Download Chemosurgery for Retinoblastoma. What we know after 5 Years.

EDITORIAL
Chemosurgery for Retinoblastoma
What We Know After 5 Years
S
UPERSELECTIVE OPHTHALMIC ARTERY DELIV-
ery of chemotherapy for retinoblastoma
(“chemosurgery”) was initially performed
just 5 years ago in an institutional review
board–approved experimental protocol (for
advanced eyes scheduled for enucleation) and was first
reported in 2008.1 It has now been performed in 26 countries worldwide (Argentina, Australia, Brazil, Canada,
China, Colombia, the Czech Republic, Egypt, France, Germany, Great Britain, Holland, India, Iran, Israel, Italy, Jordan, Korea, Pakistan, Russia, Slovakia, Spain, Switzerland, Thailand, Turkey, and the United States) and has
subsequently been featured in a number of articles in the
non–peer-reviewed literature, including stories in JAMA2
and the New York Times.3 Although some centers have
almost completely abandoned primary radiation and/or
systemic chemotherapy as a result of their experience with
chemosurgery and claim a dramatic reduction in the need
for enucleation,4 other centers have declined to perform
the procedure.5 Concern has been raised about the absence of long-term data, about full knowledge of toxicity, and about other adverse issues.6-8 What do we really
know about this approach?
See also pages 1399, 1407,
1458, 1487, and 1490
As of June 22, 2011, there have been 20 publications
on chemosurgery in peer-reviewed journals. At least 10
additional papers are in press or are under review. What
do the published papers say?
ABILITY TO DO THE TECHNIQUE
All centers are using the same protocol that we introduced for treatment.1 In our first report,1 cannulation was
successful in 9 of the 10 children. Recently, we reported
that, in nearly 300 attempts, catheterization succeeded
in 98.5% of cases.9 In Miami, successful cannulation was
achieved in 100% of cases (26 procedures),10 and in Philadelphia, catheterization was successful in 37 of 38 cases.11
Thirteen successful catheterizations were reported from
Switzerland.12
DRUGS AND DOSES USED
In New York, we have reported on the use of melphalan
(3-7.5 mg [first suggested by the Japanese]),13-16 topotecan hydrochloride (0.3-0.4 mg), carboplatin (15-30 mg),
methotrexate sodium,17 and digoxin.18 In Miami, all patients received melphalan.12,17 Eyes were initially treated
with 3 or 5 mg of the drug used, but because of inadequate responses, all children now receive 7.5 mg.
In Philadelphia, all patients received 3 mg of melphalan, and 6 of 17 patients also received concurrent carboplatin (30 mg). In Switzerland, melphalan alone was
used.
There may never be a “standard” dose for treatment.
Eye size, vascular anatomy (large vessels to the lacrimal
artery, supratrochlear artery, and middle meningeal artery), wedge flow, clinical response and prior exposure
to chemotherapy (depleting marrow reserves), carboplatin allergy, untoward reaction to previous therapy, and,
of course, clinical response will dictate the doses chosen, and clinicians must recognize that, like surgery, this
is a dynamic decision that often needs to be made in real
time. However, the importance of these dose adjustments in reducing toxicity while optimizing efficacy remains to be sorted out.
CLINICAL RESPONSE
The recent report9 of our 4-year experience emphasized
that there was a statistically different success rate between eyes that were treated de novo (“naive”) and eyes
that underwent prior, conventional therapy that failed.
Overall, 70% of eyes were salvaged at 2 years, 81.7% of
eyes initially treated with chemosurgery at 2 years were
salvaged, and 58.4% of eyes that underwent prior conventional management that failed were salvaged at 2 years.
These were mostly very advanced eyes that would have
been enucleated, and 83 of the 95 eyes were ReeseEllsworth group V eyes (73 group Vb eyes and 10 group
Va eyes). Both eyes could be treated in the same session
(“tandem therapy”).19
Eyes from Miami also had advanced intraocular disease. All tumors treated were Reese-Ellsworth group Vb
eyes (and International Classification D). When 3 or 5
mg of melphalan was used on these eyes, 36% of them
were enucleated, but when 7.5 mg was used, no eye came
to enucleation.20 Overall 76% of eyes were spared enucleation. In Switzerland, all 13 patients were felt to be “candidates for enucleation,” and all but 1 of the tumors were
classified as “D.” Enucleation and external beam irradiation were avoided in all cases.
Of 12 eyes managed with primary chemosurgery in
Philadelphia, 8 (67%) were salvaged. Eyes classified as
“C” or “D” had 100% globe salvage. Of 4 eyes treated after conventional treatments failed, 2 (50%) were saved.
To salvage 81% to 100% of eyes (most candidates for
enucleation) is unprecedented. To salvage 50% to 58%
of eyes after conventional treatment failed (where the only
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alternative was enucleation) represents a major advance
for the field.
SYSTEMIC COMPLICATIONS
All centers have reported on their systemic complications. To date, no deaths or strokes have been reported.
To our knowledge, no patient has (yet) been reported to
have a second cancer, but it is well known that patients
with germinal retinoblastoma are at significant risk for
the development of a second cancer, even if no external
beam radiation or chemotherapy is given. Because almost all of the eyes that have been treated with chemosurgery are very advanced and because it is the very advanced eyes that are predisposed to metastasis, it is
expected that some patients with retinoblastoma treated
with chemosurgery will die. We have reported 2 cases
of metastasis. Both patients are presently in remission.
Bronchospasm and decreased tidal volume during the
procedure have been noted and reported by most groups;
the frequency of these events seems to be related to the
depth of anesthesia during the procedure. We reported
iodine dye allergies and 1 transient occlusion of the superficial femoral artery. Hyperemia in the distribution of
the large supratrochlear artery has been noted in 15% of
cases.21 Neutropenia is often noted but is usually minimal and reached grade 3 or 4 in only 11.4% of our cases
(mostly when the total dose of melphalan exceeds 0.4
mg/kg). No patient in any series has required a port. To
our knowledge, there has been only 1 case in which there
was transfusion of any blood product, and there has been
only 1 patient in the literature who developed fever/
neutropenia (and that child previously had 6 months of
triple-agent systemic chemotherapy).
VISUAL FUNCTION
We have reported on visual function before and after treatment by measuring visual acuity, pupillary responses, and
electroretinographic responses to photopic and scotopic testing.1,4,17,19,22 Overall, 70% of eyes have shown the
same electroretinographic responses before and after treatment, 20% have shown a more than 25-µV improvement in 30-Hz flicker responses, and 10% have shown
worsening responses. Of the eyes with retinal detachment at the time of treatment, 30% have shown an improvement in electroretinographic function of more than
25 µV. We (and others) now have a few children who
are older and have Snellen fractions of 20/20 after treatment. However, the majority of our children are very
young, and so precise visual acuity measurements are challenging.
Only one other center (in Switzerland) has reported
on visual results. Of 13 eyes treated in this center, half
of the evaluable eyes had visual acuity of better than 20/
100, and 2 had visual acuity of 20/32. This center felt that
the treatment had no adverse effect on vision in any child.
OCULAR ADVERSE EFFECTS
15% of cases, epiphora, and temporary ciliary loss; this
was confirmed in the Philadelphia report6 that also noted
orbital congestion limiting ocular motility. All of these
cases appeared to be transient.
Recently, intraocular adverse effects have also been reported. Only one of these reports is associated with visual acuity or electroretinographic testing to know the
visual impact of the reported findings. In some cases, the
eyes had previously had extensive treatment (including
systemic chemotherapy, laser therapy, and cryotherapy), rhegmatogenous and nonrhegmatogenous retinal detachments, and surgery for retinal detachment, so
it is difficult to know whether the adverse effects are due
to tumor effects, retinal detachment, prior treatment (including retinal detachment surgery), drug effects, or wedge
flow (which causes rapid alterations in the pressure and
flow within the perfused vessel, resulting in hemorrhages) or to combinations of these many features.
We first reported on vascular occlusion in 1 eye. From
Miami, 1 eye was reported to have transient scattered intraretinal hemorrhages and peripapillary cotton wool
spots, and in 4 cases (15% of total treatments), delayed
vitreous hemorrhage led to enucleation. From Switzerland, 2 of 13 eyes (15%) had “sectoral choroidal atrophy,” and 1 of these 2 eyes also had retinal emboli. Vision was not affected, and the hemorrhages resolved. From
Philadelphia, 3 cases of “ophthalmic artery stenosis,” 2
cases of central or partial vein occlusion, and 9 cases of
“subtle retinal pigment epithelial mottling . . . that slowly
evolve to later-onset underlying choroidal atrophy” were
reported.
One report8 has raised the question of whether the radiation exposure during the procedures will possibly cause
second cancers or cataracts. A recent report23 on the longterm follow-up of the Japanese cohort (using selective
[not superselective] infusion), however, revealed no increase in either.
Within 5 years of performing the first procedure, chemosurgery has been successfully performed in 26 countries worldwide and reported in 20 peer-reviewed articles. No cases of stroke, death, a need for a port, or
significant systemic adverse effects have yet developed.
Most children required 3 outpatient treatments (range,
1-8 treatments). There has been no need for transfusion
of any blood product, and both naive eyes and advanced
eyes scheduled for enucleation have been salvaged in 81%
to 100% of cases worldwide. Fifty percent of eyes that
underwent conventional retinoblastoma treatment that
failed (and in which the only alternative was enucleation) have been salvaged. Vision has been retained or
improved in 90% of cases, but the eyes were often limited by a preexisting macula tumor and a prior extensive retinal detachment.
Despite the fact that systemic chemotherapy alone rarely
(if ever) cures solid tumors in children and despite the fact
that systemic chemotherapy alone rarely cures intraocular retinoblastoma, one-third of the eyes treated with chemosurgery are cured with chemotherapy alone. It represents one of the very few cancers that can be controlled
with single-agent chemotherapy alone.
We initially reported periocular edema, transient hyperemia in the distribution of the supratrochlear artery in
ARCH OPHTHALMOL / VOL 129 (NO. 11), NOV 2011
1493
David H. Abramson, MD
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©2011 American Medical Association. All rights reserved.
Author Affiliation: Ophthalmic Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, New
York.
Correspondence: Dr Abramson, Ophthalmic Oncology
Service, Memorial Sloan-Kettering Cancer Center, 70 E
66th St, New York, NY 1002S1 ([email protected]).
Financial Disclosure: None reported.
REFERENCES
1. Abramson DH, Dunkel IJ, Brodie SE, Kim JW, Gobin YP. A phase I/II study of
direct intraarterial (ophthalmic artery) chemotherapy with melphalan for intraocular retinoblastoma initial results. Ophthalmology. 2008;115(8):1398-1404.
2. Friedrich MJ. Retinoblastoma therapy delivers power of chemotherapy with surgical precision. JAMA. 2011;305(22):2276-2278.
3. Beck H. Lakers’ Fisher makes his plea for all to see. New York Times. June 15,
2008. http://www.nytimes.com/2008/06/15/sports/basketball/15fisher.html. Accessed June 15, 2008.
4. Abramson DH. Super selective ophthalmic artery delivery of chemotherapy for
intraocular retinoblastoma: ‘chemosurgery’ the first Stallard lecture. Br J
Ophthalmol. 2010;94(4):396-399.
5. Wilson MW, Haik BG, Dyer MA. Superselective intraophthalmic artery chemotherapy: what we do not know. Arch Ophthalmol. 2011;129(11):1490-1491.
6. Shields CL, Bianciotto CG, Jabbour P, et al. Intra-arterial chemotherapy for retinoblastoma: report no.2, treatment complications. Arch Ophthalmol. 2011;
129(11):1407-1415.
7. Shields CL, Shields JA. Intra-arterial chemotherapy for retinoblastoma: the beginning of a long journey. Clin Experiment Ophthalmol. 2010;38(6):638-643.
8. Vijayakrishnan R, Shields CL, Ramasubramanian A, Emrich J, Rosenwasser R,
Shields JA. Irradiation toxic effects during intra-arterial chemotherapy for retinoblastoma: should we be concerned? Arch Ophthalmol. 2010;128(11):14271431.
9. Gobin YP, Dunkel IJ, Marr BP, Brodie SE, Abramson DH. Intra-arterial chemotherapy for the management of retinoblastoma: four-year experience. Arch
Ophthalmol. 2011;129(6):732-737.
10. Peterson EC, Elhammady MS, Quintero-Wolfe S, Murray TG, Aziz-Sultan MA.
Selective ophthalmic artery infusion of chemotherapy for advanced intraocular
retinoblastoma: initial experience with 17 tumors. J Neurosurg. 2011;114(6):
1603-1608.
11. Shields CL, Bianciotto CG, Jabbour P, et al. Intra-arterial chemotherapy for retinoblastoma: report no.1, control of retinal tumors, subretinal seeds, and vitreous seeds. Arch Ophthalmol. 2011;129(11):1399-1406.
12. Munier FL, Beck-Popovic M, Balmer A, Gaillard MC, Bovey E, Binaghi S. Occurrence of sectoral choroidal occlusive vasculopathy and retinal arteriolar embolization after superselective ophthalmic artery chemotherapy for advanced intraocular retinoblastoma. Retina. 2011;31(3):566-573.
13. Kiribuchi M. Retrograde infusion of anti-cancer drugs to ophthalmic artery for
intraocular malignant tumors [in Japanese]. Nihon Ganka Gakkai Zasshi. 1966;
70(11):1829-1833.
14. Kaneko A, Suzuki S. Eye-preservation treatment of retinoblastoma with vitreous
seeding. Jpn J Clin Oncol. 2003;33(12):601-607.
15. Yamane T, Kaneko A, Mohri M. The technique of ophthalmic arterial infusion therapy
for patients with intraocular retinoblastoma. Int J Clin Oncol. 2004;9(2):6973.
16. Inomata M, Kaneko A. Chemosensitivity profiles of primary and cultured human
retinoblastoma cells in a human tumor clonogenic assay. Jpn J Cancer Res. 1987;
78(8):858-868.
17. Abramson DH, Dunkel IJ, Brodie SE, Marr BP, Gobin YP. Superselective ophthalmic artery chemotherapy as primary treatment for retinoblastoma
(chemosurgery). Ophthalmology. 2010;117(8):1623-1629.
18. Patel M, Paulus YM, Gobin YP, et al. Intra-arterial and oral digoxin therapy for
retinoblastoma. Ophthalmic Genet. 2011;32(3):147-150.
19. Abramson DH, Dunkel IJ, Brodie SE, Marr B, Gobin YP. Bilateral superselective
ophthalmic artery chemotherapy for bilateral retinoblastoma: tandem therapy.
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20. Vajzovic LM, Murray TG, Aziz-Sultan MA, et al. Supraselective intra-arterial chemotherapy: evaluation of treatment-related complications in advanced
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21. Marr B, Gobin PY, Dunkel IJ, Brodie SE, Abramson DH. Spontaneously resolving periocular erythema and ciliary madarosis following intra-arterial chemotherapy for retinoblastoma. Middle East Afr J Ophthalmol. 2010;17(3):207209.
22. Brodie SE, Pierre Gobin Y, Dunkel IJ, Kim JW, Abramson DH. Persistence of retinal function after selective ophthalmic artery chemotherapy infusion for
retinoblastoma. Doc Ophthalmol. 2009;119(1):13-22.
23. Suzuki S, Yamane T, Mohri M, Kaneko A. Selective ophthalmic artery injection
therapy for intraocular retinoblastoma: the long-term prognosis [published online ahead of print June 28, 2011]. Ophthalmology. doi:10.1016/j.ophtha.2011
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Correction
Error in Text. In the Clinical Sciences article titled “Outcome of Toric Intraocular Lens Implantation After Adjusting for Anterior Chamber Depth and Intraocular Lens
Sphere Equivalent Power Effects” published in the August issue of the Archives (2011;129[8]:998-1003), the
standard empirical thick lens “vertex power” formula in
the right column of page 999 should have appeared as
follows: “E = F/[1 ⫹ (d/1.336)F].” All calculations discussed in the article were performed using the correct
formula, so the published data are correct. Only the formula, as it appears in the article, is incorrect.
ARCH OPHTHALMOL / VOL 129 (NO. 11), NOV 2011
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©2011 American Medical Association. All rights reserved.