Studies reporting the impact of DI on survival outcomes in DLBCL
| Reference . | N . | Study design and period . | Inclusion criteria . | Exclusion criteria . | Age, median (range) . | Drugs . | Derivation of dose intensity . | Cutoff RDI used for analysis, % . | Impact of reduced RDI on outcomes . | Assessment of confounders and competing risk . |
|---|---|---|---|---|---|---|---|---|---|---|
| 19 | 100 | Retrospective, multicenter, 2003-2008 | Lymphoma: untreated DLBCL Chemotherapy: R-CHOP Age cutoff: not specified Minimum no. cycles: 4 | Prior radiotherapy before CHOP; T-cell NHL | 60 y (range not specified) | C, H | RDI: DDI[drug]/SDI[drug].* ARDI: mean of RDIs for C, H The term “RDI” was used in lieu of ARDI in the study. | 87.9 | UVA OS: RDI (per 10% increase): HR, 0.7; 95% CI, 0.6-0.9); P = .02 MVA OS: RDI (per 10% increase): HR, 0.8; 95% CI, 0.6-1.0; P = .08 | MVA: adjusted for IPI ≥3 |
| 11 | 152 (R-CHOP, n = 101;R-THP-COP, n = 51†) | Retrospective, single-center, 1996-2009 | Lymphoma: untreated DLBCL Chemotherapy: R-CHOP or R-THP-COP (THP-ADM as an alternative to doxorubicin for >70 y) Age cutoff: not specified Minimum no. cycles: 3 | Initial dose reduction/discontinuation due to hepatic/renal/ cardiac dysfunction or poor PS, HIV-associated, history of advanced cancers | Not reported | C, H†, O, P | SDI, DDI, and RDI ARDI: individual drugs and combined based on regimens.* | 70 | MVA: OS ARDI <70%: HR, 9.0; 95% CI, 2.2-36.7); P = .002 PFS ARDI <70%: HR, 2.6; 95% CI, 1.3-5.2; P = .007 | MVA: adjusted for IPI ≥3, albumin <3.5 g/dL, febrile neutropenia, prophylactic G-CSF |
| 9 | 198 (DI analysis, n = 183;R-CHOP/CHOP, n = 190; R-EPOCH, n = 1) | Retrospective, multicenter, 1998-2008 | Lymphoma: untreated DLBCL Chemotherapy: anthracycline-based Age cutoff: ≥80 y Minimum no. cycles: 1 | Primary cutaneous DLBCL; CNS involvement at diagnosis; lymphoma diagnosis other than DLBCL | 83.1 y (mean) | H | SDI: 50 mg/m per 21 d (H) DDI RDI: DDI [H]/SDI[H] (Hryniuk et al23 )* | 85 | KM analysis: 1-y OS rate: RDI ≥85%: 59% RDI <85%: 70%; (log-rank P = .029) | Not addressed |
| 14 | 433 (≥70 y, n = 83; 19.2%) | Retrospective, single center, 2003-2011 | Lymphoma: untreated DLBCL Chemotherapy: R-CHOP Age cutoff: not specified, stratified by age ≥70 vs <70 y Minimum no. cycles: not mentioned | Other treatments such as radiotherapy, surgery, chemo other than R-CHOP | 58 y (16-91) | H | SDI: 16.7 mg/m2 per week (H) DDI RDI: not defined, but a cutoff of 10 mg/m2 per week was 60%.* | 60 | Age <70 y, RDI ≤60% 2-y OS: HR, 3.46; 95% CI, 1.39-8.58; P = .007 2-y PFS: HR, 4.04; 95% CI, 1.76-9.31; P = .001 Age ≥70 y, RDI ≤60% 2-y OS: HR, 2.24; 95% CI, 1.04-4.85; P = .040 2-y PFS: HR, 2.52; 95% CI, 1.02-6.22; P = .045 Age ≥70 y only UVA: RDI <60% OS: HR, 0.45; 95% CI, 0.21-0.97; P = .04 MVA: RDI <60% OS: HR, 1.60; 95% CI, 0.61-4.20; P = .343 | MVA: adjusted for B symptoms, stage ≥III, ECOG PS ≥2, LDH>ULN, EN sites ≥2, IPI ≥3, BM involvement, Bulky tumor |
| 17 | 140 | Retrospective, single-center, 2004-2015 | Lymphoma: untreated DLBCL Chemotherapy: R-CHOP Age cutoff: ≥70 y Minimum no. cycles: 1 | Transformed iNHL, CLL, CNS involvement; any regimen other than R-CHOP | 78 y (70 - 90) | C, H | (1) Absolute dose [H]cycle 1/intended dose [H]cycle 1; (2) Absolute dose [H]cycle 1+2/intended dose [H]cycle 1+2; (3) Absolute dose [C]cycle 1/intended dose [C]cycle 1; (4) Absolute dose [C]cycle 1+2/intended dose [C]cycle 1+2. Mentions dose only, not dose intensity (dose/unit time). | 90 | UVA: dose[H]cycle 1 (per 10% increase): HR, 0.80; 95% CI, 0.72-0.88; P < .0001 MVA (ECOG 0-1 subgroup): dose[C]cycle 1 (per 10% increase): HR, 0.77; 95% CI, 0.64-0.92; P = .005; dose[C]cycle 1+2 (per 10% increase): HR, 0.76; 95% CI, 0.60-0.96; P = .019; dose[H]cycle 1 (per 10% increase): HR, 0.81; 95% CI, 0.70-0.94; P = .005; dose[H]cycle 1+2 (per 10% increase): HR, 0.82; 95% CI, 0.69-0.97; P = .019 Subgroup analysis by age, dose for H >90%: age <80 y: OS, HR, 0.81; 95% CI, 0.69-0.94; P = .005; age ≥80 y: OS, HR, 0.88; 95% CI, 0.74-1.06; P = .16 | MVA: adjusted for age, sex, IPI, Hb, albumin |
| 4 | 615 (total = 1011; R-CHOP/ CHOEP, n = 557; CHOP, n = 94; remainder, n = (R)CVP, palliative treatment) | Retrospective, nationwide multicenter, 2003-2012 | Lymphoma: untreated DLBCL Chemotherapy: R-CHOP Age cutoff: ≥75 y Minimum no. cycles: not specified | CNS involvement; FL grade IIIb; transformed lymphoma; indolent lymphoma | 81 y (75-101) | C, H | SD: standard full dose [drug] per cycle Planned dose: delivered dose [drug] in cycle 1 Full dose: if the planned dose of [C] and [H] ≥80% in cycle 1 | 80 | KM analysis for OS (full dose ≥80%) 75-79 y, P = .068; 80-84 y, P = 0.414; ≥85 y, P = .962 | Stratification by age groups: 75-79, 80-84, ≥85 y MVA: none; RDI not included in MVA |
| 10 | 541 (R-CHOP/miniCHOP, n = 457; R-CHOEP, n = 84) | Retrospective, multicenter, 2000-2013 | Lymphoma: untreated DLBCL, PMBCL, testicular DLBCL, transformed FL (only radiotherapy for prior FL) Chemotherapy: R-CHOP, R-CHOEP, or R-mini-CHOP Age cutoff: >18 y Minimum no. cycles: 1 | PCNSL; Burkitt lymphoma; patients too frail to receive included chemotherapy regimens | 66 y (18-91) | H | SDI, DDI RDI: DDI[H]/SDI[H] (per Yamaguchi et al 2011)24 * | 70 | Bivariate analyses: data not published MVA: RDI ≤ 70%: OS: HR, 2.04; 95% CI, 1.15-3.61; P = .014; DFS: HR, 1.88; 95% CI, 0.97-3.67; P = .063 | MVA: adjusted for PS ≥2, stage ≥III, IPI ≥3, LDH >ULN, bulky disease, EN involvement, kidney/adrenal involvement; age, BMI ≥25, chemotherapy use (CHOP vs CHOEP; vincristine omission in any course |
| 15‡ | 690 (70-79 y, n = 452; ≥80 y, n = 238) | Retrospective, multicenter, 2009-2018 | Lymphoma: untreated DLBCL, transformed iNHL Chemotherapy: R-CHOP Age cutoff: ≥70 y Minimum no. cycles: 1 | Leg-type DLBCL, PTLD, and HIV-associated; CNS involvement; previously treated transformed iNHL | 77.1 y (70-96) | C, H | Intended DI (IDI): average delivered dose [C+H] in cycle 1, expressed as a % (i.e., relative to “standard dose”) DDI (but in this study, labeled “Received” DI (RDI): total delivered dose [C+H] × correction factor (to account for time delays) RDI/IDI: ratio of RDI to IDI.* (equivalent to ARDI in other studies), defined as the relative intensity of delivered vs planned (in this case, cycle 1) dose | 80 | UVA: IDI ≥80% OS: SHR, 0.35; 95% CI, 0.35-0.58; P < .001 PFS: SHR, 0.50; 95% CI, 0.39-0.64; P < .001 Relapse (competing risks regression; IDI ≥80% SHR, 0.70; 95% CI, 0.51-0.96; P = .026 IDI/RDI ratio was not predictive of relapse, PFS, or OS SHR, for relapse risk: 0.53; 95% CI, 0.22-1.27; P = .156 MVA relapse risk: IDI<80% Age 70-79 y: SHR, 1.61; 95% CI, 1.02-2.53; P = .04. Age ≥80 y: SHR: 1.48 95% CI, 0.96-2.29; P = .078 | MVA: adjusted for age, stage, ECOG PS ≥2, LDH > ULN, albumin, Hb, male, B-symptoms, EN >1. Competing-risks survival regression: cumulative risk of relapse with nonrelapse mortality as a competing risk |
| 16 | 223 | Retrospective, single center, 2005-2013 | Lymphoma: untreated DLBCL Chemotherapy: R-CHOP Age cutoff: not specified Minimum no. cycles: 4 | Not reported | Not reported | R, C, H, O | SDI, DDI, RDI ARDI: mean RDIs for R, C, H, O* | 90 | UVA ARDI >90%: OS HR, 0.30; 95% CI, 0.20-0.46; P < .000001. PFS HR, 0.28; 95% CI, 0.18-0.44; P < .000001 MVA ARDI >90%: OS HR, 0.32; 95% CI, 0.21-0.48; P < .000001 PFS: HR, 0.31; 95% CI, 0.20-0.47; P < .000001 | MVA: adjusted for IPI ≥2 |
| 20 | 476 | Retrospective, single-center, 2004-2017 | Lymphoma: untreated DLBCL Chemotherapy: R-CHOP or R-THP-COP (THP-ADM as an alternative to doxorubicin) Age cutoff: not specified Minimum no. cycles: 3 | HIV-associated; PCNSL | 68.5 y (27-97) | C, H†, O | Standard Dose (SD): planned full dose[drug] Delivered dose (DD): total delivered dose [drug] RDI: DD[drug]/SD[drug] ARDI (termed “RDI” in the article): mean of all RDIs for C, H/THP-ADM, and O (per Hryniuk and Bush25 ) | 80 | UVA: 5-y OS: RDI ≥80%: 83.7%; 95% CI, 76.2-89.0 vs RDI <80%: 70.7%; 95% CI, 64.3-76.2; P = .01 5-y PFS, RDI ≥80%: 78.2%; 95% CI 70.2-84.4 vs RDI <80%: 63.1%; 95% CI, 56.6-68.9; P = .01 High CONUT score: RDI >80% vs ≤ 80%§ 5-y OS: 59.8% vs 50.9%; P = .73 | MVA: none; RDI not included in MVA |
| 20 | 608 (R-CHOP, n = 605; R-CVP, n =3) | Retrospective, single center, 2002-2012 | Lymphoma: DLBCL, transformed iNHL, and DLBCL variants (EBV+ DLBCL, primary cutaneous DLBCL, PMBL, LYG) Chemotherapy: R containing regimens Age cutoff: not specified Minimum no. of cycles: not specified | NR | 53.3 ± 14.1 y (mean) | C, H, O | SDI, DDI, RDI* Average RDI (ARDI): mean [RDIs] for C, H, O ARDI (per Kwak et al 199026 ) | 85 | UVA KM: ARDI<85% OS: P = .02 PFS: P = 0.01 MVA (according to NCCN-IPI): ARDI <85% OS: HR, 1.07; 95% CI, 0.72-1.61; P = .73 PFS: HR, 1.06; 95% CI, 0.75-1.50; P = .73 | MVAs: adjusted for B symptoms, Age, and IPI (either aaIPI, IPI, NCCN-IPI, or GELTAMO-IPI) |
| 13 | 127 (R-CH/THPCOP, n = 120; no R, n = 7) | Retrospective, multicenter, 2007-2017 | Lymphoma: untreated de novo DLBCL Chemotherapy: R-CHOP or R-THP-COP Age cutoff: ≥80 y Minimum no. cycles: 1 | Transformed iNHL; PTLD; HIV-associated; CNS involvement; any regimen other than CHOP or THP-COP; radiotherapy before/after chemotherapy | 83.7 y (80-96) | C, H†, O | SDI, DDI, RDI ARDI: mean [RDIs] for C, H/THP-ADM, and O per course.* tARDI: averages over each of the 6 cycles | 50 | KM analysis: tARDI >50% vs ≤50% 2-y OS = 61.8% vs 50.8%; P = .03 Cox hazards model with restricted cubic spline: effect of tARDI: P = 0.049 MVA OS: tARDI (/10%): HR, 0.89; 95% CI, 0.809-0.975; P = .013 | MVAs: adjusted for serum albumin, CCI score, IPI score (continuous) |
| 18 | 211 | Retrospective, multicenter, 2010-2018 | Lymphoma: untreated DLBCL Chemotherapy: R-CHOP Age cutoff: ≥18 y Minimum no. cycles: 1 | Recurrent DLBCL | 72 y (19-92) | C, H, O | SDI, DDI, RDI ARDI (termed “RDI” in manuscript): mean RDIs for C, H, O (per Eyre et al 201915 )* | 70 | UVA: RDI <70% OS: HR, 4.38; 95% CI, 1.60-12.7; P = .003 MVA: RDI <70% OS: HR, 3.70; 95% CI, 1.12-12.2; P = .031 | MVA: adjusted for age ≥65 y or ≥80 y, raised LDH, PS ≥2, CCI ≤1 or ≥2, stage ≥3, EN ≥2 |
| Reference . | N . | Study design and period . | Inclusion criteria . | Exclusion criteria . | Age, median (range) . | Drugs . | Derivation of dose intensity . | Cutoff RDI used for analysis, % . | Impact of reduced RDI on outcomes . | Assessment of confounders and competing risk . |
|---|---|---|---|---|---|---|---|---|---|---|
| 19 | 100 | Retrospective, multicenter, 2003-2008 | Lymphoma: untreated DLBCL Chemotherapy: R-CHOP Age cutoff: not specified Minimum no. cycles: 4 | Prior radiotherapy before CHOP; T-cell NHL | 60 y (range not specified) | C, H | RDI: DDI[drug]/SDI[drug].* ARDI: mean of RDIs for C, H The term “RDI” was used in lieu of ARDI in the study. | 87.9 | UVA OS: RDI (per 10% increase): HR, 0.7; 95% CI, 0.6-0.9); P = .02 MVA OS: RDI (per 10% increase): HR, 0.8; 95% CI, 0.6-1.0; P = .08 | MVA: adjusted for IPI ≥3 |
| 11 | 152 (R-CHOP, n = 101;R-THP-COP, n = 51†) | Retrospective, single-center, 1996-2009 | Lymphoma: untreated DLBCL Chemotherapy: R-CHOP or R-THP-COP (THP-ADM as an alternative to doxorubicin for >70 y) Age cutoff: not specified Minimum no. cycles: 3 | Initial dose reduction/discontinuation due to hepatic/renal/ cardiac dysfunction or poor PS, HIV-associated, history of advanced cancers | Not reported | C, H†, O, P | SDI, DDI, and RDI ARDI: individual drugs and combined based on regimens.* | 70 | MVA: OS ARDI <70%: HR, 9.0; 95% CI, 2.2-36.7); P = .002 PFS ARDI <70%: HR, 2.6; 95% CI, 1.3-5.2; P = .007 | MVA: adjusted for IPI ≥3, albumin <3.5 g/dL, febrile neutropenia, prophylactic G-CSF |
| 9 | 198 (DI analysis, n = 183;R-CHOP/CHOP, n = 190; R-EPOCH, n = 1) | Retrospective, multicenter, 1998-2008 | Lymphoma: untreated DLBCL Chemotherapy: anthracycline-based Age cutoff: ≥80 y Minimum no. cycles: 1 | Primary cutaneous DLBCL; CNS involvement at diagnosis; lymphoma diagnosis other than DLBCL | 83.1 y (mean) | H | SDI: 50 mg/m per 21 d (H) DDI RDI: DDI [H]/SDI[H] (Hryniuk et al23 )* | 85 | KM analysis: 1-y OS rate: RDI ≥85%: 59% RDI <85%: 70%; (log-rank P = .029) | Not addressed |
| 14 | 433 (≥70 y, n = 83; 19.2%) | Retrospective, single center, 2003-2011 | Lymphoma: untreated DLBCL Chemotherapy: R-CHOP Age cutoff: not specified, stratified by age ≥70 vs <70 y Minimum no. cycles: not mentioned | Other treatments such as radiotherapy, surgery, chemo other than R-CHOP | 58 y (16-91) | H | SDI: 16.7 mg/m2 per week (H) DDI RDI: not defined, but a cutoff of 10 mg/m2 per week was 60%.* | 60 | Age <70 y, RDI ≤60% 2-y OS: HR, 3.46; 95% CI, 1.39-8.58; P = .007 2-y PFS: HR, 4.04; 95% CI, 1.76-9.31; P = .001 Age ≥70 y, RDI ≤60% 2-y OS: HR, 2.24; 95% CI, 1.04-4.85; P = .040 2-y PFS: HR, 2.52; 95% CI, 1.02-6.22; P = .045 Age ≥70 y only UVA: RDI <60% OS: HR, 0.45; 95% CI, 0.21-0.97; P = .04 MVA: RDI <60% OS: HR, 1.60; 95% CI, 0.61-4.20; P = .343 | MVA: adjusted for B symptoms, stage ≥III, ECOG PS ≥2, LDH>ULN, EN sites ≥2, IPI ≥3, BM involvement, Bulky tumor |
| 17 | 140 | Retrospective, single-center, 2004-2015 | Lymphoma: untreated DLBCL Chemotherapy: R-CHOP Age cutoff: ≥70 y Minimum no. cycles: 1 | Transformed iNHL, CLL, CNS involvement; any regimen other than R-CHOP | 78 y (70 - 90) | C, H | (1) Absolute dose [H]cycle 1/intended dose [H]cycle 1; (2) Absolute dose [H]cycle 1+2/intended dose [H]cycle 1+2; (3) Absolute dose [C]cycle 1/intended dose [C]cycle 1; (4) Absolute dose [C]cycle 1+2/intended dose [C]cycle 1+2. Mentions dose only, not dose intensity (dose/unit time). | 90 | UVA: dose[H]cycle 1 (per 10% increase): HR, 0.80; 95% CI, 0.72-0.88; P < .0001 MVA (ECOG 0-1 subgroup): dose[C]cycle 1 (per 10% increase): HR, 0.77; 95% CI, 0.64-0.92; P = .005; dose[C]cycle 1+2 (per 10% increase): HR, 0.76; 95% CI, 0.60-0.96; P = .019; dose[H]cycle 1 (per 10% increase): HR, 0.81; 95% CI, 0.70-0.94; P = .005; dose[H]cycle 1+2 (per 10% increase): HR, 0.82; 95% CI, 0.69-0.97; P = .019 Subgroup analysis by age, dose for H >90%: age <80 y: OS, HR, 0.81; 95% CI, 0.69-0.94; P = .005; age ≥80 y: OS, HR, 0.88; 95% CI, 0.74-1.06; P = .16 | MVA: adjusted for age, sex, IPI, Hb, albumin |
| 4 | 615 (total = 1011; R-CHOP/ CHOEP, n = 557; CHOP, n = 94; remainder, n = (R)CVP, palliative treatment) | Retrospective, nationwide multicenter, 2003-2012 | Lymphoma: untreated DLBCL Chemotherapy: R-CHOP Age cutoff: ≥75 y Minimum no. cycles: not specified | CNS involvement; FL grade IIIb; transformed lymphoma; indolent lymphoma | 81 y (75-101) | C, H | SD: standard full dose [drug] per cycle Planned dose: delivered dose [drug] in cycle 1 Full dose: if the planned dose of [C] and [H] ≥80% in cycle 1 | 80 | KM analysis for OS (full dose ≥80%) 75-79 y, P = .068; 80-84 y, P = 0.414; ≥85 y, P = .962 | Stratification by age groups: 75-79, 80-84, ≥85 y MVA: none; RDI not included in MVA |
| 10 | 541 (R-CHOP/miniCHOP, n = 457; R-CHOEP, n = 84) | Retrospective, multicenter, 2000-2013 | Lymphoma: untreated DLBCL, PMBCL, testicular DLBCL, transformed FL (only radiotherapy for prior FL) Chemotherapy: R-CHOP, R-CHOEP, or R-mini-CHOP Age cutoff: >18 y Minimum no. cycles: 1 | PCNSL; Burkitt lymphoma; patients too frail to receive included chemotherapy regimens | 66 y (18-91) | H | SDI, DDI RDI: DDI[H]/SDI[H] (per Yamaguchi et al 2011)24 * | 70 | Bivariate analyses: data not published MVA: RDI ≤ 70%: OS: HR, 2.04; 95% CI, 1.15-3.61; P = .014; DFS: HR, 1.88; 95% CI, 0.97-3.67; P = .063 | MVA: adjusted for PS ≥2, stage ≥III, IPI ≥3, LDH >ULN, bulky disease, EN involvement, kidney/adrenal involvement; age, BMI ≥25, chemotherapy use (CHOP vs CHOEP; vincristine omission in any course |
| 15‡ | 690 (70-79 y, n = 452; ≥80 y, n = 238) | Retrospective, multicenter, 2009-2018 | Lymphoma: untreated DLBCL, transformed iNHL Chemotherapy: R-CHOP Age cutoff: ≥70 y Minimum no. cycles: 1 | Leg-type DLBCL, PTLD, and HIV-associated; CNS involvement; previously treated transformed iNHL | 77.1 y (70-96) | C, H | Intended DI (IDI): average delivered dose [C+H] in cycle 1, expressed as a % (i.e., relative to “standard dose”) DDI (but in this study, labeled “Received” DI (RDI): total delivered dose [C+H] × correction factor (to account for time delays) RDI/IDI: ratio of RDI to IDI.* (equivalent to ARDI in other studies), defined as the relative intensity of delivered vs planned (in this case, cycle 1) dose | 80 | UVA: IDI ≥80% OS: SHR, 0.35; 95% CI, 0.35-0.58; P < .001 PFS: SHR, 0.50; 95% CI, 0.39-0.64; P < .001 Relapse (competing risks regression; IDI ≥80% SHR, 0.70; 95% CI, 0.51-0.96; P = .026 IDI/RDI ratio was not predictive of relapse, PFS, or OS SHR, for relapse risk: 0.53; 95% CI, 0.22-1.27; P = .156 MVA relapse risk: IDI<80% Age 70-79 y: SHR, 1.61; 95% CI, 1.02-2.53; P = .04. Age ≥80 y: SHR: 1.48 95% CI, 0.96-2.29; P = .078 | MVA: adjusted for age, stage, ECOG PS ≥2, LDH > ULN, albumin, Hb, male, B-symptoms, EN >1. Competing-risks survival regression: cumulative risk of relapse with nonrelapse mortality as a competing risk |
| 16 | 223 | Retrospective, single center, 2005-2013 | Lymphoma: untreated DLBCL Chemotherapy: R-CHOP Age cutoff: not specified Minimum no. cycles: 4 | Not reported | Not reported | R, C, H, O | SDI, DDI, RDI ARDI: mean RDIs for R, C, H, O* | 90 | UVA ARDI >90%: OS HR, 0.30; 95% CI, 0.20-0.46; P < .000001. PFS HR, 0.28; 95% CI, 0.18-0.44; P < .000001 MVA ARDI >90%: OS HR, 0.32; 95% CI, 0.21-0.48; P < .000001 PFS: HR, 0.31; 95% CI, 0.20-0.47; P < .000001 | MVA: adjusted for IPI ≥2 |
| 20 | 476 | Retrospective, single-center, 2004-2017 | Lymphoma: untreated DLBCL Chemotherapy: R-CHOP or R-THP-COP (THP-ADM as an alternative to doxorubicin) Age cutoff: not specified Minimum no. cycles: 3 | HIV-associated; PCNSL | 68.5 y (27-97) | C, H†, O | Standard Dose (SD): planned full dose[drug] Delivered dose (DD): total delivered dose [drug] RDI: DD[drug]/SD[drug] ARDI (termed “RDI” in the article): mean of all RDIs for C, H/THP-ADM, and O (per Hryniuk and Bush25 ) | 80 | UVA: 5-y OS: RDI ≥80%: 83.7%; 95% CI, 76.2-89.0 vs RDI <80%: 70.7%; 95% CI, 64.3-76.2; P = .01 5-y PFS, RDI ≥80%: 78.2%; 95% CI 70.2-84.4 vs RDI <80%: 63.1%; 95% CI, 56.6-68.9; P = .01 High CONUT score: RDI >80% vs ≤ 80%§ 5-y OS: 59.8% vs 50.9%; P = .73 | MVA: none; RDI not included in MVA |
| 20 | 608 (R-CHOP, n = 605; R-CVP, n =3) | Retrospective, single center, 2002-2012 | Lymphoma: DLBCL, transformed iNHL, and DLBCL variants (EBV+ DLBCL, primary cutaneous DLBCL, PMBL, LYG) Chemotherapy: R containing regimens Age cutoff: not specified Minimum no. of cycles: not specified | NR | 53.3 ± 14.1 y (mean) | C, H, O | SDI, DDI, RDI* Average RDI (ARDI): mean [RDIs] for C, H, O ARDI (per Kwak et al 199026 ) | 85 | UVA KM: ARDI<85% OS: P = .02 PFS: P = 0.01 MVA (according to NCCN-IPI): ARDI <85% OS: HR, 1.07; 95% CI, 0.72-1.61; P = .73 PFS: HR, 1.06; 95% CI, 0.75-1.50; P = .73 | MVAs: adjusted for B symptoms, Age, and IPI (either aaIPI, IPI, NCCN-IPI, or GELTAMO-IPI) |
| 13 | 127 (R-CH/THPCOP, n = 120; no R, n = 7) | Retrospective, multicenter, 2007-2017 | Lymphoma: untreated de novo DLBCL Chemotherapy: R-CHOP or R-THP-COP Age cutoff: ≥80 y Minimum no. cycles: 1 | Transformed iNHL; PTLD; HIV-associated; CNS involvement; any regimen other than CHOP or THP-COP; radiotherapy before/after chemotherapy | 83.7 y (80-96) | C, H†, O | SDI, DDI, RDI ARDI: mean [RDIs] for C, H/THP-ADM, and O per course.* tARDI: averages over each of the 6 cycles | 50 | KM analysis: tARDI >50% vs ≤50% 2-y OS = 61.8% vs 50.8%; P = .03 Cox hazards model with restricted cubic spline: effect of tARDI: P = 0.049 MVA OS: tARDI (/10%): HR, 0.89; 95% CI, 0.809-0.975; P = .013 | MVAs: adjusted for serum albumin, CCI score, IPI score (continuous) |
| 18 | 211 | Retrospective, multicenter, 2010-2018 | Lymphoma: untreated DLBCL Chemotherapy: R-CHOP Age cutoff: ≥18 y Minimum no. cycles: 1 | Recurrent DLBCL | 72 y (19-92) | C, H, O | SDI, DDI, RDI ARDI (termed “RDI” in manuscript): mean RDIs for C, H, O (per Eyre et al 201915 )* | 70 | UVA: RDI <70% OS: HR, 4.38; 95% CI, 1.60-12.7; P = .003 MVA: RDI <70% OS: HR, 3.70; 95% CI, 1.12-12.2; P = .031 | MVA: adjusted for age ≥65 y or ≥80 y, raised LDH, PS ≥2, CCI ≤1 or ≥2, stage ≥3, EN ≥2 |
aaIPI, age adjusted IPI; ARDI, average RDI; C, cyclophosphamide; CCI, Charlson Comorbidity Index; CLL, chronic lymphocytic leukemia; E, etoposide; EBV, Epstein-Barr virus; EN, extranodal disease; FL, follicular lymphoma; H, doxorubicin; Hb, hemoglobin; iNHL, indolent non-Hodgkin lymphoma; IPI, international prognostic index; LDH, lactate dehydrogenase; LYG, lymphomatoid granulomatosis; NCCN, National Comprehensive Cancer Network; NHL, non-Hodgkin lymphoma; O, vincristine; P, prednisolone; PCNSL, primary CNS lymphoma; PFS, progression-free survival; PMBL, primary mediastinal B-cell lymphoma; PS, performance status; PTLD, posttransplant lymphoproliferative disorder; R, rituximab; SHR, sub–hazard ratio; tARDI, total ARDI; ULN, upper limit of normal; UVA, univariable analysis.
Definitions for DDI: standard dose intensity (SDI): planned full-dose[drug]/planned time to complete chemotherapy; delivered dose intensity (DDI): total delivered dose [drug]/total time to complete chemotherapy; relative dose intensity (RDI), DDI[drug]/SDI[drug]; average relative dose intensity (ARDI), mean of RDIs for drugs (varied by study).
R-THP-COP: used in Japan for >70 years, THP-ADM replaces doxorubicin, and doses of C, 500 mg/m2, and O, 1.0 mg/m2, are decreased.
Eyre et al 201627 was excluded, because all cases in that analysis were included in the larger cohort (Eyre et al15 ).
CONUT, controlling nutritional status, derived from serum albumin, cholesterol, and absolute lymphocyte count. High CONUT score, ≥4.