ANTICANCER THERAPY-INDUCED MUCOSITIS AND DIARRHOEA ...€¦ · mIAS (mTOR inhibitor associated stomatitis), 30-50% all grade, 5% high grade - Mostly occurs within the first cycle

ANTICANCER THERAPY-INDUCED MUCOSITIS AND DIARRHOEA:

Prevalence and Management Strategies

Florian SCOTTE, MDPhD

Suresnes, France

DISCLOSURES

• Consultant / Advisory Boards / Speaker: Tesaro, Sanofi, Roche, MSD, TEVA, Norgine, Prostrakan, Leo pharma, Janssen, Hospira, Boehringer, AMGEN, Pierre Fabre Oncologie, Vifor Pharma

• Associations: ESMO, ASCO, MASCC, AFSOS, AESCO

MUCOSITISThanks to Vincent Sibaud for the pictures and teaching

DEFINITION

A disorder characterized by inflammation of the oral mucosal

CTCAE 4.02 - October 15, 2009 : Gastrointestinal disorders

PREVALENCE AND PRESENTATION

Chemotherapy Induced Mucositis

Non-keratinized mucosa (buccal mucosa, floor of the mouth, ventral side of the tongue, soft palate…)

Diffuse , large, poorly circumscribed, erythematous or ulcerated lesions – covered with a pseudomembrane(epithelial debris, altered leucocytes, fibrin)

Drugs: 5FU, cisplatin, cyclophosphamide, methotrexate, taxanes, cytarabine……combination

Vigarios E, Sibaud V. Mucosal reactions to anticancer treatments. In: Atlas of Dermatologic Conditions in Oncology: Skin Reactions to Chemotherapy. Fabbrocini G, Lacouture ME, Tosti A (eds), 2018.

Radiotherapy Induced Mucositis

keratinized (hard palate, dorsal aspect of the tongue, attached gingiva) and non-keratinizedmucosa; whithin the irradiated fieldDepends dose and radiotherapy protocol

Moslemi D et al. Management of chemo/radiation-induced oral mucositis in patients with head and neck cancer: a review of the current literature. Radiother Oncol 2016; 120: 13-20.

mIAS (mTOR inhibitor associated stomatitis), 30-50% all grade, 5% high grade - Mostly occurs within the first cycle (<8weeks) –median time to onset: 10 days

Class-effect (everolimus, temsirolimus, sirolimus) - the most frequent dose-limiting toxicity

Single or multiple, painful, well-circumscribed round superficial ulcers on the nonkeratinized mucosa

Aphthous-like lesions – m TOR inhibitors (everolimus, temsirolimus)

Rugo HS, et al. Meta-analysis of stomatitis in clinical studies of everolimus: incidence and relationship with efficacy. Ann Oncol 2016; 27: 519-25.

Aphthous-like lesions – everolimus and exemestane

Incidence of all-grade stomatitis : 67% (grade 2: 33%, grade 3: 8%)

Most common severe adverse event leading to dose reduction/interruption

Second most frequent cause of discontinuation

Rugo HS, et al. Meta-analysis of stomatitis in clinical studies of everolimus: incidence and relationship with efficacy. Ann Oncol 2016; 27: 519-25.

Targeted therapy-related mucositis / stomatitis

angiogenesis inhibitors (7-29%) - sorafenib (Nexavar®), sunitinib (Sutent®), axitinib (Alymta®), pazopanib (Votrient®), cabozantinib (Cometriq®); anti EGFR (5-60%) - cetuximab (Erbitux®), erlotinib (Tarceva®), panitumumab (Vectibix®), afatinib (Giotrif®), dacomitinib (+++)…….

• Self-limiting lesions, aphtous-like lesions, dysgueusia, dysesthesia, nonspecific « stomatitis»

( diffuse mucosal hypersensitivity/dysesthesia, in some cases associated with erythema or painful inflammation of the oral mucosa +/- well-

demarcated ulcerations)

Vigarios E, Epstein J, Sibaud V. Oral mucosal changes and mucositis induced by targeted anticancer therapies. Support Care Cancer 2017; 25: 1713-39.

Geographic tongue and angiogenesis inhibitors (sorafenib, sunitinib,

pazopanib, axitinib, bevacizumab)

* VEGF (vascular endothelial growth factor) or VEGFR inhibtion

Hubiche T, Valenza B, Chevreau C, Fricain JC, Del Giudice P, Sibaud V. Geographic tongue induced by angiogenesis inhibitors. Oncologist 2013; 18: e16-7.

bevacizumab discontinuation

W+8

Geographic tongue and angiogenesis inhibitors (sorafenib, sunitinib,

pazopanib, axitinib, bevacizumab)


BRAF inhibitors (vemurafenib, dabrafenib in monotherapy)

hyperkeratotic lesions (verrucous, papillomatous) – Squamous cell carcinomas

Paradoxical activation of the MAP kinase pathway in BRAF wild-type keratinocytes

Asymptomatic hyperkeratotic multifocal mucosal lesions on both keratinized and non keratinized mucosa

Associated with cutaneous hyperkeratotic lesions (SCC, papillomas, keratoacanthoma, keratosis pilaris-like lesions…)

Vigarios E, Lamant L, delord JP, Sibaud V. Oral squamous cell carcinoma and hyperkeratotic lesions with BRAF inhibitors. Br J Dermatol 2015; 172: 1680-2.

Imatinib* and palatine pigmentary changes

* Gleevec ®: PDGF-receptor, c-Kit and BCR-ABL inhibition

“Blue-grey” asymptomatic hyperpigmentation of the hard palate

Similar to that of hyperpimentation due to antimalarials


Immune checkpoint inhibitors (PD-1, PD-L1)

< 5% of treated patients. Lichenoid reactions, xerostomia

Sibaud V, Eid C, Belum VR, Combemale P, Lamant L, Motzer R, Vigarios E, Lacouture ME. Oral lichenoid reactions associated with anti-PD-1/PD-L1 therapies: clinicopathologicalfindings. J Eur Acad Dermatol Venereol, 2017.

Oral mucosal toxicities – Key points

• chemotherapy: more diffuse mucositis, poorly limited lesions, non

keratinized mucosa

• Radiation therapy: severe mucositis localized into the irradiated field,

nonkeratinized and/or keratinized mucosa

• Targeted therapies: self-limiting lesions;well-demarcated; nonkeratinized

mucosa; sometimes very caracteristic.

• Immune checkpoint inhibitors: lichenoid reactions, xerostomia.

Vigarios E, Epstein J, Sibaud V. Oral changes and mucositis induced by targeted anticancer therapies. Support Care Cancer. 2017 May;25(5):1713-1739.

MANAGEMENT

Mucositis management –Be aggressive ! ! !

Oral supportive care: strict preventive and curative oral basic cares; soft toothbrush, non medicated oral rinses(normal saline), topical steroids, low level laser therapy, pain management, morphine mouthwash, dose modification……

Peterson DE, et al. Management of oral and gastrointestinal mucosal injury: ESMO clinical practice guidelines for diagnosis, treatment, and follow-up. Ann Oncol 2015; 26: v139-151.

Aphthous-like lesions – SWISH trial

• By 8 weeks, the incidence of grade ≥2 stomatitis was 2%, without any grade 3 - Indirect comparison with historical controls from BOLERO-2 study: 33% of grade ≥2 stomatitis (p<0·0001)

• All-grade mIAS incidence: 21% (SWISH) versus 61% (BOLERO-2)

• A US-based, non-randomised, phase 2, single-arm trial

• 85 postmenopausal women receiving everolimus and exemestane for hormone receptor-positive metastatic breast cancer

• Prophylactic use of a dexamethasone-based mouthwash , beginning on Day 1 of cycle 1 (10ml, swish for 2mn, and spit; 4 times daily for 8 weeks)

Rugo HS, et al. Prevention of everolimus-related stomatitis in women with hormone receptor-positive, HER2 negative metastatic breast cancer using dexamethasone moutwash (SWISH): a single-arm, phase 2 trial. Lancet Oncol 2017, march 14.

EVALUATION - Oral mucositis

• Grade 0 = no oral mucositis

• Grade 1 = erythema and soreness

• Grade 2 = ulcers, able to eat solids

• Grade 3 = ulcers, requires liquid diet (due to mucositis)

• Grade 4 = ulcers, alimentation not possible (due to mucositis)

National Cancer Institute CTCAE; http://evs.nci.nih.gov/ftp1/CTCAE/About.html

WHO Scale :

NCI-CTCAE V4.03 :

PREVENTIVE MEASURES

• Maintenance of optimal nutritional support throughout the entireperiod of cancer therapy

• Daily oral hygiene routine, including brushing teeth and the gums four times a day with a soft brush and using mouth rinses.

BASIC ORAL CARE

NO RECOMMENDATION

• normal saline, sodium bicarbonate, mixed medication, mouthwash, chlorhexidine

SPECIFIC / TARGETED THERAPY

• saline-containing mouthwashes (higher risk of infection)

ORAL MUCOSITIS - GUIDELINES

• Bolus 5-fluorouracil chemotherapy: 30 min of oral cryotherapy (II).

• high-dose chemotherapy and total body irradiation, followed by autologousstem cell transplantation, for a hematological malignancy:• Recombinant human keratinocyte growth factor-1 (KGF-1/palifermin) (60 μg/kg per

day for 3 days before conditioning treatment and for 3 days after transplant) (II).

• Head and neck cancer with moderate dose radiation therapy (up to 50 Gy), without concomitant chemotherapy:• benzydamine mouthwash (I).

RECOMMENDATIONS IN FAVOR OF AN INTERVENTION

PREVENTION


• HSCT conditioned with high-dose chemotherapy, with or without total body irradiation:• Low-level laser therapy (wavelength at 650 nm, power of 40 mW, and each square

centimeter treated with the required time to a tissue energy dose of 2 J/cm2), (II).

• HSCT: • controlled analgesia with morphine (II).

RECOMMENDATIONS IN FAVOR OF AN INTERVENTION

TREATMENT


• All age groups and across all cancer treatment modalities :• Oral care protocols (III).

• High-dose melphalan, with or without total body irradiation, as conditioning for HSCT :• Oral cryotherapy (III).

• Radiotherapy, without concomitant chemotherapy, for head and neck cancer :• Low-level laser therapy (wavelength ∼632.8 nm) (III).

• Oral cancer patients receiving radiation therapy or chemoradiation :• Systemic zinc supplements administered orally (III).

SUGGESTION IN FAVOR OF AN INTERVENTION

PREVENTION

LOW LEVEL LASER THERAPY

• Once a day, every day (min 3/week)

• t.(s)=D (J) x Surface (cm2) / Power (W)

Intra-oral laser application

Transcutaneous laser application

R.-J. Bensadoun and R.G. Nair. Photomedicine and Laser Surgery, Volume 30, Number 4, 2012


• Radiation therapy for head and neck cancer :• PTA (polymyxin, tobramycin, amphotericin B) and BCoG (bacitracin, clotrimazole, gentamicin)

antimicrobial lozenges and PTA paste (II).

• High-dose chemotherapy, with or without total body irradiation, for HSCT or in patients receiving radiation therapy or concomitant chemoradiation for head and neck cancer :• Iseganan antimicrobial mouthwash (II),

• Chemotherapy for cancer (I), or in patients receiving radiation therapy (I) or concomitant chemoradiation (II) for head and neck cancer :• Sucralfate mouthwash

RECOMMENDATIONS AGAINST AN INTERVENTION

PREVENTION not be used


• Chemotherapy for cancer (I), or radiation therapy (II) for head and neck cancer :• sucralfate mouthwash.

TREATMENT not be used

RECOMMENDATIONS AGAINST AN INTERVENTION

MASCC=ISOO Mucositis Guidelines/Lalla et al. Cancer 2014

RECOMMENDATIONS IN FAVOR OF AN INTERVENTION (ie, strong evidence supports effectiveness in the treatment setting listed):

• 1. The panel recommends that 30 min of oral cryotherapy be used to prevent oral mucositis in patients receiving bolus 5-fluorouracil chemotherapy (II).

• 2. The panel recommends that recombinant human keratinocyte growth factor-1 (KGF-1/palifermin) be used to prevent oral mucositis (at a dose of 60 lg/kg per day for 3 days prior to conditioning treatment and for 3 days after transplant) in patients receiving high-dose chemotherapy and total body irradiation, followed by autologous stem cell transplantation, for a hematological malignancy (II).

• 3. The panel recommends that low-level laser therapy (wavelength at 650 nm, power of 40 mW, and each square centimeter treated with the required time to a tissue energy dose of 2 J/cm2), be used to prevent oral mucositis in patients receiving HSCT conditioned with high-dose chemotherapy, with or without total body irradiation (II).

• 4. The panel recommends that patient-controlled analgesia with morphine be used to treat pain due to oral mucositis in patients undergoing HSCT (II).

• 5. The panel recommends that benzydamine mouthwash be used to prevent oral mucositis in patients with head and neck cancer receiving moderate dose radiation therapy (up to 50 Gy), without concomitant chemotherapy (I).

RECOMMENDATIONS AGAINST AN INTERVENTION (ie, strong evidence indicates lack of effectiveness in the treatmentsetting listed):

• 1. The panel recommends that PTA (polymyxin, tobramycin, amphotericin B) and BCoG(bacitracin, clotrimazole, gentamicin) antimicrobial lozenges and PTA paste not be used to prevent oral mucositis in patients receiving radiation therapy for head and neck cancer (II).

• 2. The panel recommends that iseganan antimicrobial mouthwash not be used to prevent oral mucositis in patients receiving high-dose chemotherapy, with or without total body irradiation, for HSCT (II), or in patients receiving radiation therapy or concomitant chemoradiation for headand neck cancer (II).

• 3. The panel recommends that sucralfate mouthwash not be used to prevent oral mucositis in patients receiving chemotherapy for cancer (I), or in patients receiving radiation therapy (I) or concomitant chemoradiation (II) for head and neck cancer.

• 4. The panel recommends that sucralfate mouthwash not be used to treat oral mucositis in patients receiving chemotherapy for cancer (I), or in patients receiving radiation therapy (II) for head and neck cancer.

• 5. The panel recommends that intravenous glutamine not be used to prevent oral mucositis in patients receiving high-dose chemotherapy, with or without total body irradiation, for HSCT (II).

• 58 years old – locally advanced head and neck carcinoma. Treated withchemo/radiation therapy/ targeted therapy (cetuximab). Managed forgrade 2 mucositis.

Quiz

Which is the most likely offending agent? (choose the single best response):

1. Chemotherapy

2. Anti EGFR (cetuximab)

3. Radiation therapy

4. candida albicans superinfection

• 58 years old – locally advanced head and neck carcinoma. Treated withchemo/radiation therapy/ targeted therapy (cetuximab). Managed forgrade 2 mucositis.

Quiz

Which is the most likely offending agent? (choose the single best response):

1. Chemotherapy

2. Anti EGFR (cetuximab)

3. Radiation therapy

4. candida albicans superinfection

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DIARRHOEA

DEFINITION

A disorder characterized by frequent and watery bowel movements

CTCAE 4.02 - October 15, 2009 : Gastrointestinal disorders

GI INJURIES

Jervoise Andreyev et al, Lancet Oncol 2014; 15: e447–60

UNDER-REPORTING

Di Maio M et al. J Clin Oncol 2015; 33:910-915Basch E et al. N Engl J Med 2010; 362;10: 865-869

PREVALENCE

• Chemotherapy induced = 5 – 47% (grade 3-4)• Warning dihydropyrimidine dehydrogenase (DPD) mutation (5FU)

• TKI induced = 28% (grade ≥ 3) but 50% (all grades)

• VEGF inhibitors = 66% (pazopanib, sunitinib, sorafenib)

• Check Point Inhibitors = 10-25% (Grade ≥3) but > 50% (all grades)


TKI induced diarrhoea

• Could be related to excess chloride secretion caused by dysregulated EGFR signalling.

• gut motility altered

• colonic crypt damage

• changes to intestinal microfl ora

• altered nutrient metabolism

• altered transport in the colon.


IT induced diarrhoea

• Dysimmune enterocolitis

• Celiac disease

• Dysimmune hyperthyroidism


Safety profile

N= 670

Ipilimumab + nivolumab Nivolumab alone Ipilimumab alone

Treatment-related adverse events 91 -95 % 82.4% 93%

grade 3/4 adverse events 54% 16.3% 24%

GI select adverse events

(colitis ,diarrhea..)

51% (21% grade 3) 19.5% 37% (10.9% grade 3)

Hepatic select adverse events

(hepatitis, transaminitis..)

27.7% 6.4% 4.3%

Pulmonary select adverse events 7-11.7% 1.6% 1.9-4.3%

Endocrine select adverse events (thyroid disorders, hypophysitis, adrenal insuffiiency..)

34% 14.4% 17%

Skin select adverse events

(rash, pruritus, vitiligo..)

59-71.3% 41.9% 58.7%

Treatment related AE leading to discontinuation

36.4% 7.7% 14.8%

Anti PD-1 and anti CTLA-4 - Safety profile in melanoma

Sibaud V, Delord JP. Dermatologic complications of anti-PD-1 / PD-L1 immune checkpoint antibodies. Curr Opin Oncol 2016; 28: 254-63


TREATMENTSDrug Indication Mechanism Dosing Administration

Loperamide 1st line Decrease motilityIncrease anal sphincter tone

Initial 4 mg dose followedby 2 mg every 2–4 h or after every loose stoolNo more than 16 mg/d

Oral

Codeine Alternative loperamide Delay transit 15-60 mg x4/d Oral

Octreotide Grade 1-2 high riskGrade 3-4Loperamide fall

Somatostatin analogDecrease hormone secretionReduce motilityPromote absorption

100 μg three times dailyIncrease after 24h (max 500 µg/d)Severe : 500 µg X 3/d

Sub CutaneousOr IV (25–50 μg/h)

Budesonide 2nd line Topically active corticosteroidRestore mucosalfunction and fluidabsorption

9 mg once daily for 3–5 days

Oral

Atropine Acute diarrhea / irinotecan

inhibition ofacetylcholine

0.25 mg Sub Cutaneous


TREATMENTSDrug Indication Mechanism Dosing Administration

Antibiotics Grade 3-4 + Neutropenia in outpatients

Target intestinal bacterial overgrowth

ciprofloxacin250–500 mg twice daily;

Oral

Bile acidsequestrants

steatorrhoea causedby bile acidmalabsorption

Prevent water secretion

Colestyramine initially 2–4 g per day (max 24 mg/d)

Oral

Oral rehydrationtherapy

Grade 1-2 Increases sodium and waterabsorption in smallintestine

Five sachets in 1 L water†, but consider8–10 sachets in 1 L is for replacingelectrolye defi cits

Oral

ElectrolytesMagnesiumCalciumPhosphates

24 mmol oral magnesiumin divided doses;10–50 mmol calcium daily0.2–0.5 mmol/kg per day

Oral

Probiotics Prevention Unknown Various Lactobacillus spp Oral


Weber J S et al. JCO 2012;30:2691-2697

Checkpoint inhibitors SAE induced


Champiat S. et al Annals of Oncology 27: 559–574, 2016

Immune Mediated Colitis

Grade

• Mild grade 1: < 4 stools/d abovebaseline

• Moderate grade 2: increase 4-6 stools/d above baseline

• Severe grade ≥ 3: > 7 stools/d abovebaseline

Management

• Manage symptomatically (bland diet, PPI, antidiarrheal) / Consider delayingtreatment until symptoms improve

• Colonoscopy and steroids / Low dose steroids may be sufficient / Holdtreatment

• Initiate high dose steroids / Discontinue treatment

CTCAE Grading Scale in Managing Immune-Mediated Adverse Events . Wendy Crabbe


Champiat S. et al Annals of Oncology 27: 559–574, 2016

Documents

ANTICANCER THERAPY-INDUCED MUCOSITIS AND DIARRHOEA ...€¦ · mIAS (mTOR inhibitor associated stomatitis), 30-50% all grade, 5% high grade - Mostly occurs within the first cycle