Lung cancer chemotherapy - Iressa is back.

Iressa / Gefitinib was the great white hope on the lung cancer scene about 6 years ago, then faded into obscurity for a while. The problem was that the ISEL study did not demonstrate that this oral chemotherapeutic agent ( a tyrosine kinase inhibitor) was better than placebo in terms of survival benefit. There was, however, evidence of tumour response. That is, tumours seemed to get smaller, but people didn't live longer.

Further studies have demonstrated benefit in more select patient groups - much to the relief, I am sure, of AztraZeneca. The drug has recently been licensed in Australia for use in patients with locally advanced or metastatic non-small cell lung cancer if their tumours express activating mutations of the epidermal growth factor (EGFR) tyrosine kinase.

The IPASS trial, conducted in Asia, demonstrated that, in patients with a previous light smoking or non-smoking history, who had mutations of the EGFR tyrosine kinase and who had not received previous chemotherapy, Iressa was superior to a combination of carboplatin/paclitaxel in terms of disease free survival (9.5 vs 6.3 months). The INTEREST trial demonstrated equivalency of Iressa when compared with docetaxal in patients with locally advanced or metastatic NSCLC who had previously received platinum-based chemotherapy.

It's noteworthy that Iressa is now indicated as a first line chemotherapy in appropriately selected patients (ie those meeting the above criteria). Tarceva/Erlotinib, another EGFR tyrosine kinase inhibitor, is still only licensed for patients whose NSCLC has progressed in spite of first-line platinum based chemotherapy (ie second line). As far as I am aware.

It is bound to become more clear, over the next few months / years, exactly which patients do benefit from these medications - and others like them. Perhaps this will even give us a clearer indication of prognosis in patients with lung cancer.

Andrew

To nap or not to nap?

The concept of sleep inertia has presented it's self to me a couple of times in the past few weeks. Once when I mentioned to a sleep scientist that I am like 'a bear with a sore head' if I have a day time nap (the cause most likely sleep inertia). Another time was when I was talking to an emergency services worker, discussing the pro's and con's of napping during night shift. I also saw a promo for a morning show that was airing a segment on 'Napping the key to health and happiness' but I missed watching this.

So what are the pro's and con's of napping?
One of the cons can be sleep inertia. This is especially relevant to emergency services workers who may take naps during night shift. Sleep inertia is bascially a temporary state of lowered arousal occurring immediately after awakening from sleep and producing a temporary decrease in cognitive performance. Sleep inertia can be influenced by factors such as the duration of prior sleep, and the sleep stage prior to awakening. Abrupt awakening during a slow wave sleep (stage 3 and 4) episode produces more sleep inertia than awakening in stage 1 or 2, REM sleep being intermediate. Studies have demonstrated that sleep inertia can last from 1 min to 4 h but usually last around 15 to 30min. The practical implications for those working in our emergency service is that being woken to respond to an immediate emergency gives them no time to recover from the effects of sleep inertia. Being awaken for deep NREM sleep has been shown to decrease reaction time which is highly dangerous for those driving (fire and ambulance crews) and health professionals responding to an emergency.

Conversely, the benefits of a power nap (15 to 30 minutes) have been well document as a way to ward off fatigue and improve cognitive function. There is still a level of sleep inertia but this can be minimised by a short nap (stage 1&2) and having adequate time to 'wake up' after this nap before preforming any important tasks.

Health and Safety recommendations such as these from the Queensland Government reinforce this with recommendations sleep inertia can be minimised for workers who are on-call for emergencies by the following steps;

• Minimising naps taken at work that exceed 40 minutes; and
• Planning for recovery times of up to 30 minutes for workers who may be subject to sleep inertia, before they are to perform hazardous tasks.

Jessica

Home sleep study update

A couple of years ago, in 2008, there was a moment of angst in the sleep-medicine specialist field, when Medicare decreed that they were no longer going to pay for home sleep studies.

At that time, there was no ‘item number’ to cover a home sleep study. The place of home sleep studies in the diagnosis and management of obstructive sleep apnoea, let alone other sleep disorders, had been examined in only a few studies in the literature and there was not a consensus from the community of specialist sleep physicians as to how and when these studies should be done.

Nevertheless, home sleep studies could be done and were being done. Aggressive expansion of home sleep study business models, some industry-driven (ie CPAP companies) and some physician-owned, was occurring. And it was occurring in the country.

From where I sit (that is, in Hamilton) the reason given for this expansion didn’t really hold water. City based specialists and companies were saying that home sleep studies needed to be done because patients such as mine needed access to services. Reading between the lines, that meant that it was easier to stay in the big cities and to negotiate with a chain of pharmacies to put 200 home sleep study devices in towns around the state than to negotiate with hospital administrators to set up state-of-the-art sleep labs, and to back them up with specialist consulting services. The resulting service was limited. The development of skills in regional centres was scant (pharmacy staff trained to put on leads). Medicare fees were drained from the country back to Melbourne, rather than reinvested locally (for example, in a local medical practice or sleep lab). When things got tricky, country people still had to travel to the city to see a sleep specialist. And the impression was given that sleep studies are easy. Like getting your blood pressure checked.

In spite of the above uncertainty, a review of the evidence did suggest that home sleep studies were useful in people with a very high clinical probability of having severe obstructive sleep apnoea. After careful consideration, we decided that it was a service that we should carefully offer, and so we established a handful of home sleep study outlets in our region. We considered the distinctives of our service to be; a sleep specialist reviewed every referral to ensure that a home sleep study is appropriate, prior to authorising performance of the home sleep study; analysis and reporting of the sleep study occur locally (it can’t be assumed that sleep study analysis for home sleep studies in Australia even occurs in Australia any more, with at least one of the major providers of home sleep studies outsourcing analysis of data to sleep scientists in India); the reporting sleep specialist always analyses the raw data (not just the analysis summary provided by the scientist); sleep specialist clinical review is available locally if required.

When Medicare declared a moratorium of sorts on home sleep studies I thought that sounded reasonable. Of course, with substantial business under threat the big providers of home sleep studies negotiated hard for an allowance to continue to provide home sleep studies as they already were. And that permission was granted, in October 2008, although with a much lower fee from medicare for the service, while the whole area was carefully reevaluated.

The Medical Services Advisory Committee has just reported to the Minister for Health after an evaluation of all the literature related to ‘unattended’, or home based, sleep studies. Eighty studies were identified, evaluating home sleep studies performed in ‘non-specialist’ (for example a GP clinic or pharmacy) setting, a ‘referral setting’ (ie referred to a specialist for the study) and a paediatric setting. (14, 60 and 6 studies applicable to each setting respectively).

The document reads:

The Committee recommended funding of Type 2 (unattended) studies in patients >18 years of age once within a 12 month period with the following conditions.
(a) the patient is referred for the investigation by a medical practitioner who has formed a reasonable clinical view that the patient has a high probability of having OSA
*[(b) the necessity for the investigation is determined by a qualified sleep medicine practitioner (as defined in the explanatory notes to the MBS) prior to the investigation;] [*referred study]
(c) a qualified sleep medicine practitioner has:
(i) established quality assurance procedures for the data acquisition; and
(ii) personally analysed the data and written the report;
(d) during a period of sleep, the investigation is a recording of a minimum of seven channels which must include continuous EEG, continuous ECG, airflow, thoraco‐abdominal movement , oxygen saturation; and two or more of EOG, chin EMG and body position.
(e) interpretation and report of the investigation (with analysis of sleep stage, arousals, respiratory events and assessment of clinically significant alterations in heart rate) are provided by a qualified sleep medicine practitioner based on reviewing the parameters recorded under (d) above.


The home sleep study service which we provide, and the business behind it (for example, who reports the sleep study, and how carefully is the data analysed by the sleep specialist, all of which is invisible to the ‘consumer”) meets all of the above requirements. We will continue to provide this service.

A home sleep study service in country towns does not, however, live up to our goal of providing a regional sleep medicine service which is equal to anything available in the major cities. Excellent inpatient sleep laboratories and availability of clinical expertise in sleep medicine (doctors, nurses, psychologists), along with access to therapeutic devices such as CPAP at reasonable prices, are all required. We’ve achieved a lot in this regard over the last 4 to 5 years, but there’s more on the agenda.

Andrew

Chill out and sleep

The title of this blog could refer to a couple of areas of sleep hygiene. One being body temperature and sleep, while the other relaxation and sleep. The former will be discussed.

Body temperature is an important factor in sleep onset. A drop in body temperature normally happens 1 to 1.5 hours prior to falling asleep. As the core body temperature drops (only a matter of .5 to 1 degree) people begin to feel sleepy signaling its time for bed.

One hypothesis is that in some insomniac subjects their core body temperature remains higher than is necessary to initiate and maintain sleep. Studies have been conducted looking at sleep and core body temperature throughout the night. It has been demonstrated that the trough in temperature occurs prior to the longest sleep period and studies with insomniacs show they may may be a limited ability to cool the core body temperature sufficiently for optimal sleep.

What does this means in a particle sense.

• taking a hot bath 90 minutes prior to bed may help reduce core body temperature, as once out of the bath temperature will drop quickly. Make sure this in not immediately prior to bed as there needs to be sufficient time for the bodies temperature to drop.
  
• Avoid strenuous exercise immediately prior to bed
• take notice of when you feel sleepy in the evening and heed these cues

Jessica

Tablets for OSA?

Are there any new treatments on the horizon for obstructive sleep apnoea?

Well, yes … and no. One reason we follow up our patients who have significant obstructive sleep apnoea is so that we can offer them the benefit of alternative therapy if they are unhappy with CPAP therapy. While there are no particularly exciting new options available at present, occasionally a paradigm-changing treatment possibility comes along. If there were a simple treatment available in tablet form for obstructive sleep apnoea, a treatment that caused no side effects, wouldn’t that be terrific?

Now, there’s no reason to get particularly excited – but I think some cause to be interested – in the results of a trial of two tablets, Ondansetron and Fluoxetine – which was published in Sleep journal at the start of this month.

Each of these medications works on serotonin receptors. Serotonin is a neurotransmitter – a chemical messenger between nerves. It is found in many places in the body. The authors of this study commented particularly on two of these sites, and their associated effects.

Firstly, serotonin in the brainstem can promote muscle tone in the muscles that dilate the upper airway when we are awake via 5-HT2 receptors. Secondly, other serotonin receptors (5-HT3) in the ‘nodose’ ganglion (great name) promote REM-related apnoea (cessation of breathing in REM sleep). The hypothesis was that if they could stimulate the former and block the latter receptor then they might be able to effectively treat OSA.

So they randomized 44 patients to treatment with either placebo, placebo plus ondansetron (which is an anti-nausea tablet and blocks 5-HT3 receptors) or fluoxetine (5-HT2 receptor agonist/stimulator and antidepressant) and ondansetron, in two doses – lower and higher.

Interestingly they found that the treatment was very well tolerated, and that treatment with the highest dose of medications in combination led to a reduction in apnoea-hypopnoea index of 13 respiratory events per hour, or 40.5% from baseline, by day 28 of treatment. There was no change on the placebo or ondansetron alone, and a tend towards change on the low dose combination.

I think these results represent a very interesting direction in investigation, which needs to be developed much more fully. Characteristics of patients in whom such a treatment may be beneficial will need to be clearly defined, and it certainly is too early to be recommending this treatment to anyone.

Serotonin agonists are commonly used in treatment of depression, and those of us who report sleep studies consider the possibility that they might have an impact on the severity of sleep-disordered breathing we observe while reporting (as well as on sleep quality in general). I suspect, however, that within a few years we will be treating some OSA patients with tablets that have minimal side effects.

Andrew

Sitting verus supine vital capacity

Whilst working in Mt Gambier recently one of our Respiratory Physicians, Dr Borta asked me to measure a patient’s supine vital capacity which is one of our less common noninvasive respiratory function test measures.

Evaluation of diaphragm strength can be accomplished by measuring the vital capacity in an upright or sitting position followed by a measurement made in the supine position.

Here Lisa, one of our Respiratory Nurses demonstrates the supine and sitting positions.

It is well established in healthy volunteers that lung volume and vital capacity decrease after moving from the upright to supine position. This phenomenon is thought to be due to the shifting of blood to the pulmonary vasculature, changes in the position of the diaphragm, and the weight of the abdominal viscera pressing against the diaphragm. In healthy adults, the FVC falls by approximately 7.5 ± 5.7%.This change is exaggerated in many patients with severe diaphragmatic weakness, though it has not been well evaluated in Amyotrophic Lateral Sclerosis (ALS) patients, the assessment of ΔFVC has been suggested as a screening test for diaphragmatic weakness.
Interpreting an increased reduction in vital capacity in the supine position as diaphragm dysfunction should be made cautiously if the patient’s body mass index is greater than 45 kg/m² as a reduction may not indicate diaphragm dysfunction, but rather an increase in the resistance to diaphragm descent.

Lechtzin et al. studied 25 patients with ALS and demonstrated that supine FVC is an excellent measure of diaphragmatic strength in patients with ALS. It is apparent that the diaphragm becomes weak well before the upright FVC is reduced but using the supine FVC < 75% predicted as a cutoff is a highly sensitive and specific measure of diaphragmatic weakness. Longitudinal studies need to be performed to determine whether supine FVC is a better predictor of future outcomes than measures currently in use. It is not known whether early detection of respiratory muscle weakness and intervention leads to improved outcomes in ALS but it will allow interventions to be developed that target mild respiratory impairment.

Vanessa

An evening @ Portland Sleep Lab

On Monday night I had the opportunity to spend a few hours at the Portland Sleep Lab working with Gerri. I have been there many times but never when the lab has been operating.

For those who have never been to the Portland District Hospital, where the sleep lab is based, the picture provided shows the wonderful view that can be seen from some rooms in the hospital. Not a bad place to spend a night!

Apart from the great views, the Portland Sleep lab is equipped with sophisticated technology. Operating the latest version of profusion (sleep study software package). Since January this year when the E-series from compumedics was installed the communication process between Hamilton and Portland sleep labs has been streamlined.

It's fantastic for Western Victoria to boast two high quality sleep laboratories operating within this region. Next on the agenda is a sleep laboratory in Dimboola to service our patients that come from the Wimmera.

More information about this in the coming weeks.....

Jessica