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British Journal of Radiology (2009) 82, 28-34
© 2009 British Institute of Radiology
doi: 10.1259/bjr/43911400
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British Journal of Radiology 82 (2009),28-34 ©2009 The British Institute of Radiology

Full paper

Advanced pancreatic cancer: the use of the apparent diffusion coefficient to predict response to chemotherapy

T NIWA, MD1, M UENO, MD2, S OHKAWA, MD2, T YOSHIDA, MD1, T DOIUCHI, MD1, K ITO, MD1 and T INOUE, MD3

Departments of 1 Radiology and, 2 Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Centre, 1-1-2 Nakao, Asahi-ku, Yokohama, 241-0815 and 3 Department of Radiology, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan

Correspondence: Tetsu Niwa, Department of Radiology, Kanagawa Children's Medical Centre, 2-138-4 Mutsukawa, Minami-ku, Yokohama, 232-8555, Japan. E-mail: tniwa{at}kcmc.jp


   Abstract
Top
 Abstract
Introduction
 Methods and materials
 Results
 Discussion
 References
 
The purpose of this study was to determine if the apparent diffusion coefficient (ADC) on diffusion-weighted MRI could predict the response of patients with advanced pancreatic cancer to chemotherapy. Diffusion-weighted MRI was performed in 63 consecutive patients with advanced pancreatic cancer who were subsequently treated with chemotherapy. The ADC values of the primary tumour with a middle b-value (400 s mm–2) and a high b-value (1000 s mm–2) were determined; cystic or necrotic components were avoided. The patients were classified into two groups: (i) those with progressive disease and (ii) those who were stable 3 months and 6 months after initial treatment. The groups were compared with respect to the ADC and clinical factors, including gender, age, Union International Contre le Cancer (UICC ) stage, initial tumour size and chemotherapy agents used. Local tumour progression rates were evaluated using the Kaplan–Meier method. The middle b-value ADC of the pancreatic cancers ranged from 0.93–2.42 x10–3 mm2 s–1 (mean, 1.50 x10–3 mm2 s–1), and the high b-value ADC ranged from 0.72–1.88 x10–3 mm2 s–1 (mean, 1.20 x10–3 mm2 s–1). The high b-value ADC was significantly different between the progressive and stable groups at 3 months' and 6 months' follow-up (p = 0.03 and p = 0.04, respectively). The rate of tumour progression was significantly higher in those with a lower high b-value ADC than in those with a higher b-value ADC (median progression time, 140 days vs 182 days; p = 0.01). In conclusion, a lower high b-value ADC in patients with advanced pancreatic cancer may be predictive of early progression in chemotherapy-treated patients.


   Introduction
Top
 Abstract
 Introduction
Methods and materials
 Results
 Discussion
 References
 
Pancreatic cancer is often diagnosed when the disease is in an advanced stage. Currently, radical surgery is the only curative therapy for pancreatic cancer; however, only 5–20% of patients present with potentially resectable disease [1–3]. Patients with inoperable pancreatic cancer have a limited survival rate, which averages only 3–4 months [4]. For locally advanced, unresectable and metastatic disease, palliative treatment with chemotherapy or chemoradiation is the only option. The results of chemotherapy for pancreatic cancer have generally been disappointing [5]. Recently, however, systemic chemotherapy with gemcitabine or gemcitabine plus platinum, or chemotherapy plus radiation, was reported to have some positive effects (1-year survival, 18–36%) [6–8]. Indications for chemotherapy should be carefully evaluated because of the relatively high risk of complications and side effects. Therefore, prognostic factors permitting the identification of patients who will benefit from such treatment would be clinically useful [9].

Diffusion-weighted MRI is a technique in which phase-defocusing and -refocusing gradients are used to evaluate the rate of microscopic water diffusion within tissue. Quantitative measurements of the diffusivity of water are described by the apparent diffusion coefficient (ADC). Investigators have reported the usefulness of ADC measurement for characterizing tumours [10–15]. The ability to measure the rate of water diffusion within tissue is important, as water diffusion is frequently altered in various disease processes and may reflect physiological and morphological characteristics, such as cell density and tissue viability [12, 16]. The results of several studies have suggested that the initial ADC of a tumour can serve as a predictive parameter for a patient's response to chemotherapy [12, 13, 15, 17]. Therefore, a method that enables pre-treatment imaging assessment of tumour malignancy and which would allow a more effective therapeutic strategy to improve prognosis would be of considerable clinical benefit. To the best of our knowledge, the predictive value of ADC in patients with advanced pancreatic cancer has not been reported. The purpose of this study was to evaluate the use of ADC to predict the response of patients with advanced pancreatic cancer to chemotherapy.


   Methods and materials
Top
 Abstract
 Introduction
 Methods and materials
Results
 Discussion
 References
 
Patients
From July 2003 to August 2006, 63 consecutive patients (31 male, 32 female; mean age, 64.6 years; age range, 43–83 years) with advanced pancreatic cancer who had not received any previous anticancer treatment were enrolled in this study. Their medical records, as well as their CT and MRI data, were reviewed retrospectively. The ethics committee of our institute approved this retrospective study and did not require patient informed consent. The initial diagnosis and the possibility of local tumour resection were assessed using contrast-enhanced dynamic CT, multiplanar reformation images, CT angiography and MR images. CT scanning was performed with either an 8- or a 16-detector CT scanner (Aquilion 8 or Aquilion 16; Toshiba Medical Systems, Tokyo, Japan). All images were assessed to determine the local extent of the tumour and the presence of metastases. The criteria used to consider a tumour non-resectable included the presence of a distant metastasis, multiple liver metastases, peritoneal dissemination with ascites, and involvement of a major vascular system (i.e. obstruction or bilateral invasion of the portal vein and/or tumour encasement of the coeliac axis or superior mesenteric arteries). Involvement of the superior mesenteric vein or the main portal vein was not a contraindication to resection, as the tumour could be resected and the portal venous system could be reconstructed. Chest CT was performed when necessary. Histopathological proof was obtained when possible; if histopathological confirmation was absent, the diagnosis was made on the basis of clinical and imaging findings. Tumour staging was performed using the Union International Contre le Cancer (UICC) classification [18].

MRI
All patients were examined using a 1.5 T superconducting MR system (Excelart XGS; Toshiba Medical Systems) with a 25 mT m–1 maximum gradient capability, a maximum slew rate of 130 mT m–1 ms–1 and gradient acoustic noise reduction system. An eight-element quadrature phased-array surface coil was used to optimize the signal-to-noise ratio. All patients underwent diffusion-weighted MRI in addition to the routine pancreatic MR protocol; pancreatic lesions suitable for ADC measurement were identified and selected. All MR examinations were performed with breath holding. The routine MR protocol included a transverse T1 weighted fast gradient echo (fast field echo; repetition time/echo time (TR/TE), 187 ms/4 ms; flip angle, 77°; matrix, 160 x 320; section thickness, 8 mm; intersection gap, 1 mm; one signal acquired; field of view, 300 mm; 19 slices; asymmetric k-space acquisition in the read-out), a transverse T2 weighted fast spin-echo (TR/TE, 3000 ms/100 ms; echo train length, 19; matrix, 192 x 288; section thickness, 8 mm; intersection gap, 1 mm; one signal acquired; field of view, 300 mm; 13 slices), and a transverse T2 weighted single-shot fast spin-echo (TR/TE, 15 000 ms/80 ms; echo train length, 64; matrix, 192 x 192; section thickness, 8 mm; intersection gap, 1 mm; one signal acquired; field of view, 300 mm; 15 slices; asymmetric k-space acquisition in the phase-encoding). MR cholangiopancreatography used a single-shot fast spin-echo sequence (effective TE, 250 ms; matrix size, 320 x 320; field of view, 350 mm) with thick (20–45 mm) or thin (4 mm) slices in the coronal or oblique coronal plane. Diffusion-weighted imaging was performed with different b-values to assess their ability for characterization of the tumour. Diffusion-weighted imaging was performed in a transverse plane using a spin-echo single-shot echo-planar imaging sequence with two sets of diffusion gradients, a middle b-value (b = 400 s mm–2) and a high b-value (b = 1000 s mm–2), along with three orthogonal directions: phase-encoding, frequency-encoding and section-select directions. In addition, images without motion-probing gradients (MPGs) (b = 0 sec mm–2) were obtained simultaneously. The following parameters were used to obtain the diffusion-weighted images: TR/TE, 4000 ms/110 ms; echo train length, 19; matrix, 128 x 208; section thickness, 8 mm; intersection gap, 1 mm; one signal acquired; field of view, 350 mm; 11 slices; asymmetric k-space acquisition in the phase-encoding; and acquisition time, 24 s. To reduce chemical shift artefacts, the selective water excitation technique was used for fat suppression. Diffusion-weighted imaging was performed using the parallel imaging technique, with a reduction factor of 2 to improve the signal-to-noise ratio.

Data analysis
All diffusion-weighted imaging data were transferred to a commercially available workstation (MKDN-008A, Toshiba Medical Systems). Isotropic images were created by averaging the data from all three orthogonal diffusion-weighted images. The ADC maps were generated by the workstation using the following equation:


Formula 001

where S1 and S2 are the signal intensities of diffusion-weighted images obtained with one of the two b values (b1 and b2, respectively) on a voxel-by-voxel basis.

Each ADC of the primary tumour was determined by measurements of the region of interest (ROI) created on each ADC map. To analyse tumour characterization, cystic or necrotic areas were avoided when measuring the ADC. Several ROIs were placed within the largest area of the tumour on each ADC map, avoiding (if possible) cystic, necrotic or haemorrhagic components of the tumour seen on conventional MR images. The size of the ROI was chosen to be appropriate for each lesion, so that the maximum ROI was used without volume averaging. To ensure the same areas were measured, the ROI was copied and pasted onto each middle and high b-value ADC map. Tumour ADCs were determined by averaging each measured ADC. The tumour size was estimated by measuring the greatest diameter of the lesion on T1 weighted MR images.

Patient follow-up
Patients were treated with gemcitabine at a dose of 1000 mg mm–2 given intravenously every week for 3 weeks, followed by 1 week's rest until disease progression or unacceptable toxicity was observed. When the patient agreed, both gemcitabine and TS-1 (a combination preparation consisting of tegafur, gimeracil and oteracil potassium [19]) were given simultaneously as part of a Phase I clinical trial. When severe toxicity was observed, the next chemotherapy session was omitted and postponed to the next scheduled treatment day. Follow-up CT was performed every month to evaluate tumour response. Local tumour progression was determined according to RECIST (Response Evaluation Criteria in Solid Tumours) [20].

Statistical analysis
The patients were classified into two groups (progressive and stable) depending on their status 3 months and 6 months after the initial treatment. The groups were compared with respect to their ADC and clinical characteristics, including age, gender, tumour stage (UICC III/IV), anticancer agents used (gemcitabine only or gemcitabine and TS-1) and initial tumour size. The Wilcoxon signed rank test and the {chi}2 test were used to compare the two groups.

To assess the relationship between progression and the ADC of the pancreatic cancer, patients were grouped based on the median value of each ADC. The two groups were compared with respect to tumour progression using the Kaplan–Meier method and the log-rank test. Statistical analyses were performed using SPSS software (Version 11.0; SPSS Inc., Chicago, IL). A difference with a p-value <0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods and materials
 Results
Discussion
 References
 
A diagnosis of pancreatic cancer was histologically confirmed in 54 (85.7%) patients; the biopsy was performed at the primary site in 42 (66.7%) patients and at a metastatic liver site in 12 (19.0%) patients. In the other nine (14.3%) patients, the final diagnosis was made on the basis of the clinical evaluation, including a complete history, physical examination, laboratory data and radiological findings. The UICC classification tumour stage was III in 27 (42.9%) patients and IV in 36 (57.1%) patients. Metastases included the liver in 25 patients, liver and para-aortic lymph nodes in 1 patient, liver and lungs in 2 patients, para-aortic lymph nodes in 5 patients, peritoneal dissemination in 2 patients, and vertebra in 1 patient. Pancreatic tumour size ranged from 1.8–12.0 cm (mean, 4.4 cm). The middle b-value ADC in the ROI ranged from 0.80–2.57 x 10–3 mm2 s–1, whereas the high b-value ADC ranged from 0.70–2.02 x 10–3 mm2 s–1. The size of the ROIs ranged from 0.63–2.87 cm2. The average middle b-value ADC of the pancreatic cancer ranged from 0.93–2.42 x 10–3 mm2 s–1 (mean, 1.50 x 10–3 mm2 s–1; median, 1.46 x 10–3 mm2 s–1), whereas the average high b-value ADC ranged from 0.72–1.88 x 10–3 mm2 s–1 (mean, 1.21 x 10–3 mm2 s–1; median 1.23 x 10–3 mm2 s–1). The median duration between the initial MR examination and the first day of chemotherapy was 9 days (range, 2–36 days).

34 (54.0%) patients were treated with gemcitabine, whereas 29 (46.0%) patients were treated with concomitant gemcitabine and TS-1. On follow-up, progression was local in 39 (61.9%) patients and metastatic in 12 (19.0%) patients, including 10 patients with hepatic metastases and 2 patients with para-aortic lymph node metastases; newly recognized lesions were found in 10 (15.9%) patients, of whom 2 had hepatic metastases, 7 had peritoneal dissemination and 1 had a lung metastasis. Two (3.2%) patients did not show progression at the time of this analysis. 25 (40.0%) patients showed progression at 3 months, whereas 46 (73.0%) patients showed progression at 6 months after initial treatment. Progression time from the initial treatment ranged from 31–533 days (median, 123 days).

A comparison of the progressive and stable patients (Table 1Go) showed that the high b-value ADC of the progressive patients was significantly lower than that of the stable patients at 3 months (mean ADC, 1.11±0.04 vs 1.25±0.03 x 10–3 mm2 s–1; p = 0.03) and 6 months (mean ADC, 1.17±0.03 vs 1.28±0.05 x 10–3 mm2 s–1; p = 0.04) (GoFigures 1 and 2Go). The middle b-value ADC was not significantly different between progressive and stable patients. Clinical factors, including age, gender, UICC stage and tumour size, and the chemotherapy agents used, were not significantly different between the progressive and the stable patients at 3 months and 6 months.


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  		Table 1. Comparison of clinical factors and the apparent diffusion coefficent(ADC) with respect to tumour progression

 

Figure 1
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  		Figure 1. Images from a 65-year-old man with advanced pancreatic cancer who showed early progression. Progression was noted on the 2-month follow-up CT. (a) Transverse T1 weighted fast-field echo image shows an irregularly shaped tumour at the pancreatic head (arrows). (b,c) Isotropic diffusion-weighted image (b) and the apparent diffusion coefficient (ADC) map (c) using the middle b-value (400 s mm–2) show an inhomogeneous high-signal mass (arrows). The ADC was 0.98x10–3 mm2 s–1. (d) Isotropic diffusion-weighted image and (e) ADC map with a high b-value (1000 s mm–2) show an inhomogeneous high-signal mass (arrows). The ADC was 0.84x10–3 mm2 s–1.

 

Figure 2
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  		Figure 2. Images from a 66-year-old man with relatively stable advanced pancreatic cancer. Progression was noted on the 8-month follow-up CT. (a) Transverse T1 weighted fast-field echo image shows an irregularly shaped tumour at the pancreatic head (arrows). (b) Isotropic diffusion-weighted image and (c) the apparent diffusion coefficient (ADC) map using the middle b-value (400 s mm–2) show an inhomogeneous high-signal mass (arrows). The ADC was 1.42x10–3 mm2 s–1. (d) Isotropic diffusion-weighted image and (e) the ADC map with a high b-value (1000 s mm–2 ) show an inhomogeneous high-signal mass (arrows). The ADC was 1.40x10–3 mm2 s–1.

 
Based on the Kaplan–Meier method and the log-rank test, the tumour progression rates were significantly higher in patients with a lower high b-value ADC than in those with a higher high b-value ADC (median progression time, 140 days vs 182 days; p = 0.01) (Figure 3Go). Although patients with a lower middle b-value ADC showed a tendency towards higher rates of progression than those with a higher middle b-value ADC, there was no significant difference using the log-rank test (median progression time, 101 days vs 140 days; p = 0.10).


Figure 3
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  		Figure 3. The graph shows the rates of local tumour progression in patients with advanced pancreatic cancer treated with chemotherapy. Patients with a lower apparent diffusion coefficient(ADC) using the high b-value (1000 s mm–2) had a significantly higher rate of progression than those with a higher ADC (p<0.01, log-rank test).

 

   Discussion
Top
 Abstract
 Introduction
 Methods and materials
 Results
 Discussion
References
 
Despite major recent advances in the management of cancer, pancreatic cancer remains a challenge to clinicians because of the difficulties encountered in early diagnosis and its relative chemoresistance. Some patients show improvements in survival and tumour response, whereas others only suffer from inconvenience and increased toxicity. It has been suggested that the burden of treatment should not add to the suffering of those with advanced pancreatic carcinoma. Therefore, the identification of prognostic factors before treatment would be helpful in selecting the subgroups of patients for which chemotherapy improves survival and in determining efficient treatment strategies with reference to expected survival [21].

Among patients with advanced pancreatic cancer treated with chemotherapy, it was found that a lower pre-treatment high b-value ADC was correlated with early progression. Several reports relating to brain tumours and animal models have indicated a relationship between ADC and histological features [11–14, 16, 22]. ADC is a quantitative expression of the tissue diffusion characteristics; it is related to the proportion of extracellular and intracellular components. A high ADC is thought to reflect the presence of a necrotic fraction, which leads to increased extracellular water, whereas a low ADC is thought to reflect higher tumour cellularity or cell density, which results in more restricted water diffusion. Cell density may be indicative of tumour aggressiveness. The results of several clinical studies suggest that tumours with a high cellularity have an increased metastatic capacity [23]. Although the reason for the correlation between a lower pancreatic cancer ADC and early progression is unclear, it is possible that a lower ADC reflects a higher cellularity and a more aggressive tumour. Conversely, pancreatic cancers generally include desmoplastic tissue in the baseline tumour volume, which may also affect ADC independent of the cellularity. To the best of our knowledge, there have been no previously published reports dealing with the correlation between diffusion-weighted imaging and histological examination findings in pancreatic cancer. In this study, we did not look for any correlation between histology grade and ADC because it was inappropriate to analyse specimens of a part, small amount or metastatic site of the tumour. Further studies are needed to correlate the pancreatic cancer ADC with the tumours' histological features.

Several investigators have attempted to use the ADC as a pre-treatment predictor of response to chemotherapy or chemoradiation. Investigators have used various methods to analyse the data and their results have varied. Higano et al [24] reported that a lower minimum pre-treatment ADC correlated with brain tumour progression. The ADC of the tumour that was analysed avoided cystic or necrotic areas, and they hypothesized that the relationship between a lower tumour ADC and early progression was related to high cellularity or a highly proliferative portion of the tumour; our results are similar to these. Conversely, several investigators reported that a higher pre-treatment ADC was related to a poor response to chemotherapy in rectal cancer patients, patients with colorectal hepatic metastasis and animal models [12, 13, 15, 17]. In these studies, the ROI for ADC measurement involved the whole tumour; the investigators hypothesized that the reason for the poor response with a higher pre-treatment ADC may be due to the presence of necrosis in the tumour. In this situation, the tumour may experience hypoxia and thus have a slower metabolism, which would result in a lower sensitivity to chemotherapy [12]. Although measuring ADC values of a whole tumour might be less subjective and more reproducible, we attempted to measure the ADC while avoiding cystic or necrotic components of the tumour in this study, which might reflect tumour cell characterization. In the future, a proper method for analysis of pancreatic cancer needs to be developed.

In the present study, early progression did not correlate with the middle b-value ADC but did with the high b-value ADC. Middle b-value diffusion-weighted imaging produces relatively good imaging quality, but the middle b-value ADC is affected by so-called "T2-shine through" and a local vessel perfusion effect. These factors may affect the middle b-value ADC in pancreatic cancer; as a result, the middle b-value ADC may not truly reflect tumour characteristics. Other scanning factors, such as MPG pulse direction, b-factor, matrix size and the reduction factor on parallel imaging, may also affect imaging quality.

The present study had several potential limitations. Firstly, single-shot echo planar imaging has a relatively low spatial resolution, a low signal-to-noise ratio and shows imaging distortion. We used all of the currently available techniques to improve imaging quality. However, the ADCs of small lesions may still be unreliable. The use of high field-strength imagers or pulse-triggered scanning can potentially improve the signal in diffusion-weighted MRI [25, 26]. Secondly, although a high b-value of 1000 s mm–2 on diffusion-weighted imaging was used to reduce confounding relaxation phenomena, the so-called T2-shine through effects and the perfusion effect, these factors may still have affected the ADC [27–29]. Diffusion-weighted images with a higher b-value (i.e. 4000 s mm–2) should provide more information about the slow diffusion of water molecules, which may be more sensitive at distinguishing cellular or tissue characteristics [12]. However, on abdominal scanning, current MR units cannot provide enough higher b-value signals. Thirdly, the patient population was relatively small, and substantial overlap was noted between progressive and stable patients. Tumour stage and size varied in this study; however, these factors were not significantly different between progressive and stable patients. In addition, some patients had not been histologically proven to have pancreatic cancer. Although primary pancreatic lymphoma might mimic pancreatic cancer, we carefully reviewed clinical data, and patients with a doubtful clinical diagnosis were not included in this study [30, 31]. Further larger clinical studies are needed to fully characterize pancreatic cancer for an appropriate analysis of ADC with tumour stage and size. Finally, the measurement reproducibility of ADC was not assessed in this study. Instead, we measured several ROIs in the tumour and then averaged these.

In conclusion, in patients with advanced pancreatic cancer treated with chemotherapy, a lower high b-value ADC may be predictive of early progression.

This study was supported in part by Grant-in-Aid from Kanagawa Health Foundation.


   Acknowledgments
 
The authors would like to thank Mr Masahiko Sato for technical advice.

This study was supported in part by a Grant-in-Aid from Kanagawa Health Foundation.

Received for publication October 15, 2007. Revision received January 1, 2008. Accepted for publication February 8, 2008.


   References
Top
 Abstract
 Introduction
 Methods and materials
 Results
 Discussion
 References
 

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