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Assessment of tumour response to chemotherapy for metastatic colorectal cancer: accuracy of the RECIST criteria

¹ Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, ² Université Claude Bernard EA 643, Lyon, ³ Centre Régional de Lutte Contre le Cancer Léon Bérard, Lyon, ⁴ Clinique Saint Jean, Lyon, ⁵ Hospices Civils de Lyon, Hôpital Edouard Herriot, ⁶ Hospices Civils de Lyon, Hôpital de la Croix Rousse, ⁷ Clinique Pasteur de Valence, ⁸ Centre Hospitalier de Roanne, ⁹ Centre Hospitalier de Valence, ¹⁰ Centre Hospitalier Général Lucien Hussel, Vienne, ¹¹ Centre Hospitalier de Privas, ¹² Centre Hospitalier de Bourgoin, ¹³ Centre Hospitalier de Villefranche, Gleizé, ¹⁴ Clinique Pasteur de Saint Priest, ¹⁵ Hospices Civils de Lyon, Département d'Information Médicale and ¹⁶ Aventis, France

Correspondence: Véronique Trillet-Lenoir, Hospices Civils de Lyon, Department of Medical Oncology, Centre Hospitalier Lyon Sud, 69495 Pierre Bénite, France

	Abstract

Top Abstract Introduction Patients and methods Results Discussion References

 
Evaluation of tumour size modifications in response to treatment is a critical issue in the management of advanced malignancies. In 1981, the World Health Organization (WHO) established guidelines for tumour response assessment. These WHO1981 criteria were recently simplified in a revised version, named RECIST (Response Evaluation Criteria in Solid Tumours), which uses unidimensional instead of bidimensional measurements, a reduced number of measured lesions, withdrawal of the progression criteria based on isolated increase of a single lesion, and different shrinkage threshold for definitions of tumour response and progression. In order to validate these new guidelines, we have compared results obtained with both classifications in a prospective series of 91 patients receiving chemotherapy for metastatic colorectal cancer. Data from iterative tomographic measurements were fully recorded and reviewed by an expert panel. The overall response and progression rates according to the WHO1981 criteria were 19% and 58%, respectively. Using RECIST criteria, 16 patients were reclassified in a more favourable subgroup, the overall response rate being 28% and the progression rate 45% (non-weighted kappa concordance test 0.72). When isolated increase of a single measurable lesion is not taken into account for progression with the WHO1981 criteria, only 7 patients were reclassified and the kappa test was satisfying, i.e. 0.75, for the whole population as well as for each of the responding and progressive subgroups. Since it provides concordant results with a simplified method, the use of RECIST criteria is recommended for evaluation of treatment efficacy in clinical trials and routine practice.

	Introduction

Top Abstract Introduction Patients and methods Results Discussion References

 
Medical decision making guidelines for potentially active new drugs, as well as routine practice in cancer treatment, is based on evaluation of tumour response. On the initiative of the World Health Organization (WHO), recommendations were developed in the early 1980s in an attempt to standardize the criteria for response assessment [1]. However, as far as the definition of tumour progression is concerned, these rules are not easily applicable and often not strictly followed in daily oncology practice and even in the clinical research setting. Furthermore, since the measurement methods and selection of target lesions were not precisely described in these guidelines, assessment of tumour response is shown to be poorly reproducible from one investigator, or group of investigators, to another [2, 3].

The objectives of the present study were to attempt to clarify and simplify these recommendations and to evaluate the validity of a simpler definition for tumour progression, and less time consuming methods to select and measure target lesions. This prospective study on tumour response evaluation in a consecutive series of patients receiving cytotoxic chemotherapy for metastatic, inoperable colorectal carcinoma was started in 1997. Since chemotherapy is the recommended therapeutic option in this clinical situation [4], it offers a relevant clinical model for the study of tumour response evaluation methods. Usually metastases are bidimensionnally measurable, confined to a maximum of two types of organs, namely liver and lungs, and mainly investigated through the use of a unique radiological technique, i.e. spiral CT, which is considered at the present time as the reference technique [5]. A revised version of the WHO recommendations was proposed in 1999 [6] and adopted in early 2000 by the Response Evaluation Criteria In Solid Tumours (RECIST) group [7]. We therefore took the opportunity to add to our evaluation these new criteria, which have until now been validated only by retrospective analyses of clinical trials data.

	Patients and methods

Top Abstract Introduction Patients and methods Results Discussion References

 
Selection of patients
From March 1997 to January 1999, 91 consecutive patients, from 13 participating centers, with metastatic (proven by fine-needle aspiration or biopsy) adenocarcinoma of the colon or rectum requiring intravenous chemotherapy as first or second line treatment were enrolled in the study. Selection criteria included Karnofsky index 50%, presence of at least one bidimensionally measurable hepatic or pulmonary metastasis 10 mm, and no evidence of peritoneal carcinomatosis on a CT scan performed no more than 21 days prior to entry in the study. All patients were fully informed, however, no written consent was required for participating in the study according to the recommendation of the local ethical committee.

Choice of chemotherapy regimen was left to the investigators' discretion from the published active combinations: modulated fluorouracil, either alone [8], or in combination with oxaliplatin [9] or irinotecan [10], and raltitrexed single agent [11], or continuous fluorouracil. Investigators were advised to continue treatment until documented disease progression, unacceptable toxicity and/or any opportunity for surgical resection. The decision to continue chemotherapy or not according to tumour response was made on the basis of the radiological interpretation prior to its revision by the study review committee.

Methodology for tumour assessment
Tumour evaluation was carried out using spiral CT scans of the thorax, abdomen and pelvis performed every 8 weeks until disease progression, for a maximum of five consecutive visits following baseline evaluation. The radiological technique was fully indicated in the study protocol and recommended the use of spiral CT with 10 mm collimation, 10 mm s^-1 speed and a maximum 10 mm reconstruction. In each participating center, a single radiologist was designated as responsible for the study and asked to provide, for each examination, a copy of the images mentioning the selected target lesions and corresponding measurements, and to complete the case report forms. Each report form contained evaluation date, involved organ and location and bidimensional measurements of as many target lesions as possible up to a maximum of 10 per organ. Both the number of detected and measured lesions was recorded at each visit. Each lesion was given a number and repeatedly assessed at each visit. The evaluation review committee was composed of four expert radiologists (AF, PK, OP, PJV) who gathered together in order to verify, and eventually modify, the selection of lesions and the measurement procedures for each examination.

Criteria for response assessment
Since the study started in 1997, tumour response was first assessed using WHO1981 criteria as the reference criteria, as follows [1]:

• A lesion was considered to be measurable if its longest dimension was 10 mm. Although all lesions were counted for assessment of the total number of lesions, only the 10 largest measurable target lesions per organ were considered for tumour size evaluation.
  
• Complete response (CR) was defined as complete disappearance of all known disease.
  
• Partial response (PR) was defined as 50% decrease in total tumour load, defined as the sum of the tumour areas of bidimensionally measured lesions [(largest diameter (LD) x greatest perpendicular diameter) + sum of LD of unidimensionally measured lesions], taking as reference the baseline corresponding values, without the appearance of a new lesion.
  
• No change (NC) was defined as <50% decrease or <25% increase in the tumour area of one or more measurable lesions.
  
• Progressive disease (PD) was defined as occurrence of one or a more of the 3 following situations. PD1, 25% increase in total tumour load, taking as reference the smallest similar value recorded since treatment started; PD2, 25% increase in tumour area of at least one measurable lesion, taking as reference the smallest similar value recorded since the treatment started; PD3, appearance of at least one new lesion.
  

Results were compared with those obtained by varying the following evaluation parameters.

• Criteria for tumour progression. Classical definition of progression including the PD1, PD2 or PD3 criteria vs progression restricted to PD1 or PD3 without taking into account the PD2 criteria (in this case patients with 25% increase in tumour area of a single measurable lesion without significant increase in total tumour load are not considered as progressive).
  
• Number of measured lesions. Up to 10 lesions per organ vs only the largest 5.
  
• Tumour response assessment according to the RECIST method.
  

These recently published RECIST recommendations are based on the use of unidimensional, rather than bidimensional, measurements. Using mathematical comparisons between changes for maximum dimensions and the product of the largest perpendicular dimensions in spheroidal tumours, the authors conclude that the level of tumour decrease should then be 30% instead of 50% for PR. In addition, they propose to switch the PD level from 25% to 20%. Comparison between WHO1981 and RECIST criteria for classification is presented in Table 1.

Statistical methods
The reviewed data were collected on an Excel® spreadsheet specifically designed to allow an automatic recalculation of each patient's response according to the following variables: criteria selected for the definition of progression; maximum number of lesions considered; unidimensional or bidimensional measurements; threshold values (%) of tumour size variations for response assessment. The overall result of each recalculation was then compared using a non-weighted kappa test. Using this test, concordance may be considered as very satisfactory for values 0.75 [12].

	Results

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Patient characteristics
104 patients were initially recruited, but 13 were considered not eligible for documented radiological assessment of tumour response; 6 because the CT scan was not available for review, 3 because they had no measurable lesion and 4 because they died or were lost to follow-up prior to the first assessment of response. The main characteristics of the remaining 91 evaluable patients are presented in Table 2. Median age was 65 years. Following baseline evaluation, a total of 183 assessments were performed with a mean of 2 (range 1–5) assessments per patient. A total of 1041 liver lesions and 652 lung lesions were identified at baseline evaluation. Using a maximum of 10 lesions per organ, a total of 349 liver target lesions and 27 lung lesions were measured with a mean of 4.1 lesions per patient.

Restricted criteria for tumour progression
The use of a definition of tumour progression restricted to PD1 and/or PD3 (BIDIM/L10/PD1-3) led to a kappa test equal to 0.82. The withdrawal of the criteria based on the progression of at least one target lesion (PD2) resulted in the reclassification of 10 of the 91 patients. All 10 patients were initially considered as in the standard BIDIM/L10/PD1-2-3 criteria. Seven were reclassified as NC and three as PR. This classification will be further developed as "routine reference criteria".

Restricted number of measured lesions
When the 5 largest lesions per organ were taken into account instead of 10 (BIDIM/L5/PD1-2-3), the kappa coefficient was equal to 0.96. A change in tumour response assessment was observed in 2 of 91 patients. These two patients were initially considered as PD with the reference criteria BIDIM/L10/PD1-2-3. The use of 5 instead of 10 lesions resulted in their reclassification as PR.

Restricted criteria for tumour progression and number of measured lesions
When using both the PD1-3 definition of progression, and 5 instead of 10 target lesions (BIDIM/L5/PD1-3), the kappa test was equal to 0.82. A change in tumour response assessment was observed in 10 of 91 patients. These 10 patients were switched from the PD to the NC (7 patients) or PR (3 patients) group.

RECIST recommendations
When RECIST recommendations were used, (UNIDIM/L5/PD1-3), the kappa test was equal to 0.72. 16 patients were reclassified. 12 were switched from the PD group; 8 to the NC group and 4 to the PR group. Four patients were switched from the NC to the PR group. Overall, population distribution according to best ever observed tumour response with RECIST criteria was as follows: CR, 3 patients (3.3%); PR, 22 patients (24.2%); CR+PR, 27.5%; NC, 25 patients (27.5%); and PD, 41 patients (45.1%). Direct comparisons between WHO1981 and RECIST classifications are shown in Table 3. It should be noted that the use of unidimensional measurements did not modify the number of measurable lesions.

Results in terms of objective response and progression rates obtained with the reference criteria, routine reference criteria and RECIST criteria are shown in Table 4. When compared with the reference WHO1981 (BIDIM/L10/PD1-2-3) criteria, RECIST criteria do not reach the concordance level, especially in terms of rates of progression (kappa test =0.50). When compared with routine reference criteria (BIDIM/L10/PD1-3), the concordance level becomes optimal for comparisons of both response rates (kappa test =0.75) and progression rates (kappa test =0.91).

	Discussion

Top Abstract Introduction Patients and methods Results Discussion References

 
Reporting of cancer treatment results has, since 1981, relied on the rules described by Miller et al [1]. Such standardization of guidelines for tumour response assessment has helped greatly in the methodology of new drugs screening, as well as in the comparisons of drug efficacy in a given randomized trial or between one trial and another. In addition, there is increasing evidence of a strong relationship between tumour response and survival, the major clinical endpoint in cancer treatment [13]. However, most investigators and research groups have had to face the problem of criteria complexity. Since no precise indication was given as regards selection of target lesions, considerable time-consuming efforts have been spent repeatedly assessing the bidimensional measurements of a maximum of, and if possible all, initially detected clinical and radiological abnormalities, whereas the PD2 criteria for progression might have been seldom used. In an attempt to describe and validate a possible simplification of the guidelines, in 1997 our group started a prospective study on colorectal cancer metastasis measurement by CT. A similar approach for clarification and simplification of tumour response assessment rules led the RECIST group to publish the new criteria where bidimensional measurement, use of the PD2 criteria and exhaustive measurement of all lesions were abandoned. However, previous recommendations have been used for almost 20 years in thousands of cancer trials and still appear as a reference criteria for any historical comparison. For this reason, any proposal for modification of such criteria is worth evaluating prospectively [14]. Our database offers the opportunity to compare results obtained using the two successive WHO criteria for treatment efficacy.

In our series of 91 patients receiving various treatments for inoperable metastatic colorectal cancer, overall response rate was 19% and progression rate 58% according to WHO1981 criteria. These figures are concordant with the literature in a population of patients of which 58% received 5 fluorouracil modulated by leucovorin [15]. When assessed using RECIST criteria, CR rate, by definition, remains the same, overall response rate increases to 28% and progression rate drops to 45%. Use of RECIST criteria leads to the reclassification of 16 patients (17.6%) from the PD to NC and PR groups, and from the NC to PR groups. As already mentioned by Therasse et al [7] in their retrospective comparison between the use of WHO1981 and RECIST criteria in six trials including 795 patients, the switch from WHO1981 to RECIST criteria results in a more favourable classification.

When using the strict WHO1981 definitions in our study, the kappa test shows low concordance for progression rates. However, it is known [6] that many groups have not taken into account the change in a solitary lesion, PD2 in the present paper, in the classification of a patient in the "progressive" category. In fact, the theoretical reference criteria have been replaced in most groups by the routine reference criteria. Under these conditions, concordance between the response and progression rates appears very good, as summarized in Table 4. This is due to the fact that the lack of PD2 criteria (BIDIM/L10/PD1-3) accounts for the majority of discrepancies (10 patients), while the reduction in the number of measured target lesions per organ from 10 to 5 (BIDIM/L5/PD1-2-3) only changes the response status in 2 patients. It is of interest that when both criteria are retained (BIDIM/L5/PD1-3), differences in classifications are not cumulative and 10 patients are classified differently. In fact, most of the lesions progressing according to PD2 criteria only are among the smallest, and are no longer taken into account when only the five largest lesions are considered.

Overall, our work provides evidence for the accuracy and usefulness of RECIST criteria and validates the use of unidimensional measurement, the simplification of the definition of progressing tumours, and the selection of the biggest five lesions per organ. However, the consequent variations in assessment of efficacy should be kept in mind in various clinical situations. Any comparison between non-randomized trials performed before and after publication of the RECIST criteria should be performed with caution. Data analysis on investigational new drugs might slightly overestimate efficacy based on the response rate when compared with previous phase I trials.

Metastatic colorectal cancer is a quite simple model where the lesions are, most of the time, confined to either lung and/or liver, detectable on CT and usually assessable. The validation of RECIST criteria might also have to be tested in more complex situations such as clinically measurable masses, bone metastases or central nervous system tumours. Furthermore, as mentioned in both WHO types of criteria, tumour response evaluation is not restricted to the measurement of radiological lesions. For instance, the use of CA 125 has recently been integrated into the RECIST criteria for ovarian tumours and prostate-specific antigen in prostate cancer [16] might soon be validated and added to clinical and radiological tumour measurement.

	Acknowledgments

 
The authors acknowledge the work of the following participants: L Descos, B Flourié, S Claudel-Bonvoisin and VA Tran Minh, Centre Hospitalier Lyon Sud; Pierre-Bénite, JC Souquet, P Douek and G Picaud, Hôpital de la Croix Rousse, Lyon; JA Cayvialle and T Ponchon, Hôpital Edouard Herriot, Lyon; C Trepo, C Jouisse and F Rabatel, Hôpital de l'Hôtel Dieu, Lyon; C Colin, Medical Information Department, Lyon; T Fontanges, M Cuinet and C Loubier, Centre Hospitalier de Bourgoin; W Mehzer, Centre Hospitalier de Privas; JC Montoy, Centre Hospitalier de Roanne; H Hamon, S Gerenton, F Deplus, P Jaillot and E Tixier, Centre Hospitalier de Valence; E Vaillant and H Kayayan, Centre Hosipitalier Général Lucien Hussel, Vienne; JM Moreau and P Fougier, Centre Hospitalier de Villefranche, Gleizé; S Négrier, Centre Régional de Lutte Contre le Cancer Léon Bérard; B Napoleon and M Bretagnolle, Clinique Saint Jean, Lyon; E Leprince and P Lorenzelli, Clinique Pasteur de Saint Priest; and P Amoyal, D Rouhier and R Leclercq, Clinique Pasteur de Valence.

	Footnotes

 
This work was supported by a grant from Aventis, Paris, France.

Received for publication January 30, 2002. Revision received May 15, 2002. Accepted for publication May 21, 2002.

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