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Journal of Clinical Oncology, Vol 23, No 6 (February 20), 2005: pp. 1136-1143 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.06.129 [18F]Fluorodeoxyglucose Uptake by Positron Emission Tomography Predicts Outcome of Non–Small-Cell Lung CancerFrom the Departments of Radiation Oncology, Nuclear Medicine, Thoracic and Cardiovascular Surgery, Thoracic/Head and Neck Medical Oncology, and Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and Division of Radiology, Kobe University Graduate School of Medicine, Hyogo, Japan Address reprint requests to Ritsuko Komaki, MD, Department of Radiation Oncology, Unit 97, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: rkomaki{at}mdanderson.org
PURPOSE: To determine whether the standardized uptake value (SUV) of [18F]fluorodeoxyglucose uptake by positron emission tomography could be a prognostic factor for non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS: One hundred sixty-two patients with stage I to IIIb NSCLC were analyzed. Overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS), and local-regional control (LRC) were calculated by the Kaplan-Meier method and evaluated with the log-rank test. The prognostic significance was assessed by univariate and multivariate analyses.
RESULTS: There were 93 patients treated with surgery and 69 patients treated with radiotherapy. A cutoff of 5 for the SUV for the primary tumor showed the best discriminative value. The SUV for the primary tumor was a significant predictor of OS (P = .02) in both groups. Low SUVs ( CONCLUSION: The SUV of the primary tumor was the strongest prognostic factor among the patients treated by curative surgery or radiotherapy.
Tumor stage is considered the most important prognostic factor in patients with non–small-cell lung cancer (NSCLC) and the most important guide in treatment decisions. However, it is not completely reliable. For example, although surgery is usually performed in patients with stage I or II disease and in selected patients with stage IIIa disease, approximately 50% of patients who undergo a complete and presumably curative resection suffer relapse.1,2 In addition, despite the use of many different multimodal therapeutic strategies in patients with stage III NSCLC, the overall survival (OS) rate in these patients is still unsatisfactory.3,4 Therefore, better ways to predict prognosis and guide therapy are needed. Recently, various methods of imaging tumor metabolism have been investigated.5,6 One of these, [18F]fluorodeoxyglucose positron emission tomography (FDG-PET), plays a central role in the staging of various types of cancer, including breast cancer, lymphoma, head and neck cancer, and NSCLC.7-13 Indeed, FDG-PET for NSCLC has been found useful for initial staging,10-12 restaging at recurrence,13 estimating radiotherapeutic or chemotherapeutic responses,13-15 and delineating radiotherapeutic targets.16 A few studies have further shown that standardized uptake values (SUVs), semi-quantitative values guided by FDG-PET, are useful for determining prognosis in patients with NSCLC treated with surgery.17,18 However, their usefulness in determining prognosis in patients treated primarily by radiotherapy remains uncertain. It is also unclear whether the SUV could predict the likelihood of either local relapse or distant metastasis in these patients. Likewise, the prognostic significance of the SUV for the regional lymph nodes and its agreement with the SUV for the primary tumor have not been clarified. In this study, we assessed the prognostic ability of the SUVs in patients with stage I to IIIb NSCLC who were able to receive curative therapy. The ability of the SUVs to predict the outcomes of patients treated with surgery or radiotherapy was independently evaluated for each treatment group. We also studied patterns of failure and whether the SUV for the primary tumor predicted both local tumor control and the likelihood of distant metastasis.
Patients The medical records of 171 consecutive patients who underwent one or more FDG-PET studies at our institution from October 2000 to May 2002 were retrospectively reviewed. The follow-up was completed and closed out on August 31, 2003. In the follow-up evaluation, nine patients for whom follow-up was less than 6 months were excluded from this study. Therefore, 162 patients were determined to be eligible for the following criteria. Those patients were identified through a search of the database at the University of Texas M.D. Anderson Cancer Center. Patients had to have been diagnosed with stage I to IIIb NSCLC before initial curative treatments after a staging work-up that included FDG-PET. Patient ages ranged from 34 to 89 years, with a median age of 66 years. Patients were categorized into two treatment groups, the surgery group and the radiotherapy group. Patients in the surgery group were treated primarily by surgery with or without adjuvant therapy that consisted of or included radiotherapy, and patients in the radiotherapy group were treated with radiotherapy or chemoradiotherapy without surgery. At M.D. Anderson Cancer Center, routine follow-up evaluation was performed every 3 months for 2 years, every 6 months for 5 years, and then annually thereafter. However, in some cases, follow-up was performed at another hospital. In such cases, we contacted the patients or their physicians to obtain follow-up information. Before every follow-up visit, at least a chest x-ray or computed tomography scan of the chest was performed to check for evidence of recurrence. This study was approved by the institutional review board. Patient and tumor characteristics are listed in Table 1.
Semi-Quantitative Analysis by FDG-PET Patients were first injected with 10 to15 mCi of FDG, and then 60-minute uptake phases and all images were scanned by one scanner (CTI-Siemens HR+ scanner; CTI-Siemens, Knoxville, TN), with vendor-provided software used for interpreting image data. The scans were all acquired in two dimensions at 5 minutes per field of view with attenuation correction at 3 minutes per field of view. The vendor-provided software used for image reconstruction performed iterative reconstruction and segmented attenuation correction. Patients fasted for at least 6 hours before the PET study. This was confirmed in all patients by a blood sugar level of less than 150 mg/dL. Measurements were conducted consistently in each patient. For purposes of the staging work-up, the SUV was used to quantify tumor and lymph node uptake of the FDG. In our analysis, regions of interests were manually drawn on the transaxial images around the focal FDG uptake zone in the primary tumor, and the maximum SUV for each patient was used to minimize the partial-volume effects. The SUVs of the primary tumor and the regional lymph nodes were calculated using the following formula: SUV = activity concentration (µCi/mL)/(injected dose [mCi]/body weight [kg]).
Statistical Analysis Survival time was measured from the date of the pathologic diagnosis to the first occurrence of the considered event (death, local-regional recurrence alone, distant metastasis alone, or any local-regional or distant recurrence). OS was defined as the time between diagnosis and death from any cause. Disease-free survival (DFS) was defined as the time between diagnosis and the first recurrence of the disease (local-regional or distant recurrence). Local-regional control (LRC) was defined as the time between diagnosis and the first local-regional failure. For the patients treated with radiotherapy, local-regional failure was defined as recurrence in the radiation field or the development of a malignant pleural effusion. Distant metastasis-free survival (DMFS) was defined as the time between diagnosis and the occurrence of the first distant metastasis. The Cox proportional hazards model was used for the multivariate analysis to assess the effect of patients' characteristics and other prognostic factors of significance on the end points. The estimated hazard is reported. The Wald test was used to assess the role of covariates in the model.20
Patients and Treatments There were 93 patients (57%) in the surgery group. The breakdown by the extent of resection was as follows: pneumonectomy, six patients; lobectomy, 67 patients; segmentectomy, six patients; wedge resection, 14 patients. Mediastinal lymph node dissection was performed in 86 (92%) of the 93 patients. In 17 patients (18%) who had undergone one to three courses of induction chemotherapy, we used the SUVs and clinical stages determined before induction chemotherapy in our analysis. Adjuvant therapy was administered postoperatively in 17 patients whose surgical margins were expected to be positive: 11 patients (65%) received radiotherapy (range, 50 to 66 Gy; median, 50 Gy), and six patients (35%) received concurrent chemoradiotherapy (radiotherapy, 50 to 64.8 Gy [median, 63.5 Gy]; chemotherapy, one to four courses of combination therapy with carboplatin and paclitaxel). Our treatment policy for adjuvant therapy was as follows: 50 Gy was delivered when microscopic residual tumor was present (eight patients), and more than 60 Gy, either alone (three patients) or in combination with concurrent chemotherapy when macroscopic residual tumor was present (six patients). There were 69 patients (43%) in the radiotherapy group: 51 patients (74%) had stage IIIa or IIIb disease and 18 patients (26%) had medically inoperable stage I or II disease. Sixty-one patients (88%) underwent conventional radiotherapy 5 days a week, for a total dose of 60 to 66 Gy over 6 to 7 weeks. Six patients underwent hyperfractionated radiotherapy over 5.8 weeks for a total dose of 69.6 Gy delivered in 58 fractions. Two patients received higher doses of conventional radiotherapy alone (70 Gy in 35 fractions and 84 Gy in 42 fractions). In total, the median dose in the radiotherapy group was 63 Gy. In those patients who received chemotherapy, 45 patients (65%) underwent concurrent chemoradiotherapy, and two patients (3%) underwent sequential chemotherapy and radiotherapy. Of these 47 patients, 42 patients (89%) received two to seven courses of carboplatin and paclitaxel in combination. Other regimens were used in the remaining five patients (single-agent treatment with paclitaxel or cisplatin or combination treatment with cisplatin and etoposide, cisplatin and gemcitabine, or gemcitabine and vinorelbine).
FDG Uptake
SUV for Primary Tumor and Survival The median follow-up duration at the close-out date was 17.0 months. The 2-year OS rates in the surgery group, the radiotherapy group, and both groups combined were 76%, 71%, and 74%, respectively. However, when examined by SUV for primary tumor, the 2-year OS rate in the 43 patients with low SUVs (  5.0) was significantly better than that of the 119 patients with high SUVs (> 5.0; 2-year OS, 94% v 65%; P = .02; Fig 2).
SUV for Primary Tumor and Tumor Progression In 11 patients, it was difficult to distinguish each primary tumor accumulation of FDG from their lymph node accumulation. In these cases, the FDG accumulation was therefore regarded as the SUV for the primary tumor. As a result, the SUVs for primary tumors ranged from 0 to 27. The median SUVs for the primary tumor in the surgery group, the radiotherapy group, and both groups combined were 8.8, 8.2, and 8.4, respectively. Patients with low SUVs ( 5.0) showed significantly better DFS rates than those with high SUVs (> 5.0), both in the surgery group (2-year DFS, 69% v 50%; P = .02) and the radiotherapy group (88% v 29%; P = .0005; Fig 3), despite the fact that the two groups had quite different clinical stage distributions (Table 1; P < .0001).
The LRC and DMFS rates were then independently evaluated to clarify the pattern of relapse (Fig 4). In this analysis as well, patients with low SUVs showed better tumor control from the standpoint of both the LRC rate and the DMFS rate, regardless of whether they underwent surgery or radiotherapy (2-year LRC rate: surgery group, 83% v 61%, P = .05; radiotherapy group, 100% v 59% P < .0001; 2-year DMFS rate: surgery group, 75% v 66%, P = .08; radiotherapy group, 87% v 42%, P = .009).
Next, to confirm the discriminatory ability of the cutoff SUV of 5, the DFS by stage of disease (stage I or II [early] v stage IIIa or IIIb [advanced]) was assessed. Interestingly, in both stage subgroups, patients with low SUVs showed a significantly better 2-year DFS rate than those with high SUVs (stage I or II, 76% v 57%, P = .02; stage IIIa or IIIb, 90% v 31%; P = .004; Fig 5).
SUV for Regional Lymph Nodes The prognostic ability of the SUVs for the regional lymph nodes was analyzed separately in 151 patients. The SUVs for the regional lymph nodes ranged from 0 to 3.5 in patients with N stage of 0 (median, 0), 0 to 9.1 in patients with N stage of 1 (median, 3.6), 0 to 15.7 in patients with N stage of 2 (median, 6.0), and 2.6 to 17.9 in patients with N stage of 3 (median, 5.6). In the event that several accumulations of FDG were observed in the regional lymph nodes, the maximum SUV was used for the evaluation as the SUV for the regional lymph nodes. Using the cutoff point of 5, the SUVs for the lymph nodes were not a significant prognostic factor for the 2-year DFS (58% v 30%; P = .19), the 2-year LRC (71% v 77%; P = .97), or the 2-year DMFS (71% v 37%; P = .17). Other cutoff SUVs between 3 and 10 were also evaluated, but these also did not yield significant results for DFS (0.07 < P < .52). It is noteworthy, however, that eight patients (5%) who had high (> 5.0) SUVs for their regional lymph nodes (range, 5.6 to 17.9; median, 8.4) but low ( 5) SUVs for their primary tumors (range, 0 to 4.8; median, 3.3) did not experience any recurrence.
SUV As a Prognostic Factor
Our principal finding in this study was that the SUV for the primary tumor on FDG-PET was the most powerful significant prognostic factor in patients with stage I to IIIb NSCLC, regardless of whether they underwent curative surgery or radiotherapy. Several other investigators have explored the usefulness of FDG-PET in predicting the outcome of surgical treatment for NSCLC and proposed several cutoff SUVs.13,17,18 In particular, Vansteenkiste et al17 showed that a cutoff of 7 had discriminative ability in their series of 125 patients (91 of whom underwent complete resection), and Higashi et al18 used a cutoff of 5 in 56 patients with stage I to III disease who were surgically treated. We observed that a cutoff SUV of 5 for the primary tumor was a significant prognostic factor in our 93 surgically treated patients. Our results therefore confirmed those of previous studies. Interestingly, we also observed quite similar results in our 69 patients treated with radiotherapy. Although Ryu et al13 reported that an SUV of 3 was useful for monitoring therapeutic effects after neoadjuvant chemoradiotherapy, our results seem to be the first to show that the SUV is a significant prognostic factor in patients treated with radiotherapy. Above those previous and the present data, more data accumulation, especially analyses with larger numbers of cases or independent study, seem to be warranted to determine the most appropriate cutoff point and to avoid the overestimation of the value of the cutoff or to decrease the risk of false-positive results for the SUV. It is noteworthy that the treatment group (surgery or radiotherapy) did not prove to be a significant prognostic factor (Tables 2 and 3) and that the SUV for the primary tumor was a significant prognostic factor for both early-stage (stage I or II) and advanced-stage (stage IIIa or IIIb) disease (Fig 5). These data also seem to be original to our study. Although other factors, including the T stage and tumor size, N stage, and clinical stage, were also identified as significant prognostic covariables for OS and DFS in those univariate analyses, the SUV for the primary tumor showed stronger prognostic ability. Weight loss was not a significant factor in our analyses, unlike the findings of other studies.21,22 This may be because we included in our analysis only patients who could undergo curative therapy. Patients with severe weight loss therefore might not have been included in this study because they might have undergone palliative treatment or supportive care. Vansteenkiste et al23 showed that the accuracy of FDG-PET and computed tomography in the evaluation of regional lymph nodes was 93% to 95%. However, the prognostic ability of the SUV for the regional lymph nodes remains uncertain. In our analysis, the SUV for the regional lymph nodes was not a significant prognostic factor in terms of the DFS when analyzed using cutoff SUVs of 3 to 10. It has also not been clarified whether the SUVs for primary tumors and regional lymph nodes are alike in their ability to predict prognosis. In our study, we observed that eight patients (5%) who had high SUVs for their regional lymph nodes and low SUVs for their primary tumors did not experience any local or distant relapse. Therefore, it is at least speculated that the SUVs for the regional lymph nodes do not agree with and are not stronger prognostic factors than the SUVs for the primary tumor. The SUVs for regional lymph nodes may also not be reliable because of the higher background activity within the mediastinum. Moreover, several factors, such as a history of chronic pulmonary inflammatory disease, might have affected the outcomes. Further investigation is warranted to learn more about the contribution of these factors. On the basis of our findings that the SUV for a primary tumor predicted both local tumor control and distant metastasis, we hypothesize that tumor glucose metabolism is related to the metastatic potential of the tumor. Several investigators have also speculated that SUVs are correlated with cellular proliferation or biologic factors such as Ki-67, proliferating cell nuclear antigen, Glut-1, and hexokinase.24,25 However, the molecular mechanisms of FDG uptake in tumors are still a matter of debate. Our data further indicated that primary tumors showing high SUVs have the potential to be resistant to therapy and to metastasize. Further assessments of the correlation of SUVs with histopathology are ongoing to elucidate these molecular mechanisms. In conclusion, the SUV for the primary tumor was the strongest prognostic factor in patients with early- and advanced-staged NSCLC, regardless of whether they underwent curative surgery or radiotherapy. Although a cutoff of 5 seems to be the most valuable in our study, analysis with larger numbers of cases or with longer follow-up is warranted for confirmation. These results thus indicated that the SUVs for primary tumors could be an important guide to decision making for patients with NSCLC.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/advisory role: Ritsuko Komaki, Amgen, MedImmune; Homer Macapinlac, Gemedial Systems, Siemens; Donald A. Podoloff, GE Healthcare, IDEC, Siemens, Bexuar. Honoraria: Ritsuko Komaki, MedImmune; Donald A. Podoloff, GE Healthcare, IDEC, Siemens, Bexuar. Research funding: Donald A. Podoloff, GE Healthcare, IDEC, Bexuar.
We thank Kazuro Sugimura, MD, professor in the Division of Radiology, Kobe University Graduate School of Medicine, and Peng Huang, PhD, an associate professor in the Department of Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, for their generous advice and encouragement to R.S. We also thank Cora Bartholomew in the Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, for assisting in the preparation of this manuscript.
R.S. is supported by a research fellowship grant from the Uehara Memorial Foundation, Kobe City, Japan. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test was used to assess measures of association in a frequency table. The survival function was carried out using Kaplan-Meier estimates.
