Variations in the management and outcome of non-small cell lung cancer in Ontario

I:tAO,OrHSRAPY

&ONCOLOGY

ELSEVIER

Radiotherapy and Oncology 32 (1994) 106-115

Variations in the management and outcome of non-small cell lung cancer in Ontario W.J. Mackillop a'b'*, P. Dixon a'b, Y. Zhou a'b, C.T. Ago c, G. Eged, D.I. Hodson e, J.F. Kotalik f, C. Lochrin g, L. Paszat", D. Harris ] aThe Radiation Oncology Research Unit, Queen's University, Apps Level 4. Kingston General Hospital, Kingston. Ontario. K7L 2V7. Canada bDepartment of Radiation Oncology. Kingston Regional Centre of the Ontario Cancer Treatment and Research Foundatian. Kingston. Ontario. Canada CDepartment of Radiation Oneology, London Regional Centre of the Ontario Cancer Treatment and Research Foundation, London. Ontario, Canada dDepartment of Radiation Oneology, Toronto-Bayview Regional Centre of the Ontario Cancer Treatment and Research Foundation. Toronto, Ontario, Canada eDepartment of Radiation Oneology. Hamilton Regional Centre of the Ontario Cancer Treatment and Research Foundation, Hamilton, Ontario, Canada fDepartment of Radiation Ontology, Thunder Bay Regional Centre of the Ontario Cancer Treatment and Research Foundation, Thunder Bay, Ontario, Canada gDepartment of Radiation Ontology, Ottawa Regional Centre of the Ontaria Cancer Treatment and Research Foundation, Ottawa, Ontario, Canada hDepartment of Radiation Oncology, Windor Regional Centre of the Ontario Cancer Treatment and Research Foundation, Windsor, Ontario, Canada iDepartment of Information Systems, Ontario Cancer Treatment and Research Foundation, Toronto, Ontario, Canada

Received 22 September 1993; revision received 18 April 1994; accepted 10 May 1994

Abstract

Prospectively gathered information in the Ontario Cancer Foundation's computerized clinical database was analysed to provide a description of the management of 12 399 patients with unresected non-small cell lung cancer (NSCLC) registered at seven regional cancer centres in Ontario between 1982 and 1991. Overall, 44% received initial thoracic radiotherapy, 19% received initial radiotherapy to metastatic sites, and 36% received no immediate radiotherapy. Of those who received thoracic radiation 41% received doses ~ 40 Gy and 59% received doses < 40 Gy. Among the seven centres, the proportion of patients receiving initial thoracic radiotherapy ranged from 41% to 56% (p < 0.001), and the proportion of those receiving doses _>40 Gy ranged from 30% to 68% (p < 0.001). Between 1982 and 1991, the overall proportion of patients who received initial thoracic radiotherapy decreased from 48% to 38%, the proportion of those receiving high dose treatment decreased from 55"/o to 28%, and the mean number of fractions given to the chest decreased from 17 to 10. Only 10%oreceived chemotherapy at any time, and that proportion ranged from 3% to 21% (p < 0.001) among the seven centres. Between 1982 and 1991 the proportion of patients receiving chemotherapy decreased significantly from 15% to 8% (p < 0.001) across the Cancer Foundation as a whole. These wide variations in management policies were not associated with any significant differences in survival, which was similar at all seven centres, and remained constant between 1982 and 1991. Keywords: Non-small cell lung cancer; Radiotherapy; Chemotherapy; Patterns of care; Practice variation

* Corresponding author. 0167-8140/94/$07.00 © 1994 Elsevier Science Ireland Ltd. All rights reserved SSDI 0167-8140(94)01405-R

W..L Mackillop et al. / Radiother. Oncol. 32 (1994) 106-115

1. Introduction

2. Materials and methods

Despite the intensive activity of clinical trialists over the last 20 years, the management of lung cancer remains highly controversial [3]. The depth of controversy which surrounds even the most common presentations of this disease is clearly demonstrated by the wide variation in the 'standard treatment' arms of recent randomized clinical trials. For example, in Phase III trials of clinical stage IIIb non-small cell lung cancer, the 'standard treatment' in the USA and in some parts of Europe at the end of the 1980s was high-dose radiotherapy administered over about 6 weeks which was compared with more aggressive therapy in the experimental arm [3,6,14]. Meanwhile, in the UK similar patients were eligible for the MRC trial of fractionation where the 'standard treatment' was a 10-day course of palliative radiotherapy, which was compared with even shorter fractionation in the experimental arm [1,3]. In the North American and European studies the primary outcome measurement was usually survival [3,6,14], whereas in the MRC studies the primary outcome measurement was the patient's symptomatic status [1,3]. Thus, in North America, stage IIIb non-small cell lung cancer is seen as a curable problem in which it is appropriate to study more aggressive therapy with curative intent, whereas in the UK, Stage llIb is seen as an incurable problem in which it is important to establish the most effective and convenient way of controlling the patient's symptoms with the least possible toxicity. The results of this last generation of trials may have moved opinions further apart, since the American and European studies have demonstrated modest increases in median survival with the addition of chemotherapy [6,14] and the UK trials have revealed equivalent symptom control with even shorter courses of treatment than had been accepted as the standard in the past [1]. The management of other common presentations of lung cancer is equally controversial, with the UK and the USA often at opposite poles of the controversy [3]. Surveys using clinical scenarios, or 'paper patients' have also shown wide transatlantic variations in the management of other malignant diseases which suggest a preoccupation with survival in the USA and greater concern with function and quality of life in the UK [21,23]. Canada lies at the crossroads of the UK and USA schools of oncology, and several mail surveys have shown that Canadian doctors hold widely varying beliefs about the optimal management of non-small cell lung cancer [16,25,281. This makes it possible to study the influence of diverse management policies on the outcome of the disease in different cancer centres in a single country. The purpose of this study was to describe variations in the management and outcome of non-small cell lung cancer among seven regional cancer centres in the Canadian province of Ontario.

2.1. The cancer system in Ontario

107

The Ontario Cancer Treatment and Research Foundation (OCTRF) manages the regional cancer centres in Ontario which, together with the Princess Margaret Hospital/Ontario Cancer Institute (PMH/OCI) in Toronto, provide all radiotherapy services in the Province of Ontario. Residents of Ontario make no direct payments for the services of radiation oncologists or for radiation treatment in these centres, and there are no private radiotherapy facilities in the province. Radiation therapists (technologists), radiation physicists and all support staff are full-time employees of the OCTRF or PMH/OCI. Radiation oncologists receive a component of their income from salary from OCTRF or PMH/OCI, and a component from 'fee for service' paid by the Ontario Health Insurance Plan. Radiation oncologists charge fees for consultations and follow-up visits, but not for the planning or administration of radiation treatment. Their income does not, therefore, depend on the decision to treat, or on the number of fractions of radiation prescribed. The Health Care Accessibility Act of Ontario makes it illegal for doctors to charge fees in excess of those paid by the provincial health insurance plan, and private practice outside the provincial system is not permitted [22]. 2.2. Sources o f data

In 1982, the OCTRF established a province-wide computerized clinical database containing information about all patients with cancer registered at any one of the OCTRF clinics. The current overall database (Oncology Patient Information System, OPIS) includes demographic data, details of the histological diagnosis and extent of the disease at diagnosis, a description of the patient's treatment and follow-up information. The computerized treatment record provides detailed and complete information regarding, for example, dates of radiation treatment, sites irradiated, radiation dose, number of fractions and overall time. Seven of Ontario's eight cancer centres were established before 1982, and contributed data to this study. An eighth centre which was established in 1987, was excluded because its experience did not span the entire 10-year period studied. The Ontario Cancer Registry is a population-based registry which contains information on all incident cases in Ontario since 1964, and all cancer deaths since 1950. Details of the registration of incidence and mortality have been reported [4,19]. 2.3. Data analysis

A preliminary analysis of the clinical database at the Kingston Cancer Centre was first undertaken to evalu-

108

W.J. Mackillop et al./Radiother. Oncol. 32 (1994) 106-115

ate the quality of the data, and to develop a preliminary strategy for describing the process and outcome of treatment. One of the investigators then visited each of the other six radiation oncology departments involved in the survey to present the preliminary Kingston data for discussion. Agreement was reached about the parameters which would be assessed and reported, and about the rules which would be used in defining subgroups for analysis. Consensus was established that a multi-centre analysis was of potential value, and each centre agreed to contribute its own data. Several centres made it a condition of their participation that the identity of individual departments should not be linked to the data in the published report and we have, therefore, used code names where we describe centre to centre variations in practice. All patients with a diagnosis of NSCLC registered at any one of the seven Centres between 1982 and 1991 were then identified. Selected information was downloaded from the OPIS database at each centre, and transferred to the mainframe computer system of Queen's University for analysis using SAS (Statistical Analysis Software). In describing both practice and outcome the primary unit chosen for analysis was the entire cohort of unresected NSCLC patients seen at a given cancer centre. Staging information was not used because of the overwhelming problems of stage migration in a longitudinal study involving seven different cancer centres over 10 years. Subgroups of patients were created only in order to gain some insight into the specific changes in practice which were responsible for global changes in resource utilization. For this purpose, we have assigned patients to three initial treatment groups: those who only received thoracic radiation treatment within 2 months of diagnosis; those who were treated to other sites for metastatic disease with or without concurrent thoracic treatment; and those who received no immediate radiotherapy treatment. The choice of 2 months as the cut-off point in describing initial management was based on a detailed review of the paper records at the Kingston Centre where it was found that when radiotherapy to the chest was part of the initial treatment strategy, treatment was almost always initiated within 60 days of diagnosis. Subsequent analysis of data from other centres suggested that treatment resource limitations may occasionally have a delayed implementation of the initial treatment strategy beyond the 2month limit. However, we opted to maintain the 60-day cut-off point for all centres because this provided an accurate and comparable reflection of the patients' management, although it may not always have reflected the physician's intentions. The patients who received initial thoracic radiation were arbitrarily divided into those receiving 'high dose' (_>40 Gy) and those receiving 'low dose' (<40 Gy) radiotherapy treatment. The cut-off

point was set at 40 Gy because this was deemed to be the lowest dose which could be considered potentially curative, regardless of fractionation. Treatment intent was recorded in the majority of cases, but the decision was made not to use this variable because it was highly subjective, and because it had not been used consistently. Only 10% of patients with unresected NSCLC received chemotherapy at any point in the evolution of their illness between 1982 and 1991 (see below), and treatment strategies involving chemotherapy were not analysed in detail. Outcome was described in terms of survival. The frequency of retreatment to the chest after initial thoracic radiation was reported as a crude indicator of symptomatic loco regional recurrence or progression. No quality of life information is available in the computerized database.

2.4. Data quality The database was remarkably complete. All the patient and disease related variables used in the analyses were recorded in > 99% of patients. However, in checking radiotherapy records, we found that Cancer Centre E had almost no records of radiotherapy between 1989 and 1991. It emerged that Centre E had decided to stop entering the radiotherapy data during this period because of pressure of workload in the radiation therapy department which had responsibility for entry of radiotherapy records. This centre's experience over this period was, therefore, excluded from the analysis of treatment. With the exception of the patients seen at Centre E between 1989 and 1991, the database is >98% complete with respect to date of treatment, site irradiated, radiation dose, fraction number, and overall time. Field size was not recorded in the database, and it was not possible accurately to define the volumes irradiated. The Ontario Tumour Registry was checked to determine the status of any patients who were alive at their last contact with their Cancer Clinic but who had not been seen for more than 6 months. Many patients coded as alive when last seen in follow-up in the clinical database proved to be dead, and the database was corrected accordingly. The median follow-up at the time of the analysis was 60 months, and only 0.1% were lost to follow-up.

2.5. Statistical methods Temporal and geographic variations of practice were evaluated using the x2-test to compare proportions. Non-parametric methods were used to compare distributions of continuous variables. The life table and product limit methods were used to describe survival. The survival of different subgroups of patients was compared using the log-rank test and the Wilcoxon rank sum test.

W.J. Mackillop et al. / Radiother. Oncol. 32 (1994) 106-115

3. Remits

3.1. Patients A total of 12 399 with unresected NSCLC were seen at the seven OCTRF centres between 1982 and 1991. Twenty-nine percent of the patients were female, and this proportion was similar at all seven Cancer Centres (range, 26.1-30.5%). The overall median age was 66.6 years and ranged from 66.1 years at Centre D to 67.6 years at Centre A. Forty-three percent of patients had squamous carcinoma, 25% had adenocarcinoma, 17% had a large-cell anaplastic carcinoma, and 15% had large-cell cancer of unspecified histological type usually based on a cytological diagnosis. These proportions varied from centre to centre as follows: squamous carcinoma, 38-55%; adenocarcinoma, 17-32%; large-cell anaplastic carcinoma, 8-30%; and large-cell cancer of unspecified histology, 7-24%. The histologies were entered into the database as initially reported by the pathologist who made the diagnosis, and there was no central review of the slides. There was no significant difference in the age of patients between the first and second halves of the period studied (1982-1986, 66.3 years; 1987-1991, 66.8 years). The proportion of females increase significantly from 26.5% to 31.1% (p < 0.001) with a similar trend affecting all seven centres. There were small but statistically significant changes in the range of histologies reported in the first and second halves of the period studied. The proportion of squamous carcinoma decreased from 46% to 41% (p < 0.001); the proportion of adenocarcinoma increased from 22% to 27% (p < 0.001), while the proportions of large-cell anaplastic carcinoma and of unspecified large-cell carcinoma remained constant at 17% and 15%, respectively. 3.2. Management The 936 patients registered at Centre E between 1989

109

and 1991, who had incomplete radiotherapy records, were excluded from this section of the analysis which focuses on the remaining 11 463 patients. Table 1 shows that within 2 months of diagnosis 5010 (44%) were treated with thoracic radiation alone, 2134 (19%) were treated to other sites for metastatic disease with or without concurrent thoracic treatment, and 4096 (36%) received no immediate radiation treatment. A total of 223 (2%) could not be categorized by initial treatment strategy because these patients had incomplete records of date of diagnosis, or starting date of first radiotherapy, or site irradiated in the first course of radiation treatment, all of which were required to determine their initial treatment category. Initial management varied from centre to centre. The proportion of patients who received thoracic radiation alone ranged from 41% to 56% (t9 < 0.001), the proportion of patients who received no immediate radiation ranged from 26% to 41% (p < 0.001), and the proportion of patients who had radiation treatment to metastatic sites ranged from 15% to 20% (p < 0.001). Table 1 also compares the patients' initial management in the 1982-1986 and 1987-1991 periods. The proportion of patients who received initial thoracic radiation in the seven centres combined decreased significantly from 48% between 1982 and 1986 to 40% between 1987 and 1991 (p < 0.001). The percentage of patients who had no immediate radiotherapy treatment increased significantly from 32% to 39% (p < 0.001), but the proportion of patients who had initial radiation to metastatic sites remained constant at 19%. Table 1 also demonstrates that the changes in clinical management between the first and second halves of the time period were not universal. For example, at Centres A, B, C, D and E, the proportion of patients who had initial thoracic radiation decreased significantly (p < 0.001), but at Centres F and G, this proportion remained constant. Of the 5010 patients who received thoracic radiation

Table 1 Geographic and temporal variations in the use of radiotherapy: initial role of radiotherapy Time period

Proportion of patients

Centre OCTRF

A

B

C

D

E

F

G

1982-1991

X R T Chest X R T Mets No X R T

44% 19% 36%

48% • 19% 31%

43% 20% 35%

41% 15% 41%

42% 20% 36%

45% 20% 34%

56% 15% 26%

42% 20% 36%

1982-1986

X R T Chest X R T Mets No X R T

48% 19% 32%

53% 20% 25%

48% 21% 29%

47% ! 6% 35%

46% 18% 34%

47% 20% 32%

57% 17% 23%

42% 17% 39'70

1987-1991

X R T Chest X R T Mets No X R T

40% 19% 39%

45% 18% 36%

40% 20% 38%

36% 15% 46%

38% 22% 38%

41% 20°/,, 38%

56% 14% 29°/,,

42% 23% 34%

II0

W.J. Mackillop et al. / Radiother. Oncol. 32 (1994) 106-115

alone initially, 4412 patients (88%) received continuous radiation treatment, and only 598 patients (12%) received split course treatment. The proportion of patients who received their thoracic radiation in a split course of treatment varied from 3% to 21% from centre to centre (p < 0.0001). The proportion of patients who received their thoracic radiation as a split course, decreased from 15% between 1982 and 1986 to 9% between 1987 and 1991 (p < 0.001). Of the 4096 patients who received no radiation treatment within 2 months of diagnosis, 2583 (63%) were never treated, and 1513 (37%) had radiation treatment later. The proportion of patients that received no immediate radiotherapy, but who were treated later ranged from 25% to 45% from centre to centre (p < 0.001). The proportion of patients that received no immediate radiotherapy, but who were treated later, increased from 34% between 1982 and 1986 to 41% between 1987 and 1991 (p < 0.001). Only 1215 of the 12 399 patients (10%) received chemotherapy at any point in the evolution of their illness. This proportion ranged from 3% to 21% among the seven centres (p < 0.001). The overall proportion who received chemotherapy decreased from 13% between 1982 and 1986 to 8% between 1987 and 1991. Variations in the specific role of chemotherapy in the patients management are not described further here, but a more detailed report is in preparation.

100% 8O% 6O% 40% 20% O% •4.-,

80%

c-

60% O 40% i._ (1)

21

m

3.4. The use of thoracic radiation

The doses received by 5010 patients who were initially treated with radiotherapy to the chest only are shown in Fig. 2a. A wide range of doses was employed to treat patients over the 10-year period studied. In the seven centres combined, 2974 (59%) patients received doses <40 Gy (the 'low dose' group), and 2036 (41%) patients received doses _>40 Gy (the 'high dose' group). The proportion of patients who were treated with high dose radiation varied significantly from centre to centre (p < 0.001) and ranged from 30% in Centre A to 68% in Centre G. Fig. 3 demonstrates that the proportion of

~

Centre F

Centre C

Centre G

Centre D

OCT~

80% -~>

>

60%

I,-

40%

:3

20% 0% 8O% 60% 40% 20% O% 0

1

2

3

4

0

1

2

3

4

5

Time (Years)

3.3. Overall survival

The median survival of the total group of 12 399 patients, was 5.8 months (95% C.I., 5.7-5.9 months). Overall survival at 1, 2, and 5 years was 25%, 9.1%, and 1.6%, respectively. Fig. 1 shows the survival of the 1982-1986 and 1987-1991 cohorts in each of the seven centres and in the OCTRF as a whole. The overall median survival remained constant at 5.8 months. Survival at 1, 2, and 5 years was 25.0%, 9.3%, and 1.7% in the 1982-1986 period, and 25.1%, 8.9%, and 1.4% in the 1987-1991 period. Furthermore, there was no significant difference in survival between the two cohorts at any of the seven cancer centres.

~

i

Fig. 1. Temporal and geographic variations in overall survival. The eight panels illustrate the actuarial survival of patients registered at the seven cancer clinics in Ontario (Centres A-G), and in the Ontario Cancer Foundation as a whole (OCTRF) between 1982 and 1986 (O), and between 1987 and 1991 (O).

patients who received 'high dose' radiation treatment to the chest decreased significantly from 55% to 28%, over the 10 years of this survey (p < 0.001). A statistically significant trend toward treating a lower proportion of

30%

E •--~ 25%

b

m 20%

25% 20%

15% 10%

10%

5%

o_

O%

0 10 20 30 40 50 60 700

Dose (Gray)

0% 5 10 15 20 25 30 35

Number of Fractions

Fig. 2. Thoracic radiation: variations in dose and number of fractions. Panel a shows the frequency distribution of doses for patients who received initial thoracic radiotherapy. Panel b shows the frequency distribution of the number of fractions of radiation used in patients who receive initial thoracic radiotherapy.

l¥.J. Mackillop et al. / Radiother. Oncol. 32 (1994) 106-115

100% I

I--

80%

2C

60% ~52%

15

40%

C e n t r e 'F 60%

ti t(1) °20!n~! +" O

5

20%

60%

I..

40%

t--

20%

O

•~

0%

i~

iiiii

11

._o

40%

t~

18 15

Q. ¢/~ 15 14 11 ( - lO

8O%

"0 (1) 8o% -70%

Centre E

Centre A

(1)

~O3 20%

t'~

25

Centre E

Centre A

111

0 Centre C

Centre G

Centre D

OCTRF

,•

•

CentCre

20 18

CentGre

16

15

!nt!Di i i 2°I17

16 15

16 14

10

0 80% EL 0 60%

L_

40% 20% 0%

i~

1

N

N

~x--j

N

N

~.

N

N

~

N

Calendar Years Calendar Years Fig. 3. Thoracic radiation: temporal and geographic variations in the proportion of patients receiving high dose radiotherapy. The eight histograms illustrate the proportion of patients receivingdoses of radiation equal to or greater than 40 Gy to the chest at the seven cancer centres (Centres A-G), and in the Ontario Cancer Foundation as a whole (OCTRF), in five 2-year periods between 1982 and 1991.

patients to a 'high dose' was observed at five o f the seven centres. The number o f fractions used in primary thoracic radiation treatment in the O C T R F as a whole is shown in Fig. 2b. Hyperfractionation has not been adopted as routine treatment for lung cancer anywhere in Ontario, and multiple fractions per day were not being investigated in lung cancer in clinical trials in Ontario between 1982 and 1991. Fig. 4 shows that across Ontario, the mean number o f fractions of thoracic radiation has decreased significantly from 16 fractions in 1982 and 1983 to 10 in 1990 and 1991 (p < 0.001). This trend was observed in five o f the

Fig. 4. Thoracic radiation: temporal and geographic variation in fraction number. The eight histograms illustrate the mean number of fractions administered to the chest in patients who received initial thoracic radiotherapy at the seven centres (Centres A-G), and in the Ontario Cancer Foundation as a whole (OCTRF), for each of five 2-year periods between 1982 and 1991.

seven individual centres. Between 1982 and 1991, the mean number o f fractions decreased from 18 to 8 at Centre A, from 14 to 8 at Centre B, from 18 to 11 at Centre C, from 17 to 12 at Centre D, and from 18 to 11 at Centre G, and all o f these changes were statistically significant (p < 0.001). At Centre F, the mean n u m b e r o f fractions o f thoracic radiation remained constant at approximately 17 over the 10-year period, and inadequate data were available to establish the trend at Centre E.

3.5. The outcome of thoracic radiation As shown in Fig. 5, there was no statistically significant difference in survival between patients who receiv-

112

W.J. Mackillop et aL /Radiother. Oncol. 32 (1994) 106-115

100% 80% 6O% 4O% 2O% 0% . . . . . .

100%~ 80%I 60%I

OCTRF

~,4°~ I ~- 2o% I Centre A

40%,~20%i .,~,~_..Centre B~ e

F1

~--~ ::%t~~

40%1-

i

0 %

1

'

CentreC ~ ~

,

.

CentreG . . . . . .

:.

~i 80%

80%[\

f Centre D

:3 80%

O9 6O%

.u~ > 60% "I="-40% 20% 0%,

L_ 0%L

i CentreD~

,

]

,

,

H.,====,

40% 20% 0"I°0 1 2 3 4 0 1 2 3 4 5

L ......

Time (Years)

4° I\ 0 1 2 3 4 0 1 2 3 4 5

Time (Years) Fig. 5. Thoracic radiation: geographic and temporal variations in survival. The eight panels illustrate the actuarial survival of patients who received initial thoracic radiation treatment at the seven cancer centres (Centres A-G), and in the Ontario Cancer Foundation as a whole (OCTRF), between 1982 and 1986 (O) and 1987 and 1991 (O).

ed primary thoracic radiotherapy between 1982 and 1986, and those treated between 1987 and 1991, either in the OCTRF as a whole (p = 0.61) or at any of the seven cancer centres (p-values ranging from 0.13 to 0.95). Fig. 6 illustrates the survival of the subgroups of patients who initially received high and low dose thoracic radiation treatment in the OCTRF as a whole, and also at centres A and D. Fig. 6a illustrates that the survival of the high dose group is significantly higher than that of the low dose group for the OCTRF for the full 10year period (p < 0.001). The median survival of the high dose and low dose subgroups were 10.6 and 5.3 months, respectively. Fig. 6(b,c) which shows similar data for Centres A and D, respectively, illustrates that the magnitude of the difference between the high and low dose groups varied among the centres. The 2-year survival of the high dose group was almost 4 times greater than that of the low dose group at Centre A, but only 2 times greater at Centre D. However, the overall survival at the Centres A and D is very similar and the differences observed are consistent with the higher degree of selection for high dose treatment at Centre A where only

Fig. 6. Thoracic radiation: survival as a function of radiation dose. Panels a, b, and c show the survival of all patients who received initial thoracic radiation (13), the survival of the 'high dose' subgroup (O), and the survival of the 'low dose' (T) subgroup in the Cancer Foundation as a whole (panel a), at Centre A (panel b), and at Centre D (panel c). Panels d, e, and f show the survival of the 1982-1986 (O), and 1987-1991 (O) high dose subgroups, and the 1982-1986 (~'), and 1987-1991 (V), low dose subgroups, in the Cancer Foundation as a whole (panel d), at Centre A (panel e), and at Centre D (panel f).

30% received high dose treatment compared with 50% at Centre D. Fig. 6d demonstrates that there was no statistically significant difference in survival between patients treated with low dose radiation (p = 0.10) in the two halves of the 10-year period, but patients treated with high. dose radiation between 1987 and 1991 appeared to live significantly longer (p < 0.001). Given that overall survival did not vary in the least over this period (see Fig. 5), the apparent improvement in the outcome of high dose subgroups can only be explained by stricter selection of cases for high dose treatment in the later period. This is consistent with the observation that between 1982 and 1986, 1292 of2611 patients (50%) received high dose treatment, and between 1987 and 1991, 744 of 2399 (31%) received high dose treatment. The trend varied from centre to centre. Fig. 6(e,f) shows the survivals of the high and low dose subgroups in the first and second halves of the 10-year period at Centres A and D, respectively. At Centre A, where the proportion of patients who received high dose thoracic radiation treatment decreased by 53% between the 1982-1986 period and the 1987-1991 period, there was a statistically significant improvement in the survival of

W.J. Mackillop et al. / Radiother. Oncol. 32 (1994) 106-115 100%

Centre A

Centre E

80%

¢- 60% O t._

Q.

40%' ~

"

20% O%

.,,,~.

,-~

Centre B

¢- 80% 60% E

40%

20% (1) t..,

0%

(1) so%

n"

f-Centre C

Centre G

60%

,.I,-I

0%

ability of retreatment in survivors greatly exceeds the absolute value of retreatment because most patients do not survive long enough to require retreatment. In the OCTRF as a whole, the actuarial probability of retreatment at 5 years increased from 25% between 1982 and 1986 to 35% between 1987 and 1991. However, the absolute proportion of patients retreated at any time during the follow-up period only increased from 6.9% to 9.5%. The minimum follow-up time for patients treated between 1987 and 1991 is only 1 year, and a few survivors may still be expected to undergo retreatment, but the scope for error is already limited by the short natural history of the disease. 4. Discussion

0 40% >~ 2o%

"~-

113

Centre D

OCTRF

¢l:1 ao%

¢'~ 60% 0 40% 13_ 2O% O%

12 24 36 48

0 12 24 36 48 60

Time (Months) Fig. 7. Temporal and geographic variations in the probability of retreatment to the chest. The eight panels show actuarial estimates of the probability of subsequent treatment to the chest in patients who received initial thoracic radiation at each of the seven cancer centres (Centres A-G), and in the Cancer Foundation as a whole (OCTRF), for the whole 10-year period (ll) and for the 1982-1986 (O) and 1987-1991 (O) subgroups.

the high dose group (p = 0.01). At Centre D, where the proportion of patients who received high dose thoracic radiation treatment decreased by only 28%, there was a smaller increase in the survival of the high dose group which did not reach statistical significance. The overall survival at Centres A and D remained constant (see Fig. 1), and these changes in the outcome of subgroups of patients are consistent with changes in case selection. 3.6. Retreatment

Overall, only 8% of patients who had initial thoracic radiation received another course of radiotherapy to the chest later in the illness. The absolute proportion who were ever retreated varied significantly from 3% to 14% among the seven centres (p < 0.01). Fig. 7 shows actuarial estimates of the probability of retreatment to the chest as a function of time. Patients who died were censored in this analysis which, therefore, indicates the probability that a patient will require retreatment if she or he survives for a given period. This actuarial prob-

There are wide variations in the use of radiotherapy in patients with unresected non-small cell lung cancer in Ontario today, but this group of patients is generally treated less intensively than it was 10 years ago. It may be argued that the geographic variation in practice, and the change in practice over time are appropriate responses to variations in the 'case mix', or spectrum of patients, seen in different centres at different times. However, the OCTRF is the sole provider of radiotherapy treatment in Ontario, except in Toronto where the referral base of one OCTRF clinic overlaps with that of PMI-I/OCI, and there have been no major changes in patterns of referral over the last 10 years. It is, therefore, difficult to envisage any mechanism which could produce large enough variations in case mix to explain the wide variations in practice. What limited collateral information we have about these patients provides no evidence of variation in referral patterns. Age profiles are near identical among centres and have not changed at all over the last 10 years. There was a small increase in the proportion of females, consistent with the wellknown trend in incidence. There was also a small but statistically significant change in the spectrum of histologies but this is more likely to be due to changes in reporting than to real changes in the spectrum of disease. The overall trend toward lesser use of radiotherapy in NSCLC is not consistent with most of the recommendations published in the North American medical literature over this period. Although a few observers were more conservative [26], there was a strong movement in the 1980s toward the more intensive use of radiotherapy in the management of non-small cell lung cancer. This was based on the RTOG's demonstration that, although long-term survival was unaffected, higher doses conferred a modest increase in median survival in patients with Stage III disease [5]. The two UK MRC trials of lesser fractionation in the palliation of advanced disease, which have had a large influence on practice in the UK [18,311, were not published until the early 1990s [1,20].

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Canadian radiation oncologists may have been aware of these ongoing studies before they were published, but this does not provide an explanation for our results. Few radiation oncologists in the OCTRF ever used either one or two fractions in the 1982-1991 period (see Fig. 2). The big change in Canadian practice has been toward treating a smaller proportion of patients with long radical courses of radiotherapy. There is no clear explanation for this trend, but Ontario's cancer centres were under increasing pressure of workload in the 1980s, and this led to growing waiting lists for radiotherapy [17]. The use of radiotherapy may, therefore, have decreased because of resource limitations rather than because of any change in the state of knowledge. Although there are significant institution to institution variations in the use of chemotherapy, only 8% of patients registered in 1991 received chemotherapy compared with 15% in 1982. The trend towards the lesser use of chemotherapy is not consistent with the direction expected based on the results of clinical trials reported during the 10-year period covered by this study. At the beginning of the 1980s there was no evidence that chemotherapy prolonged survival in any clinical setting in NSCLC, but evidence has since accumulated that chemotherapy produces a modest but statistically significant prolongation of survival in selected patients with advanced disease [10]. We do not know why the trend in the clinic is different from the trend in the literature, but many doctors do not regard the small gain in survival as sufficient to justify the toxicity of chemotherapy [10]. At the beginning of the 1980s many Ontario centres were participants in a multicentre trial of systemic therapy in advanced disease which may explain why more patients received chemotherapy at that time [29]. It should be noted that the information about chemotherapy reported here is less complete and more prone to error than the information about radiotherapy because in some parts of the province, patients receive chemotherapy outside the OCTRF/OCI network of clinics, and we have no record of this. Our survey fails to show the association between treatment intensity and survival which would be expected based on the RTOG results [5]. Neither the wide variations in practice among centres, nor the large temporal changes in the use of radiotherapy in unresected NSCLC were associated with any significant differences in survival. Variations in the outcome of subgroups of patients, defined on the basis of the treatment which they received, have been identified but these are adequately explained by variations in case selection. It may be argued that staging information is necessary to permit interpretation of these data, but we contend that the appropriate outcome measurement in a largescale audit of this kind must be the overall survival of the entire group. Variations in the application of staging rules among centres, or even across time in an individual

centre, make it very dangerous to compare reports of outcome by stage [2,7,24]. Randomized clinical trials are a more sensitive way of studying the efficacy of treatment in well-defined subgroups of patients. However, there may be doubts about the generalizability of the results of clinical trials because they usually include only a small number of patients who may not be representative of the population at large [3]. This problem, however, is essentially absent in a large scale audit in which the sample size approaches that of the population of interest. While it is possible to gather and analyse only a limited amount of information about every patient seen in routine practice, simple measurements of outcome applied to very large groups of patients are a useful indicator of the value of any clinical intervention. Clinical trials and large scale audits should, therefore, be regarded as complementary rather than competing spheres of research. Our failure to demonstrate a difference in survival does not mean that the different management policies described here produce medically equivalent results. Some doctors believe that intensive treatment to the chest is justified because it provides long-term local control and that this enhances quality of life [28]. Our data do not disprove this, although we were surprised that large variations in the intensity of initial treatment were associated with small variations in the frequency of retreatment to the chest. Studies which use quality of life or symptom control as endpoints are required before it will be possible to reach rational decisions about medically optimal treatment. It would even be unwise to conclude that the less intensive use of radiotherapy and chemotherapy necessarily saves money. This may be true from the narrow perspective of an agency responsible only for providing these specific services, but from the perspective of a ministry of health which funds a comprehensive health care system, it may well be entirely incorrect. The overall cost of the management of nonsmall cell lung cancer is dominated by the cost of hospitalization [11], and since ambulatory treatment with radiotherapy is relatively cheap [8,9], it may actually save money if it keeps patients functioning and out of hospital. There is already evidence that the use of chemotherapy in high performance status patients with NSCLC diminishes the time spent in hospital to an extent which more than compensates for the cost of the drugs [11]. The diversity of practice reported here is consistent with the diversity of Canadian doctor's beliefs about the optimal management of NSCLC demonstrated previously in a series of three mail surveys [16,25,28]. There is a growing literature which shows that unexplained variations in practice are widespread in oncology in general, and that the harder you look the more variation you will find [12,13,21,23,27]. The problem is not confined to oncology [15,31], but radiotherapy pro-

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grammes often have unusually good records, and the excellence of our information systems makes variations in our practice highly visible. Health care managers are searching for ways to cut spending, and in future, we will have to be prepared to justify variations in practice which are appropriate, and to eliminate those which are not.

Acknowledgement The authors thank Mary Nemes for helpful advice and Darlene Dale and Catherine Bell at the Ontario Tumour Registry for help in updating death records. We are grateful to the clinicians who provided access to their computerized records, to the Medical Records staff whose diligent work over many years made this study possible, and to Beverley Shortt for her skill and patience in the preparation of the manuscript. This work was supported by grants from the Ministry of Health of Ontario, and the Ontario Cancer Treatment and Research Foundation.

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