Introduction
Definitive radiotherapy (RT) is the cornerstone of treatment
for early-stage nasopharyngeal carcinoma (NPC),
offering excellent local control and favorable survival
rates, with current guidelines specifically recommending
RT alone for stage I disease.[] By contrast, the survival
benefit of adding induction and concurrent chemotherapy
(CHT) to RT for patients with stage III-IV
NPC has been well-documented for over two decades.
[,] Yet, in stage II NPC, the role of CHT remains uncertain
and a topic of ongoing research, even in the current era of advanced cancer care. Limited evidence in
the literature supports a distinct clinical benefit of adding
CHT to RT in stage II NPC, prompting concerns
about the potential for overtreatment and added toxicity.[] To address these gaps in knowledge, the present
study investigates clinical outcomes in patients with
stage II NPC treated with either RT alone or combined
RT and CHT in a comprehensive cancer center.
Methods
Study Population
A retrospective cohort analysis was conducted on
patients diagnosed with NPC who underwent definitive
RT ± CHT at our institution from 1994 to 2021.
Clinical and pathological data, including demographic
and tumor characteristics, staging, treatment modality,
and follow-up outcomes, were systematically extracted
from individual patient records and the institution"s
electronic medical records system. Staging was
uniformly assigned according to the 8th edition of the
American Joint Committee on Cancer (AJCC) classification
system. The study cohort was limited to patients
classified as AJCC 8th stage II disease (T1N1M0,
T2N0M0, T2N1M0). Exclusion criteria included patients
with incomplete follow-up data after definitive
treatment. This study was conducted in accordance
with the declaration of Helsinki and was approved by
the by the Ethics Committee of Hacettepe University
Health Sciences (No: SBA 24/118, Date 23/01/2024).
Treatment
RT was administered using one of two techniques, depending
on the available technology at the time of
treatment: two-dimensional radiotherapy (2DRT) or
intensity-modulated radiotherapy (IMRT). None of the
patients included in the study were treated with threedimensional
conformal radiotherapy (3DCRT). Early in
the treatment period, 2DRT was commonly employed;
however, IMRT gradually became the preferred method
in recent years. The choice of CHT administration was
determined at the discretion of the treating physician
and both induction and concurrent CHT regimens also
evolved over time, reflecting advancements in treatment
protocols and improved understanding of optimal dosing
strategies. In more recent cases, cisplatin became the
standard concurrent CHT regimen, administered either
as a weekly dose of 40 mg/m² or a higher dose of 100 mg/
m² every three weeks. Induction CHT typically consisted
of three cycles, including docetaxel (75 mg/m²), cisplatin
(75 mg/m²), and fluorouracil (750-1000 mg/m²).
Toxicity and Follow-up
Toxicity was evaluated in patients with available data
using the Common Terminology Criteria for Adverse
Events (CTCAE), version 5.0. Post-treatment followup
was scheduled at 3-month intervals for the first 2
years, followed by 6-month intervals for the next 3
years, and annually thereafter. At each follow-up visit,
patients underwent routine physical examinations and
magnetic resonance imaging of the nasopharynx and
neck to monitor for recurrence and assess late treatment-
related toxicities.
Statistical Analysis
All statistical analysis, including descriptive statistics,
overall survival (OS), locoregional recurrence-free
survival (LRRFS), and distant metastasis-free survival
(DMFS), were performed using the Statistical Package
for the Social Sciences (SPSS), version 25.0 (IBM,
Armonk, NY, USA). The follow-up period was measured
from the initiation of RT. OS was defined as the
time from RT initiation to death from any cause, while
LRRFS and DMFS were defined as the time from RT
initiation to either locoregional recurrence (LRR) or
distant metastasis (DM), respectively, or death. The
variables between the RT alone and combined RT
and CHT groups were analyzed using independent
samples t-test, Mann-Whitney U test, or Chi-square
test, depending on whether they were numerical or
categorical, and based on their distribution characteristics,
including normality. Survival outcomes were
analyzed using the Kaplan-Meier method, with comparisons
made via the log-rank test. Univariate analysis
(UVA) was employed to assess potential prognostic
factors, with a significance threshold of p<0.05.
Variables with a potential significance level (p<0.1) in
UVA were included in the multivariate Cox proportional
hazards model (MVA), with hazard ratios (HR)
and 95% confidence intervals (CI) reported.
Results
Patient, Tumor and Treatment Characteristics
Baseline patient, tumor, and treatment characteristics
are summarized in Table 1. The median age of the
patients was 50 years (Range: 17-74), with a cohort
consisting of 71 males (66%) and 36 females (34%).
TNM classifications, as per the AJCC 8th staging system,
are shown in Figure 1. The most common tumor
histology was non-keratinizing undifferentiated carcinoma
(WHO type III, n=58, 54%), followed by nonkeratinizing
differentiated carcinoma (WHO type II, n=43, 40%) and keratinizing squamous cell carcinoma
(WHO type I, n=6, 7%). In terms of treatment,
74 patients (69%) received a combination of RT and
CHT, while 33 patients (31%) were treated with RT
alone. Among those receiving concurrent CHT with
RT, cisplatin alone was administered in 81% of cases.
For patients receiving induction CHT before RT or
concurrent chemoradiotherapy, the median number
of cycles was three (Range: 1-3 cycles). Baseline
characteristics were generally similar between the RT
alone and RT + CHT groups, with two notable differences:
the RT + CHT group had a significantly higher
proportion of patients with lymph node (LN) metastasis
(88% vs. 70%, p=0.03) and a greater use of the
IMRT technique (46% vs. 6%, p=0.01) compared to
the RT alone group (Fig. 2).
Fig. 1. American Joint Committee on Cancer 8th edition
TNM classifications of the patients.
TNM: Tumor, node, metastasis.
Table 1: Patient, tumor and treatment characteristics
Fig. 2. Kaplan-Meier survival curve illustrating overall
survival stratified by treatment.
RT: Radiotherapy; CHT: Chemotherapy.
Recurrence Patterns and Survival Outcomes
The median follow-up duration for this cohort was 98
months (Range: 11-381 months), with 69 out of 107
patients (64%) having a follow-up period exceeding five
years. The overall LRR rate was 15%, with 9 cases (8%) of isolated LR, 2 cases (2%) of isolated LN recurrence,
and 5 cases (5%) of both local and LN recurrence. DM
were observed in 14 patients (13%), with the most frequent
metastatic sites being bone (n=9), lungs (n=9),
liver (n=5), and brain (n=2). The 10-year OS, LRRFS
and DMFS rates were 69%, 68%, and 67%, respectively.
Prognostic Factors
Figure 3 illustrates the incidence rates of LRR and
DM in patients treated with RT alone compared to
those receiving combined RT and CHT. The rates of
LRR (18% vs. 18%, p=0.564) and DM (14% vs. 11%,
p=0.355) did not show a statistically significant difference
between the RT alone and combined RT and
CHT groups. The UVA of survival outcomes, summarized
in Table 2, identified age as a significant factor
for OS, with younger patients (≤50 years) achieving
a higher 10-year OS rate (76% vs. 59%, p=0.04)
compared to those over 50. Gender also had a notable
impact, female patients demonstrated improved
10-year OS (78% vs. 64%, p=0.04), LRRFS (78% vs.
63%, p=0.009), and DMFS (78% vs. 61%, p=0.01) compared to male patients. The 10-year OS, LRRFS
and DMFS rates were 73%, 71% and 71% for patients
who received induction CHT, 74%, 73% and 70% for
those who received only concurrent CHT, and 61%,
57% and 57% for those treated with RT alone (p=0.72,
p=0.51 and p=0.54, respectively). The combination
of RT and CHT provided no additional oncological
benefit across subgroups, including those treated
with 2DRT technique (Fig. 4a) or patients with LN
metastasis (Fig. 4b), compared to RT alone. In MVA,
age emerged as the sole independent predictor of OS
(HR: 1.4, 95% CI: 1.2-5.8, p=0.04), while female gender
was the only independent predictor for both LRRFS
(HR: 1.3, 95% CI: 1.1-2.8, p=0.02) and DMFS
(HR: 1.3, 95% CI: 0.5-3.8, p=0.01).
Fig. 3. The rates of locoregional recurrence and distant
metastasis stratified by treatment.
LRR: Locoregional recurrence; DM: Distant metastasis.
Table 2: Univariate analysis for overall, locoregional recurrence-free and distant metastasisfree
survival rates
Fig. 4. Kaplan-Meier survival curves illustrating overall survival stratified by treatment for patients who received twodimensional
radiotherapy (a) and those with lymph node metastasis (b).
RT: Radiotherapy; CHT: Chemotherapy.
Toxicity
Data on acute toxicity were incomplete for most patients
due to the retrospective design of the study and
thus were excluded from the analysis. Among late toxicities
of grade 3 or higher, xerostomia was the most
prevalent, affecting 21 patients (20%), followed by
hearing loss in six patients (6%), trismus in two patients
(2%), osteoradionecrosis in two patients (2%),
brain necrosis in one patient (1%), and optic neuropathy
in one patient (1%). No statistically significant difference
was observed in the incidence of severe late
toxicities between the RT alone and combined RT +
CHT groups (33% vs. 29%, p=0.75).
Discussion
In this 27-year, single-center retrospective study, the
incorporation of either induction or concurrent CHT
alongside definitive RT demonstrated no significant
effect on preventing recurrence or improving survival
rates in patients with stage II NPC as classified by the
AJCC 8th edition.
While definitive RT alone provides excellent local
control for early stage NPC, the addition of induction
and concurrent CHT significantly improves oncological outcomes in more advanced stages.[,] However, for
stage II disease, the optimal treatment strategy is still a
topic of debate. When examining the historical progression
of this debate, several small retrospective studies
from past decades, utilizing older RT techniques, suggested
that the addition of concurrent CHT to RT in
stage II NPC improved oncological outcomes.[,] In
the only prospective randomized phase III trial available
on this subject, Chen et al.[] evaluated 230 patients with
stage II NPC. Their findings demonstrated that a notable
improvement in 5-year OS, showing an 8.7% increase
in patients who received concurrent CHT compared
to those treated with RT alone. Although concurrent
CHT significantly increased the rates of acute toxicity,
late toxicity rates remained comparable between groups.
Moreover, the 10-year results of the study confirmed
that the OS benefit from concurrent CHT persisted,
compared to RT alone.[] However, it is important to
critically assess the study"s methodology, as it utilized
the 2DRT technique for all patients and relied on the
outdated 1992 Chinese staging system, potentially limiting
the generalizability of its findings in the modern era.
In contrast, our study demonstrated that even when the
71 patients treated with 2DRT technique were analyzed
separately, the combination of RT and CHT did not
yield a statistically significant improvement in survival
outcomes for stage II NPC patients classified according
to the AJCC 8th edition, compared to RT alone.
Advances in RT technologies have led to improved
outcomes for patients with NPC and studies have
shown that patients treated with IMRT experience
significantly better local control and progression-free
survival (PFS) compared to those treated with older
techniques, highlighting the superiority of modern
techniques of RT in enhancing both disease control
and survival.[-] Thus, with advancements in technology
and a more interconnected world, the critical
question now becomes whether concurrent CHT will
continue to offer benefits for stage II NPC patients who
are treated with IMRT technique. A 2018 systematic review
and meta-analysis, incorporating six retrospective
and one prospective randomized study, revealed that
the addition of concurrent CHT to treatment in stage
II NPC patients during the IMRT era did not enhance
LRRFS, DMFS, PFS or OS.[] Furthermore, it significantly
increased the rates of severe acute hematologic
toxicities, highlighting the potential risks without clear
survival benefits in this context. In another meta-analysis,
also published in 2018, incorporating 16 studies
with a total of 3,038 stage II NPC patients, it was found
that concurrent CHT improved OS in the entire cohort. [] However, when focusing solely on patients treated
with IMRT, the analysis revealed that adding CHT did
not result in better oncological outcomes compared to
RT alone, suggesting that the benefit of CHT may not
extend to those receiving modern RT techniques. In a
randomized phase II trial published in 2020, 84 patients
with stage II NPC treated with IMRT were analyzed.
[] The study concluded that adding concurrent CHT
did not improve survival outcomes but was associated
with an increase in hematologic toxicity. Beyond concurrent
CHT, the role of induction CHT has also been
examined in numerous retrospective studies for stage
II NPC.[] For instance, in a retrospective study by
Fangzheng et al.,[] no significant differences in survival
parameters were observed among 37 patients treated
with IMRT alone, 25 patients treated with concurrent
CHT and IMRT, and 180 patients who received induction
CHT followed by either IMRT alone or concurrent
CHT and IMRT. Furthermore, in a subgroup analysis
of 137 patients with T2N1M0 disease, they found that
IMRT alone yielded similar oncological outcomes compared
to IMRT combined with either concurrent and/
or induction CHT. Similarly, in our study, induction
CHT did not show any oncological benefit for stage II
NPC patients, as classified by the AJCC 8th staging system,
in any subgroup, including those with node-positive
disease or those treated with the 2DRT technique.
Although current literature suggests that combining
CHT with IMRT may lead to overtreatment in stage II
NPC, the heterogeneity within this patient population
underscores the importance of individualized treatment
approaches. Certain patients may still derive
significant benefit from concurrent CHT, particularly
those with high-risk features. Tang et al.[] conducted
a randomized study targeting a lower-risk subgroup of
NPC patients, specifically those with stage II/T3N0M0
disease and favorable clinical characteristics, defined as
LNs smaller than 3 cm, no involvement of level IV/Vb
nodes, absence of extranodal extension, and Epstein-
Barr virus DNA levels below 4000 copies/mL.[-]
By excluding higher-risk patients, the study aimed to
evaluate treatment outcomes within a more homogeneous,
lower-risk cohort and demonstrated that
IMRT alone yields survival rates comparable to those
achieved with concurrent IMRT and CHT. However,
while no studies have specifically addressed patients
with unfavorable clinical features, combining RT with
CHT may still provide therapeutic benefits in high-risk
populations, highlighting the need for focused research
targeting these subgroups. Although LN metastasis is a
key high-risk feature, a 2023 meta-analysis found that adding concurrent CHT to IMRT in stage II NPC did
not significantly improve survival outcomes, even in
patients with LN involvement.[] Similarly, in our
study, a subgroup analysis of patients with LN metastasis
showed no additional survival benefit from the inclusion
of induction or concurrent CHT. However, the
10-year survival rates were marginally lower in patients
with LN metastasis, indicating that node-positive patients
may be appropriate candidates for future studies
exploring intensified treatment approaches.
In the era of advanced medical technology, integrating
sophisticated tools with clinicopathological
features offers significant potential for refining risk
stratification in stage II NPC. Liang et al.[] conducted
a retrospective analysis of 999 stage II NPC patients
and developed a prognostic model that combines deep
learning-derived MRI features with clinical data to
stratify patients into distinct risk categories. Their findings
revealed that low-risk patients achieved satisfactory
PFS rates with IMRT alone, while high-risk patients
experienced substantial therapeutic benefits from the
addition of concurrent CHT. Despite these promising
advancements, the identification of factors to better
determine which patients may benefit from combining
CHT with RT remains an area requiring further exploration.
Additionally, high-quality evidence supporting
reliable and practical approaches for guiding treatment
decisions in this heterogeneous population is still lacking,
underscoring the need for continued research.
Limitations of the Study
Although our study included a homogeneous patient
population uniformly diagnosed with stage II NPC
according to the AJCC 8th staging system, it has several
limitations. The retrospective design of the study
introduces selection bias, and the small sample size
may have reduced the statistical power needed to detect
subtle differences between treatment groups. For
instance, the higher rate of LN metastasis in the combined
RT and CHT group may have masked potential
benefits of CHT. On the other hand, as 94% of patients
in the RT alone group were treated with 2DRT technique,
this may have negatively impacted survival rates
in the RT alone group. The absence of Epstein-Barr
virus DNA data, a now-recognized key prognostic
marker, further restricted our ability to conduct subgroup
analyses that could identify patients most likely
to benefit from concurrent CHT. Furthermore, 19% of
patients received non-standard concurrent CHT regimens,
and the cumulative dose data for those treated
with cisplatin were incomplete.
Conclusion
In conclusion, our findings suggest that adding CHT to
RT does not significantly improve survival outcomes in
patients with AJCC 8th edition stage II NPC compared
to RT alone, even among those with LN involvement or
those treated with 2DRT. Avoiding unnecessary CHT
in this population may reduce treatment-related toxicity
and improve overall quality of life. However, stage
II NPC, as classified by the AJCC 8th edition, is a heterogeneous
disease, and certain patients-such as those
with node-positive disease and elevated Epstein-Barr
virus DNA levels-may still benefit from more intensive
treatment. Future research should focus on identifying
these specific subgroups through tumor biology, molecular
profiling, and other key prognostic factors to enable
more personalized and effective treatment strategies.
Ethics Committee Approval: The study was approved by
the Hacettepe University Faculty of Medicine Ethics Committee
(no: SBA 24/118, date: 23/01/2024).
Conflict of Interest: All authors declared no conflict of interest.
Financial Support: None declared.
Use of AI for Writing Assistance: No AI technologies utilized.
Authorship Contributions: Concept - A.K., M.T.Y., S.M.,
S.Y.S., M.C., İ.G., S.A., G.Ö., G.Y.; Design - A.K., M.T.Y., S.M.,
S.Y.S., M.C., G.Ö., G.Y.; Supervision - S.Y.S., M.C., G.Ö., G.Y.;
Funding - S.Y.S., M.C., G.Ö., G.Y.; Materials - A.K., M.T.Y.,
S.M.; Data collection and/or processing - A.K., M.T.Y., S.M.;
Data analysis and/or interpretation - A.K., M.T.Y.; Literature
search - A.K., M.T.Y.; Writing - A.K.; Critical review - A.K.,
M.T.Y., S.M., S.Y.S., M.C., İ.G., S.A., G.Ö., G.Y.
Peer-review: Externally peer-reviewed.
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