Abstract
Objective
The value of additional use of cetuximab with the classical cisplatin, docetaxel and 5-fluorouracil regimen in larynx preservation remains unknown. This study was designed to resolve this issue and appraise its toxicity.
Materials and methods
Thirteen untreated patients with stage III–IV larynx or hypopharynx squamous cell carcinoma were recruited and received two cycles of C + TPF regimen (cetuximab plus docetaxel, cisplatinand and 5-fluorouracil), followed by one more cycle of C + TPF and intensity-modulated radiotherapy (70 Gy). Primary endpoint was larynx preservation (LP) rate at 3 months. Secondary endpoints were larynx function preservation (LFP) and overall survival (OS) at 12, 36 and 60 months.
Results
With a two-cycle induction treatment of C + TPF protocol, four (31%) and nine (69%) patients achieved complete and partial response, respectively. The top three toxicities were dermatitis (9 cases), nausea/vomiting (6 cases), and anemia (4 cases). After the full-course treatment, 12 out of 13 patients (92.3%) obtained LP at 3 months. This strategy demonstrated relatively high LFP rates of 92.3%, 69.2% and 54.5% and satisfactory OS rates of 100%, 84.6% and 54.5% at 12, 36 and 60 months, respectively.
Conclusions
These preliminary results suggest induction treatment with C + TPF regimens, followed by intensity-modulated radiotherapy is well-tolerated, which warrants further evaluation.
1
Introduction
Treatment strategies for head and neck squamous cell cancer (HNSCC), particularly larynx and hypopharynx squamous cell carcinomas, include surgical and non-surgical procedures. Both preservation of the organ and its function determine a patient’s quality of life. Surgery can often result in various degrees of anatomical, functional and psychological disorders in surviving patients . As such, non-surgical approaches, aimed at functional organ preservation and disease control, have been explored .
Several non-surgical strategies, including chemotherapy or radiotherapy alone, sequential or concurrent radiochemotherapy, and targeted therapy combined with chemotherapy or radiotherapy have been explored for larynx preservation (LP) . While it plays a central role in the LP, radiotherapy alone or combined with the conventional chemotheraeutic drug of cisplatin, 5-fluorouracil and docetaxel cannot yield satisfactory long-term local control . Over the last few decades, advances in understanding the molecular and cellular causes of cancer have led to the discovery of various molecular targets for the development of cancer therapeutics . The use of monoclonal antibodies that inhibit EGFR (epidermal growth factor receptor), one of the best-known targets for HNSCC , has been extensively explored . Cetuximab is the primary antibody that targets the aberrant signaling of EGFR in malignant cells . Several studies have reported that cetuximab combined with cisplatin and 5-fluorouracil regimen improved tumor response rate of HNSCC compared to cisplatin and 5-fluorouracil regimen alone . However, the efficacy and safety of a four-drug regimen, cetuximab plus docetaxel, cisplatin and 5-fluorouracil (C + TPF), remains largely unknown in LP treatment, and therefore requires further investigation.
Because of potentially additional side-effect of multiple drugs, it is still being debated whether adding targeted therapy to conventional chemotherapy makes an effective contribution to larynx-preservation therapy. The current study was designed to resolve this controversy. We explored a novel non-surgical strategy for larynx preservation and local disease control instead of laryngectomy in patients with resectable advanced laryngeal and hypopharyngeal cancer. In the current trial, two cycles of TPF-C regimen were administrated as the induction treatment. Subsequently, one more cycle induction treatment and radical radiotherapy (70Gy) were applied for the patients who yielded complete or partial response, and finally five-year follow-up was carried out for those patients. Alternatively, for the patients with stable or progressive disease after two cycles of induction treatment or for the patients without complete response after the full course therapy, a salvage surgery was recommended. Here, we demonstrated the short-term and long-term outcomes and major toxicities of the combination of four-drug chemotherapy and radiotherapy.
2
Materials and methods
2.1
Patients
During July 2010 and August 2013, we prospectively enrolled eligible patients for the current trial. Patients were eligible if they met the following criteria: aged 18–75 years; histologically proven stage III–IV larynx or hypopharynx squamous cell carcinoma suitable for total laryngectomy (TL); no evidence of distant metastases or a synchronous cancer; no tumor-specific pretreatment; has at least one measurable lesions according to the Response Evaluation Criteria In Solid Tumors (RECIST) 1.0 criteria detected by computed tomography or magnetic resonance imaging; Karnofsky Performance Scale (KPS) Index ≥70 and no major impairment of liver, kidney, or hematopoietic function.
Ineligibility criteria included highly infiltrative transglottic tumors, tumors extending through the cartilage, tumors resectable by partial laryngectomy or tumors requiring a circumferential total pharyngolaryngectomy, pretreatment tracheotomy, prior or present history of malignancy, a comorbidity or biological disorder contraindicating administration of docetaxel, cisplatin, or 5-fluorouracil, or expected poor compliance with treatment.
The protocol used was approved by the ethics committee of Sun Yat-sen University Cancer Center, Guangdong, China, and all patients gave informed written consent prior to entry into the trial.
2.2
Treatment and follow-up
Eligible patients received 2 cycles of cetuximab 400 mg/m 2 , docetaxel 60 mg/m 2 and cisplatin 60 mg/m 2 on day 1, and 5-fluorouracil 600 mg/m 2 per day on days 1–5 (C + TPF) at 3-week intervals. Pretreatment consisted of diphenhydramine 50 mg and dexamethasone 8 mg. Setrons were given before and after cisplatin administration, and hydration was delivered according to institutional protocols.
After two treatment cycles, clinical tumor response was assessed by computed tomography or magnetic resonance imaging scan of the neck. The study protocol stipulated that only those patients who experienced complete response (CR) or partial response (PR) were eligible for a further C + TPF cycle, followed by intensity-modulated radiotherapy (one 2-Gy fraction per day, 5 days per week, for a total of 70 Gy). Patients with stable disease (SD) or progressive disease (PD) underwent immediate salvage surgery.
Following the full course of treatment, an endoscopic evaluation was scheduled per protocol at 3, 12, 36 and 60 months, and in cases of suspected recurrence. A computed tomography or magnetic resonance imaging scan of the neck, and chest radiography, were scheduled at 3 and 6 months post-treatment and every 6 months thereafter.
2.3
Endpoints and statistics
The primary endpoint was LP rate 3 months post-treatment (defined as the absence of any residual disease that would justify salvage total laryngectomy) . Secondary endpoints were larynx function preservation (LFP) (defined as a disease-free larynx in place, without tracheotomy or feeding tube) and overall survival (OS) at 12, 36 and 60 months post-treatment. Acute toxicity was graded according to the National Cancer Institute – Common Toxicity Criteria for Adverse Events version 3.0. Late toxicity was graded according to the Radiation Therapy Oncology Group (RTOG) Late Radiation Morbidity Scoring Criteria. Descriptive statistics were used to report the study endpoints.
2
Materials and methods
2.1
Patients
During July 2010 and August 2013, we prospectively enrolled eligible patients for the current trial. Patients were eligible if they met the following criteria: aged 18–75 years; histologically proven stage III–IV larynx or hypopharynx squamous cell carcinoma suitable for total laryngectomy (TL); no evidence of distant metastases or a synchronous cancer; no tumor-specific pretreatment; has at least one measurable lesions according to the Response Evaluation Criteria In Solid Tumors (RECIST) 1.0 criteria detected by computed tomography or magnetic resonance imaging; Karnofsky Performance Scale (KPS) Index ≥70 and no major impairment of liver, kidney, or hematopoietic function.
Ineligibility criteria included highly infiltrative transglottic tumors, tumors extending through the cartilage, tumors resectable by partial laryngectomy or tumors requiring a circumferential total pharyngolaryngectomy, pretreatment tracheotomy, prior or present history of malignancy, a comorbidity or biological disorder contraindicating administration of docetaxel, cisplatin, or 5-fluorouracil, or expected poor compliance with treatment.
The protocol used was approved by the ethics committee of Sun Yat-sen University Cancer Center, Guangdong, China, and all patients gave informed written consent prior to entry into the trial.
2.2
Treatment and follow-up
Eligible patients received 2 cycles of cetuximab 400 mg/m 2 , docetaxel 60 mg/m 2 and cisplatin 60 mg/m 2 on day 1, and 5-fluorouracil 600 mg/m 2 per day on days 1–5 (C + TPF) at 3-week intervals. Pretreatment consisted of diphenhydramine 50 mg and dexamethasone 8 mg. Setrons were given before and after cisplatin administration, and hydration was delivered according to institutional protocols.
After two treatment cycles, clinical tumor response was assessed by computed tomography or magnetic resonance imaging scan of the neck. The study protocol stipulated that only those patients who experienced complete response (CR) or partial response (PR) were eligible for a further C + TPF cycle, followed by intensity-modulated radiotherapy (one 2-Gy fraction per day, 5 days per week, for a total of 70 Gy). Patients with stable disease (SD) or progressive disease (PD) underwent immediate salvage surgery.
Following the full course of treatment, an endoscopic evaluation was scheduled per protocol at 3, 12, 36 and 60 months, and in cases of suspected recurrence. A computed tomography or magnetic resonance imaging scan of the neck, and chest radiography, were scheduled at 3 and 6 months post-treatment and every 6 months thereafter.
2.3
Endpoints and statistics
The primary endpoint was LP rate 3 months post-treatment (defined as the absence of any residual disease that would justify salvage total laryngectomy) . Secondary endpoints were larynx function preservation (LFP) (defined as a disease-free larynx in place, without tracheotomy or feeding tube) and overall survival (OS) at 12, 36 and 60 months post-treatment. Acute toxicity was graded according to the National Cancer Institute – Common Toxicity Criteria for Adverse Events version 3.0. Late toxicity was graded according to the Radiation Therapy Oncology Group (RTOG) Late Radiation Morbidity Scoring Criteria. Descriptive statistics were used to report the study endpoints.
3
Results
3.1
Patient characteristics
Thirteen patients were enrolled in the present study. All subjects were patients with stage III–IV, locally advanced, larynx (n = 4) or hypopharynx (n = 9) squamous cell carcinoma. There were 12 males and 1 female, with a median age of 53.3 years (range 38–68 years). The KPS indices of all enrolled patients were >80. Patient characteristics are summarized in Table 1 .
| No. | Age (years) | Sex | KPS | Primary tumor site | Larynx mobility | Disease stage |
|---|---|---|---|---|---|---|
| 1 | 41 | Male | 90 | Hypopharynx | Impaired | III |
| 2 | 64 | Male | 80 | Hypopharynx | Normal | III |
| 3 | 68 | Female | 90 | Larynx | Normal | III |
| 4 | 57 | Male | 90 | Larynx | Normal | IVA |
| 5 | 63 | Male | 90 | Hypopharynx | Impaired | III |
| 6 | 59 | Male | 80 | Hypopharynx | Normal | III |
| 7 | 51 | Male | 90 | Hypopharynx | Normal | III |
| 8 | 44 | Male | 90 | Hypopharynx | Normal | III |
| 9 | 38 | Male | 90 | Hypopharynx | Normal | III |
| 10 | 64 | Male | 80 | Larynx | Normal | IVA |
| 11 | 42 | Male | 90 | Hypopharynx | Normal | III |
| 12 | 56 | Male | 80 | Larynx | Normal | IVA |
| 13 | 46 | Male | 90 | Hypopharynx | Normal | III |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
