(Chest. 2005;127:738-747.)
© 2005
American College of Chest Physicians
Significant Progress in Palliative Treatment of Non-small Cell Lung Cancer in the Past Decade*
Frank Waechter;
Jakob Passweg, MD, MS;
Michael Tamm, MD;
Martin Brutsche, MD, PhD;
Richard Herrmann, MD and
Miklos Pless, MD
* From the Departments of Medical Oncology (Mr. Waechter and Dr. Herrmann) and Hematology (Dr. Passweg), and the Thoracic Tumor Center (Drs. Tamm, Brutsche, and Pless), University Hospital of Basel, Basel, Switzerland.
Correspondence to: Miklos Pless, MD, Department of Medical Oncology, University Hospital of Basel, Petersgraben 4, CH-4031 Basel, Switzerland; e-mail: mpless{at}uhbs.ch
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Abstract
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Study objectives: Prospective randomized trials (PRTs) have suggested that third-generation agents (eg, gemcitabine, the taxanes, and vinorelbine) improve the survival time of patients with non-small cell lung cancer (NSCLC). However, < 30% of unselected NSCLC patients fulfill the eligibility criteria of such trials. We analyzed the outcomes of all consecutive and unselected patients with inoperable NSCLC in a single institution to determine whether there was an improvement in survival over time, and if so, to identify the factors that were associated with improved survival.
Methods: A total of 230 documented patients with NSCLC at the Basel University Hospital treated after 1990 were analyzed retrospectively. Break points by year of treatment were determined using sequential Cox proportional hazards regression models and the Kaplan-Meier estimator. Multivariate analysis was used to determine which factors were associated with improved survival over time.
Results: A marked improvement of survival was found since the introduction of the third-generation agents in 1997. The 1-year (40% vs 19%, respectively) and 2-year survival rates (23% vs 5%, respectively, p < 0.0001) of patients in whom NSCLC had been diagnosed since 1997 were significantly better than those prior to 1997. The two cohorts did not differ significantly in sex, stage, performance status, weight loss, and lactate dehydrogenase levels. The improvement since 1997 was due to better best supportive care (p < 0.025), better first-line chemotherapy (median overall survival [OS] time (9.2 vs 6.9 months, respectively; p < 0.0016), and better second-line chemotherapy (p < 0.0001). Finally, patients who received therapy with platinum plus a third-generation drug had significantly better outcomes than those who received an older therapy regimen (median OS time, 9.3 vs 6.7 months, respectively; p < 0.027).
Conclusions: A significant improvement of survival in patients with NSCLC was observed in the last decade. The results of PRTs for palliative treatment of NSCLC seem to be applicable to an unselected group of patients with NSCLC, and therapeutic nihilism in the palliative setting seems not to be justified.
Key Words: non-small cell lung cancer • palliative chemotherapy • survival • third-generation cytotoxic drugs
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Introduction
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Historically, the median overall survival (OS) time of patients with metastasized non-small cell lung cancer (NSCLC) receiving best supportive care (BSC) was 4 to 5 months, and the 1-year survival rate was approximately 10%.1 For decades, attempts have been made to improve survival time by the use of palliative chemotherapy. Until the beginning of the 1990s, the value of palliative chemotherapy was controversial. Its use was recommended only in the context of clinical trials.
This changed when the results of several metaanalyses were published in 1993 and 1995. They concluded that, compared to BSC, palliative chemo-therapy with platinum improved the median OS time by 6 weeks and the 1-year survival rate by 10%.234 Importantly, palliative chemotherapy also seemed to improve quality of life (QOL).35
During the past decade, new cytotoxic drugs were developed (ie, third-generation drugs, such as vinorelbine, docetaxel, paclitaxel, and gemcitabine) and were tested in several prospective randomized trials (PRTs) for the palliative treatment of patients with NSCLC. The results were remarkably similar for all four drugs. In combination with cisplatin or carboplatin, third-generation drugs significantly improved OS time, compared to a traditional platinum-containing drug combination. In the pivotal study by Le Chevalier et al,6 the median OS time with vinorelbine-cisplatin therapy was 9.2 months compared to 7.4 months with vindesine-cisplatin, and in the Southwest Oncology Group trial7 of vinorelbine/cisplatin vs cisplatin therapy the median OS time was 8.0 vs 6.0 months, respectively. For gemcitabine/cisplatin vs cisplatin treatment, the median OS time was 9.1 vs 7.6 months,8 respectively, and the combination therapy of gemcitabine/cisplatin compared to etoposide/cisplatin showed a significant advantage in OS time too (8.7 vs 7.2 months, respectively).9 Finally, the PRT comparing therapy with paclitaxel/cisplatin with etoposide/cisplatin resulted in median OS times of 9.5 and 7.6 months, respectively.10 The median OS time in these studies using the new cytotoxic drugs was around 9 months, and the average 1-year survival rate was approximately 35%.
The new drugs were similarly effective as monotherapy as the traditional platinum-containing combination therapies (eg, vinorelbine vs cisplatin/vindesine6; and gemcitabine vs cisplatin/etoposide11), and were better than BSC (eg, paclitaxel/BSC vs BSC12; gemcitabine/BSC vs BSC1314; and vinorelbine15). In addition, they caused fewer side effects and improved QOL compared to the older platinum-containing drug combinations.16
For these reasons, the present standard of care for patients with stage IV NSCLC at the University Hospital of Basel consists of a combination chemotherapy with cisplatin or carboplatin, and one of the third-generation drugs. The survival benefit of these treatments has been established in carefully designed PRTs. However, it is possible that the lessons learned from these studies apply only to the selected population of patients fulfilling the eligibility criteria. In fact, a recent study17 showed that only 27% of patients with stage IIIB (pleural effusion) or IV NSCLC in the Sydney Cancer Center would have been eligible for typical NSCLC trials. Therefore, it is possible that the benefits of the newer therapies do not apply to an unselected group of patients in an average oncology clinic. In order to verify whether these improvements are valid in the real world of everyday cancer treatment, we conducted an observational analysis of all consecutive patients with advanced-stage NSCLC who had been treated since 1990 in the Division of Oncology of the University Hospital of Basel, either with palliative chemotherapy or with BSC. We further asked whether there was any progress in terms of OS time in this period, and if so, when it occurred and what the possible reasons for the improvement might be.
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Materials and Methods
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Patients
A total of 230 consecutive patients who were treated at the Department of Medical Oncology at the University Hospital of Basel were included. All patients had pathologically proven NSCLC and had to be treated at least once with palliative chemotherapy or with BSC. Patients with stage III NSCLC who were treated with curative intent, either with neoadjuvant chemotherapy, or with definitive chemoradiation or radiotherapy were excluded from the study. The following data were assessed: age; sex; performance status (PS); histology; stage; smoking history; laboratory values (ie, hemoglobin level, leukocyte count, serum albumin level, calcium level, and neuron-specific enolase [NSE]); duration and type of chemotherapy; objective response rate (according to World Health Organization [WHO]), OS time; and symptoms (ie, dyspnea, cough, pain [assessed by usage of pain medication], appetite, and weight loss before and while receiving treatment).
Data Acquisition
The relevant data were taken from the patients’ charts. The staging of all patients included CT scans of the chest and upper abdomen (including the liver and adrenal glands). Bone scans and CT scans of the brain were performed only if the patients were symptomatic. Staging with positron emission tomography scanning was not used in this analysis. The staging procedures did not change during the time of this analysis. At each visit, a medical history was taken and a physical examination was performed. The Swiss association for the study of cancer has a standardized form (called a flow sheet) that is filled in at every visit. The following data are recorded: pain; fever; night sweats; bleeding; cough; shortness of breath; nausea; vomiting; neurologic symptoms; infections; digestion; urinary tract problems; appetite; sleep; and all medication. In addition, a physical examination should be performed with the following minimal examinations: PS; weight; BP; lung and heart auscultation; palpation of the abdomen and lymph nodes; and short neurologic examination. All findings are graded according to the WHO grading system. At the first visit, blood samples were obtained from all patients for hematology and chemistry analyses. Patients receiving chemotherapy were seen weekly, and during follow-up or while receiving BSC patients were seen every 6 to 12 weeks.
Definitions
Objective response rate was defined according to the WHO-criteria. Clinical benefit was defined by assessment of the following parameters: PS; cough; dyspnea; pain; weight loss; and change of appetite. Pain was quantified indirectly through the use of the following four classes of pain medication: (1) acetaminophen or acetylsalicylate; (2) nonsteroidal antiinflammatory drugs; (3) weak opiates (eg, codeine and tramadol); and (4) strong opiates (eg, morphine, pethidine, and fentanyl). Weight loss was defined as the loss of 
5% of body weight. The other symptoms or findings were quantified according to WHO criteria (scale, 0 to 4) or New York Heart Association criteria (for dyspnea). Changes in WHO grading (by at least 1 WHO grade), weight (± 5%), and class of pain medication (by at least one class) were computed and were used to determine clinical benefit.
Statistical Analysis
To determine whether outcome has improved over the years, patients were divided into two cohorts based on the year of diagnosis, using Cox proportional hazards regression models to determine the time periods that best modeled changes in survival over time. Multiple cut points were examined, and the one giving the largest partial likelihood was selected. The year break most significantly associated with outcome was 1997. Variables related to patients, diseases, and treatments in Table 1
, which are shown as proportions or median and range, were compared among cohorts using the 
2 test for discrete variables and the Mann-Whitney U test for continuous variables. Probabilities of survival were calculated using the Kaplan-Meier estimator. The log-rank test was used for making comparisons among groups. The following variables were analyzed for association with survival: patient characteristics (ie, age, sex, smoking history, weight loss, and PS); disease characteristics (ie, disease stage and histology); and laboratory values (ie, WBC count, and levels of lactate dehydrogenase [LDH], hemoglobin, calcium, albumin, and NSE).
A Cox model was fit, using a forward stepwise selection procedure to evaluate the impact of patient-related, disease-related, and treatment-related variables on survival. A series of nested models was used to determine the relative impact of year break, while receiving chemotherapy or BSC, using a p < 0.05 significance level for the inclusion of variables.
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Results
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Patients
From 1991 to 2002, 230 consecutive patients with NSCLC receiving either BSC or palliative chemotherapy were included in the study. The patients’ characteristics are shown in Table 1. There were 70 female patients and 160 male patients, and 180 of 210 patients had a history of smoking. At diagnosis, 150 patients (65.2%) had stage IV disease, 49 (21.3%) had stage IIIB disease, 19 (8.3%) had stage IIIA disease, 7 (3%) had stage II disease, and 5 (2.2%) had stage I disease. All patients with stage I or II disease were medically inoperable. There were 129 adenocarcinomas (56.1%), 53 squamous cell cancers (23%), and 36 large cell carcinomas (15.7%). In 12 cases (5.2%), histology was NSCLC-not further specified.
Thirty-one patients (13.5%) received BSC only, and 199 patients (86.5%) were treated with palliative chemotherapy. Of the patients who were treated with chemotherapy, there were 138 patients (60%) who received one of the newer cytotoxic drugs (ie, vinorelbine, gemcitabine, docetaxel or paclitaxel, with or without a platinum agent [ie, cisplatin or carboplatin]), 44 patients (19.1%) received some other type of chemotherapy, and 17 patients (7.4%) were treated with an experimental drug in the context of a clinical study. Fifty-eight (25.2%) patients received a second-line drug for palliative chemotherapy.
Prognostic Factors
In a first analysis, disease-related and patient-related parameters were examined for their prognostic impact: age; sex; stage; smoking history; PS; histology; weight loss at diagnosis; serum-LDH level; albumin level; hemoglobin level; WBC count; serum NSE level; and serum calcium level. In a univariate analysis, two widely accepted prognostic factors could be confirmed in our cohort. PS > 1 and elevated LDH level was associated with significantly worse OS time (p = 0.008 and p = 0.029, respectively). In addition, we found low serum albumin levels and elevated WBC counts to be adverse prognostic factors (p = 0.0001 and p = 0.003, respectively; Table 2
). In a next step, treatment-related factors and their impact on survival were assessed.
Survival
The primary end point of this analysis was OS time. Two cohorts of patients were created according to the time period in which they were treated. We analyzed every year break between 1992 and 2001, and found that the biggest survival difference that was seen between the patients treated before or during/after 1997. There was a highly significant advantage in OS time for the patients treated after 1996 for the 1-year survival rate (40 ± 8% vs 19 ± 9%, respectively) and for the 2-year survival rate (23 ± 7% vs 5 ± 5%, respectively; p = 0.0001) [Table 2, Fig 1
]. The median difference in survival time was 9 weeks, and the 1-year survival rate improved by 21%.
In a multivariate analysis (MVA), using all disease-related and patient-related prognostic factors that had been determined in the univariate analysis and using 1997 as the year break of treatment, treatment administered after 1996 remained a significant independent prognostic factor, while LDH was not confirmed (Table 3 ). Except for the serum albumin level (p = 0.04), these two patient cohorts were comparable with regard to the prognostic factors determined above (Table 1). Stage, PS, elevated LDH level, or WBC count were equally distributed. The analysis was repeated for patients with stage IV NSCLC only (n = 150), and the results are shown in Table 2 and Figure 2
. The survival benefit of treatment since 1997 was even more pronounced (median OS time, 33 weeks vs 23 weeks, respectively; p = 0.0006). In order to rule out lead-time bias (ie, that patients in the former period were treated later, only when symptomatic, whereas more recent patients were given treatment immediately), we performed two additional analyses. First, we compared the time between diagnosis and the initiation of treatment in the two cohorts. Surprisingly, before 1997 the median delay was 20 days, whereas since 1997 the median delay was 30 days. In addition, we calculated the survival time from the date of diagnosis rather than from day 1 of treatment. This did not change the significant prognostic impact of whether treatment had been received before or since 1997. In a next step, we attempted to define the possible reasons for this improvement over time, such as improved BSC, improved chemotherapy, and/or use of second-line therapies since 1997.
Impact of BSC
In an analysis of patients who received BSC without chemotherapy before or since 1997 (n = 31), there was a significant difference in median OS time, and in 1-year and 2-year survival rates in favor of the group treated since 1997 (p = 0.025) [Table 2, Fig 3
], implying an improvement in BSC.
Chemotherapy
In the group of patients receiving palliative chemotherapy (n = 199), there was also a significant improvement in OS duration over time (median OS time: treatment since 1997, 40 weeks; treatment before 1997, 30 weeks; p = 0.0016) [Table 2, Fig 4
]. The 2-year survival rate was > 20% for this group of patients.
Role of Third-Generation Cytotoxic Drugs
To determine the impact of the third-generation drugs, two subgroups of patients were analyzed. The first group of patients received platinum, plus either vinorelbine, gemcitabine, or one of the taxanes (called modern treatment; n = 86). The other group consisted of the patients who were treated with any other chemotherapy regimen (ie, with a single agent or combination therapy; n = 113). A significant benefit for OS time (40 vs 29 weeks, respectively; p = 0.027) and 1-year survival rate (39% vs 31%, respectively) for the group receiving the third-generation cytotoxic drugs was found (Table 2, Fig 5
).
In addition, a comparison of therapy with platinum doublets with third-generation drugs vs that with other platinum combinations was performed. Treatment with the platinum/third-generation doublets yielded a superior median OS time compared to combination therapy with platinum plus other drugs (40 vs 32 weeks, respectively) and a superior 1-year OS rate (39 ± 11% vs 33 ± 16%, respectively), however, these differences were not significant (p = 0.11).
Second-Line Chemotherapy
The effects of second-line chemotherapy before 1997 (n = 16) and since 1997 (n = 42) were significantly greater in the latter group. The median survival times were 18 and 43 weeks, respectively, and the 1-year survival rate improved from 13 to 37%, respectively (p = 0.0001) [Table 2, Fig 6
].
MVA
All prognostic factors were analyzed in an MVA [Table 3]. Good PS, normal WBC count, normal serum albumin level, and treatment since 1997 were independent prognostic variables. Alternatively, if modern chemotherapy had been used in the MVA (instead of therapy since 1997), it turned out to be of prognostic relevance. In a third MVA model, we used both treatment since 1997 and modern therapy. In this case, only the former retained a significant impact on survival.
Because BSC had such an important contribution on survival in the univariate analysis, a last MVA was performed to rule out the possibility that the whole improvement of OS time was merely due to better BSC. In this model, the significant disease-related factors, and both BSC and chemotherapy before and since 1997 were examined (Table 4
). The most significant contribution to OS time was chemotherapy administered since 1997, while BSC was also an independent prognostic factor.
Response Rate
Data for 115 of the 121 patients who received platinum-containing treatment were available for analysis (95%). The differences in objective response rates were not significant (p = 0.14). There was a trend toward increased partial responses with the new platinum combination therapies (22.2% vs 14.7%, respectively), but also more cases of progressive disease compared to the old platinum combinations (59.3% vs 50%, respectively), while fewer patients had stable disease (18.5% vs 35.5%, respectively).
Clinical Benefit
Due to the retrospective nature of this analysis, not all data were available. Two separate groups were investigated for changes in clinical benefit: First, the group treated before 1997 vs those treated since 1997 (with 55 to 61% and 63%, respectively, of all patient data available); and second, patients receiving a third-generation drug plus platinum vs patients receiving other therapies (with 85% and 67%, respectively, of all data available). The only significant change in the patient group that had been treated since 1997 was an improvement of cough after 1997 (p = 0.02). There was a nonsignificant trend toward better appetite (p = 0.08) and improvement of dyspnea (p = 0.12). In the second analysis, there were no significant changes found, only a trend toward improvement of pain (p = 0.12) with modern platinum-containing therapies. There was no influence of the third-generation drugs found on other QOL parameters.
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Discussion
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A well-known analysis of PRTs on palliative treatment of NSCLC revealed that very little progress had been made until 1994.18 Due to the availability of the third-generation drugs, the survival consistently increased after 1994. In our retrospective analysis, we found a significant improvement in OS time for patients receiving palliative treatment for NSCLC since 1997. The 1-year and 2-year survival rates have improved by 20%, and the median OS time has improved by > 2 months. How was this improvement achieved? The increase in OS time coincides with a change of treatment at our institution. Most patients treated before 1997 received the older drug combinations, and most patients treated since 1997 were given the third-generation drugs. The patients treated before and since 1997 are comparable with respect to known prognostic factors. Importantly, the factors with significant prognostic impact in the two cohorts (ie, PS, LDH level, and WBC count) were evenly distributed, so they cannot explain the differences in survival duration over time. However, patients treated after 1997 had significantly higher serum albumin levels, which might have played a role in outcomes. One can ask whether the diagnostic procedures have changed over time and whether a stage-migration bias was introduced. However, the diagnostic workup at the University Hospital of Basel has not changed. Only 25 patients underwent a positron emission tomography scan, and none of these patients had a change in stage compared to the results using conventional staging with CT scanning.
Two other potential biases have to be considered. First, in considering the possibility of lead-time bias, we assumed that in the era before 1997 patients were treated later in the course of their disease, usually on the occurrence of symptoms. Surprisingly, the time from diagnosis to treatment initiation was 10 days longer after 1996. Accordingly, an analysis using the day of first diagnosis to assess OS time rather than of the first day of treatment confirmed our results with a significant gain in OS time since 1997. The second potential bias was that in the earlier period treatment would be given preferentially to patients with good PS, whereas since 1997 more patients with PS 2 would be considered for palliative chemotherapy. However, our patients did not differ in PS before or since 1997. Therefore, the improvement in OS time has to be explained by the existence of better therapeutic options. For example, considerable progress has been made in BSC, such as improvements in intravascular and intrabronchial stents. In our study, only a few patients received BSC alone, therefore the impact of BSC has to be interpreted with caution. More importantly, progress in first-line and second-line chemotherapies, especially when third-generation drugs were used, seems to have contributed to the better results. It is of interest that our 1-year and 2-year survival data for both periods (ie, before and since 1997) are in line with the results from PRTs from this time. This was achieved in an unselected patient population. Thus, we are confident that the results obtained in PRTs, with carefully selected patients, are applicable to a wider patient population that is typically found in a general oncology outpatient clinic. Our cohort of patients contained very few patients with a PS of 3 or 4 (5%), which may reflect a referral bias. Therefore, our conclusions should not be extended to this group of patients. Due to the retrospective nature of these data, the results concerning the clinical benefit, objective response rate, and QOL are incomplete, and should not be overinterpreted.
In conclusion, the analysis of our data confirmed that considerable progress has been made in the palliative treatment of NSCLC in the last decade. Among other factors, the third-generation cytotoxic drugs have had a positive impact on survival time in patients with NSCLC. Furthermore, the knowledge gained in PRTs in very selected patient populations seems to be applicable to the unselected patients in an oncology outpatient clinic.
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Footnotes
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Abbreviations: BSC = best supportive care; LDH = lactate dehydrogenase; MVA = multivariate analysis; NSCLC = non-small cell lung cancer; NSE = neuron-specific enolase; OS = overall survival; PRT = prospective randomized trial; PS = peformance status; QOL = quality of life; WHO = World Health Organization
Received for publication March 26, 2004.
Accepted for publication August 31, 2004.
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References
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Abstract
Introduction
