© 2007 Foundation for Promotion of Cancer Research
A phase I–II Study of Bi-weekly Docetaxel Combined with Radiation Therapy for Patients with Cancer of the Larynx/hypopharynx
1 Otorhinolaryngology, Head and Neck Surgery, Tokyo Medical University Hachioji Medical Center, Hachioji, Tokyo
2 Otorhinolaryngology, Tokyo Medical University
3 Radiology, Tokyo Medical University, Tokyo, Japan
For reprints and all correspondence: Tomoyuki Yoshida, Otorhinolaryngology, Head and Neck Surgery, Tokyo Medical University Hachioji Medical Center, 1163 Tatemachi, Hachioji city, Tokyo 193-0998, Japan. Hachioji, Tokyo. E-mail: jibitom{at}tokyo-med.ac.jp
Received January 13, 2007; accepted May 21, 2007
 |
Abstract |
|---|
 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
Background: We performed a phase I/IIstudy of bi-weekly docetaxel in combination with concurrent radiotherapy to enhance the cytotoxic effect and radiosensitization and improve the rate of laryngeal preservation.
Methods: Patients with T2N0-1M0, T3N0M0 hypopharyngeal cancer or T2N0-1M0, T3N0-1M0 larynx cancer were enrolled. Docetaxel was administered bi-weekly (days 1, 15, 29) from the first day of radiotherapy, while 2 Gy/day of radiation was given on 5 days weekly from day 1, reaching a total of 60 Gy in 30 fractions.
Results: 12 patients took part in the phase I study. The maximum tolerated dose (MTD) was 40 mg/m2 and the recommended dose (RD) was determined as 35 mg/m2. The phase II study was conducted with docetaxel at 35 mg/m2 for 25 patients. Treatment was completed without interruption in 24 patients, with a protocol implementation rate of 96%. The complete response rate was 100% in laryngeal cancer, and 80% in hypopharyngeal cancer, and total (including partial response) overall response rate was 100%. The laryngeal preservation rate was 96%, and the overall local control rate was 92%. All patients have been alive for at least 3 years without any recurrence.
Conclusions: The chemoradiation therapy using bi-weekly docetaxel is an extremely effective treatment for cancer of the larynx/hypopharynx, provided that it is used for the specified stage of cancer.
Key Words: larynx cancer • hypopharyngeal cancer • chemoradiation • docetaxel • laryngeal preservation
|
INTRODUCTION |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
Concurrent chemoradiotherapy for head and neck cancer confers a survival benefit (1), and therefor the regimen of cisplatin (CDDP) and 5-fluorouracil (5-FU) with radiation is widely used. However, some patients with renal complications can tolerate only limited treatment. Docetaxel (DOC) is an antineoplastic taxoid obtained by partial chemical modification of a splenocytotoxic precursor (10-docetyl baccatin III) extracted from the needles of the European yew tree. It stabilizes microtubules and elicits hyperplasia of microtubular bundles by promoting polymerization and also by inhibiting depolymerization of the microtubular proteins, thereby blocking cell division in the M phase (2). Since these cells are synchronized in the G2/M phase that is most sensitive to radiation, DOC has a strong radiosensitizing potential (3,4). In a phase I study of weekly DOC combined with radiation in Japan, the dose-limiting factor was mucositis, and the recommended dose was 10 mg/m2(5). However, the dose intensity of weekly administration (10 mg/mg/m2, i.e. 40 mg/m2/month) seems insufficient to enhance the cytotoxic effect, and is just enough for a radiosensitization effect only. On the other hand, bi-weekly DOC administration enabled an increase in the dose. Furthermore bi-weekly DOC was found to be more convenient and tolerable than weekly DOC for breast cancer (6).
To improve the rate of laryngeal preservation, we investigated whether a bi-weekly bolus administration would produce enhanced cytotoxic effects, in addition to radiosensitization, and sought to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and the recommended dose (RD) in combined DOC and radiation therapy. Using the RD and the same protocol, we then conducted the phase II study.
|
PATIENTS AND METHODS |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
Patient Eligibility
The study population consisted of patients with T2N0-1M0, T3N0M0 hypopharyngeal cancer or T2N0-1M0, T3N0-1M0 laryngeal cancer, who met the protocol conditions. Inclusion criteria specified that patients should be aged 20–75 years and have a definitive pathological diagnosis of cancer of the head and neck, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, no previous radiotherapy, lesion(s) evaluated by imaging, provided informed consent and a life expectancy of at least 3 months. If the patients had previously received treatment, there had to be a minimum period of 1 month since the last treatment. Adequate hematological function (white blood cell count
4000/mm3, neutrophil count 2000/mm3, platelet count 100000/mm3 and hemoglobin level 9.5 g/dl). Adequate hepatic function (aspartate aminotransferase and alanine aminotransferase 
1.5 times the normal upper limit, total bilirubin 1.5 mg/dl and alkaline phosphatase 2.5 times the normal upper limit), and adequate renal function (creatinine serum <1.2 mg/dl). Excluded patients were those with a history of hypersensitivity to the test drug or preparations containing Polysorbate 80, serious concurrent disease or apparent infection with fever, pregnant or lactating women or women who may possibly be pregnant, and other patients considered by the attending physician to be unsuitable for participation in the study. Criteria for discontinuation of therapy were defined as apparent exacerbation of the disease or a serious complication, or a serious adverse event making continuation of treatment difficult, interruption of radiation for two consecutive weeks, refusal of the patient to continue therapy, or any other condition judged by the attending physician to contraindicate continued therapy. If the disease process was evaluated as no change or progressive disease (NC/PD) at the end of 3 weeks or more after the initiation of treatment, the present therapy could be discontinued and replaced by another therapy. This study was conducted in accordance with the Guidelines for the Clinical Evaluation of Antineoplastic Drugs based on the ethical principles of the Declaration of Helsinki, and in compliance with Standards for Good Clinical Practice (GCP), after approval by the institutional review board of Tokyo Medical University.
Treatment Schedule
The approved dose and schedule for DOC in head and neck cancer in Japan is 60–70 mg/m2 every 3–4 weeks. In general, 60 mg/m2 DOC is given every 4 weeks, thus the dose intensity is calculated as 60 mg/m2/4 weeks. The bi-weekly dose intensity is calculated as 30 mg/m2/2 weeks, which was considered enough to enhance the cytotoxic effect. In lung cancer, bi-weekly DOC plus carboplatin (CBDCA) with concurrent radiation therapy in patients with unresectable stage, non-small cell lung cancer has been reported (7). The dose of DOC was administered 30 mg/m2 and CBDCA was area under the curve (AUC) 3 on Day 1, 15, 29, 43 and 60 Gy radiation was concurrently delivered. This report showed a high response rate (90%) and the grade 3–4 toxicities were neutropenia in 6%, esophagitis in 3% and pneumonia in 9%; thus the toxicity was tolerable. Considering this report, we set the starting dose level (level 1) of DOC at 30 mg/m2, level 2 at 35 mg/m2 and level 3 at 40 mg/m2; level 0 (25 mg/m2) was set for when severe toxicity occurred. DOC was administered on days 1, 15 and 29.
We gave radiotherapy to the primary and neck regions once a day at 4 MeV photons, using the cone-down technique, and limiting the radiation field to the primary tumor site and/or involved lymph node with a sufficient margin. The radiation fields in the phase I and the phase II studies are shown in Tables 1 and 3. We gave 30 fractions of 2 Gy at each rate totaling 60 Gy of five fractions per week. Once 40 Gy had been delivered, the spinal cord was excluded, and the clinical target volume was reduced to only the primary region and involved neck nodes. Figure 1 shows the treatment schedule.
|
|
|
Dose Escalation and Definition of Dose-limiting Toxicity
The dose was at level 1 initially, and, if level 1 was not achieved, it was reduced to level 0 and the patient was followed carefully. If level 1 was achieved, the dose was increased to level 2. Three patients were assigned to each dose level, and if one or two patients showed DLT, three patients were added at the same dose level, to allow six patients to make up a cohort. If DLT was not detected in three or more of six patients, a dose higher by one level was administered to three new patients. If DLT was recognized in three of three patients or three or more of six patients, that dose level was regarded as the MTD, and the dose was not increased thereafter. The dose was also not increased in the remaining same-level patients. On the basis of the above principles, the Efficacy Safety Evaluation Committee judged whether or not to step up the dose level. DLT was defined as grade 4 leukopenia or neutropenia continuing for more than 5 days even with G-CSF, grade 4 neutropenia with fever (>38°C) even with G-CSF rescue, platelet count less than 30 000/mm3 and grade 3 or 4 non-hematological toxicity, excluding nausea, vomiting, anorexia, fatigue and stomatitis, based on the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2.0.
Treatment Assessment and Statistical Methods
Tumors were assessed by computed tomography (CT) scan or magnetic resonance imaging (MRI) scan every 2 weeks after the initial day of treatment. Patients were assessed within 4 weeks after completing three cycles of DOC plus 60 Gy of radiation. Safety was assessed every week. All patients were assessed for recurrence by endoscopy every 4 weeks, and CT scan or MRI scan every 3 months after the treatment. The design of this study was based on a binominal distribution with no planned interim analysis. In the phase II part of this study, the primary end point was the overall response rate (ORR). Assuming a null hypothesis of a 70% ORR, with a one-sided 
error of 0.05 and ß error of 0.2, it was necessary to enroll a minimum of 24 patients at the recommended dose (RD), including those treated at the RD during the phase I part of the study. The secondary endpoints were the protocol implementation rate, rate of preservation of the larynx and survival outcome.
|
RESULTS |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
Phase I Study
Table 1 shows the characteristics of the patients. In three patients at level 1 adverse reactions of grade 3 or more were not observed, while grade 2 mucositis was seen in two patients and radiation dermatitis in all patients. At level 2, 1 patient with hypopharyngeal cancer developed an eating disorder, which required intravenous hyperalimentation (IVH) management, so that this was evaluated as grade 4 toxicity. For this reason, three patients were added. In one additional patient with hypopharyngeal cancer, grade 4 mucositis appeared. Grade 4 toxicity occurred in two of six patients, but another four patients had only grade 2 adverse event and did not show DLT. In three patients at level 3, one patient with laryngeal cancer had only grade 2 adverse events, but one patient with hypopharyngeal cancer developed grade 4 mucositis, and another patient with laryngeal cancer developed serious blood toxicity when the second dose of DOC was given and the radiation dose reached 40 Gy, and disseminated intravascular coagulation (DIC) turned into septicemia, requiring dialysis in the ICU. This patient was saved and in the 3 years since then, the primary lesion and cervical metastasis have been controlled and the patient's activities of daily living have not been compromised. Toxicities in the above two patients were judged to be DLT, and level 3 was set as the MTD. From these findings, RD was placed at level 2, which was 35 mg/m2. Table 2 shows the occurrence of toxicities at each level. Apart from the DIC in the patient with laryngeal cancer, grade 4 mucositis occurred in a patient with hypopharyngeal cancer with an irradiation field of 17 x 13 cm, and it seemed highly likely that the level 3 dose could be tolerated in laryngeal cancers that require only 6 x 6–8 cm narrow fields of irradiation. The present series of patients has been followed up for at least 3 years. The larynx was preserved in all patients and no recurrence was observed during follow-up.
|
Phase II Study
In 10 patients with laryngeal cancer and 15 patients with hypopharyngeal cancer, the DOC dosage was fixed at 35 mg/m2 and the same protocol was used. About half of the 25 patients were treated on an outpatient basis. Table 3 shows the characteristics of patients and outcome of patients of the phase II study. In three hypopharyngeal cancer cases, the local lesion could not be controlled and pharyngolaryngectomy with resection of the cervical esophagus had to be performed in one patient, and neck dissection in two patients. The protocol implementation rate was 100% in laryngeal cancer and 93.3% in hypopharyngeal cancer because surgery was performed on one patient when 30 Gy of radiation had been delivered. Overall, treatment was completed without interruption in 24 patients, with a protocol implementation rate of 96%, which proved that this protocol was tolerable. In laryngeal cancer, all patients (100%) achieved complete response (CR). Adequate effect can these be anticipated even in patients with T2-3N1 cancer. In hypopharyngeal cancer, the primary lesion was surgically treated in one patient, and neck dissection alone was additionally performed in two patients. Twelve patients achieved CR, and the CR rate was 80%. Three patients achieved partial response (PR). Since CR was obtained even in patients with T3 cancer and the larynx was lost only in one of 10 patients, the present treatment was considered sufficiently effective. The ORR was 100%. The overall local control rate was 92% because surgery was performed, but operation consisted only of neck dissection in two patients. The rate of laryngeal preservation was 100% in the laryngeal cancer group and 93.3% in the hypopharyngeal cancer group, 96% in total. All patients treated by the present method have been alive for at least 3 years without recurrence. Table 4 shows the occurrence of toxicity in the phase II study. Grade 3 or 4 adverse events consisted of mucositis in 36%, radiodermatitis in 20%, and loss of appetite in 16% of the patients. Their toxicities were manageable. It has been demonstrated that bi-weekly docetaxel combined with radiation therapy for cancer of the larynx/hypopharynx is an extremely effective treatment, provided that it is indicated for the specific stage of cancer.
|
|
DISCUSSION |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
The incidence of head and neck cancer is gradually increasing with the increased aging of the society, and a 1995 report estimated the annual incidence to be approximately 40 000 in the Unites States (8). However, prognosis has not dramatically improved in advanced squamous cell carcinoma of the head and neck, and the prospect of functional preservation is still poor, even with multidisciplinary treatment. Since squamous cell carcinoma, which accounts for the majority of head and neck cancers, is sensitive to radiation to a certain degree, there is hope for a new therapy involving powerful chemotherapy incorporated with curative treatment regimens. Various chemoradiation therapies have been tried using 5-FU, bleomycin, mitomycin, methotrexate among others. Since 1977, when the usefulness of cisplatin for head and neck cancers was reported (9), the efficacy of combination chemotherapy with multiple drugs including cisplatin has been reported, and multi-agent chemotherapy using cisplatin as the chief drug is utilized at present (10,11).
Meanwhile, the reviews of chemoradiation therapy for advanced head and neck cancers have showed that, in many clinical trials comparing chemoradiation therapy using cisplatin (or carboplatin) ± 5-FU with radiation therapy alone, the combination therapy group compared favorably with the radiation-only group with respect to local control rate and survival rate (12,13). With the progress of reconstructive surgery, survival rates are improving thanks to extended surgery. However, larygectomy or pharygolarygectomy means loss of phonation and swallowing functions, and a great deterioration in quality of life. Recently, chemoradiation therapy has been used to preserve the organ in consideration of the quality of life while achieving permanent cure by radiation therapy as far as possible, and large-scale clinical studies are being conducted such as the Veterans Administration Lung Cancer Study Group and Groupe d'Etude des Tumeurs de la Tete et du Cou for improvement of the prognosis of advanced cancer or preservation of organs (14–16).
More recently, studies have been conducted on combination of radiation with taxanes, which synchronize cells in the M phase, which is most sensitive to radiation (17,18). In Japan, a late phase II clinical study of DOC in advanced/recurrent head and neck cancers was conducted in 29 institutions between April 1995 and August 1997. In 63 patients eligible for evaluation (therapy completed in 59 patients), the response of tumor was CR in one patient and PR in 13 patients, thus the response rate was 22.2%. Major adverse effects with grade 3 or higher were leukopenia in 59.7% and neutropenia in 79.0% (19). In addition, a phase I/II study of weekly DOC and radiation for head and neck cancer in Japanese was conducted; the RD of weekly DOC was decided at 10 mg/m2 and the ORR was 96.9%. However, the CR rate of primary site was 59.4% (5). We considered the dosage insufficient for enhancing cytotoxic effect, and sufficient only for radiosensitization effect.
To improve the rate of laryngeal preservation, we evaluated, using the occurrence of adverse events as an index, the tolerability of a combination therapy with bi-weekly DOC administration and radiation, which can be expected to produce a cytotoxic effect, and determined MTD as well as the RD for T2N0-1M0, T3N0M0 hypopharyngeal cancer or T2N0-1M0, T3N0-1M0 laryngeal cancer. T3N1M0 hypopharyngeal cancer was omitted, since such cases undergo surgery. In the phase I study, the DLT was mucositis and neutropenia at level 3, and the MTD was 40 mg/m2. Particularly in hypopharyngeal cancer, grade 3 or higher mucositis and swallowing disorder occurred because of the greater size of the irradiation field, but the recommended dose was placed at 35 mg/m2. The phase II study was conducted with a DOC dosage of 35 mg/m2 using the same schedule. In the phase II study, 10 patients with laryngeal cancer and 15 patients with hypopharygeal cancer were enrolled. The protocol implementation rate was 96%, the CR rate was 100% in laryngeal cancer and 80% in hypopharyngeal cancer, and total (including PR) ORR was 100%. The larynx preservation rate was 96%, and the overall local control rate was 92%. From these results, the present treatment appears to be indicated in patients with advanced N stage if combined with planned neck dissection, etc. All patients have been alive for at least 3 years without any recurrence. Since this protocol was applicable on an outpatient basis, this seemed to have greater benefit to patients than cisplatin-based chemoradiotherapy. This protocol is extremely useful provided that it is indicated for the specific stage of cancer.
Conflict of interest statement
None declared.
|
References |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
1 Pignon JP, Bourhis J, Domenge C, Designe L. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet (2000) 355:949–55.[Web of Science][Medline]
2 Ringel I, Horwitz SB. Studies with RP56976 (taxotere): a semisynthtic analogue of taxol. J Natl Cancer Inst (1991) 83:288–91.
3 Choy H, Rodriguez F, Koester S, Hilsenbeck S, Von Hoff DD. Synergistic effects of Taxol/Taxotere on radiation sensitivity on human tumor cell. Int J Radiat Oncol Biol Phys (1992) 24(Suppl 1):274–75. (abstr. 1059).
4 Hennequin C, Giocanti N, Favaudon V. Interaction of ionizing radiation with paclitaxel (Taxol) and docetaxel (Taxotere) in HeLa and SQ20B cells. Cancer Res (1996) 56:1842–50.
5 Fujii M, Tsukuda M, Satake B, Kubota A, Kida A, Kohno N, et al. Japan Cooperative Head and Neck Oncology Group (JCHNOG). Phase I/II trial of weekly docetaxel and concomitant radiotherapy for squamous cell carcinoma of the head and neck. Int J Clin Oncol (2004) 9:107–12.[CrossRef][Medline]
6 Shin E, Ishitobi M, Hiraoia M, Kazumasa F, Hideyuki M, Nishisho I, et al. Phase I study of docetaxel administered by bi-weekly infusion to patients with metastatic breast cancer. Anticancer Res (2000) 20(6C):4721–6.[Web of Science][Medline]
7 Sakai H, Yoneda S, Kobayashi K, Komagata H, Kosaihira S, Kazumoto T, et al. Phase II study of bi-weekly docetaxel and carboplatin with concurrent thoracic radiation therapy followed by consolidation chemotherapy with docetaxel plus carboplatin for stage III unresectable non-small cell lung cancer. Lung Cancer (2004) 43:195–201.[CrossRef][Web of Science][Medline]
8 Wingo PA, Tong T, Bolden S. Cancer statistics. CA Cancer J Clin (1995) 45:8–30.
9 Wittes RE, Cvitkovic E, Shah J, Gerold FP, Strong EW. cis-Dichlorodiammineplatinum(II) in the treatment of epidermoid carcinoma of the head and neck. Cancer Treat Rep (1977) 61:359–66.[Web of Science][Medline]
10 Kish J, Drelichman A, Jacobs J, Hoschner J, Kinzie J, Loh J, et al. Clinical trial of cisplatin and 5-FU infusion as initial treatment for advanced squamous cell carcinoma of the head and neck. Cancer Treat Rep (1982) 66:471–4.[Web of Science][Medline]
11 Weichselbaum RR, Clark JR, Miller D, Posner MR, Ervin TJ. Combined modality treatment of head and neck cancer with cisplatin, bleomycin, methotrexate–leucovorin chemotherapy. Cancer (1985) 55(Suppl 9):2149–55.[CrossRef][Web of Science][Medline]
12 Calais G, Alfonsi M, Bardet E, Sire C, Germain T, Bergerot P, et al. Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. J Natl Cancer Inst (1999) 91:2081–6.
13 Adelstein DJ, Lavertu P, Saxton JP, Secic M, Wood BG, Wanamaker JR, et al. Mature results of a phase III randomized trial comparing concurrent chemoradiotherapy with radiation therapy alone in patients with stage III and IV squamous cell carcinoma of the head and neck. Cancer (2000) 88:876–83.[CrossRef][Web of Science][Medline]
14 The Department of Veterans Affairs Laryngeal Cancer Study Group. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. New Engl J Med (1991) 324:1685–90.[Abstract]
15 Lefebvre JL, Chevalier D, Luboinski B, Kirkpatrick A, Collette L, Sahmoud T. Larynx preservation in pyriform sinus cancer: preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. EORTC Head and Neck Cancer Cooperative Group. J Natl Cancer Inst (1996) 88:890–9.
16 Richard JM, Sancho-Garnier H, Pessey JJ, Luboinski B, Lefebvre JL, Dehesdin D, et al. Randomized trial of induction chemotherapy in larynx carcinoma. Oral Oncol (1998) 34:224–8.[CrossRef][Web of Science][Medline]
17 Nabell L, Spencer S. Docetaxel with concurrent radiotherapy in head and neck cancer. Semin Oncol (2003) 30(Suppl 18):89–93.[CrossRef][Web of Science][Medline]
18 Sunwoo JB, Herscher LL, Kroog GS, Thomas GR, Ondrey FG, Duffey DC, et al. Concurrent paclitaxel and radiation in the treatment of locally advanced head and neck cancer. J Clin Oncol (2001) 19:800–11.
19 Inuyama Y, Kataura A, Togawa K, Saijo S, Satake B, Takeoda S, et al. Late phase II clinical study of RP56976 (docetaxel) in patients with advanced/recurrent head and neck cancer. Jpn J Cancer Chemother (1999) 26:107–16.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||