text:
Radiation Oncology/NSCLC/Locally Advanced Resectable

 * See also: Post-op RT (in Early Stage Resectable)

Criteria for resectability
Generally stage IIIA and lower is considered resectable, since all sites of disease can be removed by extended surgery. In contrast, stage IIIB disease (N3 or T4) is generally considered unresectable due to contralateral lymph node involvement or extensive local tumor. However, a subset of T4 patients may actually be able to undergo surgical resection.

 * Pulmonary function: FEV1 > 2 L. Predicted post-surgical FEV1 should be > 0.8 L based on qualitative VQ scan.

Epidemiology

 * 16% of NSCLC is IIIA

Heterogenous:
 * T3N1 vs. T1-3N2
 * N2 nodes: single vs. multiple
 * N2 nodes: bulky vs. macroscopic vs. microscopic involvement

 * Gustave Roussy, 2000 (France) PMID 10944131 -- "Survival of patients with resected N2 non-small-cell lung cancer: evidence for a subclassification and implications." (Andre F, J Clin Oncol. 2000 Aug;18(16):2981-9.)
 * Retrospective. 702 patients with resected N2 disease, stratified into clinically positive and clinically negative but microscopically positive at surgery. Multi-institutional, 6 centers. Median F/U 4.3 years
 * 5-year OS treated with surgery only:
 * single level microscopic N2: 34% (site of LN+ had no prognostic significance)
 * multiple levels microscopic N2: 11%
 * single level clinical N2: 8%
 * multiple levels clinical N2: 3%
 * 5-year OS in clinical N2: surgery only 5% vs. preop chemo 18%

Use of PET to assess response after induction chemo/RT

 * Maryland: DeYoung CM et al (ASTRO 2004, Abstract 122)
 * 39 pts. Stage IIIA-IIIB. Induction chemo (carboplatin + Navelbine) + concurrent hyperfractionated RT (69.6 Gy). After induction, restaging with PET 4-6 weeks after and mediastinoscopy (MED) @ 6-8 weeks. If negative MED, underwent resection + consolidative therapy; otherwise, consolidation only.
 * 32 completed MED. For the mediastinum: SUV after induction could not differentiate between those with and without pCR; PET false negative 30%, false positive 45%. For the primary tumor, false negative 73%, false positive 57%.
 * PET not useful for restaging within 4-6 weeks after induction chemo/RT.

Pre-op RT vs. Surgery Only

 * VA Trial
 * Randomized. 331 patients, with centrally located tumors amenable to endoscopic biopsy (peripheral lesions excluded). Arm 1) Pre-op RT vs. Arm 2) Surgery alone. RT given 40-50 Gy to primary tumor + mediastinum. Surgery 4-6 week later (maximum 12 weeks). Lobectomy 12%, majority pneumonectomy.
 * 4-years; 1972 PMID 5083076 -- "Preoperative radiation therapy in the treatment of bronchial carcinoma." (Shields TW, Cancer. 1972 Nov;30(5):1388-94.)
 * Outcome: pCR 25%. 1-year OS pre-op RT 44% vs. surgery only 60% (SS); 4-year OS 12% vs. 21%. Survival decrement during first 6 months, then curves comparable. Survival also worse with higher pre-op RT dose
 * Toxicity: post-op mortality 12% both groups
 * Conclusion: Pre-op RT worse survival, manifested during first 6 months

Induction Chemo/RT + Surgery

 * RTOG 02-29 - Phase II
 * 2010 RedJournal Abstract: Stage IIIA(T1-3N2) or IIIB(N3) resectable at diagnosis. Treated with induction chemo/RT, carboplatin and taxol weekly x 6 weeks and RT to 61.2 Gy. Surgery evaluation 4-6 wks after chemo/RT. Consolidative carbo/taxol x 2 cycles. Recommended prophylactic cranial irradiation (on RTOG 02-14). RT dose: 50.4 Gy (offcord by 45 Gy) + 10.8 Gy boost
 * Result: 43 pts (75%) were evaluable; 36 pts underwent resection. 7 pts had residual mediastinal dz. 27/43 (63%) achieved mediastinal clearance: improved mediastinal sterilization (50-->70%, power of 80%, p=0.05)
 * Med f/u 20 months,** med OS: 26.6 mos; med PFS: 13.1 mos; 1-y OS: 77%; 1-y PFS: 52%
 * Toxicity: 14% (5/37) G3 post-op pulmonary complications; 1 post-op G5 toxicity (3%).
 * Conclusion: confirms the ability of neoadj CCRT to sterilize known mediastinal nodal disease.

 * SWOG 8805 - Phase II
 * 1999 PMID 7636530 — "Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805." Albain KS et al. J Clin Oncol. 1995 Aug;13(8):1880-92.
 * 126 pts. Biopsy proven N2, N3, or T4. IIIA 60%, IIIB 40%. 85% of IIIA and 80% of IIIB were resected. Concurrent chemo/RT (2 cycles cisplatin + etoposide + 45 Gy RT), followed by surgery.
 * Median f/u 2.4 yrs. 2-yr OS 37%, 3-yr 24-27%. Strongest predictor of survival was pCR in mediastinal LN (30 months vs 10 month MS; 5-yr OS 33% vs 11)%.
 * Conclusion: induction chemo/RT before surgery is feasible

 * Duke, 1994
 * PMID 8055445 — "Phase II study of neoadjuvant chemotherapy and radiation therapy with thoracotomy in the treatment of clinically staged IIIA non-small cell lung cancer." Deutsch M et al. Cancer. 1994 Aug 15;74(4):1243-52.
 * 28 pts. Carbo/etoposide followed by carbo + 60 Gy followed by surgery.
 * Conclusion: well tolerated

Induction Chemo/RT + Surgery vs Definitive Chemo/XRT

 * Intergroup INT-0139 (RTOG 93-09, SWOG 93-36) (1994-2001) -- induction CRT + surgery vs definitive CRT
 * Randomized. 396 patients with stage IIIA (pN2) lymph node positive NSCLC. Arm 1) Induction chemo-RT (cisplatin 50 mg/m2 x2 cycles, etoposide 50 mg/m2 x2 cycles, concurrent RT 45/25), followed by CT restaging 2-4 weeks later, and complete surgical resection with LN evaluation vs. Arm 2) Same cisplatin/etoposide + concurrent RT 61 Gy. Consolidation cisplatin/etoposide in both groups x2 cycles. Primary endpoint OS.
 * 2003 ASTRO Abstract 2497 Video Presentation — Turrisi et al.
 * Initial results suggest a disease-free survival benefit for the surgical arm (median, 13.4 vs. 11.8 months) without any difference in overall survival at a follow up of 22 months.
 * 2005 ASCO Abstract -- "Phase III study of concurrent chemotherapy and radiotherapy (CT/RT) vs CT/RT followed by surgical resection for stage IIIA(pN2) non-small cell lung cancer (NSCLC): Outcomes update of North American Intergroup 0139 (RTOG 9309). (Albain KS, Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings. Vol 23, No. 16S, Part I of II (June 1 Supplement), 2005: 7014). Median F/U 2.5 years
 * Outcome: median PFS: CRT+S 12.8 months vs. CRT 10.5 months (SS); 5-year PFS 22% vs. 11% (SS); median OS: 23.6 month vs. 22.2 months (NS); 5-year OS: 27% vs. 20% (p=0.1)
 * Subgroup analysis revealed better survival for patients who underwent a lobectomy (p = .002).
 * Trimodality therapy was not optimal when a pneumonectomy was required owing to the high mortality risk.
 * N0 status at surgery significantly predicted a higher 5-year survival rate.
 * Conclusion: significantly improved PFS but not OS with trimodality
 * 2009 Lancet, PMID 19632716 -- "Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial" (Albain KS, The Lancet, Early Online Publication, 27 July 2009). Median F/U 1.8 years, for survivors 5.8 years
 * Outcome: Median OS Induction 24 months vs. definitive 22 months (NS). 5-year OS 27% vs. 20% (NS). Median PFS 13 months vs. 11 months (SS). 5-year DFS 22% vs 11%. First relapse: primary tumor site 2% vs. 14%, regional LNs 7% vs. 3%, brain 11% vs. 15%, other DM 37% vs. 42%
 * Subset analysis: Lobectomy vs matched CRT 2.8 years vs. 1.8 years (SS); pneumonectomy vs matched CRT 1.6 years vs. 2.4 years (NS)
 * Toxicity: Treatment-related death 8% vs. 2%. Grade 3-4 esophagitis 10% vs. 23% (SS), no difference in pneumonitis or nausea/vomiting
 * Conclusion: Chemo-RT with or without resection (preferably lobectomy) all options for IIIA NSCLC

Induction before Surgery vs Surgery alone
Meta-Analysis
 * MRC; 2007 (UK) PMID 17636828 -- "Chemotherapy and surgery versus surgery alone in non-small cell lung cancer." (Burdett SS, Cochrane Database Syst Rev. 2007 Jul 18;(3):CD006157.)
 * Meta-analysis. 12 randomized trials, data available for 988 patients (75%)
 * Outcome: Pre-op chemo increased OS with HR 0.82 (SS), equivalent to 5-year OS benefit 6% (14% to 20%)
 * Conclusion: Significant increase in survival attributable to pre-op chemotherapy

Randomized Trials

 * Roth (MDACC) (1987-93)
 * 60 patients with resectable IIIA NSCLC randomized to induction chemo (cyclophosphamide, etoposide, cisplatin) x 3 cycles followed by surgery, followed by 3 more cycles chemo if response, vs. immediate surgical resection alone. Both groups received RT if incompletely resected at the discretion of treating physician (66 Gy for gross residual, 60 Gy for microscopic). Trial stopped early as stoppage criteria met.
 * >50% of patients received RT in each arm
 * 1994: PMID 8158698 -- "A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer." (Roth JA, J Natl Cancer Inst. 1994 May 4;86(9):673-80.)
 * estimated 3-year OS 56% vs. 15% for perioperative chemo vs. immediate surgery, respectively. MS 64 months vs 11 months. Clinical response rate of 35% with preoperative chemotherapy.
 * 1998: PMID 9792048 -- "Long-term follow-up of patients enrolled in a randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer." (Roth JA, Lung Cancer. 1998 Jul;21(1):1-6.) -- Median f/u 82 months.
 * updated 3- and 5-year OS, respectively, 43% and 36% for periop chemo, 19% and 15% for immediate surgery.

 * Rosell (Spain) (1989-?)
 * 60 patients with resectable IIIA NSCLC randomized to induction chemo (mitomycin, ifosphamide, cisplatin) x 3 courses followed by surgery, followed by 50 Gy thoracic RT, vs. immediate surgical resection followed by 50 Gy thoracic RT
 * 1994: PMID 8043059 -- "A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer." (Rosell R, N Engl J Med. 1994 Jan 20;330(3):153-8.)
 * median OS 26 months vs. 8 months, median DFS 20 months vs. 5 months (p < 0.001 for both)
 * 7-year, 1999: PMID 10574676 -- "Preresectional chemotherapy in stage IIIA non-small-cell lung cancer: a 7-year assessment of a randomized controlled trial." (Rosell R, Lung Cancer. 1999 Oct;26(1):7-14.)
 * updated median OS 22 months vs. 10 months, updated 3- and 5-year OS, respectively, 20% and 17% for pre-op chemo, 5% and 0% for immediate surgery.

 * Depierre (French) (1991-97) - Induction chemo + surgery vs surgery
 * 355 pts. Stage IB - IIIA. Preoperative chemotherapy (PCT) consisted of 2 cycles mitomycin, ifosfamide, and cisplatin. 2 additional cycles were given postoperatively for pts who responded. Pts in both arms received post-op RT for pathologic T3 or N2 disease.
 * PMID 11773176, 2002 — "Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II, and IIIa non-small-cell lung cancer." Depierre A et al. J Clin Oncol. 2002 Jan 1;20(1):247-53.
 * Median survival 37 m (PCT) vs 26 m (S), N.S. Survival difference 8.6% at 4 yrs (S.S.). Survival difference was S.S. only for pts with N0-N1 disease.

Induction Chemo vs Induction Chemo-RT

 * RTOG 04-12 / SWOG S0332
 * Stage IIIA (N2). Randomized to induction chemotherapy (cisplatin/docetaxel) vs induction chemo/RT (RT to 50.4 Gy). Followed by surgical resection then consolidative chemotherapy with docetaxel. N2 status must be confirmed pathologically. RT technique : uses 3D-CRT, no field reductions, no elective nodal irradiation.
 * Terminated due to poor accrual

 * German GLCCG (1995-2003) -- Induction cisplatin/etoposide then concurrent chemo-RT followed by surgery vs. induction cisplatin/etoposide then surgery 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.
 * 2004 Abstract ASTRO Plenary Session — "Neoadjuvant chemotherapy followed by preoperative radiochemotherapy (hfRCT) plus surgery or surgery plus postoperative radiotherapy in stage III non-small cell lung cancer: results of a randomized phase III trial of the German Lung Cancer Cooperative Group." Ruebe et al.
 * 3-year OS 26.2% (Arm A) vs 24.6% (Arm B) (NS). 3-year PFS 17.8% vs 19.9% (NS). Difference was in toxicity, with worse Grade 3/4 esophagitis in Arm A (19% vs 3%), and worse Grade 3/4 pneumonitis in Arm B (6% vs 1%). No difference in treatment related toxicity.  Concluded that both regimens are effective.
 * 2008 PMID 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

Induction Chemo + Surgery vs Induction Chemo + RT

 * EORTC 08941 -- Induction platinum x3 cycles, then surgery vs. RT
 * Randomized. 579 patients with unresectable IIIA-N2 NSCLC. Unresectable considered N2 non-squamous; or N2 squamous exceeding Station 4R for right or Station 5/6 for left side. Platinum-based induction x3 cycles, then randomized to surgical resection or RT. Had to show at least "minor" response. Induction response rate 61%.
 * RT: Start within 70 days of last chemo cycle. 3D planning + tissue correction. Dose 60-62.5 Gy involved mediastinum and 40-46 uninvolved mediastinum. Post-op RT given to 40% patients in the surgery-only arm (if R1/R2, to 56 Gy). RT arm compliance 55%
 * 5-years, 2007 PMID 17374834 -- "Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer." (van Meerbeeck JP, J Natl Cancer Inst. 2007 Mar 21;99(6):442-50.)
 * 5-year outcome: OS resection 16% vs. RT 14% (NS); median OS 16 months vs. 17 months (NS)
 * Toxicity: After surgery 4% deaths. After RT Grade 3-4 pulmonary toxicity 7%, one death of RT pneumonitis (0.6%)
 * Conclusion: Surgery did not improve OS or PFS. Given low morbidity and mortality, RT should be preferred modality
 * Editorial PMID 17374824: high number of pneumonectomies, which have negative outcome after induction chemo; better local control with surgery. Surgery may be an option if patients experience "downstaging" and clear their mediastinal LNs. On the other hand, RT techniques also improving for better toxicity. Conclusion that chemotherapy-radiation is appropriate for IIIA patients with initial N2 disease
 * RT Arm, 2006 PMID 16785054 -- "Quality assurance of thoracic radiotherapy in EORTC 08941: a randomised trial of surgery versus thoracic radiotherapy in patients with stage IIIA non-small-cell lung cancer (NSCLC) after response to induction chemotherapy. (Kramer GW, Eur J Cancer. 2006 Jul;42(10):1391-8.)
 * QA Review
 * Surgery Arm, 2005 PMID 16055865 -- "Morbidity and mortality in the surgery arm of EORTC 08941 trial." (Van Schil P, Eur Respir J. 2005 Aug;26(2):192-7.)
 * 167 patients in surgery arm: 50% R0; 47% pneumonectomies worse survival on subgroup analysis
 * Outcome: 50% R0, 40% pathologic downstaging to N0/N1
 * Toxicity: 30-day perioperative mortality 4%; reoperation 8%
 * Conclusion: morbidity and mortality acceptable

 * RTOG 89-01 (1990-1994) -- Induction chemo, then surgery vs. RT
 * 2002 PMID 12243809 -- "Phase III study comparing chemotherapy and radiotherapy with preoperative chemotherapy and surgical resection in patients with non-small-cell lung cancer with spread to mediastinal lymph nodes (N2); final report of RTOG 89-01. Radiation Therapy Oncology Group." (Johnstone DW, Int J Radiat Oncol Biol Phys. 2002 Oct 1;54(2):365-9.)
 * Randomized. Trial stopped early after initiation of INT 0139. 73 (goal 224) patients, mediastinoscopy-verified N2 NSCLC (T1-T3N2). Induction with cisplatin/vinblastine x2 cycles, then Arm 1) surgery vs. Arm 2) RT 64/32. Adjuvant cisplatin/vinblastine. 45 patients actually randomized post induction.
 * Outcome: Median OS chemo + surgery 1.6 years vs chemo + RT 1.4 years (NS); 1-year OS 70% vs. 66% (NS). If induction chemo only, median OS 9 months. No difference in PFS or LC
 * Conclusion: Trial inconclusive due to limited accrual, nevertheless, surgery and RT arms comparable and similar to historical controls

Neoadjuvant Chemotherapy +/- Neoadjuvant Immunotherapy

 * CheckMate 816 -- Induction platinum-doublet x3 cycles, with or without nivolumab, then surgery.
 * Randomized 358 patients with stage IB-IIIA resectable NSCLC (64% Stage IIIA)
 * 2022 PMID 35403841 -- "Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer," (PM Forde, NEJM 2022, 386(21):1973)
 * Median event free survival: ChemoImmunotherapy 32 months; Chemo alone 21 months (SS)
 * Pathological CR: ChemoImmunotherapy 24%, Chemo alone 2%
 * Toxicity similar.

Surgery +/- Adjuvant Chemo

 * Adjuvant chemo has become standard of care in patients who are treated with surgery and found to have stage IIIA disease. This is based on the IALT trial, as well as by extrapolating from NCIC (Stage I-II) and CALGB 9633 (Stage IB) trials
 * Please see early stage operable NSCLC section

Surgery + Adjuvant RT +/- Chemo

 * Please see Early stage operable NSCLC section

Induction Chemo biology

 * Netherlands; 2003 PMID 14676792 -- "Accelerated regrowth of non-small-cell lung tumours after induction chemotherapy." (El Sharouni SY, Br J Cancer. 2003 Dec 15;89(12):2184-9.)
 * Retrospective. 23 patients with NSCLC. Interval times between end of induction of start of RT evaluated. Mean time to RT 80 days
 * Outcome: 41% potentially curable patients became incurable; tumor median doubling 29 days (8.3-171 days)
 * Conclusion: Accelerated tumor cell proliferation, much shorter doubling time than for untreated tumors. Gain from chemo (tumor decrease) was lost with waiting for RT

Superior sulcus (Pancoast) tumors
Complete resection in 50%, 5-year OS 30%.

 * SWOG 9416 / Intergroup 0160, 2001 (1995-99) - Phase II
 * PMID 11241082 — "Induction chemoradiation and surgical resection for non-small cell lung carcinomas of the superior sulcus: Initial results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160)." Rusch VW et al. J Thorac Cardiovasc Surg. 2001 Mar;121(3):472-83.
 * 111 pts. T3-4 N0-1, mediastinoscopy negative. Treated with 2 cycles of cisplatin and etoposide concurrent with 45 Gy RT. Pts who responded or had stable disease underwent resection 3-5 weeks later. Two additional cycles of adjuvant chemotherapy were given.
 * Of 95 pts eligible for surgery, 83 had thoracotomy and 76 (92%) had complete resection. 54 (65%) showed pCR or microscopic residual disease. 2-year OS 55% for all pts and 70% for those with complete resection.

Practice Guideline

 * ACCP; 2007 PMID 17873172 -- "Treatment of non-small cell lung cancer-stage IIIA: ACCP evidence-based clinical practice guidelines (2nd edition)." (Robinson LA, Chest. 2007 Sep;132(3 Suppl):243S-265S.)
 * Stage IIIA NSCLC evidence review
 * Conclusion: Combination chemo-RT is preferred treatment for prospectively recognized IIIA. Neoadjuvant therapy followed by surgery is not supported by current evidence


text:
Chess Opening Theory/1. c4/1...e5

=English Opening=

1...e5
This move creates a reverse Sicilian but it's White's move and the aim for White to create an advantage leads generally to different positions. White's choices are now:
 * 2. Nc3, the normal move
 * 2. g3 many transposition possibilities
 * 2. Nf3 can lead to a reversed Alekhine's Defence of sorts if Black replies with ...e4, with the option of cxd5 if Black tries to advance the d-pawn
 * 2. d4 gives away any advantage

=Theory Table= .
 * 1.c4 e5

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: Chess Opening Theory/1. c4/1...e5


text:
Radiation Oncology/NSCLC/Locally Advanced Unresectable

Locally Advanced Unresectable NSCLC

Subpages:
 * RT Only
 * Induction-Chemo RT
 * Concurrent Chemo-RT

Treatment Overview

 * Patients were initially treated with radiation only, usually split course
 * Dose-escalation in RTOG 73-01 established 60 Gy in 2 Gy/fx as the standard regimen
 * Median survival was ~10 months, with 3-year survival <10%
 * Hyperfractionated RT alone did not show any benefit
 * Continuous Hyperfractionated Accelerated RadioTherapy (CHART) showed a significant improvement in OS. However, logistics of delivering RT TID x12 days straight, combined with OS improvement with chemotherapy have limited its adoption
 * CALGB, RTOG, and UK studies in mid-1990's established induction chemo + RT superior for median OS, although absolute benefit was not large (2-4 months). There was a significantly higher proportion of long term survivors. There was no impact on local progression, but distal failure was significantly less
 * Hyperfractionated RT after chemo induction did not show any benefit over standard RT
 * Induction chemo alone, without RT, was comparable in median OS, but inferior in long term survivors compared to induction chemo + RT. RT was considered a necessary component of treatment
 * At the same time, concurrent chemotherapy and RT were evaluated. The only survival benefit of concurrent chemo-RT over RT alone was in an EORTC trial, which used split-course RT with a 3 week rest. The other 3 trials with standard RT fractions were negative. The chemo used was a single agent.
 * Concurrent chemo (2 agents) with hyperfractionated RT resulted in OS benefit in 2 Yugoslavian trials
 * Small overall chemo benefit was demonstrated in a meta-analysis setting in 1995, and confirmed to be 4% absolute benefit at 2 years in a subsequent meta-analysis. Essentially any two agents are superior to any single agent; adding a third drug did not provide additional benefit
 * However, the timing of giving chemotherapy and RT was unclear. Both induction and concurrent chemo appear to provide survival benefit, induction chemo via improved distal control and concurrent chemo via improved local control.
 * Direct comparisons in several randomized trials established concurrent chemo-RT as the superior regimen, at the cost of increased in-field toxicity (especially esophagitis)
 * There is no benefit to induction chemotherapy, followed by concurrent chemo-RT (CALGB B39801, LAMP). The later RT starts, the worse the outcomes
 * The role of consolidative chemo after concurrent chemo-RT is under evaluation
 * The role of elective nodal irradiation is also evolving, with single institution series suggesting minimal benefit, and one randomized trial (China) finding that dose escalation to 68-74 Gy due to lower volume treated resulted in improved overall survival
 * The current standard of care can be considered concurrent chemo with 2 agents containing platinum, and thoracic RT to 60 Gy in QD fractions.

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 PMID 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 months 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

Radiation alone

 * ''Please see the RT Only section for detailed literature review
 * Survival: 7-10 months
 * RT dose:
 * Standard 2D: 60Gy in 2Gy/fx established in RTOG 73-01; but insufficient to control disease
 * RT alone (3D-CRT): 83.8 Gy tolerable, 90.3 Gy excess mortality (from RTOG 93-11)
 * RT with chemotherapy: maximum 70-74 Gy appears tolerable
 * Hyperfractionated RT alone did not show any beneft
 * Continuous hyperfractionated thereapy (CHART) showed a significant improvement in OS. However, logistics of delivering RT TID x12 days straight, combined with OS improvement with chemotherapy have limited its adoption
 * In mid-1990's induction chemotherapy followed by RT was shown to have modestly better OS over RT alone (see below), and efforts since have been targeted at optimizing CRT

RT alone vs. Chemo alone vs. Chemo-RT

 * Vanderbilt, 1990 - PMID 2161633 — "Thoracic radiotherapy does not prolong survival in patients with locally advanced, unresectable non-small cell lung cancer." Johnson DH et al. Ann Intern Med. 1990 Jul 1;113(1):33-8.
 * 319 pts, locally advanced, unresectable. Randomized to 1) Vindesine weekly, 2) RT to 60 Gy (2 Gy/fx), or 3) Vindesine + RT. Vindesine was given weekly for 6 weeks then every other week. Cross over to the other arm was done for disease progression.
 * Minimum f/u 42 months. Response rate was 30% (RT alone), 34% (chemo + RT), 10% (chemo). No difference in survival. Median survival was 8.6 vs 9.4 vs 10.1 months; 5-yr OS 3% vs 3% vs 1%.
 * Conclusion: RT failed to improve survival.

RT alone vs. Induction Chemo-RT

 * CALGB 8433 published in 1990 (Dillman) PMID 2169587
 * Phase III trial of 155 patients with Stage III non-small cell lung cancer
 * RT only arm received 60 Gy in 2 Gy fractions; experimental arm received cisplatin 100 mg/m2 with vinblastine 5 mg/m2 for two cycles sequentially with same radiation starting day 50.
 * Median OS improved 13.8 vs 9.7 months (p<0.01) with chemoRT vs RT alone. 3-year OS improved 23% vs 11% as well.
 * 1996 update PMID: 8780630
 * OS after years 1 through 7 were 54, 26, 24, 19, 17, 13, and 13 for the CT-RT group and 40,13,10, 7, 6, 6, and 6 for the RT group.

 * Overall, there appeared to be a modest survival benefit with induction chemo followed by RT, in patients with good performance status and no weight loss.
 * There was a significantly higher proportion of long term survivors and improved distant failure-free survival, but essentially no impact on local recurrence
 * Later studies comparing induction chemo/RT versus concurrent chemo/RT demonstrated the superiority of concurrent chemo/RT

Please see the Induction Chemo RT section for literature review

Induction Chemo-RT vs. Induction Chemo Alone

 * Same median survival, but RT significantly improves long-term survival rate. Chemotherapy alone is not sufficient

 * Sakai (Japan) PMID 8040666 -- "Role of radiotherapy in combined modality treatment of locally advanced non-small-cell lung cancer." (Kubota K, J Clin Oncol. 1994 Aug;12(8):1547-52.)
 * Randomized. 92 patients treated with chemotherapy (VP vs. MVP vs. EP/VM) x2 cycles, then randomized to RT or not. 50-60 Gy in 2 Gy/fx. 63 patients in second (RT) randomization
 * Median OS: comparable at 15 months. But 1-year, 2-year, 3-year OS: CT alone 66%, 9%, 3% vs. CT-RT 58%, 36%, 29%
 * Conclusion: No difference in median OS, but significantly better long-term survivors with CT-RT. Chest RT necessary.

RT Alone vs. Concurrent Chemo-RT

 * Only survival benefit of concurrent chemo-RT was in an EORTC trial, which used split-course RT with a 3 week rest. Three other trials with standard RT fractions were negative.
 * Two trials out of Yugoslavia, using hyperfractionated RT, were also positive
 * Meta-analysis of 9 trials showed a 4% absolute OS benefit with chemo-RT at 2 years, and established RT with chemotherapy as standard of care

Please see the Concurrent-Chemo RT section for literature review

Sequential vs. Concurrent Chemo and RT
Meta-analysis
 * NSCLC Collaborative Group; 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.)
 * Meta-analysis. Individual patient data from 6 trials (CALGB 8831, WJLCG, RTOG 9410, GMMA Ankara, GLOT-GFPC NPC 95-01, EORTC 08972). 1205 patients. Median F/U 6 years
 * Outcome: Benefit of concomitant chemo-RT over sequential chemo->RT on OS (HR 0.84, SS), with absolute benefit at 3-years of 5.7% (18% to 24%), 5-years 4.5% (11% to 15%). No difference in PFS (HR 0.9, p=0.07). Decrease in locoregional progression (HR 0.777, SS), with absolute decrease of 6% at 5 years (35% to 29%). No difference on distant progression (HR 1.04, NS), with 5-year rate of ~40%
 * Toxicity: Acute Grade 3-4 esophageal toxicity worse (RR 4.9, SS), increase from 4% to 18%; no significant difference in acute pulmonary toxicity
 * Conclusion: Concomitant chemo-RT compared with sequential chemo-RT improved overall survival, primarily through better locoregional control, at cost of manageable increase in acute esophageal toxicity

Randomized evidence
 * CTRT99/97 Bronchial Carcinoma Therapy Group (Germany) (1997-2002) - Phase III
 * 303 pts. Stage IIIA-IIIB. Treated with induction chemo: carbo/taxol x 2 cycles. Then randomized to: 1) RT only 60 Gy, or 2) Chemo-RT with weekly taxol.
 * 2006 PMID 16983107 -- "Simultaneous chemoradiotherapy compared with radiotherapy alone after induction chemotherapy in inoperable stage IIIA or IIIB non-small-cell lung cancer: study CTRT99/97 by the Bronchial Carcinoma Therapy Group." (Huber RM, J Clin Oncol. 2006 Sep 20;24(27):4397-404.)
 * 214 pts randomized. Median f/u 13.6 mo. Induction therapy was well tolerated with mild toxicities. Median survival 14.1 mo (RT) vs 18.7 mo (Chemo-RT), NS. Median TTP 11.5 mo vs 14.7 mo (SS). No significant differences in toxicity between the two arms.
 * Conclusion: Induction chemo followed by chemo-RT is feasible. Response, time to progression, and survival favor chemo-RT vs RT.

 * GLOT-GFPC NPC 95-01 (French) (1996-2000) PMID 16087956 — "Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d'Oncologie Thoracique-Groupe Francais de Pneumo-Cancerologie NPC 95-01 Study." Fournel P et al. J Clin Oncol. 2005 Sep 1;23(25):5910-7.
 * Randomized 205 pts. Stage III. Treated A) Sequential: induction cisplatin/vinorelbine followed by RT 66 Gy vs. B) Concurrent/Consolidation: RT 66 Gy with cisplatin/etoposide, then cisplatin/vinorelbine
 * Median OS: sequential 14.5 months vs concurrent/consolidative 16.3 months (NS). 4-year OS: sequential 14% vs concurrent/consolidative 21% (NS)
 * Toxicity: Worse esophageal toxicity in concurrent arm (32% vs 3%)
 * Conclusion: no significant difference, but trend suggestive of potential benefit for concurrent therapy

 * Prague, 2004 (Czech) PMID 15364136 — "Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally advanced non-small cell lung cancer: a randomized study." Zatloukal P et al. Lung Cancer. 2004 Oct;46(1):87-98.
 * Randomized. 102 patients (15 IIIA, 87 IIIB) treated with A) concurrent chemo-RT vs. B) sequential chemo-RT, with RT starting within 2 weeks. RT given as 60/30. Chemo given as cisplatin/vinorelbine
 * Median OS: concurrent 16.6 months vs. sequential 12.9 months (SS). Time-to-progression: 11.9 months vs. 8.5 months (SS)
 * Toxicity: Grade 3/4 more frequent in concurrent arm, leukopenia 53% vs. 19% (SS), nausea/vomiting 39% vs. 15% (SS)
 * Conclusion: concurrent significantly better survival, time to progression. Worse but acceptable toxicity

 * RTOG 94-10 (1994-98) PMID 21903745 — "Sequential vs Concurrent Chemoradiation for Stage III Non-Small Cell Lung Cancer: Randomized Phase III Trial RTOG 9410." Curran W et al. J Natl Cancer Inst. 2011 Sep 8. [Epub ahead of print]
 * Inoperable / unresectable Stage II-IIIB, ineligible for RTOG 93-03. Randomized. Elective nodal irradiation is required.
 * Arm 1 : sequential chemo (vinblastine + cisplatin) followed by RT beginning on day 50. Vinblastine weekly x 5. Cisplatin 100 mg/m2 q3w x 2. RT 45 Gy + 2 Gy x 9 boost (63 Gy total).
 * Arm 2 : concomitant chemo/RT (same chemo & RT as in Arm 1). (Based on RTOG 90-15 but with qd RT)
 * Arm 3 : concomitant chemo (oral etoposide and cisplatin) and hyperfractionated RT. Oral etoposide 50 mg BID given on RT days only for weeks 1-4.  Cisplatin 50 mg/m2 on days 1,8,29,36. RT dose 69.6 Gy at 1.2 Gy BID. (Based on RTOG 91-06)
 * Published at a median f/u of 11 yrs (prior ASTRO Abstract in 2003).
 * Median OS: SEQ 14.6 mo vs. CON-QD 17.0 mo (SS vs. SEQ) vs. CON-BID 15.6 mo
 * 5-year OS: SEQ 10% vs. CON-QD 16% (SS vs. SEQ) vs. CON-BID 13%
 * Conclusion: Concurrent chemo-RT with cisplatin confers a long-term survival benefit over sequential therapy.
 * RTOG 90-15 - PMID 7712445 - Phase I/II - BID RT with concurrent vinblastine + cisplatin. (Provided Arm 2 of RTOG 94-10)
 * RTOG 91-06 - PMID 8648357 - Phase II - BID RT with concurrent oral daily etoposide + IV cisplatin. (Provided Arm 3 of RTOG 94-10)

 * WJLCG; Japan (1992-94)
 * 1999 PMID 10561343 — "Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer." Furuse K et al. J Clin Oncol. 1999 Sep;17(9):2692-9.
 * 320 pts. Unresectable Stage III. Randomized Phase III.
 * Arm 1 : Concurrent. Cisplatin (80 mg/m2, days 1 & 29) + vindesine (3 mg/m2, days 1, 8, 29, 36) + mitomycin C (8 mg/m2, days 1 & 29). RT began on day 2. 28 Gy, break of 10 days, then 28 Gy (total 56 Gy).
 * Arm 2 : Induction. Same chemotherapy. RT began after chemotherapy, 56 Gy non-split course.
 * Median survival 16.5 months (concurrent) vs 13.3 months (sequential). Survival at 2, 3, 4, and 5 years in concurrent group (34.6%, 22.3%, 16.9%, and 15.8%) vs (27.4%, 14.7%, 10.1%, and 8.9%) in sequential group. Difference is S.S
 * Conclusion: Concurrent chemo/RT leads to better survial in selected pts than sequential chemo/RT.

Concurrent Chemo-RT +/- Induction Chemo

 * There appears to be no benefit to induction chemotherapy prior to concurrent chemo-RT in 2 randomized trials

 * CALGB B39801 (1998-2002) -- Induction carboplatin/paclitaxel -> 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 PMID 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.

 * Locally Advanced Multimodality Protocol (LAMP), 2005 (1998-2001) - Randomized Phase II. Closed early due to nonaccrual. Opened before concurrent chemo-RT was established as standard, with Arm 1 sequential chemo-RT as control. Arm 2 was closed early at interim analysis. Eventually interest in Arm 1 slowed down, and trial was closed. Results compared to historical RTOG 88-08
 * 257 pts. Stage IIIA or IIIB (medically inoperable N2, T4, or T3). KPS >= 70%, wt loss <= 10%.
 * Arm 1 : Sequential chemotherapy followed by RT. 2 cycles of paclitaxel (200 mg/m2) and carboplatin (AUC 6) every 3 weeks. RT on day 42 (3 weeks after last chemotherapy cycle), 45 Gy + 18 Gy = 63 Gy, to postchemo volume.
 * Arm 2 : Induction chemotherapy followed by concurrent chemo/RT. Two cycles of chemotherapy (as in Arm 1) followed by RT (as in Arm 1) given concurrently with weekly Taxol (45 mg/m2) + 2 cycles of carboplatin (AUC 2) q3weeks x 2 cycles
 * Arm 3 : Concurrent chemo/RT followed by consolidative chemotherapy. Concurrent chemo/RT (as in Arm 2) followed by two cycles of chemotherapy (as in Arms 1&2) 3-4 weeks after completion of concurrent therapy.
 * PMID 16087941, 2005 — "Combined Chemoradiotherapy Regimens of Paclitaxel and Carboplatin for Locally Advanced Non-Small-Cell Lung Cancer: A Randomized Phase II Locally Advanced Multi-Modality Protocol." Belani CP et al. J Clin Oncol. 2005 Sep 1;23(25):5883-5891.
 * Median f/u 39.6 months. Median survivals 13 months vs 12.7 months vs 16.3 months. Overall survival at 1,2,and 3 years for Arm 1: 57%, 30%, 17; Arm 2: 53%, 25%, 15%; Arm 3: 63%, 31%, 17%. No S.S. difference for any of the arms compared to RTOG 88-08.
 * Conclusion: No statistically significant difference in survival for any of the arms (vs. RTOG 88-08). Suggestion of improved outcome for Concurrent chemo/RT -> consolidative chemo.

Induction chemo alternatives + chemo-RT

 * CALGB 30105 -- Induction/concurrent carbo/taxol vs. carbo/gemcitabine
 * 2008 PMID 18487565 -- "Randomized phase II trial of induction chemotherapy followed by concurrent chemotherapy and dose-escalated thoracic conformal radiotherapy (74 Gy) in stage III non-small-cell lung cancer: CALGB 30105." (Socinski MA, J Clin Oncol. 2008 May 20;26(15):2457-63.)
 * Randomized Phase II. Arm 2 closed prematurely due to toxicity. 69 patients, Stage IIIA-B. Arm 1) induction carboplatin AUC6 + paclitaxel 225 mg/m2 followed by concurrent carboplatin AUC2 + paclitaxel 45 mg/m2 + RT 74 Gy vs. Arm 2) induction carboplatin AUC5 + gemcitabine 35 mg/m2, followed by concurrent gemcitabine + RT 74 Gy. Primary endpoint OS at 1.5 years
 * Outcome: median OS carbo/taxol 2.0 years vs. carbo/gem 1.0 years
 * Toxicity: High Grade 4-5 rate in carbo/gem arm
 * Conclusion: Carbo/taxol arm better and will be compared with standard dose TRT

Chemo-RT +/- Chemotherapy Consolidation

 * Hoosier Oncology Group (Indiana) (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 PMID 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 + 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 PMID 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

 * SWOG S9504 PMID 12743155 -- "Consolidation docetaxel after concurrent chemoradiotherapy in stage IIIB non-small-cell lung cancer: phase II Southwest Oncology Group Study S9504." (Gandara DR, J Clin Oncol. 2003 May 15;21(10):2004-10.)
 * Phase II. Stage IIIB. Concurrent chemo (cisplatin/etoposide) and RT 61 Gy, followed by consolidation docetaxel 4-6 weeks later
 * Median OS: 26 months; 3-year OS 37%; brain mets most common site of failure

Chemotherapy combinations with RT
Ongoing studies:
 * RTOG 0617 (ongoing) - Phase III. Concurrent RT + Carbo/Taxol +/- Cetuximab

Completed studies:
 * RTOG 0324 -- Phase II. Concurrent RT + Cetuximab / Carbo / Taxol
 * 87 pts. Stage III unresectable. Received cetuximab weekly (17 weeks beginning 1 week prior to CRT), RT 63 Gy / 35 fx with weekly carboplatin (AUC 2) and paclitaxel (45 mg/m2) for 6 weeks, followed by 2 doses of carbo (AUC 6) + paclitaxel (200 mg/m2) on weeks 12 - 17.
 * 2011 PMID 21555682 -- "Phase II Study of Cetuximab in Combination With Chemoradiation in Patients With Stage IIIA/B Non-Small-Cell Lung Cancer: RTOG 0324." (Blumenschein GR Jr, J Clin Oncol. 2011 Jun 10;29(17):2312-8.)
 * Median f/u 21.6 m. Response rate 62%, MS 22.7 m, 2-yr OS 49.3%.
 * Conclusion: combination of cetuximab and chemo/RT is feasible with promising activity. The median and OS were longer than any previous regimen in the RTOG.

 * CALGB 30407 -- Randomized Phase II. Carbo / Pemetrexid + RT +/- Cetuximab
 * 101 pts. Stage III. Arm A) Carboplatin (AUC 5) and Pemetrexid (500 mg/m2) q3w x 4 cycles concurrent with RT 70 Gy, Arm B) Same treatment plus Cetuximab concurrent with RT. Consolidation therapy with up to 4 cycles of Pemetrexid in both arms.
 * 2011 PMID 21747084 -- "Randomized Phase II Study of Pemetrexed, Carboplatin, and Thoracic Radiation With or Without Cetuximab in Patients With Locally Advanced Unresectable Non–Small-Cell Lung Cancer: Cancer and Leukemia Group B Trial 30407" (Govindan R, J Clin Oncol. Published online before print July 11, 2011.)
 * Adenoca in 44%, squamous in 35%. 18-mo OS 58% (Arm A) vs 54%. No significant difference in survival between pts with adenoca and squamous.
 * Conclusion: The regimen of carbo/pemetrexid/RT should be further studied.

Meta-analysis
 * Gustave-Roussy, 2004 PMID 15280345 -- "Benefits of adding a drug to a single-agent or a 2-agent chemotherapy regimen in advanced non-small-cell lung cancer: a meta-analysis. (Delbaldo C, JAMA. 2004 Jul 28;292(4):470-84.)
 * 65 randomized trials performed 1980-2003 (13,601 patients)
 * Doublet vs. single-agent: better tumor response (OR 0.42), median OS (OR 0.3), 1-year OS (OR 0.80)
 * Triplet vs. doublet: better tumor response (OR 0.66), no impact on survival (OR 1.01, 1.00)
 * Conclusion: doublet better than single-agent; triplet no additional survival benefit

RT Dose
With Concurrent Chemo:
 * RTOG 0617 (2007 - 2011) - Phase III. 4 arm randomization. 60 Gy vs 74 Gy. Concurrent RT + Carbo/Taxol +/- Cetuximab.
 * Randomized, 2x2 factorial. 544 patients. Unresectable Stage III NSCLC, PS 0-1, no SCL/contralateral hilar adenopathy. Arm A) 60 Gy vs Arm B) 74 Gy vs Arm C) 60 Gy + cetuximab vs Armd D) 74 Gy + cetuximab. All arms concurrent paclitaxel 45 mg/m2 and carboplatin AUC 2 weekly. 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.
 * Results; 2015 PMID 25601342 -- "Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study." (Bradley JD, Lancet Oncol. 2015 Feb;16(2):187-99. doi: 10.1016/S1470-2045(14)71207-0. Epub 2015 Jan 16.) Median follow up 22.9 months
 * Outcome: median OS 60 Gy 29 months vs 74 Gy 20 months (HR 1.4, SS). Median OS cetuximab 25 months vs no cetuximab 24 months (NS)
 * Toxicity: RT dose comparison - no difference in grade 3+ toxicity. Cetuximab comparison - grade 3+ 86% vs 70% (SS). Esophagitis 74 Gy 21% vs 60 Gy 7% (SS). No difference in pulmonary events.
 * Conclusion: 74 Gy radiation with concurrent chemotherapy not better than 60 Gy plus concurrent chemotherapy. Addition of cetuximab provides no benefit in overall survival
 * Quality of Life; 2015 PMID 26606200 -- "Quality of Life Analysis of a Radiation Dose-Escalation Study of Patients With Non-Small-Cell Lung Cancer: A Secondary Analysis of the Radiation Therapy Oncology Group 0617 Randomized Clinical Trial." (Movsas B, JAMA Oncol. 2015 Nov 25:1-9. doi: 10.1001/jamaoncol.2015.3969. [Epub ahead of print])
 * FACT-TOI collected in 75% at baseline. No difference at baseline
 * Outcome: Clinically meaningful decline at 3 months 74 Gy 45% vs 60 Gy 30% (SS). IMRT better than 3D-CRT (21% decline vs 46% decline, SS)
 * Conclusion: Clinically meaningful decline in 74 Gy arm compared with 60 Gy arm

IMRT compared to 3D-conformal

 * Secondary analysis of NRG Oncology/RTOG 0617 PMID 28034064, PMID 28068179 -- "Impact of Intensity-Modulated Radiation Therapy Technique for Locally Advanced Non-Small-Cell Lung Cancer: A Secondary Analysis of the NRG Oncology RTOG 0617 Randomized Clinical Trial." (Chun SG et al. J Clin Oncol. 2017 Jan 1;35(1):56-62.)
 * Methods: secondary analysis of RTOG 0617 based on stratification by RT technique (3D-CRT or IMRT)
 * 482 patients, 53% 3D-CRT, 47% IMRT
 * IMRT patients had worse clinicopathologic features: significantly larger PTVs, more advanced AJCC stage disease and worse socioeconomic status
 * Toxicity: IMRT had less Grade 3+ pneumonitis compared to 3D-CRT (3.5% vs. 7.9%, p < 0.05)
 * Survival, local control, PFS, and DMFS similar for 3D-CRT and IMRT
 * Dosimetry: the lung V20 was associated with grade 3+ pneumonitis, lung V5 low-dose bath was not associated with any kind of toxicity, heart doses (V20, V40, V60) were independently associated with survival
 * Conclusion: IMRT should be routinely considered for locally-advanced NSCLC because it yielded lower Grade 3+ pneumonitis rates and reduced heart doses. Spread of the low dose bath was protective against pneumonitis; plans should not be optimized by V5 because this reduces conformity.

 * MD Anderson; 2007 (2002-2005) PMID 17321067 -- "Initial evaluation of treatment-related pneumonitis in advanced-stage non-small-cell lung cancer patients treated with concurrent chemotherapy and intensity-modulated radiotherapy." (Yom SS, Int J Radiat Oncol Biol Phys. 2007 May 1;68(1):94-102. Epub 2007 Feb 22.)
 * Retrospective. 68 patients, advanced NSCLC, treated with IMRT and concurrent chemotherapy. Compared with 222 similar patients treated with 3D-CRT. Median F/U 9 months
 * Dosimetry: Median dose IMRT 63 Gy vs. 3D-CRT 63 Gy. Median tumor volume 194 mL vs. 142 mL
 * Toxicity: 1-year Grade 3+ pneumonitis IMRT 8% vs. 3D-CRT 32% (SS)
 * Conclusion: In advanced NSCLC treated with concurrent chemo-RT, IMRT resulted in significantly lower level of Grade 3+ pneumonitis

Without Concurrent Chemo

 * Memorial Sloan Kettering
 * 2007 PMID 17762758 -- "High-dose radiotherapy for the treatment of inoperable non-small cell lung cancer." (Sura S, Cancer J. 2007 Jul-Aug;13(4):238-42.)
 * Retrospective. 82 patients, inoperable NSCLC Stage I-IIIB (I-II n=55; III n=27). Dose >= 80 Gy using 3D-CRT with sequential chemotherapy
 * 5-year Outcome: Stage I/II LC 67%, OS 36%, median OS 3.4 years; Stage III LC 39%, OS 31%, median OS 2.7 years
 * Conclusion: OS and LC comparable with other dose-escalation studies
 * 2005 (1991-2003) PMID 15830346 -- "Results of a phase I dose-escalation study using three-dimensional conformal radiotherapy in the treatment of inoperable nonsmall cell lung carcinoma." (Rosenzweig KE, Cancer. 2005 May 15;103(10):2118-27.)
 * Phase I dose escalation. 104 patients, 28% Stage I-II, 33% IIIA, 32% IIIB, 6% recurrent. Pneumonitis NTCP had to be <25%. Dose 70.2 -> 75.6 -> 81.0 -> 84.0 -> 90 (1.8 Gy fx for 70.2-81; 2.0 Gy for 84-90). Protocol amended to omit elective nodal irradiation. Chemo: induction given in 16%; no concurrent chemo.
 * Outcome: Unacceptable toxicity at 90 Gy; 84.0 Gy considered MTD. 2-year LC 52%. OS improved significantly if dose >= 80.0 Gy
 * Toxicity: Crude late pulmonary toxicity 7%
 * Conclusion: MTD for NSCLC with NTCP constraint of 25% is 84.0 Gy

 * Michigan (1992-1999)
 * Phase I trial. 104 patients (Stage I 23%, Stage II 4%, Stage IIIA 41%, Stage IIIB 25%, Recurrent 7%). Patients stratified based on Veff into 5 groups, each group escalated independently. Starting doses were 63 Gy, 63 Gy, 65.1 Gy, 69.3 Gy, and 84 Gy. No ENI.
 * 2001 PMID 11134205 -- "Dose escalation in non-small-cell lung cancer using three-dimensional conformal radiation therapy: update of a phase I trial." (Hayman JA, J Clin Oncol. 2001 Jan 1;19(1):127-36.)
 * Outcome: MTD only established for largest Veff group at 65.1 Gy. Dose levels for other groups were 75.6 Gy, 84 Gy, 102.9 Gy, and 102.9 Gy
 * Conclusion: Dose escalation protocol reported
 * 2005 PMID 16168827 -- "High-dose radiation improved local tumor control and overall survival in patients with inoperable/unresectable non-small-cell lung cancer: long-term results of a radiation dose escalation study." (Kong FM, Int J Radiat Oncol Biol Phys. 2005 Oct 1;63(2):324-33.)
 * Median f/u 8.5 yrs. MS 19 mos. 5-yr OS 13%. On multivariate analysis, weight loss and RT dose were significant predictors for OS. 5-yr OS 4% (63-69 Gy), 22% (74-84 Gy), and 28% (92-103 Gy). 5-yr LRC 12%, 35%, and 49%.
 * Conclusion: higher radiation doses associated with improved outcome.

Accelerated RT
Concomitant boost
 * RTOG 84-07 (1984-89)
 * Phase I/II. 355 pts, ? stage. 45 Gy large fields (primary + regional nodes) + 18 Gy boost (primary and involved nodes only) = 63 Gy. Given as 45/1.8 Gy/5 weeks. Boost given as 10 fractions 2-3 times per week as 2nd fraction separated by 4-6 hrs. Dose escalated from 45+18=63 to 70.2 Gy/5.5 wks (50.4 + 19.8 Gy) to 70.2 Gy/5 wks (45 + 25.2 Gy).
 * PMID 7836079, 1993 — "A phase I/II study to evaluate accelerated fractionation via concomitant boost for squamous, adeno, and large cell carcinoma of the lung: report of Radiation Therapy Oncology Group 84-07." Byhardt RW et al. Int J Radiat Oncol Biol Phys. 1993 Jun 15;26(3):459-68.
 * Acute grade 3 toxicity in 7% vs 14% vs 17%. Grade 4 toxicity in 2-3% for all arms. Late toxicity in 5-9% grade 3 and 0-2% grade 4.
 * Survival not statistically different between arms. MS 9 months, 1-yr OS 39-44%, 2-yr OS 16-21%. For pts with Stage III/KPS > 70/no weight loss (i.e. eligible for CALGB 8433) 2-yr OS, 18-22%.

Hyperfractionated RT with chemotherapy

 * RTOG 92-04 (1992-94) - phase II randomized
 * 164 pts. Unresectable Stage IIIA-B. Randomized to 1) induction chemotherapy + concurrent chemo/RT (weekly vinblastine x 5, cisplatin days 1+29 followed by RT to 45+18=63 Gy beginning on day 50 with concurrent cisplatin q3week x 3) vs 2) concurrent chemotherapy + hyperfractionated RT (1.2 Gy BID to 50.4+19.2=69.6 Gy in 4 wks with oral etoposide on days 1-10 + cisplatin days 1+8)
 * First report, 1997 - PMID 9212017
 * PMID 12062596, 2002 — "Randomized phase II chemotherapy and radiotherapy trial for patients with locally advanced inoperable non-small-cell lung cancer: long-term follow-up of RTOG 92-04." Komaki R et al. Int J Radiat Oncol Biol Phys. 2002 Jul 1;53(3):548-57.
 * Lower in-field progression for Arm 2 than Arm 1 (26% vs 45% at 2 years; 30% vs 49% at 4 yrs; S.S.). Median, 2-yr OS, and 5-yr OS similar between arms. Higher rate of acute and chronic esophagitis in Arm 2 (37% vs 3.3% acute grade 3-4; 17% vs 4% late grade 3-4).
 * Conclusion: Hyperfractionation with chemo leads to improved local control at the expense of esophageal toxicity.

 * RTOG 94-10 - see above

 * Australia 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

Elective nodal irradiation

 * International Atomic Energy Agency; 2008 PMID 18793953 -- "Report from the International Atomic Energy Agency (IAEA) consultants' meeting on elective nodal irradiation in lung cancer: non-small-Cell lung cancer (NSCLC)." (Belderbos JS, Int J Radiat Oncol Biol Phys. 2008 Oct 1;72(2):335-42.)
 * Consultant meeting conference in 9/2006.
 * Conclusion: Routine omission may not be advisable in all patients, and may depend on stage, location, and other variables.

 * MSKCC (1991-2005)
 * 2007 PMID 17984185 -- "Involved-field radiation therapy for inoperable non small-cell lung cancer." (Rosenzweig KE, J Clin Oncol. 2007 Dec 10;25(35):5557-61.)
 * Retrospective. 524 patients, definitive IFRT. Only LN+ by biopsy or >=1.5 cm short axis by CT included in CTV. Elective nodal failure (ENF) defined as recurrence in initially LN- in absence of local failure. Median F/U 3.4 years
 * Outcome: ENF in 6%; 2-year elective nodal control 92%, local control 51%; median time to nodal failure 6 months
 * Nodal dose-response (from incidental nodal irradiation): 86% failures in regions receiving dose <45 Gy vs. 14% failures if receiving >45 Gy (SS). In nodal regions receiving <45 Gy, failure rate 1.4% vs. if >45 Gy failure rate 0.6% (SS)
 * Conclusion: IFRT didn't cause significant failure in LN regions not included in CTV
 * Editorial (PMID 17984182): Discrepancy between surgical data and RT data about LN failures. Discussion about incidental nodal irradiation and its dose-effect on nodal failure
 * 2001 PMID 11395236 -- "Elective nodal irradiation in the treatment of non-small-cell lung cancer with three-dimensional conformal radiation therapy." (Rosenzweig K, Int J Radiat Oncol Biol Phys. 2001 Jul 1;50(3):681-5.)
 * 171 pts tx'd w/ 3D-CRT at MSKCC b/w 1991-98. Only +nodes by biopsy or >/= 1.5 cm in short axis on CT were included in CTV.
 * Tumor control at 2 yrs 38%, elective nodal control 91%.
 * Conclusion: Local control much more problematic than elective nodal control; omission of elective nodal irradiation did not significantly worsen nodal failures outside of CTV.

 * Shandong, 2006 (China) PMID 17551299 -- "A randomized study of involved-field irradiation versus elective nodal irradiation in combination with concurrent chemotherapy for inoperable stage III nonsmall cell lung cancer.." (Yuan S, American Journal of Clinical Oncology, 2007 30(3):239-44)
 * Randomized. 200 patients, inoperable Stage III NSCLC, treated with induction chemo x2 cycles followed by concurrent chemo-RT, followed by 2-3 cycles. RT randomized to elective nodal irradiation (ENI) vs. involved-field radiation (IFRT). Dose IFRT to 68-74 Gy and ENI to 60-64 Gy. IFRT defined as pre-CHT tumor volume and any mediastinal nodes bx+ or >1cm short-axis on CT. Chemo cisplatin-based doublet.
 * Toxicity: Pneumonitis ENI 29% vs. IFRT 17% (SS)
 * 2-year failure: local ENI 49%, IFRT 41%. Omission of ENI did not lead to isolated nodal failures
 * Survival: 2-years ENI 26% vs. IFRT 39% and 3-years 19% vs. 27% (SS)
 * Conclusion: No isolated nodal failures, local control still major issue, successful dose escalation to 68-74Gy and survival difference by omitting elective nodal irradiation
 * RTOG Analysis, 2003 PMID 12871784 -- "The impact of regional nodal radiotherapy (dose/volume) on regional progression and survival in unresectable non-small cell lung cancer: an analysis of RTOG data." (Emami B, Lung Cancer. 2003 Aug;41(2):207-14.)
 * 1705 pts from 4 RTOG trials (7811, 7917, 8311, 8407) analyzed for in-field/out-of-field recurrence patterns.
 * Neither in-field progression or 2yr OS were affected by adequacy of nodal coverage in mediastinum, ipsi supraclav, contralat hilum.

 * Rotterdam, 2002 PMID 12419425 -- "Can elective nodal irradiation be omitted in stage III non-small-cell lung cancer? Analysis of recurrences in a phase II study of induction chemotherapy and involved-field radiotherapy." (Senan S, Int J Radiat Oncol Biol Phys. 2002 Nov 15;54(4):999-1006.)
 * 50 pts w/ stage III NSCLC tx'd w/ sequential chemo + xrt to 70 Gy w/ omitted elective nodal irradiation.
 * 27% had in-field recurrences, 18% had distant mets alone, no elective nodal failures

Reviews
 * PMID 11040331, 2000 — "Point: the potential importance of elective nodal irradiation in the treatment of non-small cell lung cancer." Liengswangwong V et al. Semin Radiat Oncol. 2000 Oct;10(4):308-14.
 * PMID 11040332, 2000 — "Counterpoint: better radiation treatment of non-small cell lung cancer using new techniques without elective nodal irradiation." Williams TE et al. Semin Radiat Oncol. 2000 Oct;10(4):315-23.

Induction chemo followed by conventional RT vs. HART

 * No difference in survival or response rate

 * ECOG 2597, 2005 (1998-2001) - After induction chemotherapy, standard fractionation RT vs hyperfractionated accelerated radiation therapy (HART). No concurrent chemo. Closed early due to low accrual.
 * PMID 15837967 — "Phase III Study of the Eastern Cooperative Oncology Group (ECOG 2597): Induction Chemotherapy Followed by Either Standard Thoracic Radiotherapy or Hyperfractionated Accelerated Radiotherapy for Patients With Unresectable Stage IIIA and B Non-Small-Cell Lung Cancer." Belani CP et al. J Clin Oncol. 2005 Jun 1;23(16):3760-7.
 * 141 pts. Unresectable IIIA or IIIB. Induction chemo with carbo/taxol x 2 cycles q3weeks. Randomized to once-daily RT (QD) 64 Gy at 2 Gy/fx vs HART 57.6 Gy TID in 12 fx over 15 days. For HART, 1st and 3rd daily fractions were 1.5 Gy large field, 2nd fx was boost field 1.8 Gy; at least 4 hours between fractions.
 * No diffence in OS or response, but there was a trend for improved survival.
 * Weak study since no concurrent chemo/RT

RT Timing

 * Kragujevac (Yugoslavia) PMID 15577441 -- "Interfraction interval in patients with stage III non-small-cell lung cancer treated with hyperfractionated radiation therapy with or without concurrent chemotherapy: final results in 536 patients." (Jeremic B, Am J Clin Oncol. 2004 Dec;27(6):616-25.)
 * Retrospective review of 3 Phase III and 1 Phase II. 536 patients treated with Hfx RT, 285 patients interfraction interval (IFI) 4.5-5.0 hrs, 251 patients IFI 5.5-6.0 hrs
 * Survival: short IFI significantly better OS, LRFS

Chemotherapy

 * 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 PMID 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

 * ECOG 4599 PMID 17167137 -- "Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer." (Sandler A, N Engl J Med. 2006 Dec 14;355(24):2542-50.)
 * Randomized. 878 patients with IIIB (malignant pleural effusion) or IV NSCLC, no squamous cell tumors, no brain mets, no hemoptysis, no ECOG >1. Treated with 1) Paclitaxel/carboplatin vs. 2) paclitaxel/carboplatin + bevacizumab, until disease progression or toxicity
 * Median OS: carbo/taxol 10.3 months vs. carbo/taxol/bevacizumab 12.3 months (SS)
 * Treatment related deaths: 2 vs. 15 (5 pulmonary hemorrhage)
 * Conclusion: Bevacizumab improves survival, but significant risk of treatment-related death

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 PMID 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
 * 2009 PMID 19858383 -- "Quality of Life Supersedes the Classic Prognosticators for Long-Term Survival in Locally Advanced Non-Small-Cell Lung Cancer: An Analysis of RTOG 9801." (Movsas B, J Clin Oncol. 2009 Oct 26. [Epub ahead of print])
 * 239 patients, 91% baseline QOL score. Multivariate analysis for OS: KPS, stage, sex, age, race, marital status, histology, location, Hgb, tobacco, amifostine, QoL scores (QLQ-C30, LC-13). Median F/U 5 years if alive, 17 months for all
 * Outcome: On multivariate analysis, only baseline global QoL score was prognostic for survival; no other variables were significant. Patients with QoL score <67 (median value) had 70% higher rate of death (SS); 10-point increase in QoL corresponded to 10% decrease in hazard of death. Both physical functioning (QLQ-30) and dyspnea (LC-13) were independently predictive for OS on univariate analysis
 * Conclusion: Quality of life score replaced all known prognostic factors as sole predictor for long-term survival

Metoclopramide

 * Institute for Cancer Research, Oslo (1995-1998) -- observation vs metoclopramide
 * 2010 PMID 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

Reviews and Guidelines

 * ASCO 2003 - PMID 14691125 — "American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003." Pfister DG et al. J Clin Oncol. 2004 Jan 15;22(2):330-53.


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Rebol Programming/Language Features/Database

Rebol/Command, Rebol Technologies enterprise product, is the only version that comes with database abilities out of the box. This includes support for Oracle, ODBC, and MySql. It is the stated intention of Rebol Technologies to release the source code for the database protocols, but in the meantime third party developers have written interfaces for the free Rebol/Core to some of the more popular database products.

In many instances, the database adaptor has been written as a Rebol protocol, and access to the database is via a virtual port. Database queries are then inserted ( sent ) into the port, and results are retrieved by reading from the port.

Berkeley DB
Rebol Berkeley DB interface

DyBase
DyBase download

MySQL
MySQL database interface - a scheme for /Core that will allow to connect to a MySQL database server, send queries and retrieve resulting recordsets. This driver is 100% written in Rebol and doesn't require any additional library (like libmysql). Open-source : BSD-like license.

Rebol3 MySQL

PostgreSQL
PostgreSQL interface - a scheme for /Core that will allow you to connect to a PostgreSQL database server, send queries and retrieve resulting recordsets. This driver is 100% written in Rebol and doesn't require any additional library. It works with all Rebol products (/View, /Pro, /Command, /Link,...) and on all platforms supported by Rebol. You only need one file to make it work and its size is less 20Kb. Open-source : BSD-like license.

RebDB
RebDB is a small but highly efficient pseudo-relational DBMS written entirely in Rebol/Base syntax, meaning that it will run on any platform that Rebol/Core runs on. Open-source : BSD-like license.

SQL-Protocol
SQL-Protocol is also a small but efficient RDBMS written entirely in Rebol and run on any platform that Rebol/Core runs on. SQL-Protocol use an SQL like dialect and allows you to make JOINs in your query. Moreover, SQL-Protocol can use text databases compatible with the Microsoft OBDC text driver and allows you to share data between the Rebol and the Microsoft world. License: public domain.

SQLite
SQLite database interface - a simplified wrapper to the SQLite library. Usable in freeware interpreter since version 2.7.6. Open source: BSD-like license.

Redis
Rebol3 Redis