1Department of Radiochemotherapy, San Raffaele H Scientific Institute, Milan, Italy; 2Unité Cytokines et Cancers, Hopital E. Herriot et Centre Léon Bérard, Lyon, France; 3Divisione di Radioterapia, Ospedale di Circolo Fondazione Macchi, Varese, Italy; 4Divisione Clinicizzata di Oncologia Medica, Ospedale Civile Maggiore, Verona, Italy; 5Haematology and Intensive Care Department, Haematological Centre of Russian Academy of Medical Sciences, Moscow, Russia; 6Divisione of Medical Oncology A, Centro di Riferimento Oncologico, National Cancer Institute, Aviano, Italy; 7Institut für Medizinische Onkologie Inselspital, Bern, Switzerland; 8Istituto Oncologico della Svizzera Italiana, Ospedale San Giovanni, Bellinzona, Switzerland; 9Divisione di Ematologia, Ospedale Riuniti di Bergamo, Bergamo, Italy; 10Service de Pathologie, Centre Léon Bérard, Lyon, France; 11Divisione de Pathologie Clinique CMU, Hôpitaux Universitaires de Genève, Hôpital Cantonal, Genève, Switzerland; 12Service de Pathologie, Centre Hospitalier Lyon-Sud, Pierre Bénite, France; 13Department of Pathology, San Raffaele H Scientific Institute, Milan, Italy
Received 25 July 2002; revised 21 September 2001; accepted 5 October 2001.
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Abstract |
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Reported data regarding intraocular lymphoma (IOL) management are anecdotal. Cases of IOL included in an international multicentre series of 378 immunocompetent patients with primary central nervous system lymphomas (PCNSLs) were reviewed.
Patients and methods
Staging included slit-lamp examination in 170 patients: IOL was diagnosed in 22 cases (13%). A concomitant brain lesion was detected in 21 cases. Planned treatment was chemotherapy followed by radiotherapy in 13 cases, chemotherapy alone in three and radiotherapy, followed by or not by chemotherapy in five; one patient was not treated. Chemotherapy included high-dose methotrexate in 12 cases. Ten patients received intrathecal chemotherapy. Radiotherapy consisted of whole brain irradiation, followed by or not by a tumour bed boost; ocular irradiation was planned in 15 cases. Irradiation in one patient without brain lesions was limited to the orbits only (50 Gy).
Results
IOL was positively correlated to systemic symptoms and meningeal disease. Fifteen patients (71%) achieved an objective response; 16 patients experienced a failure (2-year failure-free survival 34 ± 10%). Failures involved the eyes in eight cases, with a 2-year time to ocular relapse of 59 ± 11%. Ocular failure was less common in patients treated with chemotherapy plus ocular irradiation and was associated with a significantly shorter survival. Seven patients are alive [median follow-up 53 months, 2-year overall survival (OS): 39 ± 11%], five of whom were treated with ocular irradiation. The patient with isolated IOL is alive and disease-free at 14 months. OS of the entire series was similar to that of PCNSL patients with negative slit-lamp examination.
Conclusions
IOL is usually associated with concomitant brain disease and shows a survival similar to that of the rest of PCNSLs. Chemotherapy combined with ocular irradiation resulted in better control of ocular disease, which seems to be associated with survival. In view of the potential role of ocular irradiation, the use of chemotherapy alone in phase II trials should be critically reconsidered in PCNSL patients with ocular disease.
Key words: chemotherapy, combined treatment, eye, intraocular lymphoma, ocular irradiation, primary central nervous system lymphoma
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Introduction |
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The optimal treatment for IOL remains to be defined. With the use of radiotherapy (RT) alone in symptomatic patients, almost all subjects developed early CNS progression and died [1113]. Promising anecdotal results in a few case reports and small retrospective series treated with chemotherapy (CHT) have been reported [6, 11, 12, 1417]. A small number of cases of IOL have also been included in prospective trials evaluating new strategies in PCNSL, with conflicting and disappointing outcomes [3, 18]. Ultimately, the efficacy of CHT is dependent on intraocular pharmacokinetics, which are not well understood [19].
This paper reports the clinical features, behaviour and therapeutic results of a series of 22 patients with IOL. These patients were identified in an international multicentre series of 378 immunocompetent patients with PCNSL. The analysis focuses on the clinical and therapeutic variables related to ocular disease control and the impact of ocular control on survival.
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Patients and methods |
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All but four patients (case Nos 1013) completed the planned treatment (Table 2). It had been planned that these patients were to receive CHTRT, but they were not irradiated due to early progression, toxic death (n = 2) or refusal. It had been planned for all four of these patients to receive ocular irradiation.
Statistical considerations
Response rates and clinical characteristics of the different groups of patients were compared using the 2 test or Fishers exact test for categorical variables, according to the sample size. Survival curves were generated by the KaplanMeier method. Overall survival (OS) was calculated from the date of histological diagnosis to death or last date of follow-up, while failure-free survival (FFS) was calculated from the first day of treatment to relapse, progression, death or to last date of follow-up. The time to ocular relapse was analysed with ocular failure as the event. Ocular failure was defined as residual disease, relapse or progression, associated or not with brain recurrence. Cerebral relapse or progression without concomitant ocular disease was considered censored for this analysis. Survival curves were compared through the log-rank test. All probability values were two-sided.
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Results |
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Objective response and relapse rates
Fifteen of 21 treated patients (71%) achieved an objective response (Table 2), which was complete in 13 cases (complete remission rate 62%). Four patients experienced progression and two died of toxicity during primary CHT. The two patients who had partial remission (case Nos 5 and 7) had residual disease in the brain, but not in the eyes. They had been treated with CHTRT, including ocular irradiation. Sixteen patients experienced a failure (Table 2): two toxic deaths (case Nos 11 and 13), four cases of progressive disease during treatment and 10 relapses after an initial objective response. Lymphoma involved the primary sites of disease in all failed cases: the brain in seven cases, brain plus eyes in six (including cases of toxic death), eyes in two and brain plus meninges in one. No cases of systemic dissemination were observed. Table 3 summarises the relapse rates and sites in patients grouped according to the result of the slit-lamp examination. The ocular relapse rate is clearly higher in IOL patients with respect to patients who had negative slit-lamp examination at diagnosis.
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Ocular disease control and OS
The patient with isolated IOL (case No. 19) was blind at diagnosis. He achieved a complete remission following the irradiation of the orbits with 50 Gy but without symptomatic improvement, and was relapse-free after 14 months from RT.
Ocular failure was detected among eight patients with concomitant brain and ocular lymphoma, with a 2-year time to ocular relapse of 59 ± 11%. Excluding the cases of toxic death, ocular failure was observed in one of the eight patients treated with combined CHT and RT with a field that included the eyes, in three of the eight patients treated with CHT with or without RT with a field that excluded the eyes and in both patients treated with RT with a field that included the eyes but without CHT (2; P = 0.09). The median time to ocular failure for these groups was 20, 15 and 2.5 months, respectively. The poor disease control observed in patients treated with RT alone does not seem to be attributable to bias selection since both patients were younger than 65 years and had ECOG performance status <2. Depending on which drug was used, ocular failure was observed in three of the six patients receiving HD-MTX and in one of the six patients treated with CHOP regimen, while none of the patients treated with a HD-MTXHD-cytarabine combination experienced an ocular relapse (
2; P = 0.09).
Seven patients are alive [six with no evidence of disease (NED)] with a median follow-up of 53 months (range 1296 months). Five of them had been treated with RT including ocular irradiation. Actuarial survival of the entire series was similar to those of PCNSL patients with negative slit-lamp examination results (2-year OS: 39 ± 11% compared with 42 ± 4%; P = 0.31; Figure 1). The detection of ocular relapse was associated with a shorter survival (2-year OS: 12 ± 11% compared with 55 ± 14%; P= 0.01). Excluding toxic deaths, five of the six patients with ocular relapse and seven of the 13 patients without ocular relapse died (2-year OS: 16: ± 15% and 55 ± 14%; P = 0.03). According to the therapeutic strategy, median OS was 47+, 9.5+ and 10 months, respectively for the eight patients treated with combined CHT and RT with a field that included the eyes, the 10 patients treated with CHT with or without RT with a field that excluded the eyes and the three patients treated with RT alone with a field that included the eyes.
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Discussion |
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The optimal treatment for IOL has not yet been defined. In the past, patients with symptomatic disease were treated with RT alone, but almost all patients developed early CNS progression and died, with a median OS of 20 months and a 2-year OS lower than 20% [1113]. A few case reports and small retrospective series alluded to the efficacy of CHT, and promising anecdotal results using HD-cytarabine, HD-MTX, procarbazine and nitrosoureas have been reported [6, 11, 12, 1417]. In six patients with IOL, including one case of ocular relapse from a systemic non-Hodgkins lymphoma, HD-cytarabine produced one complete and four partial responses [17]. Therapeutic levels in intraocular fluids and prolonged objective tumour regression following systemic high doses of this drug have been documented in a case of relapsed IOL [16]. The use of this drug in combination with ocular irradiation has been recommended in IOL patients [16]. In the present series, none of the four patients who completed the planned treatment, including HD-cytarabine-containing CHT, experienced ocular relapse, with a near significantly better ocular disease control with respect to the other drugs. However, no definitive conclusions could be drawn because these patients also received ocular irradiation as part of the first-line treatment. Data suggesting the efficacy of HD-cytarabine in IOL patients should be confirmed in larger series.
Some prospective trials evaluating new strategies in PCNSL included cases of IOL [18, 21, 2426]. In those series, IOL were managed like other PCNSLs, with only minor differences in the extent of RT field and dose. However, IOL cases have been analysed separately from the rest of PCNSLs cases in just a few series. The efficacy of CHT seems to be strongly conditioned by intraocular pharmacokinetics, which are not well understood. The intraocular concentrations of MTX and cytarabine after intravenous administration have been analysed in a few case reports, with conflicting results [16, 17, 27]. Four hours after an intravenous infusion of MTX 8 g/m2, the vitreous concentration of MTX was 100-fold lower than in the serum [19]. These difficulties in achieving therapeutic concentrations of MTX in the vitreous humour seem to be confirmed by clinical data. In fact, a 27% response rate and a 90% treatment failure rate after first-line CHT containing HD-MTX and/or cytarabine were reported [3]. In five patients with cerebral and ocular lymphoma treated with HD-MTX-containing CHT, despite the fact that brain lesions completely disappeared in all patients, persistent ocular disease was observed in two cases, and relapses involving the eyes were observed in the other two [18].
The poor results obtained with conventional CHT have prompted investigators to search for alternative approaches for IOL patients. HD-CHT followed by autologous bone marrow transplantation [3, 21] and intravitreal injections of MTX, with or without thiotepa [28], have been proposed. Intriguing results have been reported in five patients with relapsed IOL treated with HD-CHT with thiotepa, busulfan and cyclophosphamide and autologous bone marrow transplantation [3]. All five patients achieved a complete remission and were alive (three NED) after a median follow-up of 26 months. More recently, a median survival after relapse of 53+ months was reported in 11 patients with relapsed or refractory IOL treated with the same strategy [21]. On the other hand, promising results with reduced morbidity were reported in four patients treated with repeated intravitreal injections of MTX 400 µg [29].
The addition of RT, including the irradiation of both orbits with 30 Gy, to HD-MTX-based CHT has been associated with a higher response rate [26, 30]. Although most of these patients experienced an aggressive relapse involving brain and meninges, no cases of ocular recurrence were reported. In another series, 11 of 12 cases of IOL treated with different strategies developed brain disease with a median time between onset of IOL and onset of brain disease of 14 months (range 185 months) [7]. Five of these patients had been treated with ocular irradiation as a part of first-line treatment: one of them also received prophylactic whole brain RT and was relapse-free at 18 months; two patients relapsed in the eyes and, after 17 and 29 months, in the brain; and two had relapses only in the brain at 12 and 85 months from treatment. Median survival of patients treated with ocular irradiation at diagnosis was 19+ months compared with 37 months for the rest [7]. Ocular irradiation as exclusive salvage therapy also seems to be an effective approach in patients with recurrent IOL, with a median post-failure survival of 20+ months for 13 previously reported cases [7, 18, 31, 32]. Considering this and the above-mentioned difficulties in achieving intraocular therapeutic levels of the most commonly used drugs, RT has been proposed as the first-line therapy for IOL [19]. The irradiation of the posterior two-thirds of the ocular globes with a dose between 35 and 45 Gy has been recommended [5, 6]. Higher doses should not been used for treating the full bilateral orbits considering the potential risk of severe toxicity. More recent experiences suggest irradiation of the entire orbit up to 20 Gy, followed by an additional 10 Gy after shielding the anterior chambers of the eyes [26, 30]. Considering the high frequency of bilateral involvement, the irradiation of both eyes has been recommended, even in the presence of monolateral disease. In the present series, ocular irradiation was associated with a better ocular disease control. In particular, the combination of MTXcytarabine-containing CHT with ocular irradiation was associated with a lower ocular relapse rate, and the positive effect on ocular disease control of ocular irradiation suggests that it has a potential role in survival. In effect, the detection of ocular relapse was significantly associated with shorter survival compared with those patients without ocular failure. Considering the retrospective nature of the present study, no reliable data regarding ocular toxicity are available. However, in the authors experience [33], the irradiation of the posterior two-thirds of the eyes with 30 Gy has not been associated with a significant ocular toxicity in PCNSL patients.
Considering the presence of concomitant brain lesions, at either diagnosis or relapse, in the vast majority of IOL cases, and the similarity in clinical characteristics and survival between IOL patients and the rest of PCNSL cases, therapeutic management for IOL patients should follow the same guidelines used for other PCNSL patients. Despite the retrospective nature and the relatively small number of patients included in the present series, our results seem to suggest that the combination of CHT and RT with a field including the eyes could have a positive effect on ocular disease control, which is a limiting factor significantly associated with survival. It is noteworthy that the survival benefit related to ocular irradiation may be biased by the high incidence of concomitant brain failure, which is the most important recognised prognostic event in PCNSL. In conclusion, IOL patients should be treated with a HD-MTX-based CHT followed by irradiation of the whole brain with 3640 Gy and the posterior two-thirds of both eyes with 30 Gy and a standard fractionation.
Future advances in primary CHT improving brain disease control may permit a more objective evaluation of the potential role of irradiation of the eyes in PCNSL patients. This issue may gain major importance in modern phase II trials designed to assess the efficacy of CHT as exclusive treatment, to reduce the incidence of treatment-related neurotoxicity. In view of the difficulties of systemic CHT in obtaining remission in vitreous humor and the potential role of ocular irradiation, the use of CHT as exclusive treatment could be critically reconsidered in PCNSL patients with ocular disease.
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Acknowledgements |
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Footnotes |
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Members of the International Extranodal Lymphoma Study Group are listed in the Acknowledgements.
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References |
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![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2. Ferreri AJ, Reni M, Villa E. Primary central nervous system lymphoma in immunocompetent patients. Cancer Treat Rev 1995; 21: 415446.[ISI][Medline]
3. Soussain C, Merle-Beral H, Reux I et al. A single-center study of 11 patients with intraocular lymphoma treated with conventional chemotherapy followed by high-dose chemotherapy and autologous bone marrow transplantation in five cases. Leuk Lymphoma 1996; 23: 339345.[ISI][Medline]
4. Akpek EK, Ahmed I, Hochberg FH et al. Intraocularcentral nervous system lymphoma: clinical features, diagnosis, and outcomes. Ophthalmology 1999; 106: 18051810.[ISI][Medline]
5. Rockwood EJ, Zakov ZN, Bay JW. Combined malignant lymphoma of the eye and CNS (reticulum-cell sarcoma). Report of three cases. J Neurosurg 1984; 61: 369374.[ISI][Medline]
6. Qualman SJ, Mendelsohn G, Mann RB, Green WR. Intraocular lymphomas. Natural history based on a clinicopathologic study of eight cases and review of the literature. Cancer 1983; 52: 878886.[ISI][Medline]
7. Peterson K, Gordon KB, Heinemann MH, Deangelis LM. The clinical spectrum of ocular lymphoma. Cancer 1993; 72: 843849.[ISI][Medline]
8. Cassoux N, Merle-Beral H, Leblond V et al. Ocular and central nervous system lymphoma: clinical features and diagnosis. Ocul Immunol Inflamm 2000; 8: 243250.[ISI][Medline]
9. Ursea R, Heinemann MH, Silverman RH et al. Ophthalmic, ultrasonographic findings in primary central nervous system lymphoma with ocular involvement. Retina 1997; 17: 118123.[ISI][Medline]
10. ONeill BP, Illig JJ. Primary central nervous system lymphoma. Mayo Clin Proc 1989; 64: 10051020.[ISI][Medline]
11. Char DH, Ljung BM, Deschenes J, Miller TR. Intraocular lymphoma: immunological and cytological analysis. Br J Ophthalmol 1988; 72: 905911.[Abstract]
12. Freeman LN, Schachat AP, Knox DL et al. Clinical features, laboratory investigations, and survival in ocular reticulum cell sarcoma. Ophthalmology 1987; 94: 16311639.[ISI][Medline]
13.
Fine HA, Mayer RJ. Primary central nervous system lymphoma. Ann Intern Med 1993; 119: 10931104.
14. Whitcup SM, de Smet MD, Rubin BI et al. Intraocular lymphoma. Clinical and histopathologic diagnosis. Ophthalmology 1993; 100: 13991406.[ISI][Medline]
15. Siegel MJ, Dalton J, Friedman AH et al. Ten-year experience with primary ocular reticulum cell sarcoma (large cell non-Hodgkins lymphoma). Br J Ophthalmol 1989; 73: 342346.[Abstract]
16. Baumann MA, Ritch PS, Hande KR et al. Treatment of intraocular lymphoma with high-dose Ara-C. Cancer 1986; 57: 12731275.[ISI][Medline]
17. Strauchen JA, Dalton J, Friedman AH. Chemotherapy in the management of intraocular lymphoma. Cancer 1989; 63: 19181921.[ISI][Medline]
18. Sandor V, Stark-Vancs V, Pearson D et al. Phase II trial of chemotherapy alone for primary CNS and intraocular lymphoma. J Clin Oncol 1998; 16: 30003006.[Abstract]
19. Henson JW, Yang J, Batchelor T. Intraocular methotrexate level after high-dose intravenous infusion. J Clin Oncol 1999; 17: 1329.[ISI][Medline]
20. National Cancer Institute sponsored study of classifications of non-Hodgkins lymphomas: summary and description of a working formulation for clinical usage. The Non-Hodgkins Lymphoma Pathologic Classification Project. Cancer 1982; 49: 21122135.[ISI][Medline]
21. Soussain C, Suzan F, Hoang-Xuan K et al. Results of intensive chemotherapy followed by hematopoietic stem-cell rescue in 22 patients with refractory or recurrent primary CNS lymphoma or intraocular lymphoma. J Clin Oncol 2001; 19: 742749.
22. Wilson DJ, Braziel R, Rosenbaum JT. Intraocular lymphoma. Immunopathologic analysis of vitreous biopsy specimens. Arch Ophthalmol 1992; 110: 14551458.[Abstract]
23.
Whitcup SM, Chan CC, Buggage RR et al. Improving the diagnostic yield of vitrectomy for intraocular lymphoma. Arch Ophthalmol 2000; 118: 446.
24. Schultz C, Scott C, Sherman W et al. Preirradiation chemotherapy with cyclophosphamide, doxorubicin, vincristine, and dexamethasone for primary CNS lymphomas: initial report of Radiation Therapy Oncology Group Protocol 88-06. J Clin Oncol 1996; 14: 556564.[Abstract]
25.
Blay JY, Bouhour D, Carrie C et al. The C5R protocol: a regimen of high-dose chemotherapy and radiotherapy in primary cerebral non-Hodgkins lymphoma of patients with no known cause of immunosuppression. Blood 1995; 86: 29222929.
26. Glass J, Gruber ML, Cher L, Hochberg FH. Preirradiation methotrexate chemotherapy of primary central nervous system lymphoma: long-term outcome. J Neurosurg 1994; 81: 188195.[ISI][Medline]
27. Stark-Vancs V, Setser A, Kohler D et al. Combination chemotherapy in the treatment of primary central nervous system and intraocular lymphoma. Proc Am Soc Clin Oncol 1995; 14: A306 (Abstr).
28.
de Smet M, Vancs VS, Kohler D et al. Intravitreal chemotherapy for the treatment of recurrent intraocular lymphoma. Br J Ophthalmol 1999; 83: 448451.
29. Fishburne BC, Wilson DJ, Rosenbaum JT, Neuwelt EA. Intravitreal methotrexate as an adjunctive treatment of intraocular lymphoma. Arch Ophthalmol 1997; 115: 11521156.[Abstract]
30. Gabbai AA, Hochberg FH, Linggood RM et al. High-dose methotrexate for non-AIDS primary central nervous system lymphoma. Report of 13 cases. J Neurosurg 1989; 70: 190194.[ISI][Medline]
31. Sarazin M, Ameri A, Monjour A et al. Primary central nervous system lymphoma: treatment with chemotherapy and radiotherapy. Eur J Cancer 1995; 31A: 20032007.[Medline]
32. Shibamoto Y, Tsutsui K, Dodo Y et al. Improved survival rate in primary intracranial lymphoma treated by high-dose radiation and systemic vincristinedoxorubicincyclophosphamideprednisolone chemotherapy. Cancer 1990; 65: 19071912.[ISI][Medline]
33. Ferreri AJM, Reni M, DellOro S et al. Combined treatment with high-dose methotrexate, vincristine and procarbazine, without intrathecal chemotherapy, followed by consolidation radiotherapy for primary central nervous system lymphoma in immunocompetent patients. Oncology 2001; 60: 134140.[ISI][Medline]