Abstract

Objective

The current standard of care for post-operative high-risk squamous cell carcinoma of the head and neck is concurrent chemoradiotherapy with a 3-weekly cycle of cisplatin (3W-CDDP/RT). In previous pivotal trials, the complete delivery rate of three cycles of cisplatin and radiation therapy was only ∼60%. Here, we evaluated the feasibility and safety of 3W-CDDP/RT in a Japanese population.

Methods

The study enrolled post-operative high-risk squamous cell carcinoma of the head and neck patients. High-risk factors were a microscopically incomplete resection, extracapsular extension and two or more lymph node metastases. Subjects received three cycles of cisplatin at a dose of 100 mg/m2 concomitant with radiation therapy (66 Gy/33 Fr).

Results

From August 2006 to May 2009, 25 eligible subjects were accrued, including 13 males, with a median age of 59 years, Eastern Cooperative Oncology Group performance status 0/1 (18/7), Stage III/IVA/IVB/recurrent (1/18/1/5) and oral cavity/oropharynx/hypopharynx/larynx (17/4/3/1). Protocol completion rate was 80%. The lower limit of the one-sided 90% confidence interval was 66%, which met the predefined statistical criteria. Grade 3/4 acute and late toxicities were almost identical to those in previous pivotal trials. No treatment-related deaths were observed. With a median follow-up of 39 months, 14 have had progression and 10 have died. Estimated 3-year locoregional control rate, relapse-free survival and overall survival were 74, 43 and 60%, respectively. On univariate analysis, oral cavity cancer and a cumulative cisplatin dose below 240 mg/m2 appeared to be poor prognostic factors.

Conclusions

This is the first Phase II feasibility trial of adjuvant chemoradiotherapy with 3-weekly cisplatin for post-operative high-risk squamous cell carcinoma of the head and neck in a Japanese population. This treatment was feasible and the safety profile was identical to those in pivotal Phase III trials.

INTRODUCTION

The current standard of care for post-operative high-risk squamous cell carcinoma of the head and neck (SCCHN) is concurrent chemoradiotherapy with a 3-weekly cycle of cisplatin at a dose of 100 mg/m2 (3W-CDDP/RT). In two pivotal trials (RTOG 9501 and EORTC22931), post-operative 3W-CDDP/RT showed a significant improvement in locoregional control (LRC) and disease-free survival compared with radiation therapy alone, and EORTC 22931 also showed a significant improvement in overall survival (OS) (1,2). These significant benefits of post-operative 3W-CDDP/RT were further supported by a combined analysis of RTOG 9501 and EORTC 22931 (3). However, post-operative 3W-CDDP/RT is associated with greater toxicity than post-operative radiation therapy alone and the complete delivery rate of three cycles of cisplatin and RT in prior pivotal trials was only ∼60% (1,2,4).

Few prospective data for post-operative 3W-CDDP/RT in Asian populations are available, and acceptance of adjuvant chemoradiotherapy in Japan is low. Here, we evaluated the feasibility and safety of post-operative 3W-CDDP/RT in a Japanese population.

PATIENTS AND METHODS

Patient Selection

All patients had pathologically confirmed locally advanced SCCHN arising in the oral cavity, oropharynx, hypopharynx or larynx without distant metastasis and had undergone surgical resection without gross residual disease. Patients with local recurrence who underwent surgical resection with curative intent were also enrolled in this feasibility trial.

At least one of the following high-risk pathologic features was required: (1) microscopically involved (5 mm or less) resection margins, (2) extracapsular spread in at least one lymph node and (3) two or more positive lymph nodes. Additional entry criteria included age 20–75 years; Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1; and adequate hematologic and organ function, namely a white-cell count of at least 3500/m3, platelet count of at least 100 000/m3 and creatinine clearance of more than 70 ml/min. Patients with a history of previous chemotherapy or radiotherapy were excluded. The trial was conducted under a multi-institutional design in four institutions in Japan, the National Cancer Center Hospital East, Kobe University Hospital, Miyagi Cancer Center and Shizuoka Cancer Center. The study protocol was approved by the institutional review committee of each center, and all patients gave written informed consent before study entry in accordance with institutional guidelines.

Treatment Plan

All eligible patients underwent definitive surgery with curative intent. The extent of surgical resection of the primary tumor and/or neck dissection procedures followed accepted criteria for adequate excision, which depend on the volume and location of the tumor.

All patients underwent radiation therapy within 8 weeks after definitive surgery consisting of conventionally fractionated doses of 2 Gy each in 5-weekly sessions. Target-volume doses and maximal dose to the spinal cord were recorded. Treatments were conducted on linear accelerators of 4–6 MV using egocentric techniques. A large volume encompassing the primary site and all draining lymph nodes at risk received a dose of more than 40 Gy in 20 fractions over a period of 4 weeks. Regions that were adjacent to the high-risk area received a dose of more than 46 Gy in 23 fractions over a period of 4.5 weeks. Regions that were at high risk for malignant dissemination or that had inadequate resection margins received a total of 66 Gy in 33 fractions over a period of 6.5 weeks. The dose to the spinal cord was limited to 46 Gy.

Concurrent chemotherapy consisted of three courses of cisplatin 100 mg/m2 infused on Days 1, 22 and 43 of the course of radiotherapy. Patients received prophylactic hydration and antiemetic agents. Aprepitant was approved in Japan in October 2009, and was therefore not available during the study period. We therefore recommended the use of a 5-HT3 antagonist and dexamethasone 16–20 mg on Day 1 and dexamethasone 8–16 mg on Days 2–3. Cisplatin was postponed if the absolute neutrophil count fell below 1000/mm3 or platelet count fell below 75 000/mm3. Cisplatin dose was decreased to 80 mg/m2 if creatinine clearance dropped to 50–60 ml/min, and to 60 mg/m2 if it dropped to 40–50 ml/min. Dose was also decreased with Grade 4 hematological toxicity or febrile neutropenia from 100 to 80 mg/m2 or from 80 to 60 mg/m2; with neurotoxicity or hearing loss Grade 2 to 60 mg/m2 and administration was discontinued in the case of neurotoxicity or hearing loss Grade 3 or more. We routinely recommend prophylactic insertion of a percutaneous endoscopic gastrostomy (PEG) for nutrition support before chemoradiotherapy.

Follow-up

Patients were evaluated every 3 months for the first 12 months and every 4 months for the next 24 months. Adverse effects, weight and performance status were assessed at baseline, weekly for the first 8 weeks, and at all follow-up assessments, which were conducted every 3 months.

Study Design

Patients were enrolled after surgery and assigned to receive adjuvant concurrent chemoradiotherapy with cisplatin. Principal eligibility criteria were checked at enrollment.

In accordance with the intention-to-treat principle, all patients were included in all statistical analyses. The primary endpoint was treatment completion rate. Treatment completion was defined as delivery of 66 Gy radiation and a cumulative cisplatin dose of more than 240 mg/m2. Secondary endpoints were OS, relapse-free survival (RFS), LRC and adverse events. OS was defined as the time from initiation of chemoradiotherapy to death from any cause, and RFS as the time from initiation of chemoradiotherapy to recurrence or death from any cause. The duration of LRC was defined as the time from initiation of chemoradiotherapy to the occurrence of locoregional recurrence. Survival curves were estimated using Kaplan–Meier methods (5) and comparisons between survival curves were performed using the log-rank test. Treatment-related adverse events were scored according to the Common Toxicity Criteria of the National Cancer Institute, version 3.0, and categorized as acute (occurring within 90 days after initiation of chemoradiotherapy) or late (continuing or occurring after 90 days). We also assessed the 1-year feeding tube rate, which was defined as the proportion of patients using tube feeding 1 year after the initiation of chemoradiotherapy without recurrence.

Based on the previous trials (1,2,4), we considered the results as positive when the estimated treatment completion rate was around 60%, with adequate precision. Twenty or more patients were required to ensure that the lower limit of the one-sided 90% confidence interval (CI) of the treatment completion rate would be >43%. We therefore planned to recruit 25 patients. An interim futility analysis was conducted after 10 patients were enrolled.

All analyses were conducted using the Windows version of SPSS Statistics version 18 (IBM Corporation, NY, USA).

RESULTS

Patient Characteristics

Twenty-five patients were enrolled between August 2006 and June 2009. Patient characteristics are summarized in Table 1. By age, the 13 females and 12 males ranged from 26 to 68 years, with a median of 59 years. Eighteen patients were ECOG PS 0 and seven were ECOG PS 1. Sixteen patients had primary sites in the oral tongue, four in the hypopharynx, three in the oropharynx and one each in the larynx and oral floor. Twenty patients had locally advanced disease and five had locoregional recurrent disease. All 25 patients underwent definitive surgery with curative intent. By pathological stage, 1 patient was classified as having Stage III disease, 18 as having Stage IVA and 1 as having Stage IVB. All five patients who experienced locoregional recurrence did so after partial glossectomy for T1N0 or T2N0 disease, and all five received definitive surgery for locoregional recurrent disease. Fifteen patients received reconstruction surgery using the following reconstruction methods: free rectus abdominis flap in five, free jejunal flap in four, free anterolateral thigh flap in three and free radial forearm flap in three. Regarding high-risk features, 6 patients had a microscopically involved margin (incomplete resection: ICR), 15 had extracapsular extension (ECE) and 22 had multiple lymph node metastases (two or more lymph nodes). Twenty patients had at least ICR or ECE and five had only multiple lymph nodes. Three of these five patients received definitive surgery for locoregional recurrent disease, while the other two had three or more lymph node metastases. The median number of metastatic lymph nodes was 4, ranging from 0 to 28.

Table 1.

Patient characteristics (n = 25)

 Number of patients 
Age: median (range) 59 (26–68) 
Gender: female/male 13/12 
PS: 0/1 18/7 
Primary site 
 Oral cavity 17 
 Oropharynx 
 Hypopharynx 
 Larynx 
Stage 
 III 
 IVA 18 
 IVB 
 Locoregional recurrent disease 
High-risk features 
 ICR 
 ECE 15 
 Multiple lymph node metastases 22 
Histology: squamous cell carcinoma 
 Well differentiated 13 
 Moderately differentiated 
 Poorly differentiated 
 Number of patients 
Age: median (range) 59 (26–68) 
Gender: female/male 13/12 
PS: 0/1 18/7 
Primary site 
 Oral cavity 17 
 Oropharynx 
 Hypopharynx 
 Larynx 
Stage 
 III 
 IVA 18 
 IVB 
 Locoregional recurrent disease 
High-risk features 
 ICR 
 ECE 15 
 Multiple lymph node metastases 22 
Histology: squamous cell carcinoma 
 Well differentiated 13 
 Moderately differentiated 
 Poorly differentiated 

ICR, incomplete resection; ECE, extracapsular extension.

Compliance with and Delivery of Treatment

Median interval from surgery to the initiation of chemoradiotherapy was 47 days (range 28–56 days). Median duration of radiation was 49 days (range 45–58 days) and 24 of 25 patients completed radiation therapy of up to 66 Gy in 33 fractions, as specified in the protocol. One patient was considered to have not completed radiation therapy because of an unacceptable fraction size (66 Gy in 30 fractions).

A total of 23 patients received three cycles of cisplatin and 2 received two cycles. Dose reduction of cisplatin was conducted as specified in the protocol: reduction was necessary in 7 patients in the second cycle and in 12 in third cycle due to renal impairment in 13, hearing impairment in 2, infection in 1, and prolongation of anorexia 1, patient refusal and unacceptable deviation from the protocol in 1 each. In the case with unacceptable deviation from the protocol, the patient received a third cycle of cisplatin divided into four doses of 20 mg/m2 each. Median relative dose intensity (RDI) of cisplatin was 0.83 (range 0.51–1.00).

Treatment completion was defined as 66 Gy radiation delivery with a cumulative cisplatin dose of more than 240 mg/m2. A total of 20 patients met these criteria, with radiation up to 66 Gy in 33 fractions. Treatment completion rate was thus 80% and the lower limit of the one-sided 90% CI was 66%, which met the statistical criteria specified in the protocol.

Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria version 3.0 and are listed in Tables 2 and 3. Grade 3/4 acute toxicity included mucositis (44%), dysphagia (28%), dermatitis (24%), nausea/vomiting (16%), neutropenia (32%) and anemia (36%). Grade 3/4 late toxicity included dysphagia (10%), xerostomia (5%) and osteonecrosis (5%). Twenty patients received prophylactic PEG insertion. During and within 30 days after adjuvant 3W-CDDP/RT, 17 of 20 patients used PEG for nutritional support, while 1 of 20 used total parenteral nutrition (TPN) instead of PEG and 2 of 20 did not use PEG at all. Two of five patients without PEG used a naso-gastric tube, one patient used TPN and one patient did not receive nutritional support. Finally, 84% (21/25) of patients received nutritional support during and within 30 days after adjuvant 3W-CDDP/RT. Among the disease-free patients, 3-, 6-month and 1-year feeding tube rates were 48% (10/21), 40% (6/15) and 20% (3/15), respectively. There were no major complications with the reconstruction flap and no treatment-related deaths within 30 days.

Table 2.

Acute adverse events (n = 25)

Adverse event Number of patients
 
Grade 1 Grade 2 Grade 3 Grade 4 % Grade 3/4 
Leucopenia 12 48 
Neutropenia 11 32 
Anemia 11 36 
Thrombocytopenia 14 
Nausea 17 16 
Vomiting 13 
Anorexia 11 10 40 
Constipation 
Dysphagia 13 28 
Mucositis 12 11 44 
Dermatitis 10 24 
Hearing loss 
Taste alteration 18 — — — 
Xerostomia 18 
Febrile neutropenia — 
Infection 20 
Creatinin 
Heart failure 
Adverse event Number of patients
 
Grade 1 Grade 2 Grade 3 Grade 4 % Grade 3/4 
Leucopenia 12 48 
Neutropenia 11 32 
Anemia 11 36 
Thrombocytopenia 14 
Nausea 17 16 
Vomiting 13 
Anorexia 11 10 40 
Constipation 
Dysphagia 13 28 
Mucositis 12 11 44 
Dermatitis 10 24 
Hearing loss 
Taste alteration 18 — — — 
Xerostomia 18 
Febrile neutropenia — 
Infection 20 
Creatinin 
Heart failure 
Table 3.

Late adverse events (n = 21)

Adverse event Number of patients
 
Grade 1 Grade 2 Grade 3 Grade 4 % Grade 3/4 
Leucopenia 10 
Neutropenia 
Anemia 24 
Thrombocytopenia 
Dysphagia 10 
Taste alteration 14 — — — 
Xerostomia 12 
Peripheral neuropathy 
Hearing loss 
Osteonecrosis 
Creatinin 
Infection 
Hypothyroidism 
Adverse event Number of patients
 
Grade 1 Grade 2 Grade 3 Grade 4 % Grade 3/4 
Leucopenia 10 
Neutropenia 
Anemia 24 
Thrombocytopenia 
Dysphagia 10 
Taste alteration 14 — — — 
Xerostomia 12 
Peripheral neuropathy 
Hearing loss 
Osteonecrosis 
Creatinin 
Infection 
Hypothyroidism 

Disease recurrence was observed in 14 patients, consisting of locoregional recurrence in 3, locoregional recurrence and distant metastasis in 2, and distant metastasis in 9. By site, nine cases of recurrence occurred in the lung, three in the cervical lymph nodes, one in the primary site and three in other sites.

Survival outcomes were estimated by the Kaplan–Meier method. With a median follow-up period for survivors of 39 months (range 19–56 months), 3-year LRC, RFS and OS were 74, 43 and 60%, respectively (Figures 1–3).

Figure 1.

Kaplan–Meier estimates of locoregional control rate (n = 25).

Figure 1.

Kaplan–Meier estimates of locoregional control rate (n = 25).

Figure 2.

Kaplan–Meier estimates of relapse-free survival (n = 25).

Figure 2.

Kaplan–Meier estimates of relapse-free survival (n = 25).

Figure 3.

Kaplan–Meier estimates of overall survival (n = 25).

Figure 3.

Kaplan–Meier estimates of overall survival (n = 25).

Univariate Analysis

Univariate analyses for LRC, RFS and OS were performed using the following variables: gender, ECOG PS, site of the primary tumor, disease status (locoregional recurrence or not), tumor cell differentiation and cumulative cisplatin dose (Table 4). Allowing for the small sample size of this Phase II feasibility study, RFS was significantly poorer when the primary site was in the oral cavity (P = 0.038) and in patients who received a cumulative cisplatin dose below 240 mg/m2 (P = 0.005). Moreover, OS was significantly poorer in patients who received a cumulative cisplatin dose below 240 mg/m2 (P = 0.033).

Table 4.

Univariate analysis for survival (n = 25)

 No. of patients Three-year locoregional control rate (%) P value Three-year RFS (%) P value Three-year OS (%) P value 
Gender 
 Female 13 79.1 0.399 59.3 0.09 69.2 0.281 
 Male 12 74.1  25.0  50.0  
ECOG PS 
 0 18 70.7 0.721 42.9 0.663 66.2 0.307 
 1 85.7  42.9  42.9  
Site of primary tumor 
 Oral cavity 17 58.8 0.987 23.5 0.038 46.3 0.055 
 Other 75.0  75.0  87.5  
Disease status 
 Locally advanced disease 20 75.0 0.784 48.9 0.157 65.0 0.29 
 Locoregional recurrent disease 80.0  20.0  40.0  
Tumor differentiation 
 Well or moderately differentiated 19 65.5 0.176 39.5 0.835 62.7 0.48 
 Poorly differentiated 100  50.0  50.0  
Cumulative cisplatin dose 
 ≥240 mg/m2 22 76.3 0.36 48.5 0.005 68.2 0.033 
 <240 mg/m2 66.7    
 No. of patients Three-year locoregional control rate (%) P value Three-year RFS (%) P value Three-year OS (%) P value 
Gender 
 Female 13 79.1 0.399 59.3 0.09 69.2 0.281 
 Male 12 74.1  25.0  50.0  
ECOG PS 
 0 18 70.7 0.721 42.9 0.663 66.2 0.307 
 1 85.7  42.9  42.9  
Site of primary tumor 
 Oral cavity 17 58.8 0.987 23.5 0.038 46.3 0.055 
 Other 75.0  75.0  87.5  
Disease status 
 Locally advanced disease 20 75.0 0.784 48.9 0.157 65.0 0.29 
 Locoregional recurrent disease 80.0  20.0  40.0  
Tumor differentiation 
 Well or moderately differentiated 19 65.5 0.176 39.5 0.835 62.7 0.48 
 Poorly differentiated 100  50.0  50.0  
Cumulative cisplatin dose 
 ≥240 mg/m2 22 76.3 0.36 48.5 0.005 68.2 0.033 
 <240 mg/m2 66.7    

LRCR, locoregional control rate; RFS, relapse-free survival; OS, overall survival; ECOG PS, Eastern Cooperative Oncology Group performance status.

DISCUSSION

The current standard of care for post-operative high-risk SCCHN is concurrent chemoradiotherapy with a 3-week cycle of cisplatin at a dose of 100 mg/m2 (3W-CDDP/RT). In two pivotal trials (RTOG 9501 and EORTC22931), post-operative 3W-CDDP/RT showed a significant improvement in LRC and disease-free survival, and EORTC 22931 also showed a significant improvement in OS (1,2). These significant benefits of post-operative 3W-CDDP/RT were further supported by combined analysis of RTOG 9501 and EORTC 22931 (3). However, post-operative 3W-CDDP/RT is associated with greater toxicity than post-operative radiation therapy alone, and the complete delivery rate of three cycles of cisplatin and RT was only ∼60% (1,2,4). This poor treatment compliance with 3W-CDDP/RT in the post-operative setting is of considerable concern. In their retrospective analysis of 3W-CDDP/RT at a reduced dose of 75 mg/m2 in a post-operative setting, Franchin et al. (6) found that despite the reduced dose of cisplatin, only 48% (68/142) of patients were able to receive three cycles of cisplatin concurrent with radiation. Further, in their report of the safety and feasibility of 3W-CDDP/RT at a dose of 100 mg/m2 in three nasopharyngeal cancer patients, Isobe et al. (7) concluded that 3W-CDDP/RT at 100 mg/m2 was not tolerable for Japanese patients, while Nishimura et al. (8) recommended a dose reduction to 60–70 mg/m2 owing to the poorer renal function of head and neck cancer patients in Japan than in western countries. In our Phase II feasibility trial, 20 patients (80%) received a total cisplatin dose of more than 240 mg/m2 concurrent with RT and achieved an RDI of cisplatin of 0.83. Moreover, the incidence of adverse events was almost identical to that in previous pivotal trials (1,2,4) and no treatment-related deaths or severe complications with the reconstruction flap were seen. Considering that most patients (72%) were ECOG-PS 0 and the small sample size, these results indicted the tolerability and feasibility of adjuvant 3W-CDDP/RT for Japanese patients with post-operative high-risk SCCHN.

Against this, the relatively high incidence and severity of acute toxicities of 3W-CDDP/RT are also of concern. Among these, G3/4 hematological toxicities were seen in around 40% of patients who received with 3W-CDDP/RT (1,2,9). In our Phase II trial, 32% (8/25) of patients experienced G3/4 neutropenia. These may lead to infection at the surgical site after definitive surgery for advanced SCCHN. Moreover, 32% (8/25) of patients experienced Grade 2 or more serum creatinin elevation, and decreases in creatinin clearance led to a dose reduction of cisplatin in 52% (13/25) of patients. Given the suggested association between efficacy and total dose of cisplatin in concurrent chemoradiation for SCCHN (10–12), administration with a view to minimal renal impairment is important in maintaining the efficacy of concurrent chemoradiotherapy with cisplatin. Attempts to improve treatment compliance and safety in the adjuvant setting have also resulted in the investigation of weekly cisplatin concurrent with radiation (W-CDDP/RT) (13–16). In this regard, we are now planning a Phase III trial of adjuvant chemoradiotherapy comparing weekly with 3-weekly cisplatin in post-operative high-risk patients with SCCHN.

With regard to efficacy, 3-year RFS and OS after a median follow-up period for survivors of 39 months were 43 and 60%, respectively. In RTOG 95-01, 3-year event-free survival and OS were 47 and 56% (1), while 5-year event-free survival and OS in EORTC 22 931 were 47 and 53% (2), respectively. Considering that our present data included cases with local recurrence, survival in our study appears identical with the results of these previous pivotal Phase III trials (1,2).

In univariate analysis, prognosis appeared to be poorer in patients with oral cavity cancer and those who received a cumulative cisplatin dose of <240 mg/m2. Three-year RFS and OS for patients with oral cavity cancer were 23.5 and 46.3%, respectively. The poor prognostic significance attached to oral cavity cancer is well known (17–20), and our present results appeared consistent with these previous reports. In contrast, the relationship between cumulative cisplatin dose and the efficacy of chemoradiotherapy has been a matter of debate. From their analysis of previous trials (10–12), Ang et al. noted that a cumulative cisplatin dose of ∼200 mg/m2 might be sufficient to yield a beneficial antitumor effect, independently of schedule. These authors also reported that LRC was significantly worse in patients receiving two cycles of cisplatin than in those receiving three [hazard ratio (HR): 1.7, 95% CI: 1.20–2.54] and that OS with only a single cycle was significantly worse than that with three cycles (HR: 2.1, 95% CI: 1.35–3.32) (21). Our data also suggested that survival outcome deteriorated with a cumulative cisplatin dose below 240 mg/m2, which may suggest the superiority of continuing cisplatin cycling for as long as possible.

In conclusion, this is the first Phase II feasibility trial of adjuvant chemoradiothrapy with 3-weekly cisplatin for post-operative high-risk patients with SCCHN in a Japanese population. This treatment was feasible and had an identical safety profile to those in pivotal Phase III trials. Oral cavity cancer and a cumulative cisplatin dose below 240 mg/m2 appeared to be associated with a poor survival outcome.

Funding

This study was supported in part by the National Cancer Research and Development Fund (23-A-21).

Conflict of interest statement

None declared.

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