Author : Bhadresh Bundela
Stages of lung cancer
CT scanning of the chest and abdomen is good practice, firstly to search the central chest (mediastinum) for cancer in the lymph nodes that drain the lungs and which are often the first port of call for cancer cells spreading from the primary lung cancer. Secondly, scanning of the abdomen searches for spread to abdominal organs and particularly the liver.
If the CT scan has only been through the chest, then ultrasound scanning of the abdomen may be used to stage the abdomen. A whole body bone scan is essential staging as all lung cancers have a tendency to spread (metastasise) to bone as well as liver, other lung sites and also brain. Whether brain scanning is essential staging is a contreversial subject but many would wish to check out this by scanning before going ahead with a lung operation.
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 anaaesthetised, 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.
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 – although that day has yet to arrive in most centres currently.
Whole body PET is replacing many other scanning modalities as the staging investigation of choice in lung cancer. By the above means, the first stage of lung cancer (stage 1), 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 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.. This is still an operable stage.
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.
Outcomes of lung cancer
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, moreso 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).
Futhermore, 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.
Treatment of lung cancer
For all patients except those with the small cell type of tumour, surgery is recommended for early stage disease. This applies to stages 1-2 and may apply selectively to stage 3 disease – vide infra. 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. For example, he will wish to know whether it is possible to take all the cancer away by performing less than a total pneumonectomy (the removal of the entire lung). 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; for example, if the patient has bad emphysema he may not be left with adequate lung function after the removal of either a whole lung or even a lobe. 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, etc.
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. There is no advantage in a debulking operation (c.f. some other tumours).
Where the disease is confined to the lung or the stage 2 disease that the pre-operative imaging defined, then the resection proceeds as planned.
There is still no concensus 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.
In the UK at present, approximately two thirds of all patients presenting with the disease are inoperable at the outset, due to staging and medical contra-indications to proceeding. Of the rest, 15% are found to be inoperable at the operation, a statistic which is undesirably high and may be reduced in the future by better preoperative work-up (e.g. the more standard use of PET scanning and newer techniques – such as video assisted thoracoscopy in which the surgeon can explore the outer areas of the lung via a small telescope inserted through the chest wall).
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.
The risks from operation are finite. There is a mortality rate of 2-4% but a major complication rate of 7%. Older patients and those with significant antecedent medical problems, particularly cardiac or pulmonary, are at higher risk for these complications.
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. It is also given where the operation has been aborted because of local invasion and in some stage 3 cases in conjunction with surgery and/or chemotherapy or both., usually here in a trial setting.
The radiotherapy is now 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, which is very sensitive to high dose radiation therapy and ‘scars up’. This is clearly detrimental to lung function overall and therefore lung function is also a consideration in the pre-radiotherapy of these patients.
The patients undergoing radical radiotherapy attend a Radiotherapy Department every week day for at least several weeks (and this may be up to six weeks) and during this time, and particularly at the end of the course and a weeks or so afterwards, they may feel tired and have soreness on swallowing (due to the proximity of the gullet/oesophagus to the high dose region). This latter can be ameliorated by some local anaesthetic containing liquid for swallowing before meals.
In recent years, there has been a qualified success in finding drugs that have some impact on this cancer. Mainly these cancer chemotherapy drugs are given in combinations (both to gain greater effectiveness on the cancer and to reduce the chance of drug resistance) and tend to have cis-platinum as the backbone drug. This is clearly the therapy of choice if there is spread of the disease to distant sites and the patient is well enough to withstand strong drug treatment for a carefully audited trial period.
However, there is now much interest in bringing these same chemotherapy drug regimes further ‘up front’ and using them earler in the disease when, it is argued, that they have more chance of effecting cure because the bulk of cancer (i.e. the shere weight of numbers of cells having a chance of acquiring resistance by Darwinian evolution) is least. In this situation, for example stage 3 disease, when there is established disease in the central chest nodes but nothing detectable further afield, then it might be that chemotherapy stands its highest chance of cure as the number of cancer cells around is small. Additionally, it may also be argued that adding radiotherapy to the central chest, after post-operative chemotherapy will also reduce the chance of relapse by reducing the cell burden in the one site where there is greater than microscopic disease. These are all theses that are currently under trial assessment.
The chemotherapy is usually given via an intravenous drip and causes nausea in the first day or so after its administration. Modern anti-nausea drugs are usually effective at minimising the vomiting but nausea to some degree occurs. Hair loss is a side effect with which most lay people are familiar and occurs with most chemotherapy regimens; all depilation/hair loss is reversible after cessation of chemotherapy and is due to temporary arrest of growth at the depths of hair follicles.
Patients who develop fevers between chemotherapy courses (which are usually given once three weekly as this is the interval needed for blood count recovery) may have contracted serious infection, due the low white cell count that usually occurs after chemotherapy; such episodes (called febrile neutropenic episodes within the profession) are always taken seriously by the doctors who will admit the patient for intravenous antibiotics.
Other side effects are drug specific. The place of chemotherapy in the curative therapy of lung cancer is still under trial. Although chemotherapy can make advanced lung cancer regress for some time and in some patients, it has yet to be shown that giving it ‘up-front’ in conjunction with surgery and/or radiotherapy increases the overall survival of patients with early lung cancer.
Small Cell Cancer: The therapy options for the patient with small cell cancer (oat cell cancer) are different. The disease 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: the ‘horse has bolted’. However, although a fast growing and potentially lethal tumour in the short term, this particular cancer has proved to be very chemosensitive compared to other types of lung cancer (and radiosensitive too). Therefore, the logical and preferred method of therapy is to start with chemotherapy (i.e. to get at the disease wherever it may be – in the chest or beyond) and follow a good chemotherapy response with radiotherapy to the chest (the site of most likely first relapse in patients who presented with small cell lung cancer and negative staging for metastatic disease).
Whereas small cell cancer used to be considered a death sentence before effective combinations of chemotherapy, there is nowadays a 12-20% survival rate at two years in those who present with disease apparently localised to the chest on initial staging.
The chemotherapy regimens are frequently based on cis-platinum and etoposide as the partnering drug and this two drug regime (known as PE in the profession) may alternate with an adriamycin (doxorubicin) containing regime.
Radiotherapy is usually employed after the chemotherapy has caused good tumour regression and is beamed at the primary region in the chest and the central chest nodes. However, there is an ongoing controversy as to whether some radiation should also be given to the head in the prophylactic setting (‘insurance policy’ setting). The reasons for this are to do with the very high predilection of small cell cancer to spread to the brain at some time in its natural history. Considering the seriousness of brain relapse, there is a case for forestalling this by prophylactic radiation of the head, during the initial radical courser of therapy, and trials do show that such early cranial radiotherapy does indeed reduce the later relapse rate in the brain. Recently, a completely new form of therapy has been demonstrated to be useful in some patients with non-small cell lung cancer - interestingly with a higher chance of success in those with adenocarcinoma (and in non-smokers)and those with bronchioloalveolar cell carcinoma. The treatment is with tyrosine kinase inhibitors (orally active medicine in tablet form) hwich block the effector function of the epidermal growth factor receptor gene, which appears to be a growth promoter in some of these patients. The current best agent of this group is erlotinib (tarceva) and we have seen some dramatic resoponders. In general, inoperable patients will be offered chemotherapy and radiotherapy first but tyrosine kinase inhibitor (TKI)therapy will be offered after relapse through these standard therapies.
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