Evidences for chemoprevention in Head and neck cancer, #Head and neck cancer Vitamin A, Retinoic acid, Chemoprevention

1. CHEMOPREVENTION IN
HEAD AND NECK CANCER
Dr Ankit Vishwani
Mch head and neck
Rcc trivandrum

2. CANCER RISK–REDUCING AGENTS
(CHEMOPREVENTION)
Drugs ,isolated dietary components to whole-diet modulation
Block, reverse, or prevent the development of invasive cancer.
Primary
de novo premalignant
lesions
Secondary
● After curative
therapy
● to prevent recurrent
disease or second
primary tumors

3. Inhance is a collaboration of research groups

4. Other Approaches for oral dysplasia
1 Avoidance of further carcinogen exposure-
● Important but not sufficient
● As critical genetic alterations already occurred in early
premalignant lesions.

5. ● pooled data 18 case–control studies within the
International Head and Neck Cancer Epidemiology
(INHANCE) consortium
● 30% lower risk -stopping smoking for >1 to 4 years.
● never smokers - having quit for 20 or more years.
● never drinkers- having quit for 20 or more years.

6. Other Approaches for oral dysplasia
2 Screening Individuals
● High risk ( alcohol ,tobacco)
● Premalignant lesions
Oral visual screening can reduce mortality in high-risk
individuals and has the potential of preventing at least 37000
oral cancer deaths worldwide.

7. More facts of Kerala study

8. Restriction of screening to ever-tobacco and/or ever-alcohol users with no
additional risk stratification would substantially enhance efficiency
Accepted on December 2, 2020 and published at ascopubs.

9. RATIONALE FOR CHEMOPREVENTION
● Field cancerization- Multi focal areas at precancerous stage in
whole arodigestive tract.
● Multistep carcinogenesis – intermediate stages, leading to fully
transformed, invasive, and metastatic cancer

10. Field carcinogenesis
● premalignant dysplastic lesions in the oral mucosa
● significant risk of cancer at noncontiguous
mucosal sites
● precluded the routine use of surgical resection of
premalignant lesions as a curative approach.
September 1953

11. Genetically abnormal precursor cells have the capacity to migrate
extensively within the mucosa
Normal mucosa may contain evidence of genetically abnormal cells at
discrete sites

12. Field carcinogenesis supported by molecular studies
● Mutated p53 in epithelium either adjacent or at significant
distance from the primary tumors
.
● molecular basis for the development of multiple tumors.

13. The goal of chemoprevention is to decrease the number
of cancers that develop in the anatomic area at risk.
CHALLENGES
Direct demonstration of a decreased
incidence
● Large numbers of patients
● Long follow up

14. Surrogate markers and potential target
agents ??
Defining alternative surrogate endpoints
● to evaluate the efficacy of chemopreventive
therapies
● to serve as molecular prognostic factors

15. Chemoprevention studies with
retinoids allowed unique prospective
collections of biospecimens that led
to biomarker development.

16. Journal of the National Cancer Institute,1998
N-22 premalignant lesions
retinoic acid, interferon alfa, and a-tocopherol -12 months
● loss of heterozygosity (LOH) 9p21, 3p14, and 17p13
● the genetic loss persisting in some patients who exhibited complete
histologic responses
OL harboring LOH at 3p14 and/or 9p21 - 37 % risk of invasive
cancer vs 6 %
● clinical and histologic assessments of the response insufficient
● genetic alterations -be used as biomarkers to increase efficacy

17. ● N-116 was analyzed for LOH
● LOH at 3p and/or 9p -3.2 fold increase
● individuals with additional losses (on 4q, 8p, 11q, or
17p)-showed 33fold increase in relative cancer
risk.
In conclusion, analysis of LOH at 3p and 9p could
serve as an initial screening

18. 3 biomarkers
● Baseline p53 Protein expresssion in parabasal layer
● Chromosomal polysomy
● LOH at 3p/9p
can identify high risk patients in our sample.
1988 and 1991, 70 advanced OPL patients
high dose isotretinoin 3 months ,f/b low dose isotretinoin or B carotene ( 9
months)
For high risk individuals more -efficient chemoprevention
trials and molecular targeting studies can be designed.

19. Podoplanin
Delta np 63

20. Chemoprevention studies with
retinoids allowed unique prospective
collections of biospecimens that led
to biomarker development.

21. CHEMOPREVENTION TRIALS
● Vitamin A, vitamin E, and beta-carotene
● Synthetic Retinoids
● Epidermal growth factor receptor (EGFR)
inhibitors
● Cyclooxygenase 2 (COX-2) inhibitors
● Natural compounds
● P53 agents

22. None of these studies resulted in a
strategy that can be considered
standard of care.

23. Vitamin A, vitamin E, and beta-carotene
● antioxidants
● Apparent efficacy in inducing regression of oral
leukoplakia.
● have been studied relatively extensively,
● both for primary and secondary chemoprevention,
● none has an established role

24. Primary prevention trials for VITAMIN A,E
Beta Carotene

25. ● Oral oncology 1997
● double-blind placebo-controlled trial
● evaluate the chemopreventive potential of vitamin A or beta
carotene, in oral leukoplakia in Kerala
● 160 fishermen and women
● receive oral vitamin A(50) or beta carotene(55) or placebo (55)

26. Complete regression rates were:
● 10% placebo arm,
● 52% vitamin A
● 33% beta carotene
Homogeneous leukoplakias and smaller lesions responded better than
non-homogeneous and larger lesions.
No major toxicities were observed.
● Half of the responders with beta carotene and two thirds
with vitamin A relapsed after stopping supplementation.
● Need for further trials

27. Draw back
● Relapse
● No genetic studies
Advantage
Oral cancer as end point
Vitamin a ( no increase in retinol levels )
that is no major toxicities reported

28. Toxic effects of retinoids
oxic effects were frequent and severe, with two-thirds of the retinoid-treated
patients experiencing mucocutaneous adverse events and hypertriglyceridemia

29. 2007; The Cancer (Finland )
AlphaTocopherol( Vitamin E), Beta-Carotene( precursor of vitamin
A)Cancer Prevention (ATBC) study
● a double-blind, placebo-controlled
● daily supplementation with 50 mg/dl a-tocopheryl and/or 20 mg b-carotene
● N -29,133 male smokers, 50–69 years and free of cancer at baseline, were
randomized
● supplementation regimen for 5–8 years
Incident cancers of the oral cavity ,pharynx (n 65), esophagus
(n24), larynx (n 56) -Finnish Cancer Registry.

30. The results do not provide support for a protective effect of
vitamin E or b-carotene supplementation on upper aerodigestive
tract cancers

31. 1988 Helkinsi , Finland
Alpha tocopherol B carotene cancer prevention study
N 409 male , smokers
Alpha tocopherol, b carotene , both ,placebo, follow up 5-7 years
Did not support the hypothesis

32. These two placebo-controlled studies, which randomly assigned patients to
beta-carotene, alpha-tocopherol, both, or neither, did not provide any evidence to
support a protective effect from these agents.

33. Secondary prevention trials for
Vitamin A , E , B carotene

34. Oral oncology 1996
N -106 ,complete treated with radiotherapy and/or surgery.
randomised to
● receive retinyl palmitate (200,000 IU per week for 1 year)
● placebo
1 year supplementation; 3 year follow up

35. Higher frequency of recurrences in the vitamin A group

36. multicenter, doubleblind, placebo-controlled, randomized chemoprevention trial among 540
patients with stage I or II head and neck cancer treated by radiation therapy between
October 1, 1994, and June 6, 2000.
α-tocopherol (400 IU/day) and β-carotene (30 mg/day) or placebo
first day of radiation therapy to 3 years after the end of radiation therapy.
Follow-up of 52 months,
second primary cancers and recurrences of the first tumor were diagnosed in 113 and 119
participants respectively.

37. After enrollment of 156 patients, betacarotene supplementation was discontinued given the
increased risk of lung cancers observed in other ongoing chemoprevention studies.
The remaining of the patients received alphatocopherol or placebo. After a median
follow-up of 52 months, there was a higher rate of second primary cancers during the
alpha-tocopherol supplementation period, but a lower rate after supplementation was
discontinued. After 8 years of follow-up, the proportion of patients free of second primary
tumors was similar between the groups.

38. The largest study to prevent second primary aerodigestive tumors
was conducted by the (EORTC).
European Study on Chemoprevention with Vitamin A and
N-Acetylcysteine (EUROSCAN)
Journal of national cancer institute 2000

39. randomized 2,592 patients with treated lung (40%) or head and neck
(60%) malignancies
receive
● no intervention,
● retinyl palmitate (300,000 IU/day for 1 year followed by 150,000 IU
for 2 year)
● N-acetylcysteine (600 mg/day)for 2 years
● both
Follow up 6 years

40. no benefit—in terms of overall survival,
event-free survival, or second primary tumors

41. N- Acetylcysteine has proven to be effective in decreasing the direct mutagenicity
of several chemical compounds by inhibiting the in vivo formation of
carcinogen–DNA adducts, DNA damage, and urethane-induced lung tumors in
mice (11–

42. SYNTHETIC RETINOIDS
PRIMARY PREVENTION

43. The mechanism by which retinoids affect premalignant lesions has not been fully
elucidated. Many premalignant dysplastic lesions (60 percent in one series
compared with none in normal specimens) express very low levels of the nuclear
retinoid receptor beta (RAR beta), a component of several bipartite transcription
factors responsive to retinoic acid [75]. This deficiency is reversed with retinoid
therapy, which may reestablish many aspects of normal growth and differentiation
in the aberrantly proliferating premalignant clone

44. ● randomized placebo-controlled
study
● isotretinoin (1 to 2 mg/kg per
day)vs placebo in 44 patients with
leukoplakia
● Pretreatment and posttreatment
histologic evaluation ( after 3
months)
● Follow up for 6 months

45. ● Overall clinical
response rates (67
versus 10 percent)

46. ● Histological
response
rates(54 versus
10 percent)

47. Toxicity of retinoids
● Chellitis, facial erythema, dryness and
peeling of skin(79 %)
● conjunctivitis (54%)
● Hyper triglyceridemia (71%)
● 47 percent of patients requiring dose reduction
● 50 percent of responders relapsed within three months
of treatment cessation.

48. N -70 leukoplakia
induction therapy with high dose isotretinoin (1.5 mg /kg per day) for 3
months; F/b
maintenance therapy beta carotene or isotretinoin for 9 months ( in responders
or stable lesions)
low-dose isotretinoin therapy was significantly more
active against leukoplakia than beta carotene ( 92 vs 45 %)
and was easily tolerated.

49. Long-term follow-up( 66 months),
Incidence of in situ or invasive carcinoma was not different between
the isotretinoin and beta-carotene (23% vs. 27%, respectively).

51. The follow-up trial to the phase IIb study by Lippman et al.
was designed
● prolong even more the duration of treatment.
● the doses were once again reduced

52. ● 13-cis retinoic acid (0.5 mg/kg/day for 1 year followed by 0.25
mg/kg/day orally for 2 years)
● vitamin A (retinyl palmitate 25,000 IU/day) plus beta-carotene (50 mg/
day) for 3 years.
3 years treatment , follow up 2 years
● during the conduct of the study, data became
available
● increased lung cancer with beta carotene from
other studies
As a result, the experimental arm was modified to vitamin A single
agent.

53. The final analysis of the trial demonstrated
● 13cRA -even at low doses -grade 2 or higher toxicities.
● 13cRA (48.1%)
● Vitamin A single agent lower 3-month clinical response rate (20%)
● beta-carotene plus vitamin A (32.5%)
● the 5-year oral cancer-free survival was similar across the treatment groups
(78%–84%).
● largest and longest term study in oral premalignant lesions
ever conducted

54. Secondary chemoprevention
-Retinoids

55. N -1190 ,treated for stage I or II HNSCC
randomly asssigned
to receive either low-dose isotretinoin (30 mg/day) or placebo for 3 years.
Follow up 4 more years
● Isotretinoin did not statistically significantly reduce the rate of second
primary tumors
● Current smokers had a higher rate of second primary tumors than that
of never or former

56. ● At present, 13cRA( isotretinoin) , BC plus vitamin
A (RP) and Vitamin A (RP) alone cannot be
recommended for chemoprevention
● New, better agents are needed in this setting.

57. COX INHIBITORS

58. COX INHIBITORS
(NSAIDs) prevents the development of intraepithelial neoplasia in the
colon and rectum.
MOA
inhibition COX and diminished synthesis of prostaglandins
Both premalignant and malignant lesions of the oral cavity
overexpress COX inhibitors
Renkonen J, Wolff H, Paavonen T. Expression of cyclo-oxygenase-2 in human tongue carcinoma and its
precursor lesions. Virchows Arch 2002; 440:594.

59. COX INHIBITORS
Mulshine et al. randomized 57 patients with oral premalignant lesions
● receive placebo or
● 0.1% oral rinse solution of the pan COX inhibitor ketorolac for 30
days.
placebo group- higher rate of clinical response (32%), and there were
no significant differences in histological response.

60. Selective COX INHIBITORS
Papadimitrakopoulou et al.
Patients (premalignant lesions )were treated with
● placebo
● celecoxib( selective cox 2 inhibitor)100 mg twice daily
Celecoxib was well tolerated, but there were no
differences in the response rates between the groups.

61. ● Two aforementioned COX inhibitor- chemoprevention
trials do not support there use
● Cardiovascular toxicities with cox 2 inhibitors in colonic
polyp trials decreased the enthusiasm in HNSCC

62. EGFR INHIBITORS

63. Epidermal growth factor receptor inhibition
● Overexpression of the EGFR -head and neck, lung,
breast, prostate, bladder, and pancreatic cancers
● Dysregulation of EGFR -80%-90% of HNSCC specimens
● Blocking the EGFR is an excellent approach to treat and
prevent head and neck cancer.

64. ● randomized, placebo-controlled, double-bind trial.
● EPOC
Median follow-up time of 35 months
N = 379 they were classified as high-risk (LOH-positive) or
low-risk (LOH-negative)
150 LOH-positive patients.
● Oral erlotinib treatment (75)(150 mg/d)
● placebo (75)
For 12 months

65. ● The 3-year CFS was significantly lower for
LOH-positive
● Increased EGFR gene copy number correlated with
LOH-positive status
Erlotinib did not, however, improve CFS in
patients with LOH-positive or
high-EGFR-gene-copy-number OPLs.

66. A phase I chemoprevention trial of combined erlotinib and celecoxib revealed an overall
pathologic response rate of 71% at time of data analysis.
mouse xenograft tissues
combined treatment modulated the EGFR and mTOR signaling pathways.
Though worth exploring, mTOR inhibitors have not reached clinical applications in SCCHN
chemoprevention

67. NATURAL COMPOUNDS
An array of natural compounds,
● green tea extract
● curcumins
● Lycopene
● luteolin
● pomegranate juice
● soybeans
under investigation in head and neck chemoprevention trials.

68. Green Tea
● Polyphenon E (PPE)
● Epigallocatechin gallate (EGCG)
● antioxidant properties and inhibit carcinogenesis
mediated by downstream signaling pathways
● limited evidence

69. On the basis of synergistic effects green tea polyphenon E and
EGFR-tyrosine kinase inhibitor in preclinical studies.
Phase Ib study of the PPE and erlotinib combination

70. ● n 21 , 17 completed the study
● PPE (200 mg 3x day) and dose escalation of erlotinib (50, 75,
100 mg daily) for 6 months
● tissue biopsy at baseline and 6-months
● Pathologic responses in 17 evaluable patients: pCR (47%)
and pPR (18%).
● The 5-year CFS and OS were 66.3% and 93%.

71. IN EPOC study, treatment with single agent erlotinib
did not show any impact on CFS
Combination appears to be much more effective and
synergistic
Just a small pilot phase 1 study.
Combination well deserves to move forward in
larger chemoprevention trials

72. ● AACR journals 2016
● extracted from the plant Curcumin longa( turmeric)
● antiproliferative, proapoptotic, and prodifferentiation properties
● Curcumin, a potent inhibitor of NF-kB/COX-2,
oral leukoplakia (n -223) randomized (1:1 ratio)
Oral capsules
3.6 g/day of curcumin (n -111) or placebo (n -112), for 6 months.

73. No relapse after 6 month follow up

74. Curcumin may effective, with good tolerance and durable
clinical response.

75. P 53 agents

76. P 53 agents
ONYX-015 attenuated adenovirus- cytotoxic to cells with
dysfunctional p53
Rudin et al. 2003 enrolled 22 patients with dysplastic lesions
● mouthwash of ONYX-015.
● Histologic resolution 37%
Lesions with histologic regression - decrease in p53 expression
levels by immunohistochemistry over time
responses were short lived.

77. Li et al. 2009 intraepithelial injections of a recombinant human
adenovirus
22 patients with dysplastic OL.
24 months follow-up,
22.7%CR, 50% PR
● potential role
● greatest limitation mode of delivery
Strategies using topical therapies may not be useful for
remaining aero digestive mucosa at risk

78. Oral pathology 2011
● might have beneficial effects in the management of pre- malignant lesions
● may be an adjunct in the prevention of oral cancer.
RCT of large sample size are necessary to further confirm

79. Prevention of HPV-related
oropharyngeal carcinoma??????
Vaccine: Is an immuno-biological substance designed to produce
specific protection against a given disease

80. Three databases (MEDLINE, ScienceDirect, and the Cochrane Library),
First meta analysis Six studies—(2 RCT 4 cross-sectional studies)—N 15,240
participants.
Vaccinated individuals were 46% less likely to develop oral HPV 16 infection (P =
0.02).
A second meta-analysis of 4 studies (1 RCT and 3 cross-sectional studies)
N 13,285 participants showed 80% less likelihood of oral HPV16 infection (P <

81. more evidence of the vaccine's efficacy or effectiveness is needed to support this.
US Food and Drug Administration approved an
expanded indication of HPV vaccine in June 2020
(HPV) 9-valent vaccine, recombinant Gardasil 9 (Merck), for the prevention of OPC and other
head and neck cancers

84. Conclusion
● Vitamin A clinical response rate (20%) high relapse
● beta-carotene plus vitamin A (32.5%) ( beta carotene - long term s/e
lung cancer
● 13cRA (48.1%) -even at low doses - toxicities.
After 3 decades of intensive research - cannot
be recommended for chemoprevention
Biomarkers -LOH at 3p14 and/or 9p21 for risk stratification
Euroscan 2000
ATBC study 2007

85. Conclusion
1 Cox 2 inhibitors
No role
2 Erlotinib alone
EPOC( erlotinib prevention of oral cancer )study - did not support
3 Green tea + Erlotinib combination
● Good cfs and os in small pilot phase 1 study
● Combination deserves further trials

86. CONCLUSION
4 Curcumin
● good tolerance , good clinical response
● Limited studies
5 P 53 agents - onyx o15 adeno virus mouthwash
● potential role
● Limited studies,mode of delivery
6 HPV Vaccine
● Approved by US FDA June 2020
● Limited evidence

87. Chemoprevention👎
Habbit cessation 🤟
Screening of high risk🤟

88. Thank you