Japanese Journal of Clinical Oncology Advance Access originally published online on November 7, 2005
Japanese Journal of Clinical Oncology 2005 35(11):639-644; doi:10.1093/jjco/hyi175
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© 2005 Foundation for Promotion of Cancer Research
Acute Toxicity and Preliminary Clinical Outcomes of Concurrent Radiation Therapy and Weekly Docetaxel and Daily Cisplatin for Head and Neck Cancer
1 Department of Radiation Oncology and 2 Department of Otolaryngology, Gunma University Graduate School of Medicine, Maebashi, Japan
For reprints and all correspondence: Tetsuo Akimoto, Department of Radiation Oncology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan. E-mail: takimoto{at}showa.gunma-u.ac.jp
Received June 28, 2005; accepted August 25, 2005
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Objective: To examine the feasibility and efficacy of concurrent weekly docetaxel and radiation therapy as a definitive treatment for head and neck cancer (HNC).
Methods: Thirty-two patients with primary HNC, who were treated with concurrent weekly docetaxel and radiation therapy, were analysed. The distribution of the disease stage was as follows: Stage II, 18 patients; Stage III, 3 patients; Stage IVA, 7 patients; Stage IVB, 3 patients; the patient of cervical lymph node metastasis with unknown primary tumor was not assessable. The average total dose of radiotherapy was 67.5 Gy. Docetaxel (10 mg/m2, intravenously, once a week) was given to all patients up to four cycles, and cisplatin (6 mg/m2, intravenously, five times a week) was also administered to all patients for up to 3 weeks from the beginning of the radiation therapy.
Results: Only in two patients did the radiotherapy need to be temporarily interrupted due to the development of acute mucositis. Grade 3 toxicity was observed in six patients. Grade 4 acute mucositis was seen in one patient. The response rate was 100%, and complete response (CR) was observed in 30 patients (94%). At the time of the analysis, the 2 year local control and relapse-free rates in the 30 patients showing CR were 90 and 76%, respectively.
Conclusions: Concurrent weekly docetaxel and radiation therapy did not affect the compliance of the patients for the radiation therapy, indicating that the acute toxicities were within acceptable limits.
Key Words: radiation therapy • chemotherapy • docetaxel • cisplatin • acute toxicity
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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In the selection of the treatment modality for patients with head and neck cancer (HNC), it is important to take into consideration the preservation of organ function, so as to maintain a satisfactory quality-of-life (QOL) of the patients. From this standpoint, radiation therapy is probably superior to surgical resection, although reconstructive surgery has recently been introduced for the treatment of HNC. However, so far, the results of radiation therapy alone for advanced HNC have not been satisfactory (1). A number of strategies have been attempted, including the use of altered fractionation schema (2,3) and intensity-modulated radiation therapy, to improve the local control, and positive results have been reported with several of these approaches. Use of chemotherapy in combination with radiation therapy was one of these approaches that have been reported to be effective (4–6). Regarding the sequence of administration of radiation therapy and chemotherapy, induction chemotherapy (5) and alternating radiotherapy and chemotherapy (6) have been tried, and concurrent chemoradiotherapy has been reported to be a promising approach for improving the clinical outcomes. Among the chemotherapeutic agents, cisplatin and 5-FU have been established as effective agents for HNC, however, taxanes are recently attracting attention as promising antineoplastic drugs. Docetaxel is a representative of taxanes which acts by binding to cellular ß-tubulin, increasing its polymerization and promoting microtubule assembly. Because this drug–tubulin binding inhibits tubulin depolymerization, the cells become arrested in the M-phase of the cell cycle (7). Induction of mitotic arrest by these agents served as the rationale for exploring taxanes as possible radiosensitizing agents (8). In addition to mitotic arrest, docetaxel possibly also exerts cytotoxicity on radioresistant S-phase cells via another cell-cycle mechanism (9). Docetaxel has been reported as an effective anticancer agent against HNC. Response rates of 21–42% have been reported following therapy with docetaxel as a single agent in patients with locally advanced, recurrent and/or metastatic HNC (10,11). Regarding the effects of combined docetaxel and radiation therapy, Airoldi et al. (12) conducted a Phase I and Phase II study on cases unresectable squamous cell carcinoma of the head and neck, and concluded that therapy with carboplatin, docetaxel administered concurrently with conventional radiotherapy is a feasible and effective treatment method for unresectable HNC. However, reports of concurrent chemoradiotherapy using docetaxel-based chemotherapy are still scarce.
Under these circumstances, we conducted a study of concurrent docetaxel-based chemotherapy and radiation therapy for HNC patients whose clinical outcomes were not expected to be satisfactory with radiotherapy alone. The purpose of this study was to analyse the incidence of acute toxicity, including that of mucositis and hematological and non-hematological toxicities, in order to evaluate feasibility of this approach in these patients. In addition, the response rate and preliminary clinical outcomes were also evaluated.
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PATIENTS AND METHODS |
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PATIENTS
Between March 2001 and March 2004, 32 patients with primary HNC with a good performance status [Eastern Cooperative Oncology Group (ECOG) performance status: 0 or 1] who had not undergone any previous treatment were enrolled in this study. All the 32 cases were histologically diagnosed to have squamous cell carcinoma. Of the 32 patients, 28 were male, with an average age of 67 years (45–81 years). The distribution of the primary site of cancer was as follows: nasopharynx, 2 cases; oropharynx, 5 cases; hypopharynx, 3 cases; larynx, 21 cases (including glottic cancer in 19 cases and supraglottic cancer in 2 cases); unknown primary, 1 case. Patients were staged according to the Union International Contre le Cancer criteria (13), and the distribution of primary site versus stage was shown in Table 1. The initial examination before the start of the treatment included medical history, biopsy, clinical ear, nose and throat examination, complete blood count, blood biochemical examination, electrocardiography, chest X-ray, computed tomography (CT) of the chest and abdomen, and CT and magnetic resonance imaging (MRI) of the head and neck. Written informed consent was obtained from all of the patients earlier to the commencement of treatment. The median follow-up duration was 18 months (range 8–45 months).
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RADIATION THERAPY AND CHEMOTHERAPY
The treatment schedule in this study is summarized in Table 2. All the patients received external-beam radiation therapy. The radiotherapy was administered with high-energy photons of 6 MV X-rays from a linear accelerator. Basically, parallel-opposed fields were employed and three-dimensional conformal radiation therapy was administered as a boost where needed. The average total dose of radiation was 67.5 Gy (range 64–72 Gy). Of the 32 patients, 28 were treated using the conventional fractionation schema (2 Gy per fraction, five times a week), and a patient with cervical lymph node cancer with unknown primary were treated using a hyperfractionation (HF) schema (1.2 Gy per fraction, twice a day), and three patients with hypopharyngeal cancer were treated using an accelerated hyperfractionation (AHF) schema (1.6 Gy per fraction, twice a day, split after 38.4 Gy). The reasons why we adopted AHF in those with hypopharyngeal cancer was that hypopharyngeal cancer is one of the cancers that is difficult to achieve satisfactory local control by conventional fractionated radiation therapy, and it has been suggested that altered fractionation schema, especially accelerated fractionation such as AHF (14), is a promising approach to improve local control. In these settings, we have been treating patients with hypopharyngeal cancer by AHF, however, there are still enough rooms for improvement of local control and prognosis of hypopharyngeal cancer. Hence, we adopted AHF in limited to those with hypopharyngeal cancer to test feasibility and efficacy of the combined approach of AHF and docetaxel-based chemotherapy in this study. The field size differed according to the primary site and extent of the disease. The median initial radiation field size was 110 cm2 (range 36–250 cm2).
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Docetaxel (10 mg/m2, intravenously, once a week) was given to all patients up to four cycles, and cisplatin (6 mg/m2, intravenously, five times a week) was administered to all patients who were in reasonably good general condition and had adequate renal function, for up to 3 weeks from the commencement of the radiation therapy. Radiation was administered as soon as possible after the infusion of docetaxel or cisplatin.
Local response was estimated one month after the completion of radiotherapy, by CT or MRI of the head and neck. The patients were then followed up regularly as outpatients.
EVALUATION OF TOXICITY
Toxicity was monitored by daily medical examinations and weekly laboratory examinations. Sequelae were classified according to the National Cancer Institute (NCI) Common Toxicity Criteria (CTC) guidelines, version 2.0 (15).
STATISTICS
The Kaplan–Meier method was use to draw the time-to-event curves (16). The length of follow-up for estimation of the overall and cause-specific survival rates was calculated from start of the treatment. Analysis between two groups was performed by unpaired two-tailed t-test. A P-value of <0.05 was considered as denoting statistical significance.
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RESULTS |
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The radiation therapy could be completed in all the patients, although interruption was necessitated in five patients. Of these, three patients were receiving AHF, and the planned split-time was placed after 38.4 Gy. The duration of the planned split-time during AHF was <14 days (14) and the actual average split-time was 11.8 days (range 10–14 days). Only in two patients, the radiotherapy had to be temporarily interrupted for up to 7 days due to the development of acute mucositis. The duration of the split-time in these two patients was 6 and 7 days, respectively. The averaged overall treatment time was 47.9 days (range 37–61 days). Weekly docetaxel and daily cisplatin administered to all patients, and mean cycle of docetaxel was 3.5 cycles (completion rate, 69%), and the mean treatment duration of daily cisplatin was 12 days. Discontinuation of docetaxel or cisplatin is usually necessitated by impairment of renal function or temporary myelosuppression, however, all the patients in our series maintained normal renal function at the time of the analysis. The acute toxicities, including mucositis and hematological and non-hematological toxicities, are summarized in Table 3. Grade 3 toxicity, estimated based on the NCI-CTC toxicity criteria, was observed in six patients (19%), including mucositis in one patient, hematologic toxicity in five patients. Grade 4 acute mucositis (mucous hemorrhage) was seen in one patient, but no Grade 4 hematological and non-hematological toxicity were observed. There were no treatment-related deaths. As described in ‘Patients and Methods’, the mean radiation field size in all the patients initially irradiated with up to 40 Gy was 100 cm2 (range 36–250 cm2). Since it is easy to speculate that the radiation field size might be closely associated with the severity of mucositis, the correlation between the severity of mucositis and the size of the initial radiation field was evaluated. The mean radiation field sizes in the patients who suffered from Grade 1, Grade 2 and Grades 3–4 mucositis were 60, 125 and 174 cm2, respectively. The average size of the radiation field in the patients with Grade 2 or more severe mucositis was significantly larger than that in the patients with Grade 1 mucositis (P < 0.01) (Fig. 1).
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At the time of the analysis after a median follow-up duration of 18 months (range 8–47 months), eight patients (25%) had died. Of these eight patients, four had died from disease progression or metastasis and the remaining four died of intercurrent diseases, including adult respiratory distress syndrome, lung cancer or hepatic cancer. The 2 year overall survival and cause-specific survival rates of all patients were 68 and 70%, respectively (Fig. 2). The response rate was 100%, and complete response (CR) was observed in 30 patients (94%). Among the patients with CR, recurrence occurred in five patients, and the average time to recurrence from the time of completion of the radiation therapy was 7 months (range 6–19 months). All the two patients who showed only partial response died because of progressive disease. The 2 year local control and relapse-free rates in the 30 patients showing CR were 90 and 76%, respectively (Fig. 3). This included 18 patients who had Stage II laryngeal cancer. Response and prognosis of these patients differ from those with more advanced stage or oropharyngeal and hypopharyngeal cancer. Therefore, we analysed the clinical outcomes of laryngeal cancer and non-laryngeal cancer (hypopharyngeal cancer, oropharyngeal cancer and primary unknown cancer). Two year overall and cause-specific survival rates were 89 and 89% in patients with laryngeal cancer, and 31 and 29% in those with non-laryngeal cancer.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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With regard to the radiotherapeutic management of HNC, it has been reported that chemoradiotherapy yields a superior clinical outcome to radiotherapy alone, if the chemotherapy is given concurrently with the radiation therapy (17,18). Pignon et al. (19) performed a meta-analysis of 63 trials and reported significant improvement of the clinical outcomes with the use of concurrent chemoradiotherapy, but not with that of induction chemotherapy or adjuvant chemotherapy, even though there was marked heterogeneity among the trials with regard to the tumor and patient characteristics, and the therapeutic regimens. The Radiation Therapy Oncology Group conducted a Phase II study of concurrent radiation therapy and high-dose cisplatin (100 mg/m2 given every 3 weeks during the radiation therapy) for advanced HNC (20), and reported a CR rate and 4 year survival rate of 71 and 34%. The ECOG reported the results of a Phase II study of cisplatin and fluorouracil chemotherapy with concurrent radiation therapy in 52 patients with unresectable HNC in 1991 (21); the radiation therapy course in this study was split after 30 Gy to allow for the possibility of midcourse surgery in patients rendered resectable by the induction chemoradiotherapy. CR and 4 year survival rates of 77 and 49%, respectively, were reported from this study.
Recently, docetaxel has drawn attention as a new chemotherapeutic agent for the treatment of HNC. In this study, cisplatin was administered in addition to weekly docetaxel therapy in all patients who showed adequate renal function. The advantages of using docetaxel in combination with cisplatin are that the absence of no cross-resistance between the two drugs has been demonstrated in several tumor cell lines (22,23), and both agents have been shown to enhance radiosensitivity in several cancer cell lines. Regarding the dose schedule of docetaxel and cisplatin in this study the results of following studies were taken into consideration. Hainsworth et al. (24) reported the results of Phase I study for weekly docetaxel, demonstrating that the maximum-tolerated dose (MTD) was 43 mg/m2/week, however, they also suggested that weekly scheduling allowed a maximization of docetaxel dosing, with the MTD being 20 mg/m2/week when used concurrently with radiation therapy (25). In this study, cisplatin was also administered in addition to weekly docetaxel; hence, we adopted 10 mg/m2 as a dose of docetaxel. Concerning the validity for applying this approach to those with Stage II HNC, especially laryngeal cancer, dose of docetaxel and cisplatin considered to be mild compared with other studies. Mudad et al. (26) reported the result of dose finding study for concomitant weekly docetaxel, cisplatin for 6 weeks and radiation therapy in locally advanced non-small cell lung cancer, and demonstrated that the MTD of weekly docetaxel to be 25 mg/m2 when combined with cisplatin 25 mg/m2 and radiation therapy for locally advanced NSCLC (non-small cell lung cancer). Total dose of docetaxel and cisplatin of Mudad et al. was 150 mg/m2, and those of current study were 40 and 90 mg/m2, respectively. Considering from these difference, the dose schedule of this approach considered being mild and optimal for the treatment of Stage II laryngeal cancer. Local control rate of Stage II laryngeal cancer after conventional radiation therapy ranged from 70 to 80%, and there are much rooms for improvement. Altered fractionation is one of promising approaches, but combined radiation therapy with chemotherapy as radiosensitizer considers to be alternative method for improvement of local control.
In the current study, we have reported the preliminary clinical outcomes, including the local response rate and acute toxicities, of concurrent weekly docetaxel and daily cisplatin and radiation therapy for HNC. From the standpoint of the severity of acute toxicity, concurrent weekly docetaxel and daily cisplatin and radiation therapy was demonstrated to be feasible. Grade 3 or more severe mucositis was observed only in two patients (6%), and acute toxicity necessitating treatment interruption occurred in only two patients. This indicates that the acute mucositis occurring with this treatment approach was manageable and did not cause unacceptable treatment delay. However, the average size of the initial radiation field was significantly larger in the patients with Grade 2 or more severe acute mucositis than in those with Grade 1 acute mucositis. Hence, a higher incidence of severe mucositis may have occurred if a larger number of patients with oropharyngeal or hypopharyngeal cancer had been included in the study. In addition, administration of docetaxel-based chemotherapy did not cause acute mucositis severe enough to cause interruption of the radiation therapy in the four patients who received HF or AHF. As described before, the split-time duration in the three patients who were treated with AHF was within the intended split-time. The results of clinical trials combining radiation therapy with an altered fractionation schema and chemotherapy showed that there may be some additional benefit from the addition of chemotherapy, however, the therapeutic window was narrow (27). Two trials revealed that split-course altered fractionation schedules (HF and AHF) in combination with cisplatin and fluorouracil yielded better loco-regional control than the use of an altered fractionation schema alone (28,29); however, the acute toxicities of chemotherapy with AHF without split-course were unacceptable (30). There have been a few reports describing acute toxicity or feasibility of docetaxel-based chemotherapy with concurrent HF or AHF, but it is possible that a planned break during AHF increases compliance of the patients for concurrent docetaxel-based chemotherapy and radiotherapy using an altered fractionation schema.
In regard to hematological toxicity, Grade 3 or more severe hematological toxicity was observed in five patients (16%). In regard to non-hematological toxicity, temporary impairment of renal function, as evaluated by the creatinine clearance, necessitated discontinuation of chemotherapy, especially of cisplatin, in several patients, although the planned number of chemotherapy cycles could be completed in two-thirds of all the patients. Kodaira et al. (31) reported, based on the results of a Phase I trial of weekly docetaxel and concurrent radiotherapy for HNC in elderly patients or patients with complications, that the recommended dose of docetaxel is 12 mg/m2, and that the most common dose-limiting toxicity was stomatitis within the radiation field and not hematological toxicity. Fujii et al. (32) also reported, based on the results of Phase I/II trial of weekly docetaxel and concomitant radiotherapy for squamous cell carcinoma of the head and neck, that the Grades 3 and 4 adverse events encountered consisted of lymphopenia, stomatitis and anorexia, although all the toxicities were manageable.
The response and CR rates in this study were 100 and 94%, respectively, and the 2 year overall survival and 2 year cause-specific survival rates were 68 and 70%, respectively. Needless to say, the median follow-up duration of 18 months was not sufficient to allow a reasonable evaluation of the long-term outcomes, however, the response rate and short-term outcome seemed to be comparable to those of cisplatin-based concurrent chemotherapy and radiation therapy.
In conclusion, the results of this study demonstrated that weekly docetaxel and daily cisplatin administered concurrently with radiation therapy did not affect compliance of the patients for the radiation therapy, indicating that the acute toxicities were within acceptable limits of severity. In addition, the response rate and the short-term clinical outcome were also satisfactory. However, longer follow-up is needed to evaluate the late complications and long-term clinical outcomes, including the survival rate, of this approach.
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Acknowledgments |
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This study was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan.
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References |
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