In Reply to Drs. Mehta and Khuntia (Int J Radiat Oncol Biol Phys 2010 March 5. [Epub ahead of print.])

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

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treatment-related pneumonitis greater than grade 3. The details of neoadjuvant and concurrent chemotherapy regimen were described in Supplementary Table 1 (available at: www.redjournal.org). In conclusion, we largely agree with Drs. Mehta’s and Khuntia’s comments that HT is an excellent device for the treatment of NSCLC. However, their patients have been treated with HT alone without the addition of concurrent chemotherapy. Radiotherapy alone is no longer a standard treatment option for most patients with locally advanced NSCLC, and CCRT should be strongly recommended to these patients, whenever feasible. In this case, HT has to be applied concurrently with chemotherapy with caution, and the V5 value of the contralateral lung should be kept as low as possible, according to our data. As Drs. Mehta and Khuntia stated, the use of concurrent chemotherapy with hypofractionated IMRT/IGRT dose escalated radiation therapy needs to be evaluated prospectively through well-controlled clinical trials. CHANG HOON SONG, M.D. Department of Radiation Oncology Seoul National University College of Medicine Seoul, Korea HONGRYULL PYO, M.D. Department of Radiation Oncology Samsung Medical Center Sungkyunkwan University School of Medicine Seoul, Korea

Volume 78, Number 4, 2010 Residency Review Committee in Urology, I think I can advise these seven affected training programs to go where the patients are, as long as the training and supervision are superior in quality. In my two stints as chairman, there were intervals when surgical volume was inadequate at the University facility, causing me to seek community rotations to satisfy Residency Review Committee requirements. This worked! One such training arrangement has evidently been established between ‘‘town’’ and ‘‘gown,’’ as discovered in this poll. I am sure similar collegial relations would solve the problem for the remaining seven programs as well. CARL A OLSSON, M.D. John K Lattimer Professor of Urology, emeritus College of Physicians and Surgeons Columbia University New York, NY doi:10.1016/j.ijrobp.2010.05.069 1. Anscher MS, Anscher BM, Bradley CJ. The negative impact of Stark law exemptions on graduate medical education and health care costs: The example of radiation oncology. Int J Radiat Oncol Biol Phys 2010;76:1289– 1294.

IN REPLY TO DR. OLSSON

doi:10.1016/j.ijrobp.2010.05.021 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.].

RESPONSE TO ‘‘THE NEGATIVE IMPACT OF STARK LAW EXEMPTIONS ON GRADUATE MEDICAL EDUCATION AND HEALTH CARE COSTS: THE EXAMPLE OF RADIATION ONCOLOGY.’’ (INT J RADIAT ONCOL BIOL PHYS 2010;76;1289–1294) To the Editor: I would like to comment on an article in your April issue (1). This article presents the result of a poll taken of directors of the 81 Radiation Oncology Training Programs in the United States. There was a 73% response rate (59 directors responded). The questions posed to respondents included these: (1) Are there any self-referral arrangements in your community that take advantage of the in-office ancillary service exemption of the Stark laws (e.g., urology practices that hire radiation oncologists to perform imageguided radiotherapy for prostate cancer)? (2) Has this self-referral arrangement in your community affected the patient volumes in your practice? (3) Has this self-referral arrangement in your community affected your residency program? My concerns are many. First, how did the authors establish the ownership of the practices taking advantage of the in-office exemptions? Many such integrated care relationships are jointly owned by urologists and radiation oncologists together. Second, several of the reported percentages are misleading. Thirty-one of the 59 respondents reported the presence of such practice arrangements in their communities. One of the 31 programs was cooperating with such a practice. By focusing on the 30 remaining programs, the authors artificially inflated the significance of their calculations. Thus, the number of programs whose volume has been reduced is not 87%, but rather 45%, of the remaining programs polled (26/58). Even if one concedes the qualification to consider the 30 remaining programs alone, it does not justify the statement made just after Table 3b: ‘‘Overall, 87% of responding programs..felt their programs had been negatively affected by these business arrangements.’’ This statement is patently misleading, inasmuch as these 26 programs responded positively only to Question 2 above, which does in no way mention any effect on the training program! Similarly, the 26% of programs truly affected negatively become 12% of all programs polled (7/59). As a former chairman of two urology training programs (Boston University School of Medicine, 1974–1980, and College of Physicians and Surgeons, Columbia University, 1980–2006) and former member of the

To the Editor: We appreciate Dr. Olsson’s comments and in particular the concern he expressed for the radiation oncology training programs adversely affected by attempts to circumvent the Stark law. Apparently, members of the United States Congress share his concern over the exemptions to this law, but for different reasons. In their letter of April 16, 2010, to the Acting Comptroller General of the United States, Representative Henry Waxman (Chair, Committee on Energy and Commerce), Representative Sandor Levin (Chair, Committee on Ways and Means), and Representative Pete Stark (Chair, Subcommittee on Health, Committee on Ways and Means) pointed out that ‘‘.the potential financial incentives associated with self-referral could lead to the overprovision of . radiation oncology services’’ . and that .‘‘self-referral may be a contributing factor in the rapid increase in the use of these services.’’ Congressmen Waxman, Levin, and Stark go on to request the General Accounting Office (GAO) to conduct a study to determine ‘‘.the extent of physician self-referral arrangements for . radiation oncology services provided to Medicare beneficiaries and the effect that such arrangements have on Medicare spending.’’ As we discussed in our article, overutilization of expensive services may be the single biggest contributor to the high cost of health care in the United States, and it is likely that this GAO study will find evidence to support this conclusion. Most likely, physicians profiting from the self-referral system are concerned about the attention that Congress and the GAO are paying to Stark law exemptions. But ethical physicians need to consider, as Dr. Olsson correctly points out, that business arrangements designed to take advantage of loopholes in the Stark law regarding the provision of radiation oncology services could not work without the willing participation of the radiation oncology community. It is a shame that some physicians may be mortgaging the future of the specialty by compromising the training of the next generation of radiation oncologists. To protect the integrity of the specialty, we believe that the ethics of physician self-referral should be debated by the American Society for Radiation Oncology (ASTRO) in the near future. Despite claims made by supporters of the Stark law exemptions that the ability to self-refer may be beneficial to patients (e.g., by improving continuity of care), the data we cite indicate that, in radiation oncology, there is no evidence of improved outcomes and no evidence to suggest that self-referral improves access to care. MITCHELL S. ANSCHER, M.D. BARBARA M. ANSCHER, M.A., J.D. CATHY J. BRADLEY, PH.D. Department of Radiation Oncology Massey Cancer Center Virginia Commonwealth University Medical Center Richmond, VA doi:10.1016/j.ijrobp.2010.05.070