This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Knisely, J. Search for Related Content PubMed PubMed Citation Articles by Knisely, J. Social Bookmarking                            What's this?

Conformal Radiotherapy for High-Grade Gliomas: How Much Is Too Much?

Yale University School of Medicine, New Haven, CT

To the Editor:The March 15, 2002, issue of the Journal of Clinical Oncology contained an article by Chan et al¹ that draws conclusions that I believe are untenable from the data presented. In the study that was reported, an ongoing dose escalation protocol for glioblastoma multiforme was reported, in which the contrast-enhancing tumor was treated to a dose of 90 Gy using sophisticated, state-of-the-art treatment planning and delivery techniques. They claim to have demonstrated localized tumor recurrence despite this treatment. It would seem that they have only demonstrated that external-beam irradiation to 90 Gy can cause blood-brain barrier abnormalities in the high-dose volume.

In the Patients and Methods section, the determination of failure (progression of tumor) was made by visual inspection of computed tomography or magnetic resonance imaging studies. For the purposes of the study, failure was deemed to have occurred when one of three events occurred: (1) an increase in the volume of 25% or 10 cm² (I presume they mean 10 cm³), (2) the reappearance of a lesion that had previously had a complete response, or (3) the appearance of any new lesions. These criteria cannot possibly determine for the vast majority of their reported cases whether the contrast enhancement is from radiation necrosis or from recurrent tumor.

If a lesion that has been treated with very high-dose irradiation is increasing in size, it may be from radiation necrosis rather than from progressive tumor. If a lesion reappears after complete response to treatment, it may be a delayed side effect on late-reacting stromal cells that leads to radiation necrosis-induced blood-brain barrier breakdown. Only new lesions appearing outside the high-dose volume provide almost incontrovertible evidence of progression, and they had a very low percentage of patients who developed failures outside the high-dose volume.

No data are provided by the authors on the number or proportion of patients who had additional invasive treatment (for whom a tissue confirmation of recurrent tumor should be possible). Surprisingly, the authors seem to have used additional radiosurgery or brachytherapy for some patients in whom the radiographically evident lesion may very well have been from radiation injury.

It is nearly impossible to tell, even for skilled observers, whether contrast enhancement after high-dose irradiation of a glioma is from tumor progression or from radiation necrosis.² Radiation necrosis is dependent on the volume that is treated and the dose that is delivered.³ Large volumes, such as are shown in the figures, treated to doses fully 50% above the standard dose of 60 Gy in 30 fractions are very likely to have treatment-related necrosis develop.

The careful attention to technique has apparently spared study subjects any overt injury. There is possible evidence, however, of subtle injury to the patients enrolled onto these studies. No hint of a survival advantage has appeared with spending an additional 3 weeks on treatment; median survival has decreased with each increase in dose from 70 Gy to 80 Gy, and now to 90 Gy. Could this be evidence of treatment-related harm?

I have concerns about the authors’ stated plans in the Discussion section for further dose escalation that includes a higher daily dose of radiation. In addition to using jargon in this section, which is most certainly nonstandard ("biogray"), the planned increase in the dose per fraction delivered to the tumor is almost certainly going to increase the likelihood of harm to study subjects. As gliomas are infiltrating tumors, there is going to be normal brain tissue treated with higher daily doses of radiation, which will ultimately be more likely to cause injury in any patients who may survive long enough to have injury expressed.

As regards their plans for monitoring their patients with noninvasive imaging studies, there has heretofore been a great deal of uncertainty about the actual sensitivity and specificity of any positron emission tomography or single-photon emission computed tomography findings in patients treated with high-dose radiation for gliomas.^4,5 Without pursuing tissue confirmation of the presence or absence of recurrent tumor in such a cohort of patients, how can noninvasive studies with uncertain sensitivity and specificity help guide therapeutic decisions?

REFERENCES

1. Chan JL, Lee SW, Fraass BA, et al: Survival and failure patterns of high-grade gliomas after three-dimensional conformal radiotherapy. J Clin Oncol 20: 1635-1642, 2002[Abstract/Free Full Text]

2. Schultheiss TE, Kun LE, Ang KK, et al: Radiation response of the central nervous system. Int J Radiat Oncol Biol Phys 31: 1093-1112, 1995[CrossRef][Medline]

3. Marks JE, Baglan RJ, Prassad SC, et al: Cerebral radionecrosis: Incidence and risk in relation to dose, time, fractionation, and volume. Int J Radiat Oncol Biol Phys 7: 243-252, 1981[Medline]

4. van der Hiel B, Pauwels EK, Stokkel MP: Positron emission tomography with 2-[18F]-fluoro-2-deoxy-D-glucose in oncology: Part IIIa. Therapy response monitoring in breast cancer, lymphoma and gliomas. J Cancer Res Clin Oncol 127: 269-277, 2001[CrossRef][Medline]

5. Samnick S, Bader JB, Hellwig D, et al: Clinical value of iodine-123-alpha-methyl-L-tyrosine single-photon emission tomography in the differential diagnosis of recurrent brain tumor in patients pretreated for glioma at follow-up. J Clin Oncol 20: 396-404, 2002[Abstract/Free Full Text]

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Knisely, J. Search for Related Content PubMed PubMed Citation Articles by Knisely, J. Social Bookmarking                            What's this?