Japanese Journal of Clinical Oncology Advance Access published online on October 8, 2007
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hym106
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© 2007 Foundation for Promotion of Cancer Research
Feasibility Study of Single Agent Cisplatin and Concurrent Radiotherapy in Japanese Patients with Squamous Cell Carcinoma of the Head and Neck: Preliminary Results
1 Division of Radiation Oncology
2 Division of Digestive Endoscopy and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba
3 Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Sunto-gun, Shizuoka
4 Department of Radiology, Shinshu University, School of Medicine, Matsumoto, Japan
For reprints and all correspondence: Sadamoto Zenda, Division of Radiation Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. E-mail: szenda{at}east.ncc.go.jp
Received May 29, 2007; accepted June 23, 2007
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Background: Concurrent chemoradiotherapy with the single agent cisplatin (CDDP + RT) has been recognized worldwide as the standard treatment for unresectable locally advanced SCCHN. The objective of this study was to clarify the feasibility of CDDP + RT in Japanese patients.
Patients and methods: Patients with unresectable squamous cell carcinoma of the head and neck were given single daily fractionated radiation (70 Gy at 2 Gy/day) and chemotherapy consisting of a 2 h infusion of CDDP 100 mg/m2 on days 1, 22 and 43. The primary endpoint was the rate of completion of CDDP + RT.
Results: Between November 2005 and January 2007, 20 patients were enrolled, 19 males and one female with a median age of 61.5 years (range 50–74). One patient had recurrent unresectable disease after surgery and the remaining 19 had stage IV disease. No grade 4 hematologic toxicities were observed. The incidence of grade 3 mucositis was 55% and no treatment-related death occurred. Full-dose irradiation was performed in all patients, with a median duration of radiotherapy of 50 days (range 48–54). Although all patients received the first two administrations of CDDP, the third dose was administed in 17 patients (85%). The rate of completion of CDDP + RT was 85% and the dose intensity of CDDP was 28.9 mg/m2/week (relative dose intensity 89%). Overall complete response rate was 50% and the rate of primary complete response was 90%.
Conclusion: Concurrent chemoradiation therapy with the standard dose of CDDP is feasible in Japanese patients. Treatment modification based on racial differences is not necessary.
Key Words: cisplatin • squamous cell carcinoma • head and neck • chemoradiotherapy • racial difference
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer in the world (1). The majority of patients present with locally or regionally advanced disease (2,3). Following Pignon et al.'s (4) large meta-analysis of locally advanced SCCHN showing the superiority of concurrent chemoradiotherapy over radiotherapy alone or a sequential strategy, concurrent chemoradiotherapy is now considered the optimal nonsurgical treatment of this disease.
For unresectable SCCHN, a phase III randomized trial (INT0126) by the Head and Neck Intergroup comparing radiation therapy alone with two chemoradiotherapy regimens showed that radiotherapy and concurrent high-dose single-agent cisplatin were significantly superior to radiation therapy alone (5). On the basis of these results, concurrent radiotherapy with high-dose single-agent cisplatin is now the standard of care for nonsurgical treatment for unresectable SCCHN.
However, Asians accounted for fewer than 7% of the total INT 0126 study population, raising concerns that, given perceived differences between Asian and Western people, the study may not have provided sufficient data to validate the use of the regimen in Asian patients. As a result, this regimen is still not widely used in Japan. Moreover, a retrospective study in three Japanese patients with nasopharyngeal cancer receiving cisplatin and concurrent radiotherapy reported severe acute toxicities (6).
Recently, several randomized phase III studies have confirmed the value of radiotherapy and concurrent high-dose single-agent cisplatin in almost all stages of locally advanced head and neck cancer (7–11). We therefore considered it desirable to confirm the feasibility of this regimen in Japanese patients. Here, we report a multicenter prospective study conducted to clarify the feasibility of this regimen for Japanese SCCHN patients.
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PATIENTS AND METHODS |
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Patients
Entry criteria were: (1) pathologically confirmed squamous cell carcinoma of the hypopharynx, oropharynx or larynx; (2) clinically diagnosed stage III or IV nonmetastatic disease considered unresectable, or locoregional recurrent disease considered unresectable; (3) patient age between 20 and 75 years inclusive; (4) Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1 or less; (5) adequate organ function; (6) no active concomitant malignancy; and (7) no prior chemotherapy or radiotherapy. The trial was approved by each of the respective institutional review boards (IRB), and written informed consent to treatment was obtained from all patients before the initiation of treatment.
Pre-treatment clinical evaluation included cervical-thoracic computed tomography (CT), magnetic resonance imaging (MRI) of the involved head and neck region, and laryngoscopy and upper gastrointestinal endoscopy. Lymph node metastasis was diagnosed if lymph nodes of greater than 10 mm or with central necrosis were detected. Tumor staging was performed using the TNM classification of UICC6th (12). Radiological evaluations for staging were jointly reviewed by radiologists, surgeons and oncologists at each institution.
A complete blood count as well as serum chemistry tests were performed on all patients at entry. Patients who fulfilled any of the following criteria were ineligible: (1) white blood cell count less than 4000/mm3; (2) platelet count less than 100 000/mm3; (3) hemoglobin less than 10 g/dl; (4) bilirubin greater than 1.5 mg/dl; (5) aminotransferase greater than 100 IU/l; and (6) serum creatinine greater than 1.2 mg/dl or creatinine clearance less than 70 ml/min.
Cases satisfying any of the following criteria were defined as unresectable: (i) T4b or N3 disease; (ii) N2b-c disease with at least 4 lymph node metastases; (iii) Rouviere lymph node metastases; (iv) nodal fixation to the carotid artery; and (v) a diagnosis that the cancer was technically unresectable by the attending surgeon.
Treatment Methods
The treatment schema is shown in Fig. 1. Concomitant radiation treatment with 4–6 MV was administered at 2 Gy/day on 5 days/week for 7 weeks. Gross tumor volume (GTV) was determined as the region judged on endoscopic or radiographic examination to contain the gross primary tumor or metastatic lymph nodes. Clinical target volume (CTV) was defined as the GTV plus volumes considered at risk of containing microscopic disease. The CTV was further categorized into two volumes, a CTV boost (CTVb), which included the primary tumor with a 1 cm margin craniocaudally and any metastatic nodes with a 0.5 to 2 cm margin, and a CTV subclinical (CTVs), which included the CTVb plus regional nodes.
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In this study, the bilateral level II–IV cervical lymph nodes and Rouviere lymph nodes were included in the CTVs as a minimum requirement. The CTVs was treated with 40 Gy by the multiple field technique or lateral opposed beams with a wedge filter. A booster dose of 30 Gy was given to the CTVb using the multiple field technique and electron beams to shield the spinal cord for a total dose of 70 Gy. Intensity-modulated radiotherapy (IMRT) was not permitted in this protocol.
Chemotherapy consisted of a 2 h infusion with CDDP at 100 mg/m2/day on days 1, 22 and 43. Patients were required to fulfill all of the following conditions before each administration: (a) white blood cell count more than 2500/mm3; (b) platelet count greater than 100 000/mm3; (c) serum creatinine less than 1.5 mg/dl or creatinine clearance more than 50 ml/min; and (d) no sign of infection. Treatment in those not meeting these requirements was delayed until subsequent retesting could be done. CDDP dose was reduced to 80% if grade 4 hematologic toxicity or febrile neutropenia was observed, and to 60% if serum creatinine levels greater than 1.5 mg/dl or creatinine clearance between 40 and 50 ml/min were observed. Chemotherapy was cancelled completely if both serum creatinine level was greater than 1.5 mg/dl and creatinine clearance was less than 40 ml/min on the administration day.
Further, preparation for percutaneous endoscopic gastrostomy (PEG) feeding before treatment is recommended. Moreover, to avoid the synergistic toxicity of CDDP and nonsteroidal anti-inflammatory drugs (NSAIDs) on renal function, the avoidance of NSAIDs during treatment is also recommended.
Toxicity and Response Evaluation
Toxicities were graded using the Common Terminology Criteria for Adverse Events (NCI-CTCAE version 3.0). For measurable lesions, response was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST). CT and MRI were performed at 6–10 weeks after the end of radiotherapy as a convenient means of determining target lesion progress and identifying emerging new lesions. Findings of positron emission tomography (PET) and PET-CT was used to support the diagnosis.
Study Design
The primary endpoint was treatment compliance. Complete treatment delivery was defined as administration of the 70 Gy radiotherapy dose within 63 days and three courses of CDDP no later than 14 days after the end of irradiation. Treatment compliance was evaluated by the rate of complete treatment delivery.
A total of 18 patients were schedule to be enrolled, comprising six in the first step and 12 in the second. Enrollment was temporarily halted after enrollment of the 6th patient to allow evaluation of the degree of acute toxicity by a trial review committee consisting of persons who did not contribute to the study. The protocol required that, if the trial review committee judged that the overall degree of acute toxicity in these six patients was serious, patient recruitment was to be restarted with the CDDP dose reduced to 80 mg/m2/day, or the study was to terminated and reported accordingly. Further, after patient recruitment was restarted, the study was also to be terminated and reported accordingly on the occurrence of 10 or more cases of withdrawal for any reason or of three or more cases of treatment-related death.
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Patients Characteristics
From November 1, 2005 through January 15, 2007, 20 patients were enrolled, including the six in the first step. Patient characteristics of all 20 are listed in Table 1. Median age was 61.5 years (range 50–74). One patient had recurrent unresectable disease at the oropharynx, while the remaining 19 had stage IV disease. Tumor (T) and Nodal (N) classification is detailed in Table 2. Nineteen patients had lymph node metastases, among whom five had an N status of N3.
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Response and Survival
Ten of 20 patients (50%) were designated as achieving an overall complete response (CR). With regard to the primary site, 18 patients achieved a CR and the rate of primary CR was 90%. Because the data were preliminary, disease-free survival and overall survival are not described.
Adverse Events
Acute adverse events, including hematological and nonhematological toxicities, are summarized in Table 3. No grade 4 hematological toxicity was observed. Grade 3 anemia was observed four patients, two of whom required blood transfusion at the end of radiotherapy. Neither case had shown active bleeding. Grade 3 mucositis/stomatitis (clinical exam) and (function/symptom) occurred in nine patients (45%), while 11 patients (55%) experienced at least one of these.
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Mild to intermediate renal dysfunction was also observed, with grade 2 creatinine noted in six patients (30%), all of whom subsequently recovered to grade 1 or better after the end of chemotherapy. No treatment-related death (0%) occurred throughout the study.
Total Treatment Compliance
All patients were able to receive the full dose of radiotherapy (70 Gy), given with a median duration of 50 days (range 48–54). When it occurred, extensions beyond 50 days were the result of holidays and machine maintenance rather than treatment toxicity. One patient (5%) temporarily declined further radiation owing to severe toxicity, but restarted when his general condition improved, and completed the 70 Gy dose.
With regard to chemotherapy, all patients completed at least one course. Eleven patients (55%) were administered chemotherapy on time and without delay. Chemotherapy was stopped in three patients (15%) after two courses, while one patient received two cycles at the full dose and one cycle at a 60% dose. Dose intensity of CDDP was 28.9 mg/m2/week (relative dose intensity 89%) and the rate of complete treatment delivery was 85% (17/20).
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Although preliminary, the results of this prospective study confirm the feasibility of single agent cisplatin and concurrent radiotherapy in the treatment of Japanese patients with squamous cell carcinoma of the head and neck.
Notwithstanding that conclusive evidence had already established single agent cisplatin and concurrent radiotherapy as the standard of care in this condition, the number of Asian enrollees in the Western phase III studies, including Japanese, was relatively low.
The existence of racial differences between Asian and Western populations is established in other site of cancers. In gastric cancer, for example, the established maximum-tolerated dose (MTD) of S-1 differs considerably between Japanese and Western patients, with Western patients showing substantially lower toleration than Japanese patients (13,14).
Moreover, in lung cancer, one clinical trial revealed significant variation in the response to gefitinib, with higher responses seen in Japanese patients than in a predominantly European-derived population (27.5 vs 10.4%, in a multi-institutional phase II trial) (15). Further, epidermal growth factor receptor mutations are more frequent in Japanese than US patients (16). Given the relatively low number of Asian patients in the INT 0126 study, it was therefore considered that broad adoption of this global standard regimen in Japan required a feasibility study in Japanese patients.
The Japan Society for Head and Neck Cancer Registry Committee reports that more than half of SCCHN patients in Japan are aged over 60 years (17), while mean age in the concurrent chemoradiotherapy arm of the INT 0126 study was 56.8 years (5).
In our study, median age was 61.5 years (range 50–74) and 7 (35%) of the 20 patients enrolled were aged over 65 years. This population was thus substantially representative of the overall Japanese head and neck cancer patient population.
In our study, overall CR rate was 50% and the rate of primary-CR was 90%. These results were thus comparable to those in previous Western studies. However, patient number in the present study was too small to evaluate the efficacy of this regimen statistically, because the primary endpoint of the study was neither response nor overall survival.
With regard to toxicity, the rate of grade 3 or greater neutropenia and mucositis in the concurrent chemoradiotherapy arm of the INT 0126 study was 42.1 and 45.2%, respectively. In contrast, rates of grade 3 or greater hematologic toxicity and mucositis with concurrent chemoradiotherapy in the RTOG 91-11 study (7), which identified the superiority of concurrent chemoradiotherapy over radiotherapy alone in laryngeal preservation, were 47 and 43%, respectively. In the present study, seven patients (35%) experienced grade 3 neutropenia while 11 (55%) had grade 3 mucositis/stomatitis. These results are closely similar to those of the above studies in Western patients.
The primary endpoint of our study was treatment compliance. The rate of complete treatment delivery was 85% (17/20), and thus roughly comparable with the 73 and 70% in the chemoradiotherapy arms of the RTOG 91-11 and INT 0126 studies, respectively. Renal dysfunction by CDDP was mild to intermediate, with grade 2 creatinine occurring in six patients (30%), all cases of which subsequently recovered to grade 1 or less after the end of treatment.
We consider these results to preclude the need for treatment modification based on racial differences in single agent cisplatin and concurrent radiotherapy. The reason for the low CDDP dosages reported in previous reports from Japan was not due to racial differences, but rather technical difficulties, and we suspect that an excessively conservative approach to treatment has been adopted. Further, while the toxicity of the treatment regimen has increased with the introduction of chemoradiotherapy, little mention has been made of supportive care during treatment.
In the present study, in contrast, various supportive procedures were adopted during treatment. In particular, most patients (19/20) were provided with PEG before treatment, which facilitated the administration of pain killers and nutrition even when oral intake was not possible. Moreover, given major concerns about renal dysfunction with high-dose cisplatin, pain control was mainly done using morphine in place of NSAIDs. These measures are considered to have improved compliance, and are likely to have attenuated the possibility of serious renal dysfunction.
Qualifying this, however, Nishimura et al. (18) reported that renal function in Japanese decreases quickly with age, indicating the need for care against renal dysfunction in elderly and severely ill patients.
In conclusion, this study provides preliminary confirmation that the single agent cisplatin and concurrent radiotherapy regimen is feasible for the treatment of Japanese patients with squamous cell cancer of the head and neck, and does not require the modification of the treatment plan to account for racial differences. This treatment should be considered for Japanese patients in relatively good condition.
Conflict of interest
None declared.
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References |
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