precautions and challenges in delivering intense radiotherapy protocols with/without chemotherapy in head and neck cancers

1. IS

2. Naso-pharynx
Oro-pharynx
Oral Cavity
Larynx

3. Nasopharynx:
Oral Cavity:
1. Ant 2/3 Tongue
2. Lip
3. Floor of mouth
4. Buccal mucosa
5. Retromolar trigone
6. Gum.
Oro-pharynx: Hypo-pharynx:
1. Post 1/3 Tongue 1. Pyriform sinus
2. Post. Pharyngeal wall 2. Post. Pharyngeal wall
3. Tonsil. 3. Post. Cricoid area

4. Larynx:
I) Supra-Glottic:
1. Supra-hyoid epiglottis
2. Laryngeal aspect of AE Fold
3. Arytenoid
4. Infra-hyoid epiglottis
5. Ventricular bands
II) Glottic:
1. Vocal cord
2. Ant. Commissure
3. Post. Commissure
III) Sub-Glottis :

5. HEAD AND NECK

6. WHY RT IMPORTANT
• Usually localized disease at presentation.
• Remains localized for long even after diagnosis.
• Curable with local form of treatment.
• Only 5-10% distant metastasis without local
recurrence.
• Local control improves OS & DFS
• Organ Preservation possible.

7. PRESENT STATUS HEAD AND NECK

8. PRESENT STATUS HEAD AND NECK
• In developing countries most of the pt present in
stage IIIB – IV A
• So we need intensive treatment to improve LC by
10- 20 %

9. Which are the intensive regimens ?
– Altered fraction
• Hyperfractionatin/ Accelerated Fractionation/ CHART
– CT+RT
• Cisplatin/ 5FU/ Taxanes/ Gemcitabine/Combinations
– Targeted therapies + RT
• Trantuzumab/ cituximab / Monotuzumab
– Altered fractionation + CTRT

10. NEED ?
Toxicities
Local control
• We need to device regimens which give
increase LC, Survival without increasing
toxicities

11. Toxicities depends upon
Patient Related Treatment Related Tumor Related Physician Related
KPS Ports used Site Competence
Nutrition Energy selection Stage Convenience
Hydration Dose Location cost
Skin care Beam modifying Nodal Status Facilities
devices
Oral Hygiene Fractionation Depth of invasion
Dental Hygiene Setup Errors
Quality Assurance

12. CONVENTIONAL RT
• Conventional regimens
• 1.8 - 2 Gy/ #, 1 #/day & 5 days/week
• Weekly Dose accumulation of 9 -10 Gy

13. Altered fractionations
Conventional fractionation:
70Gy/35 F/ 7 W  HYPER
FRACTIONATION –Any
schedule employing a
dose per fraction of less
Hyperfractionation:
81.6 Gy / 68 F / 6.8 W than 1.8 Gy
 ACCELERATED – a
schedule in which the
Accelerated: 67.2 Gy / 42 F / 6w rate of dose-
accumulation exceeds
10 Gy/week
Accelerated: concomitant boost
72 Gy / 42 F / 6 W

14. ALTERED FRACTIONATION
HYPERFRACTIONATION ACCELERATED FRACTIONATION
PURE HYBRID
CHART
SPLIT COURSE
CONCOMITANT BOOST

15. Accelerated fractionation
• Reduction in overall treatment time reduces the chance of
accelerated tumor cell repopulation
• Greater probability of tumor regression for a given total
radiation dose.
• No increase in late normal tissue reactions-if dose per fraction
is not increased and adequate interval is allowed between 2
fractions.
• Increase in acute reactions -reduction in overall treatment
time.

16. ACCELERATED TREATMENT
Pure accelerated Hybrid accelerated fractionation
• conventional total • ↓ overall treatment time with
dose changes in fraction size, total dose,
• conventional fraction and time distribution.
number • Type A - shortened OTT with ↓ in
• overall time is approx. the total dose (CHART)
• Types B and C-duration modestly
halved (2#/ day)
shortened but the total dose is
• Intent- to reduce same
repopulation in rapidly • split-course (type B)
proliferating tumours. • concomitant boost (type C)

17. Pure accelerated regimen
Ref #/day # Dose Results
/wee
k
Jackson 2(2.0) 10 66.0 CR 35%vs 29% (p=0.18)
(Vancouver) 1(2.0) 5 66.0 no diff in relapse free survival
Acute toxicity- 27%vs 8 % (p=.00006)
Skaldowski 1(1.6-2) 7 70.0 3 yr LC 82%vs 37% (p<0.0001)
CAIR (Polish) 1(1.6-2) 5 70.0 3yrOS 78% vs32% (p<0.0001)
Acute toxicity-1·5 weeks earlier(66%vs 26%)
Overgaard 1 (2.0 ) 6 66.0 5 yr LRC 66%vs 57% (p=0.01)
DAHANCA 1(2) 5 66.0 5 yr DFS 72%vs 65% (p=0.004)
Hliniak 1-2(2 ) 6 66.0 5yrLRC 52%vs47%(p 0.3)
1(2) 5 66.0 5yrDFS 41%vs 35% (p=0. 3)

18. DAHANCA 6&7
January, 1992 and December, 1999
726 stage I-IV 750
Conventional Accelerated
66-68Gy/33-35# 66-68Gy/33-35#
Wk 1 ♦ ♦ ♦ ♦ ♦
Wk 1 ♦ ♦ ♦ ♦ ♦ ♣
Wk 2 ♦ ♦ ♦ ♦ ♦
Wk 2 ♦ ♦ ♦ ♦ ♦ ♣
Wk3 ♦ ♦ ♦ ♦ ♦
Wk3 ♦ ♦ ♦ ♦ ♦ ♣
Wk4 ♦ ♦ ♦ ♦ ♦
Wk4 ♦ ♦ ♦ ♦ ♦ ♣
Wk5 ♦ ♦ ♦ ♦ ♦ Wk5 ♦ ♦ ♦ ♦ ♦ ♣
Wk6 ♦ ♦ ♦ ♦ ♦ Wk6 ♦ ♦ ♦ ♦ ♦
Wk7 ♦ ♦ ♦ ♦ ♦
Overgaard, Lancet 2003; 362: 933–40

19. DAHANCA 6&7
For the first time showed improved
• 5 yr locoregional control (66% vs 57%). [p=0.005].
• 5 yr disease free survival ( 72% vs 65%). [p=0.01].
• Improved voice preservation (80% vs 68%) [p=0.007]
Overgaard, Lancet 2003; 362: 933–40

20. DAHANCA 6 and 7 trials
Mucositis Late Morbidity
53% VS 33% P<0.0001
Overgaard, Lancet 2003; 362: 933–40

21. ACCELERATION TYPE A
Fraction Total dose Tumour response Complications
per day (Gy)
Dische 3 (1.5) 54.0(2wk No difference in More acute mucositis, less
CHART 1 (2.0) 66.0(6.5wks LRC,DFS &OS epidermal telangiectasia, and
) oedema with AF
Poulsen 2 (1.8) 59.4(3.5wks 5 yr LRC- Severe acute Mucositis
TTROG 1 (2) ) 52%vs47%(p=0.35 yr (p=0.0006),lower frequency of
70(7wks) DFS 41%vs 35% grade >2 late side effects
(p=0.32) (p<0.05)with AF
Bourhis 2 (2) 63.0(3.3wks 2 yr LRC Early stopping due to higher
GORTEC ) treatment related deaths.
2(1) 58%vs 34%(p<0.01)
70.0(7wks) no diff in OS
Lancet Oncology vol3 Nov 2002

22. CHART - unique form of hybrid
fractionation.
• 36 fractions over 12 consecutive days using 3
fractions per day,1.5Gy/fraction.
• Total dose - 54Gy.(dose reduction by19%).
• Acceleration of treatment time by 4.5 wks.
Radiother Oncol. 44:123–36 (1997).

23. CHART Regime
• MRC Trial-918 patients.
• Mostly Laryngeal cancers.
• Non-significant improvement in disease free survival.
• Strong trend for improved benefit in patients with advanced
disease(p=0.065).
• Lesser late effects(mucosal ulceration, necrosis and telangiectasia).
• Acute mucositis more severe 73% VS 43% (occurring in 3rd week).
Radiother Oncol. 44:123–36 (1997).

24. Accelerated radiotherapy with delayed
concomitant boost
• Initial target volume- conventional daily fractions
• Boost - second daily fraction in last 2 weeks
• Total dose -63 Gy/35 days
Grade 3 mucositis -50%
DFS- 56%
OAS -76%
MACKENZIE I JROBP( 45, No. 3) 589–595, 1999

25. HYPERFRACTIONATION
• To further separate the early and late effects
• overall treatment time 6-8 wks
• two fractions / per day
• number of fractions are doubled to 60-80
• dose per fraction - decreased
• Intent - further reduce late effects while achieving the same or
better tumour control and the same or slightly increased early
effects.

26. TRIALS OF HYPERFRACTIONATION
# per
dose Tumour response Complications
day
2 (1.2) 81.6 LRC-higher with HF and CB
Marcial 1-2(1.6) 72.0 (p=0.045 & .06) More acute Mucositis
RTOG 2(1.6) 67.2 DFS trend favours HF; no no difference in late complications
1 (2.0) 70.0 difference in OS
5 yr LRC – More acute mucositis with No
Horiot 2 (1.15) 80.5
56%vs38%(p=0.02), difference with late complications
EORTC 1 (2.0) 70.0 rate
5 yr LRC
Cummings 2(1.4) 58.0 More acute mucositis with
45% vs. 37% (p=0.01)
PMH 1 (2.5) 51.0 Late Toxicity-8%vs.14% (p= 0.31)
5 yr OS 40%vs30%(p=0.01)
(Lancet Oncology vol3 Nov 2002)

27. Effect of time interval between two fractions
Usually > 6 hrs of gap
between two fractions

28. Phase III Randomized Trial of Very Accelerated Radiation
Therapy Compared With Conventional Radiation Therapy
in Squamous Cell Head and Neck Cancer: A GORTEC Trial
 Conventional -70 Gy/ 35
# of 2 Gy over 49 days
 very accelerated RT-62 -
64 Gy/ 31-32 # over 22 to
23 days (2 Gy/fraction
bid).
J Clin Oncol. 2006 Jun 20;24(18):2873-8.

29. Phase III Randomized Trial of Very Accelerated Radiation
Therapy Compared With Conventional Radiation Therapy
in Squamous Cell Head and Neck Cancer: A GORTEC Trial
J Clin Oncol. 2006 Jun 20;24(18):2873-8.

30. RTOG 9003 TRIAL (1073 PATIENTS)
ARMS Dose/#; Dose Rx time LRC DFS OS Grade Late
No. of # III/IV Toxicitie
reactions s
Standard 2Gy/#; 35 70Gy 7 week 46% 31.7% 46% 35% 9%
fractionation #
Accelerated 1.6Gy/#; 67.2Gy 6 week 47.5% 33.2% 46.2% 51% 8%
fractionation 42 #
with split
Hyperfraction 1.2Gy/#; 81.6Gy 7 week 54% 37.6% 54.5% 55% 9%
ation 68#
Accelerated 1.8Gy/#; 50.4Gy 6 week 54.5% 39.3% 50.9% 59% 9%
fractionation 30+12# + 8 Gy
with CB
Int J Radiat Oncol Biol Phys. 48:7-16 (2000).

31. Conclusion – Altered Fractionation
• Local control and overall survival better at the
cost of increased toxicities.

32. CHEMORADIOTHERAPY (MACH-NC Update)
• 24 new trials,87 in total( 50 concurrent), 16,000 patients
• Absolute benefit (overall) 5% at 5yrs
• Concurrent RT, HR - 0.81(p=0.0001)
• Absolute benefit (concurrent) 8% at 5 yrs
•No difference between mono chemo (0.84) and poly chemo
(0.77)
• Magnitude of benefit higher for platinum based chemo (0.75)
than for other chemo (0.86) [p=0.01].
JCO vol 22, No 14S (July 15 Supplement:5505(2004).

33. A Three-arm Randomized Trial
TMH Experience
Interim Analysis (Apr 2000 - Dec 2004, n= 150)
Conventional Radiotherapy
versus
Concurrent Chemotherapy and Radiotherapy
versus
Accelerated Radiotherapy
Advanced (Stage III & IV) Non- Nasopharyngeal
Squamous Cell Carcinoma Of The Head and Neck

34. CONCLUSION
(TMH Experience Interim Analysis (Apr 2000 - Dec 2004, n= 150)
• Accelerated fractionation and Concomitant chemo
radiotherapy is feasible in our setup
• Acceptable Increased Acute Toxicity with
chemoradiotherapy (reflected as increased hospitalisation)

35. Combination of altered fractionation and
chemotherapy
 Several trials evaluated altered fractionation with
chemotherapy.
 Showed some improvement in locoregional control
and improved survival.
 100% patients developed severe and early mucositis.
 Combination should only be used in a trial setting.

36. Randomized study -concurrent twice-a-day RT and
chemotherapy (BIRCF) : results at 2 years (FNCLCC-
GORTEC)
Hyper fractionation(1.2 • Treatment compliance
Gy/# ,Twice-daily 80.4 was quite satisfactory
Gy/46 day • Mucositis grade 3–4
-69.5% /82.6%
Chemotherapy (arm B): • OS: 20.1% /37.8%(p<
Cisplatin 100 mg/m2 0.038)
5FU750 mg/m2/day • DFS: 48.2% vs. 25.2%
cycle 1 (p < 0.002)
IJROBP 64(4) 983–994, 2006

37. Hyper fractionated accelerated radiotherapy alone
and with concomitant chemotherapy
• 4 yr OAS - 18% /33%, (p =
 Arm A- 77.2 Gy (16 Gy as
0.25 )
2Gy /#→rest as 1.4 Gy /#
• 4-year DFS- 36%/ 41% (p =
twice daily)
 Arm B- RT 70.6 Gy(30 Gy 0.5)
as 2Gy /#→rest as 1.4 • Mucositis III/IV occurred in
Gy /# twice daily) 27% in chemotherapy arm
+MMC+5FU
HEHR R&O July 2006,

38. INTENSIVE RADIOTHERAPY ± CHEMOTHERAPY PROTOCOLS
• Leads to ↑ LRC and OS
• Allow for Organ Preservation
• By minimizing Sx, ↓potential cosmetic Sequelae
• ↓functional impairment
• Impose severe acute toxicities
• Some degree of chronic impairment

39. INTENSIVE RADIOTHERAPY ± CHEMOTHERAPY PROTOCOLS
• While on t/t performance and functional status
decline dramatically
• Corresponding increase in symptoms
• Improvement in most domains by 12 mths
• 1/3 continue to report difficulty in speech,
swallowing and pain
• Similar pretreatment magnitude.

40. INTENSIVE RADIOTHERAPY ± CHEMOTHERAPY PROTOCOLS
• The most salient persistent difficulties :
– Dry mouth
– Taste
– Sticky saliva
– Comfort in eating/socializing with others
– Ability to eat a full range of solid foods
• Associated with QOL

41. TOXICITIES
• Not unique with intensive protocols
• Also seen in XRT or Sx+RT
• In general, comparison across studies is difficult
• Many reports include both early and late-stage
patients at various times after treatment
• Data are presented in terms of mean scores on a
variety of measures

42. TOXICITIES

43. TOXICITIES
• Unfortunately Late effects also
• Just now being studied
• Validated tools
• Objective measures
• Profound impact on pts. Physical, functional &
emotional well being.

44. Patient Selection for Aggressive Treatment Regimens
• Careful Selection of pts
• Who are capable of withstanding added toxicity
burden
• Careful medical, psychological, and social history
• Spend quality time with pt. for councelling
• History of smoking or alcoholism: related
comorbidities
• Social support network and financial condition

45. Patient Selection for Aggressive Treatment Regimens
• Age
• Performance score ( KPS)
• Education/ Literacy
• Stage and Histology
• Pretreatment nutritional assessment
Thus most of Aggressive treatment regimens/ trials
tend to skew more younger, healthier, educated
pts.

46. Patient Selection for Aggressive Treatment Regimens
Treatment Benefit Decreases With Increasing Age  2 meta-analyses
Meta-Analyses of Radiotherapy in Head
Age Alt-RT vs standard RT Concomitant CT+RT vs
and Neck Cancer; Bourhis J, ASTRO 2002 &
RT
ASCO 2004
# HR P Trend # HR P Trend
Patients Test Patients Test Patients aged 71 years or older had
< 50 1311 0.78 .007 2584 0.76 .003 lower performance status
lower stage at presentation
51-60 2300 0.95 3306 0.78 higher rate of laryngeal primaries
higher percentage were women
61-70 2346 0.92 2698 0.88
proportion of deaths due to causes other
71+ 1085 1.08 692 0.97 than head and neck cancer increased with
age
Bourhis J Sr., Abstract 5501, Journal of Clinical Oncology, 24, 280s

47. Patient Selection for Aggressive Treatment Regimens
"How do we generalize clinical trial results to the
broader head and neck population, which is
plagued with medical, social, and financial
problems?"

48. NUTRITION
• Significant proportion of pts. are malnourished at
presentation
• Malnutrition has significant impact on morbidity,
mortality and QOL
• Causes
– ↓Nutrient intake
– ↑ demand
– Tx induced Derangements

49. NUTRITION
• ↓ intake may be due to
– Alcohol & Tobacco
– Poor dentition
– Partial or complete obstruction of aerodigestive tract
– Trismus
– Post-surgical functional and anatomic impairments of chewing
and swallowing
– Post-XRT mucositis, odynophagia, dysphagia, xerostomia
– Chemotherapy-induced nausea, vomiting
• ↑ nutrient loss: Vomiting

50. NUTRITION
• ↑ Demand due to acute metabolic stress.
• Stage III/IV head & neck cancer treated with multiple
modalities—the strongest independent predictor of
survival was pretreatment weight loss (Mick, et al).
• Head & neck cancer patients shown to have a significant
decrease in survival at 2 years if malnourished (57.5% vs.
7.5%) (Brookes, et al).

51. NUTRITION
• Impact:
– Immunocompetence
– Inability to tolerate antineoplastic treatments
– Toxicities more severe—treatment delays, higher costs
• Assessment:
– History & physical exam
– Anthropomorphic measurements
– Skin testing
– Laboratory values
– Weight loss as percentage of baseline weight
– Dietitian referral

52. NUTRITION
• Symptomatic treatment
– Mucositis : Oral hygiene
– Dental care
– Nausea Vomiting: Ondensetron/ Graniseteron
– Odynophagia
• Nutritional counseling
– Who tolerate PO
– High calorie ,High protein Diet
– Plenty of fluids
– Diet modification: Bland, not very hot/cold, Soft consistency
– Maintain Diet book

53. NUTRITION
• Oral Supplementation: Commercially available : Costly
• Enteral nutrition
– Nasogastric tube feeding :
• weight loss >5%
• Need replacement when narrow lumen clogs/ discolouration/ hygiene
• Pt. tolerance
• Reflux
– Gastrostomy/Jejunostomy feeding tube:
• Open, endoscopic, flouroscopic

54. NUTRITION
• Gastrostomy/Jejunostomy feeding tube:
– Appropriate for patients who will need longer-term enteral feeds
(at least 2 weeks)
– Can be easily maintained and used in outpatient setting, less
cosmetic impact
– Fewer but severe complications
– Complications: leak, infection, skin excoriation,dysfunction, pain
– Isolated case reports of metastatic deposits

55. NUTRITION

56. NUTRITION
• Impact of nutritional support:
• Scolapio, et al showed that PEG placement before XRT
resulted in prevention of weight loss, treatment
interruption, and hospitalization for hydration.
• Shaleen kumar et al. showed that PEG placement can
improve compliance in delivering intensive
chemoradiation.

57. Does the Use of a Percutaneous Endoscopic Gastrostomy (Peg) Improve Compliance
to Intensive Chemo-Radiotherapy (Crt) Protocols in Advanced Head-Neck Cancers?
Shaleen Kumar et al, SGPGI, UICC World Cancer Congress 2006
• Stage III and IV SCC of Head and Neck region
• 68 patients ( Aug 2003-Oct 2005)
• 6 fraction-a-week radiotherapy protocol (70Gy/35fx/6 weeks)
concurrent with weekly cisplatin 35mg/m2
The two groups were
balanced for patient,
disease and CRT
interventions.

58. Results
intensive CRT protocols are feasible provided there is a doable and effective nutrition
supportive system (i.e. PEG) in place. This measure limits treatment related mortality which
otherwise would negate any potential benefits of intensification

60. Patterns of change over time
Likert Scale

63. MUCOSITIS
• Most devastating Acute toxicity
• Physical manifestation of tissue damage
• Incidence (Gr 3-4) ↑
– 30-40%( RT alone) to 60-100%( CMR)
• No proven agent to prevent or treat till date
• Current recommendation: supportive care
– Pain control
– Oral Hygiene
– Nutritional counseling

64. MUCOSITIS
• Grading requires visual examination
• Predominantly based on presence of erythema and
ulceration
• Only visualized in oral cavity and oropharynx
• Difficult to assess in nasopharynx, hypopharynx,
larynx
• Greatly underrepresent the extent and impact

65. MUCOSITIS
• Underlying inflammation has many profound physiologic,
functional, and symptom control implications
• Not captured by assessment of mucosal integrity only
• Inflammation results in
– Edema
– Pain
– Dysphagia
– Odynophagia
– Altered diatery intake
– Systemic manifestations

66. MUCOSITIS
• Pt. self administered tool by Epstein and colleagues
– Oral Mucositis Weekly Questionnaire -- Head and Neck (OMWQ-HN)
• Self report that measures impact of mucositis
• Used along with
– Performance Status Scale for Head and Neck Cancer (PSS-HN)
– Functional Assessment of Cancer Therapy (FACT-HN)
• Found valid and reliable*
• ↑oral pain was associated with decreasing oral function
Epstein JB, Beaumont JL, Gwede CK, et al. Preliminary results of the validation of a patient (pt) self-administered questionnaire (Oral Mucositis
Weekly Questionnaire-Head and Neck [OMWQ-HN]) to assess the impact of OM on pain and functioning in head and neck cancer (HNC). Proc
Am Soc Clin Oncol. 2006;24:292s

67. MUCOSITIS
• Used prospectively in 75 pts undergoing CCR
– ↑Oral pain from baseline to week 6
– 76% by the end of week 6 : severe pain due to mouth and throat
soarness
– High % of patients were on opoids : Pain remained problamatic
– Oral pain associated with ↓in swallowing and vocal function
– Results in costly utilization of resources
• Feeding tube placement
• Unanticipated visits
• Hospitalization
Isitt J, Murphy BA, Beaumont JL, et al. Oral mucositis (OM) related morbidity and resource utilization in a prospective study of head and neck
cancer (HNC) patients. Proc Am Soc Clin Oncol. 2006;24:289s

68. MUCOSITIS
• No proven agents available to treat
• Oral hygeine and pain is the dominant factor
• Salt and soda gargles: cost effective
• Micronized sucralfate suspension
• Newer agents, such as palifermin (recombinant human
keratinocyte growth factor-1) showed some benefit
• Saforis (an oral glutamine suspension) may also promote
recovery from mucosal damage
• Wobe-Mugos (proteolytic enzymes)

69. MUCOSITIS
• Wobe-Mugos comprised papain 100 mg, trypsin 40 mg, and
chymotrypsin 40 mg
• Efficacy of Wobe-Mugos((R)) E for Reduction of Oral Mucositis
after Radiotherapy : Results of a Prospective, Randomized,
Placebo-Controlled, Triple-Blind Phase III Multicenter Study
• Result: tolerated well but no promising results

70. MUCOSITIS
• GM-CSF:phase III study by RTOG 9901
• Aim: reduce the severity and duration of mucositis
• SC injection of GM-CSF 250 µg/m2 3 times a week
• Result : no significant effect
• New formulation : RK 0202(N-acetyl-L-cysteine )
– 6 times a day as oral rinse
– Chambers et al showed some promising results.
– Less mucositis(by 19 – 29% for 60Gy- 50 Gy),less FT and opoids

71. MUCOSITIS
How To Control and reduce the severity and duration of mucositis?

72. SKIN REACTIONS

73. SKIN REACTIONS
•Prophylactic : Pt. education and self care instructions
•Avoid tight clothes: Friction
•Oral intake of fluids: 3 – 4 lit/day
•Avoid Shaving, soaps, cosmetics: irritation & dryness
•Protection from temperature, Sun, Ice pack, Heating pads

74. SKIN REACTIONS
• Dry desquamation: Flaky peeling of epidermis
• Cracks and fissures are common
• Sense of pain and pruritus
• Effect of dose, friction
• Can progress to moist desqumation
• bacterial/ fungal infection

75. SKIN REACTIONS
• Moist desq: Maintain hygiene
– Prevent secondary infection
– Promote reepithelization
• Ulceration/necrosis
– Use of Amniotic membrane: Available at tissue bank
– May require tissue graft

76. SKIN REACTIONS

77. SKIN REACTIONS
• Dini and colleagues: mixture of staeric acid,
propylene glycol, glycerol & polysaturated alcohols
• Hydrophilic+ Hydrophobic in a foam emultion
• Form protective barrier without rubbing.
• Complete dissaperance of symptoms in 58%
– 50 % reduction in 38 %
• Steroidal preparations : Betnovate-N ™

78. SKIN REACTIONS
To delay the occurrence and reduces the grade of acute skin
reactions.

79. DENTAL CARE
• Radiation induced decay, necrosis and subsequent
need for dental extraction
• Prophylactic care reduces incidence by 1/3rd
• Already decayed teeth: pretreatment extraction
• FGA : protection against acidic degradation
• Damage to periodontal membrane: tooth decay
• Decreased salivation

80. DENTAL CARE
• Normal salivation acts as buffer
• Prevention of salivary function may be useful
• Use of Fluoride toothpaste

81. LORHAN
• Prospective development of Longitudinal Oncology
Registry of Head and Neck Carcinoma
– document the outcome (tumor control, survival)
– determine the incidence and severity of major dose-
limiting and other important treatment toxicities such as
• mucositis/stomatitis
• skin reactions
• infusion reactions
• allergic reactions/hypersensitivity

82. LORHAN
– identify supportive care received
• for managing nutrition
• Pain
• Nausea
• other complications such as feeding or tracheotomy tube use
• opioid analgesic use
• antiemetic use
• use of other selected supportive care agents

83. LORHAN
– Approximately 25,000 patients will be enrolled on the
registry over the next 10 years
– FU for at least 2 years and up to 10 years
– If successful, the LORHAN database may provide
invaluable insight into treatment outcomes in various
head and neck patient populations
Curran W, Chen A, Harari P, et al. Longitudinal Oncology Registry of Head and Neck Carcinoma
(LORHAN), a new national cancer registry. Proc Am Soc Clin Oncol. 2006;24:300s

84. Patients forget acute toxicities when they are
cured
AND
Doctors forget late toxicities when they are
treating

85. Pre-treatment and treatment related risk factors for severe late
toxicity after chemo-RT for head and neck cancer: an RTOG analysis.
Machtay M, Moughan J, Trotti A, et al Proc Am Soc Clin Oncol. 2006;24:280s
• 3 CCR protocols (RTOG 91-11, 97-03, 99-14)

86. Pre-treatment and treatment related risk factors for severe late
toxicity after chemo-RT for head and neck cancer: an RTOG analysis.
Machtay M, Moughan J, Trotti A, et al Proc Am Soc Clin Oncol. 2006;24:280s
• 25 patients had a feeding tube at least 2 years after
completion of therapy
• Overall % of late effect = 43%
• Predictors OR p Value
– Age 1.05 .01
– Stage 3.08 .004
– Tumor Size 4.41 .03
– Neck dissection 2.55 .011

87. Pre-treatment and treatment related risk factors for severe late
toxicity after chemo-RT for head and neck cancer: an RTOG analysis.
Machtay M, Moughan J, Trotti A, et al Proc Am Soc Clin Oncol. 2006;24:280s
• % of late effects is high as compared to reported by
Large RCTs
• ↑Awareness and efforts to capture late effects

88. OTHER CHALLENGES
• Normal tissue complication probability
– Eg. cord tolerance
– Due to addition of chemo
• Second malignancies
• Hypoxia
• No surrogate markers
• Strict QA

89. But,
Activity does not
always mean
progress
89

90. nor
Progress is an
hypothesis….
90

91. Thank you
Progress is definite
gain in knowledge
for the future…. 91

93. Purpose: safety and efficacy of CBRT and concurrent Cisplat in Advanced H&N cancers
Feb 2000 to June 2001, n= 95
CBRT : ph I—44 Gy/22fx/4.5 weeks,
ph IIa—16 Gy/8fx/1.5 weeks
Ph IIb—10 Gy/8fx (delivered as a second daily fraction after a gap of 6 h along with
phase IIa)
CT: cisplatin 35 mg/m2 weekly usually preceding CBRT by an hour

98. Conclusion
On present evidence, in the settings of a developing
country, CBRT with concurrent cisplatin cannot be
recommended as primary therapy in advanced
head and neck cancers without formal comparison
with other treatment modalities.

100. Some other useful data

101. Author No. of patients
T-stage Dose Local Control
(Institute) (Year)
Cellai.E 205 (Early Glottic Ca)
(Univ. of Florence) (1970-1985) T1a: 45 61-64Gy 43(96%)
T1b: 110 97(88%)
T2 : 50 38(76%)
Chang 74 (Pharyngeal Ca)
(Univ. of Oregon) (1971-1991) T1:6 60-70Gy 100%
T2:27 59-72Gy 55%
T3:32 59-74Gy 31%
T4:9 60-70Gy 29%
Overgaard 478 T1larynx
(Danish Cancer Soc.) (1963-1985) Glottic:358 81%
Supra: 117 55%
Sub: 3
Dinshaw 568
(1990 - 1996)
All sites (except nasophx) 60 - 70 Gy 53%
(Clinical oncology 2006 All stages

104. Bonner JA,et al. N Engl J Med 2006;354:567-578 .
424 Patients RT RT + CMab
OS 45 55
3 Years
LRC 34 47
3 Years
Gr ¾ Mucositis 52 56

105. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma:
three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-
Analysis of Chemotherapy on Head and Neck Cancer
PignonJP et al.Lancet 2000;355:949-955
• Meta-analysis of 63 trials (10,741 patients)
• Absolute survival benefit of 4% at 2 and 5
years in favour of chemotherapy
• Chemotherapy given concomitantly to
radiotherapy gave significant benefits.

106. Underperformance in Radiotherapy arm?
Brizel DM et al.N Engl J Med 1998;338:1798-1804
122 patients HF RT HF CTRT
7500cGY/30#/ 125 7000cGY/28#/ 125
cGy bid cGy bid
OS 34 55
3 Years
LRC 44 70
3 Years
Gr3 Mucositis 75 77

107. Randomized trial of radiation therapy versus concomitant
chemotherapy and radiation therapy for advanced-stage
oropharynx carcinoma.
Calais G et al.J Natl Cancer Inst 1999;91:2081-2086 .
226 patients RT CT RT
7000Cgy/35# 7000Cgy/35#
OS 31 55
3 Years
LRC 42 66
3 Years
Gr ¾ Mucositis 39 71

108. Final results of the 94-01 French Head and Neck Oncology and
Radiotherapy Group randomized trial comparing radiotherapy alone
with concomitant radiochemotherapy in advanced-stage oropharynx
carcinoma
Denis F et al J Clin Oncol 2004;22:69-76
226 patients RT CT RT
7000Cgy/35# 7000Cgy/35#
OS 16 22
5 Years
LRC 25 48
5 Years
Gr ¾ Mucositis 30 56

111. A Radiation Therapy Oncology Group (RTOG) phase III
randomized study to compare hyperfractionation and
two variants of accelerated fractionation to standard
fractionation radiotherapy for head and neck squamous
cell carcinomas: first report of RTOG 9003.
FU KK et al.Int J Radiat Oncol Biol Phys 2000;48:7-16
• .

112. 2 Year
endpoint
CFRT
70Gy/35#
HFRT
.
81.6 Gy/68#
AccSpRT
67.2 Gy/42#
AccCon
BoostRT
7 weeks 7 weeks 6 weeks 72 Gy/42#
6 weeks
OS 46 54.5 46.2 50.9
LRC 46 54 47.5 54.5
Gr3 25 41 40 41
Mucositis

113. Intensified hyperfractionated accelerated radiotherapy limits
the additional benefit of simultaneous chemotherapy: results
of a multicentric randomized German trial in advanced head-
and-neck cancer.
StaarS et al.Int J Radiat Oncol Biol Phys 2001;50:1161-1171
• With accelerated radiotherapy, the efficiency
of simultaneously given chemotherapy may
be not as high as expected when compared to
standard fractionated RT.