8-A842A-2018-Multiple-00021-Chapter 29-ROUND-2

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Section II Techniques, Modalities, and Modifiers in Radiation Oncology

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bladder, 14 and skin 15 showed no benefit from the addition of HBO. Randomized trials conducted in carcinoma of the cervix 16 and head and neck 17,18 did, however, show improvements in locoregional control and overall survival. The cumbersome logistics associated with HBO delivery in conjunction with RT necessitated the utilization of nonconventional hypofraction- ated treatment regimens. This reality has prevented HBO from being incorporated into routine clinical use. Carbogen (95% oxygen [O 2 ]/5% carbon dioxide [CO 2 ]) breathing, with or without concurrent nicotinamide adminis- tration, has also been utilized in attempts to improve tumor oxygenation and enhance RT response. The rationale for CO 2 addition in the gas breathing mixture is the generation of a mild acidosis that right shifts the oxyhemoglobin association curve, facilitating more unloading of oxygen into the most hypoxic tissues. The rationale for adding nicotinamide, a vita- min B derivative, is based on preclinical studies showing enhancement of tumor blood flow. 19,20 Polarographic electrode assessments in cervix and head and neck cancer have demon- strated that carbogen breathing and nicotinamide administra- tion improve tumor oxygenation in some patients. 21–23 A randomized trial of hyperfractionated RT with or without carbogen was conducted at the University of Florida from 1996 to 2002. 24 The study included patients with T2 to T4 squamous cell carcinoma of the oropharynx, larynx, and hypopharynx and was designed to detect a 20% improvement in 2-year local con- trol in the carbogen arm relative to the RT alone arm, with a 15% improvement in 4-year cause-specific survival. Virtually all enrolled patients in both arms completed their prescribed courses of treatment. The addition of carbogen to RT did not appear to improve any of the planned end points of this trial. Most important, however, was the fact that while the design of this trial called for the enrollment of 675 patients, only 101 were entered over a 5-year period. The trial was therefore significantly underpowered in terms of its ability to detect the desired treat- ment effects. The inability to accrue patients, however, also called into question the overall viability of strategies utilizing carbogen. The use of accelerated RT with carbogen and nicotinamide was tested in a phase II trial of 215 head and neck cancer patients. 25 Ninety-seven percent had stage III or IV disease, and the primary tumor site was laryngeal in 46%, hypopharyngeal in 23%, and oropharyngeal in 23%. Full compliance with carbo- gen breathing during RT was obtained in 88% of patients. Nicotinamide was administered 1 to 1.5 hours prior to RT at 60 to 80 mg/kg. Nicotinamide-induced nausea and vomiting neces- sitated discontinuation of the drug in 10% of patients receiving the lower dose and 31% of patients receiving the higher dose. Five-year locoregional control rates were 48% for hypopharynx primaries, 77% for larynx and 72% for oropharynx primaries. 26 Allosteric modifiers of hemoglobin structure have been identified that can shift the oxyhemoglobin dissociation curve to the right and increase O 2 delivery to hypoxic tissues. 27 One such compound, RSR-13 (efaproxiral) has been tested in ani- mal models and shown to improve tumor oxygenation 28 and enhance the effectiveness of RT. 29 A phase III open label trial of whole-brain RT and oxygen breathing with or without daily infusion of efaproxiral was conducted in 538 patients with brain metastases. 30 Fifty-four percent of the patients had meta- static non–small cell lung cancer and 20% had metastatic breast cancer. Overall, no improvement in survival was detected. A planned subset analysis suggested significant improvement in median survival time in breast cancer patients with sufficient levels of efaproxiral in their erythrocytes. 31 However, the phase III ENRICH trial, which examined efaproxiral and supplemental oxygen with whole-brain radiotherapy in breast cancer patients with brain metastases, showed no significant difference in overall survival. 32 Anemia is a very powerful adverse prognostic factor in vari- ous malignancies, including carcinomas of the lung, 33 cervix, 34 and head and neck. 35–37 Polarographic electrode oxygen

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Figure 29.2.  The correlation between pretreatment head and neck tumor oxygenation and local-regional disease control after radiotherapy with or without concurrent chemother- apy. Dashed line represents tumor median partial pressure of oxygen (Po 2 ) > 10 mm Hg. Solid line represents tumor median Po 2 < 10 mm Hg.

Clinical data clearly demonstrate the existence of tumor hypoxia in head and neck cancer 4,5 and extremely strong cor- relations between hypoxia and both in-field treatment failure and overall survival (Figs. 29.2 and 29.3). 6 This effect is inde- pendent of presenting stage of disease. 7 Tumor hypoxia has also been correlated with local and distant recurrence in carci- noma of the cervix treated with surgery 8,9 or RT 10 and with distant failure in soft tissue sarcomas treated with surgery and adjuvant RT. 11 Augmentation of Tumor Oxygenation Therapeutic attempts to overcome the deleterious effect of tumor hypoxia have followed three general lines of investiga- tion: increased delivery of oxygen to tumor, preferential sensiti- zation of hypoxic cells with oxygen mimetic agents, or cytotoxic agents that selectively target hypoxic tumor cells. Hemoglobin concentration is the major determinant of the oxygen delivery capability of blood to tissue. Hemoglobin oxygen saturation exceeds 90% when the arterial P o 2 is > 70 mm Hg. Still, oxygen is relatively insoluble in plasma under normobaric conditions. Under hyperbaric conditions, considerable quantities of oxy- gen can be dissolved into plasma and thus be potentially avail- able for delivery to hypoxic tissues. Clinical trials of hyperbaric oxygen (HBO) and RT were con- ducted from the 1950s to the 1970s. Trials conducted in patients with cancers of the central nervous system, 12 lung, 13

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Figure 29.3.  The correlation between pretreatment head and neck tumor oxygenation and local-regional disease control after radiotherapy with or without concurrent chemother- apy. Dashed line represents tumor median partial pressure of oxygen > 10 mm Hg.