Managing cancer-related anaemia in congruence with the EORTC guidelines is an independent predictor of haemoglobin outcome: Initial evidence from the RESPOND study

1. Introduction 

The EORTC guidelines for erythropoietic proteins (EPs)1, 2 provide evidence-based guidance for differential diagnosis, treatment and target outcomes. The RESPOND system is a web-based clinical guidance tool based on these guidelines. It asks clinicians for information on their cancer patients. These data are analysed by means of a set of algorithms based on the EORTC guidelines. Any deviation from the guidelines triggers a diagnostic or treatment recommendation citing the applicable guideline(s). Two validation studies3 showed that the algorithms were accurate4; that anaemia management was more likely to be aligned with the EORTC guidelines when using the RESPOND system; and that system use had an incremental effect above and beyond the pharmacotherapeutic effect of EPs.5

As part of the validation methodology, we designed a scoring method to quantify the extent to which the care of an anaemic cancer patient is congruent with the EORTC guidelines. Though the validation study was not designed specifically to examine the association between congruence scores and haemoglobin (Hb) outcomes,3 we noticed a relationship between both variables. We examined whether practicing in accordance with the EORTC guidelines is associated with better Hb outcomes.

2. Patients and methods 

The methodology for the scientific validation of RESPOND has been described in detail elsewhere.3

2.2. Congruence score 

The congruence score (CS) quantifies the extent to which a patient’s anaemia management is in accordance with the EORTC guidelines (Table 1). It is an indication of the diagnostic and treatment patterns over time for a given patient relative to the EORTC guidelines.

Table 1. Calculation of the congruence score (CS).

	Item	Scoring
	Rule out/treat other causes of anaemia: iron deficiency	+0.25
	Rule out/treat other causes of anaemia: bleeding	+0.25
	Rule out/treat other causes of anaemia: nutritional deficits	+0.25
	Rule out/treat other causes of anaemia: haemolysis	+0.25
	ESA treatment initiated at haemoglobin (Hb) range 9.0–11.0g/dL	+1.00
	If Hb<9.0g/dL patient was considered for blood transfusion; OR: no need for blood transfusion	+1.00
	Anaemic asymptomatic patient with Hb<11.9g/dL was considered for ESA treatment on individual basis; OR: patient does not fall in this category	+1.00
	Hb target set at Hb range 12.0–13.0g/dL	+1.00
	Initial ESA dose=40,000IU epoetin alfa Q1W; 30,000IU epoetin beta Q1W; or darbepoetin alfa Q1W or Q3W	+1.00
	Initial ESA dose was fixed and not weight adjusted	+1.00
	Hb target achieved at 4–8 weeks; if not, individualised dose escalation	+1.00
	Hb levels maintained in Hb range 12.0–13.0g/dL for up to 8 weeks (+125 per week)	+1.00
	ESA discontinued if Hb⩾13.0g/dL	+1.00
	Maximum possible score	10.00

3. Results 

Differences between the two cohorts in mean Hb were not statistically significant at visit 1 but were significant at visit 4 (p=0.007; Table 2). The differences in proportions of patients in each cohort reaching Hb⩾11g/dL and Hb⩾12g/dL at visit 4 were statistically significant (respectively, p=0.027 and p=0.038), and so was the mean change in Hb over time (HbΔ, p=0.006).

Table 2. Haemoglobin levels.

		All patients	Pre-cohort	Post-cohort	p
		M±SD (95% confidence interval (CI))	M±SD (95% CI)	M±SD (95% CI)
	Hb at visit 1 (g/dL)	10.27±0.62 (10.12–10.42)	10.30±0.47 (10.14–10.47)	10.23±0.74 (9.98–10.49)	n.s.
	Hb at visit 2 (g/dL)	10.92±1.30 (10.60–11.24)	10.57±1.08 (10.16–10.95)	11.28±1.42 (10.76–11.79)	0.026
	Hb at visit 3 (g/dL)	11.35±1.39 (11.02–11.69)	10.97±1.18 (10.55–11.38)	11.76±1.49 (11.23–12.28)	0.019
	Hb at visit 4 (g/dL)	11.58±1.54 (11.20–11.96)	11.10±1.40 (10.61–11.59)	12.11±1.53 (11.55–12.67)	0.007
	Change in Hb from visit 1 to visit 4 (HbΔ) (g/dL)	1.33±1.64 (0.92–1.73)	0.80±1.51 (0.27–1.33)	1.90±1.61 (1.31–2.49)	0.006
	Hb at visit 4	%	%	%
	>11g/dL	70.8	58.8	83.9	0.027
	<11g/dL	29.2	41.2	16.1
	>12g/dL	41.5	29.4	54.8	0.038
	<12g/dL	58.5	70.6	45.2

Mean congruence scores were 3.00±1.48 for the retrospective cohort and 8.18±1.38 for the prospective cohort (p<0.001).

Linear regression models controlling for cohort were fitted for HbV4 and HbΔ (for both, pfit<0.001; Table 3). Congruence scores accounted for 40% of the variation observed in HbV4, which increased by 0.60g/dL for each one-point increase in congruence score. Congruence scores also explained 33% of the variation in HbΔ, and each one-point increase was associated with a 0.56g/dL rise in HbΔ.

Table 3. Summary of regression models.

	Linear regression	F		b0	b1	95% CI of b1
	Hb at visit 4	22.05⁎	0.40	9.30⁎	0.60⁎	0.39–0.81
	HbΔ	16.39⁎	0.33	–0.88⁎⁎	0.56⁎	0.32–0.80
	Logistic regression	–2LL		Odds ratio		95% of OR
	Hb at visit 4⩾11g/dL	55.62⁎	0.42	3.14		1.56–6.30
	Hb at visit 4⩾12g/dL	61.83⁎	0.45	2.77		1.67–4.59

Hb=haemoglobin; HbΔ=change in Hb from visit 1 to 4; –2LL=–2 log likelihood; and OR=odds ratio.

⁎ p<0.001. ⁎⁎ p=0.044.

Logistic regression models controlling for cohort examined the improved odds of reaching Hb⩾11g/dL and Hb⩾12g/dL (for both, pfit<0.001). Congruence scores accounted for 42% and 45% of the respective variances. A one-point increase in congruence score was associated with increased odds of 3.14 for attaining Hb⩾11g/dL and 2.77 for achieving Hb⩾12g/dL.

4. Discussion 

The principal finding is that congruence scores are independent predictors of Hb levels after 4 months of treatment with EPs, whether expressed in Hb values at visit 4, Hb change scores, or proportions of patients reaching Hb levels ⩾11g/dL and ⩾12g/dL. The recent call to use EPs to manage anaemia in cancer patients according to guidelines is underscored by the results reported here.6 For instance, if a given patient A was managed at a congruence level of 8 compared to a patient B managed at a level of 5, patient A’s Hb at visit 4 could be 1.80g/dL higher and his/her Hb change from visit 1 to 4 could exceed B’s by 1.68g/dL. A’s odds of attaining Hb⩾11g/dL would be 9.42 higher than B’s and A’s odds of reaching Hb⩾12g/dL would be 8.41 higher.

With due caution because the data reported here are from a validation and not an outcomes study, with a limited sample size and conducted at one centre, our results nonetheless provide the first evidence that practicing in accordance with the EORTC guidelines translates in improvements in Hb outcomes. This finding must be replicated in multi-centre outcomes studies with larger samples and designed specifically to model the relationships between guideline-congruent anaemia management and Hb outcomes under consideration of potential confounding variables such as type of cancer, disease stage, type and line of chemotherapy treatment and selected demographics. In the interim, there is preliminary evidence that guideline-adherent management of cancer-related anaemia may have significant beneficial effects on Hb outcomes.

Conflict of interest statement 

M. Aapro has consulted with, received research grants and contracts from, and/or served as a sponsored speaker for the following companies: Roche, Amgen and Novartis. He declares no conflict with regard to the work described in this manuscript.

J. Van Erps has consulted with, received research grants and contracts from, and/or served as a sponsored speaker for the following companies: Roche and Novartis. She declares no conflict with regard to the work described in this manuscript.

I. Abraham and K. MacDonald have consulted with, received research grants and contracts from, and/or served as a sponsored speaker for the following companies and, as applicable, their subsidiaries: Novartis, Johnson & Johnson (including Centocor, Ortho-Biotech, Janssen Pharmaceutica, Janssen-Cilag and Janssen-Ortho), Eli Lilly, Roche, Pfizer, Amgen, Merck, Bristol-Myers Squibb, Schering-Plough, Astra-Zeneca, Bayer, GlaxoSmithKline, Lundbeck and Innogenetics (including Xcellentis). Matrix45 has been contracted by sponsor to provide support with project conceptualisation, project design, protocol development, development of project materials, training, project management and implementation, development of statistical plan, and quality assurance. Per company policy, I. Abraham, K. MacDonald and T. Albrecht are barred from holding equity in any client companies and are subjected to internal and external review of their work to assure objectivity and transparency. They have taken the necessary steps to assure independence and do not declare a conflict of interest with regard to the work described in this manuscript.

P. Soubeyran has consulted with, received research grants and contracts from, and/or served as a sponsored speaker for the following companies: Roche, Amgen, Johnson & Johnson, Sanofi-Aventis, Schering AG, Schering-Plough, Pfizer, Chugai and Baxter Oncology. He declares no conflict with regard to the work described in this manuscript.

M. Turner and H. Warrinnier are employees of F. Hoffmann-La Roche and its subsidiaries. They have refrained from undue influence throughout the project and manuscript preparation.

T. Albrecht has consulted with the following companies: Roche, Novartis and Schering-Plough. She does not declare a conflict of interest with regard to the work described in this manuscript.

Disclosure of associated publications