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Keywords:

  • lung carcinoma;
  • nonsmall cell lung carcinoma;
  • chemotherapy;
  • paclitaxel;
  • carboplatin;
  • second-line treatment

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND

Second-line chemotherapy with docetaxel improves survival and quality of life (QoL) in patients with nonsmall cell lung carcinoma (NSCLC) who fail first-line platinum-based regimens. The authors sought to determine the activity of second-line, low-dose, weekly paclitaxel in patients with NSCLC who failed first-line chemotherapy with carboplatin plus paclitaxel.

METHODS

Patients with Stage IIIB/IV NSCLC who had received first-line carboplatin/paclitaxel were treated with low-dose (80 mg/m2), weekly paclitaxel at the time of disease progression. Response rates, QoL, and survival were outcome end points.

RESULTS

Sixty-two patients were included in this analysis. The median age was 62 years (range, 32–76 years), 55% of patients were male, 89% of patients had Stage IV NSCLC, and the Karnofsky performance status was 90–100% in 31% of patients, 70–80% in 55% of patients, and 60% in 14% of patients. Twenty-six percent of patients experienced disease progression as their best response to first-line carboplatin plus paclitaxel, whereas 52% of patients had stable disease, and 23% of patients had achieved a response. The median time from first-line carboplatin plus paclitaxel to second-line, low-dose, weekly paclitaxel was 9.5 weeks (range, 1–78 weeks). The toxicity profile was extremely favorable, with no Grade 4 toxicity and < 10% Grade 3 hematologic or nonhematologic toxicity in all patients with the exception of neuropathy. Ten percent of patients experienced both Grade 2 and Grade 3 neuropathy. The overall objective response rate was 8%. The median survival was 5.2 months (95% confidence interval [95%CI], 3.6–6.2 months), and the 1-year and 2-year survival rates were 20% (95%CI, 10–30%) and 9% (95%CI, 1–16%), respectively.

CONCLUSIONS

Second-line, low-dose, weekly paclitaxel had activity in selected patients with Stage IIIB/IV NSCLC who failed first-line chemotherapy with carboplatin plus paclitaxel. The toxicity profile of this approach is extremely favorable, and outcome expectations are similar to the outcome expectations with other single agents in this setting. Cancer 2002;95:1265–73. © 2002 American Cancer Society.

DOI 10.1002/cncr.10835

Lung carcinoma remains the leading cause of cancer-related death in the United States.1 The majority of patients with lung carcinoma have nonsmall cell lung carcinoma (NSCLC) and present with locally advanced (Stage III) or metastatic disease (Stage IV).2 In patients with Stage IV NSCLC, first-line platinum-based combination chemotherapy improves survival, palliates symptoms, and improves quality of life.3 Despite these advantages, patients ultimately will experience disease progression and/or disease-related complications, because first-line therapy is not curative. At the time of disease progression, many patients may be suitable candidates for second-line treatment. Two randomized Phase III trials evaluating docetaxel in this setting have been published recently.4, 5 In the first trial,4 docetaxel (100 mg/m2 and 75 mg/m2 every 3 weeks) was compared with best supportive care (BCS) in taxane-naïve patients who had received first-line cisplatin-based regimens. Docetaxel improved survival particularly at a dose of 75 mg/m2 every 3 weeks. In the second trial,5 docetaxel at doses of both 100 mg/m2 and 75 mg/m2 every 3 weeks was compared with a third arm of either vinorelbine or ifosfamide. All patients had received previous platinum; however, only 37% of patients had received a prior taxane. Although the median survivals were similar for all three arms, docetaxel at a dose of 75 mg/m2 every 3 weeks produced a significant improvement in 1-year survival compared with the other two arms. In addition, both trials included quality of life (QoL) studies, and both suggested an improvement in QoL and disease-related symptoms in the patients who received second-line docetaxel.6, 7 Consequently, as a result of these two trials, docetaxel at a dose of 75 mg/m2 given every 3 weeks recently was approved by the Food and Drug Administration in the United States for use in patients who develop progressive disease on or after receiving first-line, cisplatin-based regimens.

The taxanes are an important class of new agents in the treatment of patients with NSCLC. In addition to the docetaxel indication in the second-line setting, paclitaxel, in combination with cisplatin, is indicated as first-line therapy in patients with NSCLC. The most commonly used platinum-based combination regimen in the United States in the initial treatment of patients with Stage IV NSCLC is carboplatin plus paclitaxel.8 One of the important clinical questions regarding the taxanes is the issue of optimal schedule. Preliminary analyses of weekly administration schedules suggest that this approach yields equivalent efficacy results, maintains dose intensity, and is associated with less toxicity.9 Chang and colleagues10 have reported the results of a Phase I–II trial of weekly paclitaxel in patients with advanced NSCLC that included both previously treated patients and patients with a poor performance status. A dose of 80 mg/m2 per week given 3 of every 4 weeks was recommended as the Phase II dose. Toxicity, both hematologic and nonhematologic, was minimal. Response and survival data were encouraging; an overall response rate of 30% was reported with a median survival of 6 months and a 1-year survival of 33%. In other tumor types (breast11 and ovary12), patients who were refractory to every-3-week administration schedules of paclitaxel have responded to a weekly administration schedule of paclitaxel. Therefore, a change in the schedule of a taxane at the time of disease progression may yield some benefit and is associated with a very tolerable toxicity profile in this setting. Given these findings, we were interested in evaluating the activity of weekly paclitaxel in patients with Stage IIIB/IV NSCLC who developed progressive disease on or after receiving first-line carboplatin plus paclitaxel. We previously reported the results of a trial evaluating the optimal duration of first-line treatment with carboplatin plus paclitaxel.13 In the design of that trial, patients were to receive weekly paclitaxel at a dose of 80 mg/m2 per week at the time of disease progression after they received first-line carboplatin plus paclitaxel. This report summarizes the experience with weekly, low-dose paclitaxel as second-line therapy in this setting.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patient Eligibility

Patients on this study had received first-line carboplatin plus paclitaxel on a multi-institutional, Phase III trial examining the effect of duration of therapy in patients with advanced NSCLC.13 All patients had to have experienced disease progression during or after first-line treatment with carboplatin plus paclitaxel. Patients had histologic or cytologic proof of Stage IIIB/IV NSCLC and either measurable disease or evaluable disease. Prior radiotherapy was allowed; however, patients had to be at least 1 week beyond completion of radiotherapy. Patients were required to have a Karnofsky performance status (PS) > 60% and adequate end-organ function, which was defined as an absolute neutrophil count > 1500/mm3, platelets > 100,000/mm3, creatinine < 2.0 times the institutional upper normal limits (IUNL), bilirubin < 1.5 IUNL, aspartate aminotransferase < 2.5 IUNL, and Grade ≤ 2 peripheral neuropathy. All patients were required to participate in the QoL component of the study and were required to provide written informed consent. This trial was reviewed by the Protocol Review Committee of the Lineberger Comprehensive Cancer Center (LCCC) and the Institutional Review Board of the University of North Carolina School of Medicine (as well as all participating centers), and the trial was labeled LCCC 9719.

Patients were divided further based on their initial response to and duration of first-line treatment with carboplatin plus paclitaxel. Subgroup 1 was comprised of patients who experienced disease progression during the first two cycles of first-line carboplatin plus paclitaxel. Subgroup 2 was comprised of patients who received four cycles of first-line carboplatin plus paclitaxel and subsequently experienced disease progression. Subgroup 3 was comprised of patients who received more than four cycles of first-line carboplatin plus paclitaxel and, in general, experienced disease progression while they still were receiving first-line therapy.

Treatment Plan and Response Assessment

For second-line therapy, patients received paclitaxel at a dose of 80 mg/m2 per week until they experienced further disease progression. Standard medications included dexamethasone 20 mg intravenous (IV), diphenhydramine 50 mg, and ranitidine 50 mg IV or cimetidine 300 mg IV 30 minutes prior to weekly paclitaxel; however, a reduction in the dose of dexamethasone was allowed if patients exhibited no signs of hypersensitivity. Patients were assessed for disease progression every 8 weeks. After the initial 8 weeks of weekly paclitaxel, patients were allowed 1–2-week treatment breaks at the discretion of the treating physician.

Standard criteria for response to chemotherapy were used. Patient response to treatment was categorized as either a complete response (CR), a partial response (PR), stable disease (SD), or progressive disease according to these criteria. For toxicity assessment, the National Cancer Institute Common Toxicity Criteria (version 1.0) was used.

QoL

The Functional Assessment of Cancer Therapy (FACT)—Lung questionnaire14 and the FACIT-Taxane (TAX) toxicity subscale15 were used to evaluate QoL end points in this study. Two primary outcome measures were used: the Trial Outcome Index—Lung (TOI-L) and the Trial Outcome Index (TAX; TOI-TAX). The TOI-L combines scores from the physical, functional, and lung carcinoma specific subscale scores, whereas the TOI-TAX combines scores from the physical, functional, and TAX subscales.

The study protocol specified that participants had to complete the QoL measures at the time they developed progressive disease after first-line treatment, then 5 weeks and 11 weeks after starting second-line paclitaxel. All assessments were completed by telephone interview. Unfortunately, a low completion rate resulted from lapses in the process by which the QoL data collection site was notified by the clinical sites of a patient with disease progression. Twenty-eight patients (45%) provided QoL data at the beginning of first-line treatment, at the time of disease progressions, and at the 5-week follow-up interview: Of these, 8 patients were in Subgroup 1, 16 patients were in Subgroup 2, and 4 patients were in Subgroup 3. Only 16 of 28 patients also completed the Week-11 interview. Thus, Week-11 data were not included in the data analysis. Subgroup analyses were not performed because of the very small sample sizes in Subgroups 1 and 3.

Statistical Analysis

The patients reported in this study originally were included in a Phase III, randomized trial that attempted to define the optimal duration of therapy for patients with advanced NSCLC.13 Patients in that trial were randomized to either four cycles of carboplatin plus paclitaxel (Arm A) or continuous treatment until disease progression with the same regimen (Arm B). At the time of objective progression during or after they received first-line treatment with carboplatin plus paclitaxel, patients were to receive low-dose weekly paclitaxel. Because the role of second-line, low-dose, weekly paclitaxel had not been defined in this setting, and because the investigators participating in the randomized Phase III trial did not wish to offer ineffective therapy, this trial was designed to evaluate the effect of low-dose, weekly paclitaxel in three separate groups, as noted above: Subgroup 1 included patients who experienced disease progression during or after the first two cycles of carboplatin plus paclitaxel (from either Arm A or Arm B); Subgroup 2 included patients who were randomized to Arm A and who completed four cycles of carboplatin plus paclitaxel and subsequently experienced disease progression; and Subgroup 3 included patients who were randomized to Arm B who received continuous treatment until they experienced disease progression. A two-stage minimax design16 was used with either response or disease stabilization at the initial 8-week assessment defined as the end point. At least 1 of 13 patients had to achieve this end point to proceed to the second stage, in which at least 4 of 27 patients overall had to achieve the end point to conclude that the therapy was effective. A response/disease stabilization rate (including patients who achieved CRs, PRs, or SD) of 5% was considered ineffective, whereas a rate of 20% was considered effective. This design yielded an α = 0.05 with 80% power. The Kaplan–Meier technique was used for survival analyses.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patients Demographics

The characteristics of the 62 patients entered on this study are shown in Table 1. The median age was 62 years (range, 32–76 years). Fifty-five percent of patients were male. The majority of patients had Stage IV NSCLC (89%) and nonsquamous histology (85%). The Karnofsky PS was 90–100% in 31% of patients, 70–80% in 55% of patients, and 60% in 14% of patients. Minorities comprised 25% of patients. Regarding the best response to first-line therapy with carboplatin plus paclitaxel, 23% of patients had a PR, 52% of patients had SD, and 26% of patients developed disease progression. The median time from the end of first-line treatment with carboplatin plus paclitaxel to the start of second-line, weekly, low-dose paclitaxel for all patients was 9.4 weeks (range, 1–78 weeks) and is shown for the subgroups in Table 1. Six patients (10%) had experienced Grade 2 peripheral neuropathy on first-line carboplatin plus paclitaxel.

Table 1. Patient Demographics
CharacteristicNo. (%)Median (range)
  1. PS: performance status; CR: complete response; PR: partial response; C/P: carboplatin/paclitaxel; P: paclitaxel.

Total patients62 (100) 
Median age in yrs (range)62 (32–76)
Gender  
 Male34 (55)
 Female28 (45)
Stage  
 IIIB7 (11)
 IV55 (89)
Karnofsky PS (%)  
 90–10019 (31)
 70–8034 (55)
 609 (14)
Histology  
 Nonsquamous53 (85)
 Squamous9 (15)
Race  
 White47 (76)
 Black14 (23)
 Other1 (2)
Best response to first-line C/P  
 Progressive disease16 (26)
 Stable disease32 (52)
 PR/CR14 (23)
Median time (in weeks) from first-line C/P to second-line weekly P (range)  
 All patients62 (100)9.4 (1–78)
 Subgroup 116 (26)3.4 (1–14)
 Subgroup 228 (45)16.0 (3–62)
 Subgroup 318 (29)5.5 (3–78)

Treatment Administration and Toxicity

The median number of weekly paclitaxel treatments delivered was 8 treatments (range, 1–32 treatments), and this did not differ much among the 3 subgroups (Table 2). Hematologic and nonhematologic toxicity is shown in Table 3. In general, weekly, low-dose paclitaxel was tolerated very well in this patient population. No Grade 4 hematologic toxicity and very little Grade 3 hematologic toxicity were seen during treatment. The most prominent nonhematologic toxicities were peripheral neuropathy and malaise/fatigue. Overall, six patients (10%) experienced Grade 2 peripheral neuropathy and six patients (10%) experienced Grade 3 peripheral neuropathy on second-line, low-dose, weekly paclitaxel. Of the six patients with Grade 3 peripheral neuropathy, two patients had Grade 2 neuropathy, three patients had Grade 1 neuropathy, and one patient had no neuropathy on first-line carboplatin plus paclitaxel. Of the six patients with Grade 2 peripheral neuropathy, four patients had Grade 2 neuropathy, and two patients had Grade 1 neuropathy on first-line carboplatin plus paclitaxel. An additional four patients experienced Grade 1 neuropathy on first-line carboplatin plus paclitaxel that did not worsen on second-line, low-dose, weekly paclitaxel.

Table 2. Summary of Treatment Administration and Response
ResponseAll patientsSubgroup
123
  • P: paclitaxel; PR: partial response; SD: stable disease; PD: progressive disease.

  • a

    Unknown denotes patients who discontinued treatment prior to the first assessment of response time.

Total patients62162818
Median no. of weekly P treatments (range)8 (1–32)8 (2–32)8 (2–32)7 (1–22)
Best response to weekly P: No. (%)    
 PR5 (8)0 (0)5 (18)0 (0)
 SD23 (37)7 (44)10 (35)6 (33)
 PD28 (45)7 (44)10 (35)11 (61)
 Unknowna6 (10)2 (12)3 (11)1 (6)
Table 3. Percent of Patients with Grade 2–4 Toxicity
ToxicityGrade
234
Hematologic   
 Neutropenia330
 Thrombocytopenia000
 Anemia2430
Nonhematologic   
 Neuropathy10100
 Anorexia500
 Malaise/fatigue1550
 Myalgia/arthralgia000
 Hypersensitivity reaction300

QoL

Interpretation of the QoL data was limited severely by the poor compliance with this portion of the study. Complete data that included QoL assessment at the time of disease progression and 5 weeks later was available in only 28 of 62 patients. Analysis of the QoL data examined change in the TOI-L and the TOI-TAX from the initiation of first-line carboplatin plus paclitaxel (T1), to the time of disease progression (T2), to the assessment conducted 5 weeks into the administration of second-line paclitaxel (T3). A repeated-measures general linear model demonstrated that TOI-L scores remained stable across all three time points (F[2,54] = 0.15; P = 0.86). Change in the TOI-TAX was also statistically nonsignificant (F[2,54] = 2.34; P = 0.105). The mean differences were of a magnitude that may be considered clinically significant, although the greatest decrease in this measure of QoL occurred prior to the initiation of second-line therapy.

Response and Survival

Table 2 shows the response rate to weekly, low-dose paclitaxel in the second-line setting. Overall, an 8.1% objective response rate was seen, with 5 of 62 patients achieving a PR. All five responses were seen in Subgroup 2, producing an 18% response rate within that subgroup. Four of these five patients had responded to first-line carboplatin plus paclitaxel, whereas one patient had SD as their best response. A 37.1% rate of SD was seen and was similar among the three subgroups. Continued progression of disease was seen in 45.2% of patients, and 11% of patients discontinued treatment prior to the first response assessment at 8 weeks. This study consisted of three parallel Phase II trials (for the three subgroups identified by the first-line trial13). The goal for each subgroup was to have at least 4 of 27 patients achieve a CR, a PR, or SD, with at least 1 of these responses occurring among the first 13 patients. All subgroups achieved the response or SD goals, even though Subgroups 1 and 3 only enrolled 16 patients and 18 patients, respectively. Twenty-eight patients were enrolled in Subgroup 2, with 5 PRs and 10 patients achieving SD. Thus, for all three subgroups, we can conclude that the therapy was effective according to the two-stage design rules discussed above (see Statistical Analysis).

The median survival of all 62 patients from the initiation of second-line, weekly, low-dose paclitaxel was 5.2 months (95% confidence interval [95%CI], 3.6–6.2 months). The 1-year and 2-year survival rates were 20% (95%CI, 10–30%) and 9% (95%CI, 1–16%), respectively (Fig. 1). Table 4 shows the survival data for the three subgroups from the initiation of both first-line treatment with carboplatin plus paclitaxel and second-line, weekly, low-dose treatment with paclitaxel. Survival was poorest for the patients in Subgroup 1 compared with Subgroups 2 and 3, particularly when measured from the start of first-line therapy. This is due to the inherent refractoriness of Subgroup 1 patients to systemic chemotherapy compared with patients in the other two subgroups. When evaluating survival from the initiation of second-line, low-dose, weekly paclitaxel, Subgroup 1 had a median survival of 3.6 months (95%CI, 2.4–6.2) compared with a median survival of 5.2 months and 6.9 months (95%CI, 4.0–8.0) for Subgroup 2 and 3 (log-rank test; P = 0.12), respectively. The estimated percent of patients alive at 1 year was 6% (95%CI, 0–18%) for Subgroup 1 versus 25% (95%CI, 13–38%) for Subgroups 2 and 3 (Fisher exact test; P = 0.16).

thumbnail image

Figure 1. Survival from the start of second-line therapy of patients who received second-line weekly paclitaxel. For the median, 1-year, and 2-year survival data, see Table 4.

Download figure to PowerPoint

Table 4. Survival
ParameterAll patientsSubgroup
123
  • 95% CI: 95% confidence interval.

  • a

    P < 0.0001.

Total patients62162818
Survival from the start of first-line treatment    
 Median months (95% CI)11.0 (9.3–12.5)5.8 (3.8–7.6)a12.2 (10.9–19.6)12.1 (10.2–15.7)
 1-yr % (95% CI)40.0 (28.0–53.0)13.0 (0.0–29.0)50.0 (31.0–69.0)50.0 (27.0–73.0)
 2-yr % (95% CI)17.0 (8.0–27.0)0.028.0 (11.0–45.0)17.0 (0.0–34.0)
Survival from the start of second-line treatment    
 Median months (95% CI)5.2 (3.6–6.2)3.6 (2.4–6.2)6.9 (3.6–8.9)5.2 (3.6–6.0)
 1-yr % (95% CI)20.0 (10.0–30.0)6.0 (0.0–18.0)31.0 (13.0–48.0)17.0 (0.0–34.0)
 2-yr % (95% CI)9.0 (1.0–16.0)0.015.0 (2.0–29.0)0.0

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Although first-line, platinum-based chemotherapy improves survival and palliates disease-related symptoms in patients advanced, metastatic NSCLC, nearly all patients eventually will experience disease progression. Two recently reported trials,4, 5 which examined the impact of docetaxel as second-line therapy in patients who experienced disease progression after receiving first-line, platinum-based therapy, represent pivotal trials, because they demonstrated that chemotherapy can have an impact on survival and palliation in this setting. Because the role of chemotherapy has expanded to include patients with Stage III NSCLC17 (and, eventually, perhaps patients with Stage I and II NSCLC as well), second-line therapy likely will play a larger role in the overall management of patients with NSCLC. The two randomized trials mentioned above not only documented a benefit for these patients, they provided a rationale for continued clinical investigation in this area.

Carboplatin plus paclitaxel remains the most commonly used first-line regimen for the treatment of patients with advanced, metastatic NSCLC in the United States.8 Insufficient data exist with regard to the optimal sequencing of various antineoplastic agents in the overall management of patients with NSCLC. One concern is the efficacy of a taxane in the second-line setting when a taxane has been used as first-line therapy. In the trial by Shepherd et al.,4 previous taxane exposure was an exclusion criteria. In the trial by Fossella et al.,5 approximately 82 of 250 patients (33%) who were randomized to receive docetaxel had received prior paclitaxel. In a subset analysis, prior paclitaxel exposure did not appear to affect the likelihood of response, nor did it have a differential impact on overall or 1-year survival. Although the results were somewhat reassuring, insufficient information was provided in that trial to instill confidence about this issue. No information was provided regarding the prior response to paclitaxel and the interval from first-line platinum plus paclitaxel to second-line docetaxel. These factors may have an impact on the response rate of a single agent in the second-line setting, as noted above. In our subgroup analysis, patients who initially were refractory to first-line carboplatin plus paclitaxel (Subgroup 1) had no response to low-dose, weekly paclitaxel. However, patients who initially were responsive or had SD (Subgroups 2 and 3) had an overall response rate of 11% (pooled data from Subgroups 2 and 3).

The results from previous studies that involved paclitaxel as second-line therapy (summarized in Table 5) were somewhat inconsistent and disappointing.18–23 The characteristics of patients regarding first-line regimens, response to those regimens, and time from the first-line regimen often are not reported in sufficient detail to fully evaluate the trials. Most of the trials have every 3-week administration schedules with doses ranging from 140 mg/m2 to 250 mg/m2 and infusion schedules of 1 hour, 3 hours, 24 hours, and 96 hours. Combining the patients reported in these trials, the pooled overall reported response rate was 10% with a range across all studies of 0–38%. Survival is difficult to assess in this group of patients, because these trials generally were small in patient numbers and did not report this end point consistently.

Table 5. Activity of Single-Agent Paclitaxel in Second-Line Therapy for Patients with Nonsmall Cell Lung Carcinoma
StudyNo. of patientsDose (mg/m2)Schedule (hours)RR (%)Comments
  • RR: response rate; NR: Not reported.

  • a

    Phase I trial.

Murphy et al.1840175243Marginal response, 20%
Ruchdeschel et al.19142502414Alive 6–11 + months, 36%
Tan et al.2011135–400a3/249
Hainsworth et al.21     
 16200138
 1013510
Nauman et al.2216130–175NRNRMedian survival, 10 months; 1-year survival, 45%
Socinski et al.2313140960Stable disease, 23%
Chang et al.101380Weekly (3 of 4)NR

Patient selection undoubtedly influences the outcome of any trial, and trials that enroll few patients are at the greatest risk of bias based on this issue. Two recent trials that evaluated the activity of gemcitabine in the second-line setting are good examples. Crino and colleagues24 reported a 19% response rate to gemcitabine (1000 mg/m2 on Days 1, 8, and 15 every 28 days) in a group of patients with refractory NSCLC who failed first-line therapy. Of 83 patients, 34 patients (41%) had Stage III NSCLC, and 56 patients (67%) had either a response or SD while on first-line therapy. The median time from the completion of first-line therapy to the start of second-line gemcitabine was 22 weeks. The median survival was 7.9 months, and the 1-year survival rate was 45%. By contrast, Gillenwater and colleagues25 reported a 6% response rate to gemcitabine (1250 mg/m2 on Days 1, 8, and 15 every 28 days) in a group of 33 patients with Stage IV NSCLC. Seventy-four percent of those patients had refractory disease that was defined as progression on or within 3 months of first-line therapy. The median time from the completion of first-line therapy to the start of second-line gemcitabine was 14 weeks. The median survival was 5.1 months, and the 1-year survival rate was 16%.

Table 6 compares the data reported in this trial with the data from the recently completed randomized trials that evaluated the role of docetaxel in this setting. In general, the patients who were included in these trials were similar demographically, with the exception of exposure to a first-line taxane. In our trial, all patients had received first-line carboplatin plus paclitaxel, whereas exposure to a previous taxane was an exclusion criteria in the trial by Shepherd et al.,4 and only 33% of patients in the trial by Fossella et al.5 had received a previous taxane. The impact of this difference in patients entered onto these various trials is uncertain. Also, in the two docetaxel trials,4, 5 no data were given with regard to the time interval from first-line to second-line therapy. The overall response and disease stabilization rates for low-dose weekly paclitaxel were similar to the rates achieved in the two docetaxel trials. Although the median survival was similar, our 1-year survival rate appears to be somewhat lower. However, the lower 1-year survival may be attributable to the differences in first-line exposure to a taxane noted above. It also should be noted that our trial included more patients with a less favorable PS, which also may account for this difference.

Table 6. Comparison of Weekly Low-Dose Paclitaxel with Recent Randomized Trials of Second-Line Treatment in Patients with Advanced Nonsmall Cell Lung Carcinoma
VariableDocetaxel 75 mg/m2VNR/IFF (Fossella et al.5)Weekly paclitaxela
Shepherd et al.4Fossella et al.5
  • VNR: vinorelbine; IFF: ifosfamide; NR: not reported; PS: performance status; PR: partial response; CR: complete response; PD: progressive disease.

  • a

    Current study.

  • b

    From Table 1: Karnofsky PS 80-100 = PS 0-1; Karnofsky PS 60-70 = PS 2.

  • c

    Represents both PR/CR and stable disease.

Demographic factors    
 No. of patients5512512362
 Male (%)64666555
 Median age in yrs (range)61 (37–73)59 (NR)60 (NR)62 (32–76)
 Stage IIIA/IIIB (%)2710911
 Stage IV (%)73909189
 PS 0–1 (%)74828558b
 PS 2 (%)26181542b
 Percentage receiving first-line taxane03433100
Best response to first-line therapy    
 PR/CR (%)3423
 Stable (%)4867c68c52
 PD (%)18333226
Second-line results    
 Response rate (%)    
  PR/CR5.56.70.88.1
  Stable43.036.031.035.0
 Survival    
  Median (months)7.55.75.65.2
  One year (%)37.032.019.020.0

The toxicity profile of low-dose, weekly paclitaxel in this setting is quite favorable. No significant hematologic toxicity was seen. In comparison, 8% of the patients who received docetaxel at a dose of 75 mg/m2 experienced Grade 4 febrile neutropenia in the report by Fossella and colleagues.5 Nonhematologic toxicity was minimal in that study, with the exception of peripheral neuropathy. Most patients who experienced Grade 2–3 peripheral neuropathy on second-line weekly paclitaxel had some degree of peripheral neuropathy on first-line weekly paclitaxel (11 of 12 patients). Eight of 12 patients (two-thirds) experienced a worsening of their neuropathy, whereas 4 of 12 patients (one-third) did not.

It is significant that QoL, as measured by physical and functional well-being, lung carcinoma specific concerns, and self-reported neurotoxicity/taxane toxicity, remained roughly stable during the first 5 weeks of the administration of second-line therapy. In this case of a life-threatening illness that will be fatal within a short time, the maintenance of QoL is a worthy goal. In addition, the stability of functional well-being suggests that the average patient is able to continue to engage in daily functioning and activities that may provide meaning to that shortened life. Although it may not be significant statistically, it also appears that the majority of treatment toxicity that is discernible to, and reportable by, the patient occurs during the administration of first-line therapy rather than during receipt of the subsequent paclitaxel. These results must be qualified, however, by the small number of patients for whom QoL data were available: These findings, therefore, await confirmation in a larger sample.

In summary, it has been shown that second-line treatment of patients who progress after receiving first-line platinum-based regimens provides a benefit in terms of both survival and QoL.4, 5 The selection of patients who are most likely to benefit from second-line treatment is complicated by the treatment response and toxicity profile experienced by patients in the first-line setting. Although favorable prognostic factors from second-line treatment have not been identified clearly, undoubtedly performance status, previous response, and a reasonable progression free interval are likely to be important selection factors. Our data support a role for treatment with low-dose, weekly paclitaxel for selected patients who experience disease progression after receiving first-line treatment with carboplatin plus paclitaxel. Also, the toxicity profile of low-dose, weekly paclitaxel is extremely favorable, which is an advantage in this pretreated population. Given the number of regimens currently used in the first-line setting for patients with advanced, metastatic NSCLC, further study is needed in the second-line setting to better define the optimal approach for a given patient.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  • 1
    Greenlee RT, Hill-Harmon MD, Murray T, Thun M. Cancer statistics, 2001. CA Cancer J Clin. 2001; 51: 1536.
  • 2
    Ihde DC, Minna JD. Non-small cell lung cancer. Part I: biology, diagnosis, and staging. Curr Probl Cancer. 1991; 15: 61104.
  • 3
    Bunn PA Jr., Kelly K. New Chemotherapeutic agents prolong survival and improve quality of life in non-small cell lung cancer: a review of the literature and future directions. Clin Cancer Res. 1998; 4: 10871100.
  • 4
    Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol. 2000; 18: 20952103.
  • 5
    Fossella FV, Devore R, Kerr RN, et al. Randomized Phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small cell lung cancer previously treated with platinum-containing regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol. 2000; 18: 23542360.
  • 6
    Dancey J, Shepherd F, Ramlau R, et al. Quality of life (QoL) assessment in randomized study of taxotere (TAX) versus best supportive care (BSC) in non-small cell lung cancer (NSCLC) patients (pts) previously treated with platinum-based chemotherapy [abstract]. Proc Am Soc Clin Oncol. 1999; 18: 491a.
  • 7
    Miller VA, Fossella FV, Devore R, et al. Docetaxel (D) benefits lung cancer symptoms and quality of life (QoL) in a randomized Phase III study of non-small cell lung cancer (NSCLC) patients previously treated with platinum-based therapy [abstract]. Proc Am Soc Clin Oncol. 1999; 18: 491a.
  • 8
    Choy H, Shur Y, Cmelak AJ, Mohr PJ, Johnson DH. Patterns of practice survey for non-small cell lung cancer in the U.S. Cancer. 2000; 88: 13361346.
  • 9
    Belani CP. Interim analysis of a Phase II study of induction weekly paclitaxel/carboplatin regimens followed by maintenance weekly paclitaxel for advanced and metastatic non-small cell lung cancer. Semin Oncol. 2001; 28(4 Suppl 14 ): 1416.
  • 10
    Chang AY, Rubins J, Asbury R, Boros L, Huc LF. Weekly paclitaxel in advanced non-small cell lung cancer. Semin Oncol. 2001; 28(4 Suppl 14 ): 1013.
  • 11
    Alvarez AM, Mickiewicz E, Brosio C, et al. Reinduction of response with weekly taxol (T) in advanced breast cancer (ABC) [abstract]. Proc Am Soc Clin Oncol. 1999; 18: 165a.
  • 12
    Fennelly D, Aghajanian C, Shapiro F, et al. Phase I and pharmacologic study of paclitaxel administered weekly in patients with relapsed ovarian cancer. J Clin Oncol. 1997; 15: 187192.
  • 13
    Socinski MA, Schell MJ, Peterman A, et al. A Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced Stage IIIB/IV non-small cell lung cancer. J Clin Oncol. 2002; 20: 13351343.
  • 14
    Cella DF, Bonomi AE, Lloyd SR, Tulsky PS, Kaplan E, Bonomi P. Reliability and validity of the Functional Assessment of Cancer Therapy-Lung (FACT-L) quality of life instrument. Lung Cancer. 1995; 12: 199220.
  • 15
    Cella D. Manuel of the Functional Assessment of Chronic Illness Therapy (FACIT) scales. Evanston: Center on Outcomes, Research, and Education, 1997.
  • 16
    Simon R. Optimal two-stage designs for Phase II clinical trials. Control Clin Trials. 1989; 10: 110.
  • 17
    Hensing TA, Socinski MA. Combined modality therapy in the non-surgical management of unresectable Stage III non-small cell lung cancer. Curr Opin Pulm Med. 1999; 5: 194200.
  • 18
    Murphy WK, Winn RJ, Huber M. Phase II study of taxol in patients with non-small cell lung cancer who have failed platinum containing chemotherapy [abstract]. Proc Am Soc Clin Oncol. 1994; 13: 363a.
  • 19
    Ruchdeschel J, Wagner H, Williams C. Second-line chemotherapy for resistant metastatic non-small cell lung cancer: the role of taxol [abstract]. Proc Am Soc Clin Oncol. 1994; 13: 357a.
  • 20
    Tan V, Herrera C, Einzig AI. Taxol is active as a 3-hour or 24-hour infusion non-small cell lung cancer [abstract]. Proc Am Soc Clin Oncol. 1995; 14: 366a.
  • 21
    Hainsworth JD, Thompson DS, Greco FA. Paclitaxel by 1-hour infusion: an active drug in metastatic non-small cell lung cancer. J Clin Oncol. 1995; 13: 16091614.
  • 22
    Nauman C, DeLaney TF, Park J, Zaner KS. Paclitaxel (Taxol®) as a single agent salvage therapy in non-small cell lung cancer (NSCLC) [abstract]. Proc Am Soc Clin Oncol. 1997; 16: 476a.
  • 23
    Socinski MA, Steagall A, Gillenwater H. Second-line chemotherapy with 96-hour infusion paclitaxel in refractory non-small cell lung cancer. Report of a Phase II trial. Cancer Invest. 1999; 17: 181188.
  • 24
    Crino L, Mosconi AM, Scagliotti G, et al. Gemcitabine as second-line treatment for advanced non-small cell lung cancer: a Phase II trial. J Clin Oncol. 1999; 17: 20812085.
  • 25
    Gillenwater HH, Tynan M, Natoli S, Schell MJ, Socinski MA. Second-line gemcitabine in refractory Stage IV non-small cell lung cancer: a Phase II trial. Clin Lung Cancer. 2000; 2: 133138.