Clinical Oncology and Chemotherapy, Nagoya University Graduate School of Medicine, Nagoya, Japan

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1 Relationship Between Hematotoxicity and Serum Albumin Level in the Treatment of Head and Neck Cancers with Concurrent Chemoradiotherapy Using Cisplatin Masako Ishizuka 1,*, Yasushi Fujimoto 2, Yoshiyuki Itoh 3, Koichi Kitagawa 4, Motoki Sano 1, Yasuhiro Miyagawa 1, Atsushi Ando 2, Mariko Hiramatsu 2, Naoki Hirasawa 3, Shunichi Ishihara 3, Tsutomu Nakashima 2 and Kiyofumi Yamada 1 1 Department of Pharmacy, 2 Department of Otorhinolaryngology, 3 Department of Radiology and 4 Department of Clinical Oncology and Chemotherapy, Nagoya University Graduate School of Medicine, Nagoya, Japan *For reprints and all correspondence: Masako Ishizuka, Department of Pharmacy, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa, Nagoya, Aichi , Japan. masako-i@med.nagoya-u.ac.jp Received January 6, 2011; accepted May 8, 2011 Jpn J Clin Oncol 2011;41(8) doi: /jjco/hyr076 Advance Access Publication 21 June 2011 Objective: Patients with locally advanced head and neck cancer were treated with concurrent chemoradiotherapy using three courses of cisplatin. However, many patients were unable to complete the scheduled cisplatin treatment due to adverse effects. The objective of this study was to retrospectively elucidate the source of the low completion rate of cisplatin courses. Methods: Between November 2007 and 28 May 2010, patients with head and neck cancer were treated with curative intent according to the concurrent chemoradiotherapy protocol (66 70Gyat2Gy/daywithcisplatin80mg/m 2 on Days 1, 22 and 43). Treatment courses, hematological data and other parameters were investigated, and the treatment completion rates and reasons for treatment failure were analyzed. Results: Among the 28 patients, cisplatin was administered during the period of radiotherapy a total of 3 times in 9 (32%) patients, 2 times in 15 (54%) patients and only 1 time in 4 (14%) patients. Multiple regression analysis of the development of neutropenia at 3 weeks after the first cisplatin administration revealed that the serum albumin level was a significant explanatory variable (R 2 ¼ 0.664, b ¼ 0.517, P, 0.01). Pearson s product-moment correlation coefficient showed a strong correlation between the serum albumin level and the neutrophil count after 3 weeks (r ¼ 0.605, P, 0.01). Conclusions: The treatment completion rate by this protocol was low in head and neck cancer patients even when the cisplatin dose was reduced to 80 mg/m 2. This tendency was seen in patients with a low serum albumin level. Key words: completion rate neutropenia chemotherapy radiotherapy serum albumin level correlation INTRODUCTION Anticancer agents are often administered concurrently with radiotherapy to improve the rates of organ preservation and local disease control in patients with head and neck cancers that are locally advanced (Stage III or IV) and unresectable, or in patients who refuse surgery [1,2]. Many clinical studies have shown that concurrent chemoradiotherapy improves therapeutic efficacy for local advanced head and neck cancers compared with radiotherapy alone [3 5]. Furthermore, it has been demonstrated that the therapeutic effect is greater when the chemotherapy and radiotherapy are administered concurrently rather than at different times [6,7]. Combined chemoradiotherapy presents some problems, however, with more severe adverse events, resulting in a reduced treatment completion rate [8]. In numerous randomized clinical studies in various countries, although the usefulness of the treatment was demonstrated, the completion rate was only 53 70% for a treatment protocol that are called for the administration of three courses of 100 mg/m 2 cisplatin during the period of radiotherapy [6,9 12]. # The Author (2011). Published by Oxford University Press. All rights reserved.

2 974 Hematotoxicity and serum albumin level At the department of Otorhinolaryngology of Nagoya University Hospital, patients with advanced head and neck cancer were treated with concurrent chemoradiotherapy consisting of radiotherapy at 2 Gy/day, 5 days/week, to a total dose of Gy, in combination with cisplatin 80 mg/m 2 at 3-week intervals. Cisplatin at a reduced dosage of 80 mg/ m 2 was used instead of 100 mg/m 2, so that enrolled patients could complete the planned protocol design in clinical practice. Nevertheless, the completion rate was low. The objective of this study was to elucidate the source of the low completion rate of cisplatin courses in our institute. Here, the results of our retrospective analysis of the protocol completion rate, the reasons for patients discontinuation of the treatment and the limiting factors of this therapy are presented. PATIENTS AND METHODS PATIENT BACKGROUND Between November 2007 and May 2010, at the Department of Otorhinolaryngology of Nagoya University Hospital, 28 patients with head and neck cancer were treated with curative intent according to the protocol for concurrent cisplatin chemotherapy with radiotherapy. All cancers were histologically diagnosed as squamous cell carcinoma. Eligibility for this protocol was as follows. The patients were required to be older than 20 years. They underwent a physical examination, blood examinations, chest radiographs, an electrocardiogram and a 24 h creatinine clearance test. They were also required to have adequate hepatic and renal function (creatinine clearance. 50 ml/min). The laboratory values needed to meet the following criteria: white blood cell count.4000/mm 3, platelet count /mm 3, serum creatinine,1.5 mg/dl, hemoglobin.10 g/dl and bilirubin,1.5 mg/dl. The patients were also required to have a performance status based on the Eastern Cooperative Oncology Group system of %1. Table 1 summarizes the clinical characteristics of the 28 patients who were included in this study. The patients, 25 males and 3 females, ranged in age from 39 to 77 years, with a median age of 63 years. The disease diagnosis was oropharyngeal cancer in 11 patients, hypopharyngeal cancer in 10 patients, laryngeal cancer in 3 patients, nasopharyngeal cancer in 2 patients, maxillary cancer in 1 patient and cancer of unknown origin in 1 patient. This analysis excluded patients who underwent chemoradiotherapy as postoperative adjuvant therapy and those who underwent chemoradiotherapy due to recurrence of nodal disease. All patients gave their written informed consent before starting treatment. This study was approved by the ethics committee at Nagoya University Hospital. PROTOCOL DESIGN The protocol used in this study consisted of concurrent cisplatin chemotherapy and radiotherapy. Radiotherapy was Table 1. Characteristics of 28 patients Male/female 25/3 Age (mean), year 63 (39 77) Performance status Oropharyngeal cancer 11 Stage* III 1 IVa 8 IVb 2 Hypopharyngeal cancer 10 Stage* II 2 III 3 IVa 3 IVb 1 Vc 1 Laryngeal cancer 3 Stage* II 2 III 1 Nasopharyngeal cancer 2 Stage* III 1 IVa 1 Maxillary cancer 1 Stage* IVb 1 Cancer of unknown origin 1 *Disease diagnoses according to UICC2002. administered at 2 Gy/day, 5 days/week, starting on Day 1 and continuing until total doses ranging from 66 to 70 Gy were delivered. The entire neck was irradiated with 40 Gy. Thereafter, the portal was reduced at the primary site and clinically positive nodes to spare the spinal cord. Meanwhile, chemotherapy consisting of three courses of cisplatin was administered every 3 weeks, beginning with radiotherapy on Day 1 and followed by administration of 80 mg/m 2 cisplatin on Days 22 and 43 of radiotherapy. Complete treatment delivery was defined as both administration of Gy and three courses of cisplatin during the radiotherapy. Dose modification or discontinuation of cisplatin was based on not only renal function but also nadir blood counts and interim toxicities during the preceding course. For the first course of cisplatin, the dosage was adjusted on the basis of the 24-h pooled urine creatinine clearance value. For the second and third courses, the creatinine clearance was estimated from the serum creatinine value using the Cockcroft Gault formula. A 100% dose of cisplatin was administered when the creatinine clearance was 60 ml/min or more. When the creatinine clearance was at least 50 ml/min but,60 ml/min, a 75% dose was administered, while a 60% dose was administered when the creatinine clearance was 40 ml/min or greater but

3 Jpn J Clin Oncol 2011;41(8) 975,50 ml/min. Cisplatin administration was discontinued when creatinine clearance dropped to,40 ml/min. In order to reduce renal function damage by cisplatin, the patients were given aggressive hydration and antiemetic therapy around the time of cisplatin administration. To reduce nausea and vomiting, premedication consisting of a serotonin antagonist and dexamethasone (Decadron) was also given on Days 1 5. After aprepitant (Emend) became commercially available in December 2009, it was also co-administered. With regard to the delay or discontinuation of cisplatin, the next planned administration was postponed in the case of a neutrophil count of,1500 /mm 3 or a platelet count of, emsp14;/mm 3 and was resumed only after the neutrophil count recovered to at least 1500 /mm 3. Radiotherapy was continued even during periods of postponement of cisplatin administration, if there was no normal tissue reaction such as confluent mucositis. No granulocyte colony-stimulating factor products were given prophylactically. For patients with poor nutritional status, percutaneous endoscopic gastrostomy (PEG) tubes were recommended. Nine patients were considered to require a PEG before the start of treatment, but only six of them used PEG feeding during concurrent chemoradiotherapy. One of the remaining three patients was suspected to have stomach cancer at PEG tube placement. Another patient developed a gastric ulcer after he started using the PEG tube. The last patient underwent PEG tube placement but refused to use it and continued oral intake. One patient received total parenteral nutrition without PEG tube placement. In total, 21 patients (75%) started concurrent chemoradiotherapy with oral intake. Appropriate pain management was used for mucositis, including xylocaine gargle, morphine or oxycodone. Patients continued oral intake for as long as possible to preserve swallowing, but in order to maintain their nutritional status, they used a nasogastric tube when they became unable to obtain more than half of their caloric needs orally. Nutritionists supported the food form and contents. INVESTIGATED PARAMETERS The following parameters were investigated for each of the 28 patients: age, sex, weight on the day before cisplatin administration, actual radiation dose, cisplatin dosage and intervals between doses, and changes in hematological data. Adverse events were graded for severity in accordance with NCI CTCAE (Ver. 4.0). The data for the completion rate are presented for the patients as a group and also for subgroups stratified by radiation dose. In an attempt to identify the potential factors leading to prolonged neutropenia, PASW statistics 18 and multiple regression analysis were used to identify relationships between various factors and the neutrophil count at 3 weeks after cisplatin administration. Pearson s product-moment correlation coefficient was also used to investigate the relation between the pre-cisplatin serum albumin level and the neutrophil count at 3 weeks after cisplatin administration. RESULTS RADIATION DOSE The total doses of radiation administered were 66 Gy in 14 (50%) patients, 70 Gy in 10 (36%) patients, 60 Gy in 3 (11%) patients and 30 Gy in 1 (4%) patient. The patients who were discontinued at 60 Gy had the following adverse events: grade 3 dermatitis in one patient, grade 4 mucositis in one patient and concurrent grade 4 dermatitis and mucositis in one patient. The one patient who was discontinued at 30 Gy underwent surgery because of a very poor tumor response. DOSAGE OF CISPLATIN The dosage of cisplatin was reduced in patients with insufficient renal function in accordance with the previously mentioned criterion. In the first course, 26 (93%) patients received a 100% dose of cisplatin, and the remaining 2 (7%) patients received a 75% dose. In the second course, 17 (61%) patients received a 100% dose of cisplatin, 5 (18%) patients received a 75% dose and 2 (7%) patients received a 60% dose. Finally, in the third course, eight (29%) patients received a 100% dose of cisplatin, and one (4%) patient received an 80% dose. ADVERSE EVENTS AND THEIR GRADES Adverse events were graded for severity in accordance with NCI CTCAE (Ver. 4.0) (Table 2). Grade 3 leucopenia was seen in five (17.9%) patients in the first course, six (25.0%) patients in the second course and one (11.1%) patient in the third course. Grade 3 neutropenia was seen in one (3.6%) patient in the first course, four (16.7%) patients in the second course and one (11.1%) patient in the third course. Grade3anemiawasseeninone(3.6%)patientinthefirst course, three (12.5%) patients in the second course and no patients in the third course. There were no cases of grade 3 or higher thrombocytopenia. Throughout the treatment period, there were no hematological adverse events evaluated as grade 4 or higher. With regard to renal dysfunction, no patients had a serum creatinine value greater than 1.5 mg/dl. However, prior to administration of the first course of cisplatin, 27 patients had a serum creatinine value,1.0 mg/dl, and in 6 (22%) of these patients, the value had increased slightly to mg/dl at 3 weeks after cisplatin administration. Grade3andgrade4mucositiswasseeninfive(17.9%) and two (7.1%) patients, respectively. Grade 3 and grade 4 dermatitis was seen in three (10.7%) and one (3.6%) patient, respectively. Of the 21 patients who started concurrent chemoradiotherapy with oral food intake, nasogastric tubes were inserted into 10 patients during concurrent chemoradiotherapy. No treatment-related deaths occurred.

4 976 Hematotoxicity and serum albumin level Table 2. Side effects and their grades Side effects of myelosupression and their grade First course (n ¼ 28) Second course (n ¼ 24) COMPLETION RATES FOR THREE COURSES OF CISPLATIN Third course (n ¼ 9) Leucocyte count Grade 1 5 (17.9%) 5 (20.8%) 5 (55.6%) Grade 2 11 (39.3%) 9 (37.5%) 2 (22.2%) Grade 3 5 (17.9%) 6 (25.0%) 1 (11.1%) Neutrophil count Grade 1 8 (28.6%) 5 (20.8% 1 (11.1%) Grade 2 8 (28.6%) 6 (25.0%) 0 (0%) Grade 3 1 (3.6%) 4 (16.7%) 1 (11.1%) Hemoglobin value Grade 1 19 (67.9%) 14 (58.3%) 5 (55.6%) Grade 2 5 (17.9%) 7 (29.2%) 4 (44.4%) Grade 3 1 (3.6%) 3 (12.5%) 0 (0%) Platelet count Grade 1 1 (3.6%) 3 (12.5%) 0 (0%) Grade 2 2 (7.1%) 1 (4.2%) 0 (0%) Grade 3 0 (0%) 0 (0%) 0 (0%) Side effects of mucositis, dermatitis and their grade Mucositis Dermatitis Grade 1 8 (28.6%) 11 (39.3%) Grade 2 13 (46.4%) 13 (46.4%) Grade 3 5 (17.9%) 3 (10.7%) Grade 4 2 (7.1%) 1 (3.6%) Cisplatin was administered three times to 9 (32%) of the 28 patients during the period of radiotherapy, two times to 15 (54%) patients and only one time to 4 (14%) patients (Fig. 1A). Cisplatin was administered only one time to four patients for the following reasons: a decrease in renal function in one patient, aspiration pneumonia in one patient, a decrease in liver function in one patient and inadequate efficacy in one patient. Cisplatin was administered only two times to 15 patients for the following reasons: neutropenia in 8 patients, a decrease in renal function in 3 patients, anemia in 2 patients, aspiration pneumonia in 1 patient, infection in 1 patient, thrombocytopenia in 1 patient, thrombosis in 1 patient and refusal to undergo chemotherapy in 1 patient. Of these reasons, two applied to three of these patients. In 24 patients given a total radiation dose of Gy, 9 (37.5%) were given all three doses of cisplatin, while 13 (54%) were given two doses and 2 (8%) were given only one dose (Fig. 1B). No patients were administered cisplatin after the radiotherapy had been completed. MULTIPLE REGRESSION ANALYSIS OF NEUTROPENIA Multiple regression analysis was performed for the 28 patients. The independent variables were as follows: age, sex, 24-h pooled urine creatinine clearance, serum Na, serum BUN, serum albumin, serum total bilirubin values prior to the first cisplatin course, and administered cisplatin dose (give as a percentage, with a total dose of 80 mg/m 2 defined as 100%). The dependent variable was the neutrophil count at 3 weeks after the first cisplatin administration. Only the serum albumin level (b ¼ 0.517, P, 0.01) was a significant explanatory variable (R 2 ¼ 0.664) for the neutrophil count at 3 weeks after the first cisplatin administration. Other factors (age, sex, 24-h pooled urine creatinine clearance, serum Na, serum BUN and serum total bilirubin) were not significant explanatory variables for the neutrophil count (P. 0.05). RELATIONSHIP BETWEEN THE PRE-CISPLATIN SERUM ALBUMIN LEVEL AND NEUTROPHIL COUNT 3 WEEKS AFTER CISPLATIN ADMINISTRATION For the 28 patients, the relationship between the serum albumin level prior to the first cisplatin course and the neutrophil count at 3 weeks after cisplatin administration was plotted (Fig. 2A). Pearson s product-moment correlation coefficient showed a strong correlation between these two parameters (r ¼ 0.605, P, 0.01). In addition, the relationship between the serum albumin level in the case of the 100% cisplatin dose and the neutrophil count at 3 weeks after cisplatin administration (for the first and second courses) was plotted (Fig. 2B). After exclusion of two patients who developed infections, 41 pairs of variables were also analyzed, resulting in a strong correlation between these two parameters (r ¼ 0.595, P, 0.01). RELATIONSHIP BETWEEN BODY MASS INDEX OR HEMOGLOBIN LEVEL AND NEUTROPHIL COUNT 3 WEEKS AFTER CISPLATIN ADMINISTRATION Body mass index (BMI) and hemoglobin levels are commonly evaluated together with serum albumin. Thus, the relationship between BMI or hemoglobin level and neutrophil count at 3 weeks after cisplatin administration was investigated using Pearson s product-moment correlation coefficient. There was no relationship between BMI and the neutrophil count (r ¼ 0.277, P ¼ 0.15). However, there was a relatively strong relationship between the hemoglobin level and the neutrophil count (r ¼ 0.545, P, 0.01), but it was weaker than that between the neutrophil count and the serum albumin level. Furthermore, there was a strong relationship between the hemoglobin level and the

5 Jpn J Clin Oncol 2011;41(8) 977 Figure 1. (A) Number of cisplatin administrations (28 patients). (B) Number of cisplatin administrations (24 patients receiving radiotherapy of 66 Gy). serum albumin level (r ¼ 0.77, P, 0.01). The hemoglobin level and the serum albumin could not be used at the same time in the multiple regression analysis because they were not independent variables in this study, but the serum albumin level was the strongest parameter affecting the neutrophil count at 3 weeks after cisplatin administration. DISCUSSION Many clinical studies have reported the efficacy of concurrent chemoradiotherapy using cisplatin in the treatment of head and neck cancers. However, there have been few reports regarding the appropriate dosage of cisplatin and the treatment completion rate in Japanese patients. Zenda et al. [13] have proved the feasibility of 100 mg/m 2, without modification of the cisplatin dosage, for Japanese patients. But, compared with the previous overseas reports [9 11], our patients were older (average age: 62.3 years). Additionally, it is known that Japanese patients have lower creatinine clearances with aging; so dose adjustment of cisplatin is important [14]. Many patients, nine patients (32.1%) in this study, had a creatinine clearance of less than 70 ml/min. Furthermore, our patients might have had poor nutritional status. Therefore, we gave cisplatin at a reduced dosage of 80 mg/m 2, which were more suitable for our study population. However, even at that dosage, not all patients could complete the planned protocol design. Our analysis of the 28 patients included in this retrospective study found that the actual completion rate for the three planned cisplatin courses wasverylow,atonly32%.infourofthepatients,completion of the treatment regimen was not possible because the total radiation dose was reduced. Even for the remaining 24 patients who were exposed to the planned radiation dose of Gy, only 37.5% were able to complete all three cisplatin courses. The main reason was prolonged myelosuppression. Because our patients received cisplatin only while they were undergoing radiotherapy, they could not receive cisplatin three times when they had delay of the schedule. In order to improve the completion rate, it is of great importance to elucidate the tendency to develop prolonged neutropenia. It is said that 90% of cisplatin is bound to albumin within 3 h after administration, and the free drug thus reaches a steady-state level [15]. The free cisplatin that is not bound to albumin is excreted from the kidneys [16]. For this reason, the amount of cisplatin that is bound to albumin greatly influences the area under the curve of cisplatin. Experiments were carried out in which the administration method and the dose rate of cisplatin were varied, and then the pharmacokinetics and adverse events were compared [17,18]. The results of these experiments showed that the amount of free cisplatin decreased as the dose rate decreased, and there was a tendency for the incidence of adverse events to decrease. On the other hand, it has been shown that the half-life of cisplatin decreases when the serum albumin level is low [19]. In patients with a low serum albumin level, the cisplatin concentration in blood temporarily becomes high compared with the level in patients with normal albumin levels, and there may be a transient increase in the free cisplatin level in blood. The reason for adverse events during chemoradiotherapy with cisplatin may be the increased free cisplatin level in blood. For our investigation of the factors that influence the neutrophil count at 3 weeks after administration of cisplatin, multiple regression analysis using the serum Na value as a variable was performed to exclude an apparent decrease in the blood cell count arising from edema. Additionally, in order to exclude any influences arising from hepatic dysfunction and/or renal dysfunction, the analysis was carried out using the serum total bilirubin value, 24-h pooled urine creatinine clearance value and serum BUN value as variables. In the case of decreased renal function, cisplatin was administered at a reduced dosage in accordance with the criteria for dose reduction. This dose reduction method was shown to be appropriate.

6 978 Hematotoxicity and serum albumin level Figure 2. (A) Relationship between pre-cisplatin albumin level and neutrophil count after 3 weeks (first course). (B) Relationship between pre-cisplatin albumin level and neutrophil count after 3 weeks (first and second courses, without infection). The only factor found to be associated with the neutrophil count at 3 weeks after cisplatin administration was the precisplatin serum albumin level. When the relationship between the pre-cisplatin serum albumin level and the neutrophil count at 3 weeks after cisplatin administration was plotted, strong correlations were seen for both the first and second cisplatin courses. These findings showed that there is prolonged neutropenia following cisplatin administration to patients with a reduced serum albumin level. Many patients with locally advanced cancer have low serum albumin levels. Therefore, it is important to maintain good nutritional status in order not to cause prolonged neutropenia. Aprepitant became commercially available in December 2009, and beginning in mid-december, this drug was administrated to all of study patients. Prior to that time, 20 patients had received a radiation dose of Gy; of these, 6 (30%) received all 3 courses of cisplatin therapy, 12 (60%) received 2 courses and 2 (10%) received only 1 course. On the other hand, of the four patients treated with aprepitant, three (75%) received all three courses of cisplatin and the remaining one (25%) patient received two courses. Although this sample size was small, the patients appetite may have been better maintained after the start of this therapy due to the effects of aprepitant, which could have contributed to the maintenance of the serum albumin level at the time of the second cisplatin course. Completion of treatment according to the treatment protocol is extremely important in order to achieve sufficient

7 Jpn J Clin Oncol 2011;41(8) 979 therapeutic efficacy. To that end, it is necessary to provide appropriate support to patients with the adverse events and to elucidate the potential factors that exacerbate adverse events. The present analyses demonstrate that the rate of completion of concurrent chemoradiotherapy in patients with head and neck cancers is low, that administration of cisplatin is delayed by a decrease in the neutrophil count and that there is a relationship between the serum albumin level and neutropenia. Many patients with locally advanced head and neck cancers are susceptible to a decline in nutritional status due to reduced food intake. Therefore, nutritional management before the cisplatin administration is important to complete the planned treatment. It is desirable to adopt an aggressive approach to instruction in nutrition, not only during the course of treatment but also before therapy is initiated. Higher completion rate can be expected by maintaining good nutritional status before and through concurrent chemoradiotherapy. Funding This work was supported in part by the Grant-in-Aid for Cancer Research (21-7-2) from the Ministry of Health, Labour and Walfare. Conflict of interest statement None declared References 1. Seiwert TY, Salama JK, Vokes EE. The chemoradiation paradigm in head and neck cancer. Nat Clin Pract Oncol 2007;4: Choong N, Vokes E. Expanding role of the medical oncologist in the management of head and neck cancer. CA Cancer J Clin 2007;58: 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: Browman GP, Hodson DI, Mackenzie RJ, Bestic N, Zuraw L. Choosing a concomitant chemotherapy and radiotherapy regimen for squamous cell head and neck cancer: a systematic review of the published literature with subgroup analysis. Head Neck 2001;23: Fountzilas G, Ciuleanu E, Dafni U, Plataniotis G, Kalogera-Fountzila A, Samantas E, et al. Concomitant radiochemotherapy vs radiotherapy alone in patients with head and neck cancer; a Hellenic Cooperative Oncology Group Phase Study. Med Oncol 2004;21: Forastiere AA, Goepfert H, Mayor M, Pajak TF, Weber R, Morrison W, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003;349: Adelstein DJ, Ji Y, Adams GL, Wagner H, Jr, Kish JA, Ensley JF, et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 2003;21: Wendt TG, Grabenbauer GG, Rödel CM, Thiel HJ, Aydin H, Rohloff R, et al. Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicenter study. J Clin Oncol 1998;16: Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Eng J Med 2004;350: Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefèbvre JL, Greiner RH, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Eng J Med 2004;350: Lee AW, Lau WH, Tung SY, Chua DT, Chappell R, Xu L, et al. Preliminary results of a randomized study on therapeutic gain by concurrent chemotherapy for regionally-advanced nasopharyngeal carcinoma: NPC-9901 Trial by the Hong Kong Nasopharyngeal Cancer Study Group. J Clin Oncol 2005;23: Marcial VA, Pajak TF, Mohiuddin M, Cooper JS, al Sarraf M, Mowry PA, et al. Concomitant cisplatin chemotherapy and radiotherapy in advanced mucosal squamous cell carcinoma of the head and neck. Long-term results of the Radiation Therapy Oncology Group study Cancer 1990;66: Zenda S, Onozawa Y, Tahara M, Kawashima M, Shikama N, Sasaki S, et al. Feasibility study of single agent cisplatin and concurrent radiotherapy in Japanese patients with squamous cell carcinoma of head and neck: preliminary results 2007;37: Nishimura G, Tsukuda M, Horiuchi C, Satake K, Yoshida T, Taguchi T, et al. Decrease of creatinine rate with aging in patients with head and neck cancer in Japan. Int J Clin Oncol 2007;12: Gouyette A, Apchin A, Foka M, Richard JM. Pharmacokinetics of intra-arterial and intravenous cisplatin in head and neck cancer patients. Eur J Cancer Clin Oncol 1986;22: Vermorken JB, van der Vijgh WJ, Klein I, Gall HE, Pinedo HM. Pharmacokinetics of free platinum species following rapid, 3-hr and 24-hr infusions of cis-diamminedichloroplatinum(ii) and its therapeutic implications. Eur J Cancer Clin Oncol 1982;18: Kurihara N, Kubota T, Hoshiya Y, Otani Y, Ando N, Kumai K, et al. Pharmacokinetics of cis-diamminedichloroplatinum (II) given as low-dose and high dose infusions. J Surg Oncol 1996;62: Nagai N, Ogata H. Quantitative relationship between pharmacokinetics of unchanged cisplatin and nephrotoxicity in rats: importance of area under the concentration-time curve (AUC) as the major toxicodynamic determinant in vivo. Cancer Chemother Pharmacol 1997;40: Vermorken JB, van der Vijgh WJ, Klein I, Gall HE, van Groeningen CJ, Hart GA, et al. Pharmacokinetics of free and total platinum species after rapid and prolonged infusions of cisplatin. Clin Pharmacol Ther 1986;39: