Lung Cancer (2005) 49S1, S37—S40

CT, RECIST, and malignant pleural mesothelioma

Anna K. Nowak ∗

Department of Medicine and Pharmacology, University of Western Australia and Department of MedicalOncology, 4th Floor, G block, Sir Charles Gairdner Hospital. Hospital Avenue, Nedlands, WA 6009Australia

KEYWORDSMalignantmesothelioma;RECIST;

Summary The unique growth pattern of malignant pleural mesothelioma (MPM)presents challenges for clinical investigators assessing tumour response to treat-ment. Assessment of response is an important surrogate for patient benefit, partic-ularly in phase II clinical trials. Neither the previous WHO criteria nor the more recent

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RECIST criteria are well suited to tumour measurement in this disease. This paper dis-cusses uni-dimensional measurement of tumour response in pleural mesothelioma,and the development and validation of the modified RECIST criteria for MPM, whichattempt to overcome some of the shortcomings of the RECIST criteria in this setting.© 2005 Elsevier Ireland Ltd. All rights reserved.

. Challenges of tumor measurement inleural mesothelioma

umor measurement in pleural mesothelioma pro-ides many challenges for clinical investigators.irstly, mesothelioma has a unique growth pat-ern, growing as a ‘rind’ around the hemithorax,nd along interlobar fissures. It does not conformo the roughly spherical growth pattern of manyther malignancies. Multiple thoracic levels maye involved, and while anatomical landmarks foreasurement are available in the upper and mid

horax (carina, arch of the aorta), there are fewandmarks in the lower thorax where levels of mea-urement can be reproducibly identified from onecan to another. There may or may not be bi-imensionally measurable lesions, and where le-ions are bi-dimensionally measurable, they mayot always be the most representative and appro-riate sites. Furthermore, it is often difficult to

distinguish tumor from pleural effusions or atelec-tasis without measuring Hounsfield units. In manycentres, tumor measurement is performed by clini-cians, not radiologists, who may only have accessto hard copies of images, as may central reviewboards.

2. Why measure tumor response?

When discussing tumor measurement, it is im-portant to remember why we want to measureresponse. Palliative chemotherapy aims to bene-fit patients by decreasing symptoms and prolongingsurvival, rather than to decrease tumor size alone.A decrease in tumor size may or may not achievepalliation in individual patients. However, tumor re-sponse is an important surrogate for patient benefitin non-randomized clinical trials where symptomimprovement and increased survival are difficultto assess. Objective tumor response remains the

* Tel.: +61 8 9346 3841; fax: +61 8 9346 3390.E-mail address: anowak@cyllene.uwa.edu.au.

most important primary endpoint in many phaseII trials, allowing us to determine drug activity in

169-5002/$ — see front matter © 2005 Elsevier Ireland Ltd. All rights reserved.oi:10.1016/j.lungcan.2005.03.030

S38 A.K. Nowak

a short time frame, with fewer patient numbersthan required for phase III studies. For conven-tional cytotoxic agents, the use of objective re-sponse as a surrogate allows active drugs to befast tracked, and inactive drugs to be discardedearly.

3. The WHO criteria and pleuralmesothelioma

The previously widely-used WHO tumor responsecriteria were poorly suited to the growth pattern ofpleural mesothelioma [1]. These response criteriawere most useful for measuring bi-dimensional le-sions, taking the sum of the products of the longestdiameter of each lesion and its perpendicular di-ameter as the baseline tumor measurement. A par-tial response (PR) was defined by a 50% decrease inthe sum of these products. Whilst uni-dimensionalmeasurements were allowed, the required 50% de-crease in the sum of uni-dimensional measurementsactually equated mathematically to a 75% decreasein the sum of the products of perpendicular diame-ters, making it more difficult for tumors measured

‘non-target lesions’ is difficult in view of the rind-like growth pattern of this disease.

In pleural mesothelioma, there are numerouspossible interpretations of the RECIST criteria, andmore guidelines for applying these criteria areneeded if investigators from different sites andcountries are to be consistent in their definition ofresponse. Consistency is vital for interpretation ofresults, particularly in phase II clinical trials. Forexample, what constitutes the ‘longest diameter’of the tumor? The longest diameter commonly fol-lows the curve of the chest wall; however, defin-ing the limits of such lesions is often difficult orimpossible. While tumor thickness may change inresponse to successful treatment, the extent of tu-mor along the chest wall, and thus this putative‘longest diameter’, may change a little. Further-more, the longest diameter may be between twofixed structures, such as the carina and thoracicvertebra, and should not be used to assess response.More guidance is needed to choose the anatom-ical level of tumor measurement, how many lev-els should be assessed, how to choose five lesionsfrom the hemithorax, and what lesions should berecorded, if any, as ‘non-target lesions’.

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uni-dimensionally to meet the criteria for partialresponse.

4. The RECIST criteria and pleuralmesothelioma

In contrast, the RECIST criteria, which are becom-ing increasingly widely used in clinical trials, useuni-dimensional measurements only [2]. A partialresponse is defined as a 30% decrease in the sum ofuni-dimensional tumor measurements.

Despite the use of uni-dimensional measure-ments, application of the RECIST criteria is not sim-ple in pleural mesothelioma. The RECIST criteriaevolved from measurement of the roughly sphericallesions common in other solid malignancies, and as-sume concordant changes in the length, width andheight of tumors as for spherical lesions. They sug-gest that ‘‘All measurable lesions up to a maximumof 5 lesions per organ and 10 lesions in total, rep-resentative of all involved organs, should be identi-fied as target lesions and recorded and measured atbaseline’’. In pleural mesothelioma, the hemitho-rax is often extensively involved with tumor at mul-tiple levels without involvement of other organs.The RECIST criteria do not guide the investigator asto which lesions should be considered ‘target le-sions’. Furthermore, the requirement to identifyand record all other lesions or sites of disease as

Van Klaveren et al. recently reported a series ofumor measurements comparing the use of RECISTnd WHO criteria for assessment of response [3].hey found a discrepancy in response as defined byhe two sets of criteria in 9 of 34 cases (27%). 8f 34 cases demonstrated progression on the WHOriteria which was missed by RECIST at some timeoint. These results were no better in the subset ofatients with bi-dimensionally measurable lesions.owever, problems with both the WHO criteria andhe unmodified RECIST criteria suggest that neitherhould be considered a ‘gold standard’ for tumoreasurement in this disease.

. The history of uni-dimensionaleasurement in pleural mesothelioma

ichael Byrne, from Perth, Western Australia, firsteveloped a modification of the WHO criteria in997, to assess response in a clinical trial of cis-latin and gemcitabine in pleural mesothelioma4]. In this study, both bi-dimensionally and uni-imensionally measurable disease was consideredn assessment of response, but the uni-dimensionalesponse criteria differed from the WHO criterian being mathematically more equivalent to a 50%ecrease in the sum of the perpendicular diam-ters. In this study, the thickness of the pleuralumour was measured at three separate levels on

CT, RECIST, and malignant pleural mesothelioma S39

transverse cuts on the thoracic CAT scan, and thesum of the measurements of tumour thickness atthe three levels defined a uni-dimensional mea-sure. All bi-dimensionally measurable lesions werealso measured and used in assessing response. Par-tial response was defined as per the WHO crite-ria for bi-dimensionally measurable lesions, but foruni-dimensionally measurable lesions, greater thanor equal to 30% decrease in the sum of linear tu-mour measurements was required to define PR. Pro-gressive disease (PD) was defined as greater thanor equal to 25% increase in the size of lesions orthe appearance of any new lesions for either bi-dimensionally or uni-dimensionally measurable dis-ease. Response was assessed in 21 patients usingthese criteria.

The same criteria were used in 53 patients ina follow-up multicentre trial of this regimen, in-creasing the number of uni-dimensional measure-ments to two at each of the three levels [5]. Again,bi-dimensionally measurable lesions were included.One difficulty identified in the practical applica-tion of this hybrid measurement system was howto interpret response when it differed betweenuni- and bi-dimensionally measurable lesions. How-eatcrm

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be measured at the same position and level. Ex-tensive documentation of non-measurable lesionsis not required, however nodal, subcutanous, andother bi-dimensionally measurable lesions are mea-sured uni-dimensionally as per the RECIST criteria.Uni-dimensional measurements are added to pro-duce a total tumor measurement.

Definitions of complete and partial response areconcordant with the RECIST criteria:

• Complete response (CR) requires disappearanceof all target lesions with no evidence of tumorelsewhere.

• PR requires at least a 30% reduction in the totaltumor measurement.

• Both PR and CR should be maintained for no lessthan 4 weeks to confirm response.

• PD requires an increase of at least 20% in thetotal tumor measurement over the nadir mea-surement, or the appearance of one or more newlesions.

• Stable disease (SD) is defined as neither meetingthe criteria of PR nor PD.

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ver, the measurement criteria used in these tri-ls generated enough interest internationally forhe landmark phase III trial of pemetrexed andisplatin to include similar uni-dimensional crite-ia [6]. Hence, uni-dimensional measurement inesothelioma pre-dated the RECIST criteria.

. The ‘modified RECIST criteria’ forleural mesothelioma

ith the widespread adoption of the RECIST cri-eria in other malignancies, the need to use bothni-dimensional and bi-dimensional lesions to as-ess response in mesothelioma became less impor-ant. We then concentrated on clarifying the usef uni-dimensional response criteria as per RECIST,ith more explicit definitions for the number andhoice of measurement sites and how to measurehe longest diameter. These criteria have been re-ently published as the ‘modified RECIST criteria’7].

The modified RECIST criteria use uni-dimensionaleasurement of tumor thickness perpendicular to

he chest wall or mediastinum, measured in 2 sitest 3 different levels on CT scan. Transverse cutssed for measurement must be at least 1 cm apart,nd related to anatomical landmarks in the thorax,referably above the level of division of the mainronchi. At reassessment, pleural thickness must

. Validation of the ‘modified RECISTriteria’

here were subtle differences between the modi-ed RECIST criteria and the original criteria used inhe two clinical trials from Western Australia, whichre-dated RECIST. These two patient data sets weree-assessed and used to validate the modified RE-IST criteria.

Single-centre phase II trial of cisplatin and gem-citabine in 21 patients, 48% ORR [4].Multicentre phase II trial of cisplatin and gemc-itabine in 53 patients, audited ORR 33% [5].

The complete CT scan series was available for3 patients, and all 236 CT scans were re-assessedor response at each time point according to theodified RECIST criteria, and compared with the re-

ponse outcomes recorded in the two clinical trials.n general there was a close correlation betweenhe original response criteria and the modified RE-IST. At individual time points, some responsesere re-classified (Table 1). However, the overallonfirmed response rate as assessed by the two sys-ems did not differ as two patients classified as SDecame PR and two patients classified as PR weree-classified as SD.

The most important aspect of validation was toonfirm that response, as measured by the modi-ed RECIST criteria, was reflecting some benefit toatients in terms of survival and lung function, and

S40 A.K. Nowak

Table 1 Concordance between the original response criteria and the modified RECIST criteria

Modified RECIST criteria

CR PR SD PD Total

Original response criteria

CR 0 0 0 0 0PR 0 72 5 4 81SD 0 11 93 1 105PD 0 1 2 47 50Total 0 84 100 52 236

was therefore a valid clinical trial endpoint. Therewas a statistically significant difference in survivalbetween the two patient groups (Log-rank test,p = 0.03), with a median survival of 15.1 monthsfor responding patients and 8.9 months for non-responding patients. Lung function as measured byforced vital capacity (FVC) improved significantlyover the course of treatment for responding pa-tients as compared with non-responding patients(p = 0.0001), and there was a significant correlationbetween FVC and change in linear tumour measure-ment (R = 0.63, p = 0.001). These findings confirmedthe modified RECIST criteria as a valid endpointwith some clinical meaning for patients. Althoughthe correlation between change in health-relatedquality of life (HRQL) and response would also beof interest, this was not examined as HRQL data wasnot available for all patients.

8. Moving forward with the ‘modifiedRECIST criteria’

Although the ‘modified RECIST criteria’ are alreadybeing used in current and proposed clinical trials,

trials, and to test whether these criteria are asurrogate for HRQL benefit.

Conflict of interest: The author declares no con-flict of interest.

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[2] Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, KaplanR, Rubenstein L, et al. New guidelines to evaluate the re-sponse to treatment in solid tumors. J Natl Cancer Inst2000;92:205—16.

[3] Van Klaveren RJ, Aerts JGJV, de Bruin HG, Giaccone G, Mane-gold C, Van Meerbeeck JP. Inadequacy of the RECIST criteriafor the evaluation of response in patients with malignantpleural mesothelioma. Lung Cancer 2004;43:63—9.

[4] Byrne MJ, Davidson JA, Musk AW, Dewar J, Van Hazel G, BuckM, et al. Cisplatin and gemcitabine treatment for malignantmesothelioma: a phase II study. J Clin Oncol 1999;17:25—30.

[5] Nowak AK, Byrne MJ, Williamson R, Ryan G, Segal A, Field-ing D, et al. A multicentre phase II study of cisplatinand gemcitabine for malignant mesothelioma. Br J Cancer2002;87:491—6.

[6] Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C,

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ideally, they should be further evaluated. Testsof inter-observer variability are important, as hasbeen demonstrated in the assessment of responsein lung cancer [8]. To confirm the practicality ofthe criteria they should be tested by cliniciansboth with and without extensive experience inthe measurement of mesothelioma in clinicaltrials. There are opportunities for internationalcollaboration to confirm that response has beenmeasured comparably across different clinical

Kaukel E, Ruffie P, et al. Phase III study of pemetrexedin combination with cisplatin versus cisplatin alone in pa-tients with malignant pleural mesothelioma. J Clin Oncol2003;21:2636—44.

7] Byrne MJ, Nowak AK. Modified RECIST criteria for assessmentof response in malignant pleural mesothelioma. Ann Oncol2004;15:257—60.

8] Erasmus JJ, Gladish GW, Broemeling L, Sabloff BS, TruongMT, Herbst RS, et al. Interobserver and intraobserver vari-ability in measurement of non-small-cell carcinoma lung le-sions: implications for assessment of tumor response. J ClinOncol 2003;21:2574—82.