multidisciplinary management of advanced laryngeal cancer
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Locally Advanced Vocal Cord Tumors- Evidence Based Approach
Dr. Rajesh Balakrishnan
Associate Professor
Christian Medical College, Vellore
LEARNING OBJECTIVES
Staging and Grouping
Current treatment protocols
Evidence – Clinical trials
Radiotherapy Volume delineation Guidelines
What to do after CRT / ICT
MILESTONES IN LARYNX/HYPOPHARYNX MANAGEMENT
1st TL
1st PLs
1st RT Laser CO2
SCPL
Trial VA
Trial EORTC
Trial RTOG
Trial EORTC
Trial GORTEC
SURGERY RADIOTHERAPY LASER
CT MRI
ASCO1982
1873 1878 1903 1970s 1994 1996 2003 2005 2007
Courtesy Dr. J-L Lefebvre
ORGAN PRESERVATION PROTOCOLS
TIME TREND ANALYSIS - LARYNX
FIVE- YEAR RELATIVE SUVIVAL RATE
STAGING AND GROUPING
ANATOMY
Ref: Book - Target Volume Delineation
and Field Setup
ANATOMY
STAGE GROUPING
T1< 2cm
T22-4 cm
T3>4cm
T4a+
Invasion
T4b++Invasio
n
M1
N0 I II III IV A IV B IV C
N1<3cmSIPSI
III III III IV A IV B IV C
N23-6cm
BILIV 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
CLASSIFICATION – LARYNGEALTUMORS
T1< 2cm
T22-4 cm
T3>4cm
T4a+
Invasion
T4b++Invasio
nM1
N0 EARLY LOCALLY ADVANCED
META
STATIC
N1<3cmSIPSI
LOCALLY ADVANCED
N23-6cm
BIL
N3>6cm
Very Locally Advancedo T4bo Unresectable No Unfit for surgery
TREATMENT MODALITIES IN LARYNX TUMORS 2014
Surgery
Radiotherapy (RT)
Chemotherapy (CT)Combined therapy
Palliative therapy
Targeted TherapyAlone or in combination with CMT, RT, CT
} As a single modality
1. Induction Chemotherapy(ICT)2. Concomitant CT and RT3. Sequential therapy (ICT > CCRT)4. Adjuvant CT (ART) 5. Postoperative (RT /CCCRT)
TREATMENT OPTIONS
T1< 2cm
T22-4 cm
T3>4cm
T4a+ Invasion
T4b++Invasion
M1
N0I- II
EARLYRESECTABLE
III -IV B LOCALLY ADVANCED
META
STATIC
CH
EMO
THER
AP
Y
III??RESECTABLE
IV A??
IV BIRRESECTABLE
N1<3cmSIPSI
IIILOCALLY
ADVANCEDRESECTABLE
III??RESECTABLE
IV A??
IV BIRRESECTABLE
N23-6cm
BIL
IV ALOCALLY ADVANCED
?? RESECTABLE
N3>6cm
IV BLOCALLY ADVANCED
?? IRRESECTABLE
TREATMENT OPTIONST1
< 2cmT2
2-4 cmT3
>4cmT4a
+ InvasionT4b
++InvasionM1
N0 EARLYRESECTABLE
S = RT
LOCALLY ADVANCED
IV CMETCT
??RESECTABLECRT
??CRT
IRRESECTABLECRT
N1<3cmSIPSI
LOCALLY ADVANCEDRESECTABLES > RT / CRT
??RESECTABLECRT
??CRT
IRRESECTABLECRT
N23-6cm
BIL
LOCALLY ADVANCED?? RESECTABLE
CRT
N3>6cm
LOCALLY ADVANCED?? IRRESECTABLE
CRT
T1< 2cm
T22-4 cm
T3>4cm
T4a+ Invasion
T4b++Invasion
M1
N0 LOCALLY ADVANCED
IV CMETCT
??RESECTABLE
S > RTS > CRT CRT > S
??CRT > s
IRRESECTABLECRT
N1<3cmSIPSI
LOCALLY ADVANCEDRESECTABLES > RT /CRT
N23-6cm
BIL
LOCALLY ADVANCED?? RESECTABLE
CRT > S
N3>6cm
LOCALLY ADVANCED?? IRRESECTABLE
CRT
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
HOW TO CHOOSE THE TREATMENT DECISION ?
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 ATREATMENT DECISION?
PATIENT PRIORITIES
Treatment decision making flow charts
https://tmc.gov.in/clinicalguidelines/EBM/Vol11/TreatmentofAlgorithms.pdfhttps://tmc.gov.in/clinicalguidelines/EBM/Vol11/HeadandNeck.pdf
Larynx – T1-2 N2-3Normal 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)
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
Laryngeal Function
and Framework
Function Intact
Cartilage - N
Cr ClNormal
CRT
NTL /TL + BLND
+ RT/CRT
Cr ClCompromised
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
• CRT or ICT RT/CRT
• ± Surgery to T and N if feasablePS 0-1• RT or CRT
• ± Surgery to T and N if feasablePS 2• Palliative RT
• Single agent Chemotherapy
• Reassess for Surgery if feasablePS 3
• Best Supportive CarePS 4
Very locally-advanced HNCInclude T4b, unresectable N, unfit for surgery
CCRT VS ICT /Sequential therapy
PARADIGM TRIAL
SPANISH TRIAL
ORGAN PRESERVATION TRIALS
RTOG 91-11: LFS and OS
3 YRS DATA
5 YRS DATA
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
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
MACH-HN Meta-Analysis
Pignon et al. Lancet, 2000
MACH- NC 2009 Update
Radiotherapy and Oncology 92 (2009) 4–14
MACH- NC 2009 UpdateCCRRT vs Induction (Indirect comparisons)
MACH- NC 2011 UpdateHN Subsites
MACH- NC 2011 UpdateHN Subsites
Pignon et al, Radiother Oncol 2009; Blanchard Radiother Oncol 2011)
MACH –HN Recent Data
ICT IN LRA-SCCHN IN 2014 CONCLUSIONS
BIORADIOTHERAPY
RTOG 0522Does Adding Cetuximab to RT improve Outcome
RTOG 0522 – Larynx subsiteDoes Adding Cetuximab to RT improve Outcome
RTOG 0522 Does Adding Cetuximab to RT improve Outcome
5 Trials – Total of 1808 patientsConclusions: 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)
Concomitant RT PLUS Cisplatin vs CetuximabA meta-analysis
RADIOTHERAPY FOR LARYNGEAL TUMORS
EVIDENCE FOR NEED FOR POST OP RT
EORTC 22931 / RTOG 9501
Bernier, Cooper. Head Neck 2005;27:843
Combined EORTC /RTOG Analysis
Overall Survival Status
Combined EORTC /RTOG Analysis
Bernier, Cooper. Head Neck 2005;27:843
Overall Survival for Patients WITHOUT Positive Margin and/or ECE
Bernier, Cooper. Head Neck 2005;27:843
Combined EORTC /RTOG Analysis
Overall Survival for Patients WITH Positive Margin and/or ECE
5 yr Follow up Data
Long term followup of RTOG 9501Patients with Positive Margin and/or ECE
Cooper et al. IJROBP 201210 yr Follow up Data
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
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
RADIOTHERAPY TECHNIQUES AND VOLUME DELINEATION
Target Volume Delineation (1)
• If neoadjuvant chemotherapy has been givenprior to radiation, the targets should beoutlined on the planning CT according totheir prechemotherapy extent.
• Review the operation notes and discuss withsurgeon to know more about areas ofconcern.
• Review the detailed HPE report and ifnecessary discuss with the pathologist
Target Volume Delineation (2)
• May deliver RT as soon as the wound ishealed
• Ideally initiate after 2 weeks but within 6weeks after surgery
• Registration of Pre-Op images to sim CT
• Use proper immobilisation device and to doPlanning CT with Contrast and atleast 3 mmslice thickness
• PET – CT for fusion where ever possible
Post operative RT Dose
• 60 Gy in 30 fractionsNegative Margins
• 66 Gy in 33 fractionsMicroscopically positive
margins
• 70 Gy in 35 fractionsGross Residual Disease
• Stoma Boost – With Electrons 10 Gy in 5 fractions (Level II Evidence)
Subglottic Extension
• If positive Margin or ECE present.Chemotherapy
Text book: Practical Essentials of IMRT –Chao, 3rd Edition
Nodal Volume Delineation - Larynx
• N2c Cases when Level 2 is involvedSubmandibular nodes
• Ipsilateral Neck in all casesUpper Deep jugular nodes
(Junctional / Parapharyngeal)
• Bilaterally all cases (Level 2-4)Jugulodigastric, mid jugular,
SCLN
• All cases - Ipsilateral if jugular nodes are involvedPosterior Cervical nodes (Level
5)
• If evidence of metastases is presentRetropharyngeal nodes
Text book: Practical Essentials of IMRT –Chao, 3rd Edition
Postoperative IMRT
• Residual Tumor and adjacent region
• Surgical bed with soft tissue invasion
• Extracapsular extension of nodesCTV1
• Prophylactically the treated neck CTV2
Text book: Practical Essentials of IMRT –Chao, 3rd Edition
Post op IMRT
T2 N2b MoCA SupraglottisClinically Level 2 node +
TL + BLND
HPE- Sq cell carcinoma4 nodes positiveNo ECE
CTV 1 – Surgical BedCTV 2 – Prophylactic neck
Post op IMRT for Laryngeal Cancer
Definitive IMRT
• Gross Tumor (Primary and Nodes) and the region adjacent to itCTV1
• High risk regions in the Ipsilateral neckCTV2
• Prophylactically treated neckCTV 3Text book: Practical Essentials of IMRT –Chao, 3rd Edition
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 pGTV n CTV 1 GTVp+n + 5mmCTV 2 IN(Adjacent LN)CTV 3 IN + CN + RPLN
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 pGTV nCTV 1 GTVp+n + 5mmCTV 2 IN(Adjacent LN)CTV 3 IN + CN + RPLN
CTV Guidelines – Definitive IMRT Larynx
Tumor Site Stage CTV 1 CTV 2 CTV3
Glottis
T1-2 N0 GTVp +5mm ----- -----
T3-4 N0 GTVp+5mmWhole 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+5mmWhole laryngeal apparatus
IN + CN (II-V)
Any T , N+GTVp+n+5mm
IN(Adjacent LN)+Whole laryngeal apparatus
IN + CN + RPLN*
Text book: Practical Essentials of IMRT –Chao, 3rd Edition
Adjacent LN – with in 3 cm of CTV 1RPLN * --- Include when midline tumors/ advanced tumors
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
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 12weeks
• Thyroid Function tests after 6 months orsymptomatic whichever is earlier
• Swallowing Therapy To initiate in pre treatmentsetting and continue during and after radiation
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
Time Line for Salvage Surgery after CRT
ee
Salvage surgery within 4-6 months after CRT
• Radical RT onlyCR – Both T and
N
• RT and then assess for node
• If residual post RT – Neck dissectionCR – T only
• RT /CCRT and follow up
• If Residual post RT – Salvage SurgeryPR – T only
• Surgery Post op RT /CRTSD or PD at T
Treatments after ICT Induction therapy
• Chemo radiotherapy (concomitant or sequential) isbetter than RT alone in irresectable HN cancer andresectable glottic or supraglottic malignancies
• CCRT is better than SCRT in laryngeal preservation
• SCRT is not significantly inferior to CCRT inirresectable tumors
Conclusion
THANK YOU
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)
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