Step by Step Guide to Efficacy Analysis in Solid Tumors Oncology Clinical Trials
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Statistical Programming Analyst, Anastasiia Tiurdo, introduces her presentation given at the 2018 PhUSE Conference in Frankfurt, Germany
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Step by Step Guide to Efficacy Analysis in Solid Tumors Oncology Clinical Trials
- 1. Step-by-Step Guide to Efficacy Analysis in Solid Tumors Oncology Clinical Trials Frankfurt 2018 Anastasiia Tiurdo, Intego Group, Kharkiv, Ukraine
- 2. Introduction Cancer is no longer a death sentence!
- 3. I n t r o d u c t i o n Page 3 European Organization Research and Treatment for Cancer (EORTC) and others, 2000 (V1.0) and 2009 (V1.1) RECIST CriteriaFeatures Widely accepted and readily applied Subject of interest – assessment of a change in the tumor burden Covers the whole analysis process: data collection efficacy conclusion Required for all the clinical trials where ORR or PFS are study endpoints RECIST 1.1 currently in use
- 5. B a s e l i n e T u m o r D o c u m e n t a t i o n Page 5 ScreeningRequirements Evaluation within 4 weeks before TX start As many lesions as possible to be documented >= 1 measurement for the lesion All the tumors to be classified:
- 6. B a s e l i n e T u m o r D o c u m e n t a t i o n Page 6 Study Eligibility is required if ORR is a primary efficacy endpoint (typical for Phase II studies) can be accepted if Time to Progression is a primary efficacy endpoint (typical for Phase III studies). Progression Disease Definition to be clarified!
- 7. B a s e l i n e T u m o r D o c u m e n t a t i o n Page 7 Methods of Tumor Assessment Main Chest X-Ray Clinical Examination (CE) Supportive Ultrasound Endoscopy & Laparoscopy Tumor Markers Cytology & Histology
- 8. B a s e l i n e T u m o r D o c u m e n t a t i o n Page 8 Methods of Tumor Assessment The same technique to be used to one lesion at baseline and during the follow-up!
- 9. B a s e l i n e T u m o r D o c u m e n t a t i o n Page 9 Lesions Measurability.Tumor Lesions Measurement Characteristic - Lesion is Measurable if LD has min size of: 10 mm by CT scan / calipers 20 mm by chest X-ray Lesion is Non-measurable if: LD < 10 mm by CT / calipers or LD < 20 mm by X-ray Truly non-measurable
- 10. B a s e l i n e T u m o r D o c u m e n t a t i o n Page 10 Lesions Measurability.MalignantLymph Nodes Measurement Characteristic – because of normal anatomical structure Longest Diameter Short Axis Measurable: SA >= 15 mm by CT scan Non-measurable: 10 mm <= SA < 15 mm by CT scan Non-pathological: SA < 10 mm – should not be followed
- 11. B a s e l i n e T u m o r D o c u m e n t a t i o n Page 11 TumorCategorization Two separate tumor groups: and Different follow-up approaches Valid until the end of the study
- 12. B a s e l i n e T u m o r D o c u m e n t a t i o n Page 12 Target Lesions The largest & the most reproducible Measurable by definition Representatives of all cancer- affected organs Max 5 in total & max 2 per organ Documentation: LD (SA) of each lesion & Sum of Diameters. = 25 + 15 + 18 = 58 mm
- 13. B a s e l i n e T u m o r D o c u m e n t a t i o n Page 13 Non-Target Lesions All lesions excluded from the target Not required to be measurable Number is not limited Multiple lesions in the same organ in one item - Okay Documentation: the fact of the presence is enough!
- 14. B a s e l i n e T u m o r D o c u m e n t a t i o n Page 14 Non-Target Lesions. Examples
- 16. P o s t - B a s e l i n e T u m o r E v a l u a t i o n Page 16 Time Point Response
- 17. P o s t - B a s e l i n e T u m o r E v a l u a t i o n Page 17 Frequency of the tumor assessments Based on the treatment schedule and study phase Independent of a study drug delay & omission & interruption Tumor evaluation after the TX end? Depends on the study primary endpoints
- 18. P o s t - B a s e l i n e T u m o r E v a l u a t i o n Page 18 Target Response Sum of Diameters calculated NADIR - the smallest sum of diameters reported at prior study visits Criteria to be met Complete Response (CR) All the target lesions disappeared and the lymph nodes are non-pathological Partial Response (PR) >= 30% in the Sum of Diameters compared to the BSD Progressive disease (PD) >= 20% (>= 5mm) in the Sum of Diameters compared to NADIR Stable Disease (SD) No significant changes in the target lesions size
- 19. P o s t - B a s e l i n e T u m o r E v a l u a t i o n Page 19 Target Response Special lesions occasions ‘too small to measure’ disappeared LD = 0 mm, faintly seen LD = 5 mm split up LD of fragmented portions to Sum of Diameters coalesce a plane between lesions LD of each individual lesion
- 20. P o s t - B a s e l i n e T u m o r E v a l u a t i o n Page 20 Example of TargetResponse Derivation BSD = 110 mm NADIR = 68 mm 19% Decrease from BSD 31% Increase from NADIR Target Response is PD NADIR = 110 mm 11% Decrease from BSD Target Response is SD NADIR = 99 mm 38% Decrease from BSD Target Response is PR NADIR = 68 mm 34% Decrease from BSD 7% Increase from NADIR Target Response is PRNADIR - the smallest sum of diameters reported at prior study visits
- 21. P o s t - B a s e l i n e T u m o r E v a l u a t i o n Page 21 Non-Target Response No quantitative result available Criteria to be met Complete Response (CR) All the non-target lesions disappeared All the lymph nodes are non-pathological The tumor-marker level is normal Non-CR/Non-PD At least one non-target lesion is persistent OR the tumor marker level is above normal Progressive disease (PD) Unequivocal progression
- 22. P o s t - B a s e l i n e T u m o r E v a l u a t i o n Page 22 New Lesion Appearance Always means PD Must be unequivocal. Otherwise – additional evaluation!
- 23. P o s t - B a s e l i n e T u m o r E v a l u a t i o n Page 23 OverallResponse. MeasurableDisease Target Response Non-target Response New Lesion Overall Response CR CR No Complete Response CR Non-CR/non-PD No Partial Response CR NE* No Partial Response PR Non-PD or NE* No Partial Response SD Non-PD or NE* No Stable Disease NE* Non-PD No Unevaluable PD Any Yes or No Progressive Disease Any PD Yes or No Progressive Disease Any Any Yes Progressive Disease * NE - Not All Evaluated
- 24. P o s t - B a s e l i n e T u m o r E v a l u a t i o n Page 24 OverallResponse. Non-Measurable Disease only Non-target Response New Lesion Overall Response CR No Complete Response Non-CR/non-PD No Non-CR/non-PD NE* No Unevaluable Unequivocal PD Yes or No Progressive Disease Any Yes Progressive Disease * NE - Not All Evaluated
- 26. B e s t O v e r a l l R e s p o n s e Page 26 Best OverallResponse (BOR) the best response across all the time points up to the treatment/study end or the start of the new therapy –> to be confirmed? –> to be confirmed? –> min time from baseline!
- 27. B e s t O v e r a l l R e s p o n s e Page 27 Complete Response Confirmation First Time Point Response Subsequent Time Point Response Best Overall Response (BOR) CR Complete Response PR Stable Disease* or Progressive Disease** or Partial Response SD Stable Disease* or Progressive Disease** PD NE Stable Disease* or Unevaluable** Min time from baseline criterion: *- met,**- notmet.
- 28. B e s t O v e r a l l R e s p o n s e Page 28 Partial Response Confirmation Min time from baseline criterion: *- met,**- notmet. First Time Point Response Subsequent Time Point Response Best Overall Response (BOR) CR Partial Response PR Partial Response SD Stable Disease PD Stable Disease* or Progressive Disease** NE Stable Disease* or Unevaluable**
- 29. B e s t O v e r a l l R e s p o n s e Page 29 Best OverallResponse. Example 1 Requirements: - min SD duration - 7 weeks - min 4 weeks between assessments to confirm BOR Unconfirmed BOR is CR Confirmed BOR is PR
- 30. B e s t O v e r a l l R e s p o n s e Page 30 Best OverallResponse. Example2 Requirements: min SD duration - 7 weeks min 4 weeks between assessments to confirm BOR Unconfirmed BOR is PR Confirmed BOR is SD
- 32. O t h e r E f f i c a c y E n d p o i n t s Page 32
- 33. O t h e r E f f i c a c y E n d p o i n t s Page 33 Endpoint Name Start Time Point Event of Interest Censoring Date First PR/CR Date First PD Date Last non-PD Tumor Assessment Date First Treatment / Randomization Date First PD Date Last non-PD Tumor Assessment Date First Treatment / Randomization Date First PD or Death Date Last non-PD Tumor Assessment Date Time to Event Endpoints
- 34. Conclusion
- 35. C o n c l u s i o n Page 35 All Lesions Identified at Baseline Target Lesions Non-Target Lesions Target Response New Lesions Non-Target Response Overall Responses from Follow-up Time Points 1-st PD Date SD Duration BOR PFS DOR CBR Time to PD ORR Efficacy Analysis Process
Editor's Notes
- We are living in the time when the number of cancer patients is shocking. Fortunately, from year to year cancer ceases to be a mortal diagnosis because the diagnostic methods and treatments are constantly changing and improving. Surely, in some cases cancer cannot be cured completely. However, it can be successfully controlled for many years. It has become possible due to the achievements of different pharmaceutical companies that have been working hard on discovering a treatment that will fight different types of this disease. As mentioned in the paper title, today I am going to talk about solid tumors oncology, namely about RECIST Criteria. It is the main instrument to evaluate an objective response to the study treatment in oncology clinical trials nowadays. The abbreviation is commonly used in a clinical programmer’s daily routine but not everyone has a deep understanding of the RECIST requirements and we are going to change it right now. At first, I was assigned to support oncology clinical trial approximately 3 years ago and, for sure, I had very many questions at that time. The worst thing was that I could not understand the efficacy data to identify data issues. What I mean now, most of us know that if the reported diastolic blood pressure is higher than the corresponding systolic blood pressure, then it is definitely a case of data issue. However, if we have some tumor measurements collected and the response that is based on these measurements, it is not so obvious to see whether the response has been defined correctly.
- So, what is the RECIST? – Response Evaluation Criteria in Solid Tumors. It is the widely accepted and readily applied standard criteria used in the majority of oncology clinical trials today. The main object of the RECIST Guideline is the assessment of changes in the anatomical tumor burden during the study follow-up. The criteria are required to be applied to all clinical trials where the Objective Response or Progression-Free Survival are in the list of the study endpoints. The Guideline provides with the details of efficacy analysis in solid tumors oncology studies starting from the data collection process and up to the final RECIST compliant statistical results Two versions of RECIST criteria have been provided so far by the European Organization Research and Treatment for Cancer in collaboration with other organizations. Version 1.0 in 2000 and version 1.1 in the 2009. The latter one is the most up-to-date and has been described in the paper.
- Now let us talk about RECIST 1.1 it in details. The first point is Baseline Tumor Documentation.
- To ensure the most honest tumor response RECIST1.1 gives some requirements to take into account at baseline. Namely, all the evaluations should be done as close to the study treatment start as possible and never more than 4 weeks before the beginning of the treatment. As many lesions presented at baseline as possible should be documented per patient. The study protocol can contain the list of organ sites for obligatory evaluation at baseline defined by the type of cancer investigated in a particular clinical trial. Each lesion must be accurately measured in at least one direction and all the measurements should be recorded in a metric notation. Then, all the examined tumor lesions and lymph nodes must be categorized as measurable or non-measurable.
- If at least one measurable lesion is present, it is said that the patient has a Measurable Disease, otherwise the patient has a Non-Measurable disease only. In case the objective tumor response is a study primary endpoint, only patients with a measurable disease can be involved in the efficacy analysis. However, if primary endpoints include only the time to tumor progression, the study protocol must specify whether the patients without a measurable disease are also eligible. Since the restriction to a measurable disease may slow down the recruitment to the study, trials often allow entering both types of patients. In such cases, the protocol should contain the description of findings that could be classified as the disease progression for patients with only a non-measurable disease.
- The slide shows all possible methods of tumor assessments. The best currently available and reproducible methods to evaluate a tumor size are CT and MRI. Also X-Ray and Clinical examination can be used.
- What you really need to know about the method of tumor assessment is that RECIST requires the same technique of assessment to be used to describe each particular lesion at baseline and during the follow-up. This will ensure the most accurate and meaningful feedback.
- Now let us look at the concept of measurability. RECIST 1.1 suggests two different approaches, namely for the lesions other than lymph nodes and for lymph nodes separately. I am going to start from the tumor lesions that are not lymph nodes. The Longest Diameter should be used as a measurement characteristic of all of them. Measurability criterion depends on the method of the tumor assessment. A measurable tumor lesion is defined as a lesion with the minimum size of 10 mm by CT scan or caliper and 20 mm by chest X-ray. All the other lesions are considered non-measurable. These are small lesions with the longest diameter less than 10 mm as well as the lesions that cannot be accurately measured with caliper or imaging techniques. The latter ones are called truly non-measurable.
- Unlike other tumor types, a short axis is used as a measurement characteristic of lymph nodes. Such a decision has been made in order to provide with a more objective measurement since the lymph nodes are normal anatomical structures, which may be visible by imaging even if a lymph node does not contain any tumor cells. In the picture, there is an example of nodal measurement. The nodal size is normally reported in two dimensions. The longest of these measures is called the longest diameter and the smallest of them is the short axis. RECIST 1.1 gives the following idea of lymph nodes classification: Malignant lymph nodes with the short axis 15 mm or longer when assessed by CT scan are considered measurable. All the other lymph nodes with the short axis between 10 and 15 mm are presumed to be non-measurable. Nodes with the short axis less than 10 mm are non-pathological and should not be recorded or followed.
- As soon as lesions measurability have been documented, the next step is to divide all the tumors into two separate groups - target and non-target. This step is important, since different approaches will be used to follow-up each of the types. The classification will be valid until the study discontinuation. It means that a tumor defined as target at baseline cannot become non-target during the follow-up and vice versa.
- The target lesions are selected based on the tumors size and their suitability for accurately repeated measurements. It can be the case that the largest lesion is not suitable for the follow-up because of the unstable configuration. Therefore, the largest most reproducible measurable lesions up to a maximum of two per organ and five in total should be defined as target lesions and recorded at baseline. The target lesions should be represented in as many cancer-affected organs as possible. As soon as the list of target lesions is prepared, a baseline sum of the diameters should be calculated. BSD includes the longest diameter for non-nodal lesions and a short axis for nodes. It will be used as a reference to describe post-baseline target lesions responses. The examples of target lesions and BSD calculation can be seen in the slide.
- All the other lesions that have not been defined as target should be identified as non-target lesions. Their number is not limited and it is allowed to report multiple non-target lesions located in the same organ as a single item. Although some non-target lesions may actually be measurable, they should be reported only qualitatively, so the fact of presence at baseline is enough. In the slide, you can also see examples of non-target lesions.
- In this slide, you can also see examples of non-target lesions: non-measurable, cystic, located in previously treated area and so on.
- This is the end of the baseline tumors documentation process. Let us see what is going on during post-baseline visits.
- A post-baseline response of the oncology disease itself is called Overall Response. It is based on three main factors, namely, target disease response, non-target disease response, and the appearance of new lesions.
- The frequency of the tumor evaluation depends on the study phase and schedule of the treatment, and should not be affected by a study drug delay, omission or interruption. The necessity and frequency of tumor evaluation after the end of the study therapy depends on the study endpoints.
- The first thing to discuss is Target Lesions Response. Similar to what has been done at baseline, the longest diameter or short axis of each target lesion should be measured and added to the Sum of Diameters. Then RECIST 1.1 suggests considering Complete Response if all target non-nodal lesions disappeared and all lymph nodes became non-pathological. Partial Response should be reported if there is at least 30% decrease in the Sum of Diameters comparing to Baseline. Progressive disease is documented if Sum of Diameters increased by 20% or more comparing to the smallest sum of diameters reported at prior study visits that is called NADIR. The increase should be at least 5 mm. Otherwise, if there was no significant Sum of Diameters changes, Stable Disease is assumed.
- Sometimes target lesion may become too faint that it is impossible to provide an exact measure. In such a case ‘too small to measure’-status is reported with one of the default values for the diameter: 0 mm if the lesion is likely to have disappeared, or 5 mm if the lesion is still faintly seen. If non-nodal target lesion has split up, the longest diameters of the fragmented portions should be added to the Sum of Diameters. If the lesions coalesce, a plane between them may be used to measure the diameter of each individual lesion.
- Here you can see how Target Response is defined. Let us look at the visit Week 24 in details: Sum of the Diameters is 73 mm, Baseline Sum is 110 mm, The best prior reported result is 68 mm. This means 34 % Decrease from Baseline and 7% Increase from NADIR. Looking to the previous table, we consider Partial Response.
- The definition of the Non-target response is not so transparent since no numeric results are reported for non-target lesions. RECIST 1.1 says that Complete Response should be concluded if all non-target tumors disappeared, lymph nodes became non-pathological, and tumor marker level is normal. Non-Complete Response/ Non–Progressive Disease status takes place if at least one non-target lesion is visible or tumor marker level is above normal. Otherwise, Unequivocal Progression should be reported. Usually, a minor tumor size increase is not sufficient to report unequivocal progression. There must be such overall substantial worsening in a non-target disease that even providing target response is SD or PR, the overall tumor burden has increased sufficiently.
- The appearance of a new lesion always means disease progression, so it should be carefully defined. The finding should be unequivocal and not related to the differences in the scanning technique. Otherwise, if a new lesion is equivocal because of its small size or any other reason, an additional evaluation is recommended. A lesion identified in a location that was not examined at baseline should be considered a new one as well.
- As soon as the Target and Non-target responses are received and all the new lesions documented, Overall Response can be defined. Two fundamentally different cases are described in the RECIST 1.1 Guideline. The first one is when the patient has a Measurable Disease and you can see it in the slide now. The most important point is that the Progression in at least one of the three components gives the Overall Response equal to PD. Complete response can be concluded only if both the target and non-target tumors show Complete Response and no new lesion has been found. Concerning the situation when not all target tumors have been evaluated, it is likely to lead to Unevaluable Overall Response. However, Overall Disease Progression can be reported if it is clear that the contribution of non-assessed lesions would not influence the response.
- In the second case, when no measurable disease is available, the algorithm is much easier. Note that the list of possible overall responses is different since no Partial Response can be claimed. In addition, Non-Complete Response/Non-Progressive Disease Status is used instead of Stable Disease Response.
- Finally, when all the time point responses are collected, we can switch to efficacy endpoints derivations. The first point is Best Overall Response.
- The best overall response is the best response reported for the patient during the treatment or study period depending on what is said in the protocol. The period can be shortened by the start of additional cancer therapy before disease progression. If a Stable Disease is assumed as BOR, it must meet the minimum time from baseline criterion, generally 6 - 8 weeks. If the time minimum has not been achieved, the response should be defined based on the subsequent assessment. If there is no subsequent assessment available, BOR should be considered unevaluable.
- Depending on the study requirements, Complete and Partial Responses may need a confirmation. RECIST 1.1 recommends using confirmation for clinical trials without a control group or for the studies where the objective response rate is a primary efficacy endpoint. The idea of the confirmation is that the BOR should be derived taking into account a subsequent time point assessment result. Sufficient subsequent assessments for BOR confirmation should be performed no less than 4 weeks in between. The confirmation scheme for Complete Response is now in the slide. It is quite straightforward except for the case when Complete Response had been reported at the first time point but was not confirmed on a subsequent visit, so Partial Response has been reported. The problem is that even Partial Response, which was met at the subsequent time point, would mean disease progression comparing to the previous result. In fact, three outcomes are possible. If minimum duration criterion for Stable Disease was met, then Stable Disease would be reported, otherwise – Progressive Disease. Nevertheless, sometimes the subsequent scan may clarify that small lesions are still in place but not measurable any longer. This would mean that at the first time point the patient experienced a Partial, but not Complete Response. In this case, BOR should be set to Partial Response.
- In the next slide, you can see the confirmation scheme for Partial Response case but it is similar to the Complete Response case.
- This slide provides you with an example of the Best Overall Response Definition. Let us assume that the tumor evaluations were repeated each 8 weeks. The minimum criterion for SD duration is 7 weeks. Subsequent assessments sufficient for BOR confirmation should be performed no less than 4 weeks in between. In this example, Unconfirmed BOR is Complete Response while Confirmed BOR is Partial Response. The reason is no record to confirm CR is available but there are two consequent PR observations with more than 28 days in between.
- In the second example, Unconfirmed BOR is Partial Response, while Confirmed BOR is Stable Disease. The reason is no record to confirm PR is available but the first PR assessment has met minimum criterion for stable disease duration.
- Finally, we are going to have a quick look at the other efficacy endpoints that could be derived using RECIST compliant data.
- First two ones are based on the BOR results. Objective Response Rate is the ratio of the patients with the Best Overall Response equal to Complete or Partial Response to the total number of patients. Clinical Benefit Rate is the ratio of the patients with the Best Overall Response equal to Complete Response, Partial Response or Stable Disease to the total number of patients.
- Time to event analysis is a powerful statistical instrument widely used in oncology clinical trials. The list of target endpoints includes progression free survival, duration of response and duration of stable disease. Unfortunately, there is not enough time to discuss it in details but you can find some additional information in my paper.
- Now it is time to sum up. We have discussed the whole process of the RECIST compliant efficacy analysis in solid tumors oncology clinical trials. You can see all the steps that we have covered in the picture. We started from the baseline tumor assessments, and then continued with tumors categorization, follow up evaluations, overall response definition, and finished with the efficacy endpoints derivations. Thanks for your attention! Any questions are welcome!