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(Chest. 2000;117:123S-126S.)
© 2000 American College of Chest Physicians

Locally Advanced, Unresectable Non-Small Cell Lung Cancer*

New Treatment Strategies

David H. Johnson, MD

* From the Division of Medical Oncology, Vanderbilt Cancer Center, Nashville, TN.

Correspondence to: David H. Johnson, MD, Division of Medical Oncology, 1956 The Vanderbilt Clinic, Nashville, TN 37232-5536


   Abstract
TOP
 Abstract
Introduction
 Current Management of Locally...
 Improving Local Tumor Control
 Improved Control of Systemic...
 Summary
 References
 
Approximately 40% of non-small cell lung cancer (NSCLC) patients present with locally advanced, unresectable lesions. Treatment with thoracic radiotherapy yields survivals averaging just 9 to 10 months, and long-term survival at 5 years is poor. Recent studies indicate that chemotherapy followed by thoracic radiotherapy improves 5-year survival by three- to fourfold. Nevertheless, most patients do ultimately die of the underlying disease. New strategies designed to enhance local tumor control—use of radiation-sensitizing drugs, three-dimensional treatment planning techniques, or altered radiation fractionation schedules—may further improve survival outcome. In addition, newer cisplatin-based regimens containing either paclitaxel or vinorelbine improve survival over that achieved with older vinca alkaloid or podophyllotoxin combination regimens. Accordingly, the newer drug regimens combined with radiotherapy can be expected to further improve survival in this subset of NSCLC patients. Prospective studies are underway to test this conjecture.

Key Words: distant metastases • fractionation • local control • radiation sensitization • radiotherapy • three-dimensional planning


   Introduction
TOP
 Abstract
 Introduction
Current Management of Locally...
 Improving Local Tumor Control
 Improved Control of Systemic...
 Summary
 References
 
Non -small cell lung cancer (NSCLC) is a leading cause of cancer deaths worldwide.1 The high death rate is due to the fact that NSCLC is usually in an advanced stage not amenable to surgical resection when first diagnosed. Although the outlook for NSCLC patients remains fairly dismal, there is reason for guarded optimism, as modest therapeutic advances have been realized in this disease over the course of the past 2 decades. For example, in stage IV disease, survival can be lengthened and symptom palliation is possible with cisplatin-based chemotherapy.2 3 Similarly, survival for individuals with locally advanced, stage III NSCLC has improved with combined-modality therapy.4 5 6 Historically, patients with locally advanced NSCLC were treated with thoracic radiotherapy alone. However, because so many patients develop recurrent disease outside the chest, chemotherapy was added to standard thoracic radiotherapy in an attempt to diminish this problem with a resultant fourfold increase in 2-year survival rates.4 5 6 Despite these noteworthy advances, the overwhelming majority of NSCLC patients continue to die of their underlying malignancy, leaving considerable room for further refinement in the management of this disease. This review will focus on strategies aimed at improving outcome in locally advanced NSCLC.


   Current Management of Locally Advanced, Unresectable NSCLC
TOP
 Abstract
 Introduction
 Current Management of Locally...
Improving Local Tumor Control
 Improved Control of Systemic...
 Summary
 References
 
Approximately 40% of patients with newly diagnosed NSCLC first present with locally advanced disease, and the majority are inoperable.1 Traditionally, these patients were treated with radiotherapy alone, resulting in a median survival of approximately 9 to 10 months and a 5-year survival rate of approximately 7%.7 These discouraging results were largely due to the eventual development of extrathoracic metastases. Several investigators have tried combining local therapy (ie, radiotherapy) with systemic therapy (ie, chemotherapy) in an attempt to overcome the obstacle of systemic recurrence. Although the initial results with this approach were somewhat disappointing,8 9 possibly due to the modest activity of chemotherapy regimens initially employed, there appeared to be a subset of patients with locally advanced disease who derived a modest survival benefit,4 10 particularly those with good performance status and little or no weight loss. Most thoracic oncologists now advocate the routine use of chemotherapy plus radiotherapy in this group of patients with locally advanced, unresectable NSCLC.


   Improving Local Tumor Control
TOP
 Abstract
 Introduction
 Current Management of Locally...
 Improving Local Tumor Control
Improved Control of Systemic...
 Summary
 References
 
Although combined-modality treatment with chemotherapy and radiotherapy has improved survival in some patients with stage III NSCLC, most still succumb to the underlying disease.1 Tumor progression remains problematic, both locally within the chest and in extrathoracic sites. We will first examine the problem of local tumor control.

It is commonly estimated that radiotherapy alone affords intrathoracic control in up to 50% of NSCLC cases, provided a total dose >= 60 Gy is employed.11 However, such estimates are based on studies conducted > 20 years ago, which are probably not very accurate. The signs and symptoms associated with an extrathoracic lesion usually so dominate the clinical picture that even if local progression is present, it is commonly overlooked. Indeed, a patient who progresses outside of the chest rarely undergoes a thorough restaging. Consequently, the true incidence of local failure is almost certainly much higher than is commonly believed. In those rare circumstances where a careful reevaluation has been performed, the frequency of local control is disappointingly low, even when total radiotherapy doses are > 60 Gy.12 Fewer than 20% of irradiated patients undergoing repeat bronchoscopy have evidence of complete tumor control at the site of the primary lesion.12 13

Does this lack of local control really matter given our failure to adequately control systemic disease? The available data suggest improved local control is worthwhile. Strategies employed in recent years to further improve local tumor control include the use of radiation-sensitizing drugs, altered radiotherapy fractionation schedules, and the use of three-dimensional treatment planning techniques. Several antineoplastic agents including cisplatin, topoisomerase-inhibiting agents, paclitaxel, and gemcitabine all have radiation-sensitizing potential.14 15 16 17 This approach was tested in a European randomized trial showing that concomitant cisplatin and irradiation improved survival compared with radiotherapy alone.18 The survival benefit was clearly attributable to improved local tumor control because the rate of distant failure was not affected (Table 1 ). Although this approach warrants additional study, it is worth noting that the simultaneous use of radiation and drugs can be a double-edged sword. Administering chemotherapy and radiotherapy concomitantly may increase host toxicities, necessitating dose reductions in one or both treatment modalities. Esophagitis and pulmonary toxicities are particularly worrisome in this regard.19 20 21


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  		Table 1. Concomitant Cisplatin Plus Radiotherapy in Locally Advanced NSCLC*

 
There appears to be a linear correlation between radiotherapy dose and local control of NSCLC.7 22 Accordingly, one theoretically could improve control at the primary tumor merely by increasing the dose of radiotherapy. However, it is difficult to increase the radiation dose > 60 Gy, due to toxicities engendered in normal tissues. Three-dimensional treatment planning may permit use of increasing total radiation doses without causing excessive host toxicity.23 Preliminary studies indicate radiotherapy doses can be escalated to as high as 85 to 90 Gy without causing major damage to normal tissues with this technique.24 25 26 27

Yet another means of increasing radiotherapy dose while minimizing normal tissue toxicity is the use of multiple daily radiation fractions.28 Pilot studies indicate this approach also is feasible.29 30 In fact, the results of several studies suggest hyperfractionated irradiation yields a survival benefit comparable to that achieved with combined-modality therapy (Table 2 ).29 31 32 These tantalizing data lend strong support to the notion that improving local tumor control is a worthwhile goal, even in the absence of improved control of extrathoracic disease.


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  		Table 2. Radiotherapy Plus Chemotherapy and Hyperfractionated Radiotherapy in Locally Advanced NSCLC*

 
In further support of this position are the results of a recently completed British trial in which continuous hyperfractionated accelerated radiotherapy (CHART) was compared with standard daily radiotherapy (total dose, 60 Gy in 30 fractions) for the treatment of patients with unresectable NSCLC.33 34 CHART consisted of thrice-daily 1.5-Gy fractions of irradiation given for 12 consecutive days to a total dose of 54 Gy (36 fractions). Median and long-term survival favored the CHART-treated group (Table 3 ), as did local control group rates. If these results are validated in confirmatory trials, the impact on the practice of NSCLC treatment could be profound.


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  		Table 3. CHART vs Conventional TRT in the Treatment of Unresectable NSCLC*

 

   Improved Control of Systemic Disease
TOP
 Abstract
 Introduction
 Current Management of Locally...
 Improving Local Tumor Control
 Improved Control of Systemic...
Summary
 References
 
Several meta-analyses clearly showed that cisplatin-based chemotherapy can improve survival in patients with NSCLC.2 35 36 The modest survival advantage benefits primarily those patients treated with cisplatin-based combination regimens, although there is a trend toward improved survival with regimens containing vinca alkaloids or etoposide.2 Within the past few years, several new drugs have shown excellent activity against NSCLC, including the taxanes (paclitaxel and docetaxel), vinorelbine, gemcitabine, and irinotecan.37 Importantly, some of these agents possess unique mechanisms of action and, with rare exception, appear to be less toxic than many of the older agents used in the management of NSCLC.

In recently completed randomized studies, the combinations of cisplatin plus paclitaxel or cisplatin plus vinorelbine yielded modest survival advantages over older cisplatin-based combination regimens.38 39 Given these observations, it is reasonable to anticipate these newer regimens will provide similar (or greater) survival benefit in locally advanced NSCLC. Already there is considerable preliminary data to suggest this is likely to be true, and randomized trials are in progress. Furthermore, combining chemotherapy with newer techniques of thoracic radiotherapy may well provide additional survival benefit as suggested by the results of several pilot studies 19 and at least one recently reported randomized trial.40


   Summary
TOP
 Abstract
 Introduction
 Current Management of Locally...
 Improving Local Tumor Control
 Improved Control of Systemic...
 Summary
References
 
In summary, better local control, as well as greater control of extrathoracic micrometastases, should result in improved survival among patients with locally advanced NSCLC. The methods of improving local control are quite varied, and each merits continued investigation. Potentially, these techniques will lead to further improvement in the survival of NSCLC patients with locally advanced disease.


   Footnotes
 
Abbreviations: CHART = continuous hyperfractionated accelerated radiotherapy; NSCLC = non-small cell lung cancer


   References
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 Abstract
 Introduction
 Current Management of Locally...
 Improving Local Tumor Control
 Improved Control of Systemic...
 Summary
 References
 

  1. Ginsberg, RJ, Vokes, EE, Raben, A (1997) Non-small cell lung cancer. DeVita, VT Hellman, S Rosenberg, SA eds. Cancer: principles and practice of oncology 4th ed. ,858-910 Lippincott-Raven Philadelphia, PA.
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