There are several types of lung cancer, distinguished by the appearance under the microscope. The two main types are non small cell lung cancer and small cell lung cancer. The sub type of small cell lung cancer is important to recognise separately as the as the management of this condition differs from its more common counterpart, non small cell lung cancer.
Non small cell lung cancer consists of different sub types including squamous cell carcinoma, adenocarcinoma, a combination of adeno and squamous carcinoma, large cell carcinoma. There are rare types of primary lung cancer including giant cell carcinoma and lepidic (bronchioloalveolar) lung carcinoma.
Many cancers arising from other organs of the body can spread to the lung (lung metastases) and it is important to differentiate these from a primary lung cancer which has arisen from within the lung as the management would be dictated by organ from which they have arisen.
The rise in lung cancer mortality during the twentieth century was statistically linked with the increase in smoking tobacco (with tar products) in a dose dependent (i.e. cumulative ‘pack year’) relationship. On cessation of smoking, the risk falls but remains above that of the background population even after 15 years. Passive smoking (the inhalation of the smoke from smokers in the vicinity) also raises the chance of developing a lung cancer.
Further factors that may increase the chance of developing lung cancer include ionizing radiation, occupational exposure to carcinogens such as asbestos, arsenic, chromium. There is renewed interest in the familiar inheritance of lung cancer.
Lung cancer is the leading cause of cancer deaths in the Western world, accounting for 30% of male cancer related deaths, which translates into a total death toll in excess of 30,000 persons per year in the UK.
Interestingly, the only group in UK with an increasing incidence of lung cancer is young women who are the only part of the population who have not cut back on smoking.
Symptoms, diagnosis and staging: Lung cancer
Early lung cancer may not cause symptoms. For patients with symptoms of lung cancer may be due to the local development of the tumour in the lung or from the spread of the disease. Local symptoms include a cough that may persist, breathlessness, chest pain, coughing up blood, a hoarse voice, and recurrent infections of the chest.
General symptoms include fatigue, weight loss, burning pain from metastatic spread or symptoms from spread to other organs e.g. headaches from brain metastases.
The doctor first performs a chest x-ray and if this shows anything suspicious he will run a CT scan of the chest. If there is an opacity in the lung fields that is suspicious for cancer the doctor will ask for a PET scan (Fluorodeoxy glucose Positron Emission Tomography); this is not an anatomic scan like a CTscan (indeed it is inferior to CT for defining a lump in size and surface margins) but it detects how metabolically active a lump is (and it is a characteristic of lung cancer that it is hypermetabolic – i.e. using glucose avidly) and hence the PET is the most sensitive scan we have for helping in the diagnosis and staging of lung cancer.
The analysis of the sputum for abnormal cells is the next test (sputum cytology) and is a very accurate diagnostic tool if positive, and this is usually the case if the patient is coughing up blood; it is less often positive otherwise.
If the tumour is not diagnosed by the sputum cytology, the doctor orders a bronchoscopy (a test where a fibreoptic telescope is manipulated down the throat into the wind-pipe (the trachea) and into the bronchial tubes to directly see any tumour arising from the walls of these tubes and then to biopsy any abnormality.
If the suspected mass is peripheral in the lung, then it may not be reached by bronchoscopy and a transthoracic lung biopsy may be needed, via a thin needle.
It is worth noting here that almost all lung cancers are bronchial cancers and arise from the walls of the bronchi. When the tumour is seen or an abnormal area discovered at bronchoscopy, the doctor will take a piece of tissue (biopsy) from this area for subsequent analysis down the microscope for a certain/pathological diagnosis.
If the tumour is not easily seen down the bronchoscope and a single lung shadow on the x-ray could be a birthmark (hamartoma etc.) then the PET scan is at its most useful. This functional scan is ‘hot’ when there is a cancer there in the lung but ‘cold’ when the chest x-ray abnormality is one of any of the lung benign shadows which include congenital hamartomas or scars from old injury. If the result is equivocal or PET scan positive and the lesion not able to be biopsied on bronchoscopy, then a transthoracic fine needle biopsy directed by CT is diagnostic in most cases.
The message from all the above is that the diagnosis of lung cancer has to be made from sputum cytology or biopsy (which is the analysed down the microscope). Sometimes the patient presents with spread of the cancer outside the chest and then the diagnosis can be made from biopsy of a metastasis, e.g. an abnormal lymph node in the neck.
Nowadays, the Oncologist needs (particularly for non-small cell lung cancer) more than cytology for him to take the correct treatment decision – he requires at least 1cc of the tumour for the genomics and predictive immunotherapy tests – so, a tissue biopsy is preferred. However, if the Oncologist is certain that the patient has non-small cell cancer and the staging dose not preclude surgery, then the extra material that is required for these further tests can be obtained from the surgical specimen.
Assessment of non small cell lung cancer
The medical team will want to know whether the tumour is localised to the lung or whether it has spread to the local lymph nodes or further.
A clinical examination would allow a general assessment of lung cancer and this would be supplemented by a chest x-ray. Performing a PET scan and CT scan of the chest and abdomen provides a specific anatomical detail to delineate the primary lung cancer and possible sites of spread. It is prudent to also scan the head as brain metastases occur with a relatively high incidence in lung cancer and it is important that the Oncologist know about this form the start.
Where an operation to remove part or the whole of a lung is being contemplated, the surgeon may well wish to perform a rigid bronchoscopy of mediastinoscopy first. In these techniques, and with the patient anaesthetised, a rigid tube is placed down the bronchial tree or mediastinal tissues (in this latter instance, via a small incision at the root of the neck) to assess the local extent of the disease, for example, by biopsying the mediastinal lymph nodes for microscopic analysis.
Imaging investigations and surgical assessment allows non small cell lung cancer to be staged into 4 categories. Stage 1 and 2 lung cancers are considered suitable for surgical resection depending on the patients’ fitness and lung function.
Stage 1 lung cancer which is diagnosed in only a minority of patients at their initial work-up refers to patients who have disease of up to 3 cm in diameter within the lung. There must be normal lung surrounding the lesion and no extension into the major bronchi feeding the lungs, nor involvement of the lymph nodes of the central chest. This is a potentially highly curable stage.
In the second stage of lung cancer, the tumour in the lung is allowed to be greater than 3 cm and may involve the periphery of the lung (the pleura) or extend up to 2cm from the main division of the trachea into the two main bronchi. There may be involved lymph nodes at the root (hilum) of the lung but not into the central chest/mediastinal nodes or any evidence of spread further afield.
The third stage (stage 3) refers to patients who have more extensive chest (nodal) disease but no evidence of disease outside the chest. Where there is disease further afield, the stage is stage 4.
The TNM staging system is used by Oncologists:
T1: The cancer is not more that 3cm in diameter (T1a up to 1cm and T1b <1 but <2cm). * T2: The cancer is 3-5cm in diameter. * T3: The cancer is 5-7 cm in diameter. * T4: the cancer is >7cm and/or invading adjacent structures.
N1: Nodes positive at the root (hilum) of the lung on the side of the cancer.
N2: Nodes positive at the bifurcation of the trachea or upper chest (mediastinum) on the side of the cancer.
N3: nodes positive on the other side of the chest from the side of the cancer or in the root of the neck.
M+: Distant spread present.
Assessment of small cell lung cancer
The extent of small cell lung cancer can be assessed by a combination of CT scans and PET scans and a brain scan. For the majority of patients, there is no role for curative surgery and they should be considered for a combination of chemotherapy and radiotherapy.
In the UK, small cell lung cancer is staged as localised disease or extensive disease. Localised disease refers to patients whose disease is confined to a part of the lung and local lymph nodes only. Extensive disease refers to patients whose disease can be demonstrated beyond the lung and local lymph nodes/chest.
Treatment & outcomes: Lung cancer
Treatment of non small cell lung cancer
Surgery is recommended for early stage disease. This applies to stages 1-2 and may apply selectively to stage 3 of the disease. Before operating on an early stage non-small cell lung cancer, the surgeon will take matters other than the fact that the disease is early on staging into account. This will depend on the size and situation of the cancer. He will want to know that the patient’s lung function, which is often impaired due to a lifetime of smoking, can withstand the loss of lung tissue that will result. This lung ‘reserve’ can now be adequately assessed before any planned operation nowadays, and must be known to the surgeon prior to the planned operation. Similarly, the patient’s heart must be in good enough shape for operation.
Thus, after the staging of the disease as outlined above and the pre-operative medical assessment, the patients who ‘qualify’ proceed to lung resection (either lobectomy – lobe removal or pneumonectomy – removal of the whole lung) at a chest splitting operation called a thoracotomy. At operation, the surgeon will re-assess the situation. If the disease is actually more extensive within the chest than the scans regarded it to be (and this happens despite the most careful pre-operative assessment, then there is no advantage in proceeding to major lung surgery without the possibility of removing all the disease and the surgeon will close the chest without having carried out a definitive operation. Otherwise, the surgeon will go forward with the radical (hopefully curative resection).
Where the disease is confined to the lung or the stage 2 disease that the pre-operative imaging defined, the resection proceeds as planned.
Radical (this term refers to therapy given with curative intent) radiotherapy is given to patients with stage 1 and 2 disease where surgery is contraindicated on medical grounds or the patient declines operation. Radiotherapy is another form of locally ablative therapy and can replace surgery where the patient’s condition is too frail to withstand surgery. With modern techniques, it is possible to deliver highly ablative doses to tumours and a modern form of focal radiation therapy called the Cyberknife may be the ultimate technique in this regard. With Cyberknife, some 200 pencil beams of radiation target the tumour and only deposit their full dose where all these pencil beams coincide. They are so directed at the cancer that that coincidence of all the beams is only on the cancer and, as the distance from the edge of the cancer increases, the dose deposited ‘falls away’ rapidly (i.e. fast falling dose gradient) such that the surrounding lung is spared from full large doses of radiation.
Cyberknife has become an important form of radical/curative therapy in those who are old or infirm.
For stage 3 disease, the use of radical dose radiotherapy (not Cyberknife as stage 3 disease requires coverage of the chest nodal regions as well as the primary lung cancer) in combination with chemotherapy – the two given together over a 6+ week period. This therapy has produced the best survival results for stage 3 disease. The surgeon sometimes does a resection of the primary and hilar nodes first.
Trials are in progress to explore whether the addition of immunotherapy to this chemo-radiation policy brings added advantages (vide infra).
At least one trial has found support for adding Durvalumab to the chemo-radiotherapy programme.
For patients with more advanced disease, the emphasis of therapy has to be on systemic therapy (i.e. therapy that reaches all around the body). Once again, traditionally, this has been chemotherapy,which has undoubtedly improved over the last decade, both in terms of efficacy and tolerance of the patient to therapy. For adenocarcinoma of lung the couplet of cisplatin and pemetrexed is the current best therapy regime, whilst another platinum doublet (such as platin with gemcitabine or vinorelbine) is used for squamous cancer.
However, the genomic profiling of the cancer and the predictive test for immunotherapy (PDL1 expression) have become relevant tests whose results will now alter the recommendations of the treating Oncologist.
If the cancer has a driver mutation in the form a particular mutations of the EGFR gene (most typically exon 9 deletion or L858 mutation), then a tyrosine kinase inhibitor, such as Osimertininb stands a very high chance of putting the cancer into remission as the downstream effector pathway of that activated oncogene can be inhibited by that drug, (which also blocks a common escape pathway that the cancer frequently adopts to escape the EGFR inhhibition).
If the genomics testing shows such a EGFR mutation, then osimertinib would be first line therapy (and has better brain penetration than other therapies – so reduces the risk of brain metastases also). Non-smoking Asians are more likely than others to have lung cancer with this mutation.
If the cancer has a mutation of ALK or ROS1, then the drugs ceritinib and crizotinib have proved useful and the drug alectininb has more recently proved very successful in this situation – again blocking the driver mutated gene’s command structure and often putting the patient into a long remission. Once again, if the genomics shows that these mutations are present in the cancer, then these drugs are used as first line therapy. Non-smoking Asians are more likely to have this genetic phenotype
If the MET gene is a driver mutation then the possibility of inhibitors for therapy is being explored., as they are for other potential driver oncogenes in this disease. Other rare driving mutations are noteworthy as they are also potentially ‘druggable by ‘Smart Drugs’ – e.g. RET mutations by vandetanib or LOXO192
It is now realised that lung cancer is a tumour that contains many mutations that are all potentially antigenic. However, the lung cancer puts up a ‘smoke screen’ that informs the potentially cancer-destructive immune system that the cancer is in fact part of the normal tissues of the body. The system works via the PDL1 surface expression by the tumour. Non-small cell lung cancers that have a high expression of PDL1 on their surfaces are putting up a strong ‘smokescreen’. In patients with >50% expression of PDL1 on their cancer cells are likely to respond to immunotherapy in the form of a PD1 (or PDL1) inhibitor – such as pembrolizumab or nivolumab (or atezolizumab). indeed, the likelihood of a good response is so good that his is now regarded as first line therapy for patients with non-small cell lung cancer that has metastasised. ( The rationale for checkpoint immunotherapy is expanded in the treatment section of the melanoma category).
So, now we have two alternatives to chemotherapy as first line therapy for non-small cell lung cancer – if the genomics suggests that genomically targeted therapy with a TKI such as osimertinib or alectinib will be effective, then they are used as first line therapy.
If the PDL1 expression is high, then there is such a good chance of immunotherapy working that this can be offered as first line therapy – instead of chemotherapy.
Even more intriguing was the 2018 report that the combination of pembrolizumab (immunotherapy) with chemotherapy was better than chemotherapy alone for metastatic non-squamous, non-small cell lung cancer; this was irrespective of the PDL1 status of the cancer. This fascinating discovery is thought to be connected with the release of antigens by the chemotherapy damaged cancer leading to a enhanced immune attack, although the exact mechanism is not known. These findings have thrown optimal first line therapy for NSCLC into some confusion, as many now consider that chemotherapy with immunotherapy is first line therapy for advanced NSCLC, irrespective of the PDL1 expression status of the cancer – this is an ongoing area of intense Oncological interest.
What to do if the cancer relapses despite all the foregoing therapies?
We recommend that he patient has a new biopsy or has cell-free DNA analysis of the cancer to establish the current genomics of the cancer (and this will have changed over the time that other systemic therapies have been delivered: firstly because cancers are always genomically unstable and are always mutating and secondly under the pressure of the previous systemic therapies – in a classic Darwinian evolutionary way.
For example, if the patient has been on an EGFR inhibitor for EGFR mutated lung cancer and has been responding to this for a year but now relapses, then it is likely that there has been an ‘escape mutation’ – i.e. there has been a mutation to allow another oncogene (activated gene which stimulates the cancer to grow) to come to the fore and be the lead ‘driver’ for this cancer (we have recently had such a case where the escape mutation was via the PIK3Kinase pathway – usually associated with breast cancer escape mechanisms and ‘druggable’ by taselisib). There is a minority chance for finding such a therapy but, for sure, one that we need to seek, that here will be an inhibitor for this escape route.
The current author has one patient who has had 12 more serial cfDNA analyses over three years and we have followed the genomic evolution of the cancer over time with the development of new driver mutations – his recent analysis showed the emergence of the escape path: PI3K ( which is usually associated with breast cancer escape from therapy) and for which, importantly, there is now an inhibitor: taselisib/copanlisib.
One advantage of cfDNA ( if the cancer is a ‘releaser’ of this in sufficient quantities) is that the analysis gives the mean of the cancer’s genomics and is not at the mercy of a single site tissue biopsy
Therefore, at the time of relapse through standard therapies, an NGS analysis with regard to therapeutic options – perhaps most concentrated on genomics – is recommended.
Credit: P N Plowman MD, The Oncology Clinic, 20 Harley Street, London W1G 9PH . (Advanced Genomics; tel: +44-2076311632).
Small cell lung cancer
Small cell lung cancer has a much higher predisposition to spread/metastasise to other organs early in its natural history and it is for this reason that it is very rare that surgery is ever thought appropriate for this disease, with the possible exception of T1N0M0 disease.
Fit patients with limited stage disease should be considered for a combination of chemotherapy and radiotherapy treatment. Chemotherapy is administered at the start of radiotherapy but is some cases can precede the radiotherapy treatment. Radiotherapy may be given twice daily over a period of 3 weeks or once daily over a period of 5 weeks. A proportion of patients with small cell lung cancer relapse with brain metastases. The addition of radiotherapy to the brain during or after the course of lung radiotherapy has been shown to reduce the rate of brain metastases (prophylactic cranial irradiation) as the drugs tend to fail to enter the brain as well as elsewhere in the body and there is a high risk of seeding of this disease to the brain.
In patients with extensive stage small cell lung cancer the treatment intent is palliative. Chemotherapy can reduce the tumour burden in fitter patients.
Immunotherapy with drugs such as pembrolizumab can indeed be active in this disease – as we have discussed in non-small cell lung cancer, but the literature is more immature at present. However the author has a man, whose metastatic small cell lung cancer had resisted chemotherapy, and has been in full remission for a year so far on pembrolizumab therapy. Hopefully genomics will assist in the future.
Local palliative radiotherapy can reduce symptoms from metastatic disease e.g. bone pain, brain metastases. Surveillance with symptom control should be considered for those patients who are frail and not fit to tolerate more aggressive therapies.
What to do when the foregoing has been used and the small cell cancer is refractory?
The patient should have up to date genomics performed to look for an escape gene mutation which can be ‘drugged. This can be done by a new tissue biopsy or via cell-free DNA (obtained from a blood draw – not always possible but worth a try).
If this is not helpful, then immunotherapy (less well established in small cell cancer as in non-small cell cancer) is certainloy woth a trial and the current author has a man, who had failed all first line chemotherapies for his small cell caner that was metastatic who went into a full remission on the checkpoint inhibitor: pembrolizumab ana is holding that com[plkete remission on PET now at greater than a year after start of therapy.
Credit: Dr. P. N. Plowman MD, The Oncology Clinic. 20 Harley Street, London W1G 9PH. (Advanced Genomics; tel: +442076311632).
Of the 20% of patients who undergo curative resection, regrettably only 25-30% of these are alive at five years due to local/chest relapse in a quarter of this number and further afield/metastatic spread in three quarters. Of course, within this group are better outcome patients; thus, a patient with a true, early and small stage 1 tumour has a greater than 50% chance of being alive and disease free at this time point, but regrettably such patients account for only 5% of the population of patients presenting with this diagnosis.
With the better understanding of genomics and =immunotherapy, it is clearly anticipated that he future of therapy in this malicious disease will be better.
Nevertheless, given the exciting new drugs that have been described above, there is now cautious optimism that he survival for patients with lung cancer will improve over the next five years..
Unfortunately, the majority of patients with lung cancer relapse, and the sites of relapse vary between individuals. Sometimes the relapse is in the original site and, once again, may present with coughing up of blood or imminent collapse of a lung due to tumour obstructing the bronchial tree. In these situations, radiotherapy is needed to relieve the problem.
Where the patient has had previous radiotherapy, this may be problematic as it is not always safe to repeat the course, although with modern planning methods (IMRT, tomotherapy)to reduce the re-treatment dose to critically sensitive structures such as the thoracic spinal cord, it is more feasible than in previous times.
However, the possibility of intraluminal brachytherapy should also be considered in these situations. In this technique, sealed radioactive sources are implanted, down a bronchoscope, to a localised area within the bronchial tree to deliver a highly focal; re-treatment radiation dose to this region. By the inverse square law (the law that says that if you are in a ship at sea and you treble your distance from a lighthouse, then the intensity of the lighthouse beam reduces to one ninth) the intense re-treatment dose is confined to the local tumour recurrence. Considerable success has been achieved with brachytherapy in this situation, more so than laser therapy down a bronchoscope, which is an alternative method which has been tried.
For disease relapse outside the chest, chemotherapy makes the most sense and is recommended for all those fit enough to withstand a course. However, particular relapse situations may require more individual attention. For example, painful bone relapses may be most simply and effectively treated by a short course of radiotherapy directed just to the metastasis within the bone.
A spine metastasis causing pain is similarly treated by local radiotherapy as is brain metastatic relapse. If a bone metastasis is threatening to cause a fracture of a long bone such as the femur (the thigh bone) then an orthopaedic operation to stabilise the bone prior to radiation is required.
In general terms, when a patient with lung cancer has relapsed, particularly with metastatic relapse, then the patient is incurable and has an outlook for life measured in months. This being the case, so it is the strategy of the doctors looking after such a patient to concentrate on the patients’ comfort rather than striving to give every last agent that might prolong life a little but detract from its quality, due to treatment toxicity, in the process. Therefore, chemotherapy will be used carefully bearing in mind both the patient’s tolerance of the drug regime and the regression of the tumour equally. Tyrosine kinase inhibitor (TKI) therapy is much better tolerated than chemotherapy and may be indicated in these patients. Otherwise, therapy is palliative (i.e. entirely directed at alleviating symptom.
Screening for lung cancer
Currently, there is no accepted screening programme for lung cancer. Studies are underway to assess patients with high risk factors such as smoking and regular imaging assessments may produce an advance in reduction or detection of cancer at an early stage.