Pemetrexed and carboplatin, an active option in first-line treatment of elderly patients with advanced non-small cell lung cancer (NSCLC): A phase II trial

Lung Cancer 80 (2013) 185–190

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Pemetrexed and carboplatin, an active option in first-line treatment of elderly patients with advanced non-small cell lung cancer (NSCLC): A phase II trial夽 Radj Gervais a , Gilles Robinet b , Christelle Clément-Duchêne c , Fabrice Denis d , Claude El Kouri e , Philippe Martin f , Nadia Chouaki g , Nawel Bourayou g , Jean-Franc¸ois Morère h,∗ a

Oncology Department, Centre Franc¸ois Baclesse, Caen, France Oncology-Pneumology Department, Hôpital Morvan, Brest, France c Pneumology Department, Hôpital Brabois, Nancy, France d Oncology-Radiotherapy Department, Clinique Victor Hugo, Le Mans, France e Oncology-Radiotherapy Department, Centre Catherine De Sienne, Nantes, France f Oncology Department, Centre Bourgogne, Lille, France g Medical Oncology Department, Eli Lilly, Neuilly-Sur-Seine, France h Medical Oncology Department, Hôpital Avicenne, Université Paris XIII, Bobigny, France b

a r t i c l e

i n f o

Article history: Received 20 September 2012 Received in revised form 3 January 2013 Accepted 4 January 2013 Keywords: Carboplatin Elderly First-line Non-small cell lung cancer Pemetrexed Stage IIIB-IV

a b s t r a c t The synergistic activity of pemetrexed with platinum agents in non-small cell lung cancer (NSCLC) and the renal safety of carboplatin suggest a balanced benefit/risk profile for this combination in elderly patients. This multicenter, single-arm, phase II study included 62 patients (≥70 years) with chemonaïve advanced NSCLC, Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1, and assigned to receive 6 cycles of 3-weekly pemetrexed 500 mg/m2 and carboplatin AUC 5. The primary endpoint was objective tumor response rate (ORR). Sixty-two patients received at least one dose of chemotherapy. Median age was 76.4 years [70.2–86] and all patients had PS 0 (16.1%) or PS 1 (83.9%). Stage IIIb disease in 21% patients and stage IV in 79% patients. Non-squamous cell carcinoma in 66.1% patients (adenocarcinoma 51.6%, large cell carcinoma 8.1%, other 6.5%) and squamous cell carcinoma in 33.9% patients. ORR was 28.6% (95% confidence interval [CI], 16.58–43.26), all were partial responses. Stable disease rate was 42.9%. Grade 3/4 toxicities related to study drugs were: asthenia 16.1%, anorexia 4.8%, diarrhea 3.2%, neutropenia 51.6%, leucopenia 30.7%, thrombocytopenia 29%, anemia 19.4%. One related fatal septic shock occurred. In advanced NSCLC, pemetrexed use is restricted to non-squamous histology. The combination pemetrexedcarboplatin could be a valuable treatment option in elderly patients. Neutropenia was the most common toxicity. The ORR is within the range of data reported for pemetrexed-carboplatin in the general NSCLC population (24–31%). © 2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction The incidence of non-small cell lung cancer (NSCLC) is increasing among the elderly and 30–40% of NSCLC patients are over 70 years old at diagnosis [1,2]. Age and related comorbidities impair physiological processes and reduce the therapeutic index of drugs. Consequently, the elderly are more sensitive to cytotoxic agents and frequently excluded from clinical trials in advanced disease [3].

夽 Previously presented at ECCO-ESMO, Berlin, Germany, September 20–24, 2009 and SIOG, Berlin, Germany, October 15–17, 2009. ∗ Corresponding author at: Medical Oncology Department, Hôpital Avicenne, 125 Route de Stalingrad, 93009 Bobigny Cedex, France. Tel.: +33 01 48 95 50 32; fax: +33 01 48 95 59 52. E-mail address: [email protected] (J.-F. Morère). 0169-5002/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.lungcan.2013.01.008

According to international guidelines, there is no evidence for the selection of specific first-line chemotherapy drugs or combinations based on age alone [4]. Elderly without comorbidities and with a performance status (PS) of 0–1 could be treated like younger patients [5]. The standard and recommended approach in unselected elderly patients was single-agent chemotherapy with a third generation agent (vinorelbine, gemcitabine, or taxanes) [4,6,7]. Recent guidelines, now recommend to use in selected elderly patients with good PS the treatment options recommended for younger individuals [4, 6, 8 Ganti]. Platinum-based doublets are considered the standard of care in the first-line treatment of advanced NSCLC in fit patients. Although cisplatin-based doublets offer a slight survival benefit compared to carboplatin-based doublets, carboplatin has, in addition to its ease of administration, a more favorable toxicity profile than cisplatin in terms of digestive and renal toxicity. Despite, the greater hematologic toxicity of carboplatin, carboplatin-based doublets are more feasible in elderly

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patients unsuitable for cisplatin, mainly because this toxicity can be prevented by concomitant G-CSF [9]. At the initiation of the present study, no elderly-specific platinum-based prospective phase III trials were available. Published data were mainly retrospective age-specific subgroup analyses, with selection bias since inclusion was limited to elderly considered by their treating physician to be able to tolerate the toxicity of chemotherapy [7]. Pemetrexed (AlimtaTM ), a multi-targeted anti-folate [12], is indicated with cisplatin in the first-line treatment and as single agent maintenance and second-line treatment of patients with locally advanced or metastatic non-squamous NSCLC. Two phase II trials investigated pemetrexed combined with carboplatin in chemonaive NSCLC patients, before the approval of the histology-based indication. In a single-arm study, the partial response rate was 24%, median time to progression was 5.4 months, 1-year survival was 56.0%, and median survival 13.5 months [9]. In a randomized study, objective tumor response rates were 26.8% for pemetrexed/oxaliplatin patients (95% confidence interval [CI], 14.2–2.9) and 31.6% for pemetrexed/carboplatin patients (95% CI, 17.5–48.7) [10]. Median overall survival (OS) times were 10.5 months for both treatment groups. The 1-year survival rate was 49.9% for pemetrexed/oxaliplatin and 43.9% for pemetrexed/carboplatin. These efficacy results were encouraging with an acceptable toxicity profile. Based on the above data, suggesting a balanced benefit/risk profile of pemetrexed combined with carboplatin in the general population, we conducted this phase II study assessing the efficacy and safety of this combination as first-line treatment for chemonaive elderly patients with advanced NSCLC and a good PS (0 or 1). 2. Materials and methods 2.1. Study design This multicenter, open-label, single-arm, phase II study of pemetrexed/carboplatin was conducted in elderly with locally advanced or metastatic NSCLC (Fig. 1). The trial was approved by the local Ethics Committee, conducted in accordance with good clinical practices and the Declaration of Helsinki and registered in clinical trials.gov (NCT00350792). A Data Safety Monitoring Board (DSMB) reviewed the safety data of the first 10 and 25 patients receiving at least one dose of study drug. 2.2. Patients Eligible patients were men and women ≥70 years of age with a histological or cytological diagnosis of NSCLC Stage IIIb (not amenable to radiotherapy) or IV and measurable disease as defined by response evaluation criteria in solid tumors (RECIST) 1.0 [13]. They had no prior chemotherapy for NSCLC, an Eastern Cooperative Oncology Group (ECOG) PS of 0–1, adequate renal, hepatic and

Study Period I Baseline

Eligible paents

bone marrow functions no documented brain metastases unless the patient had completed successful local therapy. Prior radiation therapy was allowed to <25% of the bone marrow. Weight loss was not an exclusion criterion. Patients provided signed, informed consent before any study procedure. 2.3. Treatment plan Patients were treated with pemetrexed 500 mg/m2 , 10 min IV on day 1 of a 21-day cycle and adequate premedication: daily folic acid 350/1000 ␮g/day from 7 days prior to pemetrexed first dose until 3 weeks after the last dose; intramuscular vitamin B12 , at 1000 ␮g one week prior to pemetrexed first dose and repeated approximately every 9 weeks until 3 weeks after the last pemetrexed dose; oral dexamethasone 4 mg, twice daily on days −1, 0, and + 1 of pemetrexed infusion; IV carboplatin area under the curve (AUC) 5 (Calvert formula) was administered 30 min after pemetrexed on day 1 of a 21-day cycle. The planned treatment duration was six cycles of pemetrexed/carboplatin, the routine use of colonystimulating factors (CSF) was not allowed [14]; granulocyte-(G) CSF was allowed for neutropenic fever and documented neutropenic infection and left to the investigator’s discretion for uncomplicated Grade 4 neutropenia. 2.4. Study endpoints The primary efficacy endpoint was tumor response rate measured every 3 cycles using spiral or conventional CT scan, assessed by the investigators, according to RECIST V 1.0 [13]. Clinical progressions without radiological assessments were reviewed by an expert committee to confirm or decline the progression status based on clinical signs. Secondary efficacy endpoints were oneyear and overall survival, progression-free survival (PFS), time to treatment failure (TTF including any cause of early study treatment discontinuation) and safety. 2.5. Statistical considerations The primary endpoint was the overall response rate (ORR). A sample size of 44 qualified patients was required to estimate an exact 95% CI of the true response with a maximum width of 31%. Assuming that about 20% of patients would not qualify, at least 55 patients were to be recruited. The primary analysis was planned in qualified patients defined as receiving at least one dose of pemetrexed/carboplatin and at least one tumor assessment after baseline. A secondary analysis of the primary endpoint was conducted in the ITT population. ORR was presented with its exact 95% CI based on the F distribution method. Kaplan–Meier techniques were used to assess secondary efficacy time-to-event endpoints. Safety analyses performed in the ITT population summarized adverse events by maximum CTCAE Grade (version 3.0, NCI 2003) and seriousness, during the treatment period or within 30-days

Study Period II

Study Period III

Chemotherapy

Follow-up

Pemetrexed 500 mg/m², 10 min IV Day 1 Carboplan AUC 5 IV Day 1 1 cycle: 21 days Maximum cycles: 6 Vitamin and dexamethasone supplementaon

Fig. 1. Study design.

1 month aer the last infusion and then every 3 months

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following the last dose. Descriptive subgroup analyses were planned in patients ≥80 years. Statistical analyses were performed using SAS Software (version 9.1.3; SAS Institute, Cary, NC). 3. Results 3.1. Patient and disease characteristics From August 2006 to November 2008, 66 elderly patients were enrolled in 7 Thoracic Oncology sites in France and 62 patients received at least one dose of pemetrexed/carboplatin. Four patients were untreated (2 entry criteria not met, 1 rapid disease progression, and 1 death). During the enrollment period, a low number of qualified patients for the primary objective analysis was observed, leading to the extension of the enrollment period and the sample size, thus leading to the higher effective number of enrolled patients compared to the initial sample size planned. Patient characteristics are presented in Table 1. The median age was 76.4 years [range 70.2–86], 11 patients (17.7%) were octogenarians, and 52 patients (83.9%) had a baseline ECOG PS of 1. All patients had a concomitant disease at baseline, mainly vascular (69.4% of patients), pulmonary (54.8%), metabolic (51.6%) and musculoskeletal (32.3%) diseases. 3.2. Treatment exposure The median number of administered cycles was 5 [range 1–6]. Overall, 29 (46.8%) patients completed the planned 6 cycles and 48 (77.4%) patients received at least 3 cycles of chemotherapy. The median relative dose-intensity was 92.7% [47.2–101.1] and 93.6% [47.2–108.0] for pemetrexed and carboplatin, respectively. Dose reductions of pemetrexed or carboplatin were required in 27.4% of patients mainly for thrombocytopenia and neutropenia. Cycles were delayed in 51.6% of patients, due to hematological toxicity (22.6% of patients), other adverse events (19.4%), and scheduling conflict (17.7%). G-CSF was administered to 14.5% of patients during study treatment. In the ITT population, 33 (53.2%) patients discontinued the study, one-third (11 patients) for adverse events and one-third for lack of efficacy. Four patients died during the study (1 death related to the disease, 1 related to study drug, and 2 reported as not related

Table 1 Patient and disease characteristics at baseline – all treated patients.

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Table 2 Overall tumor response assessed by investigators. Tumor response rate, n (%)

Patients qualified for tumor response analysis n = 49

All treated patients n = 62

Partial response Partial response (unconfirmed) Stable disease Progressive disease Unknown

14 (28.6) 10 (20.4) 21 (42.9) 4 (8.2) –

14 (22.6) 10 (16.1) 21 (33.9) 4 (6.5) 13 (21.0)

13 patients were considered as non-qualified and excluded due to early discontinuation before tumor assessment.

to study drug). Seven patients discontinued for other reasons (1 protocol violation, 4 patient’s decision, 2 physician’s decision). 3.3. Efficacy In the ITT population (n = 62), the ORR rate was 22.6% (95% CI, 12.93–34.97) and the disease control rate was 56.5%. In the 49 qualified patients, as defined in the protocol, 13 patients were considered as non-qualified and excluded due to early discontinuation before tumor assessment; the ORR was 28.6% (95% CI, 16.58–43.26), all were partial responses. The stable disease rate was 42.9%. In addition, the disease control rate (DCR), including partial response and stable disease, was 71.5% in qualified patients. See Table 2 for both ITT and qualified populations. Median PFS assessed by investigators was 5.5 months (95% CI, 4.7–6.7) in the ITT population (Fig. 2). In the qualified population median PFS was 5.3 months (95% CI, 4.3–6.7) and median TTF was 4 months (95% CI, 2.5–∞). Median survival in the ITT population was 10.4 months (95% CI, 9.1–12.9) and the one-year survival rate was 41.9% (95% CI, 29.7–54.2) (Fig. 3). 3.4. Toxicity The two planned safety reviews performed by the DSMB showed no unacceptable toxicity and thus led to the continuation of the study without protocol modifications. Safety results are summarized in Table 3. The most frequent Grade 3/4 drug-related toxicities were hematologic, occurring mainly during the first 3 cycles. Drugrelated Grade 4 sepsis, bone marrow failure, febrile bone marrow aplasia, febrile neutropenia, and pancytopenia occurred in 1 patient each.

All treated patients n = 62 Age (years) Median [min/max] Gender, n (%) Female Male

76.4 [70.2/86.0] 11 (17.7) 51 (82.3)

Smoking habits, n (%) Ex and/or current smoker Non smoker

50 (80.6) 12 (19.4)

ECOG performance status, n (%) 0 1

10 (16.1) 52 (83.9)

Pathological diagnosis, n (%) Large cell lung carcinoma Adenocarcinoma Squamous cell carcinoma Other

5 (8.1) 32 (51.6) 21 (33.9) 4 (6.5)

Stage of disease, n (%) IIIB IV

13 (21.0) 49 (79.0)

ECOG = Eastern Cooperative Oncology Group.

Fig. 2. Progression-free survival – Kaplan–Meier curve – all treated patients (n = 62ITT).

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failure, diarrhea and sepsis/septic shock reported in the same patient, dyspnea, and leukopenia.

4. Discussion

Fig. 3. Overall survival – Kaplan–Meier curve – all treated patients (n = 62-ITT).

Drug-related serious adverse events (SAE) were mainly hematologic: anemia and thrombocytopenia in 4 patients each (6.5%) and neutropenia in 3 patients (4.8%). Serious diarrhea was observed in 3 patients (4.8%) and renal failure in 1 patient who did not receive the required 25% of dose reduction according to the protocol. One patient died due to a drug-related septic shock, he was ≥80 years old and the safety review revealed no dose adjustment of study drugs regarding the previous hematologic toxicities, although this was required by the protocol. 3.5. Planned subgroup analysis of octogenarian patients Eleven patients, all men, median age 81.7 years [80–86], were included in this study and 10 patients had an ECOG PS of 1. Eight patients had stage IV NSCLC, six patients had at least one significant comorbidity at baseline (hypertension, weight decrease, anorexia, and dyspnea). Overall, 7/11 patients did not progress, four patients had a partial response, three patients had a stable disease, 1 patient progressed and the response was classified as unknown for 3 patients (one early death and two unknown). Due to the small sample size, other efficacy data (PFS, TTF and OS) were not analyzed. Median relative dose-intensity was 98.7% [57.8–100.8] for pemetrexed and 98.4% [53.6–100.2] for carboplatin. Two patients had at least one dose reduction of pemetrexed and carboplatin and at least one cycle delay was necessary in 5 patients. Three patients experienced a total of 7 drug-related SAEs including: one each of fatigue, mucosal inflammation, bone marrow

Table 3 Most frequent Grade 3/4 (in at least 2 patients) possibly related AEs to study treatment/procedures – all treated patients. Non-hematological, n (%)

Asthenia Anorexia Dyspnea Diarrhea Febrile neutropenia/febrile bone marrow aplasia Hematological, n (%) Neutropenia Anemia Leukopenia Thrombocytopenia

All treated patients (n = 62) Grade 3

Grade 4

10 (16.1) 3 (4.8) 2 (3.2) 2 (3.2) 0 (0.0)

0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (3.2)

19 (30.6) 12 (19.4) 14 (22.6) 10 (16.1)

13 (21.0) 0 (0) 5 (8.1) 8 (12.9)

Hematological toxicities are reported from laboratory values; AE = adverse event.

The SEER database review on treatment of the elderly with advanced NSCLC [15] reported that only 25.8% of the 21,285 included patients (≥66 years), received first-line chemotherapy, indicating that most elderly patients did not receive systemic treatment. To date, platinum-based doublets are the standard of care in advanced NSCLC, whatever the patient age [8], the debate regarding the benefit from platinum-based doublets over single agents in the elderly is over. The primary objective of this first phase II study investigating the combination pemetrexed/carboplatin in elderly NSCLC patients was reached. The ORR of 28.6% is in the same range [24–31%] as data reported for the overall NSCLC population treated with pemetrexed and carboplatin [9–11]. Additional efficacy results are also consistent with those reported in the general population regarding DCR (71.5%), median PFS (5.5 months), and median OS (10.4 months). Patient selection in this study was not based on histology type as the restriction of pemetrexed label to non-squamous histology occurred after enrollment closure. In addition, given the limited sample size, an unplanned subgroup analysis according to histology was not considered. To our knowledge, until 2010, there was no published prospective phase III data investigating platinum-based combinations in the elderly and most available data were obtained from limited retrospective age-specific subgroup analyses [16,17]. Recently, a large, French multicenter, randomized phase III study (IFCT 05–01) conducted by Quoix et al. [18] in 451 patients aged 70–89, with PS 0, 1, and 2 and advanced NSCLC, compared a 3-weekly single-agent therapy (gemcitabine 1150 mg/m2 or vinorelbine 25 mg/m2 , D1, D8: arm A) with a doublet (monthly carboplatin AUC 6 and weekly paclitaxel 90 mg/m2 ), for 5 and 4 cycles, respectively. Secondline treatment at disease progression was erlotinib 150 mg/day. Results showed a significantly longer survival with the platinumbased doublet compared to monotherapy (10.3 vs. 6.2 months; HR 0.64, 95% CI 0.52–0.78; p < 0.0001), irrespective of PS (0–1 or 2), age (≤80 or >80 years), activity of daily living score (ADL = 6 or < 6) or mini mental state examination score (MMSE ≥ 24 or <24). There was also a significant improvement in PFS (6.0 vs. 2.8 months; p < 0.0001). DCR (PR + SD) was also significantly higher with the doublet (65.3% vs. 56.2%; p = 0.047). Pemetrexed therapy combined with cisplatin in the first-line and the maintenance treatment of elderly patients PS 0–1 with non-squamous NSCLC was retrospectively assessed from data of two large phase III trials for patients ≥65 years (n = 410) and ≥70 years (n = 160) [19,20]. Results showed that OS was significantly longer in patients ≥65 years treated with first-line pemetrexed plus cisplatin (n = 410) compared to those treated with gemcitabine plus cisplatin, (HR 0.75; 95% CI, 0.59–0.94). However the authors reported that the number of patients 70 years was small (9%), and it is quite challenging to draw meaningful clinical conclusions about survival advantage for such a limited subgroup of patients. [21]. Another randomized phase III study conducted in 436 patients with stage IIB/IV NSCLC showed that pemetrexed/carboplatin provides similar HRQoL health related quality of life (the primary endpoint) and survival when compared with gemcitabine/carboplatin with less hematologic toxicity and less need for supportive care [22]. In terms of safety, the combination pemetrexed/carboplatin in the general population in the study by Zinner et al. [9] presented a favorable safety profile: Grade 3/4 neutropenia (26% of patients), Grade 3/4 thrombocytopenia (2%). In the study by Scagliotti et al. [10], main Grade 3/4 hematologic toxicities in the

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pemetrexed/carboplatin arm were neutropenia (26% of patients), febrile neutropenia (5.1%), thrombocytopenia (18%), and anemia (8%). In both studies, Grade 3 non-hematologic toxicities did not exceed 8%. In our elderly population, the combination pemetrexed/carboplatin generated a relatively high rate of Grade 3/4 hematologic toxicities, especially neutropenia (51.6%), but a low rate of febrile neutropenia (3.2%) comparable to the general population. We observed a trend toward more hematologic toxicities during the first 3 cycles. However, this was not limiting for treatment delivery as 77.4% of patients received at least 3 cycles and only 14.5% of patients received concomitant G-CSF. The higher carboplatin myelosuppressive effect compared to cisplatin may partly explain these hematologic toxicities. In addition, the safety review performed at the time of database lock revealed that a number of patients received a higher dose of study drugs than planned (22 patients received more than 5% of the allowed dose variation), probably due to non-dose adjustment as required by the protocol without excluding the potential risk of error in carboplatin dose calculation (Calvert formula). Indeed, among patients with Grade 3/4 neutropenia (32) who required a dose reduction of at least 25%, 7 (21.9%) received the full dose of study drugs and toxic death (septic shock) occurred in an octogenarian patient with a lack of dose adjustment regarding previous hematologic events. In the Quoix et al. study [18], the combination paclitaxel/carboplatin also generated a high rate of Grade 3/4 neutropenia (48.4%). Moreover, a significant number of Grade 3/4 febrile neutropenia (9.4% vs. 2.7%) were reported compared to single agent, toxic deaths (4.4% vs. 1.3%) were not significant. During the retrospective study pooling results of 2 phase III studies with pemetrexed, rates of most hematologic toxicities appeared to increase with age. In patients ≥70 years, the rate of neutropenia was 22.6%, and thrombocytopenia was 7.2%. However, in this age group, the incidence of anemia did not increase with age (2.4%). Fatigue rates were consistent throughout all age groups and 10.7% in patients ≥70 years. The febrile neutropenia rate was 2.8% in patients ≥65 years. The toxic death rate was 2% in patients ≥70 years [21]. Des Guetz et al. [23] reported updated results of a large metaanalysis of 12 single-agent versus doublet studies with or without platinum in 2530 elderly patients and concluded that platinum efficacy results favored doublet therapy. Platinum doublets including the Quoix et al. [18] study, largely contributed to these results and yet hematologic toxicities were less pronounced for single agents. Consistently, in the SEER database review, there was a clear survival benefit for elderly patients receiving chemotherapy, with a greater benefit for patients receiving platinum-based doublets (adjusted 1-year survival 30.1% over single agents 19.4%). All the above data are consistent with our results, indicating that appropriate patients with good PS, regardless of age, can benefit from carboplatin-based doublets. In addition, the combination pemetrexed-carboplatin offers a convenient 21-day administration schedule which is of importance for patient comfort. In order to ensure a benefit/risk balance, monitoring of hematologic toxicities as well as compliance with dose adjustment when required are highly recommended and discussion of G-CSF use may be justified according to ASCO guidelines 2006. Likewise, the potential contribution of standardized geriatric evaluation is critical in customizing the treatment of elderly patients based on their fragility status [7]. In France, a promising large, randomized, multicenter, phase III study – ESOGIA (Elderly Selection On Geriatric Assessment) [24] conducted by the academic GFPC group (Groupe Franc¸ais de Pneumo-Cancerologie) is currently recruiting patients to address this question. It compares a control group of elderly NSCLC patients for whom treatment selection (chemotherapy doublet or docetaxel monotherapy) is based on patient PS (0–1 or 2) and age (≤75 or >75) to a group of patients with a treatment selection based on

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a standardized geriatric evaluation. The chemotherapy doublet of choice is pemetrexed/carboplatin in non-squamous patients and gemcitabine/carboplatin in squamous patients, with a total of 490 expected patients. 5. Conclusions In conclusion, this phase II feasibility study, showed that the combination pemetrexed-carboplatin could be a valuable treatment option in elderly patients with advanced NSCLC and good PS. To date, the pemetrexed label in advanced NSCLC is restricted to non-squamous histology. The validation in clinical practice of a lung cancer-specific geriatric scale is eagerly awaited to better customize treatment in elderly patients. Conflict of interest statement Pr Jean-Franc¸ois Morère is the coordinator of this trial for Eli Lilly, consultant in R & D and speaker in symposia for Eli Lilly. Dr. Nawel Bourayou and Dr. Nadia Chouaki are Lilly employees. Dr. Radj Gervais, Dr. Gilles Robinet, Dr. Christelle ClémentDuchêne, Dr. Claude El Kouri, Dr. Philippe Martin and Dr. Fabrice Denis have no conflict of interest. Funding The trial was funded by Eli Lilly – France. Acknowledgements The authors thank Dr. Hervé Le Caer and Dr. Pierre-Jean Souquet, as members of the safety monitoring board for their involvement. The authors thank Dr. Samia Rahal (ELTIUM) who provided medical writing services on behalf of Lilly France. References [1] GLOBOCAN 2008. Cancer incidence and mortality worldwide: IARC CancerBase No. 10. Lyon, France: International Agency for Research on Cancer; 2008. Available at: http://globocan.iarc.fr/age-specific table n PDF.asp [accessed 15.09.11]. [2] Altekruse SF, Kosary CL, Krapcho M, et al. SEER cancer statistics review, 1975–2007. Bethesda, MD: National Cancer Institute; 2010. http://seer. cancer.gov/csr/1975 2007/, based on November 2009 SEER data submission, posted to the SEER web site. [3] Talarico L, Chen G, Pazdur R. Enrollment of elderly patients in clinical trials for cancer drug registration: a 7-year experience by the US Food and Drug Administration. J Clin Oncol 2004;22:4626–31, 12. [4] Azzoli CG, Baker Jr S, Temin S, Pao W, Aliff T, Brahmer J, et al. American Society of Clinical Oncology clinical practice guideline update on chemotherapy for stage IV non-small-cell lung cancer. J Clin Oncol 2009;27:6251–66. [5] Trigo Pérez JM, Garrido López P, Felip Font E, Isla Casado D, SEOM (Spanish Society for Medical Oncology). SEOM clinical guidelines for the treatment of non-small-cell lung cancer: an updated edition. Clin Transl Oncol 2010;12:735–41. [6] D’Addario G, Fruh M, Reck M, Baumann P, Klepetko W, Felip E. Metastatic non-small-cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010;21(Suppl. (5)):v116–9. [7] Pallis AG, Gridelli C, van Meerbeeck JP, Greillier L, Wedding U, Lacombe D, et al. EORTC elderly task force and lung cancer group and international society for geriatric oncology (SIOG) experts’ opinion for the treatment of non-small-cell lung cancer in an elderly population. Ann Oncol 2010;21:692–706. [8] Ganti A, DeShazo M, Weir III A, Hurria A. Treatment of non-small cell lung cancer in the older patient. JNCCN 2012;10:230–9. [9] Zinner RG, Fossella FV, Gladish GW, Glisson BS, Blumenschein Jr GR, Papadimitrakopoulou VA, et al. Phase II study of pemetrexed in combination with carboplatin in the first-line treatment of advanced non-small cell lung cancer. Cancer 2005;104:2449–56. [10] Scagliotti GV, Kortsik C, Dark GG, Price A, Manegold C, Rosell R, et al. Pemetrexed combined with oxaliplatin or carboplatin as first-line treatment in advanced non-small cell lung cancer: a multicenter, randomized, phase II trial. Clin Cancer Res 2005;11:690–6. [11] Ardizzoni A, Boni L, Tiseo M, Fossella FV, Schiller JH, Paesmans M, et al. Cisplatinversus carboplatin-based chemotherapy in first-line treatment of advanced

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