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Originally published as JCO Early Release 10.1200/JCO.2007.13.2191 on November 5 2007 © 2007 American Society of Clinical Oncology. Involved-Field Radiation Therapy for Inoperable Non–Small-Cell Lung Cancer
From the Departments of Radiation Oncology and Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, NY Address reprint requests to Kenneth E. Rosenzweig, MD, Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; e-mail: rosenzwk{at}mskcc.org
Purpose Dose escalation has been shown to improve local control in non–small-cell lung cancer (NSCLC) treated with definitive radiation therapy, but with increased complications. We implemented the use of involved-field radiotherapy (IFRT) in an effort to reduce toxicity while treating the gross tumor to higher doses. This analysis reports failure rates in uninvolved nodal regions with the use of IFRT. Patients and Methods A total of 524 patients with NSCLC treated with three-dimensional conformal radiotherapy at Memorial Sloan-Kettering Cancer Center between 1991 and 2005 were reviewed. Only lymph node regions initially involved with tumor by either biopsy or radiographic criteria were included in the clinical target volume. Elective nodal failure (ENF) was defined as a recurrence in an initially uninvolved lymph node in the absence of local failure. Results Only 32 patients (6.1%) with ENF were identified. The 2-year actuarial rates of elective nodal control and primary tumor control were 92.4% and 51%, respectively, with a median follow-up of 41 months in survivors. In patients who achieved local disease control, the 2-year elective nodal control rate was 91%. The median time to ENF was 6 months (range, 0 to 56 months). Many patients experienced treatment failure in multiple lymph node regions simultaneously. Conclusion The use of IFRT did not cause a significant amount of failure in lymph node regions not included in the tumor volume. Therefore, IFRT remains an acceptable method of treatment that allows for dose escalation while minimizing toxicity.
Local failure continues to be a major cause of mortality in patients with inoperable non–small-cell lung cancer (NSCLC) treated with radiation therapy (RT). Trials with standard RT even with the addition of chemotherapy show 2-year local control rates as low as 27% in patients with locally advanced disease.1 Standard RT for NSCLC typically entails delivering a dose of 40 Gy to the entire mediastinum, supraclavicular fossa, and ipsilateral hilum even without evidence of disease in these areas, followed by a 20-Gy boost to the gross tumor volume (GTV).2 However, elective nodal irradiation (ENI) has not been shown to be effective, and the toxicity associated with this treatment has added considerably to the morbidity of RT and can limit the degree of dose escalation.3,4 In 1991, after our experiences with toxicity in a phase I dose-escalation study,5 we abandoned the practice of including elective nodal regions in our treatment volumes to reduce toxicity. Subsequently, our planning target volume (PTV) consisted of only the GTV with an appropriate margin.6,7 This report examines the consequence of that treatment technique modification.
Records of 524 patients with biopsy-proven NSCLC stages I-IIIB who were treated at Memorial Sloan-Kettering Cancer Center (MSKCC; New York, NY) between 1991 and 2005 with three-dimensional conformal radiotherapy (3D-CRT) to a dose of 50 Gy or more were reviewed as part of an institutional review board–approved retrospective study. Three hundred twelve patients (60%) had a [18F]fluorodeoxyglucose positron emission tomography scan (FDG-PET) for staging before radiation treatment was initiated. A lymph node was included in the GTV if the biopsy was positive, if it was greater than 15 mm on its shortest axis when assessed radiographically, or had increased standard uptake value on FDG-PET. For treatment, patients were immobilized in a supine position with their arms raised in a customized mold (Alpha Cradle Molds, Akron, OH) and received a planning computed tomography (CT) scan (PQ5000; Picker, Bothell, WA). The GTV consisted of all known sites of disease. The PTV was determined from the GTV by a radiation oncologist who used an automatic margining tool that added typically a standard margin of 10 to 15 mm. Critical normal structures were contoured by the physician or by the treatment planner. Treatment planning was performed with the MSKCC 3D treatment-planning system using the beam's-eye-view technique; dose calculations included tissue inhomogeneity corrections.8,9 As the technology became available at MSKCC, 61 patients (11%) were treated using intensity-modulated radiation therapy. All patients were treated with conventional fractionation (1.8 to 2.0 Gy) with no planned treatment breaks. The prescription doses for this group of patients ranged between 50 and 90 Gy, with a mean prescription dose of 66 Gy. The spinal cord and total lung were the dose-limiting tissues. For the lung, using the dose-volume histogram reduction scheme of Kutcher and Burman and the model parameters of Burman et al for severe radiation pneumonitis, we required that the normal tissue complication probability (NTCP) not exceed 25%,6 as calculated with the Lyman model.10-12 A parallel architecture model was also used in the evaluation process.13 This model views an organ in terms of functional subunits (fdam) working in parallel and provides a scheme for calculating fdam from the dose-volume histogram; the destruction of a critical fraction of subunits is required to cause a complication.14 When the NTCP exceeded 25%, treatment to the initially intended dose was still permitted if fdam did not exceed 28%. The maximum spinal cord dose was kept below 50 Gy. Given that most 3D-CRT plans often involved the use of lateralized beams, elective nodal regions often received significant doses incidentally. The doses to these regions were defined by reviewing treatment plans of each patient. The nodal areas were divided into seven anatomic regions: ipsilateral supraclavicular, contralateral supraclavicular, ipsilateral superior mediastinum, contralateral superior mediastinum, ipsilateral inferior mediastinum, contralateral inferior mediastinum, and the subcarinal region. The aortic arch divided the superior mediastinum from the inferior mediastinum. The elective nodal dose was defined as the minimum dose that encompassed the entire anatomic region. Therefore, if a portion of any region did not receive any radiation dose, it was recorded as 0 Gy. Patients were seen in follow-up 1 month after completion of radiation treatment and then every 3 to 4 months for the first 2 years. For the next 3 years, they were seen every 6 months. After 5 years, patients were usually seen once a year. Each follow-up visit consisted of a physical examination and a CT scan of the chest. Elective nodal failure was defined by recurrence in any lymph node region that was initially uninvolved in the absence of local failure. If the patient had distant metastatic disease as the first site of failure without local recurrence, failure in any originally uninvolved lymph node region was considered an elective nodal failure (ENF). Local failure was defined as an increase in radiographic abnormality within the irradiated volume that was not believed to be radiation-induced scarring or pneumonitis. Local control was assessed using a combination of clinical assessment, CT, and pathology. FDG-PET scan was not used routinely for follow-up, but was used frequently to characterize new abnormalities seen on CT. Estimates of ENF, local control, local failure, and overall survival were calculated from the initiation of treatment, whether it was chemotherapy or radiotherapy, using the Kaplan-Meier method.15
Five hundred twenty-four patients with inoperable NSCLC were treated with involved-field radiotherapy (IFRT) to doses between 50 and 90 Gy using 3D-CRT or intensity-modulated radiation therapy between 1991 and 2005 at MSKCC. Patient characteristics are listed in Table 1. Sixty-three percent (329 patients) had tumors that were inoperable based on site and stage, 36% (188 patients) were medically unfit for surgery because of comorbidities, and 1% (seven patients) chose RT over surgery. Two hundred nineteen patients (42%) were treated with radiotherapy alone, 210 patients (41%) were treated with sequential platinum-based chemotherapy followed by radiotherapy, and 78 patients (15%) were treated with concurrent platinum-based chemoradiotherapy. The first 17 consecutive patients (3%) who received RT alone had ENI. Two of these patients (12%) experienced treatment failure in an elective nodal region (supraclavicular fossa) despite receiving 40 Gy. Among the 524 patients, results from the first 171 have been reported previously.7
Median follow-up among all patients was 17 months (range, 0 to 166 months) and 41 months (range, 0 to 166 months) in survivors (n = 112). Two-year and 5-year local control was 51% and 39%. Overall survival at 2 and 5 years was 43% and 19%, respectively, with a median survival time of 21 months (Fig 1).
Thirty-two patients (6.1%) with 42 lesions were identified as experiencing ENF, with a median time to treatment failure of 6 months (range, 1 to 56 months) after finishing RT. The 2-year ENF rate was 7.6% (Fig 1) among all patients and 9% among patients who achieved local control. Among the 32 patients with ENF, 20 (63%) had stage IIIA/IIIB disease and 19 (59%) were treated with either sequential or concurrent cisplatin-based chemotherapy. Of all the stage IIIA/IIIB patients (n = 341), 72% (n = 247) were treated with either sequential or concurrent cisplatin-based chemotherapy, whereas the remaining 28% (n = 94) received RT alone. The 2-year ENF rate in stage IIIA/IIIB patients who were treated with either sequential or concurrent chemotherapy was 9.2% compared with 3.25% in those stage IIIA/IIIB patients treated with RT alone, but this difference was not statistically significant (P = .98). Patients with a pretreatment PET scan had an 8.6% 2-year rate of ENF compared with 6% in patients without a pretreatment PET scan, but this result was also not statistically significant (P = .73). The regions with the highest ENF rates were the ipsilateral mediastinum (3%) followed by the ipsilateral and contralateral supraclavicular regions (both at 1.8%).
The median doses delivered to the seven lymph node regions and the regional nodal failure rates are listed in Table 2. Among the 42 nodal lesions, six failures (14%) were in nodal regions that incidentally received
This report demonstrates that IFRT is an acceptable technique in the treatment of inoperable NSCLC. The omission of ENI resulted in an acceptably low failure rate in uninvolved lymph node regions and suggests that ENI may not be necessary. Interestingly, the highest nodal failure rates were seen in the ipsilateral inferior mediastinum that was partially included in the PTV, based on the location of most tumors, and received a median dose  45 Gy, which would be considered an elective dose based on the standard treatment technique. Local failure remains a major challenge when treating NSCLC with radiotherapy. In Radiation Therapy Oncology Group study 73-01 a dose-response relationship was observed in elective-nodal regions with an ENF rate as low as 2% when the dose exceeded 45 Gy. However, local failure rates remained high, ranging from 48% to 80%.17 In a review of four Radiation Therapy Oncology Group trials consisting of 1,705 NSCLC patients, Emami et al18 examined the impact of ENI and found that treatment of the ipsilateral hilar region was the only elective nodal region that influenced outcome. Other trials have used ENI in the setting of early-stage disease with limited toxicity and excellent clinical results.19,20 IFRT has become of greater interest in the clinical setting in an attempt to achieve better local control by escalating doses to the GTV while limiting pulmonary toxicity.7,21 In a phase I dose-escalation trial using IFRT, Hayman et al21 reported no isolated ENF in initially uninvolved nodes. Two patients (4%) had ENF simultaneously with distant metastasis and one patient (2%) had ENF concurrently with recurrence within the PTV. Senan et al22 conducted a phase II study of 42 stage III NSCLC patients who were treated with sequential chemotherapy followed by 70 Gy IFRT using 3D-CRT and found no cases of isolated ENF. The in-field failure rate was 27%, with a median follow-up time of 16 months and a median survival of 18 months. Sulman et al23 found an isolated ENF rate of 4% and local recurrence rate of 27% among 118 patients who were treated without ENI. All patients were staged using either FDG-PET or CT, and were treated using 3D-CRT. The role of ENI has been studied in patients with inoperable early-stage NSCLC. Hayakawa et al24 reported on 36 patients with inoperable stage I NSCLC to examine the role of ENI. Among patients treated with IFRT, only one ENF (4%) was observed. Cheung et al25 reported an ENF rate of 6.6% among 102 stage I/II inoperable NSCLC patients treated to 52.5 Gy with IFRT. Local recurrence in this study was high at 68.9%, but was attributed to the delivery of a subtherapeutic dose. Bradley et al26 compared overall survival rates in 56 patients with inoperable stage I disease treated with 3D-CRT. Twenty-two patients had received ENI to doses of 45 to 50 Gy and 33 patients were treated using IFRT. The median dose was 70 Gy and median follow-up time was 20 months. The ENF rate in the patients treated with IFRT was 6% (two patients) and radiation dose was the only prognostic factor of overall survival. Most recently, in a prospective randomized trial, Yuan et al27 evaluated the effects of IFRT in 193 patients with stage III NSCLC who were treated with two to three cycles of cisplatin-based chemotherapy before and after RT. Patients were randomly assigned to IFRT to 68 to 74 Gy or ENI to 60 to 64 Gy using 3D-CRT. Preliminary results report an improvement in overall survival (38.7% v 25.6% at 2 years; P = .048) in the IFRT group. The ENF rate was 7% in the IFRT group, similar to the rate observed in our study. The main cause of failure was local failure, reported as 49% in the ENI group and 41% in the IFRT group at 2 years. Although preliminary, results from this study show that dose escalation with IFRT combined with chemotherapy may lead to more favorable outcomes in patients with inoperable stage III NSCLC.27 Our study represents the largest patient population in which IFRT has been used for NSCLC. Our ENF rate of 8% is comparable to those observed at other centers. We observed a local control rate of 51% at 2 years, which is higher than that reported in many studies treating patients with standard RT. Several factors, however, may have influenced our results. It is possible that because our patients had advanced disease and therefore were at higher risk of experiencing local failure, any ENF would have been masked based on our definition. In addition, in patients who developed distant metastasis, ENF may not have been evaluated vigilantly. In this study, 60% of patients received pre-RT FDG-PET scans for staging and GTV delineation, and surprisingly, the use of FDG-PET did not influence the ENF rate. This study confirms that ENF rates remain low despite the use of IFRT in treatment of inoperable NSCLC with radiation. It has also been established that even when IFRT is used, certain nodal regions may receive an adequate elective dose.16,28 Our study also demonstrates that incidental doses to elective nodal areas can be substantial, despite the attempt not to treat these regions. It has been suggested that in some clinical situations the dose to at-risk nodal regions is large enough to consider the treatment to have included ENI.29 Local recurrence continues to be a major challenge in treating NSCLC with radiotherapy. Dose escalation has been shown to reduce local failure rates but in the setting of ENI is often limited by pulmonary toxicity.17,29,30 Therefore, currently, we advocate the use of IFRT in patients with inoperable NSCLC.
The author(s) indicated no potential conflicts of interest.
Conception and design: Kenneth E. Rosenzweig, Andrew Jackson, Ellen Yorke Administrative support: Kenneth E. Rosenzweig Provision of study materials or patients: Kenneth E. Rosenzweig Collection and assembly of data: Kenneth E. Rosenzweig, Sonal Sura, Ellen Yorke Data analysis and interpretation: Kenneth E. Rosenzweig, Sonal Sura, Andrew Jackson, Ellen Yorke Manuscript writing: Kenneth E. Rosenzweig, Sonal Sura, Andrew Jackson, Ellen Yorke Final approval of manuscript: Kenneth E. Rosenzweig
published online ahead of print at www.jco.org on November 5, 2007. Supported by Gant No. PO1-CA-59017 from the National Cancer Institute, National Institutes of Health. Presented at the American Society for Therapeutic Radiation Oncology Annual Meeting, November 7, 2006, Philadelphia, PA. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Rosenzweig KE, Mychalzhak B, Fuks Z, et al: Final report of the 70.2-Gy and 75.6-Gy dose levels of a phase I dose escalation study using three-dimensional conformal radiotherapy in the treatment of inoperable non-small cell lung cancer. Cancer J 6:82-87, 2000[Medline] 7. Rosenzweig KE, Sim SE, Mychalczak B, et al: Elective nodal irradiation in the treatment of non-small-call lung cancer with three-dimensional conformal radiation therapy. Int J Radiat Oncol Biol Phys 50:681-685, 2001[CrossRef][Medline] 8. Mohan R, Barest G, Breqster LJ, et al: A comprehensive three-dimensional radiation treatment planning system. Int J Radiat Oncol Biol Phys 15:481-495, 1988[CrossRef][Medline] 9. Mohan R: Dose computations for three-dimensional radiation treatment planning. Australas Phys Eng Sci Med 12:241-251, 1989[Medline] 10. Lyman JT: Complication probability as assessed from dose-volume histograms. Radiat Res Suppl S13-S19, 1985 11. Kutcher Gj, Burman C, Brewster L, et al: Histogram reduction method for calculating complication probabilities for three-dimensional treatment planning evaluations. Int J Radiat Oncol Biol Phys 21:137-146, 1991[Medline] 12. Burman C, Kutcher GJ, Emami B, et al: Fitting of normal tissue tolerance data to an analytic function. Int J Radiat Oncol Biol Phys 21:123-135, 1991[Medline] 13. Withers HR, Taylor JMG, Maciejewski B: Treatment volume and tissue tolerance. Int J Radiat Oncol Biol Phys 14:751-759, 1988[Medline] 14. Yorke ED, Jackson A, Rosenzweig KE, et al: Dose-volume factors contributing to the incidence of radiation pneumonitis in non-small cell lung cancer patients treated with three-dimensional conformal radiation therapy. Int J Radiat Oncol Biol Phys 54:329-339, 2002 (2 suppl)[Medline] 15. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef] 16. 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] 17. Perez CA, Pajak TF, Rubin P: Long-term observations of the patterns of failure with unresectable non-oat cell carcinoma of the lung treated with definitive radiotherapy. Cancer 59:1874-1881, 1987[CrossRef][Medline] 18. 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] 19. Jeremic B, Shibamoto Y, Acimovic LJ, et al: Hyperfractionated radiotherapy alone for clinical stage I non-small cell lung cancer. Int J Radiat Oncol Biol Phys 38:521-525, 1997[CrossRef][Medline] 20. Jeremic B, Shibamoto Y, Acimovic LJ, et al: Hyperfractionated radiotherapy alone for clinical stage II non-small cell lung cancer. Radiother Oncol 51:141-145, 1999[CrossRef][Medline] 21. Hayman JA, Martel MK, Ten Haken RK, et al: Dose escalation in non-small cell lung cancer using three-dimensional conformal radiation therapy: Update of a phase I trial. J Clin Oncol 19:127-136, 2001 22. Senan S, Burgers S, Samson MJ, et al: Can elective nodal irradiation be omitted in stage III non-small-cell lung cancer? Analysis of recurrences in a phase II study of induction chemotherapy and involved-field radiotherapy. Int J Radiat Oncol Biol Phys 54:999-1006, 2002[CrossRef][Medline] 23. Sulman EP, Chang JY, Liao Z, et al: Exclusion of elective nodal irradiation does not decrease local regional control of non-small cell lung cancer. Int J Radiat Oncol Biol Phys 63:S226-S227, 2005 (abstr 1) 24. Hayakawa K, Mitsuhashi N, Saito Y, et al: Limited field irradiation for medically inoperable patients with peripheral stage I non-small cell lung cancer. Lung Cancer 26:137-142, 1999[CrossRef][Medline] 25. Cheung PCF, Mackillop WJ, Dixon P, et al: Involved-field radiotherapy alone for early-stage non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 48:703-710, 2000[CrossRef][Medline] 26. Bradley JD, Wahab S, Lockett MA, et al: Elective nodal failures are uncommon in medically inoperable patients with stage I non-small-cell lung carcinoma treated with limited radiotherapy fields. Int J Radiat Oncol Biol Phys 56:342-347, 2003[CrossRef][Medline] 27. Yuan S Sr, Yu J, Sun X Sr, et al: Three-dimensional conformal involved-field radiotherapy for stage III non-small cell lung cancer. J Clin Oncol 24:375s, 2006 (suppl; abstr 7044) 28. Martel MK, Sahijdak WM, Hayman JA, et al: Incidental dose to clinically negative nodes from conformal treatment fields for non-small cell lung cancer. Int J Radiat Oncol Biol Phys 45:244, 1999 (abstr)[CrossRef] 29. Jeremic B: Incidental irradiation of nodal regions at risk during limited-field radiotherapy (RT) in dose-escalation studies in non-small cell lung cancer (NSCLC): Enough to convert no-elective into elective nodal irradiation (ENI)? Radiother Oncol 71:123-125, 2004[CrossRef][Medline] 30. Pu AT, Harrison AS, Robertson JM, et al: The toxicity of elective nodal irradiation in the definitive treatment of non-small cell carcinoma of the lung. Int J Radiat Oncol Biol Phys 39:196, 1997 (abstr) Submitted June 26, 2007; accepted July 31, 2007.
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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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ABSTRACT
INTRODUCTION
