Treatment/Prognosis

Question 1

Generally, what is a Tx paradigm for a stage I–II medically operable NSCLC pt?

Answer 1

Stages I–II medically operable NSCLC Tx paradigm: surgical resection (lobectomy) + mediastinal LND → adj chemo for everybody except stage IA, margin-negative resection. Stage IB and IIA with negative margins warrant chemo depending on other high-risk factors (grade, LVSI, >4 cm size, visceral pleural involvement, incomplete LN staging). (NCCN 2018)

Question 2

What should be the 1st step for a stage I–II medically operable NSCLC pt with a +margin resection?

Answer 2

Re-resection, if possible +/– chemo depending on other clinical factors. (NCCN 2018)

Question 3

If re-resection is not possible, what RT dose is used for a +margin after Sg?

Answer 3

Microscopic +margin: 54–60 Gy

Gross +margin: 60–70 Gy

Question 4

Generally, what is the Tx paradigm for a stage I–II medically inoperable NSCLC pt?

Answer 4

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. (NCCN 2018)

Question 5

Name 3 surgical options to resect a T1–T2 tumor.

Answer 5

Surgical options to resect a T1–T2 tumor:

1. Wedge or segmental resection
2. Lobectomy
3. Pneumonectomy

Question 6

For a T1N0 NSCLC, what is the estimated LC for wedge/segmental resection vs. lobectomy?

Answer 6

Wedge/segmental LC is 82% vs. lobectomy LC is 94% (LF 18% vs. 6%) based on RCT LCSG 821 (Ginsberg RJ et al., NEJM 1995). Lobectomy is preferred when feasible. However, CALGB 140503 is a currently ongoing phase III trial of lobectomy vs. sublobar resection for ≤2 cm peripheral NSCLC (smaller tumors than those treated in LCSG 821).

Question 7

What % of stage I NSCLC pts will develop a 2nd primary after definitive surgical resection?

Answer 7

Up to 30% of pts develop a 2nd primary.

Question 8

What is the estimated 5-yr OS of completely resected T1–2N0 NSCLC with no adj chemo?

Answer 8

T1N0 ∼80%; T2N0 ∼68% (Martini N et al., J Thorac Cardiovasc Surg 1999)

Question 9

What is the 5-yr OS, CSS, and MS for pts who refuse any Tx for T1–2N0 NSCLC?

Answer 9

5-yr OS is 6%, CSS is 22%, and MS is 13 mos (Raz DJ et al., Chest 2007). Tumor size is a prognostic factor, independent of T stage.

Question 10

What are the indications for adj chemo after definitive resection for stages I–II NSCLC?

Answer 10

Indications for adj chemo after definitive resection for stages I–II NSCLC:

1. High-risk stages IB–IIB
2. N1 Dz (category 1)
3. T2N0 (stage IB), if the tumor is >4 cm as per unplanned analysis of CALGB 9633 (Sg +/– carboplatin/paclitaxel). (Strauss GM et al., JCO 2008)

Other risk factors include poorly differentiated tumor, LVSI, wedge resection, visceral pleural involvement, and incomplete nodal sampling.

Question 11

What is the estimated 5-yr OS benefit with adj chemo for pts with completely resected stage I or II NSCLC?

Answer 11

∼5% at 5 yrs for adj cisplatin-based chemo based on LACE meta-analysis of recent trials (Pignon JP et al., JCO 2008). However, HR for stages IA and IB were not significant. Adj chemo for stage IA may even be detrimental.

Question 12

What are possible chemo regimens in the adj or neoadj setting per NCCN 2018?

Answer 12

Cisplatin 50 mg/m2 days 1 and 8; vinorelbine 25 mg/m2 days 1, 8, 15, 22, q28 days for 4 cycles

Cisplatin 100 mg/m2 day 1; vinorelbine 30 mg/m2 days 1, 8, 15, 22, q28 days for 4 cycles

Cisplatin 75–80 mg/m2 day 1; vinorelbine 25–30 mg/m2 days 1 + 8, q21 days for 4 cycles

Cisplatin 100 mg/m2 day 1; etoposide 100 mg/m2 days 1–3, q28 days for 4 cycles

Cisplatin 75 mg/m2 day 1; gemcitabine 1250 mg/m2 days 1, 8, q21 days for 4 cycles

Cisplatin 75 mg/m2 day 1; docetaxel 75 mg/m2 day 1 q21 days for 4 cycles

Cisplatin 75 mg/m2 day 1, pemetrexed 500 mg/m2 day 1 for nonsquamous q21 days for 4 cycles

Question 13

Is there a role for preop chemo in early-stage lung cancer pts?

Answer 13

No. Based on a meta-analysis, the survival gain is the same as for adj chemo (5%). The largest randomized trial (MRC LU22/EORTC 08012) for 519 pts randomized to preop chemo vs. Sg alone found good RR (49%) and downstaging (31%) but no survival benefit to preop chemo (Gilligan D et al., Lancet 2007). The CHEST Trial tested preop gemcitabine + cisplatin and found no significant benefit for stages IB/IIA but improved OS for stages IIB and IIIA (Scagliotti DV et al., JCO 2012). The NATCH Spanish Trial tested Sg vs. preop chemo + Sg vs. Sg + adj chemo and found no significant differences. However, more pts were able to rcv chemo in the neoadj setting. (Felip E et al., JCO 2010)

Question 14

Is there a benefit of full mediastinal dissection vs. nodal sampling in early-stage pts undergoing surgical resection?

Answer 14

Possibly. A recent pooled analysis of 3 trials demonstrated a 4-yr OS benefit in stages I–IIIA NSCLC pts (HR 0.78). Mediastinal dissection involves removal of the right 2R, 4R, 7, 8R, and 9R and the left 5, 6, 7, 8L, and 9L. (Manser R et al., Cochrane Database Syst Rev 2005)

Question 15

What are the indications for PORT after definitive resection for stages I–II NSCLC?

Answer 15

+Margins, +ECE, and unexpected N2 Dz. Per NCCN 2014, give concurrent CRT for an R2+ margin and sequential for R1 Dz (chemo → RT). Although not specified in NCCN, chemo → RT may also be considered for ECE.

Question 16

Which randomized study demonstrated improved LC and survival with PORT after surgical resection for early-stage (stages IA and IB) NSCLC?

Answer 16

Italian study: 104 pts, stage I, resected with LND (pN0), randomized to PORT vs. observation; PORT encompassed the bronchial stump + ipsi hilum (mean area, 50 cm2) to 50.4 Gy. There were better LF rates (2% vs. 23%) with a trend to improved 5-yr survival (67% vs. 58%, p = 0.048). There was min toxicity and no worsened pulmonary function. (Trodella L et al., Radiother Oncol 2002)

Question 17

What is the max RT dose that has been used for definitive RT alone in stages I–II NSCLC?

Answer 17

Up to 84 Gy in standard fractionation if lung dose–volume constraints are respected. RTOG 9311 dose-escalation study found that 90.3 Gy dose level was too toxic. (Bradley J et al., IJROBP 2005)

Question 18

What is the 2-yr LR rate for RT alone using standard fractionation?

Answer 18

50%–78% 2-yr LR is based on RTOG 9311, but this study included stage III pts as well.

Question 19

In stages I–II NSCLC pts being treated with definitive RT alone, should elective nodal regions be treated? What is the estimated elective nodal failure rate if untreated?

Answer 19

No. Elective nodal failure rate was <10% in RTOG 9311. In most series with stage I lung cancer treated with hypofractionated SBRT, the regional nodal failure rate ranged from 5%–10%. From the Indiana University dose-escalation study using SBRT for stage I lung cancer, regional nodal failure as the site of 1st failure was 10%. (Hoopes DJ et al., Lung Cancer 2007) Multiple retrospective reviews have also shown low elective nodal failure rates.

Question 20

What are the estimated 3- to 5-yr LC and OS for medically inoperable stage I pts treated with definitive hypofractionated SBRT?

Answer 20

In most series using hypofractionated SBRT for stage I lung cancer pts, the 3-yr LC ranged from 85%–95% and the 3-yr OS was 55%–91%.

Question 21

How does SBRT compare to lobectomy for operable stage I NSCLC?

Answer 21

In the Chang et al. pooled analysis of the STARS and ROSEL trials (Lancet Onc 2015), OS at 3 yrs was 95% in the SBRT group compared to 79% for the Sg group (HR 0.14; log rank p = 0.037). This remains controversial. In a recent SEER analysis (Shirvani S et al., JAMA Surg 2014), a propensity score matched analysis showed no difference b/t SBRT and Sg.

However, recent NCDB analysis of early stage NSCLC, in a propensity matched cohort of surgery vs. SBRT in 27,200 pts, surgery had significantly higher 30 and 90 days mortality, and highest in those >70 years old and with more extensive surgery. (Stokes WA et al., J Clin Oncol 2018)

Question 22

What BED should be achieved to attain max LC and survival in pts with stage I lung cancer treated with SBRT?

Answer 22

According to Japanese data, if the BED is ≥100 Gy, then the 5-yr LC rate is 92% and the 5-yr OS is 71%. However, if the BED is <100 Gy, then the 5-yr LC rate is 57% and the 5-yr OS is 30%. (Onishi H et al., JTO 2007)

Question 23

What is the estimated 5-yr rate of nodal failure, LF, and DM in early-stage NSCLC after definitive SBRT?

Answer 23

LRR (nodal) tends to be higher in SBRT pts than surgical pts and appears to increase with time. In RTOG 0236, 5-yr LR was 7%, involved lobar recurrence was 20% and regional recurrence was 38%. Distant recurrence rate was 31% (RTOG 0236; ASTRO 2014)

Question 24

What is the SBRT technique that was evaluated in RTOG 0236? What is the 2-yr LC and OS rate for this group of inoperable pts?

Answer 24

SBRT using 20 Gy × 3 (without heterogeneity correction [HC]), or 18 Gy × 3 with HC) given in 1.5–2 wks. 3-yr primary tumor control is 97.6%, but the 3-yr primary tumor and involved lobe control is 90.6%, DFS was 48.3%, and OS was 55.8%. (Timmerman R et al., JAMA 2010)

Question 25

How should the SBRT dose be modified for centrally located tumors?

Answer 25

Lesions located centrally (i.e., within 2 cm of the central bronchial tree) are not good hypofractionated RT candidates using 20 Gy × 3 fx d/t the risk of grades 3–5 toxicity (Timmerman R et al., JCO 2006). MDACC (Chang JY et al., IJROBP 2008) proposed 12.5 Gy × 4, with LC at 17 mos of 100%. There were grades 2–3 dermatitis and CW pain in 11%. There was no pneumonitis for newly diagnosed stage I pts. RTOG 0813 has demonstrated that 10–11 Gy × 5 fx may be safe for centrally located lesions. Other options include 70 Gy in 10 fx (MDACC).

Question 26

What CTV and PTV margins are used for SBRT?

Answer 26

At MDACC, there is no GTV to CTV expansion. ITV (around GTV) + 5 mm → PTV when four dimensional computed tomography (4D-CT) simulation and daily CBCT are used. According to RTOG 0915, GTV + 5 mm in axial plane and GTV + 1 cm in longitudinal plane if no 4D-CT used.

Question 27

What studies have attempted to address the role of SBRT in both operable and inoperable early-stage lung cancer pts?

Answer 27

Operable:

RTOG 0618: phase II, operable stages I–II NSCLC, accrued 33 pts using 18 Gy × 3 (with HC) (Timmerman R et al., ASCO 2013): Median f/u 25 mos, 2-yr LF (primary tumor + involved lobe) 19.2%, PFS 65.4%, and OS 84.4%.

ROSEL (Dutch): phase III SBRT vs. Sg for operable stage I pts. RT 20 Gy × 3 for T1, 12 Gy × 5 for T2, and 7.5 Gy × 8 for central tumors. Primary endpoint is 2- and 5-yr LC, QOL, and cost. Trial closed to lack of accrual.

STARS (Accuray/MDACC): phase III SBRT (CyberKnife) vs. Sg in operable stage I pts. RT 12.5 Gy × 4 for central lesions and 16.7 Gy × 3 fx for peripheral tumors. Primary endpoint is OS, DFS, and toxicity at 3 yrs but closed to poor accrual. Now a single arm phase II trial in operable pts. Now a single arm phase II trial in operable pts which has completed accrual in 2017.

JCOG 0403: phase II study for stage IA medically inoperable or operable pts. 48 Gy in 4 fx over 4–8 days with HC. Primary endpoint: 3-yr OS and target size of 165 pts.

Inoperable:

TROG 09.02: phase III. T1/T2aN0 for pts who are medically inoperable/refuse Sg. 54 Gy in 3 fx over 2 wks vs. conventional RT 60–66 Gy in 30–33 fx +/– concomitant carboplatin/paclitaxel. Primary endpoint: time to LF.

RTOG 0915: phase II study in inoperable stage T1/T2 (<5 cm) NSCLC and peripherally located lesions. 34 Gy single fx vs. the Japanese regimen of 12 Gy × 4 fx. The winning arm will be compared to the current RTOG reference 20 Gy × 3 fx in a future phase III trial. Early results in ASTRO 2013 showed trial met prespecified 1-yr toxicity endpoint. Longer f/u needed.

SPACE (Scandinavian): phase II randomized trial of 3D-CRT 70 Gy in 35 fx vs. SBRT 45 Gy in 3 fx.

RTOG 0813: trial has completed accrual to the phase I/II study of dose-escalated SBRT (9, 10, 11, and 12 Gy × 5 fx over 2 wks) for centrally located tumors. 1 pt developed grade 3 RP in the 12 Gy group. No Tx-related grade 3 or greater toxicity from 9–11 Gy. Phase II completed at 11 Gy × 5 fx. No LFs presented at ASTRO 2011. Final results pending.