Abstract
Background
Chemoimmunotherapy is the first-line therapy for patients with recurrent or metastatic nasopharyngeal carcinoma (NPC) and is currently the main induction treatment option for patients with locoregionally advanced NPC. However, it remains unclear whether combining immunotherapy with standard induction chemotherapy enhances its efficacy. This study aimed to evaluate the efficacy, toxicity, and survival outcomes of induction chemoimmunotherapy in patients with locoregionally advanced NPC.
Methods
This study analyzed 50 patients with stage IVa NPC between January 2020 and December 2023 in our hospital. Among them, 23 received induction chemoimmunotherapy, and 27 received induction chemotherapy. All patients underwent standard platinum-based concurrent intensity-modulated radiation therapy. We compared tumor response and toxicity during induction treatment and concurrent chemoradiotherapy (CCRT) between the two groups.
Results
The objective and complete response rates were significantly higher in the induction chemoimmunotherapy group compared to the induction chemotherapy group (95.7% vs 77.8%, and 39.1% vs 22.2%, respectively). All patients completed radical CCRT. Median follow-up was 24 months. Patients who received induction chemoimmunotherapy had longer event-free survival (EFS) compared to those who received induction chemotherapy (p = 0.029, Hazard Ratio and 95%confidence interval [CI]: 0.24 [0.07–0.85]). The 24-month EFS was higher in the induction chemoimmunotherapy group compared with the chemotherapy group (24-month EFS rates and 95%CI: 88.9% [95%CI: 68.3%–100%] vs 62.6% [95%CI: 43.1%–82.1%]). No significant differences in adverse events were observed between the two groups during induction treatment and CCRT.
Conclusions
Adding immunotherapy to induction chemotherapy may be an effective and safe choice for treating patients with stage IVa NPC.
Keywords: Induction treatment, immunotherapy, chemotherapy, chemoimmunotherapy, nasopharyngeal carcinoma
GRAPHICAL ABSTRACT
Introduction
Nasopharyngeal carcinoma (NPC) is a prevalent malignancy in South China, with an annual incidence of approximately 2–3 per 100,000 [1]. In 2022, statistics from the National Central Cancer Registry revealed that approximately 51,000 new cases and 28,400 NPC-related deaths occurred in China [2]. Despite advances in intensity-modulated radiotherapy and chemotherapy, the 5-year overall survival (OS) rate now exceeds 90% for early-stage NPC [3]. However, the prognosis of advanced-stage NPC and metastatic disease remains poor. Over the last decade, immunotherapy has made breakthroughs in becoming the first-, second-, and later-line treatments for recurrent or metastatic NPC [4,5].
Immunotherapy is applied in various forms for locoregionally advanced NPC, including induction therapy, concurrent radiotherapy, adjuvant therapy, and full-course treatment. Ongoing phase 3 studies suggest that immunotherapy plays a significant role in locally advanced NPC; however, the optimal treatment approach remains unclear. The CONTINUUM study demonstrated that adding sintilimab, a programmed cell death protein-1 inhibitor, to induction chemotherapy and concurrent chemoradiotherapy (CCRT) improved event-free survival (EFS) in non-metastatic high-risk locoregionally advanced NPC [6]. Previous phase 3 trials suggest that immunotherapy plus CCRT showed no EFS benefit in patients with locoregionally advanced head and neck squamous cell carcinoma [7,8], possibly due to timing differences in immunotherapy administration before radiotherapy. The role of immunotherapy in the induction phase for locoregionally advanced NPC remains unclear. Patients with stage IVa NPC have the poorest prognosis among locoregionally advanced NPC, necessitating urgent improvement in therapeutic outcomes.
Therefore, we conducted a real-world study to evaluate the efficacy and safety of immunotherapy plus chemotherapy as first-line induction treatment before radiotherapy in patients with stage IVa NPC.
Materials and methods
Patients
This study utilized patient records from Heyuan Hospital of Guangdong Provincial People’s Hospital from January 2019 to December 2023. This study was approved by the Ethics Committee of Heyuan Hospital of Guangdong Provincial People’s Hospital (ethics approval ID: No. HYYXYJ-iit202411) and conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent. The eligible patients were histologically diagnosed with NPC. TNM staging was performed according to the eighth edition of the American Joint Committee on Cancer Staging System for NPC.
The inclusion criteria were as follows: (1) histologically diagnosed NPC; (2) primary clinical stage IVa (T4NanyM0/TanyN3M0); and (3) at least two cycles of PD-1 inhibitor therapy (sintilimab, toripalimab, camrelizumab, or pembrolizumab) and/or chemotherapy followed by locoregional radiotherapy. The exclusion criteria encompassed patients unable to tolerate immunotherapy or chemotherapy, including those with severe coronary heart disease, cerebral infarction, or serious infections.
Induction chemoimmunotherapy
Patients received immunotherapy according to clinical guidelines from the Chinese Society of Clinical Oncology. Specific drug instructions included administering the following drugs on day 1: sintilimab (200 mg), triplizumab (200 mg), toripalimab (240 mg), and camrelizumab (200 mg). Chemotherapy regimens included docetaxel (75 mg/m2; day 1), nab-paclitaxel (260 mg/m2; day 1), gemcitabine (1000 mg/m2; days 1 and 8), cisplatin (75–80 mg/m2; day 1), nedaplatin (80–100 mg/m2; day 1), carboplatin (AUC 4–6; day 1), lobaplatin (30 mg/m2; day 1), and 5-fluorouracil (1000 mg/m2; days 1–5). Immunotherapy and chemotherapy were prescribed every 21 days for at least two cycles.
CCRT
A medical linear accelerator (Elekta Precise Treatment System) served as the radioactive source. Following induction therapy (chemoimmunotherapy or chemotherapy), patients received one fraction of intensity-modulated radiation therapy daily for 5 consecutive days per week. The prescribed doses were as follows: 95% planning gross target volume nasopharynx (PGTVnx), 70–72 Gy/32–33 F; 95% planning gross target volume lymph node (PGTVnd), 66–70 Gy/32–33 F; 95% planning target volume 1 (PTV1), 60 Gy/32–33 F; and 95% planning target volume 2 (PTV2), 54 Gy/32–33 F. The radiotherapy technique and dosing adhered to guidelines from the Chinese Society of Clinical Oncology. During radiotherapy, patients received concurrent chemotherapy with a single platinum for 1–3 cycles and/or nimotuzumab (100–200 mg/m2 weekly for six doses).
Treatment assessment and toxicity evaluation
Treatment response was assessed using the Response Evaluation Criteria in Solid Tumor version 1.1, with evaluations performed every 2–3 cycles during induction therapy. The objective response rate (ORR) was the proportion of patients who achieved complete remission (CR) and partial remission (PR). EFS was the time from therapy initiation to first relapse, progression, or death from any cause. OS, the time from therapy initiation to death from any cause was calculated, and living patients were censored at the last follow-up. Locoregional recurrence-free survival (LRFS) assessed the period from therapy initiation to the first locoregional failure, whereas distant metastasis-free survival (DMFS) was defined as the period from therapy initiation to distant failure. The study concluded follow-up in June 2024, with a median follow-up period of 24 months (range: 7–48 months). Follow-ups were performed from the first day of treatment until the last visit or death. Acute adverse effects were graded using Common Toxicity Criteria for Adverse Events (CTCAE) v5.0, while the Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer (EORTC) were used for late adverse effects.
Statistical analysis
All statistical analyses were performed using SPSS (version 22.0; Chicago, USA) and MedCalc (version 20; Ostend, Belgium). Kaplan–Meier curves were used to present time-to-event data, which were compared using a log-rank test. Hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using unstratified Cox proportional hazards models. Two-sided P values <0.05 were considered statistically significant.
Results
Characteristics of patients and treatment
Figure 1 outlines the patient inclusion process. Among the 50 enrolled patients, 38 (76.0%) were male, and 12 (24.0%) were female, with a median age of 57 years. All patients had clinical stage IVa NPC, with 30 (60.0%) classified as T4 and 30 (60.0%) as N3. Overall, 23 patients who received immunotherapy plus induction chemotherapy for 2–6 cycles were classified into the induction chemoimmunotherapy group, and 27 patients who received induction chemotherapy alone for 2–5 cycles were classified into the induction chemotherapy group. Immunotherapies administered during induction included sintilimab (n = 16, 69.6%), toripalimab (n = 4, 17.4%), tislelizumab (n = 2, 8.7%), and camrelizumab (n = 1, 4.3%). Table 1 presents detailed clinical characteristics of the treatment groups.
Figure 1.
Flow chart of participant inclusion. NPC: nasopharyngeal carcinoma; CCRT: concurrent chemoradiotherapy; PD-1: programmed cell death 1.
Table 1.
Characteristics of the NPC patients.
| Characteristics n(%) | Induction chemoimmunotherapy group (n = 23) | Induction chemotherapy group (n = 27) |
|---|---|---|
| Age | ||
| <60 years | 12 (52.2) | 16 (59.3) |
| ≥60 years | 11 (47.8) | 11 (40.7) |
| Sex | ||
| Male | 20 (87.0) | 18 (66.7) |
| Female | 3 (13.0) | 9 (33.3) |
| Ethnicity | ||
| Chinese | 23(100) | 27(100) |
| Other | 0 (0) | 0 (0) |
| Smoking | ||
| Never smoked | 3(13.0) | 11(40.7) |
| Current or former smoker | 20(87.0) | 16(59.3) |
| T stage | ||
| T1 | 3 (13.0) | 1 (3.7) |
| T2 | 3 (13.0) | 2 (7.4) |
| T3 | 6 (26.1) | 5 (18.5) |
| T4 | 11 (47.9) | 19 (70.4) |
| N stage | ||
| N0 | 0 (0) | 1 (3.7) |
| N1 | 3 (13.0) | 5 (18.5) |
| N2 | 2 (8.7) | 9 (33.3) |
| N3 | 18 (78.3) | 12 (44.5) |
| Cycles of neoadjuvant therapy | ||
| 2 | 2 (8.7) | 6 (22.2) |
| 3 | 10 (43.6) | 13 (48.1) |
| 4 | 7 (30.4) | 7 (26.0) |
| 5 | 3 (13.0) | 1 (3.7) |
| 6 | 1 (4.3) | 0 (0) |
| PD-1 inhibitor | ||
| Sintilimab | 16 (69.6) | / |
| Toripalimab | 4 (17.4) | / |
| Tislelizumab | 2 (8.7) | / |
| Camrelizumab | 1 (4.3) | / |
| Chemotherapy | ||
| TP | 21 (91.3) | 25 (92.6) |
| TPF | 2 (8.7) | 0 (0) |
| GP | 0(0) | 2 (7.4) |
NPC: nasopharyngeal carcinoma; T: tumor; N: lymph nodes; TP: paclitaxel/platinum; TPF: paclitaxel/platinum/5-fluorouracil; GP: gemcitabine/platinum.
Treatment response
Detailed induction treatment outcomes for patients are shown in Figure 2 and Table 2. The chemoimmunotherapy group had higher CR and PR rates compared to the chemotherapy group. In the induction chemoimmunotherapy group, nine (39.1%) patients achieved CR, 13 (56.6%) achieved PR, and one (4.3%) had stable disease (SD). In the induction chemotherapy group, CR, PR, and SD occurred in six (22.2%), 15 (55.6%), and six (22.2%) patients, respectively. After induction treatment, the ORR was significantly higher in the chemoimmunotherapy group compared to the chemotherapy group (95.7% [95%CI:78.1–99.9%) versus 77.8% [95%CI:57.7–91.4%]). The ORR for primary lesions in the induction chemoimmunotherapy group was 91.3% (95%CI: 72.0–98.9%) (21 of 23) and 70.4% (95%CI: 49.8–86.2%) (19 of 27) in the induction chemotherapy group. Moreover, the ORR of regional lymph nodes was 87.0% (20/23) in the induction chemoimmunotherapy group, with CR in 17 patients and PR in 3, compared to 76.9% (20/26, a patient had no lymph node metastasis) in the chemotherapy group (CR in 12 patients and PR in 8). Figure 2 illustrates a waterfall plot of the radiographic response to induction treatment for individual patients. Overall, the ORR was relatively higher in the induction chemoimmunotherapy group than in the induction chemotherapy group.
Figure 2.
Waterfall plot of best response from baseline. The maximum percentage change in target lesion compared with baseline for each patient. CR: complete response; PR: partial response; SD: stable disease.
Table 2.
Summary of tumour response to induction treatment.
| Induction chemoimmunotherapy group (n = 23) | Induction chemotherapy group (n = 27) | |
|---|---|---|
| Response of global lesion | ||
| Complete response, n(%) | 9 (39.1) | 6 (22.2) |
| Partial response, n(%) | 13 (56.6) | 15 (55.6) |
| Stable disease, n(%) | 1 (4.3) | 6 (22.2) |
| Progressive disease, n(%) | 0 (0) | 0 (0) |
| Objective response rate, n, % (95% CI) | 22, 95.7% (78.1%-99.9%) | 21, 77.8% (57.7%-91.4%) |
| Rate difference, % (95% CI) | 17.9% (0.2%-35.6%) | |
| Response of primary lesion | ||
| Complete response, n(%) | 11 (47.8) | 7 (26.0) |
| Partial response, n(%) | 10 (43.5) | 12 (44.4) |
| Stable disease, n(%) | 2 (8.7) | 8 (29.6) |
| Progressive disease, n(%) | 0 (0) | 0 (0) |
| Objective response rate, n, % (95% CI) | 21, 91.3% (72.0%-98.9%) | 19, 70.4% (49.8%-86.2%) |
| Rate difference, % (95% CI) | 20.9% (0.2%-41.7%) | |
| Response of regional lymph nodes | ||
| Complete response, n(%) | 17 (74.0) | 12 (46.1) |
| Partial response, n(%) | 3 (13.0) | 8 (30.8) |
| Stable disease, n(%) | 3 (13.0) | 6 (23.1) |
| Progressive disease, n(%) | 0 (0) | 0 (0) |
| Objective response rate, n, % (95% CI) | 20, 87.0% (66.4%–97.2%) | 20, 76.9% (56.4%–91.0%) |
| Rate difference, % (95% CI) | 10.0% (0%–33.1%) |
Detailed treatment outcomes of CRRT are summarized in Table 3. All patients underwent radical CCRT. The chemoimmunotherapy group had a higher CR rate than the chemotherapy group, with 91.3% (21/23) achieving CR in the induction chemoimmunotherapy group, whereas the rate was 70.4% (19/27) in the induction chemotherapy group.
Table 3.
Summary of tumour response to concurrent chemoradiotherapy.
| Induction chemoimmunotherapy group (n = 23) | Induction chemotherapy group (n = 27) | |
|---|---|---|
| Complete response, n(%) | 21 (91.3) | 19 (70.4) |
| Partial response, n(%) | 2 (8.7) | 8 (29.6) |
| Stable disease, n(%) | 0 (0) | 0 (0) |
| Progressive disease, n(%) | 0 (0) | 0(0) |
Survival outcomes
The induction chemoimmunotherapy group exhibited a significantly improved EFS compared to the induction chemotherapy group (p = 0.029, HR, and 95%CI: 0.24 [0.07–0.085], Figure 3(A)). The median OS was not reached in either group. The median follow-up period was 24 months. 24-month EFS was higher in the induction chemotherapy group than in the chemotherapy group (24-month EFS rate and 95% CI: 88.9% [68.3–100%] vs. 62.6% [43.1–82.1%]). OS data were not obtained. At the survival analysis cutoff date of June 2024, four deaths had been reported, one (4.3%) in the induction chemoimmunotherapy group and three (11.1%) in the induction chemotherapy group, all attributed to non-cancer-related causes. The 2-year OS, LRFS, and DMFS rates for the chemoimmunotherapy and chemotherapy groups were 89.8% and, 88.9%, 100% and 85.4%, and 100% and 86.7%, respectively. There were no significant differences in the OS (p = 0.497, Figure 3(B)), LRFS (p = 0.146, Figure 3(C)), or DMFS (p = 0.122, Figure 3(D)) between the two groups.
Figure 3.
Kaplan–Meier analysis of survival. (A) Event-free survival. (B) Overall survival. (C) Locoregional recurrence-free survival. (D) Distant metastasis-free survival. NA: not applicable; NR: not reached; OS: overall survival; EFS: event-free survival; LRFS: locoregional recurrence-free survival; DMFS: distant metastasis-free survival.
Adverse events
During induction therapy, all patients in both groups experienced at least one treatment-emergent adverse event, mostly graded as 1–2 (Table 4 and Figure S1). Only one case of grade 3 increased aminotransferase levels was observed in the induction chemoimmunotherapy group, and one case of grade 4 thrombocytopenia was noted in the induction chemotherapy group. Grade 1–2 nausea, vomiting, and anemia were the most common toxic effects, occurring in 18 (78.2%), 11 (47.8%), and 13 (56.5%) patients in the induction chemoimmunotherapy group and 21 (77.8%), 16 (59.3%), and 14 (51.9%) patients in the induction chemotherapy group, respectively. Immune-related adverse events were observed in three (13.0%) patients in the induction chemoimmunotherapy group, including one patient with concurrent grade 3 increased aminotransferase and grade 1 arthralgia and two patients with grade 1 arthralgia and pruritus.
Table 4.
Induction treatment-related adverse events.
| Event (%) | Induction chemoimmunotherapy group (n = 23) |
Induction chemotherapy group(n = 27) |
||
|---|---|---|---|---|
| Grade 1/2 | Grade 3/4 | Grade 1/2 | Grade 3/4 | |
| Treatment-related adverse event | ||||
| Leucopenia | 6(26.1) | 0(0) | 9(33.3) | 0(0) |
| Neutropenia | 6(26.1) | 0(0) | 6(22.2) | 0(0) |
| Anemia | 13(56.5) | 0(0) | 14(51.9) | 0(0) |
| Thrombocytopenia | 3(13.0) | 0(0) | 2(7.4) | 1(3.7) |
| Nausea | 18(78.2) | 0(0) | 21(77.8) | 0(0) |
| Vomiting | 11(47.8) | 0(0) | 16(59.3) | 0(0) |
| Diarrhea | 0(0) | 0(0) | 1(3.7) | 0(0) |
| Aminotransferase increased | 2(8.7) | 1(4.3) | 6(22.2) | 0(0) |
| Cholerythrin increased | 1(4.3) | 0(0) | 3(11.1) | 0(0) |
| Cholesterol increased | 4(17.4) | 0(0) | 5(18.5) | 0(0) |
| Pneumonia | 1(4.3) | 0(0) | 0(0) | 0(0) |
| Creatinine increased | 2(8.7) | 0(0) | 0(0) | 0(0) |
| Pruritus | 1(4.3) | 0(0) | 1(3.7) | 0(0) |
| Peripheral neuropathy | 4(17.4) | 0(0) | 8(29.6) | 0(0) |
| Arthrodynia | 2(8.7) | 0(0) | 0(0) | 0(0) |
| Immune-related adverse events | ||||
| Pruritus | 1(4.3) | 0(0) | / | / |
| Arthrodynia | 2(8.7) | 0(0) | / | / |
| Aminotransferase increased | 0(0) | 1(4.3) | / | / |
During CCRT, five (21.7%) of the 23 patients in the induction chemoimmunotherapy group and six (22.2%) of the 27 patients in the induction chemotherapy group experienced grade 3–4 adverse events (Table 5 and Figure S2). Specifically, these included leukopenia (17.4% vs. 7.4%), neutropenia (13.0% vs. 7.4%), anemia (4.3% vs. 3.7%), thrombocytopenia (13% vs. 14.8%), and weight loss (8.7% vs. 7.4%) in both groups. The commonest acute adverse events of grade 1–2 for CCRT were anemia (18 [78.2%] of 23 patients in the induction chemoimmunotherapy group vs. 23 [85.2%] of 27 patients in the induction chemotherapy group), weight loss (15 [65.2%] vs. 18 [66.6%]), leucopenia (13 [56.5%] vs 16 [59.3%]), and dysphagia (11 [47.8%] vs 12 [44.4%]). The most common late adverse events of CCRT were grade 1–2 hearing impairment (26.1% vs. 37.0%) and dry mouth (30.4% vs. 33.3%) (Table 5 and Figure S2). No treatment-related death occurred in either group. Overall, adverse events were predominantly grade 1–2 and well tolerated, with no significant differences observed between the groups during the induction treatment and CCRT periods.
Table 5.
Concurrent chemoradiotherapy-related adverse events.
| Event (%) | Induction chemoimmunotherapy group (n = 23) |
Induction chemotherapy group(n = 27) |
||
|---|---|---|---|---|
| Grade 1/2 | Grade 3/4 | Grade 1/2 | Grade 3/4 | |
| Acute adverse events | ||||
| Leucopenia | 13(56.5) | 4(17.4) | 16(59.3) | 2(7.4) |
| Neutropenia | 10(43.5) | 3(13.0) | 9(33.3) | 2(7.4) |
| Anemia | 18(78.2) | 1(4.3) | 23(85.2) | 1(3.7) |
| Thrombocytopenia | 8(34.8) | 3(13.0) | 8(29.6) | 4(14.8) |
| Nausea | 9(39.1) | 0(0) | 10(37.0) | 0(0) |
| Vomiting | 9(39.1) | 0(0) | 9(33.3) | 0(0) |
| Dry mouth | 7(30.4) | 0(0) | 9(33.3) | 0(0) |
| Weight loss | 15(65.2) | 2(8.7) | 18(66.6) | 2(7.4) |
| Mucositis | 5(21.7) | 0(0) | 10(37.0) | 0(0) |
| Dermatitis | 7(30.4) | 0(0) | 9(33.3) | 0(0) |
| Dysphagia | 11(47.8) | 0(0) | 12(44.4) | 0(0) |
| Cholerythrin increased | 3(13.0) | 0(0) | 0(0) | 0(0) |
| Late adverse events | ||||
| Hearing impaired | 6(26.1) | 0(0) | 10(37.0) | 0(0) |
| Dry mouth | 7(30.4) | 0(0) | 9(33.3) | 0(0) |
| Dysphagia | 1(4.3) | 0(0) | 3(11.1) | 0(0) |
| Dysgeusia | 3(13.0) | 0(0) | 4(14.8) | 0(0) |
| Dental disorders | 1(4.3) | 0(0) | 3(11.1) | 0(0) |
| Peripheral neuropathy | 3(13.0) | 0(0) | 3(11.1) | 0(0) |
| Temporal lobe injury | 1(4.3) | 0(0) | 2(7.4) | 0(0) |
Discussion
This study evaluated the efficacy and safety of induction chemoimmunotherapy in patients with stage IVa NPC. We found that induction chemoimmunotherapy resulted in a higher ORR and significantly improved EFS without increasing adverse events. These findings suggest induction chemoimmunotherapy is a promising novel induction treatment strategy for stage IVa NPC, with manageable safety profiles.
Induction chemotherapy followed by cisplatin-based CCRT is currently the standard first-line treatment for advanced NPC [9]. Despite advances, the prognosis of patients with locoregionally advanced NPC, especially stage T4 or N3 NPC, remains poor [10]. Patients with stage T4 NPC have the highest risk of local failure, with a 5-year local failure-free survival (FFS) of 76%, compared to over 90% for T1–3 stages [11]. Compared with 79.8–88.6% of patients with N1–2 disease, N3 disease had significantly poorer distant FFS (approximately 66%) [11]. Recent phase 3 trials have established immunotherapy plus chemotherapy as a new standard for recurrent or metastatic NPC [12–15]. Similar approaches in head and neck squamous cell carcinoma have demonstrated higher ORRs and acceptable safety profiles compared to chemotherapy alone [16]. In a real-world retrospective study of locally advanced oral or oropharyngeal squamous cell carcinoma, induction chemoimmunotherapy followed by surgery achieved a 66.7% ORR before surgery, 54.5% major pathological response rate, and 33.3% pathological complete response (pCR) rate after surgery [17]. Moreover, three single‑arm phase 2 clinical trials of resectable locally advanced head and neck squamous cell carcinoma suggested that the ORR was 96.7%, 57.0%, and 89.6% in patients who completed induction chemoimmunotherapy, respectively, and the pCR rates were 37.0%, 29.0%, and 55.6% in patients who underwent surgery [18–20]. Additionally, the high ORR (86.7%) was attributed to the combined use of induction chemotherapy and immunotherapy in 15 patients with head and neck squamous cell carcinoma or NPC [21]. Our results showed that induction chemoimmunotherapy led to a satisfactory ORR rate of 95.7% in patients with stage IVa NPC. Consistent findings were reported by Yao et al. who observed an ORR improvement to 88.1% with the addition of immunotherapy to induction chemotherapy in stage III-IVa disease [22]. In an observational, propensity score-matched analysis, although the induction chemoimmunotherapy group showed a notably higher CR compared to standard induction chemotherapy, the ORRs were not significantly different (92.7% vs. 94.7%) [23]. After the induction treatment from CONTINUUM study, there were 192 patients (92%) in the sintilimab plus GP (gemcitabine and platinum) group who demonstrated a complete or partial response to induction therapy, whereas 194 patients (91%) in the standard GP therapy group showed the same kind of response [6]. This variation in ORR may stem from differences in immunotherapy combined with various chemotherapy regimens. It is worth noting that, in the context of induction treatment for locoregionally advanced NPC, the GP regimen, which already has a relatively high ORR, might not derive additional benefits from immunotherapy to a greater extent compared to the TP (paclitaxel/docetaxel and platinum) regimen. It is worth our further attention that there are some other potential biases related to the efficacy of induction treatment. Interestingly, a phase 2 randomized controlled trial showed that the ORR after induction treatment was only 17% in patients with locoregionally advanced NPC who received neoadjuvant toripalimab without chemotherapy [24].
The incorporation of immunotherapy into standard chemoradiotherapy has significantly enhanced the survival outcomes of patients with locoregionally advanced NPC. The phase 3 CONTINUUM study showed that the addition of immunotherapy with sindlimab throughout the whole process (the induction period, the concurrent chemoradiotherapy period, and the adjuvant period) could improve the EFS, DMFS, and LRFS of patients with locally advanced nasopharyngeal carcinoma, but there was no significant improvement in the overall survival [6]. Similarly, the phase 3 DIPPER study also indicated that adjuvant immunotherapy with camrelizumab significantly improved EFS, DMFS and LRFS in locoregionally advanced NPC [25]. Previous clinical trials have suggested that patients with locoregionally advanced NPC who achieved CR/PR after induction chemotherapy had longer FFS than those with SD/PD [26,27]. Thus, we retrospectively analyzed the role of adding immunotherapy during the induction chemotherapy in patients with locally advanced NPC, and found induction chemoimmunotherapy resulted in a higher ORR and significantly improved EFS. Although a retrospective study indicated that the incorporation of immunotherapy into neoadjuvant and adjuvant treatments could potentially result in improved DMFS and OS in high-risk non-metastatic NPC, the differences were not statistically significant [23]. Summarily, OS benefits were not observed across various immunotherapy application modes in locoregionally advanced NPC. The application of immunotherapy in locally advanced NPC involves the induction period, CCRT period, and adjuvant period. Which period is the most suitable for its application still requires further clinical studies to determine the optimal immunotherapy strategy. Due to the failure of the application of CCRT combined with immunotherapy in patients with head and neck squamous cell carcinoma [7,8], the benefit from the application of immunotherapy during CCRT in patients with locally advanced NPC might be minimal. Referring to the timing of immunotherapy administration in locally advanced non-small cell lung cancer, although neoadjuvant and peri-operative chemoimmunotherapy had comparable overall survival outcomes, neoadjuvant chemoimmunotherapy can be considered the current multimodality combination of choice due to its shorter duration and lower costs [28,29]. Due to the limited sample size and the potential biases present in our study, it is worthwhile to pay attention to the relevant randomized controlled trials and to conduct them further.
Induction chemoimmunotherapy demonstrated satisfactory safety, with no significant difference in adverse events compared to induction chemotherapy during induction treatment and CCRT period. Although the incidence of severe adverse events during induction treatment did not differ significantly between PD-1 and standard treatments, 6.7% of patients experienced severe immune-related adverse events in the PD-1 group [23]. The CONTINUUM study suggested that adding immunotherapy to chemoradiotherapy increased adverse events, mostly grade 1–2 immune-related events, with grade 3–4 events occurring in 10% of patients [6]. A retrospective cohort study indicated that combining immunotherapy and chemotherapy in induction treatment did not increase hematological toxicity; however, hyponatremia and increased creatine kinase levels were noted in the chemoimmunotherapy group [22]. Generally, adding immunotherapy to induction therapy demonstrated excellent tolerance and fewer treatment-related adverse events than the full course of immunotherapy or neoadjuvant immunotherapy plus adjuvant immunotherapy models.
Our study had some limitations. This single-center, retrospective study, despite its small sample size, demonstrated real-world insights into the clinical application of induction immunotherapy. Biomarkers like plasma Epstein-Barr virus DNA and PD-L1 expression status were not collected due to testing limitations.
In summary, adding immunotherapy to induction chemotherapy demonstrated a better ORR and significantly improved EFS in patients with stage IVa NPC, suggesting it is a viable option to be explored in the future to improve prognosis in locoregionally advanced NPC.
Supplementary Material
Acknowledgments
We would like to thank all the patients enrolled in the study and their families, who have made a strong contribution to the fight against NPC. Meanwhile, we were profoundly grateful to Qiaozhu Yang for her support in proofreading clinical data and Editage (www.editage.cn) for English language editing. The abstract of our study was presented as a poster (publication number: 455P) at the 2024 ESMO-Asia and published in the Annals of Oncology (DOI: 10.1016/j.annonc.2024.10.478).
Glossary
Abbreviations
- NPC
nasopharyngeal carcinoma
- CCRT
concurrent chemoradiotherapy
- PD-1
programmed cell death 1
- OS
overall survival
- PFS
progression-free survival
- EFS
event-free survival
- FFS
failure-free survival
- LRFS
locoregional recurrence-free survival
- DMFS
distant metastasis-free survival
- ORR
objective response rate
- CR
complete response
- PR
partial response
- SD
stable disease
- PD
disease progression
- RECIST
international response evaluation criteria in solid tumor
- CTCAE
common terminology criteria for adverse events
- MPR
pathological response
- pCR
pathological complete response
Funding Statement
This study was supported by grants from the Medical Scientific Research Foundation of Guangdong Province (Grant No.B2023476), the High-level Hospital Construction Project of Heyuan People’s Hospital (Grant No. YNKT202203, Grant No. YNKT202218), the Science and Technology Project for Social Development of Heyuan (Grant No. 2021036), Guangdong Basic and Applied Basic Research Foundation (Grant No. 2024A1515030265), Youth S&T Talent Support Programme of Guangdong Provincial Association for Science and Technology (GDSTA) (Grant No. SKXRC202420).
Author contributions
KPW conducted the data acquisition, and statistical analysis, and wrote the original draft. QQL and XQL developed the figures as well as the tables concerned. XLW and LYW were responsible for follow-up work. XXW, YZL, DT, HCY, QML, DZ, and SJC Collected clinical data. YSL was responsible for the conception and design, the review and approval of the manuscript. All authors reviewed and agreed on the final manuscript.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
The data that support the findings of this study are available on request from the corresponding author. The data underlying this article cannot be shared publicly due to the privacy of individuals who participated in the study.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data underlying this article cannot be shared publicly due to the privacy of individuals who participated in the study.