Dear Sir,
We are writing this letter in response to a “letter to the editor” from Drs. Leahey and Meadows about our recently published paper “Second primary malignancies in retinoblastoma patients treated with intra-arterial chemotherapy: the first 10 years”.1 There are a number of incorrect statements in their letter and we hope this letter will clarify those errors made by them.
1) Drs. Leahey and Meadows state that…”the author’s report is profoundly misleading with regard to the risk of SPMs following OAC”. To prove that they then state that the median follow-up range is 2.5 years with a maximum follow-up of 12 years. How is that “profoundly misleading”? In the same paragraph they then state that patients failing OAC required radiation therapy and suggest that all of these second neoplasms are a consequence of radiation. That is not true. In our paper (page 273, Table 3) we documented that not one of the children who developed a second tumor had received radiation. How could radiation be the cause of a second tumor if the patients never received radiation? Dr. Leahey and Meadows also wrote that…”patients failing OAC require radiation”. That’s not true. On page 272 we stated that…”patients who received external beam radiation prior to presentation at our clinic were excluded from analysis”. None of the patients in this series received radiation after OAC and no patient in our center has received radiation in the past 10 years. We do not dispute that radiation affects the development of second cancers in germline affected retinoblastomas-but that is not the explanation for these cancers in our report.
2) In the many large series published worldwide on second cancers in retinoblastoma patients secondary AML does not appear to be a cancer that develops2,3 unless systemic chemotherapy is used4. In fact there are published series of secondary AML in retinoblastoma patients published prior to the introduction of OAC and in each case systemic chemotherapy was implicated as the cause. There has not been an increase in sAML in our patients treated with OAC and no other center has suggested or reported an increase in sAML after adopting OAC.
3) Drs. Leahey and Meadows imply that the Melphalan given for OAC is responsible for the secondary AML but that seems unlikely and is not consistent with the published, peer review literature. The Japanese used similar doses of Melphalan in their series of patients treated with intra-arterial chemotherapy (published in 2011) between 1988 and 2007.5 In their 343 patients they meticulously pointed out that long-term follow-up of these patients did not reveal an increase in second cancers and in fact all of the second cancers but one they attributed to the use of external beam radiation combined with chemotherapy. The one patient they had who developed secondary AML they attributed to the four courses of systemic chemotherapy utilizing Vincristine, Carboplatin and Etoposide. We don’t understand why Dr. Leahey and Meadows implicate the Melphalan but not the seven cycles of multiagent systemic chemotherapy they delivered. This child did not have AML while under our care. Finally, FLT3 mutations (present in this child) have usually been associated with topoisomerase induced sAML and de novo (no prior chemotherapy) sAML and not sAML from alkylating agents (e.g. Melphalan). 6 Their child’s sAML may be unrelated to any chemotherapy but more likely the systemic chemotherapy (with doses a hundred times the small amount of Melphalan delivered by OAC) is the culprit.
4) Secondary AML from chemotherapy is well known in pediatric oncology and well known by Drs. Leahey and Meadows. It is a devastating and often lethal complication of systemic chemotherapy and was the subject of a paper by Drs. Leahey and Meadows in 1999.7 They described this complication as a…”late effect of chemotherapy” in their cohort of 228 patients. We agree that secondary AML can be a late and devastating effect of systemic chemotherapy and that is why we have abandoned it for intraocular retinoblastoma and one of the reasons we developed OAC.
5) Drs. Leahey and Meadows correctly state that the goal of retinoblastoma is to cure the child of cancer (and suggest that OAC does not do that). A large, collaborative manuscript (which included their patients) was published a December 2017 on the worldwide experience with OAC8 since we introduced it in 20069. In 1139 patients who received 4396 infusions only three patients died of metastatic disease (all from Argentina and all had prior systemic chemotherapy). The conclusion is clear: using OAC to save children’s eyes and vision does not compromise patient survival.
6) Drs. Leahey and Meadows and the Philadelphia retinoblastoma team have considerable experience with OAC over the past 10 years and have published more than 20 papers on the subject. They have not published on their second tumor experience in the OAC era. We challenge them to collect and publish their data on second cancers in germline patients treated with OAC alone. If they have additional sAML cases we suggest their use of multi-agent systemic chemotherapy for retinoblastoma is the cause (as we abandoned that 12 years ago because of that well documented adverse effect).
7) We are saddened by this patient’s course but have no way of evaluating the risk/benefit discussion that Drs. Leahey and Meadows had with the family when they decided to use adjuvant multiagent chemotherapy which may have induced resistance and then a total of seven cycles of multiagent chemotherapy which are proven to cause secondary AML. The conclusion from this case is that we should all avoid systemic chemotherapy in retinoblastoma if there is a better option…and for intraocular disease fortunately there is: OAC.
References
1. Habib LA, Francis JH, Fabius AW, Gobin PY, Dunkel IJ, Abramson DH. Second primary malignancies in retinoblastoma patients treated with intra-arterial chemotherapy: the first 10 years. Br J Ophthalmol. 2018;102(2):272–275. doi:10.1136/bjophthalmol-2017-310328.
2. Kleinerman RA, Yu C-L, Little MP, et al. Variation of second cancer risk by family history of retinoblastoma among long-term survivors. J Clin Oncol. 2012;30(9):950–957. doi:10.1200/JCO.2011.37.0239.
3. Abramson DH, Frank CM. Second nonocular tumors in survivors of bilateral retinoblastoma: a possible age effect on radiation-related risk. Ophthalmology. 1998;105(4):573–9–discussion579–80. doi:10.1016/S0161-6420(98)94006-4.
4. Gombos DS, Hungerford J, Abramson DH, et al. Secondary acute myelogenous leukemia in patients with retinoblastoma: is chemotherapy a factor? Ophthalmology. 2007;114(7):1378–1383. doi:10.1016/j.ophtha.2007.03.074.
5. Suzuki S, Yamane T, Mohri M, Kaneko A. Selective ophthalmic arterial injection therapy for intraocular retinoblastoma: the long-term prognosis. Ophthalmology. 2011;118(10):2081–2087. doi:10.1016/j.ophtha.2011.03.013.
6. Godley LA, Larson RA. Therapy-related myeloid leukemia. Semin Oncol. 2008;35(4):418–429. doi:10.1053/j.seminoncol.2008.04.012.
7. Leahey AM, Teunissen H, Friedman DL, Moshang T, Lange BJ, Meadows AT. Late effects of chemotherapy compared to bone marrow transplantation in the treatment of pediatric acute myeloid leukemia and myelodysplasia. Med Pediatr Oncol. 1999;32(3):163–169.
8. Abramson DH, Shields CL, Jabbour P, et al. Metastatic deaths in retinoblastoma patients treated with intraarterial chemotherapy (ophthalmic artery chemosurgery) worldwide. Int J Retina Vitreous. 2017;3:40. doi:10.1186/s40942-017-0093-8.
9. 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):1398–404–1404.e1. doi:10.1016/j.ophtha.2007.12.014.
Dear Sir,
We are writing this letter in response to a “letter to the editor” from Drs. Leahey and Meadows about our recently published paper “Second primary malignancies in retinoblastoma patients treated with intra-arterial chemotherapy: the first 10 years”.1 There are a number of incorrect statements in their letter and we hope this letter will clarify those errors made by them.
1) Drs. Leahey and Meadows state that…”the author’s report is profoundly misleading with regard to the risk of SPMs following OAC”. To prove that they then state that the median follow-up range is 2.5 years with a maximum follow-up of 12 years. How is that “profoundly misleading”? In the same paragraph they then state that patients failing OAC required radiation therapy and suggest that all of these second neoplasms are a consequence of radiation. That is not true. In our paper (page 273, Table 3) we documented that not one of the children who developed a second tumor had received radiation. How could radiation be the cause of a second tumor if the patients never received radiation? Dr. Leahey and Meadows also wrote that…”patients failing OAC require radiation”. That’s not true. On page 272 we stated that…”patients who received external beam radiation prior to presentation at our clinic were excluded from analysis”. None of the patients in this series received radiation after OAC and no patient in our center has received radiation in the past 10 years. We do not dispute that radiation affects the development of second cancers in germline affected retinoblastomas-but that is not the explanation for these cancers in our report.
2) In the many large series published worldwide on second cancers in retinoblastoma patients secondary AML does not appear to be a cancer that develops2,3 unless systemic chemotherapy is used4. In fact there are published series of secondary AML in retinoblastoma patients published prior to the introduction of OAC and in each case systemic chemotherapy was implicated as the cause. There has not been an increase in sAML in our patients treated with OAC and no other center has suggested or reported an increase in sAML after adopting OAC.
3) Drs. Leahey and Meadows imply that the Melphalan given for OAC is responsible for the secondary AML but that seems unlikely and is not consistent with the published, peer review literature. The Japanese used similar doses of Melphalan in their series of patients treated with intra-arterial chemotherapy (published in 2011) between 1988 and 2007.5 In their 343 patients they meticulously pointed out that long-term follow-up of these patients did not reveal an increase in second cancers and in fact all of the second cancers but one they attributed to the use of external beam radiation combined with chemotherapy. The one patient they had who developed secondary AML they attributed to the four courses of systemic chemotherapy utilizing Vincristine, Carboplatin and Etoposide. We don’t understand why Dr. Leahey and Meadows implicate the Melphalan but not the seven cycles of multiagent systemic chemotherapy they delivered. This child did not have AML while under our care. Finally, FLT3 mutations (present in this child) have usually been associated with topoisomerase induced sAML and de novo (no prior chemotherapy) sAML and not sAML from alkylating agents (e.g. Melphalan). 6 Their child’s sAML may be unrelated to any chemotherapy but more likely the systemic chemotherapy (with doses a hundred times the small amount of Melphalan delivered by OAC) is the culprit.
4) Secondary AML from chemotherapy is well known in pediatric oncology and well known by Drs. Leahey and Meadows. It is a devastating and often lethal complication of systemic chemotherapy and was the subject of a paper by Drs. Leahey and Meadows in 1999.7 They described this complication as a…”late effect of chemotherapy” in their cohort of 228 patients. We agree that secondary AML can be a late and devastating effect of systemic chemotherapy and that is why we have abandoned it for intraocular retinoblastoma and one of the reasons we developed OAC.
5) Drs. Leahey and Meadows correctly state that the goal of retinoblastoma is to cure the child of cancer (and suggest that OAC does not do that). A large, collaborative manuscript (which included their patients) was published a December 2017 on the worldwide experience with OAC8 since we introduced it in 20069. In 1139 patients who received 4396 infusions only three patients died of metastatic disease (all from Argentina and all had prior systemic chemotherapy). The conclusion is clear: using OAC to save children’s eyes and vision does not compromise patient survival.
6) Drs. Leahey and Meadows and the Philadelphia retinoblastoma team have considerable experience with OAC over the past 10 years and have published more than 20 papers on the subject. They have not published on their second tumor experience in the OAC era. We challenge them to collect and publish their data on second cancers in germline patients treated with OAC alone. If they have additional sAML cases we suggest their use of multi-agent systemic chemotherapy for retinoblastoma is the cause (as we abandoned that 12 years ago because of that well documented adverse effect).
7) We are saddened by this patient’s course but have no way of evaluating the risk/benefit discussion that Drs. Leahey and Meadows had with the family when they decided to use adjuvant multiagent chemotherapy which may have induced resistance and then a total of seven cycles of multiagent chemotherapy which are proven to cause secondary AML. The conclusion from this case is that we should all avoid systemic chemotherapy in retinoblastoma if there is a better option…and for intraocular disease fortunately there is: OAC.
References
1. Habib LA, Francis JH, Fabius AW, Gobin PY, Dunkel IJ, Abramson DH. Second primary malignancies in retinoblastoma patients treated with intra-arterial chemotherapy: the first 10 years. Br J Ophthalmol. 2018;102(2):272–275. doi:10.1136/bjophthalmol-2017-310328.
2. Kleinerman RA, Yu C-L, Little MP, et al. Variation of second cancer risk by family history of retinoblastoma among long-term survivors. J Clin Oncol. 2012;30(9):950–957. doi:10.1200/JCO.2011.37.0239.
3. Abramson DH, Frank CM. Second nonocular tumors in survivors of bilateral retinoblastoma: a possible age effect on radiation-related risk. Ophthalmology. 1998;105(4):573–9–discussion579–80. doi:10.1016/S0161-6420(98)94006-4.
4. Gombos DS, Hungerford J, Abramson DH, et al. Secondary acute myelogenous leukemia in patients with retinoblastoma: is chemotherapy a factor? Ophthalmology. 2007;114(7):1378–1383. doi:10.1016/j.ophtha.2007.03.074.
5. Suzuki S, Yamane T, Mohri M, Kaneko A. Selective ophthalmic arterial injection therapy for intraocular retinoblastoma: the long-term prognosis. Ophthalmology. 2011;118(10):2081–2087. doi:10.1016/j.ophtha.2011.03.013.
6. Godley LA, Larson RA. Therapy-related myeloid leukemia. Semin Oncol. 2008;35(4):418–429. doi:10.1053/j.seminoncol.2008.04.012.
7. Leahey AM, Teunissen H, Friedman DL, Moshang T, Lange BJ, Meadows AT. Late effects of chemotherapy compared to bone marrow transplantation in the treatment of pediatric acute myeloid leukemia and myelodysplasia. Med Pediatr Oncol. 1999;32(3):163–169.
8. Abramson DH, Shields CL, Jabbour P, et al. Metastatic deaths in retinoblastoma patients treated with intraarterial chemotherapy (ophthalmic artery chemosurgery) worldwide. Int J Retina Vitreous. 2017;3:40. doi:10.1186/s40942-017-0093-8.
9. 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):1398–404–1404.e1. doi:10.1016/j.ophtha.2007.12.014.