Advanced-stage (III-IV) Non-small cell lung cancer

Question 1

What is the most common hallmark of locally advanced NSCLC?

Answer 1

Mediastinal or supraclavicular nodal involvement

Question 2

What % of patients present with stage IIIA non-small cell lung cancer?

Answer 2

~30% of all NSCLC patients have stage IIIA disease at presentation

Question 3

What % of patients will have occult N2 NSCLC at the time of surgery?

Answer 3

25% of patients will have occult N2 disease found at surgery

Question 4

After definitive treatment of a primary lung tumor, what is the time period after which it is considered a second primary?

Answer 4

A tumor that develops >2y after definitive treatment of primary lung cancer is likely a second primary. A recurrence with identical histology identified <2y from definitive treatment is considered a metastasis

Question 5

What percentage of patients with locally advanced NSCLC develop brain metastases as a 1st site of relapse?

Answer 5

15-30% of NSCLC develop brain mets as a site of 1st relapse

Question 6

What is Pancoast syndrome?

Answer 6

Apical tumors (aka superior sulcus tumors) invading the thoracic inlet causing compression of sympathetic ganglion, brachial plexus, recurrent laryngeal nerve and vasculature causing shoulder/arm pain, Horner syndrome, parasthesias, hoarseness, and SVC syndrome

Question 7

What is Horner’s syndrome?

Answer 7

The result of tumor compression on the sympathetic ganglion resulting in a triad of symptoms: ipsilateral miosis, ptosis and anhidrosis

Question 8

How prevalent are superior sulcus tumors?

Answer 8

Rare, around 3% of NSCLC

Question 9

What are the types of M+ disease in AJCC 8th edition?

Answer 9

M1a = separate tumor nodules in a contralateral lobe; tumor with pleural or pericardial nodules or malignant pleural or pericardial effusion
M1b = single extrathoracic metastasis
M1c = multiple extrathoracic mets in 1 or more organs

Question 10

What is the TNM staging (8th edition) that defines advanced NSCLC?

Answer 10

Stage IIIA: T3N1, T1–T3N2, T4N0–1
Stage IIIB: T1–T2N3, T4N2
Stage IIIC: T3–T4N3
Stage IVA: TXNXM1a/b
Stage IVB: TXNXM1c

Question 11

What is the mean survival for patients presenting with a malignant pleural effusion?

Answer 11

3-9 months - M1a disease

Question 12

What are the survival outcomes for stage IIIA disease with T3N1 vs. TXN2?

Answer 12

Stage IIIA is a heterogenous group, T3N1 have 5yr survival 25-30% whereas TXN2 have 5yr survival 15-20%

Question 13

What is the utility of PET/CT to determine the resectability of the lung cancer patients?

Answer 13

PET/CT may improve staging to spare patients from futile thoracotomies

Question 14

What are the treatment options for patients with cN2, stage IIIA disease?

Answer 14

Induction chemo –> surgery +/- PORT (Roth 1994)
Neoadjuvant CRT –> lobectomy (Albain 2009)
Definitive CRT (RTOG 9410)

Question 15

What are the treatment options for patients with cN3, stage IIIB disease?

Answer 15

Definitive CRT is the only treatment option for cN3, stage IIIB disease

Question 16

Which trials have demonstrated a survival benefit with adding induction chemo to surgery for stages IIIA-B NSCLC patients?

Answer 16

MDACC (Roth 1994) - improved MS (21mo vs. 14mo)
Madrid (Rosell 1994) - improved MS (22mo vs. 10mo)
Spanish lung cancer group trial 9901 - MS 16mo

Question 17

Did any trial fail to demonstrate a benefit for induction chemo prior to surgery?

Answer 17

JCOG 9209 - no difference in MS (16-17mo) or 5yr OS between patients getting +/- neoadj chemo followed by surgery

Question 18

Are there data to demonstrate the need for adding PORT to adjuvant chemotherapy in patients with completely resected stage IIIA N2 NSCLC?

Answer 18

Not at this point
CALGB 9734 tried but was closed due to poor accrual. There was no difference in DFS or OS however some evidence suggests that patients with N2 disease should be evaluated for chemo + PORT

Question 19

What is the evidence for PORT? What subset of patients may benefit from PORT?

Answer 19

In subset analysis from RCTs and meta-analysis, patients with N2 disease may benefit from PORT. There are ongoing phase III trials testing the role of PORT in pN2 patients

Question 20

Do patients who have a complete pathologic nodal response after induction chemo + surgery still need PORT?

Answer 20

Possibly. Still have a high LRR (retrospective data)

Any pN2 patient regardless of chemo response may still benefit from PORT

Question 21

Is there an advantage of postop CRT vs. PORT alone for stage III N2 NSCLC?

Answer 21

No. INT-0115/RTOG 9105/ECOG tested PORT vs. CRT in resected stage II-III NSCLC and found no difference in OS (3.2 yr) or LC

Question 22

What are the anatomic areas targeted with PORT when given for unexpected N2 NSCLC? What is the recommended dose?

Answer 22

Per ongoing European LungART trial, the bronchial stump, ipsilateral hilum and extension to mediastinal pleura facing resected tumor bed should be included. Standard doses after complete resection are 50-54 Gy but boost to positive margins or extracapsular extension (60-70Gy) are appropriate.

Question 23

What should be the rate of treatment related deaths following PORT for NSCLC?

Answer 23

20-30% based on old data/old techniques - due to pulmonary or CV excess deaths
Newer data much lower, 2-3%

Question 24

Is preop chemo alone adequate as an induction regimen in stages IIIA-B lung cancer patients or is perop CRT better?

Answer 24

2 trials have tried to answer this:
RTOG 0412/SWOG 0332 - closed due to poor accrual
German Lung cancer coop group trial: used BID RT, greater pCR rate with RT but no difference in PFS or survival

Question 25

If CRT is given for stage IIIA NSCLC, is there a benefit of adding surgery afterward?

Answer 25

For all comers, possible LC benefit but no survival benefit INT-0139 (Albain 2009) - RCT induction CRT (45Gy) + Sg vs. definitive CRT (61Gy) alone - improved LR in surgery arm but no difference in DM or OS. Subset analysis w/ OS benefit in patients receiving lobectomy (rather than pneumonectomy) ESPATUE trial: randomized resectable patients after induction chemo to surgery vs. completing CRT to 65-71Gy - closed early but did not show any difference in OS or PFS

Question 26

What is the RT dose for neoadjuvant CRT if consolidative surgery is planned?

Answer 26

45 Gy. >50Gy has been shown to increase risk for complications - bronchopleural fistula, prolonged air leak with empyema, prolonged postop ventilation

Question 27

After an objective response to induction chemo for a patient with stage IIIA disease, is adding postinduction surgical resection more beneficial than sequential radiotherapy?

Answer 27

No. Resection is not more beneficial than radiotherapy. EORTC 08941 - RCT for stage IIIA, N2 NSCLC after induction chemo randomized to RT 60Gy/30fx vs. surgery. Poor compliance with either arm although 4% 30 day mortality. No difference in OS or PFS. CRT should be standard of care

Question 28

Does including surgical resection in therapy for stages IIIA-B lung cancers in general improve outcomes?

Answer 28

No clear benefit to adding surgery to CRT for locally advanced NSCLC. INT-0139 and EORTC 08941 failed to find superior outcomes with surgery over definitive RT in stage III disease. Definitive CRT preferred to trimodality therapy in most patients

Question 29

Is there a subset of stage IIIA NSCLC that is likely to benefit from trimodality therapy?

Answer 29

Pts with minimal, nonbulky N2 disease who can get a lobectomy are the best candidates based on the INT-0139 subgroup analysis

Question 30

What RCT established the minimum dose of 60 Gy for definitive RT for stage III NSCLC?

Answer 30

``` RTOG 7301 (Perez, 1980) - dose escalation trial with RT alone, 40Gy, 50Gy and 60Gy all 2 Gy/fx - LC improved with 60Gy ```

Question 31

Is there a benefit of altered fractionation of definitive RT for stage III NSCLC?

Answer 31

Yes. Severeal phase II-III trials have shown benefit RTOG 8311 - randomized phase I/II trial - 1.2Gy BID, pts receiving >69.6 Gy had better 3yr OS CHART - phase III RCT 54Gy TID x 12 days vs. 60Gy for 6 weeks, 10% improved 3yr absolute survival; c/b severe eophagitis (19%)

Question 32

What are 2 seminal studies demonstrating the importance of adding chemo to radiotherapy compared to radiotherapy alone?

Answer 32

CALGB 8433: "Dillman regimen" - improved MS from 10 to 14m with chemo --> RT compared to RT alone RTOG 88-08: RCT, 3 arms: 60 Gy/30 fx vs. 69.6Gy in 1.2 Gy BID fx vs. sequential chemo --> 60Gy/30 fx - Improved MS in sequential chemoRT arm

Question 33

Which 2 randomized studies demonstrated the superiority of concurrent chemoRT over sequential chemoRT for unresectable or medically inoperable stages II-III NSCLC?

Answer 33

West Japan Lung Cancer Study Group: stages II-III patients randomized to sequential vs. concurrent; better OS and PFS in concurrent group (MS 16.5 vs. 13.3m, 5yr OS 15.8 vs. 8.9%) RTOG 9410: 3 arm RCT - sequential vs. concurrent CRT (63Gy) vs. concurrent hyperfractionated RT (1.2 BID 69.6Gy) + chemo; Definitive concurrent CRT had better MS (17 vs 14mo) and 5yr OS (16% vs. 10% vs. 13%) *Increased toxicity in concurrent arm

Question 34

Which chemo regimen allows a full dose and which would need to be dose reduced during a course of concurrent chemoradiotherapy?

Answer 34

Cisplatin/etoposide and cisplatin/vinblastine allow a full dose to be administered with RT. Carboplatin/paclitaxel, gemcitabine, or vinorelbine require significant dose reduciton during RT administration

Question 35

Is there a benefit to adding induction chemo to CRT for patients with unresectable stages IIIA-B NSCLC?

Answer 35

No. 2 prostpective studies - LAMP and CALGB 39801 demonstrated no benefit to neoadjuvant chemo. Definitive CRT alone is the standard of care.

Question 36

What is the role for consolidation chemotherapy after definitive CRT?

Answer 36

Uncertain. SWOG 9504 phase II supported consolidation docetaxel but phase III trial showed no benefit and increased toxicities/treatment related deaths

Question 37

What are the different chemo regimens used with concurrent CRT for locally advanced NSCLC? Are there differences in clinical outcomes for these regimens?

Answer 37

Low dose weekly carboplatin and paclitaxel --> high dose consolidation carboplatin/paclitaxel Cisplatin and etoposide --> consolidation platinum doublet chemotherapy Cisplatin and pemetrexed --> consolidation pemetrexed No difference between regimens

Question 38

Is there a role for elective nodal irradiation for treatment of inoperable, locally advanced NSCLC?

Answer 38

No. CRT recommended only to involved areas (imaging or pathology) to optimize dose escalation and improve toxicity. MSKCC retrospective data - in patients treated involved field only, elective nodal failure rates at 2yr 7.6% Prospective phase III data showed better overall response and improved 5 yr local control without ENI (51% vs. 36%)

Question 39

Is there a benefit of dose escalation in locally advanced NSCLC?

Answer 39

No. No evidence that dose > 60 Gy with concurrent chemo is beneficial based on results of RTOG 0617 Prior studies: RTOG 7301 made 60 Gy standard of care; RTOG 9311 (w/o chemo) 70.9 - 90.3 Gy; Michigan study: correlated RT dose with survival

Question 40

What is the design of RTOG 0617?

Answer 40

RCT phase III comparison for stages IIIA-B NSCLC treated with CRT with 2 randomizations: 60Gy vs. 74 Gy and carboplatin/paclitaxel +/- cetuximab

Question 41

What was the outcome of the dose escalation portion of RTOG 0617?

Answer 41

Closed early at interim analysis. Patients receiving 74 Gy had worse grade 5 toxicity and grade 3 esophagitis, higher rates of LFs, and worse OS.

Question 42

What are some possible explanations for the counterintuitive findings in the higher dose arm of RTOG 0617?

Answer 42

Too tight margins in high dose arm lead to higher LFs, worse survival Unmeasured or underreported toxicities, more treatment deaths, worse survival Extended duration of therapy, worse LC, worse survival

Question 43

Was there a benefit of adding cetuximab to CRT in RTOG 0617?

Answer 43

No. There was no survival benefit except for worse toxicities in the cetuximab arm.

Question 44

What is the benefit of IMRT over 3D-CRT in RTOG 0617?

Answer 44

Secondary analysis demonstrated 60% decrease in grade 3 RT pneumonitis (3.5% vs. 7.9%) with similar survival and control. Also showed lower heart dose and QOL benefit in IMRT group compared to 3D-CRT group.

Question 45

What consolidation therapy is recommended after CRT for stage III NSCLC?

Answer 45

Immune checkpoint blockade with 1 year of Durvalumab based on PACIFIC trial : improved median PFS by 11 months for all patients regardless of PDL1 status

Question 46

What should be done in NSCLC patients with incidental N2 disease found at the time of surgery?

Answer 46

Surgical resection should proceed with lung resection + mediastinal LND. Follow with adjuvant chemo and consideration of PORT.

Question 47

For patients who receive upfront surgery, what is the role of platinum based chemotherapy?

Answer 47

It should be given for N+ disease, or primary tumors > 4cm in patients with T2N0 (stage IB) tumors LACE meta-analysis for 5 adj showed 5yr survival benefit of 5% CALGB 9633 subset analysis showed survival benefit for IB pts with tumor sizes > 4cm

Question 48

What is considered bulky, unresectable disease in NSCLC?

Answer 48

Histologically involved LN > 3cm on CT, +Extranodal involvement, multistation nodal disease

Question 49

What is preferred treatment strategy for patients with stage IIIB T4N0 disease?

Answer 49

Neoadjuvant chemo or CRT or definitive CRT. 5yr OS may approach 25-30%. R0 resection should be attempted if technically feasible

Question 50

What is the 5 year OS of patients with satellite nodules in teh same lobe?

Answer 50

5 yr OS in 33% if patients undergo lobectomy. Carefal nodal assessment to exclude N2 disease must be done

Question 51

What are the treatment paradigms and survival outcomes for resectable T3-4N0-1 superior sulcus tumors?

Answer 51

1) preop CRT --> surgery -- > chemo (SWOG 9416/INT-0160) | 2) upfront surgery --> chemoRT (60 Gy if neg margin, 64.8 Gy if pos margin) (MDACC phase II study, Gomez)

Question 52

What trial established the role of induction CRT for superior sulcus NSCLC? What is the induction regimen and primary outcome of this study?

Answer 52

SWOG 9416/INT-0160: single arm phase II trial CRT + surgery for T3-4, N0-1, superior sulcus tumors induction regimen: cisplatin, etoposide with RT to 45 Gy

Question 53

What are appropriate treatment volumes, dose, and field arrangement for a superior sulcus tumor?

Answer 53

GTV defined by PET + 2cm and ipsilateral SCV region. AP/PA to 41.4 Gy , then off-cord to 45 Gy. Cord should not exceed 110% of the Rx dose

Question 54

Are all patients with stage IIIB NSCLC unresectable?

Answer 54

No. Patients with T4 dz with invasion of vertebral bodies and multiple nodules in different ipsilateral lung lobes are still resectable

Question 55

What are the treatment options for patients with malignant pleural effusion?

Answer 55

Treat as stage 4: thoracentesis, chest tube/drainage, sclerotherapy with talc or bleomycin or placement of chronic indwelling catheter. Depending on PS, chemo can be considered

Question 56

What should be done for patients with 2 synchronous nodules of NSCLC (in different lobes)?

Answer 56

If identical histology, consider M1. If a different histology or genetic signature, can be considered synchronous stage I NSCLC and definitive surgery or SBRT can be considered

Question 57

Is there evidence for local consolidative therapy in patients with stage IV disease when there is no progression to initial systemic therapy?

Answer 57

Yes. 2 Randomized trial showed benefit of local consolidative therapy after induction systemic therapy is stage IV NSCLC with limited metastatic disease - Gomez 2016: improved PFS 11.9m vs 3.9m - UTSW 2017: improved PFS 9.7m vs. 3.5m

Question 58

How should patients with newly diagnosed NSCLC with a solitary brain lesion be managed?

Answer 58

Surgical resection should be considered especially if symptomatic or to exclude possible primary brain tumor. Then either SRS or WBRT. Otherwise SRS +/- WBRT should be used (per NCCN). Primary lung tumor should be managed according to T/N stage.

Question 59

What is the 5yr OS for NSCLC patients with solitary brain mets?

Answer 59

20-40% as a group

Question 60

Is there a role for PCI after treatment for locally advanced NSCLC?

Answer 60

No. 4 older randomized trials showed improvement in brain relapse but no survival benefit to adding PCI. RTOG 0214 is modern phase III RCT that failed to show improvement in 1 yr OS or PFS

Question 61

What molecular testing should be done in patients who present with metastatic NSCLC?

Answer 61

For adenocarcinoma/large cell/ NSCLC NOS: EGFR, ALK, ROS1, PDL-1 For SCC: EGFR, ALK

Question 62

What types of patients are EGFR and KRAS mutations common in? What % of patients have overlapping EGFR and KRAS mutations?

Answer 62

EGFR mutations are more common in Asian pts (prevalent in ∼10% of Western and ∼50% of Asian pts), in nonsmokers, females, and nonmucinous adenocarinoma. KRAS mutations are more common in non-Asians, smokers,and mucinous adenocarcinoma. These 2 mutations are nearly mutually exclusive, since <1% of pts have overlapping EGFR/KRAS mutations.

Question 63

How do EGFR and KRAS mutations predict for response to targeted therapy?

Answer 63

EGFR mutations predict for response to EGFR TKIs. However, pts with KRAS mutations have primary resistance to EGFR TKIs.

Question 64

What type of patients are ALK rearrangements common in, and what is its prevalence? What treatment does it predict response for?

Answer 64

ALK gene rearrangements are common in the same type of pts (adeno, nonsmokers) that are likely to have EGFR mutations, but they are usually mutually exclusive. They are present in ∼2%–7% of pts with NSCLC. ALK gene rearrangements predict for sensitivity to crizotinib and alectinib.

Question 65

Should pts with stage IV Dz rcv chemo or targeted therapy first?

Answer 65

Chemo should be given only if pts have negative or unknown ALK or ROS1 rearrangements, sensitizing EGFR mutation, or PD-L1 expression status. Common 1st-line chemo regimens in the United States include cisplatin or carboplatin and pemetrexed, carboplatin and paclitaxel (+/– bevacizumab), and gemcitabine/cisplatin

Question 66

How are chemo regimen efficacy and NSCLC histology types associated?

Answer 66

Cisplatin/pemetrexed has sup efficacy and decreased toxicity in non-SCC histology pts; cisplatin/gemcitabine has increased efficacy in SCC histology pts.

Question 67

For metastatic Dz pts who are found to be positive for sensitizing EGFR mutation, ALK/ROS1 rearrangement, or ≥50% PD-L1, what should their 1st-line systemic therapy be?

Answer 67

EGFR mutation --> osimertinib (#1), erlotinib, afatinib, gefitinib ALK/ROS1 rearrangement --> alectinib (#1), crizotinib PDL1>50% --> pembrolizumab

Question 68

What is the FDA-approved therapy for T790M positive advanced NSCLC who have progressed on prior EGFR TKI?

Answer 68

Osimertinib is the oral TKI that specifically inhibits EGFR receptors with T790M mutation. It is recommended as 2nd-line and beyond therapy for pts with EGFR T790M who have progressed on prior oral TKIs. Based on phase III trials which showed superiority in OS, PFS and toxicities compared to standard platinum-based chemo, it is also recommended as 1st-line therapy for T790M positive NSCLC (Mok TS et al., NEJM 2017). Based on the FLAURA phase III trial, it also has greater efficacy as 1st-line therapy compared to erlotinib or gefitinib in EGFR mutant NSCLC in general, with reduced CNS relapse and less toxicity. (Soria JC et al., NEJM 2018)

Question 69

What is the role of endobronchial/intraluminal brachytherapy for palliation for lung cancer?

Answer 69

Various fractionation schemes (15 Gy × 2 or 8–10 Gy × 1, prescribed to 0.5 cm) have been used in prior irradiated pts with endobronchial Dz causing Sx. Sx relief can be seen in 80% of pts. Complications included fatal hemoptysis (5%–10%), bronchoesophageal fistula (2%), and bronchial edema (1%). MDACC published a series of 81 previously irradiated lung cancer pts who were treated with palliative HDR endobronchial brachytherapy, 15 Gy × 2, 6-mm depth, over 2 wks. Response was seen in 84%. Pts with excellent response had better survival (MS 13.3 mos) vs. those with poor response (MS 5.4 mos) (p = 0.01). 2 fatal complications were d/t fistula and tracheomalacia. (Delclos ME et al., Radiology 1996)

Question 70

What fractionation scheme is optimal for pts with lung cancers treated with palliative RT for Sx such as hemoptysis, cough, pain, and shortness of breath?

Answer 70

Conventional fractionation is probably no better than hypofractionation. In a Norwegian RCT, Sundstrom S et al. tested 30 Gy in 10 fx vs. 17 Gy in 2 fx (1 wk apart) vs. 10 Gy in 1 fx. All achieved equivalent palliation

Question 71

What is the typical f/u schedule of pts treated for lung cancer?

Answer 71

Typical lung cancer f/u: Stage I/II treated w/ Sg: H&P, CT chest with contrast q6mos yrs 1–3, then low-dose noncontrast CT chest annually yrs 3–5. Stage III or treated with RT: CT chest with contrast q3–6 mos for yrs 1–3, then q6 mos for yrs 4–5, then low-dose noncontrast CT chest annually. Continued smoking cessation counseling for all.

Question 72

What are the expected acute and late toxicities of RT for lung cancer?

Answer 72

Acute: Skin reaction, fatigue, dysphagia, odynophagia, cough Subacute and late: RT pneumonitis, lung fibrosis, brachial plexopathy, Lhermitte syndrome, RT myelitis, esophageal fibrosis/stricture, pericarditis, 2nd cancers

Question 73

What are the signs and Sx of RT pneumonitis, and how is it managed?

Answer 73

RT pneumonitis is a subacute reaction that begins as early as 3–6 mos after RT. Typically, Sx include chest pain, shortness of breath, fever, and hypoxia. CT scan shows ground glass changes within the RT port. Check oxygenation and supplement if necessary. If symptomatic, treat with prednisone 1 mg/kg/day for at least 3 wks with a very slow taper. Bactrim can be used for PCP prophylaxis.

Question 74

What is the total lung V20 dose-volume constraint for RT alone and concurrent CRT in definitive lung cancer Tx?

Answer 74

NCCN: V20 <37% MDACC: RT alone → V20: <40%; CRT → V20: <35%

Question 75

What is the mean lung dose (MLD) constraint for definitive RT to lung cancer?

Answer 75

MLD ≤20 Gy.

Question 76

What is the heart RT dose-volume constraint?

Answer 76

1. NCCN 2018: V40 ≤80%, V45 ≤60%, V60 ≤30%; Mean ≤35 Gy 2. MDACC: RT alone → V40: <50%; CRT → V40: <40% Lower dose exposure may also be important: RTOG 0617 also found that increased heart V5 and V30 were associated with inf OS on MVA.

Question 77

What is the dose constraint for the brachial plexus?

Answer 77

The dose constraint is 1 cc below 60 Gy; the max dose point should be <66 Gy. 2 retrospective studies showed that the dose could be higher. (MDACC, Amini A et al., IJROBP 2012; median dose >69 Gy, max dose >75 Gy to 2cc; and UPenn, Eblan MJ et al., IJROBP 2013: V76 <1 cc)

Question 78

What is the max esophageal dose?

Answer 78

Ideally, MLD <34 Gy. Try to minimize the V60 as much as possible (V60 <33%, V50 <50%, ≤45 Gy to the entire esophagus, max dose point <70 Gy).

Question 79

What is the expected grade 3–4 esophagitis rate in pts treated with sequential CRT vs. concurrent CRT in locally advanced NSCLC?

Answer 79

Sequential: ∼4%. Concurrent: ∼22%

Question 80

What are the strategies for delivering external RT to lung tumors if dose constraints cannot be met (there are 6)?

Answer 80

1. Induction chemo for debulking 2. Breath-hold 3. IGRT (e.g., daily CBCT to decrease PTV margins) 4. Adaptive planning during Tx 5. Alternative modalities (i.e., protons) 6. Sequential chemo → accelerated hypofractionated RT (45 Gy in 15 fx)