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Research Article

Feasibility and efficiency of concurrent chemo-radiotherapy for nasopharyngeal carcinoma patients

Imene Essaidi, Chiraz Nasr, Lotfi Kochbati, Mongi Maalej

Radio-Oncology Department Salah Azaiz Cancer Institute, boulevard du 9-Avril, 1006 Tunis, Tunisia

Citation: Essaidi I, Nasr C, Kochbati L, Maalej M. Feasibility and efficiency of concurrent chemo-radiotherapy for

nasopharyngeal carcinoma patients. J Nasopharyng Carcinoma, 2015, 1(21): e21. doi:10.15383/jnpc.21.

Competing interests: The authors have declared that no competing interests exist.

Conflict of interest: None.

Copyright: 2014 By the Editorial Department of Journal of Nasopharyngeal Carcinoma. This is an open-access article

distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution,

and reproduction in any medium, provided the original author and source are credited.

Abstract:

Purpose: To evaluate the feasibility and efficiency of concurrent chemo-radiotherapy (CCRT) in nasopharyngeal

carcinoma (NPC) patients. Patients and Methods: We reviewed data of 33 non-metastatic NPC patients who had

been treated with CCRT between January 2004 and December 2006.The Median age of patients was 41 year-old

and the male/female ratio was 3.According to the 2002 TNM staging system, T3-T4 locally advanced tumors and

N2-N3 nodal status rates were 67% and 46%, respectively. All patients had undifferentiated carcinoma and received

conventional fractionated 2D conventional radiotherapy (RT)with a total dose of 70-74 Gyand concurrent weekly

intravenous cisplatin (40 mg/m2). Results: The acute toxicities were all manageable. Grade 3-4 mucositis and skin

reaction were seen in 6 patients (18%). RT interruption for a week occurred in 1 patient because of a Grade 3

dysphagia. All patients finished their planned RT. Four patients (12%) refused to complete the concurrent

chemotherapy (CT) and 5 other patients (15%) did not receive the planned cycles of CT because of renal and/or

hematologic toxicities. After a median follow-up of 58 months, 6 patients (18%) developed loco-regional relapse

associated with distant metastasis in 4 cases (12%), and 6 patients (18%) developed distant metastases alone. Five-

year overall survival and disease-free survival rates were 70 and 63%, respectively. A univariate analysis for

prognostic factors was also performed. Overall survive was affected by Stage T4, Stage N3, age >40 years, and

cycles of CT ≤ 5.Patients who received more than 5 cycles of cisplatin had also significantly better disease free

survival and metastasis free survival. Conclusion: The results of our study have shown that CCRT for loco

regionally advanced NPC is both feasible and effective, with acceptable toxic effects. On univariate analysis, the

age >40 years, Stage T4, Stage N3, and cycles of CT ≤ 5 had a significantly poor outcome.

Keywords: chemo-radiotherapy; nasopharyngeal carcinoma; feasibility; efficiency; toxicities

BACKGROUND pathology, clinical presentation and response to treatment [1, 2].

Nasopharyngeal carcinoma (NPC) is distinct from other This neoplasm has a notable ethnic and geographic distribution

malignancies in the head and neck with respect to its epidemiology, with a high prevalence in Southeast Asian and North African

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populations. It is relatively frequent in Tunisia with incidence rates Median 41 years Range (11-66 years)

of 3.4/ 100.000 population in males and 1.6/ 100.000 population in Sex

females [3]. NPC ishighlyradiosensitive.Although early-stage NPC Male 25 76

is highly radiocurable, the cure rate with RT alone for Female 8 24

locoregionally advanced NPC is low [4-6]. Because NPC is a Pathology

chemosensitive tumor, CT added to RT in various manners should WHO type III 33 100

be a method to improve survival rates [7-17]. Since the early T stage (TNM 2002)

1990s, more than 15 randomized clinical trials and 4 meta- T0 1 3

analyses have been published on the use of induction, concurrent T1 2 6

and adjuvant CT in the treatment of locoregionally advanced NPC T2 8 24

[6-22].The predominant finding of these studies is a survival T3 15 46

advantage associated with the use ofCCRTwith or without T4 7 21

adjuvant CT (ACT)over RT alone.Since then, CCRT with or N stage (TNM 2002)

without ACT has become the standard treatment modality for N0 6 18

patients with advanced NPC, although the rate of acute toxicities N1 12 36

was significant especially when ACT was prescribed. N2 11 34

The aim of this retrospective study is to evaluate the feasibility and N3 4 12

efficiencyof CCRT in locoregionally advanced NPC patients.

Treatment plan: All patients were treated with a radical intent

PATIENTS AND METHODS
using a combination of CT and RT. They received conventional
Patient characteristics:A total of 33 patients with a histologically
2D RT using a telecobalt unitwith bilateral parallel opposing fields
confirmed diagnosis of non-metastatic NPC were treated with
to the primary tumor and upper neck, and a single anterior field to
CCRT at Salah Azaiz Institute between January 2004 and
the lower neck with a central shield. After 42-44Gy, the primary
December 2006.The patient age at presentation ranged from 11 to
tumor was boostedusing bilaterally opposed reduced portals and
66 years (median, 41). Of the 33 patients, 25 were males and 8
the posterior cervical lymphatic chains were treated with
were females(male/female ratio=3).The initial staging evaluation
appropriate electrons (6-9 MeV). The total dose planned was70-74
included a complete history and physical examination, endoscopy
Gy to the primary tumourand the involved lymph nodesin daily
and biopsy, complete blood count determination, liver and renal
fractions of 2 Gy, 5 d/wk. Patients received IV cisplatin at 40
function tests, chest X-ray, abdominal ultrasonography, CT-scan
mg/m2 weekly during the entire duration of a 7 weeks course of
of the nasopharynx and neck region, and bone scintigraphy.
external RT. The complete blood picture and biochemistry were
Patients underwent clinically staging according to the 2002 TNM
checked weekly before CT was administered. The number of
staging system.T3-T4 locally advanced tumors and N2-N3 nodal
cycles of cisplatin that could be given depending on the patient’s
status rates were 67 and 46%, respectively. All 33 patients had the
tolerance.
undifferentiated (WHO Type III) variant of NPC (Table 1).

Patient evaluation and follow-up: Acute RT-related toxicities were

Table 1. Patient characteristics documented according to the Radiation Therapy Oncology Group

Characteristics No. of patients Percentage (%) guidelines [23] and CT-related toxicities by the WHO criteria [24].

Age At each follow-up visit, a complete physical examination

(including endoscopy if required) was performed. A post-therapy

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CT scan or MRI of head and neck was obtained for all patients at 3

months after treatment. Table 2. Acute toxicities

Acute toxicities Grade 1-2 Grade 3 (%) Grade 4

Statistical methods: Study endpoints include acute toxicities,
(%) (%)
overall survival (OS), disease-free survival (DFS), loco-regional
Mucositis 26 (79%) 5 (15%) 1 (3%)
relapse-free survival (LRRFS) and metastasis relapse-free survival
Skin reaction 25 (76%) 4 (12%) 2 (6%)
(MRFS). All survivals were calculated from the date of
Dysphagia 16 (48%) 1 (3%) -
histologically confirmed diagnosis to the date of the observed
Vomiting 21 (64%) 4 (12%) -
endpoints or to the date of the last follow-up. Survival endpoints
Leukopenia 13 (39%) 2 (6%) -
were analyzed using the Kaplan-Meier method. Univariateanalyse
Anemia 6 (18%) 1 (3%) -
was performed for evaluation of the prognostic factors. The Log-
Thrombocytopenia 1 (3%) - -
rank test was used to compare the curves and p-values < 0.05 were
Renal impairment 4 (12%)
considered to be statistically significant.

RESULTS
Table 3. Compliancetotreatment
Toxicity and Compliance: The acute toxicities were all reversible
Cycles of cisplatin No. of patients Percentage (%)
and acceptable. The major side effects were mucositis (97%), skin
≤ 5 cycles 19 58
reaction (94%), nausea and vomiting (76%), dysphagia (51%), and
> 5 cycles 14 42
leukopenia (45%). Most of these side effects were Grade 1-2.

Severemucositis and skin reaction (Grade 3-4) were seen in 6

Events and survival: After a median follow-up of 58 months
patients (18%). RT interruption for a week occurred in 1 case
(range, 3-94 months), 6 patients (18%) developed loco-regional
because of a Grade 3 dysphagia. Renal function impairment was
relapse associated with distant metastasis in 4 cases (12%), and 6
found in 4 cases (12%). All the 33 patients included in this study
patients (18%) developed distant metastases alone. Five-year
finished their planned RT. The median number of cycle of
overall survival (OS), disease-free survival (DFS), loco-regional
cisplatin administrated was 5 cycles (range, 2-7 cycles). Four-teen
relapse-free survival (LRRFS) and metastasis relapse-free survival
patients (42%) received more than 5 cycles of cisplatin.
(MRFS) rates were 70, 63, 80, and 68%, respectively (Fig. 1).
Fourpatients (12%) refused to complete the concurrent CT, while 5

other patients (15%) did not receive the planned cycles of CT

because of renal and/or hematologic toxicities (Tables 2 and 3).

Figure 1. Overall survival (OS), Disease-Free Survival (DFS), Loco-regional Relapse-free Survival (LRRFS) and Metastasis Relapse-Free Survival (MRFS).

Prognostic factors: On univariate analysis, the age >40 years, significant pejorative impact on OS(Table 4 and Fig.2). On the

Stage T4, Stage N3, and cycles of CT ≤ 5 had a statistically other hand, Stage T4 had a statistically significant influence on

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LRRFS, Stage N3had a statistically significant influence on MRFS significantly better DFSand MRFS than those who received less

and patients who received more than 5 cycles of cisplatin had than or equal to 5 cycles of CT.

Table 4. Prognostic factors for clinical outcome.

OS DFS LRRFS MRFS

Prognosticfactors 5-y (%) p 5-y (%) p 5-y (%) P 5-y (%) P

Age 0.018 0.003 0.046 0.002

≤ 40 years 88 88 94 94

> 40 years 50 44 65 37

T stage 0.026 0.085 0.005 0.619

T0T1T2a 80 80 100 80

T2bT3 81 70 90 70

T4 28 29 34 57

N stage 0.028 0.03 0.491 0.018

N0N1 82 74 88 79

N2 67 58 73 67

N3 25 25 67 25

Cycles of cysplatin

> 5 cycles 87 0.033 87 0.007 87 0.31 87 0.002

≤ 5 cycles 53 39 72 49

Figure 2. Overall survival (OS) stratified by prognostic factors: Age, T stage, N stage, and cycles of CT.

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DISCUSSION improve overall survival (OS), especially in the T3 to T4

NPC is highly radiosensitive andchemosensitive, and an excellent subgroup(For the CCRT arm, the 5-year OS and PFS rates were

disease control can be achieved using combined modality 70.3 and 60.2%, respectively). In terms of toxicity and compliance

chemoradiation even in patients with locally advanced disease [25]. to CT, the systemic and local toxicities were generally acceptable,

The American Intergroup 0099 study, using both concurrent 60% of patients completed at least 5 cycles of concurrent cisplatin,

cisplatin and RT followed by ACT with cisplatin and fluorouracil and only 44% completed the planned 6 cycles of concurrent

(FU) was the first randomized trial to show a survival benefit with cisplatin during RT [10]. Kim and al have retrospectively reviewed

CCRT.Its outcome established the treatment standard in the United their experience of both weekly and 3-weekly regimens. They

States as standard of care for locally advanced NPC [7].Afterward, have found weekly scheduling practical and feasible for CCRT in

even in Asian countries where NPC is prevalent, the treatment NPC, resulting in decreased interruptions in radiation treatment

efficacy of CCRT with or without ACT was confirmed in many and minimal acute toxic events without compromising local

clinical studies. Since then, we conclude that CCRT with or control [27]. There is a trend for centers in the endemic regions

without ACT is also applicable to patients in endemic areas and opting for the weekly regimen due to the more favorable toxicity

should be standard of practice in locally advanced disease [8-10]. profile and comparable efficacy. For these reasons, we adopted in

The overall magnitude of benefit of CCRT has been previously our study a concurrent weekly cisplatin (40 mg/m2) protocol, all

reported in the Meta-analysis of Chemotherapy in Nasopharyngeal patients had relatively good compliance, and 58% of patients

Carcinoma (MAC-NPC) study [19]. This analysis demonstrated completed at least 5 cycles of concurrent cisplatin. No fatal

that CT led to asignificant benefit in overall survival (OS) and toxicity related to planed treatment was observed. Although a high

progression-free survival (PFS). The effect was most significant incidence of grade 1 or 2 mucositis, vomiting, and leukopenia, our

for the concurrent group. Combined modality treatment using CCRT protocol was more tolerable, with less severe grade 3 to 4

concurrent cisplatin-based CT is thus far the only strategy toxicities than many previous trials.

supported by several large randomized studies to improve survival. Interestingly, 2 retrospective reports revealed that the dose of

Since the publication of this meta-analysis, many clinical trials cisplatin during the CCRT had a significant prognostic impact.

[13-17, and 22] and meta-analyses [20, 21] have clearly They found that the number of cycles of concurrent cisplatin-based

demonstrated that CT administered concurrently with RT as the CT was significantly associated with OS in the stage III subgroup,

most efficacious. The roles of neoadjuvantCT (NACT), and ACT but not in stage IV [28, 29]. A possible explanation for this may be

in OS, and their impact on locoregional control and distant the fact CCRT for these patients with such high-risk disease may

metastases still remain controversial. not be enough to improve their outcome significantly. This will

At present, concurrent CT during the course of RT should be thus warrant further exploration of NACT or ACT as an additional

considered the standard of care. Weekly (30-40 mg/m2) as well as treatment modality of this subset of patients. In our study, patients

3-weekly (100 mg/m2) cisplatin-based regimens are accepted as who received more than 5 cycles of cisplatin during CRT had

standard practice. Toxic effects are considerable with the 3-weekly betterprognosis than those who did not. This is consistent with the

schedule as revealed by the Intergroup study[7] in which only 63% findings of the previous study [28, 29]. Limited by the fact that

of patients having received all three 3-weekly-courses of these were retrospective analyses, the causal relationship between

concurrent 100mg/m2 cisplatin. In the phase III randomized trial cycles of cisplatin and improvement in OS is not clearly defined.

from Hong Kong, low-dose cisplatin (40 mg/m2) given in a However, until further confirmatory studies are available, these

weekly cycle during the entire course of RT has been shown to results should at least enable us to advise our patients that

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compliance to CT during CCRT may influence prognosis. advanced NPC.They found that NACT followed by CCRT was

Despite patients included in our retrospective study did not receive well tolerated but could not significantly improve prognosis in

ACTfollowing CCRT, a 5-year OS rate of 70% a 5-year DFS rate terms of overall survival, loco-regional failure-free survival or

of 63% were obtained. These results are in line with published data distant metastasis failure-free survival [36]. Perhaps, this might be

[7-10] and highlight the need of further phase III trials to assess related with the fact that NACTdelayed the time of RT.

the role of ACT following CCRT.Recently, Chen and al have While results of numerous randomized clinical trials have

published the findings of their randomized phase III trial of CCRT confirmed efficacy of CCRT over RT alone for loco-regionally

and ACT versus CCRT alone involving over 500 patients with advanced NPC, the question arises as to whether the CCRT has an

non-metastatic stage III-IV NPC. At a median follow-up for 38 impact on the outcome of early stage disease. Chen and colleagues

months, there was no significant difference in the estimated 2-year published their randomized phase III prospective study of stage II

failure free survival rate in the CCRT and ACT versus the CCRT NPC patients. Patients were randomized to either conventional RT

alone arms. In terms of toxicity, 42% of the 205 patients on the alone (n = 114) or CCRT (n = 116) with concurrent weekly

ACT arm experienced grade 3-4 toxicities during ACT, with 17% cisplatin at 30 mg/m2. At a median follow-up at 60 months, the

of patients having experienced significant hematological addition of CT statistically improved the 5-year OS rate (94.5 vs

toxicities[30].A recent meta-analysis hasshown similar 85.8%, p= 0.007), PFS (88 vs 79%, p=0.017, and MRFS (95 vs

findings[31].One possible way to select better patients suitable for 84%, p=0.007). Surprisingly, there was no statistically significant

an adjuvant approach may be assessment of plasma EBV DNA difference in the 5-year LRRFS rate (93 vs 91.1%, p= 0.29) [37].

levels. An early post-CCRT detection of high EBV DNA levels The intensity-modulated radiotherapy (IMRT) is widely employed

may be an indication to administer ACT. Chan and al are as an alternative to conventional RT in NPC patients with stage I-

conducting a clinical trial with the use of post-RT EBV DNA to II disease, but its role in association with CT is still unknown.

select high-risk patients to be randomized to receive ACT versus Thamet al evaluated the treatment outcome of 107 patients with

observation. This study is ongoing and results expected in the stage IIB NPC after IMRTwith or without CT. They found that

coming 2 years [32]. IMRT without concurrent CT provides good treatment outcome

Lin and al pointed out that CCRT was inadequate for high-risk with acceptable toxicityand without significant difference in

patients (nodal size >6 cm, supraclavicular node metastases, 1992 patients treated with CT [38].As there are no published prospective

AJCC stage T4N2, and multiple neck node metastases with 1 data on the impact of CCRT in stage II NPC patients treated with

node >4 cm) with similar 5-year OS compared to RT alone (55.8% IMRT, a defining conclusion of CCRT in the IMRT-era for early

vs. 46.3%, p= 0.176) [33]. One strategy to further improve the stage NPC patients cannot be drawn. The practice of CCRT in

efficacy of CT for high-risk NPC patients is to use more stage II disease is acceptable as long as a balance is taken with the

aggressive treatment with NACT in addition to CCRT. Induction associated short and long-term toxicities of concurrent CT.In

CT is generally better tolerated than ACT and might provide early anothertrial, 868 non-metastatic NPC patients treated by IMRT

eradication of distant micro-metastases. In addition, NAC could were analyzed retrospectively. With a median follow-up of 50

shrink the primary tumor to give wider margins for irradiation. A months, the 5-year estimated disease specific survival (DSS), local

several phase II clinical studies, using intensive NACT followed recurrence-free survival (LRFS), regional recurrence-free survival

by CCRT, have shown encouraging toxicity profiles and disease (RRFS) and distant metastasis-free survival (DMFS) were 84.7%,

control [34, 35].Liang and al have published the first meta- 91.8%, 96.4% and 84.6%, respectively. The toxicity profile was

analysisto evaluate the efficacy and toxicity of the NACT followed very low. Concurrent chemotherapy failed to improve survival

by CCRT versus CCRT with or without AC for loco-regionally rates for patients with advanced locoregional disease and increased

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the severity of acute toxicities [39]. alone for advanced nasopharyngeal carcinoma: positive effect on

overall and progression-free survival. J ClinOncol. 2003;2:631-7.

CONCLUSION 9. Kwong DL, Sham JS, Au GK, Chua DT, Kwong PW, Cheng

Our study confirms that weekly cisplatin concurrent with RT for AC, Wu PM, Law MW, Kwok CC, Yau CC, Wan KY, Chan RT,

locally advanced nasopharyngeal cancers was found tolerable with Choy DD.Concurrent and adjuvant chemotherapy for

a high efficiency and provides further evidence on the prognostic nasopharyngeal carcinoma: a factorial study. J ClinOncol.

significance of CT dosing during the concurrent phase with RT. 2004;22:2643-53.

10. Chan AT, Leung SF, Ngan RK, Teo PM, Lau WH, Kwan WH,

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JNPC ★ http://www.journalofnasopharyngealcarcinoma.org/ e-ISSN 2312-0398 Published:2015-03-23 ★ DOI:10.15383/jnpc.21