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Response monitoring during neoadjuvant targeted treatment in early stage non‐
small cell lung cancer
van Gool, M.H.
Publication date
2019
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Citation for published version (APA):
van Gool, M. H. (2019). Response monitoring during neoadjuvant targeted treatment in early
stage non‐small cell lung cancer.
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18F-FLUODEXYGLUCOSE POSITRON EMISSIION
TOMOGRAPGY VERSUS COMPUTED TOMOGRAPHY IN
PREDICTING HISTOPATHOLOGICAL RESPONSE TO
EPIDERMAL GROWTH FACTOR RECEPTOR-TYROSINE
KINASE INHIBITOR TREATMENT IN RESECTABLE
NON-SMALL CELL LUNG CANCER
Matthijs H. van Gool, Tjeerd S. Aukema, Eva E. Schaake, Herman Rijna, Henk E. Codrington, Renato A. Valdes Olmos, Hendrik J. Teertstra, Renee van Pel, Sjaak A. Burgers, Harm van Tinteren, and Houke M. Klomp, on behalf of the NEL‐study group Ann Surg Oncol. 2014;21(9):2831‐7
Abstract
Purpose. To prospectively evaluate diagnostic computed tomography (CT) and 18F‐
fluorodeoxyglucose positron emission tomography/computed tomography (FDG‐PET/ CT) for identification of histopathologic response to neo‐adjuvant erlotinib, an epidermal growth factor receptor–tyrosine kinase inhibitor in patients with resectable non‐small cell lung cancer (NSCLC).
Methods. This study was designed as an open‐label phase 2 trial, performed in four
hospitals in the Netherlands. Patients received preoperative erlotinib 150 mg once daily for 3 weeks. CT and FDG‐PET/CT were performed at baseline and after 3 weeks of treatment. CT was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. FDG‐PET/CT, tumor FDG uptake, and changes were measured by standardized uptake values (SUV). Radiologic and metabolic responses were compared to the histopathologic response.
Results. Sixty patients were enrolled onto this study. In 53 patients (22 men, 31 women),
the combination of CT, FDG‐PET/CT, and histopathologic evaluation was available for analysis. Three patients (6%) had radiologic response. According to European Organization for Research and Treatment of Cancer (EORTC) criteria, 15 patients (28%) showed metabolic response. In 11 patients, histopathologic response (C50% necrosis) was seen. In predicting histopathologic response, relative FDG change in SUVmax showed more SUVmax decrease in the histopathologic response group (‐32%) versus the group with no pathologic response (‐4%) (P=0.0132). Relative change in tumor size on diagnostic CT was similar in these groups with means close to 0.
Conclusions. FDG‐PET/CT has an advantage over CT as a predictive tool to identify
histopathologic response after 3 weeks of EGFR–TKI treatment in NSCLC patients.
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Introduction
In early stage non‐small cell lung cancer (NSCLC), treatment is focused on curative surgery. The effect of neoadjuvant chemotherapy is as limited as in the adjuvant setting, with an estimated survival benefit of 4% at 5 years.1,2 Recent advances in targeted therapy have provided novel treatment options for NSCLC, with promising results. Possibilities to improve survival in patients with NSCLC include strategies of standard therapy combined with a more individualized treatment approach based on serum and tissue markers.3‐5
Epidermal growth factor receptor (EGFR) is overexpressed or may harbor activating mutations in adenocarcinoma in particular. EGFR–tyrosine kinase inhibitors (TKIs), such as erlotinib, bind reversibly to the EGFR tyrosine kinase, competing with the substrate, and can block the catalytic activity of the enzyme that is involved in tumor cell proliferation, angiogenesis, invasion, and metastasis.6 It has shown to be able to induce swift response and to be effective in patients with advanced NSCLC. Erlotinib is approved by the U.S. Food and Drug Administration and the European Medicines Evaluation Agency for treatment of patients with advanced (chemotherapy refractory) NSCLC.7
Although neoadjuvant use of EGFR–TKI is experimental, theoretically, these agents may be suitable as induction treatment as a result of their mild toxicity and rapid onset of response.8
If EGFR–TKIs are able to induce responses in patients with early stage NSCLC, these agents may contribute to curative treatment of patients with NSCLC. On the other hand, unnecessary toxicity and costs from inappropriate therapy should be minimized. Therefore, early decision making as to the effect of treatment is essential in neoadjuvant treatment.
Over recent years, 18F‐fluorodeoxyglucose positron emission tomography, acquired together with‐low dose computed tomography (FDG‐PET/CT), has proven its role as a staging modality in patients with NSCLC.9‐11 After correction for scattering and tissue attenuation, FDG‐PET is fused with low‐dose CT to anatomically localize FDG‐avid lesions. In addition, FDG‐PET/CT has been evaluated as a method to monitor tumor response to systemic treatment. Several studies demonstrated that FDG‐PET/CT is able to identify response to treatment and to avoid (continued) ineffective treatment in advanced stage NSCLC.12‐15 However, diagnostic CT has been the clinical standard for response evaluation, and discussion has been ongoing regarding the performance of FDG‐PET/CT compared to CT.16‐18
We thus designed a phase 2 study to monitor histopathologic response of erlotinib using both diagnostic CT and FDG‐PET/CT in patients with NSCLC. The objective was to prospectively evaluate radiologic and metabolic response after 3 weeks of neoadjuvant EGFR–TKI treatment and to relate the data to histopathologic response.
Patients and methods
Study design
The design, eligibility criteria, and treatment schedule have been described in detail elsewhere.8 In short, this study was designed as an open‐label, noncomparative phase 2 study performed in four hospitals in the Netherlands and was approved by each local independent ethics committee. Patients with newly diagnosed resectable NSCLC, i.e., clinical T1–3 N0–1 disease, were enrolled in the study. The primary lesion had to be measurable, i.e., the longest diameter being ≥1 cm measured by diagnostic spiral CT scan. Sixty patients received neoadjuvant erlotinib in a dosage of 1 tablet of 150 mg daily during an intended course of 3 weeks. Surgical resection was scheduled in the fourth week after initiation of treatment. Written informed consent was obtained from each patient before the start of study treatment.
Imaging
A baseline FDG‐PET/CT scan and a diagnostic CT scan were obtained during routine staging in all patients. The baseline was within 1 month before the initiation of erlotinib treatment. For response monitoring, a FDG‐PET/CT scan and CT scan were planned for 21 days after the initiation of erlotinib therapy. Imaging data were sent to the Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital (NKI‐AVL), for central review. Diagnostic CT scans and FDG‐PET/CT scans performed after treatment with erlotinib were compared to baseline scans.
Diagnostic CT studies were performed with one of two multidetector scanners (Philips Gemini TF 16 row, Eindhoven, the Netherlands; or Siemens Sensation 40 row, Erlangen, Germany). Standard CT of the thorax was performed 40 s after the injection of non‐ionic contrast material (Omnipaque 300 mg/ml, GE Health Care, quantity in milliliters equal to body weight in kilograms, minimum 50 ml, maximum 90 ml) with an injection rate of 3 ml/s. Slice thickness was 1.5 or 2 mm; after acquisition, the images were reformatted into 5‐mm‐thick axial slices, then displayed and viewed (in three directions) using a Carestream PACS (Genova, Italy). The CT studies were interpreted by one radiologist
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(HT). Tumor response was assessed following RECIST version 1.1.19 In short, complete radiological response was classified as the disappearance of all target lesions and partial response as at least 30% decrease in the sum of diameters of the target lesions. Progressive radiological disease was defined as at least a 20% increase in the sum of diameters of the target lesions. Stable radiological disease was defined as neither sufficient shrinkage nor sufficient increase to qualify for partial radiological response or progressive radiological disease respectively. FDG‐PET imaging was performed using a hybrid system (Gemini TF, Philips, Eindhoven, the Netherlands) 60 min after 18F‐FDG injection. 18F‐FDG was administered in doses of 180–240 MBq. Patients fasted for 6 h before imaging. Diabetes mellitus was regulated in advance, with plasma glucose <10 mmol/l. The interval between 18F‐FDG administration and scanning was 60 ± 10 min. Low‐dose CT images (40 mAs, 5 mm slices) were acquired without intravenous contrast.
The generated images (fused PET/ CT, low‐dose CT and PET) were displayed using an Osirix Dicom viewer in a Unix‐based operating system (iMac, Apple, Cupertino, CA, USA) and were evaluated on the basis of two‐dimensional orthogonal reslicing. The images were evaluated by one nuclear physician (RVO). FDG‐PET imaging was only evaluable when scans were acquired with the same scanner, acquisition protocol, and reconstruction software, and with similar intervals from tracer injection to scanning 18F‐ FDG. Tumor uptake was quantified by standardized uptake values (SUVmax, maximum activity concentration of 18F‐FDG divided by the injected dose and corrected for the body weight of the patient). For the determination of the SUVmax, the maximum 18F‐ FDG uptake was searched within the volume of the primary tumor. These regions of interest were manually drawn. Metabolic response was assessed following the EORTC criteria for tumor response.20 In short, progressive metabolic disease was classified as an increase in SUVmax of more than 25%; stable metabolic disease as an increase of SUVmax less than 25% or a decrease of SUVmax of less than 25%; and partial metabolic response as a SUVmax reduction of a minimum of 25%.
Histopathologic assessment
The resection specimens were scored for residual vital tumor and the presence of morphological signs of therapy‐induced regression such as necrosis with foam cell reaction, giant cell reaction, cholesterol clefts, and fibrotic alterations (Junker classification).21 For reporting in this study, a cutoff of 50% necrosis (with morphological signs of therapy‐induced regression) was used for partial histopathologic response. If
more than 90% necrosis was present in the resected specimen, tumor regression was defined as near complete histopathologic response. Mutation testing was performed centrally at the certified laboratory of the NKI‐AVL. Tumors were tested for EGFR mutation an k‐ras mutation.8
Statistical analyses
Patient and imaging characteristics were described in tables. The association of relative change by histopathologic response for each of the imaging techniques was tested with a linear‐by‐linear association test. Differences in SUVmax measurements by EGFR mutation status were tested by the Kruskal‐Wallis test. All analyses were performed with R software, version 2.15.2.
Results
From December 2006 until November 2010, 60 patients were enrolled onto this study. The patient flow diagram is shown in Figure 3.1. In 53 patients (22 men, 31 women), CT scans, FDG‐PET scans, and histopathologic evaluations were available. Median age was 64 years (range 36 to 76 years). Patients received treatment for a median of 20 days (range 5 to 28 days). Five (9%) of 53 patients used erlotinib for less than 14 days as a result of adverse effects (data reported elsewhere).8 Patient characteristics of this group are listed in Table 3.1.Diagnostic CT scan
At baseline CT, the median diameter of the tumor was 32 mm (range 11 to 100 mm). The median diameter of the tumor after 3 weeks of treatment was 32 mm (range 11 to 101 mm) (Figure 3.2A). Median difference in diameter between baseline and monitoring CT was 0 (range ‐36% to 35%) According to RECIST version 1.1, 3 patients (6%) had a partial radiologic response. Forty‐nine patients (91%) had stable disease. In 1 patient (2%), progressive disease was observed.
FDG‐PET/CT
FDG‐PET/CT showed a median baseline SUVmax of 9.1 (range 1.6 to 24.3). After 3 weeks of treatment, median SUVmax was 8.1 (range 0.6–22.7) (Figure 3.2B). The median relative difference in SUVmax between baseline and monitoring scan was ‐10% (range ‐ 78% to 74%). According to EORTC criteria, 15 patients (28%) showed partial metabolic
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response. Thirty‐two patients (60%) had stable metabolic disease, and 6 patients (11%) had progressive metabolic disease. Figure 3.1 Patient flow diagram Table 3.1 Characteristics of 53 patients. Characteristic Value Gender M/F 22 (42 %)/31 (58 %) Age at diagnosis, mean (range) 62 (36–76) Smoking status Never 14 (27 %) Former 24 (45 %) Current 15 (28 %) Clinical stage before treatment IA 17 (32 %) IB 18 (34 %) IIA 6 (11 %) IIB 6 (11 %) IIIA 3 (6 %) IV 3 (6 %) Mutation status EGFR 6 (11 %) KRAS 11 (21 %) Wild type 33 (62 %) Unknown 3 (6 %) Inclusion n = 60 Malignancy (NSCLC) proven n = 56 Malignancy (NSCLC) highly probable n = 4 Baseline imaging available (within 1 month before start treatment) FDG‐PET n = 60 CT n = 59 Surgical resection n = 56 Monitoring imaging available (3 weeks after start treatment) FDG‐PET n = 58 CT n = 59 Erlotinib treatment n = 60 Full 21‐day n = 42 15‐21 days n = 9 < 15 days n = 9 FDG‐PET & CT & pathology available n = 53 Inclusion n = 60 Malignancy (NSCLC) proven n = 56 Malignancy (NSCLC) highly probable n = 4 Baseline imaging available (within 1 month before start treatment) FDG‐PET n = 60 CT n = 59 Surgical resection n = 56 Monitoring imaging available (3 weeks after start treatment) FDG‐PET n = 58 CT n = 59 Erlotinib treatment n = 60 Full 21‐day n = 42 15‐21 days n = 9 < 15 days n = 9 FDG‐PET & CT & pathology available n = 53Figure 3.2A Change in diameter (mm) between baseline CT and monitoring CT. Figure 3.2B Change in SUVmax between baseline FDG‐PET and monitoring FDG‐PET.
Histopathologic response
The median percentage of tumor necrosis in the resection specimen was 30% (range 0% to 97%). In 3 patients (6%), more than 90% tumor necrosis was observed. In 1 patient, more than 90% necrosis was seen, but no preoperative histopathologic diagnosis of NSCLC was obtained. Tumor specimens of 9 patients (17%) showed between 50% and 90% necrosis. In 40 patients (75%), less than 50% necrosis was seen.1
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Imaging and histopathologic response
Relative change in tumor diameter on diagnostic CT was not significantly associated with histopathologic response. Relative change was similar in the three groups determined by histopathologic evaluation with means close to 0 (P=0.29) (Table 3.2). Relative change in FDG SUVmax showed significantly more SUVmax decrease in the histopathologic response group versus the group with no pathologic response (P=0.0132) (Table 3.2; Figure 3.3). The area under the receiver operating characteristic (ROC) curve for FDG‐ PET/CT was 0.69 (95% CI 0.51 to 0.87) with an optimal threshold of 28%. The ROC curve of CT was 0.53 (95% CI 0.34 to 0.71) with an optimal threshold of 35%.
Table 3.2 Relative change by imaging technique and histopathologic response.
Histopathologic response Technique Mean change (%) pCR CT ‐9 pPR CT ‐1 pNR CT 0 pCR FDG‐PET ‐39 pPR FDG‐PET ‐25 pNR FDG‐PET ‐4
Difference in relative change shown by FDG‐PET associated with histopathologic response is significant (P=0.0132). For CT, it is nonsignificant (P=0.2937) pCR histopathologic complete response, pPR histopathologic partial response, pNR no histopathologic response, CT computed tomography, FDG‐PET 18F‐ fluorodeoxyglucose positron emission tomography.
Figure 3.3 Relative change between baseline and monitoring scan using CT and FDG‐PET, respectively, by category of histopathologic response. Bold horizontal lines indicate means of different subgroups (Table 2). Difference in relative change shown by FDG‐PET associated with histopathologic response is significant (P=0.0132). For CT, it is nonsignificant (P=0.2937)
Mutation status and response
Of the 3 patients (6%) with radiological response, 2 patients (4%) had a tumor with an EGFR mutation; the other patient had wild‐type EGFR tumor. Four (28%) of 15 patients with a metabolic response had an EGFR‐mutated tumor, and 11 patients had a wild‐type tumor (21%). There was no difference in FDG uptake (SUVmax) at baseline between EGFR‐positive and ‐negative tumors (respectively, mean ± SD 9.3 ± 6.0 vs. 10.5 ± 6.0, P=0.63). After 3 weeks of treatment, tumors with an EGFR mutation had a lower FDG uptake than tumors without an EGFR mutation (respectively, mean ± SD 3.7 ± 2.4 vs. 9.9 ± 5.6, P=0.0046).
Discussion
This study shows that patients with histopathologic response to EGFR–TKI treatment demonstrate a larger decrease in FDG uptake on PET/CT than patients without histopathologic response. Furthermore, the area under the curve for predicting histopathologic response to treatment is higher for FDG‐PET/CT than for diagnostic CT.
The use of neoadjuvant therapy allows for assessment of response to anticancer drugs in vivo. After a favorable response to neoadjuvant therapy, the drug can potentially also be administered as adjuvant treatment. Alternatively, neoadjuvant treatment may be continued in case of a favorable response. In addition, downstaging of tumors preoperatively by systemic therapy can make patients eligible for surgery. Schaake et al. concluded that erlotinib has a mild toxicity profile and was as safe as neoadjuvant treatment in early NSCLC.8 In a similar study with preoperative gefitinib, Lara‐Guerra et al. showed similar results.22 Adequately predicting tumor response may avoid unnecessary toxicity and the additional costs of ineffective treatment.
There is an ongoing discussion on the prediction of response and survival in NSCLC patients receiving (neo)adjuvant chemotherapy. Some authors conclude that FDG tumor uptake as measured by PET/CT is a better predictor than morphological tumor changes as measured by diagnostic CT.16,23‐25 Diagnostic CT for early response evaluation in TKI therapy has many limitations. TKI therapy is expected to induce response via cytostasis rather than objective morphologic response.26 RECIST version1.1 is further confounded by structural abnormalities, before and after treatment, that may not actually contain tumor.27 However, others conclude that CT is superior to FDG‐PET/CT for the prediction of response or survival in this patient group.18,28
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To our knowledge, this is the first clinical study on the role of changes in tumor glucose metabolic activity as measured by FDG‐PET/CT and coupled diagnostic CT data during neoadjuvant EGFR–TKI therapy. Furthermore, for the first time, a correlation to histopathologic response has been demonstrated. Su et al. studied whether tumors responding to EGFR inhibitors could be identified by measuring treatment‐induced changes in glucose utilization in a mouse model.29 They used a panel of cell lines with a spectrum of sensitivity to EGFR–TKI and measured the change in glucose utilization with FDG. Uptake of FDG reflected immediate cellular response to EGFR treatment. They concluded that FDG tumor uptake as measured by PET/CT may be a valuable clinical predictor for therapeutic responses to EGFR–TKI. In patients with advanced NSCLC, Benz et al. showed that FDG‐PET/CT performed early after the start of erlotinib treatment can help to identify patients who benefit from this targeted therapy.13 Although the efficacy of EGFR–TKIs is higher in patients with EGFR‐mutated tumors, prediction of response is not optimal by mutation analysis only. It is known that several patients without sensitizing EGFR mutations do benefit from erlotinib therapy. This may be due to heterogeneity within the tumor, and biopsy samples will not always show relevant mutations.6
Some limitations of this study should be acknowledged. The patient population includes a heterogeneous group of NSCLC subtypes. It has become clear that adenocarcinomas are more likely to respond to EGFR–TKI treatment than tumors with different histopathology.30 However, histological classification of squamous cell carcinoma and adenocarcinoma is unreliable.31 This difficulty is even bigger in the preoperative setting, where classifying tumor in small diagnostic samples acquired by percutaneous biopsy is hampered by the paucity of tumor cells and the absence of tissue architecture.32
Another limitation is that there is no consensus regarding the optimal timing in performing either CT or FDG‐ PET during or after some weeks or months of treatment. According to RECIST version 1.1, the best radiologic response evaluation can be claimed at least 4 weeks after initiation of therapy.19 In our study, we performed monitoring CT scans 3 weeks after initiation of therapy. Therefore, the relatively small number of patients with radiologic response could be explained by the time of monitoring CT scan. In contrast, several authors concluded that in advanced NSCLC, metabolic response on FDG‐ PET/CT scan as early as 1–2 weeks can predict progression‐free survival and overall survival.15,17,33
Conclusion
This study shows that response evaluation of neoadjuvant erlotinib with FDG‐PET/CT has an advantage over diagnostic CT. Tumor FDG uptake decrease may be used as a predictive tool to identify patients with histopathologic response after 3 weeks of EGFR– TKI treatment in NSCLC patients.
Acknowledgment
This phase 2 study is an investigator‐ initiated study, supported by an unrestricted educational grant from Roche, the Netherlands. We thank the data center of the Netherlands Cancer Institute for their data management and logistic support. Appendix The NEL study group members are as follows: H. M. Klomp, MD, PhD, I. Kappers, MD, M. W. Wouters, MD, (Department of Surgical Oncology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands) E. E. Schaake, MD, N. van Zandwijk, MD, PhD, J. A. Burgers, MD, PhD, P. Baas, MD, PhD, M. van den Heuvel, MD, PhD, W. Buikhuisen, MD, (Department of Thoracic Oncology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands); R. A. Valdés Olmos, MD, PhD, T. S. Aukema, MD, PhD, (Department of Nuclear Medicine, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands); H.J. Teertstra, MD, (Department of Radiology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands); D. de Jong, MD, PhD, R. van Pel, MD, (Department of Pathology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands); H. van Tinteren, PhD, O. Dalesio, PhD, (Department of Biometrics, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands); H. Rijna, MD, PhD, (Department of Thoracic Surgery, Kennemer Gasthuis, Haarlem, The Netherlands); C. Weenink, MD, (Department of Pulmonology, Kennemer Gasthuis, Haarlem, The Netherlands); A. Dingemans, MD, PhD, (Department of Pulmonology, Maastricht Academic Medical Centre, Maastricht, The Netherlands); J. Brahim, MD, H.E. Codrington, MD, (Department of Pulmonology, Haga Hospital, The Hague, The Netherlands)
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References
1. Pisters KM, Le Chevalier T. Adjuvant chemotherapy in completely resected non‐small‐cell lung cancer. J Clin Oncol. 2005;23(14):3270‐8.
2. Gilligan D, Nicolson M, Smith I, Groen H, Dalesio O, Goldstraw P, et al. Preoperative chemotherapy in patients with resectable non‐small cell lung cancer: results of the MRC LU22/NVALT 2/EORTC 08012 multicentre randomised trial and update of systematic review. Lancet. 2007;369:1929‐37.
3. Cobo M, Isla D, Massuti B, Montes A, Sanchez JM, Provencio M, et al. Customizing cisplatin based on quantitative excision repair cross‐complementing 1 mRNA expression: a phase III trial in non‐small‐cell lung cancer. J Clin Oncol. 2007;25(19):2747‐54.
4. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non‐small‐cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129‐39.
5. Sun S, Schiller JH, Spinola M, Minna JD. New molecularly targeted therapies for lung cancer. J Clin Invest. 2007;117(10):2740‐50.
6. Soria JC, Mok TS, Cappuzzo F, Janne PA. EGFR‐mutated oncogene‐addicted non‐small cell lung cancer: current trends and future prospects. Cancer Treat Rev. 2012;38(5):416‐30.
7. Cohen MH, Johnson JR, Chattopadhyay S, Tang S, Justice R, Sridhara R, et al. Approval summary: erlotinib maintenance therapy of advanced/metastatic non‐small cell lung cancer (NSCLC). Oncologist. 2010;15(12):1344‐51.
8. Schaake EE, Kappers I, Codrington HE, Valdes Olmos RA, Teertstra HJ, van Pel R, et al. Tumor response and toxicity of neoadjuvant erlotinib in patients with early‐stage non‐small‐cell lung cancer. J Clin Oncol. 2012;30(22):2731‐8.
9. Lardinois D, Weder W, Hany TF, Kamel EM, Korom S, Seifert B, et al. Staging of non‐small‐cell lung cancer with integrated positron‐emission tomography and computed tomography. N Engl J Med. 2003;348(25):2500‐7.
10. Antoch G, Stattaus J, Nemat AT, Marnitz S, Beyer T, Kuehl H, et al. Non‐small cell lung cancer: dual‐ modality PET/CT in preoperative staging. Radiology. 2003;229(2):526‐33. 11. van Tinteren H, Smit EF, Hoekstra OS. FDG‐PET in addition to conventional work‐up in non‐small‐cell lung cancer. J Clin Oncol. 2005;23(7):1591; author reply ‐2. 12. Aukema TS, Kappers I, Olmos RA, Codrington HE, van TH, van PR, et al. Is 18F‐FDG PET/CT useful for the early prediction of histopathologic response to neoadjuvant erlotinib in patients with non‐small cell lung cancer? JNuclMed. 2010;51(9):1344‐8. 13. Benz MR, Herrmann K, Walter F, Garon EB, Reckamp KL, Figlin R, et al. (18)F‐FDG PET/CT for monitoring treatment responses to the epidermal growth factor receptor inhibitor erlotinib. J Nucl Med. 2011;52(11):1684‐9.
14. O'Brien ME, Myerson JS, Coward JI, Puglisi M, Trani L, Wotherspoon A, et al. A phase II study of (1)(8)F‐ fluorodeoxyglucose PET‐CT in non‐small cell lung cancer patients receiving erlotinib (Tarceva); objective and symptomatic responses at 6 and 12 weeks. EurJCancer. 2012;48:68‐74.
15. Zander T, Scheffler M, Nogova L, Kobe C, Engel‐Riedel W, Hellmich M, et al. Early prediction of nonprogression in advanced non‐small‐cell lung cancer treated with erlotinib by using [(18)F]fluorodeoxyglucose and [(18)F]fluorothymidine positron emission tomography. J Clin Oncol. 2011;29(13):1701‐8.
16. Hoekstra CJ, Stroobants SG, Smit EF, Vansteenkiste J, van TH, Postmus PE, et al. Prognostic relevance of response evaluation using [18F]‐2‐fluoro‐2‐deoxy‐D‐glucose positron emission tomography in patients with locally advanced non‐small‐cell lung cancer. JClinOncol. 2005;23(33):8362‐70.
17. Mileshkin L, Hicks RJ, Hughes BG, Mitchell PL, Charu V, Gitlitz BJ, et al. Changes in 18F‐ fluorodeoxyglucose and 18F‐fluorodeoxythymidine positron emission tomography imaging in patients with non‐small cell lung cancer treated with erlotinib. Clin Cancer Res. 2011;17(10):3304‐15.
18. Tanvetyanon T, Eikman EA, Sommers E, Robinson L, Boulware D, Bepler G. Computed tomography response, but not positron emission tomography scan response, predicts survival after neoadjuvant chemotherapy for resectable non‐small‐cell lung cancer. J Clin Oncol. 2008;26(28):4610‐6.
19. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228‐47. 20. Young H, Baum R, Cremerius U, Herholz K, Hoekstra O, Lammertsma AA, et al. Measurement of clinical
and subclinical tumour response using [18F]‐fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European Organization for Research and Treatment of Cancer (EORTC) PET Study Group. EurJCancer. 1999;35:1773‐82.
21. Junker K, Thomas M, Schulmann K, Klinke F, Bosse U, Muller KM. Tumour regression in non‐small‐cell lung cancer following neoadjuvant therapy. Histological assessment. J Cancer Res Clin Oncol. 1997;123(9):469‐77.
22. Lara‐Guerra H, Waddell TK, Salvarrey MA, Joshua AM, Chung CT, Paul N, et al. Phase II study of preoperative gefitinib in clinical stage I non‐small‐cell lung cancer. J Clin Oncol. 2009;27(36):6229‐36. 23. Macmanus MP, Seymour JF, Hicks RJ. Overview of early response assessment in lymphoma with FDG‐
PET. Cancer Imaging. 2007;7:10‐8. 24. Cerfolio RJ, Ojha B, Mukherjee S, Pask AH, Bass CS, Katholi CR. Positron emission tomography scanning with 2‐fluoro‐2‐deoxy‐d‐glucose as a predictor of response of neoadjuvant treatment for non‐small cell carcinoma. J Thorac Cardiovasc Surg. 2003;125(4):938‐44. 25. Zhang C, Liu J, Tong J, Sun X, Song S, Huang G. 18F‐FDG‐PET evaluation of pathological tumour response to neoadjuvant therapy in patients with NSCLC. Nucl Med Commun. 2012. 26. Tuma RS. Sometimes size doesn't matter: reevaluating RECIST and tumor response rate endpoints. J Natl Cancer Inst. 2006;98(18):1272‐4.
27. Vansteenkiste J, Fischer BM, Dooms C, Mortensen J. Positron‐emission tomography in prognostic and therapeutic assessment of lung cancer: systematic review. Lancet Oncol. 2004;5(9):531‐40.
28. Port JL, Kent MS, Korst RJ, Keresztes R, Levin MA, Altorki NK. Positron emission tomography scanning poorly predicts response to preoperative chemotherapy in non‐small cell lung cancer. Ann Thorac Surg. 2004;77(1):254‐9; discussion 9.
29. Su H, Bodenstein C, Dumont RA, Seimbille Y, Dubinett S, Phelps ME, et al. Monitoring tumor glucose utilization by positron emission tomography for the prediction of treatment response to epidermal growth factor receptor kinase inhibitors. Clin Cancer Res. 2006;12(19):5659‐67.
30. Besse B, Ropert S, Soria JC. Targeted therapies in lung cancer. Ann Oncol. 2007;18 Suppl 9:ix135‐42. 31. Stang A, Pohlabeln H, Muller KM, Jahn I, Giersiepen K, Jockel KH. Diagnostic agreement in the
histopathological evaluation of lung cancer tissue in a population‐based case‐control study. Lung Cancer. 2006;52(1):29‐36.
32. Field RW, Smith BJ, Platz CE, Robinson RA, Neuberger JS, Brus CP, et al. Lung cancer histologic type in the surveillance, epidemiology, and end results registry versus independent review. J Natl Cancer Inst. 2004;96(14):1105‐7.
33. Kahraman D, Scheffler M, Zander T, Nogova L, Lammertsma AA, Boellaard R, et al. Quantitative analysis of response to treatment with erlotinib in advanced non‐small cell lung cancer using 18F‐FDG and 3'‐ deoxy‐3'‐18F‐fluorothymidine PET. JNuclMed. 2011;52(12):1871‐7.
