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Flashcards in Head & Neck Deck (37):
1

How is HPV status important ?

A/w >90% of HPV-related HNSCC
HPV is a small dsDNA virus

HPV E6 and E7 oncogenes bind and inactivate p53 and pRb.
- p53 and pRb are tumor suppressor genes
- unchecked cellular replication hence results
Inactivation of pRb result in over expression of p16
- p16 is an upstream tumor suppressor protein

Viral oncoproteins E6 and E7 inactive main Tumors suppressor genes resulting in:
- proliferation
- overexpression of p16

HPV + relates to:
- higher response to chemotherapy or ChemoRT
- improved OS
- improved PFS

2

What are the treatment goals for resectable H&N disease?

1) Improve locoregional control
2) Improve OS
3) Organ and function preservation for appropriate patients
- Laryngeal
- Hypopharyngeal
- Oropharyngeal

3

Which H&N cancers are a/w higher likelihood of micromets at diagnosis?

Nasopharynx
Hypopharynx

* Hence they require better systemic control to improve survival

4

What are the strategies that can be used to improve locoregional control and/or survival in stage III/IV disease?

1) Altered fractionation radiation
2) Systemic treatment
- radiosensitisation to improve locoregional control
- reduction of tumor bulk with induction therapy to facilitate locoregional therapy
- improve systemic control
- select patients for organ preservation (Larynx/hypopharynx)

5

What is the evidence for concurrent high-dose single agent CDDP to conventional RT for H&N cancers?

Aldestein JCO 2003

Aim of study: Test the benefit of adding chemo to RT in Unresectable SCC H&N
N=300 (study closed early due to not enough enrollment)

3arms:
A) = control arm = Single daily fractionated RT, 70Gy at 2Gy/day
B) = Identical Group A RT + CDDP on D1, 22 43
C) = Chemoradiotherapy:
- 3# of D1-4 CI 5FU (1000) + Bolus CDDP (75) D1
- Q4w
- RT at 2Gy/day split between first chemo course and 3rd chemo course (total 60-70Gy)
- Chemo break is to allow for possibility of surgical resection

RESULTS:
3y OS 20% (A) vs 35% (B) vs 30% (C)
3y DFS 50% (CDDP/RT) vs 30% (RT alone)

6

Tell me about the Forastiere study

RTOG 91-11
Forastiere NEJM 2003

Question:
1) value of adding chemo to RT?
2) Optimal timing of chemo

Locally advanced cancer of larynx patients, n=550
3 arms:
1) Induction CDDP/5FU --> RT
2) Concurrent CDDP/RT
3) RT alone

RESULTS med f/u almost 4 y:
1) Intact larynx at 2 years: 90% (concurrent) vs 75%(induction) vs 70% (RT alone)
2) 5y Rate of locoregional control 80% (Concurrent) vs 70%(induction) vs 65% (RT)
3) Better DFS when chemo added
4) OS similar I all groups
5) High-grade toxic effects greatest with chemo-based regimens
- mucosal toxicity of concurrent ChemoRT nearly 2x that of the other 2 regimens
6) 5y Laryngeal preservation rate 80%(CRT) vs 70% (IC) vs 65%(RT)

7

What is the MACH-NC study about?

Pignon Radiotherapy and Oncology 2009

Meta-analysis of chemo in H&N cancer
93 RCTs, 17 000 patients

Aim: To confirm that chemotherapy improved survival

RESULTS:
1) Chemo added additional 4.5% at 5 years in terms of OS
2) Concurrent ChemoRT better; HR 0.8 and absolute benefit of 6.5% at 5 years

8

What is the ideal treatment for maxillary/oral cavity cancers?

Surgery + adjuvantRT

Btwn Surgery and ChemoRT,
- Med DFS 5.5y (Sx) Vs 1y
5y DFS 55% vs 15%
- Med OS 5.5y (Sx) vs 1y
5 OS 55% vs 20%

9

In Oropharyngeal Ca, what is preferred? ChemoRT or surgery?

No difference noted in terms of DFS and OS

10

Is there a value of induction CDDP/5FU (PF) in Unresectable disease?

Yes. Zorat et al. JNCI 2004
--> 10% benefit 10y OS

Phase 3 study
1) Locoregional treatment alone
2) 4# Induction PF--> Locoregional treatment

*Locoreginal treatment =
- Resectable disease = Sx + Adjuvant RT
- Unresetable disease = RT alone

RESULTS:
1) Resectable disease: No difference in OS at 5 and 10y
2) Unresectable disease:
- 5y OS 20% vs 10%
- 10y OS 15% vs 5%

11

What is the evidence for TPF?

1) TAX 324 Posner et al NEJM 2007

N=500
Stage III/IV, no distant mets
Considered to be Unresectable OR were candidates for organ preservation

2 arms:
1) Induction TPF --> ChemoRT with weekly Carbo
2) Induction PF --> ChemoRT with weekly Carbo

RESULTS:
3y OS 60% (TPF) vs 50%(PF)
Med OS 70m (TPF) vs 30m
Better locoregional control in TPF
Incidence of distant mets ~
ORR 90% (CR 40%)
================

2) TAX 323 Vermoken NEJM 2007

N=350
Stage III/IV, no distant mets
2 arms:
1) 4# Induction TPF --> RT
2) 4# Induction PF --> RT

RESULTS:
Med PFS 11m (TPF) vs 8m
Med OS 19m vs 14.5m
Rates of death from toxic effects: 2% (TPF) vs 5.5% (PF)
ORR 70% vs 55% (PF)

12

What is the evidence for TPF, specifically for organ preservation?

Pointreau et al JNCI 2009

Aim: Determine if adding Docetaxel to PF could increase the Larynx preservation rate.

N=200
Larynx and hypopharynx cancer
2 arms:
1) 3# TPF
2) 3# PF

Those who respond:
- RT +/- additional chemo
Those who DID NOT Respond:
- Total laryngectomy --> RT +/- chemo

RESULTS after 3y f/u:
3y larynx preservation rate 70% (TPF) vs 55%
ORR 80% (TPF) vs 60%
OS~ 60%

13

What is the role of Cetuximab combined with RT?

Bonner et al Lancet Oncol 2010

N=400
Locally advanced SCC of Oropharynx, hypopharynx, larynx with measurable disease.
2 arms:
1) H&N RT for 6-7 weeks
2) H&N RT + weekly Cetuximab
- 400mg/m2 initial dose, followed by 7 weekly doses of 250mg/m2
RT consists of 1 of 3 regimens:
- once daily RT at 2Gy/day to total 70Gy gross disease
- twice-daily RT 1.2Gy in 2 separate fractions each day, 6h or more apart, total 72-77Gy
- 72Gy/42# + concomitant boost RT 18Gy for 30#, with a 2nd fraction 1.5Gy >6 hours after the first fraction during the last 12 days of tax.

Results:
- Med OS 50m (Cetux) vs 30m
- 5y OS 45% vs 35%
- Cetuximab OS significantly improved in those who experienced an acne inform rash of at least G2 severity
- Seems to benefit oropharynx most
- Once daily seems to do worst.

14

Any value in adding Cetuximab to Concurrent CDDP/RT?

No. Ang KK JCO 2014
RTOG 0522

B/g: CDDP OR Cetux + RT improved OS in Stage III/IV HNSCC
Cetux+platinum also increased OS in met HNC
QTN: whether adding Cetux to CDDP/RT will improve PFS

N=900
2 arms:
1) Cetux+ CDDP/RT
2) CDDP/RT

RESULTS:
1) Cetux resulted in more frequent interruptions in RT 25% vs 15%
2) Cetux resulted in more G3/4 radiation mucositis 40% vs 30%
3) No differences in 30-day mortality/locoregional failure/distant met/3y PFS/3y OS
- 3y PFS ~60%
- 3y OS ~75%
4) p16+ had better 3y PFS 70% vs 50% and OS 85% vs 60%

15

Give me some General conclusions of the Staging for H&N Cas

T1N0M0 = Stage I
T2N0M0 = Stage II
T3N0M0 = Stage II
T4aN0M0 = Stage IVA
T4bN0M0 = Stage IVB

TxN2M0 = Stage IVA
TxN3M0 = Stage IVB

M1 = Stage IVC

16

Any evidence for TKIs?

Yes. Sewart in JCO 2009

RECURRENT/MET setting of HNSCC

3 arms:
1) Gefitinib 250 mg/day
2) Gefitinib 500 mg/day
3) IV MTX 40 mg/m2 weekly

RESULTS:
Med OS: 5.5m vs 6m vs 6.5 m
ORR 3% vs 7.5% vs 4%
Tumor-hemorrhage-type events with Gefitinib. 9% with 250mg/d dose and 11.5% with 500mg/day dose.
QoL 13.5% vs 18% vs 6%

17

Tell me about the PARADIGM study

Haddad et al Lancet Oncol 2013

Aim: to compare induction chemo--> CRT vs CRT alone

Treatment naive, non-met newly Dx HN CA
Unresectable or low surgical durability due to T3/4 or N2/3 (Except T1N2)
Included also if they were for organ preservation
n= 150

2 arms:
1) 3# Induction TPF --> CRT
- CRT with either Docetaxel/Carboplatin
2) CRT with 2# Bolus CDDP

RESULTS:
1) 3yOS 75% (Induction group) vs 80% [trend]
2) FN higher in induction chemo group

18

What led to the approval of TPF for pts with resectable and Unresectable HNSCC?

1) TAX 323
2) TAX 324
3) GORTEC laryngeal study

19

What do you consider for a pt for organ preservation?

1) Patient characteristics:
- voice quality
- swallow
- Respiratory function
- social support, age
2) Tumor characteristics
- TNM
- cartilage involvement

20

What is EUA useful for?

Assess superior and inferior extent of disease
Assess for involvement of pre-vertebral fascia

21

What constitutes Unresectable disease?

Tumor involvement of the following sites would be worrying:
- involvement of pterygoid muscles, esp when a/w severe trismus or pterygopalatine fossa involvement with Cranial neuropathy
- gross extension of tumor to skull base
- direct extension to the superior nasopharynx or deep extension into Eustachian tube and lateral nasopharyngeal walls
- invasion/encasing of common or internal carotid artery. (Surrounding vessel by 270 degrees or greater)
- direct extension of neck disease to involve external skin
- direct extension to mediastinal structures, pre vertebral fascia or cervical vertebrae
- presence of sub dermal mets

22

What are the trials supporting concurrent ChemoRT?

Aldestein study
MACH-NC meta-analysis

23

What are the trials assessing induction vs CCRT?

Hitt study
PARADIM
ASCO Trial by Grazia presented ASCO 2014
DeCIDE study presented ASCO 2012

24

Tell me about the Hitt study comparing induction chemo regimens

Hitt JCO 2005

Aim: Compare 2 induction regimens

N=400, tx-naive, Stage III/IV locally advanced HNC
2 arms:
1) CF
- CDDP (100) D1, CI FU(1000) D1-5
2) PCF
- Paclitaxel (175) D1
- CDDP (100) D2
- CI 5FU (500) D2-6

Both regimens Q21 days, for 3#

Those with CR or PR >80% then received additional CRT
- CDDP (100) D1, 22, 43 +70Gy)

RESULTS:
CR 15% (CF) vs 35% (PCF)
Median TTTF 12m (CF) vs 20m (PCF)
OS 37m (CF) vs 43m (PCF) [Trend]
- but significant when looking at pts with Unresectable disease 26m vs 36m
CF patients with higher occurrence of G2-4 mucositis 50% vs 15%

25

Tell me about the T staging for Oro/hypo-pharynx staging

T1 = 2cm or less

T2 = 2-4cm

T3 = >4cm

T4a =
Oro: Larynx, mandible, tongue
Hypo: Thyroid cartilage, hold

T4b =
Oro: Muscles, nasopharynx
Hypo: Prevertebral space, carotid, mediastinum

26

Tell me about the T staging for Larynx

T1a = 1 vocal cord
T1b = 2 vocal cords

T2 = extends to glottis or decreased vocal cord mobility

T3 = Invasion of vocal cord/paraglottic space

T4a = soft tissue cartilage beyond larynx, thyroid cartilage

T4b = Prevertebral space, carotid, mediastinum

27

Tell me about the N staging for Oro/hypopharynx and larynx staging

N1 =
3cm or less, ipsilateral side affected only

N2 =
N2a = 1 ipsilateral side 3-6cm
N2b = Multiple ipsilateral LN, 6cm

28

How does Cetuximab work?

Cetuximab is an IgG1 monoclonal Ab that inhibits ligand binding to the EGFR

Stimulates Antibody-dependent cell-mediated cytotoxicity

Enhances activity of a number of chemo agents

29

What is the evidence for Cetuximab in 1st line setting of metastatic/platinum-resistant recurrent HNSCC?

EXTREME study, Vermoken NEJM 2008

N=450
Untreated recurrent/metastatic HNSCC

4 arms:
1) CDDP + 5FU
2) Carboplatin +5FU
3) CDDP + 5FU + Cetuximab
4) Carboplatin + 5FU + Cetuximab

Those with stable disease then go on to receive Cetuximab until PD/toxicities

RESULTS:
Med OS 7.5 to 10m (Cetux)
Med PFS 3.5m to 5.5m
RR 20% to 35%

30

Tell me the profile of HPV-related HNSCC

Younger patients30-40yo
Risk factors:
- certain sexual practices
- less exposure to Etoh and tobacco
Frequently: poorly differentiated, non-Keratinising with Basaloid features
Predominantly oropharynx
- usually tonsil and BOT
Molecularly:
- wt p53
- Down regulation of Rb
- Up regulation of p16
Usually low T, high N staging

31

What will make you decide to offer adjuvant treatment after definitive surgery?

Positive surgical margins
Extracapsular nodal extension

32

What post-op adjuvant trials do you know about?

1) Intergroup trial - Cooper et al NEJM 2004
N=460
S/p resection of all visible and palpable disease

2 arms:
1) RT 60-66Gy /30-33#
- 13% received 66Gy
2) RT + CDDP (100) Weeks 1,4,7

RESULTS:
1) Rate of local and regional control better with combination therapy
HR 0.6
2) 2y LC and 2y Regional control 80% (combined) vs 70%
3) DFS longer in combined group HR 0.8
4) OS~
===========
2) EORTC study, Bernier NEJM 2004
N=400
S/p surgery

2 arms:
1) RT alone 66Gy over 6.5 weeks
- 90% received 66Gy
2) RT + CDDP (100) W1,4,7

RESULTS:
- PFS better in combination group HR 0.75
- OS better in combination group HR 0.7
>> 50% vs 40%
- Local/regional relapses lower in combined group.
>> 5y 30% (RT) vs 20% (combi)

33

When will you give Adjuvant RT alone?

1) 2 or more LN
2) T4 primary
3) Perivascular/peri neural invasion
4) Level 4/5 LN
- Level 4: Jugular LN
- Level 5: posterior triangle LN (spinal accessory group, transverse cervical artery group, supraclavicular group)

Consider if:
- pT3/pT4
- N2/N3
- Microscopically + Surgical margins
- Extracapsular nodal involvement
- peri neural/Perivascular invasion
- Level 4/5 nodal involvement in oral cavity or oropharyngeal site

34

Which are the 2 organs involved when we talk about organ preservation?

1) Larynx
2) Hypopharynx

35

What are the 3 trials for organ preservation?

1) Veterens Affairs (VA) Laryngeal study NEJM 1991 Wolf et al.
2) Lefebvre et al EORTC JNCI 1991
3) RTOG 99-11 Foratiere NJEM 2004

36

Tell me about the VA Laryngeal study

Wolf et al NEJM 1991

Aim: Compare induction chemo--> Definitive RT vs Conventional layngectomy + postop RT

N=300
Tx-naive, Stage III/IV laryngeal SCC

2 arms:
1) 3#CDDP/5FU+RT
- No RT but salvage laryngectomy if no tumor response or clinically recurrent
2) Surgery + RT

RESULTS:
- CR 30% PR 55%
- 2y OS 70%~
- larynx preservation rate 65% in preservation arm

37

What does the Larynx consists of?

1) Supraglottis
2) Glottis
3) Subglottis