- Email: [email protected]
Efficacy and Toxicity of Second-Course Ophthalmic Artery Chemosurgery for Retinoblastoma
Efficacy and Toxicity of Second-Course Ophthalmic Artery Chemosurgery for Retinoblastoma Jasmine H. Francis, MD,1,2 David H. Abramson, MD,1,2 Y. Pierre Gobin, MD,1,3 Brian P. Marr, MD,1,2 Irwin Tendler, BS,4 Scott E. Brodie, MD, PhD,5 Ira J. Dunkel, MD4 Objective: Assess the usefulness of second-course ophthalmic artery chemosurgery (OAC) for patients with intraocular retinoblastoma that recurred after prior OAC. This study evaluated the efficacy and toxicity of secondcourse OAC. Design: Single-arm retrospective study of 29 eyes of 30 patients treated with second-course OAC at Memorial Sloan Kettering Cancer Center between May 2006 and July 2013, with a median follow-up of 25.9 months. Participants: Retinoblastoma patients who underwent a course of OAC, with a minimum of 2 months of progression-free follow-up at monthly examinations, but who subsequently received additional OAC for recurrent tumor. Methods: To determine efficacy, Kaplan-Meier survival estimates were generated and the Mantel-Cox test was used to compare curves. To determine toxicity, electroretinography (ERG) amplitudes were measured in response to 30-Hz photopic flicker stimulation before and after OAC treatment; systemic adverse events were graded according to the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE 4.0). Main Outcome Measures: For efficacy, ocular progression-free survival, ocular event-free survival (e.g., enucleation, external-beam radiation, or intravitreal melphalan), and ocular survival. For toxicity, peak-to-peak comparisons between ERG studies before and after OAC treatment and CTCAE 4.0-graded systemic adverse events. Results: Fifty percent of all recurrences were within 4.4 months and 90% were within 16 months of completion of the first course of OAC. The 2-year Kaplan-Meier ocular survival, event-free survival, and progression-free survival estimates after second-course OAC were 82.8% (95% confidence interval [CI], 60.1%e93.2%), 57.3% (95% CI, 36.1%e73.7%), and 26.5% (95% CI, 11.0%e45.0%), respectively. All eyes without vitreous seeding were progression free, whereas eyes with vitreous seeding were associated significantly with worse ocular survival after second-course OAC (P ¼ 0.03). After second-course OAC, 90% of eyes had stable or improved ERG responses. Of all evaluable cases, there was no increased risk of systemic toxicity during the second course compared with the initial course of OAC. Conclusions: Retinoblastoma eyes requiring second-course OAC after initial OAC treatment have good salvage rates, and the treatment has an acceptable ocular and systemic toxicity profile. However, these eyes often require additional (third- or fourth-course) OAC or other treatment methods because of progression of disease after second-line OAC, particularly if vitreous seeds are present at the time of initial OAC failure. Ophthalmology 2015;-:1e7 ª 2015 by the American Academy of Ophthalmology.
There is limited information regarding outcomes after retreatment of recurrent retinoblastoma using the same method that was successful initially. One study cites a salvage rate of 2.2% of eyes with second-course externalbeam radiation (EBR)1; however, there is a dearth of published material on second-course systemic chemotherapy. Likewise for chemotherapy delivered via the ophthalmic artery, our knowledge extends only to secondary ophthalmic artery chemosurgery (OAC) given after failure of the initial non-OAC therapy (typically systemic chemotherapy or radiation).2e4 In this study, we considered a critical question that has yet to be addressed: Is OAC an option for eyes with 2015 by the American Academy of Ophthalmology Published by Elsevier Inc.
recurrent disease after initially successful OAC treatment? The efficacy of second-line chemotherapy is an important question for both patients and their physicians. What are the benefits and drawbacks of subjecting a patient to the time, resources, and effort of additional chemotherapy? The answer is different depending on the tumor type and the regimen used. Some tumors such as gastric cancer and other solid tumors have responded unsatisfactorily to second-line treatment,5 whereas other tumors (or the same tumors subjected to different regimens) have shown promise.6,7 This study reviewed cases that required second-course OAC and determined the response and associated burden of ocular and systemic toxicity. http://dx.doi.org/10.1016/j.ophtha.2014.11.029 ISSN 0161-6420/15
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Methods This retrospective, single-institution, institutional review boardeapproved study included all eyes of retinoblastoma patients meeting the inclusion criteria treated at Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College from May 30, 2006, through July 31, 2013. Informed consent was obtained for each patient. This study complied with the Health Insurance Portability and Accountability Act and adhered to tenets of the Declaration of Helsinki. The study included patients who underwent a course of OAC that was discontinued because of the clinical impression of disease control, with a minimum of 2 months of progression-free follow-up at monthly examinations, but who subsequently demonstrated recurrent tumor and were treated with a second course of OAC. Patient data included age, gender, laterality, weight at start of initial course of OAC and second course of OAC, prior treatment status (naïve vs. prior treatment involving systemic chemotherapy or radiation therapy), age at initial OAC, and follow-up time from beginning of second course of OAC. Treatment data included time from initial OAC completion to recurrence, number of infusions, and drug types and doses during initial- and second-course OAC. Tumor data included ReeseEllsworth classification, International Classification, absence or presence of vitreous seeds, and response to treatment. A complete blood count was requested (or perhaps ordered, because they were not always truly obtained) after each infusion of OAC and considered evaluable if performed within 7 to 14 days after the previous OAC or if grade 3 or 4 toxicity was noted at any time point. The standard Common Terminology Criteria for Adverse Events version 4.0 (CTCAE 4.0) was used to grade hematologic toxicity. Eyes were examined initially under anesthesia at 3- to 4-week intervals. Evaluation consisted of visual assessment, motility and pupillary responses, indirect ophthalmoscopy, fundus photography with RetCam (Massie Industries, Dublin, CA), ophthalmic ultrasonography (OTI Ophthalmic Technologies, Inc, Toronto, Canada), and electroretinography (ERG; Espion ColorBurst, Diagnosys LLC, Lowell, MA). Ophthalmic artery chemosurgery was performed every 3 or 4 weeks in a manner that was described in detail previously.8,9 Focal treatment (transpupillary thermotherapy or cryotherapy) was performed if indicated. Reported here are the response amplitudes to 30-Hz photopic flicker stimulation, which are representative of the full ERG protocol. As previously described,10 ERG amplitudes were classified according to the following scale: less than 0.1 mV, undetectable; 0.1 to 25 mV, poor; 25.1 to 50 mV, fair; 50.1 to 75 mV, good; 75.1 to 100 mV, very good; and more than 100 mV, excellent. A change in 30-Hz response amplitude of 25 mV was considered clinically meaningful, based on statistical analysis of ERG amplitudes during examination under anesthesia of normal eyes (unpublished data, December 2014, ARVO abstract). In the absence of scotopic data, photopic responses to single International Society for Clinical Electrophysiology of Vision standard light-adapted 3.0 flashes also were analyzed. Electroretinography responses were analyzed in 2 groups: measurements before and 1 month after completion of (1) the initial course of OAC and (2) the second course of OAC. Twenty-five eyes had evaluable ERG amplitudes for the initial course of OAC and 29 eyes had evaluable ERG amplitudes for the second course of OAC. Inevaluable ERG amplitudes were the result of having no baseline measurements because of the absence of an electrophysiologist. Outcome measurements included ocular progression-free survival, ocular event-free survival, and ocular survival. Progression of disease was defined as instances of recurrent disease that required additional OAC, EBR, plaque brachytherapy, intravitreal
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melphalan, or enucleation. For event-free survival, an event was defined as enucleation, EBR, or treatment by injection of intravitreal melphalan, but excluded further courses of OAC. This analysis was intended to isolate the potential of salvage OAC from the potentially confounding effect of intravitreal chemotherapy. Statistical analysis was performed using Prism (GraphPad Software, Inc, La Jolla, CA). Kaplan-Meier survival data with the log-rank test were used to evaluate ocular and progression-free survival, and the Mantel-Cox test was used to compare curves. Survival estimates were compared for data that evaluated disease, treatment, and drug-dose features. Disease features included vitreous seed status (the presence or absence of vitreous seeds at the time of initial OAC failure) and latency of relapse (less than, more than, or equal to the median interval of 4.4 months).
Results Patient and Eye Characteristics Twenty-nine eyes of 28 patients fulfilled the inclusion criteria and were included in this study, with a median follow-up of 25.9 months (range, 1e66 months) from the beginning of the second course of OAC. Table 1 summarizes patient, eye, treatment, and outcome characteristics, including details of third-, fourth-, or fifth-line therapy. Eyes received a median of 3.0 infusions (range, 1e6) during the initial OAC course and a median of 2 infusions (range, 1e4) during the second course. Progression of disease and necessity for second-course OAC developed at a median of 4.4 months (range, 2.8e42.5 months) after completion of the initial OAC. Ninety percent of eyes (n ¼ 26 of 29) developed progression of disease and necessity for second-course OAC within 16 months of the initial OAC.
Treatment Treatment features are shown in Table 2. Fifty-five percent of eyes (n ¼ 16 of 29) had no increase in maximum melphalan dose per kilogram and 62% of eyes (n ¼ 18 of 29) had no increase in the maximum dose per kilogram of any drug during the second course compared with the initial course of OAC. Furthermore, 6 eyes had no increase in the maximum drug dose per kilogram of any drug, nor addition of a new drug during the second course compared with the initial course of OAC.
Ocular Survival, Event-Free Survival, and Progression-Free Survival As shown in Figure 1, the 2-year Kaplan-Meier ocular survival, event-free survival, and progression-free survival estimates after the second course of OAC were 82.8% (95% confidence interval [CI], 60.1%e93.2%), 57.3% (95% CI, 36.1%e73.7%), and 26.5% (95% CI, 11.0%e45.0%), respectively. Vitreous seeds were present in 17 (58%) eyes requiring a second course of OAC and were associated significantly with worse ocular survival and event-free survival after the second course of OAC (P ¼ 0.03 and P ¼ 0.03, respectively), but not with progression of disease. KaplanMeier ocular survival estimates at 2 years after the second course of OAC were 100% for eyes without vitreous seeds and 73.9% (95% CI, 44.2%e89.4%) for eyes with vitreous seeds (Fig 1). Kaplan-Meier event-free survival estimates at 2 years after the second course of OAC were 76.2% (95% CI, 33.2%e93.5%) for eyes without vitreous seeds and 47.1% (95% CI, 23.0%e68.0%) for eyes with vitreous seeds (Fig 1). During the second course of OAC, eyes without vitreous seeding received a mean of 1.5 OAC infusions, whereas eyes with vitreous seeding received a mean of
Table 1. Characteristics of Patients, Eyes, and Treatment
Patient No.
Eye Right Right Left Right Left
6 7
11.0 6.3 197.9 3.1 14.0
Cumulative Drug Dose (mg) for Initial Ophthalmic Artery Chemosurgery*
Latency (mos)
VA VB VB IIIA VB
D D E B D
Yes No Yes No Yes
3 4 3 1 3
M5.5, T0.9, C25 M11 M21, T1.2, C120 M2 M8, T0.3
7.0 10.2 15.2 20.0 7.0
3 1 2 3 2
M8, C60, T0.8 M4,T0.3 M8, T0.5, C110 M12, T.9 M11, T.9, C70
Right 24.9 Left 32.5
M M
U B
VB VB
D D
No Yes
3 3
M15 M12, T0.9
4.3 13.3
3 1
C95 M6, T0.4, C30
8 9
Right 24.5 Left 14.0
M M
B B
IVA VB
B D
Yes Yes
1 1
M4 M3
4.9 14.7
2 4
M9, T0.4 M25, T1.6
10 11 12 13
Right Right Right Left
F M M M
B U U B
VB VA IVA VB
D D C E
Yes No Yes No
3 3 3 6
M9.5 M10, T1 M8, T2, C40 M37.5, T2.5, C250
3.3 3.0 3.7 14.5
1 1 2 1
C30 M4 M10, T3, C100 M7.5, T0.5, C50
14 15 16
Left 6.9 Right 7.9 Right 7.2
M M F
B B B
IIA IB VB
B B D
Yes Yes Yes
3 1 3
M8 M2.5 M7.5, T.3
38.7 3.1 13.5
1 1 1
M7.5, T.5 M3, T.2 M4, T.5
17 18 19
Right 25.3 Right 8.9 Right 4.4
M F F
B B B
VB VA VA
D D E
Yes No Yes
5 3 3
M29, T1.3 M4, T.5, C80 M6, T.9, C30
4.6 3.5 2.8
1 2 1
T.4, C40 M9, T2, C110 M3, T.3, C30
20
Left
15.7
M
U
VB
D
No
4
M16, T1.3, C30
2.8
2
M10, T1.5, C80
21 22
33.3 10.6 6.7 63.5
M F
23
Right Right Left Right
F
U B B U
VB IB VB VB
D B D D
No No No No
3 1 2 5
M15, T.4 M3, T.3 T.8, C60 M28, T1.8, C30
3.7 4.2 3.0 7.5
3 1 1 2
M15, T1.2 M3, T.3 T.3, C30 M15, T2.5, C30
24
Right 8.6
M
B
VB
D
No
6
M21, T1.6, C30
3.0
2
M9, T.7, C55
25
Right 53.0
F
B
IIA
D
Yes
3
M15, T.8, C60
4.4
1
M6, T.5, C50
26 27 28
Left Left Left
M M F
U B U
VB VB VB
D D D
No Yes No
3 4 4
C150 M13 M19, T4
3.5 8.4 42.5
2 2 3
M8, T4 M8, T.3 M18, T.5, C100
15.6 5.2 9.9 28.6
10.0 96.6 57.3
3
B ¼ bilateral; EBR ¼ external-beam radiation; F ¼ female; M ¼ male; OAC ¼ ophthalmic artery chemosurgery; U ¼ unilateral. *M ¼ melphalan, T ¼ topotecan, and C ¼ carboplatin and number refers to dose of drug in milligrams.
EBR Enucleation None OAC OAC, enucleation Enucleation Intravitreal melphalan, enucleation OAC OAC, enucleation OAC None None Plaque brachytherapy, intravitreal melphalan OAC None OAC, intravitreal melphalan OAC None OAC, intravitreal melphalan OAC, plaque brachytherapy, intravitreal melphalan Enucleation OAC None OAC, plaque brachytherapy Intravitreal melphalan OAC, intravitreal melphalan None Enucleation None
1 1
1 1 1
2 2 1 1 2
2 2
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Efficacy and Toxicity of Second-Course OAC
B U B B B
F F F F F
Third-, Fourth-, and Fifth-Line Treatments
No. of Additional Ophthalmic Artery Chemosurgery Courses
Francis et al
1 2 3 4 5
ReeseEllsworth Age Classification (mos) Gender Laterality at Diagnosis
No. of Initial Ophthalmic International Artery Classification Prior Chemosurgery at Diagnosis Treatment Infusions
Cumulative No. of Second- Drug Dose (mg) Course for SecondOphthalmic Course Artery Ophthalmic Chemosurgery Artery Infusions Chemosurgery*
Ophthalmology Volume -, Number -, Month 2015 Table 2. Factors Related to Efficacy of Second-Course Ophthalmic Artery Chemosurgery P Value Variable Vitreous seeds Prior treatment status Latency of relapse Age at initial OAC (yrs) No. of initial infusions Addition of new drug No. of second infusions Maximum melphalan Maximum melphalan per kilogram Cumulative melphalan Cumulative melphalan per kilogram Increasing maximum melphalan Increasing maximum melphalan per kilogram Increasing maximum topotecan per kilogram Increasing maximum carboplatin per kilogram Increasing maximum dose any drug Increasing maximum dose per kilogram any drug Increasing cumulative melphalan Increasing cumulative melphalan per kilogram Increasing cumulative topotecan per kilogram Increasing cumulative carboplatin per kilogram Increasing cumulative any drug Increasing cumulative dose per kilogram any drug Increasing maximum dose per kilogram any drug/ new drug
Comparison
No.
Progression-Free Survival
Ocular Survival
Presence vs. absence of vitreous seeds Previously treated vs. treatment naïve Interval between initial OAC end & relapse (mos): <4.4 vs. 4.4 <1 or 1 during initial OAC <3 infusions vs. 3 infusions during initial OAC Absence vs. addition of new drug during second course 1 vs >1 infusion during second course Maximum melphalan (mg): <5 vs. during second course Maximum melphalan per kg (mg/kg): <0.4 vs. 0.4 during second course Cumulative melphalan (mg): <8 vs. 8 during second course Cumulative melphalan per kg (mg/kg): <0.6 vs. 0.6 during second course Increasing vs. decreasing maximum melphalan during second course Increasing vs. decreasing maximum melphalan per kg during second course Increasing vs. decreasing maximum topotecan per kg during second course Increasing vs. decreasing maximum carboplatin per kg during second course Increasing vs. decreasing maximum dose any drug during second course Increasing vs. decreasing maximum dose per kg any drug during second course Increasing vs. decreasing cumulative melphalan during second course Increasing vs. decreasing cumulative melphalan per kg during second course Increasing vs. decreasing cumulative topotecan per kg during second course Increasing vs. decreasing cumulative carboplatin per kg during second course Increasing vs. decreasing cumulative dose any drug during second course Increasing vs. decreasing cumulative dose per kg any drug during second course Increasing maximum dose per kg any drug or new drug vs. not during second course
29 29 29
0.35 0.40 0.22
0.03 0.86 0.34
29 29
0.45 0.56
0.15 0.23
29
0.93
0.23
29 29
0.37 0.86
1.00 0.49
29
0.43
0.66
29
0.56
0.21
29
0.83
0.50
28
0.88
0.63
28
0.22
0.13
20
0.04
0.28
12
0.42
1.00
29
0.67
0.75
29
0.07
0.75
29
0.85
0.40
29
0.39
0.83
19
0.09
0.25
12
0.99
1.00
29
0.86
0.45
29
0.14
0.62
29
0.24
0.79
OAC ¼ ophthalmic artery chemosurgery. Boldface values represent P < 0.05.
2 OAC infusions. Eight eyes with vitreous seeds were salvaged, and 5 (63%) of these went on to receive intravitreal melphalan at some point in their treatment course. A total of 7 eyes received intravitreal melphalan during their treatment course. Representative cases of eyes with and without vitreous seeding at the time of recurrence are shown in Figures 2 and 3. The other significant factor included significantly worse (P ¼ 0.04) progression-free survival for eyes that had an increasing maximum topotecan dose per kilogram from the initial to second course of OAC versus those that did not: 1-year estimates of 44.4% (95% CI, 10.3%e74.8%) and 54.5% (95% CI, 22.8%e77.9%), respectively. Ninety-one percent of eyes receiving a higher maximum topotecan dose per kilogram of any drug during the second course of OAC had vitreous seeds, compared with 0% of eyes that did not receive an increased maximum dose per kilogram.
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Other factors shown in Table 2 were not associated significantly with progression-free survival or ocular survival (P>0.05).
Toxicity Electroretinography measurements before and after the second course of OAC were stable in 83%, decreased in 10%, and increased in 7% of eyes. This outcome was similar to ERG measurements before and after the initial course of OAC, which were stable in 68%, increased in 12%, and decreased in 20% of eyes. The mean change in ERG measurement from baseline was 3.5 mV and 4.7 mV after the initial and second course of OAC, respectively. During the initial and second course of OAC, 65.2% (60 of 92) and 70.0% (35 of 50) of complete blood count results were
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Efficacy and Toxicity of Second-Course OAC
Figure 1. Kaplan-Meier survival curves for (A) ocular survival of all eyes, (B) event-free survival of all eyes, (C) progression-free survival of all eyes, (D) ocular survival comparing eyes with and without vitreous seeds, (E) event-free survival comparing eyes with and without vitreous seeds, and (F) progressionfree survival of eyes with and without vitreous seeds. Note that ocular survival is significantly worse for eyes with vitreous seeds at the time of recurrence. KM ¼ Kaplan-Meier.
evaluable, respectively. During the initial and second course of OAC, 25.0% (15 of 60) and 14.2% (5 of 35) of evaluable OAC infusions had grade 3 or 4 hematologic toxic events, respectively. More specifically, during the initial course of OAC, there were 14 events of grade 3 or 4 neutropenia, 2 events of grade 3 anemia, and no events of grade 3 or 4 thrombocytopenia (a case of neutropenia and anemia occurred together in 1 instance). During the second course of OAC, there were 5 events of grade 3 or 4 neutropenia and no events of grade 3 or 4 anemia or thrombocytopenia.
Discussion This study examined the unexplored question of safety and efficacy of second-course OAC in eyes treated previously with an initial course of OAC. We demonstrate 2-year
ocular survival estimates of 82.8% for all eyes, which is notable given that more than half of the eyes received the same or a lower weight-corrected maximum dose of drugs during the second course, and of those eyes, only half were given a new drug during the second course of OAC. Twoyear event-free survival until enucleation, EBR, or intravitreal melphalan was 57% for all eyes and was significantly better for eyes without vitreous seeds compared with those with vitreous disease. This demonstrates that more than half the eyes can be salvaged with multiline OAC in the absence of intravitreal melphalan or EBR. We also showed that ocular and hematologic toxicity was no worse during second-course OAC compared with initial-course OAC, despite the higher drug doses for some eyes. For instance, after second-course OAC, 90% of eyes maintained stable or had improved ERG recordings (compared with 80% after
Figure 2. Fundus photographs from a representative case without vitreous seeds. A, After completion of the first course of ophthalmic artery chemosurgery (OAC), the tumors regressed. However, the peripapillary tumor (B) recurred 7 months later and (C) successfully responded to second-course OAC.
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Figure 3. Fundus photographs from a representative case with vitreous seeds. A, After successful completion of the first course of ophthalmic artery chemosurgery (OAC), the tumor recurred with vitreous disease. Recurrent tumor (B) responded to second-course OAC, but (C) vitreous disease (yellow arrows) worsened and the eye was enucleated.
the initial course of OAC). Moreover, 25% of initial-course OAC infusions were associated with grade 3 or 4 hematologic toxicity, compared with 14% of second-course OAC infusions. It is striking that all eyes without vitreous seeds could be saved. Eyes with vitreous seeding did not do as well and had significantly worse ocular survival. The dismal progressionfree survival (26.5% at 2 years for all eyes) is another notable trend for eyes receiving a second course of OAC, which often require a third and sometimes fourth course of treatment in the form of additional OAC, radiation, or intravitreal melphalan. Most of these eyes were treated in the era before intravitreal melphalan, and with the use of this relatively novel treatment, it is possible that more of the eyes with vitreous seeding could have been saved11e13 (and even spared second-line or multiline OAC). For instance in this study, most (63%) salvaged eyes with vitreous seeding received intravitreal melphalan at some point after the second course of OAC. Another significant factor associated with worse ocular survival was the maximum dose of topotecan per kilogram during the second course compared with the initial course of OAC. More eyes receiving higher weight-corrected maximum topotecan doses had vitreous seeding (91% vs. 0%), and therefore it is likely that the inferior ocular survival estimates may be reflective of eyes with more advanced tumors and vitreous disease status. In other fields of oncology, there are established features that predict the success of second-line chemotherapy. For instance, in neuroblastoma, a shorter latency until recurrence predicts poor response to second-line chemotherapy.6 In our cohort, none of these factors seemed to have had an impact: there was no significant difference between previously treated eyes and treatment-naïve eyes, between children receiving an initial course of OAC at younger than 1 year of age compared with older than 1 year of age, or between eyes with a latency to recurrence less than compared with more than the median of 4.4 months. There is no clear explanation for this. There may be something about retinoblastoma as a disease or the delivery method of OAC that defies the trends of secondline chemotherapy that are put forth by other areas of oncology.
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This study is limited by its retrospective design and the relatively small sample size and should be interpreted with these limitations in mind. Although the median follow-up is 26 months, it is possible that with a longer duration of follow-up, additional recurrences or complications may occur. In conclusion, eyes with recurrent tumor after initially successful OAC can have good salvage rates after a second course of OAC, particularly eyes without vitreous seeding. Second-course OAC offers an acceptable ocular and systemic toxicity profile that is no worse than that of initialcourse OAC, despite higher drug doses for some eyes. However, these eyes often require additional (third- or fourth-course) OAC or other treatment methods (intravitreal melphalan, plaque) because of progression of disease after second-line OAC. Ocular survival is worse if vitreous seeds are present at the time of initial OAC failure. However, the increased use of intravitreal chemotherapy may improve the outlook for these eyes.
References 1. Abramson DH, Ellsworth RM, Rosenblatt M, et al. Retreatment of retinoblastoma with external beam irradiation. Arch Ophthalmol 1982;100:1257–60. 2. Bracco S, Leonini S, De Francesco S, et al. Intra-arterial chemotherapy with melphalan for intraocular retinoblastoma. Br J Ophthalmol 2013;97:1219–21. 3. Shields CL, Manjandavida FP, Lally SE, et al. Intra-arterial chemotherapy for retinoblastoma in 70 eyes: outcomes based on the international classification of retinoblastoma. Ophthalmology 2014;121:1453–60. 4. Shields CL, Kaliki S, Al-Dahmash S, et al. Management of advanced retinoblastoma with intravenous chemotherapy then intra-arterial chemotherapy as alternative to enucleation. Retina 2013;33:2103–9. 5. Wesolowski R, Lee C, Kim R. Is there a role for second-line chemotherapy in advanced gastric cancer? Lancet Oncol 2009;10:903–12. 6. Donfrancesco A, Jenkner A, Castellano A, et al. Ifosfamide/ carboplatin/etoposide (ICE) as front-line, topotecan/cyclophosphamide as second-line and oral temozolomide as thirdline treatment for advanced neuroblastoma over one year of age. Acta Paediatr Suppl 2004;93:6–11.
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7. Rino Y, Yukawa N, Sato T, et al. Phase II study on the combination of irinotecan plus cisplatin as a second-line therapy in patients with advanced or recurrent gastric cancer. Mol Clin Oncol 2013;1:749–52. 8. Gobin YP, Dunkel IJ, Marr BP, et al. Intra-arterial chemotherapy for the management of retinoblastoma: four-year experience. Arch Ophthalmol 2011;129:732–7. 9. Gobin YP, Dunkel IJ, Marr BP, et al. Combined, sequential intravenous and intra-arterial chemotherapy (bridge chemotherapy) for young infants with retinoblastoma. PLoS ONE 2012;7:e44322. 10. Francis JH, Abramson DH, Gobin YP, et al. Electroretinogram monitoring of dose-dependent toxicity after ophthalmic artery
chemosurgery in retinoblastoma eyes: six year review. PLoS ONE 2014;9:e84247. 11. Munier FL, Gaillard M-C, Balmer A, et al. Intravitreal chemotherapy for vitreous disease in retinoblastoma revisited: from prohibition to conditional indications. Br J Ophthalmol 2012;96:1078–83. 12. Shields CL, Manjandavida FP, Arepalli S, et al. Intravitreal melphalan for persistent or recurrent retinoblastoma vitreous seeds: preliminary results. JAMA Ophthalmol 2014;132:319–25. 13. Francis JH, Schaiquevich P, Buitrago E, et al. Local and systemic toxicity of intravitreal melphalan for vitreous seeding in retinoblastoma: a preclinical and clinical study. Ophthalmology 2014;121:1810–7.
Footnotes and Financial Disclosures Originally received: October 11, 2014. Final revision: November 28, 2014. Accepted: November 30, 2014. Available online: ---.
Presented at: Association for Research in Vision Ophthalmology Annual Meeting, May 2014, Orlando, Florida. Manuscript no. 2014-1613.
1
Ophthalmic Oncology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
2
Department of Ophthalmology, Weill Cornell Medical College, New York Presbyterian Hospital, New York, New York.
3
Interventional Neuroradiology, Departments of Radiology, Neurosurgery, and Neurology, Weill Cornell Medical College, New York Presbyterian Hospital, New York, New York.
4
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
5
Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, New York.
Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Supported by the Fund for Ophthalmic Knowledge (New York, NY). The funding organization had no role in the design or conduct of this research. Abbreviations and Acronyms: CI ¼ confidence interval; CTCAE 4.0 ¼ Common Terminology Criteria for Adverse Events version 4.0; EBR ¼ external-beam radiotherapy; ERG ¼ electroretinography; OAC ¼ ophthalmic artery chemosurgery. Correspondence: Jasmine H. Francis, MD, Ophthalmic Oncology Service, Memorial Sloan Kettering Cancer Center, 70 East 66th Street, New York, NY 10065. E-mail: [email protected].
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There is limited information regarding outcomes after retreatment of recurrent retinoblastoma using the same method that was successful initially. One study cites a salvage rate of 2.2% of eyes with second-course externalbeam radiation (EBR)1; however, there is a dearth of published material on second-course systemic chemotherapy. Likewise for chemotherapy delivered via the ophthalmic artery, our knowledge extends only to secondary ophthalmic artery chemosurgery (OAC) given after failure of the initial non-OAC therapy (typically systemic chemotherapy or radiation).2e4 In this study, we considered a critical question that has yet to be addressed: Is OAC an option for eyes with 2015 by the American Academy of Ophthalmology Published by Elsevier Inc.
recurrent disease after initially successful OAC treatment? The efficacy of second-line chemotherapy is an important question for both patients and their physicians. What are the benefits and drawbacks of subjecting a patient to the time, resources, and effort of additional chemotherapy? The answer is different depending on the tumor type and the regimen used. Some tumors such as gastric cancer and other solid tumors have responded unsatisfactorily to second-line treatment,5 whereas other tumors (or the same tumors subjected to different regimens) have shown promise.6,7 This study reviewed cases that required second-course OAC and determined the response and associated burden of ocular and systemic toxicity. http://dx.doi.org/10.1016/j.ophtha.2014.11.029 ISSN 0161-6420/15
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Methods This retrospective, single-institution, institutional review boardeapproved study included all eyes of retinoblastoma patients meeting the inclusion criteria treated at Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College from May 30, 2006, through July 31, 2013. Informed consent was obtained for each patient. This study complied with the Health Insurance Portability and Accountability Act and adhered to tenets of the Declaration of Helsinki. The study included patients who underwent a course of OAC that was discontinued because of the clinical impression of disease control, with a minimum of 2 months of progression-free follow-up at monthly examinations, but who subsequently demonstrated recurrent tumor and were treated with a second course of OAC. Patient data included age, gender, laterality, weight at start of initial course of OAC and second course of OAC, prior treatment status (naïve vs. prior treatment involving systemic chemotherapy or radiation therapy), age at initial OAC, and follow-up time from beginning of second course of OAC. Treatment data included time from initial OAC completion to recurrence, number of infusions, and drug types and doses during initial- and second-course OAC. Tumor data included ReeseEllsworth classification, International Classification, absence or presence of vitreous seeds, and response to treatment. A complete blood count was requested (or perhaps ordered, because they were not always truly obtained) after each infusion of OAC and considered evaluable if performed within 7 to 14 days after the previous OAC or if grade 3 or 4 toxicity was noted at any time point. The standard Common Terminology Criteria for Adverse Events version 4.0 (CTCAE 4.0) was used to grade hematologic toxicity. Eyes were examined initially under anesthesia at 3- to 4-week intervals. Evaluation consisted of visual assessment, motility and pupillary responses, indirect ophthalmoscopy, fundus photography with RetCam (Massie Industries, Dublin, CA), ophthalmic ultrasonography (OTI Ophthalmic Technologies, Inc, Toronto, Canada), and electroretinography (ERG; Espion ColorBurst, Diagnosys LLC, Lowell, MA). Ophthalmic artery chemosurgery was performed every 3 or 4 weeks in a manner that was described in detail previously.8,9 Focal treatment (transpupillary thermotherapy or cryotherapy) was performed if indicated. Reported here are the response amplitudes to 30-Hz photopic flicker stimulation, which are representative of the full ERG protocol. As previously described,10 ERG amplitudes were classified according to the following scale: less than 0.1 mV, undetectable; 0.1 to 25 mV, poor; 25.1 to 50 mV, fair; 50.1 to 75 mV, good; 75.1 to 100 mV, very good; and more than 100 mV, excellent. A change in 30-Hz response amplitude of 25 mV was considered clinically meaningful, based on statistical analysis of ERG amplitudes during examination under anesthesia of normal eyes (unpublished data, December 2014, ARVO abstract). In the absence of scotopic data, photopic responses to single International Society for Clinical Electrophysiology of Vision standard light-adapted 3.0 flashes also were analyzed. Electroretinography responses were analyzed in 2 groups: measurements before and 1 month after completion of (1) the initial course of OAC and (2) the second course of OAC. Twenty-five eyes had evaluable ERG amplitudes for the initial course of OAC and 29 eyes had evaluable ERG amplitudes for the second course of OAC. Inevaluable ERG amplitudes were the result of having no baseline measurements because of the absence of an electrophysiologist. Outcome measurements included ocular progression-free survival, ocular event-free survival, and ocular survival. Progression of disease was defined as instances of recurrent disease that required additional OAC, EBR, plaque brachytherapy, intravitreal
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melphalan, or enucleation. For event-free survival, an event was defined as enucleation, EBR, or treatment by injection of intravitreal melphalan, but excluded further courses of OAC. This analysis was intended to isolate the potential of salvage OAC from the potentially confounding effect of intravitreal chemotherapy. Statistical analysis was performed using Prism (GraphPad Software, Inc, La Jolla, CA). Kaplan-Meier survival data with the log-rank test were used to evaluate ocular and progression-free survival, and the Mantel-Cox test was used to compare curves. Survival estimates were compared for data that evaluated disease, treatment, and drug-dose features. Disease features included vitreous seed status (the presence or absence of vitreous seeds at the time of initial OAC failure) and latency of relapse (less than, more than, or equal to the median interval of 4.4 months).
Results Patient and Eye Characteristics Twenty-nine eyes of 28 patients fulfilled the inclusion criteria and were included in this study, with a median follow-up of 25.9 months (range, 1e66 months) from the beginning of the second course of OAC. Table 1 summarizes patient, eye, treatment, and outcome characteristics, including details of third-, fourth-, or fifth-line therapy. Eyes received a median of 3.0 infusions (range, 1e6) during the initial OAC course and a median of 2 infusions (range, 1e4) during the second course. Progression of disease and necessity for second-course OAC developed at a median of 4.4 months (range, 2.8e42.5 months) after completion of the initial OAC. Ninety percent of eyes (n ¼ 26 of 29) developed progression of disease and necessity for second-course OAC within 16 months of the initial OAC.
Treatment Treatment features are shown in Table 2. Fifty-five percent of eyes (n ¼ 16 of 29) had no increase in maximum melphalan dose per kilogram and 62% of eyes (n ¼ 18 of 29) had no increase in the maximum dose per kilogram of any drug during the second course compared with the initial course of OAC. Furthermore, 6 eyes had no increase in the maximum drug dose per kilogram of any drug, nor addition of a new drug during the second course compared with the initial course of OAC.
Ocular Survival, Event-Free Survival, and Progression-Free Survival As shown in Figure 1, the 2-year Kaplan-Meier ocular survival, event-free survival, and progression-free survival estimates after the second course of OAC were 82.8% (95% confidence interval [CI], 60.1%e93.2%), 57.3% (95% CI, 36.1%e73.7%), and 26.5% (95% CI, 11.0%e45.0%), respectively. Vitreous seeds were present in 17 (58%) eyes requiring a second course of OAC and were associated significantly with worse ocular survival and event-free survival after the second course of OAC (P ¼ 0.03 and P ¼ 0.03, respectively), but not with progression of disease. KaplanMeier ocular survival estimates at 2 years after the second course of OAC were 100% for eyes without vitreous seeds and 73.9% (95% CI, 44.2%e89.4%) for eyes with vitreous seeds (Fig 1). Kaplan-Meier event-free survival estimates at 2 years after the second course of OAC were 76.2% (95% CI, 33.2%e93.5%) for eyes without vitreous seeds and 47.1% (95% CI, 23.0%e68.0%) for eyes with vitreous seeds (Fig 1). During the second course of OAC, eyes without vitreous seeding received a mean of 1.5 OAC infusions, whereas eyes with vitreous seeding received a mean of
Table 1. Characteristics of Patients, Eyes, and Treatment
Patient No.
Eye Right Right Left Right Left
6 7
11.0 6.3 197.9 3.1 14.0
Cumulative Drug Dose (mg) for Initial Ophthalmic Artery Chemosurgery*
Latency (mos)
VA VB VB IIIA VB
D D E B D
Yes No Yes No Yes
3 4 3 1 3
M5.5, T0.9, C25 M11 M21, T1.2, C120 M2 M8, T0.3
7.0 10.2 15.2 20.0 7.0
3 1 2 3 2
M8, C60, T0.8 M4,T0.3 M8, T0.5, C110 M12, T.9 M11, T.9, C70
Right 24.9 Left 32.5
M M
U B
VB VB
D D
No Yes
3 3
M15 M12, T0.9
4.3 13.3
3 1
C95 M6, T0.4, C30
8 9
Right 24.5 Left 14.0
M M
B B
IVA VB
B D
Yes Yes
1 1
M4 M3
4.9 14.7
2 4
M9, T0.4 M25, T1.6
10 11 12 13
Right Right Right Left
F M M M
B U U B
VB VA IVA VB
D D C E
Yes No Yes No
3 3 3 6
M9.5 M10, T1 M8, T2, C40 M37.5, T2.5, C250
3.3 3.0 3.7 14.5
1 1 2 1
C30 M4 M10, T3, C100 M7.5, T0.5, C50
14 15 16
Left 6.9 Right 7.9 Right 7.2
M M F
B B B
IIA IB VB
B B D
Yes Yes Yes
3 1 3
M8 M2.5 M7.5, T.3
38.7 3.1 13.5
1 1 1
M7.5, T.5 M3, T.2 M4, T.5
17 18 19
Right 25.3 Right 8.9 Right 4.4
M F F
B B B
VB VA VA
D D E
Yes No Yes
5 3 3
M29, T1.3 M4, T.5, C80 M6, T.9, C30
4.6 3.5 2.8
1 2 1
T.4, C40 M9, T2, C110 M3, T.3, C30
20
Left
15.7
M
U
VB
D
No
4
M16, T1.3, C30
2.8
2
M10, T1.5, C80
21 22
33.3 10.6 6.7 63.5
M F
23
Right Right Left Right
F
U B B U
VB IB VB VB
D B D D
No No No No
3 1 2 5
M15, T.4 M3, T.3 T.8, C60 M28, T1.8, C30
3.7 4.2 3.0 7.5
3 1 1 2
M15, T1.2 M3, T.3 T.3, C30 M15, T2.5, C30
24
Right 8.6
M
B
VB
D
No
6
M21, T1.6, C30
3.0
2
M9, T.7, C55
25
Right 53.0
F
B
IIA
D
Yes
3
M15, T.8, C60
4.4
1
M6, T.5, C50
26 27 28
Left Left Left
M M F
U B U
VB VB VB
D D D
No Yes No
3 4 4
C150 M13 M19, T4
3.5 8.4 42.5
2 2 3
M8, T4 M8, T.3 M18, T.5, C100
15.6 5.2 9.9 28.6
10.0 96.6 57.3
3
B ¼ bilateral; EBR ¼ external-beam radiation; F ¼ female; M ¼ male; OAC ¼ ophthalmic artery chemosurgery; U ¼ unilateral. *M ¼ melphalan, T ¼ topotecan, and C ¼ carboplatin and number refers to dose of drug in milligrams.
EBR Enucleation None OAC OAC, enucleation Enucleation Intravitreal melphalan, enucleation OAC OAC, enucleation OAC None None Plaque brachytherapy, intravitreal melphalan OAC None OAC, intravitreal melphalan OAC None OAC, intravitreal melphalan OAC, plaque brachytherapy, intravitreal melphalan Enucleation OAC None OAC, plaque brachytherapy Intravitreal melphalan OAC, intravitreal melphalan None Enucleation None
1 1
1 1 1
2 2 1 1 2
2 2
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Efficacy and Toxicity of Second-Course OAC
B U B B B
F F F F F
Third-, Fourth-, and Fifth-Line Treatments
No. of Additional Ophthalmic Artery Chemosurgery Courses
Francis et al
1 2 3 4 5
ReeseEllsworth Age Classification (mos) Gender Laterality at Diagnosis
No. of Initial Ophthalmic International Artery Classification Prior Chemosurgery at Diagnosis Treatment Infusions
Cumulative No. of Second- Drug Dose (mg) Course for SecondOphthalmic Course Artery Ophthalmic Chemosurgery Artery Infusions Chemosurgery*
Ophthalmology Volume -, Number -, Month 2015 Table 2. Factors Related to Efficacy of Second-Course Ophthalmic Artery Chemosurgery P Value Variable Vitreous seeds Prior treatment status Latency of relapse Age at initial OAC (yrs) No. of initial infusions Addition of new drug No. of second infusions Maximum melphalan Maximum melphalan per kilogram Cumulative melphalan Cumulative melphalan per kilogram Increasing maximum melphalan Increasing maximum melphalan per kilogram Increasing maximum topotecan per kilogram Increasing maximum carboplatin per kilogram Increasing maximum dose any drug Increasing maximum dose per kilogram any drug Increasing cumulative melphalan Increasing cumulative melphalan per kilogram Increasing cumulative topotecan per kilogram Increasing cumulative carboplatin per kilogram Increasing cumulative any drug Increasing cumulative dose per kilogram any drug Increasing maximum dose per kilogram any drug/ new drug
Comparison
No.
Progression-Free Survival
Ocular Survival
Presence vs. absence of vitreous seeds Previously treated vs. treatment naïve Interval between initial OAC end & relapse (mos): <4.4 vs. 4.4 <1 or 1 during initial OAC <3 infusions vs. 3 infusions during initial OAC Absence vs. addition of new drug during second course 1 vs >1 infusion during second course Maximum melphalan (mg): <5 vs. during second course Maximum melphalan per kg (mg/kg): <0.4 vs. 0.4 during second course Cumulative melphalan (mg): <8 vs. 8 during second course Cumulative melphalan per kg (mg/kg): <0.6 vs. 0.6 during second course Increasing vs. decreasing maximum melphalan during second course Increasing vs. decreasing maximum melphalan per kg during second course Increasing vs. decreasing maximum topotecan per kg during second course Increasing vs. decreasing maximum carboplatin per kg during second course Increasing vs. decreasing maximum dose any drug during second course Increasing vs. decreasing maximum dose per kg any drug during second course Increasing vs. decreasing cumulative melphalan during second course Increasing vs. decreasing cumulative melphalan per kg during second course Increasing vs. decreasing cumulative topotecan per kg during second course Increasing vs. decreasing cumulative carboplatin per kg during second course Increasing vs. decreasing cumulative dose any drug during second course Increasing vs. decreasing cumulative dose per kg any drug during second course Increasing maximum dose per kg any drug or new drug vs. not during second course
29 29 29
0.35 0.40 0.22
0.03 0.86 0.34
29 29
0.45 0.56
0.15 0.23
29
0.93
0.23
29 29
0.37 0.86
1.00 0.49
29
0.43
0.66
29
0.56
0.21
29
0.83
0.50
28
0.88
0.63
28
0.22
0.13
20
0.04
0.28
12
0.42
1.00
29
0.67
0.75
29
0.07
0.75
29
0.85
0.40
29
0.39
0.83
19
0.09
0.25
12
0.99
1.00
29
0.86
0.45
29
0.14
0.62
29
0.24
0.79
OAC ¼ ophthalmic artery chemosurgery. Boldface values represent P < 0.05.
2 OAC infusions. Eight eyes with vitreous seeds were salvaged, and 5 (63%) of these went on to receive intravitreal melphalan at some point in their treatment course. A total of 7 eyes received intravitreal melphalan during their treatment course. Representative cases of eyes with and without vitreous seeding at the time of recurrence are shown in Figures 2 and 3. The other significant factor included significantly worse (P ¼ 0.04) progression-free survival for eyes that had an increasing maximum topotecan dose per kilogram from the initial to second course of OAC versus those that did not: 1-year estimates of 44.4% (95% CI, 10.3%e74.8%) and 54.5% (95% CI, 22.8%e77.9%), respectively. Ninety-one percent of eyes receiving a higher maximum topotecan dose per kilogram of any drug during the second course of OAC had vitreous seeds, compared with 0% of eyes that did not receive an increased maximum dose per kilogram.
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Other factors shown in Table 2 were not associated significantly with progression-free survival or ocular survival (P>0.05).
Toxicity Electroretinography measurements before and after the second course of OAC were stable in 83%, decreased in 10%, and increased in 7% of eyes. This outcome was similar to ERG measurements before and after the initial course of OAC, which were stable in 68%, increased in 12%, and decreased in 20% of eyes. The mean change in ERG measurement from baseline was 3.5 mV and 4.7 mV after the initial and second course of OAC, respectively. During the initial and second course of OAC, 65.2% (60 of 92) and 70.0% (35 of 50) of complete blood count results were
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Efficacy and Toxicity of Second-Course OAC
Figure 1. Kaplan-Meier survival curves for (A) ocular survival of all eyes, (B) event-free survival of all eyes, (C) progression-free survival of all eyes, (D) ocular survival comparing eyes with and without vitreous seeds, (E) event-free survival comparing eyes with and without vitreous seeds, and (F) progressionfree survival of eyes with and without vitreous seeds. Note that ocular survival is significantly worse for eyes with vitreous seeds at the time of recurrence. KM ¼ Kaplan-Meier.
evaluable, respectively. During the initial and second course of OAC, 25.0% (15 of 60) and 14.2% (5 of 35) of evaluable OAC infusions had grade 3 or 4 hematologic toxic events, respectively. More specifically, during the initial course of OAC, there were 14 events of grade 3 or 4 neutropenia, 2 events of grade 3 anemia, and no events of grade 3 or 4 thrombocytopenia (a case of neutropenia and anemia occurred together in 1 instance). During the second course of OAC, there were 5 events of grade 3 or 4 neutropenia and no events of grade 3 or 4 anemia or thrombocytopenia.
Discussion This study examined the unexplored question of safety and efficacy of second-course OAC in eyes treated previously with an initial course of OAC. We demonstrate 2-year
ocular survival estimates of 82.8% for all eyes, which is notable given that more than half of the eyes received the same or a lower weight-corrected maximum dose of drugs during the second course, and of those eyes, only half were given a new drug during the second course of OAC. Twoyear event-free survival until enucleation, EBR, or intravitreal melphalan was 57% for all eyes and was significantly better for eyes without vitreous seeds compared with those with vitreous disease. This demonstrates that more than half the eyes can be salvaged with multiline OAC in the absence of intravitreal melphalan or EBR. We also showed that ocular and hematologic toxicity was no worse during second-course OAC compared with initial-course OAC, despite the higher drug doses for some eyes. For instance, after second-course OAC, 90% of eyes maintained stable or had improved ERG recordings (compared with 80% after
Figure 2. Fundus photographs from a representative case without vitreous seeds. A, After completion of the first course of ophthalmic artery chemosurgery (OAC), the tumors regressed. However, the peripapillary tumor (B) recurred 7 months later and (C) successfully responded to second-course OAC.
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Ophthalmology Volume -, Number -, Month 2015
Figure 3. Fundus photographs from a representative case with vitreous seeds. A, After successful completion of the first course of ophthalmic artery chemosurgery (OAC), the tumor recurred with vitreous disease. Recurrent tumor (B) responded to second-course OAC, but (C) vitreous disease (yellow arrows) worsened and the eye was enucleated.
the initial course of OAC). Moreover, 25% of initial-course OAC infusions were associated with grade 3 or 4 hematologic toxicity, compared with 14% of second-course OAC infusions. It is striking that all eyes without vitreous seeds could be saved. Eyes with vitreous seeding did not do as well and had significantly worse ocular survival. The dismal progressionfree survival (26.5% at 2 years for all eyes) is another notable trend for eyes receiving a second course of OAC, which often require a third and sometimes fourth course of treatment in the form of additional OAC, radiation, or intravitreal melphalan. Most of these eyes were treated in the era before intravitreal melphalan, and with the use of this relatively novel treatment, it is possible that more of the eyes with vitreous seeding could have been saved11e13 (and even spared second-line or multiline OAC). For instance in this study, most (63%) salvaged eyes with vitreous seeding received intravitreal melphalan at some point after the second course of OAC. Another significant factor associated with worse ocular survival was the maximum dose of topotecan per kilogram during the second course compared with the initial course of OAC. More eyes receiving higher weight-corrected maximum topotecan doses had vitreous seeding (91% vs. 0%), and therefore it is likely that the inferior ocular survival estimates may be reflective of eyes with more advanced tumors and vitreous disease status. In other fields of oncology, there are established features that predict the success of second-line chemotherapy. For instance, in neuroblastoma, a shorter latency until recurrence predicts poor response to second-line chemotherapy.6 In our cohort, none of these factors seemed to have had an impact: there was no significant difference between previously treated eyes and treatment-naïve eyes, between children receiving an initial course of OAC at younger than 1 year of age compared with older than 1 year of age, or between eyes with a latency to recurrence less than compared with more than the median of 4.4 months. There is no clear explanation for this. There may be something about retinoblastoma as a disease or the delivery method of OAC that defies the trends of secondline chemotherapy that are put forth by other areas of oncology.
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This study is limited by its retrospective design and the relatively small sample size and should be interpreted with these limitations in mind. Although the median follow-up is 26 months, it is possible that with a longer duration of follow-up, additional recurrences or complications may occur. In conclusion, eyes with recurrent tumor after initially successful OAC can have good salvage rates after a second course of OAC, particularly eyes without vitreous seeding. Second-course OAC offers an acceptable ocular and systemic toxicity profile that is no worse than that of initialcourse OAC, despite higher drug doses for some eyes. However, these eyes often require additional (third- or fourth-course) OAC or other treatment methods (intravitreal melphalan, plaque) because of progression of disease after second-line OAC. Ocular survival is worse if vitreous seeds are present at the time of initial OAC failure. However, the increased use of intravitreal chemotherapy may improve the outlook for these eyes.
References 1. Abramson DH, Ellsworth RM, Rosenblatt M, et al. Retreatment of retinoblastoma with external beam irradiation. Arch Ophthalmol 1982;100:1257–60. 2. Bracco S, Leonini S, De Francesco S, et al. Intra-arterial chemotherapy with melphalan for intraocular retinoblastoma. Br J Ophthalmol 2013;97:1219–21. 3. Shields CL, Manjandavida FP, Lally SE, et al. Intra-arterial chemotherapy for retinoblastoma in 70 eyes: outcomes based on the international classification of retinoblastoma. Ophthalmology 2014;121:1453–60. 4. Shields CL, Kaliki S, Al-Dahmash S, et al. Management of advanced retinoblastoma with intravenous chemotherapy then intra-arterial chemotherapy as alternative to enucleation. Retina 2013;33:2103–9. 5. Wesolowski R, Lee C, Kim R. Is there a role for second-line chemotherapy in advanced gastric cancer? Lancet Oncol 2009;10:903–12. 6. Donfrancesco A, Jenkner A, Castellano A, et al. Ifosfamide/ carboplatin/etoposide (ICE) as front-line, topotecan/cyclophosphamide as second-line and oral temozolomide as thirdline treatment for advanced neuroblastoma over one year of age. Acta Paediatr Suppl 2004;93:6–11.
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7. Rino Y, Yukawa N, Sato T, et al. Phase II study on the combination of irinotecan plus cisplatin as a second-line therapy in patients with advanced or recurrent gastric cancer. Mol Clin Oncol 2013;1:749–52. 8. Gobin YP, Dunkel IJ, Marr BP, et al. Intra-arterial chemotherapy for the management of retinoblastoma: four-year experience. Arch Ophthalmol 2011;129:732–7. 9. Gobin YP, Dunkel IJ, Marr BP, et al. Combined, sequential intravenous and intra-arterial chemotherapy (bridge chemotherapy) for young infants with retinoblastoma. PLoS ONE 2012;7:e44322. 10. Francis JH, Abramson DH, Gobin YP, et al. Electroretinogram monitoring of dose-dependent toxicity after ophthalmic artery
chemosurgery in retinoblastoma eyes: six year review. PLoS ONE 2014;9:e84247. 11. Munier FL, Gaillard M-C, Balmer A, et al. Intravitreal chemotherapy for vitreous disease in retinoblastoma revisited: from prohibition to conditional indications. Br J Ophthalmol 2012;96:1078–83. 12. Shields CL, Manjandavida FP, Arepalli S, et al. Intravitreal melphalan for persistent or recurrent retinoblastoma vitreous seeds: preliminary results. JAMA Ophthalmol 2014;132:319–25. 13. Francis JH, Schaiquevich P, Buitrago E, et al. Local and systemic toxicity of intravitreal melphalan for vitreous seeding in retinoblastoma: a preclinical and clinical study. Ophthalmology 2014;121:1810–7.
Footnotes and Financial Disclosures Originally received: October 11, 2014. Final revision: November 28, 2014. Accepted: November 30, 2014. Available online: ---.
Presented at: Association for Research in Vision Ophthalmology Annual Meeting, May 2014, Orlando, Florida. Manuscript no. 2014-1613.
1
Ophthalmic Oncology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
2
Department of Ophthalmology, Weill Cornell Medical College, New York Presbyterian Hospital, New York, New York.
3
Interventional Neuroradiology, Departments of Radiology, Neurosurgery, and Neurology, Weill Cornell Medical College, New York Presbyterian Hospital, New York, New York.
4
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
5
Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, New York.
Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Supported by the Fund for Ophthalmic Knowledge (New York, NY). The funding organization had no role in the design or conduct of this research. Abbreviations and Acronyms: CI ¼ confidence interval; CTCAE 4.0 ¼ Common Terminology Criteria for Adverse Events version 4.0; EBR ¼ external-beam radiotherapy; ERG ¼ electroretinography; OAC ¼ ophthalmic artery chemosurgery. Correspondence: Jasmine H. Francis, MD, Ophthalmic Oncology Service, Memorial Sloan Kettering Cancer Center, 70 East 66th Street, New York, NY 10065. E-mail: [email protected].
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