JR If Radioterapi

Cetuximab in Combination With Chemoradiotherapy in
The Treatment of Recurrent and/or Metastatic

Nasopharyngeal Carcinoma
Tingting Xu , Xiaomin Ou , Chunying Shen and Chaosu Hu
Presented by : Ilman Fathony Martanegara

1 Supervisor : Dr.dr.Setiawan Soetopo, dr.., Sp.Rad., Sp.Onk.Rad
Departement of Otorhinolaryngology Head and Neck Surgery

Hasan Sadikin General Hospital
Bandung
2019
Background
2
The disease-free survival of NPC has achieved >
70% of all stages with the use (IMRT) technique and
optimal chemotherapy.
However, about 5–15% and 15–20% patients will develop

local recurrence and distant metastasis, after the primary
treatment.
In the past decades, the median duration of survival

among patients with (R/M) NPC was < 12 months ,
although > 50% patients would have a response after re-
chemotherapy.
Tingting Xu et all . Cetuximab in Combination With Chemoradiotherapy in The Treatment of Recurrent and/or Metastatic Nasopharyngeal Carcinoma, Anti-Cancer
Drugs Volume 27, p p. 66-75, Wolters Kluwer( 2016)
Background
3
The most effective chemotherapy regimens are platinum

based
No standard recommended regimen
Toxicity is a major problem in multiple lines of

chemotherapy
Introduction
4
It was proved to be effective

The epidermal growth factor
Cetuximab is a chimeric & feasible in a local regional
receptor (EGFP) , is
antibody constructed on an advanced and R/M HNSCC)
expressed in over 90% of
IgG1 framework. when combined with RT
NPC
and/or chemotherapy.
Introduction
5
Nevertheless, efforts have been focused on the outcomes of HNSCC

patients treated with cetuximab and few studies can be found for
NPC, especially the R/M disease.
Chan et al. : cetuximab + carboplatin in heavily pretreated patients

with R/M NPC -> clinical activity & acceptable toxicity.
To further evaluate the target drug as part of multimodal treatment,

we reported our experience of using cetuximab in combination with
chemoradiotherapy for patients with R/M NPC.
Methods
6
Between March 2007 and November 2011, a

total of 30 R/M NPC patients treated with
systemic therapy + cetuximab at Fudan
University Shanghai Cancer Center were
retrospectively enrolled.
All patients had to have a histologic

diagnosis of NPC and imaging [computed
tomography (CT)/MRI]- confirmed recurrent
and/or metastatic disease.
Patient selection
7
 Pre-Treatment evaluations :
1. Complete blood cell count,
2. Biochemical profile,
3. MRI of the nasopharynx and neck,
4. Chest CT,
5. Ultrasound of the abdomen,
6. Bone scan, and/or PET/CT.
7. Enhanced CT/MRI imaging of the metastatic regions
 This study was approved by the Institutional Review Boards of Fudan
University Shanghai Cancer Center. All the patients provided their
written informed consent to participate in this study.
Cetuximab and Chemotherapy
8
Cetuximab was administered at an initial dose of 400 mg/m2, followed by weekly infusions
of 250 mg/m2.
All patients received chemotherapy along with cetuximab. The medical oncologist
decided the chemotherapy regimens according to the previous treatment.
Generally, TP/TPF (docetaxel 60–75 mg/m2 d1 + DDP 25 mg/m2 d1–3 ± 5-FU 500 mg/m2/day
with 120-h infusion), GP (gemcitabine 1.0 g/m2 d1–d8+DDP 25 mg/m2 d1–3), and PC
(paclitaxel 60 mg/m2/week d1 +carboplatin AUC 2/week d1) were administered.
Cetuximab was generally delivered 1 week before chemotherapy and then administered
weekly until intolerable toxicities or disease progression.
Radiotherapy
9
All recurrent patients (except three in whom distant metastases

were discovered at the time of recurrence) received
reirradiation to the recurrent location. They underwent CT-based
planning at 3mm thickness with custom immobilization.
IMRT plans consisted of seven to nine coplanar fields using 6-MV

photons. Target and organs at risk were contoured by radiation
oncologists. Gross tumor volume was defined as gross disease
shown by imaging.
Radiotherapy
10
Planning target volume was defined as gross tumor volume plus a
max margin of 10mm depending on the proximity of critical
structures.
Fourteen patients received a median total dose of 60 Gy (54–66 Gy)

with a 2.0 Gy fraction. The following constraints to critical structures
were used: 45 Gy for the brainstem, 30 Gy for the spinal cord, 45 Gy
for the optic nerve and chiasm, and 50 Gy for the temporal lobe.
Verification of the treatment plan and dose was performed before

treatment delivery.
Toxicity
11
Acute toxicity was defined as occurring within 90 days of

treatment completion.
A complication that occurred during treatment that
persisted after 90 days was also considered late toxicity.
The Common Terminology Criteria for Adverse Events

v3.0 were used to evaluate the acute toxicity. Late
toxicity was evaluated using the RTOG scale.
Endpoints and statistical analysis
12 Assessment was performed by the investigators using the
Response Evaluation Criteria in Solid Tumors. The true
response rate was estimated by the proportion of eligible
patients who achieved a confirmed complete response
(CR) or partial response (PR).
Tumor response and progression were evaluated

every other cycle of chemotherapy and every 3
months after treatment, respectively, using
consistent imaging techniques (CT or MRI).
Other end points were to examine the median

survival time, time to progression (TTP), overall
survival (OS), and the incidence of adverse
effects.
Endpoints and statistical analysis
13
Progression/survival time was defined to be the time from the

starting of cetuximab to the date of events (progression or death).
The distribution of TTP and survival time was estimated using the
Kaplan–Meier method.
All analyses were carried out using the SPSS software (v16.0; IBM
Corporation, Armonk, New York, USA) at a 5% level of significance.
Results
14
Patient & Tumor Characteristics
15
Exposure to cetuximab and chemotherapy
16
During the entire study period, 30 patients

received a median of seven cetuximab
infusions (range 3–18).
Nineteen patients (63.3%) received no less

than seven infusions.
Twenty-eight patients (93.3%) received more

than one chemotherapy regimen during the
entire multimodal treatment.
Response rate
17
Toxicity
18
Survival
19
Survival
20
Discussion
21
Cetuximab in combination with radiotherapy and/or platinum-based chemotherapy was

proved to improve outcome in HNSCC.
In the first-line setting, the success of the phase III randomized study by Bonner et al. has
been hailed as a landmark study.
It showed a significant improvement in OS without adversely affecting quality of life with

addition of cetuximab to radiotherapy in patients with locally advanced HNSCC.
The results of the EXTREME study in R/M HNSCC also yielded satisfactory outcome. With the
addition of cetuximab to standard chemotherapy, there was a statistically significant
improvement in the OS from 7.4 to 10.1 months (HR 0.80 ).
Discussion
22
In a subset analysis, there was a greater benefit for the following

subgroups: those younger than 65 years of age, those with better
performance status, and those who received cisplatin.
Besides the efficacies, Mesía et al also reported that adding

cetuximab to the platinum–fluorouracil regimen chemotherapy
did not adversely affect the quality of life of patients in the
EXTRME study.
Recently, de Mello et al reported the use of a regimen of
cetuximab in combination with PF in 121 previously untreated R/M
HNSCC patients; they achieved an OS of 11 months (95%
confidence interval, 8.684–13.316), with welltolerated toxicity.
Discussion
23
Discussion
24
Before the Bonner study was published, Chua et al. [20] had reported the
efficacy and tolerability of cetuximab in combination with carboplatin
after the failure of previous platinum-based chemotherapy regimens.
Of the 59 patients assessable for efficacy, the overall response rate was
11.7% (95% confidence interval, 4.8–22.6%). Nineteen patients (31.7%) had
grade 3/4 toxicities related cetuximab.
In the 2014 ASCO meeting report [26], the overall response rate was 27.4%
for the 29 patients available for assessment. Grade 3 cutaneous toxicities
occurred in two patients (5.7%).
Discussion
25
We considered the better results came from the good

performance status of our patients and fewer
pretreatment regimens delivered to them.
A total of 96.2% of patients had KPS of at least 80, and

76.6% of these had only received one chemotherapy
regimen before starting cetuximab treatment.
Discussion
26
We used two-agent or three-agent combination chemotherapy

regimens along with radiotherapy (in 14 recurrent diseases)
concurrently with cetuximab.
In the study by Chua et al, patients were heavily treated and 30%
patients had received more than one previous chemotherapy
regimens and failed.
They only used carboplatin as a single agent in combination with

cetuximab and the treatment intensity may not have been sufficient
Conclusion
27
This study showed that, to a clinically

meaningful extent, the addition of
cetuximab to chemoradiotherapy as
a treatment alternative for R/M NPC
was effective, with tolerable toxicities.
Future studies should aim at defining

the predictive markers for response to
cetuximab to select the responsive
tumor for the correctly targeted
agents and with larger sample sizes
Writer
Tingting Xu, Xiaomin Ou, Chunying Shen and Chaosu Hu
Institution
Department of Radiation Oncology, Fudan University Shanghai Cancer
Center, Shanghai, China
Document
Research Articl
Published
Wolters Kluwer, Anti-Cancer Drugs, Volume 27, pp. 66-75
Publication Date
January 1, 2016
28
29 Metodology & Statistical Analysis
 Retrospective Study
 Analyzed by SPSS
30 Implementation
 May be considered applcated in Indonesia/ Hasan

Sadikin Hospital
 Sample just 30 patient
 Other confounding Factor ?
 Incusion/ exclusion criteria?
 In Indonesia , there is Goverment Rules Cetuximab Can
not be Given for NPC
31 Integrity of Researcher
 Researcher are staff of Department of Radiation Oncology and

Oncology, Fudan University Shanghai Cancer Center, Shanghai,
China
 Usually write NPC article research
32 Summary of Reserach
 There is no Incusion/ exclusion criteria

 Few Sample
 There is no explanation of confounding factor
 There is no predictive biomarker for targetted therapy
 Multimodality treatment is only used for R/M NPC
33

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Cetuximab in Combination With Chemoradiotherapy in

The Treatment of Recurrent and/or Metastatic

Presented by : Ilman Fathony Martanegara

Departement of Otorhinolaryngology Head and Neck Surgery

However, about 5–15% and 15–20% patients will develop

In the past decades, the median duration of survival

The most effective chemotherapy regimens are platinum

No standard recommended regimen

Toxicity is a major problem in multiple lines of

It was proved to be effective

Nevertheless, efforts have been focused on the outcomes of HNSCC

Chan et al. : cetuximab + carboplatin in heavily pretreated patients

To further evaluate the target drug as part of multimodal treatment,

Between March 2007 and November 2011, a

All patients had to have a histologic

All recurrent patients (except three in whom distant metastases

IMRT plans consisted of seven to nine coplanar fields using 6-MV

Fourteen patients received a median total dose of 60 Gy (54–66 Gy)

Verification of the treatment plan and dose was performed before

Acute toxicity was defined as occurring within 90 days of

The Common Terminology Criteria for Adverse Events

Tumor response and progression were evaluated

Other end points were to examine the median

Progression/survival time was defined to be the time from the

During the entire study period, 30 patients

Nineteen patients (63.3%) received no less

Twenty-eight patients (93.3%) received more

Cetuximab in combination with radiotherapy and/or platinum-based chemotherapy was

It showed a significant improvement in OS without adversely affecting quality of life with

In a subset analysis, there was a greater benefit for the following

Besides the efficacies, Mesía et al also reported that adding

We considered the better results came from the good

A total of 96.2% of patients had KPS of at least 80, and

We used two-agent or three-agent combination chemotherapy

They only used carboplatin as a single agent in combination with

This study showed that, to a clinically

Future studies should aim at defining

 May be considered applcated in Indonesia/ Hasan

 Researcher are staff of Department of Radiation Oncology and

 There is no Incusion/ exclusion criteria

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