpowered. Overall, results of the 5 studies reviewed were somewhat contradictory, but showed suggestions of improvement in sedation and myoclonus. Negative effects cited were fluid retention leading to peripheral edema, ascites, and pleural effusion. In their conclusion, the authors acknowledge the difficulty of conducting clinical research in the palliative care population. They also comment “the issue of medically assisted hydration in palliative care patients causes such divergent views, yet there are so few studies to guide clinical practice properly. As well as looking at further RCTs in this area, the evidence base will be improved with at least more prospective controlled trials.” It should be noted that the "best" study had quite a few patients with reasonably good performance status, especially in the intervention group. It was not really helpful, therefore, in answering the question: "is medically assisted hydration a helpful intervention in patients in the last days of life?" One of the included studies, a prospective controlled trial, attempted to mimic real world decision-making by allowing physician preference in allocating to the intervention arm. This introduces bias,of course, but downgrading the score on the study design because of it may make some clinicians grind their teeth. The whole point in reading a study is to find help in making real world decisions, isn't it? That raises questions for a future conversation.

Opioid antagonists for opioid-induced bowel dysfunction (OBD):
Naloxone, nalbuphine, methylnaltrexone, and alvimopan were reviewed. There was only one study of nalbuphine. All studies were placebo-controlled RCTs (which makes sense in this case; active-controlled studies would also be welcome). Some studies of the newer agents (methylnaltrexone & alvimopan) were in healthy volunteers. The authors report that their task was made more difficult by use of various opioids in trials, and by inconsistent definitions of postoperative ileus. In general, though, they found (in a limited number of studies with small numbers) that methylnaltrexone and alvimopan were sufficiently safe and effective (increased transit time/decreased constipation) to be labeled “promising.” It should be noted that methylnaltrexone was administered parenterally in these trials, and that oral methylnaltrexone has yet to be reviewed. Alvimopan trials were interrupted because of excess cardiac events. The current target indication for alvimopan (not yet approved) is postoperative ileus.

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Just as an aside, the last author on this review is Dan Carr, cited above in the EBM discussion.

There is another recent review here.

A just-published RCT was not part of either review. Subcutaneous methylnaltrexone (Relistor) was approved by the FDA last week for patients in late-stage advanced illness and should be available next month.

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So, who among our readers is waiting impatiently for methylnaltrexone to become available? Given the route, cost, and limited research, are you eager to give it a try? In general, are we adequately treating opioid-induced constipation, but need this for backup? How will you determine which patients receive it? How many other interventions do you need to go through before you determine that constipation is r