FDG–PET in staging and restaging non-small cell lung cancer after neoadjuvant chemoradiotherapy: correlation with histopathology
Introduction
The incidence of lung cancer continues to increase, and this tumor is the leading cause of cancer death in both men and women. Locally advanced stage III non-small cell lung cancer (NSCLC) accounts for 35% of all lung cancer patients, and when the disease has progressed to this late stage, surgery or radiation therapy alone results in a 5-year survival rate of ∼10%. Although an optimal therapy regimen has yet to be defined for these patients, preoperative neoadjuvant chemoradiotherapy for marginally resectable stage IIIA (N2) NSCLC has been studied in phase II settings with encouraging results [1], [2], [3], [4].
Conventional imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI) are inadequate for providing accurate information about therapeutic response in these patients [5]. Consequently, many patients are subjected to repeated courses of the same regimen of chemotherapy even in the absence of adequate tumor response, and also to surgery in study settings of preoperative chemoradiotherapy for potentially resectable stage IIIA (N2) disease [4], [6]. Recently, there has been significant progress in imaging biochemical and metabolic process in tumor tissue using positron emission tomography (PET). The glucose analog, 18F 2-fluoro-2-deoxy-d-glucose (FDG), because of its biochemical characteristics, accumulates intracellularly and remains trapped within tumor cells. The combination of modern PET scanners and FDG has provided a powerful technique for characterizing tumor metabolism and numerous investigations have established that FDG–PET imaging is an accurate and cost effective method for establishing if an indeterminate solitary pulmonary nodule is malignant versus benign and for staging lung cancer [7], [8], [9]. FDG–PET also shows promise for monitoring response to therapy and restaging after therapy [10], [11]. Accumulation of FDG is greater in metabolically active tumor than in necrotic tissues. However, FDG also accumulates in inflammatory cells that are present in tumor stroma and accumulation of FDG can be enhanced following radiotherapy. To date, data supporting the hypothesis that FDG–PET is useful for accurate evaluation of tumor metabolism within 6 months after initiation of radiotherapy is inadequate [12], and the role of FDG–PET for restaging patients with NSCLC after neoadjuvant chemoradiotherapy has not been fully investigated.
We conducted an institutional phase II study in which patients with marginally resectable stage IIIA (N2) NSCLC were treated with a combined approach of preoperative accelerated radiation and concurrent chemotherapy, and subsequent surgery. This study was approved by the Massachusetts General Hospital Subcommittee on Human Studies and informed consent was obtained in all patients prior to the initiation of the protocol therapy. The results of this study were published earlier [13]. In brief, the eligibility criteria included: (1) histologically or cytologically documented NSCLC excluding bronchoalveolar cell carcinoma, (2) stage IIIA, N2 (T1N2M0, T2N2M0, T3N2M0) disease defined by the International Staging System for Lung Cancer excluding T3N0M0 and T3N1M0 lesions, (3) histologically confirmed N2 lesions by biopsies of ipsilateral mediastinal and/or subcarinal lymph nodes via mediastinoscopy and/or Chamberlain procedure for left upper lobe lesions, (4) adequate pulmonary function reserve for planned surgical resection, (5) performance score of 70 or higher on the Karnofsky scale, (6) weight loss of 5% or less in 3 months prior to diagnosis, (7) >18 years of age, (8) no prior chemotherapy or radiation therapy, (9) non-pregnant and (10) no other serious medical or psychiatric illness. Patients with clinically enlarged N2 status alone without histological confirmation of N2 lesions were ineligible for this study. Also excluded were patients with extensive involvement of high paratracheal lymph nodes at the level of innominate vessels where complete lymph node dissection may not be feasible.
The treatment plan included preoperative concurrent chemo-radiotherapy, surgery on day 57, and postoperative chemo-radiotherapy. The preoperative radiation therapy consisted of 42 Gy in two sessions using a twice daily treatment schedule: (a) 21 Gy in 1.5 Gy dose fractions, twice daily with an intertreatment interval of 5 h, 5 days a week for 7 treatment days starting day 1 with the first course of chemotherapy; (b) 10-day rest; (c) an additional dose of 21 Gy in the same way as the first starting on day 19. Postoperatively, patients received two levels of additional doses: Either 18 Gy for positive resection margins or gross residual tumor in the resected specimen or 12 Gy for microscopic residual disease only or pathological complete remission for a total dose of 60 and 54 Gy, respectively, using the same twice daily schedule beginning day 85 with the third course of concurrent chemotherapy. The chemotherapy regimen consisted of 5-FU 30 mg/kg/day by 72 h continuous intravenous infusion beginning day 1 of each cycle, cisplatin 100 mg/m2 IV over 30 min with prior hydration, 2–6 h after initiating 5-FU on day 1, and vinblastine 4 mg/m2/IV bolus on day 1 of each course. Chemotherapy was given beginning on days 1 and 29 preoperatively for two courses. The third course began postoperatively on day 85 of the protocol. Growth factors were not given as a part of this protocol. Following preoperative chemoradiotherapy, all patients were restaged with CT of the chest and upper abdomen, bone scan, and CT of the head. Patients, who remained free of distant metastasis were subjected to a thoracotomy on day 57 with an aim for complete resection of the primary lesion and involved regional lymph nodes.
The current study with FDG–PET for the initial staging and restaging after preoperative chemotherapy and accelerated radiotherapy was designed as a companion study to the phase II study described above [13]. It was conducted with an informed consent approved by the Subcommittee on Human Studies. A highly selected subset of patients with stage IIIB NSCLC who were judged to be resectable and were treated in a similar fashion to the patients with stage IIIA (N2) NSCLC were also included in this companion study.
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Patients
The study population consisted of 26 patients with histologically confirmed stage III NSCLC who were accrued from April 1993 to July 1998 at the Massachusetts General Hospital. These 26 patients included 21 with stage IIIA (N2) NSCLC by virtue of histologically confirmed metastatic involvement of ipsilateral mediastinal lymph nodes, and 5 with a highly selected subset of stage IIIB disease defined by the presence of microscopic metastatic disease in contralateral mediastinal lymph nodes (n=3),
Visual assessment
Prior to chemoradiotherapy, 25 of 26 (96%) primary tumors showed level 3 or 4 uptakes by visual analysis of the FDG–PET images. Surgical pathology after chemoradiotherapy demonstrated complete absence of residual tumor in 8 of 26 lesions. However, none of these 8 patients achieved clinical complete remission and residual mass lesions persisted on CT scan; size varied from 1.1 to 4.5 cm (Table 1).
When changes in primary tumor uptake were visually assessed after chemoradiotherapy, 15 of 26
Discussion
For appropriate decision making in the clinical management of cancer patients, there is increasing demand for more sensitive and specific noninvasive imaging procedures for staging and monitoring treatment [16]. In a large perspective study, the sensitivity and specificity of CT and MRI for mediastinal staging of patients with NSCLC were reported to be 52/48% and 69/64%, respectively [5]. Clearly, as both of these imaging modalities are based on anatomic parameters, distinction between tumor
Conclusion
FDG–PET is useful for monitoring the therapeutic effect of radiation and chemotherapy in patients with NSCLC. For the primary tumor, FDG–PET has high sensitivity, but limited specificity for differentiating residual tumor from necrosis and/inflammation. For restaging of mediastinal lymph nodes, FDG–PET is highly specific, but has limited sensitivity. These findings could have a major impact on the design of future therapy monitoring protocols for patients with lung cancer.
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Present address: Department of Nuclear Medicine, Asian Medical Center, University of Ulsan Medical School, Seoul, Republic of Korea.