Locally Advanced, Unresectable Non–Small-Cell Lung Cancer

December 1, 2007

A significant proportion of patients with non-small cell lung cancer (NSCLC) present with locally advanced, unresectable disease. For the most part, fit patients with this diagnosis are treated with combined-modality therapy. Relatively few are rendered resectable. Over the past two decades, combination chemotherapy and radiation, preferably concurrent chemoradiation, has emerged as the standard of care. However, survival gains have been offset, to some extent, by local, normal-tissue, in-field toxicity, particularly esophagitis and pneumonitis.

 

Continuing Medical Education InformationLocally Advanced, Unresectable Non–Small-Cell Lung Cancer:
Recent Phase III Trials Undermine the Dogma of Consolidation and Maintenance Treatment

 

Activity Release Date: December 1, 2007
Activity Expiration Date: December 1, 2008

About the Activity
This activity is based on a brief article developed as part of the E-Update Series and posted on the Web. It was developed from an identified educational need for information about practical management issues in the practice of medical, surgical, and radiation oncology. This activity has been developed and approved under the direction of Beam Institute.

Activity Learning Objectives
After reading this article, participants should be able to:

Compare concurrent chemoradiation and sequential therapy for locally advanced non-small-cell lung cancer (NSCLC).Explore the role of consolidation chemotherapy for locally advanced NSCLC.Review the early findings with newer forms of radiation, such as 3D conformal radiotherapy.Appreciate the impact of the difficult, yet common, late toxicity radiation pneumonitis.Discuss recent study findings focusing on the role of EGFR inhibitors in locally advanced NSCLC.

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This activity targets physicians in the fields of oncology and hematology.

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This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Beam Institute and The Oncology Group. Beam Institute is accredited by the ACCME to provide continuing medical education for physicians.

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The Beam Institute designates this educational activity for a maximum of 2 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

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This activity is an independent educational activity under the direction of Beam Institute. The activity was planned and implemented in accordance with the Essential Areas and policies of the ACCME, the Ethical Opinions/Guidelines of the AMA, the FDA, the OIG, and the PhRMA Code on Interactions with Healthcare Professionals, thus assuring the highest degree of independence, fair balance, scientific rigor, and objectivity.

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Financial Disclosures

Dr. Govindan receives research support from Bristol-Myers Squibb, Eli Lilly, Genentech, Pfizer, and Sanofi-Aventis, and he serves on the speakers' bureau for Eli Lilly and Genentech. Dr. Langer receives research grants and serves on the speaker's bureau for Genentech and Sanofi-Aventis and he also serves on the advisory board for Genentech.

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Copyrights owned by Beam Institute, a division CME LLC. Copyright 2007. All rights reserved.

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Introduction

A significant proportion of patients with non-small cell lung cancer (NSCLC) present with locally advanced, unresectable disease. For the most part, fit patients with this diagnosis are treated with combined-modality therapy. Relatively few are rendered resectable. Over the past two decades, combination chemotherapy and radiation, preferably concurrent chemoradiation, has emerged as the standard of care. However, survival gains have been offset, to some extent, by local, normal-tissue, in-field toxicity, particularly esophagitis and pneumonitis.

Over the past 5 years, based on a single-arm phase II trial, consolidative therapy with docetaxel (Taxotere) became increasingly popular. The Southwest Oncology Group (SWOG) 9504, which featured a platform regimen of etoposide, cisplatin, and radiation therapy (RT) followed by 3 cycles of docetaxel (EP/RT → Doc), yielded a median survival of 27 months, and a 5-year survival rate of 29%, results unprecedented in the treatment of locally advanced NSCLC. However, the results of a phase III trial orchestrated by the Hoosier Oncology Group (HOG) proved sobering, with no obvious survival advantage for consolidative docetaxel versus standard observation in patients who received concurrent EP/RT alone. Moreover, the use of maintenance therapy with gefitinib (Iressa), a prototypic EGFR (epidermal growth factor receptor) tyrosine kinase inhibitor, after EP/RT → Doc not only failed to evince a survival advantage but resulted in an unanticipated survival decrement.

Consequently, the routine use of consolidative or maintenance therapy in this setting has been undermined. Future strategies will incorporate the testing of three-dimensional (3D) conformal RT with escalated RT doses, using modern imaging techniques including 3D conformal RT to limit the field size. In addition, the role of other cytotoxics, such as pemetrexed (Alimta), and selected targeted agents, such as cetuximab (Erbitux) and bevacizumab (Avastin), are being explored. Finally, we need to conquer the typical toxicities associated with concurrent chemoradiation, most notably esophagitis and pneumonitis; a relative paucity of studies address this ubiquitous issue. 

The Modern Era of Combined-Modality Therapy

In 2007, 35,000 to 40,000 people in the United States will be diagnosed with locally advanced NSCLC.1 Relatively few are candidates for surgical resection, and likely little more than half are good candidates for combined-modality therapy, based on performance status and recent weight loss. The presentation of CALGB (Cancer and Leukemia Group B) 8433 in 1990 ushered in the modern era with respect to combined-modality therapy.2 This relatively small trial, which accrued just over 150 patients, demonstrated a conclusive survival advantage for induction chemotherapy (5 weeks of cisplatin and vinblastine) followed by definitive RT (60 Gy) versus RT alone. The median survival improved by 4 months (14 vs 10 months; P = 0.0066), with persistent, consistent improvement in long-term survival rates. At 6 years, the overall survival was more than double in the combined-modality arm (13%) than in the control group (6%).3

Much larger studies by the Radiation Therapy Oncology Group (RTOG)4,5 and by French investigators6 (Le Chevalier et al) confirmed these results, though long-term survival figures in both efforts were a bit less impressive for sequential chemotherapy followed by RT than in the CALGB study (Table 1). Chemotherapy produced a systemic effect with reduction in distant failure, which translated into a survival benefit. A recent meta-analysis reported by Le Chevalier and colleagues on behalf of the NSCLC Collaborative Group confirmed the survival advantage for sequential chemoradiation compared with radiation alone.7 A total of 22 trials testing this concept, with 3,839 patients enrolled and follow-up of nearly 7 years, demonstrated a statistically significant survival benefit: an increase from 8.7% to 11.3% at 3 years (hazard ratio [HR] = 0.88; 95% confidence interval [CI], 0.82−0.94; P = 0.0001). There was no clear evidence of difference in effect by the type or timing of chemotherapy, or in any particular subgroup, defined by age, gender, performance status, histology, or stage.

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At the same time, sequential chemoradiation became the standard; several trials reported a therapeutic benefit for concurrent chemoradiation compared with RT alone. A landmark effort by Schaake-Koning et al of the European Organization for Research and Treatment of Cancer (EORTC) showed a clear-cut survival advantage for daily cisplatin (6 mg/m2) during split-course RT over split-course RT alone.8 At 2 years, 26% of those receiving concurrent daily chemotherapy and radiation were alive, compared with 13% in the control arm and 19% in a separate group receiving weekly cisplatin and RT (P = 0.04).

Two additional efforts from Jeremic and colleagues evaluating twice-daily RT, first in combination with weekly carboplatin and etoposide, the second in combination with daily carboplatin/etoposide, yielded a clear-cut advantage over RT alone.9,10 The benefits were due to enhanced local control, presumably radiosensitization. There was no systemic benefit.

A companion meta-analysis of 21 separate trials7 reported by Le Chevalier et al reinforced these results. Individual patient data (IPD) were obtained from 15 randomized controlled trials (RCTs) with 2,733 patients accrued, with survival from 1 additional RCT without IPD also included. Among 2,910 eligible patients with a median follow-up of 5.3 years, a significant benefit was observed for concomitant chemoradiation, with a 3.2% improvement in 3-year survival rate: 16.6% versus 13.4% (HR = 0.88; 95% CI, 0.81−0.95; P = 0.0008). Whether these patients truly reflect the types of individuals typically seen in North America is open to question, since 82% were male and more than 50% had squamous cell histology. Nevertheless, both meta-analyses, as proof of principle, confirmed the primacy of combined chemoradiation versus RT alone.

Concurrent Chemoradiation Versus Sequential, Asynchronous Therapy

Two separate studies have shown a clear-cut benefit for concurrent treatment compared with sequential chemotherapy followed by RT. The West Japan Cancer Group enrolled 320 patients onto a prospective randomized, phase III trial comparing sequential MVP (mitomycin, vinblastine, cisplatin) followed by thoracic RT (56 Gy, split course) versus identical chemotherapy and RT given concurrently.11 Patients receiving concurrent therapy realized a 3.3-month improvement in median survival (16.6 vs 13.3 months; P = 0.03), which translated, in turn, into an improved 5-year survival rate (15.8% vs 8.9%).

The large RTOG 9410 trial randomized 610 patients to receive sequential chemotherapy and radiation, established as a standard by the CALGB 8433, versus concurrent once-daily or twice-daily RT with chemotherapy.12 Patients enrolled in the once-daily arm received chemotherapy identical to that used in the sequential arm (vinblastine and cisplatin), although both modalities were given simultaneously on day 1. Patients enrolled on the sequential twice-daily arm received 69.6 Gy in combination with cisplatin (50 mg/m2) on days 1, 8, 29, and 36 as well as oral etoposide. The once-daily approach yielded a median survival of 17 months, versus 14.6 months for the sequential approach. The P value of 0.038 was nearly identical to that observed in the West Japan trial, as were the 5-year survival rates (16% vs 10%, respectively). These trials in combination are the largest phase III efforts to show a clear-cut survival advantage for concurrent therapy over sequential treatment.

A smaller effort by Fournel et al randomized 212 patients to receive sequential chemotherapy utilizing cisplatin (120 mg/m2) every 4 weeks in combination with vinorelbine (30 mg/m2) weekly followed by RT or concurrent chemoradiation with cisplatin and etoposide for 2 cycles during RT. Patients enrolled in both arms received consolidative chemotherapy. The concurrent arm yielded a median survival of 16.3 months, compared with 14.5 months in the sequential arm; these results, in turn, translated into relative 4-year survival rates of 20.7% and 14.2%.13

Yet another, more recent meta-analysis underscored the benefits of concurrent chemoradiation compared with sequential therapy.14 Seven separate trials, randomizing a total of 1,301 patients, were eligible for review. In aggregate, 76% of trial participants were male; 46% had squamous cell histology and 43% were younger than age 60. At 5 years, an absolute survival advantage of 4.4% (15% vs 11%) was observed for concurrent chemoradiation (HR, 0.83; 95% CI, 0.73−0.94; P = 0.002). However, these benefits came at a considerable cost, with a marked increase in acute grade 3/4 esophageal toxicity (18% vs 3%; P < 0.0001), albeit no significant difference in long-term pulmonary risks. It should be noted that the majority of these trials were conducted in patients with a good performance status and minimal weight loss, a group that arguably constitutes less than 50%−60% of all patients newly diagnosed with locally advanced NSCLC. 

Consolidation Chemotherapy

The trials substantiating the therapeutic superiority of concurrent chemoradiation over sequential treatment have laid the groundwork for recently reported efforts evaluating consolidation chemotherapy in this setting. In the meta-analysis previously mentioned, concurrent chemoradiation significantly decreased local regional tumor progression (HR = 0.76; 95% CI, 0.62−0.94; P = 0.011), but there was no difference in the rate of distant tumor progression.

A landmark phase II trial (SWOG 9504) evaluated 83 patients with documented stage IIIB NSCLC in the absence of pleural or pericardial effusions. Patients were treated with concurrent RT (61 Gy) and chemotherapy (2 cycles of cisplatin or etoposide) followed by 3 cycles of docetaxel (75 mg/m2) every 3 weeks, with a proviso to escalate the dose to 100 mg/m2 in the absence of significant toxicity. This trial yielded a median survival of 26 months, a 3-year survival rate of 37%, and a 5-year survival rate of 29%, unprecedented results in this setting.15 In particular, the outcome in SWOG 9504 appeared “superior” to the cooperative group’s previous effort (SWOG 9019), which employed the same platform regimen but continued etoposide and cisplatin in the consolidative setting; this approach yielded a median survival of 15 months and a 5-year survival rate of only 15%.16 Intriguingly, in the absence of phase III data, many practitioners have adopted the SWOG 9504 regimen as their “standard.” 

However, at this year’s ASCO meeting, and again at the World Lung Meeting, Hanna et al presented the results of a critical HOG trial, which isolated the role of consolidative docetaxel and clearly short-circuited enthusiasm for this therapeutic strategy.17 This prospective, randomized phase III HOG effort enrolled 203 patients with locally advanced NSCLC, 147 of whom made it to randomization. The EP/RT regimen employed was identical to that used in SWOG 9504. Patients were randomized to receive either 3 cycles of docetaxel consolidation or “standard” observation. Based on an interim analysis conducted by the Data Safety Monitoring Committee, which showed no difference between the two arms with respect to progression-free survival, median survival, or 3-year survival, the study was closed (Table 2). Consolidation docetaxel yielded an increased incidence of infections, pneumonitis, and treatment-related deaths compared with the observation-only arm, but these rates were no different from those observed in SWOG 9504. 

Maintenance Therapy with Non-Cross-Resistant Treatment

SWOG 9504 was also employed as a platform regimen for a subsequent phase III trial evaluating the role of maintenance gefitinib versus placebo in patients who completed chemoradiation and docetaxel. SWOG 002320 was set to enroll well over 800 patients, with the expectation that 70%−80% would complete the platform regimen and go onto randomization. Like the HOG trial, this study was also closed early by its Data Safety Monitoring Committee, when it was apparent that the underlying hypothesis that gefitinib would lead to improved survival would never be realized.

At the time of the initial analysis, the placebo control arm had a more favorable outcome (P = 0.09); in a more recent update, the P value had declined to 0.01, confirming a significant disadvantage for the gefitinib arm.21 The median survival for patients randomized to receive gefitinib maintenance from the time of randomization was 23 months, compared with 35 months for those assigned to the placebo arm (P = 0.01). Toxicity was not the reason for this difference; the primary cause of death on the interventional arm was disease progression. However, the final analysis evaluating the role of maintenance therapy included only 200 patients. The possibility of molecular imbalance is being investigated retrospectively. In addition, the median survival for all patients enrolled was only 19 months, considerably lower than that observed in both the phase II SWOG 9504 effort and the randomized phase III HOG trial.

Therapeutic Implications of SWOG Studies

As a result of these two efforts, a role for consolidative treatment with docetaxel and/or maintenance therapy with an EGFR tyrosine kinase inhibitor has not been substantiated. Many clinicians have concluded, perhaps erroneously, that concurrent chemoradiation alone is the standard, although this mind-set has been questioned by those who use radiosensitizing chemotherapy during RT followed by full-dose chemotherapy after RT is completed. This type of approach has generally been used by clinicians who have opted to institute paclitaxel and carboplatin during RT, rather than “standard” etoposide and cisplatin. Nor is the potential role of consolidation as a therapeutic strategy necessarily refuted.

Ongoing studies are evaluating pemetrexed as well as other agents in this setting. In addition, a recent prospective randomized phase II trial evaluating concurrent etoposide, platinum, and RT followed either by single-agent gemcitabine (Gemzar) or the combination of gemcitabine/docetaxel suggested an advantage for the combination consolidation arm.22 The median event-free survival in this arm was 14.6 months, compared with 7.1 months for those receiving gemcitabine. At the time of analysis, median survival had not been reached in the docetaxel/gemcitabine arm, whereas a median survival of 18.5 months had been recorded for single-agent gemcitabine. Although CIs clearly overlap in this relatively small, randomized phase II trial, the suggestion that non−cross-resistant doublet therapy may have a role needs to be explored further.

As one would expect, toxicity was clearly worse for the doublet. Grade 3/4 neutropenia for the doublet was 42.9%, versus 17.4% for gemcitabine alone, and the relative incidence of grade 3/4 fatigue for the doublet was 17.9%, versus 4.3%. Despite the use of a radiomimetic like gemcitabine, there was no evidence of grade 3/4 recall esophagitis, and the incidence of pneumonitis was only 4.3% in the gemcitabine-only arm. Treatment delivery, however, was compromised:  Only 61% of those receiving the doublet were able to tolerate all 3 cycles of consolidative therapy, compared with 87% receiving gemcitabine alone.

Current Strategies and Future Directions

As a result of the SWOG 0023 and HOG efforts, enthusiasm for investigating consolidative therapy has waned. However, there are multiple other issues still to be addressed. Those who treat locally advanced NSCLC appear to be divided into two separate camps: one favoring low-dose, more-frequent, potentially less toxic, radiosensitizing chemotherapy during RT, and the other favoring full-dose, systemic treatment during RT. To date, these paradigms have not been prospectively compared in the context of a uniform chemotherapy regimen. The majority of full-dose studies have employed etoposide and cisplatin, whereas the majority of radiosensitizing studies have employed paclitaxel and carboplatin.

In phase II efforts, the median survival observed in paclitaxel/carboplatin trials has generally been lower than that obtained with cisplatin (Table 3). However, the pool of patients eligible for carboplatin-based treatment is clearly greater than that for cisplatin. Cisplatin is unsafe in frailer patients, those with baseline ototoxicity and renal dysfunction, and patients with significant cardiopulmonary disease who cannot tolerate the obligatory intravenous fluid load. Thus far, the commonly employed carboplatin/paclitaxel/RT regimen has not been compared prospectively with EP/RT with and without docetaxel, nor has full-dose paclitaxel and carboplatin (175 –200 mg/m2 and an area under the curve [AUC] of 6, respectively every 3 weeks) been compared with radiosensitizing doses of paclitaxel and carboplatin (50 mg/m2 and AUC 2 weekly) during RT, although the safety of cyclic every-3-week therapy in this context has been verified.23

Introducing New Technology

Newer forms of radiation, including 3D conformal RT (CRT), have potentially revolutionized how we deliver RT, enabling clinicians to reduce the dose to adjacent normal tissues and to escalate the dose to tumor volume. Multiple phase I trials have assessed 3D CRT in the context of weekly paclitaxel and carboplatin. With virtually no exceptions, the maximum tolerated dose obtained in these efforts has been 74 Gy,24−28 though larger doses have proven feasible in patients with somewhat smaller tumors. To date, the median survival with carboplatin/paclitaxel has consistently equaled or exceeded 22 months, suggesting a potential advantage for 3D CRT in the treatment of patients with locally advanced NSCLC. The addition of FDG-PET fusion with CT imaging has also helped delineate RT fields, potentially avoiding the unnecessary irradiation of tumor-induced atelectasis and consolidation.29 Four-dimensional PET has further refined the approach, permitting clinically relevant dose adjustments as a result of respiratory gating during RT. 30,31

Based on the promising results of prospective phase II trials, the proper role of 3D conformal RT must be assessed prospectively. RTOG has just initiated a randomized, prospective phase III trial comparing standard, full-dose RT (60 Gy) and 3D CRT at a total dose of 74 Gy. The statistical hypothesis of this trial targets a total accrual of 512 patients; an expected median survival of 24 months on the 3D conformal arm versus 17 months for the historic control should generate a power of 80% and a type 1 error of less than 0.05. Although many practitioners consider etoposide and cisplatin the standard cytotoxics in this setting, there is a relative paucity of efforts grafting 3D CRT onto cisplatin-based therapy. 

Attempts to integrate other third-generation cytotoxics like gemcitabine into 3D conformal regimens have fallen by the wayside. CALGB 30105, a randomized phase II effort reported by Blackstock28 et al, grafted 3D CRT (74 Gy) onto either weekly paclitaxel (45 mg/m2) and carboplatin (AUC 2) or gemcitabine (35 mg/m2 twice a week) during the course of full-dose RT. A total of 69 patients were enrolled. The median survival for the paclitaxel/carboplatin arm was 24.2 months, compared with 17 months for the carboplatin/gemcitabine arm. In addition, the gemcitabine arm was marred by a grade 5 pulmonary event rate of 13%, unacceptable by any criteria, whereas toxicities on the carboplatin/paclitaxel arm matched those of other efforts. 

Toxicity Management

Esophageal and pulmonary toxicities remain the bte noire of combined-modality therapy. Although we have observed a modest improvement in median survival of 3−4 months using concurrent chemoradiation compared with sequential strategies, the incidence of esophagitis has risen sixfold. At this year’s ASCO (American Society of Clinical Oncology) meeting, RTOG 9801 was updated by Movsas et al.32 In this study, the role of amifostine (Ethyol) as a mucoprotectant was tested in combination with twice-daily RT (69.6 Gy) and weekly paclitaxel and carboplatin at conventional doses.

Unfortunately, amifostine failed to reduce the objective incidence of esophagitis compared with the control arm. However, patient-reported outcomes suggested some improvement in swallowing function. Because this was not the primary endpoint of the trial, the trial itself has been considered negative. Importantly, this trial showed conclusively that amifostine did not lead to tumor protection.  Median survival times in both arms were virtually identical, in the range of 17−18 months, with 5-year survival rates of 16%−17%. These results establish a benchmark for comparison in upcoming trials, particularly those featuring 3D CRT.

Radiation pneumonitis is still a difficult challenge. To date, this problem has been relatively unexplored therapeutically. RTOG is conducting a trial evaluating the role of captopril. Clinicians at Karmanos Cancer Center in Detroit have elucidated the incidence of late pneumonitis in patients treated with chemotherapy and RT.33 These investigators retrospectively evaluated patients who underwent combined, concurrent or sequential chemotherapy and thoracic radiation over a 3-year period. The median dose of thoracic radiation was 5,940 cGy. A total of 53% of patients received etoposide and cisplatin; 24%, carboplatin and paclitaxel; 88% received concurrent chemoradiation; 36% developed radiation pneumonitis (RP); and 18% experienced RTOG grade ≥ 3 pneumonitis.

The time to development of RP was 4.6 months, and the rate of RP in patients with a history of a pulmonary disorder at baseline was 49%, compared with 28% in others (P = 0.068). One-year hospitalization rates were double: 74% versus 37% in RP and non-RP patients (P = 0.0015). Despite these toxicities, the length of median survival did not differ significantly between patients experiencing RP and those who did not. The median survival of the 15 patients with severe RP was 16.6 months, compared with 19.5 months for the overall group. The authors concluded that the rate of RP was higher than that cited in the published literature.  Their efforts underscore the glaring need to tackle this difficult, yet common, late toxicity. As more and more patients enjoy long-term survival, the impact of this troublesome sequela is likely to grow.

Targeted Agents

Many recent studies in locally advanced NSCLC have focused on the role of EGFR inhibitors. Although gefitinib has failed to prolong survival in the maintenance setting, there may be a role for other EGFR tyrosine kinase inhibitors as well as monoclonal antibodies during the initial phase of treatment.

Cetuximab (C225), a prototypic humanized monoclonal antibody that targets the extracellular domain of EGFR, has been tested by RTOG.34 Patients on RTOG 0324 received concurrent RT, paclitaxel (50 mg/m2), and carboplatin (AUC 2) followed by 2 cycles of full-dose paclitaxel (200 mg/m2 every 3 weeks) and carboplatin (AUC 6 every 3 weeks). Cetuximab was given weekly during the course of chemoradiation and during the 2 cycles of consolidative therapy.

Although data remain relatively immature, the median survival will likely exceed 18 months,35 and if the results appear sufficiently promising, they will lay the groundwork for an upcoming phase III trial isolating the role of cetuximab in locally advanced NSCLC. Interest in this trial has been fueled by the recent press release showing a survival advantage for cetuximab in combination with vinorelbine and cisplatin compared with chemotherapy alone (FLEX trial). Unfortunately, details regarding this phase III effort in advanced/recurrent NSCLC are not yet available. 

Others have tested the role of gefitinib. CALGB 3016 stratified patients into two separate cohorts: a poor-risk group (performance status [PS] of 2) and a good-risk group (PS of 0−1). All enrollees received 2 cycles of induction chemotherapy with paclitaxel (200 mg/m2) and carboplatin (AUC 6) every 3 weeks for 2 cycles along with gefitinib (250 mg daily).36 After induction chemotherapy, the high-risk strata received thoracic RT (66 Gy), in combination with gefitinib (250 mg daily) alone. Patients in the lower risk strata received the same regimen as well as concurrent radiosensitizing chemotherapy: paclitaxel (50 mg/m2) and carboplatin (AUC 2) weekly.

The poor-risk cohort fared unexpectedly well, with an event-free survival of 11.5 months (95% CI, 5.6−21.2 months) and a median overall survival of 19 months. Paradoxically, the low-risk group did poorly, with an event-free survival of 9.2 months (95% CI, 6.7–12 months) and a median overall survival of only 12 months. The relatively small sample size precludes clear conclusions but suggests a potentially antagonistic relationship between the oral EGFR tyrosine kinase inhibitors and chemoradiation. This is potentially underscored by prior experience with phase III trials in advanced disease (TRIBUTE, TALENT, INTACT 1, INTACT 2).37−40 

A phase I study conducted by the University of Chicago Consortium confirmed the safety of erlotinib (Tarceva, 150 mg daily) grafted onto standard EP/RT, as well as paclitaxel/carboplatin/RT.41 Long-term survival results from this effort are not yet available. Until we have a better handle on the role of oral agents in this setting, it is best to avoid their empiric use and to confine their implementation to well-monitored clinical trials.

SWOG is conducting a phase II trial integrating bevacizumab into combination EP/RT and docetaxel. Patients are divided into two strata based on the risk of hemorrhage. Cohort 1 will receive bevacizumab during consolidative docetaxel. Cohort 2 will receive bevacizumab half way through chemoradiation, and cohort 3, if safety has been confirmed, will receive bevacizumab up front, at the initiation of chemoradiation.

Reassessing Prognostic Criteria in the Modern Era of Chemoradiation

The standard stratification criteria used in clinical trials were established in the pre-chemotherapy era; they generally included gender, disease stage, and weight loss. Langer and colleagues retrospectively assessed RTOG 9801, a phase III trial evaluating induction chemotherapy with paclitaxel and carboplatin followed by concurrent twice-daily RT, weekly paclitaxel and carboplatin with and without amifostine, as well as patients enrolled in RTOG 9410.42 The authors assessed the distribution of prognostic variables in each study and then analyzed HRs, CIs, and P values for each prognostic factor, including age, disease stage, N status, histology, gender, Karnofsky Performance Status (KPS), tumor location, and hemoglobin level. A total of 824 evaluable patients were available for this analysis; 82% were younger than age 70, 56% had stage IIIB NSCLC, 37% had squamous cell histology, 64% were male, 53% had N2 disease, and 27% had N3 disease. The KPS was 90%−175%. A total of 22% had primary tumors located in the lower lobe or multiple lobes, and 18% had a baseline hemoglobin level under 12 g/dL. 

In univariate analysis, by Cox modeling, the KPS (90%−100% vs 70%−80%, P = 0.0002) and N status (N0/1 vs N2/3, P = 0.0048) were highly prognostic. Gender (P = 0.0481 favoring women) and lobar location (upper lobe vs lower or multilobe, P = 0.0206) were borderline prognostic. A trend toward inferior outcome was also observed in older patients or those with stage IIIB disease, squamous cell histology, or lower hemoglobin levels, but these differences were not statistically significant.

A multivariate analysis, dichotomizing each of these factors into two levels (one corresponding to a worse prognosis and the other, a better prognosis) then grouped patients into three cohorts of combined poor prognostic factors:  0, 1; 2, 3; > 3. Those with more than three adverse prognostic factors had a median survival of 13.5 months, compared with 17.3 months for patients with two to three prognostic factors and 22.7 months for those with no or one poor prognostic factor. These results delineate prognosis in this large cohort of patients and suggest that this form of joint analysis may improve our prognostic ability and constitute a more clear-headed approach toward therapeutic stratification in the presence of multiple prognostic variables. Observations from this analysis will help to determine future stratification in RTOG trials.

Conclusion

Concurrent chemoradiation has become the standard approach in locally advanced NSCLC. Enhancing efficacy and controlling toxicity are two of our primary goals. The empiric use of standard platinum compounds needs to be challenged. Recent trials in the adjuvant setting have suggested that ERCC1 may predict those who are more likely to benefit from chemotherapy, compared with those who are not likely to profit from platinum-based chemotherapy. Those with high levels of ERCC1 expression may be best served by nonplatinum regimens or targeted therapy. Prospective analyses of molecular phenotyping are crucial if we are to approach management logically.

Tackling late toxicities, particularly pulmonary dysfunction, should become a priority. Unfortunately, little regard has been given to this arena. The use of 3D conformal RT and intensity-modulated RT as well as four-dimensional radiation with pulmonary gating may help to mitigate long-term pulmonary toxicity, but a biologic approach aimed at reducing tissue inflammation and scarring should also be considered. There is no reason that biologics and technical innovations cannot be paired.

Finally, the routine use of hybrid PET-CT imaging has altered the therapeutic baseline. The results of the HOG study strongly suggest that median survival, regardless of treatment, will likely move into the range of 18−24 months, provided we select patients carefully. Trials in which patients are routinely imaged by PET must be assessed separately from those where PET imaging is not employed routinely. In the absence of this consideration, cross-trial comparisons are especially worrisome and almost routinely invalid. 

Key Points

  • In patients with suspected locally advanced non-small cell lung cancer (locally advanced NSCLC), adequate assessment of the mediastinum is essential.

  • Minimum workup for locally advanced NSCLC includes a dedicated CT of the chest and upper abdomen, PET scan, brain MRI, and performance function tests.

  • Fit patients with locally advanced NSCLC merit combined-modality therapy, including radical thoracic radiation (RT) to doses of 60−66 Gy.

  • Concurrent chemoradiation with either weekly paclitaxel and carboplatin or full-dose etoposide and cisplatin has yielded the best survival results and should be considered “standard” options.

  • Thus far, phase III data have failed to confirm a significant survival benefit for docetaxel in the consolidation setting. Hence, the use of docetaxel or other agents after full-dose chemotherapy and RT remains investigational and ideally should be considered only in the context of clinical trials.

  • In patients who have received concurrent radiosensitizing chemotherapy during RT (eg, weekly carboplatin and paclitaxel), there may still be a role for full-dose consolidative chemotherapy after completion of concurrent chemoradiotherapy for locally advanced NSCLC.

  • There is no proven role for amifostine or other “mucoprotective” agents in individuals with locally advanced NSCLC receiving RT with and without chemotherapy.

 

 

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Disclosures:

Sponsored by educational grants from Genentech and Sanofi Aventis.

References:

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