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Every-day clinical practice in patients with advanced non-small-cell lung cancer
Lung Cancer 68 (2010) 273–277
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Every-day clinical practice in patients with advanced non-small-cell lung cancer V. Zietemann a , T. Duell b,∗ a b
Public Health Nutrition Unit, Technische Universität München, D-85350 Freising, Germany Oncology Department, Asklepios Lungenfachkliniken Muenchen-Gauting, Robert-Koch-Allee 2, D-82131 Gauting, Germany
a r t i c l e
i n f o
Article history: Received 12 May 2009 Received in revised form 24 June 2009 Accepted 29 June 2009 Keywords: Non-small-cell-lung cancer First-line therapy Second-line therapy Third-line therapy Systemic therapy Radiotherapy Observational study
a b s t r a c t Little data is available on the treatment of patients with advanced non-small-cell lung cancer (NSCLC) in every-day clinical practice. Clinical trials hardly reflect reality due to strict selection criteria and a focus on the treatment line of interest. Thus, we aimed to describe the prevalence of treatment measures in a cohort of unselected patients with advanced NSCLC. From January 2003 to July 2007, we included 416 consecutive NSCLC patients treated at a single institution in this observational study, with a follow-up until August 2008. At each treatment line the time, duration and kind of therapy (drugs used, radiotherapy, surgery), response and time of progression were documented. Of the 405 patients receiving first-line systemic therapy, 52%, 26% and 10% received a second-, third- and fourth-line systemic therapy, while 31%, 40% and 50% of the patients died during or after their first-, second- and third-line therapy, respectively. About 35% of all patients received radiotherapy at any time. About half of the patients with advanced NSCLC undergoing systemic therapy in first-, second- or third-line also receive subsequent therapy. Although this is expected to influence overall survival, previous or further lines are seldom presented in trials in detail and are usually not included in statistical analyses. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction For systemic treatment of advanced non-small-cell lung cancer (NSCLC) numerous therapeutic options exist, nevertheless the prognosis from patients suffering from this disease is still poor. Besides the classical cytotoxic agents newer developments have become available such as monoclonal antibodies or other targeted therapies. While there is no standard defined as first line treatment, platinum-based doublets are still considered the first choice [1,2]. For second-line therapy several drugs have been approved, i.e. docetaxel, pemetrexed and erlotinib. Currently, there are no predictors to identify patients who will benefit from such second- and also further-line treatments [3], nevertheless it is generally accepted to offer further line treatment to those patients who are fit enough [1,2]. The interdependency of treatment lines is ignored in most clinical studies, where usually only detailed information is given on the therapy line of interest. Since every therapeutic measure within the treatment plan may influence the outcome, biased effect estimates can result if subsequent or previous therapies are not included in the statistical analyses. If, for example an individually ineffective first-line treatment guides the decision on an effective second-line regime this could result in a longer overall survival (OS). Standard
∗ Corresponding author. Tel.: +49 89 85791; fax: +49 89 85791 3106. E-mail address: [email protected] (T. Duell). 0169-5002/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2009.06.023
analyses could attribute this beneficial effect falsely to the first-line treatment. It is fairly unknown how many patients in fact receive different lines of chemo- and/or radiotherapy in every-day clinical practice and if the frequency of serial therapy measures beyond second-line may influence the outcome, neither in normal daily practice, nor in clinical trials. We present an observational study reflecting the “real life conditions” of patients suffering from advanced NSCLC with a focus on the sequence of different lines of therapy. It gives information on the complete course of radiotherapy, surgery and systemic therapy of most of the observed patients including data on survival as well as on the losses to follow-up. 2. Methods 2.1. Patients Patients with histologically confirmed primary advanced NSCLC (stage IIIB wet with pleural effusion or stage IV) were included in this prospective observational study. From January 2003 to July 2007, 519 unselected and treatment-naive patients were admitted to a single oncological ward of the Asklepios Lungenfachkliniken Gauting for either diagnostics and/or therapy. For treatment, 80 patients were referred to other centers because of local proximity or patient’s choice, and 23 patients were excluded because of their poor clinical performance. For 416 patients information on the primary treatment was available, they were followed-up until
274
V. Zietemann, T. Duell / Lung Cancer 68 (2010) 273–277
Table 1 Characteristics of patients at baseline. Characteristic
No. of patients
Sample size
416
Sex Male Female
261 155
63 37
Stage of disease IV IIIB, wet
353 63
85 15
Histology Adenocarcinoma Squamous cell carcinoma Othera
246 112 58
59 27 14
Weight loss as reported by the patients Yes No
142 274
34 66
Karnofsky performance score Score ≥ 90 70 ≤ Score < 90 Score < 70
186 180 50
45 43 12
Smoking status Never-smoker Smoker
105 311
25 75
Metastasis location at diagnosis Bone Liver Brain Adrenal gland Lung
125 57 67 59 202
30 14 16 14 49
No. of metastasis locations at diagnosis 1 2 ≥3
219 99 35
53 24 8
Median age (years) (Q1, Q3)
%
Median follow-up time was 242 days (range from 3 to 1838 days), median OS time for patients, who had received at least one systemic therapy, was 268 days (95% CI: 245–304) or 8.8 months. For 81% of the patients death has been recorded by the end of the study. The 1-year survival rate was 35% and the 2-year survival rate 10%. The treatment flow for all patients is presented in Fig. 1. Thirtyseven patients documented as lost to follow-up died more than 3 months after their last visit in our institution, namely 20, 14 and 3 after beginning a first-line, second-line and third-line therapy, respectively. Four percent of the total population had been censored for administrative reasons. Twenty-one patients were initially irradiated, 76% because of brain metastases, 10% because of bone metastases and 14% locally. Fourteen of these received chemotherapy after radiotherapy, 5 patients died after the initial radiotherapy. Six patients had thoracic surgery as initial therapy, three had brain surgery. Five of the nine patients received chemotherapy after surgery. Ninety three percent (386 of 416) of the treated patients received a systemic therapy as initial treatment, 11 of these a combination of radiation and chemotherapy. Forty-three percent of the patients were clinical trial participants within different trials for advanced NSCLC at the time of their first- and/or second-line treatment.
3.2. Systemic first-line therapy
65 (57, 73)
a
Large cell carcinoma: 3 patients; undifferenciated: 27 patients; not specified: 28 patients.
August 2008. At first contact, demographical and disease specific data were recorded, including histology, disease stage, localization of metastases, symptoms and Karnofsky performance score. At each treatment line the time, duration and kind of therapy (drugs used, radiotherapy, surgery), number of cycles when applicable, response and time and kind of progression (locally and/or metastasis) were documented. Patients were censored if information about possible further therapies was missing for more than 3 months before reported death. 2.2. Statistical analysis Overall survival (OS) was calculated as the time between the first chemotherapy and death from any cause. The Kaplan–Meier method was used to estimate survival [4]. All analyses were carried out using SAS version 9.1 (SAS Institute Inc., Cary, NC). 3. Results 3.1. Patient characteristics, outcome, and treatment flow Patient characteristics are given in Table 1. The population included 63% male patients and 75% former or current smokers, regarding the histological subtype 59% were adenocarcinoma and 27% squamous cell carcinoma. Fifteen percent of patients suffered from malignant pleural effusion (stage IIIB) and 85% from metastatic disease (stage IV), 45% had a Karnofsky performance score of more than 80% and 12% of less than 70%.
Eleven patients died or were lost to follow-up after primary radiotherapy or surgery, in total 405 patients received a systemic first-line therapy. Of these 84% were treated with platinum-based doublets, 13% received a monotherapy (Table 2) and 114 patients were treated within clinical trial studies. Eighty-nine patients were irradiated after first-line chemotherapy, 45% because of brain metastases, 17% because of bone metastases and 38% locally. During or after the systemic first-line therapy, 97 of the 405 patients died, further 28 after subsequent radiotherapy. Sixty-eight of the 125 deceased patients died within 2 months after stopping first-line chemotherapy (Table 3). The majority of patients (43%) received 3–4 cycles. Of the 127 patients (31%) who received a maximum of 2 cycles, 53 died without any other therapy, 47 of them within 2 months after stopping therapy. Fifty-nine of the surviving patients received a second-line therapy and 15 patients were lost to follow-up. Correspondingly, for 3 or more cycles see Table 3. For 31 patients the information about number of cycles is not available, for 13 of these patients because of the use of oral erlotinib. In summary, 31% of the first-line patients did not receive secondline therapy because of prior death, 52% received a systemic secondline therapy and 17% of them were lost to follow-up.
3.3. Systemic second-line therapy Two hundred and ten patients have been initiated with a secondline systemic therapy. For drugs used see Table 2. Sixty-one of these patients were treated within clinical trial studies. Thirty-one patients were irradiated after second-line, 67% because of brain metastases, 10% because of bone metastases and 23% locally. During or after systemic second-line therapy, 72 of the 210 patients died, additional 11 after subsequent radiotherapy (Table 3). The majority of patients (51%) received a maximum of 2 cycles, only. For detailed information and correspondingly to the first-line setting see Table 3. In summary, 40% of the patients with second-line systemic therapy had died prior to further systemic therapy, 51% received a systemic third-line therapy and 9% were lost to follow-up.
V. Zietemann, T. Duell / Lung Cancer 68 (2010) 273–277
275
Fig. 1. Treatment flow for the 416 patients with advanced non-small-cell lung cancer. CT: chemotherapy; RT: radiotherapy; OP: surgery; lfu: lost to follow-up.
3.4. Systemic third-line therapy
4. Discussion
In total, 107 patients received a third-line therapy. Eight patients were irradiated after third-line chemotherapy. For drugs used see Table 2. Thirty-five of these patients were treated within clinical trial studies. During or after systemic third-line, 49 of the 107 patients died, another 4 after subsequent radiotherapy. For detailed information see Table 3. In summary, 50% with third-line systemic therapy had died prior to any further systemic therapy, 38% received a systemic fourth-line therapy and 12% were lost to follow-up.
To our knowledge this is the first report on the course of treatment of a larger cohort of unselected patients with advanced NSCLC. Eighty-four percent of our patients received platinum-based doublets at first-line. More than 50% received systemic therapy beyond first-line in our study. Stinchcombe and Socinski noted, that it is difficult to estimate the proportion of patients who receive secondline treatment and they approximated 40–50% of the patients [5]. At least 10% of the patients received at least a fourth-line therapy. Okamoto et al. [6] analysed the courses of 222 consecutive patients who had received some kind of initial treatment, but information for further therapy is only given for 17 patients with more than 2 years of survival. It was concluded, that there are two different groups among long-time survivors regarding the clinical course. One group included those who had chemotherapy-sensitive tumors and they received long-term chemotherapy alone. The second group received multimodality therapy including systemic chemotherapy plus any local-control therapy such as surgery or radiotherapy during the clinical course. This prospective observational study has not only limitations, but also strengths. Because there was no patient selection for inclusion, the results represent the treatment situation in every-day clinical practice. Since data derive from only one department of a single institution the results cannot be generalised. Randomised trials seldom take post-randomisation treatments under consideration when analysing overall survival, as a consequence standard methods such as time-dependent Cox models may produce biased effect estimates even in randomised clinical trials. This may be due to time-dependent confounders which are on one side effected by previous treatment and on the other side effect the choice regarding subsequent therapy as well as the outcome. Causal models have been proposed in this context as alternative analysis strategy leading to unbiased effect estimates [7]. However, we could
3.5. Further systemic therapy lines Forty-one patients received a fourth-line therapy. Twenty-two of these patients were treated within clinical trial studies. At least 18 patients died after the fourth-line, at least 12 patients received a systemic fifth-line therapy, and 4 patients a sixth-line therapy.
3.6. Summary of the treatment plan Of a total of 405 patients at least 52% received a systemic secondline therapy, at least 26% and 10% underwent a systemic third- and fourth-line therapy, respectively. About 35% of the observed patients had at least one course of radio-(chemo-) therapy. Of these, 54% were irradiated because of brain metastases, 14% because of bone metastases and 31% received a local radiotherapy of the mediastinum or primary tumor region. Death occurred during or within 2 months after stopping the first-, second- or third-line therapy in 17%, 25% and 21%, respectively. In total, at least 11 patients died treatment related, for at least 12 patients death was documented as being not directly related to the malignant disease.
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Table 2 Overview on the systemic therapy measures. Primary drug
No. of patients
% of total
In combination with
No. of patients
Partner of primary drug %
First-line therapy Cisplatin
405 117
29
Carboplatin
225
56
Vinorelbine Erlotinib Docetaxel Others
37 13 11 2
9 3 3 0
Gemcitabine (±others) Vinorelbine Paclitaxel Vinorelbine Gemcitabine Mitomycin + vinblastin Mitomycin
73 40 84 62 41 31 14
62 34 37 27 18 14 38
210 64 41 24 19
30 20 11 9
Mitomycin
10
24
7 5 3 3
37 26 16 16
19 15 12 16
9 7 6 8
107 22 14 30 14 8 6 13
21 13 28 13 7 6 12
41 6 11 10 4 10
15 27 24 10 24
Second-line therapy Docetaxel Gemcitabine Vinorelbine Carboplatin
Erlotinib Gefitinib Pemetrexed Others Third-line therapy Docetaxel Gemcitabine Erlotinib Gefitinib Vinorelbine Pemetrexed Others Fourth-line therapy Docetaxel Erlotinib Vinorelbine Pemetrexed Others
Paclitaxel Vinorelbine Gemcitabine Docetaxel
Table 3 Number of patients who died, received next line or were lost to follow-up, stratified for line of therapy and number of cycles received. No. of patients at this point
No. of patients dying during/after this point
No. of patients who died within 2 months after stopping treatment at this point
No. of patients receiving next systemic treatment
No. of patients lost to follow-up after this point
First-line ≤2 cycles 3–4 cycles ≥5 cycles Unknown
405 127 174 73 31
125 53 46 13 13
68 47 12 3 n.e.
210 59 104 43 4
70 15 24 17 14
Second-line ≤2 cycles 3–4 cycles ≥5 cycles Unknown
210 108 43 19 40
83 50 15 3 15
52 35 4 0 n.e.
107 50 22 14 21
20 8 6 2 4
Third-line ≤2 cycles 3–4 cycles ≥5 cycles Unknown
107 40 13 7 46
53 15 6 0 32
23 7 2 0 n.e.
41 21 4 6 10
13 4 3 1 4
n.e.: not evaluable.
detect only one study using causal models to adjust for different proportions of second-line treatment in cancer clinical trials [8]. At our institution 114 patients were treated within a clinical study at first-line and 61% and 32% of these patients received second- and third-line systemic therapy, respectively. Thus, second- or higher order lines are quite prevalent among patients enrolled in clinical trials.
5. Conclusion At least 50% of patients with advanced NSCLC receiving systemic first-line therapy are subsequently being treated with a second-, at least 25% with a third-, and at least 10% with a fourth-line systemic chemotherapy. Under the assumption of an additional survival benefit this suggests that previous or particularly subsequent lines of
V. Zietemann, T. Duell / Lung Cancer 68 (2010) 273–277
treatment should be considered in statistical analyses and the presentation of clinical trials. Acknowledgements We thank Prof. Matthias Schulze, Prof. Loems Ziegler-Heitbrock and Dr. med. Petra Machens for critical comments on the manuscript and Prof. D. Hoelzel for the provision with data from the tumour registry Munich. References [1] Grossi F, Gridelli C, Aita M, De Marinis F. Identifying an optimum treatment strategy for patients with advanced non-small cell lung cancer. Crit Rev Oncol Hematol 2008;67:16–26.
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[2] Vansteenkiste J. Improving patient management in metastatic non-small cell lung cancer. Lung Cancer 2007;57(Suppl 2):S12–7. [3] Ramalingam S, Sandler AB. Salvage therapy for advanced non-small cell lung cancer: factors influencing treatment selection. Oncologist 2006;11:655– 65. [4] Kleinbaum DG, Klein M. Survival analysis—a self-learning text. 2nd ed. New York: Springer-Verlag/Business Media; 2005. [5] Stinchcombe TE, Socinski MA. Considerations for second-line therapy of nonsmall cell lung cancer. Oncologist 2008;13(Suppl 1):28–36. [6] Okamoto T, Maruyama R, Shoji F, Asoh H, Ikeda J, Miyamoto T, et al. Longterm survivors in stage IV non-small cell lung cancer. Lung Cancer 2005;47:85– 91. [7] Hernan MA, Brumback B, Robins JM. Marginal structural models to estimate the causal effect of zidovudine on the survival of HIV-positive men. Epidemiology 2000;11:561–70. [8] Yamaguchi T, Ohashi Y. Adjusting for differential proportions of secondline treatment in cancer clinical trials. Part II. An application in a clinical trial of unresectable non-small-cell lung cancer. Stat Med 2004;23:2005– 22.
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Every-day clinical practice in patients with advanced non-small-cell lung cancer V. Zietemann a , T. Duell b,∗ a b
Public Health Nutrition Unit, Technische Universität München, D-85350 Freising, Germany Oncology Department, Asklepios Lungenfachkliniken Muenchen-Gauting, Robert-Koch-Allee 2, D-82131 Gauting, Germany
a r t i c l e
i n f o
Article history: Received 12 May 2009 Received in revised form 24 June 2009 Accepted 29 June 2009 Keywords: Non-small-cell-lung cancer First-line therapy Second-line therapy Third-line therapy Systemic therapy Radiotherapy Observational study
a b s t r a c t Little data is available on the treatment of patients with advanced non-small-cell lung cancer (NSCLC) in every-day clinical practice. Clinical trials hardly reflect reality due to strict selection criteria and a focus on the treatment line of interest. Thus, we aimed to describe the prevalence of treatment measures in a cohort of unselected patients with advanced NSCLC. From January 2003 to July 2007, we included 416 consecutive NSCLC patients treated at a single institution in this observational study, with a follow-up until August 2008. At each treatment line the time, duration and kind of therapy (drugs used, radiotherapy, surgery), response and time of progression were documented. Of the 405 patients receiving first-line systemic therapy, 52%, 26% and 10% received a second-, third- and fourth-line systemic therapy, while 31%, 40% and 50% of the patients died during or after their first-, second- and third-line therapy, respectively. About 35% of all patients received radiotherapy at any time. About half of the patients with advanced NSCLC undergoing systemic therapy in first-, second- or third-line also receive subsequent therapy. Although this is expected to influence overall survival, previous or further lines are seldom presented in trials in detail and are usually not included in statistical analyses. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction For systemic treatment of advanced non-small-cell lung cancer (NSCLC) numerous therapeutic options exist, nevertheless the prognosis from patients suffering from this disease is still poor. Besides the classical cytotoxic agents newer developments have become available such as monoclonal antibodies or other targeted therapies. While there is no standard defined as first line treatment, platinum-based doublets are still considered the first choice [1,2]. For second-line therapy several drugs have been approved, i.e. docetaxel, pemetrexed and erlotinib. Currently, there are no predictors to identify patients who will benefit from such second- and also further-line treatments [3], nevertheless it is generally accepted to offer further line treatment to those patients who are fit enough [1,2]. The interdependency of treatment lines is ignored in most clinical studies, where usually only detailed information is given on the therapy line of interest. Since every therapeutic measure within the treatment plan may influence the outcome, biased effect estimates can result if subsequent or previous therapies are not included in the statistical analyses. If, for example an individually ineffective first-line treatment guides the decision on an effective second-line regime this could result in a longer overall survival (OS). Standard
∗ Corresponding author. Tel.: +49 89 85791; fax: +49 89 85791 3106. E-mail address: [email protected] (T. Duell). 0169-5002/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2009.06.023
analyses could attribute this beneficial effect falsely to the first-line treatment. It is fairly unknown how many patients in fact receive different lines of chemo- and/or radiotherapy in every-day clinical practice and if the frequency of serial therapy measures beyond second-line may influence the outcome, neither in normal daily practice, nor in clinical trials. We present an observational study reflecting the “real life conditions” of patients suffering from advanced NSCLC with a focus on the sequence of different lines of therapy. It gives information on the complete course of radiotherapy, surgery and systemic therapy of most of the observed patients including data on survival as well as on the losses to follow-up. 2. Methods 2.1. Patients Patients with histologically confirmed primary advanced NSCLC (stage IIIB wet with pleural effusion or stage IV) were included in this prospective observational study. From January 2003 to July 2007, 519 unselected and treatment-naive patients were admitted to a single oncological ward of the Asklepios Lungenfachkliniken Gauting for either diagnostics and/or therapy. For treatment, 80 patients were referred to other centers because of local proximity or patient’s choice, and 23 patients were excluded because of their poor clinical performance. For 416 patients information on the primary treatment was available, they were followed-up until
274
V. Zietemann, T. Duell / Lung Cancer 68 (2010) 273–277
Table 1 Characteristics of patients at baseline. Characteristic
No. of patients
Sample size
416
Sex Male Female
261 155
63 37
Stage of disease IV IIIB, wet
353 63
85 15
Histology Adenocarcinoma Squamous cell carcinoma Othera
246 112 58
59 27 14
Weight loss as reported by the patients Yes No
142 274
34 66
Karnofsky performance score Score ≥ 90 70 ≤ Score < 90 Score < 70
186 180 50
45 43 12
Smoking status Never-smoker Smoker
105 311
25 75
Metastasis location at diagnosis Bone Liver Brain Adrenal gland Lung
125 57 67 59 202
30 14 16 14 49
No. of metastasis locations at diagnosis 1 2 ≥3
219 99 35
53 24 8
Median age (years) (Q1, Q3)
%
Median follow-up time was 242 days (range from 3 to 1838 days), median OS time for patients, who had received at least one systemic therapy, was 268 days (95% CI: 245–304) or 8.8 months. For 81% of the patients death has been recorded by the end of the study. The 1-year survival rate was 35% and the 2-year survival rate 10%. The treatment flow for all patients is presented in Fig. 1. Thirtyseven patients documented as lost to follow-up died more than 3 months after their last visit in our institution, namely 20, 14 and 3 after beginning a first-line, second-line and third-line therapy, respectively. Four percent of the total population had been censored for administrative reasons. Twenty-one patients were initially irradiated, 76% because of brain metastases, 10% because of bone metastases and 14% locally. Fourteen of these received chemotherapy after radiotherapy, 5 patients died after the initial radiotherapy. Six patients had thoracic surgery as initial therapy, three had brain surgery. Five of the nine patients received chemotherapy after surgery. Ninety three percent (386 of 416) of the treated patients received a systemic therapy as initial treatment, 11 of these a combination of radiation and chemotherapy. Forty-three percent of the patients were clinical trial participants within different trials for advanced NSCLC at the time of their first- and/or second-line treatment.
3.2. Systemic first-line therapy
65 (57, 73)
a
Large cell carcinoma: 3 patients; undifferenciated: 27 patients; not specified: 28 patients.
August 2008. At first contact, demographical and disease specific data were recorded, including histology, disease stage, localization of metastases, symptoms and Karnofsky performance score. At each treatment line the time, duration and kind of therapy (drugs used, radiotherapy, surgery), number of cycles when applicable, response and time and kind of progression (locally and/or metastasis) were documented. Patients were censored if information about possible further therapies was missing for more than 3 months before reported death. 2.2. Statistical analysis Overall survival (OS) was calculated as the time between the first chemotherapy and death from any cause. The Kaplan–Meier method was used to estimate survival [4]. All analyses were carried out using SAS version 9.1 (SAS Institute Inc., Cary, NC). 3. Results 3.1. Patient characteristics, outcome, and treatment flow Patient characteristics are given in Table 1. The population included 63% male patients and 75% former or current smokers, regarding the histological subtype 59% were adenocarcinoma and 27% squamous cell carcinoma. Fifteen percent of patients suffered from malignant pleural effusion (stage IIIB) and 85% from metastatic disease (stage IV), 45% had a Karnofsky performance score of more than 80% and 12% of less than 70%.
Eleven patients died or were lost to follow-up after primary radiotherapy or surgery, in total 405 patients received a systemic first-line therapy. Of these 84% were treated with platinum-based doublets, 13% received a monotherapy (Table 2) and 114 patients were treated within clinical trial studies. Eighty-nine patients were irradiated after first-line chemotherapy, 45% because of brain metastases, 17% because of bone metastases and 38% locally. During or after the systemic first-line therapy, 97 of the 405 patients died, further 28 after subsequent radiotherapy. Sixty-eight of the 125 deceased patients died within 2 months after stopping first-line chemotherapy (Table 3). The majority of patients (43%) received 3–4 cycles. Of the 127 patients (31%) who received a maximum of 2 cycles, 53 died without any other therapy, 47 of them within 2 months after stopping therapy. Fifty-nine of the surviving patients received a second-line therapy and 15 patients were lost to follow-up. Correspondingly, for 3 or more cycles see Table 3. For 31 patients the information about number of cycles is not available, for 13 of these patients because of the use of oral erlotinib. In summary, 31% of the first-line patients did not receive secondline therapy because of prior death, 52% received a systemic secondline therapy and 17% of them were lost to follow-up.
3.3. Systemic second-line therapy Two hundred and ten patients have been initiated with a secondline systemic therapy. For drugs used see Table 2. Sixty-one of these patients were treated within clinical trial studies. Thirty-one patients were irradiated after second-line, 67% because of brain metastases, 10% because of bone metastases and 23% locally. During or after systemic second-line therapy, 72 of the 210 patients died, additional 11 after subsequent radiotherapy (Table 3). The majority of patients (51%) received a maximum of 2 cycles, only. For detailed information and correspondingly to the first-line setting see Table 3. In summary, 40% of the patients with second-line systemic therapy had died prior to further systemic therapy, 51% received a systemic third-line therapy and 9% were lost to follow-up.
V. Zietemann, T. Duell / Lung Cancer 68 (2010) 273–277
275
Fig. 1. Treatment flow for the 416 patients with advanced non-small-cell lung cancer. CT: chemotherapy; RT: radiotherapy; OP: surgery; lfu: lost to follow-up.
3.4. Systemic third-line therapy
4. Discussion
In total, 107 patients received a third-line therapy. Eight patients were irradiated after third-line chemotherapy. For drugs used see Table 2. Thirty-five of these patients were treated within clinical trial studies. During or after systemic third-line, 49 of the 107 patients died, another 4 after subsequent radiotherapy. For detailed information see Table 3. In summary, 50% with third-line systemic therapy had died prior to any further systemic therapy, 38% received a systemic fourth-line therapy and 12% were lost to follow-up.
To our knowledge this is the first report on the course of treatment of a larger cohort of unselected patients with advanced NSCLC. Eighty-four percent of our patients received platinum-based doublets at first-line. More than 50% received systemic therapy beyond first-line in our study. Stinchcombe and Socinski noted, that it is difficult to estimate the proportion of patients who receive secondline treatment and they approximated 40–50% of the patients [5]. At least 10% of the patients received at least a fourth-line therapy. Okamoto et al. [6] analysed the courses of 222 consecutive patients who had received some kind of initial treatment, but information for further therapy is only given for 17 patients with more than 2 years of survival. It was concluded, that there are two different groups among long-time survivors regarding the clinical course. One group included those who had chemotherapy-sensitive tumors and they received long-term chemotherapy alone. The second group received multimodality therapy including systemic chemotherapy plus any local-control therapy such as surgery or radiotherapy during the clinical course. This prospective observational study has not only limitations, but also strengths. Because there was no patient selection for inclusion, the results represent the treatment situation in every-day clinical practice. Since data derive from only one department of a single institution the results cannot be generalised. Randomised trials seldom take post-randomisation treatments under consideration when analysing overall survival, as a consequence standard methods such as time-dependent Cox models may produce biased effect estimates even in randomised clinical trials. This may be due to time-dependent confounders which are on one side effected by previous treatment and on the other side effect the choice regarding subsequent therapy as well as the outcome. Causal models have been proposed in this context as alternative analysis strategy leading to unbiased effect estimates [7]. However, we could
3.5. Further systemic therapy lines Forty-one patients received a fourth-line therapy. Twenty-two of these patients were treated within clinical trial studies. At least 18 patients died after the fourth-line, at least 12 patients received a systemic fifth-line therapy, and 4 patients a sixth-line therapy.
3.6. Summary of the treatment plan Of a total of 405 patients at least 52% received a systemic secondline therapy, at least 26% and 10% underwent a systemic third- and fourth-line therapy, respectively. About 35% of the observed patients had at least one course of radio-(chemo-) therapy. Of these, 54% were irradiated because of brain metastases, 14% because of bone metastases and 31% received a local radiotherapy of the mediastinum or primary tumor region. Death occurred during or within 2 months after stopping the first-, second- or third-line therapy in 17%, 25% and 21%, respectively. In total, at least 11 patients died treatment related, for at least 12 patients death was documented as being not directly related to the malignant disease.
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V. Zietemann, T. Duell / Lung Cancer 68 (2010) 273–277
Table 2 Overview on the systemic therapy measures. Primary drug
No. of patients
% of total
In combination with
No. of patients
Partner of primary drug %
First-line therapy Cisplatin
405 117
29
Carboplatin
225
56
Vinorelbine Erlotinib Docetaxel Others
37 13 11 2
9 3 3 0
Gemcitabine (±others) Vinorelbine Paclitaxel Vinorelbine Gemcitabine Mitomycin + vinblastin Mitomycin
73 40 84 62 41 31 14
62 34 37 27 18 14 38
210 64 41 24 19
30 20 11 9
Mitomycin
10
24
7 5 3 3
37 26 16 16
19 15 12 16
9 7 6 8
107 22 14 30 14 8 6 13
21 13 28 13 7 6 12
41 6 11 10 4 10
15 27 24 10 24
Second-line therapy Docetaxel Gemcitabine Vinorelbine Carboplatin
Erlotinib Gefitinib Pemetrexed Others Third-line therapy Docetaxel Gemcitabine Erlotinib Gefitinib Vinorelbine Pemetrexed Others Fourth-line therapy Docetaxel Erlotinib Vinorelbine Pemetrexed Others
Paclitaxel Vinorelbine Gemcitabine Docetaxel
Table 3 Number of patients who died, received next line or were lost to follow-up, stratified for line of therapy and number of cycles received. No. of patients at this point
No. of patients dying during/after this point
No. of patients who died within 2 months after stopping treatment at this point
No. of patients receiving next systemic treatment
No. of patients lost to follow-up after this point
First-line ≤2 cycles 3–4 cycles ≥5 cycles Unknown
405 127 174 73 31
125 53 46 13 13
68 47 12 3 n.e.
210 59 104 43 4
70 15 24 17 14
Second-line ≤2 cycles 3–4 cycles ≥5 cycles Unknown
210 108 43 19 40
83 50 15 3 15
52 35 4 0 n.e.
107 50 22 14 21
20 8 6 2 4
Third-line ≤2 cycles 3–4 cycles ≥5 cycles Unknown
107 40 13 7 46
53 15 6 0 32
23 7 2 0 n.e.
41 21 4 6 10
13 4 3 1 4
n.e.: not evaluable.
detect only one study using causal models to adjust for different proportions of second-line treatment in cancer clinical trials [8]. At our institution 114 patients were treated within a clinical study at first-line and 61% and 32% of these patients received second- and third-line systemic therapy, respectively. Thus, second- or higher order lines are quite prevalent among patients enrolled in clinical trials.
5. Conclusion At least 50% of patients with advanced NSCLC receiving systemic first-line therapy are subsequently being treated with a second-, at least 25% with a third-, and at least 10% with a fourth-line systemic chemotherapy. Under the assumption of an additional survival benefit this suggests that previous or particularly subsequent lines of
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treatment should be considered in statistical analyses and the presentation of clinical trials. Acknowledgements We thank Prof. Matthias Schulze, Prof. Loems Ziegler-Heitbrock and Dr. med. Petra Machens for critical comments on the manuscript and Prof. D. Hoelzel for the provision with data from the tumour registry Munich. References [1] Grossi F, Gridelli C, Aita M, De Marinis F. Identifying an optimum treatment strategy for patients with advanced non-small cell lung cancer. Crit Rev Oncol Hematol 2008;67:16–26.
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[2] Vansteenkiste J. Improving patient management in metastatic non-small cell lung cancer. Lung Cancer 2007;57(Suppl 2):S12–7. [3] Ramalingam S, Sandler AB. Salvage therapy for advanced non-small cell lung cancer: factors influencing treatment selection. Oncologist 2006;11:655– 65. [4] Kleinbaum DG, Klein M. Survival analysis—a self-learning text. 2nd ed. New York: Springer-Verlag/Business Media; 2005. [5] Stinchcombe TE, Socinski MA. Considerations for second-line therapy of nonsmall cell lung cancer. Oncologist 2008;13(Suppl 1):28–36. [6] Okamoto T, Maruyama R, Shoji F, Asoh H, Ikeda J, Miyamoto T, et al. Longterm survivors in stage IV non-small cell lung cancer. Lung Cancer 2005;47:85– 91. [7] Hernan MA, Brumback B, Robins JM. Marginal structural models to estimate the causal effect of zidovudine on the survival of HIV-positive men. Epidemiology 2000;11:561–70. [8] Yamaguchi T, Ohashi Y. Adjusting for differential proportions of secondline treatment in cancer clinical trials. Part II. An application in a clinical trial of unresectable non-small-cell lung cancer. Stat Med 2004;23:2005– 22.