CLINICAL RESPONSE ASSESSMENT Dr. Varun Goel Medical oncologistRajiv gandhi cancer institute
INTRODUCTION• Evaluating the efficacy of anti-cancer treatment is important for medical decisions • in practice as well as in clinical trials.• The methodology used to evaluate the response has evolved substantially over the past decades • complete subjective evaluation complex set of objective criteria attempting to standardize the response evaluation process
INTRODUCTION• Early attempts were made in the early 1960s • Zubrod CG, et al. J Chronic Dis 1960;11:7–33• Tumour shrinkage• In 1976, 16 experienced oncologists, gathered to decide what would be considered a reliable measure of response to therapy. • Measurement tool - product of the perpendicular diameters of a sphere.
• When two investigators measure same sphere • ideally there should be no difference. – Measurement differed by 50% • 7.8% of the time – Differences of 25% • 19% of the time –unacceptably high
• Moertel and Hanley recommended: – 50% reduction criterion should be applied in clinical settings and – that the investigator should anticipate an objective response rate of 5 to 10% due to human error in tumor measurement.” • Moertel CG, Hanley JA. Cancer 1976;38:388.
• In the early 1980s, the WHO developed recommendations in an attempt to standardize criteria for response assessment
Principles of response evaluation overall cancer burdenquantitative evaluation qualitative evaluation (measurable) (not measurable) target lesions non target lesions combination estimation of the treatment effect CR/ PR/ SD/ PD
Specificity of the WHO criteria• Recommends bi-dimentional measurement – multiply the longest diameter by the greatest perpendicular diameter.• Response Categories: • two observations not less than 4 weeks apart – CR = disappearance of all known disease – PR = 50% decrease in the sum of the products of the perpendicular diameters – PD = 25% increase in size of lesion or appearance of new lesions.
• Mid 1990s: International working group began to meet to address some shortcomings of WHO. For example: – Complexity (bidimensional measurements) – measuring methods and selection of target lesions were not clearly described in the WHO guidelines – New technologies (CT)
Response Evaluation Criteria in Solid Tumors: “RECIST” Working Group• 1995: International representation from different research organizations• Revisit definitions, assumptions, implications• Harmonize to the best standards• Simplify where possible• Update with new concepts
Key features of the RECIST• Definitions of minimum size of measurable lesions,• Instructions on how many lesions to follow• Use of unidimensional, rather than bidimensional,• Measures for overall evaluation of tumour burden.
RECIST• RECIST is a combination of both qualitative and quantitative assessment• Based on concept of target lesions and non- target lesions • Target lesions are quantitatively assessed • Non-target lesions are qualitatively assessed
RECISTTarget lesions are chosen based on 3 factors: • Must be EASILY (and reproducibly) measurable • Must be representative of the disease (clearly metastasis) • Must be representative of distribution (choose measurable lesions from all involved organs)• Non-target lesions are all other presumed manifestations of the disease • All non-measurable lesions • Measurable lesions that were not chosen as target lesions • Lesions that may be (but not definitely) metastases
Target LesionsDefinition of Measurable Lesions – Conventional CT or MRI (non-spiral): • If slice collimation <10mm, minimum lesion size is 20 mm • If slice collimation >10mm, minimum lesion size is 2 x collimation ex. Slice collimation = 15mm, minimum lesion size = 30mm – Spiral CT • If slice collimation <5mm, minimum lesion size is 10 mm • If slice collimation >5mm, minimum lesion size is 2 x collimation ex. Slice collimation = 7mm, minimum lesion size = 14mm
Target LesionsDefinition of reproducibly measurable lesions – Pick lesions with well defined edges or margins – Always measure longest diameter – Measure lesions on same phase or same sequence (MRI) – Pick lesions that are stable in position, try to avoid mobile lesions (Avoid mesenteric masses that change in position)
Target Lesionsshould represent distribution of disease – Pick lesions from disparate areas of the body – For lymphoma choose nodes from different nodal stations
Target Lesions• Measurable lesions up to a maximum of – 5 lesions per organ – 10 lesions total• Sum of longest diameter (SLD) for all target lesions will be calculated at baseline and used as reference to characterize objective tumor response
Quantitative Assessment• The “SLD” is the quantitative assessment• SLD = sum of the longest diameters of target lesions• Strict rules and definitions of: • Complete response = No measurable disease • Partial Response = Greater than 30% decrease in score • Stable Disease = Between 30% decrease and 20% increase • Progression = Greater than 20% increase in score• the threshold chosen, a 30% reduction in one dimension, was comparable to the 50% decrease in the sum of the products of the perpendicular diameters used in WHO criteria.
Non – Target Lesions• Non- measurable lesions Not suitable for accurate repeated measurements • Ascites • Leptomeningeal disease • Pleural effusions • Inflammatory breast disease • Cystic lesions • Lymphangitis cutis/pulmonis • Bone lesions • Brain lesions • Irradiated lesions • Ground glass lung lesions
Tumor Response - Target Lesions• Complete response (CR): Disappearance of all target lesions• Partial response (PR): > 30% decrease in the SLD• Stable decrease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD• Progression (PD): > 20% increase in the SLD
Tumor Response – Non-Target Lesions• Complete Response (CR): Disappearance of all non-target lesions• Incomplete Response/Stable Disease (SD): If one or more is Unchanged or Improved and no PD, “not assessed”• Progression (PD): If at least one “Clearly worse” is present• Unknown (UN): If “not assessed” or “not imaged” is present
Tumor Response – New Lesions• New Lesions = Progression (PD) • Any new malignant lesion • Any re-appearing lesion
Tumor Response - Summarized Target Non-target Overall New LesionsLesions Lesions Response CR CR No CR CR SD No PR PR CR or SD No PR SD CR or SD No SD PD Any Yes or No PD Any PD Yes or No PD Any Any Yes (PD) PD
WHO RECIST 1.0 Unidimensional, longest diameter,Measurable lesion Uni- and bidimensionala ≥10 mm (spiral CT); ≥20 mm other definition modalitiesDisease burden to Measurable target lesions up to be assessed at All (not specified) ten total (five per organ); other baseline lesions nontarget Sum of products of bidimensional diameters or Sum of longest diameters all Baseline sum Sum of linear unidimensional measurable lesions diameters Disappearance of all known Disappearance of all known CR disease disease Measurable target lesions, 30% Bidimensional disease, 50% decrease in sum of longest PR decrease in sum of products of diameters; all other disease, no diametersb evidence of progression Measurable disease, 20% increase Measurable disease, ≥25% in sum longest diameters, taking increase in size of one or more Progression as reference smallest sum in measurable lesionsc or study; or appearance of new appearance of new lesions lesions
WHO vs RECIST •33% higher threshold to meet PD •PR definitions are almost identical
• Several studies have shown a good concordance between RECIST and WHO for response but less good concordance for time to progression.• This should be taken into account for planning of future trials
• Since RECIST was published in 2000, the use of unidimensional criteria seems to perform well in solid tumour phase II studies.
However, a number of questions and issues have arisen – whether fewer than 10 lesions can be assessed – whether or how to utilize newer imaging technologies such as FDG-PET and MRI; – how to handle assessment of lymph nodes;Revision of the RECIST guidelines includes updates that touch on these points.
Major changes in RECIST 1.1• Number of target lesions;• Assessment of pathologic lymph nodes;• Clarification of disease progression;• Clarification of unequivocal progression of non-target lesions;• Inclusion of 18F-FDG PET in the detection of new lesions
• number of target lesions was reduced – from 5 per organ to 2 per organ and – from a maximum of 10 total to a maximum of 5. assessment of five lesions per patient did not influence the overall response rate and only minimally affected progression-free survival• Lymph nodes with a short axis of ≥ 15 mm are considered measurable. – as opposed to the longest axis used for other target lesions
• PD for target lesions according to RECIST 1.1, – in addition to a 20% increase also consider – a 5-mm absolute increase of the SLD. small-volume disease• Clarification of Unequivocal Progression of Nontarget Lesions – SD or PR in target disease + substantial worsening in nontarget disease = PD – extremely rare
• One of the major changes in RECIST 1.1 is the inclusion of FDG PET Summary of guideline for including FDG PET
WHO RECIST 1.0 RECIST 1.1 Unidimensional, longest Unidimensional, longest Measurable diameter tumor lesions ≥10 mm Uni- and bidimensionala diameter, ≥10 mm (spiral CT);lesion definition (CT; skin by calipers); ≥20 mm if ≥20 mm other modalities CXRMeasurable node Not defined Not defined ≥15 mm short axis definitionDisease burden Measurable target lesions up Measurable target lesions up toto be assessed All (not specified) to ten total (five per organ); five total (two per organ); other at baseline other lesions nontarget lesions nontarget Sum of products of Sum of diameters target lesions, bidimensional diameters or Sum of longest diameters all Baseline sum short axis nodes, longest Sum of linear unidimensional measurable lesions diameter others diameters Disappearance of all known Disappearance of all known Disappearance of all known CR disease; malignant nodes must disease disease be <10 mm Measurable target lesions, Measurable target lesions, 30% Bidimensional disease, 50% 30% decrease in sum of decrease in sum of longest PR decrease in sum of products longest diameters; all other diameters; all other disease, no of diametersb disease, no evidence of evidence of progression progression 20% increase in sum of Measurable disease, 20% Measurable disease, ≥25% diameters, with minimum increase in sum longest increase in size of one or absolute increase of 5 mm, Progression diameters, taking as reference more measurable lesionsc or taking as reference smallest smallest sum in study; or appearance of new lesions sum in study; or appearance of appearance of new lesions new lesions
Overall response rate• ORR has been used both in drug development and in clinical practice to indicate antitumor efficacy of a given agent or regimen.• According to US FDA ORR = PR + CR – not willing to include SD, as part of the ORR. – as it is often indicative of the underlying disease biology rather than attributed to the drug’s therapeutic effect• Def. - Portion of patients with a tumor size reduction of a predefined amount for a minimum time period• ORR (often) correlates with OS.
clinical benefit rate• To include stable disease – meaningful responses• CBR = CR + PR + SD• Originally delineated to assess the benefit of gemcitabine in pancreatic cancer. – a composite of measurements of pain, – Karnofsky performance status, and – weight.• CB required a sustained (4 weeks or longer) improvement in at least one parameter without worsening in any others
Alternate Response Criteria• Not every tumor type has been amenable to standardized definitions. E.g. – bony disease in prostate cancer, – pleural and peritoneal surface disease in mesothelioma and ovarian cancer, – and gastrointestinal stroma tumors (GIST),• often remain the same size as the center of the tumor mass undergoes necrosis• Different strategies have emerged to quantify these diseases – biomarkers and positron emission tomography (PET) criteria
Serial Biomarker Levels• multiple purposes: – for screening, – for early detection of recurrent disease, and – for monitoring response to systemic therapy.
Type Baseline Response ProgressionCA 125 in ovarian Two pretreatment CA 125 decline ≥50% 2 × nadir ORcancer (GCIG criteria) samples >2 × ULN confirmed at 28 days 2 × ULN if normalized on therapyPSA in prostate cancer ≥5 ng/mL and PSA decline of 50% PSA increase by 25%2(PSA WG 1)a documentation of two from baseline above nadir or entry consecutive increases (measured twice 3 to 4 value (50% increase if in PSA over a previous weeks apart) response achieved) reference value AND >5 ng/mL, or back to baseline, whichever is lowerhCG and AFP in Long half-life oftesticular cancer decay(>3.5 days for hCG, >7 days for AFP) is indicative of a poor
Type ResponseChoi Criteria for GISTChoi criteria for CT images in ≥10% decrease in tumor size ORGIST ≥15% reduction in tumor density
Type Baseline Response ProgressionEORTC Criteria for PETEORTC criteria for ROI should be drawn, CMR: Complete PMD: SUV increase ofresponse when using a SUV calculated resolution of uptake >25% in regionsPET scan PMR: SUV reduction defined on baseline, or ≥25% after more than appearance of new one treatment cycle FDG avid lesions SMD: <25% increase and <15% decrease in SUV
International Working Group Criteria for Lymphoma• sometimes called the Cheson criteria• CR posttreatment residual mass is allowed if it becomes PET-negative.• For lymphomas that are not consistently FDG avid, or FDG avidity is unknown, – CR • <= 1.5 cm LD if >1.5 cm at baseline, or • <= 1 cm LD if between 1.1 to 1.5 cm at baseline – PR • >= 50% decrease in SPD at baseline
Waterfall Plots• WHY? – Arbitrary initial 50% cutoff, and current RECIST threshold of 30% reduction• Ideally all responses should be confirmed after a period of at least 4 weeks.
• On the left represent patients whose tumors increased, while on the right represent patients whose tumors regressed.• The vertical red lines at +20% and –30% define the boundaries of stable disease according RECIST
• In cancer drug development – in phase 2 trial • ORR - indicator of activity, – In phase 3 trials • other end points, including PFS and time to progression (TTP)
Progression Free Survival and Time to Progression• PFS - from the time of randomization to the time of disease progression or death.• TTP - the time from randomization to the time of disease progression • deaths are censored
• For PFS - death might be an adverse effect of the therapy.• For TTP - if a patient dies but the tumor has not meet criteria for progression, one cannot accurately estimate when progression might have occurred, so the data should be censored.
Overall Survival• Time from randomization to death – gold standard of clinical trial end points • Unambiguous, • does not suffer from interpretation bias.
• No convincing evidence PFS is a surrogate for OS• Advantage in PFS or TTP disappears when one looks to OS • PFS is a shorter interval • Patients may receive multiple lines of therapy following the clinical trial, the results may be confounded by those subsequent therapies.• Magnitude of the difference does not disappear, only the statistical validity.
• Besides earlier mentioned cancer outcomes (response to treatment, duration of response) second set of outcomes in a clinical trial are patient outcomes. • i.e. increase in survival, and the quality of life before and after therapy.
Quality of LifeCore Domains Typical items• Psychological • Depression/Anxiety/ Adjustment to illness• Social • Personal relationships, sexual interest, social & leisure activities• Occupational • Employment, cope household• Physical • Pain/mobility/sleep/ sexual functioningNote order of domains; doctors tend to emphasize physical
Quality of Life• Several instruments to assess QOL have been developed and refined in the past two decades.• Acc. to earlier studies – QOL = performance status – Related but weak correlations
• Examples that have well-established levels of reliability and validity include – the Functional Living Index-Cancer (FLIC), – the Cancer Rehabilitation Evaluation System Short Form (CARES-SF), – the Functional Assessment of Cancer Therapy- General (FACT-G), and – the EORTC Core Quality of Life Questionnaire (EORTC QLQ-C30).
FLIC (Finkelstein 1988) – • a 22 item instrument • measures quality of life in the following domains: physical/occupational function, psychological state, sociability and somatic discomfort. • originally proposed as an adjunct measure to cancer clinical trials. CARES-SF (Schag 1991) – • 59 item scale • measures rehabilitation and quality of life in patients with cancer. • This has been modified to the HIV Overview of Problems Evaluation Systems (HOPES, Schag 1992) EORTC QOL-30 (Aaronson 1993) – • composed of modules to assess quality of life for specific cancers in clinical trials. • The current instrument is 30 items with physical function, role function, cognitive function, emotional function, social function, symptoms, and financial impact. FACT-G (Cella 1993) – • a 33 item scale • developed to measure quality of life in patients undergoing cancer treatment.