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 bronchial alveolar lung cell 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. On cessation of smoking, the risk falls but remains above that of the background population even after 15 years.
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.
Symptoms & diagnosis: 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. 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 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.
It is worth noting here that almost all lung cancers are bronchial cancers and arise from the walls of these 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 a PET scan is useful. This is a functional scan which is ‘hot’ when there is tumour 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 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.
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 CT scan of the chest and abdomen provides a specific anatomical detail to delimitate the primary lung cancer and possible sites of spread. A bone scan may be recommended if there was a suggestion of spread to the bone.
A recently introduced technique called PET scanning (positive emission tomography) is rapidly coming into practice in the standard work-up of patients. The PET scan differs from the CT/MR/ultrasound imaging in that it does not image on anatomic details (e.g. a lump in the liver) but on metabolic activity, thus in the usual type of PET scan, the patient is injected with a radioactive analogue of glucose which is concentrated in fast metabolising tissues, such as cancers, and not in scars or other benign problems. The PET image thus discriminates benign problems from malignant ones (both within the chest; the primary lung mass and the central chest nodes and at distant metastatic sites) and there is a move towards utilising CT scans and PET scans only in the work up of lung cancer patients.
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 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 disease but no evidence of disease outside the chest. Where there is disease further afield, the stage is stage 4.
Assessment of small cell lung cancer
The extent of small cell lung cancer can be assessed by a combination of CT scans and bone scans. 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.
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. In selected patients, there is a benefit in consideration of chemotherapy following surgery, and this will be (to a large extent) determined by the histology review of the resected specimen. Then, there is a detailed discussion with the oncologist as the balance of side effects against the benefits need to be carefully appraised. for example, where there is lymph node invasion at the root of the lung, there is a statistical benefit in favour of four courses of post-operative chemotherapy; similarly for all patients with tumours above 2cm in size.
There is still no consensus as to the place of radical surgical resection, as just outlined, where there is early central chest/mediastinal lymph nodal disease on the pre-operative staging, and the early stage 3 patient may additionally gain advantage from chemotherapy and mediastinal radiotherapy. There are many clinical trials currently underway trying to sort out the use of radical surgery plus chemo- and/or radiotherapy in stage 3 disease, and the order in which they should be delivered (e.g chemotherapy first and then definitive surgery)
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. At other times, it is important to cover a wide area around the primary lung cancer (e.g. the local draining lymph nodes other superior vena cava) and then conventionally fractionated radiotherapy is indicated.
As with surgery, the profession is researching into how best to combine chemotherapy with radiotherapy.
The radiotherapy is given via high energy linear accelerators and using conformational techniques to mould the high dose therapy around the primary tumour in the lung and its immediate draining lymph nodes at the root of the lung, whilst minimising the dose to the normal lung tissue. The patients undergoing radical radiotherapy attend a Radiotherapy Department from three to six weeks depending on the type of radiotherapy prescribed. In general, a course of radiotherapy may be given on weekdays over 6 weeks. In some centres, treatment may be given up to 3 times a day including weekends over a period of 3 weeks. For the highly localised form of therapy (Cyberknife) the treatments may only number one to three, but the daily dose is much larger than orthodox fraction size.
A proportion of patients will have advanced disease that is not amenable to cure. The management options in these patients include surveillance until there is symptomatic progression of disease, chemotherapy treatment to prevent progression of disease and palliative treatment with radiotherapy for local symptoms such as chest pain or a persistent cough due to tumour. Chemotherapy drugs continue to evolve and the newer combinations are generally well tolerated with improvements in symptom control and some improvement in survival. Newer agents including biological drugs that can disrupt blood vessel formation and drugs which identify certain receptors on cancer cells have also proven of benefit and can be added to chemotherapy regimens (e.g bevacizumab – avastin, although this has risks if combined with chest radiotherapy).
In spite of advance in lung cancer treatments and good responses in many patients, the overall outlook for many patients remains poor. Studies or clinical trials are underway to assess the benefit of chemotherapy prior to surgery, the combination of chemotherapy and biological drugs given in conjunction with radiotherapy, and the extended use of these drugs after surgery or a course of radiation.
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:
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. 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.
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.
Patients with squamous cancers have a marginally better outlook, stage for stage, than those with adenocarcinomas.
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 symptoms).
Furthermore, where a patient has liver metastases that have resisted chemotherapy and has a life expectancy of weeks or a month or so only, then the development of brain metastases would usually not be an indication for brain radiotherapy.
Sadly, this disease usually ends in death and palliative care teams such as the MacMillan palliative care nursing teams who practice home nursing care and work in conjunction with the hospice movement are important professionals in the last months of life for many lung cancer patients.
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.
Questions & answers about lung cancer
The patient (aged 70) had two biopsies performed. From the first, the patient was given 2 pathology reports; one reported poorly differentiated small cell lung cancer and the other report showed
spindle cell sarcoma.
The second biopsy was positive for malignancy and features were most suggestive of indifferentiated malignant large cell neoplasm.
Based on the two biopsies, the patient was diagnosed as having mixed small cell /non-small cell lung cancer. The patient was treated with chemotherapy consisting of carboplatin and etoposide (6 cycles). A repeat CT scan after the sixth cycle showed an increase in the size of the right lung mass with stable liver lesions. He also experiences bone pain.
As a result of this last increase of the size of the right lung mass, he was advised that the type of chemotherapy to be received for second line chemotherapy has to be changed to treat the Large Cell Lung Cancer diagnosed by the second biopsy. Hence, he is to receive two cycles of Pemetrexate now, followed by a 2nd 3 weeks later.
- Is this patient on the right track with respect to treatment received?
- And can this treatment lead to a complete cure?
The patient was originally diagnosed with a stage four carcinoma of the lung,
histopathology suggested a mixed small cell and non-small cell element based on two pathology reports. At diagnosis the imaging CT scan also demonstrated multiple lesions on the liver consistent with metastatic disease. The patient was treated with first line chemotherapy carboplatinum and etoposide for six cycles with a CT scan at the end of treatment demonstrating an increase in the lung tumour mass but stable liver disease.
The patient has now been recommended pemetrexate chemotherapy as second line treatment in view of his known progressive disease.
The request for information has been made on the basis of whether the pemetrexate treatment is appropriate. The second question is whether the treatment can lead to a complete cure.
Based on the available information, if the patient is still of good fitness (performance status of zero or one), then further treatment with chemotherapy such as pemetrexate is entirely reasonable. It would be important to acknowledge that any treatment provided for this patient from the outset of this disease would not be curative as he had established metastatic disease on his original scan.
In the UK, any treatment intent from the outset would have been for palliation with an aim to reduce the cough, pain and maintain quality of life. It is unlikely that any treatment would lead to a cure.
In the UK, the symptoms of bone pain would also be further assessed by a bone scan or appropriate imaging to define whether there are additional bone metastases. If this is the case and the pain continues then palliative radiotherapy can be considered for the bony metastases. Additionally, if the patient is frail and further chemotherapy cannot be tolerated then radiotherapy to the lung tumour can be considered for palliation as it can help with a reduction in cough, pain and also reduction in the production of blood in the sputum.