Episode 72: Lung CA-Part 2/2

Welcome to Med Pods, the audio podcast from the Department of Internal Medicine at AFMC. In our last episode, we were talking to the current GS Jyothri, head of the Department of Melignan Diseases Treatment Center, who is a professor in medicine and medical oncologist at the Command Hospital here in Pune and is a faculty here at the AFMC and sir had actually simplified the way we approach cancers as in the epidemiology, the various risk factors and with specific details about cigarette smoking and how it leads to certain molecular changes and which drive mutations leading to cancers and which sort of opened our eyes to this huge burden which lies in front of us both globally as well as in our own country. So, welcome back sir. Thank you very much. The feedback on the first episode has been extremely heartening because this is a topic that we have never covered till now and also the fact that we understand this is all around us, people need to know and so after having created a sort of a base with the fundamentals that you spoke about last time, let us move on to the further details of this topic and so when it comes to lung cancer, how do you classify them? Well lung cancer is normally classified into non-small cell lung cancer which accounts for around 85% to 90% of lung cancers or we say it as small cell lung cancer. This depends on light microscopy on the size of the cell which is causing lung cancer. Further subdividing it, non-small cell lung cancer has further subtypes like adenocarcinoma, squamous cell carcinoma, mixed adenocarcinoma or large cell carcinoma and many times the pathologist writes NOS or not otherwise specified when he can't put his finger on a subtype of lung cancer. One said that there is a histological shift from lung cancer over the past 5 decades for having more central cancers which are squamous cell cancers attributed to beady smoking or arising from squamous metathlasia of the tracheobronchial tree. Now we more often see that as the cigarette filters have become thicker and the tar content has changed, more intense puffing of methanolized cigarettes leads to the particle size being distributed more to the periphery of the lung so there is not only a radiological shift from having central lung cancers which are squamous to more peripheral lung cancers which have adenocarcinoma in them and the approach to them has also changed in the sense that central lung cancers had to be diagnosed by a bronchoscopic biopsy under the respiratory physician whereas peripheral lung cancers need to undergo a CT guided trans thoracic biopsy in the radiology sector. Other than this small cell lung cancers whenever we diagnose and we do an immunohistochemistry to diagnose small cell lung cancer we have to be aware that they should not be mixed up with the carcinoid of the lung or other types of lung cancer. It may surprise you to know that squamous cell lung cancer and small cell lung cancer have the strongest association with cigarette smoke right so we did talk about the classical risk factor that is happens to be tobacco but are there any other risk factors which are also associated with all these types of cancer that you spoke of? In smoking also I would like to add some part which I had left out that we know that those countries which have the highest production of tobacco in the world for example China would be mirroring the rate of lung cancer that means the Chinese couldn't expect a boom of lung cancer in the next few years because the lag period between lung cancer between cigarette smoking to developing lung cancer is roughly 2 to 3 decades. Other than smoking the risk factors for lung cancer are also a genetic predisposition very often you would find that a relative who has lung cancer like a father had lung cancer in his time and his son also developed lung cancer the odds ratio for this being around 1.63 if you have two or more relatives who have lung cancer then the odd ratio doubles to more than 3.6 other than this there is second hand smoke which I had mentioned that the spouse of the individual who is a heavy smoker is also at an added risk of lung cancer other than this as we see daily environmental pollution is increasing and we keep measuring the AQI index and the various particles particulate material in the environment these are definite risk factors for developing lung cancer. Lung cancer can also be caused by occupational hazards like for example people working in the poultry industry which are exposed to various kinds of pneumoconiosis say in the cotton wool industry woodworkers can develop interstitial lung disease specifically of the pulmonary fibrosis subtype would have a enhanced risk of lung cancer other than this people working with in the arsenic industry were you dealing with cadmium chromium nickel or even redon exposure especially in the mining industry would be at a higher risk other than this wherever we are you having insulation for houses where we are using asbestos asbestosis itself can be enhanced the risk of lung cancer especially with the crocodile light and the other subtypes of asbestos used in insulation. Then rarely we can also have smoking as I said because of second hand smoke or side stream smoke from the cigarette hookah tobacco exposure from any such source right. So now we have understood that it is a very common problem and also the good part is that if we pick it up early the treatment becomes easier and it is the prognosis is better. So this is one condition that I can look at as a condition which should be screened for in a population so what are the screening methods which one follows as far as carcinoma lung is concerned. So firstly a high level of alertness in the clinician so it is sad to learn that even in today's era many times a person has come to four different doctors with chronic cuff and he has been given symptomatic treatment at four different points without realizing that this is a person who could have something more than a simple cuff many times patients tell us that they are having hemoptysis or blood in the sputum or they are losing weight or they are having a change in the quality of their voice which is told by the more often by their relatives these should alert us that the individual may be harboring underlying lung cancer. Earlier common screening methods like doing a sputum examination for malignant cells could detect many lung cancers which were central in location and could be cuffed out and in the sputum around 40% of them would have squamous cancer cells however because of the histological shift from central to peripheral cancers and from squamous to edinocasinomas this is no longer the case and we have also realized over the years that doing a sputum cytology with or without a chest x-ray examination is rather inadequate to develop a lung cancer to detect a lung cancer. So we are now enlightened by an NLTS or the National Lung Trial Study which took about 53,000 patients in the age group of 55 to 75 who were smokers for more than 30 back years. So they underwent three rounds of either a chest x-ray or a low volume low dose CT scan which we also know as a helical scan where an individual can just hold his breath for about a second and a spiral CT is run and for this we realized that about a 20% reduction in the lung cancer mortality compared to simple x-ray screening was detected and this is now being declared in the US as a standard of care for people who are high risk groups in the age of group of 55 to 80 years and who have smoked for more than 30 back years or who have left smoking as recent as less than 15 years. Having said that low dose CT scanning is obviously a very expensive tool. It also brings us in the harm's way by exposing us to a certain amount of radiation. So universal coverage in an emerging economy like in India may not be practically possible. And when it comes to the other specialized imaging like PET CT, what is the role as far as CA lung is concerned? So in PET CT is rather known for its negative predictive value. That means if a PET CT scan doesn't have an uptake of a lung mass or a lung nodule then we can be pretty sure that this may not be lung cancer. The PET CT scan works on the principle of Warbur. That means the cancer cells have a malignant phenotype where they start increased uptake of glucose even when there is enough oxygen available. They undergo a process of enhanced aerobic and anaerobic glycolysis. When a PET scan, when we label the glucose molecule with an 18 FDG addition, this leads to a metabolic block. Normally when a cell would uptake glucose, it would get converted into glucose 6-phosphate and thereafter by the action of the enzyme glucose 6-phosphatase would go down to pyruvate and generate ATP necessary for the cells living. However, cancer utilizes this process and the PET scan in a very enhanced manner. That means the blood receptors which facilitate the glucose to go into the cell are increased several fold. The hexokinase gene enzyme is increased several fold and the glucose 6-phosphatase gene which breaks down glucose further is reduced in quantity. So these metabolic changes are the one which are taken advantage of in a PET scan and we have something known as a standard uptake value. Generally a value of SUV more than 2.5 would indicate that this would be sinister for malignancy. In PET scanning compared to when we want to distinguish inflammation versus malignancy, when we look at a same lung mass and if after some time let us say 2 to 3 hours of imaging, the amount of standard uptake value of glucose reduces, then it suggests an inflammatory tissue whereas in malignancy a delayed imaging will have increased uptake as the cancer cells even in the absence of oxygen or even in the necrotic areas would have enhanced uptake. So we can not only image the lung mass, we can also image the media standard and in PET scan will upstage the media standard staging compared to a CT scan by about 14 to 16 percent. However, the gold standard for media standard staging in a lung cancer and the primary in the lung remains a tissue diagnosis by a biopsy or a endobronchial ultrasound guided FNAC. So PET CT will also tell us maybe where to biopsy from, it will give us. Yes, the PET CT scan has a advantage and a disadvantage, the advantage being that in case the patient has let us say for example visceral meds in the liver distant from the lung, then it would also stage the patients to a stage 4 malignancy and we can and as I said the concordance between the primary and the metastatic site are very high as much as 95 percent and hence it would give us normally the stage but the diagnosis. The disadvantage being that in the brain, the imaging of a PET, the normal brain takes up a lot of glucose for its own metabolism. So we may miss metastasis in the brain on a PET scan and this led to the mandatory requirement of doing a contrast enhanced MRI in all patients of non-small and small cell lung cancer to stage the brain. So now we've reached a stage where we are fairly clear that there is lung cancer. Now we have to stage them like you just mentioned now. How do we approach a patient who has been diagnosed to have lung cancer? So our job as an oncologist starts from having a tissue diagnosis with a biopsy, then we do an MRI brain and we do a PET scan. This is enough to tell us the stage of the lung cancer and we would make a foundation by staging them as stage 1, 2, 3 or 4 and we follow the common criteria for classification by seeing the TNM classification and then group them into a stage. The T standing for the tumor, size N for the nodal status, NM for metastasis. The tumor size in lung cancer less than 3 cm is taken as T1, 3 to 5 as T2, 5 to 7 as T3 and more than 7 cm as T4. This has for a few more caveats like mediasanal invasion of a tumor would classify it as T4 disease. Similarly, lung collapse would make it T3. The nodal status is epsilon nodal involvement that means if we have a lung cancer on the left side and we have enlarged hyaluronodes on the left side would stage it as N1, a subcarinol node would stage it as N2 and N3 would be a contralateral mediasanal node involvement like a right sided hyaluronome in cases of a left sided lung mass. The metastatic sites can further be staged as local thoracic metastasis to the pericardium or the pleura or which is classified as M1A or extra thoracic single site, let us say a liver met solitary would be M1B and multiple extra thoracic sites which would make it M1C. The stage one treatment would be, I will go to the treatment part now. So the treatment for stage one lung cancer after we have done the TNM classification and stage grouped it would be surgical resection and surgical resection, the minimum surgical resection for a lung cancer and expert ants is a lobectomy with a epilepsy lateral mediasanal lymph node dissection or epilepsy lateral mediasanal lymph node sampling. That means we have to remove as much of the lung as possible. There are many people who are experts who handle high volume lung cancer surgeries where they can even do a vats assisted segmentectomy or less than a lobectomy with two negative margins. In stage two again we would prefer to do surgery but in those patients who are elderly or due to comorbid illness cannot undergo surgery for some reasons. They undergo a stereotactic ablative dose of radiotherapy or they can undergo radiofrequency ablation of a limited disease where there is little or no nodal involvement. In stage three we tend to combine modalities to increase the to reduce mobility and increase longevity and this would include giving combination chemo radiotherapy with and this is we strengthen by the fact that we have recently done the pass we follow the pacific study which was a phase three double banded trial which showed that about 713 people with unresectable stage three lung cancer were divided between giving duralumab which is a immunotherapeutic agent or a placebo after completing the combination chemo radiotherapy in stage three patients and their progression free survival that means the survival of these patients was much much longer of 16.8 versus 5.6 months irrespective of a PDL1 stages which guides us to give immunotherapy and has now become the standard of care for patients with stage three lung cancer. Stage four lung cancer requires a different approach. So what what how different it is than stage four so I presume it would be more palliative. Absolutely stage four lung cancer is only a palliative situation given the dynamic nature of lung cancer where the patient can tends to change in the pattern of his metastasis almost on a daily basis. So here we have now tried to and first we have to try to identify at the molecular level whether the patient has any particular genetic mutation in him. If he is found to have genetic mutations as I mentioned which happen roughly in one fourth of these lung cancer patients then they can be targeted. So we have drugs like Jeff Tineb, Osimert Tineb, Afatineb and Dakomert Tineb which can be given for EGFR mutated lung cancer. We have a breakthrough with a very interesting drug known as Lollatinib which has as much as a 80% CNS clearance. That means if a patient has lung cancer with brain myths that patient we are having patients now for five to seven years who are alive just with the drug taking one pill popping a pill of Lollatinib 100 milligram a day which is an amazing in fact new change therapeutically. Similarly we are having various breakthroughs with patients having ret mutations they are actionable and we have developing drugs against them and it's very good to see patients with brain metastasis whom earlier had a survival just of six weeks to six months now living up to even six years. This has been a remarkable change. The other group is we should also look at the immunotherapy angle and immunotherapy has had a very big breakthrough in lung cancer as in other cancers and there are drugs which act on the PDL1 and PD1 so let me just explain a little bit in detail. The cancer cells have a receptor known as PDL1 and we can see this as a cloak that means like we wear a lab coat we just mask ourselves so PDL1 receptor mask the lung cancer cells and they undergo immune evasion that means they evade the immunity of the body PD1 is present on the T cells which are cytotoxic the CD8 T cells and we reinvigorate this immune response from the body so immunotherapy is a kind of therapy and we use drugs with like PDL1 anti PD1 inhibitors or PDL1 inhibitors the anti PD1 inhibitors being like nebulomab or pembroluzimab and pembroluzimab has 14 to 17 indications as of today which is an expensive drug but then it also gives adds value and quality of life. Anti PDL1 inhibitors like atizolizomab, durvalumab and evilumab are commonly used in our cancer center and we have anti CTLF4 inhibitors and as you know these have been recently been discovered and the novel price has been awarded for discovery of these immune checkpoints and anti CTLF4 like epilumab and tremidimumab are available with us. So I just want to end by saying that PDL1 receptor presence is a sign that the inhibition of anti tumoral activity is not happening so the higher levels of PDL1 the higher levels are so immune evasion by the cancer cells but however we can have a favorable response to monoclonal antibodies when the PDL1 receptor levels are high. So you would in any patient of lung cancer would you screen them for these receptors or only in stage 4? So in now at the moment FDA recommends us to stage only for stage 4 lung cancer to use genomic markers and do the molecular imaging and also to test for PDL1 and if both of these are not present then we have to give them a platinum doublet therapy which would look after the disease or control the disease and thereafter after giving 4 to 6 cycles we will assess them by a PET response and either go for a continuation to 6 cycles of chemotherapy or if there is progression on PET scan we would do a switch maintenance meaning we would change over to another agent. So from what I understand lung cancers are not as sort of a killer now compared to what they were a few years earlier purely because of the fact that now we were able to identify at least a subset of these patients who will respond to these new molecules which seem to be really part breaking as far as therapy is concerned and like you mentioned about the survival increase it is very heartening but what I would like you to know from you is firstly the cost if you could just briefly tell us how expensive is it and from what I understand these drugs will be required lifelong in such patients. Absolutely now that is not only an ethical dilemma but we deal with it from day to day so pharmacoeconomics in cancer at such is a very debatable topic specifically in lung cancer a single vial of 100mg of pembrolizumab costs to us in an institution at a reduced rate of around 1.49 lakhs that means we are spending about 3 lakhs per dose 3 weekly for every patient whom we put on pembrolizumab so the cost is high having said that even in targeted mutations like an eGFR mutated lung cancer patient where we give osimertenep a treatment for one month is more than 2.5 lakhs so only those patients who have insurance or come to governmental institutions are able to afford such expensive treatment or if they go into clinical trials but for the lay public it is becoming more and more unapproachable if a mutation is formed. And what about the duration of therapy? The duration of therapy has to be lifelong and what we find with immunotherapy is sometimes we get a response which remains prolonged so we have to titrate giving immunotherapy with its adverse effects many times people would develop adverse effects of colitis in immune related skin changes like eczema or psoriform lesions or they would develop pneumonitis. Now these are treatment limiting steps so what we do is after 2 to 3 years of immunotherapy we may increase the dose and reduce the interval of giving immunotherapy and what we have seen is that the primary reduces in size but doesn't disappear but the metastatic sites disappear with any kind of immunotherapy in any kind of cancer and as we advance into the years into the future it is a very exciting field and not only are we trying to detect cancers by doing a liquid biopsy where we are looking at circulating tumour cells, we are looking at circulating tumour DNA, we are looking at cell free DNA, micro RNAs, we are just a liquid biopsy can tell us whether a particular mutation of the molecule level is present and then start treating the patient even by avoiding a more invasive procedure like a bronchoscopic or a trans thoracic biopsy. So we have exciting times ahead and I am sure over the years the FDA and other big companies like Novartis, Pfizer and Rosh would ethically reduce the cost of the drug and I would also like to give a caution to patients that we should not go to the second hand or the black markets to obtain these drugs because these drugs may not contain what they tell you to contain and you may be spending your money, wasting your money over a drug which is going to be ineffective. So although the, it is very heartening to see the way these drugs are working and there are challenges, challenges like you mentioned about the cost and the duration of therapy. Now the fair or more wise option remains is of preventing the cancer. So would you say something about how can one prevent these? As we realize that when we are healthy we do not realize that cancer can be such a bad killer and we always feel that this is affecting somebody who is distant from us and we think that we have a shield around us but that is not the case. Like I mentioned earlier one in five people in the world may develop cancer by 2030 and this burden seems to be increasing and as countries industrialize an unknown carcinogen comes into the environment which increases the cancer by many fold right from children to the adult world. As we have seen in Japan in the 40's, the US in the 50's and the European countries in the 60's and now in India. In India surprisingly cancer comes almost a decade earlier and we have a lot of infectious causes of cancer also. So we feel this prevention aspect is so we definitely need to prevent cancers, all cancers and the common part would be that we have to maintain physical activity. That means we must take a walk or exercise and we sweat for at least 30 to 45 minutes every day and you can have a rest day maybe once a week but then we should inculcate this as a habit. We should have food which contains a variety of nutrients reduce or sugar intake to some extent which is controversial but definitely if we reduce or sugar intake we will prevent or other diseases from setting in as well and we need to take at least 5 portions of vegetables and fruit in a day. That means we need to be more intensive on taking green leafy vegetables. Other than this for lung cancer specifically we need to reduce smoking. We need to avoid people who smoke when we need to be cognizant of the fact that environmental pollution when it's there if we wear a mask we could keep our car windows up and try to use air purifiers definitely we would reduce the particulate material which we are inhaling and I cannot say this more than required that we must definitely try to stop others from smoking in the community as well. So this is extremely informative and in fact what it has done is it has made me more optimistic about a disease like cancer. Now I feel that it is not so bad however I would still sort of put my finger on prevention more than actually treating this condition which remains a challenge. So thank you very much sir for contributing your time and effort to this resource that we are creating and it would be wonderful to have you back again with us for some more such topics. Thank you for this very energetic platform. [Music]