Immunotherapy Complications & Nutritional Challenges · The Royal Marsden An example of...

The Royal Marsden

Immunotherapy.June2019 1

Immunotherapy Complications & Nutritional Challenges

Lucy Eldridge

Dietetic Team Leader, Royal Marsden NHS Foundation Trust

Chair of BDA Oncology Specialist Group

June 2019

The Royal Marsden

Outline of session

1. What is immunotherapy

2. What are the side effects of immunotherapy

3. GI toxicity

4. Case study

5. Future recommendations

Immunotherapy.June20192

Best Supportive

Care

Surgery

Chemotherapy

Immunotherapy

Radiotherapy

Nutrition is part of the cancer pathway

– Malnutrition can occur at any

stage

– Good nutrition has a role

throughout the pathway

– Arends J, et al. Clin Nutr 2017;36:11–48

Nutrition is important.Dec184

Arends et al, 2016

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Prevalence of overt malnutrition by cancer site: PreMiO study

Malnutrition defined as MNA score <17 (N=1925); M0 = stage I–III, M1 = stage IV

Muscaritoli M, et al. Oncotarget 2017;8:79884–96.

5

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Weight loss & symptom burden at diagnosis

151 new patients (122 GI & 29 Lung) – symptom burden at diagnosis

33% lost ≥10% body weight in 6/12 prior to presentation

Khalid U, et al. Support Care Cancer 2007;15:39–46.

6

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Fearon K, et al. Lancet Oncol 2011;12:489–95.

7

Cancer Cachexia

Identification of nutritional issues is vital

Nutrition is

important.Dec18

8

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What is immunotherapy?

• Cancer immunotherapy—treatments that harness and enhance the innate powers of the immune system to fight cancer (Cancer Research, 2019)

• Immune checkpoint inhibitor therapies are a novel group of monoclonal antibodies with a proven effectiveness in a wide range of malignancies:

• Melanoma

• Renal cell carcinoma

• Non-small-cell lung cancer

• Urothelial carcinoma

• Hodgkin lymphoma

• Under investigation at present is their use in:

• Gastrointestinal

• Head and neck



www.roche.com

1. Mutations in cancer cells

cause the release of

antigens

2. Immune cells that

specialise in locating the

antigens & taking to T cells

3. T cells become primed by

the antigens & so begins

the immune response

against cancer cells

4. T cells travel back to the

tumour

5. T cells infiltrate the

tumour to attack it

6. T cells recognise the

cancer cell due to the

antigens

7. T cells destroy the cancer

cells leading to cell death

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An example of immunotherapy treatment: Nivolumab

• a fully human IgG4 PD-1 immune checkpoint inhibitor

antibody

• a type of immunotherapy drug designed to target the PD-1

Protein receptor.

• Cancer cells send a signal to the PD-1 via the PD-L1 molecule,

tricking the T-cell into recognizing the cancer cell as normal.

• Designed to disrupt that signal &

expose the cancer cell to the immune

system.


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Which patient will respond? (Cogdill et al, 2017)


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Toxicity related to immunotherapy

Immune cell rich

barrier tissues:

– Lungs: pneumonitis

– Gut: Colitis

– Skin: rashes

– Many other –itises

High dose steroids

Infliximab

Autoimmune prone

tissues:

– Endocrine system:

Subclinical hypothyroidism

Fulminant type 1 DM

Hypoadrenalism


Immune checkpoint therapy: bystander tissue damage (immune cell

rich), tissues prone to auto immune attack

Josephs , 2018

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Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment

and follow-up†

Haanen et al. Ann Oncol. 2017;28(suppl_4):iv119-iv142. doi:10.1093/annonc/mdx225

Toxicity related to immunotherapy


From: Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for

diagnosis, treatment and follow-upHaanen et al Ann Oncol. 2018;29(Supplement_4):iv264-iv266. doi:10.1093/annonc/mdy162

Gastrointestinal toxicity guide (ESMO, 2018)Immunotherapy.June201915

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Grading of Diarrhoea & Colitis (Marin-Acevedo et al, 2018 & Haanen et al, 2018)


Gra

deDiarrhoea Colitis Suggested diet but

?evidence

1 Increase of <4 stools per

day (over baseline (OB))

Asymptomatic

(pathological or

radiographic findings

only

To avoid high fibre &

lactose for 2 weeks

2 Increase of 4-6 stools per

day OB; not interfering with

activities of daily living

(ADL)

Abdominal pain; mucus

or blood in stool

As above for 3 days –

if no improvement

follow the advice for

G3

3 Increase of ≥7 stools per

day OB; incontinence;

hospitalisation; interfering

with ADL

Abdominal pain; fever;

change in bowel habits

with ileus; peritoneal

signs

Refer to

gastroenterology & rv

diet: NBM/clear fluids/

PN

4 Life threatening

consequences (eg.

Hemodynamic collapse)

Life threatening

consequences (eg.

Perforation, bleeding,

ischemia, necrosis,

toxic megacolon)

As above

5 Death Death

The Royal Marsden Immunotherapy.June201917

Jo’s story

– 51 year old man

– Diagnosed 2009 Stage IV Mucosal melanoma

– Surgery

– 2012 metastatic disease liver & lungs

– Treated with Temozolomide

– May 2013 commenced CHECKMATE037 trial

– March 2015 continues Nivolumab two-weekly

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Nivolumab

• a fully human IgG4 PD-1 immune checkpoint inhibitor

antibody

• a type of immunotherapy drug designed to target the PD-1

Protein receptor.

• Cancer cells send a signal to the PD-1 via the PD-L1 molecule,

tricking the T-cell into recognizing the cancer cell as normal.

• Designed to disrupt that signal &

expose the cancer cell to the immune

system.


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Aug 2016 diagnosed with immune related colitis

Admitted due to:

1) Admitted with grade 3 colitis secondary to immunotherapy • Severe abdominal pain• Change in bowel habits

2) Portal vein thrombosis

3) Deranged LFTs - improving

4) Steroid induced hyperglycemia - started on Insulotard

5) Thrombocytopaenia

6) Leg weakness - likely steroid induced proximal myopathy


Dietetic Input

– Early Sept 2016

• First met due to Steroid

Induced Diabetes

• Lost 10kg due to

diarrhoea related colitis

• Asked to keep a food &

bowel diary

• Self restricting some

fibre

• History of IBS which he

self managed

• Given refined sugar

advice

– Diet History

– BF Rice Krispies & milk

– Toast & butter

– L Soup, ham sandwich, plain low fat yogurt

– EM Fish & cream potato

– banana


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Dietetic Input

30th Sept

• commenced on PN due to D+ to allow for bowel rest• Required a bespoke bag due to Mg needs and to reduce Na

7th Oct• reduced PN due to concerns over LFT’s (note: were deranged from

admission)

• advised Soft diet & concentrated supplements

• Steroids increased due to colitis


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PN and immunotherapy colitis

Limited evidence although included in algorithms such as the ESMO

guidelines (2018)

A review of IBD & acute colitis literature suggests:

• PN fails to show benefits compared to enteral feeding

• Increased adverse effects with PN

• Increased length of stay

• Increased costs

(Pham et al, 2015; Seo et al, 1999; Triantafillidis et al, 2013)


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Dietetic Input

October 2016

• Muscle atrophy increases

• emphasis on high protein foods

• doesn’t want any supplements

• cautious about food


Energy Requirements

– A 80kg patient would require

2000 – 2400kcals

Nutritional Support November 201624

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Increasing fat energy intake

Food Kcals

1 tablespoon olive oil 135

1 tablespoon clotted cream 115

1 tablespoon peanut butter 130

1 tablespoon mayonnaise 100

1 tablespoon French dressing 70

1 teaspoon butter 75

1 tablespoon Greek yogurt 45


Fat:CHO Ratio’s


Protein Requirements

– A 80kg patient would

require 80 – 120g

protein per day

(potential 160g/day)


Oral Nutritional interventions


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Dietetic Input

Oct 16 – June 17

• Remained an In patient, social issues, requires high input.

• Intensive rehabilitation – due to muscle atrophy secondary to steroid

use for colitis

June 2017

• Eating well

• Bowels opening 3-5 times a day but not indicative of malabsorbtion

• Further weight loss


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Dietetic Input

Early July 2017

Discussions between teams re PN – differing opinions.

Consideration for surgical intervention

Ended up on PN and following a “light diet”

Mid July 2017

Open total Colectomy & end-ileostomy

Weaned off PN

Eating & drinking well

Given salt advise


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Today – October 2018

• Latest MRI shows no evidence of relapse or active disease

• Finally home – a year in hospital & a further year in rehabilitation

Nutritionally

• Weight stable

• Normal appetite

• Some diarrhoea but manageable


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Reflections….

• Complex series of events: • compromised nutritional status, • steroid induced diabetes & muscle atrophy, • impact of immunotherapy on body composition combined with colitis

• Low fibre guidance is not conclusive – in the literature guidance is vague especially for moderate to severe colitis• Descriptions used for fibre restrictions need clarity:

• Light, soft, low etc.

• Melanoma is not routinely on a dietitians radar


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What food means…

Nutrition is important.Dec1833

Harmful

Hope

Control

Comfort

FearEnjoyment

Anxiety

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Coming soon…

• It is recognized that there is a need for national guidelines for GI toxicity. A group of gastroenterologists have formed a working party led by Dr Nick Powell.

• He has invited the Oncology Special Interest Group (BDA) to add a dietary component to the guidelines

• They also acknowledge the need for nutrition research and opportunities are being explored


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Recommendations (awaiting publishing, 2019):

1. Aim should be to maintain nutritional status

2. Screening with a cancer specific validated screening tool.

3. All those at risk of malnutrition and or those with Grade 3 diarrhoea, that is impacting on their weight and or nutritional status, must referred to an Registered Dietitian with expertise in oncology.

4. The aim would be to meet energy and protein needs as defined by Arends et al, 2016, ideally through a balanced oral dietary approach.

5. To follow the guidance for IBD (Forbes et al, 2017), that is to eat a varied diet to meet their energy and nutrient requirements, including dietary fibre

6. Where oral intake cannot be maintained consideration must be made for enteral or parenteral nutrition.


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Ideas for research

• the use of pre & probiotics;

• use of PN to allow bowel rest;

• use of modified diets including elemental, a low

FODMAPS diet

• manipulation of dietary fibre intake.


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Probiotics & Immunotherapy

Preliminary study from MD Anderson looked at the link between immunotherapy, the gut

microbiome, and diet in people with cancer (113 participants)

• Completed a lifestyle survey on their diet, medication, and use of supplements.

• Analysed their fecal samples to build up a picture of each individual gut microbiome.

• Tracked treatment progress.

Results:

1. Taking over-the-counter probiotic supplements correlated with a 70 percent lower

chance of responding to checkpoint inhibitor immunotherapy. Almost half (42 percent)

of the participants reported taking such supplements.

2. Dietary choices appeared to have an impact. People who ate a high-fiber diet were five times

as likely to respond to immunotherapy and had more bacteria linked to a positive response.

https://www.medicalnewstoday.com/articles/324886.php


https://www.medicalnewstoday.com/articles/324886.php

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Probiotics

This is a very small study the guidance at present is:

Not to take probiotics whilst on immunotherapy


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Conclusions

• Need for an MDT approach

• Gain greater understanding of the nutritional needs of

each individual – most with GI symptoms would benefit

from some form of nutritional guidance from a qualified

health professional

• Lack of evidence/agreement regarding the appropriate

nutritional intervention


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