Volume=20 36, Supplement=20 2, Pages S25-S34 (August = 2009)

6 of 10

ABSTRACT

FULL=20 TEXT

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Should Intra-cerebrospinal Fluid = Prophylaxis=20 Be Part of Initial Therapy for Patients With Non-Hodgkin = Lymphoma:=20 What We Know, and How We Can Find Out More

Ulrich Herrlingera 3D"Corresponding

, Michael Glantzb, = Uwe Schlegelc, = Christian Gisselbrechtd, = Franco Cavallie

Central nervous system (CNS)=20 involvement is a serious complication of non-Hodgkin = lymphoma (NHL),=20 with an extremely poor outcome. In most cases, relapse in = the CNS=20 manifests as leptomeningeal disease. The relatively short = interval=20 between the initial diagnosis of NHL and CNS involvement = implies=20 that seeding of the cerebrospinal fluid occurs early in the = natural=20 history of the disease and suggests a role for CNS = prophylaxis=20 during initial treatment. However, CNS prophylaxis in = patients with=20 aggressive NHL remains controversial because of the = relatively low=20 incidence of CNS recurrence (5%=E2=80=937%) in these = patients and lack of=20 consensus on the best therapies and protocols. Risk factors = for CNS=20 relapse in patients with aggressive NHL have been identified = and may=20 help define a subpopulation of patients for whom CNS = prophylaxis is=20 justified. Because of variation in current practice and a = paucity of=20 high-quality evidence, well-designed and controlled trials = are=20 needed to assess the benefits of prophylactic treatment in = such a=20 population. This article reviews the current role of CNS = prophylaxis=20 in patients with NHL and discusses issues in the conception, = design,=20 and execution of a clinical trial to elucidate the role of = CNS=20 prophylaxis in patients with aggressive = NHL.

Article Outline

=E2=80=A2 Abstract

=E2=80=A2 The=20 Impact of Intra-CSF Therapy in Patients With Aggressive = NHL

=E2=80=A2 PCNSL

=E2=80=A2 Limitations=20 and Considerations for a CNS Prophylaxis Trial in Patients = With=20 NHL

=E2=80=A2 Risk=20 Factors Determine Patient Population

=E2=80=A2 Availability=20 of Effective Therapies

=E2=80=A2 Choice=20 of Therapy and Randomization

=E2=80=A2 Assumptions=20 in Determining Benefits and Risks

=E2=80=A2 Conclusion

=E2=80=A2 References

=E2=80=A2 Copyright

Central nervous system (CNS) relapse = is a=20 highly morbid and generally fatal complication of = non-Hodgkin=20 lymphoma (NHL),1, 2, 3, 4 with = a median=20 survival after CNS disease diagnosis of 2.4 to 4.4 months.3, 4, 5, 6, 7, 8 CNS = involvement=20 can occur at any time during the clinical course of NHL, and = for 50%=20 of patients, the CNS is the site of first relapse following = complete=20 remission.3, 4, 9, 10, = 11 = The median=20 time from diagnosis to detection of CNS disease is less than = 1 year,=20 suggesting that seeding of the cerebrospinal fluid (CSF) = occurs=20 early in the course of the disease and that the CSF acts as = a=20 sanctuary for surviving tumor cells.3, 7, 8, 12 = Further=20 support for this hypothesis is provided by the frequent = presence of=20 malignant cells in the CSF at the time of initial diagnosis = both in=20 primary CNS lymphoma (PCNSL)13 = and in neural=20 NHL.2, 9, 14

The frequency of CNS recurrence = varies=20 according to the aggressiveness of the lymphoma, being = uncommon in=20 indolent lymphomas and frequent in very aggressive lymphomas = such as=20 Burkitt lymphoma and lymphoblastic lymphoma (Table 1).1, 4, 7, 8, 9, 11, = 15, = 16, = 17, = 18, = 19, = 20 In = recognition=20 of this variability in the frequency of CNS relapse, CNS = prophylaxis=20 is not administered in patients with indolent NHL, but it is = almost=20 always included as part of the primary treatment of = lymphoblastic=20 lymphoma and Burkitt lymphoma, where it has been shown to = reduce=20 relapse rates and improve survival.21, = 22, = 23, = 24, = 25 = Comparable=20 therapeutic benefits have not been conclusively demonstrated = in=20 patients with other aggressive NHL subtypes such as diffuse = large=20 B-cell lymphoma (DLBCL).2, 10, = 26, = 27, = 28 = Few published=20 studies are available to guide the management of patients = with NHL=20 with regard to CNS prophylaxis, and most of the existing = data are=20 limited by their retrospective nature. In addition, the = results of=20 these studies are conflicting and difficult to interpret = because of=20 wide variations among study populations and different = prophylactic=20 regimens (Table 2).3, 4, 5, 6, 7, 8, 11, = 12, = 29, = 30, = 31 = Furthermore,=20 some practitioners consider the overall frequency of CNS = relapse in=20 patients with aggressive NHL to be too low (approximately = 5%-7% for=20 DLBCL) to justify including a potentially toxic CNS = prophylactic=20 regimen as part of therapy for all patients.

Table 1.

Frequency of Central = Nervous=20 System Involvement in Non-Hodgkin Lymphoma=20 Subtypes


	NHL Subtype	Frequency of Lymphomatous Meningitis = (%)
	Indolent lymphoma7, 15, 16	0-<5
	DLBCL1, 4, 7, 8, 11, 15, 17, 18	=E2=88=BC5-7
	Lymphoblastic=20 and Burkitt lymphoma9, 19, 20	30-50

Abbreviations: NHL, = non-Hodgkin=20 lymphoma; DLBCL, diffuse large B-cell=20 lymphoma.

Table 2.

Central Nervous System = Relapses=20 in Patients With Aggressive Non-Hodgkin Lymphoma = (excluding=20 lymphoblastic lymphoma and Burkitt=20 lymphoma)


First Author, Year	N	Systemic Therapy	CNS Prophylaxis	CNS Relapse Rate (%)
van Besien, 19983	605	CHOP-like	None	4.5
Bos, 199811	193	CHOP	None	5.0
Zinzani, 19994	175	MACOP-B	None	5.2
Feugier, 20048	399	CHOP v = CHOP-R	None	5.0
Haioun, 20006	974	ACVBP	IT + HD MTX	1.6
Hollender, 20027	1220	CHOP-like	12 mg IT MTX (n =3D = 141)	4.2
Tilly, 200329	635	ACVBP + GELA Cons or = HDT/PBSCT=20 v CHOP	IT + HD MTX v = none	2.8 = vs 8.3
Boehme, 20075	1693	CHOP-like	Systemic = etoposide	2.2
Bj=C3=B6rkholm, = 200830	444	CNOP	12 mg IT MTX	6.5
Bernstein, 200812	899	ProMACE-CytaBOM and = m-BACOD	WBRT or 12 mg IT MTX + = IT=20 Ara-C 30 mg (n =3D 121)	2.8
Pfreundschuh,=20 200831	1217	CHOP-14 = R=20 v CHOP-14	15 mg IT = MTX	4.8

Abbreviations: CNS, = central=20 nervous system; NHL, non-Hodgkin lymphoma; CHOP, = regimen=20 consisting of cyclophosphamide, doxorubicin, = vincristine, and=20 prednisone; MACOP-B, regimen consisting of bleomycin,=20 cyclophosphamide, doxorubicin, leucovorin, = methotrexate,=20 prednisone, and vincristine; ACVBP, regimen consisting = of=20 doxorubicin, cyclophosphamide, vindesine, bleomycin, = and=20 prednisone; IT, intrathecal; MTX, methotrexate; GELA, = Adult=20 Lymphomas Study Group; Cons, consolidation; HDT/PBSCT, = high-dose chemotherapy with peripheral blood stem cell = transplant; HD, high-dose; CNOP, regimen consisting of = cyclophosphamide, mitoxantrone, prednisone, and = vincristine;=20 ProMACE-CytaBOM, regimen consisting of = cyclophosphamide,=20 doxorubicin, etoposide, cytarabine, bleomycin, = vincristine,=20 prednisone, and methotrexate; m-BACOD, regimen = consisting of=20 methotrexate, bleomycin, doxorubicin, = cyclophosphamide,=20 vincristine, and dexamethasone; WBRT, whole-brain=20 = radiotherapy.

Although patient and disease = characteristics=20 have been identified that define high-risk subpopulations = that may=20 warrant CNS prophylaxis, there is little agreement and large = practice variability with regard to the composition and = application=20 of prophylactic regimens.3, 5, 6, 7, 32, = 33 = For example, a=20 survey conducted among clinicians in the United Kingdom who = treat=20 NHL (N =3D 158) revealed little consensus regarding which = risk factors=20 needed to be present to warrant CNS prophylaxis.32 = The most=20 common reasons for initiating prophylaxis in this survey = were=20 involvement of paranasal sinuses (88%), testes (85%), = orbital=20 cavities (78%), or bone marrow (65%); stage IV disease = (34%); high=20 International Prognostic Index (IPI) score (21%); = involvement of=20 more than one extranodal site (16%); and high lactate = dehydrogenase=20 (LDH) (10%).32 = The majority=20 of respondents (90%) who did use prophylaxis employed = intrathecal=20 therapy; only 4% used prophylactic systemic chemotherapy.32 = Similar=20 variations in treatment practice were evident in a survey of = Canadian physicians (N =3D 77) that evaluated CNS = surveillance,=20 prophylaxis, and treatment of adult patients with NHL.33 = CNS=20 prophylaxis was most commonly used in patients with NHL = involving=20 the testes (45%) or epidural space (41%).33 A = higher=20 proportion of tertiary care physicians initiated = prophylactic=20 treatment when there was testicular (53%) or epidural (50%)=20 involvement compared with community oncologists (32% and = 26%,=20 respectively).33 = Intrathecal=20 therapy with methotrexate (MTX) or MTX in combination with=20 cytarabine was used by almost three quarters (74%) of = physicians.33 = Systemic=20 prophylaxis was used by 20% of physicians but always in = combination=20 with intrathecal prophylaxis. Clearly, evidence-based data = from=20 randomized, controlled trials are needed to clarify the role = of CNS=20 prophylaxis in patients with aggressive NHL.

The Impact of = Intra-CSF=20 Therapy in Patients With Aggressive NHL

PCNSL

PCNSL represents a special case of = DLBCL with=20 a neural origin, a very aggressive course, and almost = universal CNS=20 recurrence after treatment.34, = 35, = 36 = CNS relapse=20 often manifests as lymphomatous meningitis (LM) or LM in = association=20 with parenchymal involvement.13, = 37 = The exact=20 frequency of LM in PCNSL remains controversial. Estimates = vary=20 according to the diagnostic strategy used, ranging from 8% = when=20 assessed by magnetic resonance imaging (MRI)37 to = 18% when=20 assessed by lumbar puncture CSF cytology13 to = 78% when=20 assessed by ventricular CSF cytology.38 = There is=20 currently no universally accepted approach to therapy or = consensus=20 on CSF prophylaxis.35, = 39

Cranial irradiation combined with = chemotherapy=20 results in improved survival and extended time to recurrence = compared with radiotherapy alone, but radiation carries a=20 substantial risk of long-term neurotoxicity, especially in = patients=20 older than 60 years of age.40, = 41, = 42, = 43, = 44, = 45, = 46

Motivated by a desire to avoid the = delayed=20 toxic effects of radiation, several investigators have = studied the=20 benefits of chemotherapy alone.34, = 47, = 48, = 49, = 50 = Because=20 systemically administered high-dose MTX (1=E2=80=938 = g/m2) crosses the blood-brain = barrier (BBB)=20 and achieves therapeutic concentrations in the CSF,51 = systemic=20 chemotherapy with high-dose MTX as a single agent or in = combination=20 with other active agents (eg, corticosteroids, cytarabine, = thiotepa,=20 vincristine, cyclophosphamide, temozolomide, rituximab) has = become=20 the basis of PCNSL therapy.52

McAllister et al48 = reported that=20 among 74 patients with PCNSL treated with high-dose, = MTX-based (2.5=20 g/m2) = BBB-disruption=E2=80=93enhanced=20 chemotherapy, 65% (n =3D 48) achieved a complete response, = and the=20 median survival time was 40.7 months. No cognitive decline = occurred=20 in patients who continued to experience a complete response = after 1=20 year of therapy.48 = However, the=20 role of systemic chemotherapy alone in PCNSL is still = unclear. A=20 prospective trial in which 37 patients with PCNSL received = high-dose=20 MTX (8 g/m2) was terminated = due to a=20 low complete response rate (30%).49 = The overall=20 median survival in this study was 25 months.50 = Other=20 investigators have reported complete response rates of 52% = and 65%=20 with similar treatment.34, = 53 = Conversely, a=20 study that combined both systemic and intra-CSF treatment = reported a=20 79% complete response achieved in 14 immunocompetent = patients with=20 PCNSL.47 = Patients were=20 treated with a combination of high-dose MTX (8.4 g/m2), thiotepa, vincristine, and=20 dexamethasone and intrathecal cytarabine (15=E2=80=9350 mg) = and MTX (12=20 mg).

The multicenter Bonn Protocol, the = largest=20 prospective study to date in patients with PCNSL, was = designed to=20 assess whether targeting the CSF during initial therapy for = PCNSL=20 with an intensified chemotherapy-only regimen would result = in=20 durable tumor response while avoiding neurotoxicity.54, = 55 = Frequent=20 administration of low-dose intraventricular chemotherapy=20 (concentration =C3=97 time approach) via Ommaya reservoir, = which produces=20 a more uniform and constant drug concentration in the CSF, = was=20 employed.56 = Patients with=20 newly diagnosed PCNSL (N =3D 65) were enrolled in a pilot = phase II,=20 open-label study.54, = 55 = High-dose MTX-=20 (5 g/m2) and cytarabine- (3 = g/m2) based systemic therapy, also = including=20 vincristine (2 mg), ifosfamide (800 mg/m2), and dexamethasone (10 = mg/m2), was combined with = intraventricular MTX=20 (3 mg), cytarabine (30 mg), and prednisolone (2.5 mg) (Table 3).55 = The median age=20 of patients was 62 years (range, 27=E2=80=9375), and their = median Karnofsky=20 performance score (KPS) was 70 (range, 20=E2=80=9390). = Follow-up was 0 to 87=20 months (median, 26 months). Median event-free survival = (EFS), the=20 primary study end point, was 21 months, and overall survival = was 50=20 months. The overall response rate was 71%, with 61% of = patients=20 achieving a complete response and 10% achieving a partial=20 response.55 = Nineteen=20 percent of patients progressed during therapy, and 8% of = patients=20 died of treatment-related causes.

Table 3.

Bonn Chemotherapy = Protocol for=20 Primary Central Nervous System=20 Lymphoma


Chemotherapy	Day
1	2	3	4	5	6	7
Cycle A
Systemic:
Methotrexate IV (5 g/m2)	+
Vincristine IV (2 mg)	+
Ifosfamide IV (800 mg/m2)		+	+	+	+
Dexamethasone PO (10 mg/m2)		+	+	+	+
Intraventricular:
Prednisolone ICV (2.5 mg)	+	+	+	+
Methotrexate ICV (3 mg)	+	+	+	+
Ara-C ICV (30 mg)					+
Cycle B
Systemic:
Methotrexate IV (5 g/m2)	+
Vincristine IV (2 mg)	+
Cyclophosphamide IV (200 mg/m2)		+	+	+	+
Dexamethasone PO (10 mg/m2)		+	+	+	+
Intraventricular:
Prednisolone ICV (2.5 mg)	+	+	+	+
Methotrexate ICV (3 mg)	+	+	+	+
Ara-C ICV (30 mg)					+
Cycle C
Systemic:
Ara-C IV (3 g/m2)	+	+
Vindesine IV (5 mg)	+
Dexamethasone PO (20 mg/m2)			+	+	+	+	+
Intraventricular:
Prednisolone ICV (2.5 mg)			+	+	+	+
Methotrexate ICV (3 mg)			+	+	+	+
Ara-C ICV (30 mg)							+

NOTE. Treatment = consisted of six=20 chemotherapy cycles separated by intervals of 2 weeks = between=20 each cycle. Cycle A was given on days 1=E2=80=935 and = 64=E2=80=9368, cycle B=20 was given on days 2=E2=80=9326 and 85=E2=80=9389, and = cycle C was given on=20 days 43=E2=80=9349 and 106=E2=80=93112. The protocol = was modified in the=20 multicenter phase 2 study: no ICV therapy was given on = day 1=20 of cycles A and B, and systemic methotrexate was = reduced to 3=20 g/m2 in patients = older than 64=20 years of age.

Abbreviations: CNS, = central=20 nervous system; Ara-C, cytarabine; ICV,=20 intracerebroventricular; IV, intravenous; PO, = orally.

Reprinted with = permission.54=20 Copyright =C2=A9 2003 American Society of Clinical = Oncology. All=20 rights = reserved.

As in other trials, a markedly = better clinical=20 outcome was observed in younger patients (=E2=89=A460 years = of age, n =3D 30).=20 Kaplan-Meier estimates for median overall survival, = progression-free=20 survival, and EFS have not yet been reached for these = patients.55 = The overall=20 response rate in the younger population was 86%, with = complete=20 responses and partial responses achieved in 76% and 10% of = patients,=20 respectively. Disease progression during treatment occurred = in 7% of=20 patients, and early death occurred in 7%. Older patients = (>60=20 years of age, n =3D 35) had a median EFS of only 15 months = and a=20 median overall survival of 34 months. The 5-year survival = was 75% in=20 patients =E2=89=A460 years of age and 19% in those >60 = years of age.55 = Results from=20 this study suggest that a chemotherapy-only regimen based on = high-dose and intra-CSF MTX and cytarabine is effective in = younger=20 patients with PCNSL and frequently results in long-term = remission=20 and even cure in some patients. These data compare favorably = with=20 the best results reported in combined chemotherapy and = radiotherapy=20 trials43, = 45 = and other=20 poly-chemotherapy trials.47, = 48

No chemotherapy-related = neurotoxicity was=20 observed in patients at follow-up, and systemic toxicity was = mainly=20 hematologic (ie, leukopenia and thrombocytopenia). Infection = of the=20 Ommaya reservoir occurred in 19% of patients,55 a = rate higher=20 than has been reported in other series.40, = 47, = 57, = 58 = Although=20 infection was managed, it resulted in treatment interruption = or=20 delay.55 = The=20 investigators postulated that the numerous intraventricular=20 injections required by the protocol, therapy-induced=20 myelosuppression, and the immunocompromised status of some = patients=20 may have contributed to the high infection rate.55 In = light of=20 this, and because other studies suggested that intrathecal = MTX did=20 not improve survival in patients with PCNSL receiving = systemic=20 high-dose MTX,59, = 60 = the=20 investigators decided to omit intraventricular treatment in=20 subsequent cohorts of patients (modified Bonn protocol).61

Fifty patients were enrolled in the = modified=20 Bonn protocol study, of whom 35 were evaluable for = response.61 = The median=20 follow-up was 9 months (range, 1=E2=80=9326 months). = Response rates were=20 comparable to those obtained in the original Bonn protocol; = however,=20 omitting intraventricular therapy resulted in a = significantly=20 shorter median progression-free survival than that in the = original=20 protocol.61, = 62 = Assessment of=20 KPS, LDH levels, and CSF protein at diagnosis63 = indicated that=20 study populations were balanced with regard to these = prognostic=20 factors.61, = 62 = The results=20 from these two trials strongly suggest a benefit from = including=20 intra-CSF therapy in the initial treatment of PCNSL and = support the=20 assumption that targeting the CSF is necessary to achieve = sustained=20 remission. These data also suggest that, when active therapy = is=20 completed, the CSF may act as a reservoir for surviving = tumor cells=20 that may repopulate the CNS or extraneural loci and lead to=20 relapse.

While the examples provided by the = PCNSL=20 studies suggest an important role for intra-CSF prophylaxis = in=20 patients with NHL, they do not provide indisputable evidence = of its=20 benefit. Trials specifically designed to elucidate the role = of CNS=20 prophylaxis in patients with NHL are needed.

Limitations and = Considerations=20 for a CNS Prophylaxis Trial in Patients With = NHL

Key considerations in the design and = execution=20 of a CNS prophylaxis trial include the factors used to = select=20 patients at high risk of CNS relapse, the choice of = prophylactic=20 regimen, and the overall risks and benefits of prophylaxis = in=20 patients with NHL.

Risk Factors = Determine Patient=20 Population

Because of the relatively low = incidence of CNS=20 involvement in patients with NHL, = =E2=80=9Cenriching=E2=80=9D the trial population=20 with patients at higher risk for developing CNS involvement = is=20 necessary to prevent overtreating the population not at = risk. The=20 two most important independent predictors of CNS disease, = identified=20 by multivariate regression analysis of large series of = patients with=20 NHL, are the presence of more than one extranodal site = (relative=20 risk [RR], 2.9=E2=80=935.5] and elevated LDH [RR, = 2.1=E2=80=937.0]) (Table 4).3, 5, 6, 7 van = Besien and=20 colleagues3 = identified a=20 group of patients for whom the cumulative risk of CNS = relapse was=20 20%. Hollender and colleagues7 = retrospectively=20 identified three additional independent risk factors that = conferred=20 a higher risk of CNS disease among 1,220 patients: young age = (<60=20 years) [RR, 2.8], serum albumin <3.5 g/L [RR, 2.5], and=20 retroperitoneal lymph node involvement [RR, 1.9].7 = Increasing the=20 number of risk factors considerably increased the chance of = CNS=20 relapse. Patients with four or five risk factors represented = 12% of=20 the patients with NHL in this study and 54% of those with = relapse=20 (Table 5).7

Table 4.

Relative Risk of = Central Nervous=20 System Relapse Associated With Prognostic Factors = Identified=20 in Multivariate = Analyses


First Author, Year	Increased LDH	>1 Extranodal Site	IPI	Age <60 Years	Albumin <3.5 g/L	Retroperitoneal Lymphadenopathy
van Besien, 19983	RR, 7.0; 95% CI, = 2.0=E2=80=9338.0;=20 P=3D.0008	RR, 5.5; 95% CI, = 2.1=E2=80=9314.9;=20 P=3D.0005	=E2=80=94	=E2=80=94	=E2=80=94	=E2=80=94
Haioun, 20006	RR, 5.0; P=3D.05	RR, 3.0; P=3D.05	RR, 7.0;=20 P=3D.002	=E2=80=94	=E2=80=94	=E2=80=94
Boehme, 20075	RR, 3.7; 95% CI, = 1.8=E2=80=937.5;=20 P <.001	RR, 2.9; 95% CI, = 1.5=E2=80=935.9;=20 P=3D.002	=E2=80=94	=E2=80=94	=E2=80=94	=E2=80=94
Hollender,=20 20027	RR, 2.1; = 95% CI,=20 1.0=E2=80=934.4; P=3D.049	RR, 3.0; = 95% CI,=20 1.7=E2=80=935.4	=E2=80=94	RR,=20 2.8; 95% CI, 1.5=E2=80=935.4; P=3D.002	RR,=20 2.5; 95% CI, 1.3=E2=80=934.6; P=3D.005	RR,=20 1.9; 95% CI, 1.0=E2=80=933.5; P=3D.037

Abbreviations: CI, = confidence=20 interval; CNS, central nervous system; LDH, lactate=20 dehydrogenase; IPI, International Prognostic Index; = RR,=20 relative risk.

LDH =E2=89=A5450 U/I = v <450=20 U/I.

Table 5.

Probability of Central = Nervous=20 System Relapse According to the Number of Risk Factors = Present


No. of Risk Factors	% of Population	Probability of CNS Recurrence Within 5 = Years, %=20 (95% CI)
0	13.3	1.9(0=E2=80=934.6)
1	30.5	2.0(0.4=E2=80=933.6)
2	26.7	2.8(0.5=E2=80=935.2)
3	17.3	6.2(1.9=E2=80=9310.5)
4	9.8	25.3(14.8=E2=80=9335.8)
5	2.5	32.7(11.6=E2=80=9353.8)

Abbreviations: CNS, = central=20 nervous system; CI, confidence interval.

Adapted with = permission.7 =C2=A9 2002=20 European Society for Medical=20 Oncology.

These studies indicate that it is = possible to=20 select patients with NHL and a high risk of developing CNS=20 disease=E2=80=94high enough, perhaps, to justify inclusion = in a CNS=20 prophylaxis trial. However, the higher the likelihood of = developing=20 the disease in a population, the smaller the fraction of the = population one is left with, resulting in study design = issues of=20 sample size and generalizability (Table 5).7

Availability of = Effective=20 Therapies

The therapeutic benefit of CNS = prophylaxis has=20 been clearly demonstrated in the very aggressive NHLs = (lymphoblastic=20 lymphoma and Burkitt lymphoma).21, = 22, = 23, = 24, = 25 = However, most=20 studies assessing the therapeutic value of CNS prophylaxis = in NHL=20 are retrospective in nature, and the results are = conflicting.

In their retrospective analysis of = 1,693=20 patients with aggressive lymphoma, Boehme and colleagues5 = reported a 2.2%=20 frequency of CNS relapse. Of note, CNS prophylaxis was = administered=20 to fewer than 5% of patients.5 In = another=20 retrospective analysis of 68 patients with aggressive NHL in = complete remission following systemic chemotherapy, = significantly=20 fewer patients who received prophylactic treatment with = intra-CSF=20 MTX and hydrocortisone experienced CNS relapse compared with = patients who did not receive prophylactic treatment (0% = v=20 15%; P =3D .03).64 = The absence of=20 prophylaxis was identified by multivariate regression = analysis as a=20 significant factor for CNS relapse (P =3D .01; RR, = 0.0000006).=20 Overall 5-year survival rates were 80% in the group that = received=20 prophylaxis, compared with 58% for those who did not = (P =3D=20 .05).64 A=20 retrospective analysis by Haioun and colleagues6 = showed a low=20 (1.6%) rate of isolated CNS relapse among 974 patients with=20 aggressive NHL in complete remission following treatment = with=20 systemic chemotherapy (ACVBP regimen [doxorubicin, = cyclophosphamide,=20 vindesine, bleomycin, prednisone]) combined with intra-CSF = and=20 systemic high-dose MTX. In a prospective, randomized study, = older=20 patients (61=E2=80=9369 years of age) with high-risk = aggressive NHL were=20 treated with an ACVBP regimen that included CNS prophylaxis = with=20 intra-CSF MTX and two courses of systemic high-dose MTX (n = =3D 323) or=20 standard CHOP (cyclophosphamide, doxorubicin, vincristine,=20 prednisone) (n =3D 312).29 = Nine patients=20 exhibited CNS progression in the ACVBP group, compared with = 26=20 patients in the CHOP group [RR, 2.99; P =3D .002].29 At = 5 years,=20 EFS and overall survival rates were significantly higher for = those=20 who received prophylaxis (39% and 46%) compared with those = who did=20 not (29% [P =3D .005] and 38% [P =3D .036],=20 respectively).29 In = contrast, a=20 20-year follow-up analysis of CNS relapse in patients with=20 aggressive NHL retrospectively compared high-risk patients = (those=20 with large cells in their pretreatment bone marrow biopsy) = who=20 received prophylactic intra-CSF MTX and cytarabine on an = m-BACOD=20 regimen (methotrexate, bleomycin, doxorubicin, = cyclophosphamide,=20 vincristine, dexamethasone) or prophylactic cranial = irradiation on a=20 ProMACE (prednisone, methotrexate, doxorubicin, = cyclophosphamide,=20 etoposide)=E2=80=93CytaBOM (cytarabine, bleomycin, = vincristine, prednisone)=20 regimen with patients on regimens that did not incorporate = CNS=20 prophylaxis.12 = This analysis=20 found that patients who had received any form of CNS = prophylaxis did=20 not experience a significantly lower rate of CNS relapse = than=20 patients who received no prophylaxis (2.8% v 3.6%,=20 respectively; P =3D .74),12 = but overall=20 CNS relapse rates were low in this trial compared with other = studies, and one of the CNS prophylaxis regimens (cranial=20 irradiation) was not sufficient to sterilize the entire CSF=20 space.

The use of systemic and/or intra-CSF = MTX=20 provides CNS prophylaxis that is safe, feasible, and = possibly=20 effective. Other intra-CSF therapies useful in the = treatment, and=20 perhaps in the prevention, of LM include cytarabine, = liposomal=20 cytarabine, thiotepa, and rituximab.65 = Because CNS=20 relapse is often meningeal,3, 7, 8 = further=20 discussion of a trial investigating CNS prophylaxis will = focus on=20 leptomeningeal metastases in NHL.

Choice of Therapy = and=20 Randomization

Conventional intra-CSF therapy for = the=20 treatment of LM consists of MTX, cytarabine, liposomal = cytarabine,=20 or thiotepa administered by lumbar puncture or via an Ommaya = reservoir. However, since MTX, cytarabine, and thiotepa have = short=20 half-lives within the CSF (MTX, 4.5=E2=80=938 hours; = cytarabine, 3.4 hours,=20 thiotepa, 3=E2=80=935 minutes),66, = 67, = 68 = frequent=20 administration is needed to maintain cytotoxic drug = concentrations=20 in the CSF. Numerous intralumbar injections may = substantially=20 compromise patients' well-being and may not be appropriate = in the=20 context of prophylaxis.

Liposomal cytarabine, a = lipid-encapsulated=20 chemotherapeutic agent, produces sustained cytotoxic = concentrations=20 of free cytarabine in both the ventricular and lumbar CSF = (>14=20 days in most patients), decreasing the need for repeated=20 injections.69 = Clinical=20 trials have demonstrated that the resulting prolonged tumor = exposure=20 to cytotoxic levels of free cytarabine improves response in = patients=20 with leptomeningeal disease.70 In = a=20 randomized, controlled trial, patients with LM were = randomized to=20 receive liposomal cytarabine 50 mg once every 2 weeks (n =3D = 14) or=20 unencapsulated cytarabine 50 mg twice a week (n =3D 14) for = 1 month of=20 induction therapy.70 = Responders=20 received an additional 3 months of consolidation therapy = followed by=20 4 months of maintenance therapy. Response to treatment was = defined=20 as CSF cytology conversion from positive to negative at all=20 previously positive sites, and neurological stabilization. = The=20 response rate in patients treated with liposomal cytarabine = was=20 significantly higher compared with that in patients treated = with=20 unencapsulated cytarabine (71% v 15%, respectively; = P=20 =3D .006).69 = These results=20 indicate that liposomal cytarabine may be another viable = agent for=20 investigation in a CNS prophylaxis trial.

Randomization in an LM prophylaxis = trial=20 remains complicated. A logical randomization would be = between=20 liposomal cytarabine=E2=80=94or another intra-CSF agent such = as cytarabine=20 or thiotepa=E2=80=94and no CSF treatment. The ethical basis = to support a =E2=80=9Cno=20 treatment=E2=80=9D arm includes the wide variation in = current practice=20 together with the potential morbidity of treatment and the = lack of=20 randomized controlled trial data, providing true clinical = equipoise.=20 Since there is some, albeit disputable, evidence that = prophylaxis is=20 effective, some might argue that the only ethical = randomization=20 would be between liposomal cytarabine and another CSF-active = regimen=20 (eg, high-dose intravenous MTX, intra-CSF MTX, or = cytarabine).=20 Because of sample size constraints, only a non-inferiority=20 randomized trial could be considered, the ethics of which = would rest=20 on the expectation that liposomal cytarabine might be more = tolerable=20 (fewer administrations) and possibly more effective. The = most=20 practical type of study, in terms of study size, would be a = phase II=20 model: a randomized phase II or single-arm trial with = pre-planned=20 historical comparisons, or a single-arm mini-max = design.

Assumptions in = Determining=20 Benefits and Risks

Even with an enriched trial = population based=20 on high-risk characteristics, placing a patient with no CNS = disease=20 on potentially toxic chemotherapy remains an important=20 consideration. The benefit-to-risk ratio in the setting of a = clinical trial (toxicity v efficacy) must therefore = be=20 considered. One strategy for quantifying this trade-off is = to=20 compare the number of patients needed to treat (NNT) to = prevent one=20 case of CNS relapse with the number needed to harm = (NNH)=E2=80=94the number=20 of patients required to receive treatment in order to result = in one=20 treatment-related adverse event. On the basis of available = studies,=20 we estimated the NNT and NNH for a potential CNS prophylaxis = trial=20 in patients with DLBCL using the following assumptions:

=E2=80=A2The efficacy of=20 prophylaxis will at least equal that observed in studies of=20 treatment of actual leptomeningeal = disease.

=E2=80=A2The toxicity of=20 prophylaxis will not be worse than in patients who are = treated for=20 overt leptomeningeal disease.

=E2=80=A2Only grade 3=20 and 4 toxicities are = considered.

The range of NNT and NNH calculated = using=20 these assumptions fell within the range usually considered=20 acceptable in other disease models (Table 6).

Table 6.

Potential Risk and = Benefit of=20 Central Nervous System Chemoprophylaxis in Non-Hodgkin = Lymphoma


% of Population in Whom LM Develops	No. Needed to Treat	No. Needed to Harm	Odds Ratio (95% CI)
100	1.4	3.5	=E2=80=94
50	3.0	3.6	5.2(1.1=E2=80=9325.4)
30	4.6	3.6	4.7(1.3=E2=80=9316.5)
25	5.7	3.6	4.2(1.3=E2=80=9314.2)
20	7.0	3.5	4.0(1.3=E2=80=9311.9)
15	9.2	3.5	4.0(1.3=E2=80=9312.6)
10	13.6	3.5	3.9(1.4=E2=80=9311.0)
6	24.0	3.5	3.5(1.4=E2=80=938.5)

Abbreviations: LM, = lymphomatous=20 meningitis; CI, confidence=20 interval.

Based on these considerations, we = propose a=20 study in patients with DLBCL with increased LDH and more = than one=20 extranodal site, or patients with DLBCL and disease at = specific=20 anatomic sites that convey a high risk of CNS relapse (eg = testicular=20 or ocular lymphoma and patients with large cell involvement = of bone=20 marrow). Patients with known brain or CSF metastases at = diagnosis=20 would be excluded. Eligible patients would be randomized to = an=20 R-CHOP-like regimen (rituximab, cyclophosphamide, = vincristine,=20 doxorubicin, prednisone) with or without intra-CSF liposomal = cytarabine. Since most CNS relapses occur within 1 year of=20 diagnosis, the 2-year CNS relapse rate would constitute a=20 scientifically sound and logistically practical primary end = point.=20 EFS, site of disease recurrence, time to neurologic = progression, and=20 overall survival could be assessed as secondary efficacy = outcomes.=20 Alternatively, patients matching these high-risk profiles = could be=20 randomized using a phase II =E2=80=9Cpick the = winner=E2=80=9D model, to one of the=20 two treatment arms described above, both of which would then = be=20 compared independently to a prespecified historical control = arm. Table 5 in Smith and Glantz's article = elsewhere=20 in this supplement provides sample size estimates for = various=20 response assumptions, and =CE=B1 and power choices for these = two=20 randomized trial models, and for a single-arm phase II model = with an=20 historical comparison.

Conclusion

CNS relapse, including = leptomeningeal=20 metastasis, is a generally fatal complication of NHL. = Despite the=20 relatively low frequency of relapse, the devastating effects = of LM=20 can justify treating patients at high risk of relapse=20 prophylactically. Because CSF invasion appears to be an = early event=20 in patients with DLBCL, and because untreated CSF lymphoma = may=20 provide a reservoir of malignant cells that can reseed tumor = both=20 throughout the CNS and systemically, targeting the CSF may=20 constitute an important part of the primary treatment = regimen for=20 patients with aggressive NHL. A number of studies have = provided=20 evidence suggesting that prophylaxis is beneficial in these=20 patients, but due to their retrospective nature as well as=20 variations in protocols, target patients, and therapies = used,=20 incontrovertible proof remains elusive. The availability of = multiple=20 agents that are effective in treating LM should encourage=20 investigators to study the efficacy of these agents in = prophylaxis=20 in well-designed and well-controlled clinical=20 trials.

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69.=20 69Phuphanich S, Maria B,=20 Braeckman R, Chamberlain M. A pharmacokinetic study of intra-CSF=20 administered encapsulated cytarabine (DepoCyt) for the = treatment of=20 neoplastic meningitis in patients with leukemia, lymphoma, = or solid=20 tumors as part of a phase III study. J = Neurooncol.=20 2007;81:201=E2=80=93208. CrossRef=20

70.=20 70Glantz MJ, LaFollette S,=20 Jaeckle KA, Shapiro W, Swinnen L, = Rozental JR,=20 et al. Randomized trial=20 of a slow-release versus a standard formulation of = cytarabine for=20 the intrathecal treatment of lymphomatous meningitis. = J Clin=20 Oncol. 1999;17:3110=E2=80=933116.

a Division of Clinical Neuro-oncology, = Department=20 of Neurology, University of Bonn, Bonn, Germany

b Department of Neurosurgery, Penn = State Hershey=20 Medical Center, Hershey, PA

c Department of Neurology,=20 Knappschaftskrankenhaus, Bochum, Germany

d Hematology Institute, Saint-Louis = Hospital,=20 Paris, France

e Oncology Institute of Southern = Switzerland,=20 Bellinzona, Switzerland

Address = correspondence=20 to Ulrich Herrlinger, MD, Division of Clinical = Neuro-oncology,=20 Department of Neurology, University of Bonn, = Sigmund-Freud-Str. 25,=20 D-53105 Bonn, Germany

STATEMENT OF CONFLICT OF = INTEREST:=20 U.H. received speakers and advisory honoraria from = Mundipharma. M.G.=20 has received honoraria and research support from Enzon=20 Pharmaceuticals. The other authors have nothing to=20 disclose.

PII: S0093-7754(09)00094-3

doi:10.1053/j.seminoncol.2009.05.004

=C2=A9 2009 = Published by=20 Elsevier Inc.

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