Questa è la versione dell’autore dell’opera:
Predictive role of erythrocyte macrocytosis during
treatment with pemetrexed in advanced non-small cell lung
Buti S, Bordi P, Tiseo M, Bria E, Sperduti I, Di Maio M, Panni S, Novello S, Rapetti SG, Pilotto S, Genestreti G, Rossi A, Pezzuolo D, Camisa R, Tortora G,
Ardizzoni A. Lung Cancer. 2015 Jun;88(3):319-24. doi:
10.1016/j.lungcan.2015.03.016. Epub 2015 Apr 1. PubMed PMID: 25870156.
La versione definitiva è disponibile alla URL:
PREDICTIVE ROLE OF ERYTHROCYTE MACROCITOSYS DURING
TREATMENT WITH PEMETREXED IN ADVANCED NON-SMALL
CELL LUNG CANCER PATIENTS.
Sebastiano Buti¹, Paola Bordi1
, Marcello Tiseo¹, Emilio Bria2
, Isabella Sperduti3
Massimo Di Maio4
, Stefano Panni5
, Silvia Novello6
, Simonetta Grazia Rapetti6
, Giovenzio Genestreti7
, Antonio Rossi8
, Debora Pezzuolo9
and Andrea Ardizzoni¹.
Oncology Unit, University Hospital of Parma, Parma, Italy.
²Oncology Unit, University of Verona, Azienda Ospedaliera Universitaria
Integrata, Verona, Italy.
Biostatistics Unit, Regina Elena National Cancer Institute, Roma, Italy.
Clinical Trials Unit, Istituto Nazionale dei Tumori Fondazione 'G. Pascale'
-IRCCS, Napoli, Italy.
Oncology Unit, Azienda Istituti Ospitalieri di Cremona, Cremona, Italy.
Department of Oncology, University of Turin; Azienda
Ospedaliero-Universitaria “San Luigi Gonzaga”, Orbassano, Torino, Italy.
Department of Oncology, AUSL Rimini, Cervesi Hospital, Cattolica (RN),
Division of Medical Oncology, S.G. Moscati Hospital, Avellino, Italy.9
Oncology Day Hospital, Guastalla Hospital, AUSL of Reggio Emilia, Italy.
Sebastiano Buti, M.D.
Oncology Unit, University Hospital of Parma Viale Antonio Gramsci, 14
43126, Parma (Italy) Tel +39 0521/702894 Fax +39 0521/995448 E-mail: email@example.com
OBJECTIVES: Pemetrexed has been approved for the treatment of advanced non-small cell
lung cancer (NSCLC) non-squamous histology, both as first- and second-line therapy. Pemetrexed is an antimetabolite drug, that inhibits enzymes involved in nucleotides bio-synthesis arresting cancer cells cycle. The aim of this study was the evaluation of the impact of pemetrexed on erythrocyte mean corpuscolar volume (MCV) change and its possible correlation with disease control rate (DCR), progression-free (PFS) and overall survival in NSCLC patients.
MATERIALS and METHODS: A retrospective collection of clinical and laboratory data
(including basal MCV and maximum MCV occurred during therapy) in advanced NSCLC patients treated with pemetrexed at seven Italian centres was performed. Nonparametric tests, univariate and multivariate analisys were used to assess correlation between variables and to identify predictors of outcomes.
RESULTS: 191 patients were enrolled: median age 62, 60% male, 61% performance status
(PS) 0, 91% stage IV, 88% adenocarcinoma histotype, 25% never smoker, 62% received pemetrexed as first-line. Mean MCV significantly increased from basal (89 fL) to during treatment (94 fL), with mean ΔMCV = 4 fL. The median time from therapy start to maximum MCV was 2.2 months. Median PFS was 7 [CI95% 6-8] and 3 [CI95% 2-4] months [p = 0.0016], and median survival was 17 [CI95% 12-23] and 10 [CI95% 8-12] months [p = 0.02], in patients with ΔMCV > 5 fL (n = 80) and ΔMCV ≤ 5 fL (n = 111), respectively. Multivariate analysis identified age ≥ 62, PS 0, adenocarcinoma histology and ΔMCV > 5 fL as independent predictors of longer PFS. A ΔMCV > 5 fL significantly correlates with DCR.
correlated with better DCR, PFS and OS. A larger prospective study could be useful to better clarify these findings.
Non-small cell lung cancer, macrocytosis, mean corpuscolar volume, pemetrexed, prognostic, predictive role.
Lung cancer is still the leading cause of cancer related death in the world . Non-small cell lung cancer (NSCLC) represents approximately 85% of all cases and is mostly diagnosed in advanced stage. In this setting, palliative platinum-based chemotherapy, is the only therapeutic approach for most patients, aiming to control symptoms and prolong survival [2-4].
Pemetrexed has been licensed both in association with platinum and alone, as first and second line treatment respectively, in patients with advanced non-squamous NSCLC. [5-9]. Indeed, non-squamous histology represents the principal predictor of efficacy in NSCLC patients treated with pemetrexed. This evidence emerged from retrospective analyses and is probably related to low expression of thymidylate synthase (TS) enzyme, principal target of pemetrexed, in non-squamous lung cancer [7-11]. However, to date, predictive factors of pemetrexed efficacy in patients with non-squamous histology are missing.
Pemetrexed is an antimetabolite drug interfering with enzymes involved in DNA synthesis. In particular, by inhibiting TS, dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyltransferase (GARFT), pemetrexed interferes with folate-dependent metabolic processes necessary to DNA replication and homocysteine homeostasis. Considering that pemetrexed is non target specific, the effects of its activity involve also other tissues than lung cancer, such as bone marrow. In 2002 a correlation between higher toxicity during pemetrexed was identified in patients carrying folate deficiency, expressed indirectly as hyperhomocysteinemia . Since then, concomitant implementation with folic acid and B12 vitamin is recommended during pemetrexed treatment, demonstrating to reduce toxicity without compromising efficacy [13,14].
Methylenetetrahydrofolate reductase (MTHFR) is another enzyme involved in folate metabolism and catalyzes the synthesis of l-5-methyltetrahydrofolate, essential in DNA synthesis and homocysteine metabolism [15,16]. Polymorphisms of MTHFR have been reported in literature, resulting in low enzymatic activity  potentially able to predict survival differences in pemetrexed-treated NSCLC . Patients undergoing pemetrexed therapy receive vitamin supplementation with folic acid and B12 vitamin as indicated, therefore a folate deficiency can be excluded . However, the conversion of folic acid synthetic form is inhibited by the activity of pemetrexed on DHFR. Therefore, despite supplementation, pemetrexed could reduce the amount of substrate available for MTHFR activity revealing a possible condition of low enzymatic activity, due to polymorphism . Finally, in bone marrow, this could affect normal erythropoiesis and result in increased red cell MCV. Hence, MCV growth could be indirect expression of the MTHFR polymorphisms presence, identifying a subgroup of patients mainly sensitive and exposed to pemetrexed activity, in whom pemetrexed could be more toxic but also more effective.
The correlation between MCV and antimetabolite drugs has been previously reported in a group of patients treated with capecitabine [20,21]. Moreover, some data suggest that, in women with metastatic breast cancer, MCV elevation while on capecitabine could represent a response predicting factor [22,23].
We designed this retrospective multicentric study in a population of advanced NSCLC treated with pemetrexed, to identify changes in MCV value during treatment and possible role of its variation as predictive and prognostic factor.
2. MATERIALS and METHODS
2.1 Study population. This was a retrospective, observational multicenter study of medical records from October 2007 to February 2012 for patients with advanced NSCLC treated with chemotherapy at seven different centers in Italy. Patients were enrolled consecutively to avoid selection bias. Data were retrospectively collected from medical chart reviews and electronic records. Inclusion criteria were: patients of all ages who received intravenous chemotherapy with cisplatin/carboplatin in combination with pemetrexed or pemetrexed alone (in accordance with their treating physician’s practice), histologic or cytologic diagnosis of inoperable NSCLC (any histology), administration of at least one dose of pemetrexed, availability of laboratory and clinical data from the baseline to at least one month after the end of chemotherapy, written informed consent (for alive patients). Our study includes also patients affected by squamous NSCLC and treated with pemetrexed before 2009, when the differential efficacy of pemetrexed according to NSCLC histology was not yet discovered . Patients were excluded from the analysis if they had missing key information (i.e. laboratory data, clinical assessment, survival data) or other cancer treated with pemetrexed-based chemotherapy (i.e. pleural mesothelioma).
Patient characteristics and clinic-pathological variables considered in this study were: gender, age, Eastern Cooperative Oncology Group (ECOG) performance status (PS), previous chemotherapy, stage, histological subtype, smoking history, MCV value within one week before the start of pemetrexed chemotherapy, maximum MCV value (and its date) obtained during the time ranging from the day after the first cycle and one month after the last cycle (“during treatment” MCV), concurrent administration of platinum, toxicity. In particular tumor response and progression were determined by the investigators on the basis of the Response Evaluation Criteria in Solid Tumors 1.1 every 3 cycles of treatment (or before
in the case of clinically suspected disease progression); toxicity data were graded using the National Cancer Institute Common Toxicity Criteria Version 4.0 .
This study was carried out in accordance with the approval by the ethical committee of the institutions included in this analysis.
2.2 Statistics. Descriptive statistics was used to summarize pertinent study information. Follow-up was analyzed and reported according to Shuster . The correlation between variables were analyzed according to chi-square, Student's t, and Mann–Whitney (nonparametric) tests. The hazard ratio (HR) and the 95% confidence intervals (95% CI) were estimated for each variable using the Cox univariate model [28,29]. A multivariate Cox proportional hazard model was developed using stepwise regression (forward selection, enter/remove limits P = 0.10 and P = 0.15), to identify independent predictors of outcomes. The receiver operating characteristic (ROC) curve analysis was adopted for dichotomization of continuous variables according to outcome . PFS and OS were calculated by the Kaplan–Meier product limit method from the date of treatment start until progression or death for any cause . The log-rank test was adopted to assess differences between those variables resulted to be independent at multivariate analysis. Significance was defined at the p<0.05 level. The SPSS® (18.0), and MedCalc® (10.0.1) licenced statistical programs were used for all analyses.
3.1 Patients. Overall, 191 patients were considered in our analysis (Table 1); 60% of patients were men, the median age was 62 years (range 36-83), 61% were ECOG PS 0, 91% were advanced (stage IV), 88% were adenocarcinoma histotype, and 75% were current or ex-smokers. Pemetrexed was administered as first chemotherapy in 62% of patients; concurrently with a platinum compound in the 72%; the median of the administered cycles was 4. All patients received vitamin B12 and folic acid supplementation. 94% of patients presented with normal basal MCV (< 97 fL). The mean MCV increased from basal (89 fL; range 64-113) to “during treatment” (94 fL; range 69-123), with a mean maximum MCV difference of 4 fL. Almost the 42% of patients showed a > 5 fL MCV increment, during pemetrexed treatment. The median time from the start of chemotherapy to the maximum MCV value was 2.2 months (range 0.1-4.3; 25°-75° percentile 0.8-3.7).
3.2 Correlation between MCV and efficacy. A > 5 fL MCV difference resulted to best dichotomize survival curves at the ROC analysis, when correlating MCV as continuous variable with PFS. Median PFS was 7 [CI95% 6-8] and 3 [CI95% 2-4] months [p = 0.0016] in patients with a “during treatment” MCV variation (ΔMCV) > 5 fL (n = 80) and ΔMCV ≤ 5 fL (n = 111), respectively (Figure 1A). At the multivariate analysis, age ≥ 62 years, ECOG PS = 0, adenocarcinoma histology and a > 5 fL of MCV increment represented independent predictors of longer PFS (Table 2). The median OS of entire population was 10 months. Median OS was 17 [CI95% 12-23] and 10 [CI95% 8-12] months [p = 0.02] in patients with ΔMCV > 5 fL and ΔMCV ≤ 5 fL, respectively (Figure 1B). At the multivariate analysis, ECOG PS = 0, combination with a platinum compound and response (partial and complete response) were significant independent predictors of better survival (Table 3).
Overall response rate RR and DCR in the entire population was 33% and 63%, respectuvely. RR was 39% and 28% in patients with ΔMCV > 5 fL and ΔMCV ≤ 5 fL, respectively (p = non significant). In addition, a difference in MCV > 5 fL significantly correlates with DCR (partial response plus stable disease): it was 80% and 56% (p = 0.001) in patients with ΔMCV > 5 fL and ΔMCV ≤ 5 fL, respectively (Figure 2).
3.3 Toxicity. The observed toxicity (Table 1) was consistent with expected. Although the number of administered cycles was different between patients with maximum MCV increment ≤ or > 5 fL [3 (range 1-8) versus 6 (range 1-32), respectively], no differences in toxicity profile were detected among the two groups (data not shown).
With the recent increasing of therapeutic options for NSCLC, clinical and molecular predictors of drug efficacy have become increasingly relevant to select the treatment best tailored to individual patients. In particular, pemetrexed is emerging for its approval and widespread use as first-, second-line and maintenance therapy for advanced non-squamous histology NSCLC. However, there are currently no known predictive factors, in addition to histology, that can identify a subgroup of patients who may benefit more than others to treatment with pemetrexed. Some recent retrospective studies indentified MTHFR polymorphisms as possible biologic predictors of survival differences in pemetrexed-treated NSCLC, but no clinical (easily obtainable) factors were never detected .
that this drug causes macrocytosis, increasing MCV from basal to “during treatment” of 4.1 fL, despite an expected frequency of anemia and regular supplementation with folic acid and vitamin B12. A > 5 fL MCV difference on pemetrexed therapy appears to be correlated with better DCR and PFS and OS, even if only in univariate analysis for the latter: OS could be influenced by several other factors not measured in this study such as epidermal growth factor receptor and/or anaplastic lymphoma kinase mutational status and subsequent lines of therapy. These data could be explained by a decreased metabolism of pemetrexed (i.e due to a polymorphisms of MTHFR gene) and subsequent increased drug exposure in patients who develop higher MCV variation during treatment. Therefore, the MCV elevation could represent an indirect expression of pemetrexed impaired metabolism. Similar results in terms of MCV increase were reported in a smaller population (54 patients treated with pemetrexed-based chemotherapy) by Velez et al. and Santos et al. Also the authors reported that 12 out of the 19 patients still on pemetrexed therapy showed increased MCV. Furthermore, in 5 of these 12 patients plasma levels of folic acid, vitamin B12, homocysteine and methylmalonic acid were tested and resulted normal, allowing to exclude other causes of macrocytosis [33,34].
Surprisingly, no differences in toxicity emerged between patients with maximum MCV increment ≤ or > 5 fl, despite an higher number of administered cycles in the latter group. Our study presents some limitations: the data were collected retrospectively; studied population was heterogeneus because of the enrollment of patients treated with pemetrexed as first or second line and, in both cases, alone or in association with a platinum salt; even if macrocytosis development on pemetrexed treatment is a time-dependent phenomenon, no landmark analysis was performed, because during treatment only maximum value of MCV was collected making difficult to establish with certainty the cause-effect relationship between
outcome and macrocytosis. In particular, our data clearly show that the group of patients selected because of a maximum MCV increment > 5 fL had a longer exposition to the drug, receiving a number of cycles substantially higher than those patients who did not experience that increment during treatment. Time to maximum MCV was quite heterogeneous among patients, with a median time to maximum value slightly higher than 2 months. In order to confirm our interesting findings, however, a prospective evaluation could be conducted, with a landmark analysis comparing the outcome of patients obtaining an early MCV increment (for instance, in the first or second treatment cycle) versus those not obtaining such increase. In conclusion, macrocytosis development could help the clinician to early discriminate which patients will benefit from continuation of treatment with pemetrexed and this information may be more relevant for those patients undergoing maintenance therapy. A larger prospective evaluation could be useful to better clarify these findings.
Figure 1: Progression free survival [panel A] and overall survival [panel B] according to ∆MCV from basal to “during treatment” value (> 5 or ≤ 5 fL).
Figure 2:Disease control rate (Progression disease or partial response + stable disease) according to ∆MCV from basal to “during treatment” value (> 5 or ≤ 5 fL).
Table 1: Patients characteristics.
Table 2: Progression Free Survival analysis Table 3: Overall Survival analysis
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