Management of Advanced Laryngeal tumors with multidisciplinary approach

1. Locally Advanced Vocal Cord Tumors
- Evidence Based Approach
Dr. Rajesh Balakrishnan
Associate Professor
Christian Medical College, Vellore

2. LEARNING OBJECTIVES
Staging and Grouping
Current treatment protocols
Evidence – Clinical trials
Radiotherapy Volume delineation Guidelines
What to do after CRT / ICT

3. MILESTONES IN LARYNX/HYPOPHARYNX
MANAGEMENT
1st TL
1st PLs
1st RT Laser CO2
SCPL
Trial
VA
Trial
RTOG
Trial
EORTC
Trial
GORTEC
Trial
EORTC
1873 1878 1903 1970s 1994 1996 2003 2005 2007
SURGERY RADIOTHERAPY LASER
CT
MRI
ASCO
1982
ORGAN PRESERVATION
PROTOCOLS
Courtesy Dr. J-L Lefebvre

4. TIME TREND ANALYSIS - LARYNX
FIVE- YEAR RELATIVE SUVIVAL RATE

5. STAGING AND GROUPING

6. ANATOMY

7. Ref: Book - Target
Volume Delineation
and Field Setup
ANATOMY

8. STAGE GROUPING
T1
< 2cm
T2
2-4 cm
T3
>4cm
T4a
+
Invasion
T4b
++Invasio
n
M1
N0 I II III IV A IV B IV C
N1
<3cm
III III III IV A IV B IV C
SIPSI
N2
3-6cm
BIL
IV A IV A IV A IV A IV B IV C
N3
>6cm IV B IV B IV B IV B IV B IV C

9. CLASSIFICATION – LARYNGEAL
TUMORS
T1
< 2cm
T2
2-4 cm
T3
>4cm
T4a
+
Invasion
T4b
++Invasio
n
M1
N0 EARLY LOCALLY ADVANCED
METASTATIC
N1
<3cm
SIPSI
LOCALLY ADVANCED
N2
3-6cm
BIL
N3
>6cm
Very Locally Advanced
o T4b
o Unresectable N
o Unfit for surgery

10. TREATMENT MODALITIES IN
LARYNX TUMORS 2014
Surgery
Radiotherapy (RT)
Chemotherapy (CT)
} As a single modality
Combined therapy
Palliative therapy
Targeted Therapy
Alone or in
combination with CMT,
RT, CT
1. Induction Chemotherapy(ICT)
2. Concomitant CT and RT
3. Sequential therapy (ICT > CCRT)
4. Adjuvant CT (ART)
5. Postoperative (RT /CCCRT)

11. TREATMENT OPTIONS
T1
< 2cm
T2
2-4 cm
T3
>4cm
T4a
+ Invasion
T4b
++Invasion
M1
N0
I- II
EARLY
RESECTABLE
III -IV B LOCALLY ADVANCED
METASTATIC
CHEMOTHERAPY
III
??RESECTABLE
IV A
??
IV B
IRRESECTABLE
N1
<3cm
SIPSI
III
LOCALLY
ADVANCED
RESECTABLE
III
??RESECTABLE
IV A
??
IV B
IRRESECTABLE
N2
3-6cm
BIL
IV A
LOCALLY ADVANCED
?? RESECTABLE
N3
>6cm
IV B
LOCALLY ADVANCED
?? IRRESECTABLE

12. TREATMENT OPTIONS
T1
< 2cm
T2
2-4 cm
T3
>4cm
T4a
+ Invasion
T4b
++Invasion
M1
N0 EARLY
RESECTABLE
S = RT
LOCALLY ADVANCED
IV C
MET
CT
??RESECTABLE
CRT
??
CRT
IRRESECTABLE
CRT
N1
<3cm
SIPSI
LOCALLY
ADVANCED
RESECTABLE
S > RT / CRT
??RESECTABLE
CRT
??
CRT
IRRESECTABLE
CRT
N2
3-6cm
BIL
LOCALLY ADVANCED
?? RESECTABLE
CRT
N3
>6cm
LOCALLY ADVANCED
?? IRRESECTABLE
CRT

13. T1
< 2cm
T2
2-4 cm
T3
>4cm
T4a
+ Invasion
T4b
++Invasion
M1
N0 LOCALLY ADVANCED
IV C
MET
CT
??RESECTABL
E
S > RT
S > CRT
CRT > S
??
CRT > s
IRRESECTABLE
CRT
N1
<3cm
SIPSI
LOCALLY
ADVANCED
RESECTABLE
S > RT /CRT
N2
3-6cm
BIL
LOCALLY ADVANCED
?? RESECTABLE
CRT > S
N3
>6cm
LOCALLY ADVANCED
?? IRRESECTABLE
CRT

14. Treatment of locally advanced Laryngeal Tumors
Stage III-IVB: T3-4ab, N1-3
Resectable --T3 N1
Surgery RT
CRT
Borderline -- T4a , N2 Treat as Irresectable
Irresectable-- T4b , N3
CCRT / BRT  Surg
ICT Surg or RT/CRT
ICT Surg  RT/CRT
ICT RT/CRT  ? Surg

15. HOW TO CHOOSE THE
TREATMENT DECISION ?

16. Patient Factor
• Pretreatment condition
• Chronic diseases,
malnutirtion, poor oral
health
• Patient priorities
• Cure, live long , Pain
free, Disability free
Disease Factor
• TNM Stage
• Early / LA / Metastatic
• Emerging prognostic
biomarkers
• EGFR / p16 / HPV
• Specific Risk factors for LR
/DM
Treatment Factor
• Morbidity of treatment
offered
• Surgery
• RT + Chemo
• Targeted agents
HOW TO MAKE A
TREATMENT DECISION?

17. PATIENT PRIORITIES

18. Treatment decision making flow
charts
https://tmc.gov.in/clinicalguidelines/EBM/Vol11/TreatmentofAlgorithms.pdf
https://tmc.gov.in/clinicalguidelines/EBM/Vol11/HeadandNeck.pdf

19. Larynx – T1-2 N2-3
Normal Cord mobility
Larynx T1-2,
N2-3
Non Surgical
Options
Normal Cr Cl CRT
Cr Cl – poor
Poor PS
Concurrent
Targeted therapy
with RT
Surgical
Options
Trans oral Laser microsurgery +
BLND+RT /CRT
Open Partial Laryngectomy + BLND +
RT/CRT
Split
therapy
Neck Dissection with Adjuvant
therapy (RT/CRT)

20. Larynx T3 Any N , Operable nodes
Larynx T3 , Any N
(Operable
nodes)
Laryngeal
Function Intact
Normal Cr CL CRT
Poor Cr Cl
Concurrent Targeted
therapy with RT
Altered Fraction RT for
N0-1
Open PL + Ipsi ND (N0)
and BLND (N+) with
Adjvuant RT /CRT
Laryngeal
function
Compromised NTL / TL with BLND
+ Adjuvant RT/CRT

21. Laryngeal
Function
and
Framework
Function Intact
Cartilage - N
Cr Cl
Normal
NTL /TL + BLND
+ RT/CRT
CRT
Cr Cl
Compromised
Concurrent Targeted
Therapy
Altered Fraction RT
NTL/TL with BLND +
RT/CRT
Function
Compromised
Cartilage damaged
NTL/TL with BLND +
RT/CRT
Larynx T4 Any N

22. Very locally-advanced HNC
Include T4b, unresectable N, unfit for surgery
• CRT or ICT  RT/CRT
• ± Surgery to T and N if feasable PS 0-1
• RT or CRT
• ± Surgery to T and N if feasable PS 2
• Palliative RT
• Single agent Chemotherapy
• Reassess for Surgery if feasable PS 3
PS 4 • Best Supportive Care

23. CCRT VS ICT /Sequential therapy

24. PARADIGM TRIAL
SPANISH TRIAL

29. ORGAN PRESERVATION TRIALS

32. RTOG 91-11: LFS and OS

35. 3 YRS DATA

36. 5 YRS DATA

37. Organ Preservation – Larynx cancer
• Compared with RT alone, LFS significantly better
with
– ICT followed by RT
– RT/concurrent cisplatin
• Compared with ICT followed by RT or RT alone
– Laryngeal Preservation and locoregional control
significantly better with RT/concurrent cisplatin
• No significant difference in OS
• CRT now the standard of care in organ preservation

38. MACH-NC
• 2000:
– 63 trial (10 741 patients) between 1965-1993
– oropharynx, oral cavity, larynx, or hypopharynx
• 2007 update:
– 63 +24 trials (87 trials) (16 665 patients) between 1965 -
2000
– oropharynx, oral cavity, larynx, or hypopharynx, Npx
• 2009 update
• 2011:
– Site analysis

39. MACH-HN Meta-Analysis
Pignon et al. Lancet, 2000

40. MACH- NC 2009 Update
Radiotherapy and Oncology 92 (2009) 4–14

41. MACH- NC 2009 Update
CCRRT vs Induction (Indirect comparisons)

42. MACH- NC 2011 Update
HN Subsites

43. MACH- NC 2011 Update
HN Subsites

44. MACH –HN Recent Data
Pignon et al, Radiother Oncol 2009; Blanchard Radiother Oncol 2011)

46. ICT IN LRA-SCCHN IN 2014 CONCLUSIONS

47. BIORADIOTHERAPY

50. RTOG 0522
Does Adding Cetuximab to RT improve Outcome

51. RTOG 0522 – Larynx subsite
Does Adding Cetuximab to RT improve Outcome

52. RTOG 0522
Does Adding Cetuximab to RT improve Outcome

53. Concomitant RT PLUS Cisplatin vs Cetuximab
A meta-analysis
5 Trials – Total of 1808 patients
Conclusions: Platinum-based CTRT still remains the standard of care in LAHNC
until prospective trials can demonstrate equivalence.
J Clin Oncol 32:5s, 2014 (suppl; abstr 6014)

54. RADIOTHERAPY FOR LARYNGEAL
TUMORS

55. EVIDENCE FOR NEED FOR POST OP RT

56. EORTC 22931 / RTOG 9501

57. Combined EORTC /RTOG Analysis
Bernier, Cooper. Head Neck 2005;27:843

58. Overall Survival Status

59. Combined EORTC /RTOG Analysis
Overall Survival for Patients WITHOUT Positive Margin
and/or ECE
Bernier, Cooper. Head Neck 2005;27:843

60. Combined EORTC /RTOG Analysis
Overall Survival for Patients WITH Positive Margin and/or ECE
Bernier, Cooper. Head Neck 2005;27:843
5 yr Follow up Data

61. Long term followup of RTOG 9501
Patients with Positive Margin and/or ECE
Cooper et al. IJROBP 2012
10 yr Follow up Data

62. Postoperative RT- Indications
1. Positive resection margins
2. Extracapsular lymph node
spread
Any 2 of the following
3. Close margins < 5 mm.
4. Invasion of soft tissues. (T3/T4)
5. Two or more lymph nodes positive.
6. More than one positive nodal group.
7. Involved node > 3 cm in diameter.
8. Multicentre primary.
9. Perineural invasion.
10. Lymphovascular Invasion
OR
1 or 2 --- Post op ChemoRT Any 2 of 3-10 ---- Post op RT only

63. Other factors to be considered
11. Poor differentiation
12. Stage T3/4
13. Oral cancer with Level 4/5 positive node
14. CIS, dysplasia at edge of resection margin
15. Uncertainties concerning surgical/pathological
findings
16. HPV negativity

64. RADIOTHERAPY TECHNIQUES AND
VOLUME DELINEATION

65. Target Volume Delineation (1)
• If neoadjuvant chemotherapy has been given
prior to radiation, the targets should be
outlined on the planning CT according to
their prechemotherapy extent.
• Review the operation notes and discuss with
surgeon to know more about areas of
concern.
• Review the detailed HPE report and if
necessary discuss with the pathologist

66. Target Volume Delineation (2)
• May deliver RT as soon as the wound is
healed
• Ideally initiate after 2 weeks but within 6
weeks after surgery
• Registration of Pre-Op images to sim CT
• Use proper immobilisation device and to do
Planning CT with Contrast and atleast 3 mm
slice thickness
• PET – CT for fusion where ever possible

67. Post operative RT Dose
Negative Margins • 60 Gy in 30 fractions
• 66 Gy in 33 fractions
Microscopically positive
margins
Gross Residual Disease • 70 Gy in 35 fractions
• Stoma Boost – With Electrons 10 Gy in 5
fractions (Level II Evidence)
Subglottic Extension
Chemotherapy • If positive Margin or ECE present.
Text book: Practical Essentials of IMRT –Chao, 3rd Edition

68. Nodal Volume Delineation - Larynx
Submandibular nodes • N2c Cases when Level 2 is involved
• Ipsilateral Neck in all cases
Upper Deep jugular nodes
(Junctional / Parapharyngeal)
• Bilaterally all cases (Level 2-4) Jugulodigastric, mid jugular,
SCLN
• All cases - Ipsilateral if jugular nodes are involved Posterior Cervical nodes (Level
5)
Retropharyngeal nodes • If evidence of metastases is present
Text book: Practical Essentials of IMRT –Chao, 3rd Edition

69. Postoperative IMRT
• Residual Tumor and adjacent region
• Surgical bed with soft tissue invasion
• Extracapsular extension of nodes
CTV1
CTV2 • Prophylactically the treated neck
Text book: Practical Essentials of IMRT –Chao, 3rd Edition

70. Post op IMRT
T2 N2b Mo
CA Supraglottis
Clinically Level 2 node +
TL + BLND
HPE- Sq cell carcinoma
4 nodes positive
No ECE
CTV 1 – Surgical Bed
CTV 2 – Prophylactic neck

71. Post op IMRT for Laryngeal Cancer

72. Definitive IMRT
• Gross Tumor (Primary and Nodes)
and the region adjacent to it CTV1
• High risk regions in the Ipsilateral
CTV2 neck
CTV 3 • Prophylactically treated neck
Text book: Practical Essentials of IMRT –Chao, 3rd Edition

73. Radical IMRT
T3 N2b Mo , Ca Supraglottis
Presentation - Hoarseness and
sore throat.
DL Scopy – A Tumor in the left
false vocal cord and AEF.
Multiple left-sided lymph nodes
GTV p
GTV n
CTV 1 GTVp+n + 5mm
CTV 2 IN(Adjacent LN)
CTV 3 IN + CN + RPLN

74. Radical IMRT
T3 N2b Mo , Ca Supraglottis
Presentation - Hoarseness
and sore throat.
DL Scopy – A Tumor in the
left false vocal cord and AEF.
Multiple left-sided lymph
nodes
GTV p
GTV n
CTV 1 GTVp+n + 5mm
CTV 2 IN(Adjacent LN)
CTV 3 IN + CN + RPLN

75. CTV Guidelines – Definitive IMRT Larynx
Tumor Site Stage CTV 1 CTV 2 CTV3
Glottis
T1-2 N0 GTVp +5mm ----- -----
T3-4 N0 GTVp+5mm
Whole laryngeal
apparatus
IN + CN (II-V)
Any T , N+
GTVp+n
+ 5mm
IN(Adjacent LN) +
Whole Laryngeal
Apparatus
IN + CN + RPLN*
Supraglottis
Any T , N0 GTVp+5mm
Whole laryngeal
apparatus
IN + CN (II-V)
Any T , N+
GTVp+n
+5mm
IN(Adjacent LN)
+Whole laryngeal
apparatus
IN + CN + RPLN*
Adjacent LN – with in 3 cm of CTV 1
RPLN * --- Include when midline tumors/ advanced tumors
Text book: Practical Essentials of IMRT –Chao, 3rd Edition

76. Dose Prescription – Definitive IMRT Larynx
Dose for
ChemoRT
CTV 1 CTV 2 CTV3
33 fractions 70 Gy in 33 # 59.4 Gy in 33 # 54 Gy in 33 #
35 fractions 70 Gy in 35 # 63 Gy in 35 # 56 Gy in 35 #
Text book: Practical Essentials of IMRT –Chao, 3rd Edition

77. Post Organ Preservation Treatment Evaluation
• DL Scopy / NPL scopy and CT scan 6 weeks after
treatment
• PETCT scan if ordered to be done only after 12
weeks
• Thyroid Function tests after 6 months or
symptomatic whichever is earlier
• Swallowing Therapy To initiate in pre treatment
setting and continue during and after radiation

78. Treatments following CRT in LA Larynx Tumors
CR (T + N)
Follow up
Residual
(PR /SD)
Resectable
• R0 in T and N – Follow up
• R1 /R2 – Chemotherapy
Unresectable
• Treat as PD
• Chemotherapy
Metastases
Progression
Palliative
Chemotherapy

79. Time Line for Salvage Surgery after CRT
ee
Salvage surgery within 4-6 months after CRT

80. Treatments after ICT Induction therapy
• Radical RT only
CR – Both T and
N
• RT and then assess for node
• If residual post RT – Neck dissection CR – T only
• RT /CCRT and follow up
• If Residual post RT – Salvage Surgery PR – T only
SD or PD at T • Surgery Post op RT /CRT

81. Conclusion
• Chemo radiotherapy (concomitant or sequential) is
better than RT alone in irresectable HN cancer and
resectable glottic or supraglottic malignancies
• CCRT is better than SCRT in laryngeal preservation
• SCRT is not significantly inferior to CCRT in
irresectable tumors

82. THANK YOU

83. Increase the Likelihood of Successful Larynx
Preservation (cont’d)
• Factors Associated with Decreased Larynx-Preservation Outcomes:
– Male / Smoker
– Anemia (at start of treatment)
– Advanced T stage
– Clinically detectable impaired vocal cord mobility
– Subglottic extension
– Involvement of anterior commissure
– Large tumor volume
– Invasion of specific anatomic sites (determined by CT or MRI)