The detection of disease recurrence and treat¬ment monitoring pose high demands on diag¬nostic modalities. Whereas serum marker levels in most cases allow an assessment of tumor load and a respective response to therapy, they do not confer information on the localization of disease. Although this diagnostic gap is filled by imag¬ing modalities, most techniques based on mor-phology will come to a limit when fibrotic tissue alterations have to be differentiated from viable tumor tissue in case of suspected recurrence or when residual masses after chemotherapy have to be assessed. The metabolic information on tumor cells gained by fluorodeoxyglucose-posi-tron emission tomography (FDG-PET) imaging appears not only to be more sensitive and reliable in this respect, but also appears to allow assump¬tions on response to therapy, and ultimately on patient prognosis.
12.1 Definition of Tumor Recurrence and Epidemiological Aspects
Pancreatic carcinoma is characterized by its poor prognosis. Only a minority of patients are eli¬gible for curative surgery upon tumor detection (Birk et al. 1998).
Even in those patients operated with curative intent, 5-year survival is only 31%-51% (Panta-lone et al. 2001). This observation can partly be explained by the fact that even in patients with small tumors (<2 cm), lymph-node metastases are present in about 50% of all cases (Cleary et al. 2004; Meyer et al. 2003). Similarly, in a re¬cent analysis of the Japanese National Pancreas
Cancer Registry, only 16.5% of all patients with tumors smaller than 2 cm did not have an infil-tration of adjacent tissue or vessels, lymph node, or distant metastases (Egawa et al. 2004). As a consequence, a small size of the primary tumor does not necessarily signify an early stage of dis-ease. Unfortunately, even a more radical surgical approach often fails to lead to an improvement of survival rate, and at the cost of a reduced quality of life (Riall et al. 2005). Therefore, disease recur-rence has to be expected even in the small sub-group of patients operated with curative intent.
12.2 Disease Recurrence
Apart from clinical symptoms such as pain, weight loss, or jaundice, the increase in serum tumor markers is usually a sensitive indicator for disease recurrence. Probably the most important of these markers is the carbohydrate antigen CA 19-9. Although it is not specific for pancreatic cancer and may also be elevated in other cancers of the gastrointestinal tract, serial assessments have shown its usefulness as a parameter for the monitoring of therapy and the assessment of prognosis (Micke et al. 2003). Whereas factors such as bile retention have to be taken into con-sideration when assessing high tumor marker levels, a greater problem is probably caused by the fact that CA 19-9 is not expressed in all pa-tients with pancreatic cancer. It has been shown that individuals who are negative for the expres-sion of the Lewis (Lea and Leb) blood antigen (accounting for approx. 10% of the general pop-ulation) also do not synthesize CA 19-9. Thus, they cannot not be monitored by its serum deter-mination (Goggins 2005).
Moreover, a drawback of serological tumor markers is the lack of information they provide on the localization of disease recurrence. Locally confined recurrence might be treatable by sur¬gery or interventional procedures in conjunction with systemic chemotherapy. Moreover, even in case of disseminated disease an assessment of tumor response to therapy is desirable. Thus, im¬aging modalities do play a crucial role in recur¬rence detection.
Most recurrences occur locally due to lym-phatic spread or microscopic perineural inva¬sion (Griffin et al. 1990). In contrast to the good results achieved with endoscopic/endoluminal procedures in the assessment of suspicious pan-creatic masses prior to surgery (Harewood and Wiersema 2002), changes in intestinal continuity and the respective anastomoses may limit their use for recurrence detection in patients after Whipple's operation or pylorus preserving pan-creatoduodenectomy (PPPD).
Although cross-sectional morphologic imag¬ing by computed tomography (CT) or magnetic resonance imaging (MRI) is of great value for the assessment of postoperative complications and immediate follow-up (Scialpi et al. 2005), there are problems in the interpretation of findings in the former pancreas bed, where the differentia¬tion of fibrotic scar tissue from tumor recurrence is often difficult (Mortele et al. 2000). Func¬tional imaging by positron emission tomography (PET) offers a solution to these negative or in-determinate findings in morphological imaging
(Fig. 12.1). Unfortunately, the general scarcity of studies on recurrence detection is also true for PET studies, as only a few preliminary studies have addressed this issue (Franke et al. 1999; Jad-var and Fischman 2001; Rose et al. 1999; Higashi et al. 2003).
In a recent study, our group demonstrated the value of fluorodeoxyglucose-positron emission tomography (FDG-PET) for the assessment of suspected pancreas cancer recurrence (Ruf et al. 2005). Included were 31 patients with suspected recurrence after surgery who either showed weight-loss, pain, increased CA 19-9 levels, or a combination of these symptoms. All patients were examined by whole-body FDG-PET and contrast-enhanced multidetector CT (n = 14) or MR (n = 17) imaging. In accordance with the literature, 25/31 patients had local recurrences upon follow-up, which had been diagnosed by imaging modalities in 23/25 patients. FDG-PET detected 96% (22/23) of these cases, whereas morphological imaging by CT or MRI was posi-tive in only 39% (9/23). Liver metastases were, in contrast, better depicted by MRI and CT imag¬ing, with a detection rate of 92% (11/12) vs 42% (5/12) for FDG-PET. The possible explanation for this observation is the improved detection of small hepatic lesions made possible by dynamic multiphase MRI/CT examinations in contrast to PET, which in the case of small lesions suffers from partial volume effects that make tumor-specific FDG uptake indiscernible from physi¬ologic hepatic activity. Despite the drawback of limited anatomical orientation, FDG-PET was again superior to MRI/CT with regards to ab-dominal lymph-node involvement, as focal up-take was more indicative of tumor recurrence than the mere size assessment of lymph nodes by morphologic imaging. Moreover, as FDG-PET is routinely performed in a whole-body technique, unknown extra-abdominal metastases were de-tected in 2 patients.
Since FDG-PET was superior to morphologi¬cal imaging, it is imaginable that it allows for an earlier detection of recurrence and therefore an earlier initiation of therapy. However, other po-tential influential factors on FDG uptake have to be addressed (please also refer to Chap. 3). As pancreatic surgery may lead to a diabetic meta-bolic state (if not already present prior to sur-gery), a potential decrease in FDG sensitivity has to be considered especially in those patients with a low compliance with regards to antidiabetic medication or in which euglycemia is difficult to achieve (Diederichs et al. 1998). Moreover, as in the initial assessment of pancreatic masses, cellu-larity, the expression of glucose transporters and enzymatic activity of glycolytic enzymes, has to be heeded (Higashi et al. 2002).
12.3 Response to Therapy and Prognosis
Apart from the clinical patient reexamination, the response to radiation treatment or chemother¬apy is usually assessed by morphological imaging modalities such as ultrasound, CT or MRI, using both the number of lesions and their respective size as parameters. However, whereas an increase or decrease of the number lesions is relatively easy to discern, changes in lesion size as assessed either by WHO (perpendicular diameter) or the EORTC's area measurement approach (response evaluation criteria in solid tumors, RECIST) may be rendered more difficult by necrotic, fibrotic, and/or cystic transformation of metastases under therapy (Miller et al. 1981; Therasse et al. 2000). The value of metabolic imaging for the differen-tiation of residual vital tumor tissue vs necrotic or fibrotic residue has been demonstrated, e.g., in the neoadjuvant treatment of colorectal cancer, where FDG-PET correlated far better than mor-phological imaging to the histopathology of the resected tumor (Amthauer et al. 2004). In con-cordance with morphological imaging, attempts have also been made to standardize the response to therapy by the use of quantification measure-ments (Young et al. 1999).
Interestingly, apart from the determination of the primary diagnosis, prognosis rather than response to therapy has been assessed by the ma-jority of FDG-PET studies (Table 12.1). A possi-ble reason for this is the simple fact that response to therapy requires at least two studies of the at the time of the rather costly PET examination. In 1997, Nakata and coworkers pioneered with a study on 14 patients suffering from pancreatic cancer that received conventional imaging as well as FDG-PET prior to treatment. FDG up¬take was semiquantified by the determination of the standardized uptake value (SUV) of the pri¬mary tumor, which was correlated to patient sur¬vival. Using a cut-off SUV of 3.0 for high and low glucose uptake respectively, they observed a sig-nificant difference in the patient group with low uptake (14 months) and high uptake (5 months). Using a SUV of 6.1, Zimny and coworkers (2000) were able to reproduce these results in 52 pa¬tients with 5 months survival in case of an SUV exceeding 6.1 vs 9 months survival in the case of an SUV below 6.1 (p = 0.0321), with multivariate analysis revealing the SUV as an independent prognostic factor. These results were strength¬ened by an Italian study on 60 patients, which came to a similar conclusion using a cut-off for SUV of 4 (Sperti et al. 2003).
Although the wide range of cut-offs for SUV in these studies can be explained by differing examination protocols utilized at the respective institutions, it is doubtful that there actually is an "ideal" SUV threshold (please also refer to Chap. 3). Moreover, only the glucose avidity of the primary tumor has been primarily assessed, whereas the correlation of SUV to tumor stage or the SUV of metastases has only been poorly investigated (Higashi et al. 2003).
Nevertheless, these studies indicate the poten-tial of metabolic imaging by FDG-PET in patients diagnosed with pancreatic cancer, leaving aside the pitfalls associated with the primary diagno¬sis of pancreatic cancer, i.e., the differentiation of glucose-avid inflammation from glucose-avid cancer (please refer to Chap. 3). With regards to
one-time examinations, dual-phase imaging, i.e., the measurement of glucose uptake at two time-points during one imaging session, not only ap¬pears to improve the differentiation of benign from malignant disease, but potentially allows for a more precise assessment of prognosis, more ap¬propriately reflecting the kinetics of glucose me¬tabolism. Using a dual-phase approach, Lyshchik and coworkers (2005) determined an intraindi-vidual retention index (RI) based on the respec¬tive SUVs measured 1 h (1) and 2 h (2) after tracer injection (RI = SUV2 - SUV1/ SUV1 x 100%) for each of their 65 patients. RI was an independent marker for survival in the multivariate analy¬sis, and showed the strongest prognostic differ¬ence for an RI cut-off of 10% (UICC stage I—III: 15.3 months vs 11.5 months; stage IV: 9.5 months vs 4.9 months).
Moreover, it is imaginable that a more appro-priate estimation of prognosis can be derived not from a single examination upon tumor detec¬tion but rather when the response to therapy is assessed (Table 12.1). In one study, nine patients underwent FDG imaging both before and 4 weeks after chemoradiation therapy. Instead of the de-termination of a cut-off for SUV, the change in SUV was assessed. The group observed that a de¬crease in SUV larger than 50% was present in all patients that showed good histological response to therapy (Rose et al. 1999). Another study ex¬amined 11 patients both before and 1 month af¬ter chemotherapy (Maisey et al. 2000). Although their evaluation of PET data was rather simple, as only visual analysis was performed, they saw a significantly extended survival in those patients that showed no FDG uptake in the control scan as opposed to the group in which tumor activity was still visible (mean survival: 318 vs 139 days).
Both studies draw their conclusions from serial PET examinations that, just as with dual-phase imaging, might deliver more robust re¬sults, since they are based on intraindividual comparisons in which the biological factor, the patient, remains a constant.
Furthermore, as metabolic changes usually occur earlier than morphological changes, it might be possible to estimate the response of a patient undergoing (rather than after) therapy and to switch to a another therapeutic regimen in case of nonresponse. The potential of FDG-PET in this setting has been demonstrated e.g., in esophageal cancer. In one study on patients with carcinoma of the gastroesophageal junc¬tion, the change in FDG uptake between baseline examination and a control examination as early as 14 days after initiation of neoadjuvant chemo-therapy was indicative for the differentiation of patients who profited from therapy vs those who did not according to conventional follow-up and postoperative histology (Weber et al. 2001). With regards to pancreatic cancer, however, further studies are required.
12.4 Summary
Due to the high percentage of patients with pan-creatic carcinoma that can only be palliatively treated and the high rate of recurrence in pa¬tients operated with curative intent, reliable im¬aging modalities for therapy control, the assess¬ment of prognosis, and recurrence detection are desirable.
Whereas MRI and CT will remain the basic imaging modalities for therapy control and pa-tient follow-up due to their availability, meta¬bolic imaging by FDG-PET has the potential to improve both the monitoring of therapy and the assessment of prognosis.
12.1 Definition of Tumor Recurrence and Epidemiological Aspects
Pancreatic carcinoma is characterized by its poor prognosis. Only a minority of patients are eli¬gible for curative surgery upon tumor detection (Birk et al. 1998).
Even in those patients operated with curative intent, 5-year survival is only 31%-51% (Panta-lone et al. 2001). This observation can partly be explained by the fact that even in patients with small tumors (<2 cm), lymph-node metastases are present in about 50% of all cases (Cleary et al. 2004; Meyer et al. 2003). Similarly, in a re¬cent analysis of the Japanese National Pancreas
Cancer Registry, only 16.5% of all patients with tumors smaller than 2 cm did not have an infil-tration of adjacent tissue or vessels, lymph node, or distant metastases (Egawa et al. 2004). As a consequence, a small size of the primary tumor does not necessarily signify an early stage of dis-ease. Unfortunately, even a more radical surgical approach often fails to lead to an improvement of survival rate, and at the cost of a reduced quality of life (Riall et al. 2005). Therefore, disease recur-rence has to be expected even in the small sub-group of patients operated with curative intent.
12.2 Disease Recurrence
Apart from clinical symptoms such as pain, weight loss, or jaundice, the increase in serum tumor markers is usually a sensitive indicator for disease recurrence. Probably the most important of these markers is the carbohydrate antigen CA 19-9. Although it is not specific for pancreatic cancer and may also be elevated in other cancers of the gastrointestinal tract, serial assessments have shown its usefulness as a parameter for the monitoring of therapy and the assessment of prognosis (Micke et al. 2003). Whereas factors such as bile retention have to be taken into con-sideration when assessing high tumor marker levels, a greater problem is probably caused by the fact that CA 19-9 is not expressed in all pa-tients with pancreatic cancer. It has been shown that individuals who are negative for the expres-sion of the Lewis (Lea and Leb) blood antigen (accounting for approx. 10% of the general pop-ulation) also do not synthesize CA 19-9. Thus, they cannot not be monitored by its serum deter-mination (Goggins 2005).
Moreover, a drawback of serological tumor markers is the lack of information they provide on the localization of disease recurrence. Locally confined recurrence might be treatable by sur¬gery or interventional procedures in conjunction with systemic chemotherapy. Moreover, even in case of disseminated disease an assessment of tumor response to therapy is desirable. Thus, im¬aging modalities do play a crucial role in recur¬rence detection.
Most recurrences occur locally due to lym-phatic spread or microscopic perineural inva¬sion (Griffin et al. 1990). In contrast to the good results achieved with endoscopic/endoluminal procedures in the assessment of suspicious pan-creatic masses prior to surgery (Harewood and Wiersema 2002), changes in intestinal continuity and the respective anastomoses may limit their use for recurrence detection in patients after Whipple's operation or pylorus preserving pan-creatoduodenectomy (PPPD).
Although cross-sectional morphologic imag¬ing by computed tomography (CT) or magnetic resonance imaging (MRI) is of great value for the assessment of postoperative complications and immediate follow-up (Scialpi et al. 2005), there are problems in the interpretation of findings in the former pancreas bed, where the differentia¬tion of fibrotic scar tissue from tumor recurrence is often difficult (Mortele et al. 2000). Func¬tional imaging by positron emission tomography (PET) offers a solution to these negative or in-determinate findings in morphological imaging
(Fig. 12.1). Unfortunately, the general scarcity of studies on recurrence detection is also true for PET studies, as only a few preliminary studies have addressed this issue (Franke et al. 1999; Jad-var and Fischman 2001; Rose et al. 1999; Higashi et al. 2003).
In a recent study, our group demonstrated the value of fluorodeoxyglucose-positron emission tomography (FDG-PET) for the assessment of suspected pancreas cancer recurrence (Ruf et al. 2005). Included were 31 patients with suspected recurrence after surgery who either showed weight-loss, pain, increased CA 19-9 levels, or a combination of these symptoms. All patients were examined by whole-body FDG-PET and contrast-enhanced multidetector CT (n = 14) or MR (n = 17) imaging. In accordance with the literature, 25/31 patients had local recurrences upon follow-up, which had been diagnosed by imaging modalities in 23/25 patients. FDG-PET detected 96% (22/23) of these cases, whereas morphological imaging by CT or MRI was posi-tive in only 39% (9/23). Liver metastases were, in contrast, better depicted by MRI and CT imag¬ing, with a detection rate of 92% (11/12) vs 42% (5/12) for FDG-PET. The possible explanation for this observation is the improved detection of small hepatic lesions made possible by dynamic multiphase MRI/CT examinations in contrast to PET, which in the case of small lesions suffers from partial volume effects that make tumor-specific FDG uptake indiscernible from physi¬ologic hepatic activity. Despite the drawback of limited anatomical orientation, FDG-PET was again superior to MRI/CT with regards to ab-dominal lymph-node involvement, as focal up-take was more indicative of tumor recurrence than the mere size assessment of lymph nodes by morphologic imaging. Moreover, as FDG-PET is routinely performed in a whole-body technique, unknown extra-abdominal metastases were de-tected in 2 patients.
Since FDG-PET was superior to morphologi¬cal imaging, it is imaginable that it allows for an earlier detection of recurrence and therefore an earlier initiation of therapy. However, other po-tential influential factors on FDG uptake have to be addressed (please also refer to Chap. 3). As pancreatic surgery may lead to a diabetic meta-bolic state (if not already present prior to sur-gery), a potential decrease in FDG sensitivity has to be considered especially in those patients with a low compliance with regards to antidiabetic medication or in which euglycemia is difficult to achieve (Diederichs et al. 1998). Moreover, as in the initial assessment of pancreatic masses, cellu-larity, the expression of glucose transporters and enzymatic activity of glycolytic enzymes, has to be heeded (Higashi et al. 2002).
12.3 Response to Therapy and Prognosis
Apart from the clinical patient reexamination, the response to radiation treatment or chemother¬apy is usually assessed by morphological imaging modalities such as ultrasound, CT or MRI, using both the number of lesions and their respective size as parameters. However, whereas an increase or decrease of the number lesions is relatively easy to discern, changes in lesion size as assessed either by WHO (perpendicular diameter) or the EORTC's area measurement approach (response evaluation criteria in solid tumors, RECIST) may be rendered more difficult by necrotic, fibrotic, and/or cystic transformation of metastases under therapy (Miller et al. 1981; Therasse et al. 2000). The value of metabolic imaging for the differen-tiation of residual vital tumor tissue vs necrotic or fibrotic residue has been demonstrated, e.g., in the neoadjuvant treatment of colorectal cancer, where FDG-PET correlated far better than mor-phological imaging to the histopathology of the resected tumor (Amthauer et al. 2004). In con-cordance with morphological imaging, attempts have also been made to standardize the response to therapy by the use of quantification measure-ments (Young et al. 1999).
Interestingly, apart from the determination of the primary diagnosis, prognosis rather than response to therapy has been assessed by the ma-jority of FDG-PET studies (Table 12.1). A possi-ble reason for this is the simple fact that response to therapy requires at least two studies of the at the time of the rather costly PET examination. In 1997, Nakata and coworkers pioneered with a study on 14 patients suffering from pancreatic cancer that received conventional imaging as well as FDG-PET prior to treatment. FDG up¬take was semiquantified by the determination of the standardized uptake value (SUV) of the pri¬mary tumor, which was correlated to patient sur¬vival. Using a cut-off SUV of 3.0 for high and low glucose uptake respectively, they observed a sig-nificant difference in the patient group with low uptake (14 months) and high uptake (5 months). Using a SUV of 6.1, Zimny and coworkers (2000) were able to reproduce these results in 52 pa¬tients with 5 months survival in case of an SUV exceeding 6.1 vs 9 months survival in the case of an SUV below 6.1 (p = 0.0321), with multivariate analysis revealing the SUV as an independent prognostic factor. These results were strength¬ened by an Italian study on 60 patients, which came to a similar conclusion using a cut-off for SUV of 4 (Sperti et al. 2003).
Although the wide range of cut-offs for SUV in these studies can be explained by differing examination protocols utilized at the respective institutions, it is doubtful that there actually is an "ideal" SUV threshold (please also refer to Chap. 3). Moreover, only the glucose avidity of the primary tumor has been primarily assessed, whereas the correlation of SUV to tumor stage or the SUV of metastases has only been poorly investigated (Higashi et al. 2003).
Nevertheless, these studies indicate the poten-tial of metabolic imaging by FDG-PET in patients diagnosed with pancreatic cancer, leaving aside the pitfalls associated with the primary diagno¬sis of pancreatic cancer, i.e., the differentiation of glucose-avid inflammation from glucose-avid cancer (please refer to Chap. 3). With regards to
one-time examinations, dual-phase imaging, i.e., the measurement of glucose uptake at two time-points during one imaging session, not only ap¬pears to improve the differentiation of benign from malignant disease, but potentially allows for a more precise assessment of prognosis, more ap¬propriately reflecting the kinetics of glucose me¬tabolism. Using a dual-phase approach, Lyshchik and coworkers (2005) determined an intraindi-vidual retention index (RI) based on the respec¬tive SUVs measured 1 h (1) and 2 h (2) after tracer injection (RI = SUV2 - SUV1/ SUV1 x 100%) for each of their 65 patients. RI was an independent marker for survival in the multivariate analy¬sis, and showed the strongest prognostic differ¬ence for an RI cut-off of 10% (UICC stage I—III: 15.3 months vs 11.5 months; stage IV: 9.5 months vs 4.9 months).
Moreover, it is imaginable that a more appro-priate estimation of prognosis can be derived not from a single examination upon tumor detec¬tion but rather when the response to therapy is assessed (Table 12.1). In one study, nine patients underwent FDG imaging both before and 4 weeks after chemoradiation therapy. Instead of the de-termination of a cut-off for SUV, the change in SUV was assessed. The group observed that a de¬crease in SUV larger than 50% was present in all patients that showed good histological response to therapy (Rose et al. 1999). Another study ex¬amined 11 patients both before and 1 month af¬ter chemotherapy (Maisey et al. 2000). Although their evaluation of PET data was rather simple, as only visual analysis was performed, they saw a significantly extended survival in those patients that showed no FDG uptake in the control scan as opposed to the group in which tumor activity was still visible (mean survival: 318 vs 139 days).
Both studies draw their conclusions from serial PET examinations that, just as with dual-phase imaging, might deliver more robust re¬sults, since they are based on intraindividual comparisons in which the biological factor, the patient, remains a constant.
Furthermore, as metabolic changes usually occur earlier than morphological changes, it might be possible to estimate the response of a patient undergoing (rather than after) therapy and to switch to a another therapeutic regimen in case of nonresponse. The potential of FDG-PET in this setting has been demonstrated e.g., in esophageal cancer. In one study on patients with carcinoma of the gastroesophageal junc¬tion, the change in FDG uptake between baseline examination and a control examination as early as 14 days after initiation of neoadjuvant chemo-therapy was indicative for the differentiation of patients who profited from therapy vs those who did not according to conventional follow-up and postoperative histology (Weber et al. 2001). With regards to pancreatic cancer, however, further studies are required.
12.4 Summary
Due to the high percentage of patients with pan-creatic carcinoma that can only be palliatively treated and the high rate of recurrence in pa¬tients operated with curative intent, reliable im¬aging modalities for therapy control, the assess¬ment of prognosis, and recurrence detection are desirable.
Whereas MRI and CT will remain the basic imaging modalities for therapy control and pa-tient follow-up due to their availability, meta¬bolic imaging by FDG-PET has the potential to improve both the monitoring of therapy and the assessment of prognosis.
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