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A. Epidemiology [1]

  1. Leading cause of cancer death in men and women
  2. In 2004, ~174,000 new cases and ~165,000 deaths expected
  3. Incidence is >70 per 100,000 men in USA
  4. Overall 5-year survival is 14% with little improvement over 2 decades
  5. Over 75% of deaths from lung cancer (lung Ca) are attributable to smoking tobacco
  6. Cases and death rates declining from 1973 to 1996
  7. Types of LC
    1. Divided into Small Cell (SCLC) and Non-Small Cell (NSCLC) Lung Ca
    2. SCLC is neuroendocrine derived, highly metastatic, "responsive" to chemotherapy
    3. NSCLC comprises several histologies, "responsive" to surgery, less to chemotherapy
  8. Paraneoplastic syndromes are commonly associated with lung Ca
  9. Frequently associated with systemic symptoms including anorexia, weight loss, fatigue
  10. Increase in smoking rates in adolescents may lead to increasing cases in future

B. Types and Characteristics

  1. Small Cell Lung Ca (SCLC) [4]
    1. Neuroendocrine origin
    2. Comprises ~20% of lung cancers
    3. Strongly associated with smoking tobacco
    4. Essentially all SCLC are metastatic at diagnosis with short doubling times
    5. Most patients present with symptoms and have a hilar mass on imaging
    6. Associated with paraneoplastic syndromes
    7. Paraneoplastic syndromes include Cushing's Syndrome and SIADH
    8. Chemotherapy response is best of all lung cancers (70% overall, 30% complete response)
    9. Responses (including complete) are not generally durable and disease becomes refractory
  2. Non-Small Cell Lung Ca (NSCLC)
    1. NSCLC type comprises ~80% of all lung Ca
    2. Four main histologic types: distinct biological characteristics and proteomic patterns [13]
    3. Squamous Cell Carcinoma (~25% in North America)
    4. Adenocarcinoma (most common type in North America, ~40% overall)
    5. Large Cell Carcinoma (most undifferentiated type, ~10% overall)
    6. Bronchoalveolar Carcinoma (~4% overall) - often considered a subtype of adenocarcinoma
    7. Some 4-50% of NSCLC patients present with Stage IV (metastatic) disease
    8. Pancoast Tumor is a term for uipper lobe NSCLC: invasion of pleura, vertebral bodies, and nerves, often leading to Horner Syndrome
    9. Overall, ~20% of NSCLC are cured with surgery
  3. Squamous Cell Ca
    1. Most commonly (>90%) associated with smoking tobacco
    2. Lesions most often centrally (67%) located of all lung cancers
    3. Often associated with hypercalcemia (secretion of PTH-related peptide)
    4. Lesions may be solitary when discovered
    5. Expression of bcl-2 gene may be good prognostic marker (unclear mechanism)
  4. Adenocarcinoma
    1. Comprise ~40% of all lung cancers in North America (most common NSCLC type)
    2. Lesions most often peripherally (67%) located
    3. Associated with smoking less frequently than other lung cancers
    4. Incidence is increasing
    5. Often metastatic at discovery
    6. Muations in K-ras oncogenes are common
    7. Papillary adenocarcinoma may be associated with asbestosis and mesothelioma [2]
    8. Bronchioloalveolar adenocarcinoma is a distinct well-differentiated variant, least related to smoking, increased inflammatory component
  5. Large Cell Ca
    1. NSCLC type, most undifferentiated type of all lung cancers
    2. Comprises ~15% of all lung cancers
    3. Generally most aggressive
    4. Pathogenesis may be "de-differentiation" (precursor) of SCLC
    5. Clinical behavior more similar to other NSCLC types, however
  6. Non-SCLC Neuroendocrine Lung Tumors [46]
    1. Large cell neuroendocrine tumors were not distinguishable by gene profiling from SCLC
    2. These tumor types are distinct from lung carcinoids by gene profiling
    3. SCLC can be divided into two groups based on gene profiling
    4. Histologically large cell neuroendocrine tumors fall into both of these groups
    5. One of the SCLC subtypes had excellent (>80%) 5 year survival versus 15% for other
    6. Gene expression profiling can be used to predict clinical outcomes
  7. Mesothelioma (see below)

C. Risk Factors

  1. Polluted Air
    1. Primary tobacco smoke ("Smoking")
    2. Secondary tobacco smoke
    3. Asbestos (aerosolized)
    4. Fine particulate air pollution (heavy industrial pollution) [36]
  2. Smoking
    1. ~10-15X increased risk of lung cancer development compared with average controls
    2. Causes >80% of all lung cancers
    3. Most strongly associated with small cell and squamous cell types
    4. Lung cancer risk is highly dependent on amount and duration of smoking
    5. Second hand smoke is clearly a risk factor for development of lung cancer
    6. ß-carotene, a vitamin A derivative with antioxidant activity, increases risk of lung cancer in smokers; risk is normalized on cessation of ß-carotene [43]
    7. In patients who smoked >15 cigarettes per day, quitting reduces the risk of lung cancer by >50% [11]
    8. The lung cancer risk in "never smokers" is about 9% of that for heavy smokers [11]
  3. Asbestos Exposure
    1. 4-5X increased risk of parenchymal lung cancer compared with unexposed controls
    2. Pleural plaques are not an independent risk factor
    3. Smoking combined with asbestos exposure carries ~50X increased risk of cancer
    4. Greatly increased risk for mesothelioma [2] and bronchogenic carcinomas
  4. Radon
    1. Risk is ~1.3-1.8X in exposed compared with unexposed controls
    2. Major source of exposure to ionizing radiation in most countries
  5. Occupational Lung Ca [25]
    1. Asbestos (see above)
    2. Arsenic Compounds - overall risk ~3.4X with high exposure; synergistic with smoking [9]
    3. Bis(chloromethyl)ether and chloromethyl methyl ether
    4. Cadmium elemental and compounds
    5. Chromium and certain (hexavalent) chromium compounds
    6. Crystalline silica (silicosis associated)
    7. Mustard Gas (alkylating agent)
    8. Nickel
    9. Ionizing radiation (and radon as above)
    10. Polycyclic aromatic hydrocarbons (soots, tars, mineral oils)
  6. Genetic Component [10]
    1. Some familial cases but primarily in smokers
    2. First degree relative 2.3X risk, second degree ~1.4X risk
    3. Increased risk mainly for early onset (age <50 years) disease
    4. Increased risk in relatives of early onset patients higher in blacks than in whites [12]

D. Screening and Diagnosis

  1. Screening for Lung Ca [19,29,49]
    1. Most lung cancers have spread to mediastinum or to distant sites at time of detection with convential chest radiography (X-ray)
    2. Early detection (pre-metastasis) is critical to long term survival [3]
    3. Spiral (low-dose) computerized tomography (CT) scans in smokers and others at high risk may detect earlier, curable lung Ca [19]
    4. Unclear if standard CT scanning reduces overal mortality from lung Ca [34]
    5. NeoTect® Tc99-somatostatin can be used to image lung Ca
    6. Overall evidence is insufficient to recommend for or against screening asymptomatic persons for lung Ca with chest X-ray or sputum cytology [49,50]
    7. Screening persons with at least a 20-pack year smoking history with spiral CT is likely to be beneficial and should be considered [18,19]
  2. Spiral (Low-Dose) CT
    1. Early screening of high risk persons with spiral CT
    2. Tumors as small as 1-2mm in diameter may metastasize [29]
    3. Spiral CTcan now obtain 0.625mm slices in seconds
    4. Spiral CT scans may detect tumors as small as 3mm diameter [24]
    5. These small tumors have usually not metastasized and may be curable surgically
    6. Strongly consider spiral CT scans in patients at high risk for lung Ca [18,19]
    7. Positron emission tomography (PET) with fluorodeoxyglucose (FDG) has high sensitivity and specificity for detection of malignant pulmonary lesions at least 1cm [30]
    8. Spiral CT combined with PET had excellent detection rates for stage I lung Ca (all were NSCLC) and led to surgical resection [44]
    9. Lesions <5mm on initial CT/PET can be evaluated in 12 months without high risk [44]
    10. Sputum cytology usually detects large tumors, late stage disease, is insensitive
    11. Unclear if standard CT scanning reduces overal mortality from lung Ca [34]
  3. PET Scan [30,37]
    1. Optimal sensitivity and specificity of PET±FDG ~91% for detecting malignant lesions
    2. In current practice, sensitivity ~97% and specificity for malignant lesions ~78%
    3. PET is more accurate than CT for mediastinal staging in NSCLC [23]
    4. Detection of lesions 1-3cm versus >3cm was similar
    5. PET+FDG may be suitable for noninvasively ruling out malignant pulmonary lesions
    6. PET+FDG probably eliminates ~20% of unnecessary diagnostic surgeries
    7. Combination with low dose spiral CT considered for screening in high risk patients [44]
  4. Screening Chest Radiographs [29]
    1. Evaluated as screen for LC in patients (smokers) at high risk the disease
    2. Do not appear to improve overall outcomes in smokers
  5. Abnormal Chest Radiography should be followed up with
    1. Computerized tomographic (CT) scan
    2. Bronchoscopy with biopsy OR
    3. Thoracoscopic biopsy
    4. Open thoracotomy with biopsy (unusual as a diagnostic method)
  6. Sputum Cytology has also not shown utility as a screening test for LC
    1. May be useful for endobronchial tumors such as small cell and squamous cell types
    2. Very poor yeilds for adenocarcinomas
  7. Biomarkers in Lung Cancer [24]
    1. Detection of rare cancer cells in sputum using biomarkers is under investigation
    2. K-ras mutations and/or genomic instability of homogenated sputum DNA
    3. HnRNP A2/B1 protein in sptum cells may also be useful in early detection
  8. Tissue Biopsy [68]
    1. Mediastinoscopy is standard for staging and pathological confirmation
    2. Minimal endoscopic staging with needle aspiration is used
    3. Traditional transbronchial needle aspiration (TBNA)
    4. Endobronchial ultrasound-guided FNA (EBUS-FNA)
    5. Transesophageal endoscopic US-FNA (TEUS-FNA)
    6. EBUS-FNA more sensitive than TBNA (70% versus 36%) for malignant node detection
    7. Combination of TEUS-FNA and EBUS-FNA had 93% sensitivity and 97% negative predictive; superior to other methods
    8. Combined TEUS-FNA and EBUS-FNA may allow near-complete minimally invasive mediastinal staging in patients with suspect Lung Ca

E. Metastatic Sites and Staging [1]

  1. Lymphangitic (lymph nodes, LN) and Hematogenous Spread
  2. Often bone, liver, central nervous system (CNS) invasion
  3. Tumor (T) Levels
    1. TIS: Carcinoma in Situ
    2. T1: Tumor <3cm greatest dimension, no evidence of invasion proximal to lobar bronchus
    3. T2: Tumor >3cm, or involvement of main bronchus, or visceral pleural invasion
    4. T3: Tumor invading any lung component, parietal pericardium, involvement of entire lung
    5. T4: Tumor invading mediastinum, heart, great vessels, other non-pulmonary structures
  4. Lymph Node Involvement (N)
    1. N0: no demonstrable metastasis to regional lymph node
    2. N1: metastasis to LN in peribronchial or ipsilateral hilar region, or both
    3. N2: metastasis to ipsilateral mediastinal LN and subcarinal LN
    4. N3: contralateral mediastinal or hilar LN, or to any scalene or supraclavicular LN
  5. Metastases (M): present is M1, absent is M0
  6. Staging (AJCC/UICC)
    1. Stage 0: Occult tumor (malignant cells in sputum / bronchial washings), in situ tumor
    2. Stage IA: T1 and no LN (N0) or distant metastases (M0)
    3. Stage IB : T2 N0 M0
    4. Stage IIA: T1 N1 M0
    5. Stage IIB: T2 N1 M0 or T3 N0 M0
    6. Stage IIIA: T3 N1 M0 or T1-3 N2 M0
    7. Stage IIIB: T4 N0-3 M0 OR T1-4 N3 M0
    8. Stage IV: Any T, any N, with distant metastases (M1)
  7. Bony Metastases
    1. Present most often with bone pain
    2. Increase in heat-labile Alkaline Phosphatase
    3. Always image patients with a bone scan (99mTc-MDP) in lung cancer
  8. Accurate Staging
    1. Routine staging with bone scan, head computerized tomography (CT), chest and liver CT
    2. Accuracy of CT for LN detection is ~60% based on subsequent surgical exploration
    3. PET is more accurate that CT scan for lung mass and for LN evaluations
    4. Combination of PET and CT is more accurate than either test alone for staging [41]
    5. PET scanning is now part of routine evaluation for most patients [5]
    6. Endoscopic ultrasonography ± fine needle apiration is accurate in ~80% of cases
    7. Gold standard for LN evaluation is mediastinoscopy at time of biopsy or subsequently
  9. Immopathology [5]
    1. Keratin (broad spectrum): all carcinomas
    2. Keratin 7: lung cancer
    3. Keratin 20: gastrointestinal cancer
    4. Carcinoembryonic antigen (CEA): adenocarcinoma
    5. Thyroid transcription factor 1: lung and thyroid cancers
    6. Calretinin and WT-1: mesothelioma
    7. CA 19-9: pancreatic cancer
    8. Neuroendocrine markers: neuron-specific enolase, synaptophysin, chromogranin (SCLC)
    9. ERCC1 expression appears to correlate with improved prognosis in resectable NSCLC [64]
  10. Gene-Expression Prognostic Score [20]
    1. 5-gene signature (DUSP6, MMD, STAT1, ERBB3, LCK) can be used to predict outcome
    2. High risk 5-gene signature associated with 20 month versus low-risk 40 month survival
    3. Gene signature may be useful for prognosis in Stage I and II (and IIIA) disease
  11. Gene Methylation and Stage I NSCLC [69]
    1. Gene promoter methylation patterns for four genes were associated with early recurrence following surgical resection of Stage I NSCLC
    2. These genes are p16-INK4a (CDKN2A), H-cadherin gene CDH13, RASSF1A, APC
    3. These are independent recurrence risk factors
    4. Methylation of p16 and CDH13 associted with >25X increased risk of recurrence

F. Treatment Overview [8]

  1. Treatment is by stage and tumor histology
  2. Major treatment differences and responses are observed for SCLC versus NSCLC
  3. Classical Treatment Modalities
    1. Surgery
    2. Radiation - conventional and accelerated
    3. Prophylactic radiotherapy (thoracic and cranial) for SCLC
    4. Chemotherapy (see below)
    5. Combinations of these modalities is most effective for lung cancer
    6. Interventional pulmonary procedures for central airway obstruction [31]
    7. Supplemental oxygen is often needed [33]
  4. Contraindications for Surgery
    1. Small Cell Histology
    2. Metastatic Disease - Stages IIIB and IV (unless mass effect is a problem)
    3. Superior vena cava syndrome (see below)
    4. Vocal Paralysis
    5. Malignant Pleural Effusion
    6. High likelihood that post-operative lung function has FEV1 < 1 Liter
  5. Stage I NSCLC
    1. Five year survival 40-67% with surgery alone
    2. Survival better for Stage IA (~75%) than for Stage IB (~40%)
    3. Stage IA prognosis appears best predicted with gene-expression profiling [16]
    4. Primary radiotherapy for patients who refuse or are unfit for surgery
    5. Radiotherapy has 5 year survival in 25% range
    6. Post-operative radiation therapy is detrimental for Stage I/II NSCLC
    7. Pancoast Tumor curable with surgery + irradiation only
    8. Cisplatin-vinorelbine adjuvant therpay after complete resection is beneficial [28,58]
    9. Cisplatin adjuvant therapy for completely resected stages I-III lung cancer is beneficial with tumors that do not express ERCC1 (DNA excision repair enzyme) [64]
    10. Uracil-tegafur (UFT) adjuvant therapy daily po for 1-2 years is beneficial in Stage I adenocarcinoma, particularly for tumors >2cm at surgical resection [46]
  6. Stage II NSCLC
    1. Usually treated with surgery with five year survival 25-55%
    2. Cisplatin-based adjuvant therpay after complete resection is likely beneficial [28]
    3. Cisplatin-vinorelbine improved disease-specific and overall survival versus placebo following complete resection of Stage Ib/II NSCLC [58]
    4. Completely resected Stages I-III NSCLC which lack ERCC1 expression benefit from cisplatin adjuvant therapy [64]
    5. Post-surgical radiation therapy appears detrimental in Stage I/II NSCLC [15]
  7. Stage III NSCLC [5]
    1. Locally or regionally advanced disease usually treated with surgery + chemoradiotherapy
    2. Stage IIIA is marginally resectable in most cases
    3. For treatment of locally advanced unresectable NSCLC therapy, chemotherapy + radiation is more effective than radiation alone [56]
    4. For treatment of locally advanced completely resected IIIa NSCLC, adjuvant chemotherapy based on cisplatin improved disease free and overall survival [28]
    5. Continuous hyperfractionated accelerated radiotherapy may be prefered in NSCLC
    6. Chemotherapy is clearly beneficial
    7. Cisplatin + etoposide are often used (see below)
    8. Neoadjuvant chemoradiotherapy or post-operative chemoradiotherapy usually used [5]
    9. Minimal or no overall survival improvement with neo-adjuvant chemotherapy in any-stage operable NSCLC [66]
  8. Stage IV NSCLC
    1. Systemic 2-drug chemotherapy (3 cycles) - generally beneficial though cures <2%
    2. Chemotherapy as beneficial in persons >70 years as <70 years
    3. Second line therapy with docetaxel
    4. Palliative radiation ± surgery
    5. Whole brain radiation with stereotactic radiosurgery boost for patients with 1-3 brain metastases (mainly with NSCLC adenocarcinoma) improved performance, mortality [53]
  9. SCLC [4]
    1. Chemotherapy is mainstay (see below)
    2. Radiation in palliative or adjuvant setting is often added with clear benefit
    3. Limited disease should be treated with chemotherapy + concurrent chest irradiation
    4. Extensive disease should be treated with combination chemotherapy
    5. Prophylactic cranial irradiation reduces brain recurrence from ~70%, improves mortality in extensive SCLC [32]
    6. All patients with complete remission should be considered prophylactic cranial irradiation
    7. Surgery reserved for paliation of very large masses
  10. Malignant Pleural Effusion
    1. Treatable with chest tube (or thorascopic) pleuradesis
    2. Pleuradesis carried out with talc, tetracycline, or bleomycin
  11. Newer Therapy
    1. Dose intensification chemotherapy with autologous stem cell support
    2. Lymphokine infusions are under study
    3. Prophylactic cranial irradiation for SCLC in initial complete remission
    4. Photodynamic Therapy - squamous cell type treatment with hematoporphyrin agent

G. Radiotherapy [8]

  1. Usually delivered by external beam from linear accelerator
  2. Standard dose for unresectable disease is 60 Gy divided over 30 sessions in 6 weeks
  3. Three dimensional computerized tomogram (CT) to focus therapy, reduce side effects
  4. Recommended for Stages II-IIIA disease
  5. Typical Side Effects
    1. Pneumonitis
    2. Esophagitis
    3. Skin desquamation
    4. Myelopathies
    5. Cardiac abnormalities
  6. Concurrent chemotherapy can increase radiation effectiveness, also potentiates esophagitis
  7. Concurrent chemoradiotherapy improves survival in nonresectable tumors

H. Chemotherapy [8,27]

  1. Most effective in prolonging survival in SCLC compared with NSCLC
    1. Platinum agents are most effective: cisplatin, carboplatin
    2. Topoisomerase inhibitors, microtubule inhibitors are next most potent
    3. Alkylating agents, anthracyclines, gemcitabine have activity as well
    4. Epidermal growth factor (EGF) blockade has shown moderate to good efficacy [45]
    5. Neoadjuvant radiotherapy (given before surgery) has very modest improvement in overall survival in operable NSCLC [66]
  2. SCLC [4,14]
    1. Etoposide and platinum combination is standard for limited and extensive disease
    2. Four to 6 cycles are given
    3. Median survival 10-12 months with etoposide-cisplatin in extensive disease
    4. Cisplatin-irinotecan had 12.8 month median survival versus 9.4 months with cisplatin- etoposide [14]
    5. Addition of chest radiation for limited disease provides 25% survival at 4 years
    6. Cisplatin-irinotecan had 19.5% survival at 2 years [14]
    7. Good results obtained with radiotherapy in limited small cell disease
    8. Early prophylactic cranial radiotherapy after complete remission is beneficial
    9. Cyclophosphamide, Doxorubicin, Vincristine: Median Survival 8 months
    10. Cyclophosphamide, Doxorubicin, Etoposide: Median Survival 12 months
    11. G-CSF rescue for myelosuppression
    12. Oral Etoposide is not as effective as standard intravenous chemotherapy
    13. Etoposide + cisplatin + radiotherapy in limited small cell disease is effective
    14. Topotecan, paclitaxel, docetaxel are also active
    15. In patients with recurrence, use different chemotherapy regimen
  3. Stage IIIA NSCLC [1]
    1. Radiotherapy alone: Median Survival 11 months (mo)
    2. Radiotherapy + Vinblastine and Cisplatin: Median Survival 14 months
    3. Radiotherapy + Daily Cisplatin: Median Survival 14 months
    4. Pre-operative chemotherapy (3 agent) appears to significantly improve survival
    5. Cisplatin + vinblastine should precede radiotherapy (56% versus 43% response)
    6. Addition of tubulin inhibitor vinorelbine (Navelbine®) prolongs survival [56]
  4. Stage IIIB and IV NSCLC [1,27]
    1. Chemotherapy with platinum combinations is standard first line
    2. Carboplatin is increasingly used instead of cisplatin
    3. Cisplatin or carboplatin with gemcitabine or a taxane [26] are usually used
    4. Platinum + taxanes or gemcibaine provides ~30% (mainly partial) responses first line
    5. Platinum combined with paclitaxel is more effective than with etoposide [26]
    6. Both cisplatin+docetaxel and gemcitabine+docetaxel have 32% first line response
    7. Platinum + taxane (docetaxel or paclitaxel) or cisplatin+gemcitabine all had ~20% response rate and ~8 month median survival [35]
    8. Cisplatin + vindesine is usually used in Europe
    9. Addition of a 3rd chemotherpy to platinum+2nd drug does not improve outcomes and increases toxicity [54]
    10. Bevacizumab (monoclonal anti-VEGF Ab, Avastin®) added to paclitaxel-carboplatin improves overall survival by 2 months in non-squamous cell NSCLC [22]
    11. Adding bevacizumab to standard chemotherapy increases risk of serious hemorrhage [22]
    12. Second line therapy usually includes docetaxel or gemcitabine
    13. Pemetrexed provides imilar outcomes as docetaxel in Stage III or IV NSCLC [63]
    14. Vinorelbine also has activity and is often used second or third line
    15. Standard multimodality therapy, median survival for patients with Stage IV disease is now ~8-10 months; adding bevacizumab increases to ~12 months [22]
  5. EGF Receptor 1 (EGF-R1, HER-1) Blockade [38,42,45]
    1. EGF appears to be a growth factor for many NSCLC
    2. Overexpression and/or mutation of EGF-R1 is observed in a subset of NSCLC patients
    3. Erlotinib and gefitinib are specific small molecule oral inhibitors of EGF-R1 [70]
    4. Gefitinib (Iressa®) has shown response rates in 2nd-3rd line NSCLC 10-15%
    5. Improves quality of life and symptoms in 3rd line NSCLC [45]
    6. Activating (kinase-domain) mutations in EGF-R1 in primary tumors correlate with response to gefitinib [51]
    7. Resistance to gefitinib due to mutations in EGF-R1 protein demonstrated [57]
    8. Gefitinit not improve survival or quality of life when used in first line NSCLC in combination with standard (platinum/taxane) chemotherapy [42]
    9. No improvement in survival when combined with best supportive care in 2nd or 3rd line NSCLC versus best supportive care alone [17]
    10. Some benefit of gefitinib in Asian patients and never-smokers with advanced NSCLC [17]
  6. Erlotinib (Tarceva®) [52,59,67,70]
    1. Potent anti-EGF-R1 inhibitor, FDA approved for NSCLC and pancreatic cancer
    2. Pivotal study in Stage IIIB/IV NSCLC performance status 0-3, after 1-2 prior regimens
    3. Erlotinib increased survival by 2 months following first relapse from 4.7 to 6.7 months
    4. Median response duration 7.9 months and improved symptoms (cough, pain, dyspnea)
    5. Highest responses in women, Asians, never-smokers, adenocarcinoma pathology
    6. Appears to be more active than gefitinib, and should be used in earlier stage disease
    7. Presence of mutations in EGF-R increases likelihood of response to, but not survival with, erlotinib [60]
    8. Neither erlotinib nor gefitinib showed activity in combination with chemotherapy
    9. Main side effects are acne-like rash and some diarrhea, mainly at higher doses
    10. Increased risk of severe acute interstitial pneumonia [39]
  7. Mesothelioma Treatment [47]
    1. First line FDA approved is pemetrexed + cisplatin
    2. Pemetrexed is an antimetabolite inhibits several enzymes involved in folate metabolism:
    3. Dihydrofolate reductase
    4. Thymidylate synthase
    5. Glycinamide ribonucleotide formyltransferase
    6. Median survival is cisplatin/pemetrexed 12.1 months versus 9.3 months cisplatin alone
    7. Pemetrexed dose is 500mg/m2 IV over 10 minutes q3 weeks
    8. Do not use pemetrexed in patients with creatinine clearance <45mL/min

I. Prognosis

  1. Histologic type of tumor and Staging are most important factors
    1. Proteomic and transcriptional genomic patterns are being evaluated for prognosis [13]
    2. 5-gene signature in NSCLC can be used to predict clinical outcomes (see above) [20]
  2. SCLC
    1. Pre-chemotherapy: ~2% 5 year survival; overall median survival 3 months
    2. Combination Therapy: ~1-10% survival, depends on disease extent; median 6-12 months
    3. Combination therapy for limited SCLC has 44% 2 year and 23% 5 year survival
    4. For SCLC after complete remission, prophylactic radiotherapy increases survival to 20% at 3 years (versus 15% at three years without it)
  3. NSCLC Overall Survival by Stage [1,8]
    1. Stage IA: ~95% 1 year, ~70% 5 year
    2. Stage IB: ~85% 1 year, ~60% 5 year
    3. Stage IIA: ~90% 1 year, ~55% 5 year
    4. Stage IIB: ~75% 1 year, ~35% 5 year
    5. Stage IIIA: ~65% 1 year, 25% 5year
    6. Stage IIIB: ~35% 1 year, ~5% 5 year
    7. Stage IV: ~20% 1 year, <2% 5 year
  4. Gene Expression
    1. L-Myc also expressed by some of these cancers
    2. Patients with diploid NSCLC tumors survive longer than those with aneuploid tumors
    3. Her2/neu (p185) is associated with many of these cancers, as well as breast Ca
    4. Her2/neu overexpression in breast Ca associated with poorer prognosis; unclear for lung
    5. High RRM1 (regulatory subunit ribonucleotide reductase) and ERCC1 (excision repair) levels in early stage NSCLC correlated with increased (120 versus ~60 month) survival [21]

J. Superior Vena Cava (SVC) Syndrome [65]

  1. Occurs in ~15,000 patients per year in USA
  2. Syndrome occurs due to obstruction of SVC
  3. Symptoms and Signs
    1. Increased venous pressure in upper body
    2. Edema of head (~80%), neck, arms (~45%)
    3. Often with cyanosis, plethora, distended subcutaneous vessels (50-65%)
    4. Dyspnea is present in ~55% of cases
    5. Laryngeal edema (~20%) may manifest as cough, hoarseness, dyspnea, stridor
    6. Dysphagia can occur due to pharyngeal edema
    7. Cerebral edema may lead to headache, confusion, coma (may be fatal)
    8. Decreased venous return may result in hemodynamic compromise, including syncope ~10%
  4. Symptoms develop over ~2 weeks in ~35% of the patients
  5. Pathophysiology
    1. Generally gradual obstruction of the SVC
    2. Increase in cervical enous pressure from normal of 2-8 mmHg to 20-40 mmHg
    3. Leads to engorgement of azygos ven and inferior vena cava
    4. Collateral vessels dilate and grow usually requiring several weeks
  6. Causes
    1. Malignancy in ~65% of cases
    2. Of malignant causes, non-small cell (50%) and small cell (25%) lung cancers most common
    3. Lymphoma and metastatic lesions each ~10% of malignant causes
    4. Nonmalignant conditions in ~35% of cases - thrombosis most commonly, aortic aneurysm
  7. Imgaging with CT with contrast of chest is usually first step
  8. Treatment of Malignancy Associated SVC Syndrome
    1. Glucocorticoids followed by radiation
    2. Systemic chemotherapy and/or surgery
    3. Stents are also used

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