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

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Concurrent Chemo-RT

## Standard RT

* RTOG 94-04 (1994-1998) PMID 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 PMID 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 PMID 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 PMID 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 PMID 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 PMID 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) PMID 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) PMID 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 PMID 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 PMID 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) PMID 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 PMID 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 PMID 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 PMID 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.