Treatment-Related Pneumonitis and Acute Esophagitis in Non-Small-Cell Lung Cancer Patients Treated With Chemotherapy and Helical Tomotherapy: In Regard to Song et al.

Letters to the Editor TREATMENT-RELATED PNEUMONITIS AND ACUTE ESOPHAGITIS IN NON-SMALL-CELL LUNG CANCER PATIENTS TREATED WITH CHEMOTHERAPY AND HELICAL TOMOTHERAPY: IN REGARD TO SONG ET AL. To the Editor: In a recently published article by Song et al. (1), the authors present a retrospective review of 37 consecutive patients treated definitively with helical tomotherapy for unresectable non-small-cell lung cancer (NSCLC). This is one of an emerging series of studies evaluating dose escalation for treatment of NSCLC, although we published a more definitive clinical trial earlier (2). What is unique in the study by Song et al. (1) is that patients were treated concurrently with chemotherapy, and several were treated with hypofractionated radiation therapy, and that the study included patients with poor performance status as well as those with involved supraclavicular nodes, resulting in very large planning target volumes (PTVs), a patient group that is typically excluded from most clinical trials (by the authors’ own admission). Despite selecting a cohort with such advanced disease and poor PS, the authors present very impressive 2-year local control and survival rates of 63% and 56%, respectively. However, there was a notable rate of treatment-related deaths (11%). That important paper raises several issues that need to be considered as we apply advanced technologies in managing NSCLC. First, given the retrospective nature of the study (1) and the small number of patients included, the conclusions should be regarded for exactly what they are worth: not definitive, by any stretch, but merely hypothesis-generating. Second, the clear selection bias toward treating large-volume disease in poor-PS patients with intensitymodulated radiation therapy (IMRT)/image-guided radiation therapy (IGRT) does not have the historical control comparable to traditional twodimensional (2D)/three-dimensional (3D) approaches, using similar combination therapy approaches, and therefore, no definitive comparative conclusions regarding toxicities can be made. The authors indicated that treatment with helical tomotherapy was restricted to patients with a tumor burden that was higher than could be treated safely with 3D conformal radiation. Those patients would therefore certainly be more likely to develop more complications. Furthermore, the authors state that only gross disease was treated (i.e., no elective nodal coverage). However, there was a substantial difference in the gross tumor volume (GTV) versus the PTV (patients with grade 3 or higher toxicity had an average GTV of 257 cm3 versus a PTV of 698 cm3, a 272% increase in volume). Part of this may be secondary to the large expansions used. In our ongoing, prospective, dose-per-fraction-escalation clinical trial, we have to date enrolled 74 patients with no grade 3 esophagitis or pneumonitis. This may be related to the tighter margins used in our study, as well as a very deliberate effort to maximally deploy the IMRT capabilities of helical tomotherapy to minimize doses to esophagus and lungs, with very stringent dose guidelines, as well as a strategy of ‘‘volume-binning,’’ so that the highest volume-binned patients do not receive inordinately high doses (2). Also, in their planning procedures, Song et al. allowed doses up to 125% of the prescription dose. What the maximum dose is outside of the PTV is not stated, but given the large expansions used, some of this dose is likely in the normal lung. Another major issue is that the optimization used in the study included the standard lung V20 and V30 values. When altered fractionation is used (anything beyond 1.8-2 Gy per fraction is used), these criteria can be quite misleading. Other optimization algorithms such as equivalent uniform dose (EUD) or normalized total dose mean (NTDmean) doses are far more useful for plan evaluation, and the authors did attempt to use the latter, with the maximum capped at 20 Gy (which parenthetically was calculated as mean dose but not as normalized mean dose, and furthermore, as Table 2 shows, the mean lung dose in patients who developed grade 3 or greater pneumonitis was 23 Gy, significantly higher than the 17 Gy in the group that did not develop this toxicity). At the University of Wisconsin, we have been treating patients with helical tomotherapy since 2002, and based on our experience, very early on, we implemented an NTDmean limit of 18 Gy or less in all patients, as an absolute requirement, and unsurprisingly, we have seen no cases of grade 3 pneumonitis or esophagitis, despite significant doseper-fraction escalation. Our results would therefore suggest that patients can indeed be treated safely with high-dose radiation therapy with IMRT/ IGRT techniques, as long as stringent normal tissue requirements are adhered to; furthermore, our data were not obtained with concomitant chemotherapy. The combination therapy issue takes on further significance in light of the fact that specific chemotherapy details are not available from that paper, and also because it is not completely clear whether patients continued with adjuvant chemotherapy; in our clinical trial, the incidence of grade 2 pneumonitis was higher in patients receiving postradiation chemotherapy, an issue that needs further study. Song et al. are to be congratulated for having obtained such excellent clinical results in a group of patients, who according to the authors, could not be

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conventionally treated; the toxicities need to be seen in the appropriate context of the patient cohort, large tumor volumes, concurrent therapies, and high mean lung doses. The use of concurrent chemotherapy with hypofractionated IMRT/IGRT dose-escalated radiation therapy needs to be evaluated prospectively through well-controlled clinical trials, without directly extrapolating from conventional 2D and 3D data.

MINESH P. MEHTA, M.D. DEEPAK KHUNTIA, M.D. Department of Human Oncology University of Wisconsin School of Medicine and Public Health Madison, Wisconsin Disclosures: Dr. Mehta serves as a consultant for Tomotherapy and Dr. Khuntia currently serves as a PI on a lung cancer study partially funded by Tomotherapy, Inc grant and has previously received speaker honorariums. doi:10.1016/j.ijrobp.2010.05.020 1. Song CH, Pyo H, Moon SH, et al. Treatment-related pneumonitis and acute esophagitis in non-small-cell lung cancer patients treated with chemotherapy and helical tomotherapy. Int J Radiat Oncol Biol Phys 2010 March 5 [Epub ahead of print.]. 2. Adkison JB, Khuntia D, Bentzen SM, et al. Dose escalated, hypofractionated radiotherapy using helical tomotherapy for inoperable non-small cell lung cancer: preliminary results of a risk-stratified phase I dose escalation study. Technol Cancer Res Treat 2008;7(6):441–447.

IN REPLY TO DRS. MEHTA AND KHUNTIA (INT J RADIAT ONCOL BIOL PHYS 2010 MARCH 5. [EPUB AHEAD OF PRINT.]) To the Editor: We would like to thank Drs. Mehta and Khuntia for their invaluable comments. Concurrent chemoradiotherapy (CCRT) is the first-choice treatment option for locally advanced non-small-cell lung cancer (NSCLC). However, many patients with large tumor volumes cannot be treated safely with this treatment option due to the high possibilities of excessive toxicities such as severe esophagitis or pneumonitis. In this case, they are frequently treated with sequential chemoradiotherapy or even with either treatment alone, and the treatment outcomes using these modalities are usually inferior to that of CCRT, and the chance of cure decreases. Therefore, introducing intensitymodulated radiation therapy (IMRT) or helical tomotherapy (HT) for the patients with large tumor volumes has an important meaning if these techniques allow these patients to be treated with CCRT. These techniques with a concurrent combination of chemotherapy may increase the chance of cure in these patients with acceptable toxicities. We observed four treatment-related deaths in 37 patients (11%) treated with HT for their unresectable NSCLC (1). Although the cause of death in many of these cases could have been considered as other than treatmentrelated complications, because most of the patients had several comorbidities during the treatment period, we concluded that HT might have at least provided a triggering factor for these fatal outcomes. Contributing factors for these fatal complications might consist of one or more among the following: large planning tumor volume (PTV), and therefore large lung volume irradiated by HT; concurrent chemotherapy; hypofractionated radiotherapy; or poor performance status and comorbidities of patients. As stated in the paper, we could not address the precise factors contributing to treatment-related death. At the moment, we propose that HT should be applied with great caution to the patients with large unresectable NSCLC. In regard to the differences between the gross tumor volume (GTV) and the PTV, we did not allow elective nodal irradiation but included the involved nodal area in the PTV. We used 5-mm to 15-mm expansions (from GTV) to draw the PTV, which is not an excessive amount, considering respiratory motion. The median maximum dose to the lung was 104% of the prescribed dose (range, 81%-112%). Drs. Mehta and Khuntia point out that the mean lung dose in patients who develop grade 3 or greater pneumonitis was 23 Gy, significantly higher than the 17 Gy in the group with less treatment-related pneumonitis. I think they misread it. Mean lung dose (for total lung) in patients who developed grade 3 or greater pneumonitis was 18 Gy in Table 2, not 23 Gy, which is within their acceptable range. Regarding the role of adjuvant chemotherapy, only 2 patients received adjuvant chemotherapy as their initial treatment, and they did not develop