Pediatr Blood Cancer 2015;62:533–535
BRIEF REPORT Leptomeningeal Failure of Retinoblastoma Amber Orman,
MD,
1
* Arnold Markoe,
MD, ScD,
Leptomeningeal (LM) failure of retinoblastoma (Rb) has not previously been reported. Upon review of our institutional experience of external beam radiotherapy (EBRT) for Rb, we found three LM failures. We sought to better define the clinical parameters of this type of recurrence. All children with LM failure had Reese-Ellsworth stage
1
and Peter A.S. Johnstone,
2 MD, FACR
Vb eyes. Otherwise, no variables were significantly associated with LM failure. We theorize that this phenomenon is a function of the late-stage eyes for which EBRT is being reserved in the modern era. Pediatr Blood Cancer 2015;62:533–535. # 2014 Wiley Periodicals, Inc.
Key words: leptomeningeal disease; pediatric malignancy; retinoblastoma
INTRODUCTION Upon review of University of Miami (UM) experience with Rb between 1992 and 2012, we were struck by the fact that of five episodes of disease recurrence, three patients failed in the LM. Review of other published series [1–11] revealed that LM failure was uncommon. Thus, we specifically analyzed these cases to ascertain whether clinical, patient, or treatment variables might correlate with LM failure of Rb.
METHODS After institutional review board approval, the medical records of all patients with Rb who received EBRT at any point in the course of their treatment from June 1, 1992 through March 31, 2012 at either Jackson Memorial Hospital or Sylvester Comprehensive Cancer Center were reviewed. Attention was placed on survival and disease control outcomes with regard to radiotherapy techniques and clinical and patient factors. Two predominant EBRT techniques were used for most patients: a modified lens sparing (MLS) technique [12] of two lateral oblique photon fields and one lateral electron field, and a relative lens-sparing (RLS) technique [13] of a wedged pair of photon beams. Each technique aims to treat the entire globe and include the orbital conus. For the purpose of this manuscript, specific analysis was made of the three patients who developed disease recurrence in the LM. Descriptive statistics and chi-square analyses were sufficient for analysis of this small patient subset. Staging was performed per the Reese-Ellsworth system [14]. Survival was calculated as the elapsed time between the dates of radiation treatment completion and death.
ral lesion since it occurred 5 years after the contralateral primary lesion was treated with enucleation and adjuvant chemoradiotherapy; presence of the Rb1 mutation was confirmed. The three LM failures occurred within a median of 7 months (range 6–8) after completion of ipsilateral therapy. Each of these three children had Reese-Ellsworth stage Vb [14] lesions, as did the vast majority of the cases reviewed. Two of these patients underwent initial enucleation with positive margins noted on the optic nerve in the final specimen. However, six other patients with positive margins did not suffer LM recurrence (chi share P ¼ 0.47). One of the three had germline Rb1 mutations; the other two did not. The ipsilateral EBRT dose delivered was 4,500 cGy in all three children. The patient failing in delayed fashion in the contralateral optic nerve and LM (patient 3) had been treated with enucleation and adjuvant chemoradiotherapy five years prior using RLS technique to a dose of 4,140 cGy. All three patients were among the 25 total treated with RLS technique. None of the five patients treated with the MLS technique developed such a recurrence; radiation technique was not statistically significant. No child with LM recurrence survived the episode. Median survival after development of the LM lesion was 11 months (range 1–14).
DISCUSSION On focused analysis of the particulars of these three children, there were no obvious correlates of LM failure. Notably, these results may be extrapolated only to children with stage Vb eyes since those provided the vast majority of the UM data. In this cohort, we must assume that many children are at risk for LM seeding and ultimate failure. Other retinal processes such as choroidal
RESULTS In total, the review included 41 eyes of 30 patients. Patient data for the three children with LM failure are in Table I. Age at diagnosis was 5 years, 2 years, and 7 years for patient number 1, 2, and 3, respectively. None of the LM recurrences occurred in children with synchronous bilateral Rb. Of these three failures, all were diffuse within the LM. Two of the three LM recurrences presented adjacent to the ipsilateral orbit, and the last (patient 3) resulted from progression of an isolated contralateral optic nerve recurrence after definitive EBRT in a patient with bilateral disease. Clinically, this represents a germline-related metachronous bilate C
1
Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida; 2Department of Radiation Oncology, H. Lee Moffitt Cancer Center & Research Institute, South Florida, Florida Conflicts of interest: Nothing to declare Correspondence to: Amber Orman, Department of Radiation Oncology Sylvester Comprehensive Cancer Center University of Miami Miller School of Medicine 1475 NW 12th Ave, Suite 1500 Miami, FL, 33136. Email: [email protected]
Received 13 May 2014; Accepted 12 August 2014
2014 Wiley Periodicals, Inc. DOI 10.1002/pbc.25244 Published online 27 September 2014 in Wiley Online Library (wileyonlinelibrary.com).
534
Orman et al.
TABLE I. Patient and Treatment Details in Those With Leptomeningeal Recurrence
Pt
Bilat?
RB1 mut?
Enuc?
EBRT timing
EBRT technique
Dose (cGy)
Chemo timing
Site of rec
1 2 3
No No Yes
No No Yes
Yes Yes No
Adj Adj Def
RLS RLS AP mixed photon and electron
4500 4500 4500
Adj/conc Adj/conc Adj/conc
LM LM L optic nerve, progressing to LM
Pt, patient; bilat, bilateral disease; RB1 mut, RB 1 mutation; Enuc, enucleation; EBRT, external beam radiotherapy; Adj, adjuvant; Def, definitive; RLS, relative lens sparing; AP, anterior posterior; cGy, centigray; Chemo, chemotherapy; Conc, concurrent; Rec, recurrence; LM, leptomeninges; L, left.
metastases [15] or vitreous lesions such as primary vitreoretinal lymphoma [16] have distinct predilections to fail in the CNS or meninges. Treatment of acute lymphoblastic leukemia often requires coverage of the CSF [17]. Two of the three had positive margins on the optic nerve after enucleation. The patient with bilateral disease had undergone neoadjuvant chemotherapy and enucleation of the right eye previously. As right optic nerve involvement was noted, the patient received adjuvant chemotherapy and EBRT, to a total dose of 4,110 cGy using 6 MV photons and RLS technique. The optic chiasm received a dose of 1,100–2,200 cGy. Five years later the patient presented with isolated left optic nerve involvement. Because there was no tumor documented in the left eye, it was theorized that the bilateral optic nerves had been involved initially. Chemotherapy for the right eye may have reduced the amount of viable tumor in the left optic nerve and delayed its presentation. However, the prior right-sided EBRT compromised the dose available to the left orbit. Therefore, a technique using a direct anterior mixed photon/electron beam setup was designed with equal dosing from each beam (18 MeV electrons and 6 MV wedged photons). This was done to minimize further dose to the optic chiasm, but would have provided a suboptimal dose to the orbital
conus. There are no portal images of any fields for these patients available. We may not presume that a positive optic nerve margin is inextricably linked to LM failure because six other such children in this experience did not suffer that outcome. There was no observed correlation between EBRT technique and local control or survival. As increased local failure has been reported with MLS technique [13], most patients at UM are treated with RLS technique. Regardless, strict attention must be paid to the posterior border of the field. We reviewed prior published institutional experiences for frequency of local recurrence and/or LM failure in cases treated with curative EBRT (Table II). While we included modern surgical, chemotherapy, and EBRT techniques exclusively in this cohort, we consider it possible that the stage shift to more involved eyes in modern EBRT literature may have rendered such a drastic site of failure more frequent. In our institution, EBRT is reserved for cases that have failed all other treatment modalities, including intraarterial chemotherapy, focal treatments, and frequently enucleation. Reserving the most challenging cases for EBRT could explain the unique outcomes. This is the sole series documenting LM disease after EBRT. In Abramson and colleague’s report, which studied 63 stage Vb eyes
TABLE II. Recurrences and Leptomeningeal Disease in Published Retinoblastoma Series
Authors [ref] Hernandez et al. [2] Foote et al. [3] Fontanesi et al. [4] Abramson et al. [5] Egbert et al. [6] Blach et al. [7] Pradhan et al. [8] Schipper et al. [9] Merchant et al. [10] Hungerford et al. [11] Toma et al. [12] University of Miami experience
Number of eyes
Number of Stage V eyes (Va, Vb)
Total number of recurrences
Number of LM recurrences
34 25 44 63 38 180 64 54 49 175 67 41
3, 8 6 7 0, 63 15 72 13, 15 5, 0 7 29 5 1, 37
19 14 15 26 6 79 42 32 19 76 19 5
0 0 0 0 0 0 0 0 0 0 0 3
Ref, reference; Group V, not otherwise specified. Pediatr Blood Cancer DOI 10.1002/pbc
Leptomeningeal Failure of Retinoblastoma exclusively, no LM failures were reported [4]. We await other modern experiences of late stage Rb to see if others have observed this phenomenon as well.
REFERENCES 1. Hernandez JC, Brady LW, Shields JA, et al. External beam radiation for retinoblastoma: Results, patterns of failure, and a proposal for treatment guidelines. Int J Radiat Oncol Biol Phys 1996;35:125–132. 2. Foote RL, Garretson BR, Schomberg PJ, et al. External beam irradiation for retinoblastoma: Patterns of failure and dose-response analysis. Int J Radiat Oncol Biol Phys 1989;16:823–830. 3. Fontanesi J, Pratt CB, Kun LE, et al. Treatment outcome and dose-response relationship in infants younger than 1 year treated for retinoblastoma with primary irradiation. Med Pediatr Oncol 1996;26: 297–304. 4. Abramson DH, Beaverson KL, Chang ST, et al. Outcome following initial external beam radiotherapy in patients with Reese-Ellsworth group Vb retinoblastoma. Arch Ophthalmol 2004;122:1316–1323. 5. Egbert PR, Donaldson SS, Moazed K, et al. Visual results and ocular complications following radiotherapy for retinoblastoma. Arch Ophthalmol 1978;96:1826–1830. 6. Blach LE, McCormick B, Abramson DH. External beam radiation therapy and retinoblastoma: Longterm results in the comparison of two techniques. Int J Radiat Oncol Biol Phys 1996;35:45–51.
Pediatr Blood Cancer DOI 10.1002/pbc
535
7. Pradhan DG, Sandridge AL, Mullaney P, et al. Radiation therapy for retinoblastoma: A retrospective review of 120 patients. Int J Radiat Oncol Biol Phys 1997;39:3–13. 8. Schipper J, Tan KE, van Peperzeel HA. Treatment of retinoblastoma by precision megavoltage radiation therapy. Radiother Oncol 1985;3:117–132. 9. Merchant TE, Gould CJ, Hilton NE, et al. Ocular preservation after 36 Gy external beam radiation therapy for retinoblastoma. J Pediatr Hematol Oncol 2002;24:246–249. 10. Hungerford JL, Toma NM, Plowman PN, et al. External beam radiotherapy for retinoblastoma: I. Whole eye technique. Br J Ophthalmol 1995;79:109–111. 11. Toma NM, Hungerford JL, Plowman PN, et al. External beam radiotherapy for retinoblastoma: II. Lens sparing technique. Br J Ophthalmol 1995;79:112–117. 12. McCormick B, Ellsworth R, Abramson D, et al. Radiation therapy for retinoblastoma: Comparison of results with lens-sparing versus lateral beam techniques. Int J Radiat Oncol Biol Phys 1988;15: 567–574. 13. Scott IU, Murray TG, Feuer WJ, et al. External beam radiotherapy in retinoblastoma: Tumor control and comparison of 2 techniques. Arch Ophthalmol 1999;117:766–770. 14. Shoch D. Tumors of the eye. JAMA 1963;185:1046–1046. 15. Chang EL, Lo S. Diagnosis and management of central nervous system metastases from breast cancer. Oncologist 2003;8:398–410. 16. Chan CC, Sen HN. Current concepts in diagnosing and managing primary vitreoretinal (intraocular) lymphoma. Discov Med 2013;15:93–100. 17. Kalapurakal JA, Sathiaseelan V, Bista T, et al. Adverse impact of multileaf collimator field shaping on lens dose in children with acute leukemia receiving cranial irradiation. Int J Radiat Oncol Biol Phys 2000;48:1227–1231.
BRIEF REPORT Leptomeningeal Failure of Retinoblastoma Amber Orman,
MD,
1
* Arnold Markoe,
MD, ScD,
Leptomeningeal (LM) failure of retinoblastoma (Rb) has not previously been reported. Upon review of our institutional experience of external beam radiotherapy (EBRT) for Rb, we found three LM failures. We sought to better define the clinical parameters of this type of recurrence. All children with LM failure had Reese-Ellsworth stage
1
and Peter A.S. Johnstone,
2 MD, FACR
Vb eyes. Otherwise, no variables were significantly associated with LM failure. We theorize that this phenomenon is a function of the late-stage eyes for which EBRT is being reserved in the modern era. Pediatr Blood Cancer 2015;62:533–535. # 2014 Wiley Periodicals, Inc.
Key words: leptomeningeal disease; pediatric malignancy; retinoblastoma
INTRODUCTION Upon review of University of Miami (UM) experience with Rb between 1992 and 2012, we were struck by the fact that of five episodes of disease recurrence, three patients failed in the LM. Review of other published series [1–11] revealed that LM failure was uncommon. Thus, we specifically analyzed these cases to ascertain whether clinical, patient, or treatment variables might correlate with LM failure of Rb.
METHODS After institutional review board approval, the medical records of all patients with Rb who received EBRT at any point in the course of their treatment from June 1, 1992 through March 31, 2012 at either Jackson Memorial Hospital or Sylvester Comprehensive Cancer Center were reviewed. Attention was placed on survival and disease control outcomes with regard to radiotherapy techniques and clinical and patient factors. Two predominant EBRT techniques were used for most patients: a modified lens sparing (MLS) technique [12] of two lateral oblique photon fields and one lateral electron field, and a relative lens-sparing (RLS) technique [13] of a wedged pair of photon beams. Each technique aims to treat the entire globe and include the orbital conus. For the purpose of this manuscript, specific analysis was made of the three patients who developed disease recurrence in the LM. Descriptive statistics and chi-square analyses were sufficient for analysis of this small patient subset. Staging was performed per the Reese-Ellsworth system [14]. Survival was calculated as the elapsed time between the dates of radiation treatment completion and death.
ral lesion since it occurred 5 years after the contralateral primary lesion was treated with enucleation and adjuvant chemoradiotherapy; presence of the Rb1 mutation was confirmed. The three LM failures occurred within a median of 7 months (range 6–8) after completion of ipsilateral therapy. Each of these three children had Reese-Ellsworth stage Vb [14] lesions, as did the vast majority of the cases reviewed. Two of these patients underwent initial enucleation with positive margins noted on the optic nerve in the final specimen. However, six other patients with positive margins did not suffer LM recurrence (chi share P ¼ 0.47). One of the three had germline Rb1 mutations; the other two did not. The ipsilateral EBRT dose delivered was 4,500 cGy in all three children. The patient failing in delayed fashion in the contralateral optic nerve and LM (patient 3) had been treated with enucleation and adjuvant chemoradiotherapy five years prior using RLS technique to a dose of 4,140 cGy. All three patients were among the 25 total treated with RLS technique. None of the five patients treated with the MLS technique developed such a recurrence; radiation technique was not statistically significant. No child with LM recurrence survived the episode. Median survival after development of the LM lesion was 11 months (range 1–14).
DISCUSSION On focused analysis of the particulars of these three children, there were no obvious correlates of LM failure. Notably, these results may be extrapolated only to children with stage Vb eyes since those provided the vast majority of the UM data. In this cohort, we must assume that many children are at risk for LM seeding and ultimate failure. Other retinal processes such as choroidal
RESULTS In total, the review included 41 eyes of 30 patients. Patient data for the three children with LM failure are in Table I. Age at diagnosis was 5 years, 2 years, and 7 years for patient number 1, 2, and 3, respectively. None of the LM recurrences occurred in children with synchronous bilateral Rb. Of these three failures, all were diffuse within the LM. Two of the three LM recurrences presented adjacent to the ipsilateral orbit, and the last (patient 3) resulted from progression of an isolated contralateral optic nerve recurrence after definitive EBRT in a patient with bilateral disease. Clinically, this represents a germline-related metachronous bilate C
1
Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida; 2Department of Radiation Oncology, H. Lee Moffitt Cancer Center & Research Institute, South Florida, Florida Conflicts of interest: Nothing to declare Correspondence to: Amber Orman, Department of Radiation Oncology Sylvester Comprehensive Cancer Center University of Miami Miller School of Medicine 1475 NW 12th Ave, Suite 1500 Miami, FL, 33136. Email: [email protected]
Received 13 May 2014; Accepted 12 August 2014
2014 Wiley Periodicals, Inc. DOI 10.1002/pbc.25244 Published online 27 September 2014 in Wiley Online Library (wileyonlinelibrary.com).
534
Orman et al.
TABLE I. Patient and Treatment Details in Those With Leptomeningeal Recurrence
Pt
Bilat?
RB1 mut?
Enuc?
EBRT timing
EBRT technique
Dose (cGy)
Chemo timing
Site of rec
1 2 3
No No Yes
No No Yes
Yes Yes No
Adj Adj Def
RLS RLS AP mixed photon and electron
4500 4500 4500
Adj/conc Adj/conc Adj/conc
LM LM L optic nerve, progressing to LM
Pt, patient; bilat, bilateral disease; RB1 mut, RB 1 mutation; Enuc, enucleation; EBRT, external beam radiotherapy; Adj, adjuvant; Def, definitive; RLS, relative lens sparing; AP, anterior posterior; cGy, centigray; Chemo, chemotherapy; Conc, concurrent; Rec, recurrence; LM, leptomeninges; L, left.
metastases [15] or vitreous lesions such as primary vitreoretinal lymphoma [16] have distinct predilections to fail in the CNS or meninges. Treatment of acute lymphoblastic leukemia often requires coverage of the CSF [17]. Two of the three had positive margins on the optic nerve after enucleation. The patient with bilateral disease had undergone neoadjuvant chemotherapy and enucleation of the right eye previously. As right optic nerve involvement was noted, the patient received adjuvant chemotherapy and EBRT, to a total dose of 4,110 cGy using 6 MV photons and RLS technique. The optic chiasm received a dose of 1,100–2,200 cGy. Five years later the patient presented with isolated left optic nerve involvement. Because there was no tumor documented in the left eye, it was theorized that the bilateral optic nerves had been involved initially. Chemotherapy for the right eye may have reduced the amount of viable tumor in the left optic nerve and delayed its presentation. However, the prior right-sided EBRT compromised the dose available to the left orbit. Therefore, a technique using a direct anterior mixed photon/electron beam setup was designed with equal dosing from each beam (18 MeV electrons and 6 MV wedged photons). This was done to minimize further dose to the optic chiasm, but would have provided a suboptimal dose to the orbital
conus. There are no portal images of any fields for these patients available. We may not presume that a positive optic nerve margin is inextricably linked to LM failure because six other such children in this experience did not suffer that outcome. There was no observed correlation between EBRT technique and local control or survival. As increased local failure has been reported with MLS technique [13], most patients at UM are treated with RLS technique. Regardless, strict attention must be paid to the posterior border of the field. We reviewed prior published institutional experiences for frequency of local recurrence and/or LM failure in cases treated with curative EBRT (Table II). While we included modern surgical, chemotherapy, and EBRT techniques exclusively in this cohort, we consider it possible that the stage shift to more involved eyes in modern EBRT literature may have rendered such a drastic site of failure more frequent. In our institution, EBRT is reserved for cases that have failed all other treatment modalities, including intraarterial chemotherapy, focal treatments, and frequently enucleation. Reserving the most challenging cases for EBRT could explain the unique outcomes. This is the sole series documenting LM disease after EBRT. In Abramson and colleague’s report, which studied 63 stage Vb eyes
TABLE II. Recurrences and Leptomeningeal Disease in Published Retinoblastoma Series
Authors [ref] Hernandez et al. [2] Foote et al. [3] Fontanesi et al. [4] Abramson et al. [5] Egbert et al. [6] Blach et al. [7] Pradhan et al. [8] Schipper et al. [9] Merchant et al. [10] Hungerford et al. [11] Toma et al. [12] University of Miami experience
Number of eyes
Number of Stage V eyes (Va, Vb)
Total number of recurrences
Number of LM recurrences
34 25 44 63 38 180 64 54 49 175 67 41
3, 8 6 7 0, 63 15 72 13, 15 5, 0 7 29 5 1, 37
19 14 15 26 6 79 42 32 19 76 19 5
0 0 0 0 0 0 0 0 0 0 0 3
Ref, reference; Group V, not otherwise specified. Pediatr Blood Cancer DOI 10.1002/pbc
Leptomeningeal Failure of Retinoblastoma exclusively, no LM failures were reported [4]. We await other modern experiences of late stage Rb to see if others have observed this phenomenon as well.
REFERENCES 1. Hernandez JC, Brady LW, Shields JA, et al. External beam radiation for retinoblastoma: Results, patterns of failure, and a proposal for treatment guidelines. Int J Radiat Oncol Biol Phys 1996;35:125–132. 2. Foote RL, Garretson BR, Schomberg PJ, et al. External beam irradiation for retinoblastoma: Patterns of failure and dose-response analysis. Int J Radiat Oncol Biol Phys 1989;16:823–830. 3. Fontanesi J, Pratt CB, Kun LE, et al. Treatment outcome and dose-response relationship in infants younger than 1 year treated for retinoblastoma with primary irradiation. Med Pediatr Oncol 1996;26: 297–304. 4. Abramson DH, Beaverson KL, Chang ST, et al. Outcome following initial external beam radiotherapy in patients with Reese-Ellsworth group Vb retinoblastoma. Arch Ophthalmol 2004;122:1316–1323. 5. Egbert PR, Donaldson SS, Moazed K, et al. Visual results and ocular complications following radiotherapy for retinoblastoma. Arch Ophthalmol 1978;96:1826–1830. 6. Blach LE, McCormick B, Abramson DH. External beam radiation therapy and retinoblastoma: Longterm results in the comparison of two techniques. Int J Radiat Oncol Biol Phys 1996;35:45–51.
Pediatr Blood Cancer DOI 10.1002/pbc
535
7. Pradhan DG, Sandridge AL, Mullaney P, et al. Radiation therapy for retinoblastoma: A retrospective review of 120 patients. Int J Radiat Oncol Biol Phys 1997;39:3–13. 8. Schipper J, Tan KE, van Peperzeel HA. Treatment of retinoblastoma by precision megavoltage radiation therapy. Radiother Oncol 1985;3:117–132. 9. Merchant TE, Gould CJ, Hilton NE, et al. Ocular preservation after 36 Gy external beam radiation therapy for retinoblastoma. J Pediatr Hematol Oncol 2002;24:246–249. 10. Hungerford JL, Toma NM, Plowman PN, et al. External beam radiotherapy for retinoblastoma: I. Whole eye technique. Br J Ophthalmol 1995;79:109–111. 11. Toma NM, Hungerford JL, Plowman PN, et al. External beam radiotherapy for retinoblastoma: II. Lens sparing technique. Br J Ophthalmol 1995;79:112–117. 12. McCormick B, Ellsworth R, Abramson D, et al. Radiation therapy for retinoblastoma: Comparison of results with lens-sparing versus lateral beam techniques. Int J Radiat Oncol Biol Phys 1988;15: 567–574. 13. Scott IU, Murray TG, Feuer WJ, et al. External beam radiotherapy in retinoblastoma: Tumor control and comparison of 2 techniques. Arch Ophthalmol 1999;117:766–770. 14. Shoch D. Tumors of the eye. JAMA 1963;185:1046–1046. 15. Chang EL, Lo S. Diagnosis and management of central nervous system metastases from breast cancer. Oncologist 2003;8:398–410. 16. Chan CC, Sen HN. Current concepts in diagnosing and managing primary vitreoretinal (intraocular) lymphoma. Discov Med 2013;15:93–100. 17. Kalapurakal JA, Sathiaseelan V, Bista T, et al. Adverse impact of multileaf collimator field shaping on lens dose in children with acute leukemia receiving cranial irradiation. Int J Radiat Oncol Biol Phys 2000;48:1227–1231.
