Treatment strategies for nodal and gastrointestinal follicular lymphoma: Current status and future development

Table 1 Lugano staging classification of gastrointestinal tract lymphoma[29]

Stage
I	Tumor confined to GI tract
	Stage primary site or multiple, noncontiguous lesions
II	Tumor extending into abdomen from primary GI site
	Nodal involvement
II1	Local (paragastric in cases of gastric lymphoma and paraintestinal for intestinal lymphoma)
II2	Distant (mesenteric in the case of an intestinal primary; otherwise paraaortic, paracaval, pelvic, inguinal)
IIE	Penetration of serosa to involve adjacent organs or tissues [enumerate actual site of involvement, e.g. IIE (pancreas), IIE (large intestine), IIE (post intestinal wall)]
	Where there is both nodal involvement and penetration involving adjacent organs, the stage is denoted using both a subscript (1 or 2) and E, e.g. II1E (pancreas)
IV	Disseminated extra-nodal involvement, or a GI tract lesion with supradiaphragmatic nodal involvement

GI: Gastrointestinal.

Table 2 Results of different randomized trials comparing chemotherapy with chemotherapy plus rituximab in previously untreated patients with follicular lymphoma

Study	No. of patients, pathological types, staging	Median age (yr)	Complete response rate	End point
				Median progression-free survival	Event-free survival	Median response duration	Time to treatment failure	Overall survival
CVP[40]	n = 321, FL, Stage II-IV	52	P < 0.0001b			P < 0.0001b	P < 0.001b	P = 0.029a
R-CVP	n = 162	Unknown	41%	34 mo		Prolonged than CVP alone (lower relapse rate than CVP alone)	Prolonged than CVP alone	83% (at 4 yr)
CVP	n = 159	Unknown	11%	15 mo				77% (at 4 yr)
GLSG[38,39]	n = 428, FL, Stage III or IV(advanced stage)	55	P > 0.05 (not significant)			P = 0.001b	P < 0.001b	P = 0.016a
R-CHOP	n = 223	54	20%	Not reached		Lower relapse rate than CHOP alone	28/233 (12.0%)	95% (at 2 yr)
CHOP	n = 205	57	17%	31 mo			61/205 (29.8%)	90% (at 2 yr)
FL2000[41]	n = 358, FL, 89% > stage II	61	P = 0.001b		P = 0.001b	P = 0.012a		P > 0.05 (not significant)
R-CHVP/IFN	n = 175	Unknown	67% (at 18 mo)	Not reached	53% (at 5 yr)	64% (at 4 yr)		84% (at 5 yr)
CHVP/IFN	n = 183	Unknown	50% (at 18 mo)	35 mo	37% (at 5 yr)	44% (at 4 yr)		79% (at 5 yr)
OSHO[42]	n = 201, FL, Stage II and IV	59	P = 0.0004b	P < 0.0001b	P < 0.0001b	P < 0.0001b		P = 0.0096b
R-MCP	n = 105	60	52/105 (50%)	Not reached	Not reached	Not reached		87% (at 4 yr)
MCP	n = 96	57	25/96 (25%)	28.8 mo	26 mo	35 mo		74% (at 4 yr)

^aP < 0.05,

^bP < 0.01, statistically significant. (R-)CVP: (Rituximab plus) cyclophosphamide, vincristine, and prednisone; FL: Follicular lymphoma; GLSG: German Low-Grade Lymphoma Study Group; (R-)CHOP: (Rituximab plus) cyclophosphamide, doxorubicin, vincristine, and prednisone; (R-)CHVP/IFN: (Rituximab plus) cyclophosphamide, adriamycin, etoposide, prednisolone plus interferon-α2a; (R-)MCP: (Rituximab plus) mitoxantrone, chlorambucil, and prednisolone; OSHO: East German Study Group Hematology and Oncology.

Table 3 Results of different randomized trials comparing chemotherapy with chemotherapy plus rituximab in relapsed or refractory follicular lymphomas

Study	No. of patients, target disease	Median age (yr)	Complete response rate	End point
				Median progression-free survival	Overall survival
GLSG[43]	n = 65, relapsed FL		P = 0.011a	P = 0.0139a	P = 0.0943 (not significant)
R-FCM	n = 35	60	94%	Near 36 mo	90% (at 2 yr)
FCM	n = 30	59.5	70%	21 mo	70% (at 2 yr)
EORTC, HOVON, NCIC, CTG, BNLI, ALLG, NLG and EORTC Data Center-multicenter study[44]	n = 465, relapsed/resistant FL		P < 0.001b	P < 0.001b	P = 0.096 (not significant)
R-CHOP	n = 234	54	29.5%	33.1 mo	82.5% (at 3 yr)
CHOP	n = 231	55	15.6%	20.2 mo	71.9% (at 3 yr)

^aP < 0.05,

^bP < 0.01, statistically significant. GLSG: German Low-Grade Lymphoma Study Group; FL: Follicular lymphoma; EORTC: European Organization for Research and Treatment of Cancer; HOVON: Hemato-Oncologie voor Volwassenen Nederland; NCIC: National Cancer Institute of Canada; CTG: Clinical Trial Group (Canada); BNLI: British National Lymphoma Investigation; ALLG: Australasian Leukaemia and Lymphoma Group; NLG: Nordic Lymphoma Group; (R-)CHOP: (Rituximab plus) cyclophosphamide, doxorubicin, vincristine, and prednisone; (R-)FCM: (Rituximab plus) fludarabine, cyclophosphamide, mitoxantrone.

Table 4 Results of different randomized trials comparing no maintenance with maintenance therapy with rituximab or interferon after first line therapy in patients with follicular lymphoma

Author(s) or studies, maintenance therapy	No. of patients, target disease and randomization to therapies	Median age (yr)	Initial therapy,n (%)	CR rate	End point
					Median PFS	Median response duration	Overall survival
GLSG[43,46]	n = 105, relapsed or refractory FL					P = 0.035a
R-FCM	n = 52	59	R-FCM: 41 (79)		Not reached	32/41 (78%)
			FCM: 11 (21)
Observation	n = 53	61	R-FCM: 40 (75)		Not reached	21/40 (53%)
			FCM: 13 (25)
ECOG1496 study[47]	n = 311, stage III-IV indolent lymphoma (282 of 311 had FL)	61	CVP	P = 0.00006b		P = 0.012a	All: P = 0.05
							FL: P = 0.08 (trend towards significance)
R-CVP	n = 153		CVP	22%		All: 68% (at 3 yr)	All: 92% (at 3 yr)
						FL: 64% (at 3 yr)	FL: 91% (at 3 yr)
Observation	n = 158		CVP	7%		All: 33% (at 3 yr)	All: 86% (at 3 yr)
						FL: 33% (at 3 yr)	FL: 86% (at 3 yr)

^aP < 0.05,

^bP < 0.01, statistically significant. CR: Complete response; PFS: Progression-free survival; FL: Follicular lymphoma; GLSG: German Low-Grade Lymphoma Study Group; (R-)FCM: (Rituximab plus) fludarabine, cyclophosphamide, mitoxantrone; ECOG: Eastern Cooperative Oncology Group; (R-)CVP: (Rituximab plus) cyclophosphamide, vincristine, and prednisone.

Table 5 Results of phase III clinical trials of idiotype vaccines in follicular lymphoma

Study	No. of patients, target disease	Regimen of induction therapy	Eligibility	Vaccine type	Vaccine production methodology	Primary end point
						Survival types, P-value, significance
Biovest	n = 177, untreated FL	PACE or R-CHOP	CR	Id-KLH/GM-CSF	Rescue hybridoma	Disease-free survival, P > 0.05, not significant
Genitope	n = 287, untreated FL	CVP	CR, PR	Id-KLH/GM-CSF	Recombinant DNA	Progression-free survival, P > 0.05, not significant
Favrille	n = 349, untreated or recurrent FL	Rituximab	CR, PR, SD	Id-KLH/GM-CSF	Recombinant DNA	Time to progression, P > 0.05, not significant

FL: Follicular lymphoma; PACE: Prednisolone, doxorubicin, cyclophosphamide and etoposide; R-CHOP: Rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisolone; CVP: Cyclophosphamide, vincristine, prednisolone; CR: Complete response; PR: Partial response; SD: Stable disease; Id-KLH: Idiotype-keyhole limpet hemocyanin; GM-CSF: Granulocyte-macrophage colony stimulating factor.