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Keywords:

  • advanced stage;
  • long-term survival;
  • maintenance therapy;
  • non-small cell lung cancer

ABSTRACT

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Background and objective:  Only a small proportion of patients with advanced non-small cell lung cancer (NSCLC) have a life expectancy greater than 2 years. The aim of this study was to identify the factors associated with long-term survival of patients with advanced NSCLC.

Methods:  Patients who had received chemotherapy for stage IIIb or IV NSCLC that was not amenable to radiotherapy were studied retrospectively. Data were gathered prospectively from a comprehensive database. Long-term survivors (>2 years) were compared with the other patients, with respect to clinical, biological and tumour–node–metastasis criteria.

Results:  Data for 245 consecutive patients were collected. Thirty nine patients (15.9%) survived for more than 2 years. Long-term survivors were more likely to have had metastases at fewer sites (P = 0.008), an absence of bone metastases (P = 0.01), a performance status (PS) of 0–1 at first progression of the tumour (P = 0.002), a tumour that was controlled with first (P < 0.0001) and second-line (P = 0.004) chemotherapy, maintenance therapy (P = 0.001), curative surgery (P < 0.0001), time to first progression of the tumour of >3 months (P < 0.0001), normal LDH levels at diagnosis (P = 0.049), and a haemoglobin concentration >110 g/L at first progression of the tumour (P = 0.02). In multivariate analysis, surgery, maintenance treatment, time to first progression of the tumour of >3 months, a PS of 0–1 at first progression, the number of chemotherapy agents received, and LDH levels, were significant predictors of long-term survival.

Conclusions:  Assessment of these factors, and the use of maintenance therapy, when possible, may identify a population of patients with NSCLC that is likely to have a prolonged life expectancy.


INTRODUCTION

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death throughout the world.1 In over two-thirds of patients, lung cancer is diagnosed at an advanced stage and the associated mortality is high.2 Determining the prognosis for a patient with extensive NSCLC is difficult, in part because of the clinical heterogeneity of the disease.

Early identification of long-term survivors among patients with advanced NSCLC is an important issue as treatment options change. Long-term survivors have been defined as those surviving for more than 2 years after a diagnosis of extensive NSCLC. In phase III trials, the survival rates at 2 years were 18.93 and 23%,4 but in retrospective studies of unselected populations, this rate varied between 7.25 and 12.8%.6 Factors essential to decision making are the extent of disease, weight loss and performance status (PS), as these are the indicators most predictive of patient survival.6–9

In patients with a good PS, systemic chemotherapy improves median survival.10 The standard first-line therapy for patients with advanced NSCLC consists of a platinum-based combination regimen.11 Since 2000, the development of new agents, including bevacizumab, pemetrexed and erlotinib, has allowed great improvements in survival; median overall survival (OS) has increased to 12.3 months, with a 2-year survival of 23% with bevacizumab plus carboplatin–paclitaxel,4 and median OS of 12.6 months in patients with adenocarcinoma, and a 2-year survival of 18.9% with pemetrexed–cisplatin.3 Recently, pemetrexed has demonstrated efficacy as maintenance therapy in nonsquamous cell lung cancer, after first-line platinum-based therapy.12 Unfortunately, patients with NSCLC experience relapses. Currently, docetaxel, erlotinib and pemetrexed are the only approved second-line treatments with significant survival benefit for all lung cancer patients.13–15 Erlotinib, an epidermal growth factor receptor (EGFR) inhibitor, is also approved as a third line treatment.15 Improvements in first and second-line chemotherapy for NSCLC have led to a greater proportion of patients being considered for third-line treatment, increasing from 6% in the 1990s16 to 28.2% in 2009.17

The aim of this study was to estimate the number of long-term survivors among a population of patients with advanced NSCLC, and to identify tumour, host or treatment-related factors that were associated with long-term survival.

METHODS

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Patients

All patients diagnosed with lung cancer were registered in a prospective database. Data for patients diagnosed with advanced NSCLC (stages IIIb and IV, not amenable to radiotherapy) in the Respiratory Diseases Department of the Hôpital Tenon, Paris, between January 2003 and December 2006 were retrospectively reviewed to identify patients who survived long-term. Patients with stage IIIb disease not amenable to radiotherapy were those with too large field for radiotherapy and those with poor lung function.

Factors investigated

All patients presented with histologically proven NSCLC, according to the World Health Organization criteria, and tumour stage was defined according to the sixth revision of the tumour–node–metastasis classification.18

Host-related factors

For each patient, the following data were collected: age, gender, smoking status, demographic data, marital status, and co-morbidities (Charlson score19). PS, as assessed according to the Eastern Cooperative Oncology Group (ECOG) criteria, weight loss, and the presence of vena cava syndrome or peripheral adenopathies were noted at diagnosis and at the first relapse.

Tumour-related factors

For each tumour, the following characteristics were noted at diagnosis and at relapse: tumour stage, histology, metastatic status (stage IIIb vs IV), the number and localization of the different metastatic sites, the presence of pleural or pericardial effusions, the node (N) status (N0-N1 vs N2-N3), and the sites of mediastinal invasion according to the classification of Mountain and Dresler20 (right mediastinal: areas 2R, 4R; left mediastinal: areas 2L, 4L, 5, 6; subcarinal area: 7; other).

Treatment-related factors

The following data were collected for each patient: first- and second-line chemotherapy, the number of chemotherapy agents administered, the number of cycles received, the response rates to first- and second-line chemotherapy, according to the World Health Organization criteria,21 the time to progression (TTP) after first-line chemotherapy, the use of maintenance chemotherapy, and whether or not surgical resection was performed.

Biological parameters

The biological parameters assessed at diagnosis and at the time of first progression were whether the patient was anaemic (haemoglobin concentration <110 g/L), LDH level (>500 IU/L), and whether the patient was hypercalcaemic (calcium >2.5 g/L).

Statistical analyses

Normality of the data was checked using the Shapiro–Wilk test. For statistical comparisons between groups, Student's t-test was used for continuous variables with a normal distribution and the Mann–Whitney U-test was used for continuous variables that were not normally distributed. Qualitative variables were compared using the chi-square test. Survival rates were assessed using the Kaplan–Meier method. Relevant parameters that might influence survival were assessed by univariate analysis, using the log-rank test, and by multivariate analysis, using a stepwise Cox proportional hazards method. Values of P < 0.05 were considered statistically significant. Statistical analyses were performed using Xlstat software (Addinsoft, Paris, France).

Ethics committee approval

The collection of data from a prospective database conformed to the rules concerning compulsory declaration to the Commission Nationale Informatique et Libertés (CNIL). According to French law, this retrospective study was exempt from institutional review board approval.

RESULTS

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Consecutive patients (n = 256) with extensive stage IIIb or stage IV NSCLC that was not amenable to radiation were included in the database between January 2003 and December 2006. Eleven patients were not treated because of poor PS (3 or 4). Median OS for the 245 patients who were treated was 11.3 months (range 6 days to 5.1 years) with a 2-year survival of 15.9% (39 long-term survivors). Survival at 3 and 5 years was 4.1% and 0.41%, respectively. The median survival of the long-term survivors was 2.9 years (range 24.7 months to 5.1 years), compared with 9.5 months for the other patients (range 6 days to 23.9 months)

Host-related factors

There were no significant differences in age, gender or smoking status between the long-term survivors and the other patients (Table 1). A good PS at diagnosis was not significantly associated with long-term survival, although a trend was detected (P = 0.06). However, a good PS at first progression of the tumour was significantly associated with long-term survival (88%, vs 63% for the other patients, P = 0.02).

Table 1.  Clinical, biological and tumour-related data
 LS− (n = 206)LS+ (n = 39)All patients (n = 245)P value
  • Data are numbers (%) of patients unless indicated otherwise.

  •  

    Student's t-test.

  •  

    Chi-square test.

  • LS+, long-term survivors; LS−, non-long-term survivors; NSCLC, non-small cell lung cancer; PS, performance status.

Age, years, mean (range)61.66 (25–85)61.39 (33–91)61.61 (25–91)0.89
Gender   0.47
 Males142 (69)24 (62)166 (68) 
 Females64 (31)15 (38)79 (32) 
Tobacco   0.19
 Nonsmokers25 (12)9 (23)34 (14) 
 Former smokers70 (35)13 (33)83 (34) 
 Smokers108 (53)17 (44)125 (52) 
 Missing values303 
Initial PS   0.06
 0–1159 (78)32 (82)191 (78) 
 ≥246 (22)7 (18)53 (22) 
 Missing values101 
PS at first progression of tumour   0.02
 0–1106 (63)29 (88)135 (67) 
 ≥263 (37)4 (12)67 (33) 
 Missing values303 
Weight loss >10%   0.74
 Yes45 (22)7 (18)51 (21) 
 No156 (78)31 (82)187 (79) 
 Missing values516 
Charlson score   0.66
 0106 (51)17 (44)123 (50) 
 1–273 (35)15 (38)88 (36) 
 3–419 (9)4 (10)23 (9) 
 >45 (2)0 (0)5 (2) 
Anaemia (Hb <110 g/L)    
 Initial28 (14)3 (8)31 (13)0.45
 At first progression of tumour64 (38)3 (9)67 (33)0.002
 Missing values (first progression)404 
LDH ≥500 IU/L    
 Initial43 (23)2 (6)45 (20)0.049
 Missing values17623 
 At first progression39 (27)5 (17)36 (25)0.67
 Missing values701686 
Hypercalcaemia    
 Initial11 (6)2 (6)13 (6)0.72
 Missing values13316 
 At first progression of tumour5 (4)2 (13)7 (5)0.43
 Missing values551772 
Lung cancer stage   0.14
 IIIb26 (13)9 (23)35 (14) 
 IV180 (87)30 (77)210 (86) 
Histology   0.73
 Squamous cell45 (22)7 (18)52 (21) 
 Adenocarcinoma111 (54)23 (59)134 (55) 
 Large cell18 (9)5 (13)23 (9) 
 NSCLC and other33 (15)4 (10)37 (15) 
Number of sites of metastasis   0.008
 026 (12)9 (23)35 (14) 
 196 (47)24 (62)120 (49) 
 >184 (41)6 (15)90 (37) 
Adrenal metastasis    
 Initial42 (20)4 (10)46 (19)0.21
 Apparent at first progression of tumour9 (6)0 (0)9 (5)0.35
 Missing values (first progression)12113 
Brain metastasis    
 Initial44 (21)3 (8)47 (19)0.08
 Apparent at first progression of tumour9 (6)3 (9)12 (6)0.7
 Missing values (first progression)12113 
Liver metastasis    
 Initial35 (17)4 (10)39 (17)0.41
 Apparent at first progression of tumour8 (5)3 (9)11 (6)0.59
 Missing values (first progression)12113 
Bone metastasis    
 Initial73 (35)5 (17)78 (32)0.01
 Apparent at first progression of tumour18 (11)0 (0)18 (9)0.09
 Missing values (first progression)12113 
Lung metastasis    
 Initial84 (41)22 (56)106 (43)0.1
 Apparent at first progression of tumour8 (5)2 (6)10 (5)0.87
 Missing values (first progression)12113 
Node status   0.74
 N0-N167 (33)14 (36)81 (34) 
 N2-N3133 (67)23 (64)156 (66) 
 Missing values (first progression)527 

Tumour-related factors

Long-term survivors more often had a single site of metastasis (62% vs 41%, P = 0.008) (Table 1). There were no significant differences in histology of the tumour, the frequency of stage IIIb versus stage IV disease, or the frequency of lymph node invasion between the two groups. Long-term survivors were less likely to have bone metastases at diagnosis (long-term survivors 17% vs other patients 35%, P = 0.01). The distribution of other sites of metastasis was similar for the two groups.

Treatment-related factors

There were major differences in therapy for long-term survivors compared with that for the other patients (Table 2). Eighteen percent of long-term survivors underwent surgery (five for pulmonary metastasis, two with stage IIIb disease), compared with only 2% of the other patients (one with a brain metastasis, one with a pulmonary metastasis, one with an adrenal metastasis, one with bone and liver metastases) (P < 0.0001). Patients who underwent surgery received adjuvant radiotherapy if they had pN2-N3 disease or parietal invasion. The median survival of patients who underwent surgery was 3.8 years.

Table 2.  Comparison of treatment regimens between long-term survivors
 LS− (n = 206)LS+ (n = 39)All patients (n = 245)P value
  • Data are numbers (%) of patients unless indicated otherwise.

  •  

    Mann–Whitney U-test.

  •  

    Chi-square test.

  • IQR, interquartile range; L1, first-line therapy; L2, second-line therapy; LS+, long-term survivors; LS−, non-long-term survivors.

Number of treatment lines, median (IQR)2 (1–3)3 (1.5–5)2 (1–3)<0.0001
 179 (39)10 (24)89 (36) 
 271 (33)3 (8)74 (30) 
 334 (17)10 (26)44 (18) 
 >322 (11)16 (42)38 (16) 
Number of cycles, L1, median (IQR)5 (3–6)5 (3.5–6)5 (3–6)0.29
Drugs, L1   0.54
 Platinum-based doublet with155 (75)33 (85)188 (77) 
  Gemcitabine80 (39)19 (49)99 (40) 
  Taxane69 (33)13 (33)82 (33) 
  Vinorelbine2 (1)0 (0)2 (<1) 
  Etoposide4 (2)1 (3)5 (2) 
 Monotherapy34 (17)3 (8)37 (15) 
  Gemcitabine21 (10)2 (5)23 (9) 
  Vinorelbine8 (4)0 (0)8 (3) 
  Taxane5 (3)1 (3)6 (3) 
 Tyrosine kinase inhibitors10 (5)3 (8)13 (5) 
 Other7 (3)0 (0)7 (3) 
Maintenance therapy7 (3)5 (13)12 (5)0.04
Drugs, L2   0.34
 Taxane21 (17)5 (17)26 (17) 
 Pemetrexed60 (47)14 (48)74 (47) 
 Targeted therapy36 (28)7 (24)43 (28) 
 Vinorelbine4 (3)0 (0)4 (3) 
 Gemcitabine4 (3)1 (3)5 (3) 
 Platin-taxane1 (<1)2 (7)3 (2) 
 Other1 (<1)0 (0)1 (<1) 
Response, L1   <0.0001
 Objective response (complete + partial)45 (23)16 (43)61 (26) 
 Stable disease33 (17)12 (33)45 (19) 
 Progressive disease120 (60)9 (24)129 (55) 
 Missing values325 
Response, L2   0.001
 Partial response4 (3)3 (11)7 (5) 
 Stable disease8 (7)7 (26)15 (10) 
 Progressive disease108 (90)17 (63)125 (85) 
 Missing values729 
Surgery4 (2)7 (18)11 (4)<0.0001
Time to first progression of tumour   <0.0001
 During L1 therapy100 (49)8 (21)108 (44) 
 <3 months50 (24)3 (8)53 (22) 
 3–6 months39 (19)11 (28)50 (20) 
 6–12 months12 (6)5 (13)17 (7) 
 >1 year1 (<1)6 (15)7 (3) 
 No progression3 (1)6 (15)9 (4) 
 Missing values101 

Among long-term survivors, the median number of chemotherapy agents received was significantly greater (3 vs 2) (P < 0.0001). Thus, 42% of long-term survivors received more than three chemotherapy agents, compared with only 11% of the other patients. Although maintenance therapy was not part of standard care at that time, this treatment option was considered for some patients. Maintenance chemotherapy was more frequently administered to long-term survivors (13% vs 3%, P = 0.04). The maintenance therapy was gemcitabine (after induction treatment that included gemcitabine) (n = 10), or early second-line chemotherapy with docetaxel (n = 1) or erlotinib (n = 1).

Tumour response and control after first-line (P < 0.0001) and second-line chemotherapy (P = 0.001) were better in the long-term survivors. TTP after first-line chemotherapy differed between the two groups; 73% of non-long-term survivors progressed in <3 months after first-line treatment, compared with only 29% of long-term survivors (P < 0.0001).

Biological factors

At diagnosis, the number of patients with anaemia was similar in the two groups, whereas at progression, anaemia was significantly less frequent among long-term survivors (9%) than among the other patients (38%) (P = 0.002) (Table 1). High LDH levels at diagnosis were significantly more frequent among the other patients (23%) than among long-term survivors (6%) (P = 0.049). The frequency of hypercalcaemia was similar in the two groups.

Survival analysis

The results of the univariate analysis are shown in Table 3. In the multivariate analysis, the factors that independently predicted long-term survival were LDH <500 IU/L (hazard ratio (HR) 0.50, 95% CI: 0.34–0.74), absence of surgical resection (HR 4.4, 95% CI: 1.63–11.88), first progression of tumour after more than 3 months (HR 0.25, 95% CI: 0.14–0.45), absence of maintenance therapy (HR 4.42, 95% CI: 2.03–9.64), the number of chemotherapy agents administered (HR 0.69, 95% CI: 0.57–0.84), and a PS of 0–1 at first progression of the tumour (HR 0.14, 95% CI: 0.023–0.76) (Table 4).

Table 3.  Univariate analysis of factors associated with survival of patients with non-small cell lung cancer
VariablenSurvival, months, medianP value (log-rank)
  1. L1, first-line treatment; L2, second-line treatment; PS, performance status.

PS at first progression of tumour   
 0–113515.9<0.0001
 2–4677.8 
Number of initial sites of metastasis   
 0–115512.20.001
 >1909.1 
Number of treatment lines  <0.0001
 1894.5 
 27410.3 
 34416.8 
 >33822.5 
Response, L1   
 Control (response + stability)10617.2<0.0001
 Progression of tumour1296.9 
Response, L2   
 Control (response + stability)2223.50.0002
 Progression of tumour12514.1 
Time to first progression of tumour   
 <3 months after L11617.7<0.0001
 >3 months after L18319.7 
LDH level at diagnosis  0.001
 <500 IU/L17712.2 
 ≥500 IU/L456 
Anaemia at first progression of tumour  <0.0001
 Hb <110 g/L13416.3 
 Hb ≥110 g/L679.1 
Bone metastases  <0.0001
 No16712.6 
 Yes787.7 
Surgery  <0.0001
 No23411.1 
 Yes1145.7 (3.8 years) 
Maintenance treatment  0.001
 No23310.8 
 Yes1223.3 
Table 4.  Multivariate analysis (Cox model) of factors associated with survival of patients with non-small cell lung cancer
VariableHazard ratio95% CIP value
  •  

    Continuous variable.

  • PS, performance status.

Number of treatment lines0.690.57–0.840.0002
PS of 0–1 at first progression of tumour0.140.03–0.760.02
LDH <500 IU/L0.500.34–0.740.0005
No surgery4.401.63–11.880.003
No maintenance therapy4.422.03–9.640.0002
Time to first progression of tumour >3 months0.250.14–0.45<0.0001

DISCUSSION

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

A survival benefit for patients with NSCLC has been noted in randomized trials of novel chemotherapy regimens. However, the prognosis for patients with extensive NSCLC is still poor. In this study of 245 consecutive patients with stages IIIb–IV NSCLC, 39 patients (15.9%) were alive after 2 years. This survival rate is somewhat greater than that reported from previous studies of long-term survivors (12.8% in the study of Satoh et al.6). The focus of this study was the prognostic factors associated with long-term survival.

Six prognostic factors associated with long-term survival were identified in this study; a PS of 0–1 at first progression of the tumour, normal LDH levels at diagnosis, use of maintenance therapy, surgical resection, TTP of >3 months, and the number of chemotherapy agents received.

As expected, good PS was a prognostic factor. In this study, PS at diagnosis was not significantly associated with long-term survival, although a trend was detected. However, good PS at first progression of the tumour was significantly associated with long-term survival (HR 0.14, 95% CI: 0.03–0.76). These results confirm previously published data of Hanna et al. that compared pemetrexed or docetaxel as second-line chemotherapy with best supportive care, and showed that PS was prognostic.14,22 In the present study, survival was better in each subgroup, with a median survival of 15.9 months for patients with a PS of 0–1 versus 7.8 months for those with PS of 2–4 (P < 0.0001). There were no associations between age, gender, exposure to tobacco smoke, or histology of the tumour and survival. Furthermore, mediastinal invasion and the number or localization of metastases (except bone metastases) were not related to long-term survival. The LDH level at diagnosis was an independent prognostic factor. The prognostic value of LDH levels has been proven in several studies,23,24 and it may be a marker of tumour hypoxia or increased anaerobic metabolism.25,26 A high LDH level is frequently associated with the aggressiveness of tumours.27

Major differences in therapy for long-term survivors were noted. Surgical resection of oligometastases (lung, brain or adrenal metastases) was associated with longer survival. These results confirm previously published data.5,28,29 Long-term survivors had a significantly longer TTP (≥3 months) and subsequent OS. These results were also consistent with previously published data.22,30,31 Although maintenance therapy was not standard care at that time, this treatment option was considered for some patients. Maintenance chemotherapy, mainly based on gemcitabine, was a strong independent prognostic factor (P < 0.04). Recent phase III trials have shown promising results. Patients receiving maintenance therapy with gemcitabine showed a significant improvement in TTP (3.6 months, vs 2 months in the placebo arm, P < 0.001), but not OS.32 Pemetrexed has also demonstrated efficacy as maintenance therapy in patients with nonsquamous cell lung cancer, in terms of TTP (4.3 vs 2.6 months, P < 0.0001) and OS (13.4 vs 10.6 months, P = 0.012).12 Recently, maintenance therapy with erlotinib was also shown to be beneficial in terms of TTP and OS.33 Pemetrexed and erlotinib have now been approved as maintenance therapy after platinum doublet chemotherapy. This study, as far as we know, is the first to show that maintenance chemotherapy is associated with longer survival.

The main limitation of this study was that inclusion of patients ceased in 2006 and treatment options have changed since then. The efficacy of pemetrexed as maintenance therapy has been demonstrated and it is now widely used. Furthermore, the mutational status of the EGFR and Kras genes is routinely assessed and this helps in the selection of patients for first- or second-line treatment with EGFR inhibitors. Indeed, in patients with sensitive EGFR mutations, first-line therapy with an EGFR tyrosine kinase inhibitor (TKI) is currently recommended, and has shown a tumour response of 70%, with prolonged progression-free survival.34 In addition, EGFR/Kras mutations are prognostic; EGFR mutations are associated with a good prognosis, whereas mutated Kras is associated with poor survival.35 However, the present study was based on prospective collection of data and included all patients who were consecutively treated in the department.

This retrospective study was also subject to some biases. This was a single centre study and was therefore subject to practice-related biases. Treatments were not randomized, so it might be hypothesized that patients with better expected survival at diagnosis received more aggressive treatments, such as surgery or maintenance therapy, and this might have interfered with the interpretation of these results. With regard to the number of treatment regimens, this variable was difficult to interpret because patients surviving longer were more likely to receive multiple treatment regimens. Furthermore, the number of patients studied was limited. However, all consecutive, unselected patients treated in the department were included in the study, and it therefore reflected the daily recruitment and management of patients with advanced NSCLC.

In conclusion, the survival rate at 2 years for patients with advanced NSCLC was almost 16% in this study. Several prognostic factors for long-term survival were identified and these were mainly related to treatment. The use of chemotherapy, and particularly maintenance therapy, was associated with prolonged survival. Further studies based on biological markers, and particularly the mutational status of the EGFR or Kras genes, are essential to better describe the prognostic factors in this population.

REFERENCES

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES
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