Treatment/Prognosis

Question 1

What is the Tx paradigm for pts with LS-SCLC?

Answer 1

LS-SCLC Tx paradigm: 4 cycles of EP chemo (etoposide [120 mg/m2, days 1–3] + cisplatin [60 mg/m2, day 1, q3wks]) + concurrent RT (only 1 cycle is concurrent). Current standard RT regimen is based on INT-0096: 45 Gy in 1.5 Gy bid × 30 fx

Question 2

What is the Tx paradigm for pts with T1–2N0M0 SCLC?

Answer 2

Lobectomy with mediastinal dissection and adj full course chemo. (NCCN 2018) This situation is seen in ∼5% of SCLC cases. The importance of adj chemo and PCI after complete resection for early-stage SCLC was highlighted in an NCDB analysis (Yang G et al., JCO 2016). If there are nodal involvement, consideration is made for adj mediastinal RT concurrent with chemo. PCI is also recommended. For more advanced lesions, 2 randomized studies (LCSG 832 [Lad T, Chest 1994] and the MRC [Fox W et al., Lancet 1973]) showed no benefit to Sg over definitive RT.

For medically inoperable pts, consideration can be made for SBRT + consolidation full course chemo and PCI. Mediastinal staging with EBUS should be made prior to SBRT. This is based on a multicenter case series and NCDB analysis, demonstrating comparable outcomes as surgical series. (Verma V et al., IJROBP 2017; Stahl et al., Lung Cancer 2017)

Question 3

What is the OS and LC benefit of adding RT to chemo in LS-SCLC?

Answer 3

There is an OS benefit of 5% based on Pignon J-P et al. meta-analysis (NEJM 1992), with LC benefit of 25%–30%. (Warde P et al., NEJM 1992 [meta-analysis])

Question 4

What is the benefit of smoking cessation prior to Tx in pts with limited-stage SCLC?

Answer 4

↓ Toxicity and ↑ survival, based on a retrospective review (Videtic GMM et al., IJROBP 2003)

Question 5

What are the typical response rates seen after concurrent CRT for LS-SCLC?

Answer 5

Typical response rates are 80%–95% with CR rates of 40%–60%.

Question 6

What is the median duration of response for pts with LS-SCLC after definitive Tx?

Answer 6

6–8 mos is the median duration of response.

Question 7

What is the preferred Tx approach for elderly pts (age >70 yrs) with LS-SCLC?

Answer 7

Depends on PS. In pts with good PS, combined CRT is preferred; they were shown to have 16% absolute 3-yr OS benefit with addition of RT to chemo (Corso CD et al., JCO 2015). Otherwise, standard combination chemo is better than single-agent cytotoxic agents.

Question 8

What is the MS of SCLC pts after recurrence if treated with salvage chemo?

Answer 8

4–5 mos is the MS for these pts.

Question 9

Why is EP the preferred regimen in concurrent CRT for LS-SCLC?

Answer 9

EP causes little mucosal toxicity, offers low risk of interstitial pneumonitis, and has lower cardiac toxicity compared to doxorubicin. Full systemic doses can be administered with RT, and there is modest hematologic toxicity. EP has a better therapeutic ratio over the older regimen of CAV (cyclophosphamide, doxorubicin, and vincristine), but it confers no survival benefit.

Question 10

What are the benefits and disadvantages of substituting carboplatin for cisplatin in EP for Tx of SCLC? Is there a difference in efficacy?

Answer 10

Carboplatin is less emetic, neuropathic, nephropathic, ototoxic, but there is more heme toxicity. A meta-analysis found no difference b/w cisplatin vs. carboplatin regimens. (Rossi A et al., JCO 2012)

Question 11

Is there a benefit to maintenance chemo after the initial 4–6 cycles in the Tx of SCLC?

Answer 11

No. Maintenance chemo only produces minor prolongation of response without improving survival and increasing cumulative toxicity.

Question 12

Is there a benefit of irinotecan compared to etoposide when added to cisplatin in the Tx of SCLC?

Answer 12

No. A Japanese RCT demonstrated a survival benefit with irinotecan, but this was not reproduced in 3 larger trials conducted outside Japan. However, a phase III trial found slightly improved OS with irinotecan over oral etoposide with carboplatin (Hermes A et al., JCO 2008), so irinotecan + carboplatin is an option. (NCCN 2018)

Question 13

What is the optimal sequence of combining chemo with RT?

Answer 13

Concurrent is better than sequential (JCOG: Takada M et al., JCO 2002): MS 27 mos vs. 20 mos; 5-yr OS 30% vs. 20% (10% OS benefit)

Question 14

What evidence supports early concurrent CRT over late RT with induction CT → CRT?

Answer 14

NCIC data (Murray N et al., JCO 1993): phase III, 308 pts. 5-yr OS was 20% (early RT) vs. 11% (late RT).

Yugoslavia data (Jeremic B et al., JCO 1997): an early vs. late RT trial showed better MS (34 mos vs. 26 mos) and 5-yr OS (30% vs. 15%) for early.

Meta-analysis of 7 trials (Fried DB et al., JCO 2004): early (<9 wks) vs. late (>9 wks) after chemo. There was 5.2% better 2-yr OS with early RT.

Question 15

What is the recommended RT dose in CRT for LS-SCLC?

Answer 15

45 Gy in 1.5 Gy BID or 60–70 Gy in 2 Gy QD (NCCN 2018)

CONVERT (European phase III trial) comparing 66 Gy/2.0 Gy QD vs. standard 45 Gy/1.5 Gy BID showed similar OS and toxicity (Faivre-Finn C et al., Lancet Oncol 2017)

CALGB 30610 is currently testing 70 Gy/2.0 Gy QD vs. standard 45 Gy/1.5 Gy BID. Previous RTOG 0712 regimen of 61.2 Gy in 5 wks (1.8 Gy qd × 16 fx → BID) was d/c in CALGB trial although it was not more toxic than the 7-wk regimen.

Question 16

What randomized trial demonstrated a clear superiority of altered fractionation with chemo compared to qd RT in the Tx of SCLC?

Answer 16

INT-0096 (Turrisi AT et al., NEJM 1999): phase III, 381 pts, EP × 4 cycles + RT at 1st cycle; randomization with 1.5 Gy bid × 3 wks vs. 1.8 Gy qd × 5 wks (both to 45 Gy); all rcvd prophylactic cranial irradiation (PCI) to 25 Gy. There was better 5-yr OS (26% vs. 16%) and LC (64% vs. 48%) in the bid arm. There was increased grade 3 esophagitis (27% vs. 11%) in the bid regimen, but not in the grade 4 toxicity. Criticism: 45 Gy qd is not biologically equivalent to the accelerated hyperfx of 45 Gy in 30 fx.

Question 17

Do any studies support dose escalation with conventional fractionation rather than traditional bid approach?

Answer 17

CALGB 8837 (Choi H et al., JCO 1998): phase I MTD in 50 pts of 2 RT regimens: 1.5 Gy/fx bid or 2.0 Gy/fx qd; MTD of bid was 45 Gy, whereas MTD of qd regimen was >70 Gy. Updated survival results were that 6-yr OS was better in the qd regimen compared with bid (36% vs. 20%). CALGB 30610 is an ongoing phase III trial comparing 45 Gy in 3 wks (arm A: INT-0096) vs. 70 Gy in 35 fx (arm B: CALGB regimen). (Arm C, 61.2 Gy in 5 wks (1.8 Gy qd × 16 fx → bid, as in RTOG 97–12, was dropped.)

Question 18

Describe classic RT targets for LS-SCLC?

Answer 18

Gross tumor, ipsi hilum, bilat MN from T inlet (1st rib) down to 5 cm below the carina. CTV = GTV + 1.5 cm (and elective hilum and MN regions + 8 mm), PTV = CTV + 1 cm.

Question 19

What T RT field arrangements are classically used for treating LS-SCLC?

Answer 19

Minimize contralat lung exposure with AP/PA to 15 Gy (1.5 Gy bid × 5 days) with oblique field to 45 Gy (AP/PA in AM and obliques for PM sessions).

Question 20

Should elective nodal irradiation be performed?

Answer 20

Historically, clinically uninvolved MNs were included. However, several modern studies showed that omission of ENI results in very low rates of isolated nodal recurrences of <5% if PET staging used. The CALGB 30610 and CONVERT trials have omitted ENI.

Question 21

Should you cover the pre- or postinduction systemic therapy Dz for the tumor and nodal volumes?

Answer 21

In pts who have systemic therapy before RT, the tumor GTV can be limited to the postchemo volume, based on 2 trials comparing pre- vs. postchemo volumes (Kies MS et al., JCO 1987; Hu X et al., Cancer 2011). The nodal GTV should include prechemo involved nodes but does not need to cover the entire extent of prechemo Dz.

Question 22

Are there circumstances where IMRT may be beneficial?

Answer 22

Consider IMRT if V20 >30% or FEV1 <1 L.

Question 23

What PTV margins should be used with/without 4D-CT simulation?

Answer 23

PTV is CTV + 0.5 cm if daily setup imaging is used and if ITV assessment is done during simulation and the planning process (either breath-hold or 4D-CT imaging). If a free-breathing non-ITV approach is used (non–4D-CT simulation), the PTV is CTV + 1.5 cm (sup–inf direction) and 1.0 cm in the axial direction. If a breath-holding non-ITV, PTV is CTV + 1.0 cm (sup–inf direction) and 0.5 cm in the axial direction.

Question 24

Is IMRT associated with worse outcomes compared to 3D-CRT?

Answer 24

Retrospective review of MDACC experience demonstrated no difference in LC or OS when IMRT was compared to 3D-CRT. PEG tube placement was significantly lower in IMRT cohort. (Shirvani SM et al., Int J Radiat Oncol Biol Phys 2013)

Question 25

What is the role of PCI in LS-SCLC? Is there an OS benefit with it?

Answer 25

Auperin meta-analysis of 7 RCTs (NEJM 1999) compared PCI vs. no PCI after CR following induction chemo +/– RT and no evidence of brain mets before randomization. There was ↓ 3-yr incidence of brain mets (33% vs. 59%) and 5.4% better 3-yr OS (20.7% vs. 15.3%) and improved DFS. There was a trend to a better outcome with ↑ doses and RT <4 mos from the start of chemo.

Question 26

What PCI dose is now standard for LS-SCLC?

Answer 26

25 Gy in 10 fx is now the standard dose for PCI for LS-SCLC. (RTOG 0212-Intergroup: Le Pechoux C et al., Lancet Oncol 2009)

Question 27

For pts with LS-SCLC what PCI doses were compared in RTOG 0212?

Answer 27

Standard doses (25 Gy in 10 fx) vs. higher doses (36 Gy in either 18 fx qd or 24 fx bid). There was no difference in the 2-yr incidence of brain mets, but there was an OS and chest relapse advantage for the standard arm (42% vs. 37%, p = 0.05) d/t greater cancer-related mortality in the high-dose group. There was higher 1-yr chronic neurotoxicity in the higher-dose arm (∼85%–90% vs. 60%). (Le Pechoux C et al., Lancet Oncol 2009; Wolfson AH et al., IJROBP 2011)

Question 28

What is the effect of PCI timing after the initiation of chemo for SCLC?

Answer 28

Based on Auperin meta-analysis, there was a ↓ in risk of brain mets with earlier PCI (<4–6 mos vs. >6 mos) without an effect on risk of death.

Question 29

Are there data demonstrating greater neuropsychologic complications after PCI for SCLC?

Answer 29

No. The data actually demonstrate no difference with or without PCI in a randomized trial addressing the question of neuropsychologic changes after PCI (Arrigada et al., JNCI 1995). Most pts (97%) actually have abnl neuropsychologic testing after chemo and before PCI, without a difference after PCI. (Komaki R et al., IJROBP 1995)

Question 30

What is the recommended adj Tx for SCLC if the MNs are found to be involved after attempted surgical resection?

Answer 30

Concurrent CRT directed at the MN (per NCCN 2018); if node–, adj chemo alone

Question 31

What is the Tx paradigm for pts with extensive-stage SCLC?

Answer 31

Extensive-stage SCLC Tx paradigm: multiagent chemo regimen including EP. Consider consolidation RT to the thorax for pts who achieve a CR to distant Dz after initial chemo (Jeremic B et al., JCO 1999). Also, PCI found to offer survival benefit even if extensive-stage Dz. (Slotman B et al., NEJM 2007)

Question 32

How many cycles of chemo should be given for extensive-stage SCLC?

Answer 32

4–6. Giving >4–6 cycles only modestly prolongs response duration and does not improve survival, while increasing cumulative toxicity.

Question 33

What additional chemo agents, when added to EP, have been shown to modestly improve the survival of pts with extensive-stage SCLC?

Answer 33

Ifosfamide or cyclophosphamide + an anthracycline have been shown to modestly improve survival.

Question 34

Is there evidence to support consolidative RT to T Dz in extensive-stage SCLC?

Answer 34

Yes. 2 RCTs supported this.

A European multicenter trial (Slotman et al., Lancet 2015) randomized 498 extensive-stage SCLC pts who had any response to 4–6 cycles of platinum-based chemo (70% had PR) to T RT (30 Gy in 10 fx) + PCI or PCI alone. The primary endpoint, 1-yr OS, was not significantly improved (p = 0.07), but the 2-yr OS was improved in those receiving T RT (2-yr OS 13% vs. 3%, p = 0.004). There was a 50% reduction in intrathoracic recurrences, improved 6-mo PFS, but no difference in progression at any site. T RT was well tolerated with no severe toxicity. The benefit of consolidation T RT was mostly limited to the pts who had residual Dz after systemic therapy.

Jeremic et al. (JCO 1999) enrolled 210 extensive-stage pts. All rcvd EP × 3. The subset of 109 pts who achieved a CR at all distant sites was randomized to rcv consolidative RT (accelerated hyperfx to 54 Gy) with concurrent carboplatin/etoposide or not. In both arms, pts rcvd PCI and consolidative EP. Consolidative CRT improved 5-yr OS (9.1% vs. 3.7%) and MS (17 mos vs. 11 mos). There was a trend in favor of LC but not DM-free survival.

Question 35

What are some salvage chemo agents used at the time of recurrence for SCLC?

Answer 35

Oral topoisomerase I inhibitors are standard for postchemo failure. (Topotecan was tested in RCTs showing doubling of survival [26 wks vs. 14 wks] compared with supportive care; irinotecan as a single agent was not tested.) Paclitaxel, docetaxel, TMZ, nivolumab +/– ipilimumab, vinorelbine, oral etoposide, gemcitabine, and CAV are some others.

Question 36

What seminal study demonstrated a survival benefit with PCI in pts with extensive-stage SCLC with any response to chemo? What are some main criticisms of this study?

Answer 36

EORTC 08993 RCT (Slotman BJ et al., NEJM 2007): 286 pts with extensive-stage SCLC treated with chemo; primary endpoint was time to symptomatic brain mets; pts randomized to +/– PCI after any response to chemo; most PCI pts given 20 Gy in 5 fx. PCI lowered the risk of symptomatic mets and improved DFS and OS (5.4 mos –PCI vs. 6.7 mos +PCI). 1-yr OS nearly doubled (13% –PCI vs. 27% +PCI).

Criticisms: Pre-Tx brain imaging is not required. The RT group was more likely to rcv chemo at the time of extracranial progression (68% vs. 45%). Only about half (59%) of pts in the control group rcvd WBRT for intracranial progression of Dz.

Question 37

Is there a benefit of PCI for extensive-stage pts who have a (negative) staging brain MRI?

Answer 37

Controversial, but likely not. Although the EORTC 08993 trial showed OS benefit with PCI for extensive-stage SCLC, the trial did not require pre-Tx brain imaging. The Japanese phase III randomized trial of PCI vs. no PCI in extensive-stage SCLC pts who had a negative staging brain MRI, closed early d/t futility of PCI after 163 pts were enrolled. There was no improvement of OS for PCI vs. no PCI; in fact, there was a trend toward a negative impact on median OS. (10.1 mos [PCI] vs. 15.1 mos [no PCI], p = 0.09). (Takahashi T et al., Lancet Oncol 2017)

Question 38

What was the greatest QOL alteration after PCI in the EORTC trial for extensive-stage SCLC?

Answer 38

3-mo QOL assessment showed that the largest negative impact of PCI was fatigue and hair loss. Worsening role, emotional, and cognitive function were also seen after PCI. (Slotman BJ et al., JCO 2009)

Question 39

What PCI dose should be given for extensive-stage SCLC?

Answer 39

The preferred dose is still 25 Gy in 10 fx, similar to LS-SCLC, however a shorter course (e.g., (20 Gy in 5 fx) can be considered for selected pts, such as those with less than a CR (most pts rcvd 20 Gy in 5 fx in the Slotman trial)).

Question 40

What is the current recommendation for PCI in pts with SCLC?

Answer 40

Indicated for limited stage and considered for extensive stage (NCCN 2018), CR/PR after chemo +/– consolidation RT, +/– MRI brain, PS of ECOG 0–2, within 3–6 wks of last cycle of chemo, 25 Gy in 10 fx. Also rcvd for pts who have had a complete resection. In pts with less than a CR, PCI is at the discretion of the treating physician.

Question 41

How do you treat SCLC pts who present with a limited number brain mets?

Answer 41

Whole brain radiotherapy (30 Gy in 10 fx). SRS should not be offered outside a clinical trial since these pts tend to develop multiple CNS mets, although may be considered if pts have rcvd prior PCI in selected pts. (NCCN 2018)

Question 42

In SCLC pts with SVCO, cord compression, or brain mets, what regimen is preferred as upfront palliative Tx: RT or chemo?

Answer 42

In a chemonaive pt presenting with SVCO, RCTs have shown a similar symptomatic response rate with chemo compared with RT. But in a chemorefractory pt, RT is the preferred regimen. In pts with cord compression/brain mets, RT is standard (in both chemonaive and chemorefractory pts).

Question 43

How is palliative RT delivered for SVCO syndrome in pts with SCLC?

Answer 43

Generally, a few large fx upfront (3–4 Gy × 2–3) → more definitive dosing in conventional fractionation (qd or bid regimen)

Question 44

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 44

Conventional is probably no better than hypofractionation. In a Norwegian RCT, Sundstrom et al. tested 30 Gy in 10 fx vs. 17 Gy in 2 fx (1 wk apart) vs. 10 Gy for 1 fx. All achieved similar levels of palliation. (JCO 2007)

Question 45

How should a tumor characterized as a high-grade neuroendocrine carcinoma, or as large cell neuroendocrine carcinoma, is managed?

Answer 45

Treat per non-SCLC guidelines (NCCN 2018)

Question 46

How should a pt with a carcinoid tumor of the lung be managed?

Answer 46

Sg is 1st line if it is resectable. Some centers will treat atypical carcinoid per the SCLC paradigm (nonsurgical).

Per NCCN 2018:

1. Stages I–IIIA typical carcinoid tumor can be observed after R0 resection.
2. For unresectable or medically inoperable stage IIIA or IIB, RT +/– EP is rcvd for atypical carcinoid, and can be considered for typical carcinoid tumors.
3. For atypical carcinoid tumors, resected stage I–II can be observed. However, for resected stages IIIA tumors, adj chemo (EP) +/– RT is recommended.

Question 47

How should stages IIIB–IV or unresectable carcinoid of the lung be managed?

Answer 47

Systemic therapy (EP), or octreotide if octreotide scan positive or symptomatic from paraneoplastic syndrome (NCCN 2018)