Seminars in Oncology
Volume 32, Issue 3 , Pages 284-292, June 2005

Current Standards and Ongoing Controversies in the Management of Locally Advanced Non-Small Cell Lung Cancer

  • Howard West

      Affiliations

    • Swedish Cancer Institute, Seattle, WA
    • Corresponding Author InformationAddress reprint requests to Howard (Jack) West, MD, Swedish Cancer Institute, 1221 Madison St, Second Floor, Seattle, WA 98104
    • ,
  • Kathy S. Albain

      Affiliations

    • Loyola University Medical Center, Maywood, IL

Article Outline

Despite the fact that nearly half of all patients with non-small cell lung cancer (NSCLC) present with stage III disease, this is the treatment setting with the least well-established standards. Generally treated with curative intent, patients with stage III disease usually receive more than one of the three main therapeutic approaches to lung cancer—surgery, radiation, and chemotherapy. In addition, the staging system encompasses a remarkably heterogeneous range of tumor burden and location within the rubric of stage III. Consequently, an individualized approach is often invoked to address particular concerns for resectability, toxicity, and patient and physician preferences. For patients with locally advanced NSCLC, therapeutic outcomes have improved overall for this population over the past few decades. While there exists a range of acceptable standard approaches to the treatment of stage III NSCLC, this review will describe several conclusions that have emerged and how they evolved.

 

Despite the fact that nearly half of all patients with non-small cell lung cancer (NSCLC) present with stage III disease, this is the treatment setting with the least well-established standards. Generally treated with curative intent, patients with stage III disease usually receive more than one of the three main therapeutic approaches to lung cancer— surgery, radiation, and chemotherapy. In addition, the staging system encompasses a remarkably heterogeneous range of tumor burden and location within the rubric of stage III. Consequently, an individualized approach is often invoked to address particular concerns for resectability, toxicity, and patient and physician preferences. For patients with locally advanced NSCLC, therapeutic outcomes have improved overall for this population over the past few decades (Table 1). While there exists a range of acceptable standard approaches to the treatment of stage III NSCLC, this review will describe several conclusions that have emerged and how they evolved.

Table 1. Outcomes of Patients With Locally Advanced NSCLC: Several Key Cooperative Group Trials
Clinical Trial and ArmMedian Survival (mo)3-Year Survival (%)
CALGB 843311
TRT alone9.610
Sequential chemotherapy → TRT13.724
West Japan15
Sequential chemotherapy → TRT13.322
Concurrent chemotherapy/TRT16.515
RTOG 941016
Concurrent chemotherapy/TRT17.137
SWOG 950425
Concurrent chemotherapy/TRT → chemotherapy2637

Abbreviation: TRT, thoracic radiation therapy.

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Resectable Locally Advanced Non-Small Cell Lung Cancer 

Although the tumor-node-metastasis (TNM) system provides a universal definition of stage III NSCLC, the definition of what constitutes resectable disease within stage III is largely dependent on the surgeon reviewing the case. While many surgeons will routinely undertake a surgical approach for even bulky stage IIIA N2 disease, stage IIIB disease, with either T4 or N3 involvement, is usually but not universally treated with a nonsurgical approach. Consequently, stage IIIA NSCLC is generally considered to be the highest stage for which surgery is routinely employed, and it is in this setting that the role of induction therapy has been most studied. A series of small randomized trials1, 2, 3 published about a decade ago demonstrated striking improvements in overall and disease-free survival in the group of patients that received chemotherapy prior to surgery (Table 2). The conclusion from these trials that induction therapy prior to surgery improves survival requires several caveats: (1) these trials were all quite small due to marginal accrual or early termination; (2) many of the patients included would not be considered to have stage IIIA disease by the current staging system after revision in 19974; and (3) putative prognostic markers in one study3 were imbalanced in favor of the arm receiving induction chemotherapy and associated with a worse survival than would be expected. Nevertheless, the compelling differences between arms and concordance of data across these studies supported the general conclusion that induction therapy prior to surgery for stage IIIA NSCLC is associated with improved survival and has become widely employed as a standard approach for this group of patients. No standard induction chemotherapy has emerged, and there is considerable variability in preferred regimens in routine practice.

Table 2. Early Randomized Trials of Chemotherapy Followed by Surgery Versus Surgery Alone
Trial and ArmNMedian Survival (mo)2-Year Survival (%)
Pass1
Surgery141629
Chemotherapy + surgery132963
Rosell2
Surgery30810
Chemotherapy + surgery302637
Roth3
Surgery321134
Chemotherapy + surgery286450

A couple of more recent trials, however, challenge the conclusion that there is a clinical benefit of induction therapy for stage IIIA disease. A French trial by Depierre et al5 randomized 345 patients with stage IB-IIIA NSCLC to surgery alone or two cycles of mitomycin, ifosfamide, and cisplatin before surgery and for an additional two cycles postoperatively in responding patients; patients with pT3 and/or pN2 disease also received thoracic radiotherapy. While the authors reported a trend toward improved median survival for the arm that received chemotherapy (37 v 26 months, P = .15), subset analysis demonstrated improved survival with chemotherapy in stages I-II but not stage IIIA NSCLC, in contrast with the aforementioned trials. In addition, the recently published Japanese Cooperative Oncology Group trial 9209,6 which targeted 100 patients per arm over 3 years but closed prematurely with 62 total patients over a 5-year accrual period, demonstrated no survival benefit from induction chemotherapy with cisplatin and vindesine for three cycles compared to surgery alone. While the French trial may be hard to interpret due to the eligibility of patients with quite bulky mediastinal disease, and the Japanese trial had a considerably lower response rate (28%) than would be expected and poor accrual, these trials certainly indicate that questions about the optimal management of stage IIIA NSCLC remain unanswered.

Despite these issues, most oncologists in the United States employ preoperative chemotherapy, and many administer preoperative radiation. The trials described above administered radiotherapy variably and did not systematically evaluate the role of radiation. The Southwest Oncology Group established a compelling rationale for an induction chemoradiotherapy approach in S8805, a phase II trial of 126 patients with stage IIIA or IIIB NSCLC who received two cycles of cisplatin and etoposide (PE) along with concurrent thoracic radiation therapy (TRT) to 45 Gy, followed by surgery in cases of nonprogression.7 While this trial included many patients who would widely be considered to be unresectable, 85% of stage IIIA patients and 80% of IIIB patients were able to undergo surgery, and an encouraging 3-year survival rate of 26% was achieved overall (27% and 24% for stages IIIA and IIIB, respectively). This trial, as well as many others since then, demonstrated the highly significant predictive value of achieving mediastinal lymph node sterilization after induction therapy, with a 3-year survival rate of 44% versus 18% (P = .0005). Positron emission tomography (PET) scans after induction therapy may be of assistance in assessing mediastinal sterilization and overall response, and some recent data suggest that serial PET scans may be highly predictive of survival after induction therapy.8

The report that long-term survival is highly associated with response to treatment prior to surgical resection questions whether surgery adds considerably to the curability of the overall approach; this is a critical question in light of the added morbidity and potential mortality (10% in SWOG 8805) of a trimodality approach of chemoradiation followed by surgery. North American Intergroup trial 0139 (INT 0139) was initiated to specifically address this issue. In this trial, 439 medically fit patients with T1-3N2M0 NSCLC enrolled over more than 7 years were first randomized to a surgical or nonsurgical arm, then all patients received chemotherapy with PE for two cycles and concurrent TRT to 45 Gy. All patients were evaluated for response, and those without progression then received either surgery and two cycles of consolidation PE chemotherapy or continuation of TRT to 61 Gy without a treatment break, followed by two cycles of the same chemotherapy (Fig 1). Outcomes from this randomized trial were most recently presented by Albain and colleagues at the World Conference on Lung Cancer in Vancouver, Canada, with a median follow-up of 71 months.9 While progression-free survival favored the arm that received trimodality therapy (median, 13.4 v 11.8 months; 3-year, 28% v 19%; Fig 2), there were more treatment-related deaths on the surgical arm; overall survival was very similar between the two groups (median, 22.0 v 22.3 months; 3-year, 37% v 34% for surgical and nonsurgical arms, respectively; Fig 3). Among 161 patients with surgical details available, pathologic complete responses were seen in 18% of patients, and clearance of mediastinal nodes in 46%, in whom a 3-year overall survival of 53% was observed. Further follow-up will be required to determine whether the modestly better overall survival in the trimodality arm emerges as statistically significant over time.

While the INT 0139 trial addresses the role of surgery for stage IIIA N2 NSCLC, it does not address the question of the optimal induction treatment strategy. The Intergroup trial underscored the potential for excessive toxicity in a trimodality approach, in that the improvement in disease-free survival after induction chemoradiotherapy followed by surgery was nullified by the additional mortality of such an ambitious approach compared to definitive chemoradiotherapy. The less toxic approach of induction chemotherapy alone has not been adequately compared to induction chemoradiotherapy in the resectable stage IIIA N2 setting. Because of the relevance of this question, the Radiation Therapy and Oncology Group (RTOG) and SWOG will lead an intergroup effort to compare cisplatin-based chemotherapy alone as neoadjuvant therapy to the same agents with concurrent thoracic irradiation to 45 Gy, with all nonprogressing patients proceeding to surgery (Fig 4). This trial will focus on a patient population with a more limited, nonbulky definition of IIIA N2 NSCLC than was included in INT 0139 and will clarify the contribution of radiation therapy in this setting. This trial will also study molecular correlates in tumor and blood samples, evaluate quality of life during treatment, and assess the value of PET scans before and after induction therapy, in addition to the primary end point of overall survival.

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Unresectable Stage III Non-Small Cell Lung Cancer 

Historically, radiation alone has been the standard approach to treatment of locally advanced NSCLC. In light of the significant risk of distant recurrence after this local therapy, the potential value of chemotherapy was assessed in a landmark trial, Cancer and Leukemia Group B (CALGB) 8433, by Dillman et al.10 In this trial, 155 eligible patients with stage III NSCLC were randomized to receive induction chemotherapy with two cycles of cisplatin and vinblastine followed by definitive TRT to 60 Gy, or the standard treatment of TRT alone. The results of this trial demonstrated a significant survival benefit favoring recipients of multimodality therapy with sequential chemotherapy and radiation. The median survival improved from 9.7 to 13.8 months and 5-year survival improved highly significantly, from 6% to 17%, with the addition of chemotherapy. These conclusions, initially published in the New England Journal of Medicine for their potential implications as a new standard of care, have also held up with additional follow-up.11

Schaake-Koning et al compared TRT alone to chemoradiotherapy with cisplatin, administered either daily or weekly during TRT.12 In this trial, 331 patients received radiation over 2 weeks followed by a 3-week rest and then 2 more weeks of radiation, for a total of 55 Gy; for the chemoradiotherapy arms, this unusual schedule was combined with cisplatin 30 mg/m2 weekly on the first day of each treatment week, or 6 mg/m2 daily on each radiation treatment day. Compared to the TRT alone standard arm, 3-year survival was significantly improved for the recipients of daily cisplatin as well (16% v 2%, P = .009), with intermediate and nonsignificantly different results seen in arm receiving weekly cisplatin during TRT. Local recurrence in particular was markedly reduced with chemoradiotherapy, more so with daily than weekly cisplatin. Toxicity, however, was problematic with cisplatin-based chemoradiotherapy, particularly nausea and vomiting. These results are quite intriguing, but the split-course radiotherapy is suboptimal and daily cisplatin was generally felt infeasible and prohibitively toxic. This approach, therefore, has not been widely practiced and the study was less influential than the Dillman trial, but the encouraging efficacy of concurrent chemoradiotherapy has been corroborated, as described further below.

The RTOG, along with the Eastern cooperative Oncology Group (ECOG) and SWOG, performed an intergroup trial to confirm the encouraging results of the Dillman trial, as well as to determine the potential value of hyperfractionated radiation, in which radiation is administered in more than one fraction daily, which optimizes the radiobiologic effects of TRT. In RTOG 8808, 498 patients (458 eligible) were randomized to one of three arms: standard TRT alone, two cycles of cisplatin and vinblastine followed by standard TRT, or hyperfractionated (twice daily) TRT.14 This trial demonstrated a modest survival benefit from the addition of chemotherapy (median survival, 13.2 v 11.4 months; 5-year survival, 8% v 5%), with no significant benefit seen from hyperfractionated radiation compared to a standard, daily approach (median survival, 12 months; 5-year survival, 6%).

These negative results for hyperfractionation in the RTOG trial conflicted with early promising work in the United Kingdom. Saunders et al published results of their work with continuous hyperfractionated accelerated radiation therapy (CHART) compared to standard TRT.14 CHART consisted of 36 fractions of 1.5 Gy three times per day over 12 consecutive days. Chemotherapy was not employed in the trial of 563 patients with unresectable NSCLC. Relative risk of death was reduced by 22% for patients on CHART (P = .008); 3-year overall survival was 20% for recipients of CHART and 13% for recipients of conventional TRT. Symptomatic dysphagia was greater in patients receiving CHART, but radiologic findings and clinical symptoms of radiation pneumonitis were actually higher in the conventional TRT group. Despite these encouraging findings, the growing trend toward integrating chemotherapy with radiation for locally advanced NSCLC along with the practical challenges of administering CHART in the outpatient setting greatly limited adoption in the United States of hyperfractionated TRT for NSCLC.

Over the past several years, a bimodality approach of chemoradiation has become widely practiced for unresectable stage III NSCLC in the United States, and much of the recent debate has been on whether these therapies should be delivered concurrently or sequentially. One landmark trial that helps to answer this question was conducted by Furuse et al on behalf of the West Japan Lung Cancer Group.15 In this study, 320 patients with stage IIIA or IIIB NSCLC were randomized to receive mitomycin, vinblastine, and cisplatin (MVP) chemotherapy for two cycles prior to or concurrent with TRT to 56 Gy, with a break for patients who received concurrent chemoradiotherapy, but no break for patients who received sequential treatment. Despite the fact that the split-course radiation is a radiobiologically inferior treatment that would theoretically handicap the concurrent arm, the concurrent approach was associated with a significantly higher survival (median survival, 16.5 v 13.3 months; log-rank P = .04; 5-year survival, 15.8% v 8.9%). Concurrent chemoradiotherapy was associated with more myelosuppression, but there were no differences in acute nonhematologic toxicity or chronic toxicity. Interestingly, the concurrent arm experienced a significantly higher percent of subsequent failures within the brain: 19% versus 9% (P = .018). This trial has been criticized for using a lower than standard dose of TRT, but the results suggest a promising improvement in efficacy by delivering chemotherapy and radiation concurrently.

These conclusions were reinforced by the emerging results from RTOG trial 9410, with data presented in abstract form and updated in 2003.16 This large phase III trial included 610 unresectable stage II-III NSCLC patients who were randomized to sequential chemotherapy and conventional radiation (daily, to 60 Gy), concurrent chemotherapy and conventional radiation, or chemotherapy and hyperfractionated radiation (twice daily, to 69.6 Gy). Emerging results demonstrate a significant improvement in median survival for patients from 14.6 to 17.0 months, and 4-year survival of 12% versus 21% (P = .46) among patients receiving chemoradiation versus the previous standard of sequential chemotherapy and radiation. As in RTOG 8808, there was no significant benefit seen for hyperfractionated radiation, with a median survival of 15.2 months and 4-year survival of 17%. Overall, these findings were reassuringly similar to the Japanese experience.

Finally, several smaller trials also suggested an improvement in survival for a concurrent versus sequential approach.17, 18, 19 Taken together, while the modest improvement in efficacy may be considered too marginal by some physicians or patients to justify the higher toxicity and difficulty administering concurrent chemotherapy and radiation, the converging evidence of superior survival from Japan, the RTOG, and several additional trials has helped to crystallize the concurrent approach as an optimal strategy if feasible.

One recently presented trial does suggest an intriguing potential benefit from hyperfractionated radiation. At the 2003 annual meeting of the American Society of Clinical Oncology (ASCO), Belani et al20 presented results from ECOG 2597, a study that attempted to evaluate the contribution of hyperfractionated accelerated radiation therapy (HART) (three times per day over 12 days to 54 Gy) to a bimodality approach with conventional TRT (daily to 64.8 Gy) in a sequential approach for both arms following two cycles of chemotherapy of carboplatin and paclitaxel. This study was closed prematurely with 112 patients due to poor accrual, in part because of the emerging standard of concurrent chemoradiotherapy eclipsing the sequential approach employed in this trial. While not statistically significant in this small study, the 3-year survival benefit of 23% for HART versus 14% for sequential standard chemoradiotherapy suggests that HART may confer added efficacy. However, this approach was also associated with higher toxicity, with grade 3/4 esophagitis in 25% versus 12.5%. Choy, discussing the results of this trial in the context of a growing number of trials demonstrating superior survival for stage III NSCLC accompanied by higher acute toxicity for concurrent chemoradiotherapy, concluded that sequential chemotherapy and HART provided similar efficacy and toxicity to a concurrent approach.21 The ECOG results have renewed some interest in HART, but the practical challenges to both patients and physicians will limit the enthusiasm for this strategy, particularly if comparable results are obtained from the increasingly established standard of concurrently administered chemotherapy and TRT.21

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Integrating Newer Agents Into Treatment for Locally Advanced Disease 

Over the past decade several newer agents, including vinorelbine, the taxanes, gemcitabine, and the camptothecins, have been studied and increasingly established as effective in platinum-based combinations for metastatic disease, and then extended into the locally advanced NSCLC setting. Many of these agents have been evaluated and reported in only small, phase I and II studies in combination with radiation for stage III patients. Recently, however, some larger and increasingly influential trials have been presented and published that incorporate these newer agents into chemoradiation approaches.

Vokes et al22 published the CALGB experience of a randomized phase II trial with 175 patients who all received induction cisplatin-based chemotherapy followed by concurrent lower-dose chemotherapy during TRT to 66 Gy. The three groups were randomized to receive cisplatin paired with gemcitabine, paclitaxel, or vinorelbine. Although the phase II design precludes statistical comparison among the groups, they demonstrated comparable efficacy, and all three of these approaches were associated with activity and survival numbers similar to that seen with older cisplatin-based regimens. Of note, the extremely potent radiosensitizer gemcitabine was dosed empirically at half of a standard systemic dose during the radiation, and this arm experienced a high incidence (51%) of severe esophagitis. This study demonstrated on a larger scale the feasibility and efficacy of induction chemotherapy followed by concurrent chemoradiotherapy, although the CALGB has proceeded with a carboplatin/paclitaxel regimen as its chemotherapy backbone in subsequent trials, based on limited phase I and II studies and increasingly frequent use of this regimen in the community setting. The recently completed CALBG trial 39801 compared induction carboplatin/paclitaxel every 3 weeks for two cycles followed by weekly carboplatin/paclitaxel for 7 weeks during concurrent TRT with an approach of chemoradiotherapy alone, without induction systemic therapy (Fig 5).23 This study enrolled 366 patients over 4 years and demonstrated a numerically superior results for the group receiving induction therapy, both in terms of median survival (13.7 v 11.4 months) and 3-year overall survival (24% v 18%); however, these differences were not statistically significant. Of note, the survival outcomes in both arms are numerically inferior to those seen in recent trials employing cisplatin-based chemotherapy and concurrent TRT, raising the question of whether weekly carboplatin/paclitaxel and concurrent TRT may be an inferior approach to that of cisplatin-based concurrent chemoradiotherapy.

Investigators at the University of North Carolina have modified this approach, systematically escalating the radiation dose, based on the hypothesis that the widely practiced limits in conventional TRT are insufficient to sterilize the often large tumor volumes present with locally advanced NSCLC.24 Accordingly, 62 patients received induction chemotherapy with carboplatin and paclitaxel every 3 weeks for two cycles, followed by weekly carboplatin and paclitaxel along with concurrent TRT increasing from 60 to 74 Gy over the course of the trial. The 3-year overall survival rate was 40%, approximately doubling the results generally seen for this patient population. The investigators also noted that 10 of the 35 (29%) patients with progression had a brain-only relapse, suggesting a potential benefit for prophylactic cranial irradiation for locally advanced NSCLC.

An alternate approach to chemoradiation has been adopted by the SWOG, which has been studying initial concurrent chemoradiotherapy with cisplatin and etoposide, followed by “consolidation” chemotherapy alone. In the phase II SWOG trial S9019, 50 patients with pathologically (mediastinoscopy) staged IIIB NSCLC received cisplatin and etoposide for two cycles with TRT to 61 Gy, followed by two more cycles of cisplatin/etoposide.25 This treatment was well tolerated overall, and results were similar to those seen in other trials for this patient population, with a median survival of 15 months and 5-year overall survival of 15%. More recently, however, SWOG 9504 substituted three cycles of single-agent docetaxel for the two additional cycles of cisplatin/etoposide that followed concurrent chemoradiotherapy, in a group of 83 eligible patients who shared identical eligibility criteria as the earlier SWOG trial 9019.26 This cohort of patients was recently reported to have a remarkable median survival of 26 months, and a 3-year survival of 37%. As had been noted in other concurrent chemoradiotherapy trials, the SWOG reported a 33% incidence of first relapse in the central nervous system (33%), including 18% of total patients with brain-only relapse after concurrent and consolidation therapy. Although this is a phase II trial, these very promising results have led to widespread use of a consolidation strategy after concurrent chemoradiotherapy, often but not invariably with docetaxel. In the ongoing phase III trial SWOG 0023 (Fig 6), all patients receive two cycles of cisplatin and etoposide along with concurrent TRT to 61 Gy, followed by three cycles of docetaxel, with subsequent randomization of nonprogressing patients to either maintenance daily oral gefitinib or placebo. This trial will not only evaluate the potential value of maintenance gefitinib after chemoradiation and subsequent consolidation chemotherapy, but it will provide an opportunity to confirm or challenge in a much larger setting the very encouraging results attributed to consolidation docetaxel in SWOG 9504. The Hoosier Oncology Group is also conducting a trial designed specifically to isolate the contribution of consolidation docetaxel; in this trial, all patients receive concurrent cisplatin and etoposide with TRT, and then half are randomized to three cycles of docetaxel, while the other half are randomized to no further therapy (Fig 7). With these two trials and a much wider clinical experience with consolidation therapy, the role of this approach will become clarified in the coming years.

The Locally Advanced Multimodality Protocol (LAMP) trial is an industry-sponsored randomized phase II trial that included three arms of carboplatin/paclitaxel combined with radiation; one arm received sequential chemotherapy followed by radiation, another received induction chemotherapy (every 3 weeks) followed by concurrent chemoradiotherapy, and a third received concurrent chemoradiotherapy followed by chemotherapy27 (Fig 8). Since the phase II design and limited number of 276 total patients on the trial preclude comparisons within the trial, all three arms were compared with benchmark results from RTOG trial 8808.28 Early results (Table 3) demonstrate an inferior survival on the arm receiving chemotherapy followed by chemoradiotherapy (median survival, 12.8 months v 14.5 months for concurrent chemoradiotherapy for RTOG 8808), potentially because this group was much less likely to receive all of the intended chemotherapy during radiation than the arm that started with chemoradiotherapy. The arm receiving chemoradiotherapy followed by “consolidation” chemotherapy had the numerically superior median survival at 16.1 months.

Table 3. Efficacy Results of the LAMP Trial26
Sequential Chemotherapy → TRTInduction Chemo → Concurrent Chemotherapy + TRTConcurrent Chemotherapy + TRT → Consolidation ChemotherapyRTOG 8808 (historical control)
1-yr progression (%)534647—
Median survival (mo)13.012.816.114.5
1-yr survival (%)59536458
2-yr survival (%)31223331

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Management Options for “Poor-Risk” Patients With Locally Advanced NSCLC 

With a median age for presentation with lung cancer in the mid-60s, and with most patients developing lung cancer after a prolonged smoking history, many patients have comorbidities or a marginal performance status that precludes safe administration of the cisplatin-based chemotherapy used in these trials along with concurrent thoracic irradiation. SWOG conducted a phase II multicenter trial, S9429,29 specifically for “poor-risk” patients with stage III NSCLC who were felt unable to tolerate standard cisplatin-based chemotherapy protocols because of poor pulmonary or renal function, history of congestive heart failure, significant hearing loss, peripheral neuropathy, or weight loss. Sixty-three patients were accrued over a 1-year period, receiving fixed-dose carboplatin in combination with etoposide, all with concurrent thoracic irradiation. Overall, this treatment plan was well tolerated, with primarily hematologic toxicity except for a 15% grade 3/4 acute esophagitis rate. The median overall survival of 13 months and 2-year survival rate of 21% compared favorably with larger cisplatin-based trials for good-risk patients. The rapid enrollment on this trial underscored the prevalence of a stage III NSCLC patient population that is unable to tolerate a more aggressive cisplatin-based chemoradiation approach, while the trial itself demonstrated the feasibility and encouraging clinical outcomes for the treatment employed.

SWOG has subsequently completed a follow-up trial that incorporates consolidation taxane, based on the highly encouraging results of the previously described SWOG 9504 phase II trial. In SWOG 9712, 96 poor-risk patients with unresectable stage III NSCLC received the same concurrent chemoradiation approach as in SWOG 9429, followed by consolidation paclitaxel every 3 weeks for three cycles.30 Unfortunately, while the consolidation approach in this trial was associated with a higher response rate than seen in the preceding trial (58% v 29%), there was no improvement in median and 2-year survivals with the addition of consolidation paclitaxel, potentially due to the treatment-related deaths (9.2%) during consolidation.

The poor-risk, marginal performance status patient population in NSCLC has received increasing attention over the past few years, and recently there have been a growing number of trials targeting this group specifically. While this has been particularly true in the advanced disease setting, the consistent accrual in the two SWOG phase II trials, combined with the lack of a clear optimal strategy for these patients with stage III disease, has led to increasing focus on this group, with a hope that more information on treatment options for poor-risk patients with locally advanced NSCLC will soon be available.

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Conclusions 

Clinical outcomes for stage III NSCLC are poor with surgery or radiation alone but have improved over the last two decades from the increasing adoption of a multimodality approach. While stage IIIA disease typically designates the limits of resectability, the particular surgeon reviewing the case is critically important in defining whether an individual case is better served with a surgical or nonsurgical approach. Available trials demonstrate that induction therapy with either chemotherapy or chemoradiation is feasible and that mediastinal lymph node sterilization is associated with improved overall survival. INT 0139 suggests a disease-free survival benefit for induction chemoradiotherapy followed by surgery compared to definitive chemoradiotherapy, but overall survival is not significantly different between the two groups due to the higher treatment-related mortality of the trimodality approach. While most practitioners in the United States favor induction therapy prior to surgery for stage IIIA N2 disease, there remains controversy and an absence of randomized prospective data about whether chemotherapy alone or concurrent chemoradiotherapy should be administered prior to surgery. In North America, an intergroup trial is in development that will clearly define a surgically resectable IIIA N2 NSCLC population and compare induction chemotherapy with chemoradiotherapy.

For stage IIIB disease or other locally advanced disease considered to be unresectable, treatment standards have shifted from radiation alone to bimodality therapy with chemotherapy and TRT. Several recent trials, including two randomized phase III studies, have demonstrated superior efficacy from their concurrent administration versus a sequential approach, albeit with higher acute toxicity, primarily esophagitis. Because of the greater toxicity and the relatively modest improvement in efficacy, a concurrent strategy may be particularly challenging for older and “poor-risk” patients with significant comorbidities and/or a marginal performance status. A few recent studies by the SWOG demonstrate feasibility of a carboplatin-based concurrent chemoradiotherapy approach for this population.

Hyperfractionation of TRT has been controversial, with some early studies demonstrating a significant improvement in survival compared to conventional radiation, but other studies, particularly those in which chemotherapy was also employed, showed no significant clinical benefit. Hyperfractionation is also generally associated with an increase in toxicity similar to that observed with concurrent chemoradiotherapy, while the later has been more universally shown to confer survival benefit and has been considerably more widely accepted by patients and physicians, at least in the United States.

The most recent research focus for locally advanced NSCLC has been integrating the newer chemotherapeutic agents that have become standards in advanced NSCLC. These studies often administer initial chemotherapy (induction) followed by definitive concurrent chemoradiotherapy, or alternatively initial concurrent chemoradiotherapy followed by consolidation chemotherapy alone. In addition, targeted agents are also being evaluated in the stage III NSCLC setting, generally in a sequential, maintenance fashion, since results with concurrent administration of conventional chemotherapy and targeted agents such as EGFR tyrosine kinase inhibitors has been consistently disappointing thus far.

Stage III NSCLC represents a very common presentation, for which optimal therapy still remains controversial. More recent studies have refined the management of these patients by incorporating more rigorous staging and eligibility requirements, which is particularly relevant in this treatment setting, where disease burden, location, and patient health are so variable and important to outcomes. With the increasing attention that this population has received and the multitude of clinical trials focusing on stage III NSCLC, we can hope and expect to continue the current trend toward improving survival for this patient population.13

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PII: S0093-7754(05)00084-9

doi:10.1053/j.seminoncol.2005.02.015

Seminars in Oncology
Volume 32, Issue 3 , Pages 284-292, June 2005

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