Management of Carcinoma oropharynx

1. Management of Ca
Oropharynx
By-Dr.Satyajeet Rath
Guided by-Prof.Kamal Sahni
19-07-2016

2. TNM Staging – T Staging
N Staging

3. Stage & Grade
M Staging
M X :Distant metastasis cant be
assessed
M 0 : No distant metastasis
M 1 : Distant metastasis
Histoloical Grade
G X : Grade cant be assessed
G 1 : Well differentiated
G 2 : Moderately differentiated
G 3 : Poorly differentiated
G 4 : Undiferentiated

4. Management Goals
• Maximizing the chance of cancer cure while minimizing the
functional impairment and treatment related toxicities
• Locally confined disease (stage I and stage II tumors) are
considered as early stage
• Locoregionally advanced disease - stages III and IV
(nonmetastatic) disease

5. Early stage
• For all subsites, early-stage tumors are usually well controlled
with a single local modality, either radiotherapy or surgery.
• Selection of local modality should be based on the primary
tumor size, extent of local spread, and subsite involved.
• Generally, small tumors of the tonsil can be well managed
surgically, whereas the morbidity of surgery on the soft palate
and base of tongue tumours favours radiotherapy

6. Locally Advanced
• For loco-regionally advanced disease
• Two appropriate treatment strategies are used:
• (a) either Sx followed by RT±CT based on pathologic risk
factors
• (b) radiotherapy usually given with chemotherapy,
concurrently

7. Treatment Modalities
• Surgery
• Role of Radiotherapy
• Role of chemotherapy

8. Surgical Approaches

9. Base of Tongue
• Limited role due to high morbidity and functional disability
associated with the surgical procedures

10. Tonsil cancer
• Wide local Excision –small (<1 cm ),early stage, confined to
anterior pillar
• Radical Tonsillectomy–larger tumor with extension to tongue,
mandible or soft tissue. It include resection of
• Tonsil with tonsillar pillar & fossa
• Portion of soft palate
• Tongue
• Lateral/Total pharyngectomy as needed
• Mandible
• But, in general apart from small tonsillar lesion surgery is
generally not done now a days and chemo-radiotherapy is
preferred.

11. Soft Palate
• Rarely recommended because
• Significant reflux into nasopharynx post surgery and functional
compromise
• Midline location– B/L neck involvement is common
• In general, radiotherapy alone or along with concurrent
chemotherapy is preferred.

12. Surgical Margins
• UK Royal college of pathologist guidelines: Datasets for histopathology
reports on head and neck carcinomas and salivary neoplasms (2nd edition).
• Clear margin: histological clearance >5mm
• Close margins: 1-5mm
• Positive margin: <1mm
*Langendijk JA, Ferlito A, Takes RP, Rodrigo JP, Suarez C, Strojan P et al. Postoperative strategies after primary surgery
for squamous cell carcinoma of the head and neck. Oral Oncol 2010;46:577–585.

13. Neck dissections

14. 2001 Classification of neck dissection
• Radical Neck Dissection (RND)
• Modified RND
• Selective ND (SND)
• Supraomohyoid SND (I - III/IV)
• Lateral SND (II - IV)
• Posterolateral SND (II - V)
• Anterior SND (VI)
• Extended ND
• Other Nodal groups apart from Level I-VI
Proposed by American HN Society

15. Selective neck dissection Modified RND type 1,2,3.

16. Role of Radiotherapy
• RT alone
• Pre-op RT vs Post-op RT
• Post-op RT vs Post op CRT

17. RT alone

19. • 2 arms
• CHART, where a dose of 54 Gy was given in 36 fractions over 12 days
• Conventional therapy where 66 Gy was given in 33 fractions over 6.5 weeks
• 918 patients
• 26% oropharynx patients
• Acute radiation mucositis was more severe with CHART, occurred earlier but
settled sooner

20. • Life table analyses of loco-regional control, primary tumour control, nodal
control, disease-free interval, freedom from metastasis and survival showed
no evidence of differences between the two arms

22. Fu et al IJROBP 32:577–588 ;2000
(60%)

23. Fu et al IJROBP 32:577–588, 2000
•1113 patients entered , 1073 patients randomised

24. Higher grade – III toxicities in all 3 arms

25. • Median follow up – 23 mnths
• Primary end point – 2 yr LRC
• HFX(p=0.045) & AFX-C(p=0.05) improved LRC
• Trend towards improvement in DFS for both HFX & AFX-C
• No significant difference in OS

27. 2013 , JJ Bietler , IJROBP
• When censored at 5 yrs
• Only HFX showed significant improvement in 5-yr LRC ( p - 0.05)
• HFX improved overall survival (P - 0.05)
• DFS was improved for all 3 arms (non-significant)

28. • 350 patients
• 66% oropharynx patients
• 2 arms
• single 2 Gy/day to a dose of 70 Gy in 35 fractions in 49 days
• ART, using 1.8 Gy twice a day to a dose of 59.4 Gy in 33 fractions in 24 days
• median potential follow-up time was 53 months

29. • No differences in DFS, disease-specific survival and loco-regional control
• Conclusion : ART does not produce improvements in loco-regional control
when the total dose is reduced.
Accelerated RT Convemtional
RT
P value
DFS 41% 35% 0.323
Disease specific
Survival Rate
46% 40% 0.398
LRC 52% 47% 0.300

30. • To find out whether shortening of treatment time by use of six instead of five radiotherapy
fractions per week improves the tumour response in scc
• 1485 patients
• 1476 eligible patients were randomly assigned five (n=726) or six (n=750) fractions per
week at the same total dose and fraction number (66–68 Gy in 33–34 fractions to all
tumour sites except well-differentiated T1 glottic tumours, which were treated with 62
Gy)
• 29% pharynx patients
• Primary end point was LRC

31. • Benefit of shortening of treatment time was
seen for primary tumour control (76 vs 64%
for six and five fractions, p=0·0001), but was
non-significant for neck-node control
• No improvement in overall survival
6 # 5 # P Value
LRC 70% 60% 0.0005
DFS 73% 66% 0.01
Acute Reactions 53% 33% 0.0001

32. • 15 Randomized Trials of Varied Fractionation (1970-1998)
• 6515 patients
• Mostly Oropharynx(44%) and Larynx(34%) patients
• Follow up varied from 4 to 10 years
• Median follow up – 6 years
• 74% stage III & IV disease
• IPD Meta-analysis
Bourhis J, et al . Lancet 2006;368(9538):843-854

33. Survival curves by treatment arm for all trials and for the three groups of trials according to the type of altered fractionated radiotherapy
(A) Hyperfractionation. (B) Accelerated fractionation without total dose reduction. (C) Accelerated fractionation with total dose reduction. (D) All three groups
together. The slopes of the broken lines from year 6 to year +7 are based on the overall death rates in the seventh and subsequent years
HFX
Acc.
Fractionation
without Total
dose
reduction
Acc.
Fractionation
with Total
dose
reduction
All
three
groups

34. Locoregional control curve by treatment arm according to the type of radiotherapy(A) Hyperfractionation. (B) Accelerated
fractionation without total dose reduction. (C) Accelerated fractionation with total dose reduction. (D) All three groups together.
HFX
Acc.
Fractionation
without Total
dose
reduction
Acc.
Fractionation
with Total
dose
reduction
All
three
groups

35. • Primary endpoint was OS
• Overall, 8% reduction in risk of death
• Survival benefit at 2 years – 3.3% , at 5 yrs – 3.4 %
Overall Hyper
fractionation
Accelerated
fractionation
with same total
dose
Accelerated
fractionation
with total
dose
reduction
OS Benefit 3.4% 8.2% 2% 1.7%
LRC
Benefit
6.4% 9.4% 7.3% 2.3%

36. • 2 armed study –
• Accelerated regimen of six fractions of radiotherapy per week (n=458)
• Conventional radiotherapy regimen of five fractions per week (n=450)
• Total dose of 66–70 Gy in 33–35 fractions.
• 52% pharynx patients
• Primary end point - LRC

37. •No significant differences in acute & late
radiation side-effects
6#/week 5#/week P value
5-yr
LRC
42% 30% 0.004
DFS 50% 40% 0.03
OS 35% 28% 0.07

38. Cochrane database syst review, Dec 2010
• 30 trials involving 6535 participants
• Pooling trials of any altered fractionation radiotherapy compared to a
conventional schedule showed a statistically significant reduction in total
mortality (hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.76 to 0.98)
• Statistically significant difference in favour of the altered fractionation was
shown for the outcome of locoregional control (HR 0.79, 95% CI 0.70 to
0.89)
• No statistically significant difference was shown for disease free survival.
• No statistically significant difference was shown for any other comparison.

39. Summary of evidence for RT alone
• HFX improved LRC & OS
(EORTC 22791, RTOG 9003, MARCH Meta-analysis)
• Pure acceleration (6#/week) without any dose reduction
• improved LRC by 10-12% and the advantage is mainly significant at
T-site & not N-site
• Improved DFS
(DAHANCA-10% & IAEA-12%)
• Acceleration with total dose reduction & CHART doesn’t confer
any benefit.
(CHART, T-TROG)

40. Pre-op RT vs Post-op RT

41. Pre-op vs. post-op RT
RTOG 73–03 (Kramer et al. 1987)
• patient - 354
• 23% oropharynx patients
• Patients with advanced H&N cancer
randomized to
• 50 Gy pre-op vs 60 Gy Post-op
• Post-op RT improved LRC
• Trend towards improvement in OS
• Complications not different
• Established that post-op RT is better
than pre-op RT
* Kramer S et al Head Neck Surg 1987;10:19-30
Pre-op
RT
Post-op
RT
P
Value
LRC 48% 65% 0.04
OS 33% 38% 0.10

42. Post-op CT-RT

43. EORTC 22931
Bernier J et al N Engl J Med 2004;350:1945-1952
• 334 patients
• 101 pts(34%) oropharynx
• Primary end point – PFS
• 2 arms :
• radiotherapy alone (66 Gy over a period of 61⁄2 weeks)
• same radiotherapy regimen combined with cisplatin 100 mg/m2 on days
1, 22, and 43 of the radiotherapy regimen
• Median follow-up of 60 months

44. CT-RT RT alone P value
PFS 47% 36% 0.04
OS 54% 40% 0.02
LRF 31% 18 0.007
Acute Effects 41% 21% 0.001

45. RTOG 9501
Cooper JS et al N Engl J Med 2004;350:1937-1944.
• 459 patients
• Oropharynx - 78(37%) in RT arm vs 99(48%) in CRT arm
• Median follow-up of 45.9 months
• Radiotherapy alone (60 to 66 Gy in 30 to 33 fractions over a period of 6 to 6.6
weeks)
• RT plus concurrent cisplatin
(100 mg per square meter of body-surface area intravenously on days 1, 22, and 43).
• Primary end point – Local and regional tumour control
• Oropharynx - 78(37%) in RT arm vs 99(48%) in CRT arm

46. CT-RT RT
alone
P value
2 –yr
LRC
82% 72% 0.01
Acute
Effects
77% 34% P<0.001
•No significant difference in OS & DFS

47. Head & Neck,2005

48. In summary, these
two most recent
trials, support the use
of postoperative CRT
for patients with high
risk for recurrence,
i.e, margin &
ECE+ve
Head & Neck,2005

49. So, on the basis of these trials indications
of RT & CT-RT are as follows :-
Absolute Indications of Post
op CT-RT :
• Margin +ve
• ECE +ve
Soft Indications for CT-RT:
• LVI +ve
• PNI +ve
• Close margins
• pT3 or more
• p N2a or more
• Bulky nodal disease
• Lower neck LN

50. Role of Chemotherapy
• Addition of chemotherapy
• NACT
• CTRT definitive
• CTRT adjuvant

51. NACT

52. Vermorken JB et al N Engl J Med 2007;357(17):1695-1704
• 358 patients ( 46% oropharynx)
• Unresectable stage III–IV head and neck cancer
• TPF (docetaxel/cisplatin/5-FU) vs.
• PF (cisplatin/5-FU) induction chemotherapy followed by RT alone,
• Primary end point - PFS

53. Vermorken JB et al N Engl J Med 2007;357(17):1695-1704
TPF PF P value
PFS 11 mnths 8.2 mnths 0.007
OS 18.8 mnths 14.5 mnths 0.02

54. • 501 patients ( 52% oropharynx)
• Unresectable stage III–IV head and neck cancer
• TPF (docetaxel/cisplatin/5-FU) vs.
• PF (cisplatin/5-FU) induction chemotherapy followed by RT alone
• Primary end point - OS
Posner et al N Engl J Med 2007

55. Posner et al N Engl J Med 2007
TPF PF P value
3-yr OS 62% 48% 0.006
Median Survival 71 mnths 30 mnths 0.004
LRC 70% 62% 0.04

56. CTRT
Is Concurrent CTRT better than RT alone ?

57. • 226 patients with advanced oropharyngeal Ca
• Primary end point - OS
Gortec 94-01, JNCI, Vol. 91, No. 24, December 15, 1999

58. Results
Conclusion : Significant improvement in overall survival that was obtained
supports the use of concomitant chemotherapy as an adjunct to radiotherapy
in the management of carcinoma of the oropharynx.
Combine
d
modality
Radiati
on
alone
P
value
3 yr OS 51 % 31 % 0.02
3 yr DFS 42 % 20 % 0.04
LRC 66 % 42 %
Combine
d
modality
Radiati
on
alone
P value
5 yr OS 22 % 16 % 0.05
5 yr DFS 27 % 15 % 0.01
LRC 48 % 25 % 0.002
F Denis, Final report of GORTEC 94-01,2004G Calais, Gortec 94-01, December 15, 1999

59. An Intergroup Phase III Comparison of Standard Radiation
Therapy and Two Schedules of Concurrent Chemo-RT in
Patients With Unresectable Squamous Cell Head and Neck
Cancer.
• 295 pts
• 59% oropharynx patients
• Arm A (the control)- (70 Gy at 2 Gy/d)
• Arm B, same RT with concurrent bolus cisplatin 100 mg /m2, given on days
1, 22,and 43.
• Arm C, a split course of single daily fractionated radiation and 3 cycles of
concurrent infusional fluorouracil and bolus cisplatin chemotherapy. 30 Gy
with 1st cycle and 30 – 40 Gy with 3rd cycle.
• Primary end point - OS
J Clin Oncol 21:92-98. 2003David J. Adelstein

60. • Median f/u 41 mths
• 3yrs projected OS arm A – 23 %, B – 37 %(p=0.014) and C – 27 %(non-
significant)
• Grd 3 or higher Toxicity A-52% , B-89%(p<0.0001) and C- 77%(p<0.001)
• Trial was closed prematurely, didn’t meet target accrual of 362
• Conclusion: The addition of concurrent high-dose, single agent cisplatin to
conventional single daily fractionated radiation significantly improves survival.
• This trial established the role of Chemo-RT in HNSCC.

61. Which one is better?
NACT or CTRT

62. MACH NC Meta-anaalysis Pignon, Lancet 2000; 355: 949–55
• Over 70 randomized trials
• Three comparisons
1. The effect of chemotherapy — LR treatment was compared with LR
treatment plus chemotherapy.
2. The timing of chemotherapy — NACT plus radiotherapy was compared
with concomitant or alternating Radio-Chemotherapy with the same drugs.
3. Larynx preservation with neoadjuvant chemotherapy —radical surgery plus
radiotherapy was compared with neoadjuvant chemotherapy plus
radiotherapy in responders or radical surgery and radiotherapy in non-
responders.

63. Effect of Chemotherapy on survival
• The first meta-analysis included 63 trials.
• Trials were divided according to timing of chemotherapy: Adjuvant,
neoadjuvant, and concomitant or alternating with radiotherapy.

64. Conclusion
• The addition of chemotherapy to locoregional treatment- the
most important result was a small, but statistically significant,
overall benefit in survival with chemotherapy (the absolute
benefit at 2 and 5 years was 4%).
• No significant benefit of adjuvant or neoadjuvant
chemotherapy but a significant benefit of concomitant
chemotherapy (absolute benefit at 2 and 5 years of 8%)

65. MACH-NC: Update
• Update to the meta-analysis by adding the data from the randomized trials
performed between 1994 and 2000.
• Added 24 new trials, most of them on concomittant chemotherapy
• 87 trials, 16665 pts
• median f/u 5.5 yrs
• An absolute benefit for chemotherapy of 4.4% at 5 yr.
• For concomitant CTRT group the absolute survival benefit at 5 yr is 8 %
IJROBP, Vol. 69, No. 2, Supplement, pp. S112–S114, 2007

66. MACH-NC 2009 Update
The meta-analysis included 87 randomised trials (16,485 patients)
comparing loco-regional treatment versus the same loco-regional
treatment + chemotherapy.

67. • 87 randomised control trials from period of 1965 to 2000
• 16,192 patients were analysed in a median follow up of 5.6 yrs
• Evidence of improvement in overall survival
• Absolute benefit 4.5% at 5 yrs
• Benefit more in concurrent CTRT, with HR -0.81(p<0.0001) &
absolute benefit of 6.5%
• Benefit decreases with increasing age
• Absolute benefits - oral cavity-8.9%
• oropharynx-8.1%
• larynx-5.4%
• hypopharynx-4%
MACH-NC (2011 update)

68. MACH- NC-Conclusions
• Addition of CT - Absolute benefit in survival-5% in 5 yrs.
• Induction/adjuvant - 2% survival benefit
• Concurrent CTRT 8% - 5yr survival benefit
• Platinum based regimen more effective.
• No significant difference in efficacy between mono and multiple
drug platinum regimens
• Small reduction in distant metastasis found in population of patients
with CTRT
• Inverse relation between age and impact of CT. Disappears by
around age of 70

69. Is NACT → CTRT better than CTRT?

70. • Locally advanced SCCHN
• Induction TPF→CRT vs CRT
• Three cycles of TPF followed by concurrent chemo-radiotherapy with either
docetaxel or carboplatin or concurrent chemoradiotherapy alone with two
cycles of bolus cisplatin
• 145 PTS
• Stage III-IV (55% Oropharynx)
• Median follow-up : 49 mnths
• Primary end point - OS
Lancet Oncol 2013; 14: 257–64

71. • No significant difference noted between those patients treated
with induction chemotherapy followed by chemo-radiotherapy
and those who received chemo-radiotherapy alone
TPF→CR
T
CRT P
value
OS 67% 83% 0.47
PFS 73% 83% 0.22

72. • 285 patients ( 58% oropharynx)
• Treatment-naive patients with nonmetastatic N2 or N3 SCCHN
• CRT Vs 2#TPF NACT → CRT
• CRT alone (CRT arm; docetaxel, fluorouracil, and hydroxyurea plus
radiotherapy 0.15 Gy twice per day every other week) versus two 21-day cycles
of NACT (docetaxel 75 mg/m2 on day 1, cisplatin 75 mg/m2 on day 1, and
fluorouracil 750 mg/m2 on days 1 to 5) followed by the same CRT
regimen(NACT → CRT arm)
• Primary end point - overall survival OS

73. • Minimum follow-up of 30 months
• No statistically significant
differences in OS or DFS.
• NACT did not translate into
improved OS compared with CRT
alone
• NACT didn’t improve OS when
added to CRT

74. • 1022 patients with locally advanced HNSCC
• 52% of the patients had oropharyngeal
• Additional induction TPF before CT-RT didn’t improve OS (p = 0.92)
• No statistically significant benefit of PFS (p = 0.32)
Radiotherapy and Oncology 118 (2016) 238–243

75. Treatment Intensification
• So, CTRT is better that RT alone
• Is CTRT better than hyperfractionated RT for locally advanced
head neck cancers ?

76. • 122 patients with advanced head neck cancers
• 44% Oropharynx patients (base of tongue/tonsil)
• Hyperfractionated RT 75Gy @1.25Gy BD over 6wk
• Combined modality arm
• RT 70 Gy @same fractionation with planned treatment interruption of 7 days after 40
Gy to manage mucosities
• Chemotherapy – wk 1 and wk 6
• 5 FU 600 mg/m2 /day cont. infusion for 5 days
• cisplatin 12 mg/m2/day iv bolus for 5 days
• 2 more cycles of adjuvant chemotherapy were given to all patients after completion of
local therapy
The New England Journal of Medicine, 1998

77. Results
• Median follow up 41 months
• Conclusions Combined treatment for advanced head and neck cancer is
more efficacious and not more toxic than hyperfractionated irradiation
alone.
Combined
modality
Hyperfractio
nated RT
P value
LRC 70 % 44 % 0.01
OS 55 % 34 % 0.07

78. • 130 patients with locally advanced head neck cancers
• 37 % oropharynx pts
• Arm 1- Hfx RT 77 Gy @ 1.1 Gy/ fraction twice a day over 35 days
• Arm 2 – Hfx RT + low dose daily Cisplatin
• 6 mg/m2 1-2 hr before 2 nd fraction
• In case of acute high grade reactions treatment interruption of 2 wk was
allowed with no dose reduction.
• Primary endpoint – OS
J Clin Oncol 18:1458-1464. © 2000

79. Results
• Median follow up:79 months.
Combined
modality
Hfx RT
alone
Significance
Complete
Response
75 % 48 % p = .002
2 yr OS 68 % 49 %
5 yr OS 46 % 25 % p = .0075
5 yr PFS 46 % 25 % p = .0068
Conclusion: As compared with Hfx RT alone, Hfx RT and concurrent low-dose daily
CDDP offered a survival advantage, as well as improved LRPFS and DMFS.

80. • Locally advanced head and neck cancer
• 384 patients, majority stage IV (94%)
• Oropharyngeal (59.4%), hypopharyngeal (32.3%), and oral cavity (8.3%)

81. • 2 arms -
• Concurrent fluorouracil (FU) and mitomycin (MMC) chemotherapy and
hyperfractionated accelerated radiation therapy (C-HART; 70.6 Gy)
[30 Gy (2 Gy every day) followed by 1.4 Gy bid to a total of 70.6 Gy concurrently with FU
(600 mg/m2, 120 hours continuous infusion) days 1 through 5 and MMC (10 mg/m2) on
days 5 and 36]
• Hyperfractionated accelerated radiation therapy alone (HART; 77.6 Gy)
{14 Gy (2 Gy every day) followed by 1.4 Gy bid to a total dose of 77.6 Gy }
• C-HART (70.6 Gy) is superior to dose-escalated HART (77.6 Gy) with
comparable or less acute reactions and equivalent late reactions
C-HART HART P value
LRC 49.9% 37.4% 0.001
OS 28.6% 23.7% 0.023
PFS 29.3% 26.6% 0.009

82. • Locally advanced head and neck squamous-cell carcinoma
• 840 patients (66% oropharynx pts)
• 3 arms
• Conventional CT-RT(70 Gy/35# + 3 cycles concomitant carboplatin-fluorouracil)
• Accelerated CT-RT(70 Gy in 6 weeks +2 cycles of 5 days concomitant carboplatin-
fluorouracil)
• Very accelerated radiotherapy alone (64·8 Gy [1·8 Gy twice daily] in 3·5 weeks)
• Median follow-up was 5·2 years
• Primary endpoint - PFS

83. •Conventional CT-RT improved PFS compared with very accelerated
radiotherapy
•Grade 3–4 acute mucosal toxicity
•very accelerated radiotherapy (84%) compared with
•accelerated CT-RT(76%) or
•conventional CT-RT(69%; p=0·0001)
•Acceleration of radiotherapy cannot compensate for the absence of chemotherapy

84. Biological Agents
Cetuximab
• Chimeric monoclonal antibody
• EGFR Inhibitor

85. • 424 pts, multinational study (60% oropharynx)
• Locally advanced SCCHN
• Primary end point – locoregional control
• RT v/s RT + Cetuximab
• Cetuximab 400 mg/m2 at initial dose followed by 250 mg / m2 weekly
for rest of RT.
N Engl J Med 2006;354:567-78

86. • Median f/u - 54.0 mths
• With the exception of acneiform
rash and infusion reactions, the
incidence of grade 3 or greater
toxic effects, including mucositis,
did not differ significantly
between the two groups
Cetuxi
mab +
RT
RT
alone
P
value
Median
LRC
24.4
mnths
14.9
mnths
0.005
Median
OS
49
mnths
29.3
mnths
0.03

87. • Stage III or IV HNC were randomly assigned to receive radiation and cisplatin
without (arm A) or with (arm B) cetuximab
• 891 analyzed patients, 630 were alive at analysis
• Median follow-up, 3.8 years
• Primary end point - PFS
• Cetuximab plus cisplatin-radiation, versus cisplatin-radiation alone, resulted in
• More grade 3 to 4 radiation mucositis (43.2% v 33.3%, respectively), rash, fatigue, anorexia,
• But not more late toxicity

88. • No significant differences were found between arms A and B in
• 3-year PFS (61.2% v 58.9%, respectively; P - .76)
• 3-year OS (72.9% v 75.8%,P - .32)
• Locoregional failure (19.9% v 25.9%, P - .97)
• Distant metastasis (13.0% v 9.7%, P - .08)
• Patients with p16-positive oropharyngeal carcinoma (OPC), compared with
patients with p16-negative OPC, had
• better 3-year probability of PFS (72.8% v 49.2%,P .001)
• OS (85.6% v 60.1%, P .001)
• Tumor epidermal growth factor receptor (EGFR) expression did not
distinguish outcome
• Adding cetuximab to radiation-cisplatin did not improve outcome

89. HPV

90. • HPV 16 and 18 associated with squamous cell carcinoma
More Common With nonsmoker
Not associated with p 53 mutation
Usually present with large nodal volume

91. HPV and survival
• 24 retrospective series were analysed.
• In HNSCC, HPV positivity conferred
- Better OS (HR = 0.85, 95% CI: 0.7–1.0)
- Better DFS (HR = 0.62, 95%CI: 0.5–0.8)
• Site specific analysis showed that for non-oropharyngeal HNSCC OS
and DFS were similar for both HPV positive and HPV negative
patients.

92. • Stage III or IV HNSCC
• 743 patients (60% oropharynx)
• 2 arms
• Conventional CT-RT arm
• Accelerated fractionation + Concomitant boost + CT
(72 Gy in 42 fractions over a 6-week period, with a concomitant boost of twice-
daily irradiation for 12 treatment days)
• Concurrent Cisplatin 100 mg per square meter of body-surface area
intravenously on days 1, 22, and 43 in both arms
RTOG 0129

93. • Median follow-up period - 4.8 years
• Primary end point – OS
• 60.1% [433 of 721]) had oropharyngeal scc
• HPV status was determined in 74.6% of these patients (323 of 433)
• 63.8% of patients with oropharyngeal cancer (206 of 323) were HPV+ve
HPV +ve HPV-ve P value
3 yr OS 83.6% 51.3% <0.001
PFS 74.4% 38.4% <0.001
AFC-CT CT-RT P value
3 yrs OS 59% 56% 0.18
3 yr PFS 57% 55.8% 0.80
3 yr LRC 28.2% 25.6% 0.50

94. Brachytherapy

95. Role of Brachytherapy
• Historically played a role in boosting gross disease following EBRT.
• Developed in the pre-IMRT, preconcurrent chemotherapy era.
• Low dose rate (LDR) brachytherapy has previously been the most common
type of brachytherapy.
• High dose rate (HDR) techniques are becoming much more common.
• Interstitial implants selectively used in
i) Accessible lesions
ii) Small (preferably <3cm) tumors
iii) Lesions away from bone
iv) N0 nodal status
v) Superficial lesions

96. • High rates of locoregional control have been achieved using EBRT directed at
primary and bilateral neck followed by brachytherapy boost.
• Care should be taken to delineate pre-treatment tumor extent accomplished by
tattoos or gold seeds.
• CTV as recommended by ESTRO – 5mm at minimum and more commonly 1
to 1.5 cm for base of tongue tumors.
• PTV is equal to CTV.
• Catheters are typically placed parallel and equidistant at 1 to 1.5 cm apart.
• Complication of brachytherapy for base of tongue include osteoradionecrosis
of mandible.

97. Brachytherapy guidelines - American Brachytherapy society (ABS)
• Recommend – EBRT doses of 45 to 60 Gy followed by an HDR boost of 3-4
GY per fraction for 6 to 10 doses.
• With locoregional control of 82 % to 94 %.
• Prophylactic tracheostomy is often required.

98. • The ABS recommends the use of brachytherapy as a component of the
treatment of head-and-neck tumors.
• No definite evidence on use of concomitant chemotherapy; risk of increased
mucosal toxicity compromising treatment
• Regarding the sequencing of EBRT and brachytherapy, it may be
advantageous to obtain shrinkage with EBRT before applying brachytherapy
in advanced tumors.
• In case of brachytherapy boost, placement of radio-opaque markers before
starting EBRT can help delineate the target volume, before any shrinkage
occurs
• The dose prescription volume and dose points should be clearly specified.
General concepts based on ABS recommendations

99. The European Brachytherapy group (Groupe Européen
de Curiethérapie-European Society for Therapeutic
Radiology and Oncology)GEC-ESTRO –guidelines
• Based on consensus recommendation.
• Recommend 45 to 50 Gy EBRT followed by
• 25 to 30 Gy boost for Tonsillar tumors.
• 30 to 35 Gy boost to base of tongue.
• Total brachytherapy boost dose is fraction size dependent –
• 21 to 30 Gy in 3-Gy fraction.
• 16 to 24 Gy in 4-Gy fraction

100. Types of Implants

101. Base of tongue:interstitial volume implant
• Patients who do not have palpable LN
metastasis receive elective irradiation
to the neck along with EBRT to the
primary site.
• Treatment is completed with an
implant to the base-of-tongue,
performed approximately 2-3 wks
after the completion of EBRT.

102. External Beam Radiotherapy
• Conventional Treatment
• 3-D CRT
• IMRT

103. Radiation therapy - simulation
• Preferably CT based simulation.
• Position- supine
• With rigid head holder cradling the
posterior calvarium.
• Shoulders should be positioned as
caudally as possible to allow adequate
exposure of neck.
• Anterior and Lateral reference marks
should be made on the mould

104. • Bite block – elevate the hard palate
• Head should be immobilised with a
thermoplastic cast.
• The mask should be properly fitted
and not allow the movement of the
nose, chin or forehead.
• Cast is fixed to the couch top or
base plate in at least 3 places.
• Image should be taken from above
the calvarium to the carina.

105. Conventional Treatment
• Delivered using a “shrinking-field” technique for the primary tumor bed and
upper neck, matched to an anterior-posterior (AP) supraclavicular field for the
lower neck (LAN)
• Opposed lateral fields covering the primary tumor bed and upper neck extending
to the thyroid notch are initially treated to 44 Gy in 2-Gy fractions
• Isocenter is typically placed at approximately the C1 to C2 level just anterior to
the inter-vertebral space
• Off-cord boost is then created by shifting the posterior field border anteriorly to
split the vertebral bodies vertically
• The final field reduction boost carries the tumor GTV plus a margin to 66 to 70
Gy
• Electron fields (commonly, 6 to 9 MeV; occasionally, 12 MeV for bulky nodal
disease) are matched on the skin to abut the posterior aspect of the off-cord
photon field and thereby treat the posterior neck to 50 to 54 Gy (with higher
doses if positive posterior nodes are present)

106. Conventional Field borders
• Upper margin – upto zygomatic arch
• Posteriorly – tip of mastoid
• Anteriorly – depending upon the clinical extension(2 cm beyond the
disease) [usually, kept 1.5-2 cm from angle of mouth]
• Inferiorly – thyroid notch ( for 3-field technique), below clavicle (for
2 lateral fields) [usually kept at lower border of C-6/Cricoid]{If LAN
is not to be used then to go as low as possible avoiding the humeral
heads}
• Lower neck – Apposed to the upper portal and 1 cm below the
clavicles
Principles & Practice of Radiation Oncology, 3rd edition, Perez & Brady (1997)
Textbook of Radiation Oncology, 1st edition, Rath & Mohanti (2002)

108. LAN Field
• Superior : Lower border of throid notch and match with upper neck lateral
fields (with a spinal cord/vocal cord block)
• Inferior : inferior edge of the clavicular head
• Lateral : Two thirds of the clavicle or 2 cm lateral to lymphadenopathy
(which ever more lateral)
• The treatment is generally done in 2 or 3 phases.
• In a 2 phase treatment
• Phase I : 44 Gy/22 # to B/L + LAN
• Phase II : 22-26 Gy to the cone down volume after off-cord
• In a 3 phase treatment
• Phase I : 44 Gy/22 # to B/L + LAN
• Phase II : 16 Gy to the cone down volume after off-cord
• Phase III : 10 Gy to the boost volume by further conforming to the GTV

110. Indication for ipsilateral radiotherapy
• Well lateralised Tonsillar cancer cases not involving the base of tongue
and with minimal involvement of soft palate.
• The CTV can be limited to the Ipsilateral neck which limit the exposure of
the contralateral parotid, submandibular gland and pharyngeal
musculature.
• Treatment to the contralateral neck – is based on the extremely low risk of
occult contra-lateral neck lymph node involvement.
• Low incidence of progression seen in early stage tonsil cancer – is due to
lack of invasion of soft palate and base of tongue.
• Patients with c/l cervical lymph node involvement usually seen in patients
with tumor approaching or crossing midline or have extensive I/L cervical
lymph node involvement.

111. Surgical series demonstrate – risk of contralateral
cervical lymph node involvement

112. Study related with ipsilateral-only radiotherapy

113. • No c/l neck progression in patients with T1 tumors.
• Only 1-2 % c/l involvement occur in T2 tumors.
• C/L nodal progression in T3 tumor was 3 to 10 %.
• C/L nodal progression was associated with-
• both base of tongue and soft palate involvement (13%).
• T3 stage (10%)
• Involvement of the midline of the soft palate (16.5%).

114. Radiotherapy volumes
• Based on ICRU 50
• Gross tumor volumes (GTV) – includes all known primary and cervical
lymph node tumor extension based on clinical, endoscopic and imaging
findings.
• Clinical target volume (CTV) – GTV is expanded to include a margin for
microscopic extension (not visible on clinical and imaging modalities)
• Also considering the natural avenues of spread for the particular disease and
site, including lymph node, perivascular, and perineural extensions
• Planning target volume (PTV) - The PTV is defined by specifying the
margins that must be added around the CTV to manage the effects of organ,
tumor and patient movements, inaccuracies in beam and patient setup, and
any other uncertainties

115. Clinical Target Volumes Delineation
• CTV_HR (CTV 1) – Volume to receive the highest dose, which includes the
primary with 0.5-1 cm margin. Should be more generous if tumor borders are
less well defined
• CTV_IR (CTV 2) – Volumes to receive an intermediate dose
• CTV_LR (CTV 3) – Volumes to receive an elective dose for potential
subclinical disease
Dose Prescription
• CTV_HR – 66-72 Gy
• CTV_IR – 60-66 Gy
• CTV_LR – 54-60 Gy
Practical aspects of IMRT, K S Clifford Chao

116. • Data pertaining to the natural course of nodal metastasis for each head-and-
neck cancer subsite were reviewed
• A system was established to provide guidance for nodal target volume
determination and delineation
• 126 patients (52 definitive, 74 postoperative) were treated between February
1997 and December 2000 with IMRT for head-and-neck cancer
• Median follow-up was 26 months
• Patterns of nodal failure were analyzed
Int. J. Radiation Oncology Biol. Phys., Vol. 53, No. 5, pp. 1174–1184, 2002

117. Chao et al, IJROBP, 2002

118. What volumes to take for IMRT?
Chao et al, IJROBP, 2002
Tumour
site
Clinical
Presenatation
CTV_HR CTV_IR CTV_LR
Tonsil T 1 and T 2 N
0
T 3 and T 4 N
0
Any T N +
GTVp
GTVp
GTVp + n
-
Optional
IN (adjacent
ln)
IN (IB-V)
IN + CN(IB-V,RPLN)
IN + CN + RPLN
(remaining ln)
BOT Any T N0 GTVp Optional IN + CN(IB-V,RPLN)
Soft
Palate
Any T N + GTVp + n IN (adjacent
ln)
IN + CN + RPLN
(remaining ln)

119. Neck Node Contouring Guidelines
• Som’s – Radiological Classification
• Robbin’s – Surgico-anatomico-pathological Classfication
• Rotterdam guidelines – Nowak et al.
• Brussels guidelines – Gregoire et al. 2000
• Consensus guidelines – Gregoire et al., 2003, 2006, 2014

121. • K. Thomas Robbins, Arch Otolaryngol Head Neck Surg. 2002;128(7):751-758.

122. Selection & Delineation of LN Target Volumes
2000

123. Consensus guidelines for contouring the clinically
node negative neck
2003

124. 2006
Consensus guidelines for node positive
and post operative patients

125. Consensus guidelines for nodal contouring
2014

126. Important considerations
• Irrespective of the nodal status of the patient, i.e. node-negative or node-
positive
• Holds for the post-operative situation
• Risk of microscopic extracapsular extension (ECE) was (weakly)
proportional to the size of lymph node
• 20–40% for nodes smaller than 1 cm in diameter
• >75% for bulky nodes more than 3 cm in diameter
• An isotropic expansion by 10–20 mm into these structures from the visible
edge of the node (i.e. the nodal GTV) appears reasonable. [Modification of
the previous recommendations, which arbitrarily proposed to include the
full muscle in the corresponding infiltrated levels]

127. Specific recommendations for node-positive
patients include
• Coverage of the supraclavicular fossa for patients with level IV or Vb
lymphadenopathy
• Pathologic lymphadenopathy spanning adjacent levels should trigger
inclusion of the full extent of both levels in the CTV
• For postoperative patients, coverage of the entire operative bed in the
neck is recommended to account for potential tumor spillage

129. Level Ia

130. Level Ib

131. Level II & Level III
*Coverage of the retrostyloid space was recommended for all patients with
pathologic level II involvement

132. Level II

133. Level III

134. Level IV

135. Level IV b
(Medial
supraclavicular)

136. Level V

137. Level V

138. Level V
c
(Lateral
supra
clavicular)

139. Level VI

140. Level VI
VI a
VI b
VI b
VI a

141. Level VIIa

142. Level VIIb

143. Level VIII

144. Level IX

145. Level Xa

146. Level Xb

147. Post-treatment management and surveillance
• Patients should be seen regularly for clinical evaluation.
• Current guidelines –
• examination every 1 to 3 month for first year post-therapy.
• every 2 to 4 month in second year post-therapy.
• every 4 to 6 month in the third through fifth years.

148. Recurrent Locoregionally confined squamous cell
carcinoma of oropharynx (SCCOP)

149. SCCOP: Locoregional control
Garden, et al. Patterns of disease recurrence following treatment of oropharyngeal cancer with intensity modulated
radiation therapy. Int. Journal Radiation Oncology. 2013.

150. SCCOP: Locoregional control
• MDACC
• Retrospective review of 776 patients between 2000-2007
treated with IMRT with/without chemotherapy
• 5-year overall survival: 84%
• 5-year recurrence-free survival: 82%
• 7% recurred primary site
• 4% recurred neck
• 10% developed distant metastases
• 8% had second primary cancers
Garden, et al. Patterns of disease recurrence following treatment of oropharyngeal cancer with intensity
modulated radiation therapy. Int. J. Radiation Oncology. 2013.

151. Treatment Locally Recurrent SCCOP
• Surgical salvage
• Reirradiation
• Palliative Chemotherapy
• Supportive Care

152. Re-treatment: Should Resi/ recc disease be treated?
Allen Ho, Head Neck. 2014 Jan;36(1):144-51.

153. Reirradiation
• High risk of normal tissue toxicity including upto a 20% carotid
rupture rate.
• 15% fatal toxicity.
• Patients undergoing a second course of chemotherapy and
radiation therapy should be managed with experienced centers.
• Failed phase III studies to compare systemic therapy alone or
chemotherapy and reirradiation.

154. Reirradiation
• RTOG 9610
• 79 Pts (36% oropharynx)
• 4 weekly cycles of chemoradiotherapy separated by 1 week of rest
• Each cycle - 5 days of twice-daily RT 1.5 Gy per fraction separated by a
6-hour interval
• 5-FU 300 mg/m2 IV bolus and Hydroxyurea 1.5 g by mouth were both
given before the second daily RT fraction
• 2-year survival: 15%
• 5-year survival: 4%
• Median survival 8 months
• Grade 4 or higher acute toxicity: 25%
• Treatment-related death: 8%
Spencer SA, Harris J, Wheeler RH, et al. Final report of RTOG 9610, a multi-institutional trial of reirradiation and
chemotherapy for unresectable recurrent squamous cell carcinoma of the head and neck. Head Neck. 2008;30:281-288.

155. Reirradiation
• RTOG 9911
• 105 pts (40% oropharynx)
• RT at a dose of 1.5 Gy/fx bid5 days every other week X 4 cycles
• Cisplatin 15 mg/m2/1 hour and Paclitaxel 20 mg/m2/1 hour each daily
X 5 every other week X 4
• 25% 2-year overall survival
• Median survival 12 months
• Grade 4 or worse acute toxicity: 28%
• Treatment-related death: 11%
Langer CJ, Harris J, Horwitz EM, et al. Phase II study of low-dose paclitaxel and cisplatin in combination with split-course concomitant twice-
daily reirradiation in recurrent squamous cell carcinoma of the head and neck: Results of Radiation Therapy Oncology Group Protocol 9911. J
Clin Oncol. 2007;25:4800-4805.

156. Palliative Chemotherapy
• 33% of patients have partial response to platinum-based
regimens
• Median survival 4-6 months
• 2-year overall survival 5-10%
Forastiere AA, Metch B, Schuller DE, et al. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus
methotrexate in advanced squamous cell carcinoma of the head and neck: A Southwest Oncology Group study. J Clin Oncol. 1992;10:1245-
1251.

157. • 442 patients (34% oropharynx)
• Primary endpoint: OS
Recurrent/metastatic HNSCC;
no previous chemotherapy
except for locally advanced
disease > 6 mos prior
to study entry; no
nasopharyngeal carcinoma
(N = 442)
Up to 6 cycles: cetuximab 400 mg/m2, then 250 mg/m2/wk until PD or unacceptable toxicity; carboplatin
AUC 5 or cisplatin 100 mg/m2 on Day 1; 5-FU 1000 mg/m2 on Days 1-4 every 3 wks.
Cetuximab +
Carboplatin or Cisplatin
+ 5-FU
(n = 222)
Carboplatin or Cisplatin
+ 5-FU
(n = 220)
Vermorken JB, et al. N Engl J Med. 2008.

158. 127
153
83
118
65
82
47
57
19
30
173
184
220
222
8
15
1
3
HR : 0.80 (95% CI: 0.64-0.99; P = .04)
Chemotherapy only (n = 220) 20
Chemo + cetuximab (n = 222) 36
SurvivalProbability
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 3 6 9 12 15 18 21 24
10.1 mos
7.4 mos
Pts at Risk, n
CTX only
CET + CTX
Survival Time (Mos)
Cetuximab ± First-line Platinum in Recurrent or
Metastatic HNSCC: OS
ORR, %
Vermorken JB, et al. N Engl J Med. 2008;350:1116-1127.

159. SPECTRUM:
Cisplatin + 5-FU ± Panitumumab in Recurrent/Met HNSCC
• 657 pts
• Primary endpoint: OS
Patients with distant
metastatic and/or locally
recurrent HNSCC,
ECOG PS ≤ 1
(N = 657)
Stratified by previous treatment,
primary tumor site, ECOG PS
Optional panitumumab
maintenance q3w
Panitumumab 9 mg/kg Day 1
Cisplatin 100 mg/m2 Day 1
5-FU 1000 mg/m2 Days 1-4
(n = 327)
Cisplatin 100 mg/m2 Day 1
5-FU 1000 mg/m2 Days 1-4
(n = 330)
Max six 3-wk cycles
Vermorken JB, et al. Lancet Oncol. 2013;14:697-710.

160. • Subgroup analysis in p16-negative patients significant: 11.7 vs 8.6 mos (P = .01)
• Despite questions about p16 IHC cutoff values, hypothesized that EGFR inhibitors
may be ineffective in HPV+ tumors
• Supported by lack of EGFR overexpression/amplification in HPV+ tumors
HR: 0.87 (95% CI 0.73–1.05)
P = .14
Vermorken JB, et al. Lancet Oncol. 2013;14:697-710
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32
Mos
100
80
60
40
20
0
OverallSurvival(%)
Panitumumab 11.1 (9.8-12.2)
Control 9.0 (8.1-11.2)
Median OS,
months (95% CI)
Addition of Panitumumab improves survival in HPV-ve pts

161. Metronomic Chemotherapy
• Frequent administration
• Low doses (1/10th–1/3rd of the maximum tolerated dose
[MTD]) of drugs
• Shorter intervals without interruption.

162. Metronomic chemotherapy in HNSCC patients
Author Year Study design
Patients
(n)
Protocol (n
patients)
Results
Patil et al. 2015 phase II 110
celecoxib + methot
rexate (57);
cisplatinum (53)
OS 101 vs
66 days; PFS
249 vs
152 days
Pai et al. 2013 retrospective 64
celecoxib + methot
rexate (32); no MC
(32)
2-year DFS
94.6 % vs
75.4 %
Penel et al. 2010 randomised 88
cyclophosphamide
(44); megestrol
acetate (44)
2-month PFS
20.5 % vs
9 %; median
OS 195 vs
144 days

163. NCCN Guidelines

169. Thank You