Important Studies: Limited Stage

Question 1

Benefit of RT?

Answer 1

Gustave-Roussy, Villejuif, France (Pignon et al, NEJM, 1992): Meta-analysis 13 randomized trials evaluating chemoRT vs. chemo. Absolute 5% benefit in 3-yr OS
Addition of RT to chemo gave 14% reduction in mortality

University of Toronto (Warde et al, JCO, 1992): Meta-analysis of 11 randomized trials evaluating chemoRT vs. chemo. Absolute 5% benefit in OS. Absolute 25% LC benefit to RT (48% vs. 23%)

Question 2

BID vs QD dose?

Answer 2

INT 0096 (Turrisi et al, NEJM, 1999): Limited stage SCLC: ipsilateral hilum, ipsilateral SCV, and bilateral mediastinum allowed. Exlusions: contralateral supraclavicle or hilum. →45 Gy RT in 1.8 Gy daily
vs. →45 Gy in 1.5 Gy BID fractions with concurrent cisplatin and etoposide x4 cycles q3weeks. RT started w/ cycle #1. “Median OS 23 vs. 19 mos
2-yr OS 47% vs. 41% (NS)
5-yr OS 26% vs. 16%, p=0.04
LF 36% vs 52% p=0.06
More grade 3 esophagitis 27% vs. 11%.
BID RT to 45 Gy with concurrent chemo results in improved OS compared to QD RT to 45 Gy and chemo.

Question 3

Dose escalation?

Answer 3

CONVERT (Faivre-Finn et al, Lancet Oncol, 2017
Salem et al, JAMA Oncol, 2018): cis/etoposide x1, then →45 Gy BID/30 fx vs. →66 Gy/33 fx 4-6 cycles cis/etoposide. IMRT or 3DCRT. No ENI. Followed by PCI if indicated. Outcomes trended in favor of BID RT but the difference was nonsignificant. Since the trial was designed to show superiority and did not, BID RT remains standard of care.

THORA (Gronberg et al, ASCO, 2020): “→45 Gy BID/30 fx
vs. →60 Gy BID/ 40 fx. Phase II.
2-yr OS 46% vs. 73%
Median PFS 14 vs. 20 mos
Median OS 23 vs. 42 mos
No diff in grade 3-4 esophagitis, 18-19%
neutropenic infections 36% vs. 21%, p=0.05
pneumonitis 0% vs. 4%, p=0.10
In this per protocol analysis, BID RT escalated to 60 Gy led to improved OS compared to 45 Gy BID.

Question 4

Dose escalation (ongoing)?

Answer 4

CALGB 30610 (ongoing): 45 Gy BID Turissi (BED 52) vs.
70 Gy CALGB (BED 84) vs. [arm closed early] 61.2 Gy in 1.8 concom boost, qday for 16 fx then BID for 9 fx from RTOG 0239 (BED 72) with cis/etoposide 4 cycles, then PCI if CR or near CR.

Question 5

Elective nodal irradiation?

Answer 5

Maastricht University, The Netherlands (van Loon et al, IJROBP, 2010): Prospective. RT to 45 Gy/ 1.5 Gy BID with carbo/etoposide. RT directed only to PET avid disease. 65% overall LR, 3% isolated regional node failure
Median OS 19 mos, median PFS 14 mos. In this prospective study there is low regional failure with ommission of ENI in SCLC.

Question 6

Timing of RT?

Answer 6

UNC Chapel Hill, NC (Fried et al, JCO, 2004): Meta-analysis of 7 trials evaluating early vs late RT. Clear benefit to early RT, starting at cycle 1 or 2, less than 9 weeks after start of chemo. 2 yr OS RR 1.17

Question 7

Prophylactic cranial irradiation?

Answer 7

PCI Collaborative Group Gustave-Roussy (Auperin et al, NEJM, 1999): Meta-analysis of 7 trials of SCLC with CR after chemo comparing →PCI vs. →no PCI. PCI improved 3-yr OS 20.7% vs. 15.3%
3-yr brain mets: 33% vs. 59%
Dose increase led to less mets but no change in survival
Earlier PCI resulted in less brain mets

INT PCI 99-01 / EORTC / RTOG 0212 / IFCT (Le Péchoux et al, Lancet Oncol, 2009 Le Péchoux et al, Ann Onc 2011): Limited-stage SCLC in CR after chemo and RT. →25 Gy/10 daily fx vs. →36 Gy/18 QD or 36 Gy/24 BID. Although there was some trend to benefit in LC with high dose PCI, OS was worse, compared to lower dose PCI. High dose PCI increased toxicity. 2-yr OS trend to worse with high dose 42% vs. 37%, p=0.05

Question 8

Hippocampal avoidance+memantine?

Answer 8

PREMER (Rodriguez de Dios et al, ASTRO, 2019): →PCI 25 Gy/10 fx vs. →IMRT PCI 25 Gy/10 fx with hippocampal avoidance. Better free delayed recall with hippocampal sparing RT at 3, 6, and 12 mos

Question 9

PCI QOL?

Answer 9

UKCCR/EORTC (Gregor et al, Eur J Cancer, 1997): “If CR to chemo→ PCI (36 Gy/18 fx, 24/12, 30/10, or 8/1) vs.obs. Dose options changed throughout trial. PCI results in minimal neurocognitive toxicity and QOL changes compared to obs.

Question 10

SBRT for early stage inoperable?

Answer 10

University of Nebraska (Verma et al, IJROBP, 2017): Retrospective analysis of 76 lesions in 74 patients from 24 institutions who underwent SABR for inoperable early SCLC. SABR for early stage inoperable SCLC results in favorable outcomes in this retrospective series. SABR should be considered an alternative treatment option.