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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

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statements on head and neck cancer 2006 primary radiochemotherapy

Statements on Head and Neck Cancer 2006Primary 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
Concurrent Chemoradiotherapy as Standard of Care Based on Phase III Trials
  • Organ Preservation Randomized Trials
    • Larynx INT R91-11
    • OropharynxGORTEC
  • Nasopharynx Trials in US & Asia
  • Unresectable diseaseTrials in US & Europe
  • Post-operative adjuvantEORTC & US trials
standard of care options to preserve the larynx for locally advanced disease
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
VA Laryngeal Cancer Study Group

Induction CF - RT versus Surgery + RT

NEJM 1991;324:1685-1690

  • 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
int r91 11 trial to preserve the larynx forastiere aa nejm 349 2091 2003
INT R91-11 Trial to Preserve the LarynxForastiere AA. NEJM 349:2091, 2003

CR, PR

cisplatin/5-FU RT

surgery RT

  • 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

NR

eligibility criteria
Eligibility Criteria
  • Resectable SCC of the glottis or supraglottis requiring total laryngectomy
  • Stage III or IV

T1 excluded

T4 excluded if tumor penetrated through cartilage or invaded > 1cm into base of tongue

  • No distant metastases
surgery
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
int r91 11 results larynx preservation
INT R91-11 Results: Larynx Preservation

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

No difference in survival

(76% at 2-years)

local regional control

Induction

Concurrent

RT alone

Local-regional control

78%

61%

56%

Induction vs Concurrent p =0.0031

Induction vs RT alone p= 0.16

Concurrent vs RT alone p= 0.00002

slide11

Induction

Concurrent

RT alone

Disease-free survival

Laryngectomy-free survival

66%

61%

59%

52%

53%

44%

I + RT vs CRT p= 0.49

I + RT vs RT p= 0.08

CRT vs RT p= 0.01

I + RT vs CRT p= 0.64

I + RT vs RT p= 0.017

CRT vs RT p= 0.0053

response and compliance after two cycles of induction chemotherapy
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
slide13
ResultsForastiere AA. N Eng J Med 349:2091, 2003Weber 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)
slide14

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

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

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

No differences between treatment groups at 24 mos

5 year update asco 2006
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
5-year Update

Analysis not yet complete

  • Late effects
  • Site of first failure
  • Cause of death
implications for patient management
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 management1
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
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
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

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 Cyclesunknown 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
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%)

slide25

Overall Survival by Primary Site

1.0

p=0.06

0.8

80%

58%

0.6

Survival Probability

0.4

Oropharynx

0.2

Larynx

0.0

0

10

20

30

40

Survival Time in Months

conclusions
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
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%)
slide28

Overall survival, disease-free survival and relapse pattern

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

slide29

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

Late Toxicity

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

r97 03 randomized ph ii concurrent chemradiation
R97-03: Randomized Ph II Concurrent Chemradiation
  • RT – 70 Gy/35 fx
  • Chemotherapy
    • Arm 1: cisplatin 10 mg/m2 + 5-FU 400 mg/m2/dduring 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
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%
slide32

Time to locoregional failure

Estimated 2-yr LR failure rate

41%

27.5%

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

slide33

R97-03: Disease-free Survival

Estimated 2-yr DFS

51%

49%

38%

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

slide34

R97-03: Overall survival

2-yr rate

57%

69%

67%

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

randomized trials needed
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
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
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
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