Radiation Oncology/Randomized/Protons

Randomized Evidence in Proton Therapy

Ocular melanoma

 * MGH; 2000 (1989-1998) PMID 10865313 -- "A randomized controlled trial of varying radiation doses in the treatment of choroidal melanoma." (Gragoudas ES, Arch Ophthalmol. 2000 Jun;118(6):773-8.)
 * Randomized. 188 patients with small/medium choroidal melanoma (<15mm diameter, <5mm height), within 4 disc diameters of optic disc or macula. Arm 1) 50 CGE vs. Arm 2) 70 CGE
 * 5-year outcome: visual acuity >20/200 similar at 55%; tumor regrowth similar at ~3%; mets similar at ~8%
 * Toxicity: 50 CGE significantly less visual loss; no difference in radiation papillopathy or maculopathy
 * Conclusion: Lower dose resulted in similar outcome, similar visual acuity loss, but improved visual field loss

Prostate

 * PROG 95-09 (1996-1999) -- Proton/photon 70.2 Gy vs. proton/photon 79.2 Gy
 * Randomized. 2 institutions (Harvard and Loma Linda). 392 patients, stage T1b-T2b, PSA <15 ng/mL (median PSA 6.3). Arm 1) proton boost 19.8/11 GyE followed by photons 50.4/28 vs. Arm 2) proton boost 28.8/16 followed by photons 50.4/28. Proton CTV = prostate + 5 mm margin. PTV = CTV + 7-10 mm. Loma Linda used opposed lateral beams, 250 MeV protons; Harvard used perineal boost, 160 MeV protons. Rectal Lucite probe, inflated with 25-50 mL saline. Photons were 4F plan, photon CTV = prostate/SV + 10 mm margin.
 * 5-years; 2005 PMID 16160131 -- "Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: a randomized controlled trial." (Zietman AL, JAMA. 2005 Sep 14;294(10):1233-9.) Median F/U 5.5 years
 * Outcome: 5-year bNED 70.2 Gy 61% vs. 79.2 Gy 80% (SS), 50% reduction in risk of failure. LC (defined as PSA <1.0) 48% vs. 67% (SS) No difference in OS 97% vs 96% (NS)
 * Risk stratification: low risk (PSA <10, stage <=T2a, GS <7) 60% vs. 80% (SS); high risk 63% vs. 79% (SS). Contemporary intermediate risk 63% vs. 81% (SS), but contemporary high risk (NS, but small number)
 * Late toxicity: Grade 3+ 70.2 Gy 1% vs. 79.2 2%; GU Grade 2 18% vs. 20% (NS), GI Grade 2 8% vs. 17% (SS). Most GI toxicity by 3 years; GU toxicity continuous
 * Conclusion: Men with clinically localized PCA have better bNED with high dose, without worse severe toxicity
 * 10-years; 2010 PMID 20124169 -- "Randomized Trial Comparing Conventional-Dose With High-Dose Conformal Radiation Therapy in Early-Stage Adenocarcinoma of the Prostate: Long-Term Results From Proton Radiation Oncology Group/American College of Radiology 95-09." (Zietman AL, J Clin Oncol. 2010 Mar 1;28(7):1106-11.) Median F/U 8.9 years
 * Outcome: 10-year ASTRO (backdating) bPFS low-dose 68% vs. high-dose 83% (SS). For low-risk disease 72% vs 93% (SS); for intermediate-risk 58% vs. 70% (p=0.06). No difference in OS (78% vs 83%)
 * Toxicity: Late Grade 2+ low-dose 29% vs. high-dose 39% (SS); Grade 3+ 2% in both arms (NS)
 * Conclusion: Long-term advantage for high dose in low/intermediate risk PCA patients, with comparable Grade 3 toxicity


 * Harvard (1982-1992) -- Proton (dose escalated) vs. photon boost
 * Randomized. 202 patients, Stage T3-T4Nx,0-2. Standard photons 50.4 Gy four-field, then Arm 1) Conformal protons 25.2 CGE (total 75.6 CGE) vs. Arm 2) Photons 16.8 Gy (total 67.2 Gy). Median F/U 5.1 years
 * 5-years; 1995 PMID 7721636 -- "Advanced prostate cancer: the results of a randomized comparative trial of high dose irradiation boosting with conformal protons compared with conventional dose irradiation using photons alone." (Shipley WU, Int J Radiat Oncol Biol Phys. 1995 Apr 30;32(1):3-12.)
 * Outcome: 5-year LC photon+proton 92% vs. photons 80% (NS), no difference in OS, DSS, TRFS. GS 4/5 patients 94% vs. 64% (SS)
 * Toxicity: Rectal bleeding photon+proton 32% vs. photons 12% (SS), urethral stricture 19% vs. 8% (p=0.07)
 * Conclusion: Boosting dose with protons increased LC in poorly differentiated tumors, but also worsened late toxicity