on Lung Function and Response Rate in EGFR ...

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“Impact of Smoking Cessation Treatment” on Lung Function and Response Rate in EGFR Mutated Patients: A Short-Term Cohort Study Aldo Pezzuto1, Luciano Stumbo2, Marco Russano2,*, Pierfilippo Crucitti3, Simone Scarlata4, Marco Caricato3 and Giuseppe TONINI2 1

Department of Thoracic and Cardiovascular science, Sant'Andrea Hospital, Sapienza University, Rome, Italy; 2Department of Medical Oncology, Campus Bio-Medico University, Rome, Italy; 3 Department of Surgery, Campus Bio-Medico University, Rome, Italy; 4Department of Geriatrics, Unit of Respiratory Pathophysiology, Campus Bio-Medico University, Rome, Italy Received: March 26, 2015; Accepted: July 28, 2015; Revised: August 4, 2015

Abstract: Background: Erlotinib is a validated drug “for the treatment of patients affected by advanced unresectable non small cell lung cancer (NSCLC) with EGFR mutations”. We want to focus Marco Russano on potential functional benefits deriving from a combined therapy containing TKI (erlotinib) and a nicotinic partial agonist (varenicicline) in smokers. Methods: we analyzed the records of patients affected by NSCLC treated undergoing “first line therapy with Erlotinib” and smoking cessation (with varenicicline). Response to therapy was evaluated by CT scan. Data concerning clinical history, smoking habit, nicotine dependence were collected after three months from the beginning of the recruitment. Pulmonary function tests including spirometry with pletismographic technique and exhaled carbon monoxide (CO) were performed with recording of resistances, flows, volumes. A group of ten current smokers affected by NSCLC with EGFR activating mutation and concurrent mild COPD undergoing anti-EGFR treatment without smoking cessation was used to compare clinical and functional data. A control group of NSCLC wild type with mild COPD undergoing smoking cessation was assessed for functional data. Results: Twenty-five patients were enrolled. All of them reported partial response at CT re-evaluation. All functional indexes and parameters were improved after combined treatment a significant increase of FEV1 level and a decrease of exhaled CO. In particular, a mean increase of FEV1 from 1.93 (SD 0.48) to 2.03(SD 0.46) liters was recorded. A notable reduction of sRAW (specific resistances) was also observed. The improvement of some parameters such as CO, heart rate (HR), sRAW and FEV1 resulted statistically significant. A better response to therapy was found “in the study group compared to the second group of mutated NSCLC patients”. In this second group, we also observed an improvement of functional obstructive parameters although it was less remarkable than study group. Only sRAW and FEF 25/75 were significantly increased. The group of NSCLC wild type undergoing only smoking cessation showed a lower increase of FEV1 by about 50 ml compared to the first group. Conclusion: The combination of anti-EGFR treatment and concurrent therapy for smoking cessation seems to be more effective than erlotinib alone in improving lung function and clinical response in advanced NSCLC patients with EGFR-mutations. It is conceivable that erlotinib may potentiate the action of varenicline.We have also outlined some relevant patents concerning varenicline and EGFR-TKI.

Keywords: EGFR mutation, erlotinib, NSCLC, smoking, spirometry, TKI, varenicline.

INTRODUCTION “Activating epidermal growth factor receptor (EGFR) mutations represent the first target for which specific tyrosine kinase inhibitors (TKIs) are clinically available for the personalized treatment of advanced non-small cell lung cancer (NSCLC) patients”[1]. In the last years, “three randomized Phase III studies investigated the role of two EGFRTKIs inhibitors, gefitinib [2] and erlotinib [3], as first-line *Address correspondence to this author at the Department of Medical Oncology, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 200, 00128 Rome, Italy; Tel: +39-06225411227; Fax: +30-06225411633; E-mail: [email protected] Department of Thoracic and cardiovascular science, Sant'Andrea Hospital, Sapienza University, Rome, Italy; E-mail: [email protected]

1574-8928/15 $100.00+.00

treatment compared with standard platinum-based chemotherapy, in patients affected by advanced NSCLC harboring EGFR activating mutations”. In all these trials, the main endpoint had reached with “EGFR-TKIs reporting a significant improvement in progression-free survival (PFS) and overall response rate (ORR)”. The overall survival (OS), where available, was similar between TKIs and chemotherapy arm due to the high percentage of cross-over treatment. Nevertheless, OS reached about 30 months, results which were never seen in trials addressed to advanced NSCLC patients. All these studies were performed in an Asian population and this is the main reason explaining, at the moment, that gefitinib was licensed for the treatment of “patients affected by advanced NSCLC harbouring activating EGFR mutations”[4] in any line of therapy

© 2015 Bentham Science Publishers

2 Recent Patents on Anti-Cancer Drug Discovery, 2015, Vol. 10, No. 3

worldwide except in the United States. The FDA approved Tarceva for its fourth use and the third use for lung cancer. “Tarceva was first approved in November 2004 for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen. The FDA approved Tarceva on April 16, 2010, for maintenance therapy of patients with locally advanced or metastatic NSCLC resistant to even four cycles of platinumbased first-line chemotherapy”. European Tarceva vs. Chemotherapy “(EURTAC) study was the first trial with a TKI addressed to European population affected by advanced NSCLC with activating EGFR mutations (exon 19 deletion or L858R mutation in exon 21)” [5]. In this trial erlotinib, “at the oral dose of 150mg daily, was compared with platinum-based doublets” (cisplatin or carboplatin plus gemcitabine or docetaxel) in 174 eligible patients. “Erlotinib scored significantly better than chemotherapy in terms of PFS”, main endpoint of the trial, with 9.7 versus 5.2 months, respectively (HR 0.37, 95% CI 0.250.54). ORRs were 58% and 15%, respectively. OS data are still immature [6, 7]. These results, firstly reported in the Caucasian population, later lead to the marketing of erlotinib in this setting worldwide including United States. However, the presence of a specific target is such regardless any subgroup of patients and when an inhibitor is available, also its use should be applicable regardless of any patient's specific characteristics. “Currently, Erlotinib is a validated drug for the treatment of patients affected by advanced non-small cell lung cancer” with EGFR mutations [8]. “Erlotinib is a Human Epidermal Growth Factor Receptor Type 1/Epidermal Growth Factor Receptor (HER1/EGFR) tyrosine kinase inhibitor: it inhibits the intracellular phosphorylation of the tyrosine kinases associated with the epidermal growth factor receptor (EGFRTK) expressed on the cancer cells. For the inhibition of EGFR, tyrosine kinase activity can prevent tumor growth, metastasis and angiogenesis” [1]. Erlotinib is described chemically as “N-(3ethynylphenyl)-6,7-bis(2-methoxyethoxy) quinazolin-4amine”. It is administered in the form of the hydrochloride salt. Different synthetic strategies for the preparation of erlotinib and” its salts are known” [7-10] Fig. (1). The maintenance therapy with erlotinib was also considered as very effective for survival in patients with advanced non small cell lung cancer [11]. Among the most common side effects of this drug skin rash and gastrointestinal disorders are mainly describe. Concerning lung function, “interstitial lung disease has been reported “as side effect in a small percentage of cases [1]. Smoking cessation treatment is considered to be very important “for quality of life in patients with COPD and lung cancer” [12]. Furthermore, beneficial effects of smoking cessation, even after diagnosis, have been largely demonstrated [13, 14]. “Persisting smoking after diagnosis is associated with an increased risk of all-cause mortality and decreased survival [9]. Research has demonstrated significant

Pezzuto et al.

differences in actuarial OS favoring the non-smoking group among subjects with lung cancer” [15]. “There is also evidence that tobacco smoking aggravates and prolongs radiotherapy-induced complications. Smoking is associated with adverse effects during anti-cancer treatment and seems to promote tumor progression and increased resistance to chemotherapy due to nicotine-induced resistance to apoptosis by modulating mitochondrial signaling” [15]. Finally, “continued smoking might also be related to inferior outcomes of treatment with novel targeted therapies such as erlotinib” [16]. In fact, this drug undergoes metabolic negative interference by the tobacco smoke. The pharmacokinetics of erlotinib is different in current smokers and no-smokers. In particular, an increase on metabolic clearance of the drug in current smokers was found. On the other hand, “quitting smoking after lung cancer diagnosis is associated with a better performance status, whereas persistent smokers have worse overall quality of life [17]. Subjects who continue to smoke despite being diagnosed with cancer report more severe pain than subjects who have never smoked and greater pain-related functional impairment” [18]. “An update on therapeutics for tobacco dependence” was provided by Lancaster at al [19] in a review reporting the clinical trial “evidencing for the efficacy of four classes of pharmacological treatment for nicotine dependence”: nicotine replacement, antidepressants, nicotine receptor partial agonists and drugs blocking cannabinoid receptors. Varenicline, selective nicotinic partial agonists, resulted to be the best treatment option in first line with a poor side effects. Varenicline is chemically close to benzodiazepine, used as tartrate salt in the treatment of smoke-addition. This compound binds to neuronal nicotinic acetylcholine specific receptor sites, and is useful in modulating cholinergic function [19, 20]. So, Varenicline mimics the effect of nicotine and therefore, it both reduces the urge to smoke and relieves withdrawal symptoms. Recent strategies to prepare varenicline intermediates and salts have been patented (Fig (1) and varenicline showed the best results in clinical settings compared with other therapies including nicotine replacement and bupropione [21] However, few data are available concerning the effectiveness of erlotinib on lung function combined with smoking cessation. In this study, we aim to focus on the potential functional benefits deriving from a combined therapy with TKI and a nicotinic partial agonist treatment in NSCLC with EGFR mutation. We also highlight the clinical benefits coming from the combination of the two treatment, in particular the improvement of response to the TKI therapy. PATIENTS AND METHODS Study Population Twenty-five patients affected by advanced stage NSCLC, with adenocarcinoma histotype and activating EGF-R (ERB1) mutation, were evaluated. The inclusion criteria for patient enrollment were: positive smoke history and EGFR mutated lung cancer with stage IIIb or stage IV at diagnosis candidate to a first line therapy, ECOG Performance Status of 1 or less and a mild stage I COPD according to GOLD guidelines. A previous radiotherapy treatment, a major lung

Smoking Cessation and Erlotinib in EGFR Mutated Patients

Recent Patents on Anti-Cancer Drug Discovery, 2015, Vol. 10, No. 3

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Fig. (1). Chemical structures of erlotinib and varenicline.

surgery and/or recent history of heart failure were considered exclusion criteria. Patients underwent a combination therapy with Erlotinib 150mg daily and a smoking cessation treatment with Varenicline at the” following schedule”: 0.5mg a day for three days, 0.5 twice a day for four days, then 1mg twice a day. All patients stopped smoking during the three months of combination treatment. A second group of ten patients that were still smoking at the time of the study, affected by NSCLC with activating EGFR mutation and mild COPD, were tested for the detection of certain functional parameters. These patients underwent only the” anti-EGFR tyrosine kinase inhibitor treatment as first line. Finally, a control group of ten patients with non-small cell lung cancer wild type undergoing only smoking cessation was considered for functional evaluation.

measurements. Respiratory function evaluation was carried according to ATS-ERS guidelines [24]. Airflows and volumes were measured by pneumotacographic method whereas static volumes and resistances were evaluated by pletismography. Single breath carbon monoxide diffusion test was also performed as recommended by ATS-ERS guidelines [25]. The following maneuvers were performed: tidal volume breath, panting maneuver for resistances curves, slow expiratory maneuver, forced expiratory maneuver. In case of airway obstruction, a post bronchodilation maneuver was carried by administrating inhaled salbutamol 400μg. The above mentioned pulmonary function tests were performed at baseline and after three months of therapy. Finally, exhaled CO was detected by smokerlyzer (Bedfont, USA). Oxymetry (Minolta, USA) was used to detect heart rate and oxygen saturation. Statistical Analysis

Measurements Enrolled patients were asked to undergo two selfadministered questionnaires to test their smoking dependence and mood levels: the Fagestrom test (FTND) for nicotine dependence testing and the Depression Hamilton Test (HAMD) [22]. The FTND range score is 0-10 (low dependence for value < 4), HAMD range score is 8-17 for low depression, 18-24 for moderate depression and > 25 for high depression. Clinical records about smoking consumption, age, smoking onset, Body mass index (BMI) were collected. A chest-abdomen CT scan with iodinated contrast agent was performed at the beginning of the treatment and three months later. “Response to Erlotinib treatment was evaluated according to RECIST 1.1 criteria” [23]. Toxicity was reported according CTCAE 4.0 (common toxicity criteria of adverse events). All patients underwent a comprehensive respiratory function assessment including post-bronchodilator

All data are expressed as means (+ standard deviations, SD or 95% confidence intervals, CI)” for continuous variables, or as percentages for categorical variables. The Wilcoxom test was used to detect differences within the groups. “MannWhitney test was used to compare” the changes in functional values between study and control groups. Graphdad system version 5 (La Jolla, CA, USA) was used for analysis. PATIENT CONSENT “Written informed consent was obtained” from the patients enrolled in the study and for the publication of the results. RESULTS All patients with activating EGFR mutation (10 with deletion of exon 19, 15 with mutation 21) were affected by chronic obstructive bronchitis (COPD). Demographic characters of the study population are summarized in Table 1. Inside the Table, we can find that the mean score of Fag-


Pezzuto et al.

estrom dependence test indicates a severe dependence. Seventy percent of included participants were stage IIIb NSCLC, among which 80% were T4 N2. The average age of beginning smoking was found to be 14 + 2. The male/female rate was 1.5, 15 males and 10 females. The pack-year was 22.5 + 2.4. The exon 21 mutation was prevalent.

cific resistances (sRAW). In fact, FEV1 improved by about 100ml, FEF 25/75 (recorded as percentage of predicted) improved by about 7%, specific resistances (sRAW) (represented as percentage of predicted) were reduced significantly by about 40%. The DLCO test (diffusion lung CO test) did not change significantly. On the other hand the Hamilton Depression test (HAMD) showed a significant decrease after treatment by about 3 points in the score. The Heart rate and exhaled CO were also significantly improved after Erlotinib treatment combined with smoking cessation treatment after three months of observation. No significant change was observed for the vital capacity. All the enrolled patients had a clinical and radiological response to treatment. Concerning Erlotinib treatment, a sta-

In Table 2, we have represented the demographic characteristics about the second group not very different from the study group. In particular the stage IIIb T4N2 was prevalent as well as the prevalence of the exon 21 mutation. Functional results (Table 3) reveal an “improvement in forced expiratory flow” (FEF 25/75) and forced expiratory one second volume (FEV1) as well as the reduction of spe-

Table 1.

Study Population Characteristics. Values Expressed as Mean and Standard Deviation. Study Population Characteristics

(Mean )

SD

Age (years)

54.0

5.3

BMI (Kg/cm2)

22.0

2.0

Pack-Year

22.5

2..4

Staging IIIb

70%

2.7 %

Stage IIIb:T4N2M0

80% of IIIb total

1.0%

Stage IIIb:T2/3N3M0

20% of IIIb total

1.0%

Childhood exposure (%)

63%

3.6 %

FTND

5.0

2.5

Smoking onset (age)

14.0

2.0

Daily cigarette smoke

22.5

4.3

Male/female rate

1.5

0.0

Exon 19 deletion

32% of patients

0.0

Exon 21 mutation

68% of patients

0.0

“FTND: Fagerstrom Test for Nicotine Dependence”; “BMI: Body Mass Index”

Table 2.

Second Group of Patients Undergoing the only Erlotinib Treatment: Demographic Characteristics. Values Expressed as Mean and Standard Deviation. Study Population Characteristics

(Mean )

SD

Age (years)

58

3.0

BMI (Kg/cm2)

21.5

3.0

Pack-Year

23.0

3.5

Staging IIIb

75%

3%

Stage T4N2

90% of total IIIb

0.0

Childhood exposure (%)

85%

4.5 %

FTND

6.4

3.5

Smoking onset (age)

15.5

3.5

Daily cigarette smoke

23.5

3.5

Male/female rate

1.5

0.0

Exon 19 deletion

40% of patients

0.0

Exon 21 mutation

60% of patients

0.0


Table 3.


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Functional Parameters before (T0) and Three Months after Treatment (T1). Data are Referred to the Study Group.

Functional Parameters

Mean

SD

p

HAMD - T0

21,33 95% IC:15.7-26.9

2.89

< 0.01

HAMD - T1

18,43 95%IC:15.13-21.7

1.69

CV% T0

94,38 95%IC:85.9-102.3

4.24

CV% T1

94,80 95%IC: 84-105.3

5.34

FEV1/FVC T0 (ratio)

67.5 95% IC: 62.6-72.4

2.5

FEV1/FVC T1

68 95%IC: 62-74

3.1

FEV1* T0 (liters)

1,93 95%IC: 1.13-2.93

0.48

FEV1 T1

2,03 95%IC: 1.2-3

0.46

FEV1 T0%

72% of predicted 95%IC: 65-82

2.4

FEV1 T1%

79% of predicted 95%IC: 68-85

2.3

FEF 25/75 T0

55% 95%IC: 49.9-60.1

2.6

FEF 25/75 T1

62% 95%IC: 56.3-67.7

2.9

sRAW T0** percentage

95% 95%IC: 91.9-98.1

1.6

sRAW T1

55% 95%IC: 47.9-62.1

2.1

CO T0 ppM

13,80 95%IC: 2.4-25.2

5.85

CO T1

4,31 95%IC: 1.4-7.2

1.51

HR T0 Beat/minute

82,13 95%IC: 63-101

10.20

HR T1

71,59 95%IC: 61.1-81.9

6.31

DLCO T0 mmol/min/KPa/l

89.2% 95%IC: 84-94.4

2.7

DLCO T1

91.3% 95%IC: 86.4-96.2

2.5

NS

NS

< 0.01

< 0.01

NS

< 0.01

< 0.001

< 0.01

NS

Wilcoxon rank test HAMD: Hamilton Depression Rating Scale; VC%: % Vital Capacity as percentage of predictum; FEV1 Forced Expiratory One Second Volume; sRAW Specific Resistances; HR Heart Rate; DLCO Diffusion Lung Test; “CO exhaled Carbon Monoxide ; FEF 25/75 Forced Expiratory Flow”25/75% of vital capacity. *Mann Whitney test, p < 0.05 for comparison of FEV1 increments’ values between treated group and control group T0 is time at the beginning of therapy with Erlotinib and smoking cessation T1: three months from beginning of treatment

tistically significant partial response was observed at CT scan evaluation after 3 months in all patients treated with combination therapy (Table 4) with a reduction of “the sum of the longest diameter” of the measurable solid lesions. On

the contrary, the response rate to Erlotinib treatment in the second group was lower with a substantial stable disease (Table 5).


Table 4.

Pezzuto et al.

Study Group Response to Therapy at Three Months, Primary Tumor Evaluation.

Time to the beginning treatment

Mean

SD

p

T0

2.9cm

0.9cm

< 0.01

T1

1.3cm

0.8cm

It is intended the mean of the sum of longest diameters of solid lesions (RECIST 1.1 criteria) The Wilcoxon rank test was applied

Table 5.

Second Group Response to Therapy at Three Months’ Check, Primary Tumor Evaluation.


Mean

SD

p

T0

2.5cm

0.5cm

ns

T1

2.3cm

0.7cm

Table 6.

Study Group Response to Therapy at Three Months’ Check. Lymph Nodes Short Axis Evaluation.


Mean

SD

p

T0

1.5cm

0.5cm

< 0.01

T1

0.3cm

0.7cm

Table 7.

Second Group Response to Therapy at Three Months’ Check. Lymph Nodes Short Axis Evaluation.


Mean

SD

p

T0

2.1cm

0.5cm

ns

T1

1.8cm

0.7cm

It is intended the mean of the sum of longest diameters of solid lesions The Wilcoxon rank test was applied

Tables 6 & 7 show the response in short axis mean value of lymph nodes. The improvement was greater in the study group compared to the second. In terms of lung function, the second group obtained a minor advantage from the anti-EGFR treatment alone (Table 8). In fact, we observed a significant better increment of values in the study group compared to control, referring to FEV1 post-bronchodilator detection and sRAW. Only FEF 25/75 and sRAW were significantly improved in the control group. “The increase obtained in the study group compared to control group” is shown in Table 9. Only significant differences are underlined, thus showing the benefit achieved from therapy with varenicline. In Table 10, the functional data obtained in patients with wild type NSCLC are represented undergoing only smoking cessation. We observe that the improvement in FEV1 was less remarkable than in the study groupSide effects related to Erlotinib treatment were mostly irrelevant except for grade one (G1) skin rash (3 patients). The main side effect reported after Varenicline assumption was nausea.

DISCUSSION In this trial, we observed that erlotinib combined with varenicline could potentiate its effectiveness on response rate and at the same time determine a lung function improvement in smoker people affected by lung cancer with activating mutation for EGFR gene. An improvement of flows and resistances in lung cancer is also probably due to mass reduction and anti-inflammatory effects on the bronchial tree. We could assume a synergistic action between the two drugs. According to literature, the frequency of interstitial side effects caused by erlotinib observed related to the drug was very low [26]. We hypothesize a potential anti-inflammatory property of the TKI combined with smoking cessation therapy. Literature shows that toxicities like myelosuppression and vomiting are not dose limiting and that a small portion of subject in the Japanese study experienced lung fibrosis with cough and dyspnea and fever, showing a feasibility and effectiveness of Erlotinib [26]. However, the percentage of


Table 8.


Second Group: Lung Cancer Patients with Mild COPD Undergoing Anti- EGFR Treatment without Smoking Cessation. Differences between T0 (before Treatment) and T1 (Three Months after).


Mean

SD

p

CV% T0

94.38

4.24

NS

Percentage

95%IC: 85.9-102.3

CV% T1

94.80

5.34

95%IC: 84-105.3 FEV1/FVC T0

67.5

2.5

(ratio)

95%IC: 62.6-72.4

FEV1/FVC T1

68

NS

3.1

95%IC: 62-74 FEV1* T0 (liters)

1.89

0.52

NS

95%IC: 0.91-2.83 FEV1 T1

1.95

0.96

95%IC: 1.2-3 FEV1 T0%

75%predicted

2.3

NS

95%IC: 68-83 FEV1 T1%

78%predicted

2.4

95%IC: 65-82 FEF 25/75 T0

50%

Percentage

95%IC: 49.9-60.1

2.6

FEF 25/75 T1

55%

< 0.001

2.9

95%IC: 49.3-60.7 sRAW T0**

85%

Percentage

95%IC: 80.5-89.5

sRAW T1

75%

2.3

< 0.01

2.8

< 0.01

95%IC: 69.6-80.4 *p < 0.05 significant differences of increments values between groups Wilcoxon rank test to detect differences within the group before and after treatment NS means not significant

Table 9.

7

Comparison of the Increases between the Two Groups after Three Months of Treatment.


Study Group

Control Group

Mean Difference

DS

Mean Difference

DS

p

FEV1 liters

+ 1.00

0.02

+ 0.5

0.02

< 0.01

FEF25/75 percentage of predicted

+ 7.00

0.30

- 5.00

0.03

< 0.01

sRAW percentage

- 40

0.5

- 10

0.5

< 0.001

Mann-Whitney test


Table 10.

Pezzuto et al.

Control Group treated with Varenicline Alone: Lung Cancer wild type Patients with Mild COPD. Differences between T0 (before Treatment) and T1 (Three Months after).


Mean

SD

p

CV % T0

92.30

3.7

NS

Percentage

95%IC: 85.1-99.2

CV % T1

94.50

4.5

95%IC :85.7-103.3 FEV1/FVC T0

66.5

(ratio)

95%IC: 60.9-78.6

FEV1/FVC T1

68.6

2.9

NS

3.1

95%IC: 62.6-74.6 FEV1* T0 (liters)

1.99

0.53

NS

95%IC: 0.99-2.99 FEV1 T1

2.05

0.86

95%IC: 0.3-3.6 FEV1 T0%

77% predicted

2.7

NS

95%IC: 72-83.4 FEV1 T1%

81% predicted

2.9

95%IC: 75.4-86.5 FEF 25/75 T0

55%

Percentage

95%IC: 50.9-59.1

FEF 25/75 T1

65%

2.1

< 0.01

2.8

95%IC: 63.8-66.5 sRAW T0**

89%

Percentage

95%IC: 83.6-94.4

sRAW T1

81%

2.8

< 0.01

3.1

< 0.01

95%IC: 75.6-86.4 *p < 0.05 significant differences of increments values between groups

patients with lung dysfunction from anti-EGFR therapy is about 2% in the same study and the clinical effectiveness in EGFR mutated patients justifies the use of drug in the first line therapy.

these cases in reproductive age. Gonzales et al. carried on a randomized trial showing that varenicline was significantly more efficient for smoking cessation than bupropion [30, 31].

The effect of cigarette smoking on response to EGFRTKI in lung cancer with activating EGFR mutations was observed in a retrospective study [27]. The study showed that the objective response rate of smokers was lower than never-smokers.

In addition, it seems that Erlotinib works better after smoking cessation because of metabolic cytochrome P450(CYP)-induced interaction with nicotine [32]. It was found that smoking may affect the pharmacokinetic of Erlotinib through an action “on CYP-3A4 and to a lesser extent on CYP1A2”.

On the other hand smoking cessation in COPD patient, according to current literature, improves lung function, instead the continuing of smoking habit causes FEV1 and function decline [28, 29]. Tobacco is a predominant risk factor for lung cancer as well as respiratory system Diseases and addiction to it is a disease included in the 10th revision of International Classification of Diseases (WHO smoking related morbidity manual and users’ guide). At least half of long-term smokers are estimated to die due to tobacco dependence with 50% of

The presence of mutation of EGFR gene was more frequent in eastern people and in female and could affect clinical response and survival. The mutation is more frequent for exon 19 and 21 than for exon 18 and 20 [33] and it is present especially in patients with well-differentiated tumor. The difference in exon type mutation, if deletion of 19 or mutation of 21 is used as stratified criteria for different TKI choice in rendomised trial. In fact, afatinib a more recent irreversible inhibitor of EGFR showed a more activity in



patients with exon 19 deletion than for patients with EGFR harbouring exon 21 L858 mutation [34,3 5].

[9]

This situation is different for the other TKI such as, erlotinib, gefitinib, icotinib because their action don’t depends on type of mutation but there are some variables that always affect the lung cancer clinical response and prognosis. The latter are female sex, ethnicity and mostly the non-smoking status [36].

[10]

[11]

[12]

CURRENT & FUTURE DEVELOPMENTS The findings observed in our retrospective analysis seem “to support the hypothesis” that personalized therapy for lung cancer in association with smoking cessation may help patients obtain an improvement in lung function and in effectiveness of TKI treatment with a subsequent better level of quality of life. Further investigations are needed to validate these results in a larger population. Therefore, the synergism of the combination therapy may represent a good aim to pursue in future phase III clinical trials.

[13] [14]

[15]

[16]

CONFLICT OF INTEREST No conflicts exist for the specified authors A. Pezzuto, L. Stumbo, M. Russano, P. Crucitti, S. Scarlata, M. Caricato and G. Tonini

[17] [18]

ACKNOWLEDGEMENTS

[19]

All authors made substantial contributions to concept and design of the study, drafting and revising the manuscript and gave their approval to the final version of the manuscript.

[20] [21]

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