Radiation Oncology/SCLC/Randomized

Randomized Evidence for Small Cell Lung Cancer

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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
 * 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 6.5 months vs. RT 9.9 months (SS); 10-year OS 0% vs. 4%
 * Conclusion: Radical RT provides better survival than surgery in operable patients

Early vs Late Thoracic RT

 * 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 &mdash; "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). Chest relapse early RT 26% vs. late RT 37% (SS)
 * Toxicity: Early RT 39% vs late RT 23% (SS)
 * 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 &mdash; "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 (1988–1992) -- RT week 1 vs week 6
 * Randomized. 107 patients with LS-SCLC treated with ACC HFX RT 54 Gy in 1.5 Gy BID + concurrent carboplatin/etoposide, and 4 sequential cycles of cisplatin/etoposide. Timing randomized 1) Concurrent CRT at weeks 1-4 vs. 2) concurrent CRT at weeks 6–9. PCI if CR
 * 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.)
 * Survival: median early 2.8 years vs. 2.2 years; 5-year 30% vs. 15% (SS). Higher LC but no difference in DM. Toxicity comparable
 * Conclusion: Initial thoracic concurrent ACC HFX RT with chemo better LC and survival than delayed RT
 * NCI Canada (1985–1988) -- RT during weeks 3-6 vs weeks 15-18
 * 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 &mdash; "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 &mdash; "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

Hyperfractionation

 * NCCTG (1990–96) -- Late 50.4 q D  Vs. 48/32 split-course BID RT
 * 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 RT (24 Gy in 16 fractions, a 2.5-week break, and 24 Gy in 16 fractions) to the chest. Patients then received a sixth cycle of etoposide and cisplatin followed by prophylactic cranial RT (30 Gy/15#)
 * 7-years; 2004 PMID 15234027 &mdash; "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: The median survival and 5-year survival rate from randomization was 20.6 months and 21% for patients who received q.d. RT compared with 20.6 months and 22% for those who received b.i.d. RT. 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.
 * 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 &mdash; "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%. LR 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.

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

Extensive Stage

 * Kragujevac, Yugoslavia (1988–1993) -- Consolidation RT vs consolidation cisplatin/etoposide
 * Randomized. 210 patients treated w/ 3 cycles of cisplatin/etoposide (PE).  Pts w/ distant-CR + local-CR/PR randomized to RT (54 Gy in 36 fx over 18 days) with concurrent carboplatin/etoposide followed by 2 more cycles of PE vs 4 additional cycles of PE.
 * 1999 PMID 10561263 "Role of radiation therapy in the combined-modality treatment of patients with extensive disease small-cell lung cancer: A randomized study." (Jeremic B et al. J Clin Oncol. 1999 Jul;17(7):2092-9.)
 * Outcome: Median OS RT 17 months vs chemo 11 months (SS); 5-year OS 9% vs 4%. No difference in DMFS.
 * Conclusion: Patients with good response to initial chemo may have improved overall survival with consolidative RT

PCI vs Observation

 * EORTC 08993/22993 (2001–2006) -- PCI (20/5 to 30/12) vs Observation
 * Randomized. 286 patients. Extensive stage SCLC and any response to 4-6 cycles of chemo. Treated with 1) PCI (20/5-30/12) vs. 2) no PCI.
 * 1-year; 2007 PMID 17699816 &mdash; "Prophylactic Cranial Irradiation in Extensive Small-Cell Lung Cancer." (Slotman B et al. N Engl J Med. 2007 Aug 16;357(7):664-72.)
 * 1-year outcome: decreased symptomatic brain mets: PCI+ 15% vs. PCI- 40% (SS), improved OS PCI+ 27% vs. PCI- 13% (SS); extracranial progression of 90%
 * Toxicity: PCI side effects, but clinically not significant
 * RT dose: 60% received 20/5 with impressive benefit. Given short survival, authors suggest shorter courses
 * Conclusion: PCI reduces risk of symptomatic brain mets, and improves DFS and OS in ED SCLC
 * Gustave-Roussy PCI-85 (1985–1993) -- PCI 24/8 vs Observation
 * Randomized. 294 patients with SCLC, in CR after initial therapy. Limited (~80%) or extensive stage eligible. Arm 1) PCI 24/8 vs Arm 2) observation. Extensive neuropsych testing. Primary endpoing occurrence of brain mets
 * 1995 PMID 7707405 -- "Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission." (Arriagada R, J Natl Cancer Inst. 1995 Feb 1;87(3):183-90.)
 * Outcome: 2-year isolated brain failure PCI+ 19% vs PCI- 45% 19% (SS); Development of brain mets 40% vs 67% (SS). 98% of brain mets in first 2 years. 2-year OS: PCI + 29% vs PCI- 21% (NS)
 * Toxicity: No difference on neuropsychological function or CT scan
 * Conclusion: PCI in patients with CR decreases risk of brain mets, potential effect on OS should be tested with higher power

PCI Dose

 * Intergroup PCI99-01 / EORTC 00223-08004 / RTOG 02-12 (1999–2005) -- PCI 25/10 vs PCI high dose (36/18 or 36/24)
 * Randomized. 720 pts with L-SCLC, in CR after chemo+thoracic RT. Arm 1) PCI with standard dose 25/10 vs Arm 2) PCI with high dose (36/18 QD or 36/24 1.5 Gy BID). All had brain imaging at baseline. Primary endpoint incidence of brain mets at 2 years
 * 2009 PMID 19386548 -- "Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomised clinical trial." (Le Pechoux C, Lancet Oncol. 2009 Apr 20. [Epub ahead of print]). Median F/U 39 months
 * Outcome: 2-year incidence of brain mets standard 29% vs. high dose 23% (NS). 2-year OS 42% vs. 37% (p=0.05)
 * Toxicity: fatigue 30/34%, headaches 24/28%, N/V 23/28%
 * Conclusion: No significant reduction of brain mets after higher dose PCI, but significant increase in mortality. PCI at 25/10 should remain standard of care