Chest
Volume 123, Issue 1, Supplement, January 2003, Pages 226S-243S
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Chemotherapeutic Management of Stage IV Non-small Cell Lung Cancer*

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Stage IV non-small cell lung cancer (NSCLC) denotes the presence of metastatic disease and is largely incurable using present-day therapies. Chemotherapy remains a therapeutic option in this patient population, and there are many pertinent issues surrounding its use in patients with stage IV NSCLC. Eleven questions were framed by the American College of Chest Physicians Lung Cancer Guidelines Committee, and these were addressed by a systematic search of the available literature. The issues addressed included the identification of prognostic factors in selecting patients for chemotherapy and a critical analysis of the survival benefit provided by chemotherapy. Given the development of several new chemotherapy agents over the past decade, the impact that these agents have made was addressed as well as the definition of a standard of care regarding chemotherapeutic regimens. Given the fact that chemotherapy does not represent a curative option, other issues addressed were the optimal duration of treatment as well as its impact on symptom relief and quality of life, the role of second-line therapy, and the outcomes expectations from both first-line and second-line chemotherapy. The question of what specialty delivered the chemotherapy also was addressed. Once the data were identified, a critical analysis was undertaken attempting to objectively portray the data in support of answers for each of the questions posed. We believe the data support the fact that properly selected patients benefit from chemotherapy with regard to survival and palliation in both first-line and second-line settings. It appears that in trials addressing the duration of first-line therapy, this survival and palliative benefit occurs early, and prolonged therapy is not indicated. Therapy in this setting is cost-effective, and there are several regimens that can be considered to be “standard-of-care” options. Physicians involved in the diagnosis of these patients should be aware of the potential benefits of chemotherapy, allowing them to give recommendations to patients that are based on data derived from clinical trials. In addition, this awareness will allow them to make referrals, when appropriate, to physicians who are trained in the administration of chemotherapy and the management of patients undergoing such therapy.

Section snippets

Are There Identifiable Prognostic Factors That Should Be Used When Selecting Patients for Systemic Chemotherapy?

The prognosis of patients with advanced NSCLC is poor. Most large phase III trials have shown a median survival time of 8 to 10 months and a 1-year survival rate of 30 to 35%.2 Given the consistent improvement in the survival of patients who have been treated with chemotherapy over those receiving supportive care alone, clinicians struggle to stratify these patients into different prognostic groups. One would like to identify those patients who are the most likely to benefit from aggressive

What Is the Evidence That Platinum-Based Chemotherapy Improves Survival?

Ten randomized clinical trials have been published23242526272829303132 comparing platinum-based chemotherapy to best supportive care (BSC) [Table 2]. It should be noted that BSC in these trials included aggressive symptom management (eg, antitussive agents, supplemental oxygen, and nonnarcotic and narcotic analgesic agents) as well as palliative radiotherapy when indicated. In all 10 trials, the median survival time of the treated patients was numerically superior to that of patients receiving

Do “New Agents” Improve Survival as Single Agents Compared to BSC?

Since 1990, several new agents with significant single-agent activity in NSCLC have been developed including paclitaxel, docetaxel, vinorelbine, gemcitabine, and irinotecan. These agents are commonly referred to as third-generation agents. Several randomized trials have been reported in which these new agents were tested against BSC using survival as the primary end point (Table 5). Both taxanes (ie, paclitaxel and docetaxel) have been compared to BSC in a randomized trial.3739 Survival was

Do the New Agents in Combination With the Platinum-Based Agents Improve Survival Over Second-Generation Platinum-Based Regimens?

As noted above, a number of new chemotherapy agents (ie, paclitaxel, docetaxel, gemcitabine, vinorelbine, and irinotecan) have been identified over the last 10 years as having documented activity in patients with advanced NSCLC. These third-generation agents have been incorporated into clinical trials and have been reported to have an improved toxicity profile, but is there proof that these new drugs also improve survival compared to older standard therapies?

The first of the new drugs to be

Is There a Standard of Care Regarding the Choice of Chemotherapy in the First-Line Setting?

Two large randomized trials that were reported within the last 2 years compared several of the new-generation regimens in the treatment of patients with advanced NSCLC. The first trial,58 conducted by the Southwest Oncology Group, compared the use of cisplatin-vinorelbine with carboplatin-paclitaxel. There was no difference in objective response, median survival time, or 1-year survival rates between patients receiving the two combinations. The second trial,59 by ECOG, compared

Is There an Optimal Duration of Chemotherapy?

Given the noncurative nature of stage IV NSCLC, the duration of chemotherapy must be weighed against the toxicity it engenders. Until recently, few trials addressed this issue, and chemotherapy would be administered for six or more cycles. In the 1997 guideline issued by the American Society of Clinical Oncology,61 the lack of data pertaining to this issue was cited. The consensus of the expert panel was that chemotherapy should be administered for no more than eight cycles in patients with

Does Second-Line Chemotherapy Improve Survival?

Since the first-line therapy used in patients with stage IV NSCLC is not curative, patients will eventually experience disease progression unless they develop another fatal comorbid illness. Once the disease progresses, the median survival time is approximately 3 months. The proportion of patients receiving second-line therapy following disease progression after receiving first-line platinum-based therapy has not been well-described but is generally < 50%.4248 Many of these patients retain a

Is There Evidence To Support the Use of Chemotherapy To Relieve Symptoms and Improve QOL?

The majority of patients with advanced NSCLC are symptomatic at some point as a result of their disease.71 Symptoms may be either disease-specific (eg, cough, hemoptysis, chest pain, or dyspnea) or disease-nonspecific (eg, weight loss, malaise, or declining PS).

At least seven studies72737475767778 have documented palliation of symptoms by chemotherapy in patients with advanced NSCLC (Table 7). These phase II studies generally have reported percentages of patients with a specific symptom in whom

What Are Patients' Preferences and Attitudes Toward Chemotherapeutic Treatment Options for Advanced NSCLC?

Two descriptive studies utilizing cancer patients who previously had been treated addressed the issue of patient preferences and attitudes toward receiving palliative cisplatin-based chemotherapy compared to BSC for survival and/or QOL benefit. Using a time-tradeoff technique, 60 patients were interviewed to address attitudes toward the improved median survival time and 1-year survival rate for the addition of cisplatin chemotherapy and BSC compared to BSC alone. Attitudes ranged from

Is There Any Evidence That Would Support Who Administered the Chemotherapy Made a Difference?

The MEDLINE search addressing this issue yielded no citations that were relevant with regard to addressing this question. Since the evaluation of NSCLC patients for chemotherapy requires an understanding of its indication as well as the proper selection of patients, physicians performing these duties should have experience and specialized training. This specialized training also should include experience with the proper administration of chemotherapy protocols as well as a working knowledge of

What Are the Outcome Expectations and Adverse Effects Seen With Chemotherapy and How Do They Compare With the Natural History?

The natural history of untreated stage IV NSCLC is best documented in the randomized trials of chemotherapy vs BSC ((Tables 2and 5). The impact that chemotherapy has on survival is significant and has been discussed in the previous sections. When QOL has been examined, patients receiving chemotherapy report better scores compared to patients receiving only BSC,313239 supporting the contention that the disease is worse than the treatment. The expectations regarding survival and toxicity when

Conclusion

Chemotherapy improves survival and palliates symptoms, thereby improving QOL in patients with stage IV NSCLC in both the first-line and second-line setting. Selecting patients based on PS is important as patients significantly compromised by their disease may not benefit from therapy and may experience excessive toxicity. Both platinum-based regimens as well as individual single-agent regimens have an impact on survival. However, platinum-based combination regimens using the new

Summary of Recommendations

  • 1.

    When selecting patients for systemic chemotherapy, PS at the time of diagnosis should be used because it is a consistent prognostic factor for survival. Patients with a PS (PS) of ECOG 0 or 1 should be offered chemotherapy (level of evidence, good; benefit, substantial; grade of recommendation, A). Data are not yet sufficient to routinely recommend chemotherapy to patients with a PS of ECOG level 2 (level of evidence, poor; benefit, small/weak; grade of recommendation, I). Patients with a PS of

Appendix

The following search terms were used in the study: age and lung cancer; antineoplastic agents, combined; carcinoma, non-small cell lung; carcinoma, non-small cell lung/drug therapy; carcinoma, non-small cell lung/therapy; chemotherapy; clinical trials; combination chemotherapy; duration of therapy; lung neoplasms; lung neoplasms/drug therapy; lung neoplasms/therapy; outcomes; performance status and lung cancer; prognosis factors and lung cancer; prognosis and lung cancer; prognosis and

ACKNOWLEDGMENT

Thanks to Lenka Cook for the creation of Figure 2.

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