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Organ-Preservation Strategies in head and neck cancer

Teresa Bonfill Abella

Oncologia Mèdica

Parc Taulí Sabadell. Hospital Universitari

Larynx Hypopharynx

Witch is the optimal primary endpoint? - Larynx preservation rate - Larynguectomy- FS? - Survival Rate at 2, 5, 10 years? - QoL ………………………………………….

“The goal of treatment is to achieve larynx preservation with good function without compromising survival”

Summary of the Relevant Literature

Surgery + RT Surveillance

PF x 3

no response surgery + RT surveillance

response RT +/- salvage surgery

3 randomized studies:

- VA - EORTC 24891 - GETTEC

larynx

hypopharynx

T3 larynx

VALCSG. N Engl J Med 1991

Lefebvre JL et al. J Natl Cancer Inst 1996

Richard JM et al. Oral Oncol 1998

Induction chemotherapy

New England Journal of Medicine 1991; 324: 1685-1690

332 pts, laryngeal SCC stage III/IV

Surgery

Surgery +/- RT

IC x 2

Cisplatin 100mg/m2, D1

5FU 1000mg/m2/d x 5d q3w

RT: 5000cGy/25fx Adjuvant RT

Definitive RT

RT: 6600-7600cGy

IC x 1

Residual disease Poor

respond

2yr DFS OS Recur at

primary

Recur at

regional

Distant

mets Laryngectomy-

free survival

Surgery 75% 68% 2% 5% 17%

IC RT 65% 68% 12% 8% 11% 39%

p value 0.12 0.98 0.001 NS 0.001

T1/T2 9%

T3 65%

T4 26%

Glottis 37%

Supraglottis 63%

Veterans Affairs Laryngeal Cancer Study Group

LPR: 64% (2y)

Journal of National Cancer Institute 1996; 8: 890-899

194 pts, hypopharynx SCC stage II/III/IV

Surgery

Surgery +/- RT

IC x 2

Cisplatin 100mg/m2, D1

5FU 1000mg/m2/d x 5d q3w

RT: 5000cGy/25fx Adjuvant RT

Definitive RT

RT: 7000cGy

IC x 1

Residual disease Poor

respond

5yr DFS OS Recur at

local

Recur at

regional

Distant

mets Laryngectomy-

free survival

Surgery 32% 35% 17% 23% 36%

IC RT 25% 30% 12% 19% 25% 42% (2y)

35% (5y)

p value NS NS NS NS 0.041

T2 20%

T3 75%

T4 5%

Pyriform

sinus 78%

Aryepiglottic

fold 22%

EORTC 24891

Trial/ site of tumour

N Therapy aproach Larynx Preservation

LFS

Survival Difference

VALCSG

(larynx)

332 S RT

vs

PF1x3 RT

64%(2y)

39%(2y)

No difference

EORTC 24891 (hypopharynx)

202 S RT

vs

PFx3 RT

40,5% (5y) 42% (2y)

35% (5y)

No difference

1CDDP 100mg/m²/ev d1

5-FU 1000mg/m²/ev d 1-5 (ic)

every 3w x 3courses

Induction PF + RT can be effective in preserving the

larynx in a high percentage of patients, without

compromising overall survival

Induction chemotherapy

PF induction

RT-CT concomitantly (cisplatin days 1, 22 and 43)

RT

no response surgery + RT surveillance

response RT +/- salvage surgery

RTOG 91-11 (USA) larynx

Forastiere A et al. N Engl J Med 2003

Chemoradiotherapy

T2 12%

T3 78%

T4 10%

Supraglottis 69%

Glottis 31%

N=547pt 1CDDP 100mg/m²/ev d1

5-FU 1000mg/m²/ev d 1-5 (ic)

every 3w x 3courses

2yr DFS OS Intact

larynx

LR

control LFS

Distant

mets

A: RT 27% 56

% 70% 56%

53%

38%

(5y)

22%

B: CCRT 36% 54

% 88% 78%

66%

45%

(5y)

12%

C:

ICRT 38%

55

% 75% 61%

59%

43%

(5y)

15%

p

0.02(C v

A)

0.006(B v

A)

NS

0.005(B v

C)

0.001(B v

A)

0.004(B v

C)

0.001(B v

A)

0.49(BvC)

0.01 (AvB)

0.03(B v

A) Difficulties in Speech/swallow : similar (2y) 15%

RTOG 91-11 (USA) larynx

Chemoradiotherapy

Forastiere A et al. N Engl J Med 2003

Toxicity: - The rate of high grade toxic effects was greater in Ch-based regimens

81% (Chi->RT), 82% (Ch-RT) & 61% (XRT) - The mucosal toxicity of concurrent RT-CDDP was nearly twice as

frequent as the mucosal toxicity of the other two treatments during RT

- No differences in late toxicity or speech or swallowing function were demonstrated between treatment groups

Calais G, et al. ASCO 2006, abstract 5506.

GORTEC 2000-01

Induction CT Larynx Preservation

Primary Objective: larynx preservation rate

Larynx or hypopharynx

tumors

Resectable tumors or

nodes requiring total

(pharyngo[P] laryngectomy)

No previous treatment

TPF arm Docetaxel (75 mg/m² d1)

Cisplatin (75 mg/m² d1)

5-FU (750 mg/m²/dx5)

Q 3 weeks x 3 cycles

PF arm

Cisplatin (100 mg/m²) 5-FU (1000 mg/m²/dx5)

Q 3 weeks x 3 cycles

Non-responders:

Total

(P)laryngectomy

+ post-op RT

Responders:

RT

Response

to

induction

treatment

Yes

No

Induction chemotherapy

Pointreau et al. ASCO 2006

T2 18%

T3 67%

T4 15%

Induction chemotherapy GORTEC 2000-01

Pointreau Y, et al. Cancer/Radiotherapie. 2006:10:493, Abstract C03;

Calais G, et al. ASCO 2006, Abstract 5506.

GORTEC 2000-01

Grade 3/4 Acute Toxicities

NCI/CTC Grade 3/4* TPF PF p

Mucositis 4.6 7.8 0.49

Neutropenia 55.6 37.3 0.01

Febrile neutropenia 13.9 7.8 0.24

Thrombocytopenia 1.9 7.8 0.09

Deaths 3.6 2.9 0.71

% of patients

*Among patients treated with RT alone, no differences were observed between

the 2 arms in: xerostomia, fibrosis, larynx edema, dysphagia, % of patients with

permanent feeding tube.

Induction chemotherapy

Sequential therapy for locally advanced larynx and hypopharynx cancer: Subgroup analysis from TAX 324

study

Induction chemotherapy

TAX 324

Induction chemotherapy

TAX 324

ASCO 2008

-Significant improvement in PFS (Hazard Ratio 0.61 (0.40-0.96) p=0.033 -Strong trend for OS (Hazard Ratio 0.67 (0.41-1.11) p =0.12

Five phase III trials

(VALSG, EORTC 24891, RTOG 91-11, GORTEC 2000-01, TAX 324)

STUDY LFS LPR

VETERANS (L)

EORTC 24891 (H)

RTOG 91-11 PF (L)

RTOG 91-11 QT+RT (L)

GORTEC 2000-01 PF (L&H)

GORTEC 2000-01 TPF (L&H)

TAX 324 PF (L&H)

TAX324 TPF (L&H)

39% (2y)

42% (2y) 35% (5y)

59% (2y) 43% (5y)

66% (2y) 45% (5y)

37% (3y)

53%(3y)

32% (3y)

52%(3y)

64% (2y)

75%(2y)

88%(2y)

57% (3y)

70%(3y)

TREMPLIN: French randomized phase II study of laryngeal preservation

TPF x 3

No resp. S + PORT

Resp.

RT + cetuximab

RT + cisplatin

Randomized phase II, GORTEC-GETTEC)

Larynx/hypopharynx suitable for TL

N=153

ASCO 2009 i ASCO 2011 JCO 2013

• From these studies we have learnt that:

None of the ch-based protocols has provided better results than surgery

except in terms of larynx preservation

- Ch combined with RT has allowed to preserve a significant number of larynx without compromising survival

- PF followed by RT and Ch-RT show similar efficacy in LFS - LCR and LPR were significantly improved with Ch-RT

- Ch decreased the incidence of DM without impact in OS

- TPF is better than PF in LFS & PFS - Chemoradiotherapy & Induction Chemotherapy are alternatives

-TPF-based ICT followed CRT or BRT was feasible but had

substantial overall toxicity

There is currently no good evidence base from larynx preservation trials with which to assess

the functional outcomes achieved with different larynx preservation strategies

The Oncologist 2010;15 (suppl3): 25-29

Suggested approaches to management

T1, T2

• TT Intent to preserve the larynx

• RT or larynx preservation surgery

• tt selection depends on: pt factors, local expertise & rehabilitation services

• Concurrent Ch-RT only in:

– Stage III, T2 N+ pts whom total LT is the only surgical option OR larynx-preservation surgery is expected to yield an unsatisfactory functional outcome OR organ-preservation surgical expertise is unavailable

“Narrow –margin excision” followed by postoperative radiation therapy IS NOT an acceptable treatment

approach”

T3, T4

• Organ preservation surgery, Ch-RT , Chi RT and Rt alone offer potential for larynx preservation without compromising survival

• Tt selection depends on: pt factors, local expertise and rehabilitation services

• Pt with tumor penentration through cartilage into soft tissues are considered poor candidates for larynx-preservation approach. LT is recommended in these cases

Factors associated with decreased larynx-preservation outcomes:

• Male gender

• Anemia (at start of treatment)

• Smoking

• 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)

Recommended management approach for treatment of resectable T3-4 N0-3 laryngeal cancer

JCO, Vol 31, No7 (march1), 2013:pp840-844

CONCLUSIONS

• Larynx-preservation therapy is intended to offer improved function and quality of life without compromising survival.

• All patients with T1-T2 should be treated initially with intent to preserve the larynx.

• Pt with T3- selected T4 should be offered a larynx-preservation treatment option.

• Chemoradiotherapy & Induction Chemotherapy are alternatives

CONCLUSIONS

• Preservation of the laryngeal structure is not considered a functional success if persistent dysphagia, aspiration, or chronic tracheostomy.

• Selection of treatment for laryngeal cancer should always depend on patient factors, local expertise, and appropiated support and rehabilitative services.

• A multidisciplinary team with specialized expertise is necessary to ensure optimal outcomes.