Neoadjuvant Chemo-Immunotherapy in Very Advanced (T4) Head and Neck Squamous Cell Carcinoma: A Real-World Study

doi:10.21203/rs.3.rs-5290964/v1

Aims

This study aimed to evaluate the efficacy and safety of neoadjuvant chemo-immunotherapy in patients with very advanced (T4) head and neck squamous cell carcinoma (HNSCC), while also exploring outcomes in the specific subgroup of T4b stage patients.

Methods

We retrospectively analyzed 87 initially diagnosed T4 HNSCC patients who received neoadjuvant chemo-immunotherapy between April 2020 and March 2023 at the Sun Yat-sen University Cancer Center. The primary endpoint of this study was overall survival (OS) and the secondary endpoint was event-free survival (EFS).

Results

The overall response rate (ORR) after neoadjuvant chemo-immunotherapy was 75.8%, with 10.3% achieving a complete response (CR) and 69.0% achieving a partial response (PR). The 1-year and 3-year OS rates for the total cohort were 90.8% and 66.7%, while the 1-year and 3-year EFS rates were 81.3% and 56.0%, respectively. Cox regression analyses indicated that receiving 3–4 cycles of treatment, pretreatment clinical N0 stage, and favorable radiographic responses (CR and PR) were significantly associated with improved OS and EFS. Remarkably, among the 12 T4b patients, 11 (91.7%) achieved a PR while one experienced stable disease (SD). Furthermore, 8 T4b patients (66.7%) were converted to resectable status, and 5 of them underwent surgical treatment following neoadjuvant therapy. Grade 3 or 4 treatment-related adverse events occurred in 7 patients (8.0%).

Conclusion

Neoadjuvant chemo-immunotherapy demonstrates promising survival outcomes and manageable toxicity in very advanced T4 HNSCC patients, highlighting its potential as an effective treatment strategy for this challenging subgroup.

Neoadjuvant chemo-immunotherapy

T4 HNSCC

prognosis

OS

EFS

Head and neck cancers, predominantly of squamous-cell origin, rank as the eighth-most common cancer globally, with an estimated 770,000 new cases and 380,000 deaths in 2022 ¹. Approximately 60% of head and neck squamous cell carcinoma (HNSCC) patients present with locally advanced disease, which carries a dismal 5-year overall survival (OS) rate of just 50% ². The standard treatment for locally advanced HNSCC (LAHNSCC) typically involves a multimodal approach, integrating surgery, radiotherapy, and chemotherapy. However, these treatments often lead to severe tissue damage, functional impairment, and psychological distress.

T4 staging, particularly T4b, is a significant negative prognostic factor for patients with LAHNSCC ^3–6. T4b indicates involvement of the pterygoid muscles, pterygoid plates, skull base, carotid arteries, cervical vertebrae, or superior nasopharynx, which typically prevents surgical resection due to inadequate margins⁶. Consequently, T4b HNSCC poses a major clinical challenge, with most patients relapsing locally after chemoradiation and a low 5-year survival rate of only 10–15%². Unfortunately, T4b patients were usually excluded from most clinical studies, more clinical evidence and novel treatment strategies are still urgently needed for this subgroup of HNSCC patients.

In recent years, immunotherapy has emerged as a promising area of cancer research due to its ability to enhance the patient’s own systemic immunity, induce durable responses, and apply to a range of malignancies. Immunotherapy has demonstrated remarkable benefits in earlier studies ^7–11 and is now recommended as a first-line treatment for recurrent/metastatic HNSCC ¹².

Encouraging results have emerged from studies using immunotherapy alone or in combination with other anti-tumor treatments as neoadjuvant therapy for LAHNSCC ^11,13–17. For instance, 44% of resectable LAHNSCC patients experienced a pathological response after neoadjuvant monotherapy with pembrolizumab ¹⁶. A Phase II trial reported that combining camrelizumab with albumin-bound paclitaxel/cisplatin as neoadjuvant chemo-immunotherapy for stage III–IVB HNSCC resulted in an excellent response, with a major pathological response (MPR) rate of 74.1% and a pathological complete response (pCR) rate of 37.0%. The 1-year disease-free survival (DFS) rate was 95.8%, with a favorable safety profile ¹⁸. Wu et al. also reported optimistic results with an objective response rate (ORR) of 89.6% and a pCR rate of 55.6% in 48 stage II–IV HNSCC patients, with 1-year DFS and OS rates of 97.9% ¹⁹. Additionally, high responsiveness to neoadjuvant immunotherapy appears to facilitate surgical de-escalation, with a Phase II clinical trial showing an 88.7% larynx preservation rate in locally advanced laryngeal and hypopharyngeal cancer patients ²⁰. Overall, combining neoadjuvant immunotherapy with chemotherapy has shown enhanced therapeutic efficacy in LAHNSCC patients.

Despite these advancements, there is considerable heterogeneity in tumor stages across previously published studies ^19,20. Data on the efficacy of neoadjuvant chemo-immunotherapy for T4, especially T4b, remain limited and imprecise. Thus, this study aims to retrospectively analyze the therapeutic and functional outcomes of very advanced (T4) HNSCC patients following neoadjuvant chemo-immunotherapy at a large single cancer center.

Patients

This study retrospectively reviewed T4 HNSCC patients who received neoadjuvant chemo-immunotherapy between April 2020 and March 2023 at the Sun Yat-sen University Cancer Center (SYSUCC). Inclusion criteria were: (1) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; (2) clinically diagnosed with T4 HNSCC (oral cavity, oropharynx, larynx, or hypopharynx) according to the 8th edition of the American Joint Committee on Cancer (AJCC) staging manual; (3) received at least 2 cycles of neoadjuvant chemo-immunotherapy. Exclusion criteria included: (1) history of previous malignancy; (2) prior antitumor treatment for HNSCC; (3) evidence of distant metastases; (4) recurrent HNSCC. This study was approved by the institutional review board of Sun Yat-sen University Cancer Center, and informed consent was waived due to its retrospective design.

Treatment and follow-up procedures

Neoadjuvant chemo-immunotherapy consisted of cisplatin 60 mg/m², albumin-bound paclitaxel 260 mg/m², and a programmed cell death protein 1 (PD-1) inhibitor administered on day one of each 3-week cycle. Subsequent treatment strategies were determined based on remission rate, physical condition, physician recommendation, and patient preference. Two to three weeks after the completion of neoadjuvant chemo-immunotherapy, a comprehensive evaluation, including CT, MRI, and/or PET-CT, was carried out to guide subsequent therapy, following a discussion among a multidisciplinary team comprising a surgeon, medical oncologist, and radiologist. Postoperative adjuvant (chemo)radiotherapy was prescribed as clinically indicated, adhering to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines. Radiographic assessments were conducted at baseline, 9 weeks after treatment initiation, and every 6 months thereafter, following RECIST v1.1 criteria. Pathologic response was evaluated by senior pathologists.

The primary endpoint of this study was OS and the secondary endpoint was event-free survival (EFS). OS was defined as the interval between initial diagnosis of HNSCC and death or last follow-up. EFS was defined as the time from initial diagnosis to disease progression that was unable to achieve surgery, local recurrences, distant metastases, occurrence of second primary malignancies, or death from any cause. Throat and hypopharyngeal function retention was defined as the preservation of glottal phonation without a prosthesis, the ability to swallow food without aspiration or a feeding tube, and the capacity to breathe without a permanent tracheostomy ²¹. The follow-up for this study concluded in July 2024.

Data collection

Demographic and clinicopathological features, including age at diagnosis, gender, smoking and alcohol history, tumor subsites, clinical stage, neoadjuvant regimen, number of cycles, radiographic response, pathological response, and subsequent therapy after neoadjuvant chemo-immunotherapy, were collected from electronic records. Survival outcomes were obtained through clinical records or telephone follow-ups.

Statistical analysis

Categorical variables and continuous variables were summarized as proportions and medians, respectively. Kaplan–Meier curves were generated to visualize OS and EFS rates, and a log-rank test was used for comparing differences among several groups. Multivariate Cox proportional hazards models were created to identify predictors of OS and EFS. Hazard ratios (HRs) with 95% confidence interval (CI) estimated from the Cox analysis were reported as relative risks. A two-sided P value of <0.05 was considered statistically significant. SPSS software version 25.0 (IBM Corp., Armonk, NY, USA) was used for the statistical analysis.

Demographics

A total of 87 T4 HNSCC patients who received neoadjuvant chemo-immunotherapy between April 2020 and March 2023 were included in this study (Fig 1). Patient and tumor characteristics are presented in Table 1. The median age was 58 years (range from 23 to 75), and the majority of patients were male (92%). Forty-two patients had tumors located in the hypopharynx (48.3%), 22 in the oral cavity (25.3%), 17 in the larynx (19.5%), and 6 in the oropharynx (6.9%). T4a and T4b stages accounted for 86.2% and 13.8% of patients, respectively. Seventy-six patients (87.4%) had cervical lymph node metastasis, with 56 of them classified as clinical N2 stage (64.4%). No involvement of the carotid artery or cervical spine by cervical lymph nodes was observed.

Table 1 Baseline characteristics of all patients (n = 87)

Characteristics	Cases	Percentage (%)
Age, median (range), years	58（23，75）
Gender
Male	80	92.0
Female	7	8.0
Smoking
No	46	52.9
Yes	41	47.1
Alcohol use
Never	40	46.0
Ever	47	54.0
Subtypes
Oral cancer	22	25.3
Oropharyngeal cancer	6	6.9
Laryngeal cancer	17	19.5
Hypopharyngeal cancer	42	48.3
Histology
Well differentiated	8	9.2
Moderately differentiated	30	34.5
Poorly differentiated	24	27.6
Not otherwise specified	25	28.7
Pretreatment Clinical T stage
T4a	75	86.2
T4b	12	13.8
Pretreatment Clinical N stage
N0	11	12.6
N1	2	2.3
N2	56	64.4
N3	18	20.7
Pretreatment AJCC stage
IV A	61	70.1
IV B	26	29.9
Neoadjuvant cycle
2	11	12.6
3	61	70.1
4	15	17.2
Best radiographic response
CR	9	10.3
PR	60	69.0
SD	16	18.4
PD	2	2.3
Therapy after neoadjuvant chemo-immunotherapy
Palliative care	3	3.4
Surgery alone	3	3.4
(Chemo)radiotherapy	53	60.9
Surgery + (Chemo)radiotherapy	28	32.2

Treatment characteristics

Sixty-one patients (70.1%) received 3 cycles of neoadjuvant chemo-immunotherapy, 15 patients (17.2%) received 4 cycles, and 11 patients (12.6%) received 2 cycles. After neoadjuvant chemo-immunotherapy, 3 patients did not complete the intended subsequent treatment, including 2 patients with a disease progression (PD) and 1 patient with an stable disease (SD). Among the 84 patients who received subsequent treatment, 31 (36.9%) underwent surgical resection, while 53 (63.1%) received (chemo)radiotherapy without surgery. Of the 31 patients who underwent surgery, 11 achieved a pCR, and of these, three declined further (chemo)radiotherapy, while the remaining 28 patients received adjuvant (chemo)radiotherapy after surgery.

Response rates and survival outcomes

The overall response rate after neoadjuvant chemo-immunotherapy was 75.8%, comprising 9 patients (10.3%) with a complete response (CR) and 60 patients (69.0%) with a partial response (PR). Additionally, 16 patients (18.4%) had an SD, and 2 patients (2.3%) had a PD (Fig 2).

Among the 87 T4 HNSCC patients enrolled, 25 patients (28.7%) died after a median follow-up of 24.6 months (IQR, 17.1 – 33.2 months), and the median OS had not been reached. The 1-year and 3-year OS rates were 90.8% and 66.7%, respectively (Fig 3A). As shown in Supplementary Table 1, a total of 31 patients (35.6%) experienced an event or death as their first event, including 18 patients with local recurrence, 4 patients with distant metastasis, 4 patients who died, 3 patients with second primary cancer, and 2 patients with a PD that precluded definitive surgery. The 1-year and 3-year EFS rates were 81.3% and 56.0%, and the median EFS was either not reached (Fig 3B). Various salvage treatment approaches were employed after the first event occurred in these 26 patients, with the most common being chemotherapy-based strategies (17 patients, 65.4%). Additionally, 2 patients underwent salvage surgery, 1 patient received combined immunotherapy and targeted therapy, and the remaining 6 patients received only palliative care. Among 59 patients with tumor located in the hypopharynx or larynx, 41 (69.5%) achieved retention of throat and hypopharyngeal function.

Prognostic factors for OS and EFS

Results from univariable Cox regression analysis (Table 2 and Table 3) showed that 3-4 cycles of neoadjuvant treatment, pretreatment clinical N0 stage, and favorable radiographic response (CR and PR) were associated with better OS and EFS, while pretreatment clinical T4b stage had a negative prognostic impact on OS. Even after adjusting for variables found to be significant in univariable analyses, 3-4 cycles of neoadjuvant treatment, pretreatment clinical N0 stage, and favorable radiographic response (CR and PR) remained significantly associated with improved OS and EFS. Kaplan-Meier analyses also revealed significant differences in survival outcomes among patients with varying radiographic responses (Fig 4).

Table 2 Univariable and Multivariable Cox Proportional Hazards Regression for predicting Overall Survival

Variables	Univariable analysis		Multivariable analysis
Variables	HR (95% CI)	p value	HR (95% CI)	p value
Gender		0.596
Female	1 (referent)
Male	0.50 (0.04-6.38)
Age (years)		0.416
<60	1 (referent)
≥60	0.66 (0.24-1.82)
Smoking		0.716
No	1 (referent)
Yes	1.19 (0.46-3.09)
Alcohol use		0.146
Never	1 (referent)
Ever	2.34 (0.75-7.35)
Subtypes		0.742
Oral cancer	1 (referent)
Oropharyngeal cancer	0.58 (0.05-6.64)
Laryngeal cancer	0.32 (0.04-2.60)
Hypopharyngeal cancer	0.50 (0.09-2.77)
Histology		0.377
Well differentiated	1 (referent)
Moderately differentiated	1.51 (0.38-6.01)
Poorly differentiated	0.48 (0.08-2.77)
Not otherwise specified	1.50 (0.29-7.72)
Neoadjuvant cycle		0.038		0.017
2	1 (referent)		1 (referent)
3	0.80 (0.25-2.57)		0.44 (0.18-1.08)
4	0.05 (0.01-0.49)		0.05 (0.01-0.45)
Pretreatment Clinical T stage		0.032		0.052
T4a	1 (referent)		1 (referent)
T4b	4.72 (1.14-19.51)		3.23 (0.99-10.56)
Pretreatment Clinical N stage		0.030		0.048
N0	1 (referent)		1 (referent)
N1-3	10.98 (1.26-95.53)		8.10 (1.02-64.39)
Best radiographic response		0.000		0.001
CR + PR	1 (referent)		1 (referent)
SD + PD	6.12 (2.21-16.93)		4.82 (1.92-12.14)
Subsequent therapy		0.277
Surgical therapy	1 (referent)
Non-surgical therapy	2.32 (0.51-10.55)

Table 3 Univariable and Multivariable Cox Proportional Hazards Regression for predicting Event-free Survival

Variables	Univariable analysis		Multivariable analysis
Variables	HR (95% CI)	p value	HR (95% CI)	p value
Gender		0.628
Female	1 (referent)
Male	0.63 (0.06-6.32)
Age (years)		0.390
<60	1 (referent)
≥60	0.68 (0.28-1.64)
Smoking		0.817
No	1 (referent)
Yes	1.10 (0.49-2.46)
Alcohol use		0.107
Never	1 (referent)
Ever	2.26 (0.84-6.09)
Subtypes		0.946
Oral cancer	1 (referent)
Oropharyngeal cancer	0.55 (0.06-5.10)
Laryngeal cancer	0.69 (0.12-4.17)
Hypopharyngeal cancer	0.87 (0.21-3.60)
Histology		0.383
Well differentiated	1 (referent)
Moderately differentiated	1.20 (0.33-4.34)
Poorly differentiated	0.50 (0.11-2.28)
Not otherwise specified	1.35 (0.30-6.03)
Neoadjuvant cycle		0.043		0.031
2	1 (referent)		1 (referent)
3	0.97 (0.33-2.83)		0.60 (0.25-1.41)
4	0.12 (0.02-0.71)		0.11 (0.02-0.57)
Pretreatment Clinical T stage		0.089		0.166
T4a	1 (referent)		1 (referent)
T4b	2.95 (0.85-10.27)		2.07 (0.74-5.81)
Pretreatment Clinical N stage		0.018		0.026
N0	1 (referent)		1 (referent)
N1-3	13.28 (1.56-113.13)		9.94 (1.31-75.46)
Best radiographic response		0.001		0.001
CR + PR	1 (referent)		1 (referent)
SD + PD	5.48 (2.05-14.64)		4.08 (1.81-9.19)
Subsequent therapy		0.533
Surgical therapy	1 (referent)
Non-surgical therapy	1.50 (0.42-5.39)

We then analyzed the relationship between subsequent therapy after neoadjuvant chemo-immunotherapy and survival outcomes in patients that finished the intended treatment procedure. Among these 84 patients, 31 underwent surgery-based treatment, while the other 53 received nonsurgical treatment. Kaplan-Meier estimates of OS and EFS (Fig 5) showed no significant difference between the surgical group and the nonsurgical group (p = 0.839 and 0.862, respectively). When we focused on the 60 patients with a PR after neoadjuvant treatment, Kaplan-Meier analyses also revealed equivalent OS and EFS between the surgical group and the nonsurgical group.

Thirty-one patients (35.6%) underwent surgical resection, including twenty with oral cancer (all radical surgeries), nine with hypopharyngeal cancer (five total laryngectomies with lymph node dissection and four simple neck lymph node dissections), one with laryngeal cancer (total laryngectomy with lymph node dissection), and one with oropharyngeal cancer (tonsil resection with neck lymph node dissection). Among these 31 patients who underwent surgery after neoadjuvant therapy, 11 patients (35.5%) achieved a pCR. OS was higher in patients with a pCR although it did not reach statistical significance (log-rank 3.24, p = 0.072), while EFS was significantly higher in patients who achieved a pCR (log-rank 5.04, p = 0.025) compared to those without a pCR, as determined by Kaplan-Meier analysis (Fig 6). In the 11 patients who achieved a pCR, 8 continued with subsequent (chemo)radiotherapy, while the other 3 did not. Ten out of these 11 patients (90.9%) were alive and disease-free until the end of follow-up, whereas only one patient who did not undergo subsequent (chemo)radiotherapy developed local recurrence and eventually died.

In our analysis, 12 out of 87 patients (13.8%) were classified as T4b pretreatment. Among these 12 patients, 11 (91.7%) achieved a PR, while one had an SD following neoadjuvant chemo-immunotherapy. Notably, 8 of the 12 patients (66.7%) were successfully converted to resectable status. Of these 8 patients, 5 underwent surgical treatment, and none required free flap reconstruction for the resulting defect. Importantly, 3 of the 5 patients who had surgery demonstrated a pCR and remained alive and disease-free throughout the follow-up period. In addition to these 5 patients, the remaining 7 received (chemo)radiotherapy after neoadjuvant therapy. During the follow-up, 5 of the 12 patients (41.7%) developed local recurrence or distant metastasis, and 4 of these 5 patients died due to tumor progression. The OS rate was 66.7%, and the EFS rate was 58.3%, following a median follow-up period of 24.6 months.

Fig 7 illustrates notable tumor regression in two representative cases from this study. In Fig 7A-F, a patient (P85) with T4aN0M0 HNSCC involving the left larynx had his primary tumor completely disappear after neoadjuvant therapy, followed by (chemo)radiotherapy without surgery. In Fig 7G-H, another patient (P32) with T4bN0M0 HNSCC in the left posterior region of the maxilla experienced significant reduction of the primary tumor bulk, achieving a PR following neoadjuvant therapy. Surgery was subsequently performed on this patient, resulting in a pCR. Both patients remained alive and free of disease during the follow-up periods of 31.0 and 17.8 months, respectively.

Adverse events

The most common treatment-related adverse events (TRAEs) were alopecia (100.0%), nausea/vomiting (63.2%), fatigue (46.0%), and pain (40.2%) of all grades (Supplementary Table 2). 6 patients experienced grade 3 TRAEs, including 3 patients with leukopenia, 2 patients with pneumonitis, and 1 patient with peripheral neuropathy. One patient experienced grade 4 TRAEs (leukopenia). No previously unknown or unexpected TRAEs were observed. No TRAEs leading to death occurred.

This study is, to our knowledge, the first long-term analysis evaluating the efficacy and safety of neoadjuvant chemo-immunotherapy specifically for T4 HNSCC. The ORR was 79.3%, with generally manageable toxicities. The 1-year and 3-year OS rates for the total cohort were 90.8% and 66.7%, while the 1-year and 3-year EFS rates were 81.3% and 56.0%, respectively. Notably, neoadjuvant chemo-immunotherapy demonstrated impressive results in T4b stage HNSCC patients, with 66.7% converting to resectable status. These findings indicate that neoadjuvant chemo-immunotherapy provides favorable survival benefits for T4 HNSCC, based on a relatively large cohort of 87 patients with a median follow-up of 24.6 months.

LAHNSCC, particularly at T4 staging, presents limited treatment options and poor clinical prognosis. Radical surgery, when feasible, often involves increased surgical risks, significant functional impairment, and reduced quality of life ^3-5. Neoadjuvant chemotherapy aims to reduce the extent of required surgery and radiotherapy, though it has not significantly improved OS in HNSCC patients ²². Immune checkpoint inhibitors (ICIs), which block immune checkpoints responsible for T cell dysfunction and immune evasion in tumors, have emerged as promising treatments. The KEYNOTE-048 trial established that pembrolizumab alone or in combination with chemotherapy resulted in better OS compared to the EXTREME regimen for recurrent or metastatic HNSCC ⁸. Additionally, neoadjuvant immunotherapy has shown excellent radiographic responses and encouraging survival benefits in several clinical trials for LAHNSCC ^18-20.

However, patients with T4 stage constitute only a small proportion (27.6% to 37.5%) in these studies ^15,18-20,23. The efficacy and safety of neoadjuvant immunotherapy in this subgroup remain unclear due to the lack of specific analysis, highlighting the need for further research focused exclusively on T4 HNSCC.

In the current study, neoadjuvant chemo-immunotherapy yielded a high ORR rate of 75.8% in 87 T4 HNSCC patients. Many previous studies have reported even higher ORR rates, with Wu et al. reporting 89.6% (43/48) and Zhang et al. reporting 96.7% (29/30) in patients with locally advanced HNSCC receiving neoadjuvant camrelizumab plus chemotherapy ^18,19. This discrepancy may be attributed to the greater tumor burden indicated by T4 staging, which can lead to decreased sensitivity to drug therapy.

A high ORR after neoadjuvant chemo-immunotherapy expands opportunities for de-escalation in subsequent treatment modalities. Remarkably, 60.9% (53/87) of the patients in this study achieved radical (chemo)radiotherapy while avoiding surgery. One possible explanation is the relatively high proportion of tumors located in the larynx (19.5%) and hypopharynx (48.3%), which had higher ORR rates of 88.2% and 81.0%, respectively, compared to oral cancer (68.2%). Gong et al. observed a similar ORR of 82.4% in hypopharyngeal carcinoma patients after induction therapy ²⁴. Wu et al. also reported a higher ORR for throat cancers (oropharynx, larynx, and hypopharynx), which are more sensitive to chemotherapy than oral cancers ¹⁹. Additionally, we classified patients according to whether they underwent surgery after neoadjuvant therapy and found no significant association between subsequent surgery and survival outcomes in univariable analysis. More prospective studies, such as the ongoing multicenter trial NCT05872880, are needed to evaluate the impact of de-escalation surgery following neoadjuvant chemo-immunotherapy on prognosis of HNSCC.

Among the 31 patients who underwent surgery after neoadjuvant therapy, 11 (35.5%) achieved a pCR, which is lower than previously reported rates of 55.6% by Wu et al. ¹⁹ and 37.0% by Zhang et al. ¹⁸ in LAHNSCC. This discrepancy may be due to differences in patient populations across studies. Notably, patients with a pCR were strongly associated with higher OS rates (90.9% vs. 60.0%) and EFS rates (90.9% vs. 45.0%) compared to those without a pCR. Ten out of these 11 patients (90.9%) who achieved a pCR were alive and disease-free until the end of follow-up. Similarly, Trisha et al. reported significantly increased 1-year progression-free survival (PFS) (93% vs. 72%) and OS (100% vs. 93%) rates when comparing patients with any pathological response to those without in previously untreated, resectable LAHNSCC receiving neoadjuvant and adjuvant pembrolizumab with (chemo)radiotherapy ²⁵. The final analysis of a phase II trial of neoadjuvant chemo-immunotherapy for locoregionally advanced HNSCC reported a similar survival rate of 90.0% in patients with a pCR after a median follow-up of 33.7 months ²⁶. Further evaluation system is required to assess the de-escalation of radiotherapy in patients who achieve a pCR after neoadjuvant therapy.

In this study, neoadjuvant chemo-immunotherapy followed by surgery and/or (chemo)radiotherapy in locally advanced (T4) HNSCC showed encouraging survival outcomes, with high 1-year and 3-year OS rates of 90.8% and 66.7%. Cox regression analysis revealed that pretreatment clinical lymph node metastasis, poor radiographic response (SD and PD), and having only 2 cycles of neoadjuvant treatment were significantly associated with decreased OS. Therefore, greater attention should be given to subsequent treatment modalities in patients with these characteristics. Our results showed a throat and hypopharyngeal function retention rate of 69.5%, slightly lower than previously reported studies ^19,24,27. However, these results remain promising, considering the very advanced stage of patients included in the current study.

This study is the first to report the surgical conversion rate and prognosis of patients with T4b stage HNSCC after neoadjuvant chemo-immunotherapy. In our analysis, 91.7% of T4b patients achieved a PR and 66.7% of patients were successfully converted to resectable status. The OS rate was 66.7%, while the EFS rate was 58.3% after a median follow-up period of 24.6 months. These results are encouraging, particularly given the limited treatment options and previously reported poor outcomes for this specific subgroup. ^4,28-30.

Events, including disease progression that precluded definitive surgery, local or distant recurrence, development of a second primary cancer, or death from any cause, occurred in 31 (35.6%) patients. Among them, local recurrence was the most frequently observed first event, occurring in 18 cases. Sixteen out of 18 of these patients eventually died during follow-up, despite various therapies being administered after local recurrence, which remains the greatest challenge in treating LAHNSCC.

Limitations of this study include the relatively small sample size, despite it being one of the largest cohorts for T4 HNSCC, and the potential for omissions or inaccuracies inherent in a retrospective design. Several variables that may also have prognostic significance for functional or oncologic outcomes were not available, including PD-L1 expression levels, tumor mutational burden (TMB), and tumor-infiltrating immune cells.

In conclusion, this study conducted induction therapy with a PD-1 inhibitor combined with cisplatin and albumin-bound paclitaxel in 87 patients with T4 HNSCC, yielding a favorable ORR rate. Following definitive surgery and/or (chemo)radiotherapy, the OS and EFS rates were also promising. These results suggest that the regimen of neoadjuvant chemo-immunotherapy is an effective treatment option with good tolerance for the very advanced (T4) subgroup of HNSCC. Further prospective clinical studies are essential to investigate these findings.

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. The authors have no relevant financial or non-financial interests to disclose. All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Ke Jiang, Qi Fang, Fei Cao, and Pengfei Xu. The first draft of the manuscript was written by Ke Jiang and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. This retrospective study was approved by the Institutional Review Board of SYSUCC, one of the largest cancer centers in China (No. B2024-678-01). Informed consent was obtained from all individual participants included in the study. The authors affirm that human research participants provided informed consent for publication of the images in Fig 7.

Author Contribution

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Ke Jiang, Qi Fang, Fei Cao, and Pengfei Xu. The first draft of the manuscript was written by Ke Jiang and all authors commented on previous versions of the manuscript.

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No competing interests reported.

Neoadjuvant Chemo-Immunotherapy in Very Advanced (T4) Head and Neck Squamous Cell Carcinoma: A Real-World Study

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