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CT is an independent prognostic biomarker for extensive-disease small cell lung cancer
Lung Cancer 81 (2013) 218–225
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Extra-thoracic tumor burden but not thoracic tumor burden on 18 F-FDG PET/CT is an independent prognostic biomarker for extensive-disease small cell lung cancer Jong-Ryool Oh a , Ji-Hyoung Seo b , Chae Moon Hong a , Shin Young Jeong a , Sang-Woo Lee a , Jaetae Lee a , Jung-Joon Min c , Ho-Chun Song c , Hee-Seung Bom c , Young-Chul Kim d , Byeong-Cheol Ahn a,∗ a
Department of Nuclear Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea Department of Nuclear Medicine, Daegu Fatima Hospital, Daegu, Republic of Korea c Department of Nuclear Medicine, Chonnam National University Hospital, Gwangju, Republic of Korea d Department of Internal Medicine, Chonnam National University Hospital, Gwangju, Republic of Korea b
a r t i c l e
i n f o
Article history: Received 18 January 2013 Received in revised form 11 March 2013 Accepted 1 May 2013 Keywords: Extensive disease small cell lung cancer 18 F-FDG PET/CT Prognosis Metabolic tumor volume Oligometastases Biomarker
a b s t r a c t Purpose: The aim of this study was to evaluate the relationship and difference in prognostic significance between whole-body tumor burden, thoracic tumor burden, and extra-thoracic tumor burden on 18 F-FDG PET/CT for patients with extensive-disease small cell lung cancer (ED-SCLC). Materials and methods: We performed a retrospective, two-center analysis for patients with ED-SCLC who underwent pretreatment 18 F-FDG PET/CT. Metabolic tumor burden was estimated using whole-body metabolic tumor volume (MTVWB ), thoracic metabolic tumor volume (MTVTRX ), extra-thoracic metabolic tumor volume (MTVEXT ), and the number of extra-thoracic tumor foci. Uni- and multivariate analyses were performed using various clinical factors and the metabolic indices. Results: A total of 91 patients were eligible for this study. MTVWB showed stronger correlation with MTVEXT than MTVTRX (r2 = 0.804 vs. 0.132, p < 0.001, both), whereas no correlation was observed between MTVEXT and MTVTRX (r2 = 0.007, p = 0.428). Patients with smaller MTVWB , MTVEXT , and extra-thoracic tumor foci showed longer survival than patients with larger MTVWB , MTVEXT , and extra-thoracic tumor foci, respectively, whereas the survival difference between patients with smaller MTVTRX and those with larger MTVTRX was not significant. Results of uni- and multivariate analyses showed that ECOG performance status (HR = 2.31, p = 0.015), initial chemotherapy cycles (HR = 0.24, p < 0.001), and the number of extrathoracic tumor foci (HR = 2.75, p < 0.001) were independent prognostic factors for overall survival, and initial chemotherapy cycles (HR = 0.25, p < 0.001), and MTVEXT (HR = 2.04, p = 0.013) were independent prognostic factors for progression-free survival. Conclusion: These data provide evidence indicating that extra-thoracic tumor burden but not thoracic tumor burden is an independent prognostic biomarker for ED-SCLC, and support further exploration of novel treatment strategies targeting extra-thoracic tumor burden in order to improve the clinical outcomes of patients with ED-SCLC. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Small cell lung cancer (SCLC), accounting for 13–20% of all new cases of lung cancer, is an aggressive malignancy characterized by widespread dissemination at presentation with rapid doubling time [1]. SCLC is staged as either limited disease (LD) or extensive disease (ED) according to the suitability for thoracic radiotherapy. Over the past 20 years, ED-SCLC has mainly been treated with chemotherapy alone. Despite initial response rates of 60–70%,
∗ Corresponding author at: Department of Nuclear Medicine, Kyungpook National University School of Medicine and Hospital, 50, Samduk 2-ga, Jung gu, Daegu 700721, Republic of Korea. Tel.: +82 53 420 5583; fax: +82 53 422 0864. E-mail address: [email protected] (B.-C. Ahn). 0169-5002/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.lungcan.2013.05.001
the median duration of response for initial treatment is too short and the median survival time is only 9–11 months [1,2]. Prophylactic cranial irradiation (PCI) has recently been suggested as a promising treatment option for improvement of the clinical outcomes of patients with ED-SCLC [3], however, otherwise, only small advances have been made including molecular-targeted agents, thoracic radiotherapy, and extra-thoracic radiosurgery [4–7]. To reduce expenses and enhance the efficacy of upcoming clinical investigations, identification of more optimized biomarkers that can validate effectiveness of new treatment strategy and select patients who might benefit from it is essential. 18 F-fluorodeoxyglucose (FDG), an analog of glucose, is actively taken up within most tumor cells. Positron emission tomography/computed tomography (PET/CT) using 18 F-FDG, with its advantage for whole body assessment and quantification of tumor
J.-R. Oh et al. / Lung Cancer 81 (2013) 218–225
activity, has already been successfully applied in oncologic practice [8]. Metabolic tumor volume (MTV), defined as the volume of tumor tissues with increased FDG uptake, can estimate the total extent of activated tumor cells. Our group has reported optimistic results that whole-body metabolic tumor volume, which reflects systemic tumor burden including primary tumor, lymph nodes, and distant foci, could be a prognostic marker for both LD and ED-SCLC patients [9]. However, prior to its clinical translation, more detailed metabolic profiling that may allow better insight into tumor biology is required. Therefore, the aim of this study was to evaluate the prognostic significance of whole-body tumor burden, thoracic tumor burden, and extra-thoracic tumor burden on 18 F-FDG PET/CT for patients with ED-SCLC. 2. Materials and methods 2.1. Patients Patients with pathologically proven ED-SCLC who underwent pretreatment 18 F-FDG PET/CT scan at two centers from January 2004 to December 2010 were retrospectively reviewed. ED was pathologically or clinically defined as disease extending to a contralateral hemithorax or extra-thoracic lesion. Patients who did not receive any treatment or did not have available follow-up data were excluded. For evaluation of the significance of extra-thoracic tumor burden, patients with intra-thoracic ED [N3 (contralateral supraclavicular involvement beyond the radiation field) and M1a (separate tumor nodule in contralateral lung/pleural metastasis/malignant pleural effusion) disease based on the 7th edition of the American Joint Committee on Cancer Staging (AJCC) for nonsmall cell lung cancer (NSCLC)] were also excluded for analysis. Routine staging work-up, including history and physical examination, complete blood cell counts and chemistry panel, CT of chest and upper abdomen, brain MRI, and 18 F-FDG PET/CT, were completed prior to initiation of therapy. The main treatment was based on chemotherapy consisting of platinum with either etoposide or irinotecan administered every three weeks for six cycles. PCI was recommended for patients who showed complete or partial remission after initial therapy. During follow-up, palliative radiotherapy to thorax, brain, or extra-thoracic metastasis was also added according to the patients’ performance status and clinical situation. The standard response evaluation consisted of chest X-ray prior to each cycle and CT scan every two cycles of chemotherapy. Follow-up 18 F-FDG PET/CT scan was performed three weeks after the last cycle of chemotherapy or when disease progression or recurrence was suspected by standard examinations. All patients were followed up for at least nine months after diagnosis or until death. The local ethical committees approved the study and all enrolled patients gave written informed consent for 18 F-FDG PET/CT study. 2.2. Imaging acquisitions Combined PET/CT scanners (Discovery ST System, GE Medical Systems, Milwaukee, WI, USA; Reveal RT HiREZ, Siemens, Knoxville, TN, USA) were used in performance of 18 F-FDG PET/CT studies. All patients fasted for at least 6 h prior to intravenous administration of 18 F-FDG. Patients’ blood glucose levels were measured prior to injection of 18 F-FDG; if the level was over 8.3 mmol/L, then PET/CT was deferred. No oral or intravenous contrast material was administered. Image acquisitions for torso scanning were started approximately 1 h after injection of 7.4 MBq 18 F-FDG per kilogram of body weight. CT scan was performed for generation of an attenuation correction map for the PET scan using the following settings: 120 kVp; 10–130 mA; tube rotation time, 0.7 s per rotation; and
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section thickness, 3.75 mm in discovery PET/CT unit and 130 kVp; 95 mA; tube rotation time, 0.8 s per rotation; and section thickness, 2.5 mm in reveal PET/CT unit. Immediately following CT acquisition, PET data were acquired in the same anatomic locations with a 15.7 cm axial field of view acquired in the 2D mode with 180 s/bed position. CT data were used for attenuation correction and the PET images were reconstructed using a conventional iterative algorithm, ordered-subsets expectation-maximization (OSEM). 2.3. Image analysis An Advantage Workstation 4.4 (GE Medical Systems, Milwaukee, WI, USA), providing multiplanar reformatted images, was used in performance of image display and analysis. Maximum standardized uptake value (SUVmax) based on body weight and metabolic tumor volume were determined by the attenuation-corrected PET data using volume viewer software, as described in a previous study [9]: (1) automatic production of the boundaries of voxels presenting SUV intensity exceeding 3.0 encasing targeted metabolic tumor burden, (2) subtraction of normal organ, (3) subtraction of false-positive lesions. Thoracic metabolic tumor volume (MTVTRX ) was measured in the tumor within the thoracic cavity, including both lungs, pleura, mediastinum, and both hilar and supraclavicular lymph nodes. Extra-thoracic metabolic tumor volume (MTVEXT ) was measured in the tumor beyond the thoracic cavity. Wholebody metabolic tumor volume (MTVWB ) was calculated by the sum of MTVTRX and MTVEXT . The number of extra-thoracic tumor foci was estimated by the foci that present abnormal FDG uptake in any organ beyond the thoracic cavity. Due to high physiologic FDG uptake, brain was excluded for evaluation of extra-thoracic tumor burden. 2.4. Statistical analysis SPSS 18 for Windows (SPSS Inc., Chicago, IL, USA) was used in performance of statistical analysis. For detailed classification for prognosis, median values of SUVmax, MTV, and the number of extra-thoracic tumor foci were used [9,10]. Pearson correlation coefficient was used for assessment of correlations between MTVWB , MTVTRX , and MTVEXT . Survival time was derived from the date of 18 F-FDG PET/CT scan to the date of death/recurrence or last follow-up. Kaplan–Meier methods were used for production of overall survival (OS) and progression free survival (PFS) curves and the log-rank test was used for assessment of survival differences between groups. Cox regression analysis was used for development of uni- and multivariate models describing the association of the independent variables with OS and PFS. Independent variables analyzed included gender, age, smoking, comorbidity, Eastern Cooperative Oncology Group (ECOG) performance status, lactate dehydrogenase (LDH), initial chemotherapy regimen, number of initial chemotherapy cycles received, thoracic radiotherapy, prophylactic cranial irradiation, palliative brain radiotherapy, palliative extra-thoracic radiotherapy, brain metastasis, brain-only metastasis, bone metastasis, distant nodal metastasis, liver metastasis, SUVWB , SUVTRX , SUVEXT , MTVWB , MTVTRX , MTVEXT , and the number of extra-thoracic tumor foci. A value of p < 0.05 was considered statistically significant. The 95% confidence interval (95% CI) was determined for each parameter. 3. Results 3.1. Patient characteristics A total of 128 patients with ED-SCLC who underwent pretreatment 18 F-FDG FDG PET/CT were scanned. Among them, 103 patients who received at least one cycle of chemotherapy with
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Table 1 Patient characteristics. All patients (N = 91) Gender Male Female Age (years) <70 ≥70 Smoking Never Yes One or more comorbiditya No Yes ECOG performance status 0 or 1 2 or 3 LDHb Normal Increased Initial chemotherapy regimen Platinum + etoposide Platinum + irinotecan No. of cycles of initial chemotherapy received <3 ≥3 Thoracic radiotherapy No Yes Prophylactic cranial irradiation No Yes Palliative brain radiotherapy No Yes Palliative extra-thoracic radiotherapy No Yes Sites of distant metastasisc Brain Brain-only Bone Distant lymph nodes Liver Adrenal glands Pancreas Muscles Kidney Thyroid Small bowel Spleen Submandibular gland
stronger correlation with MTVWB than MTVTRX (r2 = 0.804 vs. 0.132, p < 0.001, both) (Fig. 1A), whereas no correlation was observed between MTVTRX and MTVEXT (r2 = 0.007, p = 0.428) (Fig. 1B).
75 (82%) 16 (18%)
3.3. Survival analyses
56 (62%) 35 (38%)
At the time of analysis, 86 of 91 patients had died. Median OS and PFS of the entire cohort were 8.6 and 5.1 months, respectively (range: 0.5–32.1 months for OS and 0.5–15.3 months for PFS). Median survival of patients with smaller MTVWB was significantly longer than that of patients with larger MTVWB [10.0 vs. 8.0 months (p = 0.005)] (Fig. 2A). Median survival of patients with smaller MTVEXT or a smaller number of extra-thoracic tumor foci was significantly longer than that of patients with larger MTVEXT or a larger number of extra-thoracic tumor foci [9.7 vs. 8.6 months for MTVEXT (p = 0.008) and 10.9 vs. 6.8 months for extra-thoracic tumor foci (p < 0.001)], whereas median survival between patients with smaller MTVTRX and larger MTVTRX was not significantly different [9.4 vs. 8.1 months (p = 0.102)] (Fig. 2B–D). These results were also replicated in the PFS analysis (Fig. 3). Following performance of univariate analysis, age, ECOG performance status, number of initial chemotherapy cycles, thoracic radiotherapy, PCI, bone metastasis, liver metastasis, MTVWB , MTVEXT , and number of extra-thoracic tumor foci were found to be significant prognostic factors for OS, and ECOG performance status, number of initial chemotherapy cycles received, bone metastasis, MTVWB , MTVEXT , and number of extra-thoracic tumor foci were significant prognostic factors for PFS (Table 2). Neither SUV parameters nor MTVTRX was found to be a significant factor for prediction of OS or PFS. On multivariate analysis, ECOG performance status, number of initial chemotherapy cycles, and number of extra-thoracic tumor foci were independent prognostic factors for OS, and number of initial chemotherapy cycles and MTVEXT were independent prognostic factors for PFS (Fig. 4).
14 (15%) 77 (85%) 32 (35%) 59 (65%) 78 (86%) 13 (14%) 51 (56%) 38 (42%) 62 (68%) 29 (32%) 26 (29%) 65 (71%) 65 (71%) 26 (29%) 86 (95%) 5 (5%) 72 (79%) 19 (21%) 68 (75%) 23 (25%) 27 (30%) 8 (9%) 51 (56%) 37 (41%) 32 (35%) 16 (18%) 9 (10%) 3 (3%) 2 (2%) 1 (1%) 1 (1%) 1 (1%) 1 (1%)
ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; no, number. a Presence of one or more of the following diseases: ischemic heart disease, diabetes, or chronic obstructive pulmonary disease. b Not assessed in two patients. c On the initial staging.
available follow-up data were initially assessed. We excluded 12 patients for intra-thoracic (N3 or M1a) disease beyond tolerable radiation field, yielding a 91-patient cohort (mean age: 67 years, range: 42–89 years) consisting of 75 men and 16 women. Details regarding baseline patient demographics, prior treatment histories, and sites of distant metastasis are shown in Table 1. 3.2. Comparisons between metabolic indices The median MTVWB was 233 cm3 (range: 13–1415 cm3 ) and the median SUVWB was 10.2 (range: 4.3–22.1). The median MTVTRX was 120 cm3 (range: 11–526 cm3 ), the median SUVTRX was 9.8 (range: 4.4–22.1), the median MTVEXT was 21 cm3 (range: 0–1321 cm3 ), and the median SUVEXT was 7.9 (range: 0–20.6). MTVEXT showed
4. Discussion In this study, we compared relationship and prognostic significance between whole-body, thoracic, and extra-thoracic tumor burdens on 18 F-FDG PET/CT. Clinical outcomes for patients with ED-SCLC showed strong correlation with extra-thoracic tumor burden but not thoracic tumor burden. Our results shows that 18 F-FDG PET/CT can provide a more accurate survival prognostification for patients with ED-SCLC and warrant further exploration of new treatment paradigms targeting extra-thoracic tumor burden for patients with ED-SCLC. For over 20 years, the treatment of ED-SCLC has been mainly dependent on systemic chemotherapy. A paradigm of control of extra-thoracic metastasis, although it was intended for prevention but not for palliative care, and was limited to brain metastasis, had already been validated by results of a phase III randomized trial [3]. According to findings from a recent retrospective analysis by Komatsu et al., high-dose radiosurgery for treatment of bone metastasis in patients with lung cancer, although 12% of SCLC were included, showed an association with a better prognosis [7]. An ongoing clinical trial also proposes to determine the role of consolidation radiotherapy for extra-cranial, extra-thoracic metastatic sites alongside PCI after a response to systemic chemotherapy in patients with ED-SCLC [11]. A large body of evidence on the use of stereotactic body radiation therapy (SBRT) for treatment of primary and metastatic tumors in various sites, including lung, liver, spine, adrenal glands, distant lymph nodes, has been accumulated over the past 10–15 years, and efficacy and safety of the SBRT have been demonstrated [12–16]. Our results suggest the potential role of metabolic indices on 18 F-FDG PET/CT as imaging biomarkers for
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Fig. 1. Correlations between whole-body metabolic tumor volume (MTVWB ), thoracic metabolic tumor volume (MTVTRX ), and extra-thoracic metabolic tumor volume (MTVEXT ). MTVEXT showed stronger correlation with MTVWB than MTVTRX (A). No correlation was observed between MTVTRX and MTVEXT (B).
selection of patients who benefit from the addition of SBRT to conventional chemotherapy. We found that the extent of thoracic tumor burden did not show correlation with that of extra-thoracic tumor burden. In addition, some patients with a larger extra-thoracic tumor burden had a relatively smaller extent of thoracic tumor burden (Fig. 1B). Our observation coincided with the parallel progression model of metastasis in which dissemination of tumor cells may occur early in malignant progression, and colonization of multiple secondary sites at different times may occur independently from those incurred by the primary tumor [17]. Our results also provide direct evidence that patients with a larger metastatic tumor burden had
a higher risk of progression and death than patients with a smaller metastatic tumor burden. Application of gene expression profiling to patient tumor cells has already revealed an association of poor prognosis signatures with increased frequency of metastatic events [18,19]. Circulating tumor cells, which are known to circulate in the peripheral blood in patients with several types of malignancies, were recently reported as having a strong prognostic significance in patients with SCLC, particularly in the ED subset [20,21]. A higher number of circulating tumor cells has been reported as an indicator of the presence of distant metastases. Although the competence of circulating tumor cells informing secondary lesions is currently under investigation, there may be a close correlation between
Fig. 2. Kaplan–Meier analyses of overall survival according to MTVWB (A), MTVTRX (B), MTVEXT (C), and the number of extra-thoracic tumor foci (D). MTV, metabolic tumor volume; WB, whole-body; TRX, thorax; EXT, extra-thorax; no, number.
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Fig. 3. Kaplan–Meier analyses of progression-free survival according to MTVWB (A), MTVTRX (B), MTVEXT (C), and the number of extra-thoracic tumor foci (D). MTV, metabolic tumor volume; WB, whole-body; TRX, thorax; EXT, extra-thorax; no, number.
circulating tumor cells and the extent of extra-thoracic tumor burden. We applied a 3.0 threshold of SUV for automatic delineation of tumor volume, as described in previous report [9]. There has been no optimized cut-off value that can accurately estimate the ‘true’ tumor burden so far. In our experience, a threshold of 3.0 can minimize unwanted physiologic FDG uptake in normal tissue during estimation of MTV, and thereby increasing the reproducibility of
MTV measurement. Although it is variable according to tumors, a SUV of 3.0 is a general cut-off set for differentiating malignant and benign lesions. Using 18 F-FDG PET/CT, we validated several metabolic indices, including SUV, MTV, and the number of extrathoracic tumor foci as prognosticators in patients with ED-SCLC. In accordance with results of previous reports [9,22], MTV showed much better prognostic power than SUV, because MTV can represent the total extent of FDG uptake by tumor tissues, whereas
Fig. 4. Multivariate survival analyses with Cox-proportional hazard models for overall survival (A) and progression-free survival (B). HR, hazard ratio; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group, no, number; MTV, metabolic tumor volume; WB, whole-body; TRX, thorax; EXT, extra-thorax.
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Table 2 Univariate survival analyses with Cox-proportional hazard models. Overall survival HR (95% CI) Gender Male Age (years) ≥70 Smoking Yes One or more comorbidity Yes ECOG performance status 2 or 3 LDH Increased Initial chemotherapy regimen Platinum + irinotecan No. of cycles of initial chemotherapy received ≥3 Thoracic radiotherapy Yes Prophylactic cranial irradiation Yes Palliative brain radiotherapy Yes Palliative extra-thoracic radiotherapy Yes Brain metastasis Yes Brain-only metastasis Yes Bone metastasis Yes Distant nodal metastasis Yes Liver metastasis Yes SUVWB ≥10.2 SUVTRX ≥9.8 SUVEXT ≥7.9 MTVWB (cm3 ) ≥233 MTVTRX (cm3 ) ≥120 MTVEXT (cm3 ) ≥21 No. of extra-thoracic tumor foci ≥4
1.49 (0.84–2.64)
Progression-free survival P
HR (95% CI) 0.179 §
P
1.72 (0.97–3.03)
0.063
1.60 (1.03–2.50)
0.041
1.22 (0.79–1.87)
0.373
1.20 (0.67–2.18)
0.543
1.24 (0.70–2.22)
0.463
1.40 (0.89–2.21)
0.147
1.47 (0.94–2.31)
0.093
1.94 (1.05–3.60)
0.036§
1.87 (1.03–3.39)
0.041§
1.05 (0.68–1.64)
0.804
1.01 (0.66–1.55)
0.956
1.04 (0.63–1.51)
0.346
1.06 (0.68–1.65)
0.794
0.29 (0.17–0.47)
<0.001* (<0.0001)
0.33 (0.21–0.54)
0.42 (0.25–0.70)
<0.001† (0.0009)
0.78 (0.49–1.24)
0.294
§
<0.001* (<0.0001)
0.28 (0.09–0.89)
0.033
0.48 (0.19–1.18)
0.112
0.71 (0.42–1.18)
0.187
0.62 (0.37–1.03)
0.066
0.80 (0.49–1.29)
0.358
1.02 (0.64–1.64)
0.928
1.06 (0.67–1.69)
0.813
1.24 (0.79–1.96)
0.351
0.48 (0.22–1.05)
0.067
0.53 (0.26–1.13)
0.102
1.73 (1.12–2.69)
0.014§
1.55 (1.02–2.36)
0.043§
1.09 (0.71–1.68)
0.688
1.01 (0.66–1.54)
0.970
§
1.70 (1.08–2.69)
0.023
1.39 (0.90–2.16)
0.141
0.88 (0.57–1.35)
0.548
0.84 (0.56–1.28)
0.419
0.84 (0.54–1.30)
0.426
0.96 (0.64–1.46)
0.863
1.10 (0.72–1.68)
0.667
0.97 (0.64–1.48)
0.900
1.87 (1.20–2.90)
0.006‡
1.81 (1.18–2.78)
0.007‡
1.44 (0.93–2.22)
0.104
1.41 (0.92–2.15)
0.120
1.82 (1.17–2.83)
0.009‡
2.12 (1.37–3.28)
<0.001† (0.0008)
2.20 (1.41–3.42)
<0.001† (0.0005)
2.65 (1.67–4.20)
<0.001* (<0.0001)
HR, hazard ratio; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; SUV, maximum standardized uptake value; WB, wholebody; TRX, thorax; EXT, extra-thorax; MTV, metabolic tumor volume. * p < 0.0001. † p < 0.001. ‡ p < 0.01. § p < 0.05.
SUV only represents the maximal intensity of FDG uptake in certain lesions. However, the obstacle of MTV in clinical application is standardization. MTV can be easily changed according to the cut-off value of SUV, partial-volume effect, time between tracer injection and imaging, plasma glucose level, PET scanner, and so on. In addition, in clinical practice, routine measurement of MTV in all cancer patients is still cumbersome. Therefore, we also measured the number of extra-thoracic tumor foci, which is more easily accessible and interpretable in the reading of 18 F-FDG PET/CT. And the prognostic power of extra-thoracic tumor foci was stronger than that of MTV. The small number of metastatic sites, so called ‘oligometastases’, is an early concept of metastasis that has shown better prognosis, compared with extensively metastasized disease [23,24]. The authors also stated that patients who—while they may have had widespread metastases before systemic treatment—have only
limited discrete foci of tumor amenable to focal ablation after such therapy may benefit from discrete treatment of metastatic cancer, such as testicular cancer, Wilms’ tumor, and SCLC [25]. To the best of our knowledge, this is the first study to assess 18 F-FDG PET/CT as an imaging tool for selection of patients with oligometastases for prognostication in oncologic practice. 18 F-FDG PET has already shown superior ability to conventional staging in detection of additional metastatic sites or reduction of false-positive lesions, resulting in change of stage in 8.3–33% of patients with SCLC [26–29]. Combination of new treatment paradigms targeting metastatic tumor burden, particularly in patients with oligometastases, and selection of such patients using 18 F-FDG PET/CT would be a promising strategy for patients with SCLC, as well as other metastasized cancer. Recently, several evidences that SUV changes from two serial 18 F-FDG PET/CT scans, before and after initial chemoradiotherapy,
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allow prediction of the treatment response in advanced NSCLC have been postulated [30,31]. Although the result is not showing, in a small subset of patients (17/91) who received restaging 18 FFDG PET/CT after initial chemotherapy in this study, there showed promising results about correlation between decline of SUV and prognosis of the patients. Further studies to validate the prognostic role of restaging 18 F-FDG PET/CT in patients with SCLC are also needed. We acknowledge several limitations of the current study. First, due to the retrospective nature of the study design, heterogeneity of clinical factors and detailed treatment modalities could affect the treatment outcomes. However, using uni- and multivariate analyses, we attempted to control for possible compounding factors. Prognostic factors identified in the current study include age, ECOG performance status, chemotherapy cycles, thoracic radiotherapy, and PCI in univariate analysis, and ECOG performance status and chemotherapy cycles in multivariate analysis; these results also correspond well with those of previous studies [3,5,32,33]. Second, two different PET/CT scanners may cause some heterogeneity during image acquisition and reconstruction. However, metabolic indices were measured using single software to minimize the differences between institutions. Third, not all concerned lesions were confirmed histopathologically. Instead, all possible clinical assays identifying the metastases, combined with other imaging modalities, including CT, MRI, bone scintigraphy, followup 18 F-FDG PET/CT finding, and response to therapy, were assessed for confirmation of metastasis. Fourth, due to high physiologic FDG uptake in normal brain, brain metastasis was not included in the analysis for extra-thoracic tumor burden. However, the prognostic value of brain or brain-only metastasis was not significant in the survival analysis for the entire cohort. Conduct of additional controlled prospective studies will be needed in order to assure the utility of 18 F-FDG PET/CT as a gatekeeper for management of patients with ED-SCLC. 5. Conclusion Metabolic indices on 18 F-FDG PET/CT are promising imaging biomarkers for patients with ED-SCLC, and the strongest prognostic factor was extra-thoracic tumor burden, particularly the number of extra-thoracic tumor foci, but not thoracic tumor burden. These results support further exploration of novel treatment paradigms combining targeted therapy for treatment of extra-thoracic tumor burden, especially in patients with oligometastases, and selection of such patients using 18 F-FDG PET/CT for patients with ED-SCLC.
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16] [17] [18] [19] [20]
[21]
[22]
Conflict of interest statement None declared. Acknowledgements This work was supported by the Nuclear Research and Development Program of the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (MEST) [No. 2012M2A2A7014020 and 2011-0006332]; and a grant from the Korea Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea and the Ministry of Knowledge Economy (MKE) [A102132].
[23] [24] [25] [26]
[27]
[28]
[29]
References [1] Simon GR, Turrisi A. Management of small cell lung cancer: ACCP evidencebased clinical practice guidelines (2nd edition). Chest 2007;132:39S–24S. [2] Socinski MA, Smit EF, Lorigan P, Konduri K, Reck M, Szczesna A, et al. Phase III study of pemetrexed plus carboplatin compared with etoposide plus
[30]
carboplatin in chemotherapy-naive patients with extensive-stage small-cell lung cancer. J Clin Oncol 2009;27:4787–92. Slotman B, Faivre-Finn C, Kramer G, Rankin E, Snee M, Hatton M, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 2007;357:664–72. Yee D, Butts C, Reiman A, Joy A, Smylie M, Fenton D, et al. Clinical trial of postchemotherapy consolidation thoracic radiotherapy for extensive-stage small cell lung cancer. Radiother Oncol 2012;102:234–8. Zhu H, Zhou Z, Wang Y, Bi N, Feng Q, Li J, et al. Thoracic radiation therapy improves the overall survival of patients with extensive-stage small cell lung cancer with distant metastasis. Cancer 2011;117:5423–31. Demedts IK, Vermaelen KY, van Meerbeeck JP. Treatment of extensive-stage small cell lung carcinoma: current status and future prospects. Eur Respir J 2010;35:202–15. Komatsu T, Kunieda E, Oizumi Y, Tamai Y, Akiba T. An analysis of the survival rate after radiotherapy in lung cancer patients with bone metastasis: is there an optimal subgroup to be treated with high-dose radiation therapy? Neoplasma 2012, e-pub. Fletcher JW, Djulbegovic B, Soares HP, Siegel BA, Lowe VJ, Lyman GH, et al. Recommendations on the use of 18F-FDG PET in oncology. J Nucl Med 2008;49:480–508. Oh JR, Seo JH, Chong A, Min JJ, Song HC, Kim YC, et al. Whole-body metabolic tumour volume of 18F-FDG PET/CT improves the prediction of prognosis in small cell lung cancer. Eur J Nucl Med Mol Imaging 2012;39: 925–35. Lee YJ, Cho A, Cho BC, Yun M, Kim SK, Chang J, et al. High tumor metabolic activity as measured by fluorodeoxyglucose positron emission tomography is associated with poor prognosis in limited and extensive stage small-cell lung cancer. Clin Cancer Res 2009;15:2426–32. Gore E. Randomized phase II study comparing prophylactic cranial irradiation along to prophylactic cranial irradiation and consolidative extra-cranial irradiation for extensive disease small cell lung cancer (EDSCLC) – RADIATION THERAPY ONCOLOGY GROUP. http://www.rtog.org/ ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=0937 Alongi F, Arcangeli S, Filippi AR, Ricardi U, Scorsetti M. Review and uses of stereotactic body radiation therapy for oligometastases. Oncologist 2012, epub. Dahele M, Senan S. The role of stereotactic ablative radiotherapy for earlystage and oligometastatic non-small cell lung cancer: evidence for changing paradigms. Cancer Res Treat 2011;43:75–82. Almaghrabi MY, Supiot S, Paris F, Mahe MA, Rio E. Stereotactic body radiation therapy for abdominal oligometastases: a biological and clinical review. Radiat Oncol 2012;7:126. Lo SS, Fakiris AJ, Chang EL, Mayr NA, Wang JZ, Papiez L, et al. Stereotactic body radiation therapy: a novel treatment modality. Nat Rev Clin Oncol 2010;7:44–54. Siva S, MacManus M, Ball D. Stereotactic radiotherapy for pulmonary oligometastases: a systematic review. J Thorac Oncol 2010;5:1091–9. Klein CA. Parallel progression of primary tumours and metastases. Nat Rev Cancer 2009;9:302–12. Ramaswamy S, Ross KN, Lander ES, Golub TR. A molecular signature of metastasis in primary solid tumors. Nat Genet 2003;33:49–54. Sethi N, Kang Y. Unravelling the complexity of metastasis – molecular understanding and targeted therapies. Nat Rev Cancer 2011;11:735–48. Hiltermann TJ, Pore MM, van den Berg A, Timens W, Boezen HM, Liesker JJ, et al. Circulating tumor cells in small-cell lung cancer: a predictive and prognostic factor. Ann Oncol 2012, e-pub. Naito T, Tanaka F, Ono A, Yoneda K, Takahashi T, Murakami H, et al. Prognostic impact of circulating tumor cells in patients with small cell lung cancer. J Thorac Oncol 2012;7:512–9. Zhu D, Ma T, Niu Z, Zheng J, Han A, Zhao S, et al. Prognostic significance of metabolic parameters measured by (18)F-fluorodeoxyglucose positron emission tomography/computed tomography in patients with small cell lung cancer. Lung Cancer 2011;73:332–7. Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol 1995;13:8–10. Weichselbaum RR, Hellman S. Oligometastases revisited. Nat Rev Clin Oncol 2011;8:378–82. Hellman S, Weichselbaum RR. Importance of local control in an era of systemic therapy. Nat Clin Pract Oncol 2005;2:60–1. Brink I, Schumacher T, Mix M, Ruhland S, Stoelben E, Digel W, et al. Impact of [18F]FDG-PET on the primary staging of small-cell lung cancer. Eur J Nucl Med Mol Imaging 2004;31:1614–20. Bradley JD, Dehdashti F, Mintun MA, Govindan R, Trinkaus K, Siegel BA. Positron emission tomography in limited-stage small-cell lung cancer: a prospective study. J Clin Oncol 2004;22:3248–54. Fischer BM, Mortensen J, Langer SW, Loft A, Berthelsen AK, Petersen BI, et al. A prospective study of PET/CT in initial staging of small-cell lung cancer: comparison with CT, bone scintigraphy and bone marrow analysis. Ann Oncol 2007;18:338–45. Kamel EM, Zwahlen D, Wyss MT, Stumpe KD, von Schulthess GK, Steinert HC. Whole-body (18)F-FDG PET improves the management of patients with small cell lung cancer. J Nucl Med 2003;44:1911–7. van Elmpt W, Ollers M, Dingemans AM, Lambin P, De Ruysscher D. Response assessment using 18F-FDG PET early in the course of radiotherapy correlates with survival in advanced-stage non-small cell lung cancer. J Nucl Med 2012;53:1514–20.
J.-R. Oh et al. / Lung Cancer 81 (2013) 218–225 [31] Huang W, Zhou T, Ma L, Sun H, Gong H, Wang J, et al. Standard uptake value and metabolic tumor volume of (1)(8)F-FDG PET/CT predict short-term outcome early in the course of chemoradiotherapy in advanced non-small cell lung cancer. Eur J Nucl Med Mol Imaging 2011;38:1628–35. [32] Paesmans M, Sculier JP, Lecomte J, Thiriaux J, Libert P, Sergysels R, et al. Prognostic factors for patients with small cell lung carcinoma: analysis of a series
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of 763 patients included in 4 consecutive prospective trials with a minimum follow-up of 5 years. Cancer 2000;89:523–33. [33] Stahel RA, Ginsberg R, Havemann K, Hirsch FR, Ihde DC, Jassem J, et al. Staging and prognostic factors in small cell lung cancer: a consensus report. Lung Cancer 1989;5:119–26.
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Extra-thoracic tumor burden but not thoracic tumor burden on 18 F-FDG PET/CT is an independent prognostic biomarker for extensive-disease small cell lung cancer Jong-Ryool Oh a , Ji-Hyoung Seo b , Chae Moon Hong a , Shin Young Jeong a , Sang-Woo Lee a , Jaetae Lee a , Jung-Joon Min c , Ho-Chun Song c , Hee-Seung Bom c , Young-Chul Kim d , Byeong-Cheol Ahn a,∗ a
Department of Nuclear Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea Department of Nuclear Medicine, Daegu Fatima Hospital, Daegu, Republic of Korea c Department of Nuclear Medicine, Chonnam National University Hospital, Gwangju, Republic of Korea d Department of Internal Medicine, Chonnam National University Hospital, Gwangju, Republic of Korea b
a r t i c l e
i n f o
Article history: Received 18 January 2013 Received in revised form 11 March 2013 Accepted 1 May 2013 Keywords: Extensive disease small cell lung cancer 18 F-FDG PET/CT Prognosis Metabolic tumor volume Oligometastases Biomarker
a b s t r a c t Purpose: The aim of this study was to evaluate the relationship and difference in prognostic significance between whole-body tumor burden, thoracic tumor burden, and extra-thoracic tumor burden on 18 F-FDG PET/CT for patients with extensive-disease small cell lung cancer (ED-SCLC). Materials and methods: We performed a retrospective, two-center analysis for patients with ED-SCLC who underwent pretreatment 18 F-FDG PET/CT. Metabolic tumor burden was estimated using whole-body metabolic tumor volume (MTVWB ), thoracic metabolic tumor volume (MTVTRX ), extra-thoracic metabolic tumor volume (MTVEXT ), and the number of extra-thoracic tumor foci. Uni- and multivariate analyses were performed using various clinical factors and the metabolic indices. Results: A total of 91 patients were eligible for this study. MTVWB showed stronger correlation with MTVEXT than MTVTRX (r2 = 0.804 vs. 0.132, p < 0.001, both), whereas no correlation was observed between MTVEXT and MTVTRX (r2 = 0.007, p = 0.428). Patients with smaller MTVWB , MTVEXT , and extra-thoracic tumor foci showed longer survival than patients with larger MTVWB , MTVEXT , and extra-thoracic tumor foci, respectively, whereas the survival difference between patients with smaller MTVTRX and those with larger MTVTRX was not significant. Results of uni- and multivariate analyses showed that ECOG performance status (HR = 2.31, p = 0.015), initial chemotherapy cycles (HR = 0.24, p < 0.001), and the number of extrathoracic tumor foci (HR = 2.75, p < 0.001) were independent prognostic factors for overall survival, and initial chemotherapy cycles (HR = 0.25, p < 0.001), and MTVEXT (HR = 2.04, p = 0.013) were independent prognostic factors for progression-free survival. Conclusion: These data provide evidence indicating that extra-thoracic tumor burden but not thoracic tumor burden is an independent prognostic biomarker for ED-SCLC, and support further exploration of novel treatment strategies targeting extra-thoracic tumor burden in order to improve the clinical outcomes of patients with ED-SCLC. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Small cell lung cancer (SCLC), accounting for 13–20% of all new cases of lung cancer, is an aggressive malignancy characterized by widespread dissemination at presentation with rapid doubling time [1]. SCLC is staged as either limited disease (LD) or extensive disease (ED) according to the suitability for thoracic radiotherapy. Over the past 20 years, ED-SCLC has mainly been treated with chemotherapy alone. Despite initial response rates of 60–70%,
∗ Corresponding author at: Department of Nuclear Medicine, Kyungpook National University School of Medicine and Hospital, 50, Samduk 2-ga, Jung gu, Daegu 700721, Republic of Korea. Tel.: +82 53 420 5583; fax: +82 53 422 0864. E-mail address: [email protected] (B.-C. Ahn). 0169-5002/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.lungcan.2013.05.001
the median duration of response for initial treatment is too short and the median survival time is only 9–11 months [1,2]. Prophylactic cranial irradiation (PCI) has recently been suggested as a promising treatment option for improvement of the clinical outcomes of patients with ED-SCLC [3], however, otherwise, only small advances have been made including molecular-targeted agents, thoracic radiotherapy, and extra-thoracic radiosurgery [4–7]. To reduce expenses and enhance the efficacy of upcoming clinical investigations, identification of more optimized biomarkers that can validate effectiveness of new treatment strategy and select patients who might benefit from it is essential. 18 F-fluorodeoxyglucose (FDG), an analog of glucose, is actively taken up within most tumor cells. Positron emission tomography/computed tomography (PET/CT) using 18 F-FDG, with its advantage for whole body assessment and quantification of tumor
J.-R. Oh et al. / Lung Cancer 81 (2013) 218–225
activity, has already been successfully applied in oncologic practice [8]. Metabolic tumor volume (MTV), defined as the volume of tumor tissues with increased FDG uptake, can estimate the total extent of activated tumor cells. Our group has reported optimistic results that whole-body metabolic tumor volume, which reflects systemic tumor burden including primary tumor, lymph nodes, and distant foci, could be a prognostic marker for both LD and ED-SCLC patients [9]. However, prior to its clinical translation, more detailed metabolic profiling that may allow better insight into tumor biology is required. Therefore, the aim of this study was to evaluate the prognostic significance of whole-body tumor burden, thoracic tumor burden, and extra-thoracic tumor burden on 18 F-FDG PET/CT for patients with ED-SCLC. 2. Materials and methods 2.1. Patients Patients with pathologically proven ED-SCLC who underwent pretreatment 18 F-FDG PET/CT scan at two centers from January 2004 to December 2010 were retrospectively reviewed. ED was pathologically or clinically defined as disease extending to a contralateral hemithorax or extra-thoracic lesion. Patients who did not receive any treatment or did not have available follow-up data were excluded. For evaluation of the significance of extra-thoracic tumor burden, patients with intra-thoracic ED [N3 (contralateral supraclavicular involvement beyond the radiation field) and M1a (separate tumor nodule in contralateral lung/pleural metastasis/malignant pleural effusion) disease based on the 7th edition of the American Joint Committee on Cancer Staging (AJCC) for nonsmall cell lung cancer (NSCLC)] were also excluded for analysis. Routine staging work-up, including history and physical examination, complete blood cell counts and chemistry panel, CT of chest and upper abdomen, brain MRI, and 18 F-FDG PET/CT, were completed prior to initiation of therapy. The main treatment was based on chemotherapy consisting of platinum with either etoposide or irinotecan administered every three weeks for six cycles. PCI was recommended for patients who showed complete or partial remission after initial therapy. During follow-up, palliative radiotherapy to thorax, brain, or extra-thoracic metastasis was also added according to the patients’ performance status and clinical situation. The standard response evaluation consisted of chest X-ray prior to each cycle and CT scan every two cycles of chemotherapy. Follow-up 18 F-FDG PET/CT scan was performed three weeks after the last cycle of chemotherapy or when disease progression or recurrence was suspected by standard examinations. All patients were followed up for at least nine months after diagnosis or until death. The local ethical committees approved the study and all enrolled patients gave written informed consent for 18 F-FDG PET/CT study. 2.2. Imaging acquisitions Combined PET/CT scanners (Discovery ST System, GE Medical Systems, Milwaukee, WI, USA; Reveal RT HiREZ, Siemens, Knoxville, TN, USA) were used in performance of 18 F-FDG PET/CT studies. All patients fasted for at least 6 h prior to intravenous administration of 18 F-FDG. Patients’ blood glucose levels were measured prior to injection of 18 F-FDG; if the level was over 8.3 mmol/L, then PET/CT was deferred. No oral or intravenous contrast material was administered. Image acquisitions for torso scanning were started approximately 1 h after injection of 7.4 MBq 18 F-FDG per kilogram of body weight. CT scan was performed for generation of an attenuation correction map for the PET scan using the following settings: 120 kVp; 10–130 mA; tube rotation time, 0.7 s per rotation; and
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section thickness, 3.75 mm in discovery PET/CT unit and 130 kVp; 95 mA; tube rotation time, 0.8 s per rotation; and section thickness, 2.5 mm in reveal PET/CT unit. Immediately following CT acquisition, PET data were acquired in the same anatomic locations with a 15.7 cm axial field of view acquired in the 2D mode with 180 s/bed position. CT data were used for attenuation correction and the PET images were reconstructed using a conventional iterative algorithm, ordered-subsets expectation-maximization (OSEM). 2.3. Image analysis An Advantage Workstation 4.4 (GE Medical Systems, Milwaukee, WI, USA), providing multiplanar reformatted images, was used in performance of image display and analysis. Maximum standardized uptake value (SUVmax) based on body weight and metabolic tumor volume were determined by the attenuation-corrected PET data using volume viewer software, as described in a previous study [9]: (1) automatic production of the boundaries of voxels presenting SUV intensity exceeding 3.0 encasing targeted metabolic tumor burden, (2) subtraction of normal organ, (3) subtraction of false-positive lesions. Thoracic metabolic tumor volume (MTVTRX ) was measured in the tumor within the thoracic cavity, including both lungs, pleura, mediastinum, and both hilar and supraclavicular lymph nodes. Extra-thoracic metabolic tumor volume (MTVEXT ) was measured in the tumor beyond the thoracic cavity. Wholebody metabolic tumor volume (MTVWB ) was calculated by the sum of MTVTRX and MTVEXT . The number of extra-thoracic tumor foci was estimated by the foci that present abnormal FDG uptake in any organ beyond the thoracic cavity. Due to high physiologic FDG uptake, brain was excluded for evaluation of extra-thoracic tumor burden. 2.4. Statistical analysis SPSS 18 for Windows (SPSS Inc., Chicago, IL, USA) was used in performance of statistical analysis. For detailed classification for prognosis, median values of SUVmax, MTV, and the number of extra-thoracic tumor foci were used [9,10]. Pearson correlation coefficient was used for assessment of correlations between MTVWB , MTVTRX , and MTVEXT . Survival time was derived from the date of 18 F-FDG PET/CT scan to the date of death/recurrence or last follow-up. Kaplan–Meier methods were used for production of overall survival (OS) and progression free survival (PFS) curves and the log-rank test was used for assessment of survival differences between groups. Cox regression analysis was used for development of uni- and multivariate models describing the association of the independent variables with OS and PFS. Independent variables analyzed included gender, age, smoking, comorbidity, Eastern Cooperative Oncology Group (ECOG) performance status, lactate dehydrogenase (LDH), initial chemotherapy regimen, number of initial chemotherapy cycles received, thoracic radiotherapy, prophylactic cranial irradiation, palliative brain radiotherapy, palliative extra-thoracic radiotherapy, brain metastasis, brain-only metastasis, bone metastasis, distant nodal metastasis, liver metastasis, SUVWB , SUVTRX , SUVEXT , MTVWB , MTVTRX , MTVEXT , and the number of extra-thoracic tumor foci. A value of p < 0.05 was considered statistically significant. The 95% confidence interval (95% CI) was determined for each parameter. 3. Results 3.1. Patient characteristics A total of 128 patients with ED-SCLC who underwent pretreatment 18 F-FDG FDG PET/CT were scanned. Among them, 103 patients who received at least one cycle of chemotherapy with
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Table 1 Patient characteristics. All patients (N = 91) Gender Male Female Age (years) <70 ≥70 Smoking Never Yes One or more comorbiditya No Yes ECOG performance status 0 or 1 2 or 3 LDHb Normal Increased Initial chemotherapy regimen Platinum + etoposide Platinum + irinotecan No. of cycles of initial chemotherapy received <3 ≥3 Thoracic radiotherapy No Yes Prophylactic cranial irradiation No Yes Palliative brain radiotherapy No Yes Palliative extra-thoracic radiotherapy No Yes Sites of distant metastasisc Brain Brain-only Bone Distant lymph nodes Liver Adrenal glands Pancreas Muscles Kidney Thyroid Small bowel Spleen Submandibular gland
stronger correlation with MTVWB than MTVTRX (r2 = 0.804 vs. 0.132, p < 0.001, both) (Fig. 1A), whereas no correlation was observed between MTVTRX and MTVEXT (r2 = 0.007, p = 0.428) (Fig. 1B).
75 (82%) 16 (18%)
3.3. Survival analyses
56 (62%) 35 (38%)
At the time of analysis, 86 of 91 patients had died. Median OS and PFS of the entire cohort were 8.6 and 5.1 months, respectively (range: 0.5–32.1 months for OS and 0.5–15.3 months for PFS). Median survival of patients with smaller MTVWB was significantly longer than that of patients with larger MTVWB [10.0 vs. 8.0 months (p = 0.005)] (Fig. 2A). Median survival of patients with smaller MTVEXT or a smaller number of extra-thoracic tumor foci was significantly longer than that of patients with larger MTVEXT or a larger number of extra-thoracic tumor foci [9.7 vs. 8.6 months for MTVEXT (p = 0.008) and 10.9 vs. 6.8 months for extra-thoracic tumor foci (p < 0.001)], whereas median survival between patients with smaller MTVTRX and larger MTVTRX was not significantly different [9.4 vs. 8.1 months (p = 0.102)] (Fig. 2B–D). These results were also replicated in the PFS analysis (Fig. 3). Following performance of univariate analysis, age, ECOG performance status, number of initial chemotherapy cycles, thoracic radiotherapy, PCI, bone metastasis, liver metastasis, MTVWB , MTVEXT , and number of extra-thoracic tumor foci were found to be significant prognostic factors for OS, and ECOG performance status, number of initial chemotherapy cycles received, bone metastasis, MTVWB , MTVEXT , and number of extra-thoracic tumor foci were significant prognostic factors for PFS (Table 2). Neither SUV parameters nor MTVTRX was found to be a significant factor for prediction of OS or PFS. On multivariate analysis, ECOG performance status, number of initial chemotherapy cycles, and number of extra-thoracic tumor foci were independent prognostic factors for OS, and number of initial chemotherapy cycles and MTVEXT were independent prognostic factors for PFS (Fig. 4).
14 (15%) 77 (85%) 32 (35%) 59 (65%) 78 (86%) 13 (14%) 51 (56%) 38 (42%) 62 (68%) 29 (32%) 26 (29%) 65 (71%) 65 (71%) 26 (29%) 86 (95%) 5 (5%) 72 (79%) 19 (21%) 68 (75%) 23 (25%) 27 (30%) 8 (9%) 51 (56%) 37 (41%) 32 (35%) 16 (18%) 9 (10%) 3 (3%) 2 (2%) 1 (1%) 1 (1%) 1 (1%) 1 (1%)
ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; no, number. a Presence of one or more of the following diseases: ischemic heart disease, diabetes, or chronic obstructive pulmonary disease. b Not assessed in two patients. c On the initial staging.
available follow-up data were initially assessed. We excluded 12 patients for intra-thoracic (N3 or M1a) disease beyond tolerable radiation field, yielding a 91-patient cohort (mean age: 67 years, range: 42–89 years) consisting of 75 men and 16 women. Details regarding baseline patient demographics, prior treatment histories, and sites of distant metastasis are shown in Table 1. 3.2. Comparisons between metabolic indices The median MTVWB was 233 cm3 (range: 13–1415 cm3 ) and the median SUVWB was 10.2 (range: 4.3–22.1). The median MTVTRX was 120 cm3 (range: 11–526 cm3 ), the median SUVTRX was 9.8 (range: 4.4–22.1), the median MTVEXT was 21 cm3 (range: 0–1321 cm3 ), and the median SUVEXT was 7.9 (range: 0–20.6). MTVEXT showed
4. Discussion In this study, we compared relationship and prognostic significance between whole-body, thoracic, and extra-thoracic tumor burdens on 18 F-FDG PET/CT. Clinical outcomes for patients with ED-SCLC showed strong correlation with extra-thoracic tumor burden but not thoracic tumor burden. Our results shows that 18 F-FDG PET/CT can provide a more accurate survival prognostification for patients with ED-SCLC and warrant further exploration of new treatment paradigms targeting extra-thoracic tumor burden for patients with ED-SCLC. For over 20 years, the treatment of ED-SCLC has been mainly dependent on systemic chemotherapy. A paradigm of control of extra-thoracic metastasis, although it was intended for prevention but not for palliative care, and was limited to brain metastasis, had already been validated by results of a phase III randomized trial [3]. According to findings from a recent retrospective analysis by Komatsu et al., high-dose radiosurgery for treatment of bone metastasis in patients with lung cancer, although 12% of SCLC were included, showed an association with a better prognosis [7]. An ongoing clinical trial also proposes to determine the role of consolidation radiotherapy for extra-cranial, extra-thoracic metastatic sites alongside PCI after a response to systemic chemotherapy in patients with ED-SCLC [11]. A large body of evidence on the use of stereotactic body radiation therapy (SBRT) for treatment of primary and metastatic tumors in various sites, including lung, liver, spine, adrenal glands, distant lymph nodes, has been accumulated over the past 10–15 years, and efficacy and safety of the SBRT have been demonstrated [12–16]. Our results suggest the potential role of metabolic indices on 18 F-FDG PET/CT as imaging biomarkers for
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Fig. 1. Correlations between whole-body metabolic tumor volume (MTVWB ), thoracic metabolic tumor volume (MTVTRX ), and extra-thoracic metabolic tumor volume (MTVEXT ). MTVEXT showed stronger correlation with MTVWB than MTVTRX (A). No correlation was observed between MTVTRX and MTVEXT (B).
selection of patients who benefit from the addition of SBRT to conventional chemotherapy. We found that the extent of thoracic tumor burden did not show correlation with that of extra-thoracic tumor burden. In addition, some patients with a larger extra-thoracic tumor burden had a relatively smaller extent of thoracic tumor burden (Fig. 1B). Our observation coincided with the parallel progression model of metastasis in which dissemination of tumor cells may occur early in malignant progression, and colonization of multiple secondary sites at different times may occur independently from those incurred by the primary tumor [17]. Our results also provide direct evidence that patients with a larger metastatic tumor burden had
a higher risk of progression and death than patients with a smaller metastatic tumor burden. Application of gene expression profiling to patient tumor cells has already revealed an association of poor prognosis signatures with increased frequency of metastatic events [18,19]. Circulating tumor cells, which are known to circulate in the peripheral blood in patients with several types of malignancies, were recently reported as having a strong prognostic significance in patients with SCLC, particularly in the ED subset [20,21]. A higher number of circulating tumor cells has been reported as an indicator of the presence of distant metastases. Although the competence of circulating tumor cells informing secondary lesions is currently under investigation, there may be a close correlation between
Fig. 2. Kaplan–Meier analyses of overall survival according to MTVWB (A), MTVTRX (B), MTVEXT (C), and the number of extra-thoracic tumor foci (D). MTV, metabolic tumor volume; WB, whole-body; TRX, thorax; EXT, extra-thorax; no, number.
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Fig. 3. Kaplan–Meier analyses of progression-free survival according to MTVWB (A), MTVTRX (B), MTVEXT (C), and the number of extra-thoracic tumor foci (D). MTV, metabolic tumor volume; WB, whole-body; TRX, thorax; EXT, extra-thorax; no, number.
circulating tumor cells and the extent of extra-thoracic tumor burden. We applied a 3.0 threshold of SUV for automatic delineation of tumor volume, as described in previous report [9]. There has been no optimized cut-off value that can accurately estimate the ‘true’ tumor burden so far. In our experience, a threshold of 3.0 can minimize unwanted physiologic FDG uptake in normal tissue during estimation of MTV, and thereby increasing the reproducibility of
MTV measurement. Although it is variable according to tumors, a SUV of 3.0 is a general cut-off set for differentiating malignant and benign lesions. Using 18 F-FDG PET/CT, we validated several metabolic indices, including SUV, MTV, and the number of extrathoracic tumor foci as prognosticators in patients with ED-SCLC. In accordance with results of previous reports [9,22], MTV showed much better prognostic power than SUV, because MTV can represent the total extent of FDG uptake by tumor tissues, whereas
Fig. 4. Multivariate survival analyses with Cox-proportional hazard models for overall survival (A) and progression-free survival (B). HR, hazard ratio; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group, no, number; MTV, metabolic tumor volume; WB, whole-body; TRX, thorax; EXT, extra-thorax.
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Table 2 Univariate survival analyses with Cox-proportional hazard models. Overall survival HR (95% CI) Gender Male Age (years) ≥70 Smoking Yes One or more comorbidity Yes ECOG performance status 2 or 3 LDH Increased Initial chemotherapy regimen Platinum + irinotecan No. of cycles of initial chemotherapy received ≥3 Thoracic radiotherapy Yes Prophylactic cranial irradiation Yes Palliative brain radiotherapy Yes Palliative extra-thoracic radiotherapy Yes Brain metastasis Yes Brain-only metastasis Yes Bone metastasis Yes Distant nodal metastasis Yes Liver metastasis Yes SUVWB ≥10.2 SUVTRX ≥9.8 SUVEXT ≥7.9 MTVWB (cm3 ) ≥233 MTVTRX (cm3 ) ≥120 MTVEXT (cm3 ) ≥21 No. of extra-thoracic tumor foci ≥4
1.49 (0.84–2.64)
Progression-free survival P
HR (95% CI) 0.179 §
P
1.72 (0.97–3.03)
0.063
1.60 (1.03–2.50)
0.041
1.22 (0.79–1.87)
0.373
1.20 (0.67–2.18)
0.543
1.24 (0.70–2.22)
0.463
1.40 (0.89–2.21)
0.147
1.47 (0.94–2.31)
0.093
1.94 (1.05–3.60)
0.036§
1.87 (1.03–3.39)
0.041§
1.05 (0.68–1.64)
0.804
1.01 (0.66–1.55)
0.956
1.04 (0.63–1.51)
0.346
1.06 (0.68–1.65)
0.794
0.29 (0.17–0.47)
<0.001* (<0.0001)
0.33 (0.21–0.54)
0.42 (0.25–0.70)
<0.001† (0.0009)
0.78 (0.49–1.24)
0.294
§
<0.001* (<0.0001)
0.28 (0.09–0.89)
0.033
0.48 (0.19–1.18)
0.112
0.71 (0.42–1.18)
0.187
0.62 (0.37–1.03)
0.066
0.80 (0.49–1.29)
0.358
1.02 (0.64–1.64)
0.928
1.06 (0.67–1.69)
0.813
1.24 (0.79–1.96)
0.351
0.48 (0.22–1.05)
0.067
0.53 (0.26–1.13)
0.102
1.73 (1.12–2.69)
0.014§
1.55 (1.02–2.36)
0.043§
1.09 (0.71–1.68)
0.688
1.01 (0.66–1.54)
0.970
§
1.70 (1.08–2.69)
0.023
1.39 (0.90–2.16)
0.141
0.88 (0.57–1.35)
0.548
0.84 (0.56–1.28)
0.419
0.84 (0.54–1.30)
0.426
0.96 (0.64–1.46)
0.863
1.10 (0.72–1.68)
0.667
0.97 (0.64–1.48)
0.900
1.87 (1.20–2.90)
0.006‡
1.81 (1.18–2.78)
0.007‡
1.44 (0.93–2.22)
0.104
1.41 (0.92–2.15)
0.120
1.82 (1.17–2.83)
0.009‡
2.12 (1.37–3.28)
<0.001† (0.0008)
2.20 (1.41–3.42)
<0.001† (0.0005)
2.65 (1.67–4.20)
<0.001* (<0.0001)
HR, hazard ratio; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; SUV, maximum standardized uptake value; WB, wholebody; TRX, thorax; EXT, extra-thorax; MTV, metabolic tumor volume. * p < 0.0001. † p < 0.001. ‡ p < 0.01. § p < 0.05.
SUV only represents the maximal intensity of FDG uptake in certain lesions. However, the obstacle of MTV in clinical application is standardization. MTV can be easily changed according to the cut-off value of SUV, partial-volume effect, time between tracer injection and imaging, plasma glucose level, PET scanner, and so on. In addition, in clinical practice, routine measurement of MTV in all cancer patients is still cumbersome. Therefore, we also measured the number of extra-thoracic tumor foci, which is more easily accessible and interpretable in the reading of 18 F-FDG PET/CT. And the prognostic power of extra-thoracic tumor foci was stronger than that of MTV. The small number of metastatic sites, so called ‘oligometastases’, is an early concept of metastasis that has shown better prognosis, compared with extensively metastasized disease [23,24]. The authors also stated that patients who—while they may have had widespread metastases before systemic treatment—have only
limited discrete foci of tumor amenable to focal ablation after such therapy may benefit from discrete treatment of metastatic cancer, such as testicular cancer, Wilms’ tumor, and SCLC [25]. To the best of our knowledge, this is the first study to assess 18 F-FDG PET/CT as an imaging tool for selection of patients with oligometastases for prognostication in oncologic practice. 18 F-FDG PET has already shown superior ability to conventional staging in detection of additional metastatic sites or reduction of false-positive lesions, resulting in change of stage in 8.3–33% of patients with SCLC [26–29]. Combination of new treatment paradigms targeting metastatic tumor burden, particularly in patients with oligometastases, and selection of such patients using 18 F-FDG PET/CT would be a promising strategy for patients with SCLC, as well as other metastasized cancer. Recently, several evidences that SUV changes from two serial 18 F-FDG PET/CT scans, before and after initial chemoradiotherapy,
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allow prediction of the treatment response in advanced NSCLC have been postulated [30,31]. Although the result is not showing, in a small subset of patients (17/91) who received restaging 18 FFDG PET/CT after initial chemotherapy in this study, there showed promising results about correlation between decline of SUV and prognosis of the patients. Further studies to validate the prognostic role of restaging 18 F-FDG PET/CT in patients with SCLC are also needed. We acknowledge several limitations of the current study. First, due to the retrospective nature of the study design, heterogeneity of clinical factors and detailed treatment modalities could affect the treatment outcomes. However, using uni- and multivariate analyses, we attempted to control for possible compounding factors. Prognostic factors identified in the current study include age, ECOG performance status, chemotherapy cycles, thoracic radiotherapy, and PCI in univariate analysis, and ECOG performance status and chemotherapy cycles in multivariate analysis; these results also correspond well with those of previous studies [3,5,32,33]. Second, two different PET/CT scanners may cause some heterogeneity during image acquisition and reconstruction. However, metabolic indices were measured using single software to minimize the differences between institutions. Third, not all concerned lesions were confirmed histopathologically. Instead, all possible clinical assays identifying the metastases, combined with other imaging modalities, including CT, MRI, bone scintigraphy, followup 18 F-FDG PET/CT finding, and response to therapy, were assessed for confirmation of metastasis. Fourth, due to high physiologic FDG uptake in normal brain, brain metastasis was not included in the analysis for extra-thoracic tumor burden. However, the prognostic value of brain or brain-only metastasis was not significant in the survival analysis for the entire cohort. Conduct of additional controlled prospective studies will be needed in order to assure the utility of 18 F-FDG PET/CT as a gatekeeper for management of patients with ED-SCLC. 5. Conclusion Metabolic indices on 18 F-FDG PET/CT are promising imaging biomarkers for patients with ED-SCLC, and the strongest prognostic factor was extra-thoracic tumor burden, particularly the number of extra-thoracic tumor foci, but not thoracic tumor burden. These results support further exploration of novel treatment paradigms combining targeted therapy for treatment of extra-thoracic tumor burden, especially in patients with oligometastases, and selection of such patients using 18 F-FDG PET/CT for patients with ED-SCLC.
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16] [17] [18] [19] [20]
[21]
[22]
Conflict of interest statement None declared. Acknowledgements This work was supported by the Nuclear Research and Development Program of the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (MEST) [No. 2012M2A2A7014020 and 2011-0006332]; and a grant from the Korea Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea and the Ministry of Knowledge Economy (MKE) [A102132].
[23] [24] [25] [26]
[27]
[28]
[29]
References [1] Simon GR, Turrisi A. Management of small cell lung cancer: ACCP evidencebased clinical practice guidelines (2nd edition). Chest 2007;132:39S–24S. [2] Socinski MA, Smit EF, Lorigan P, Konduri K, Reck M, Szczesna A, et al. Phase III study of pemetrexed plus carboplatin compared with etoposide plus
[30]
carboplatin in chemotherapy-naive patients with extensive-stage small-cell lung cancer. J Clin Oncol 2009;27:4787–92. Slotman B, Faivre-Finn C, Kramer G, Rankin E, Snee M, Hatton M, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 2007;357:664–72. Yee D, Butts C, Reiman A, Joy A, Smylie M, Fenton D, et al. Clinical trial of postchemotherapy consolidation thoracic radiotherapy for extensive-stage small cell lung cancer. Radiother Oncol 2012;102:234–8. Zhu H, Zhou Z, Wang Y, Bi N, Feng Q, Li J, et al. Thoracic radiation therapy improves the overall survival of patients with extensive-stage small cell lung cancer with distant metastasis. Cancer 2011;117:5423–31. Demedts IK, Vermaelen KY, van Meerbeeck JP. Treatment of extensive-stage small cell lung carcinoma: current status and future prospects. Eur Respir J 2010;35:202–15. Komatsu T, Kunieda E, Oizumi Y, Tamai Y, Akiba T. An analysis of the survival rate after radiotherapy in lung cancer patients with bone metastasis: is there an optimal subgroup to be treated with high-dose radiation therapy? Neoplasma 2012, e-pub. Fletcher JW, Djulbegovic B, Soares HP, Siegel BA, Lowe VJ, Lyman GH, et al. Recommendations on the use of 18F-FDG PET in oncology. J Nucl Med 2008;49:480–508. Oh JR, Seo JH, Chong A, Min JJ, Song HC, Kim YC, et al. Whole-body metabolic tumour volume of 18F-FDG PET/CT improves the prediction of prognosis in small cell lung cancer. Eur J Nucl Med Mol Imaging 2012;39: 925–35. Lee YJ, Cho A, Cho BC, Yun M, Kim SK, Chang J, et al. High tumor metabolic activity as measured by fluorodeoxyglucose positron emission tomography is associated with poor prognosis in limited and extensive stage small-cell lung cancer. Clin Cancer Res 2009;15:2426–32. Gore E. Randomized phase II study comparing prophylactic cranial irradiation along to prophylactic cranial irradiation and consolidative extra-cranial irradiation for extensive disease small cell lung cancer (EDSCLC) – RADIATION THERAPY ONCOLOGY GROUP. http://www.rtog.org/ ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=0937 Alongi F, Arcangeli S, Filippi AR, Ricardi U, Scorsetti M. Review and uses of stereotactic body radiation therapy for oligometastases. Oncologist 2012, epub. Dahele M, Senan S. The role of stereotactic ablative radiotherapy for earlystage and oligometastatic non-small cell lung cancer: evidence for changing paradigms. Cancer Res Treat 2011;43:75–82. Almaghrabi MY, Supiot S, Paris F, Mahe MA, Rio E. Stereotactic body radiation therapy for abdominal oligometastases: a biological and clinical review. Radiat Oncol 2012;7:126. Lo SS, Fakiris AJ, Chang EL, Mayr NA, Wang JZ, Papiez L, et al. Stereotactic body radiation therapy: a novel treatment modality. Nat Rev Clin Oncol 2010;7:44–54. Siva S, MacManus M, Ball D. Stereotactic radiotherapy for pulmonary oligometastases: a systematic review. J Thorac Oncol 2010;5:1091–9. Klein CA. Parallel progression of primary tumours and metastases. Nat Rev Cancer 2009;9:302–12. Ramaswamy S, Ross KN, Lander ES, Golub TR. A molecular signature of metastasis in primary solid tumors. Nat Genet 2003;33:49–54. Sethi N, Kang Y. Unravelling the complexity of metastasis – molecular understanding and targeted therapies. Nat Rev Cancer 2011;11:735–48. Hiltermann TJ, Pore MM, van den Berg A, Timens W, Boezen HM, Liesker JJ, et al. Circulating tumor cells in small-cell lung cancer: a predictive and prognostic factor. Ann Oncol 2012, e-pub. Naito T, Tanaka F, Ono A, Yoneda K, Takahashi T, Murakami H, et al. Prognostic impact of circulating tumor cells in patients with small cell lung cancer. J Thorac Oncol 2012;7:512–9. Zhu D, Ma T, Niu Z, Zheng J, Han A, Zhao S, et al. Prognostic significance of metabolic parameters measured by (18)F-fluorodeoxyglucose positron emission tomography/computed tomography in patients with small cell lung cancer. Lung Cancer 2011;73:332–7. Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol 1995;13:8–10. Weichselbaum RR, Hellman S. Oligometastases revisited. Nat Rev Clin Oncol 2011;8:378–82. Hellman S, Weichselbaum RR. Importance of local control in an era of systemic therapy. Nat Clin Pract Oncol 2005;2:60–1. Brink I, Schumacher T, Mix M, Ruhland S, Stoelben E, Digel W, et al. Impact of [18F]FDG-PET on the primary staging of small-cell lung cancer. Eur J Nucl Med Mol Imaging 2004;31:1614–20. Bradley JD, Dehdashti F, Mintun MA, Govindan R, Trinkaus K, Siegel BA. Positron emission tomography in limited-stage small-cell lung cancer: a prospective study. J Clin Oncol 2004;22:3248–54. Fischer BM, Mortensen J, Langer SW, Loft A, Berthelsen AK, Petersen BI, et al. A prospective study of PET/CT in initial staging of small-cell lung cancer: comparison with CT, bone scintigraphy and bone marrow analysis. Ann Oncol 2007;18:338–45. Kamel EM, Zwahlen D, Wyss MT, Stumpe KD, von Schulthess GK, Steinert HC. Whole-body (18)F-FDG PET improves the management of patients with small cell lung cancer. J Nucl Med 2003;44:1911–7. van Elmpt W, Ollers M, Dingemans AM, Lambin P, De Ruysscher D. Response assessment using 18F-FDG PET early in the course of radiotherapy correlates with survival in advanced-stage non-small cell lung cancer. J Nucl Med 2012;53:1514–20.
J.-R. Oh et al. / Lung Cancer 81 (2013) 218–225 [31] Huang W, Zhou T, Ma L, Sun H, Gong H, Wang J, et al. Standard uptake value and metabolic tumor volume of (1)(8)F-FDG PET/CT predict short-term outcome early in the course of chemoradiotherapy in advanced non-small cell lung cancer. Eur J Nucl Med Mol Imaging 2011;38:1628–35. [32] Paesmans M, Sculier JP, Lecomte J, Thiriaux J, Libert P, Sergysels R, et al. Prognostic factors for patients with small cell lung carcinoma: analysis of a series
225
of 763 patients included in 4 consecutive prospective trials with a minimum follow-up of 5 years. Cancer 2000;89:523–33. [33] Stahel RA, Ginsberg R, Havemann K, Hirsch FR, Ihde DC, Jassem J, et al. Staging and prognostic factors in small cell lung cancer: a consensus report. Lung Cancer 1989;5:119–26.