Rowa’ al Ramahi 1

 Lung carcinomas arise from normal bronchial epithelial cells that have acquired multiple genetic lesions and are capable of expressing a variety of phenotypes. 2

 Activation of protooncogenes, inhibition or mutation of tumor suppressor genes, and production of autocrine growth factors contribute to cellular proliferation and malignant transformation.  Molecular changes, such as overexpression of c-KIT in SCLC and epidermal growth factor receptor (EGFR) in NSCLC, also affect disease prognosis and response to therapy. 3

 Cigarette smoking is responsible for about 80% of lung cancer cases. Other risk factors include exposure to respiratory carcinogens (e.g., asbestos, benzene), genetic risk factors, and history of other lung diseases (e.g., COPDs & asthma).  The major cell types are SCLC (~15% of all lung cancers), adenocarcinoma (~50%), squamous cell carcinoma (less than 30%), and large cell carcinoma. The last three types are grouped together and referred to as NSCLC. 4

 The most common initial signs and symptoms include cough, dyspnea, chest pain or discomfort, with or without hemoptysis. Many patients also exhibit systemic symptoms such as anorexia, weight loss, and fatigue.  Disseminated disease can cause neurologic deficits from CNS metastases, bone pain or pathologic fractures secondary to bone metastases, or liver dysfunction from hepatic involvement. 5

 Paraneoplastic syndromes commonly associated with lung cancers include cachexia, hypercalcemia, syndrome of inappropriate antidiuretic hormone secretion, and Cushing’s syndrome. These syndromes may be the first sign of an underlying malignancy 6

 Chest x-ray, endobronchial ultrasound, computed tomography (CT) scan, and positron emission tomography (PET) scan are the most valuable diagnostic tests. Integrated CT-PET technology appears to improve diagnostic accuracy in staging NSCLC over CT or PET alone.  Pathologic confirmation of lung cancer is established by examination of sputum cytology and/or tumor biopsy by bronchoscopy, mediastinoscopy, percutaneous needle biopsy, or open-lung biopsy. 7

 All patients must have a thorough history and physical examination to detect signs and symptoms of the primary tumor, regional spread of the tumor, distant metastases, paraneoplastic syndromes, and ability to withstand aggressive surgery or chemotherapy. 8

 The World Health Organization has established a TNM staging classification for lung cancer based on the primary tumor size and extent (T), regional lymph node involvement (N), and the presence or absence of distant metastases (M).  A simpler system is commonly used to compare treatments.  Stage I includes tumors confined to the lung without lymphatic spread  stage II includes large tumors with ipsilateral peribronchial or hilar lymph node involvement 9

 Stage III includes other lymph node and regional involvement  And stage IV includes any tumor with distant metastases.  A two-stage classification is widely used for SCLC. Limited disease is confined to one hemithorax and can be encompassed by a single radiation port. All other disease is classified as extensive. 10

 NON-SMALL CELL LUNG CANCER  Desired Outcome  The stage of NSCLC and the patient’s comorbidities and performance status (i.e., the ability to perform activities of daily living) determine which treatment modalities will be used. The intent of treatment—curative or palliative— influences the aggressiveness of therapy. 11

 Recommendations for Chemotherapy, Radiation Therapy, and Surgery  Local disease (stages IA, IB, and IIA) is associated with a favorable prognosis. Surgery is the mainstay of treatment and may be used with radiation and/or adjuvant (postoperative) chemotherapy. The adjuvant treatment regimen of choice is not clear. 12

 Patients with locally advanced disease (stages IIB and IIIA) may undergo surgery. Adjuvant chemotherapy is the standard of care. Some centers use neoadjuvant (preoperative) chemoradiation, but this is not considered the standard of care. Nonresectable locally advanced diseasemay be treated with both an active cisplatin-based regimen and radiotherapy. 13

 Four to six cycles of doublet chemotherapy with cisplatin or carboplatin plus docetaxel, gemcitabine, paclitaxel, pemetrexed, or vinorelbine are recommended as first-line palliative chemotherapy for patients with unresectable stage III or IV disease. Cisplatin-based doublets improve survival and quality of life in this patient population as compared with best supportive care or single-agent chemotherapy. No combination was found to be superior; tolerance of expected toxicities may contribute to the decision. 14

 Non-platinum-based combination regimens (e.g., gemcitabine–paclitaxel and gemcitabine–docetaxel) are recommended as first-line therapy of advanced NSCLC in patients with a contraindication to a platinum (cisplatin or carboplatin) agent. 15

 Docetaxel, pemetrexed, and an oral epidermal growth factor receptor inhibitor, erlotinib, are options for unresectable stage III or IV NSCLC patients with good performance status who progress during or after first-line therapy.  Cetuximab, a monoclonal antibody that binds to the extracellular portion of the EGFR receptor, in combination with cisplatin and vinorelbine, prolongs median overall survival by 1 month in patients with advanced NSCLC. 16

 Bevacizumab, a recombinant, humanized monoclonal antibody, neutralizes vascular endothelial growth factor. The addition of bevacizumab to carboplatin-paclitaxel chemotherapy is recommended in advanced NSCLC of nonsquamous cell histology in patients with no history of hemoptysis and no CNS metastasis who are not receiving therapeutic anticoagulation. 17

 Palliative radiation therapy with chemotherapy may help control local and systemic disease and reduce disease-related symptoms. The optimal delivery method, schedule and radiation therapy dosages when used with hemotherapy are yet to be determined. 18

 Desired Outcome  The goal of treatment is cure or prolonged survival, which requires aggressive combination chemotherapy.  Surgery and Radiation Therapy  There is no clear role of surgery in SCLC.  SCLC is very radiosensitive. Radiotherapy has been combined with chemotherapy to treat limited disease SCLC. This combined-modality therapy prevents local tumor recurrences but only modestly improves survival over chemotherapy alone. 19

 Radiotherapy is used to prevent and treat brain metastases, a frequent occurrence with SCLC. Prophylactic cranial irradiation is used in selected patients with limited or extensive disease to reduce the risk of brain metastases. Neurologic and intellectual impairment is associated with prophylactic cranial irradiation, although other factors may contribute. 20

 Radiotherapy followed by combination chemotherapy is recommended for patients with symptomatic brain metastases. Dexamethasone and anticonvulsants are also administered for symptom control and seizure prevention, respectively. 21

 Chemotherapy  Chemotherapy with concurrent radiation is recommended for limited and extensive- disease SCLC. Single-agent chemotherapy is inferior to doublet chemotherapy.  The most frequently used regimen is cisplatin or carboplatin combined with etoposide. Irinotecan in combination with cisplatin has also been shown to be active. Overall response rates and survival durations are generally superior for patients with limited stage versus those with extensive stage disease. 22

 Recurrent SCLC is usually less sensitive to chemotherapy. If recurrence occurs in >3 months, national guidelines recommend gemcitabine, topotecan, irinotecan, paclitaxel, docetaxel, CAV (cyclophosphamide, doxorubicin, and vincristine), and vinorelbine.  Patients with SCLC that recurs within 3 months of first-line chemotherapy are considered refractory to chemotherapy and unlikely to respond to a second-line regimen. 23

 Tumer response to chemotherapy for NSCLC should be evaluated at the end of second or third cycle and at the end of every second cycle thereafter. Patients with stable disease, objective response or measurable decrease in tumor size should continue treatment until 4-6 cycles have been administered. Responding patients with nonsquamous histology should be considered for maintenance therapy with pemetrexed. 24

 Efficacy of induction therapy for SCLC should be determined after two to three cycles of chemotherapy. If there is no response or progressive disease, therapy can be discontinued or changed to a non–cross-resistant regimen. If responsive to chemotherapy, the induction regimen should be administered for four to six cycles. 25

 Intensive therapeutic monitoring is required for all lung cancer patients to avoid drug-related and radiotherapy-related toxicities. These patients frequently have numerous concurrent medical problems requiring close attention.  References should be consulted for management of common toxicities associated with the aggressive chemotherapy regimens used for lung cancer. 26