Stage 3 Lung Cancer - Know YourSurviving Conditions

Transcription

1 Survival of Stage IIIb and IV Non-Small Cell Lung Cancer Patients on Best Supportive Care in Manitoba, Canada Erich Kliewer Alain Demers Sri Navaratnam Coreen Hildebrand Grace Musto Report for AstraZeneca Canada Inc. October, 2002

2

3 TABLE OF CONTENTS 1. BACKGROUND METHODS Population Data Analysis RESULTS Lung cancer in Manitoba Age and stage of BSC NSCLC cases Representativeness of BSC NSCLC cases Chemotherapy Metastases Performance status Survival DISCUSSION REFERENCES i

4 TABLES Table 1. Type of incident trachea, bronchus and lung cancer cases by year of diagnosis and sex, Manitoba Table 2. Morphology of the trachea, bronchus and lung cancer cases by year of diagnosis and sex, Manitoba Table 3. Age at diagnosis of NSCLC cases by year of diagnosis and sex, Manitoba Table 4. Age at diagnosis of BSC NSCLC cases by year of diagnosis and sex, Manitoba January June Table 5. Stage distribution of BSC NSCLC cases by year of diagnosis and sex, Manitoba June, Table 6. Stage distribution of BSC NSCLC cases by age at diagnosis and sex, Manitoba June Table 7. Characteristics of all Manitoba NSCLC cases and 150 BSC NSCLC cases...9 Table 8. Length (days) of chemotherapy lines and time between lines...10 Table 9. Patients who had changes in their chemotherapy drugs by number of changes and line...10 Table 10. Reason for changing the chemotherapy drug by line...11 Table 11. Reason for stopping chemotherapy by line...11 Table 12. Type of chemotherapy by year of diagnosis and line (intent to treat)...12 Table 13. Type of chemotherapy administered to the BSC NSCLC cases by stage at diagnosis and line (intent to treat)...13 Table 14. Distribution of chemotherapy by dose (intent to treat) and line for BSC NSCLC cases...14 Table 15. Distribution of chemotherapy by dose (intent to treat) and line for stage IIIb BSC NSCLC cases...15 Table 16. Distribution of chemotherapy by dose (intent to treat) and line for stage IV BSC NSCLC cases...16 Table 17. Sequence of chemotherapy treatments for the BSC NSCLC cases who received line 2 and line 3 treatments...17 Table 18. Number of metastases in the BSC NSCLC cases by site...17 Table 19. Performance status of BSC NSCLC cases...18 Table 20. Number of person-weeks accrued by BSC NSCLC cases from diagnosis date, first and last chemotherapy date and BSC date...19 Table 21. Survival of BSC NSCLC patients from diagnosis date, by stage at diagnosis and line...21 Table 22. Survival of BSC NSCLC patients from first date of chemotherapy, by stage at diagnosis and line...21 Table 23. Survival of BSC NSCLC patients from last day of chemotherapy, by stage at diagnosis and line...21 Table 24. Survival of BSC NSCLC patients from BSC date, by stage at diagnosis and line...22 ii

5 FIGURES Figure 1. Age (at diagnosis) distribution of BSC NSCLC cases by sex... 7 Figure 2. Survival distribution of BSC NSCLC cases by diagnosis date, dates of first and last chemotherapy and BSC date APPENDICES Appendix 1. Classification of lung cancer according to morphology...29 Appendix 2. Morphology of the trachea, bronchus and lung cancer cases diagnosed in Manitoba, Appendix 3.1 Distribution of chemotherapy according to schedule (line and cycle) for BSC NSCLC cases...31 Appendix 3.2 Distribution of chemotherapy according to schedule (line and cycle) for stage IIIb BSC NSCLC cases...32 Appendix 3.3 Distribution of chemotherapy according to schedule (line and cycle) for stage IV BSC NSCLC cases...33 Appendix 3.4 First line chemotherapy for the 17 stage IIIb and IV BSC NSCLC cases who received second line chemotherapy...34 Appendix 3.5 First and second line chemotherapy for the stage IV BSC NSCLC cases who received second line chemotherapy...35 iii

6 iv

7 1. BACKGROUND Lung cancer is the second most common form of cancer in Canadian men and women and the leading cause of cancer death. 1 It has been estimated that 21,200 Canadians were diagnosed with lung cancer cases in The two predominant types encountered are non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLC is a heterogeneous aggregate of distinct histological types of lung cancer, including squamous cell carcinoma, adenocarcinoma, large cell carcinoma and some rare subtypes such as adenosquamous cell carcinoma, mucoepidermoid carcinoma and adenoid cystic carcinoma. NSCLC tends to be extremely lethal and respond poorly to chemotherapy. SCLC includes pure small and large cell cancer, mixed small cell carcinoma and combined (small cell and squamous) carcinoma. 2 These cancers are more responsive to chemotherapy than NSCLC. 3,4 Approximately 75 to 80% of lung cancers are NSCLC 2,5-7 and of these, approximately 50% to 65% are of stage IIIb and IV, 7-10 depending on the study population. Most people diagnosed with lung cancer die of the disease. It was reported that only 14% of Canadian men and 17% of Canadian women diagnosed with lung cancer in 1992 survived five years or more. 11 Survival, however, varies considerably according to the stage at which tumors are diagnosed. While 38% to 61% of stage I lung cancer patients are expected to survive five years, only 1% of stage IV cancer patients are expected to live that long. 3, 5 As noted by Dranitsaris et al. 12, The role of chemotherapy in advanced NSCLC became more clearly defined with the publication of four meta-analyses that showed a prolongation of survival after chemotherapy compared with best supportive care Clinical guidelines from several countries have recommended chemotherapy for stage IIIB and IV NSCLC patients who have a relatively good performance status (ECOG 0,1 and select 2) The meta-analysis by the Non-Small Cell Lung Cancer Collaborative Group indicated that late stage NSCLC patients receiving BSC plus chemotherapy had a 10% increase in one-year survival or an increased median survival of 1.5 months relative to patients on BSC only. 16 According to Giaccone, the use of chemotherapy for patients with stage III NSCLC and malignant pleural effusion, or with stage IV disease, can result in a 1-year survival of about 35-40% and a median survival of approximately 9 months. 22 However, once a patient has progressed on or relapsed after chemotherapy, s/he is treated with best supportive care (BSC) which usually consists of symptomatic therapy and palliative radiation in some cases. 1

8 This report focuses on patients diagnosed with late stage (stages IIIb and IV) NSCLC in Manitoba during the period 1997 to June, 2000 and who were receiving BSC. The objective of the report is to define the characteristics of the BSC patients and their tumors, their chemotherapy treatment prior to being placed on BSC, and their survival. A second report will examine the treatment received during BSC and will estimate the costs associated with treatment patients receive during BSC. 2.1 Population 2. METHODS Manitoba residents diagnosed with trachea, bronchus and lung cancer (ICD-9 162) between 1997 and June, 2000 were identified from the Manitoba Cancer Registry. It was possible to identify which of these cases were NSCLC from the morphology information recorded in the registry. The morphology codes used to define NSCLC cases are shown in Appendix 1. The charts of patients with NSCLC were reviewed in order to determine those who had been diagnosed at stage IIIb and had pleural effusions or supraclavicular involvement, or those who had been diagnosed at stage IV. Of these patients, those who had been on chemotherapy and who survived 28 or more days after their last chemotherapy were considered to be in the BSC phase of their disease. Four weeks was chosen in order to ensure the patient was no longer on chemotherapy. 2.2 Data The information for this report was derived from a variety of sources including the Manitoba Cancer Registry (MCR), the OpTx system and chart review. The MCR is legally mandated to collect information on people diagnosed with cancer in Manitoba, as well as information on their tumor and treatment. Although the MCR does include some treatment information, it is incomplete. Vital status is recorded in the registry based on death records provided by the provincial Department of Vital Statistics. The MCR has been population-based since OpTx is a software package that has been specifically developed for cancer treatment centers for the purposes of tracking patients' appointments, treatment and other health care use. 2

9 Patient demographic and diagnostic information is also contained in OpTx. Not all Manitoba cancer cases are included in OpTx as it is primarily used for patients seen at CancerCare Manitoba or at one of the regional sites associated with the Manitoba Community Cancer Network. In order to identify cases of NSCLC that met our BSC definition we first obtained a listing of 300 records from the Manitoba Cancer Registry that included only the NSCLC cases diagnosed in Manitoba between January 1, 1997 and December 31, 1999 and who received chemotherapy. The electronic registry abstract, progress notes, and progression screens of these 300 cases were reviewed to determine eligibility according to the study proposal (stage IIIb with either pleural effusion or supraclavicular lymph node metastasis) or stage IV (distant metastatic disease). Ninety cases did not meet these criteria. The OpTx and paper records of the resulting 210 cases were reviewed to assess BSC and to confirm staging. Cases where the staging or progression could not be confirmed by electronic record review were also included in the paper chart review. Approximately 120 cases were eligible for the study. Since we required a minimum of 150 cases, this process was repeated for lung cases diagnosed between January 1, 2000 and June 20, 2000 (approximately 100 electronic records, 40 paper records). A detailed chart review was done in four Winnipeg hospitals for 50 cases (diagnosis years 1997 through 2000) for whom insufficient data could be obtained from the CancerCare Manitoba records in order to determine BSC status. The procedure, ancillary drug, hospital/clinic admission, radiotherapy treatment, and chemotherapy dates and dosage data were abstracted from the paper and electronic records and recorded on an access database. 2.3 Analysis Survival time was measured from the initial cancer diagnosis date, from the dates of first and last chemotherapy, as well as from the time at which a patient entered into the BSC phase (i.e. had been diagnosed at stage IIIb with pleural effusions or supraclavicular involvement, or had been diagnosed at stage IV and had been on chemotherapy and had survived at least 28 days from date of last chemotherapy). The end date was either the death date, emigration date (derived form the Manitoba Health Population Registry) or the study end date of March 31, Survival was calculated by the Kaplan-Meier method using SAS v

10 3. RESULTS 3.1 Lung cancer in Manitoba In the four-year period there were 3,091 new cases of trachea, bronchus and lung cancer diagnosed in Manitoba. Of these, 35 were second primaries. The cases consisted predominantly of cancers of the upper lobe (46.6%), followed by the lower lobe (23.4%). These percentages were similar for males and females (Table 1). The majority (79.7%) of these cancers were NSCLC (Table 2). The proportion of cancers that were NSCLC was similar in males (80.3%) and females (78.8%). The distribution of first primary cases by detailed morphology is provided in Appendix 2. Table 1. Type of incident trachea, bronchus and lung cancer cases by year of diagnosis and sex, Manitoba Total 1 ICD-9 Site N % N % N % N % N % Males 1620 Trachea Main bronchus Upper lobe Middle lobe Lower lobe Other parts Unspecified Total Females 1620 Trachea Main bronchus Upper lobe Middle lobe Lower lobe Other parts Unspecified Total Total 1620 Trachea Main bronchus Upper lobe Middle lobe Lower lobe Other parts Unspecified Total individuals were diagnosed with a total of 3091 primary cancers 4

11 Table 2. Morphology of the trachea, bronchus and lung cancer cases by year of diagnosis and sex, Manitoba Total 2 Type 1 N % N % N % N % N % Males NSCLC SCLC Other Total Females NSCLC SCLC Other Total Total NSCLC SCLC Other Total There was one case who had an unknown tumor type individuals were diagnosed with a total of 3091 primary cancers The majority of Manitoba NSCLC cases were males (58.1%). The age distribution of the NSCLC cases are shown in Table 3. NSCLC is concentrated in individuals over the age of 54. Compared to females (64.4%), a somewhat greater proportion of men (69.7%) were 65 years of age and over. 3.2 Age and stage of BSC NSCLC cases For the period 1997-June, 2000 we identified 150 NSCLC cases that met the criteria for the BSC case definition. The age (at diagnosis) distribution of these cases is shown in Table 4 by year of diagnosis and sex. Fifty-six percent of the BSC cases were males. The male cases tended to be older than the female cases. The majority of male BSC cases were years of age at the time of diagnosis, whereas the majority of female cases were years old (Figure 1). Overall, a slightly greater percentage of males (79.8%) than females (75.8%) were diagnosed at stage IV NSCLC (Table 5). However, the percentage of females diagnosed with stage IV disease has been increasing since 1997, although this is based on a relatively small number of cases. 5

12 Table 3. Age at diagnosis of NSCLC cases by year of diagnosis and sex, Manitoba Total 2 Age N % N % N % N % N % Males < Total Females < Total < Total Total 1. There was one case who had an unknown tumor type individuals were diagnosed with a total of 3091 primary cancers There was a greater proportion of people under the age of 55 among those diagnosed at Stage IV (27.4%) than among those diagnosed at Stage IIIb (12.1%) (Table 6). This was evident for both males and females. As noted above, women tended to be diagnosed at an earlier age than men, and this pattern occurred among both stage IIIb and stage IV cases. 6

13 Table 4. Age at diagnosis of BSC NSCLC cases by year of diagnosis and sex, Manitoba January June Total Age N % N % N % N % N % Males < Total Females < Total < Total Total Figure 1. Age (at diagnosis) distribution of BSC NSCLC cases by sex Female Male Percent < > 74 Age 7

14 Table 5. Stage distribution of BSC NSCLC cases by year of diagnosis and sex, Manitoba June, Total Stage N % N % N % N % N % Males IIIb IV Total Females IIIb IV Total Total IIIb IV Total Table 6. Stage distribution of BSC NSCLC cases by age at diagnosis and sex, Manitoba June 2000 IIIb IV Total Age N % N % N % Males < Total Females < Total < Total Total 8

15 3.3 Representativeness of BSC NSCLC cases From the data available for this report, it is not possible to determine how representative the sample of 150 BSC NSCLC (as defined for this report) cases are of all Manitoba BSC NSCLC cases. In order to do so, we would require information on other Manitoba BSC cases. As noted, meta-analyses have shown the benefit of receiving chemotherapy in the BSC phase and clinical guidelines have called for chemotherapy for certain late stage NSCLC cases. As the case definition used for this report excludes any cases who had chemotherapy while on BSC and those who survived less than 28 days after last receiving chemotherapy, the sample may well not be representative of all Manitoba BSC cases. Table 7 provides a limited comparison of the characteristics of the 150 BSC cases relative to all NSCLC cases in Manitoba. A similar proportion of NSCLC cases was diagnosed in each of the years in the period In contrast, the majority of BSC were diagnosed in Fewer cases were diagnosed in 2000, as in deriving our sample we only examined cases up to June, The sex distribution of the two groups was similar, with males predominating in both. The BSC cases were substantially younger than all NSCLC cases, with there being approximately 20-30% fewer people over the age of 64 in the BSC sample than in the NSCLC cases. In both groups, there was a greater proportion of males than females who were aged 65 years and over. Since it was part of the case definition, all BSC cases had had chemotherapy, but only 16.8% of NSCLC cases had had chemotherapy ( %, %, %, %). It should be noted that the chemotherapy information for all NSCLC cases was derived from the Manitoba Cancer Registry, which may not be complete. Table 7. Characteristics of all Manitoba NSCLC cases and 150 BSC NSCLC cases Characteristic NSCLC (%) n=2463 BSC (%) n=150 Diagnosis year Sex Males Females Over 64 years of age Males Females Received chemotherapy

16 3.4 Chemotherapy As part of the case definition for BSC, all patients had to have received at least one line of chemotherapy. Seventeen (11.3%) of the 150 BSC patients received a second line of chemotherapy, while only one patient had a third line. The mean length of time people spent on line 1 chemotherapy was 82.3 days (Table 8). The mean length of time on chemotherapy was slightly shorter for those on their second line (75.2 days). For people receiving a second line of chemotherapy, it started on average days after ending their first line of chemotherapy. Table 8. Length (days) of chemotherapy lines and time between lines Time length N Mean Median Minimum Maximum Line Time between line 1 and Line Time between line 2 and Line A total of 20 patients had changes in their chemotherapy drugs during line 1 (Table 9). Of these, three had two changes and one had three changes. During line 2, three patients (17.6%) changed their drugs once, while the only patient on line 3 had no changes. It should be noted that these changes are considered by oncologists to be a continuation of first line chemotherapy and not a move to second line chemotherapy. The reason for changing the chemotherapy drug was only recorded in the medical charts for 10 of the 25 occurrences (Table 10). Of these, 60% were due to the toxicity of the first drug tried. Similarly, toxicity was the principal reason for patients stopping chemotherapy during line 1 (Table 11). Of the five patients on line 2 chemotherapy for whom the reason for stopping was recorded, three stopped because of disease progression and two stopped because of toxicity. Table 9. Patients who had changes in their chemotherapy drugs by number of changes and line Number of Line 1 Line 2 Line 3 changes N % N % N % Total

17 Table 10. Reason for changing the chemotherapy drug by line Reason for Line 1 Line 2 changing N % N % Adverse reaction Intolerance Lack of effect Toxicity NS Total NS: not stated Table 11. Reason for stopping chemotherapy by line Reason for Line 1 Line 2 Line 3 Total stopping N % N % N % N % Adverse reaction Disease progression Patient refused Side effects Toxicity NS Total NS: treatment was completed as scheduled or that the reason for stopping was not stated Overall, cisplatin (51.3%) and carboplatin (42.0%) based chemotherapy were the most common forms of first line treatment for the patients prior to their entering the BSC phase of their disease (Table 12). Carboplatin based chemotherapy only started to be used extensively in Cisplatin was most commonly administered in combination with vinorelbine or etoposide, although the use of etoposide decreased markedly since Carboplatin was most commonly administered in combination with paclitaxel or vinorelbine. The use of vinorelbine in conjunction with carboplatin has been steadily increasing. Of the BSC patients who received a second line of chemotherapy, the most common treatment was cisplatin based (35.3%). Only one patient had a third line of chemotherapy, and that was docetaxel. The detailed distribution of chemotherapy according to line, cycle and stage are shown in Appendix 3. 11

18 Table 12. Type of chemotherapy by year of diagnosis and line (intent to treat 1 ) Total Drug(s) 1 N % N % N % N % N % Line 1 Cisplatin CIS + VIN CIS + ETO CIS + GEM CIS + PAC Carboplatin CAR + PAC CAR + VIN CAR + ETO Vinorelbine Other Total Line 2 Cisplatin CIS + VIN CIS + ETO CIS + GEM Carboplatin CAR + PAC CAR + VIN CAR + ETO + ADR + BLE Vinorelbine Docetaxel Total Line 3 Docetaxel Dose given on first cycle 2. ADR: adriamycin, BLE: bleomycin, CAR: carboplatin, CIS: cisplatin, ETO: etoposide, GEM: gemcitabine, PAC: paclitaxel, VIN: vinorelbine There were some variations in the chemotherapy treatment of patients depending on the stage of their disease at the time of diagnosis (Table 13). For their first line treatment, stage IIIb patients primarily received cisplatin (63.6%) based chemotherapy. For stage IV patients, first line chemotherapy was equally divided between cisplatin (42.9%) and carboplatin (42.9%). Unlike stage IIIb patients, some stage IV patients received vinorelbine or other types of first line chemotherapy. Although second and third line chemotherapy have been included in Table 13, there are too few patients to make any reliable observations. 12

19 Table 13. Type of chemotherapy administered to the BSC NSCLC cases by stage at diagnosis and line (intent to treat 1 ) IIIb IV Total Drug(s) 1 N % N % N % Line 1 Cisplatin CIS + VIN CIS + ETO CIS + GEM CIS + PAC Carboplatin CAR + PAC CAR + VIN CAR + ETO Vinorelbine Other Total Line 2 Cisplatin CIS + VIN CIS + ETO CIS + GEM Carboplatin CAR + PAC CAR + VIN CAR + ETO + ADR + BLE Vinorelbine Docetaxel Total Line 3 Docetaxel Dose given on first cycle 2. ADR: adriamycin, BLE: bleomycin, CAR: carboplatin, CIS: cisplatin, ETO: etoposide, GEM: gemcitabine, PAC: paclitaxel, VIN: vinorelbine There was often a wide range in the dose of a particular drug or combination of drugs that was administered. Table 14 provides the dose distribution for each drug or combination of drugs for each line. Overall and for Stage IV patients (Table 16), the single most frequently administered chemotherapy on the first cycle of the first line was 6 mg/ml.min of carboplatin and 25 mg/m 2 of vinorelbine, while 6 mg/ml.min of carboplatin and 200 mg/m 2 of paclitaxel was the second most common form of chemotherapy. For stage IIIb patients, 6 mg/ml.min of carboplatin and 25 mg/m 2 of vinorelbine or 75 mg/m 2 of cisplatin and 25 mg/m 2 of vinorelbine were equally common treatments (Table 15). 13

20 Table 14. Distribution of chemotherapy by dose (intent to treat 1 ) and line for BSC NSCLC cases Line 1 Line 2 Line 3 Drug(s) 2 Dose N % N % N % CIS + VIN 75 mg/m mg/m mg/m mg/m mg/m mg/m mg/m mg/m mg/m mg/m mg/m mg/m NS CIS + ETO 25 mg/m mg/m mg/m mg/m mg/m mg/m mg/m mg/m mg/m mg/m mg/m mg/m NS CIS + GEM 75 mg/m mg/m mg/m mg/m mg/m mg/m CIS + PAC NS CAR + PAC 3 mg/ml.min + 60 mg/m mg/ml.min mg/m mg/ml.min mg/m mg/ml.min mg/m mg/ml.min mg/m NS CAR + VIN 6 mg/ml.min +25 mg/m NS CAR + ETO 6 mg/ml.min+ 75 mg/m NS CAR + ETO + ADR + BLE NS VIN 25 mg/m mg/m NS DOC 36 mg/m mg/m mg/m NS Other NS Total Dose given on the first cycle 2. ADR: adriamycin, BLE: bleomycin, CAR: carboplatin, CIS: cisplatin, DOC: docetaxel, ETO: etoposide, GEM: gemcitabine, PAC: paclitaxel, VIN: vinorelbine, NS: not stated 14

21 Table 15. Distribution of chemotherapy by dose (intent to treat 1 ) and line for stage IIIb BSC NSCLC cases Drug(s) 2 Dose Line 1 Line 2 Line 3 N % N % N % CIS + VIN 75 mg/m mg/m mg/m mg/m mg/m mg/m mg/m mg/m NS CIS + ETO 25 mg/m mg/m mg/m mg/m mg/m mg/m NS CIS + GEM 50 mg/m mg/m CAR + PAC 3 mg/ml.min + 60 mg/m mg/ml.min mg/m CAR + VIN 6 mg/ml.min +25 mg/m CAR + ETO + ADR + BLE NS VIN 25 mg/m Total Dose given on the first cycle 2. ADR: adriamycin, BLE: bleomycin, CAR: carboplatin, CIS: cisplatin, DOC: docetaxel, ETO: etoposide, GEM: gemcitabine, PAC: paclitaxel, VIN: vinorelbine, NS: not stated 15

22 Table 16. Distribution of chemotherapy by dose (intent to treat 1 ) and line for stage IV BSC NSCLC cases Drug(s) 2 Dose Line 1 Line 2 Line 3 N % N % N % CIS + VIN 75 mg/m mg/m mg/m mg/m mg/m mg/m mg/m mg/m mg/m mg/m NS CIS + ETO 25 mg/m mg/m mg/m mg/m mg/m mg/m mg/m mg/m mg/m mg/m mg/m mg/m NS CIS + GEM 75 mg/m mg/m mg/m mg/m CIS + PAC NS CAR + PAC 3 mg/ml.min mg/m mg/ml.min mg/m mg/ml.min mg/m mg/ml.min mg/m NS CAR + VIN 6 mg/ml.min +25 mg/m NS CAR + ETO 6 mg/ml.min+ 75 mg/m NS VIN 25 mg/m mg/m NS DOC 36 mg/m mg/m NS Other NS Total Dose given on the first cycle 2. ADR: adriamycin, BLE: bleomycin, CAR: carboplatin, CIS: cisplatin, DOC: docetaxel, ETO: etoposide, GEM: gemcitabine, PAC: paclitaxel, VIN: vinorelbine, NS: not stated Although few of the BSC patients received more than one line of chemotherapy, Table 17 shows the chemotherapy they received in subsequent lines, relative to what they received in the first line. There was no common pattern. 16

23 Table 17. Sequence of chemotherapy treatments for the BSC NSCLC cases who received line 2 and line 3 treatments Chemotherapy Line 1 Line 2 Line 3 Count % CAR + PAC CAR + VIN CAR + PAC CIS + ETO CAR + PAC CIS + GEM DOC CAR + PAC CIS + VIN CAR + VIN CIS + GEM CIS + ETO CAR + VIN CIS + ETO DOC CIS + GEM DOC CIS + VIN CAR + ETO + ADR + BLE CIS + VIN DOC CIS + VIN VIN VIN CAR + PAC Total ADR: adriamycin, BLE: bleomycin, CAR: carboplatin, CIS: cisplatin, DOC: docetaxel, ETO: etoposide, GEM: gemcitabine, PAC: paclitaxel, VIN: vinorelbine 3.5 Metastases In order to be classified as a Stage IIIb or IV lung cancer, metastases must have occurred. Of the 150 BSC patients, 119 (79.3%) had at least two metastases at the time of diagnosis or since diagnosis, and three had six metastases (Table 18). Of the patients that had at least one metastases, the majority were to the lymph nodes (24.7%), followed by the chest wall (20.7%) and bone (16.0%). Table 18. Number of metastases in the BSC NSCLC cases by site Total Site N % N % N % N % N % N % N % Lymph nodes extrathoracic Lymph nodes supraclavicular Lymph nodes mediastinal Chest wall Lung Bone Adrenal CNS Liver Cutaneous Other Total If a person had more than one metastasis at the same site it was only counted once. 17

24 3.6 Performance status The performance status of patients was measured by oncologists at CancerCare Manitoba using the Eastern Cooperative Oncology Group (ECOG) Performance Status. 24 Unfortunately, this information was poorly reported by physicians. Although comments were often present in the charts, it was not possible to derive an ECOG score from the comments alone. At the start of treatment the ECOG was not recorded for 55.3% of patients (Table 19). The ECOG was not available for 86% of the patients at the time they entered the BSC phase of their treatment. For those for whom the ECOG was available, at the start of treatment 53.7% were status 1. This proportion had declined somewhat at the time of BSC to 42.9%. Although the numbers were too small to track changes over time for individuals, there was an overall decline in status by the time the patients reached the BSC phase. At start of treatment 23.9% of patients had an ECOG status code of 2 or greater, while at the time of BSC the percentage had increased to 42.9%. Table 19. Performance status of BSC NSCLC cases Before chemotherapy At BSC date 2 ECOG code 1 Number % Number % NS Total ECOG codes 0: Fully active, able to carry on all pre-disease performance without restriction 1: Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work 2: Ambulatory and capable of all self-care but unable to carry out any work activities. Up about more than 50% of waking hours 3: Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 4: Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 5: Dead 2. For three people, the death and BSC dates were the same 3. NS: not stated 18

25 3.7 Survival Of the 150 BSC patients, 140 had died and 2 had moved out of the province as of March 31, At the end of follow-up, the 150 BSC patients had accrued a total of person-weeks (mean 51.6 weeks) accrued from the date they were diagnosed with cancer and person-weeks (mean 26.1) from the date they went onto BSC (Table 20). Table 20 also shows the results from the date of first and last chemotherapy. Table 20. Number of person-weeks accrued by BSC NSCLC cases from diagnosis date, first and last chemotherapy date and BSC date From N Total Mean Median Minimum Maximum From diagnosis date First day of chemotherapy Last day of chemotherapy From BSC date BSC date was defined as 28 days after the last chemotherapy treatment ended The survival curves based on these four dates are shown in Figure 2. Tables provide survival information from each of the four dates by line and stage at diagnosis. The median survival time since diagnosis was 40.6 weeks, with 30.7% of the cases surviving one year and 11.7% surviving at least two years (Table 21). Since the BSC date the median survival was 13.8 weeks with 16.8% surviving one year and 5.8% surviving two years (Table 24). The median survival of people diagnosed with stage IV NSCLC was less than that of those diagnosed with stage IIIb NSCLC, although the differences were not statistically significant. For example, from BSC date the median survival of stage IV patients was 12.4 weeks compared to 21.4 weeks for Stage IIIb patients. The impact of receiving one or two lines of chemotherapy on survival varied according to the starting point from which survival was calculated, although it needs to be recognized that these findings are based on only a small number of patients who received more than one line of chemotherapy. Median survival from date of diagnosis (Table 21) and from date of first chemotherapy (Table 22) was significantly longer for patients receiving two lines of chemotherapy than those receiving only one line. However, from the date of last chemotherapy (Table 23) or from the date of BSC (Table 24), the patients who received more than one line of chemotherapy had a slightly shorter median survival than those who received only one line of 19

26 chemotherapy, although the differences were not significant. A similar pattern was observed among patients diagnosed at stage IV. Patients diagnosed with stage IIIb NSCLC and who received two lines of chemotherapy had a shorter, but not significantly shorter, survival than the IIIb patients who received only one line. Figure 2. Survival distribution of BSC NSCLC cases by diagnosis date, dates of first and last chemotherapy and BSC date Survival Diagnosis Date First Day of Chemotherapy Last Day of Chemotherapy BSC Date Weeks 20

27 Table 21. Survival of BSC NSCLC patients from diagnosis date, by stage at diagnosis and line Median Survived 1 year Survived 2 years Stage Line N (weeks) 95% CI 1 (%) (%) Total IIIb IV % confidence interval Table 22. Survival of BSC NSCLC patients from first date of chemotherapy, by stage at diagnosis and line Median Survived 1 year Survived 2 years Stage Line N (weeks) 95% CI 1 (%) (%) Total IIIb IV % confidence interval Table 23. Survival of BSC NSCLC patients from last day of chemotherapy, by stage at diagnosis and line Median Survived 1 year Survived 2 years Stage Line N (weeks) 95% CI 1 (%) (%) Total IIIb IV % confidence interval 21

28 Table 24. Survival of BSC NSCLC patients from BSC date, by stage at diagnosis and line Median Survived 1 year Survived 2 years Stage Line N (weeks) 95% CI 1 (%) (%) Total IIIb IV % confidence interval 4. DISCUSSION This report has provided some descriptive epidemiological information on all lung cancer patients diagnosed in Manitoba between 1997 and Similar descriptive information as well as survival analyses have been provided for 150 patients diagnosed with stage IV/IIIB (supraclavicular node involvement or pleural effusion) NSCLC who received either first or second line chemotherapy and survived more than 28 days after completion of chemotherapy. The majority of lung cancer patients in Manitoba (79.7%) were NSCLC. Similar proportions have been reported in other regions. 2,5-7 The NSCLC cases consisted of more males (58.1%) than females. Women with NSCLC tended to be diagnosed at a younger age than men. Similar findings have been reported by Radzikowska et al. 25 The sample of BSC NSCLC patients may not be representative of all Manitoba BSC patients. All the patients in the BSC sample received chemotherapy prior to BSC, but it is not known what percentage of all Manitoba BSC patients had similar treatment. Also, amongst all BSC patients chemotherapy may have been provided to some after they were put on BSC in order to improve quality of life. 16,26,27 None of the BSC sample had chemotherapy after the BSC date. The BSC sample also had to have survived at least 28 days after their last chemotherapy treatment. There were 150 patients who were initially diagnosed with NSCLC in the period of 1997 to June 2000 and who subsequently met our BSC definition. The proportion of these patients 22

29 increased with time, i.e. in % of patients met the criteria for BSC and 40% of patients did so in This suggests that oncologists are recognizing more and more the survival benefit of treating late stage NSCLC patients with chemotherapy. The majority of the sample of BSC NSCLC patients was 55 to 74 years of age. However, it is interesting to note that patients over 75 years of age were also being treated with chemotherapy and presumably benefiting from it. Gridelli reported that patients over 70 years of age with late stage NSCLC who received BSC plus vinorelbine survived longer and had a better quality of life than those patients who received BSC only. 28 Of the 150 patients, only a small number (17), received second line chemotherapy, which is not surprising given the fact that the benefit of second line chemotherapy in NSCLC has only become evident recently A small proportion of patients who had second line chemotherapy received the treatment on average 16 weeks after completion of first line treatment, suggesting that most of the patients would have had good initial response to first line chemotherapy, and second line treatment was initiated primarily for subsequent progression. Given the recency of the evidence indicating a benefit of second line chemotherapy, in the future there may well be an increasing proportion of patients receiving second line chemotherapy. Most (93.3%) of the patients in the sample has received either cisplatin or carboplatin in combination with other drugs. This is in keeping with the American Society of Clinical Guidelines that suggest that chemotherapy should be a platinum based combination regimen. 20 There have been many large randomized trials comparing various chemotherapy regimens for metastatic NSCLC. Apart from small differences in tolerability, there were no significant differences seen in response rates or survival. 5,19,32-36 One of the most commonly used combination regimens in the studies was vinorelbine with a platinum agent. Vinorelbine is the preferred choice in Canadian centres due to its low drug acquisition cost. The median survival time during the phase of BSC was 13.8 weeks. This indicates a substantial proportion of patients tolerated the chemotherapy well and lived a reasonable period of time following the 10 to 12 weeks of chemotherapy. The one and two year survival percentages from the date of first chemotherapy were 26.7% and 8.9% respectively, and the median was 31.8 weeks. Without chemotherapy, approximately 5% of patients with stage IV NSCLC cases live one year. 16 Giaccone, in a review of selected randomized trials conducted between 1994 and 2000, concluded that present chemotherapy can 23

30 induce a median survival of about 9 months in patients with stage IV and stage III with malignant pleural effusion, with a 1-year survival of about 35-40%. 22 More recently, Schiller et al. found that a group of late stage NSCLC patients randomized to four different platinum based chemotherapy regimens had a median survival time of 8.0 months and a survival rate at one year of 34%. 35 The survival of these patients has improved with chemotherapy. It is very encouraging to observe that the survival results for our population-based BSC sample was only slightly lower than the survival reported in the clinical studies. However direct comparisons with the results from this study and most clinical trials are problematic, as most of the latter measured survival from date of randomization, whereas the closest comparable date in this study was date of first chemotherapy. Furthermore, most clinical trials have strict inclusion criteria, such as good performance status, whereas the present study included all cases. When one considers that the date of first chemotherapy will be after the randomization date, then the results of this study would be similar to those reported by Schiller et al. 35 Similar to results reported in recent studies 29-32, the BSC patients who received second line chemotherapy appear to have a significantly better one-year survival than patients who received only first line chemotherapy, from both time of diagnosis (56% vs. 27%) and time of first chemotherapy (56% vs. 23%). There wasn t a significant survival difference between the two groups from time of last chemotherapy or from BSC date. However, it needs to be noted that only a small number of patients (n=17) had two lines of chemotherapy, and as previously stated, the patients who received second line chemotherapy had a relatively long progression free interval between lines. In conclusion, this report has provided extensive detail about the chemotherapy those NSCLC patients in their BSC phase received and information about their survival. Due to the relatively small sample of patients, there was not enough power to statistically test if there were differences in survival among patient subgroups. For example, given the relatively recent introduction of the use of second line chemotherapy treatment for BSC patients there were few patients who had this treatment, and thus it was not possible to determine if second line chemotherapy resulted in an increased survival. This question could be addressed by expanding the study sample to include BSC cases diagnosed since June of Relevant issues not examined in this study include what was the response rate to first line chemotherapy, what were the indications for second line chemotherapy, that is who responded to first line chemotherapy 24

31 and who did not, and were there any differences in the survival of patients who responded relative to those that did not. Unfortunately, these questions are not easily answered, as the databases do not have any information of responder status. In order to answer these questions, which are of great interests to oncologists, would require an extensive review of the charts to determine responder status. 5. REFERENCES National Cancer Institute of Canada. Canadian Cancer Statistics Toronto, Canada, Sekido Y, Fong KM, Kinna JD. Cancer of the lung. In: DeVita VT, Jr., Hellman S, Rosenberg SA, eds. Cancer Principles and Practice of Oncology. Philadelphia: Lippincott Williams and Wilkins; 2001: Gloeckler Ries LA. Influence of extent of disease, histology, and demographic factors on lung cancer survival in the SEER population-based data. Semin Surg Oncol 1994;10: Janssen-Heijnen MLG, Coebergh J-WW. Trends in incidence and prognosis of the histological subtypes of lung cancer in North America, Australia, New Zealand and Europe. Lung Cancer 2001;31: Chemotherapy and non-small-cell lung cancer. Drug Ther Bull. Feb 2002;40(2): Sörenson S, Glimelius B, Nygren P. A systematic overview of chemotherapy effects in non-small cell lung cancer. Acta Oncol 2001;40: Evans WK, Will BP, Berthelot J-M, Wolfson MC. Estimating the cost of lung cancer diagnosis and treatment in Canada: the POHEM model. Can J Oncol 1995;5: Sloan J, Nemecek A, Khoo K, et al. Experiences in Constructing Cancer Patient Trajectories through the Manitoba Health Care System. Winnipeg: Manitoba Cancer Treatment and Research Foundation, July Dillman RO, Berry C, Ryan KP, Green MR, Seagren SL. Recent outcomes for patients with carcinoma of the lung. Cancer Invest 1991;9: Houle C, Will BP, Berthelot J-M, Evans WK. The cost of managing lung cancer in Canada. Oncology 1995;9(11-supp): Ellison LF, Gibbons L, et al. Five-year relative survival from prostate, breast, colorectal and lung cancer. Health Reports 2002;13: Dranitsaris G, Cottrell W, Evans WK. Cost-effectiveness of chemotherapy for nonsmall-cell lung cancer. Curr Opin Oncol 2002;14: Grilli R, Oxman AD, Jullian JA: Chemotherapy for advanced 1on-small cell lung cancer: How much benefit is enough? J Clin Oncol 1993;11: Souquet PI, Chauvin F, Boissel JP, et al: Polychemotherapy in advanced non-small cell lung cancer: A meta-analysis. Lancet 1993;342: Marino P, Pampallona S, Preatoni A, Cantoni A, Invernizzi F. Chemotherapy vs supportive care in advanced non-small-cell lung cancer. Results of a meta-analysis of the literature. Chest 1994;106: