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e-Session n 539000 - 8th September 2020

Nausea and vomiting in advanced cancer

Dr Bosnjak: Hello, good afternoon. Greetings from Belgrade. Thank you for joining us. I appreciate the
opportunity to be able to share with you this presentation. I'm joined by my distinguished colleague,
Professor Karin Jordan. And thank you Karin for joining us. We will be discussing the topic together and
answering your questions. I'd like to clarify at the beginning, that I'm not going to cover bowel obstructions,
since this has already been covered by Dr Carla Ripamonti, and you can find her excellent presentation at
the e-ESO website. So, I'd like to start this presentation with this slide, showing the general approach to
patients with symptoms of advanced cancer, and we find it very useful in our daily practice. We start with
evaluation or a comprehensive assessment of the symptom, to clarify potential etiology, followed by
education, to explain to the patient and caregivers, what is the cause of the symptom and what are we
going to do to manage to it. Then management is based on a personalized treatment plan, which includes
both pharmacologic and non-pharmacologic measures. And it is followed by monitoring. I'd like to say here
that attention to details and holistic approach is really essential for every successful symptom
management. Symptom assessment, in fact, starts with screening, with routine screening. At our institute,
we screen all patients with advanced cancer for the presence of symptoms. And when symptoms are
reported, you have to evaluate cancer and its treatment, to distinguish, for example, between cancer
related and treatment-induced nausea and vomiting. Clinical features of nausea and vomiting. And I'm
going to discuss it later. And finally, the patient. Collect details from history, physical examination,
laboratory analysis, imaging studies, ask about comorbidities, concomitant medications, and finally, explore
the whole patient experience of the symptom and symptom-related distress. This is the Edmonton
Symptom Assessment Scale that we use for screening. This is a patient reported-outcome-instrument with
eight scales. For "eight", the most common symptoms of advanced cancer. And "one", general question
about best well-being. And symptoms are reported on a zero to 10 scale. The zero means no symptom and
10 means worst possible symptom. I'd like to say here that the prevalence of nausea and vomiting in
patients with advanced cancer in all patients, is between 20 to 30%. And it is the highest among those with
advanced gastrointestinal and gynecological cancers, up to 70%. I would also like to say here that with this
instrument, you can also capture other associated symptoms, like pain or lack of appetite or anxiety, which
can help you to understand the cause of the symptom. So, after this short introduction, I'd like to start the
more specific parts of my talk with definitions. Nausea is a subjective experience. This is an unpleasant
sensation of needing to, or being about to, vomit. And can occur alone or can accompany vomiting.
Vomiting, on the other hand, is an objective clinical sign. This is a forceful expulsion of gastric contents
through the mouth. Clinical features of nausea and vomiting are very important, since they provide clues to
the underlying etiology. So, first of all, how severe the symptom is? Is it acute or chronic? When does it
happen during the day? Only after meals? Only in the morning? Only after head motion? How was it
previously treated? Are there any associated symptoms? And it's very important to ask about the presence
of constipation. Constipation is a frequent cause of nausea and vomiting in patients with advanced cancer.
And finally, you have to explore the whole patient experience of the symptom, and nausea and vomiting-
related distress, originated not only in the body, but also in the mind and spirit. These are the common
causes of nausea and vomiting, listed on this slide. And starting from systemic ones, such as organ failure or
other metabolic causes, different medications, or infection or some toxic substances. Through local causes,
for example, related to the central nervous system, such as in patients with brain involvement, or vestibular
system. Migraine, anxiety and pain also belong here. And finally local causes are related to the
thoracoabdominal organs, like myocardial infarction, for example. And I'd like to say here that anything,
any infection, inflammation, irritation of the GI mucosa can trigger nausea and vomiting. In addition,
anything that disrupts motility. For example, poor motility, like in gastroparesis, or compression or
obstruction, either gastric or bowel, as well as severe constipation can trigger nausea and vomiting. And
this is a quite long list of causes. And I find it helpful to group them in this way. So, just to remind you that
you can ask questions. You can send your comments at any time by using Q and A button and chat-box at
the bottom of the page. So, I'd like to move-on to pathophysiology. Pathophysiology of vomiting is well
understood. It is shown on this slide. Vomiting signals are transmitted to the vomiting center in the brain-
stem via four emetic pathways: Vestibular system, cortex, chemoreceptor trigger-zone, and periphery or
thoraco-abdominal organs. Chemoreceptor trigger-zone lacks blood brain barrier. And therefore, it is
capable to detect different toxic substances, metabolic influences, as well as drug in systemic circulation or
in CS fluid. And when these inducers are detected, then the signal is sent to the vomiting center. In the
vomiting center, signals are processed and integrated. And then vomiting reflex is initiated. In contrast with
vomiting, little is known about the pathophysiology of nausea. Nausea is probably mediated by different
mechanism. And one proposed mechanism is a disturbed gastric rhythm. So, my message from this slide is
that nausea and vomiting seem to be physiologically different. And that vomiting is not simply a more
severe nausea. Nausea and vomiting are mediated through different neurotransmitters. Receptors for
these neurotransmitters are present in these four stimulating parkways, as you can see on this slide. As
well as in the vomiting center and in the effector pathways. So, our strategy for pharmacologically manage
nausea and vomiting, is to block receptors for these neurotransmitters. So, these are the main
neurotransmitters involved in the emetic reflex. And I'd like to say here that Dopamine, Histamine and the
Acetylcholine are more important for nausea and vomiting in advanced cancer. While Serotonin and
Substance-P are more involved in treatment-related nausea and vomiting, such as chemotherapy or
radiotherapy-related. What is also important here is to say that nausea and vomiting are not only
physiologically distinct, but they seem to be also pharmacologically distinct. Because current anti-emetics
are more effective against vomiting than against nausea. So, I'd like to move-on to management now. First
of all, to successfully manage nausea and vomiting, try to identify the cause. And if it is reversible, fix it. In
accordance with the principle, treat the treatable, or correct correctable. And this is so called etiological
approach. For example, treat bowel obstruction with surgical intervention or stenting. Treat hypercalcemia
with bisphosphonates, Uremia with dialysis. Or correct cerebral edema with Dexamethasone. If you can't
fix the cause, if the cause is not reversible, or while waiting for specific treatment to start working, help
your patients with anti-emetics that are recommended with the guidelines. And this is so-called empirical
approach. Always, explore non-pharmacologic measures. And correct the consequences of nausea and
vomiting, such as dehydration or hypokalemia for example. This is the list of medications that are
recommended for the treatment of nausea and vomiting in advanced cancer. Metoclopramide, Haloperidol
and Levomepromazine are all first line agents, recommended by the guidelines. And they are all mainly
anti-dopaminergic agents. Metoclopramide, for example, also has direct pro-kinetic properties. Olanzapine
blocks multiple receptors. And it is now gaining more attention in palliative care. And I'm going to talk
about this later. The exact mechanism of anti-emetic action of Dexamethasone is not known. But
Dexamethasone reduces edema around tumor and also in the bowel wall. And therefore, it can be used for
nausea and vomiting-related to the central nervous system involvement and increased intracranial pressure
or gastric or bowel, either, compression or obstruction. H1-antagonists are used when nausea and vomiting
are related to the vestibular system. And further 5-HT3 receptor antagonists are considered second line
agent in the nausea and vomiting-induced by advanced cancer. General guidelines for the use of
medications for the treatment of any symptom also apply here. If the symptom is chronic, is persistent,
then you should schedule your medications. And provide regular doses around the clock and rescue doses if
needed. You have to select the appropriate route of administration, having in mind that oral route may not
be possible in patients with nausea and vomiting. So, try alternative routes, like subcutaneous or IV, or
transdermal or even rectum. Guidelines recommend monotherapy for nausea and vomiting-induced by
advanced cancer. So, use one agent and titrate the dose-effect or tolerance. And if that agent is ineffective,
then use another with a different mechanism of action. Adding another seems to be better than switching
medications. And always treat associated symptoms. Again, you can ask questions. You can send
comments. And we will answer and discuss them at the end of my presentation. So, these are the
MASCC/ESMO guidelines for the management of nausea and vomiting in advanced cancer published in
2016. There is an update on the MASCC website from 2019. The anti-emetic drug of choice in advanced
cancer is Metoclopramide. Of course, provided complete bowel obstruction is excluded. Alternative options
include Haloperidol, Levomepromazine or Olanzapine. And I'd like to focus now on Olanzapine. Olanzapine
as I mentioned before, is now gaining attention also in palliative care. It is an atypical antipsychotic. It has a
broad spectrum of activity against different neurotransmitters, involved in the emetic reflex. As you can see
here. And two studies have been recently published in advanced cancer. One last year, and the other this
year. The first study was a prospective, non-randomized study in 40 patients who received 10 milligram of
Olanzapine daily, at bedtime, for five days. And Olanzapine has been proved to be effective in the majority
of patients. The difference was statistically significant even after one day. And also, on day seven. However,
dose had to be reduced in three patients due to adverse events. Mainly sedation, fatigue and dizziness. The
study published this year in JAMA was randomized study with also, a small 1 in 30 patients, who were
randomized to receive either five milligrams of Olanzapine or Placebo. And the Lancet showed a statistically
significant increase in nausea and vomiting, with no excess sedation or any other adverse events. So, based
on the results of these two studies, Olanzapine could be recommended as an effective anti-emetic for
short-term management of nausea and vomiting in advanced cancer. But I would say that the trial
comparing Olanzapine with established Metoclopramide or Haloperidol is still needed. This one slide on
opioid-induced Emesis. According to MASCC/ESMO, no recommendation can be made about specific anti-
emetics. Opioid rotation, route-switching are effective approaches. And there is no data to support
prophylactic, anti-emetics or opioid-induced Emesis. I'd like to finish with non-pharmacologic measures.
They are effective and should be provided either alone or together with anti-emetics. Some measures are
really common-sense approaches. Like modifying meals, or food, or environment to reduce aggravating,
exacerbating factors. And some of them are measures of complimentary and integrative medicine. These
methods were mainly studied in treatment-related nausea and vomiting. Especially chemotherapy-induced
nausea and vomiting. But their benefits in palliative care are currently uncertain. So, to conclude, nausea
and vomiting is distressing, challenging and multi-causal syndrome. In order to successfully manage it, try
to identify the cause and treat it if reversible. If not or while waiting for the specific treatment to start
working, relieve nausea and vomiting with anti-emetics that target neurotransmitters involved. Guidelines
are always there to help you. So, be guided by the sidelines. And assess the whole person, alleviate whole
symptom-related distress. And I would like to conclude by saying that you have to rely on your team, and
provide multidisciplinary care. So, thank you for the opportunity to present this to you and sorry for the
troubles at the beginning. I believe we are going now to answer some questions.

Dr Jordan: Yes. Dr Bosnjak, thank you very much for this really great presentation. And for this
comprehensive overview. It was perfect. And I think there are a lot of questions from the audience. And if
you allow me, I would like to start with one question, and I will read it. Do you find ESAS useful in everyday
practice in the evaluation of nausea? Meaning the Edmonton Symptom Assessment Scale. Do you think it's
useful in everyday practice?
Dr Bosnjak: Yes, I think it is. We use it every day. And [Audio Not Clear] and nausea is reported with zero to
10 scale. Patients find it easy and easily understandable. And what is also nice in ESAS is that with this
instrument, you can also reveal other associated symptoms. And then the pattern of different symptoms
together can guide you towards the cause. So, I think it's really useful. We use it every day. And it's also well-
validated in palliative care.

Dr Jordan: Indeed, indeed. So, Snezana, just your estimation about other symptoms. So, do you think this
might be sometimes a kind of cluster. For example, if a patient has nausea and vomiting, so, many patients
also have pain. Or is it usually a kind of separate symptom?

Dr Bosnjak: No, exactly. It's all about clusters. And if someone has nausea and vomiting and abdominal pain,
then we should explore, is it a bowel obstruction ongoing or constipation? Yes. It's about clusters. Or for
example, patients with cachexia, they do have persistent nausea and fatigue. And lack of appetite. So, yes.
And these clusters are easier to capture when you have ESAS to systematically kind of assess the presence of
symptoms, systematically screen.

Dr Jordan: Okay, yes, indeed. So, I just received another question, which I would like to ask to you. What is
your opinion on the role of 5-HT3 receptor antagonists, in the treatment of nausea in patients, with advanced
cancer?

Dr Bosnjak: So, regarding 5-HT3 receptor antagonists, they are considered second line medication in the
MASCC guidelines. I think that their use is theoretically justified. 5-HT3 receptors are present in the GI tract
as well as in the chemoreceptor trigger zone. So, theoretically, yes. But I'd like to say here that their efficacy,
at least in the acute phase, in the CINV, is based on the fact that there is a massive destruction of
enterochromaffin cells and massive release of serotonin after chemotherapy. I'm not aware of such situation
in advanced cancer. It may be the case in bowel obstruction. And for example, I found in German guidelines,
palliative care, that 5-HT3 receptor antagonists are recommended for bowel obstruction. But definitely, the
setting of nausea and vomiting in advanced cancer is different. And currently, 5-HT3 receptor antagonists are
recommended only if first line agent, anti-dopaminergic agents are contraindicated or ineffective.

Dr Jordan: Yes, that's really true. And just I would like to add, as you just mentioned, with the 5-HT3 receptor
antagonists, we have also to consider one significant side effect, which is constipation in bowel of the patient.
So indeed, involve obstruction. It's difficult to use. And Snezana just one question, which I would like to ask
you as well. When it comes to opioid-induced nausea and vomiting, so, what I hear is often that my colleagues
use indeed 5-HT3 receptor antagonists. What is your opinion to treat nausea and vomiting coming from
opioids? Is it effective or rather take Metoclopramide?

Dr Bosnjak: Well, again, the mechanism for opioid-induced Emesis is complex. It is a result of their action
both on the bowels, as well as on the chemoreceptor trigger zone. This is the mechanism. And again, there
is a theoretical justification to use 5-HT3. But there are no studies around that. And 5-HT3 receptor
antagonists, as you said, their adverse event is constipation. Again, adverse effects of opioids have different
side effects on bowels. And I would not personally use 5-HT3 receptor antagonists for opioid-induce Emesis.
I think our clinical experience is the greatest with Metoclopramide and also Haloperidol. Because Haloperidol
mainly acts at chemoreceptor trigger zone. And Metoclopramide acts on both. Plus, Metoclopramide has
direct pro-kinetic properties, which is nice. Because opioids-induce gastroparesis, and inhibit the whole
bowel intestinal system. This is a well-known opioid-induced effect on intestinal system. And constipation is
just one part of it.

Dr Jordan: Indeed, indeed. So, I just received a question from ??Demo Mano??, which I would like to read.
About Metoclopramide, actually. What is the appropriate dose of Metoclopramide in the management of
nausea and vomiting in advanced cancer? Is it current in the recommendation of giving 30 milligrams per
day, enough for symptom control in this setting?

Dr Bosnjak: Yes. I would say, no. It's not enough. Be used to use 40 or 60. You can give Metoclopramide
before every meal, and at bed time. And then PRN, we used to give between 40 and 60. But yes, currently
EMA is saying only 30. I don't think it's enough. I don't think it's enough.

Dr Jordan: Yeah. This also refers to the studies, which was done mainly by Richard Gralla. In the early '70s
received high-dose Metoclopramide, in chemotherapy-induced nausea and vomiting. And the dose was just
enormous.

Dr Bosnjak: Yes, when I start working, based on these studies from Richard Gralla, I used to give patients
these doses. Like one milligram per kilo. Or even 1.5, 2 milligrams per kilo. So, very high doses of
Metoclopramide. Because in these high doses, Metoclopramide blocks 5-HT3 receptors. This was before
specific 5-HT3 receptor antagonists were discovered.

Dr Jordan: Yeah. But like the EMA actually recommends 30 milligram of Metoclopramide per day. Do you
give them other doses? I must say, in our hospital, we stick to the 30 milligrams of Metoclopramide per day,
due to this recommendation. Or do you have other views of that, Snezana?

Dr Bosnjak: Well, I think we stick to the palliative care guidelines.

Dr Jordan: Yeah, yeah, yeah.

Dr Bosnjak: So, we tend to give between 40 and 60. I must say, yes.

Dr Jordan: Okay. So, that's another question. Could you comment on the use of corticosteroids in the
treatment of nausea and vomiting? And specifically, on the duration of a therapy of Dexamethasone and the
doses? So also, very practical and important questions.

Dr Bosnjak: Yes, the exact mechanism of anti-emetic action or Dexamethasone is not known. We believe that
Dexamethasone could reduce edema around tumor. And also, in the bowel wall. So, we use it. And
Dexamethasone is indeed recommended. For example, in the NCCN palliative care guidelines for nausea and
vomiting-induced by increased intracranial pressure. So, in patients with brain involvement. Then in gastric
outlet, either obstruction or compression. For example, when you have enlarged liver due to liver metastases
or abdominal tumor mass that causes gastric outlet obstruction, or compression. Also, in bowel obstruction,
Dexamethasone is used after Octreotide and anti-emetics to decompress bowels. Either from the pressure
outside or also to decompress, to reduce bowel wall edema. But these are mainly clinical situations where
we would use Dexamethasone. And regarding the dose. Doses are different. Whether you are in Europe or
in US. I think they are between 8 and 20 milligrams per day. So, what are your experience for does?

Dr Jordan: Actually, we try, actually, the lowest dose as possible. And just to give an example, we usually
start with 8 milligrams. And then try to taper-down to 4 milligrams. Because when we do a long-time
treatment, we do have concerns regarding the side effects of Dexamethasone. Like the caching symptoms,
or the myopathy, the proximal myopathy. And these are very unpleasant symptoms. So, our experience is
actually 4 milligrams, for let's say then, 10 of 14 days. And I'm aware of studies in other symptoms. Let's say
the fatigue studies, which were done in the MD Anderson Cancer Center. If I remember correctly, but Snezana
please, correct me. I think it was 8 milligrams for 14 days.

Dr Bosnjak: Yes. This is the study of Eduardo Pereira and his team. 8 milligrams for 14 days for fatigue. And I
would say that 8 milligrams for 14 days is quite safe. And this was also shown in that study when
Dexamethasone was compared to placebo. So, yes, I would say that dose for two weeks.

Dr Jordan: Yeah. So, again, another question from Demo, again. First, thank you for your comprehensive
answer. And if there is some more time left. Yes, we do have time left. I would like to hear your opinion on
whether there is place for the combination of Metoclopramide and Olanzapine, as there has been some
concerning data about the safety of this combination. So, do you combine it?

Dr Bosnjak: Well, we don't usually combine Metoclopramide and Olanzapine. We use either, or. But, if one
is ineffective, then you can add. You can add another. Maybe, if I started with Olanzapine, I would add
Metoclopramide. If I need some pro-kinetic properties, but again, Olanzapine could block some. Because pro-
kinetic is based on anticholinergic action. And then Olanzapine could block that effect. So, we usually do not
combine Metoclopramide with either Haloperidol or Olanzapine.

Dr Jordan: Yeah. And just coming from your broad experience, Dr Bosnjak, what do you think about
combining Olanzapine and Dexamethasone? It's an analogy to chemotherapy-induced nausea and vomiting.
Would this be suitable? Or would you rather avoid this combination?

Dr Bosnjak: I think it depends on clinical situation. For example, we have a good experience with using
Olanzapine for nausea and vomiting-induced by brain involvement, especially for patients who have nausea
and vomiting associated with vertigo-dizziness.

Dr Jordan: Yeah.

Dr Bosnjak: So, if this is your clinical situation, then we would combine Olanzapine and Dexamethasone. They
act by different mechanism and can help a patient in that clinical situation. But in analogy with
chemotherapy-induced nausea and vomiting, we did a study with ??Dr Pereira?? and his team and showed
that when we added Dexamethasone to Haloperidol in patients with advanced cancer, it generally didn't
produce benefits. So, it is not a rule. But if you have such clinical situation where decompression with
Dexamethasone could help, like in bowel obstruction or in CNS involvement, then yes, I would combine it.
Because both medications have different mechanism of action. But not as a rule. The difference between
nausea and vomiting-induced by advanced cancer and CINV, is that here guidelines mainly recommend
monotherapy. Not a combination of therapy, like we do in chemotherapy-induced nausea and vomiting. So
again, instead of thinking, what shall I give? Try to think about mechanism. And then how different
medications fit into that proposed mechanism.

Dr Jordan: Yes, yes. Very true. So, another question. Very interesting, also, an important question. Snezana,
in patients with constipation and with nausea and vomiting, related to constipation, while waiting for
constipation to resolve? Which anti-emetic would you recommend in this setting?

Dr Bosnjak: Well, certainly not 5-HT3.

Dr Jordan: Yeah.

Dr Bosnjak: Certainly not. Then, if this constipation is still not creating fecal impaction, you have to do
radiography of the abdomen to exclude fecal impaction. If there is still a room for move the bowels, then I
would use Metoclopramide. If you are afraid that it's not just constipation, but fecal impaction, and you don't
want to move the bowel and create, for example, cramps, then I would use either Haloperidol or Olanzapine.
But with this category of patients, we try Metoclopramide and, unless and if patient doesn't have cramps,
then we go with Metoclopramide. If yes, then we switch to either Haloperidol or Olanzapine.

Dr Jordan: And just coming back to the guidelines. Or guidelines or in other symptoms as well, is there any
role of Octreotide in this setting?

Dr Bosnjak: Octreotide has a central role in nausea and vomiting-induced by bowel obstruction. Because it
is an antisecretory agent. But again, the topic for today was not bowel obstruction. But in the guidelines, yes.
Octreotide is recommended in the MASCC guidelines together with specific anti-emetics. And guidelines
recommend Haloperidol in this setting. I would say Olanzapine would also be effective. Yes, Octreotide in
bowel obstruction. Or also in gastric outlet obstruction, yes.

Dr Jordan: Yeah, true, true. So, any other questions from the audience? So, anything Snezana you would like
to add to our very nice discussion?

Dr Bosnjak: Well, I would like to thank ESO for the opportunity to present this topic. And I would like to thank
you Karin, for joining us. And for being with us. And of course, all participants for asking questions, and
enabling our session to be so interactive.

Dr Jordan: Yeah, and thank you Snezana for doing this very, very nice presentation. It was a great pleasure
to join this ESO session. And thank you to the participants for this really nice discussion. And for all the
questions we received, I think it was very, very interactive. And I really enjoyed it.

Dr Bosnjak: Yes, me too.

Dr Jordan: Thank you very much. And what shall I say? Have a nice evening. And see you soon in class
Snezana.
Dr Bosnjak: Thank you. Thank you all.

Dr Jordan: Thank you. Yes.

Dr Bosnjak: Bye-bye.

Dr Jordan: Bye-bye.