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Keywords:

  • small cell lung cancer;
  • second-line chemotherapy;
  • prognostic factor;
  • performance status;
  • sensitive recurrence;
  • refractory recurrence

Abstract

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

BACKGROUND

To the authors' knowledge, the prognostic factors in recurrent small cell lung cancer (SCLC) patients treated with second-line chemotherapy have not yet been clearly identified to date.

METHODS

Between July 1992 and December 2003, 232 of 515 patients who were diagnosed to have SCLC at the National Cancer Center Hospital East were administered second-line chemotherapy for recurrent disease. The authors retrospectively analyzed the relation between clinical factors evaluated at the time of recurrence and the response to second-line chemotherapy or survival in these patients.

RESULTS

The results of univariate analyses revealed that response was significantly associated with the performance status (PS) alone, whereas survival was significantly associated with the PS, disease extent, and sensitivity to first-line chemotherapy. Multivariate analysis identified PS (P < .0001) and sensitivity to first-line chemotherapy (P = .0024) as the independent prognostic factors for survival. When the patients were grouped according to these 2 significant prognostic factors, the survival of patients with a PS of 0 to 1 was significantly better than that of the patients with a PS of 2 to 4 both among cases that were sensitive and those that were refractory to first-line chemotherapy. Although the survival of sensitive recurrent cases was significantly better than that of the refractory recurrent cases among the patients with a PS of 0 to 1 patients, no survival difference was observed between the sensitive and refractory recurrent cases in the patients with a PS of 2 to 4.

CONCLUSIONS

Both PS and sensitivity to initial chemotherapy were found to be significant prognostic factors for survival in recurrent SCLC patients treated with second-line chemotherapy. These 2 factors should therefore be used as stratification factors in future clinical trials. Cancer 2008. © 2008 American Cancer Society.

Although the proportion of small cell lung cancer (SCLC) among cases of lung cancer has been decreasing in recent years, it still accounts for 14% of all new lung cancer cases, and the actual number of patients was estimated to be 77,000 in the US and Europe in 2004.1 In general, SCLC is an exceedingly aggressive cancer, and greater than 66% of patients have clinically obvious metastatic disease at the time of diagnosis.2 SCLC is also extremely sensitive to chemotherapy; therefore, the main treatment strategy for SCLC is systemic chemotherapy. Currently, both cisplatin plus etoposide (PE) and cisplatin plus irinotecan (IP) are considered as standard chemotherapeutic regimens for SCLC.3, 4 Despite the high initial sensitivity to chemotherapy, the majority of patients develop disease recurrence. The prognosis of patients with recurrent SCLC is usually abysmal, and the overall survival time after recurrence is reportedly 2 to 4 months.5

In general, second-line chemotherapy is considered for cases with recurrent SCLC, and a few studies have reported on the efficacy of some second-line treatments.6, 7 For example, a prospective randomized trial comparing oral topotecan with best supportive care (BSC) revealed the benefits of treatment with oral topotecan in terms of the survival and quality of life.7

Although some studies have shown the importance of both response and the duration of the response to initial chemotherapy in predicting the efficacy of second-line chemotherapy,8–10 the number of studies conducted to identify the prognostic factors in recurrent SCLC patients is quite limited. In this retrospective study, we investigated the prognostic factors in recurrent SCLC patients administered second-line chemotherapy to determine the factors that need to be used for stratifying the patients in future clinical trials.

MATERIALS AND METHODS

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

Patient Flow

Between July 1992 and December 2003, 515 patients were diagnosed to have SCLC at the National Cancer Center Hospital East, and 474 of these patients received initial chemotherapy with or without thoracic radiotherapy. Of 474 patients, radiographic response was observed in 409 patients, with 98 demonstrating complete response and 311 demonstrating partial response. An evaluation in April 2007 revealed that among these responders, 322 had developed disease recurrence, 75 had maintained responses, and 12 patients could not be evaluated for disease recurrence. Thus, 387 patients (including the 322 with disease recurrence and the 65 nonresponders) were considered potential candidates for second-line chemotherapy. Of these, 232 received second-line chemotherapy, whereas the remaining 155 did not. There were no distinct eligibility criteria for second-line chemotherapy, and the decision to administer chemotherapy was based on the patient's general condition and willingness to undergo second-line therapy. The patient flow is shown in Figure 1. Among patients who received second-line chemotherapy, those who deemed to have stable disease or not to be evaluable to first-line chemotherapy were treated right after completion of front-line therapy. All patients' data were obtained from our database.

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Figure 1. Patient flow is depicted. CR indicates complete response; NE, not evaluable; PD, progressive disease; PR, partial response; Pts, patients; SCLC, small-cell lung cancer; SD, stable disease; +, positive; −, negative.

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Analyzed Clinical Factors

The correlations between clinical factors evaluated at the time of disease recurrence, such as the age (<70/≥70), sex (women/men), Eastern Cooperative Oncology Group performance status (PS) (0-1 or 2-4), disease extent (limited disease [LD]/extensive disease), sensitivity to first-line chemotherapy (sensitive/refractory), and response to second-line chemotherapy or survival after disease recurrence were retrospectively investigated in the 232 patients. In this study, patients who responded to initial chemotherapy and developed disease recurrence more than 3 months after the completion of chemotherapy were defined as sensitive recurrence cases, whereas patients who did not respond to initial chemotherapy or developed disease recurrence within 3 months were defined as refractory recurrence cases.

Tumor Evaluation and Statistical Analysis

Tumor response was re-evaluated by 2 physicians (Y.H.K. and K.G.) using the Response Evaluation Criteria in Solid Tumors (RECIST).11 The survival time was measured from the date of disease recurrence. The survival curve was estimated by the Kaplan-Meier method, and compared by the log-rank test. Comparison between each clinical factor and response was performed by the chi-square test. Multivariate analysis was conducted according to the Cox proportional hazard model. P < .05 was considered to denote statistical significance. All statistical analyses were performed using StatView statistical software (version 5.0; Abacus Concepts, Berkley, Calif).

RESULTS

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

Patient Characteristics

The characteristics of the 387 patients who were believed to be potential candidates for second-line chemotherapy (of whom only 232 eventually received second-line chemotherapy, designated as the chemotherapy group) are listed in Table 1. The patients in the chemotherapy group were significantly younger (P < .0001), had better PS (P < .0001), and had a higher frequency of LD (P = .0476) than the nonchemotherapy group. Whereas the response to first-line chemotherapy was significantly different (P < .0001), the sensitivity to first-line chemotherapy was not significantly different (P = .1661) between the 2 groups, and approximately 33% of the patients who received second-line chemotherapy were refractory recurrence cases. As first-line chemotherapy, 156 patients (67%) had received platinum plus etoposide combination chemotherapy, and 24 (10%) had received the IP regimen. The second-line chemotherapy regimens administered to the 232 patients are listed in Table 2. At our hospital, the vast majority of the patients had received some kind of platinum-based combination chemotherapy, such as cisplatin, vincristine, doxorubicin, and etoposide; cisplatin, etoposide, and irinotecan (PEI); IP; PE; or carboplatin plus etoposide. The distribution of these regimens was similar in the sensitive and refractory recurrence patients.

Table 1. Characteristics of All Patients at the Time of Disease Recurrence (N = 387)
CharacteristicsSecond-line ChemotherapyP
(+) (n=232)(−) (n=155)
  1. + indicates positive; −, negative; PS, performance status; LD, limited disease; ED, extensive disease; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.

Age at recurrence, y  <.0001
 Median6568 
 Range30-8028-87 
Gender  .9867
 Women38 (16%)25 (16%) 
 Men194 (84%)130 (84%) 
PS at recurrence  <.0001
 0-1162 (70%)43 (28%) 
 2-470 (30%)112 (72%) 
Disease extent at recurrence  .0476
 LD65 (28%)30 (19%) 
 ED167 (72%)125 (81%) 
Response to first-line chemotherapy  <.0001
 CR/PR216 (93%)108 (70%) 
 SD/PD16 (7%)47 (30%) 
Sensitivity to first-line chemotherapy  .1661
 Sensitive146 (63%)63 (41%) 
 Refractory86 (37%)92 (59%) 
Table 2. Second-line Chemotherapy Regimens Administered to 232 Patients
RegimenNo. of PatientsNo. Sensitive (%)No. Refractory (%)
  1. CODE indicates cisplatin, vincristine, doxorubicin, and etoposide; PEI, cisplatin, etoposide, and irinotecan; IP, cisplatin and irinotecan; PE, cisplatin and etoposide; CE, carboplatin and etoposide; TOP, topotecan; CPT-11, irinotecan; AMR, amrubicin.

CODE8050 (34)30 (35)
PEI4417 (12)27 (31)
IP3428 (19)6 (7)
PE1913 (9)6 (7)
CE1412 (8)2 (2)
TOP149 (6)5 (6)
CPT-11139 (6)4 (5)
AMR65 (4)1 (1)
Others83 (2)5 (6)
Total232146 (100)86 (100)

Predictive and Prognostic Factors

According to the results of the univariate analyses, response was significantly associated with the PS alone, whereas survival was significantly associated with the PS, disease extent, and sensitivity to first-line chemotherapy (Table 3). Survival curves drawn according to the PS and sensitivity to first-line chemotherapy are shown in Figure 2 and 3, respectively. Multivariate analysis identified PS (P < .0001) and sensitivity to first-line chemotherapy (P = .0024) as the independent prognostic factors for survival (Table 4). The survival of patients with a PS of 2 to 4 (P = .005) (Fig. 2) and refractory disease recurrences (P < .0001) (Fig. 3) was significantly better than that of those who did not receive second-line chemotherapy.

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Figure 2. Survival curves according to the performance status (PS) at the time of disease recurrence. + indicates positive; −, negative.

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Figure 3. Survival curves according to sensitivity to first-line chemotherapy. + indicates positive; −, negative.

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Table 3. Univariate Analysis for Response and Survival
CharacteristicsNo. of PatientsResponse Rate, %PMST, MonthsP
  1. MST indicates median survival time; PS, performance status; LD, limited disease; ED, extensive disease.

Age at recurrence, y     
 <7016756.50589.0.6347
 ≥706562 8.8 
Gender     
 Women3868.182610.0.5672
 Men19455 8.7 
PS at recurrence     
 0-116263.012611.0<.0001
 2-47044 4.9 
Disease extent at recurrence
 LD6562.508512.6.0043
 ED16756 7.3 
Sensitivity to first-line chemotherapy
 Sensitive14660.441310.6.0016
 Refractory8653 6.8 
Table 4. Multivariate Analysis for Survival
VariablesOdds Ratio95% CIP
  1. 95% CI indicates 95% confidence interval; PS, performance status; LD, limited disease.

PS at recurrence, 0-13.1712.307-4.357<.0001
Disease extent at recurrence, LD1.3080.956-1.790.093
Sensitivity to first-line chemotherapy, sensitive1.5441.166-2.043.0024

In addition, we performed further analysis, in which all patients who received second-line chemotherapy were divided into 4 groups according to the combination of the 2 identified independent prognostic factors for survival: Group A (PS of 0-1/sensitive recurrence), Group B (PS of 0-1/refractory recurrence), Group C (PS of 2-4/sensitive recurrence), and Group D (PS of 2-4/refractory recurrence). The survival curves for each group are shown in Figure 4. The survival of patients with a PS of 0 to 1 was significantly better than that of the patients with a PS of 2 to 4 among both cases with sensitive (Group A vs Group C; P < .0001) and those with refractory recurrence (Group B vs Group D; P = .0001). Whereas the survival of the sensitive recurrence cases was significantly better than that of the refractory recurrence cases among the patients with a PS of 0 to 1 (Group A vs Group B; P = .0013), no survival difference was observed between the sensitive and refractory recurrence cases among the patients with a PS of 2 to 4 patients (Group C vs Group D; P = .4252).

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Figure 4. Survival curves according to the 2 independent prognostic factors. PS indicates performance status.

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Among the 232 patients who received second-line chemotherapy, 29 received the same regimen as first-line chemotherapy, and the rest received a regimen different from first-line chemotherapy. However, these differences did not appear to have an impact on either response (P = .7519) or survival (P = .5873).

DISCUSSION

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

Some studies have shown the importance of both response and the duration of the response to initial chemotherapy in predicting the survival of recurrent SCLC patients receiving second-line chemotherapy,8–10 and currently it is widely accepted that recurrent SCLC patients should be classified into 2 groups: cases with sensitive recurrence and those with refractory recurrence.12 In contrast, Sundstrom et al, who recently analyzed 19 clinical factors at both the time of initial diagnosis and the time of recurrence, have suggested that the PS at the time of disease recurrence, and not the sensitivity status to first-line chemotherapy, was the only significant prognostic indicator for survival after second-line chemotherapy.13 In this study, we investigated the relation between clinical factors evaluated at the time of disease recurrence and survival after recurrence, and identified both PS and sensitivity to first-line chemotherapy as being significant prognostic factors for survival.

Some may argue that the survival time of the patients with a PS ≥3 in this study was too short, which might have strongly influenced the inferior survival of the patients with a PS of 2 to 4 as compared with that of the patients with a PS of 0 to 1. Although our study included 18 cases with a PS ≥3 among the patients administered second-line chemotherapy, the results of the analyses were found to be the same even after exclusion of these patients with a PS ≥3 (data not shown). This finding suggests that the prognosis of the patients with a PS of 2 is clearly different from that of the patients with a PS of 0 to 1 patients. The diversity of our second-line regimens may be criticized as well, because the differences in the regimens could have affected the patients' outcomes. However, to our knowledge, there are no comparative studies suggesting the superiority of any particular regimen for second-line chemotherapy. At our hospital, as shown in Table 2, mainly platinum-based combination chemotherapy is used even for second-line chemotherapy, and various agents are combined with platinum agents.

The results of the current study indicate that the prognosis of patients with impaired PS is inevitably poor. In such patients, no survival difference was found between the cases with sensitive and those with refractory recurrence. Does this mean that patients with a PS ≥2 should not receive second-line chemotherapy? A phase 3 trial comparing oral topotecan with BSC demonstrated a significant survival advantage of oral topotecan, and such survival benefit was also found to be preserved for patients with a PS of 2 who accounted for approximately 30% of the enrolled patients.7 Conversely, with regard to the patients with a PS ≥3, there is no evidence as yet to suggest the clinical benefit of administering second-line chemotherapy. In our study, however, response rates of 64% in patients with a PS of 3 (n = 14) and 25% in patients with a PS of 4 (n = 4) were observed. These results suggest that second-line chemotherapy might be beneficial for adequately selected patients with a PS of ≥2, although the survival benefit is limited as compared with that for the patients with a PS of 0 to 1. Further studies are required for precise selection of criteria for second-line chemotherapy.

In this study, the survival of patients who received second-line chemotherapy with a PS of 2 to 4 or refractory recurrences was still significantly better than that of those who did not receive second-line chemotherapy. However it was not surprising, because the patient selection for second-line chemotherapy was performed pragmatically, and patients who were thought to be unfit for chemotherapy were not administered second-line chemotherapy. The finding that the nonchemotherapy group had more patients with a PS of 2 to 4 and refractory recurrence, the 2 independent prognostic factors identified in this study, suggests that our patient selection was reasonable.

The prognosis of recurrent SCLC patients is generally poor, and to our knowledge no standard treatment has been established for these patients. In addition to the randomized trial comparing oral topotecan with BSC mentioned above, 2 phase 3 trials for recurrent SCLC have been reported to date.14, 15 A trial comparing intravenous topotecan with the combination of cyclophosphamide, doxorubicin, and vincristine demonstrated comparable response rates and survival; however, intravenous topotecan yielded greater symptomatic improvement for 4 of the 8 symptoms evaluated.14 In the other trial, comparing oral topotecan with intravenous topotecan, no survival difference was observed.15 Currently, topotecan is the only drug approved by the US Food and Drug Administration for recurrent SCLC. Recently, however, promising results of phase 2 studies have been reported for drugs other than topotecan for recurrent SCLC. In particular, amrubicin16, 17 and PEI18, 19 have been shown to yield excellent response rates and survival in not only sensitive but also refractory recurrent cases. In Japan, a phase 3 randomized trial comparing topotecan with PEI is now ongoing.

In conclusion, we identified PS and sensitivity to initial chemotherapy as being significant prognostic factors for survival in patients with recurrent SCLC treated with second-line chemotherapy. PS was also found to be predictive in terms of response. In future clinical trials of second-line chemotherapy, both PS and sensitivity to initial chemotherapy should be incorporated as stratification factors. The survival benefit of second-line chemotherapy is limited in patients with impaired PS, even among sensitive recurrence cases. Therefore, careful consideration of the potential risks and benefits is required in the treatment of these patients.

REFERENCES

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