Chemotherapy in Early Nasopharyngeal Cancer
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Transcript of Chemotherapy in Early Nasopharyngeal Cancer
Chemotherapy in Early Nasopharyngeal Cancer
ZAKIFMAN
Principles of Chemotherapy
Thirty years ago there was no effectivetherapy available for advanced malignanttumors. The prognosis for widespread tumorswhich could not be resected or irradiated wasinvariably fatal within a short periode of timeafter diagnosis. Today, the outlook has changeconsiderably, although much remains to bedone in order to effectively control manytumors 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 d1every 3 weeks.
3. Paclitaxel 175 mg/m2 d1Carboplatin AUC VI
every 3 weeks.4. Docetaxel 75 mg/m2 d1
Cisplatin 75 mg/m2 d1every 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 inselected 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
Extracellular Domain
Transmembrane Domain
Intracellular Domain
EGFr Is a Transmembrane Protein
The EGFR (erbB) family
Membrane
Extracellular
Intracellular
Cysteine-richReceptor domain
K
EGFTGF-Amphiregulin-cellulinHB-EGFEpiregulin
Tyrosine kinasedomain
erbB4HER4
erbB3HER3
erbB1HER1EGFR
erbB2HER2neu
Ligands
K
No specific ligands -often acts as dimer partner
K
Heregulins
K
NRG2NRG3Heregulins-cellulin
Wells 1999
Shc
PI3-K
RafMEKK-1
MEKMKK-7
JNK
ERK
Ras
mTOR
Grb2
AKT
Sos-1
EGFR Activation Mediates Multiple Processes
EGFr Activation Mediates Multiple Processes
Proliferation MetastasisAngiogenesisApoptosis Resistance
Shc
PI3-K
RafMEKK-1
MEKMKK-7
JNK
ERK
Ras
mTOR
Grb2
AKT
Sos-1
Ligands Induce Dimerization of EGFR
III
Ferguson KM. Biochem Soc Trans. 2004;32:742-745.Dawson JP, et al. Mol Cell Biol. 2005;25:7734-7742.
IV
III
Ligands Induce Dimerization of EGFR
III
IVIII
Ligands Induce Dimerization of EGFR
Ferguson KM. Biochem Soc Trans. 2004;32:742-745.Dawson JP, et al. Mol Cell Biol. 2005;25:7734-7742.
III
IVIII
Ligands Induce Dimerization of EGFR
Ferguson KM. Biochem Soc Trans. 2004;32:742-745.Dawson JP, et al. Mol Cell Biol. 2005;25:7734-7742.
III
IVIII
Ligands Induce Dimerization of EGFR
Ferguson KM. Biochem Soc Trans. 2004;32:742-745.Dawson JP, et al. Mol Cell Biol. 2005;25:7734-7742.
III
IV
III
Ligands Induce Dimerization of EGFR
Ferguson KM. Biochem Soc Trans. 2004;32:742-745.Dawson JP, et al. Mol Cell Biol. 2005;25:7734-7742.
III
IV
III
Ligands Induce Dimerization of EGFR
Ferguson KM. Biochem Soc Trans. 2004;32:742-745.Dawson JP, et al. Mol Cell Biol. 2005;25:7734-7742.
III
(D279 H280)
III
IV
Ligands Induce Dimerization of EGFR
Ferguson KM. Biochem Soc Trans. 2004;32:742-745.Dawson JP, et al. Mol Cell Biol. 2005;25:7734-7742.
Ferguson KM. Biochem Soc Trans. 2004;32:742-745.Dawson JP, et al. Mol Cell Biol. 2005;25:7734-7742.
Shc
PI3-K
RafMEKK-1
Ras
Grb2
AKT
Sos-1
Ligands Induce Dimerization of EGFR
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
Shc
PI3-K
RafMEKK-1
MEKMKK-7
Ras
mTOR
Grb2
AKT
Sos-1
EGFR TK Inhibitors
Extracellular
Intracellular
Shc
PI3-K
RafMEKK-1
MEKMKK-7
Ras
mTOR
Grb2
AKT
Sos-1
Anti-EGFR Monoclonal Antibodies
Extracellular
Intracellular
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 trialsPositive MAb accumulation in tumors
Lung AdenocarcinomaColon adenocarcinomaAnterior 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
34% mouse protein
Chimeric
10% mouse protein
Humanized
100% mouse protein
Mouse
100% human protein
Fully Human
Murine
Mab
ior egf/r3
100 % murine
h-R3HumanizedMab10 % murine90 % human
HumanMab100 % Human
ChimericMab30 % murine70 % human
VERY LOW IMMUNOGENICITY
Nimotuzumab Chinese Study
Nasopharyngeal tumors
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 tumorsNumber 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)
Clinical Protocol
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
Nimotuzumab Chinese Study: Phase II Clinical Trial Report
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≥4109 /L,platelet count≥100109 /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 fieldear-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
WHO histopathology type
WHO (Type 2)
WHO (Type 3)
59
70
67
IMC ( EGFR Expression )
Moderate 80
Strong 57
UCNT
Patient distribution
• The patients were included in the present phase II trial of Nimotuzumab and were randomized to two groups:
Control group: monotherapy of RT
Test group:Nimotuzumab + RT
137 patients
70 patients
67 patients
Comparison of complete responses rate (CR%)in combination therapy vs monotherapy (radiation alone)
ITT PP
Monotherapy (n=66)
Comb. Therapy (n=64)
x2 P Monotherapy (n=65)
Comb. Therapy(
n=61)
x2 P
5 weeks post treatment
Primary Tumor 51.52 90.63 18.66 <0.01 52.31 93.44 19.92 <0.01
Neck Lymph node
72.73 89.06 4.33 0.03 72.31 91.80 5.12 0.02
General Evaluation
42.42 87.50 22.67 <0.01 43.08 90.16 23.49 <0.01
17 weeks post treatment
Primary Tumor 63.64 92.19 10.86 0.01 64.62 95.08 12.51 <0.01
Neck Lymph node
80.30 93.75 4.30 0.03 80.00 96.72 6.11 0.01
General Evaluation
51.52 90.63 19.37 <0.01 52.31 93.44 20.3 <0.01
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)
Radi at i on
al one
Radi at i on +
Ni mot uzumab
0
1
2
3
4
5
6
7
8
Met ast ase I nci dence ( %)
GroupCases of distant
metastasisNo. of Pt. Incidence P*
Radiation alone 5 64 7.81%
0.21Radiation + Nimotuzumab
1 66 1.52%
* Fisher’s test evaluation at 17th weeks
Cases of distant metastasis Incidence
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 from50 to 400 mg. After the doses of 50 to 100 mg, 2 of 6 patientsachieved complete response, while after doses of 200 and 400mg, 4 of 6 patients had complete response. Another patientstreated 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, whilethe patients receiving 200 & 400 mg was 44,30 months.
The 3 years survival rate was 16,7% for subjects with twolowest 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 weretreated with 200 & 400 mg. 9 achieved objective responseand 5 had complete responses.
Since the additional 10 subjects were included, finally:
14 (87,5%) of 16 patients achieved objective response and 9had 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 DesignProof of Principle: Phase II Trial - BEST Study
First Line, Unresectable, Stage
III/IVa SCCHN Nimo 200mg + RT (60 – 66Gy)
+ CDDP 50mg/w
RT (60 – 66Gy)
+ CDDP 50mg/w
Nimo 200mg + RT (60 – 66Gy)
RT (60 – 66Gy)Group A
Group B
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 Site (N=92)
0 10 20 30 40 50 60
Maxillary Sinus
Larynx
Hypopharynx
Oral Cavity
Oropharynx
Pri
ma
ry T
um
or
Sit
e
Number of patients
Number of patients
Primary Tumor Sites (N=92)
EGFR Expression
0 5 10 15 20 25 30 35
3+
2+
1+
Negative
Not performed
Number of patients
EG
FR
Exp
ressio
n
EGFR Expression (N=92)
No 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 IIIND 001
37%
76%70%
100%
RT RT+nimotuzumab CRT CRT + nimotuzumab
Overall Response Rate (CR+PR)
BEST Trial - Phase IIIND 001
CRT
CRT+ nimotuzumab
RT
RT+ nimotuzumab
Overall Survival – Evaluable Population – 30 months
0.00
0.25
0.50
0.75
1.00
Months
0 5 10 15 20 25 30
BEST Trial - Phase IIIND 001
Combined Group Analysis: Overall Survival – Nimotuzumab vs No Nimotuzumab
Unplanned post-hoc analysis
0.00
0.25
0.50
0.75
1.00
months
0 5 10 15 20 25 30
HR= 0.34, p=0.0018
No nimotuzumab (n=38)nimotuzumab (n=37)
Overall Survival at 48 Months F-UpEvaluable Population
Overall Survival at 48 Months F-UpITT 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
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
Nimotuzumab AEs
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, BassamMattar, 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 cellcarcinoma of the head and neck results in medianprogression-free survival ( PFS) of 2 months. Thesecancers are rich in epidermal growth factor receptor(EGFR). They wish to determine whether the additionof cetuximab which inhibits activation ofEGFR, 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 randomlyassigned to receive Cisplatin 100 mg/m2 every 4 weeks, withweekly cetuximab 400 mg/m2 on day 1 for cycle 1 only andsubsequent cycles were administered 250 mg/m2 (arm A) orplacebo (arm B). Tumor tissue was assayed for EGFRexpression by immunohistochemistry. The primary end pointwas PFS. Secondary end points of interest were responserate, toxicity, overall survival, and correlation of EGFR withclinical 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 was2.7 months for armB and 4.2 months for arm A. The hazardratio for progession of arm A to arm B was 0,78 (95% CI,0.54to 1.12). Median overall survival was 8.0 months for arm Band 9.2 months for arm A (P=0.21). The hazard ratio forsurvival by skin toxicity in cetuximab-treated patients was0.42 (95% CI, 0.21 to 0.86). Objective response rate was 26%for arm A and 10% for arm B (P=0.03). Enhancement ofresponse was greater for patients with EGFR staining presentin 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 improvesresponse rate. There was a survival advantage fordevelopment of rash. Progression-free and overall survivalwere not significantly improved by the addition of cetuximabin 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 wererandomly assigned to treatment with high-dose radiotherapyalone (213 patients) or high-dose radiotherapy plus cetuximab(211 patients). The primary endpoint was the duration ofcontrol of locoregional disease; secondary end points wereoverall survival, progession-free survival, the responserate, 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 infusionreactions, the incidence of grade 3 or greater toxiceffects, including mucositis, did not differ significantly betweentwo groups
Conclusion
• The median progression-free survival for patients withrecurrent or metastatic disease is reported to be 2months, novel systemic treatments are urgently needed forthese patients.
• EGFR represents a promising new teurapeutic target in cancer.
• Nimotuzumab and cetuximab were monoclonal antibodies toinhibit EGFR, both agents consistenly demonstrated betteractivity when administered in conjunction with chemotherapyor radiotherapy.
Conclusion
• Both agents were tolerated in all patients ( the typical sideeffects associated with cetuximab are skin reactions ) withoutincreased toxicity in concurrent combination withchemotherapy or radiotherapy.
• There was a substansial improvement of clinicaloutcome, long lasting objective responses and diseasecontrol.