Low-dose fractionated radiation with induction docetaxel... : Hematology/Oncology and Stem Cell Therapy (2025)

Introduction

Nasopharyngeal carcinoma (NPC) is a distinct head and neck malignancy. It is highly sensitive to chemotherapy and radiation therapy. The majority of patients with NPC present with locally advanced disease (LANPC). Combined modality treatment using induction chemotherapy followed by concurrent chemoradiation is commonly used in LANPC, with improved progression-free (PFS) and overall survival (OS) [^1-5]. In recent years, various radiation treatment strategies are currently being investigated aiming at improved local control and enhanced survival, such as altered fractionation [^6,7], and hyper-radiosensitivity (HRS). HRS using low-dose fractionated radiotherapy (LDFRT) in the range of 50–80 cGy was found to act as a chemosensitizer that potentiates the chemotherapy effect. Preclinical and clinical data suggest a benefit from adding LDFRT to induction chemotherapy. LDFRT was found to increase tumor response and improve local control. Recent data suggest promising results for LDFRT in squamous cell cancer of the head and neck (SCCHN) [^8,9]. The current trial is designed to investigate chemosensitization strategy using LDFRT as part of the induction regimen in LANPC.

Patients and methods

Study design and participants

The current study is a single-institute, phase II–III, prospectively controlled randomized trial conducted at King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. Patients aged 18–70 years, with WHO type II and III, stage III–IVB NPC, Eastern Cooperative Oncology Group performance score of 0–2, with adequate hematological, renal, and hepatic function were eligible.

The staging system American Joint Committee on Cance (AJCC) 7th edition was used for staging purpose in the current study.

All patients received two cycles of induction docetaxel 75 mg/m² and cisplatin 75 mg/m² chemotherapy on Days 1 and 22, followed by definitive radiation therapy 70 Gy in 33 fractions using intensity-modulated radiation therapy (IMRT), helical tomotherapy (HT), and image-guided radiation therapy (IGRT), with concurrent cisplatin 25 mg/m² for 4 days on Day 43 and 64. Patients were randomly assigned to either receive induction chemotherapy only (control arm) or LDFRT 0.5 Gy twice daily 6 hours apart for 2 days with induction chemotherapy (experimental arm).

Clinical target volume (CTV) for LDFRT includes the delineated gross target volume for the primary disease and lymph nodes >1 cm in all diameters with 1 cm margin. Planning target volume includes CTV with 3 mm in all directions.

For definitive radiation therapy, previously published IMRT guidelines were followed [¹⁰].

Statistical analysis and study endpoints

Sample size was estimated using Simon’s optimal two-stage designs for phase II clinical trials. A sample size of 108 was calculated to detect a difference of 15% in the complete response rate (RR) in LDFRT treatment arm under a power of 80% and a confidence level of 90%. The complete RR for the chemotherapy arm was 25%.

Simple randomization was performed using random numbers that generates random sequences in order to allow for unbiased treatment allocation among the study and the standard arms. Random numbers were generated using a computer software program.

Patient characteristics were summarized using medians with ranges for continuous variables. Categorical variables were summarized using frequencies and percentages.

Complete and overall clinical RRs at the primary and nodal sites for the two comparative arms were summarized using contingency tables. Comparison was made using chi- square test.

The primary objective was to assess the efficacy of LDFRT given in combination with induction docetaxel and cisplatin chemotherapy, followed by radiation therapy with concurrent cisplatin in patients with LANPC. The primary endpoint was the RR after the induction phase. All patients underwent positron emission tomography–computed tomography evaluation at the end of treatment to assess the final response.

Clinical complete RR at the primary site and lymph nodes was assessed using the RECIST (Response Evaluation Criteria in Solid Tumors) criteria. Toxicity was scored using revised National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.03.

The secondary endpoints were 3-year OS, locoregional control (LRC), and distant metastases-free survival (DMFS). Analyses were done based on intention to treat. The probabilities of OS, LRC, and DMFS were calculated using the Kaplan-Meier estimator with variance estimated using Greenwood’s formula. Survival curves were compared using log-rank test. A p value < 0.05 was considered significant. Statistical analysis was performed using IBM SPSS Statistics for Windows, version 19 (IBM Corp., Armonk, NY, USA).

Ethical approval and consent to participate

The study was approved by the local Ethics Committee of King Faisal Hospital & Research Centre (project # 2121 063), and has been registered at the Clinical Trials.gov (ID#: NCT03890185). Written informed consent was obtained from each participant before entering the trial.

Results

Between March 31, 2013 and February 11, 2018, 108 patients were enrolled in this trial. They were randomly assigned to either the experimental arm receiving LDFRT added to induction chemotherapy (54 patients) or to the control arm receiving induction chemotherapy alone (54 patients). All patients then received concurrent chemoradiation. Data were available for all patients, with a median follow up of 37 (3–72) months. All patients completed planned treatment except one patient who died after induction chemotherapy and was included in the analysis. Patient demographics are displayed in Table 1. There was no significant difference in RRs or toxicity between the two treatment arms (Table 2). The 3-year OS, LRC, and DMFS rates for the experimental and control arms were 94% versus 93% (p = .8), 84.8% versus 87.5% (p = .58), and 84.1% versus 91.6%, (p = .25), respectively (Figs. 1–3). The acute toxicity profile of the control arm was slightly better than that of the experimental arm, though the difference was not significant (Table 3). The rates of grade 3 and 4 neutropenia were higher in the experimental arm than in the control arm (48.1% vs 33.4%). The addition of LDFRT did not increase the rate of radiation-induced grade 3 and 4 mucositis.

Discussion

Nasopharyngeal cancer is the commonest head and neck cancer in Saudi Arabia, and most of the patients present with advanced locoregional disease [¹¹]. Induction chemotherapy followed by concurrent chemoradiation has been commonly used for the treatment of locoregionally advanced NPC [^12-14]. Our previous results using induction epirubicin and cisplatinum plus concurrent chemoradiation in 235 patients with NPC treated throughout 1998–2000 were published elsewhere [¹⁵]. Our practice with induction chemotherapy regimen has evolved since then, substituting docitaxel for epirubicin along with cisplatin, followed by concurrent chemoradiotherapy. This regimen has become the standard of care in the management of NPC at our institution. Modern radiation treatment delivery and techniques (IMRT, volumetric modulated arc therapy, and IGRT) have permitted better dose distribution and higher delivery precision. Over the past decade, all head and neck cases at our institution were treated using IMRT/HT.

Preclinical and clinical data suggest a benefit from adding LDFRT to induction chemotherapy. LDFRT was found to increase tumor response and improve local control. In vitro preclinical studies demonstrated improved efficacy in some radio-resistant and aggressive tumor cell lines [^16-18]. The rationale of using LDFRT is to potentiate the effect of chemotherapy by overcoming the antiapoptotic effects of bcl-2 and nuclear factors. At the cellular level, the cell does not recognize the LDRT-induced DNA damage as significant as in case of double-strand DNA breaks induced by conventional fractionation, and hence does not initiate DNA repair, thereby inducing apoptotic death. HRS seems to be independent of DNA-dependent protein kinase, a complex engaged in DNA damage repair. Preclinical data showed hyperradiation sensitivity using LDFRT at doses of 0.1–80 cGy (optimal window of 50–80 cGy) in several cell lines [^16-19]. The use of this dose window is meant to overcome induced radiation resistance seen in conventional standard chemora- diation regimens. LDFRT was found to potentiate the effects of paclitaxel-induced clonogenic inhibition in both wild-type and mutant p53 head and neck tumor cell lines [²⁰]. Several clinical trials explored the efficacy of LDFRT with standard chemotherapy and suggested promising results with HRS in several tumor types, such as breast, uterine, cervix, ovarian, and metastatic pancreatic cancer [^21-24]. Most of these studies described clinical benefit in terms of overall RRs as a primary endpoint, OS and PFS as secondary endpoints. None of these studies were randomized trials, and in many of these studies the number of patients was too small, and the median follow-up was not reached. Such studies remain exploratory and can only be used to generate hypothesis, and they warrant confirmation by randomized clinical trials to draw solid conclusions. Two phase II studies at the Markey Cancer Centre Kentucky explored the value of LDFRT with carboplatin paclitaxel induction chemotherapy in stage III and IV SCCHN including the oropharynx, larynx, and hypopharynx [^8,9]. In the first study, OS and PFS were 62% and 58%, respectively. The RR was higher in p16- positive patients [⁸]. Higher RRs in human papillomaviruspositive oropharynx and p16-positive subgroups were also observed in another study [²⁵].

NPC is a particularly attractive site for testing LDFRT as these are radiosensitive tumors, primarily treated with definitive radiation plus different sequencing of chemotherapy combination without surgery. LDFRT is expected to potentiate the effect of chemotherapy in LANPC and maximize tumor cell killing by exploiting the above mentioned mechanisms.

To our knowledge, this is the first randomized study exploring the efficacy of LDFRT as chemo-potentiator in a relatively large cohort of patients with NPC diagnosis. Post-induction chemo/LDFRT RR was the primary endpoint of the current study. A comparison of RRs to induction phase in both arms is displayed in Table 2. The overall RRs (complete + partial) were similar in both arms: 98% for the control arm and 94.4% for the experimental arm. The complete RRs at primary site were similar in both arms, whereas there was a trend for higher locoregional complete RR, though not significant, in the control arm compared with the experimental arm (27.8% vs 13.2%). In the current study, the overall RRs were similar to those reported in other SCCHN studies (96%). In a Chinese series, using induction TPF (docetaxel, cisplatin, and 5-fluorouracil) followed by concurrent chemoradiation in LANPC, the overall RR after induction chemotherapy was 94.9%. Similar to our results, complete RRs to induction chemotherapy at the primary site and the neck region were low (25.4% and 19.6%, respectively). However, 3 months after radiation, the complete RRs increased to 96.6% and 90.2%, respectively [²⁶]. The RRs in our study were also similar to those reported for the induction chemotherapy arm in a recently published large phase III trial of 480 patients with LANPC using gemcitabine and cisplatin induction chemotherapy plus concurrent chemoradiotherapy and concurrent chemoradio- therapy alone [³].

The acute toxicity rates in the current study were similar to those reported in other series using LDFRT, carboplatin, and paclitaxel-docitaxel in SCCHN other than nasopharynx [^4,5,8,9].

Overall LRC and OS rates were comparable to other published LANPC series. The addition of LDFRT did not improve the 3-year OS, LRC, or DMFS.

Conclusions

The current study demonstrates a lack of efficacy of LDFRT in LANPC treatment. Our results showed no benefit from adding LDFRT to induction chemotherapy in terms of RR, OS, and DMFS. NPC response to conventional chemoradiation may perhaps be very good, leaving very little room for improvement when adding LDFRT.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Authors’ contributions

All authors contributed substantially to the trial reported. NA and EK conceived and designed the study. Data collection and analysis were done by DF and SA, and NA and YK wrote the manuscript. All authors reviewed and approved the final manuscript.

Acknowledgments

The authors would like to acknowledge King Abdul-Aziz City for Science and Technology for funding this clinical trial. This trial was funded by a grant from King Abdul-Aziz City for Science and Technology (Fund 12-MED2423-20).

References