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Head & Neck Flashcards

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1
Q

How is HPV status important ?

A

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
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2
Q

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

A

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

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3
Q

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

A

Nasopharynx
Hypopharynx

  • Hence they require better systemic control to improve survival
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4
Q

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

A

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)

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5
Q

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

A

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)

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6
Q

Tell me about the Forastiere study

A

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)

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7
Q

What is the MACH-NC study about?

A

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

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8
Q

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

A

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%
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9
Q

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

A

No difference noted in terms of DFS and OS

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10
Q

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

A

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%

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11
Q

What is the evidence for TPF?

A

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)
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12
Q

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

A

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%

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13
Q

What is the role of Cetuximab combined with RT?

A

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.
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14
Q

Any value in adding Cetuximab to Concurrent CDDP/RT?

A

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%

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15
Q

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

A 
T1N0M0 = Stage I
T2N0M0 = Stage II
T3N0M0 = Stage II
T4aN0M0 = Stage IVA
T4bN0M0 = Stage IVB
TxN2M0 = Stage IVA
TxN3M0 = Stage IVB

M1 = Stage IVC

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16
Q

Any evidence for TKIs?

A

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
Q

Tell me about the PARADIGM study

A

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
Q

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

A

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

19
Q

What do you consider for a pt for organ preservation?

A

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

20
Q

What is EUA useful for?

A

Assess superior and inferior extent of disease

Assess for involvement of pre-vertebral fascia

21
Q

What constitutes Unresectable disease?

A

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
Q

What are the trials supporting concurrent ChemoRT?

A

Aldestein study

MACH-NC meta-analysis

23
Q

What are the trials assessing induction vs CCRT?

A

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

24
Q

Tell me about the Hitt study comparing induction chemo regimens

A

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
Q

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

A

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
Q

Tell me about the T staging for Larynx

A 
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
Q

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

A

N1 =
3cm or less, ipsilateral side affected only

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

28
Q

How does Cetuximab work?

A

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
Q

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

A

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
Q

Tell me the profile of HPV-related HNSCC

A 
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
Q

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

A

Positive surgical margins

Extracapsular nodal extension

32
Q

What post-op adjuvant trials do you know about?

A

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
Q

When will you give Adjuvant RT alone?

A

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
Q

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

A

1) Larynx

2) Hypopharynx

35
Q

What are the 3 trials for organ preservation?

A

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
Q

Tell me about the VA Laryngeal study

A

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
Q

What does the Larynx consists of?

A

1) Supraglottis
2) Glottis
3) Subglottis

Medical oncology (53 decks)

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