«1234567»Seite
11 articles, page 1 of 11

Review article

Smoking Cessation in Lung Cancer—Achievable and Effective

Dtsch Arztebl Int 2013; 110(43): 719-24; DOI: 10.3238/arztebl.2013.0719

Andreas, S; Rittmeyer, A; Hinterthaner, M; Huber, R M

Stefan Andreas and Achim Rittmeyer have equally contributed to the manuscript.
Lung Hospital Immenhausen, pneumological training hospital of Göttingen University:
Prof. Dr. med. Andreas, Dr. med. Rittmeyer
Department of Thoracic and Cardiovascular Surgery, University Medical Center Göttingen: Dr. med. Hinterthaner
Department of Pneumology and Thoracic Oncology, LMU Munich: Prof. Dr. med. Huber

Background: Lung cancer is the leading cause of death from cancer in Germany. 90% of cases are due to the inhalation of tobacco smoke. About 40% of patients with newly diagnosed lung cancer are still smokers. A structured smoking cessation program is medically reasonable in this situation but is only rarely offered.

Methods: This review is based on a selective search in the PubMed database combined with a manual search for current publications.

Results: Many cross-sectional and longitudinal studies have shown that patients with lung cancer benefit from smoking cessation. After resection with curative intent, second tumors are 2.3 times more common, and recurrent tumors 1.9 times more common, in patients who continue to smoke than in those who stop. The overall mortality in smokers is 2.9 times higher. Smoking cessation also lowers the rate of radiation pneumonitis and infection during radiotherapy and prolongs the median survival after chemoradiotherapy for small-cell lung cancer (18.0 vs. 13.6 months). For patients with non-small-cell lung cancer, smoking cessation is associated with a better general state of health (77.5% vs. 57.6%). For the many patients with lung cancer who are treated palliatively, smoking cessation offers the advantages of improved pulmonary function, weight gain, and better overall quality of life.

Conclusion: Smoking cessation in patients with lung cancer is an important means of increasing the efficacy of treatment and improving their quality of life.

Tobacco smoke is an aerosol containing more than 4000 substances, more than 50 of which are known to be carcinogenic. These include polonium 210, benzene, formaldehyde, lead, and cadmium (1). If human bronchial epithelial cell cultures are exposed to tobacco smoke, the cultures show evidence of an increased growth rate, weakened adhesion, and increased frequency of malignant transformations after only a few days. These effects are suspected to be mediated by alteration of intracellular signal transduction, not by long-term mutagenic or carcinogenic effects of the known carcinogens (2).

Tobacco smoke’s long-term carcinogenicity and short-term intracellular effects may explain why patients who continue to smoke despite having recently been diagnosed with lung cancer develop secondary cancers more frequently and present worse cure rates (3).

In Germany, lung cancer is the leading fatal cancer in men, and the second-most common in women (4). In 2011 almost 44 000 people died as a result of lung cancer in Germany. This is significantly higher than for colon and breast cancers combined (approximately 17 000) (Federal Statistical Office [Statistisches Bundesamt], www.destatis.de). Approximately 90% of lung cancers are caused by tobacco smoke inhalation (5). The cumulative lifetime risk of dying of lung cancer before the age of 75 years for a continual smoker is 16%. There is no threshold below which exposure is risk-free. All histological lung cancer types can be caused by tobacco smoke (6). The fact that even lung cancers eligible for curative treatment have a better prognosis the earlier tobacco use is ended before disease manifestation highlights the importance of smoking cessation for every person who smokes, even if he or she has no manifest disease (7).

The Guideline of the American College of Chest Physicians (ACCP) recommends smoking cessation for all lung cancer patients (recommendation grade: 1A) and bases this on several older papers (8). The German guideline recommends smoking cessation with level of evidence of 2A (4). The advantages of smoking cessation in manifest lung cancer (Box), however, are seldom taken into account in everyday clinical practice.

Box
The positive effects of Smoking cessation in lung cancer patients

This review article aims to provide the reader with up-to-date information on smoking cessation in lung cancer patients that is relevant to clinical practice. To this end, a selective search of the literature was performed in PubMed, in October 2012, with the following keywords: “cessation” (any field), “lung cancer” (title), and “smoking” (any field). This identified 463 abstracts, which were then analyzed. The bibliographies of recent papers were also evaluated.

The positive effects of quitting smoking

Fewer surgical complications, better prognosis following resection

A systematic review that evaluated six studies on the effect of smoking cessation before surgery for lung cancer found no clear advantage in favor of smoking cessation before surgery (9). However, this study focused on whether surgery in active smokers should be postponed in order to allow smoking cessation or even pulmonary rehabilitation first so that the patient’s perioperative risk could be reduced. The six analyzed studies did not find any confirmation of this (9).

However, another meta-analysis for patients with stage I–IIIA non-small-cell lung cancer (NSCLC) did show a clear advantage for abstaining from smoking in terms of survival, recurrence, and secondary cancer after adjusting for other risk factors, particularly cardiovascular risk factors (3). Smokers developed secondary cancer following curative surgery 2.3 times more frequently, and recurrence 1.9 times more frequently. Overall mortality in smokers was 2.94 times higher (3). Data from 7990 patients who had undergone primary resection for lung cancer and were included in the dataset of the American Society of Thoracic Surgeons between 1999 and 2007 also showed a reduction in mortality and the pulmonary complication rate in patients who had not smoked for more than 12 months before surgery (10). The multivariate-adjusted perioperative mortality risk after surgery for lung cancer, when compared to those who had never smoked, was 3.5 for active smokers and only 2.5 for patients who had stopped smoking at least 12 months before surgery. The risk of perioperative pulmonary complications was increased 1.8-fold for active smokers, 1.6-fold for patients who had stopped smoking within the last year, and 1.3-fold for patients who had already been nonsmokers for at least 12 months (all figures multivariate-adjusted and compared to those who had never smoked) (10). A further study involving 569 patients who had undergone resection for stage I NSCLC and were followed up for a median of 5.9 years subsequently showed absolutely no cases of secondary pulmonary cancer in 45 patients who had never smoked, 2.72 per 100 patient years in active smokers, and 1.77 per 100 patient years in ex-smokers. The hazard ratio for secondary lung cancer in active smokers versus ex-smokers was 1.9 (11).

Smoking cessation also improves quality of life following pulmonary resection. One prospective study recorded the quality of life of 70 patients who had undergone lobectomy or pneumonectomy. Smoking cessation at any time before surgery was advantageous, whereas continued smoking up to the time of surgery was associated with a worse postoperative quality of life (12). For example, active smokers continued to complain of shortness of breath as much as six months after lung cancer surgery, while patients who had stopped smoking upon diagnosis of lung cancer continued to report the same values as before surgery. Active smokers also complained of chest pain significantly more frequently (12).

Better response to chemotherapy

A retrospective study of 285 Brazilian lung cancer patients, 63% of whom were active smokers, showed that significantly more patients who did not respond to treatment (n = 191) smoked than patients who did respond (67.8%±35.1 versus 38.7±2.1 pack years, p <0.001). Heavy tobacco use (≥40 pack years) was the most significant independent negative predictor of response to chemotherapy (adjusted odds ratio [OR]: 10.4; 95% confidence interval [95% CI]: 5.1 to 21.3) (13). A smaller study in Asian NSCLC patients yielded similar results (14).

An older article showed that in patients who had been successfully treated for small-cell lung cancer (SCLC) continued smoking was a risk factor for further malignant lung disease (15, 16). The risk of developing secondary lung cancer five to nine years after initial diagnosis of SCLC was 7.5 for active smokers (95% CI: 1.8 to 19.7) versus 3.8 (95% CI: 0.9 to 9.8) for patients who had stopped smoking (15, 16).

A recent meta-analysis which included five studies with a total of 1069 SCLC patients shows that the adjusted risk of secondary lung cancer in active smokers versus ex-smokers is increased by a factor of 4.31 (3).

The explanation for the findings described above may be the effect of smoking tobacco on the pharmacokinetics of chemotherapy agents. Irinotecan, which among other applications is used in patients with lung cancer, has been well researched. The area under the curve (AUC) of irinotecan is significantly lower in smokers; this is explained by the CYP3A modulation associated with tobacco (17). The AUC of irinotecan in the first 100 hours following application was 21.9 mg × h/mL in nonsmokers, versus 18.9 mg × h/mL in smokers (p = 0.003). The lower plasma levels suggest an increased risk of chemotherapy failure (17). Future studies should systematically investigate the effect of tobacco smoking on the pharmacokinetics of chemotherapy agents (18).

Greater efficacy of targeted therapy

The effect of tobacco smoke on drug metabolism must be taken into account in lung cancer patients who smoke. The oral EGFR (epidermal growth factor receptor) inhibitor erlotinib is metabolized more actively in smokers as a result of cytochrome P450 (CYP1A1/1A2) induction and was therefore less effective (19). In a Phase I/II study in smokers receiving first-line chemotherapy for advanced NSCLC, the maximum tolerated dose of erlotinib was 300 mg. Plasma levels of erlotinib at this dose were approximately the same as those measured at a dose of 150 mg/day in an earlier study in nonsmokers (20). For the clinically relevant association between the development of treatable mutations and tobacco smoking, see further literature (21, 22).

Better radiotherapy and radiochemotherapy outcomes

In a study involving 83 lung cancer patients who had received radiotherapy with curative intent, 17/75 (23%) of active smokers developed radiation pneumonitis, versus 0/8 of nonsmokers (23). Smoking was also a risk factor for lung infections during radiotherapy (24). In patients who had received radiation for stage I or II NSCLC, the two-year survival rate was only 41% in smokers but 56% in ex-smokers and those who had never smoked (25).

The positive effects of smoking cessation on radiochemotherapy were shown by a Canadian study of 215 patients with limited-stage SCLC. Patients who refrained from smoking during therapy had a median survival time of 18.0 months, whereas the corresponding figure for those who continued to smoke was only 13.6 months. In addition, the statistically significant increase in five-year survival rate, which more than doubled from 4% to 8.9% (p = 0.017), shows that smoking cessation substantially improves long-term prognosis (26) (Figure 1).

Figure 1
The association between Smoking and mortality in limited-stage small-cell lung cancer (SCLC)

Improved quality of life

Some professionals are afraid that emphasizing smoking cessation with lung cancer patients reduces their quality of life. Fortunately, this is not the case. In both smokers with chronic obstructive pulmonary disease (COPD) and “healthy” smokers, quality of life improves after smoking cessation (1). In large cohorts with more than 1500 patients, non-smoking lung cancer patients (both those who had never smoked and ex-smokers) reported a higher tumor-specific quality of life than those who smoked (27) (Figure 2). Interestingly, all scores for the various types of quality improve gradually with the length of time since smoking cessation; they were therefore most favorable for those who had never smoked and worst for active smokers. Even the values of patients who did not stop smoking until they were diagnosed with lung cancer were still better than those of active smokers (27) (Figure 2).

Figure 2
Quality of life by smoker status

Similarly, there were improvements in the general health of a cohort of 206 NSCLC patients who had stopped smoking, as assessed by their treating physicians using the ECOG (Eastern Cooperative Oncology Group) Performance Status, in 77.5% of patients, versus only 42.4% of patients who continued to smoke. In the same patient group, general health worsened in 22.5% of patients who stopped smoking and 57.6% of patients who continued to smoke (28). After adjusting for age, sex, concomitant illnesses, stage, and method of treatment in multivariate analysis, the risk of deterioration in general health after 6 and 12 months was seven times higher for smokers (28). For SCLC patients too, smoking cessation at diagnosis led to a lasting improvement in quality of life and symptoms (29). The overall QoL (quality of life) score for active smokers after four years was only 62, versus 69 for patients who had stopped smoking due to their SCLC diagnosis and 72 for patients who had stopped smoking at least one year earlier (p = 0.0382). In addition, the increase in body weight after smoking cessation is a positive effect in almost all tumor patients.

Lung cancer patients can stop smoking

Approximately 40% of patients with newly diagnosed lung cancer smoke (30, 31). Patients are particularly willing to stop smoking immediately after initial diagnosis. This effect, known as the “teachable moment,” has been observed in studies into lung cancer screening (32, 33) and for many other diseases, particularly cardiovascular diseases. However, cancer patients who continue to smoke often present symptoms of major tobacco dependence (34). Nevertheless, cancer patients can stop smoking. For example, the rates of smoking cessation of two cohorts containing 201 participants each—lung cancer patients in one and patients with other types of tumors in the other—were compared when given targeted smoking cessation treatment. The abstinence rate after six months was 22% in the lung cancer group and 14% in the group containing patients with other cancers (35).

When diagnosed, the majority of lung cancer patients would like to stop smoking (35). These findings were confirmed in a review that included 11 studies and was published in 2003 (34). In two other studies, approximately 50% of patients were still nonsmokers six months after stopping (36, 37). Importantly, nicotine replacement therapy is not associated with any increase in the incidence of cancer, even in long-term follow-up (38).

Consequences for care

The positive effects of smoking cessation described above are clinically relevant and comparable in power to the effects of established therapeutic interventions in lung cancer patients. For lung cancer patients, as for other patients with diseases that are triggered or worsened by tobacco use, smoking cessation is often unsuccessful without professional support, and its importance is often underappreciated and underrated by treating physicians and nursing staff. Centers must therefore provide intensive treatment for tobacco dependence. This must entail professional smoking cessation treatment that is tailored to the needs of lung cancer patients (39). Further studies should evaluate the optimal form of smoking cessation treatment for lung cancer patients.

In collaboration with other medical societies, the German Respiratory Society (DGP, Deutsche Gesellschaft fur Pneumologie und Beatmungsmedizin) has published an S3 Guideline on the diagnosis and treatment of lung cancer (4). This guideline establishes the following: “Each consultation must include inquiry into and documentation of lung cancer patients’ smoking habits. Lung cancer patients who continue to smoke should be encouraged to stop. They must have easy access to smoking cessation programs that include pharmacological and psychological intervention options.” The current guideline of the European Society for Medical Oncology (ESMO) also includes a similar recommendation (40). These recommendations are structurally incorporated into lung cancer centers’ certification by the German Cancer Society (Deutsche Krebsgesellschaft). Certified lung tumor centers therefore do provide structured smoking cessation treatment.

Conflict of interest statement

Prof. Andreas has received consultancy fees from GSK, Pfizer, and Almirall. He has received lecture and training fees from Boehringer Ingelheim, Pfizer, GSK, Novartis, and Roche. He has received funding for clinical study conduct from GSK, Pfizer, and Roche.

Dr. Rittmeyer has received consultancy and lecture fees and reimbursement of travel expenses from Boehringer Ingelheim, Lilly, and Roche. Conference fees have been paid on his behalf by Lilly and Roche. He has received funding for clinical study conduct from Astellas, GSK, Lilly, Pfizer, and Roche.

Prof. Huber has received consultancy fees Boehringer Ingelheim, Lilly, Pfizer, Pierre Fabre, and Roche. He has received funding for clinical study conduct from Boehringer Ingelheim, Pfizer, Pierre Fabre, and Roche.

Dr. Hinterthaner declares that no conflict of interest exists.

Manuscript received on 13 March 2013, revised version accepted on
5 August 2013.

Translated from the original German by Caroline Devitt, M.A.

Corresponding author:
Prof. Dr. med. Stefan Andreas
Lung Tumor Center, Göttingen
Specialized Lung Hospital, Immenhausen, Pulmonology Teaching Hospital
University of Göttingen
Robert-Koch-Str. 3
34376 Immenhausen, Germany
sandreas@lungenfachklinik-immenhausen.de

1.
Andreas S, Herth FJ, Rittmeyer A, Kyriss T, Raupach T: Tabakrauchen, chronisch obstruktive Lungenerkrankung und Lungenkarzinom. Pneumologie 2007; 61: 590–4. CrossRef MEDLINE
2.
Lemjabbar-Alaoui H, Dasari V, Sidhu SS, et al.: Wnt and Hedgehog are critical mediators of cigarette smoke-induced lung cancer. PLoS One 2006; 1: e93. CrossRef MEDLINE PubMed Central
3.
Parsons A, Daley A, Begh R, Aveyard P: Influence of smoking cessation after diagnosis of early stage lung cancer on prognosis: systematic review of observational studies with meta-analysis.
BMJ 2010; 340: b5569. CrossRef MEDLINE PubMed Central
4.
Goeckenjan G, Sitter H, Thomas M, et al.: Prävention, Diagnose, Therapie, and Nachsorge des Lungenkarzinoms. S3 LL. Pneumologie 2010; 64 Suppl 2: e1–164. CrossRef MEDLINE
5.
Alberg AJ, Samet JM: Epidemiology of lung cancer. Chest 2003; 123: 21S–49S. CrossRef MEDLINE
6.
Pesch B, Kendzia B, Gustavsson P, et al.: Cigarette smoking and lung cancer—relative risk estimates for the major histological types from a pooled analysis of case-control studies. Int J Cancer 2012; 131: 1210–9. CrossRef MEDLINE PubMed Central
7.
Zhou W, Heist RS, Liu G, et al.: Smoking cessation before diagnosis and survival in early stage non-small cell lung cancer patients. Lung Cancer 2006; 53: 375–80. CrossRef MEDLINE
8.
Rubins J, Unger M, Colice GL: Follow-up and surveillance of the lung cancer patient following curative intent therapy: ACCP evidence-based clinical practice guideline (2nd edition). Chest 2007; 132: 355S–367S. MEDLINE
9.
Schmidt-Hansen M, Page R, Hasler E: The effect of preoperative smoking cessation or preoperative pulmonary rehabilitation on outcomes after lung cancer surgery: a systematic review. Clin Lung Cancer 2013; 14: 96–102. CrossRef MEDLINE
10.
Mason DP, Subramanian S, Nowicki ER, et al.: Impact of smoking cessation before resection of lung cancer: a Society of Thoracic Surgeons General Thoracic Surgery Database study. Ann Thorac Surg 2009; 88: 362–70. CrossRef MEDLINE
11.
Rice D, Kim HW, Sabichi A, et al.: The risk of second primary tumors after resection of stage I nonsmall cell lung cancer. Ann Thorac Surg 2003; 76: 1001–7. CrossRef MEDLINE
12.
Balduyck B, Sardari Nia P, Cogen A, et al.: The effect of smoking cessation on quality of life after lung cancer surgery. Eur J Cardiothorac Surg 2012; 40: 1432–7. MEDLINE
13.
Duarte RL, Luiz RR, Paschoal ME: The cigarette burden (measured by the number of pack-years smoked) negatively impacts the response rate to platinum-based chemotherapy in lung cancer patients. Lung Cancer 2008; 61: 244–54. CrossRef MEDLINE
14.
Mohan A, Singh P, Kumar S, et al.: Effect of change in symptoms, respiratory status, nutritional profile and quality of life on response to treatment for advanced non-small cell lung cancer. Asian Pac J Cancer Prev 2008; 9: 557–62. MEDLINE
15.
Johnson BE, Cortazar P, Chute JP: Second lung cancers in patients successfully treated for lung cancer. Semin Oncol 1997; 24: 492–9. MEDLINE
16.
Johnson BE, Linnoila RI, Williams JP, et al.: Risk of second aerodigestive cancers increases in patients who survive free of small-cell lung cancer for more than 2 years. J Clin Oncol 1995; 13: 101–11. MEDLINE
17.
van der Bol JM, Mathijssen RH, Loos WJ, et al.: Cigarette smoking and irinotecan treatment: pharmacokinetic interaction and effects on neutropenia. J Clin Oncol 2007; 25: 2719–26. CrossRef MEDLINE
18.
Zevin S, Benowitz NL: Drug interactions with tobacco smoking. An update. Clin Pharmacokinet 1999; 36: 425–38. CrossRef MEDLINE
19.
Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al.: Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005; 353: 123–32. CrossRef MEDLINE
20.
Hughes AN, O'Brien ME, Petty WJ, et al.: Overcoming CYP1A1/1A2 mediated induction of metabolism by escalating erlotinib dose in current smokers. J Clin Oncol 2009; 27: 1220–6. CrossRef MEDLINE PubMed Central
21.
Couraud S, Zalcman G, Milleron B, Morin F, Souquet PJ: Lung cancer in never smokers--a review. Eur J Cancer 2012; 48: 1299–311. CrossRef
22.
Lee YJ, Cho BC, Jee SH, et al.: Impact of environmental tobacco smoke on the incidence of mutations in epidermal growth factor receptor gene in never-smoker patients with non-small-cell lung cancer. J Clin Oncol 2009; 28: 487–92. CrossRef MEDLINE
23.
Monson JM, Stark P, Reilly JJ, et al.: Clinical radiation pneumonitis and radiographic changes after thoracic radiation therapy for lung carcinoma. Cancer 1998; 82: 842–50. CrossRef MEDLINE
24.
Sarihan S, Ercan I, Saran A, et al.: Evaluation of infections in non-small cell lung cancer patients treated with radiotherapy. Cancer Detect Prev 2005; 29: 181–8. CrossRef MEDLINE
25.
Fox JL, Rosenzweig KE, Ostroff JS: The effect of smoking status on survival following radiation therapy for non-small cell lung cancer. Lung Cancer 2004; 44: 287–93. CrossRef MEDLINE
26.
Videtic GM, Stitt LW, Dar AR, et al.: Continued cigarette smoking by patients receiving concurrent chemoradiotherapy for limited-stage small-cell lung cancer is associated with decreased survival. J Clin Oncol 2003; 21: 1544–9. CrossRef MEDLINE
27.
Garces YI, Yang P, Parkinson J, et al.: The relationship between cigarette smoking and quality of life after lung cancer diagnosis. Chest 2004; 126: 1733–41. CrossRef MEDLINE
28.
Baser S, Shannon VR, Eapen GA, et al.: Smoking cessation after diagnosis of lung cancer is associated with a beneficial effect on performance status. Chest 2006; 130: 1784–90. CrossRef MEDLINE
29.
Chen J, Qi Y, Wampfler JA, et al.: Effect of cigarette smoking on quality of life in small cell lung cancer patients. Eur J Cancer 2012; 48: 1593–601. CrossRef MEDLINE PubMed Central
30.
Park ER, Japuntich SJ, Rigotti NA, et al.: A snapshot of smokers after lung and colorectal cancer diagnosis. Cancer 2012; 118: 3153–64. CrossRef MEDLINE PubMed Central
31.
Barlesi F, Scherpereel A, Rittmeyer A, et al.: Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol 2013; epub ahead of print. CrossRef MEDLINE
32.
Taylor KL, Cox LS, Zincke N, et al.: Lung cancer screening as a teachable moment for smoking cessation. Lung Cancer 2007; 56: 125–34. CrossRef MEDLINE
33.
van der Aalst CM, van den Bergh KA, Willemsen MC, de Koning HJ, van Klaveren RJ: Lung cancer screening and smoking abstinence: 2 year follow-up data from the Dutch-Belgian randomised controlled lung cancer screening trial. Thorax 2010; 65: 600–5. CrossRef MEDLINE
34.
Cox LS, Africano NL, Tercyak KP, Taylor KL: Nicotine dependence treatment for patients with cancer. Cancer 2003; 98: 632–44. CrossRef MEDLINE
35.
Sanderson Cox L, Patten CA, Ebbert JO, et al.: Tobacco use outcomes among patients with lung cancer treated for nicotine dependence. J Clin Oncol 2002; 20: 3461–9. CrossRef MEDLINE
36.
de Bruin-Visser JC, Ackerstaff AH, Rehorst H, Retel VP, Hilgers FJ: Integration of a smoking cessation program in the treatment protocol for patients with head and neck and lung cancer. Eur Arch Otorhinolaryngol 2012; 269: 659–65. CrossRef MEDLINE PubMed Central
37.
Cooley ME, Wang Q, Johnson BE, et al.: Factors associated with smoking abstinence among smokers and recent-quitters with lung and head and neck cancer. Lung Cancer 2012; 76: 144–9. CrossRef MEDLINE PubMed Central
38.
Murray RP, Connett JE, Zapawa LM: Does nicotine replacement therapy cause cancer? Evidence from the Lung Health Study. Nicotine Tob Res 2009; 11: 1076–82. CrossRef MEDLINE PubMed Central
39.
Cataldo JK, Dubey S, Prochaska JJ: Smoking cessation: an integral part of lung cancer treatment. Oncology 2010; 78: 289–301. CrossRef MEDLINE PubMed Central
40.
Peters S, Adjei AA, Gridelli C, et al.: Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012; 23: 56–64. CrossRef MEDLINE

 Date HTM PDF 
10 / 2014 66 10
9 / 2014 48 2
8 / 2014 72 11
7 / 2014 55 1
6 / 2014 64 2
5 / 2014 56 10
2014 580 56
2013 303 92
Total 883 148

Letters to the Editor

All Letters

Specalities