Why are tumors found too late?

Often recognized late and hardly treatable

Lung cancer

Often recognized late and hardly treatable

by Carola Seifart, Marburg


Lung cancer is the second most common tumor in women and men. The high mortality rate is alarming. Although the cancer is curable at a very early stage, it is seldom discovered that early. Much more common are advanced stages that can only be treated to a limited extent. New therapy strategies create hope.


Lung carcinoma is a malignant degeneration of the lungs. It is the form of cancer with the highest mortality. If you add up all cancer deaths worldwide, bronchial carcinoma takes first place on this list (1, 2). In Europe, 2,887,000 patients were diagnosed with cancer in 2004; 1,711,000 people have died from their tumor disease. Among the new cases, lung cancer was the most common with 13.3 percent, followed by colon and breast cancer (13.2 and 13 percent, respectively). Lung cancer was by far the number one deaths: it was responsible for 342,000 deaths.


Many types of cancer are on the decline - but not lung cancer. Over the past 50 years, its incidence has increased by 249 percent and its mortality has increased by 259 percent. Although the numbers are no longer increasing among men in Germany, women are becoming increasingly ill (3). The number of infected women has doubled in the last 20 years, which means that bronchial carcinoma is currently the second most common tumor of both sexes (1, 2). Unfortunately, no relevant decline in the number of diseases is to be expected until 2030.


Classification by tissue type


Lung cancer is not all lung cancer. There are many sub-forms that are generally assigned to two large groups. This assignment is based on the tissue from which the tumor originally arose. If small cells predominate in the tumor tissue, this is what is known as small cell lung carcinoma (SCLC: small cell lung carcinoma). If another cell type predominates, they are referred to as non-small cell lung carcinoma (NSCLC: non small cell lung carcinoma). The latter are further subdivided into tumors of different tissue origins, with squamous cell carcinoma, which originates from the squamous epithelium of the bronchi, and adenocarcinoma, which arises from gland cells, being by far the most important and most common subtypes.


This classification does not arise from academic taxonomy desires, but has a meaning that goes far beyond that. Tumors of the two classes differ greatly in terms of prognosis and treatment options. Small cell carcinoma shows a high growth rate and is discovered very late in the vast majority of cases (over 90 percent); Although it responds well to chemotherapy, it often relapses after a short time and therefore has a very poor prognosis. In the NSCLC group, on the other hand, there are tumors that are relatively easy to treat.


How does lung cancer develop? It is well known that cigarette smoking is the most important risk factor for all histological types. However, there are small differences. The influence of cigarette smoking has the greatest impact on the development of small cell carcinomas. Adenocarcinomas (NSCLC) can develop without the influence of cigarette smoke. Passive smoking also poses a risk: the risk of lung cancer from pure passive smoking increases by at least 26 percent. Other risk factors for the development of bronchial carcinoma that are independent of cigarette smoking are, in addition to rare, work-related exogenous noxae (in shipbuilding, in opencast mines and in refineries), permanent narrowing and inflammation of the airways, as is the case with chronic bronchitis (4-10) . Therefore, patients with chronic smoker's cough or chronic obstructive bronchitis should have regular checkups.


Unfortunately, unlike with uterine or prostate cancer, there are no really reliable methods for early detection. To be visible on a normal x-ray, a lump must be large (1 to 2 cm). The detection of small tumors is more successful with computed tomography (CT), even if this cannot guarantee absolute certainty. If you examine long-term smokers who have a high risk of lung cancer using CT, you will find small, round tumors in around 20 to 30 percent. Most of it is benign, with actual cancer rates around 1 to 2 percent.


A large-scale study is currently underway in the USA that compares conventional X-rays with CT screening in high-risk groups. 50,000 smokers were included and will be followed up for eight years. It is hoped that this will provide more reliable information about the question of whether screening examinations make sense at all and, if so, to what extent.


Prevention is only possible to a limited extent


The best protection against lung cancer is of course not to smoke cigarettes. But not everyone succeeds in giving up smoking, or nicotine consumption has been going on for so long that a high risk can be assumed. It is good to know that the risk of lung cancer decreases in any case if a smoker refrains from further nicotine consumption, regardless of how long he has smoked before.


In addition to abstaining from nicotine, other prevention options were investigated. A few years ago, for example, a study with vitamins A and b-carotene for the prevention of lung cancer began. A total of 18,314 participants were assigned to a group and took one of the two substances regularly as a prophylactic. The study had to be stopped prematurely in 1996 because the interim evaluation produced astonishing results: the incidence of lung cancer had not been reduced, but increased by 28 percent. Afterwards, all participants were asked to stop taking the substances and were monitored for the next five years. Although the overall risk was reduced after these five years with retinoic acid and β-carotene, it is more likely that the preparations increase the risk of lung cancer.


Further chemoprevention substances are currently being tested. For example those that influence lipid metabolism, such as 15-hydroxyprostaglandin dehydrogenase, or growth factors such as insulin-like growth factors. The metabolism of the polyunsaturated fatty acids and the enzymes of the arachidonic acid metabolism can have pro- and anti-tumorigenetic effects, for example in angiogenesis, immunosuppression and resistance to apoptosis. 15-hydroxyprostaglandin dehydrogenase, for example, has a »tumor suppressor« activity. The results of these studies on chemoprevention so far give reason to hope for success.


The chances of surviving the diagnosis of cancer of whatever kind are quantified using what is known as the five-year survival rate. This indicates what percentage of cancer patients with cancer are still alive after five years. The five-year survival rates for lung cancer are shockingly low (11): They are between 13 and 15 percent. Unlike other types of cancer, they have hardly changed in advanced stages in recent years. On the one hand, this is due to the fact that bronchial carcinomas are still discovered very late. On the other hand, the therapy options are unfortunately very limited.


For well over 20 years, new therapy options have been vigorously researched and developed. However, a drastic improvement in survival in the advanced stages has not yet been achieved. Now there are new drugs that can be hoped for at least a partial improvement.


From suspicion to diagnosis


The doctor suspects bronchial carcinoma if patients report coughing up blood or complain of a long-standing combination of cough and shortness of breath that cannot be attributed to another lung disease. An X-ray examination is the first measure that can provide further information about the suspected diagnosis. Very often it is also a conspicuous X-ray that was taken for completely different reasons, for example before an operation or as a routine check, and suggests a previously undiscovered bronchial carcinoma.


Before further examinations or even therapies are initiated, it is imperative that the doctor confirm the diagnosis by means of a tissue examination, because not all lung tumors are malignant. Sometimes an old tuberculosis or other benign tumors hide behind a tumor that is visible on an X-ray. In many cases, tissue can be obtained from a lung specimen (bronchoscopy). If it is established that a malignant tumor is present, the rest of the body is examined by means of ultrasound, CT or scintigraphy to find out whether there are daughter settlements and thus determine the tumor stage.


Selection of the therapy strategy


Lung cancer therapy is based on its tissue-typical classification (small-cell or non-small-cell carcinoma) and its spread, which is indicated by the tumor stage. The size of the tumor, its location, the involvement of neighboring or more distant lymph nodes and the presence of settlements in other organs (distant metastases) are particularly important for determining the tumor stage.


Doctors are particularly interested in the lymph nodes in the vicinity of the tumor. Determining whether or not they are affected can quickly clarify which stage the tumor is to be assigned to. The more distant lymph nodes are infiltrated, the worse the stage. Unfortunately, at the initial diagnosis one often not only finds settlements in the lymph nodes, but also distant metastases. The brain, bones, liver and the other lung are preferably affected. If such a settlement has taken place, the tumor is well advanced and automatically belongs to the latest stage.


In principle, there are also three classic tumor therapies for lung cancer: radiation and chemotherapy and surgery. Often two or even all three methods are combined. For example, chemotherapy (with or without radiation therapy) is used before the operation of a carcinoma in order to reduce it in size and thus offer the surgeon a better starting position. If the patient has recovered from the last chemotherapy, this procedure can often be operated on quite successfully. The procedure is known as neoadjuvant chemotherapy. Adjuvant chemotherapy is used when chemotherapy is given after an operation to reduce the risk of relapse.


Little therapy success with SCLC


Standard therapy for the early stages of small cell lung cancer (around 10 percent) is combined chemo-radiation therapy. Usually the patient is given a combination of cisplatin and etoposide; this has so far proven to be the most effective. The patient's chances of survival are improved by additional radiation.


Surgical removal of the tumor focus as a therapy option is currently much discussed and is becoming more and more common. It is only possible in the very rare early stages in which the tumor can still be operated on because of its location and extent. The aim of the intervention is actually healing (curative intention). If it is known before the operation that it is a small cell carcinoma, the patient can also receive chemotherapy beforehand (neoadjuvant therapy). If the tissue affiliation is only clarified after the operation, for example because no tissue could previously be obtained due to the location of the tumor, chemotherapy (adjuvant therapy) is started after the operation. It is currently being investigated whether additional radiation is beneficial for the patient.


The above-mentioned combinations of chemotherapy and radiation therapy as well as surgery can achieve five-year survival rates in the early stages of up to a maximum of 50 percent. In the advanced stages (around 90 percent of diagnoses) of small cell lung cancer, surgery is no longer an option. The tumor itself is no longer curable in these stages. Chemotherapy is aimed at extending life and improving quality of life, including reducing possible pain. The patient receives a combined chemotherapy consisting of at least two substances. Depending on the previous illness and age, several options are available that lead to approximately equivalent response rates and median survival: cisplatin / etoposide (PE) (standard therapy), carboplatin / etoposide (CE), adriamycin / cyclophosphamide / vincristine (ACO) or carboplatin / Etoposide / Vincristine (CEV). With such a therapy, the tumor can be reduced in size or made to disappear in around 60 to 70 percent of patients, whereby in the vast majority of cases it relapses after an initial good response after around four months. The median survival time averages 40 weeks, which corresponds to a one-year survival rate of about 30 to 37 percent.


In the last few years there have been increasing attempts to improve the response rate and survival through the use of new cytostatics such as irinotecan or topotecan. The tested substances are all effective, but no relevant improvement in survival compared to a platinum-based dual therapy with etoposide could be demonstrated for any combination with new substances (there is a positive study for irinotecan, the advantage of which is not reproduced in another study could). Experimental therapy studies with imatinib (tyrosine kinase inhibitor) or bortezomib (proteosome inhibitor) were also unsuccessful.


Small cell lung cancer remains one of the most recently diagnosed forms of cancer with limited treatment options and low survival rates.


Better chances at NSCLC


The early stages of non-small cell lung cancer are also operated on if possible. However, even with NSCLC, distant metastases are found in more than 40 percent at the time of diagnosis. However, if it is at an early stage, five-year survival rates between 40 and 75 percent can be achieved by means of surgical intervention. Adjuvant chemotherapy, i.e. chemotherapy after a successful operation, seems to bring about a further improvement in survival of around 5 to 12 percent, but is not yet established as a standard procedure.


So-called multimodal therapy is used in the stages with a larger tumor spread but still without distant organ metastases. It consists of chemotherapy and radiation therapy and (if possible) surgery. Here, too, the therapy depends on the stage: If possible, the attending physician will always first try to push back the tumor with neoadjuvant chemo- or chemoradiotherapy so that an operation is still possible. This then basically aims at healing, but the chances of this are slim. The current chemotherapy protocols combine at least two substances and in particular include the new cytostatics of the "third generation". These include, for example, docetaxel, gemcitabine, paclitaxel and vinorelbine. They are usually combined with a platinum-containing cytostatic such as carboplatin or cisplatin. The choice of medication depends on the patient's age, previous illnesses and general condition, which is described using various score systems. Table 1 shows an example.