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© 2001 American Society for Clinical Oncology Dose Escalation in Non–Small-Cell Lung Cancer Using Three-Dimensional Conformal Radiation Therapy: Update of a Phase I TrialFrom the Departments of Radiation Oncology and Internal Medicine, Division of Hematology/Oncology, University of Michigan Health System, Ann Arbor, MI, and Department of Radiation Oncology, Medical University of South Carolina, Charleston, SC. Address reprint requests to James A. Hayman, MD, Department of Radiation Oncology, University of Michigan, UH-B2C490, Box 0010, 1500 East Medical Center Dr, Ann Arbor, MI 48109; email hayman{at}umich.edu
PURPOSE: High-dose radiation may improve outcomes in non–small-cell lung cancer (NSCLC). By using three-dimensional conformal radiation therapy and limiting the target volume, we hypothesized that the dose could be safely escalated.
MATERIALS AND METHODS: A standard phase I design was used. Five bins were created based on the volume of normal lung irradiated, and dose levels within bins were chosen based on the estimated risk of radiation pneumonitis. Starting doses ranged from 63 to 84 Gy given in 2.1-Gy fractions. Target volumes included the primary tumor and any nodes RESULTS: At the time of this writing, 104 patients had been enrolled. Twenty-four had stage I, four had stage II, 43 had stage IIIA, 26 had stage IIIB, and seven had locally recurrent disease. Twenty-five received chemotherapy, and 63 were assessable for escalation. All bins were escalated at least twice. Although grade 2 radiation pneumonitis occurred in five patients, grade 3 radiation pneumonitis occurred in only two. The maximum-tolerated dose was only established for the largest bin, at 65.1 Gy. Dose levels for the four remaining bins were 102.9, 102.9, 84 and 75.6 Gy. The majority of patients failed distantly, though a significant proportion also failed in the target volume. There were no isolated failures in clinically uninvolved nodal regions. CONCLUSION: Dose escalation in NSCLC has been accomplished safely in most patients using three-dimensional conformal radiation therapy, limiting target volumes, and segregating patients by the volume of normal lung irradiated.
APPROXIMATELY 40,000 to 50,000 patients are diagnosed with locally advanced non–small-cell lung cancer (NSCLC) each year in the United States. Currently, radiation therapy is the principal modality used in the treatment of this disease. However, when administered using conventional doses and treatment techniques, radiation therapy is generally associated with a poor outcome. In several recent randomized studies, the median survival after treatment with conventional radiation therapy alone has averaged only 8 to 10 months and the 2-year survival has only been in the range of 10% to 20%.1-4 Although treatment with conventional radiation therapy has been reported to result in local control rates of 65% to 80%, when Le Chevalier et al2 used a strict definition of local control (ie, complete clinical, radiographic, and pathologic response), they reported a local control rate of only 15% at 1 year. Although improvements in outcome have been achieved through the addition of chemotherapy,1-5 the magnitude of this benefit has been relatively modest (ie, a maximum of 4 months). Accordingly, there is still a tremendous need for improvements in the treatment of stage III NSCLC. To improve on our current results, it is obvious that local control must be enhanced. One potential approach is to escalate the dose of radiation therapy. Evidence exists that increasing the dose of radiation therapy may lead to an improvement in local control. In a landmark trial conducted by the Radiation Therapy Oncology Group, patients with T1 to 3/N1 to 2 tumors were treated randomly with four different dose schedules. The best local control, clinical complete response, and 2-year survival were achieved with the highest total dose regimen (ie, 60 Gy in conventional fractionation).6 In addition, Vijayakumar et al7 have shown that when local control is plotted against dose using data from published studies, a relationship between increasing dose and local control can be demonstrated. However, when dose escalation has been attempted using conventional treatment techniques and volumes, investigators have reported increased toxicity.8,9 Although doses to the spinal cord, esophagus, and heart must be considered, it is generally accepted that the dose of radiation that can be administered safely with such an approach seems to be limited primarily by the risk of radiation pneumonitis, which in turn is a function of both the dose and volume of normal lung irradiated. We hypothesized that by using three-dimensional conformal treatment techniques and limiting our treatment volumes, we could minimize the volume of normal lung irradiated, thereby allowing us to safely escalate the dose of radiation therapy without increased toxicity. We also hypothesized that an increase in the dose might translate into an improvement in local control and, ultimately, survival. To test this hypothesis, we initiated a phase I dose escalation trial at the University of Michigan in 1992 with the primary objective of establishing the maximum-tolerated dose (MTD) of radiation therapy that could be given safely using three-dimensional conformal treatment techniques and conventional fractionation. We also hoped to better define the relationship between pulmonary toxicity, dose, and volume. Given the nature of the trial, the occurrence of grade 3 radiation pneumonitis was chosen as our primary end point. Rather than use an escalation schema in which all patients received the same dose regardless of the volume of normal lung irradiated, we opted to develop a dose escalation schema in which the dose delivered depended on an estimate of the risk of radiation pneumonitis. In creating the escalation schema, the decision was first made to stratify patients into five bins based on effective volume (Veff), a measure of the volume of normal lung irradiated. A normal tissue complication probability (NTCP) model capable of estimating the risk of radiation pneumonitis was then used to set the dose levels within each group so that, as the dose was escalated, the risk of pneumonitis increased in a predictable manner.
Dose-Escalation Schema The method used in creating our original single-lung dose escalation schema has been described in detail in several publications.10,11 Briefly, using Lyman’s NTCP model,12,13 a series of isocomplication plots were first generated, which specified the doses and volumes of uniformly irradiated ipsilateral normal lung expected to result in the same probability of grade 2 or higher radiation pneumonitis. Initially, the values of two of the three parameters used in the NTCP model were based on published estimates of the tolerance of normal lung (n = 0.87 and m = 0.18).14,15 We chose to use a TD50 of 29 Gy, rather than 24.5 Gy, to adjust for our use of average lung density corrections.16 The model assumes uniform irradiation of the lung. However, because uniform irradiation never occurs in routine clinical practice, Kutcher’s dose volume histogram reduction method was used to estimate the volume of lung that would have to be uniformly irradiated to a given reference dose to result in a similar risk of pneumonitis.17 This volume is known as Veff. Rather than escalating the dose of radiation in all patients regardless of the volume of normal lung irradiated, patients were stratified into five bins based on Veff and each bin was escalated independently. Using historical data, we selected the boundaries of the five original Veff bins so that accrual to each bin would be expected to occur at roughly the same rate. The Veffs for the original bins were as follows: 0 to 0.20, greater than 0.20 to 0.25, greater than 0.25 to 0.31, greater than 0.31 to 0.40, and greater than 0.40. Once the bins had been established, the dose levels within each bin were chosen using the isocomplication plots so that the risk of radiation pneumonitis increased in a predictable manner. Rather than beginning at the same NTCP in all bins, which would have resulted in the use of doses well below what is considered safe when using conventional treatment techniques in the largest bins, we used clinical judgement in determining the starting doses in these bins. Accordingly, the starting doses and NTCPs ranged from 84 Gy and 5% in the smallest bin to 63 Gy and 40% in the largest bin. Our original escalation schema was based on empiric estimates of the tolerance of only the ipsilateral normal lung. However, because more recent data suggested a stronger correlation between the risk of pneumonitis and the dose and volume of both lungs irradiated, rather than just the ipsilateral lung,16 the escalation schema was modified in 1997 to take this into account. In addition, rather than using the empiric parameters in the model, existing data collected in the course of the trial were analyzed using the maximum likelihood method18,19 and new values for the model parameters were estimated (n = 1.00, m = 0.33, and TD50 = 33.00) (R.K.T.H., unpublished data). Using the new parameters, a new set of isocomplication plots was generated and, after reanalyzing the treatment plans of all previously treated patients to determine their Veffs based on both lungs, the boundaries of the five bins were adjusted. The Veffs for the revised bins were as follows: 0 to 0.12, greater than 0.12 to 0.18, greater than 0.18 to 0.24, greater than 0.24 to 0.31, and greater than 0.31 to 0.40. Using the new isocomplication plots, we determined the dose levels within each bin and reassigned the patients to the appropriate bin and dose level based on their Veff and the dose of radiation administered. The revised dose escalation schema is outlined in Table 1.
Selection Criteria To be eligible for this study, subjects had to have a histologically confirmed diagnosis of NSCLC. Although mixed tumors were categorized by their predominate cell type, patients with tumors that contained any component of small-cell lung cancer were excluded. To be eligible, patients must also have had measurable or assessable disease, received no prior thoracic radiation, and had a performance status of 0 to 2, a WBC count of  3,500/µL, and a platelet count of 100,000/µL. There was not a restriction based on either the degree of weight loss or pulmonary compromise. Patients with a history of a prior malignancy were generally considered eligible if disease-free for 5 or more years. Initial evaluation consisted of a history and physical examination, routine blood work, including complete blood count and liver function tests, chest x-ray, a computed tomography (CT) scan of the chest and upper abdomen, including the liver and adrenal glands, pulmonary function tests, bone scan, and, more recently, a CT or magnetic resonance imaging scan of the brain. Patients with medically inoperable stage I or II disease, stage IIIa or IIIb disease (excluding patients with biopsy-proven supraclavicular adenopathy, documented malignant pleural or pericardial effusion, or noncontiguous involvement of the parietal pleura), or local-regional recurrence after surgery for stage I or II disease were eligible for participation. Although histologic confirmation was highly encouraged, hilar or mediastinal lymph nodes greater than 1.0 cm in short-axis diameter were considered to contain tumor. Written informed consent was obtained from all patients in accordance with the procedures of the Institutional Review Board of the University of Michigan Health System.
Radiation Therapy
The goal of treatment planning in this study was to develop a plan that minimizes the volume of normal lung irradiated (ie, Veff) while providing coverage of the PTV by at least the 95% isodose surface and minimizing dose to the surrounding normal tissues. The 100% isodose line was defined at the isocenter, and dose was prescribed to this point. Constraints were placed on the dose to the spinal cord (50 Gy), esophagus (Veff < 0.33, using a reference dose of first 65, then 72, and then 80 Gy), heart (Veff < 0.33 and 1.00, using a reference dose of 65 and 40 Gy, respectively), and normal lung (initially, an NTCP of < 2% for the contralateral lung when using just the ipsilateral lung, but later, using both lungs, Veff
Chemotherapy
Escalation and Follow-Up The following rules governed escalation. Within each bin, a minimum of three patients were treated at each dose level. Three patients must then have been followed for a minimum of 6 months from the initiation of radiation therapy before dose escalation was permitted. Dose escalation in each bin continued until one of the first three patients treated at a given dose level experienced a dose-limiting toxicity (DLT), which was defined as grade 3 or higher radiation pneumonitis for the purpose of this study. On the occurrence of a DLT, three additional patients were enrolled at the dose level at which DLT occurred. When DLT was observed in two patients at a given dose level in a bin, dose escalation in that bin was discontinued, and the MTD in that bin was defined as the dose level below that which induces a DLT in two patients. Accrual was allowed to continue at a given dose level within a given bin until the third patient successfully completed treatment and was observed for 6 months. Toxicity was scored using the Southwest Oncology Group toxicity criteria. According to these criteria, we scored grade 1 radiation pneumonitis when patients experienced symptoms and/or radiologic changes that did not require treatment with corticosteroids, grade 2 when patients required treatment with corticosteroids, grade 3 when patients required oxygen, and grade 4 when patients required mechanical ventilation. We observed patients for 6 months because radiation pneumonitis typically occurs within 6 months after the start of treatment.9,20 For patients who received chemotherapy to be eligible to be treated at the next dose level, at least one of the three patients must have received chemotherapy. If that was not the case, patients who received chemotherapy were treated at the lower dose level until at least one such patient was observed for 6 months without experiencing DLT. Patients who received chemotherapy were then eligible to be treated at the higher dose level. To preliminarily assess whether dose escalation might be of benefit and whether omission of clinically uninvolved nodal regions might compromise survival, we also examined its impact on survival, progression-free survival, and the patterns of first failure for those patients who had completed the intended treatment, although these were not major end points of this phase I trial. Survival was calculated from the date of the initiation of protocol therapy to the date of death or last follow-up. Progression-free survival was defined as the time from the date of initiation of protocol therapy to the date of first progression based on clinical, radiographic, or bronchoscopic findings, death, or last follow-up. When appropriate, an attempt was made to obtain pathologic confirmation of all first recurrences. Survival and progression-free survival were assessed using the Kaplan-Meier life-table method. In addition, for the purposes of this analysis, first recurrences and/or progression were categorized as occurring either within the PTV, in lymph node regions outside the PTV (including the supraclavicular regions), or distantly.
Accrual to this study began in August 1992, and as of April 1999, 104 patients had been enrolled onto this study. Patients were treated at either the University of Michigan Hospitals or at one of three affiliate centers. Twenty-five of these patients also received neoadjuvant chemotherapy. For a variety of reasons, only 81 of those 104 patients had completed treatment with radiation therapy as specified by the protocol (Fig 1). Early in the trial, three patients who were unable to meet a normal tissue dose constraint were reassigned to the prevailing dose level in the next lowest Veff bin so as to meet the constraint. Accordingly, in retrospect, these patients were ineligible to be considered assessable for escalation. More recently, eight patients who had received chemotherapy were unable to meet all of the normal tissue dose constraints (usually for the esophagus) when planned using the prevailing dose level within their Veff bin. These patients were subsequently taken off study and received treatment with a conventional dose of radiation therapy. Three patients were receiving either protocol chemotherapy or radiation therapy at the time of this writing, and two had died while receiving protocol therapy. One patient died of an apparent heart attack within several days of receiving his first dose of chemotherapy, and another patient who was treated with radiation therapy alone died of an apparent pulmonary embolus after developing a deep vein thrombus in his upper extremity and refusing recommended treatment. Six patients progressed at distant sites during treatment and were taken off study. One patient treated with radiation alone who was to receive 69.3 Gy decided to discontinue treatment early at 63 Gy because of pressing family matters, not toxicity. Of the 81 patients who completed their radiation therapy according to the protocol, seven were observed and 11 died less than 6 months from the start of their radiation therapy, leaving 63 patients assessable for escalation. Median follow-up for all subjects was 9.4 months (range, 1.6 to 56.9 months).
The pretreatment characteristics of the patients enrolled onto our trial are listed in Table 2. The patients had ages ranging from 39 to 82 years, with a median age of 64 years. Seventy-five percent were male, whereas 92% were white and 8% black. Sixty percent had a performance status of 0, whereas 35% and 5% had performance status of 1 and 2, respectively. Sixty-three percent had no weight loss, 12% had less than 5% weight loss, and 25% had 5% weight loss. Twenty-four patients had stage I disease, four stage II, 43 stage IIIA, 26 stage IIIB, and seven had local recurrences after surgery alone for early-stage NSCLC. The majority of cancers were either squamous (50%) or adenocarcinomas (30%).
The number of patients assessable for escalation and enrolled at each dose level within each bin is listed in Table 3. Because accrual was not halted after three patients were enrolled at a given dose level within a bin and because patients were reassigned to different bins after the decision to use the new parameters and both lungs to recalculate patients’ Veff (see above), the number of patients at each dose level was somewhat variable. The dose in each bin was escalated at least two times. Two patients in the largest-volume bin who received 69.3 Gy experienced grade 3 radiation pneumonitis (ie, DLT). Although both patients had stage IIIB disease, one received neoadjuvant chemotherapy and the other did not. Accordingly, the MTD in the highest-volume bin was 65.1 Gy. At the time of this writing, patients who underwent treatment with radiation therapy alone received 102.9 Gy in the two smallest-volume bins, 84 Gy in the middle bin and 75.6 Gy in the second–largest-volume bin. Patients who received neoadjuvant chemotherapy received the same doses in the two remaining larger-volume bins but only 92.4 Gy in the two smallest bins.
Several patients experienced serious (ie, grade 3 or greater) acute toxicity as a result of treatment with chemotherapy and radiation therapy. As a result of treatment with chemotherapy, four patients experienced grade 3 or greater hematologic toxicity and two experienced grade 3 or greater nausea and vomiting (ie, no significant oral intake and six to 10 episodes in 24 hours, respectively). As noted above, one patient also died during treatment with chemotherapy. As a result of treatment with radiation therapy, six patients experienced grade 3 esophagitis (ie, unable to eat solids or require narcotics to eat), one experienced grade 4 esophagitis (ie, required entera1 support), one experienced a grade 3 skin reaction (ie, confluent moist desquamation), and another experienced grade 3 nausea. The patient with grade 4 esophageal toxicity had stage IIIB disease, was in the largest-volume bin and received a dose of 63 Gy without neoadjuvant chemotherapy. Although the total dose was relatively low, the majority of the length of his esophagus received the full dose and he required placement of a nasogastric feeding tube. There was not an increase in acute toxicity during radiation therapy in those patients who had received chemotherapy, and as noted above, one patient also died during treatment with radiation therapy. Five patients experienced grade 2 radiation pneumonitis, and all were able to be weaned off of corticosteroids eventually. Two patients with nodal masses invading the mediastinum experienced fatal pulmonary hemorrhages just weeks after receiving only 65.1 Gy. Given the dose, these two deaths were not believed to be directly a result of dose escalation. In terms of late complications, one patient experienced grade 3 pulmonary fibrosis (ie, radiographic changes with symptoms). He had stage IIIB disease, was in the third–highest-volume bin, received a dose of 65.1 Gy, and did not receive neoadjuvant chemotherapy. No patients experienced significant cardiac or spinal cord toxicity. Although not major end points of this phase I trial, survival and progression-free survival rates for those 81 patients who actually completed the intended treatment were examined to assess preliminarily whether dose escalation might be of benefit (Fig 2 and Table 4). The median survival for the entire group was 18 months, with 1-, 2-, and 3-year survival rates of 69%, 40%, and 18%, respectively. Not surprisingly, the patients with stages I and II disease did better than those with stage III and recurrent disease, with a median survival of 20 months and 1-, 2-, and 3-year survival rates of 79%, 49%, and 29% versus a median survival of 16 months and 1-, 2-, and 3-year survival rates of 61%, 36%, and 14% for those with stage III and recurrent disease. For the entire group, the median time to progression was 9 months, with 1-, 2-, and 3-year progression-free survival rates of 39%, 17%, and 11%, respectively. The patients with early-stage disease did better than those with locally advanced and recurrent disease, with a median time to progression of 12 months and 1-, 2-, and 3-year progression-free survival rates of 50%, 24%, and 19%, compared with a median time to progression of 7 months and 1-, 2-, and 3-year progression-free survival rates of 29%, 12%, and 7% in patients with locally advanced and recurrent disease.
When we examined the pattern of initial failure in those patients who had completed dose-escalated radiation and then failed, we found that the majority of patients failed distantly but a significant proportion also failed locally within the PTV (Fig 3). Of the 53 patients who failed, 28 (52%) failed in a distant site as their sole site of failure, whereas four (8%) failed simultaneously in both a distant site and the PTV, two (4%) failed simultaneously in both a distant site and a nodal region outside the PTV, and one (2%) failed simultaneously in a distant site, the PTV, and a nodal area outside the PTV. In contrast, 18 (34%) of the 53 patients failed in the PTV as their sole site of failure. Of the 23 patients who failed initially in the PTV, two had received 63 Gy, five had received 65.1 Gy, nine had received 69.3 Gy, two had received 75.6 Gy, four had received 84 Gy, and one had received 92.4 Gy. One might have predicted that our decision not to purposely treat clinically uninvolved nodal regions would have led to isolated failures. However, we did not see any isolated failures in nodal areas outside the PTV, and only three patients (6%) experienced failures in nodal regions outside the PTV simultaneously with local and/or distant failure.
Dose escalation in the treatment of NSCLC with radiation therapy was accomplished safely for most patients in this study by using conformal three-dimensional treatment techniques, limiting the target volume, and stratifying patients based on the volume of normal lung irradiated. With the exception of the largest Veff bin, we had not reached, at the time of this writing, the MTD in most of the bins, even though the dose levels in these bins exceeded doses thought to be safe with conventional radiation therapy treatment techniques by as much as 70%. In the largest Veff bin, the MTD was only 65.1 Gy, which suggests that dose escalation cannot yet be accomplished safely in all patients using existing treatment planning and delivery techniques. In addition, our patients did not experience isolated failures in nodal regions outside the PTV, which suggests that intentional prophylactic treatment of clinically uninvolved nodes may be unnecessary. Although they were not the primary end points of our study, the median and 1-, 2-, and 3-year overall survival rates for those patients with stage III disease who completed treatment with dose-escalated radiation therapy are also encouraging. Much of the clinical research in the last decade in the treatment of stage III NSCLC has revolved around four basic concepts: (1) adding chemotherapy to radiation therapy,1-5 (2) using altered fractionation,3,21 (3) using trimodality therapy (ie, surgery, chemotherapy, and radiation therapy),22,23 and (4) escalating the dose of radiation therapy using conventional fractionation.8,24-26 Although median survivals have increased by as much as 4 months with the addition of chemotherapy and the use of accelerated hyperfractionation,1,21 there is still significant room for improvement in the treatment of NSCLC in terms of local control, systemic control, and survival. Over the last 7 years, our studies primarily focused on dose escalation as a strategy to improve patients’ outcomes. To examine the efficacy of dose escalation, it was first necessary to establish the MTD of radiation therapy that could be administered using conformal treatment techniques and limited treatment volumes. Despite the paucity of significant toxicity to date, we have not yet established the maximally tolerated dose for a number of reasons. First, rather than escalating the dose of radiation in all patients regardless of the volume of normal lung irradiated, we chose to stratify patients into five volume bins and to escalate each bin independently. In some ways, this means that we have been conducting five independent dose escalation trials. Second, we chose to wait a relatively long interval (ie, 6 months) before deeming patients eligible to be counted for escalation, which for safety’s sake has prolonged the study. Third, it seems that the published estimates of the tolerance of normal lung and esophagus using conventional treatment techniques are significantly lower than those when using conformal treatment techniques and smaller treatment volumes. Despite modifying the parameters in the Lyman model, the observed incidence of pneumonitis in the larger Veff bins is clearly lower than the risk predicted by the model (Table 1). In addition, we had only one occurrence of grade 4 esophageal toxicity even though the current constraint on the dose to the esophagus allows one third of it to receive the equivalent of 80 Gy. Accordingly, by being too conservative and setting our starting dose levels and normal tissue constraints too low, we have unintentionally prolonged this study. Lastly, it had been our intention originally to determine the MTD of radiation therapy in the absence of chemotherapy. However, because the use of chemotherapy had become standard practice during the early years of this trial, the fact that we did not allow patients to receive chemotherapy during the first 5 years of this trial clearly slowed accrual. Because we began to allow select patients to receive treatment with neoadjuvant chemotherapy, accrual increased considerably and we did not see an increase in radiation therapy–related acute or late toxicities. Although evaluating the efficacy of the use of dose-escalated radiation therapy was not the primary objective of our study, the preliminary overall and progression-free survival rates for those patients who completed protocol therapy are nevertheless somewhat encouraging. Although we readily admit that examining the outcomes for only those patients who completed treatment biases the results in favor of dose escalation, it seems reasonable to initially evaluate the potential efficacy of the strategy based solely on those patients who actually received it. The patients with stage III and recurrent disease in our trial who completed protocol therapy had a median overall survival of 16 months and a 2-year survival of 36%, which seem comparable to the results achieved with continuous, hyperfractionated, accelerated radiotherapy (CHART) 21 or the addition of neoadjuvant chemotherapy.1-3,5 The results achieved by the patients with stages I and II medically inoperable disease are comparable to those reported previously in the literature after treatment with conventional radiation therapy.27-30 The decision not to purposely include clinically uninvolved nodal regions in our target volume is based on the premise that we should only begin to worry about including areas that may contain microscopic disease after we are able to consistently control known gross disease. Adding elective nodal irradiation clearly increases the volume of normal lung irradiated,31-33 which may limit or impair escalation of the total dose of radiation.8 Although we have no doubt that some of the nodes outside our target volumes harbor microscopic disease, in reality our decision not to include these regions in our target volume does not seem to have negatively influenced our failure patterns. No patients had isolated failure in a nodal region outside the PTV as a sole site of first failure, and only three patients failed simultaneously in these regions and locally and/or distantly. Perhaps this is a result in part of the fact that, although not intentionally included in our target volume, the ipsilateral hilum and mediastinum often receive a meaningful dose of radiation (ie, 40 to 50 Gy) incidentally in some patients because of their proximity to the primary lesion and/or enlarged nodes.34,35 Nevertheless, the majority of patients failed either distantly or in the PTV, which suggests that improvements in both systemic and local therapies should take priority. Of course, a phase III trial in which patients are randomly allocated to treatment with and without comprehensive elective nodal radiation would be the best method for evaluating the necessity of elective nodal radiation. In a further attempt to limit the amount of normal lung irradiated, the expansions used to create both the CTV from the GTV and the PTV from the CTV in this phase I dose-escalation study were purposely chosen to be relatively modest (ie, 0.5 cm). Although the margins in this trial were comparable to those used in other dose-escalation trials in NSCLC (eg, Radiation Therapy Oncology Group 93-11, Memorial Sloan-Kettering25), there was little actual data to help guide this decision at the time of the initiation of this trial and these margins were chosen empirically. More recently, investigators have become increasingly aware of the potential for both daily patient setup error and significant movement of targets in the chest as a result of free breathing.36-39 Although we adjusted for respiratory motion by increasing the expansion used in the creation of the PTV (typically by 0.5 cm) after observing the excursion of the GTV on fluoroscopy at the time of simulation, other methods, such as active breathing control and the deep inspiratory breath hold are being developed, which attempt to limit respiratory motion by treating patients at a reproducible point in the respiratory cycle.40,41 In addition, it also seems likely that positron emission tomography scanning will be of increasing assistance in the future in helping to define the GTV, which should in turn provide further reassurance regarding the adequacy of the margins being used.42-44 Accordingly, additional research still needs to be done to establish how best to set these margins when treating patients with NSCLC with conformal radiation. Even if we find that we can safely further escalate the dose, it seems probable that the local recurrence rate will still be unacceptably high. Therefore, it is likely that modifications will need to be made in our current approach that will facilitate further dose escalation and possibly enhance the efficacy of high-dose radiation therapy in this setting. One area for future research is the use of intensity modulation and optimization in the treatment planning and delivery process. As the dose in this study was escalated, increasing numbers of patients either were not eligible to participate or received protocol chemotherapy but then did not go on to receive protocol radiation therapy because of our inability to design treatment plans that met our normal tissue constraints. We hypothesize that, by using intensity modulation in the setting of optimized treatment planning, we will be able to design treatment plans that will meet our normal tissue constraints and allow us to further escalate the dose without excessive toxicity. These techniques may also allow us to reduce the volume of normal lung irradiated in those patients who would have fallen into the largest-volume bin, thereby allowing us to safely escalate their dose beyond 65.1 Gy. Other areas to explore include the use of accelerated fractionation to shorten the overall treatment time and the use of concurrent chemotherapy. Recent evidence suggests that both strategies result in improved outcomes in patients with NSCLC treated with radiation therapy.21,45 Because our study always used conventional once-a-day fractionation, the overall duration of treatment continued to lengthen as we escalated the dose (eg, the maximum duration of treatment at the time of this writing was just < 10 weeks). In addition, our study also only allowed for treatment with sequential chemotherapy. Accordingly, alternative approaches might be to investigate the use of twice-daily fractionation toward the end of treatment to limit the overall treatment time and/or the use of concurrent chemotherapy. We anticipate that both strategies could result in increased acute and possibly late toxicity and, therefore, expect that only through the development of new conformal three-dimensional treatment techniques using intensity modulation and treatment plan optimization will we be able to make these modifications and still safely treat patients at these higher dose levels.
Presented at the Thirty-Fifth Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, May 15-18, 1999.
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Sause WT, Scott C, Taylor S, et al: Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: Preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer. J Natl Cancer Inst 87: 198-205, 1995 4. Schaake-Koning C, van den Bogaert W, Dalesio O, et al: Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl J Med 326: 524-530, 1992[Abstract]
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
0.40). In other words, for the esophagus and heart, this means that the probability of a complication must be no greater than the risk associated with uniform irradiation of one third of the esophagus, one third of the heart, and the whole heart to 80, 65, and 40 Gy, respectively. The constraint on the esophagus was gradually loosened based on the lack of complications seen compared with the risks predicted by our NTCP model for the esophagus. The decision to use a Veff 
