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Survey on the treatment of non-small-cell lung cancer in Italy
Annals of Oncology 11: 807-813, 2000. © 2000 Kluwer Academic Publishers. Printed in the Netherlands.
Original article Survey on the treatment of non-small-cell lung cancer in Italy A. Alexanian & V. Torri Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
Introduction
In Italy lung cancer accounts for 30,000 deaths per year [1], non-small-cell histologic types representing 75%80% of cases [2]. Five-year survival rate is less than 10% and this proportion has not substantially changed in the last 15 years [3]. Mortality reduction can be achieved with primary prevention (successful campaigns against smoking in order to reduce incidence), secondary prevention (discover of screening tests allowing for usefully early diagnoses) or better therapy. The most obvious way to improve present patients' prognoses consists in the optimal exploitation of already available treatments. Surgery with curative intent is the treatment of choice for patients with NSCLC, but because of disease extent and/or patients'clinical conditions less than one third of patients presents for treatment with potentially resectable disease [4]. Indeed, there are many debates even about the local extent of disease that should be regarded as potentially curable by this means [5]. Only few patients with inoperable, non-metastatic disease will be deemed suitable for radical radiotherapy, as a potentially curative treatment [6]. For the others, palliative radiotherapy may be considered or supportive care alone [7]. In spite of a large number of randomised trials, there remains substantial disagreement about whether chemotherapy should be given in addition to any of the above primary treatments [8, 9]. On the whole, in NSCLC radio- and chemotherapy have not led to the
reductions in mortality expected on the basis of the results obtained in other tumours. Single studies evaluating these approaches, however, were too small to show the presence of any small - but still clinically relevant in such a frequent disease - effect; indeed, given the prevalence of NSCLC, a relative reduction in mortality of a 10%-15% order would be important in terms of public health. The present study was planned in the framework of the meta-analysis of the Non-Small-Cell Lung Cancer Collaborative Group, to establish whether there was reliable evidence that chemotherapy improved survival in NSCLC. It was based on 52 published and unpublished randomised trials making an unconfounded comparison of primary treatment vs. primary treatment plus chemotherapy [10]. Hereafter we present a survey of Italian clinicians, undertaken to determine their views on the current role of chemotherapy in the treatment of NSCLC; in particular, how they would manage three clinical situations given in three case histories, to ascertain their opinion on prognosis, their therapeutic preferences, the perceived efficacy of chemotherapy and what benefits from it would be required for them to change their practice. The way to express the efficacy of a treatment - understanding of results as a premise to a correct transfer of knowledge from research to clinical practice - was also evaluated. This project was initiated by the Clinical Trials Group of the National Cancer Institute of Canada [11]
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Results: Overall, there were 287 evaluable responses, 89% of respondents were males, mean age was 46 years, years from Background: The results of the Italian part of an international graduation 21 and charge of patients per clinician 82. The most survey on therapeutic preferences and opinions about prognosis important result is the wide variation of answers both about of patients affected by non-small-cell lung cancer (NSCLC) therapy and prognosis. Expectations about size of prognosis improvement with a new chemotherapy seem to be excessive. are shown. Patients and methods: The investigation was conducted by Conclusions: The results are discussed in relation to the the means of a postal questionnaire aiming to gather informa- twin surveys of Canada and England and Wales and to the tion on preferences about treatment and beliefs about survival meta-analyses on the efficacy of chemotherapy as an adjunct to of three hypothetical patients affected by NSCLC in different primary treatment and on postoperative radiotherapy in nonstages (T2N1M0, T2N3Mo, M\); three sources of Italian physi- small-cell lung cancer. cians potentially treating patients affected by NSCLC were the target population: participants in the Adjuvant Lung Project Italy (Alpi) trial, a 20% random sample of the Italian Medical Oncology Association (AIOM) and representatives of almost Key words: adjuvant chemotherapy, clinicians' opinions, nonall the pneumology wards in Italy. small-cell lung cancer Summary
808 and has been applied also in France, England and Wales [12]. Patients and methods Target population
Case 1 (T2NiMo) A 65-year-old man presents to you complaining of two minor episodes of haemoptysis and he has no other symptoms. There is a 4 cm diameter mass in his right lower lobe on chest X-ray. A bronchoscopy and biopsy confirm the diagnosis of a squamous-cell carcinoma. A full metastatic work-up is negative. At surgery a microscopically positive right hilar node is found but all the other nodes are negative. A right pneumonectomy is done and the resection is considered complete both macroscopically and microscopically. Following surgery, the patient comes back for a follow-up visit. He has no symptoms and he is doing well. Case 2 (T2N3Mo). A 4 cm mass in the left upper lobe with mediastinal widening is found on a routine chest X-ray of an asymptomatic 65-year-old man. At mediastinoscopy, enlarged lymph nodes involved with squamous carcinoma are found on both sides of the trachea. The rest of the metastatic work-up is negative. The patient is in good condition and willing to follow any of your recommendations. Case 3 (M|). A 65-year-old man presents to you complaining of minor haemoptysis and no other symptoms. His chest X-ray shows a 4 cm mass in the right upper lobe. A bone scintigram shows two areas of increased uptake in his right humerus and one in his skull. A biopsy of the humerus reveals squamous cell carcinoma. The rest of the metastatic work-up is negative. The patient is in good conditions and willing to follow any of your recommendations.
Table 2 Sample characteristics (n = 287). n (%)
The questionnaire Practical activity The questionnaire was in four sections. The first three sections depicted Pneumology three common clinical presentations of NSCLC with controversial Oncology treatment options (Table 1). The fourth section requested background Surgery information about respondents and their practice, including their Oncology + other (radiotherapy in 11 cases) precise speciality. Internal medicine Each case was followed by questions on preferences about treatRadiotherapy ment (responses were not required to be mutually exclusive) and beliefs about survival. Respondents were asked to complete the questionnaire Hospital geographical site North only for those types of patients that they themselves treated. In the first Centre case, questions relating to prognosis were phrased in terms of five-year South survival. In the second and third case, respondents could choose Hospital number of beds between survival rate (five-year and one-year, respectively) or median <200 survival (in years or months). In the third case, respondents were asked 200-399 whether they would recommend chemotherapy according to age (65 or 400-599 50 years old). 600-800 The questionnaire is shown in full in the England and Wales report >800 [12]. Teaching hospitals Statistics
Yes No
111 (39) 86 (30) 36(13) 27(9) 14(4.5) 13(4.5) 151 (53) 90(31) 46(16) 41 (14) 30(11) 32(11) 56(19) 128(45) 95 (33) 192(67)
Radiotherapy facilities availability Some continuous variables, such as age, years since graduation, charge of patients per clinician (number of new lung cancer patients seen annually) and time devoted to clinical practice and research were categorised using the median value as cut-off. The results have been analysed only aggregated and not individually. Risk (i.e., the influence of clinicians' characteristics on treatment preferences) was measured in terms of odd ratios (OR) with their 95% confidence intervals (95% CI). Statistically significant values for differences between proportions were based on the %2 test -
Yes No
166(58) 121(42)
Questionnaires returned
with lung cancer were 47. Thus, available forms were 287: 96 Alpi trialists (64% of eligible), 87 AIOM associates (39%) and 104 HCP (52%). Males were 256 (89%); mean age was 46 years (range 30-67, median 45), years from graduation 21 (range 3-45, median 20) and charge of patients per clinician 82 (range 3-800, median 50). Median time devoted to clinical activity and research were, respectively, 70% and 10%. Other characteristics are illustrated in Table 2.
On the whole 620 questionnaires were sent out and responses were obtained from 334 clinicians, giving a compliance rate of 54%. Clinicians not treating patients
Case 1: T2, Nj, Mo disease Clinicians treating patients in this category were 273 (95%) and their recommendations - after primary treat-
Results
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The questionnaire (translated into Italian from the originally bilingual - English and French - version), a letter explaining its purpose and drawing attention to its international dimension, and a stamped addressed envelope for its return were mailed to 620 Italian clinicians - thoracic surgeons, hospital chest physicians (HCP) and medical and radiation oncologists — during spring 1994. The target population included three sources, with no overlap among them: a) all the 150 clinicians participating in the Alpi, a randomised clinical trial with patients affected by stage I, lie Ilia NSCLC assigned to observation or adjuvant cisplatin-based chemotherapy (mitomycin + vindesine + cisplatin for three courses every three weeks, MVP) after primary therapy (complete resection, with radiotherapy given at the discretion of the treating physician) [8, 13]; b) 250 members (a random sample of approximately 20% of the total) of the AIOM; and c) 220 HCP, representative of almost all the pneumology wards in Italy. After two months a reminder was sent to all non-responders, with the aim to reach a 50% response rate, at least.
Table 1. Clinical features of three NSCLC patients set out in the questionnaire.
809 Table 3. Case 1: clinicians' (n = 273) estimates of five-year survival after successful surgical resection. Probability of patients being alive in five years (%)
Clinicians, n (%)
5(2) 95 (38) 143(57) 6(2) -(-) 24 3(1) 67 (32) 124(58) 19(9)
Additional benefit in five-year survival rate required (%)
Clinicians, n (To)
0-5 6-10 11-15 16-20 21-25 26-100 NA
23(15) 37 (25) 29(19) 38 (25) 7(5) 16(11) 52
Abbreviation: NA - not answered. The percentage values refer to those clinicians who answered the question.
60 Table 5. Case 2: treatment recommended by clinicians (n = 280). 70(31)
140(61) 16(7) 45
1(1) 54 (28) 113(58) 22(11) 3(2) 80
Abbreviation: NA - not answered. The percentage values refer to those clinicians who answered the question.
merit consisting in complete reduction - were: radiotherapy in 111 (41%), no further treatment in 79 (29%) cases, chemotherapy in 42 (15%), both treatments in 25 (9%); 16 clinicians (6%) ticked the 'Yes' box against 'other therapy' and specified that they would recommend a) entry to a trial of adjuvant treatment, b) only immunotherapy, c) immunotherapy and chemotherapy and/or radiotherapy. Clinicians' recommendations of radio- or chemotherapy were similar whatever their age, sex, years from graduation, prevailing practical activity, amount of time devoted to clinic or research, hospital size and involvement in undergraduate teaching. Significantly more clinicians working in hospitals where a radiotherapy facility was available recommended radiotherapy {P < 0.03; OR = 1.26, 95% Cl: 1.02-1.55), while its absence favoured chemotherapy (P < 0.0003; OR = 1.71, 95% CI: 1.32-2.22). The clinicians' expectations of patients' survival are presented in Table 3. With simple follow-up, 2% of clinicians who answered expected no chance of survival tofiveyears; 38% expected a l%-25% chance of survival, and a further 57% a 26%-50% chance. There was little expectation that adjuvant treatment could influence probabilities: clinicians who indicated afive-yearsurvival rate greater than 50% were at most 13% (in the case of radiotherapy and chemotherapy combined). Among the
Treatment recommended
Clinicians, n (%)
Chemotherapy + radiotherapy Only radiotherapy Surgery + chemotherapy + radiotherapy 3 Only chemotherapy Chemotherapy + surgeryb Surgery + radiotherapy 0 Only surgery Only follow-up
139(50) 58(21) 32(12) 20(7) 14(5) 9(3) 4(1) 4(1)
Neoadjuvant treatments: a = 27, b = 14, c = 2.
60 clinicians who did not answer the question for chemotherapy, only 9 recommended it; similarly only 9 out of 45 who did not answer for radiotherapy recommended it, and only 4 out of 80 who did not answer for combined treatment recommended it. In the hypothetical situation that a new combination of drugs had been developed as adjuvant treatment, those clinicians who had not recommended adjuvant chemotherapy (all but 71 of the 273) were asked what five-year survival rate would have to be achieved by such treatment for them to adopt it routinely. Their responses are presented in Table 4. Tn general, clinicians required substantial survival improvements with adjuvant chemotherapy for them to recommend it routinely, 41% of the 150 who answered the question requiring an additional absolute benefit of more than 15%. Case 2: T2, N3, Mo disease
Clinicians treating patients in this category were 280 (98%) and their recommendations are reported in Table 5. Medical oncologists were more likely than other clinicians to recommend chemotherapy (P < 0.001; OR = 1.91, 95% CI: 1.24-2.94). Recommendations were not influenced by other aspects of the clinicians or of their hospitals. The clinicians' expectations of patients' survival are presented in Table 6. Of the 280 clinicians, 155 (55%) expressed their expectations as five-year survival rates, and 125 (45%) as median survival. With best supportive
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Without adjuvant therapy 0 1-25 26-50 51-75 76-100 NA With adjuvant chemotherapy 0 1-25 26-50 51-75 76-100 NA With adjuvant radiotherapy 0 1-25 26-50 51-75 76-100 NA With both adjuvant treatments 0 1-25 26-50 51-75 76-100 NA
Table 4. Case 1: improvement in five-year survival rates that would have to be achieved with adjuvant chemotherapy for clinicians to adopt such treatment routinely (n = 202).
810 Table 6. Case 2: clinicians' (« = 280) estimates of survival. Estimation of percentage alive in five years
Estimation of duration of survival
Probability
Median duration (months)
Table 7. Case 2: improvement in five-year survival rates and median survival rates that would have to be achieved with adjuvant chemoradiotherapy for clinicians to adopt such treatment routinely (n = 109). Additional benefit required (%)
Clinicians, n (%)
With optimal radiotherapy alone 0 15(12) 1-5 41 (32) 6-10 50 (39) 11-15 11(9) 16-20 6(5) 3=21 5(4) NA 27 With optimal chemotherapy alone 0 24(19) 1-5 43 (34) 6-10 37 (30) 11-15 5(4) 16-20 10(8) 3*21 6(5) NA 30
0 1-6 7-12 13-18 3=19
0(0) 32 (43) 55 (50) 4(4) 4(4)
NA
30
0 1-6 7-12 13-18 3=19
0(0) 12(11) 64(61) 17(16) 12(11)
NA
20
0 1-6 7-12 13-18 3=19
0(0) 12(12) 61 (60) 21 (21) 7(7)
NA
24
With optimal chemotherapy and radiotherapy 0 11(8) 0 1-6 26(19) 1-5 7-12 44(32) 6-10 13-18 19(14) 11-15 3=19 16-20 20(14) 3=21 18(13) NA NA 17 With other treatment 0 7(8) 1-5 17(19) 6-10 27(30) 11-15 8(9) 16-20 9(10) 3=21 23(25) NA 64
0(0) 5(5) 36(32) 42 (38) 28 (25) 14
0 1-6 7-12 13-18 3=19
0(0) 3(4) 36 (32) 26(34) 17(22)
NA
48
Abbreviation: NA - not answered. The percentage values refer to those clinicians who answered the question.
care only, 47% of clinicians considered there was no chance of survival to five years, and a further 35% a chance of <5%. Expectations were greater for the combination of chemotherapy and radiotherapy than for either of these on its own. The findings expressed in terms of median survival showed a similar pattern. Those clinicians who did not currently recommend multimodality treatment with radiotherapy plus chemotherapy (109 of the 280) were asked what survival rate or median survival would have to be achieved for them to adopt this treatment routinely. Their responses in terms of additional benefit required are presented in Table 7. Among the clinicians who answered in terms of five-
n (%) Clinicians using five-year survival
0-5 6-10 11-15 16-20 21-25 3=26 Not answered
11(28) 15(38) 3(8) 3(8) 3(8) 4(10) 22
Total
61 Median survival
0 1-20 21-40 41-60 61-80 3=81 Not answered
3(14) 2(10) 6(29) 7(33) 1(5) 2(10) 27
Total
48
The percentage values refer to those clinicians who answered the question.
year survival rates, 66% of the 39 who responded would be satisfied by a 10% or less absolute five-year survival improvement with a new combination of chemotherapy and radiotherapy to recommend it routinely. In contrast, the clinicians who answered in terms of median survival were more demanding: 76% of the 21 who responded required an improvement of more than 20% (48% requiring an improvement of more than 40%). Case 3: M, disease Clinicians treating patients in this category were 275 (96%). On detecting metastases in a 65-year-old patient in good condition, 191 (69%) clinicians would recommend chemotherapy, while 229 (83%) would do so for an otherwise similar patient aged 50 years. The great majority, 190 (69%); would recommend chemotherapy for both patients. Chemotherapy for 65-year-old patients was more often indicated by medical oncologists (P < 0.005; OR = 1.68, 95% CI: 1.15-2.46) and respondents devoting at least 10% of their work-time to research (P < 0.005; OR = 1.56, 95% CI: 1.13-2.16). Recommendations were not influenced by other aspects of the clinicians or their hospitals. The clinicians' expectations of patients survival are presented in Table 8. Of the 275 clinicians, 135 (49%) expressed their expectations as one-year survival rates (Table 8a), and 140 (51%) as median survival (Table 8b). With best supportive care only, 13% of clinicians considered there was no chance of survival to one year, and a further 51% a chance of < 10%. Their expectations were better for optimal chemotherapy, the equivalent percentages being 4% and 28%, with a shift towards more favourable one-year survival rates. Similarly, among
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With best supportive care only 0 62 (47) 1-5 46 (35) 6-10 14(10) 11-15 7(5) 16-20 4(3) 3=21 1(1) NA 21
Clinicians, n (%)
811
Discussion Some preliminary consideration about response rates and composition of respondents is worthwhile. The overall compliance rate (54%) is very similar to previous surveys; in a French survey about small-cell lung cancer, 52% of the physicians returned the questionnaire [14]. A telephone survey on a sample of AIOM nonresponders (the group with the lowest response rate) showed that many of them were not involved in the management of lung cancer patients. The 39% AIOM response rate is anyway close to the 36% obtained in the same period by the ASCO (American Society of Clinical Oncology) [15], its American equivalent. The same circumstance - chest physicians not involved in oncological practice - applied to the HCP subgroup. The likely overrepresentation of chest physicians, along with the underrepresentation of radiotherapists should be viewed in the light of the usual diagnostic path of these patients in Italy: they traditionally first encounter a chest physician or an oncologist (78% of respondents in our series) as first specialist. The survey provides a comprehensive assessment of the attitudes of consultants in Italy towards the treatment of lung cancer. The distribution of respondents on the countryside reflects the distribution of services. Among therapeutic recommendations, two of them are particularly notable: a) half of respondents deems that radiotherapy has a role in T2NiM0 patients and the percentage grows to 86% in T2N3M0 - this proportion is rather surprising when matched with the true (much lower) rate of utilisation of radiotherapy in Italy [16] and might hopefully have changed after the publication of the PORT meta-analysis [17] which has shown a detrimental effect of post-operative radiotherapy, especially in early-stage NSCLC; b) 84% of respondents would advise a chemotherapy to a 50-year-old asympto-
Table 8. Case 3: clinicians' (n = 275) estimates of survival. Clinicians' estimate
Clinicians, n (%)
(a) Probability of patient being alive in one year % With best supportive care only 0 1-10 11 20 21-30 31-40 >41 Not answered With optimal chemotherapy 0 1-10 11-20 21-30 31^0 3=41 Not answered (b) Expected median survival months With best supportive care only 1-6 7-12 13-18 Not answered With optimal chemotherapy 1-6 7-12 13-18 19-24 >25 Not answered
16(13) 65(51) 30 (23) 9(7) 4(3) 4(3) 7 5(4) 37 28) 49 (37) 18(13) 9(7) 16(12) 1
86 (65) 45 (34) 1(1) 8 29 (22) 84 (63) 15(11) 4(3) 1(1) 7
The percentage values refer to those clinicians who answered the question.
Table 9. Case 3: improvement in one-year survival rates and median survival rates that would have to be achieved with chemotherapy for clinicians to adopt it routinely (« = 84). Additional benefit required (%)
n (%) Clinicians using five-year survival
0-5 6-10 11-15 16-20 21-25 Not answered
2(5) 12(29) 6(15) 9(22) 4(10) 8(20) 6
Total
47 Median survival
0 1-20 21-40 41-60 61-80 5=81 Not answered
1(4) -(-) 2(7) 4(14) 22 (76) 8
Total
37
The percentage values refer to those clinicians who answered the question.
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the clinicians expressing their expectations in terms of median survival, 35% would have expected a median survival of ^ 7 months with best supportive care only and 78% with optimal chemotherapy. Those clinicians that did not currently recommend chemotherapy (84 of the 275) were asked what one-year survival rate or median survival would have to be achieved by a new combination of drugs for them to adopt such new treatment routinely. Their responses in terms of additional benefit required are presented in Table 9. Of the 47 clinicians that answered in terms of one-year survival rates, 66% would want to see an absolute improvement of more than 10%. As for case 2, the requirements of the clinicians who answered in terms of median survival were more demanding: 97% of the 37 who responded would want to see an improvement of more than 40%. Table 10 describes clinicians' attitudes towards the opportunity of sharing with patients the choice of cure.
812 group of 8 studies comparing cisplatin-based regimens vs. only supportive care the median survival shifted from How do you decide treatment in a metastatic patient? n (%) 4-5.5 months [10]). The wide variability of answers about (n = 287) prognostic provisions again supports the hypothesis 1. I recommend the patient the treatment which I deem to 115 (41) that opinions are often based on premises not supported be the best for him/her by consistent epidemiologic evidence. The attitude of clinicians about the opportunity to 2. I describe different types of available treatments and I 158 (56) recommend the best for the patient share with patients the choice of treatment conceals a problem of information. A patient affected by advanced 3. I describe different possible treatments to the patient 10(3) NSCLC is generally assigned to one of two policies: and he/she makes the final choice observation, with supportive care only, or administra4. Not answered 4 tion of an active treatment (chemo- or radiotherapy) at the price of various degrees of toxicity. The evaluation matic patient with bone metastases - in this case a of these two options involves consideration of several comparison is possible with what emerged from a similar variables (symptomatic or asymptomatic disease, durastudy made about ten years ago in Canada: when physi- tion and efficacy of treatments, toxicity, duration of cians exposed to the same scenario (NSCLC with bone benefit, quality of life, and so on) which can be differmetastases) were asked which treatment they would have ently viewed by patient and clinician [24, 25]. Indeed, chosen for themselves, the chemotherapy option (alone or the essential premise to such a choice is the full awareness of diagnosis on the part of patient, an often eluded plus radiotherapy) gathered only 16% of consents [18]. On the whole the most relevant feature is represented circumstance in the Italian reality. The presence of some national specificity in the cliniby the wide range of answers. The variety of opinions cians' therapeutic approach and prognostic evaluations about NSCLC therapy means a still unsatisfactory indiis made possible by the comparison with the previously viduation of care strategies (with some of them clearly published Canadian and English-Welsh surveys [11,12]. better than others) and represents a strong determinant The results in the three studies were derived from different of the variety of behaviours, both in clinical practice and populations of respondents according to specialties, as in research [19]. there were equal proportions of chest physicians, thoracic Radiotherapy availability inside the hospital influences surgeons, medical oncologists, and radiation oncologists the choice of treatment after radical intervention in a (about 25% each) in Canada while in England and patient withT2N1M0 disease; this result is relevant to the Wales radiotherapists were more represented (30%) and point of view of the unequal distribution of radiotherapy (6%). There was, however, little medical oncologists less wards in the nation [20]. systematic difference in response between specialities in To be an oncologist favors the indication to medical all the studies, and so comparisons between their findtreatment in cases 2 and 3, as it could be expected ings can reasonably be made. because of specialists' broader familiarity with chemoFor case 1 (T2, N 1; Mo), the main difference was in therapy regimens [21]. treatment recommendations: simple follow-up was adThe large increase in survival that the respondents vised by 29% of clinicians in Italy, 74% in England and would require to change their practice - and recommend Wales and 68% in Canada; instead, chemotherapy (alone a new chemotherapy instead of a policy of only close or in combination with radiotherapy) was recommended follow-up gives shape to probably excessive expectations by 24% in Italy, 1% in England and Wales and 4% in (primarily in the first - but also the second - scenario); Canada, while radiotherapy (alone or in combination the meta-analysis of chemotherapic treatments helps in with radiotherapy) was recommended by 50% in Italy, estimating the degree of benefit that one can realistically 24% in England and Wales and 31% in Canada. This expect from a new regimen: among adjuvant treatments a probably reflects a peculiar uneasiness of Italian clinipositive result stems out only from the more recent subcians towards the option of 'offering nothing' to the group of studies using platinum yielding an absolute 5% patients, as is confirmed by the fact that the predictions improvement in five-year survival (from 50%-55%) [10]. The incongruous size of expectations about a new of survival after surgery showed a very similar distribuchemotherapy in the case of the patient with advanced tion, with little expectation from the adding of whatever disease because of bone metastases means that the adjuvant treatment, in the three surveys. Recommended treatment for the patient described in relative value of median survival and one-year survival case 2 (T 2 , N 3 , Mo) confirmed the somewhat more rate is probably misunderstood. 'aggressive' attitude of Italian clinicians, as the respecPrognosis data shown in Tables 4 and 6 can be tive proportions of only supportive care and surgery compared with the overall five-year survival rates (39% proposals in Italy, Canada, England and Wales were: 1% and 0%-5% for patients with T2N,M0 and T2N3M0 21%, 17% and 0, 23% and 1%. Similarly, combined and disease, respectively) reported in the last international radiochemo-therapy was recommended by 50% (plus staging classification [22], indeed substantially unchanged 12% if associated to surgery) of respondents in the over the last 15 years [23]. For the metastatic patients in 11% (at best) from England and Wales, Italian survey, Table 8 we can rely on the meta-analysis (in the subTable 10. Clinicians' attitudes.
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and 16% from Canada. However, Italian clinicians showed themselves also more confident that multimodality treatment would achieve a better survival than the administration of only chemotherapy or radiotherapy. The same pattern applies when consultants from the three countries are called to express their recommendations for the patient described in case 3 (Mj): in Canada 80% of clinicians would give best supportive care, a similar 70% would not give chemotherapy in England and Wales, while in Italy 69% would give it (83% if the patient was 50 years old or younger). In terms of estimates of survival, Italian clinicians felt more expectations from optimal chemotherapy than their AngloSaxon colleagues. This study did not address problems of appropriateness of prescriptions, instead limited itself to depict the current situation. In conclusion, the three reports show striking similarities, characterized by a wide range of answers in terms of recommendations and of differing levels of expectation of outcome. In Italy there is a generally greater anticipation of benefit from active treatments in any of the three clinical settings presented. The routine use of chemotherapy and radiotherapy would apparently only be adopted if relatively large (unrealistic?) survival benefits accrued. It is possible that this reflects uncertainty as to the true benefits, since clinical trials of treatment with radio-therapy or chemotherapy have given widely differing results. Indeed, as shown by open answers about the opportunity of implementing trials in patients affected by stage II disease and by proposals of neoadjuvant therapies in stage Illb, therapeutic approaches are still largely a matter of research [26]. A greater uniformity of beliefs might result if very large trials give a more precise estimate of benefit/effect. Currently, at least 8 trials on adjuvant cisplatin-based chemotherapy are ongoing [8]. Among them is the Italian Alpi trial [13], a National Collaborative Study, that closed the accrual period in January 1997, with 1086 stage I, II and Ilia patients randomised, while EORTC contributed with further 111 patients. Alpi was designed to detect a 20% relative reduction in mortality following adjuvant MVP with 80% power at the 5% level of significance.
Original article Survey on the treatment of non-small-cell lung cancer in Italy A. Alexanian & V. Torri Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
Introduction
In Italy lung cancer accounts for 30,000 deaths per year [1], non-small-cell histologic types representing 75%80% of cases [2]. Five-year survival rate is less than 10% and this proportion has not substantially changed in the last 15 years [3]. Mortality reduction can be achieved with primary prevention (successful campaigns against smoking in order to reduce incidence), secondary prevention (discover of screening tests allowing for usefully early diagnoses) or better therapy. The most obvious way to improve present patients' prognoses consists in the optimal exploitation of already available treatments. Surgery with curative intent is the treatment of choice for patients with NSCLC, but because of disease extent and/or patients'clinical conditions less than one third of patients presents for treatment with potentially resectable disease [4]. Indeed, there are many debates even about the local extent of disease that should be regarded as potentially curable by this means [5]. Only few patients with inoperable, non-metastatic disease will be deemed suitable for radical radiotherapy, as a potentially curative treatment [6]. For the others, palliative radiotherapy may be considered or supportive care alone [7]. In spite of a large number of randomised trials, there remains substantial disagreement about whether chemotherapy should be given in addition to any of the above primary treatments [8, 9]. On the whole, in NSCLC radio- and chemotherapy have not led to the
reductions in mortality expected on the basis of the results obtained in other tumours. Single studies evaluating these approaches, however, were too small to show the presence of any small - but still clinically relevant in such a frequent disease - effect; indeed, given the prevalence of NSCLC, a relative reduction in mortality of a 10%-15% order would be important in terms of public health. The present study was planned in the framework of the meta-analysis of the Non-Small-Cell Lung Cancer Collaborative Group, to establish whether there was reliable evidence that chemotherapy improved survival in NSCLC. It was based on 52 published and unpublished randomised trials making an unconfounded comparison of primary treatment vs. primary treatment plus chemotherapy [10]. Hereafter we present a survey of Italian clinicians, undertaken to determine their views on the current role of chemotherapy in the treatment of NSCLC; in particular, how they would manage three clinical situations given in three case histories, to ascertain their opinion on prognosis, their therapeutic preferences, the perceived efficacy of chemotherapy and what benefits from it would be required for them to change their practice. The way to express the efficacy of a treatment - understanding of results as a premise to a correct transfer of knowledge from research to clinical practice - was also evaluated. This project was initiated by the Clinical Trials Group of the National Cancer Institute of Canada [11]
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Results: Overall, there were 287 evaluable responses, 89% of respondents were males, mean age was 46 years, years from Background: The results of the Italian part of an international graduation 21 and charge of patients per clinician 82. The most survey on therapeutic preferences and opinions about prognosis important result is the wide variation of answers both about of patients affected by non-small-cell lung cancer (NSCLC) therapy and prognosis. Expectations about size of prognosis improvement with a new chemotherapy seem to be excessive. are shown. Patients and methods: The investigation was conducted by Conclusions: The results are discussed in relation to the the means of a postal questionnaire aiming to gather informa- twin surveys of Canada and England and Wales and to the tion on preferences about treatment and beliefs about survival meta-analyses on the efficacy of chemotherapy as an adjunct to of three hypothetical patients affected by NSCLC in different primary treatment and on postoperative radiotherapy in nonstages (T2N1M0, T2N3Mo, M\); three sources of Italian physi- small-cell lung cancer. cians potentially treating patients affected by NSCLC were the target population: participants in the Adjuvant Lung Project Italy (Alpi) trial, a 20% random sample of the Italian Medical Oncology Association (AIOM) and representatives of almost Key words: adjuvant chemotherapy, clinicians' opinions, nonall the pneumology wards in Italy. small-cell lung cancer Summary
808 and has been applied also in France, England and Wales [12]. Patients and methods Target population
Case 1 (T2NiMo) A 65-year-old man presents to you complaining of two minor episodes of haemoptysis and he has no other symptoms. There is a 4 cm diameter mass in his right lower lobe on chest X-ray. A bronchoscopy and biopsy confirm the diagnosis of a squamous-cell carcinoma. A full metastatic work-up is negative. At surgery a microscopically positive right hilar node is found but all the other nodes are negative. A right pneumonectomy is done and the resection is considered complete both macroscopically and microscopically. Following surgery, the patient comes back for a follow-up visit. He has no symptoms and he is doing well. Case 2 (T2N3Mo). A 4 cm mass in the left upper lobe with mediastinal widening is found on a routine chest X-ray of an asymptomatic 65-year-old man. At mediastinoscopy, enlarged lymph nodes involved with squamous carcinoma are found on both sides of the trachea. The rest of the metastatic work-up is negative. The patient is in good condition and willing to follow any of your recommendations. Case 3 (M|). A 65-year-old man presents to you complaining of minor haemoptysis and no other symptoms. His chest X-ray shows a 4 cm mass in the right upper lobe. A bone scintigram shows two areas of increased uptake in his right humerus and one in his skull. A biopsy of the humerus reveals squamous cell carcinoma. The rest of the metastatic work-up is negative. The patient is in good conditions and willing to follow any of your recommendations.
Table 2 Sample characteristics (n = 287). n (%)
The questionnaire Practical activity The questionnaire was in four sections. The first three sections depicted Pneumology three common clinical presentations of NSCLC with controversial Oncology treatment options (Table 1). The fourth section requested background Surgery information about respondents and their practice, including their Oncology + other (radiotherapy in 11 cases) precise speciality. Internal medicine Each case was followed by questions on preferences about treatRadiotherapy ment (responses were not required to be mutually exclusive) and beliefs about survival. Respondents were asked to complete the questionnaire Hospital geographical site North only for those types of patients that they themselves treated. In the first Centre case, questions relating to prognosis were phrased in terms of five-year South survival. In the second and third case, respondents could choose Hospital number of beds between survival rate (five-year and one-year, respectively) or median <200 survival (in years or months). In the third case, respondents were asked 200-399 whether they would recommend chemotherapy according to age (65 or 400-599 50 years old). 600-800 The questionnaire is shown in full in the England and Wales report >800 [12]. Teaching hospitals Statistics
Yes No
111 (39) 86 (30) 36(13) 27(9) 14(4.5) 13(4.5) 151 (53) 90(31) 46(16) 41 (14) 30(11) 32(11) 56(19) 128(45) 95 (33) 192(67)
Radiotherapy facilities availability Some continuous variables, such as age, years since graduation, charge of patients per clinician (number of new lung cancer patients seen annually) and time devoted to clinical practice and research were categorised using the median value as cut-off. The results have been analysed only aggregated and not individually. Risk (i.e., the influence of clinicians' characteristics on treatment preferences) was measured in terms of odd ratios (OR) with their 95% confidence intervals (95% CI). Statistically significant values for differences between proportions were based on the %2 test -
Yes No
166(58) 121(42)
Questionnaires returned
with lung cancer were 47. Thus, available forms were 287: 96 Alpi trialists (64% of eligible), 87 AIOM associates (39%) and 104 HCP (52%). Males were 256 (89%); mean age was 46 years (range 30-67, median 45), years from graduation 21 (range 3-45, median 20) and charge of patients per clinician 82 (range 3-800, median 50). Median time devoted to clinical activity and research were, respectively, 70% and 10%. Other characteristics are illustrated in Table 2.
On the whole 620 questionnaires were sent out and responses were obtained from 334 clinicians, giving a compliance rate of 54%. Clinicians not treating patients
Case 1: T2, Nj, Mo disease Clinicians treating patients in this category were 273 (95%) and their recommendations - after primary treat-
Results
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The questionnaire (translated into Italian from the originally bilingual - English and French - version), a letter explaining its purpose and drawing attention to its international dimension, and a stamped addressed envelope for its return were mailed to 620 Italian clinicians - thoracic surgeons, hospital chest physicians (HCP) and medical and radiation oncologists — during spring 1994. The target population included three sources, with no overlap among them: a) all the 150 clinicians participating in the Alpi, a randomised clinical trial with patients affected by stage I, lie Ilia NSCLC assigned to observation or adjuvant cisplatin-based chemotherapy (mitomycin + vindesine + cisplatin for three courses every three weeks, MVP) after primary therapy (complete resection, with radiotherapy given at the discretion of the treating physician) [8, 13]; b) 250 members (a random sample of approximately 20% of the total) of the AIOM; and c) 220 HCP, representative of almost all the pneumology wards in Italy. After two months a reminder was sent to all non-responders, with the aim to reach a 50% response rate, at least.
Table 1. Clinical features of three NSCLC patients set out in the questionnaire.
809 Table 3. Case 1: clinicians' (n = 273) estimates of five-year survival after successful surgical resection. Probability of patients being alive in five years (%)
Clinicians, n (%)
5(2) 95 (38) 143(57) 6(2) -(-) 24 3(1) 67 (32) 124(58) 19(9)
Additional benefit in five-year survival rate required (%)
Clinicians, n (To)
0-5 6-10 11-15 16-20 21-25 26-100 NA
23(15) 37 (25) 29(19) 38 (25) 7(5) 16(11) 52
Abbreviation: NA - not answered. The percentage values refer to those clinicians who answered the question.
60 Table 5. Case 2: treatment recommended by clinicians (n = 280). 70(31)
140(61) 16(7) 45
1(1) 54 (28) 113(58) 22(11) 3(2) 80
Abbreviation: NA - not answered. The percentage values refer to those clinicians who answered the question.
merit consisting in complete reduction - were: radiotherapy in 111 (41%), no further treatment in 79 (29%) cases, chemotherapy in 42 (15%), both treatments in 25 (9%); 16 clinicians (6%) ticked the 'Yes' box against 'other therapy' and specified that they would recommend a) entry to a trial of adjuvant treatment, b) only immunotherapy, c) immunotherapy and chemotherapy and/or radiotherapy. Clinicians' recommendations of radio- or chemotherapy were similar whatever their age, sex, years from graduation, prevailing practical activity, amount of time devoted to clinic or research, hospital size and involvement in undergraduate teaching. Significantly more clinicians working in hospitals where a radiotherapy facility was available recommended radiotherapy {P < 0.03; OR = 1.26, 95% Cl: 1.02-1.55), while its absence favoured chemotherapy (P < 0.0003; OR = 1.71, 95% CI: 1.32-2.22). The clinicians' expectations of patients' survival are presented in Table 3. With simple follow-up, 2% of clinicians who answered expected no chance of survival tofiveyears; 38% expected a l%-25% chance of survival, and a further 57% a 26%-50% chance. There was little expectation that adjuvant treatment could influence probabilities: clinicians who indicated afive-yearsurvival rate greater than 50% were at most 13% (in the case of radiotherapy and chemotherapy combined). Among the
Treatment recommended
Clinicians, n (%)
Chemotherapy + radiotherapy Only radiotherapy Surgery + chemotherapy + radiotherapy 3 Only chemotherapy Chemotherapy + surgeryb Surgery + radiotherapy 0 Only surgery Only follow-up
139(50) 58(21) 32(12) 20(7) 14(5) 9(3) 4(1) 4(1)
Neoadjuvant treatments: a = 27, b = 14, c = 2.
60 clinicians who did not answer the question for chemotherapy, only 9 recommended it; similarly only 9 out of 45 who did not answer for radiotherapy recommended it, and only 4 out of 80 who did not answer for combined treatment recommended it. In the hypothetical situation that a new combination of drugs had been developed as adjuvant treatment, those clinicians who had not recommended adjuvant chemotherapy (all but 71 of the 273) were asked what five-year survival rate would have to be achieved by such treatment for them to adopt it routinely. Their responses are presented in Table 4. Tn general, clinicians required substantial survival improvements with adjuvant chemotherapy for them to recommend it routinely, 41% of the 150 who answered the question requiring an additional absolute benefit of more than 15%. Case 2: T2, N3, Mo disease
Clinicians treating patients in this category were 280 (98%) and their recommendations are reported in Table 5. Medical oncologists were more likely than other clinicians to recommend chemotherapy (P < 0.001; OR = 1.91, 95% CI: 1.24-2.94). Recommendations were not influenced by other aspects of the clinicians or of their hospitals. The clinicians' expectations of patients' survival are presented in Table 6. Of the 280 clinicians, 155 (55%) expressed their expectations as five-year survival rates, and 125 (45%) as median survival. With best supportive
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Without adjuvant therapy 0 1-25 26-50 51-75 76-100 NA With adjuvant chemotherapy 0 1-25 26-50 51-75 76-100 NA With adjuvant radiotherapy 0 1-25 26-50 51-75 76-100 NA With both adjuvant treatments 0 1-25 26-50 51-75 76-100 NA
Table 4. Case 1: improvement in five-year survival rates that would have to be achieved with adjuvant chemotherapy for clinicians to adopt such treatment routinely (n = 202).
810 Table 6. Case 2: clinicians' (« = 280) estimates of survival. Estimation of percentage alive in five years
Estimation of duration of survival
Probability
Median duration (months)
Table 7. Case 2: improvement in five-year survival rates and median survival rates that would have to be achieved with adjuvant chemoradiotherapy for clinicians to adopt such treatment routinely (n = 109). Additional benefit required (%)
Clinicians, n (%)
With optimal radiotherapy alone 0 15(12) 1-5 41 (32) 6-10 50 (39) 11-15 11(9) 16-20 6(5) 3=21 5(4) NA 27 With optimal chemotherapy alone 0 24(19) 1-5 43 (34) 6-10 37 (30) 11-15 5(4) 16-20 10(8) 3*21 6(5) NA 30
0 1-6 7-12 13-18 3=19
0(0) 32 (43) 55 (50) 4(4) 4(4)
NA
30
0 1-6 7-12 13-18 3=19
0(0) 12(11) 64(61) 17(16) 12(11)
NA
20
0 1-6 7-12 13-18 3=19
0(0) 12(12) 61 (60) 21 (21) 7(7)
NA
24
With optimal chemotherapy and radiotherapy 0 11(8) 0 1-6 26(19) 1-5 7-12 44(32) 6-10 13-18 19(14) 11-15 3=19 16-20 20(14) 3=21 18(13) NA NA 17 With other treatment 0 7(8) 1-5 17(19) 6-10 27(30) 11-15 8(9) 16-20 9(10) 3=21 23(25) NA 64
0(0) 5(5) 36(32) 42 (38) 28 (25) 14
0 1-6 7-12 13-18 3=19
0(0) 3(4) 36 (32) 26(34) 17(22)
NA
48
Abbreviation: NA - not answered. The percentage values refer to those clinicians who answered the question.
care only, 47% of clinicians considered there was no chance of survival to five years, and a further 35% a chance of <5%. Expectations were greater for the combination of chemotherapy and radiotherapy than for either of these on its own. The findings expressed in terms of median survival showed a similar pattern. Those clinicians who did not currently recommend multimodality treatment with radiotherapy plus chemotherapy (109 of the 280) were asked what survival rate or median survival would have to be achieved for them to adopt this treatment routinely. Their responses in terms of additional benefit required are presented in Table 7. Among the clinicians who answered in terms of five-
n (%) Clinicians using five-year survival
0-5 6-10 11-15 16-20 21-25 3=26 Not answered
11(28) 15(38) 3(8) 3(8) 3(8) 4(10) 22
Total
61 Median survival
0 1-20 21-40 41-60 61-80 3=81 Not answered
3(14) 2(10) 6(29) 7(33) 1(5) 2(10) 27
Total
48
The percentage values refer to those clinicians who answered the question.
year survival rates, 66% of the 39 who responded would be satisfied by a 10% or less absolute five-year survival improvement with a new combination of chemotherapy and radiotherapy to recommend it routinely. In contrast, the clinicians who answered in terms of median survival were more demanding: 76% of the 21 who responded required an improvement of more than 20% (48% requiring an improvement of more than 40%). Case 3: M, disease Clinicians treating patients in this category were 275 (96%). On detecting metastases in a 65-year-old patient in good condition, 191 (69%) clinicians would recommend chemotherapy, while 229 (83%) would do so for an otherwise similar patient aged 50 years. The great majority, 190 (69%); would recommend chemotherapy for both patients. Chemotherapy for 65-year-old patients was more often indicated by medical oncologists (P < 0.005; OR = 1.68, 95% CI: 1.15-2.46) and respondents devoting at least 10% of their work-time to research (P < 0.005; OR = 1.56, 95% CI: 1.13-2.16). Recommendations were not influenced by other aspects of the clinicians or their hospitals. The clinicians' expectations of patients survival are presented in Table 8. Of the 275 clinicians, 135 (49%) expressed their expectations as one-year survival rates (Table 8a), and 140 (51%) as median survival (Table 8b). With best supportive care only, 13% of clinicians considered there was no chance of survival to one year, and a further 51% a chance of < 10%. Their expectations were better for optimal chemotherapy, the equivalent percentages being 4% and 28%, with a shift towards more favourable one-year survival rates. Similarly, among
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With best supportive care only 0 62 (47) 1-5 46 (35) 6-10 14(10) 11-15 7(5) 16-20 4(3) 3=21 1(1) NA 21
Clinicians, n (%)
811
Discussion Some preliminary consideration about response rates and composition of respondents is worthwhile. The overall compliance rate (54%) is very similar to previous surveys; in a French survey about small-cell lung cancer, 52% of the physicians returned the questionnaire [14]. A telephone survey on a sample of AIOM nonresponders (the group with the lowest response rate) showed that many of them were not involved in the management of lung cancer patients. The 39% AIOM response rate is anyway close to the 36% obtained in the same period by the ASCO (American Society of Clinical Oncology) [15], its American equivalent. The same circumstance - chest physicians not involved in oncological practice - applied to the HCP subgroup. The likely overrepresentation of chest physicians, along with the underrepresentation of radiotherapists should be viewed in the light of the usual diagnostic path of these patients in Italy: they traditionally first encounter a chest physician or an oncologist (78% of respondents in our series) as first specialist. The survey provides a comprehensive assessment of the attitudes of consultants in Italy towards the treatment of lung cancer. The distribution of respondents on the countryside reflects the distribution of services. Among therapeutic recommendations, two of them are particularly notable: a) half of respondents deems that radiotherapy has a role in T2NiM0 patients and the percentage grows to 86% in T2N3M0 - this proportion is rather surprising when matched with the true (much lower) rate of utilisation of radiotherapy in Italy [16] and might hopefully have changed after the publication of the PORT meta-analysis [17] which has shown a detrimental effect of post-operative radiotherapy, especially in early-stage NSCLC; b) 84% of respondents would advise a chemotherapy to a 50-year-old asympto-
Table 8. Case 3: clinicians' (n = 275) estimates of survival. Clinicians' estimate
Clinicians, n (%)
(a) Probability of patient being alive in one year % With best supportive care only 0 1-10 11 20 21-30 31-40 >41 Not answered With optimal chemotherapy 0 1-10 11-20 21-30 31^0 3=41 Not answered (b) Expected median survival months With best supportive care only 1-6 7-12 13-18 Not answered With optimal chemotherapy 1-6 7-12 13-18 19-24 >25 Not answered
16(13) 65(51) 30 (23) 9(7) 4(3) 4(3) 7 5(4) 37 28) 49 (37) 18(13) 9(7) 16(12) 1
86 (65) 45 (34) 1(1) 8 29 (22) 84 (63) 15(11) 4(3) 1(1) 7
The percentage values refer to those clinicians who answered the question.
Table 9. Case 3: improvement in one-year survival rates and median survival rates that would have to be achieved with chemotherapy for clinicians to adopt it routinely (« = 84). Additional benefit required (%)
n (%) Clinicians using five-year survival
0-5 6-10 11-15 16-20 21-25 Not answered
2(5) 12(29) 6(15) 9(22) 4(10) 8(20) 6
Total
47 Median survival
0 1-20 21-40 41-60 61-80 5=81 Not answered
1(4) -(-) 2(7) 4(14) 22 (76) 8
Total
37
The percentage values refer to those clinicians who answered the question.
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the clinicians expressing their expectations in terms of median survival, 35% would have expected a median survival of ^ 7 months with best supportive care only and 78% with optimal chemotherapy. Those clinicians that did not currently recommend chemotherapy (84 of the 275) were asked what one-year survival rate or median survival would have to be achieved by a new combination of drugs for them to adopt such new treatment routinely. Their responses in terms of additional benefit required are presented in Table 9. Of the 47 clinicians that answered in terms of one-year survival rates, 66% would want to see an absolute improvement of more than 10%. As for case 2, the requirements of the clinicians who answered in terms of median survival were more demanding: 97% of the 37 who responded would want to see an improvement of more than 40%. Table 10 describes clinicians' attitudes towards the opportunity of sharing with patients the choice of cure.
812 group of 8 studies comparing cisplatin-based regimens vs. only supportive care the median survival shifted from How do you decide treatment in a metastatic patient? n (%) 4-5.5 months [10]). The wide variability of answers about (n = 287) prognostic provisions again supports the hypothesis 1. I recommend the patient the treatment which I deem to 115 (41) that opinions are often based on premises not supported be the best for him/her by consistent epidemiologic evidence. The attitude of clinicians about the opportunity to 2. I describe different types of available treatments and I 158 (56) recommend the best for the patient share with patients the choice of treatment conceals a problem of information. A patient affected by advanced 3. I describe different possible treatments to the patient 10(3) NSCLC is generally assigned to one of two policies: and he/she makes the final choice observation, with supportive care only, or administra4. Not answered 4 tion of an active treatment (chemo- or radiotherapy) at the price of various degrees of toxicity. The evaluation matic patient with bone metastases - in this case a of these two options involves consideration of several comparison is possible with what emerged from a similar variables (symptomatic or asymptomatic disease, durastudy made about ten years ago in Canada: when physi- tion and efficacy of treatments, toxicity, duration of cians exposed to the same scenario (NSCLC with bone benefit, quality of life, and so on) which can be differmetastases) were asked which treatment they would have ently viewed by patient and clinician [24, 25]. Indeed, chosen for themselves, the chemotherapy option (alone or the essential premise to such a choice is the full awareness of diagnosis on the part of patient, an often eluded plus radiotherapy) gathered only 16% of consents [18]. On the whole the most relevant feature is represented circumstance in the Italian reality. The presence of some national specificity in the cliniby the wide range of answers. The variety of opinions cians' therapeutic approach and prognostic evaluations about NSCLC therapy means a still unsatisfactory indiis made possible by the comparison with the previously viduation of care strategies (with some of them clearly published Canadian and English-Welsh surveys [11,12]. better than others) and represents a strong determinant The results in the three studies were derived from different of the variety of behaviours, both in clinical practice and populations of respondents according to specialties, as in research [19]. there were equal proportions of chest physicians, thoracic Radiotherapy availability inside the hospital influences surgeons, medical oncologists, and radiation oncologists the choice of treatment after radical intervention in a (about 25% each) in Canada while in England and patient withT2N1M0 disease; this result is relevant to the Wales radiotherapists were more represented (30%) and point of view of the unequal distribution of radiotherapy (6%). There was, however, little medical oncologists less wards in the nation [20]. systematic difference in response between specialities in To be an oncologist favors the indication to medical all the studies, and so comparisons between their findtreatment in cases 2 and 3, as it could be expected ings can reasonably be made. because of specialists' broader familiarity with chemoFor case 1 (T2, N 1; Mo), the main difference was in therapy regimens [21]. treatment recommendations: simple follow-up was adThe large increase in survival that the respondents vised by 29% of clinicians in Italy, 74% in England and would require to change their practice - and recommend Wales and 68% in Canada; instead, chemotherapy (alone a new chemotherapy instead of a policy of only close or in combination with radiotherapy) was recommended follow-up gives shape to probably excessive expectations by 24% in Italy, 1% in England and Wales and 4% in (primarily in the first - but also the second - scenario); Canada, while radiotherapy (alone or in combination the meta-analysis of chemotherapic treatments helps in with radiotherapy) was recommended by 50% in Italy, estimating the degree of benefit that one can realistically 24% in England and Wales and 31% in Canada. This expect from a new regimen: among adjuvant treatments a probably reflects a peculiar uneasiness of Italian clinipositive result stems out only from the more recent subcians towards the option of 'offering nothing' to the group of studies using platinum yielding an absolute 5% patients, as is confirmed by the fact that the predictions improvement in five-year survival (from 50%-55%) [10]. The incongruous size of expectations about a new of survival after surgery showed a very similar distribuchemotherapy in the case of the patient with advanced tion, with little expectation from the adding of whatever disease because of bone metastases means that the adjuvant treatment, in the three surveys. Recommended treatment for the patient described in relative value of median survival and one-year survival case 2 (T 2 , N 3 , Mo) confirmed the somewhat more rate is probably misunderstood. 'aggressive' attitude of Italian clinicians, as the respecPrognosis data shown in Tables 4 and 6 can be tive proportions of only supportive care and surgery compared with the overall five-year survival rates (39% proposals in Italy, Canada, England and Wales were: 1% and 0%-5% for patients with T2N,M0 and T2N3M0 21%, 17% and 0, 23% and 1%. Similarly, combined and disease, respectively) reported in the last international radiochemo-therapy was recommended by 50% (plus staging classification [22], indeed substantially unchanged 12% if associated to surgery) of respondents in the over the last 15 years [23]. For the metastatic patients in 11% (at best) from England and Wales, Italian survey, Table 8 we can rely on the meta-analysis (in the subTable 10. Clinicians' attitudes.
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and 16% from Canada. However, Italian clinicians showed themselves also more confident that multimodality treatment would achieve a better survival than the administration of only chemotherapy or radiotherapy. The same pattern applies when consultants from the three countries are called to express their recommendations for the patient described in case 3 (Mj): in Canada 80% of clinicians would give best supportive care, a similar 70% would not give chemotherapy in England and Wales, while in Italy 69% would give it (83% if the patient was 50 years old or younger). In terms of estimates of survival, Italian clinicians felt more expectations from optimal chemotherapy than their AngloSaxon colleagues. This study did not address problems of appropriateness of prescriptions, instead limited itself to depict the current situation. In conclusion, the three reports show striking similarities, characterized by a wide range of answers in terms of recommendations and of differing levels of expectation of outcome. In Italy there is a generally greater anticipation of benefit from active treatments in any of the three clinical settings presented. The routine use of chemotherapy and radiotherapy would apparently only be adopted if relatively large (unrealistic?) survival benefits accrued. It is possible that this reflects uncertainty as to the true benefits, since clinical trials of treatment with radio-therapy or chemotherapy have given widely differing results. Indeed, as shown by open answers about the opportunity of implementing trials in patients affected by stage II disease and by proposals of neoadjuvant therapies in stage Illb, therapeutic approaches are still largely a matter of research [26]. A greater uniformity of beliefs might result if very large trials give a more precise estimate of benefit/effect. Currently, at least 8 trials on adjuvant cisplatin-based chemotherapy are ongoing [8]. Among them is the Italian Alpi trial [13], a National Collaborative Study, that closed the accrual period in January 1997, with 1086 stage I, II and Ilia patients randomised, while EORTC contributed with further 111 patients. Alpi was designed to detect a 20% relative reduction in mortality following adjuvant MVP with 80% power at the 5% level of significance.