Download Lung Cancer

Lung
Cancer
Overview
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Mortality trends
Risk factors
Screening
Solitary pulmonary nodule
Staging /Survival by stage
Histology
Molecular Testing
Presentations/patterns of spread
Paraneoplastic phenomena
Management of resectable disease
– Adjuvant therapy
– Neoadjuvant therapy
• Management of unresectable disease
Peter
Jennings
Vincent Schiavelli
Don Knotts
Dana Reeves
Joe Paterno
Lung cancer mortality trends
Lung cancer “epidemic” - has peaked in men – appears to have leveled in women
2011 Estimated US Cancer Cases*
Men
822,300
Women
774,370
Prostate
29%
30%
Breast
Lung & bronchus
14%
14%
Lung & bronchus
Colon & rectum
9%
9%
Colon & rectum
Urinary bladder
6%
6%
Uterine corpus
Melanoma of skin
5%
4%
Non-Hodgkin lymphoma
Non-Hodgkin lymphoma
4%
4%
Melanoma of skin
Kidney & renal pelvis
5%
5%
Thyroid
Leukemia
3%
3%
Kidney & renal pelvis
Oral cavity
3%
3%
Ovary
Pancreas
3%
3%
Pancreas
19%
22%
All Other Sites
*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.
All Other Sites
Source: American Cancer Society, 2011.
LUNG CANCER Epidemiology
• Estimated 239,320 in U.S. 20111
– 128,890 male
– 110,430 female
• Most common cancer overall
• 2nd most common cancer in men and women
• Leading cause of cancer related death (161,250 deaths)
• Also leading cause of cancer related death worldwide
1. Seigel et al: Clinical Cancer Advances 2011
2. Citation: Cancer Care Ontario. Cancer Fact: International trends in lung cancer deaths rates
reflect smoking patterns. January 2011.. Available at
http://www.cancercare.on.ca/cancerfacts.
Lung cancer – risk factors
• Cigarette smoking accounts for about 90% of all lung cancer
– Increased use increases risk: 40 pk-yr = 20xRR of a non-smoker
– Corollary: reduction from 2PPD to ½ PPD will reduce risk
– Environmental (second-hand) tobacco smoke increases risk
• Radiation therapy
– RT after breast ca – increased Lung Cancer among smokers –
ipsilateral lung
– RT for Hodgkin’s Lymphoma assoc w/increased risk of Lung Cancer
– Caveat: Improved RT techniques to reduce exposure of lung is
hoped to reduce this complication in the future
Lung cancer – risk factors
• Other known/ascribed risk factors
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Radon (emanation from soil - unpredictable)
Asbestos
Metals (arsenic, chromium, nickel)
Ionizing radiation (occupational/accidental)
Pulmonary fibrosis (independent of smoking)
Polycyclic aromatic hydrocarbons (inhaled from incomplete combustion - auto
pollution, cooking oils, soot)
– HIV infection
– Genetic factors – Family History = 2x risk (after controlling for smoking)
• Major susceptibility locus (chromosome 6q23–25) for inherited lung cancer
Screening – National Lung Screening Trial (NLST)
• Diagnosis of lung cancer generally based upon evaluation
of individuals with symptoms.
• Screening for lung cancer has not been widely used
– CXR and sputum cytology not shown to reduce lung ca mortality
• National Lung Screening Trial (NLST)
– Multicenter (33 medical centers)
– Screening of high-risk pts for 3 yrs, N=53,454
– Age 55-74, “High-risk” = 30+ pack-years (allowed prior use if quit
within 15 yrs of enrollment)
– Annual Low-dose chest CT versus CXR
– (+) findings = noncalcified nodule ≥4 mm on CT scan or any
noncalcified nodule on x-ray.
Screening – National Lung Screening Trial (NLST)
• Interim analysis 11/2010 benefit for CT scanning at a Median follow-up of 6.5 years
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(+) screen
False (+)/complication rate
Cases/100K person
Stage I/II at dx
Lung Ca deaths
CT group
24%
96.4% / 1.4%
645
70%
247
CXR group
6.9%
94.5% / 1.6%
572
56.7%
309 (Relative Risk Reduction 20%)
• Conclusions: NLST demonstrated that CT screening reduced mortality in a high-risk
population, compared to screening by x-ray
• Number needed to screen w/CT to prevent one lung cancer death was 320
• Cost per life saved high, given high false-positive rate and subsequent w/u
• NELSON trial is a randomized CT-based lung cancer trial being conducted in the
Netherlands and Belgium; CT screening is being compared to no screening in 7,557
current or former smokers
Tumor is the Rumor
Is Cancer the Answer?
• Solitary pulmonary nodule represents potentially curable stage of lung
cancer
– Stage I Lung cancers are within the definition of a SPN
• Goal – identify and resect potentially curable cancer and avoid surgical
resection of benign nodules
• The SPN also represents a host of other “non-malignant” processes
• CT scan with fine cuts through nodule helpful to characterize
Size
Low Risk
High Risk Per Up-To-Date Jan2012
• 4-6 mm
12
12, 24 Repeat scan (months)
• 6 to 8 mm
12, 24
6, 12, 24
• >8 mm
3, 9, 24
3, 9, 24
– A nodule that has clearly grown on serial imaging tests should be excised
– If > 1 cm … FDG-PET sensitivity of 95% / specificity 78% for malignancy
Tissue is the ISSUE!
?
Heartworm!
NSCLC TNM definitions - 2011
Tumor Characteristics
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T1:  3cm, surrounded by lung/visceral pleura, not in main bronchus
T1a  2, T1b >2-3 cm
T2: >3 to 7 cm, or tumor involving:
– Main bronchus involvement and  2 cm distal to the carina
– Visceral pleura invasion
– Assoc w/ atelectasis or obstructive pneumonitis extending to hilar region but not
involve the entire lung
T2a > 3 but  5, T2b > 5 to 7
T3: Tumor > 7 cm or involves
– Chest wall (including superior sulcus), diaphragm, phrenic nerve, mediastinal pleura,
or parietal pericardium
– Main bronchus and < 2 cm distal to the carina but without involvement of the carina
– Assoc atelectasis or obstruct pneumonitis of entire lung
– Separate/multiple nodules in same lobe
T4: Tumor invading:
– Mediastinum, heart, great vessels, trachea, esophagus, vertebral body, carina;
– Separate tumor nodules in different ipsilateral lobe
TOO MUCH TO COMMIT TO MEMORY –
LOOK THIS UP IN NCCN GUIDELINES
NSCLC TMN (Continued)
Regional lymph nodes (N)
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N0: No regional lymph node metastasis
N1: Ipsilateral peribronchial, intrapulmonary, hilar
N2: Ipsilateral LN within the mediastinal and/or subcarinal
N3: Contralat mediastinal, contralat hilar, any scalene, or SC LN(s)
Distant metastasis (M)
• M0: No distant metastasis
• M1: Distant metastasis
– M1a Separate tumor nodule(s) in contralateral lobe or malignant
effusion (pleural or pericardial)
– M1b Distant mets
TOO MUCH TO COMMIT TO MEMORY –
LOOK THIS UP IN NCCN GUIDELINES
Staging NSCLC – 7th Edition
N0
N1
N2
N3
T1
IA
IIA
IIIA
IIIB
T2A
IB
IIA
IIIA
IIIB
T2B
IIA
IIB
IIIA
IIIB
T3
IIB
IIIA
IIIA
IIIB
T4
IIIA
IIIA
IIIB
IIIB
M1
IV
IV
IV
IV
TOO MUCH TO COMMIT TO MEMORY –
LOOK THIS UP IN NCCN GUIDELINES
Non Small Cell Lung Cancer
Most people are diagnosed Stage III and IV.
25% stage I
7% stage II
32% stage III
36% stage IV
70% with Stage I-III, will have their disease recur
NSCLC: survival by stage
Histologic Classification
• Squamous cell carcinoma (20%)
– Decreasing incidence - ? Filters - smaller
particles or having to suck moves smoke
to the periphery
Keratinization and
intercellular bridges
c/w SCC
• Adenocarcinoma (38%)
– bronchioloalveolar
• F>M and non-smokers
– acinar , papillary , solid with mucus
formation
• Small cell carcinoma (13%)
• Other variants (29%)
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Large cell carcinoma (5%)
Spindle cell variant
Giant cell
Clear cell
Undifferentiated carcinoma
Other NOS
Adenocarcinoma
Bronchioloalveolar –
well-differentiated
columnar cells
proliferating along the
framework of alveolar
septae.
Small cell - cells are
almost only blue nucleus
(DNA) material making
them "small" under the
microscope
Genetics of NSCLC
Hecht S S JNCI J Natl Cancer Inst 1999;91:1194-1210
• Smoking causes many chromosomal abnormalities
– Del 3p – ~90% Small cell Ca and ~50% NSCLC
– Del 8p (21.3-22) ~ 50% NSCLC
– Deletions and point mutations p53 gene
• (loss of inhibition of proliferation)
– Loss of PTEN (inhibits PI3K/Akt pathway)
• - PI3Ks-Akt constitutively activated in NSCLCs
– K Ras mutations
• highly assoc w/ resistance to TKIs
• lack of response to platinum/vinorelbine treatment
Required Molecular Testing
Epidermal Growth Factor Receptor (EGFR)
• Del Exon 19 or point mutation in Exon 21 confer EGFR TKI sensitivity
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Exon 20 mutations associated with resistance to EGFR TKI
• More common Asians, females, non-smokers – REMEMBER IT!
• EGFR TKIs appropriate to use front line if mutation present
Non-Asian
Asian
Total
Never Smokers
35%
60%
54%
Smokers
4%
17%
11%
Female
30%
58%
46%
Male
9%
22%
16%
Adenoca
20%
49%
42%
Non-adenoca
1%
4%
3%
Janne, ASCO Educational Session, 2007 Pooled results from 7 trials
Mok TS, et al. N Engl J Med 2009;361: 941-57.
Required Molecular Testing
EML4-ALK translocations
• Identified in small subset of NSCLC (5-7%) – does not overlap with kRas or EGFR
Fusion protein – Can be detected FISH, RT-PCR, or IHC
Vast majority tend to be adenocarcinoma (some reports in SqCC)
Tend to be younger, non-smokers/light smokers
Associated with response to Crizotinib
Kwak et al. N Engl J Med
2010;363:1693-703.
Lung Cancer Mutation Consortium:
Incidence of single-driver mutations
NO MUTATION
DETECTED
KRAS
22%
AKT1
NRAS
MEK1
MET AMP
EGFR
17%
HER2
PIK3CA
BRAF 2%
DOUBLE
MUTANTS 3%
EML4-ALK
7%
Kris MG et al. Proc ASCO 2011;Abstract CRA7506.
Mutation found in 54% (280/516) of
tumors completely tested
(CI 50-59%)
Presentations
Panoply of Presentations – seen them all ...
Occult presentations
• Asymptomatic pulmonary nodule
• Lung mass/mediastinal adenopathy
Subacute/Insidious Presentations
• Unexplained weight loss
• Non-resolving /post-obstructive PNA
• New onset clubbing
• New hoarseness (recurrent laryngeal nerve)
DRAMATIC PRESENTATIONS
• SVC syndrome (flushing/ headache/plethora)
• Pericardial/Pleural effusion
• New onset Hypercalcemia
• Seizure/weakness from CNS met
• Pain C8, T1, T2 distro (Pancoast tumor)
• Tumor expectoration (uncommon but exciting!)
Panoply of Presentations – seen them all ...
Common/Typical Presentations
• Cough (New or Worsening chronic cough) (50-75%)
• Hemoptysis (25-50%)
• Chest pain from local invasion (20%)
• Increased DOE (obstruction with collapse/effusion) (25%)
• Bone pain – back > rib > pelvis
Tissue Is the Issue but . . .
“Typical” Patterns of disease
• Squamous
– Centrally located, can be
associated with necrosis
• Bronchoalveolar
– Patchy infiltrates -Spreads
along airways
• Adenocarcinoma
– Often more peripheral
lesions
• Small cell
– Mediastinal adenopathy
– Early and WIDELY metastatic
disease
Patterns of metastasis
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Bone
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Liver
Adrenal
Brain
Hypercalcemia
• Most common in SQUAMOUS CELL CA
• Polyuria, metab alkalosis, hyperuricemia, ARF
• Hypomotility with anorexia, N/V, constipation, also
pancreatitis
• Weakness/lethargy/coma/seizures.
• Can suggest bony mets or PTH-related-peptide
• PTHrP binds PTH receptors  Ca2+ mobilization
• TX: Volume repletion, saline diuresis, bisphosphonate,
effective treatment of the tumor
Hypertrophic Osteoarthropathy
• Primarily seen in NSCLC – rare in SCLC
• DOES NOT INDICATE METASTASIS
• HPO - subperiosteal cancellous bone at distal
ends of long bones.
– Radius and ulna (80%) or tibia/fibula (74%).
– Sx’s: pain, swelling, erythema
– Long bone x-rays can show subperiosteal
bone formation
– Clubbing
– Bone scan  activity long bones
• Etiology ? Neurogenic / humoral.
– Neurogenic theory – vagotomy can result
in ipsilateral remission.
– Humoral theory - ? substance related to
the malignancy - resection of tumor can
result in immediate symptom relief.
Paraneoplastic syndromes
Small Cell Lung Cancer
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Cushing's syndrome due to excess ACTH
SIADH
Lambert-Eaton myasthenic syndrome
Cerebellar ataxia, subacute sensory neuropathy
• THESE ARE ASSOC WITH SMALL CELL CANCER
• TOMORROW’S LECTURE WITH DR. CARTER!
Decision making
• Resectability – surgery remains the foundation of therapy
– Resectable  surgery  +/- adjuvant
– “Potentially” resectable due to primary  “neoadjuvant”
• Convert necessary surgery from a pneumonectomy (which the patient
cannot tolerate) to a lobectomy (which the patient could tolerate)
– “Potentially” resectable due to specific mets
• Solitary mets to adrenal
• Mets to different lobes in unilateral lung
• Solitary brain mets – resection of primary as well as metastatectomy with
additional whole-brain XRT – prolonged survival
– Unresectable
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Poor PS due to comorbidities or inadequate lung function
Bulky mediastinal (N2) adenopathy
Contralateral disease
Metastatic to bilateral lung, bone, liver, or brain (with exceptions above)
Stage I-IIIA
Can the patient tolerate surgery?
• Rule of thumb – PFT’s can suggest what surgery a patient can tolerate
– Pneumonectomy – FEV1 2.0 L
– Lobectomy – FEV1 1.5 L
• Better to use post-operative % predicted FEV1
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Postop FEV1 at least 800 cc and FEV1 predicted >40%
Split function testing (nuc-med) helps estimate postop function
Marginal pts: get CPEX: if VO2 max > 15 will tolerate most resections w/ normal M&M
Limited resection – segmentectomy (preferred) or wedge resection can be considered
• Low DLCO predicts increased morbidity and need for post-resection home O2
• Mortality is different based on location!!
– Right Pneumonectomy 12% Mortality
– Left Pneumonectomy 6% Mortality
Survival by stage s/p curative resection
Van Rens M et al
Chest:2000:117:374
Betticher DC,
Lung Ca: 2005: S9-16
Post-surgery treatment (Adjuvant)
Post-surgery treatment (Adjuvant)
• Improved disease free survival
• Improved overall survival absolute
IALT, NEJM 350;4, 2004
JBR-10, NEJM, 352;25, 2005
ANITA, LancetOnc, 2006
Post-surgery treatment (Adjuvant)
• Meta-analysis of studies
– Disease free survival HR 0.84 (0.78-0.91)
– Overall Survival HS 0.89 (0.82-0.96)
– Absolute overall survival benefit at 5 yrs = 5.4%
J Clin Oncol. 2008 Jul 20;26(21):3552-9.
Post-surgery treatment (Adjuvant)
• For Stage IA disease – generally observation
– Caveat: positive margins – re-resection or RT
• For Stage IB-III disease – Adjuvant chemotherapy
– “Platinum based” doublet
• Cisplatin (preferred) or carboplatin
• Combined with another agent
– vinorelbine, etoposide, vinblastine, gemcitabine,
paclitaxel, docetaxel, or pemetrexed
– May seem random, but decision is based off of
comorbidities, histology, patient preference,
physician preference
• If positive margins – chemo-RT followed by chemo
What about patients who have large tumors
with local invasion (i.e.; surgery, if possible, is
going to leave tumor at the margins)?
Superior sulcus Chest Wall Invasion Mediastinal Invasion
Management of local invasion
• If it appears to be resectable
– Preoperative concurrent chemotherapy with radiation
followed by surgery . . . Then adjuvant chemo
Pre-op Chemo-RT
Phase III RTOG 9309 (INT 0139)
• 396 patients, PS 0-1, Stage IIIA (T1–3N1-3M0)
• All received concurrent chemoRT (45Gy)
– Cisplatin 50mg/m2 D1, 8 x 2 cycles q28 d
– Etoposide 50 mg/m2 D1-5 x 2 cycles q28 d
• Randomization: Surgery vs Definitive RT up to 61 Gy
• All received 2 more cycles of Cis-Etoposide
• Early treatment related mortality
– Surgery 7.9% vs RT 2.1%
Lancet. 2009 Aug 1;374(9687):379-86.
Pre-op Chemo-RT
Phase III RTOG 9309 (INT 0139)
Surgery
• Median OS 23.6 mo
• 5-yr PFS
21%
• 5-yr OS
27%
RT
22.2 mo (p=NS)
11% (p=0.008)
20% (p=NS)
• Pneumonectomy 26% postop mortality
• Lobectomy 1% postop mortality
Conclusions: surgery after chemo-RT can be
considered in fit pts requiring lobectomy
Concurrent Chemo-Radiation should continue
uninterrupted if pneumonectomy would
be required
Lancet. 2009 Aug 1;374(9687):379-86.
Management of UNRESECTABLE disease
• Chemotherapy with radiation
– Concurrent treatment > sequential
– About 20-25% OS at 5 years
Curran WJ, J Natl Cancer Inst. 2011 Oct 5;103(19):1452-60.
Lancet. 2009 Aug 1;374(9687):379-86.
Management of metastatic disease
• Complete discussion beyond the scope
of this talk
• IM Board testable questions
– “Platinum based doublet” is the standard
front line regimen
• EXCEPT EGFR sensitive mutation – should
receive EGFR Tyrosine Kinase inhibitor (e.g.,
erlotinib)
• EXCEPT EML-ALK translocation – may receive
crizotinib frontline
• EXCEPT elderly or extensive comorbidities –
single agent regimens
• No benefit of systemic chemotherapy for
ECOG PS 3-4
Schiller JH. N Engl J Med.
2002 Jan 10;346(2):92-8.
Management of metastatic disease
• Important concepts – but probably
not board testable
– Bevacizumab marginal
improvement added to doublet –
but only for NON-SQUAMOUS
– Cetuximab marginal improvement
added to doublet – regardless of
histology
– Platinum-pemetrexed may be
more efficacious for adenoca
– Platinum-gemcitabine may be
more efficacious for squamous cell
ca
– Maintenance therapy after initial
chemo delays progression and
improves OS (but is it just early
second line therapy?)
Management of metastatic disease
• Second line therapy and beyond – all dependent on
performance status
• Single agent therapy
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Pemetrexed
Docetaxel
Paclitaxel or Nab-paclitacel
Erlotinib
Vinorelbine