Dr. Nag and colleagues provide an overview of brachytherapy, describe its application in pediatric oncology, and review the clinical experience in childhood solid tumors. The limited number of publications includes Dr. Nags own important, innovative clinical research using remote afterloading high-dose-rate (HDR) brachytherapy with twice-daily fractions in children with sarcoma.
Advantages and Disadvantages of Brachytherapy in Children
In children, brachytherapy in general and remote afterloading HDR brachytherapy in particular have several advantages. They include: the elimination of potential radiation risks to parents and hospital caregivers; the feasibility of outpatient therapy; reduced fraction number and, hence, reduced episodes of anesthesia; restricted treatment volume; elimination (or dose reduction) of external-beam radiotherapy; potentially greater acceptance than external-beam radiotherapy by parents; and the potential for preservation of form and function.
The last advantage has not been carefully addressed in the literature. The limited experience with pediatric brachytherapy, the diversity of anatomic sites to which it has been applied, and the difficulty in quantifying cosmetic and functional morbidity have precluded such an analysis.
Nevertheless, anecdotal reports confirm the preservation of form and function in pediatric patients where its loss would be assumed were surgery or external-beam radiotherapy employed. An example reported by French investigators is the birth of normal infants after gynecologic brachytherapy.
The main disadvantage of pediatric brachytherapy is its applicability to only a small proportion of patients. In turn, the practice of pediatric brachytherapy is limited by the small number of radiation oncologists with sufficient experience and expertise.
Dose and Volume Issues
Pediatric brachytherapy challenges our understanding of treatment planning in several critical areas. The first is the concept of biological dose. Much remains to be learned about how to convert a standard external radiotherapy dose to a low-dose-rate (LDR) or HDR implant in children. Similarly, when brachytherapy is given as part of a course that will later include fractionated external-beam irradiation, the safe and effective dose of each modality when combined is uncertain.
The practice of pediatric brachytherapy raises several treatment volume issues. First, Dr. Nag and colleagues demonstrate a substantial volume increment in their illustrations (Figure 1 and Figure 2) for an external-beam conformal plan compared to a hypothetical brachytherapy plan. Although it will almost always be true that a brachytherapy plan will treat the smaller planning target volume (PTV), the illustration suggests a difference that would be unlikely to occur in an actual patient. The PTV for external beam is usually only an increment of 5 to 10 mm beyond the margin that describes the clinical target volume (CTV).
Second, volume selection for pediatric brachytherapy requires determination of tumor response to the induction chemotherapy that typically precedes radiation therapy for most childhood sarcomas. Foci of occult tumor surround sarcomas. Historically, radiotherapy guidelines developed by the Intergroup Rhabdomyosarcoma Study (IRS) have recommended 5 cm and, more recently, 2 cm beyond the gross tumor volume (GTV) to determine the CTV. The issue for assessing implant volume (or delayed surgical resection volume) after chemotherapy-induced response is whether or not there has been a corresponding contraction of the CTV. In other words, does a partial response of gross tumor imply a complete response of all or part of the initial occult disease volume (the CTV)? Data to support this contention are lacking, and therefore the initial brachytherapy PTV should not be based on the post-chemotherapy tumor volume.
In an earlier report, Nag et al argue for the use of the post-chemotherapy volume, however, based on 12 patients, 6 in IRS clinical group I or II, and 5 in group III, of whom 4 had post-induction surgery to achieve microscopic residual status. For the group I and II patients, there is no opportunity to assess response and, therefore, no question about response-based volume reduction. For the group III patients, data for tumor volumes at diagnosis and at time of implant are not given.
For a selected patient population of median age 18 months, one may presume that the initial volumes were small both by relative (age-related) and absolute criteria, and that, therefore, tumor volume reduction by chemotherapy was small in absolute terms; meaning that the impact on the implant volume may have been minimal. The presence of residual post-chemotherapy (or post-surgery) gross tumor raises concern over the volume occupied by occult disease, and Dr. Nag rightly argues for larger volume implants or supplementary external-beam radiation therapy to achieve an appropriate CTV in this circumstance.
The most challenging aspect of pediatric brachytherapy is patient selection. Dr. Nag and colleagues recommend that pediatric patients selected for brachytherapy alone should have only microscopic or small-volume residual disease following an initial surgical procedure or a second-look resection, or should have a good response to induction chemotherapy. In addition, such patients should have accessible tumor sites: head and neck (but generally not orbit and parameningeal sites); genitourinary sites; and small lesions of the chest wall, abdominal wall, and extremities.
Very young age and small primary tumor size may be correlated. Conventional radiation therapy techniques may not allow sufficient volume restriction for such lesions, and, therefore, as the experience of Nag et al indicates, very young age is also a selection factor that potentially favors brachytherapy. Conformal approaches would facilitate smaller volumes but have the disadvantage of requiring daily anesthesia for the very young patient.
An early experience with brachytherapy for parameningeal rhabdomyosarcoma suggests that the aforementioned selection criteria might be expanded. Investigators at the University of Amsterdam have managed 15 such patients with postinduction surgery and intraoperative placement of a cavity-conforming mold (which accommodates afterloaded catheters using iridium-192) to treat the tumor bed. The goal of this approach is to reduce the craniofacial sequelae of radiotherapy. More patients and longer follow-up are required to determine whether this goal is accomplished without a decrement in the very good local control rate accomplished with conventional radiation therapy or the potentially reduced morbidity promised by conformal therapy.
Opportunity for Further Investigation
Finally, radiation oncologists who manage pediatric patients should anticipate that the forthcoming merger of the four pediatric clinical cooperative trials groups will afford a timely opportunity to investigate the potential benefits of brachytherapy and other newer radiotherapy technologies in children with solid tumors.