Radiation Oncology/NSCLC/Locally Advanced Unresectable/Concurrent-Chemo RT

Concurrent Chemo-RT Standard RT RTOG 94-04 (1994-1998) 11955727 -- "A phase III comparison of radiation therapy with or without recombinant beta-interferon for poor-risk patients with locally advanced non-small-cell lung cancer (RTOG 93-04)." (Bradley JD, Int J Radiat Oncol Biol Phys. 2002 Apr 1;52(5):1173-9.) Randomized. 123 patients, poor status (KPS 50-70, or weight loss >5%). RT 60/30 +/- Betaseron (recombinant human interferon beta). Median F/U 4 years Median OS: 9.5 months vs. 10.3 months (NS), 1-year OS: 44% vs. 42% (NS) Toxicity: only 76% completed Betaseron arm due, primarily noncompliance for toxicity. Grade 3/4 toxicity (lung, esophagus) worse in betaseron arm (SS), including 1 death Conclusion: Failed; same outcome, much worse toxicity with beta interferon Australia, 1999 1989-1995 10577698 -- "A randomised phase III study of accelerated or standard fraction radiotherapy with or without concurrent carboplatin in inoperable non-small cell lung cancer: final report of an Australian multi-centre trial." (Ball D, Radiother Oncol. 1999 Aug;52(2):129-36.) Phase III. 204 with inoperable NSCLC randomized to 1) 60/30 in 6 weeks (R6), 2) 60/30 in 3 weeks (R3), 3) R6 + concurrent carboplatin, or 4) R3 + concurrent carboplatin No difference in OS among groups. Toxicity: hematologic greater with chemo, esophageal greater with ART (R3) Critique 11258343: underpowered for 2x2 design. ART hazard ratio 0.86 (0.56, 1.30), which is consistent with CHART trial results (0.78, SS). Recommend not sacrificing dose intensification at expense of concurrent chemotherapy Indiana, 1995 7751888 -- "Phase III trial of thoracic irradiation with or without cisplatin for locally advanced unresectable non-small-cell lung cancer: a Hoosier Oncology Group protocol." (Blanke C, J Clin Oncol. 1995 Jun;13(6):1425-9.) Randomized. 215/240 patients, Stage III or lower Stage unresectable. Treated 1) RT 60-65 Gy vs. 2) RT + cisplatin 70 mg/m2 q3 weeks x3 cycles concurrent Median OS: 10.7 months vs. 11.5 months (NS). 1-year, 2-year, 5-year OS: 43% vs. 45%, 18% vs. 13%, 5% vs. 2% (NS) Conclusion: No difference EORTC Randomized Phase III. 1) Split-course RT alone (30/10, 3 week rest, 25/10), 2) Split-course RT + 30mg/sqm cisplatin weekly, 3) Split-course RT + 6mg/sqm daily 1992 1310160 -- "Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer." (Schaake-Koning C, N Engl J Med. 1992 Feb 20;326(8):524-30.) Surival: 1-year RT + daily cisplatin 54% vs. RT alone 46%, 2-years RT + daily cisplatin 26% vs. RT alone 13%, 3-years RT + daily cisplatin 16% vs. RT alone 2%. RT + weekly cisplatin intermediate. Benefit due to better local control: 1-year RT + daily cisplatin 59% vs. RT alone 41%, 2-year RT + daily cisplatin 31% vs. RT alone 19% Substantial side effects: cisplatin 78% N/V, severe in 28% Conclusion: Survival and local control benefit, at cost of severe side-effects 1990 2170309 — "Radiotherapy combined with low-dose cis-diammine dichloroplatinum (II) (CDDP) in inoperable nonmetastatic non-small cell lung cancer (NSCLC): a randomized three arm phase II study of the EORTC Lung Cancer and Radiotherapy Cooperative Groups." (Schaake-Koning C et al. Int J Radiat Oncol Biol Phys. 1990 Oct;19(4):967-72.) Randomized Phase II. 100 pts. Inoperable. Randomized to 1) Split-course RT alone, 2) Split-course RT with weekly low-dose cisplatin, or 3) Split-course RT with daily cisplatin. The 1 and 2-yr OS were 38% and 14% (RT alone), 49% and 17% (weekly cisplatin), and 50% and 32% (daily cisplatin). Conclusion: supports the addition of chemotherapy. Study converted to Phase III. GOCCNE 1992 (Italy) (1987-1991) 1324895 -- "Radiotherapy versus radiotherapy enhanced by cisplatin in stage III non-small cell lung cancer." (Trovo MG, Int J Radiat Oncol Biol Phys. 1992;24(1):11-5.) Randomized. 173 patients. RT 45/15 vs. RT 45/15 + platinum 6mg/m2 daily Median OS: 10.3 vs. 10.0, time-to-progression: 10.6 vs. 14.2 months (NS) Toxicity: acceptable Conclusion: no benefit Milan 1988 (1986-1987) 2851172 -- "A randomized clinical trial comparing radiation therapy v radiation therapy plus cis-dichlorodiammine platinum (II) in the treatment of locally advanced non-small cell lung cancer." (Soresi E, Semin Oncol. 1988 Dec;15(6 Suppl 7):20-5.) Randomized. 95 patients with IIIA/B to 1) RT 50 Gy vs. 2) RT 50 Gy + platinum 15mg/m2 qw Median OS: 11 months vs. 16 months (NS), PFS 7 months vs. 9 months (NS) LR rate: 46% vs 27% (SS); platinum seen as RT potentiator Mild toxicity Conclusion: no benefit Hyperfractionated RT 1996 Kragujevac - Jeremic II (Yugoslavia) 1990-1991 8648358 -- "Hyperfractionated radiation therapy with or without concurrent low-dose daily carboplatin/etoposide for stage III non-small-cell lung cancer: a randomized study." (Jeremic B, J Clin Oncol. 1996 Apr;14(4):1065-70.) Randomized. 131 patients with Stage III NSCLC, KPS >=50 treated with 1) Hfx RT 69.6 Gy in 1.2 Gy/fx BID, 2) Hfx RT + carboplatin/etoposide daily OS: median 14 months vs. 22 months (SS), 4-year OS: 9% vs. 23% (SS) Recurrence: 4-year LR 19% vs. 42% (SS), distant mets comparable Toxicity comparable Conclusion: combined modality better 1995 Kragujevac - Jeremic I 7844608 -- "Randomized trial of hyperfractionated radiation therapy with or without concurrent chemotherapy for stage III non-small-cell lung cancer." (Jeremic B, J Clin Oncol. 1995 Feb;13(2):452-8.) Randomized. 169 pts. Stage III NSCLC treated with 1) Hfx RT 64.8 Gy in 1.2 Gy/fx BID, 2) Hfx RT + carboplatin/etoposide weekly, 3) Hfx RT + carboplatin/etoposide every other week OS: median 8 months vs. 18 months vs. 13 months. (SS). 3-year OS: 7% vs. 23% vs. 16% Recurrence: best in group 2. Toxicity: higher in group 2,3 but no deaths Conclusion: combination therapy better 2005 Kragujevac (Serbia) 15718310 -- "Concurrent hyperfractionated radiotherapy and low-dose daily carboplatin and paclitaxel in patients with stage III non-small-cell lung cancer: long-term results of a phase II study." (Jeremic B, J Clin Oncol. 2005 Feb 20;23(6):1144-51.) Phase II. 64 patients treated with Hfx RT (67.6 Gy in 1.3 Gy/fx BID) and concurrent carboplatin + paclitaxel Response rate: CR 42%, PR 41%, SD 16%, PD 2% Survival: median OS 28 months, 3-year OS 37%, 5-year OS 26%. Local control 3-year 37%, 5-year 33% Toxicity (Grade 3+): hematologic 25%, esophageal 17%, pulmonary 13% Conclusion: Results among best reported, warrants prospective evaluation Dose Escalation RTOG 0617 (ongoing) - Phase III. 4 arm randomization. 60 Gy vs 74 Gy. Concurrent RT + Carbo/Taxol +/- Cetuximab. Arms B and D (the two 74 Gy arms) were closed in 6/2011 after an interim analysis showed the high dose arms crossed a futility boundary. The trial will continue to accrue the 60 Gy arms A and C. See details at Radiation Oncology/NSCLC/Locally Advanced Unresectable RTOG 0117 (closed) Phase I/II. Stage I-IIIB NSCLC. RT + concurrent paclitaxel 50 mg/m2 + carboplatin AUC 2. Arm I 75.25/35 (17 patients) -> MTD (acute Grade 5 pneumonitis, acute Grade 3 pneumonitis; also late Grade 3 pneumonitis and Grade 4 pain) -> de-escalated to 74/37 + concurrent carbo/taxol. See details at Radiation_Oncology/NSCLC/Early_Stage_Inoperable#Dose escalation Chemo Meta-analysis Gustave-Roussy 2006 16500915 -- "Concomitant radio-chemotherapy based on platin compounds in patients with locally advanced non-small cell lung cancer (NSCLC): a meta-analysis of individual data from 1764 patients." (Auperin A, Ann Oncol. 2006 Mar;17(3):473-83.) 12 trials found, 9 trials data available (1764 patients) comparing RT alone vs RT with concurrent cisplatin or carboplatin. Median f/u 7.2 years 2-year OS: 4% absolute benefit to CRT (HR 0.89) Platin + etoposide more effective than platin alone 2010 20351327 -- "Meta-Analysis of Concomitant Versus Sequential Radiochemotherapy in Locally Advanced Non–Small-Cell Lung Cancer." (Auperin A, J Clin Oncol 2010 May 1;28(13):2181-2190.) 7 trial found, 6 trials data available (1205 patients) comparing concomitant vs sequential chemo/RT. OS: benefit for concomitant chemo/RT, 5.7% absolute benefit at 3 years and 4.5% at 5 years (HR 0.84) Decreased locoregional progression (HR 0.77). No difference in distant progression. Increase in acute gr 3-4 esophageal toxicity from 4% to 18%. No difference in acute lung toxicity Conclusion: increased survival with concurrent chemo/RT most likely due to decreased locoregional failure Non-small Cell Lung Cancer Collaborative Group 1995 7580546 — "Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials." BMJ. 1995 Oct 7;311(7010):899-909.