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In Reply

University of Texas Southwestern Medical Center, Dallas, TX

We thank Dr Senan and the investigators from the VU University in the Netherlands for their careful review of our article. The main purpose of our initial report on the phase II portion of the Indiana University (Indianapolis, IN) prospective trial of stereotactic body radiation therapy (SBRT) for medically inoperable lung cancer was to warn practitioners using this particular dosing regimen about potentially severe toxicity when treating central tumors.¹ Contrary to what seemed implied by the correspondence, it was not our intention to condemn the use of SBRT altogether for central lung tumors. The nearly 120-patient prospective Indiana University phase I/II trial formed the initial basis for ongoing investigation in the Radiation Therapy Oncology Group (RTOG) in North America. RTOG 0236 used the same 60 Gy/three fraction SBRT regimen, but excluded central tumors based on preliminary data from our report. RTOG 0236 completed enrollment of 56 patients in September 2006. The RTOG continues to investigate the use of SBRT in lung cancer including alternative dose fractionation schedules for central lesions on a pending phase I trial (RTOG 0633, Andrea Bezjak, MD, principal investigator).

As pointed out in the correspondence of Senan et al, the criteria for assigning toxicity to be treatment related was important in this trial. In particular, there was no time limit beyond which adverse events would be considered treatment related. As these frail patients were generally accustomed to being hospitalized frequently for emphysema and other medical problems even before SBRT, the possibility of an adverse event was very high. Whether adverse events are treatment related or not is often debated. In our series, it is true that the adverse events were deemed possibly related to treatment with a low threshold as stated in our Methods section. Other reported series may not be so strict, and results must be interpreted accordingly. Nonetheless, the relative increased rate of adverse events observed when treating central lesions as opposed to peripheral in our study was quite dramatic, justifying our warnings.

The treatment conduct and margins used in the Indiana phase II experience are not so outdated as suggested by Dr Senan et al. For example, computed tomography scans were performed before each treatment to verify treatment position. Even in 2006 few centers have four-dimensional scanners, and the 5 mm to 10 mm motion plus set-up margin range is common at experienced centers across the world. While efforts should be made with technology or conduct to reduce unnecessary irradiation of healthy tissue, margin reduction should only be carried out after validation of ongoing targeting accuracy before and during each treatment.

The letter by Senan et al indicated that we delivered treatment dose far in excess of the dose "required for optimal local control." Optimal dose is one which balances tumor control with treatment-related toxicity. In order to define an optimal dose for SBRT, investigators would have to consistently manage groups of uniformly selected patients in a prospective trial where treatment dose was the only variable (ie, a phase I study). With ample patient and follow-up in each dose group, data for both local control and toxicity would then be plotted as a function of dose to select an appropriate control/toxicity combination. To our knowledge, the only such prospective phase I studies carried out for lung SBRT have been the three fraction regimen at Indiana University^2,3 and the one fraction regimens at Heidelberg⁴ and Cleveland.⁵ None of the references defining Senan et al's optimal dose relating to a biologically effective dose of 100 Gy are published prospective dose-escalation studies. ^6-8 Indeed, in our population of patients such dose potency was associated with actuarial 2-year local control around 75% to 80%, not the 90+% observed in our prospective phase II study. While the higher dose levels are also likely associated with higher toxicity, late tumor recurrence associated with lower treatment dose is harmful as well and must be factored into the decision of dose selection. As most of our patients have peripheral tumors, the dose levels of 60 Gy for T1 and 66 Gy for T2 (in three fractions) used in our study are convenient, safe, and clearly efficacious for many in this population.

Finally, we would strongly warn Dr Senan and colleagues against embracing biologic models intended for small dose per fraction treatment extrapolated to SBRT dose ranges. In particular, the linear-quadratic model which forms the basis for the biologically effective dose correlations referred in their correspondence is prone to error and misunderstanding. This model grossly overpredicts the potency of doses beyond the shoulder of the cell survival curve leading to erroneous conclusions about local control.⁹ In turn, using this linear-quadratic formalism to predict healthy tissue dose tolerance may lead to excessive toxicity. In our opinion, prospective testing with defined treatment and patient characteristics as in our phase I/II studies would obviate such reliance on unconfirmed predictive models.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author indicated no potential conflicts of interest.

REFERENCES

1. Timmerman R, McGarry R, Yiannoutsos C, et al: Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J Clin Oncol 24:4833-4839, 2006[Abstract/Free Full Text]

2. Timmerman R, Papiez L, McGarry R, et al: Extracranial stereotactic radioablation: Results of a phase I study in medically inoperable stage I non-small cell lung cancer. Chest 124:1946-1955, 2003[CrossRef][Medline]

3. McGarry RC, Papiez L, Williams M, et al: Stereotactic body radiation therapy of early-stage non-small-cell lung carcinoma: Phase I study. Int J Radiat Oncol Biol Phys 63:1010-1015, 2005[CrossRef][Medline]

4. Hof H, Herfarth KK, Munter M, et al: Stereotactic single-dose radiotherapy of stage I non-small-cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys 56:335-341, 2003[CrossRef][Medline]

5. Whyte RI, Crownover R, Murphy MJ, et al: Stereotactic radiosurgery for lung tumors: Preliminary report of a phase I trial. Ann Thorac Surg 75:1097-1101, 2003[Abstract/Free Full Text]

6. Fowler JF, Tome WA, Fenwick JD, et al: A challenge to traditional radiation oncology. Int J Radiat Oncol Biol Phys 60:1241-1256, 2004[CrossRef][Medline]

7. Onishi H, Araki T, Shirato H, et al: Stereotactic hypofractionated high-dose irradiation for stage I nonsmall cell lung carcinoma: Clinical outcomes in 245 subjects in a Japanese multi-institutional study. Cancer 101:1623-1631, 2004[CrossRef][Medline]

8. Wulf J, Baier K, Mueller G, et al: Dose-response in stereotactic irradiation of lung tumors. Radiother Oncol 77:83-87, 2005[CrossRef][Medline]

9. Guerrero M, Li XA: Extending the linear-quadratic model for large fraction doses pertinent to stereotactic radiotherapy. Phys Med Biol 49:4825-4835, 2004[CrossRef][Medline]

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