Statements on Head and Neck Cancer 2006

Primary Radiochemotherapy

Arlene A. Forastiere, M.D.

Johns Hopkins University School of Medicine

Department of Oncology

Concurrent Chemoradiotherapy as Standard of Care Based on Phase III Trials

• Organ Preservation Randomized Trials– Larynx INT R91-11 – Oropharynx GORTEC

• Nasopharynx Trials in US & Asia

• Unresectable disease Trials in US & Europe

• Post-operative adjuvant EORTC & US trials

Standard of Care Options to Preserve the Larynx for locally advanced disease

• Conservation laryngeal surgery

• Concurrent RT and cisplatin 100 mg/m2 x 3

• RT alone

VA Laryngeal Cancer Study Group

• No difference in survival

• Larynx preserved in 64%; 2-year LFS rate 41%

• Pattern of failure (CT v S)– local, 12% v 2%– distant, 11% v 17%

• Risk factors for surgery–T4 or N2-3–56% of T4 eventually required laryngectomy

Induction CF - RT versus Surgery + RTNEJM 1991;324:1685-1690

INT R91-11 Trial to Preserve the LarynxForastiere AA. NEJM 349:2091, 2003

Cisplatin/5-FU*x 2

Radiotherapy + cisplatin 100 mg/m2 x 3

Radiotherapy

• RT 70 Gy/7 wks, 2 Gy/fx *cisplatin 100 mg/m2 day 1 5-FU 1000 mg/m2 CIVI days 1-5

cisplatin/5-FU RT

surgery RT

CR, PR

NR

Eligibility Criteria

• Resectable SCC of the glottis or supraglottis requiring total laryngectomy

• Stage III or IVT1 excludedT4 excluded if tumor penetrated through

cartilage or invaded > 1cm into base of tongue

• No distant metastases

Surgery

• Planned neck dissection – N2 or N3 at initial staging

• Total laryngectomy

– Inadequate response (<PR) of primary to induction chemotherapy

– Biopsy proven disease after completing RT– Laryngeal dysfunction or necrosis

Patient Characteristics, in %

InductionN=173

ConcurrentN=172

RTN=173

Supraglottis 68 66 72

T3 78 78 79

N0-1 72 73 68

Stage III 64 67 64

INT R91-11 Results: Larynx Preservation

Larynx preservation

%

P R

E S

E R

V E

D

0

25

50

75

100

YEARS FROM RANDOMIZATION0 1 2 3 4 5

ConurrentInduction RT alone

88%

75%

70%

Induction vs Concurrent p= 0.0047Induction vs RT alone p= 0.27Concurrent vs RT alone p= 0.00012

Intergroup R91-11: 43% absolute reduction in laryngectomy rate with RT/cisplatin

No difference in survival

(76% at 2-years)

Local-regional control%

L

/ R C

O N

T R

O L

0

25

50

75

100

YEARS FROM RANDOMIZATION0 1 2 3 4 5

ConcurrentInduction RT alone

78%

61%

56%

Induction vs Concurrent p =0.0031Induction vs RT alone p= 0.16Concurrent vs RT alone p= 0.00002

% A

L I V

E (N

E D)

0

25

50

75

100

YEARS FROM RANDOMIZATION0 1 2 3 4 5

ConcurrentInduction RT alone

61%

52%

44%

I + RT vs CRT p= 0.64I + RT vs RT p= 0.017CRT vs RT p= 0.0053

Disease-free survival

% A

L I V

E &

P R E

S E R

V E D

0

25

50

75

100

YEARS FROM RANDOMIZATION0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0

Laryngectomy-free survival

66%

59%

53%

I + RT vs CRT p= 0.49I + RT vs RT p= 0.08CRT vs RT p= 0.01

Response and compliance after two cycles of induction chemotherapy

• CR 21%, PR 64%, total 85%

• 24 (15%) < PR

–29% had laryngectomy per protocol–25% other chemo or unknown rx– 46% had RT with/without third cycle of CT;

all achieved CR post XRT, one failed later

ResultsForastiere AA. N Eng J Med 349:2091, 2003

Weber RS. Arch Otolaryngol Head Neck Surg 129:44, 2003

• Chemotherapy suppressed metastasis– Concurrent 8% vs RT 16%

• Chemotherapy added toxicity– Gr 3-4 toxicity: chemotherapy 81%, 82% vs

RT 61% • Laryngectomy was required in 25% of all

patients (16% chemorad, 28% induction, 32% RT alone)

Induction Concurrent RT alone

12 mos 6% 11% 13%

24 mos 3% 6% 8%

Moderate impairment: unable to be understood on the telephone or worse

Function and QOL Assessments: no difference in speech at 12 and 24 mos

Swallowing function at 12 mos: delay in recovery with concurrent treatment

Swallowing function

Induction Concurrent RT alone

Soft foods,

liquids only

9% 23% 15%

Unable to swallow

0 3% 3%

No differences between treatment groups at 24 mos

5-Year Update (ASCO 2006)

• Confirms the 2-year analysis• Survival – no significant difference• Function excellent – no significant difference• Concurrent CRT is significantly better than

RT alone for all endpoints except OS• Induction was not better than RT alone for

larynx preservation and LR control• Concurrent CRT and induction were better

than RT alone for laryngectomy-free survival and DFS

5-year Update

Analysis not yet complete

– Late effects

– Site of first failure

– Cause of death

Implications for Patient Management

• For larynx preservation of T3 and low volume T4 disease, chemotherapy and RT should be given concurrently

• For high volume T4 disease– Glottic cancer or penetration through cartilage into

soft tissues: surgery– Supraglottic cancer: option for concurrent

chemoradiotherapy

.

Implications for Patient Management

• RT alone for patients unable to tolerate the added toxicity of concurrent chemoradiotherapy

• No role for induction chemotherapy outside of a clinical trial

Concepts in Development

Separate intermediate and advanced stages: improved survival as primary endpoint

• RT (altered fx or std) + biologic – Inhibitors of EGFR or angiogenesis

• Standard fx RT + cisplatin + biologic• Induction followed by cisplatin/RT

Other Questions

• Alternative chemotherapy regimens

• Impact of changing epidemiology (human papilloma virus) and prevalence of oropharynx cancer

• Patient selection or therapeutic effect?

ECOG 2399: Schema

Primary endpoints: organ preservation rate, toxicity, assess utility of organ function instruments

Median follow-up 33 months (11.8 months – 47 months)

TREATMENT DELIVERY (FEASIBILTY)TREATMENT DELIVERY (FEASIBILTY)Larynx (36) Oropharynx (69) Overall (105)

# Induction Cycles unknown 0 2 (4%) 2 (3%)

1 0 3(4%) 3(3%)

2 36 (100%) 64 (93%) 100 (95%)

# Concurrent Cycles unknown 0 3 (3%) 3 (3%)0 5 (14%) 7 (10%) 12 (12%)4 0 7 (10%) 7 (7%)

5 4 (11%) 10 (15%) 14 (13%) 6 6 (17%) 86% 18 (26%) 24 (23%) 7 21 (58%) 24 (25%) 45 (43%) 5, 6, or 7 cycles 83 (79%)

Radiation (≥66Gy) 31 59 90 (87%)

SURGICAL INTERVENTIONS

Larynx (n=36) Oro (n=69) Overall (n=105)

Neck Dissection Only 11 (31%) 18 (26%) 29 (28%)

Primary Site Only 7 (19%) 6 (9%) 13 (13%)

Both 5 (14%) 6 (9%) 11 (11%)

Primary Overall 12 (33%) 12 (18%) 24 (23%)

Survival Time in Months

Su

rviv

al P

rob

ab

ility

0 10 20 30 40

0.0

0.2

0.4

0.6

0.8

1.0

OropharynxLarynx

Overall Survival by Primary SiteOverall Survival by Primary Site

p=0.06

80%

58%

CONCLUSIONS

• Feasible regimen to deliver

• Surgical salvage rate for larynx cancer, 33% suggests:

– that weekly paclitaxel concurrent with RT is not effective for LR control

– Induction chemotherapy does not impact LR control or allow for a less intense concurrent chemoRT regimen

• DFS and OS results are excellent for OP (probable impact of HPV?)

• ASCO update in 2006

R99-14: Concomitant Boost RT + Concurrent Cisplatin

• 72 Gy/42 fx over 6 wks (daily for 3.5 wks then bid for 2.5 wks) + cisplatin 100 mg/m2 day 1 & 22

• 76 analyzable pts– Median age 57 (range 40-76)– Stage IV 88%; T3-4 64%, N2-3 78%– Oral cavity 9 (12%)– Oropharynx 50 (66%)– Hypopharynx 8 (11%)– Larynx 9 (12%)

Copyright © American Society of Clinical Oncology

Ang, K. K. et al. J Clin Oncol; 23:3008-3015 2005

Overall survival, disease-free survival and relapse pattern

Copyright © American Society of Clinical Oncology

Ang, K. K. et al. J Clin Oncol; 23:3008-3015 2005

Cumulative incidence of all treatment-related late grade 3 to 5 and grade 4 to 5 toxicity

Late Toxicity

R97-03: Randomized Ph II Concurrent Chemradiation

• RT – 70 Gy/35 fx• Chemotherapy

– Arm 1: cisplatin 10 mg/m2 + 5-FU 400 mg/m2/d during last 10 days of RT

– Arm 2: hydroxyurea + 5-FU + RT every other week (U. Chicago FHX)

– Arm 3: cisplatin 20 mg/m2 + paclitaxel 30 mg/m2 weekly

R97-03: Randomized Phase II Concurrent Chemradiation

• 231 eligible pts randomized• Median age 56 (range 21-83)• T3-4 75%; N2-3 70%• Primary site

– Oral cavity 16%– Oropharynx 67%– Hypopharynx 17%

Copyright © American Society of Clinical Oncology

Garden, A.S. J Clin Oncol 22:2856-2864, 2004

Time to locoregional failure

41%

27.5%

Estimated 2-yr LR failure rate

Copyright © American Society of Clinical Oncology

Garden, A.S. J Clin Oncol; 22:2856-2864, 2004

R97-03: Disease-free Survival

Estimated 2-yr DFS

51%

49%

38%

Copyright © American Society of Clinical Oncology

( R91-14: 2-yr survival 72% )

R97-03: Overall survival

2-yr rate57%69%67%

Randomized trials needed

• RTOG H0129 Stage III/IV OC, OP, HP & Lx

Accelerated fx/concomitant boost + cisplatin x 2

versus

Standard fractionation + cisplatin x 3• RTOG H0522 Stage III/IV OC, OP, HP & Lx

Accelerated fx/comcomitant boost + cisplatin 100 mg/m2 x 2 +/- cetuximab

E1303: Non-operative rx for resectable patients (E2399

replacement)Induction paclitaxel + carboplatin + C225 (PCC) concurrent PCC + RT 70 Gy

Response assessment after induction and 50 Gy, surgery if < pCR after 50 Gy

Endpoints: 90% disease-free at

completion of treatment

Phase II trial of C225 with RT and cisplatin in unresectable

patients• E3303: RT 70 Gy + C225 weekly + cisplatin

75 mg/m² days 1, 22 & 43 CR, PR, SD continue C225 for 6 mos

• Rationale: INT E1392 – improved 3-yr survival with RT/CDDP ( 37% vs 23%)

• Endpoints: PFS and survival, toxicity, molecular correlates

• Accrual: 68 pts to increase 2-yr PFS (35% to 50%)

Chemoradiotherapy

• Mixed site trials are useful for hypothesis generation and feasibility testing

• Efficacy for local-regional control may differ by primary site mandating site-specific trials– e.g. HPV related oropharynx cancer

• Alternative concurrent chemotherapy regimens to cisplatin 100 mg/m2 or PF should not be assumed to have equivalent efficacy