Episode 71: Lung Cancer- Part 1/2

Welcome to MedPod, the audio podcast from the Department of Internal Medicine at AFMC. We've been doing these podcasts for the benefit of our undergraduate students, postgraduate residents in medicine and allied subjects and young medical officers in field. Our aim is to bring reliable, validated resources from our own eminent faculty in various subjects and that brings a resource to the students right to their ears where they can prepare for their exams and also it helps them when they treat patients. Continuing with our series, today we shall be interviewing Colonel G.S. Chaudhary who is head of the Department of Melignan Diseases Treatment Center at the Command Hospital in Southern Command here in Pune, who is a professor of medicine and medical oncology and he shall be talking to us on a very important and clinically relevant topic and that happens to be of lung cancer. So welcome to MedPod sir. Thank you for inviting me. So this, like I mentioned, this resource actually addresses students who are fairly new to the subject and so our aim is to keep it as simple as possible and in that process we always bring faculty who are senior, who are eminent and also have the professorial way of simplifying things and which is exactly what we expect from you with your vast experience. So talking about lung cancer, what is the overall global burden of this disease in the world? The global burden of cancer as such is increasing many fold and it is one of the common non-communicable diseases which is killing a lot number of people. The in a population, world population of around 8.1 billion people as per the global can data and the international agency for research on cancer the IARC data in 2022 released that the cancer burden is around 20 million cancer cases out of which 9.7 million people would die in that particular year. So if we start counting the number of people alive for the five year period after the diagnosis of cancer, we have around 53.5 million people alive with cancer. This also tells us that one in five men would develop cancer, one in five people will develop cancer in the lifetime, which implies that around 9 men or one in 12 women will ultimately die from cancer and this is a very alarming trend. So what about the lung cancer part of it, is it large enough to be worried about? So when we look at the commonest cancers globally, we know that lung breast, colorectal cancer are the commonest three cancers world over around 2.5 million people in the world suffer from lung cancer out of which 1.8 million die in that year. That means that the incidence rate and the mortality rate mirror each other in lung cancer which is a very dynamic disease and despite many years of treatment, its overall survival rates have remained dismal. And what about the problem as far as our country is concerned? Well in India again, lung cancer is the commonest killer and we have lung cancer, breast cancer, cervical cancer and gastrointestinal cancers which are worrisome. Other than that in the northeast part of the country, we are infamous for having mesoram in the world map for head and neck cancer because of the trends of reverse smoking and known as chutta. The there has been a 12.8% increase in the cancer burden in just the last 5 years. In 2022, we had about 1.4 million new cancer cases in India and the crude incidence rate tells us that around 100 in a lack of population suffer from cancer. The major contributors for this non-communicable disease of cancer is mainly of physical inactivity, alcohol and tobacco use, a less intake of fruit and vegetables and an increased salt intake which are very common factors which lead to malignancy in our country. And also to add to this the late diagnosis of cancer to reach from a peripheral hospital or a B.H.C. to a tertiary care hospital where the facilities for both diagnosis and treatment are available. Right, so when we talk about lung cancer almost simultaneously, the thing that comes to mind is smoking. This is a problem that is huge and so how do you correlate smoking with cancer? So while smoking in most of the patients who come to our clinic with cancer, lung cancer in particular and aero digestive cancers, smoking is a very common risk factor and about 90% of smokers land up with this terrible disease. Now cigarette smoke as we all know is a complex aerosol and it contains nicotine which is the editing factor and as we remove nicotine and water from this complex aerosol we are left behind with tar. Tar as we learn is a very strongly carcinogenic element and hence the government regulations have tried to reduce the amount of tar content of cigarettes. It will surprise you to know that tar contains more than 50 types of carcinogens. Out of these we group them into two different types of carcinogens one which require metabolic activation which are tobacco specific nitrosamines which require nitrosolation to get activated like NNKs poly aromatic hydrocarbons. These form DNA adepts and activate Keras pathway they were leading to malignancy. The other contents of cigarette smoke like benzene, phenyl chloride, arsenic, polonium do not require metabolic activation and are per se carcinogenic. So it is in our interest to increase the filter content of the cigarette smoke by government regulation. We need to reduce the tar content of cigarette smoke and it may surprise you to know that when we measure effects of cigarette smoke on the spouse or the partners of a person who is a smoker they also are at a higher risk of lung cancer and other aerodiastive cancers due to second hand smoke. So when we talk about smoking and cancer there is a mention of this study called the dolls and hill study. If you could elaborate on that yeah as we now are aware that cigarette smoke definitely is carcinogenic this was not so well known at the turn of the century and somewhere around 1916 there is a person called Adler who in his autopsy studies showed that the incidence of lung cancer world over was just about 0.5 percent. In another four decades lung cancer became so common that there was a suspicion that is it linked to smoking or due to the pollution in our environment. And doll and hill are two British epidemiologist Sir Richard Doll and Sir Albert Hill who proved to us that by studying patients they made two groups of patients who were exposed to cigarette smoke and had lung cancer and those who were not exposed to cigarette smoke and they found that the odds ratio in this population was definitely favouring that the theory that cigarette smoke causes lung cancer and it is only after that that people became aware that smoking can kill. So when we talk about smoking we also talk about a very important parameter called smoking index not just in the relevance to cancer but also do with chronic lung diseases. So how do you define this index? So we know that smoking is harmful in a multitude of ways and we need to quantify how much an individual smokes because as we approach patients in the clinic they never tell us the exact figure. So we need a smoking index as one of these one of these markers where we can absolutely quantify the risk and this includes the number of cigarettes smoked a day into the number of years the individual has smoked and we normally it would come supposing an individual has smoked 20 cigarettes a day for 10 years the smoking index would be 20 into 10 which is 200 then we quantify them as less than 200 which is mild which is a low smoking index 200 to 400 and intermediate smoking index and more than 400 as a high smoking index. And you did mention briefly but if you could elaborate on the this that what are the parts of the cigarette smoke which are actually carcinogenic and how do they actually lead to this cancer? So cigarette smoke we know is harmful first if we start with just taking in India it will surprise you to know that having a beady a cigar or a cigarette have the same quantity of nicotine in all of them and despite government legislation and those gory pictures on cigarette packs people still continue to smoke which is definitely a element of peer pressure or as they progress from their teens into adulthood due to peer pressure they continue to smoke. Now the tip of the cigarette contains a very high temperature and this itself can be damaging it can cause burns in the lips and people in the northeast are very commonly reversing the cigarette and putting the burning end inside which can damage the soft palate and not only lead to lung cancer but oral cancers as well. Other than the high temperature of the cigarette itself they are a number of carcinogens which I mentioned earlier and these carcinogens are commonly like benzene, vinyl chloride, arsenic, nickel, polonium these are commonly present in cigarette smoke and they cause a damage to the DNA and they form adepts in the DNA. Smoking as little as 100 cigarettes in a lifetime can cause a damage to the DNA which after one genetic hit another genetic hit subsequently can lead to the initiation of cancer and we know that all cancers require a accumulation of genetic mutations to cause damage. Other than this I mentioned poly aromatic hydrocarbons and nitrosamines and tobacco specific nitrosamines are the ones which are highly carcinogenic. Right, so it is very interesting to note that it is not purely the physical effects or chemical effects of these carcinogens but they are acting right at the level of the genes. So if you could just elaborate on what are these molecular changes that happen or what are the driver mutations that eventually lead to this development of cancer. So as we have explored the cancer genome specifically after the human genome project came into light where we could make out that which are the mutations at the molecular level in the genes which are driving these cancers and these driver mutations are the ones which are responsible for the progression of cancer. Ultimately the cancer tends to survive in a human environment where everything every force is against the cancer from developing. These driver mutations then lead to more complex mutations which are called branch mutations. So the basic mutation in a biopsy can be made out by subjecting a biopsy of a lung cancer patient either from the primary in the lung or from a metastatic site and there is a huge amount of concordance up to 95% between both of these. The mutations which we commonly see are some things like EGFR mutation. Now EGFR is a membrane receptor which is implicated in many other diseases and this activates downstream signals within the cell on getting activated and causes cancer. The Asian women who are non-smokers are commonly having EGFR mutations and we find there is no history of smoking yet they have adenocarcinomas which are EGFR mutated which are periphery located. So around 21% of patients would have EGFR mutations and these are actionable that means there is a therapeutic advantage of this we can treat these drugs, treat this with drugs. Similarly they are ALC, MET, RET, ROS1, HER2NEU, DRAF mutations which are now actionable and various drugs are being developed against this. The total number of patients who have oncogenic driver mutations would be almost 40% roughly and in a large percentage of patients 32% we may find no mutations as such. In 25% of such patients we will also have KRAS mutations and recently we have started developing drugs even to act against the KRAS mutations. So when there is a cancer you would look for a mutation and if it is an actionable mutation it makes it all the more beneficial for the patient as far as the prognosis is concerned. So now in most cancers we do have certain precancerous conditions and which are sort of a situation where one can intervene and prevent cancers. Now if we apply the same logic here and smoking being a risk factor commonly seen with chronic lung diseases. Now are chronic obstructive lung disease or interstitial lung disease diseases which predispose patients to develop lung cancers? That is a very appropriate question because most smokers would develop chronic obstructive lung disease and many non-smokers also would come commonly to the clinic saying that they have having cough and productive sputum for more than 2-3 weeks which is not getting away and many a times they would also come with saying that the inhalers are no longer acting and the disease seems to be getting worse. Many of these patients with chronic obstructive lung diseases are found to be an independent risk factor for lung cancer and this increases the risk of lung cancer by about 2.5 fold. And being a chronic inflammatory disease there is also an activation of certain cancer pathways through the factors like the protease, antiprotease imbalance or the NF Kappa Beta pathways which we have learned about previously. Secondly you had asked me about interstitial lung disease. For some reason interstitial lung disease seems to be increasing, increasingly diagnosed in our country as we tend to have longevity. And elderly patients who have a restrictive lung disease due to pulmonary fibrosis have an increased fold of lung cancer and the odds ratio for this is as much as 8.25 that means definitely it does increase the risk of lung cancer and I would also like to add that there are certain ground glass opisties which we see in the imaging in interstitial lung disease which is present in non-dependent areas or there is honey combing which is often a nidus for the development of lung cancer which can be missed by a PET scan because the sensitivity of PET scan for picking up cancer in ground glass opisties is rather low. So in this brief conversation that we have had on this issue till now what it has actually done is that it sort of has opened my ideas about why cancer happens especially when it comes to lung cancer specifically and you start off generally with all cancers and the fact that the burden is increasing. So it is something that we all need to be more aware about and of course then we went into the aspect of cigarette smoking which seems to be a big risk factor and we spoke on how cigarette smoke actually leads to changes at the cellular level which lead to cancer. With this we will end this topic and what it has done is that it has created a base for us to go on to further discussing the topic of lung cancers in more detail which we shall do in our next episode. We thank you sir for sparing your time and enlightening us with your vision. Thank you so much for making me a part of this podcast.