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1. Introduction
Radiation oncology is an important player in the treatment of lung cancer either alone taking advantage of the new technological developments (stereotactic radiotherapy, intensity modulated radiotherapy, image guide radiotherapy) or with surgery and systemic treatment (chemotherapy, immunotherapy, targeted drugs). To-day, radiotherapy may even challenge surgery as the loco-regional treatment both for stage I and III non-small cell lung cancer (NSCLC) and is the local treatment for small cell lung cancer (SCLC). In the present chapter, we will discuss those different clinical situations and presenting the current knowledge.
2. Stage I lung cancer: radiotherapy as an alternative to surgery
2.1 Stereotactic radiotherapy for early stage lung cancer (SBRT)
Surgery is the treatment of reference for early stage lung cancer and a lobectomy or an anatomical segmentectomy in selected cases coupled with a lymph node dissection is the preferred approach [1]. For early stages, surgery is generally technically less complex and associated with less toxicity and mortality than for more advanced stages. Still, some patients cannot undergo surgery due to medical comorbidities. In the past, conventional (long course) radiotherapy or even no treatment was often proposed to those patients; the outcome was very poor: in a review, the 2-year survival rates range from 22 to 72% and the 5-year survival rates from 0 to 42% [2].
In early 1990’s, a new radiotherapy technique emerged in Europe and Japan, built on the experience with intracranial stereotactic treatments, called stereotactic hypofractionated radiotherapy, stereotactic irradiation (STI), or extracranial stereotactic radioablation (ESR), and now more commonly referred to Stereotactic Body Radiation Therapy (SBRT) or Stereotactic Ablative Radiotherapy (SABR) [3, 4]. This is a novel form of high-precision, image-guided radiotherapy and aims to deliver higher radiation doses in a reduced number of fractions resulting in a higher Biologically Effective Dose (BED) than “conventional RT”, i.e. a higher biological impact for a given physical dose. This approach treats only the tumour without any coverage of the hilar or mediastinal lymph nodes.
Several retrospective studies observed encouraging results for early stage lung cancers and in 2006, the results of a prospective phase II trial testing SBRT for inoperable patients was published by Timmerman et al.: encouraging oncological outcomes were confirmed with 60 Gy or 66 Gy delivered in 3 fractions for T1 or T2 tumours [5, 6, 7]. However, the trial also showed an 11-fold increase in high grade toxicity, including even death. This was associated with the treatment of perihilar/centrally located tumours, those in a region close to the proximal bronchial tree that was later referred to as the “no-fly-zone”.
In 2010, the phase II trial NRG Oncology Radiation Therapy Oncology Group (RTOG) 0236 reported a 97.6% 3-year local control (LC) rate (95% CI 84.3–99.7) for a cohort of 55 patients with a T1–T2N0M0 peripheral lesion (tumour diameter less than 5 cm) treated with 3 fractions of 18 Gy [8]. Toxicity was limited with 2 grade 4 events and no grade 5. This trial updated results was reported in 2018 with a median follow-up of 48 months: recurrences at the primary site were rare at 5 years (7.3%) but the 5-year disease-free survival and overall survival (OS) rates were respectively 25.5% and 40.0% [9]. If SBRT is very effective to treat a specific lesion, occult spread may already occur and impact prognosis as well as intercurrent death related to the patient comorbidity. Data from larger cohorts and many other phase 2 trials also confirmed that SBRT is an effective and safe approach for inoperable patients but some studies also included medically operable patient who had refused a surgery [10, 11, 12, 13]. The latter group showed a better outcome due to less intercurrent death with even long term survival data close to the surgical series [14]. Furthermore, in the US National Cancer Data Base, Nanda et al. reported better survival for elderly patients (70 years or older) treated with SBRT than no treatment and this was still valid regardless of patient age [15]. Last but not least, SBRT was compared to conventional RT in two randomised trials: a better outcome was observed with less toxicity and was more convenient for the patients by reducing the travels to the radiotherapy department [16, 17].
2.2 Central tumours
Central tumours represent a challenge after the toxicity reported by the RTOG phase II trial [7]. Different groups have tried to identify treatment possibilities for these patients, mainly with different dose-fractionation schemes or with lower doses to the periphery of the planning target volume (PTV) than 3 fractions of 20 Gy [18, 19, 20, 21]. With more data available from many centres, a distinction was necessary within the central tumours located within the no-fly-zone: the distance to the bronchial tree and the oesophagus was crucial in determining the toxicity risk and leading to the definition of ultra-central tumours (UC): meaning the PTV overlaps the proximal bronchial tree or the oesophagus [21, 22]. A systematic review published in 2019 reported on the results of nine trials with at least 5 UC tumours, for a total of 291 patients but all studies have a slightly different definition for an UC [23]. SBRT treatments delivered a BED (for a α/β ratio of 10 Gy, BED10 Gy) of 67.2 Gy (48 Gy in 12 fractions) to 112.5 Gy (50 Gy in 4 fractions). Grade 3 toxicity or more ranged from 0% in two smaller-sized trials up to 55.5% at 2 years including 10 deaths in a cohort of 47 patients. In this particular trial there was no dose limit to the trachea and main bronchi and there was a great difference between the prescribed dose and the maximum dose delivered. In total, 8 studies reported grade 5 complications, mostly due to haemorrhage (15 of 22 cases). All studies reporting statistical comparisons of outcomes did not find differences in OS (6 studies) or LC (4 studies) between central and ultra-central tumours. Furthermore, six trials described a statistical comparison of toxicity rates without any significant difference.
The question of the best radiation management for non-peripheral tumours is currently still open and being examined by the LungTech and SUNSET trials, respectively investigating central and ultra-central localizations [24, 25]. In current clinical practice, SBRT is commonly performed for central tumours or isolated mediastinal lymph nodes at lower doses than peripheral tumours. In Onishi experience, a BED10 Gy > 100 Gy was decisive to obtain a high local control and survival with SBRT [6]. For (ultra-)central tumours, this cannot always be achieved, but at the same time, dose constraints for central airways and oesophagus can be observed to avoid severe toxicity but at the price of a lower efficacy.
2.3 SBRT vs. surgery
Since the early 2010’s, SBRT is accepted as a standard treatment for patients medically inoperable or refusing surgery. As comorbidities can also prevent a safe biopsy, SBRT is now accepted for the management of lesions highly suspicious of lung cancer without necessary a histological confirmation. SBRT has a favourable toxicity profile and a good local efficacy and SBRT may challenge surgery. Survival outcomes of SBRT could seem somewhat poor when compared to surgical series. However, most patients treated with SBRT present severe comorbidities or were older and such a direct comparison of survival is not appropriate. These comorbidities could dramatically impact prognosis by influencing further treatments, non-cancer related survival…
Several studies performed propensity score matching to compare surgical and SBRT patients’ outcomes with controversial results. A meta-analysis of propensity score matched studies was published in 2019 including 15 studies [26]. The results seemed to confirm a better 3-year OS after surgery but these results were questionable as unbalance remained in the matchings, meaning that patients were not similar after all. When restricting the analyses to studies with comparable covariates, no statistically significant difference in OS was found anymore. Selection biases seem inevitable in clinical practice, and so the need for randomised trials is generally recognised.
Several phase III trials randomised patients for SBRT or surgery and were initiated by different groups. STARS (registered as NCT00840749 on ClinicalTrials.gov), started in 2008 in the United States, aiming to identify a difference in 3-year OS, which required enrolment of 1030 patients over an expected period of 7 years. After having recruited 36 patients in 4 years, enrolment was prematurely closed. The ROSEL trial (NCT00687986) that started in the Netherlands, also in 2008, faced a similar situation as only 22 of the 900 patients planned could be enrolled.
A pooled analysis of the STARS and ROSEL cohorts was published in 2015 [27]. These trials were quite similar in terms of inclusion criteria and interventions, although central tumours were eligible in the STARS trial only (two were included). For the 58 patients enrolled, 31 were treated with SBRT (20 in STARS, 11 in ROSEL) and 27 with surgery. All surgical patients had hilar lymph node dissection and either dissection or sampling of several mediastinal nodal levels. Radiotherapy treatments for peripheral lesions were 54 Gy in three 18 Gy fractions in both trials but could also have been 60 Gy in five fractions in ROSEL trial (which happened for 5 patients), based on the practice of treating centres. It should be noted that, as often the case in RT, the prescription corresponded to technically slightly different treatments between the two trials.
Although based on few patients, the Chang analysis showed a statistically significant difference in OS with estimated survival rates at 1 and 3 years of 100% (95% CI 100–100) and 95% (85–100) in the SBRT arm for 88% (95% CI 77–100) and 79% (95% CI 64–97) in the surgical group (log rank p = 0.037, HR 0.34, 95% CI 0.017–1.19). Only seven deaths were reported: one patient in the SBRT group who died of cancer progression and six patients in the surgery group (three from lung cancer including a second primary, two from comorbidities and one from attributed to the surgical treatment). Both the STARS and ROSEL trials surgical groups included patient treated with the older thoracotomy technique and not the more actual and less morbid Video-Assisted Thoracoscopy (VATS).
To put things into perspective, a meta-analysis based on 40 SBRT studies (10 prospective, 30 retrospective) and 23 surgery studies (all retrospective), for respectively 4850 and 7071 patients, reported unadjusted 3-year OS for SBRT, lobectomy and sublobar resections of 56.6%, 80.7%, and 77.8%, respectively [28]. After adjustment for suitability for surgery (which integrates comorbidities and age), the estimated survival rates were higher for SBRT patients, although not statistically different, with 89% (95% CI 76–95) vs. 81% (95% CI 76–85) for lobectomy and 80% (95% CI 76–86) for limited lung resection. Currently, the Veteran administration is running a large phase III trial comparing surgery to SBRT (VALOUR trial) [29]. Interesting, the trial includes operable patients with tissue confirmation of NSCLC, staging with FDG-PET/CT, and biopsies of all hilar and/or mediastinal lymph nodes >10 mm that have a SUV >2.5. SBRT doses depend on the tumour location: peripheral tumours will receive either 18 Gy x 3,14 Gy x 4, or 11.5 Gy x 5 fractions, while central tumours will be treated with 10 Gy x 5. The surgery will be either a lobectomy or anatomic pulmonary resection (a segmentectomy) and mediastinal lymph node sampling.
If indeed new decisions regarding patients’ management cannot be made based on a post-hoc analysis of two very small sample trials and observational data, the superiority of the surgical approach might not be certain anymore and randomising large numbers of patients is still necessary to provide level-I evidence to answer the question.
The major accrual problem in these trials was attributed to the lack of equipoise in the physicians’ minds, or maybe to financial considerations. The two treatment modalities are very different, which can have strong impact on both patients and physicians limiting the acceptability of leaving the treatment choice to chance. Surgery is performed on in-patient basis. As the tumour is removed, it is easier to identify local recurrences. Mediastinal nodal dissection or sampling also allows to identify false negative of PET/CT staging and to guide the decision for an adjuvant treatment. In many SBRT series, the mediastinal evaluation is often limited to the CT or the PET-CT with fewer patients having a mediastinal sampling with Endobronchial Ultrasonography – Transbronchial Needle Aspiration (EBUS–TBNA). Even though an operable patient could be safely operated for salvage in the rare cases of regional relapse, it is probably better to provide the most exhaustive staging possible before choosing the treatment modality.
Another issue is the extra-thoracic failure suggesting to add a systemic treatment. The patients treated currently with a SBRT have often many co-morbidities and are not the good candidate for adjuvant chemotherapy due to the acute toxicity. An answer may be immunotherapy following the impressive positive results for more advanced stages: pembroluzimab, durvalumab and atezolumab are tested in different trials (KEYNOTE-867, PACIFIC-4, SWOG S1914) as an adjuvant treatment or concurrently with SBRT. An important issue will be the tolerance and the toxicity in this elderly population.
In conclusion, SBRT is an effective treatment modality and a very acceptable alternative to surgery for patients at high surgical risk. For fit patients, a large scale randomised trial is still considered necessary to answer the question: can SBRT replace safely surgery?
3. Stage III non-small cell lung cancer
To-day, most fit patients with a stage III NSCLC are treated with a program of chemoradiotherapy favouring a concurrent approach (CRT) [30]. The results remain far from satisfactory in term of overall survival. This is due to distant metastases and loco-regional failure. Using all our technological developments (IMRT, image guided radiotherapy, PET-CT based planning), local failure is still a major challenge even after doses in excess of 60 Gy. In the recent trial conducted by the RTOG comparing 60 to 74 Gy, the 5 year local failure rates are 49.7% after 60 Gy and 55.4% after 74 Gy [31]. Adding a third modality, surgery, is an appealing approach already proposed many years ago by Strauss and Sugerbacker in their literature review [32]. From a theoretical point of view, there is a clear synergism between radiotherapy and surgery: failure after radiotherapy is often observed in the bulk of the tumour, an area of hypoxia less sensitive to radiation while for surgery, local relapses occur at the margins of resection. Another approach is to improve the systemic treatment by adding immunotherapy.
There are several ways of combining the three modalities: induction chemoradiotherapy (concurrent or sequential) followed by surgery or a sequential approach with an induction chemotherapy followed by surgery and postoperative radiotherapy (PORT). The latter has the advantage to have less toxicity, the ability to evaluate the response to the chemotherapy especially the possible downstaging of mediastinal nodes allowing selecting the best candidate for surgery, the use of full dose of chemotherapy, to treat the possible micro metastatic spread and to have a full pathological evaluation. The drawback is that PORT will be less efficient due to the poor vascularization and the loss of lung volume especially in case of a pneumonectomy. The former allows taking advantage of the radiosensitizing properties of many drugs to obtain a higher rate of tumour response including pathologic complete response but at the price off more surgical complications and more toxicity. The ultimate goal of a three-modality approach is to improve survival while local control and progression free survival (PFS) are only surrogate endpoints.
3.1 Induction chemoradiotherapy before surgery
Many phase II trials reported a higher response rate, more downstaging and pathologic complete response but also more postoperative complications with CRT compared to chemotherapy alone. Using the National Cancer database including more than 11,000 patients with stage III NSCLC, the trimodality approach let to a better outcome with a 5-year survival around 32% [33]. In another analysis from the same database, 1936 patients with a T1, T2 N2 disease were treated with preoperative CRT or induction chemotherapy [34]. The pathologic complete response was higher after CRT (14.2% vs. 4%) but with an increased perioperative mortality and no improvement in OS. One problem with databases even a large one is certainly all the possible biases of patient selections but also the difference in local medical facilities. Indeed, academic facilities were more likely to treat patient with the trimodality than in a community hospital [35]. This is well illustrated by a recent paper including more than 83,000 patients presenting a stage III NSCLC treated in 1319 facilities. Those treated in a high volume centre (more than 15 patients) were more likely to have surgery or a trimodality and had significantly a lower risk of death [36]. This is one reason to look more to randomised trials to answer the question.
The role of surgery after a concurrent CRT compared to an exclusive CRT approach was tested by two trials conducted in Germany and in the US [37, 38]. Both trials did not observe any difference in OS but only a better local control after a surgical resection or a better PFS. Do we need to include radiotherapy in an induction program? The main advantage of avoiding RT is to reduce the acute toxicity and the surgical complications. Three randomised trials compared induction chemotherapy to a CRT approach for patients presenting with N2 disease initially considered resectable. The Swiss trial is the largest one and the most recent [39]. 232 patients were randomised between induction chemotherapy followed 4 weeks later by surgery and induction chemotherapy followed by RT (44 Gy in 22 fractions and 3 weeks) without any chemotherapy and surgery 3 to 4 weeks later. PFS and OS were not found different between the two arms. A R0 resection was observed in 91% and 81% in the arm with or without RT respectively. The pathologic complete responses were very similar with respectively 16 and 12%. Interestingly, no operative mortality was reported after RT. The main criticism is the use of a sequential approach perhaps explaining the low rate of pathological complete response. Recently, our Spanish colleague reported 99 patients treated with either preoperative CRT or induction chemotherapy. CRT significantly increased the pathologic complete response rate and nodal down staging and reduced the loco-regional recurrence; unfortunately, this did not translate in any survival benefit [40].
PreCRT is a commonly used strategy in patients with superior sulcus tumours. In two phase II trials including 110 and 76 patients, a CRT delivered 45 Gy combined with cisplatin, etoposide or cisplatin, vindesine, mitomycin chemotherapy. A N2 disease was an exclusion criterion. The 5-year survival rates were 44% and 56%, respectively [41, 42]. Important prognostic factors were R0 resection and pathologic complete response. One drawback is the relatively low RT dose in case of no surgery or incomplete resection. Another approach is to deliver a full RT dose. In a Dutch series, 49 patients treated with CRT before surgery (19 patients) or as a definitive treatment (30 patients) [43]. 5-year survival was 33% for the three modalities and 18% for the definitive RT. Clearly, patients selected for the trimodality were highly selected.
3.2 Induction chemotherapy followed by surgery and postoperative radiotherapy
Most trials evaluating PORT were carried out in an era of old radiation technique and not after induction chemotherapy. The meta-analysis showed a detrimental effect of PORT especially for stage I and II disease [44]. Another meta-analysis stratified the trials according to the use of a cobalt 60 unit or a linear accelerator [45]. PORT carried out with a linear accelerator increased OS and local control for stage III disease. Many retrospective analyses from single centre or from large data base look at the impact of PORT for stage III: if local control was improved, the impact on survival led to conflicting results.
RT technique is a key factor to avoid an excessive toxicity. The radiation plans used in the trials included in the meta-analysis were compared to our current RT techniques [46]. The older technique led to poor target coverage and an excessive toxicity. The target coverage reached only 65% and the heart V30Gyand the lung V20Gywere higher with the technique used in the randomised trials. A Polish study evaluated the cardio-respiratory functions in patients who did and did not receive modern PORT technique: they observed no increase in non-cancer radiation-induced mortality or deterioration of lung functions [47].
Currently, another issue is the role of PORT after induction chemotherapy for N2 disease since local relapse is a common feature as observed in several prospective phase II series. The cumulative loco regional recurrence rose even to 60% in the Betticher trial including 75 patients treated with upfront chemotherapy followed by surgery [48]. Persistent N2 disease after ICT is a pejorative factor but several questions on PORT remain: the place of PORT according to the pathologic response ypN0 versus ypN2 and PORT only or with sequential or concurrent chemotherapy. The data were coming from retrospective studies but the results of the LungArt trial were just presented at the ESMO congress: this phase III trial compared mediastinal PORT (54 Gy in 27–30 fractions) to no PORT. Patients included had a complete resection with nodal exploration, proven N2 disease and neo or adjuvant chemotherapy. PORT was associated with a non- statistically significant 15% increase in DFS at 3 years but without an OS benefit [49].
3.3 Discussion
All those trials have a major problem: they were conducted many years ago and are not in agreement with our current practice due to technological developments in diagnostic procedure (MR, PET-CT), in radiotherapy and in surgery and to the new drugs available including target agents and immunotherapy. Clearly, those data do not help us to choose between a trimodality and a concurrent chemoradiotherapy as the results suggest similar outcome in term of survival. Furthermore, stage III is a very heterogeneous group of tumours and the TNM has evolved over the years with different stage grouping both for the T and the N components in the different UICC classifications. Many trials have only included N2 patients or stage IIIA while other also included stage IIIB.
Nevertheless, there are a few lessons we have learned. One concern using induction chemotherapy before a local treatment is the delay between its termination and the start of the local treatment: accelerated repopulation of cancer cells and tumour regrowth can occur [50]. This is even more valid when the decision to do the surgery is taken after the induction treatment to see the possibility of a resection with free margins. In case of no resection or incomplete resection, the patient may have not an optimal curative treatment as the preoperative RT dose is often too low to achieve a good local control. Moreover, the addition of a boost delivered after several weeks of RT interruption is not very effective due to tumour repopulation.
The decision between both approaches should be discuss on individual base after a careful patient evaluation with a full staging including PET-CT and brain MR to avoid a futile treatment and an evaluation of patient fitness to undergo surgery or even radiotherapy. Many patients have a long history of tobacco smoking and are suffering from many co-morbidities increasing the risk of complications or even not allowing a surgical resection. The decision is to be taken during a tumour board involving all specialties: the feasibility of a complete resection with free margins should be evaluated; an incomplete resection is by definition a futile thoracotomy and salvage treatments have limited efficacy. Another issue is the possibility to deliver a full course of radiotherapy with concurrent chemotherapy. This implies to be able to deliver doses in excess of 60 Gy or a biological equivalent dose taken into account the tolerance of the different organs at risk including the normal lung but also the heart. Finally yet importantly, an essential parameters are the local treatment facilities and the local clinical expertise but also the discussion with the patient of the pros and cons.
3.4 Immunotherapy with anti PDL1 drugs
If immunotherapy approach was in the past not very successful especially the vaccination strategies; the current approach is to play on T-cell activation or modulation in the tumour or microenvironment using anti-PD-1/PD-L1 drugs. Those drugs have fully changed the pattern of care for stage IV NSCLC with marked improved survival. It was often consider that RT had an immunosuppressive effect. Nowadays, there is a body of evidence suggesting that RT may increase the immune response both locally and systematically [51]. RT may act through a spectrum of cellular and molecular alterations and through the release of tumour-associated antigen. There are now a lot of observations suggesting a synergistic action of RT with anti-immune-checkpoint blockades with anti-PD-(L)1. Experimental data showed an increase in the expression of PD-L1 at the surface of tumoral cells after RT, improving the survival [52].
An interesting observation was seen in the phase I trial with pembrolizumab in stage IV NSCLC: in the phase I trial Keynote-001, patients treated with radiotherapy prior to pembrolizumab had a better survival regardless of the site irradiated [53]. In case of chest RT, 3 patients out of 24 developed a grade 3 lung toxicity after prior RT compared to one 1 out of 73 for pembroluzimab.
PACIFIC is a large scale phase III trial comparing durvalumab (an anti-PD-L1 antibody) to a placebo as a consolidation treatment after chemoradiotherapy [54]. Patients had to have received two cycles of cisplatin-based chemotherapy and a response or stable disease. The randomisation was performed 1 to 42 days after the end of radiotherapy. Few data are available regarding the initial chemoradiotherapy. Durvalumab was administered every 2 weeks for up to 12 months. The three year OS was 66.3% versus 43.5% for the placebo arm, results highly statistically significant. The PD-L1 status was not known for all patients but a post hoc analysis found similar results regardless of PD-L1 status. The lung toxicity was 13% after durvalumab and 8% in the placebo arm but grade 3 pneumonitis rates were very similar (3.4% vs. 2.6%). It is also not easy to compare the observed survival to others series as randomisation in PACIFIC is done after initial chemoradiotherapy, excluding those patients progressing or not tolerating the initial treatment. Nevertheless, this trial has changed our daily practice by adding durvalumab quickly after the end of chemoradiotherapy in locally advanced NSCLC.
The question of finding the best combination of immunotherapy and radiotherapy remains. Experimental data suggest better results when the drug is given during radiotherapy rather after its end: this was seen in an experimental study conducted on mice with colon carcinoma CT26 tumours [52]. One concern is the risk of increased toxicity especially at the level of lungs and heart: pneumonia is a classical complication of anti-PD-L1 drugs but also after chest radiotherapy. The NICOLAS phase II trial was designed specifically to answer this question [55]. Patients were treated with three cycles of a cisplatin-based chemotherapy and radiotherapy started with the second cycle together with nivolumab given up to 1 year. The endpoint was grade 3 or more pneumonitis observed during 6 months after the end of RT. Amongst the 80 patients included, 8 developed grade 3 pneumonitis after radiotherapy.
Radiation may also release tumoral antigens allowing a better recognition by the immune system but also acting against tumour cells outside the radiation field (the so called “abscopal effect”). In the Pembroluzimab-RT phase II trial, patients with stage IV NSCLC were randomised between pembroluzimab alone and pembroluzimab given after SBRT to a single metastatic site [56]. The goal was to test if SBRT increases the response rate: 17 patients out of 36 presented a response with the combined approach vs. 9 out of 40 patients in the pembroluzimab alone arm. The disease control rates at 12 weeks were respectively 63% vs. 40%. A retrospective study included 117 patients: 54 received SBRT with concurrent immune checkpoint inhibition and 63 SBRT alone. The risk of grade 3 radiation pneumonitis was higher in the combined approach (10.7% vs. 0%) [57]. In patients with a oligometastatic disease, the addition of a local treatment such as SBRT is a very exciting approach but a close monitoring for pneumonitis should be considered. Several trials are currently on-going.
Ultimately, there are a lot of unresolved questions: what is the optimal dose (low or high as the one used with SBRT), the actual volume to be treated, the timing…? Clearly, it is not easy to use a SBRT approach in stage III NSCLC as it is done for smaller metastatic lesions in stage IV NSCLC; the total volume to irradiate in stage III disease is much larger and could potentially lead to an excessive toxicity. Another issue lies in the volume of circulating immune cells during RT: the current technique to irradiate stage III NSCLC uses IMRT techniques delivering very low doses spread across large normal tissue volumes which may decrease the lymphocytes counts (a very sensitive cell to low RT dose), and subsequently the immune response. A retrospective study has observed a lower survival in case of lower absolute lymphocyte blood count [58]. So, blood-containing organs such as great vessels, heart and bone marrow may become a new organ at risk to spare in the future. Ideally, there is an urgent need to find a biomarker allowing to better select patients candidate for a combined approach in order to avoid futile treatments and also to decrease the expenses of those new treatments.
4. Small cell lung cancer (SCLC)
SCLC accounts for around 15% of all diagnosed lung cancers worldwide [59]. It is a highly aggressive, undifferentiated neoplasia characterised by a high proliferation rate and early metastatic spread. Although SCLC is very responsive to initial chemotherapy and radiotherapy, early recurrences are common and the prognosis of SCLC remains poor with 5-year overall survival rates of under 10% [60].
In the late 60’s, SCLC was staged as limited disease to the thorax (LS) or extensive stage (ES) according to the Veterans’ Affairs Lung Study Group classification and later modified by the International Association for the Study of Lung (IASLC) [61, 62]. Interestingly, limited disease include tumour confined to the ipsilateral hemithorax and regional lymph nodes in order to be encompassed in a radiation field. More recently, the IASLC recommends to use the revised TNM staging classification for lung cancer (American Joint Committee on Cancer AJCC 7th edition) for clinical decision making and clinical trials instead of the LS- and ES-categories, as it better discriminate the prognostic impact [63, 64].
4.1 Limited stage-small cell lung cancer (LS-SCLC)
CRT is the current standard of care [65]. In the early 90’s two meta-analyses have outlined the benefit of adding chest RT to chemotherapy [66, 67]. The Pignon meta-analysis was the most interesting due to the utilisation of the patient individual data from 13 randomised trials: chest RT improved the OS by 5.4% at 3 years but at the price of more esophagitis [67]. The benefit was greater for patients under 55 years (the relative risk of death was 0.72), than for those over 70 years. Two meta-analyses of randomised controlled trials have looked to the timing of chemotherapy and RT: concurrent CRT should start as early as the 1st or 2nd cycle of platinum-based chemotherapy to be more effective in terms of survival, compared to delaying the start of RT to the 3rd cycle or later [68, 69].
Another question was the optimal dose and fractionation. In the Intergroup 0096 trial, 471 patients were randomised between 45 Gy in 30 fractions twice daily (BiD), in a total of 3 weeks and 45 Gy in 25 fractions, once a day in 5 weeks. In both arm, RT started with the first of the 4 cycles of chemotherapy (cisplatin and etoposide) [70]. Overall survival rates at 2 and 5 years were respectively 41 vs. 47%, and 16 vs. 26% (p = 0.04) in favour of the BiD treatment. The drawback was more acute toxicity, mainly grade 3–4 esophagitis, from 16–32% with the BiD but without any increase in the risk of grade 3 or higher pneumonitis (6% in both arms). Given the highly proliferative nature of SCLC, a shorter time between RT fractions and a shorter overall treatment time (3 weeks instead of 5) could explain the better results of BiD fractionation against tumour repopulation. However, the major limitation in the design of the Turrisi trial is that the two arms have not the same biologically equivalent dose, a higher dose for the BiD arm. Nevertheless, this pivotal trial confirmed the impact of a better local turning in a benefit of survival and cure. However, many radiation oncology centres did not use the BiD fractionation because of the increased oesophageal toxicity and the inconvenience for the patient linked to have two treatments on the same day with an interval of minimum 6 h between the 2 fractions but also for busy radiation facilities [71].
The Japan Clinical Oncology group JCO 9104 phase III trial compared a concurrent CRT to a sequential CRT and included 231 patients. Chest RT was delivered with the first of the 4 cycles of chemotherapy (cisplatine and etoposide) or one month after the last cycle. The chest RT was a BiD delivering 45 Gy in 30 fractions over 3 weeks [72]. The median OS was significantly better for the concurrent arm compared to the sequential one (27.2 vs. 19.7 months, p = 0.02 after adjustment for performance status, age, and stage in a Cox model). The oesophageal toxicity was quite similar between the two arms (4% vs. 9% for sequential vs. concurrent, respectively) but the haematological toxicity was increased with the concurrent treatment (grade 3–4 leukopenia: 88% vs. 54%, p < 0.001).
The CONVERT trial designed to answer the question rose by the Turrisi trial and included 547 patients [73]. The trial compared a BiD approach (45 Gy delivered in 30 fractions over 3 weeks) to an escalated daily RT (66 Gy in 33 fractions over 6.5 weeks). The study was designed to show superiority for the once daily experimental arm over the control BiD arm. While there was no difference in toxicity and OS between the two groups, the BiD arm showed a trend toward an improved median OS (30 vs. 25 months, p = 0.14), leading to the conclusion that BiD remains the standard of care. Still, a lot of radiotherapy centres prefer to use the more convenient once daily fractionation (at the total dose of 66 Gy) since survival and toxicity were similar in both arms [74]. A recent Scandinavian randomised phase II trial presented at the annual ASCO meeting randomised between high-dose BiD CRT of 60 Gy in 40 fractions (4 weeks) vs. 45 Gy in 30 fractions (3 weeks), both arms with 4 courses of platinum. The survival rate at 2 years were in favour of the 60 Gy arm (73% vs. 46%, p = 0.001), and they had a significantly longer median OS (42 months vs. 23 months; HR 0.63, p = 0.031) without any significant differences in term of toxicity (esophagitis or grade 3–4 pneumonitis) [75]. Those promising results need a confirmation through a phase III trial including more than the 160 patients. The RTOG is conducting a three arm trial comparing 70 Gy in 7 weeks, 61.2 Gy delivered with one fraction daily of 1.8 Gy for 16 days followed by 1.8 Gy BiD for 9 days to the classical 45 Gy in 3 weeks BiD (RTOG 0538 trial); the second arm was prematurely closed.
Durvalumab has also showed activity for extensive SCLC and is tested as adjuvant treatment for limited disease with or without tremalimumab (The Adriatic trial). In a phase III trial, Atezolumab is delivered concurrently with chest RT and cisplatine-etoposide(NRG-LU005). The results of the Stimuli trial were presented at the last ESMO congress. After the end of chemoradiotherapy including also PCI, patients were randomised to receive ipilinumab and nivolumab for 12 months. No difference was observed in PFS neither in OS but increase the toxicity [76].
There is also the question of the target volume for radiotherapy: an elective nodal irradiation including the full mediastinum to treat the possible microscopic nodal sites was typically used in the past but at the cost of increased toxicity, an era of no PET-CT. In several prospective studies, the RT volume was limited to the known macroscopic disease as seen on a PET-CT and failures outside were a rare event: 3% and 2% in two different series of 60 patients from the Netherlands and the USA [77, 78].
Currently, the indications for surgery are limited to the very limited disease mainly stage I and II disease for fit patients and adjuvant chemotherapy is then necessary.
4.2 Extensive stage-small cell lung cancer (ES-SCLC)
The treatment cornerstone is a platinum-based chemotherapy regimens including cisplatin or carboplatin and etoposide combined with immunotherapy. This first line treatment yields often excellent initial responses and improved survival. However, recurrent or persistent intrathoracic disease is observed in more than 75% patients and local control remains a major problem during the first year of follow-up. A phase III study compared chest radiotherapy (54 Gy in 38 fractions over 18 days with concurrent cisplatin/etoposide) to only additional cycles of chemotherapy [79]. Patients had to have obtained a complete response at the metastatic sites and a complete or partial response in the thorax. The combined approach led to a better survival: median survival time of 17 months vs. 11 months and a 5-year survival rate of 9.1% vs. 3.7%.
The CREST trial randomised 498 patients to evaluate the benefit in term of OS by adding chest RT (30 Gy in 10 fractions over 2 weeks) as a local consolidation after first line cisplatin-based chemotherapy [80]. Although the study failed to achieve its initial endpoint of survival at 1-year, an interesting observation is certainly the slight survival improvement seen at 2 years: 13% vs. 3%, (p = 0.004). Importantly, RT allowed a marked 50% reduction in loco-regional recurrences. The radiation target volumes included the post-chemotherapy tumour and the nodal stations initially involved before the start of first line chemotherapy. These results lead to consider consolidative chest RT as a standard treatment after a response to chemotherapy, in addition to prophylactic cranial radiotherapy. Nevertheless, this is now questionable: two trials have showed a survival improvement by adding atezolumab to a platinum doublet [81, 82]. A trial is now on-going to evaluate the role of consolidative radiotherapy to up to 5 sites after a partial response or stable disease after a doublet of cisplatinum with atezolumab (Raptor trial).
4.3 Prophylactic cranial irradiation (PCI)
Brain metastases (BM) represent a major challenge in the management of SCLC, with an incidence as high as 50% at 2 years. The brain is considered a sanctuary site due to the blood brain barrier and the limited access for most available drugs. Based on prior experiences in leukaemia, Heine Hansen introduced in 1973 the concept of PCI for SCLC [83]. The aim of PCI is to prevent BM, avoiding the potential neurological complications, and ultimately to improve survival.
Several randomised trials demonstrated that PCI decreased the incidence of BM and Auperin’s meta-analysis using the individual data of 987 SCLC patients from 7 randomised trials confirmed clearly the survival benefits (both OS survival and PFS): PCI reduced by 25% the incidence of BM and increased the survival by 5,4% at 3 years (20,7% vs. 15,3%) [84, 85, 86]. Most patients had a limited-stage disease (85%) considered in complete response to the initial chemotherapy. A more recent meta-analysis including 1983 patients from 16 randomised trials showed a similar survival benefit without any impact of disease extent [87]. One problem with many trials is the lack of brain imaging in the initial staging and the CR evaluation: BM incidence is reduced by PCI from 53–40% in the absence of brain imaging while it reduces BM from 33 to 10% in case of brain CT-scan [88]. Today, MRI has increased the detection rate of BM from 10 to 24%. Importantly, the patients detected with BM by CT scan were often symptomatic while they had no symptoms in case of brain MRI.
The optimal radiation dose for PCI was tested by the large Intergroup PCI99–01 trial: 720 patients were randomised between 25 Gy in 10 fractions in 2 weeks vs. 36 Gy in 18 daily fractions or 24 BiD fractions [89]. This study failed to show any benefit with a higher radiation dose, neither on the incidence of BM or in survival; furthermore, the incidence of brain metastases remained high (35% at 3 years). Therefore, the recommended radiation schedule for PCI remains 25 Gy in 10 fractions delivered in 2 weeks.
Toxicity remains a major concern: acute (hair loss, fatigue,..) or late (hearing and cognitive impairment, dementia, leukoencephalopathy,…). The cognitive functions were evaluated before, at 6 and 12 months after PCI with the self-reported cognitive functions tests of EORTC: a threefold cognitive decline was observed at 6 months as well as at 12 months after PCI [90]. Those neurocognitive functions are highly depending on the hippocampus area. Currently trials are on-going to evaluate the efficacy and safety of a PCI using a hippocampus avoidance technique. Most guidelines recommend PCI for patients in complete response but it is also challenge by a close brain MRI follow-up [91, 92].
For patients presenting an extensive disease, PCI is also proposed after a response to platinum-based chemotherapy. This is based on the results of the EORTC phase III trial: patients with any response to chemotherapy were randomised between PCI and no PCI. PCI reduced the incidence of BM from 40–16% at one year, leading to a significant survival increase (13–27%) [93]. A pooled analysis of the North Central Cancer Treatment Group (NCCTG) trials including 421 patients observed similar results [94].
In contrast, a recent Japanese phase III trial randomised patients between PCI (25 Gy in 10 fractions) or no PCI after any response to initial chemotherapy and a recent MRI showing no BM [95]. The observation arm required to have brain MRI at 3-month intervals up to 12 months and at 18 and 24 months after enrolment. PCI reduced the incidence of BM but without any overall survival benefit: median survival was 11.6 months in the PCI group and 13.7 months in the observation group (HR = 1.27, 95% CI = 0.96–1.68; p = 0.094). Consequently, the Japan Lung Cancer Society removed PCI from their treatment guidelines in ES-SCLC. In those two trials, the patient population is quite different just by looking to the difference in survival. This trial and the concerns on PCI toxicity have led the SWOG to launch a trial comparing PCI to a MRI surveillance for extensive but also limited small cell lung cancer.
5. Conclusion
Over the past few years, major improvements have been made in the management of lung cancer due to the introduction of SBRT and immunotherapy. Both have changed the daily practice not only of early stage lung cancer but also for stage IV diseases. A major development in the future will be to include (SB) RT in the management of metastatic lung cancer to promote the immune system but also to treat local lung tumours. So, there is still a long way to understand how to optimise those modalities for each individual patient but also to understand the disease.
\n',keywords:"SBRT, trimodality stage III, small cell lung cancer chest RT, PCI",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/73835.pdf",chapterXML:"https://mts.intechopen.com/source/xml/73835.xml",downloadPdfUrl:"/chapter/pdf-download/73835",previewPdfUrl:"/chapter/pdf-preview/73835",totalDownloads:321,totalViews:0,totalCrossrefCites:0,totalDimensionsCites:0,totalAltmetricsMentions:0,impactScore:0,impactScorePercentile:27,impactScoreQuartile:2,hasAltmetrics:0,dateSubmitted:"July 15th 2020",dateReviewed:"October 13th 2020",datePrePublished:"October 30th 2020",datePublished:"June 2nd 2021",dateFinished:"October 30th 2020",readingETA:"0",abstract:"Many major technical developments have occurred during the last decades in radiotherapy: our efficacy has improved with less toxicity. Nowadays, it allows us to challenge the role of surgery as a local modality for lung cancer both for early, advanced and even metastatic disease. In the present paper, we will mainly discuss the role of SBRT for stage I lung cancer, the place of conventional radiotherapy for stage III and we will review the current treatment of small cell lung cancer from a radiation oncologist perspective.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/73835",risUrl:"/chapter/ris/73835",book:{id:"10437",slug:"lung-cancer-modern-multidisciplinary-management"},signatures:"Paul Van Houtte, Charlier Florian, Luigi Moretti and Dirk Van Gestel",authors:[{id:"327322",title:"Emeritus Prof.",name:"Paul",middleName:null,surname:"Van Houtte",fullName:"Paul Van Houtte",slug:"paul-van-houtte",email:"paul.vanhoutte@bordet.be",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"KU Leuven",institutionURL:null,country:{name:"Belgium"}}},{id:"328338",title:"Prof.",name:"Luigi",middleName:null,surname:"Moretti",fullName:"Luigi Moretti",slug:"luigi-moretti",email:"luigi.moretti@bordet.be",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"331846",title:"Dr.",name:"Charlier",middleName:null,surname:"Florian",fullName:"Charlier Florian",slug:"charlier-florian",email:"Charlier.florian@bordet.be",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"332039",title:"Prof.",name:"Dirk",middleName:null,surname:"Van Gestel",fullName:"Dirk Van Gestel",slug:"dirk-van-gestel",email:"dirk.vangestel@bordet.be",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Stage I lung cancer: radiotherapy as an alternative to surgery",level:"1"},{id:"sec_2_2",title:"2.1 Stereotactic radiotherapy for early stage lung cancer (SBRT)",level:"2"},{id:"sec_3_2",title:"2.2 Central tumours",level:"2"},{id:"sec_4_2",title:"2.3 SBRT vs. surgery",level:"2"},{id:"sec_6",title:"3. Stage III non-small cell lung cancer",level:"1"},{id:"sec_6_2",title:"3.1 Induction chemoradiotherapy before surgery",level:"2"},{id:"sec_7_2",title:"3.2 Induction chemotherapy followed by surgery and postoperative radiotherapy",level:"2"},{id:"sec_8_2",title:"3.3 Discussion",level:"2"},{id:"sec_9_2",title:"3.4 Immunotherapy with anti PDL1 drugs",level:"2"},{id:"sec_11",title:"4. Small cell lung cancer (SCLC)",level:"1"},{id:"sec_11_2",title:"4.1 Limited stage-small cell lung cancer (LS-SCLC)",level:"2"},{id:"sec_12_2",title:"4.2 Extensive stage-small cell lung cancer (ES-SCLC)",level:"2"},{id:"sec_13_2",title:"4.3 Prophylactic cranial irradiation (PCI)",level:"2"},{id:"sec_15",title:"5. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann. Thorac. Surg. 1995;60:615-622'},{id:"B2",body:'Rowell NP, Williams CJ. Radical radiotherapy for stage I/II non-small cell lung cancer in patients not sufficiently fit or declining surgery (medically inoperable): a systematic review. Thorax. 2001;56:628-638'},{id:"B3",body:'Blomgren H, Lax I, Naslund I, Svanström R. Stereotactic high dose fraction radiation therapy of extracranial tumors using an accelerator: Clinical experience of the first thirty-one patients. 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Journal of Clinical Oncology. 1992;10:890-895'},{id:"B67",body:'Pignon JP, Arriagada R, Ihde C, et al. A meta-analysis of thoracic radiotherapy for small-cell lung cancer. The New England Journal of Medicine. 1992;327:1618-1624'},{id:"B68",body:'Fried DB, Morris DE, Poole C, et al. Systematic review evaluating the timing of thoracic radiation therapy in combined modality therapy for limited-stage small-cell lung cancer. Journal of Clinical Oncology. 2004;22:4785-4793'},{id:"B69",body:'De Ruysscher D, Lueza B, Le Péchoux C, et al. Impact of thoracic radiotherapy timing in limited-stage small-cell lung cancer: Usefulness of the individual patient data meta-analysis. Annals of Oncology. 2016;27:1818-1828'},{id:"B70",body:'Turrisi AT, Kim K, Blum R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. The New England Journal of Medicine. 1999;340:265-271'},{id:"B71",body:'Komaki R, Khalid N, Langer C, et al. Penetration of recommended procedures for lung cancer staging and management in the United States over 10 years: A quality research in radiation oncology survey. International Journal of Radiation Oncology, Biology, Physics. 2013;85:1082-1089'},{id:"B72",body:'Takada M, Fukuoka M, Kawahara T, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: Results of the Japan clinical oncology group study 9104. Journal of Clinical Oncology. 2002;20:3054-3060'},{id:"B73",body:'Faivre-Finn C, Snee M, Ashcroft L, et al. Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): An open-label, phase 3, randomised, superiority trial. The Lancet Oncology. 2017;18:1116-1125'},{id:"B74",body:'Glatzer M, Faivre-Finn C, De Ruysscher D, et al. Once daily versus twice-daily radiotherapy in the management of limited disease small cell lung cancer - decision criteria in routine practise. Radiotherapy and Oncology. 2020;150:26-29'},{id:"B75",body:'Henning Gronberg B., Toftaker Killingberg K, Fløtten O. et al. Randomized phase II trial comparing the efficacy of standard-dose with high-dose twice-daily thoracic radiotherapy (TRT) in limited disease small-cell lung cancer (LD SCLC). J. Clin. Onco.l 38: 2020 (suppl; abstr 9007). DOI:10.1200/JCO.2020.38.15_suppl.9007'},{id:"B76",body:'Peters S, Pujol J., Dafni U.et al Consolidation ipilimumab and nivolumab vs observation in limited stage SCLC after chemo-radiotherapy – results from the ETOP/IFCT 4-12 STIMULI trial – Ann Oncol 2020; 31(suppl 4): s1142-s1215 10.106 annonc/annonc 325'},{id:"B77",body:'Van Loon J, De Ruysscher D, Wanders R, et al. Selective nodal irradiation on basis of (18)FDG-PET scans in limited-disease small-cell lung cancer: A prospective study. International Journal of Radiation Oncology, Biology, Physics. 2010;77:329-336'},{id:"B78",body:'Shrivani SM, Komaki R, Heymach JV, et al. Positron emission tomography/computed tomography-guided intensity-modulated radiotherapy for limited-stage small-cell lung cancer. International Journal of Radiation Oncology, Biology, Physics. 2012;82:e91-e97'},{id:"B79",body:'Jeremic B, Shibamoto Y, Nikolic N, et al. Role of radiation therapy in the combined-modality treatment of patients with extensive disease small-cell lung cancer: A randomized study. Journal of Clinical Oncology. 1999;17:2092-2099'},{id:"B80",body:'Slotman BJ, van Tinteren H, Praag JO, et al. Use of thoracic radiotherapy for extensive stage small-cell lung cancer: A phase 3 randomised controlled trial. Lancet. 2015;385:36-42'},{id:"B81",body:'Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinume-etoposide versus platinum-etopisde in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN) : a phase randomised, controlled, open-label, phase 3 trial. Lancet. 2019;394:1929-1939'},{id:"B82",body:'Horn L, Mansfield AS, Szcesna A, et al. First-line Atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. NEJM. 2018;379:2220-2229'},{id:"B83",body:'Hansen H. Should initial treatment of small cell lung cancer carcinoma include systemic chemotherapy and brain irradiation ? Cancer Chemother.Rep. 1973;4:239-241'},{id:"B84",body:'Arriagada R, Le Chevalier T, Borie F, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. J Natl. Cancer Inst. 1995;87:183-190'},{id:"B85",body:'Gregor A, Cull A, Stephens RJ, et al. Prophylactic cranial irradiation is indicated following complete response to induction therapy in small cell lung cancer: Results of a multicenter randomized trial (UKCCCR and EORTC). European Journal of Cancer. 1997;33:1752-1758'},{id:"B86",body:'Auperin A, Arriagada R, Pignon JP, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic cranial irradiation overview collaborative group. N. Engl. J. Med. 1999;341:476-484'},{id:"B87",body:'Viani GA, Boin AC, Ikeda VY, et al. Thirty years of prophylactic cranial irradiation in patients with small cell lung cancer: A meta-analysis of randomized clinical trials. Jornal Brasileiro de Pneumologia. 2012;38:372-381'},{id:"B88",body:'Seute T, Leffers P, ten Velde GP, et al. Detection of brain metastases from small cell lung cancer: Consequences of changing imaging techniques (CT versus MRI). Cancer. 2008;112:1827-1834'},{id:"B89",body:'Le Péchoux C, Dunant A, Senan S, et al. Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited stage small cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI99-01, EORTC22003-08004, RTOG0212 and IFCT99-01): A randomized clinical trial. The Lancet Oncology. 2009;10:467-473'},{id:"B90",body:'Gondi V, Paulus R, Bruner DW, et al. Decline in tested and self-reported cognitive functioning after prophylactic cranial irradiation in lung cancer: Pooled secondary analysis of radiation oncology group randomized trials 0212 and 0214. International Journal of Radiation Oncology, Biology, Physics. 2013;86:656-664'},{id:"B91",body:'Manapov F, Käsmann L, Roengvoraphoj O, et al. Prophylactic cranial irradiation in small-cell lung cancer: Update on patient selection, efficacy and outcomes. Lung Cancer (Auckl). 2018;9:49-55'},{id:"B92",body:'Rusthoven C.G., Kavanagh B.D. Prophylactic Cranial Irradiation (PCI) versus Active MRI Surveillance for Small Cell Lung Cancer: The Case for Equipoise. J. Thorac. Oncol. 2017;.12:1746-54.'},{id:"B93",body:'Slotman BJ, Faivre-Finn C, Kramer GW, et al. Prophylactic cranial irradiation in small-cell lung cancer. The New England Journal of Medicine. 2007;357:664-672'},{id:"B94",body:'Schild SE, Foster NR, Meyers JP, et al. Prophylactic cranial irradiation in small-cell lung cancer: Findings from a north central cancer treatment group pooled analysis. Annals of Oncology. 2012;23:2919-2924'},{id:"B95",body:'Takahashi T, Yamanaka T, Seto T, et al. Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell lung cancer: A multicentre, randomised, open-label, phase 3 trial. The Lancet Oncology. 2017;18:663-671'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Paul Van Houtte",address:"paul.vanhoutte@bordet.be",affiliation:'
Department of Radiation Oncology, Institut Jules Bordet, Université Libre de Bruxelles, Belgium
Department of Radiation Oncology, Institut Jules Bordet, Université Libre de Bruxelles, Belgium
'},{corresp:null,contributorFullName:"Dirk Van Gestel",address:null,affiliation:'
Department of Radiation Oncology, Institut Jules Bordet, Université Libre de Bruxelles, Belgium
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1. Introduction
Nepal is an agrarian country and 60.4% of its population is dependent on agriculture and it contributes to 26.8% of national GDP [1, 2]. Commercialization of agriculture is needed to accelerate the economic growth in the country, which is largely subsistence type. Since Nepal has entered World Trade Organization (WTO) as a member country in 2004, it is necessary to exploit the globalized trade for the nation [3]. Most of the people who are engaged in agriculture are rural dwellings and they are the prime driver of the agriculture of the country, Nepal. However, the commercialization of agriculture demands high-value inputs, which are often associated with higher use of improved, and hybrid cultivars, machinery, fertilizers, pesticides, etc.
Pesticides are those chemical substances that are used to control pests of an agricultural and urban setting. These substances include fungicides, insecticides, rodenticides, herbicides, molluscicides, nematicides, miticides, avicides, etc. Insecticides are used for a very long time to deter, minimize, and manage insect pests in an agricultural field, forest land, and in human settlements. In agricultural crop production only, insects and other pests cause around 35% yield decline [4].
The role of insecticides to reduce the insect pests attack on various crops, damage to the health of humans and livestock is crucial. Due to the advantage of the rapid action of these chemicals over target organisms, these are widely being used all over the world. Nepal could not be an exception regarding the use of chemical insecticides. Insecticides encompass a broad range of chemicals that are toxic not only to insects but also to other organisms. These chemicals often lead to pesticide resistance, the resurgence of insect pests, and the decline of beneficial organisms, along with the detrimental impact on human health and the environment [5]. Unscientific use of pesticides is of major concern to the farmers of the developing countries and Nepal could not be the exception, which further exacerbates the situation.
Phytophagous insects only do the damage to grown crops, on average of 35–40%. Sometimes, it exceeds more than that based on the severity of the pest [6]. Commercial growers mainly depend on various insecticides to get rid of the various insect pests. But, the exact amount of import of these insecticides, their use, and the effect on human health and the environment is of major concern to Nepalese agriculture [7].
2. Material and methods
A rigorous and thorough study was done to collect and synthesize information on the topic of the review. Different research papers, review articles, reports, governmental websites, and their publications were studied and screened for data compilations. Gathered data were coded in the MS-Excel and subsequent tabulation and column graphs were generated.
3. Results and discussion
3.1 History of pesticide use in Nepal
The use of insecticides started in Nepal in early 1950s with intention of control of malaria, especially to eradicate the disease transmitted by mosquitoes for the Gandaki Hydropower Project [8]. First introduced chemicals to Nepal were Paris green, gramaxone, nicotine sulfates, Dichloro-diphenyl –trichloroethane (DDT), and these all were brought from the USA. These chemicals were followed by other organochlorines, organophosphates, carbamates, and synthetic pyrethroids [8, 9]. In the agricultural field, pesticides were started to use in the early sixties. This is the era of the green revolution where farmers were instructed to get maximum yield from a crop by using higher inputs such as improved seeds, chemical fertilizers, pesticides, etc. Until that period, farmers were unaware of the chemicals and insecticides to manage the various insect pests of agricultural crops. At the time, farmers have a preference over broad-spectrum pesticides due to the effective work to knock down the pests [10]. Nepal does not produce any insecticides till now but imported primarily from six countries, that is, India, China, Malaysia, Singapore, Italy, and Japan [3]. Till now, 54 types of insecticides were introduced to Nepal with 14 bio-pesticides, which are depicted in Tables 1 and 2. Organochlorines and some other highly toxic chemical pesticides were banned in Nepal, which are shown in Table 3. Insecticides were registered in 1787 commercial names by Plant Quarantine and Pesticide Management Center (PQPMC) under the Department of Agriculture, Nepal. In Nepal, there are altogether 16,110 retailers, 5 pesticide formulators, 37 pesticide applicators, and 286 pesticide importers [11]. Traders of pesticides are mainly concentrated in the commercial agricultural areas such as in plain regions, in the valley, and in and around the major cities of the country. Still, pesticide business has not penetrated the mid-hills, hills, and larger rural areas of the country.
Registered pesticides in Nepal till 14 July, 2020.
S. No.
Common name
Origin
1
Azadirachtin
Neem based
2
Bacillus amyloliquefaciens D 203
Bacteria
3
Bacillus subtilis
Bacteria
4
Bacillus thuringiensis
Bacteria
5
Pseudomonas fluroscens
Bacteria
6
Beauveria bassiana
Fungus
7
Metarhizium anisopliae
Fungus
8
Verticillium lecanii
Fungus
9
Trichoderma viridae
Fungus
10
Trichoderma harzianum
Fungus
11
Paecilomyces lilacinus
Fungus
12
Paecilomyces Spp (Nematicide)
Fungus
13
Heterohabditis indica
Nematode
14
Nuclear polyhedrosis virus
Virus
Table 2.
List of bio-pesticides registered in Nepal.
S. No.
Banned pesticides
Decision year
S. No.
Banned pesticides
Decision year
1
DDT
2001
13
Monocrotophus
2006
2
BHC
2001
14
Methyl Parathion
2006
3
Aldrin
2001
15
Endosulphan
2012
4
Dieldrin
2001
16
Phorate
2015
5
Endrin
2001
17
Carbofuran
2019
6
Heptachlor
2001
18
Dichlorvos
2019
7
Chlordane
2001
19
Triazophos
2019
8
Mirex
2001
20
Carbaryl
2019
9
Phosphamidon
2001
21
Benomyl
2019
10
Organo Murcuric Fungicides
2001
22
Carbosulphan
2019
11
Lindane
2001
23
Dicofol
2019
12
Toxapheone
2001
24
Aluminium Phosphide 56%
2019
Table 3.
Banned pesticides in Nepal.
In average, consumption of pesticide inactive ingredient is very low, that is, 0.396 kg/ha compared to other countries such as India (0. 481 kg/ha), China (2.0–2.5 kg/ha), Japan (10.8 kg/ha), Europe (1.9 kg/ha) and USA (1.5 kg/ha) [12]. But, in highly commercial agricultural areas have much higher use of pesticides than the national average.
3.2 Trend of insecticide use in Nepal
Since insecticides are imported highly from foreign countries based on higher demand, farmers are using those chemicals in their fields injudiciously. Comparatively use of insecticides and other pesticides used in Nepal are lower than in developed countries, but the real problem is in the commercial pocket areas where growers are using exceedingly higher than they needed. There is a wider perception to the farmers that they have got the only chemical measures to control insect pests. Lack of awareness and knowledge of farmers, lack of alternatives of insect pests’ management other than chemicals, lack of governmental regulation and monitoring policies and actions for pesticide use are some of the reasons for improper and excessive use of insecticides in Nepal [13]. Insecticide use is reported much higher in vegetables compared to cereal crops and others. Since the vegetable growers are commercial, they tend to use insecticides more often. One study reported that more than 85% of insecticides imported were used in vegetable crops to deter various insect pests and oftentimes farmers are using insecticides even the insects are not at a damaging level. It is reported that a higher concentration of insecticides residues, that is, Cypermethrin than the permissible limit was detected in tomato and brinjal. The same study also showed that the concentration of Deltamethrin was higher in cowpea and was followed by cauliflower, tomato, and brinjal [14]. The residues of carbamate and organophosphate group of insecticides were observed in the vegetables sampled from the leading vegetable market of Nepal located in the heart of the capital city, Kathmandu. Tomato and cowpea were having higher residues of insecticides and these were grown in the commercial pocket of vegetables of Nepal, that is, Sarlahi and Kavre districts. The same study has revealed that 21.38% of tomato samples and 18.75% of cowpea samples were of sub-standard quality among the samples which were tested positive in pesticide residue analysis using the reagent kit method were [15]. The trend of insecticide use is increasing in Nepal by 10–20% per year and this signifies the prevailing crisis of Nepalese agriculture not only in terms of economic losses but also of associated detrimental effects [16].
It is reported that 25% of farmers of plain regions, 9% of mid-hills, and 7% of mountains use pesticides in their fields, and their usage in these ecological zones of Nepal is depicted inFigure 1 [17]. It is also reported that insecticides application is significantly higher in cotton and tea plantation in Nepal and it is worthwhile to mention that, compared to the cereal crops, use of insecticides and other pesticides is significantly higher in vegetables and other commercial/cash crops, as shown in Figure 2 [11]. In Kavrepalanchok district, near to the capital city, farmers were using insecticides 1–3 times whereas the same farmers were using 2–15 times in vegetables such as cabbage, potato, tomato, bitter gourd, cucumber, etc. It is even comparable to the share of pesticides in the production of various crops. Wheat has no pesticide application whereas, pesticide application in bitter gourd accounts for an 8.41% share in crop production [18] Farmers have reported the use of a cocktail spray of insecticides. Some farmers have also malpractice of dipping green vegetables in insecticide solutions such as malathion, mancozeb, etc. for a shiny and fresh look to fetch a good price in the market [12]. Farmers are very unaware and they hardly care for the waiting period to pick their harvest before they take it to the market. And, these products are purchased by the consumer and immediately taken for their food requirement and this makes the case more worsen [15].
Figure 1.
Crop wise pesticide use (a. i. gm/ha) in Nepal (Source: PQPMC, 2021).
Figure 2.
Ecological scenario of pesticide use in Nepal (Source: PQPMC, 2021).
Farmers of Nepal are very unaware of pesticide risk and it is the case of the area where people are engaged in conventional agriculture. In one survey conducted in Gaidahawa Rural Municipality of Rupandehi district, about 73% of the vegetable farmers have the practice of reusing the leftover pesticides. In the farmers’ field, researchers have reported that farmers have left the pesticide containers and packets in the open field, without thinking about the risk those containers possess [19]. Among the various pesticides reported in the area, chlorpyrifos was with higher concentration, that is, 177 μg/kg from the soil samples collected from three different depths of soil, that is, 0–5 cm, 15–20 cm, and 35–40 cm. DDT although banned in Nepal from 2001, its residues were found at all depths of the soil, which shows its persistent nature in the environment [19, 20]. The DDT mean concentration at 35–40 cm soil depth from the above-mentioned research area was found higher than 10 μg/kg, which is more than the threshold value for the safety of various soil organisms. Other insecticides such as Profenofos and imidacloprid were also found in the soil samples abundantly at different soil samples and found to be toxic to different soil organisms [19].
3.3 Impact of insecticide use
Insecticides can be used in a variety of forms, including liquid, concentrated, powder, dust, particle, aerosol, and fog, to control various insect pests of various crops. Those chemicals sprayed in a crop’s field will move and transfer to the environment via water, wind, and absorption. It can be transferred to long distances and in various forms. A large part of the most commonly used insecticides do not reach their target insect and may be affecting non-target organisms or polluting the environment. Non-target organisms include not only other insects, but also vertebrates such as wildlife, humans, and domestic animals. Insecticides can enter non-target habitats or ecosystems and affect non-target organisms [20]. Since food is a basic need and the practices of insecticide use do have a greater impact on human health. The most contaminated insecticides group, that is, carbamate and organophosphates are neurotoxic and are acetylcholinesterase inhibitors. These insecticides belong to the toxicity categories I and II. These are categorized under the most dangerous insecticides to the non-target organisms including humans and the environment [21]. These chemical insecticides may have contaminate on the environment such as soil, water (surface and ground), various flora and fauna, etc.
Since the import of pesticides including insecticides is increasing every year. The import of pesticides in the year 2013/14 was 454 tons but now, in the year 2019/20, import has been increased to 681 tons as shown in Figure 3 [11]. The residues of those chemicals on the soil and water are accumulating every year. One research has highlighted the moderate risk of cancer to the public where the soil is contaminated with organochlorine residues such as DDT and endosulfan [22]. This signifies not only the impending to the human health but also to the rich flora and fauna of the country itself. This sort of unsustainable practices in agriculture could be the cause of the loss of rich fauna which includes 17,097 species [23]. Various biotas inhabiting the soil such as bacteria, fungi, nematodes, earthworms, soil-inhabiting insects, and other arthropods with the presence of other organisms help to maintain the quality of soil and provide major ecosystem services for maintaining soil health and ultimately the quality of food production. The malpractices of insecticides along with other hazardous pesticides could have a detrimental effect on those organisms and ultimately deteriorate the quality and quantity of food production [19]. Another research conducted at Biratnagar of Nepal reported the presence of DDT and endosulfan in soil. The research also suggested that the use of DDT is still ongoing in the region but endosulfan residues were of past use [22].
Figure 3.
Scenario of yearly pesticide import into Nepal (Source: PQPMC, 2021).
These insecticides exposure to humans causes detrimental health defects such as hormonal imbalance, immune suppression, lower intelligence, reproductive anomaly, damage on kidney, liver, neural regions, and cancer. Farmworkers who have also exposure to insecticides get the symptoms of headache, drowsiness, dizziness, skin irritation, muscular twitching, respiratory discomfort, etc. [24, 25].
It is reported that the estimated health cost of the pesticide user individual who has got exposure to pesticides is Nepalese Rupee (NPR) 287. Of the total household expenditure, pesticide-induced health costs take 0.2% of annual household expenditure and 10.32% of annual health care expenditure [26].
More than the optimal concentration of insecticides also has unprecedented results human health and their expenditure on health care. One unit increase in insecticide concentration, that is, by 1 ml/L of water, would cause increased sickness cases by 6.8% and health costs by nearly NPR 30. Similarly, more hours of insecticide or any other pesticides application would bring unintended results to the health of the farmers and their expenditure [26].
It is also upsetting to mention the intentional or suicidal attempts of pesticide poisoning are common in Nepal. Most of the time, insecticides; mainly organophosphate are used by suicidal attempters. The most commonly used insecticides for self-pesticide poisoning were methyl parathion, dichlorvos, aluminum phosphide, and zinc phosphide [27].
3.4 Lesson learned from other countries
It is speculated that the insecticide reduction will cause a decline in the yield of the crops. But, it is not the case of the countries which are following a reduction in pesticide use because of their focus on the ecology of pests and agro-ecosystem. In that scenario, their production has been affected as speculated. Sweden has reduced pesticide use by 68% and public health poisonings by 77%. Their cutoff to the pesticides did not cause increased crop losses by the various pest species including insects. Indonesia also has reduced pesticide use by 65% and on the contrary, their production of rice has increased by 12%. India is also practicing the same and reducing the use significantly over the past years. But, Nepal is doing the opposite [25]. We are quite increasing the pesticide use for the sake of higher production, but, we are not aware of the fact that we are using unwarranted pesticides. Farmers, the ones who are not trained with the Integrated Pest Management (IPM) practices, are spraying the chemical pesticides more often than the ones who are trained. It is found that the trained farmers are spraying the pesticides 2.7 more times than the optimal whereas; the ones who are not trained are spraying 4.4 times of control [27]. This suggests the need of organizing community-based IPM training and environmental awareness programs about harmful effects of pesticides and sharing the know-how of insect pest management other than chemicals. It is also reported that Nepalese farmers are willing to pay higher prices (53–79%) than the current pesticide costs to mitigate the detrimental effect on their health and environment, and this clearly shows that they are willing to adopt alternative measures of pest management. But, the IPM programs of Nepal do have a contribution to the reduction of pesticide use but do not have a significant contribution to the reduction of health damages associated with the pesticides [25].
3.5 Regulation policy of pesticides in Nepal
For the first time in Nepal’s history, the pesticide act was enacted in 1991, regulations were approved in 1993, and pesticide board was formulated in 1994 [18, 28]. Currently, Pesticides Management Act, 2019 was enacted which provisioned registration of bio-pesticides and also included the provision of facilitating warehouses for storing the date expire, band, and obsoleted pesticides in seven provinces of Nepal. It also included the provision of bringing back the pesticides which are spoiled, banned, or obsolete pesticides. It also included the provincial pesticide committee. Punishment was also provisioned in the act and upon defiance of these laws minimum of 25 thousand Nepalese Rupee (NPR) penalty, one-month prison, and maximum 200 thousand NRS penalty, and one-year prison was provisioned. Overall, the pesticide act regulates the manufacture, import, sale, transport, distribution, and use of pesticides in the country. This enabled the registration of pesticides, monitoring and inspection of pesticides, registration of importers and traders, and banning of highly toxic pesticides to minimize the exposure to humans, livestock, and other associated environmental components [29]. But, there is a great scope for proper inaction of law so that the widespread misuse of chemical pesticides in the country either by the importers, traders, and applicators could be minimized greatly. Since Nepal shares an open border with India, there are unintended pesticide imports to the country and many of them are more toxic, banned, and unregistered. Tracking the trade with India is oftentimes difficult since a porous border gives the opportunity to the persons who are involved in illegal trades.
Nepal is also a signatory country for WHO and follows the rules, regulations, and treaties proposed by them. Recently as directed by WHO, the country has banned 1a and 1b types of extremely hazardous pesticides. As a responsible member, Nepal has signed international treaties like the Basal convention, Stockholm convention, and Rotterdam convention, which have aimed to minimize the use of persistent and toxic pesticides [3].
3.6 Alternatives of conventional insecticides to Nepalese farmers
Since Nepali farmers do not have much more information and knowledge about the methods of pest management other than chemicals. But, the Nepal Government and Department of Agriculture have started to prioritize the IPM program. Integrated Pest Management (IPM) is a pest control strategy that aims to combine various techniques of pest management such as mechanical, physical, cultural, biological, and chemical to minimize the risks possessed by the pest in a given ecosystem [30]. IPM always considers the use of chemicals as a last resort and before using chemicals, it seeks out all the possible alternatives for insect pest management.
Since 1999, the Nepalese government has used the Farmer Field School approach to strengthen farmers for cultivating healthy crops with decisions based on an understanding of the field agroecosystem with having eyes on beneficial organisms such as predators and parasites of insect pests. A Farmer Field School, also known as a school without walls, is a school that teaches basic agroecology and crop management skills. A group of farmers gathers in one of their own fields to observe, discuss, record, and analyze real-world field problems from crop planting to harvest. This field school is based on the concept of “learning by doing” rather than “seeing is believing”. The FFS was specially designed for farmers to learn and adopt IPM practices to their diverse and ever-changing ecological conditions [31]. Several crop season-long FFS have been organized in Nepal in recent years to provide knowledge and know-how on IPM to vegetable farmers in the hope of reducing their use of pesticides [32].
IPM farmer’s field schools in the country have positive impacts on the farmers for using a lesser amount of pesticides. This was evident in the Bhaktapur district of the country, which is also well known for commercial vegetable production, and seasonal and off-seasonal vegetables are produced here. As reported, farmers were using a significantly higher amount of pesticides where mean active ingredient (a.i.) of fungicides and insecticides were 2373 and 1963 g respectively and on average use of pesticide use was 2011 g a.i./ha. Among the used pesticides to cruciferous vegetables, the share of insecticides was more, that is, 76% which was followed by fungicides (19%) and unknown were 5%. The participants of IPM farmer’s field school had reduced significantly lower amounts of pesticides compared to non-participants. It was reported the 36% lesser amount of pesticides due to the effect of participation of IPM farmer’s field school [32]. In another report, pesticide application by the farmers was decreased by 40% upon participation in farmer’s field school [33]. This obviously shows the importance of these programs organized by governmental institutions.
Bio-pesticide could be a viable alternatives for Nepalese farmers since it will not be toxic to humans, other organisms, and the environment at large. There are altogether 14 registered bio-pesticides in Nepal which are effective to manage various insect pests and in some instances, other pests too of various crops. In Nepal, the use of bio-pesticides started commercially roughly after 2000. The share of bio-pesticides in the year 2019/20 is 0.005% of the total quantity of pesticides imported and used. This shows the predominantly higher use of conventional pesticides compared to commercial bio-pesticides. But, the use of locally available plant resources for pest control is a long practiced tradition of the farmers of Nepal. Many plants possess pesticide properties and these are all available all around the country. Three hundred and twenty four species of botanicals are found in Nepal only and among them, 23 species have special importance to the farming community of Nepal. The most common plants used as pesticides are as follows: Neem (Azadirachta indica), Garlic (Allium sativum), Bojho (Acorus calamus), Mint (Mentha arvensis), Turmeric (Curcuma domestica), Ginger (Zingiber officinalis), Marigold (Tagetus patula), Tobacco (Nicotiana tabacum), Drum-stick (Moringa oleifera), Basil (Ocimum sanctum), Onion (Allium sepa), Sugar apple (Annonaa squamosa), Sweet flag (Acorus calamus), Artemesia vulgaris, Winged prickly ash (Zanthoxylum armatum), China berry (Melia azedarach), Urtica dioica, Malabar nut (Justicia adhatoda), Marsh pepper (Polygonum hydropiper), Euphorbia royaleana, Jatropha curcus, Lantana (Lantana camara) and Vitex nigundo [34]. Botanical pesticides are easily made with these plant materials with pungency, bitterness, sourness, and repellent and antifeedant properties that make insects unhappy or cause death due to toxicity [3]. These botanicals are being used as a pesticide for a very long time. But, commercial production of these botanicals is missing in Nepal and it offers great scope for Nepalese entrepreneurs. Nepal possesses tremendous scope of developing these plants parts as botanical pesticides.
Although Nepal shares larger scope of isolation of different micro-organisms from the soil of Nepal, it offers only the formulation of two funguses, that is, Metarhizium anisopliae and Trichoderma viridae, only two isolated till now [3]. In the new pesticide act, the government of Nepal has made it easier to register the bio-pesticides compared to conventional pesticides, and obviously that would have positive impacts in the days to come. Nepal Government also have prioritized and started to give emphasis on organic agriculture since the 10th five-year plan [35], the scope of commercializing the bio-pesticides is certainly the need of the country.
4. Conclusion
Nepal, an agrarian country located in Southeast Asia is going to face unprecedented changes in human health, environment, and ecosystems due to more use of insecticides to deter insect pests in the farmer’s field. Large amounts of insecticides are imported from foreign countries. These chemicals certainly have negative impacts on the farming community and the environment at large. The situation seems even worse because of a lack of knowledge and skills related to the safety aspects of the farming community about the use of insecticides and its negative effects not only to the consumers but on them too. Many researches have confirmed the presence of undesirable residues of insecticides in vegetables, fruits, and other agricultural commodities. Incidences of human diseases such as immune dysfunction, kidney failure, cancer, etc. are also increasing in the country which somehow has a direct or indirect relation to the more use of insecticides in the field. Because farmer knowledge and behavior can reduce the ecological risk of pesticides, programs such as IPM training and farmer’s field school (FFS), etc. could be determined to change the status quo. Prioritizing the botanicals by the Nepal government and its respective agricultural agencies to the area where there is no practice of using conventional pesticides has special significance to protect the health of humans, various flora and fauna, and the environment.
Acknowledgments
The author wishes to appreciate the contribution of all the individuals and organizations who are constantly working on pesticides, their residues, effects, and mitigation in Nepal, and who has helped the author directly and indirectly in preparing this manuscript.
\n',keywords:"agrarian, GDP, insecticides, health, act, farmer",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/79363.pdf",chapterXML:"https://mts.intechopen.com/source/xml/79363.xml",downloadPdfUrl:"/chapter/pdf-download/79363",previewPdfUrl:"/chapter/pdf-preview/79363",totalDownloads:142,totalViews:0,totalCrossrefCites:0,dateSubmitted:"September 23rd 2021",dateReviewed:"October 6th 2021",datePrePublished:"December 21st 2021",datePublished:null,dateFinished:"November 18th 2021",readingETA:"0",abstract:"Nepal is an agrarian country whose population is primarily dependent on agriculture but the contribution to national Gross Domestic Product (GDP) is low as expected. There are many constraints to agricultural crop production and the farmers are facing those problems in their day-to-day lives. Deployment of insecticides and others to mitigate various insects and pests is one of them. Although abundant with locally available plant resources for pest management, farmers, especially in commercial pocket areas, are primarily dependent on conventional pesticides and those chemicals have detrimental effects on human health, including various flora, fauna, and environment. Although the Nepal government has formulated an act and worked on that basis, there is plenty of room to work on. Since farmer knowledge and behavior have a positive impact on reducing the use of conventional insecticides and work on alternative measures for pest management, these sorts of programs should be prioritized by the Government of Nepal and its allied agricultural organizations.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/79363",risUrl:"/chapter/ris/79363",signatures:"Sushil Nyaupane",book:{id:"11015",type:"book",title:"Insecticides",subtitle:null,fullTitle:"Insecticides",slug:null,publishedDate:null,bookSignature:"Dr. Ramón Eduardo Rebolledo Ranz",coverURL:"https://cdn.intechopen.com/books/images_new/11015.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-83969-027-3",printIsbn:"978-1-83969-026-6",pdfIsbn:"978-1-83969-028-0",isAvailableForWebshopOrdering:!0,editors:[{id:"193813",title:"Dr.",name:"Ramón Eduardo",middleName:null,surname:"Rebolledo Ranz",slug:"ramon-eduardo-rebolledo-ranz",fullName:"Ramón Eduardo Rebolledo Ranz"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. 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Use of chemical pesticides in Nepal—The prospects for organic agriculture. Environmental Sciences and Ecology: Current Research. 2020;1:1002'},{id:"B4",body:'Palikhe RB. Challenges and options of pesticide use: In the context of Nepal. Landschaftsökologie und Umweltforschung. 2002;38:130-141'},{id:"B5",body:'Matsukawa M, Ito K, Kawakita K, Tanaka T. Current status of pesticide use among rice farmers in Cambodia. Applied Entomology and Zoology. 2016 Nov;51(4):571-579'},{id:"B6",body:'Pavela R. History, presence and perspective of using plant extracts as commercial botanical insecticides and farm products for protection against insects—A review. Plant Protection Science. 2016 Sep 26;52(4):229-241'},{id:"B7",body:'Rijal JP, Regmi R, Ghimire R, Puri KD, Gyawaly S, Poudel S. Farmers’ knowledge on pesticide safety and pest management practices: A case study of vegetable growers in Chitwan, Nepal. Agriculture. 2018 Jan;8(1):16'},{id:"B8",body:'Dahal L. Study on Pesticide Pollution in Nepal. National Conservation Strategy Implementation Project, National Planning Commission, HMG Nepal, in collaboration with IUCN-The World Conservation Union. Kathmandu, Nepal; 1995'},{id:"B9",body:'Giri YP, Thapa RB, Shrestha SM, Pradhan SB, Maharjan R, Sporleder M, et al. Pesticide use pattern and awareness of pesticides users with special reference to potato growers in Nepal. International Journal of Development Research. 2014;4(11):2297-2302'},{id:"B10",body:'Neupane FP. Agricultural entomology in Nepal. Review of Agricultural Entomology. 1995;83(12):1291-1304'},{id:"B11",body:'PPQMC. List of Registered Pesticides and Consumption Data. Plant Quarantine and Pesticide Management Centre (PQPMC), Ministry of Agriculture and Livestock Development, Government of Nepal. Lalitpur, Nepal; 2021'},{id:"B12",body:'Sharma DR. Status of Chemical Pesticides Use and Their Regulation in Nepal. Hariharbhawan, Lalitpur: Plant Quarantine and Pesticides Management Centre; 2019'},{id:"B13",body:'GC Y, Palikhe BR. From the field to dining table: Pesticides residues. Journal of Agriculture and Environment. 2021;22(1):1'},{id:"B14",body:'Sharma DR. Use of pesticides and its residue on vegetable crops in Nepal. Journal of Agriculture and Environment. 2015;16:33-42'},{id:"B15",body:'Ghimire P. Status of Pesticide Residue in Vegetable and Fruit Samples Collected from Kalimati Wholesale Market of Kathmandu, Nepal. Singhdurbar, Kathmandu: Ministry of Agriculture and Livestock Development; 2020'},{id:"B16",body:'Diwakar J, Prasai T, Pant SR, Jayana BL. Study on major pesticides and fertilizers used in Nepal. The Scientific World Journal. 2008;6(6):76-80'},{id:"B17",body:'CBS. National Sample Census of Agriculture, Nepal, 2001/02: Highlights. Kathmandu, Nepal: Central Bureau of Statistics; 2003'},{id:"B18",body:'Shrestha PL, Neupane FP. Socio-economic contexts on pesticide use in Nepal. Landschaftsökologie und Umweltforschung. 2002;38:205-223'},{id:"B19",body:'Bhandari G, Atreya K, Vašíčková J, Yang X, Geissen V. Ecological risk assessment of pesticide residues in soils from vegetable production areas: A case study in S-Nepal. Science of the Total Environment. 2021;21:147921'},{id:"B20",body:'Boul HL. DDT residues in the environment—A review with a New Zealand perspective. New Zealand Journal of Agricultural Research. 1995;38(2):257-277'},{id:"B21",body:'Gill HK, Garg H. Pesticide: Environmental impacts and management strategies. Pesticides - Toxic Aspects. 2014;8:187'},{id:"B22",body:'Van den Bosch H, Chaowen L, Pham Van Hoi TH, Van den Brink PJ, Yunliang P, Groenwold JG, et al. Environmental Risks of Pesticide Use in Intensive Vegetable Farming Systems in Peri-Urban Hanoi (Dong Anh) and Chengdu (Pengzhou). Vol. 1285. Wageningen, The Netherlands: Alterra; 2006. p. 166'},{id:"B23",body:'Yadav IC, Devi NL, Li J, Zhang G, Shakya PR. Occurrence, profile and spatial distribution of organochlorines pesticides in soil of Nepal: Implication for source apportionment and health risk assessment. Science of the Total Environment. 2016;573:1598-1606'},{id:"B24",body:'MoFE. Nepal’s Sixth National Report to the Convention on Biological Diversity. Kathmandu: Ministry of Forests and Environment; 2018. p. 137'},{id:"B25",body:'Atreya K, Johnsen FH, Sitaula BK. Health and environmental costs of pesticide use in vegetable farming in Nepal. Environment, Development and Sustainability. 2012;14(4):477-493'},{id:"B26",body:'Atreya K, Kumar Sitaula B, Overgaard H, Man Bajracharya R, Sharma S. Knowledge, attitude and practices of pesticide use and acetylcholinesterase depression among farm workers in Nepal. International Journal of Environmental Health Research. 2012;22(5):401-415'},{id:"B27",body:'Jha RK, Regmi AP. Productivity of Pesticides in Vegetable Farming in Nepal. SANDEE, Kathmandu, Nepal; 2009'},{id:"B28",body:'Gupta SK, Joshi MP. Pesticide poisoning cases attending five major hospitals of Nepal. Journal of Nepal Medical Association. 2002;41:447-456'},{id:"B29",body:'NPPO. Pesticides Management Act. Government of Nepal. Kathmandu, Nepal; 2019'},{id:"B30",body:'Romeh AA. Integrated pest management for sustainable agriculture. In: Sustainability of Agricultural Environment in Egypt: Part II. Cham: Springer; 2018. pp. 215-234'},{id:"B31",body:'Kafle L, Yubak Dhoj GC, Yang JT, Bhattarai S, Tiwari S, Katuwal M. Integrated pest management in Nepal. In: The 5th International Conference on Clinical Plant Science. NPUST, Pingtung, Taiwan; 2014'},{id:"B32",body:'Jha RK. An assessment of farm-level use of biopesticides in Nepal: A case study based on IPM farmers’ field schools of Bhaktapur District. In: Third Annual Meeting of Plant Protection Society of Nepal. Plant Protection Society, Kathmandu, Nepal; 2008'},{id:"B33",body:'GC Y. Status of plant protection activities in Nepal. In: Conference on Capacity Building in Use of the International Phytosanitary Portal and APPPC Website for Information Exchange. IPP & APPPC. Malaysia; 2011. pp. 4-9'},{id:"B34",body:'Budhathoki P, Gnawali P, Baral D, Gyawali A. Pesticidal potential of ethnobotanically important plants in Nepal—A review. Acta Scientifica Malaysia. 2020;4(2):69-74'},{id:"B35",body:'NPC. Tenth five year plan, National Planning Commission. Kathmandu, Nepal; 2003'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Sushil Nyaupane",address:"sunyaupane@gmail.com",affiliation:'
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Radiotherapy and Nuclear Medicine Technology has always been my aspiration and my life. As years passed I accumulated a tremendous amount of skills and knowledge in Radiotherapy and Nuclear Medicine, Conventional Radiology, Radiation Protection, Bioinformatics Technology, PACS, Image processing, clinically and lecturing that will enable me to provide a valuable service to the community as a Researcher and Consultant in this field. My method of translating this into day to day in clinical practice is non-exhaustible and my habit of exchanging knowledge and expertise with others in those fields is the code and secret of success.",institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"313277",title:"Dr.",name:"Bartłomiej",middleName:null,surname:"Płaczek",slug:"bartlomiej-placzek",fullName:"Bartłomiej Płaczek",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/313277/images/system/313277.jpg",biography:"Bartłomiej Płaczek, MSc (2002), Ph.D. (2005), Habilitation (2016), is a professor at the University of Silesia, Institute of Computer Science, Poland, and an expert from the National Centre for Research and Development. His research interests include sensor networks, smart sensors, intelligent systems, and image processing with applications in healthcare and medicine. He is the author or co-author of more than seventy papers in peer-reviewed journals and conferences as well as the co-author of several books. He serves as a reviewer for many scientific journals, international conferences, and research foundations. Since 2010, Dr. Placzek has been a reviewer of grants and projects (including EU projects) in the field of information technologies.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"35000",title:"Prof.",name:"Ulrich H.P",middleName:"H.P.",surname:"Fischer",slug:"ulrich-h.p-fischer",fullName:"Ulrich H.P Fischer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/35000/images/3052_n.jpg",biography:"Academic and Professional Background\nUlrich H. P. has Diploma and PhD degrees in Physics from the Free University Berlin, Germany. He has been working on research positions in the Heinrich-Hertz-Institute in Germany. Several international research projects has been performed with European partners from France, Netherlands, Norway and the UK. He is currently Professor of Communications Systems at the Harz University of Applied Sciences, Germany.\n\nPublications and Publishing\nHe has edited one book, a special interest book about ‘Optoelectronic Packaging’ (VDE, Berlin, Germany), and has published over 100 papers and is owner of several international patents for WDM over POF key elements.\n\nKey Research and Consulting Interests\nUlrich’s research activity has always been related to Spectroscopy and Optical Communications Technology. Specific current interests include the validation of complex instruments, and the application of VR technology to the development and testing of measurement systems. He has been reviewer for several publications of the Optical Society of America\\'s including Photonics Technology Letters and Applied Optics.\n\nPersonal Interests\nThese include motor cycling in a very relaxed manner and performing martial arts.",institutionString:null,institution:{name:"Charité",country:{name:"Germany"}}},{id:"341622",title:"Ph.D.",name:"Eduardo",middleName:null,surname:"Rojas Alvarez",slug:"eduardo-rojas-alvarez",fullName:"Eduardo Rojas Alvarez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/341622/images/15892_n.jpg",biography:null,institutionString:null,institution:{name:"University of Cuenca",country:{name:"Ecuador"}}},{id:"215610",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sarfraz",slug:"muhammad-sarfraz",fullName:"Muhammad Sarfraz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/215610/images/system/215610.jpeg",biography:"Muhammad Sarfraz is a professor in the Department of Information Science, Kuwait University. His research interests include computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, intelligent systems, information technology, and information systems. Prof. Sarfraz has been a keynote/invited speaker on various platforms around the globe. He has advised various students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He is a member of various professional societies and a chair and member of the International Advisory Committees and Organizing Committees of various international conferences. Prof. Sarfraz is also an editor-in-chief and editor of various international journals.",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"32650",title:"Prof.",name:"Lukas",middleName:"Willem",surname:"Snyman",slug:"lukas-snyman",fullName:"Lukas Snyman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/32650/images/4136_n.jpg",biography:"Lukas Willem Snyman received his basic education at primary and high schools in South Africa, Eastern Cape. He enrolled at today's Nelson Metropolitan University and graduated from this university with a BSc in Physics and Mathematics, B.Sc Honors in Physics, MSc in Semiconductor Physics, and a Ph.D. in Semiconductor Physics in 1987. After his studies, he chose an academic career and devoted his energy to the teaching of physics to first, second, and third-year students. After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/267434/images/system/267434.jpg",biography:"Dr. Rohit Raja received Ph.D. in Computer Science and Engineering from Dr. CVRAMAN University in 2016. His main research interest includes Face recognition and Identification, Digital Image Processing, Signal Processing, and Networking. Presently he is working as Associate Professor in IT Department, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur (CG), India. He has authored several Journal and Conference Papers. He has good Academics & Research experience in various areas of CSE and IT. He has filed and successfully published 27 Patents. He has received many time invitations to be a Guest at IEEE Conferences. He has published 100 research papers in various International/National Journals (including IEEE, Springer, etc.) and Proceedings of the reputed International/ National Conferences (including Springer and IEEE). He has been nominated to the board of editors/reviewers of many peer-reviewed and refereed Journals (including IEEE, Springer).",institutionString:"Guru Ghasidas Vishwavidyalaya",institution:{name:"Guru Ghasidas Vishwavidyalaya",country:{name:"India"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:null},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:null,institution:{name:"Beijing University of Technology",country:{name:"China"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"243698",title:"M.D.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. Dr. Wang was awarded two research project grants focused on multimodal optical coherence tomography imaging and deep learning in cataract and retinal disease, from the National Natural Science Foundation of China. He has published around 30 peer-reviewed journal papers and four book chapters and co-edited one book.",institutionString:"Shanxi Eye Hospital",institution:{name:"Shanxi Eye Hospital",country:{name:"China"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Igor Victorovich Lakhno was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPh.D. – 1999, Kharkiv National Medical Univesity.\nDSC – 2019, PL Shupik National Academy of Postgraduate Education \nProfessor – 2021, Department of Obstetrics and Gynecology of VN Karazin Kharkiv National University\nHead of Department – 2021, Department of Perinatology, Obstetrics and gynecology of Kharkiv Medical Academy of Postgraduate Education\nIgor Lakhno has been graduated from international training courses on reproductive medicine and family planning held at Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor in the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics, and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s been a professor in the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics, and gynecology department. He’s affiliated with Kharkiv Medical Academy of Postgraduate Education as a Head of Department from November 2021. Igor Lakhno has participated in several international projects on fetal non-invasive electrocardiography (with Dr. J. A. Behar (Technion), Prof. D. Hoyer (Jena University), and José Alejandro Díaz Méndez (National Institute of Astrophysics, Optics, and Electronics, Mexico). He’s an author of about 200 printed works and there are 31 of them in Scopus or Web of Science databases. Igor Lakhno is a member of the Editorial Board of Reproductive Health of Woman, Emergency Medicine, and Technology Transfer Innovative Solutions in Medicine (Estonia). He is a medical Editor of “Z turbotoyu pro zhinku”. Igor Lakhno is a reviewer of the Journal of Obstetrics and Gynaecology (Taylor and Francis), British Journal of Obstetrics and Gynecology (Wiley), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for a DSc degree “Pre-eclampsia: prediction, prevention, and treatment”. Three years ago Igor Lakhno has participated in a training course on innovative technologies in medical education at Lublin Medical University (Poland). Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: are obstetrics, women’s health, fetal medicine, and cardiovascular medicine. \nIgor Lakhno is a consultant at Kharkiv municipal perinatal center. He’s graduated from training courses on endoscopy in gynecology. He has 28 years of practical experience in the field.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. RELACION DE PONENCIAS DE LA SOCIEDAD ESPAÑOLA DE OFTALMOLOGIA. 10/2014.",institutionString:null,institution:null},{id:"265335",title:"Mr.",name:"Stefan",middleName:"Radnev",surname:"Stefanov",slug:"stefan-stefanov",fullName:"Stefan Stefanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/265335/images/7562_n.jpg",biography:null,institutionString:null,institution:null},{id:"7227",title:"Dr.",name:"Hiroaki",middleName:null,surname:"Matsui",slug:"hiroaki-matsui",fullName:"Hiroaki Matsui",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Tokyo",country:{name:"Japan"}}},{id:"318905",title:"Prof.",name:"Elvis",middleName:"Kwason",surname:"Tiburu",slug:"elvis-tiburu",fullName:"Elvis Tiburu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Ghana",country:{name:"Ghana"}}},{id:"336193",title:"Dr.",name:"Abdullah",middleName:null,surname:"Alamoudi",slug:"abdullah-alamoudi",fullName:"Abdullah Alamoudi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"318657",title:"MSc.",name:"Isabell",middleName:null,surname:"Steuding",slug:"isabell-steuding",fullName:"Isabell Steuding",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"318656",title:"BSc.",name:"Peter",middleName:null,surname:"Kußmann",slug:"peter-kussmann",fullName:"Peter Kußmann",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"338222",title:"Mrs.",name:"María José",middleName:null,surname:"Lucía Mudas",slug:"maria-jose-lucia-mudas",fullName:"María José Lucía Mudas",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Carlos III University of Madrid",country:{name:"Spain"}}}]}},subseries:{item:{id:"86",type:"subseries",title:"Business and Management",keywords:"Demographic shifts, Innovation, Technology, Next-gen leaders, Worldwide environmental issues and clean technology, Uncertainty and political risks, Radical adjacency, Emergence of new business ecosystem type, Emergence of different leader and leader values types, Universal connector, Elastic enterprise, Business platform, Supply chain complexity",scope:"
\r\n\tThe Business and Management series topic focuses on the most pressing issues confronting organizations today and in the future. Businesses are trying to figure out how to lead in a time of global uncertainty. In emerging markets, issues such as ill-defined or unstable policies, as well as corrupt practices, can be hugely problematic. Changes in governments can result in new policy, regulations, and interest rates, all of which can be detrimental to foreign businesses and investments. A growing trend towards economic nationalism also makes the current global political landscape potentially hostile towards international businesses.
\r\n
\r\n\tThe demographic shifts are creating interesting challenges. People are living longer, resulting to an aging demographic. We have a large population of older workers and retirees who are living longer lives, combined with a declining birthrate in most parts of the world. Businesses of all types are looking at how technology is affecting their operations. Several questions arise, such as: How is technology changing what we do? How is it transforming us internally, how is it influencing our clients and our business strategy? It is about leveraging technology to improve efficiency, connect with customers more effectively, and drive innovation. The majority of innovative companies are technology-driven businesses. Realizing digital transformation is today’s top issue and will remain so for the next five years. Improving organizational agility, expanding portfolios of products and services, creating, and maintaining a culture of innovation, and developing next -generation leaders were also identified as top challenges in terms of both current and future issues.
\r\n
\r\n\tThe most sustained profitable growth occurs when a company expands its core business into an adjacent space. This has significant implications for management because innovation in business ecosystems differs from traditional, vertically integrated firms. Every organization in the ecosystem must be aware of the bigger picture. Innovation in ecosystems necessitates collaborative action to invent and appraise, efficient, cross-organizational knowledge flows, modular architectures, and good stewardship of legacy systems. It is built on multiple, interconnected platforms. Environmental factors have already had a significant impact in the West and will continue to have an impact globally. Businesses must take into account the environmental impact of their daily operations. The advantage of this market is that it is expected to grow more rapidly than the overall economy. Another significant challenge is preparing the next generation of leaders to elevate this to the number one priority within the next five years. There can be no culture of innovation unless there is diverse leadership or development of the next generation of leaders; and these diverse, next-generation leaders are the ones who will truly understand the digital strategies that will drive digital transformation.
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\r\n\tThis series will provide a comprehensive overview of recent research trends in business and management, economics, and marketing. Topics will include asset liability management, financial consequences of the financial crisis and covid-19, financial accounting, mergers and acquisitions, management accounting, SMEs, financial markets, corporate finance and governance, managerial technology and innovation, resource management and sustainable development, social entrepreneurship, corporate responsibility, ethics and accountability, microeconomics, labour economics, macroeconomics, public economics, financial economics, econometrics, direct marketing, creative marketing, internet marketing, market planning and forecasting, brand management, market segmentation and targeting and other topics under business and management. This book series will focus on various aspects of business and management whose in-depth understanding is critical for business and company management to function effectively during this uncertain time of financial crisis, Covid-19 pandemic, and military activity in Europe.
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\r\n\tThe Business and Management series topic focuses on the most pressing issues confronting organizations today and in the future. Businesses are trying to figure out how to lead in a time of global uncertainty. In emerging markets, issues such as ill-defined or unstable policies, as well as corrupt practices, can be hugely problematic. Changes in governments can result in new policy, regulations, and interest rates, all of which can be detrimental to foreign businesses and investments. A growing trend towards economic nationalism also makes the current global political landscape potentially hostile towards international businesses.
\r\n
\r\n\tThe demographic shifts are creating interesting challenges. People are living longer, resulting to an aging demographic. We have a large population of older workers and retirees who are living longer lives, combined with a declining birthrate in most parts of the world. Businesses of all types are looking at how technology is affecting their operations. Several questions arise, such as: How is technology changing what we do? How is it transforming us internally, how is it influencing our clients and our business strategy? It is about leveraging technology to improve efficiency, connect with customers more effectively, and drive innovation. The majority of innovative companies are technology-driven businesses. Realizing digital transformation is today’s top issue and will remain so for the next five years. Improving organizational agility, expanding portfolios of products and services, creating, and maintaining a culture of innovation, and developing next -generation leaders were also identified as top challenges in terms of both current and future issues.
\r\n
\r\n\tThe most sustained profitable growth occurs when a company expands its core business into an adjacent space. This has significant implications for management because innovation in business ecosystems differs from traditional, vertically integrated firms. Every organization in the ecosystem must be aware of the bigger picture. Innovation in ecosystems necessitates collaborative action to invent and appraise, efficient, cross-organizational knowledge flows, modular architectures, and good stewardship of legacy systems. It is built on multiple, interconnected platforms. Environmental factors have already had a significant impact in the West and will continue to have an impact globally. Businesses must take into account the environmental impact of their daily operations. The advantage of this market is that it is expected to grow more rapidly than the overall economy. Another significant challenge is preparing the next generation of leaders to elevate this to the number one priority within the next five years. There can be no culture of innovation unless there is diverse leadership or development of the next generation of leaders; and these diverse, next-generation leaders are the ones who will truly understand the digital strategies that will drive digital transformation.
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\r\n\tThe topic on Economics is designed to disseminate knowledge around broad global economic issues. Original submissions will be accepted in English for applied and theoretical articles, case studies and reviews about the specific challenges and opportunities faced by the economies and markets around the world. The authors are encouraged to apply rigorous economic analysis with significant policy implications for developed and developing countries. Examples of subjects of interest will include, but are not limited to globalization, economic integration, growth and development, international trade, environmental development, country specific comparative analysis, technical innovation and knowledge management, political economy analysis, and banking and financial markets.
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\r\n\tMarketing is an important aspect in the functioning of all types of organizations. The external environment is characterized by constant and dynamic changes, that pose risks to the company. It is associated with changes in macroeconomic, political, legal, and demographic, as well as new consumer trends. It is necessary to carefully plan marketing activities in order to provide the market with products that satisfy consumers' needs and desires, provide them with value, and bring satisfaction and contentment. Therefore, in this topic, we focus on overall marketing efforts, including marketing communications through traditional and social media, pricing strategies, distribution strategies, branding, innovation, and new product launches, as well as researching the current market and consumer trends. We also analyze the latest trends and tendencies in marketing, such as product placement and neuromarketing.
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