Table 2.
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 |
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.