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Clinical Investigation |
1 Center For Molecular Imaging, The Peter MacCallum Cancer Center, Melbourne, Victoria, Australia; 2 Department of Nuclear Medicine, Alfred Hospital, Monash University, Melbourne, Victoria, Australia; 3 Division of Surgery, The Peter MacCallum Cancer Center, Melbourne, Victoria, Australia; 4 Center for Biostatistics and Clinical Trials, The Peter MacCallum Cancer Center, Melbourne, Victoria, Australia; and 5 Department of Medicine, St Vincent's Medical School, Melbourne University, Melbourne, Victoria, Australia
Correspondence: For correspondence or reprints contact: Rodney J. Hicks, MD, Center for Molecular Imaging, The Peter MacCallum Cancer Center, 12 Cathedral Pl., East Melbourne, Victoria 3002, Australia. E-mail: rod.hicks{at}petermac.org
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
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Key Words: therapy monitoring • rectal cancer • chemoradiation • curative surgery • 18F-FDG PET
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
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However, quantitative 18F-FDG PET approaches using a reduction in the standardized uptake value (SUV) as the criterion for therapeutic response require a baseline study and are significantly impacted by the initial 18F-FDG uptake intensity. Specifically, tumors with very high SUVs have a greater potential for a large percentage reduction in SUV compared with less-avid tumors for which a return to background levels of activity may represent a relatively small percentage reduction in the SUV. Evaluation of the percentage reduction in SUV is also complicated by issues related to changes in tumor volume and changes in regional radiotracer distribution within the radiation treatment volume, rendering assignment of regions of interest for semiquantitative analysis difficult and, therefore, prone to interobserver variability. Several groups have previously demonstrated that simple qualitative interpretation of 18F-FDG PET after radical chemoradiation for non–small cell lung cancer (17) or treatment of non-Hodgkin's lymphoma (18) provides powerful prognostic stratification and, by application of pattern recognition, may be less affected by chemoradiation (19). The current study was therefore performed to assess whether application of a similar simple, visual assessment scale of changes in 18F-FDG uptake induced by chemoradiation is able to also stratify outcome in a consecutive group of patients with advanced rectal carcinoma who underwent surgery with curative intent.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
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Patients
The study population was selected from a consecutive series of patients with biopsy-proven rectal cancer who were prospectively considered suitable for aggressive neoadjuvant chemoradiation with a potential view to radical surgery after presenting with locally advanced rectal carcinoma. Each patient had to have undergone a staging 18F-FDG PET scan and a second 18F-FDG scan after completion of their chemoradiation, usually just before surgery in those patients who underwent this procedure. Patients with known metastatic disease (M1 disease) on conventional imaging (10 patients) were excluded, leaving 34 patients eligible for this study. Conventional TNM staging using current AJCCS (American Joint Committee on Cancer Staging) criteria was obtained from each remaining patient's CT scans and also, in 32 of 34 patients, by findings on pelvic MRI (23 patients) and transrectal ultrasound (31 patients). Only 2 patients had neither ultrasound nor MRI scan assessment of T stage 1 with involved paraaortic nodes at initial PET, which changed the stage from T3 N0 M0 to T3 N2 M0 and, therefore, the T stage was deemed to be of limited importance. The other progressed to M1 on postchemoradiation PET and was excluded from the surgical series.
Treatment Protocols
All 34 patients had intermittent megavoltage radiotherapy, over 5–6 wk to a total dose of 50.4 Gy to the pelvis given in at least 10 fractions. The target volume included the primary tumor and regional pelvic nodal regions. Treatment planning and dosimetric evaluation with CT was used in all cases. This included conventional simulation with endoluminal contrast material. PET-defined nodal disease was incorporated into the treatment volume even if not involved by CT criteria. Chemotherapy was given for the duration of radiotherapy to all but 2 patients in whom side effects caused early cessation (at 4 wk and after 3 d). In all 34 patients, this consisted of intermittent high-dose 5-fluorouracil infusions with leukovorin rescue or continuous oral medication of capecitabine, a fluoropyrimidine prodrug of 5-fluorouracil. Two other patients received additional oxaliplatin and 1 patient received additional carboplatin. Biopsy confirmation of nodal involvement was not routinely performed.
The decision to proceed to radical surgery was made by the surgeons in consultation with the patients' specialist oncologists and review of PET and CT results in a multidisciplinary clinical review meeting. Of the 34 patients, 30 patients underwent total mesorectal excision by a specialist colorectal surgeon. The surgery was anterior resection in 20, abdominoperineal resection in 9, and pelvic exenteration in 1. The surgical specimens were examined in detail in a university hospital pathology department setting and reports were obtained to determine the presence or absence of residual tumor cells within the primary tumor. All of the excised lymph nodes were examined for the presence or absence of residual tumor, as were any accompanying organ biopsies.
PET Scan Procedure and Interpretation
From 2000 to 2002, PET scans were performed on a GE Healthcare Quest 300-H scanner (UGM Medical Systems Inc.). Emission data were processed using iterative reconstruction both with and without attenuation correction. Transmission data used for attenuation correction were acquired using a 137Cs (single photon) collimated point source. The performance characteristics of this scanner and processing methods have been described previously (20,21). From January 2002, patients were studied on a dedicated PET/CT scanner (Discovery; GE Healthcare) 1 h after injection of 300–400 MBq of 18F-FDG unless the baseline scan had been performed on the older scanner. Bladders were routinely catheterized for studies performed on the 3-dimensional (3D) Quest system and on most studies performed on the 2-dimensional (2D) Discovery system. Images were acquired from the neck to upper thigh. The first scan was performed just before the commencement of treatment. The posttherapy 18F-FDG PET scan was to be performed 3–4 wk after completion of chemoradiation but was dependent on the timing of surgery and booking constraints of a busy clinical PET Center. Posttherapy scanning occurred in all but 1 patient who had a midtherapy PET study (which showed no response) but he refused to undergo a posttherapy scan before surgery.
All baseline PET studies were reported at the time of the scan, in conjunction with the structural imaging data (which was available in all cases), by physicians experienced in PET and CT interpretation. Qualitative analysis of PET metabolic response was determined from side-by-side visual inspection of PET images from the baseline and follow-up PET study and did not rely on the posttreatment CT except for purposes of anatomic localization in the case of PET/CT images. Both PET studies were displayed on a liquid crystal diode screen in a standardized format (22) normalized to background soft tissues outside the radiation treatment volume.
The changes in a tumor's 18F-FDG pattern were scored as follows:
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This grading system is potentially limited by using PMR for any degree of incomplete improvement. To determine whether PMR patients could be further stratified by the quantitative degree of their response to chemoradiotherapy, a ratio of the initial SUVmax/posttherapy SUVmax (SUVmax is maximum SUV) was obtained for this subgroup. The absolute SUVmax was not considered suitable for analysis because the study used PET scanners of different generations and crystal type, particularly because one system used a 3D acquisition protocol and the other studies were acquired in 2D mode.
The initial imaging TNM status was determined as follows. The T stage was always obtained from structural imaging (generally either MRI or endorectal ultrasound). A separate N stage was determined independently from pretherapy PET and structural imaging findings. No method of determining the outcomes in discordant results was available because biopsy of suggestive or discordant lesions was not routinely performed before chemoradiation. However, the predictive power of each of the 2 staging methods was compared. The M stage was obtained from structural imaging and PET. Patients with systemic metastasis were defined as having M1 disease with any discordance being resolved by confirmation at surgery or biopsy or on subsequent follow-up imaging.
Clinical Follow-up
Patient follow-up was performed at 3- to 6-mo intervals, in conjunction with medical review and follow-up scans, to establish the presence or absence of ongoing disease. Each patient received further therapy if necessary, as determined by the treating oncologist. Progressive disease was defined as new or expanding lesions on structural imaging; new areas of 18F-FDG uptake, which were subsequently followed by corresponding structural imaging abnormalities; histologic examination of subsequent biopsy specimens from needle biopsies or colonoscopy examinations; or progressive increases in biochemical parameters such as carcinoembryonic antigen (CEA) measurements. Surviving patients were classified as either free from disease (FFD) or alive with disease (AWD) at their dates of last contact. For all patients who died, a cause of death was established from their hospital records or contact with the treating doctor.
Statistical Analysis
Survival was measured from the date of radical surgery to the date of death from any cause. Time to progression was measured from the date of radical surgery to the date of progression. The data were analyzed with a closeout (study censor) date of January 17, 2005. The only patient whose status was unknown at the closeout date was known to be alive and free from progression in November 2004. His survival time and time to progression were censored at this date. Patients who died without progression on, or before, the closeout date had their times to progression censored at the date of death. Survival estimates were obtained using the Kaplan–Meier method. Because of the small number of deaths in the 30 patients undergoing radical surgery, survival comparisons were made using the exact value of the log-rank test for comparing 2 groups. The Cox proportional hazards regression model was used to obtain a test for trend where appropriate. The Fisher exact test was used to compare binomial proportions. All statistical analyses were performed using S-PLUS 2000 (MathSoft, Inc.), SPSS for Windows (10.0.7; SPSS Inc.), and StatXact statistical software (StatXact 6.0; CYTEL Software Corp.). Ninety-five percent confidence intervals (95% CIs) have been given for the main results. One-sided P values have been reported for testing trends with increasing extent of disease, anticipating that the greater the extent of disease, the worse the prognosis. No adjustment has been made for multiple comparisons. Comparisons within the PMR subgroup were performed using a 2-sided Mann–Whitney U test.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
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The pathologic findings from the surgical specimens and the effect of therapy on the 18F-FDG PET scans are found in Table 1. Note that only 6 of 30 M0 patients who had potentially curative surgery had a complete pathologic response. These included 5 of 17 (29%) apparently CMR patients and 1 false-positive PMR patient, where the only abnormality was a site of abscess formation around the rectum at the prior tumor site. This patient remains FFD at 3.6 y. Examination of the surgical specimens also demonstrated clear surgical margins in 28 patients. One T3 patient (PET CMR) had tumor cells at >2 mm from the radial margin of the tumor and just beyond l0 mm from the distal longitudinal margin, and a T4 patient (PET PMR) had tumor at the margin of the operative specimen. Both remain FFD.
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Follow-up of the 4 patients who completed chemoradiation but were excluded from survival analysis because surgery with curative intent was not performed found that 3 died of distant disease at 11, 12, and 20 mo. One PET-defined M1 patient had palliative surgery (abdominoperineal resection) and remains alive with extensive distant disease at 32 mo, having responded well to initial chemoradiation and subsequent chemotherapy.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
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Local tumor recurrence after resection of rectal cancer is a challenging problem for both surgeons and oncologists. High surgical patient numbers (25), subspecialty colorectal training (26), resection with total mesorectal excision (27), and adequate longitudinal (28) and circumferential margin (29) have all correlated with improved outcome. Patients with T4 rectal cancers can achieve survival rates similar to those with less advanced tumors if en bloc resection of involved structures is performed with clear margins (30). All patients in this study had optimal definitive tumor resection performed by colorectal surgeons in tertiary hospitals. Within a predefined group of patients with locally advanced rectal cancer, this study has found that metabolic response after completion of chemoradiation may provide the most useful information regarding medium-term prognosis. The good prognosis of M0 patients achieving a CMR compared with those with a PMR or NoMR, even when all patients underwent surgery with curative intent, suggests that PET can accurately evaluate biologic response to chemoradiation. Presumably this may be because responsiveness of cells at sites of macroscopic disease, able to be visualized by PET, and included within radiation and surgical resection volumes, reflects the responsiveness of microscopic foci of disease beyond the treatment margins and undetected by current imaging techniques.
The presence of at least microscopic disease in the surgical specimens of most of the M0 patients with apparently complete remission on 18F-FDG PET is in keeping with the known spatial limitations of 18F-FDG PET. Other 18F-FDG PET rectal cancer studies with more comprehensive pathologic examination of the operative specimens after adjuvant chemoradiation (12,13,16) have found that, although the degree of 18F-FDG uptake was proportional to the percentage of malignant cells present in the operative specimen, very few were completely clear of histologically evident disease. Thus, until it can be proven that the apparently viable tumor cells have lost their ability to proliferate, surgery in CMR patients is still required. This conclusion is further supported by an early study (31) which found that an apparently complete 18F-FDG response to adjuvant radiotherapy alone without surgery was still associated with early local recurrences in one third of cases.
Our findings are consistent with other studies of neoadjuvant chemoradiation in that the majority of patients responded favorably to the initial chemoradiation (12,13,16) and that prognosis was related to the presence of residual disease in the primary or resected nodes, as has been generally found in larger surgical series (6,7,32,33). The poor stratification of patient outcome by CT or MRI response is in keeping with the known limitations of structural imaging in this situation. The low frequency (22%) of complete resolution of structural abnormalities with chemoradiation seen in this study and the inability of these imaging modalities to determine the presence or absence of residual disease in these structures appear to account for these difficulties.
Quantitation of 18F-FDG uptake (34) is appealing because the degree of 18F-FDG uptake appears to reflect tumor aggressiveness and, therefore, potentially an independent predictor of patient outcome (35). However, the optimum methodology for quantitative analysis and the accuracy of retrospectively determined threshold values for such approaches have not been prospectively validated in rectal cancer (13–16). Whatever the technique, considerable variability still remains in the outcome of those patients with values close to the cutoff values of the derived thresholds. Our PMR subgroup likely corresponds to the group with intermediate reduction in quantitative parameters of 18F-FDG uptake; thus, it is not surprising that the percentage of SUV change did not further stratify this subgroup.
The potential reasons for the limitations of quantitative approaches (22,36) include variability in tumor size, true disease burden, tumor aggressiveness, responsiveness to therapy, degree of inflammatory response generated by therapy, size of radiation field, degree of tumor hypoxia, and adequacy of surgical resection. However, our study suggests that these complex interactions are less predictive of outcome than the simple qualitative assessment of whether 18F-FDG PET abnormalities have responded to therapy. In particular, resolution of 18F-FDG–defined disease after chemoradiation appears to be the best predictor of survival in patients undergoing surgery with curative intent. These findings are consistent with the prognostic utility of standardized qualitative scoring of metabolic response in lymphoma (18) and lung cancer (17). Thus, given the lack of consensus regarding the optimum methodology for semiquantitative or quantitative analysis and classification of therapeutic response, qualitative reporting represents a reasonable approach for clinical implementation and should be further tested in other oncologic therapeutic intervention studies.
There are several limitations in this study. The initial part of the study used a sodium iodide PET camera, which has a lower sensitivity for small-volume intraabdominal disease than contemporary PET scanners (37). Nevertheless, we have demonstrated that this older system has good diagnostic accuracy and is clinically useful in colorectal malignancy (21,38). Further, the good prognosis of patients with a CMR in this series suggests that false-negative results did not significantly impact outcome in those undergoing curative resection. The longer follow-up of patients imaged on this system warrants their inclusion in a series evaluating the prognostic ability of metabolic response in rectal cancer. PET/CT significantly improves certainty of separation of disease from normal physiologic uptake (12) but it remains to be established to what degree it will improve stratification beyond having the ability to perform contemporaneous correlation of structural and functional imaging. The change to a dedicated PET/CT camera precluded the use of the initial or posttherapy SUVmax measurement as a potential prognostic indicator. Because follow-up studies were performed on the same scanner as the baseline scans, it was possible to determine the percentage change in SUVmax in PMR patients. This parameter did not appear to further stratify this patient subgroup, but larger patient numbers may enable further prognostic stratification within partial metabolic responders.
Another potential limitation was the necessity to image some patients <3 wk after chemoradiation, thereby possibly reducing the likelihood of PMR patients becoming complete responders. However, both PMR patients who were imaged early after treatment still had residual viable tumor, suggesting that this was not a major confounder in this study. The incidence of radiation proctitis was also quite low and did not limit image analysis, although some contribution to activity seen in the PMR patients cannot be excluded and remains a potential problem for all PET studies.
The relatively small number of patients also prevented us from examining the interrelationships between several of the variables analyzed and was possibly responsible for some of them not reaching statistical significance. However, the observed trends were generally in the directions to be expected and were consistent with clinically important differences in outcome. The fact that the 18F-FDG PET response remained a powerful prognostic factor suggests that the signal measured by 18F-FDG PET is robust.
Finally, although the prognostic ability of this technique appears quite useful for a medium-term outlook, the time of follow-up in our surviving subjects precludes us from offering valid comment on the long-term survival benefit of 18F-FDG findings. This may require up to 6 y as radiotherapy alone for advanced rectal cancer has a median time to relapse of 34 mo for local and 24 mo for distant metastases (39).
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
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ACKNOWLEDGMENTS |
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References |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
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