New criteria refine PET/CT post-treatment follow-up

Integrated PET/CT scanners entered clinical practice in 2001. Their quasisimultaneous acquisition of complementary anatomic and functional information has revolutionized diagnosis and treatment monitoring for many oncological diseases.

PET/CT has the advantage of acquiring whole-body examinations in a single step. This enables referring oncology physicians to plan therapy according to the imaging and complementary laboratory results. Defining the extent of disease according to existing guidelines is not easy, however. These guidelines are generally based on experiences with stand-alone CT and PET systems and long follow-up studies. Questions then arise: Do we need combined PET/CT response criteria, and for which cancers might these be useful?

CT-based evaluations of therapy use changes to tumor size and/or characteristic contrast enhancement patterns to indicate changes to underlying morphology. Either Response Evaluation Criteria for Solid Tumors (RECIST)1 or World Health Organization criteria for solid tumors can be used to define therapy response. These criteria have also been adapted for other solid tumors, such as pleural mesothelioma.2

RECIST has become the most widely used response tool in routine clinical applications, following evidence that unidimensional and bidimensional criteria show no relevant differences in response evaluation or prognostic impact.3 Contrast-enhancement patterns can also play an important role in monitoring treatment response. Central necrosis of lesions and cystic degeneration are widely accepted parameters, and they were used routinely prior to PET/CT imaging.

PET uses radioisotope tracers to depict metabolic changes indicative of malignancy. Fluorine-18 FDG is used most widely for general oncological tasks. A high proportion of experience in diagnosis and therapy response with PET is based on F-18 FDG. Other PET tracers under investigation include carbon-11 methionine, F-18 tyrosine, and F-18 DOPA.

Measurements of functional information generally include a standardized uptake value (SUVmax). This measurement is regarded as the gold standard. Alternative methods, such as total lesion glycolysis or tumor volume defined by PET measurements, are currently the subject of trials. Therapy monitoring with FDG-PET is generally based on consensus criteria from the European Organisation for Research and Treatment of Cancer (EORTC).4 The criteria have not been revised since their introduction in 1999, though they have been adapted for several tumor entities. Combined PET/CT response criteria are likely needed to assess tumor regression properly.

LIKELY APPLICATIONS

Combined PET/CT evaluation has already been shown to have a huge impact on the diagnosis of several cancers and is expected to expand to other applications.

• Lymphoma. The imaging subcommittee of the International Harmonization Project in lymphoma has produced a new guideline on PET and PET/CT response criteria for Hodgkin's disease and aggressive non-Hodgkin's lymphoma.5 The "basic" EORTC parameters had previously defined progressive metabolic disease, stable metabolic disease, partial metabolic response, and complete metabolic response in terms of percentage differences between actual SUVmax and baseline SUVmax. The new criteria take CT parameters into account as well.

The guidelines state that contrast-enhanced CT may serve as an adequate alternative for therapy assessment. They recommend that either contrast-enhanced CT or PET/CT be used, at least for initial staging. The PET component of PET/CT, however, is still highlighted as the leading response tool. CT parameters are used partly to define the location of lesions and extent of involvement for certain indications, such as hepatic and splenic lesions and lymph nodes.

Some problems related to combined response evaluation are not discussed. Gross disease will shrink and glucose metabolism decrease, causing a reduction in SUV in most patients. Residual morphological tissue (up to 2-cm diameter, short axis) without metabolic activity can be found during therapy or at the end of treatment in some patients, however. This is especially the case for patients starting treatment with large lymph node masses. If PET is taken to be the main response tool, then these residual masses are not considered relevant. An assessment based on CT alone would have classified these patients as partial responders. PET/CT, on the other hand, classifies them as complete metabolic responders (Figure 1).

Data evaluating the clinical significance of these residual nonactive masses are not yet available. Prospective studies are needed to determine if these patients relapse early or tend to have a higher overall relapse rate.

• Colorectal cancer. Contrast-enhanced abdominal CT is generally performed in patients with colorectal cancer. The presence and extent of liver metastases, or other distant metastases, are of particular interest. The therapeutic strategy is different in rectal cancer. Diagnosis of a T3-stage cancer and any N-stage disease will be followed by neoadjuvant radio/chemotherapy. Pelvic MRI is considered the reference standard in these patients.

PET has already been shown to be more accurate than contrast-enhanced CT in staging colorectal cancer. This is especially true for M-staging, owing to PET's superior detection of distant metastases. PET has additionally shown potential in monitoring treatment response in patients with hepatic metastases.6

PET/CT colonography has shown superior results in TNM-staging compared with CT alone.7 Combining PET and CT criteria could still be useful for the evaluation of rectal cancer after radio/chemotherapy and for the assessment of hepatic metastases. Decreases in metabolic activity and lesion size, according to EORTC and RECIST criteria, correlate in most cases. Histological evaluation of residual masses with normalized FDG uptake, however, reveals viable tumor tissue in the majority of cases (Figure 2).

Data on the relationship among FDG avidity, the size and number of lesions after neo-adjuvant chemotherapy, and patient outcome are not yet available. A combination of CT- and PET-based criteria could consequently help when planning treatment strategies for patients with colorectal cancer.

• Breast cancer. CT plays no role in diagnosing primary breast cancer, though it can be used to detect distant bone and soft-tissue metastases. PET has again shown encouraging results in the detection of lymph nodes and distant metastases. PET/CT has performed better than PET alone when diagnosing metastatic and recurrent breast cancer.8

The evaluation of bone metastases during therapy is rather complicated. Osteoblastic metastases may initially be overlooked on PET in certain cases, due to an absence of FDG uptake. These same metastases will be clearly visible on CT.9,10 How should they be evaluated? Analysis of these metabolically inactive masses should seemingly be based on morphological criteria. But RECIST criteria regard bone metastases as nonmeasurable lesions, which makes post-therapy follow-up challenging.

Osteolytic metastases, on the other hand, are detected easily on CT and PET. PET can often detect these metastases earlier than CT; an uptake is visible, but no morphological change can be seen at that time. The metastases' size remains stable after therapy, but they become more sclerotic and lose their metabolic activity. How should they be handled? Some authors claim if a metastasis changes from lytic to blastic and is no longer FDG-avid, then it has been cured. But these metastases may still be viable for several indications.

There is a clear need for combined PET/CT evaluation criteria in patients whose breast cancer has metastasized, particularly if these lesions are in the bone.

• Gastrointestinal stromal tumor. Several studies have been published concerning therapy response in gastrointestinal stromal tumors.11,12 Most studies found PET/CT to be more accurate at assessing therapy response than either CT alone or PET alone. PET/CT also provided relevant prognostic information. Patients with an absence of elevated glucose metabolism after initiation of treatment survived for a statistically significantly longer period than did patients with detectable glucose uptake.

The CT part of the PET/CT study was less accurate in terms of evaluating therapy response when RECIST criteria were applied, mainly because liver metastases of gastrointestinal stromal tumors do not shrink much when treated, even in long-term survivors. A significant number of patients will thus not be regarded as responders. Alternative CT-based criteria for assessing the response of gastrointestinal stromal tumors to treatment have been proposed. These advocate that a 10% reduction in tumor size or a 15% decrease in tumor density should be enough to qualify a patient as a partial responder. A figure of 25% was used in previous studies.13

PET-specific criteria and modified morphological parameters may be included in an optimized combined PET/CT response assessment for gastrointestinal stromal tumors. These findings could also lead researchers to explore other tumor entities using disease-adapted response criteria.

• Ear, nose, and throat cancers. The primary methods for the detection and characterization of ear, nose, and throat cancers are CT and MRI, based on international guidelines.14 FDG-PET has already shown remarkable results for the detection of tumors and lymph nodes in ENT cancer.15,16 Diagnosis can be impaired by artifacts and inflammatory lesions, however. Detection of pathologically involved cervical lymph nodes on CT is based on typical contrast enhancement patterns as well as size criteria.17 FDG-PET defines tumor response as a decrease in FDG uptake of more than 25%. Any remaining pathological focal glucose metabolism is taken to indicate tumor persistence.

Interpretation of CT is often complex. Lesions may decrease in size, but contrast enhancement may still be present owing to the widening of extracellular space in radiotherapy scar tissue.

Small lesions that have shrunk can easily be overlooked on morphological imaging alone. The use of multislice CT technology, particularly 64-slice CT, means that functional perfusion studies can be integrated into a clinical routine protocol. CT perfusion can be useful in detecting and determining therapy response in several tumor entities.18,19

Evaluations of therapy response on PET/CT are likely to rely more on PET in cases in which the interpretation of CT findings are difficult or PET and CT findings are not concordant. Because most advanced ENT cancers are treated with radio/chemotherapy, the time at which post-therapy FDG-PET/CT is performed is important. We find that four to six weeks after completion of treatment is sufficient.

• Mesothelioma. CT-based modified RECIST criteria and PET evaluation with EORTC-based criteria have each been found to be valuable in assessing the response of pleural mesothelioma to treatment.2,20 Data comparing modified RECIST and EORTC criteria in the same patient, and their possible correlation to clinical outcome, are not yet available.

Decreasing FDG uptake during therapy may be taken as a sign of response. Concurrent CT measurements, however, may not change enough to be considered significant (Figure 3).

CT criteria may need some fine-tuning to classify patients' response appropriately, as in the case of gastrointestinal stromal tumors. Reliable definition of combined PET/CT response criteria, through further studies, will help to ensure correct stratification of patients into the appropriate response classes and ensure that therapy can be cost-effective and enhance patients' quality of life.

CASE FOR NEW CRITERIA

As more and more PET/CT systems are being installed worldwide, clinical experience of combined modality cancer imaging is growing exponentially. We may expect future studies to examine the role of PET/CT in following up cancers additional to the ones mentioned above.

Novel approaches in quantifying therapy response that go beyond standard RECIST or EORTC criteria are needed, as seen in the cases of lymphoma, gastrointestinal stromal tumors, and mesothelioma. These will have to be evaluated for dual-modality imaging. Visualization tools that can display and analyze baseline and follow-up studies simultaneously, together with new techniques for evaluating response (e.g., CT perfusion) may follow. These may be incorporated in future therapy response protocols too.

DR. VEIT-HAIBACH, DR. STROBEL, and DR. HANY are radiologists and nuclear medicine physicians in the department of medical radiology, division of nuclear medicine, at Zurich University Hospital.

References

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• Findlay M, Young H, Cunningham D, et al. Noninvasive monitoring of tumor metabolism using fluorodeoxyglucose and positron emission tomography in colorectal cancer liver metastases: correlation with tumor response to fluorouracil. J Clin Oncol 1996;14(3):700-708.

• Veit-Haibach P, Kuehle CA, Beyer T, et al. Diagnostic accuracy of colorectal cancer staging with whole-body PET/CT colonography. JAMA 2006;296(21) 2590-2600.

• Fueger BJ, Weber WA, Quon A, et al. Performance of 2-deoxy-2-[F-18]fluoro-D-glucose positron emission tomography and integrated PET/CT in restaged breast cancer patients. Mol Imaging Biol 2005;7(5):369-376.

• Nakai T, Okuyama C, Kubota T, et al. Pitfalls of FDG-PET for the diagnosis of osteoblastic bone metastases in patients with breast cancer. Europ J Nucl Med Mol Imaging 2005;32(11):1253-1258.

• Fogelman I, Cook G, Israel O, Van der Wall H. Positron emission tomography and bone metastases. Semin Nucl Med 2005;35(2):135-142.

• Goerres GW, Stupp R, Barghouth G, et al. The value of PET, CT and in-line PET/CT in patients with gastrointestinal stromal tumors: long-term outcome of treatment with imatinib mesylate. Europ J Nucl Med Mol Imaging 2005;32(2):153-162.

• Antoch G, Kanja J, Bauer S, et al. Comparison of PET, CT, and dual-modality PET/CT imaging for monitoring of imatinib (STI571) therapy in patients with gastrointestinal stromal tumors. J Nucl Med 2004;45(3):357-365.

• Choi H, Charnsangavej C, Faria SC, et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol 2007;25(13):1753-1759.

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• Wong WL CE, McGurk M, Hussain K, et al. A prospective study of PET-FDG imaging for the assessment of head and neck squamous cell carcinoma. Clin Otolaryngol Allied Sci 1997;22(3):209-214.

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• Goh V, Halligan S, Taylor SA, et al. Differentiation between diverticulitis and colorectal cancer: quantitative CT perfusion measurements versus morphologic criteria-initial experience. Radiology 2007;242(2):456-462.

• Ceresoli GL, Chiti A, Zucali PA, et al. Early response evaluation in malignant pleural mesothelioma by positron emission tomography with [18F]fluorodeoxyglucose. J Clin Oncol 2006;24(28):4587-4593.