Radiological evaluation, with RECIST criteria, of treatment response of non-microcytic lung cancer. Routine follow-up.

Transcription

1 Original article Anales de Radiología México 2015;14: Radiological evaluation, with RECIST criteria, of treatment response of non-microcytic lung cancer. Routine follow-up. Cuituny-Romero AK 1, Onofre-Castillo J 2 Abstract BACKGROUND: The incidence of non-microcytic lung cancer has increased 25% in recent years; with 10% survival at 5 years. Treatment response evaluation is required using the Response Evaluation Criteria In Solid Tumors (RECIST), three-dimensional measurement methods, or both. OBJECTIVE: Stage response to treatment with RECIST and compare such measurements with those of the three- dimensional and volume radiological methods. MATERIAL AND METHOD: We studied 11 patients with histological diagnosis of pulmonary carcinoma (except small cell carcinoma) from January to September RESULTS: We found only one case of agreement between conventional three-dimensional radiological measurements and RECIST criteria; in the rest of the population studied there was a 5 to 43% range of difference between the two measurements. DISCUSSION: In the patients studied we found: progression of disease in 5, stability in 3, partial response in 2, and only in 1 complete response based on RECIST criteria and the three-dimensional method. This shows that a uniform protocol is needed to monitor patients with lung cancer, using evaluation by three-dimensional measurements, RECIST, or both. CONCLUSION: Use of RECIST to classify response in all patients with pulmonary tumors should be considered, regardless of histological subtype and stage of disease, to standardize monitoring and evaluate not only of the target lesion or but all present (metastasis) for optimal treatment control. KEYWORDS: pulmonary neoplasms; radiology; evaluation; followup studies 1 2nd year resident of Diagnostic Imaging and Treatment. 2 Appointed professor of Diagnostic Imaging and Treatment. Departamento de Radiología e Imagen del Hospital Christus Muguerza Alta Especialidad, Miguel Hidalgo 2525, Col. Obispado, 64060, Monterrey, Nuevo León. Received: October 8, 2014 Accepted: December 18, 2014 Correspondence Alma Karime Cuituny Romero cuituny@gmail.com This paper must be quoted as Cuituny-Romero AK, Onofre-Castillo J. Evaluación radiológica, con criterios RECIST, de la respuesta al tratamiento del cáncer pulmonar no microcítico. Seguimiento de rutina. Anales de Radiología México 2015;14:

2 Anales de Radiología México 2015 January;14(1) INTRODUCTION A response is defined as the effect meant to be obtained with a certain action. In the Oncological and Radiological field a treatment response is measured with imaging biomarkers to decide continuation of treatment or to stop it to avoid possible toxicities and unnecessary expense. Treatment response of solid tumors is based on change in size, a basic element for the response evaluation criteria in solid tumors.: Response Evaluation Criteria In Solid Tumors, RECIST. 1 To apply the RECIST criteria it is necessary to define, in the initial study, the representative and reproducible target during follow-up. Their great variability (confluence, fragmentation, poor outline, imaging technique, appreciation) as well as measuring difficulties, as happens in mobile organs, leads to intra-observer and inter-observer discrepancies. The evaluation of response will be done with the same technique used for the initial study, verifying the duration of response. The sum of target from the baseline study will be used to follow and objectively evaluate the response. When a target lesion is fragmented during treatment, its parts will be measured, added and considered as a single lesion. 1 The RECIST criteria are a series of rules published to define when cancer patients improve ( respond ), are the same ( stable ) or worsen ( disease progression ) during treatments. 2 Lung cancer is the most common type of cancer and the main cause of death in the United States, in males as well as females. In 2003, new cases were estimated, and deaths. In spite of every effort, the survival rate at 5 years in patients with lung cancer is 14% for all stages (clinical staging): 61% for stage IA, 38% for IB, 34% for IIA, 24% for IIB, 13% for IIIA, 5% IIIB and 1% for stage IV. 3 The staging of non-microcytic lung cancer follows the International Staging System for Lung Cancer. This system describes the extension of non-microcytic cancer in terms of size, location, and extension of primary tumor (named T), presence and location of involved lymph nodes (named N) and the absence of distant metastasis (named M). Resection, radiotherapy, chemotherapy or the combination of these modalities and radiological images play an important role in the evaluation of staging. 3 The criteria for evaluation of response in solid tumors, RECIST, from the English acronym, were introduced in the year 2000 by an international work group, to standardize and simplify the response criteria of tumors. The key features of the original RECIST criteria (version 1.0) include definitions of minimal size of measurable in CAT scans, instructions on the number of to follow (above 10 with a maximum of 5 per organ) and the use of unidimensional measurements in CAT for the evaluation of tumor burden. The RECIST criteria replaced the evaluation of bidimensional size of the tumor that had been commonly used. 4 At the end of the 90 s, last century, the World Health Organization unified the evaluation of response, recurrence, and disease free interval; also establishing a grading for treatment toxicity. In the year 2000 the RECIST criteria came forth as a modification of such criteria and were updated in 2009 including MRI and PET CT with 18F-FDG as accepted imaging modalities to evaluate response. 1 The RECIST criteria are used for the evaluation of treatment response in solid tumors. They are internationally accepted criteria, used to evaluate response to treatment; to confirm if a certain treatment is working and to define that a patient with cancer is properly responding to treatment. 5 32

3 Cuituny-Romero AK and Onofre-Castillo J. Non microcytic lung cancer treatment The RECIST criteria have been widely accepted as a standardized measurement of tumor response, especially in clinical trials where the primary criteria are objective response and time to disease progression. 4 These criteria are described as follows: I. Measurable/non-measurable Measurable lesion. The longest diameter in long axis should be 10 mm or more, if the acquisition is with helical CT and 5mm thickness reconstruction in axial views. 5 Non measurable lesion. Includes small size (longest diameter less than 10 mm) as well as those really non measurable (pleural or pericardial effusion, cutaneous or pulmonary lymphangitic carcinomatosis). 5 Pathological lymph nodes. In metastatic lymph node disease tumor colonization is in itself not visualized but rather shown as an increase in nodal size (since they are visible anatomical structures in images, even when there is no disease). Nodal growth then is used as an indicator of metastatic involvement. The short axis must be used for size measurement, since it is the best predictive factor of metastasis (lymph nodes usually grow and shrink mainly at the expense of the shortest diameter). In case of lymph node disease, in order to consider the increase in pathological size and therefore measurable, they must be 15mm or more in short axis size). The rest of the pathological nodes, with short axis measurement between 10 and 15 mm, are considered non-measurable. Lymph nodes less than 10 mm in short axis are considered non-pathological and therefore do not require any sort of evaluation. 5 Bone metastasis. Lytic or mixed (lytic and blastic) metastases with soft tissue components are considered measurable and when the soft tissue component follows the previous definition of measurable lesion. Blastic and lytic metastases are non-measurable. 5 Cystic and necrotic. The that radiologically meet the criteria for simple cysts are not considered malignant (not considered as measurable or non-measurable). 5 Cystic metastases (necrotic ) are considered measurable as long as they follow the previously mentioned definition of measurable lesion. In any case, whenever there are other non cystic in the same patient, they will preferably be selected as target. Lesions with previous local treatment. Lesions located on previously irradiated areas or subjected to any other local and regional treatment are usually considered non measurable, unless a clear progression of the lesion is shown. 5 II. Target/non target Target. Target are the measurable, a maximum of five (and no more than two per organ), representative of all the involved organs (for example, in patients with a single organ involved, a maximum of two target are selected, and in the case of two organs involved, a maximum of four target will be selected). The target are the ones to be selected and measured in the baseline study and subsequently in the follow-up evaluation. Size is used for selection (the longest are chosen) as well as reproducibility of measurement in future follow-up studies. 5 Non target. They include non-measurable and measurable ; of the measurable, those that exceed two per organ or a total of five are included. (These do not need to be measured in the follow-up studies but any change must be reported). 5 33

4 Anales de Radiología México 2015 January;14(1) III. Evaluation of target/non target Target. In RECIST, only measurement of the longest diameter of the selected target is required in the plane in which images are obtained. In case of the CAT scan in the axial plane (only when isotropic reconstruction of the source images has been performed) measurements can be taken in the reconstructions of the other planes. Only the short diameter will be measured (short axis) in case of having selected malignant lymph nodes as target. The sum diameter of all target (longest diameter in the and the short diameter if pathological lymph nodes are selected) must be calculated and documented as the sum total of diameters in the baseline study. This sum of diameters in the baseline study is the one used for follow-up and objective evaluation of tumor response in terms of measurable disease. 5 Non-target. All other not included in the sum of target are considered non-target. Measurements are not required but they have to be documented in the baseline study. In case of multiple non-target affecting the same organ, they will be documented as: multiple pathological lymph nodes, multiple liver metastasis. 5 IV. Types of response Target. Complete response (CR) is considered when there is no longer measurable and assessable disease, with no appearance of new, absence of symptoms, and normal markers during at least 4 weeks. Partial response (PR) is when the sum diameter of target is reduced at least 30%. Disease progression (DP) is when there is 20% increase, an absolute increase of at least 5 mm is found (in the sum of diameters of the target ) or there are new metastasis, or the non-target show progression. Stable disease (SD) means that there is not enough shrinkage or growth to consider a complete response or disease progression. The definition of overall response (OR) is the best response after initiation of treatment before there is recurrence or disease progression. 1 Non-target lesion. Complete response (CR): disappearance of the total number of non-target and normal level of tumor markers (in case of lymph nodes they must have non-pathological size, under 10 mm). No complete remission/ no disease progression (No-CR/No-DP): persistence of one or more non-target and/or tumor marker level above normal limit. Disease progression (DP) or inequivocal progression of non-target disease: if the increase in tumor burden based on changes in non-target is comparable in magnitude to what would be a necessary increase to consider disease progression in case of measurable disease (for example, change from minimal pleural effusion to massive pleural effusion, or from localized carcinomatosis to generalized carcinomatosis). 5 The final categorization of response must be supported on the evaluation of changes in target as well as non-target, as well as in the report of presence or absence of new. The guide to use in the categorization of the final response is described next. 5 New. Once a new lesion appears, the tumor is classified as disease progression. 5 Measurement of the tumor using CAT scan and evaluation of treatment response in nonmicrocytic lung cancer treated with target therapy is critically important to determine the time to adjust the treatment schedule to extend survival. 4 Non-microcytic lung cancer. Lung cancer is the diagnosis that leads to the greatest number of deaths. Non small cell lung cancer has increased in the last few years with nearly 25% of new cases in the world with no improvement in 5 34

5 Cuituny-Romero AK and Onofre-Castillo J. Non microcytic lung cancer treatment year survival (10%). It is a multifactorial disease, but smoking is the most important risk factor. 6 Non small cell lung cancer is an uncontrolled and progressive growth of such cells. This term is used to refer to all pulmonary carcinomas, except that of small cells. 6 A chest CT scan with pulmonary and mediastinal window and contrast, including the liver and adrenal glands, has an 80% sensitivity and 70% specificity for detection of small cancers (nodules). 6 The objective of this paper was to evaluate, using the RECIST criteria, the treatment response and document the similarities of the routine radiological follow-up, using the image reformatting applications as part of evaluation, tracing and categorization of solid lung tumors. The specific goals were to document treatment response by means of staging the response to therapy according to the RECIST criteria and classify patients according to their course in categories of treatment response as total, partial, stable disease and/or disease progression. The conventional radiological methods based on bidimensional measurement of pulmonary solid tumors have been used according to the World Health Organization 6 and it is proposed that the use of unidimensional measurements used in the RECIST criteria is another alternative to follow treatment response, as part of the international standardization for evaluation of patients with non-microcytic lung tumors. MATERIAL AND METHODS With previous authorization from the Departamento de Educación e Investigación en Salud del Grupo (Department of Education and Research of the Group) and with and observational technique using images from the Picture Archiving and Communication System, PACS, a retrospective, observational and descriptive study was conducted. The sample size was determined by means of consecutive non-probabilistic sampling. Patients with confirmed diagnosis of non-microcytic lung cancer who had a CAT scan before and after treatment with radiotherapy were studied. The sample size for the series was two tailed: 59 patients with a confidence interval of 95% and statistical power of 80%. Inclusion criteria: adult patients in an age range of 18 years and over; diagnosis confirmed by anatomic pathology; no history of previous radiotherapy and/or surgery and with no other history of cancer. Exclusion criteria: pediatric patients, patients with no confirmed diagnosis, a history of radiotherapy and/ or surgery; advanced age with distant metastasis. Patients with confirmed diagnosis using pathology report of non-small cell lung cancer and with CT scans before and after clinical treatment were selected. This study was conducted in the hospital and only patients who met the inclusion criteria were selected. Subsequently, measurements of the target and non-target were taken according to the RECIST criteria in CAT scans performed before treatment and after treatment to classify patients according to their response (Figures 1 and 2). Also, the bidimensional conventional radiological method was used for measurements (Figura 3) as well as the three-dimensional method (Figure 4) to compare both groups. The equipment used was a General Electric multisection CT scanner 7. Images were evaluated in axial, coronal and sagittal sequences. They were read by a second year Radiology resident and a certified radiologist. Technical considerations of imaging methods 5 The new RECIST 1.1 guide adds the annex II with specifications about the imaging techniques. It talks about the protocols for image acquisition in CAT scans recommended for patients included in clinical trials where the RECIST criteria will be used. The purpose is to reach standardization in 35

6 Anales de Radiología México 2015 January;14(1) Figure 1. Axial section, venous phase CAT scan. Target lesion measurement in the longest diameter according to RECIST criteria. Figure 3. Axial section, CAT scan of the lung with mediastinal window in simple phase, bidimensional measurement. Figure 2. Axial section, contrast enhanced CAT scan of the lung, IV venous phase. Mediastinal node short axis measurement according to RECIST criteria. image requirements as well as in image acquisition parameters, allowing optimal comparison between subjects in the same study as well as results among different studies. 6 The imaging technique used to evaluate (and the window or sequence used) must always be the same to characterize each one of the identified and documented in the baseline study and subsequently. It is of great help to save the measurements obtained in a metric system for the next follow-up, nowadays an easy task with the new computer programs that are found in the Diagnostic Radiology services. 5 Figure 4. 3D reconstruction of pulmonary node. Anatomy coverage. The optimal coverage in most solid tumors includes chest, abdomen and pelvis. Although in every case the sites where metastasis tend to be found should be covered, also sites that can be affected based on indiidual signs and symptoms of patients should be 36

7 Cuituny-Romero AK and Onofre-Castillo J. Non microcytic lung cancer treatment included. Since finding a lesion in a part of the body not scanned in the baseline study must be considered as a new lesion, and therefore it means disease progression, we must be very careful in the choice of extension of coverage in baseline as well as follow-up studies. 5 Intravenous contrast delivery. Enhancement with intravenous contrast is the preferred method in the RECIST criteria for optimal visualization and measurement of metastases in solid tumors. Therefore, it needs to be used in this type of studies, even though the vascular phases in which the study must be acquired are not specified. What is really essential is that the study should always be performed in the same vascular phase, in the baseline study as well as in follow-up, so that the greatest reproducibility in the enhancement of is obtained allowing proper comparison of known and to find new. 1 (Figures 5 and 6). Variables were studied: name, gender, quantitative, age, continuous. Measurements of solid lung tumors based on RECIST criteria, qualitative, classification in the RECIST criteria, presence or absence of treatment response. The letter of the Bioethics Committee of the Hospital was used for informed consent to use the images saved in the PACS program. Figure 5. Axial section, lung CAT scan, simple phase. Node lesion with soft tissue density. RESULTS Eleven patients who had chest CAT scan as a baseline study and as follow-up study after treatment were analyzed. Concerning age of patients, the mean was 53 years. The predominant gender was male, 5 (55%) and female 4 (45%). Pathological diagnosis: 5 patients did not have histology subtype, 3 patients with bronchioalveolar subtype, 1 with adenocarcinoma, 1 squamous cell carcinoma and 1 adenoid. Subsequently, a comparison was made of conventional measurements in a baseline study and after treatment, as seen on Tables 1 and 2. A comparison of RECIST measurements is also shown on Table 3 after treatment. Table 4 shows Figure 6. Axial section, contrast enhanced CAT scan of the lung, IV arterial phase. Enhancement of node lesion. the correlation between both measurements. Finally, the treatment response of each patient studied was defined. Table 5. Differences were 37

8 Anales de Radiología México 2015 January;14(1) Table 1. Treatment response. Taken from SERAM module 5 Target found between measurements taken with the conventional three-dimensional radiological method and the unidimensional measurements of the RECIST criteria. Table 6. DISCUSSION Non target New Final response CR CR No CR CR No CR No DP No PR CR NE No PR PR No DP or NE No PR SD No DP or NE No SD NE No DP No NE DP Any Yes or No DP Any DP Yes or No DP Any Any Yes DP SD: stable disease; NE: not evaluable; DP: disease progression; CR: complete response; PR: partial response. Among the patients studied, 5 were found to have disease progression, 3 had stable dis- ease, 2 had partial response and only one had complete response. There was only one case of agreement between the conventional radiological three-dimensional measurements and the unidimensional RECIST measurement; in all the other population studied there was a range of difference between both measurements from 5 to 43%. Thus, when following a patient with lung cancer a uniform protocol is required, either with three-dimensional measurements or with RECIST. The mean age was 53 years with male predominance (55%). 6 The most common histological diagnosis was bonchioalveolar carcinoma; 3 however, a limitation was found in that 5 patients did not have a histopathology report from the hospital where the study was performed. Among the other patients 3 there was one case of adenoid carcinoma, another case of squamous cell carcinoma and one of adenocarcinoma. According to the specialized literature, the most common histological subtype is adenocarcinoma, found in 40% of all cases. Currently, emphasis is made on separating the histological subtypes to determine prognosis and treatment options. 7 Table 2. Comparison of baselina/post treatment study, conventional measures Case number Baseline study conventional measures Post-treatment study conventional Average conventional measures % baseline /post-treatment study short axis long axis volume (cm 3 ) short axis long axis volume (cm 3 ) Baseline/post treatment study (cm 3 ) Conventional measures (%)

9 Cuituny-Romero AK and Onofre-Castillo J. Non microcytic lung cancer treatment Table 3. Baseline/ post-treatment comparison, RECIST measurements Baseline study (RECIST measurements) Post-treatment (RECIST measurements) Average measurements RECIST % baseline/ post treatment study Case Number of target Target Number of nontarget Non target Number of target Target measurements Non-target measurements Non target measurements Baseline/posttreatment study RECIST average Table 4. Average baseline/post-treatment correlation: conventional measurements vs. RECIST Case number % baseline/posttreatment study. Conventional measurements % baseline/posttreatment study. RECIST average Table 5. RECIST response Case number Target RECIST response Non target New Final response RECIST Measurements were taken in the baseline study for short and long axis, and width of, to get the volume and subsequently the measurements were repeated for the post-treatment study. The volume measurements increased in 5 cases (average increase of 33%, 8.6 cm 3 ) and 39

10 Anales de Radiología México 2015 January;14(1) Table 6. Differences between conventional measurements and RECIST Case % Conventional measurements % % RECIST measurements Conventional measurement/ RECIST with criteria to define disease progression in spite of treatment. Stable disease in three patients showed differences in the response rate because in using conventional measurements, when the baseline study was compared to the post-treatment study, an average response of 33.6% was found. According to RECIST criteria, when the target are identified according to size (longest diameter), consecutive measurements are taken in follow-up studies to estimate de sum of the longest diameters to determine treatment response Table 1. 8 The difference in the evaluation using the RECIST method compared to 2D or 3D is that measurements are taken in the axial plane, not in the sagittal or coronal plane as in the methods already mentioned. 9 RECIST measurements in baseline studies and studies after treatment showed a response rate of 15.6%. Considering the values obtained with the RECIST method the patient does not have enough response rate to be classified as having a partial response ( 30); however, such classification is reached with conventional measurements. The median decrease was 5.7 mm with RECIST and a volume decrease of 8.6 cm 3 in these patients. 10,11 The two patients who had partial response ( 30) also showed substantial differences in response using conventional measurements which was 82.5% with volume decrease, 39.5 cm 3 in average; using RECIST the response rate was 40% with a mean decrease of 20 mm. As was already mentioned only one of the patients had complete response in both measurements. Concerning non-target, 5 patients were found with no complete remission, 5 patients with non-target and one with complete response. None of the patients had new in follow-up studies after treatment. In the Pearson correlation for both measurements (conventional vs. RECIST) no lineal relation nor perfect positive relation was found (r = ). RECIST is now the method of choice to evaluate treatment response, already defined as complete response (with no tumor evidence), treatment response (30% decrease tumor size in RECIST 1.0 and 25% in RECIST 1.1), stable disease (no change in size) and disease progression (at least 20% increase in tumor size). It must be noted that new metastatic disease indicates disease progression. This assessment is purely related to tumor size and is not functional. 10,11 The limitations considered for this study are the small number of patients, not knowing the type of medical and drug treatment that patients received, since there is no contact between the medical staff in charge of patients (Oncology) and the Radiology Department to follow responses, as well as the use of chest CT without intravenous contrast in baseline or follow-up studies. 40

11 Cuituny-Romero AK and Onofre-Castillo J. Non microcytic lung cancer treatment CONCLUSION Assessment of treatment response of tumors involves comprehensive work that has become more important for radiologists who evaluate images in the oncological field. Imaging studies pay a crucial and objective role to quantify tumor response to a wide range of physical, surgical and drug treatments. 11 The RECIST criteria allow a standardized assessment of patients with solid tumors from the time of diagnosis, following their course and to stage treatment response. These criteria are better than the conventional bidimensional and 3D in the following points: 1. Unidimensional measurement using the long axis of the target lesion. This helps to avoid errors in the subsequent measurements. 2. Target, non-target and new are taken into account. 3. Treatment response is classified according to previously established parameters internationally accepted. Remember that for partial response, in the RECIST 1.1 version, an equal or greater than 30% decrease of the total sum of the maximum diameter size is considered, and for total response all must disappear in a 4 week period in both, and for progression an increase in size more than 20% is required. The use of RECIST criteria must be considered to classify response in all patients with lung tumors, regardless of the histological subtype and the disease stage so as to standardize follow-up and evaluate, not only the target lesion or, but also to consider all current (metastases) for optimal treatment control. This will lead to greater and broader knowledge of response types and treatment outcomes that are now resulting in success rates, treatment failure or stability of disease. REFERENCES 1. Cervera Deval J. RECIST y el radiólogo. Radiología 2012;59(3):193: RECIST (Response Evaluation Criteria In Solid Tumors) Munden RF et al. Imaging of the patient with non-small cell lung cancer. Radiology 2005;237(3): Nishino M et al. New response evaluation criteria in solid tumor (RECIST) guidelines for advanced non-small cell lung cancer: Comparison with original RECIST and impact on assessment of tumor response to targeted therapy. Am J Roentgenology 2010;195(3): Pelechano P, Barrios M, Marhuenda A, Martín I, Santos J, Cervera J. Nuevos criterios RECIST (versión 1.1). Manual para radiólogos. Fundación Instituto Valenciano de Oncología. Sociedad Española de Radiología Médica Guía de Práctica clínica para la detección, diagnóstico y tratamiento del cáncer pulmonar., México: Secretaria de Salud; gpc/.../imss_030_08_eyr.pdf Bhure UN et al. Accuracy of CT parameters for assesment of tumor size and aggresiveness in lung adenocarcinoma with broncoalveolar elements. Brit J Radiol 2010;83: Nishino M et al. Revised RECIST guideline version 1.1: What oncologists want to know and what radiologists need to know. Am J Roentgenolgy 2010;195: Suzuki M. Radiologic Measurements of tumor response to treatment practical approaches and limitations. Radiographics 2008;28: Munden RF et al. Imaging of the patient with non-small cell lung cancer. Radiology 2005;237: Padhani AR et al. The RECIST criteria: implications for diagnostic radiologist. The Brit J Radiol 2001;74: