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Original Research |
1 Radiotherapy Department, S. Maria della Misericordia Hospital, Rovigo,
Italy.
2 Nuclear Medicine Service-PET Unit, S. Maria della Misericordia Hospital,
Rovigo, Italy.
3 Nuclear Medicine Service-PET Center, Castelfranco Veneto General Hospital,
Castelfranco Veneto, Italy.
4 Medical Oncology Department, S. Maria della Misericordia Hospital, Rovigo,
Italy.
5 Nuclear Medicine Service-PET Unit, S. Orsola-Malpighi Hospital, University of
Bologna Medical School, Bologna, Italy.
6 Health Physics Service, S. Maria della Misericordia Hospital, Rovigo,
Italy.
7 Regional Center of Nuclear Medicine, University of Pisa Medical School, Via
Roma 67, Pisa, Italy I-56126.
Received May 26, 2005;
accepted after revision August 22, 2005.
Address correspondence to G. Mariani.
Abstract
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SUBJECTS AND METHODS. Eighty-eight patients with histologically proven rectal cancer classified at clinical TNM stages II and III were enrolled. Six weeks after radiochemotherapy completion, all patients were restaged by sonography, CT, MRI, endoscopy, and 18F-FDG PET. Surgery was performed in all patients within 8-9 weeks from completion of radiochemotherapy. Median follow-up after surgery was 38 months (range, 6-66 months).
RESULTS. The 5-year overall survival and disease-free survival were 83% and 73%, respectively. Cox multivariate analysis showed that only two parameters at restaging were independent prognostic predictors of both overall survival and disease-free survival: pathologic stage and, especially, after radiochemotherapy 18F-FDG PET findings. The 5-year overall survival was 91% in patients with a negative PET after radiochemotherapy versus 72% in those with a positive PET (p = 0.024) after radiochemotherapy, whereas disease-free survival was 81% and 62% (p = 0.003) for those with the negative and positive PET findings, respectively. Statistical data were further enhanced when combining the pathologic stage with the 18F-FDG PET results: 95% 5-year overall survival in the PET-negative pathologic stages 0 and I patients versus 70% in PET-positive pathologic stages II-IV patients (p = 0.001), whereas disease-free survival was 93% and 65% (p = 0.0003) for the negative and positive PETs, respectively.
CONCLUSION. In patients with locally advanced rectal cancer previously treated with neoadjuvant radiochemotherapy, the combined evaluation of pathologic stage and after-radiochemotherapy 18F-FDG PET at restaging identified a subgroup of patients characterized by good response to radiochemotherapy and a more favorable prognosis. In these patients, a conservative surgical approach might be considered.
Keywords: 18F-FDG • genitourinary tract imaging • PET • radiochemotherapy • rectal cancer
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The pathologic stage at completion of neoadjuvant radiochemotherapy better correlates with prognosis than the clinical stage [11], whereas the extent of residual cancer after radiochemotherapy is related to prognosis irrespective of anatomic location of the primary tumor [12]. When restaging patients after neoadjuvant radiochemotherapy, 18F-FDG PET has proved to be more accurate in detecting residual tumors than any other technique [13-15], although some relationship has preliminarily been reported between 18F-FDG PET results after radiochemotherapy and patient outcome [16, 17]. The aim of our study was to further assess and validate the prognostic value of after-radiochemotherapy 18F-FDG PET in a large series of patients with locally advanced rectal cancer who had previously undergone neoadjuvant therapy.
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CT was always performed both before and after IV injection of iodinated contrast medium, with slice thickness of 3-5 mm. MRI was performed using a 1.5-T scanner after patients received an injection of gadopentetate dimeglumine. Coronal and transaxial images based on T1- and T2-weighted 2D turbo spin-echo sequences were acquired. For the present analysis, all the CT and MR images were blindly reviewed by two experienced radiologists. In cases of differing interpretations, a third radiologist reviewed the disputed images, and the final classifications (both before and after neoadjuvant radiochemotherapy) were reached by consensus.
Written informed consent was obtained from all patients according to the study protocol previously approved by the institutional review board of the S. Maria della Misericordia Hospital in Rovigo, Italy.
Neoadjuvant Radiation Therapy and Chemotherapy Schedule
Neoadjuvant radiation therapy and chemotherapy were performed
simultaneously. Details of the external radiation therapy technique used in
this study were described previously
[19]. Briefly, three pelvic
volumes were identified in each patient: the standard posterior pelvis, the
mesorectum space, and the neoplastic volume. These volumes were treated with
total radiation doses of 50 Gy, 53 Gy, and 56 Gy, respectively, in the same
sessions (25 fractions in 33 consecutive days). The patients also received a
concurrent boost radiation technique. Patient were placed in the decubitus
position (12-15°) on an upright table with a hypogastric compressor, with
the legs and pelvis immobilized by a vacuum fix technique as previously
described [20].
Simultaneously, chemotherapy with 5-fluorouracil was administered as a
continuous infusion for 32 days at a daily dose of 300 mg/m2.
Fluorine-18 FDG PET Imaging
PET was performed approximately 7 weeks after completion of
radiochemotherapy using a dedicated tomograph (ECAT EXACT 47, Siemens Medical
Solutions) with a spatial resolution (full width at half maximum) of 6 mm and
an axial field of view of 16.2 cm. Fluorine-18 FDG (370-440 MBq) was injected
after the patient fasted for at least 6 hours, and a whole-body scan was
acquired 60 minutes later, usually from 6-7 bed positions (6 minutes each),
accurately standardizing the beginning of acquisition at 60 minutes after the
tracer was injected. Correction for tissue attenuation was performed using the
transmission data acquired with the in-built gadolinium-68 source of the
tomograph. Visual inspection of attenuation-corrected coronal, sagittal, and
axial PET images was performed independently by three nuclear medicine
physicians skilled in 18F-FDG PET studies. The agreement rate among
the three observers was 96%; in the few cases of discrepancy, a final
diagnosis was reached by consensus. The maximum standardized uptake value
(SUVmax) was routinely calculated for all patients starting with
patient number 15; this information was not available for the first 14
patients for technical reasons (i.e., recent acquisition and learning curve
for using the PET equipment). The intensity of 18F-FDG uptake was
graded with a five-point scale (intense, SUVmax > 6; moderate,
SUVmax between 3 and 5.9; mild, SUVmax between 1.5 and
2.9; faint, SUVmax between 1 and 1.4; absent uptake,
SUVmax < 0.9), further distinguishing the pattern of uptake as
focal or diffuse (Fig. 1).
Fluorine-18 FDG PET was considered positive in cases with intense, moderate,
or mild focal or diffuse uptake, whereas it was classified as negative in
cases with faint and diffuse uptake. In the 14 patients for whom it was not
possible to calculate the SUVmax, the intensity of
18F-FDG uptake was assessed visually by consensus among three
experienced nuclear physicians. A PET examination was not performed before
radiochemotherapy in the patients enrolled for this study, mainly because of
the poor availability of PET scanners in our country when we began the
study.
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Histopathology
Pathologic examination of surgical specimens was performed according to the
protocol of Quirke and Dixon
[21], also including tumor
grading. Pathologically confirmed complete remission was defined as no cancer
cells found. Downstaging was considered as any reduction in the pathologic TNM
stage after radiochemotherapy versus the clinical TNM stage before
radiochemotherapy. Downstaged tumors were defined as pathologic stages 0-I.
Responder tumors were defined as one pathologic tumor category less than the
clinical tumor category.
The greatest reductions in tumor stage induced by radiochemotherapy were seen in the T3 N+ group (from 41 patients before radiochemotherapy to seven patients after radiochemotherapy) and in the T3 N-group (from 37 patients to 13 patients); whereas the T4 N+ group decreased from seven patients to one patient, and the T4 N-group decreased from three to two patients. Most of the downstaged patients (65 of 88 cases [74%] for the T stage and 35 of 49 cases [71%] for the N stage) moved to the pathologic T0 N-group (30 patients, including one with an in situ tumor) and to the pathologic T2 N-group (22 patients). One, five, and six patients moved to the T0 N+, T1 N-, and T2 N+ groups, respectively. No correlation was observed between inflammatory changes in the surgical specimen and the pattern of 18F-FDG uptake observed on the PET scan performed approximately 10 days before surgery.
Adjuvant Chemotherapy
Patients with pathologic stages II-IV after neoadjuvant radiochemotherapy
were treated also with adjuvant chemotherapy after surgery (four cycles of
5-fluorouracil). In particular, after surgery 30 of 88 patients (34%) were
still found in stages II-IV; 26 of them received adjuvant chemotherapy, and
four patients refused further treatment.
Statistical Analysis
The following variables were included in the analysis: age at diagnosis,
sex, tumor grading, maximum tumor diameter, cancer circumferential
infiltration (percent fraction of rectal wall involved), distance of tumor
from anal ring, clinical stage before radiochemotherapy, pathologic stage
after radiochemotherapy, after-radiochemotherapy 18F-FDG PET
findings, and combined after-radiochemotherapy 18F-FDG PET and
pathologic stage. The distribution of ordered categories was analyzed by
gamma, Kendall's, and Stuart's tests
[22]. When one categoric
variable was dichotomous and the other ordered, the chi-square test for the
linear trend of proportions was used
[23]. Disease-free survival
and overall survival were estimated according to the Kaplan-Meier actuarial
method. The statistical significance of the variables as predictors of outcome
at follow-up was assessed by the Cox regression model
[24]. Differences of
p < 0.05 were considered statistically significant. Sensitivity
and specificity of the 18F-FDG PET results were calculated in
relation to the presence or absence of complete pathologic response. All
statistical procedures were performed using SPSS version 10.0 (Statistical
Package for the Social Sciences) for Windows (Microsoft).
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A total of 11 deaths were recorded during follow-up, 10 were tumor-related and one was non-tumor-related. Of the remaining 77 patients, 70 had no evidence of disease on follow-up. Patterns of failure included local recurrence in one case, distant metastasis in nine cases, and both local recurrence and distant metastases in two cases. The site of distant metastases was the liver in nine cases, lungs in eight, bone in four, and brain in one. Five-year survivals in terms of absence of local recurrence, disease-free survival, and overall survival were 96%, 73%, and 83%, respectively (Fig. 2). The 5-year disease-free survivals for pathologic stages 0, I, II, and III-IV (assessed at surgery after radiochemotherapy) were 84%, 86%, 52%, and 63%, respectively (Fig. 3). These results show a better prognosis for the responder patients (pathologic stages 0 and I) than for the nonresponder patients (pathologic stages II-IV) in terms of disease-free survival (p = 0.023) and in terms of overall survival (p = 0.012 [not shown in Fig. 3]).
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In a univariate analysis (Table 2), the percentage of circumferential cancer infiltration of the rectal wall, pathologic stage, and after-radiochemotherapy 18F-FDG PET findings were significantly correlated both with overall survival and with disease-free survival, whereas tumor grading was correlated only with disease-free survival.
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With the Cox multivariate analysis, only two variables were found to be significant and independent predictors both for overall survival and for disease-free survival: the pathologic stage (p < 0.001) and, even more so, the after-radiochemotherapy 18F-FDG PET findings (p < 0.0001).
Concerning, in particular, the after-radiochemotherapy 18F-FDG PET findings, the 5-year disease-free survival was 81% in patients with a negative PET examination after neoadjuvant radiochemotherapy versus 62% in those whom 18F-FDG PET identified residual tumor after radiochemotherapy (p =0.024) (Fig. 4). However, when combining the after-radiochemotherapy 18F-FDG PET findings with the pathologic stage after radiochemotherapy, the 5-year disease-free survival was 93% in patients with negative PET, pathologic stages 0 and I, versus 65% in those with positive PET, pathologic stages II-IV (p = 0.0003) (Fig. 5).
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This study confirms prior data reported by this group and others on the value of 18F-FDG PET for predicting downstaging induced by preoperative radiochemotherapy and immediate response to neoadjuvant treatment [14, 15, 28]. Additionally, the results show an important prognostic property of 18F-FDG PET: the prediction of long-term clinical outcome of patients with locally advanced rectal cancer who submitted to neoadjuvant radiochemotherapy and to surgery.
It is well known that 18F-FDG PET has virtually 100% sensitivity in newly diagnosed rectal cancer [29, 30] and that high SUV values indicate increased tumor aggressiveness and poor long-term prognosis as evaluated by 3-year survival [16]. However, local metabolic changes induced by neoadjuvant radiochemotherapy may hamper the diagnostic yield of 18F-FDG PET in patients with locally advanced rectal cancer [13]. In this regard, the degree of reduced 18F-FDG uptake after radiochemotherapy versus the baseline value has been proposed as an index for predicting early regrowth of several solid tumors treated by radiochemotherapy, based on the identification of significant residual tumors as defined on a "retention index" for 18F-FDG [31]. However, conflicting results have been reported on a possible correlation between mean percent reduction in the 18F-FDG SUV and either response to irradiation or disease-free survival after neoadjuvant radiochemotherapy in patients with locally advanced rectal cancer [16, 17, 31, 32]. In this regard, preliminary observations in a group of 40 patients with rectal cancer suggest that only after-radiochemotherapy, not before-radiochemotherapy, 18F-FDG PET is correlated with patient outcome (Oku S et al., presented at the 2002 annual congress of the European Association of Nuclear Medicine, EANM).
In our group of 88 patients with locally advanced rectal cancer treated with neoadjuvant radiochemotherapy followed by surgery, only three had local recurrences at 5-year follow-up, whereas 10 patients died because of distant metastases. Fluorine-18 FDG PET and pathologic stage were statistically correlated with patient outcome both at univariate and multivariate analyses. In particular, and in agreement with prior observations (Oku S et al., 2002 EANM annual congress), even the after-radiochemotherapy 18F-FDG PET findings alone identified two groups of patients with different prognoses (Fig. 4). Because of the high prognostic value of pathologic stage alone, observed both in this study and in prior studies [8-12, 31, 33, 34], we combined the two parameters with the highest statistical power (i.e., after-radiochemotherapy 18F-FDG PET and pathologic stage). The results of this combination identified two groups of patients with even more widely differing prognoses: The combined after-radiochemotherapy 18F-FDG PET negative and pathologic stages 0 and I group had an especially favorable prognosis (93% disease-free survival at 5-year follow-up), and the combined after-radiochemotherapy 18F-FDG PET positive and pathologic stages II-IV group had a poor prognosis (65% disease-free survival at 5-year follow-up).
Especially in regions of the body where areas with physiologically increased 18F-FDG accumulation and tumor lesions can be very close (such as the perineum), the intrinsically high performance of 18F-FDG PET is further enhanced by the possibility of fusing functional images with anatomic landmarks. In the case of rectal cancer, favorable results of such image fusion procedures have been reported using either postacquisition software protocols [35, 36] or hybrid PET and CT equipment [37]. Considering, in particular, local metabolic changes induced by tumor treatments (surgery and radiation therapy), diagnostic benefits are expected from the newer image fusion techniques (hybrid PET and CT equipment), especially in discriminating, nonspecific 18F-FDG accumulation (e.g., in the endoluminal space) from true tumor foci (e.g., increased 18F-FDG uptake in the intestinal wall).
In conclusion, the results of the present long-term follow-up study indicate that after-radiochemotherapy 18F-FDG PET findings (possibly combined with pathologic staging at subsequent surgery) can be used to predict the long-term prognosis of these patients. On the basis of the combined evaluation described in this article, a conservative surgical approach might be offered to the patients who have more favorable prognoses.
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] PET
findings after neoadjuvant radiochemotherapy).