original articles

Annals of Oncology Annals of Oncology 24: 986–992, 2013 doi:10.1093/annonc/mds578 Published online 15 November 2012

Randomized phase 2 trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed versus cisplatin and vinorelbine: the TREAT study M. Kreuter1,2,20*, J. Vansteenkiste3, J. R. Fischer4, W. Eberhardt5, H. Zabeck6, J. Kollmeier7, M. Serke8, N. Frickhofen9, M. Reck10, W. Engel-Riedel11, S. Neumann12, M. Thomeer13, C. Schumann14, P. De Leyn15, T. Graeter16, G. Stamatis17, I. Zuna18, F. Griesinger19 & M. Thomas1,20, on behalf of the TREAT investigators Departments of 1Thoracic Oncology; 2Pneumology, Thoraxklinik, University of Heidelberg, Heidelberg, Germany; 3Respiratory Oncology Unit, Universities Hospital Leuven, Leuven, Belgium; 4Department of Internal Medicine II, Oncology, Klinik Loewenstein, Loewenstein; 5Department of Medicine (Cancer Research), West German Tumor Centre, University Hospital of University Duisburg-Essen, Essen; 6Department of Thoracic Surgery, Thoraxklinik, University of Heidelberg, Heidelberg; 7Department of Pneumology, Lungenklinik Heckeshorn, Helios-Klinikum Emil von Behring, Berlin; 8Department of Pneumologie III, Lungenklinik Hemer, Hemer; 9Department of Hematology/Oncology, Dr.-Horst-Schmidt-Kliniken GmbH, Wiesbaden; 10Department of Thoracic Oncology, Krankenhaus Großhansdorf, Grosshansdorf; 11Lungenklinik Merheim, Kliniken der Stadt Köln, Cologne; 12Department of Hematology and Oncology, Georg-August-Universität, Göttingen, Germany; 13Department of Respiratory Medicine Ziekenhuis Oost Limburg, Genk, Belgium; 14Department of Internal Medicine II, University Clinic Ulm, Ulm, Germany; 15Department of Thoracic Surgery, Universities Hospital Leuven, Leuven, Belgium; 16Department of Thoracic Surgery, Klinik Loewenstein, Loewenstein, Germany; 17Department of Thoracic Surgery, Ruhrlandklinik Essen, University Hospital of University Duisburg-Essen, Essen; 18Department of Statistics, HZM Pharmaservice, Wiesbaden; 19Department of Hematology and Oncology, Pius-Hospital Oldenburg, Oldenburg; 20Translational Lung Research Center Heidelberg, German Center for Lung Research, Heidelberg, Germany

Received 20 May 2012; revised 25 September 2012; accepted 26 September 2012

Background: Adjuvant chemotherapy is beneficial in non-small-cell lung cancer (NSCLC). However, balancing toxicity and efficacy mandates improvement.

Patients and methods: Patients with completely resected stages IB-pT3N1 NSCLC were randomly assigned to either four cycles cisplatin (C: 50 mg/m2 day (d)1 + 8) and vinorelbine (V: 25 mg/m2 d1, 8, 15, 22) q4 weeks or four cycles cisplatin (75 mg/m2 d1) and pemetrexed (Px: 500 mg/m2 d1) q3 weeks. Primary objective was the clinical feasibility rate (no grade (G)4 neutropenia/thrombocytopenia or thrombocytopenia with bleeding, no G3/4 febrile neutropenia or nonhematological toxicity; no premature withdrawal/death). Secondary objectives were drug delivery and efficacy. Results: One hundred and thirty two patients were randomized (stages: 38% IB, 10% IIA, 47% IIB, 5% pT3pN1; histology: 43% squamous, 57% non-squamous). The feasibility rates were 95.5% (cisplatin and pemetrexed, CPx) and 75.4% (cisplatin and vinorelbine, CVb) (P = 0.001); hematological G3/4 toxic effects were 10% (CPx) and 74% (CVb) (P < 0.001), non-hematological toxic effects were comparable (33% and 31%, P = 0.798). Delivery of total mean doses was 90% of planned with CPx, but 66% (cisplatin) and 64% (vinorelbine) with CVb (P < 0.0001). The median number of cycles [treatment time (weeks)] was 4 for CPx (11.2) and 3 for CVb (9.9). Time to withdrawal from therapy differed significantly between arms favoring CPx (P < 0.001). Conclusion: Adjuvant chemotherapy with CPx is safe and feasible with less toxicity and superior dose delivery compared with CVb. Key words: adjuvant chemotherapy, clinical feasibility, dose delivery, non-small-cell lung cancer, pemetrexed, toxicity

introduction Early metastatic spread limits long-term survival after complete resection, even in early-stage non-small-cell lung cancer *Correspondence to: Dr M. Kreuter, Pneumology and Respiratory Critical Care Medicine, Thoraxklinik, University of Heidelberg, Amalienstr. 5, 69126 Heidelberg, Germany. Tel: +49-6221-3961201; Fax: +49-6221-3961202; E-mail: [email protected]

(NSCLC). Of patients with pathological stage I/II, 40%–60% die of their disease, mainly due to distant recurrence [1]. Evidence from meta-analyses clearly shows a survival benefit with adjuvant cisplatin-based chemotherapy [2–8]. The largest proportion of patients randomized to adjuvant chemotherapy received cisplatin / vinorelbine (CVb, 41%) [9], which also was the most homogeneous subgroup in terms of drug doses and eligibility. Moreover, as shown in a meta-analysis, it was

© The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].

original articles

Annals of Oncology

associated with a substantially superior survival benefit compared with other cisplatin-based regimens [2–6, 9]. However, toxicity has been a critical issue in platinum-based adjuvant protocols. Particularly in combination with vincaalkaloids substantial grade 3/4 hematologic toxicity rates, mainly neutropenia up to 85% and febrile neutropenia up to 9%, were reported [2, 3, 10]. Further points of concern are incomplete treatment delivery in up to 50% of the patients, mainly due to toxicity and patient refusal, treatment delays in 55% and a high proportion of dose reductions amounting to 77% [2, 5, 10]. Thus, the reduction of toxicity, improvements of dose delivery and of patient compliance remain important issues to be addressed in the adjuvant treatment of NSCLC. Consequently, it seems reasonable to assess these issues based on a regimen with better tolerability and promising efficacy. In several phase II and III trials in advanced NSCLC and mesothelioma, the combination of cisplatin and pemetrexed (CPx), a multitarget folate antimetabolite, showed promising efficacy comparable with other platinum combinations, with a good safety profile and convenient administration schedule. With regard to hematologic toxicity, rates of ∼25% grade 3/4 neutropenia were reported with febrile neutropenia 7 days; febrile grade 3/4 neutropenia; grade 4 thrombocytopenia >7 days or any grade with bleeding; grade 3/4 nonhematologic toxicity related to chemotherapy (except nausea/vomiting/hair loss). Secondary objectives were safety, dose delivery (defined as the effectively delivered chemotherapy dose considering all reductions, omissions and withdrawn patients) and efficacy. Efficacy parameters were time to treatment failure (TTTF, time from surgery to time patient is withdrawn due to adverse events, tumor relapse, death, failure to return, refusal of treatment or consent withdrawal), relapse-free survival (RFS), overall survival (OS), distant metastases-free survival, local relapse-free survival and site of relapse. Patients were followed up 30 days after the last cycle, and then every 3 months for 2 years, every 6 months thereafter. This investigator-initiated trial was designed in 2005 by the AIO Lung Cancer Study Group, Germany and the LLCG Leuven Lung Cancer Group, Belgium, and data were collected, managed and analyzed under responsibility of the principle investigator at the clinic for thoracic diseases, University of Heidelberg, Germany. Eli Lilly and Medac provided pemetrexed (Eli Lilly and Company, Bad Homburg, Germany), vinorelbine (Medac GmbH, Wedel, Germany) and cisplatin (Medac GmbH, Wedel, Germany), respectively, and an unrestricted grant to perform the trial, but had no part in the writing of the manuscript.

toxicity management Toxic effects were classified by grade, type, duration, onset and relationship to study treatment according to CTCAE version 3.0 [17]. If the criteria for drug administration (absolute neutrophil count ≥1500/μl, platelets ≥100 000/μl, serum creatinine 7 days G4 thrombocytopenia >7 days G3/4 febrile neutropenia Thrombocytopenia with bleeding G3/4 non-hematologic toxicity

0 0 1 0 2

4 0 5 0 1

a

Multiple reasons possible. DLT: dose-limiting toxicity.

failure for CVb occurred mainly at d15 and d22 of Vb. For CPx, therapy interruption or delay were mostly due to administrative reasons (47.5%), therapy-related hematologic (17.5%) and non-hematologic adverse events (15%). For CVb, these were mainly due to therapy-related hematologic adverse

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events (Vb 60% and C 38.5%), administrative reasons (Vb 8.7% and C 18.5%) and non-hematologic adverse event (without relation to the study: Vb 6.3% and C 12.3%; therapy related: Vb 9.5% and C 6.2%). Earlier termination of therapy occurred for CPx and CVb in 22.4% and 63.1% of the patients. Reasons for earlier termination are shown in Table 4 and were mainly due to unacceptable toxicity according to the protocol or as perceived by patient, due to the medical decision by the investigator or– only for CVb–due to withdrawal of consent. TTTF differed significantly between arms favoring CPx (P < 0.0001) with the median TTTF not reached for CPx and a median of 3.6 months for CVb. In an univariate Cox analysis, including the established risk factors (e.g. age, PS, resection type, pT and pN status and histology), only the factor therapy arm showed a statistical significance (P = 0.001).

toxicity The mean number of AEs and severe adverse events for CPx was 6.8 and 0.3, while it was 6.9 and 0.2 for CVb, respectively. Grade 3/4 hematologic toxicity was significantly lower for CPx with 10.5% compared with 78.2% for CVb (P < 0.0001). In detail, G3/4 anemia occurred in 0% for CPx and in 1.5% for CVb, G3/4 thrombocytpenia occurred in neither of the arms, G3/4 neutropenia in 9% for CPx and in 69% for CVb, and febrile neutropenia in 1.5% for CPx and in 7.7% in CVb. However, the rates of severe G3/4 non-hematologic toxicity did not differ between treatment arms with 33% for CPx and 31% for CVb (P = 0.7988). Table 5 outlines toxic effects as experienced in both treatment arms.

efficacy The preliminary efficacy analysis showed one death (due to a gastrointestinal bleed) in the CPx and two deaths (due to cardiopulmonary failure and suspected pulmonary event) in the CVb arm. No death was treatment related. One relapse occurred in the CPx and three in the CVb arm; neither OS nor PFS differed at the time of this preliminary efficacy analysis significantly between arms.

discussion This randomized phase 2 study is the first to compare CPx to the current standard regimen in adjuvant NSCLC chemotherapy [2, 9, 14]. In terms of clinical feasibility as defined in this trial, CPx showed significant superiority to CVb in the adjuvant treatment of early-stage NSCLC, mainly due to a lower DLT (largely hematological) and a lower withdrawal of consent rate. This is in line with previous reports on the favorable toxicity profile of CPx in other treatment settings [11–14]. The decrease of hematologic toxicity, particularly febrile neutropenia, increases the safety of adjuvant chemotherapy for NSCLC [9]. In this respect, another important factor is the rate of pneumonectomies, which was 14% in this study, compared with 29% in the LACE meta-analysis [2]. According to an analysis of the JBR-10 study, patients with pneumonectomies were more likely to experience significant toxic effects, fail to

doi:10.1093/annonc/mds578 | 

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Annals of Oncology

Table 3. Dose delivery

Planned cumulative dose p.p. (mg/m2) Treatment interval/duration p.p. (weeks) Application schedule Px/Vb p.p. Proportion of patients receiving treatment p.p. (%) Dose delivery % planned Mean doses [mg/m2 (range)] Mean dose density [mg/m2/week (range)] Mean duration of therapy [weeks (range)] Median number of cycles [n (range)] Dose delays/interruptions [over all cycles] (%)

CPx

CVb

Px: 2000 C: 300 3/12 d1 74.6 (95% CI 62.5–84.5) Px: 90 C: 90 Px: 1810 (500–2000) C: 271 (75–300) Px: 151 (42–167) C: 23 (6–25) 11.2 (3–19.4) 3.64 (1–4) Px: d1 (15.6)

Vb: 400 C: 400 4/16 d1, 8, 15, 22 20.0 (95% CI 11.1–31.8) Vb: 64 C: 66 Vb: 256 (25–400) C: 263 (50–400) Vb: 16 (2–25) C: 16 (3–25) 9.9 (0–24) 2.74 (1–4) Vb: d1 (11.9) d8 (16.7) d15 (35.1) d22 (38.4) C: d1 (14.1) d8 (18.4)

C: d1 (15.1)

p.p., per protocol. Table 4. End of therapy

Table 5. Toxic effects

EOT

CPx

CVbs

Toxicity

CPx

CVb

Regular EOT (%) Earlier termination of therapy (%) Reasons for earlier termination (events)a

77.6 22.4 patients (n = 15)

36.9 63.1 patients (n = 41)

Mean number (AE/SAE) Hematologic toxicity G3/4 (%) Non-hematologic toxicity G3/4 (%) Hematologic toxicity (%)

6.8/0.3 10.5 33 G3/4

6.9/0.2 78.2 31 G3/4

Unacceptable toxicity according to protocolb Unacceptable toxicity perceived by patient Relapse of disease Withdrawal of consent Death (therapy related) Non-compliance to protocol Medical decision by investigator Major protocol violation Other reasons

4

19

6

7

0 0 1 (0) 0 4 0 0

2 4 2 (0) 2 5 1 4

Anemia Thrombocytopenia Neutropenia Febrile neutropenia Non-hematologic toxicity (%)

0 0 9 1.5 G3/4

1.5 0 69 7.7 G3/4

Fatigue Anorexia Nausea/vomiting Constipation Abdominal discomfort Infection Tinnitus/vertigo Sensomotoric disturbance Thrombembolic events Renal impairment Mucositis Hypersensitivity/rash

6.0 0 7.5 1.5 1.5 1.5 0 0 1.5 3 0 0

5.5 0 5 0 0 1.5 1.5 0 0 0 0 0

a

Multiple reasons possible. Delay >2 weeks due to toxicity or in case of G3/4 non-hematologic toxicity. EOT, end of therapy.

b

complete chemotherapy and discontinue therapy than patients with a lesser extent of surgery [10]. However, this does not explain the significant relevant rates of earlier treatment termination between CPx and CVb in our trial. Besides different toxicity rates also withdrawal of consent and unacceptable toxicity perceived by the patient were disadvantageous for CVb. Consistent with this, TTTF significantly differed between arms favoring CPx. Therefore, one might argue that a less toxic regimen leads to better therapy compliance and may be to a better quality of life

 | Kreuter et al.

(QOL). However, the latter was not assessed in our trial. In this context, one could discuss the chosen primary end point ‘feasibility’, which has not been evaluated before. A more QOL-based approach as analyzed by Jang et al. [19] might also have been appropriate. They derived quality-adjusted survival estimates of the JBR.10 trial utilizing a quality-adjusted time without symptoms or toxicity analysis and reported an improvement of quality-adjusted survival despite

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chemotherapy toxic effects. A prior analysis of the same study with regard to QOL during chemotherapy reported a decline of QOL only to be temporary with improvements in most patients [20]. Also to be included into the decision of initiating adjuvant chemotherapy and to be considered in the context of potentially less toxic regimens are age and comorbidities [21], the latter integrated into our feasibility analysis. Similar to our study, Schmid-Bindert et al. [22] recently presented a phase II study comparing feasibility of CPx to carboplatin–pemetrexed in adjuvant NSCLC treatment. Yet, reported feasibility rates were lower than those reported here. This might be explained by the different and very strict definition of feasibility in their study, which was compliance to four cycles with ≥95% of planned dose without ≥G3 toxic effects. However, similar to our results, hematologic toxicity was low with a high dose density and a low incidence of dose reductions. In another phase II study, Karapanagiotou et al. [23] reported on progression-free survival and toxicity in adjuvant chemotherapy with carboplatin–pemetrexed. In that small, nonrandomized study, toxic effects were mild to moderate with a mean time to disease progression of 26 months. However, the study lacked a comparator arm, and PFS is not an optimal outcome parameter in resected NSCLC patients. Chemotherapy dose intensity is related to survival in certain cancers [24, 25], though this has not been clearly demonstrated for NSCLC [26, 27]. However, a meta-analysis in advanced NSCLC showed that drug-induced neutropenia, a surrogate for dose intensity, predicted superior outcome [28]. Likewise, the LACE meta-analysis reported a survival benefit for higher cisplatin doses [2]. In a recently presented study, there was a trend towards inferior survival in advanced NSCLC with cisplatin 50 mg/m2 plus gemcitabine versus cisplatin 80 mg/m2 plus gemcitabine every 3 weeks (median OS 8.2 versus 9.5 months, respectively; log rank 0.09) [29]. However, data from advanced stages have to be transferred to early stages with caution. Although cisplatin dose and dose intensities differed markedly between the two arms, differences between total doses were only modest that might be attributed to the different therapy schedules. Still, it is remarkable that, with a lower intended cisplatin dose for CPx, a higher absolute dose was achieved. Yet, the impact of this has to be clarified further. Both the milder toxicity and better dose delivery may theoretically increase survival. However, our efficacy data are still pending, and the limitations of the size of a phase II trial without therapy-related deaths have to be considered. Moreover, as discussed below, efficacy data have to interpreted with regard to the patients’ characteristics, i.e. the inclusion of patients with stage IB and patients with squamous cell carcinoma under pemetrexed therapy [7, 11]. Still, adverse long-term outcome effects of adjuvant NSCLC treatment, potentially due to late toxic effects of chemotherapy, have been reported in the large IALT study [30] and in other cancer types [31–33]. However, in the IALT trial, neither the survival advantage has decreased at 5 years nor the incidence of secondary malignancies has increased with time [30]. Lowering of acute toxicity may reduce delayed toxic treatment effects, better dose delivery may improve efficacy and both may be beneficial for outcome. Only long-term follow-up can help to explore this question.

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One critical issue of our trial is the application of pemetrexed in squamous cell NSCLC, with regard to the results of a recent phase III study where differential efficacy of pemetrexed according to histology in advanced NSCLC was reported [11]. Yet, at initiation of our trial, this correlation was still unknown. Also, the predictive effect of histology for pemetrexed activity was reported only in advanced NSCLC, and it is not yet clear that this is true for resected early-stage NSCLC as well. Moreover, thymidylate synthase expression—a biomarker related to pemetrexed sensitivity [34]—has also been reported as a determinant of survival in stage I NSCLC [35]. Reports on the correlation of histology to outcome in adjuvant therapy are conflicting with no impact in IALT, an advantage for squamous NSCLC in the JBR-10 study, a positive impact of CVb chemotherapy but a poor outcome in the observation arm for adenocarcinoma in ANITA, and finally no chemotherapy effect on histology in the LACE metaanalysis [2, 5, 6, 36]. Therefore, in the adjuvant treatment setting, the predictive effect of histology and the correlation of efficacy and chemotherapy applied are still open questions with high need for further evaluation. Another limitation of our study is that it was designed to determine clinical feasibility and not to conclude on efficacy. In the BR.19 trial, gefitinib was associated with modest toxicity, but failed to demonstrate a survival advantage in the adjuvant setting of NSCLC [37]. Therefore, our data do not proof the effectiveness of CPx in adjuvant therapy of NSCLC, which can only come from a very large phase III trial. Data on the use of adjuvant CPx are expected from the ITACA (EudraCT #: 2008001764-36) and ECOG E1505 (NCT00324805) trials. Moreover, one might argue that the CVb schedule with weekly vinorelbine administration [5] might have influenced our results of delivery failures for CVb occurring mainly on days 15 and 22. Still, this schedule of CVb is the only one with proven value in the adjuvant setting, which was the reason to choose it in the present study [5, 9]. One further aspect to be considered is the high number of patients with stage IB, where a more differentiated analysis of tumor size may be applied [7]. In summary, our trial provides evidence, that CPx is feasible in the adjuvant chemotherapy of early NSCLC, with a significant reduction of toxicity and better dose delivery compared with the standard adjuvant therapy used so far. However, for efficacy data, the limitations of the size of a phase II trial, and of a large proportion of patients with stage IB or with squamous cell carcinoma, have to be taken into account. Longer follow-up to observe possible differences in outcome is ongoing.

acknowledgements We thank all participating patients and centers as well as the supporting companies Eli Lilly and Medac. This study has been presented at the Annual Conference of the American Society of Clinical Oncology, Chicago, IL, 2011.

funding This work was supported by unrestricted grants of Eli Lilly and Company, Germany and by Medac GmbH, Wedel, Germany.

doi:10.1093/annonc/mds578 | 

original articles disclosure JV and MT received research funding by Eli Lilly. The other authors have declared no conflicts of interest.

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