Activity of Pemetrexed on brain metastases from Non ... - Lung Cancer

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Corresponding author at: Division of Medical Oncology A, IRCCS-CRO, Via ..... [15] Dziadziusko R, Ardizzoni A, Postmus PE, Smit EF, Price A, Debruyne C, et al.
Lung Cancer 68 (2010) 264–268

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Activity of Pemetrexed on brain metastases from Non-Small Cell Lung Cancer Alessandra Bearz a,∗ , Isabella Garassino b , Marcello Tiseo c , Orazio Caffo d , Hector Soto-Parra e , Massimo Boccalon f , Renato Talamini g , Armando Santoro b , Marco Bartolotti c , Viviana Murgia d , Massimiliano Berretta a , Umberto Tirelli a a

Medical Oncology A, IRCCS-CRO, Aviano (PN), Italy Department of Medical Oncology and Haematology, IRCCS Humanitas, Rozzano (MI), Italy Oncology, General Hospital, Parma, Italy d Oncology, General Hospital, Trento, Italy e Oncology, Garibaldi Hospital, Catania, Italy f Oncology, General Hospital, Pordenone, Italy g Epidemiology Unit, IRCCS-CRO, Aviano (PN), Italy b c

a r t i c l e

i n f o

Article history: Received 29 April 2009 Received in revised form 15 June 2009 Accepted 20 June 2009 Keywords: Non-Small Cell Lung Cancer Metastases Brain localization Pemetrexed Chemotherapy Second-line treatment

a b s t r a c t Brain metastases from Non-Small Cell Lung Cancer are usually associated with poor prognosis and up to now chemotherapy has shown a modest activity upon cerebral localizations. We investigated the role of Pemetrexed, a new, well tolerated multi-target antifolate, on brain metastases. Patients and methods: We collected 39 patients with evidence of cerebral nervous system (CNS) localizations from Non-Small Cell Lung Cancer (NSCLC) before starting treatment with Pemetrexed as second-line or further-line therapy. Results: We confirmed the good tolerability of Pemetrexed even in that setting of patients and we reported a progressive disease (PD) in 12 patients (30.8%), a stable disease (SD) and partial response (PR) in 12 (30.8%) and 15 (38.4%) patients respectively, with an overall clinical benefit obtained in 69% of patients. The cerebral response to Pemetrexed was interesting with a cerebral radiological benefit obtained in 32 patients (82%), while 7 patients only showed brain progressive disease. Overall median survival was 10 months. All irradiation-naïve patients and those with clear radiological evidence of cerebral progression after brain radiotherapy and before Pemetrexed, overall 22 patients, were included in one group, in order to avoid overlapping effects between brain radiotherapy and Pemetrexed over CNS localizations. Within that setting, we demonstrated an overall clinical benefit (SD + PR) and cerebral benefit in 63% and 68%, of patients respectively. Distribution of patients by overall response to Pemetrexed and CNS response was highly suggestive of activity of Pemetrexed on brain metastases. Conclusion: We demonstrated the good tolerability of Pemetrexed even in patients with advanced NSCLC and brain metastases, and we found a very good overall response rate with evidence of activity on brain localizations. © 2009 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Lung cancer is the leading cause of yearly cancer-related deaths worldwide, with Non-Small Cell Lung Cancer (NSCLC) accounting for about 80% of all cases. Upon presentation 70% of the patients have advanced disease, and platinum-based doublet chemotherapy is the standard treatment [1].

∗ Corresponding author at: Division of Medical Oncology A, IRCCS-CRO, Via Franco Gallini 2, 33081 Aviano (PN), Italy. Tel.: +39 0434 659x294/284; fax: +39 0434 659531. E-mail addresses: [email protected], [email protected] (A. Bearz). 0169-5002/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2009.06.018

To date several drugs have proved to be active in the secondline setting following disease progression after platinum-based chemotherapy, namely: Docetaxel [2], Pemetrexed [3], and Erlotinib [4]. Recent studies have demonstrated the activity of Pemetrexed in patients with non-squamous cell carcinoma is significantly superior over Gemcitabine [5,6]. The reported incidence of brain metastases in patients with NSCLC ranges from 20% to 40% depending on whether autopsy, surgical or radiological data are reviewed [7–9]. Multiple cerebral lesions are associated with poor prognosis, and median overall survival from the time of diagnosis is 4 months [10,11]. The optimal treatment for patients with brain metastases is controversial, and the use of chemotherapy has been limited because of

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a presumed lack of effectiveness due to the blood–brain barrier. However, a number of phase II studies reported response rates to cisplatinum-based combinations ranging from 35% to 50% [12–14], while temozolamide remained ineffective [15]. In particular, we were interested in understanding the role of Pemetrexed, a new multi-target antifolate agent, on brain metastases from NSCLC. To our knowledge, there are no data in the literature showing any activity of Pemetrexed on brain metastases from NSCLC, except one case report [16]. To date, it is not definitely known whether Pemetrexed crosses the blood–brain barrier [17]. There is only little information in the literature concerning its use in non-human primates, in which the drug exhibited a very poor penetration into the cerebrospinal fluid [18–20]. One of those studies also suggests that the blood–brain barrier penetration of Pemetrexed may be higher than that of Methotrexate, an antimetabolite whose mechanism of action is similar to Pemetrexed [18]. Overall, there is no enough evidence to reach a conclusion on the blood–brain barrier permeability of Pemetrexed and its activity on brain metastases.

Table 1 Characteristics of 39 patients with NSCLC and CNS metastases treated with Pemetrexed.

2. Patients and methods Data from patients with advanced stage IV Non-Small Cell Lung Cancer (NSCLC) and radiological evidence of central nervous system (CNS) metastases treated with second- or further-line Pemetrexed were used in a retrospective analysis whose aim was to evaluate the drug activity on CNS metastases. The study group included 39 patients affected by advanced NSCLC with brain metastases who had been treated with Pemetrexed following disease progression after first-line or second-line chemotherapy. The patients came from various Italian Institutions. They had been given Pemetrexed 500 mg/m2 (Alimta® , Eli Lilly and Company, Indianapolis, IN) every 21 days, administered i.v. in saline solution in 10 min. All patients were adult and Caucasian. Admission criteria were adequate bone marrow reserve, good hepatic and renal function, no active infection, and ECOG Performance Status (PS) between 0 and 2. Furthermore, life expectancy had to be at least 2 months. Pregnant or breast-feeding females had not been allowed to receive Pemetrexed; treatment had been discontinued in any case of evidence of disease progression, unacceptable toxicity or patient’s decision to interrupt. All patients had been pre-treated with folic acid, vitamin B12 supplement, as well as corticosteroids. NCI CTC 2.0 was used to rate toxicity. The evaluation of the best tumour response rate was performed at the end of the treatment period and the Response Evaluation Criteria in Solid Tumours (RECIST) were recommended [21]. Tumour response rate was calculated as the proportion of patients qualified as having a confirmed best response of stable disease or complete response or partial response. Survival data was collected through an active followup based on the verification of the vital status of the patients, and Kaplan–Meier survival analysis was measured from the day Pemetrexed had been started to death or last follow-up visit [22]. Distribution of responses was analyzed by the Chi-square test. 3. Results From May 2005 to July 2008 we collected 268 patients with advanced NSCLC and treated with second-line or further-line Pemetrexed from several Italian Institutions: out of this pool of patients we found 39 patients with CNS metastases (of which 6 from IRCCSCRO, Aviano; 16 from IRCCS Humanitas, Rozzano-Milano; 7, 5, 3 and 2 patients from Parma, Trento, Catania and Pordenone’s General Hospitals, respectively). CNS metastases had been diagnosed radiologically on the whole study group before beginning treatment

N (%) Histology Adenocarcinoma Squamous cell carcinoma Large cell Undifferentiated

24 (61.6) 4 (10.2) 1 (2.6) 10 (25.6)

Median age (years) (range)

63 (34–77)

Performance Status (ECOG) 0 1 2

11 (28.2) 27 (69.2) 1 (2.6)

Sex Female Male

9 (23.0) 30 (77.0)

Site of metastases Visceral and cerebral Bone and cerebral

32 (82.0) 7 (18.0)

Number of previous chemotherapy lines 1 2

34 (87.2) 5 (12.8)

Response to first-line treatment SD PR PD

9 (23.0) 26 (66.7) 4 (10.3)

Radiotherapy before Pemetrexed Yes No

28 (71.8) 11 (28.2)

NSCLC: Non-Small Cell Lung Cancer; CNS: central nervous system; PR: partial response; SD: stable disease; PD: progressive disease.

with Pemetrexed. The patient characteristics are summarized in Table 1. The group included 9 (23.0%) females and 30 (77.0%) males; most of the patients had adenocarcinoma except for 4 (10.2%), who were affected by squamous cell carcinoma, 10 (25.6%) and 1 (2.6%) with undifferentiated and large cell carcinoma, respectively; ECOG Performance Status was between 0 and 1, namely 0 in 11 patients (28.2%) and 1 in 27 (69.2%), and only in one case it was 2; 7 patients had both bone and brain metastases, while 32 out of 39 (82.0%), had both visceral and cerebral metastases. All patients had received Pemetrexed as second-line treatment, except for 5 (12.8%) who had been administered it as third-line. Prior radiotherapy had been administered to 28 patients (71.8%), with a median time of 6.2 months (0.5–19 months) between the end of irradiation and the beginning of Pemetrexed. The radiation doses had been as follows: whole brain (WBRT) 30 Gy in 15 patients (15 out of 28, 53.6%) and stereotactic irradiation 20 Gy in 13 patients (13 out of 28, 46.4%). Out of the remaining 11 patients, 6 had never received radiotherapy because of little and asymptomatic cerebral metastatic disease, and 5 had been irradiated after Pemetrexed. Following brain radiotherapy prior to Pemetrexed 13 patients (46.5%) had showed partial response, 2 (7.1%) complete response, while 11 (39.3%) and 2 (7.1%) patients had exhibited stable and progressive disease, respectively. Radiological evidence of cerebral disease progression and involvement of other possible extra-cranial sites had been collected from 11 patients out of 28 (39.3%) before starting Pemetrexed; median time to disease progression following brain radiotherapy had been 6.8 months. The median number of Pemetrexed cycles had been 5 per patient (range 2–10). No relevant haematological or non-haematological toxicities had been observed except for G4 neutropenia in only one patient, which required G-CSF; no treatment delay had been reported. Overall response to Pemetrexed had been as follows: 12 patients reported

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Table 2 Distribution of 39 patients with NSCLC and CNS metastases by overall response to Pemetrexed and CNS response. Response to Pemetrexed* PR

SD

PD

No. (%)

No. (%)

No. (%)

CNS response after Pemetrexed PR 10 (66.6) SD 5 (33.4) PD –

1 (8.3) 11(91.7) –

– 5 (41.6) 7 (58.4)

Total

12 (100)

12 (100)

15 (100)

PR: partial response; SD: stable disease; PD: progressive disease; CNS: central nervous system. * Chi-square test (2 = 33.3; p ≤ 0.01).

progressive disease (PD) (30.8%), 12 (30.8%) and 15 (38.4%) patients showed stable disease (SD) and partial response (PR) respectively, with a clinical benefit obtained in 69% of patients. Distribution of cerebral response by overall response to Pemetrexed had been as follows: brain disease progression was observed in 7 patients, while a radiological cerebral benefit (SD or PR) was obtained in 32 patients (82%) (Table 2). In order to avoid overlapping effects between brain radiotherapy and Pemetrexed, all irradiation-naïve patients and those with clear radiological evidence of cerebral progression after brain radiother-

Table 3 Distribution of 22 patients (11 brain radiotherapy-naïve patients and 11 patients with cerebral progression after CNS radiotherapy and before Pemetrexed) by overall response to Pemetrexed and CNS response. Response to Pemetrexed* PR

SD

PD

No. (%)

No. (%)

No. (%)

CNS response after Pemetrexed PR 4 (50.0) SD 4 (50.0) PD –

1 (16.7) 5 (83.3) –

– 1 (12.5) 7 (87.5)

Total

6 (100)

8 (100)

8 (100)

PR: partial response; SD: stable disease; PD: progressive disease; CNS: central nervous system. * Chi-square test (2 = 20.63; p ≤ 0.01).

apy and before Pemetrexed for a total of 22 patients were included in the same group. Within that setting, 11 patients had never received radiotherapy, while the remaining 11 had showed cerebral progression before starting Pemetrexed. Median time between the end of radiotherapy and the beginning of Pemetrexed had been 8.8 months (4–19 months). The overall response for those patients had been as follows: 8 (36.4%) and 6 (27.2%) patients had showed partial response and stable disease, respectively, and 8 (36.4%) had progressive disease; within this group distribution of cerebral response to Pemetrexed by overall response is shown in Table 3.

Fig. 1. In the picture a brain response after three cycles of second-line treatment with Pemetrexed is reported. This 49-year-old male patient was affected by advanced adenocarcinoma previously treated with cisplatinum and Gemcitabine and not submitted to brain radiotherapy. The CT-scan shows the presence of frontal single brain metastasis: (a) before and (b) after three cycles of Pemetrexed, with evident size reduction.

Fig. 2. In the picture a brain response after six cycles of Pemetrexed was documented by CT-scan. This 72-year-old male patient was affected by advanced lung adenocarcinoma previously treated with cisplatinum and Vinorelbine and not submitted to brain radiotherapy. The CT-scan shows the presence of occipital single brain metastasis: (a) before and (b) after six cycles of Pemetrexed, with evident size reduction.

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Fig. 3. Overall survival of 39 patients affected by NSCLC with CNS metastasis and treated with Pemetrexed.

Here we show two examples of radiological response in the brain after Pemetrexed treatment (Figs. 1 and 2). Overall median survival for all 39 patients with brain metastases from NSCLC and treated with Pemetrexed was 10 months (Fig. 3). 4. Discussion Brain metastases are a frequent complication in lung cancer patients and a significant cause of morbidity and mortality. The use of chemotherapy for the treatment of brain metastases has been limited because of a presumed lack of effectiveness due to the blood–brain barrier. A poor prognosis is still associated with intracranial lesions, median survival after diagnosis being about 1 month with no treatment [9], approximately 2 months with corticosteroids [23], and 3–6 months with WBRT [9,24,25]. Despite the advent of new therapies for metastatic non-small cell lung carcinoma, brain metastases are still a challenge for their clinical implication, e.g. poor prognosis, and patients with brain involvement are usually excluded from clinical trials. Evidence in the literature about chemotherapy activity in patients with brain metastases come from small phase II studies of 23, 26 and 30 patients, respectively [12–14], which show the limited role of cisplatinum-containing associations. Among the new therapeutic options for Non-Small Cell Lung Cancer, Pemetrexed has showed activity in non-squamous carcinomas with good tolerability. Our interest has been to analyze the drug activity in brain metastases, since its toxicity profile could make it a good candidate also for frail patients like those with CNS metastases. There is one only case report in the literature suggesting the activity of Pemetrexed on CNS in humans’ [16], and we have found data from preclinical studies, which are all negative. Within the limitation of a small group of only 39 patients, we have found interesting preliminary data, which suggests the activity of Pemetrexed in CNS metastases. Nevertheless, all previous reports from the literature about this topic are the results of investigations on small groups of patients, too. The overall response to Pemetrexed is interesting, and a clinical benefit (PR + SD) with good tolerance had been demonstrated in 69% of the patients, according to previous reports about the activity of second-line Pemetrexed [3,5,26]. Response had been observed also on cerebral metastases, with PR in 11 patients (28.2%) and SD in 21 (53.8%), meaning a clinical benefit rate of 82% for cranial metastases. In particular, all patients experiencing an overall response (SD or PR) to Pemetrexed had reported a benefit over cerebral metastases as well. Cerebral progressive disease had been observed only in some non-responders to Pemetrexed. Overall survival is extremely good as compared with data derived from the literature on CNS metastases in NSCLC patients. Median overall survival for our group of patients was 10 months.

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In order to avoid overlapping effects between cerebral radiotherapy and Pemetrexed on cerebral metastases, all irradiation-naïve patients and those with clear radiological evidence of cerebral progression after brain radiotherapy and before Pemetrexed (22 patients totally) have been included in one group. The overall response for this setting had exhibited an overall good clinical benefit (SD + PR in 63% of the patients), and cerebral response had been confirmed in 10 and 5 patients with stable disease and partial response, respectively, with an overall cerebral benefit in 68% of patients. Again, all patients experiencing an overall benefit from Pemetrexed had shown a cerebral response as well. It should be stressed that the positive clinical benefit observed in our group of patients after treatment with Pemetrexed was due to the presence of good prognostic factors such as Performance Status, response to first-line treatment and histotype. By comparing our group to some recent data, our patients had several good prognostic indicators for response to Pemetrexed, such as Performance Status (within 0 or 1 for almost all of them), positive response to first-line treatment (four patients only reported progressive disease after first-line therapy), and prevalence of adenocarcinoma. However, distribution of patients by overall response to Pemetrexed and CNS response is highly suggestive that Pemetrexed may play an effective role also on brain metastases, when present. A similar distribution was observed also in the group of 22 patients in whom cerebral radiotherapy played no role either because it had not been performed before Pemetrexed or, if it had, because cerebral progression had been detected before starting Pemetrexed. In conclusion, although our group of patients had good prognostic factors, an extremely good response rate was observed even on cerebral metastases, which shows that Pemetrexed may be an active and effective option for patients with brain involvement. Conflict of interest All authors state no financial or personal relationships with other people or organizations that inappropriately influenced their work. References [1] Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy regimens for advanced non-small cell lung cancer. N Engl J Med 2002;346:92–8. [2] Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O’Rourke M, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non small cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000;18:2095–103. [3] Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, et al. Randomized phase III trial of Pemetrexed versus docetaxel in patients with non small cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004;22:1589–96. [4] Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123–32. [5] Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-smallcell lung cancer. J Clin Oncol 2008;26:3543–51. [6] Peterson P, Park P, Fossella F, Gatzmeier F, Ulrich J, Scagliotti G. Is Pemetrexed more effective in adenocarcinoma and large cell lung cancer than in squamous cell carcinoma? A retrospective analysis of a phase III trial of pemetrexed vs docetaxel in previously treated patients with advanced non small cell lung cancer. J Thoracic Oncol 2007;2(Suppl. 4):S851. WCLC 2007. [7] Cairncross JG, Kim JH, Poster JB. Radiation therapy for brain metastases. Ann Neurol 1980;7:529–41. [8] Delattre JY, Krol G, Thaler HT, Posner JB. Distribution of brain metastases. Arch Neurol 1988;45:741–4. [9] Patchell RA. Brain metastases. Neurol Clin 1991;9:817–24. [10] Hazuka MB, Burleson WD, Stround DN, Leonard CE, Lillehei KO, Kinzie JJ. Multiple brain metastases are associated with poor survival in patients treated with surgery and radiotherapy. J Clin Oncol 1993;11:369–73. [11] Nussbaum ES, Djalilian HR, Cho KH, Hall WA. Brain metastases. Cancer 1996;78:1781–8.

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