Accepted 27 August 2009 Published online 2 November 2009 in Wiley InterScience ( DOI: /hed.

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1 ORIGINAL ARTICLE ACCELERATED FRACTIONATION RADIOTHERAPY AND LATE INTENSIFICATION WITH 2 INTRA-ARTERIAL CISPLATIN INFUSIONS FOR LOCALLY ADVANCED HEAD AND NECK SQUAMOUS CELL CARCINOMA Kwok Hung Yu, FRCR, 1 Simon C. H. Yu, FRCR, 2 Edwin P. Hui, MRCP, 1 Michael K. M. Kam, FRCR, 1 Alexander C. Vlantis, FCS(SA)ORL, 3 Edmund Yuen, FRCR, 2 Anthony T. C. Chan, MD 1 1 Department of Clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong. yukh@ha.org.hk 2 Department of Diagnostic Radiology and Organ Imaging, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong 3 Department of Otorhinolaryngology, Head and Neck Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong Accepted 27 August 2009 Published online 2 November 2009 in Wiley InterScience ( DOI: /hed Abstract: Background. This study was established to determine the maximum tolerated dose of intra-arterial cisplatin (IAC) concurrent with accelerated fractionation radiotherapy for locally advanced head and neck squamous cell carcinoma (HNSCC). Methods. We conducted a phase I study. Treatment consisted of 70 Gy/35 fractions/5.8 weeks and 2 weekly IAC infusions during the last 2 weeks. Results. Ten patients were recruited. Two patients had stage III, 1 had stage IVa, and 7 had stage IVb disease. Three patients received IAC at 100 mg/m 2, 3 at 125 mg/m 2, and 4 at 150 mg/m 2. Nine patients received both planned infusions. Dose-limiting toxicity occurred at 150 mg/m 2 as transient grade 4 leukopenia and prolonged grade 3 acute skin reactions. The maximum tolerated dose was 125 mg/m 2. Six patients survived disease-free at 39 to 67 months. Conclusions. It was feasible to give IAC concurrent with accelerated fractionation radiotherapy for locally advanced Correspondence to: K. H. Yu VC 2009 Wiley Periodicals, Inc. HNSCC. The maximum tolerated dose of cisplatin was 125 mg/m 2. VC 2009 Wiley Periodicals, Inc. Head Neck 32: , 2010 Keywords: intra-arterial cisplatin; accelerated fractionation radiotherapy; head and neck cancer; late intensification; phase I study Surgery, with adjuvant radiotherapy (RT) or chemoradiotherapy, is used commonly for operable advanced head and neck squamous cell carcinoma (HNSCC). Locoregional control rates range from 70% to 82%, and 5-year survival rates from 30% to 53%. 1 3 However, surgical resection is often functionally or cosmetically debilitating despite advances in reconstructive technique. Concurrent chemoradiotherapy has been used to preserve organ function for patients with operable HNSCC, while achieving survival results equivalent to those of surgery, 4 8 and it is an effective treatment for inoperable Accelerated RT and Intra-arterial Cisplatin HEAD & NECK DOI /hed July

2 tumors Addition of concurrent chemotherapy to locoregional treatment results in an absolute survival benefit of 8% at 5 years, and platinum-based regimens are most effective. 6,7 RT with selective high-dose intra-arterial cisplatin (IAC) infusion is an efficacious treatment for locoregionally advanced HNSCC Selective IAC infusion delivers the drug directly to the tumor, achieving dose intensities of cisplatin equivalent to 10-fold that of standard intravenous (IV) cisplatin. This approach may circumvent acquired cisplatin resistance and improve tumor response. 13,17 Given that the systemic toxicity of IAC can be minimized by simultaneous IV infusion of its neutralizing agent, sodium thiosulfate, high doses of IAC can be given with moderate systemic toxicity. 16,17 The most commonly used concurrent IAC RT regimen for locally advanced HNSCC is a treatment protocol with a combination of radiation and cisplatin (RADPLAT), which consists of 4 weekly doses of cisplatin of 150 mg/m 2 and conventional fractionation RT of 68 to 72 Gray (Gy). 13,17 However, the optimal IAC RT regimen has not been defined. It has been shown that accelerated fractionation RT with 6 daily fractions per week enhances locoregional control compared with conventional fractionation RT and that addition of concurrent chemotherapy improves overall survival and locoregional control compared with accelerated fractionation RT alone. 22,23 Tumor control may be enhanced with late concurrent chemotherapy to counteract accelerated tumor repopulation during RT, and local toxicity may be minimized by giving chemotherapy during the cone-down radiation boost for gross disease. 24,25 Thus, we hypothesized that using only 2 IAC infusions, instead of 4, given in the latter part of accelerated fractionation RT, would decrease treatment complications without compromising tumor control. We conducted a prospective phase I study to determine the maximum tolerated dose of 2 weekly IAC doses given during the last 2 weeks of accelerated fractionation RT. MATERIALS AND METHODS Patient Eligibility. Between December 2003 and May 2005, 10 patients with locoregionally advanced HNSCC were recruited in a prospective phase I study to determine the maximum tolerated dose of IAC that could be given as 2 weekly infusions during the last 2 weeks of accelerated fractionation RT. Staging investigations included CT or MRI of the head and neck, ultrasonography of the neck and fine-needle aspiration cytology (FNAC) of suspicious lymph nodes, examination under anesthesia with endoscopy of the upper aerodigestive tract, and chest radiograph. CT thorax and abdominal ultrasound were performed if distant metastases were suspected. Laboratory tests included complete blood picture, prothrombin time and activated partial thromboplastin time, renal and liver function tests, plasma calcium and magnesium, creatinine clearance, and baseline electrocardiogram. Inclusion criteria were histologically confirmed squamous cell carcinoma (SCC) of head and neck sites except the nasopharynx; stage III or IV disease (American Joint Committee on Cancer 1997 staging system) with no distant metastasis; Eastern Cooperative Oncology Group performance status 0 or 1; age 70 years; white blood cell count /L, platelet count /L, plasma creatinine < 150 lmol/l, creatinine clearance 70 ml/ min, alkaline phosphatase and serum glutamate pyruvate < twice the upper limit of normal, and bilirubin < 24 lmol/l. The tumor was assessed by a multidisciplinary team to be either unresectable or resectable but suitable for organpreservation treatment. Exclusion criteria were previous or synchronous malignancy other than curatively treated nonmelanoma skin cancer; previous systemic cytotoxic chemotherapy; previous RT (except superficial RT for nonmelanoma skin cancers); any medical contraindication to RT or chemotherapy; and suspected or confirmed pregnancy. All patients gave written informed consent, and the study was approved by the institutional research ethics committee. Accelerated Fractionation Radiotherapy. RT was delivered in daily fractions of 2 Gy, 6 days (Monday to Saturday) per week (see Figure 1). The dose to gross disease was 70 Gy/35 fractions/5.8 weeks, and the dose to sites of microscopic disease was 50 Gy/25 fractions/4.2 weeks. Dose to the spinal cord and brainstem was limited to 45 Gy; optic chiasma, 50 Gy; and brachial plexus, 66 Gy. In 6 patients, RT was initially planned with 2-dimensional shrinking field technique to allow RT to start early. In phase I, lateral opposed Accelerated RT and Intra-arterial Cisplatin HEAD & NECK DOI /hed July 2010

3 FIGURE 1. Treatment schedule of intra-arterial cisplatin (IAC) and accelerated fractionation radiotherapy (RT). MV photon faciocervical fields were used to cover the primary tumor and bilateral upper jugular and posterior cervical nodes. Remote wax compensators were used. A dose of 2 Gy per fraction was delivered at midplane, 6 fractions per week, to 40 Gy/20 fractions/3.3 weeks. The lower neck was treated with a matching 6- MV photon anterior field with a 2-cm-wide median shield and infraclavicular shields to a dose of 2 Gy/fraction at 90% isodose line, 6 fractions/ week, to 50 Gy/25 fractions/4.2 weeks. In phase II, the lateral field size was reduced to avoid the spinal cord, delivering another 10 Gy in 5 fractions over 0.9 week. Bilateral posterior cervical strips were treated using 6- to 9-MeV electron beams with wax bolus as appropriate to limit total maximum spinal cord dose to 45 Gy. In phase III, the gross tumor plus 1.5-cm margins was boosted by 3-dimensional (3D) conformal technique at 2 Gy/fraction to 20 Gy/10 fractions/ 1.7 weeks. In 4 patients, intensity-modulated radiotherapy (IMRT) was used because of anticipated difficulty to adequately cover bulky gross disease with lateral opposed photon fields and posterior cervical electron strips, and difficulty to adequately boost gross disease with 3D conformal RT. In the IMRT technique, the initial clinical target volume (CTV) included the gross tumor with at least 5-mm margins and microscopic disease sites. The gross tumor CTV was gross disease with 5-mm margins. The initial planning target volume (PTV) and gross tumor PTV were generated from the respective CTV with 3-mm margins. The dose to the initial PTV was 50 Gy/25 fractions/4.2 weeks. Then, a sequential boost of 20 Gy/10 fractions/1.7 weeks was delivered to the gross tumor PTV. Intra-arterial Cisplatin and IV Sodium Thiosulfate Infusions. Two weekly IAC infusions were given during the last 2 weeks of RT at the 25th and 31st fractions (see Figure 1). The second dose of IAC was delayed if absolute neutrophil count (ANC) was < /L, platelet count was < /L, plasma creatinine was >150 lmol/l, or creatinine clearance was <50 ml/minute. In case of severe toxicity of infection, hyponatremia 125 mmol/l or hypomagnesemia 0.30 mmol/l caused by the first dose of IAC, the second dose was omitted. Details of the hydration scheme and simultaneous administration of IAC and IV sodium thiosulfate have been reported previously. 13 Briefly, cisplatin (1 mg/ml) in normal saline was infused rapidly through an angiographically placed microcatheter into the dominant blood supply of the targeted tumor. In patients with bilateral disease, bilateral transfemoral catheterizations were performed for simultaneous infusions of cisplatin doses proportional to tumor bulk, as estimated from the extent of feeding vasculature on digital angiography during the procedure. Likewise, in patients with bulky (>4 cm) nodes involving the upper neck, an amount of cisplatin, proportional to the estimated tumor bulk, was delivered to the nodal region when the superior thyroid artery was selectively infused. At the start of IAC infusion, IV sodium thiosulfate 9 g/m 2 was given over 3 minutes, followed by continuous infusion of another 12 g/m 2 in 1 L of 5% dextrose over 12 hours. Dexamethasone and granisetron were given before each cisplatin infusion as antiemetic treatment. Intra-arterial Cisplatin Dose Levels, Dose-limiting Toxicity, and Maximum Tolerated Dose. Cohorts of at least 3 patients each were recruited. The starting dose level of each IAC infusion was 100 mg/m 2. In-field dose-limiting toxicity was defined as grade 3 mucositis or skin reactions (Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer [RTOG/EORTC] Acute Radiation Morbidity Scoring Criteria), which lasted >8 weeks after completion of RT. Systemic dose-limiting toxicity was grade 4 hematologic, infective, metabolic, or hearing toxicity; or grade 3 renal, hepatic, or neurological toxicity according to the National Cancer Institute (NCI) Common Toxicity Criteria Version 2.0. In the absence of doselimiting toxicity at 6 weeks post-treatment in the first cohort of 3 patients, the IAC dose would be escalated by 25 mg/m 2 in successive cohorts to a maximum of 200 mg/m 2. If 1 patient Accelerated RT and Intra-arterial Cisplatin HEAD & NECK DOI /hed July

4 developed dose-limiting toxicity, then an additional 3 patients would be treated at the same dose level. If no additional patients developed dose-limiting toxicity, the dose would be escalated with another 3 patients. Otherwise, the previous lower dose level would be considered the maximum tolerated dose. If 2 or 3 patients among the initial cohort of 3 experienced doselimiting toxicity, then the dose would be de-escalated to 70 and 40 mg/m 2 in the next 2 cohorts. Monitoring of Treatment Toxicity. A complete blood picture, liver and renal function tests, plasma magnesium level, and creatinine clearance were performed before the second IAC infusion and repeated 1 week later. Acute chemotherapy toxicity was assessed weekly using the NCI Common Toxicity Criteria Version 2.0. Acute RT toxicity was assessed weekly using the RTOG/EORTC Acute Radiation Morbidity Scoring Criteria. The patients were monitored until acute toxicities had subsided. Nasogastric tube feeding was instituted if the patients had significant difficulty with oral feeding attributed to mucositis. Follow-up. At 6 weeks post-treatment, acute RT and chemotherapy toxicities were recorded, and tumor response was assessed with physical examination and endoscopy. At 12 weeks posttreatment, CT and MRI of the head and neck and ultrasound of the neck with FNAC of suspicious lymph nodes were performed to assess maximum tumor response. Subsequent visits took place every 6 weeks in the first year, every 8 weeks in the second year, every 12 weeks in the third year, every 16 weeks in the fourth year, and every 24 weeks thereafter. Chest radiograph and thyroid function tests were performed at 1 year after treatment and annually thereafter. CT, MRI, and ultrasound of the head and neck, and examination under anesthesia with biopsy were done whenever there was suspected tumor persistence or relapse. If treatment failure was confirmed, the patient would be assessed by surgeons for salvage surgery. No planned neck dissection was performed. Beginning at the second follow-up visit, late RT toxicity was recorded at each visit, using the RTOG/EORTC Late Radiation Morbidity Scoring Criteria. Response to Treatment. Tumor response was determined by clinical examination, endoscopy, biopsy, and imaging results. Complete response was disappearance of all known tumor as determined by 2 evaluations not <4 weeks apart. Partial response was 50% or greater decrease in the sum of products of the largest and perpendicular diameters of the lesions as determined by 2 evaluations not <4 weeks apart, in the absence of new lesions or progression of any lesion. Stable disease occurred when there was neither a 50% decrease in total tumor size nor a 25% increase in the size of any measurable lesions. Progressive disease was a 25% or greater increase in size of any measurable lesions, or the appearance of a new lesion. Statistical Considerations. The objective of this phase I study was to determine the maximum tolerated dose of IAC. To avoid possible excessive toxicity, the starting IAC dose level was 100 mg/m 2, which is the usual dose for IV cisplatin. The lowest permissible IAC dose level was 40 mg/m 2, to ensure useful radiosensitization effect. The study would be closed if the highest dose level of 200 mg/m 2 or the lowest level of 40 mg/m 2 was reached. The maximum number of patients required was 30. RESULTS Ten patients were recruited in the study. Patient characteristics are shown in Table 1. Seven patients had stage IVb disease with T4b or N3 tumors. Three patients received IAC at a dose level of 100 mg/m 2, 3 patients at 125 mg/m 2, and 4 patients at 150 mg/m 2. There was no treatment-related mortality. Table 2 summarizes the maximum acute toxicity by IAC dose level. RT was delivered as planned in 8 patients, despite grade 3 skin or mucosal reactions in most of the patients. Only 2 patients experienced an unplanned interruption in RT. In both patients, the 1-day delay was the result of fever without confirmed sepsis. Five patients required temporary nasogastric tube feeding during RT. There were no significant catheterization-related complications. All patients received the 2 planned IAC doses except 1 at the lowest dose level. The patient developed grade 3 hyponatremia after the first dose and the second dose was withheld. Dose-limiting toxicity occurred in 2 patients at the 150 mg/m 2 IAC dose level. One of them developed grade 4 leukopenia with grade 3 neutropenia after the second dose of cisplatin. Blood 916 Accelerated RT and Intra-arterial Cisplatin HEAD & NECK DOI /hed July 2010

5 Table 1. Patient characteristics (n ¼ 10). No. by N classification Characteristic No. N0 N1 N2 N3 Sex Male 10 Age, y Median 56.5 Range ECOG performance status Tumor site Oropharynx 5 Larynx 2 Oral cavity 2 Hypopharynx 1 Tumor classification T1 2 T2 1 T3 1 1 T4a 1 T4b 1 3 Stage III 2 IVa 1 IVb 7 Cartilage involvement Present 4 Absent 6 Gross tumor volume, cm 3 Median Range Abbreviation: ECOG, Eastern Cooperative Oncology Group. culture confirmed systemic infection, which subsided with IV antibiotics. The other patient had grade 3 acute skin reactions that healed at 8.5 weeks after completion of RT (Table 2). By definition, the maximum tolerated dose of IAC was 125 mg/m 2. As for late treatment toxicity (Table 3), 1 patient with hypopharyngeal tumor developed grade 3 pharyngeal stricture, which required dilatation after treatment at the 150 mg/m 2 IAC dose level. There were no events of soft tissue or bone radionecrosis. Patient outcome is detailed in Table 4. Only 1 patient (patient 10) had salvage surgery after IAC RT. He had residual neck masses and underwent radical neck dissection. Pathological examination did not reveal any residual tumor in the specimen. Patients 1 and 4 developed locoregional failures, which were assessed to be unresectable. At a median follow-up of 41 months, 6 patients remained alive and disease-free. DISCUSSION The most commonly used concurrent IAC RT regimen for locally advanced HNSCC is the RADPLAT protocol, which uses 4 early IAC infusions during conventional fractionation RT. 13,17 However, the optimal IAC RT regimen is not yet defined. 13,17,26 28 In contrast with RADPLAT, our protocol used accelerated RT and late intensification with only 2 IAC infusions during the RT boost to gross disease, aiming at overcoming accelerated tumor repopulation and reducing local RT toxicity. 27 The treatment was feasible, and all except 1 patient received both planned IAC doses. As defined by the study protocol, doselimiting toxicity occurred at the IAC dose level of 150 mg/m 2, and maximum tolerated dose was 125 mg/m 2. Dose-limiting toxicity manifested as manageable grade 4 leukopenia and slight delay in healing of acute skin reactions. Two previous studies reported that when used with altered fractionation RT, concurrent IAC at 150 mg/m 2 resulted in severe toxicity and fatal infective complications. 27,28 However, they did not have data on the efficacy of a lower IAC dose level. There were advantages to using only 2 IAC infusions with a lower total cisplatin dose instead of 4 infusions as in most other studies. Despite the use of sodium thiosulfate, grade 4 5 hematologic toxicity occurred in 17% and 20% of patients and treatment-related deaths in 2.8% and 3.8% of patients in 2 RADPLAT series. 29,30 In the present study, only 1 of 7 patients at the 2 highest dose levels experienced transient grade 4 leukopenia, and there was no treatment-related mortality. Besides, arterial catheterization related complications are expected to decrease by half with 2 IAC infusions. The RAD- PLAT protocol carries a 2.3% risk of permanent neurologic deficits related to arterial catheterization. 13 Each IAC infusion has an increased risk of developing neurologic complications compared with a diagnostic angiographic procedure because of possible introduction of air bubbles into the cerebral arterial system during chemotherapy infusion, longer catheter indwelling time allowing thrombus development, and cisplatin damage to arterial endothelial cells It should be noted that, although grade 3 hyponatremia was not included as dose-limiting toxicity in our study protocol, this adverse effect could result in serious morbidity or mortality. Grade 3 hyponatremia and hypomagnesium Accelerated RT and Intra-arterial Cisplatin HEAD & NECK DOI /hed July

6 Table 2. Maximum acute toxicity by dose level of intra-arterial cisplatin. Dose level 100 mg/m 2 (n ¼ 3), Dose level 125 mg/m 2 (n ¼ 3), Dose level 150 mg/m 2 (n ¼ 4), Factor Anemia Leukopenia * Neutropenia Thrombocytopenia Febrile neutropenia Infection with grade 3 or grade 4 neutropenia Infection without neutropenia Skin Oral mucosa Pharynx Larynx Nausea Vomiting Anorexia Renal Hyponatremia Hypomagnesemia Hepatic Neurological: sensory Neurological: motor Hearing * Patient 10 developed dose-limiting toxicity with grade 4 leukopenia and infection with grade 3 neutropenia, which resolved with intravenous administration of antibiotics. One of the patients (patient 9) had grade 3 skin reaction, which healed at 8.5 weeks after completion of radiotherapy. It was considered dose-limiting toxicity. should be included as dose-limiting toxicity in the design of future studies. Despite the use of accelerated RT in our protocol, treatment was well tolerated in most of the patients. The timing of IAC during the late cone-down boost to gross disease may explain the moderate but tolerable mucosal and cutaneous acute reactions that were observed. Only 1 patient, who received IAC at 150 mg/m 2 and the full radiation dose at skin surface for a fungating nodal mass, had slightly delayed healing of acute skin reactions. Although the event was counted as dose-limiting toxicity, it was of only little clinical significance. For in-field toxicities, Table 3. Maximum late toxicity by dose level of intra-arterial cisplatin. Dose level 100 mg/m 2 (n ¼ 3), Dose level 125 mg/m 2 (n ¼ 3)*, Dose level 150 mg/m 2 (n ¼ 4), Factor Skin Subcutaneous tissue Oral mucosa Pharynx/esophagus Larynx Eye Salivary gland Hypothyroidism Lung Neurological: sensory Neurological: motor Hearing *One patient at this dose level died at 4 months of follow-up before late treatment toxicity could be evaluated. 918 Accelerated RT and Intra-arterial Cisplatin HEAD & NECK DOI /hed July 2010

7 Patient Initial-arterial cisplatin dose level, mg/m 2 Primary site Classification Table 4. Treatment outcome. Initial locoregional tumor response after IAC RT Local failure at last follow-up Regional nodal failure at last follow-up Distant metastasis Disease status at last follow-up Follow-up, mo Oropharynx T3N1M0 CR þ DOD Larynx T3N0M0 CR ANED Oral cavity T4bN2M0 CR þ DOD Oropharynx T4bN2M0 SD þ þ DOD Oropharynx T4bN2M0 CR ANED Larynx T4aN2M0 CR DI (2nd BOT 30 carcinoma at 24 mo) Oropharynx T1N3M0 CR ANED Oral cavity T4bN0M0 CR ANED Oropharynx T2N3M0 CR ANED Hypopharynx T1N3M0 CR ANED 39 Abbreviations: IAC RT, intra-arterial cisplatin and radiotherapy; CR, complete response; DOD, died of disease; ANED, alive with no evidence of disease; SD, static disease; DI, died of disease; BOT, base of tongue. it would be difficult to differentiate the impact of radiation and cisplatin. Nevertheless, our protocol included severe in-field toxicities as doselimiting toxicity because it would be important to evaluate the adverse effects of the combined treatment. To our knowledge, only 1 previous RADPLAT study has correlated patient outcome with gross tumor volume. For patients with primary tumor volume > 19.6 cm 3, local control and overall survival rates at 30 months were 57% and 14%, respectively. 34 In a study using IV chemotherapy and RT, locoregional relapse free survival and overall survival rates at 28 months were 64.7% and 59.2%, respectively, for total tumor volume > 25 cm However, for patients with total tumor volumes > 110 cm 3, IV chemotherapy and RT resulted in 3-year locoregional control and overall survival rate of only 25% and 19% to 22%, respectively. 36,37 A recent randomized study comparing RADPLAT with IV cisplatin RT for advanced head and neck cancer showed that there was no significant difference in locoregional control and overall survival at 2 years between the treatment arms. 17 However, the study did not stratify the tumors by gross tumor volume to explore whether IA cisplatin RT was more efficacious than IV cisplatin RT for the more bulky tumors. Further studies on IA cisplatin are required to answer this important question. It is acknowledged that the results of our small phase I study were subject to variability in treatment delivery, patient tolerance to treatment, tumor biology, and responsiveness to treatment. Our report has provided data for planning a larger study to find the optimal RT IAC regimen for locally advanced HNSCC. We conclude that it is feasible to deliver 2 weekly IAC infusions during the last 2 weeks of accelerated fractionation RT for locally advanced HNSCC. The maximum tolerated dose of IAC was 125 mg/m 2. REFERENCES 1. Wolf GT, Forastiere A, Ang K, et al. Workshop report: organ preservation strategies in advanced head and neck cancer: current status and future directions. Head Neck 1999;21: Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004;350: Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350: Taylor SG, Murthy AK, Griem KL, et al. Concomitant cisplatin/5-fu infusion and radiotherapy in advanced head and neck cancer: 8-year analysis of results. Head Neck 1997;19: Adelstein DJ, Saxton JP, Lavertu P, et al. A phase III randomized trial comparing concurrent chemotherapy and radiotherapy with radiotherapy alone in resectable stage III and IV squamous cell head and neck cancer: preliminary results. Head Neck 1997;19: Pignon JP, Bourhis J, Domenge C, et al. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. Lancet 2000;355: Browman GP, Hodson DI, Mackenzie RJ, et al. Choosing a concomitant chemotherapy and radiotherapy regimen Accelerated RT and Intra-arterial Cisplatin HEAD & NECK DOI /hed July

8 for squamous cell head and neck cancer: a systemic review of the published literature with subgroup analysis. Head Neck 2001;23: Adelstein DJ, Saxton JP, Rybicki LA, et al. Multiagent concurrent chemoradiotherapy for locoregionally advanced squamous cell head and neck cancer: mature results from a single institution. J Clin Oncol 2006;24: Taylor SG, Murthy AK, Vannetzel J-M, et al. Randomized comparison of neoadjuvant cisplatin and fluorouracil infusion followed by radiation versus concomitant treatment in advanced head and neck cancer. J Clin Oncol 1994;12: Brockstein BE, Vokes EE. Chemoradiotherapy for head and neck cancer. In: Rosenberg SA, editor. Principles and practice of oncology updates, vol. 10. Philadelphia, PA: Lippincott-Raven; pp Marcial VA, Pajak TF, Mohiuddin M, 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: Kumar P, Robbins K, Harris J, et al. Intra-arterial (IA) cisplatin (P) and radiation therapy (RT) is feasible in a multi-institutional setting for the treatment of stage IV- T4 head/neck (H/N) squamous cell carcinoma (SCCa): initial results of Radiation Therapy Oncology Group (RTOG) trial Proc ASCO Robins KT, Kumar P, Wong FSH, et al. Targeted chemoradiation for advanced head and neck cancer: analysis of 213 patients. Head Neck 2000;22: Samant S, Robbins KT, Kumar P, et al. Bone or cartilage invasion by advanced head and neck cancer: intra-arterial supradose cisplatin chemotherapy and concomitant boost radiotherapy for organ preservation. Arch Otolaryng Head Neck Surg 2001;127: Kovacs AF, Turowski B, Ghahremani MT, et al. Intraarterial chemotherapy as neoadjuvant treatment of oral cancer. J Cran-Max Surg 1999;27: Abe R, Akiyoshi T, Koba F, et al. Two-route chemotherapy using intra-arterial cisplatin and intravenous sodium thiosulfate, its neutralizing agent, for hepatic malignancies. Eur J Cancer Clin Oncol 1988;24: Rasch C, Schornagel J, Kroger R, et al. Intra-arterial versus intravenous chemoradiation for advanced head and neck cancer: early results of a multi-institutional trial. Radiother Oncol 2006;81 (Suppl 1):S147 (abstract). 18. Overgaard J, Sand Hansen H, Sapru W, et al. Conventional radiotherapy as the primary treatment of squamous cell carcinoma (SCC) of the head and neck. A randomized multicenter study of 5 versus 6 fractions per week: preliminary report from the DAHANCA 6 trial. Radiother Oncol 1996;40 (Suppl 1):S31 (abstract). 19. 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 Int J Radiat Oncol Biol Phys 2000;48: Ang KK, Thames HD, Peters LJ. Altered fractionation schedules. In: Perez CA, Brady LW, editors. Principles and practice of radiation oncology, 3rd edition. Philadelphia, PA: Lippincott-Raven; pp Horiot JC, Bontemps P, van den Bogaert W, et al. Accelerated fractionation (AF) compared to conventional fractionation (CF) improves loco-regional control in the radiotherapy of advanced head and neck cancers: results of the EORTC randomized trial. Radiother Oncol 1997;44: Wendt TG, Grabenbauer GG, Rodel CM, et al. Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicenter study. J Clin Oncol 1998;16: Dobrowsky W, Naude J, Widder J, et al. Continuous hyperfractionated accelerated radiotherapy with/without mitomycin C in head and neck cancer. Int J Radiat Oncol Biol Phys 1998;42: Garden AS, Glisson BS, Ang KK, et al. Phase I/II radiation with chemotherapy boost for advanced squamous cell carcinomas of the head and neck: toxicities and responses. J Clin Oncol 1999;17: Corry J, Rischin D, Smith JG, et al. Radiation with concurrent late chemotherapy intensification ( chemoboost ) for locally advanced head and neck cancer. Radiother Oncol 2000;54: Yoshizaki T, Wakisaka N, Murono S, et al. Intra-arterial chemotherapy less intensive than RADPLAT with concurrent radiotherapy for resectable advanced head and neck squamous cell carcinoma: a prospective study. Ann Otol Rhinol Laryngol 2007;116: Regine WF, Valentino J, Arnold SM, et al. High-dose intra-arterial cisplatin boost with hyperfractionated radiation therapy for advanced squamous cell carcinoma of the head and neck. J Clin Oncol 2001;19: Foote RL, Kasperbauer JL, Okuno SH, et al. A pilot study of high-dose intraarterial cisplatin chemotherapy with concomitant accelerated radiotherapy for patients with previously untreated T4 and selected patients with T3N0 N3M0 squamous cell carcinoma of the upper aerodigestive tract. Cancer 2005;103: Robbins KT, Kumar P, Harris J, et al. Supradose intraarterial cisplatin and concurrent radiation therapy for the treatment of stage IV head and neck squamous cell carcinoma is feasible and efficacious in a multi-institutional setting: results of Radiation Therapy Oncology Group Trial J Clin Oncol 2005;23: Balm AJ, Rasch CR, Schornagel JH, et al. High-dose superselective intra-arterial cisplatin and concomitant radiation (RADPLAT) for advanced head and neck cancer. Head Neck 2004;26: Waugh JR, Sacharias N. Arteriographic complications in the DSA era. Radiology 1992;182: Heiserman JE, Dean BL, Hodak JA, et al. Neurologic complications of cerebral angiography. AJNR 1994;15: Gemmete JJ. Complications associated with selective high-dose intraarterial cisplatin and concomitant radiation therapy for advanced head and neck cancer. J Vasc Interv Radiol 2003;14: Doweck I, Denys D, Robbins KT. Tumor volume predicts outcome for advanced head and neck cancer treated with targeted chemoradiotherapy. Laryngoscope 2002;112: Chufal KS, Rastogi M, Srivastava M, et al. Analysis of prognostic variables among patients with locally advanced head and neck cancer treated with late chemointensification protocol: impact of nodal density and total tumor volume. Jpn J Clin Oncol 2006;36: Rudat V, Dietz A, Schramm O, et al. Prognostic impact of total tumor volume and hemoglobin concentration on the outcome of patients with advanced head and neck cancer after concomitant boost radiochemotherapy. Radiother Oncol 1999;53: Grabenbauer GG, Steininger H, Meyer M, et al. Nodal CT density and total tumor volume as prognostic factors after radiation therapy of stage III/IV head and neck cancer. Radiother Oncol 1998;47: Accelerated RT and Intra-arterial Cisplatin HEAD & NECK DOI /hed July 2010