2.2.5 Target Volumes in Small Cell Lung Cancer

Target Volumes in Small Cell Lung Cancer 111 2.2.5 Target Volumes in Small Cell Lung Cancer Yolanda I. Garces and James A. Bonner CONTENTS 2.2.5.1 Introduction 111 2.2.5.2 Tumor Volume Definitions 111 2.2.5.3 Case Example 112 2.2.5.4 Prechemotherapy vs. Postchemotherapy Volumes 115 2.2.5.4.1 Randomized Study 115 2.2.5.4.2 Retrospective Studies 116 2.2.5.5 Advantages and Disadvantages of Prechemotherapy and Postchemotherapy Treatment Volumes 118 2.2.5.6 Our Treatment Model 118 2.2.5.7 Factors for a Radiation Oncologist to Consider 119 2.2.5.8 Conclusions 120 References 120 2.2.5.1 Introduction Advances have been made in the last 30 years in the treatment of limited-stage small cell lung cancer (LSSCLC). Cisplatin-based chemotherapy, the integration of radiotherapy concurrent with chemotherapy, and the incorporation of prophylactic cranial irradiation into the curative treatment of this group of patients have been responsible for these advances. However, key issues related to planning and delivery of radiotherapy remain unsettled. These interwoven issues include radiobiology, timing, dose, fractionation, and the volume of disease treated with radiotherapy. The focus of this chapter is on the evolution of treatment volumes over time Y. I. Garces, MD Consultant, Division of Radiation Oncology, Mayo Clinic; Assistant Professor in Oncology, Mayo Clinic College of Medicine; Charlton Building, 200 1st Street, S.W., Rochester, MN 55905, USA J. A. Bonner, MD Merle M. Salter Professorship, Chair Department of Radiation Oncology; Department of Radiation Oncology, University of Alabama at Birmingham; Wallace Tumor Institute Suite 105, 1824 6th Avenue, South, Birmingham, AL, 35233, USA and the controversies surrounding radiation target volumes for patients with LSSCLC. The possible considerations for radiation oncologists wanting to encompass appropriate treatment volumes for patients with LSSCLC are reviewed. Initially, radiation was the treatment of choice for LSSCLC. However, systemic recurrences of disease were commonplace, and eventually the pendulum swung to chemotherapy as the main treatment. In the 1970s and early 1980s, it was noted that the addition of radiotherapy to chemotherapy improved overall survival and local control in the chest, and this was confirmed by meta-analyses reported in the early 1990s (Pignon et al. 1992; Warde and Payne 1992). More recently, radiation in the form of prophylactic cranial irradiation has also been shown to improve survival (Aupérin et al. 1999); thus, both radiotherapy and chemotherapy are integral components in the successful treatment of LSSCLC. Thoracic radiation was typically directed at the primary tumor, ipsilateral hilum, entire mediastinum, and supraclavicular fossae bilaterally. This was the treatment for LSSCLC as long as radiation was delivered to a tolerable radiation field. Elective nodal irradiation for LSSCLC has not been the subject of clinical trials or retrospective studies except possibly when treating the supraclavicular areas. Therefore, the focus of this chapter is on radiotherapy tumor volumes, specifically prechemotherapy versus postchemotherapy volumes in the treatment of LSSCLC. 2.2.5.2 Tumor Volume Definitions First, to discuss radiotherapy treatment volumes adequately, some standard definitions have to be reviewed. Report number 62 (a supplement to report number 50) of the International Commission on Radiation Units (ICRU) and Measurements (1999) provides guidance and makes recommendations for the use of radiotherapy. The report provides

112 Y. I. Garces and J.A. Bonner radiation oncologists, physicists, and dosimetrists with a common language and standard definitions so that radiation doses conform to uniform guidelines from study to study. The gross tumor volume (GTV) can consist of the primary tumor, the nodal volumes, or metastatic disease that is grossly evident on clinical examination or the Tumor Node Metastasis American Joint Committee on Cancer (TNM AJCC)-approved imaging modalities used for staging (Greene et al. 2002). The clinical target volume (CTV) contains the GTV or any microscopic or subclinical extension (or both) and is the volume that must be treated for radical therapy. The CTV can encompass the entire GTV, whereby the GTV is within the CTV. Alternatively, the CTV can be separate from the primary GTV. This could occur, for example, in a patient who has a lung tumor in the right lower lobe (GTV) and an elective nodal site (mediastinal nodes), which would be called CTV II ; therefore, the two volumes may not be contiguous [GTV (or CTV I) and CTV II]. However, the lymphatics that drain the peribronchial lymph nodes may also be at risk and may need to be included as an additional intervening CTV. The planning target volume (PTV) includes the GTV and CTV volumes as well as margins to allow for physiologic movement (internal margin) and set-up errors (set-up margin). It is a geometric concept used by physicists and dosimetrists. This volume becomes the volume that allows one to select the beam angles and energies needed to deliver the appropriate dose to the CTV. These definitions are relatively recent and are currently being incorporated into the standard treatment of LSSCLC. They should be used for newly designed trials as well as for studies of dose escalation so that comparisons can be made between studies that likely use widely different treatment planning techniques and three-dimensional conformal radiation fields. Certainly, these definitions have not been used in most of the studies that have been reported on LSSCLC. Therefore, in the rest of this chapter, we will review the field design with respect to gross disease within lung parenchyma as well as nodal regions intended to be included within the radiation field and will not focus on GTV, CTV, or PTV. 2.2.5.3 Case Example An example of a case is given in Figs. 2.2.5.1 2.2.5.4. This is the case of a 61-year-old man who stopped smoking 18 years earlier. He presented with cough, left scapular pain, and mild shortness of breath. He was otherwise healthy and had not lost weight. The Karnofsky performance score was 90. The findings on physical examination, including a detailed examination of the lungs and lymph nodes, were entirely normal. Computed tomography (CT) showed a large left upper lobe mass (Fig. 2.2.5.1a,b). Pulmonary function studies demonstrated a forced expiratory volume in 1 s of 3.24 (81% of predicted); the diffusing capacity of lung for carbon monoxide was 35.5 (122% of predicted). Bronchoscopy disclosed erythema and mucosal nodularity in the distal left main bronchus and complete obstruction of the apical posterior segment of the left upper lobe by an extrinsic process. Brushings from the bronchial tree and biopsy specimens from the precarinal region and left upper lobe bronchus were positive for small cell carcinoma. The staging work-up was completed and was negative. The diagnosis was LSSCLC. Physicians in radiation and medical oncology were consulted and treatment options discussed. The patient elected to participate in an ongoing North Central Cancer Treatment Group (NCCTG) study. He received two cycles of chemotherapy (topotecan and paclitaxel) and was reevaluated 1 month later (Fig. 2.2.5.1c,d). He had a partial response to chemotherapy. Next, he received concurrent chemotherapy (cisplatin and etoposide) and radiotherapy. The radiotherapy was given, according to protocol, to the postchemotherapy volume. However, for illustrative purposes, we fused the prechemotherapy CT scan with the radiation-planning scan. The prechemotherapy volume was outlined. Next, we used the postchemotherapy CT data set (radiation-planning scan) and planned a treatment for the prechemotherapy and postchemotherapy volumes. This enabled us to use the same CT data for the lung volumes. This is how one typically would treat the prechemotherapy volume. Figure 2.2.5.2 shows a digitally reconstructed radiograph with the prechemotherapy volume outlined in red and the postchemotherapy volume indicated with a wire frame in green. No field borders are shown on these digitally reconstructed radiographs; the fields included the superior mediastinum, GTV, ipsilateral hilum, and subcarinal region. A 1.5-cm margin was used for gross disease and a 1.0-cm margin for the lymph node regions. Inferiorly, the field edge was 5 cm below the carina. For this study, the supraclavicular fossae were not included in either treatment plan; whether they should be is a matter of controversy. Both plans were designed to treat with

Target Volumes in Small Cell Lung Cancer 113 a total dose of 54 Gy. Figure 2.2.5.3 shows the two plans just above the level of the carina, with one treatment plan based on the prechemotherapy volume (Fig. 2.2.5.3a) and the other based on the postchemotherapy volume (Fig. 2.2.5.3b). The dose volume histograms for treatment of prechemotherapy volumes and postchemotherapy volumes are shown in Fig. 2.2.5.4. The lung V20 was calculated by dividing the volume of lung receiving 20 Gy or more by the total volume of the lung. This case demonstrates that the difference in V20 would be significant if one were to treat the prechemotherapy volume and the postchemotherapy volume with a V20 of 36% and 28.6%, respectively. It is also possible that if non-coplanar beams had been chosen and a CTV had been used, the V20 would have been even lower. Non-coplanar beams were not allowed for the study in which this patient participated. Concurrent chemotherapy and radiotherapy began 6 weeks after two cycles of induction chemotherapy. a b c d Fig. 2.2.5.1a d. Prechemotherapy CT at the level of (a) the carina and (b) the hilum. Postchemotherapy CT scan (6 weeks) at the level of (c) the carina and (d) the hilum

114 Y. I. Garces and J.A. Bonner a b Fig. 2.2.5.2a,b. Digitally reconstructed radiograph (DRR) demonstrating the prechemotherapy volume (red outline) and postchemotherapy volume (green wire-frame outlines) on an anterior-posterior simulation DRR (a) and oblique DRR (b)

Target Volumes in Small Cell Lung Cancer 115 2.2.5.4 Prechemotherapy vs. Postchemotherapy Volumes The treatment volumes of radiotherapy for LSSCLC have not been studied extensively. This topic needs further thought and should be incorporated into clinical trials. Only one randomized study has addressed this issue, and few retrospective studies have focused on it. In the following sections, the randomized study, the retrospective studies, and some observations about this issue are reviewed, including the advantages and disadvantages of treating the prechemotherapy or postchemotherapy volumes. a b Fig. 2.2.5.3a,b. Isodose curves demonstrating a radiotherapy plan both to 5,400 cgy: one plan is based on the prechemotherapy volume (a, red) and the other is based on the postchemotherapy volume (b, green) Fig. 2.2.5.4. Dose volume histogram of the left and right lungs. The vertical line represents lung volume 2.2.5.4.1 Randomized Study In a Southwest Oncology Group (SWOG) study, all patients were treated initially with vincristine, methotrexate, doxorubicin, and cyclophosphamide for 6 weeks (Kies et al. 1987). After chemotherapy, the disease was restaged to determine if the patient had a complete response, partial response (a decrease in tumor mass by 50% in the largest cross-sectional diameter), stable disease (less than a partial response, but no progressive disease), or progressive disease. Patients with a complete response were assigned randomly to splitcourse thoracic radiation (48 Gy) or to continuation of chemotherapy without thoracic radiation. Patients with a partial response or stable disease were given the same split-course radiation as those with a complete response, but the randomization was based on prechemotherapy or postchemotherapy volumes as determined from chest radiography. This study showed that among the eligible patients with a partial response or stable disease (n=191), there were no differences in failure or survival patterns between those randomly assigned to the prechemotherapy volume and those randomly assigned to the postchemotherapy volume. Toxicity, specifically the risk of radiation pneumonitis, was also similar for the two groups. The frequency of life-threatening or fatal leukopenia was slightly higher in the prechemotherapy volume group (17 of 93 patients) than in the postchemotherapy volume group (8 of 98 patients). The amount of lung tissue spared by the use of postchemotherapy volumes was not quantified. Although the SWOG study failed to show differences in outcomes for those in the prechemotherapy and postchemotherapy volume groups, the conclusions should be viewed circumspectly. The chemotherapy was not cisplatin-based, and it was not given

116 Y. I. Garces and J.A. Bonner concurrently with radiotherapy. The recurrence of disease was defined as intrathoracic or systemic. The authors stated that the port films and followup chest radiographs were reviewed again in only a small proportion of cases and may not reflect infield radiation failures (Kies et al. 1987). The imaging studies and treatment planning were crude by current standards. Chest radiographs were required and lung tomograms were optional for initial staging. These chest radiographs were used to establish the prechemotherapy and postchemotherapy radiation volumes. Because the study was conducted before CT fusion could be accomplished, there possibly was underdosing of prechemotherapy volumes or inaccurate field designs (or both). We have some evidence that even with CT fusion for non-small cell lung carcinoma (NSCLC) the interobserver differences in treatment volumes can be large (Lagerwaard et al. 2002). Also, the patients who had a complete response were randomly assigned to different treatments from those who had a partial response or stable disease, thus leading to questions about the exact volumes that were used for the patients with a complete response. Despite these limitations, this study was important and warrants further consideration in the design of future studies (Wagner 1997). In the future, patterns of disease recurrences need to be collected prospectively and correlated with the radiation volumes so that marginal recurrences and intrathoracic recurrences (in and out of the radiation field) can be described and reported. 2.2.5.4.2 Retrospective Studies Several retrospective studies have focused on treatment volumes and patterns of recurrences. They all have the limitations of retrospective studies, but the information they provide is valuable and contributes to the small body of literature on this subject. Liengswangwong and colleagues (1994) reviewed the cases of 67 consecutive patients. Of these patients, adequate information was available for 59, who were not treated according to any research protocol at Mayo Clinic from 1982 through 1990. Most of these patients received two or three cycles of induction cyclophosphamide-based chemotherapy before thoracic radiotherapy, which was given concurrently with chemotherapy to 55 of the 59 patients. Treatment of the prechemotherapy or the postchemotherapy volume was at the discretion of the treating radiation oncologist, and all treatment planning was based on CT scans. A double split course of radiotherapy was used for 51 patients, with two 3-week intervals separating the 15 Gy in five fractions, for a total dose of 45 Gy in 15 fractions. The local recurrences were reviewed retrospectively and categorized as in-field, marginal (±1 cm out of the margin of the field), or outside the field of radiation. The two comparison groups consisted of 31 patients in whom the prechemotherapy volume was treated and 28 patients in whom the postchemotherapy volume was treated. On average, the postchemotherapy volumes were about 2.5 cm smaller than the prechemotherapy volumes (range, 0.5 5.0 cm). As first site of recurrence, ten of the 31 patients in the prechemotherapy group had in-field failures compared with nine of the 28 patients in the postchemotherapy group. The 14 patients who were assigned to the prechemotherapy group because they did not have a response to chemotherapy may have had a worse prognosis; these patients were analyzed separately. There were no differences in outcomes between the 14 patients in the prechemotherapy group who had no response and the 14 who had a complete and/or partial response. Furthermore, there were no differences in disease-specific or overall survival among the three groups. However, the study had some limitations: (1) The chemotherapy was not cisplatin-based; (2) split-course radiotherapy was used however, it was used uniformly in the majority of patients; (3) the study was small, resulting in even smaller subgroups. Despite these limitations, the study suggested that treating the postchemotherapy volume does not lead to marginal recurrences. A large multicenter randomized clinical trial was conducted by the NCCTG. Building on the off-study experience of Liengswangwong and colleagues (1994), the NCCTG study used postchemotherapy volumes in a prospective manner (Bonner et al. 1999). This trial compared split-course hyperfractionated radiotherapy with once-a-day radiotherapy for LSSCLC, in which all patients had the postchemotherapy volume treated following three cycles of chemotherapy. The authors retrospectively evaluated in-field and out-of-field recurrences. Among 90 patients who had local progression of disease as a component of their initial progression, only seven had out-of-field recurrences. Two of these recurrences were less than 2 cm from the field edge and would have been included had prechemotherapy volumes been treated. Thus, this study strongly suggested that postchemotherapy volumes were appropriate and safe for treating LSSCLC, minimizing the amount of normal lung volume irradiated without compromising disease control.

Target Volumes in Small Cell Lung Cancer 117 Brodin and colleagues (1990) retrospectively reviewed the cases of 53 of their patients who received cyclophosphamide-based chemotherapy followed by a continuous course of radiation (40 Gy in 2-Gy fractions). The radiation was delivered only to the primary tumor with a 1.5-cm margin and included only the adjacent mediastinum. No effort was made to treat all the nodal areas or the supraclavicular fossa unless they were involved. Two of the authors reviewed the radiation simulation films and the prechemotherapy and postchemotherapy chest radiographs. They determined if the prechemotherapy or postchemotherapy volume was covered or if neither volume was covered (protocol violation). The authors reported cure rates and local control rates for patients with limited-stage disease (n=23). Among the 13 patients who had the prechemotherapy volume treated, seven were cured locally, six had in-field recurrences, and none had marginal or out-of-field intrathoracic recurrences. Among the six patients who had the postchemotherapy volume treated, one was cured locally, four had in-field recurrences, none had marginal recurrence, and one had an intrathoracic recurrence outside the radiation field. Among the four patients in the protocol violation group in whom neither the prechemotherapy nor postchemotherapy volume was covered adequately, two were cured locally, one had in-field recurrence, none had marginal recurrence, and one had intrathoracic out-of-field recurrence. The unique feature of this study was that an autopsy was performed on 76% of the subjects, providing reliable data about treatment failure. However, the authors acknowledged it occasionally was difficult to distinguish between recurrent tumor and radiation fibrosis; also, the total dose of radiation was low, which could have led to the increased number of in-field recurrences. In contrast to the report of Brodin and colleagues (1990), Mira and Livingston (1980) showed that the majority of intrathoracic recurrences in their study originated outside the radiation field. These authors reviewed the cases of 45 patients treated at their institution over a 2-year period, including the years 1976 and 1977. This retrospective review included 34 patients who had chemotherapy and radiotherapy as well as follow-up notes and chest radiographs adequate for focusing on the patterns of failure. In total, 17 of the patients had limited-stage disease. Chemotherapy was administered first, followed by radiation to the primary tumor, mediastinum, and both supraclavicular fossae with a 1- to 2-cm margin. The radiation dose varied, but most patients received 3 Gy per day to a total dose of 30 45 Gy (with a split course for the latter). Nine patients died of chest complications, seven of whom had recurrent tumor in the chest. The majority of the recurrences were intrathoracic but outside the radiation field. Similar to the other retrospective studies, the study of Mira and Livingston (1980) was limited by the small number of patients, the limited imaging modalities, the radiation techniques used, and the lack of cisplatin-based chemotherapy. Arriagada and colleagues (1991) reviewed their experience at Institut Gustave-Roussy with two phase II trials that evaluated induction chemotherapy followed by thoracic radiotherapy and additional maintenance chemotherapy between 1980 and 1983. In both studies, thoracic radiotherapy was delivered as a split course. In one study, 15 Gy was given in six fractions over 10 days (three sessions every 4 weeks, for a total dose of 45 Gy); in the other study, a higher total dose (55 Gy) was given. In all, 62 patients with complete remission were included in the review for in-field and marginal recurrences. Twenty-two local recurrences were observed: 16 in-field and six marginal. The authors also reviewed the fields to determine if it was evident whether coverage of the initial tumor volume was adequate ( safety margin of at least 1 cm) or inadequate (initial tumor area not included in the radiation field). Of the 62 patients with complete remission, 50 had inadequate coverage, which was attributed to the reluctance of the radiation oncologist to treat the prechemotherapy volume after significant shrinkage had occurred with induction chemotherapy. There was no difference in outcomes between the patients who had adequate coverage and those who had inadequate coverage, which can be considered to represent prechemotherapy or postchemotherapy volumes, respectively. The study of Arriagada and colleagues (1991) had many of the same limitations as the other studies with regard to the difficulty with assessing volumes retrospectively, the lack of cisplatin-based chemotherapy, the small number of patients, and the split-course radiotherapy. Perez and colleagues (1981) reported on a randomized trial of patients with LSSCLC in a Southeastern Cancer Study Group trial of chemotherapy followed by radiotherapy versus radiotherapy followed by chemotherapy at the time of progression. In contrast to the studies mentioned above, Perez et al. (1981) found, in retrospect, that patients who had inadequate coverage of the radiation volume had an intrathoracic recurrence rate of 69% (9/13 patients) compared with 33% (13/50 patients) for those who had adequate coverage (p=0.026). Inadequate coverage was not defined clearly, but the authors stated that

118 Y. I. Garces and J.A. Bonner this was primarily because of the lack of inclusion of the contralateral hilum or mediastinum. These findings are consistent with those of Liengswangwong and colleagues (1994), because most failures occurred centrally. It is not clear whether these regions were the initial sites of disease, elective nodal areas, or areas that were not treated initially in the radiation field. Nonetheless, the study of Perez and colleagues (1981) stressed the importance of adequate coverage of disease. The patients were treated with posterior spinal cord blocks, which can lead to underdosing of the midline mediastinal structures; this would not be done with contemporary radiation planning. 2.2.5.5 Advantages and Disadvantages of Prechemotherapy and Postchemotherapy Treatment Volumes Treatment of either the prechemotherapy or postchemotherapy volume has potential advantages and disadvantages. An advantage of treating the prechemotherapy volume is that all sites initially involved by disease would be included because it could be hypothesized that microscopic disease may remain in all areas of initial gross disease and, hence, may benefit from radiotherapy. However, when postchemotherapy volumes have been used after the initial therapy was chemotherapy alone, no significant increase in marginal recurrences has been found. The majority of the retrospective studies discussed above have shown that patients in the postchemotherapy volume group tend to have a preponderance of central recurrences. Therefore, the above hypothesis would be correct only if it is assumed that in previous studies marginal recurrences had gone undetected. Furthermore, some authors have suggested that the radiation should be administered early in the course of treatment because there may be a survival advantage with early radiotherapy (Murray 1998; Williams and Turrisi 1997). By necessity, the prechemotherapy volume must be included when radiotherapy is given with the first cycle of chemotherapy. In this case, the tumor volume will be evident on the radiation-planning CT scan. However, prechemotherapy volume radiotherapy has possible disadvantages if the initial treatment is chemotherapy alone. If radiotherapy is started after the second or third cycle of chemotherapy, it could be difficult to delineate the prechemotherapy target volume on the treatment-planning CT scan. This would require additional time for the radiation oncologist to fuse the initial study or to transpose the prechemotherapy volume onto the planning CT, which could lead to errors (Lagerwaard et al. 2002). Another disadvantage is that normal structures, including the lung and possibly the heart or esophagus, may receive additional treatment that could exceed tolerance levels; however, there is no evidence, other than theoretical concerns, that this additional treatment volume is necessary. In some centers, the radiation-planning CT scan is performed at the same time as the first cycle of chemotherapy, and radiotherapy is initiated with the second cycle of chemotherapy. Thus, the prechemotherapy volumes are treated; however, if the tumor has shrunk, then a substantial volume of normal lung and other healthy structures may be treated, possibly leading to untoward toxicity. The patient s V20 may appear to be lower than it actually is had the radiation oncologist scanned the patient again and planned with the prechemotherapy volumes on a postchemotherapy planning CT scan. Possible advantages of treating the postchemotherapy volume have been alluded to above. We favor this approach if the initial treatment has been chemotherapy. The advantages of treating the postchemotherapy volume include minimized toxicity, the possibility for dose escalation of smaller volume disease, and, because radiotherapy has not been given with the initial chemotherapy cycles, the medical oncologist will know whether the patient has a response to a particular chemotherapeutic agent. Possible disadvantages of treating the postchemotherapy volume include underdosing of microscopically involved areas, which could lead to marginal recurrences. Although this has not been demonstrated in the studies described above, they were mainly retrospective and included a small number of patients. Another disadvantage could be the possible decrease in efficacy if the radiation is delivered too late after the start of treatment. The question How late is too late? has not been answered, as evidenced by a discussion of presentations at the 10th World Conference on Lung Cancer (Bonner et al. 2003; Fried et al. 2003; James et al. 2003; Komaki et al. 2003; Kubota et al. 2003; Schild et al. 2003). 2.2.5.6 Our Treatment Model Our treatment strategy for LSSCLC is complex. All eligible patients are invited to participate in a clinical

Target Volumes in Small Cell Lung Cancer 119 trial. If they are not interested in participating and have small-volume disease, medially located tumors, or disease in which toxicity of normal tissue is not a concern because the radiation fields would likely not change substantially even after chemotherapy, we favor early treatment. We typically would use the Intergroup regimen of 45 Gy twice daily (Turrisi et al. 1999). The volume consists of the prechemotherapy volume and includes the primary tumor, ipsilateral hilum, and mediastinum. We do not treat the supraclavicular fossae unless they are involved. However, the ipsilateral supraclavicular fossa should be considered in the target volume for upper lobe lesions or for patients with high mediastinal nodal involvement. If the patient has large-volume disease that may possibly shrink with chemotherapy, allowing for significantly less irradiation of healthy tissue, we favor treating with between two and three cycles of induction chemotherapy, after which we offer once-daily radiotherapy to 50.4 54 Gy to the postchemotherapy volume with concurrent chemotherapy. Usually, the postchemotherapy volume is the target. The NCCTG multicenter trial showed only two out-of-field failures that could have been in-field if a prechemotherapy volume had been treated. However, these two cases were complicated by atelectasis and scarring and the postchemotherapy volume was difficult to discern (reviewed by J.A.B.) (Bonner et al. 1999). Thus, for patients who have not had a response, the prechemotherapy volume is the target. We offer once-a-day radiation as a viable alternative to twicedaily radiation because a prospective multicenter NCCTG study with once-daily treatments achieved results similar to those of the Intergroup trial, with results reported out to 8 years (Schild et al. 2003). 2.2.5.7 Factors for a Radiation Oncologist to Consider The following is a list of possible factors that a radiation oncologist should consider when making decisions about prechemotherapy volume or postchemotherapy volume radiation: 1. The volume of gross disease at diagnosis and the volume of normal structures that would be treated to cover the volume of disease adequately. If the volume of disease is small and the fields are not likely to change significantly with chemotherapy, early radiotherapy to the prechemotherapy volume should be considered. If the volume of disease is large and chemotherapy will shrink the tumor volume significantly, allowing for less of a radiation dose to normal structures, then one to three cycles of chemotherapy followed by radiotherapy to the postchemotherapy volume should be considered. 2. Elective nodal irradiation. Elective nodal irradiation involves the treatment of nodal stations that have a high risk of harboring microscopic disease. Historically, the field design for LSSCLC included comprehensive treatment of bilateral supraclavicular regions (the inferior mediastinum, superior mediastinum, and ipsilateral hilar and subcarinal regions). Recently, the trend has been to exclude the supraclavicular regions bilaterally unless they have been shown radiographically or histologically to be involved. Some investigators have even suggested that a viable option may be not to treat elective sites, as in NSCLC, to allow for dose escalation studies (Williams and Turrisi 1997). 3. Current lung function and overall functional status. If the patient has poor lung function or poor performance status, chemotherapy alone may be considered as the initial therapy. This choice may allow patients the opportunity to participate in a lung rehabilitation program and to stop smoking if they currently are cigarette smokers. Most aggressive combined modality studies have been performed primarily with patients who had good performance scores, and this should be considered when making treatment decisions. 4. Any urgent need for radiation or impending need for early radiation. If there is an urgent or impending need for early radiation, radiation should be given. 5. Referral pattern. A radiation oncologist needs to be involved as early as possible so that multidisciplinary decisions about treatment management can be made in order to plan for optimal integration of various treatments. With all the recent studies on LSSCLC and NSCLC favoring the use of concurrent chemotherapy and radiotherapy, it is mandatory that the radiation oncologist review the patient s case before treatment is initiated. Management is complex and requires a fully functional multidisciplinary team. 6. Disease location. It is important to consider sites of initial involvement and to ensure that those sites are included in your initial fields and boost volume so that you do not underdose areas that have experienced a complete response. Using the AJCC staging manual s lymph node map as a guide to treat the entire nodal station is helpful when

120 Y. I. Garces and J.A. Bonner outlining nodal areas that have had a complete response (Greene et al. 2002). For example, if the pleura appears to be involved initially, the radiation oncologist needs to ensure good coverage of this area because microscopic disease will likely remain even if the patient has had a complete response. However, if a lymph node station group initially projected into the lung tissue and the patient has a partial response after chemotherapy, we believe it is reasonable to target the smaller mass or the nodal region and not overexpose the lung unnecessarily. Another unsettled issue concerning disease location is complete response of a peripheral tumor nodule. In this situation, we are inclined to treat the prechemotherapy volume if the patient s lung function studies suggest that this treatment is feasible. 2.2.5.8 Conclusions Tumor volumes for LSSCLC are an evolving field that requires future study. The topic is neither straightforward nor simple. The clinical situations vary greatly from patient to patient. With limited class I evidence to guide treatment decisions, whether the prechemotherapy or postchemotherapy volume should be the target volume still depends on the radiation oncologist s best judgment. Acknowledgments We would like to thank Pamela R. Lemish for her radiation planning skills and providing the prechemotherapy and postchemotherapy plans for our comparison. We also would like to thank Jessica A. Gardner for her assistance with manuscript preparation and Dr. Paul D. Brown for his review and comments about the manuscript. References Arriagada R, Pellae-Cosset B, de Guevara JCL et al (1991) Alternating radiotherapy and chemotherapy schedules in limited small cell lung cancer: analysis of local chest recurrences. 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