Japanese Journal of Clinical Oncology 33:297-301 (2003)
© 2003 Foundation for Promotion of Cancer Research
Phase I Study of Weekly Docetaxel Infusion and Concurrent Radiation Therapy for Head and Neck Cancer
1 Department of Radiology and 3 Department of Otolaryngology – Head and Neck Surgery, Kinki University, School of Medicine, Osaka Sayama, Osaka, and 2 Radiation Oncology Research Laboratory, Research Reactor Institute, Kyoto University, Sennan-gun, Osaka, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Objective: This study was designed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of weekly docetaxel in combination with concurrent radiotherapy for treating head and neck cancer.
Methods: Twelve patients with unresectable or postoperative head and neck cancers were enrolled in a dose-escalating phase I study. Eleven of the 12 patients were postoperative patients with intermediate or high pathological risk features. Radiotherapy was delivered as a standard fractionation regimen (2 Gy/day, 5 fractions/week) to a total dose of 60–70 Gy. The starting dose of docetaxel was 10 mg/m2 (once per week) with a subsequent dose escalation of 5 mg/m2 in cohorts of three patients. In 2001 and 2002, 12 patients completing three dose levels were included in the study.
Results: The MTD of docetaxel was 20 mg/m2. With the third dose level (20 mg/m2), DLT was observed in two of three patients. One experienced grade IV mucositis and another suffered from prolonged grade III mucositis-enforced treatment delay for 13 days. Hematological toxicity was minimal. Mucositis was the DLT of concurrent chemoradiotherapy using weekly docetaxel administration for head and neck cancer.
Conclusions: We identified the recommended phase II dose of docetaxel as 15 mg/m2 administered weekly with concurrent radiotherapy for head and neck cancers.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Recently, promising results were reported on concurrent chemoradiotherapy using paclitaxel or docetaxel in the treatment of non-small cell lung cancer, advanced breast cancer, esophageal cancer and brain tumors (1–6). These taxanes bind tightly to the ß-subunit of microtubules and stabilize them (7). Tumor cells treated with these drugs are blocked in the G2/M phase of the cell cycle (8,9). This phase is more radiosensitive than other cycles (10). Because of this mechanism, paclitaxel and docetaxel have been suggested to enhance the cytotoxic effect of irradiation.
According to recent phase I and II studies on chemoradiotherapy using docetaxel for thoracic tumors, the dose-limiting toxicity (DLT) was esophagitis, which was suggested to be enhanced by docetaxel (2,4). For treating head and neck cancer with radiotherapy, on the other hand, the common toxicity is mucositis. Since esophageal and oral mucosa are highly proliferative tissues susceptible to radiation injuries, severe mucositis was expected to occur following docetaxel–chemoradiotherapy. We designed a dose escalation phase I study to determine the maximum tolerated dose (MTD) and DLT of weekly docetaxel in combination with concurrent radiotherapy for treating head and neck cancer.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patient Eligibility
The study was reviewed and approved by the Kinki University School of Medicine’s Institutional Review Board. In this phase I study, patients with stage III, IV advanced head and neck cancers or postoperative patients with one or more risk factors for loco-regional recurrence were included. The risk factors for loco-regional recurrence following the operation are listed as follows: (1) positive margin, (2) surgical close margin <5 mm, (3) presence of extra-capsular extension (ECE) of nodal disease and (4) presence of perineural invasion. In 2001 and 2002, 12 patients with histologically confirmed head and neck cancers were enrolled in this study. Written informed consent was obtained from all patients. The eligibility criteria included 20–70 years of age, Eastern Cooperative Oncology Group (ECOG) performance status 0–2, serum creatinine
2.0 mg/dl, total bilirubin 1.5 mg/dl, GOT 80 IU/l, GPT 70 IU/l, white blood cell count 
4000/mm3, hemoglobin 9.5 g/dl and platelets 100 000. Patients previously treated with radiotherapy or chemotherapy were excluded. Pregnant women or patients with major heart or infectious disease or uncontrolled diabetes mellitus were also excluded.
Patient and Tumor Characteristics
Twelve patients (11 males and one female) with a median age of 51 years were enrolled in this study. One patient with stage IVA gingival cancer was treated with chemoradiation alone. One patient with stage IVA laryngeal cancer was treated with chemoradiation following bilateral neck dissection without laryngectomy. The remaining 10 patients were treated with chemoradiation following resection of the tumors. All had one or more of the risk factors mentioned above for the loco-regional recurrence: three patients (30%) had positive margin, six (60%) had close margin, one (10%) had ECE and one (10%) had perineural invasion.
The primary sites were as follows: oral cavity (seven patients), oropharynx (two patients), larynx (one patient), submandibular gland (one patient) and paranasal sinus (one patient). The histology was squamous cell carcinoma in nine patients, adenoid cystic carcinoma in two and malignant mixed tumor in one. One patient was included who had undergone operation for malignant mixed tumor of submandibular gland and then salvage resection for nodal recurrence. Original diseases except for the recurrent submandibular cancer were staged according to the 1997 International Union Against Cancer TNM classification (UICC 1997); one patient was staged with stage I, two patients with stage II, two patients with stage III and six patients with stage IVA. Table 1 gives details of patient profiles and tumor characteristics.
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Radiotherapy Schedule
Radiation therapy was delivered with 4 MV photons. The initial treatment field encompassed the primary tumor site and the loco-regional lymph nodes up to 46 Gy in 2.0 Gy single daily fractions five times per week. Two patients (gingival cancer and sphenoid sinus cancer) were treated with intensity-modulated radiotherapy (IMRT) using five or seven beams. In the case of the patient with gingival cancer, a total dose of 70 Gy was required for controlling the tumor with chemoradiotherapy alone. IMRT was applied to the patient for delivering a high dose to the target volume with excellent conformity. The reason for using IMRT for the patient with sphenoid cancer was to spare the organs at risk, such as lens, retina and optic nerve. The other 10 patients were treated with a conventional technique of external radiotherapy. Nine patients with oral cavity, oropharyngeal and submandibular gland cancers were treated using lateral opposed fields and one patient with stage IVA laryngeal cancer was treated using lateral opposed fields for the upper neck with matching anteroposterior field for the supraclavicular area. The spinal cord dose was limited to 46 Gy. The dissected lymph node region with extracapsular extension of metastasis, marginally resected or gross tumors, received a total dose of 60–70 Gy (2 Gy/day) with shrinking fields. The planned overall treatment time was 6–7 weeks. Radiotherapy was interrupted if grade 4 leukocytopenia, neutropenia or thrombocytopenia, fever of >38°C, grade 4 mucositis or grade 4 dermatitis occurred.
Docetaxel Administration and Dose Escalation
Patients received an antiemetic intravenously 15 min before chemotherapy. On days 1, 8, 15, 22, 29 and 36, docetaxel was infused 2 h prior to radiotherapy for 90 min. The starting dose of docetaxel was 10 mg/m2 once weekly and was escalated by 5 mg/m2 increments in every three patients. The dose escalation was planned if two or three of the three patients in a cohort did not show any DLT. Six weekly cycles of the drug were delivered during the 6- or 7-week course of concurrent radiotherapy. Chemotherapy was interrupted if grade 3/4 leukocytopenia or neutropenia, platelets <20 000, fever of >38°C, grade 3/4 non-hematological toxicity except for nausea, vomiting, alopecia or fatigue occurred.
Definition of Dose-limiting Toxicity
Acute toxicity was graded using the National Cancer Institute Common Toxicity Criteria (version 2.0). Complete blood cell count, serum urea and liver enzymes were analyzed once per week during the radiotherapy. Acute radiation toxicity was monitored and graded twice weekly by two radiation oncologists during the radiotherapy. The DLT was defined as (1) grade 4 leukocytopenia or neutropenia, platelets <20 000 lasting for more than 3 days; (2) any non-hematologic toxicity of grade 3 or more other than alopecia, nausea, vomiting, fatigue, mucositis, dysphasia or dermatitis; (3) grade 4 nausea, vomiting, fatigue, mucositis, dysphasia or dermatitis; (4) radiation- or chemotherapy-induced toxicities of grade 3/4 resulting in a delay of radiotherapy of >8 days; (5) chemotherapy-induced toxicities requiring two skips of chemotherapy. The dose level in which two-thirds of patients experienced the DLT was defined as the MTD. The dose level just below the MTD was defined as the recommended dose.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Hematological Toxicity
Table 2 shows the hematological toxicities observed by dose level. Hematological toxicities were minimal in all cohorts. Grade 1 hemoglobin toxicity was seen in four of nine patients. Grade 1 leukocytopenia occurred in three of nine patients. No patients experienced thrombocytopenia or neutropenia. Dose-limiting hematological toxicity was not observed in any cohorts.
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Non-hematological Toxicity
Table 3 shows the non-hematological toxicities observed by dose level. The most significant toxicity in the radiation field was mucositis. Of the 12 patients, nine experienced grade 3 mucositis and one patient at the level III dose level (20 mg/m2) suffered from grade 4 mucositis. The characteristics of 10 patients experiencing mucositis of grade 3 or more are summarized in Table 4. The onset of grade 3 mucositis after the start of radiotherapy at level III ranged from 15 to 23 days, which was earlier than that at level I or II (22–37 days). One patient at level I and two patients at level III experienced grade 3 dysphasia due to severe mucositis which needed intravenous fluid transfusion. Grade 1 and 2 dermatitis were observed in six and six patients, respectively. Other non-hematological toxicities included grade 1/2 fatigue (4/12), grade 1 nausea (2/12) and grade 1 GPT elevation (1/12). Eight patients completed the whole protocol without treatment delay or interruption of the chemotherapy. However, owing to grade 3 mucositis with pain, one patient at level I had a 2-day treatment delay and another patient at level I had one skip of chemotherapy and at the level III dosage, one patient experienced DLT with grade 4 mucositis while another patient showed grade 3 mucositis with pain-enforced 13-day delay of radiotherapy, which was considered as the DLT. Two of three patients at level III showed DLT and the dose escalation was stopped. Level III, 20 mg/m2, was determined as the MTD. For safety reasons, thereafter, three patients were added to level II (15 mg/m2). Since six patients at level II experienced no DLT, the second dose level (15 mg/m2) was determined as the recommended dose.
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Response and Follow-up
The median length of follow-up from the start of radiotherapy was 13 months (range, 1–21 months). Both patients treated by definitive chemoradiation therapy showed complete regression (CR). Two patients developed distant metastases including lung and bone metastases.
One patient with oral floor cancer at level II showed a late toxicity of bone exposure at the mandible 2.5 months after radiotherapy. This patient was treated with conservative therapy using antibiotics. Although sequestrum appeared in the area of the bone exposure, at 1.5 months after the therapy with antibiotics, the lesion recovered without developing osteomyelitis. Another patient with laryngeal cancer at level II, who received a 66 Gy dose to the larynx, experienced dyspnea due to laryngeal edema 1 month after radiotherapy. The patient was hospitalized and dyspnea disappeared after corticosteroid therapy.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The MTD and the recommended dose of the weekly docetaxel were determined to be 20 and 15 mg/m2, respectively. Several phase I/II studies of weekly docetaxel concurrent chemoradiotherapy for head and neck cancers have been reported (11–13). In these studies, a weekly dose of 20 or 25 mg/m2 was set as the recommended dose regardless of combination with either induction chemotherapy or co-administration of other chemotherapeutic agents (11,12). Tishler et al. reported clinical results of induction chemotherapy (cisplatin plus 5-fluorouracil) followed by weekly docetaxel concurrent chemoradiotherapy for head and neck cancers (11). In their study, the recommended dose of weekly docetaxel was 25 mg/m2 and the DLT was grade 3/4 mucositis, dermatitis and dehydration requiring treatment break. Koukourakis et al. reported that 12 patients with advanced head and neck cancer were treated with a combination of 66–70 Gy radiotherapy and weekly docetaxel and irinotecan (12). In their phase I/II study, the recommended weekly doses during concurrent radiotherapy were 20 mg/m2 for docetaxel and 40 mg/m2 for irinotecan. The DLT was also grade 3/4 mucositis. Hesse et al. reported a phase I study for weekly docetaxel and radiotherapy for the treatment of head and neck cancers (13). At the first dose level of 15 mg/m2, which included six patients, two patients developed grade 3 neurological toxicities and two patients experienced grade 4 dermatitis and grade 4 pneumonia. Several DLTs were observed at the first dose level, although the MTD was not determined. In the present study, no neurological or pulmonary toxicity was observed.
Although the reason for the difference in the MTD between the present and previous studies is not obvious, the variation in the studies with respect to the definition of the DLT, supportive care for mucositis or the difference of susceptibility to the chemotherapeutic agent among races may have influenced the determination of the DLT. In some studies (11,14), a percutaneous endoscopic gastrostomy was placed in all patients prior to chemoradiotherapy to ensure sufficient nutrition during treatment. To complete chemoradiotherapy using paclitaxel or docetaxel, this type of intensive supportive care may be indispensable.
We applied IMRT to the treatment of two patients. Enrolling the cases treated with IMRT in the phase I study may have caused some problems, because the side effects of IMRT would be different from those of conventional radiotherapy. However, we allowed IMRT in the present study because IMRT should be used in certain clinical situations, as mentioned in the Patients and Methods section. Both patients experienced no DLT. One patient, with gingival cancer, suffered from grade 3 mucositis. The other patient, with sphenoid cancer, did not experience greater than grade 3 mucositis.
The present phase I study included 10 postoperative patients with risk factors for loco-regional recurrence. It is still controversial whether adjuvant chemoradiotherapy for postoperative patients with advanced head and neck cancers is justified. However, local recurrence for patients with advanced head and neck cancers following surgery alone ranges from 20 to 75% and, in addition, the patients with loco-regional recurrence showed poor outcome following salvage radiotherapy (15). Therefore, to prevent loco-regional recurrence following surgery, intensive therapy including adjuvant chemoradiotherapy may be warranted. Kovács et al. reported a study in which patients with oral and oropharyngeal cancer were initially treated with neoadjuvant chemotherapy and radical surgery followed by concurrent chemoradiotherapy using weekly docetaxel (25 mg/m2) (14); 44% of the patients (32/73) completed the whole protocol and 76% of the patients treated with adjuvant docetaxel–chemoradiotherapy (32/42) completed the chemoradiotherapy without reducing chemotherapy. The cumulative survival rate was 74% at four years.
In the present phase I study, weekly docetaxel–chemoradiotherapy did not lead to any complications associated with surgical wounds, such as wound breakdown. Therefore, we are planning to initiate a phase II study of concurrent chemoradiotherapy using weekly docetaxel at 15 mg/m2 for both locally advanced head and neck cancers and postoperative patients with high risk of loco-regional recurrence.
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FOOTNOTES |
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+ For reprints and all correspondence: Minoru Suzuki, Radiation Oncology Research Laboratory, Research Reactor Institute, Kyoto University, Noda, Kumatori-cho, Sennan-gun, Osaka 590-0494, Japan. E-mail: msuzuki{at}rri.kyoto-u.ac.jp
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Received 9 April 2003; accepted 31 May 2003
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