CHEMORADIOTHERAPY IN HEAD AND NECK CANCER Dr David Boote Consultant in Clinical Oncology Portsmouth Oncology Centre May 2007

CHEMORADIOTHERAPY IN HEAD AND NECK CANCER

Dr David Boote

Consultant in Clinical Oncology

Portsmouth Oncology Centre

May 2007

MANAGEMENT OF THE PRIMARY TUMOUR

• Most T1 and T2 tumours controlled equally well by surgery or RT

• Choice of treatment influenced by:- tumour site, accessibility, histological grade, fitness and patient preference

• Surgery preferable when tumour involves bone

MANAGEMENT OF THE PRIMARY TUMOUR

• Most T3 and T4 tumours require combinations of radiotherapy, chemotherapy and surgery

• Chemoradiotherapy becoming more popular for inoperable tumours

RADIOTHERAPY

a) Primary treatment – typical dose 66Gy in 33 fractions over 6½ weeks

b) Post-operative (adjuvant) – indications include close or involved resection margins, poorly differentiated tumours, extensive lymph node involvement

c) Palliative e.g. bleeding, pain

RADIOTHERAPY CONSIDERATIONS

• Unhealthy teeth in the radiotherapy treatment volume need to be removed before starting radiotherapy

• Treat in a plastic mask (shell) to ensure accuracy and to avoid ink marks on skin

• A mouth-bite can be used when treating e.g. Ca tongue, floor of mouth, to dispace the upper jaw out of the field

CLINICAL CHALLENGES

• Excess alcohol/tobacco intake

• Poor nutrition, ? Need PEG

• Medically unfit e.g. COPD

• Poor social support

• May need dental extractions

• RT planning is complex and time-consuming

TREATMENT OPTIONS IN ADVANCED DISEASE

Surgery ± Radiotherapy ± Chemotherapy

CHEMOTHERAPY OPTIONS IN HEAD AND NECK

CANCER

Can use chemo in 4 main ways:-

1. Neoadjuvant (Induction) chemotherapy2. Concurrent (Concomitant) chemotherapy3. Adjuvant (Post-op) chemotherapy4. Palliative chemotherapy

1. INDUCTION CHEMOTHERAPY

• Given prior to radiotherapy or surgery• “gold standard” Cisplatin + 5-FU for 2-3 courses• Leads to a major response in 60 – 90% patients• Until recently, no significant effect on overall

survival• Can be used for organ sparing e.g. as alternative to

laryngectomy• ? Use dropped after Pignon meta analysis (Lancet

2000)

EFFECTS OF CHEMOTHERAPY ON SURVIVAL

AT 5 YEARS:FROM THE META-ANALYSIS

Trial No. of No. DifferenceCategory Trials Patients (%) P value

All trials 65 10850 +4<0.0001

Adjuvant 8 1854 +10.74

Induction 31 5269 +20.10

PF 15 2487 +50.01

Other Chemo 16 2782 00.91

Concomitant 26 3727 +8 <0.0001

ADVANTAGES INDUCTION CHEMOTHERAPY

survival

• organ preservationdistant mets

• Prompt symptom relief

• Use whilst waiting for RT

DISADVANTAGES INDUCTION CHEMOTHERAPY

• Toxicity e.g. neutropenia

• Toxic deaths

• Delays (C)RT

2. CONCURRENT CHEMOTHERAPY

• Most commonly single agent Cisplatin for 2–3 courses• Pignon meta-analysis showed an 8% absolute survival

benefit when chemo added to RT• Several randomised trials in unresectable disease show

significant improvement in local control and survival• Regarded by most clinicians as the best time to give

chemotherapy• Increased toxicity (especially mucositis) means only

suitable for fit patients

ADVANTAGES/DISADVANTAGES CONCURRENT CHEMOTHERAPY

Advantages survival

local control

Disadvantages • Toxicity

• RT mucositis

Induction CT + Locoregional RT

Remenar E, et al. ASCO 2006, abstract 5516. Bernier J, et al. ASCO 2006, abstract 5522.

Vermorken JB, et al. ASCO 2004, abstract 5508.

EORTC 24971/TAX 323 - Study Design

Neck Dissectio

nInoperable

SCCHNStage 3-4.

Stratification:

1º tumor site

Institution

TPF arm (n=177) Docetaxel (75

mg/m²) Cisplatin (75

mg/m²) 5-FU (750

mg/m²/dx5)Q 3 weeks x 4 cycles

PF arm (n=181) Cisplatin (100

mg/m²) 5-FU (1000

mg/m²/dx5)Q 3 weeks x 4 cycles

Radiotherapy(~70 Gy over

7 weeks)Follow up

Surgery for

Residual Disease

Treatment arms were well balanced in baseline

characteristics

Primary Objective: PFS

Overall Survival

EORTC 24971/TAX 323

(months)0

0

10

20

30

40

50

60

70

80

90

100

6 12 18 24 30 36 42 48 54 60 66 72

Treatment

PFTPF

Remenar E, et al. ASCO 2006, abstract 5516. Bernier J, et al. ASCO 2006, abstract 5522.

Vermorken JB, et al. ASCO 2004, abstract 5508.

PF TPF

Median OS, mo 14.2 18.6

Hazard ratio (95% CI)

0.71 (0.56, 0.90)

P-value 0.0055

Toxicity

EORTC 24971/TAX 323

NCIC-CTC Grade 3-4Toxicity

PF (n=179)patient

percentage

TPF (n=173) patient

percentage

Anemia/thrombocytopenia

13/18 9/3

Neutropenia 53 77

Nausea/vomiting 7/4 <1/<1

Diarrhea 3 3

Stomatitis 11 5

Infection 6 7

Febrile neutropenia 3 5Primary prophylactic antibiotics were givenper protocol for TPF

QOL Analysis: PSS-HN

Bernier et al. ASCO 2006; Abstract 5522.

EORTC 24971/TAX 323

PSS-HN data showed that eating disturbances and disturbances of speech were higher in patients treated with PF vs those

treated with TPF

ParameterTreatment

s

Results End of

Treatment(difference in least

square mean)

Results End of Follow-up

(difference in leastsquare mean)

P-value

Normal dietTPF vs

PF + 5.5 + 16.8 0.0064

SpeechTPF vs

PF + 3.7 + 3.9 <0.0001

Public eating

TPF vs PF + 6.6 + 17.3 0.0002

Performance Status Scale – Head & Neck

Conclusions

EORTC 24971/TAX 323

Treatment with TPF was superior to PF Median PFS (primary endpoint; p=.007) Median overall survival (p=.013)TPF has a manageable toxicity profile

Health-related QOL and clinical benefit outcomes generally favored TPF

Induction CT CRT Surgery

Posner RM, et al. ASCO 2006, abstract SPS24.

TAX 324 - Study Design

Treatment arms were well balanced in baseline demographic

and disease characteristics

Primary Objective: OS

Radiotherapy(70Gy d1-5)+ Weekly

Carboplatin(AUC 1.5 7)

Surgery is

needed

PF arm (n=246) Cisplatin (100

mg/m²/d1) 5-FU (1000 mg/m²/d

5) Q 3 weeks x 3 cycles

TPF arm (n=255) Docetaxel (75

mg/m²) Cisplatin (100

mg/m²d1) 5-FU (1000

mg/m²/d 4)Q 3 weeks x 3 cycles

N=538Stage III/IVEpidermoidcarcinoma,

no prior surgery,

no hospitalizationfor COPD 1y

Stratification:• Center• N status• Primary site

Posner RM, et al. ASCO 2006, abstract SPS24.

TAX 324 - Study Design

Primary Endpoint: Overall Survival

0 6 12 18 24 30 36 42 48 54 60 66 720

3-Year OSTPF 62%PF 48%

2-Year OSTPF 67%PF 54%

Survival Time (months)

Log-Rank p = .0058Hazard ratio = 0.70

TPF (n=255)

PF (n=246)

TPF significantly improvedoverall survival vs PF30% reduction in mortality

Su

rviv

al P

rob

ab

ilit

y (

%)

10

20

30

40

50

60

70

80

90

100

Posner et al. ASCO 2006.

TAX 324

Specific Safety During Chemotherapy

TPF(N=251)

PF(N=243)

Deaths due to toxicity 1% 2%

Neutropenia Grade 3/4 84% 56%

Febrile NeutropeniaNeutropenic Infection

12% 12%

7% 9%

Primary prophylactic antibiotics were given per protocol for TPF

Conclusions

TPF significantly improves survival in 2 phase IIItrials TAX 323: 29% reduction in mortality (p=0.0055) TAX 324: 30% reduction in mortality (p=0.0058)

Sequential therapy with TPF is tolerable and safe

Hitt R, et al. ASCO 2006, abstract 5515.

Phase III Trial PF ± Docetaxel CRT vs CRT

Study Design

Primary endpoint phase III: TTF

SCHNNStage III, IV

(locally advanced)Unresectable

PF 3 cycles q 21

days Cisplatin Infusional 5-

FU

(N=340)

TPF 3 cycles q 21

days Docetaxel Cisplatin Infusional 5-

FU CRT

CRT



Patient Characteristics

TPF PF CRT

Age, years Median (range) 57 (35-78) 58 (36-85) 55 (25-79)

Gender, % Men 93 92 89

PS (ECOG), % 0 8 13 8

1 92 87 92

Anatomic site, % Oropharynx 41 43 43

Hyppharynx 19 18 19

Larynx 19 17 18

Oral cavity 21 22 20

Tumor grading, % T4 N0 19 10 17

T4 N1 18 16 21

T4 N2 43 41 32

T4 N3 0 8 6

No significant differences between treatments arms in baseline patient characteristics



Efficacy ResultsTime to Treatment Failure (TTF) favored

the docetaxel-containing (TPF) arm

1.000

0.875

0.750

0.625

0.500

0.375

0.250

0.125

0.000

0.0 3.5 7.0 10.5 14.0 17.5 21.0 24.5 28.0 31.5 35.0

Time to treatment failure

Times (months)

TPF PF CRT

Median: TPF 16 months, PF 12 months, CRT 8 months.Log rank 0.031



Toxicity During Chemotherapy

Patient Percentage

Grade 3/4 Toxicity TPF PF CRT

Leucocytes 9 11 11

Granulocytes 28 18 18

Platelets 7 6 6

Febrile neutropenia 6 1 2

Asthenia 11 9 5

Mucositis 53 58 35

Renal 2 4 6

Dermatitis 7 22 13

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

GORTEC 2000-01 - Study Design

Induction CT Larynx Preservation

Primary Objective: larynx preservation rate

Larynx orhypopharynx

tumors

Resectabletumors or

nodes requiringtotal

(pharyngo[P]laryngectomy)

No previoustreatment

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)laryngecto

my+ post-op RT

Responders:RT alone

Responseto

induction

treatmentYe

s

No

Pointreau Y, et al. Cancer/Radiotherapie. 2006:10:493, Abstract C03;Calais G, et al. ASCO 2006, Abstract 5506.

GORTEC 2000-01

Patient and Disease Characteristics

TPF (n=110) PF (n=103)

Age, years Median (range)

56.6 (38-75)

56.8 (32-75)

Gender, % Men/women 101/9 97/6

PS (ECOG), % 0 51 51

1 59 52

Anatomic site, %

Hypopharynx 61 54

Larynx 49 49

Tumor grading, % T2 15 24

T3 80 63T4 15 16

p=(0.14)


GORTEC 2000-01

Larynx Preservation

0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

0.90

1.00

0 6 12 18 24 30 36

TPF

PF

Time from randomization(months)

Lary

nx p

reserv

ati

on

, %

Median follow-up: 30 months

Larynx preservation rate higherin TPF group p=0.036


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 betweenthe 2 arms in: xerostomia, fibrosis, larynx edema, dysphagia, % of patients with permanent feeding tube.

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

GORTEC 2000-01

Relative to Other Studies of PFInduction Followed by RT

Study 5-Year LPR (N function)

Veteran (larynx) 39%

EORTC (hypopharynx) 35%

RTOG 91-11 (larynx) 43%*

GORTEC 2000-01 41.4% (3-year)

*Endpoint was 5-year laryngectomy-free survival(45% in the concomitant group).

Results with PF arm from GORTEC 2000-01 are consistent with those observed in other studies

Adding Targeted Therapies in SCCHN- The Next Step

Potential role in induction, adjuvant treatment, and radiation sensitization

These agents can be added to induction/sequential

therapy and to chemoradiotherapy to improve

outcomesAgents with early experiences for recurrent/advanced disease:

EGFR-inhibitors Combined EGFR/HER2 inhibitors Angiogenesis Other targets

EGFR is an important target for cancer therapy

• EGFR over-expression is associated with a poor prognosis3-7

• Erbitux® specifically targets EGFR, which is over-expressed in SCCHN8,9

References:

1. Baselga J et al. Eur J Cancer 2001;Suppl 4:S16-S22.2. Wells A. Int J Biochem Cell Biol 1999;31(6):637-643.3. Ang KK et al. Cancer Res 2002;62(24):7350-7356.4. Rubin Grandis J et al. J Nat Cancer Inst 1998;90:824-832.5. Maurizi M et al. Br J Cancer 1996;74:1253-1257.

6. Magne N et al. Eur J Cancer 2001;37(17):2169-2177.7. Hitt R et al. Eur J Cancer 2005;41(3):453-460.8. Baselga J et al. J Clin Oncol 2005;23(24):5568-5577.9. Bonner JA et al. N Engl J Med 2006;354:567-578.

Erbitux® specifically targets EGFR1

• Erbitux® is an innovative chimeric monoclonal antibody1

• By binding to EGFR, Erbitux® inhibits the signalling cascade leading to

multiple effects2,3

• Erbitux® inhibits post-radiation DNA damage repair4

References:

1. Baselga J et al. Eur J Cancer 2001;Suppl 4:S16-S22.2. Ciardiello F and Tortora G. Clin Cancer Res 2001;7(10):2958-2970.3. Arteaga CL. J Clin Oncol 2001;19(18 Suppl):32S-40S.4. Huang SM et al. Clin Cancer Res 2000;6(6):2166-2174.

A new approach: Erbitux® + radiotherapy in locally advanced SCCHN

Reference:

1. Bonner JA et al. N Engl J Med 2006;354:567-578.

Characteristics RT (n=213)

Erbitux® + RT (n=211)

Karnofksy performance status: 60–80 90–100

71141

63147

Site of primary tumour: Oropharynx Larynx Hypopharynx

1355127

1185736

Nodal involvement: NONodal involvement: N+

38175

42169

Tumor stage: T1–3Tumor stage: T4

14865

14862

Fractionation:RT was administered as: once-daily (26%), twice daily (18%) or concomitant boost (56%)

Erbitux® + radiotherapy significantly prolongs locoregional control in SCCHN1

The addition of Erbitux® to RT vs RT alone:

• significantly prolongs the duration

of locoregional control by almost

10 months (24.4 months vs 14.9 months, p=0.005)1

• resulted in a 32% reduction in the risk of locoregional progression (Hazard ratio = 0.68,

95% CI = 0.52-0.89)1

Reference:


Erbitux® + radiotherapy significantly prolongs

survival in SCCHN1

The addition of Erbitux® to RT vs RT alone:

• significantly prolongs median overall survival by almost 20 months

(49.0 vs 29.3 months, p=0.03)1

• resulted in a 26% reduction in the risk of death (Hazard ratio = 0.74,

95% CI = 0.57-0.97)1

Reference:


Frequently observed* adverse events (grades 3–5)1

RT (%)Erbitux® + RT (%)

p value‡

Adverse event n=212 n=208

Mucositis 52 56 0.44

Acneform rash 1 17 <0.001

Radiation dermatitis 18 23 0.27

Weight loss 7 11 0.12

Dry mouth 3 5 0.32

Dysphagia 30 26 0.45

Asthenia 5 4 0.64

Nausea 2 2 1.00

Constipation 5 5 1.00

Erbitux® does not significantly increase radiotherapy-related side effects

• Erbitux® does not significantly exacerbate typical radiotherapy-associated toxicities such as

mucositis, xerostomia and dysphagia in locally

advanced SCCHN1

• The most frequently observed

adverse events related to Erbitux® are skin reactions1

Reference:


* Frequently observed = All grades in ≥30% of subjects‡ p values were determined with the use of a Fisher’s exact test

Erbitux® in practice

• No EGFR testing is required

• An average patient treatment cost for

Erbitux® is approximately £5,700

• Erbitux® + RT is associated with

an incremental cost per QALY of approximately £6,870 compared

to RT alone over the expected patient lifetime1

• Erbitux® + RT is estimated to cost: – £6,558 per extra life year1

– £5,688 per progression-free life year1

Reference:

1. Data on file, UKECRC05020.

INDUCTION CHEMOTHERAPY IN PORTSMOUTH

• Until 2000 – Cisplatin + 5-FU (“waiting list chemo”)• Nov 1999, JCO, Colevas et al, phase 2 study, TPF (+

leucovorin) induction chemo in H+N Ca 93% RR (63%CR) but 1 toxic death (neutropenic sepsis) and generally toxic. Also needed g-csf and prophylactic antibiotics

• Decided to use TPF but lower doses, omitting leucovorin, no g-csf or prophylactic antibiotics

DRUG DOSES (mg/m2)

T

P

F

323

75

75

3750

324

75

100

4000

Boote

40

80

2800

PORTSMOUTH RESULTS

• Approximately 80 patients treated so far

• Have audited results on first 43 patients

• Average age 58 (range 44-81)

• Male 79%, Female (21%)

• Primary:- Tonsil 28%, Base tongue 23%, unknown 13%, Hypopharynx 10%, Larynx 8%, other 18%

PORTSMOUTH RESULTS (cont’d)

• Stage:- nodes unknown primary 13%, stage II 5%, stage III 38%, stage IV 44%

• Majority (70%) received 2 cycles (range 1-3)• 39/43 underwent radical RT• 2 underwent surgery followed by RT• 1 underwent surgery alone• Overall response rate 85% (70% CR, 15%PR)• Average follow-up (first 43 pts) 18 months

PORTSMOUTH RESULTS (cont’d)

• Of the CR’s 4 patients recurred at an average of 10 months (range 6-15 months)

• 3 of the PR’s have progressed at an average of 6 months after treatment. One of these PR’s underwent surgery and remains disease free,

• All patients who progressed on treatment have died

CHEMOTHERAPY TOXICITY

• No toxic deaths

• No grade 4 toxicity

• One grade 3 toxicity (neutropenia)

• One grade 2 toxicity (vomiting)

• Most patients grade 1 toxicity only

• Most toxicity seen in PS2 patients

CHEMOTHERAPY TOXICITY (cont’d)

• 2 patients had impaired renal function after their first cycle and were changed to Carboplatin

• 1 myocardial infarction ? Treatment related

• 6 extravasations – no long term complications

• 1 episode of hypotension ? Cause

• No increase in radiotherapy toxicity

ACTUAL CASE

• Mr D.K. age 56• Presented with lump in neck December 2000• Investigations showed carcinoma of base of

tongue with bilateral neck nodes (stage T2, N2)• Given 3 courses TPF, well-tolerated (bursitis)• Complete response after chemo• Then had RT (66Gy/33/6½ weeks)• Last seen in clinic July 2006 – alive and well –

discharged

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CHEMORADIOTHERAPY IN HEAD AND NECK CANCER Dr David Boote Consultant in Clinical Oncology Portsmouth Oncology Centre May 2007