Mucositis

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Mucositis
Jordi Giralt Radiation Oncology Department Vall
dHebron University Hospital
EIS
Supportive Care
ESMO International Symposium
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Magnitude of the problem

• Frequent and often severe complication of cancer
  therapy, associated with
• Pain
• QoL impairment
• Risk of sepsis
• Dose-limiting toxicity
• Consequences
• Dose reductions
• Treatment delay

OUTCOME
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Phases
EPITHELIAL ULCERATION/ ATROPHY BACTERIAL
INFECTION
INFLAMMATION HEALING
Day 0 Day 6 Day 12 Day 16 Chemotherapy
Radiation
Oral Mucosa
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Pathogenesis

• Direct damage to the basal epithelial cell loss
  of the renewal capacity of the epithelium
• Microvascular injury may play a significant role
• RT/CT produce reactive oxygen species (ROS),
  crucial mediators of downstream biological events
• ROS stimulates a number of transcription factors
  and initiates other biological events
• Nuclear factor- ?B
• Proinflammatory cytokines TNF-a, IL-1ß and IL-6
• ROS directly damages cells, tissue, and blood
  vessels

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Epidemiology

• Mucositis rates 10 25
• Adyuvant CT 10
• Advanced disease CT 40
• High-risk situations
• 5FU grade 3-4 OM gt10
• Irinotecan grade 3-4 GIM gt 20
• Bone marrow transplantation 75 - 85
• Radiotherapy gt 90

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Patient-related factors

• Age young and elderly
• Impairment of nutritional status
• Previous oral conditions
• Xerostomia
• Poorly fitting dental prostheses
• Periodontal disease
• Gastritis, oesophagitis or colitis
• Infections
• Type of malignancy

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Cancer diagnosis
Sonis ST, et al. Cancer. 20041001995-2025.
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Clinical assessment

• Scoring
• Objective
• Validated
• Reproducible
• The scale should be
• Sensitive
• Consistent
• Patient-friendly process

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Scoring of Oral Mucositis

• Scales that rate the overall status of the mouth
  regarding to
• appearance
• pain
• function
• Relevant scales NCI - CTC
• Training and standardization assure accuracy and
  consistency
• Severity hampers accurate scoring
• Clinical research trials separately scored
• objective endpoints
• subjective endpoints

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Scoring of Gastro-Intestinal Mucositis

• Accurate evaluation hampered by inaccessibility
  gastro-intestinal tract
• Inaccuracy of imaging procedures
• Scales are based on
• symptoms
• functional changes
• Different GI sites mean different scales

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Treatment

• Non-specific treatment
• Symptom-related treatments
• New agents
• Mechanism-defined strategies

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MASCC Clinical Practice Guidelines 2004

• Evidence was insufficient to support a guideline
  for use of several agents including
• Amifostine
• Azelastine
• Chlorhexidine
• Clarithromycin
• Pilocarpine
• Povidone iodine
• Amifostine
• Butyric acid
• Glutamine
• Misoprostol

Prevention of oral mucositis
Treatment of GI mucositis
MASCC Clinical Practice Guidelines. Rubenstein
EB, et al. Cancer. 2004100(suppl)2026-2046.
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Prevention of Oral Mucositis
Rubenstein EB, et al. Cancer. 2004100(suppl)202
6-2046.
? recommended (?) suggested ? not
recommended
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Prevention and Treatment of GI Mucositis
Rubenstein EB, et al. Cancer. 2004100(suppl)202
6-2046.
? recommended (?) suggested ? not
recommended
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A Double-blind, Multicenter, Randomized,
Placebo-Controlled Nutritional Trial of the
Efficacy of Fermented Milk with the Probiotic
Lactobacillus Casei Dn-114001 in Preventing
Radiation-induced Diarrhea in Patients with
Gynecologic Cancer Treated with Pelvic
Radiotherapy

• Jordi Giralt, Carlos Regueiro, Ramona Verges,
• Isabel de la Fuente, Albert Biete, Meritxell
  Arenas,
• José Perez Regadera, Jose Maria Cobo and
  Francisco Guarner

This trial has been funded by DANONE
ASTRO 06, Int J Radiat Oncol Biol Phys 66 sup128
abstr 1001
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Phase III study design
Arm 1 (Placebo) Pelvic Radiation therapy
Placebo
R A N D O M I Z E

• Stratify by
• Centre
• Diagnosis site
• Cervix vs Uterus

BLIND
Arm 2 (Probiotic) Pelvic Radiation therapy
Probiotic

• Pelvic radiotherapy 3D conventional, total
  dose 45-50 Gy (1.8 Gy/d)
• Chemotherapy Cisplatin 40 mg/m2 I.v. weekly

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Study products
Probiotic Placebo Presentation liquid
yogurt liquid yogurt Unit quantity 96 grams 96
grams L. casei contents 108 cfu / 1 g.
absent Other probiotics L. bulgaris
absent S. termophilus Prescription 3 units
/day 3 units /day

• Study products started one week before and
  continued throughout external radiation

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(No Transcript)
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Patient characteristics
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Grade 2
Diarrhea-free survival
Bristol 6
P 0.048
Survival rate
Probiotic
Placebo
days
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Treatment

• Past Non-specific treatment
• Symptom-related treatments
• Future New agents
• Mechanism-defined strategies

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Keratinocyte Growth Factor, KGF

• Heparin-binding member of the fibroblast growth
  factors family
• Natural ligand for the KGF receptor (KGFR)
• Specific activity for epithelial tissue and
  stimulate proliferation, differentiation and
  survival
• Palifermin
• A recombinant Human KGF (rHuKGF)
• Is an N-terminal, truncated version of endogenous
  KGF
• Has similar biologic activity and increased
  stability

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Palifermin protects 5-FU induced enteritis
5-FU
Control
Palifermin ? 5-FU
Farrell CL, et al. Cancer Res. 199859933-939.
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No Effect on Tumor Growth
Comparable sizes of tumors growing in the flanks
of nude mice that were implanted with a KGFR
adenocarcinoma cell line with or without
palifermin pretreatment
500
control/untreated 3 mg palifermin for 3 days 5 mg
palifermin for 3 days 5-FU for 5 days 3 mg
palifermin for 3 days prior to 5 days 5-FU 5 mg
palifermin for 3 daysprior to 5 days 5-FU
400
300
Cloning efficiency ( of control)
200
100
0
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7
8
9
10
11
12
13
14
15
16
Days
Adapted from Farrell-CL, et al., Cancer Research
1998 58933-939
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Palifermin Clinical Studies

• Phase 1
• Dose Escalation Trial in Hematologic PBPC
  transplantation (Durrant, ASH 1999)
• Colorectal Cancer (Meropol N, ASCO 2000)
• Head and Neck Cancer (Brizel D, ASTRO 2001)
• Phase 2
• Hematologic PBPC Transplantation (Spielberger R,
  ASCO 2001)
• Colorectal Cancer (Clarke S, ASCO 2001)
• Head and Neck Cancer (Brizel D, ASTRO 2002)
• Phase 3
• Hematologic PBPC Transplantation (Spielberger R,
  NEJM 2004)
• Colorectal Cancer (Rosen LS, JCO 2006)
• Head and Neck Cancer (ongoing)

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NEJM 20043512590-8
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Phase III Study Design
VP-16
60 mg/kg
Cyclophosphamide 100 mg/kg
peripheral-blood hematopoietic stem cells
12 Gy total
hematologic cancers autologous stem-cell
transplantation
Study end
Filgrastim
f T B I
Stratify by center and primary tumor
Day
11
8
4
2
0
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Placebo
Placebo
Randomize
Palifermin (rHuKGF)
Palifermin (rHuKGF)
60 µg/kg/day Palifermin rHuKGF
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Patients Characteristics

• Characteristic Palifermin Placebo
• (N106) (N106)
• Male sex Nº () 59 (56) 72 (68)
• Age - Median 48 yr 49 yr
• - Range 1869 1968
• Diagnosis Nº ()
• Non-Hodgkins lymphoma 72 (68) 69 (65)
• Hodgkins disease 21 (20) 23 (22)
• Multiple myeloma 11 (10) 9 (8)
• Leukemia 2 (2) 5 (5)
• KPS
• 70 3 (3) 1 (1)
• 80 15 (14) 19 (18)
• 90 59 (56) 58 (55)
• 100 29 (27) 28 (26)
• Total Nº of CD34 cells reinfused
• Median 5.2 5.0
• Range 1.887.0 1.541.0

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Results
Incidence of Oral Mucositis
Mean WHO Grade of Oral Mucositis
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Results

• Palifermin Placebo p value
• Oral mucositis G 3 - 4
• Incidence Nº () 67 (63) 104 (98) lt0.001
• Duration days 6.0 9.0 lt0.001
• Patient-reported outcomes
• soreness of mouth and throat 29.0 46.8 lt0.001
• Swallowing-limitation score 22.5 38.3 lt0.001
• Analgesics lt0.001
• cumulative dose 212 mg 535 mg
• median duration 7.0 days 11.0 days

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Palifermin 40 µg/kg
Rosen LS et al J Clin Oncol 245194-5200, 2006,
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Patient Characteristics
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Incidence and severity of oral mucositis
First cycle
Second cycle
Grade 2 or higher 61 vs 29 P .016
Grade 2 or higher 47 vs 11 P .003
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Update systematic review 2005

• In haematological malignancies treated with HD-CT
  TBI palifermin is recommended 60 µg/kg/d x 3
• Not recommended
• Local GM-CSF mouthwash
• Topical antimicrobials
• Mucosal coating agents (sucralfate)
• Topical anesthesic / analgesic treatment
  (fentanyl)
• Nutritional supplements (parentheral alanyl
  glutamine)
• New agents
• Repifermin (KGF-2, FGF-10)
• Curnicum (inhibitor of nuclear factor-kappa B)

Support Care Cancer (2006) 14 519-527 and 528-532
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Summary

• Mucositis is a relevant issue
• The accuracy of scoring methods needs to be
  improved
• Palifermin reduced the duration and severity of
  oral mucositis after
• Intensive chemotherapy for hematologic
  malignances
• Metastatic colorectal cancer treated with 5FU
• New agents targeting mucositis are on evaluation

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