Optimizing therapy for locally advanced larynx cancer:

techniques, advances and trials of RT-based therapy

Yong Chan Ahn, MD, PhD Dept. of Radiation Oncology

Samsung Medical Center

Sungkyunkwan University School of Medicine

2007, Green

Goals in HNC Management

• Early stage disease (stage I/II):

– 40% of patients.

– Single modality (surgery or RT alone) is

recommended.

– Two modalities result in similar LC and OS.

• Locally advanced disease (stage III/IV):

– 60% of patients.

– Combined modality is recommended.

2007, Green

EBM and RT technique

• 3-D CRT remains minimal standard of RT

technique.

• Whenever possible, IMRT should be

implemented.

2007, Green

EBM for CRT

• Level 1 evidence showed in favor of CCRT

in advanced HNSCC.

• DM rate remains high (15%~20% at 5 years),

which might be reduced by Ind CTx + CCRT.

• Ind CTx + CCRT is not supported by level 1

evidence and should remain investigational.

• RT alone remains alternative to CCRT to unfit

patients to CCRT (>70 years, heavy

comorbidities).

2007, Green

2007, Green

2007, Green

2006, JCO

Summary of ASCO Panel (2006)

• All patients with T1-2 laryngeal cancer, with rare

exception, should be treated initially with intent to

preserve larynx.

• For most patients with T3-4 disease without tumor

invasion through cartilage into soft tissues, LP approach

is appropriate, standard treatment option, and CCRT is

most widely applicable approach.

• To ensure optimum outcome, special expertise and

multidisciplinary team are necessary, and team should

fully discuss with patient advantages and disadvantages

of LP options compared with treatments that include TL.

2009, HN

2009, HN

Question 1

• Q1: Which patients are suitable for LP trials? Once

selected, what are stratification variables of highest

importance to obtain most valuable information from

randomized trials?

• A1: Trial population should include patients with

T2-3 laryngeal or hypopharyngeal squamous cell

carcinoma not considered for partial laryngectomy

and exclude those with laryngeal dysfunction or age

more than 70 years.

2009, HN

Question 2

• Q2: What are optimal assessments to conduct in

patients enrolled in LP trials to assess risks and

benefits of study treatment?

• A2: Functional assessments should include speech

and swallowing. Voice should be routinely assessed

with a simple, validated instrument.

2009, HN

Question 3

• Q3: What are optimal endpoints to use in LP trials?

How are these endpoints defined?

• A3: Primary endpoint should capture survival and

function. Panel created new endpoint: laryngo-esophageal

dysfunction-free survival. Events are death, local relapse,

total or partial laryngectomy, tracheotomy at 2 years or

later, or feeding tube at 2 years or later. Recommended

secondary endpoints are OS, PFS, LRC, time to

tracheotomy, time to laryngectomy, time to discontinuation

of feeding tube, and QoL/patient reported outcomes.

2009, HN

Question 4

• Q4: What are most promising translational research

opportunities that should be explored? What clinical

trial practices will foster translational research?

• A4: Correlative biomarker studies for near-term

trials should include EGFR, ERCC-1, Ecadherin and

b-catenin, epiregulin and amphiregulin, and TP53

mutation.

2009, HN

Summary

• By focusing on 3 important treatment goals

(survival, disease control, and laryngeal-

esophageal function), clinical trials can more

effectively evaluate and quantify therapeutic

benefit of novel treatment options for locally-

advanced laryngeal and hypopharyngeal cancer.

2009, HN

2014, Green

2014, Green

2014, Green

Conclusion

• LP is feasible by CCRT, alternating CRT and

Ind CTx followed by RT/CCRT.

• Still there is no one standard LP treatment

accepted worldwide.

• Heterogeneity exists both for population and

endpoints.

– LP endpoint – local cure vs. functional outcomes.

– Primary endpoint combining survival and function is

recommended.

2014, Green

Conclusion

• Optimal LP approach has yet to be determined

and clinical investigations are warranted.

• Next generation LP trials:

– should compare standard Tx (alternating CRT, CCRT,

Ind CTx + RT) with emerging approaches (Ind TPF +

RT, CCRT or Cetuximab-RT).

– should be conducted in accordance with recently

developed consensus guidelines.

2014, Green

2015, OL Clin NA

Larynx Function after RT

• Organ and function preservation are not

necessarily synonymous.

• Current evidence documents high rates of

locoregional control and reasonably good

swallowing and voice outcome after CRT.

• Newer techniques (IMRT, IGRT or proton

therapy) can minimize swallowing dysfunction

with promising results.

2015, OL Clin NA

2015, OL Clin NA

2015, OL Clin NA

• Conservation surgery deserve to maintain role in

specific advanced and recurrent laryngeal cancer.

• QOL is high priority issue to be considered.

2015, OL Clin NA

2015, JCO

2015, JCO

Locally advanced larynx cancer

• Requires experienced multidisciplinary team

evaluation and frank discussion of options and

expectations with patients.

• To achieve good function outcomes and

minimizing risk for recurrence and salvage

laryngectomy.

• Not only tumor extent and pretreatment

laryngeal function, but also expected tolerance

of treatment should be considered.

2015, JCO

Locally advanced larynx cancer

• Current level I evidence endorses

CCRT/CDDP for T2N+, T3, and selected low

volume T4 tumors.

• Carboplatin or cetuximab instead of CDDP

concurrent with RT could be considered.

• Induction TPF + RT (lower-level evidence).

• Induction chemo + CCRT (investigational).

2015, JCO

Locally advanced larynx cancer

• Endoscopic resection is as single modality for

early-stage larynx cancer, if likelihood of

positive margin is low.

• For more advanced disease, patients suitable

for endoscopic resection must be carefully

selected by skilled, experienced team.

2015, JCO

Evidence-based Medicine?

BMJ 2003

Natural history of gravitational challenge

• Effectiveness needs to be judged:

– Intervention vs. non-intervention

• Natural history of free fall:

– Survival has been reported after gravitation

challenges of more than 10,000 meters.

– Use of parachutes is associated with morbidity and

mortality.

• Studies are required to calculate balance of

risks and benefits of parachute use.

Parachute and healthy cohort effect

• Possibility of selection and reporting bias:

– Jumping from aircraft without parachute -- likely to

have psychiatric morbidity

– Using parachutes – less likely to have psychiatric

morbidity

Apparent protective effect may be “healthy

cohort” effect.

Parachutes and military industrial complex

• Parachute industry has earned billions of

dollars.

• One would not be brave enough to test product

in randomized controlled trial, with vast

commercial concerns.

• Industry sponsored trials are more likely to

conclude in favor of commercial product, and it

is unclear whether results of such industry

sponsored trials are reliable.

Is preferred Tx evidence-based?

• Single modality with surgery or RT to stages

I/II (40% of patients).

• Combined modality treatment to stages III/IV

(60% of patients).

• No single therapeutic regimen offers clear-cut

superiority over others.

• Many different regimens yield little difference.

• More indicated options are not always

evidence-based.

The man jumped out without a

parachute over 7,600 m!

Potential pathologic outcomes

following induction CTx

To irradiate or not? Where to/How to irradiate?

Confusion often leads to improper target

delineation, Tx failure and side effects.

Summary or Personal Bias?

• For early stage disease, RT alone may be

sufficient.

• For loco-regionally advanced disease, CCRT

should be considered first (whenever possible).

– Satisfactory clinical outcomes (LC, DFS and OS)

without compromising functional impairment.

– Little confusion in target delineation as in induction

chemo.