Radiation Oncology/Randomized/Technology

Randomized Trials of Radiation Therapy Technology

Radiation Therapy Machines

• Hopital Timone, Marseille (2006) -- Gamma Knife 4C vs PerfeXion
  • Randomized. 200 patients. Arm 1) GammaKnife 4C vs Arm 2) GammaKnife PerfeXion
  • 2009 PMID 19190462 -- "Radiosurgery with the world's first fully robotized Leksell Gamma Knife PerfeXion in clinical use: a 200-patient prospective, randomized, controlled comparison with the Gamma Knife 4C." (Regis J, Neurosurgery. 2009 Feb;64(2):346-55; discussion 355-6.)
    • Outcome: No technical failures. Median # of collimator sizes 4C 1 vs PerfeXion 2. Median treatment time 60 min vs 40 min (SS), but median beam-on time 33.4 vs 34.0 minutes (NS). Single run 42% vs. 99%. Collision risk requiring gamma angle 24% vs 0%.
    • Toxicity: Less dose with PerfeXion to vertex (8x), thyroid (10x), sternum (13x), and gonads (15X)
    • Conclusion: Technological advances with PerfeXion

Immobilization

Head & Neck

• Princess Margaret (2006-2008) -- standard immobilization mask vs skin-sparing immobilization mask
  • Randomized. 762 CBCT scans in 20 patients. Arm 1) standard mask (SM) vs Arm 2) skin-sparing mask (SSM) modified with low neck cutouts
  • 2010 PMID 20056344 -- "Cone-beam CT assessment of interfraction and intrafraction setup error of two head-and-neck cancer thermoplastic masks." (Velec M, Int J Radiat Oncol Biol Phys. 2010 Mar 1;76(3):949-55. Epub 2010 Jan 7.)
    • Outcome: Initial interfraction sigma SM 1.6 mm or 1.1 degrees vs SSM 2.0 mm and 0.8 degrees. No difference after CBCT correction. Initial intrafraction sigma <1 mm and <1 degree for both masks.
    • Conclusion: Interfraction and intrafraction setup error not significantly different between masks. Mask cutouts should be considered to reduce skin toxicity

• Karolinska Hospital (Sweden)(1998-2001) -- head mask vs head-and-neck mask setup
  • Randomized. 241/260 patients. H&N cancers excluding NPC. Arm 1) Head mask vs. Arm 2) Head-and-shoulder mask. Both Posicast thermoplastic masks. Assessed reproducibility (port films and table positions), patient tolerability (fit, pain, movement within, claustrophobia), and skin damage
  • 2005 PMID 15629618 -- "Randomized trial on two types of thermoplastic masks for patient immobilization during radiation therapy for head-and-neck cancer." (Sharp L, Int J Radiat Oncol Biol Phys. 2005 Jan 1;61(1):250-6.)
    • Outcome: No difference in reproducibility of setup
    • Toxicity: Claustrophobia head mask 45% vs. head-and-shoulder maks 58% (SS), otherwise no difference in tolerability. Skin toxicity Grade 3 head mask 21% vs. head-and-shoulder mask 39% (SS)
    • Conclusion: Smaller head makes reduced claustrophobial and skin reactions, without compromising reproducibility of the setup

Prostate

• Princess Margaret -- VacLok vs BodyFix
  • Randomized. 32 patients. Arm 1) VacLok immobilization vs. Arm 2) BodyFix adbominal compression. Interfraction motion >3 mm corrected pre-treatment
  • 2008 PMID 18279985 -- "A randomized comparison of interfraction and intrafraction prostate motion with and without abdominal compression." (Rosewall T, Radiother Oncol. 2008 Feb 13 [Epub ahead of print])
    • Outcome: No difference in interfraction or intrafraction motion with or without adominal compression
    • Conclusion: Addition of abdominal compression didn't influence interfraction or intrafraction prostate motion

• Nijmegen, The Netherlands -- 3D-CRT +/- endorectal balloon
  • Randomized. 48 patients, treated with 3D-CRT to 67.5 Gy. Arm 1) No endorectal balloon (ERB-) vs. Arm 2) with endorectal balloon (ERB+). Rectosigmoidoscopy at 3 months, 6 months, 1 year, 2 years. 146 endoscopies and 2,336 mucosal areas analyzed
  • 2007 PMID 17161552 -- "Reduced late rectal mucosal changes after prostate three-dimensional conformal radiotherapy with endorectal balloon as observed in repeated endoscopy." (van Lin EN, Int J Radiat Oncol Biol Phys. 2007 Mar 1;67(3):799-811. Epub 2006 Dec 8.) Median F/U 2.5 years
    • Outcome: ERB group significantly lower rectal wall volume exposed to high doses. Late rectal toxicity G1: ERB- 58% vs. ERB+ 21%; G2 4% vs. 0%; G3 4% vs. 0%. Overall G1+ rectal toxicity 67% vs. 21% (SS)
    • Endoscopy: Telangiectasia ERB- vs ERB+ @ 6 months 16% vs. 24%; 1 year 45% vs. 28%; 2 years 39% vs. 24% (SS). High grade telangiectasia @ 1 years 20% vs. 10%; 2 years 19% vs. 9% (SS). Significantly less high grade telangiectasia at lateral and posterior part of Rwall
    • Conclusion: ERB reduced rectal wall volume exposed to >40 Gy, resulting in reduction of late mucosal changes and reduced late rectal toxicity

Radiation Delivery: 3D Conformal RT

Prostate

• Rotterdam, Netherlands (1994-1996) -- conformal RT vs conventional RT
  • Randomized. 266 patients, prostate cancer Stage T1-4N0. RT 66/33. PTV expansion 15 mm. Arm 1) conventional RT (rectangular, open fields) vs. Arm 2) conformal RT (conformally shaped fields with MLC). PTV = GTV + 1.5 cm
  • 1999 PMID 10098427 -- "Acute morbidity reduction using 3DCRT for prostate carcinoma: a randomized study." (Koper PC, Int J Radiat Oncol Biol Phys. 1999 Mar 1;43(4):727-34.)
    • Outcome: Acute GI Grade 2 conventional 32% vs. conformal 19% (SS); Acute GU Grade 2 in 17% vs. 18% (NS). Further GI analysis: rectal symptoms 18% vs. 14% (NS) but anal symptoms 16% vs. 8% (SS)
    • Conclusion: Significant reduction in GI toxicity, driven by anal symptoms. No difference between rectum/sigmoid and bladder toxicity
  • 2004 PMID 15465140 -- "Gastro-intestinal and genito-urinary morbidity after 3D conformal radiotherapy of prostate cancer: observations of a randomized trial." (Koper PC, Radiother Oncol. 2004 Oct;73(1):1-9.) F/U 2 years
    • Toxicity: Grade 2 conventional 10% vs 3D-CRT 7% (NS), Grade 1 47% vs. 40% (NS). Most bothersome symptoms: urgency, soiling, and fecal loss
    • Predictors: Anal/rectal V90% for rectal toxicity. Acute anal/rectal toxicity for late rectal toxicity. Pretreatment urgency for later bladder toxicity
    • Conclusion: Conformal RT at 66 Gy doesn't significantly decrease incidence of rectal, anal, and bladder toxicity compared with conventional RT

• Royal Marsden (1988-1995) -- conformal RT vs conventional RT
  • Randomized. 225 men with prostate CA, T1-T4N0. NACHT in 68%. RT 64/31. Arm 1) conformal RT vs. Arm 2) conventional RT
  • 1999 PMID 9929018 -- "Comparison of radiation side-effects of conformal and conventional radiotherapy in prostate cancer: a randomised trial." (Dearnaley DP, Lancet. 1999 Jan 23;353(9149):267-72.) Median F/U 3.6 years
    • Outcome: Radiation-induced proctitis G1+ conformal RT 37% vs. conventional RT 56% (SS), G2+ 5% vs. 15% (SS). No difference in bladder toxicity. No difference in bPFS (78% vs 83%, NS)
    • Conclusion: Conformal RT significantly reduced risk of late proctitis

Radiation Delivery: IMRT

Head & Neck

• Prince of Wales Hospital; 2007 (Hong Kong)(2001-2003) PMID 17971582 -- "Prospective randomized study of intensity-modulated radiotherapy on salivary gland function in early-stage nasopharyngeal carcinoma patients." (Kam MK, J Clin Oncol. 2007 Nov 1;25(31):4873-9.)
  • Randomized. 60 patients with T1-2bN0-1 nasopharynx. Arm 1) IMRT 66 Gy (CTV=GTV + 1cm; at-risk anatomic sites; LN Levels IB-II, LN upper Level V, LN retropharyngeal; PTV=CTV+3mm), lower neck LN+ 66 Gy anterior field, LN- 54-60 Gy + intracavitary BT boostvs. Arm 2) 66 Gy 2D + intracavitary BT boost
  • Outcome: observer-rated severe xerostomia IMRT 39% vs. 2D-RT 82% (SS), stimulated parotid flow (SS), unstimulated parotid flow (SS), but no difference in patient-reported feeling of xerostomia
  • Conclusion: IMRT superior in preserving objective parotid function, but no difference in patient-reported benefit
  • Editorial (PMID 17971579): Observer-rated scoring underestimates patient reports and has low agreement among various observers. Suspect sparing of parotid alone not sufficient. Parotid gland produces saliva without mucins (lubricants, bind water, and provide selective permeability barrier). Mucin-secreting glands (e.g. minor salivary glands, submandibular glands) produce <10% saliva but >50% mucins. May need to spare these glands as well for subjective feeling of benefit

• Queen Mary Hospital; 2006 (Hong Kong)(2000-2004) PMID 17145528 -- "Xerostomia and quality of life after intensity-modulated radiotherapy vs. conventional radiotherapy for early-stage nasopharyngeal carcinoma: initial report on a randomized controlled clinical trial." (Pow EH, Int J Radiat Oncol Biol Phys. 2006 Nov 15;66(4):981-91.)
  • Randomized. 51 patients, Stage II (T2N0-1, AJCC 1997). Arm 1) conventional RT 68 Gy, neck 66 Gy vs. Arm 2) IMRT, GTV dose 68-72 Gy, PTV 66-68 Gy. Stimulated whole (SWS) and parotid (SPS) saliva flow evaluated, QoL SF-36, EORTC Core, EORTC QLQ-H&N35 questionnaires. Minimum F/U 1 years
  • 1-year outcome: 25% whole flow (SWS) IMRT 50% vs. 2D 5% (SS), 25% parotid flow (SPS) 83% vs. 9% (SS). At 2 months, both group had xerostomia, but IMRT group improved significantly better over time. Also improvements in QoL
  • Conclusion: IMRT significantly better than conventional RT for salivary function and QoL

Breast

• Canada (2003-2005) -- 2D vs. IMRT
  • Randomized. 331 patients, early-stage BCA (no >=4 LN+) treated with breast-only RT. Arm 1) 2D tangent + wedge vs. Arm 2) IMRT. RT dose 50/25 + optional 16 Gy electron boost.
  • 2008 PMID 18285602 -- "A Multicenter Randomized Trial of Breast Intensity-Modulated Radiation Therapy to Reduce Acute Radiation Dermatitis." (Pignol JP, J Clin Oncol. 2008 Feb 19 [Epub ahead of print])
    • IMRT associated with decreased moist desquamation ), in inframammary fold (26% vs 43%). The breast volume (V95) is associated with acute skin toxicity.
    • Outcome: Dose distribution: IMRT better. Moist desquamation anywhere in breast: IMRT 31% vs 2D 48% (SS), 26% vs. 43% (SS), no difference in pain 23% vs. 25% (NS) or QoL
    • Conclusion: Breast IMRT reduced occurrence of moist desquamation

• Royal Marsden -- 2D vs. IMRT
  • Randomized. 240/306 patients. Early stage. Treated with Arm 1) IMRT vs. Arm 2) 2D using standard wedges. Dose 50/25 + boost 11.1/5.
  • 2007 PMID 17224195 -- "Randomised trial of standard 2D radiotherapy (RT) versus intensity modulated radiotherapy (IMRT) in patients prescribed breast radiotherapy." (Donovan E, Radiother Oncol. 2007 Mar;82(3):254-64.) Minimum F/U 5 years
    • Change in breast: IMRT 40% vs. 2D 58% (SS); significantly fewer developed palpable induration. No difference in pain, hardness, or QoL
    • Conclusion: Minimisation of inhomogeneity reduces late adverse effects

Middle ear ventilation tube

• Hong Kong; 2002 PMID 12512893 -- "Randomized evaluation of the audiologic outcome of ventilation tube insertion for middle ear effusion in patients with nasopharyngeal carcinoma." (Ho WK, J Otolaryngol. 2002 Oct;31(5):287-93.)
  • Randomized. ? patients. NPC and middle ear effusion. Arm 1) pre-RT ventilation tube insertion vs. Arm 2) observation. Audiologic assessment throughout. F/U 4 years
  • Outcome: No difference in hearing changes up to 4 years
  • Conclusion: Ventilation tube insertion before RT did not offer hearing benefit