Treatment/Prognosis

Question 1

What are the Tx options for pts with cN2, stage IIIA Dz?

Answer 1

Tx options with cN2, stage IIIA Dz:

1. Induction chemo → Sg ± PORT (Roth J et al., JNCI 1994; Rosell R et al., NEJM 1994)
2. Neoadj CRT → lobectomy (INT-0139) (Albain KS et al., Lancet 2009)
3. Definitive CRT (RTOG 9410, Curran W et al., JNCI 2011)

Question 2

What are the Tx options for pts with cN3, stage IIIB Dz?

Answer 2

Definitive CRT is the only Tx option for cN3, stage IIIB Dz.

Question 3

Which clinical trials have demonstrated a survival benefit with adding induction chemo to Sg for stages IIIA–B NSCLC pts?

Answer 3

MDACC data (Roth JA et al., JNCI 1994; Roth JA et al., Lung Cancer 1998): 60 pts randomized to Sg alone vs. cisplatin/etoposide/cyclophosphamide × 1 cycle → Sg. MS was 21 mos (induction chemo) vs. 14 mos for Sg alone.

Madrid data (Rosell R et al., NEJM 1994; Rosell R et al., Lung Cancer 1999): 60 pts randomized to Sg alone vs. cisplatin/ifosfamide/mitomycin-C × 3 cycles → Sg. MS was 22 mos (chemo) vs. 10 mos for Sg alone.

Spanish Lung Cancer Group Trial 9901 (Garrido P et al., J Clin Oncol 2007): phase II study, 136 pts, all with stage IIIA (N2) or stage IIIB (T4N0–1) Dz. Pts underwent cisplatin/gemcitabine/docetaxel × 3 cycles → Sg. There was pCR in 13%. MS was 48.5 mos for R0 resection vs. 12.9 mos for R1–R2 resection. The overall complete resection rate was 69%. MS was 16 mos, 3-yr OS was 37%, and 5-yr OS was 21%.

Question 4

Did any trial fail to demonstrate a benefit for induction chemo f/b Sg?

Answer 4

Not in RadOncTables. JCOG 9209 (Japan: Nagai K et al., J Thorac Cardiovasc Surg 2003): trial closed early d/t poor accrual. 62 pts with stage IIIA N2 NSCLC randomized to Sg alone vs. cisplatin/vindesine × 3 cycles → Sg. There was no difference in MS (16–17 mos) or 5-yr OS (10% with chemo vs. 22% with Sg).

Question 5

Are there data to demonstrate the need for adding PORT to adj chemo in pts with completely resected stage IIIA N2 NSCLC?

Answer 5

This cannot be adequately answered at this point. CALGB 9734 attempted to address this question (adj chemo alone vs. chemo → RT), but the trial was closed d/t poor accrual. (Perry C et al., Lung Cancer 2007) There was no difference in DFS or OS. However, some evidence suggests that pts with N2 Dz should be evaluated for chemo → PORT.

Question 6

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

Answer 6

In subset analysis from randomized trials and meta-analysis, pts with N2 Dz may benefit from PORT. There are ongoing prospective phase III trials testing the role of PORT in pN2 pts.

LCSG 773 (Weisenburger TH et al., NEJM 1986): RCT, 210 pts, stages II–IIIA (T3 or N2), margin– resection, randomized to PORT or observation. RT: ≥Co-60 to the mediastinum to 50 Gy on postop day 28 (turned out to be nearly all SCC). Overall LR was better in PORT (3% vs. 41%), and DFS was better in N2 pts. There was no difference in OS b/t the arms.

PORT Meta-Analysis Trialist Group, Cochrane database, 2005 (Burdett S et al., Lung Cancer 2005): meta-analysis of 10 trials of pts treated after 1965. Suggested OS was a detriment to PORT overall. Subset analysis showed a detriment in resected stages I–II Dz but no adverse effect in N2 Dz.

Criticisms: (1) 25% of pts were T1N0; (2) the staging technique is no longer used; (3) the RT technique is no longer used (large fields and fx, high total doses, Co-60 machines); (4) >30% of the meta-analysis relied on a poorly done study using poor techniques/technology (Dautzenberg B et al., Cancer 1999) that showed PORT to be detrimental d/t a high 5-yr mortality from PORT (31% vs. 8%), mostly d/t Tx-related cardiac or respiratory deaths.

SEER analysis (Lally BE et al., JCO 2006): 7,465 pts, stages II–III NSCLC from 1988–2002, PORT vs. observation, median f/u 3.5 yrs. Overall, PORT did not affect OS. However, for the N2 subset, PORT was associated with better OS (HR 0.85) but detrimental for N0–N1.

Reanalysis of the ANITA trial (Douillard JY et al., IJROBP 2008): RCT of adj cisplatin/vinorelbine vs. observation for stages IB–IIIA pts after resection. 232 pts rcvd PORT. Overall, as a group, PORT was detrimental on survival (HR 1.34). In subset analysis based on pN stage, PORT was detrimental for pN0 pts. However, there was improved survival in pN1 Dz in the observation arm but detrimental in the chemo arm. PORT improved survival for both observation and chemo arms in pN2 pts.

PORT National Cancer Data Base Review (Robinson CG et al., JCO 2015): 4,483 pts (PORT, n = 1,850; no PORT, n = 2,633), all pN2, 2006–2010 with modern techniques. PORT conferred OS benefit over adj chemo alone (SS on MVA).

Question 7

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

Answer 7

Possibly. These pts may still have high LRR (retrospective analysis of MDACC and MSKCC data, 3y LRR ∼ 20%). (Amini A et al., Ann Surg Onc 2013) Therefore any pts with pN2, regardless of chemo response, have high LRR and may still benefit from PORT.

Question 8

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

Answer 8

No. INT-0115/RTOG 9105/ECOG (Keller MB et al., NEJM 2000) tested PORT vs. CRT in resected stage II or III NSCLC. There was no difference in OS (3.2 yrs) or LC.

Question 9

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

Answer 9

Per the ongoing European LungART trial, the bronchial stump, ipsi hilum, and extension to mediastinal pleura facing resected tumor bed should always be included. In the mediastinum: level 7 and level 4 (all), level 5/6 (left-sided tumor), the upper and lower LN station to the involved LN area; all LNs in b/w 2 noncontiguous LN stations involved.

Standard doses after complete resection are 50–54 Gy but a boost can be administered to areas of positive margins or extracapsular extension (per NCCN 2018). Doses b/t 60–70 Gy are appropriate for gross residual Dz.

Question 10

What should be the rate of Tx-related deaths (death from intercurrent Dz [DID]) following PORT for NSCLC?

Answer 10

Based on old data with old techniques, DID was 20%–30%, mainly d/t pulmonary or cardiovascular excess deaths from PORT. New data suggest much lower rates (2%–3%).

Penn retrospective (Machtay M et al., JCO 2001): 202 pts, Tx with Sg + PORT; 4-yr DID PORT (13.4%), vs. matched controls (10%). If <54 Gy, DID was 2%; but ≥54 Gy, DID was 17%.

ECOG 3590 reanalysis (Wakelee H et al., Lung Cancer 2005): 488 pts randomized to PORT vs. PORT + chemo; 50.4 Gy RT. Overall, 4-yr DID was 12.9% vs. matched controls at 10.1%.

Question 11

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

Answer 11

2 trials have attempted to address this question:

RTOG 0412/SWOG 0332: pts randomized to induction chemo +/– RT → Sg. Unfortunately, this trial was closed d/t poor accrual.

German Lung Cancer Cooperative Group Trial (Thomas M et al., Lancet Oncol 2008): 558 pts, stages IIIA–B NSCLC, randomized to induction chemo etoposide/cisplatin (EP) × 3 cycles → Sg → RT (arm 1) vs. chemo → CRT (bid RT with carboplatin/vindesine) → Sg (arm 2). If +margin/unresectable Dz, the pt rcvd more bid RT. There was greater pCR (60% vs. 20%) and mediastinal downstaging (46% vs. 29%) in the CRT group but no difference in PFS or survival. If pts required a pneumonectomy, postop mortality ↑ in the CRT group. This study has been criticized for its nonstandard RT regimen.

Question 12

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

Answer 12

For all-comers, there may be an improvement in LC, but there is no survival benefit. Subset analysis demonstrates that those receiving lobectomy may have an improved survival outcome.

INT-0139 (Albain KS et al., Lancet 2009): 396 technically resectable stage IIIA pts randomized to induction CRT to 45 Gy (50.4 Gy with heterogeneity correction) + Sg vs. definitive CRT (61 Gy) alone. Both therapies were proceeded with 2 additional cycles of chemo, which was cisplatin (50 mg/m2 days 1, 8) with etoposide (50 mg/m2 days 1–5), q28 day cycle. In the group overall, local relapse was much better for the Sg arm (10% vs. 22%, p = 0.002), but there was no difference in DM and no OS benefit. There was OS benefit in subset analysis in matched pts with lobectomy (5-yr OS 36% vs. 18%; MS 34 mos vs. 22 mos, p = 0.002) but not in pts who had pneumonectomy. 26% of pts with pneumonectomy died, but only 1% died from lobectomy.

The ESPATUE trial (Eberhardt EE et al., JCO 2015) studied 246 pts with pN2 or resectable IIIB NSCLC who rcvd 3 cycles of induction cis/etop, then CRT (cis/vinorelbine) to 45 Gy in 1.5 Gy BID, and assessed for resectability. 161 pts were deemed resectable and were randomized to complete CRT to 65–71 Gy vs. Sg. The trial was closed early d/t slow accrual but did not show any difference in OS or PFS.

Question 13

What is the RT dose for neoadj CRT if consolidative Sg is planned?

Answer 13

45 Gy. >50 Gy has been shown to have complications of bronchopleural fistula, prolonged air leak with empyema, and prolonged postop ventilation.

Question 14

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

Answer 14

No. In this circumstance, resection is not more beneficial than radiotherapy.

EORTC 08941 (Van Meerbeeck J et al., JNCI 2007): randomized trial for stage IIIA–N2 Dz. Pts responding to platinum-based induction chemo were randomized to RT 60 Gy in 2 Gy/fx (arm 1) vs. Sg (arm 2). Only 50% had radical resection, with only 5% pCR (42% pathologic downstaged). Operative 30-day mortality was 4%. There was only 55% compliance in the RT arm. There was no difference in OS or PFS. Conclusion from this study is that concurrent CRT should be the standard of care for stage III NSCLC.

Question 15

In light of all the evidence above, does including surgical resection in therapy for stages IIIA–B lung cancers in general improve outcomes?

Answer 15

The studies above do not show a clear benefit to adding Sg to CRT for locally advanced NSCLC. Both INT-0139 and EORTC 08941 failed to find sup outcomes with Sg over definitive RT in stage III Dz (albeit in different contexts). Definitive CRT is probably preferred over trimodality therapy in most pts with stages IIIA–B lung cancers.

Question 16

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

Answer 16

Pts with min, nonbulky N2 Dz who can get lobectomy are the best candidates based on the INT-0139 subgroup analysis.

Question 17

What randomized study established the min dose of 60 Gy for definitive RT for stage III NSCLC?

Answer 17

RTOG 7301 (Perez C et al., Cancer 1980): stages IIIA–B pts, dose-escalation trial with RT alone of 40 Gy, 50 Gy, and 60 Gy vs. 40 Gy (split course), all in 2 Gy/fx. LC improved with 60 Gy. 60 Gy was established as the standard.

Question 18

Is there a benefit of altered fractionation of definitive RT (without chemo) for stage III NSCLC?

Answer 18

Yes. Several phase II–III trials have demonstrated this benefit.

1. RTOG 8311 (Cox JD et al., J Clin Oncol 1990): randomized phase I–II, 848 pts with unresectable N2, 1.2 Gy bid to 60, 64.8, 69.6, 74.4, and 79.2 Gy. Pts with good PS who rcvd ≥69.6 Gy had significantly better 3-yr OS.
2. CHART (Saunders MI et al., Lancet 1997): phase III, 563 pts randomized to 54 Gy at 150 tid (450/day) × 12 consecutive days vs. 60 Gy for 6 wks. There was 10% improvement in 3-yr absolute survival for CHART compared to standard RT. Severe esophagitis was common (19% vs. 3%).

Question 19

What were the 2 seminal studies that demonstrated the importance of adding chemo to radiotherapy compared to radiotherapy alone?

Answer 19

1. CALGB 8433 “Dillman regimen” (Dillman RO et al., NEJM 1990): 155 pts with stage IIIA Dz (T3 or N2) treated with (1) RT alone (60 Gy) or (2) sequential chemo (cisplatin [CDDP]/vinblastine). Sequential chemo → RT improved MS from 10 mos to 14 mos, 2-yr OS from 13% to 26%, and 5-yr OS from 7% to 19%.
2. RTOG 88–08 (Sause W et al., Chest 2000): 458 pts with unresectable NSCLC (stages II–IIIB) randomized to 3 arms: 2 Gy qd/60 Gy alone (arm 1); 1.2 bid/69.6 Gy alone (arm 2); or sequential chemo (CDDP/vinblastine) + 60 Gy RT (arm 3). There was improved MS in arm 3 with sequential chemo (arm 1) c/w conventional RT (11.4 mos) or bid RT (12 mos).

Question 20

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

Answer 20

1. West Japan Lung Cancer Study Group (Furuse K et al., JCO 1999): 320 stages II–III pts randomized to sequential vs. concurrent CRT. Concurrent arm: CDDP/vindesine/MMC split-course RT (28 Gy × 2). Sequential arm: same chemo RT (Gy conventional, nonsplit course). There was better OS and PFS in pts with concurrent CRT. MS was 16.5 mos vs. 13.3 mos (SS); 5-yr OS was 15.8% vs. 8.9% (SS).
2. RTOG 9410 (Curran W et al., JNCI 2011): 610 pts randomized to 3 arms: sequential (Dillman regimen with RT to 63 Gy) (arm 1); concurrent CRT (to 63 Gy) (arm 2); and concurrent hyperfractionated RT (1.2 bid/69.6 Gy) + chemo (arm 3). Chemo was CDDP/vinblastine (except EP for arm 3). Definitive concurrent CRT (arm 2) had a better outcome in MS (17 mos) vs. 14.6 mos (arm 1) or 15.6 mos (arm 3) and 5-yr OS (16% vs. 10% vs. 13%). However, there was ↑ toxicity in the concurrent CRT arm.

Question 21

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

Answer 21

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

Question 22

Is there a benefit of adding induction chemo → CRT for pts with unresectable stages IIIA–B NSCLC?

Answer 22

No. 2 prospective studies (LAMP and CALGB 39801 trials) demonstrated no benefit to neoadj chemo. Definitive CRT alone is the standard of care.

1. LAMP trial (Belani CP et al., JCO 2005): randomized phase II, 276 pts with stages IIIA–B NSCLC randomized to arm 1: chemo × 2 cycles → 63 Gy RT (Dillman regimen); arm 2: induction chemo × 2 cycles → concurrent CRT (63 Gy); and arm 3: concurrent CRT → consolidation chemo × 2 cycles. Chemo was carboplatin/paclitaxel. Arm 3 (concurrent CRT) had a better outcome, where MS was 16.3 mos vs. 13 mos (arm 1) or 12.7 mos (arm 2).
2. CALGB 39801 (Vokes E et al., JCO 2007): randomized phase III trial, enrolled 366 pts with unresectable stages IIIA–B randomized to arm 1: CRT vs. arm 2: induction chemo × 2 cycles → CRT. Chemo was carboplatin/paclitaxel. There was no difference in MS or OS. MS 12 mos (CRT) vs. 14 mos (induction) (p = NS), 2-yr OS 29% vs. 31% (p = NS). Upfront chemo ↑ grades 3–4 heme toxicity.

Question 23

What is the role for consolidation chemo after definitive CRT?

Answer 23

Uncertain. Despite initial enthusiasm with the SWOG 9504 phase II study showing ↑ MS with consolidation docetaxel in stage IIIB pts after definitive CRT with cisplatin and etoposide (26 mos), the randomized phase III trial (Hanna N et al., JCO 2008) demonstrated no benefit of consolidation chemo with docetaxel but only ↑ toxicities and Tx-related deaths. Thus, there may not be a role of consolidation with docetaxel, but there may be a role for other agents, such as pemetrexed, as maintenance therapy. When low-dose weekly carboplatin/paclitaxel is used as concurrent regimen with RT, consolidation full dose carboplatin/paclitaxel × 2 cycles is often recommended after completing CRT. The place for consolidation chemo is now even more uncertain given the recommendation for consolidation durvalumab from the PACIFIC trial. (NCCN 2018)

Question 24

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

Answer 24

1. Low-dose weekly carboplatin (AUC 2.0) and paclitaxel (40–50 mg/m2) (CP) → high-dose consolidation carboplatin (AUC 6.0)/paclitaxel (150–200 mg/m2) q3wks × 2 cycles
2. Cisplatin (50 mg/m2) and etoposide (50 mg/m2) (q4wks per cycle × 2) (PE) → consolidation platinum doublet chemo × 2 cycles
3. Cisplatin (75 mg/m2) and pemetrexed (500 mg/m2) (q3wks per cycle × 3) (PP) → consolidation pemetrexed q3wks × 4 cycles

No, there are essentially no differences b/t the different chemo regimen, except some differences in toxicity profiles.

1. Systematic review of published studies comparing CP vs. PE + RT in 3,090 pts (Steuer CE et al., JAMA Oncol 2017) found no differences in PFS and OS. PE had higher grade 3–4 hematologic and n/v toxicities. No differences in RT pneumonitis or esophagitis.
2. PROCLAIM trial was a phase III randomized trial comparing PE vs. PP CRT in 598 pts. (Senan S et al., JCO 2016) There were no differences in OS. PP had less grade 3–4 adverse events, including neutropenia.

Question 25

Is there a role for ENI for the Tx of inoperable, locally advanced NSCLC?

Answer 25

No. The current recommendation is to treat with CRT only the involved areas (assessed either by imaging or pathology) to improve dose escalation and improve toxicity.

MSKCC data (Rosenzweig K et al., JCO 2007): retrospective analysis of pts treated with IFRT alone. 524 pts treated with definitive 3D-CRT to areas of gross Dz; mean dose 66 Gy. Total elective nodal failures (ENF) (initial uninvolved nodal areas that fail) were 6.1%. The 2-yr primary tumor control rate was 51%. Overall, 2-yr ENF was 7.6%. Pts with local Dz control had a 2-yr ENF of 9%. Ipsi mediastinum had ↑ nodal failures (3%).

Prospective phase III trial (Yuan et al., ASCO 2007): inoperable stage III NSCLC randomized to involved-field irradiation vs. ENI. Involved-field irradiation achieved better overall response and improved 5-yr LC of 51% vs. 36% (p = 0.032).

Question 26

What are the volumes and Tx techniques used for RT of locally advanced NSCLC?

Answer 26

GTV is defined by +FDG uptake areas, Bx-proven LN areas, or any LN >15 mm on CT. PTV = GTV + 1–1.5 cm. 3D-CRT or IMRT technique to 60 Gy or higher in 1.8–2 Gy/fx should be given.

Question 27

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

Answer 27

No, there is currently no evidence that a dose >60 Gy with concurrent chemo is beneficial based on results from RTOG 0617 (see below). The rationale for dose escalation was based on prior studies which suggested that dose escalation improves LC and possibly survival.

RTOG 73–01: RCT testing 40 Gy split vs. 40 Gy continuous vs. 50 Gy continuous vs. 60 Gy continuous. The 60 Gy continuous had the best survival. 60 Gy became standard b/c of this trial, and since then 55–66 Gy is standard.

RTOG 93–11: dose escalation without chemo to 70.9 Gy, 77.4 Gy, 83.8 Gy, and 90.3 Gy. The 90.3 Gy is too toxic, but 77.4 Gy and 83.8 Gy are safe if V20 is 25%–36% and <25%, respectively. LC 50%–78%, with LF in elective nodal areas <8%.

Michigan study (Kong FM et al., IJROBP 2005): 106 pts, stages I–III NSCLC, treated with 63–103 Gy in 2.1 Gy/fx with 3D-CRT; primary tumor + LN + ≥1 cm; no chemo in 81%. MS was 19 mos. MVA showed that the RT dose was the only predictor of better survival.

Question 28

What was the design of RTOG 0617?

Answer 28

RCT phase III comparison for stages IIIA–B NSCLC treated with CRT with 2 randomizations:

1. 60 Gy vs. 74 Gy

2.Carboplatin/paclitaxel +/– cetuximab

Question 29

What was the outcome of the dose escalation portion of the study?

Answer 29

Closed early at interim analysis. Pts receiving 74 Gy had worse grade 5 toxicity and grade 3 esophagitis, higher rate of LFs, and worse OS. Pts who rcvd 74 Gy also had worse QOL at 3 mos. (Movsas B et al., JAMA Oncol 2016)

Question 30

What are some possible explanations for the counterintuitive findings in the higher-dose arm?

Answer 30

1. Too tight margins in the high-dose arm → higher LFs → worse survival
2. Unmeasured or underreported toxicities → more Tx deaths → worse survival
3. Extended therapy duration → worse LC → worse survival
4. Combination of the above

Question 31

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

Answer 31

No. There was no survival benefit except for worse toxicities in the cetuximab arm. In a subset analysis, there was suggestion that higher tumor H-score for EGFR predicted for better outcome with cetuximab.

Question 32

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

Answer 32

In RTOG 0617, 53% were treated with 3D-CRT; 47% with IMRT. In a secondary analysis (Chun S et al., JCO 2016), IMRT was associated with a 60% decrease in grade 3 RT pneumonitis (3.5% vs. 7.9%), with similar survival and control, in spite of the fact that more pts treated with IMRT were stage IIB and had larger Tx volumes. Lung V20 was associated with grade 3+ pneumonitis. IMRT plans also had lower heart doses, and the heart V40 was significantly associated with OS. IMRT (vs. 3D-CRT) also had less clinically meaningful decline in QOL measure at 12 mos (FACT-LCS, 21% vs. 46%, p = 0.003). (Movsas B et al., JAMA Oncol 2016)

Question 33

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

Answer 33

Immune checkpoint blockade for 1 yr with durvalumab based on the PACIFIC trial. (Antonia SJ et al., NEJM 2017) Pts in the trial were not allowed consolidation chemo and had not progressed after CRT or with pneumonitis were randomized. In the 1st interim report of this phase III randomized trial in 713 pts, adding durvalumab (engineered hIgG1 anti–PD-L1) at 10 mg/kg q2wks up to 12 mos vs. placebo after CRT significantly improved median PFS by over 11 mos (16.8 mos vs. 5.6 mos, HR 0.52, p < 0.001), and an 18-mo PFS time of 44.2% vs. 27.0%. The PFS benefit was seen across most pt subsets, regardless of PD-L1 status. The median time to death or DM was also significantly improved with durvalumab (23.2 mos vs. 14.6 mos, HR 0.52, p < 0.0001).

Question 34

What should be done in NSCLC pts with incidental N2 Dz found at the time of Sg?

Answer 34

If technically resectable, with only an occult, single-station mediastinal nodal met at Sg, surgical resection should proceed with lung resection + mediastinal LND → adj chemo, with consideration of PORT.

Question 35

For pts who rcv Sg upfront, what is the role of adj platinum-based chemo?

Answer 35

It should be given for pts with N+ Dz or primary tumors >4 cm in pts with T2N0 (stage IB) tumors.

LACE meta-analysis for 5 adj trials demonstrated 5-yr OS advantage of 5.4%. (Pignon JP et al., JCO 2008)

CALGB 9633 unplanned subset analysis demonstrated a survival benefit for stage IB pts with tumors >4 cm. (Strauss GM et al., JCO 2008)

Question 36

What is considered bulky, unresectable Dz in NSCLC pts?

Answer 36

Pts with a histologically involved LN >3 cm on CT, +extranodal involvement, or multistation nodal Dz (regardless of size)

Question 37

What is the preferred Tx strategy for pts with stage IIIB T4N0 Dz?

Answer 37

Neoadj chemo or CRT, or definitive CRT. 5-yr OS may approach 25%–30%. R0 resection should be attempted if this is technically feasible.

Question 38

What is the 5-yr OS of pts with satellite nodules in the same lobe?

Answer 38

5-yr OS is 33% if pts undergo lobectomy. Careful nodal assessment to exclude N2 Dz must be done.

Question 39

What are the Tx paradigms and survival outcomes for resectable T3–4N0–1 sup sulcus tumors?

Answer 39

Resectable T3–4N0–1 sup sulcus tumor Tx paradigms: (1) preop CRT → Sg → chemo × 2 (SWOG 9416/INT-0160), with a 5-yr OS of 44%, or (2) upfront Sg → CRT to 60 Gy (1.2 Gy BID) for negative margin, and 64.8 Gy (1.2 Gy BID) for positive margin with concurrent and adj cisplatin (50 mg/m2) and etoposide (50 mg/m2) × 5 cycles. (MDACC Phase II study: Gomez DR et al., Cancer 2012) The 5-yr and 10-yr OS for the MDACC study is 50% and 45%, respectively.

Question 40

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

Answer 40

SWOG 9416/INT-0160 (Rusch VW et al., JCO 2007) was a single-arm phase II trial which evaluated induction CRT + Sg for resectable T3–4N0–1 sup sulcus tumors. The induction regimen was with concurrent cisplatin, etoposide, and RT to 45 Gy → restage; if no progression, then Sg → chemo × 2 cycles. Chemo was cisplatin (50 mg/m2 days 1 and 8) with etoposide (50 mg/m2 days 1–5), repeated q28 days for a total of 4 cycles. 95% completed induction therapy. Of the pts who had thoracotomy (88 of 110 pts [80%]) based on preop judgment of resectability, 94% had complete resection (83 pts). The study showed a 56% pCR or near CR rate and a 5-yr OS of 44% (compared to 30% for historical controls). Survival was better with complete resection (54%). There was no difference b/t T3–T4 tumors.

Question 41

What are the appropriate Tx volumes, dose, and field arrangement for a sup sulcus tumor?

Answer 41

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

Question 42

Are all pts with stage IIIB NSCLC unresectable?

Answer 42

No. Pts with T4 Dz with invasion of vertebral bodies and multiple nodules in different ipsi lung lobes are still resectable.

Question 43

What are the Tx options for pts with malignant pleural effusion?

Answer 43

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

Question 44

What should be done for pts with 2 synchronous nodules of NSCLC (i.e., occurring in different lobes)?

Answer 44

If there is identical histology, consider M1. If a different histology or genetic signature, it can be considered synchronous stage I NSCLC and definitive Sg and/or SBRT can be considered after full workup for nodal/distant involvement is excluded.

Question 45

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

Answer 45

Yes, 2 small randomized trials demonstrated the benefit of local consolidative therapy after induction systemic therapy in stage IV NSCLC with limited metastatic Dz.

1. A small multicenter randomized phase II trial (Gomez DR et al., Lancet Oncol 2016) enrolled pts with stage IV NSCLC with ≤3 mets and no Dz progression after 1st-line systemic therapy. 49 pts were randomized to local therapy (CRT/RT or resection) of all lesions (+/– subsequent maintenance Tx) vs. maintenance Tx alone (which included observation only). The median PFS was improved in the local consolidative therapy group (11.9 vs. 3.9 mos).
2. A small single institution randomized phase II trial at UTSW (Iyengar P et al., JAMA Oncol 2017) randomized 29 pts after induction chemo to maintenance chemo alone vs. SABR up to 5 metastatic sites + hypofractionated RT to primary site) + maintenance chemo. PFS was found to be significant on interim analysis (9.7 mos vs. 3.5 mos, p = 0.01) in the RT consolidation arm, with fewer recurrence overall.

Question 46

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

Answer 46

Surgical resection should be considered, especially if the pt is symptomatic or to exclude a possible primary brain tumor, then either SRS or WBRT. Otherwise, SRS +/– WBRT should be used (per NCCN). The primary lung tumor should be managed according to the appropriate TN stage.

Question 47

Overall, what is the 5-yr OS in the group of NSCLC pts with solitary brain mets?

Answer 47

5-yr OS is 20%–40% as a group.

Question 48

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

Answer 48

1. No. 4 older randomized trials showed only improvement in brain relapse rates (9% vs. 19%) but no survival benefit in adding PCI (Cox JD et al., JAMA 1981; Umsawasdi T et al., J Neurooncol 1984; Miller TP et al., Cancer Ther 1998; Russell AH et al., IJROBP 1991). A meta-analysis summarizes these data. (Lester JF et al., IJROBP 2005)
2. RTOG 0214 is a modern phase III randomized trial testing the utility of PCI for locally advanced NSCLC. The trial was closed d/t futility after enrolling 356 pts (planned 1,058). There was a significant improvement for brain relapse with PCI (1-yr relapse 7.7% vs. 18.0%, p = 0.004) but no difference in 1-yr OS or PFS. (Gore EM et al., JCO 2011)

Question 49

What molecular testing should be done in pts who present with metastatic Dz?

Answer 49

For adenocarcinoma, large cell, NSCLC NOS: EGFR mutation, ALK, ROS1, PDL-1, should be tested as part of broad molecular profiling. For SCC, EGFR mutation and ALK testing should be considered in never smokers, small Bx specimens, or mixed histology.

Question 50

What type of pts are EGFR and KRAS mutations common in? What % of pts have overlapping EGFR and KRAS mutations?

Answer 50

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 51

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

Answer 51

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

Question 52

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

Answer 52

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 53

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

Answer 53

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 54

How are chemo regimen efficacy and NSCLC histology types associated?

Answer 54

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

Question 55

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 55

1. EGFR mutation pts should rcv osimertinib (preferred based on the FLAURA trial [Soria JC et al., NEJM 2018]), erlotinib, afatinib, or gefitinib. Osimertinib has better CNS penetration than the other oral TKIs and can improve PFS in EGFR mutant NSCLC pts with brain mets.
2. ALK or ROS1 rearrangement pts should rcv alectinib based on the phase III randomized trial (ALEX) that compared alectinib vs. crizotinib (prior 1st-line standard). (Peters S et al., NEJM 2017) Alectinib has reduced Dz progression and death, as well as less grade 3–5 toxicities. It also has better CNS penetration, resulting in better CNS metastatic control.
3. Pts with ≥50% tumor cell PD-L1 staining (using the Dako 22c3 antibody) should rcv pembrolizumab. (Keynote-024, Reck M et al., NEJM 2016)
4. If these mutations are discovered prior to 1st-line chemo, they should rcv the targeted therapy. If discovered during 1st-line chemo, they can either complete planned chemo or interrupt and switch to the appropriate targeted therapy.

Question 56

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

Answer 56

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 57

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

Answer 57

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 58

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 58

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. (JCO 2007)