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


every 3 weeks

7. Paclitaxel 175 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 :


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


III

IVIII



III

IVIII



III

IVIII



III

IV

III



III

IV

III



III

(D279 H280)

III

IV




Shc

PI3-K

RafMEKK-1

Ras

Grb2

AKT

Sos-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

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 ).


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.


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)


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


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.



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.



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.


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.


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.

Documents

Chemotherapy in Early Nasopharyngeal Cancer