2.2.5 Target Volumes in Small Cell Lung Cancer
Yolanda I. Garces and James A. Bonner
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 CONTENTS
2.2.5.1 Introduction 111
2.2.5.2 Tumor Volume Defi nitions 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 can-cer (LSSCLC). Cisplatin-based chemotherapy, the integration of radiotherapy concurrent with che-motherapy, 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 plan-ning and delivery of radiotherapy remain unsettled. These interwoven issues include radiobiology, tim-ing, dose, fractionation, and the volume of disease treated with radiotherapy. The focus of this chapter is on the evolution of treatment volumes over time
and the controversies surrounding radiation target volumes for patients with LSSCLC. The possible considerations for radiation oncologists wanting to encompass appropriate treatment volumes for pa-tients 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 confi rmed 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 radio-therapy and chemoradio-therapy are integral components in the successful treatment of LSSCLC. Thoracic ra-diation was typically directed at the primary tumor, ipsilateral hilum, entire mediastinum, and supra-clavicular fossae bilaterally. This was the treatment for LSSCLC as long as radiation was delivered to a “tolerable” radiation fi eld. Elective nodal irradiation for LSSCLC has not been the subject of clinical trials or retrospective studies except possibly when treat-ing the supraclavicular areas. Therefore, the focus of this chapter is on radiotherapy tumor volumes, specifi cally prechemotherapy versus postchemo-therapy volumes in the treatment of LSSCLC.
2.2.5.2
Tumor Volume Defi nitions
First, to discuss radiotherapy treatment volumes adequately, some standard defi nitions have to be re-viewed. Report number 62 (a supplement to report number 50) of the International Commission on Radiation Units (ICRU) and Measurements (1999) provides guidance and makes recommenda-tions for the use of radiotherapy. The report provides
radiation oncologists, physicists, and dosimetrists with a common language and standard defi nitions so that radiation doses conform to uniform guide-lines from study to study. The gross tumor volume (GTV) can consist of the primary tumor, the nodal volumes, or metastatic disease that is grossly evi-dent 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 sepa-rate 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 contigu-ous [GTV (or CTV I) and CTV II]. However, the lym-phatics 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 do-simetrists. 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 defi nitions are relatively recent and are cur-rently being incorporated into the standard treat-ment of LSSCLC. They should be used for newly de-signed 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 radia-tion fi elds. Certainly, these defi niradia-tions 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 fi eld design with respect to gross disease within lung parenchyma as well as nodal re-gions intended to be included within the radiation fi eld 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 fi ndings on physical examination, including a detailed exam-ination 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 dif-fusing 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 api-cal 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 re-sponse to chemotherapy. Next, he received concur-rent chemotherapy (cisplatin and etoposide) and radiotherapy. The radiotherapy was given, accord-ing to protocol, to the postchemotherapy volume. However, for illustrative purposes, we fused the pre-chemotherapy 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 fi eld borders are shown on these digitally reconstructed radiographs; the fi elds in-cluded 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 fi eld edge was 5 cm below the carina. For this study, the supra-clavicular fossae were not included in either treat-ment plan; whether they should be is a matter of controversy. Both plans were designed to treat with
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 vol-ume (Fig. 2.2.5.3a) and the other based on the post-chemotherapy volume (Fig. 2.2.5.3b). The dose vol-ume histograms for treatment of prechemotherapy volumes and postchemotherapy volumes are shown in Fig. 2.2.5.4. The lung V20 was calculated by divid-ing the volume of lung receivdivid-ing 20 Gy or more by the total volume of the lung.
This case demonstrates that the difference in V20 would be signifi cant if one were to treat the preche-motherapy volume and the postchepreche-motherapy vol-ume 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 al-lowed 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
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-pos-terior simulation DRR (a) and oblique DRR (b)
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 ad-dressed this issue, and few retrospective studies have focused on it. In the following sections, the random-ized study, the retrospective studies, and some obser-vations about this issue are reviewed, including the advantages and disadvantages of treating the preche-motherapy or postchepreche-motherapy volumes.
2.2.5.4.1
Randomized Study
In a Southwest Oncology Group (SWOG) study, all pa-tients were treated initially with vincristine, methotrex-ate, 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 progres-sive disease), or progresprogres-sive disease. Patients with a complete response were assigned randomly to split-course 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 com-plete 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, specifi cally 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 pa-tients) than in the postchemotherapy volume group (8 of 98 patients). The amount of lung tissue spared by the use of postchemotherapy volumes was not quantifi ed. Although the SWOG study failed to show differ-ences in outcomes for those in the prechemotherapy and postchemotherapy volume groups, the conclu-sions should be viewed circumspectly. The chemo-therapy was not cisplatin-based, and it was not given
a
b
Fig. 2.2.5.4. Dose volume histogram of the left and right lungs. The vertical line represents lung volume
Fig. 2.2.5.3a,b. Isodose curves demonstrating a radiotherapy plan both to 5,400 cGy: one plan is based on the prechemo-therapy volume (a, red) and the other is based on the post-chemotherapy volume (b, green)
concurrently with radiotherapy. The recurrence of disease was defi ned as “intrathoracic” or “systemic.” The authors stated that the port fi lms and follow-up chest radiographs were reviewed again in only a small proportion of cases and may not refl ect “in-fi eld” radiation failures (Kies et al. 1987). The imag-ing studies and treatment plannimag-ing 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 inaccu-rate fi eld designs (or both). We have some evidence that even with CT fusion for non-small cell lung car-cinoma (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 re-sponse. Despite these limitations, this study was im-portant and warrants further consideration in the de-sign of future studies (Wagner 1997). In the future, patterns of disease recurrences need to be collected prospectively and correlated with the radiation vol-umes so that marginal recurrences and intrathoracic recurrences (in and out of the radiation fi eld) can be described and reported.
2.2.5.4.2
Retrospective Studies
Several retrospective studies have focused on treat-ment 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) re-viewed the cases of 67 consecutive patients. Of these patients, adequate information was available for 59, who were not treated according to any research pro-tocol at Mayo Clinic from 1982 through 1990. Most of these patients received two or three cycles of induc-tion 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 sepa-rating the 15 Gy in fi ve fractions, for a total dose of 45 Gy in 15 fractions. The local recurrences were re-viewed retrospectively and categorized as “in-fi eld,” “marginal” (±1 cm out of the margin of the fi eld), or “outside the fi eld of radiation.”
The two comparison groups consisted of 31 pa-tients in whom the prechemotherapy volume was treated and 28 patients in whom the postchemother-apy volume was treated. On average, the postchemo-therapy volumes were about 2.5 cm smaller than the prechemotherapy volumes (range, 0.5–5.0 cm). As fi rst site of recurrence, ten of the 31 patients in the prechemotherapy group had in-fi eld failures com-pared with nine of the 28 patients in the postchemo-therapy 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 differ-ences in disease-specifi c or overall survival among the three groups. However, the study had some limita-tions: (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 sub-groups. 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 vol-umes in a prospective manner (Bonner et al. 1999). This trial compared split-course hyperfractionated ra-diotherapy with once-a-day rara-diotherapy for LSSCLC, in which all patients had the postchemotherapy vol-ume treated following three cycles of chemotherapy. The authors retrospectively evaluated in-fi eld and out-of-fi eld recurrences. Among 90 patients who had local progression of disease as a component of their initial progression, only seven had out-of-fi eld recur-rences. Two of these recurrences were less than 2 cm from the fi eld edge and would have been included had prechemotherapy volumes been treated. Thus, this study strongly suggested that postchemotherapy vol-umes were appropriate and safe for treating LSSCLC, minimizing the amount of normal lung volume irra-diated without compromising disease control.
Brodin and colleagues (1990) retrospectively re-viewed 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 fi lms and the pre-chemotherapy and postpre-chemotherapy chest radio-graphs. 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 pa-tients with limited-stage disease (n=23). Among the 13 patients who had the prechemotherapy volume treated, seven were cured locally, six had in-fi eld re-currences, and none had marginal or out-of-fi eld in-trathoracic recurrences. Among the six patients who had the postchemotherapy volume treated, one was cured locally, four had in-fi eld recurrences, none had marginal recurrence, and one had an intrathoracic recurrence outside the radiation fi eld. Among the four patients in the protocol violation group in whom neither the prechemotherapy nor postchemotherapy volume was covered adequately, two were cured lo-cally, one had in-fi eld recurrence, none had marginal recurrence, and one had intrathoracic out-of-fi eld re-currence. The unique feature of this study was that an autopsy was performed on 76% of the subjects, pro-viding reliable data about treatment failure. However, the authors acknowledged it occasionally was diffi -cult to distinguish between recurrent tumor and ra-diation fi brosis; also, the total dose of rara-diation was low, which could have led to the increased number of in-fi eld 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 fi eld. These au-thors 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 fi rst, 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 com-plications, seven of whom had recurrent tumor in the chest. The majority of the recurrences were intratho-racic but outside the radiation fi eld. 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 radia-tion 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 fol-lowed by thoracic radiotherapy and additional main-tenance 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 re-mission were included in the review for in-fi eld and marginal recurrences. Twenty-two local recurrences were observed: 16 in-fi eld and six marginal. The au-thors also reviewed the fi elds to determine if it was evident whether coverage of the initial tumor volume was adequate (“safety” margin of at least 1 cm) or in-adequate (initial tumor area not included in the radia-tion fi eld). 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 signifi cant shrinkage had occurred with induction chemotherapy. There was no difference in outcomes between the patients who had adequate coverage and those who had inad-equate coverage, which can be considered to represent prechemotherapy or postchemotherapy volumes, re-spectively. The study of Arriagada and colleagues (1991) had many of the same limitations as the other studies with regard to the diffi culty 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 random-ized 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 inade-quate coverage of the radiation volume had an intra-thoracic recurrence rate of 69% (9/13 patients) com-pared with 33% (13/50 patients) for those who had adequate coverage (p=0.026). “Inadequate coverage” was not defi ned clearly, but the authors stated that
this was primarily because of the lack of inclusion of the contralateral hilum or mediastinum. These fi nd-ings are consistent with those of Liengswangwong and colleagues (1994), because most failures oc-curred 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 fi eld. 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 post-chemotherapy volume has potential advantages and disadvantages. An advantage of treating the preche-motherapy volume is that all sites initially involved by disease would be included because it could be hy-pothesized that microscopic disease may remain in all areas of initial gross disease and, hence, may benefi t from radiotherapy. However, when postchemother-apy volumes have been used after the initial therpostchemother-apy was chemotherapy alone, no signifi cant increase in marginal recurrences has been found. The major-ity of the retrospective studies discussed above have shown that patients in the postchemotherapy volume group tend to have a preponderance of central re-currences. 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 pre-chemotherapy volume must be included when radio-therapy is given with the fi rst cycle of chemoradio-therapy. In this case, the tumor volume will be evident on the radiation-planning CT scan. However, preche-motherapy volume radiotherapy has possible dis-advantages if the initial treatment is chemotherapy alone. If radiotherapy is started after the second or third cycle of chemotherapy, it could be diffi cult to delineate the prechemotherapy target volume on the treatment-planning CT scan. This would require
ad-ditional 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 disadvan-tage is that normal structures, including the lung and possibly the heart or esophagus, may receive addi-tional treatment that could exceed tolerance levels; however, there is no evidence, other than theoreti-cal concerns, that this additional treatment volume is necessary. In some centers, the radiation-planning CT scan is performed at the same time as the fi rst cycle of chemotherapy, and radiotherapy is initiated with the second cycle of chemotherapy. Thus, the pre-chemotherapy volumes are treated; however, if the tumor has shrunk, then a substantial volume of nor-mal 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 postchemo-therapy volume have been alluded to above. We favor this approach if the initial treatment has been chemo-therapy. The advantages of treating the postchemo-therapy volume include minimized toxicity, the pos-sibility for dose escalation of smaller volume disease, and, because radiotherapy has not been given with the initial chemotherapy cycles, the medical oncolo-gist will know whether the patient has a response to a particular chemotherapeutic agent.
Possible disadvantages of treating the postchemo-therapy volume include underdosing of microscopi-cally involved areas, which could lead to marginal re-currences. Although this has not been demonstrated in the studies described above, they were mainly ret-rospective and included a small number of patients. Another disadvantage could be the possible decrease in effi cacy 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 dis-cussion 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
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 fi elds 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 prechemo-therapy 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, allow-ing for signifi cantly less irradiation of healthy tis-sue, 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 chemo-therapy. Usually, the postchemotherapy volume is the target. The NCCTG multicenter trial showed only two out-of-fi eld failures that could have been “in-fi eld” if a prechemotherapy volume had been treated. However, these two cases were complicated by atelectasis and scarring and the postchemotherapy volume was dif-fi cult 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 twice-daily 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 radia-tion oncologist should consider when making deci-sions about prechemotherapy volume or postchemo-therapy 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 fi elds are not likely to change signifi cantly with chemother-apy, early radiotherapy to the prechemotherapy volume should be considered. If the volume of
disease is large and chemotherapy will shrink the tumor volume signifi cantly, allowing for less of a radiation dose to normal structures, then one to three cycles of chemotherapy followed by radio-therapy to the postchemoradio-therapy volume should be considered.
2. Elective nodal irradiation. Elective nodal irradia-tion involves the treatment of nodal stairradia-tions that have a high risk of harboring microscopic disease. Historically, the fi eld design for LSSCLC included comprehensive treatment of bilateral supraclavic-ular 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 histologi-cally 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 escala-tion studies (Williams and Turrisi 1997). 3. Current lung function and overall functional status.
If the patient has poor lung function or poor per-formance 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 smok-ing 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 consid-ered when making treatment decisions.
4. Any urgent need for radiation or impending need for early radiation. If there is an urgent or impend-ing need for early radiation, radiation should be given.
5. Referral pattern. A radiation oncologist needs to be involved as early as possible so that multidis-ciplinary decisions about treatment management can be made in order to plan for optimal integra-tion 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 func-tional 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 fi elds 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
outlining nodal areas that have had a complete response (Greene et al. 2002). For example, if the pleura appears to be involved initially, the radia-tion 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 con-cerning 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 fi eld that requires future study. The topic is neither straightfor-ward nor simple. The clinical situations vary greatly from patient to patient. With limited class I evidence to guide treatment decisions, whether the prechemo-therapy or postchemoprechemo-therapy volume should be the target volume still depends on the radiation oncolo-gist’s best judgment.
Acknowledgments
We would like to thank Pamela R. Lemish for her radiation planning skills and providing the preche-motherapy and postchepreche-motherapy plans for our comparison. We also would like to thank Jessica A. Gardner for her assistance with manuscript prepara-tion and Dr. Paul D. Brown for his review and com-ments about the manuscript.
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