Byrne1* & A. K. Nowak1,2 *Correspondence to: Dr M. J. Byrne, Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, WA 6009, Australia. Tel: +61-8-93463841; Fax: +61-8-93463390; E-mail: mjbyrne@cyllene.uwa.edu.au1Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, WA 6009; 2Department of Medicine, University of Western Australia, Nedlands, WA 6009, Australia Received 29 May 2003; revised 5 August 2003; accepted 30 September 2003 Background: The growth pattern of malignant pleural mesothelioma makes the use of RECIST (response evaluation criteria in solid tumours) response crite ria difficult. We have developed and validated Modified RECIST criteria adapted to the growth pattern of malignant pleural mesothelioma. Patients and methods: We evaluated 73 patients from two clinical trials of cisplatin/gemcitabine chemo- therapy in malignant pleural mesothelioma. Tumour thickness perpendicular to the chest wall or mediastinum was measured in two positions at three separate levels on thoracic CT scans. The sum of the six measurements defined a pleural unidimensional measure. Bidimensionally measureable lesions were measured unidimension-ally as for RECIST. All measurements were added to obtain the total tumour measurement. A reduction of at least 30% on two occasions 4 weeks apart defi ned a partial response; an increase of 20% over the nadir measurement, progressive disease. The validity of the modified criteria was gauged by evaluating survival and pulmonary function. Results: Response according to these criteria predicted for superior survival (15.1 versus 8.9 months; P = 0.03) and forced vital capacity (FVC) increase during treatment ( P <0.0001). A significant correlation between change in linear tumour measurement and FVC was seen ( R = 0.63; P = 0.0001). Conclusion: These Modified RECIST criteria for tumour response correlate with survival and lung function and can be used to measure outcome in pleural mesothelioma. Key words: chemotherapy, clinical trials, mesothelioma, RECIST, response criteria, validation Introduction The ability to measure reproducibly tumour response to treatment is vital in the development of new drugs and therapeutic combina-tions, particularly for the conducting of phase II studies. Con- ventional response criteria have always been difficult to apply to malignant mesothelioma due to its unique pattern of growth. Malignant mesothelioma most commonly grows as a ‘rind’ around the pleural surface, and on computed tomography (CT)scan may not produce spherical lesions with bidimensionallymeasurable diameters. The WHO criteria [1] are poorly suited toevaluating response in mesothelioma, as they were developedprincipally to assess bidimensionally measurable disease. Whenused for unidimensional measurement, these criteria require a 50%decrease in the sum of unidimensional measurements to define apartial response (PR). This equates to a 75% decrease in the sumof the products of perpendicular diameters rather than the 50%decrease required to define response in bidimensionally measur- able lesions.The recently developed RECIST (response evaluation criteria in solid tumours) criteria [2] are more suited to tumour assessment in mesothelioma, as they specify the use of unidimensional measure- ments, with PR defined as a 30% decrease in the sum of the longest diameter for all target lesions. However, the selection of measurement sites in mesothelioma is difficult, and without fur- ther definition of the method of measurement, the RECIST criteriacould be applied differently by different investigators (Figure 1A). Early experience suggests that modification of the criteria may be required in the special case of mesothelioma [3]. We have developed a modification of the RECIST criteria specifically to address the diffi culties of measurement inherent in assessing changes in tumour bulk in pleural mesothelioma. We have previously performed two phase II clinical trials of the use ofcisplatin and gemcitabine in patients with measurable pleuralmesothelioma; a single centre st udy [4] and a subsequent confirm- atory multicentre study [5]. In these studies, response rates of 47.6% [4] and 33% [5] were seen. Response criteria that incor- porated both unidimensional and bidimensional measurements had been developed and used to assess response in these two trials(‘original response criteria’). Using Modified RECIST criteria,we have now reassessed the response to treatment for a total of 73 patients who entered these two studies. To validate these new by guest on October 28, 2011 http://annonc.oxfordjournals.org/ Downloaded from Aduro Biotech, Inc. Protocol ADU-CL-02-v8 CRS-207 with Pemetrexed and Cisplatin Version 8, 08 March 2018 Page 77 258 criteria we have related response to survival and to serial changes in pulmonary function on treatment. Patients and methods Patient population Data on the 73 patients entered in the two previous clinical trials of cisplatin and gemcitabine in malignant pleural mesothelioma were obtained. All patients had measurable disease, defined as pleural tu mour thickness of at least 1.5 cm on spiral CT scan, and histologically or cytologically confirmed mesothelioma.CT scans had been performed in all patients prior to the first cycle of chemo-therapy, and then before the second, fourth and sixth cycles. Further CT scans were performed after the final cycle of chemotherapy, and then twice a month until disease progression. Forced vital capacity (FVC) had been measuredprior to study entry and on day 1 of each chemotherapy cycle in 52 patientsentered on the second study. The original response criteria used in both trials were as follows. Tumour measurements were performed on transverse cuts on thoracic CT scans at three separate anatomically reproducible levels on the study entry CT scan and at the same levels on subsequent scans. Where possi ble, bidimensional lesions were measured. If there were no bidimensiona lly measurable lesions, unidimen- sional measurements of pleural tum our thickness were performed. Bidimen- sionally measurable lesions were m easured using the longest dimension and the length perpendicular to the longest measurement. For unidimensionally measurable lesions, thickness of pleural tumour was measured at two separate sites on each of the three levels and the six measurements summated to pro- duce a total measurement. Palpable mass es were measured clinically on day 1 of each cycle as for bidimensionally measurable lesions. A pleural effusion was not considered a measurable lesion. Tumour response was defined as: (i) complete response (CR): disappear- ance of all known disease, determined by two observations not less than 4 weeksapart; (ii) PR: a ≥50% decrease in the sum of the products of perpendicular diameters of bidimensionally measured lesions on two occasions not less than4 weeks apart, or a ≥30% decrease in the sum of linear tumour measurements on two observations not less than 4 weeks apart; (iii) no change: a decrease in bidimensional tumour area of <50% or an increase of <25%, or a decrease in the sum of unidimensional measurements of <30% or an increase of <25%,provided no new lesions have appe ared; (iv) progressive disease: a ≥25% increase in the size of the tumour be ing measured (unidimensi onal or bidimen- sional) or the appearance of new lesions. Where response at sites measured bidimensionally differed from that at sites measured unidimensionally, the overall patient response was assessed byan audit group. The sites with dominant tumour bulk were favoured. The protocols for each study were approved by the Committee for Human Rights of the University of Western Australia and the Sir Charles Gairdner Hospital Clinical Drug Trials Commi ttee. Written informed consent was obtained from each patient before entry. Modified RECIST criteria Modified RECIST criteria were developed. The major problems in applying the RECIST criteria to malignant ple ural mesothelioma are in the interpreta- tion of the meaning and placement of th e ‘longest unidimensi onal diameter’ of the target tumour mass to be measured. The longest diameter of a tumour mass is frequently that which follows the inner curve of the chest wall. Defining thelimits of such a diameter is often problematical. When the tumour regresses with treatment the line may cross an area outside the tumour margin because ofthe curve of the chest wall. This may produce difficulty with reproducibility ofmeasurement. Furthermore, the longest tumour diameter may be between two fixed structures, such as the thoracic vertebrae and the carina, and measure- ment in these areas may not fully reflect tumour response.The Modified RECIST criteria we have developed were as follows. Tumour thickness perpendicular to the chest wall or mediastinum was measured in two positions at three separate levels on transverse cuts of CT scan (Figure 1B).The sum of the six measurements defi ned a pleural unidimensional measure. Transverse cuts at least 1 cm apart and related to anatomical landmarks in thethorax were chosen to allow reproducible assessment at later time points. If measureable tumour was present, transverse cuts in the upper thorax, above thelevel of division of the main bronchi were preferre d. At reassessment, pleural thickness was measured at the same position at the same level and by the sameobserver. This was not necessarily the greatest tumour thickness at that level.Nodal, subcutaneous and other bidimensionally measurable lesions were measured unidimensionally as per the RECIST criteria. Unidimensional measurements were added to obtain the total tumour measurement. CR was defined as the disappearance of all target lesions with no evidence of tumour elsewhere, and PR was defined as at least a 30% reduction in the total tumour measurement. A confirmed response required a repeat obser-vation on two occasions 4 weeks apart. Progressive disease (PD) was definedas an increase of at least 20% in th e total tumour measurement over the nadir measurement, or the appearance of one or more new lesions. Patients withstable disease (SD) were those who ful filled the criteria for neither PR nor PD. Figure 1.