Editorial: Lung Cancer Worldwide| Volume 14, ISSUE 9, P1504-1509, September 2019

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# Lung Cancer in Chile

Open Archive

## Introduction

Chile is a long and narrow country located in South America; its population as of 2017 was 18,419,192. Life expectancy is 83 years for women and 77 years for men.
Censo2018
Estimaciones y proyecciones de la población de Chile 1992-2050. Methodology and main results [Spanish].
Cancer is currently the second leading cause of death in Chile, causing 25.6% of total annual deaths, and recent estimations report that cancer will be the leading cause of death by 2030. It is also the main cause of disease burden measured in terms of disability-adjusted life-years.
Censo2018
Estimaciones y proyecciones de la población de Chile 1992-2050. Methodology and main results [Spanish].
The increasing incidence of cancer can be explained by aging of the Chilean population and known risk factors such as obesity, cigarette smoking, sedentary lifestyle, and other environmental factors. The Chilean health system has universal coverage; it is based on a two-tier system with both private and public health providers. This has led to significant health inequalities, which have been the focus of several health reforms. Current public health spending is 8.1% of the gross domestic product. The new National Cancer Plan is still being debated in Congress, and it is hoped that this plan will improve prevention, diagnosis, and treatment for Chilean patients.

## Epidemiology

Lung cancer in Chile, as in many countries in the world, is one of the most common cancers in the country. According to Globocan statistics, 53,365 new cases of cancer and 28,443 deaths were projected for Chile in 2018. The reported annual incidence of new cases of lung cancer in 2018 in both sexes was 3873, with lung cancer being the first cause of cancer death and accounting for approximately 3581 deaths.
World Health Organization
International Agency for Research on Cancer. Rates: cancers by population: Chile; source: Globocan 2018.
The incidence of lung cancer in two different regions of Chile that are Antofagasta and De Los Rios are shown in Figure 1.

Primer informe de registros poblacionales de cáncer de Chile, Quinquenio 2003–2007. https://www.paho.org/chi/index.php?option=com_docman&view=download&alias=174-informe-rpc-chile-2003-2007&category_slug=cancer&Itemid=1145. Accessed January 13, 2019.

Torres-Avilés et al. analyzed the m (e.ortality rate in Chile for lung cancer between 1990 and 2009 and observed that there was a 19.9% reduction in the lung cancer mortality rate in male patients but an increase of 28.4% in female patients.
• Torres-Avilés F.
• Moraga T.
• Núñez L.
• Icaza G.
Lung cancer mortality trends in Chile and six-year projections using Bayesian dynamic linear models.
Considering traditional risk factors, smoking is an important problem in Chile. According to data from the national health survey, 32.5% of the population are active smokers. Subgroup analysis shows that the prevalence of active smokers between the ages of 25 and 44 years has remained stable, although in the group of those 15 to 24 years old the prevalence of smoking has declined in recent years.
Departamento de Epidemiología División de Planificación Sanitaria Ministerio de Salud, Chile. Consumo de tabaco. Informe Encuesta Nacional de Salud 2016-2017.
This could be due to the restrictive legislation and tax rate increase that were implemented in Chile in 2010. Exposure to secondhand smoke remains a big problem in Chile. Nicotine concentrations in the indoor air of public places and workplaces in Santiago were among the highest in Latin America, particularly in restaurants and bars. Erazo et al. measured air nicotine concentrations, which were 3.2, 35.5, and 56.2 times higher in nonsmoking areas in mixed venues, smoking areas in mixed venues, and smoking venues, respectively, than in smoke-free venues in 30 bars in Santiago, Chile.
• Erazo M.
• Iglesias V.
• Droppelmann A.
• et al.
Secondhand tobacco smoke in bars and restaurants in Santiago, Chile: evaluation of partial smoking ban legislation in public places.
A special consideration is arsenic exposure in the Chilean population. Marshall et al. compared two different regions of Chile according to exposure to water contamination with arsenic between the years 1950 and 2000. The lung and bladder cancer mortality rate ratios for the region Antofagasta (region II), which was exposed to water contamination, compared with those for the region Valparaiso (region V) started to increase about 10 years after high levels of arsenic exposure commenced and continued to rise until peaking in 1986–1997.
• Marshall G.
• Ferreccio C.
• Yuan Y.
• et al.
Fifty-year study of lung and bladder cancer mortality in Chile related to arsenic in drinking water.
Despite installation of treatment plants in 1970 and 1978, which reduced concentrations to less than 10 μg/L, combined lung and bladder cancer mortality rates in region II were highest in the period 1992–1994, with mortality rates of 153 and 50 per 100,000 men and women, respectively, compared with 54 and 19 per 100,000 in region V. An update published in 2017 by Smith et al. demonstrated that the population exposed to arsenic-contaminated water had increased risks of bladder and lung cancer, even 40 years after reduction of the exposure.
• Smith A.H.
• Marshall G.
• Roh T.
• Ferreccio C.
• Liaw J.
• Steinmaus C.
Lung, bladder, and kidney cancer mortality 40 years after arsenic exposure reduction.

## Screening

As of this moment, there is no national screening program for lung cancer in Chile. Considering the recently published positive results of the NELSON trial, in which computed tomography (CT) screening was shown to be effective in assessing lung nodules in people at high risk for lung cancer, major efforts are needed to implement effective strategies for the near future.

De Koning H, Van Der Aalst C, Ten Haaf K, et al. Effects of volume CT lung cancer screening: mortality results of the NELSON randomized-controlled population based trial. Abstract presented at the 19th World Conference on Lung Cancer. September 25, 2018; Toronto, Canada.

Saldias et al. studied 160 high-risk patients who underwent screening for 3 years with CT scans and follow-up for 5 years. Lung cancer was diagnosed in 5.6% of those patients. In most patients, the diagnosis was made in early stages of the disease, and 92% of patients had false-positive results.
• Saldias P.F.
• Diaz P.J.C.
• Rain M.C.
• Illanes C.
• Diaz T.R.
• Diaz P.O.
Detección precoz de cáncer pulmonar con tomografía computarizada de tórax en pacientes con enfermedad pulmonar obstructiva crónica tabáquica.
In countries such as Chile, funding efforts in screening have to be balanced with the eventual different findings of CT and the resolution capacity of our health system. In most of the public hospitals in Chile, lack of radiologists specialized in lung pathology and thoracic surgeons make it unreasonable to pursue a screening program at this moment.

## Lung Cancer Management in Chile

Chile has universal health coverage for its population; coverage is based on a two-tier system: a publicly funded system (called Fonasa), which provides health to approximately 80% of citizens, and a privately funded system, in which several companies cover the remaining 20%. These companies are called Isapres. The public sector has an oncology network with 25 centers capable of providing surgery and chemotherapy.
Chilean Ministry of Health
National cancer plan 2018–2028 [Spanish].
The private system budget is almost three times higher per capita than the public system,
Chilean Ministry of Health
Financial sustainability of the public health system: establishing the bases for a new management and financing system [Spanish].
which is reflected in the different availability and reimbursement for some therapies, as we will discuss later. This problem of health inequality is well documented,
• Gallardo K.
• Varas L.
• Gallardo M.
Inequality of opportunity in health: evidence from Chile.
• Mardones F.
[Inequality of health care for the elderly in Chile].
and there have been efforts to correct it through health reforms and public health spending: measured as percentage of the Chilean gross domestic product, public health spending has grown from to 6.6% in 2005 to 8.1% in 2017.
• Cabieses B.
• Cookson R.
• Espinoza M.
• Santorelli G.
Did socioeconomic inequality in self-reported health in Chile fall after the equity-based healthcare reform of 2005? A concentration index decomposition analysis.
Organization for Economic Cooperation and Development
OCDE studies on public health: Chile. Evaluation and recommendations [Spanish].
In very general terms, NSCLC management in Chile follows international guidelines, and can be outlined by stage as follows: stage I, surgery alone; stage II, surgery followed by adjuvant chemotherapy; stage III, definitive concurrent chemoradiation (which is the most frequent approach) and induction chemotherapy followed by surgery in select patients; and stage IV, chemotherapy and palliative care.
As for SCLC, a similar broad approach can be summarized as follows: stages I and II, surgery followed by adjuvant chemotherapy; stage III, definitive concurrent chemoradiation; and stage IV, chemotherapy and palliative care.

### Surgical Approaches

As already mentioned, in NSCLC stage I and stage II disease is always managed with surgery if pulmonary function allows it. As for stage III disease, if no nodal disease is evident on staging studies, surgery is also the preferred approach. If suspicious nodes are detected, one of several methods can be used for nodal staging, depending on which stations are to be studied; they are endobronchial ultrasound, endoscopic ultrasound, or mediastinoscopy. A significant gap exists in available staging methods in Chile, as most public centers do not yet have endobronchial ultrasound or endoscopic ultrasound available. If nodal disease is confirmed, the usual approach is concurrent chemotherapy and radiotherapy regimens, although chemotherapy induction followed by surgery remains as an alternative for specific patients.
In general, lobectomy is preferred over limited resections, and video-assisted thoracoscopic surgery is preferred over open surgery if technically feasible; most centers performing lung surgery have the technical capabilities for video-assisted thoracoscopic surgery, but the final decision on the surgical approach will depend on a case-by-case analysis by the surgical team. Three centers in Chile have robotic-assisted surgery capabilities, but the use of this technique is very low in lung cancer locally.

Radiation therapy is an essential component in lung cancer management, and as such, it is available on a national level. There are a total of 21 radiotherapy centers counting both private and public institutions.
Chilean Ministry of Health
General technical norm No. 51: Oncologic Radiotherapy [Spanish].
The public sector has seven centers with three-dimensional conformal radiation therapy capabilities, and five of them also have intensity-modulated radiation therapy capabilities; this figure is expected to grow significantly according to the new National Cancer Plan
• Saldias P.F.
• Diaz P.J.C.
• Rain M.C.
• Illanes C.
• Diaz T.R.
• Diaz P.O.
Detección precoz de cáncer pulmonar con tomografía computarizada de tórax en pacientes con enfermedad pulmonar obstructiva crónica tabáquica.
that was recently presented by the government. As for stereotactic body radiation therapy, it is still in the very early stages, with only one public center and two private centers using this technique in lung cancer.
When definitive chemoradiation is used for stage III NSCLC, the standard approach is external beam radiotherapy, 60 to 70 Gy in 2-Gy fractions with concurrent platinum-based chemotherapy. Radiation is also an alternative for earlier stages when patients are not surgical candidates; in this case, stereotactic body radiation therapy is the preferred approach, but as we have already mentioned, access to this technique is still very limited, and some centers will use intensity-modulated radiation therapy in this setting.
Another indication for radiotherapy is prophylactic brain irradiation in SCLC if there is response to initial treatment. Radiation therapy also plays an important role in the palliative care setting, as painful bone lesions have good response to external beam radiotherapy, and this is widely available for Chilean patients as part of palliative care programs.

### Systemic Therapy

Chemotherapy agents utilized in the management of NSCLC and SCLC, including cisplatin, carboplatin, etoposide, gemcitabine, and docetaxel, are available and covered by the health systems, both public and private. Novel agents such as EGFR tyrosine kinase inhibitors (TKIs), ALK receptor tyrosine kinase inhibitors, and BRAF inhibitors pose a significant problem given their high cost. In general, these drugs are not reimbursed by the public health sector, so they must be paid for by patients who can afford them. In the private health sector reimbursement is possible, although limited, and will ultimately depend on the insuring company (Isapre) to determine this.
A similar situation applies to immunotherapy: pembrolizumab is approved by local regulatory authorities for metastatic NSCLC in the first-line setting for programmed death ligand-1–positive patients, whereas both atezolizumab and nivolumab are approved in second-line treatment after progression to EGFR TKIs, ALK receptor tyrosine kinase inhibitors, or platinum-based therapy. A recent analysis by the Chilean Health Ministry deemed these agents not cost-effective in the local setting.
Chilean Ministry of Health
Nivolumab, pembrolizumab: report of available scientific evidence [Spanish].
They are not covered by the public health system, and although some Isapre programs do reimburse these treatments, the reimbursement is available for only a very small segment of the population. A summary of drugs available in Chile and their reimbursement is presented in Table 1.
Chilean Ministry of Health
Nivolumab, pembrolizumab: report of available scientific evidence [Spanish].
The treatment algorithm shown in Figure 2 reflects current drug approvals and clinical standard of care; however, availability of the full array of treatment options will depend on the patients health insurance, as we have previously mentioned.
Table 1Novel Drugs Approved in Chile for Advanced/Metastatic NSCLC
DrugApproved in First LineApproved in Second LineReimbursement (Public System)Reimbursement (Private System)
ErlotinibNoYes
AfatinibNoPartial
The term Partial indicates that is up to each specific private insurance company to decide whether they reimburse the drug, usually on a case-by-case analysis. Indicated approvals are based on publicly available information16 from the local drug regulatory authority (National Institute of Public Health) as of January, 2019.
GefitinibNoYes
OsimertinibNoPartial
CrizotinibNoPartial
CeritinibNoPartial
AlectinibNoPartial
Dabrafenib + trametinib (If BRAF V600F mutation is present)NoPartial
PembrolizumabNoPartial
NivolumabNoPartial
AtezolizumabNoPartial
a The term Partial indicates that is up to each specific private insurance company to decide whether they reimburse the drug, usually on a case-by-case analysis. Indicated approvals are based on publicly available information
Organization for Economic Cooperation and Development
OCDE studies on public health: Chile. Evaluation and recommendations [Spanish].
from the local drug regulatory authority (National Institute of Public Health) as of January, 2019.

## Discussion

Lung cancer is the deadliest cancer in Chile, with increasing mortality in the female population. This grim outlook underscores the need to improve prevention, detection, and treatment in an urgent manner.
Tobacco control is one of the areas that has received attention in the past few years, with new laws restricting smoking spaces, increasing taxation, and requiring better labeling of cancer risk on cigarette boxes. The impact of these measures has been significant, as the percentage of active smokers has decreased from 43% in 2003 to 33% in 2017.
Departamento de Epidemiología División de Planificación Sanitaria Ministerio de Salud, Chile. Consumo de tabaco. Informe Encuesta Nacional de Salud 2016-2017.
An area that clearly needs improvement is local data on lung cancer; there is no lung cancer registry, and the only existing data are mortality data obtained through death certificates of the Chilean national registry service. There are no established early detection programs, and we should consider implementing low-dose CT screening for high-risk patients.
As established in the report of the Economist Intelligence Unit, in which economic modeling to estimate the direct and indirect costs of lung cancer in 12 countries in the region was performed, the estimated direct health care cost for lung cancer in Chile is $118,494,725, and the estimated per-patient direct cost for lung cancer is$30,679, which is one of the highest costs in Latin America.

Economist Intelligence Unit. Lung Cancer in Latin America: Time to Stop Looking Away. https://perspectives.eiu.com/sites/default/files/EIU_Roche%20-%20Lung%20cancer%20in%20Latin%20America_Time%20to%20stop%20looking%20away.pdf. Accessed January 20, 2019.

This, in association with a well-documented health inequality problem in Chile that is reflected in a significant gap in access to effective therapies (because of which more than 80% of the population does not have access to EGFR TKIs and other costly drugs that are considered standard of care), makes lung cancer one of the important priorities in the near future. An additional effort is needed from authorities to increase coverage and access for the population.
In this setting, clinical trial involvement is a good alternative for patients to access newer and more effective therapies. The new National Cancer Plan project will be a significant milestone for the country, and it is undergoing discussion in Congress right now. This is a great opportunity to change the landscape of cancer in our country, and it is hoped that the plan will implement some of the needed improvements discussed in this article.
Finally, we have to understand lung cancer and tobacco control as a global challenge, with regional and international partnerships playing a crucial role in improving the future of our patients.

## References

• Censo2018
Estimaciones y proyecciones de la población de Chile 1992-2050. Methodology and main results [Spanish].
• World Health Organization
International Agency for Research on Cancer. Rates: cancers by population: Chile; source: Globocan 2018.
(Accessed January 15, 2019)
1. Primer informe de registros poblacionales de cáncer de Chile, Quinquenio 2003–2007. https://www.paho.org/chi/index.php?option=com_docman&view=download&alias=174-informe-rpc-chile-2003-2007&category_slug=cancer&Itemid=1145. Accessed January 13, 2019.

• Torres-Avilés F.
• Moraga T.
• Núñez L.
• Icaza G.
Lung cancer mortality trends in Chile and six-year projections using Bayesian dynamic linear models.
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(Accessed January 15, 2019)
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• Iglesias V.
• Droppelmann A.
• et al.
Secondhand tobacco smoke in bars and restaurants in Santiago, Chile: evaluation of partial smoking ban legislation in public places.
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• Marshall G.
• Ferreccio C.
• Yuan Y.
• et al.
Fifty-year study of lung and bladder cancer mortality in Chile related to arsenic in drinking water.
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• Smith A.H.
• Marshall G.
• Roh T.
• Ferreccio C.
• Liaw J.
• Steinmaus C.
Lung, bladder, and kidney cancer mortality 40 years after arsenic exposure reduction.
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• Diaz P.J.C.
• Rain M.C.
• Illanes C.
• Diaz T.R.
• Diaz P.O.
Detección precoz de cáncer pulmonar con tomografía computarizada de tórax en pacientes con enfermedad pulmonar obstructiva crónica tabáquica.
Rev Med Chil. 2016; 144 ([Spanish]): 202-210
• Chilean Ministry of Health
National cancer plan 2018–2028 [Spanish].
• Chilean Ministry of Health
Financial sustainability of the public health system: establishing the bases for a new management and financing system [Spanish].
• Gallardo K.
• Varas L.
• Gallardo M.
Inequality of opportunity in health: evidence from Chile.
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• Mardones F.
[Inequality of health care for the elderly in Chile].
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• Cabieses B.
• Cookson R.
• Espinoza M.
• Santorelli G.