CancerCalc

Clinical tools for oncology professionals

Acute Oncology Breast oncology CNS oncology Genetics GI oncology Gynae oncology Hemato-oncology Head and Neck oncology Lung oncology Palliative care Pharmacology Surgical oncology Uro-oncology
Terms of use Contact About us
ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS) tool

ESMO-MCBS assesses the value of a new anti-cancer therapy, taking into account the magnitude of clinical benefit, toxicity and cost within a reproducible scale. This calculator has been developed based on ESMO-MCBS version 1.1 (1). Please see guidance notes below.
1. Select evaluation form:


Form 1: Adjuvant or potentially curative therapies


Form 2A: Non-curative therapies with primary end-point of OS.


Form 2B: Non-curative therapies with primary end-point of PFS.


Form 2C: Non-curative therapies where primary outcome is toxicity OR Quality of Life (QoL) or non-inferiority OR response rate.


Form 3: Single arm studies where primary outcome is PFS or ORR: Where patients have 'orphan disease' or disease with high unmet need.


Grade A:
OS improvement: Abolute improvement in OS (overall survival) >5% at ≥3 years follow-up
DFS Where DFS (disease free survival) is primary end-point and where OS data is not mature improvement alone: HR < 0.65 The lower limit of the Hazard Ratio confidence interval should encompass the required HR.
Grade B:
OS improvement: Abolute improvement in OS (overall survival) ≥ 3% BUT ≤ 5% at ≥3 years follow-up
DFS Where DFS (disease free survival) is primary end-point and where OS data is not mature improvement alone: HR 0.65 to 0.80 The lower limit of the Hazard Ratio confidence interval should encompass the required HR.
Non-inferior OS or DFS with reduced treatment toxicity or improved QoL (with validated scales)
Non-inferior OS or DFS with reduced treatment cost Where reduced treatment cost reported as study outcome (with equivalent outcomes and risks)
Grade C:
OS improvement: Abolute improvement in OS (overall survival) < 3% at ≥3 years follow-up
DFS Where DFS (disease free survival) is primary end-point and where OS data is not mature improvement alone: HR >0.8 The lower limit of the Hazard Ratio confidence interval should encompass the required HR.
PCR improvement alone: Where PCR (pathological complete response) is primary end-point and where OS data is not mature >15% absolute improvement AND >30% relative gain
Select median OS with the standard treatment:
≤12 months
> 12 and ≤24 months
> 24 months
Select ESMO-MCBS Grade
Grade 4:
HR ≤0.65 The lower limit of the Hazard Ratio confidence interval should encompass the required HR. AND OS gain ≥3 months
Increase in 2 year survival ≥10%
Grade 3:
HR ≤0.65 The lower limit of the Hazard Ratio confidence interval should encompass the required HR. AND OS gain ≥2-<3 months
Grade 2:
HR ≤0.65 The lower limit of the Hazard Ratio confidence interval should encompass the required HR. AND OS gain ≥1.5-<2 months
HR >0.65-≤0.7 The lower limit of the Hazard Ratio confidence interval should encompass the required HR. AND OS gain ≥1.5months
Grade 1:
HR >0.70 The lower limit of the Hazard Ratio confidence interval should encompass the required HR. OR OS gain <1.5 months
Adjustments:
Intervention arm associated with improved quality of life AND/OR less G3-4 toxicities.
Long term plataeu in the survival curve is observed AND OS advantage continues to be observed at 5 years.
When long term plateau is observed in survival curve and OS advantage observed at 5 years, also score using form below used for treatments with curative potential.

Grade A:
OS improvement: Abolute improvement in OS (overall survival) >5% at ≥3 years follow-up
DFS Where DFS (disease free survival) is primary end-point and where OS data is not mature improvement alone: HR < 0.65 The lower limit of the Hazard Ratio confidence interval should encompass the required HR.
Grade B:
OS improvement: Abolute improvement in OS (overall survival) ≥ 3% BUT ≤ 5% at ≥3 years follow-up
DFS Where DFS (disease free survival) is primary end-point and where OS data is not mature improvement alone: HR 0.65 - 0.80 The lower limit of the Hazard Ratio confidence interval should encompass the required HR.
Non-inferior OS or DFS with reduced treatment toxicity or improved QoL (with validated scales)
Non-inferior OS or DFS with reduced treatment cost Where reduced treatment cost reported as study outcome (with equivalent outcomes and risks)
Grade C:
OS improvement: Abolute improvement in OS (overall survival) < 3% at ≥3 years follow-up
DFS improvement alone: Where DFS (disease free survival) is primary end-point and where OS data is not mature HR >0.8 The lower limit of the Hazard Ratio confidence interval should encompass the required HR.
PCR improvement alone: Where PCR (pathological complete response) is primary end-point and where OS data is not mature >15% absolute improvement AND >30% relative gain
Select ESMO-MCBS Grade
Grade 4:
HR ≤0.70 The lower limit of the Hazard Ratio confidence interval should encompass the required HR. AND OS gain ≥5 months
Increase in 3 year survival ≥10%
Grade 3:
HR ≤0.70 The lower limit of the Hazard Ratio confidence interval should encompass the required HR. AND OS gain ≥3-<5 months
Grade 2:
HR ≤0.70 The lower limit of the Hazard Ratio confidence interval should encompass the required HR. AND OS gain ≥1.5-<3 months
HR >0.70-≤0.75 The lower limit of the Hazard Ratio confidence interval should encompass the required HR. AND OS gain ≥1.5months
Grade 1:
HR >0.75 The lower limit of the Hazard Ratio confidence interval should encompass the required HR. OR OS gain <1.5 months
Adjustments:
Intervention arm associated with improved quality of life AND/OR less G3-4 toxicities.
Long term plataeu in the survival curve is observed AND OS advantage continues to be observed at 5 years.
When long term plateau is observed in survival curve and OS advantage observed at 5 years, also score using form below used for treatments with curative potential.

Grade A:
OS improvement: Abolute improvement in OS (overall survival) >5% at ≥3 years follow-up
DFS Where DFS (disease free survival) is primary end-point and where OS data is not mature improvement alone: HR < 0.65 The lower limit of the Hazard Ratio confidence interval should encompass the required HR.
Grade B:
OS improvement: Abolute improvement in OS (overall survival) ≥ 3% BUT ≤ 5% at ≥3 years follow-up
DFS Where DFS (disease free survival) is primary end-point and where OS data is not mature improvement alone: HR 0.65 to 0.80 The lower limit of the Hazard Ratio confidence interval should encompass the required HR.
Non-inferior OS or DFS with reduced treatment toxicity or improved QoL (with validated scales)
Non-inferior OS or DFS with reduced treatment cost Where reduced treatment cost reported as study outcome (with equivalent outcomes and risks)
Grade C:
OS improvement: Abolute improvement in OS (overall survival) < 3% at ≥3 years follow-up
DFS Where DFS (disease free survival) is primary end-point and where OS data is not mature improvement alone: HR >0.8 The lower limit of the Hazard Ratio confidence interval should encompass the required HR.
PCR improvement alone: Where PCR (pathological complete response) is primary end-point and where OS data is not mature >15% absolute improvement AND >30% relative gain
Select ESMO-MCBS Grade
Grade 4:
HR ≤0.70 The lower limit of the Hazard Ratio confidence interval should encompass the required HR. AND OS gain ≥9 months
Increase in 5 year survival ≥10%
Grade 3:
HR ≤0.70 The lower limit of the Hazard Ratio confidence interval should encompass the required HR. AND OS gain ≥6-<9 months
Grade 2:
HR ≤0.70 The lower limit of the Hazard Ratio confidence interval should encompass the required HR. AND OS gain ≥4-<6 months
HR >0.70-≤0.75 The lower limit of the Hazard Ratio confidence interval should encompass the required HR. AND OS gain ≥4.0 months
Grade 1:
HR >0.75 The lower limit of the Hazard Ratio confidence interval should encompass the required HR. OR OS gain <4.0 months
Adjustments:
Intervention arm associated with improved quality of life AND/OR less G3-4 toxicities.
Long term plataeu in the survival curve is observed AND OS advantage continues to be observed at 5 years.
When long term plateau is observed in survival curve and OS advantage observed at 5 years, also score using form below used for treatments with curative potential.

Grade A:
OS improvement: Abolute improvement in OS (overall survival) >5% at ≥3 years follow-up
DFS Where DFS (disease free survival) is primary end-point and where OS data is not mature improvement alone: HR < 0.65 The lower limit of the Hazard Ratio confidence interval should encompass the required HR.
Grade B:
OS improvement: Abolute improvement in OS (overall survival) ≥ 3% BUT ≤ 5% at ≥3 years follow-up
DFS improvement alone: Where DFS (disease free survival) is primary end-point and where OS data is not mature HR 0.65 to 0.80 The lower limit of the Hazard Ratio confidence interval should encompass the required HR.
Non-inferior OS or DFS with reduced treatment toxicity or improved QoL (with validated scales)
Non-inferior OS or DFS with reduced treatment cost Where reduced treatment cost reported as study outcome (with equivalent outcomes and risks)
Grade C:
OS improvement: Abolute improvement in OS (overall survival) < 3% at ≥3 years follow-up
DFS Where DFS (disease free survival) is primary end-point and where OS data is not mature improvement alone: HR >0.8 The lower limit of the Hazard Ratio confidence interval should encompass the required HR.
PCR improvement alone: Where PCR (pathological complete response) is primary end-point and where OS data is not mature >15% absolute improvement AND >30% relative gain
Select median PFS with the standard treatment:
≤6 months
> 6 months
Select ESMO-MCBS Grade
Grade 3:
HR ≤0.65 The lower limit of the Hazard Ratio confidence interval should encompass the required HR. AND PFS gain ≥1.5 months
Grade 2:
HR ≤0.65 The lower limit of the Hazard Ratio confidence interval should encompass the required HR. AND PFS gain <1.5 months
Grade 1:
HR >0.65 The lower limit of the Hazard Ratio confidence interval should encompass the required HR.
Toxicity assessment
Is the new treatment associated with statistically significant incremental Incremental rate refers to compared to standard therapy in the control arm. rate of (select):
Death >2%
Cardiovascular ischaemia >2%
Hospitalisation for toxicity >10%
Excess rate of severe congestive heart failure >4%
G3 neurotoxicity >10%
Severe other irreversible or long lasting toxicity >2%
Adjustments Select if one more adjustments below apply.
Treatment only leads to PFS benefit Mature data shows no overall survival benefit. AND QoL data shows no improvement
Treatment demonstrates improved QoL or less G3-4 toxicities that bother patients
Study had early crossover or stopping because of detection survival advantage at interim analysis
Long term plateau in PFS curve AND >10% improvement in PFS at 1 year.
Select ESMO-MCBS Grade
Grade 3:
HR ≤0.65 The lower limit of the Hazard Ratio confidence interval should encompass the required HR. AND PFS gain ≥3.0 months
Grade 2:
HR ≤0.65 The lower limit of the Hazard Ratio confidence interval should encompass the required HR. AND PFS gain <3.0 months
Grade 1:
HR >0.65 The lower limit of the Hazard Ratio confidence interval should encompass the required HR.
Toxicity assessment
Is the new treatment associated with statistically significant incremental Incremental rate refers to compared to standard therapy in the control arm. rate of (select):
Death >2%
Cardiovascular ischaemia >2%
Hospitalisation for toxicity >10%
Excess rate of severe congestive heart failure >4%
G3 neurotoxicity >10%
Severe other irreversible or long lasting toxicity >2%
Adjustments Select if one more adjustments below apply.
Treatment only leads to PFS benefit Mature data shows no overall survival benefit. AND QoL data shows no improvement
Treatment demonstrates improved QoL or less G3-4 toxicities that bother patients
Study had early crossover or stopping because of detection survival advantage at interim analysis
Long term plateau in PFS curve AND >10% improvement in PFS at 1 year.
Primary outcome is Toxicity or QoL AND Non-inferiority studies
Grade 4:
Reduced toxicity or improved QoL (using a validated scale) with evidence for statistical non-inferiority or superiority in PFS/OS
Grade 3:
Improvement in some symptoms (using a validated scale) but without evidence of improved overall QoL


Primary outcome is Response Rate (RR)
Grade 2:
RR is increased ≥20% but no improvement in toxicity/QoL/PFS/OS
Grade 1:
RR is increased <20% but no improvement in toxicity/QoL/PFS/OS
Grade 3:
PFS ≥6 months
ORR (CR + PR) ORR = Overall response rate. CR = Complete response, PR = Partial response ≥ 60%
ORR (CR + PR) ≥20 - <60% AND DoR ≥ 9 months ORR = Overall response rate. CR = Complete response, PR = Partial response. DoR= Duration of response.
Grade 2:
PFS ≥3 - <6 months
ORR (CR + PR) ORR = Overall response rate. CR = Complete response, PR = Partial response ≥ 40% - <60%
ORR (CR + PR) ≥20 - <40% AND DoR ≥ 6 - <9 months ORR =Overall response rate. CR =Complete response, PR=Partial response. DoR=Duration of response.


Grade 1:
PFS ≥2 - <3 months
ORR (CR + PR) ≥ 20% - <40% AND DoR < 6 months ORR = Overall response rate. CR = Complete response, PR = Partial response. DoR= Duration of response.
ORR (CR + PR) ≥ 10% - <20% AND DoR ≥ 6 months ORR = Overall response rate. CR = Complete response, PR = Partial response. DoR= Duration of response.
ESMO-MCBS score:

ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS) tool


The ESMO Magnitude of Clinical Benefit Scale was developed to assess the value of new anti-cancer therapies, taking into account the magnitude of clinical benefit, toxicity and cost within a reproducible scale and according to the public policy standard of ‘accountability for reasonableness’(1).

The tool aims to address the public policy issue of value in cancer therapies by providing a structured and consistent approach to determine the relative benefit of an anti-cancer therapy.

Guidance notes:

Hazard ratios:
Where a grading is based on a Hazard Ratio (HR) cutoff, the lower limit of the 95% confidence interval should be used rather than the point estimate. For instance if trial Y shows overall survival HR of 0.69 (95% CI 0.58 – 0.82), this meets the threshold of HR <0.65.

Modelling studies showed that the use of the lower limit of the HR can be advantageous in reducing the risk of excluding big benefit positive studies and when combined with absolute benefit assessment (OS, PFS or DFS), increases the probability of downgrading a trial with a statistically significant but clinically insignificant benefit(2)

Statistical significance:
Only adequately powered studies showing statistically significant improvement in the primary outcome defined by p value <0.05 should be graded.

Subgroup analyses:
Pre-planned subgroup analyses with maximum of 3 subgroups can be graded separately provided there is adjustment for multiple comparisons.
When statistically significant results are reported for any subgroup, then each of these should be graded separately.
Subgroups not showing statistically significant results are not graded.
Unplanned (post-hoc) subgroup analyses cannot be graded except for studies that incorporate collection of tissue samples to enable re-stratification based on new genetic or other biomarkers.

Background
The ESMO-MCBS was first developed in 2015 by an expert task-force which was reviewed by the ESMO faculty, team of biostatisticians, guidelines committee and invited experts(3). Separate forms were created for the curative and non-curative setting. The tool was extensively tested in a wide range of solid tumors and threshold values used for hazard ratios and absolute gain in OS, DFS and PFS were explored in extensive simulation studies. The use of the lower limit of the 95% confidence interval for hazard ratio rather than the point estimate was used after extensive simulations demonstrated this to be advantageous (2). In 2017 an updated version of the tool was published after feedback from the oncology community (1). The revision involved a 9-step process which was field tested followed by review by the ESMO faculty, guidelines committee, MCBS working group and executive board. Version 1.1 incorporates 9 amendments and includes an additional form to score single arm studies.

References:
  1. Cherny NI, Dafni U, Bogaerts J, et al. ESMO-Magnitude of Clinical Benefit Scale version 1.1. Ann Oncol Off J Eur Soc Med Oncol. 2017;28(10):2340-2366. doi:10.1093/annonc/mdx310
  2. Dafni U, Karlis D, Pedeli X, et al. Detailed statistical assessment of the characteristics of the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS) threshold rules. ESMO Open. 2017;2(4):e000216. doi:https://doi.org/10.1136/esmoopen-2017-000216
  3. Cherny NI, Sullivan R, Dafni U, et al. A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). Ann Oncol. 2015;26(8):1547-1573. doi:10.1093/annonc/mdv249