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Clinical Investigations |
Department of Diagnostic Imaging, Pratt Foundation Statistical Centre, and Division of Radiation Oncology, Peter MacCallum Cancer Institute, East Melbourne, Victoria, Australia
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Key Words: lung cancer • FDG • recurrence • PET
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Although no conclusive data support the use of any therapies in relapsed lung cancer, some patients with localized relapse may be cured with appropriate aggressive therapy. Preliminary data suggest that PET can identify such patients (7). Detection of widespread disease would, however, make curative therapies futile and a waste of scarce health care resources in addition to unnecessarily subjecting the patient to morbidity. Conversely, the use of active therapies in the absence of malignancy is also clearly inappropriate.
In a previous prospective evaluation of the clinical impact of PET on the management of NSCLC (8), we showed that the results of PET had a substantial impact on the management of 34 patients with suspected relapse >6 mo after completion of therapy delivered with curative intent. The aim of the current study was to confirm the appropriateness of these management changes by longer follow-up of a larger patient cohort. In particular, we sought to further validate the utility of PET in such patients by examining the relationship between disease status as assessed by PET and patient survival.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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PET Scan Acquisition and Processing
PET scans were acquired on a PENN-PET 300-H scanner (UGM Medical Systems, Inc., Philadelphia, PA). Patients fasted for a minimum of 4 h before the scan. Emission data were acquired 1 h after intravenous administration of 74–120 MBq FDG. The scan routinely incorporated the lower neck, thorax, and upper abdomen, consistent with the usual extent of staging CT scans. If additional but unconfirmed sites of metastatic disease were suggested on conventional staging, the scan was extended to include the appropriate regions. PET was not used to evaluate the brain. The performance characteristics of this scanner and processing methods have been described previously (9–11).
The emission scan was reconstructed using the iterative technique of ordered-subset expectation maximization. Image sets, both with and without measured attenuation correction, were reviewed on a computer console using a display program that allows interactive review of orthogonal slices. An experienced nuclear medicine physician generated a clinical report after reviewing previous imaging results and clinical information. This included, in almost all cases, direct correlation with the recent CT scan. When the CT scan was unavailable, the report of the CT investigation was obtained. Standard uptake values were not routinely calculated. Once issued, the PET report was entered into the database and was not reinterpreted in the light of subsequent clinical information.
Determination of Disease Extent
The medical record was reviewed to determine the disease stage at initial diagnosis according to the 1997 update of the international staging system for lung cancer (12), and the primary treatment delivered subsequent to this diagnosis was recorded.
The staging schema used for classification of newly diagnosed NSCLC was believed to be inappropriate for the restaging setting. Rather, the patients were classified according to the extent of apparent relapse based on information available on conventional staging investigations performed before the PET scan (pre-PET extent category) and based on incorporation of the PET information with the previous information (post-PET extent category). The pre-PET extent category included biopsy results when they were available before the PET scan. The PET results were not interpreted in a masked manner; thus, this study evaluated the incremental, not the independent, information provided by PET.
Patients were classified as negative if imaging showed no abnormality suggestive of recurrence or, in the case of pre-PET evaluation, if biopsy of a residual structural abnormality had negative findings. Patients with abnormality confined to the previous primary tumor site and potentially suitable for salvage surgery or radical radiotherapy were classified as having local relapse. Patients with abnormalities involving intrathoracic lymph nodes and potentially amenable to radical radiotherapy were classified as having limited nodal relapse. Patients with intrathoracic lymph node abnormalities too extensive for radical radiotherapy or with lymphadenopathy beyond the thorax were classified as having extensive nodal relapse. Finally, patients with abnormalities involving major organs or the skeleton were classified as having systemic relapse.
Conventional restaging routinely involved CT with dynamic contrast medium, unless contraindicated because of contrast allergy. Bone scanning was performed only for patients with musculoskeletal symptoms or elevated alkaline phosphatase levels. CT or MRI of the brain was performed only for patients with clinically suspected cerebral metastasis. On CT scans, symptomatic or progressively enlarging lobular masses were considered suggestive of residual disease unless found to be negative for disease on histologic examination, whereas bandlike abnormalities were considered likely to reflect scarring. Mediastinal and hilar lymph nodes were regarded as positive for tumor on CT if they were >1 cm in maximum transverse diameter and larger than on the baseline evaluation. Histologically unconfirmed systemic metastases found on conventional staging were considered positive for disease if active treatment was planned on their basis but equivocal if, despite their presence, the referring clinician was still considering curative salvage treatment of suspected more localized relapse.
The post-PET extent of disease relied fully on the results of PET when these were discordant with other imaging findings, even when the results of prior biopsy had been negative. Focal areas of increased activity of greater intensity than mediastinal soft tissues on attenuation-corrected images were considered positive for active disease. However, diffuse changes in the lung or pleural reflections conforming to a prior radiotherapy treatment volume were generally reported as negative for active disease. These appearances are common after high-dose radiotherapy and are believed likely to be inflammatory. When a baseline PET scan was available, it was used for comparisons of the extent and intensity of ongoing abnormalities at previously documented sites of PET abnormality.
In addition to extent, the specific sites of abnormality indicating relapsed disease were recorded for both conventional imaging and PET. These sites were used for validation. Both the status of relapse and the distribution of disease were confirmed whenever possible by histologic examination. When histologic confirmation was unavailable, evidence of progression on serial imaging within 6 mo was considered to indicate a site of disease relapse, whereas no evidence of progression after at least 12 mo of follow-up was considered to confirm absence of active disease at that site. Patients who died without clear evidence of disease progression on conventional imaging were considered not assessable. Lack of imaging evidence of progressive disease after delivery of radical or high-dose palliative radiotherapy to a suspected localized recurrence was not considered to confirm this as a site of relapse unless relapse had been histologically confirmed before treatment began.
Assessment of Impact
Referring clinicians are asked to prospectively record a pre-PET management plan on our routine clinical request form. This plan was entered in a database. If not explicitly recorded on the referral request, treatment intent was categorized by an oncologist experienced in lung cancer management, who synthesized the available pre-PET clinical and imaging information. For 20 patients, a pre-PET management plan had not been recorded on the request form, and we relied on the patient’s pre-PET medical record. The post-PET plan and intent were determined from the medical record or contact with the referring clinician and in all but 1 patient reflected the treatment actually delivered.
The impact on management was considered high when the treatment intent or modality was changed (e.g., from palliative to curative treatment or from surgery to radiotherapy). Although not immediately altering treatment delivery, the change of a patient from expectant palliative treatment for suspected relapse to observation on the basis of negative PET findings was classified as of high impact because of the potential for psychologic reassurance of the patient from such a change. The impact was recorded as medium when the method of treatment delivery was changed (e.g., a change in radiation treatment volume). When the PET results did not indicate a need for change, the impact was considered to be low. PET was considered to have had no impact when the management chosen conflicted with post-PET disease extent and was believed to be inappropriate on the basis of a synthesis of all available information.
Patients within any given disease category could have a range of impact outcomes. For example, patients whose CT findings showed extensive local recurrence amenable only to palliative treatment could be converted to curative salvage surgery if PET showed a small recurrence, even though both the pre-PET extent and the post-PET extent would be categorized as localized recurrence. Alternatively, discordance between extent categories did not necessarily affect management. For example, the palliative radiotherapy planned for some patients with symptomatic local recurrence was still considered appropriate even though additional but asymptomatic sites of disease were detected.
Follow-Up
After treatment, progress updates were obtained from the medical record, family physician, or treating oncologist. When relevant, details of the date and cause of death were obtained. The disease status at the time of death was recorded. For patients treated with curative intent, the site or sites of first progression were recorded.
Statistical Methods
Survival was measured from the date of the restaging PET scan to the date of death from any cause. Survival estimates were obtained using the Kaplan–Meier product-limit method and compared using the Cox proportional hazards regression model. The prognostic significance of individual factors has been summarized using hazard ratios representing the relative death rate for a given group relative to a baseline group. The 95% confidence interval (CI) is given for the main results. Unless otherwise indicated, 2-sided probability values are reported with no adjustment for multiple comparisons.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Detection of Relapse
Relapse involving at least 1 site was confirmed in 42 (67%) of 63 patients by death from progressive disease (n = 30), by pathologic examination (n = 5), or by serial imaging (n = 7). PET was positive for disease in 41 (98%) of these patients. The 1 false-negative PET result was for a study that was limited because of the patient’s claustrophobia and that did not include the site of confirmed recurrence. Conventional staging suggested relapse in all 42 of these patients, yielding a sensitivity of 100%. In 1 patient whose CT scan showed a suspected isolated systemic metastasis but whose PET findings were negative, a small metachronous primary bronchial malignancy subsequently developed and was detected on follow-up bronchoscopy. The site of structural abnormality did not progress, and the PET result was considered true-negative for systemic relapse at this site but incorrect for extent because the developing metachronous primary tumor was missed.
At the study censor date and with a minimum follow-up of 12 mo, 17 patients (27%) had no evidence of relapse. The PET findings were negative in 14 of these patients, giving a specificity of 82%. All but 2 had abnormal CT findings suggestive of thoracic relapse, giving a specificity of only 12% for conventional imaging. Both of the patients without abnormal imaging findings had other clinical evidence of relapse (progressive loss of weight in one and a recurrent pleural effusion in the other). Three PET studies had false-positive findings, all in patients also incorrectly thought to have intrathoracic relapse on the basis of CT findings. One of these scans, seen early in our experience, clearly showed postirradiation changes and was incorrectly interpreted. Because of the discordance in the distribution of abnormality seen on CT compared with that seen on PET, ongoing observation rather than planned palliative radiotherapy was instituted for this patient when the hemoptysis that had led to her referral settled. The other 2 false-positive PET scans showed abnormalities confined to the neck that, in retrospect, may have reflected asymmetric uptake in strap muscles. Neither patient had active treatment, and they remained free from progression of disease in the neck after 707 and 840 d of follow-up. PET correctly excluded suspected intrathoracic relapse in both these patients. In 4 patients, the disease status could not be evaluated because of death from other illnesses (2 patients) or because of treatment introduced on the basis of imaging findings that were not pathologically confirmed (2 patients).
Comparison of Disease Extent as Evaluated Conventionally and by PET
The relapse extent determined by PET was different from the conventionally determined extent in 44 (70%) of 63 patients (95% CI, 57%–81%). Overall, 33% of patients had less extensive disease and 37% had more extensive disease than conventional evaluation suggested (Table 1). Within each category were also some differences in the distribution of active disease that had an impact on patient management. Overall, conventional staging was correct in its assignment of extent category in 12 (24%) of 49 evaluable patients, whereas PET was correct in 42 (86%) of 49 patients.
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PET had no impact on management in 2 other patients (3%) who had discordant PET and CT findings. These 2 patients received active treatment despite negative PET findings and remain free from progression at >19 mo. One underwent resection of a lung mass and associated nodes with pathologic confirmation of a complete response to previous chemoradiation, whereas the other received radical radiotherapy of a chest wall mass that was negative for tumor on PET.
The post-PET management plan differed from the treatment actually delivered in 1 patient who died before commencing palliative radiotherapy. This patient was found to have local relapse on both pre-PET and post-PET assessment, and the treatment decision was therefore unaffected by the PET result. Another patient thought to have only local relapse on CT was found to have possible right peritracheal nodal disease also on PET and was to undergo palliative radiotherapy, but because her hemoptysis settled, this therapy was not subsequently delivered. Definite recurrent disease had not been evident during a follow-up of 722 d, and the findings of both studies are therefore considered to have been false-positive. This patient was the one mentioned earlier with the false-positive result related to suspected postradiotherapy inflammatory change.
Confirmation of PET Results in Patients with High- and Medium-Impact Studies
Of the 40 patients in the high-impact group, confirmation of the true disease status was assessable by histology or by serial imaging in 37 (93%). Of these 37 patients, PET was shown to be correct in 33 (89%). The 4 instances in which PET was incorrect included the study that was false-negative but technically limited by claustrophobia, the 2 studies that showed false-positive lower neck uptake, and a study in which PET correctly excluded systemic metastasis but failed to detect a metachronous lung primary. All 4 assessable cases in which PET modified delivery of a planned therapy (medium impact) were confirmed.
Prediction of Survival by PET
Survival data were analyzed with a closeout (study censor) date of July 1, 1999. Thus, the potential follow-up ranged from 6 to 31 mo (0.5–2.6 y), with a median of 19 mo (1.5 y). All 63 patients entered into the study had a known status at the closeout date. All patients with negative PET findings were followed for a minimum of 12 mo after the scan (range, 371–849 d).
Estimated survival at 1 y was 62% (95% CI, 50%–75%), and estimated survival at 2 y was 40% (95% CI, 22%–59%). Neither the stage at initial diagnosis nor the primary treatment delivered was associated with survival in this selected patient cohort. Positive PET findings were, however, associated with a poorer prognosis than were negative findings (Fig. 2). Further, the extent of relapse assessed after the PET scan was a highly significant prognostic factor (P < 0.0001) (Table 4; Fig. 3).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Our results suggest that PET is an accurate technique for detecting recurrent or persistent disease. The sensitivity of PET for relapse was 98% (41/42 patients), whereas the specificity was 82% (14/17 patients), giving an overall accuracy of 93%. Our sensitivity results are in keeping with those of earlier studies (4,5) in which FDG PET correctly detected intrathoracic relapse in 34 (97%) of 35 patients and 26 (100%) of 26 patients, respectively. The specificity in these earlier studies differed substantially, at 8 (100%) of 8 and 8 (61.5%) of 13, respectively. The study with lower specificity looked only at the intensity and not the pattern of uptake for diagnosing thoracic recurrence. Curvilinear pleural abnormalities within the prior radiation therapy field were graded as positive even though the authors of this report specifically commented that such abnormalities were, in their experience, most commonly inflammatory. In general, our practice has been to call these abnormalities negative, but postradiotherapy inflammatory changes accounted for 1 of 3 false-positive results in our series. The concordance of the distribution of disease relapse between PET and CT was not addressed in either of these studies, and because extrathoracic regions were not evaluated by PET, the occurrence of false-positive results in the lower neck could not be compared with that found in our study.
Our study suggests that PET, in addition to accurately confirming or excluding disease relapse, more accurately assesses the distribution of disease than do conventional techniques used for restaging when relapse of lung cancer is suspected. This accuracy is particularly important in patients for whom the PET result altered management. Of 28 evaluable patients whose PET findings were discordant with conventional imaging findings and led to altered treatment intent or modality (Table 2), the extent of disease suggested by imaging findings was correct in 25 (89%) for PET versus only 1 (3%) for CT.
Another study has also documented discordance between the PET and CT estimations of the extent of disease relapse (7). The rate of discordant findings between PET and CT was lower in that study (25%) than in ours (69%), probably because that study’s PET imaging protocol included only the lung fields, whereas we routinely included the lower neck, upper abdomen, and any areas that appeared clinically suggestive on conventional restaging investigations. The more extensive evaluation of our patients would be expected to increase the likelihood of detection of metastatic disease unrecognized on conventional restaging investigations and also to exclude disease in false-positive sites found by other modalities.
An earlier study on the use of FDG PET after primary treatment of NSCLC evaluated a variable time after this treatment ranging from 2 d to 108 mo (6) and also suggested powerful stratification of patients based on whether their PET findings were positive or negative. The current study evaluated the role of PET for detecting relapse >6 mo from primary treatment, when any acute effects from treatment would be anticipated to have largely subsided, and might not, therefore, be directly comparable. Nevertheless, our study supported the earlier study in finding powerful prognostic stratification between positive and negative PET results (Fig. 2). After correction for changes in management induced by the PET result, the extent of disease relapse determined by FDG PET remained predictive of survival.
The markedly better survival in patients who received no active treatment after negative PET findings than in patients who received either palliative or supportive care after positive FDG PET findings attests to the appropriate stratification of patient prognosis by PET results (Table 5). Of interest is the relatively good survival of patients assigned to salvage curative treatment after PET, a finding consistent with limited earlier data suggesting that patients with early relapse detected on PET can have good survival (7). This suggests that current nihilistic views regarding the management of relapsed lung cancer may reflect poor patient selection by conventional restaging techniques rather than inefficacy of available treatments.
Of potential economic and clinical importance was the observation that 15 patients (24%) in this series who were suspected to have relapsed by conventional evaluation subsequently received no active treatment after a negative PET evaluation. Only 1 of these patients had relapse confirmed on follow-up. Because the area of relapse was not imaged adequately on account of patient claustrophobia, serial CT was arranged and there was only a minor delay in initiation of active treatment. Survival for the group not treated actively was markedly superior to that for patients shown to have incurable relapse by PET (Table 5). By preventing treatment in these patients, PET is likely to have not only reduced expenditure but also spared these patients unwarranted toxicity.
Although comparison of a masked reading of PET with a masked reading of CT may be appropriate if PET were to be suggested as a replacement for CT, the main purpose of this study was to evaluate the incremental diagnostic value and impact of PET in routine clinical practice. The very high false-positive rate and associated poor specificity of CT in this series is likely related to the clinical selection of patients for PET in our facility. Patients with definite relapse on conventional restaging techniques or by biopsy are not offered PET in our facility unless curative treatment is being contemplated. We believe that this selection bias is appropriate given the relative costs of CT and PET.
The minimum follow-up of at least 12 mo in all patients with negative PET findings may be too short to exclude residual disease in these patients, but all PET studies were performed at least 6 mo after the completion of treatment. Therefore, progression-free survival in these patients was in excess of 18 mo, which would appear to be a reasonable time to detect relapse of this disease process. Because of intercurrent treatment or the intervening death of some patients, not all cases in which the PET stage differed from the conventionally found stage could be validated.
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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For correspondence or reprints contact: Rodney J. Hicks, MD, Centre for Positron Emission Tomography, Peter MacCallum Cancer Institute, 12 Cathedral Pl., East Melbourne, Victoria 3002, Australia.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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