A review of the risks of long-term consequences associated with components of the CHOP chemotherapy regimen

Figures & data

Table 1. Inclusion and Exclusion Criteria.

INCLUSION CRITERIA	EXCLUSION CRITERIA
Endpoint criteria
Acute myeloid leukemia Bladder malignancy Cardiac toxicity Cataracts Clinical leukoencephalopathy Dental abnormalities Hepatic dysfunction Impaired spermatogenesis Myelodysplasia Neurocognitive deficits Osteonecrosis (avascular necrosis) Ovarian hormone deficiencies Pulmonary fibrosis Pulmonary toxicity Reduced bone mineral density (BMD) Reduced ovarian follicular pool Renal toxicity Sinusoidal obstruction syndrome (SOS) Urinary tract toxicity Adverse psychosocial/quality of life effects Mental health disorders Fatigue Sleep problems Socioeconomic issues Psychosocial disability due to pain Peripheral sensory neuropathy	Limitations in healthcare and insurance access Ototoxicity Risky behaviors (i.e. alcohol use)
Research concept-related criteria
Publications assessing long-term adverse events in the context of CHOP and its components	Publications not assessing long-term adverse events in the context of CHOP and its components
Study countries and publication year
All	All
Publication language
English; foreign language papers with English abstracts	Foreign language publications
Publication type and study design
Randomized controlled trials (n > 100) Observational study (n > 100) Cross-sectional study (n > 100) Systematic review Case series (n > 20)	News Video-audio media Webcast Case reports Case series (n < 20) Letter Commentary Review Treatment/practice guidelines Consensus development Note RCT, observational study, or cross-sectional study with n < 100

Figure 1. PRISMA Flowchart.

Figure 2. Characteristics of included studies.

Table 2. Results summary: overview of identified late effects, reported frequency, time to onset, and risk factors.

LATE EFFECTS (Number of studies)		DRUG CLASS	NUMBER OF PATIENTS IMPACTED	INCIDENCE/ PREVALENCE	TIME TO ONSET	RISK FACTORS
Cardiac toxicity (N = 14)	Heart failure	ATC	High	1.7% at 5 yrs* to 68.1% at 17.3 yrs^	NR	Dose, age, homozygous for the CBR3 V244M G allele, Hodgkin’s lymphoma, Non-Hodgkin’s lymphoma, hypertension
	Abnormal echocardiogram	ATC	High	14.7% at 15.8 yrs* to 35% at 8 yrs*	1 yr*
	Valvular disease	ATC	High	1.5% by 45 yrs of age to 28% at 22.6 yrs^	NR
	Structure and function disorder	ATC	High	1.3% by 45 yrs of age to 48% at 28 yrs^	NR
	Cardiomyopathy	ATC	Low	5% at 10 yrs^ to 7.4% at 22.6 yrs^	NR
	Artery disease	ATC	Low	3.8% at 22.6 yrs^ to 5.3% by 45 yrs of age	NR
Hormone deficiencies, infertility (N = 14)	Male	ALK	High	50% at 4.9 yrs* to 60% at 3.32 yrs*	NR	Dose, age, radiation use, Hodgkin’s lymphoma, non-Hodgkin’s lymohoma
	Female	ALK	High	7.6% NR to 83% at 4.9 yrs*	NR
Secondary leukemia (N = 7)	t-MDS/AML	ATC ALK	Moderate	0.3% at 30 yrs* to 11% at 5 yrs*	2.6 to 4.4 yrs*	Dose, Hodgkin’s lymphoma
Osteonecrosis (N = 6)	Avascular necrosis	CTS	Low	0.43% at 20 yrs* to 9.7% at 6 months^	1.8 to 2.4 yrs*	Dose, age, sex, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma
Urotoxicity, bladder malignancy (N = 4)	Hemorrhagic cystitis	ALK	NR	NR	NR	Dose, radiotherapy
	Bladder cancer	ALK	Moderate	0.5% at 8.5yrs* to 10.7% at 12 yrs*	5 to 8.5 yrs*

*=after treatment; ^=after diagnosis; AML, acute myeloid leukemia; ATC, anthracycline; AMT, antimicrotubular; ALK, alkylating agents; CTS, corticosteroids; NR, not reported; yr(s), years. High ≥20% of patients affected; Moderate = 10–20% of patients affected; Low ≤10% of patients affected.

Table 3. Results summary: overview of selected quantitative comparative risks (expressed as HR, RR, RTR, OR) reported by identified studies.

CATEGORY	LATE EFFECTS	RISK FACTOR	TREATMENT CLASS	COMPARISON	DETAILS	REPORTED INCREASE IN RISKS Expressed as HR, RR, RTR, OR (95% CI)
Cardiac toxicity	Cardiac toxicity (including heart failure, myocardial infarction, pericardial disease, valvular abnormalities, abnormal echocardiogram)	Dose [27]	ATC	Heart failure in exposed cancer survivors	DAU ≤ 300 mg/m^2-<400 mg/m^2 DRN ≤ 300 mg/m^2-<400 mg/m^2	HR 4.33 (1.73 to 10.84) HR 13.19 (9.04 to 19.25)
		Primary cancer diagnosis [32]	ATC	Myocardial infarction in exposed Hodgkin’s Lymphoma survivors vs. other tumors	Hodgkin’s Lymphoma Non-Hodgkin’s Lymphoma	HR 12.2 (5.2 to 28.2) p < .001 HR 2.9 (0.9 to 9.6) p = .085
		Age at treatment start [23]	ATC	Abnormal echocardiogram in younger vs. older exposed cancer survivors	Aged 1–4 years	HR 1.89 (1.08 to 3.31)
		CV risk factors [24]	ATC	Exposed cancer survivors with vs. without CV risk factors (diabetes, hypertension, dyslipidemia, obesity)	Hypertension Hypertension + dyslipidemia Hypertension + diabetes Hypertension + obesity	RTR 12.4 (7.6 to 20.1) p < .001 RTR 11.3 (4.6 to 27.5) p < .001 RTR 16.9 (5.1 to 55.7) p < .001 RTR 6.5 (2.5 to 16.5) p < .001
		Homozygous for the CBR3 V244M G allele	ATC	Exposed cancer survivors homozygous for G allele in CBR3 vs. unexposed patients with at least one copy of variant A allele in CBR3	1–100mg/m^2 301 + mg/m^2	OR 2.16 (0.47 to 10.05) OR 27.71 (7.42 to 103.44)
Hormone deficiencies, infertility	Diminished ovarian reserve (AMH level)	Dose [46]	ALK	Exposed vs. unexposed cancer survivors	CPS > 7.5 g/m^2	OR: 12.0 (1.3 to 107.4) p = .03
	Acute ovarian failure/Early menopause	Drug exposure/age [38]	ALK	Exposed younger vs. unexposed older cancer survivors	Aged 21–25 yrs, ALK + RTb	RR: 27.39 (12.42 to 60.35) p ≤ .01
		Age at diagnosis [39]	ALK	Older vs. younger exposed cancer survivors	13–20 years (vs. 0–12)	OR 1.8 (1.4 to 2.4) p < .0001
		Primary cancer diagnosis [39]	ALK	Hodgkin’s and non-Hodgkin’s Lymphoma survivors vs. other tumors	Hodgkin’s Lymphoma Non-Hodgkin’s Lymphoma	OR 3.8 (2.7 to 5.4) p < .001 OR 3.2 (1.8 to 5.3) p < .001
	Risk of pregnancy	Drug exposure [42,43]	ALK	Exposed cancer survivors vs. unexposed same sex siblings	Female Male	RR 0.81 (0.73 to 0.90) p < .001 RR 0.56 (0.49 to 0.63) p < .001
Secondary leukemia	t-MDS/AML	Dose [52]	ALK	High dose vs. low dose treatment	DRN 450mg/m^2 + CPS 17.6g/m^2 + IFO 140g/m^2	RR 15.91 (3.84 to 65.82)
		Dose [51]	ALK ATC	High dose vs. low dose treatment	ALK ≥ 10g/m^2 ATC ≥ 0.2g/m^2	RR 6.2 (2.4 to 16.1) p = .00001 RR 1.6 (0.7 to 4.0) p = .103
		Primary cancer diagnosis [51]	ALK ATC	Exposed Hodgkin’s Lymphoma survivors vs. other tumors	Hodgkin’s Lymphoma	OR 2.0 (0.6 to 6.6) p = .525
		Primary cancer diagnosis [56]	ALK ATC	Exposed Hodgkin’s Lymphoma survivors vs. other tumors	Hodgkin’s Lymphoma	RR 6.4 (1.6 to 24) p = .004
Osteonecrosis	Osteonecrosis	Drug exposure [60]	CTS ± RT/SG	Exposed cancer survivors vs. unexposed siblings	Chemotherapy including CTS ± RT/SG	RTR 6.2 (2.3 to 17.2)
		Drug exposure [60]	CTS	Exposed cancer survivors vs. unexposed siblings	DEX ± PRN	RTR 4.0 (1.8 to 8.9) p < .001
		Age at diagnosis [59]	CTS	Older vs. younger exposed cancer survivors	Aged ≥ 10 years	OR 5.52 (4.7 to 6.5) p < .0001
		Sex [63]	CTS	Female vs. male exposed cancer survivors	Females	OR 2.23 (1.04 to 4.81) p = .04
		Primary cancer diagnosis [60]	CTS	Exposed Hodgkin’s and Non-Hodgkin’s lymphoma survivors vs. unexposed siblings	Hodgkin’s Lymphoma Non-Hodgkin’s Lymphoma	RTR 6.7 (2.0 to 22.2) p = .002 RTR 6.7 (1.8 to 25.1) p = .005
Urotoxicity, bladder malignancy	Bladder cancer	Dose [67]	ALK	Exposed vs. unexposed cancer survivors	CPS 20‒49 g CPS ≥ 50 g	MRR 6.3 (1.3 to 2.9) MRR 14.5 (2.3 to 94)
		Duration of exposure [67]	ALK	Exposed vs. unexposed cancer survivors	CPS 1–2 years CPS ≥ 2 years	MRR 3.7 (0.6 to 22) MRR 11.88 (2.3 to 61)

ATC: anthracycline; ALK: alkylating agents; AMH: Anti‐Müllerian hormone; CI: confidence intervals; CTS: corticosteroids; CV: cardiovascular; CPS: cyclophosphamide; DAU: daunorubicin; DEX: dexamethasone; DRN: doxorubicin; HR: hazard ratio; IFO: ifosfamide; MRR: matched relative risk; OR: odds ratio; PRN: prednisone; RR: relative risk; RTb: radiation below the diaphragm; RTR: rate ratio; SG: surgery; vs.: versus.