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Originally published as JCO Early Release 10.1200/JCO.2007.13.8164 on November 5 2007 © 2007 American Society of Clinical Oncology.
Low Incidence of Isolated Nodal Failures After Involved-Field Radiation Therapy for Non–Small-Cell Lung Cancer: Blinded by the Light?
International Atomic Energy Agency, Vienna, Austria More than 15 years ago, National Cancer Institute contracted with several institutions to introduce three-dimensional (3D) treatment planning in radiotherapy (RT) of various tumors. Four institutions embarked on this project in lung cancer; Memorial Sloan-Kettering Cancer Center (New York, NY) was one of these. In this issue of the Journal of Clinical Oncology, Rosenzweig et al1 present the data that can be seen as one of the final stages of that endeavor in lung cancer, with the largest number of patients with stages I-III non–small-cell lung cancer (NSCLC) presented to date, addressing the issue of involved-field RT (IFRT) in this disease. They have shown that using IFRT led to only an 8% rate of isolated nodal failures, similar to observations by other investigators in a similar setting. These data fit perfectly with other three-dimensional conformal radiotherapy (3D-CRT) data and more conventional data obtained before 3D-CRT, which are all uniform, regardless of the total RT dose, fractionation regimen, or geography. As previously summarized,2 uniformity of the data (a range of 0% to 7% of isolated nodal recurrences was observed) clearly indicate IFRT as the preferred treatment option. In addition, some (stage III) patients do not live long enough for their nodal failures after IFRT to become evident. Finally, nodal recurrences are few in RT series and we do not have clear indication about salvage therapy, although postsurgical nodal recurrences treated with RT have poor prognosis.3 Overshadowing RT data are legitimate fears that none of these studies actually looked at nodal recurrences prospectively, especially once distant failures occurred. In addition, none of these studies provided pathologic confirmation of the status of nodal disease, nor data from autopsy findings. Interestingly, the best overall results were achieved when elective nodal irradiation (ENI) was used.4-12
Then come cold-blooded surgical data were obtained. When the initial clinical staging based on computed tomography scanning was ultimately verified during surgery, the incidence of nodal metastases in stage I NSCLC was as high as 25% to 35%.13-19 Even in the smallest tumors, unsuspected lymph node metastasis was observed to be 18% in T1a (< 2 cm) and 23% in T1b (2 to 3 cm) tumors.20 With increasing tumor size (< 1.0, 1.1 to 2.0, and > 2.0 cm) the incidence of lymphatic invasion/metastasis increases (0%, 17%, and 38%, respectively).21 When immunohistochemistry was used in patients with peripheral adenocarcinomas of Thus, we have a large discrepancy among RT data, suggesting no ENI on one end of the spectrum, and at the opposite pole, interpretation of the surgical data (by a radiation oncologist) leading to a suggestion that larger RT field, using ENI (corresponding to a surgical field), should be used. There may be intrinsic differences between the biologic characteristics of tumors of surgical patients and those of RT patients, but to date there is no clear answer to that provocative question.28 Assuming no such differences between the biologic characteristics of tumors, what should one then do? Discard RT data as low-quality data and reinstitute ENI based on surgery-only data? This approach does not seem either reasonable or realistic. Radiation oncologists would continue using IFRT based on the data available and the low incidence of nodal failures without ENI. Furthermore, there is not much opportunity to escalate the 3D-CRT dose meaningfully without IFRT, which remains the most compelling reason for insisting on IFRT. If this is going to happen, what is the future in this field— indiscriminate use of IFRT? In addition, this approach is neither reasonable nor realistic, given that radiation oncologists dealing with lung cancer cannot simply leave their heads in the sand, saying they have never heard of surgical data; it would be similar to claiming Editors are not the biggest band in the United Kingdom nowadays. Ultimately, the question is not whether we should use ENI, but that if we should, how then would we identify the target population? One possible scenario would be to include more translational research in this field by gathering more information on the biologic properties and differences between various subgroups of patients/tumors (eg, stage I v stage II v stage III; histology, tumor grade, and so on) before one can advocate IFRT, ENI, or, likely, selective ENI, in various patient populations.
One may start with clear documentation of incidental nodal irradiation, which is among the greatest assets of the article by Rosenzweig et al.1 They have reviewed the treatment plans to provide detailed analysis of RT doses to nodal regions believed to be at risk in these patients to document existence, amount, and effects of incidental nodal irradiation, which may have converted no-ENI into ENI (at least partially). Using multiple limited RT fields to conform escalated total RT dose to the tumor/target itself, one may assume limited character of RT (ie, IFRT), and therefore, no ENI, given that no large (ie, elective) fields were used from the beginning of RT. However, beams from these limited RT fields may incidentally pass (while exiting) through some nodal regions at risk. Therefore, no ENI can convert into ENI, if sufficient RT doses are received. This matter has only rarely been a subject of either investigation or discussion.28-32 Martel at al29 showed that 3D-IFRT doses of 69.3 to 84 Gy to gross tumor volume resulted in 100% of the ipsilateral hilum, 59% of the low paratracheal region, 57% of the aortopulmonary region, 97% of the subcarinal region, and 57% of the contralateral hilum receiving In an additional and important effort, Sawyer et al33 used the data from patients undergoing complete resection of stage I/II NSCLC to identify predictors of subclinical nodal involvement. By using findings of preoperative bronchoscopy, tumor size, tumor grade, and histology to create risk groups for N1-2 local-regional recurrence, they have found that in the best (low risk) subgroup, the risk of subclinical nodal involvement was at least 15.6%, whereas all other patients had at least a 35% risk. Increasing risk correlated with increasing size and grade of tumor, accompanied with positive findings of bronchoscopy. Similarly, Suzuki et al34 determined predictors of lymph node metastasis in patients with clinical stage IA NSCLC undergoing surgery. Eighty-eight patients (23%) had pathologic lymph node involvement or intrapulmonary metastases, with grade of differentiation and pleural involvement predicting local or regional spread. With both risk factors present, more than 40% of clinical stage IA NSCLC patients had pathologic involvement of lymph nodes or intrapulmonary metastases. In addition, tumor size, high serum carcinoembryonic antigen level, and adenocarcinoma histology were significant predictors of N2 disease in patients with clinical N0-1 disease.35 Radiation oncologists, unintentionally I assume, also add confusion by presenting the data from very different patient subgroups combined, in contrast to clear and simple surgical data. Although there remains significant heterogeneity among lung cancer patients and controversy clearly will continue, we will have to agree that the importance of the issue of IFRT/ENI is not of the same magnitude in stage I, II, and III NSCLC, respectively. In stage III NSCLC, it merely deserves a discussion because of existing tumor/node bulk, which is the main reason of local-regional failures and existing microscopic spread, leading to a short time to both local and distant failures, especially in stage IIIB patients. It is likely that RT alone will not be curative in a substantial proportion of patients with stage III NSCLC. Furthermore, their general health status (the reason for excluding them from consideration of receiving combined radiochemotherapy) is unlikely to lead to prolonged periods of life, raising questions regarding the appropriate role and place of ENI. Thus, patients with stage I-II NSCLC seem to be the main population in which investigating this issue is worthy of consideration. Again, the difference between the two stages is larger than we can anticipate, but also is burdened by the facts that we still use an inappropriate staging system, that widely accepted prognostic factors are lacking, and that negative patient selection adversely contributes to the overall investigation. However, I firmly believe that patients with stage I/II NSCLC are the group in whom we should start using either 3D-CRT or perhaps stereotactic RT, which is showing promising local control data. Perhaps we could start with small and simple (still potential) variables such as tumor location or size/volume or histology, and correlate these variables with documented incidental nodal irradiation. Then, we could make these correlations prospectively and systematically, and seek every opportunity to verify them not only clinically and radiographically, but also pathologically, if possible. Is there a better way of doing all this than through multi-institutional collaboration, teaching our younger colleagues not to repeat our mistakes?
Finally, one of the most important findings of the study by Rosenzweig et al1 is a hint that there may be a dose-response for subclinical disease in nodal regions at risk. Although the median time to nodal failure of 6 months speaks for itself, only 14% of nodal failures occurred in regions receiving AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. ACKNOWLEDGMENTS This editorial is dedicated to Thomas Daniels, MD, David Schwartz, MD, Andrew Kee, MD, Justin Juliano, MD, Heath Mackley, MD, Hiram Gay, MD, and others—continue to keep your appropriate sunglasses on. NOTES published online ahead of print at www.jco.org on November 5, 2007. REFERENCES
1. Rosenzweig KR, Sura S, Jackson A et al: Involved-field radiation therapy for inoperable non-small cell lung cancer. J Clin Oncol 25:5557-5561, 2007 2. Jeremi 3. Jeremi 4. Jeremi 5. Jeremi 6. Zhang HX, Yin WB, Zhang LJ, et al: Curative radiotherapy of early operable non-small cell lung cancer. Radiother Oncol 14:89-94, 1989[CrossRef][Medline] 7. Jeremi 8. Jeremi 9. Jeremi 10. Jeremi 11. Jeremi 12. Jeremi 13. Glazer GM, Orringer MB, Gross BH, et al: The mediastinum in non-small cell lung cancer. AJR Am J Roentgenol 142:1101-1105, 1984 14. Heavey LR, Glazer GM, Gross BH, et al: The role of CT in staging radiographic T1N0M0 lung cancer. AJR Am J Roentgenol 146:285-290, 1986 15. Black WC, Armstrong P, Daniel TM: Cost effectiveness of chest CT in T1N0M0 lung cancer. Radiology 167:373-378, 1988 16. Conces DJ Jr, Klink JF, Tarver RD, et al: T1N0M0 lung cancer: Evaluation with CT. Radiology 170:643-646, 1989 17. Martini N, Beattie E: Results of surgical treatment in stage I lung cancer. J Thorac Cardiovasc Surg 74:499-505, 1977[Abstract] 18. Naruke T, Goya T, Tsuchiya R, et al: Prognosis and survival in resected lung carcinoma based on the new international staging system. J Thorac Cardiovasc Surg 96:440-447, 1988[Abstract] 19. Ginsberg RJ, Rubinstein LV: Randomised trial of lobectomy versus limited resection in patients with T1N0 non-small cell lung cancer: Lung Cancer Study Group. Ann Thorac Surg 60:908-913, 1995 20. Koike T, Terashima M, Takizawa T, et al: Clinical analysis of small-sized peripheral lung cancer. J Thorac Cardiovasc Surg 115:1015-1020, 1998 21. Ishida T, Yano T, Maeda K: Strategy for lymphadenopathy in lung cancer 3 cm or less in diameter. Ann Thorac Surg 50:708-713, 1991 22. Wu J, Ohta Y, Minato H, et al: Nodal occult metastasis in patients with peripheral lung adenocarcinoma of 2.0 cm or less in diameter. Ann Thorac Surg 71:1772-1777, 2001 23. Chen ZL, Perez S, Holmes EC, et al: Frequency and distribution of occult micrometastasis in lymph nodes of patients with non-small cell lung carcinoma. J Natl Cancer Inst 85:493-498, 1993 24. Passlick B, Izbicki JR, Kubuschok B, et al: Detection of disseminated lung cancer cells in lymph nodes: Impact on staging and prognosis. Ann Thorac Surg 61:177-182, 1996 25. Dobashi K, Sugio K, Osaki T, et al: Micrometastatic P53-positive cells in the lymph nodes of non-small-cell lung cancer: Prognostic significance. J Thorac Cardiovsc Surg 114:339-346, 1997 26. Maruyama R, Sugio K, Mitsudomi T, et al: Relationship between early recurrence and micrometastases in the lymph nodes of patients with stage I non-small cell lung cancer. J Thorac Cardiovasc Surg 114:535-543, 1997 27. Takizawa T, Terashima M, Koike T, et al: Lymph node metastasis in small peripheral adenocarcinoma of the lung. J Thorac Cardiovasc Surg 116:276-280, 1998 28. Jeremi 29. Martel MK, Sahijdak WM, Hayman JA, et al: Incidental dose to clinically negative nodes from conformal treatment fields for nonsmall cell lung cancer. Int J Radiat Oncol Biol Phys 45:244, 1999 (suppl 3; abstr 186)[CrossRef] 30. Rosenzweig KE, Sim SE, Mychalczak B, et al: Elective nodal irradiation in the treatment of non-small-cell lung cancer with three-dimensional conformal radiation therapy. Int J Radiat Oncol Biol Phys 50:681-685, 2001[CrossRef][Medline] 31. Zhao L, Chen M, Ten Haken R, et al: Three-dimensional conformal radiation may deliver considerable dose of incidental nodal irradiation in patients with early stage node-negative non-small cell lung cancer when the tumor is large and centrally located. Radiother Oncol 82:153-159, 2007[CrossRef][Medline] 32. Emami B, Mirkovic N, Scott C, et al: The impact of regional nodal radiotherapy (dose/volume) on regional progression and survival in unresectable non-small cell lung cancer: An analysis of RTOG data. Lung Cancer 41:207-214, 2003[CrossRef][Medline] 33. Sawyer TE, Bonner JA, Gould PM, et al: Predictors of subclinical nodal involvement in clinical stages I and II non-small cell lung cancer: Implications in the inoperable and three-dimensional dose-escalation settings. Int J Radiat Oncol Biol Phys 43:965-970, 1999[CrossRef][Medline] 34. Suzuki K, Nagai K, Yoshida J, et al: Predictors of lymph node and intrapulmonary metastasis in clinical stage IA non-small cell lung carcinoma. Ann Thorac Surg 72:352-356, 2001 35. Suzuki K, Nagai K, Yoshida J, et al: Clinical predictors of N2 disease in the setting of a negative computed tomographic scan in patients with lung cancer. J Thorac Cardiovasc Surg 117:593-598, 1999
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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2.0 cm, occult nodal metastases were detected in 20% of patients
50 Gy. Previously, Rosenzweig et al
