(2024) 22:314
Jiang et al. BMC Medicine
https://doi.org/10.1186/s12916-024-03541-6

BMC Medicine

RESEARCH ARTICLE

Open Access

Postoperative radiotherapy with docetaxel
versus cisplatin for high‑risk oral squamouscell carcinoma: a randomized phase II trial
with exploratory analysis of ITGB1 as a potential
predictive biomarker
Wen Jiang1,3,4†, Lan Chen2,3,4†, Rongrong Li1,3†, Jiang Li5, Shengjin Dou1,3, Lulu Ye1,3, Yining He6, Zhen Tian5,
Yanli Yao2,3,4* and Guopei Zhu1,3,4*Abstract
Background Oral squamous cell carcinoma (OSCC) causes significant mortality and morbidity worldwide. Surgicalresection with adjuvant radiotherapy remains the standard treatment for locally advanced resectable OSCC. Resultsfrom landmark trials have established postoperative concurrent cisplatin-radiotherapy (Cis-RT) as the standard treatment for OSCC patients with high-risk pathologic features. However, cisplatin-related toxicity limits usage in clinicalpractice. Given the need for effective but less toxic alternatives, we previously conducted a single-arm trial showing
favorable safety profiles and promising efficacy of concurrent docetaxel-radiotherapy (Doc-RT).
Methods In this randomized phase 2 trial, we aimed to compare Doc-RT with the standard Cis-RT in postoperative
OSCC patients. Eligible patients had AJCC stage III–IV resectable OSCC with high-risk pathologic features. Two hundred twenty-four patients were enrolled and randomly assigned to receive concurrent Doc-RT or Cis-RT. The primary
endpoint was 2-year disease-free survival (DFS). Secondary endpoints included overall survival (OS), locoregionalfree survival (LRFS), distant metastasis-free survival (DMFS), and adverse events (AEs). Integrin β1 (ITGB1) expression
was analyzed as a biomarker for efficacy.
Results After a median 28.8-month follow-up, 2-year DFS rates were 63.7% for Doc-RT arm and 56.1% for Cis-RT arm(p = 0.55). Meanwhile, Doc-RT demonstrated comparable efficacy to Cis-RT in OS, LRFS, and DMFS. Doc-RT resulted
in fewer grade 3 or 4 hematological AEs. Low ITGB1 was associated with improved Doc-RT efficacy versus Cis-RT.
Conclusions This randomized trial directly compared Doc-RT with Cis-RT for high-risk postoperative OSCC patients,
with comparable efficacy and less toxicity. ITGB1 merits further validation as a predictive biomarker to identify OSCC
patients most likely to benefit from Doc-RT. Findings indicate docetaxel may be considered as a concurrent chemoradiation option in this setting.
†

Wen Jiang, Lan Chen, and Rongrong Li contributed equally to this work.

*Correspondence:
Yanli Yao
yaoyanli@shsmu.edu.cn
Guopei Zhu
antica@gmail.com
Full list of author information is available at the end of the article© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0
International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as longas you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if
you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article orparts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicatedotherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To
view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Jiang et al. BMC Medicine(2024) 22:314

Page 2 of 13

Trial registration www.​Clini​calTr​ials.​gov. NCT02923258 (date of registration: October 4, 2016)
Keywords Oral squamous cell carcinoma, Postoperative chemoradiotherapy, Docetaxel, Integrin beta 1 (ITGB1),
Pharmacogenomics

Background
Oral squamous cell carcinoma (OSCC) is one of the mostcommonly diagnosed cancers worldwide [1]. Surgicalresection with adjuvant radiotherapy (RT) remains thestandard treatment for locally advanced OSCC [1–4].
Results from two landmark randomized controlled trials in patients with head and neck squamous carcinoma(HNSCC), including OSCC, have consolidated concurrent cisplatin with radiotherapy as the standard treatment for patients with high-risk pathologic features
after surgical resection [5, 6]. Research studies involving extensive cohorts of HNSCC have revealed that thepresence of multiple lymph node metastases, in conjunction with classic high-risk features such as extracapsular
nodal extension (ENE) and positive surgical margins,
portend a substantially elevated risk profile, with postoperative chemoradiotherapy (CRT) conferring a survival
benefit over RT alone in OSCC patients [7–9]. However,cisplatin-related adverse events (AEs) such as myelosuppression and nephrotoxicity remain major concerns,
which have limited the real-world clinical usage of concurrent cisplatin [5, 6, 10, 11]. No pharmacologic agent
has yet been identified that mitigates the acute toxicity ofconcurrent cisplatin-based chemoradiotherapy without
negatively impacting the tolerability and efficacy of thiscombined modality regimen.
Docetaxel has exhibited promise as a radiosensitizing agent [12]. It has been hypothesized to enhance theeffects of radiotherapy by inducing cell cycle synchronization in the highly radiosensitive G2/M phase, as well as
by modulating the expression of various genes involvedin the cellular radiation response [13, 14]. Multiple phase
II trials have indicated that concurrent docetaxel-radiotherapy is tolerable and achieves favorable response
rates in patients with HNSCC [15–17]. Recently, a single-center phase II/III trial by Patil et al. demonstrated
that docetaxel could act as a radiosensitizer in HNSCC
patients who are ineligible for cisplatin [18]. However, forcisplatin-eligible postoperative HNSCC patients, there
remains a paucity of studies investigating alternatives tocisplatin for concurrent chemotherapeutic regimens. In
our previous single-arm phase II trial comprising OSCC
patients with high-risk features, concurrent docetaxel
with radiotherapy demonstrated favorable toxicity profiles and achieved improved disease-free survival (DFS)
and overall survival (OS), compared to the outcomes
reported in the historical study (RTOG-9501) utilizing acisplatin-based chemoradiotherapy [19]. These promising results prompted us to consider docetaxel as a potentially effective and better-tolerated option for concurrent
chemotherapy in cisplatin-eligible patients.
Determining predictive biomarkers through pharmacogenomics is imperative for understanding response
heterogeneity and enabling personalized therapy in cancer [20]. Previously, our integrated pharmacogenomic
study of OSCC combining multi-omics and drug screening revealed that elevated integrin β1 (ITGB1) expression
mediated docetaxel resistance [21]. ITGB1 is a transmembrane receptor protein that regulates diverse processes
involved in chemoresistance and radioresistance [22].
Its intracellular domain contains a microtubule-binding
region that interacts with microtubule proteins [23].
Activation and binding of ITGB1 can stabilize the microtubule cytoskeleton, while its inhibition leads to microtubule depolymerization [24, 25]. Given these interactions
modulating docetaxel response, further investigation of
the relationships between ITGB1 expression and clinicalcharacteristics in docetaxel-treated OSCC patients may
provide additional insights into biomarker-based treatment selection and design of chemoradiotherapy regimens. Detailed profiling of the ITGB1 landscape and its
predictive power holds promise to inform personalized
strategies and improve patient outcomes in OSCC. Basedon the research results mentioned above, we initiated aprospective, open-label, randomized trial aimed at evaluating the efficacy of docetaxel-radiotherapy (Doc-RT)
compared with the standard cisplatin-radiotherapy (CisRT) in cisplatin-eligible OSCC patients. Further, we present a prespecified biomarker assessment of the potential
association between tumor ITGB1 expression and efficacy of Doc-RT versus Cis-RT in the trial.

Methods
Study design

This study was a phase II, open-label, single-center,randomized trial conducted at Shanghai Ninth People’s Hospital. The protocol was approved by the Ethics Committee of Shanghai Ninth People’s Hospital andregistered at Clinicaltrials.gov (NCT02923258, CRTI
number: 2016–129-T78). All patients provided written informed consent to participate in the study. The
study was approved by our institutional ethics committee and was monitored by the data safety and monitoring

Jiang et al. BMC Medicine(2024) 22:314

subcommittee. The trial was conducted according to theprinciples laid down by the 18th Helsinki World Medical
Assembly.
Patients and eligibility criteria

Eligible patients include patients who had stage III or
IV OSCC according to the 8th edition of the American Joint Committee on Cancer (AJCC) staging system.
Patients had at least one pathologic high-risk factor
including ENE, positive margins, and/or involvement of
two or more regional lymph nodes. Eastern Cooperative
Oncology Group (ECOG) performance status 0–1; aged
18–75 years.
Randomization

Patients were stratified according to pathological features (positive margin and/or ENE vs. ≥ 2 positive lymph
nodes) and randomly assigned in a 1:1 ratio to receive
either concurrent chemoradiotherapy with cisplatin or
docetaxel. Randomization was performed centrally using
a computer-generated sequence with randomly permuted block sizes.
Postoperative chemoradiotherapy

All patients were immobilized in thermoplastic headand-shoulder masks with treatment-planning CT scansfor defining target volumes. The target volumes andradiation doses were determined based on clinical information, physical examination, and contrast-enhanced
computed tomography (CT) and/or magnetic resonanceimaging (MRI). Postoperative intensity-modulated radiotherapy (IMRT) was delivered at 5 days per week over
6–7 weeks, to a total dose of 60–66 Gy (200 cGy/fraction/day). Clinical target volumes (CTV) were delineatedas follows: CTV60 (60 Gy dose) covered high-risk target
volumes, CTV54 (54 Gy dose) for low-risk regions, anda CTV6 boost (6 Gy dose) was added for positive margin and/or ENE, at the discretion of the treating radiation
oncologist. Planning target volume (PTV) was definedas the CTV plus a 5-mm margin to account for potential variabilities in treatment setup and internal organ
motion. Radiotherapy planning and delivery followed
standardized departmental protocols.
In the Doc-RT arm, patients received intravenous (IV)docetaxel at 20 mg/m2 weekly for six cycles during the
RT period. In the Cis-RT arm, patients received cisplatin at a dose of 100 mg/m2 IV every 3 weeks. Patients
received routine hydration for the Cis-RT group. All
patients received prophylactic antiemetic medications.
Before the administration of chemotherapy, dexamethasone (at a dose of 5 mg or the equivalent) was given intravenously in both groups.

Page 3 of 13

Chemotherapy was administered concurrently withradiotherapy until the last day of radiotherapy, but notbeyond. Concurrent chemoradiotherapy was only given
to patients with adequate bone marrow function (absolute neutrophil count ≥ 1.5 × ­109/L; hemoglobin ≥ 10 g/dL) and adequate liver and kidney function (aspartatetransaminase and alanine transaminase ≤ 2.5 × institutional upper limit of normal (ULN); total bilirubin ≤ institutional ULN; creatinine clearance ≥ 50 mL/min; serum
creatinine ≤ institutional ULN). Administration of docetaxel/cisplatin was withheld for grade 4 mucositis ordermatitis, dehiscence of surgical incision, grade 3 anemia, and grade 3 neutropenia. Docetaxel was discontinued permanently for grade 4 hypersensitivity reactions.
Dose modifications included reduction of docetaxel to
15 mg/m2/week and cisplatin to 80 mg/m2 if toxicities
occurred.
Assessments

During the study, patients underwent assessments
including physical examination and blood tests every
week. Oncological assessments including physical examination, CT or MRI imaging of the head and neck, and CT
or ultrasound imaging of the upper abdomen were mandated every 3 months for the first 2 years, every 6 months
from years 2 to 5, and annually thereafter. All patientswere intended to be followed until death for data collection and analysis. AEs were summarized and recorded
according to the National Cancer Institute Common
Terminology Criteria for Adverse Events (NCI CTCAE)
version 5.0 weekly during the treatment. Acute AEs wereanalyzed in patients who received at least one administration of cisplatin or docetaxel.
Study endpoints

The primary endpoint was a 2-year DFS, defined as thetime from randomization to the first recurrence or deathfrom any cause. Secondary endpoints included OS,
locoregional failure-free survival (LRFS), distant metastasis-free survival (DMFS), and AEs. OS was defined as thetime in months between the date of random assignment
and the date of death from any cause. LRFS was definedas the time in months between random assignment andthe date of first locoregional recurrence or death fromany cause, whichever occurred first. DMFS was definedas the time from random assignment to the first distantmetastasis or death from any cause. Additional analysis
includes subgroup analysis regarding survival outcomes.
ITGB1 expression

Immunohistochemistry (IHC) staining was carried out
on full slides of Formalin-Fixed, Paraffin-Embedded(FFPE) tumor specimens as previously described, asJiang et al. BMC Medicine(2024) 22:314

per the manufacturer’s instructions for ITGB1 (1:200,
Cat#9699, Cell Signaling Technology) staining [21].
Images were captured using the ZEISS Axioscan 7 Microscope Slide Scanner. Results were interpreted by a certified pathologist using a standardized scoring algorithm
involving the evaluation of the entire tissue slide. The
staining intensity (negative = 0, weak = 1, moderate = 2,strong = 3) and percentage of positive tumor cells (0% = 0,
1–10% = 1, 11–50% = 2, 51–80% = 3, 81–100% = 4) were
evaluated. An immunoreactive score (IRS) ranging from
0–12 was calculated by multiplying the numeric staining intensity and percentage. In previous studies, we
divided patients into low and high expression groups
based on the median value [21]. Considering a considerable number of intermediate expression samples, we
refined the ITGB1 categorization in this study, dividing
patients into three groups: low, medium, and high. The
following ITGB1 expression categories were used: IRS 0
to < 3: ITGB1 low; IRS 3 to < 6: ITGB1 medium; IRS 6 to
12: ITGB1 high.
Sample size and statistics

The sample size was estimated to provide 80.2% power
to detect a hazard ratio of 0.5788 for the improvement
in DFS, using a two-sided log-rank test at a 0.050 significance level [26], accounting for a 10% loss to followup. A total of 224 subjects (112 per arm) were required,
which could detect an improvement in 2-year DFS from54 to 70%, assuming 54% 2-year DFS in the control arm
based on the RTOG-9501 cohort [6]. The accrual patterncomprises a 3-year accrual period and a minimum 2-year
follow-up.
Survivals were estimated by the Kaplan-Meier method
and compared using the log-rank test. Cox models estimated hazard ratios (95% confidence interval [CI]) for
subgroup analyses. ITGB1 subgroup treatment outcomes
were compared using t-tests or Wilcoxon tests. Analyses
used SPSS version 27. Intention-to-treat (ITT) analysis was used for survival, per-protocol for AEs. P-values
assessed treatment difference significance at 0.05 level.

Results

Page 4 of 13

Table 1 Patient characteristics
Variable

Doc-RT (n = 112)

Cis-RT (n = 112)59.5 (37–73)

56 (24–72)

Male

68 (60.7)

86 (76.8)

Female44 (39.3)

26 (23.2)

Positive margin

6 (5.4)1 (0.9)ENE

57 (50.9)

63 (56.3)

Positive margin and ENE

6 (5.4)6 (5.4)Multiple lymph nodes

43 (38.4)

42 (37.5)

Tongue57 (50.9)

60 (53.6)

Buccal15 (13.4)

17 (15.2)

Mouth floor

13 (11.6)

11 (9.8)

Gingival

22 (19.6)

21 (18.8)

Hard palate

5 (4.5)3 (2.7)

Smoking

47 (42.0)

58 (51.8)

Regular alcohol

31 (27.2)

34 (30.4)

T1

21 (18.8)

22 (19.6)

T2

53 (47.3)

39 (34.8)

T3

32 (28.6)

42 (37.5)T4

6 (5.4)9 (8.0)N03 (2.7)1 (0.9)N2a

22 (19.6)

17 (15.2)

N2b

43 (38.4)

36 (32.1)N2c

1 (0.9)5 (4.5)N3b43 (38.4)

53 (47.3)

III

22 (19.6)

16 (14.3)

IV

90 (80.4)

96 (85.7)

Age, No. (range)
Median, years
Sex, No. (%)

High-risk features, No. (%)

Subsite of oral cavity, No. (%)

Habits, No (%)

Pathologic T stage, No. (%)

Pathologic N stage, No. (%)

Total Stage, No. (%)

ENE Extranodal extension, Doc-RT Docetaxel-radiotherapy, Cis-RT Cisplatinradiotherapy, No. Number

this study database locked on April 30, 2023, for final
data analysis.

Baseline characteristics

Between April 2018 and February 2022, a total of 224
patients were enrolled in this randomized controlled
trial. The baseline characteristics of the study participants
are summarized in Table 1. The consolidated standards ofreporting trials (CONSORT) flow diagram delineating
patient recruitment and retention is outlined in Fig. 1.
High-risk features included positive surgical margins
and/or ENE, and two or more metastatic lymph nodes.
Baseline demographic and clinical parameters were balanced between the two treatment arms. We conducted

Treatment compliance and chemotherapy delivery

IMRT was administered to all patients. In Doc-RT
and Cis-RT arm, 107 (95.5%) and 110 (98.2%) patients
received at least 95% of the prescribed RT dose, respectively. Two patients in the Doc-RT arm and one in the
Cis-RT arm had RT-interruption over 5 days. Fourpatients in the Doc-RT arm (one with hypersensitivity
reaction and subsequently received weekly cisplatin) and
one in the Cis-RT arm terminated RT early and received
salvage surgery or systemic therapy due to tumor

Jiang et al. BMC Medicine(2024) 22:314

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Fig. 1 CONSORT diagram: enrollment, intent-to-treat and safety populations, and patient withdrawals. Doc-RT, docetaxel-radiotherapy; Cis-RT,
cisplatin-radiotherapy; ITT, intention-to-treat; RT, radiotherapy

recurrence during treatment. RT for another patient in
the Doc-RT arm was discontinued due to the need for
emergency medical intervention following a cerebrovascular accident. The overall duration and interruptions of
RT were comparable between the two arms (Table 2).
In the Doc-RT arm, two patients deviated from the prescribed regimen due to hypersensitivity reactions upon
initial administration of docetaxel. Subsequently, thesepatients received weekly cisplatin as an alternative concurrent chemotherapy, per the discretion of the attending
physician. Among the 107 patients in the docetaxel without early RT termination, 95 (88.8%) were administeredat least five doses of docetaxel, with one patient requiring dose modification. In the Cis-RT arm, 103 of the
112 patients received at least two cycles, with 41 requiring dose modifications. The compliance details for eachtreatment group are presented in Table 2.
Survival

After a median follow-up of 28.8 months (interquartile
range (IQR): 17–49 months), 98 DFS events occurred,with 47 in the Doc-RT arm (25 local regional progressions (LRP), 15 distant metastases (DM), 4 LRP with DM,
1 s primary tumor (SPT) and 2 deaths as first events) and

51 in the Cis-RT arm (including 27 LRP, 15 DM, 5 LRP
with DM, 1 SPT and 4 deaths as first events). The 2-year
DFS was 63.7% (95% CI, 55.2% to 73.2%) in the Doc-RT
arm versus 56.1% (95% CI, 49.3% to 67.7%) in the Cis-RT
arm (p = 0.55; Fig. 2A). The hazard ratio (HR) of DFS for
docetaxel versus cisplatin was 0.92 (95% CI, 0.61 to 1.4).
Median DFS were not reached in both groups.
Overall, 72 deaths occurred, with 34 in the Doc-RT arm
and 38 in the Cis-RT arm. Median OS was not reached inboth arms. The 2-year OS was 71.2% (95% CI, 61.5% to78.8%) for the Doc-RT arm versus 70.4% (95% CI, 61% to78%) for the Cis-RT arm (p = 0.56, Fig. 2B). The HR of OS
for docetaxel versus cisplatin was 0.87 (95% CI, 0.55 to1.38). The 2-year LRFS rate was 76.4% for the docetaxel
arm versus 71.5% for the cisplatin arm (Fig. 2C). For
DMFS, the 2-year rate was 81.9% in the docetaxel arm
versus 77.9% in the cisplatin arm (Fig. 2D).
In a subgroup analysis, the HR of DFS for docetaxel
versus cisplatin was 0.41 (95% CI, 0.18 to 0.91, p = 0.028)
among patients with two or more metastatic lymph
nodes, indicating an advantage for the Doc-RT arm(Fig. 3A). Subgroup analyses of other subgroups did
not demonstrate any statistically significant differences
between the two treatment arms with respect to DFS andJiang et al. BMC Medicine(2024) 22:314

Page 6 of 13

Table 2 Compliance details for CRT​
Parameter

Doc-RT (n = 112)

Cis-RT (n = 112)

Disease progression

4 (3.57)

1 (0.89)

Patient defaulted

0 (0)1 (0.89)

Stroke1 (0.89)0 (0)45 (40–45)

45 (40–45)

Any interruption

34 (30.36)

37 (33.04)

Interruption over 5 days

2 (1.79)

1 (0.89)

Oral mucositis

2 (1.79)

0 (0)Surgical wound dehiscence

0 (0)1 (0.89)

Myelosuppression

2 (1.79)

4 (3.57)

Oral mucositis

5 (4.46)

0 (0)Defaulted

0 (0)2 (1.79)

Disease progression

3 (2.68)

1 (0.89)

COVID-19 disease

2 (1.79)0 (0)Malnutrition

1 (0.89)

2 (1.79)

Stroke1 (0.89)0 (0)Herpes zoster infection

1 (0.89)0 (0)Reason for termination of RT, No. (%)

Treatment duration, days, median (IQR)
Patients with interruption of RT, No. (%)

AEs leading to interruption of RT over 5 days, No. (%)

Reasons for < 5 cycles of docetaxel or < 2 cycles of cisplatin, No. (%)

CRT​ Chemoradiation, Doc-RT Docetaxel-radiotherapy, Cis-RT Cisplatin-radiotherapy, RT Radiotherapy, IQR Interquartile range, COVID-19 Coronavirus disease 2019, AE
Adverse events, No. Number

OS (Fig. 3A–B). Further subgroup analysis of LRFS demonstrated an HR of 1.16 (95% CI, 0.63 to 2.12, p = 0.567)
in the ENE and/or positive margins subgroup, and an
HR of 0.49 (95% CI, 0.20 to 1.18, p = 0.121) in the multiple lymph node metastasis subgroup. The HR for DMFS
was 1.19 (95% CI 0.75–1.91, p = 0.735) in the ENE and/or positive margin subgroup, and 0.20 (95% CI 0.04–
0.97, p = 0.105) in the multiple lymph node metastasis
subgroup.
ITGB1 expression and efficacy outcomes

Among the 224 patients treated with Doc-RT or Cis-RT,
archival tumors were evaluated for ITGB1 expression in
206 patients (Doc-RT arm: 100; Cis-RT arm: 106). In the
Doc-RT cohort, 39 patients (39%) displayed low IRS for
ITGB1, while 20 (20%) and 41 (41%) had medium andhigh IRS, respectively. A similar distribution of ITGB1
expression was observed in the Cis-RT cohort, with 44(41.5%), 21 (19.8%), and 41 (38.7%) patients exhibiting
low, medium, and high IRS, respectively.
Stratified by ITGB1 expression level, Doc-RT treatedpatients with low, medium, and high expression exhibited 2-year DFS of 73.8% (95% CI 56.7 to 84.99%), 75.0%(95% CI 50.0 to 88.7%) and 48.7% (95% CI 32.8 to 62.8%),
respectively. In comparison, Cis-RT treated patients withcorresponding low, medium, and high ITGB1 expression

had 2-year DFS of 54.5% (95% CI 38.7 to 67.7%), 52.4%(95% CI 29.7 to 70.9%) and 58.5% (95% CI 42.0 to 71.8%),
respectively (Fig. 4A). Among Doc-RT patients, low
ITGB1 expression was associated with improved prognosis compared to high expression, including significantly
higher 2-year DFS (73.8% vs 48.7%; p = 0.016, Fig. 4A),
and numerically but not significantly elevated 2-year OS(79.0% vs 60.9%; p = 0.083, Fig. 4B), locoregional relapsefree survival, and distant metastasis-free survival. No
prognostic correlation with ITGB1 expression was evident in the Cis-RT cohort (Fig. 4A–B).
Despite the limited sample size, the consistently superior survival across endpoints in the Doc-RT/low ITGB1
subgroup suggests this population may benefit morefrom Doc-RT than Cis-RT. Notably, the ITGB1 prognostic value was only evident in the Doc-RT arm, not Cis-RT.
This indicates ITGB1 may act as a predictive biomarker
to identify sensitive and resistant subgroups specificallyfor Doc-RT.
Adverse events

Adverse events (AEs) were analyzed by per-protocol
analysis and are presented in Table 3. Regarding nonhematologic toxicities, the incidence of grade 3 oral
mucositis was higher in patients treated with Doc-RT
compared to Cis-RT (29.1% vs 19.6%, χ2 = 2.69, p = 0.1),

Jiang et al. BMC Medicine(2024) 22:314

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Fig. 2 The Kaplan–Meier curve for DFS (A), OS (B), LRFS (C), and DMFS (D) for all randomly assigned patients. The symbols indicate censoredobservations. Doc-RT, docetaxel-radiotherapy; Cis-RT, cisplatin-radiotherapy; No., number

while grade 3 dysphagia occurred less frequently in
the Doc-RT than the Cis-RT (5.5% vs 14.3%, χ2 = 4.85,
p = 0.028). Oral candidiasis was detected in five patients
receiving Doc-RT and one patient receiving Cis-RT. As
for hematologic toxicities, 24 patients (21.4%) developed
grade 3–4 neutropenia in the cisplatin arm, while only
one patient in the Doc-RT arm exhibited grade 3 neutropenia (χ2 = 23.38, p < 0.001).

Discussion
In patients with OSCC exhibiting high-risk features,
curative surgery with postoperative chemotherapy
remains the standard method of reducing recurrence[27]. In this setting, concurrent high-risk cisplatin and
RT have a modest OS benefit, but are associated withincreased toxicities [28]. The purpose of this study was tocompare the efficacy and safety of docetaxel as a concurrent chemotherapy regimen with high-dose cisplatin inthis population. Although this trial was not designed as a
non-inferiority study, comparable oncological outcomes
were demonstrated between the Doc-RT arm and theCis-RT arm, including DFS, LRFS, DMFS, and OS. Additionally, the Doc-RT group experienced fewer hematological adverse events. This study also indicated that the
ITGB1 status may be useful for identifying subgroups ofpatients who are sensitive to docetaxel.
For resectable high-risk OSCC, 3-weekly cisplatin at
100 mg/m2 with postoperative RT is recommended by
all international guidelines [29, 30]. Adding chemotherapy modestly improves OS at the expense of increased
toxicities [5, 6]. Previous studies have demonstrated
grade 3 or higher myelosuppression in approximately
49–78% of patients receiving high-dose cisplatin,
requiring treatment delays and dose reductions [6, 31].
Consequently, due to the considerable AEs associatedwith cisplatin, there exists an unmet clinical need toJiang et al. BMC Medicine(2024) 22:314

Page 8 of 13

Fig. 3 Subgroup analysis of DFS (A) and OS (B) in all patients. Forest plot depicting the impact of the treatment effect on DFS (A) and OS (B)across multiple subgroups. Doc-RT, docetaxel-radiotherapy; Cis-RT, cisplatin-radiotherapy; ENE, extranodal extension; MLN, multiple lymph nodes; T,tumor; N, node; HR, hazard ratio; CI, confidence interval

identify novel radiosensitizers characterized by reduced
toxicity profiles without compromising therapeutic efficacy. Our previous exploratory single-arm study demonstrated that concurrent weekly docetaxel at 20 mg/
m2 with adjuvant radiotherapy was well-tolerated andexhibited promising survival benefits compared tohistorical controls in high-risk OSCC [19]. This randomized trial further evaluated weekly docetaxel versus
standard high-dose cisplatin with RT. As demonstrated
in our study, grade 3–4 hematological and dysphagia rates were significantly lower with docetaxel, withsimilar oncological outcomes. Grade 3–4 oral mucositis

Jiang et al. BMC Medicine(2024) 22:314

Page 9 of 13

Fig. 4 ITGB1 expression and efficacy outcomes. A Disease-free survival by ITGB1 expression. B Overall survival by ITGB1 expression; ITGB1, integrin
β1; Doc-RT, docetaxel-radiotherapy; Cis-RT, cisplatin-radiotherapy; No., number

occurred slightly more with docetaxel, but < 10% of
patients required treatment modifications or discontinuation. Therefore, 20 mg/m2 weekly docetaxel concurrently with postoperative RT could serve as a tolerable
alternative for high-risk OSCC patients.

In recent years, several randomized controlled trials
have explored the efficacy of docetaxel as concurrent
chemoradiation for HNSCC. The RTOG-0234 phase
II randomized trial investigated cetuximab-docetaxel
versus cisplatin-cetuximab as concurrent regimens inJiang et al. BMC Medicine(2024) 22:314

Page 10 of 13

Table 3 Treatment-related acute adverse events by assigned
treatment
Doc-RT (n = 110)
AE

Cis-RT (n = 112)

Any Grade Grade 3–4 Any Grade Grade 3–4

Hematologic, No. (%)
Anemia47 (42.7)

0 (0)93 (83)14 (12.5)

Neutropenia

5 (4.5)1 (0.9)67 (59.8)

24 (21.4)

Thrombocytopenia

2 (1.8)0 (0)8 (7.1)1 (0.9)Non-hematologic, No. (%)
Mucositis

104 (94.5)

32 (29.1)

107 (95.5)

22 (19.6)

Dysphagia

51 (46.4)

6 (5.5)67 (59.8)

16 (14.3)

Dermatitis

110 (100)

8 (7.3)112 (100)

11 (9.8)

Nausea13 (11.8)0 (0)59 (52.7)

5 (4.5)

Vomiting

5 (4.5)0 (0)15 (13.4)

1 (0.9)Stroke0 (0)1 (0.9)

0 (0)

0 (0)

Raised creatinine

1 (0.9)0 (0)32 (28.6)

0 (0)ALT increased

3 (2.7)0 (0)31 (27.7)

3 (2.7)

AST increased

2 (1.8)0 (0)18 (16.1)

2 (1.8)AE Adverse events, Doc-RT Docetaxel-radiotherapy, Cis-RT Cisplatin-radiotherapy,
No. Number, ALT Alanine aminotransferase, AST Aspartate aminotransferase

high-risk postoperative HNSCC patients [15]. Bothregimens showed promising outcomes with improved
DFS and OS compared to historical high-dose cisplatin
controls [15]. However, the high cost of cetuximab anda greater than 50% rate of severe oral mucositis limit its
practical clinical application. Notably, cetuximab-docetaxel with RT showed favorable DFS compared to cetuximab-cisplatin (65.9% vs 57.3%, respectively), implyingthat single-agent docetaxel may also lead to favorable
survival. Therefore, we further investigated concurrent
docetaxel in this current study. As shown in our findings,
the 2-year DFS in the Doc-RT arm were comparable tothose reported for the docetaxel-cetuximab-RT regimen in RTOG-0234, while exhibiting a lower frequencyof grade 3–4 oral mucositis. The DHANUSH trial by
Patil et al. was a randomized study in cisplatin-ineligible HNSCC patients, demonstrating that adding weekly
15 mg/m2 docetaxel improved 2-year DFS compared toradiotherapy alone (42% vs 30%) [18]. However, the survival outcomes of concurrent docetaxel and radiotherapy
in this trial appeared suboptimal compared to historical RTOG-9501 controls, with no statistically significant
survival benefit with concurrent docetaxel in DFS and
OS for adjuvant setting or OSCC patients [6, 18]. This
could be attributed to the relatively low 15 mg/m2 doseof docetaxel, which may have radiosensitizing effects but
be insufficient for distant control of micrometastases. In
light of our findings, a higher dose docetaxel regimen at
20 mg/m2 concurrently with radiotherapy may represent

a well-tolerated and efficacious option for postoperative concurrent chemoradiotherapy in high-risk OSCC
patients.
It is noteworthy that this study specifically focused on
OSCC, not other head and neck subsites with different
survival expectations, like human papillomavirus (HPV)related oropharyngeal cancer [32–34]. Firstly, surgery
followed by postoperative radiotherapy (with or without
chemotherapy) remains the standard treatment modality for OSCC [35], in contrast to definitive chemoradiation, which is widely employed for oropharyngeal cancer.
Furthermore, although ENE and positive margins wereconsidered conventional high-risk features based on two
milestone studies [5, 6, 27], these trials included less than
one-third of OSCC patients, potentially suggesting an
incomplete consideration of high-risk factors in this specific population. Notably, recent analyses involving large
cohorts have identified multiple lymph node metastases
as an additional high-risk feature associated with adverse
outcomes in HPV-unrelated HNSCC, such as OSCC
[7–9]. Concurrent chemoradiotherapy has been demonstrated to improve prognosis for patients with multiple
lymph node metastases [7, 8]. Consequently, our findings
directly inform chemotherapy selection for postoperative
chemoradiation in OSCC patients harboring these risk
features. Additionally, all patients received IMRT, providing evidence for a concurrent chemotherapy regimen in
the context of modern radiotherapy techniques.
Precision oncology promises to transform cancer
treatment by accounting for the molecular heterogeneity of tumors between patients [36]. While standardized protocols remain the norm, biomarkers that predictpatient-specific drug responses may enable personalized
regimens with improved safety and efficacy [37, 38]. Previously, we found ITGB1 mediates resistance to docetaxel
in OSCC models [21]. ITGB1 is implicated in multiple
drug resistance mechanisms across cancers [39–41].
In OSCC cells, ITGB1 regulates cell stemness, which inturn modulates perineural invasion and radioresistance[42]. Our present clinical study newly demonstrates that
ITGB1 expression correlates with docetaxel radiotherapy
response in OSCC patients, whereas cisplatin sensitivity
was independent of ITGB1 status. Looking ahead, molecular profiling of ITGB1 and other pharmacogenomic
markers could potentially guide optimal personalized
therapy selection for each patient.
It is imperative to acknowledge certain limitations. As asingle-institution study, our findings may be constrainedby the limited patient diversity and potential heterogeneity in radiotherapy planning practices compared to a
multi-institutional setting, potentially restricting the generalizability of our results to broader patient populations.
Additionally, the increasing adoption of weekly cisplatin

Jiang et al. BMC Medicine(2024) 22:314

regimens in recent years may introduce more variability
in cisplatin administration schedules in real-world clinical practice [31, 43, 44], in contrast to the bolus triweekly
cisplatin utilized as the control arm in this study. Consequently, large-scale, multi-institutional studies will beessential to validate these findings across diverse realworld patient populations and further investigate potential heterogeneity in clinical responses.
New strategies involving docetaxel are still being
explored. The ongoing RTOG-1216 phase II/III trial will
provide high-quality evidence on postoperative concurrent weekly docetaxel-cetuximab and cisplatin-PD-1
inhibitor chemoradiotherapy for high-risk HNSCC. Its
results may inform the utility of docetaxel and cetuximab
with postoperative radiotherapy [45]. Studies have combined immune checkpoint inhibitors with chemotherapy regimens to improve HNSCC outcomes. Given thepotential ITGB1-docetaxel association indicated in ourstudy, biomarkers like ITGB1 could help select patientsfor future regimens combining docetaxel and otheragents.

Conclusions
In conclusion, this is the first prospective randomized
trial directly comparing concurrent docetaxel-radiotherapy versus standard cisplatin-radiotherapy in the postoperative setting of OSCC patients. Although the primary
endpoint was not achieved in this study, Doc-RT demonstrated comparable efficacy to the standard Cis-RT regimen, as measured by DFS, OS, LRFS, and DMFS. Severe
hematological AEs were rarely observed in the Doc-RTgroup, and non-hematological AEs were generally manageable. ITGB1 may serve as a potential biomarker tohelp guide the selection of concurrent chemotherapy
agents in these patients, warranting further investigation
to elucidate the mechanisms involved and validation inlarger global patient cohorts.
Abbreviations
AE	Adverse event
AJCC	American Joint Committee on Cancer
Cis-RT	Cisplatin-radiotherapy
CONSORT	Consolidated Standards of Reporting Trials
CT	Computed tomography
CTV	Clinical target volumes
DFS	Disease-free survival
DMFS	Distant metastasis-free survival
Doc-RT	Docetaxel-radiotherapy
ECOG	Eastern Cooperative Oncology Group
ENE	Extracapsular nodal extension
FFPE	Formalin-Fixed Paraffin-Embedded
HNSCC	Head and neck squamous cell carcinoma
IHC	Immunohistochemistry
IMRT	Intensity-modulated radiotherapy
ITGB1	Integrin β1
LRFS	Locoregional-free survival
MRI	Magnetic resonance imaging
OS	Overall survival

Page 11 of 13

OSCC	Oral squamous cell carcinoma
PTV	Planning target volume
RT	Radiotherapy
Acknowledgements
The authors would like to thank the patients and their families for participating in this trial.
Authors’ contributions
GZ designed the study. WJ, LC, RL, JL, SD, LY, ZT, YY, and GZ were responsible
for patient recruitment, collection and analysis of clinical data, preparation ofpatient samples, or conducting biomarker detection and analysis. WJ, YY, LC,
RL, SD, and HY performed statistical analysis and interpreted the data. WJ, YY,
and LC reviewed the literature and drafted and revised the manuscript. All
authors contributed to data interpretation and reviewed the manuscript for
language and intellectual content. All authors read and approved the final
manuscript.
Funding
This work was funded by the Innovative Research Team of High-level Local
Universities in Shanghai (SSMU-ZLCX20180500, SHSMU-ZLCX20212300),
Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical
Sciences (CIFMS) (2019-I2M-5-037), Shanghai Clinical Research Center for Oral
Diseases (19MC1910600), Shanghai Municipal Health Commission Research
Project (20194Y0298), and Project of Xisike Clinical Oncology Research Foundation (Y-XD2019-110).
Availability of data and materials
The datasets generated and/or analyzed during the current study are notpublicly available due to the participants not consenting to open access data
sharing but are available from the corresponding author upon reasonable
request.

Declarations
Ethics approval and consent to participate
This study was reviewed and approved by the Ethics Committee of Shanghai
Ninth People’s Hospital and registered at Clinicaltrials.gov (NCT02923258,
CRTI number: 2016–129-T78). All patients provided written informed consent
to participate in the study. The study was approved by our institutional
ethics committee and was monitored by the data safety and monitoring
subcommittee.
Consent for publication
Not applicable.
Competing interests
No potential competing interests were reported by the authors.
Author details
1
Department of Oral and Maxillofacial‑Head Neck Oncology, Division of Radiation Oncology, College of Stomatology, Shanghai Ninth People’s Hospital,
Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China. 2 Department of Oral and Maxillofacial‑Head Neck Oncology, College of Stomatology, Shanghai Ninth People’s Hospital, Shanghai Jiao
Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai,
China. 3 National Center for Stomatology, National Clinical Research Center
for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai ResearchInstitute of Stomatology, Shanghai, China. 4 Research Unit of Oral and Maxillofacial Regenerative Medicine, Chinese Academy of Medical Sciences, Shanghai, China. 5 Department of Oral Pathology, College of Stomatology, Shanghai
Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine,
Shanghai Jiao Tong University, Shanghai, China. 6 Biostatistics Office of ClinicalResearch Unit, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University
School of Medicine, Shanghai, China.
Received: 30 January 2024 Accepted: 24 July 2024

Jiang et al. BMC Medicine(2024) 22:314

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