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(Chest. 2000;117:133S-137S.)
© 2000 American College of Chest Physicians

Evolution of Cisplatin-Based Chemotherapy in Non-Small Cell Lung Cancer*

A Historical Perspective and The Eastern Cooperative Oncology Group Experience

David H. Johnson, MD

* From the Division of Medical Oncology, Vanderbilt University School of Medicine, Nashville, TN.

Correspondence to: David H. Johnson, MD, Division of Medical Oncology, 1956 The Vanderbilt Clinic, Nashville, TN 37232-5536; e-mail: david.johnson{at}vanderbilt.edu


   Abstract
TOP
 Abstract
Introduction
 Historical Overview
 Best Supportive Care
 Cisplatin-Related Issues
 Quality-of-Life Benefits
 Patient Selection
 Summary
 References
 
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in most industrialized nations, including the United States. Frequently, patients with unresectable disease are treated with symptomatic care alone or, in the case of locally advanced, unresectable lesions, with radiotherapy alone. In general, chemotherapy is viewed as ineffective, and therefore rarely recommended except by medical oncologists. Over the past 2 decades, however, it has become clear that chemotherapy, and in particular cisplatin-based chemotherapy, provides a modest survival advantage. In addition, recent studies indicate that chemotherapy can improve tumor-related symptoms and quality of life. With modern chemotherapy, median survival averages around 9 to 10 months in advanced NSCLC, a figure comparable to that achieved with treatment of extensive-stage small cell lung cancer, a malignancy generally viewed as chemotherapy sensitive. Importantly, existing data indicate that chemotherapy is also cost-effective. Given these observations, it is appropriate today for patients with advanced NSCLC to receive chemotherapy.

Key Words: carboplatin • cisplatin • combination chemotherapy • non-small cell lung cancer • performance status • survival


   Introduction
TOP
 Abstract
 Introduction
Historical Overview
 Best Supportive Care
 Cisplatin-Related Issues
 Quality-of-Life Benefits
 Patient Selection
 Summary
 References
 
Non -small cell lung cancer (NSCLC) is a leading cause of cancer-related death in much of the industrialized world.1 It is well recognized that the best chance for cure of NSCLC lies in its early detection and surgical resection. Unfortunately, few patients with NSCLC present with surgically resectable disease, and those who do frequently relapse and die. Patients with locally advanced NSCLC also frequently die after "curative" radiotherapy due to recurrent disease.2 Given this pattern of failure (namely, extrathoracic systemic relapse), effective systemic therapy obviously is necessary if survival is to be improved. For > 2 decades, the most effective systemic chemotherapy was based on cisplatin combinations. This article will briefly review the history of cisplatin-based combination chemotherapy in the treatment of NSCLC.


   Historical Overview
TOP
 Abstract
 Introduction
 Historical Overview
Best Supportive Care
 Cisplatin-Related Issues
 Quality-of-Life Benefits
 Patient Selection
 Summary
 References
 
Prior to 1990, only a few drugs (including cisplatin, mitomycin C, vinblastine, ifosfamide, vindesine, and possibly etoposide) had confirmed consistent activity against NSCLC.3 A drug is considered active against NSCLC if it can induce an objective response rate of >= 15%, an admittedly dubious definition. Several new drugs recently shown to be active against NSCLC will be discussed elsewhere in this supplement. For the most part, however, single-agent therapy has not been associated with notable survival or improvement in tumor-related symptoms. In keeping with accepted tenets of oncologic chemotherapy, two or more of these agents were frequently combined in an effort to achieve higher response rates with the goal of improving survival. Indeed, some drug combinations did improve median survival,4 5 particularly regimens employing cisplatin in combination with a vinca alkaloid or etoposide.6 7

The results of promising pilot studies prompted Eastern Cooperative Oncology Group (ECOG) investigators to undertake a series of randomized trials designed to identify an optimal chemotherapy regimen for metastatic NSCLC. These prospective studies, begun in the late 1970s, continued throughout the subsequent decade. All ECOG trials employed fairly standard eligibility requirements that included no prior treatment, a good performance status (PS; ie, ECOG PS 0 to 2), and stage IV disease only. The chemotherapy regimens selected for evaluation had all shown promising results in single-institutional trials and were generally cisplatin-based.8 9 10 11 12 13 The results of these trials are summarized in Tables 1 2 3 .


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  		Table 1.. Results of EST-2575-Generation V*

 

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  		Table 2.. Results of EST-1581*

 

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  		Table 3.. Results of EST-1583*

 
Several conclusions can be drawn from the data from these trials: (1) objective response rates averaged approximately 25%, irrespective of the regimen; (2) median survival averaged approximately 6 months (or approximately 25 weeks); and (3) 1-year survival was usually <= 20% (Table 4 ).13 These figures represent important historical benchmarks against which the newer therapies of today can be compared. Note that no regimen emerged as superior to the others with respect to overall survival, although three-drug combinations often yielded slightly higher objective response rates. However, the three-drug regimens were usually more toxic as well.


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  		Table 4.. Typical Results With Cisplatin-Based Chemotherapy in ECOG Stage IV NSCLC Trials

 
Among the various regimens tested, cisplatin/etoposide provided the most consistent 1-year survival rate (approximately 20 to 25%) and was associated with the least amount of host toxicity.13 For this reason, ECOG investigators selected cisplatin/etoposide as a reference arm for later phase III trials (including drug discovery trials).

Several important lessons were learned (or perhaps affirmed) from the ECOG studies. First, although PS did not impact response rates per se, individuals with a higher PS proved to be at greater risk for developing life-threatening toxicity than those with lower PS. Patients with ECOG PS of 2 had a much higher rate of life-threatening toxicity compared with those with lower PS scores.13 Second, survival directly correlated with PS. This observation affirms previous doctrine14 that is, surprisingly perhaps, rediscovered every few years. For example, with an ECOG PS of 0, NSCLC patients survived an average of approximately 9 months following cisplatin-based chemotherapy. If the individual had an ECOG PS of 1, median survival was approximately 6 months; with a PS of 2, median survival was much less, averaging only about 3 months.


   Best Supportive Care
TOP
 Abstract
 Introduction
 Historical Overview
 Best Supportive Care
Cisplatin-Related Issues
 Quality-of-Life Benefits
 Patient Selection
 Summary
 References
 
While ECOG investigators were prospectively comparing chemotherapy regimens in advanced NSCLC, other investigators questioned the wisdom of administering any chemotherapy, arguing that survival benefits were modest at best and that quality of life was diminished. This controversy prompted a series of studies in which chemotherapy was prospectively compared to best supportive care without chemotherapy.15 16 17 18 19 20 Best supportive care usually entailed administration of palliative radiotherapy, corticosteroids for hypercalcemia or increased intracranial pressure, analgesics, and antibiotics if required. Although these studies yielded conflicting results, a meta-analysis of the data revealed that cisplatin-based chemotherapy provided a modest survival benefit in virtually all stages of NSCLC, including stage IV disease.21 For example, treating stage IV disease with cisplatin-based chemotherapy reduces the probability of death in the year following diagnosis by 27% compared with supportive care alone (Table 5 ).


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  		Table 5.. Chemotherapy vs Supportive Care in NSCLC*

 
More recently, chemotherapy regimens containing newer active agents, such as paclitaxel or vinorelbine, have been shown to provide a modest survival benefit compared with older cisplatin-based combinations, such as cisplatin/etoposide or cisplatin/vindesine.22 23 These newer data will be discussed elsewhere in this supplement.


   Cisplatin-Related Issues
TOP
 Abstract
 Introduction
 Historical Overview
 Best Supportive Care
 Cisplatin-Related Issues
Quality-of-Life Benefits
 Patient Selection
 Summary
 References
 
Although cisplatin has been a central building block of combination chemotherapy regimens for NSCLC for the past 2 decades, its optimal use in NSCLC remains poorly defined. In addition, carboplatin is commercially available and is widely substituted for cisplatin in NSCLC treatment regimens due to its perceived superior therapeutic index. However, there has never been a head-to-head comparison of cisplatin and carboplatin as single agents in NSCLC.

Cisplatin Dose Response
Although in vitro studies suggest a dose-response relationship with cisplatin in NSCLC,24 its relevance to the clinical situation is dubious. Nearly 20 years ago, Gralla and colleagues6 reported an apparent survival benefit for high-dose cisplatin, 120 mg/m2, compared with low-dose cisplatin, 60 mg/m2, among responders to chemotherapy. This study established a practice standard that has been slow to change. This is despite the fact that in subsequent randomized trials, no relationship has been demonstrated between cisplatin dose (60 to 200 mg/m2) and survival.25 26 27 In fact, the existing evidence indicates there is no clinically relevant dose-response activity for cisplatin in NSCLC. Rather, more likely there is a dose below which no therapeutic benefit is obtained. However, the exact threshold dose has not been well characterized.

Cisplatin vs Carboplatin
Much has been written about the relative activities of cisplatin and carboplatin in NSCLC.28 29 Initial cooperative group trials indicated that the objective response rate for carboplatin was < 15%.30 31 32 For example, ECOG investigators administered carboplatin, 400 mg/m2, to stage IV NSCLC patients and reported an overall response rate of just 9%.12 Similar results were obtained by the Southeastern Cancer Study Group, whereas Cancer and Leukemia Group B investigators reported slightly better results,31 32 both using a 400-mg/m2 dose. In addition, cisplatin appears to be more active than carboplatin in several malignancies known to be more chemotherapy sensitive than NSCLC.33 These observations, coupled with the somewhat unpredictable nature of carboplatin toxicity when dosed based on body surface area, led some investigators to conclude that carboplatin is inferior to cisplatin in the management of NSCLC.

However, several developments indicate this conjecture is probably incorrect. First, the activity of single-agent cisplatin more closely matched that observed with carboplatin in completed trials (Table 6 ).12 31 32 34 35 36 For example, in Southwest Oncology Group 9308, single-agent cisplatin effected an overall response rate of just 10% in patients with metastatic NSCLC.35 In ECOG 1583, the activity of carboplatin in a similar patient population was 9%.12 Second, with the recognition that carboplatin is renally excreted, more rational dosing schedules have been developed.37 Consequently, toxicity is diminished and patients receive a more appropriate individualized dose. Even if there is no dose-response relationship, individualizing drug dosing helps ensure the patient receives an appropriate dose of carboplatin and minimizes the likelihood of excessive toxicity. Finally, in at least two randomized trials involving patients with metastatic NSCLC, carboplatin (given in combination with other active drugs) yielded equivalent or superior survival rates compared with an identical regimen containing cisplatin.38 39 Taken together, these data indicate one can appropriately substitute carboplatin for cisplatin in the treatment of NSCLC patients.


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  		Table 6.. Comparison of Cisplatin and Carboplatin Response Rates in Advanced NSCLC*

 

   Quality-of-Life Benefits
TOP
 Abstract
 Introduction
 Historical Overview
 Best Supportive Care
 Cisplatin-Related Issues
 Quality-of-Life Benefits
Patient Selection
 Summary
 References
 
Despite widespread perceptions to the contrary, combination chemotherapy improves quality of life in patients with NSCLC.40 Tumor-related symptoms such as cough, dyspnea, chest pain, and hemoptysis frequently improve following combination chemotherapy, even when there is no overt evidence of tumor regression.41 42 43 44


   Patient Selection
TOP
 Abstract
 Introduction
 Historical Overview
 Best Supportive Care
 Cisplatin-Related Issues
 Quality-of-Life Benefits
 Patient Selection
Summary
 References
 
In light of the available data, individuals with stage IV NSCLC with good PS and no medical or psychological contraindication to treatment would appear to benefit from chemotherapy. Chemotherapy should be reserved for those patients who are ECOG PS 0 or 1,13 45 as ECOG PS 2 patients experience substantially greater rates of serious life-threatening toxicity. Whether such patients could be treated with less aggressive therapy (eg, single-agent gemcitabine) remains to be determined.43 44 Substantial weight loss also bodes against combination chemotherapy, and instead might warrant supportive care measures or single-agent therapy if treatment is desired.

The optimal number of chemotherapy courses also is controversial. Extrapolating from small cell lung cancer, it seems reasonable to discontinue therapy after four to eight cycles of treatment unless there is evidence of continued tumor shrinkage and the patient is tolerating therapy without major complication.46 47


   Summary
TOP
 Abstract
 Introduction
 Historical Overview
 Best Supportive Care
 Cisplatin-Related Issues
 Quality-of-Life Benefits
 Patient Selection
 Summary
References
 
Chemotherapy clearly plays a central role in the management of advanced NSCLC. In addition to symptom palliation and a modest but real survival benefit,21 41 patients enjoy an improved quality of life.40 Furthermore, the use of chemotherapy is cost-effective.48 Indeed, the survival benefits achieved with newer drug regimens rival those obtained with chemotherapy in extensive-stage small cell lung cancer, a malignancy generally conceded to be "chemotherapy sensitive." Thus, we can conclude that it is appropriate to offer chemotherapy to all NSCLC patients with advanced disease, a good PS, and no medical or psychological contraindication to its use. Although there remains broad resistance to the use of chemotherapy in this disease,49 50 51 the available data should help dispel these attitudes.


   Footnotes
 
Abbreviations: ECOG = Eastern Cooperative Oncology Group; NSCLC = non-small cell lung cancer; PS = performance status


   References
TOP
 Abstract
 Introduction
 Historical Overview
 Best Supportive Care
 Cisplatin-Related Issues
 Quality-of-Life Benefits
 Patient Selection
 Summary
 References
 

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