Journal of Otology & RhinologyISSN: 2324-8785

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Research Article, J Otol Rhinol Vol: 3 Issue: 4

Efficacy and Safety of Sequential Chemoradiation with Docetaxel, Cisplatin, and 5-Fluorouracil (TPF) in Treating the Patients with Squamous Cell Carcinoma of the Hypopharynx: A Phase II Clinical Trial

Niloofar Ahmadloo1, Sayed Hasan Hamedi2, Samira Razzaghi2, Bijan Khademi3,4, Seyed Basir Hashemi4, Leila Moaddabshoar2, Ahmad Mosalaei1,3, Mansour Ansari1, Shapour Omidvari1,Hamid Nasrolahi1 and Mohammad Mohammadianpanah5*
1Department of Radiation Oncology, Namazi Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
2Student Research Committee, Department of Radiation Oncology, Shiraz University of Medical Sciences, Shiraz, Iran
3Shiraz institute for Cancer Research, Shiraz University of Medical Sciences,Shiraz, Iran
4Department of Otolaryngology, Head and Neck Surgery, Khalili Hospital,Shiraz University of Medical Sciences, Shiraz, Iran
5Colorectal Research Center, Shiraz University of Medical Sciences, Shiraz,Iran
Corresponding author : Mohammad Mohammadianpanah
Colorectal Research Center, Department of Radiation Oncology, Namazi Hospital, Shiraz University of Medical Sciences, Shiraz 71936-11351, Iran
Tel: 0098-711-6125170; Fax: 0098-711-6474320
E-mail: [email protected]
Received: April 07, 2014 Accepted: June 03, 2014 Published: June 15, 2014
Citation: Ahmadloo N, Hamedi SH, Razzaghi S, Khademi B, Hashemi SB (2014) Efficacy and Safety of Sequential Chemoradiation with Docetaxel, Cisplatin, and 5-Fluorouracil (TPF) in Treating the Patients with Squamous Cell Carcinoma of the Hypopharynx: A Phase II Clinical Trial. J Otol Rhinol 3:4. doi:10.4172/2324-8785.1000160

Abstract

Efficacy and Safety of Sequential Chemoradiation with Docetaxel, Cisplatin, and 5-Fluorouracil (TPF) in Treating the Patients with Squamous Cell Carcinoma of the Hypopharynx: A Phase II Clinical Trial

Background: The present study aimed to investigate the efficacy and safety of sequential chemoradiation with docetaxel, cisplatin, and 5-Fluorouracil (TPF) in the patients with Squamous Cell Carcinoma (SCC) of the hypopharynx.

Patients and Methods: In this single arm phase II clinical trial, eligible patients had to have newly diagnosed, locally advanced (T3-T4 and/or N2-N3, M0) hypopharyngeal SCC, no prior therapy, Eastern Cooperative Oncology Group performance scale ≤1, and normal or acceptable organ function. The patients were assigned to receive three cycles of 3-weekly induction chemotherapy in an outpatient setting with docetaxel 75 mg/m2, cisplatin 75 mg/m2, and 5-fluorouracil 750 mg/m2 × 3 days of 8-hour infusion, followed by definite radiotherapy with a total dose of 70 Gy with concurrent cisplatin 30 mg/m2 weekly. Tumor response rates and treatmentrelated toxicity were the primary and secondary study endpoints, respectively.

Keywords: Locally advanced hypopharyngeal cancer; Induction chemotherapy; Docetaxel; Cisplatin; 5-Fluorouracil; TPF regimen; Chemoradiation

Keywords

Locally advanced hypopharyngeal cancer; Induction chemotherapy; Docetaxel; Cisplatin; 5-Fluorouracil; TPF regimen; Chemoradiation

Introduction

Squamous Cell Carcinoma (SCC) encompasses a vast majority (Over 95%) of hypopharyngeal cancers. It accounts for 5-10 percent of all head and neck cancers [1]. Hypopharyngeal SCC is more common in men than in women and is more frequent in western countries compared to developing ones. It usually occurs in the seventh decade of life with a median age of 65 years for men and 68 years for women at present [2,3]. These neoplasms tend to present at locally advanced stages and to have poor outcome compared to other head and neck cancers. Location and extend of the tumor, patient’s age, performance status, and preference, and treating center’s experience are the most important factors in selection of the treatment approach [4-6]. The traditional treatment approach for most of the patients with locally advanced disease includes combined surgical resection followed by adjuvant radiotherapy or chemoradiation. Despite this aggressive treatment approach, locoregional and distant failure is frequent [5,6]. Induction chemotherapy is a promising treatment modality shrinking the tumor bulk and controlling potential micrometastatic foci. Consequently, induction chemotherapy can potentially enhance the final response to chemoradiation, allow organ preservation, and improve locoregional and distant control rates [7,8]. Earlier studies showed that local control and survival of the patients treated with three cycles of induction chemotherapy with cisplatin and 5-FU (PF regimen) followed by radiotherapy was comparable to those of the patients treated with radical surgery followed by adjuvant radiotherapy. However, local control and survival remained poor [7]. Recent evidences suggested that addition of taxanes to the conventional induction regimen consisting of cisplatin and 5-FU (TPF) improved response rates, local control, and survival compared to cisplatin and 5-FU (PF) in locally advanced head and neck cancer [9,10]. Up to now, a limited number of studies have specifically evaluated the use of TPF regimen induction chemotherapy in the patients with hypopharyngeal cancers [11,12]. Therefore, the present study aims to investigate the efficacy and safety of sequential chemoradiation with TPF regimen in the patients with hypopharyngeal SCC.

Patients and Methods

This single arm phase II clinical trial was conducted on 20 patients with diagnosis of hypopharynx cancer who were referred to Namazi academic hospital for treatment between January 2011 and September 2012. The diseases were staged according to the seventh edition of the American Joint Committee on Cancer (AJCC) staging classification. Besides, the patients’ performance statuses were scored according to the Eastern Cooperative Oncology Group (ECOG) performance scaling system. The eligible patients had to have newly diagnosed, locally advanced (T3-T4 and/or N2-N3, M0) hypopharyngeal cancer, no prior therapy, ECOG performance scale ≤1, and normal or acceptable kidney, liver, cardiovascular, and bone marrow functions. In this study, we considered serum creatinine <1.4 mg/dl and creatinine clearance >60 ml/min as adequate renal function. The exclusion criteria of the study were prior therapy, any evidence of distant metastases before or during the trial, known contraindication for chemotherapy (such as allergy to taxane drugs), positive history of receiving radiotherapy for other head and neck neoplasms, documented heart, liver, renal, or blood coagulation diseases, and patients’ refusal to participate in the trial or to sign the consent form. Tumor response rates and treatment-related toxicity were the primary and secondary study endpoints, respectively. The study was approved by the Clinical Research Ethics Committee of Shiraz University of Medical Sciences in accordance with the code of ethics of the world medical association (Declaration of Helsinki) for experiments involving humans. Additionally, written informed consent was obtained from all the patients before the trial.
Patient Evaluation
Pre-treatment evaluation included a complete medical history, physical examination with special attention to the status of cervical lymph nodes regarding their size, location, and fixation, assessment of ECOG performance scale, direct laryngopharyngoscopy to determine tumor extension, and taking biopsy, chest radiograph, ultrasound imaging of the abdomen, and contrast-enhanced Computed Tomography (CT) scan and Magnetic Resonance Imaging (MRI) of the hypopharynx and neck. Other tests included Complete Blood Count (CBC), Liver Function Test (LFT), and Renal Function Test (RFT). In addition, cardiovascular evaluation was carried out in highrisk patients, including those above 60 years old, heavy smokers, and the patients suffering from underlying diseases such as hypertension or diabetes mellitus. Also, all the patients were carefully evaluated for dental caries and all the necessary dental repairs and treatments were completed well before starting the Radiation Therapy (RT). The CONSORT flow diagram of the trial is shown in Figure 1.
Figure 1: The CONSORT flow diagram of the study.
Treatment
All patients were assigned to receive induction chemotherapy with TPF regimen (docetaxel 75 mg/m2 for day 1, cisplatin 75 mg/ m2 for day 1, 5-FU 750 mg/m2/day with 8-h infusion on days 1-3) in an outpatient setting every 3 weeks for 3 cycles. Antiemetic medication, including a selective 5-hydroxytryptamine-3 (5HT3) antagonist and steroids, were also prescribed intravenously for all the chemotherapy cycles. In addition, prophylactic Granulocyte-Colony Stimulating Factor (G-CSF) (as 5 μg/kg filgrastim) was considered for all the patients following each cycle of TPF regimen during days 5-9. Clinical condition, regional lymph node status, treatment toxicity, and patients’ complaints were evaluated and recorded before each cycle of chemotherapy. Three weeks after completion of induction chemotherapy, all the patients were assigned to receive concurrent chemoradiation with weekly cisplatin (30 mg/m2) from the first day of RT up to 7 cycles. External beam RT using megavoltage (6 MV) linear accelerator was performed. The hypopharynx and regional cervical lymph nodes were treated with conventional fractionation and a total dose of 70 Gy was delivered in 35 fractions (5 fractions per week). The primary site and upper cervical lymph nodes were treated with two lateral parallel opposed fields, while the lower cervical lymph nodes were treated with a separate en face anterior field. The spinal cord was excluded from the radiation fields after 44 Gy. After 50 Gy, RT was continued to the primary site up to 70 Gy. Metastatic lymph nodes received a boost dose of 15-20 Gy. Each cycle of induction chemotherapy or weekly cisplatin was administered only if the patient’s general condition and blood tests were acceptable (Hb > 9 g/dl, absolute neutrophil count [ANC] >1500, platelet > 100000, SGPT, SGOT, ALP < 1.5 fold of normal upper limit, normal bilirubin and creatinine). Tumor response was evaluated 3 weeks after at the 3rd cycle of induction chemotherapy and again 4 weeks after completion of concurrent chemoradiation. Response evaluation included clinical examination and CT scan of the hypopharynx. In addition, 4 weeks after completion of concurrent chemoradiation, direct laryngopharyngoscopy and biopsy of the hypopharynx were performed to evaluate the pathologic response. Tumor response assessment was based on Response Evaluation Criteria In Solid Tumors (RECIST) as follows: complete response was defined as the complete disappearance of all assessable lesions, partial response was defined as over 30% reduction in the sum of the longest diameters of all measurable diseases compared to baseline, stable disease was considered as less than 30% reduction or less than 20% increase in the sum of the longest diameters of all measurable diseases, and progressive disease was defined as more than 20% increase in the longest diameters of original measurable diseases or appearance of a new lesion [13]. Treatment complications during induction chemotherapy and concurrent chemoradiation were recorded using Common Terminology Criteria for Adverse Events, version 4.0 (CTCAE 4). Clinical response rates and safety were the primary and secondary endpoints, respectively.
Statistical Methods
Descriptive analysis was used for calculating the clinical response rates and the clinicopathological characteristics of the patients. The statistical analyses were performed according to the sum of the longest diameters of all measurable lesions. All the analyses were carried out using the SPSS statistical software, version 17.

Results

This study was conducted on 20 eligible patients with locally advanced hypopharyngeal carcinoma. All patients were treated with curative intent. The study participants included 11 men and 9 women with a median age of 61 years (range 36-78). Among the patients, 3 (20%), 15, and 1 was presented with stage III, stage IVA, and stage IVB disease, respectively. The median dose of radiation was 64 Gy (range 60-70). In addition, all the patients but one received 3 cycles of neoadjuvant chemotherapy as well as a median 4 cycles (range 1-8) of concurrent weekly cisplatin. Patient, tumor, and treatment characteristics are listed in Table 1. After excluding 2 patients who refused to continue induction chemotherapy and 1 patient who expired during the treatment, 17 patients were enrolled into the study. Overall, 59 courses of induction chemotherapy with TPF regimen was administered for the patients. Only one of the patients could not receive the third cycle of induction chemotherapy because of severe reaction to docetaxel (grade 4 dyspnea) during the second course of chemotherapy. Three weeks after the last cycle of induction chemotherapy, 8 patients (44.4%) achieved a clinical complete response, 8 (44.4%) achieved a clinical partial response, and 2 patients (11.1%) had no response. Therefore, after induction chemotherapy, the overall clinical response rate was 88.9%. However, imaging evaluation with CT scan revealed that 4 patients (22.2%) achieved a complete radiologic response and 12 (66.7%) achieved a partial radiologic response. However, 2 patients showed no radiologic response (Table 2).
Table 1: Patient and disease characteristics.
Table 2: Response rates to induction chemotherapy and chemoradiation.
Four weeks after completing concurrent chemoradiation, 12 patients (70.6%) achieved a complete clinical response at regional nodes in clinical examination, 4 ones (23.5%) showed partial clinical response and 1 patient (5.9%) showed stable disease (Table 2). However, by considering response in the primary site (hypopharynx) that was evaluated through CT scan images, 9 patients (52.9%) had complete response, 7 ones (41.2%) had partial response, and the remaining patients (5.9%) had stable disease. At last, endoscopic evaluation and biopsy taking through laryngopharyngoscopy indicated that 5 patients (29.4%) had residual tumor and 12 ones (70.6%) had complete response. In the 3 patients (17.6%) who had residual tumor in CT scan images, only necrosis and inflammation were found. Two-year disease free survival rate (for responder case) and progression free survival rate (for non-responder cases) were 90% and 71.8%, respectively. Two years after the intervention, out of the 17 study patients, 10 were alive and free of disease, 6 were alive with locoregional recurrent disease, and a patient died due to recurrent disease. Overall, treatment-related toxicities were common but manageable (Table 3). During 59 cycles of chemotherapy, grade 1-2 anemia was the most common hematologic toxicity, being detected in 25 cycles (41.7%). Additionally, 4 patients (6.7%) developed uncomplicated grade 1-2 neutropenia and 1 (1.7%) developed grade 4 neutropenia. Also, one patient developed uncomplicated, culture negative febrile neutropenia. Nausea and diarrhea were the other disturbing side effects. Grade 3 nausea and diarrhea occurred in 10.2% and 1.7% of the cycles, respectively and were managed properly. The most common chemoradiation-related hematologic toxicity was grade 1-2 anemia that occurred in 11 patients (64.7%) (Table 4). Grade 3 anemia occurred in 1 case and was managed with packed cell injection. Besides, grade 3 nausea, oral mucositis, and xerostomia developed in 6 patients (35.3%) and made radiotherapy break for 3-7 days. Due to these non-hematologic toxicities, radiotherapy was stopped before 70 Gy in 5 patients (29.4%). In addition, all the patients developed some grades of nausea, oral mucositis, xerostomia, and dermatitis.
Table 3: Acute chemotherapy-related toxicity during 59 cycles of induction chemotherapy.
Table 4: Acute toxicity related to concurrent chemoradiation.

Discussion

Treatment of locally advanced hypopharyngeal SCC was initially concentrated upon radical surgery with adjuvant radiation or radiation therapy alone for unresectable tumor. In an attempt to improve functional organ preservation, locoregional control, and survival rates, clinical trials aimed to investigate the use of concurrent or sequential chemoradiation. Utilization of induction chemotherapy in locally advanced hypopharyngeal SCC potentially controls distant failure, improves survival rates, and allows for organ preservation [3,14]. The combination of cisplatin and 5-fluorouracil (PF) has been accepted as the standard induction chemotherapy in head and neck cancer as well as hypopharyngeal SCC for more than 3 decades. The standard schedule of this combination consisted of cisplatin 100 mg/m2 on day 1 and 5-FU 1000 mg/m2/d continuous infusion×5 days, every 21 days [15]. This combination showed a small but significant 4.5% absolute improvement in 5-year overall survival rate compared to control treatments. However, due to frequent development of metastatic diseases during the post-treatment followup, this combination failed to control the metastatic diseases [16]. Addition of a taxane to cisplatin and 5-FU (TPF) can significantly potentiate the efficacy of PF regimen and provide better response rate and survival without any significant toxicity [17]. Posner et al. performed a subgroup analysis of locally advanced laryngeal and hypopharyngeal cancer in TAX 324 clinical trial. They found that in comparison to PF, sequential chemoradiation with induction TPF significantly increased overall and progression free survival as well as laryngeal preservation rate in the patients with locally advanced laryngeal and hypopharyngeal cancer [18]. In addition, TPF was associated with less treatment-related toxicity and mortality and stable quality of life [19].
Up to now, several researchers have evaluated the role of induction TPF in heterogeneous mixed head and neck primary sites [20,21]. Posner et al. in a randomized phase 3 clinical trial investigated the survival benefit of induction TPF to that of PF in treatment of head and neck SCC. They randomly allocated 501 patients with locally advanced head and neck SCC to receive either TPF or PF induction chemotherapy, followed by chemoradiotherapy.
Their primary study end point was overall survival. They concluded that induction TPF achieved a higher 3-year overall survival rate compared to induction PF in the patients with locally advanced head and neck SCC (62% vs. 48%) [20]. In another study, Vermorken et al. conducted a randomized phase 3 clinical trial to compare the efficacy and safety of induction TPF to PF in treatment of head and neck SCC. They randomly assigned 358 patients with unresectable head and neck SCC to receive either TPF or PF induction chemotherapy, followed by chemoradiotherapy. They found that compared to induction PF, induction TPF was more effective, safer, and associated with higher progression-free and overall survival in the patients with unresectable head and neck SCC [21].
There is no report in the literature specifically investigating induction TPF followed by concurrent chemoradiation in the patients with locally advanced hypopharyngeal SCC. However, there are three studies evaluating induction chemotherapy with taxanes and cisplatin followed by concurrent chemoradiation in the patients with laryngeal and hypopharyngeal SCC [12,22,23]. In a randomized phase 3 clinical trial, Pointreau et al. compared the efficacy and safety of induction TPF to PF in treatment of the patients with locally advanced laryngeal and hypopharyngeal SCC. They demonstrated that induction TPF was associated higher grade 2 alopecia, grade 4 neutropenia, and febrile neutropenia, while induction PF was associated with higher grade 3 and 4 mucositis, thrombocytopenia, and severe (grade 4) elevated creatinine. The overall response was also in favor of TPF rather than PF (80.0% vs. 59.2%; P=0.002) [22]. In a multicenter single arm phase II trial, Dietz et al. used induction chemotherapy with paclitaxel and cisplatin followed by accelerated hyperfractionated radiotherapy for laryngeal preservation in 71 patients with stage III-IV laryngeal and hypopharyngeal cancer. The 42-month laryngectomy free- and overall survival were 41.3% and 56.5%, respectively [12]. In another single arm trial, Pfreundner et al. evaluated the efficacy and safety of 2 cycles of induction chemotherapy with paclitaxel and cisplatin in 50 patients with laryngeal or hypopharyngeal SCC who were eligible for total laryngectomy or laryngopharyngectomy. The patients with complete or partial tumor response were subsequently treated with definite 3-dimentional radiotherapy (3DRT). The overall response rate to induction chemotherapy was 88% (10% complete, 78% partial response). Besides, two-year laryngeal preservation and overall survival rates were 845 and 72.3%, respectively [23]. In the present study, the overall response rate (70.6%) was comparable with the results of other major series [22-24]. Also, treatment-related toxicities of our cases were comparable or even lower than those of other reported studies. This may be partly attributable to our modified chemotherapy schedule and routine usage of G-CSF support leading to lower rates of leucopenia and stomatitis.
Table 5 shows the response rates, treatments, and major toxicities of 3 recent clinical trials and the present study in the patients with locally advanced laryngeal and hypopharyngeal SCC.
Table 5: The response rates, treatments, and major toxicities of 3 recent clinical trials and the present study in the patients with locally advanced laryngeal and hypopharyngeal SCC.

Conclusion

Sequential chemoradiation with TPF regimen was feasible with manageable toxicity, and resulted in high complete response rate in the patients with hypopharynx SCC.

Conflict of Interest

All the authors have no conflicts of interest to declare.

Acknowledgements

The authors would like to thank Ms. A. Keivanshekouh at the Research Improvement Center of Shiraz University of Medical Sciences for improving the use of English in the manuscript.

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