Chemotherapy in Early

Nasopharyngeal Cancer

ZAKIFMAN
Principles of Chemotherapy
Thirty years ago there was no effective
therapy available for advanced malignant
tumors. The prognosis for widespread tumors
which could not be resected or irradiated was
invariably fatal within a short periode of time
after diagnosis. Today, the outlook has change
considerably, although much remains to be
done in order to effectively control many
tumors with medical treatment.
Principles of Chemotherapy
Some neoplasms are completely
curable with chemotherapy ( alone or
within combined modality treatment). In
many other cases it is possible to
obtain consistent palliation with
objective remission of measurable
lession and prolongation of survival in
responsive patients.
Single agent chemotherapy

1. When combination chemotherapy is no

longer effective.
2. When the patients is over 70 years old.
3. In the presence of a low performance
status.
4. When other systemic non malignant
disease (e.g,cardiovascular,renal,etc) are
concomitanly present.
5. When combined with other modality.
 Combination chemotherapy

1. Increasing the therapeutic synergism by exploiting

the different mechanism of action with consequent
improvement of therapeutic activity.
2. Preventing or delaying the emergence of resistance
cell clones through the mechanism of action of the
drug used.
3. Increasing patients tolerance to the side effects of
the drug used.
4. Making use of the differing pharmacologic characte-
ristics of the various compounds to achieved rapid,
complete regression.
 Treatment Modalities.
1. Radiation therapy.
2. Chemotherapy.
3. Targeted therapy.
4. Surgery.
5. Combined modalities.
 Combination chemotherapy.
1. Cisplatin 100 mg/m2 d1
5 Fluoro uracil 1000 mg/m2 d1-5.
every 3 weeks.
2. Cisplatin 60 mg/m2 d1
Epirubicin 110 mg/m2 d1
every 3 weeks.
3. Paclitaxel 175 mg/m2 d1
Carboplatin AUC VI
every 3 weeks.
4. Docetaxel 75 mg/m2 d1
Cisplatin 75 mg/m2 d1
every 3 weeks.
 Combination chemotherapy
5. Gemcitabine 1250 mg/m2 d1 & 8
Cisplatin 60 mg/m2 d1
every 3 weeks
6. Oxaliplatin 135 mg/m2 d1
Cisplatin 60 mg/m2 d1
every 3 weeks
7. Paclitaxel 175 mg/m2 d1
Cisplatin 75 mg/m2 d1
5 Fluoro uracil 1000 mg/m2 d1-5
every 3 weeks
 Chemo-irradiation
1. Cisplatin 40 mg/m2 weekly (every Monday)
+ irradiations 5 days a week ( 60-70 Gy).
2. Paclitaxel 60-90 mg/m2 weekly (Monday)
+ irradiations.
3. Docetaxel 25 mg/m2 weekly (Monday)
+ irradiations.
4. Gemcitabine 200 mg/m2 weekly (Monday)
+ irradiations.
 Targeted Therapy + Irradiation
1. Cetuximab loading dose 400 mg/m2 follow by
250 mg/m2 weekly ( every Monday )
+ Irradiations 5 days a week ( 60-70Gy ).
2. Nimotuzumab 200mg (actual dose) weekly
+ Irradiations.
 Chemo+Targeted Therapy
1. Cetuximab loading dose 400 mg/m2 follow by
250 mg/m2 weekly ( every Monday ).
OR
2. Nimotuzumab 200 mg (`actual dose ) weekly
( every Monday ).
COMBINED WITH CHEMOTHERAPY :
Cisplatin 100 mg/m2 d1
5 Fluoro Uracil 1000 mg/m2 d1-5
every weeks.
 EGFR
– The EGFR is a member of the ErbB family of tyrosine kinase
(TK) receptors found on the cell surface of normal and
malignant tumor cells
– EGFR is a central regulator of several key pathways in the
function of normal and malignant cells
– EGFR activation is associated with enhanced cellular
proliferation, protection from apoptosis, and the production of
proinflammatory and proangiogenic cytokines
– EGFR activation seems to protect malignant cells from
chemotherapy- and radiotherapy-induced cell death
– Blocking EGFR activation enhances tumor specific destruction
by standard chemotherapy agents and radiotherapy
 EGFR expression in
selected human tumors
Tumor type % of tumors expressing EGFR (range)
Head and neck 90 - 100%
Colon 75 - 89%
Prostate up to 100%
Pancreatic up to 95%
Breast up to 91%
Renal up to 90%
Cervix up to 82%
Non-small cell lung cancer up to 80%
Ovarian up to 77%
Bladder up to 72%
Primary glioblastoma up to 63%
EGFR in Cancer
 EGFR Structure and Normal Biological
Function

• EGFR structure
• EGFR ligands
• Intracellular signaling pathways and receptor
cross-talk
• Events that follow EGFR/ligand binding
EGFr Is a Transmembrane Protein
Extracellular
Domain
Transmembrane
Domain

Intracellular
Domain
 The EGFR (erbB) family
EGF
TGF-
Ligands Amphiregulin No specific NRG2
-cellulin ligands - NRG3
HB-EGF often acts as Heregulins
Epiregulin dimer partner Heregulins -cellulin

Cysteine-rich Extracellular
Receptor domain
Membrane

Intracellular
Tyrosine kinase K K K
K
domain

erbB1 erbB2 erbB3 erbB4

HER1 HER2 HER3 HER4
EGFR neu

Wells 1999
 EGFR Activation Mediates
Multiple Processes

Shc
Grb2
PI3-K Sos-1

Ras
AKT
Raf
MEKK-1

MEK
mTOR MKK-7

ERK
EGFr Activation Mediates Multiple Processes

Shc
Grb2
PI3-K Sos-1

Ras
AKT
Raf
MEKK-1

MEK
mTOR MKK-7

ERK
JNK

Apoptosis Proliferation Angiogenesis Metastasis

Resistance
Ligands Induce Dimerization of EGFR
 Ligands Induce Dimerization of EGFR
I
II

IV

III

Ferguson KM. Biochem Soc Trans. 2004;32:742-745.

Dawson JP, et al. Mol Cell Biol. 2005;25:7734-7742.
 Ligands Induce Dimerization of EGFR
I
II

IV
III

Ferguson KM. Biochem Soc Trans. 2004;32:742-745.

Dawson JP, et al. Mol Cell Biol. 2005;25:7734-7742.
 Ligands Induce Dimerization of EGFR
I
II

III IV

Ferguson KM. Biochem Soc Trans. 2004;32:742-745.

Dawson JP, et al. Mol Cell Biol. 2005;25:7734-7742.
 Ligands Induce Dimerization of EGFR
I
II

III IV

Ferguson KM. Biochem Soc Trans. 2004;32:742-745.

Dawson JP, et al. Mol Cell Biol. 2005;25:7734-7742.
 Ligands Induce Dimerization of EGFR
I
II

III

IV

Ferguson KM. Biochem Soc Trans. 2004;32:742-745.

Dawson JP, et al. Mol Cell Biol. 2005;25:7734-7742.
 Ligands Induce Dimerization of EGFR
I
II

III

IV

Ferguson KM. Biochem Soc Trans. 2004;32:742-745.

Dawson JP, et al. Mol Cell Biol. 2005;25:7734-7742.
 Ligands Induce Dimerization of EGFR
I
II

III

(D279 H280)
IV

Ferguson KM. Biochem Soc Trans. 2004;32:742-745.

Dawson JP, et al. Mol Cell Biol. 2005;25:7734-7742.
 Ligands Induce Dimerization of EGFR

Shc
Grb2
PI3-K Sos-1

Ras
AKT
Ferguson KM. Biochem Soc Trans. 2004;32:742-745.
Dawson JP, et al. Mol Cell Biol. 2005;25:7734-7742. Raf
MEKK-1
How Current Therapeutics Exploit EGFR
as a Target
• Small molecules
– Erlotinib, gefitinib
– EGFR tyrosine kinase mutations identify responsive subsets in NSCLC
• Monoclonal antibodies
– Cetuximab
– Nimotuzumab
– Panitumumab
– Matuzumab
 EGFR TK Inhibitors
Extracellular

Intracellular
Shc
Grb2
PI3-K Sos-1

Ras
AKT
Raf
MEKK-1

MEK
Anti-EGFR Monoclonal Antibodies
Extracellular

Intracellular
Shc
Grb2
PI3-K Sos-1

Ras
AKT
Raf
MEKK-1
Nimotuzumab
 Ior egf/ r3(murine Mab)
• Generated in 1989 in Havana Cuba, using a purified fraction
of human placenta, enriched in EGF-R
• Murine IgG2a
• Recognizes an epitope located in the extra cellular domain of
human EGF-R, with high affinity, inhibiting tyrosine kinase
activation
• Has a KD = 10-9 M

Potent antitumor effect in vitro and in vivo on EGF-R over expressing cell lines.
58 advanced cancer patients were treated with mAb at doses from 160 to 3200 mg, acumulative dose, in 4
clinical trials
Anaphylactic reactions in 4 patients probably related with the development of HAMA response
 Murine ior egf/r3 in diagnostic clinical trials
Positive MAb accumulation in tumors

Colon adenocarcinoma
Lung Adenocarcinoma Anterior and posterior view

Immunoscintigraphy in 148 patients with 99mTc labeled

mAb, showed an overall sensitivity of 84 %,for in vivo
detection of epithelial tumors.

Glioblastoma Multiforme
Right and left lateral view
 Hybridoma Technology: Evolution
Mouse Chimeric Humanized Fully Human

100% mouse protein 34% mouse protein 10% mouse protein 100% human protein
Murine Human
Mab
Mab 100 % Human
ior egf/r3
100 % murine

h-R3
Humanized
Chimeric Mab
10 % murine
Mab
90 % human
30 % murine
70 % human

VERY LOW IMMUNOGENICITY

Nimotuzumab
Chinese Study

Nasopharyngeal tumors
 Clinical Protocol

Phase II Trial of Recombinant Humanized Antihuman Epidermal Growth Factor Receptor

Monoclonal Antibody (h-R3) in combination with radiotherapy in nasopharynx tumor treatment

Design:
Phase II, a multicenter, open randomized clinical study
Objective:
To study safety and efficacy when given in association with standard radiotherapy in
patients with locally advanced nasopharynx tumors
Number and Type of Pts:
137 pts, with histologically documented advanced nasopharynx tumors who are suitable
candidates for radiotherapy
Dose and treatment schedule:
100 mg, every week for 8 weeks starting with the first radiotherapy
dose (70 Gy)
 Nimotuzumab Chinese Study:
Phase II Clinical Trial Report
PARTICIPATING AND COORDINATING INSTITUTIONS
 Coordinating Institution: Tumor Hospital, China Academy of Medical Science, Dr. Xu
Guozhen, Gao Li
 Original Data Stored at: National Clinical Trial Base of Study Drugs, China Academy of
Medical Science
 Participating Institutions:
 Tumor Hospital, China Academy of Medical Science
 Center of Tumor Prevention and Cure, Zhongshan University
 Guangzhou General Hospital, Guangzhou Military Region
 The 4th Affiliated Hospital, Hebei University of Medical Science
 Fujian Province Tumor Hospital
 Hunan Province Tumor Hospital
 Sichuan Province Tumor Hospital

 Duration of the trial: August 2002- October 2004

 INCLUSION CRITERIA
 All patients should have signed a written informed consent containing a detailed
description of the trial.
 Age 18~70 years, sex not limited.
 Locally advanced nasopharyngeal squamous cell cancer (poorly differentiated
squamous cell carcinoma) as confirmed by imaging or histological diagnosis, and
candidates of radical radiotherapy.
 EGFR expression is medium to high as determined by immunohistochemical test.
 Karnofsky performance status scores > 70.
 Anticipated survival is not less than 6 months.
 Female patients of child-bearing age should avoid pregnancy during the treatment.
 Patients should also meet laboratory testing criteria as follows: hamoglobin ≥120 g/L;
WBC≥4109 /L，platelet count≥100109 /L; indicators of hepatic and renal functions
are lower than 1.25 times of the upper limits of normal; blood glucose is within the
normal range.
 EXCLUSION CRITERIA
 Prior with other malignant tumors (not included non-melanin skin cancer and primary tumor
at cervix).
 Prior immunotherapy.
 Prior chemotherapy during the last three months.
 Prior RT at the area to be treated.
 Prior operation because of head and neck cancer (not included of biopsy sampling operation).
 Historical record indicated distant metastasis or concurrent active cancer.
 Weak or negative expression of EGFR as determined by immunohistochemical test.
 Participating on-side trials of any other drugs.
 Female during pregnancy or lactation, or those at children-bearing age who refused
contraception.
 Historical documented severe allergy or allergic habitus.
 Radiotherapy
 All patients received radiation of 6 MV X-ray from a linear accelerator;
 The planning of irradiation fields was as follows :
 Face-neck fields : DT 36Gy/19F/24D, Reduced field
 ear-front fields:34Gy/17F/23D
 Doses of Radiotherapy:7 0-76Gy/7-8W
 Ordinary fractionation was applied, as factions of 2Gy once per day
and 5 days per week.
 Metastatic neck nodes were treated with up to the maximum doses
 Patient Demographics

Total 137

PP Population 126

ITT Population 130

Total Evaluable Cases 137

h-R3 + Radiotherapy 70
Radiotherapy 67

Gender ( M / F ) 97／40

Age ( Median ） 21~70（46）

Karnofsky Score （ Median ） 80~90（90）

Clinical Stage (AJCC)

Ⅲ 78

Ⅳ 59
WHO histopathology type
WHO (Type 2) 70
WHO (Type 3) 67
UCNT
IMC ( EGFR Expression )

Moderate 80

Strong 57
 Patient distribution

• The patients were included in the present phase II trial of

Nimotuzumab and were randomized to two groups:

Test group:Nimotuzumab
70
+ RT
patients

137 patients

Control group: 67
monotherapy of RT patients
 Comparison of complete responses rate (CR%)
in combination therapy vs monotherapy (radiation alone)
ITT PP
Monotherapy Comb. x2 P Monotherapy Comb. x2 P
(n=66) Therapy (n=65) Therapy(
(n=64) n=61)

5 weeks post treatment

Primary Tumor 51.52 90.63 18.66 <0.01 52.31 93.44 19.92 <0.01
Neck Lymph 72.73 89.06 4.33 0.03 72.31 91.80 5.12 0.02
node
General 42.42 87.50 22.67 <0.01 43.08 90.16 23.49 <0.01
Evaluation
17 weeks post treatment
Primary Tumor 63.64 92.19 10.86 0.01 64.62 95.08 12.51 <0.01

Neck Lymph 80.30 93.75 4.30 0.03 80.00 96.72 6.11 0.01
node
General 51.52 90.63 19.37 <0.01 52.31 93.44 20.3 <0.01
Evaluation
 Summary of Safety on h-R3
 Adverse reactions related to hR3
 Fever : 4.28%(2 degree rising: 1 case; 1 degree: 2 cases; highest 39ºC )
 Skin rash : 1.43% ; Grade I , no infection on the treatment;
 Hypotension/dizziness : 2.86%（2 cases, lowest 80/50mmHg); Released
after rests, no infection on the treatment.
 Comparison of distant metastasis (ITT)

8 Radi at i on
al one
7
6
5
4
Radi at i on +
3 Ni mot uzumab
2
1
0 Met ast ase I nci dence ( %)

Cases of distant metastasis Incidence

Cases of
Group distant No. of Pt. Incidence P*
metastasis
Radiation alone 5 64 7.81%
Radiation + 0.21
1 66 1.52%
Nimotuzumab
* Fisher’s test evaluation at 17th weeks
 Use the humanized Anti-Epidermal Growth Factor
Receptor Monoclonal Antibody h-R3 in Combination
With Radiotherapy in the Treatmant of Locally
Advanced Head and Neck Cancer Patients.

Tania Crombet, Marta Osorio, Teresa Cruz et al.

Use the humanized Anti-Epidermal Growth Factor Receptor Monoclonal
Antibody h-R3 in Combination With Radiotherapy in the Treatmant of
Locally Advanced Head and Neck Cancer Patients.
Tania Crombet, Marta Osario, Teresa Cruz et al.

Patients characteristic.
24 patients with advanced SCCHN were included.
Patients received concurrent RT at doses from 60 to
66 Gy, depending on the response and toxicity ( total
cumulative dose 60 Gy was only administered to
three subjects ).
Use the humanized Anti-Epidermal Growth Factor Receptor Monoclonal
Antibody h-R3 in Combination With Radiotherapy in the Treatmant of
Locally Advanced Head and Neck Cancer Patients.
Tania Crombet, Marta Osario, Teresa Cruz et al.

Patients and methods.

This was a single-center phase I/II clinical trial. At this was the first
h-R3 combination trial-in which safety was the primary end point-
the starting dose was suboptimal according to pharmacokinetics.
Each patient received six once-weekly infusions of h-R3 at the
following levels: 50, 100, 200, and 400 mg in combination with RT.
Total cumulative doses were 300, 600, 1.200, and 2400 mg,
administered by intravenous infusions, diluted in 250 mL of sodium
chloride, over 30 minutes, (before RT).
After finishing, patients with residual macroscopic disease at the
primary site had complete excision of the remaining tumor.
Use the humanized Anti-Epidermal Growth Factor Receptor Monoclonal
Antibody h-R3 in Combination With Radiotherapy in the Treatmant of
Locally Advanced Head and Neck Cancer Patients.
Tania Crombet, Marta Osario, Teresa Cruz et al.

Clinical Response.
In the first trial section, 12 patients were treated at doses from
50 to 400 mg. After the doses of 50 to 100 mg, 2 of 6 patients
achieved complete response, while after doses of 200 and 400
mg, 4 of 6 patients had complete response. Another patients
treated with 200 mg, who originally achieved a partial response,
was rendered disease free after the excision of the residual tumor,
6 weeks after the irradiation.
The median survival for 50 and 100 mg was 8,60 months, while
the patients receiving 200 & 400 mg was 44,30 months.
The 3 years survival rate was 16,7% for subjects with two
lowest doses and 66,7 % for the highest doses.
Use the humanized Anti-Epidermal Growth Factor Receptor Monoclonal Antibody h-
R3 in Combination With Radiotherapy in the Treatmant of Locally Advanced Head
and Neck Cancer Patients.
Tania Crombet, Marta Osario, Teresa Cruz et al.

After the protocol was amended , 10 new patients were

treated with 200 & 400 mg. 9 achieved objective response
and 5 had complete responses.
Since the additional 10 subjects were included, finally:
14 (87,5%) of 16 patients achieved objective response and 9
had complete response at 200 or 400 mg dosage levels.
At the present, the overall mean survival is 22 months.
 A Phase IIb, 4 Arm, Open-label, Randomized Trial,
To assess the Safety and Efficacy of Concurrent
h-R3 (nimotuzumab) monoclonal Antibody against EGFR in
combination with Chemo Radiation therapy or with Radiotherapy
alone in patients with advanced inoperable (stage III or IVA) Head
and Neck Cancer

Lokesh Viswanth1. & B Krishnamurthy Reddy1, M.S. Vidyasagar2, Kamalaksha Shenoy3, Ashok shenoy1,
K. Govind Babu1, T.Naveen1, B. Joseph1, R. Bonanthaya1, C.R.Tanvir Pasha1, A.S. Aravind4, A. Eswaraiah4,
N.Gupta4, P.P.Bapsy1.

Kidwai Memorial Institute of Oncology1, Bangalore, Shirdi Sai Baba Cancer Hospital,Manipal2, KMC Hospital,
Mangalore3, Biocon/Clinigene Bangalore4
 Study Design
Proof of Principle: Phase II Trial - BEST Study

Nimo 200mg + RT (60 – 66Gy)

Group A
RT (60 – 66Gy)
First Line,
Unresectable, Stage
III/IVa SCCHN Nimo 200mg + RT (60 – 66Gy)
+ CDDP 50mg/w
Group B
RT (60 – 66Gy)
+ CDDP 50mg/w

 Patients were allocated at the discretion of the physician to RT alone or

Chemoradiotherapy and then randomized to +/- nimotuzumab
48 months follow up (as of August 2009)
 TNM Staging (N=92)

Stage No . Of Patients

Stage III 12

Stage IVA 80

Total 92
 Primary Tumor Sites (N=92)

Primary Tumor Site (N=92)

Oropharynx
Primary Tumor Site

Oral Cavity

Hypopharynx Number of patients

Larynx

Maxillary Sinus

0 10 20 30 40 50 60
Number of patients
 EGFR Expression
EGFR Expression (N=92)

Not performed
EGFR Expression

Negative

1+ No of patients

2+

3+

0 5 10 15 20 25 30 35

Number of patients

1+ : < 70% of Tumor Cells positive 2+: 70-90% of Tumor Cells positive 3+: 90% of Tumor Cells positive
Negative: <25% of Tumor Cells positive
 BEST Trial - Phase II
IND 001

Overall Response Rate (CR+PR)

100%

76%
70%

37%

RT RT+nimotuzumab CRT CRT + nimotuzumab

 BEST Trial - Phase II
IND 001
Overall Survival – Evaluable Population – 30 months
1.00

0.75

0.50

0.25

0.00

0 5 10 15 20 25 30
Months

CRT+ nimotuzumab RT+ nimotuzumab

CRT RT
 BEST Trial - Phase II
IND 001
Combined Group Analysis: Overall Survival – Nimotuzumab vs No Nimotuzumab
Unplanned post-hoc analysis

1.00

0.75

0.50

HR= 0.34, p=0.0018

0.25

0.00

0 5 10 15 20 25 30
months
nimotuzumab (n=37)
No nimotuzumab (n=38)
Overall Survival at 48 Months F-Up
Evaluable Population
Overall Survival at 48 Months F-Up
ITT Population
Combined Group Analysis: Overall Survival –Evaluable Population
at 48 months F-up Nimotuzumab Vs No Nimotuzumab

HR= 0.36, p= 0.0019

Combined Group Analysis: Overall Survival – ITT Population
at 48 months F-up Nimotuzumab Vs No Nimotuzumab

HR= 0.52, p= 0.018

 Nimotuzumab AEs

RT+hR3 N RT+CT+hR3 N
Chills 1 loose stools 2
Pyrexia 4 vomiting 3
Headache 4 asthenia 1
Pruritis 2 blood in urine 3
Rash 2 dizziness 2
Urticaria 1
BP fluctuation 2
CAUSALITY CAUSALITY
Certain 3 Certain -
Possible 2 Possible 4
Probable 1 Possible 7
Treatment-Related Grade 3 & 4 AEs
Phase III Randomized Trial of Cisplatin plus Placebo
Compared With Cisplatin plus Cetuximab in
Metastatic/Recurrent Head and Neck Cancer: An
eastern Cooperative Oncology Group Study.

Barbara Burtness, Meredith A.Goldwasser, William Flood, Bassam

Mattar, and Arlene A.Forastiere.
 Phase III Randomized Trial of Cisplatin plus Placebo Compared With Cisplatin plus
Cetuximab in Metastatic/Recurrent Head and Neck Cancer: An eastern Cooperative
Oncology Group Study.

Purpose :
Therapy or recurrent/metastatic squamous cell
carcinoma of the head and neck results in median
progression-free survival ( PFS) of 2 months. These
cancers are rich in epidermal growth factor receptor
(EGFR). They wish to determine whether the addition
of cetuximab which inhibits activation of
EGFR, would improve PFS.
 Phase III Randomized Trial of Cisplatin plus Placebo Compared With
Cisplatin plus Cetuximab in Metastatic/Recurrent Head and Neck Cancer: An
Eastern Cooperative Oncology Group Study.

Patients and methods.

Patients with recurrent/metastatic SCC H&N were randomly
assigned to receive Cisplatin 100 mg/m2 every 4 weeks, with
weekly cetuximab 400 mg/m2 on day 1 for cycle 1 only and
subsequent cycles were administered 250 mg/m2 (arm A) or
placebo (arm B). Tumor tissue was assayed for EGFR
expression by immunohistochemistry. The primary end point
was PFS. Secondary end points of interest were response
rate, toxicity, overall survival, and correlation of EGFR with
clinical end points.
 Phase III Randomized Trial of Cisplatin plus Placebo Compared With
Cisplatin plus Cetuximab in Metastatic/Recurrent Head and Neck Cancer: An
Eastern Cooperative Oncology Group Study.

Results.
There were 117 analyzable patients enrolled. Median PFS was
2.7 months for armB and 4.2 months for arm A. The hazard
ratio for progession of arm A to arm B was 0,78 (95% CI,0.54
to 1.12). Median overall survival was 8.0 months for arm B
and 9.2 months for arm A (P=0.21). The hazard ratio for
survival by skin toxicity in cetuximab-treated patients was
0.42 (95% CI, 0.21 to 0.86). Objective response rate was 26%
for arm A and 10% for arm B (P=0.03). Enhancement of
response was greater for patients with EGFR staining present
in less than 80% of cells.
 Phase III Randomized Trial of Cisplatin plus Placebo Compared With
Cisplatin plus Cetuximab in Metastatic/Recurrent Head and Neck Cancer: An
Eastern Cooperative Oncology Group Study.

Conclusion.
Addition of cetuximab to cisplatin significantly improves
response rate. There was a survival advantage for
development of rash. Progression-free and overall survival
were not significantly improved by the addition of cetuximab
in this study.
Radiotherapy plus Cetuximab for
Squamous-Cell Carcinoma of the
Head and Neck.

James A .Bonner,MD., Paul M Harari,MD., Jodi Giralt, MD etc

Radiotherapy plus Cetuximab for Squamous-Cell Carcinoma of
the Head and Neck.

Background.
We conducted a multinational, randomized study to
compare radiotherapy alone with radiotherapy plus
cetuximab, a monoclonal antibody againts the EGFR, in
the treatment of locoregionally advanced squamous-cell
carcinoma of the head and neck.
Radiotherapy plus Cetuximab for Squamous-Cell Carcinoma of
the Head and Neck.

Methods.
Patients with locoregionally advanced H&N cancer were
randomly assigned to treatment with high-dose radiotherapy
alone (213 patients) or high-dose radiotherapy plus cetuximab
(211 patients). The primary endpoint was the duration of
control of locoregional disease; secondary end points were
overall survival, progession-free survival, the response
rate, and safety.
Radiotherapy plus Cetuximab for Squamous-Cell Carcinoma of the Head and
Neck.

Results.
The median duration of locoregional control was 24.4 months
among patients treated with cetuximab plus radiotherapy and
14.9 months among those given radiotherapy alone
(P=0.005). With a median follow-up of 54.4 months, the
median duration of overall survival was 49.0 months among
patients treated with combined therapy and 29.3 months
among those treated with radiotherapy alone (P=0.03).
Radiotheraspy plus cetuximab significantly
prolonged progression-free survival (P=0.006).
With the exception of acneiform rash and infusion
reactions, the incidence of grade 3 or greater toxic
effects, including mucositis, did not differ significantly between
two groups
 Conclusion
• The median progression-free survival for patients with
recurrent or metastatic disease is reported to be 2
months, novel systemic treatments are urgently needed for
these patients.

• EGFR represents a promising new teurapeutic target in cancer.

• Nimotuzumab and cetuximab were monoclonal antibodies to

inhibit EGFR, both agents consistenly demonstrated better
activity when administered in conjunction with chemotherapy
or radiotherapy.
 Conclusion
• Both agents were tolerated in all patients ( the typical side
effects associated with cetuximab are skin reactions ) without
increased toxicity in concurrent combination with
chemotherapy or radiotherapy.

• There was a substansial improvement of clinical

outcome, long lasting objective responses and disease
control.