Early-stage (I-II) Non-small cell lung cancer Flashcards
Estimated annual # of new lung cancer cases diagnosed in the US and the # of deaths from lung cancers
2017 ACS estimates - 222,500 new cases and 155,870 deaths
What is the lifetime risk of developing lung cancer - in men and women? Any differences by race?
Men: 1 in 14; Women: 1 in 17
Black men have a 20% higher incidence of lung cancer than white men. Black women have a 10% lower incidence than white women
What is the 5 yr survival rate for lung cancer patients by stage?
Stage IA: 49% Stage IB: 45% Stage IIA: 30% Stage IIB: 31% Stage IIIA: 14% Stage IIIB: 5%
How many lobes are in the lung? How many segments are there per lobe?
There are 5 lobes in the lung (RUL, RML, RLLL, LUL, LLL)
The lingula is part of the LUL
There are 5 segments per lobe, except the RUL and RML have 3 and 2 segments respectively
What are the 9 N2 nodal stations?
Station 1: highest mediastinal Station 2: upper paratracheal Station 3: prevascular (3A) and retrotracheal/prevertebral (3P) Station 4: lower paratracheal Station 5: subaortic (AP window) Station 6: P-A Station 7: subcarinal Station 8: paraesophageal Station 9: pulmonary ligament
Where are the intrapulmonary and hilar nodes located?
Intrapulmonary nodes are along the secondary bronchi
The hilar nodes are along the mainstem bronchi
These are all considered N1 nodes
What are the 5 N1 nodal stations?
Station 10: hilar Station 11: interlobar Station 12: lobar Station 13: segmental Station 14: subsegmental
What are the 3 histologic subtypes of NSCLC in decreasing order of frequency?
Adenocarcinoma (>50%) > SCC (35%) > Large cell (15%)
In addition to tobacco smoke, what are 3 other environmental exposure risk factors for developing lung cancers?
Radon
Asbestos
Occupational exposure
What is the estimated RR for lung cancer in heavy smokers vs. nonsmokers?
Heavy smokers have a 20-fold excess of lung cancer
Also have a 2-3% per yr risk of tobacco induced 2nd primary cancer
What is the risk of lung cancer in former smokers compared to current smokers?
The risk of developing lung cancer in former smokers is around half that of current smokers
What is the risk of lung cancer from passive smoke exposure?
RR 1.24 for developing lung cancer from passive smoke exposure
What % of smokers develop lung cancer?
<20% of smokers actually develop lung cancer
What histology subtype of NSCLC is least associated with smoking?
Adenocarcinoma is least associated with smoking
Name 3 histologic variants of adenocarcinoma of the lung
Adenocarcinoma in situ (previously bronchoalveolar)
Acinar
Papillary
Discuss the natural history and treatment response of adenocarcinoma in situ (formerly bronchoalveolar) carcinoma
Not associated with smoking. Presents as solitary nodule or multifocally. Pneumonitic form can spread along alveoli without basement membrane invasion. These tumors have good response rates to TKIs
Name 2 variants of large cell cancer of the lung
Giant cell and clear cell
What is the most common stage at initial presentation?
Stage IV (30%)
What are the most common sites of distant metastases for lung cancer?
Bone, adrenals and brain
What are the paraneoplastic syndromes associated with lung cancers?
Hypercalcemia of malignancy - PTHrP SIADH - leads to hyponatremia Cushing - increased ACTH Lambert-Eaton syndrome Hypercoagulability (adenocarcinoma) Gynecomastia (large cell) Carcinoid (vasoactive intestinal peptide), diarrhea Hypertrophic osteoarthropathy (adenocarcinoma)
What is the cause of Lambert-Eaton syndrome? Clinically how do you distinguish L-E syndrome from myasthenia gravis?
Circulating antibodies against against presynaptic P/Q calcium channel. With repeat motion, patients with L-E have improved strength whereas MG patients fatigue with repitition
What histologic subtypes of lung cancer are associated with peripheral and central lesions?
Peripheral: adenocarcinoma, large cell
Central: squamous cell
With which histologic subtypes of lung cancer is Thyroid Transcription Factor-1 (TTF-1) staining associated?
Adenocarcinoma, nonmucinous bronchioalveolar carcinoma (adenocarcinoma in situ) and neuroendocrine tumors
TTF-1 is rare in squamous cell
In NSCLC what is the role of CXR or CT screening for high risk patients?
CXR is not recommended. The USPSTF recommends annual screening with LDCT in people between ages 55 and 80 with a greater than 30 pack-year smoking history in current smokers and those who quit <15 yrs ago
What RCT reported low dose CT screening for lung cancer?
The national lung cancer screening trial - prospective RCT comparing LDCT vs. annual CXR for 3 years
LDCT reduced RR of lung cancer death by 20%
To prevent 1 death: 320 high risk pts need to be screened
What factors define high risk group for lung cancer according to NCCN?
Age 55-74 and >30 pack-year smoking history and <15 years cessation OR age >50 and >20 pack-year history of smoking and additional risk factors that increase risk (COPD, cancer hx, FHx, ethnicity)
What is lead-time bias and how could it affect the results of a screening trial?
Lead time in diagnosis is the time between detecting the cancer from screening and when the diagnosis would have otherwise occurred due to symptoms or imaging studies. This can lead to an apparent increase in survival.
What is length-time bias and how could it affect the results of a screening trial?
Length-time bias occurs when a screening test detects cancers that take longer to become symptomatic due to the detection of slower growing or indolent cancers. This leads to an apparent increase in survival.
What is the single most clinically significant acquired genetic abnormality in NSCLC?
EGFR mutation in exon 19 and exon 21
Among patients with NSCLC, in what particular groups are the EGFR mutations common and for what do these mutations predict?
EGFR mutations only occur in ~10% but at high rates in nonsmokers, adenocarcinomas and Asians
These predict a high response rate >80% to TKIs (gefitinib, erlotinib, afatinib, osimertinib)
Is EGFR overexpression more common in SCC or adenocarcinoma?
EGFR may be overexpressed in 80-90% of SCCs vs. 30% of adenocarcinomas
What are common mechanisms associated with TKI resistance?
T790M is a point mutation that accounts for 60% of TKI resistence, usually devlop after 9-13 months of therapy
Other mechanisms: KRAS, ALK, ROS1, exon 20 insertion, small cell transformation, epithelial-mesenchymal transition phenotype
What is the initial workup for a patient suspected of having lung cancer?
H&P, focus on weight loss >5% over prior 3 months, KPS, tobacco history, neck exam for N3 disease, CBC, CMP, CT chest (include adrenals), PET/CT scan, MRI brain for presumed stage II-III, MRI for paraspinal/superior sulcus tumors, biopsy via bronch or FNA, mediastinoscopy, PFTs
What is the most cost effective first step in a patient presenting with a new lung lesion on CXR or CT?
Obtain prior imaging for comparison
What are the 3 most common presenting symptoms of NSCLC?
Dyspnea, cough, weight loss, chest pain, hemoptysis
What is the sensitivity and specificity of sputum cytology for diagnosis of lung cancer?
Sensitivity <70%, specificity >90%
Accuracy increases with more # of specimens, at least 3 are recommended
What is the sensitivity and specificity of FDG-PET compared to CT for staging of lung cancers?
PET: sensitivity 83%, specificity 91%
CT: sensitivity 64%, specificity 74%
What is the estimated % of patients who will have false + N2 nodes on PET/CT?
10-20%. N2 nodes by PET/CT need pathologic confirmation before deferring to potentially curative surgery
What is the estimated % of patients who will have false - N2 nodes based on PET/CT?
5-16%.
What is the rate of occult mets from lung cancer detected by FDG-PET?
6-18%
If a PET is being ordered, should a bone scan be ordered to evaluate for bone mets as well?
No. In NSCLC, PET is just as sensitive as a bone scan but more specific. However, consider pathologic confirmation of solitary PET+ lesions given the risk of false + results
What clinical characteristics are important to focus on to determine the nature of a solitary pulmonary nodule?
Nodule size (and whether there are changes in size in the past 2 years), history of smoking, age, and nodule margin on CT (spiculation?)
Stage for stage, does adenocarcinoma or SCC have a worse prognosis? Why?
Adenocarcinoma has worse prognosis as it has a greater propensity to metastasize, particularly to the brain
Does large cell carcinoma have a natural history and prognosis more similar to SCC or adenocarcinoma?
Large cell carcinoma has a natural history and prognosis more similar to adenocarcinoma
Describe the T-staging of NSCLC
T1: ≤3 cm, surrounded by lung parenchyma (T1a ≤1 cm; T1b 1.1–1.9 cm; T1c 2.0–2.9 cm)
T2: >3 but ≤5 cm, + visceral pleura, main bronchus (not carina), +atelectasis of lobe (T2a 3.1–3.9 cm; T2b 4.0–4.9 cm)
T3: >5 but ≤7 cm, tumor invading invasion to CW, pericardium, phrenic nerve or separate tumor nodule in same lobe
T4: >7 cm any size, invading mediastinum, diaphragm, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, or with separate tumor nodules in a different ipsi lung lobe
Describe the N staging of NSCLC
N1: ipsi hilar or pulmonary nodes
N2: ipsi mediastinal or subcarinal nodes
N3: any SCV/scalene nodes or contralat mediastinal/hilar nodes
How are malignant pleural/pericardial nodules/effusion or opposite lung tumor nodules noted in the newest TNM staging?
M1a includes malignant pleural/pericardial nodules/effusion and opposite lung tumor nodules
According to AJCC 8th ed, is a single brain met staged the same as brain mets and bone mets. What about 2 brain mets?
A single extrathoracic met is M1b
Multiple extrathoracic mets (1 organ or >1 organ) is M1c
What is the nodal subclassification in AJCC 8th edition?
N1: N1a-Single station N1 involvement, N1b-Multiple station N1 involvement; N2a1-single station N2 without N1 involvement (skip), N2a2-single station N2 with N1 involvement, N2b-multiple station N2 involvement; N3-N3 LN involvement
What is considered early stage NSCLC?
Stages I and II
What procedures prior to thoracotomy can be used to evaluate the level 1 L and R stations, 2, 4 and 7. What aboust stations 5 and 6?
Mediastinoscopy or EBUS can evaluate L/R 2, 3 and 7
VATS or anterior mediastinotomy can evaluate stations 5-6
When should pre-treatment mediastinal nodal assessment be done?
To confirm PET or CT + nodes
All suspicous sulcus tumors
If T3 or central T1-2 lesions
What PFT results indicate that patient needs further testing prior to undergoing resection?
FEV1 < 80% predicted or DLCO < 80% predicted
What is the minimum absolute FEV1 necessary for pneumonectomy and lobectomy
Pneumonectomy >2L
Lobectomy: Postop >1.0L
Which subset of lung cancer patients are at high risk for surgical morbidity?
pCO2 > 45, pO2 <50, Preop FEV1 <40%, poor exercise tolerance, DLCO <40% (desired > 60%), postop FEV1 < 0.71 or <30% predicted value, cardiac problems, obesity
What are some factors that predict postop complications?
Active smoking, poor nutrition, advanced age, poor lung function
What % of patients clinically at stage I are upstaged at surgery?
5-25% of stage I lung cancer patients are upstaged at surgery
In addition to stage, name 3 poor prognostic factors in lung cancer patients?
KPS < 80%, weight loss >5% in 3 months (10% in 6 months), age > 60y
What is the treatment paradigm for stage I-II medically operable NSCLC?
Surgical resection (lobectomy) + mediastinal LND followed by adjuvant chemo (unless stage IA w/ negative margins)
What should be the first step for a stage I-II medically operable NSCLC patient with a positive margin resection
Re-resection if possible, +/- chemothearpy depending on other factors
If re-resection is not possible, what RT dose is used for a +margin after surgery?
Microscopic +margin: 54-60Gy
Gross +margin: 60-70 Gy
What is the treatment paradigm for stage I-II medically inoperable NSCLC?
Stages I-II medically inoperable NSCLC Tx paradigm: if T1-2N0, consider definitive hypofractionated SBRT or SABR. If T1-T2N1 or T3N0 use definitive CRT
Name 3 surgical options to resect a T1-T2 tumor
Surgical options to resect a T1-T2 tumor:
wedge or segmental resection
lobectomy
pneumonectomy
For a T1N0 NSCLC, what is the estimated LC for wedge/segmental resection vs. lobectomy?
Wedge/segmental LC is 82% vs. lobectomy LC is 94% based on RCT LCSG 821. Lobectomy is preferred when feasible.
*CALGB 140503 is ongoing phase III trial of lobectomy vs. sublobar resection for <2cm peripheral NSCLC
What % of stage I NSCLC patients will develop a 2nd primary after definitive surgical resection?
Up to 30% will develop a 2nd primary
What is the estimated 5 yr OS of completely resected T1-2N0 NSCLC with no adjuvant chemo?
T1N0 ~80%
T2N0 ~68%
What is the 5yr OS, CSS and MS for patients who refuse any treatment for T1-2N0 NSCLC?
5yr OS 6%, CSS 22%, MS is 13 months
Tumor size is a prognostic factor independent of T stage
What are the indications for adjuvant chemo after definitive resection for stages I-II NSCLC?
High risk stages IB-IIB
N1 disease
T2N0, if tumor > 4cm
Also consider: poorly differentiated, LVSI, wedge resection, visceral pleural involvement, incomplete nodal sampling
Whats the estimated 5 yr OS benefit with adjuvant chemo for patients with completely resected stage I or II NSCLC?
~5% at 5 yrs for adjuvant cisplatin based regimens based on LACE meta-analysis
What are possible chemo regimens for adjuvant/neoadjuvant treatment of NSCLC per NCCN?
Cisplatin/vinorelbine Cisplatin/etoposide Cisplatin/gemcitabine Cisplatin/docetaxel Cisplatin/pemetrexed
Is there a role for preop chemotherapy in early stage lung cancer patients?
No. Meta-analysis did not show survival difference between pre and postop chemo.
Trials: MRC LU22/EORTC 08012, The CHEST Trial, NATCH Spanish Trial
Is there a benefit of full mediastinal dissection vs. nodal sampling in early stage patients undergoing surgical resection?
Possibly. Pooled analysis of 3 trials demonstrated a 4yr OS benefit of mediastinal dissection in stages I-IIIA NSCLC (HR 0.78)
What are the indications for PORT after definitive resection for stages I-II NSCLC?
+Margins, +ECE, unexpected N2 disease
NCCN: Concurrent CRT for R2+ margin, sequential chemo followed by RT for R1+ margin
Which randomized study demonstrated improved LC and survival with PORT after surgical resection for early stage (IA and IB) NSCLC?
Italian study: 104 stage I patients resected with N0, randomized to PORT vs. observation PORT: bronchial stump + ipsilateral hilum, 50.4 Gy LF rates (2% vs. 23%), trend to improved 5yr OS (67% vs. 58%)
What is the maximum RT dose that has been used for definitive RT alone in stage I-II NSCLC?
Up to 84 Gy in standard fractionation if lung dose-volume constraints are respected.
RTOG dose escalation study found 90.3 Gy was too toxic
What is the 2 year LR rate for RT alone using standard fractionation?
50-78% 2 yr LR based on RTOG 9311 (although this includes stage III pts)
In stages I-II patients treated with definitive RT alone, should elective nodal regions be treated? What is the estimated elective nodal failure rate if untreated?
No. Elective nodal failure rate < 10% in RTOG 9311.
In hypofrac/SBRT trials, nodal failure rate 5-10%
What are the estimated 3-5yr LC and OS for medically inoperable stage I patients treated with definitive SBRT?
3 yr LC 85-95%
3 yr OS 55-91%
How does SBRT compare to lobectomy for operable stage I NSCLC?
Pooled analysis of STARS and ROSEL trials, 3yr OS was 95% with SBRT and 79% for surgery
Still controversial, ongoing RCTs
SEER and NCDB analysis have conflicting results
What BED should be achieved to attain maximum LC and survival in patients with stage I lung cancer treated with SBRT?
Japanese data suggset BED > 100 Gy results in 5 yr LC rate 92% and 5 yr OS 71%
BED < 100 Gy results in 5 yr LC 57% and OS 30%
What is the estimated 5 yr rate of nodal failure, LF, and DM in early stage NSCLC after definitive SBRT?
LRR (nodal) tends to be higher in SBRT patients and increased with time - 5yr LR 7% (RTOG 0236), involved lobar recurrence 20% and regional recurrence 38%
Distant recurrence was 31%
What is the SBRT technique evaluated in RTOG 0236? What is the 2 yr LC and OS rate for this group of inoperable patients?
SBRT 20Gy x 3 fractions (18Gy x 3 fractions with heterogeneity correction)
3yr primary tumor control 97.6%, but 3yr primary tumor and involved lobe control 90.6%, DFS 48.3% and OS 55.8%
How should the SBRT dose be modified for centrally located tumors?
Lesions located centrally (w/in 2 cm of bronchial tree) are not good candidates for 20Gy/3 fraction due to risk for grade 3-5 toxicities. Studies have shown 12.5Gy x 4 fx (MDACC) and 10-11Gy x 5 fx (RTOG 0813) to be safe for centrally located lesions
MDACC also looked at 70Gy in 10 fx
What CTV and PTV margins are used for SBRT?
PTV = ITV + 5mm (MDACC) w/ 4D CT scan (MDACC)
PTV = GTV + 5mm (axial) + 1cm (long) w/o 4D CT scan (RTOG 0915)
What studies have attempted to address the role of SBRT in both operable early stage lung cancer patients?
- RTOG 0618: phase II, 33 pts w/ stage I-II NSCLC 18Gy x 3 fx
- ROSEL (dutch): phase III, stage I NSCLC 20Gy x 3 (T1), 12Gy x 5 (T2), 7.5Gy x 8 (central) vs. surgery
- STARS (Accuracy/MDACC): phase III cyberknife vs. surgery. 12.5Gy x 4 (central), 16.7 Gy x 3 (peripheral)
- JCOG 0403: phase II, 48Gy in 4 fx
What studies have attempted to address the role of SBRT in both inoperable early stage lung cancer patients?
- TROG 09.02: phase III, T1/T2aN0, 54 Gy in 3 fx vs. conventional 60-66Gy/30-33fx
- RTOG 0915: phase II, T1/T2 NSCLC, peripheral tumors, 34Gy single fraction vs. 12Gy in 4 fractions
- SPACE (scandinavian): phase II 3D CRT 70 Gy in 35 fx vs. SBRT 45 Gy in 3 fx
- RTOG 0813: phase I/II dose escalated SBRT for centrally located tumors
What are the toxicities seen with SBRT for early stage lung cancer?
Pneumonitis, lung fibrosis/consolidation, cough, dermatitis, chest wall pain, esophagitis and hemoptysis
What is the total lung V20 dose-volume constraint for RT alone?
The total lung V20 is <35% (NCCN 2018)
What is the MLD constraint for definitive RT to lung cancer?
MLD < 20Gy (NCCN 2018)
What is the distinction between grade 2 and grade 3 RTOG pneumonitis?
Grade 2: symptomatic, need for steroids
Grade 3: dyspnea at rest and O2 supplementation needed
What are the heart dose-volume constraints for conventionally fractionated RT?
Heart V40<80%, V45 < 60%, V60 < 30%
Mean < 35 Gy
What is the dose constraint for the brachial plexus with conventional fractionation?
Max dose <= 66Gy
What is the rate of brachial plexopathy seen for patients treated with SBRT for early stage lung cancer?
Max dose < 26 Gy in 3-4 fractions
Dose > 26 Gy –> 46% risk of plexopathy vs. 8% if <26 Gy
At a minimum what other (beyond lung,heart, brachial plexus) normal tissue constraints should be considered?
Esophagus, trachea, main bronchus, bronchial tree, major vessels, skin, chest wall
What is the esophageal dose constraint for conventionally fractionated RT?
Mean dose < 34 Gy, max < 105% of prescription dose
What is the max BED for SBRT resulting in significant complications when centrally located tumors were treated?
180-210 Gy with grade 3 pulmonary complications
BED > 100 may be sufficient for LC and may avert toxicities for central lesions
Is a normal SUVmax of FDG-PET required to be considered a good clinical response in f/u scans after SBRT?
No. SUVmax remains elevated for extended period after SBRT d/t an inflammatory response but there is no evidence of correlation with recurrence
What % of patients treated with SBRT for early stage lung cancer have grade 3-5 toxicities?
15% of patients have grade 3-5 toxicities based on a review of 15 studies (683 pts)
In RTOG 0236, 16% of patients had grade 3-4 toxicity, no grade 5 toxicities
What factors predict grade 3-5 toxicities after SBRT for early lung cancer seen on the IU phase II study?
Location (46% hilar/pericentral, 17% peripheral) and tumor size (GTV > 10cc 8x risk for G3-5 toxicity)
What are the PFT changes before and after SBRT for early stage NSCLC?
Minmal based on institutional review of 92 patients
FEV1 -0.05
DLCO -2.59%
No association with location (central vs. peripheral) or dose administered
