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Radiation Oncology Residency > Advanced-stage (III-IV) Non-small cell lung cancer > Flashcards

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

1
Q

What is the most common hallmark of locally advanced NSCLC?

A

Mediastinal or supraclavicular nodal involvement

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2
Q

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

A

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

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3
Q

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

A

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

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4
Q

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

A

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

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5
Q

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

A

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

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6
Q

What is Pancoast syndrome?

A

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

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7
Q

What is Horner’s syndrome?

A

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

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8
Q

How prevalent are superior sulcus tumors?

A

Rare, around 3% of NSCLC

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9
Q

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

A 
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
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10
Q

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

A 
Stage IIIA: T3N1, T1–T3N2, T4N0–1
Stage IIIB: T1–T2N3, T4N2
Stage IIIC: T3–T4N3
Stage IVA: TXNXM1a/b
Stage IVB: TXNXM1c
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11
Q

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

A

3-9 months - M1a disease

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12
Q

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

A

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

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13
Q

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

A

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

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14
Q

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

A

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

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15
Q

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

A

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

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16
Q

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

A

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

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17
Q

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

A

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

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18
Q

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

A

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

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19
Q

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

A

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

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20
Q

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

A

Possibly. Still have a high LRR (retrospective data)

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

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21
Q

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

A

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

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22
Q

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

A

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.

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23
Q

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

A

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

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24
Q

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

A

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

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25
Q

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

A

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

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26
Q

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

A

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

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27
Q

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

A

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

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28
Q

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

A

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

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29
Q

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

A

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

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30
Q

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

A 
RTOG 7301 (Perez, 1980) - dose escalation trial with RT alone, 40Gy, 50Gy and 60Gy all 2 Gy/fx
- LC improved with 60Gy
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31
Q

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

A

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%)

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32
Q

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

A

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

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33
Q

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

A

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

34
Q

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

A

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

35
Q

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

A

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

36
Q

What is the role for consolidation chemotherapy after definitive CRT?

A

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

37
Q

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

A

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

38
Q

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

A

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%)

39
Q

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

A

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

40
Q

What is the design of RTOG 0617?

A

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

41
Q

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

A

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.

42
Q

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

A

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

43
Q

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

A

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

44
Q

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

A

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.

45
Q

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

A

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

46
Q

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

A

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

47
Q

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

A

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

48
Q

What is considered bulky, unresectable disease in NSCLC?

A

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

49
Q

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

A

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

50
Q

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

A

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

51
Q

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

A

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)

52
Q

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

A

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

53
Q

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

A

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

54
Q

Are all patients with stage IIIB NSCLC unresectable?

A

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

55
Q

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

A

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

56
Q

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

A

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

57
Q

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

A

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
58
Q

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

A

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.

59
Q

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

A

20-40% as a group

60
Q

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

A

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

61
Q

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

A

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

62
Q

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

A

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.

63
Q

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

A

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

64
Q

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

A

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.

65
Q

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

A

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

66
Q

How are chemo regimen efficacy and NSCLC histology types associated?

A

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

67
Q

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?

A

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

68
Q

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

A

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)

69
Q

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

A

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)

70
Q

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?

A

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

71
Q

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

A

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.

72
Q

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

A

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

73
Q

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

A

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.

74
Q

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

A

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

75
Q

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

A

MLD ≤20 Gy.

76
Q

What is the heart RT dose-volume constraint?

A
  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.

77
Q

What is the dose constraint for the brachial plexus?

A

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)

78
Q

What is the max esophageal dose?

A

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).

79
Q

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

A

Sequential: ∼4%.
Concurrent: ∼22%

80
Q

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

A
  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)

Radiation Oncology Residency (44 decks)

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