Radiation Oncology/NSCLC/Randomized

Non-Small Cell Lung Cancer Randomized In process of being cross-linked ... Early Stage Operable NSCLC Primary surgery vs. primary RT Medical Research Council/Hammersmith Hospital (1954-1958) -- RT vs Surgery Randomized. 58 patients, no clinical or radiologic evidence of mediastinal involvement. Biopsy proven carcinoma. Arm 1) RT - using 8 MeV linac, 45 Gy in 4 weeks daily. Target + 2cm + hilar/mediastinal areas; vs. Arm 2) Surgery - pneumonectomy or lobectomy + hilar/mediastinal LND. However 13/30 weren't operable/refused. Histology squamous 64%, adenocarcinoma 3%, small cell/anaplastic 33% 1963, doi:10.1016/S0140-6736(63)91444-2 --"THE TREATMENT OF CARCINOMA OF THE BRONCHUS A Clinical Trial to Compare Surgery and Supervoltage Radiotherapy" (Morrison R, Lancet. 1963. Mar 30; 281(7283):683-684) Outcome: 1-year OS RT 64% vs. Surgery 43%; 2-year OS 14% vs. 27%; 4-year 7% vs. 23% (NS). By histology: squamous 6% vs. 30% (SS); small cell 10% both (NS) Conclusion: In squamous cell tumors, surgical resection is significantly better than RT; no difference in small cell. Limited resection vs. lobectomy North American Lung Cancer Study Group 821, 1995 (1982-88)- 7677489 — "Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer." Ginsberg RJ et al. Ann Thorac Surg. 1995 Sep;60(3):615-22 Randomized. 247/276 patients with peripheral pT1N0. Treated with limited resection (segmental resection or large wedge with 2cm margin) Locoregional recurrence: limited resection 17% vs. lobectomy 6% (SS, 3x higher). Death rate: 39% vs. 30% (NS) Tumor volume: lobectomy better, regardless of tumor size (<3 cm3, 3-8 cm3, 8-27 cm3) Toxicity: perioperative morbidity, mortality, and late post-op pulmonary function comparable Conclusion: Higher LR and death rate, without improved post-op function Pre-op RT vs Surgery Alone Nijmegen (The Netherlands)(1971-1976) -- Pre-op Mediastinal RT vs Surgery Alone Randomized, pilot. 33 patients, clinical T1-2N0 NSCLC, mediastinoscopy LN-. Arm 1) Pre-op RT 20/5 to hilar, subcarinal, tracheo-bronchial, and paraesophageal LNs followed by surgery following Monday vs. Arm 2) Surgery alone. Either lobectomy or pneumonectomy 1984 6378851 -- "Evaluation of short-course preoperative irradiation in the treatment of resectable bronchus carcinoma: long-term analysis of a randomized pilot-study." (Kazem I, Int J Radiat Oncol Biol Phys. 1984 Jul;10(7):981-5.) Minimum F/U 7 years Outcome: 5-year OS pre-op RT 58% vs. surgery alone 43%; 5-year DSS 78% vs. 67% (NS); median OS 6 years vs. 2.5 years. R0 resection in pre-op 57% vs surgery only 28% Subgroup analysis: If lobectomy, RT beneficial only during first year, then no difference. If pneumonectomy, RT beneficial during entire follow-up (5-year OS 66% vs. 42%). Toxicity: 9% operative mortality (all patients in surgery only arm); delayed wound healing comparable Conclusion: Pre-op RT well tolerated, and results are encouraging Germany Randomized. 196 operable patients. Arm 1) Pre-op RT 5500 RHD (Co-60) vs. Arm 2) Surgery only 1975 173257 -- "[Results of a controlled clinical trial for evaluation of intensive preoperative irradiation in operable bronchial cancer (author's transl)] - [Article in German]" (Eichhorn HJ, Arch Geschwulstforsch. 1975;45(4):376-84.) Outcome: No difference in annual survival. Significantly reduced LR rate Toxicity: Post-op mortality and complications "a bit more favorable" Conclusion: No difference NCI Trial (1963-1966) -- Pre-op RT vs. Surgery only Randomized. 17 institutions. 568 patients operable (no carina, no mediastinum/SCV, no chest wall invasion). Arm 1) immediate surgery vs. Arm 2) Pre-op RT, given as >40 Gy supravoltage 1975 171057 -- "Preoperative irradiation of cancer of the lung: final report of a therapeutic trial. A collaborative study." (Warram J, Cancer. 1975 Sep;36(3):914-25.) Outcome: 5-year OS pre-op RT 13% vs. surgery 16% (NS); 5-year RFS 11% vs. 14% (NS) Toxicity: Post-op mortality in surgery alone 11%, not estimated for pre-op RT group Conclusion: No difference Surgery +/- adjuvant EBRT Rome (Italy)(1989-1997) Randomized. 104 patients with Stage I only. Surgery +/- RT (corrected 50.4/28 to bronchial stump and homolateral hilum; mean treated area 50 cm2) 2002 11830308 -- "Adjuvant radiotherapy in non-small cell lung cancer with pathological stage I: definitive results of a phase III randomized trial." (Trodella L, Radiother Oncol. 2002 Jan;62(1):11-9.) 5-year outcome: OS: RT 67% vs. observation 58% (p=0.048); LR: 2% vs. 23% Toxicity: 11% acute toxicity; no long term clinical toxicity, 37% radiographic fibrosis Conclusion: RT gave good results in LC, promising OS and DFS Beijing (China) (1982-95) Randomized. 366 pts, positive N1 or N2 nodes after surgery. Randomized to RT 60 Gy vs no further therapy. Field included bronchial stump, ipsilateral hilum, and most of the mediastinum; included SCLV for pts with upper mediastinal node involvement; mediastinum down to diaphragm for lower lobe primary. 2000 10863061 — "A study of postoperative radiotherapy in patients with non-small-cell lung cancer: a randomized trial." Feng QF et al. Int J Radiat Oncol Biol Phys. 2000 Jul 1;47(4):925-9. 3-yr OS (51.9% vs 50.2%), 5-yr OS (42.9% vs 40.5%), not S.S. Trend toward improved OS in T3-4 and N1 pts receiving RT. Comments: More pts with N2 disease in RT group (45% vs 27%) GETCB (France)(1986-94) Randomized. 728 pts (Stage I-III) randomized after resection to RT 60 Gy or observation. 1999 10421262 — "A controlled study of postoperative radiotherapy for patients with completely resected nonsmall cell lung carcinoma. Groupe d'Etude et de Traitement des Cancers Bronchiques." Dautzenberg B et al. Cancer. 1999 Jul 15;86(2):265-73. 5-yr OS 30% (RT) vs 43% (Obs). Excess mortality due to increase in intercurrent deaths (31% vs 8%). More intercurrent deaths for higher dose per fraction. ON subgroup analysis, detrimental effect of RT significant in Stage I-II but not Stage III. No effect on local recurrences or distant mets. Critique: included N0 patients, majority treated with Co-60, with fractions up to 2.5 Gy/fx Graz (Austria)(1985-1995) Randomized. 155 pts, pT1-3 pN0-2. Randomized to RT 50 Gy (if pN0) or 56 Gy (if pN1-2) vs no further treatment. Treatment included the bronchial stump + 2cm margin, ipsilateral hilum, and mediastinum; SCLV included for apical tumors. 2F AP/PA or 3F with off-cord after 42 Gy 1997 9377958 Full text — "Postoperative radiotherapy in radically resected non-small cell lung cancer." Mayer R et al. Chest. 1997 Oct;112(4):954-9. 5-yr outcome: OS: RT 30% vs observation 20% (NS). DFS: 20% vs. 16% (NS). LR 6% vs. 24% (SS) Conclusion: Significant reduction in local recurrences, tendency to OS benefit Medical Research Council (1986-93) Randomized. 308 pts. Were pN1 or pN2. Randomized after surgery +/- RT 40 Gy in 15 fx. 1996 8761382 — "The role of post-operative radiotherapy in non-small-cell lung cancer: a multicentre randomised trial in patients with pathologically staged T1-2, N1-2, M0 disease. Medical Research Council Lung Cancer Working Party." Stephens RJ et al. Br J Cancer. 1996 Aug;74(4):632-9. Overall, no survival difference. On subgroup analysis, trend to survival benefit for N2 pts (21% vs 36% at 3 yrs, p=0.18). No benefit in N1 pts. France (1985-91) Randomized. 163 pts, T2N0. Randomized to RT 60 Gy or no further treatment. 1996 8784014 — "Postresection irradiation for T2 N0 M0 non-small cell carcinoma: a prospective, randomized study." Lafitte JJ et al. Ann Thorac Surg. 1996 Sep;62(3):830-4. No difference in survival, OS 44.2% (survival figures not given for each arm). No difference in local or distant mets. Lung Cancer Study Group 773 Randomized. 230 pts. Resected squamous cell carcinoma, Stage II or III. Randomized to +/- RT 50 Gy to mediastinum. 1986 2877397 — "Effects of postoperative mediastinal radiation on completely resected stage II and stage III epidermoid cancer of the lung." The Lung Cancer Study Group. N Engl J Med. 1986 Nov 27;315(22):1377-81. Local recurrences were reduced: 20% vs 1% local failure, but overall treatment failures were the same. Conclusion: Improved LR, but no effect on survival. Van Houtte (1966-1975) 224 pts. N0. Randomized after resection to RT (60 Gy) vs observation. 1980 6998936 — "Postoperative radiation therapy in lung cancer: a controlled trial after resection of curative design." Van Houtte P et al. Int J Radiat Oncol Biol Phys. 1980 Aug;6(8):983-6. Survival was worse in the RT group: 5-ys OS 24% vs 43% (NS). Surgery +/- adjuvant chemotherapy CALGB 9633 (1996-2003) -- Surgery +/- paclitaxel and carboplatin Randomized. Stopped early after interim analysis showed survival benefit. 344 patients (target 500). NSCLC, T2, pN0 by mediastinoscopy, resected with lobectomy/pneumonectomy. Arm 1) adjuvant paclitaxel 200 mg/m2 + carboplatin AUC 6 Q3W x4 cycles vs. Arm 2) observation. Primary endpoint OS 2008 18809614 -- "Adjuvant Paclitaxel Plus Carboplatin Compared With Observation in Stage IB Non-Small-Cell Lung Cancer: CALGB 9633 With the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups." (Strauss GM, J Clin Oncol. 2008 Sep 22. [Epub ahead of print]) Median F/U 6.2 years Outcome: median OS chemo 7.9 years vs. observation 6.5 years (NS); 5-year OS 60% vs. 58% (NS); 5-year DFS 52% vs. 48% (NS). Subgroup analysis: survival difference for tumors >=4cm Toxicity: Grade 3/4 neutropenia in 35% Conclusion: Negative trial, adjuvant chemo should not be standard of care in Stage IB. Survival advantage for large tumors on subset analysis International Adjuvant Lung Trial (IALT) (1995-2000) -- Surgery +/- cisplatin and vinca alkaloids Randomized. Terminated early due to slow accrual. 1867 patients (target 3300). Stages I-III (Stage I 36%, Stage II 24%, Stage III 40%), complete resection. Arm 1) Adjuvant cisplatin with either etoposide (in 56%) or vinca alkaloid (vinorelbine, vinblastine, vindesine) x3-4 cycles. ~25% also received RT based on institutional preference. 2004 14736927 — "Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer." Arriagada R et al. N Engl J Med. 2004 Jan 22;350(4):351-60. Median F/U 4.7 years Outcome: 5-year OS chemo 44% vs. 40% control (SS); DFS 39% vs. 34% (SS). Also benefit for local control, distant control. However, no OS benefit on Stage I subset analysis (HR 0.95, NS) Toxicity: 1% died due to chemo effects Conclusion: Cisplatin-based adjuvant chemo improves survival 2006 16957145 -- "DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy." (Olaussen KA, N Engl J Med. 2006 Sep 7;355(10):983-91.) Expression of ERCC1. 761 tumors analyzed. 44% positive, 56% negative ERCC1 negative: 5-year OS 47% chemo vs. 39% control (SS). Median OS 56 months chemo vs. 40 months control (14 month benefit) ERCC1 positive: 5-year OS 40% chemo vs. 46% control (NS). Median OS 50 months chemo vs. 55 months control (NS) Conclusion: In completely resected NSCLC, patients with ERCC1- tumors benefit from cispaltinsimilar to cisplatin September 2022, while ERCC1+ tumors do not. ERCC1+ tumors have a better overall OS NCI-Canada JBR.10 / INT (1994-2001) -- Surgery +/- cisplatin and vinorelbine Randomized. 482 patients with Stage IB-II (T3 excluded), complete resection. Arm 1) Adjuvant cisplatin 50 mg/m2 and vinorelbine 25 mg/m2 Q4W x4 cycles vs Arm 2) observation. No RT given. 5-years; 2005 15972865 — "Vinorelbine plus Cisplatin vs. Observation in Resected Non–Small-Cell Lung Cancer." Winton T et al. N Engl J Med. 2005 June 23;352(25):2589-2597. Median F/U 5 years. Outcome: Median OS chemo 7.8 years vs 6.1 years (SS); 5-year OS 69% vs 54%. Median RFS 61% vs. 49% (SS). Subgroup analysis showed no benefit for chemotherapy for Stage IB. Conclusion: Improvement in overall survival Adjuvant Navelbine International Trialist Association (ANITA) (1994-2000) -- Surgery +/- cisplatin and vinorelbine Randomized. 840 patients. Stage IB-IIIA (36% IB, 24% II, 39% IIIA), complete resection. Arm 1) Adjuvant Cisplatin 100mg/m2 + Vinorelbine 30mg/m2 x4 cycles vs Arm 2) observation. Post-op RT not mandatory, and done according to each center's policy (given to 28%) 6-years; 2006 16945766 -- "Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial." (Douillard JY, Lancet Oncol. 2006 Sep;7(9):719-27.). Median F/U 6.3 years Outcome: 5-year OS chemo 51% vs observation 43% (SS); decreased death by 21%. Median OS 5.5 years vs 3.6 years (SS). Median RFS 3.0 years vs 1.7 years (SS). No benefit for Stage IB on subgroup analysis (5-year OS 62% vs 64%, NS). For Stage II, 52% vs. 39%; Stage IIIA 42% vs. 26%. If N0, 58% vs. 61% (NS); if N1 52% vs. 36%; if N2 40% vs. 19% Toxicity: neutropenia 92%, febrile neutropenia 9%, toxic deaths 2% Conclusion: Adjuvant vinorelbine/cisplatin extends survival See also: Radiotherapy from the ANITA trial (discussed under PORT section) Adjuvant Lung Project Italy (ALPI) (1994-1999) -- Surgery +/- MVP Randomized, multi-institutional. 1209 patients with Stage I-IIIA. Treated with 1) surgery + adjuvant mitomycinC/vindesine/cisplatin (MVP) vs. 2) Surgery alone. 43% also received RT. 2003 14519751 — "Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell Lung cancer." Scagliotti GV et al. J Natl Cancer Inst. 2003 Oct 1;95(19):1453-61. Median F/U 5.4 years Median OS: no difference; PFS no difference. Elective RT: Arm 1 65% vs. Arm 2 82% Toxicity: only 69% received MVP x3 cycles Conclusion: No difference in outcomes Critique: MVP not a good regimen, with pulmonary toxicity of Mitomycin C Japan JLCRG (1994-1997) -- Surgery +/- uracil-tegafur (UFT) Randomized. 999 patients, pathologic Stage I adenocarcinoma. Arm 1) adjuvant oral uracil-tegafur (tegafur 250 mg/m2) x2 years vs. Arm 2) observation. Primary end point OS 2004 15102997 -- "A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung." (Kato H, N Engl J Med. 2004 Apr 22;350(17):1713-21.) Median F/U 6.1 years Outcome: 5-year OS UFT 88% vs. observation 85% (p=0.047). Stage IA 89% vs. 90% (NS), Stage IB 85% vs. 74% (SS). Toxicity: Grade 3 in 2% Conclusion: Adjuvant chemotherapy improves survival Rome Tor Vergata (1988-1994) -- Surgery +/- cisplatin and etoposide Randomized. 140 patients, Stage IB (pT2N0), sublobar (34%) or great resection. Arm 1) Adjuvant cisplatin 100 mg/m2 and etoposide 120 mg/m2 Q4W x6 cycles vs Arm 2) observation. Primary endpoint OS 2006 16550600 -- "Postsurgical chemotherapy in stage IB nonsmall cell lung cancer: Long-term survival in a randomized study." (Roselli M, Int J Cancer. 2006 Aug 15;119(4):955-60.) Mean F/U 3.4 years Outcome: 5-year OS chemo 62% vs. observation 42% (SS). If anatomic resection, 75% vs. 50% (SS)); if sublobar resection, 40% vs. 39% (NS) Toxicity: Grade 3 in 18% Conclusion: Adjuvant chemotherapy may improve long-term survival in Stage IB Big Lung Trial (Surgical arm) 2004 15200998 — "Chemotherapy for patients with non-small cell lung cancer: the surgical setting of the Big Lung Trial." Waller D et al. Eur J Cardiothorac Surg. 2004 Jul;26(1):173-82. Randomized to chemotherapy vs observation. 3 cycles of chemotherapy q3week. Multiple cisplatin-based regimens. No survival benefit. Adjuvant chemo vs. adjuvant chemo-RT CALGB 9734 - post-op chemo +/- RT Randomized. 37/44 patients. Completely resected Stage IIIA. Adjuvant paclitaxel x4 cycles, then 2-4 weeks later +/- RT. Closed early due to slow accrual 2007 17311692 -- "A phase III study of surgical resection and paclitaxel/carboplatin chemotherapy with or without adjuvant radiation therapy for resected stage III non-small-cell lung cancer: Cancer and Leukemia Group B 9734." (Perry MC, Clin Lung Cancer. 2007 Jan;8(4):268-72.) Outcome: Median DFS RT 1.4 years vs. no RT 2.8 years (NS); 1-year OS 72% vs. 74% (NS) Conclusion: Small study, no improvement in outcome INT 0115 ECOG EST 3590 / RTOG 91-05 - chemo/RT vs RT Randomized. 488 patients. Stage II-IIIA. Cisplatin/etoposide x4 cycles + concurrent RT vs RT alone. Cisplatin 60 mg/m2, etoposide 120 mg/m2. RT 50.4/28 2000 11071672 — "A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-small-cell lung cancer." Keller SM et al. N Engl J Med. 2000 Oct 26;343(17):1217-22. Outcome: median OS 3.2 years vs. 3.2 years (NS). In-field recurrence 13% vs. 12% (NS) Toxicity: treatment-related mortality RT 1.2% vs. CRT 1.6% Conclusion: No difference in recurrence or survival. SBRT Set Up University of Toronto (2008-2009) -- abdominal compression vs Body fix immobilization Randomized. 24 patients, 25 lesions (16 upper lobe, 2 middle lobe, 7 lower lobe), medically inoperable Stage I NSCLC or pulmonary mets. All patients underwent 4D-CRT with free breathing, Bodyfix, and abdominal compression plate (ACP). After sim randomized to immobilization with Arm 1) Bodyfix or Arm 2) ACP. CBCT acquired before and after each treatment 2010 20189669 -- "A comparison of two immobilization systems for stereotactic body radiation therapy of lung tumors." (Han K, Radiother Oncol. 2010 Feb 26. [Epub ahead of print]) Outcome: Both Bodyfix and ACP reduced sup-inf (4.6 mm vs 4.0 mm vs 5.3 mm) and overall tumor motion (5.3 mm vs 4.7 mm vs 6.1 mm) compared to free-breathing (SS). ACP further reduced sup-inf (SS) and overall tumor motion (SS) compared to Bodyfix Toxicity: ACP faster to set up and more comfortable by patients (SS) Conclusion: Abdominal compression superior to Bodyfix in immobilization and patient comfort Advanced Stage Operable NSCLC Induction Chemo vs Induction Chemo-RT German GLCCG (1995-2003) -- Induction cisplatin/etoposide then concurrent chemo-RT then surgery vs. induction cisplatin/etoposide then postop RT Randomized. 524 patients with NSCLC Stage IIIA (33%) or resectable IIIB (67%). Arm 1) Induction cisplatin 55 mg/m2 + etoposide 100 mg/m2 x3 cycles, then concurrent RT 45/30 in 1.5 Gy BID with carboplatin 100 mg/m2 + vindesine 3mg, followed by surgery vs. Arm 2) Same induction, followed by surgery, followed by RT (54/30 if R0, 68.4/38. Surgery after 4-6 weeks. Primary endpoint PFS 2008 18583190 -- "Effect of preoperative chemoradiation in addition to preoperative chemotherapy: a randomised trial in stage III non-small-cell lung cancer." (Thomas M, Lancet Oncol. 2008 Jul;9(7):636-648. Epub 2008 Jun 24.) Outcome: Surgery chemo 59% vs. chemo-RT 59%; mediastinal downstaging 29% vs. 46% (SS). Median PFS (primary endpoint) 10.0 months vs. 9.5 months (NS). Toxicity: If pneumonectomy (35% in both groups), worse mortality 14% vs. 6% Conclusion: Preop chemo-RT increases mediastinal downstaging, but doesn't improve survival. After induction, pneumonectomy should be avoided Prophylactic Cranial Irradiation (PCI) German Multicenter (1994-2001) Terminated early due to slow accrual after benefit of adjuvant chemo shown. Randomized. 112 patients with operable Stage IIIA NSCLC based on mediastinoscopy staging. Arm 1) primary resection + adjuvant RT 50-60 Gy vs. Arm 2) preoperative chemo (cisplatin/etoposide x3 cycles) + concurrent chemo-RT (cisplatin/etoposide RT 45 Gy in 1.5 Gy BID) + definitive surgery + PCI 30/15 2007 17971598 -- "Prophylactic cranial irradiation in operable stage IIIA non small-cell lung cancer treated with neoadjuvant chemoradiotherapy: results from a German multicenter randomized trial." (Pottgen C, J Clin Oncol. 2007 Nov 1;25(31):4987-92.) 5-year outcome: brain first failure PCI 8% vs no PCI 35% (SS); any brain failure 9% vs. 27% (SS) Toxicity: no difference; slightly decreased neurocognition in both groups compared to age-matched controls Conclusion: PCI effective in preventing brain mets after trimodality therapy Unresectable RT vs. Placebo VA Lung Group (VALG) -- RT vs. placebo vs. chemotherapy Randomized, 3 arms. 800 patients. Localized but inoperable (mostly due to bulky disease). KPS 80-100 33%, KPS 50-70 55%. Arm 1) RT vs. Arm 2) placebo (lactose) vs. Arm 3) chemo (not reported here). RT given: orthovolatage in 90% (200-260 kV), Cobalt-60 in 10%. Target dose 40-50 Gy, but 33% received <40 Gy (2/3 died, 1/3 medical complications) 1968 4170866 -- "The survival of patients with inoperable lung cancer: a large-scale randomized study of radiation therapy versus placebo." (Roswit B, Radiology. 1968 Apr;90(4):688-97.) Outcome: Median OS: RT 4.6 months vs. placebo 3.7 months (NS); 1-year survival: RT 18% vs. placebo 14% (p=0.05). Long-term survivors (top 25%): RT 10 monts vs. 7.6 months (SS). Better survival if longer symptomatic prior to diagnosis, suggesting slower rate of growth Conclusion: RT does not impact median OS, but improves long-term survival Concurrent Chemo-RT +/- Induction Chemo CALGB B39801 (1998-2002) -- Induction carboplatin/paclitaxel -> chemo-RT vs chemo-RT Randomized. 366 patients with unresectable Stage III NSCLC. Randomized to Arm 1) Concurrent carboplatin (AUC=2)/paclitaxel (50 mg/sq m) with RT 66 Gy. Arm 2) Induction with carboplatin(AUC=6)/paclitaxel (200 mg/sq m) x2 cycles, then concurrent chemo-RT as Arm 1 2007 17404369 -- "Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III Non-small-cell lung cancer: Cancer and Leukemia Group B." (Vokes EE, J Clin Oncol. 2007 May 1;25(13):1698-704.) Outcome: MS induction 12 months vs. no induction 14 months (NS); 2-year OS 29% vs. 31% (NS) Toxicity: Induction chemo neutropenia (20% Grade 3-4), no difference between concurrent CRT arms Conclusion: Addition of induction chemo added toxicity without survival benefit. Comment: Low survival compared to other trials, possibly due to lower chemo dose due to using carboplatin and not cisplatin. Chemo-RT +/- chemotherapy consolidation Hoosier Oncology Group (2002-2006) -- Chemo-RT +/- docetaxel Randomized. Stopped early due to interim analysis of futility. 147/203 patients with stage IIIA-B, FEV1 >=1 L, wt loss <5%. Concurrent RT 59.4 Gy with cisplatin/etoposide, then if no progression Arm 1) docetaxel 75 mg/m2 x3 cycles vs. Arm 2) observation 2008 19001323 -- "Phase III study of cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage III non-small-cell lung cancer: the Hoosier Oncology Group and U.S. Oncology." (Hanna N, J Clin Oncol. 2008 Dec 10;26(35):5755-60. Epub 2008 Nov 10.) Outcome: Median OS docetaxel 1.8 years vs. observation 1.9 years (NS) Toxicity: Grade 3+ febrile neutropenia 11%, pneumonitis 10%, hospitalization 29% vs. 8%, death 5% Conclusion: Consolidation with docetaxel increased toxicity with no impact on survival SWOG 0023 (2001-2005) -- Chemo-RT and adjuvant docetaxel +/- adjuvant gefitinib Randomized. Closed early after worse survival with gefitinib. 243/672 patients, Stage III NSCLC. Concurrent cisplatin 50 mg/m2 + etoposide 50 mg/m2 + RT 61 Gy, then docetaxel 75 mg/m2 x3 cycles. If no progression, randomized Arm 1) gefitinib 250 mg/d vs. Arm 2) placebo until progression, toxicity or 5 years 2008 18378568 -- "Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023." (Kelly K, J Clin Oncol. 2008 May 20;26(15):2450-6. Epub 2008 Mar 31.) Median F/U 2.2 years Outcome: median OS gefitinib 1.9 years vs. placebo 2.9 years (SS) Toxicity: death rate gefitinib 2% vs. placebo 0% Conclusion: Gefitinib didn't improve survival; decreased survival result of tumor progression and not gefitinib toxicity Radiosensitization Metoclopramide Institute for Cancer Research, Oslo (1995-1998) -- observation vs metoclopramide 2010 20165821 -- "CT Density in Lung Cancer Patients After Radiotherapy Sensitized by Metoclopramide : A Subgroup Analysis of a Randomized Trial." (Dale E, Strahlenther Onkol. 2010 Feb 22. [Epub ahead of print]) Randomized. Trial stopped prematurely due to financial difficulties. 30 patients enrolled, 16 analyzable, NSCLC stage IIIA/IIIB. RT 60/33. Arm 1) observation vs Arm 2) concurrent metoclopramide 2mg/kg TIW. Analysis of CT density Outcome: Lung density increased with dose (SS). Patients on metoclopramide less increase in tissue density (SS) Conclusion: Metoclopramide and large radiation dose seemed to protect against fibrosis development Metastatic Japan WJTOG 3405 Randomized. 172 chemo-naive patients, age <=75, Stage IIIB/IV NSCLC or postop recurrence, with EGRF mutation (exon 19 deletion or L858R point mutation). Arm 1) Gefitinib 250 mg QD vs Arm 2) cisplatin 80 mg/m2 and docetaxel 60 mg/m2 Q3W x 3-6 cycles. Primary endpoint PFS 2009 20022809 -- "Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial." (Mitsudomi T, Lancet Oncol. 2009 Dec 18. [Epub ahead of print]) Outcome: Median PFG gefitinib 9 months vs. cisplatin/docetaxel 6 months (SS) Toxicity: Myelosuppression, alopecia, and fatigue more frequent in cisplatin/docetaxel group, but skin toxicity, liver dysfunction, and diarrhoea more frequent in the gefitinib group. Two patients (2%) developed interstitial lung disease Conclusion: Patients with EGFR mutations have longer PFS on gefitinib than on cisplatin/docetaxel Quality of Life Amifostine RTOG 9801 -- Induction -> concurrent chemo-AHFX RT +/- amifostine Randomized. 243 patients with unresectable NSCLC (II-IIIB). Induction paclitaxel 225 mg/m2 and carboplatin AUC6 x2 cycles, then concurrent chemo-RT. RT 69.6/58 @ 1.2 GY BID with concurrent paclitaxel 50 mg/m2 and carboplatin AUC2. During chemo-RT Arm 1) placebo vs. Arm 2) amifostine 500 mg IV (72% received it per protocol) 2005 15800308 -- "Randomized trial of amifostine in locally advanced non-small-cell lung cancer patients receiving chemotherapy and hyperfractionated radiation: radiation therapy oncology group trial 98-01." (Movsas B, J Clin Oncol. 2005 Apr 1;23(10):2145-54.) Outcome: Grade 3+ acute esophagitis AM 30% vs no AM 34% (NS); patient reported dysphagia significantly better with AM (p=0.02). But, AM higher acute nausea (SS), vomiting (SS), CV toxicity (SS), and infection/neutropenia (SS). No difference in QOL Survival: AM 17.3 months vs. no AM 17.9 months (NS) Conclusion: Amifostine did not significantly reduce grade 3+ esophagitis, though patient self-assessment suggested an advantage