Introduction
According to the National Comprehensive Cancer
Network (NCCN) guidelines (1), the
recommended initial treatment for oral squamous cell carcinoma
(OSCC) is surgical resection, followed by postoperative
radiotherapy (RT) or cisplatin-based concomitant chemoradiotherapy
(CCRT) when histopathological examination identifies adverse
pathologic features such as extranodal extension (ENE) involving
the cervical lymph nodes or a positive resection margin of the
primary tumor. Other adverse pathologic features, classified by the
NCCN guidelines as other risk features, include close margins,
pathological (p)T3 or pT4 primary tumors, pN2 or pN3 nodal disease,
nodal disease at levels IV or V, perineural invasion (PNI),
vascular invasion (VI), and lymphatic invasion (LI). When these
features are identified, RT or consideration of CCRT is recommended
as postoperative adjuvant therapy. A multicenter study comprising
Japanese patients with OSCC and high-risk features (positive margin
and ENE) showed that surgery followed by RT alone or high-dose
cisplatin-based CCRT improved overall survival (OS) compared with
surgery alone (2,3). However, evidence regarding the benefit
of postoperative adjuvant therapy in patients with OSCC who present
with other risk features is limited. Regarding late adverse events
of RT, osteoradionecrosis (ORN), which develops in 13.4% of
patients with head and neck cancer (4), is rarely cured with conservative
treatment and impairs oral function and quality of life (QOL).
Therefore, considering QOL and adverse events, categorizing all
patients with other risk features into a single group may not be
appropriate.
Regarding the presence of other risk features,
postoperative adjuvant therapy (RT or CCRT) may have additional
benefits for disease-free survival or OS (5,6).
Conversely, other studies have shown no survival benefit for
postoperative RT in patients with intermediate risk factors
(7,8). A systematic review also revealed no
evidence to support the application of postoperative RT based
solely on histological risk factors (9). Thus, the indications for postoperative
RT in patients with other risk features remain controversial, with
treatment decisions left to the discretion of clinicians.
In the present study, we investigated the clinical
outcome of other risk features in patients with OSCC treated with
standardized therapy to assess whether all patients with other risk
features are appropriate candidates for postoperative adjuvant
therapy. The specific aims of this study were to determine which
other risk features were independently associated with
disease-specific survival (DSS), OS, and recurrence-free survival
(RFS), and to clarify the indications for postoperative adjuvant
therapy based on survival and salvage outcomes.
Materials and methods
Study design
The study population comprised all patients
presenting to the Department of Oral and Maxillofacial Surgery at
Nagasaki University Hospital to undergo management of
histologically confirmed OSCC between April 2001 and March 2024. A
total of 194 patients (108 males and 86 females) were enrolled. The
median age was 70 years (range, 23–93 years). The inclusion
criteria were as follows: i) Patients who underwent primary surgery
with simultaneous radical or elective neck dissection and ii) had a
minimum follow-up of more than 18 months. The exclusion criteria
were i) patients who had received neoadjuvant chemotherapy, RT, or
CCRT, ii) those with a history of previous OSCC, and iii) those
with missing/insufficient information.
Electronic or paper medical records were used to
identify the demographic, tumor, and treatment variables. The final
follow-up was conducted on July 30, 2025. At our institute, the
standard treatment for OSCC is surgery, and patients with positive
margins and/or ENE routinely receive postoperative adjuvant
therapy. In contrast, postoperative adjuvant therapy was not
routinely administered to patients with other risk features. In
these cases, the decision to administer postoperative adjuvant
therapy was made at the physician's discretion after considering
the pathological findings, the patient's general condition,
comorbidities, and overall clinical status. Postoperative RT/CCRT
with a dose of 60–66 Gy and a high dose of cisplatin (100
mg/m2 tri-weekly or 40 mg/m2 weekly) was
administered. Elective neck dissection was not routinely performed;
when indicated, either a supraomohyoid or conventional neck
dissection was performed.
Study variables
Predictor variables
Adverse pathologic features were defined in
accordance with the NCCN clinical practice guidelines as
histological evidence of ENE, positive margins, close margins, pT3
or pT4 primary tumors, pN2 or pN3 nodal disease, nodal disease at
levels IV or V, PNI, VI, and LI (1). ENE and positive margins were
considered high-risk features, while the remaining adverse
pathologic features were classified as other risk features. The
predictor variables comprised these other risk features. In this
study, ENE was defined as complete rupture of the lymph node
capsule; tumor involvement close to the lymph node capsule or the
surrounding adipose tissue was not considered ENE in the absence of
capsular rupture. A positive margin was defined as the presence of
tumor cells at the surgical margin. A close margin was defined as
tumor cells located within 0–5 mm of the surgical margin on
microscopy. Classification of pT and pN was performed according to
the TNM system (8th edition) of the International Union Against
Cancer (10). The American Academy
of Otolaryngology-Head and Neck Surgery criteria were used to
delineate the location of lymph node disease in the neck. PNI, VI,
and LI were determined based on the presence or absence of tumor
cell invasion on microscopy (11).
Patients with one or more other risk features were classified as
patients with other risk (+) features and divided into two groups:
those who underwent surgery alone and those who underwent surgery
followed by postoperative adjuvant therapy. Comparison groups
comprised patients without other risk features and those with
high-risk features.
Outcome variables
The main outcome variables were DSS, OS, and RFS.
The secondary outcome variable was the salvage rate, which was
assessed by comparing the surgery-alone group with the group that
received surgery followed by postoperative adjuvant therapy.
Similarly, local recurrence (LR), regional recurrence (RR), and
distant metastasis (DM) were also assessed. Covariates included
demographic (age, sex, and performance status) and tumor
characteristics (primary site, pT, pN, surgical margin, metastatic
level, PNI, VI, LI, and the number of positive nodes).
Statistical analysis
All statistical analyses were conducted using SPSS
version 29.0 (Japan IBM Co., Tokyo, Japan). Continuous variables
are presented as the median (range) and were compared using the
Kruskal-Wallis test, followed by the Steel-Dwass post hoc test when
the overall comparison was statistically significant. Categorical
variables were compared using Fisher's exact test. Survival
analysis was performed using the Kaplan-Meier method and compared
using the log-rank test. Pairwise comparisons were adjusted using
the Bonferroni correction. Multivariate Cox proportional hazards
regression analyses were performed in the combined cohort of
patients with other risk (+) features and those with high-risk
features, as well as in the subgroup of patients with other risk
(+) features who did not receive postoperative adjuvant therapy.
P<0.05 was considered to indicate a statistically significant
difference.
Results
Patient characteristics and clinical
outcomes
The demographic and clinicopathological
characteristics of patients with other risk (+) features (n=112),
patients without other risk features (n=17), and patients with
high-risk features (n=65) are summarized in Table I. In patients with other risk (+)
features, the mandibular gingiva was the most common site, followed
by the tongue and the floor of the mouth. Nine patients had close
margins, 87 had pT3 or pT4 primary tumors, and 21 had pN2 or pN3
nodal disease. Additionally, one patient had level IV lymph node
metastasis. Fifty patients had PNI, 63 had VI, and 19 had LI. Only
eight patients received postoperative adjuvant therapy. Compared
with patients with other risk (+) features and those without other
risk features, patients with high-risk features showed
significantly worse 5-year DSS, OS, and RFS rates (P<0.001,
P=0.005, and P<0.001, respectively). No significant differences
were observed between patients with other risk (+) features and
those without other risk features (P=0.65, P=1.0, and P=0.24,
respectively) (Fig. 1A-C).
Multivariate Cox proportional hazards regression analysis comparing
patients with other risk (+) features and those with high-risk
features showed that high-risk status was an independent prognostic
factor for DSS, OS, and RFS (Table
II).
 | Table I.Patient characteristics. |
Table I.
Patient characteristics.
| Variable | Total (n=194) | Other risk (+)
(n=112) | Other risk (−)
(n=17) | High-risk (n=65) | P-value |
|---|
| Sex, n (%) |
|
|
|
| 0.3 |
| Male | 108 (55.7) | 61 (54.5) | 7 (41.2) | 40 (61.5) |
|
|
Female | 86 (44.3) | 51 (45.5) | 10 (58.8) | 25 (38.5) |
|
| Median age, years
(range) | 70 (23–93) | 70 (23–93) | 77 (39–88) | 68 (32–91) | 0.4 |
| ECOG PS, n (%) |
|
|
|
| 0.4 |
| 0 and
1 | 171 (88.1) | 96 (85.7) | 16 (94.1) | 59 (90.8) |
|
| 2 and
3 | 23 (11.9) | 16 (14.3) | 1 (5.9) | 6 (9.1) |
|
| Primary site, n
(%) |
|
|
|
| 0.4 |
|
Tongue | 51 (26.3) | 26 (23.2) | 3 (17.6) | 22 (33.8) |
|
|
Mandibular gingiva | 76 (39.2) | 50 (44.6) | 5 (29.4) | 21 (32.3) |
|
| Maxillary
gingiva | 20 (10.3) | 9 (8.0) | 1 (5.9) | 10 (15.4) |
|
| Floor of
the mouth | 23 (11.9) | 13 (11.6) | 6 (35.3) | 4 (6.2) |
|
| Buccal
mucosa | 13 (6.7) | 7 (6.3) | 1 (5.9) | 5 (7.7) |
|
| Hard
palate | 2 (1.0) | 1 (0.9) | 0 (0) | 1 (1.5) |
|
| Lip | 1 (0.5) | 0 (0) | 1 (5.9) | 0 (0) |
|
|
Intraosseous | 8 (4.1) | 6 (5.4) | 0 (0) | 2 (3.1) |
|
| Surgical margin, n
(%) |
|
|
|
|
<0.001a |
|
Clear | 153 (78.9) | 103 (92.0) | 17 (100) | 33 (50.7) |
|
|
Close | 13 (6.7) | 9 (8.0) | 0 (0) | 4 (6.2) |
|
|
Positive | 28 (14.4) | 0 (0) | 0 (0) | 28 (43.1) |
|
| pT stage, n (%) |
|
|
|
|
<0.001a |
| T1 | 17 (8.8) | 6 (5.4) | 8 (47.1) | 3 (4.6) |
|
| T2 | 35 (18.0) | 19 (17.0) | 9 (52.9) | 7 (10.8) |
|
| T3 | 37 (19.1) | 26 (23.2) | 0 (0) | 11 (16.9) |
|
|
T4a | 102 (52.6) | 60 (53.5) | 0 (0) | 42 (64.6) |
|
|
T4b | 3 (1.5) | 1 (0.9) | 0 (0) | 2 (3.1) |
|
| pN stage, n
(%) |
|
|
|
|
<0.001a |
| N0 | 94 (48.5) | 69 (61.6) | 12 (70.6) | 13 (20.0) |
|
| N1 | 31 (16.0) | 22 (19.6) | 5 (29.4) | 4 (6.2) |
|
|
N2a | 9 (4.6) | 1 (0.9) | 0 (0) | 8 (12.3) |
|
|
N2b | 22 (11.3) | 20 (17.9) | 0 (0) | 2 (3.1) |
|
|
N2c | 1 (0.5) | 0 (0) | 0 (0) | 1 (1.5) |
|
|
N3b | 37 (19.1) | 0 (0) | 0 (0) | 37 (56.9) |
|
| Metastasis level, n
(%) |
|
|
|
|
<0.001a |
|
None | 93 (47.9) | 68 (60.7) | 12 (70.6) | 13 (20.0) |
|
| Level
1/2/3 | 94 (48.5) | 43 (38.4) | 5 (29.4) | 46 (70.8) |
|
| Level
4/5 | 7 (3.6) | 1 (0.9) | 0 (0) | 6 (9.2) |
|
| Perineural
invasion, n (%) |
|
|
|
|
<0.001a |
|
(−) | 102 (52.6) | 62 (55.4) | 17 (100) | 23 (35.4) |
|
|
(+) | 92 (47.4) | 50 (44.6) | 0 (0) | 42 (64.6) |
|
| Vascular invasion,
n (%) |
|
|
|
|
<0.001a |
|
(−) | 86 (44.3) | 49 (43.8) | 17 (100) | 20 (30.8) |
|
|
(+) | 108 (55.7) | 63 (56.2) | 0 (0) | 45 (69.2) |
|
| Lymphatic invasion,
n (%) |
|
|
|
| 0.001a |
|
(−) | 152 (78.4) | 93 (83.0) | 17 (100) | 42 (64.6) |
|
|
(+) | 42 (21.6) | 19 (17.0) | 0 (0) | 23 (35.4) |
|
| Adjuvant therapy, n
(%) |
|
|
|
|
<0.001a |
|
(−) | 152 (78.4) | 104 (92.9) | 17 (100) | 31 (47.7) |
|
|
(+) | 42 (21.6) | 8 (7.1) | 0 (0) | 34 (52.3) |
|
| Differentiation, n
(%) |
|
|
|
| 0.6 |
|
Well | 156 (80.4) | 90 (80.4) | 15 (88.2) | 51 (78.5) |
|
|
Moderately | 28 (14.5) | 16 (14.3) | 2 (11.8) | 10 (15.4) |
|
|
Poorly | 7 (3.6) | 3 (1.5) | 0 (0) | 4 (6.1) |
|
|
Others | 3 (1.5) | 3 (1.5) | 0 (0) | 0 (0) |
|
| Number of positive
lymph nodes, median (range) | 1 (0–12) | 0 (0–5) | 0 (0–1) | 2 (0–12) |
<0.001a |
| ENE (patients with
pN+), n (%) |
|
|
|
|
<0.001a |
|
(−) | 69 (60.5) | 44 (100) | 5 (100) | 20 (30.8) |
|
|
(+) | 45 (39.5) | 0 (0) | 0 (0) | 45 (69.2) |
|
| Table II.Multivariate Cox regression analyses
of OS, DSS and RFS in patients with other risk (+) features and
high-risk features. |
Table II.
Multivariate Cox regression analyses
of OS, DSS and RFS in patients with other risk (+) features and
high-risk features.
|
| OS | DSS | RFS |
|---|
|
|
|
|
|
|---|
| Variable | P-value | HR | 95% CI | P-value | HR | 95% CI | P-value | HR | 95% CI |
|---|
| Sex |
|
|
|
|
|
|
|
|
|
| Female
vs. male | 0.1 | 1.5 | 0.9–2.5 | 0.2 | 1.5 | 0.8–2.7 | 0.09 | 1.5 | 0.9–2.4 |
| Age, years |
|
|
|
|
|
|
|
|
|
| <70
vs. ≥70 | 0.004 | 2.2 | 1.3–3.8 | 0.07 | 1.8 | 0.96–3.3 | 0.09 | 1.5 | 0.9–2.5 |
| ECOG PS |
|
|
|
|
|
|
|
|
|
| 0-1 vs.
2–3 | 0.045 | 2.1 | 1.01–4.2 | 0.09 | 2.1 | 0.9–4.8 | 0.75 | 1.1 | 0.5–2.4 |
| Primary site |
|
|
|
|
|
|
|
|
|
| Other
site vs. tongue | 0.2 | 1.5 | 0.8–2.6 | 0.4 | 1.3 | 0.7–2.5 | 0.07 | 1.6 | 0.96–2.6 |
| Group |
|
|
|
|
|
|
|
|
|
| Other
risk (+) vs. high-risk | <0.001 | 2.3 | 1.4–3.6 | <0.001 | 3 | 1.7–5.3 | <0.001 | 2.2 | 1.4–3.5 |
Characteristics of patients with other risk (+)
features are presented in Table
III. Patients who underwent surgery followed by postoperative
adjuvant therapy (n=8) had significantly younger age, pN2 or pN3
nodal disease, LI, and a higher number of metastatic lymph nodes
than those who underwent surgery alone (n=104). No other
significant factors were found to influence decisions regarding
postoperative adjuvant therapy. Clinical outcomes of LR, RR, and DM
were not significantly different between the two subgroups. Of the
36 patients who underwent surgery alone and experienced recurrence,
23 underwent salvage surgery. In comparison, two of four patients
who underwent surgery followed by postoperative adjuvant therapy
and then experienced recurrence underwent salvage surgery. The
salvage rates were 41.7 and 25%, respectively. The two subgroups
showed no significant difference (Table IV).
| Table III.Association between postoperative
adjuvant therapy and clinicopathological variables. |
Table III.
Association between postoperative
adjuvant therapy and clinicopathological variables.
|
| Other risk (+)
(n=112) |
|---|
|
|
|
|---|
| Variable | Surgery-only
(n=104) | Surgery + adjuvant
(n=8) | P-value |
|---|
| Sex, n (%) |
|
| 1 |
|
Female | 47 (45.2) | 4 (50.0) |
|
|
Male | 57 (54.8) | 4 (50.0) |
|
| Median age, years
(range) | 70 (23–93) | 61.5 (40–76) | 0.047a |
| ECOG PS, n (%) |
|
| 0.6 |
| 0 and
1 | 88 (84.6) | 8 (100) |
|
| 2 and
3 | 16 (15.4) | 0 (0) |
|
| Primary site, n
(%) |
|
| 0.08 |
|
Tongue | 22 (21.2) | 4 (50.0) |
|
|
Others | 82 (79.8) | 4 (50.0) |
|
| Surgical margin, n
(%) |
|
| 0.1 |
|
Clear | 97 (93.3) | 6 (75.0) |
|
|
Close | 7 (6.7) | 2 (25.0) |
|
| pT stage, n
(%) |
|
| 1 |
| 1 and
2 | 27 (26.0) | 2 (25.0) |
|
| 3 and
4 | 77 (74.0) | 6 (75.0) |
|
| pN stage, n
(%) |
|
|
<0.001a |
| 0 and
1 | 89 (85.6) | 2 (25.0) |
|
| ≥2 | 15 (14.4) | 6 (75.0) |
|
| Metastasis level, n
(%) |
|
| 1 |
|
I–III | 103 (99.0) | 8 (100) |
|
| IV and
V | 1 (1.0) | 0 (0) |
|
| Perineural
invasion, n (%) |
|
| 0.5 |
|
(−) | 59 (56.7) | 3 (37.5) |
|
|
(+) | 45 (43.3) | 5 (62.5) |
|
| Vascular invasion,
n (%) |
|
| 1 |
|
(−) | 46 (44.2) | 3 (37.5) |
|
|
(+) | 58 (55.8) | 5 (62.5) |
|
| Lymphatic invasion,
n (%) |
|
|
<0.001a |
|
(−) | 87 (83.7) | 2 (25.0) |
|
|
(+) | 17 (16.3) | 6 (75.0) |
|
| Number of positive
nodes | 0 (0–5) | 2 (1–4) |
<0.001a |
| Table IV.Relationship between postoperative
adjuvant therapy and recurrence. |
Table IV.
Relationship between postoperative
adjuvant therapy and recurrence.
|
| Other risk (+)
(n=112) |
|---|
|
|
|
|---|
| Variable | Surgery-only
(n=104) | Surgery + adjuvant
(n=8) | P-value |
|---|
| Local recurrence, n
(%) |
|
| 1 |
|
(−) | 81 (77.9) | 7 (87.5) |
|
|
(+) | 23 (22.1) | 1 (12.5) |
|
| Regional
recurrence, n (%) |
|
| 0.2 |
|
(−) | 86 (82.7) | 5 (62.5) |
|
|
(+) | 18 (17.3) | 3 (37.5) |
|
| Distant metastasis,
n (%) |
|
| 0.5 |
|
(−) | 96 (92.3) | 7 (87.5) |
|
|
(+) | 8 (7.7) | 1 (12.5) |
|
| Salvage surgery, n
(%) |
|
| 0.6 |
|
(−) | 13 (36.1) | 2 (50) |
|
|
(+) | 23 (63.9) | 2 (50) |
|
| Salvage rate
(%) | 15/36 (41.7) | 1/4 (25) | 1 |
Association of individual risk
features with survival among patients with other risk (+) features
who did not receive postoperative adjuvant therapy
Multivariate Cox proportional hazards regression
analysis (Table V) identified LI as
an independent prognostic factor for poorer DSS (HR, 8.8;
P<0.001), OS (HR, 5.82; P<0.001), and RFS (HR, 6.0;
P<0.001). In addition, pT3 or pT4 primary tumors were an
independent prognostic factor for poorer DSS (HR, 9.5; P=0.03) and
OS (HR, 4.45; P=0.007). Furthermore, pN2 or pN3 nodal disease and
VI were independent prognostic factors for poorer RFS (HR, 3.2;
P=0.003 and HR, 2.45; P=0.03, respectively). Metastatic nodal
disease at levels IV or V was excluded from the multivariate
analysis because of the small number of cases.
| Table V.Multivariate Cox regression analysis
of factors associated with OS, DSS, and RFS in 104 other risk (+)
patients without adjuvant therapy. |
Table V.
Multivariate Cox regression analysis
of factors associated with OS, DSS, and RFS in 104 other risk (+)
patients without adjuvant therapy.
|
| OS | DSS | RFS |
|---|
|
|
|
|
|
|---|
| Variable | P-value | HR | 95% CI | P-value | HR | 95% CI | P-value | HR | 95% CI |
|---|
| Sex |
|
|
|
|
|
|
|
|
|
| Female
vs. male | 0.3 | 1.5 | 0.7–3.2 | 0.75 | 1.2 | 0.44–3.42 | 0.8 | 1.1 | 0.6–2.1 |
| Age, years |
|
|
|
|
|
|
|
|
|
| <70
vs. ≥70 | 0.14 | 2.2 | 0.8–6.0 | 0.7 | 0.8 | 0.28–4.45 | 0.5 | 1.3 | 0.6–2.9 |
| ECOG PS |
|
|
|
|
|
|
|
|
|
| 0 and 1
vs. 2 and 3 | 0.036 | 3.2 | 1.08–9.5 | 0.1 | 3.3 | 0.7–13.23 | 0.38 | 1.6 | 0.58–4.36 |
| Primary site |
|
|
|
|
|
|
|
|
|
| Others
vs. tongue | 0.38 | 0.58 | 0.2–2.0 | 0.1 | 0.3 | 0.06–1.74 | 0.5 | 0.7 | 0.3–1.9 |
| Surgical
margin |
|
|
|
|
|
|
|
|
|
| Clear
vs. close | 0.96 | 1.03 | 0.3–3.4 | 0.3 | 2.1 | 0.48–7.92 | 0.9 | 0.93 | 0.3–2.6 |
| pT stage |
|
|
|
|
|
|
|
|
|
| 1-2 vs.
3–4 | 0.007 | 4.45 | 1.5–13.3 | 0.03 | 9.5 | 1.19–71.44 | 0.4 | 1.38 | 0.66–2.88 |
| pN stage |
|
|
|
|
|
|
|
|
|
| 0 and 1
vs. ≥2 | 0.86 | 0.9 | 0.3–2.8 | 0.4 | 1.7 | 0.46–6.14 | 0.003 | 3.2 | 1.5–6.9 |
| Perineural
invasion |
|
|
|
|
|
|
|
|
|
| (−) vs.
(+) | 0.15 | 2 | 0.8–4.9 | 0.3 | 2 | 0.52–6.41 | 0.13 | 1.89 | 0.8–4.3 |
| Vascular
invasion |
|
|
|
|
|
|
|
|
|
| (−) vs.
(+) | 0.08 | 2.2 | 0.9–5.5 | 0.15 | 2.5 | 0.79–9.52 | 0.03 | 2.45 | 1.1–5.56 |
| Lymphatic
invasion |
|
|
|
|
|
|
|
|
|
| (−) vs.
(+) | <0.001 | 5.82 | 2.5–13.3 | <0.001 | 8.8 | 3.01–23.25 | <0.001 | 6.0 | 2.9–12.5 |
The association between postoperative adjuvant
therapy and survival was further evaluated according to pT stage
and LI status. Among patients with pT3 or pT4 primary tumors, the
5-year DSS rates were 75.9% in the surgery-alone group and 66.7% in
the surgery plus postoperative adjuvant therapy group, with no
significant difference between groups. Similarly, among patients
with LI, the corresponding 5-year DSS rates were 41.2 and 50.0%,
respectively, with no significant difference between groups
(Fig. 2A and B).
Discussion
Currently, postoperative adjuvant therapy is
recommended for patients with OSCC when other risk features are
identified on histopathological examination. However, categorizing
all patients with other risk features into a single group may not
be appropriate, and clarifying the indications for postoperative
adjuvant therapy is considered useful for clinical practice.
Previously, some authors reported that categorizing all patients
with ENE into a single group may not be appropriate; ENE minor
(tumor extension <2 mm beyond the capsule) may not require
postoperative adjuvant therapy (12,13).
Similarly, all patients with other risk features should not be
classified into a single group, but rather analyzed using more
detailed data. In the present study, we compared DSS, OS, and RFS
between patients with other risk features, without other risk
features, and with high-risk features, and found that patients with
high-risk features had significantly poorer survival. In contrast,
no significant differences in DSS, OS, or RFS were observed between
patients with and without other risk features. These findings
suggest that the prognostic impact of individual other risk
features may differ. Multivariate analysis comparing patients with
other risk (+) features and those with high-risk features showed
that high-risk status was independently associated with poorer
survival outcomes. These findings suggest that adverse pathologic
features should not be considered a homogeneous group, as their
prognostic significance may differ. Therefore, further analyses
were performed of the patients with other risk (+) features who did
not receive postoperative adjuvant therapy to identify the
prognostic factors.
One of the main findings of the present study was
that multivariate analysis identified pT3 or pT4 primary tumors and
LI as independent prognostic factors for poorer DSS and OS among
patients with other risk (+) features who did not receive
postoperative adjuvant therapy. Although postoperative adjuvant
therapy was not associated with improved DSS in patients with pT3
or pT4 primary tumors and LI, only a small number of patients
received postoperative adjuvant therapy. Therefore, these results
should be interpreted with caution and cannot be generalized.
Nevertheless, our results suggest that pT3 or pT4 primary tumors
and LI may represent important adverse pathologic features to be
considered when selecting patients for postoperative adjuvant
therapy.
Another important finding was that multivariate
analysis identified pN2 or pN3 nodal disease and VI as independent
prognostic factors for worse RFS, but not DSS or OS. These findings
suggest that recurrence did not necessarily lead to poorer DSS or
OS, possibly because a proportion of recurrent tumors could be
successfully salvaged. Although pN2 or pN3 nodal disease has
traditionally been considered an indication for postoperative
adjuvant therapy (5,6), our findings suggest that the
indication for postoperative adjuvant therapy in patients with pN2
or pN3 nodal disease should be carefully considered, taking into
account the potential for successful salvage treatment, as well as
treatment-related adverse events and QOL.
To the best of our knowledge, several studies have
reported an association between other risk features (minor or
intermediate) and survival outcomes (OS, DSS, or RFS), although the
risk features evaluated differed among studies (5,6,14–16).
Collectively, these reports suggest that close margins, invasion
pattern, pT3 or pT4 primary tumors, pN2 or pN3 nodal disease, and
PNI or LI are associated with poor prognosis, although the
prognostic significance of individual risk features has varied
across studies. Our findings regarding pT3 or pT4 primary tumors
and LI are consistent with previous reports. However, our findings
regarding pN2 or pN3 nodal disease are not consistent with previous
studies. Several previous studies have suggested that pN2 or pN3
nodal disease is a significant prognostic factor for poor
prognosis, but other reports suggest that the presence of four or
more lymph node metastases is associated with significantly worse
survival (17). Because of the
limited number of cases in our study, we were unable to stratify
patients according to the number of metastatic lymph nodes.
Regarding salvage rates, Brown et al (7) reported a significantly decreased
salvage rate of 11% for surgery followed by postoperative adjuvant
therapy compared with 47% for surgery alone, suggesting that
salvage treatment may be less successful after postoperative RT.
Conversely, Liu et al (5)
reported no difference in the salvage rate between these two groups
at the time of recurrence. ORN is a well-recognized late adverse
event arising from RT in patients with OSCC, and it can critically
affect QOL (4,18). From this perspective, patients with
other risk features that were not identified as independent
prognostic factors may not require consideration for postoperative
adjuvant therapy. Instead, treatment decisions should be made based
on tumor aggressiveness, the likelihood of successful salvage
treatment, treatment-related late adverse events, and QOL.
This study has limitations, including its
single-center, retrospective design, small sample size, and the
fact that eligibility for postoperative adjuvant therapy was
determined by physician discretion, general condition, and/or
disease status. In addition, only eight patients with other risk
features received postoperative adjuvant therapy, which limited the
ability to evaluate its therapeutic impact. These factors may have
introduced significant selection bias into the analysis of
treatment outcomes and limited the generalizability of our
findings. Therefore, further large-scale multicenter studies are
needed to enhance the generalizability of the results and establish
a more comprehensive understanding of other risk features.
In conclusion, among patients with other risk (+)
features, pT3 or pT4 primary tumors and LI were identified as
independent prognostic factors for DSS and OS. These findings may
help refine patient selection for postoperative adjuvant therapy
among patients with other risk (+) features.
Acknowledgements
Not applicable.
Funding
Funding: No funding was received.
Availability of data and materials
The data generated in the present study may be
requested by the corresponding author.
Authors' contributions
TN, HF and TY contributed to study conception and
design. Data were collected by HF, TN, KO, KM and TM, and analyzed
by TN and HF. The draft of the manuscript was written by TM, and
all authors commented on previous versions of the manuscript. TN,
HF and KO confirm the authenticity of all the raw data. All authors
read and approved the final manuscript.
Ethics approval and consent to
participate
The study protocol conformed to the ethical
principles of The Declaration of Helsinki and the Ethical
Guidelines for Medical and Health Research Involving Human Subjects
of the Ministry of Health, Labor, and Welfare, Japan. Approval was
obtained from the Institutional Review Board of Nagasaki University
Hospital (approval no. 25080704). As this was a retrospective
study, the research plan was published on the homepages of the
participating hospitals' websites using an opt-out approach for
consent in accordance with the ethics committee's requirements.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing
interests.
Use of artificial intelligence tools
During the preparation of this work, AI tools
(ChatGPT; OpenAI) were used to improve the readability and language
of the manuscript or to generate images, and subsequently, the
authors revised and edited the content produced by the AI tools as
necessary, taking full responsibility for the ultimate content of
the present manuscript.
Glossary
Abbreviations
Abbreviations:
|
CCRT
|
concomitant chemoradiotherapy
|
|
DM
|
distant metastasis
|
|
DSS
|
disease-specific survival
|
|
ENE
|
extranodal extension
|
|
LI
|
lymphatic invasion
|
|
LR
|
local recurrence
|
|
NCCN
|
National Comprehensive Cancer
Network
|
|
ORN
|
osteoradionecrosis
|
|
OS
|
overall survival
|
|
OSCC
|
oral squamous cell carcinoma
|
|
p
|
pathological
|
|
PNI
|
perineural invasion
|
|
QOL
|
quality of life
|
|
RFS
|
recurrence-free survival
|
|
RR
|
regional recurrence
|
|
RT
|
radiotherapy
|
|
VI
|
vascular invasion
|
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