Lung Cancer Diagnosis, Symptoms and Treatment
Lung cancer is a solid tumor originating from bronchial epithelial cells. This chapter distinguishes between non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) because they have different natural histories and responses to therapy.
Lung carcinomas arise from pluripotent epithelial cells after exposure to carcinogens, which cause chronic inflammation that leads to genetic and cytologic changes and ultimately to carcinoma.
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 P53 mutations and overexpression of epidermal growth factor receptor (EGFR), also affect disease prognosis and response to therapy.
Cigarette smoking is responsible for about 83% of lung cancer cases. Exposure to asbestos, chloromethyl ethers, heavy metals, polycyclic aromatic hydrocarbons, and radon has also been implicated.
The major cell types are SCLC (20% of all lung cancers), adenocarcinoma (40%), squamous cell carcinoma (less than 30%), and large cell carcinoma (15%). The last three types are grouped together and referred to as NSCLC.
The most common initial signs and symptoms include cough, dyspnea, chest pain, sputum production, and 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.
Paraneoplastic syndromes commonly associated with lung cancers include cachexia, hypercalcemia, syndrome of inappropriate antidiuretic hormone secretion, and Cushing’s syndrome.
In a patient with signs and symptoms of lung cancer, chest x-ray, 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 fiberoptic bronchoscopy, percutaneous needle biopsy, or open-lung biopsy.
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.
The American Joint Committee on Cancer 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, stage IIIA includes locally advanced disease, stage IIIB includes bulky regional disease, 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 the regional lymph nodes. All other disease is classified as extensive.
NON-SMALL CELL LUNG CANCER
The goal of treating NSCLC depends on the disease stage. Stages I, II, and possibly III disease can be cured with appropriate therapy. In contrast, stage IV disease is not curable, but chemotherapy can decrease symptoms and prolong survival.
Surgery is the treatment of choice for localized disease (stage I or IIA).
Radiation therapy is used as adjuvant therapy after surgery, as primary therapy if the tumor is not operable or the patient is not a good surgical candidate, and as palliative therapy for advanced disease.
Historically, NSCLC has been considered to be insensitive to chemotherapy. New drugs and new combination regimens are yielding promising results. For example, a 3-drug regimen was recently shown to prolong survival when used as adjuvant therapy after surgery for stages I, II, and III disease.
Management of locally advanced NSCLC (stages IIB, IIIA, and IIIB) is controversial. Postoperative adjuvant and preoperative neoadjuvant chemotherapy, with or without concurrent radiation therapy, have been used.
New combinations improve response and survival rates in patients with stage IV disease. Patients most likely to benefit from chemotherapy have a good performance status, no or minimal weight loss, and less extensive disease.
No single regimen is considered standard, so selection should be based on the patient’s ability to tolerate expected toxicities and likelihood of radiation therapy (and impact on chemotherapy-induced toxicities).
The most widely used and recommended regimens include cisplatin or carboplatin combined with another agent (Table 61-1). Historically, cisplatin combined with etoposide was considered to be the most active regimen for advanced NSCLC. Addition of a third drug does not appear to provide benefit and can increase toxicity.
Vinorelbine and cisplatin improves survival compared with either agent alone. Vinorelbine has the advantage of minimal toxicity and is easily administered in the outpatient setting over 6 to 10 minutes followed by a 75- to 100-mL IV flush.
More studies are needed to clarify how paclitaxel should be combined with other agents, whether the dose should be high or low, and whether the dose should be infused over 1 or 3 hours or given as a continuous 24-hour infusion. The 1-hour infusion is easy to administer in the outpatient setting and causes minimal myelosuppression, but it increases the rate of peripheral sensory neuropathy. Studies are being conducted to determine whether continuous infusion or high doses are more effective; these approaches are more myelosuppressive and require granulocyte colony-stimulating factor (G-CSF) support.
Docetaxel, a taxane without the schedule-dependent efficacy and toxicity issues of paclitaxel, is given IV over 1 hour every 3 weeks. Docetaxel is approved as a single agent after failure of first-line therapy and in combination with platinum as first-line therapy. The dose-limiting toxicity is neutropenia.
Gemcitabine is approved as first-line therapy when combined with cisplatin based on studies showing prolonged survival compared with cisplatin with or without etoposide. In a 4-way comparison of combination regimens, gem- citabine combined with cisplatin was associated with the least neutropenia but the most thrombocytopenia and renal dysfunction.
Irinotecan is being evaluated in many combination regimens. Irinotecan is also being evaluated with chest radiotherapy at a dose selected to avoid the esophagitis, diarrhea, and unexpected severe pneumonitis seen at higher doses.
Two oral EGFR inhibitors are indicated as single-agent therapy after failure of first-line therapy. Although not compared in a head-to-head study, erlotinib appears to be more active because it significantly prolonged survival whereas gefitinib did not.
SMALL CELL LUNG CANCER
The goal of treatment is cure or prolonged survival, which requires aggressive combination chemotherapy.
Surgery and Radiation Therapy
Surgery is almost never indicated because SCLC disseminates early in the disease.
SCLC is very radiosensitive. Radiotherapy has been combined with chemotherapy to treat tumors limited to the thoracic cavity. This combined-modality therapy prevents local tumor recurrences but only modestly improves survival over chemotherapy alone.
Radiotherapy is utilized to prevent and treat brain metastases, a frequent occurrence with SCLC. Prophylactic cranial irradiation is controversial because of neurologic and cognitive impairment and should be limited to patients with limited disease and complete response to chemotherapy.
Aggressive combination chemotherapy produces a four to fivefold increase in median survival for patients with SCLC.
Combination chemotherapy is clearly superior to single-agent therapy. The most frequently used regimen is a platinum combined with etoposide or, less frequently, irinotecan.
Cisplatin-containing regimens yielded improved survival and less life-threatening myelosuppression than regimens without cisplatin. Carboplatin is frequently used in place of cisplatin because it has similar efficacy and is less toxic.
Alternating nonâ€“cross-resistant regimens and dose intensity are theoretically attractive, but neither provided substantial benefit in clinical studies. Dose-intensive regimens significantly increase toxicity such as granulocytopenia, febrile neutropenia, mucositis, and weight loss.
Recurrent SCLC is usually less sensitive to chemotherapy. If recurrence is more than 6 months after induction chemotherapy, that regimen can be repeated. If recurrence is less than 6 months, another regimen should be used such as ifosfamide, taxane, gemcitabine, topotecan, CAV (cyclophosphamide, doxorubicin, and vincristine), gemcitabine, oral etoposide, methotrexate, or vinorelbine.
EVALUATION OF THERAPEUTIC OUTCOMES
The efficacy of induction therapy should be determined after two to three cycles of chemotherapy. If there is no response or progressive disease, a nonâ€“cross-resistant or investigational regimen should be considered.
The optimal duration of chemotherapy after induction of response is controversial. Guidelines for NSCLC recommend a maximum of six or eight cycles of chemotherapy, but some experts recommend only three or four cycles. Induction therapy for SCLC is administered for four to six cycles, but more than four cycles have not demonstrated a survival advantage and may reduce quality of life.
Intensive therapeutic monitoring is required because of underlying medical problems in patients with lung cancer and because of drug- and radiotherapy-related toxicity.
Patients receiving radiation therapy may experience esophagitis, fatigue, radiation pneumonitis, and cardiac toxicity.
The aggressive chemotherapy regimens used for lung cancer cause many toxicities. Although a comprehensive review is beyond the scope of this chapter, cisplatin-induced acute and delayed emesis merits consideration because the problem is common and severe, requiring aggressive management with serotonin antagonists and dexamethasone. Appropriate references should be consulted for management of other common toxicities such as dose-limiting myelosuppression, mucositis, nephrotoxicity, peripheral neuropathy, and ototoxicity.