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Originally published as JCO Early Release 10.1200/JCO.2005.95.028 on August 8 2005 © 2005 American Society of Clinical Oncology.
Optimal Therapy for Unresectable Stage III Non–Small-Cell Lung CancerSection of Hematology/Oncology, Department of Medicine and Cancer Research Center, University of Chicago, Chicago, IL The treatment of patients with unresectable regionally advanced non–small-cell lung cancer (NSCLC) has continued to evolve over the last two decades. In the 1980s, radiotherapy alone led to a median survival of less than 10 months and 3-year survival rates below 10%. The identification of drugs with single-agent activity in stage IV NSCLC allowed for subsequent investigations in the curative intent treatment setting. Combined-modality therapy initially focused on a sequential approach, using induction chemotherapy. Randomized phase III studies demonstrated an increase in median survival from 10 months to approximately 13 months with the addition of two cycles of cisplatin-based chemotherapy administered before radiotherapy.1-3 Since locoregional control is infrequently achieved with radiotherapy alone, and most agents with single-agent systemic activity are also radiation sensitizers, the concomitant administration of both modalities has also been explored. Most studies evaluating single-agent cisplatin had negative results, but concomitant chemoradiotherapy using two drugs was shown to be superior to radiotherapy alone.4-6 Thus, sequential and concomitant combined-modality strategies were each established to be superior to radiotherapy alone, although their effects might be mediated by different mechanism because concomitant chemoradiotherapy appears to prolong survival mainly by increasing locoregional control, whereas induction chemotherapy improves systemic control. The next generation of randomized trials directly compared induction chemotherapy with concomitant chemoradiotherapy in an effort to determine the most effective approach. Several randomized phase II and III studies have been presented that suggest that the concomitant approach results in a higher median survival of approximately 16 to 17 months, although in-field toxicity, in particular esophagitis, is also increased (grade 3 or 4 in approximately 25%).7-9 The two largest of these randomized trials utilized chemotherapy regimens that applied full doses of chemotherapy during radiotherapy, to allow for systemic therapy of micrometastatic disease while contributing to locoregional control through a radiation-enhancing effect.7,9 This is also true for the phase II experience by the Southwest Oncology Group (SWOG), who used a combination of cisplatin, etoposide, and radiotherapy followed by consolidation chemotherapy.10,11 Recent early survival data for this combination in a randomized phase III trial also confirm the activity of this combination.12 Together, these studies have led to the current acceptance of initial concomitant chemoradiotherapy as a preferred standard therapy. The new drugs of the last decade, in particular paclitaxel, have also been evaluated with concomitant radiotherapy in stage III disease.13-16 Phase II trials demonstrated feasibility and activity, and regimens were rapidly adopted by oncologists in the absence of direct comparisons with any of the regimens mentioned in the preceding paragraphs. Furthermore, the newer regimens differed conceptually from the older regimens by utilizing a strategy of weekly chemotherapy administered at low doses, for which the single modality activity in the stage IV setting and their systemic antitumor effects are not well characterized.13-16 It is possible, therefore, that these lower dose regimens mainly provide a sensitizing effect without sufficient systemic exposure. The activity of low doses of weekly carboplatin, in particular, is poorly described, and two randomized trials adding it to radiation after induction chemotherapy showed no survival benefit.17,18 Because both induction and concomitant chemoradiotherapy are superior to radiotherapy alone, it can be postulated that combining sequential chemotherapy (induction or consolidation) with a concomitant approach could result in a further improvement in treatment outcome over concomitant chemoradiotherapy alone. At least three trials have explored the value of adding a sequential component to a concurrent approach. In this issue of the Journal of Clinical Oncology, Belani et al18A report on the Locally Advanced Multimodality Protocol (LAMP) trial. This ambitious randomized phase II trial opened in 1998 and aimed at exploring the optimal sequencing approach to combined-modality therapy. Since its design preceded the establishment of the concomitant approach as preferred standard, the study used a control arm of induction chemotherapy followed by radiotherapy instead of a concomitant chemoradiotherapy-alone control arm, and aimed at comparing all three treatment arms to a historical control derived from the Radiation Therapy Oncology Group (RTOG 88-08)3 database. A total of 276 patients were entered, but 19 were excluded from the final analysis primarily due to ineligibility. An interim analysis suggested that the statistical goal of showing a benefit would not be reached for arm 2 (induction followed by concomitant) and this arm was therefore terminated early. The entire study was subsequently closed when interest in arm 1 (induction alone) weakened and accrual rates slowed. The authors report median survival times of 13 months for patients treated with induction chemotherapy followed by radiation alone (arm 1), consistent with historic controls, compared with 13 and 16 months for arms 2 (induction followed by concomitant) and 3 (concomitant followed by consolidation), respectively. These differences are not statistically significant, but the trial was not designed or statistically powered for such comparisons. Rather, the trial was designed to compare each arm against a historical control (RTOG 88-08 trial)3 for which the observed median survival time was 13.7 months and to demonstrate an improvement to 20 months. This goal was not achieved on any of the study arms. The authors state that "sample sizes for arms 1 and 3 were expanded to accommodate a phase III design," but do not elaborate on the statistical guidelines they used for this process.
Imbalances in pretreatment patient characteristics may have played a role in the observed survival differences. Most studies of combined-modality therapy in stage III NSCLC have excluded patients with a performance status of 2 and those with a pretreatment weight loss of > 5%, while this trial allowed for pretreatment weight loss of By its statistical design, no arm in this trial can be declared a winner. However, within the larger literature, the study seems to support that an initial concomitant approach (arm 3) is superior to induction chemotherapy followed by radiotherapy (arm 1) and does not support investigations of induction chemotherapy before concomitant chemoradiotherapy (arm 2). Clinically, its findings are consistent with previous survival reports for induction chemotherapy (13 months) and concomitant chemotherapy and radiation (16 to 17 months), although the data provided here are not by themselves sufficiently to support one strategy over another and can be interpreted only within the larger context of recent randomized trials. Ultimately, the optimal sequencing of combined-modality therapy can be determined only by phase III studies. Two such trials have been designed. In CALGB 39-801, all patients were randomly assigned to concomitant chemoradiotherapy alone or induction chemotherapy followed by concomitant chemoradiotherapy using a carboplatin-/paclitaxel-based regimen.19 The addition of induction chemotherapy resulted in no survival advantage, thus confirming concomitant chemoradiotherapy as preferred standard. Furthermore, patients with good performance status but higher pretreatment weight loss were shown to have a poor prognosis. Survival times on both study arms were disappointing, possibly due to broader patient entry criteria. The value of consolidation chemotherapy as supported by the SWOG experience is currently being investigated by the Hoosier Oncology Group.10-12 What should be considered current standard therapy for unresectable stage III NSCLC? Randomized clinical trials demonstrate that concomitant chemoradiotherapy results in superior survival in patients with good performance status, although toxicity is also increased. There is no value to adding induction chemotherapy with currently established agents. The role of consolidation chemotherapy remains to be confirmed in a randomized trial. Current evidence suggests that regimens using systemic doses of chemotherapy may be optimal presumably by addressing early the micrometastatic spread of NSCLC. Such regimens should form the basis of any comparative studies and function as platform regimens to explore targeted therapies. Targeted therapies could be of benefit in the consolidation setting or when added to concomitant therapy, particularly if they can function as radiation sensitizers with better tumor cell specificity. For example, a radiation-sensitizing effect of antiangiogenic agents is well supported by preclinical experiments, and they also increase the efficacy of chemotherapy.20,21,25 A role for more intensive radiotherapy or radiotherapy administered to higher doses is also under investigation.22-24 The survival data from this LAMP trial and other recently reported studies in stage III disease16,19 should serve as a reminder that clinical trials should be offered to patients with stage III NSCLC whenever possible and that improved survival times remain an important task and goal for thoracic oncologists. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. Acknowledgment The author acknowledges statistical advice and review by Theodore Karrison, PhD, and assistance in the preparation of the manuscript by Shanda Maaskant. REFERENCES
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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10%. More patients on arm 2 had high pretreatment weight loss, which may have contributed to the disappointing numerical outcome on that arm. Also, 20% of patients on that arm received no chemotherapy at all during radiotherapy, suggesting low tolerance of therapy for this group. A survival analysis excluding the patients with a 70% performance status and/or high pretreatment weight loss would have been of interest, as would a pattern of failure analysis. 
