Cancer therapies serve the purpose of curing the patient of the disease (“curative” = healing therapy) or to stop the further growth and spread of the tumor as long as possible, to relieve discomfort and to prolong the lifetime (“palliative” = alleviative) Therapy). An indispensable component of oncological care is the so-called “supportive therapy” (supportive therapy). It treats and prevents complications of cancer and survival-related but often aggressive cancer therapies.
How is lung cancer operated?
If the tumor has not exceeded a certain size and has not yet formed distant metastases, surgery is sought with the aim of completely removing the tumor tissue and the lymph nodes affected by tumor cells. The operation plays an important role especially in non-small cell lung cancer – as small cell lung cancer is often diagnosed at a later stage, then other treatments are in the foreground.
The surgical procedure is preceded by extensive research. In particular, it must be ensured that after the removal of part of the lung, the remaining lung sections are able to sufficiently take over the respiratory function. The condition for the operation is a good general condition of the patient; Severe comorbidities often rule out surgery. Furthermore, removal of the tumor should not pose a risk to neighboring vital organs such as large blood vessels or the esophagus. If the expected burdens and restrictions are too great, a different therapy strategy must be chosen.
During surgery, the tumor-bearing lung section and the adjacent lymph nodes are removed. The most common procedure is the removal of a lung lobe (lobectomy). With very large tumors the removal of an entire lung wing may be necessary (pneumectomy). In many cases, however, it is possible to avoid the removal of the entire lung through special, organ-preserving surgical techniques.
Possible side effects:
As a result of the operation, the available breathing area of the patient is reduced. However, if the lung function before surgery is sufficient, it will not be a major problem for the patient, and he will usually be able to compensate well for the loss of lung tissue. Special breathing exercises in rehabilitation also help to improve lung performance after tumor therapy. The first exercises can already be learned in the clinic under the guidance of a physiotherapist and later be continued at home. For smokers, however, they should stop smoking immediately before the operation to improve their lung function.
What happens during an irradiation?
Radiation therapy is the only therapy for non-small cell lung cancer in stages I and II when surgery is not possible and for selected patients in stage III. Otherwise, it is usually combined with chemotherapy in patients with stage III and small cell lung cancer. If cancer has secondary tumors, called metastases, in other organs such as the brain or the bones, they may also be irradiated.
The high-energy ionizing radiation, which is directed from the outside to the tumor, destroys the cancer cells. The total radiation dose is divided into several single doses, which are administered about five times a week. In the so-called hyperfractionated radiation, which can be used in lung cancer, is even twice a day at intervals of several hours, but then irradiated with lower single doses.
In addition to conventional radiotherapy, the so-called stereotactic radiotherapy is also used. Here, the disease is in a few sessions, sometimes in only one, irradiated with a high dose of radiation. This is possible because the beams are directed to the target area from different directions after computer-controlled irradiation planning. There, all the rays meet at one point and add up to the total dose, which is thus maximum at the site of the disease, while the surrounding healthy tissue is largely spared. For this reason, stereotactic radiotherapy is particularly well suited for small tumors and tumors in delicate environments, such as brain metastases.
Possible Side Effects:
Side effects of radiotherapy may be hoarseness and difficulty swallowing. The skin is also sensitive to the treatment. In combination with chemotherapy in particular, mucous membrane inflammation and fungal infections can occur in the oral cavity. A late consequence is a pneumonitis, an inflammation of the irradiated lung tissue. Overall, the severity of side effects depends on the type and intensity of the radiation used.
How does the chemotherapy work?
Chemotherapy uses cell-growth-inhibiting drugs known as cytostatics. They act primarily against fast-growing cells and thus especially against cancer cells. For the treatment of lung cancer several chemotherapeutic drugs are available, which are selected according to individual requirements.
Which medicines are used depends on various factors, including the stage of the disease, the general condition, and concomitant diseases. Usually, two or three substances are combined, with cisplatin or carboplatin as the basic drug in most cases. Commonly used cytostatic drugs in non-small cell lung carcinoma include cisplatin, carboplatin, vinorelbine, docetaxel, gemcitabine, paclitaxel, pemetrexed and etoposide, small cell lung carcinoma cisplatin, carboplatin, bendamustine, cyclophosphamide, doxorubicin, etoposide, irinotecan, paclitaxel, topotecan and vinca alkaloids such as vincristine.
Possible side effects:
Chemotherapy affects all rapidly dividing lines. These include not only the malignant cancer cells but also healthy cells such as the mucous membrane cells of the digestive tract and the hair root cells. The most common side effects of chemotherapy include nausea, diarrhea, mouth sores, and hair loss. Red blood and white blood cells may also be reduced during chemotherapy, leading to anemia and increased susceptibility to infection. In addition, the various cytotoxic drugs can each cause specific side effects. A good education, as well as preventive and accompanying (supportive) medications, can avoid or at least alleviate many side effects. As a rule, they stop when the chemotherapy is over.
Which targeted medical therapies are used?
Novel therapeutic approaches, termed “targeted therapy,” are designed to target cancer cells exclusively or preferentially. The active ingredients are directed, for example, against factors that promote tumor growth, they prevent the blood supply to the tumor, repair defects in the genome or eliminate their consequences or prevent the signal transmission between tumor cells, so that cell division and growth signals are absent. Targeted therapies are currently used exclusively in advanced (metastatic) non-small cell lung cancer because good efficacy has not yet been demonstrated in small cell lung cancer. Since intensive research is being carried out in this field, it can be expected that more targeted substances will be approved for the treatment of lung cancer in the near future.
Tyrosine kinase inhibitor of epidermal growth factor (EGFR tyrosine kinase inhibitor)
Activating genetic alterations in the Epidermal Growth Factor Receptor (EGFR) cause tyrosine kinases, located in the cell interior of the receptor, to activate a signaling chain that promotes the division of the cancer cells and their multiplication. The EGFR tyrosine kinase inhibitors can stop this. The tiny molecules penetrate the cells through the cell wall and occupy the internal part of the EGF receptor. This breaks the signal chain for cell division and slows down the proliferation of cancer cells.
Currently, three EGFR tyrosine kinase inhibitors are approved for the treatment of lung cancer: erlotinib, gefitinib, and afatinib. These medicines are available in tablet form. The therapy can, therefore, be performed by the patients at home, which for many means a gain in quality of life. EGFR tyrosine kinase inhibits the progression of the disease and alleviates symptoms.
Possible side effects:
Although tyrosine kinase inhibitors are well tolerated compared to chemotherapy, they are no side effects. A common side effect is the appearance of an acne-like rash on the face and upper body, also called Rash. It can be a sign that the medication works well. Other typical side effects include diarrhea, concomitant weight loss, and prolonged fatigue. Preventive concomitant therapy for rash and diarrhea is recommended.
Drugs for resistance to EGFR tyrosine kinase inhibitors
Tumors can become resistant to the therapy with an EGFR tyrosine kinase inhibitor, ie resistant. In the majority of cases, it is the so-called gatekeeper mutation T790M. It causes the tyrosine kinase inhibitors of the first (gefitinib, erlotinib) and second generation (afatinib) to be displaced from binding to the tyrosine kinase and unable to inhibit the growth factor. A novel EGFR tyrosine kinase inhibitor that selectively acts even when a T790M mutation is present is osimertinib. It is given in tablet form.
Possible side effects:
The most common side effects with osimertinib therapy are diarrhea, exanthematic rash, nausea, loss of appetite, and constipation. These side effects are significantly less pronounced than with the first and second generation drugs (gefitinib, erlotinib, afatinib).
Although cancer cells on their surface form the “normal” (wild-type) EGF receptor, as is sometimes the case with squamous cell carcinomas of non-small cell lung cancer, cell division is increasingly initiated and tumor growth promoted. In this case, a combination of the chemotherapeutic agents cisplatin/gemcitabine and the anti-EGFR antibody necitumumab may be worthwhile. If this therapy starts and is well tolerated, maintenance therapy with necitumumab is possible. The side effects of Necitumumab are similar to those of the EGFR tyrosine kinase inhibitors but more pronounced in their severity than in the first and second generation of active agents.
Tyrosine kinase inhibitors of ALK and ROS1 kinases
Tyrosine kinase inhibitors of this group of drugs are directed against proteins in the cell that stimulate cell growth. The binding of the active ingredients to the proteins blocks certain signaling pathways and restricts uncontrolled cell growth in the tumor. For example, the ALK tyrosine kinase inhibitor crizotinib is approved for the first and second treatment (after chemotherapy) of patients with ALK translocation. Second generation ALK tyrosine kinase inhibitors are alectinib and ceritinib. They have an even more specific effect on ALK kinase. Other effective ALK inhibitors currently being tested in studies are Brigatinib and Lorlatinib.
Rarer than ALK translocations are activating ROS1 translocations. The affected patients can be treated with the tyrosine kinase inhibitor crizotinib in the first therapy. A newer ROS1 inhibitor is lorlatinib.
Possible side effects:
ALK and ROS1 kinase inhibitors can also cause side effects, with each drug having its own specific side-effect profile. Often liver dysfunction, diarrhea, nausea, vomiting, abdominal pain, and prolonged fatigue, but also visual disturbances and taste changes may occur.
Angiogenesis means the formation of blood vessels. These blood vessels are needed by the tumor to supply itself with oxygen and nutrients. Ultimately, angiogenesis thus supports tumor growth and the spread of the tumor in the body.
Angiogenesis inhibitors hinder the blood supply to tumors by blocking the vascular cell growth factor VEGF (Vascular Endothelial Growth Factor). Studies have shown that cancer cells grow less and that given chemotherapies work better. Such angiogenesis inhibitors are bevacizumab, ramucirumab, and nintedanib. Bevacizumab may be used in patients with metastatic (stage IV) non-small cell non-epithelial lung carcinoma in combination with platinum-based chemotherapy for initial treatment. Ramucirumab (regardless of tumor type) and nintedanib (adenocarcinoma only) are used in patients undergoing second-line therapy in combination with docetaxel chemotherapy if relapses have occurred.
Possible side effects:
Patients with bevacizumab have an increased risk of bleeding and therefore good monitoring is essential. Often, high blood pressure occurs. Other typical but less common side effects include blood vessel obstruction (embolism), increased urinary protein excretion, and wound healing disorders. Common side effects of ramucirumab in combination with docetaxel are a lack of white blood cells with and without fever (neutropenia and febrile neutropenia), persistent fatigue and hypertension, and the side effects described with bevacizumab. The side effects of nintedanib are similar, with side effects such as EGFR tyrosine kinase inhibitors.
Other targeted agents
One to two percent of all non-small cell lung carcinomas have BRAF mutations, about half of which are V600E alterations. The BRAF gene produces a protein (B-Raf), which is involved in the normal growth and survival of cells as an important component of the so-called mitogen-activated protein kinase (MAPK) pathway. Changes in the gene can cause this signaling pathway to become overly active, leading to uncontrolled cell growth and cancer. So-called BRAF inhibitors can stop this. However, experience has shown that tumors develop rapid resistance to BRAF inhibitors. However, inhibiting the so-called MEK kinases 1 and 2 in the MAP kinase pathway simultaneously with BRAF inhibition effectively prevents the development of resistance. Preliminary study results indicate that good response rates and disease control rates are achieved in multiple-chemotherapy patients with a progressive disease by combining the BRAF inhibitor dabrafenib with the MEK inhibitor trametinib.
Nearly one-third of all patients who do not have a KRAS, ALK, ROS or EGFR mutation in the tumor have RET mutations. In this case, therapy with cabozantinib can be beneficial. Around two percent of all adenocarcinomas of non-small cell lung cancer show changes in the HER2 receptor. Affected patients often respond well to HER2 inhibitors such as trastuzumab or afatinib. For MET amplification and/or MET mutations, MET tyrosine kinase inhibitors such as capmatinib may be used.
Activate the immune system: immunotherapies
Activating one’s own immune system in such a way that it recognizes the tumor as “ill/foreign” and fights it is the goal of immunotherapy. Cancer cells can escape the natural immune defense, such as by losing their tumor-specific antigens, by which they would recognize the immune system as sick, by mutations, inhibit the activity of immune cells or manipulate so-called immune checkpoints. The latter regulates the intensity and quality of the activity of so-called T cells of the immune system. In lung cancer, the PD-1 checkpoint plays an important role. The PD1 receptor is typically produced on T cells of the immune system, the associated “ligand” PD-L1 of dendritic cells of the immune system, but also of cancer cells. When PD-L1 binds to its PD-1 receptor on the T cells, they are inactivated. If the tumor cells now release more PD-L1 themselves, they can escape the clutches of the immune system because they “paralyze” the T-cells. If the immune checkpoint PD-1 or PD-L1 is blocked by so-called PD-1 inhibitors such as pembrolizumab or nivolumab or PD-L1 inhibitors such as atezolizumab, its damaging effect on the immune cells is eliminated – these become active and fight the tumor cells.
Pembrolizumab may be used as the sole treatment for chemotherapy in patients with metastatic stage IV non-small cell lung cancer with> 50% PD-L1 expression and no EGFR and ALK alterations of tumor cells. In second-line therapy, when metastatic non-small cell lung cancer continues to grow or return despite therapy, immunotherapy with nivolumab, pembrolizumab (> 1% PD-LD1 expression) may be initiated.
Possible side effects:
In addition to fatigue, loss of appetite and general weakness, the PD-1, and PD-L1 blocker therapy can be associated with side effects related to the immune system, such as disorders of thyroid function, pneumonia, hepatitis, and renal dysfunction. Also, side effects on the skin are possible, for example, rash, itching, and vitiligo (white spot disease). In addition, diarrhea can occur as a result of colitis.
Treatment of bone metastases
Lung tumors tend to form secondary tumors in the bones. These can cause significant pain and increase the risk of fractures. Single bone metastases can be removed by surgery or stereotactic radiotherapy. In addition, the administration of substances that inhibit bone loss, so-called bisphosphonates, reduces the risk of complications, alleviating pain. Another group of drugs used to treat bone metastases are so-called targeted therapies. In Germany, the antibody denosumab from this group is approved. It binds itself in the body specifically to a protein called RANKL, which normally activates bone-degrading cells. When denosumab blocks RANKL, bone-degrading cell activity diminishes, bone mass is retained and fractures become less common.
The medical care of cancer patients is not only the antitumoral therapy, the cure or cancer as long as possible to push back – an integral part is also the so-called supportive therapy. Irrespective of the stage of the tumor, it ensures that cancer patients do not suffer too much from the complications of cancer and as well as possible tolerate the survival-related but often aggressive tumor therapies. The catalog of measures for possible supportive therapies is long; Prevention and treatment of nausea and vomiting are also included, such as the treatment of anemia and missing white blood cells (neutropenia), the prevention of infections, the prevention, and treatment of oral mucosal inflammation and the prevention and treatment of skin manifestations.
When lung cancer is too advanced, therapy is no longer focused on healing, but on relieving tumor-related symptoms and maintaining the quality of life for patients and their relatives. This includes not only the prevention and treatment of pain and other physical ailments but also assistance and therapy in psychosocial stress situations and problems that may be associated with cancer. In the case of physical symptoms, respiratory distress and pain are most prominent for lung cancer patients with advanced disease. They can be well-alleviated in many cases with the medicines and methods available today. Even if certain standards play a role in this, the therapy is always individually tailored to the patient’s situation.
Lung Cancer Centers
The treatment of lung cancer is complex and requires the cooperation of specialists in different disciplines. In addition, research into new therapies is in constant flux. In order to be able to guarantee optimal treatment for lung cancer patients based on the latest scientific findings and treatment guidelines, so-called lung cancer centers are being certified by the German Cancer Society. For certification, the facilities must meet strict standards, e.g. a minimum number of qualified specialists and a minimum number of lung cancer patients treated there each year. Only then can the centers gain sufficient experience with the disease and constantly expand it. The treatment in the lung cancer center is interdisciplinary by pulmonary specialists, thoracic surgeons, radiation therapists, oncologists, pathologists, and radiologists. They participate in regular tumor conferences, where individual treatment plans are developed for each patient. The treatment team is supplemented by psycho-oncologists, social workers, pastoral workers, and physiotherapists.
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