Radiation Oncology/SCLC/Randomized

Randomized Evidence for Small Cell Lung Cancer In process of being cross-linked... 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 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 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 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). 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 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 (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 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 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 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 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 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 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: 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 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%. 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 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 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 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 Prophylactic Cranial Irradiation 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 17699816 — "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 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 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