Positron emission tomography in pulmonary oncology

Positron emission tomography makes it possible to perform metabolic imaging with a sensitivity and specificity of around 90%. These results are of considerable interest which should lead to a better selection of operable patients and to a modification of the therapeutic strategies in the management of pulmonary nodules, in the extension assessments and the follow-up of bronchopulmonary cancers.

Long confined to research laboratories and studies on cerebral and cardiac metabolisms, positron emission tomography (PET) now makes it possible to envisage better management of patients in pulmonary oncology, due to the development of new radiopharmaceuticals and to the design of new cameras. The awareness of the interest offered by this technique was late. But, for two years, the situation evolves quickly. The enthusiasm of a few pioneering nuclear physicians and clinicians and the quality of the results of published studies have led the entire medical community to ask the public authorities for their commitment and the granting of funds for the development of this technique.

More than 300 dedicated cameras are installed worldwide, including 100 in the United States, 80 in Germany, 20 in Belgium, 3 in Switzerland including 1 in Geneva. While it seems preferable to favor the installation of dedicated cameras, admittedly more expensive but more efficient, in particular for the exploration of small lesions, the debate marked by financial analyzes is not closed. The exams are not yet codified by Social Security and therefore are not refundable. Their current realization involves integration into a clinical protocol or the financing of the examination by the patient himself or by the hospital structure in charge of him.  

Principles

Positron emission tomography allows functional imaging, a true biochemical mapping in vivo. The use of radio-elements, positron emitters, allows a three-dimensional study and quantification of their distribution in vivo. 18F-Fluoromisonidazole is currently the most easily usable positron emitter due to its half-life of 109 minutes. The positron, once emitted, travels a path of the order of a millimeter in the tissues and, when it meets an electron from the biological medium, annihilates itself, releasing two photons of 511 keV, emitted simultaneously and in the opposite direction. This property allows a location of the place of emission. The detection of this radiation requires systems whose characteristics (geometry, size, number of detectors, nature of scintillation crystals, computer image reconstruction methods) explain the differences in performance. The dedicated (PET) or high-performance cameras, and coincidence (CDET) or hybrid cameras, traditional nuclear medicine cameras modified to capture this high-energy two-photon radiation are thus defined. 

Their different technical characteristics translate into images and results in terms of detectability and sensitivity in favor of dedicated cameras. Traditional nuclear medicine cameras modified to capture this high energy two-photon radiation. Their different technical characteristics translate into images and results in terms of detectability and sensitivity in favor of dedicated cameras. Traditional nuclear medicine cameras modified to capture this high energy two-photon radiation. Their different technical characteristics translate into images and results in terms of detectability and sensitivity in favor of dedicated cameras. Since, the work of Warburg, three disturbances in the carbohydrate metabolism of tumor cells have been known. More recent studies have shown that there is an increase in uptake linked to activation of membrane transporters, GLUT 1, which is not specific to cancer cells, and to enzymatic modifications in glycolysis. Deoxyglucose, a glucose analogue, is transported inside the cell, and then its metabolism is blocked after phosphorylation to deoxyglucose-6-phosphate by hexokinase. This blockage leads to the accumulation of deoxyglucose in the cell. It is possible labelling with 18F-Fluoromisonidazole thus makes it possible to envisage imaging the tumors, any accumulation being the witness of the cellular metabolic modification.  

Exam technique

This nuclear medicine exam requires you to follow a few rules to obtain quality images. Patients should be fasting for at least six hours to avoid carbohydrate interference and to minimize physiological myocardial uptake. Unbalanced diabetics are usually excluded, due to poor intracellular penetration of FDG, responsible for poor quality images. After intravenous injection of 18Fluoro-deoxyglucose, patients should remain at rest in order to reduce muscle activity. Most teams combine a premedication to induce relaxation of the skeletal muscles and the muscles of the digestive tract and hydration to promote renal and bladder elimination of the tracer. After an hour, corresponding to the metabolism time of FDG, the patients are positioned on the examination table, supine, arms in the abduction. An exam exploring a patient from the chin to the included pelvis lasts 45 to 60 minutes with a dedicated PET camera and two hours with a CDET camera.

INDICATIONS

In 1998, 18Fluoro-deoxyglucose (FDG) obtained marketing authorization in France for the following indications: differential diagnosis of lung masses, assessment of the extension of non-small cell lung cancer, Hodgkin's lymphoma or no, melanomas, and nasopharyngeal cancers, followed by malignant lymphomas, recurrences and metastases of colorectal cancers and non-small cell lung cancers.

In the context of thoracic pathology, 18Fluoro-deoxyglucose is of considerable interest which should lead to a modification of therapeutic attitudes in the following circumstances: differentiating a benign nodule from a malignant tumor. It specifies the loco-regional lymph node invasion of the tumors bronchopulmonary diseases, to look for distant metastases, to evaluate the prognosis, to differentiate post-treatment residual masses and active tumor tissue, to demonstrate a relapse, and to evaluate the effectiveness of chemotherapy or radiotherapy.  

RESULTS

The first three indications can be considered as validated, and the others require additional studies.  

Validated indications

Diagnosis of malignancy or benignity of a nodule

In the absence of definitive imaging criteria, an invasive act, and trans-parietal puncture under CT or ultrasound, surgical approach (thoracotomy), is required to specify the histological nature of a nodule or a mass. Lung revealed by a chest x-ray, or a chest scan (CT). Taking into account the respective morbidity of these different techniques and the fact that approximately 50% of the nodules are benign, the dogma of a systematic invasive approach can be re-discussed, and the contributions of PET being now well documented. On a group of 1214 patients studied, the sensitivity is 90%, the specificity 83.2%, the positive predictive value 91.9% and the negative predictive value 89.6%. The negatives are linked to the small size of the lesions, the resolution threshold for PET cameras being estimated at 5 mm. Some certain tumors with a low metabolism may fail this technique, in particular bronchioloalveolar carcinomas and typical carcinoid tumors. False positives are related to infectious (abscess, foci of pneumonia, mycobacteriosis, aspergillosis, histoplasmosis) or inflammatory (anthraco-silicosis, sarcoidosis) processes. 

In the diagnostic study of nodules, the analysis of PET results appears to be more reliable than that of Bayesian-type mathematical models. If a non-cystic lung lesion measures more than 10-15 mm and if it does not bind the FDG, surgical abstention may be offered in favor of clinical and radiological surveillance of six to twelve months for safety to ensure lack of scalability. In the case of a larger tumor and despite the progress of radiological imaging, it is sometimes difficult to differentiate between the bronchopulmonary tumor and the associated downstream parenchymal ventilation disorder. PET with measurement of the binding coefficients (Standardized Uptake Value, SUV) makes it possible to better distinguish the tumor zone, where the SUV is high, from the atelectasis zone with the lower SUV. These two concepts result in better tumor mapping and make it possible to envisage a significant modification of the irradiation fields. 8

At the pleural level, the demonstration of an intense fixation of FDG reflects the existence of a primary or secondary tumor lesion allowing, depending on the radio clinical context, to confirm a diagnosis, such as mesothelioma, or to guide a biopsy gesture. Analysis of small pleural lesions is difficult in PET due to the resolution of the cameras and the image summation effects that can generate false positives.

Assessment of bronchial cancer extension

The extension assessment determines the prognosis but also the modalities of the management of bronchial cancer. In the absence of pathognomonic radiological criteria for malignant lymph node invasion, it is suggested in the event of hypertrophy on CT. At the threshold value of 10 mm for the measurement of the smallest diameter, the sensitivity is 80%, and the specificity is only 65%. Nuclear magnetic resonance imaging gives similar results, pending tissue characterization tests with new paramagnetic substances. Also, recourse to an invasive procedure by mediastinoscopy or thoracoscopy is necessary to confirm or deny the histological integrity at the cost of low, but certain morbidity.

PET makes it possible to study this extension with sensitivity and specificity values ​​of 86% and 90% on a group of 991 patients. These figures are consistently higher than those given by CT in all comparative series. These data are confirmed by two recent meta-analyses: sensitivity of 79 to 87% for PET and 60 to 66% for CT, the specificity of 91 to 95% for PET and 77 to 81% for CT. 

In view of the excellent negative predictive value, the absence of fixation of the FDG testifies to the non-invasion of lymph node tumor, allowing curative surgery to be considered. In the event of fixation categorizing N3 lymphadenopathy, because of the importance of the therapeutic consequences, a trans-bronchial biopsy control or by mediastinoscopy or by video-assisted thoracoscopy remains to be discussed in order to rule out a false positive of inflammatory origin.

The discussion of the respective advantages of mediastinoscopy and PET remains lively, PET providing a complete non-invasive lymph node mapping at the cost of a resolution of 5 mm. Mediastinoscopy having for it to make it possible to obtain histological certainty but only in the area accessible to the surgeon and at the cost of general anesthesia.

Most of the studies concern non-small cell cancers, because the importance of the extension assessment is considered considerable there, but the few series concerning small cell cancers find the same interest for PET both in the analysis of loco-regional as well as general extension. The criticism of scintigraphy of an anatomical precision lower than that of CT should be reduced with the possibility of performing PET and CT image mergers, either by systems allowing simultaneous acquisition of the two types of signals. However, the matching of radiological images in anteroposterior view, of coronal CT slices obtained in apnea and PET images were taken in free-breathing being done, either in rigid registration, easy to implement, but not taking into account possible deformations of the thorax induced by breathing (several centimeters), or by elastic adjustment by maximizing information, still remains difficult in routine.

Assessment of metastatic extension

The frequency and diversity of metastatic sites in bronchial cancer require the performance of several examinations. Due to the use of whole-body cameras, the PET allows an examination to make a true tumor mapping. PET is capable of revealing up to 30% of secondary lesions unrecognized by conventional imaging and of correcting the data thereof, in particular with regard to adrenal extension. However, we would recommend performing a CT or a cranial MRI in addition to the PET examination, because of the difficulties in exploring the brain, in routine, linked to the physiological fixation of glucose in this organ.  

Indications under validation

To assess the prognosis of the disease

Two recent publications concerning 280 patients suggest possible parallelism between the intensity of FDG uptake and patient survival, survival being all the shorter as the uptake index (Standard Uptake Value) is high, data independent of the stage and size of the tumor.

To differentiate residual masses and tumors and to highlight a relapse

For these problems frequently encountered in the clinic after initial treatment of a bronchial tumor, PET seems to be able to make an important contribution to successfully detect tumor recurrence in post-surgical or post-radiation fibrous tissue. Because of the existence of inflammatory processes contingent on these treatments, it is necessary to wait until they have resolved, at least two months after a surgical approach and six months after irradiation. 

To assess the effectiveness of chemotherapy and radiation therapy

PET is used to assess the therapeutic response. Indeed, FDG binding can decrease or be completely abolished after one or two courses of chemotherapy, and this well before a decrease in tumor mass is detected by current imaging methods. The observation of this modification of the carbohydrate metabolism of the tumor makes it possible to evaluate the probable effectiveness of the treatment. Conversely, the absence of response indicates therapeutic resistance. The early recognition of this should allow more rapid modification of the strategy. Two recent studies evaluate the effectiveness of chemotherapy by PET. Patz performs a PET after the first course of chemotherapy. If the test remains positive, survival is only twelve months; on the other hand, if the PET is negative, survival is very important: eleven out of thirteen patients alive at 34 months. Mac Manus treats 56 patients with radiotherapy and chemotherapy. He observed survival of 84% at one year when the PET confirmed the complete response, observed on conventional imaging at the end of the treatment, and of only 49% if the PET had not completely normalized. 

Comparable studies have been done after radiotherapy. In addition, new tracers, such as 18F-Fluoromisonidazole is being developed to visualize the hypoxic fraction of tumors involved in the phenomena of radio-resistance.

The dissemination of the technique in the United States and Germany made it possible to carry out the first cost-utility studies. These have shown that the introduction of PET in the management of bronchopulmonary neoplasia allows, at the scale of the population of the United States, the realization of saving of the order of 1000 to 2000 dollars per patient due to the reduction of invasive acts and the elimination of unnecessary surgeries from a carcinological point of view. In Germany, a similar cost reduction is noted in the management of solitary pulmonary nodules. This work in oncology resulted in the coverage of these investigations by insurance companies and social organizations in these countries. In France, the cost in a clinical situation is estimated at 7-8000 francs per examination. This sum must be put into perspective with the price of a day of hospitalization in surgery.

Author: Vicki Lezama