Position of Nuclear Medicine Modalities in the Diagnostic Workup of Cancer Patients: Lung Cancer - 1


Lung cancer is the most common cancer in the world and accounts for 12.3% of all new cancer cases with millions of deaths per year. In Europe too, lung cancer is the most commonly diagnosed cancer with nearly 400 000 new cases each year (303 000 in men and 72 000 in women) and continues to be the most frequent cause of death from cancer in men over 45 years of age with over 280 000 deaths attributable to lung cancer every year and 67 000 deaths in women.

 There are substantial differences in incidence and mortality of lung cancer in  lung cancer surgery the different regions and populations within Europe. In men, incidence and cumulative risk is highest in eastern and lowest in northern Europe (e.g., in Hungary 95.5/105, in Sweden 21.4/105); in women, the highest rates are observed in northern, the lowest incidence rates are seen in southern Europe (e.g., in Denmark 27.7/105, in Spain 4.0/105) 1. Lung cancer is four times more common in men than in women, the median age at diagnosis is of about 61 years.

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Tobacco smoking is well established as the main cause of lung cancer and about 90% of cases are thought to be tobacco related.For the prognosis and for therapeutic strategies, the differentiation of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) is important which contribute for nearly 80% and 20% of the lung cancers, respectively.

NSCLC occurs in several histological subtypes, mainly squamous cell carcinoma and adenocarcinoma (each nearly 30% of the cases), as well as large cell carcinomas (10% of the cases) and less frequent types like adenosquamous carcinoma, carcinoid tumors, muco-epidermoid carcinoma, adenoid-cystic carcinoma, and other unspecified carcinomas.

The mean survival time for untreated NSCLC is a  mere 6 months and only 2 months for untreated SCLC. Today, curative treatment (mainly based on surgery) is only possible for NSCLC in early stages of lung cancer. Chemotherapy and radiotherapy play an important role in adjuvant and neoadjuvant treatment strategies as well as in a palliative situation. Currently new concepts with multimodality treatments are under investigation.

Diagnostic strategies in lung cancer

Lung cancer can cause a broad spectrum of unspecific symptoms and is often first diagnosed on a chest radiography performed after initial presentation of the patient. The indeterminate solitary pulmonary nodule (SPN) is a challenge for diagnostic methods. It can be cured by thoracotomy with resection of the nodule; however, in nearly half of the cases, no malignancy is found by histology after SPN resection.

Therefore, a method with a high diagnostic accuracy - and especially with a high negative predictive value - is needed for a better patient selection to avoid unnecessary surgery without missing a lung cancer in an early stage with curative treatment options. Further diagnostic tests in patients with suspected lung cancer aim at the confirmation of the diagnosis, and the evaluation of the tumor spread (staging). The cardiopulmonary status is important before therapy to ascertain whether a patient is medically operable and to predict residual lung function.

Table I summarizes the recommended  diagnostic tests for all patients with suspected lung cancer. The diagnostic procedures have to be adapted to the stage of the disease and to the corresponding therapeutic options; therefore, extended diagnostic procedures are recommended for specific indications only (Table II). Staging should be performed in accordance to the International Staging System (ISS) (Table III).

The TNM system 10 classifies the size and the proximity of the primary tumor to important anatomical structures by the T factor. The N factor assigns the metastatic spread to peribronchial, hilar (N1), ipsilateral mediastinal (N2) and contralateral mediastinal or supraclavicular lymph nodes (N3). An M1 status is given by pulmonary metastases outside the lung lobe of the primary tumor, and in cases with extrathoracic metastases. Various T, N and M factors are grouped to form different stages (I to IV). In the new guidelines, the use of the ISS is recommended also for small cell lung cancer.

Morphological imaging in lung cancer

X-ray Computed Tomography (CT) is a keystone in the diagnostic evaluation of suspected lung cancer, because it provides the most detailed anatomical images.  CT is a routine imaging modality with the ability to detect lesions in the lung with excellent sensitivity.

It is widely used for the determination of tumor resectability and for the diagnosis of intra- and extrathoracic spread of lung cancer. In some cases magnetic resonance imaging (MRI) is needed to evaluate a possible chest wall infiltration or the invasion of the great vessels by the tumor. CT examinations are nowadays performed as spiral or multislice-CT with contrast enhancement, including the upper abdomen to provide information about the liver and the adrenals.

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CT scanning is also used for the radiotherapy treatment planning for the delineation of the primary tumour to define the gross target volume (GTV) and the planning target volume (PTV). Even with the ongoing (dramatic) improvements of instrumentation technology, CT shows limitations in the characterization of amorphological lesion, mainly due to the utilization of size criteria ("anatomic imaging") for defining a malignancy. Problems arise mainly for the characterization of pulmonary nodules, the evaluation of the mediastinal lymph nodes, the assessment of the viability of previously treated malignant tumors, and for the detection of tumor recurrences.

Treatment of lung cancer

Before initiation of a tumor-specific treatment, a histopathological diagnosis must be established from a bronchoscopic, tru cut or surgical biopsy; at least a cytological diagnosis (fine needle aspiration) should be obtained. The therapeutic strategy is adapted to the stage of the disease and should follow current recommendations. At present, therapeutic concepts and guidelines are changing, especially for locally advanced non-small cell lung cancer.

The overall 5-year survival rate has remained essentially unchanged for the last decade and is about 15%;further studies are urgently needed to improve the prognosis. Table IV and Table V list the recommendations of the German Scientific Medical Societies for the treatment of non-small cell and small cell lung cancer, respectively About 80% of lung cancers are non-small cell bronchial carcinomas which are treated in curative intention by an anatomically appropriate radical surgical resection (R0) of the tumor-involved lung lobe or several lobes.

This applies to early tumor stages in which mediastinal lymph node involvement (N2 or N3) and distant metastases have been ruled out preoperatively. Systematic lymphadenectomy of the mediastinum is performed in any case. Approximately 45% of all lung cancers are limited to the chest, where surgical resection is a curative treatment option.In order to achieve complete (R0) resection, the surgeon must be experienced in bronchoplastic and angioplastic techniques, including expanded resection techniques

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for neighbour organs to the lung, especially the mediastinum and/or chest wall. If N2 status is suspected (i.e., CT reveals lymph nodes with a diameter of >1 cm), currently mediastinoscopy is recommended.A positive result requires multimodality treatment. The N3 status (contralateral mediastinal or  supraclavicular lymph node involvement) is regarded as contraindication for a surgical resection.

Chemotherapy

Cytostatic chemotherapy is the standard treatment in SCLC and in stage IV NSCLC. It is essentially palliative, increases survival and improves the quality of life.In locally advanced NSCLC with metastatic spread to mediastinal lymph nodes or in non-resectable tumors, multimodality treatment concepts including chemotherapy and radiotherapy followed by surgery in responding patients, are currently under investigation.

Radiotherapy

Primary radiotherapy using tumor doses of 60 Gy and more is a potentially curative treatment in early stages of NSCLC for inoperable patients (due to concurrent diseases) or for those who do not agree to surgery. For the preoperative radiotherapy of pancoast tumors (T3 N0 M0), doses up to 50 Gy are recommended.

Adjuvant radiotherapy is performed in patients with mediastinal lymph node metastases or incomplete tumor resection with doses of 50 Gy, followed by a boost dose of 10 to 16 Gy to the residual tumor. Palliative radiotherapy of the primary tumor or metastatic lesions has a temporary favourable effect on secondary tumor symptoms in most patients.

Combined radiation therapy and chemotherapy is being studied intensively, in particular for stage III patients.In SCLC, the irradiation of the tumor site after chemotherapy and prophylactic cranial irradiation is the recommended treatment.