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Radiotherapy Dose Escalation in High-Grade Gliomas

Evanston Northwestern Health Care, Evanston, IL

To the Editor:The article by Chan et al¹ in the March 15, 2002, issue of the Journal of Clinical Oncology shows the continued lack of measurable progress in the treatment of high-grade gliomas with radiotherapy. The study used both dose escalation and intensity-modulated radiotherapy, yet failed to show improvement in median, 1-year, or 2-year survival when compared with prior studies.

We are skeptical about the authors’ concluding sentence that "further dose escalation may prove to be beneficial in this setting." When comparing the group of patients treated to 90 Gy with the prior subsets of patients treated to 70 and 80 Gy, median, 1-year, and 2-year survival all decreased with increasing dose (although not statistically significant). Patterns of recurrence do not seem to have been affected by dose escalation.

The sequelae of nonstandard radiotherapy are likely to be late effects, only seen in those patients who survive long enough. It is likely that dose escalation has no impact on survival or toxicity in those with poor prognostic factors. It is feasible that, for patients with favorable prognostic features, the tumoricidal advantage of dose escalation is outweighed by increased life-shortening toxicity. This toxicity may not be evident when evaluating the entire group. Radiation Therapy Oncology Group trial 90-06 found that patients with high-grade gliomas under the age of 50 had decreased survival when treated with hyperfractionation compared with standard treatment. This was not seen when patients of all ages were evaluated. With longer expected survival, younger patients lived to experience the increased toxicity of treatment.²

It is not obvious that the patients treated to 90 Gy are comparable to those treated to 70 and 80 Gy. In this study, and in the referenced article by Lee et al,³ there is incomplete information regarding comparative prognostic factors. While the surgical status of the patients treated to 90 Gy is reported, the data on the patients treated to lower doses are incomplete. Other treatment-related prognostic variables are not reported. These include patient age, Karnofsky performance status, elapsed time from first symptom to initiation of treatment, and histology. Scott et al⁴ and Curran et al⁵ have shown the validity of these variables in predicting outcome in this group of patients.

Additionally, it would seem that the patients treated to a maximum dose of 90 Gy were treated with intensity-modulated radiotherapy, while those treated to 70 and 80 Gy were treated via three-dimensional conformal therapy techniques. In three-dimensional conformal therapy, there is sequential volume reduction without reduction in dose per fraction to deliver a greater total dose to the center of the target volume. With intensity-modulated radiotherapy, there is variability in dose per fraction within a constant volume. By simple calculation, if planning target volume (PTV) 1 was treated to 90 Gy at 2 Gy per fraction, then the area designated as PTV3 received only 1.33 Gy per fraction (60 Gy total to PTV3). The effectiveness of this low-dose fractionation has not been established in gliomas. Although increased recurrence at the periphery of the tumor volume was not seen, we question the radiobiologic efficacy.

The conclusions of this dose escalation trial are worrisome. Further dose escalation beyond 90 Gy does not seem to be indicated.

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. Scott CB, Curran WJ, Yung WKA, et al: Long term results of RTOG 90-06: A randomized trial of hyperfractionated radiotherapy (RT) to 72.0 Gy & carmustine vs standard RT & carmustine for malignant glioma patients with emphasis on anaplastic astrocytoma (AA) patients. Proc Am Soc Clin Oncol 17: 401a, 1998 (abstr 1546)

3. Lee SW, Fraass BA, Marsh LH, et al: Patterns of failure following high-dose 3-D conformal radiotherapy for high-grade astrocytomas: A quantitative dosimetric study. Int J Radiat Biol Phys 43: 79-88, 1999

4. Scott CB, Scarantino C, Urtasun R, et al: Validation and predictive power of Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis classes for malignant glioma patients: A report using RTOG 90-06. Int J Radiat Biol Phys 40: 51-55, 1998

5. Curran WJ, Scott CB, Horton J, et al: Recursive partition analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst 85: 704-710, 1993[Abstract/Free Full Text]

Response

University of Michigan Medical Center, Ann Arbor, MI

In Reply to Drs Knisely and LaCombe:We thank Dr Knisely and Dr LaCombe for their comments in regard to our recent article in the Journal of Clinical Oncology.¹ They highlight several important aspects of our work.

As far as we know, there is no clearly accepted definition of tumor recurrence or progression for high-grade gliomas. Our definition was a modification of well-known protocol criteria for tumor progression and was primarily based on radiographic enlargement of the cross-sectional diameters, in square centimeters, of enhancing masses seen on serial magnetic resonance imaging. As part of the multidisciplinary neuro-oncology team at the University of Michigan, patients who participated in this study had their serial imaging scans reviewed at a weekly brain tumor board, where an experienced group of investigators helped define tumor recurrence versus radiation necrosis. Although noninvasive techniques cannot rule out radiation necrosis, the long-term clinical picture, seen beyond the initial scan identifying recurrence, usually delineates the ultimate nature of these lesions. The classification used for tumor recurrence in this study was, thus, an attempt to use our working definition and allow others to have a means for comparison.

LaCombe calculated that "[planning target volume; PTV]3 received only 1.33 Gy per fraction (60 Gy total to PTV3)." It should be pointed out that the dose to the PTV3 was actually 60 biogray (see Table 1 in our article¹). The term "biogray" refers to the equivalent dose received, accounting for differences in dose per fraction, for a given alpha:beta ratio. For example, 60 biogray is equivalent to 60 Gy given at 2 Gy per fraction. That being said, patients on this study received the biologic equivalent of 60 Gy in 2-Gy fractions to PTV3. Our data indicate that the prescribed biogray levels to the outer annuli have not resulted in more marginal misses. The word "biogray" may not be considered standard terminology; however, if we are to more accurately compare radiation treatment plans in the three-dimensional/intensity-modulated radiotherapy era, a system for comparing differing fractionation schemes will be needed. Terms like "biogray," as defined in our article, may help unify our definitions and perhaps become the new standard terminology.

As stated in our Discussion,¹ any further dose escalation would involve keeping the outer PTVs (gross tumor volume + 2.5 cm and gross tumor volume + 1.5 cm) at the same biogray levels while only increasing the total central dose. The methods of achieving this have been covered extensively in the article by Lee et al.² Although the concern that higher daily doses of radiation to normal brain tissue (ie, outer PTVs) could result in increased toxicity is certainly valid, the techniques used are meant to change only the final dose to the central volume.

Malignant high-grade glioma remains a diagnosis with a poor prognosis despite aggressive attempts at controlling it with combinations of surgery, chemotherapy, and radiation. Our statement that "further dose escalation may prove to be beneficial in this setting" was not meant to suggest that this is the only reasonable approach. It is likely that radiation dose escalation will need to be combined with chemotherapeutic agents and/or molecularly targeted therapies to achieve success.

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. Lee SW, Fraass BA, Marsh LH, et al: Patterns of failure following high-dose 3-D conformal radiotherapy for high-grade astrocytomas: A quantitative dosimetric study. Int J Radiat Biol Phys 43: 79-88, 1999

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