1.Measurement of tumor lesions
(1) Definition of tumor lesion baseline
Tumor lesion baseline is divided into measurable lesions (at least one measurable lesion): lesions that can be accurately measured with conventional techniques, lesion diameter length 320mm or spiral CT 310mm. Non-measurable lesions: all other lesions (including small lesions i.e. conventional technique with length diameter <20mm or spiral CT <10mm ) including bone lesions, meningeal lesions, ascites, pleural fluid, pericardial effusion, inflammatory breast cancer, cancerous lymphangitis of the skin or lung, abdominal masses and cystic lesions that cannot be diagnosed and followed up by imaging.
(2) Measurement methods
The same techniques and methods were applied to assess lesions at baseline and follow-up.
(a) Clinically superficial lesions such as palpable lymph nodes or skin nodules can be used as measurable lesions, and color photographs with scale size should be used for skin lesions.
(b) Chest X-ray: a clear and definite lesion can be used as a measurable lesion, but a CT scan is preferable.
(c) CT and MRI: For judging measurable target lesions to evaluate the efficacy, CT and MRI are currently the best and repeatable follow-up methods. For thoracic, abdominal and pelvic cavities, CT and MRI are scanned with 10 mm or thinner layers, spiral CT with continuous scans at 5 mm layers, while special protocols are used for the head and neck and special sites.
(d) Ultrasound pick-up: When the endpoinst of the study is objective tumor efficacy, ultrasound cannot be used to measure tumor lesions, but only superficially palpable lymph nodes, subcutaneous nodules and thyroid nodules, and can be used to confirm the complete disappearance of superficial lesions after clinical examination.
(e) Endoscopy and laparoscopy: as objective tumor efficacy evaluation has not been widely and fully applied so far, only in controversial lesions or in high level study centers with clear validation purposes. Biopsy specimens obtained by this method can confirm CR on pathological tissues.
(f) Tumor markers: They cannot be applied alone to determine the efficacy. However, when tumor markers are higher than normal levels before treatment, all markers need to be restored to normal when CR is clinically evaluated. The requirement for disease progression is that an increase in tumor markers must be accompanied by visible lesion progression.
(g) Cytology and pathological histology: In a few cases, cytology and pathological histology can be used to differentiate between CR and PR and to distinguish between benign or residual malignant lesions after treatment. Cytology is needed to distinguish tumor remission, stability and progression for any exudate that occurs during treatment.
2.Evaluation of tumor remission
(1) Evaluation of tumor lesion at baseline
To establish the full tumor load at baseline, which is compared in subsequent measurements, at least one measurable target lesion, such as a limited number of curved lesions needs to be confirmed histopathologically.
(a) Measurable target lesions: should be representative of all organs involved, with a maximum of 5 lesions per organ and a maximum of 10 total lesions as target lesions, measured and recorded at baseline. Target lesions should be selected based on lesion length and diameter size and accurate repeatability of measurement. The sum of the lengths of all target lesions is used as the reference baseline for effective remission documentation.
(b) Non-target lesions: All other lesions should be treated as non-target lesions and recorded at baseline, and lesions not requiring measurement should be noted for their presence or absence during follow-up.
(2) Criteria for remission
Evaluation of target lesions
CR : All target lesions disappeared.
PR : 3 30% reduction in the total length and diameter of the baseline lesions.
SD: Baseline lesion length and diameter were reduced but did not reach PR or increased but did not reach PD.
PD: Increase of 3 20% in the total length and diameter of the baseline lesion or the appearance of a new lesion.
Evaluation of non-target lesions
CR: All non-target lesions disappeared and tumor marker levels were normal.
PD: The presence of one or more new lesions or/and the presence of non-target lesion progression.
SD: One or more non-target lesions and/or tumor markers above normal persist.
3. Overall efficacy evaluation
(1) Optimal remission assessment
Optimal remission assessment is defined as the smallest measurement recorded after the start of treatment until disease progression/recurrence (the smallest measurement recorded as a reference for progression); although there is no evidence of PD, those who stop treatment due to systemic deterioration should have “symptomatic deterioration” and detailed documentation of objective tumor progression after stopping treatment. Patients with early progression, early death, and those who cannot be evaluated should be identified. In some cases, it is difficult to distinguish the residual tumor lesions from normal tissues. When evaluating CR, a fine needle aspiration or biopsy should be used to examine the residual lesions before confirmation after 4 weeks.
(2) Frequency of tumor re-evaluation
The frequency of tumor re-evaluation is determined by the treatment plan. In fact, the benefit time of treatment is unclear, and re-evaluation every 2 cycles (6-8 weeks) is reasonable, which should be adjusted to shorter or longer time in special cases. After the end of treatment, the tumor needs to be re-evaluated to determine the endpoints of the clinical trial, whether it is the remission rate or the time to event (Time to event, TTE) that is, the time to progression/death (TimetoprogressionTTP/Time todeath, TTD) If it is TTP/TTD that needs to be routinely repeated, the secondary evaluation interval time is not strictly defined.
(3) Confirmation
The objective of objective efficacy confirmation is to avoid high RR, and changes in CR and PR tumor measurements must be confirmed by repeated judgments and must be reviewed and confirmed at least 4 weeks after the first evaluation, and longer confirmation determined by the trial protocol is also appropriate. For clinical studies with end points of Progression-Free Survival (PFS) and Overall survival (OS) it is not necessary to repeatedly confirm changes in tumor size.
(4) Remission period
It is the period from the first measurement of CR or PR until the first disease recurrence or progression.
(5) Stable phase
It is the time from the start of treatment to disease progression. The relevance of SD stage to clinical practice varies with different tumor types and different degrees of differentiation.
The remission stage, stable stage and PFS are influenced by the frequency of follow-up after baseline evaluation. Due to the influence of various factors such as the type of disease, stage, treatment cycle and clinical practice, the basic follow-up frequency cannot be determined yet, which affects the accuracy of trial endpoints to some extent.
(6) PFS/TTP
In some cases ( such as brain tumor or non-cytotoxic drug studies) PFS/TTP can be considered as endpoints for studies, especially for the initial assessment of biological drugs with non-cytotoxic mechanisms of action.
(7) Independent expert committee
For CR, PR are the main studyend points, it is emphasized that all remissions must be examined by an independent expert committee outside the study.
4. Outcome reporting
All patients in the trial including those who deviated from the treatment regimen or failed must be judged on the efficacy of the treatment (Intend to treatment, ITT) and each patient must be classified as follows CR, PR, SD, PD, died of tumor, died of toxicity, died of other tumor, unknown (not enough information to assess). All patients meeting the criteria for eligibility should be included in the analysis of RR, and all PD and death should be considered as treatment failure. Conclusions are based on patients meeting the criteria, and subsequent further analysis can be done in different subgroups of patients and provide 95% confidence limit intervals.
5, A comparison of WHO and RECIST efficacy evaluation criteria is shown in Table 2
Table 1 Total efficacy evaluation
Target lesion Non-target lesion New lesion Total efficacy
CR CR None CR
CR Not reached CR/SD No PR
PR No PD No PR
PD Any Yes/No PD
Any PD Yes/No PD
Any Any Yes PD
SD No PD No SD
Table 2 Comparison of WHO and RECIST efficacy evaluation criteria
Efficacy WHO RECIST
(Change in the product of the two largest draped diameters) (Change in the sum of the longest diameters)
CR Total disappearance of lesions maintained for 4 weeks Total disappearance of lesions maintained for 4 weeks
PR 50% reduction in size for 4 weeks 30% reduction in size for 4 weeks
PD increase by 25% increase by 20%
Non-CR/PR/SD before lesion increase Non-CR/PR/SD before lesion increase
SD Non-PR/PD Non-PR/PD