1. Diagnostic Imaging, The Peter MacCallum Cancer Institute, Melbourne, Vic
2. Radiation Oncology, The Peter MacCallum Cancer Institute, Melbourne, Vic
3. Dept of Oncology and Radiotherapy, Turku University Hospital, Turku, Finland
Lung cancer is currently the leading cause of cancer-related death in both men and women in most Western countries. In Australia there is a falling incidence in males that is not matched in females, tracking smoking trends1. Non-small cell lung cancer comprises 75-80% of all new cases of lung cancer2. Early diagnosis of lung cancer is difficult, and screening is currently limited to investigational studies. The lack of specificity of radiologic screening techniques means that many unnecessary biopsy procedures are required to exclude malignacy in lung nodules identified in asymptomatic individuals. Alternatively, serial imaging is required to exclude the progressive enlargement that chartacterises malignant nodules. This “watchful waiting” approach carries the risk of disease dissemination during surveillance. At the time of clinical diagnosis, most patients are symptomatic and have what is considered to be locoregionally-advanced disease. Many also have systemic metastases at presentation. Even in those cases in which an apparently complete resection is able to be achieved, over 50% relapse, with the majority of these relapses occurring at distant sites3,4. Early systemic relapse is likely to reflect the presence of metastatic disease that was not detected by conventional staging techniques at the time of initial diagnosis. When surgery is not indicated, suitable patients with locoregionally-confined disease have a chance for prolonged survival and even cure with radical platinum-based chemoradiotherapy5. Five-year survival rates, however, remain poor. Selected patients with stage III disease are now also being treated with neoadjuvant chemotherapy prior to surgery in an attempt to improve long term survival. Improvements in radiotherapy delivery using conformal techniques offer the hope of improving local control by administering higher tumour doses while sparing adjacent normal tissues. These more aggressive treatments aimed at improving the still disappointing cure rates come at considerable cost both to the healthcare economy and in terms of morbidity to patients. Accordingly, their appropriate use relies on accurate patient selection and precise definition of tumoural extent. In particular, accurate staging avoids futile aggressive over-treatment of patients with incurable disease.
Unfortunately, conventional staging has significant limitations. Although primary tumoural relations are generally well-defined on CT scanning due to high contrast between the tumour mass and adjacent aerated lung, secondary consolidation of lung beyond obstructing bronchial lesions can impair characterisation of true tumour extent. This is particularly relevant to radiotherapy planning, where the aim is to minimise radiation dose to normal structures. Clinical staging of the mediastinum with CT or MRI is based on lymph node size and is therefore unable to identify nodal metastases that are less than one centimetre in diameter or to differentiate between malignant and enlarged reactive nodes. Recognising the limitations of CT, pathological mediastinal lymph node sampling has become an established technique but has associated morbidity and is also prone to sampling errors. Assessment for systemic metastases is also problematic, with limitations in both the sensitivity and specificity of conventional staging techniques often requiring a number of complementary imaging tests to be performed and in selected cases, biopsy of suspicious lesions. In the post-therapeutic settings, it is not possible to reliably differentiate viable tumour from fibrotic, or necrotic elements, even with well-visualised masses. Clearly, more accurate staging techniques would be advantageous.
PET scanning with fluorodeoxyglucose (FDG) utilises the fundamental biochemical differences in glucose metabolism between normal cells and cancer cells to differentiate between benign and neoplastic processes. As a glucose analogue, FDG is preferentially trapped inside tumour cells6 and its accumulation in cancer cells can be detected with high resolution by PET. The potential applications of FDG PET in patients with known or suspected lung cancer are discussed below.
Although FDG uptake can also occur in inflammatory or granulomatous processes, the ability of PET to differentiate between benign and malignant tissues allows the diagnostic use of FDG PET in evaluation of pulmonary masses. In a recent meta-analysis, FDG PET was found to have a high accuracy for differentiating benign from malignant lung nodules7. These data have been supported by Australian experience8 and results from Germany9. In addition to providing accurate differentiation of benign from malignant tissues, FDG PET also simultaneously provides staging of those nodules or masses identified to be malignant. In a small proportion of cases an alternative primary will be found, with implications for both management and prognosis.
In patients with histological confirmation of NSCLC, PET has proven to be more sensitive and specific than conventional staging for staging of the mediastinum10-13. Importantly, a recent meta-analysis14 has firmly established the superior accuracy of metabolic staging compared to anatomical staging for this purpose. The summary point estimates of diagnostic performance were 92%, 90% and 93% for overall accuracy, positive and negative predictive values respectively for PET and 75%, 50% and 85% for CT. An additional benefit of FDG PET is its ability to accurately detect distant metastases15-18. A recent German meta-analysis, including more than 1000 patients in whom detection of systemic disease was also evaluated, also confirmed the superior diagnostic value of PET compared to conventional staging19.
In a large study with clinical-pathological confirmation, poor correlation was found between the presence of mediastinal nodal metastases and nodal size20. On the other hand, a study which included extensive dissection of mediastinal lymph nodes (18-28 lymph nodes recovered per dissection) after CT and FDG-PET staging has shown that enlarged lymph nodes visualised at CT but negative at PET were free of metastatic involvement in 92% of cases12, attesting to the high negative predictive value of PET (a function of test sensitivity). All imaging techniques are, however, imperfect for the detection of small volume disease as a function of their finite spatial resolution. An additional issue for the sensitivity of disease detection by PET is the avidity of cancer cells for FDG. Tumour volume and FDG-avidity determine the contrast between cancer deposits and adjacent normal tissues. Patterns of uptake have been described for specific histologic subtypes21 but overall, most NSCLC has high FDG-avidity.
In addition to being the most accurate non-invasive method available to characterise mediastinal lymph node status in the preoperative staging of NSCLC, PET changes management in up to 30% of cases22,23. The use of PET in preoperative staging results in a different stage from that determined by standard methods in about half of patients, with up-staging around twice as common as down-staging with PET. This means that the predominant impact of PET is to lead to less aggressive therapy. In particular, detection of systemic disease prevents futile aggressive local therapies.
The impact of FDG PET may even be greater in patients with NSCLC who are being considered for radical radiation therapy24. The majority of such patients have this decision based on the presence of stage III disease following conventional staging procedures, and most also die of distant metastases despite treatment with curative intent. Failure to control local disease or the existence of occult disease outside the radiation treatment volume could both account for this. Recent evidence from our group suggests that underestimation of disease extent by conventional staging techniques is an important factor. We have recently reported25 an increase in the incidence of PET detection of distant metastases with increasing conventional stage from stage I (7.5%), through stage II (18%) to stage III (24%, p=0.016). In no case was the PET-detected metastasis found to be false positive. In a meta-analysis primarily including earlier stage disease, unexpected extrathoraxic metastases were detected with FDG-PET in 12% of lung cancer patients, and the therapeutic management was changed in 18% of patients as a result of PET findings19.
Definition of local tumour relations can be compromised by secondary collapse or consolidation, but is important when planning radiation treatment volumes. One of the significant advances in radiotherapy of recent times has been the development of advanced treatment delivery techniques that allow use of higher radiation doses to the tumour while sparing adjacent normal tissues. Such techniques are vitally dependent on accurate definition of tumour and normal tissue boundaries. PET imaging allows the differentiation between tumour and atelectasis, resulting in a smaller target volume in patients with bronchial obstruction and sparing of normal lung tissue and guides appropriate inclusion or exclusion from treatment of involved and uninvolved lymph nodes26-28. This has become particularly important with more sophisticated radiotherapy delivery29,30.
Preoperative evaluation has shown that FDG uptake by tumour, assessed by PET, can provide important prognostic information which could be useful in clinical decision-making31,32. Post-treatment evaluation of response to therapy with PET appears to be more accurate than with CT33,34. We have shown that metabolic response within 12 weeks after radiotherapy is strongly predictive for survival in NSCLC35. Guidelines for the use of FDG-PET in monitoring of tumour response after chemotherapy have been suggested by an EORTC committee36.
We have also demonstrated that FDG PET scanning is helpful for the surveillance of residual masses beyond six months from treatment37.
In addition to the significant benefits for patients that can be obtained with more appropriately targeted treatments, PET may also benefit healthcare providers by leading to an overall reduction of treatment costs because significant numbers of patients will receive less expensive palliative therapies rather than more expensive radical treatments. In the Australian healthcare environment, a prospective study of patients undergoing FDG PET for evaluation of a broad range of indications related to non-small cell lung cancer demonstrated a change in management in 67% of cases, with the vast majority of management changes that could be assessed being confirmed to be appropriate38. Since the majority of these changes were to avoid futile expensive and toxic therapies, there are potential savings to the community and benefits to the patient.
The process of introducing funding for new forms of technology, such as PET, in Australia is now vested with the Medicare Services Advisory Committee (MSAC). This committee advises the Minister for Health and Ageing on the strength of evidence supporting the clinical efficacy, safety and cost-effectiveness of new procedures and whether they are worthy of Government funding. In the case of PET, the potential cost implications of widespread funding circumvented the usual MSAC application process and led to a national review39. As a result of this review, interim funding was granted for a limited number of sites to collect further Australian data regarding the utility of FDG PET in a range of indications. At approved sites, FDG PET is now eligible for Medicare funding for the indications of diagnosis of solitary lung nodules that are unsuitable for and have failed histopathological characterisation and for the pre-operative staging of lung carcinoma.
Australian8 and international9,40 data support the cost-effectiveness of FDG PET for the evaluation of solitary pulmonary nodules. A recently published randomised control trial demonstrated the cost-effectiveness of FDG PET in preoperative evaluation of NSCLC patients by reducing unnecessary thoracotomies41. The potential cost benefits of PET have been demonstrated by a decision tree analysis that incorporated the effect of more accurate mediastinal nodal staging42,43. The Gambhir model has been utilised to evaluate the role of PET using Australian costings yielding evidence of potential costing savings44. Additional savings could result if PET is used to exclude patients with occult distant metastases from surgery and is supported by cost-effectiveness studies45. In the US, Medicare and many third party insurers have approved reimbursement for PET with FDG for the staging of NSCLC. In the UK, the Royal Society of Surgeons has accepted PET as part of the recommended staging for pre-surgical evaluation in lung cancer, and the use of FDG PET for lung cancer staging is now contained within the guidelines issued by the British Thoracic Society and the Society for Cardiothoracic Surgeons as it is in the recommendations of German Consensus Conference. Ongoing prospective studies will further clarify the issue of cost-effectiveness. For most indications, FDG PET is used in addition to other diagnostic modalities.
Future technical developments with novel tracer markers will enable even more accurate staging by looking at more specific tumour targeting such as DNA synthesis46. Availability of combined PET and CT devices47 will probably become the staging procedure of choice for evaluation of lung cancer due to their ability to provide simultaneous evaluation of both the structural relations of tumour deposits but also more sensitive and specific biological characterisation.
3. H Asamura, H Nakayma, H Kondo, R Tsuchiya, Y Shimasato, K Naruke. “Lymph node involvement, recurrence, and prognosis in resected small, peripheral, non-small cell lung carcinomas: are these carcinomas candidates for video-assisted lobectomy?” J Thorac Cardiovasc Surg, (1996): 1125-34.
5. F Mornex, P Van Houtte, P Scalliet, P Loubeyre. “Radiotherapy for non-small-cell bronchial cancers: definitions of volumes, patient selection. Recommendations of the International Association for the Study of Lung Cancer (IASLC).” Cancer Radiother, 2 (1998): 2579-89.
8. CJ Keith, KA Miles, MR Griffiths, D Wong, AG Pitman, RJ Hicks. “Solitary pulmonary nodules: accuracy and cost-effectiveness of sodium-iodide FDG-PET using Australian data.” Eur J Nucl Med, 29 (2002): 1016-23.
9. M Dietlein, K Weber, A Gandjour et al. “Cost-effectiveness of FDG-PET for the management of solitary pulmonary nodules: a decision analysis based on cost reimbursement in Germany.” Eur J Nucl Med, 27 (2000): 1441-56.
10. W Scott, L Gobar, J Terry, N Dewan, J Sunderland. “Mediastinal lymph node staging of non-small-cell lung cancer: a prospective comparison of computed tomography and positron emission tomography.” J Thorac Cardiovasc Surg, 111 (1996): 642-8.
11. CA Saunders, JE Dussek, MJ O’Doherty, MN Maisey. “Evaluation of fluorine-18-fluorodeoxyglucose whole body positron emission tomography imaging in the staging of lung cancer.” Ann Thorac Surg, 67 (1999): 790-7.
12. N Gupta, GJR Graebner, H Bishop. “Comparative efficacy of positron emission tomography with FDG and computed tomographic scanning in preoperative staging of non-small cell lung cancer.” Ann Surg, 229 (1999): 286-91.
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15. W Weder, RA Schmid, H Bruchhaus, S Hillinger, GK von Schulthess, HC Steinert. “Detection of extrathoracic metastases by positron emission tomography in lung cancer.” Ann Thorac Surg, 66 (1998): 886-92.
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19. D Hellwig, D Ukena, F Paulson et al. “Meta-analysis of the efficacy of positron emission tomography with F18-fluorodeoxyglucose in lung tumours. Basis for discussion of the German Consensus Conference on PET in Oncology.” Pneumonologie, 55 (2001): 355-67.
24. MP Mac Manus, RJ Hicks, DL Ball et al. “F-18 fluorodeoxyglucose positron emission tomography staging in radical radiotherapy candidates with nonsmall cell lung carcinoma: powerful correlation with survival and high impact on treatment.” Cancer, 92 (2001): 886-95.
25. MP Mac Manus, RJ Hicks, JP Matthews et al. “High rate of detection of unsuspected distant metastases by PET in apparent stage III non-small-cell lung cancer: implications for radical radiotherapy.” Int J Radiation Oncology Biol Phys, 50 (2001): 287-93.
26. JD Kiffer, SU Berlangieri, AM Scott et al. “The contribution of 18F-fluoro-2-deoxyglucose positron emission tomographic imaging to radiotherapy planning in lung cancer.” Lung Cancer, 19 (1998): 167-77.
27. U Nestle, K Walter, S Schmidt et al. “18F-deoxyglucose positron emission tomography (FDG-PET) for the planning of radiotherapy in lung cancer: high impact in patients with atelectasis.” Int J Radiat Oncol Biol Phys, 44 (1999): 593-7.
28. LJ Vanuytsel, JF Vansteenkiste, SG Stroobants et al. “The impact of F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) lymph node staging on the radiation treatment volumes in patients with non-small cell lung cancer.” Radiother Oncol, 55 (2000): 317-24.
31. JF Vansteenkiste, SG Stroobants, PJ Dupont et al. “Prognostic importance of the standardized uptake value on 18F-fluoro-2-deoxy-glucose-positron emission tomography scan in non-small-cell lung cancer: An analysis of 125 cases. Leuven Lung Cancer Group.” J Clin Oncol, 17 (1999): 3201-6.
33. JF Vansteenkiste, SG Stroobants, PR De Leyn, PJ Dupont, EK Verbeken. “Potential use of FDG-PET scan after induction chemotherapy in surgically staged IIIa-N2 non-small-cell lung cancer: a prospective pilot study. The Leuven Lung Cancer Group.” Ann Oncol, 9 (1998): 1193-8.
35. MP Mac Manus, RJ Hicks, M Wada et al. “Early F-18 FDG PET response to radical chemoradiotherapy correlates strongly with survival in unresectable non-small cell lung cancer.” Proc Am Soc Clin Oncol, 19 (2000): 1888.
36. H Young, R Baum, U Cremerius et al. “Measurement of clinical and subclinical tumour response using 18F-fluorodeoxyglucose and positron emission tomography: Review and 1999 EORTC Recommendations.” Eur J Cancer, 35 (1999): 1773-82.
37. RJ Hicks, V Kalff, MP Mac Manus et al. “The utility of 18F-FDG PET for suspected recurrent non-small cell lung cancer after potentially curative therapy: impact on management and prognostic stratification.” J Nucl Med, 42 (2001): 1605-13.
38. V Kalff, RJ Hicks, MP Mac Manus et al. “Clinical impact of 18F fluorodeoxyglucose positron emission tomography in patients with non-small-cell lung cancer: a prospective study.” J Clin Oncol, 19 (2001):111-8.
41. H Van Tinteren, OS Hoekstra, EF Smit et al. “Randomized controlled trial (RCT) to evaluate the cost-effectiveness of Positron Emission Tomography (PET) added to conventional diagnosis in non-small cell lung cancer (NCLC).” Proc Am Soc Clin Oncol, 19 (2000): 482a.
42. SS Gambhir, CK Hoh, ME Phelps, I Madar, J Maddahi. “Decision tree sensitivity analysis for cost-effectiveness of FDG-PET in the staging and management of non-small-cell lung carcinoma.” J Nucl Med, 37 (1996): 1428-36.
45. M Dietlein, K Weber, A Gandjour et al. “Cost-effectiveness of FDG-PET for the management of potentially operable non-small cell lung cancer: priority for a PET-based strategy after nodal-negative CT results.” Eur J Nucl Med, 27 (2000): 1598-609.