Italian Survey on adjuvant treatment of non-small cell lung cancer (ISA)

Lung Cancer 73 (2011) 78–88

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Italian Survey on adjuvant treatment of non-small cell lung cancer (ISA) Giuseppe Luigi Banna a,∗ , Massimo Di Maio b , Alessandro Follador c , Elena Collovà d , Jessica Menis c , Silvia Novello e , Emilio Bria f , on behalf of ISA Co-Authors1 a

Division of Medical Oncology, Cannizzaro Hospital, Catania, Italy Clinical Trials Unit, National Cancer Institute – G. Pascale Foundation, Napoli, Italy Department of Medical Oncology, University Hospital, Udine, Italy d Division of Medical Oncology, Hospital of Legnano, Milano, Italy e Thoracic Oncology Unit, University of Turin, San Luigi Hospital, Orbassano, Italy f Department of Medical Oncology, Regina Elena National Cancer National Institute, Roma, Italy b c

a r t i c l e

i n f o

Article history: Received 16 May 2010 Received in revised form 26 September 2010 Accepted 23 October 2010 Keywords: Adjuvant chemotherapy Non-small cell lung cancer Postoperative radiotherapy Survey

a b s t r a c t Background: A recent pooled analysis of randomized trials indicated significant improvement in overall survival from cisplatin-based adjuvant chemotherapy for non-small cell lung cancer (NSCLC), depending on disease stage (only in stages II and III) and PS (≤1). Post-operative radiotherapy (RT) is optional for pN2 tumours. Patients and methods: To evaluate opinions and daily clinical practice of Italian Oncologists about adjuvant treatment of NSCLC, a 46-item questionnaire was delivered via e-mail. Results: Seventy-eight physicians from 68 Centers (out of 98 contacted) returned their questionnaire. Seventy-four, 86, 94, and 78% of them give the indication for adjuvant chemotherapy for stage IIA, IIB, IIIA, and IIIB disease, respectively and 14% in stage IB disease. Stage, PS, and age are taken into consideration evaluating adjuvant approach by 97, 95 and 73%, respectively. Cisplatin–vinorelbine (64%) and cisplatin–gemcitabine (33%), for 4 cycles (81%), are the preferred regimens, while 32% use different regi-

∗ Corresponding author at: Division of Medical Oncology, Cannizzaro Hospital, Via Messina 829, 95126, Catania, Italy. Tel.: +39 3476371111; fax: +39 095 7262201. E-mail address: [email protected] (G.L. Banna). 1 ISA Co-Authors: Airoldi Mario, Division of Oncology, San Giovanni Battista Hospital, Torino; Amoroso Domenico, Division of Oncology, Hospital of Versilia, Lucca; Ardizzoia Antonio, Division of Oncology, Hospital of Lecco; Aurilio Gaetano, European Institute of Oncology, Milano; Bajetta Emilio, Division of Oncology-2, Cancer National Institute, Milano; Ballardini Pierluigi, Division of Oncology, Hospital of Delta, Ferrara; Barbieri Fausto, Division of Oncology, University Hospital of Modena; Barletta Emiddio, Division of Oncology, Rummo Hospital, Benevento; Balzelloni Maria Luisa, Division of Oncology, da Procida Hospital, Salerno; Basso Umberto, Division of Oncology - 2, University Hospital of Padova; Bernardini Ilaria, Division of Oncology, Hospital of Carpi, Modena; Boni Corrado, Division of Oncology, Hospital of Reggio Emilia; Bordin Veronica, Division of Oncology, San Paolo Hospital, Milano; Bretti Sergio, Division of Oncology, ASL 4 Torino Hospital, Ivrea, Torino; Bronte Giuseppe, Division of Oncology, University Hospital of Palermo; Brunetti Cosimo, Division of Oncology, ASL Mandria Hospital, Taranto; Buti Sebastiano, Division of Oncology, Istituti Ospitalieri Hospital, Cremona; Camerini Andrea, Division of Oncology, Hospital of Versilia, Lucca; Carillio Guido, Division of Oncology, CCO-Humanitas Institute, Catania; Casartelli Clelia, Division of Oncology, Hospital of Valduce, Como; Capanna Luigi, Division of Oncology, Hospital of Piacenza; Colombo Alfredo, Division of Oncology, Macchiarella Clinic, Palermo; Condemi Giovanni, Division of Oncology, Hospital of Siderno-Locride, Reggio Calabria; Cortinovis Diego, Division of Oncology, San Gerardo Hospital, Monza; Dambrosio Mario, Division of Oncology, IRCCS Multimedica Clinic, Sesto San Giovanni, Milano; Di Fonzo Concetta, Division of Oncology, Fiorini Hospital, Terracina, Latina; Di Lucca Giuseppe, Division of Oncology, Hospital of Saronno; Dima Gianluca, Division of Oncology, San Francesco Di Paola Hospital, Paola, Cosenza; Falzetta Amalia, Division of Oncology, ASL7 Siena Hospital, Siena; Favaretto Adolfo, Division of Oncology – 2, University Hospital of Padova; Ferraù Francesco, Division of Oncology, San Vincenzo Hospital, Taormina; Filipazzi Virginio, Division of Oncology, Luigi Sacco Hospital, Milano; Gamboni Alessandro, Division of Oncology, ASL Hospital of Ravenna; Garassino Isabella, Division of Oncology, Humanitas Clinical Institute, Rozzano, Milano; Garetto Lucia, Division of Oncology, IRCC Candiolo Hospital, Torino; Gebbia Vittorio, Division of Oncology, La Maddalena Clinic, Palermo; Genestreti Giovenzio, Division of Oncology, IRST Meldola Hospital, Forlì-Cesena; Gentile Anna Lisa, Division of Oncology, Hospital of Pescara, Pescara; Giovanardi Filippo, Division of Oncology, Hospital of Carpi, Modena; Labianca Roberto, Division of Oncology, Hospital of Bergamo; Lorusso Vito, Division of Oncology, Vito Fazzi Hospital, Lecce; Mantovani Giovanni, Division of Oncology, University Hospital of Cagliari; Martelli Olga, Division of Oncology, San Giovanni Addolorato Hospital, Roma; Massari Francesco, Division of Oncology, Sant’Orsola-Malpighi Hospital, Bologna; Mazzoli Marta, Division of Oncology, Umberto I University Hospital, Roma; Michetti Giovanni, Division of Pneumology, Hospital of Bergamo; Mordenti Patrizia, Division of Oncology, O. Guglielmo da Saliceto Hospital, Piacenza; Mucciarini Claudia, Division of Oncology, Hospital of Carpi, Modena; Munao Stefania, Mediterranean Institute of Oncology, Viagrande, Catania; Nacci Angelo, Division of Oncology, A. Perrino Hospital, Brindisi; Pogliani Claudia, Division of Oncology, Hospital of Saronno, Varese; Procopio Giuseppe, Division of Oncology - 2, Cancer National Institute, Milano; Riccardi Ferdinando, Division of Oncology, Cardarelli Hospital, Napoli; Rizzato Simona, Division of Oncology, Hospital of Udine; Rossi Antonio, Division of Oncology, Moscati Hospital, Avellino; Rosti Giovanni, Division of Oncology, Hospital of Treviso; Russo Paola, Division of Oncology, ASL Hospital of Avellino; Saladino Tiziana, Division of Oncology, Hospital of Macerata; Salesi Nello, Division of Oncology, Hospital of Latina; Santangelo Domenico, Division of Oncology, Giovanni Paolo II Hospital, Sciacca, Agrigento; Sava Teodoro, Division of Oncology, University Hospital of Verona; Savarino Antonino, Division of Oncology, Barone-Lombardo Hospital, Canicattì, Agrigento; Spinnato Francesca, Division of Oncology, Hospital of Sciacca, Agrigento; Tiseo Marcello, Division of Oncology, Hospital of Parma; Tomassi Ottaviano, Division of Oncology, Hospital of Trieste; Tondulli Luca, Division of Oncology, Fatebenefratelli Hospital, Brescia; Tonini Giuseppe, Division of Oncology, Campus Biomedico Hospital, Roma; Turano Salvatore, Division of Oncology, Mariano Hospital, Cosenza; Valerio Maria Rosaria, Division of Oncology, Giaccone University Hospital, Palermo; Verderame Franco, Division of Oncology, Giovanni Paolo II Hopsital, Sciacca, Agrigento; Zanelli Francesca, Division of Oncology, Hospital of Reggio Emilia; Zanon Elisa, Division of Oncology, Hospital of Gemona. 0169-5002/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2010.10.020

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mens. Ninety-two percent indicate RT in pN2 disease and/or positive resection margins. Real Number of patients Needed to Treat (NNT) is probably not completely known/understood and/or used by physicians. Conclusions: A substantial adherence between clinical daily practice in Italy and scientific progresses is described in this paper, even with some discordances regarding the most appropriate adjuvant chemotherapy regimen. © 2010 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Non-Small Cell Lung Cancer (NSCLC) accounts for 80% of lung cancers and it is the leading worldwide cause of cancer-related death. Overall, about half of the NSCLC patients present with resectable disease and are theoretically candidate to the radical surgical approach [1–3]. However, up to 60% of stage IB-IIIA NSCLC patients relapse after surgery; that represents an unmet medical need [3,4]. In this landscape, main goals of adjuvant treatment are: to eradicate micrometastatic disease, to reduce the risk of recurrence, and to improve survival in completely resected patients [2,5]. During the last decade, several clinical trials focused on the role of postoperative chemotherapy have reported conflicting results and the adjuvant treatment for NSCLC is still currently controversial for many of its aspects. The meta-analysis published in 1995 by the NSCLC Cooperative Group failed to demonstrate a survival advantage for adjuvant chemotherapy [6]. Thereafter, the Eastern Cooperative Oncology Group (ECOG) 3590 phase III trial on adjuvant chemo-radiotherapy [7], the Big Lung Trial (BLT) [8], the Adjuvant Lung Project Italy (ALPI) trial [9], and the Cancer and Leukemia Group B (CALGB) 9633 trial (this regarding only stage IB disease) [10], failed to show a statistically significant benefit in favour of adjuvant chemotherapy. The International Adjuvant Lung Cancer Trial (IALT) [11] was the first randomized study showing a significant 5-year survival benefit (14% reduction of risk of death) with adjuvant cisplatin and vinorelbine combination, although it was not maintained at a subsequent analysis with a median follow-up of 7.5 years (9% non-significant reduction of risk of death) [12]. Other trials showing survival benefit in this setting were the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) JBR.10 study [13] (with a 15% survival improvement at 5 year), and the Adjuvant Navelbine International Trialist Association (ANITA) trial (with a 9% survival improvement at 5 year) [14]. In contrast to the IALT trial, the updated results of the JBR.10 trial, with a median follow-up of 9.3 years, showed that the survival benefit of adjuvant cisplatin and vinorelbine was maintained with an overall improvement in survival equal to 11%, which means 22% relative reduction in the risk of death (P = 0.04) [15]. The outcome differences provided by adjuvant chemotherapy may be related to several issues, such as the type of chemotherapy, the patient populations, the use of postoperative radiation (PORT) [16]. Lung Adjuvant Cisplatin Evaluation (LACE) metanalysis [17] collected and pooled data from 5 international randomized trials (BLT, ALPI, IALT, JBR.10 and ANITA trial) and showed a 5 year absolute survival benefit of 5.4% from this approach with an HR for death equal to 0.89 (95% CI, 0.82–0.96, P = 0.005). Disease free survival (DFS) was also significantly improved with a 5.8% increase at 5 years (HR = 0.84; 95% CI, 0.78–0.91, P < 0.001). Cisplatin and vinorelbine was the optimal combination. Furthermore, in the ANITA trial [14], cisplatin and vinorelbine provided a statistically significant 5-year survival, that was maintained at 7 years. To date there is no evidence in favour of one versus other third generation drugs in combination with cisplatin, although vinorelbine is the only drug associated with data showing consistent improvement in survival. A recent metanalysis confirmed a significant advantage for adjuvant chemotherapy in completely resected stage II and III disease in terms of both relative and absolute benefit in overall survival (OS),

with a relative benefit ranging from 7 to 12% in stage II disease and an absolute benefit from 2.5 to 4.1% in stage III [18]. Moreover, a Bayesian analysis reported a 5-year absolute benefit in OS for stage II and III disease close to 7%: for stage II and stage III more than 90% probability of a 6% benefit and 50% probability of a 12% OS benefit has shown [19]. For completely resected stage IB disease, data about postoperative treatment are even more controversial. CALGB 9633 [10] showed lack of benefit from adjuvant chemotherapy in stage IB NSCLC (HR = 0.83, p = 0.125 in OS), probably due to the carboplatin-based chemotherapy and the low statistic power of the study [1,10,20]; an unplanned subset exploratory analysis demonstrated significant improvement in OS for tumours larger than 4 cm (HR = 0.69, p = 0.04) [10]. Based on these above mentioned data, the European Society for Medical Oncology (ESMO) [21], the American Society of Clinical Oncology (ASCO) [22] and the National Comprehensive Cancer Network (NCCN) [23] guidelines recommend adjuvant chemotherapy for patients with stage II and III NSCLC, and in selected stage IB (T > 4 cm); the Associazione Italiana di Oncologia Medica (AIOM—Italian Association of Medical Oncology) [24] guidelines suggest the use of adjuvant chemotherapy in patients with stage II and III disease, good performance status (PS), without comorbidities and with a brief recovery after surgery. More recently, two meta-analyses of individual patient data by the NSCLC Meta-analyses Collaborative Group were reported [25]. The first was based on 34 trial comparisons of surgery plus chemotherapy versus surgery alone, and recorded an absolute increase in survival of 4% (95% CI 3–6) at 5 years; the second based on 13 trial comparisons of surgery plus radiotherapy and chemotherapy versus surgery plus radiotherapy, recorded an absolute improvement in survival of 4% (95% CI 1–8) at 5 years. By these meta-analyses a similar effect of platinum-based chemotherapy was estimated in patients with stage II and III as well as in those with stage IB tumours. Post-operative radiotherapy (PORT) is no longer recommended for stage I and II disease based on a meta-analysis published in the 1998 by the PORT Meta-analysis Trialists Group [26]. An assessment of PORT in 7465 patients with resected stage II or III NSCLC found that it increased survival in patients with N2 disease, but not in those with N1 or N0 disease [27]. In the ANITA trial, a benefit from adding PORT to adjuvant chemotherapy was observed only in patients with pN2 tumours [28]. Based on these data showing a small but significant advantage in favour of adjuvant chemotherapy and controversial indications to PORT, physicians and their patients may not yet be convinced that the toxicity related to adjuvant chemotherapy is acceptable in the adjuvant setting; this may lead to a daily different clinical approaches among Italian Oncologists. We proposed an Italian Survey on Adjuvant therapy of NSCLC (ISA), aiming to test their opinion. 2. Material and methods A 46-item questionnaire was electronically sent to 98 Italian Centers (each represented by 2 or 3 physicians, accounting for a total of 218 contacted physicians), gathered from national or regional conferences on medical oncology held in 2008–2010. By

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Table 1 Characteristics of physicians. No. (median)

% (range)

Specialty Oncologists Other*

76 2

97 3

Area of Italy North Centre-South-Islands

41 37

53 47

Years of specialty <10 years ≥10 years Not reported

42 27 9

54 35 12

No. of disclosed pts per year Overall no. of NSCLC pts No. of operated NSCLC pts

(100) (24)

(10–1300) (4–700)

Adherence to guidelines Yes No

76 2

97 3

Type of guidelines NCCN AIOM-NCCN AIOM-ESMO-NCCN AIOM ACCP-AIOM-ESMO-NCCN ESMO-NCCN ESMO AIOM-ESMO ACCP-NCCN ACCP-AIOM-ESMO More guidelines Not reported

30 13 11 7 5 4 2 1 1 1 36 1

39 17 14 9 7 5 3 1 1 1 48 1

Abbreviations: ACCP: American College of Chest Physicians; AIOM: Associazione Italiana di Oncologia Medica; ESMO: European Society for Medical Oncology; NCCN: National Comprehensive Cancer Network; pts: patients. * Other include: one Pneumologist and one Ematologist.

the invitation email, was asked to return at least one completed questionnaire per Center. The questionnaire was sent three times from February to August 2009. Questions concerned characteristics and expertise of each physician and his/her Center, indication of adjuvant chemotherapy and/or radiotherapy for NSCLC, type of adjuvant chemotherapy applied (Fig. 1). Resubmission of three questions about disease stages considered for adjuvant chemotherapy and expected and real ratio of patients to be treated for a benefit from adjuvant chemotherapy (Fig. 1), together with a brief explanation of these questions, was done three months later the deadline to confirm previous physicians’ answers. Data have been collected into a database and are presented as number and percentage, or median and range, where necessary and appropriate. 3. Results 3.1. Physicians’ characteristics Seventy-eight physicians from 68 different Italian Centers (out of the 98 Centers contacted, 69.4%) returned the fulfilled questionnaire. Out of 30 non-responding Centers, 22 were from Centre-South-Islands (out of 56 contacted Centers, 39%) and 8 were from North (out of 42–19%), 19 were General Hospitals (out of 58–33%) and 11 were Universities or Cancer Research Centers (out of 40–27.5%). The distribution and characteristics of responding physicians are reported in Table 1. Seventy-six (97%) were Oncologist. Forty-one (53%) of them were based in the North or in the Center of Italy. Twenty-seven (35%) completed the Post Graduated School at least 10 years before. The median number of dis-

closed completely resected NSCLC patients per year was 24 (range, 4–700). Seventy-six physicians (97%) reported that they refer to international or local guidelines; 48% of them use more than one guideline. NCCN or AIOM guidelines are followed by 39% and 9% of specialists, respectively; 17% and 14% use AIOM-NCCN and AIOM-ESMO-NCCN guidelines, respectively. 3.2. Adjuvant chemotherapy Indication for adjuvant chemotherapy by pathologic disease stage is reported in Fig. 2. Ten physicians (13%) indicate adjuvant chemotherapy for stage IB disease, 59 (76%) for stage IIA, 72 (92%) for stage IIB, 69 (88%) for stage IIIA, 40 (51%) for stage IIIB; one physician did not indicate the stage (Fig. 2a). As above indicated, the question regarding disease stage considered for adjuvant chemotherapy was re-submitted to the 78 physicians aiming to have a confirmation of their previous answer (Fig. 2b). Sixty-five physicians replied with the following results: 9 physicians (14%) indicated adjuvant chemotherapy for stage IB disease, 48 (74%) for stage IIA, 56 (86%) for stage IIB, 61 (94%) for stage IIIA, 51 (78%) for stage IIIB (Fig. 2b). The explanation provided about the question regarding the indication for stage IIIB disease (Fig. 1), led to have more physicians (78% versus 51%) indicating adjuvant chemotherapy at the re-submitted question (Fig. 2b). Fifty physicians (64%) indicated cisplatin plus vinorelbine as the preferred regimen for adjuvant chemotherapy, 26 (33%) cisplatin plus gemcitabine, one (1%) carboplatin plus paclitaxel and carboplatin plus gemcitabine, respectively (Fig. 3a). Twenty-five physicians (32%) indicated more than one preferred regimen (Fig. 3b): 6 of them (24%) were in favour of cisplatin plus gemcitabine or vinorelbine, 2 (8%) of cisplatin plus vinorelbine or gemcitabine; 5 (20%) of cisplatin or carboplatin plus vinorelbine; 2 (8%) of cisplatin or carboplatin plus gemcitabine, or carboplatin plus paclitaxel; 10 (40%) indicated other options, as reported in Fig. 3b. The reasons supporting the preferred regimen were: evidences from clinical studies for 29 physicians (37%), favourable tolerability/efficacy profile for 18 (23%), manageability and expertise with that regimen for 10 (13%), adherence to guidelines for 7 (9%), efficacy for 6 (8%), elderly patients for 1 (1%), reimbursement for 1 (1%); 6 physician (8%) did not indicate any reason (Table 2). Regarding the number of cycles of adjuvant chemotherapy, 63 physicians (81%) indicate 4 cycles, 8 (10%) 3 cycles, 5 (6%) 6 cycles, 2 (3%) did not answer to this question. Concerning possible differences in activity between cisplatin and carboplatin, 64 physicians (82%) are convinced that difference exists in terms of efficacy (Table 2). 3.3. Adjuvant radiotherapy Forty-one physicians (54%) indicate PORT in those cases with pathological involvement of ipsilateral mediastinal nodes (N2) and/or surgical positive margins, 18 (24%) only when surgical margins are positive, 11 (14%) only for pathological N2; 6 (8%) do not indicate PORT in any case (Fig. 4). 3.4. Clinical, prognostic and predictive factors Seventy-six physicians (97%) use disease stage as prognostic factor for therapeutic decision on completely resected patients, 74 (95%) performance status, 57 (73%) age; comorbidity was indicated together with other factors by 5 physicians (6%), type and sequelae of surgery by 2 (3%). Other mentioned factors were: respiratory function, histopathologic features of the tumour, patient’s preference (Fig. 5). Regarding patient’s age, 63 physicians (81%)

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underlined a different approach in the adjuvant setting for some patients aged 70 years or more, 7 (9%) in all of these cases; for 7 (9%) age does not make any difference, 1 (1%) did not answer the question (Table 2). As possible predictive factors (i.e. ERCC1, RRM1, BRCA12, K-ras), 73 physicians (94%) do not use any of these for establishing adjuvant therapy, while 5 (6%) consider them: 3

81

using ERCC1, 1 BRCA, one has not indicated a preferred factor (Table 3). 3.5. Number of patients needed to treat (NNT) for a benefit Physicians were asked to provide an expected estimation of the NNT to have some benefit from adjuvant chemotherapy (Fig. 6).

Fig. 1. ISA 46-item translated questionnaire including the three resent questions.

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Fig. 1. (Continued )

As above mentioned in the methods chapter, this question was re-submitted to the 78 responding physicians to confirm and to deepen their answers, asking for the desirable number of patients to treat for benefit (Fig. 6b) and the real known number (Fig. 6c). Sixty-five physicians answered. The expected number of patients to

treat for benefit was substantially confirmed: twenty-eight physicians (43%) estimated as 10 this number, 19 (29%) as 25, 14 (22%) as 5, 3 (5%) as 2, 1 (2%) as 50 (Fig. 6b). As expected, differences between the real and the desirable number of patients to treat for benefit were reported, though approximately one third of physicians

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Fig. 1. (Continued ).

Fig. 2. Indication for adjuvant chemotherapy by stage: A) responses to the questionnaire (n = 78); B) responses to the resent question (n = 65).

83

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A

50 (64%) N.

50 45 40 35 26 (33%)

30

25 (32%)

25 20 15 10 1 (1%)

1 (1%)

Carbo-Pac

Carbo-Gem

5 0 Cis-Vin

Cis-Gem

>1 regimen

B

N. 10 (40%)

Other* 6 (24%)

Cis-Gem/Vin

5 (20%)

Cis-/Carbo-Vin Cis-/Carbo-Gem or Carbo-Pac

2 (8%)

Cis-Vin/Gem

2 (8%)

0

2

4

6

8

10

*Other include 1 preference for each of the following: Cis-/Carbo-Gem/Pem; Carbo-Gem o CisVin; Cis-Vin o Carbo-Pac; Cis-Gem/Vin o Carbo- Pac; Cis-/Carbo-Vin o Carbo-Gem; Cis-/CarboGem/Vin; Cis-/Carbo-Vin/Gem; Cis-Gem/Vin/Doc o Carbo-Pac; Cis-Gem/Eto/Pem o CarboGem/Pac; Carbo-Pac o Cis-Vin Abbreviations: Carbo, carboplatin; Cis, cisplatino; Doc, docetaxel; Eto, etoposide; Gem, gemcitabine; Pac, paclitaxel; Pem, pemetrexed; Vin, vinorelbine Fig. 3. Preferred adjuvant chemotherapy regimen: A) the most preferred regimen; B) regimen used when more than one is indicated.

Table 2 Reasons for the preferred adjuvant chemotherapy regimen, number of cycles, differences between platinum compounds and for elderly patients. No.

%

Reasons for chemotherapy regimen Scientific evidences Favourable tolerability/efficacy profile Manageability and expertise Adherence to guidelines Efficacy Elderly patients Drug registration (reimbursement) Not indicated

29 18 10 7 6 1 1 6

37 23 13 9 8 1 1 8

Number of cycles administered 3 4 6 Not indicated

8 63 5 2

10 81 6 3

Difference in activity between cis- and carboplatin Yes No

64 14

82 18

Differences in elderly patients approach (≥70 years): In some cases In all cases No, in any case Not indicated

63 7 7 1

81 9 9 1

overestimates the benefit of adjuvant chemotherapy: thirty-three physicians (51%) estimated as 25 this number, 18 (28%) as 10, 9 (14%) as 50, 4 (6%) as 5, 1 (2%) as 2 (Fig. 6c). 4. Discussion In this report, we described the results of a survey about adjuvant treatment of NSCLC, conducted by 78 Italian physicians from 68 different Centers. The objective of this first step of the survey was to evaluate physicians’ recall, and thus their perception of clinically relevant evidence, and how they claim they apply this evidence in daily practice. A second planned step, not yet conducted, is to collect clinical data regarding NSCLC patients operated and treated in 2009 year by each of the responding Center. Most of the responding physicians declared to follow one or more of the published guidelines. The choice of the chemotherapy schedules shows wide heterogeneity, with the majority indicating cisplatin plus vinorelbine, but a significant proportion indicating cisplatin plus gemcitabine or other schedules, different from the published ones. There was heterogeneity also in the recommendation of PORT. The answers about the NNT actually expected from the use of adjuvant chemotherapy shows that a relevant proportion of the responding physicians significantly overestimates treatment efficacy. The NNT, that is the number of patients who need to receive

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85

Fig. 4. Indication for post-operative radiotherapy.

N.

74 (95%)

Performance status

76 (97%)

Disease stage

57 (73%)

Age

10 (13%)

Other*

0

10

20

30

40

50

60

70

80

*Other factors indicated included: comorbidity for 5 physicians (6%), type and sequelae of surgery for 2 (3%), respiratory function for 1 (1%), histopathological features of the tumour for 1 (1%), patient’s preference for 1 (1%) Fig. 5. Prognostic factor used for indication for adjuvant therapy.

adjuvant chemotherapy, after surgery for NSCLC, in order to prevent one additional death, should be currently estimated to be 20–25, considering an absolute risk reduction of about 4–5%. In our opinion, a realistic estimation of NNT is crucial not only for treatment decisions, but also for a complete and correct patient information. As stated in the guidelines from the American Society of Clinical Oncology, for those patients preferring numbers during their informed decision process, the physician should be able to quote both the relative reduction in the risk of death (i.e., the Hazard Ratio), as well as absolute survival benefit of the therapy. Absolute measures are particularly important, because studies of communication in patients with breast cancer have found that quoting absolute survival benefit is easier for patients to understand, compared with relative risk reduction. Those patients who are quoted relative risk reduction are significantly more likely to endorse chemotherapy, but less likely to demonstrate a true understanding of the benefit [29]. However, our data suggest that physicians

Table 3 Predictive factor used for indicating adjuvant chemotherapy.

Physicians Not using predictive factors Using predictive factors Predictive factors ERCC1 BRCA NA Abbreviations: NA, not assessable.

No.

%

73 5

94 6

3 1 1

60 20 20

are probably not completely aware of the real NNT associated with the treatment they recommend to their patients. Currently, available evidence about the efficacy of adjuvant treatment has been produced with specific schedules of chemotherapy [7–15], but a great number of responding physicians do actually use other schedules in clinical practice. This is quite a peculiar problem of lung cancer, compared to other big killers. Very few physicians do recommend, for adjuvant treatment of breast or colorectal cancer, drugs or combinations that are substantially different from the ones that have proven efficacy in randomized trials. For lung cancer patients, there are probably two reasons that determine this adoption of schedules that have not shown efficacy as adjuvant treatment in randomized trials. First, the toxicity associated with the published, “old-fashioned” chemotherapy regimens, that are widely judged to be less manageable than “newer” regimens. Asking for the reasons for the preferred adjuvant chemotherapy regimen, 23% of responders declared to base their choice on a favourable tolerability/efficacy profile, and another 13% on manageability and expertise with that regimen. Second, the common feeling that several different platinum-based combinations with third-generation drugs are substantially equivalent in the treatment of advanced disease moves some physicians to consider those combinations equivalent also in the adjuvant setting. This “extrapolation” is somehow allowed also by guidelines: NCCN guidelines, describing chemotherapy regimens for adjuvant treatment, list, together with the published cisplatin-based regimens that proved efficacy in randomized trials, also other combinations, such as cisplatin plus gemcitabine, cisplatin plus docetaxel, cisplatin plus pemetrexed for patients with non-squamous tumours. These combinations are defined acceptable by the guidelines,

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Fig. 6. Number of patients to treat (NNT) for a benefit: A) expected estimation—from questionnaire (n = 78); B) expected estimation—second question (n = 65); C) known estimation—second question (n = 65).

and also carboplatin plus paclitaxel is considered acceptable for patients with comorbidities or patients not able to tolerate cisplatin. Unfortunately, the administration of the latter combinations cannot be defined evidence-based, and, although we are familiar with their administration and related side-effects, we currently do not know if the efficacy associated with their use is equivalent, higher or lower than the efficacy of published regimens. Considering the use of carboplatin, it seems that the great majority (82%) of the responding physicians states that a difference exists between cisplatin and carboplatin in the adjuvant approach, probably supported also by the cisplatin versus carboplatin (CISCA) metanalysis [30], that demonstrated an advantage of cisplatin doublets versus carboplatin doublets in advanced NSCLC, even without a statistically significant difference in terms of OS. However, many of them consider the use of carboplatin when patients’ conditions and comorbidities do not allow the use of cisplatin.

A relevant issue in the application of adjuvant treatment in clinical practice is the treatment of elderly patients. Clinical data obtained in the younger patients cannot be automatically applied to the elderly counterpart, who is at higher risk of toxicity, because of comorbidity and organ failure. The majority of responders to our survey underline the difference in management, at least in some cases, between elderly and younger patients. Unfortunately, there are no solid data from clinical trials about efficacy of treatment in elderly patients, and specifically designed trials could greatly help clinicians’ decisions. Thus, adjuvant treatment of elderly patients remains controversial. A recent meta-analysis [31] showed an HR for death equal to 0.9 (95% CI, 0.70–1.16) and no statistically significant differences for event-free survival (EFS) and OS between elderly and young patients, although elderly patients received a significantly lower dose of cisplatin and number of cycles. No significant differences between young and elderly patients were also

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reported in infection rates, haematologic, renal, gastro-intestinal and neurological toxicity. Another unmet medical need in adjuvant approach is the identification of predictive factors, that would improve treatment efficacy. None of the most known factors is currently applicable in clinical practice. Some clinical factors associated with higher local and distant disease recurrence by retrospective and prospective studies could be considered: pneumectomy (versus sleeve lobectomy), non-squamous histology, lymphatic or vascular invasion, T3–T4 and/or pN1 tumours, chemotherapy regimen, symptoms, comorbidities (especially diabetes) [1,13,32]. In the IALT study, a retrospective immunoistochemical analysis [33] showed that the benefit from adjuvant chemotherapy was restricted to ERCC1 negative tumours (HR = 0.76; 95% CI 0.59–0.98). In the JBR.10 trial, there was no overall impact of RAS status on survival. However, in patients with wild-type RAS there was a trend toward a greater benefit from adjuvant chemotherapy with respect to cancer-specific survival, even without any statistically significance [12]. RRM1 and p53 mutation have also been tested in recent trials [2]. Further retrospective analysis of biomarkers in adjuvant trials is presently ongoing within the LACE bio study and may provide more details for the clinical application of these biomarkers in the future [16]. Currently, only some clinical features may be taken into account to select suitable candidates for adjuvant chemotherapy, including: lobectomy, a short time from radical surgery (<40 days), fully recover from surgery, no severe comorbidities, aged less than 70 year, a good ECOG performance status [5,17,34]. According to current guidelines [21–24], PORT is not recommended in N0 or N1 patients, where it appears to be detrimental, whilst less clear is its role in N2 patients. Even for these patients, guidelines of the American Society of Clinical Oncology explicitly state that PORT is not recommended for routine use, because of the lack of prospective, randomized clinical trial data evaluating its efficacy. Interestingly, the great majority of physicians, in our survey, do recommend the use of PORT in some cases, especially in patients with N2 and/or positive margins. Of course, this interest in PORT moves from the consideration of the high proportion of local recurrence after resection, but, according to current evidence, many patients could be actually exposed to useless toxicity. We need definitive, experimental data about the real efficacy of radiotherapy. A large, multi-institutional European phase III trial, Lung Adjuvant Radiotherapy Trial (Lung ART—NCT00410383), is currently comparing 3D conformal PORT with no PORT [16]. The trial includes patients with N2 disease and a complete resection, regardless of systemic therapy received (adjuvant or neoadjuvant). This trial, and other trials with similar design, should better clarify the role of PORT. Some limitations of this survey may be redemption rate and small sample, that may also cause inability to discern regional or other reasons for the practice differences noted. However, the absolute number of Institutions represented by the responding physicians (68), together with the high absolute number of patients declared by those Institutions, let us suppose that the answers are quite representative of the clinical practice in Italy, at least in those Institutions which treat a significant number of cases. Furthermore, Institutions were well distributed in Italian territory, and age distribution of responders, including both younger and older physicians, suggest that our sample could be representative of the Italian oncologists facing with lung cancer patients. Another possible limitation of this survey affecting the honesty of physicians’ answers could have been the choice to conduct this survey by a mail-in questionnaire despite of an anonymous web-survey. This choice was essentially based on the need to identify responding Centers for the second planned step of the survey, that involved the collection of clinical data, but also to get reliable answers from reference Centers for thoracic oncology in Italy. The

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