Phase II Trial of Neoadjuvant Docetaxel/Cisplatin/5-Fluorouracil Combined with Pegteograstim for Unresectable, Locally Advanced Sinonasal Squamous Cell Carcinoma: KCSG HN18-07
Article information
Abstract
Purpose
The role of neoadjuvant chemotherapy in locally advanced sinonasal squamous cell carcinoma (SNSCC) has not been established prospectively. We conducted a phase II trial of neoadjuvant chemotherapy (NAC) with docetaxel/cisplatin/5-fluorouracil (TPF) in this population.
Materials and Methods
Eligible patients had unresectable, locally advanced SNSCC, defined as T3/4 category or potential compromise of critical organ function on surgery. Three TPF (docetaxel 75 mg/m2 and cisplatin 75 mg/m2 on day 1, 5-fluorouracil 1,000 mg/m2 on days 1-4 every 3 weeks) cycles were administered with prophylactic pegteograstim. The primary outcome was the objective response rate (ORR); the secondary outcomes included 2-year progression-free survival (PFS), eyeball preservation rate, and safety.
Results
Among 28 patients screened, 25 were evaluable for efficacy (one screen-failure; two evaluable for safety only). The confirmed ORR was 72.0%. The definitive post-NAC treatment comprised chemoradiotherapy (n=15) and surgery (n=10). With a median follow-up of 25.5 months, median PFS was not reached and the 2-year PFS rate was 60.4%. Response to NAC was related to prolonged PFS (p=0.038). No patient underwent eyeball exenteration at the data cutoff point. Treatment-related adverse events of grade ≥ 3 were neutropenia (48.1%) including febrile neutropenia (14.8%), followed by acute kidney injury (22.2%), nausea/vomiting (11.1%), anemia (7.4%), thrombocytopenia (7.4%), and enterocolitis (3.7%).
Conclusion
TPF NAC showed a promising efficacy and might help preserve critical structures in this population, which needs to be validated in a large prospective trial (KCT0003377).
Introduction
Sinonasal squamous cell carcinoma (SNSCC) accounts for approximately 3% of head and neck squamous cell carcinomas (HNSCCs) [1]. The most common sites are the maxillary sinus (60%), followed by the nasal cavity (25%) and ethmoidal sinus (15%) [2]. SNSCC is often diagnosed at an advanced stage because of the nonspecific symptoms in the early stages. However, its anatomical proximity to critical structures, including the eyeball and the brain, makes it difficult to achieve complete surgical resection and leads to high morbidity and a poor prognosis. The 5-year overall survival (OS) rate has been reported to be approximately 50% in the past three decades, partly owing to high rates of local recurrence [3,4]. Neoadjuvant strategies have been investigated as a part of multimodal treatment to achieve complete surgical resection and potentially improve OS [5]. However, SNSCC has been excluded from most large prospective clinical studies on neoadjuvant chemotherapy (NAC) in HNSCC [6-10]. Only a few small studies, mostly retrospective, except for one phase II single-center study, have been reported in this setting [5,11-17]. This study aimed to prospectively evaluate the efficacy of docetaxel/cisplatin/5-fluorouracil (TPF) NAC regimen in locally advanced, unresectable SNSCC. Primary prophylactic pegteograstim was used to reduce the risk of febrile neutropenia.
Materials and Methods
1. Study design and patients
This is a phase II, multicenter, single-arm, open-label, investigator-initiative trial. Four Korean Cancer Study Group affiliated hospitals were participated.
The eligibility criteria were as follows: age of 19-75 years, a histologically confirmed diagnosis of locally advanced, unresectable SNSCC, presence of measurable disease according to Response Evaluation Criteria in Solid Tumor (RECIST) ver. 1.1 [18], an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate organ function. Criteria for unresectability included clinical T3 or 4 category per American Joint Committee on Cancer (AJCC 7th edition [19]), or potential compromise of critical organ function on upfront surgery (e.g., necessitating an eyeball exenteration). Patients with distant metastasis were excluded.
The data cutoff date for the analysis was done as of July 31, 2024.
2. Study procedures
Patients received up to three cycles of NAC comprising docetaxel 75 mg/m2 and cisplatin 75 mg/m2 on day 1 with 5-fluorouracil 1,000 mg/m2 on days 1-4 administered every 3 weeks. An initial dose reduction of cisplatin to 60 mg/m² was permitted for patients aged 65 years and older. Prophylactic use of long-acting pegylated granulocyte-colony stimulating factor (G-CSF), pegteograstim 6 mg, was administered in 24 to 48 hours after the completion of each NAC cycle. The definitive treatment after NAC—surgery or chemoradiotherapy (CRT)—was discussed at a multidisciplinary team meeting at each hospital. Adjuvant radiotherapy (RT) or CRT was administered according to adverse pathologic features. Imaging studies were scheduled after NAC cycle 2 for objective response rate (ORR) assessment and after cycle 3 for ORR confirmation. Imaging assessments were repeated 1-2 months after surgery or CRT and then every 3 months for 2 years.
3. Outcomes and statistical analysis
The primary outcome was investigator-assessed ORR, which was defined as the proportion of patients who achieved a complete response (CR) or partial response (PR) to NAC based on RECIST ver. 1.1. Secondary outcomes included the 2-year progression-free survival (PFS), eyeball preservation rate, and safety. PFS was measured from the start date of NAC until progression, death from any cause, or the last censored date during follow-up. Adverse events (AEs) were graded using the National Cancer Institute Common Toxicity Criteria for Adverse Events ver. 4.03.
This study was designed to detect an improvement in the ORR with TPF NAC, with a target statistical power of 80% and an alpha error rate of 0.05. The key parameters for this calculation were a null hypothesis response rate (P0) of 45% and an alternative hypothesis response rate (P1) of 70%. A total of 25 patients are required for response assessment. Considering a 10% dropout rate, the final number of patients was calculated to be 28. The efficacy set was defined as patients who had response assessment after NAC. The Clopper-Pearson estimation method was used to calculate 95% confidence intervals (CIs) for the proportion of patients with an objective response. Safety analyses were performed on the safety set of patients who had received at least one dose of NAC.
R ver. 4.2.2 was used to perform all statistical analyses (R Foundation for Statistical Computing; http://www.R-project.org/). This trial was registered in the Korean Clinical Trials Database (identifier: KCT0003377).
Results
1. Baseline characteristics
Overall, 28 patients were screened between August 2019 and November 2023. Of these, one withdrew consent, and 27 patients started NAC (Fig. 1). The baseline characteristics of the 27 patients are shown in Table 1. The median age was 58 years (range, 41 to 71 years), and 88.9% of patients were male. Two-thirds of the patients had maxillary sinus cancer, and the others had nasal cavity cancer. Most patients had clinical T4 category disease including T4a (66.7%) and T4b (18.5%). At baseline imaging assessment, 22 (84.6%), five (19.2%), and five (19.2%) patients would require total maxillectomy, orbital exenteration, or craniotomy, respectively, in the case of upfront surgery.
CONSORT study diagram. CRT, chemoradiotherapy; NAC, neoadjuvant chemotherapy.
Baseline characteristics of the intent-to-treat population
2. Clinical efficacy
Among the 27 patients who started NAC, two dropped out of the trial after cycle 1 owing to delayed recovery from AEs (n=1) and unexpected death (n=1), and 25 patients completed three cycles of NAC and had response assessment (Fig. 1). In the efficacy set, the radiologically confirmed ORR was 72.0% (95% CI, 50.6 to 87.9) including CR in two patients and PR in 16 patients (Fig. 2). Two patients who achieved radiological PR were confirmed to have achieved pathologic CR on the assessment of their surgical specimens (Table 2). One patient experienced disease progression after NAC. Following the completion of NAC, 20 patients were technically resectable, while the tumors of five patients remained unsuitable for complete surgical resection. Definitive treatment following NAC consisted of CRT in 15 patients (60%) and surgery in 10 (40%), followed by adjuvant RT (n=6) and CRT (n=2).
Waterfall plot of maximum percent change in the sum of target lesions from baseline according to Response Evaluation Criteria in Solid Tumor ver. 1.1; each bar represents a patient. CR, complete response; CRT, chemoradiotherapy.
Efficacy outcomes
With a median follow-up duration of 25.5 months, nine patients showed disease progression, and six patients died. Detailed information of the patients who experienced treatment failure were summarized in Table 3. Median PFS was not reached and the 2-year PFS rate was 60.4%% (Fig. 3A). PFS was associated with NAC response (p=0.038) (Fig. 3B) but not with the type of definitive treatment (p=0.749) (Fig. 3C). None of the patients underwent eyeball exenteration at the data cutoff point. Median OS was not reached and the 2-year OS was 76.3%.
Clinical outcomes of patients who experienced treatment failure (n=9)
Kaplan-Meier curves for progression-free survival in total population (A), in evaluable population (n=25) by neoadjuvant chemotherapy response (B), and by type of definitive treatment (C). CR, complete response; CRT, chemoradiotherapy; PD, progressive disease; PR, partial response; SD, stable disease.
3. Safety analysis
Twenty-seven patients were included in the safety analysis set. Treatment-related AEs (TRAEs) of grade ≥ 3 are listed in Table 4. Although seven patients were started on a reduced dose of cisplatin, 14 (51.8%) experienced at least one grade ≥ 3 of TRAEs. The most common grade ≥ 3 TRAEs were neutropenia (48.1%), including febrile neutropenia (14.8%), followed by acute kidney injury (22.2%), nausea/vomiting (11.1%), anemia (7.4%), thrombocytopenia (7.4%), and enterocolitis (3.7%).
Treatment-related adverse events of grade ≥ 3 during NAC
NAC dosing was delayed in four (14.8%) patients and reduced in seven (25.9%). The main reasons for the dose reduction were thrombocytopenia (n=1), acute kidney injury (n=3), and febrile neutropenia (n=3). Two patients received only one cycle of NAC because of grade 3 acute kidney injury (n=1) and unexpected death from an unknown cause (n=1).
Discussion
This phase II study prospectively demonstrated the good efficacy and favorable eyeball preservation rate of TPF NAC in patients with unresectable locally advanced SNSCC. The response to NAC was associated with better prognosis, and toxicity was mostly manageable.
NAC is frequently used in clinical practice to achieve complete surgical resection, preserve critical structures, and potentially improve the prognosis of patients with locally advanced SNSCC. However, the efficacy of NAC has not been prospectively delineated as most large clinical trials of NAC have excluded SNSCC [6,8-10]. This exclusion may be attributed to the rarity of the disease, its biological heterogeneity, and the anatomical complexity of the sinonasal region.
A few retrospective studies have reported the clinical efficacy of NAC in patients with advanced SNSCC [5,13-17]. Most studies enrolled patients with T3, T4, stage III, or stage IV SNSCC, and NAC regimens varied from platinum-based doublet and/or cetuximab to triplet regimens, including TPF. The ORR, 2-year disease-free survival or PFS rate, or 2-year organ preservation rates were 39%-84.5%, 67.9%-81.5%, and 63%-82.4%, respectively (S1 Table).
A phase II prospective study using TPF NAC was recently reported [11]. It included patients with stage II-IV locally advanced SNSCC or poorly differentiated carcinoma (n=31). The ORR after two cycles of TPF, 2-year disease-specific survival, and organ preservation rates were 82.1%, 75%, and 63%, respectively. The difference between this previous study and our study was that it was conducted in a single center and uniform treatment was applied after two cycles of NAC. For responders, an additional cycle of NAC followed by CRT was administered. Non-responders underwent surgery with adjuvant RT. Our study allowed definitive treatment decisions at each team’s discretion owing to this study being a multicenter study. CRT was more frequently administered to NAC responders (14 of 18), whereas surgery was more frequently performed in NAC non-responders (4 of 7). Another difference is that our study enrolled patients with stage III/IV disease, while the previous study enrolled patients with stage II-IV SNSCC, which resulted in slightly better clinical efficacy than that noted in this study.
This study met the primary outcome that the ORR of NAC was 72%. Response to NAC was associated with PFS regardless of the type of definitive treatment. These findings are in line with those of other reports on NAC [13,14,16,20]. NAC responsiveness could provide prognostic information in advance, which could then guide subsequent definitive treatment options. This approach could be related to organ preservation [21], which is also critical in patients with locally advanced SNSCC. The benefits of NAC in terms of organ preservation in patients with SNSCC have been previously reported [11,13,14]. In this study, total maxillectomy (n=22), craniotomy (n=5), and orbital exenteration (n=5) were needed in cases of upfront surgery. Total maxillectomy was performed only in four patients, and no patient underwent orbit exenteration until the last follow-up date. Radiation field and normal tissue dose on adjacent structure could be reduced after NAC compared to upfront CRT (Fig. 4) which could help preserve vital organ function.
A case of a T4b maxillary sinus cancer patients treated with docetaxel/cisplatin/5-fluorouracil (TPF) neoadjuvant chemotherapy (NAC) followed by chemoradiotherapy (CRT). (A) Magnetic resonance imaging at diagnosis, after completion of three cycles of NAC, and 4-year follow up after CRT. (B) Radiation field and normal tissue dose before and after NAC.
The TPF regimen is potent, but quite toxic. In this study, grade 3/4 neutropenia and febrile neutropenia developed in 48.1% and 14.8% of patients, respectively; these rates were slightly higher than expected, considering that prophylactic G-CSF was administered from the beginning. Pegteograstim, developed by the Green Cross Corporation in Korea, is a new pegylated G-CSF formulation. It was proven to be non-inferior to pegfilgrastim in a phase II/III study [22]. Owing to the 4 days of 5-fluorouracil infusion, pegteograstim was injected on day 6 or 7, following guideline recommendations [23]. Docetaxel might have contributed the most to neutropenia, considering that the Asian population is more susceptible to docetaxel toxicity [24]. Therefore, some small studies recommended early administration of prophylactic G-CSF in cases of multi-day chemotherapy, such as TPF [25,26].
This study has some limitations. Given the rarity of SNSCC, the sample size was small. Second, the treatment decision after NAC was made at each team’s discretion owing to the nature of multicenter study. Therefore, the reasons of determining definitive CRT or surgery are not well-defined. Finally, information on potential prognostic biomarkers, such as p16 or human papillomavirus status, was not collected. Nonetheless, this is the first multicenter study to demonstrate the efficacy of TPF NAC prospectively in unresectable, locally advanced SNSCC.
Neoadjuvant TPF NAC showed the promising efficacy with manageable toxicity in patients with unresectable locally advanced SNSCC. NAC might help predict the prognosis, and preserve critical structures in this population, which needs to be validated in a large prospective trial. The current timing of prophylactic long-acting G-CSF injection with TPF regimen needs to be further optimized.
Electronic Supplementary Material
Supplementary materials are available at Cancer Research and Treatment website (https://www.e-crt.org).
Notes
Ethical Statement
The study was conducted in accordance with the Declarations of Helsinki and Good Clinical Practice and was approved by the institutional review boards of St. Vincent’s Hospital (approval number VC18MCDS0170) and the local committees of all other participating centers. Written informed consent was obtained from all the patients.
Author Contributions
Conceived and designed the analysis: Keam B, An HJ, Kim SB.
Collected the data: Keam B, An HJ, Shin SH, Kim MK, Cho JH, Seo S, Kim SB.
Contributed data or analysis tools: Keam B, An HJ, Cho JH, Kim SB.
Performed the analysis: Keam B, An HJ.
Wrote the paper: Keam B, An HJ, Shin SH, Kim MK, Seo S, Kim SB.
Conflict of Interest
Pegteograstim was provided by Green Cross Cooperation (Korea).
Funding
This study was supported by the Korean Cancer Study Group, and funded by the National Research Foundation of Korea grant funded by the Korean government (MSIT, number: RS-2023-00249672).
Acknowledgments
We would like to express our gratitude to Joo Hwan Lee for the assistance in conducting data analysis.