1. Bronchogenic Carcinoma （ Lung Cancer ） Guo Yubiao, M.D & Ph.D Pulmonary & Critical Care Medicine The first Affiliated Hospital of Sun-Yat Set University
18. Major signs and symptoms of lung cancer Baseline major presenting symptoms 0 20 40 60 80 100 Hemoptysis Loss of appetite Pain Cough Dyspnea Patients (%) Hollen et al 1999
40. NSCLC stages - an overview Mountain 1997 Disease Early Localized Advanced Stage 0 IA IB IIA IIB IIIA IIIB IV TNM TIS N0 M0 (carcinoma in situ ) T1 N0 M0 T2 N0 M0 T1 N1 M0 T2 N1 M0 T3 N0 M0 T3 N1 M0 T1-3 N2 M0 T4, Any N, M0 Any T, N3, M0 Any T, Any N, M1
41. NSCLC stages Stage 0 Stage IA Stage IIB Stage IIIB Stage IV Lymph nodes Main bronchus Contralateral lymph node Metastasis to distant organs Invasion of chest wall
42. NSCLC: clinical stage as a prognostic factor 1 year 3 years 5 years 0 10 20 30 40 50 60 70 80 90 100 IA IB IIA T2N1M0 IV IIB IIIA IIIB Clinical stage at presentation Survival (%) Mountain 1997 T3N0M0 T3N1M0 T1-3N2M0 T4 N3
51. NSCLC stage III: surgery combination regimens Study Pass et al 1992 Roth et al 1994 Rosell et al 1994 Regimens Surgery plus chemotherapy (n=13) Surgery plus radiotherapy (n=14) Surgery plus chemotherapy (n=28) Surgery alone (n=32) Surgery plus radiotherapy plus chemotherapy (n=30) Surgery plus radiotherapy (n=30) Median survival (months) 28.7 15.6 64 11 26 8 p value 0.095 <0.008 <0.001
There are major differences in the incidence and mortality rate for lung cancer in males and females. 1 The differences between males and females, can be accounted for by trends in tobacco smoking, which causes up to 90% of all lung cancer. 2 Although the prevalence of current cigarette use has generally decreased over more than 30 years, the pattern of decline has varied by sex and race. A rapid increase in cigarette smoking in the first half of this century occurred first among men and then a generation later among women. Since 1965, smoking prevalence has declined, more rapidly among males than among females. Accordingly, male lung cancer incidence and death rates peaked in 1984 and 1990 respectively and are now declining, whereas, this is not observed in women. Current trends in tobacco smoking, including increased adolescent smoking during the 1990s, may worsen the future occurrence of lung cancer. 2 1. Ries LAG, et al (eds). SEER Cancer Statistics Review, 1973-1996, National Cancer Institute, Bethesda, MD, 1999. 2. Wingo PA, et al. J Natl Cancer Inst 1999; 91: 675-690.
In a recent study of 673 patients with NSCLC, the major presenting lung cancer symptoms at diagnosis were dyspnea (87% patients), cough (86%), pain (81%), loss of appetite (75%) and hemoptysis (41%). 1 Although 81% of these patients had three or more of these symptoms, there were some patients who presented with only one symptom (5% of patients) or no symptoms (2% of patients). 1 Although not included in the Lung Cancer Symptom Scale 1 , weight loss is also a major symptom of NSCLC. 1. Hollen PJ, et al. Support Care Cancer 1999; 7: 140-148.
Non-small cell lung cancer X-ray: This X-ray shows an irregular mass (approximately 5cm x 4cm) at the right hemi thorax infiltrating into the adjacent mediastinum. Some mediastinum lymphadenopathy is present leading to a narrowing of the trachea. X-rays can give an approximate location of the tumour and an indication of the tumour size. Straight and lateral views are usually required to provide a complete picture of the depth of the tumour.
Non-small cell lung cancer CT scans: There is a mass measuring approximately 5cm x 5cm. Tiny lung metastases are also evident on the images. Computerised tomography scanning provides a more accurate location of the tumour than the X-ray; it is, therefore, valuable if surgery or radiotherapy is contemplated. CT scans can detect chest wall invasion and mediastinal lymphadenopathy, either of which are contraindications to surgical resection. Inclusion of the liver and adrenal glands can also detect distant metastasis in these organs. Some studies have shown that low dose spiral CT in comparison with conventional radiography of the chest was superior for screening and detection of small peripheral lung cancers. 1 However, a much larger-scale clinical trial is warranted to further examine this. 1 1. Kaneko M, et al. Radiol 1996; 201: 798 - 802 1. Webb WR, et al. Radiology 1991; 178: 705-713.
All patients should undergo a history-taking and physical examination, chest X-ray and chest computed tomography (CT) scans (including the adrenal glands), liver CT scan or abdominal ultrasound. Other evaluations include a complete blood count, electrolytes, liver function tests, calcium, blood urea nitrogen, and creatinine, as well as a baseline ECG. Bone scans and/or brain CT scans may be appropriate in some patients. 1 The extent of the tumor, the involvement of the lymph nodes, and chest wall or mediastinal invasion can be determined with similar efficacy using either CT or MRI. CT is used more commonly, although MRI may be preferable in specific situations, for example in evaluating superior sulcus tumors. 2 Positron emission tomography (PET) with radiolabeled fluoro-2-deoxyglucose combined with CT was significantly more accurate than CT alone in identifying lymph node involvement in NSCLC. 3 1. NCCN Guidelines. 2. Webb WR, et al. Radiology 1991; 178: 705-713. 3. Vansteenkiste JF, et al. J Clin Oncol 1998; 16: 2142-2149.
Lung cancer is staged according to three parameters: tumor (T), lymph nodes (N), and metastatic involvement (M). 1 Tumor stages: TX: primary tumor cannot be assessed T0: no evidence of primary tumor TIS: carcinoma in situ (confined to airway lining) T1: tumor <3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus T2: tumor with any of the following features: >3 cm in greatest dimension; involves main bronchus ?2 cm distal to the carina; invades the visceral pleura. Any associated atelactasis or obstructive pneumonitis should involve less than the entire lung T3: tumor of any size that directly invades into the chest wall, diaphragm, mediastinal pleura or parietal pericardium; a tumor in the main bronchus <2 cm distal to the carina but not involving the carina; a tumor with associated atelactasis or obstructive pneumonitis of the whole lung T4: tumor of any size that invades the mediastinum, heart, great vessels, trachea, esophagus, vertebral body or carina; a tumor with malignant pleural or pericardial effusion; a tumor with satellite tumor nodules within the ipsilateral primary tumor lobe of the lung. Lymph node stages: NX: regional lymph nodes cannot be assessed N0: no regional lymph node metastasis N1: metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes involved by direct extension of primary tumor N2: metastasis to ipsilateral mediastinal and/or subcarinal lymph node(s) N3: metastasis to contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s). Distant metastasis stages: MX: presence of distant metastasis cannot be assessed M0: no distant metastasis M1: distant metastasis present. 1. Mountain CF. Chest 1997; 111: 1710-1717.
Schematic diagram showing examples of some tumor stages. Stage 0 (carcinoma in situ ) - tumor is confined to the airway lining. Stage IA (T1 N0 M0) - tumor has spread to nearby lung tissue but has not reached the main bronchus. Stage IIB (T2 N1 M0) - tumor has reached main bronchus and local lymph nodes. Stage IIIB (T4 N3 M0) - tumor has invaded chest wall, trachea and the contralateral lymph nodes. Stage IV (T1 N0 M1) - distant metastasis present in the brain.
Survival progressively declines as the stage of disease at presentation advances. 1 Five-year survival is poor even at relatively early stages, reflecting the lack of satisfactory treatment. 1. Mountain CF. Chest 1997; 111: 1710-1717.
For localized tumors (stage 0, I, II), surgery is usually the treatment of choice. Radiotherapy may be used in patients who are medically unsuitable for surgery. The role of induction chemotherapy in these early stages is still under investigation. Locally or regionally advanced tumors (stage III) are usually too extensive curative surgery, but are still confined to the chest. The standard treatment is chemotherapy plus radiotherapy. Downstaging the tumor with chemotherapy (with or without radiotherapy) may allow surgery in certain cases. Advanced tumors (stage IV) are treated with chemotherapy. Palliative radiotherapy may be used to relieve symptoms. 1. PDQ Treatment Guidelines.
Surgery is the treatment of choice. It may remove all the affected lobe (lobectomy), or part of the lobe (segmentectomy or wedge resection). 1 Curative radiotherapy may be used in patients with contra-indications to surgery. 1 Endoscopic photodynamic therapy is under evaluation. 1 It involves systemic injection of a photosensitive chemical. After a delay to allow uptake into the cancer cells, an optic fiber is inserted into the lung through a bronchoscope and used to transmit laser light, which activates the photosensitive chemical and kills the tumor cells. Complete response rates of up to 85%, with a median duration of 14 months, have been reported 2 , but the limited light penetration means that the technique is currently practicable only for small tumors located in the large airways. 1. PDQ Treatment Guidelines. 2. Furuse K, et al. J Clin Oncol 1993; 11: 1852-1857.
Surgery is the treatment of choice, lobectomy, pneumonectomy (removal of entire lung), segmentectomy or wedge resection depending on the patient. 1 Curative radiotherapy may be used in patients with contra-indications to surgery. 1 30-50% of patients resected for stage I/II NSCLC may later develop regional or distant metastases. Adjuvant chemotherapy or radiotherapy following surgery, and neoadjuvant chemotherapy, are currently under investigation. 1 1. PDQ Treatment Guidelines.
The recurrence rate after surgery appears to be higher for limited surgery than for lobectomy. The left-hand graph shows the locoregional recurrence rate (per patient per year) in 247 patients with stage IA (T1 N0) NSCLC, who were randomized to either lobectomy or limited (segment or wedge) resection. The recurrence rate was three times higher in the patients undergoing limited resection, and the death rate was increased by 30%. 1 Similarly, a retrospective non-randomized study in 173 patients with stage I NSCLC found that the percentage of patients experiencing a local or regional recurrence within 5 years was higher in patients undergoing anatomic segmentectomy than lobectomy. 2 1. Ginsberg RJ, Rubinstein LV. Ann Thorac Surg 1995; 60: 615-623. 2. Warren WH, Faber LP. J Thorac Cardiovasc Surg 1994; 107: 1087-1094.
Stage IIIA: 1 surgery alone in highly selected cases chemotherapy combined with radiotherapy, chemotherapy plus radiotherapy followed by surgery, or chemotherapy after surgery (encouraging results for patients with good performance status) surgery and postoperative radiation therapy (can improve local control, but there is controversy over whether it improves survival) radiation therapy (long-term survival benefit in 5-10% of patients; patients with high performance status are most likely to benefit). Stage IIIB: 1 radiation therapy alone (patients with advanced disease and high performance status are most likely to benefit) chemotherapy combined with radiation therapy (modest survival benefits compared with radiation therapy alone) chemotherapy and/or radiation therapy followed by surgery chemotherapy alone (for patients with malignant pleural effusion). 1. PDQ Treatment Guidelines.
Comparative studies have shown that addition of chemotherapy to surgery can improve survival. 1,2,3 Thirteen patients with stage IIIA NSCLC were randomized to receive etoposide-platinum chemotherapy before and after surgery, and 14 others were randomized to surgery followed by mediastinal irradiation. Interim analysis indicated a trend (p=0.095) towards improved survival in the chemotherapy group. 1 Median survival was significantly improved by addition of chemotherapy in 60 patients with resectable stage IIIA NSCLC, who were randomized to receive either surgery alone (n=32) or three cycles of cyclophosphamide, etoposide and cisplatin before surgery and a further three cycles afterwards (n=28). 2 Sixty patients with stage IIIA NSCLC were randomized to receive either immediate surgery or three courses of chemotherapy (mitomycin 6 mg/m 2 , ifosfamide 3 g/m 2 , mesna 1 g/m 2 and cisplatin 50 mg/m 2 , repeated at 3-week intervals) followed by surgery. Both groups also received 50 Gray of radiation, beginning 4 weeks after surgery. Neoadjuvant chemotherapy significantly prolonged overall and disease-free survival. 3 1. Pass HI, et al. Ann Thorac Surg 1992; 53: 992-998. 2. Roth JA, et al. J Natl Cancer Inst 1994; 86: 673-680. 3. Rosell R, et al. N Engl J Med 1994; 330: 153-158.
A meta-analysis used data from 11 randomized clinical trials which compared radiotherapy with radiotherapy plus cisplatin-based chemotherapy in patients with locally advanced NSCLC. 1 The graph shows the hazard ratio (relative risk of death) and confidence intervals for each of the 11 trials. The square represents the mean hazard ratio for each trial, and the outer and inner bars show the 95% and 99% confidence intervals. The size of the square represents the size of the trial. The center of the diamond represents the overall hazard ratio from all the trials combined, and its ends represent the 95% confidence interval. The majority of the trials reported a hazard ratio of <1 (to the left of the solid vertical line), indicating superior survival in the groups treated with radiotherapy plus chemotherapy. The overall hazard ratio was 0.87, indicating a 13% lower risk of death for the patients receiving combination treatment (p=0.005). Combined chemotherapy and radiotherapy is an appropriate treatment for patients with good performance status and weight loss of <5%. However, radiotherapy alone may be more appropriate for patients with stage III NSCLC with poor performance status or weight loss of 5% or more during the preceding 3-6 months. 2 1. Non-small Cell Lung Cancer Collaborative Group. Br Med J 1995; 311: 899-909. 2. Juretic A, et al. Ann Oncology 1999; 10 (suppl. 6): S93-S98.
Cisplatin-containing combination regimens produce higher response rates than single-agent chemotherapy. 1 However, current treatments produce only modest survival benefits compared with supportive care alone, and there is no standard regimen. 1 New chemotherapy agents are being evaluated in clinical trials. 1 External radiation therapy may be used for palliation of symptoms such as compression of the trachea, esophagus or bronchus; bone or brain metastases; local pain; vocal cord paralysis; hemoptysis; or superior vena cava syndrome. 1 Endobronchial laser therapy or brachytherapy may be useful in treating lesions obstructing the proximal airways. 1 1. PDQ Treatment Guidelines.
Surgery and postoperative radiotherapy for patients with a solitary brain metastasis and no evidence of other tumors. 1 Stereotactic radiosurgery may be useful in highly selected patients with good performance status and with metastases confined to the brain. 1 Palliative external beam radiotherapy. 1 Chemotherapy for symptom palliation in patients with good performance status. 1 Some chemotherapy regimens may prolong time to progression and survival. Docetaxel 100 mg/m 2 every 3 weeks significantly (p=0.044) prolonged time to progression compared with vinorelbine and ifosfamide (p<0.001) in 373 patients with recurrent NSCLC after platinum-based chemotherapy. 2 Taxotere 75 mg/m 2 significantly (p<0.05) prolonged survival compared with best supportive care in patients with NSCLC previously treated with platinum-based chemotherapy. 3 Endobronchial laser therapy or interstitial radiotherapy for endobronchial lesions. 1 1. PDQ Treatment Guidelines. 2. Fossella FV, et al. ASCO 1999, abs. 1776. 3. Shepherd E, et al. ECCO 1999, abs. 979.
Current treatment for NSCLC is not satisfactory, except possibly for the small subset of patients with surgically curable T1 N0 M0 stage I disease. 1 Prevention would reduce the overall burden of disease (most lung cancer is caused by environmental factors, which could be avoided). Earlier diagnosis could increase the percentage of patients treated at stage I, where the outcome of treatment is often good. Improved treatment of regional and advanced disease. Patients with NSCLC should be considered for clinical trials. 1 1. PDQ Treatment Guidelines .
Up to 90% of cases of lung cancer can be attributed to the use of tobacco, and lung cancer incidence and death rates in the US mirror patterns of cigarette smoking. 1 Lung cancer incidence and death could be significantly reduced by: deterring people from beginning smoking helping people to stop smoking protecting non-smokers from environmental tobacco smoke. 1 Possible strategies include reducing the availability of tobacco products to adolescents, education, increasing the cost of tobacco products, and use of tobacco tax revenue to fund mass media campaigns to reduce consumption. 1 Although still investigational, there is some preliminary evidence that the risk of tumor recurrence in patients who have had one stage I NSCLC tumor completely removed by surgery may be reduced by treatment with high-dose vitamin A (retinol palmitate 300,000 IU/day for 12 months) 2 or isotretinoin. 3 1. Wingo PA, et al. J Natl Cancer Inst 1999; 91: 675-690. 2. Pastorino U, et al. J Clin Oncol 1993; 11: 1216-1222. 3. Lippman SM, University of Texas-MD Anderson Cancer Center: MDA-ID-91025, clinical trial closed 04/09/1997.
Identification of risk factors could allow more intensive monitoring of high-risk patients, which may improve diagnosis. Risk factors include: obstructive lung disease increases the risk of lung cancer approximately four-fold 1 genetic factors. There was a 30% increased risk of cancer in non-smoking women whose parents or siblings had a history of respiratory tract cancer. 1 Sputum cytology screening can identify pre-malignant dysplasia in people with chronic obstructive lung disease and a history of cigarette smoking. 1 Molecular tumor markers such as ras and p 53 can be identified in bronchoalveloar lavage fluids. 1 In a study in Sweden, a routine chest X-ray every 2 years identified 28 cases of lung cancer, and the 4-year survival for these patients was 42% (compared with 10% for patients diagnosed with symptoms). 1 Low dose spiral CT scanning detected small peripheral lung cancers in 15 patients, 11 of whom were negative on chest X-ray. Enhanced CT (taking scans before and after injection of contrast medium) accurately differentiated between benign and malignant lesions in patients with peripheral lung nodules. 1 PET with radiolabeled fluoro-2-deoxyglucose detected all but 14 of 346 lung cancers, and the tumors missed were all smaller than 1 cm. 1 PET plus CT was significantly more accurate than CT alone in staging lymph node involvement in a study of 68 patients with potentially operable NSCLC, and has the potential to reduce the need for invasive surgical staging. 2 1. Edell ES. Curr Opin Pulmonary Med 1997; 3: 247-251. 2. Vansteenkiste JF, et al. J Clin Oncol 1998; 16: 2142-2149.
Novel biological targets. Advances in molecular and cellular biology have led to the identification of a growing number of molecules in the tumor and host that are potential targets for novel anticancer drug development. New chemotherapy agents, such as topoisomerase inhibitors, taxanes and novel antimetabolites, may offer improved efficacy and/or reduced toxicity. Immunotherapy offers a range of possibilities: immunomodulators (eg interferons, interleukins) to increase the activity of the immune system passive immunisation active immunisation. Gene therapy is still in its infancy. Possible targets include oncogenes known to be associated with lung cancer, such as K-ras , or genes for powerful immunomodulators such as interleukins.
Epidermal growth factor (EGF) is an important growth factor for cells of epidermal origin. In NSCLC it may directly stimulate tumor cell proliferation, promote cancer cell adhesion (which may be important in the development of metastases), and stimulate the development of new blood vessels in the tumor (angiogenesis). EGF acts by activating a tyrosine kinase on the intracellular side of its receptor. 1 Tumors are reliant on a good blood supply from the host in order to survive and proliferate. Antiangiogenesis agents aim to prevent the development of new blood vessels within the tumor, but are of limited use when the tumor already has an established blood supply. Antivascular agents aim to inhibit the vascular function of existing tumor blood vessels, leading to tumor necrosis as a result of metabolic deprivation. 2 Metalloproteinases degrade the extracellullar matrix, allowing tumor cells to invade adjacent tissues, metastasis, and develop new blood vessels. In NSCLC, metalloproteinase activity is correlated to the degree of tumor spread. Metalloproteinase inhibitors could be a new class of anticancer compounds. 3 1. Kris M, et al. Clin Cancer Res 1999; 5: S. 2. Chaplin DJ, et al. Anticancer Res 1999; 19: 189-196. 3. Ferrante K, et al. Cancer Chemother Pharmacol 1999; 43 (suppl.): S61-S68.
Both these potential new therapies are still in their infancy. Immunotherapy works on the principle of stimulating the patient 抯 immune system to attack and destroy the tumor cells. There are three possible approaches: treatment with immunomodulators (eg interleukins, interferons), to stimulate proliferation and activation of host immune cells passive immunisation, in which ready-made antibodies raised against tumor antigens are injected into the patient. Treatment would need to be repeated at regular intervals as antibodies have a relatively short lifespan active immunisation, in which tumor antigens are injected in combination with an adjuvant (either a traditional vaccine adjuvant such as BCG, or antigen-presenting cells grown in tissue culture). This operates on the same principle as vaccination against infection, by stimulating the host to mount an immune response against the antigen. Gene therapy is at an even earlier stage of research. Two broad approaches are being explored: activation of the genes which control production of immunomodulators (eg interferons, interleukins). This should have a similar effect to external administration of such compounds modulation of the expression of known oncogenes such as K-ras .
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