Radiation therapy plays an important role in the treatment

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1 The Rationale and Use of Three-Dimensional Radiation Treatment Planning for Lung Cancer* Lawrence B. Marks, MD; and Gregory Sibley, MD Treatment of lung cancer with conventional radiation therapy is associated with suboptimal local tumor control and poor long-term survival. Poor local tumor control may result from inaccurate tumor targeting, failure to satisfactorily conform to dose distribution with the target volume, and/or inadequate radiation doses. Three-dimensional treatment planning is a radiotherapy technique that provides more accurate dose targeting via the direct transfer of three-dimensional anatomic information from diagnostic scans into the planning process. This technology can assist treatment planning by providing dose-volume histograms, an estimation of normal tissue complication probabilities, and facilitate dose escalation. Preliminary clinical studies suggest that this is a feasible approach worthy of additional study. The three-dimensional tools provide new opportunities to better understand radiation-induced changes in pulmonary function. (CHEST 1999; 116:539S 545S) Abbreviations: DVH dose-volume histogram; NSCLC non-small cell lung cancer; SCLC small cell lung cancer Radiation therapy plays an important role in the treatment of patients with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). For NSCLC, postoperative radiation is generally recommended for patients with positive nodes, or if the primary tumor is adherent/invasive into adjacent structures such as the mediastinum. In these situations, the addition of radiation clearly improves the local/regional control rate, and might also have a positive impact on survival. For patients with unresectable cancer, high-dose external beam radiation therapy, generally combined with systemic chemotherapy (either sequentially or concurrently), is typically recommended for patients with a reasonably good performance status. 1 While cures are relatively infrequent among patients with unresectable disease, most patients do have a tumor response, symptoms referable to local/regional tumor are either alleviated or prevented, and a definite fraction, albeit small, is rendered diseasefree. Radiation therapy is the most common local treatment for locally advanced NSCLC. However, when local tumor control is carefully assessed, radiation appears to control *From the Department of Radiation Oncology, Duke University Medical Center, Durham, NC. Supported in part by National Cancer Institute grant CA Correspondence to: Lawrence B. Marks, MD, Box 3085, Duke University Medical Center, Durham, NC 27710; marks@radonc.duke.edu 20% of patients intrathoracic tumors. 2 Inadequate local control likely contributes to the poor survival rate. The development and implementation of more effective radiotherapy techniques may improve local tumor control, and possibly therefore improve long-term survival. This paper provides an overview of three-dimensional treatment planning for lung cancer. Among patients with limited stage SCLC, treatment is typically multiagent systemic chemotherapy plus thoracic irradiation. The addition of thoracic radiation clearly improves intrathoracic control, and has a modest, although real and significant, beneficial impact on overall survival. 3 5 Even with thoracic irradiation, local control remains a problem in SCLC. Just as for NSCLC, three-dimensional planning might facilitate higher radiation doses and improve outcome for SCLC. 6 Rationale For Three-Dimensional Treatment Planning Conventional Treatment Planning The radiation oncologist s goal is to irradiate the target structures and minimize incidental irradiation of nontarget tissues (eg, lung, heart, spinal cord, brachial plexus, etc). Radiation oncologists typically rely on diagnostic CT images to provide three-dimensional anatomic information of structures of interest. In conventional planning, this information is transferred onto simulation films (plain radiographs obtained in the treatment position) by the radiation oncologist drawing (with a wax pencil) the volumes of interest. In this regard, radiation oncologists have been performing three-dimensional treatment planning and reconstruction for years, but basically in our heads. The essence of three-dimensional radiation treatment planning (described below) is to accurately transfer the threedimensional information for example, from CT, directly into the simulation process. With conventional planning, radiation fields are generally limited to conventional directions, such as anterior, posterior, lateral, or simple oblique orientations. Historically, radiation fields were oriented in these directions because these were the directions from which diagnostic radiologists were accustomed to viewing. As radiation beams are rotated away from these traditional directions, the relationship between intrathoracic structures becomes more difficult to understand. The computer-assisted transfer of complex threedimensional geometric information facilitates the use of unusual beams and is essential when very unconventional radiation treatment fields are used. We now routinely treat patients with radiation beams oriented from very unusual angles, and three-dimensional treatment planning tools are required. Nevertheless, it is important to recognize that three-dimensional planning does provide improved transfer of three-dimensional anatomic data to the simulation process, even when conventional beam orientations are used. Because of the intimate relationship between target and normal tissue within the thorax, it is incumbent on the radiation oncologist to accurately delineate the CHEST / 116 / 6/ DECEMBER, 1999 SUPPLEMENT 539S

2 structures that should be irradiated and minimize incidental irradiation of nontarget structures. Without three-dimensional planning, radiation oncologists often make the field larger than it needs to be in order to compensate for uncertainties in the definition of the target volume. Figures 1 6 are from the planning system used at Duke (PLUNC: Plan UNC; University of North Carolina) and illustrate the key features of three-dimensional treatment planning. Targets and beams are defined and viewed (Figs 1 3), unusual beam orientations to spare normal structures (eg, heart) can be used (Figs 4, 5), and doses can be accurately calculated (Fig 6). The details of the three-dimensional planning procedure are described below. Three-Dimensional Treatment Planning Process The procedure currently used for three-dimensional treatment planning at Duke University is described below. This system initially was conceived, developed, and implemented at the University of North Carolina at Chapel Hill. 7 9 We gratefully acknowledge the university s gracious support in helping to develop the three-dimensional treatment planning effort at Duke. The patient is immobilized in a custom-made cradle device designed specifically to maintain the patient s position consistently throughout treatment. Because radiation is delivered every day over a several-week period, it is important that use of these immobilization devices be considered to assure reproducibility of patient position throughout the prolonged treatment time. 10 The immobilization device serves to keep the patient in a consistent position, but also provides a place for setup marks to be drawn. When a cradle is not used, setup marks are limited to the patient s skin. Modest alterations in the patient s position, as well as the arm position, will move the skin, and therefore the setup marks, relative to the intrathoracic structures. Figure 2. Digitally reconstructed radiograph of the anterior beam portal designed to treat the clinical target volume (CTV) with margin. GTV gross target volume. Imaging: Three-dimensional imaging, typically CT scanning, is performed in the treatment position. The patient can go home afterwards and the staff members proceed, at their own pace, with the following steps. Outlining: In the image segmentation or outlining step, the physician, dosimetrist, or physicist defines all structures of interest on the multiple CT images, including the gross target, clinical target (gross target and areas at risk for microscopic spread, such as electively treated lymph nodes), and normal structures. Figure 1. Three-dimensional treatment planning using Plan UNC treatment planning software for a patient with T3N2 NSCLC of the right lower lobe. The gross target volume (GTV) and clinical target volume (CTV) are shown on a CT image. The path of an anterior-posterior beam that includes the CTV with margin is shown. Figure 3. The path of the off-cord boost field that includes the gross target volume (GTV) is shown on a CT image. This boost field is a left-anterior-superior oblique. This beam orientation is chosen in order to reduce the volume of heart that is irradiated (see Fig 5). 540S Multimodality Therapy of Chest Malignancies Update 98

3 Figure 6. Isodose distribution showing the contribution from the initial and boost fields. The gross target volume (GTV) receives a full dose (.98% of the prescribed dose), while the clinical taget volume receives a lesser dose (.60% of the prescribed dose). Figure 4. Digitally reconstructed radiograph of the left-anteriorsuperior oblique beam designed to treat the gross target volume (GTV) with margin while omitting the spinal cord. This beam orientation is chosen in order to reduce the volume of heart that is irradiated (see Fig 5). Treatment planning: Using three-dimensional treatment planning software, the structures of interest can be viewed in real time from any orientation, commonly as a series of wire contours. The planner is free to consider beams from any direction as the software provides a continuous display of the beam s eye view of the structures of interest.11 Desired beam orientations are chosen, and radiation treatment beams are designed on the threedimensional image data set. The computer system provides all of the information generally provided from the conventional simulator, including setup instructions, digitally reconstructed radiographs (in lieu of simulator films), dose distributions, and dose-volume histograms (DVHs). Potential Shortcomings and the Role of a Physical Simulation Figure 5. An anterior view of the patient with two off-cord oblique options shown. The left-anterior oblique field is in the axial plane and incidentally includes some of the heart. The left-anterior-superior oblique field used in this patient reduces the amount of heart irradiated. Furthermore, the field size is smaller for the superiorly obliqued beam than for the axial beam because the former is oriented along the long axis of the target. Prior to starting treatment, the patient is brought to the physical simulator wherein the computer-planned treatment beams are implemented on the patient, to test that they are indeed implementable. Occasionally, radiation beams are designed on the computer but cannot be delivered because of collisions between the patient/couch and the treatment gantry. In addition, the physician needs to check that the treatment beams look clinically appropriate on the patient because the three-dimensional treatment planning process is sometimes deceiving. For example, if one forgets to contour a particular structure of interest (such as a normal structure that should be blocked), one might forget to exclude this structure from the treatment portal defined on the computer. Bringing the patient to the physical simulator helps the physician to assess the clinical appropriateness of the treatment beams. This last step becomes increasingly difficult as very unusual treatment beams are used, because it becomes increasingly difficult for the physician to visualize whether the beam is appropriately shaped and/or positioned. In these settings, we are relying heavily on the technology. Extreme care should be taken to assure that beams are arranged as desired. There is the potential for the users of these advanced treatment planning tools to become comchest / 116 / 6 / DECEMBER, 1999 SUPPLEMENT 541S

4 placent because it must be right the computer said so. There is also a tendency to make radiotherapy fields relatively small when three-dimensional tools are used. Organ motion and setup uncertainty might lead to underdosage at the target edge if margins are inadequate. Normal Tissue Considerations One of the major advances of three-dimensional treatment planning is that we now know, for the first time, the accurate dose distribution throughout normal structures. In the past, radiation oncologists have relied on their gut feelings to determine how much lung or heart could safely be irradiated. Conventional tolerance doses/volumes were based on anecdotes and vague clinical impressions. 12 Over the last few years, however, many investigators have used three-dimensional tools to better understand the normal tissue consequences of thoracic irradiation For example, in the lung, we and others have prospectively studied radiation-induced changes in pulmonary function, and related these to the three-dimensional dose distribution A three-dimensional radiation dose distribution is usually complex, and cumbersome for the physician to assimilate. DVHs have been utilized as a tool to condense the dose data DVHs describe what percent of each organ receives what dose of radiation. Two types of histograms have been used: differential and cumulative. For the differential dose distribution, the y-axis represents the percent of the organ irradiated to whatever dose is shown on the x-axis. For the cumulative histograms, the y-axis value represents the percent of the target receiving any dose greater than or equal to the dose on the x-axis. It is important to recognize that these DVHs discard all spatial information. This might be important since some regions of the lung might be more (or less) functionally important. 23 We have been calculating the dose distribution within the perfused (functioning) portion of the lung and have developed the concept of functional DVHs. 23,24 Empiric models have been derived to relate the DVH to incidences of pulmonary complications These models have been tested in several patient data sets; overall, they are useful in predicting the relative risk of pulmonary complication. 16,17,25 In a multi-institutional study of 540 patients, the average dose delivered to the lung (a very easy quantity to calculate) appears also to be related to the relative risk of radiation-induced pulmonary dysfunction. 19 These approaches do not consider preradiotherapy pulmonary function and appear to be less predictive in patients with very poor preradiotherapy pulmonary function. 17,24,26 An alternative approach has been to relate the dose delivered to each region of the lung, with changes in function at that individual region. Advances in nuclear medicine imaging have led to single-photon emission CT lung scans that provide a three-dimensional map of relative perfusion within the lung. These scans are performed before and sequentially following radiation, and percent reductions in regional function are correlated with regional radiation dose. These studies have been conducted for many years at Duke University and at the Netherlands Cancer Institute. 27,28,42 Dose-response curves for regional radiation-induced reductions in pulmonary function have been derived. Attempts are currently underway at both institutions to assess whether the sum of regional effects is correlated with the changes in pulmonary symptoms or changes in pulmonary function tests. 27,29,30 Clinical Trials Published trials on the use of three-dimensional radiotherapy have demonstrated feasibility and reported promising outcome results with limited toxicity. The University of Michigan was one of the pioneering institutions using three-dimensional radiotherapy. At that institution, Hazuka et al 11 have reported results for 88 consecutive patients with medically inoperable or locally advanced unresectable NSCLC treated with radiotherapy alone. Many patients were treated with conventional fields with conformal planning limited to the boost fields. The median dose for all patients was 67.6 Gy (range, 60 to 74 Gy). Results are shown in Table 1. The median survival time was 15 months, and the 2- and 3-year overall actuarial survival rates were 37 and 15%, respectively. The 1- and 3-year local progression-free survivals were 76 and 44%, respectively. Sixty-two percent of patients developed local failure and no dose response was seen except in the subset of stage IIIa patients who had improved local progressionfree survival with higher doses. The authors report a 9% incidence of pneumonitis, with only one patient experiencing a grade 4 reaction. In summary, local failure was common while toxicity was acceptable, indicating a need for further dose escalation. Follow-up studies at the University of Michigan have utilized an elaborate system to group patients into dose escalation bins based on their predicted potential for pulmonary toxicity (normal tissue complication probability). 31 Forty-eight NSCLC patients receiving 2.1-Gy fractions (corrected for tissue inhomogeneity) to doses of 92.4 Gy were evaluated. No elective nodal treatment Table 1 University of Michigan Results Following High-Dose Thoracic Radiation Using Beam s-eye View in Unresectable NSCLC* No. of patients 88 Median follow-up, mo (range) 24 (12 78) Median survival time, mo 15 2-yr survival 37% 3-yr survival 15% Median time to local progression, mo 29 1-yr local progression-free survival 76% 3-yr local progression-free survival 44% Overall response, no. (%) 58 (55) Complete response, no. (%) 14 (16) Partial response, no. (%) 34 (39) *Data from Hazuka et al S Multimodality Therapy of Chest Malignancies Update 98

5 Table 2 University of Chicago: Results Following Treatment of Stage III NSCLC Using High-Dose Conformal Radiotherapy* No. of patients 37 Median follow-up, mo (range) 18.9 ( ) Median overall survival time, mo yr overall survival 75% 2-yr overall survival 37% Median local progression-free survival, mo yr local progression-free survival 23% *Data from Sibley et al. 32 was used. No radiation pneumonitis occurred in 30 patients alive with follow-up 6 months, and no isolated failures were observed in untreated nodal sites. Three of 10 patients treated to doses of 84 Gy failed locally. At Washington University, Graham et al 16 reported a series of 70 patients with inoperable stage I to IIIB lung cancer (65 with NSCLC, 5 with SCLC) who received conformal radiotherapy (5 SCLC patients received additional chemotherapy). Stage I/II cancer was diagnosed in 20 patients, stage IIIA in 36, and stage IIIB in 14. Patients were treated to a median dose of 69 Gy (range, 60 to 74 Gy). The authors found a 15% local failure rate, with no failures observed in electively untreated nodal sites. The 2-year survival rate was 44%, with a better survival rate seen in patients with local tumor control compared with those with local failure (47 and 31%, respectively). Toxicity included a 6% incidence of fatal pneumonitis, which was volume-related. The University of Chicago described results for 37 patients with stage III NSCLC who received a median dose of 66 Gy (range, 60 to 70 Gy). 32 Similar to the University of Michigan series, the 2-year survival rate was 37%, local progression was seen in 64% of the patients, and no isolated recurrences in the untreated nodal volumes were observed. The median follow-up time was 19 months (range, 10 to 40 months). Two patients developed radiation pneumonitis that resolved with corticosteroid therapy. Leibel et al 33 and Armstrong et al 34,43 at Memorial Sloan-Kettering Cancer Center treated 45 patients with stage I to IIIB NSCLC using three-dimensional radiotherapy. 33,34 Radiation doses ranged from 52.2 to 72.0 Gy (mean, 70.2 Gy). Thoracic progression occurred in 46% of patients, and the 2-year survival rate was 33%. 34 Grade 3 or greater pulmonary toxicity was observed in 9% of patients, occurring most frequently in patients in whom 30% of lung volume received a dose of 25 Gy. At Duke University, we recently reviewed 94 patients with stage I to III NSCLC receiving high-dose threedimensional conformal radiotherapy with 6 months of follow-up. The typical approach was to deliver 45 Gy at 1.25 Gy bid to electively treated sites and 73.6 Gy at 1.6 Gy bid to sites of gross disease (6-h interval, uncorrected for tissue inhomogeneity) using a concurrent boost technique. 35,36 Toxicity included 20 cases of acute grade 3 toxicity (esophagus, n 14; pneumonitis, n 2; skin, n 4) and 19 cases of grade 3 to 5 late toxicity (esophagus, n 4 [one grade 4]; pneumonitis, n 12 [one grade 5]; skin, n 5; pericarditis, n 2 [both grade 4]). Analyses relating esophageal and pulmonary toxicity to the threedimensional dose distribution are underway. 37 A biological toxicity marker, transforming growth factor, is also being examined. 38 The 5-year overall survival rates in patients with stage I, IIIA, and IIIB disease are 47%, 10%, and 7%, respectively. In a separate analysis, we prospectively surveyed treating physicians to assess the impact of threedimensional planning in the treatment of 133 patents irradiated for lung cancer from 1995 through 1997 at Duke University. Ninety-two percent had gross intrathoracic disease. Compared with what would have been done without it, three-dimensional treatment planning resulted in altered beam arrangements in 52 and 84% of initial and boost treatment fields, respectively. The field shapes were altered in 85% of cases. Three-dimensional Planning Issues in SCLC Pre- vs Postchemotherapy Tumor Volumes For patients receiving systemic chemotherapy prior to thoracic irradiation, there is often a marked shrinkage in the intrathoracic abnormality. Studies have suggested that the radiation field need only include the postchemotherapy volume. 39,40 However, one needs to be careful interpreting this clinical data. The Liengswangwong 39 study was retrospective. In the study by Kies et al 40 a group of patients was randomized to radiotherapy based on the pre- vs postchemotherapy volumes. However, only patients with stable disease or a partial response were randomized, and those who were treated to the prechemotherapy volumes had a field reduction after 18 Gy. In our opinion, the approach for nodal disease and parenchymal lung disease should be different. For a tumor within the lung parenchyma that responds, it seems reasonable to consider residual microscopic foci of tumor to be present throughout the initially involved region of the lung. If there is a complete response at the primary site to chemotherapy, should radiotherapy be omitted because there is no postchemotherapy abnormality? Conversely, is mediastinal disease that is extrapleural and displaces the lung laterally more likely to shrink medially as it regresses? Our policy in patients who have had dramatic response following chemotherapy is to irradiate previous sites of intraparenchymal disease, but treat the posttreatment central nodal mass. This approach is analogous to mediastinal lymphoma cases, in which consolidative radiation to the postchemotherapy mediastinal volume appears adequate to improve outcome. Patients often present to the radiation oncologist after chemotherapy, and treatment planning scans therefore illustrate only postchemotherapy volumes. Advanced treatment planning software is available to fuse the prechemotherapy and postchemotherapy images, such that the prechemotherapy volumes can be seen on the postchemotherapy scan. 41 CHEST / 116 / 6/ DECEMBER, 1999 SUPPLEMENT 543S

6 Multimodality Imaging Three-dimensional treatment planning tools facilitate the fusion of different diagnostic images. For example, positron emission tomography nuclear medicine studies can be used to identify areas of increased metabolic activity related to the tumor. Similarly, single-photon emission CT lung perfusion scans have been used to identify areas of relatively functioning lung so that radiation beams might be designed to avoid these regions. 23 Conclusion In summary, computer-assisted radiotherapy planning enables radiation oncologists to more accurately irradiate target tissues, and minimize incidental irradiation of nontarget structures. More accurate targeting of the radiation beam to the volume at risk should facilitate the use of higher doses of radiation, which should increase local/ regional control and, we hope, survival. Preliminary clinical studies suggest that this might be a fruitful approach. The three-dimensional tools provide new opportunities to better understand radiation-induced changes in pulmonary function. ACKNOWLEDGMENT: Thanks to G. Bentel for assistance with figures and to J. Forest for administrative support. References 1 Dillman RO, Seagren SL, Propert KJ, et al. A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer. N Engl J Med 1990; 323: Arriagada R, Le Chevalier T, Quoix E, et al. ASTRO (American Society for Therapeutic Radiology and Oncology) plenary: effect of chemotherapy on locally advanced non-small cell lung carcinoma; a randomized study of 353 patients. Int J Radiat Oncol Biol Phys 1991; 20: Warde P, Payne D. Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J Clin Oncol 1992; 10: Perry MC, Eaton WL, Propert KJ, et al. 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7 29 Theuws JCM, Kwa SLS, Wagenaar AC, et al. Prediction of overall pulmonary function loss in relation to the 3-D dose distribution, for patients with breast cancer and malignant lymphoma. Radiat Oncol 1999; 49: Fan M, Hollis D, Munley MT, et al. Can we predict radiation (RT)-induced changes in pulmonary function tests (PFTs) based on the lung dose-volume histogram [abstract]? Int J Radiat Oncol Biol Phys 1999; 45(suppl): Robertson JM, Ten Haken RK, Hazuka MB, et al. Dose escalation for non-small cell lung cancer using conformal radiation therapy. Int J Radiat Oncol Biol Phys 1997; 37: Sibley GS, Mundt AJ, Shapiro C, et al. The treatment of stage III nonsmall cell lung cancer using high dose conformal radiotherapy. Int J Radiat Oncol Biol Phys 1995; 33: Leibel SA, Armstrong JG, Kutcher GJ, et al. 3-D conformal radiation therapy for non-small cell lung carcinoma: clinical experience at the Memorial Sloan-Kettering Cancer Center. Front Radiat Ther Oncol 1996; 29: Armstrong J, Raben A, Zelefsky M, et al. Promising survival with three-dimensional conformal radiation therapy for nonsmall-cell lung cancer. Radiother Oncol 1997; 44: King SC, Acker JC, Kussin PS, et al. High-dose, hyperfractionated, accelerated radiotherapy using a concurrent boost for the treatment of nonsmall cell lung cancer: unusual toxicity and promising early results. Int J Radiat Oncol Biol Phys 1996; 36: Sibley GS, Maguire PD, Anscher MA, et al. High dose radiation therapy: the Duke experience. Proc Am Soc Ther Radiat Oncol 1999; 45(suppl): Maguire PD, Sibley GS, Zhou SM, et al. Clinical and dosimetric predictors of radiation-induced esophageal toxicity. Int J Radiat Oncol Biol Phys 1999; 45: Anscher MS, Kong FM, Andrews K, et al. Plasma transforming growth factor 1 as a predictor of radiation pneumonitis. Int J Radiat Oncol Biol Phys : Liengswangwong V, Bonner JA, Shaw EG, et al. Limitedstage small-cell lung cancer: patterns of intrathoracic recurrence and the implications for thoracic radiotherapy. J Clin Oncol 1994; 12: Kies MS, Mira JG, Crowley JJ, et al. Multimodal therapy for limited small-cell lung cancer: a randomized study of induction combination chemotherapy with or without thoracic radiation in complete responders; and with wide-field versus reduced-field radiation in partial responders: a Southwest Oncology Group study. J Clin Oncol 1987; 5: Rosenman JG, Miller EP, Tracton G, et al. Image registration: an essential part of radiation therapy treatment planning. Int J Radiat Oncol Biol Phys 1998; 40: Levinson B, Marks LB, Munley MT, et al. Regional dose response to pulmonary irradiation using a manual method. Radiother Oncol 1998; 48: Armstrong JG, Zelefsky MJ, Leibel SA, et al. Strategy for dose escalation using 3-dimensional conformal radiation therapy for lung cancer. Ann Oncol 1995; 6: CHEST / 116 / 6/ DECEMBER, 1999 SUPPLEMENT 545S