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Multiagent chemotherapy in the salvage cure of ocular lymphoma relapsing after radiotherapy
Clinical Oncology (1993) 5:315-316 © 1993 The Royal College of Radiologists
Clinical Oncology
Case Report Multiagent Chemotherapy in the Salvage Cure of Ocular Lymphoma Relapsing After Radiotherapy P. N. Plowman 1, D. S. M o n t e f i o r e 1 a n d S. L i g h t m a n 2 1 D e p a r t m e n t of R a d i o t h e r a p y , St B a r t h o l o m e w ' s Hospital, L o n d o n E C 1 A 7 B E a n d 2 D e p a r t m e n t of Clinical O p h t h a l m o l o g y , Moorfields E y e Hospital, L o n d o n E C I V 2PD, U K
Abstract. The eye has traditionally been regarded as a sanctuary site for drugs, but recent publications have shown evidence of penetration by drugs and subsequent clinical response of intraocular lymphomas. In this report, a chemotherapy regimen, including high dose methotrexate and cytosine arabinoside, was used to re-induce remission in a patient with intraocular lymphoma relapsing locally after prior radiotherapy. She remains disease free 18 months later. Keywords: therapy
Ocular
lymphoma;
Radio-
INTRODUCTION Primary ocular (intraocular) lymphoma is a rare condition, but one whose natural history is now well documented. Margolis et al. [1] described the typical case as occurring in middle age, with a long interval (up to 5 years) between ocular symptoms and the establishment of the correct diagnosis. The disease 'masquerades' as chronic uveitis, but response to steroids is temporary. In this San Francisco review of 39 patients documented in the literature in 1980, 79% of patients had bilateral tumours (of great interest in view of the absence of orbital lymphatic connections between the two eyes) and 67% of patients developed CNS lymphoma. The CNS involvement was usually a solid lymphomatous mass (8/9 patients) in the cerebrum (7/8 patients), with only one having diffuse leptomeningeal dissemination. The prognosis for patients with CNS disease was universally and rapidly fatal. Interestingly, only 23% (9/39) of patients reviewed had developed systemic lymphoma. Margolis et al. [1] concluded that most patients with primary ocular lymphoma die of progression of the disease or CNS disease, despite good initial tumour regression to 'adequate' radiotherapy. The lymphoma is usually a large cell, B cell, non-Hodgkin's lymphoma. Qualman et al. [2] contributed more to
Correspondence and offprint requests to: Dr P. N. Plowman, Department of Radiotherapy, St Bartholomew's Hospital, London EC1A 7BE, UK.
the understanding of the 'CNS link'. They observed that ocular lymphomas with involvement of vitreous, sensory retina, subretinal pigment epithelial space or nerve head were more likely than those with solitary uveal involvement to lead to CNS disease. They further observed a preponderance of CNS mass lesions ipsilateral to the affected eye. In their histopathological analysis, Qualman and colleagues describe prominent perivascular cuffing of inflammatory and lymphoid cells in the region of the optic nerve, orbital meninges, optic chiasma and the meninges of the cerebral hemisphere behind. The authors propose that this is either part of the mechanism of the multicentricity or the method of spread. The high risk of CNS disease has led some authorities to recommend prophylactic radiotherapy to the brain. Our own experience with three patients with primary ocular lymphoma is that two relapsed with intracerebral masses of lymphoma. The third patient suffered intraocular relapse after primary radiotherapy, but was salvaged by a chemoradiotherapy programme based on our current understanding of drug penetration into the eye. This case history is presented in full before the main features of interest are discussed.
CASE HISTORY This lady presented, aged 57, with a history that 18 month earlier she had noticed flashing lights in the right eye. Five months later she had noted deteriorating vision in this eye and, with a clinical diagnosis of retinitis, she had been commenced on steroids. There had been a temporary response but, on subsequent deterioration, both cyclosporin and azathioprine had been administered. By 13 months after clinical presentation the patient's vision in her right eye was reduced to hand movements and she began to notice 'flashing lights' in the left eye. A choroido-retinal biopsy from the right eye showed a non-Hodgkin's large cell lymphoma. Staging procedures did not suggest disease outside the eyes. The patient received radiotherapy to both eyes by lateral 6 MV X-ray portals, to a dose of 3000 cGy in 15 fractions over 21 days. One month after treatment the vision was much
improved on the right although some 'flickering' continued to be noticed. Ophthalmologically there was complete regression. One year after the end of radiotherapy, the patient relapsed in the left eye with development of choroidal lesions. It was felt that, although further radiotherapy would be safe and necessary, it was unlikely to cure where it had failed before. Therapy therefore recommenced with chemotherapy and a novel multiagent regimen (Ara-CHOMP), built around standard CHOP with day 8 high/intermediate dosage methotrexate and cystosine arabinoside as soon as the white count recovered:Cyclophosphamide 750 mg/m 2 i.v. bolus D1 Adriamycin (doxorubicin) 50 mg/m 2 i.v. bolus D1 Vincristine 2.0 mg i.v. bolus D1 Prednisoline 100 mg/day oral (divided dosage) D I - D 5 Methotrexate 400 mg/m 2 i.v. infusion D8; folinic acid rescue at 24 hours Cytosine arabinoside 3 g/m2 i.v. very 12 hours x 2 doses on FBC recovery The above regimen was repeated and, after 2 completed cycles, ophthalmic review concluded complete clinical regression. The patient proceeded to retreatment of ocular radiotherapy to the left eye. Through an anterior cobalt portal an applied dose of 2000 cGy was delivered in 10 fractions over 12 days. The patient is now clinically disease free at 16 months from the end of treatment.
DISCUSSION Radiotherapy has been the gold-standard definitive treatment of primary ocular lymphoma following the good responses reported by Margolis et al. [1]. Total doses delivered varied between 1500 and 4500 cGy in the San Francisco series of 9 patients and the authors concluded that doses at the higher end of this range gave the best results, although local recurrence remained a problem. The dose prescription delivered to the patient reported here was the same as is routinely delivered to primary orbital (extraocular) lymphomas at this centre, and after which local relapse is extraordinarily unusual. In this respect, as with several
316 other discussions points that follow, intraocular lymphoma more closely resembles primary cerebral lymphoma, and perhaps a higher radiotherapy dose prescription should have been delivered in the first instance to both eyes. At the time of relapse, it seemed correct to try chemotherapy ~hd the choice to use this first was based on the failure after previous radiotherapy and the more certain ability to assess response to chemotherapy when used prior to radiation. Chemotherapy is traditionally said to have poor efficacy against intraocular tumours because, it is alleged, the eye shares the blood-brain barrier with the central nervous system. However, conventional multidrug systemic breast cancer chemotherapy has been noted to cause regression of choroidal metastases [3,4] and it is now well established that certain chemotherapeutic drugs, notably intermediate to high dose methotrexate [5] and cytosine arabinoside [6], show good penetration through the blood-brain barrier. Prior radiotherapy may disrupt the response of the blood-brain barrier to drugs, which is of possible relevance in this patient. In an interesting series of six patients with ocular lymphoma reported by Strauchan et al. [7], the authors explored
P . N . Plowman et al. the use of high dose cytosine arabinoside. Five responses were observed in their six patients, (and four of their patients were previously untreated). This report of a relatively large number of cases for this rare disease makes compelling reading and it was this work that encouraged us to include high dose ara-C into the multiagent chemotherapy regimen chosen for the patient presented here. This regimen was designed to include both high dose methotrexate and ara-C. Following 2 cycles of the ara-CHOMP regimen, our patient had complete clinical response of her relapsed lymphoma. She then received 20 Gy retreatment radiotherapy (from which alone one would not expect cure, as she had relapsed following 30 Gy, similar fractionated, within one year) and now remains in remission at 18 months from completion of therapy. We believe that the ara-CHOMP regimen has played an important part in her probable cure. It is also interesting to speculate that the ara-CHOMP has provided some prophylaxis against this patient's chances of developing CNS disease. It is even more interesting to speculate whether a regimen such as araCHOMP, with designed CNS/ocular penetration, might be usefully combined with
radiotherapy to improve the cure rates of the prognostically poor primary intracerebral lymphoma.
References 1. Margolis L, Fraser R, Lichter A, et al. The role of radiation therapy in the management of ocular reticulum cell sarcoma. Cancer 1980;45:688--92. 2. Qualman SJ, Mendelsohn G, Mann RB, et al. Intraocular lymphomas. Cancer 1983;52:87886. 3. Aasvad H, Seim V. Chemotherapy in intraocular metastasis from carcinoma of breast. Acta Ophthalmol 1974;123:Suppl 142. 4. BrinkleyJR. Response of a choroidal metastasis to multiple drug chemotherapy. Cancer 1980;45:1538-9. 5. Wang JJ, Freeman AI, SinksLF. Treatment of acute lymphocytic leukemia by high dose intravenous methotrexate. Cancer Res 1976;36:1441-4. 6. Slevin ML, Piall EM, Aherne GW, et al. Effect of dose and schedule on pharmacokinetics of high dose cytosine arabinoside in plasma and cerebrospinal fluid. J Clin Oncol 1983;1:546--51. 7. Strauchan JA, Dalton J, Friedman AH. Chemotherapy in the management of intraocular lymphoma. Cancer 1989;63:1918-21.
Received for publication April 1993 Accepted following revision July 1993
Clinical Oncology
Case Report Multiagent Chemotherapy in the Salvage Cure of Ocular Lymphoma Relapsing After Radiotherapy P. N. Plowman 1, D. S. M o n t e f i o r e 1 a n d S. L i g h t m a n 2 1 D e p a r t m e n t of R a d i o t h e r a p y , St B a r t h o l o m e w ' s Hospital, L o n d o n E C 1 A 7 B E a n d 2 D e p a r t m e n t of Clinical O p h t h a l m o l o g y , Moorfields E y e Hospital, L o n d o n E C I V 2PD, U K
Abstract. The eye has traditionally been regarded as a sanctuary site for drugs, but recent publications have shown evidence of penetration by drugs and subsequent clinical response of intraocular lymphomas. In this report, a chemotherapy regimen, including high dose methotrexate and cytosine arabinoside, was used to re-induce remission in a patient with intraocular lymphoma relapsing locally after prior radiotherapy. She remains disease free 18 months later. Keywords: therapy
Ocular
lymphoma;
Radio-
INTRODUCTION Primary ocular (intraocular) lymphoma is a rare condition, but one whose natural history is now well documented. Margolis et al. [1] described the typical case as occurring in middle age, with a long interval (up to 5 years) between ocular symptoms and the establishment of the correct diagnosis. The disease 'masquerades' as chronic uveitis, but response to steroids is temporary. In this San Francisco review of 39 patients documented in the literature in 1980, 79% of patients had bilateral tumours (of great interest in view of the absence of orbital lymphatic connections between the two eyes) and 67% of patients developed CNS lymphoma. The CNS involvement was usually a solid lymphomatous mass (8/9 patients) in the cerebrum (7/8 patients), with only one having diffuse leptomeningeal dissemination. The prognosis for patients with CNS disease was universally and rapidly fatal. Interestingly, only 23% (9/39) of patients reviewed had developed systemic lymphoma. Margolis et al. [1] concluded that most patients with primary ocular lymphoma die of progression of the disease or CNS disease, despite good initial tumour regression to 'adequate' radiotherapy. The lymphoma is usually a large cell, B cell, non-Hodgkin's lymphoma. Qualman et al. [2] contributed more to
Correspondence and offprint requests to: Dr P. N. Plowman, Department of Radiotherapy, St Bartholomew's Hospital, London EC1A 7BE, UK.
the understanding of the 'CNS link'. They observed that ocular lymphomas with involvement of vitreous, sensory retina, subretinal pigment epithelial space or nerve head were more likely than those with solitary uveal involvement to lead to CNS disease. They further observed a preponderance of CNS mass lesions ipsilateral to the affected eye. In their histopathological analysis, Qualman and colleagues describe prominent perivascular cuffing of inflammatory and lymphoid cells in the region of the optic nerve, orbital meninges, optic chiasma and the meninges of the cerebral hemisphere behind. The authors propose that this is either part of the mechanism of the multicentricity or the method of spread. The high risk of CNS disease has led some authorities to recommend prophylactic radiotherapy to the brain. Our own experience with three patients with primary ocular lymphoma is that two relapsed with intracerebral masses of lymphoma. The third patient suffered intraocular relapse after primary radiotherapy, but was salvaged by a chemoradiotherapy programme based on our current understanding of drug penetration into the eye. This case history is presented in full before the main features of interest are discussed.
CASE HISTORY This lady presented, aged 57, with a history that 18 month earlier she had noticed flashing lights in the right eye. Five months later she had noted deteriorating vision in this eye and, with a clinical diagnosis of retinitis, she had been commenced on steroids. There had been a temporary response but, on subsequent deterioration, both cyclosporin and azathioprine had been administered. By 13 months after clinical presentation the patient's vision in her right eye was reduced to hand movements and she began to notice 'flashing lights' in the left eye. A choroido-retinal biopsy from the right eye showed a non-Hodgkin's large cell lymphoma. Staging procedures did not suggest disease outside the eyes. The patient received radiotherapy to both eyes by lateral 6 MV X-ray portals, to a dose of 3000 cGy in 15 fractions over 21 days. One month after treatment the vision was much
improved on the right although some 'flickering' continued to be noticed. Ophthalmologically there was complete regression. One year after the end of radiotherapy, the patient relapsed in the left eye with development of choroidal lesions. It was felt that, although further radiotherapy would be safe and necessary, it was unlikely to cure where it had failed before. Therapy therefore recommenced with chemotherapy and a novel multiagent regimen (Ara-CHOMP), built around standard CHOP with day 8 high/intermediate dosage methotrexate and cystosine arabinoside as soon as the white count recovered:Cyclophosphamide 750 mg/m 2 i.v. bolus D1 Adriamycin (doxorubicin) 50 mg/m 2 i.v. bolus D1 Vincristine 2.0 mg i.v. bolus D1 Prednisoline 100 mg/day oral (divided dosage) D I - D 5 Methotrexate 400 mg/m 2 i.v. infusion D8; folinic acid rescue at 24 hours Cytosine arabinoside 3 g/m2 i.v. very 12 hours x 2 doses on FBC recovery The above regimen was repeated and, after 2 completed cycles, ophthalmic review concluded complete clinical regression. The patient proceeded to retreatment of ocular radiotherapy to the left eye. Through an anterior cobalt portal an applied dose of 2000 cGy was delivered in 10 fractions over 12 days. The patient is now clinically disease free at 16 months from the end of treatment.
DISCUSSION Radiotherapy has been the gold-standard definitive treatment of primary ocular lymphoma following the good responses reported by Margolis et al. [1]. Total doses delivered varied between 1500 and 4500 cGy in the San Francisco series of 9 patients and the authors concluded that doses at the higher end of this range gave the best results, although local recurrence remained a problem. The dose prescription delivered to the patient reported here was the same as is routinely delivered to primary orbital (extraocular) lymphomas at this centre, and after which local relapse is extraordinarily unusual. In this respect, as with several
316 other discussions points that follow, intraocular lymphoma more closely resembles primary cerebral lymphoma, and perhaps a higher radiotherapy dose prescription should have been delivered in the first instance to both eyes. At the time of relapse, it seemed correct to try chemotherapy ~hd the choice to use this first was based on the failure after previous radiotherapy and the more certain ability to assess response to chemotherapy when used prior to radiation. Chemotherapy is traditionally said to have poor efficacy against intraocular tumours because, it is alleged, the eye shares the blood-brain barrier with the central nervous system. However, conventional multidrug systemic breast cancer chemotherapy has been noted to cause regression of choroidal metastases [3,4] and it is now well established that certain chemotherapeutic drugs, notably intermediate to high dose methotrexate [5] and cytosine arabinoside [6], show good penetration through the blood-brain barrier. Prior radiotherapy may disrupt the response of the blood-brain barrier to drugs, which is of possible relevance in this patient. In an interesting series of six patients with ocular lymphoma reported by Strauchan et al. [7], the authors explored
P . N . Plowman et al. the use of high dose cytosine arabinoside. Five responses were observed in their six patients, (and four of their patients were previously untreated). This report of a relatively large number of cases for this rare disease makes compelling reading and it was this work that encouraged us to include high dose ara-C into the multiagent chemotherapy regimen chosen for the patient presented here. This regimen was designed to include both high dose methotrexate and ara-C. Following 2 cycles of the ara-CHOMP regimen, our patient had complete clinical response of her relapsed lymphoma. She then received 20 Gy retreatment radiotherapy (from which alone one would not expect cure, as she had relapsed following 30 Gy, similar fractionated, within one year) and now remains in remission at 18 months from completion of therapy. We believe that the ara-CHOMP regimen has played an important part in her probable cure. It is also interesting to speculate that the ara-CHOMP has provided some prophylaxis against this patient's chances of developing CNS disease. It is even more interesting to speculate whether a regimen such as araCHOMP, with designed CNS/ocular penetration, might be usefully combined with
radiotherapy to improve the cure rates of the prognostically poor primary intracerebral lymphoma.
References 1. Margolis L, Fraser R, Lichter A, et al. The role of radiation therapy in the management of ocular reticulum cell sarcoma. Cancer 1980;45:688--92. 2. Qualman SJ, Mendelsohn G, Mann RB, et al. Intraocular lymphomas. Cancer 1983;52:87886. 3. Aasvad H, Seim V. Chemotherapy in intraocular metastasis from carcinoma of breast. Acta Ophthalmol 1974;123:Suppl 142. 4. BrinkleyJR. Response of a choroidal metastasis to multiple drug chemotherapy. Cancer 1980;45:1538-9. 5. Wang JJ, Freeman AI, SinksLF. Treatment of acute lymphocytic leukemia by high dose intravenous methotrexate. Cancer Res 1976;36:1441-4. 6. Slevin ML, Piall EM, Aherne GW, et al. Effect of dose and schedule on pharmacokinetics of high dose cytosine arabinoside in plasma and cerebrospinal fluid. J Clin Oncol 1983;1:546--51. 7. Strauchan JA, Dalton J, Friedman AH. Chemotherapy in the management of intraocular lymphoma. Cancer 1989;63:1918-21.
Received for publication April 1993 Accepted following revision July 1993