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Chapter 29 Chemical Modifiers of Radiation Response

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B Figure 29.5.  Confluent mucositis induced by concurrent chemoradiation in the base of tongue and supraglottic larynx regions. A: Demonstrates normal mucosa prior to the initiation of treatment. B: Demonstrates the pseudomembranous exudate, hemorrhage, and edema that are charac- teristic of this condition.

74 Gy. The study design may thus explain the discordance between the improvement in the anatomic assessment of mucosal integrity associated with benzydamine and the lack of any functional benefit, as the latter parameters were assessed throughout a patient’s entire course of RT. The most severe mucositis during a course of head and neck RT occurs beyond the 50 Gy level. Fewer than 10% of the patients enrolled in this trial received concurrent chemotherapy, even though most of them had stage III or IV disease. Concurrent CRT has become the standard of care for most patients with this extent of dis- ease. Consequently, the clinical value of benzydamine has not been proven for patients receiving high-dose RT with or with- out concurrent chemotherapy. Endogenous oral flora may exacerbate the mucosal inflam- matory process once the mucosal integrity is disrupted. Secondary infections may prolong the course of mucositis and compromise overall patient well-being. Protegrins are natu- rally occurring peptides that have broad-spectrum antimicro- bial activity. 116 Iseganan is a synthetic analog of this class of compounds. A placebo-controlled trial in patients receiving chemotherapy suggested that iseganan reduced the incidence of ulcerative stomatitis and decreased both mouth pain and swallowing difficulty. 117 A phase III double-blind, placebo-controlled trial was sub- sequently conducted to test this concept in patients receiving head and neck RT. 118 This trial mandated that a minimum dose of 60 Gy be delivered but allowed different fractionation schemes. Forty percent of the patients enrolled received con- current chemotherapy. The study contained three treatment arms: standard-of-care (SOC) oral hygiene only, placebo plus SOC, and iseganan plus SOC. Iseganan and placebo were equivalent to one another with respect to all end points in the trial. Interestingly, both iseganan and placebo arms were supe- rior to SOC oral hygiene alone. Two-thirds of the patients in both arms had confluent mucositis compared with 79% in the SOC alone arm ( P = .02). Only 2% of the SOC patients had no mucosal ulceration versus 9% in both the iseganan and pla- cebo arms ( P = .04). Peak mouth pain and difficulty swallowing were also significantly worse for the patients assigned to SOC alone. RT dose reductions were also significantly more com- mon in the SOC patients. The iseganan trial showed no benefit from the administra- tion of the study drug. It did, however, reveal the importance of

and fungal overgrowth are thought to exacerbate the local pathophysiology. Sucralfate, a basic aluminum salt of sucrose, is used in the treatment of peptic ulcer disease. It provides a protective coat- ing to ulcerated tissue by means of binding to exposed proteins in damaged cells. 109 It also stimulates mucus production, mito- sis, and surface migration of cells. Sucralfate has been tested in several double-blind placebo-controlled randomized trials. Despite the attractive conceptual nature of using it to amelio- rate mucositis, the clinical data do not show any benefit from sucralfate. 1,110–112 Benzydamine hydrochloride is a nonsteroidal anti-inflam- matory drug that also possesses antimicrobial activity. 113 It is a potent inhibitor of TNF- α . 114 Expression of this proinflamma- tory cytokine is up-regulated in mucosal tissue of the head and neck regions, with peak levels typically at approximately 20 Gy (conventionally fractionated) just prior to the first signs of mucosal ulceration. The ability of benzydamine to reduce mucositis during head and neck RT was tested in a random- ized double-blind placebo-controlled trial. 115 The primary end point of this trial was the area under the curve for the mean mucositis score over a cumulative RT dose up to a total dose of 50 Gy. Secondary end points included use of concomitant pain medication, oral pain at rest and with eating, body weight, and the use of enteral nutritional support. Benzydamine therapy resulted in a 30% reduction in mucosal erythema and ulceration. Most of this benefit was observed once doses > 25 Gy had been delivered. One-third of the benzydamine patients did not develop any mucosal ulceration, compared with only 18% of the placebo-treated patients ( P = .04). There was a nonsignificant trend toward reduction in mouth pain at rest for the patients who received benzydamine. Importantly, benzyda- mine was no more effective than placebo with respect to the reduction of pain during meals. Cumulative weight loss during RT was equivalent in the two treatment groups. There was no differ- ence in the proportion of patients who required enteral nutri- tional support between the two treatment arms. The data from the benzydamine trials suggest that this agent is active against mucositis but are inconclusive regarding whether it has any clinical role in treating this condition. There was no significant benefit regarding the functional sequelae of mucositis. Mucosal assessment was not performed beyond 50 Gy, and most patients received radiotherapy doses of 64 to

Techniques, Modalities, and Modifiers in Radiation Oncology