Int J Clin Pharm DOI 10.1007/s11096-014-9920-2
REVIEW ARTICLE
Systematic review of efficacy and safety of pemetrexed in non-small-cell-lung cancer Maria Antonia Pe´rez-Moreno • Mercedes Galva´n-Banqueri • Sandra Flores-Moreno ´ ngela Villalba-Moreno • Jesu´s Cotrina-Luque • Francisco Javier Bautista-Paloma A
•
Received: 22 August 2013 / Accepted: 5 February 2014 Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie 2014
Abstract Introduction Lung cancer accounts for 20 % of cancer deaths in Spain. The most frequent subtype (87 %) is non-small cell lung cancer (NSCLC). Pemetrexed is a recently marketed drug added to NSCLC therapeutic arsenal. It seems to have become one of the most used options for the treatment of this condition over the last 3 years. Aim of the review To evaluate the efficacy and safety of pemetrexed in NSCLC, in the different therapy lines. Method A systematic search of published literature was conducted using the main databases (MEDLINE, EMBASE, the Cochrane Library and the Center for Reviews and Dissemination) and subsequently a search of referenced literature was performed. We included clinical trials, meta-analyses and systematic reviews. The evaluation of the quality of the articles was performed by pairs using specific assessment scales, Critical Appraisal Skills Program (CASP) adapted for CASP Spain. Then we extracted data on efficacy and safety according to the treatment line assessed. Results We identified 277 references. Finally, nine clinical trials and a meta-analysis complied with inclusion criteria. In first-line induction, treatment with pemetrexed associated with a platinum was similar in terms of efficacy to other alternative chemotherapy regimens, except in patients with non-squamous histology, in whom survival was higher in the experimental group. In maintenance treatment, greater efficacy was seen with pemetrexed in patients with non-
Electronic supplementary material The online version of this article (doi:10.1007/s11096-014-9920-2) contains supplementary material, which is available to authorized users. M. A. Pe´rez-Moreno (&) M. Galva´n-Banqueri ´ . Villalba-Moreno J. Cotrina-Luque S. Flores-Moreno A F. J. Bautista-Paloma Pharmacy Department, Hospital Universitario Virgen Del Rocı´o, Manuel Siurot s/n., 41013 Seville, Spain e-mail: [email protected]
squamous histology. In second-line treatment, there were no significant differences in terms of efficacy and safety for pemetrexed treatment versus other chemotherapy options. The most frequent adverse reactions were: hematological, gastrointestinal and neurological. All were significantly less frequent with pemetrexed versus other alternative therapies, except for liver toxicity. Conclusions Due to the high degree of uncertainty as to its efficacy in certain subgroups of patients, including conflicting data; to its recent incorporation, and therefore lack of safety data in the medium and long term, and the high budgetary impact of its incorporation into health systems, it seems reasonable to optimize its use, identifying those patients who may benefit most. Keywords Cancer Efficacy Non-small-cell lung cancer Pemetrexed Safety Systematic review
Impacts on practice •
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Due to its high economic and care impact for public health systems, it is important to optimize the use of pemetrexed. There is a high level of uncertainty of the efficacy of pemetrexed in certain subgroups of patients, and clinicians should discuss if the drug should be used so frequently.
Introduction Lung cancer (LC) is the most common cancer in the world and was the most commonly diagnosed cancer as well as the leading cause of cancer death in males in 2008 globally. Among females, it was the fourth most commonly diagnosed
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cancer and the second leading cause of cancer death. LC accounted for 13 % (1.6 million) of the total cases and 18 % (1.4 million) of the deaths in 2008. In Western Europe, its incidence rate in males and females was 44.7 and 16.7 per population of 100,000 people respectively in that year [1]. In Spain, cancer accounts for 20 % of deaths, with an incidence rate of 20,000 cases per year. Incidence varies depending on age and gender. Thus, in men over 70 years of age, the incidence is 90 times higher than that observed in those under 45 years, and it is higher in men than in women. Mortality is also higher in men compared to women, although in the latter, mortality has increased significantly in recent years [2]. Epidemiological studies show that there are several different risk factors that predispose the development of this type of tumor, such as tobacco, female gender [3], diet [4], occupational factors [5] and genetic predisposition [6], with tobacco being the most significant (80–90 % of lung cancers are attributable to tobacco). In spite of the addition of new drugs to the therapeutic arsenal in recent years, disease prognosis continues to be poor, with response rates to first-line chemotherapy (Ch) of 20–40 % and a median survival of 7–12 months. Of all LC subtypes, non-small cell lung cancer (NSCLC) is the most common, accounting for 87 % of all cases. Different histologies are included in this subgroup, mainly epidermoid/squamous, adenocarcinoma and large cell carcinoma or undifferentiated carcinoma [7]. Diagnosis of the disease is usually at advanced stages of the disease (locally advanced or metastatic), mainly because the symptoms principally appear at late stages and there is no effective screening method [8]. The therapeutic approach depends on the stage of disease at diagnosis. In the case of advanced or metastatic NSCLC, the most widely used chemotherapy regimens for front-line treatment (induction) are combinations of platinum (cisplatin or carboplatin) with any of the so-called third-generation cytostatic agents (gemcitabine, vinorelbine or taxanes) [9]. Recently, new drugs of the so-called targeted therapies group have come onto the market, such as bevacizumab, which can be of benefit in selected populations, although further information is necessary [10, 11]. International guidelines suggest that patients who progress to a first line of treatment and maintain an acceptable general state of health may improve disease-related symptoms and survival [11] with chemotherapy with erlotinib or docetaxel, depending on the tumor subtype. In 2004, pemetrexed was approved, an anti-cancer agent of the group of inhibitors of the thymidylate synthetase enzyme. It is an anti-metabolite that inhibits several enzymes acting in the folate synthesis, hence disrupting essential metabolic processes necessary for folate-dependent cell replication [12]. At present, three indications are approved by regulatory agencies in locally advanced/metastatic
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NSCLC: combining with platinum in first-line induction treatment, as monotherapy, in first-line maintenance treatment and as second-line treatment. In all three situations cases with predominantly squamous histology are excluded. Despite its recent appearance on the market, there are numerous publications, although results are not always consistent. In fact, this fact together with the high economic and care impact involved in its use (the cost per patient is six times that of current treatment), makes it necessary to perform a systematic assessment of its efficacy and safety so as to identify the patient population that may significantly benefit from this therapy.
Aim of the study For the abovementioned reasons, the main aim of this review was to evaluate the efficacy and safety of pemetrexed therapy in adult patients with advanced stage NSCLC. And the specific objectives were to evaluate the efficacy of pemetrexed in NSCLC in each of the approved indications (first-line induction, maintenance and second-line), according to histology (squamous/epidermoid adenocarcima or large cell) and to assess safety according to concomitant therapy administered.
Method We conducted a systematic search of the literature published in major biomedical databases in the last 8 years (between April 2004 and April 2012). We reviewed the following databases: MEDLINE, EMBASE, the Cochrane Library and the Center for Reviews and Dissemination (CRD) database. The search strategy is summarized in Fig. 1. The search was completed by consulting various websites of drug regulatory agencies, scientific societies and other bodies that could contain information related to the subject. We also performed a search for new references in the literature of the documents found. The selection of the articles was performed based on inclusion/exclusion criteria listed in Table 1. In a first phase, we deleted duplicates and selected (by title and abstract) articles that met the inclusion criteria, reviewing the full text of those we considered doubtful. This procedure was performed independently by paired researchers; disagreements were resolved by a third party. Subsequently, we carried out a critical reading of selected full-text articles. Quality assessment was conducted using specific assessment scales Critical Appraisal Skills Program (CASP) adapted for CASP Spain (CASPe). The quality of the studies was established by scoring
Int J Clin Pharm Fig. 1 Literature search
LITERATURE SEARCH
MEDLINE (PUBMED) (pemetrexed OR Alimta) AND non-small cell lung cancer AND (efficacy OR safety) Medline limits
EMBASE #1 “Pemetrexed” OR “Alimta” #2 “efficacy” OR “safety” #3 'randomized controlled trial'/de OR 'randomization'/ de OR 'single blind procedure'/de OR ' double blind procedure'/de OR 'crossover procedure'/de OR 'placebo'/de OR random*:de,it,ab,ti OR placebo:de,it,ab,ti OR blind:de,it,ab,ti NOT (letter:it OR editorial:it OR note:it OR ('animal'/de NOT ('human'/de AND 'animal'/de))) #4'meta analysis'/de OR 'systematic review'/de OR 'meta' NEXT/3 'analysis' OR metaanalys* OR 'systematic' NEXT/3 'review' OR 'systematic' NEXT/3 'overview' NOT (letter:it OR editorial:it OR note:it OR ('animal'/de NOT ('human'/de AND 'animal'/de))) #5 #1 AND #2 AND (#3 OR #4) AND [embase]/lim
CENTER FOR REVIEWS AND DISSEIMINATION (CRD) a) Pemetrexed AND non-small cell lung cancer AND efficacy (2004-2012) b) Pemetrexed AND non-small cell lung cancer AND safety (2004-2012)
(("pemetrexed"[Supplementary Concept] OR "pemetrexed"[All Fields]) OR ("pemetrexed"[Supplementary Concept] OR"pemetrexed"[All Fields] OR "alimta"[All Fields])) AND ("carcinoma, non-small-cell lung" [MeSH Terms] OR ("carcinoma"[All Fields] AND "non-small-cell"[All Fields] AND "lung"[All Fields]) OR "non-small-cell lung carcinoma"[All Fields] OR ("non"[All Fields] AND"small"[All Fields] AND "cell"[All Fields] AND "lung"[All Fields] AND "cancer"[All Fields]) OR "non small cell lung cancer" [All Fields]) AND (efficacy[All Fields] OR ("safety"[MeSH Terms] OR "safety"[All Fields])) AND (("2004/04/01"[PDAT] : "2012/04/30"[PDAT]) AND "humans"[MeSH Terms] AND (systematic[sb] OR Meta-Analysis[ptyp] OR Clinical Trial[ptyp] OR Randomized Controlled Trial[ptyp] OR Clinical Trial, Phase II[ptyp] OR Clinical Trial, Phase III[ptyp]) AND (English[lang] OR Spanish[lang]))
Table 1 Studies selection criteria Inclusion criteria
Exclusion criteria
Population: age 18 years or older patients Study design: systematic review, randomised controlled clinical trials and metanalysis
Case reports, experts opinions, retrospective studies, no randomised clinical trials and other differents designs
Study arm: Treatment with pemetrexed versus other available therapies
If pemetrexed was administered in both treatments arms
Study variables: OS, PFS, quality of live, response rate and adverse events
Study of differents doses that those included in EPARproduct information
Languages: English or Spanish
Other languages
positive responses with a 1 and negative or doubtful (no explicit information) 0. We considered: high quality = 6; medium–high quality = 5, medium quality = 4, medium– low quality = 3 and low quality \3. We designed an ad hoc table where information was collected on the design of each of the selected studies, including: study design, inclusion and exclusion criteria, sample size, patients’ follow-up period and treatment regimens evaluated. To ensure reproducibility and minimize bias, methodological doubts were resolved by discussion with a second researcher who analyzed the data independently.
Subsequently, a table was drawn up to collect data on the efficacy and safety of each of the randomized clinical trials (RCTs). Variables to assess efficacy were: overall survival (OS), progression-free survival (PFS), survival without toxicity (SWT), response rate [Complete response rate (CR), partial response (PR) and stable disease (SD)], progression-free survival quality of life and duration of the response. For safety assessment, the most frequent adverse reactions were collected (MFAR) and grouped by system and severity. In the safety analysis, we took into account concomitant Ch administered, considering it a factor in the incidence of some MFAR. The statistical analysis was carried out using Excel 2007 and IBM SPSS Statistics software, version 19. Qualitative variables were shown as percentages and quantitative variables as central measures (mean) with dispersion measures (standard deviation, range).
Results We identified a total of 275 articles in different databases (96 in MEDLINE, 164 in EMBASE, 14 in the database of the Center for Reviews and Dissemination, 1 in the Cochrane Library) and 2 articles after consulting the referenced literature. Figure 2 shows the flowchart of the
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Int J Clin Pharm Fig. 2 Articles selection after literature search
Potentially relevant citations identified and screened for retrieval (n=275)
Potentially relevant citations after remove duplicated citations (n=238)
Potentially relevant citation excluded by tittle and abstract (n=166)
Manual search (n=2)
Potentially relevant citation excluded by full- text articles (n=64)
Articles included (n=10)
Table 2 Studies quality and CASPe score Study
CASPe score
Quality
Scagliotti et al. [13] Novello´ et al. [14]
4 4
Moderate Moderate
Gronberg et al. [15]
5
Moderate-high
Socinski et al. [16]
3
Moderate-lowa
Rodrigues-Pereira et al. [17]
4
Moderate
Ciuleanu et al. [18]
6
High
Belani et al. [19]
6
High
Paz-Ares et al. [20]
6
High
Hanna et al. [21]
5
Moderate-high
a
Some questions are not clear
process for selecting documents during the systematic review. Finally, we selected 10 articles, 9 randomized controlled clinical trials and a meta-analysis article. Of the selected RCTs, 5 evaluated the use of pemetrexed as first-line induction treatment, three as first-line maintenance and one as second-line treatment. Meta-analysis analyzed the efficacy and safety of the three treatment lines above. The CASPe score obtained and the quality of the RCTs included are shown in Table 2. Most of the articles were of medium to high quality. Tables 3 and 4 shows the characteristics of the articles selected and the populations included. Generally the
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population had a good functional status (ECOG 0-1), with a mean age of 61 years. Efficacy results are shown in Table 5. Pemetrexed as first-line induction treatment was compared with gemcitabine and docetaxel. Scagliotti et al. [13] found no superiority of pemetrexed over OS or PFS in the overall population. When a subgroup analysis was performed, different results were found in the subgroup with squamous histology, Gronberg et al. [15] did not demonstrate greater efficacy in this subgroup of patients, while Socinski et al. [16] found significant differences in the control of OS and disease. Rodrigues-Pereira et al. [17], in patients with nonsquamous histology, found no differences as to efficacy either. Ciuleanu et al. [18], in their evaluation of pemetrexed as a maintenance therapy, showed higher OS, PFS and response rate for both the overall population and the subgroup of patients with non-squamous histology. Paz-Ares et al. [20] showed improvements in PFS (pending publication of OS data) and benefits in disease control. In contrast, Belani et al. [19] found no significant differences in quality of life. In all cases, the comparator was placebo. Lastly, when comparing the efficacy of pemetrexed versus docetaxel in second-line treatment, Hanna et al. [21] found no difference in OS, PFS, response rate, or quality of life. Table S1 of electronic supplementary material shows the security variables collected, grouped by system and
Socinski et al. [16]
Gronberg et al. [15]
Novello´ et al. [14]
Scagliotti et al. [13]
Induction
Study
Every 21 days until 6 cycles
b) Pemetrexed 500 mg/m2 day 1
(a) Gemcitabine 1,250 mg/ m2 days 1 and 8
Cisplatin 75 mg/m2 day 1 plus
Every 21 days until 6 cycles
(b) Pemetrexed 500 mg/m2 day 1
(a) Gemcitabine 1,250 mg/m2 days 1 and 8
Cisplatin 75 mg/m2 day 1 plus:
Every 21 days until 6 cycles
a) Gemcitabine 1,250 mg/ m2 days 1 and 8 (b) Pemetrexed 500 mg/ m2 day 1
Cisplatin 75 mg/m2 dı´a1 ma´s
Every 21 days until 6 cycles
(b) Pemetrexed 500 mg/m2 day 1
(a) Gemcitabine 1,250 mg/ m2 days 1 and 8
Cisplatin 75 mg/m2 day 1 plus
Therapy: study arm/control arm
Multicentre randomized controlled phase III trial
Multicentre randomized openlabel controlled phase III trial
Multicentre randomized openlabel controlled phase III trial
Multicentre randomized openlabel controlled phase III trial
Study design
Inability to take corticosteroid drugs, folic acid, or vitamin B12 Acute myocardial infarction in the previous 6 months Significant weight loss (10 % body weight in the preceding 6 weeks)
Treatment with warfarine No previous chemotherapy, radiotherapy, inmunotherapy or biologic therapy
Other severe systemic disease Life expectancy [12 weeks
Pelvic radiation One or more measurable lesions (RECIST 1.0)
Patients eligible for radiotherapy curative
Inability to take corticosteroid drugs, folic acid, or vitamin B12
An inability to interrupt NSAIDs
Grade [1 peripheral neuropathy
Inability to take corticosteroid drugs, folic acid, or vitamin B12
An inability to interrupt NSAIDs
Grade [1 peripheral neuropathy
Exclusion criteria of every study
Performance status 0–1
Performance status 0–1
One or more measurable lesions (RECIST 1.0)
Non-squamous tumor histology
Without previous ratiotherapy (or 4 weeks before at least)
Performance status 0–1
One or more measurable lesions (RECIST 1.0)
No previous systemic chemotherapy for NSCLC
Without previous ratiotherapy (or 4 weeks before at least)
Performance status 0–1
One or more measurable lesions (RECIST 1.0)
No previous systemic chemotherapy for NSCLC
Inclusion criteria of every study
-70
312
13
24
24
Patient follow-up (months)
-72
-67
209
217
-219
436
1,669 (ratio 1:1)
1,669 (ratio 1:1)
Patients (N)
Table 3 Characteristics of studies included: clinical trials of pemetrexed in first-line treatment option (induction and maintenance) and clinical trials of pemetrexed in second-line treatment option
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Paz-Ares et al. [20]
Belani et al. [19]
Ciuleanu et al. [18]
Maintenance
RodriguesPereira et al. [17]
Study
every 21 days
(b) placebo ? supportive care
(a) PMX 500 mg/m2 ?supportive
(randomized; ratio 2:1)
*Maintenance phase
CDDP 75 mg/m ?PMX 500 mg/m2 every 21 days (4 cycles)
2
(non randomized)
*Induction phase
Every 21 days. Both groups received supportive care
(b) Placebo
(a) Pemetrexed 500 mg/m2
After completion of four cycles of platinum-based induction therapy:
Every 21 days. Both groups received supportive care
(b) Placebo
(a) Pemetrexed 500 mg/m2
After completion of four cycles of platinum-based induction therapy:
Every 21 days until 6 cycles
(b) Docetaxel 75 mg/m2
(a) Pemetrexed 500 mg/m2
Carboplatin AUC5 plus
Therapy: study arm/control arm
Table 3 continued
Multicentre randomized double-bind placebo controlled phase III trial
Multicentre randomized double-bind placebo controlled phase III trial
539 (ratio 2:1)
663 (ratio 2:1)
663 (ratio 2:1)
211 (ratio 1:1)
Multicentre randomized openlabel controlled phase III trial
Multicentre randomized double-bind placebo controlled phase III trial
Patients (N)
Study design
Until progression or death
Until progression
Until progression
Until grade 3/4 toxicity
Patient follow-up (months)
Four cycles of induction therapy with pemetrexed plus cisplatin with partial/complete response
Performance status 0–1
*Maintenance phase:
One or more measurable lesions
No previous systemic chemotherapy for NSCLC
*Induction phase
Without previous ratiotherapy (or 4 weeks before at least) No progression after completion of four cycles of platinum-based induction therapy
Tumour histology predominantly squamous cell, mixed small cell or both
of other antitumour therapy
Concurrent administration
Uncontrolled cardiac disease
Inability to take corticosteroid drugs, folic acid, or vitamin B12 Pleural effusions or positive supraclavicular lymph nodes Performance status 0–1
Other previous malignancy
Life expectancy [12 weeks
No progression after completion of four cycles of platinum-based induction therapy
Uncontrolled cardiac disease
Inability to take corticosteroid drugs, folic acid, or vitamin B12
Without previous ratiotherapy (or 4 weeks before at least)
Other previous malignancy
Performance status 0–1
Inability to take corticosteroid drugs, folic acid, or vitamin B12
An inability to interrupt NSAIDs
Grade [4 peripheral neuropathy
Other severe systemic disease or infectious active
Other previous malignancy
Exclusion criteria of every study
Life expectancy [12 weeks
Surgery 4 weeks before (at least)
No previous systemic chemotherapy for NSCLC
Life expectancy [8 weeks
Performance status 0–2
One or more measurable lesions (RECIST 1.0)
Non-squamous tumor histology
Inclusion criteria of every study
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571 Multicentre randomized openlabel controlled phase III trial
An inability to interrupt NSAIDs
Table 4 Characteristics of studies included: meta-analysis Line of treatment option
Studies included (N)
Patients (N)
Inclusion criteria of the meta-analysis
First line (induction)
5
3,541
Randomized controlled clinical trials
First line (maintenance) Second line
Treatment with pemetrexed versus other available active therapies or placebo in stage III–IV NSCLC Patient follow-up [12 months No radiotherapy evaluation
Al-Saleh et al. [22]
based on the use of concomitant chemotherapy. In all cases, fewer statistically significant adverse reactions were reported in patients treated with pemetrexed, especially hematological reactions with the exception of liver toxicity. Lastly, in the meta-analysis included in the review, after an initial analysis of several controlled RCTs, this showed a tendency of increased OS in patients treated with PMX, although these results were not statistically significant. The authors suggest that it may be due to the heterogeneity of the different studies. By excluding the study that evaluated PMX versus placebo from the meta-analysis, the OS was similar for pemetrexed and other schemes used both for first and second-line treatment, with the exception of patients with non-squamous histology, in which differences were found in favor of treatment with pemetrexed. Excluding the same study from the meta-analysis, AlSaleh et al. [22] found a low incidence of adverse events in patients treated with PMX, highlighting the low hematological toxicity and lower neutropenia of this drug, although there was not a statistically significant greater increase in liver enzymes.
every 21 days
(b) Docetaxel 75 mg/m2
(a) Pemetrexed 500 mg/m2
In second line treatment
Discussion
Hanna et al. [21]
Clinical trials of pemetrexed in second-line treatment option
Significant weight loss (10 % body weight in the preceding 6 weeks)
Uncontrolled pleural effusions
Prior docetaxel or pemetrexed treatment
24
Treatment with only one prior chemotherapy regimen for advanced disease (for neoadjuvant or adjuvant therapy)
Patients not amenable to curative therapy
Inclusion criteria of every study Patient follow-up (months) Patients (N) Study design Therapy: study arm/control arm Study
Table 3 continued
Performance status 0–2
Grade [3 peripheral neuropathy
Exclusion criteria of every study
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Over recent years, there has been a marked increase in the number of publications on studies evaluating the efficacy of pemetrexed in NSCLC in different lines. At the same time, numerous clinical guidelines have incorporated this treatment among the recommended treatment options, although the selection of patients to be treated varies amongst them and in many cases the recommendations are made based on expert opinion, without objective data on improvements based on this practice existing. This, coupled with the fact that this drug has a major economic impact as LC is a disease with high incidence and
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First-line therapy: induction
Scagliotti et al. [13]
Al-Saleh et al. [22]
Rodrigues-Pereira et al. [17]
Socinski et al. [16]
Gronberg et al. [15]
Study objective
Study
Table 5 Efficacy results of PMX in NSCLC
10.4 9.4
Large cell Squamous
10.8
6.7
10.9
2
3.2 12.2 3.6
SWT 3–4 SWT 4 SWT clinica
HR (OS) favours experimental group = 0.88 [0.81-1.08]
0.7
5.5
DoR (months)
1.3
5.4
6.0
5.8
14.7
14.9
Docetaxel/Cb
PFS (months)
4.1
OS (months)
Pemetrexed/Cb
6
9.2
12.7
CbD
Time to progression (months)
0.05
CbP
0.63 0.77
5.5
4.7
10.8
p
CbD
7.0
p
4.4
5.3
9.4
CG
PSF (months) CP
CbP
7.3
Non-squamous
CG
0.05
0.03
0.03
0.005
p
7.8 7.5 OS (months)
Overall population
CP
OS (months)
12.6
Adenocarcinoma
10.4
10.3
10.3 11.8
CG
CP
OS (months)
Non-squamous
Overall population
Efficacy variables Rate response (%) p \0.001
2.8 19.4 55.6 5.5
Partial response (%) Stable disease (%) Response duration (months)
CbP
\0.001
\0.001
\0.001
0.643
0.801
0.933
p HR
5.4
30
27.1
0
CbD
Rate response
28.2
CG
Complete response (%)
30.6
CP
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15.5 16.8 8.4 9.9
Non-squamous Adenocarcinoma Large cell Squamous
10.8
7.9
11.5
10.3
10.6
0.678
0.964
0.026
0.02
0.012
2.4
4.5
4.6
4.4
4.0
8.3 3.4 4.6
OS median (months) Time to progression (months) DoR (months)
2.9
PFS median (months)
Pemetrexed
4.1
74
79
\0.001
PMX
p [0.01
Placebo
PMX 2.6
6.51 PFS (months)
3 69 72 28
Partial response (%) Stable disease (%) Disease control (%)# Progression disease(%)
PMX 0
5.3
3.5
7.9
2.9
Docetaxel
35
33
33
33
33
Placebo
39
60
59
0.6
0
Placebo
Rate response (%)*
35
Complete response(%)
3.98
3.71
5.75
Overall quality of life
0.896
Interference with daily life Exitus (%) p
61
\0.0001 46
58
\0.0001 0.125
52
\0.0001
Placebo
Placebo
2.5
1.5
2.7
1.8
2.0
Rate response (%) PMX
p
Pemetrexed
* % Patients with complete response ? partial response ? stable disease
13.4
Placebo
PSF (months) PMX
p
PMX
Placebo
OS (months) Overall population
Efficacy variables
p
0.427
0.721
0.759
p
0.015
0.00
0.039
0.18
NE
p
0.512
\0.267
pHR
[0.999
0.67
\0.0001
\0.0001
\0.0001
#
Disease control (6 weeks)
* Patients with Complete response ? Partial responsel ? stable disease
Cb carboplatin, CP cisplatin/pemetrexed, CG cisplatin/gemcitabine, CbP carboplatin/pemetrexed, CbG carboplatin/gemcitabine, CbD carboplatin/docetaxel, PMX pemetrexed, DoR response duration. QoL quality of life, OS Overall survival, PFS survival progression free, pHRp Hazard ratio, R response, SWT survival without toxicity
Hanna et al. [21]
Paz-Ares et al. [20]
Second line therapy
First-line therapy: maintenance
Ciuleanu et al. [18]
Belani et al. [19]
Study objective
Study
Table 5 continued
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prevalence, and the cost of treatment is six times greater with pemetrexed as opposed to standard therapy, which means that there is a need for constant updating of the available evidence on efficacy and safety of this drug. In the case of first-line induction treatment in LC, at present, standard therapy according to the NCCN [11] remains the association of a platinum derivative with other drugs, but the results in terms of OS of such schemes remain poor, with an OS rate of around 7–12 months. Of the trials evaluated, only Scagliotti et al. [13] demonstrated an improvement in survival in the subgroup of non-squamous cell NSCLC, but not for the rest of the population studied. These results are consistent with the recently demonstrated fact that there are differential expressions of thymidylate synthase, the PMX target enzyme, depending on tumor histology [23]. However, the results seen by Gronberg et al. [15] in 2009 contradict this thesis, by failing to demonstrate greater efficacy in the subgroup of non-squamous histology when comparing carboplatin/ PMX with carboplatin/gemcitabine. Among the reasons that could explain this fact are the longer follow-up period for the first case, which can lead to worse outcomes, or that the small sample size used by Gronberg et al. [15] may have made it more difficult to find significant differences. Similarly, differences in the patients’ functional status at baseline could have determined the results obtained. Socinski et al. [16] did find significant differences in disease control when treating patients with carboplatin/PMX versus carboplatin/docetaxel, although this fact did not, in this case, lead to improvements in OS. This may be because the treatment arm Cb/PMX had a higher proportion of patients with squamous histology, which was seen not to have favorable results in previous RCTs. Indeed, when the hazard ratio was calculated according to tumor histology, superiority was observed in the subgroup of patients with non-squamous histology. Only a year later, Rodrigues-Pereira et al. [17], when comparing these same two treatment regimens only in patients with non-squamous histology, found no difference in terms of efficacy between the two arms, even considering that patients in the group that received pemetrexed, completed more cycles of treatment with fewer dose reductions for toxicity than the control group. However, Al-Saleh et al. [22], in their meta-analysis on February 2012, demonstrated the non-inferiority of pemetrexed in OS, both as first and second-line treatment, including the possible variation of efficacy results due to tumor histology. This finding is consistent with the basis of the recommendations of NICE 2011 [24], which reflect the possibility of using PMX ? Platinum as first-line treatment only in NSCLC patients diagnosed with non-squamous histology. Meanwhile, when evaluating safety, we should note that many of the articles mentioned demonstrate a clearly favorable safety profile for the treatment arms containing
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PMX, while highlighting the lower incidence of hematological reactions. Only Socinski et al. [16] include data of greater hematologic toxicity in said arm, probably because the number of cycles of chemotherapy received by the patients in the docetaxel arm was less than those receiving PMX. Thus, in 2009, Scaliotti et al. [25] found it necessary to perform a long-term analysis of the risk–benefit of pemetrexed as first-line treatment. In this respect, in their study in 2008, they assessed the degree of toxicity free survival of patients included in the study and the results obtained were significantly better for the pemetrexed arm in the subgroup of patients with non-squamous histology. During the conduct of this study, Li et al. [26] published a meta-analysis which evaluated the combination of cisplatin and PMX in first-line treatment of advanced NSCLC. Unlike the results of the meta-analysis included in this review for this line of treatment [22], better and significant survival outcomes were seen with acceptable toxicity with pemetrexed in patients with non-squamous histology. This could be due to the difference in the overall sample size of the articles included in both meta-analyses which studied pemetrexed as first-line treatment, which was greater in the case of Li et al. [26], including clinical trials studying the first-line treatment with monotherapy pemetrexed maintenance evaluated the drug versus placebo after induction therapy with platinum doublets. In this instance, this comparison versus placebo is considered adequate, given that in normal clinical practice, these patients receive support therapy, until there is disease progression. The study carried out by Ciuleanu et al. [18] showed a better efficacy profile for patients treated with PMX in respect to OS, PFS and response rate, both for the general population and the subgroup with non-squamous histology. Belani et al. [19] supplemented said study, assessing quality of life of these same patients, but their findings were comparable in both treatment arms. On the other hand, recently, Paz-Ares et al. [20] showed a significant increase in PFS in the PMX arm and a significant improvement in disease control compared to a non active comparator. In all cases, it was seen that PMX had a significantly adverse toxicity profile, as was expected. In any case it is an acceptable toxicity that makes it possible to assess risk/benefit, if any. In the case of second-line treatment, the limited data available suggests that this therapy provides no benefit to patients. As such disparate data is available, and therefore there is uncertainty as to the efficacy/safety of this treatment, coupled with its high economic impact, it is essential to carry out cost-effectiveness studies to position this drug in habitual clinical practice. In this respect, although there are few articles with cost analyses, there are articles with high quality method such
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as the article by Carlson et al. [27], which evaluated the incremental cost of second-line treatment of NSCLC with pemetrexed versus erlotinib versus docetaxel. The authors conclude that erlotinib treatment is more cost-effective. Similarly, in 2010, Fleeman et al. [28] and Greenhalgh et al. [29] carried out a review of cost-effectiveness in the use of pemetrexed in locally advanced or metastatic NSCLC in first-line induction treatment and maintenance, respectively. In both studies, it is concluded, that, due to the increased cost of using this drug, it should be used only if the tumor histology is predominantly non-squamous cells, since OS benefit has been found in these cases. Furthermore, Greenhalgh et al. [29] did not consider the use of pemetrexed appropriate for maintenance treatment if it had been previously administered in an induction cycle. These findings could be modified when generic alternatives of pemetrexed were available on the market after pemetrexed patent expires (in December 2015 in USA), as the economic impact of its use would be significantly reduced and this could affect the place of this drug in lung cancer treatment considerably.
Conclusions Due to the disparity of results available, the difficulty of identifying populations in which there is a clear benefit, the magnitude of this benefit and the budget impact of the inclusion of this drug, it is necessary to conduct further clinical trials to clearly determine the place of this drug in LC treatment and to establish a firm position. The results suggest that the subgroup of patients with non-squamous histology tumors would benefit most of the treatment with pemetrexed. At the same time, additional costeffectiveness/efficacy studies need to be conducted. Acknowledgments The authors wish to acknowledge their cooperation with other parts of the Pharmacy Department of Virgen del Rocio Hospital and to Postgraduate Department of the Faculty of Pharmacy from the University of Granada. Funding This study was supported by the Health Department of the Spanish Government. (Investigacio´n Clı´nica Independiente. Ministerio de Sanidad y Polı´tica Social). Conflicts of interest of interest.
The authors declare that they have no conflicts
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25. Scagliotti GV, ParK K, Patil S, Rolski J, Goksel T, Martins R, et al. Survival without toxicity for cisplatin plus pemetrexed versus cisplatin plus gemcitabine in chemonaı¨ve patients with advanced non-small cell lung cancer: a risk-benefit analysis of a large phase III study. Eur J Cancer. 2009;45:2298–303. 26. Li M, Zhang Q, Fu P, Li P, Peng A, Zhang G, et al. Pemetrexed plus platinum as the first-line treatment option for evinced nonsmall cell lung cancer: a meta-analysis of randomized controlled trials. PLoS One. 2012;7:e37229. 27. Carlson J, Reyes C, Oestreicher N, Lubeck D, Ramsey SD, Veenstra DL. Comarative clinical and economic outcomes of treatments for refractory non-small-cell lung cancer (NSCLC). Lung Cancer. 2008;61:405–15. 28. Fleeman N, Bagust A, McLeod C, Greenhalgh J, Boland A, Dundar Y, et al. Pemetrexed for the first-line treatment of locally advanced or metastatic non-small cell lung cancer. Health Technol Assess. 2010;14:47–53. 29. Greenhalgh J, Mc Leod C, Bagust A, Boland A, Fleeman N, Dundar Y, et al. Pemetrexed for the maintenance treatment of locally advanced or metastatic non-small cell lung cancer. Health Technol Assess. 2010;14:47–53.
REVIEW ARTICLE
Systematic review of efficacy and safety of pemetrexed in non-small-cell-lung cancer Maria Antonia Pe´rez-Moreno • Mercedes Galva´n-Banqueri • Sandra Flores-Moreno ´ ngela Villalba-Moreno • Jesu´s Cotrina-Luque • Francisco Javier Bautista-Paloma A
•
Received: 22 August 2013 / Accepted: 5 February 2014 Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie 2014
Abstract Introduction Lung cancer accounts for 20 % of cancer deaths in Spain. The most frequent subtype (87 %) is non-small cell lung cancer (NSCLC). Pemetrexed is a recently marketed drug added to NSCLC therapeutic arsenal. It seems to have become one of the most used options for the treatment of this condition over the last 3 years. Aim of the review To evaluate the efficacy and safety of pemetrexed in NSCLC, in the different therapy lines. Method A systematic search of published literature was conducted using the main databases (MEDLINE, EMBASE, the Cochrane Library and the Center for Reviews and Dissemination) and subsequently a search of referenced literature was performed. We included clinical trials, meta-analyses and systematic reviews. The evaluation of the quality of the articles was performed by pairs using specific assessment scales, Critical Appraisal Skills Program (CASP) adapted for CASP Spain. Then we extracted data on efficacy and safety according to the treatment line assessed. Results We identified 277 references. Finally, nine clinical trials and a meta-analysis complied with inclusion criteria. In first-line induction, treatment with pemetrexed associated with a platinum was similar in terms of efficacy to other alternative chemotherapy regimens, except in patients with non-squamous histology, in whom survival was higher in the experimental group. In maintenance treatment, greater efficacy was seen with pemetrexed in patients with non-
Electronic supplementary material The online version of this article (doi:10.1007/s11096-014-9920-2) contains supplementary material, which is available to authorized users. M. A. Pe´rez-Moreno (&) M. Galva´n-Banqueri ´ . Villalba-Moreno J. Cotrina-Luque S. Flores-Moreno A F. J. Bautista-Paloma Pharmacy Department, Hospital Universitario Virgen Del Rocı´o, Manuel Siurot s/n., 41013 Seville, Spain e-mail: [email protected]
squamous histology. In second-line treatment, there were no significant differences in terms of efficacy and safety for pemetrexed treatment versus other chemotherapy options. The most frequent adverse reactions were: hematological, gastrointestinal and neurological. All were significantly less frequent with pemetrexed versus other alternative therapies, except for liver toxicity. Conclusions Due to the high degree of uncertainty as to its efficacy in certain subgroups of patients, including conflicting data; to its recent incorporation, and therefore lack of safety data in the medium and long term, and the high budgetary impact of its incorporation into health systems, it seems reasonable to optimize its use, identifying those patients who may benefit most. Keywords Cancer Efficacy Non-small-cell lung cancer Pemetrexed Safety Systematic review
Impacts on practice •
•
Due to its high economic and care impact for public health systems, it is important to optimize the use of pemetrexed. There is a high level of uncertainty of the efficacy of pemetrexed in certain subgroups of patients, and clinicians should discuss if the drug should be used so frequently.
Introduction Lung cancer (LC) is the most common cancer in the world and was the most commonly diagnosed cancer as well as the leading cause of cancer death in males in 2008 globally. Among females, it was the fourth most commonly diagnosed
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cancer and the second leading cause of cancer death. LC accounted for 13 % (1.6 million) of the total cases and 18 % (1.4 million) of the deaths in 2008. In Western Europe, its incidence rate in males and females was 44.7 and 16.7 per population of 100,000 people respectively in that year [1]. In Spain, cancer accounts for 20 % of deaths, with an incidence rate of 20,000 cases per year. Incidence varies depending on age and gender. Thus, in men over 70 years of age, the incidence is 90 times higher than that observed in those under 45 years, and it is higher in men than in women. Mortality is also higher in men compared to women, although in the latter, mortality has increased significantly in recent years [2]. Epidemiological studies show that there are several different risk factors that predispose the development of this type of tumor, such as tobacco, female gender [3], diet [4], occupational factors [5] and genetic predisposition [6], with tobacco being the most significant (80–90 % of lung cancers are attributable to tobacco). In spite of the addition of new drugs to the therapeutic arsenal in recent years, disease prognosis continues to be poor, with response rates to first-line chemotherapy (Ch) of 20–40 % and a median survival of 7–12 months. Of all LC subtypes, non-small cell lung cancer (NSCLC) is the most common, accounting for 87 % of all cases. Different histologies are included in this subgroup, mainly epidermoid/squamous, adenocarcinoma and large cell carcinoma or undifferentiated carcinoma [7]. Diagnosis of the disease is usually at advanced stages of the disease (locally advanced or metastatic), mainly because the symptoms principally appear at late stages and there is no effective screening method [8]. The therapeutic approach depends on the stage of disease at diagnosis. In the case of advanced or metastatic NSCLC, the most widely used chemotherapy regimens for front-line treatment (induction) are combinations of platinum (cisplatin or carboplatin) with any of the so-called third-generation cytostatic agents (gemcitabine, vinorelbine or taxanes) [9]. Recently, new drugs of the so-called targeted therapies group have come onto the market, such as bevacizumab, which can be of benefit in selected populations, although further information is necessary [10, 11]. International guidelines suggest that patients who progress to a first line of treatment and maintain an acceptable general state of health may improve disease-related symptoms and survival [11] with chemotherapy with erlotinib or docetaxel, depending on the tumor subtype. In 2004, pemetrexed was approved, an anti-cancer agent of the group of inhibitors of the thymidylate synthetase enzyme. It is an anti-metabolite that inhibits several enzymes acting in the folate synthesis, hence disrupting essential metabolic processes necessary for folate-dependent cell replication [12]. At present, three indications are approved by regulatory agencies in locally advanced/metastatic
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NSCLC: combining with platinum in first-line induction treatment, as monotherapy, in first-line maintenance treatment and as second-line treatment. In all three situations cases with predominantly squamous histology are excluded. Despite its recent appearance on the market, there are numerous publications, although results are not always consistent. In fact, this fact together with the high economic and care impact involved in its use (the cost per patient is six times that of current treatment), makes it necessary to perform a systematic assessment of its efficacy and safety so as to identify the patient population that may significantly benefit from this therapy.
Aim of the study For the abovementioned reasons, the main aim of this review was to evaluate the efficacy and safety of pemetrexed therapy in adult patients with advanced stage NSCLC. And the specific objectives were to evaluate the efficacy of pemetrexed in NSCLC in each of the approved indications (first-line induction, maintenance and second-line), according to histology (squamous/epidermoid adenocarcima or large cell) and to assess safety according to concomitant therapy administered.
Method We conducted a systematic search of the literature published in major biomedical databases in the last 8 years (between April 2004 and April 2012). We reviewed the following databases: MEDLINE, EMBASE, the Cochrane Library and the Center for Reviews and Dissemination (CRD) database. The search strategy is summarized in Fig. 1. The search was completed by consulting various websites of drug regulatory agencies, scientific societies and other bodies that could contain information related to the subject. We also performed a search for new references in the literature of the documents found. The selection of the articles was performed based on inclusion/exclusion criteria listed in Table 1. In a first phase, we deleted duplicates and selected (by title and abstract) articles that met the inclusion criteria, reviewing the full text of those we considered doubtful. This procedure was performed independently by paired researchers; disagreements were resolved by a third party. Subsequently, we carried out a critical reading of selected full-text articles. Quality assessment was conducted using specific assessment scales Critical Appraisal Skills Program (CASP) adapted for CASP Spain (CASPe). The quality of the studies was established by scoring
Int J Clin Pharm Fig. 1 Literature search
LITERATURE SEARCH
MEDLINE (PUBMED) (pemetrexed OR Alimta) AND non-small cell lung cancer AND (efficacy OR safety) Medline limits
EMBASE #1 “Pemetrexed” OR “Alimta” #2 “efficacy” OR “safety” #3 'randomized controlled trial'/de OR 'randomization'/ de OR 'single blind procedure'/de OR ' double blind procedure'/de OR 'crossover procedure'/de OR 'placebo'/de OR random*:de,it,ab,ti OR placebo:de,it,ab,ti OR blind:de,it,ab,ti NOT (letter:it OR editorial:it OR note:it OR ('animal'/de NOT ('human'/de AND 'animal'/de))) #4'meta analysis'/de OR 'systematic review'/de OR 'meta' NEXT/3 'analysis' OR metaanalys* OR 'systematic' NEXT/3 'review' OR 'systematic' NEXT/3 'overview' NOT (letter:it OR editorial:it OR note:it OR ('animal'/de NOT ('human'/de AND 'animal'/de))) #5 #1 AND #2 AND (#3 OR #4) AND [embase]/lim
CENTER FOR REVIEWS AND DISSEIMINATION (CRD) a) Pemetrexed AND non-small cell lung cancer AND efficacy (2004-2012) b) Pemetrexed AND non-small cell lung cancer AND safety (2004-2012)
(("pemetrexed"[Supplementary Concept] OR "pemetrexed"[All Fields]) OR ("pemetrexed"[Supplementary Concept] OR"pemetrexed"[All Fields] OR "alimta"[All Fields])) AND ("carcinoma, non-small-cell lung" [MeSH Terms] OR ("carcinoma"[All Fields] AND "non-small-cell"[All Fields] AND "lung"[All Fields]) OR "non-small-cell lung carcinoma"[All Fields] OR ("non"[All Fields] AND"small"[All Fields] AND "cell"[All Fields] AND "lung"[All Fields] AND "cancer"[All Fields]) OR "non small cell lung cancer" [All Fields]) AND (efficacy[All Fields] OR ("safety"[MeSH Terms] OR "safety"[All Fields])) AND (("2004/04/01"[PDAT] : "2012/04/30"[PDAT]) AND "humans"[MeSH Terms] AND (systematic[sb] OR Meta-Analysis[ptyp] OR Clinical Trial[ptyp] OR Randomized Controlled Trial[ptyp] OR Clinical Trial, Phase II[ptyp] OR Clinical Trial, Phase III[ptyp]) AND (English[lang] OR Spanish[lang]))
Table 1 Studies selection criteria Inclusion criteria
Exclusion criteria
Population: age 18 years or older patients Study design: systematic review, randomised controlled clinical trials and metanalysis
Case reports, experts opinions, retrospective studies, no randomised clinical trials and other differents designs
Study arm: Treatment with pemetrexed versus other available therapies
If pemetrexed was administered in both treatments arms
Study variables: OS, PFS, quality of live, response rate and adverse events
Study of differents doses that those included in EPARproduct information
Languages: English or Spanish
Other languages
positive responses with a 1 and negative or doubtful (no explicit information) 0. We considered: high quality = 6; medium–high quality = 5, medium quality = 4, medium– low quality = 3 and low quality \3. We designed an ad hoc table where information was collected on the design of each of the selected studies, including: study design, inclusion and exclusion criteria, sample size, patients’ follow-up period and treatment regimens evaluated. To ensure reproducibility and minimize bias, methodological doubts were resolved by discussion with a second researcher who analyzed the data independently.
Subsequently, a table was drawn up to collect data on the efficacy and safety of each of the randomized clinical trials (RCTs). Variables to assess efficacy were: overall survival (OS), progression-free survival (PFS), survival without toxicity (SWT), response rate [Complete response rate (CR), partial response (PR) and stable disease (SD)], progression-free survival quality of life and duration of the response. For safety assessment, the most frequent adverse reactions were collected (MFAR) and grouped by system and severity. In the safety analysis, we took into account concomitant Ch administered, considering it a factor in the incidence of some MFAR. The statistical analysis was carried out using Excel 2007 and IBM SPSS Statistics software, version 19. Qualitative variables were shown as percentages and quantitative variables as central measures (mean) with dispersion measures (standard deviation, range).
Results We identified a total of 275 articles in different databases (96 in MEDLINE, 164 in EMBASE, 14 in the database of the Center for Reviews and Dissemination, 1 in the Cochrane Library) and 2 articles after consulting the referenced literature. Figure 2 shows the flowchart of the
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Int J Clin Pharm Fig. 2 Articles selection after literature search
Potentially relevant citations identified and screened for retrieval (n=275)
Potentially relevant citations after remove duplicated citations (n=238)
Potentially relevant citation excluded by tittle and abstract (n=166)
Manual search (n=2)
Potentially relevant citation excluded by full- text articles (n=64)
Articles included (n=10)
Table 2 Studies quality and CASPe score Study
CASPe score
Quality
Scagliotti et al. [13] Novello´ et al. [14]
4 4
Moderate Moderate
Gronberg et al. [15]
5
Moderate-high
Socinski et al. [16]
3
Moderate-lowa
Rodrigues-Pereira et al. [17]
4
Moderate
Ciuleanu et al. [18]
6
High
Belani et al. [19]
6
High
Paz-Ares et al. [20]
6
High
Hanna et al. [21]
5
Moderate-high
a
Some questions are not clear
process for selecting documents during the systematic review. Finally, we selected 10 articles, 9 randomized controlled clinical trials and a meta-analysis article. Of the selected RCTs, 5 evaluated the use of pemetrexed as first-line induction treatment, three as first-line maintenance and one as second-line treatment. Meta-analysis analyzed the efficacy and safety of the three treatment lines above. The CASPe score obtained and the quality of the RCTs included are shown in Table 2. Most of the articles were of medium to high quality. Tables 3 and 4 shows the characteristics of the articles selected and the populations included. Generally the
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population had a good functional status (ECOG 0-1), with a mean age of 61 years. Efficacy results are shown in Table 5. Pemetrexed as first-line induction treatment was compared with gemcitabine and docetaxel. Scagliotti et al. [13] found no superiority of pemetrexed over OS or PFS in the overall population. When a subgroup analysis was performed, different results were found in the subgroup with squamous histology, Gronberg et al. [15] did not demonstrate greater efficacy in this subgroup of patients, while Socinski et al. [16] found significant differences in the control of OS and disease. Rodrigues-Pereira et al. [17], in patients with nonsquamous histology, found no differences as to efficacy either. Ciuleanu et al. [18], in their evaluation of pemetrexed as a maintenance therapy, showed higher OS, PFS and response rate for both the overall population and the subgroup of patients with non-squamous histology. Paz-Ares et al. [20] showed improvements in PFS (pending publication of OS data) and benefits in disease control. In contrast, Belani et al. [19] found no significant differences in quality of life. In all cases, the comparator was placebo. Lastly, when comparing the efficacy of pemetrexed versus docetaxel in second-line treatment, Hanna et al. [21] found no difference in OS, PFS, response rate, or quality of life. Table S1 of electronic supplementary material shows the security variables collected, grouped by system and
Socinski et al. [16]
Gronberg et al. [15]
Novello´ et al. [14]
Scagliotti et al. [13]
Induction
Study
Every 21 days until 6 cycles
b) Pemetrexed 500 mg/m2 day 1
(a) Gemcitabine 1,250 mg/ m2 days 1 and 8
Cisplatin 75 mg/m2 day 1 plus
Every 21 days until 6 cycles
(b) Pemetrexed 500 mg/m2 day 1
(a) Gemcitabine 1,250 mg/m2 days 1 and 8
Cisplatin 75 mg/m2 day 1 plus:
Every 21 days until 6 cycles
a) Gemcitabine 1,250 mg/ m2 days 1 and 8 (b) Pemetrexed 500 mg/ m2 day 1
Cisplatin 75 mg/m2 dı´a1 ma´s
Every 21 days until 6 cycles
(b) Pemetrexed 500 mg/m2 day 1
(a) Gemcitabine 1,250 mg/ m2 days 1 and 8
Cisplatin 75 mg/m2 day 1 plus
Therapy: study arm/control arm
Multicentre randomized controlled phase III trial
Multicentre randomized openlabel controlled phase III trial
Multicentre randomized openlabel controlled phase III trial
Multicentre randomized openlabel controlled phase III trial
Study design
Inability to take corticosteroid drugs, folic acid, or vitamin B12 Acute myocardial infarction in the previous 6 months Significant weight loss (10 % body weight in the preceding 6 weeks)
Treatment with warfarine No previous chemotherapy, radiotherapy, inmunotherapy or biologic therapy
Other severe systemic disease Life expectancy [12 weeks
Pelvic radiation One or more measurable lesions (RECIST 1.0)
Patients eligible for radiotherapy curative
Inability to take corticosteroid drugs, folic acid, or vitamin B12
An inability to interrupt NSAIDs
Grade [1 peripheral neuropathy
Inability to take corticosteroid drugs, folic acid, or vitamin B12
An inability to interrupt NSAIDs
Grade [1 peripheral neuropathy
Exclusion criteria of every study
Performance status 0–1
Performance status 0–1
One or more measurable lesions (RECIST 1.0)
Non-squamous tumor histology
Without previous ratiotherapy (or 4 weeks before at least)
Performance status 0–1
One or more measurable lesions (RECIST 1.0)
No previous systemic chemotherapy for NSCLC
Without previous ratiotherapy (or 4 weeks before at least)
Performance status 0–1
One or more measurable lesions (RECIST 1.0)
No previous systemic chemotherapy for NSCLC
Inclusion criteria of every study
-70
312
13
24
24
Patient follow-up (months)
-72
-67
209
217
-219
436
1,669 (ratio 1:1)
1,669 (ratio 1:1)
Patients (N)
Table 3 Characteristics of studies included: clinical trials of pemetrexed in first-line treatment option (induction and maintenance) and clinical trials of pemetrexed in second-line treatment option
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123
Paz-Ares et al. [20]
Belani et al. [19]
Ciuleanu et al. [18]
Maintenance
RodriguesPereira et al. [17]
Study
every 21 days
(b) placebo ? supportive care
(a) PMX 500 mg/m2 ?supportive
(randomized; ratio 2:1)
*Maintenance phase
CDDP 75 mg/m ?PMX 500 mg/m2 every 21 days (4 cycles)
2
(non randomized)
*Induction phase
Every 21 days. Both groups received supportive care
(b) Placebo
(a) Pemetrexed 500 mg/m2
After completion of four cycles of platinum-based induction therapy:
Every 21 days. Both groups received supportive care
(b) Placebo
(a) Pemetrexed 500 mg/m2
After completion of four cycles of platinum-based induction therapy:
Every 21 days until 6 cycles
(b) Docetaxel 75 mg/m2
(a) Pemetrexed 500 mg/m2
Carboplatin AUC5 plus
Therapy: study arm/control arm
Table 3 continued
Multicentre randomized double-bind placebo controlled phase III trial
Multicentre randomized double-bind placebo controlled phase III trial
539 (ratio 2:1)
663 (ratio 2:1)
663 (ratio 2:1)
211 (ratio 1:1)
Multicentre randomized openlabel controlled phase III trial
Multicentre randomized double-bind placebo controlled phase III trial
Patients (N)
Study design
Until progression or death
Until progression
Until progression
Until grade 3/4 toxicity
Patient follow-up (months)
Four cycles of induction therapy with pemetrexed plus cisplatin with partial/complete response
Performance status 0–1
*Maintenance phase:
One or more measurable lesions
No previous systemic chemotherapy for NSCLC
*Induction phase
Without previous ratiotherapy (or 4 weeks before at least) No progression after completion of four cycles of platinum-based induction therapy
Tumour histology predominantly squamous cell, mixed small cell or both
of other antitumour therapy
Concurrent administration
Uncontrolled cardiac disease
Inability to take corticosteroid drugs, folic acid, or vitamin B12 Pleural effusions or positive supraclavicular lymph nodes Performance status 0–1
Other previous malignancy
Life expectancy [12 weeks
No progression after completion of four cycles of platinum-based induction therapy
Uncontrolled cardiac disease
Inability to take corticosteroid drugs, folic acid, or vitamin B12
Without previous ratiotherapy (or 4 weeks before at least)
Other previous malignancy
Performance status 0–1
Inability to take corticosteroid drugs, folic acid, or vitamin B12
An inability to interrupt NSAIDs
Grade [4 peripheral neuropathy
Other severe systemic disease or infectious active
Other previous malignancy
Exclusion criteria of every study
Life expectancy [12 weeks
Surgery 4 weeks before (at least)
No previous systemic chemotherapy for NSCLC
Life expectancy [8 weeks
Performance status 0–2
One or more measurable lesions (RECIST 1.0)
Non-squamous tumor histology
Inclusion criteria of every study
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571 Multicentre randomized openlabel controlled phase III trial
An inability to interrupt NSAIDs
Table 4 Characteristics of studies included: meta-analysis Line of treatment option
Studies included (N)
Patients (N)
Inclusion criteria of the meta-analysis
First line (induction)
5
3,541
Randomized controlled clinical trials
First line (maintenance) Second line
Treatment with pemetrexed versus other available active therapies or placebo in stage III–IV NSCLC Patient follow-up [12 months No radiotherapy evaluation
Al-Saleh et al. [22]
based on the use of concomitant chemotherapy. In all cases, fewer statistically significant adverse reactions were reported in patients treated with pemetrexed, especially hematological reactions with the exception of liver toxicity. Lastly, in the meta-analysis included in the review, after an initial analysis of several controlled RCTs, this showed a tendency of increased OS in patients treated with PMX, although these results were not statistically significant. The authors suggest that it may be due to the heterogeneity of the different studies. By excluding the study that evaluated PMX versus placebo from the meta-analysis, the OS was similar for pemetrexed and other schemes used both for first and second-line treatment, with the exception of patients with non-squamous histology, in which differences were found in favor of treatment with pemetrexed. Excluding the same study from the meta-analysis, AlSaleh et al. [22] found a low incidence of adverse events in patients treated with PMX, highlighting the low hematological toxicity and lower neutropenia of this drug, although there was not a statistically significant greater increase in liver enzymes.
every 21 days
(b) Docetaxel 75 mg/m2
(a) Pemetrexed 500 mg/m2
In second line treatment
Discussion
Hanna et al. [21]
Clinical trials of pemetrexed in second-line treatment option
Significant weight loss (10 % body weight in the preceding 6 weeks)
Uncontrolled pleural effusions
Prior docetaxel or pemetrexed treatment
24
Treatment with only one prior chemotherapy regimen for advanced disease (for neoadjuvant or adjuvant therapy)
Patients not amenable to curative therapy
Inclusion criteria of every study Patient follow-up (months) Patients (N) Study design Therapy: study arm/control arm Study
Table 3 continued
Performance status 0–2
Grade [3 peripheral neuropathy
Exclusion criteria of every study
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Over recent years, there has been a marked increase in the number of publications on studies evaluating the efficacy of pemetrexed in NSCLC in different lines. At the same time, numerous clinical guidelines have incorporated this treatment among the recommended treatment options, although the selection of patients to be treated varies amongst them and in many cases the recommendations are made based on expert opinion, without objective data on improvements based on this practice existing. This, coupled with the fact that this drug has a major economic impact as LC is a disease with high incidence and
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123
First-line therapy: induction
Scagliotti et al. [13]
Al-Saleh et al. [22]
Rodrigues-Pereira et al. [17]
Socinski et al. [16]
Gronberg et al. [15]
Study objective
Study
Table 5 Efficacy results of PMX in NSCLC
10.4 9.4
Large cell Squamous
10.8
6.7
10.9
2
3.2 12.2 3.6
SWT 3–4 SWT 4 SWT clinica
HR (OS) favours experimental group = 0.88 [0.81-1.08]
0.7
5.5
DoR (months)
1.3
5.4
6.0
5.8
14.7
14.9
Docetaxel/Cb
PFS (months)
4.1
OS (months)
Pemetrexed/Cb
6
9.2
12.7
CbD
Time to progression (months)
0.05
CbP
0.63 0.77
5.5
4.7
10.8
p
CbD
7.0
p
4.4
5.3
9.4
CG
PSF (months) CP
CbP
7.3
Non-squamous
CG
0.05
0.03
0.03
0.005
p
7.8 7.5 OS (months)
Overall population
CP
OS (months)
12.6
Adenocarcinoma
10.4
10.3
10.3 11.8
CG
CP
OS (months)
Non-squamous
Overall population
Efficacy variables Rate response (%) p \0.001
2.8 19.4 55.6 5.5
Partial response (%) Stable disease (%) Response duration (months)
CbP
\0.001
\0.001
\0.001
0.643
0.801
0.933
p HR
5.4
30
27.1
0
CbD
Rate response
28.2
CG
Complete response (%)
30.6
CP
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15.5 16.8 8.4 9.9
Non-squamous Adenocarcinoma Large cell Squamous
10.8
7.9
11.5
10.3
10.6
0.678
0.964
0.026
0.02
0.012
2.4
4.5
4.6
4.4
4.0
8.3 3.4 4.6
OS median (months) Time to progression (months) DoR (months)
2.9
PFS median (months)
Pemetrexed
4.1
74
79
\0.001
PMX
p [0.01
Placebo
PMX 2.6
6.51 PFS (months)
3 69 72 28
Partial response (%) Stable disease (%) Disease control (%)# Progression disease(%)
PMX 0
5.3
3.5
7.9
2.9
Docetaxel
35
33
33
33
33
Placebo
39
60
59
0.6
0
Placebo
Rate response (%)*
35
Complete response(%)
3.98
3.71
5.75
Overall quality of life
0.896
Interference with daily life Exitus (%) p
61
\0.0001 46
58
\0.0001 0.125
52
\0.0001
Placebo
Placebo
2.5
1.5
2.7
1.8
2.0
Rate response (%) PMX
p
Pemetrexed
* % Patients with complete response ? partial response ? stable disease
13.4
Placebo
PSF (months) PMX
p
PMX
Placebo
OS (months) Overall population
Efficacy variables
p
0.427
0.721
0.759
p
0.015
0.00
0.039
0.18
NE
p
0.512
\0.267
pHR
[0.999
0.67
\0.0001
\0.0001
\0.0001
#
Disease control (6 weeks)
* Patients with Complete response ? Partial responsel ? stable disease
Cb carboplatin, CP cisplatin/pemetrexed, CG cisplatin/gemcitabine, CbP carboplatin/pemetrexed, CbG carboplatin/gemcitabine, CbD carboplatin/docetaxel, PMX pemetrexed, DoR response duration. QoL quality of life, OS Overall survival, PFS survival progression free, pHRp Hazard ratio, R response, SWT survival without toxicity
Hanna et al. [21]
Paz-Ares et al. [20]
Second line therapy
First-line therapy: maintenance
Ciuleanu et al. [18]
Belani et al. [19]
Study objective
Study
Table 5 continued
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prevalence, and the cost of treatment is six times greater with pemetrexed as opposed to standard therapy, which means that there is a need for constant updating of the available evidence on efficacy and safety of this drug. In the case of first-line induction treatment in LC, at present, standard therapy according to the NCCN [11] remains the association of a platinum derivative with other drugs, but the results in terms of OS of such schemes remain poor, with an OS rate of around 7–12 months. Of the trials evaluated, only Scagliotti et al. [13] demonstrated an improvement in survival in the subgroup of non-squamous cell NSCLC, but not for the rest of the population studied. These results are consistent with the recently demonstrated fact that there are differential expressions of thymidylate synthase, the PMX target enzyme, depending on tumor histology [23]. However, the results seen by Gronberg et al. [15] in 2009 contradict this thesis, by failing to demonstrate greater efficacy in the subgroup of non-squamous histology when comparing carboplatin/ PMX with carboplatin/gemcitabine. Among the reasons that could explain this fact are the longer follow-up period for the first case, which can lead to worse outcomes, or that the small sample size used by Gronberg et al. [15] may have made it more difficult to find significant differences. Similarly, differences in the patients’ functional status at baseline could have determined the results obtained. Socinski et al. [16] did find significant differences in disease control when treating patients with carboplatin/PMX versus carboplatin/docetaxel, although this fact did not, in this case, lead to improvements in OS. This may be because the treatment arm Cb/PMX had a higher proportion of patients with squamous histology, which was seen not to have favorable results in previous RCTs. Indeed, when the hazard ratio was calculated according to tumor histology, superiority was observed in the subgroup of patients with non-squamous histology. Only a year later, Rodrigues-Pereira et al. [17], when comparing these same two treatment regimens only in patients with non-squamous histology, found no difference in terms of efficacy between the two arms, even considering that patients in the group that received pemetrexed, completed more cycles of treatment with fewer dose reductions for toxicity than the control group. However, Al-Saleh et al. [22], in their meta-analysis on February 2012, demonstrated the non-inferiority of pemetrexed in OS, both as first and second-line treatment, including the possible variation of efficacy results due to tumor histology. This finding is consistent with the basis of the recommendations of NICE 2011 [24], which reflect the possibility of using PMX ? Platinum as first-line treatment only in NSCLC patients diagnosed with non-squamous histology. Meanwhile, when evaluating safety, we should note that many of the articles mentioned demonstrate a clearly favorable safety profile for the treatment arms containing
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PMX, while highlighting the lower incidence of hematological reactions. Only Socinski et al. [16] include data of greater hematologic toxicity in said arm, probably because the number of cycles of chemotherapy received by the patients in the docetaxel arm was less than those receiving PMX. Thus, in 2009, Scaliotti et al. [25] found it necessary to perform a long-term analysis of the risk–benefit of pemetrexed as first-line treatment. In this respect, in their study in 2008, they assessed the degree of toxicity free survival of patients included in the study and the results obtained were significantly better for the pemetrexed arm in the subgroup of patients with non-squamous histology. During the conduct of this study, Li et al. [26] published a meta-analysis which evaluated the combination of cisplatin and PMX in first-line treatment of advanced NSCLC. Unlike the results of the meta-analysis included in this review for this line of treatment [22], better and significant survival outcomes were seen with acceptable toxicity with pemetrexed in patients with non-squamous histology. This could be due to the difference in the overall sample size of the articles included in both meta-analyses which studied pemetrexed as first-line treatment, which was greater in the case of Li et al. [26], including clinical trials studying the first-line treatment with monotherapy pemetrexed maintenance evaluated the drug versus placebo after induction therapy with platinum doublets. In this instance, this comparison versus placebo is considered adequate, given that in normal clinical practice, these patients receive support therapy, until there is disease progression. The study carried out by Ciuleanu et al. [18] showed a better efficacy profile for patients treated with PMX in respect to OS, PFS and response rate, both for the general population and the subgroup with non-squamous histology. Belani et al. [19] supplemented said study, assessing quality of life of these same patients, but their findings were comparable in both treatment arms. On the other hand, recently, Paz-Ares et al. [20] showed a significant increase in PFS in the PMX arm and a significant improvement in disease control compared to a non active comparator. In all cases, it was seen that PMX had a significantly adverse toxicity profile, as was expected. In any case it is an acceptable toxicity that makes it possible to assess risk/benefit, if any. In the case of second-line treatment, the limited data available suggests that this therapy provides no benefit to patients. As such disparate data is available, and therefore there is uncertainty as to the efficacy/safety of this treatment, coupled with its high economic impact, it is essential to carry out cost-effectiveness studies to position this drug in habitual clinical practice. In this respect, although there are few articles with cost analyses, there are articles with high quality method such
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as the article by Carlson et al. [27], which evaluated the incremental cost of second-line treatment of NSCLC with pemetrexed versus erlotinib versus docetaxel. The authors conclude that erlotinib treatment is more cost-effective. Similarly, in 2010, Fleeman et al. [28] and Greenhalgh et al. [29] carried out a review of cost-effectiveness in the use of pemetrexed in locally advanced or metastatic NSCLC in first-line induction treatment and maintenance, respectively. In both studies, it is concluded, that, due to the increased cost of using this drug, it should be used only if the tumor histology is predominantly non-squamous cells, since OS benefit has been found in these cases. Furthermore, Greenhalgh et al. [29] did not consider the use of pemetrexed appropriate for maintenance treatment if it had been previously administered in an induction cycle. These findings could be modified when generic alternatives of pemetrexed were available on the market after pemetrexed patent expires (in December 2015 in USA), as the economic impact of its use would be significantly reduced and this could affect the place of this drug in lung cancer treatment considerably.
Conclusions Due to the disparity of results available, the difficulty of identifying populations in which there is a clear benefit, the magnitude of this benefit and the budget impact of the inclusion of this drug, it is necessary to conduct further clinical trials to clearly determine the place of this drug in LC treatment and to establish a firm position. The results suggest that the subgroup of patients with non-squamous histology tumors would benefit most of the treatment with pemetrexed. At the same time, additional costeffectiveness/efficacy studies need to be conducted. Acknowledgments The authors wish to acknowledge their cooperation with other parts of the Pharmacy Department of Virgen del Rocio Hospital and to Postgraduate Department of the Faculty of Pharmacy from the University of Granada. Funding This study was supported by the Health Department of the Spanish Government. (Investigacio´n Clı´nica Independiente. Ministerio de Sanidad y Polı´tica Social). Conflicts of interest of interest.
The authors declare that they have no conflicts
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