Familial Nasopharyngeal Carcinoma 6

162 J. S. Cooperdegree the failure reflected limitations of the techniquesthen available. Larger tumors of any type aremore difficult to control than smaller ones with radiationtherapy. And, inadequate radiation therapy certainlyhas a direct effect on local and regional disease.Perhaps less obvious, there is data to suggest thatinadequate radiation therapy, which leads to localrecurrence, is also associated with a higher risk ofdistant dissemination, i.e., suggesting that local recurrencescan metastasize (Leibel et al. 1991). It is thereforeappropriate to review the previous limitations ofradiation therapy as a way of understanding how theyinfluenced outcome in the pre-chemotherapy era.12.3Radiotherapy Evolution: From 2½Dto 3D to IMRTRadiation therapy for nasopharyngeal cancer, historically,was delivered from two lateral fieldsdesigned to include the primary tumor and upperneck nodes mated to one anterior (low volumetumor) or opposed anterior and posterior (high volumetumor) lower neck portal(s). The margins of thebeams were defined by normal anatomy and clinicallyvisible and/or palpable disease. With the availabilityof CT scanners (and then MRI scanners), agreater appreciation of the extent of disease was possibleand by the late-1980s, the 3D information fromthese diagnostic scans was routinely incorporatedinto the 2D fluoroscopically designed radiation therapyportals, creating so-called 2½D treatment plans.This was the state of the art when the Intergroup0099 trial was designed.Delivering a relatively cancericidal dose to a pointin the middle of the nasopharynx has been possiblefor many years. The lateral diameter of the face poseslittle challenge to megavoltage beams. Doses ofapproximately 70Gy, still the current standard, couldbe delivered once Cobalt-60 machines became widelyavailable one half-century ago. However, that dosewas not immediately adopted everywhere and as lateas 1988, the journal Cancer considered worthy ofpublication the results of Wang et al. (1988), whichdemonstrated superior overall survival (OS) associatedwith doses greater than 4,000 rad. In fact, somedata suggested that some tumors needed to be treatedmore intensively than 70Gy. In Boston, Wang (1989)used accelerated hyperfractionation to treat 60patients who had nasopharyngeal cancers andreported better local control than was obtained followingconventionally fractionated radiation 5-yearsearlier at the same institution. He also began (Wang1991) to add a 10-15Gy intracavitary boost andreported even better local control in some patients.In the same era, the physicians at Stanford Universitybegan to investigate the use of stereotactic radiosurgeryto boost the dose delivered to the nasopharynxand reported (Cmelak et al. 1997) that 11 of 11patients who received radiosurgery as a nasopharyngealboost after standard fractionation radiotherapyremained locally free of disease with follow-up rangingfrom 2 to 34 months. However, in retrospect, theinterpretation of these findings may have been partiallyincorrect.More important than the 2½D mid-plane dosedelivered in the nasopharynx, the proximity of thebrainstem and the spinal cord sometimes limited thedose that could be delivered homogeneously tothe entire tumor when the tumor approached theserelatively radiosensitive structures. The technology todo true 3D, CT-simulator-based planning and 3D conformaltreatment delivery was not commonly availablewhen the Intergroup study was conducted. Thisraises the possibility that the reported effectiveness oftechniques to make radiation therapy more effectivethan 2½D planned, 70Gy delivered once daily over 7weeks reflects (a) true resistance to that dose, (b) serendipitouslybringing the dose in “cold spots” withinthe tumor to at least 70Gy equivalent, or (c) a combinationof (a) and (b).12.3.1Target Localization LimitationsThe quality of the CT scans (and when available MRIscans) of the late-1980s also was not equal to thosecommonly available today. The number of detectorsper machine was fewer, the scan times longer (andtherefore more susceptible to patient movement) andthe clarity of the scans worse. Yet, that was the bestinformation available.12.3.2State of the Art Circa 1980Hampered by the limitations of the technology (bothfor detection and treatment) that was available, theprospect for locoregionally advanced nasopharyngealcarcinoma treated solely by radiation therapy