Lung Cancer

2001 Update on Diagnosis, Staging, & Treatment

 James N. Allen, M.D.

 
 

A. Epidemiology:

1. 170,000 new cases per year
2. 140,000 deaths per year
3. currently the #1 cause of cancer deaths in both men and women (figure)
4. racial variations in incidence exist (figure)
5. incidence increases with age (figure)

B. Etiology (figure):

1. tobacco smoke - 85%
a) risk of cancer correlates with age of smoking onset, number of cigarettes smoked per day and duration of smoking (figure)
(1) "pack-year" = (# packs smoked per day) x (# years smoked)
b) currently 28% women and 32% of men smoke
c) 80% of smokers start before age 18
2. asbestos - 5% (figure)
3. radon - 5% (figure)
4. environmental tobacco smoke - 1% (figure)
5. other minor risk factors:
a) arsenic
b) BCME & CMME (chloromethyl ethers)
c) chromium
d) mustard gas
e) nickel
f) vinyl chloride
g) family history of lung cancer

C. Classification (figure):

1. small cell
2. non-small cell
a) adenocarcinoma
b) squamous cell carcinoma
c) large cell carcinoma
d) bronchoalveolar carcinoma

D. Clinical Manifestations:

1. Common signs & symptoms:
a) anorexia
b) cough
c) chest pain
d) dyspnea
e) hemoptysis
f) supraclavicular node enlargement
g) bone pain
h) neurologic manifestations
i) hoarseness (left recurrent laryngeal nerve involvement)
j) post-obstructive pneumonia
k) ** 5-15% asymptomatic at the time of diagnosis
2. Paraneoplastic syndromes (occur in 10-20% of patients):
a) clubbing
b) superficial thrombophlebitis
c) hypercalcemia
d) hyponatremia
e) peripheral neuropathy
f) Lambert-Eaton syndrome (myasthenia gravis - like condition)

E. Diagnostic Approach:

1. Radiography
a) screening chest x-rays not cost-effective and do not affect overall mortality
b) chest x-ray is overall 70-88% accurate in overall detection of lung cancer
(1) 61-71% accurate for hilar nodes
(2) 47-60% accurate for mediastinal nodes
c) chest CT permits identification of enlarged lymph nodes, adrenal masses, and liver metastases involving the superior portion of the liver
(1) lymph nodes and adrenal massess can be benign and if the patient is otherwise and operative candidate, nodes and/or the adrenal glands should always be biopsied if abnormal by CT (figure)
2. Sputum Cytology
a) diagnostic in up to 20% of all patients with lung cancer
(1) positive in < 5% of patients with peripheral cancers
b) false positives do occur
c) screening detects cancer earlier but due to lead time bias, there is no survival benefit
3. Bronchoscopy
a) solitary pulmonary nodules
(1) yield 10% if nodule is < 2 cm
(2) yield 40-50% if nodule is >2-4 cm
b) optimal # biopsies = 3-4
c) overall diagnostic accuracy for visible lesions = 94%
(1) washings = 76%
(2) brushings = 74%
(3) biopsy = 82%
d) overall diagnostic accuracy for peripheral lesions (all sizes) = 86%
(1) washings = 52%
(2) brushings = 52%
(3) biopsy = 61%
4. Trans-Thoracic Needle Aspirate
a) diagnostic yield is 43-97% if fluoroscopically visible
b) aspirate cytology correlates 65% with operative histology
c) complications:
(1) pneumothorax 35%
(2) hemoptysis 7%
(3) chest tube placement 6%
5. Mediastinoscopy - often useful in establishing a diagnosis of cancer if disease is limited to the mediastinum; also sometimes useful to provide staging of the mediastinal lymph nodes
6. thoracoscopy
a) can use as an initial procedure to be followed by formal thoracotomy if necessary
(1) benign Dx in 52%
(2) complications:
i) atelectasis 1.2%
ii) pneumonia 0.8%
iii) air leak > 7 days 1.6%
iv) average hospital stay for thorascopy only = 2.4 days
7. Surgery
8. Screening for lung cancer
a) initial studies using sputum or chest x-ray did not show a benefit from screening for lung cancer
b) a more recent study from Cornell using helical chest CT scanning in older smokers showed that CT was able to identify early stage lung cancers, which were presumably more curable
c) confirmatory studies involving screening with CT are underway but preliminary results indicate that in areas of high histoplasmosis exposure, 25-50% of all patients can have benign nodules (presumably due to granulomas) which can radiographically resemble small tumors
d) pending further studies, most authorities are withholding endorsement of large scale screening due to uncertainties regarding the actual beneficial effect of CT screening on long term outcome, regarding the incidence of false positive results, and because of the high cost of screening all at risk persons.
e) currently, Medicare does not cover screening for lung cancer in asymptomatic individuals
 

F. Staging System:

 

1. small cell lung cancer: it is controversial whether to use the TNM system or the limited/extensive system:

a) limited stage: confined to the hemithorax, mediastinum, & ipsilateral supraclavicular lymph nodes
b) extensive stage: any more distant metastasis
2. non-small cell lung cancer: use the TNM system for classification (figure and table)
a) definitions:
(1) Tumor (T)
TX - primary tumor cannot be assessed
T0- no evidence of primary tumor
Tis - carcinoma in situ
T1 - tumor 3 cm or less, surrounded by lung or visceral pleura and not in mainstem bronchus
T2 - tumor > 3 cm OR tumor in mainstem bronchus OR tumor invading visceral pleura OR tumor with atelectasis or pneumonia extending to the hilum but not involving the entire lung
T3 - tumor invading the chest wall, diaphragm, mediastinal pleura, or pericardium OR tumor < 2 cm from the main carina but not involving the main carina OR tumor with atelectasis or pneumonia involving the entire lung
T4 - tumor invading the mediastinum, heart, great vessels, trachea, esophagus, vertebral body, or main carina OR tumor with malignant pleural effusion OR tumor with satellite nodule within the lung
(2) Lymph nodes (N)
NX - regional nodes cannot be assessed
N0 - no regional node involvement
N1 - ipsilateral peribronchial or hilar nodes
N2 - ipsilateral mediastinal or subcarinal nodes
N3 - contralateral mediastinal or hilar nodes OR any scalene nodes OR any supraclavicular nodes
(3) Distant metastasis (M)
MX - distant metastases cannot be assessed
M0 - no distant metastases
M1 - distant metastases present
(b) overall 5-year survival = 13%, partly because the diagnosis is generally made at an advanced, surgically incurable stage (figure)

G. Treatment:

1. small cell lung cancer -
a) limited stage (1/3 of cases) - chemotherapy + radiation therapy:
(1) typical regimen:
(a) Etoposide 80-100 mg/m2 IV x 3 days q 21 days for 6 cycles
(b) Cisplatin 80-100 mg/m2 IV x 1 day
(c) Plus mediastinal/chest XRT during first 2 cycles (total ~5-6 weeks, 4500-500 rads)
(2) Expected survival for limited disease15-25% at 5 years
(3) Some people recommend prophylactic cranial radiation for those with complete responses.
(a) No effect on survival, but decreases brain relapses.
 b) extensive stage (2/3 of cases) - chemotherapy
(1) typical regimen:
(a) Etoposide 80-100 mg/m2 IV x 3 days q 21 days for 6 cycles
(b) Cisplatin 80-100 mg/m2 IV x 1 day
(2) expected survival:
(a) median survival 3 months without treatment
(b) median survival 9 months with treatment
(c) even with treatment, essentially no patients alive at 5 years
2. non-small cell lung cancer -
a) stage I & II - surgery
(1) PFT assessment of lung function prior to surgery
(a) FEV1 > 2 L or > 60% predicted
- predicts sucessful pneumonectomy
(b) DLCO > 60% predicted
- predicts sucessful pneumonectomy
(c) pCO2 > 45
- predicts increased death rate
(2) V/Q assessment of lung function
FEV1 x % perfusion to the lung which will remain after pneumonectomy > 40% predicted predicts sucessful pneumonectomy
(3) exercise assessment of lung function
(a) maximum oxygen consumption > 20 ml/kg/min
- predicts low complication rate & death rate
(b) maximum oxygen consumption between 10-20 ml/kg/min
- predicts increased complication rate
(c) maximum oxygen consumption < 10 ml/kg/min
- predicts increased death rate
b) stage IIIA - surgery post-operative radiation therapy and possibly pre-operative chemotherapy
c) stage IIIB - high dose radiation (6,000 rads) is curative in 5-7%; addition of chemotherapy may further increase survival
d) stage IV - chemotherapy adds about 8-10 weeks to median expected survival of 4-5 months
(1) taxol + cisplatin
(2) taxol + carboplatin
(3) cisplatin + navelbine
(4) cisplatin + gemcitabine
3. palliative treatment of lung cancer
a) external beam radiation therapy
b) endobronchial brachytherapy (high dose intrabronchial radiation therapy)
c) endobronchial stents
d) endobronchial laser therapy
e) endobronchial cryotherapy
f) endobronchial phototherapy
g) pleurodesis (figure)

H. Palliative Treatment:

1. External beam radiation:
a) If symptoms are mild to moderate and the patient has not exceeded the maximal radiation dose previously
b) In patients with more severe respiratory symptoms if stent placement is not available
c) In certain situations, radiation may be relatively contraindicated because of high risk of radiation fibrosis and brachytherapy, laser, cyrotherapy, or stent may be preferable:
(1) Co-existant collagen vascular disease
(2) Recent use of bleomycin, Adriamycin, or mitomycin
(3) Pre-existant pulmonary fibrosis
2. Brachytherapy:
a) Technique:
(1) A bronchoscopic catheter is placed across the obstructing tumor
(2) A radioactive iridium source is advanced through the catheter
(3) The catheter is withdrawn after Å 15 minutes
(4) The radiation delivered is high potency but has a relatively shallow depth of penetration (Å 1 cm)
b) Indications:
(1) If symptoms from the obstruction are mild to moderate
(2) In general, used only after a full course of external beam radiation
(3) If the airway is completely occluded and the patient can withstand the Å 2 weeks prior to brachytherapy-induced tumor regression
(4) In short bronchial segments where a stent will likely overhang otherwise patent bronchi (eg, right upper lobe bronchus)
c) Contraindications:
(1) Previous maximal brachytherapy to the area
d) Complications:
(1) Fibrinous obstruction
(2) Bleeding
(3) Fistula formation
3. Cryotherapy
a) Technique:
(1) Requires a 2.6 mm working channel through a fiberoptic bronchoscope
(2) Nitrous oxide cools the cryotherapy probe tip to -40°C
(3) One to three 1 minute freeze-thaw cycles
(4) Can be used for malignant or benign strictures
b) Advantages:
(1) Safer than laser
(2) May be able to cure some carcinoma in situ
(3) Equipment is less expensive than laser equipment
c) Disadvantages:
(1) Does not provide immediate effect
(2) May require multiple treatments
4. Laser
a) Indications:
(1) Airway obstruction
(2) Bleeding
(3) Carcinoma in situ
(a) Can be curative in this situation
b) Contraindications:
(1) Extrinsic compression
(2) Excessively bulky tumor
(3) Technical difficulty in aiming the laser because of tumor location
(4) Upper lobe lesions (can be difficult to appropriately direct laser due to upward direction of the lumen)
(5) Total occlusion of the airway
c) Complications:
(1) Hemorrhage
(2) Pneumothorax
(3) Respiratory failure
(4) Fire
d) Types:
(1) Carbon dioxide
(a) Shallow penetration
(b) Absorbed by water
(c) Limited hemostasis
(d) Requires rigid bronchoscope
(2) Argon
(a) Mainly used in conjunction with photosensitizing agents
(3) Neodymium YAG
(a) Greatest depth of penetration
(b) Best hemostasis
(c) Can be used with rigid or flexible bronchoscope
 
5. Photodynamic therapy
a) Technique:
(1) pre-administration of a systemic photosensitizing agent
(2) exposure of the airway to very bright white light using a modified laser
b) Advantages:
(1) no risk of ionizing radiation
(2) can be used pre-operatively to improve bronchial margins
(3) very effective for lesions involving the carina
c) Disadvantages:
(1) requires laser light source
(2) risk of severe cutaneous burns if exposed to sunlight
(3) shallow depth of penetration
(4) generally requires extensive forceps debridement
(5) typically requires admission to the hospital
(6) delay from time of administration of photosensitizing agent to regression of tumor
6. Silicone stents:
1. Advantage:
a) Removable
2. Disadvantage:
a) Reduce intralumenal diameter
b) Retained secretions
c) Migration
d) Must be placed with a rigid bronchoscope
(1) Airway should generally be pre-dilated with rigid scope prior to stent placement
3. Types:
a) Rüsch Y (Rüsch Inc., Duluth, GA)
(1) Combined tracheal/bronchial stent with a "Y"biforcation to permit simultaneous stenting of the trachea and both main bronchi
(2) Has the advantage of a silicone body with stainless steel rings which simulate the tracheal rings
(3) In general, "Y" stents are less likely than straight stents to migrate proximally
b) Hood bronchial stent (Hood Laboratories, Pembroke, MA)
(1) Sialastic stent suitable for areas of tight stenosis where proximal migration is unlikely
c) Dumon bronchial stent (Bryan Corp., Woburn, MA)
(1) Sialastic stent with struts that project into the bronchial wall to help anchor the stent in place
d) Montgomery T-tube
(1) One of the first stents available clinically
(2) Best suited for upper or mid-tracheal lesions
7. Metal stents:
1. Advantages:
a) Permanent
b) Generally become covered with new epithelial tissue consisting of ciliated pseudostratified epithelium within 3-4 months
c) Can be placed with a flexible bronchoscope
d) Do not require general anesthesia
e) Can be done on an outpatient basis
f) Can be done on ventilated patients in the ICU
2. Disadvantages:
a) Permanent
b) Can cause compression necrosis if over distended
c) If they collapse, they can cause airway obstruction
d) Tumor can re-grow through the stent with recurrent obstruction
3. Types of metal bronchoscopic stents:
a) Wallstent (Schneider, Inc., Minneapolis, MN)
(1) Soft and flexible
(2) Consist of a woven mesh of stainless steel
(a) Currently available model consists of 20 braided stainless steel filaments
(b) A polyurethane covered metal mesh stent is also available to prevent turmor growth through the stent mesh
(3) Self-expanding to a set maximal diameter as an outer covering sheath is withdrawn
(4) Do not require a balloon dilation (although this can be helpful in some circumstances)
b) Palmaz (Johnson & Johnson Interventional Systems, Warren, NJ)
(1) Very stiff
(2) Metal stent which is loaded over a balloon which is used to distend the stent to a desired diameter
(3) It can be irreversibly deformed and crushed with the force of coughing resulting in airway obstruction
c) Gianturco (Cook Inc, Bloomington, IN)
(1) "Zig-zag" metal stent
(2) More likely to migrate
(3) More likely to perforate the bronchus
(4) Not currently used in the United States
d) Ultraflex (Boston Scientific, Watertown, MA)
(1) Soft and flexible
(2) Made of a single woven nitinol wire (nitinol = titanium + nickel; nitinol is safe for patients undergoing MRI)
(3) Self-expanding to a maximum set diameter
(4) Requires initial placement of a guidewire via a flexible bronchoscope
(5) Does not require balloon dilation
(6) Has a nylon braid at either end of the stent which can be grasped by transbronchial forceps for easy re-positioning of the stent after deployment
(7) A major advantage over the Wallstent is that as it expands, it does not shorten, thus making ideal positioning of the proximal and distal ends of the stent easier
4. Placement of metal stents:
A. Stent selection
1. Of the currently available metal stents, the Ultraflex and the Wallstent are probably the safest, easiest to place, and least likely to migrate or perforate the airway. These are the stents that we use most commonly at Ohio State
2. The decision of whether to use an Ultraflex or a Wallstent requires experience with both devices. The Ultraflex is more forgiving for the less experienced operator but the Wallstent anchors itself into position better than the Ultraflex. The Wallstent also has greater radial force than the Ultraflex. At OSU, we require a minimum of 10 supervised stents for credentialling purposes.
B. Pre-stent placement assessment:
1. Normal bronchial anatomy:
a) Trachea = 60 - 90 mm in an adult (intrathoracic component only)
(1) Average transverse diameter:
(a) Women = 15.2 ± 1.4
(b) Men = 18.2 ± 1.2
b) Left mainstem bronchus Å 45 mm
c) Right mainstem bronchus Å 25 mm
d) Right upper lobe bronchus Å 10 mm
e) Bronchus intermedius Å 20 mm
f) Right middle lobe Å 12 mm
g) Left upper lobe Å 9 mm
h) Normal bronchial diameters range from 8-12 mm for main and lobar bronchi
2. Radiographic assessment:
a) Plain chest radiographs
(1) Occasionally sufficient
b) Helical CT
(1) Measure contralateral analagous bronchus
(2) Determine if the lesion is calcified (ie, firm and unlikely to open without balloon dilation)
(3) Measure the diameter of the bronchus below and above the area of obstruction
(4) Measure the distance between the desired distal end of the stent and desired proximal end of the stent
3. Bronchoscopic assessment:
a) Visualize location of lesion relative to patent bronchi
b) Determine if lesion is pliable and soft
c) If bronchoscope can be forced beyond the lesion, determine the length of the lesion and the length between patent bronchi by measuring the length of bronchoscope withdrawn as it is pulled back from beyond the lesion
C. Stents are available in multiple sizes:
1. 5 - 24 mm diameter by 20 - 90 mm length
2. Typical selections:
a) Bronchus intermedius: 8 x 20 mm
b) Right mainstem bronchus: 10-12 x 20 mm
c) Left mainstem bronchus: 10-12 x 20-42 mm
d) We generally keep 8 x 20, 10 x 20, 12 x 20, 12 x 40, 16 x 60, and 18 x 60 mm stents in stock since these are the most frequently used stents in our patient population
3. If in doubt about appropriate length, use a shorter length - a second stent can always be placed later
4. Catheter sizes (in which stents are loaded for deployment) are measured in French scale
a) 1 French = 0.33 mm
b) Transbronchoscopic stent catheters are generally 7 French (2.3 mm) and thus require at least a 2.6 mm working channel in the bronchoscope for passage
D. Placement issues:
1. Positioning
a) Fluoroscopy must be used
b) Mark desired distal position of stent with a radio-opaque marker taped to the chest (eg, a paper clip)
2. If airway is completely or near completely occluded, use a guidewire to feed the stent through
a) Flexible tipped guidewires are preferable since they less likely to perforate the bronchus
b) Need ³ 200 cm guidewire (generally .035) to extend the length of the stent and the lesion in front of it
c) Guidewires are unnecessary for most lesions, especially those with a partially patent airway
3. If airway if completely or near completely occluded, consider initial balloon dilation prior to stent placement
a) Angioplasty balloons can be fed over the same guidewire used to feed the stent over
E. Stent deployment:
1. First pass the stent catheter beyond the position of the obstruction
2. The stent is deployed slowly by sliding the the plastic sheath backward over the metal guide tube
3. Initially partially deploy stent (allow about 1/4 to 1/3 of the length of the stent to expand) 4-5 mm beyond the desired distal final position of the stent and "snug" the stent up so that the distal end to the stent coincides with the location in the bronchus previously marked with the paperclip
4. Once the distal end of the stent is appropriately positioned, slowly deploy the remaining, proximal end of the stent
5. When placing a stent in the trachea
a) If an endotracheal tube is present, it must be withdrawn up to a position well above the anticipated proximal end of the deployed stent so as to not interfer with the expansion of the stent
b) Start the deployment in the right mainstem bronchus and pull the partially deployed distal end of the stent into the carina so that it is appropriately positioned in the lower trachea, then fully deploy the stent
6. Inadequate deployment
a) Results in a stent that is too narrow and too long (for Wallstents)
b) Post-deployment balloon dilatation can result in widening of the stent diameter and shortening of the stent length to appropriate size
5. Complications:
A. Cough
1. Fairly uncommon with metal stents
2. Generally only occurs if the stent selected is too small for the airway lumen
B. Obstruction of bronchial orifaces
1. Often this is an asymptomatic condition although it can on occasion cause:
a) Localized wheezing as air passes through the mesh of the stent
b) Impaction by secretions wtih dyspnea due to obstruction of the airway lumen
c) Pneumonia
2. If the stent is so long that it overhangs an otherwise patent bronchus (eg, a right mainstem stent extends 6 mm into the trachea and obstructs the left mainstem bronchus) there are several options for treatment:
a) Use transbronchial scissors to make a longitudinal cut in the stent and allow the stent to expand open
(1) In the example, make a 6 mm longitudinal cut in the proximal left wall of the stent so that the left mainstem bronchus becomes patent
(2) This is the easiest option for most pulmonologists but does require some degree of extra skill in transbronchial scissor technique
b) Laser a hole in the stent
c) Remove the stent and replace it with a shorter stent
(1) Stent removal is difficut if even possible at all once the stent has become epithelialized; Ultraflex stents can be removed easir than Wallstents
(2) Wallstents require use of rigid bronchoscope for attempted removal
C. Secretion retention
1. Generally occurs if stent is obstructing a bronchial oriface
D. Tumor regrowth through stent mesh with recurrent obstruction
1. Can be avoided by placement of a covered stent
E. Proximal migration of stent
1. More common with fixed diameter stents (eg, Palmaz)
2. More common when stent placement is followed by radiation and/or chemotherapy with tumor regression
F. Obstruction of stent by bent wires
1. Can occur due to suction catheters, etc
2. Wires can be bent back into appropriate position by transbronchial biopsy forceps
G. Erosion into nearby blood vessels
1. More common with rigid metal stents (eg, Strecker or Palmaz)
2. Stents should be used cautiously if at all when airway obstruction is due to compression by a vessel
8. Personal preferences for malignant airway obstruction:
a) Use external beam radiation for initial management of mild-moderate symptoms of malignant obstruction
b) Use brachytherapy, cryotherapy, or laser for patients failing external beam radiation or for patients in whom external beam radiation is contraindicated
c) Use stents for patients with acute, severe symptoms of malignant obstruction and for patients who have already had brachytherapy and/or cryotherapy

I. The Solitary Pulmonary Nodule (figure):

1. solitary pulmonary nodules
a) smallest lesion detectable with CXR is 2-3 mm
b) 40-50% malignant
(1) 10-30% of these are metastatic
c) 40-50% granulomas
d) benign calcium patterns (often better visualized with CT than plain chest x-rays):
(1) laminated
(2) diffuse
(3) central
(4) note: eccentric or speckled can be seen with malignant or benign
(a) 13% of bronchogenic cancers have CT evidence of calcification (eccentric or speckled)
e) malignant nodules have a doubling time of 21 - 400 days (figure)
(1) a lesion which is unchanged in size for ³ 2 years is usually benign
f) indicators of malignancy:
(1) size
(a) < 2 cm = 20% malignant
(b) > 3 cm = 80% malignant
(2) age
(a) < 50 years old = 33% malignant
(b) > 50 years old = 65% malignant
(3) smoking
(4) history of cancer
g) PET (positron emission tomography) can be useful to distinguish benign from malignant pulmonary nodules when biopsy is medically risky (figure):
(1) sensitivity = 96%
(2) specificity = 88%

 I. References:

1. Am. J. Respir. Crit. Care Med., Volume 156, Number 1, July 1997, 320-332
2. Chest, Volume 111, Number 6, June 1997, 1710-1717
3. Chest, Volume 112, Number 4S, October 1997, 251-258
4. Chest, Volume 115, Number 1, January 1999, 233-235
5. N. Engl. J. Med. 1994; 330:159-164
6. Soc. Sci. Med. 1991; 32:1151-1159
7. JAMA 1994; 271:1752-1759
8. http://cancernet.nci.nih.gov
9. New England Journal of Medicine 343(22): 1627-1633, 2000.
 
 
last updated May 2, 2001
 
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