Advances in Cytotoxic Chemotherapy for the Treatment of Metastatic or Recurrent Non-Small Cell Lung Cancer

Article Outline

• Abstract
• First-Line Therapy for Patients With Advanced NSCLC
  • Platinum-Based Doublets
  • Cisplatin or Carboplatin?
  • Nonplatinum Doublets
  • Two Drugs Are Better Than One
  • Triplets for Advanced NSCLC
  • Duration of Front-Line Therapy
  • Conclusions on Front-Line Therapy
• Treatment of Refractory Disease
• Special Considerations
  • Patients With Limited Functional Status
  • Older Patients With Advanced NSCLC
  • Goals of Therapy
• Treatment Paradigm
• Conclusions and Future Directions
• References
• Copyright

Improvements in drug development and clinical trial design have resulted in a wider range of treatment options for patients with advanced non-small cell lung cancer (NSCLC). Combination chemotherapy is the standard of care for medically fit patients. A variety of chemotherapeutic doublets, including nonplatinum combinations, with similar clinical activity are now available, allowing oncologists to match acceptable toxicity profiles to individual patients’ comorbidities and preferences. Single-agent treatment of refractory or recurrent disease has been shown to improve survival and offer improved quality of life (QOL). For special patient populations, such as the elderly and patients with limited performance status (PS), treatment with single-agent chemotherapy results in modest survival benefits and combination chemotherapy may be appropriate for some of these patients.

“Advanced” non-small cell lung cancer (NSCLC) generally includes patients with recurrent disease, “wet IIIB” disease (stage IIIB disease with pleural or pericardial effusion), and stage IV disease in which metastatic disease is typically evident in sites such as the brain, liver, bone, lung, adrenals, or skin. Given the poor diagnostic yield of cytology specimens obtained from thoracentesis, patients with bloody or exudative effusions in the setting of NSCLC are considered to have malignant pleural effusions until demonstrated to be otherwise.¹ As these patients have a similar prognosis and similar treatment options as patients with stage IV disease, they are appropriately considered together. Some trials and reviews include patients in the category of advanced NSCLC who are stage IIIB by involvement of supraclavicular lymph nodes, although these patients remain candidates for multimodality therapy and are better considered a separate entity.

In patients with advanced NSCLC, the primary goals of therapy are prolongation of survival and palliation of symptoms to enhance the patient’s quality of life (QOL). Meta-analyses have shown that cisplatin-based, combination chemotherapy for patients with advanced NSCLC improves median survival by 2 months and offers a 10% to 15% absolute improvement in 1-year survival, as compared to treatment with best supportive care (BSC).² Similarly, such chemotherapy has been shown to improve QOL and to be cost-effective.³ These results have led to the development of several novel cytotoxic drugs for the treatment of NSCLC, including docetaxel, gemcitabine, irinotecan, paclitaxel, vinorelbine, and pemetrexed. More recently, novel targeted therapies such as the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors gefitinib and erlotinib, as well as monoclonal antibodies directed against the EGFR, such as cetuximab, have been developed.

Systemic chemotherapy is now considered a standard of care in the treatment of advanced NSCLC, so long as the patient has an adequate performance status (PS), acceptable end-organ function, and no critical metastases that require site-specific interventions, such as palliative radiation therapy. In this article, we review the literature on the treatment of advanced NSCLC with “conventional” cytotoxic chemotherapy. We analyze current first-line and second-line therapies, discuss special patient populations such as the elderly and those with limited PS, and conclude with a paradigm for the approach to treatment of patients with advanced NSCLC. As the response rate and survival data in phase II and phase III studies are often different and may lead to inaccurate comparisons, we will focus on published phase III trials. Furthermore, this article will emphasize data from published manuscripts over data published in abstract form, except in situations in which there are a limited number of published manuscripts. “Targeted” therapies for NSCLC are reviewed elsewhere in this issue of Seminars of Oncology.

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First-Line Therapy for Patients With Advanced NSCLC 

Over the past decade, a number of phase III trials have been published to help create a standard of care governing the treatment of advanced NSCLC in chemotherapy-naive patients who have good Eastern Cooperative Oncology Group PS (ECOG 0–1). In this section, we will review the roles of platinum-based doublets and nonplatinum-based doublets, the optimal duration of administration of planned initial chemotherapy, and the role of monotherapy and triplets in treatment. It is beyond the scope of this article to review the data on each of the mathematically feasible active doublets in NSCLC, so this section will concentrate on the most commonly used doublets, and those compared in selected phase III trials.

Platinum-Based Doublets 

As the past two decades have seen the development of a number of new agents with activity in NSCLC, there has been a relative explosion in the number of available platinum-based doublets. In the past few years, the most commonly used platinum-based doublets have been carboplatin/paclitaxel in the United States,⁴ cisplatin/vinorelbine in France and Canada, and cisplatin/gemcitabine in much of Europe. It is noteworthy that neither chemotherapeutic agent in the most commonly used regimen in the United States, carboplatin and paclitaxel, is currently approved by the US Food and Drug Administration for the treatment of advanced NSCLC.

One notable problem that has plagued research on the treatment of advanced NSCLC is the high number of small, underpowered phase III trials that have often raised more questions than they have answered. For example, one small study in which treatment with cisplatin/gemcitabine was compared to treatment with carboplatin/gemcitabine demonstrated conflicting results, with the cisplatin arm demonstrating numerically superior objective response rate, median time to progression, and median survival, whereas the carboplatin arm experienced numerically superior 1-year survival.⁵ It is conceivable that a larger study testing the same agents might have provided more definitive distinctions between these two treatments. So which published trials should guide the initial management of patients with advanced NSCLC? In this section, we will review the findings of seven large, appropriately sized trials comparing platinum-based doublets, as summarized in Table 1.

Table 1. Pivotal Phase III Trials Comparing Platinum-Based Doublets

NOTE. Trials were chosen based on size of enrollment, impact on standards of care, and frequency with which they are cited within the literature. This table is not meant to represent an exhaustive list of published trials comparing platinum-based doublets in chemotherapy-naive patients.

Abbreviations: SWOG, Southwest Oncology Group; ILCSG, Italian Lung Cancer Study Group; ECOG, Eastern Cooperative Oncology Group; RR, response rate; NS, not significant.

In 1994, Le Chevalier et al reported the results of a trial in which patients were randomized to receive either vinorelbine monotherapy, cisplatin/vindesine, or cisplatin/vinorelbine.⁶ Comparison of the two arms in which patients received a cisplatin/vinca doublet demonstrated that treatment with cisplatin and the newer vinca alkaloid vinorelbine offered an improved response rate (44% v 32%, P = .02) and 1-year survival (40% v 32%, P = .04) as compared to treatment with cisplatin/vindesine.

A number of subsequent phase III trials compared platinum-based doublets that incorporated newer agents. Until recently, no large, phase III trial of platinum-based doublets incorporating newer agents had ever shown significant benefit over another similar doublet. To this end, a Southwest Oncology Group trial (SWOG 9509) evaluated cisplatin/vinorelbine versus carboplatin/paclitaxel in 408 patients with advanced NSCLC and demonstrated similar outcomes, with response rates of 25% to 28%, 8 month median survival duration, and 36% to 38% 1-year survival rates.⁷ Patients in the cisplatin/vinorelbine arm experienced more frequent nausea and hematologic toxicity, whereas the patients who received carboplatin/paclitaxel experienced more peripheral neuropathy and hair loss. Similarly, the Italian Lung Cancer Study Group failed to show any significant difference in outcome for cisplatin/gemcitabine, carboplatin/paclitaxel, and cisplatin/vinorelbine in 612 patients with previously untreated advanced NSCLC. In this study, nonsignificant differences in objective response rates (30%–32%), median survival duration (10 months), and 1-year survival rates (37%–43%) were demonstrated in the three treatment arms.⁸ In both of these trials comparing platinum-based doublets, the most notable differences between regimens were related to toxicity profiles.

ECOG 1594 was a large, randomized trial of 1,207 patients that compared three platinum-based doublets to a control arm of cisplatin plus 24-hour infusion paclitaxel at a dose of 135 mg/m².⁹ Notably, the control arm is a regimen rarely employed in the care of NSCLC patients, and the statistical design of this trial precluded any rigorous comparison among the three experimental arms employing more commonly used regimens. In this trial, carboplatin plus a 3-hour infusion paclitaxel at a dose of 225 mg/m², cisplatin/gemcitabine, and cisplatin/docetaxel all documented efficacy outcomes similar to the reference regimen, with response rates ranging from 17% to 22%, median survival durations of 8 months, and 1-year survival rates ranging from 31% to 36%. Differences were once again largely limited to differences in toxicity profiles, with cisplatin/gemcitabine causing more thrombocytopenia, cisplatin/docetaxel causing more neutropenia, and the carboplatin/paclitaxel arm experiencing the lowest rate of potentially life-threatening toxicities. In the community and in the literature, this study is commonly cited to support the similar efficacy of carboplatin plus paclitaxel to the other front-line doublets.

The TAX 326 trial randomized 1218 patients to receive cisplatin/docetaxel, carboplatin/docetaxel, or the control arm of cisplatin/vinorelbine.¹⁰ Patients treated with cisplatin/docetaxel had a statistically significant higher response rate (31.6% v 24.5%, P = .029) and median survival (11.3 v 10.1 months, P = .044), with nonsignificantly superior 1-year (47% v 42%) and 2-year survival rates (21% v 14%) compared with the control arm. The carboplatin/docetaxel arm demonstrated nonstatistically significant inferior results as compared to the control arm (Table 1). The trial was not structured to make a direct comparison of the cisplatin/docetaxel and carboplatin/docetaxel arms. However, the results are often referenced by those favoring cisplatin-based over carboplatin-based chemotherapy. Both docetaxel-containing arms demonstrated improved QOL outcomes, reduction in pains scores, and less weight loss as compared to the cisplatin/vinorelbine arm, although all docetaxel-treated patients received 48 mg of dexamethasone with each cycle, possibly accounting for some of these observed differences. Toxicity was similar in all three arms, except for a slightly higher incidence of nausea and vomiting and of treatment-related hospitalizations in the cisplatin/vinorelbine arm. This study demonstrated that combinations of docetaxel and a platinum have favorable toxicity profiles and QOL benefits. Furthermore, this trial demonstrated a statistically significant, although clinically small, superiority of cisplatin/docetaxel over cisplatin/vinorelbine.

More recently, a randomized trial comparing cisplatin/docetaxel and cisplatin/vindesine confirmed these results.¹¹ A total of 311 chemotherapy-naive patients with advanced NSCLC received either cisplatin 80 mg/m² and docetaxel 60 mg/m² on day 1 of a 21- or 28-day cycle or cisplatin 80 mg/m² on day 1 and vindesine 3 mg/m² on days 1,8, and 15 of a 28-day cycle. Patients treated with cisplatin/docetaxel attained a superior objective response rate (37% v 21%, P <.01), longer median survival (11.3 v 9.6 months, P = .014), and improved QOL compared to those treated with cisplatin/vindesine. This smaller trial also demonstrated nonsignificant differences in 1-year survival (48% v 41%) and 2-year survivals (24% v 12%) favoring the cisplatin/docetaxel arm. Notable flaws in this study include the different dose density of cisplatin administration and different intervals to assess response in the two treatment arms. Nonetheless, the results of this study are consistent with those reported in the TAX 326 trial and demonstrate the superiority of the combination of cisplatin and docetaxel over cisplatin and a vinca alkaloid when administered on these schedules.

Finally, a recent trial conducted in Japan randomized 380 patients to receive cisplatin/irinotecan, cisplatin/vindesine, or irinotecan monotherapy.¹² Among the 252 patients assigned to treatment with one of the two platinum-based doublets, treatment with cisplatin/irinotecan yielded a statistically significantly higher objective response rate (43.7% v 31.7%) compared with treatment with cisplatin/vindesine. In contrast to the trials by Fossella et al¹⁰ and Kubota et al,¹¹ this improvement in response rate did not correspond to statistically significant differences in median survival (11.5 v 10.5 months) or 1-year survival (46.5% v 38.3%) for the patients who received cisplatin/irinotecan. Patients treated with cisplatin/irinotecan had a median survival of 11.5 months and 1-year survival of 46.5%, whereas patients treated with cisplatin/vindesine had a median survival of 10.5 months and 1-year survival of 38.3%. That this trial did not demonstrate statistically significant differences in survival outcomes despite the differences in objective response rates may be a result of the smaller number of patients enrolled on these treatment arms as compared to those enrolled on the trials discussed above.

Cisplatin or Carboplatin? 

Recent years have seen the pendulum swing away from the historical standard, cisplatin, to the more recently developed and more convenient platinum analogue, carboplatin. Is it fair to say that these two platinum analogues are equivalent in the management of advanced NSCLC? Three randomized trials address this, two by direct comparison and one more indirectly.

In the first trial, 618 patients were randomized to receive paclitaxel 200 mg/m² as a 3-hour infusion with either carboplatin at an area under the curve (AUC) of 6 or cisplatin 80 mg/m² every 3 weeks, with the primary end point being the demonstration of a non-inferior response rate and secondary end points of survival, toxicity, and QOL.¹³ The cisplatin combination-treated patients had a statistically superior median survival (9.8 v 8.2. months P = .019). All other clinical end points, including progression-free survival (4.2 v 3.0 months), 1-year survival (38% v 33%), and 2-year survival (15% v 9%), were nonstatistically higher in the cisplatin arm. The response rates were assessed on both intention-to-treat and response-evaluable data sets, with the carboplatin having a lower but statistically non-inferior response rate (25% and 23%) as compared to the cisplatin arm (28% and 26%). Moreover, a classical superiority test of the response-evaluable patients also failed to show significant difference in response rates of the two arms (P = .45). It is noteworthy that QOL outcomes were generally comparable, despite widespread assumptions that carboplatin is more tolerable than cisplatin. The incidence of any grade III toxicity in carboplatin- and cisplatin-treated patients was 9% and 7%, respectively. This study is the only large-sized, prospective study to evaluate the relative activity of cisplatin and carboplatin in combination with paclitaxel, and suggests that cisplatin has a slightly higher level of activity than carboplatin, at least when they are both used with this schedule and dose of paclitaxel. That it did demonstrate a superior survival for cisplatin-treated patients as compared to carboplatin-treated patients whereas the similarly sized ECOG 1594 trial⁹ did not detect any such difference means these results should be interpreted with caution.

The second study worth noting with respect to comparing the activity of cisplatin and carboplatin is the TAX 326 trial, discussed in the preceding section.¹⁰ Although this study was not designed to directly compare the 814 patients randomized to either the cisplatin or the carboplatin arms, the docetaxel dose and schedule were identical in these arms. In this study, the docetaxel/cisplatin arm demonstrated a statistically significant superior response rate and median survival as compared to the control arm of cisplatin/vinorelbine, which itself demonstrated nonsignificant superior median and 1-year survivals and a similar response rate as compared to docetaxel/carboplatin. Based on the results of these two studies, it is tempting to believe that cisplatin has slightly more activity than carboplatin in advanced NSCLC, although any such difference appears to be quite small.

One small study randomized 176 chemotherapy-naive patients with advanced NSCLC to receive gemcitabine and either cisplatin or carboplatin.⁵ The cisplatin arm demonstrated nonstatistically significant superiority in response rate (41% v 29%, P = .09), median time to progression (5.9 v 4.8 months, P = .1), and survival (8.8 v 8.0, P = .9), whereas the carboplatin arm demonstrated a nonsignificant but slightly larger proportion of patients surviving 1 year (0.36 v 0.33; 95% confidence intervals [CIs], 0.26 to 0.47 v 0.22 to 0.44). The type and incidence of toxicity were similar in each arm, although, predictably, more patients in the cisplatin arm experienced nausea and more patients in the carboplatin arm experienced thrombocytopenia. Conclusions are difficult based on this underpowered trial.

Finally, a recent meta-analysis using abstracted data identified eight trials that investigated the substitution of carboplatin for cisplatin in the setting of combination chemotherapy for advanced NSCLC.¹⁴ The pooled data from these eight trials demonstrated that cisplatin-based chemotherapy offered a statistically significantly higher objective response rate compared to carboplatin-based chemotherapy (odds ratio 1.36; 95% CI, 1.15 to 1.61; P <.001) and a nonsignificant 5% improvement in survival (hazard ratio 1.050; 95% CI, 0.907 to 1.216; P = .515). Subgroup analysis of the five trials that incorporated cisplatin or carboplatin with a new agent did, however, demonstrated a statistically significant improvement in survival for cisplatin-treated patients (hazard ratio 1.106; 95% CI, 1.005–1.218; P = .039).

The choice of which platinum compound to use in combination with other agents should continue to be decided on a case by case basis. Any such difference in activity between these two agents may be more notable in the neoadjuvant or adjuvant setting, where small differences in activity may translate to a higher cure rate from multimodality therapy. It is noteworthy that though improved tolerability is commonly cited as a major reason for using carboplatin rather than cisplatin, these trials failed to identify any significant difference in the QOL based on the agent used. The well-documented differences in types of toxicity associated with these two compounds were again confirmed in these studies.

Nonplatinum Doublets 

Many patients with advanced NSCLC are not optimal candidates to receive platinum-based chemotherapy due to the presence of comorbid conditions such as renal insufficiency, hearing loss, borderline PS, pre-existing sensory neuropathy, diabetes mellitus, or coronary artery disease. Furthermore, as platinum-based doublets are often complicated to administer, cause toxicity in a sizable minority of patients, and require intricate follow-up care, clinicians are continually searching for alternative regimens. The development of newer chemotherapeutic agents has made it possible to treat patients with advanced NSCLC without the vigilance required to avoid delayed emesis, the substantial risk for nephrotoxicity or ototoxicity, or the extensive pre- and post-treatment hydration.

To date, no published phase III trial has demonstrated a nonplatinum-based regimen to have superior activity versus a platinum-based doublet. However, a small number of phase III trials have demonstrated that some selected nonplatinum-based doublets may have activity similar to the above-mentioned platinum-based doublets and offer different toxicity profiles (Table 2). It is noteworthy that none of these phase III trials were designed as true non-inferiority studies, making rigorous conclusions of non-inferiority difficult to support. A larger number of phase II trials have reported encouraging results with other nonplatinum doublets, including docetaxel/irinotecan and gemcitabine/pemetrexed,¹⁵, ¹⁶, ¹⁷ but this section will focus on doublets with phase III data.

Table 2. Selected Phase III Trials Comparing Platinum-Based and Nonplatinum Doublets

One randomized trial with 441 patients compared docetaxel/gemcitabine with docetaxel/cisplatin at doses different from those used in TAX 326.¹⁸ In this trial, patients received either docetaxel 100 mg/m² and cisplatin 80 mg/m² on day 1 or docetaxel 100 mg/m² on day 1 and gemcitabine 1,000 mg/m² on days 1 and 8, each on a 21-day cycle. Response rates in the two treatment arms were similar (35% v 33%, respectively), with no significant differences seen in response duration, time to progression, or median survival time (10 v 9.5 months, respectively). However, patients treated with the docetaxel/gemcitabine regimen had less nonhematologic toxicity, such as nausea, vomiting, and diarrhea. Notably, this trial administered a dose of docetaxel that is higher than that used in most other phase III trials testing combination chemotherapy in chemotherapy-naive patients and is a dose considered too toxic as monotherapy in second-line treatment.

Paclitaxel/gemcitabine has also been compared to platinum-based doublets in two phase III trials. In one study, 509 patients with advanced NSCLC were randomized to receive either paclitaxel/carboplatin or paclitaxel/gemcitabine.¹⁹ The study demonstrated no statistically significant differences in median overall survival, 1-year survival, objective response rate (Table 2), or tolerability, and a retrospective evaluation revealed similar mean total costs for the two treatment arms. The rate of hematologic toxicity was better in the patients treated with paclitaxel/gemcitabine, although the rates of severe toxicity were remarkably low in both arms.

In another study comparing paclitaxel/gemcitabine to platinum-based doublets, the European Organization for Research and Treatment of Cancer (EORTC) randomized 480 patients to receive either cisplatin/paclitaxel, cisplatin/gemcitabine, or paclitaxel/gemcitabine.²⁰Although the study failed to show any statistically significant differences in survival or toxicity, it is worth noting that the paclitaxel/gemcitabine arm demonstrated a nonstatistically significant but numerically inferior response rate (28% v 32%), progression-free survival (3.5 v 4.2 months), median survival (6.7 v 8.1 months), and 1-year survival (27% v 36%) compared to the control arm of cisplatin/paclitaxel. These results suggest that this may have been an underpowered study that would have likely demonstrated statistical significance in these endpoints had the study been larger. Furthermore, analysis of cost-effectiveness demonstrated that the average treatment costs for the combination of paclitaxel/gemcitabine were 25% higher than the control arm, which was attributable to the higher price of chemotherapeutic agents despite a lower cost of administration.

Gemcitabine/vinorelbine is another regimen that has completed phase III testing. A recent phase III trial randomized 501 patients to gemcitabine/vinorelbine, cisplatin/vinorelbine, or cisplatin/gemcitabine with a 2:1:1 enrollment intended to compare the nonplatinum doublet to the composite results of the platinum-based doublets.²¹ In this trial, the platinum-based doublets demonstrated nonsignificantly superior results as compared to gemcitabine/vinorelbine in terms of response rate (30% v 25%) and median survival (8.8 v 7.4 months, P = .08) and a statistically significant difference in median progression-free survival (5.3 v 3.9 months, P = .004). Grade 3–4 myelosuppression, vomiting, alopecia, and ototoxicity were more common in the platinum-based arms, although there was no difference in QOL between the two groups after 2 months of treatment. There was also no difference in the use of second-line chemotherapy between the treatment arms. The authors of the study concluded that gemcitabine/vinorelbine is less toxic, but does not offer an improved QOL, and is slightly less active in the treatment of advanced NSCLC.

Lastly, 557 patients were enrolled in a randomized three-arm trial comparing cisplatin/gemcitabine to a regimen of alternating nonplatinum-based doublets gemcitabine/vinorelbine and ifosfamide/vinorelbine or the triplet of cisplatin/gemcitabine/vinorelbine.²² Comparison of the cisplatin/gemcitabine to alternating nonplatinum doublets demonstrated a statistically significant difference in objective response rate (42% v 27%, P = .003) and nonsignificant differences in median survival (9.3 v 8.1 months), 1-year survival (38% v 34%), and time to progression (6.3 v 5.7 months), all favoring cisplatin/gemcitabine.

Is there a clear benefit of improved efficacy in choosing platinum- over nonplatinum-based doublets for patients with advanced NSCLC? Some of these studies do demonstrate statistically significant differences in response rates and fewer have demonstrated differences in median and 1-year survivals. However, observed differences when present are small. These differences in objective outcomes could be more useful for symptomatic patients in whom a response would be meaningful despite the absence of a survival benefit. More importantly, these small differences in objective outcomes between doublets may be more meaningful in the neoadjuvant or adjuvant setting, where tumor-responsiveness and pathologic complete response may translate into improved survival. These distinctions, however, do not apply to most patients with advanced NSCLC, where the primary goal is often palliation. In this regard, it is worth noting that current American Society of Clinical Oncology (ASCO) guidelines make no distinction between platinum-based and nonplatinum doublets in recommending combinations for fit patients with advanced NSCLC.²³

Two Drugs Are Better Than One 

Despite the demonstrated activity of an increasing number of single agents, the use of two-drug regimens as front-line therapy has remained the standard of care. Numerous trials comparing doublets to single agents have demonstrated improved response rates and improved times to progression, with most studies also demonstrating improved survival (see Table 3 and Fig 1).⁶, ²⁴, ²⁵, ²⁶, ²⁷, ²⁸, ²⁹, ³⁰ Historically speaking, platinum-based doublets have been the standard of care for front-line therapy,³¹ so most of the trials comparing combination chemotherapy against single agents incorporate platinum-based doublets. There are a few published studies that have suggested equivalent or even superior outcomes for newer single agents compared to older doublets, such as cisplatin/vindesine⁶, ¹², ³² or cisplatin/etoposide,³³, ³⁴ although there are some questions as to whether etoposide actually has significant activity in this disease.³⁵, ³⁶ A recent study suggests that treatment with cisplatin/docetaxel offered no statistically significant difference in median survival as compared with docetaxel alone (10.5 v 8 months, P = .20) despite the significant difference in response rates favoring the cisplatin-treated patients (36.5% v 21.7%, P = .004).³⁷ However, this trial was powered to detect a 5-month difference in median survival, a difference rarely seen in clinical trials in advanced NSCLC. Based on these data, combination chemotherapy remains the standard of care for chemotherapy-naive patients who have advanced NSCLC and a good PS.

Table 3. Randomized Trials Comparing Monotherapy to Combination Chemotherapy

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• Figure 1. 

  Median survivals in phase III trials comparing monotherapy to combination chemotherapy.

Triplets for Advanced NSCLC 

Given the disappointing response rates and survival data offered by two-drug regimens in the treatment of advanced NSCLC, a series of studies have evaluated the potential role for the use of three-drug regimens. As a general rule, three-drug regimens have led to higher toxicity, have at times demonstrated higher objective response rates, and have not offered any statistically significant improvement in survival as compared to that offered by standard doublets (Table 4). For example, a randomized, three-arm trial evaluated cisplatin/gemcitabine versus cisplatin/gemcitabine/vinorelbine and the alternating doublets gemcitabine/vinorelbine and ifosfamide/vinorelbine.²² The trial demonstrated no statistically significant differences in response rates, times to progression, overall survivals, or median survivals between patients treated with cisplatin/gemcitabine versus those treated with cisplatin/gemcitabine/vinorelbine, but it did demonstrate a higher rate of toxicity in patients treated with the triplet. Similarly, trials of gemcitabine/vinorelbine versus gemcitabine/vinorelbine/cisplatin, cisplatin/gemcitabine versus mitomycin/ifosfamide/cisplatin, carboplatin/gemcitabine versus mitomycin/ifosfamide/cisplatin, and gemcitabine/paclitaxel versus gemcitabine/paclitaxel/vinorelbine have all demonstrated that the triplets studied lead to more toxicity and offer nonsignificant differences in survival outcomes, although some do offer higher response rates.³⁸, ³⁹, ⁴⁰, ⁴¹

Table 4. Recent Phase III Trials Comparing Doublets to Triplets

Positive findings were reported for a three-arm study that compared the triplet of cisplatin/gemcitabine/vinorelbine (PGV) to cisplatin/gemcitabine (PG) and cisplatin/vinorelbine (PV).⁴² Interim analysis of this study, with only 60 patients enrolled in each arm, demonstrated a superior response rate (PGV 47% v PG 30% v PV 25%) and median survival (PGV 11.8 months v PG 9.7 months and PV 8.1 months, P = .004 for PGV v PV) leading to the closure of the PV arm and the continuation of this trial’s other two arms. Importantly, this trial is somewhat difficult to interpret because the survival advantages were not significant using more standard statistical analyses.⁴³

The role of three-drug regimens continues to be an active area of research, with a number of phase III trials currently underway. However, the superior objective response rates offered by some of these triplets may make them attractive regimens for the neoadjuvant setting where a small difference in response rates may be more clinically meaningful. These situations would not apply to the majority of patients with advanced NSCLC. At the current time, there are insufficient data to support their routine use in the management of advanced NSCLC outside the setting of a clinical trial.

Finally, investigators are also exploring whether the combination of cytotoxic doublets with targeted agents provides additional benefit beyond that offered by conventional cytotoxic therapy alone. The Iressa NSCLC Trial Assessing Combination Treatment (INTACT)-1 and -2, the TRIBUTE (carboplatin + paclitaxel ± erlotinib), and the TALENT (erlotinib ± gemcitabine + carboplatin followed by monotherapy) trials were all large phase III trials that randomized chemotherapy-naive patients to receive a standard two-drug regimen with or without daily gefitinib or erlotinib.⁴⁴, ⁴⁵, ⁴⁶, ⁴⁷ All four trials, encompassing more than 2,000 patients, failed to identify any benefit of daily gefitinib or erlotinib in combination with a standard doublet of cytotoxic therapy, although a retrospective subset analysis demonstrated a significantly prolonged median survival for patients with no tobacco use history who were treated with erlotinib and chemotherapy in the TRIBUTE trial.⁴⁸ Investigators are also exploring whether the addition of other targeted agents, such as the protein kinase C (PKC) antisense oligonucleotide ISIS 3521, provide additional benefit when added to conventional chemotherapy.⁴⁹, ⁵⁰ However, the use of these targeted agents in combination with cytotoxic chemotherapy remains investigational and is discussed elsewhere in this issue.

Duration of Front-Line Therapy 

The optimal duration of front-line chemotherapy remains a matter of debate, largely ignored by clinical trials until recently. The importance of this topic, however, is becoming a more relevant question now that second-line therapy is available and has been shown to offer a benefit to patients who are candidates for further chemotherapy. Furthermore, treatment in this setting is by its nature palliative and prolonged chemotherapy can lead to cumulative toxicity, so it is worth asking whether duration of treatment is associated with a documented advantage in efficacy. Three recent phase III trials have attempted to address this question in advanced NSCLC.

In the first trial, Smith et al randomized 308 patients in the United Kingdom to receive either three or six cycles of a combination of mitomycin, vinblastine, and cisplatin (MVP).⁵¹ Notably, this trial was not designed to establish the non-inferiority of a shorter treatment course. There were slight, statistically nonsignificant differences in response rate (31% v 38%, P = .2), time to progression (4.0 v 4.5 months), median survival (6 months v 7 months), and 1-year survival (22% v 25%), all favoring the group randomized to receive six cycles. Similar rates of toxicity were observed in the two groups, although patients randomized to receive six cycles of chemotherapy did experience more fatigue and more nausea. Importantly, only 31% of patients in the group randomized to receive six cycles actually received all six cycles, due in a majority of cases to progressive disease and less frequently to toxicity or patient preference.

In the second trial, Socinski et al randomized 230 patients to receive carboplatin and paclitaxel delivered every 3 weeks for four cycles only, versus identical doses delivered every 3 weeks until disease progression.⁵² At progression, all patients received weekly paclitaxel. Similar to the study by Smith et al, this study was not designed to answer questions of non-inferiority. No significant differences in response or survival were detected between the two treatment arms. Similar to the previous trial, only 42% of patients in the group randomized to receive prolonged chemotherapy were actually able to receive more than the four cycles that the patients in the other group received. More than half of the patients in the prolonged chemotherapy group who did not receive more than four cycles were unable to do so because of either toxicity or progression of disease. Notably, all objective responders in this trial were identified within the first four cycles of chemotherapy. Peripheral neuropathy was cumulative in the prolonged chemotherapy group, with 20% of patients experiencing grade 2–4 neuropathy after four cycles and 43% of patients experiencing grade 2–4 neuropathy at cycle 8.

The majority of the patients assigned to the prolonged treatment arms in these two studies failed to receive such treatment, which speaks volumes about the refractoriness of advanced NSCLC and the potential toxicity of treatment. The early attrition of patients assigned to receive prolonged chemotherapy in these studies may have masked any potential benefit offered by prolonged treatment with chemotherapy. Nonetheless, both of these studies failed to produce any data supportive of the notion that patients should routinely receive indefinite or prolonged treatment with chemotherapy.

The third trial randomized chemotherapy-naive patients to one of three schedules of carboplatin and paclitaxel. Responding patients who completed 16 weeks of therapy then underwent a second randomization to either observation alone or maintenance weekly paclitaxel 70 mg/m².⁵³ Only 130 of the original 390 patients met these criteria for the second randomization. Forty-five percent of the 65 patients on the maintenance paclitaxel arm experienced at least one grade 3–4 toxicity. No statistically significant differences in outcomes were identified between patients randomized to observation and those randomized to maintenance therapy.

Whether patients who are responding to and tolerating chemotherapy benefit from treatment beyond three to four cycles remains unknown. No randomized trial has been able to adequately address this, as patient enrollment in such a study has proven difficult.⁵³, ⁵⁴ In this regard, patients are often reluctant to be randomized to receive “less” chemotherapy. These studies provide important data on the feasibility of administering more cycles of chemotherapy, the cumulative toxicity of prolonged therapy, and the likelihood of attaining a major response after the fourth cycle of treatment. The available data suggest that, for most patients, the benefits accrued beyond three to four cycles of chemotherapy will be modest at best, and may be offset by added toxicity in this palliative setting. Until more data are available to shed light on this topic, oncologists will need to continue to weigh potential and actual treatment-associated toxicity against the benefit afforded by treatment on a case-by-case and cycle-by-cycle basis. Whether stable or responding patients would benefit from switching to an alternative chemotherapy with non-overlapping toxicities also remains an open question.

Conclusions on Front-Line Therapy 

In summary, many questions remain about the optimal management of chemotherapy-naive patients with advanced NSCLC who have an ECOG PS 0–1. In general, combination chemotherapy using two agents offers better response rates and improved survival compared to single-agent therapy. Most studies comparing various doublets have failed to show any clinically meaningful difference in survival outcomes. Nonplatinum-containing doublets continue to evolve, and notably, ASCO treatment guidelines now make no distinction between platinum-based and nonplatinum-based doublets in their recommendations for front-line treatment.²³ As the list of active combinations continues to grow, it will become more important to incorporated cost-effectiveness and QOL assessments into the design of clinical trials. The choice of which doublet to use remains a decision that should be made on an individualized basis, informed by non-efficacy issues such as cost, convenience, and toxicity.

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Treatment of Refractory Disease 

The 1997 ASCO guidelines stated “there is no current evidence that either confirms or refutes that second-line chemotherapy improves survival with advanced NSCLC.”³¹ Over the past 8 years, however, a number of trials have demonstrated that chemotherapy can provide benefit for patients with disease progression after initial chemotherapy for advanced NSCLC. Regarding terminology, the phrases second-line therapy and therapy for platinum-refractory disease are no longer interchangable, as now more patients are receiving nonplatinum doublets as primary therapy.

At the current time, only docetaxel and pemetrexed are approved by the Food and Drug Administration for the treatment of advanced, platinum-refractory NSCLC. Docetaxel was approved for this indication based the results of two large phase III trials. In the TAX 317 trial, Shepherd et al randomized 204 taxane-naive patients with platinum-refractory disease to receive either salvage docetaxel 100 mg/m² (D100) or best supportive care.⁵⁵ Interim analysis identified a significant increase in toxicity in the treatment arm, requiring dose reduction to 75 mg/m² (D75) in the second half of the trial. At final analysis, the objective response rate of treated patients with measurable disease was only 6%. Treated patients demonstrated statistically significant improvement in time to progression (2.5 v 1.6 months, P <.001) and median survival (7 v 5 months, P = .047). Docetaxel-treated patients also demonstrated statistically significant improvement in QOL as measured by the Lung Cancer Symptom Scale (LCSS) questionnaire, particularly in terms of fatigue and pain, although some degree of symptomatic improvement may have been related to the dexamethasone that all docetaxel-treated patients received.⁵⁶ The differences in objective outcome were most pronounced among the subset of patients treated with D75 as compared to those treated with best supportive care.

In the TAX 320 trial, Fossella et al randomized 373 patients with platinum-refractory disease to receive either docetaxel 100 mg/m² (D100), docetaxel 75 mg/m² (D75), or “traditional” salvage chemotherapy using either vinorelbine or ifosfamide (V/I) at standard doses.⁵⁷ Approximately 40% of patients in each arm had received prior paclitaxel. Overall response rates were 11% with D100, 7% with D75, and only 1% with V/I. Although overall survival was not significantly different between the groups (around 6 months), patients treated with D75 experienced an improvement in 1-year survival (32% v 19%, P = .025) in comparison to patients treated with V/I. However, investigators noted that about 30% of patients in the control group eventually went on to receive docetaxel, perhaps diminishing observable differences between the two groups of patients. Overall, patients treated with D100 and D75 also enjoyed a QOL benefit as measured by the LCSS questionnaire,⁵⁸ although it may be worth noting that docetaxel-treated patients also received regular doses of dexamethasone whereas patients in the control group did not. Interestingly, prior exposure to paclitaxel did not adversely affect the likelihood of response to docetaxel or the survival benefit.

Why such small differences in objective response rate translated into a more robust survival benefit remains unclear. The observed benefits in QOL and 1-year survival for treated patients justify the use of docetaxel in the treatment of platinum-refractory disease. At the current time, the optimal dose in this patient population is 75 mg/m² infused over 1 hour after dexamethasone premedication, once every 3 weeks. Weekly docetaxel appears to be promising and may have less toxicity,⁵⁹, ⁶⁰ but this regimen has not completed phase III testing.

More recently, pemetrexed, a multitargeted antifolate has shown promise for patients with chemotherapy-refractory disease. Pemetrexed inhibits multiple enzymes in the folate pathway, including thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyl-transferase. Initial enthusiasm for this agent was tempered by the high rate of grade 4 neutropenia and grade 3–4 nonhematologic toxicity, until it was discovered that routine vitamin B₁₂ and folate supplementation significantly reduce the rate of these toxicities.⁶¹, ⁶² A recent phase III non-inferiority trial randomized 571 patients who had developed progressive disease after at least one prior regimen of chemotherapy to receive either docetaxel 75 mg/m² and dexamethasone or pemetrexed 500 mg/m² supplemented with vitamin B₁₂, folic acid, and dexamethasone.⁶³ Outcomes were similar in both treatment arms, which demonstrated an approximate 9% objective response rate, 8-month median survival time, and 30% 1-year survival rate. Differences were generally limited to toxicity, with pemetrexed-treated patients experiencing fewer drug-related hospitalizations and significantly less myelosuppression and alopecia.

Although at the current time only docetaxel and pemetrexed are approved by the Food and Drug Administration for treatment of advanced, platinum-refractory NSCLC, the utility of nonplatinum doublets is actively being investigated in this setting.

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Special Considerations 

Patients With Limited Functional Status 

Although patients with advanced NSCLC who have an ECOG PS of 2 constitute a sizable minority of patients with advanced NSCLC, there are limited data to guide clinical decision-making for these patients. The “standard” of care for these patients continues to evolve. Data from randomized trials in this group of patients are largely confined to subgroup analyses of larger trials. Nonetheless, the available data support the use of chemotherapy in this patient population. For example, the meta-analysis performed by the Non-Small Cell Lung Cancer Collaborative Clinical Trials Cooperative Group that demonstrated a statistically significant survival advantage for patients with advanced NSCLC who were treated with chemotherapy versus best supportive care included a subgroup analysis that demonstrated similar benefit in low-PS patients.²

If chemotherapy is appropriate for some patients with PS 2, what agents are appropriate? Subgroup analysis of the ECOG 1594 trial demonstrated that the 64 evaluable patients with PS 2 experienced intolerable toxicity with the three cisplatin-based doublets, leading to discontinuation of enrollment of low-PS patients in this trial.⁶⁴, ⁶⁵ That cisplatin-based doublets may not be appropriate for PS 2 patients was echoed in the trial initially published by Le Chevalier et al, in which subgroup analysis of 120 PS 2 patients enrolled in a three-arm trial that randomized patients to receive vinorelbine monotherapy, vinorelbine/cisplatin, or vindesine/cisplatin suggested no difference in survival among the three treatment arms but an increased rate of toxicity in patient who received the cisplatin-based doublets.⁶⁶, ⁶⁷ This study concluded that PS2 patients should be treated with active single agents or less toxic doublets.

Although cisplatin-based doublets may not be appropriate for this patient population, a subgroup analysis of the ECOG 1594 trial found that PS 2 patients treated with carboplatin/paclitaxel had a more tolerable rate of toxicity, suggesting that this regimen could be appropriate for further evaluation in this patient population. Subgroup analysis of PS 2 patients from a different trial that randomized patients to receive paclitaxel monotherapy or a combination of carboplatin and paclitaxel demonstrated a significantly superior survival in patients treated with the combination with acceptable rates of toxicity.²⁸ The possibility of administering carboplatin-based doublets to PS 2 patients is being further investigated in the STELLAR 3 trial, which is a large phase III trial for PS 2 patients who have been randomized to receive carboplatin/paclitaxel or a combination of carboplatin and a polyglutamated form of paclitaxel (Xyotax, Cell Therapeutics, Inc, Seattle WA). This trial has completed enrollment, and results are widely anticipated.

The data on the use of single agents in this patient population are similarly limited to subgroup analyses of randomized trials. A number of trials comparing monotherapy with newer agents versus best supportive care for chemotherapy-naive patients have included PS 2 patients. Vinorelbine,⁶⁸ docetaxel,⁶⁹ paclitaxel,⁷⁰ and gemcitabine⁷¹ have all demonstrated QOL benefits. Vinorelbine, docetaxel, and paclitaxel have also demonstrated survival benefits as monotherapy versus best supportive care. Although none of these studies yielded statistically significant conclusions on the subpopulation of PS 2 patients, each included a sizable minority (15%–30%) of such patients. As a result, it would be reasonable to offer one of these agents as monotherapy in this patient population.

Data on the role of nonplatinum doublets in this patient population is even more limited. A phase II study in PS 2 patients and another trial enrolling PS 0–2 patients of whom 28% were PS 2 evaluated the combination of weekly docetaxel and gemcitabine and demonstrated promising results.⁷², ⁷³ A phase III study comparing docetaxel monotherapy versus weekly docetaxel and gemcitabine is currently underway.

Until further trials are completed, it remains reasonable to offer patients with PS 2 and advanced NSCLC either combination chemotherapy using carboplatin/paclitaxel, nonplatinum monotherapy, or a nonplatinum doublet, acknowledging that such decisions should incorporate comorbid conditions and the potential toxicity of treatment. Patients with advanced NSCLC who have a performance status of 3–4 should not receive chemotherapy.

Older Patients With Advanced NSCLC 

It is important to distinguish age from PS. Age is not an independent predictor of survival or response in randomized controlled trials of chemotherapy for advanced NSCLC. Despite this fact, older patients are often managed quite differently from younger patients. In fact, a Medicare survey has indicated that 78% of patients ages 65 and older who have metastatic NSCLC never receive any chemotherapy.⁷⁴ This is likely due in part to the presence of more comorbid conditions in the elderly, although comorbid conditions alone cannot explain this practice pattern. The availability of data regarding the appropriate management of fit, older patients with advanced NSCLC are limited but growing, with some trials now designed specifically for patients 70 and older.

Do fit, older patients with advanced NSCLC benefit from conventional chemotherapy? Results of the meta-analysis performed by the Non-Small Cell Lung Cancer Collaborative Clinical Trials Cooperative Group and subgroup analyses from prospective cooperative group trials have all demonstrated that older patients benefit from conventional chemotherapy in a manner similar to that offered to younger patients.²⁸, ⁷⁵, ⁷⁶, ⁷⁷, ⁷⁸ For example, retrospective subgroup analysis of two prospective, randomized Cancer and Leukemia Group B (CALGB) studies in patients with stage IIIB NSCLC failed to identify any impact of age on response rate, survival, or duration of treatment among quartiles of patients (<50 years, 50–59 years, 60–69 years, and >70 years).⁷⁵, ⁷⁹, ⁸⁰ Similarly, retrospective subgroup analysis of a randomized trial comparing cisplatin/etoposide and cisplatin/paclitaxel failed to identify any statistically significant difference in response rate, time to progression, or survival outcomes in patients70 and older compared to those younger.⁸¹ Both of these analyses reported higher, but generally acceptable, rates of toxicity in the older patients.

These studies suggest that platinum-based chemotherapy is as effective in older patients with advanced NSCLC as in younger patients. Unfortunately, a substantial number of older patients have comorbid conditions that may hinder its use. Carboplatin has less neurotoxicity and nephrotoxicity, but is associated with more marrow toxicity, which may similarly limit the use of this agent in this patient population. Nonplatinum monotherapy is actively being investigated for use in this patient population. One phase III trial for patients ages 70 and older compared vinorelbine versus best supportive care. The Elderly Lung Cancer Vinorelbine Italian Group Study (ELVIS) demonstrated that single-agent vinorelbine given at a dose of 30 mg/m² on days 1 and 8 on a 21-day cycle improves survival over best supportive care (median survival 6.5 v 4.8 months, P = .03) and is well tolerated.⁶⁸ Several phase II studies have focused on the use of other single agents in the treatment of older patients with NSCLC, including gemcitabine,⁸² docetaxel,⁸³ and paclitaxel.⁸⁴

If nonplatinum monotherapy offers benefit in older patients with advanced NSCLC, do nonplatinum-based doublets offer more benefit? Two randomized trials have specifically addressed this question. The Southern Italian Cooperative Group (SICOG) reported the results of a trial that randomized patients 70 years and older to receive vinorelbine (30 mg/m²) alone versus the combination of vinorelbine (30 mg/m²) and gemcitabine (1,200 mg/m²), with all treatment given on days 1 and 8 of a 21-day cycle.⁸⁵ The trial was stopped after interim analysis of the 120 evaluable patients demonstrated statistically significant differences in survival outcomes. Patients who received gemcitabine/vinorelbine had superior median survival (6.7 v 4.2 months, P <.1) and 1-year survival (30% v 13%, P <.1) compared to those treated with vinorelbine monotherapy. Patients who received combination chemotherapy also had improved symptom control compared to those who received monotherapy.

The findings of the SICOG trial conflict with the larger Multicenter Italian Lung Cancer in the Elderly Study (MILES) trial (Table 5).⁸⁶ This was a three-arm trial that randomized 698 patients with advanced NSCLC who were 70 years and older to receive treatment with vinorelbine (30 mg/m²) alone, gemcitabine (1,200 mg/m²) alone, or the combination of vinorelbine (25 mg/m²) and gemcitabine (1,000 mg/m²), with all treatment given on days 1 and 8 of a 21-day cycle. Compared to monotherapy with either drug, the combination of gemcitabine/vinorelbine did not improve response rates, survival, or QOL, and was associated with greater toxicity.

Table 5. Randomized Trials of Chemotherapy in Older Patients

Abbreviations: ELVIS, Elderly Lung Cancer Vinorelbine Italian Study Group; SICOG, Southern Italian Cooperative Group; MILES, Multicenter Italian Lung Cancer in the Elderly Study.

It is interesting that the survival outcomes for the combination of gemcitabine/vinorelbine in both the SICOG trial and the MILES trial were similar (29% and 30% 1-year survivals, respectively). Notably, the patients in vinorelbine monotherapy arm in the SICOG trial had worse than expected outcomes, similar to those reported for the group treated with best supportive care in the ELVIS trial.

In addition to having poorer outcomes in the monotherapy arm compared with those demonstrated in the MILES trial, the SICOG trial also used higher doses of vinorelbine and gemcitabine in the combination arm, perhaps further explaining the positive findings of the SICOG trial as compared with the MILES trial.

A four-arm randomized trial enrolled patients with advanced NSCLC patients who were either 70 and older or had PS 2 to receive either paclitaxel monotherapy, gemcitabine monotherapy, gemcitabine/vinorelbine, or paclitaxel/gemcitabine. Interim analysis after enrollment of 264 patients demonstrated nonsignificant differences in objective response rates: 13% in the paclitaxel monotherapy group, 18% in the gemcitabine monotherapy group, 23% in the gemcitabine/vinorelbine group, and 32% in the gemcitabine/paclitaxel group.⁸⁷ Median survivals in the two groups that received nonplatinum doublets (9.2 months) reached significance when compared to that achieved in the two monotherapy groups (5.7 months, P = .028). Similarly, 1-year survivals in the two groups who received nonplatinum doublets (39%) reached significance when compared to that achieved in the two monotherapy groups (28%, P = .028). Direct comparison of median and 1-year survival outcomes among the four groups individually yielded nonsignificant results. Subset analyses of outcomes among the subsets of PS 2 or elderly patients were not reported. Notably, the study was closed prematurely amid ethical concerns of continuing with the gemcitabine-only and gemcitabine/vinorelbine arms in light of the results of the MILES trial.

The risk of treatment-related toxicity remains a common concern in the treatment of older patients. The subgroup analysis by Kelly et al demonstrated that patients 70 and older treated with cisplatin/etoposide or cisplatin/paclitaxel were more likely to experience Grade 3–5 hematologic toxicity (83%) as compared to younger patients (76%, P = .11), but developed similar rates of Grade 3–5 non-hematologic toxicity (54% v 56%, respectively, P = .63).⁷⁶ Similarly, Langer et al reported a subgroup analysis of ECOG 5592, a phase III trial that randomized patients to receive cisplatin with either etoposide or one of two dose levels of paclitaxel. Across all three treatment arms, male patients ages 70 and older experienced more Grade 4 neutropenia (80% v 64%) and any Grade 5 toxicity (7% v 3%) than did younger patients (3%).⁸¹ The two age groups developed similar rates of non-hematologic toxicity, with the notable exception of Grade ≥ 2 neuropsychiatric toxicity, which developed in 17% of the older group and only 7% in the younger (P = .002).

What conclusions can we draw from these studies? First, despite the large number of older patients with advanced NSCLC, there are too few studies specifically designed for these patients. Second, older patients with good performance status may benefit from cisplatin-based regimens to the same degree as younger patients. Third, the “best” regimen for this patient population, either as monotherapy or as a doublet, remains to be defined. At the current time, decisions regarding the treatment of a fit, older patient should be informed more by potential for toxicity, patient preferences, and comorbid conditions than on the patient’s chronologic age. It would be reasonable to offer older patients with limited performance status (PS 2) carboplatin/paclitaxel, a nonplatinum-based doublet, nonplatinum monotherapy or best supportive care, depending on toxicity, comorbid conditions, and the nature of the patient’s limited PS.

Goals of Therapy 

This review has provided data in an attempt to help physicians make informed treatment recommendations for patients with advanced NSCLC. Such a discussion would be incomplete without mention of patient preferences on the matter. It is not surprising to consider that physicians and patients may view treatment options differently. A recent study interviewed 81 patients with advanced NSCLC who had received cisplatin-based chemotherapy in a Veterans Administration (VA) hospital setting to assess patient preferences in light of survival and toxicity data.⁸⁸ These patients reported that in order to choose a “very toxic” chemotherapy (defined as having a risk of possibly severe side effects of several days duration that could involve fatigue, weakness, diarrhea, infection, fever, the potential need for hospitalization, and/or a 1% chance of death), the therapy would need to offer a 9-month median survival improvement beyond that offered by best supportive care. In these patients, the median threshold for choosing less toxic chemotherapy was a 4.5-month survival benefit beyond that offered by best supportive care. Furthermore, when these patients were then asked to choose between treatment with best supportive care or treatment with a hypothetical chemotherapy regimen that offered an average survival benefit of 3 months, 78% chose best supportive care. Conversely, 68% of these patients said they would choose chemotherapy if it were to substantially reduce symptoms even without prolonging life. Of course, this is a single, small study of selected patients who are vulnerable to the biases of the interviewing investigators and to their own inherent biases associated their prior experiences of cancer care in a VA setting. Nonetheless, these findings suggest the degree to which patients with advanced NSCLC might emphasize QOL and risk of toxicity over small differences in median survival when making their own treatment decisions.

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Treatment Paradigm 

As chemotherapy currently offers only palliation of symptoms and modest prolongation of life, it is vitally important to determine that the patient truly has stage IV disease, or stage IIIB with a malignant pleural or pericardial effusion, and is therefore not a candidate for treatment with curative intent. Confirmation of advanced disease typically involves pathologic or cytologic documentation of a malignant pleural or pericardial effusion, biopsy-proven metastatic (M1) disease, or convincing radiologic evidence of metastatic disease such as highly suspicious lesions visible on a plain radiograph or computed tomography (CT) scanning, which are also metabolically active on bone scan or positron emission tomography (PET) scan. If even a remote possibility exists that a probable site of metastatic disease is not such, biopsy of this area should be pursued. This might be the case, for example, with a patient from an area known to have a high rate of granulomatous disease who is found to have diffuse uptake on PET scan. In very rare instances, patients with a solitary metastatic site of disease can be cured with surgery or combined modality therapy.⁸⁹, ⁹⁰

Once the clinician is convinced that the patient’s disease is incurable, initiation of systemic chemotherapy is indicated. However, chemotherapy should be delayed pending control of critical metastases (examples of which would include spinal cord compression, bone metastases causing pain refractory to standard analgesic agents, and symptomatic brain metastases), which may present an immediate threat to the patient. Furthermore, a patient requires a minimum PS (≥60% on the Karnofsky scale; ≥2 on the ECOG scale) in order to be likely to benefit from systemic chemotherapy. Therefore, chemotherapy may also be delayed or withheld while the patient is afforded the best supportive medical care for their cancer and/or comorbid illnesses.

Once control of critical metastases has been achieved, and the patient has demonstrated adequate performance status, a chemotherapy regimen (Fig 2) should be chosen. Given the shortcomings of all current chemotherapy for advanced NSCLC, it would always be appropriate to enroll eligible patients in an investigational protocol whenever possible during the course of their treatment, including at presentation.

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• Figure 2. 

  Memorial Sloan-Kettering Cancer Center treatment algorithm.

The choice of treatment regimen should be based on the immediate goal of therapy. For example, if the patient is highly symptomatic from his or her lung cancer, the initial goal of chemotherapy is rapid palliation of symptoms. A drug regimen is chosen with an emphasis on its documented response rate, with less immediate concern for the toxicity of the chemotherapy in a risk-benefit analysis. Thus, for symptomatic patients, a cisplatin-containing regimen may be appropriate. If, however, the patient is relatively asymptomatic from his or her disease, the immediate goal of chemotherapy is to improve overall survival with less treatment-related toxicity. In this situation, it may be appropriate to avoid the added toxicity of cisplatin, and pursue combination chemotherapy with carboplatin. Alternatively, one could choose a nonplatinum doublet and avoid platinum analogues altogether. With the exception of bronchioloalveolar cell carcinoma (BAC) and BAC variants,⁹¹, ⁹², ⁹³ the particular histology of a patient’s NSCLC plays little role in the choice of chemotherapy.

Another scenario involves patients with borderline PS who may not be able to tolerate cisplatin-based therapy. Treatment with carboplatin/paclitaxel, a platinum-free combination, or even monotherapy with gemcitabine, vinorelbine, or a taxane, would be reasonable in some patients with a low PS (PS 2). Alternatively, patients may be treated with the combination of mitomycin/vinblastine, a regimen with some degree of activity that is well tolerated in this patient population.

Baseline radiologic studies are performed based on the location of evaluable disease. Chest radiographs or physical examination when harboring indicator lesions are often preferred as simple methods of evaluating disease response, although most patients also undergo baseline and periodic CT imaging. Response assessment is initially performed after 4 to 6 weeks of therapy with the intent to identify patients with clearly refractory disease in order to minimize treatment with ineffective therapy. This is followed by serial CT scanning every 2 to 3 months to follow the response of their disease to therapy. If the tumor shrinks in size or is stabilized by chemotherapy, the drugs are continued indefinitely, as tolerated, acknowledging that there is some controversy regarding the appropriate duration of therapy.

If a patient’s disease is refractory to first-line therapy, salvage chemotherapy may be appropriate. Selection of a second-line drug is based in part on the drugs included in the initial chemotherapy regimen. If the patient is taxane-naive, monotherapy with either docetaxel or pemetrexed are appropriate options, reinforced by the recent phase III data.⁵⁵, ⁵⁷ Although there are no mature phase III data comparing schedules of docetaxel administration, many physicians are now beginning to administer single-agent docetaxel on a weekly schedule at a dose of 25 to 36 mg/m² weekly to minimize myelosuppression and neuropathy.⁸³ If the patient has received paclitaxel up front, pemetrexed or gemcitabine may be used, although the results of the TAX 320 trial support the use of docetaxel even in patients who have failed to respond to paclitaxel. The role of the EGFR tyrosine kinase inhibitors gefitinib (Iressa, AstraZeneca, Macclesfield, UK) and erlotinib (Tarceva, Genentech, South San Francisco, CA) in the management of NSCLC is discussed elsewhere in this issue of Seminars of Oncology.

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Conclusions and Future Directions 

Chemotherapy is an appropriate treatment option for most patients with advanced NSCLC. The growing number of agents with demonstrated activity has improved the ability of oncologists to tailor a regimen for each patient according to toxicity profile, frequency of monitoring, cost, comorbid conditions, and PS. Recent studies have begun to define appropriate management of previously under-represented subpopulations of patients with advanced NSCLC, such as older patients or low PS patients. Many currently open clinical trials are expected to answer important questions related to the management of NSCLC. A number of investigational agents are currently being studied in clinical trials, with the number of potential “targeted” agents constantly growing.

Given the results offered by the currently available treatments for NSCLC presented in this review, enrollment of any patient with metastatic disease and acceptable PS onto a clinical trial of novel therapy is reasonable at any time, including as front-line therapy. Since many of the currently available chemotherapeutic regimens offer similar efficacy outcomes, trials comparing conventional cytotoxic agents need to be thoughtfully designed and conducted to answer important questions. Furthermore, trial designs will need to include non-efficacy measures, such as cost-effectiveness analysis and more thorough measures of QOL.

Despite modest improvements in response rates and survival demonstrated by trials over the past few years, many obstacles remain on the path to improved care for patients with advanced NSCLC. Primary prevention remains the ultimate goal in NSCLC. To this end, improved tobacco cessation techniques for current smokers and enhanced anti-tobacco education programs for teenagers would likely save more lives than any particular advance in the treatment of NSCLC. Improved early diagnosis is also an important goal in this disease, and studies are currently underway assessing whether early identification and downstaging of new NSCLCs by screening high-risk patients with CT scan translates into improved outcomes.

As many patients are diagnosed with advanced NSCLC with a fine-needle aspiration biopsy that yields only a few cells, there is a relative scarcity of pathologic tissue for study in the laboratory as compared to other malignancies. In order to better understand the molecular events that initiate and maintain malignant cells in NSCLC, obstacles to tissue procurement that are unique to the disease will need to be addressed, perhaps by improving the collection of cancer cells from malignant pleural effusions for study in the laboratory. The recognition of the EGFR as an important target in NSCLC and the significance of activating mutations within EGFR have served to underscore the importance of basic science research in this field and have re-energized attempts at tissue procurement. Thanks to these continued improvements in molecular science and to the recently completed human genome project, investigators will soon begin to understand some of the complex molecular abnormalities unique to tobacco-related cancers, perhaps yielding new insights for future targeted therapies.

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