LUNG CANCER TREATMENT IN GERMANY

Lung cancer (bronchogenic carcinoma) is a malignant tumour arising from the bronchial tissue or the lung parenchyma. Lung cancer is the leading cause of cancer death worldwide. In 85% of cases the disease is caused by smoking.

TYPES OF LUNG CANCER

• small cell lung cancer (SCLC) is diagnosed in roughly 10-15% of cases. It tends to follow a more aggressive course, to spread rapidly and to recur. The subtypes of small cell cancer are oat cell, intermediate cell and combined small cell lung cancer;
• non-small cell lung cancer (NSCLC) covers all the remaining types of lung cancer and is diagnosed in 85-90% of patients. NSCLC has several subcategories, the most common of which are adenocarcinoma and squamous cell carcinoma. This type of lung cancer is frequently an indication for surgery, especially in the early stages of the disease. Subcategories of NSCLC: adenocarcinoma, acinar carcinoma, bronchioloalveolar carcinoma, papillary carcinoma, solid carcinoma, adenosquamous carcinoma, large cell lung carcinoma, clear cell lung carcinoma, giant cell lung carcinoma, spindle cell lung carcinoma, squamous cell lung carcinoma.

Small cell and non-small cell lung cancer call for different approaches to surgery, radiotherapy and chemotherapy. Until recently, the simple histological distinction between NSCLC and SCLC, together with the stage, was the main basis for planning treatment in confirmed primary lung cancer. Today it has been shown that, in order to choose the optimal therapy, it is essential to distinguish adenocarcinoma, squamous cell carcinoma and the other histological forms of the tumour.

AETIOLOGY  OF LUNG CANCER

• smoking (85% of cases);
• age;
• a combination of several risk factors: exposure to toxins together with smoking;
• air pollution;
• exposure to cigarette smoke;
• passive smoking;
• exposure to carcinogens (asbestos, radiation, radon, arsenic, chromates, nickel, chloromethyl ethers, polycyclic aromatic hydrocarbons, mustard gas, coke oven gas, primitive cooking methods, heating of private homes).

COPD, α1-antitrypsin deficiency and pulmonary fibrosis are suspected of increasing the likelihood of lung cancer. Patients with areas of scarring in the lungs caused by other pulmonary diseases (tuberculosis, for example) have a potentially higher risk of developing lung cancer. In addition, the risk is increased in smokers who take β-carotene preparations. Malignant transformation of the airway epithelium develops after prolonged exposure to carcinogens and the accumulation of multiple genetic mutations. In NSCLC, several so-called genetic driver mutations with a response to targeted drug therapy have been identified, including in patients who have never smoked. About 15% of all lung cancer patients have never smoked cigarettes and are presumed to have had driver mutations.

SYMPTOMS OF LUNG CANCER

In the early stages of the disease, when treatment produces the best results, symptoms are minimal or absent, which underlines the importance of screening in patients at high risk of cancer. In many patients, however, the disease remains asymptomatic even in the presence of metastases. The diagnosis is made on the basis of chest X-ray or computed tomography and confirmed by biopsy.

CLINICAL SYMPTOMS OF LUNG CANCER

• cough;
• hoarseness;
• chest discomfort or pain;
• weight loss;
• pneumonia;
• fever;
• pleural effusion;
• haemoptysis;
• shortness of breath;
• Pancoast syndrome;
• paraneoplastic syndromes;
• superior vena cava syndrome;
• Horner's syndrome;
• metastases to the brain, liver and bones.

The appearance of symptoms usually indicates advanced disease. The diagnosis is made on the basis of chest X-ray or computed tomography and confirmed by biopsy. Less often, lung cancer presents with abnormal laboratory findings caused by metastasis to other organs (most frequently the liver, bones and brain) or by a paraneoplastic syndrome, a clinical and laboratory manifestation of a malignant tumour.

Paraneoplastic syndrome includes:

• hypercalcaemia (a raised plasma calcium concentration);
• Cushing's syndrome (excessive secretion of the hormone cortisol by the adrenal cortex);
• hypercoagulation disorders (increased blood clotting);
• various neurological syndromes (impaired coordination, balance problems, difficulty walking, difficulty speaking and swallowing, and so on).

Small cell and non-small cell lung cancer may produce identical symptoms.

Small cell cancer, however, is characterised by:

• rapid progression of symptoms;
• bulky, multiple metastases in the mediastinal lymph nodes;
• paraneoplastic syndrome;
• superior vena cava syndrome;
• bone metastases and metastases to the brain and liver.

Patients with non-small cell lung cancer frequently develop Pancoast syndrome (weakness and pain in the arm caused by an upper lobe tumour invading the brachial plexus) and hypercalcaemia

DIAGNOSING LUNG CANCER

• chest X-ray;
• CT or PET-CT;
• cytological examination of pleural effusion or sputum;
• biopsy via bronchoscopy, as well as fine needle biopsy;
• in some cases – open lung biopsy.

If lung cancer is suspected, computed tomography (CT) of the chest and upper abdomen is ordered (usually with contrast enhancement) in order to assess the extent of the primary tumour and possible metastasis to the mediastinum, liver and adrenal glands.

A definitive diagnosis of cancer can only be established on the basis of cytology (of pleural fluid, for example) or histology (a tissue biopsy).

A biopsy may be performed in one of the following ways:

• bronchoscopy;
• endobronchial ultrasound bronchoscopy, or the EBUS TBNA technique; (transbronchial needle aspiration guided by endobronchial ultrasound;
• CT-guided fine needle biopsy;
• needle aspiration;
• thoracocentesis.

Since 2003 the gold standard for staging lung cancer has been transbronchial needle aspiration guided by endobronchial ultrasound — a reliable and widely accepted technique that makes it possible to visualise and sample lesions in the mediastinum, the central part of the lung and the hilum, as well as lymph nodes located along the tracheobronchial tree.

If other biopsy procedures fail to establish the diagnosis, open surgery may be required. The most common surgical procedures are mediastinoscopy, to biopsy lymph nodes in the central part of the chest, or video-assisted thoracoscopic surgery (VATS) — a less invasive method of biopsying lung tissue; and thoracotomy, open surgery to remove large portions of lung tissue or tumours.
CT-guided fine needle biopsies allow many patients to avoid open surgery performed for diagnostic purposes.

After the biopsy, the material is sent to the Institute of Pathology at the University Hospital for histopathological assessment of the tumour characteristics, which is needed for the subsequent choice of treatment.

MOLECULAR TUMOUR ANALYSIS

The Institutes of Pathology also carry out molecular analysis of the tumour in order to identify specific tumour biomarkers or gene mutations. This makes it possible to build a so-called «molecular portrait» of the tumour and to use targeted drugs, which give better results than standard chemotherapy. The most common biomarkers in lung cancer are EGFR mutations, ALK translocations and translocations of the c-ROS oncogene 1 (the ROS1 oncogene).

Staging

Once the diagnosis has been verified, further investigations are needed to stage the disease correctly. The following may be ordered for this purpose:

• ultrasound of the pleural and abdominal cavities, the vessels and the lymph nodes (to detect possible metastases and tumour-related complications);
• MRI of the brain (if neurological symptoms are present);
• X-ray of the pelvic region (in case of pelvic pain);
• echocardiography to assess a malignant pleural effusion (in the presence of hypotension with sinus tachycardia).

Laboratory tests

When CT findings raise the suspicion of lung cancer, the following tests are performed:

• full blood count;
• electrolytes;
• calcium;
• alkaline phosphatase;
• ALT, AST, total bilirubin;
• creatinine;
• total protein, albumin and lactate dehydrogenase (optional);
• coagulation panel.

Clinical examination and laboratory tests are carried out to detect possible metastases. Abnormal laboratory results are grounds for ordering additional imaging studies.

Imaging

The first imaging method used is most often a chest X-ray. It can reveal single or multiple lesions, solid nodules in the lungs (a solitary pulmonary nodule), enlarged lung hila, widening of the mediastinum, tracheobronchial narrowing, atelectasis, non-resolving infiltrates, cavities, thickening of the pleural layers of unclear origin or pleural effusion. These changes raise the suspicion of lung cancer, but confirming the diagnosis requires a CT or PET-CT scan as well as cytological examination.

CT demonstrates many characteristic anatomical features and findings that point towards the correct diagnosis. CT can also be used to guide core needle biopsy of the lesions in question and to determine the stage of the disease. If the chest X-ray indicates a high probability of lung cancer, a CT-PET scan is performed. CT provides anatomical images and PET functional ones. PET makes it possible to distinguish an inflammatory process from a malignant one.

The standard for staging lung cancer is whole-body PET-CT, a highly accurate method. PET-CT can detect tumour deposits in lymph nodes that CT has not identified, as well as distant metastases in other organs. PET-CT findings frequently lead to a revision of the initial stage and of the treatment strategy.

The stages of non-small cell lung cancer are determined on the basis of the following factors:

• the size and location of the tumour;
• spread of the tumour to the lymph nodes and tissues inside the chest;
• spread of the tumour beyond the chest (lung cancer may metastasise to the bones, liver, adrenal glands or other organs, for example).

The stages of non-small cell lung cancer range from I to IV:

• stage I: the tumour is ≤ 3 cm in diameter and has not spread to any other tissue or lymph nodes;
• stage II: the tumour measures between 3 and 7 cm, or has spread to the lymph nodes or the tissues surrounding the lung, or has started to grow into the lumen of the bronchi;
• stage IIIA: the tumour may be > 7 cm, or may have spread to the mediastinal lymph nodes, or have invaded the ribs, heart, oesophagus or trachea;
• stage IIIB: the tumour has spread to lymph nodes outside the mediastinum or to lymph nodes above or below the collarbone. Stage IIIB also includes tumours that have spread to the ribs, heart, oesophagus or trachea without involvement of the mediastinal lymph nodes;
• stage IV: the cancer has spread beyond the chest or to the opposite side of the mediastinum. At stage IV the cancer may cause fluid to accumulate around the lung or the heart (a malignant effusion).

Stages of small cell lung cancer

Technically, small cell cancer is divided into stages in exactly the same way as non-small cell cancer. Treatment options, however, are usually determined using a simpler scheme. Small cell lung cancer is normally described as either «limited» or «extensive» disease.

• limited disease — small cell lung cancer confined to one side of the chest with involvement of the regional lymph nodes;
• extensive disease — small cell lung cancer that has spread to the opposite side of the chest and to other organs outside the chest.

LUNG CANCER TREATMENT IN GERMANY

The pulmonology departments of the German University Hospitals that msp group germany works with offer the full range of multimodal diagnostic and therapeutic options for treating patients with lung cancer in line with international standards and the guidelines of the German Cancer Society.
Every case is discussed by a multidisciplinary Tumor Board that includes pulmonary oncologists, radiologists, pathologists, radiation oncologists and surgeons; the treatment strategy is defined individually for each patient according to the features of the tumour, its stage, the age and clinical condition of the patient and any concomitant diseases.

Early-stage lung cancer usually responds well to surgery, with removal of the tumour and the surrounding lung tissue. At stage III, combined treatment is often indicated — a combination of chemoradiotherapy and surgery at various points in the course of therapy. If the cancer has spread beyond the chest (stage IV), chemotherapy and radiotherapy are used to control the disease and its symptoms.

For patients with SCLC, systemic chemotherapy is one of the most important components of treatment, since almost all patients already have extensive SCLC by the time they present. For patients with limited disease, radiotherapy of the chest is combined with chemotherapy. Prophylactic cranial irradiation is often given to reduce the incidence of brain metastases and improve survival. Prophylactic radiotherapy of the head and chest may also be of benefit in patients with a complete or partial response to first-line systemic chemotherapy.

SURGICAL TREATMENT OF LUNG CANCER

Surgical resection offers the best long-term survival and often a complete cure in patients with non-small cell lung cancer. However, even when a tumour appears at first sight to be readily resectable, the patient may be «inoperable» because of insufficient lung function or concomitant diseases, so a thorough work-up is of great importance in deciding whether surgery is indicated.

Operations in patients with suspected or confirmed lung cancer may differ considerably in their extent and purpose.
If lung cancer is suspected and material for histological examination cannot be obtained in any other way, diagnostic surgery may be required

Biopsy of the mediastinal lymph nodes is performed using modern minimally invasive techniques – video mediastinoscopy or video thoracoscopy with small surgical incisions/punctures (1-2 cm) and minimal trauma to the muscles and other tissues.

Lung biopsy is likewise performed via a video-thoracoscopic approach.

Some operations are aimed at removing the pleura or dividing adhesions in the pleural cavity. Such procedures help to relieve complications caused by pleural metastases and recurrent pleurisy. These complications can not only prevent chemotherapy from being given but also threaten the patient's life.

The choice of radical surgical treatment for lung cancer depends on the location of the tumour, its size, signs of invasion into neighbouring structures and lymph node involvement.

In terms of extent, the following operations can be distinguished:

• lobectomy;
• pneumonectomy;
• bilobectomy and lobectomy with bronchoplasty or angioplasty;
• segmentectomy.

When lung cancer is detected at an early stage, with no invasion of neighbouring organs and a tumour of less than 5-6 cm, surgery can be performed through a minimally invasive approach – using video thoracoscopy and small incisions.

RADIOTHERAPY FOR LUNG CANCER

Stereotactic radiosurgery SBRT (Stereotactic Body Radiation Therapy), also known as SABR (Stereotactic Ablative Body Radiotherapy), is an effective and safe non-invasive treatment for stage I non-small cell lung cancer, that is, for tumours of up to 5 cm with unaffected lymph nodes. Studies have shown equivalent overall survival and local tumour control when surgery (lobectomy, the current standard of care) is compared with SBRT in elderly patients or in patients who are inoperable because of comorbidity. Between 3 and 5 sessions (fractions) of SBRT are used.

The radiation oncology and radiotherapy departments use technologies based on the high-energy linear accelerators Varian Truebeam, Varian Trilogy Silhouette, Varian 21eX and BrainLab Novalis, which make the most advanced radiation treatment methods possible.

Intensity-modulated radiotherapy (IMRT), image-guided radiotherapy (IGRT), volumetric modulated arc therapy VMAT; volumetric modulated irradiation VMAT/RapidArc; with this therapy the accelerator delivers the maximum radiation dose to the defined area without harming healthy tissue

When lung tumours are irradiated, especially those located in the lower lobes, the lesion moves considerably during the different phases of breathing. Gated RapidArc technology makes it possible to irradiate the tumour allowing for its actual movement throughout the breathing cycle, or to pause irradiation when inhalation/exhalation goes beyond the defined interval.

Treatment of Pancoast tumour

A Pancoast tumour (superior sulcus tumour) is a non-small cell lung cancer located in the upper part of the lung. The tumour affects the nerves, causing the characteristic pain in the shoulder or arm, muscle weakness in the arm, flushing and excessive sweating on one side of the face

As the tumour progresses the eyelid droops (ptosis) and sweating on the affected side stops completely. In the absence of distant metastases, treatment of a Pancoast tumour consists of chemoradiotherapy followed by surgery.