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Journal of Clinical Oncology, Vol 24, No 25 (September 1), 2006: pp. 4163-4169 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.05.7851 Phase I/II Study of Docetaxel, Cisplatin, and Concomitant Boost Radiation for Locally Advanced Squamous Cell Cancer of the Head and Neck
From the Departments of Thoracic/Head and Neck Medical Oncology, Radiation Oncology, and Biostatistics and Applied Mathematics, The University of Texas M.D. Anderson Cancer Center, Houston, TX Address reprint requests to Bonnie S. Glisson, MD, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; email: bglisson{at}mdanderson.org
Purpose To investigate the feasibility of combining concomitant boost accelerated radiation with docetaxel and cisplatin and assess the regimen's toxicity, locoregional control rate, and survival in patients with locally advanced head and neck cancer (HNSCC). Patients and Methods Patients with stage III-IV HNSCC were eligible. Phase I included two schedules of docetaxel and cisplatin: arm 1, once per week during weeks 1 to 4; arm 2, every 21 days for weeks 1 and 4. Radiation consisted of 72 Gy in 42 fractions over 6 weeks (concomitant boost). Results Twenty patients were enrolled in phase I. The arm 1 maximum-tolerated dose (MTD) was defined at docetaxel 15 mg/m2 and cisplatin 20 mg/m2 based on prolonged mucositis in 29% of patients. The initial dose level in arm 2 was above the MTD. In total, 52 patients were treated using the arm 1 regimen in phase II. Acute toxicity included grade 3 mucositis and dermatitis in 81% and 44% of patients. The 2-year locoregional control rate was 71%. The 2-year progression-free and overall survival rates were 61% and 65%. Median survival was 37.8 months. Late effects included feeding tube dependence in 17% of patients alive and free of disease. Conclusion Locoregional control, survival, and acute toxicity with this regimen were comparable with other trials utilizing taxanes and/or platins and concomitant conventional or altered fractionation radiation. Our data suggest that chemotherapy added to concomitant boost fractionation may increase rates of long-term feeding tube dependence. Phase III trials are needed to assess the contribution of concomitant boost fractionation to chemoradiotherapy.
Both altered fractionation radiotherapy and adding chemotherapy to radiation are effective in improving locoregional control of advanced head and neck squamous cell carcinoma (HNSCC) compared with standard fractionation radiation. One theory for locoregional failure is the accelerated repopulation of radioresistant tumor clonogens after initial cytoreduction.1 Concomitant boost radiotherapy, a type of altered fractionation, was designed to overcome this problem by delivery of a second daily fraction to gross disease during the last 10 to 12 days of treatment.2 A randomized trial performed by the Radiation Therapy Oncology Group (RTOG) 90-03, showed that accelerated fractionation with concomitant boost improved locoregional control by approximately 10% (54% at 2 years).3 However, no survival benefit was seen. Several randomized trials have shown that adding concurrent chemotherapy to radiation also increases locoregional control by 15% to 20% in patients with locally advanced disease. A recently updated meta-analysis shows an absolute 8% improvement in 5-year survival with this approach.4-7 Although several recent studies have investigated a variety of single agents, combinations, and schedules, the optimum regimen is yet to be defined. Docetaxel, one of the most active agents against recurrent HNSCC, yields a response rate approximately 35% (reviewed by Glisson8). In preclinical studies, docetaxel leads to tumor cell reoxygenation and mitotic arrest with potent radiosensitization.9 This property has been evaluated in phase I trials10,11 using alternative docetaxel schedules combined with radiation. With thoracic radiation, a weekly docetaxel schedule allowed the most intense exposure with a maximum-tolerated dose (MTD) of 20 mg/m2.10 In patients with HNSCC, the MTD was docetaxel 25 mg/m2 weekly with conventional radiotherapy.11 In these trials, in-field mucosal toxicity was dose limiting. Building on the experience described herein, we combined docetaxel and cisplatin with concomitant boost radiotherapy in patients with locally advanced HNSCC. As there are theoretical advantages for using low-dose weekly and less frequent higher-dose chemotherapy, we studied two different schedules in phase I-II trial to define an MTD and assess toxicity and efficacy.
Patients were required to have untreated HNSCC (oral cavity, oropharynx, hypopharynx, or larynx); T3-4 and/or N2-3 M0 disease; Karnofsky performance status 70% or lower; life expectancy 6 months or longer, adequate bone marrow and hepatic function, normal coagulation parameters, normal serum calcium, and creatinine clearance higher than 50 mL/min. Patients were not eligible if they had: prior cancer history more recent than 5 years (except nonmelanoma skin cancer), synchronous primary cancer, pre-existing grades 2 to 4 peripheral neuropathy (National Cancer Institute Common Toxicity Criteria, version 2.0), or hypersensitivity to polysorbate 80 or docetaxel. The primary tumor and known/suspected lymph node disease were treated with lateral opposed fields or several beam-directed fields with a 2 cm to 3 cm margin (54 Gy as daily 1.8 Gy/fraction for 5 days/wk for 6 weeks). Boost fields had a 1 cm to 1.5 cm margin around gross disease (second daily 1.5 Gy/fraction started during week 4 for a total dose of 72 Gy). A single anterior field encompassed the neck and supraclavicular fossa below the primary tumor fields. Conformal radiation techniques, including intensity modulated radiation, were allowed if these fields were not sufficient. The phase I portion of our study administered concomitant boost radiation with 2 different schedules of docetaxel and cisplatin. Arm 1 included weekly chemotherapy (weeks 1 through 4) and arm 2 gave chemotherapy twice per week on weeks 1 and 4 of radiotherapy. The initial dose level for arm 1 was docetaxel 15 mg/m2 and cisplatin 20 mg/m2 and the dose for arm 2 was docetaxel 40 mg/m2 and cisplatin 60 mg/m2. The MTD was based on systemic toxicity and in-field effects (skin and mucosa). Patients were to accrue in cohorts of three to six patients beginning at dose level 0. As prolonged severe mucositis (grades 3-4 6 weeks or more from the completion of therapy) was an anticipated dose-limiting toxicity (DLT), each cohort was to be followed to that time point before the next cohort was enrolled. A maximum of three patients were to accrue to arm 1 and while they were treated and observed, patients were accrued to arm 2 and vice versa. Toxicity was graded using the Cooperative Group Common Toxicity Criteria version 2.0. A dose level was declared the MTD if DLT (systemic and mucosal effects) occurred in two of six patients and above the MTD if it occurred in two of three patients or three of six patients, with the exception of skin toxicity as described below. DLT in mucosa was defined as grade 3 to 4 mucositis 6 weeks or longer from completion of therapy. This occurrence in two of three patients or three of six patients in a cohort was defined as above MTD. Grade 3 skin toxicity in three of three patients or grade 4 in one of three patients prevented dose escalation. Grade 4 skin toxicity in two of six patients was defined as above the MTD. DLT for systemic effects was: febrile neutropenia, grade 4 neutropenia longer than 7 days duration, grade 4 thrombocytopenia, or irreversible grade 2 or grades 3 to 4 nonhematologic toxicity. DLT related to systemic effects in two of three patients prevented dose escalation. After determination of MTD, patients were enrolled in the phase II portion of the study. The primary objective of the phase II trial was to estimate the 2-year locoregional control rate. The study was designed to have 80% power to detect an increase in 2-year locoregional control of 20%, from the 54% rate obtained with concomitant boost radiation in RTOG 90-03 to 74% (target accrual 38 patients).3 Secondary end points were response rate, progression-free survival (PFS) and overall survival (OS). All failure end points were determined from the date of first chemotherapy. PFS was measured from the date of first chemotherapy to progression of tumor, or death from tumor if progression did not occur, or to survival date. The response rate was determined by the WHO Standardized Response Criteria12 and was based only on the clinical and radiographic assessment of tumor clearance after chemoradiotherapy. If surgical lymph node dissection was performed after chemoradiotherapy due to radiographic suspicion of residual disease, the case was not reported as a complete response, even if no pathologic evidence of tumor was found in resected nodes. Post-treatment neck dissections for N2-3 disease were not mandated. Additional objectives were to assess acute and late toxicities, including swallowing function and feeding tube dependence. The University of Texas M.D. Anderson Cancer Center (Houston, TX) institutional review board approved this study. Written informed consent was obtained from each patient before treatment was initiated. Patients received weekly evaluations while receiving concomitant boost radiotherapy. After completing therapy, patients were monitored every 4 weeks until acute reactions were resolved, then every 3 to 4 months for 3 years, then every 6 months through year 5, with history and physical examination. Chest x-rays and thyroid function tests were performed annually. Fiberoptic endoscopy and axial imaging were performed as clinically indicated. Time-to-event analyses were estimated by the Kaplan-Meier method and 95% confidence intervals were calculated.13
Phase I. Twenty patients were enrolled in phase I from September 1999 to September 2000. Patient characteristics are listed in Table 1. Of the 20 patients in the phase I, 14 patients were accrued to arm 1 and six patients were accrued to arm 2. All patients began therapy at dose level 0 (see Patients and Methods section for doses). In arm 2, five patients were assessable for toxicity. Three patients (60%) had prolonged severe mucositis and all five patients (100%) developed grade 3 skin toxicity. Thus, arm 2 dose level 0 was above the MTD. There was also one patient who required withholding of the fourth week of chemotherapy due to a declining performance status. Approximately 6 weeks after completion of radiotherapy, this patient's tracheostomy was inappropriately decannulated and the patient suffered a cardiorespiratory arrest with anoxic encephalopathy. Life support was withdrawn in 3 days after the severity of the encephalopathy was evident.
In arm 1, four (29%) of 14 patients had prolonged severe mucositis, and all 14 patients had grade 2 or 3 skin toxicity. All patients in arm 1 completed all therapy without interruption or delay due to toxicity. The DLT was defined as prolonged severe mucositis and the MTD was defined as the initial dose level (Table 2). Therefore, the arm 1 weekly cisplatin and docetaxel dose level 0 was studied in phase II.
Phase II. Thirty-eight patients were enrolled from June 2001 to October 2002. In total, there were 52 patients (38 from phase II and 14 from phase I) who received docetaxel 15 mg/m2 and cisplatin 20 mg/m2 weekly during weeks 1 to 4 with concomitant boost radiation. This group is hereafter referred to as the efficacy analysis group and combined stage distribution by tumor size and nodal status is reported in Table 3. None of the 52 patients required dose reductions or interruptions of chemotherapy. There were five patients with minor radiation delays of 1 to 2 days. One patient missed his last day of radiation therapy (2 fractions).
Acute Toxicity for the Efficacy Analysis Group Acute toxicity is reported in Table 4. Eighty-one percent of patients had grade 3 mucositis, 44% had grade 3 skin toxicity, and 44% had grade 2 fatigue. Thirty-six percent (18 of 50) of patients experienced prolonged mucositis, defined as grade 3 or higher at 6 weeks post-therapy. Information on two patients was not available because one patient missed the 6-week evaluation and one patient experienced early death. Hematologic toxicity was uncommon: one patient with grade 3 neutropenia and associated fever, and four patients with grade 3 anemia, no grade 3 to 4 thrombocytopenia. Forty-one patients (79%) had a feeding tube placed during treatment. Seventeen percent of patients received the feeding tube before or at the start (day 1) of treatment. Thirty-two patients (62%) received their feeding tubes during or right after concurrent therapy. One patient died from pneumonia 33 days after completing treatment. This was the only treatment-related death.
Late Toxicity for the Efficacy Analysis Group Twenty-two of 51 patients were partially or completely feeding tube dependent until death or last follow-up; this includes patients with recurrent disease (Table 5). Nine patients received feeding tubes before therapy initiation and six of them had long-term feeding-tube dependence or remained tube dependent until death. Of the 32 patients who had no evidence of disease (NED) at 2 years, eight (25%) were feeding-tube dependent. Five of these patients remain alive and feeding tube dependent, and three have died from other causes. As of June 2006, 17% (five of 29) of patients alive and NED are tube dependent. Only one of these patients required a feeding tube before chemoradiotherapy.
Twelve patients (23%) required a tracheostomy. Five patients (10%) had a tracheostomy placed before chemoradiotherapy for airway protection. Two of these five patients remained tracheostomy dependent post-treatment. Seven patients (13%) had tracheostomy placement for recurrent disease or development of a second laryngeal primary cancer (one patient). Two of three patients alive at 2 years with a tracheostomy had locally recurrent disease. One patient was status postlaryngectomy for a second primary larynx cancer. Table 6 details the late effects of therapy occurring 90 days or more after treatment. Four patients had documented osteoradionecrosis; two additional patients had suspicious bony erosion, but they were lost to follow-up before a definitive diagnosis.
Efficacy of Treatment The response summary of the efficacy analysis group is shown in Table 7. Seventeen patients had residual radiographic lymphadenopathy at restaging. Ten patients underwent neck dissections with 50% having no pathologic evidence of tumor. Seven patients did not receive immediate lymph node dissections because of interval development of pulmonary metastasis (one patient), residual radiographic disease was minimal and appeared to be resolving (four patients), intercurrent death (one patient), and patient refusal (one patient). This last patient eventually underwent neck dissection for progression. One of four patients who were observed with resolving adenopathy developed regional recurrence.
Of 11 patients with partial response at the primary site, one underwent salvage laryngectomy, one was treated with brachytherapy, one was unresectable, three were observed after negative direct endoscopy and biopsies, two were followed with frequent imaging without biopsy of the primary, and two were lost to follow-up after the initial post-treatment evaluation. Five of these eleven patients with partial response at the primary site eventually progressed locally. This includes one of three patients who had a negative biopsy and one of two patients who were followed without biopsy. The 2-year locoregional control rate in the efficacy analysis group was 71% (95% CI, 59 to 85). Two patients were unassessable as they were lost to follow-up. Thirty-nine percent of all assessable patients (n = 49) had recurrent disease. The pattern of first failure was mixed (Table 8). Eighteen percent had local failure, 18% had regional failure, and 14% had distant failure. The most common site of distant failure was the lung. Four of 40 patients with complete response at the primary site after chemoradiotherapy developed recurrent disease in the local area. Five of 28 patients with complete response at the lymph nodes developed recurrent regional disease.
The median survival was 37.8 months, with median follow-up of 32 months. The 2-year PFS and OS rates were 61% (95% CI, 49 to 77) and 65% (95% CI, 53 to 80), respectively (Figs 1 and 2). There were 16 HNSCC-related deaths, two deaths from second primary lung cancers, and five deaths from other causes. One patient died from pneumonia, one from vasculitis, and three from unknown causes.
The primary objectives of this phase I-II trial combining docetaxel and cisplatin with concomitant boost radiation were to establish the MTD and assess feasibility and efficacy. This regimen was feasible with aggressive supportive care. The incidence of severe acute in-field toxicity was quite similar to that seen for other chemoradiotherapy regimens, regardless of radiation fractionation scheme.8,14,15 In Table 9, the results of our trial are compared with prior taxane-containing chemoradiotherapy regimens, concomitant boost radiation alone, and concomitant boost radiation with cisplatin-based therapy.3,15,16-18 A firm conclusion drawn from comparisons across trials is problematic due to variability in patient eligibility and selection. Nevertheless, the major efficacy end points from our study seem comparable with those for other taxane- and/or platinum-based chemoradiotherapy regimens, with either conventional or concomitant boost radiation. Results from four phase I-/II studies with docetaxel (single agent and combination) and concurrent radiation for advanced HNSCC are not included in Table 9 due to the small numbers of patients in the studies, and thus, difficulty with interpretation of reported end points.11,19-21
Although there have been no phase III studies of taxane- versus platin-based chemoradiotherapy regimens, the data extant from phase II trials do not suggest striking differences in efficacy outcomes. The 98-02 Gortec trial17 showed that weekly docetaxel had similar efficacy and toxicity outcomes to the historical control of concurrent carboplatin and fluorouracil in patients with advanced oropharyngeal cancer.7,22 RTOG 97-03 was a randomized phase II trial of three chemoradiotherapy regimens: boost chemoradiotherapy with cisplatin and fluorouracil, radiation every other week with fluorouracil and hydorxyurea, and weekly paclitaxel and cisplatin with radiation.16 Reported with median follow-up of 2.6 to 2.9 years, major efficacy outcomes were not statistically different among the arms and all were superior to the historical control of RTOG 81-17 (intermittent high-dose cisplatin and daily radiation). The authors recommended further study of arm 3 (weekly paclitaxel and cisplatin) primarily based on its numerical advantage in estimated locoregional control at 2 years: 72% compared with 59% in both of the other arms. However, this regimen, and the potential benefit of a weekly taxane-based approach, has not yet been explored in phase III. Spurred by the locoregional control advantage of altered fractionation observed in RTOG 90-03, a recent trial integrated intermittent high-dose cisplatin and concomitant boost radiation (RTOG 99-14).18 As reported in Table 9, efficacy outcomes in that trial were similar to our study, arm 3 of RTOG 97-03, and the Gortec trial with weekly docetaxel. RTOG H01-29, a randomized phase III trial, recently completed accrual and includes a control arm identical to the regimen from RTOG 81-17 and an experimental arm identical to RTOG 99-14. The data from this trial should serve to define the value of altered fractionation radiation given with intermittent high-dose cisplatin. The weekly taxane-based regimens, whether single or combined with cisplatin, are more convenient than regimens containing infusional fluorouracil which require indwelling catheters and ambulatory pumps. Compared with intermittent high-dose cisplatin, taxane-based regimens cause less severe nausea/vomiting, renal insufficiency, peripheral neuropathy, and ototoxicity. Some oncologists have held the opinion that taxane-based chemoradiotherapy regimens increase long-term swallowing dysfunction and feeding tube dependence. Comparison of feeding tube dependence across studies is difficult due to variations in patient eligibility/selection, need for pretreatment feeding tubes, length of follow-up, and reporting methods. However problematic this comparison may be, the data in the last column of Table 9 suggest that chemotherapy combined with concomitant boost fractionation, as opposed to a taxane-containing regimen, explains the relatively high incidence of long-term feeding tube dependence in our study. Arm 3 of RTOG 97-03 utilized weekly cisplatin and paclitaxel with conventional fractionation and had a 6% rate of long-term feeding-tube dependence in disease-free survivors. Staar et al15 (Table 9) reports a long-term feeding tube dependence rate of 51% in patients receiving concurrent carboplatin/fluorouracil compared with 25% of those treated with concomitant boost radiation alone. More data regarding this issue will soon be available from the analysis of RTOG H01-29. In our current trial, the 2-year locoregional control rate of 71% did not meet our targeted rate of 74%, based on a 20% increase over the single-modality concomitant boost radiation 54% rate (RTOG 90-03).3 In addition, our single institution experience with the regimen used in arm 1 of RTOG 97-03 (boost chemoradiotherapy with cisplatin and fluorouracil) yielded a 2-year local (as opposed to locoregional) control rate of 80%.14 The 2-year PFS and OS rates (59% and 62%, respectively) from that study were similar to the current trial. This regimen did not appear more effective than pertinent historical controls. Demonstration of benefit with this approach, compared with bolus cisplatin, for example, would require a randomized phase III study. This is currently not planned. We continue to study docetaxel in concurrent approaches with radiation, including combinations with erlotinib and cetuximab. As discussed herein, proof of the superiority of chemoradiotherapy with concomitant boost fractionation, versus conventional fractionation, awaits analysis of RTOG H01-29. A continued focus on late effects, functional outcomes, and rehabilitation is important as locoregional approaches to the treatment of HNSCC continue to evolve.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-$99,900 (C)
Supported by a grant-in-aid from Aventis Pharmaceuticals Inc, Bridgewater, NJ, (B.S.G.) and National Institutes of Health Grant No. CCSG CA16672-27. Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, Fl, May 18-21, 2002 and the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Withers HR, Taylor JM, Maciejewski B: The hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncol 27:131-146, 2001 2. Garden AS: Altered fractionation for head and neck cancer. Oncology (Williston Park) 15:1326-1332, 2001; discussion 15: 1339-1341, 2001[Medline] 3. Fu KK, Pajak TF, Trotti A, et al: A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: First report of RTOG 9003. Int J Radiat Oncol Biol Phys 48:7-16, 2000[CrossRef][Medline] 4. Bourhis J, Amand C, Pignon J-P, et al: Update of MACH-NC (Meta-Analysis of Chemotherapy in Head & Neck Cancer) database focused on concomitant chemoradiotherapy. J Clin Oncol 23:489s, 2005 (suppl; abstr 5505) 5. Adelstein DJ, Li Y, Adams GL, et al: An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 21:92-98, 2003 6. Brizel DM, Albers ME, Fishers SR, et al: Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med 338:1798-1804, 1998 7. Calais G, Alfonsi M, Bardet E, et al: Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. J Natl Cancer Inst 91:2081-2086, 1999 8. Glisson BS: The role of docetaxel in the management of squamous cell cancer of the head and neck. Seminars in Oncol 16s:83-87, 2002 9. Milas L, Mason KA, Liao Z, et al: Chemoradiotherapy: Emerging treatment improvement strategies. Head Neck 25:152-167, 2003[CrossRef][Medline] 10. Mauer AM, Masters GA, Haraf DJ, et al: Phase I study of docetaxel with concomitant thoracic radiation therapy. J Clin Oncol 16:159-164, 1998 11. Tishler RB, Norris CM Jr, Colevas AD, et al: A phase I/II trial of concurrent docetaxel and radiation after induction chemotherapy in patients with poor prognosis squamous cell carcinoma of the head and neck. Cancer 95:1472-1481, 2002[CrossRef][Medline] 12. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47:207-214, 1981[CrossRef][Medline] 13. Brookmeyer R: A confidence interval for the median survival time. Biometrics 38:29-41, 1982[CrossRef] 14. Garden AS, Glisson BS, Ang KK, et al: Phase I/II trial of radiation with chemotherapy "boost" for advanced squamous cell carcinomas of the head and neck: Toxicities and responses. J Clin Oncol 17:2390-2395, 1999 15. Staar S, Rudat V, Stuetzer H, et al: Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy: Results of a multicentric randomized German trial in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 50:1161-1171, 2001[CrossRef][Medline] 16. Garden AS, Harris J, Vokes EE, et al: Preliminary results of Radiation Therapy Oncology Group 97-03: A randomized phase II trial of concurrent radiation and chemotherapy for advanced squamous cell carcinomas of the head and neck. J Clin Oncol 22:2856-2864, 2004 17. Calais G, Bardet E, Sire C, et al: Radiotherapy with concomitant weekly docetaxel for stages III/IV oropharynx carcinoma: Results of the 98-02 GORTEC Phase II trial. Int J Radiat Oncol Biol Phys 58:161-166, 2004[CrossRef][Medline] 18. Ang KK, Harris J, Garden AS, et al: Concomitant boost radiation plus concurrent cisplatin for advanced head and neck carcinomas: Radiation Therapy Oncology Group phase II trial 99-14. J Clin Oncol 23:3008-3015, 2005 19. Inohara H, Inoue T, Akahani S, et al: Concurrent chemoradiotherapy with cisplatin and docetaxel for advanced head and neck cancer: A phase I study. Anticancer Res 24:4135-4140, 2004 20. Schwartz D, Montgomery R, Yueh B, et al: Phase I and initial phase II results from a trial investigating weekly docetaxel and carboplatin given neoadjuvantly and then concurrently with concomitant boost radiotherapy for locally advanced squamous cell carcinoma of the head and neck. Cancer 103:2535-2543, 2005 21. Katori H, Tsukuda M, Mochimatu I, et al: Phase I trial of concurrent chemoradiotherapy with docetaxel, cisplatin and 5-fluorouracil (TPF) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). Br J Cancer 90:348-352, 2004[CrossRef][Medline] 22. Denis F, Garaud P, Bardet E, et al: Late toxicity results of the GORTEC 94-01 randomized trial comparing radiotherapy with concomitant radiochemotherapy for advanced-stage oropharynx carcinoma: Comparison of LENT/SOMA, RTOG/EORTC, and NCI-CTC scoring systems. Int J Radiat Oncol Biol Phys 55:93-98, 2003[CrossRef][Medline] Submitted February 13, 2006; accepted June 29, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
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