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)