LungCancer

Overview• 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

Lung cancer mortality trends

Lung cancer “epidemic” - has peaked in men – appears to have leveled in women

Peter Jennings

Vincent Schiavelli Don Knotts Dana Reeves Joe Paterno

2011 Estimated US Cancer Cases*

*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.

Men822,300

Women774,370

30% Breast

14% Lung & bronchus

9% Colon & rectum

6% Uterine corpus

4% Non-Hodgkin lymphoma

4% Melanoma of skin

5% Thyroid

3% Kidney & renal pelvis

3% Ovary

3% Pancreas

22% All Other Sites

Prostate 29%

Lung & bronchus 14%

Colon & rectum 9%

Urinary bladder 6%

Melanoma of skin 5%

Non-Hodgkin lymphoma 4%

Kidney & renal pelvis 5%

Leukemia 3%

Oral cavity 3%

Pancreas 3%

All Other Sites 19% 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 20112. 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

– 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

CT group CXR group– (+) screen 24% 6.9%– False (+)/complication rate 96.4% / 1.4% 94.5% / 1.6%– Cases/100K person 645 572– Stage I/II at dx 70% 56.7%– Lung Ca deaths 247 309 (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 RumorIs 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

?

Heartworm!

Tissue is the ISSUE!

NSCLC TNM definitions - 2011Tumor Characteristics• 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) • 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 I7% stage II32% 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

• Adenocarcinoma (38%)– bronchioloalveolar

• F>M and non-smokers – acinar , papillary , solid with mucus

formation

• Small cell carcinoma (13%)

• Other variants (29%)– Large cell carcinoma (5%)– Spindle cell variant – Giant cell – Clear cell – Undifferentiated carcinoma – Other NOS

Keratinization and intercellular bridges c/w SCC

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

Adenocarcinoma

Genetics of NSCLC

• 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

Hecht S S JNCI J Natl Cancer Inst 1999;91:1194-1210

Required Molecular TestingEpidermal Growth Factor Receptor (EGFR)

• Del Exon 19 or point mutation in Exon 21 confer EGFR TKI sensitivity• 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 TestingEML4-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 IHCVast majority tend to be adenocarcinoma (some reports in SqCC)Tend to be younger, non-smokers/light smokersAssociated with response to Crizotinib

Kwak et al. N Engl J Med 2010;363:1693-703.

Lung Cancer Mutation Consortium: Incidence of single-driver mutations

Kris MG et al. Proc ASCO 2011;Abstract CRA7506.

NO MUTATIONDETECTED

KRAS22%

EGFR17%

EML4-ALK7%

DOUBLE MUTANTS 3%

BRAF 2%

PIK3CA

HER2

MET AMPMEK1NRAS

AKT1

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• Bone

• Liver

• Brain

Adrenal

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 syndromesSmall Cell Lung Cancer

• 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

• 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– 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

JBR-10, NEJM, 352;25, 2005IALT, NEJM 350;4, 2004 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-RTPhase 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-RTPhase III RTOG 9309 (INT 0139)

Surgery RT• Median OS 23.6 mo 22.2 mo

(p=NS)• 5-yr PFS 21% 11%

(p=0.008)• 5-yr OS 27% 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

Lancet. 2009 Aug 1;374(9687):379-86. Curran WJ, J Natl Cancer Inst. 2011 Oct 5;103(19):1452-60.

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– Pemetrexed – Docetaxel– Paclitaxel or Nab-paclitacel– Erlotinib– Vinorelbine