ANTICANCER THERAPY-INDUCED 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, , Pierre Fabre Oncologie, Vifor Pharma • Associations: ESMO, ASCO, MASCC, AFSOS, AESCO MUCOSITIS Thanks 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 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, , 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-keratinized mucosa; whithin the irradiated field Depends 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. Aphthous-like lesions – m TOR inhibitors (everolimus, temsirolimus)

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

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%) - (Nexavar®), (Sutent®), (Alymta®), (Votrient®), (Cometriq®); anti EGFR (5-60%) - (Erbitux®), (Tarceva®), (Vectibix®), (Giotrif®), (+++)…….

• 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, )

* VEGF (vascular endothelial ) 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. Geographic tongue and angiogenesis inhibitors (sorafenib, sunitinib, pazopanib, axitinib, bevacizumab)

bevacizumab discontinuation

W+8

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

Vigarios E, Epstein J, Sibaud V. Oral mucosal changes and mucositis induced by targeted anticancer therapies. Support Care Cancer 2017; 25: 1713-39. 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: clinicopathological findings. J Eur Acad Dermatol Venereol, 2017. Oral mucosal toxicities – Key points

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

• : 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

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

• 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)

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 WHO Scale : • 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)

NCI-CTCAE V4.03 :

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

BASIC ORAL CARE • Maintenance of optimal nutritional support throughout the entire period 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.

NO RECOMMENDATION • normal saline, sodium bicarbonate, mixed medication, mouthwash, chlorhexidine SPECIFIC / TARGETED THERAPY • saline-containing mouthwashes (higher risk of infection)

ORAL MUCOSITIS - GUIDELINES

RECOMMENDATIONS IN FAVOR OF AN INTERVENTION

PREVENTION

• Bolus 5-fluorouracil chemotherapy: 30 min of oral cryotherapy (II). • high-dose chemotherapy and total body irradiation, followed by autologous stem 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). ORAL MUCOSITIS - GUIDELINES

RECOMMENDATIONS IN FAVOR OF AN INTERVENTION

TREATMENT

• 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). ORAL MUCOSITIS - GUIDELINES

SUGGESTION IN FAVOR OF AN INTERVENTION

PREVENTION

• 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). LOW LEVEL LASER THERAPY

• Once a day, every day (min 3/week) • t.(s)=D (J) x Surface (cm2) / Power (W)

Transcutaneous laser application

Intra-oral laser application

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

RECOMMENDATIONS AGAINST AN INTERVENTION

PREVENTION not be used

• 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 ORAL MUCOSITIS - GUIDELINES

RECOMMENDATIONS AGAINST AN INTERVENTION

TREATMENT not be used

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

• 58 years old – locally advanced head and neck carcinoma. Treated with chemo/radiation therapy/ targeted therapy (cetuximab). Managed for grade 2 mucositis.

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 Quiz

• 58 years old – locally advanced head and neck carcinoma. Treated with chemo/radiation therapy/ targeted therapy (cetuximab). Managed for grade 2 mucositis.

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 [email protected]

[email protected] 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; 33:910-915 Basch 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) Jervoise Andreyev et al, Lancet Oncol 2014; 15: e447–60 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.

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

• Dysimmune enterocolitis • Celiac disease • Dysimmune hyperthyroidism

Jervoise Andreyev et al, Lancet Oncol 2014; 15: e447–60 Anti PD-1 and anti CTLA-4 - Safety profile in melanoma

Safety profile Ipilimumab + nivolumab Nivolumab alone Ipilimumab alone N= 670 Treatment-related adverse events 91 -95 % 82.4% 93%

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

GI select adverse events 51% (21% grade 3) 19.5% 37% (10.9% grade 3) (colitis ,diarrhea..) Hepatic select adverse events 27.7% 6.4% 4.3% (hepatitis, transaminitis..)

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

Endocrine select adverse events (thyroid 34% 14.4% 17% disorders, hypophysitis, adrenal insuffiiency..) Skin select adverse events 59-71.3% 41.9% 58.7% (rash, pruritus, vitiligo..) Treatment related AE leading to 36.4% 7.7% 14.8% discontinuation

Sibaud V, Delord JP. Dermatologic complications of anti-PD-1 / PD-L1 immune checkpoint antibodies. Curr Opin Oncol 2016; 28: 254-63 Jervoise Andreyev et al, Lancet Oncol 2014; 15: e447–60 TREATMENTS Drug Indication Mechanism Dosing Administration Loperamide 1st line Decrease motility Initial 4 mg dose followed Oral Increase anal sphincter by 2 mg every 2–4 h or tone after every loose stool No more than 16 mg/d Codeine Alternative loperamide Delay transit 15-60 mg x4/d Oral Octreotide Grade 1-2 high risk Somatostatin analog 100 μg three times daily Sub Cutaneous Grade 3-4 Decrease hormone Increase after 24h (max Or IV (25–50 μg/h) Loperamide fall secretion 500 µg/d) Reduce motility Severe : Promote absorption 500 µg X 3/d

Budesonide 2nd line Topically active 9 mg once daily for 3–5 Oral corticosteroid days Restore mucosal function and fluid absorption Atropine Acute diarrhea / inhibition of 0.25 mg Sub Cutaneous irinotecan acetylcholine Jervoise Andreyev et al, Lancet Oncol 2014; 15: e447–60 TREATMENTS Drug Indication Mechanism Dosing Administration Antibiotics Grade 3-4 + Target intestinal ciprofloxacin Oral Neutropenia in bacterial overgrowth 250–500 mg twice daily; outpatients Bile acid steatorrhoea caused Prevent water Colestyramine initially 2–4 Oral sequestrants by bile acid secretion g per day (max 24 mg/d) malabsorption Oral rehydration Grade 1-2 Increases sodium and Five sachets in 1 L water†, Oral therapy water but consider absorption in small 8–10 sachets in 1 L is for intestine replacing electrolye defi cits

Electrolytes 24 mmol oral magnesium Oral Magnesium in divided doses; Calcium 10–50 mmol calcium daily Phosphates 0.2–0.5 mmol/kg per day Probiotics Prevention Unknown Various Lactobacillus spp Oral

Jervoise Andreyev et al, Lancet Oncol 2014; 15: e447–60 Checkpoint inhibitors SAE induced

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 Management • Mild grade 1: < 4 stools/d above • Manage symptomatically (bland diet, PPI, baseline antidiarrheal) / Consider delaying treatment until symptoms improve • Moderate grade 2: increase 4-6 stools/d above baseline • Colonoscopy and steroids / Low dose steroids may be sufficient / Hold treatment

• Severe grade ≥ 3: > 7 stools/d above baseline • Initiate high dose steroids / Discontinue treatment

CTCAE Grading Scale in Managing Immune-Mediated Adverse Events . Wendy Crabbe Checkpoint inhibitors SAE induced

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