Non-small Cell Lung Cancer

Epidemiology

  • 170,000 cases a year.
  • Peak incidence at 50-70 years.
  • While overall incidence has risen in the last 30 years, SCCA has decreased relative to adenocarcinoma.
  • Adenocarcinoma is now the dominant type.

Risk Factors

  • 80% of mortality in men and 75% in women from lung cancer is due to smoking tobacco. Smoking increases the risk to about 10-20%.
  • Passive smoke exposure causes 25% of lung cancer in non-smokers.
  • The increase in risk with asbestos is 1.5 to 13.1.
  • Radon exposure is a risk factor due to inhaled ionizing alpha producers.
  • Li-Fraumeni syndrome (p53) who smoke have x 3 risk in lung cancer compared to other smokers.

Physiology

lung1.JPG

TLC, total lung capacity; VT, //tidal volume; //IC, inspiratory capacity; FRC, functional residual capacity; ERV, expiratory reserve volume; VC, vital capacity; RV, residual volume

VC = TV + RV (inspiratory or expiratory)

Tumor Markers

  • CEA is a glycoprotein of molecular weight of \~180 kD. It produced during embryonal and fetal development.
  • CEA has high sensitivity for adenocarcinomas (primarily colon, but also breast, stomach and lung cancer).
  • Smokers have higher CEA than non-smokers. The normal range is <2.5 ng/ml in an adult non-smoker and <5.0 ng/ml in a smoker.
  • COX-2 is overexpressed in NSCLC but not in small-cell lung cancer (SCLC) and that the overexpression of COX-2 in NSCLC may be associated with a poorer prognosis.

WORK-UP

General

  • H/P
  • Labs: CBC, LFT, alkaline phosphatase (liver or bone)
  • Pulmonary Function Tests
  • Sputum Cytology: 80% can be diagnosed with 3 samples in central lesions but 20% if peripheral.
  • Imaging Studies: CXR, CT scans of chest/upper abdomen, bone scan.
  • FNA of a lesion can be done if it is not accessible by bronchoscopy with a positive yield of 95%.
lung3.jpg

Bronchoscopy

  • The scope can reach up to the 2nd or 3rd sub-segmental division and can obtain both cytology and histologic specimen (using brushes, needles, or forceps) from lesions, especially if they are 2.0cm or greater. Can also determine if evidence of mediastinal nodes.

Mediastinoscopy

  • The procedure is safe and effective in experienced hands. In two large trials the mortality rate was 0% and the major morbidity rate was less than 1%.
  • For prevascular and AP window nodes, the anterior mediastinotomy (ie. Chamberlain procedure) can be done because they may not be sampled in a regular mediastinoscopy.
  • Clinically (CT) negative T1/T2 tumors
  • 7% up staging to N2 or N3 on mediastinoscopy
  • \[Choi YS, Shim YM, Kim J, Kim K. Mediastinoscopy in patients with clinical stage I non-small cell lung cancer. Ann Thorac Surg 2003;75:364.\]
  • Post-mediastinosocpy the risk of up staging on thoracotomy are

** N0 74.2%
** N1 16.2%
** N2 9.2%
** \[Choi YS, Shim YM, Kim J, Kim K. Mediastinoscopy in patients with clinical stage I non-small cell lung cancer. Ann Thorac Surg 2003;75:364.\]

  • PET imaging for mediastinum
  • FDG-PET superior to CT or bone scans for identification of occult metastatic disease at presentation and for assessing response to radiation or chemoradiation
  • PET cannot be used to determine definitively the cause of a mass lesion or associated lymphadenopathy; tissue diagnosis remains the standard of care.
PET\[1\] PET\[2\] CT
Sensitivity 67% 64% 50%
Specificity 79% 77% 71%
Accuracy 78% 74% 68%
PPV na 45% na
NPV 87\[3\] 88% na
  • [1] Luketich JD, Friedman DM, Meltzer CC, et al. The role of positron emission tomography in evaluating mediastinal lymph node metastases in non-small-cell lung cancer. Clin Lung Cancer 2001;2:229.
  • [2] Gonzalez-Stawinski GV, Lemaire A, Merchant F, et al. A comparative analysis of positron emission tomography and mediastinoscopy in staging non-small cell lung cancer. J Thorac Cardiovasc Surg 2003;126:1900
  • [3] Reed CE, Harpole DH, Posther KE, et al. Results of the American College of Surgeons Oncology Group Z0050 trial: the utility of positron emission tomography in staging potentially operable non-small cell lung cancer. J Thorac Cardiovasc Surg 2003;126:1943

NSCLCA Staging:

  • T1 3cm or less and not involving the main bronchus at all
  • T2 > 3cm, or invades the main bronchus but is 2cm or more from

the carina, or invades visceral pleura or atelectasis/obstructive pneumonitis to not the entire lung

  • T3 any size invading CW (including superior sulcus tumors), diaphragm,

mediastinal pleura, parietal pericardium, or invades the main bronchus
2cm or less from the carina, or atelectasis/obstructive pneumonitis of the
entire lung

  • T4 any size tumor invading mediastinum, heart, great vessels, trachea, esophagus, vertebral body, and carina or separate nodules in the same lobe, malignant exudative pleural effusion
  • N1 peribronchial and/or ipsilateral hilar and/or intrapulmonary nodes
  • N2 ipsilateral mediastinal an/or subcarinal nodes
  • N3 contralateral mediastinal/hilar, scalene or supraclavicular nodes
  • M1 DM including separate nodules in different lobes
  • Stage IA T1N0
  • Stage IB T2N0
  • Stage IIA T1N1
  • Stage IIB T2N1, T3N0
  • Stage IIIA T3N1, T1/2/3N2
  • Stage IIIB any TN3, T4 any N
  • Stage IV M1

Prognostic factors:

  • Early NSCLCA (I/II):
  • stage,
  • size of disease,
  • nodal involvement.
  • Advanced NSCLCA (III/IV):
  • stage,
  • performance status,
  • weight loss (Stanley 1980),
  • sex (women do better),
  • elevated lactate dehydrogenase,
  • ploidy, enolase
  • and presence of K-ras is bad

SURIVAL CURVES BY STAGE
NSCLCA (5 year survival)

  • Stage I 50%
  • Stage II 30%
  • Stage IIIA 10-15%
  • Stage IIIB <5%
  • Stage IV <2%

CLINICAL STAGING PATHOLOGICAL STAGING

TREATMENT
ELECTIVE NODAL RADIATION

  • Traditional Teaching
  • Elective nodal irradiation of the mediastinum is unnecessary for T1 and T2 tumors
  • For more advanced tumors standard radiation therapy typically involves a dose of 40 Gy to the entire mediastinum, supraclavicular fossa, and ipsilateral hilum, even if there is no evidence of disease in these areas. (ASTRO review 2004)
  • Counter Point: IJROBP 97 - Pu (abstr)
  • Addition of mediastinum and hilum increasing the volume of lung treated and thus the normal tissue complication probability.
lung2.jpg
  • REVIEW of RTOG Data by Emami
  • Elective nodal RT had no effect on progression in the mediastinum, contralateral hilum or supraclavicular nodes
  • However, it did impact progression of disease in the ipsilateral hilum.
  • Nodal coverage had no impact on overall survival, likely due to the high number of local and distant failures.
  • It is uncertain whether chemotherapy will eradicate microscopic nodal disease
  • Rosell and Roth showed in small trials OS advantage to induction chemo for stage IIIA patients who underwent surgery.
  • However, French Thoracic Cooperative Group failed to show survival difference for micro-N2 patients (They showed a survival advantang for patients with bulky N2 and neoadjuvant chemotherapy).

PROPHYLACTIC CRANIAL IRRADIATION

  • Four randomized trials of PCI added to chest irradiation (with or without chemotherapy) for locally advanced NSCLC and have not demonstrated improved survival.
  • One study showed no relapses in the brain as the first site of recurrence for patients with CR or PR to induction chemotherapy with 30 Gy in 15 fractions.
  • Randomized controlled trials of PCI vs. observation in NSCLC treated with radical intent
Study Patients PCI dose Incidence of brain metastases (PCI vs. no PCI) Median survival (PCI vs. no PCI)
RTOG ([8]) 1991 187 patients adenocarcinoma or large-cell carcinoma confined to the chest 30 Gy/10 fraction/2 weeks 9% vs. 19%, p = 0.10 8.4 vs. 8.1 months p = 0.36
SWOG ([9]) 1998 254 patients Stage III inoperable NSCLC 37.5 Gy/15 fraction/3 weeks or 30 Gy/15 fraction/3 weeks 1% vs. 11%, p = 0.003 8 vs. 11 months p = 0.004
Umsawasdi ([10]) 1984 97 patients NSCLC; 13% Stage I/II, 87% stage III 30 Gy/10 fraction/2 weeks 4% vs. 23%, p = 0.02 NA
VALG ([11]) 1981 281 male patients inoperable NSCLC 20 Gy/10 fraction/2 weeks 6% vs. 13%, p = 0.038 35.4 vs. 41.4 weeks p = 0.5

Abbreviations: PCI = prophylactic cranial irradiation; RTOG = Radiation Therapy Oncology group; SWOG = Southwest Oncology group; NSCLC = non–small-cell lung cancer.
[8] A.H. Russell, T.E. Pajak and H.M. Selim et al., Prophylactic cranial irradiation for lung cancer patients at high risk for development of cerebral metastasis Results of a prospective randomised trial conduced by the Radiation Therapy Oncology Group, Int J Radiat Oncol Biol Phys 21 (1991), pp. 637–643.
[9] T.P. Miller, J.J. Crowley and J. Mira et al., A randomized trial of chemotherapy and radiotherapy for stage III non-small cell lung cancer, Cancer Therapeutics 4 (1998), pp. 229–236.
[10] T. Umsawasdi, M. Valdivieso and T.T. Chen et al., Role of elective brain irradiation during combined chemoradiotherapy for limited disease non-small cell lung cancer, J Neurooncol 2 (1984), pp. 253–259.
[11] J.D. Cox, K. Stanley and Z. Petrovich et al., Cranial irradiation in cancer of the lung of all cell types, JAMA 245 (1981), pp. 469–472.

Radiation Technique

  • Contraindications of high dose therapy include DM, pleural or pericardial effusions. Tumors that are >8cm tumors, KPS of <60%, FEV1 <40% of predicted, or FVC of <45% are relative contraindications.
  • Dose is 60Gy to gross tumor and 50Gy to nodal areas (except for pre-op). Deciding the absolute total dose (>60Gy at 1.8 or 2.0Gy/fraction) is determined by KPS, PFT, and the amount of lung tissue in treatment portal.
  • Target volume is tumor, involved nodes, and elective nodal areas include the ipsilateral hilum, mediastinum, subcarinal, and ipsilateral supraclavicular regions.
  • Use initially AP: PA fields and then off-cord with obliques or laterals.
  • Toxicity: Dermatitis, esophagitis, fatigue, and cough.
  • Radiation pneumonitis can be fatal in a small number of patients. They present with cough SOB, fever, tachycardia, and hypoxia. The CXR shows diffuse opacification in treatment portal. Treatment is with predisone 1mg/kg/d and taper very slowly with no antibiotics or anticoagulants.

Systemic Therapies

  • Platinum based chemotherapy is the standard
  • Bevacizumab, a humanized monoclonal antibody\*\*, is designed to bind to and inhibit vascular endothelial growth factor (VEGF). VEGF is a protein that plays a critical role in tumor angiogenesis, the formation of new blood vessels to the tumor.
  • Preliminary results from a large, randomized clinical trial for patients with previously untreated advanced non-squamous, non-small cell lung cancer show that those patients who received bevacizumab (Avastin™) in combination with standard chemotherapy lived longer than patients who received the same chemotherapy without bevacizumab.

Survival for inoperable or advanced NSCLC [1]

Group Characteristics Median Surival (mo)
I KPS ≥ 90 with chemotherapy 16.2
II KPS ≥ 90, w/o chemotherapy, w/o pleural effusion 11.9
III KPS < 90, younger than 70 years, non-large cell histology 9.7
IV KPS ≥ 90 with pleural effusion OR
KPS < 90, younger than 70 years, with large cell histology OR
Patients ≥ 70 years, w/o pleural effusion
6.1
V Patients older than 70 years, with pleural effusion 2.9

Palliation

  • Hemoptysis: 80% response with median survival of 6 months.
  • Intraluminal brachytherapy: 60% cases relieve hemorrhage, respiratory distress from blockage by placing catheter into lumen and using Ir-192 HDR system.
  • there is no evidence that a protacted course is better than a shorter course of RT. It relieves cough (60%) and hemoptysis (80%) for a median duration of 6 months. Can also use HDR with response of 80%.
Bibliography
1. MARIA WERNER-WASIK, M.D., CHARLES SCOTT, PH.D., JAMES D. COX, M.D., WILLIAM T. SAUSE, M.D.,§ ROGER W. BYHARDT, M.D., SUCHA ASBELL, M.D., ANTHONY RUSSELL, M.D., RITSUKO KOMAKI, M.D.,‡ AND JIN SOO LEE, M.D. RECURSIVE PARTITIONING ANALYSIS OF 1999 RADIATION THERAPY
ONCOLOGY GROUP (RTOG) PATIENTS WITH LOCALLY-ADVANCED NON–SMALL-CELL LUNG CANCER (LA-NSCLC): IDENTIFICATION OF FIVE GROUPS WITH DIFFERENT SURVIVAL Int. J. Radiation Oncology Biol. Phys., Vol. 48, No. 5, pp. 1475–1482, 2000
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