# Radiation Oncology/SCLC/Limited Stage

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Limited Stage Small Cell Lung Cancer

## Treatment Overview

* Early stage was initially treated with surgery; however, an MRC trial showed that radical RT provides better survival than surgery in operable patients. Meanwhile, systemic chemotherapy was also quite effective
* Two separate meta-analysis using 2 different techniques, both published in 1992, showed that addition of thoracic RT to systemic chemotherapy improves survival. Reduction in risk of death was 17%, with absolute benefit ~5% at 2 years. Combined modality therapy became the standard of care. However, RT dose, duration, and timing was not settled
* RT dose evolution:
** Dose used in most of the historical trials (and those reviewed in the meta-analyses) was 40-50 Gy QD, based on radiobiological data showing small cell radiosensitivity
** An Intergroup trial (INT-0096) showed a significant benefit to hyperfractionation, comparing standard 45 Gy QD in 5 weeks vs. 45 Gy BID in 3 weeks. There was a 10% survival advantage at 5 years, with improved local control. However, Grade 3 esophagitis was significant (27%)
** RTOG 97-12 was a hyperfractionated dose-escalation study, which reached MTD at 61.2 Gy in 5 weeks given QD/BID. Its feasibility was confirmed by RTOG 02-39. This protocol serves as one arm of a current Phase III CALGB trial
** CALGB evaluated QD dose escalation, which didn't reach MTD at 70/35. The feasibility of concurrent 70 Gy QD was confirmed by CALGB 39808. This protocol serves as another arm of a current Phase III CALGB trial
** Ongoing CALGB 30610 trial is evaluating the control arm of 45 Gy BID (INT-0096) vs. a hyperfractionated 61.2/25 arm (RTOG 97-12) vs. high dose 70/35 arm (CALGB 39808), all concurrent with cisplatin/etoposide

## Consensus guidelines

* American Radium Society™ Appropriate Use Criteria: Radiation Therapy for Limited-stage Small Cell Lung Cancer 2020
** 2020 PMID 33166720 -- Chun SG et al., J Thorac Oncol
** Evidence-based guidelines for specific limited-stage SCLC variants rated by multidisciplinary expert panel
** Conclusions:
** Unresectable LS-SCLC should receive concurrent chemotherapy with radiation delivered either once or twice daily
** For medically-inoperable T1-T2N0 LS-SCLC, either concurrent chemoradiation or stereotactic body radiation (SBRT) followed by adjuvant chemotherapy are reasonable treatment options
** Whole brain prophylactic cranial irradiation (PCI) remains recommended after response to chemoradiation for LS-SCLC
** PCI with Hippocampal avoidance and PD-1/PD-L1 directed immune therapy should not be routinely administered outside the context of clinical trials at this time

## Surgery vs. RT

* LCSG 832 -- Induction + surgery + RT vs Induction + RT
** Randomized. 328 registered, 146 randomized. Small cell lung cancer, limited stage (excluding SCV+ and positive pleural effusion), resectable disease after induction. Induction chemotherapy cyclophosphamide, doxorubicin, vincristine x5 cycles. If CR/PR (66%), randomized to Arm 1) surgery vs Arm 2) no surgery. All patients subsequently underwent thoracic RT 50/25 and PCI 30/15
** 1994 PMID 7988254 -- "A prospective randomized trial to determine the benefit of surgical resection of residual disease following response of small cell lung cancer to combination chemotherapy." (Lad T, Chest. 1994 Dec;106(6 Suppl):320S-323S.)
*** Outcome: pCR 19%. 2-year OS 20% vs 20% (NS). Median OS for all patients 12 months, for randomized 16 months
*** Conclusion: Results do not support addition of pulmonary resection to multimodality treatment
* MRC -- surgery vs. primary RT
** Randomized. 144 patients with small cell or oat cell carcinoma of the bronchus. Diagnosed on bronchial biopsy and thought to be operable. Arm 1) surgery vs. Arm 2) primary RT. Complete resection in 48%; radical RT in 85%
** 5-years; 1969 PMID 4184834 -- "Five-year follow-up of the Medical Research Council comparative trial of surgery and radiotherapy for the primary treatment of small-celled or oat-celled carcinoma of the bronchus." (Miller AB, Lancet. 1969 Sep 6;2(7619):501-5.)
*** Outcome: median OS surgery 6 months vs. RT 9 months (SS); 2-year OS surgery 4% vs. RT 10%, 5-year 1% vs. 4% (the 1 surgical arm survivor didn't have surgery but RT)
*** Conclusion: Radical RT better survival than surgery for operable patients
** 10-years; 1973 PMID 4123619 -- "Medical Research Council comparative trial of surgery and radiotherapy for primary treatment of small-celled or oat-celled carcinoma of bronchus. Ten-year follow-up." (Fox W, Lancet. 1973 Jul 14;2(7820):63-5.)
*** Outcome: median OS surgery 6 months vs. RT 10 months (SS); 10-year OS 0% vs. 4%
*** Conclusion: Radical RT provides better survival than surgery in operable patients

## Chemotherapy +/- RT
### Meta-analysis

* Pignon; 1992 PMID 1331787 — "A meta-analysis of thoracic radiotherapy for small-cell lung cancer." (Pignon JP, N Engl J Med. 1992 Dec 3;327(23):1618-24.)
** 13 trials. 2103 patients with limited stage. Pts with extensive disease were excluded. Compared chemo alone vs chemo + thoracic RT. Median F/U for survivors 3.6 years
** Outcome: Risk of death for chemo + RT group was 0.86 (SS), corresponding to 14% reduction in mortality. 3-year OS chemo alone 9% vs. chemo-RT 14% (SS), absolute benefit 5.4% . Did not show a difference between early and late thoracic RT.
** Conclusion: Thoracic RT moderately improves survival in patient with LS-SCLC treated with chemotherapy
** Comment: chemotherapy was cyclophosphamide-based or doxorubicin-based regimens; did not use cisplatin + etoposide which is the modern standard of care.
* Warde; 1992 - PMID 1316951 — "Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis." Warde P et al. J Clin Oncol. 1992 Jun;10(6):890-5.
** Does the addition of radiotherapy to chemotherapy improve survival and local control in limited stage SCLC?
** Meta-analysis. 11 randomized trials. Odds ratio for OS @ 2-years was 1.53 (benefit for RT); improves 2-year survival by 5.4%. OR for LC is 3.02, improved by 25.3%. More treatment related deaths by 1.2%.

### Concurrent Chemotherapy +/- RT

* Chemotherapy alone without RT leads to LF in 75-90% of pts. Addition of XRT reduces LF to 30-60%.
* Cisplatin + etoposide (PE) is modern standard of care. Introduced in 1970s but emerged as primary therapy in early 1980s. Advantage is that PE can be given concurrently with full doses of thoracic RT with less toxicity than older doxorubicin or cyclophosphamide-based regimens.
* CALGB, 1987 - PMID 3029592 — "Chemotherapy with or without radiation therapy in limited small-cell carcinoma of the lung." Perry MC et al. N Engl J Med. 1987 Apr 9;316(15):912-8.
** Randomized. Improved overall survival.
* SWOG 8269 (1985-1986)
** Phase II, non-randomized. 114 patients. 3 cycles of induction chemo with PEV (cisplatin, etoposide, VCR). Followed by RT to 45 Gy (1.8 Gy/fx) concomitant with 2 cycles of VCR, MTX, etoposide, doxorubicin and cyclophosphamide. PCI with 3rd cycle of induction chemo - 30 Gy in 15 fx.
** 3-years; 1990 PMID 2159055 — "Concurrent chemotherapy/radiotherapy for limited small-cell lung carcinoma: a Southwest Oncology Group Study." (McCracken JD et al. J Clin Oncol. 1990 May;8(5):892-8.)
** 13-years; 2001 PMID 11551416 — "Ten-year follow-up of Southwest Oncology Group 8269: a phase II trial of concomitant cisplatin-etoposide and daily thoracic radiotherapy in limited small-cell lung cancer." (Thomas CR Jr,Lung Cancer. 2001 Aug-Sep;33(2-3):213-9.). Min F/U 13 years
*** Outcome: 5 pts alive and progression free. Of those who died from disease, LF in 24%, DM in 35%, LF+DM in 25%. LF as any cause of failure in 49%. 5-yr OS 26%, 10-yr 11%
*** Conclusion: Few long term survivors. Continued relapses even after 10 yrs.
* NCDB Analysis 2018 (2004-2013) PMID 29302695 PMID 30073269 -- "Barriers to Combined-Modality Therapy for Limited-Stage Small-Cell Lung Cancer." (Pezzi TA et al., JAMA Oncology 2018)
** Analysis of 70,247 patients in NCDB with IASLC-defined limited-stage SCLC
** Initial treatment: 55.5% chemotherapy + radiation, 20.5% chemotherapy alone, 3.5% radiation alone, and 20.0% neither chemotherapy/radiation
** Median Survival: chemotherapy + radiation 18.2 mo, chemotherapy alone 10.5 mo, radiation alone 8.3 mo, neither chemotherapy/radiation therapy 3.7 mo
** United States Government Insurance (Medicare/Medicaid) associated with worse survival and lower likelihood of radiation delivery
** Survival better at academic centers than in other practice settings
** Conclusion: Substantial proportions of patients documented in NCDB did not receive radiation therapy or chemotherapy as part of initial treatment for limited-stage SCLC, which was associated with poor survival

### Induction chemo +/- RT

* SWOG 7924 (1979-1982)
** Randomized, 2 randomizations. 466 patients with LS-SCLC. Induction chemotherapy (VMV-VAC), then:
*** If CR (33%): randomized to Arm 1) Thoracic RT vs. Arm 2) Cyclophosphamide. RT split course 18/10 large fields (including SCV) + 30/12 reduced fields (2cm margin), to either preinduction or postinduction volume.
*** If PR/SD (58%): randomized to Arm 1) Wide-volume (pre-induction) RT vs. Arm 2) reduced-volume (post-induction) RT. RT split-course 18/10 + 30/12. Planning from CXR
** 1987 PMID 3031226 -- "Multimodal therapy for limited small-cell lung cancer: a randomized study of induction combination chemotherapy with or without thoracic radiation in complete responders; and with wide-field versus reduced-field radiation in partial responders: a Southwest Oncology Group Study." (Kies MS, J Clin Oncol. 1987 Apr;5(4):592-600.)
*** CR Outcome: OS thoracic RT 17% vs. no RT 24% (NS); LR 56% vs. 90% (SS)
*** PR/SD Outcome: median OS wide-field RT 12 months vs. reduced-field RT 11 months (NS)
*** Toxicity: severe/fatal myelosuppression wide-field 18% vs. reduced-field 8%
*** Conclusion: RT improves local control but has no impact on survival if CR after induction. There is no difference in field size, if PR after induction

## Timing of RT and Chemotherapy
### Meta-analysis

* 2007 PMID 17513057 -- "Timing of chest radiotherapy in patients with limited stage small cell lung cancer: a systematic review and meta-analysis of randomised controlled trials." (Pijls-Johannesma M, Cancer Treat Rev. 2007 Aug;33(5):461-73. Epub 2007 May 21.)
** 7 randomized trials: 2-year OS no difference, 5-year OS no difference
** 5 randomized trials (concurrent cisplatin-based chemo): 2-year OS better if early RT (HR 0.73, SS), 5-year OS also better (HR 0.65, SS). Benefit if RT started within 30 days of chemotherapy. Additional benefit if overall RT time <30 days
** Conclusion: With platinum-based chemo, RT within 30 days of chemo start better, and RT duration <30 days better
* 2006 PMID 16344277, 2006 — "Systematic review and meta-analysis of randomised, controlled trials of the timing of chest radiotherapy in patients with limited-stage, small-cell lung cancer." (De Ruysscher D et al. Ann Oncol. 2006 Apr;17(4):543-52.) and Cochrane Review; 2005 PMID 15674960 — "Early versus late chest radiotherapy for limited stage small cell lung cancer." Pijls-Johannesma MC et al. Cochrane Database Syst Rev. 2005 Jan 25;(1):CD004700.
** 7 randomized trials: No difference between early and late RT
** 6 platinum randomized trials: No difference in 2-year survival (OR 0.73, NS), early RT superior at 5-years (OR 0.64, SS). In studies with short RT (<30 days treatment time), 2-year survival no difference, but 5-year OS better (OR 0.56, SS)
** Conclusion: No significant difference in survival for early vs late chest RT. There may be a trend for improved survival with early RT (<30 days from start of chemo).
* 2004 PMID 15561810 Full text, 2004 — "A meta-analysis of the timing of chest irradiation in the combined modality treatment of limited-stage small cell lung cancer." Huncharek M et al. Oncologist. 2004;9(6):665-72.
** 8 randomized trials; 2 were split course, 3 were concurrent cisplatin/etoposide and RT
** Outcome (1-year): 1-year OS benefit for early RT OR 1.11 (NS), excluding split-course RT 1-year OS benefit OR 1.34 (SS), including only 3 concurrent cisplatin/etoposide-RT OR 1.95 (SS)
** Outcome (2-year): 2-year OS benefit for early RT OR 1.60 (SS), excluding split-course RT 2-year OS benefit OR 1.78 (SS), concurrent cis/etoposide-RT OR 1.81 (SS)
** Conclusion: Early RT improves 2-year survival by ~80%
* 2001 PMID 16505424 2006 — "Time between the first day of chemotherapy and the last day of chest radiation is the most important predictor of survival in limited-disease small-cell lung cancer." De Ruysscher D et al. J Clin Oncol. 2006 Mar 1;24(7):1057-63.
** 4 PIII studies (Murray, Jeremic, Turrisi, Takada); evaluation of "start of therapy - end of RT" time interval (SER)
** SER most important predictor of outcome; 5-year OS +20% if SER < 30 days

### Randomized evidence

* London Lung Cancer Group (1993-1999) -- RT week 3 vs week 15
** Randomized. 325 patients. Attempted to replicate NCIC study. Cyclophosphamide + Doxorubicin + Vincristine alternating with Cisplatin + Etoposide x 3 cycles each. RT dose was 40 Gy/15 fractions over 3 weeks. Arm 1) thoracic RT 40/15 week 3 vs Arm 2) thoracic RT 40/15 week 15. PCI 25/10 in patients with negative head CT after therapy
** 2006 PMID 16921033 — "Early compared with late radiotherapy in combined modality treatment for limited disease small-cell lung cancer: a London Lung Cancer Group multicenter randomized clinical trial and meta-analysis." (Spiro SG et al., J Clin Oncol. 2006 Aug 20;24(24):3823-30.)
*** Outcome: Median OS early TRT 14 months vs late TRT 15 months (NS). Completion of all cycles of chemo early RT 69% vs late RT 80% (NS)
*** Conclusion: No survival advantage for early thoracic RT
* Japanese JCOG 9104 (1991-1995) -- RT week 1 vs. week 10
** Randomized. 231 pts. All pts received 4 cycles of cisplatin 80 mg/m2 + etoposide 100 mg/m2 chemotherapy. Randomized to: Arm 1) concurrent RT 45/30 BID starting day 2 vs Arm 2) sequential RT 45/30 BID based on pretreatment volumes. PCI 24/16 BID if CR/near CR
** 2002 PMID 12118018 — "Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan Clinical Oncology Group Study 9104." (Takada M et al. J Clin Oncol. 2002 Jul 15;20(14):3054-60.)
*** Outcome: 3-year OS concurrent 30% vs. sequential 20% (NS); 5-year OS 24% vs 18% (NS). After adjustment, hazard ratio for death in concurrent arm 0.7 (SS). Brain mets concurrent 19% vs sequential 27% (no p)
*** Conclusion: Suggestion for benefit of concurrent vs sequential chemo-RT
* Kragujevac, Yugoslavia (Yugoslavia)(1988-1992) -- RT week 1 vs week 6
** Randomized. 107 patients treated by ACC Hfx RT (54 Gy in 1.5 Gy/fx BID) with concurrent carboplatin/etoposide (C/E), randomized to either:
*** (1) Initial ACC Hfx RT: Concurrent chemo-RT (wks 1-4) --> consolidation cisplatin/etoposide (P/E) x 4, vs.
*** (2) Delayed ACC Hfx RT: Induction P/E x 2 --> concurrent chemo-RT (wks 6-9) --> consolidation P/E x 2
** 1997 PMID 9060525 -- "Initial versus delayed accelerated hyperfractionated radiation therapy and concurrent chemotherapy in limited small-cell lung cancer: a randomized study." (Jeremic B, J Clin Oncol. 1997 Mar;15(3):893-900.)
*** Median survival: 34 months vs. 26 months (p=0.052), 5-year OS 30% vs. 15% (p=0.03). Significantly higher LRFS for group 1. Toxicity comparable
*** Conclusion: Initial thoracic concurrent ACC HFX RT with chemo better LC and survival than delayed RT
** 2007 PMID 17306936 -- "Influence of interfraction interval on local tumor control in patients with limited-disease small-cell lung cancer treated with radiochemotherapy." (Jeremic B, Int J Radiat Oncol Biol Phys. 2007 Jun 1;68(2):426-32.)
*** Not randomized; subset analysis. Comparison of short (4.5-5.0) vs. long (5.5-6.0) interfraction interval
*** No difference. No difference in "early RT" group; trend toward significance in "late RT" group
* NCI Canada (1985-1988) -- RT week 3 vs week 15
** Randomized. 308 patients with limited-stage SCLC. All received CAV (cyclophosphamide, adriamycin, vincristine) x 3 alternating with EP (etoposide, cisplatin) x 3, every 3 weeks. Arm 1) Early thoracic RT to 40/15 concurrent with 2nd cycle of chemo (first cycle of EP; week 3) vs Arm 2) late thoracic RT concurrent with last cycle of EP (week 15). PCI in patients without progressive disease.
** 1993 PMID 8381164 — "Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group." (Murray N et al. J Clin Oncol. 1993 Feb;11(2):336-44.) Median F/U 5 years
*** Outcome: 3-year PFS early TRT 26% vs late TRT 19% (SS). 3-year OS 30% vs 21% (SS), 5-year OS 20% vs 11%. Isolated thoracic recurrence 19% vs 15% (NS), thoracic recurrence (isolated + elsewhere) 30% vs 30%.
*** Brain mets: before PCI early TRT 4% vs late RT 9% (NS), after PCI 13% vs 19% (NS), overall brain mets 18% vs 28% (SS)
*** Conclusion: Early administration of thoracic RT is superior to later thoracic RT
* Denmark (1981-1989) -- RT week 1 vs RT week 18
** Randomized. 199 patients with limited stage SCLC. Chemotherapy cisplatin/etoposide x3 cycles and cyclophosphamide, doxorubicin, and vincristine x6 cycles. Arm 1) Initial thoracic RT week 1 vs Arm 2) Late thoracic RT week 18. RT split course 22.5/11 - 21 days of chemotherapy - 22.5/11. PCI 25/11 added in 1984 for all patients
** 1997 PMID 9294465 -- "Randomized study of initial versus late chest irradiation combined with chemotherapy in limited-stage small-cell lung cancer. Aarhus Lung Cancer Group." (Work E, J Clin Oncol. 1997 Sep;15(9):3030-7.)
*** Outcome: 2-year OS initial TRT 20% vs late TRT 19% (NS). 2-year local control 72% vs. 68% (NS). 2-year brain mets 19% vs 13% (NS)
*** Conclusion: Timing of thoracic radiation didn't influence in-field recurrence, CNS recurrence, or overall survival
* CALGB 8083 -- RT week 1 vs week 9 vs chemotherapy only
** Randomized. 399 patients, limited stage SCLC. Chemo cyclophosphamide + etoposide + vincristine (later replacing etoposide with adriamycin. Arm 1) Thoracic RT on day 1 vs Arm 2) Thoracic RT on day 64), or 3) chemotherapy only. RT dose 40 Gy + 10 Gy boost. PCI to 30 Gy.
** 1998 PMID 9667265 — "Thoracic radiation therapy added to chemotherapy for small-cell lung cancer: an update of Cancer and Leukemia Group B Study 8083." (Perry MC et al. J Clin Oncol. 1998 Jul;16(7):2466-7.)
*** Outcome: Early TRT median OS 13 month vs late TRT 15 months vs chemo only 14 months (NS). Time to clinical failure not different between the two RT arms.
** Conclusion: There is no difference between early and late thoracic RT
** 1987 PMID 3029592 -- "Chemotherapy with or without radiation therapy in limited small-cell carcinoma of the lung." (Perry MC, N Engl J Med. 1987 Apr 9;316(15):912-8.)
*** Outcome: Significant benefit for two RT regimens in terms of chest control, PFS, and OS
*** Conclusion: Addition of RT improved survival

## Treatment Technique
### Field Design

Fields from INT-0096: Gross tumor, bilateral mediastinal lymph nodes, ipsilateral hilum. No supraclav nodes. Inferiorly extended to at least 5 cm below carina, or to hilum. 1-1.5 cm margin The spinal cord limit was 36 Gy. Oblique off cord fields were used in the afternoon tx during the 2nd and 3rd weeks.

### Pre-induction vs. Post-induction Volume

* NCCTG; 1999 (1990-1996) PMID 10561342 — "Phase III comparison of twice-daily split-course irradiation versus once-daily irradiation for patients with limited stage small-cell lung carcinoma." (Bonner JA, J Clin Oncol. 1999 Sep;17(9):2681-91.)
** See below for full trial details. Randomized RT 50.4/28 vs. Split-course RT 24/16 BID + 24/16 BID. RT target post-chemo volume
** Outcome: 92% of chest failures still in-field, despite post-chemo volume
* Mayo; 1994 (1982-1990) - PMID 8120547 — "Limited-stage small-cell lung cancer: patterns of intrathoracic recurrence and the implications for thoracic radiotherapy." (Liengswangwong V, J Clin Oncol. 1994 Mar;12(3):496-502.)
** Retrospective. 59 patients. Compared 28 pts (post-induction volume) vs 31 (pre-induction). Same sequence of chemo and RT.
** No difference in marginal failure or failures outside the treatment field.
* SWOG 7924 (1979-1982)
** Randomized, 2 randomizations. 466 patients with LS-SCLC. Induction chemotherapy (VMV-VAC), then:
*** If CR (33%): randomized to Arm 1) Thoracic RT vs. Arm 2) Cyclophosphamide. RT split course 18/10 large fields (including SCV) + 30/12 reduced fields (2cm margin), to either preinduction or postinduction volume.
*** If PR/SD (58%): randomized to Arm 1) Wide-volume (pre-induction) RT vs. Arm 2) reduced-volume (post-induction) RT. RT split-course 18/10 + 30/12. Planning from CXR
** 1987 PMID 3031226 -- "Multimodal therapy for limited small-cell lung cancer: a randomized study of induction combination chemotherapy with or without thoracic radiation in complete responders; and with wide-field versus reduced-field radiation in partial responders: a Southwest Oncology Group Study." (Kies MS, J Clin Oncol. 1987 Apr;5(4):592-600.)
*** CR Outcome: OS thoracic RT 17% vs. no RT 24% (NS); LR 56% vs. 90% (SS)
*** PR/SD Outcome: median OS wide-field RT 12 months vs. reduced-field RT 11 months (NS)
*** Toxicity: severe/fatal myelosuppression wide-field 18% vs. reduced-field 8%
*** Conclusion: RT improves local control but has no impact on survival if CR after induction. There is no difference in field size, if PR after induction

### Elective Nodal Irradiation

* Maastricht; 2010 (Netherlands)(2004-2006) PMID 19782478 --"Selective nodal irradiation on basis of (18)FDG-PET scans in limited-disease small-cell lung cancer: a prospective study." (van Loon J et al, Int J Radiat Oncol Biol Phys. 2010 Jun 1;77(2):329-36.)
** Prospective, 60 pts w/ LS-SCLC with treated chemo (carboplatin/etoposide), chest RT (45 Gy BID fx's) & PCI.
** Primary GTV based on CT findings only; post-chemo volumes used if induction chemo given. Nodal GTV based on pre-chemo PET. No ENI.
** 30% difference in nodal station staging on PET vs CT-only; 15% w/ more nodal stations ID'd w/ PET and 13% w/ less on PET.
** Isolated regional failure in 2 pts (3%). Median OS 19 months.
** Conclusion: PET-based selective nodal RT resulted in low rate of isolated nodal failure (3%), in contrast to this group's experience w/ CT-based selective nodal RT (11%, see below).
* Masstricht; 2006 (Netherlands)(2002-2004) PMID 16949169 -- "Omission of elective node irradiation on basis of CT-scans in patients with limited disease small cell lung cancer: a phase II trial." (De Ruysscher D, Radiother Oncol. 2006 Sep;80(3):307-12. Epub 2006 Sep 1.)
** Phase II. 27 patients with LS-SCLC. CT staged. IFRT 45/30 BID (corrected) concurrent with carboplatin AUC 5/etoposide 120 mg/m2 (start during first cycle). Target: primary tumor (PTV = GTV + 1.5 cm) and LN+ (PTV = GTV + 1.0 cm) on pre-treatment CT, no assessment of tumor motion. PCI 25/10 or 26/18. Median F/U 1.5 years
** Outcome: Median OS 21 months, median PFS 16 months. LR 26%, isolated nodal failure 11% (all ipsilateral SCV)
** Toxicity: Acute G3 esophagitis 30%
** Conclusion: Higher than expected rate of isolated nodal failure, comparable acute esophagitis. IFRT should only be used on protocol
* Dutch NCI; 2006 (Netherlands)(1999-2001) -- "Concurrent chemotherapy (carboplatin, paclitaxel, etoposide) and involved-field radiotherapy in limited stage small cell lung cancer: a Dutch multicenter phase II study." (Baas P, Br J Cancer. 2006 Mar 13;94(5):625-30.)
** Phase II. Stopped early due to positive experience. 37 patients with LS-SCLS. CT staged. Chemo paclitaxel 200 mg/m2, carboplatin AUC 5, etoposide 100 mg. IFRT 45/25 QD. Target: primary tumor, LN+ short axis >=1 cm on planning scan after 1 cycle of chemo. RT start after 2nd chemo cycle. PCI 30/12 or 20/15
** Outcome: Median OS 19 months, 5-year OS 27%. In-field recurrence 16%, distant recurrence 51%, regional (elective LN) failure subset not reported
** Severe Toxicity: hematologic 57%, esophagitis 27%, pneumonitis 6%, dyspnea 19%, lethargy 22%
** Conclusion: Chemotherapy with concurrent IFRT effective
** Comment PMID 17595661 (Updated data, 2007): Elective node failure 5% (1 ipsilateral SCV, 1 hilar). In-field failure 24%. Difference from De Ruyscher above (PMID 16949169) less intense RT so it is possible in-field failures occurred before nodal failures. Also unclear why their failures were in SCV region only

### Hyperfractionation

Rationale: small cell lung cancers are radiosensitive and have a small shoulder in the dose response curve. Dose-limiting toxicity is 45 Gy BID in 3 weeks, or 61.2 Gy QD/BID in 5 weeks concurrent with cisplatin/etoposide.
* CONVERT (2008-2013) -- BID 45 Gy or QD RT 66 Gy
** Acronym: Concurrent ONce-daily VErsus twice-daily RadioTherapy
** Protocol: PMID 26792218 (Radiation technique and constraints in Supplement 4)
** 547 pts, LS-SCLC. Chemo RT with either 45 Gy (1.5 BID) or 66 Gy (2 Gy QD). Starting with 2nd cycle of cis/etoposide. No ENI. +PCI at discretion. Superiority trial.
** 2017 PMID 28642008 — "Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial." (Faivre-Finn C, Lancet Oncol. 2017 Aug;18(8):1116-25.)
*** Median f/u 45 mo. Median OS 30 mo (BID) vs 25 mo (QD), NS. 2-yr OS 56% vs 51% (NS).
*** Toxicity: Most toxicities similar. Worse g4 neutropenia in BID. No difference in esophagitis or pneumonitis.
*** Conclusion: "Survival outcomes did not differ between twice-daily and once-daily concurrent chemoradiotherapy .... Since the trial was designed to show superiority of once-daily radiotherapy and was not powered to show equivalence, the implication is that twice-daily radiotherapy should continue to be considered the standard of care in this setting."
** 2024 PMID 38521132 -- "Long-Term Outcomes After Concurrent Once- or Twice-Daily Chemoradiation in Limited-Stage Small Cell Lung Cancer: A Brief Report From the CONVERT Trial" (Walls GM, Int J Radiat Oncol Biol Phys. 2024 Aug 1;119(5):1386-1390. doi: 10.1016/j.ijrobp.2024.02.063. Epub 2024 Mar 21.) Median F/U 6.7 years
*** Outcome: Median OS QD 25 months vs BID 30 months (NS). PS and volume status improved survival on MVA
*** Toxicity: Worse in BID, but both arms low. Completion rate 98% vs 83%
*** Outcome: Daily not superior, so 45 BID should remain standard of care
* RTOG 97-12 (1998-2002) Protocol PMID 15890573 -- "Phase I study of thoracic radiation dose escalation with concurrent chemotherapy for patients with limited small-cell lung cancer: Report of Radiation Therapy Oncology Group (RTOG) protocol 97-12." (Komaki R, Int J Radiat Oncol Biol Phys. 2005 Jun 1;62(2):342-50.)
** Phase I. 64 patients. Concurrent chemo-RT dose escalation. RT starting Day 1, given QD initially then BID to keep treatment within 5 weeks. Dose 50.4 -> 54.0 -> 57.6 -> 61.2 -> 64.8 Gy. Chemo cisplatin/etoposide
** Outcome: MTD 61.2 Gy; 3/5 patients on 64.8 Gy developed acute Grade 3 esophagitis. 18 month survival 50.4 Gy 25% vs. 61.2 Gy 82%
** Conclusion: MTD for this accelerated RT with concurrent PE is 61.2 Gy over 5 weeks
* NCCTG (1990-96) -- late 50.4 QD vs. 48/32 split-course BID
** Randomized. 262 patients with LS-SCLC. Induction cisplatin/etoposide x3 cycles, RT start 4th cycle. Arm 1) conventional RT 50.4/28 vs 2) split-course BID 48/32 (Mayo regimen), each given in 5.5 weeks. PCI to 30 Gy/15 fx.
** 1999 PMID 10561342 — "Phase III comparison of twice-daily split-course irradiation versus once-daily irradiation for patients with limited stage small-cell lung carcinoma." Bonner JA et al. J Clin Oncol. 1999 Sep;17(9):2681-91.
*** No difference in local progression, overall progression, or survival. Higher rate of esophagitis in the BID arm.
** 2004 PMID 15234027 — "Long-term results of a phase III trial comparing once-daily radiotherapy with twice-daily radiotherapy in limited-stage small-cell lung cancer." (Schild SE, Int J Radiat Oncol Biol Phys. 2004 Jul 15;59(4):943-51.) Median F/U 7.4 years
*** Outcome: median OS QD 1.7 years vs. BID split 1.7 years (NS); 3-year OS 29% vs. 34% (NS). No difference in progression, intrathoracic failure, in-field failure (41% vs. 42%), or distant failure.
*** Toxicity: Grade 3+ esophagitis 5% vs. 12%; otherwise comparable
*** Conclusion: When RT given with the 4th cycle of chemotherapy, BID RT does not improve survival.
** Note: the BID split course (5-1/2 wks) is not the same as the Turrisi BID regimen (3 wks). The media OS & 5-yr OS for the QD/50.4 Gy group was 20.6 m / 21% compared with BID arm in the Turrisi randomized trial (45 Gy, BID in 3 wks) 23 m / 26% -- but these trials cannot be directly compared.
* ECOG / Intergroup 0096 / RTOG 8815 (1989-1992) -- early 45 Gy QD vs. 45 Gy BID
** Randomized. 417 patients with LS-SCLC (pleural effusion, contralateral hilar/SCV excluded). Arm 1) RT 45/25 @1.8 Gy QD over 5 weeks vs. Arm 2) RT 45/30 @1.5 Gy BID over 3 weeks. RT started on Day 1 of chemotherapy; 4 cycles of cisplatin 60 mg/m2 and etoposide 120 mg/m2 (EP) Q3W. RT fields included bilateral mediastinum, ipsilateral hilum. Inferior border 5 cm below carina or including hilum. Elective ipsilateral SCV forbidden. PCI 25/10 given after chemotherapy for patients with CR
** 8-years; 1999 PMID 9920950 Full text — "Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide." (Turrisi AT et al. N Engl J Med. 1999 Jan 28;340(4):265-71.) Median F/U 8 years
*** Outcome: Median OS QD 1.6 years vs. BID 1.9 years (SS); 2-year OS 41% vs 47%; 5-yr OS 16% vs 26%. Local failure QD 52% vs BID 36% (p=0.06)
*** Toxicity: Grade 3 esophagitis QD 11% vs. 27%, no difference in Grade 4 esophagitis
*** Conclusion: Survival exceeds that of any previous randomized trial. Small difference between QD and BID at 2 years but 10% improvement at 5 years.
** Comment: Not a comparison of once a day vs twice a day since the biologically effective doses weren't equivalent. 45 Gy BID is closer to about 60 Gy QD, which is the current "standard" dose (60-66 Gy) for once a day RT. However, at the time of the trial, 40-50 Gy QD was the standard dose
* Mayo; 1996 PMID 8610649 — "Infusion cisplatin chemotherapy and hyperfractionated thoracic radiotherapy for small-cell lung cancer." (Frytak S, Am J Clin Oncol. 1996 Apr;19(2):193-8.)
** Phase II. 60 patients, 29 LS-SCLC. Infusion cyclophosphamide, etoposide, and cisplatin (CEPi). Hyperfractionated split-course RT 48/32 given 24/16 @ 1.5 Gy BID with 2 week break, started cycle 4-5 of chemo (modified MGH H&N protocol). RT field post-chemo volume, GTV + 2cm + regional LNs
** Outcome: median OS 2.2 years, 2-year OS 55%
** Conclusion: Safe and effective program for treating SCLC

### Continuous vs Interdigitated split-course RT

* EORTC LCCG (1989-1995) -- continuous RT 50/20 vs interdigitated split RT 12.5/5 x4
** Randomized. 349 patients. Chemotherapy cyclophosphamide, doxorubicin, and etoposide (CDE). Arm 1) continuous RT 50/20 started week 13-19 vs Arm 2) interdigitated split course RT 50/20 on weeks 5, 9, 13, and 17 @ 12.5/5
** 1997 PMID 9256127 -- "Randomized trial of alternating versus sequential radiotherapy/chemotherapy in limited-disease patients with small-cell lung cancer: a European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group Study." (Gregor A, J Clin Oncol. 1997 Aug;15(8):2840-9.)
*** Outcome: 3-year OS continuous 15% vs interdigitated 12% (SS). No difference in local relapse
*** Toxicity: Grade 3-4 neutropenia continuous 77% vs interdigitated 90% (SS); toxicity compromised treatment dose delivery, such that full RT delivered in continuous 93% vs interdigitated 77% (SS).
*** Conclusion: Interdigitated schedule not superior; hematological toxicity compromised treatment delivery
* Wake Forest (1987-1992) -- Continuous RT 50/25 vs. Split course RT 25/10 + 25/10
** Randomized. 114 patients. Arm 1) RT continuous 50/25 during chemo cycle 1-2 vs. Arm 2) RT split-course 25/10 + 25/10 during chemo cycle 1-3. Chemo cisplatin/etoposide cycle 1, 2, and 5 + cyclophosphamide/vincristine/doxorubicin cycle 3, 4, and 6. PCI after CR
** 2005 PMID 15845179 -- "Split-course versus continuous thoracic radiation therapy for limited-stage small-cell lung cancer: final report of a randomized phase III trial." (Blackstock AW, Clin Lung Cancer. 2005 Mar;6(5):287-92.) Median F/U 1.2 years
*** Outcome: 5-year OS continuous 18% vs. split-course 17% (NS); no difference in patterns of failure
*** Toxicity: Grade 3+ esophagitis continuous 9% vs. split-course 4%
*** Conclusion: Interdigitated split-course RT not better than continuous RT

### Dose escalation

* CALGB 39808 (1999-2000) PMID 15145163 -- "70 Gy thoracic radiotherapy is feasible concurrent with chemotherapy for limited-stage small-cell lung cancer: analysis of Cancer and Leukemia Group B study 39808." (Bogart JA, Int J Radiat Oncol Biol Phys. 2004 Jun 1;59(2):460-8.)
** Phase II. 63 patients. Induction chemo (paclitaxel + topotecan) x2 cycles, followed by concurrent chemo-RT. RT 70/35 (uncorrected, prescribed to isocenter). Field included Stations 3, 4, 7 and 5, 6 on left to 44 Gy, then PTV = GTV + hilar LNs + 1cm. Chemo carboplatin AUC 5, etoposide. PCI offered for CR/PR
** Outcome: Median OS 1.9 years
** Toxicity: 90% patients proceeded to TRT. Grade 3+ dysphagia 16%. 1 treatment-related mortality
** Conclusion: 70 Gy QD can be delivered safely; initial efficacy encouraging
* CALGB; 1998 (1989-1994) PMID 9817271 -- "Phase I study to determine the maximum-tolerated dose of radiation in standard daily and hyperfractionated-accelerated twice-daily radiation schedules with concurrent chemotherapy for limited-stage small-cell lung cancer." (Choi NC, J Clin Oncol. 1998 Nov;16(11):3528-36.)
** Phase I, dose escalation. 50 patients. RT initial volume 40 Gy, increasing boost, delivered QD or BID. Chemotherapy cisplatin/cyclophosphamide/etoposide (PCE) x3 + cisplatin/etoposide x2. RT started at 4th cycle
** Escalation: MTD for BID RT was 45 Gy in 30 fractions in 3 weeks. MTD for QD RT was >70 Gy in 35 fractions in 7 weeks.
** Outcome: 2-year OS BID 52%, QD 54%
** Conclusion: MTD for BID and QD concurrent RT determined

## Current trials

* CALGB 30610 / RTOG 0538 NCI link PROTOCOL
** Randomized, 3 arms. Arm 1) 45/30 BID vs. Arm 2) 70/35 QD vs. Arm 3) 61.2/34 QD->BID. Concurrent cisplatin/etoposide
* RTOG 06-23 - Phase II trial. Same schedule as RTOG 02-39 (RT 61.2 Gy/5 weeks + cisplatin/etoposide) with growth factor support. Trial has been terminated after accruing 5/44 targeted patients.
* RTOG 02-39 (2003-2006) Protocol (PDF) - A phase II study of accelerated high dose thoracic irradiation with concurrent chemotherapy for patients with limited small cell lung cancer
** RT: 61.2 Gy in 5 weeks (concomitant boost). Concurrent chemo: Start on day 1. Cisplatin + etoposide q3week x 2 cycles. 2nd cycle starts the day before BID RT starts. Adjuvant chemo: 2 cycles cisplatin + etoposide. If CR, PCI on RTOG 02-12
** Preliminary outcomes (from RTOG 0623 protocol): 72 patients. Grade 3 esophagitis 16%, Grade 3-4 hematologic toxicity 90%, 2 deaths. As a result, opened RTOG 06-23 with growth factor support

## SVC Syndrome

* For more information, please see the SVC Syndrome page
* London, 1983 (UK) PMID 6310812 -- "Treatment of obstruction of the superior vena cava by combination chemotherapy with and without irradiation in small-cell carcinoma of the bronchus. (Spiro SG, Thorax. 1983 Jul;38(7):501-5.)
** Randomized. 366 patients with SCLC on trial, 37 presented with SVC obstruction. 9 relapsed during chemo and were not randomized Treated with chemo x4 cycles then randomized to +/- RT, followed by 8 cycles of chemo.
** Outcomes: after chemo x4 cycles, 21/37 (57%) CR of SVC symptoms. Median OS identical
** Conclusion: Chemo alone effective for SVC; no benefit to RT if given after 12 weeks of chemo