Radiation Oncology/Melanoma/Radiobiology

Radiobiology for Malignant Melanoma

• Majority of retrospective data suggests that large fractional doses result in better outcomes than small fractional doses
• Two randomized trials were performed. Dutch trial compared large fractional doses (9 Gy vs. 5 Gy) and found no difference. RTOG compared large vs smaller fractional doses (8 Gy vs 2.5 Gy) and similarly found no difference
• Best conclusion that can be drawn is that at least 2.5 Gy/fx should be used

Randomized

• RTOG 83-05 (1984-1988) -- RT 32/4 vs. RT 50/20
  • Randomized. Trial stopped prematurely due to no difference between arms. 126 patients, with measurable lesions. Arm 1) RT 32/4 vs. Arm 2) RT 50/20
  • 1991 PMID 1995527 — "Fraction size in external beam radiation therapy in the treatment of melanoma." (Sause WT, Int J Radiat Oncol Biol Phys. 1991 Mar;20(3):429-32.)
    • Outcome: CR hypofractionated 24% vs. standard 23% (NS); PR 35% vs. 34% (NS)
    • Conclusion: No difference between arms

• Denmark -- RT 27/3 vs. RT 40/8
  • 1985 PMID 4044346 -- "A randomized study comparing two high-dose per fraction radiation schedules in recurrent or metastatic malignant melanoma." (Overgaard J, Int J Radiat Oncol Biol Phys. 1985 Oct;11(10):1837-9.)
  • Randomized. 35 tumors, 14 patients, metastatic or recurrent malignant melanoma. Arm 1) RT 27/3 vs Arm 2) RT 40/8
    • Outcome: No difference
    • Toxicity: Comparable and acceptable
    • No difference between 9 Gy/fx and 5 Gy/fx

Retrospective

• University of Florida; 2006 (1980-2004) PMID 16973303 -- "Adjuvant radiotherapy for cutaneous melanoma: comparing hypofractionation to conventional fractionation." (Chang DT, Int J Radiat Oncol Biol Phys. 2006 Nov 15;66(4):1051-5. Epub 2006 Sep 12.)
  • Retrospective. 56 patients (H&N 87%), high risk disease (recurrent 52%, cervical LNs, lymph nodes >3cm, >3 LN+, ECE, gross residual disease, close/positive SM, satellitosis), treated with adjuvant RT. Hypofractionated RT 30/5 (73%) or conventional with median dose 60/30 (27%). Median F/U 4.4 years
  • Outcome: 5-year LRC 87%, CSS 57%, OS 46%. No difference between schedules (p=0.97) for any endpoint
  • Toxicity: late toxicity 4% (1 osteoradionecrosis of external auditory canal, 1 radiation plexopathy), both in hypofractionated regimens
  • Conclusion: Hypofractionation and conventional fractionation equally efficacious. Bias for hypofractionation in absence of contraindications

• Konefal et al, 1987 - PMID 3112864 — "Malignant melanoma: analysis of dose fractionation in radiation therapy." Konefal JB et al. Radiology. 1987 Sep;164(3):607-10.
  • Retrospective. 67 pts with skin lesions or nodal mets. Various dose schedules.
  • For fraction size > 5 Gy, 50% CR, vs 9% for < 5 Gy/fx. Local control @ 1 yr 25% vs 7%.

• 1986: Overgaard - PMID 2424880 — "The role of radiotherapy in recurrent and metastatic malignant melanoma: a clinical radiobiological study." Overgaard J et al. Int J Radiat Oncol Biol Phys. 1986 Jun;12(6):867-72.
  • Analysis of total dose, dose per fraction, treatment time. 618 lesions.
  • CR in 48% (sustained in 87% at 5 yrs). Correlation with high dose per fraction with response (59% CR for >4 Gy vs. 33% <= 4 Gy). Total dose, treatment time, and NSD did not correlate with response.
  • Calculated isoeffect formula for dose and volume. Use of hyperthemia: thermal enhancement ratio (TER) of 2.0.

• UK; 1978 PMID 709039 -- "The relationship between total dose, number of fractions and fractions size in the response of malignant melanoma in patients." (Hornsey S, Br J Radiol. 1978 Nov;51(611):905-9.)
  • Retrospective. 52 patients. Isoeffect curve generated
  • Conclusion: Response to 4-8 Gy/fx better than 2-3 Gy/fx

MD Anderson Regimen

• Post-op RT 30/5 (6 Gy x 5 fractions)
• Normal tissue tolerance: spinal cord < 24 Gy, small bowel < 24 Gy