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Induction methotrexate, cisplatin and 5-fluorouracil (MPF) versus cisplatin and 5-fluorouracil (PF) followed
by radiotherapy in pediatric nasopharyngeal carcinoma: A retrospective analysis in a tertiary cancer
center
Abdelatif Al Mousa MD, PhD1, Ramiz Abu-Hijlih MD1, Ahmed Salem MD2*, Iyad Sultan MD3, Layth Mula-
Hussain MD1, Taleb Ismael MD3, Issa Mohamad MD1
1. Department of Radiation Oncology, King Hussein Cancer Center, King Hussein Cancer Center, PO
Box 1269, Amman 11941, Jordan
2: Division of Molecular and Clinical Cancer Sciences, University of Manchester, 27 Palatine Rd,
Manchester M20 3LJ, UK
3. Department of Pediatric Oncology, King Hussein Cancer Center, King Hussein Cancer Center, PO Box
1269, Amman 11941, Jordan
* The author was affiliated with Department of Radiation Oncology, King Hussein Cancer Center, Jordan
during the time this project was in progress
Corresponding author: Issa Mohamad MD, Tel: +962799825592, Fax: +96265342567
Email: [email protected]
Disclosures: The authors have no conflicts of interest or funding to disclose
This work was presented at the 4th Regional Congress of Cancer and Blood Disorders of Childhood, 2012
(Amman, Jordan) and the 6th International nasopharyngeal carcinoma Symposium, 2013 (Istanbul,
Turkey).
Running title: Induction chemotherapy in pediatric nasopharyngeal carcinoma
Keywords: Nasopharyngeal; carcinoma; childhood; pediatric; chemotherapy; radiotherapy
Acknowledgments: The authors would like to acknowledge Mrs Ayat Taqash for her help with the
statistical analysis of this paper.
Word count for abstract: 200 words
Word count for main text: 2,640 words
Number of tables: 5 tables
Number of figures: 2 (1a, 1b, 2a, and 2b)
Abstract
Purpose: To compare treatment outcomes of methotrexate, cisplatin and 5-fluorouracil (MPF) or cisplatin
and 5-fluorouracil (PF) in pediatric NPC patients treated with sequential chemoradiotherapy.
Patients and methods: 25 patients aged ≤18 years with stage II-IV NPC treated with IC using PF (n=16)
or MPF (n=9) followed by radiotherapy between 2003 and 2009 were retrospectively reviewed.
Radiotherapy dose was 61.2 – 66.6Gy to the gross disease. Age, stage, radiation dose and
chemotherapy regimen were tested as prognostic factors for event-free and overall-survival (EFS and OS,
respectively) on univariate and multivariate analyses.
Results: The median age at diagnosis was 13.3 years. All patients completed planned chemotherapy. All
patients who received MPF achieved PR whereas 15 patients (93.8%) who received PF achieved PR;
p=1. There were no differences in EFS (68.75% v 66.67%; p=0.84) and OS (81.25% v 66.67%; p=0.39) at
5 years between PF and MPF, respectively. On multivariate analysis, only tumor stage (IV versus II-III)
predicted worse OS (hazard ratio (HR) 10.3, 95% confidence interval (CI); 1.197-88.974) but not EFS (HR
4.805, 95% CI; 0.95-24.336). Distant metastases was the predominant site of failure, seen in 5 patients
(20%).
Conclusions: Omission of methotrexate from the induction chemotherapy regimen did not affect
treatment outcome.
Introduction
Nasopharyngeal carcinoma (NPC) is a rare pediatric malignancy contributing less than 1% of all pediatric
tumors (1,2). NPC is endemic in southern China and Asia, but rare in Europe and North America with an
incidence lower than 1 in 100,000 (2–6). The World Health Organization (WHO) classifies NPC into three
types: squamous cell carcinoma (type I), keratinizing undifferentiated carcinoma (type II) and non-
keratinizing undifferentiated carcinoma (type III) (7). WHO type III, which is strongly associated with
Epstein–Barr virus (EBV), is the most common subtype in children.
Treatment of pediatric NPC patients is not standardized due to limited prospective studies in this disease.
Secondary to molecular and biological characteristics, NPC is relatively sensitive to chemo-radiotherapy
(8), with evidence to support cisplatin-based induction chemotherapy followed by radiotherapy (3).
Induction chemotherapy with methotrexate, cisplatin and 5-fluorouracil (MPF) followed by radiotherapy
was established as an accepted treatment option associated with long-term event-free and overall-
survival (EFS and OS, respectively) in a seminal Pediatric Oncology Group phase II study (9). Further, an
international randomized phase II study failed to detect any added efficacy, when docetaxel was added to
an induction chemotherapy regimen consisting of PF followed by concurrent chemo-radiotherapy (10).
However, in patients treated with sequential chemo-radiotherapy (induction chemotherapy followed by
radiotherapy), according to our knowledge there are no previously-published studies which have
compared induction chemotherapy regimens. Further, very little is known about the natural history,
presentation, treatment and outcome of this disease in the Middle East. The aim of this study is to
compare the therapeutic efficacy of induction chemotherapy regimens (MPV versus PF) and report the
clinical outcomes and prognostic factors of survival for pediatric NPC treated with induction chemotherapy
followed by radiotherapy in a tertiary cancer center in Jordan.
Patients and methods
Between 2003 and 2009, NPC patients aged ≤18 years treated at King Hussein Cancer Center (Amman,
Jordan) were identified via retrospective review of patient records. Patients were eligible if they had
biopsy-proven, previously-untreated stage II-IV (American Joint Committee on Cancer, 6th edition) NPC
and treated with curative intent using induction chemotherapy followed by radiotherapy. This study was
approved by the institutional review board. All patients granted written informed clinical treatment consent
before the start of their treatment.
Typical pretreatment assessments included complete history and physical examination, fiber-optic
nasopharyngoscopy, routine blood tests, magnetic resonance imaging (MRI) of head and neck, computed
tomography (CT) of the chest, abdomen and pelvis and whole-body bone scan. In addition, all patients
underwent pretreatment cardiac assessment, audiogram, dental evaluation and nutritional assessment.
All cases were discussed at a pediatric oncology multi-disciplinary meeting, prior to initiation of therapy.
Therapeutic radiological response, evaluated using RECIST criteria (version 1.1) (11), was documented
following 4 cycles of indication and at 6-8 weeks post-radiotherapy. Patients who achieved less than
complete response (CR) after radiotherapy were subsequently treated with palliative chemotherapy.
Induction chemotherapy: Two induction chemotherapy protocols were used in this study. Between 2003
and 2006, patients (n=9) were treated with methotrexate 120 mg/m2 intravenous (IV) day 1, cisplatin 100
mg/m2 IV day 1 and 5-fluorouracil (5-FU) 1000 mg/m2/day continuous infusion days 1-5. This regimen
(MPF) was repeated every 21 days for a total of 4 cycles. Between 2007 and 2009, patients (n=16) were
treated with cisplatin 100 mg/m2 IV day 1 and 5-FU 1000 mg/m2/day continuous infusion days 1-5. This
regimen (PF) was repeated every 21 days for a total of 4 cycles.
Radiotherapy: Radiotherapy was initiated one month after completion of induction chemotherapy and
delivered via 3-dimensional conformal radiotherapy (3D-CRT) using once-daily fractions, 5 days a week.
Total radiotherapy dose was determined based on induction chemotherapy response. Patients with
complete or partial response (PR) received 61.2Gy in 34 fractions while patients with stable or
progressive disease (SD and PD, respectively) received 66.6Gy in 37 fractions. An elective radiotherapy
dose of 50Gy in 25 fractions to bilateral neck nodes and areas at risk for local tumor spread was delivered
in all patients. Patients were immobilized in the supine position with a custom aquaplastic head and neck
mask. Target localization was accomplished with computed tomography (CT) simulation using 5 mm thick
slices extending from the vertex to 5 cm inferior to the clavicular heads. Target volume definition was
guided by pre-induction chemotherapy MRI, which was manually registered with planning CT. The gross
tumor volume (GTV), which included primary nasopharyngeal tumor and lymph nodes greater than 1 cm
or any node with necrotic center, was delineated. The clinical target volume (CTV) denoted the subclinical
regions at risk for tumor spread. Different CTVs were defined as follows: CTV61.2 (in patients with CR or
PR)/ 66.6 (in patients with SD or PD)-Primary = GTV + 5 mm isotropic margin around primary tumor,
CTV61.2/66.6-Nodal = GTV + 5 mm isotropic margin around gross nodes, CTV50 = GTV-Primary /Nodal
+ 1 cm margin + areas at risk for microscopic involvement (entire nasopharyngeal mucosa, skull base,
half of clivus in early-stage/ whole clivus in T3-4 disease, pterygoid fossae, bilateral parapharyngeal
spaces, sphenoid sinus, posterior third of the nasal cavity/ maxillary sinuses including the pterygopalatine
fossae, lateral retropharyngeal nodal region and levels Ib-V (node positive) or II-V (node negative)). To
account for uncertainties of daily set-up, a planning target volume (PTV) of 5 mm was added to each of
the above CTVs. Symptomatic supportive therapy was prescribed as required during treatment. Acute
radiotherapy toxicity was not completely reported but late radiotherapy toxicity was retrieved and recorded
as present (if the patient reported any significant symptoms, affection of quality of life or required
treatment) or absent.
Follow-up: Patients were followed up weekly during radiotherapy, 2 weeks pot-radiotherapy, at three
monthly intervals for the first two years and then at four monthly intervals for the third year. Follow-up
consisted of physical examination, endoscopic examination and laboratory tests. Head and neck MRI was
performed every 6 months for 2 years and then annually or as clinically indicated.
Statistical Analysis
Overall survival (OS) was defined as the time from diagnosis to death, from any cause. Patients who
remained alive were censored at the date of their last follow-up. Event-free survival (EFS) was defined as
the time from diagnosis to the first progression or relapse at any site or death from any cause. Patients
who remained alive without disease progression or relapse were censored at the date of their last follow-
up. Survival analyses were estimated using the Kaplan-Meier method. Patient groups were compared in
terms of survival using the log rank test. Cox regression model was used to identify significant prognostic
factors. Age, stage, radiation dose and chemotherapy regimen were tested as prognostic factors for EFS
and OS on univariate and multivariate analyses. Statistical significance was accepted when the p-value
was <0.05. Statistical analysis was performed using SAS version 9.4 (SAS Institute Inc., Cary, NC).
Results
Over the study period, twenty eight eligible patients were identified from the chart review. Three patients
had no follow-up information and were excluded; 25 patients were included in the analysis. All patients
had undifferentiated NPC (WHO type III). EBV testing was not routinely performed during the study
period. The majority were males (n=16). The median age at diagnosis was 13.3 years (range, 7-17.1
years). Two patients harbored stage II (8%), 13 stage III (52%) and 10 stage IV (40%). Bilateral neck
swelling (59%), hearing loss (26%) and epistaxis (19%) were the most common presenting symptoms.
The median time between onset of symptoms and diagnosis was 14 weeks (range, 4-52 weeks). Baseline
patient characteristics are summarized in table 1. As shown, the majority of patients >14 years old were
treated with MPF (88.9%) compared to PF (37.5%) induction chemotherapy; p=0.033. This difference was
also reflected in varying patient height and weight at diagnosis for the 2 chemotherapy cohorts. Follow-up
for patients treated with MPF was significantly longer (median, 86.4 months) compared to patients treated
with PF (median, 48 months) induction chemotherapy; p=0.0435.
All patients completed 4 cycles of chemotherapy, as planned. All patients who received MPF achieved PR
whereas 15 patients (93.8%) achieved PR in the PF group; p=1. One patient had PD following PF and
was switched to gemcitabine and carboplatin with SD thereafter. On follow-up imaging 6-8 weeks after
completion of radiotherapy, CR was documented in 19 patients (76%), PR in 4 patients (16%) while PD
was observed in 2 patients (8%). There was no difference in radiological response post-radiotherapy
between the 2 chemotherapy groups (table 2).
After a median follow-up of 56 months (range, 14-103 months), 19 patients (76%) were alive of whom, 17
(68%) with no evidence of disease. The 5-year EFS was 67.56% (figure 1a) while the 5-year OS was
75.79% (figure1b) for the whole patient population. Patients aged ≤14 years (c.f. >14 years) had better
EFS (90.91% versus 48.98% at 5 years respectively; p=0.02). Superior EFS (86.15% v 40% at 5 years;
p=0.01) and OS (92.86% versus 50% at 5 years; p=0.01) was seen for patients with stage II-III versus IV,
respectively. There were no differences in EFS (68.75% v 66.67% at 5 years; p=0.84) and OS (81.25% v
66.67% at 5 years; p=0.39) between PF versus MPF, respectively (figure 2). Similarly, there were no
differences in EFS (71.43% v 70.59% at 5 years; p=0.97) and OS (71.43% v 82.35% at 5 years; p=0.54)
between 66.2Gy v 61.2Gy, respectively. There was no difference in EFS and OS between male and
female genders. On multivariate analysis, only tumor stage (IV versus II-III) predicted worse OS (hazard
ratio (HR) 10.3, 95% confidence interval (CI); 1.197-88.974) but not EFS (HR 4.805, 95% CI; 0.95-
24.336); table 3. Eight patients (32%) had disease recurrent disease on follow-up (5 (31.3%) in the PF
and 3 (33%) in the MPF group; p=1). The pattern of treatment failure is shown in table 4. Overall, distant
metastases was the predominant site of failure seen in 5 patients (20%).
In the whole study population, the following late radiotherapy-related side-effects were recorded:
hypothyroidism in 10 patients (transient, n=2), xerostomia (n=9), dysphagia (n=8), dental pain (n=8),
hearing loss (n=4), trismus (n=4) and neck fibrosis, hypogonadotropic hypogonadism, short stature,
behavior problems, depression, neck pain, leukodystrophy, malnutrition and nasal speech each seen in 1
patient.
Discussion
The incidence of pediatric NPC varies widely according to racial and geographical factors. We treat
around 4-7 pediatric NPC cases every year. It is noteworthy that in Jordan, the overwhelming majority of
pediatric cancer patients are treated at our tertiary cancer referral center. This study revealed a peak
presentation in late childhood and male predominance, both findings were reported in previous studies
(1,3,5,12,13). Further, all patients were diagnosed with WHO type III tumors, a finding also similar to
previous pediatric NPC studies (14,15). Patients with WHO type III tumors are more likely to present with
advanced stage at presentation (14). In our study, 23 patients (92%) harbored stage III/ IV disease. EBV
is endemic in Jordan, positive staining for EBV by in-situ hybridization was seen in 92.3% of NPC
specimens in Jordan (16). Unfortunately, EBV status was not available in our study. Cervical
lymphadenopathy is the most common presenting symptom of NPC. Other symptoms include nasal
obstruction, epistaxis, headache and auditory dysfunction (6). Bilateral neck swelling (59%), hearing loss
(26%) and epistaxis (19%) were the most common presenting symptoms in our study. Clinical stage and
age >12 years were shown to be associated with improved OS and EFS in a relatively large analysis of
95 patients with NPC <20 years of age (17). In our study, patients aged ≤14 years had significantly better
EFS compared to their older counterparts. It is unclear whether this finding could be explained by varying
molecular tumor characteristics in younger patients.
A systematic review and meta-analysis revealed that patients treated with combined radiotherapy and
chemotherapy achieved better outcomes compared to those treated with radiotherapy alone (18). This
study showed that the mean disease-free survival rate was 66% (95 % CI, 56-76%) among fifteen studies
which included 865 patients. Induction chemotherapy with MPF followed by radiotherapy was associated
with 4-year EFS and OS rate of 77% and 75%, respectively in a seminal Pediatric Oncology Group phase
II study (9). Further, few studies have shown good outcomes with induction chemotherapy followed by
concurrent chemo-radiotherapy (19,20). A recently reported international randomized phase 2 study failed
to detect any added efficacy, evaluated by achievement of complete response, when docetaxel was
added to an induction chemotherapy regimen consisting on PF followed by concurrent chemo-
radiotherapy (10). Excellent outcomes (OS and EFS rates >90%) are achievable with the use of
chemotherapy, radiotherapy and adjuvant interferon (IFN)-beta (21,22), but this treatment is not widely
adopted in many developing countries or less-advanced cancer centers due to financial considerations or
lack of expertise.
Very few robust evidence exists to guide the choice of induction chemotherapy regimen in pediatric NPC
patients treated with radiotherapy. Younger patients are at higher risk of developing treatment-related
complications (23) particularly related to radiotherapy (14). In 2007, we omitted methotrexate form the
induction chemotherapy regimen for pediatric patients with NPC in an attempt to decrease treatment-
related side-effects. Although the rate of radiological tumor response was non-statistically higher in
patients who received MPF versus PF induction chemotherapy in our study, we failed to detect any
significant survival difference between the two regimens in pediatric NPC patients. Our findings also
demonstrate that acceptable results can be reproduced in developing countries, in lieu of international
randomized trials, with both induction chemotherapy regimens suggesting appropriate omission of
methotrexate in these patients. Distant metastases remains the main failure site in patients treated with
induction chemotherapy followed by radiotherapy/ chemo-radiotherapy (24). This was also confirmed in
our study where 5 patients (20%) developed distant metastases.
A radiation dose higher than 65Gy is associated with improved local tumor control, albeit results are
inconsistent across studies (18). Good response to induction chemotherapy is an important
prognosticator and radiotherapy dose reduction has been proposed for these patients (25). The GPOH-
NPC Study Group now recommends that radiotherapy doses can be safely reduced to 59.4-54.4Gy in
patients who achieve CR on positron emission tomography following induction PF when treated with
concurrent chemo-radiotherapy (26). We have elected not reduce our radiotherapy dose, as following
induction chemotherapy, our patients are treated with radiotherapy alone.
The use of intensity-modulated radiotherapy (IMRT) has been proposed to improve target coverage and
decrease radiotherapy-related side-effects (27–29). This is particularly true in pediatric NPC patients as
most are locally-advanced at diagnosis (30). Although complete information regarding radiotherapy side-
effects were missing from our study (e.g. grading not available), we reported a relatively high rate of late
radiotherapy-related side-effects during the study period. At the time of this study, our pediatric NPC
patients were treated using 3D-CRT technique. Recently, we adopted IMRT as the standard radiotherapy
delivery technique for these patients and anticipate that this will result in lower incidence of late
xerostomia, dysphagia and hearing loss and possibly, improved target volume coverage.
There are a number of limitations of this study. This study included a relatively small number of patients,
treated in a single center over an extended period of time (2003-2009). Chemotherapy-related side-
effects were also not available in this study. As such, we are unable to confirm whether the omission of
methotrexate leads to less treatment-related toxicity. Further, a larger percentage of patients aged >14
years were treated using MPF, while the omission of methotrexate later in the study led to a shorter
follow-up for those treated with PF chemotherapy. To overcome these limitations, there is a strong need
for large, international collaborative studies in this disease (31). In the Middle East and developing
countries with limited resources, induction chemotherapy using PF followed by radiotherapy is a valid
treatment option in pediatric NPC patients. We have shown that the omission of methotrexate from the
induction chemotherapy regimen did not affect treatment outcome. A relatively high rate of distant
metastases was demonstrated in our patients, development of more effective but economical systemic
therapies should become a research priority.
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Table 1. Baseline patient characteristics. Significant p-values in bold.
Category Value Total number Chemotherapy (%) p-value
MPF PF
Gender Female 9 4 (44.4%) 5 (31.3%) 0.671
Male 16 5 (55.6%) 11 (68.8%)
Age Age ≤14 11 1 (11.1%) 10 (62.5%) 0.033
Age >14 14 8 (88.9%) 6 (37.5%)
TNM stage II
III
IV
2
13
10
1 (11.1%)
4 (44.4%)
4 (44.4%)
1 (6.3%)
9 (56.3%)
6 (37.5%)
0.849
Category CTX group Mean (95% CI) Median (min, max) p-value
Height at
diagnosis
MPF
PF
160 (156, 164)
145 (140, 151)
160 (149, 169)
148 (125, 168)
0.0029
Weight at
diagnosis
MPF
PF
53.6 (43.6,63.5)
39.3 (33.9, 44.8)
50.5 (35.0,83.0)
39.6 (22.4,70.3)
0.0444
follow up MPF
PF
75.8 (48.5, 103)
51.4 (45.4, 57.4)
86.5 (14.0, 102)
48.0 (33.0, 70.0)
0.0435
Table 2. Radiological response post treatment in the 2 chemotherapy groups
Category Value Total number Chemotherapy (%) p-value
MPF PF
Post chemotherapy PR
PD
24
1
9 (100%)
0 (0%)
15 (93.8%)
1 (6.2%)
1.000
Post radiotherapy CR
PR
19
4
6 (66.7%)
2 (22.2%)
13 (81.3%)
2 (12.5%)
0.803
PD 2 1 (11.1%) 1 (6.3%)
Table 3. Univariate and multivariate analysis of prognostic factors for EFS and OS. Significant p-values in
bold.
Univariate analysis
Prognostic factor Category Hazard ratio
95% confidence interval
p-value
Stage
IV versus II/III
OS 10.32 1.19-88.97 0.0337
EFS 5.76 1.15-28.72 0.0339
Radiotherapy dose
66 versus 61.2Gy
OS 1.78 0.27-10.74 0.5278
EFS 1.03 0.20-5.39 0.9711
Age
>14 versus ≤14 years
OS 4.99 0.58-42.92 0.1434
EFS 7.71 0.94-63.05 0.0568
Chemotherapy
PF versus MPF
OS 0.497 0.1-2.47 0.3929
EFS 0.87 0.21-3.66 0.8492
Multivariate analysis
Stage
IV versus II/III
OS 10.32 1.19-88.97 0.0337
EFS 4.805 0.95-24.366 0.0581
Table 4. Pattern of treatment failure in the 2 chemotherapy groups.
Chemotherapy group Site of treatment failure
PF Lung metastases (n=2)
Bone metastases (n=1)
Bone and lung metastases (n=1)
Loco-regional recurrence (n=1)
MPF Loco-regional recurrence (n=2)
Bone metastases (n=1)
Table 5. abbreviations key
MPF methotrexate, cisplatin and 5-fluorouracil
PF cisplatin and 5-fluorouracil
NPC Nasopharyngeal carcinoma
EFS Event free survival
OS Overall survival
WHO World health organization
EBV Epstein bare virus
MRI Magnetic resonance imaging
CT Computed tomography
CR Complete response
PR Partial response
SD Stable disease
PD Progressive disease
3DCRT 3D conformal radiotherapy
GTV Gross tumor volume
CTV Clinical target volume
PTV Planning target volume
HR Hazard ratio
CI Confidence interval
IFN-B Interferon beta
IMRT Intensity modulated radiation therapy
Figure legends
Figure 1: Kaplan-Meier survival curve for OS (1a) and EFS (1b) in the entire study population.
Figure 2: Kaplan-Meier survival curve comparing OS (2a) and EFS (2b) in patients according to induction
chemotherapy regimen.