Stage 3 Lung Cancer - Know YourSurviving Conditions

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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

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TABLE OF CONTENTS 1. BACKGROUND... 1 2. METHODS... 2 2.1 Population... 2 2.2 Data ... 2 2.3 Analysis ... 3 3. RESULTS... 4

3.1 Lung cancer in Manitoba... 4

3.2 Age and stage of BSC NSCLC cases ... 5

3.3 Representativeness of BSC NSCLC cases ... 9 3.4 Chemotherapy ... 10 3.5 Metastases ... 17 3.6 Performance status ... 18 3.7 Survival ... 19 4. DISCUSSION... 22 5. REFERENCES... 25

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TABLES

Table 1. Type of incident trachea, bronchus and lung cancer cases by year of

diagnosis and sex, Manitoba 1997-2000...4

Table 2. Morphology of the trachea, bronchus and lung cancer cases by year of diagnosis and sex, Manitoba 1997-2000...5

Table 3. Age at diagnosis of NSCLC cases by year of diagnosis and sex, Manitoba 1997-2000 ...6

Table 4. Age at diagnosis of BSC NSCLC cases by year of diagnosis and sex, Manitoba January 1997 - June 2000 ...7

Table 5. Stage distribution of BSC NSCLC cases by year of diagnosis and sex, Manitoba 1997 - June, 2000 ...8

Table 6. Stage distribution of BSC NSCLC cases by age at diagnosis and sex, Manitoba 1997 - June 2000 ...8

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

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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. ... 20

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, 1997-2000...30 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

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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 2001.1 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”.13-16 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).17-21 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.

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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. METHODS

2.1 Population

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 1956.

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.

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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, 2002. Survival was calculated by the Kaplan-Meier method using SAS v8.223.

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3. RESULTS

3.1 Lung cancer in Manitoba

In the four-year period 1997-2000 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 1997-2000 1997 1998 1999 2000 Total1 ICD-9 Site N % N % N % N % N % Males 1620 Trachea 1 0.2 -- -- 2 0.4 -- -- 3 0.2 1622 Main bronchus 24 5.6 42 9.1 49 11.0 27 6.1 142 8.0 1623 Upper lobe 194 45.2 204 44.3 201 45.1 212 47.5 811 45.5 1624 Middle lobe 13 3.0 13 2.8 16 3.6 14 3.1 56 3.1 1625 Lower lobe 102 23.8 110 23.9 84 18.8 114 25.6 410 23.0 1628 Other parts 24 5.6 31 6.7 15 3.4 9 2.0 79 4.4 1629 Unspecified 71 16.6 60 13.0 79 17.7 70 15.7 280 15.7 Total 429 100.0 460 100.0 446 100.0 446 100.0 1781 100.0 Females 1620 Trachea 2 0.6 1 0.3 1 0.3 1 0.3 5 0.4 1622 Main bronchus 19 5.7 17 5.1 23 7.2 17 5.2 76 5.8 1623 Upper lobe 154 46.5 159 47.9 152 47.6 163 49.7 628 47.9 1624 Middle lobe 20 6.0 17 5.1 17 5.3 14 4.3 68 5.2 1625 Lower lobe 72 21.8 82 24.7 79 24.8 80 24.4 313 23.9 1628 Other parts 16 4.8 16 4.8 10 3.1 8 2.4 50 3.8 1629 Unspecified 48 14.5 40 12.0 37 11.6 45 13.7 170 13.0 Total 331 100.0 332 100.0 319 100.0 328 100.0 1310 100.0 Total 1620 Trachea 3 0.4 1 0.1 3 0.4 1 0.1 8 0.3 1622 Main bronchus 43 5.7 59 7.4 72 9.4 44 5.7 218 7.1 1623 Upper lobe 348 45.8 363 45.8 353 46.1 375 48.4 1439 46.6 1624 Middle lobe 33 4.3 30 3.8 33 4.3 28 3.6 124 4.0 1625 Lower lobe 174 22.9 192 24.2 163 21.3 194 25.1 723 23.4 1628 Other parts 40 5.3 47 5.9 25 3.3 17 2.2 129 4.2 1629 Unspecified 119 15.7 100 12.6 116 15.2 115 14.9 450 14.6 Total 760 100.0 792 100.0 765 100.0 774 100.0 3091 100.0

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Table 2. Morphology of the trachea, bronchus and lung cancer cases by year of diagnosis and sex, Manitoba 1997-2000 1997 1998 1999 2000 Total2 Type1 _N _% _N _% _N _% _N _% _N _% Males NSCLC 353 82.3 373 81.1 342 76.7 363 81.4 1431 80.3 SCLC 40 9.3 51 11.1 58 13.0 46 10.3 195 10.9 Other ₃₆ _8.4 ₃₆ _7.8 ₄₆ _10.3 ₃₇ _8.3 ₁₅₅ _8.7 Total ₄₂₉ _100.0 ₄₆₀ _100.0 ₄₄₆ _100.0 ₄₄₆ _100.0 ₁₇₈₁ _100.0 Females NSCLC 253 76.4 268 80.7 253 79.6 258 78.7 1032 78.8 SCLC 46 13.9 41 12.3 41 12.9 43 13.1 171 13.1 Other 32 9.7 23 6.9 24 7.5 27 8.2 106 8.1 Total ₃₃₁ _100.0 ₃₃₂ _100.0 ₃₁₈ _100.0 ₃₂₈ _100.0 ₁₃₀₉ _100.0 Total NSCLC 606 79.7 641 80.9 595 77.9 621 80.2 2463 79.7 SCLC 86 11.3 92 11.6 99 13.0 89 11.5 366 11.8 Other 68 8.9 59 7.4 70 9.2 64 8.3 261 8.4 Total 760 100.0 792 100.0 764 100.0 774 100.0 3090 100.0

1. There was one case who had an unknown tumor type

2. 3056 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 65-74 years of age at the time of diagnosis, whereas the majority of female cases were 55-64 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.

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Table 3. Age at diagnosis of NSCLC cases by year of diagnosis and sex, Manitoba 1997-2000 1997 1998 1999 2000 Total2 Age N % N % N % N % N % Males <35 1 0.3 2 0.5 -- -- 1 0.3 4 0.3 35-44 3 0.8 4 1.1 1 0.3 4 1.1 12 0.8 45-54 21 5.9 23 6.2 25 7.3 27 7.4 96 6.7 55-64 75 21.2 85 22.8 74 21.6 87 24.0 321 22.4 65-74 126 35.7 132 35.4 122 35.7 111 30.6 491 34.3 ≥75 127 36.0 127 34.0 120 35.1 133 36.6 507 35.4 Total 353 100.0 373 100.0 342 100.0 363 100.0 1431 100.0 Females <35 -- -- -- -- 1 0.4 1 0.4 2 0.2 35-44 3 1.2 2 0.7 7 2.8 7 2.7 19 1.8 45-54 36 14.2 20 7.5 27 10.7 26 10.1 109 10.6 55-64 53 20.9 66 24.6 60 23.7 59 22.9 238 23.1 65-74 87 34.4 83 31.0 93 36.8 74 28.7 337 32.7 ≥75 74 29.2 97 36.2 65 25.7 91 35.3 327 31.7 Total 253 100.0 268 100.0 253 100.0 258 100.0 1032 100.0 Total <35 1 0.2 2 0.3 1 0.2 2 0.3 6 0.2 35-44 6 1.0 6 0.9 8 1.3 11 1.8 31 1.3 45-54 57 9.4 43 6.7 52 8.7 53 8.5 205 8.3 55-64 128 21.1 151 20.0 134 22.5 146 23.5 559 22.7 65-74 213 35.1 215 33.5 215 36.1 185 29.8 828 33.6 75-00 201 33.1 224 34.9 185 31.1 224 36.1 834 33.9 Total 606 100.0 641 100.0 595 100.0 621 100.0 2463 100.0

1. There was one case who had an unknown tumor type

2. 3056 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.

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Table 4. Age at diagnosis of BSC NSCLC cases by year of diagnosis and sex, Manitoba January 1997 - June 2000 1997 1998 1999 2000 Total Age N % N % N % N % N % Males < 35 -- -- -- -- -- -- -- -- -- --35-44 -- -- 2 9.1 -- -- 1 5.0 3 3.6 45-54 4 23.5 4 18.2 3 12.0 1 5.0 12 14.3 55-64 4 23.5 7 31.8 11 44.0 7 35.0 29 34.5 65-74 8 47.1 7 31.8 10 40.0 6 30.0 31 36.9 ≥75 1 5.9 2 9.1 1 4.0 5 25.0 9 10.7 Total 17 100.0 22 100.0 25 100.0 20 100.0 84 100.0 Females < 35 -- -- -- -- 1 2.9 -- -- 1 1.5 35-44 -- -- -- -- 2 5.7 -- -- 2 3.0 45-54 3 33.3 4 33.3 7 20.0 4 40.0 18 27.3 55-64 3 33.3 5 41.7 12 34.3 2 20.0 22 33.3 65-74 3 33.3 2 16.7 10 28.6 4 40.0 19 28.8 ≥75 -- -- 1 8.3 3 8.6 -- -- 4 6.1 Total 9 100.0 12 100.0 35 100.0 10 100.0 66 100.0 Total < 35 -- -- -- -- 1 1.7 -- -- 1 0.7 35-44 -- -- 2 5.9 2 3.3 1 3.3 5 3.3 45-54 7 26.9 8 23.5 10 16.7 5 16.7 30 20.0 55-64 7 26.9 12 35.3 23 38.3 9 30.0 51 34.0 65-74 11 42.3 9 26.5 20 33.3 10 33.3 50 33.3 ≥75 1 3.8 3 8.8 4 6.7 5 16.7 13 8.7 Total 26 100.0 34 100.0 60 100.0 30 100.0 150 100.0

Figure 1. Age (at diagnosis) distribution of BSC NSCLC cases by sex

0 5 10 15 20 25 30 35 40 < 35 35-44 45-54 55-64 65-74 > 74 Age Percent Female Male

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Table 5. Stage distribution of BSC NSCLC cases by year of diagnosis and sex, Manitoba 1997 -June, 2000 1997 1998 1999 2000 Total Stage N % N % N % N % N % Males IIIb 5 29.4 -- -- 8 32.0 4 20.0 17 20.2 IV 12 70.6 22 100.0 17 68.0 16 80.0 67 79.8 Total 17 100.0 22 100.0 25 100.0 20 100.0 84 100.0 Females IIIb 3 33.3 3 25.0 8 22.9 2 20.0 16 24.2 IV 6 66.7 9 75.0 27 77.1 8 80.0 50 75.8 Total 9 100.0 12 100.0 35 100.0 10 100.0 66 100.0 Total IIIb 8 30.8 3 8.8 16 26.7 6 20.0 33 22.0 IV 18 69.2 31 91.2 44 73.3 24 80.0 117 78.0 Total 26 100.0 34 100.0 60 100.0 30 100.0 150 100.0

Table 6. Stage distribution of BSC NSCLC cases by age at diagnosis and sex, Manitoba 1997 -June 2000 IIIb IV Total Age N % N % N % Males < 35 -- -- -- -- -- --35-44 -- -- 3 4.5 3 3.6 45-54 1 5.9 11 16.4 12 14.3 55-64 6 35.3 23 34.3 29 34.5 65-74 8 47.1 23 34.3 31 36.9 ≥75 2 11.8 7 10.4 9 10.7 Total 17 100.0 67 100.0 84 100.0 Females < 35 -- -- 1 2.0 1 1.5 35-44 1 6.3 1 2.0 2 3.0 45-54 2 12.5 16 32.0 18 27.3 55-64 9 56.3 13 26.0 22 33.3 65-74 4 25.0 15 30.0 19 28.8 ≥75 -- -- 4 8.0 4 6.1 Total 16 100.0 50 100.0 66 100.0 Total < 35 -- -- 1 0.9 1 0.7 35-44 1 3.0 4 3.4 5 3.3 45-54 3 9.1 27 23.1 30 20.0 55-64 15 45.5 36 30.8 51 34.0 65-74 12 36.4 38 32.5 50 33.3 ≥75 2 6.1 11 9.4 13 8.7 Total 33 100.0 117 100.0 150 100.0

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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 1997-2000. In contrast, the majority of BSC were diagnosed in 1999. Fewer cases were diagnosed in 2000, as in deriving our sample we only examined cases up to June, 2000. 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 (1997 14.2%, 1998 14.7%, 1999 19.3%, 2000 19.0%). 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 1997 24.6 17.3 1998 26.1 22.7 1999 24.2 40.0 2000 25.2 20.0 Sex Males 58.1 56.0 Females 41.9 44.0

Over 64 years of age

Males 69.7 47.6

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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 112.6 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 1 150 82.3 78 1 337

Time between line 1 and 2 17 112.6 65 5 355

Line 2 17 75.2 86 1 179

Time between line 2 and 3 1 17.0 17 17 17

Line 3 1 1.0 1 1 1

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 % 0 130 86.7 14 82.4 1 100.0 1 16 10.7 3 17.6 -- --2 3 2.0 -- -- -- --3 1 0.7 -- -- -- --Total 150 100.0 17 100.0 1 100.0

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Table 10. Reason for changing the chemotherapy drug by line

Reason for Line 1 Line 2

changing N % N % Adverse reaction 2 8.0 -- --Intolerance 1 4.0 -- --Lack of effect 1 4.0 -- --Toxicity 6 24.0 -- --NS1 ₁₅ _58.3 ₃ _100.0 Total 25 100.0 3 100.0 1. 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 1 0.7 -- -- -- -- 1 0.6 Disease progression 6 4.0 3 17.6 -- -- 9 5.7 Patient refused 2 1.3 -- -- -- -- 2 1.3 Side effects 4 2.7 -- -- -- -- 4 2.5 Toxicity 11 7.3 2 11.8 -- -- 13 8.2 NS1 ₁₂₆ _84.0 ₁₂ _70.6 ₁ _100.0 ₁₄₀ _88.1 Total 150 100.0 17 100.0 1 100.0 159 100.0

1. 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 1998. Cisplatin was most commonly administered in combination with vinorelbine or etoposide, although the use of etoposide decreased markedly since 1997. 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.

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Table 12. Type of chemotherapy by year of diagnosis and line (intent to treat1) 1997 1998 1999 2000 Total Drug(s)1 _N _% _N _% _N _% _N _% _N _% Line 1 Cisplatin 23 88.5 11 32.4 30 50.0 13 43.3 77 51.3 CIS + VIN 10 38.5 5 14.7 21 35.0 12 40.0 48 32.0 CIS + ETO 13 50.0 5 14.7 8 13.3 1 3.3 27 18.0 CIS + GEM -- -- -- -- 1 1.7 -- -- 1 0.7 CIS + PAC -- -- 1 2.9 -- -- -- -- 1 0.7 Carboplatin 2 7.7 22 64.7 26 43.3 13 43.3 63 42.0 CAR + PAC -- -- 9 26.5 15 25.0 5 16.7 29 19.3 CAR + VIN 2 7.7 6 17.6 11 18.3 8 26.7 27 18.0 CAR + ETO -- -- 7 20.6 -- -- -- -- 7 4.7 Vinorelbine -- -- 1 2.9 3 5.0 3 10.0 7 4.7 Other 1 3.8 -- -- 1 1.7 1 3.3 3 2.0 Total 26 100.0 34 100.0 60 100.0 30 100.0 150 100.0 Line 2 Cisplatin -- -- 1 100.0 4 36.4 1 20.0 6 35.3 CIS + VIN -- -- -- -- 1 9.1 -- -- 1 5.9 CIS + ETO -- -- -- -- 3 27.3 -- -- 3 17.6 CIS + GEM -- -- 1 100.0 -- -- 1 20.0 2 11.8 Carboplatin -- -- -- -- 3 27.3 1 20.0 4 23.5 CAR + PAC -- -- -- -- -- -- 1 20.0 1 5.9 CAR + VIN -- -- -- -- 2 18.2 -- -- 2 11.8

CAR + ETO + ADR + BLE -- -- -- -- 1 9.1 -- -- 1 5.9

Vinorelbine -- -- -- -- 2 18.2 1 20.0 3 17.6 Docetaxel -- -- -- -- 2 18.2 2 40.0 4 23.5

Total -- 1 100.0 11 100.0 5 100.0 17 100.0

Line 3

Docetaxel -- -- 1 100.0 -- -- -- -- 1 100.0

1. 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.

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Table 13. Type of chemotherapy administered to the BSC NSCLC cases by stage at diagnosis and line (intent to treat1)

IIIb IV Total Drug(s)1 _N _% _N _% _N _% Line 1 Cisplatin 21 63.6 56 47.9 77 51.3 CIS + VIN 12 36.4 36 30.8 48 32.0 CIS + ETO 9 27.3 18 15.4 27 18.0 CIS + GEM -- -- 1 0.9 1 0.7 CIS + PAC -- -- 1 0.9 1 0.7 Carboplatin 12 36.4 51 43.6 63 42.0 CAR + PAC 6 18.2 23 19.7 29 19.3 CAR + VIN 6 18.2 21 17.9 27 18.0 CAR + ETO -- -- 7 6.0 7 4.7 Vinorelbine -- -- 7 6.0 7 4.7 Other -- -- 3 2.6 3 2.0 Total 33 100.0 117 100.0 150 100.0 Line 2 Cisplatin 3 42.9 3 30.0 6 35.3 CIS + VIN 1 -- -- -- 1 5.9 CIS + ETO 1 -- 2 20.0 3 17.6 CIS + GEM 1 -- 1 10.0 2 11.8 Carboplatin 3 42.9 1 10.0 4 23.5 CAR + PAC -- -- 1 10.0 1 5.9 CAR + VIN 2 -- -- -- 2 11.8

CAR + ETO + ADR + BLE 1 -- -- -- 1 5.9

Vinorelbine 1 14.3 2 20.0 3 17.6

Docetaxel -- -- 4 40.0 4 23.5

Total 7 100.0 10 100.0 17 100.0

Line 3

Docetaxel 1 100.0 -- -- 1 100.0

1. Dose given on first cycle

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/m2_{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/m2 of vinorelbine or 75 mg/m2 of cisplatin and 25 mg/m2 of vinorelbine were equally

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Table 14. Distribution of chemotherapy by dose (intent to treat1) and line for BSC NSCLC cases

Line 1 Line 2 Line 3

Drug(s)2 _Dose _N _% _N _% _N _% CIS + VIN 75 mg/m2 + 20 mg/m2 3 2.0 -- -- -- --75 mg/m2 + 25 mg/m2 16 10.7 1 5.9 -- --75 mg/m2 + 30 mg/m2 4 2.7 -- -- -- --100 mg/m2 + 25 mg/m2 14 9.3 -- -- -- --100 mg/m2 + 40 mg/m2 1 0.7 -- -- -- --120 mg/m2 + 30 mg/m2 1 0.7 -- -- -- --NS 9 6.0 -- -- -- --CIS + ETO 25 mg/m2 + 75 mg/m2 1 0.7 -- -- -- --25 mg/m2 + 100 mg/m2 9 6.0 -- -- -- --30 mg/m2 + 100 mg/m2 1 0.7 -- -- -- --50 mg/m2 + --50 mg/m2 3 2.0 -- -- -- --75 mg/m2 + 100 mg/m2 2 1.3 -- -- -- --100 mg/m2 + --100 mg/m2 1 0.7 -- -- -- --NS 10 6.7 3 17.6 -- --CIS + GEM 75 mg/m2 + 1000 mg/m2 1 0.7 -- -- -- --50 mg/m2 + 12--50 mg/m2 -- -- 1 5.9 -- --75 mg/m2 + 1250 mg/m2 -- -- 1 5.9 -- --CIS + PAC NS 1 0.7 -- -- --

--CAR + PAC 3 mg/ml.min + 60 mg/m2 1 0.7 -- -- --

--3 mg/ml.min + 175 mg/m2 -- -- 1 5.9 -- --5 mg/ml.min + 17--5 mg/m2 1 0.7 -- -- -- --6 mg/ml.min + 175 mg/m2 4 2.7 -- -- -- --6 mg/ml.min + 200 mg/m2 20 13.3 -- -- --

--NS 3 2.0 -- -- --

--CAR + VIN 6 mg/ml.min +25 mg/m2 26 17.3 2 11.8 --

--NS 1 0.7 -- -- --

--CAR + ETO 6 mg/ml.min+ 75 mg/m2 6 4.0 -- -- --

--NS 1 0.7 -- -- --

--CAR + ETO + ADR + BLE NS -- -- 1 5.9 --

--VIN 25 mg/m2 5 3.3 1 5.9 -- --30 mg/m2 1 0.7 -- -- -- --NS 1 0.7 2 11.8 -- --DOC 36 mg/m2 -- -- 1 5.9 -- --75 mg/m2 -- -- 1 5.9 -- --100 mg/m2 -- -- -- -- 1 100.0 NS -- -- 2 11.8 -- --Other NS 3 2.0 -- -- -- --Total 150 100.0 17 100.0 1 100.0

1. 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

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Table 15. Distribution of chemotherapy by dose (intent to treat1) 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/m2 + 20 mg/m2 1 3.0 -- -- -- --75 mg/m2 + 25 mg/m2 6 18.2 1 14.3 -- --100 mg/m2 + 25 mg/m2 1 3.0 -- -- -- --120 mg/m2 + 30 mg/m2 1 3.0 -- -- -- --NS 3 9.1 -- -- -- --CIS + ETO 25 mg/m2 + 100 mg/m2 5 15.2 -- -- -- --50 mg/m2 + --50 mg/m2 1 3.0 -- -- -- --75 mg/m2 + 100 mg/m2 1 3.0 -- -- -- --NS 2 6.1 1 14.3 -- --CIS + GEM 50 mg/m2 + 1250 mg/m2 -- -- 1 14.3 --

--CAR + PAC 3 mg/ml.min + 60 mg/m2 1 3.0 -- -- --

--6 mg/ml.min + 200 mg/m2 5 15.2 -- -- --

--CAR + VIN 6 mg/ml.min +25 mg/m2 6 18.2 2 28.6 --

--CAR + ETO + ADR + BLE NS -- -- 1 14.3 --

--VIN 25 mg/m2 -- -- 1 14.3 --

--Total 33 100.0 7 100.0 --

--1. Dose given on the first cycle

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Table 16. Distribution of chemotherapy by dose (intent to treat1) 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/m2 + 20 mg/m2 2 1.7 -- -- -- --75 mg/m2 + 25 mg/m2 10 8.5 -- -- -- --75 mg/m2 + 30 mg/m2 4 3.4 -- -- -- --100 mg/m2 + 25 mg/m2 13 11.1 -- -- -- --100 mg/m2 + 40 mg/m2 1 0.9 -- -- -- --NS 6 5.1 -- -- -- --CIS + ETO 25 mg/m2 + 75 mg/m2 1 0.9 -- -- -- --25 mg/m2 + 100 mg/m2 4 3.4 -- -- -- --30 mg/m2 + 100 mg/m2 1 0.9 -- -- -- --50 mg/m2 + --50 mg/m2 2 1.7 -- -- -- --75 mg/m2 + 100 mg/m2 1 0.9 -- -- -- --100 mg/m2 + --100 mg/m2 1 0.9 -- -- -- --NS 8 6.8 2 20.0 -- --CIS + GEM 75 mg/m2 + 1000 mg/m2 1 0.9 -- -- -- --75 mg/m2 + 1250 mg/m2 -- -- 1 10.0 -- --CIS + PAC NS 1 0.9 -- -- --

--CAR + PAC 3 mg/ml.min + 175 mg/m2 -- -- 1 10.0 --

--5 mg/ml.min + 17--5 mg/m2 1 0.9 -- -- -- --6 mg/ml.min + 175 mg/m2 4 3.4 -- -- -- --6 mg/ml.min + 200 mg/m2 15 12.8 -- -- --

--NS 3 2.6 -- -- --

--CAR + VIN 6 mg/ml.min +25 mg/m2 20 17.1 -- -- --

--NS 1 0.9 -- -- --

--CAR + ETO 6 mg/ml.min+ 75 mg/m2 6 5.1 -- -- --

--NS 1 0.9 -- -- -- --VIN 25 mg/m2 5 4.3 2 20.0 -- --30 mg/m2 1 0.9 -- -- -- --NS 1 0.9 -- -- -- --DOC 36 mg/m2 -- -- 1 20.0 1 100 75 mg/m2 -- -- 1 10.0 -- --NS -- -- 2 20.0 -- --Other NS 3 2.7 -- -- -- --Total 117 100.0 10 100.0 1 100.0

1. Dose given on the first cycle

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.

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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 1 5.9

CAR + PAC CIS + ETO 3 17.6

CAR + PAC CIS + GEM DOC 1 5.9

CAR + PAC CIS + VIN 1 5.9

CAR + VIN CIS + GEM 1 5.9

CIS + ETO CAR + VIN 1 5.9

CIS + ETO DOC 1 5.9

CIS + GEM DOC 1 5.9

CIS + VIN CAR + ETO + ADR + BLE 1 5.9

CIS + VIN DOC 2 11.8

CIS + VIN VIN 3 17.6

VIN CAR + PAC 1 5.9

Total 17 100.0

1. 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 site1

1 2 3 4 5 6 Total

Site N % N % N % N % N % N % N %

Lymph nodes –extrathoracic 21 14.0 36 30.3 11 15.7 3 11.5 1 10.0 -- -- 72 19.0 Lymph nodes –supraclavicular 16 10.7 4 3.4 3 4.3 -- -- -- -- -- -- 23 6.1 Lymph nodes –mediastinal -- -- 1 0.8 -- -- -- -- -- -- -- -- 1 0.3 Chest wall 31 20.7 14 11.8 3 4.3 -- -- 1 10.0 1 33.3 50 13.2 Lung 28 18.7 16 13.4 5 7.1 -- -- 1 10.0 -- -- 50 13.2 Bone 24 16.0 22 18.5 14 20.0 6 23.1 2 20.0 -- -- 68 18.0 Adrenal 9 6.0 8 6.7 9 12.9 3 11.5 1 10.0 -- -- 30 7.9 CNS 8 5.3 5 4.2 13 18.6 9 34.6 2 20.0 1 33.3 38 10.1 Liver 6 4.0 9 7.6 2 2.9 2 7.7 -- -- 1 33.3 20 5.3 Cutaneous 4 2.7 3 2.5 4 5.7 3 11.5 -- -- -- -- 14 3.7 Other 3 2.0 1 0.8 6 8.6 -- -- 2 20.0 -- -- 12 3.2 Total 150 100 119 100 70 100 25 100 10 100 3 100 377 100

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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 date2 ECOG code1 _Number _% _Number _%

NS3 ₈₃ _55.3 ₁₂₉ _86.0 0 15 10.0 3 2.0 1 36 24.0 9 6.0 2 15 10.0 5 3.3 3 1 0.7 1 0.7 4 -- -- -- --5 -- -- 3 2.0 Total 150 100.0 150 100.0 1. 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

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3.7 Survival

Of the 150 BSC patients, 140 had died and 2 had moved out of the province as of March 31, 2002. At the end of follow-up, the 150 BSC patients had accrued a total of 7744.4 person-weeks (mean 51.6 weeks) accrued from the date they were diagnosed with cancer and 3906.0 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 150 7744.4 51.6 40.6 8.1 206.7

First day of chemotherapy 150 6709.1 44.7 31.8 4.3 195.7 Last day of chemotherapy 150 4506.0 30.0 17.8 4.0 184.7

From BSC date1 ₁₅₀ _3906.0 _26.0 _13.8 _0.0 _180.7

1. 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 21-24 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

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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.

0.00 0.25 0.50 0.75 1.00 0 26 52 78 104 130 156 Weeks Survival Diagnosis Date

First Day of Chemotherapy Last Day of Chemotherapy BSC Date

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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% CI1 _(%) _(%)

Total 150 40.6 35.4 – 45.7 30.7 11.7 1 133 38.1 33.7 – 43.4 27.8 11.0 1 + 2 16 61.6 47.3 – 94.3 56.3 18.8 1 + 2 +3 1 41.4 -- -- --IIIb 33 53.6 36.7 – 67.0 51.5 10.1 1 26 55.4 35.4 – 79.3 53.9 13.2 1 + 2 7 47.3 36.7 – 94.3 42.9 --IV 117 38.6 32.1 – 42.7 24.8 12.0 1 107 36.3 31.4 – 41.3 21.5 10.3 1 + 2 9 83.3 47.3 - 107.1 66.7 33.3 1 + 2 +3 1 41.4 -- -- --1. 95% confidence interval

Table 22. Survival of BSC NSCLC patients from first date of chemotherapy, by stage at diagnosis and line

Total 150 31.8 28.7 – 37.7 26.7 8.9 1 133 30.4 26.7 – 34.1 23.3 8.6 1 + 2 16 60.6 36.4 – 88.4 56.3 12.5 1 + 2 +3 1 27.1 -- -- --IIIb 33 43.0 30.4 – 60.9 45.5 10.2 1 26 46.6 26.7 – 71.0 46.2 13.5 1 + 2 7 36.4 29.4 – 88.4 42.9 --IV 117 29.4 27.0 – 36.1 21.4 8.5 1 107 29.0 25.1 – 33.0 17.8 7.5 1 + 2 9 78.0 45.9 – 96.1 66.7 22.2 1 + 2 +3 1 27.1 -- -- --1. 95% confidence interval

Table 23. Survival of BSC NSCLC patients from last day of chemotherapy, by stage at diagnosis and line

Total 150 _17.8 _{14.9 – 20.3} _18.9 _5.8 1 133 18.0 14.9 – 20.4 19.6 6.3 1 + 2 16 17.4 12.3 – 29.0 14.3 --1 + 2 +3 1 6.6 -- -- --IIIb 33 25.4 17.3 – 40.9 30.3 7.6 1 26 26.1 17.6 – 52.3 34.6 9.6 1 + 2 7 14.0 10.0 – 35.6 14.3 --IV 117 16.4 13.7 – 19.1 15.6 5.5 1 107 16.4 12.6 – 19.1 15.9 5.6 1 + 2 9 19.4 14.7 – 29.0 -- --1 + 2 +3 1 6.6 -- -- --1. 95% confidence interval

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Table 24. Survival of BSC NSCLC patients from BSC date, by stage at diagnosis and line

Total 150 13.8 10.9 – 16.3 16.8 5.8 1 133 14.0 10.9 – 16.4 17.3 6.3 1 + 2 16 13.4 8.3 – 25.0 14.3 --1 + 2 +3 1 2.6 -- -- --IIIb 33 21.4 13.3 – 36.9 21.2 7.6 1 26 22.1 13.6 – 48.3 23.1 9.6 1 + 2 7 10.0 6.0 – 31.6 14.3 --IV 117 12.4 9.7 – 15.1 15.6 5.5 1 107 12.4 8.6 – 15.1 15.9 5.6 1 + 2 9 15.4 10.7 – 25.0 -- --1 + 2 +3 1 2.6 -- -- --1. 95% confidence interval

4. DISCUSSION

This report has provided some descriptive epidemiological information on all lung cancer patients diagnosed in Manitoba between 1997 and 2000. 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

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increased with time, i.e. in 1997 17% of patients met the criteria for BSC and 40% of patients did so in 1999. 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.29-32 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

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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 studies29-32, 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 2000. 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

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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

1. 1. National Cancer Institute of Canada. Canadian Cancer Statistics 2001. Toronto, Canada, 2001.

2. 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; 2001:917-1018.

3. 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;10:21-30.

4. 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;31:123-37.

5. Chemotherapy and non-small-cell lung cancer. Drug Ther Bull. Feb 2002;40(2):9-11.

6. Sörenson S, Glimelius B, Nygren P. A systematic overview of chemotherapy effects in non-small cell lung cancer. Acta Oncol 2001;40:327-39.

7. 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;5:408-19.

8. 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 1995.

9. Dillman RO, Berry C, Ryan KP, Green MR, Seagren SL. Recent outcomes for patients with carcinoma of the lung. Cancer Invest 1991;9:9-17.

10.Houle C, Will BP, Berthelot J-M, Evans WK. The cost of managing lung cancer in Canada. Oncology 1995;9(11-supp):147-53.

11.Ellison LF, Gibbons L, et al. Five-year relative survival from prostate, breast, colorectal and lung cancer.Health Reports 2002;13:1-11.

12.Dranitsaris G, Cottrell W, Evans WK. Cost-effectiveness of chemotherapy for nonsmall-cell lung cancer. Curr Opin Oncol 2002;14:375-83.

13.Grilli R, Oxman AD, Jullian JA: Chemotherapy for advanced 1on-small cell lung cancer: How much benefit is enough? J Clin Oncol 1993;11:1866-72.

14.Souquet PI, Chauvin F, Boissel JP, et al: Polychemotherapy in advanced non-small cell lung cancer: A meta-analysis. Lancet 1993;342:19-21.

15.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.

(32)

16.Non-Small Cell Lung Cancer Collaborative Group: Chemotherapy in non-small cell lung cancer: A meta-analysis using updated individual patients from 52 randomized clinical trials. BMJ 1995;311:899-909.

17.Lopez PG, Stewart DJ, Newman TE, Evans WK. Chemotherapy in stage IV (metastatic) non-small-cell lung cancer. Provincial Lung Disease Site Group. Cancer Prev Control 1997;1(1):18-27.

18.Okawara G, Rusthoven J, Newman T, Findlay B, Evans W. Unresected stage III non-small-cell lung cancer. Provincial Lung Cancer Disease Site Group. Cancer Prev Control 1997;1(3):249-59.

19.Goss GD, Logan DM, Newman TE, Evans WK. Use of vinorelbine in non-small-cell lung cancer. Provincial Lung Disease Site Group. Cancer Prev Control 1997;1(1):28-38.

20.American Society of Clinical Oncology. Clinical practice guidelines for the treatment of unresectable non-small-cell lung cancer. J Clin Oncol 1997;15(8):2996-3018.

21.Bardet E, Moro-Sibilot D, Le Chevalier T, et al. Standards, options and recommendations for

the management of locally advanced non small cell lung carcinoma. Bull Cancer

2001;88(4):369-87.

22.Giaccone G. The state of the art in systemic treatment of lung cancer. Eur J Cancer 2001;37(Suppl 7):S99-S114.

23.Rothman KJ, Greenland S. Measures of disease frequency. In: Rothman KJ, Greenland S, eds. Modern Epidemiology. Philadelphia: Lippincott Williams and Wilkins; 1998:29-46. 24.Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern

Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-55.

25.Radzikowska E, Glaz P, Roszkowski K. Lung cancer in women: age, smoking, histology, performance status, initial treatment and survival. Population-based study of 20 561 cases. Ann Oncol 2002;13:1087-93.

26.Paesmans M. Benefits of chemotherapy for quality of life in patients with advanced nonsmall-cell lung cancer. Curr Opin Oncol 2002;14:389-93.

27.Rivera MP. Management of patients with advanced non-small-cell lung cancer. Curr Opin Pulm Med 2001;7(4):247-58.

28.Gridelli C. The ELVIS trial: a phase III Study of single-agent vinorelbine as first-line treatment in elderly patients with advanced non-small cell lung cancer, Oncologist 2001;6(Suppl 1):4-7.

29.Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F, Kalman L, Miller V, Lee JS, Moore M, Gandara D, Karp D, Vokes E, Kris M, Kim Y, Gamza F, Hammershaimb L, Tax 320 Non-Small-Cell Lung Cancer Study Group. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. J Clin Oncol 2000;18:2354-62.

30.Fossella FV. Second-line chemotherapy for non-small-cell lung cancer. Curr Oncol Rep 2000;2:96-101.

31.Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O’Rourke M, Levitan N, Gressot L, Vincent M, Burkes R, Coughlin S, Kim Y, Berile J. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously

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32.Shepherd FA, Fossella FV, Lyynch T, Armand J-P, Rigas JR, Kris MG. Docetaxel (taxotere) shows survival and quality-of-life benefits in the second-line treatment of non-small cell lung cancer: a review of two phase III trials. Semin Oncol 2001;28(Suppl 2):4-9.

33.Haura EB. Treatment of advanced non-small-cell lung cancer: a review of current randomized clinical trials and an examination of emerging therapies. Cancer Control 2001;8(4):326-36.

34.Carney DN. Lung cancer – time to move on from chemotherapy. NEJM 2002;346:126-127. 35.Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH.

Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. NEJM 2002;346:92-8.

36.Ettinger DS. Is there a preferred combination chemotherapy regimen for metastatic non-small cell lung cancer. Oncologist 2002;7:226-33.

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Appendix 1. Classification of lung cancer according to morphology Type ICD-0 code Description

Non-small cell 80103 Carcinoma NOS, malignant 80123 Large cell carcinoma 80213 Anaplastic carcinoma 80313 Giant cell carcinoma

80523 Papillary squamous cell carcinoma (papillary epidermoid carcinoma) 80703 Squamous cell carcinoma, malignant

80713 Keratinizing squamous cell carcinoma 80723 Large cell, nonkeratinizing squamous

80743 Squamous cell carcinoma, spindle cell (epidermoid carcinoma, spindle cell) 81403 Adenocarcinoma, malignant

82503 Bronchiolo-alveolar adenocarcinoma

82513 Alveolar adenocarcinoma (alveolar carcinoma) 82603 Papillary adenocarcinoma

82623 Villous adenocarcinoma

83103 Clear cell adenocarcinoma, NOS 84303 Mucoepidermoid carcinoma 84803 Mucinous adenocarcinoma 84813 Mucin-producing adenocarcinoma

84903 Signet ring cell carcinoma (adenocarcinoma) 85603 Adenosquamous carcinoma

90523 Epidethelioid mesothelioma, malignant (epithelioid mesothelioma, NOS) Small cell 80023 Malignant tumor, small cell type

80413 Small cell carcinoma nos. 80423 Oat cell carcinoma (C34)

80433 Small cell carcinoma, fusiform cell 80443 Intermediate, small cell carcinoma 80453 Small cell - large cell carcinoma 80733 Small cell, nonkeratinizing squamous Other 80003 Neoplasm nos., malignant

80013 Tumor cells, malignant 80203 Undifferentiated carcinoma 80333 Pseudosarcomatous carcinoma 81233 Basaloid carcinoma

82003 Adenoid cystic carcinoma (adenocyctic carcinoma, cylindroma NOS, bronchial adenoma cylindroid, edenocarcinoma, cylindroid)

82403 Carcinoid NOS (except appendix: … 82463 Neuro-endocrine carcinoma

83233 Mixed cell carcinoma

84723 Mucinous cystadenoma, borderline malignancy (psedomucinous cystadenoma borderline malignancy, mucinous tumor NOS or low malignant potential) 85503 Acinar cell carcinoma (acinar cell adenocarcinoma, acinar adenocarcinoma,

acinar carcinoma)

87203 Malignant melanoma NOS 88003 Sarcoma NOS

88103 Fibrosarcoma 89803 Carcinosarcoma NOS 90513 Fibrous mesothelioma

96753 Diffuse lymphoma, small and large cell 96803 Diffuse lymphoma, large cell NOS 96813 Diffuse lymphoma, large cell cleav… 96843 Lymphoma, immunoblastic, NOS p 96123 97113 Monocytoid B-cell lymphoma

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Appendix 2. Morphology of the trachea, bronchus and lung cancer cases diagnosed in Manitoba, 1997-2000

1997 1998 1999 2000 Total

Type ICD-O Count % Count % Count % Count % Count %

NSCLC 80103 135 18.0 172 22.0 169 22.2 163 21.3 639 20.9 80123 41 5.5 35 4.5 22 2.9 32 4.2 130 4.3 80213 - - 2 0.3 - - 3 0.4 5 0.2 80313 3 0.4 2 0.3 4 0.5 2 0.3 11 0.4 80523 1 0.1 1 0.1 - - - - 2 0.1 80703 145 19.4 137 17.5 123 16.2 129 16.9 534 17.5 80713 13 1.7 17 2.2 19 2.5 16 2.1 65 2.1 80723 1 0.1 1 0.1 1 0.1 2 0.3 5 0.2 80743 1 0.1 0 - - - 1 -81403 205 27.4 211 26.9 193 25.4 202 26.4 811 26.5 82503 28 3.7 21 2.7 33 4.3 47 6.1 129 4.2 82513 - - 1 0.1 - - - - 1 -82603 5 0.7 7 0.9 3 0.4 3 0.4 18 0.6 82623 - - 0 - 1 0.1 - - 1 -83103 - - 3 0.4 2 0.3 - - 5 0.2 84303 - - 1 0.1 - - - - 1 -84803 4 0.5 3 0.4 1 0.1 - - 8 0.3 84813 8 1.1 16 2.0 13 1.7 5 0.7 42 1.4 84903 1 0.1 0 - 1 0.1 1 0.1 3 0.1 85603 4 0.5 2 0.3 5 0.7 7 0.9 18 0.6 90523 - - 0 - - - 1 0.1 1 -SCLC 80413 75 10.0 85 10.9 89 11.7 81 10.6 330 10.8 80423 5 0.7 4 0.5 3 0.4 1 0.1 13 0.4 80443 6 0.8 2 0.3 3 0.4 5 0.7 16 0.5 80453 - - 1 0.1 4 0.5 2 0.3 7 0.2 Other 80003 52 7.0 49 6.3 58 7.6 49 6.4 208 6.8 80013 - - 0 - - - 1 0.1 1 -80203 3 0.4 0 - 1 0.1 - - 4 0.1 80333 - - 1 0.1 1 0.1 - - 2 0.1 81233 - - 0 - 1 0.1 - - 1 -82003 1 0.1 0 - - - 1 -82403 7 0.9 6 0.8 6 0.8 7 0.9 26 0.9 82463 2 0.3 1 0.1 - - 3 0.4 6 0.2 83233 - - 0 - 1 0.1 - - 1 -84723 - - 0 - 1 0.1 - - 1 -85503 - - 0 - - - 1 0.1 1 -88003 - - 0 - 1 0.1 1 0.1 2 0.1 88103 - - 1 0.1 - - - - 1 -89803 2 0.3 1 0.1 - - 1 0.1 4 0.1 Missing - - - 0 - 1 0.1 - - 1 -Total 748 100.0 783 100.0 760 100.0 765 100.0 3056 100.0

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Appendix 3.1 Distribution of chemotherapy according to schedule (line and cycle) for BSC NSCLC cases

Cycle 1 Cycle 2 Cycle 3 Cycle4 Cycle 5 Cycle 6 Cycle 7 Cycle 8 Cycle 9 Cycle10 Total

Drugs1 _N _% _N _% _N _% _N _% _N _% _N _% _N _% _N _% _N _% _N _% _N _%

Line 1

CIS + VIN 48 31.8 36 28.8 28 29.5 15 25.0 8 24.2 4 14.8 -- -- -- -- -- -- -- -- 139 27.9

CIS + ETO 27 17.9 20 16.0 13 13.7 8 13.3 5 15.2 4 14.8 -- -- -- -- -- -- -- -- 77 15.4

CIS + ETO + ADR -- -- 1 0.8 1 1.1 1 1.7 1 3.0 1 3.7 -- -- -- -- -- -- -- -- 5 1.0

CIS + GEM 1 0.7 1 0.8 3 3.2 3 5.0 -- -- -- -- -- -- -- -- -- -- _-- _-- 8 1.6 CIS + PAC 1 0.7 1 0.8 -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- 2 0.4 CAR + PAC 29 19.2 28 22.4 16 16.8 9 15.0 8 24.2 8 29.6 -- -- -- -- -- -- _-- _-- 98 19.6 CAR + VIN 28 18.5 27 21.6 26 27.4 17 28.3 8 24.2 7 25.9 2 50.0 -- -- -- -- -- -- 115 23.0 CAR + ETO 7 4.6 5 4.0 4 4.2 3 5.0 -- -- -- -- 1 25.0 1 50.0 1 100 1 100 23 4.6 CAR + GEM -- -- -- -- -- -- -- -- 1 3.0 1 3.7 -- -- -- -- -- -- -- -- 2 0.4 VIN 7 4.6 4 3.2 4 4.2 3 5.0 2 6.1 2 7.4 -- -- -- -- -- -- -- -- 22 4.4 Other 3 2.0 2 1.6 -- -- 1 1.7 -- -- -- -- 1 25.0 1 50.0 -- -- -- -- 8 1.6 Total2 _{151 100 125 100} ₉₅ ₁₀₀ ₆₀ ₁₀₀ ₃₃ ₁₀₀ ₂₇ ₁₀₀ ₄ ₁₀₀ ₂ ₁₀₀ ₁ ₁₀₀ ₁ _{100 499 100} Line 2 CIS + ETO 3 17.6 2 20.0 2 20.0 2 22.2 2 40.0 1 33.3 -- -- -- -- -- -- -- -- 12 22.2 CIS + GEM 2 11.8 -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- 2 3.7 CIS + VIN 1 5.9 1 10.0 1 10.0 1 11.1 -- -- -- -- -- -- -- -- -- -- -- -- 4 7.4 CAR + PAC 1 5.9 1 10.0 1 10.0 1 11.1 1 20.0 1 33.3 -- -- -- -- -- -- -- -- 6 11.1 CAR + VIN 2 11.8 1 10.0 1 10.0 1 11.1 -- -- -- -- -- -- -- -- -- -- -- -- 5 9.3

CAR + ETO + ADR -- -- 1 10.0 1 10.0 1 11.1 -- -- -- -- -- -- -- -- -- -- -- -- 3 5.6

CAR + ETO + ADR + BLE 1 5.9 -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- 1 1.9

DOC 4 23.5 3 30.0 3 30.0 2 22.2 1 20.0 1 33.3 -- -- -- -- -- -- -- -- 14 25.9 VIN 3 17.6 -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- 3 5.6 Other -- -- 1 10.0 1 10.0 1 11.1 1 20.0 -- -- -- -- -- -- -- -- -- -- 4 7.4 Total 17 100 10 100 10 100 9 100 5 100 3 100 -- -- -- -- -- -- -- -- 54 100 Line 3 DOC 1 100 -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- 1 100

2. Two patients (one on cycle 1 and one on cycle 2) had their drugs changed on the same day they started treatment, which is why the sums for cycle 1 and 2 are higher than those of other tables

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Appendix 3.2 Distribution of chemotherapy according to schedule (line and cycle) for stage IIIb BSC NSCLC cases

Drugs1 _{Cycle 1} _{Cycle 2} _{Cycle 3} _Cycle4 _{Cycle 5} _{Cycle 6} _{Cycle 7} _{Cycle 8} _{Cycle 9} _Cycle10 _Total

N % N % N % N % N % N % N % N % N % N % N % :Line 1 CIS + VIN 12 36.4 10 38.5 7 33.3 3 25.0 1 12.5 1 14.3 -- -- -- -- -- -- -- -- 34 31.8 CIS + ETO ₉ 27.3 ₆ 23.1 ₃ 14.3 ₂ 16.7 ₁ 12.5 ₁ 14.3 -- -- -- -- -- -- -- -- 22 20.6 CAR + PAC 6 18.2 5 19.2 3 14.3 1 8.3 2 25.0 2 28.6 -- -- -- -- -- -- -- -- 19 17.8 CAR + VIN ₆ 18.2 ₅ 19.2 ₈ 38.1 ₆ 50.0 ₄ 50.0 ₃ 42.9 -- -- -- -- -- -- -- -- 32 29.9 Total 33 100 26 100 21 100 12 100 8 100 7 100 -- -- -- -- -- -- -- -- 107 100 Line 2 CIS + ETO 1 14.3 1 25.0 1 25.0 1 25.0 1 100 -- -- -- -- -- -- -- -- -- -- 5 25.0 CIS + GEM ₁ 14.3 _-- -- _-- -- _-- -- _-- -- -- -- -- -- -- -- -- -- -- -- 1 5.0 CIS + VIN ₁ 14.3 ₁ 25.0 ₁ 25.0 ₁ 25.0 _-- -- -- -- -- -- -- -- -- -- -- -- 4 20.0 CAR + VIN ₂ 28.6 ₁ 25.0 ₁ 25.0 ₁ 25.0 _-- -- -- -- -- -- -- -- -- -- -- -- 5 25.0

CAR + ETO + ADR _-- -- ₁ 25.0 ₁ 25.0 ₁ 25.0 _-- -- -- -- -- -- -- -- -- -- -- -- 3 15.0

CAR + ETO + ADR + BLE 1 14.3 -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- 1 5.0

VIN ₁ 14.3 _-- -- _-- -- _-- -- _-- -- -- -- -- -- -- -- -- -- -- -- 1 5.0

Total 7 100 4 100 4 100 4 100 1 100 -- -- -- -- -- -- -- -- -- -- 20 100

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Appendix 3.3 Distribution of chemotherapy according to schedule (line and cycle) for stage IV BSC NSCLC cases

Cycle 1 Cycle 2 Cycle 3 Cycle4 Cycle 5 Cycle 6 Cycle 7 Cycle 8 Cycle 9 Cycle10 Total

Drugs1 _N _% _N _% _N _% _N _% _N _% _N _% _N _% _N _% _N _% _N _% _N _%

Line 1

CIS + VIN 36 30.5 26 26.3 21 28.4 12 25.0 7 28.0 3 15.0 -- -- -- -- -- -- -- -- 105 26.8

CIS + ETO ₁₈ _{15.3 14 14.1 10 13.5} ₆ 12.5 ₄ 16.0 ₃ 15.0 _-- -- _-- -- _-- -- _-- -- 55 14.0

CIS + ETO + ADR _-- -- ₁ 1.0 ₁ 1.4 ₁ 2.1 ₁ 4.0 ₁ 5.0 _-- -- _-- -- _-- -- _-- -- 5 1.3

CIS + GEM ₁ 0.8 ₁ 1.0 ₃ 4.1 ₃ 6.3 _-- -- _-- -- _-- -- _-- -- _-- -- _-- -- 8 2.0 CIS + PAC ₁ 0.8 ₁ 1.0 _-- -- _-- -- _-- -- _-- -- _-- -- _-- -- _-- -- _-- -- 2 0.5 CAR + PAC ₂₃ _{19.5 23 23.2 13 17.6} ₈ 16.7 ₆ 24.0 ₆ 30.0 _-- -- _-- -- _-- -- _-- -- 79 20.2 CAR + VIN ₂₂ _{18.6 22 22.2 18 24.3 11 22.9} ₄ 16.0 ₄ 20.0 ₂ 50.0 _-- -- _-- -- _-- -- 83 21.2 CAR + ETO ₇ 5.9 ₅ 5.1 ₄ 5.4 ₃ 6.3 _-- -- _-- -- ₁ 25.0 ₁ 50.0 ₁ 100 ₁ 100 23 5.9 CAR + GEM _-- -- _-- -- _-- -- _-- -- ₁ 4.0 ₁ 5.0 _-- -- _-- -- _-- -- _-- -- 2 0.5 VIN ₇ 5.9 ₄ 4.0 ₄ 5.4 ₃ 6.3 ₂ 8.0 ₂ 10.0 _-- -- _-- -- _-- -- _-- -- 22 5.6 Other ₃ 2.5 ₂ 2.0 _-- -- ₁ 2.1 _-- -- _-- -- ₁ 25.0 ₁ 50.0 _-- -- _-- -- 8 2.0 Total 118 100 99 100 74 100 48 100 25 100 20 100 4 100 2 100 1 100 1 100 392 100 Line 2 CIS + ETO 2 20.0 1 16.7 1 16.7 1 20.0 1 25.0 1 33.3 -- -- -- -- -- -- -- -- 7 20.6 CIS + GEM ₁ 10.0 _-- -- _-- -- _-- -- _-- -- _-- -- -- -- -- -- -- -- -- -- 1 2.9 CAR + PAC 1 10.0 1 16.7 1 16.7 1 20.0 1 25.0 1 33.3 -- -- -- -- -- -- -- -- 6 17.6 DOC ₄ 40.0 ₃ 50.0 ₃ 50.0 ₂ 40.0 ₁ 25.0 ₁ 33.3 -- -- -- -- -- -- -- -- 14 41.2 VIN ₂ 20.0 _-- -- _-- -- _-- -- _-- -- _-- -- -- -- -- -- -- -- -- -- 2 5.9 Other _-- -- ₁ 16.7 ₁ 16.7 ₁ 20.0 ₁ 25.0 _-- -- -- -- -- -- -- -- -- -- 4 11.8 Total 10 100 6 100 6 100 5 100 4 100 3 100 -- -- -- -- -- -- -- -- 34 100 Line 3 DOC 1 100 -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- 1 100