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Section II Techniques, Modalities, and Modifiers in Radiation Oncology

Tirapazamine (also known as SR-4233; WIN 59075; 3-amino- 1,2,4-benzotriazine 1,4-dioxide) is a bioreductive agent prefer- entially cytotoxic to hypoxic cells in vitro. Twenty-five to 200 times more drug is required to produce the same level of cell killing in aerobic compared to anaerobic conditions. 61,62 Under hypoxic conditions, a free radical one-electron reduction prod- uct rapidly forms and is believed to be the toxic species, causing oxidative damage to pyrimidines and inducing DNA strand breaks. 63 Analysis of DNA and chromosomal breaks following hypoxic exposure to tirapazamine suggests that DNA double- strand breaks are the primary lesions involved in cell death. This bioreductive agent differs from oxygen-mimetic sensi- tizers, such as the nitroimidazoles, in that it is itself cytotoxic to hypoxic tissues. Therefore, unlike the oxygen-mimetic sensitiz- ers, tirapazamine-mediated therapeutic enhancement occurs whether the drug is given before or after irradiation. 64,65 In frac- tionated radiation therapy of murine tumors, tirapazamine is as effective as, if not superior to, etanidazole. 66 The efficacy of this radiation modifier depends on the number of “effective doses” that can be administered during a course of radiation therapy and the presence of hypoxic tumor cells. 67 Tirapazamine can also enhance the cytotoxicity of cisplatin. 68 Rischin et al. 69 investigated the use of concurrent tirapaza- mine, cisplatin, and RT in advanced head and neck cancer in a series of trials. A phase I trial established the dosing schedule for tirapazamine given with RT and cisplatin. A randomized phase II study compared RT with cisplatin/tirapazamine versus RT with cisplatin/5-FU and suggested a benefit in the tirapaza- mine treatment arm (3-year local regional failure-free survival 84% vs. 66%; P = .07). 70 Tumor hypoxia imaging was performed with 18-fluorodeoxyglucose-misonidazole positron emission tomography (PET) scanning in 45 of the patients on these studies. 71 Hypoxia was identified in primary or nodal sites in 71% of the patients. Eight of 13 (62%) patients with hypoxic tumors who received cisplatin/5-FU experienced subsequent local-regional failure compared to only 1 of 19 (5%) patients with hypoxic tumors who received tirapazamine (hazard ratio [HR] = 15; P = .001). Only 1 of 10 patients with nonhypoxic tumors who received cisplatin/5-FU had a local-regional failure. These find- ings strongly suggested that the benefit of tirapazamine resulted from improved treatment efficacy against tumor hypoxia. Two phase III trials were initiated to validate the use of tira- pazamine in head and neck cancer. The HeadSTART study enrolled 861 patients and compared standard fractionation RT (70 Gy) with concurrent cisplatin/tirapazamine versus concur- rent cisplatin alone. 72 The primary end point was overall sur- vival, with 2-year rates of 65.7% in the cisplatin alone arm and 66.2% in the cisplatin/tirapazamine cohort. No differences were seen in failure-free survival, time to locoregional failure, or quality of life. Of note, the patients in this study were not selected based on the presence of tumor hypoxia. Moreover, 12% had major RT planning deficiencies, with those patients having significantly worse locoregional control and overall sur- vival compared to those in protocol compliance. 73 A second trial with a planned enrollment of 550 patients was closed early due to excess number of deaths in the cisplatin/tirapazamine arm. 74 Biologic Modifiers of Radiation Response Overexpression of the epidermal growth factor receptor-1 (EGFR-1) is associated with an adverse outcome in squamous head and neck cancer. 75 Cetuximab (C225) is a chimeric mono- clonal antibody to EGFR. Preclinical studies have demonstrated that cetuximab sensitizes cells to the cytotoxic effects of ioniz- ing irradiation. 76,77 Preliminary studies demonstrated that this drug could be safely administered in conjunction with a course of RT for head and neck cancer. 78 An open-label phase III trial tested the impact of weekly injections of cetuximab added to a course of RT alone. 79 Most patients received accelerated frac- tionation with concomitant boost, although hyperfractionation and standard fractionation schemes were also permitted. Oral

cavity primary tumors were ineligible for enrollment. Two-year local regional increased from 48% with RT to 56% with RT and cetuximab ( P = .02). The initial survival advantage seen with the addition of cetuximab to RT has persisted, with updated 5-year overall survival rates of 45.6% versus 36.4% ( P = .018). 80 This trial provided an important proof of principle that add- ing a biologically targeted agent to a physically targeted modal- ity improved therapeutic outcome. One-third of the patients enrolled had stage III disease, however, and thus had less advanced disease with more favorable prognoses than a sig- nificant proportion of patients who typically undergo chemora- diotherapy (CRT). A more favorable prognosis and improved treatment response has also been seen in patients with oro- pharyngeal squamous cell cancers associated with the human papillomavirus (HPV). 81 Whether RT with cetuximab is as effective or less toxic than RT with cisplatin in this select popu- lation is being examined by the phase III RTOG-1016 study. A separate phase III study, RTOG-0522, randomized patients with locally advanced head and neck cancer to receive RT and concurrent cisplatin with or without cetuximab. Results of the study were presented at the American Society of Clinical Oncology annual meeting in 2011. 82 Treatment intensification with the addition of cetuximab to CRT did not improve 2-year progression-free or overall survival. Subset analyses of HPV- positive and HPV-negative patients are currently being per- formed. Still, EGFR inhibition remains a very active area of investigation in head and neck cancer. Agents currently in clin- ical trial include fully humanized monoclonal antibodies and orally administered small molecule inhibitors of the tyrosine kinase domains of the EGFR family of receptors. Chemical Radioprotection The protection of normal tissues from the deleterious effects of radiation is a critical component in the development of a com- prehensive treatment plan. Strategies for the accomplishment of this aim include the physical manipulation of the beam, modification of the fractionation schedule, and pharmacologic manipulation of the radiation response. Physical radiation pro- tection rests on the principle of exclusion of normal tissue from the high-dose region and may be accomplished by contouring the shape of the radiation beam, the use of multiple treatment fields, the use of different beam energies, and modulation of the dose delivery from each beam (intensity-modulated radia- tion therapy [IMRT]). Modified fractionation typically uses multiple fractions of treatment per day as opposed to the con- ventional once daily paradigm in order to exploit the differ- ing radiation repair capabilities of normal tissues as opposed to tumors. Physical modification of the treatment beam and altered fractionation are discussed elsewhere. Protection Pharmacologic radioprotection itself can be classified into three categories: protection, mitigation, and treatment. The direct cytotoxicity of ionizing irradiation results from the gen- eration of free radicals that cause DNA strand breaks and lead to mitotic cell death. Amifostine (WR2721; Ethyol, Medimmune Inc, Gaithersburg, MD) is the prototype pharmacologic radio- protector that functions via free radical scavenging. Amifostine is a thiol containing pro drug that preferentially accumulates in the kidneys and salivary glands where it is metabolized to its active moiety, WR1065. 83 An open-label phase III randomized trial was conducted from 1995 to 1997 to assess the ability of this drug to reduce the incidence of grade 2 or higher acute and late xerostomia and grade 3 or higher acute mucositis. 84 Patients enrolled in this trial received curative intent or adjuvant postoperative irradiation without concurrent chemotherapy. All treatment was delivered with conventional once daily fractionation of 1.8