# Radiation Oncology/NSCLC/Randomized

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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 PMID not available, 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)- PMID 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 PMID 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 PMID 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 PMID 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 PMID 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 PMID 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 PMID 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 PMID 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 PMID 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 PMID 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 PMID 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 PMID 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 PMID 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 PMID 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 PMID 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 cispaltin, 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 PMID 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 PMID 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 PMID 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 PMID 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 PMID 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 PMID 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 PMID 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 PMID 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 PMID 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 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

### 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 PMID 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 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 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 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.

### 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 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 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 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

### Radiosensitization

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

## 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 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

## 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 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