Proton radiation therapy of ocular melanoma at PSI - long-term clinical exam

Reviewer: Geoffrey Geiger MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 14, 2009

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Presenter: G. Goitein, A. Schalenbourg, J. Verwey, A. Bolsi, C. Ares, L. Chamot, E. Hug, L. Zografos
Presenter's Affiliation: Paul Scherrer Institute (PSI) Villigen, Switzerland
Type of Session: Scientific

Background

  • There are approximately 2200 cases of eye/orbit malignancies per year.
  • The most common primary intraocular malignancy in adults is choroidal metastases, but the most common primary eye malignancy is uveal melanoma.
  • Risk factors include: sun exposure, sunburn, and melanocytosis of the affected eye.
  • Many patients develop metastatic disease, which typically involves the liver and is spread hematogenously.
    • Disseminated disease rarely responds to even systemic therapy for a meaningful duration, and is typically fatal within one year from the onset of symptoms.
  • Treatment of ocular melanomas has been recently evolving: enucleation, previously the standard of care, has been increasingly superseded by brachytherapy, stereotactic radiation, trans-scleral radiation, proton beam radiation and surgical techniques such as transretinal resection and diode laser phototherapy.
    • Protons interact more densely with tissue, result in a greater degree of ionization per unit volume, and have a higher radiobiological effect (RBE) than photons.
    • Charged particle beam therapy with protons allows the delivery of higher doses of conformal radiation due to the dose characteristics of proton beam radiotherapy, including finite range and steep dose fall off beyond the Bragg peak.
    • Because of the superior conformality and higher radiobiological effectiveness, charged-particle radiation therapy is expected to deliver biologically equivalent doses with superior precision and with less radiation-induced morbidity than conventional photon radiation therapy.
  • The aim of this presentation was to examine the experience at the Paul Scherrer Institute (PSI) Villigen, Switzerland and the Hôpital Ophtalmique in Lausanne, France in treating patients with ocular melanoma over a nearly 25 year period.

Materials and Methods

  • Data are presented from the Paul Scherrer Institute in Villigen, Switzerland in dedicated collaboration with the Hôpital Ophtalmique in Lausanne, from patients treated between March of 1984 and December of 2008.
  • A total of greater than 5076 patients were treated with ocular lesions using a hypofractionated proton regimen of 4 x 15 centi Gray equivalents (CGE).
  • Regular clinical follow-up was performed and results analyzed for local control, survival, functional outcome and eye preservation rates after 5–15 years.
  • 2,993 patients with unilateral melanoma, negative familial history, visible fundus and no adjuvant chemotherapy were treated between March 1984 and August 2005 without a reduced safety margin and are the subject of this presentation.
    • Of these patients, the median age was 55-56 years of age and 1,433 were female.
    • 89.6% of patients had symptoms at presentation and a total of 87.2% of patients were diagnosed symptomatically.

Results

  • When examining factors influencing survival and local control:
    • With respect to overall survival (Cox regression analysis), only age <55 and large tumor diameter were statistically significant.
    • On Cox regression analysis of factors affecting local control, only location within the ciliary body was statistically associated with local control.
  • Overall local tumor control: 97% at 5 yrs and 94% at 15 yrs.
    • Tumors < 10 mm: 98/96/96% OS at 5/10/15 years, respectively.
    • Tumors 10.1-15 mm: 96/93/89% OS at 5/10/15 years, respectively.
    • Tumors 15.1-20 mm: 90/81/77% OS at 5/10/15 years, respectively.
    • Tumors > 20 mm: 77/59/46% OS at 5/10/15 years, respectively.
  • Tumor specific survival rates are: 91% at 5 yrs and 79% at 15 yrs.
  • Rates of enucleation with respect to tumor size, diameter and distance of posterior margin to optic disc:

    Tumor Thickness (mm)

    Time (yr)

    Enucleation Rate

    < 3mm

    5/10/15 yrs

    2/4/4 %

    3.1-5mm

    5/10/15 yrs

    3/5/ 5%

    5.1-10mm

    5/10/15 yrs

    10/14/19 %

    >10mm

    5/10/15 yrs

    23/26/29 %

     

    Tumor Diameter (mm)

    Time (yr)

    Enucleation Rate

    < 3mm

    5/10/15 yrs

    3/4/4 %

    3.1-5mm

    5/10/15 yrs

    6/7/7 %

    5.1-10mm

    5/10/15 yrs

    6/7/11 %

    >10mm

    5/10/15 yrs

    15/18/18 %

     

    Post. Margin to Optic Disc

    Time (yr)

    Enucleation Rate

    Invasion

    5/10/15 yrs

    11/14/27 %

    Contact

    5/10/15 yrs

    14/19/19 %

    > 0-2 mm

    5/10/15 yrs

    7/9/13 %

    > 2 mm

    5/10/15 yrs

    7/9/13 %

  • Visual acuity following proton therapy depends on tumor localization and height, retinal detachment, and age.
  • Clinical causes for enucleation included: glaucoma, loss of function, confirmed or suspicious local relapse, severe inflammation, painful eye or phtisis bulbi.
  • Factors affecting visual acuity following radiation therapy included: reduced visual acuity prior to RT, tumor thickness, small distance between optic disc and macula, degree of retina detachment and advanced age
  • Early (<2 yr) local recurrence after irradiation was independently associated with a significantly decreased likelihood of survival.

Author's Conclusions

  • Ocular melanoma patients represent the greatest number of patients treated with proton radiotherapy worldwide.
  • The data from this study demonstrate the benefit of high dose, high precision proton radiotherapy.
  • A hypofractionated regimen with high doses in several fractions is clinically appropriate and technically feasible in the case of ocular melanoma, without causing unacceptable toxicity.
  • Proton radiotherapy for ocular melanoma demonstrates excellent local control (97/96/94% at 5/10/15 years) and tumor-specific survival rates (91/83/79% at 5/10/15 years).

Clinical/Scientific Implications

  • Charged particle radiotherapy with protons (or alternatively, carbon or helium ions) affords the ability to treat tumors with minimal collateral damage due to the physical properties of charged particles (such as increased dose at the end of the beam range,called the Bragg peak, and a sharp decrease in dose of the radiation beam beyond the target volume.
  • These properties permit highly localized and homogeneous dose distributions and sparing of normal ocular structures.
  • Overall, differentiated outcome analysis shows that age, tumor size, thickness of tumor and localization within the eye have the strongest impact on local failure, enucleation rate and survival.
  • Additionally, these data demonstrate the safety and efficacy of high dose proton radiotherapy to treat ocular melanomas, including large tumors. High rates of local control (overall: 94% at 15 years of follow-up) are seen with a hypofractionated proton regimen of 4 x 15 CGE in the combined institution data from the Paul Scherrer Institute in Villigen, Switzerland in collaboration with the Hôpital Ophtalmique, Lausanne, France.


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