Journal of Thoracic Oncology ® • Volume 10, Number 5, May 2015
(SUV) ratio”; the ratio of maximum SUV between the primary tumor and mediastinal lymph nodes, on positron emission computed tomography (CT), in lung cancer patients. It was the previous work of Koksal et al. and Cerfolio et al. that sparked our own interest in the SUV ratio as a potential predictor of false-negative nodal sampling with endobronchial ultrasound-guided transbronchial needle aspiration (EBUSTBNA). In our study, the SUV ratio proved to be a powerful predictor of nodal malignancy and false-negative EBUS-TBNA and is a key element of our risk stratification model. Professor Koksal specifically asks about our experience with indeterminate 18-F-fluorodeoxyglucose (FDG) avidity tumors, for example, lepidic-type adenocarcinomas, and the usefulness of the SUV ratio in such circumstances. We use the term “indeterminate” to describe an SUVmax above that of the background mediastinal blood pool but lacking the significant FDG avidity normally associated with malignancy. Our first comment is that, in our experience, it is rare to undertake EBUS mediastinal staging in such circumstances. Lowgrade adenocarcinomas are usually peripheral ground-glass opacities on CT imaging with no or indeterminate FDG uptake and normal hilar and mediastinal nodes radiologically. These tumors are often biologically indolent tumors, and therefore, nodal spread is less common. As per the American College of Chest Physicians Staging Guidelines,1 peripheral tumors with low or indeterminate FDG avidity and normal hilar/mediastinal nodes radiologically do not require pathological nodal staging and can proceed directly to resection, assuming adequate fitness because the prevalence of nodal metastases is low. The prevalence of nodal metastases in our study was much higher as it predominantly included patients with N2/3 nodal disease on CT (376 of 509 patients, 74%). Address for correspondence: Matthew Evison, MRCP, North West Lung Centre, University Hospital South Manchester, Southmoor Road, Manchester, M23 9LT, United Kingdom. E-mail: [email protected] DOI: 10.1097/JTO.0000000000000511 Copyright © 2015 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/15/1005-0e32
It is uncommon for low-grade adenocarcinomas to present in such a way and are therefore under-represented in this study. This is reflected in the number of patients with an indeterminate primary tumor SUVmax; only 15 of 509 patients had a primary tumor SUVmax less than 4.0, and just four patients had an SUVmax less than 2.5. From these 15 patients, 11 patients had both indeterminate FDG avidity in the primary tumor and indeterminate avidity in the lymph nodes sampled by EBUS-TBNA. Ten of these tumors were adenocarcinomas plus one non-small-cell lung cancer not otherwise specified. The SUV ratio in all of the sampled lymph nodes was greater than 40% and ranged from 45% to 175%. In three cases, EBUSTBNA confirmed N2/3 metastases. In the remaining eight cases, in which the EBUS-TBNA was negative, there were two false-negatives where nodal metastases were subsequently diagnosed and six true-negatives. The risk stratification model indicated seven out of the eight cases of negative EBUS were high risk for false-negative sampling, suggesting the need for further pathological sampling and two of seven were ultimately proven to be false-negative. In summary, the SUV ratio does seem to be a useful indicator of the risk of nodal metastases in indeterminate FDG avidity tumors with indeterminate SUV FDG avidity in mediastinal lymph nodes. The risk stratification model, we presented in our study, therefore encompasses this clinical scenario and remains relevant to this patient group. We acknowledge the small number of such patients in our study and as such, our comments need be interpreted with this in mind. We would also stress the importance of using this risk stratification model for lymph nodes sampled with EBUS and deemed negative. It cannot replace pathological staging and has only been derived and validated in this setting. Matthew Evison, MRCP Philip Crosbie, PhD Richard Booton, PhD North West Lung Centre University Hospital South Manchester Manchester, United Kingdom The University of Manchester Manchester, United Kingdom
Copyright © 2015 by the International Association for the Study of Lung Cancer
Letters to the Editor
REFERENCES 1. Silvestri GA, Gonzalez AV, Jantz MA, et al. Methods for staging non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143(5 Suppl):e211S–e250S.
MET-Mutated NSCLC with Major Response to Crizotinib To the Editor: MET abnormalities, including overexpression, amplification, and mutation, have been described in nonsmall-cell lung cancer (NSCLC). Ou et al.1 reported in Journal of Thoracic Oncology in 2011 a patient with de novo MET amplification and a rapid and durable response to the oral ALK and MET inhibitor, crizotinib. The utility of MET amplification as a predictive marker was recently confirmed in a larger case series, but there have been no data regarding the clinical significance of MET mutations in NSCLC. We treated a 76-year-old female diagnosed with metastatic squamous cell carcinoma of the lung in April 2014. She was a former light smoker and quit tobacco use more than 30 years ago. Extended mutation analysis was performed, revealing a MET D1010H mutation and MDM2 amplification (Foundation Medicine, Cambridge, MA). She was initially treated with a combination of a novel MMP9 inhibitor, carboplatin, and paclitaxel and had progressive disease after three cycles. Treatment was then changed to gemcitabine, but after one cycle symptomatic disease progression occurred in the lung and bone and at a painful right
Address for correspondence: Jonathan W. Goldman, MD, The David Geffen School of Medicine, University of California, Los Angeles, 2020 Santa Monica Boulevard, Suite 600, Santa Monica, California 90404. E-mail: [email protected]. DOI: 10.1097/JTO.0000000000000491 Copyright © 2015 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/15/1005-0e33
e33
Letters to the Editor
gluteal soft tissue mass. Treatment was initiated with crizotinib. She achieved a rapid improvement in her fatigue and complete resolution of pain. After 7 weeks of therapy, computed tomography imaging showed a reduction (64.4% by the Response Evaluation Criteria in Solid Tumors v 1.1) of the target lesions and resolution of numerous nontarget pulmonary nodules. The left upper lobe primary lung mass had reduced in size, measuring 38 by 24 mm (previously 49 by 42 mm). The painful gluteal mass had shrunk from 54 by 36 mm to 14 by 8 mm. Additional imaging by F-18 fluorodeoxyglucose-positron emission tomography and computed tomography after 19 weeks on treatment demonstrated a near complete response with resolution of all lesions except for the lung primary (now decreased to 29 by 16 mm) and a near F-18 fluorodeoxyglucose-positron emission tomography complete response (decrease in standard uptake value from 20.4 to 2.1; Fig. 1). The patient has tolerated treatment well with a side effect profile consistent with crizotinib: mild taste changes, lower extremity edema, and vision changes at night. Current therapy for NSCLC often employs nonspecific agents, such as cytotoxic chemotherapy with response rates of 20% to 35% in the first-line and less than 10% in pretreated disease. The field is moving toward a molecular age in which we identify driving mutations in a tumor sample and treat with a drug targeted to that specific abnormality. The major success stories so far have been with EGFR, ALK, and ROS mutant disease, and response rates of 60% to 80% are now frequently reported. Simultaneously, extended tumor mutation testing has become available for clinical use. In this setting, a rare mutation, sometimes of uncertain significance, may be found. If an inhibitor directed against that mutation is available on or off of a research protocol, this may provide a novel treatment opportunity. MET abnormalities of several kinds have been reported in NSCLC. Protein over-expression is found in 25% to 75% of NSCLC and has been associated with a poor prognosis.2 However, two phase III trials showed no benefit with MET-targeted therapy in molecularly unselected cohorts.
e34
Journal of Thoracic Oncology ® • Volume 10, Number 5, May 2015
True MET amplification (defined as an increase in the MET/CEP7 signal ratio) is significantly more rare, reported to be 1% to 11%.3,4 Camidge et al.5 reported in 2014 responses with crizotinib therapy in patients, with the highest response rates for tumors that had high amplification (MET/ CEP7 ratio ≥5). The incidence of METmutations in NSCLC appears to be 1% to 3%.3,4 We are not aware of any previous reports in the literature for MET-directed therapy in this population. Crizotinib is a well-tolerated treatment option, and further investigation of its antitumor effect in this setting is warranted. As we progress into the modern molecular age of NSCLC therapy, it will be important to identify regulatory and financial mechanisms to provide novel targeted agents to the appropriate patients. Melody A. Mendenhall, MSN, NP The David Geffen School of Medicine University of California, Los Angeles Santa Monica, California Jonathan W. Goldman, MD The David Geffen School of Medicine
University of California, Los Angeles Santa Monica, California REFERENCES 1. Ou SH, Kwak EL, Siwak-Tapp C, et al. Activity of crizotinib (PF02341066), a dual mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK) inhibitor, in a nonsmall cell lung cancer patient with de novo MET amplification. J Thorac Oncol 2011;6: 942–946. 2. Nakamura Y, Niki T, Goto A, et al. c-Met activation in lung adenocarcinoma tissues: an immunohistochemical analysis. Cancer Sci 2007;98:1006–1013. 3. Okuda K, Sasaki H, Yukiue H, Yano M, Fujii Y. Met gene copy number predicts the prognosis for completely resected non-small cell lung cancer. Cancer Sci 2008;99:2280–2285. 4. Onozato R, Kosaka T, Kuwano H, Sekido Y, Yatabe Y, Mitsudomi T. Activation of MET by gene amplification or by splice mutations deleting the juxtamembrane domain in primary resected lung cancers. J Thorac Oncol 2009;4:5–11. 5. Camidge DR, Ou SI, Shapiro G, et al. Efficacy and safety of crizotinib in patients with advanced c-MET-amplified non-small cell lung cancer (NSCLC). J Clin Oncol 2014;32:5s (suppl; abstr 8001).
FIGURE 1. Representative F-18 fluorodeoxyglucose-positron emission tomography/CT coronal images at baseline and after 19 weeks of crizotinib therapy. Note the resolution of the large left lung primary lesion, small right lung nodule, and large right buttock mass. The muscle F-18 fluorodeoxyglucose-positron emission tomography activity on the follow-up scan is thought to be artifactual. Copyright © 2015 by the International Association for the Study of Lung Cancer
(SUV) ratio”; the ratio of maximum SUV between the primary tumor and mediastinal lymph nodes, on positron emission computed tomography (CT), in lung cancer patients. It was the previous work of Koksal et al. and Cerfolio et al. that sparked our own interest in the SUV ratio as a potential predictor of false-negative nodal sampling with endobronchial ultrasound-guided transbronchial needle aspiration (EBUSTBNA). In our study, the SUV ratio proved to be a powerful predictor of nodal malignancy and false-negative EBUS-TBNA and is a key element of our risk stratification model. Professor Koksal specifically asks about our experience with indeterminate 18-F-fluorodeoxyglucose (FDG) avidity tumors, for example, lepidic-type adenocarcinomas, and the usefulness of the SUV ratio in such circumstances. We use the term “indeterminate” to describe an SUVmax above that of the background mediastinal blood pool but lacking the significant FDG avidity normally associated with malignancy. Our first comment is that, in our experience, it is rare to undertake EBUS mediastinal staging in such circumstances. Lowgrade adenocarcinomas are usually peripheral ground-glass opacities on CT imaging with no or indeterminate FDG uptake and normal hilar and mediastinal nodes radiologically. These tumors are often biologically indolent tumors, and therefore, nodal spread is less common. As per the American College of Chest Physicians Staging Guidelines,1 peripheral tumors with low or indeterminate FDG avidity and normal hilar/mediastinal nodes radiologically do not require pathological nodal staging and can proceed directly to resection, assuming adequate fitness because the prevalence of nodal metastases is low. The prevalence of nodal metastases in our study was much higher as it predominantly included patients with N2/3 nodal disease on CT (376 of 509 patients, 74%). Address for correspondence: Matthew Evison, MRCP, North West Lung Centre, University Hospital South Manchester, Southmoor Road, Manchester, M23 9LT, United Kingdom. E-mail: [email protected] DOI: 10.1097/JTO.0000000000000511 Copyright © 2015 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/15/1005-0e32
It is uncommon for low-grade adenocarcinomas to present in such a way and are therefore under-represented in this study. This is reflected in the number of patients with an indeterminate primary tumor SUVmax; only 15 of 509 patients had a primary tumor SUVmax less than 4.0, and just four patients had an SUVmax less than 2.5. From these 15 patients, 11 patients had both indeterminate FDG avidity in the primary tumor and indeterminate avidity in the lymph nodes sampled by EBUS-TBNA. Ten of these tumors were adenocarcinomas plus one non-small-cell lung cancer not otherwise specified. The SUV ratio in all of the sampled lymph nodes was greater than 40% and ranged from 45% to 175%. In three cases, EBUSTBNA confirmed N2/3 metastases. In the remaining eight cases, in which the EBUS-TBNA was negative, there were two false-negatives where nodal metastases were subsequently diagnosed and six true-negatives. The risk stratification model indicated seven out of the eight cases of negative EBUS were high risk for false-negative sampling, suggesting the need for further pathological sampling and two of seven were ultimately proven to be false-negative. In summary, the SUV ratio does seem to be a useful indicator of the risk of nodal metastases in indeterminate FDG avidity tumors with indeterminate SUV FDG avidity in mediastinal lymph nodes. The risk stratification model, we presented in our study, therefore encompasses this clinical scenario and remains relevant to this patient group. We acknowledge the small number of such patients in our study and as such, our comments need be interpreted with this in mind. We would also stress the importance of using this risk stratification model for lymph nodes sampled with EBUS and deemed negative. It cannot replace pathological staging and has only been derived and validated in this setting. Matthew Evison, MRCP Philip Crosbie, PhD Richard Booton, PhD North West Lung Centre University Hospital South Manchester Manchester, United Kingdom The University of Manchester Manchester, United Kingdom
Copyright © 2015 by the International Association for the Study of Lung Cancer
Letters to the Editor
REFERENCES 1. Silvestri GA, Gonzalez AV, Jantz MA, et al. Methods for staging non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143(5 Suppl):e211S–e250S.
MET-Mutated NSCLC with Major Response to Crizotinib To the Editor: MET abnormalities, including overexpression, amplification, and mutation, have been described in nonsmall-cell lung cancer (NSCLC). Ou et al.1 reported in Journal of Thoracic Oncology in 2011 a patient with de novo MET amplification and a rapid and durable response to the oral ALK and MET inhibitor, crizotinib. The utility of MET amplification as a predictive marker was recently confirmed in a larger case series, but there have been no data regarding the clinical significance of MET mutations in NSCLC. We treated a 76-year-old female diagnosed with metastatic squamous cell carcinoma of the lung in April 2014. She was a former light smoker and quit tobacco use more than 30 years ago. Extended mutation analysis was performed, revealing a MET D1010H mutation and MDM2 amplification (Foundation Medicine, Cambridge, MA). She was initially treated with a combination of a novel MMP9 inhibitor, carboplatin, and paclitaxel and had progressive disease after three cycles. Treatment was then changed to gemcitabine, but after one cycle symptomatic disease progression occurred in the lung and bone and at a painful right
Address for correspondence: Jonathan W. Goldman, MD, The David Geffen School of Medicine, University of California, Los Angeles, 2020 Santa Monica Boulevard, Suite 600, Santa Monica, California 90404. E-mail: [email protected]. DOI: 10.1097/JTO.0000000000000491 Copyright © 2015 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/15/1005-0e33
e33
Letters to the Editor
gluteal soft tissue mass. Treatment was initiated with crizotinib. She achieved a rapid improvement in her fatigue and complete resolution of pain. After 7 weeks of therapy, computed tomography imaging showed a reduction (64.4% by the Response Evaluation Criteria in Solid Tumors v 1.1) of the target lesions and resolution of numerous nontarget pulmonary nodules. The left upper lobe primary lung mass had reduced in size, measuring 38 by 24 mm (previously 49 by 42 mm). The painful gluteal mass had shrunk from 54 by 36 mm to 14 by 8 mm. Additional imaging by F-18 fluorodeoxyglucose-positron emission tomography and computed tomography after 19 weeks on treatment demonstrated a near complete response with resolution of all lesions except for the lung primary (now decreased to 29 by 16 mm) and a near F-18 fluorodeoxyglucose-positron emission tomography complete response (decrease in standard uptake value from 20.4 to 2.1; Fig. 1). The patient has tolerated treatment well with a side effect profile consistent with crizotinib: mild taste changes, lower extremity edema, and vision changes at night. Current therapy for NSCLC often employs nonspecific agents, such as cytotoxic chemotherapy with response rates of 20% to 35% in the first-line and less than 10% in pretreated disease. The field is moving toward a molecular age in which we identify driving mutations in a tumor sample and treat with a drug targeted to that specific abnormality. The major success stories so far have been with EGFR, ALK, and ROS mutant disease, and response rates of 60% to 80% are now frequently reported. Simultaneously, extended tumor mutation testing has become available for clinical use. In this setting, a rare mutation, sometimes of uncertain significance, may be found. If an inhibitor directed against that mutation is available on or off of a research protocol, this may provide a novel treatment opportunity. MET abnormalities of several kinds have been reported in NSCLC. Protein over-expression is found in 25% to 75% of NSCLC and has been associated with a poor prognosis.2 However, two phase III trials showed no benefit with MET-targeted therapy in molecularly unselected cohorts.
e34
Journal of Thoracic Oncology ® • Volume 10, Number 5, May 2015
True MET amplification (defined as an increase in the MET/CEP7 signal ratio) is significantly more rare, reported to be 1% to 11%.3,4 Camidge et al.5 reported in 2014 responses with crizotinib therapy in patients, with the highest response rates for tumors that had high amplification (MET/ CEP7 ratio ≥5). The incidence of METmutations in NSCLC appears to be 1% to 3%.3,4 We are not aware of any previous reports in the literature for MET-directed therapy in this population. Crizotinib is a well-tolerated treatment option, and further investigation of its antitumor effect in this setting is warranted. As we progress into the modern molecular age of NSCLC therapy, it will be important to identify regulatory and financial mechanisms to provide novel targeted agents to the appropriate patients. Melody A. Mendenhall, MSN, NP The David Geffen School of Medicine University of California, Los Angeles Santa Monica, California Jonathan W. Goldman, MD The David Geffen School of Medicine
University of California, Los Angeles Santa Monica, California REFERENCES 1. Ou SH, Kwak EL, Siwak-Tapp C, et al. Activity of crizotinib (PF02341066), a dual mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK) inhibitor, in a nonsmall cell lung cancer patient with de novo MET amplification. J Thorac Oncol 2011;6: 942–946. 2. Nakamura Y, Niki T, Goto A, et al. c-Met activation in lung adenocarcinoma tissues: an immunohistochemical analysis. Cancer Sci 2007;98:1006–1013. 3. Okuda K, Sasaki H, Yukiue H, Yano M, Fujii Y. Met gene copy number predicts the prognosis for completely resected non-small cell lung cancer. Cancer Sci 2008;99:2280–2285. 4. Onozato R, Kosaka T, Kuwano H, Sekido Y, Yatabe Y, Mitsudomi T. Activation of MET by gene amplification or by splice mutations deleting the juxtamembrane domain in primary resected lung cancers. J Thorac Oncol 2009;4:5–11. 5. Camidge DR, Ou SI, Shapiro G, et al. Efficacy and safety of crizotinib in patients with advanced c-MET-amplified non-small cell lung cancer (NSCLC). J Clin Oncol 2014;32:5s (suppl; abstr 8001).
FIGURE 1. Representative F-18 fluorodeoxyglucose-positron emission tomography/CT coronal images at baseline and after 19 weeks of crizotinib therapy. Note the resolution of the large left lung primary lesion, small right lung nodule, and large right buttock mass. The muscle F-18 fluorodeoxyglucose-positron emission tomography activity on the follow-up scan is thought to be artifactual. Copyright © 2015 by the International Association for the Study of Lung Cancer
